Ph.d Thesis By Venugopal Rao Veeramaneni

This thesis (chapters II, III, IV and V) deals with the synthesis and formation of fused dihydro oxazolo derivatives from suitable precursors by reductive cyclization with lithium aluminum hydride. Hence, the Introduction (Chapter I) to this thesis has been described into two parts: the first part deals with reactions of LAH and the second part deals with synthesis and formation of fused oxazolo derivatives by ring closure methods.

35

1.1 REDUCTION: 1.1.1 GENERAL Reduction, one of the most widely used fundamental organic reactions, can be accomplished by several brand methods including addition of hydrogen and/or electrons, or hydride ions to a molecule or removal of oxygen or the other electronegative substituents. The most important reducing agents from a synthetic point of view are of two types, viz non-hydride reducing agents and hydride reducing reagents.1

1.1.2 Types of Reducing Agents 1.1.2 (a) Non-Hydride Reducing Agents Catalytic hydrogenation: This reaction involves addition of the elemental H2 across a double bond as shown in Equation – 1.1.

CH2 + H

H2 C

H

H3 C

CH3 (II)

(I) Equation – 1.1

Dissolving metal reductions: In general, this method is useful for the reduction conjugated systems, enones, or aromatics. For saturated carbonyl compounds, hydride reductions are better. The commonly used metals are Li, Na, K, Zn, Mg, Sn and Fe and the commonly used solvents are NH3, HMPA, THF, DME and Crown ethers. Electrochemical reductions: This reaction involves electrolysis at a mercury, lead or cadmium cathode and tetramethylammonium chloride as catalyst. Various non-hydridic procedures were developed for the reduction of organic functional groups prior to the discovery of hydride reagents.1 Reduction of aldehydes to the corresponding alcohols was achieved by zinc dust - acetic acid, sodium amalgam acetic acid, sodium in toluene - acetic acid or iron - acetic acid,2 as shown in Equation – 1.2. 2(H) CHO (III)

Fe / AcOH, Water 6.0 h, 100 oC, 75 - 80 %

(IV)

CH2OH

36

Equation – 1.2 Simple ketones were reduced to the corresponding alcohol using sodium in ethanol,3 as shown in Equation – 1.3 O

OH

Na/EtOH (V)

(VI)

65 %

Equation – 1.3 Equation 1.4 describes that the diaryl ketones were reduced to the alcohols by using zinc and sodium hydroxide mixture in ethanol.4

2 (H)

Ph Ph

Ph OH Ph (VIII)

O Zn/2NaOH/EtOH 70oC, 3.0 h, 96 %

(VII)

Equation – 1.4 Aldehydes were reduced to corresponding carbinols using aluminum ethoxide in 5

ethanol or aluminum ethoxide in isopropyl alcohol.6 This method has been applied to a variety of aldehydes and ketones popularly known as “Meerwein- Ponndorf-Verley reduction”. (Equation – 1.5)

Al/iPrOH

CHO

8 - 9 hrs, 110 oC 60 %

(IX)

Ph Ph (VII)

CH2OH

Al (iPrO)3

O

Reflux/1.0 h 99 %

(X)

Ph OH Ph (VIII)

Equation – 1.5 Carboxylic acid esters were reduced to the corresponding alcohols by sodium in ethanol which is known as Bouveault and Blanck reduction.7 (Equation -1.6)

nC11H23CO2Et (XI)

Na/EtOH

nC11H23CH2OH

Steam bath, 65 - 75 %

(XII)

37

Equation – 1.6 The non-hydridic reductive procedures often require elevated temperature, long reaction time and are associated with low yields. However, the discovery of metal hydrides and complex metal hydrides has dramatically changed the situation, not only for the reduction of carbonyl groups, but also for the reduction of a wide variety of many other functional groups.

1.1.2 (b) Hydride Reducing Agents The first hydride-reducing agent is diborane, which was discovered in 1930s, the structure of which was subject to considerable study and speculation.8 Professor H. I. Schlesinger at University of Chicago was studied the reactions of diborane. The methods available for the preparation of diborane were not satisfactory for large scale preparations. Hence, sodium borohydride was started to be used as a reducing agent,9 and improved methods were available for preparing sodium borohydride.10 The alkaline metal hydride route was successfully extended for the synthesis of the corresponding aluminum derivatives.

1.2 Lithium aluminum hydride: 1.2.1 Synthesis & Physical Properties Lithium aluminum hydride was synthesized in 1945 by the reaction of lithium hydride and aluminum chloride in ether solution.11

4LiH + AlCl3 3LiAlH4 + AlCl3 4AlH3 + 4LiH

LiAlH4 + LiCl 4AlH3 + 3LiCl 4LiAlH4

The discovery of sodium borohydride in 1942 and of lithium aluminum hydride in 1945 brought a revolutionary change in procedures for the reduction of functional groups in organic synthesis.12 As first described by W. G. Brown et al. 12 Lithium aluminum hydride is an exceedingly powerful reducing agent and capable of reducing practically all functional groups.

38

Consequently, it was quite difficult to apply this reagent for the selective reduction of multifunctional molecule. Lithium aluminum hydride is capable of reducing almost all of the organic functional groups rapidly to the lowest reduced state.13 It can hydroaluminate double and triple bonds14 and can function as a base15 It is soluble in variety of ethereal solvents such as ethyl ether (15.0 gm in 100 mL), tetrahydrofuran (13.0 gm in 100 mL), monoglyme, diglyme , triglyme and reacts violently with water and other protic solvents.

1.2.2 Reactivity & Synthetic Applications Exploratory study of the reactivity of this reagent towards representative organic functional groups is summarized below.16 Table – 1.1: Reactivity of various functional groups with LAH. S.No.

Reactant

Product

1.

Aldehyde

Alcohol

2.

Ketone

Alcohol

3.

Acid Chloride

Alcohol / Aldehyde

4.

Lactone

Alcohol (diol)

5.

Epoxide

Alcohol

6.

Ester

Alcohol

7.

Carboxylic acid

Alcohol

8.

Carboxylic acid salt

Alcohol

9.

tert.Amide

Amine / Aldehyde

10. Nitrile

Amine

11. Nitro

Amino / Azo

12. Olefin

No reaction.

The general mechanisms for reduction of some important class of carbonyl compounds are shown as below:For Ketones:-

39

Li H H

Al

H

H3Al OLi

O

H R

R

R

Li H3Al

H R

R O R

R O R

LiOH, Al(OMe) + R

OH 4H O 2

Li H2Al

R LiAl

O

R

R 4

R O

R 2

Scheme – 1.1 For Carboxylic esters:Li H H

Al

R

H

Li H3Al

H3Al OLi

O

H R

R

OR

OR R -ROAlCH3

H OR

H

R

O

H O

H+

O H

R

O

R

AlH2OR

OH

ROAlH2

Scheme – 1.2 For Carboxamides:Li H H

Al

H

R

NH2

R

Li H3Al

H3Al OLi

O

H

R

H NH2

H NH2 H

-OAlH 2

NH2

R

O H R

H NH2

H+ R

N H2

AlH2

O-

R

NH2

Scheme – 1.3 The powerful hydride transfer properties of this reagent is the reason for the high reactivity with aldehydes, ketones, esters, lactones, carboxylic acids, anhydrides, and

40

epoxides to give alcohols, and with amides, iminum ions, nitriles, and aliphatic nitro compounds to give amines. Several methods are available for the workup procedure of these reductions. A strongly recommended option16 involves a careful and successive drop wise addition of n mL of 15 % NaOH solution, and 3n mL of water to the mixture containing n grams of LiAlH4.

These conditions provide a dry granular inorganic

precipitate that is easy to rinse and filter. Alternatively, solid Glauber’s salt (Na2SO4.10H2O) can be added portion wise until the salts become white.17 In certain instances, an acidic workup (10 % H2SO4) may prove advantageous because the inorganic salts become solubilized in the aqueous phase.18 LAH can be used in dimerization of acetals and ketals along with titanium tetra chloride (Equation 1.7).19 Allylic or benzylic alcohols can be symmetrically coupled by treatment with LAH & TiCl4 (Equation 1.8). 20 Dehalogenation has been accomplished with LAH (Equation 1.9).21 Oximes and imines have been converted to the corresponding aldehyde or ketone by treatment with LAH-HMPA (Equation 1.10),22 episulfides can be converted into olefins (Equation 1.11).23

Five membered cyclic sulfones can be

converted to cyclobutenes by treatment with BuLi followed by LAH (Equation 1.12),24 ethers are stable with LAH but THF when treated with LAH-AlCl3 gives 1- butanol. LAH opens an epoxide (Equation 1.13),25 alcohols can also be reduced indirectly i.e. by converting it to a sulfonate followed by the reduction of that compound, the two reactions can be carried out without isolation of the sulfonate (Equation 1.14).

26

Fluorine

containing amide when treated with LAH alone results in amine, but when the reagent was used in combination with AlCl3, fluorine is also displaced by hydrogen. (Equation 1.15)27 1.2.1Table – I Eq. No.

Ref:

SCHEME EtO

1.7

OEt OEt (XIII)

LAH/TiCl4 85 %

19

OEt (XIV)

41

1.8

LAH/TiCl4

Ph

HO

20 Ph Ph Cis & Trans

OH

Ph

(XV)

(XVI)

x

1.9

21

LAH

x (XVII)

1.10

(XVIII)

LAH W

N

O

HMPA

22

+ W-NH2

(XX)

(XIX)

1.11

23

LAH S (XXI)

(XVIII)

1.12

24 O

BuLi

S

47

LAH

O

(XXIII)

(XXII)

LAH / AlCl3

1.13 O (XXIV)

1.14

25

OH (XXV)

26

N

N 1)TsCl OH

1.15

2) LAH

O

O

(XXVI)

(XXVII) O

O

N

O

H

LAH/AlCl3 O

N

H LAH

(XXVIII) F

N

27

H

O

O (XXIX)

O

F

(XXX) F

F

The reduction of N,N-disubstituted amides with LAH leads to aldehydes where amines are also formed as other products (Equation 1.16),28 Synthesis of Aziridines from

42

β-iodo azides by reductive cyclization with LAH (Equation 1.17),29 were reported in the literature. 1 Molar equiv of LAH with 0.25 molar equiv of TiCl4 in THF is extremely effective in reducing bromohydrins to olefins in high yields (Equation 1.18).30 Several carboxylic esters and lactones were reduced to ether derivatives employing a reagent prepared from LAH & BF3-Et2O (Equation 1.19).31 Aromatic aldehydes, ketones, acids and esters were converted to corresponding halides in one pot operation with LAH followed by treatment with HBr (Equation 1.20).32 Cyclohexene epoxides are preferentially reduced by an axial approach of the nucleophile.33 Aromatic bromides are reduced quite rapidly and quantitatively to the corresponding hydrocarbons by LAH in THF (Equation 1.21).34 LAH was used for the stereospecific reduction of acetylenes (Equation 1.22).35

1.2.1Table – I Eq. No. 1.16

Ref:

SCHEME NHMe

CHO

LAH

O

28

Et2O, 58 % (Aldehyde)

N Me

(XXXIII)

(XXXII) (XXXI)

1.17

N3 I

29

Et2O, (XXXV)

(XXXIV)

1.18

N

LAH

Br

30 LAH OH THF, 93 %

(XXXVI)

(XXXVII)

43

O O

1.19

31

O

LAH BF3.Et2O (XXXVIII)

(XXXIX) COR 1) LAH / Et2O

1.20

CH2Br

32

2) HBr, 99 % (XL)

(XLI)

R = H, OH, OCH3

Br

1.21

34

LAH THF, 90 %

(XLII)

(XLIII)

LAH

1.22

35

diglyme 96 %

(XLV)

(XLIV)

1.3. Cyclization methods: In a cyclization process the ring is made by the formation of one new bond in an intramoleculor fashion. Typical “Building Blocks” for cyclization reactions are as follows. O Me

O

. .

. .

H Me Cl

O

H

(XLVI)

O

.

.

Me

(XLVIII)

(XLVII)

eg.

. . Me N NH OH 2

Me2N

.

N

.

+

Me

N

2

NMe2 X-

(XLIX)

NMe2 N

O

Ref. 95

(L)

Bis-electrophiles

44

. MeNH2 .

. . MeNHNHMe

. NH2

. . PhNHOH

. OH

. NH2 (LII)

(LI)

. (LV)

(LIV)

(LIII)

Bis-nucleophiles O

O

NC

.

.

.

. CHO O

. NH2

.

CN (LVI)

(LVII)

(LVIII)

Nucleophile + electrophile combinations There is a vast range of simple building blocks, of which only a few are illustrated. Carbonyl groups are the most common electrophilic components, and carbanions, nitrogen, oxygen and sulfur act as the most common nucleophilic components. Saturated heterocycles can be synthesized by intramoleculor cyclization by using sodiumhydride, to give three membered ring or four membered ring.36 (Equation 1.23) Ar1

Cl

Cl

Ar2 .

NH . OMs (LIX)

Cl

Ar1 K2CO3

Cl N. .

60 - 78 %

Ar2

(LX)

Equation 1.23 Or five membered ring. (Equation 1.24)

MsO

NHBOC . OMs n . (LXI)

.. NHOH

. HN ..

n=1 2 3 60 62 53 %

n . NHBOC (LXII)

Equation 1.24 Pyrrole derivatives can be prepared by a cyclization method (Paal-Knorr Synthesis), in which carbonyl components act as electrophiles.37 (Equation 1.25)

45

Ph

CONHPh

O

Ph

RCH2NH2 75.0 %

CHMe2

Ar

CHMe2

N

Ar O R

(LXIII)

CONHPh

(LXIV)

Equation 1.25 The formation of indole derivative by intramolecular cyclization of an Nacyl-o-toluidine with strong bases at high temperatures38 is known as Madelung indole synthesis. (Equation 1.26)

N H (LXV)

-

NaOEt

O

o

N H

360 C

R

H+

O R

R

H2O

N H (LXVII)

(LXVI)

Equation 1.26 Recently some ring systems were created by the addition of bis (nucleophile) + bis (electrophile) combination.39 (Equation 1.27) CO2But

O

NH2OH.HCl

O (LXVIII)

NHBOC

N

EtOH, Reflux 62 %

NHBOC

CO2But

(LXIX)

Equation 1.27 Iodocyclization can be used to prepare heterocycles40 (Equation 1.28). Intramoleculor aza Wittig reaction is also another useful method for the preparation variety of heterocycles.41 (Equation 1.29). I R I2, K2CO3 Ts MeO2C

N H (LXX)

45 - 82 %

MeO2C

N

R

Ts (LXXI)

Equation 1.28

46

N3

87.0 % Ph Ph

N

P(OEt)3, 90 oC

O O

Me

Me

O (LXXIII)

(LXXII)

Equation 1.29 Cyclization on to arenes is useful for making some benzo fused heterocycles.42 (Equation 1.30). R

R

OH KNH2, NH3

NH2 Br (LXXIV)

(LXXV)

N H

Equation 1.30 Example for preparation of heterocycle derivative by radical cyclization,

43

(Equation 1.31) cyclization of radicals on to imines.44 (Equation 1.32) H Br

Bu3SnH AIBN, 86 %

N

N

CO2Et

(LXXVII)

(LXXVI)

CO2Et

Equation 1.31

N

NH

R (LXXVIII)

(LXXIX) R

Equation 1.32 Another cyclization method for preparation of heterocycles is via ring closing metathesis (RCM).45 (Equation 1.33)

47

R4

R4 R3

O

O

R2

(LXXXI)

R2 (LXXX)

R3

Equation 1.33

1.4 Introduction of Oxazoles: Oxazole (LXXXII) is a five membered heterocycle that contains one oxygen and one nitrogen as heteroatoms in 1 and 3 positions. The oxazolo moiety is frequently found to be an integral part of many biologically active molecules and natural products.46 - 64

2

3N

O1 5

4

(LXXXII)

Oxazole moiety is also found in fusion with other heterocycles such as pyridines, piperidines, indoles, quinolines, benzoxazines, pyrimidines, naphthyridines, quinazolines etc. A number of such structures and their use in different therapeutic areas have been listed below. O

O N

OH

CN

N

Ph

(LXXXIII) Atisine Alkaloid 46

N

O

(LXXXIV) Natural Product 47

Ph

O

(LXXXV) HIV-1 inhibitor 48

48

O O

Ph O

N

N

N

O

N

O

NBn

N H

O

(LXXXVI) Antitumor

O

F

S

CO2H

N

Anti viral Agent 51

O

O

N

(LXXXVIII)

(LXXXVII) Antihypertensive agent 50

agent 49

N

N

S

(XC)

N

Antibacterial agent 52 O

Gastric Antisecretory agents 53

EtO2C

N

N O

O

Ph

O

CO2Et

(XCI) Used in the Treatment of Congenital Disorders 54

(XCII) Antihypertensive Drug

Ph

OH O (XCV)

O (XCIV)

Synthetic important product 58

Synthetic important product 57 R1

(XCIX) O Synthetic important product 62

N

O

55

Synthetic biproduct 56

N

N O N (XCVII) O (XCVI) Synthetic important Synthetic important product 59 product 60

R2

N

O

O

N

N

N

(XCIII)

O

N O (XCVIII) Ph Synthetic important product 61

O

(XC1)

(LXXXIX)

O

N

O

N

O

N

O

O

O N

O2N R

Ar

NH (C)

Synthetic important product 63

O O

N

Ph

(CI) O (R)-(+) Salsolidine Starting material 64

49

O

O

O2N

N

S

N

N

Ph

O Synthetic importent product

O

N

NH2 Synthetic importent product

Gastric Antisecretory agents

O O

O N

N O

O

O

Used in the Treatment of Congenital Disorders

S

O N

N

O

N

O

N O

N

Gastric Antisecretory agents

O

O

O

O

O

Ph

NH2 Synthetic importent product

Used in the Treatment of Congenital Disorders

O Ph

Ph Synthetic importent product O N

N

O2N

EtO2C

CO2Et Antihypertensive Drug

N O

CO2Et Antihypertensive Drug

N

N N

O

N

N

O

S

N

Synthetic biproduct

N

Ph

O

O

O S

N Ph

O (R)-(+) Salsolidine Starting material

O

Gastric Antisecretory agents

EtO2C

Ph

O (R)-(+) Salsolidine Starting material

Ph Synthetic importent product

O

N

O

O

N O

Gastric Antisecretory agents

O

Synthetic biproduct

O Synthetic importent product

50

Synthesis of some known Oxazoles: (LXXXIV)47

3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-carbonitrile

was

prepared by condensation of phenylglycinol (CII) with glutaraldehyde (CII) in the presence of potassium cyanide to give compound LXXXIV via piperidine intermediate (CIII). (Equation – 1.34) Ph

OH

CHO CHO

KCN

NH2 (CII)

NC

N

O

(CIII)

NC

Ph (CIV)

N

O

Ph (LXXXIV)

Equation 1.34 Substituted 2,3-dihydrooxazolo [2,3-a] isoindol-5 (9bH) –one (LXXXV) was synthesized, starting from substituted 2-aminobenzophenone (CV). Compound CV was converted to the carboxylic acid (CVI) via diazotization, cyanation and hydrolysis. CVI was then reacted with 2-aminoethanol followed by cyclization to give the target compound LXXXV48 in the presence of catalytic amount of toluene-4-sulfonic acid in toluene. (Equation – 1.35) O

O

O Ph

Ph 1. NaNO2 / NaCN

COOH

NH2 2. Conc. H2SO4

NH2CH2CH2OH

N

PTSA, Toluene

Ph

and H2O

(CV)

(CVI)

O

(LXXXV)

Equation 1.35 Oxazolo[3,2-a][1,8]naphthyridine derivatives (LXXXIX), were synthesized starting from ethyl 3-(2,6-dichloro-5-fluoro-3-pyridyl)-3-oxopropionate (CVII) which was treated with carbon disulfide in the presence of sodium hydride in DMA to give CVIII. The latter on treatment with substituted 2-aminoethanol in the presence of triethylamine in toluene gives CIX. Compound CIX on cyclization in the presence of potassium tert-butoxide in dioxane gives the oxazolo derivative CX, which on treatment with N-methylpiperzine in ethanol gives CXI. Hydrolysis of CXI yields the target compound LXXXIX52 (Equation – 1.36) 51

O F Cl

O

CO2Et

F

Cl CS2/ MeI/ NaH

N

Cl

N Cl (CVIII)

(CVII)

t

BuO-K+

Cl

N

N

O

SMe NH2CH(R)CH2OH CO2Et

O N

O CO2Et

F

O

N

N

(CXI)

F

CO2Et

CO2H N

N

O

N

(CX) R

Cl (CIX) O

CO2Et N

HN

F Cl

O F

R

SMe

N

O

N

R

R (LXXXIX)

Equation 1.36 Synthesis of compound XCI was achieved starting from Sesamol (i.e. 5-hydroxy 2,3-benzodioxole, (CXII). Reacting it with carbon dioxide in the presence of sodium hydride in diglyme gave 3,4-methylenedioxysalisylic acid (CXIII), which was then treated with 2-aminoethanol in the presence of carbonyldiimidazole in dichloromethane amino ethanol derivative CXIV. Compound CXIV was treated with

yielding the

trimethyl orthoformate and formic acid in chloroform to give the final compound XCI54 (Equation – 1.37) OH CO

O

2

O

Diglyme/ 68 % (CX11)

OH

O

/ NaH

O

COOH (CXIII)

CDI / NH2CH2CH2OH CHCL3 / 79 %

OH O

OH NH

O (CXIV) O

CH(OMe)3

O

HCO2H, CHCl3 51 %

O

O

O N

(XCI) O

Equation 1.37 Substituted oxazolo [3,2-a] pyridine carboxylate (CXII)55 was synthesized starting from (2R) or (2S)-1-amino-2-propanol and ethyl acetoacetate to give the chiral

52

enamines CXVIII-R or CXVIII-S, which on reaction with acetyl phenylpropanoate (CXVII), give oxazolopyridines (CXII-R) or (CXII-S). (Equation – 1.38)

HO

O

O

O

+

Me

H2N

O

O O

RO (CXVIII - R) HN

MeO2C (CXVII)

OH

EtO2C

HO

+

Me OEt H2N (CXVI) (CXV - S)

OEt (XCVI)

(XCV - R)

O

N

RO

(CXVIII- S)

HN OH

N

EtO2C

O

O CO2R

CO2R

(CXII - R)

(CXII - S)

Equation – 1.38

1.5 References: 01. Herbert C. Brown and Krishnamurthy, S., Tetrahedron,; 1979, 35, 567-607. 02. (a) Bouis, J and Carlet, H., Libegs Ann. Chem, 1976, 124, 23; (b) Schorlemmer, C., Ibid. 1975, 177, 303; (c) Hill, A. J and E. H. Nason, J. Am. Chem. Soc. 1924, 46, 2236; (d) Clarke, H. T and Dreeger, E. E., Org. Synth. Coll. 1941, 1, 304. 03. Thoms, H and Mannich, C., Ber. Dtsch. Chem. Ges, 1903, 36, 2544. 04. Wiseloge, F. Y and H. Sonneborn, Org. Synth. Coll, 1941, 1, 90. 05. (a) Verly, Bull. Soc. Chim. Fr. 1925, 37, 537. (b) Meerwin, H and Schmidt, R., Liebigs Ann. Chem. 1925, 444, 221. 06. Pondorf, W. Z. Angew. Chem, 1926, 39, 138. 07. Buveault, L and Blanck, Bull. Soc. Chim. Fr. 1974, 31, 674.

53

08. Stock, A., Hydrides of Boron and silicon, Cornell University press, Ithaca, New Yark. 09. Schlesinger, H. I., Brown, H. C., Hoekstra, H. R and Rapp, L. R., J. Am. Chem. Soc. 1953, 75, 199. 10. Schlesinger, H. I., Brown, H. C. and. Finholt, A. E., J. Am. Chem. Soc. 1953, 75, 205. 11. Finholt, A. E., Bond, Jr, A. C and Schlesinger, H. I., J. Am. Chem. Soc.1947, 69, 1199. 12. (a) Gaylord, N. G. Reduction with complex metal hydrides. Interscience, New York (1956); (b) Wakar, E. R. H., Chem. Soc. Rev. 1976, 5, 23; (c) Brown, W. G. Org.React. 1951 6, 469, (1951). 13. W. G. Brown, Org. React. 1951, 6, 469. 14. Ziegler. K., Bond. A. C., Schesinger, H. I. ; J. Am. Chem. Soc. 1947, 69, 1199. 15. Bates. R. B., Buchi. G., Matsuura, T., Shaffer, R. R.; J. Am. Chem. Soc. 1960, 82, 2327. 16. (a) Brown, H. C and Wiseman, P. M.; J. Am. Chem. Soc. 1966, 88, 1458. (b) Fieser, L. F; Fieser, M.; F F, 1957, 1, 584. 17. Paquette, L. A., Gardlik, J. M., McCullough, K. J., Samodral, R., J. Am. Chem. Soc. 1983, 105, 7649. 18. Sroog, C. E., Woodburn, H. M., Org. Synth. Coll. 4, 1963, 271. 19. Ishikawa; Mukaima; Bull. Chem. Soc. Jpn. 1978, 51, 2059. 20. Mc Murry, Silvestri, Fleming, J. Org. Chem. 1978, 43, 3249. 21. Larak, Text book functional group transformations: 1989, 151-152. 22. Wang, Sukenik, J. Org. Chem. 1985, 50, 5448. 23. Latif, Mishriky,Zeid J. Prakt. Chem. 1970, 312, 421. 24. Photis, Paquette, J. Am. Chem. Soc. 1974, 96, 4715. 25. Bailey, Marktscheffel, J. Org. Chem. 1960, 25, 1797. 26. (a) Bonner; J. Am. Chem. Soc. 1951, 73, 2872. (b) Corey, E. J and Achiwa; J. Org. Chem. 1969, 34, 3667.

54

27. Pinder, Synthesis, 1980, 425-452. 28. Brown, Tsukamols, J. Am. Chem. Soc. 1964, 86, 1089. 29. Hassner, Mathews, J. Am. Chem. Soc., 1969, 91, 5046. 30. Mc Murry, Hoj, J. Org. Chem. 1975, 40, 3797. 31. (a) Pettit, Ghatak, Green, J. Org. Chem.,1961, 26, 1685. (b) Pettit; J. Org. Chem. 1960, 25, 875. 32. Bilger; Royer; Synthesis, 1988, 902. 33. Rickborn, B and Quartucci, J., Pettit, J. Org. Chem. 1964, 29, 3185. 34. Brown, H. C and Krishnamurthy, S., J. Org. Chem. 1969, 34, 3918. 35. Mangoon, E. F and Slaugh, L. H., Tetrahedron, 1967, 23, 4509. 36. Norbert De Kimpe, Altermann, W., J. Org. Chem., 1998, 63 ,6-11. 37. Kelvin L. B, Donald E. Butler., Tetrahedron Lett., 1992, 33,(17), 2283. 38. M.Madelung, Ber., 1912, 45, 1128. 39. Adlington, Baldwin., J. Chem. Soc. (P1), 2000, 303. 40. Knight., Synthetic letters, 1988, 731. 41. Hisato Takeuchi, Shun-ichi Yanagida.; J. Org. Chem., 1989, 54 ,431. 42. Peter Stanetty and Barbara Krumpak; J. Org. Chem., 1996, 61, 5130. 43. Eun Lee, Tae Seop Kang, Beom Jun Joo; Tetrahedron Lett., 1995, 36, 417-420. 44. Aldabbagh and Bowman; Org. Synth., 1997, 4, 267. 45. Sukbok Chang, Robert H. Grubbs J. Org. Chem., 1998, 63 ,864. 46. (a) Pellettier, S. W., Walter A. Jacobs. J. Amer. Chem. Soc. 1954, 76, 4496. (b) Pellettier, S. W., David M. Locke. J. Amer. Chem. Soc. 1965, 87 (4) 761. (c) Pellettier, S. W., Parthasarathy, P. C. J. Amer. Chem. Soc. 1965, 87 (4) 777. (d) Naresh V. Mody, Pellettier, S. W., Tetrahedron; 1978, 34, 2421. (e) Pellettier, S. W., Naresh V. Mody, Haridutt K. Desai, Janet Finer-Moore, Jacek Nowacki, and Balawant S. Joshi. J. Org. Chem., 1983, 48 (11), 1787. 47. (a) Lue Guerrier, Jacques Royer, David S. Grierson and Henri-Philippe Husson. J. Amer. Chem. Soc. 1983, 105, 7754. (b) Bonin M. Royer J. Grierson D.S and Husson H. P., Tetrahedron Lett., 1986, 27 (14), 1569. (c) Jean-Charles Quirion,

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David S. Grierson, Jacques Royer and Henri-Philippe Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (d) Naoki YYamazaki, Toshimasa Ito and Chihiro Kibayashi, Syn. Lett., 1999, 1, 37. (e) Teran, J. L. Gnecco, D. Galindo, A. Juarez, J. Bernes, S. and Enriquez, R. G. Tetrahedron Asymmetry; 2001, 12, 357. (f) Luis F. Roa, Dino Gnecco, Alberto Galindo, Jorge Juarez and Sylvan Bernes, Analytical Sciences, 2003, 19, 1223. (g) Mercedes Amat, Nuria Llor, Carmen Escolano, Marta Huguet, Maria Perez, Elies Molins and Joan Bosch. Tetrahedron Asymmetry; 2003, 14, 293. 48. Alfred, M.; Harard, Z.; Bernhard, K.; Wolfang, S.; Thomas, P.; Wolfang, K.; Hans, S.; Ulrike, L.; Herbert, L. J. Med. Chem. 1993, 36 (17), 2526. 49. JP 03, 109, 388. 50. Chia-Yang Shiau, Ji-Wang Chern, Kang-Chien Liu, Chao-Han Chan and Mou-Hsiung Yen, J. Het. Chem., 1990, 27, 1467. 51. Mertens A, Zilch H, Leseru Konig B; EP 0640087, WO 9424405. 52. Hirosato, K.; Masshiro, T.; Yosimasa, I.; Fumio, S.; Goro, T.

J. Med. Chem.

1990, 33 (7), 2012. 53. Fukumi, H. et al. Chem Pharama Bull., 1989, 47 (5), 1197. Fukumi, H., Sakamoto, T., Sugimoto, M., Tabata, K.; JP 1989242587. 54. Rogers, G. A. Santa Barbara, Christopher Marrs, Foothill Ranch, US 5985871, JP 200152705, EP 1054674, WO 9944469. 55. (a) Esther caballero, Pilar Puebla, Manual Medarde and Arturo San Feliciano, Tetrahedron; 1993, 49 (44), 10079. (b) Esther caballero, Pilar Puebla, Mar Sanchez, Miguel A. Salvado, Santiago Garcia-Granda and Arturo San Feliciano, J. Org.Chem., 1996, 61 (9), 1890. (c) Esther caballero, Pilar Puebla, Mar Sanchez, Manuel Medarde, Lourdes Moran del Prado and Arturo San Feliciano, Tetrahedron Asymmetry; 1996, 7 (7), 1985. (d) Martin, E.; Asuncion Moran, Lusia, M. Martin.; Luis San Roman, Pilar Puebla, Manual, M.; Esther, C. and Arturo San Feliciano. Bioorg Med Chem. Lett. 2000, 10 (4), 319.

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56. Noberto Farfan, Rosa Santillan, Julian Guzaman, Belinda Castillo and Aurelio Ortiz. Tetrahedron; 1994, 50 (33), 9951. 57. Crist N. Filer, Felix E. Granchelli, Albert H. Soloway and John L. Neumeyer. J. Org. Chem., 1978, 43 (4), 672. 58. Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe Husson. Tetrahedron Letters; 1988, 29 (27), 3311. 59. (a) Norton, P. Peet and Peter, B. Anzeveno, J. Het. Chem. 1979, 16, 877. (b) Hana Divisova; Helena Havlisova; Peter Broke and Pavel Pazdera. Molecules, 2000, 5, 1166. (http://www.mdpi.org, One pot synthesis of some fused quinqzolines;

Hana Divisova and Pavel Pszdera. Online publication from

[email protected]) (c) Johannes F., Shaifullah Chowdhury, Christian Hametner, Arkivoc, 2001, i, 163. 60. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A. I. Arkivoc, 2003, xiii, 166. 61. Trevor, A. Crabb and Asmita V. Patel. Heterocycles. 1994, 37 (1), 431. (b) MarieChristine Lallemand; Mathieu Gaillard; Nicole Kunesch and Henri-Philippe Husson. Heterocycles. 1998, 47 (2), 747. 62. Takayasu, Y. Jumpei, S and Kimio Higashiyama; Heterocycles, 2002, 58, 431. 63. Alexander,

A.

B

and

Eugene,

V.

B.

Molecules,

2003,

8,

460.

(http://www.mdpi.org). 64. (a) Spath, E.; Dengel, F. Chem. Ber., 1938, 71B, 113. (b) Masatoshi, Y.; Kuniko, H.; Shigetaka, I. and Nazmul, Q. Tetrahedron Letters; 1988, 29 (52), 6949.

57

58

2.1 INTRODUCTION: The oxazolo moiety is found in many biologically active compounds and synthetically important intermediates some of which were mentioned earlier in the first chapter.

2.2 Present Work: A survey of literature revealed that different oxazole derivatives showed various types of pharmacological activities. However, not much work has been done on the synthesis of fused oxazolo compounds. It was considered desirable to study the synthesis of oxazolothiazines. It is conceivable that these oxazolothiazines can be synthesized from 2-aminothiophenol by ring closure with chloroacetic acid to obtain benzothiazines in the first step. These benzothiazines can be used as building blocks for the synthesis of fused oxazolo ring units.

2.3 Results and Discussion Commercially available 2-aminothiophenol (1) was treated with chloroacetic acid in the presence of sodium hydroxide to obtain 1,4-benzothiazine-3(4H)-one (2a, i.e. 24, R = R1 = H) in 76 % yield (equation – 2.1). 2a is a compound known1 in literature. However, it was further characterized in the present work by spectral and analytical data. Thus, its IR (KBr) spectrum (Fig. 2.1) showed a peak at 3440 cm-1, which may be assigned to –NH- stretching vibration, and a strong peak at 1663 cm

–1

in the carbonyl

region which may be assigned to the amide carbonyl grouping. Its 1H NMR (in CDCl3) showed (Fig. 2.2) signals at δ 8.87 (bs, 1H, D2O exchangeable, amide proton), three aromatic signals at 7.33 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.0 Hz, 2H), 6.88 (d, J = 7.8 Hz, 1H) and S – CH2 at 3.43 (s, 2H). Its mass spectrum (Fig. 2. 3) showed the molecular ion peak at 166 (M+ +1, 100 %), as base peak. SH NH2

ClCH2CO2H, NaOH, Water 100 °C, 6.0 h, 76.0 %

(1)

S N H (2a)

O

Equation – 2.1 59

In addition to the method given above, several other methods have also been reported in the literature for the preparation of benzothiazinones. Thus, for example, condensation2 of 2-aminothiophenol and ethyl 2-halo-2-alkylacetate at 150 °C, or the addition of 2-bromo-2-alkylacetic acid esters in the presence of sodium ethoxide to ethanol (multistep), or in the presence of glacial acetic acid and hydrochloric acid, 3 from 2-(2-nitro-phenylsulfanyl)-propionic acid4 at 240 °C for 2.0 hrs, from 2-aminobenzothiol and 2-haloethyl acetate in DMF

5

at 90 – 95

°

C, from 2-bromomethyl – 4H-

benzo[1,4]thiazine-3-one in the presence of tributyltin hydride and AIBN in benzene,6 by reaction7 of 2-aminobenzothiol and 2-bromoalkylacetic acid

at

125

°

C, 2-

8

aminobenzothiol and 2-chloroalkylacetic acid amide in the presence of potassium carbonate in acetone for 16.0 hrs, from 2-(1-chloroethyl)-benzothiazole in presence of potassium tert butoxide in isopropanol,9 from bis-(2-nitro phenyl)-disulfane in the presence10 of samarium (II) iodide in THF (two steps), from 2,2-dimethyl-2,3-dihydrobenzothiazole

in

presence

of

potassium

carbonate,11

from

2-chloro-N-(2-

methylsulfanylphenyl)-2-aryl/alkyl acetamide at 195 °C under pressure,12 from 2,2,2trichloro-1-aryl-ethanol & 2-amino benzothiol in presence of KOH, methanol,13 from 2acetoxy-4H-benzo[1,4]thiazine-3-one in presence of trifluroacetic acid,14

from 2,2I-

disulfonediyl-bis-aniline in presence of sodium hydride in DMF15 from 2-chloro-4Hbenzo[1,4]thiazin-3-one with arenes in presence of aluminum chloride.16 All these reported methods involve more than one step, which are environmentally harmful with fairly long reaction times. Therefore, there is always need for the development of an improved or alternative procedure for the synthesis of substituted benzothiazines.

Table – 2.1: Some known methods to prepare compounds 2a - h S.No. 1.

Reactant SH

Product

Conditions

S

CH3CH(Br)COOH,

Ref: 2

Zuletzt, 150 oC NH2

N H

O

60

SH

S

NH2

N H S

2.

1. CH3CH(Br)COOEt, in

3

AcOH

3.

HO2C

R

O

240 oC, 2.0 hrs

4

ii) NaBH4, Pd-C, Dioxane,

S NH2 SH

4.

2. Con. HCl

N H

O

S

R

Water, 72 hrs RCH(X)COOEt

5

DMF, 90 – 95 oC NH2 5.

S

Br

N H S

SH

6.

O

R = CH3, Ph (Bu)3SnH, AIBN,

6

Benzene, Reflux

O

N H

N H S

O CH3CH(Br)COOH

7

120 – 125 oC NH2

N H S

SH

7.

O CH3CH(Cl)CONH2

8

K2CO3, Acetone, Refluxed for NH2

N H S

O

N H S

O

N H

O

H N

S

R

S

N H

O

N

8.

S 9.

O2N S

S

NO2 10.

Cl

16.0 hrs tBuO K

9

tBuOH, 64 %

R

1) SmI, THF

10

2) RCH(Br)COOH R = CH3, Ph K2CO3, Ether

11

61

11.

SMe

S

Ph

N H

O

S

Ph

N H S

O

N H S

O

195 °oC,

12

Pressure

NH O

Cl SH

12.

KOH, Methanol, 2,2,2 –

13

trichloro-1-phenyl NH2 13.

S

14.

N H H2N S

OAc O

Benzene, TFA, Refluxed

14

Ph PhCH2CO2Et, NaH, DMF, 100 15 °o

C, 86.0 %

S

NH2 15.

Ph

S

OAc

N H

O

S

Ar

ArH, AlCl3, 10 min,

16

50 oC

N H 16.

O SH

N H

O

S

CH3CH(Cl)CO2H

17

NaOH, Water NH2 17.

SH

N H S

O Ph

Refluxed for 4.0 hrs PhCH(Br)COOH,

18

Zuletzt, 150 oC NH2 18.

SH

N H S

O Ph

1) PhCH(Br)COOMe, KI

19

2) NaOMe, C6H6, 80 ° oC NH2 19.

SH

N H S

O

N H

O

Ph

1) PhCH(Cl)COOH,

20

NaOH.

NH2

62

20.

S

CO2R

NaBH4, Pd-C, Dioxane,

S

21

Water, 72 hrs

NO2

N H

SH

21.

O (CH3)2C(Br)COOH

S

22

KOH, EtOH

22.

NH2

N H

SH

S

O (CH3)2C(X)COOEt

23

1) K2CO3 NH2 23.

N H

S

O

2) Con. HCl CH3I

S

24

LDA

N H

O

N H

O

Keeping this in view, two simple but new methods were developed for the synthesis of benzothiazinones. In the first method, 2-aminothiophenol was reacted with °

ethyl bromoacetate in aqueous sodium hydroxide at 80 C for 1.0 hr, which resulted in the formation of 2a in 94 % yield. In the other method, 2-aminothiophenol was treated with ethyl 2-bromoacetate in the presence of microwaves using microwave oven for 5.0 min, to yield 2a in 80 % yield. (Equation 2.2)

63

BrCH2CO2Et, NaOH,

Water, 80 oC, 1.0 hr, 94 %

S

SH

N H (2a)

NH2 (1)

BrCH2CO2Et, NaOH,

O

Water, MW, 4 - 5 min, 80 %

Equation – 2.2

Substituted 1,4-benzothiazine-3(4H)-ones (2) were prepared in the above two methods and also all derivatives 2a-h were prepared simultaneously in one lot by using parallel synthesizer. The structures for these products were assigned on the basis of analogy and on the basis of analytical and spectral data. (Table –2.2)

SH NH2

BrRR1CCO2Et, NaOH, Water, MW, 4 - 5 min, Parallel

S

R R1

(7 Reactions at a time) 65 - 89 %

N H

O

(2a-h)

(1) Equation – 2.3

Table –2.2: Synthesis of 2 (a-h) from 1 and its data 1

H NMR (200 MHz, CDCl3); IR (KBr) / cm-1.

IR: 3196(-NH- Band), 1665(- CO - Stretching); 1

H NMR: (CDCl3) δ 9.25 (bs, 1H, D2O

Exchangeable, NH), 7.29 (d, J = 7.52 Hz, 1H),

64

7.15 (d, J = 7.52 Hz, 1H), 7.03 (t, J = 7.52 Hz, 1H), 6.93 (t, J = 7.52 Hz, 1H), 3.60 – 3.50 (q, J = 6.98 Hz, 1H, SCH), 1.49 (d, J = 6.99 Hz, 3H, SCHCH3); Mass: 180 (M++1, 100 %). IR: 3422(-NH- Band), 1667 (- CO - Stretching); 1

H NMR: (CDCl3) δ 10.57 (bs, 1H, D2O

Exchangeable, NH), 7.29 (d, J = 7.33 Hz, 1H, ), 7.18 (d, J = 7.81 Hz, 1H, ), 7.00 (d, J = 7.82 Hz, 2H, ), 1.34 (s, 6H, C(CH3)2; Mass: 194 (M+ +1, 100 %). IR: 3195 (-NH- Band), 1662 (- CO - Stretching); 1

H NMR: (CDCl3) δ 10.56 (bs, 1H, D2O

Exchangeable, NH), 7.31 (d, J = 7.81 Hz, 1H, ), 7.16 (d, J = 7.81 Hz, 1H, ), 7.00 – 6.94 (m, 2H, ), 3.45 – 3.38 (dd, J = 5.86 & 8.31 Hz, 1H, SCH), 1.81 – 1.70 (m, 1H, SCHCH2CH3), 1.54 – 1.39 (m, 1H, SCHCH2CH3), 0.96 (t, J = 7.33 Hz, 3H, SCHCH2CH3); Mass: 194 (M++1, 100 %). IR: 1670 (- CO - Stretching); 1H NMR: (CDCl3)

δ 10.56 (bs, 1H, D2O Exchangeable, NH), 7.31 (d, J = 7.81 Hz, 1H), 7.16 (m, 1H, ), 7.00 – 6.94 (m, 2H), 3.52 – 3.45 (d, J = 7.81 Hz, 1H, SCH), 1.77 – 1.67 (m, 1H, SCHCH2CH2), 1.52 – 1.33 (m, 3H, SCHCH2CH2 & SCHCH2CH2), 0.89 – 0.83 (t, J = 7.33 Hz, 3H, SCHCH2CH3); Mass: 208 (M++1, 100 %). IR: 3412 (-NH- Band), 1685 (- CO - Stretching); 1

H NMR: δ 9.17 (bs, 1H, D2O Exchangeable,

NH), 7.30 (d, J = 7.82 Hz, 1H), 7.16 (t, J = 7.81

65

Hz, 1H), 6.99 (t, J = 7.33 Hz, 1H), 6.88 (d, J = 7.81 Hz, 1H), 3.11 (d, J = 8.79 Hz, 1H, SCH), 1.97 – 1.90 (m, 1H, SCHCH(CH3)2), 1.05 (d, J = 6.83 Hz, 6H, SCHCH(CH3)2); Mass: 208 (M++1, 100 %). IR: 1663 (- CO - Stretching); 1H NMR: (CDCl3)

δ 9.10 (bs, 1H, D2O Exchangeable, NH), 7.30 (d, J = 7.33 Hz, 1H), 7.17 (t, J = 7.33 Hz, 1H), 7.00 (t, J = 7.81 Hz, 1H), 6.89 (d, J = 7.81 Hz, 1H), 3.39 (t, J = 7.08 Hz, 1H, SCH), 1.93 – 1.84 (m, 1H, SCHCH2), 1.66 – 1.50 (m, 1H, SCHCH2), 1.25 (m, 8H, SCHCH2 (CH2)4CH3), 0.86 – 0.82 (m, 3H, SCHCH2 (CH2)4CH3;

Mass: 250 (M+

+1, 100 %). IR: 3430 (-NH- Band), 1677 (- CO - Stretching); 1

H NMR (DMSOd6, 200 MHz): δ 10.43 (bs, 1H,

D2O Exchangeable, NH), 7.33 – 7.26 (m, 6H), 7.17 – 7.09 (m, 1H), 7.02 – 6.91 (m, 2H), 4.62 (s, 1H, Ph CH); Mass: 242 (M+ +1, 100 %), 241 (M++1, 20 %).

66

1,4-benzothiazine-3(4H)-one (2a) was treated with ethyl 2-bromoacetate in the presence of potassium hydroxide in acetone at 60 °C for 30 min. Processing of the reaction mixture gave a product which was found to be 3a (Equation 2.8) by comparison of its physical constants with those reported in literature.25 Compound 3a has been further characterized by spectral methods. Its IR spectrum showed no absorption above 3000 cm1

indicating absence of –NH- grouping. However, the IR spectrum showed (Fig. 2.4) two

strong sharp bands, one at 1744 cm-1 and the other at1680 cm-1. The former has been assigned to ester carbonyl grouping and the other assigned to amide carbonyl grouping. Thus, its 1H NMR spectrum (Fig. 2.5) displayed signals at δ 7.38 (d, J = 6.84 Hz, 1H, Ar - H), 7.21 (t, J = 7.33 Hz, 1H, Ar - H), 7.05 (d, J = 7.33 Hz, 1H, Ar - H), 6.87 (d, J = 8.30 Hz, 1H, Ar - H), 4.65 (s, 2H, N-CH2), 4.27 (q, J = 7.33 Hz, 2H, O – CH2), 3.46 (s, 2H, S – CH2), 1.28 (t, J = 7.33 Hz, 3H, O – CH3) while the mass spectrum showed (Fig. 2.6) m/z 252 (M++1, 100 %) and other peak at 206 (10 %) etc.

S

(2a)

N H

S

KOH / BrCH2CO2Et

N

o O acetone, 60 C, 30 min

O OEt

(3a) O Equation – 2.4

Subsequently, it has been found that 3a could also be prepared from 2a by reaction in DMF using K2CO3 as base at 80°°C for 12 hrs. (Equation 2.9) S N H

S

K2CO3, BrCH2CO2Et

N

o ODMF 80 C, 12 hrs

O OEt

(3a)

(2a)

O Equation – 2.5

40

2-Substituted-3,4-dihydro-3-oxo-2H-1,4-benzothiazine–4-acetic acid ethyl esters could also be prepared using the above method. Structures of all products (3a – h) have been assigned on the basis of analogy and on the basis of spectral & analytical data (Table – 2.3).

S

R

N H

O

S

R

N

O

K2CO3, BrR1CHCO2Et DMF 80 0C, 12.0 hrs

OEt

R1

(2a - h)

(3a - j)

O

Equation – 2.6 Table – 2.3: Synthesis of 3 (a-h) from 2 (a-j) and Data: 1

Structure

H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

IR1732 (ester- CO – Stretching), 1678 (amide- CO – Stretching); 1H NMR: δ 7.37 (d, J = 7.32 Hz, 1H), 7.21 (t, J = 7.81 Hz, 1H ), 6.86 (d, J = 8.31 Hz, 1H), 4.75 – 4.54 (dd, J = 17.58 & 22.96 Hz, 2H, NCH2), 4.30 – 4.19 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.58 – 3.50 (q, J = 7.32 Hz, 1H SCHCH3), 1.47 (d, J = 6.84 Hz, 3H, SCHCH3), 1.28 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 266 (M+ +1, 100 %). IR: 1750 (ester- CO – Stretching), 1672 (amide- CO – Stretching); 1

H NMR: δ 7.36 (d, J = 7.82 Hz, 1H), 7.24 (t, J = 7.32 Hz, 1H),

7.05 (t, J = 7.33 Hz, 1H ), 6.83 (d, J = 8.30 Hz, 1H), 4.66 (s, 2H, NCH2), 4.31 – 4.20 (q, J = 7.33 Hz, 2H, OCH2CH3), 1.47 (s, 6H), 1.29 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 280 (M+ +1, 100 %). IR: 1749(ester- CO – Stretching), 1674 (amide- CO – Stretching). 1

H NMR: δ 7.38 (d, J = 7.33 Hz, 1H), 7.23 (t, J = 7.81 Hz, 1H),

7.04 (t, J = 7.32 Hz, 1H), 6.83 (d, J = 8.31 Hz, 1H), 4.90 (d, J = 17.58 Hz, 1H, NCH2), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.25 (q, J

41

= 7.30 Hz, 2H, OCH2CH3), 3.39 (t, J = 7.57 Hz, 1H, SCHCH2CH3), 2.00 – 1.86 (m, 1H, SCHCH2CH3), 1.68 - 1.54 (m, 1H, SCHCH2CH3), 1.29 (t, J = 7.33 Hz, 3H, OCH2CH3), 1.05 (t, J = 7.32 Hz, 3H, SCHCH2CH3); Mass: 280 (M+ +1, 100 %). IR: 1748 (ester- CO – Stretching), 1674 (amide- CO – Stretching); 1

H NMR: δ 7.37 (d, J = 7.33 Hz, 1H), 7.23 (t, J = 7.81 Hz, 1H),

7.04 (t, J = 7.81 Hz, 1H), 6.83 (d, J = 7.82 Hz, 1H), 4.88 (d, J = 17.09 Hz, 1H, NCH2), 4.45 (d, J = 17.58 Hz, 1H, NCH2), 4.31 – 4.20 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.47 (t, J = 7.33 Hz, 1H, SCH), 1.89 – 1.83 (m, 1H, SCHCH2), 1.65 – 1.42 (m, 3H, SCHCH2 & SCHCH2CH2), 1.29 (t, J = 7.32 Hz, 3H, OCH2CH3), 0.91 (t, J = 6.83 Hz, 3H, SCHCH2CH2CH3); Mass: 294 (M+ +1, 100 %). IR: 1748 (ester- CO – Stretching), 1674 (amide- CO – Stretching); 1

H NMR: δ 7.36 (d, J = 7.33 Hz, 1H), 7.25 (t, J = 7.81 Hz, 1H),

7.02 (t, J = 7.81 Hz, 1H), 6.80 (d, J = 7.82 Hz, 1H), 5.09 (d, J = 17.58 Hz, 1H, NCH2), 4.30 – 4.17 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.10 (d, J = 9.77 Hz, 1H), 2.90 (d, J = 14.65 Hz, 1H), 1.87 – 1.75 (m, 1H, SCH), 1.28 (t, J = 7.33 Hz, 1H, OCH2CH3), 1.03 (t, J = 6.83 Hz, 3H, SCHCH2CH2CH3); Mass: 294 (M+ +1, 100 %). IR: 1749 (ester- CO – Stretching), 1673 (- CO - Stretching); 1H NMR: (CDCl3) δ 7.36 (d, J = 7.33 Hz, 1H), 7.25 (t, J = 7.33 Hz, 1H), 7.02 (t, J = 7.81 Hz, 1H), 6.82 (d, J = 7.81 Hz, 1H), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.29 – 4.18 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.43 (t, J = 7.08 Hz, 1H, SCH), 1.91 – 1.81(m, 1H, SCHCH2), 1.70 – 1.30 (m, 1H, SCHCH2), 1.27 (m, 8H, SCHCH2 (CH2)4CH3), 0.86 – 0.84 (m, 3H, SCHCH2 (CH2)4CH3);

Mass: 236 (M+ +1, 100 %).

IR: 1746 (ester- CO – Stretching), 1673 (amide- CO – Stretching); 1

H NMR: δ 7.43 – 7.35 (m, 2H, ), 7.31 – 7.17 (m, 5H), 6.98 (t, J =

42

7.32 Hz, 1H), 6.89 (d, J = 7.81 Hz, 1H), 4.97 (d, J = 17.58 Hz, 1H, NCH2CO), 4.77 (s, 1H, SCHPh), 4.50 (d, J = 17.58 Hz, 1H, NCH2CO), 4.34 – 4.23 (q, J = 7.33 Hz, OCH2CH3), 1.31 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 328 (M+ +1, 100 %). IR: 1739 (ester- CO – Stretching), 1676 (amide- CO – Stretching). 1

H NMR: δ 7.41 (d, J = 7.52 Hz, 1H), 7.23 (d, J = 7.79 Hz, 1H, ),

7.17 – 6.97 (m, 2H), 5.15 – 5.08 (dd, J = 5.37 & 9.94 Hz, 1H, NCH CO), 4.28 – 4.14 (m, 2H, OCH2CH3), 3.41 (s, 2H, SCH2 ), 2.27 – 2.17 (m, 1H, NCHCH2CH3), 2.11 – 1.90 (m, 1H, NCHCH2CH3), 1.23 (t, J = 7.25 Hz, 3H, OCH2CH3), 0.82 (t, J = 7.25 Hz, 3H, NCHCH2CH3); Mass: 281 (M+ +2, 15 %), 280 (M+ +1, 100 %), 234 (10 %). IR: 1740 (ester- CO – Stretching), 1678 (amide- CO – Stretching); 1

H NMR: δ 7.41 (d, J = 7.52 Hz, 1H), 7.23(d, J = 8.06 Hz, 1H), 7.17

– 6.97 (m, 2H), 5.25 – 5.18 (dd, J = 5.38 & 9.14 Hz, 1H, NCHCO), 4.28 – 4.16 (m, 2H, OCH2CH3), 3.40 (s, 2H, SCH2), 2.16 – 2.00 (m, 2H, NCHCH2), 1.27 – 1.16 (m, 5H, OCH2CH3 & NCHCH2CH2), 0.82 (t, J = 7.25 Hz, 3H, OCH2CH3); Mass: 295 (M+ +1, 30 %), 294 (100 %) and 248 (10 %).

43

It was considered desirable to study the effect of substituents in the cyclization reaction yielding oxazolothiazines. All the compounds reported in Table 2.4 contain hydrogen/alkyl groups at R1. It would be interesting to study the course of cyclisation if R1 is substituted with aryl moiety having electron releasing / withdrawing groups. Therefore, 3k and 3l, needed to build oxazolothiazines were prepared as follows:Commercially available phenylacetic acid (4) was refluxed in absolute ethanol in the presence of conc. H2SO4 to give 5, which with N-bromosuccinimide in the presence of catalytic amount of benzoyl peroxide gave 6.26 The latter was then reacted with 1,4benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate to give 3k (Scheme 2.1).

CO2H

CO2Et

Ethanol, Con.H2SO4 (cat.),

CO2Et

NBS(1.05 eq), Benzoylperoxide (Cat)

8 0 °C, 4.0 hrs

CCl4, 3.0 hrs

(4) Br

Br

(5)

(6)

CO2Me S

S

K2CO3, DMF

+ (6)

N H

O

80 °C, 12.0 hrs

N (3k)

(2a)

Ph

O CO2Me

Scheme – 2.1 The structure of the compound 3k is supported by its spectral and analytical data. Thus, its IR (KBr) showed peaks at 1748 (ester- CO – Stretching), 1676 (amideCO – Stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.41 – 7.28 (m, 7H, ArH), 7.10 – 6.95 (m, 2H, ArH), 6.23 (s, 1H, PhCH), 3.83 (s, 3H, COOCH3), 3.53 (s, 2H, SCH2). Its mass spectrum showed peaks at m/z 313 (M+ +1, 25 %), 281 (100 %),

54

226 (60 %), 211 (75 %), 121 (60 %). Elemental Analysis: Mol. F: C17H15NO3S, Cal. C: 65.160, H: 4.829, N: 4.473; Experimental, C: 64.685, H: 5.032, N: 4.236. S

S

S

(i) Morpholine, Sulfur, 100 °C, 12.0 hrs

AcCl, AlCl3, CH2Cl2,

(7) (8)

HO2C

O S

S Oxone, Acetone

EtO2C

S

(9)

O O NBS(1.05 eq) Benzoylperoxide (Cat),

S

O O

CCl4, 3.0 hrs

water, r.t., 6.0 hrs

(10)

0 - 80 °C, 6.0hrs

(ii) Aq. HCl, 100 °C, 12.0 hrs

0 - r.t, 3.0 hrs

EtO2C

SOCl2, Ethanol

EtO2C

(11)

(12)

Br

S

O O S

K2CO3, DMF,

N

O

+ N H EtO2C

O

O

80 °C, 12.0 hrs

(10)

O

S

Br O

(2a)

O

(3l)

Scheme – 2. 2

In order to prepare the intermediate 3l, thioanisole (7) was treated with acetyl chloride in the presence of aluminum chloride to obtain 8,27 which on Willgerodt reaction using morpholine and sulfur gave 4-methylthiophenylacetic acid (9).28 Compound 9 was converted to ethyl ester 10 in the presence of thionyl chloride in ethanol.29 The methylthio group of 10 was oxidized with oxone to obtain 4-methylsulfonylphenylacetic

55

acid (11). 11 was treated with N-bromosuccinimide in the presence of benzoyl peroxide as a catalyst to give Bromo-(4-methanesulfonyl-phenyl)-acetic acid ethyl ester (12)30 which was reacted with 1,4-benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate to yield 3l. (Scheme 2.2)

The structure of the compound 3l is supported by its spectral and analytical data. Thus, its IR (KBr) showed peaks at 1742 cm-1 (ester carbonyl stretching) and at 1664 cm1

(amide carbonyl stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.92 (d, J =

8.31 Hz, 2H, ArH), 7.57 (d, J = 8.31 Hz, 2H, ArH), 7.44 – 7.40 (m, 1H, ArH), 7.33 – 7.14 (m, 2H, ArH), 7.11 – 6.97 (m, 2H, ArH), 6.89 – 6.82 (m, 1H, ArH), 6.16 (s, 1H, ArCH), 4.28 – 4.21 (m, 2H, CO2CH2CH3), 3.43 (s, 2H, SCH2), 3.04 (s, 3H, SO2CH3), 1.19 (t, J = 7.33 Hz, 3H, CO2CH2CH3). Its mass spectrum showed peaks at m/z 405 (M+ +1, 30 %), 359 (100 %), 304 (95 %), 165 (70 %) and 136 (80 %).

COOH

CO2Et

Thionyl chloride Ethanol

NBS(1.05 eq) Benzoylperoxide (Cat)

0 - 80 oC, 6.0 hrs

CCl4, 3.0 hrs

OMe

OMe

(15) S

CO2Et S

K2CO3, DMF

+ N H

O

N

O O

80 oC, 12.0 hrs

OMe (15)

CO2Et

OMe

(14)

(13) Br

Br

MeO

O 3m

(2a) Scheme – 2. 3

56

To prepare 3m, commercially available 4-methoxyphenylacetic acid (13), was esterified with thionyl chloride in ethanol followed by bromination with Nbromosuccinimide in the presence of benzoyl peroxide as catalyst to obtain ethyl 2bromo-2-(4-methoxyphenyl)acetate (15).31 compound 15 was reacted with 1,4benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate as base in dry dimethylformamide resulting in ethyl 2-(4-methoxyphenyl)-2-(3-oxo-3,4-dihydro-2Hbenzo[b][1,4]thiazin-4-yl) acetate (3m). (Scheme – 2.3) The structure of the compound 3m is supported by its spectral and analytical data. Thus, its IR (KBr) showed peaks at 1742 cm-1 (ester carbonyl stretching) and at 1674 cm-1 (amide carbonyl stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.38 – 7.30 (m, 1H, ), 7.23 (d, J = 9.13 Hz, 2H, ), 7.05 – 6.90 (m, 2H, ), 6.83 (d, J = 8.86 Hz, 2H, ), 6.17 (s, 1H, Benzylic H), 4.31 – 4.18 (m, 2H), 3.77 (s, 3H), 3.50 (s, 2H), 1.20 (t, J = 7.3 Hz, 3H). Its mass spectrum showed peaks at m/z 358 (M+1, 10 %), 357 (M+, 10 %), 193 (100 %).

Reductions with Lithium Aluminum Hydride (LAH): Treatment of 3a with 1.1 eq. of LAH in THF45 followed by simple processing gave a product, which was obtained as a syrupy liquid. The compound was found to be homogenous on TLC. Its IR spectrum (Fig. 2.7) (Neat) did not show any diagnostic peaks due to –NH- and -CO- groups. Its 1H NMR (in CDCl3) showed signals (Fig. 2.8) at δ 7.14 (t, J = 7.81 Hz, 1H, Ar - H), 7.03 (d, J = 7.81 Hz, 1H, Ar - H), 6.66 (t, J = 7.32 Hz, 1H, Ar - H), 6.52 (d, J = 8.30 Hz, 1H, Ar - H), 5.00 – 5.06 (dd, J= 3.41 and 9.27 Hz, 1H, O CH CH2), 4.3 – 4.21(m, 1H, O CH2), 4.12 – 4.01 (dd, J = 8.30 & 15.63 Hz, 1H, O CH2), 3.5 (m, 2H, N CH2), 3.15 – 3.08 (dd, J = 3.42 and 11.72 Hz, 1H, S CH2), 2.70 – 2.60 (dd, J = 9.28 and 11.72 Hz, 1H, S CH2). Its mass spectrum showed peaks (Fig. 2.9) at m/z194 (M+ +1, 100 %)and other peaks at 162 (30 %), 136 40%). Elemental Composition (EIHRMS) Cal Mass: 193.05613, Exp. Mass: 193.056520, DBE: 6, C: 10, H: 11, N: 1, O:1,

S:1.

Based

on

this

data,

the

product

was

assigned

as

1,2,3a,4-

tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]thiazine (16a). (Equation – 2.7)

57

S

S

LAH N (3a)

THF, 0 °C - r.t O 1 hr OEt

N

O

(16a)

O Equation – 2.7

It may be mentioned here that the product of LAH reduction in the above reaction was expected to be 17, which was, however, not found to be formed. (Equation – 2.8) S

S

LAH N (3a)

X

O OEt

N

THF, 0 - r.t 1 hr

OH

(17)

O Equation – 2.8

The above reaction of 3a yielding 16a seems to be general one. It has been extended to other N-substituted benzothiazinones (3) yielding (17). (Equation – 2.9)

S

R LAH

N

O THF, 0 °C - r.t OEt 1.0 hr

R1

S

R

N

O

R1 (16a- m)

O (3a -m) Equation – 2.9

Structure confirmation: To further confirm the structure of the product 16 its single crystal X-ray diffraction study was undertaken. For single crystal X-ray diffraction study to be carried out, it is essential that the compound should be solid crystalline substance as a first pre-requisite. Since the product 16a obtained in the present study was

58

a syrupy liquid and others being low melting solids, nitration of 16a was prepared hoping that the nitro derivative of 16a would be a solid amenable to X-ray studies. Thus, nitration of 16a with nitric acid in acetic anhydride yielded a product, which was assigned

7-nitro-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]thiazine

(18)

structure on the basis of its spectral data and analytical data. S N

HNO3

O2N

S

Ac2O

O

N

O

(18)

16a)

Equation –2.10

O2 N

6 7

5

4 9 S

Hb 3 Ha H 2 N O 13 8 10 1 11 Ha 12 Hb Hb Ha (18)

Thus, its IR (KBr) spectrum (Fig 2.10) showed peaks indicating absence of any specific functional groups; Its 1H NMR (400 MHz, in CDCl3) showed signals (Fig 2.11) at δ 5.07 (dd, J = 8.40 & 4.40 Hz, 2H, protons from carbon 2), Ha is 3.62 (dd, J = 10.0 & 8.40 Hz), 3 Hb is 3.19 (dd, J = 10.0 & 8.40 Hz), 8.04 (d, 2.4 Hz, 1H, from 7 position), 7.94 (dd, J = 8.80 & 2.40 Hz, 1H, from 8 position), 6.43 (d, J = 8.80 Hz, 1H), 3.60 (dt, J = 7.60 & 8.80 Hz, 11Ha), 3.52 (ddd, J = 7.60, 6.40 & 2.80 Hz, 11Hb) and 4.36 (dt, J = 6.4 & 8.80 Hz, 12 Ha), 4.09 (ddd, J = 7.60, 6.40 & 2.80 Hz, 12Hb). In table 2.5 are explained the Carbon 13, COSY and gHSQC. In the steady state 1D nOe experiment on irradiation, the C-8 proton at 6.57 ppm showed the enhancement of signals at 3.7 and 3.5 ppm corresponding to C-11 Ha and Hb protons respectively. From these results, aromatic C-8 proton was fixed at 6.57

59

ppm. The splitting of C-8 proton as doublet is due to coupling with C-7 proton. Hence, the position of nitro group is assigned at C-6.

Table –2.4 Carbon 13, COSY and gHSQC of compound 18 Position

2

COSY

13

C

DEPT

gHSQC

(Fig: 2.15)

(Fig: 2.12)

(Fig: 2.13)

(Fig: 2.14)

(3Ha, 3.36)

85.82

CH

(1H, 4.88)

26.82

CH2

(2Ha, 3.36)

(3Hb, 4.61) 3

(2H, 4.88) (2H, 4.88)

(2Hb, 4.61)

5

123.39

6

145.62

CH

(5H, 7.78)

7

(8H, 6.57)

123.39

CH

(7H, 7.87)

8

(7H, 7.87)

110.27

CH

(8H, 6.57)

CH2

(11Ha, 3.49)

9

115.09

10

137.61

11

(12Ha, 4.12)

46.32

(12Hb, 4.32) (11Hb, 3.72) (12Ha, 4.12)

(11Hb, 3.72)

(12Hb, 4.32) (11Hb, 3.49) 12

(11Ha, 3.49)

65.26

CH2

(12Ha, 4.12)

(11Hb, 3.72) (12Hb, 4.32) (11Ha, 3.49)

(12Ha, 4.32)

(11Hb, 3.72) (12Hb, 4.12)

60

The possible major fragmentation pattern for 18 is deduced from Chemical ionization mass spectrum (C I M S) is shown below (Fig. 2.16) Scheme – 2.4. And from thermal analysis melting point is 160.04 °C (Fig. 2.17). O2N

+

S N

O

O2N

+

- 32 -S

N (19)

(18)

m/z = 239 M+1, 100 %

O

m/z = 207, M+, 10 %

+

- 46 N

- NO2

(20)

m/z = 161, 2.0 %

+

- 25

+

- 14 - CH2CH2

N H

OH

-N

(21)

m/z = 136, 8.0 %

O

(22)

OH

m/z = 122, 2.0 %

Scheme – 2.4 Point of attack: Having confirmed the structure of 18, it was considered desirable to study the mechanism of formation of 16a (or 18) from its precursor 3a. For that it is essential to know which of the two oxygens present in 3a would end up in 16a. This was decided on the basis of the following sets of experiments: 3a was treated with Lawsson’s reagent in dioxane to obtain thioamide derivative 3n (analytical data, Fig. 2.18, 1.19 & 2.20), which was reduced with LAH (1.1 equiv.) to obtain the tricyclic oxazolo compound 16a instead of thiazolo compound (23). This result clearly indicates that oxygen from amide was not involved in the cyclization, but that of ester carbonyl was involved in the cyclization to produce tricyclic oxazolo compound 16a. Scheme – 2.5

61

S

LAH (1.2 eq) S N

S

Lawsson's Reagent, O

N

dioxane, 100 °C, 6.0 h (3n)

(3a)

CO2Et

X

N

S

(23)

S CO2Et S

LAH (1.2 eq)

N

O

(16a)

Scheme – 2.5 Table –2.5: Synthesis of 16 (a-m) from 3 (a-m) by reduction with LAH: Analytical Data: (IR cm-1), 1H NMR (δppm) (CDCl3, 200

Structure

MHz) S

IR: Did not show any diagnostic peaks due to –NH- and -COgroups; 1H NMR: (CDCl3, 200 MHz): δ 7.14 (t, J = 7.81 Hz, 1H), 7.03 (d, J = 7.81 Hz, 1H), 6.66 (t, J = 7.32 Hz, 1H), 6.52 (d, J =

N

O

8.30 Hz, 1H, 5.00 – 5.06 (dd, J= 3.41 and 9.27 Hz, 1H), 4.3 – 4.21(m, 1H), 4.12 – 4.01 (dd, J = 8.30 & 15.63 Hz, 1H), 3.5 (m, 2H), 3.15 – 3.08 (dd, J = 3.42 and 11.72 Hz, 1H), 2.70 – 2.60 (dd, J = 9.28 and 11.72 Hz, 1H). Mass: m/z: 194 (M+ +1, 100 %)and

3a

other peaks at 162 (30 %), 136 40%). EIHRMS: Cal Mass: 193.05613, Exp. Mass: 193.056520, S

IR: Did not show any diagnostic peaks due to –NH- and -COgroups; 1H NMR: (CDCl3, 200 MHz): δ 7.11 (d, J = 7.81Hz, 1H), 7.00 (t, J = 7.81 Hz, 1H), 6.65 (t, J = 7.57 Hz, 1H), 6.51 – 6.45

N

O

(dd, J = 3.41 and 8.01 Hz, 1H), 4.62 (d, J = 8.06 Hz, 1H), 4.31 – 4.13 (m, 1H), 4.10 – 3.98 (q, J = 8.30 Hz, 1H), 3.50 – 3.42 (m,

3b

2H), 2.81 – 2.74 (dd, J = 7.81 Hz, 1H), 1.43 (d, J = 6.59 Hz, 3H); Mass: m/z 208 (M+ +1, 100 %). 56 % YIELD

62

IR: Did not show any diagnostic peaks due to –NH- and -CO-

S

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.09 – 7.00 (m, 2H), 6.64 (t, J = 7.32 Hz, 1H), 6.49 – 6.45 (dd, J = 7.81 Hz, 1H), 4.88 (s, N

O

1H), 4.29 – 4.22 (m, 1H), 4.12 – 4.00 (m, 1H), 3.53 - 3.47 (m, 2H), 1.41 – 1.40 (m, 1H), 1.44 – 1.41 (s, 6H); Mass: m/z 222 (M+

3c

+1, 100 %). IR: Did not show any diagnostic peaks due to –NH- and -COgroups; 1H NMR: (CDCl3, 200 MHz): δ 7.16 – 7.00 (m, 2H), 6.65 (t, J = 7.1 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.68 (d, J= 8.06 Hz, 1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 8.00 Hz, 1H), 3.45 (t, J = 7.3 Hz, 2H), 2.74 – 2.63 (m, 1H), 2.21 – 2.08 (m, 1H), 1.62 – 1.30 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H); Mass: 222 (M+1, 100 %).

3e

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16e

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.15 – 7.00 (m, 2H), 6.65

Pr

(t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.70 – 4.66 (d, J= 6.3

H

Hz, 1H), 4.26 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 8.3 Hz, 1H), 3.46

54

(t, J = 6.9 Hz, 2H), 2.75 – 2.71 (m, 1H), 2.05 (m, 1H), 1.66 – 1.54 (m, 1H), 1.51 – 1.43 (m, 2H), 1.00 – 0.85 (m, 3H); Mass: 236 (M+ +1, 100 %).

3f

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16f

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.16 (d, J = 7.6 Hz, 1H),

i

Pr

7.04 (t, J = 7.4 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 8.0

H

Hz, 1H), 4.83 (d, J= 8.5 Hz, 1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97

49

(q, J = 7.8 Hz, 1H), 3.48 – 3.42 (dd, J = 5.6 and 7.4 Hz, 2H), 2.80 – 2.74 (dd, J = 3.2 and 8.6 Hz, 1H), 2.50 – 2.35 (m, 1H), 1.14 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 7.1 Hz, 3H); Mass: 236 (M+ +1, 100 %).

3g

IR: Did not show any diagnostic peaks due to –NH- and -CO-

63

16g

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.15 – 6.98 (m, 2H), 6.65

Hex

(t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 4.67 (d, J= 8.1 Hz,

H

1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 7.3 Hz, 1H), 3.49 –

52

3.42 (m 2H), 2.78 – 2.70 (m, 1H), 2.07 – 2.04 (m, 1H), 1.69 – 1.30 (m, 9H), 0.88 – 0.85 (m, 3H); Mass: 278 (M+ +1, 100 %).

3h

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16h

groups. 1H NMR: (CDCl3, 200 MHz): δ 7.39 (s, 5H, ), 7.20 (d, J

Ph

= 8.79 Hz, 1H, ), 7.12 (t, J = 7.33 Hz, 1H, ), 6.71 (t, J = 7.33 Hz,

H

1H, ArH), 6.60 (d, J = 7.81 Hz, 1H, ), 5.13 (d, J = 8.31 Hz, 1H,

63

NCHO), 4.29 – 4.19 (m, 1H, SCHPh), 4.06 – 3.94 (dd, 8.30 & 15.63 Hz, 1H, OCH2CH2N), 3.73 (d, J = 8.30 Hz, 1H, OCH2CH2N), 3.54 (t, J = 7.32 Hz, 2H, NCH2CH2O). Mass: 270 (M+ +1, 100 %).

3i

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16i

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.18 – 6.96 (m, 2H,

H

ArH), 6.67 - 6.48 (m, 2H, ArH), 5.17 – 5.11 (dd, J= 3.7 and 9.1

Et

Hz, 1H), 4.23 – 4.02 (m, 2H), 3.79 – 3.72 (m, 1H), 3.09 – 3.01

71

(dd, J = 3.7 and 10.0 Hz, 2H), 2.58 – 2.48 (dd, J = 6.3 and 12.0 H, 1H), 1.96 – 1.71 (m, 1H), 1.56 – 1.43 (m, 1H), 0.99 – 0.91 (m, 3H); Mass: 222 (M+ +1, 100 %).

3j

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16j

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.18 – 6.96 (m, 2H,

H

ArH), 6.67 - 6.48 (m, 2H, ArH), 5.17 – 5.10 (dd, J= 3.7 and 9.1

Pr

Hz, 1H), 4.20 – 4.04 (m, 2H), 3.94 – 3.82 (m, 1H), 3.86 – 3.71 (m,

61

1H), 3.09 – 3.01 (dd, J = 3.7 and 10.0 Hz, 2H), 2.58 – 2.47 (dd, J = 6.3 and 12.0 H, 1H), 1.88 – 1.72 (m, 1H), 1.59 – 1.32 (m, 5H), 0.98 (t, J = 7.1 Hz, 3H); Mass: 236 (M+ +1, 100 %).

3k

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16k

groups. 1H NMR: (CDCl3, 200 MHz): δ 7.34 (s, 3H, ), 7.31 (d, J

64

H

= 3.9 Hz, 2H, ), 7.21 – 7.17 (dd, J = 1.5 & 7.8 Hz, 1H, ), 6.92 –

Ph

6.84 (m, 1H, ArH), 6.60 (d, J = 7.31 Hz, 1H, ), 6.33 (d, J = 8.31

46

Hz, 1H, NCHO), 5.48 – 4.41 (dd, J = 3.9 & 9.3 Hz, 1H), 4.82 (t, J = 7.8 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 3.76 (t, J = 8.3 Hz, 1H), 3.20 – 3.12 (dd, J = 3.5 % 12.1 Hz, 1H), 2.66 – 2.55 (dd, J = 9.2 & 12.2 Hz, 1H); Mass (m/z): 270 (M+ +1, 100 %).

3l

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16l

groups. 1H NMR: (CDCl3, 200 MHz): δ 7.95 (d, J = 8.3 Hz, 2H,

H

ArH), 7.56 (d, J = 8.3 Hz, 2H), 7.21 (s, 1H), 6.90 (t, J = 8.2 Hz,

*

1H), 6.67 (t, J = 8.2 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 5.49 – 5.42

39

(dd, J = 4.0 & 9.2 Hz, 1H), 4.9 (t, J = 6.8 Hz, 1H), 4.57 (t, J = 9.3 Hz, 1H), 3.74 (t, J = 7.8 Hz, 1H), 3.32 – 3.14 (m, 1H), 3.07 (s, 3H), 2.67 – 2.56 (dd, J = 9.3 & 18.0 Hz, 1H); Mass: 347 (M+ +1, 100 %), 304 (60 %).

3m

IR: Did not show any diagnostic peaks due to –NH- and -CO-

16m

groups. 1H NMR: (CDCl3, 200 MHz): δ 7.26 (m, 4H, ArH), 6.89

H

(d, J = 8.3 Hz, 2H), 6.62 (t, J = 7.5 Hz, 1H), 6.36 (d, J = 8.1 Hz,

**

1H, ArH), 5.47 – 5.40 (dd, J = 4.0 & 9.0 Hz, 1H), 4.77 (t, J = 7.5

41

Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 3.80 – 3.74 (m, 4H), 3.29 (d, J = 4.3 Hz, 1H), 3.19 – 3.11 (dd, J = 4 & 11 Hz, 1H), 2.65 – 2.54 (dd, J = 9.4 & 12.0 Hz, 1H).Mass: 300 (M+, 100%) * =, 4 – methylsulfonyl phenyl, ** = 4 –methoxy phenyl

65

2.4 POSSIBLE MECHANISM OF REDUCTIVE CYCLIZATION: (i)

Addition of LAH: Addition of the LAH in both the ways, that is normal addition (substrate was added to the LAH) or reversible addition (LAH was added to the substrate). In the both the ways, same product (16a) was obtained.

(ii)

Use of more than 1.1 equivalents of LAH leads to alcohol (17a) as the product. Once the cyclized product is formed, it is stable and no further reduction occurs with LAH. After isolating product by using 1.1 eq. of LAH and aq. sodium sulfate workup it was treated with 3.0 eq to 4.0 eq of LAH, no reaction was took place. Even same thing was done before work up it lead to alcohol 17a. Compound 17a is more stable with LAH, once it cyclizes.

S

S

2 - 4 eq. of LAH THF

O

N

OEt

N

OH

(17a)

(3a)

O

1.1 eq. of LAH

(16a)

N

S

2 - 4 eq. of LAH

S O

X (16a)

N OH

Scheme 2.6 Formation of tricyclic compound 16a can be rationalized through initial reduction of 3a to amino alcohol 24 which may instantaneously cyclize to the cyclic compound 25. In contrast, compound 24 may react with excess of LAH to form the diol 26 which may reduce further with LAH to give amino alcohol 17a or get cyclized to afford 16a. In the presence of excess of LAH, therefore, the yield of 16a decreases as the yield of alcohol 25 increases. In order to substantiate this mechanism as well as to develop a new method

66

to synthesize the hitherto unknown fused 1,3-oxazolo tricyclic compound 16a, reactions were carried out as shown below (Scheme – 2.7).

S

THF, LAH(1.1 eq)

N (3a)

S

O OEt r.t, 1.0 h

S O OH

N (24)

O

S

LAH

N

N

OM O

(25)

S

S OM OH

N OH

N

(17a)

O

(16a)

(26)

Scheme – 2.7

Optimization: With a view to optimize conditions, the reactions of 3a with LAH were studied under different conditions and different equivalents of LAH gave a mixture of 16a and 17a and in certain conditions almost zero yields of 16a. These results are shown in Table- 2.6 S

S

LAH

N

O

N

S O

N

OH

OEt (3a)

O

(16a)

(17a)

Equation – 2.11

Table – 2.6: Reduction of 3a with different equivalents of LAH

67

S.No.

a

LAH a eq.

Ratio of products b (%) 3a

16a

17a

01.

0.5

60

40

0

02.

1.0

4

96

0

03.

1.1

0

100

0

04.

2.0

0

97

0

05.

4.0

0

91

9

06.

6.0

0

72

28

All reactions were carried out in dry THF under inert atmosphere at room temperature

(ca, 25 °C) for 0.45 hrs, bproduct ratios were determined by HPLC; column: Inertsil ODS; mobile phase: 0.01M KH2PO4 and ACN (30:70); λmax. 235 nm; retention time: 3a, 4.37 min.; 17a, 8.2 min.

Results from above experiments indicate that only 1.1 eq. of LAH are needed for to get desired oxazolo product. The above reaction was also been studied with reducing agents other than LAH. These experiments showed some interesting results which are given in Table 2.7. The expected product 16a was not formed in these reductions. The compound 3a was treated with sodium metal (4.0 equivalents) in ethanol in order to obtain 16a. However, the product obtained was 2-(3-oxo-3,4-dihydro-2Hbenzo[b][1,4]thiazin-4-yl)acetic acid (27). Equation –2.12

S N

O

Na / EtOH

S

80 °C, 6.0 h

N

O

OEt

(3a)

OH

(27)

O

O Equation – 2.12

68

The structure of compound 27 is supported by its spectral and analytical data. Thus, its IR (KBr) spectrum showed peaks at 1732 cm-1 (acid carbonyl stretching), at 1671 cm-1 (amide carbonyl stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.39 (d, J = 7.7 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.06(t, J = 7.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.23 (bs, 1H, D2O exchangeable), 4.70 (s, 2H), 3.48 (s, 2H); while mass spectrum showed m/z 224 (M+1, 25 %) molecular ion at 223 (M+, 50 %) and other peaks at 178 (25 %), 150 (100 %), 136 (60 %) etc. Compound 3a was reacted with sodium borohydride and borane dimethyl sulfide (2.2 equivalents) in THF at 50 oC to yield 2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)1-ethanol (17a) instead of 16a. (Equation –2.13) 17a was confirmed by its spectral and analytical data. Thus, its IR (KBr) showed peak at 3396 cm-1 due to alcohol stretching, and no peaks at carbonyl stretching frequency. Its 1H NMR (in CDCl3) showed signals at

δ 7.07 – 6.96 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.69 (m, 1H), 3.84 (t, J = 6.0 Hz, 2H), 3.66(t, J = 6.0 Hz, 2H), 3.47(m, 2H), 3.05 (t, J = 6.0 Hz, 2H); mass spectrum showed m/z at 196 (M+1 60 %), 195 (M+, 60 %) and other peaks at 164 (90 %), 136 (100 %).

S

S

NaBH4 / BMS

N

O OEt

(3a)

N OH (17a)

O Equation –2.13 When 3a was reacted with borane (2.2 equivalents) for 24 hrs in THF, it gave ethyl 2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)acetate (28). (Equation –2.14) 28 was characterized by its spectral data. Thus, its IR (KBr) showed peak at 1744 cm-1 due to ester carbonyl stretching. Its 1H NMR (CDCl3, 200 MHz): showed signals at δ 7.06 – 6.91 (m, 2H), 6.63 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 8.3,1H), 4.24 – 4.14 (q, J = 7.0 Hz, 2H), 4.00 (s, 2H), 3.72 (t, J = 5.0 Hz, 2H), 3.06(t, J = 6.4 Hz, 2H), 1.25 (t, J = 7.0 Hz, 2H); mass spectrum showed peaks at m/z 238 (M+1 75 %) and other peaks at 237 (M+, 60 %), 64 (100 %), 136 (80 %). All these experiments was explained in the following 69

Table – 2.7

S

S

BH3 (2.2 eq)

N

O OEt

(3a)

r.t., 24 h

N OEt

(28)

O

O Equation –2.14

Table –2.7: Reaction of 3a with different reducing reagents, reaction conditions and results. S.No.

Reagent Name

1.

Equalents Solvent

Na

Results

Conditions Temp.

Time

(°C)

(hrs)

3a

4.0

EtOH

80

6.0

*

16a

17a

2.

Na

8.0

EtOH

80

6.0

*

3.

NaBH4

1.1

Diglyme

80

6.0

√

4.

NaBH4

2.2

Diglyme

80

6.0

√

5.

NaBH4 AlCl3

1.1 / 0.4

Diglyme

r.t

12.0

√

6.

NaBH4 / AlCl3

2.2 / 0.8

Diglyme

r.t

12.0

√

7.

NaBH4 / AlCl3

2.2 / 0.8

Diglyme

75

12.0

√

8.

NaBH4 / LiCl

1.1 /1.1

THF

r.t

12.0

√

9.

NaBH4 / I2

1.1 / 0.4

THF

r.t

4.0

√

10. NaBH4 / NiCl2

1.1 / 1.1

MeOH

r.t

4.0

√

11. NaBH3 / H2SO4

2.4 / 1.2

THF

40

12.0

√

12. BMS / NaBH4

1.1 / 0.5

THF

r.t

6.0

13. BMS

1.1

THF

r.t

6.0

14. BMS

1.1

THF

50

6.0

√

15. BMS

2.4

THF

50

6.0

√

16. L-Selectride

1.1

THF

r.t

4.0

√ √

Not clean

70

√

17. 9 BBN

1.1

THF

r.t

6.0

18. BH3

1.1

THF

r.t

6.0

√

19. BH3

2.2

THF

r.t

24.0

**

20. DIBAL-H

1.1

THF

r.t

24.0

√

* Ester was hydrolyzed, ** only amide keto was reduced.

Experimental procedure: i) Preparation of 2a: To a solution of 2-aminothiophenol (1) (50.0 gms, 400 mmol) in aq. sodium hydroxide (8 %, 200 mL) at 15 oC was added a solution of chloroacetic acid (37.8 g gms, in 100 ml of water, 400 mmol) while the temperature was kept below 40 oC. Oil starts separating out from the solution in about 60 min, time, and the resulting mixture was stirred and refluxed for 4 hrs, during which time the oil changes to granular solid. Then the mixture was cooled to room temperature, the solid was filtered and washed with cold water. The solid was triturated with acetonitrile on the filter funnel and dried to obtain 2a as colorless solid (50.0 g, 76 %). ii) Preparation of 2a - h (General procedure): First method: To a solution of 2-aminothiophenol (1) (5.0 g, 40.0 mmol) in water was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl acetate (1.2 eq) at room temperature. The reaction mixture was stirred for one hr at room temperature and then poured into dil. HCl (100 mL, 50 % v/v). The separated solid was filtered, washed with water and dried to obtain 2a-h (Table-2.3). Second method: To a solution of 2-aminothiophenol (0.250 g, 2.0 mmol) in water was added of sodium hydroxide (0.12 g, 3.0 mmol), followed by ethyl 2-bromo-2-alkyl acetate (1.2 eq) at room temperature. The mixture was irradiated with microwaves using household microwave oven for 5.0 min. The mixture was cooled and stirred with cold dil. HCl (100 mL, 50 % v/v). The separated solid was filtered, washed with water and dried to obtain 2a-h (Table-2.3).

71

iii) Preparation of 3a – j (General procedure): To a solution of 2a – h (1.0 eq) and potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2alkyl acetate (1.2 eq) drop wise at room temperature. After stirring for 24 hrs the mixture was poured in to water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain 3a – o as crude product, which was purified through column chromatography yielding pure compounds 3a – j (Table 2.2) iv) Preparation of 5: A mixture of 4 (20.0 gms, 147 mmol) in ethanol (200 mL) was refluxed for 3.0 hrs in the presence of a trace of con. H2SO4 (catalytic amount). Then the solvent was removed from the reaction mixture under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The ethyl acetate layer was washed with aq. NaHCO3 solution followed by water (2 X100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 5 (24.0 g, 99 %) as thick liquid. v) Preparation of 6: To a solution of 5 (20.0 gms, 122 mmol) in carbon tetrachloride (200 mL), was added N-bromosuccinimide (23.8 gms, 134 mmol) and catalytic amount of benzoyl peroxide. The mixture was stirred for 24.0 hrs at 60 oC. Then, the mixture was filtered, washed with CCl4 and filtrate was concentrated under reduced pressure to yield a crude residue which was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over Na2SO4 and concentrated under vacuum, to obtain 6 (25.0 gms, 86 %) as gummy solid.

vi) Preparation of 3k: A solution of 2a (2.0 gms, 12.12 mmol), 6 (3.33 gms, 14.54 mmol) and anh. potassium carbonate (2.5 gms, 18.18 mmol) was stirred in DMF at 80 oC for 12 hrs. At the end of this period, the reaction mixture was cooled to room temperature and poured in to water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to obtain the crude product, which was purified through column chromatography to yield a pure lowmelting solid of 3k (1.2 gms, 32 %).

72

vii) Preparation of 8: To a suspension of aluminum chloride (25.7 gms, 193.5 mmol) in methylene chloride (150 mL) was added acetyl chloride (15.2 mL, 193.5 mmol) slowly at 0°C. The reaction mixture was then stirred at 25° oC until clear solution was obtained. A solution of 7 (20.0 gms, 161.0 mmol) in dichloromethane (50 mL) was added slowly to this mixture at 25 oC with vigorous stirring. The stirring was continued for 4.0 hrs at 25 o

C, then the mixture was poured into crushed ice (200 g) and extracted with chloroform

(3X100 mL). Combined organic layer was washed with water (2X100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give 8 (24.0 gms, 92 %) as pale yellow powder. viii) Preparation of 9: A mixture of 8 (22.0 gms, 132 mmol), elemental sulfur (5.0 gms, 159 mmol) and morpholine (13.8 gms, 159 mmol) was stirred for 24 hrs at 130 °C. The reaction mixture was cooled to 25 °C followed by slow addition of 6N HCl (100 mL) and then allowed to proceed for 24 hrs at 140 °C with vigorous stirring. After cooling to room temperature the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 X100 ml) followed by the extraction of the combined organic layer with 10 % sodium hydroxide solution (2X100 mL). The aqueous layer was collected, combined and acidified with 6N HCl. The separated solid was filtered, washed with water and dried under vacuum to give 9 (17.0 gms, 71 %) as brown colour powder. ix) Preparation of 10: A solution of 9 (16.0 gms, 87.9 mmol) in ethanol (200 mL) was refluxed in the presence of con. H2SO4 (catalytic amount) for 4 hrs. At the end of this period, the solvent was removed from the reaction mixture and the residue was dissolved in ethylacetate (200 mL). The ethyl acetate layer was washed with aq. NaHCO3 solution followed by water (100 mL X2), dried over Na2SO4 and concentrated under vacuum to give 10 (18.0 g, quantitative) as thick liquid. x) Preparation of 11: To a solution of 10 (6.0 gms, 28.57 mmol) in acetone (50 mL), °

was added Oxone (36.89 gms, 59.99 mmol in 30 mL of water) at 25 C. The mixture was stirred for 4.0 hrs at 25 oC

Acetone was removed from the reaction mixture under

vacuum; the residue was neutralized with aq. NaHCO3 solution and extracted with ethyl

73

acetate. The ethyl acetate layer was washed with water, it was dried and concentrated to obtain 11 (6.2 g, 90 %) as low-melting solid. xi) Preparation of 12: To a solution of 11 (6.0 gms, 24.79 mmol) in carbon tetrachloride (60 mL), was added N-bromosuccinimide (4.65 gms, 27.27 mmol) and catalytic amount °

of benzoyl peroxide. The resulting mixture was stirred for 24.0 hrs at 60 C. Then the mixture was filtered, washed with CCl4 and filtrate was concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over Na2SO4 and concentrated under vacuum, to yield 12 (6.3 g, 80 %) as low-melting solid. Analytical data: IR (Neat): 1738 cm-1 (ester carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.96 – 7.92 (d, J = 8.30 Hz, 2H), 7.77 – 7.73 (d, J = 8.3 Hz, 2H), 5.36 (s, 1H), 4.31 – 4.19 (m, 2H), 3.06 (s, 3H), 1.32 –1.25 (t, J = 7.8 Hz, 3H); MS: m/z 321 (M+, 10 %), 250 (50 %), 241 (70 %), 185 (70 %), 170 (100 %), 162 (40 %), 107 (80 %), 90 (50 %). xii) Preparation of 3l: A mixture of 2a (2.0 gms, 12.12 mmol), 12 (4.7 gms, 14.5 mmol) °

and anh. potassium carbonate (2.5 gms, 18.18 mmol) in DMF was stirred at 80 C for 24 hrs. The reaction mixture was cooled to room temperature and poured into water (100 ml). The mixture was extracted with ethyl acetate (3 x 50 mL). Ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to yield a crude product, which was purified through column chromatography giving the pure product 3l (0.25 gms, 5 %) as low-melting solid. xiii) Preparation of 14: To a cooled solution of 4-methoxyphenylacetic acid (35) (5.0 g, 30.12 mmol) in ethanol (60 mL), was added thionyl chloride (45.0 mL, 60.24 mmol) °

dropwise at 0 C. Then the reaction mixture was refluxed for four hours and the solvent removed under low pressure. The crude residue was dissolved in ethyl acetate and washed with aq. NaHCO3 solution (100 mL of 10 % in water) followed by water (300 ml). The organic layer was dried and concentrated under reduced pressure to yield 14 (5.7 g, 98 %).

74

xiv) Preparation of 15: To a solution of ethyl 4-methoxyphenylacetate (5.0 g, 25.77 mmol) in carbon tetrachloride, was added N-bromosuccinimide (5.0 g, 28.35 mmol) and the mixture was refluxed for three hours using electric bulb in the presence of catalytic amount of benzoyl peroxide. Then the mixture was diluted with some more CCl4 and washed with water, it was dried and concentrated to obtain 15 (6.8 gms, 97 %). xv) Preparation of 3 m: To a mixture of 2a (0.5 gms, 3.03 mmol) potassium carbonate (1.25 gms, 9.09 mmol), dry dimethylformamide (10 mL), was added 16 (0.99 gms, 3.63 mmol) in DMF (5.0 mL) drop wise at room temperature. After stirring at 60 oC, for 12 hrs, the mixture was poured in to water (50 ml) at room temperature. The separated solid was filtered, washed with water and dried to obtain 3m ( 69 %). xvi) Preparation of 16a – m (General procedure): To a solution of 3a - o (2.0 mmol) in dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The resulting mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was filtered and the filtrate concentrated. The crude product was purified by column chromatography using ethyl acetate and pet. ether (5:95) to give 16a – m (Table-2.6). xvii) Preparation of 18: To an ice cold solution of 16a (5.0 g, 25.77 mmol) in acetic anhydride (80 mL) was added fuming nitric acid (1.78 g, 28.34 mmol) drop wise at –5 o

C, and the mixture was stirred for 3 hrs at 0 °C. The reaction mixture was poured in to

crushed ice, the separated solid was filtered, washed with water and dried. The crude product was purified through column chromatography by using ethyl acetate in petroleum ether to obtain 18 (1.0 gms, 18 %) as yellowish crystalline solid. xviii) Preparation of 3n: Method A: To a solution of 3a (1.0 g, 3.95 mmol) in dioxane was

added

Lawsson’s

reagent

[2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-

dithiadiphosphetane) (0.8 g, 1.97 mmol) and the mixture was refluxed for 6 hrs. The solvent was removed and the crude residue was purified through column chromatography, to give 3n as yellow solid (1.0 g, 95 %). xiv) Reduction of 3n with LAH: To a solution of 3n (0.534 g, 2.0 mmol) in dry THF (10 mL) at 0 °C, lithium aluminumhydride (0.0836 g, 2.2 mmoles) was added in several

75

portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The resulting mixture was then quenched with aq. sodium sulfate solution. The mixture was filtered and the filtrate concentrated. The crude product was purified by column chromatography using ethyl acetate and pet. ether (5:95) to obtain 16p.

xv) Experimental procedures of reactions which are explained in Table – 2.8: a) (i) Reduction of 3a with Sodium: In the flask are placed sodium metal (0.092 g, 4.0 mmol) in of dry toluene (20 mL) and the mixture was heated until sodium melted. Then, the mixture was cooled to 60 °C and this was added 25a (0.25 g, 1.0 mmol) in ethanol (5.0 ml), followed by more ethanol (20 mL) as rapidly as possible. The reaction mixture was refluxed for 6.0 hrs, and the solvent was removed by distillation. The crude residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water; it was dried and concentrated under reduced pressure to give 27 (0.17 g, 81 %).

(ii) Reduction of 3a with Sodium: In the flask are placed sodium metal (0.184 g, 4.0 mmol) in dry toluene (20 mL) and was heated until sodium melted. Then the mixture was cooled to 60 °C and to this was added 3a (0.25 g, 1.0 mmol) in ethanol (5.0 ml), followed by more ethanol (20 mL) as rapidly as possible. The reaction mixture was refluxed for 6.0 hours, and the solvent was removed by distillation. The crude residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to obtain 27. (0.180 g, 86 %) b) Reduction of 3a with Sodium borohydride: To a stirred solution of 3a (0.251 g, 1.0 mmol) in diglyme (10.0 mL), was added sodium borohydride (0.041 g, 1.1 mmol) pinch by pinch at room temperature. The mixture was stirred for six hours at 80 °C. Then the reaction mixture was quenched with ice-cold water (5 ml) and extracted with ethyl acetate (2X25 mL), It was washed with satd. sodium chloride solution, dried and concentrated. Instead of expected product, starting material was recovered. The same reaction was done with 2.2 eq. of sodium borohydride yet no product could be isolated. c) Reduction of 3a with sodium borohydride and aluminum chloride: First Method: To a solution of

sodium borohydride (0.041 g, 1.1 mmol) in diglyme

(11 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and

76

aluminum chloride (0.053 g, 0.4 mmol, 2.0 ml of 2M solution in diglyme) was added through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at room temperature. Second Method: To a solution of

sodium borohydride (0.083 g, 2.2 mmol) in diglyme

(22 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and aluminum chloride (0.106 g, 0.8 mmol, 4.0 ml of 2M solution in diglyme) was added through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at room temperature. Third Method: To a solution of sodium borohydride (0.083 g, 2.2 mmol) in diglyme (22 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and aluminum chloride (0.106 g, 0.8 mmol, 4.0 ml of 2M solution in diglyme) was added through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at 75 °C. In all the above methods, no product could be isolated and starting material was recovered unchanged. d) Reduction of 3a with Sodium borohydride and Lithium chloride: To a solution of sodium borohydride (0.041 g, 1.1 mmol) in THF (15 mL) was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and lithium chloride (0.046 g, 1.1 mmol) was added at room temperature. The mixture was stirred for 12.0 hours at room temperature. No product could be isolated and starting material was recovered unchanged. e) Reduction of 3a with sodium borohydride and iodine: To a solution of

sodium

borohydride (0.041 g, 1.1 mmol) in THF (15 mL) was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and iodine (0.101 g, 1.1 mmol) in THF (10 ml) was added through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at room temperature. Processing the reaction mixture gave back starting material was unchanged. f) Reduction of 3a with Sodium borohydride and Nickel chloride: To a solution of 25a (0.251g, 1.0 mmol) in methanol (15 mL) was added sodium borohydride (0.041 g, 1.1 mmol) at 0 °C, and followed by nickel chloride (0.262 g, 1.1 mmol) at same

77

temperature. The mixture was stirred for 12.0 hours at room temperature. On processing the reaction mixture, starting material was recovered unchanged. g) Reduction of 3a with sodium borohydride and sulfuric acid: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL), was added sodium borohydride (0.120 g, 2.4 mmol) at 0 °C, followed by sulfuric acid (0.117 g, 1.2 mmol) at the same temperature. The mixture was stirred for 12 hrs at 40 °C. On processing the reaction mixture, starting material was recovered unchanged. h) Reduction of 3a with borane dimethylsulfide complex and Sodium borohydride: To a solution of 3a (0.251 g, 1.0 mmol) in toluene (15 mL) was added dropwise borane dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. After 30 min of stirring, sodium borohydride (0.019 g, 0.5 mmol) was added in parts at 0 °C. The mixture was stirred for 6.0 hours at room temperature. Reaction mixture was quenched by adding methanol and solvent was removed from the mixture. The crude residue was purified through column chromatography to give reduced product i.e. alcohol 3a (0.175 g, 89 %). i) Reduction of 3a with borane dimethylsulfide complex: First Method: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop wise borane dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for 6.0 hours at room temperature. On processing the reaction mixture, starting material was recovered unchanged. Second Method: To a solution 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop wise borane dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for 6.0 hours at 50 °C. Reaction mixture was quenched by adding methanol and solvent was removed from the mixture. The crude residue was purified through column chromatography to give reduced product i.e. alcohol 17a (0.155 g, 79 %). Third Method : To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop wise borane dimethylsulfide complex (2.0 ml of 10 M, 2.2 mmol) at 20 °C. The mixture was stirred for 6.0 hours at 50 °C. Reaction mixture was quenched by adding methanol and solvent was removed from the mixture. The crude was purified through column chromatography to obtain reduced product i.e. alcohol 17a. (0.150 g, 77 %)

78

j) Reduction of 3a with Selectride: To a solution of

ethyl 2-(3,4 dihydro-3oxo-2H-

benzo[b][1,4]thiazin –4-yl)acetate (3a) (0.251 g, 1.0 mmol) in THF (15 mL) was added drop wise L- selectride(1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for 4 hrs at room temperature. On processing the reaction mixture, starting material was recovered unchanged. k) Reduction of 3a with 9BBN: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop wise 9BBN (2.2 ml of 0.5 M, 1.1 mmol) at 20 °C. The mixture was stirred for 6.0 hours at room temperature. Reaction mixture was quenched with methanol and water. Then, the mixture was extracted with ethyl acetate. Ethyl acetate layer was washed with water, dried and concentrated to yield alcohol product i.e. 3a (0.165 g, 86 %). l) Reduction of 3a with borane in THF: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added dropwise borane in THF (1.1 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for 6.0 hours at room temperature. On processing the reaction mixture, starting material was recovered unchanged. m) Reduction of 3a with borane in THF: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added dropwise borane in THF (2.2 ml of 10 M, 2.2 mmol) at 20 °C. The mixture was stirred for 24.0 hours at room temperature. Reaction mixture was quenched with methanol and water. Then, the mixture was extracted with ethyl acetate. Ethyl acetate layer was washed with water, dried and concentrated to give 28. (0.190 g, 80 %) n) Reduction of 3a with DIBAL-H: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop wise DIBAL - H in THF (1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for 24.0 hours at room temperature. On processing the reaction mixture, starting material was recovered unchanged.

REFERENCE 01. Iruvin Pachter, S. J.; Milton, C.; Kloetzel, M. C. J. Amer. Chem. Soc., 1982, 74, 1321. 02. Unger, G. Chem. Ber.; 1897, 40, 2496.

79

03. Koos,

M.,

Chem.;

Monatsh.

1994,

125

(8/9)

1011.

(Chem. Abstr. 1994, 122: 81258) 04. Goudie, R. S.; Preston, P. N. J. Chem. Soc. C. 1971, 1718. 05. Hiroyuki, T.; Yasuo, S.; Hitoshi, I.; Yuiro, Y.; Kanji, Meguro. Chem. Pharm.

Bull. 1990, 38 (5), 1238. (Chem. Abstr. 1990, 113: 132112) 06. Erker,

T.;

Bartsch,

H.

Liebihgs

Ann.

Chem.

1992,

4,

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(Chem. Abstr. 1992, 116:214473) 07. Hiroshi, S.; Norihiro, U.; Tadashi, K.; Mikio, H. Chem. Pharm. Bull. 1984, 42 (7), 2571. 08. Nair, M. D.; David, J.; Nagarajan, K. Indian. J. Chem. Sect. B, 1985, 24, 940. 09. Saverio, F.; Vito, C.; Gennara, C.; Tetrahedron; 1997, 54 (16), 5849. 10. Zhong, W.; Zhang, Y. Tetrahedron Lett. 2001, 42 (17), 4125. 11. Mikio, H.; Tadashi, K.; Hiroshi, S.; Yutaka, I. Chem. Pharm. Bull. 1979, 27 (9), 1973. 12. Takamizawa, A., Chem. Pharm. Bull., 1972, 20, 892. 13. Wilkins, R.; Rohert, W. C.

III. Can. J. Chem. 1979, 57, 444.

(Chem. Abstr. 1979, 90: 186884). 14. Norio, K.; Yuichi, H.; Koichi, S.

Heterocycles. 1984, 22 (2), 277.

(Chem. Abstr. 1984, 100: 191811) 15. Niels, J.; Hans; Kolind, A. Synthesis. 1990, 10, 911. 16. Fujita, M.; Ota, A.; Ito, S.; Yamamoto, K.; Kawashima, Y. Synthesis.1990, 8, 599. 17. Babudri, F.; Florio, S.; Indelicati, G.; Trapani, G. J. Org. Chem. 1983, 48 (22), 4082. 18. Unger, G. Chem. Ber. 1897, 40, 2496, (1897). (Ref: 12) 19. Olagbemiro, T. O.; Nyakutse, C. A.; Lajide, L.; Agho, M. O.; Chukwu, C. E.

Bull. Soc. Chim. Belg. 1987, 96 (6), 473. (Chem. Abstr. 108:112387, 1987).

80

20. Trapani, G.; Reho, A.; Morlacchi, F.; Latrofa, A.; Marchini, P.; Venturi, F.; Cantalamessa,

F.

Farmaco

Ed

Sci.

1985,

40

(5),

369.

(Chem. Abstr. 1985, 103: 87826). 21. Coutts, R. T., Sharon, J. M., Mah, E. and Pound, N. J.; Can. J. Chem. 1970, 48, 3727. 22. Langlet, B.; Till, S. Vet – Akd. Handlingar, 22, II, No 1, S 17. 23. Tawada, H.; Sugiyama, Y.; Ikeda, H.; Yamamoto, Y.; Meguro, K. Chem. Pharm.

Bull. 1990, 48 (5), 1248. 24. Shimizu, H.; Ueda, N.; Kataoka, T.; Hori, Mikio. Chem. Pharm. Bull. 1984, 42(7), 2571. (Chem. Abstr. 1984, 108:229556. 25. Iruvin Pachter, S. J.; Milton, C.; Kloetzel, M. C. J. Amer. Chem. Soc. 1952, 74, 321. 26. Bergmann; Ikan. J. Amer. Chem. Soc. 1958, 80, 3135. 27. Rahim Abdur, M.; Rao Praveen, P. N.; Knwas Edward, E. Bioorg. Med. Chem.

Lett. 2002, 12 (19), 2753. 28. Reichardt, C.; Schaefer, G.; Milart, P. Collect. Czech. Chem. Commun. 1990, 55 (1), 97. (Chem. Abstr. 1990, 113:25538.) 29. (a) Joseph, W. C.; Reuben G. J.; Quentin F. S.; Calvert W. W.; Otto K. B. J.

Amer. Chem. Soc. 1948, 70, 2837. (b) Charles, D. H.; Gene, L. O. J. Amer. Chem. Soc. 1954, 76, 50. (c) Org. Synth. Coll. Vol. 1963, IV, 176. (d) Reichardt, C.; Schaefer, G.; Milart, P. Collect. Czech. Chem. Commun. 1990, 55 (1), 97. (Chem. Abstr. 1990, 113:25538.) (e) Shah, K. S.; Conard, P. D. Jr.; Paul E. F.; Jeffrey, J. H.; William, K. H.; Karen, A. B.; Gilbert, O. C.; Amy, L. Kissinger.; Bonnie, M. A. J. Med. Chem. 1992, 35 (21), 3745. 30. Davies, l. W.; Marcoux, Jean F.; Corley, E. G.; Journet, M.; Cai Dong, W.; Palucki, M.; Wu Jimmy, R. D.; Larson Kai, R.; Pye Philip, J.; Di Michele, L.; Peter Dorner; Paul, J. Reider. J. Org. Chem. 2000, 65 (5), 8415.

81

31. (a) Harry, H. Wasserman.; Dennis, J. H.; Temper, A. W.; James, S. W.

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Org. Chem. 1981, 46 (15), 2999. (b) Nacci, V.; Fironi, I.; Garofalo, A.; Cagnotto, Alfrendo. Farmaco. 1990, 45 (5), 545. (Chem. Abstr. 1990, 114:42752)

82

CHAPTER – III STUDIES ON SYNTHESIS OF “OXAZOLO OXAZINES”

3.1 Introduction: Oxazolooaxzines were not very well documented in literature. Survey of literature shows that not much work seems to have been done i.e. hexahydrooxazolo[2,3c][1,4]oxazine (29) as byproduct was reported by Jean-Charless Quirion, David S. Grierson et. al. in Tetrahedron Letters.1 O

Ph N

OH

O N

Ph O

O

HO

(29) Compound (29) was prepared by condensation of phenylglycinol with glutaraldehyde to give piperidine intermediate which was reacted with second molecule of glutaraldehyde to give compound 29. (Equation – 3.1)

83

Ph (30)

OH

CHO CHO

NH2 + N

CHO CHO Ph

(31)

O N

O OH (32)

Ph

O (29)

Equation – 3.1 Apart from above another oxazolooxazine (33) was reported by Kukharev, B. F. Stankevich, V. K. et. al. in Arkivoc (it’s an online journal), 2003.2 It was prepared by the condensation

of

N-(2-hydroxybenzylidine)-1,2-aminoethanol

(34)

with

paraformaldehyde. Equation – 3.2 O N O

(33) N

OH

O

NH OH + CH2O

OH

O N

(34)

(35)

(33) O

Equation – 3.2

3.2 Present Work: The survey of literature revealed that synthesis of oxazolo oxazines is a difficult task to accomplish. Therefore, it was considered worth while to attempt the synthesis of new compounds containing oxazolooxazines. It is conceivable that the oxazolo moieties can be synthesized from 2-nitrophenol on reaction with ethyl 2-bromo2-alkyl/aryl and followed by ring closure in the presence of 10 % palladium carbon and hydrogen under pressure to obtain benzooxazines in the first step. These benzooxazines can be used as building blocks for the synthesis of fused oxazolo ring units.

3.3 Results and Discussion:

84

Commercially available o-nitrophenol (36a i.e. R = R1 = H) was treated with ethyl 2-bromoacetate in the presence of potassium carbonate to obtain ethyl 2(2-nitro phenoxy) acetate (37a, i.e. R = R1 = H) in quantitative yield (Equation 3.2). Compound 37a is a compound known in literature.3 However, it was further characterized in the present work by its spectral and analytical data. Thus, its IR (neat) spectrum showed (Fig 3.1) the absence of any peak above 3000 cm-1 indicating the disappearance of –OH group of starting material. Further, the IR showed a peak at 1737 cm-1 assignable to ester carbonyl stretching in the product 37a. It’s 1H NMR (in CDCl3) showed signals (Fig 3.2) at δ 7.84 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.7 Hz, 2H), O – CH2 at 4.77 (s, 2H), 4.28 – 4.18 (q, J = 7.3 Hz, 2H, -CH2CH3-), 1.25 (t, J = 7.3 Hz, 3H, CH2CH3-). Its mass spectrum (Fig 3.3) showed peaks at m/z 266 (M+1, 100%) and other peaks at m/z 179 (10 %), 152 (10 %) etc. The above reaction of 36a with ethyl 2-bromoacetate has been found to be a general and has been extended to other phenols 37b-e and the products obtained have been assigned structures 37b-e on the basis of their spectral and analytical data (Table 3.1).

R

OH

ethyl bromoacetate, R

OCH2CO2Et

R1

NO2

K2CO3, DMF, 80 °C, 4 h

NO2

(36a - e)

R1

(37 a -e)

Equation – 3.3

85

Table –3.1: Synthesis of 37 (b-e) from 36 (b-e) and their spectral data. S. No.

R

R1

Yield

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

37b

F

H

93.0 %

IR (Neat): Absence of any absorption due to –OH group and a strong band at 1748 cm-1 due to ester carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ 8.01 – 7.94 (dd, J = 5.8 and 8.8 Hz, 1H), 6.84 – 6.75 (ddd, J = 2.44, 7.33 and 11.24 Hz, 1H), 6.71 – 6.55 (dd, J = 2.45 – 9.77 Hz, 1H), 4.76 (s, 2H), 4.33 – 4.22 (q, J = 7.32 Hz, 2H), 1.33 – 1.25 (t, J = 7.32 Hz, 3H); Mass: m/z 244 (M+ +1, 100 %), 170 (30 %).

37c

Me

H

92.0 %

IR (Neat): Absence of any absorption due to –OH group and a strong band at 1745 cm-1 due to ester carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ 7.81 (d, J = 7.82 Hz, 1H), 6.88 (d, J = 8.30 Hz, 1H), 6.77 (s, 1H), 4.75 (s, 2H), 4.32 – 4.21 (q, J = 7.32 Hz, 2H), 2.39 (s, 3H), 1.32 – 1.24 (t, J = 7.32 Hz, 3H); Mass: m/z 240 (M+ +1, 100 %), 166 (40 %).

37d

H

Me 91.0 %

IR (Neat): Absence of any absorption due to –OH group and a strong band at 1757 cm-1 due to ester carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ 7.67 (s, 1H), 7.32 (d, J = 8.79 Hz, 1H), 6.91 (d, J = 8.31 Hz, 1H), 4.74 (s, 2H), 4.31 – 4.22 (q, J = 7.32 Hz, 2H), 2.35 (s, 3H), 1.28 (t, J = 7.3 2Hz, 3H); Maas: m/z 240 (M+ +1, 100 %), 166 (30 %).

37e

MeS H

87.0 %

IR (Neat): Absence of any absorption due to –OH group and a strong band at 1727 cm-1 due to ester carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ

85

7.88 (d, J = 8.31 Hz, 1H), 6.88 (d, J = 8.31 Hz, 1H), 6.75 (s, 3H), 4.75 (s, 2H), 4.32 – 4.21 (q, J = 7.33 Hz, 2H), 2.50 (s, 3H), 1.32 – 1.25 (t, J = 7.33 Hz, 3H); Maas: m/z 272 (M+ +1, 100 %), 266 (40 %), 197 (20 %) etc.

86

The compound 37e, referred in Table 3.1, above is not known in literature. It was needed in the present work and it was prepared as follows:- Commercially available 3fluro-5-nitro phenol (36b, i.e. R = F, R1 = H), was reacted with sodium thiomethoxide in HMPA to give 5-methylsulfanyl-2-nitrophenol (36e). Structure of 36e was confirmed by spectral and analytical data. Thus, its IR (KBr) showed a band at 3419 cm-1 indicating the presence of a hydroxy group. Its 1H NMR (in CDCl3) showed signals at δ 10.89 (s, 1H, D2O exchangeable), 8.00 – 7.84 (dd, J = 2.44 and 8.79 Hz, 1H), 6.86 – 6.76 (m, 2H), 2.53 (s, 3H). Its mass spectrum showed peaks at m/z 186 (M+1, 100 %). Compound 36e was reacted with ethyl 2-bromoacetate in the presence of potassium carbonate to yield 37e as a yellow solid. (Equation – 3.4)

F

(36b)

OH

NaSMe

NO2

HMPA, r.t, 5h

ethylbromoacetate,

MeS

OH NO2 (36e)

MeS

K2CO3, DMF, 80 oC, 4.0 h

OCH2CO2Et NO2 (37e)

Equation – 3.4 Reduction of 37a (i.e. R = R1 = H) with iron powder in acetic acid4 gave 3-oxo, 2H 1,4-benzoxazine (38a i.e. R = R1 = H) in 63 % yield. This compound could also be prepared from 37a by reduction with hydrogen in the presence of 10 % palladium carbon5 in 72 % yield. The structure of 38a was confirmed from its analytical and spectral data. Thus, its IR (KBr) showed (Fig 3.4) peak at 1704 cm-1 due to the amide carbonyl stretching vibration as distinct from the absorption at 1756 cm-1 in 37a due to the ester carbonyl function. The –NH- stretching vibration of the product appeared at 3430 cm-1. Its 1H NMR (in CDCl3) showed signals (Fig 3.5) at δ 9.6 (s, 1H, D2O Exchangeable,

87

NH), 6.98 - 6.89 (m, 4H, Ar - H), 4.6 (s, 2H, O – CH2). Its mass spectrum (Fig 3.6) showed peaks at 151 (M+1, 20 %), 150 (M+, 100 %). (Equation – 3.5) Fe / AcOH

R

OCH2CO2Et

R1

NO2

R

O

R1

N H

(36) 10 % Pd /C H2 Pressure

O

(38)

Equation – 3.5 The formation of 38a from 37a is probably due to the reduction of the nitro group to amino group followed by intramoleculor cyclization leading to cyclic amide formation with the alcohol moiety as shown below. R

OCH2CO2Et

R1

NO2 (37)

R

OCH2CO2Et

R1

NH2

R R1

(37l)

O N O H (38)

Equation – 3.6 In the above reaction involving formation of 38 from 37, 37l is an intermediate.

88

Table – 3.2 Syntheses of 37 (b-e) from 38 (b-e) and their spectral data: Sub.

Pdt

R

R1

Yield (%)

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

37b

38b

F

H

65.0

IR (KBr): 3429 cm-1 (amide –NH- stretching) 1694 cm-1 (amide carbonyl stretching); 1H NMR (in DMSO d6) δ 10.69 (s, 1H, D2O Exchangeable, NH), 6.87 6.76 (m, 4H, Ar - H), 4.56 (s, 2H, O – CH2); Mass: m/z (M+1, 20 %), 168 (M+ +1, 100 %).

37c

38c

Me

H

59.0

IR (KBr): 3043 cm-1 (amide –NH- stretching) 1702 cm-1 (amide carbonyl stretching); 1H NMR (in DMSO d6) δ 10.52 (s, 1H, D2O Exchangeable, NH), 6.73 (s, 3H, Ar - H), 4.49 (s, 2H, O – CH2), 2.18 (s, 3H, ArCH3; Mass: m/z (M+1, 20 %), 164 (M+, 100 %).

37d

38d

H

Me 57.0

IR (KBr): 3436 cm-1 (amide –NH- stretching) 1699 cm-1 (amide carbonyl stretching); 1H NMR (in DMSO d6) δ 10.61 (s, 1H, D2O Exchangeable, NH), 6.81 (m, 1H, Ar - H), 6.77 – 6.66 (m, 2H, Ar - H), 4.47 (s, 2H, O – CH2), 2.18 (s, 3H, ArCH3; Mass: m/z 164 (M+1, 100 %), 163 (M+, 50 %).

37e

38e

SMe

H

53.0

IR (KBr): 3455 cm-1 (amide –NH- stretching) 1684 cm-1 (amide carbonyl stretching); 1H NMR (in DMSO d6) δ 10.69 (s, 1H, D2O Exchangeable, NH), 6.87 – 6.84 (m, 3H, Ar - H), 4.55 (s, 2H, O – CH2), 2.42 (s, 3H, ArCH3; Mass: m/z 196 (M+ +1,100 %), 195 (M+, 60 %).

89

Apart from compounds 38a – e, compound 38f, an additional derivative in the present series, was prepared from compound 38e by oxidation of sulfanyl group with oxone reagent. It is versatile oxidizing agent used for oxidizing sulfanyl to sulfonyl groups and used in place of hydrogen peroxide in acetone – water solution. (Equation – 3.7) The structure of 38f was confirmed from its analytical and spectral data. Thus, its IR (KBr) showed diagnostic peak at 1697 cm-1 due to amide carbonyl stretching and twin peaks at 1299 cm-1 due to sulfonyl group. Its 1H NMR (in DMSO d6) signals showed at δ 11.14 (s, 1H, D2O Exchangeable, NH), 7.53 – 7.48 (dd, J = 1.47 and 8.30 Hz, 1H, ArH), 7.45 (s, 1H, ArH), 7.07 (d, J = 7.91 Hz, 1H), 4.69 (s, 2H, O – CH2), 3.1 (s, 3H, SCH3). Its mass spectrum showed peaks at m/z 228 (M+, 100 %).

S

O

Oxone, acetone

O S O

N O methanol, r.t, 3.0 h H (38e)

O N H (38f)

O

Equation – 3.7 Another intermediate 38g required in the present work, was prepared from commercially available 2-amino-5-nitrophenol (39) by reacting it with chloroacetyl chloride in the presence of triethylamine in dichloromethane yielding N1-(2-hydroxy-4nitrophenyl)-2-chloroacetamide

(40)

followed

by

cyclization

with

aq.

sodiumhydroxide in the presence of catalytic amount of tetrabutyl ammonium hydrogen sulfate (TBAHS) giving 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one (38g). (Equation – 3.7) The structure of 38g is supported by its analytical and spectral data. Thus, its IR (KBr) showed diagnostic amide carbonyl band at 1696 cm-1. Its 1H NMR (in DMSO d6) showed signals at δ 11.34 (s, 1H, D2O Exchangeable, NH), 7.93 – 7.87 (dd, J = 1.96 and 8.79 Hz, 1H, ArH), 7.76 (s, 1H, ArH), 7.06 (d, J = 8.30 Hz, 1H), 4.73 (s, 2H, O – CH2). Its mass spectrum showed peaks at m/z 195 (M+, 100 %).

90

O2N

OH

ClCH2COCl

NH2

Et3N, CH2Cl2 r.t 6.0 h

(39)

O2N

OH O N H

Cl

(40) aq. NaOH, TBAHS

O 2N

O N O H (38g)

CH2Cl2 r.t, 2.0 h

Equation – 3.7 The compound 38a was treated with ethyl 2-bromoacetate in the presence of potassium carbonate6 in DMF at 80 °C. Processing of the reaction mixture gave a product which was found to be 3,4 dihydro-3-oxo-2H-1,4-benzoxazine –4-acetic acid ethyl ester (41a, i.e. 341, R = R = H) (Equation – 3.9). 41a had been characterized by spectral and analytical methods. Thus, its IR (KBr) spectrum showed no absorption above 3000 cm-1 indicating absence of –NH- group.

However, IR spectrum showed (Fig 3.7) two

diagnostic sharp strong bands, one at 1739 cm-1 (ester carbonyl stretching) and 1681 cm-1 (amide carbonyl stretching). Its 1H NMR (CDCl3, 200 MHz): showed signals (Fig 3.8) at

δ 7.02 – 7.01 (m, 3H, Ar - H), 6.77 – 6.73 (m, 1H, Ar - H), 4.67(s, 2H, O- CH2 - CO), 4.65 (s, 2H, N – CH2), 4.29 – 4.19 (q, J = 7.1 Hz, 2H, O – CH2 – CH3),1.31 – 1.24 (t, J = 7.1 Hz, 3H, O – CH2 – CH3). Its mass spectrum (Fig 3.9) showed peaks at m/z 236 (M+ +1, 100 %) and at 190 (10 %) when recorded in the Q+1 mode R

O

K2CO3, BrCHCO2Et

R

O

R1

N H

O DMF 80 °C, 12.0 hrs

R1

N (41)

(38)

O OEt O

Equation – 3.9 6 or 7 substituted 3,4-dihydro-3oxo-2H-1,4-benzoxazine –4-acetic acid ethyl esters could also be prepared using the above method. Apart from 41a – g, 41h was synthesized by the reduction of nitro group of 41g with sodium borohydride in the presence of nickel (II)

91

chloride (to enhance speed of the reaction) in methanol leading to 7-nitro-3,4 dihydro-3oxo-2H-1,4-benzoxazine –4-acetic acid ethyl ester (41h) (Equation – 3.10). O2N

O

NaBH4, NiCl2

N

(41g)

O MeOH, r.t 4.0 h OEt

H2N

O N

O OEt

(41h) O

O

Equation – 3.10 Structures of all products (41a – h) were assigned based on spectral and analytical data (Table 3.3).

92

Table – 3.3: Synthesis of 41from 38 by alkylation. Sub.

Pdt.

R

R1

R2

Yield (%)

Spectral Data:

1

HNMR (200 MHz,

CDCl3); IR (KBr/Neat)/cm-1. 38b

41b

F

H

H

74.0

IR

(KBr):

1741

cm-1

(ester

carbonyl

stretching) and 1688 cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 6.78 – 6.64 (s, 3H), 4.68 (s, 2H), 4.63 (s, 2H), 4.29 – 4.19 (q, J = 7.25 Hz, 2H),1.31 – 1.24 (t, J = 7.25 Hz, 3H); Mass: m/z 254 (M+ +1, 100 %), 152 (30 %). Elemental Analysis: Mol. F: C12H12NO4F, Cal. C: 56.900, H: 4.779, N: 5.533; Experimental, C: 56.551, H: 4.940, N: 5.403. 38c

41c

Me

H

H

74.0

IR

(KBr):

1744

cm-1

(ester

carbonyl

stretching) and 1681 cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 6.82 – 6.77 (m, 2H), 6.64 – 6.60 (d, J = 7.82 Hz, 1H), 4.63 (s, 2H), 4.60 (s, 2H), 4.27 – 4.17 (q, J = 7.32 Hz, 2H), 2.27 (s, 3H), 1.33 – 1.26 (t, J = 7.32 Hz, 3H); Mass: m/z 250 (M+ +1, 100 %), 249 (M+, 75 %), 204 (40 %), 148 (40 %). 38d

41d

H

Me

H

72.0

IR

(KBr):

1742

cm-1

(ester

carbonyl

stretching) and 1685 cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 6.89 (d, J = 8.30 Hz, 1H), 6.80 (d, J = 8.30 Hz, 1H), 6.53 (s, 1H), 4.62 (s, 4H), 4.30 – 4.19 (q, J = 7.33 Hz, 2H), 2.29 (s, 3H), 1.31 – 1.24 (t, J = 7.33 Hz, 3H); Mass: m/z 250

93

(M+1, 100 %), 204 (40 %), 176 (50 %), 148 (80 %). 38e

41e

SMe

H

H

69.0

IR

(KBr):

1739

cm-1

(ester

carbonyl

stretching) and 1676 cm-1 (amide carbonyl stretching); 1H NMR (DMSO d6, 200 MHz):

δ 7.00 – 6.99 (m, 3H), 4.70 (s, 4H), 4.16 – 4.13(q, J = 7.32 Hz, 2H), 2.45 (s, 3H), 1.24 – 1.17 (t, J = 7.32 Hz, 3H); Mass: m/z 282 (M+1, 100 %), 281 (M+1, 80 %), 236 (30 %), 180 (30 %). 38f

41f

SO2Me

H

H

76.0

IR

(KBr):

1747

cm-1

stretching) and 1700 cm

-1

(ester

carbonyl

(amide carbonyl

stretching); 1H NMR (DMSO d6, 200 MHz):

δ 7.60 – 7.55 (m, 2H), 7.35 (d, J = 8.30 Hz, 1H), 4.85 (s, 2H), 4.80 (s, 2H), 4.22 – 4.11 (q, J = 7.33 Hz, 2H), 3.22 (s, 3H), 1.25 – 1.18 (t, J = 7.32 Hz, 3H); Mass: m/z 314 (M+ +1, 100 %), 212 (30 %). 38g

41g

NO2

H

H

75.0

IR

(KBr):

1736

cm-1

stretching) and 1694 cm

-1

(ester

carbonyl

(amide carbonyl

stretching); 1H NMR (DMSO d6, 200 MHz):

δ 7.96 (d, J = 1.95 Hz, 1H, Ar - H), 7.90 (d, J = 1.96 Hz, 1H), 6.84 (d, J = 8.79 Hz, 1H), 4.78 (s, 2H), 4.71 (s, 2H), 4.32 – 4.21 (q, J = 7.33 Hz, 2H), 1.30 (t, J = 7.32 Hz, 3H); Mass: m/z 281 (M+ +1, 100 %), 179 (30 %). 38g

41h

NH2

H

H

IR

(KBr):

1744

cm-1

(ester

carbonyl

stretching) and 1689 cm-1 (amide carbonyl stretching); 1H NMR (DMSO d6, 200 MHz):

94

δ 6.56 – 6.52 (d, J = 8.30 Hz, 1H), 6.36 – 6.28 (m, 2H), 4.61 (s, 2H), 4.58 (s, 2H), 4.27 – 4.17 (q, J = 7.33 Hz, 2H), 1.30 – 1.23 (t, J = 7.32 Hz, 3H); Mass: m/z 251 (M+ +1, 100 %), 177 (25 %) . 38a

41i

H

H

IR

Et

(KBr):

1740

cm-1

(ester

carbonyl

stretching) and 1692 cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.07 – 6.90 (m, 3H), 6.87 – 6.80 (m, 1H), 5.37 – 5.29 (dd, J = 5.37 & 9.94 Hz, 1H), 4.72 – 4.53 (dd, 15.04 & 21.21 Hz, 2H), 4.28 – 4.12 (m, 2H), 2.37 – 2.19 (m, 1H), 2.17 – 1.91 (m, 1H), 1.23 – 1.16 (t, J = 7.25 Hz, 3H), 0.93 – 0.86 (t, J = 7.52 Hz, 3H); Mass: m/z 264 (M+ +1, 100 %). 38a

41j

H

H

Pr

IR

(KBr):

1740

cm-1

(ester

carbonyl

stretching) and 1692 cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.07 – 6.90 (m, 3H, Ar H ), 6.87 – 6.80 (m, 1H, Ar H), 5.37 – 5.34 (dd, J = 5.37 & 9.94 Hz, 1H, NCH), 4.72 – 4.53 (dd, 15.04 & 21.21 Hz, 2H, OCH2CO), 4.28 – 4.12 (m, 2H, OCH2CH3),

2.37

–1.91

(m,

2H,

NCHCH2CH2), 1.3 (t, J = 7.52 Hz, 2H, NCHCH2CH2), 1.23 – 1.21 (t, J = 7.25 Hz, 3H, OCH2CH3), 0.98 – 0.88 (t, J = 7.52 Hz, 3H, NCHCH2CH2CH3); Mass: m/z 278 (M+ +1, 100 %). 38a

41l

H

H

Ph

58.0

IR

(KBr):

1746

cm-1

(ester

carbonyl

95

stretching) and 1681cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.36 – 7.31 (m, 5H, Ar H), 7.03 – 6.92 (m, 2H, Ar H), 6.80 – 6.70 (m, 2H, Ar H), 6.40 (s, 1H, Benzylic H), 4.76 (dd, J = 15.04 & 19.87 Hz, 2H, OCH2CO), 4.33 – 4.17 (m, 2H, OCH2 CH3), 1.19 (t, J = 7.2 Hz, 3H, OCH2 CH3); Mass: m/z 312 (M+ +1, 100 %). 38a

41m

H

H

Ar

71.0

IR

(KBr):

1744

cm-1

(ester

carbonyl

stretching) and 1691cm-1 (amide carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.31 (d, J = 8.60 Hz, 2H, Ar H), 6.98 (d, J = 8.00 Hz, 2H, Ar H), 6.91 – 6.80 (m, 4H, Ar H), 6.31 (s, 1H, Benzylic H), 4.79 – 4.61 (dd, J = 15.05 & 20.95 Hz, 2H, OCH2 CO), 4.29 – 4.19 (m, 2H, OCH2 CH3), 3.78 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H, OCH2 CH3); Mass: m/z 342 (M+ +1, 10 %) and 193 (100 %). Ar = 4-methoxy phenyl

96

Reductions with Lithium Aluminum Hydride (LAH): Treatment of 41a (41, R = R1 = H) with 1.1 eq. of LAH in THF followed by usual workup gave a product as syrupy liquid. The compound was found to be homogenous on TLC and different from the starting material. Its IR spectrum (Neat) did not show any diagnostic peaks due to the presence of –NH- and -CO- groups (Fig 3.10). Its 1H NMR (in CDCl3) showed signals (Fig 3.11) at δ 6.98 – 6.88 (m, 2H, Ar - H), 6.79 – 6.72 (m, 2H, Ar - H), 4.89 – 4.84 (dd, J= 3.42 and 6.84 Hz, 1H, O CH), 4.44 – 4.37 (dd, J= 2.93 and 10.75 Hz, 1H, OCH2), 4.14 – 3.94 (m, 2H, O CH2 & N CH2), 3.74 – 3.56 (m, 2H, O CH2 & N CH2), 3.50 – 3.42 (m, 1H, O CH2). Its mass spectrum (Fig 3.12) showed molecular ion peak at m/z 178 (M+ +1, 100 %). Elemental Analysis: Mol. F: C10H11NO2, Cal. C: 67.766, H: 6.261, N: 7.908; Experimental, C: 67.763, H: 6.694, N: 8.179. Based on this data, the product was assigned as 1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-

d][1,4]oxazine (42a). (Equation – 3.11)

R

O

R1

N

O OEt

R2

R LAH THF, 0 - r.t R1 1.0 hr

O N R2

O

(41)

O

(42) Equation – 3.11

It is noteworthy that the product expected from LAH reduction in the above reaction was 43, which however, did not form. (Equation – 3.12)

O

LAH

N

O OEt

(41a)

THF, 0 - r.t 1.0 min

O

O N

OH

(43)

Equation – 3.12 The above reaction (Equation – 3.11) of 41a yielding 42a is general one. It has been extended to other N-substituted benzoxazinones (41) yielding (42). Structures of all

97

these compounds have assigned on analogy and on the basis of spectral and analytical data (Table 3.4). Structure confirmation: To confirm the structure of the compound 42 further especially its stereochemistry, single crystal X-ray diffraction study was carried out.7 For single crystal X-ray diffraction study to be carried out, it is essential that the compound should be solid crystalline substance. Since the product 42a obtained in the present study was a syrupy liquid and other analogs also had low melting points, compound 42a was nitrated hoping that the resulting derivative 44a would be a solid amenable for X-ray studies. Nitration of 42a with nitric acid in acetic anhydride yielded 7-nitro-1,2,3a,4tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]oxazine (44). (Equation – 3.13) O N

HNO3 O2N Ac2O

O

O N

O

(44)

(42a) Equation –3.13

O2N 6 7

5

4 9 O

Hb 3

Ha H 2 O 13 8 101N 11 Ha 12 Hb Hb Ha (44)

Thus, its IR (KBr) spectrum (Fig. 3.13) showed the absence of any diagnostic peaks due to –NH- and -CO- groups. Its 1H NMR (CDCl3, 200 MHz) showed signals (Fig. 3.14) at δ 7.89 – 7.84 (dd, J = 8.8 and 2.4 Hz, 1H, ArH), 7.77 (d, J = 2.4 Hz, 1H, ArH), 6.56 (d, J = 8.8 Hz, 1H, ArH), 4.92 – 4.86 (dd, J = 8.4 and 3.4 Hz, 1H), 4.63 – 4.56 (dd, J = 10.0 and 4.0 Hz, 1H), 4.35 – 4.25 (dd, J = 9.0 and 3.2 Hz, 1H), 4.15– 4.03 (dt, J = 6.4 and 8.8 Hz, 1H), 3.75 – 3.70 (m, 1H), 3.56 – 3.30 (m, 2H). The data of 400 MHz 1

H NMR depicted in Table – 3.4. Carbon 13 and COSY data is also shown in Table 3.4.

98

The mass spectrum of 44 showed the molecular ion peak at 223 (M+1, 100 %) in Q+1 mode. In the steady state 1D nOe experiment on irradiating the C-8 proton at 6.57 ppm. The spectrum showed enhancement of signals at 3.72 and 3.49 ppm corresponding to C11 Ha and Hb protons respectively. With this information, the position of the aromatic C8 proton was fixed at 6.57 ppm. The splitting of C-8 proton is doublet due to C-7 proton coupling. Hence the position of Nitro group is fixed at C-6. NMR assignments of (44) are listed in the following page

Table 3.4: The NMR assignments of (44) Position

2

1

H

1H

δ (ppm) 4.88

J (Hz)#

dd, 8.4, 4.4

COSY

13

C

DEPT

(Fig. 3.17)

(Fig. 3.15)

(Fig. 3.16)

(3Ha, 3.36)

82.34

CH

65.70

CH2

112.13

CH

(3Hb, 4.61) 3

5

Ha

3.36

dd, 10.0, 8.4

(2H, 4.88)

Hb

4.61

dd, 10.0, 4.4

(2H, 4.88)

1H

7.78

d, 2.4

6

138.19

7

1H

7.87

dd, 8.8, 2.4

(8H, 6.57)

119.82

CH

8

1H

6.57

d, 8.8

(7H, 7.87)

111.07

CH

9

139.11

10

141.58

11

Ha

3.49

dt, 7.6, 8.8

(12Ha, 4.12)

46.73

CH2

(12Hb, 4.32) (11Hb, 3.72)

99

Hb

3.72

ddd, 7.6,6.4,2.8

(12Ha, 4.12) (12Hb, 4.32) (11Hb, 3.49)

12

Ha

4.12

dt, 6.4, 8.8

(11Ha, 3.49)

65.92

CH2

(11Hb, 3.72) (12Hb, 4.32) Hb

4.32

ddd, 7.6,6.4,2.8

(11Ha, 3.49) (11Hb, 3.72) (12Hb, 4.12)

The possible major fragments produced in the e.i mass spectrum (Fig. 3.20) of 44 are shown below:O2 N

O (45)

N

m/z = 223

O2N O

O

+ (46)

N

m/z = 206

O

(47)

N

O

m/z = 177

Melting point (150 °C) was confirmed by thermal analysis (Fig. 3.21)

Single crystal X-ray diffraction study: Single Crystal suitable for X-ray diffraction have been grown from the recrystallisation of 44 in the mixture of solvents such as ethyl acetate and petroleum ether. The compound crystallizes as yellow flakes in monoclinic space group P21/c with cell dimensions a = 12.164 (2), b = 22.079 (2), c = 7.374 (2), β = 100.82 (2) A0 and V = 1945.2

0

(6), Z = 8. There are independent

molecules in the asymmetric unit. Molecule –A adopted envelope conformation while molecule-B assumed half chair conformation.

The molecules inside the lattice are

stabilized by Van der wall interactions. The intensity data was collected on Rigaku AFC7S single crystal diffractometer using Cu Kα (λ = 1.5405 A0). The structure has been solved with direct methods and refined using the TEXSAN software. The final R factors are: R (Rw) = 0.067 (0.076) with 2683 observed reflections (I>1.50\σ(I)). All the bond

100

parameters were normal.

The results from the various physicochemical techniques

confirm the molecular structure.

Crystal Photograph of Compound 44

101

Crystal Structure of Compound 44

102

Table – 3.4 Synthesis of 41 (a-i) from 42 (a-i) by reduction with LAH: Sub

Pdt

R

R1

R2

Yield (%)

Spectral Data : 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

41b

42b

F

H

H

99.0

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups.

1

H

NMR: δ 6.76 – 6.60 (m, 3H), 4.85 – 4.80 (dd, J= 3 and 6 Hz, 1H), 4.38 – 4.31 (dd, J= 3 and 11 Hz, 1H), 4.07 – 3.90 (m, 2H), 3.75 – 4.60 (m, 2H), 3.49 – 3.34 (m, 1H); MS: m/z 196 (M+ +1, 100

%),

195

(80%).

Elemental

Analysis: Mol. F: C10H10FNO2, Cal. C: 61.517,

H:

5.166,

N:

7.179;

Experimental, C: 60.221, H: 5.468, N: 6.924.

41d

42d

Me

H

H

86.0

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR: δ 6.71 – 6.49 (m, 3H), 4.85 – 4.81 (dd, J= 3 and 6 Hz, 1H), 4.40 – 4.29 (dd, J= 2.9 and 11 Hz, 1H), 4.02 – 3.88 (m, 3H), 3.69 – 3.59 (m, 1H), 3.46 – 3.45 (m, 1H), 2.23 (s, 3H); MS: m/z 192 (M+ +1, 95 %), 191 (M+, 100 %).

41e

42e

H

Me

H

94.0

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR: δ 6.74 (d, J = 7.8 Hz, 1H), 6.56 – 6.52 (m, 2H), 4.85 – 4.78 (dd, J= 3 and 7 Hz, 1H), 4.38 – 4.31 (dd, J= 2.9 and 11 Hz, 1H), 4.08 – 3.90 (m, 2H),

103

3.69 – 3.52 (m, 2H), 3.46 – 3.34 (m, 1H), 2.26 (s, 3H); MS: m/z 192 (M+ +1, 95 %), 191 (M+, 100 %).

41f

42f

SMe

H

H

99.0

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR: δ 6.93 – 6.88 (m, 2H), 6.71 – 6.67 (m, 1H), 4.85 – 4.81 (dd, J= 3 and 8 Hz, 1H), 4.40 – 4.34 (dd, J= 3.0 and 11 Hz, 1H), 4.13 – 3.91 (m, 2H), 3.70 – 3.55 (m, 2H), 3.45 – 3.37(m, 1H), 2.41 (s, 3H); MS: (m/z) 224 (M+ +1, 80 %), 223 (M+, 100 %).

41g

42g

SO2Me

H

H

39.0

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR: δ 7.45 – 7.40 (dd, J = 1.9 & 8.4 Hz, 1H), 7.36 – 7.35 (d, J = 1.9 Hz, 1H), 6.65 – 6.61 (d, J = 8.4 Hz, 1H), 4.83 – 4.77 (dd, J = 3.8 & 8.0 Hz, 1H), 4.55 – 4.48 (dd, J = 4 & 10 HZ, 1H), 4.21 – 4.16 (m,1H), 4.08 – 4.00 (m, 1H), 3.67 – 3.61 (m, 1H), 3.44 – 3.24 (m, 2H), 2.94 (s, 3H); MS: m/z 256 (M+ +1, 100 %).

41j

42j

H

H

Et

45

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR (CDCl3, 200 MHz): δ 6.95 – 6.71 (m, 4H, Ar H), 4.92 – 4.88 (dd, J = 2.69 & 4.88 Hz, 1H), 4.35 – 4.28 (dd, J = 2.68 and 11.23 Hz, 1H), 4.10 – 4.03 (dd, J = 6.35 and 7.57 Hz, 1H), 3.91 – 3.83

104

(dd, J = 5.12 and 11.47 Hz, 1H), 3.76 – 3.70 (dd, J = 4.39 & 6.59 Hz, 1H), 3.69 – 3.59 (dd, J = 4.15 and 7.81 Hz, 1H), 1.87 – 1.76 (m, 1H), 1.71 – 1.57 (m, 1H), 1.11 – 1.04 (t, J = 7.33 Hz, 3H);

MS: m/z 206 (M+ +1,100 %), 136 (10 %).

41k

42k

H

H

Pr

42

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR (CDCl3, 200 MHz): δ 6.96 – 6.71 (m, 4H, Ar H), 4.92 – 4.88 (dd, J = 2.68 & 4.88 Hz, 1H), 4.35 – 4.28 (dd, J = 2.68 and 11.48 Hz, 1H), 4.10 – 4.02 (dd, J = 7.24 and 11.48 Hz, 1H), 3.93 – 3.85(dd, J = 4.88 and 11.48Hz, 1H), 3.82 – 3.73 (m, 1H), 3.63 – 3.57 (dd, J = 4.15 and 7.81 Hz, 1H), 1.82 – 1.70 (m, 1H), 1.59 – 1.41 (m, 3H), 1.07 – 1.00 (t, J = 7.33 Hz, 3H); MS: m/z 206 (M+ +1,100 %), 136 (10 %).

41l

42l

H

H

Ph

48

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups;

1

H

NMR (CDCl3, 200 MHz): δ 7.42 – 7.32 (m, 5H, Ar H), 6.96 – 6.91 (dd, J = 1.88 & 6.25 Hz, 1H, Ar H), 6.81 – 6.67 (ddd, J = 1.88, 6.98 & 9.13 Hz, 2H, Ar H), 6.50 – 6.45 (dd, J = 1.88 & 7.52 Hz, 1H, Ar H), 5.25 – 5.19 (dd, J = 2.76 & 7.52 Hz, 1H, OCH2CHO), 4.73 (t, J = 7.26

105

Hz, 1H, N CH Ph), 4.56 – 4.47 (m, 2H, O CH2CH), 3.79 (t, J = 8.06 Hz, 1H, OCH2CHN), 3.61 – 3.52 (dd, J = 7.52 & 2.90 Hz, 1H, OCH2CHN); MS: m/z 254 (M+ +1,100 %). Elemental Analysis: Mol. F: C16H15NO2, Cal. C: 75.856, H: 5.973, N: 5.532; Experimental, C: 75.721, H: 6.659, N: 5.258.

41m

42m

H

H

Ar

39

IR: Did not show any diagnostic peaks due to –NH- and -CO- groups; ;

1

H

NMR (CDCl3, 200 MHz): δ 7.34 (d, J = 8.59 Hz, 2H, Ar H), 6.93 (d, J = 8.59 Hz, 2H, Ar H), 6.78 – 6.69 (ddd, J = 1.88, 7.52 & 9.67 Hz, 2H, Ar H), 6.51 – 6.47 (dd, J = 1.88 & 7.25 Hz, 1H, Ar H), 5.23 – 5.18 (dd, J = 3.76 & 7.52 Hz, 1H, NCHO), 4.67 (t, J = 7.52 Hz, 1H, Benzylic H), 4.55 - 4.42 (ddd, J = 4.03, 10.30 & 14.50 Hz, 2H, OCH2CHO), 3.82 (s, 3H, OCH3), 3.80 – 3.72 (dd, J = 6.17 & 8.05 Hz, 1H, CHCH2O), 3.59 – 3.50 (dd, J = 7.52 & 10.48 Hz, 1H, CHCH2O); MS: m/z 284 (M+ +1,100 %), 151 (30%). Elemental Analysis: Mol. F: C17H17NO3, Cal. C: 72.054, H: 6.051, N: 4.946; Experimental, C: 70.797, H: 5.763, N: 6.028. Ar = 4-methoxy phenyl

106

It was considered desirable to study the effect of substitution on the cyclization reaction yielding oxazolooxazines.

All the compounds reported in Table 3.5 have

substitutions at 1, 7 and 8 positions. It would be interesting to study the course of cyclization if there are substitutions with aryl moiety at position 3.

Therefore,

preparation of 42j, which was needed in the present work, was carried out as follows:Br OH NO2

CO2Me K2CO3, Acetone

O

60 °C, 12 hrs

Ph NO2

(36a)

CO2Me

10 % Pd /C AcOH / H2gas

(37g)

O N H (38i)

Ph ethylbromoacetate,

O

Ph

K2CO3, DMF, r.t, 12 h

N

O O

O

(41j)

LAH / THF r.t, 60 min

O

Ph

N

O

(42j)

O

Scheme – 3.1 Commercially available 2-nitrophenol (36a) was reacted with 4 in the presence of potassium carbonate as base in acetone to give ethyl 2- (2-nitrophenoxy)-2 – phenylacetate (37g), which was characterized by its spectral and analytical data. Thus, its IR (Neat) showed a diagnostic peak at 1737 cm-1 due to ester carbonyl stretching. Its 1H NMR (in CDCl3) showed signals at δ 7.91 – 7.86 (dd, J = 1.07 & 8.32 Hz, 2H, Ar H), 7.64 – 7.59 (m, 5H, Ar H), 7.52 – 7.38 (m, 4H), 7.08 (t, J = 7.79 Hz, 1H, Ar H), 6.98 (d, J = 8.3 Hz, 1H, Ar H), 5.76 (s, 1H), 3.71 (s, 3H). Its mass spectrum showed peaks at 288 (M+, 20 %), 149 (M-1, 100 %). 37g was cyclized in the presence of 10 % palladium charcoal under hydrogen atmosphere in acetic acid to give 2-phenyl -3,4-dihydro-2Hbenzo[b][1,4]oxazin-3-one (38i). This was confirmed by analytical and spectral data. Thus, its IR (KBr) showed peaks at 1681cm-1 indicating amide carbonyl stretching. Thus, its 1H NMR (CDCl3) showed signals at δ 9.25 (bs, 1H, D2O exchangeable, NH), 7.45 – 7.43 (m, 2H), 7.35 – 7.32 (m, 3H), 7.04 – 6.91 (m, 3H), 6.89 – 6.78 (m, 1H), 5.69 (s, 1H). Its mass spectrum showed the molecular ion peaks at m/z 226 (M+1, 100 %) in Q+1

108

mode. The compound 38i was N- alkylated with ethyl 2-bromoacetate in the presence of potassium carbonate as a base in DMF at room temperature to give 41j. The structure of

41j was assigned based on following spectral data. Thus, its IR (KBr) showed peaks at 1748 cm-1 indicating ester carbonyl stretching as diagnostic peak. Its 1H NMR (CDCl3) showed signal at δ 7.45 – 7.42 (m, 2H, Ar H), 7.34 – 7.21 (m, 3H, Ar H), 6.96 – 6.91 (m, 3H, Ar H), 6.71 – 6.67 (m, 1H, Ar H), 5.74 (s, 1H, Benzylic H), 4.90 (d, J = 17.46 Hz, 1H, NCH2CO), 4.42 (d, J = 17.46 Hz, 1H, NCH2CO), 4.26 – 4.15 (q, J = 7.25 Hz, 2H, OCH2CH3), 1.22 (t, J = 7.25 Hz, 3H, OCH2CH3). Its mass spectrum showed peaks at 312 (M+1, 100 %), 311 (10 %) when spectrum used in the Q+1 mode. The compound 41j was reduced with lithium aluminumhydride in THF followed by simple processing to obtain a product as syrupy liquid. The compound was found to be homogenous on TLC. Its IR spectrum (Neat) did not show any diagnostic peaks due to –NH- and -CO- groups. Its 1H NMR (in CDCl3, 400 MHz) showed signals at δ 7.51 – 7.47 (m, 2H, ArH), 7.44 – 7.35 (m, 3H, ArH), 7.02 – 6.96 (dd, J = 7.80 and 12.55 Hz, 2H, ArH), 6.77 – 6.75 (d, J = 7.80 Hz, 2H, ArH), 4.72 – 4.70 (d, J = 7.32 Hz, 1H), 4.26 – 4.22 (m, 1H), 4.15 – 4.13 (d, J = 7.32 Hz, 1H), 4.04 – 3.98 (m, 1H), 3.80 – 3.76 (m, 1H), 3.45 – 3.39 (m, 1H). Its mass spectrum showed the molecular ion peak at m/z 254 (M+., 100 %). Based on this data, the product was assigned as by 4-phenyl-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-

d][1,4]oxazine structure 42j. (Scheme – 3.1)

3.4 Experimental Section i) Preparation of 37a-f (General procedure): To a suspension of 36 a-e (30 mmol) and potassium carbonate (12.4 gms, 90.0 mmol) in dry dimethyl formamide (80 mL) was added ethyl bromoacetate (4.0 mL, 36.0 mmol) at 25 °C and the mixture was stirred for 4.0 hrs at 80 °C. The reaction mixture was cooled to room temperature and water (200 mL) was added. The mixture was extracted with ethyl acetate (3 X 50 mL). The organic layer was washed with water, dried over sodium sulfate and the solvent was evaporated under reduced pressure yielding 37a-f. (Table-3.1)

109

ii) Preparation of 36f: To a solution of 5-fluoro-2-nitro phenol (40b) 5.0 g (31.80 mmol) in HMPA (50 mL) was added sodium thiomethoxide (4.68 g, 66.87 mmol) at 25 °C and the mixture was stirred for 12.0 hrs at room temperature. The reaction mixture was poured into water (200 mL) acidified with cold 6N HCl (100 mL). The separated solid was filtered washed with water and dried to obtain 36f. Yield = 5.6 gms (95 %).

iii) Preparation 38a: To a solution of 37a (5.0 gms, 22.22 mmol) in dioxane (60 mL) was added 10 % palladium-carbon (1.0 g). The reaction mixture was stirred under 60 psi of hydrogen pressure at room temperature for 6 hrs. The mixture was then filtered through a bed of Celite and the bed was washed with dioxane. The combined filtrates were concentrated under reduced pressure to give 38 a. Yield = 2.5 gms (75 %).

iv) Preparation of 38a – h (General procedure): To a solution of 37a - h in methanol (10 mL / 1 gm) was added acetic acid (15 eq.) followed by iron powder (5.0 eq). Then the reaction mixture was refluxed for 5 hrs at 80 °C. Solvent was removed from the reaction mixture by distillation and the crude residue was neutralized with NaHCO3 solution. The mixture was extracted with ethyl acetate & combined organic layers were washed with water. Finally, the organic layer was dried and concentrated under reduced pressure to obtain 38 a-h. (Table-3.2)

v) Preparation of 38 g: To a solution of 38 f (2.5 gms, 12.82 mmol) in acetone (30 mL) was added oxone (15.74 Gms, 25.6 mmol in 50 mL water) at 25 °C and the mixture was stirred for 3.0 hrs at room temperature. Acetone was removed from the reaction mixture by the distillation and residual water layer was diluted with more water. The separated solid was filtered, washed and dried to obtain 38 g yield = 2.2 gms (76 %).

vi) Preparation of 38 h: To an ice cold solution of 2-amino-5-nitro-phenol (39) (10 g, 64.93 mmol), in dichloromethane (100 mL), was added triethylamine (18.0 mL, 129.86 mmol) followed by chloroacetylchloride (8.8 g, 77.92 mmol) at 0 °C. The mixture was

110

stirred for 6 hrs at room temperature and then made basic (to pH = 14) with aqueous sodium hydroxide solution. The resulting mixture was stirred for 6.0 hours at room temperature and acidified with dil hydrochloric acid; the separated solid was filtered, washed with ethanol and dried to obtain 38 h as brown solid. Yield = 6.0 gms (48 %).

vii) Preparation of 41a-g (General procedure): To a suspension of 38 a-g and potassium carbonate (3.0 eq) in dry dimethyl formamide (10 mL / 1.0 gm) was added ethyl bromoacetate (1.2 eq) at 25 °C and the mixture was stirred for 12.0 hrs at room temperature. The reaction mixture was poured into cold water; the separated solid was filtered, washed and then dried to obtain 41 a-g. (Table-3.3).

viii) Preparation of 41h: To a suspension of 41g (2.0 gms, 7.1 mmol) in methanol (40 mL) was added nickel chloride (5.06 gms, 21.3 mmol) at 0 °C and followed by pinch by pinch of sodiumborohydride (1.08 gms, 28.57 mmol) at 0 °C. The reaction mixture was stirred for 4 hrs at room temperature, then the solvent was removed from the mixture under reduced pressure. Then the crude residue was dissolved in ethyl acetate, and organic layer was washed with water dried and concentrated to give 41h.

ix) Preparation of 42a-h (General Procedure): To a solution of 41a-h (2.0 mmol) in dry THF (10 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The reaction mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was filtered and the filtrate concentrated. The crude residual product was purified by column chromatography using ethyl acetate and pet. ether (5:95) to give 42a-h. (Table-3.4).

x) Preparation of 44: To an ice cold solution of 47a (6.0 g, 33.8 mmol) in acetic anhydride (100 mL) was added fuming nitric acid (2.34 g, 37.18 mmol) drop wise at –5 °

C, and the mixture was stirred for three hours at 0 °C. The reaction mixture was poured

in to crushed ice; the separated solid was filtered, washed with water and dried well. The

111

crude was purified through column chromatography using ethyl acetate & petroleum ether to give 44 as yellowish crystalline solid, Yield: 1.5 g (44 %).

xi) Preparation of 37f: To a solution of 2-nitrophenol (36f) (4.0 g, 28.7 mmol) and potassium carbonate (12.0 g) in acetone was added ethyl α-bromo phenylacetate (7.9 g, 34.5 mmol) at room temperature and the mixture was refluxed for 12.0 hrs. Then the reaction mixture was filtered, washed with acetone and filtrate was concentrated under reduced pressure. Crude residue was dissolved in ethyl acetate and washed with water. Ethyl acetate layer was dried and concentrated under reduced pressure to give 37f in 82 % yield.

xii) Preparation of 38h: Palladium carbon (3.0 gm of 10 % ) was charged in 1000 mL hydrogenation flask, made wet with acetic acid (50 mL) and to this 37f (15.0 gm, in150 mL of acetic acid) was added at room temperature. Then the flask was arranged for Parr hydrogenation for 6.0 hrs at 60 psi H2 pressure. The reaction mixture was filtered through a pad of Celite to remove palladium carbon and the filter bed washed with acetic acid. The filtrate was stirred with 2000 mL of water and the separated white solid was filtered, washed with water and dried to obtain 38h. (8.0 gms, 67 %)

xiii) Preparation of 41i: To a solution of 38h(1.0 gm, 4.42 mmol) and potassium carbonate (1.8 gm, 13.2 mmol), in 20 mL of dry dimethylformamide was added ethyl bromoacetate (0.6 mL, 5.3 mmol) drop wise at room temperature. After 12.0 hrs stirring the mixture was poured in to water and the separated solid was filtered, washed with water and dried to give 83 % of 41i.

xiv) Preparation of 42i: To a solution of 41i (2.0 mmol) in dry THF (10 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The reaction mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was filtered and the filtrate

112

concentrated. The crude product was purified by column chromatography using ethyl acetate and pet. ether (5:95) to give 42i.

3.5 Reference: 01. (a) Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (b) Lue Guerrier, Jacques Royer, David S. Grierson and Henri-Philippe Husson. . J. Amer. Chem. Soc. 1983, 105, 7754. 02. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A. I. Arkivoc, 2003, xiii, 166. 03. (a) Sicker Dieter, Praetotius Birgitt, Mann Gerhard, Meyer Lutz.; Synthesis; 1989, 3, 211. (b) Atkinson, J. Morand Peter, Arnason John T, Niemeyer Harmann M., Bavo Hector R., J. Org. Chem., 1990, 56 (5), 1788. (c) Banzatti Carlo, Heidempergher

113

Franco, Melloni Piero; J. Heterocycl. Chem.; 1983, 20, 259. (d) Sicker, Dieter; Praetorius, Birgitt; Mann, Gerhard; Meyer, Lutz; Synthesis; 1988, 3, 211. 04. Finger, J. Amer. Chem. Soc.; 1959, 81, 94. 05. (a) Schlaeger, Leeb. Monatsh. Chem., 1950, 81, 714. (b) Blout, Silverman,

J.

Amer. Chem. Soc., 1944, 66, 1442. 06. (a) Hogale, M. B.; Nikam, B. P. J. Indian Chem. Soc. 1988, 60 (10), 735. (b) Caliendo, G.; Grieco, P.; Perissutti, E.; Santagada, V.; Santini, A. Eur. J. Med.

Chem. Ther. 1975, 33 (12), 957. (c) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, Akira,; Takayama, Kazuhisa.; Yoden, T. Chem. Pharm. Bull. 1996, 44 (1), 103. 07. S. Vishnu Vardhan Reddy, A. Sivalakshmidevi, K. Vyas. Veeramaneni,

Venugopal Rao

Koteswar Rao Yeleswarapu, A. Venkateswarlu and P. K. Dubey.

Acta Cyrstallographia Section E, 2003, E59, 0369.

CHAPTER – IV STUDIES ON SYNTHESIS OF “OXAZOLO [3,2-a]QUINOXALINES”

114

4.1 Introduction: Oxazolo quinoxalines are not well documented in literature. Not much work have been done in this area.

One oxazolo quinoxaline, i.e. N, N’-[(4”, 5”-dimethyl)-1”, 2”-

phenylene]-2,2’-dimethyl-bisoxazolidine (49) seems to be well-known.1 N

O

N

O

(49) 2,3-Butanedione (50) was condensed with ethanol amine (52) in benzene1 for 5 hrs at room temperature. Processing of the reaction mixture and separation of products gave 49 along with 52, 53 and 54. (Equation 4.1) O (50) O

H2N

Benzene

Room OH temperature 5.0 hrs (51)

N N (52)

OH OH

O

H N

HO N

N H

O

O

(53)

NH

(54)

OH CH3 OH CH3

N

O

N

O

(49)

Equation – 4.1

4.2 Present Work: Survey of literature revealed that preparation of oxazoloquinoxalines has not been carried out very extensively. Therefore, it was considered desirable to prepare new compounds containing oxazoloquinoxalines.

It is conceivable that these oxazolo

moieties can be synthesized from 1,2-diaminobenzene by ring closure with chloroacetic

115

acid to obtain quinoxalin-2-one in the first step. The latter can be used as a building block for the synthesis of fused oxazolo ring units.

4.3 Results and Discussion: Commercially available o-phenylenediamine (55a) was treated with ethyl 2bromoacetate in the presence of triethylamine2 as a base in dichloromethane and tetrahydrofuran as solvent to obtain 1,2,3,4-tetrahydro-2-quinoxalinone (56a R = H) in 67.0 % yield. (Equation – 4.2) NH2

BrCH2CO2Et

H N

NH2

TEA, CH2Cl2 THF

N H

(55)

O

(56a)

Equation – 4.2 Compound 56a is known in literature. However, it was further characterized in the present work by analytical and spectral data. Thus, its IR (KBr) spectrum showed (Fig 4.1) a peak at 3367 cm-1 (due to –NH stretching) and at 1681 cm-1 (due amide carbonyl stretching) as diagnostic peaks. Its 1H NMR (DMSO d6): showed signals (Fig 4.2) at δ 10.21 (bs, 1H, D2O Exchangeable, NH), 6.78 – 6.54 (m, 4H, ArH), 5.93 (bs, 1H, D2O Exchangeable, NH), 3.34 (s, 2H, NCH2CO), and its mass spectrum (Fig 4.3) showed the molecular ion peak at m/z 149 (M++1, 100 % ) as the base peak in the spectrum. In addition to the method given above, several other methods have also been reported in literature for the preparation of 2-quinoxalinones.

Thus, for example,

condensation3 of o-phenylenediamine and ethyl 2-halo-2-alkylacetate in the presence of zinc dust, or the addition4 of chloroacetic acid in the presence of ammonia, or the addition5 of 2-chloroacetamide in the presence of aqueous sodium hydroxide at 100 °C, from N-(2-nitrophenyl)glycine in the presence of tin hydrochloride,6 o-phenylenediamine and chloro acetic acid in the presence of sodium carbonate.7and from other methods.8

Table – 4.1: Some known methods to prepare compounds 56a - g

116

S.No 1.

Reactant NH2 NH2

2.

NH2 NH2

3.

NH2 NH2

4.

NH2 NH2

5.

NH2 NH2

6.

NH2 NH2

7.

NH2 NH2

8.

NH2 NH2

9.

NH2 NH2

Conditions Ethyl 2-bromo acetate,

Product

Ref:

H N

2

Triethylamine, THF N H

Chloro

acetic

acid,

O

H N

3

Diluted Ammonia N H

Chloro acetamide

O

H N

4

Diluted Ammonia N H

Bromo acetic acid

O

H N

5

Zinc dust, HCl N H

Ethyl

2-bromo-2,21-

O

H N

6

dimethyl acetate N H

Trichloromethane

O

H N

7

Acetone, NaOH, PTS N H

1,1,1-trichloro-2-

O

H N

7

methylpropan-2-ol, NaOH, PTS

N H

1,1,1-trichloro

H N

O

8

compound, KOH 3-phenyloxirane-2,2-

N H

O

H N

Ph

N H

O

9

dicarbonitrile, ethanol

117

10.

11.

NH2

Ethyl α-bromo phenyl

NH2

acetate,

NH2

H N

Ph

NaOEt

N H

O

Ethyl bromo acetae

H N

K2CO3,

KI,

N H

O

H N

O

12

OH N H O

H2 Pressure / 10 % OEt

H N N H

Pd(dba)2,

H N

O

2

Palladium Carbon.

NO2

14.

11

H N

Tin, HCl

NO2

13.

10

Pot. tert. butoxide

NH2

12.

H N

Carbon

O

H N

13

monoxide. N H

NO2

15.

N

Ph

Palladium

N H

O

Hydrogen pressure

carbon,

O

H N

Ph

N H

O

14

Keeping this in view two simple but new methods were developed for the synthesis of quinoxalines. In the first method o-phenylenediamine was treated with ethyl 2-bromo acetate in DMF in the presence of microwave irradiation for 5.0 min to obtain 56a in 72 % yield. (Equation – 4.3)

118

BrCH2CO2Et, NaOH, Water, 80 °C, 1.0 hr,

H N

NH2

N O H (56a)

NH2 (55)

BrCH2CO2Et, DMF 4 - 5 min

Equation – 4.3

Substituted 1,2,3,4-tetrahydro-2-quinoxalinone (56a-i) were prepared in the above two methods. The structures for these products were assigned on the basis of analogy and on the basis of analytical and spectral data. (Table –4.2) H R N R1

NH2 NH2 (55)

N H (56 a-i)

O

Equation – 4.4

119

Table – 4.2: Synthesis of 56 (a-h) from o-phenylenediamine. S. No.

R

R1

Yield %

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

56a

H

H

72

IR (KBr): 3367 (Amide NH band), 1681 cm-1 (Amide Keto). 1H NMR (In DMSO d6): δ 10.21 (bs, 1H, D2O Exchangeable, NH),

6.78 – 6.54 (m, 4H, ArH), 5.93 (bs, 1H, D2O Exchangeable, NH), 3.38 (s, 2H, NCH2CO); Mass: 149 (M+ +1, 100%). 56b.

H

Me

69

IR (KBr): 1665 cm-1 (Amide Keto); 1H NMR (In DMSO d6): δ

12.17 (bs, 1H, D2O Exchangeable, NH), 7.72 (d, J = 7.81 Hz, 1H, ArH), 7.5), 7.70 – 7.21 (m, 3H, ArH), 2.95 (m, 1H, NHCHCH3), 2.55 (s, 3H, CHCH3); Mass: 162 (M+, 10%), 161 (100 %). 56c.

Me Me

73

IR (KBr): 3422 cm-1 (amide NH band), 1667 cm-1 (Amide

carbonyl stretching); 1H NMR (CDCl3, 200 MHz): 10.57 (bs, 1H, D2O Exchangeable, NH), 7.29 (d, J = 7.33 Hz, 1H, Ar H), 7.18 (d, J = 7.79 Hz, 1H, Ar H), 7.00 (d, J = 7.79 Hz, 2H, Ar H), 1.34 (s, 6H, C(CH3)2; Mass: m/z 194 ((M+ +1, 20 %). 56d.

H

Et

65

IR (KBr): 3440 cm-1 (amide NH band), 1659 cm-1 (Amide

carbonyl stretching);

1

H NMR (In CDCl3): δ 11.99 (bs, 1H,

D2O Exchangeable, NH), 8.10 (d, J = 7.81 Hz, 1H, ArH), 7.78 – 7.71 (m, 1H, ArH), 7.59 – 7.52 (m, 2H, ArH), 3.32 – 2.21 (m, 1H, CHCH2CH3), 1.72 – 1.56 (m, 2H, CHCH2CH3), 1.44 – 1.36 (t, = 7.33 Hz, 3H, CH2CH3); Mass: 177 ((M+ +1, 10 %), 175 (M+, 100 %). 56e.

H

Pr

68

IR (KBr): 3384 (amide NH band), 1668 cm-1 (Amide carbonyl

stretching);

1

H NMR (In DMSO d6): δ 12.16 (bs, 1H, D2O

Exchangeable, NH), 7.70 (d, J = 7.82 Hz, 1H, ArH), 7.45(t, J = 7.81 Hz, 1H, ArH), 7.29 – 7.22 (m, 2H, ArH), 2.75 (t, J = 7.33 Hz, 1H, CHCH2CH2CH3), 2.53 (t, J = 5.36 Hz, 2H,

122

CHCH2CH2CH3), 1.73 (t, J = &.32 Hz, 2H, CHCH2CH2CH3), 0.95 (t, J = 7.32 Hz, 3H, CHCH2CH2CH3); Mass: 191 (M+1, 50 %), 189 (M+, 100 %). 56f.

H

i

Pr

59

IR (KBr): 3433 (amide NH band), 1665cm-1 (Amide carbonyl

stretching);

1

H NMR (In DMSO d6): δ 11.92 (bs, 1H, D2O

Exchangeable, NH), 7.71 (d, J = 7.82 Hz, 1H, ArH), 7.45(d, J = 7.33 Hz, 1H, ArH), 7.29 – 7.22 (m, 2H, ArH), 3.49 – 3.42 (m, 1H, CH(CH3)2), 1.23 (s, 3H, CH(CH3)2),

1.19 (s, 3H,

CH(CH3)2); Mass: 191 (M+1, 10 %), 189 (M+, 100 %), 188 (40). 56g.

H

Ph

63

IR (KBr): 3425 (amide NH band), 1664cm-1 (Amide carbonyl

stretching);

1

H NMR (In DMSO d6): δ 12.57 (bs, 1H, D2O

Exchangeable, NH), 8.32 – 8.27 (m, 2H, ArH), 8.29 – 8.27 (d, J = 7.33 Hz, 1H, ArH), 7.59 –7.49 (m, 4H, ArH), 7.74 (d, J = 7.81 Hz, 1H, ArH), 7.51 (s, 3H, CHPh); Mass: 224 ((M+ +1, 10 %), 223 (M+, 100 %), 194 (10).

123

Compound 56a was treated with benzyl bromide in the presence of sodium carbonate in aq.ethanol15 to give 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57a). (Equation 4.5)

H N

PhCH2Br

N H (56a)

O

Na2CO3 aq. EtOH 80 °C, 12 hrs

CH2Ph N N H

O

(57a)

Equation – 4.5

Substituted 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinones (57b and 57c) were prepared in the above method. (General Equation 4.6) The structures for these products were assigned on the basis of analogy and on the basis of analytical and spectral data. (Table – 4.3) H N

R

N H

O

BnBr Na2CO3 aq. EtOH

Bn N N H

R O

(56b &c)

(56c & h)

Equation – 4.6

124

Table – 4.3: Synthesis of 57 from 56 Sub.

Pdt.

R

Yield %

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

56a

57a

H

79.0

IR (KBr): (Fig 4.4) 3438 (NH band stretching), 1684 cm-1

(Amide carbonyl stretching); 1H NMR (in CDCl3): (Fig 4.5) δ 9.29 (bs, 1H, D2O Exchangeable, NH), 7.31- 7.25 (m, 5H, Ar H), 6.94 – 6.82 (m, 1H, Ar H), 6.79 – 6.72 (m, 3H, Ar H), 4.41 (s, 2H, PhCH2), 3.81 (s, 2H, NCH2); Mass: m/z (Fig 4.6) 239 (M+1, 100 %) and 238((M+ +1, 30 %). 56h

57b

Ph

59

IR (KBr): 3431 (NH band stretching), 1682 cm-1 (Amide

carbonyl stretching); 1H NMR (in CDCl3): δ 8.69 (bs, 1H, D2O exchangeable, NH proton), 7.29 – 7.17 (m, 10H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.77 – 6.71 (m, 3H, ArH), 4.97 (s, 1H, NCH (Ph)), 4.67 (d, J = 15.62 Hz, 1H, NCH2Ph), 4.09 (d, J = 15.62 Hz, 1H, NCH2Ph); Mass: 315 ((M+ +1, 100 %). 56c

57c

DiMe

74.0 %

IR (KBr): 3445 (NH band stretching), 1680 cm-1 (Amide

carbonyl stretching); 1H NMR (in CDCl3): δ 8.06 (bs, 1H, D2O Exchangeable, NH), 7.32- 7.21 (m, 5H, Ar H), 6.82 – 6.78 (m, 1H, Ar H), 6.71 (d, J = 3.43 Hz, 2H, Ar H), 6.51 (d, J = 7.79 Hz, 1H, Ar H), 4.51 (s, 2H, PhCH2), 1.51 (s, 6H, NC(CH3)2); Mass: m/z 267 ((M+ +1, 100 %).

125

4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57a) was treated with ethyl 2bromoacetate in the presence of K2CO3 as base in DMF at 80 °C for 12 hrs. (Equation 4.7) Processing of the reaction mixture gave a product which was found to be ethyl 2-(4benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetate (58a) which was characterized by spectral methods. Thus, in its IR spectrum (Fig 4.3.1) peaks were found at 1749 cm-1 (due to ester carbonyl stretching) and at 1678 cm-1 (due to amide carbonyl stretching) were observed. Its 1H NMR (In CDCl3) showed (Fig 4.3.2) signals at δ 7.32 (m, 5H, ArH), 6.98 (t, J = 7.33 Hz, 1H), 6.87 – 6.70 (m, 3H), 4.67 (s, 2H), 4.38 (s, 2H), 4.29 – 4.18 (q, J = 7.33 Hz, 2H), 3.81 (s, 2H), 1.28 (t, J = 7.33 Hz, 3H). Its mass spectrum (Fig 4.3.3) showed peaks at m/z 325 (M+1, 100 %) and at 324 (M+, 30 %) in the Q+1 mode. Bn N

Bn N

K2CO3 / BrCHCO2Et DMF 80 0C, 12.0 hrs

N H (57a)

N

O OEt

O (58a) O

Equation – 4.7

Substituted ethyl 2-(4-benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl) acetates could also be prepared using the above method. Structures of all the products (58a – h) have been assigned on the basis of analogy and on the basis of spectral & analytical data (Table – 4.4). Bn N

R

K2CO3, BrR1CHCO2Et

N H

O

DMF 80 0C, 12.0 hrs

Bn N N R1

(57a - h)

R O OEt

O (58a - i)

Equation – 4.8

126

Table – 4.4: Synthesis of 58 (a-h) from 57 (a-c) Sub.

Pdt.

R

R1

Yield %

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

57a

58a

H

H

78

IR (KBr): 1749 (Ester carbonyl stretching), 1677 cm-1

(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.32 (m, 5H, ArH), 6.98 (t, J = 7.33 Hz, 1H, ArH), 6.87 – 6.70 (m, 3H, ArH), 4.67 (s, 2H, NCH2Ph), 4.38 (s, 2H, NCH2CON), 4.29 – 4.18 (q, J = 7.33 Hz, 2H, CO2CH2CH3), 3.81 (s, 2H, NCH2CO2Et), 1.28 (t, J = 7.33 Hz, 3H, CO2CH2CH3); Mass: 325 (M+1, 100 %), 324 (M+, 10 %). 57b

58b

Ph

H

81

IR (KBr): 1749 (Ester carbonyl stretching), 1679 cm-1

(Amide carbonyl stretching);

1

H NMR (CDCl3): δ 7.98 –

7.16 (m, 10H, ArH), 7.02 – 6.94 (m, 2H, ArH), 6.88 – 6.71 (m, 2H), 5.15 (s, J = 1H, NCHPh), 5.05 (m, 2H, NCH2Ph), 4.64 (d, J = 15.14 Hz, 1H, NCH2CO2Et), 4.40 (d, J = 17.10 Hz, 1H, NCH2CO2Et), 4.28 – 4.06 (m, 2H, CO2CH2CH3), 1.15 (t, J = 7.33 Hz, 3H, CO2CH2CH3); Mass: 401 ((M+ +1, 100 %), 309 (10 %). 57a

58c

H

Me

63

IR (KBr): 1741 (Ester carbonyl stretching), 1682 cm-1

(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.32 (m, 5H, ArH), 7.21 – 6.95 (m, 2H, ArH), 6.89 – 6.79 (m, 2H, ArH), 5.49 – 5.56 (m, 2H, NCH2Ph), 5.28 – 5.25 (m, 2H, NCH2CON), 4.26 – 4.13 (m, 2H, CO2CH2CH3), 3.73 – 3.72 (m, 2H, NCH2CO2Et), 1.75 (d, J = 8.0 Hz, 3H, CHCH3), 1.30 – 1.16 (m, 3H, CO2CH2CH3); Mass: 339 (M+1, 100 %), 338 (M+, 30 %). 57a

58d

H

Et

57

IR (KBr): 1739 (Ester carbonyl stretching), 1683 cm-1

(Amide carbonyl stretching );

1

H NMR (In CDCl3): δ 7.31

(m, 5H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.81- 6.77 (m, 3H,

127

ArH), 5.36 – 5.28 (m, 1H, NCHCH2CH3), 4.49 – 4.42 (d, J = 15.44 Hz, 1H, NCH2Ph), 4.32 – 4.24 (d, J = 15.44 Hz, 1H, NCH2Ph), 4.22 – 4.13 (m, 2H, CO2CH2CH3), 3.75 (s, 2H, NCH2CON), 2.32 – 2.22 (m, 1H, NCHCH2CH3), 2.14 – 2.03 (m, 1H, NCHCH2CH3), 1.19 (t, J = 7.33 Hz, 3H, CO2CH2CH3), 0.89 (t, J = 7.33 Hz, 3H, NCHCH2CH3); Mass: 261 (M+ -1, 100 %). 57a

58e

H

Hex

49

IR (KBr): 1740 (Ester carbonyl stretching), 1685 cm-1

(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.31 (m, 5H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.81- 6.76 (m, 3H, ArH), 5.48 (s, 1H), 4.36 (d, J = 15.44 Hz, 1H, NCH2Ph), 4.27 (d, J = 15.44 Hz, 1H, NCH2Ph), 4.25 – 4.14 (m, 2H, CO2CH2CH3), 3.75 (s, 2H, NCH2CON), 2.23 – 2.03 (m, 1H, NCHCH2CH3), 1.23 – 1.16 (m, 11H), 0.82 (m, 3H); Mass: 407 (M+, 100 %). 57a

58f

H

Ph

56

IR (KBr): 1748 (Ester carbonyl stretching), 1683 cm-1

(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.34 – 7.31 (m, 10H), 6.97 – 6.79 (m, 2H), 6.75 – 6.68 (m, 2H), 6.24 (s, 1H), 4.54 – 4.30 (m, 2H), 3.86 – 3.82 (m, 2H), 3.77 (s, 3H); Mass: m/z 387 (M+1, 100 %) and 253 (10 %). 57b

58g

Ph

Ph

61

IR (KBr): 1744 (Ester carbonyl stretching), 1678 cm-1

(Amide carbonyl stretching);

1

H NMR (CDCl3): δ 7.35 –

7.08 (m, 15H, ArH), 6.99 – 6.91 (m, 1H, ArH), 6.83 – 6.80 (m, 1H), 6.76 – 6.64 (m, 2H), 6.06 (s, 1H), 5.14 (d, J = 7.60 Hz, 1H, NCHPh), 4.83 – 4.70 (dd, J = 10.8 & 15.1 Hz, 1H, NCH2CO2Et), 4.22 (t, J = 5.1 Hz, 1H, NCH2CO2Et), 3.82 (s, 3H), 3.60 (s, 1H); Mass: 463 ((M+ +1, 100 %), 371 (20 %), 265 (30 %). 57c

58h

DiMe

H

65

IR (KBr): 1739 (Ester carbonyl stretching), 1678 cm-1

128

(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.337.21 (m, 5H, Ar H), 6.87 – 6.80 (m, 4H, Ar H), 4.69 (s, 2H, NCH2), 6.71 – 6.59 (m, 2H), 4.53 (s, 2H, PhCH2), 4.30 – 4.19 (q, J = 7.32 Hz, 2H, OCH2CH3), 1.51 (s, 6H, NC(CH3)2), 1.25 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: m/z 353 ((M+ +1, 100 %), 337.

129

Reductions with Lithium Aluminum Hydride (LAH):

Treatment of 58a with 1.1 eq. of LAH in THF followed by simple processing gave a product, which was obtained as a syrupy liquid. The compound was found to be homogenous on TLC. Its IR spectrum (Neat) (Fig 4.10) did not show any diagnostic peaks due to –NH- and -CO- groups. Its 1H NMR (in CDCl3) showed (Fig 4.11) signals at δ 7.32 (m, 5H, ArH), 6.95 – 6.61 (m, 4H, ArH), 4.90 – 4.84 (dd, J = 3.90 & 7.32 Hz, 1H), 4.61 – 4.53 (d, J = 15.63 Hz, 1H), 4.33 – 4.26 (d, J = 15.13 Hz, 1H), 4.21 – 4.11 (m, 1H), 4.06 – 3.94 (m, 2H), 3.66 – 3.37 (m, 4H), 2.72 – 2.63 (dd, J = 7.33 & 10.74 Hz, 1H). Its mass spectrum (Fig 4.12) showed peaks at m/z 267 ((M+ +1, 90 %) and m/z 266 (M+, 100 %) in the Q+1 mode. Based on this data, the product was assigned as 5-benzyl1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-a]quinoxaline (59a). (Equation – 4.9) Bn N LAH THF, 0 °C O OEt to r.t 1.0 hr

N

Bn N N

O

O (58a)

(59a)

Equation – 4.9

The above reaction of 58a yielding 59a general. It has been extended to other substituted ethyl 2-(4-benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetates (58a-h) yielding (59a-h). (Equation – 4.10)

130

Bn N

R LAH

N

THF, 0 - r.t O OEt 1.0 min

R1

Bn N

R

N

O

R1

O (58a-h)

(59a-h)

Equation – 4.10 Table –4.5: Synthesis of 59 (a-h) from 58 (a-h) with LAH was explained by data: Sub.

Pdt. S.No

R

R1

Yiel

Analytical Data: (IR cm-1), 1H NMR (δppm) (CDCl3,

d

200 MHz) & Mass

% 58a

59a

H

H

75

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.32 – 7.25 (m, 5H), 6.95 – 6.61 (m, 4H), 4.90 – 4.84 (m, 1H), 4.61 – 4.26 (dd, J = 15.63 and 15.13 Hz, 2H), 4.21 – 4.11 (m, 1H), 4.03 – 3.94 (m, 2H), 3.65 – 3.37 (m, 4H), 2.72 – 2.63 (dd, J = 7.33 and 10.74 Hz, 1H); Mass (m/z): 267 ((M+ +1, 90 %), 266 (M+, 100 %). 8b

59b

Ph

H

69

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.33 – 7.14 (m, 10H), 6.81 – 6.71 (m, 2H), 6.63 – 6.56 (m, 2H), 5.02 (d, J = 3.90 Hz, 1H), 4.89 – 4.51 (m, 2H), 4.30 – 3.96 (m, 3H), 3.66 – 3.34 (m, 3H); Mass: (m/z) 343 ((M+ +1, 90 %), 342 (M+, 100 %).

131

58c

59c

H

Me

54

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.32 – 7.25 (m, 5H, Ar H), 6.82 – 6.63 (m, 4H, Ar H), 5.03 – 4.97 (dd, J = 4.36 and 7.24 Hz, 1H), 4.60 – 4.45 (m, 2H), 4.26 – 4.13 (m, 2H), 4.03 – 3.91 (m, 2H), 3.57 – 3.41 (m, 2H), 2.68 – 2.59 (m, 1H), 1.39 (d, J = 6.17 Hz, 3H); Mass: (m/z) 281 ((M+ +1, 90 %), 280 (M+, 100 %). 58d

59d

H

Et

66

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups.

1

H NMR: δ 7.34 – 7.25 (m, 5H, Ar H),

6.81 – 6.64 (m, 4H, Ar H), 5.00 – 4.94 (dd, J = 4.36 and 6.75 Hz, 1H), 4.55 (d, J = 15.08 Hz, 1H), 4.25 (d, J = 15.08 Hz, 1H), 4.12 – 4.05 (m, 1H), 3.85 – 3.75 (m, 1H), 3.67 – 3.60 (m, 2H), 3.49 – 3.41 (dd, J = 4.0 and 11.0 Hz, 1H), 2.72 – 2.63 (dd, J = 6.99 and 11.01 Hz, 1H), 1.90 – 1.71 (m, 1H), 1.68 – 1.56 (m,1H), 1.02 (t, J = 7.30 Hz, 3H); Mass: (m/z) 295 ((M+ +1, 90 %), 294 (M+, 100 %). 58e

59e

H

Hex

49

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.34 – 7.25 (m, 5H, Ar H), 6.81 – 6.63 (m, 4H, Ar H), 4.99 – 4.94 (dd, J = 4.31 and 6.71 Hz, 1H), 4.58 – 4.51 (d, J = 15.04 Hz, 1H), 4.24 (d, J = 15.04 Hz, 1H), 4.06 (d, J = 7.52 Hz,1H), 3.85 – 3.82 (m, 1H), 3.64 – 3.58 (dd, J = 4.83 and 7.79 Hz, 2H), 3.48 – 3.41 (dd, J = 4.30 and 11.02 Hz, 1H), 2.72 – 2.63 (dd, J = 16.98 and 10.98 Hz, 1H), 1.83 – 1.64 (m, 1H), 1.55 – 1.47 (m,1H), 1.32 – 1.26 (m, 8H), 0.98 – 0.88 (m, 3H); Mass: (m/z) 351 ((M+ +1, 90 %), 350 (M+, 100 %).

132

58f

59f

H

Ph

58

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.41 – 7.25 (m, 12H, Ar H), 6.77 – 6.56 (m, 2H, Ar H), 6.41 – 6.37 (m, 1H), 5.27 – 5.21 (dd, J = 11.57 and 7.79 Hz, 1H), 4.77 (t, J = 8.32 Hz, 1H), 4.23 (d, J = 14.77 Hz, 1H), 3.72 (t, J = 8.33 Hz, 1H), 3.58 – 3.51 (dd, J = 4.60 and 15.31 Hz, 1H), 2.67 – 2.58 (dd, J = 7.74 and 10.48 Hz, 1H); Mass: (m/z) 343 (M+ +1, 90 %), 342 (M+, 100 %). 58g

59g

Ph

Ph

49

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.41 – 7.16 (m, 19H, Ar H), 6.65 – 6.44 (m, 2H, Ar H), 5.30 (d, J = 6.45 Hz, 1H), 4.88 (m, 1H), 4.53 – 4.43 (m, 2H), 4.05 (d, J = 16.65 Hz, 1H), 3.84 (d, J = 6.45 Hz, 1H), 3.69 (t, J = 8.06 Hz, 1H); Mass: (m/z) 419 ((M+ +1, 90 %), 418 (M+, 100 %). 58h

59h

Di Me

H

63

IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.32 – 7.19 (m, 5H, Ar H), 6.65 (m, 1H, Ar H), 6.52 (t, J = 7.3 Hz, 2H, Ar H), 6.37 (d, J = 7.2 Hz, 1H, Ar H), 4.62 (d, J = 14 Hz, 2H), 4.29 – 4.09 (m, 2H), 3.61 – 3.49 (m, 2H), 0.97 (s, 6H); Mass: (m/z) 295 ((M+ +1, 50 %), 294 (M+, 100 %), 223 (90 %).

133

It was considered desirable to study the effect of substitution in the cyclization reaction yielding oxazolooxazines. All the compounds which are N-benzyl derivatives are reported in Table 4.5. It would be interesting to study the course of cyclisation in Nethyl substituted derivatives instead of N-benzyl substituted derivatives.

Therefore,

preparation of 59i, was needed in the present work was carried as follows: - Compound 56a was treated with ethyl bromide in the presence of sodium carbonate in aq.ethanol8 to

give 4-ethyl-1,2,3,4-tetrahydro-2-quinoxalinone (57d) and its structure was confirmed from spectral and analytical data. Thus, its IR (KBr) showed a peak at 3443 cm-1 indicating presence of – NH – group and another at 1686 cm-1 indicating presence of amide carbonyl group. Its 1H NMR (In CDCl3) showed signals at δ 10.32 (bs, 1H, D2O exchangeable Amide NH proton), 6.89 – 6.60 (m, 4H), 3.82 (s, 2H), 3.67 (s, 2H), 3.32 – 3.22 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). Its mass spectrum showed peaks at m/z 177 (M+1, 100 %) and at m/z 176 (M+, 10 %) in the Q+1 mode. Compound 57d was treated with ethyl 2-bromoacetate in the presence of K2CO3 as base in DMF at 80 °C for 12.0 hrs. Processing of the reaction mixture gave a product which was found to be ethyl 2-(4-ethyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetate (58i) characterized by spectral methods. Thus, its IR showed peaks at1748 cm-1 due to carbonyl carbon stretching and another peak at 1684 cm-1 due to amide carbonyl stretching. Its 1H NMR (In CDCl3) showed signals at δ 7.04 – 6.90 (m, 2H), 6.83 – 6.67 (m, 3H), 4.65 (s, 2H), 4.30 – 4.21 (m, 2H), 3.83 (s, 2H), 3.37 – 3.27 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.0 Hz, 3H). Its mass spectrum showed peaks at 277 (M+1, 100 %) in the Q+1 mode. Treatment of compound 58i with 1.1 eq. of LAH in THF yielded syrupy product. The compound was found to be homogenous on TLC. Its IR spectrum (Neat) did not show any diagnostic peaks due to of –NH- and -CO- groups. Its 1H NMR (in CDCl3) show signals at δ 6.77 – 6.65 (m, 3H), 6.63 – 6.57 (m, 1H), 4.90 – 4.84 (dd, J = 4.0 and 8.7 Hz, 1H), 4.17 – 4.09 (m, 1H), 4.05 – 3.93 (q, J = 7.3 Hz, 2H), 3.64 – 3.24 (m, 3H), 2.72 – 2.63 (dd, J = 7.3 and 10 Hz, 1H), 1.17 (t, J = 7.3 Hz, 3H). Based on this data, the product was assigned as 5-ethyl-1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-a]quinoxaline (59i).

135

H N N H

O

EtBr

N

Na2CO3 aq. EtOH

N H

Ethyl bromoacetate K2CO3, DMF

O

80 °C

(57d)

(56a)

N

N

LAH

N

O O

N

THF

(58i)

O

(59i) O

Scheme – 4.1

When N-ethyl derivative 58i was subjected to reduction with LAH it gave the final product 59 in lower yield than the corresponding N-benzyl derivatives.

This

indicates that for good yields N-benzyl protection is preferable than N-ethyl protection. Another advantage with N-benzyl derivatives is that it is easy to remove the benzyl group from tricyclic oxazolo quinoxaline to yield the parent ring system which can be utilized for further chemical reactions.

4.4 Experimental procedure: i) Preparation of 56a - h (General procedure): Method A: To a solution of o-phenylenediamine (55, 5.0 gms, 46.0 mmol) in

water was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl acetate (1.2 eq) at room temperature. The reaction mixture was stirred for one hour at 80 °

C, cooled to room temperature and neutralized with aq. HCl (50 %, v/v). The separated

solid was filtered, washed with water and dried to obtain 56a-h (Table-4.1).

136

Method B: To a solution of o-phenylenediamine (55, 0.5 gms, 4.6 mmol) in DMF

was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl acetate (1.2 eq) at room temperature. The mixture was irradiated with microwaves using household microwave oven for 5.0 min. Then, the mixture was cooled, and neutralized with aq. HCl (50 %, v/v). The separated solid was filtered, washed with water and dried to obtain 56a-h (Table-4.1).

ii) Preparation of 57a - c (General procedure): To a solution of compounds 57a -h and

sodium carbonate (2.0 eq) in aqueous ethanol (10 mL ethanol: 1.0 mL water for 1.0 gm of substrate) was added benzyl bromide (1.2 eq.) and the mixture refluxed for 12 hrs. The reaction mixture was cooled to room temperature and poured into water. The separated solid was filtered, washed with water and dried to obtain 57a-c (Table-4.2).

iii) Preparation of 57d: To a solution of compounds 56a (2.0 gms, 13.51 mmol) and

sodium carbonate (2.75 gms, 27.07 mmol) in aqueous ethanol (20 mL ethanol: 2.0 mL water) was added ethyl bromide (1.26 mL, 16.21 mmol) and refluxed for 12 hrs. The reaction mixture was cooled to room temperature and poured into water. The separated solid was filtered, washed with water and dried to obtain 57d (1.78 gm, 75 %).

iv) Preparation of 58a – i (General procedure): To a solution of 57 a – d (1.0 eq) and

potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2alkyl acetate (1.2 eq) drop wise at room temperature. After 12.0 hrs stirring at 80 °C, the mixture was poured in to water. The separated solid was filtered, washed with water and dried to give 58a –i (Table-4.3).

v) Preparation of 59a – i (General procedure): To a solution of 58a - i (2.0 mmol) in

dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The reaction mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was

137

filtered and the filtrate concentrated. The separated crude product was purified by column chromatography using ethyl acetate and pet. ether (5:95) to give 59a – m (Table-4.4).

4.5 References: 01. Noberto Farfan, Rosa Santillan, Julian Guzaman, Belinda Castillo and Aurelio Ortiz.

Tetrahedron; 1994, 50 (33), 9951.

02. Ruth, E. TenBrink, Wha, B. Im, Vimala, H. Sethy, Andrew, H. Tang and Don, B. Carter, J. Med. Chem., 1994, 37, 758. 03. Motylewski, et. al. Chem. Ber. 41, 800 (1908). 04. Perkin, Riley, J. Chem. Soc., 1923, 123, 2406. 05. Holley, J. Amer. Chem. Soc., 1952, 74, 3069. 06. Ploechl; Chem. Ber.; 1886, 19, 10. 07. Borthakur N, Bhattacharyya A. K., Rastogi R. C., Indian J. Chem. Sect. B., 1981, 20

(9), 822.

08. (a) Harsanyi k et. al; Chem. Ber.; 1972, 105, 805. (b) Cuiban F; Bull. Soc. Chim.

Fr.; 1963, 356. (c) Taylor, Thompson; J. Org. Chem.; 1961, 26, 3511. (d) Bell, Childress; J. Org. Chem.; 1964, 29, 506. (e) Heller.; J. Prakt. Chem.; 1925, 111, 19. (f) Hinsberg, Justus Liebigs Ann Chem., 1896, 292, 246. (g) Lai John T.,

Synthesis.; 1982, 1, 72. (h) Clark – Lewis. Aust J Chem.; 1970, 23, 1249. (i) Clark – Lewis.; Aust J Chem.; 1964, 17, 877. (j) Soederberg Bjoern C. G., Wallace Jeffery M, Tamariz Joaquin; Org. Lett.; 2002, 4 (8), 1339. (k) Taylor Edward C., Maryanoff Cynthia A., Skotnicki Jerauld S., J. Org. Chem., 1980, 45 (12), 2512. (l)

138

Olagbemiro, T. O., Nyakutse, C. A., Lajide, L., Agho, M. O., Chukwu, C. E., Bull.

Soc. Chim. Belg., 1987, 96 (6), 473. (m) De La Fuente, Julio R., Canete Alvaro, Zanocco Antonio L., Saitz Claudio, Jullian Carolina., J. Org. Chem., 2000, 65 (23), 7949. 09. Taylor Edward C., Maryanoff Cynthia A., Skotnicki Jerauld S., J. Org. Chem., 1980,

45 (12), 2512.

10. Olagbemiro, T. O., Nyakutse, C. A., Lajide, L., Agho, M. O., Chukwu, C. E., Bull.

Soc. Chim. Belg., 1987, 96 (6), 473. 11. Ruth, E. TenBrink, Wha, B. Im, Vimala, H. Sethy, Andrew, H. Tang and Don, B. Carter, J. Med. Chem., 1994, 37, 758. 12. Ploechi; Chem. Ber., 1886, 19, 10. 13. Bjorn C. G. Sederberg, Jeffery M. Wallace and Joaquin Tamariz; Org. Lett.; 2002, 4 (28), 1339.

14. De La Fuente, Julio R., Canete Alvaro, Zanocco Antonio L., Saitz Claudio, Jullian Carolina., J. Org. Chem., 2000, 65 (23), 7949. 15. (a) Laurinvicius Valdas, Krutinatiene Bogumila, Liauksminas Virgnijus, Puodziunatie Benedikta Janciene., Monatsh Chem., 1999, 130 (10), 1269. (b) Smith., J. Org. Chem., 1959, 24, 205.

139

CHAPTER –V STUDIES ON SYNTHESIS OF “OXAZOLO QUINOLINES”

5.1 INTRODUCTION: Hexahydro-oxazolo[3,2-a]pyridine (60) or tetrahydro-oxazolo[3,2-a]pyridine (61) is a fused heterocycle, in which piperidine or tetrahydropyridine is fused with 1.3-oxazole in an angular fashion. These moieties are frequently found to be an integral part of many biologically active molecules, synthetically important compounds and natural products.1-8

N

(60)

O

N

O

(61) 140

A number of such structures and their use in different therapeutic areas have been listed below in Table – 5.1. Hexahydro-oxazolo[3,2-a]pyridine (60) is an integral part of Atisine (62),1 which is a natural product (aconite alkaloid). Oxazole derivative 64 was used as starting material for synthesis of Salsolidine9 which is an isoquinoline alkaloid found to posses anti tumor activity. Table – 5.1: Some known Oxazolopyridines / Isoquinolines.

S.No.

Structure of derivative OH

1.

N

Importance

Ref.

Atisine Alkaloid

1

O

(62) 2.

2 N O

(63) 3.

O

Starting material for N

O

Ph

O

3

(R)-(+) Salsolidine Anti tumor

(64) CO2Et

4.

HO

N

4

O

Ph

(65) 5.

5 N O

(66)

141

6.

6 N

O

Ph

(67) 7.

(-)-Pumiltoxin NC

N

7

Natural product

O

Ph

(68)

Oxazolo[2,3-a]tetrahydroisoquinoline (64) was synthesized starting from 6,7dimethoxy-1-methyl-isochroman (69) which gives 70 in the presence of bromine in CCl4. The latter on stirring with D-phenylglycinol (71) in the presence of triethylamine as base at -78 °C gives compound 64.3 This compound 64 is useful as key intermediate for the synthesis of isoquinoline alkaloid i.e. Saisolidine (72). (Equation - 5.1) NH2 O

Br2, CCl4 O

O

80°

O

Br

O

CHO (70)

(69)

Ph

OH (13)

Et3N

O

O N

O (64)

Ph

NH

O

O

(72)

Me

(R)-(+) Saisolidine

Equation - 5.1

3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-carbonitrile (68)6-7 was prepared by condensation of phenylglycinol (71) with glutaraldehyde (73) in the presence of potassium cyanide to give compound 68 via piperidine intermediate (681). (Equation 5.2)

142

Ph

OH

CHO CHO

KCN

NH2

NC

(71)

N

(73) Ph

O

NC

N

O

Ph (68)

(681)

Equation - 5.2

Synthesis of compound 65 was achieved starting from 68. Reacting it with alumina (Al2O3) and DEAD (diethyl acetylenedicaboxylate) in ethanol was refluxed to give

8-Hydroxy-1-phenyl-1,2,4,5-tetrahydro-3aH-oxazolo[3,2-a]quinoline-6-carboxylic

acid ethyl ester (65).4 (Equation - 5.3) Ph NC

Ph N

O HCN

CO2Et OH

N

Al2O3 DEAD HO

(68)

(74)

N (65) Ph

O

Equation - 5.3

5.2 Present Work: Survey of literature thus, revealed that different oxazolo isoquinolines have shown diverse types of biological activities and these are used in synthesis of some other natural products. Therefore, it was considered desirable to prepare new compounds containing oxazolo quinolines. Not much information is found in literature in the area of oxazolo quinolines. It is conceivable that these oxazolo moieties can be synthesized from 2-nitro benzaldehyde by condensation with phenylacetic acid and followed by reductive cyclization in the presence of hydrogen gas over palladium carbon to yield quinolines in the first step. These can be used as building blocks for the further structural modification leading to fused oxazolo ring units.

5.3 Results and Discussion:

143

Commercially

available

2-nitrobenzaldehyde

(75)

was

reacted

with

triphenylphosphine ylide (76) in benzene to obtain ethyl (E)-3-(2-nitrophenyl)-2propenoate (77 a, i.e. R = H) in 90.0 % yield (Equation – 5.4). 77a is a compound known9 in literature. However, it was further characterized in the present work by spectral and analytical data. Thus, its IR spectrum the absence of absorption at 1650 cm-1 typical of the aromatic aldehyde group. However, the IR spectrum showed (Fig 5.1) a peak at 1716 cm-1, which was assigned to ester carbonyl stretching. Its 1H NMR (in CDCl3) showed signals (Fig 5.2) at δ 8.14 – 8.02 (m, 2H), 7.65 – 7.63 (m, 1H), 7.58 – 7.49 (m, 2H), 6.36 (d, J = 15.7 Hz, 1H), 4.34 – 4.23 (q, J = 7.30 Hz, 2H), 1.31 (t, J = 7.30 Hz, 3H). Its mass spectrum (Fig 5.3) showed the molecular ion peak at 222 ((M+ +1, 100 %), and other peaks at m/z 192 (30 %), 176 (40 %, indicative of loss of ethoxy). O CHO + Ph3P=CHCO2Et (75)

NO2

Benzene 80 0C, 6.0 hrs

(76)

OEt NO2 (77a)

Equation – 5.4 In order to prepare the intermediate 77b, 2-nitrobenzaldehyde (75) was reacted with phenylacetic acid (4) in the presence of triethylamine and acetic anhydride10 to give (E)-2-phenyl-3-(2-nitrophenyl)-2-propenoic acid (77b) in 65.0 % yield. (Equation – 5.5) The structure of 77b was confirmed by its analytical and spectral data. Thus, its IR showed a peak at 1683 cm-1 indicative of carbonyl group, which has been assigned to COOH group.

Its 1H NMR (in DMSO d6) showed signals at 12.96 (bs, 1H, D2O

exchangeable), 8.10 - 8.05 (m, 1H, Ar H), 7.47 – 7.43 (m, 1H, Ar H), 7.20 (s, 1H), 7.08 – 7.07 (m, 1H, Ar H), 6.97 – 6.93 (m, 1H, Ar H). Its mass spectrum showed peaks at 254 (M+ +1) and 240 (100 %).

144

CO2H Ac2O, Et3N

CHO +

CO2H NO2

NO2 (4)

(75)

(77b)

Equation – 5.5

In order to prepare another intermediate 77c, 2-nitrobenzaldehyde (75) was reacted with 4-methoxyphenylacetic acid (13) in the presence of triethylamine and acetic anhydride to give (E)-2-(4-methoxyphenyl)-3-(2-nitrophenyl)-2-propenoic acid (77c) in 65.0 % yield. (Equation – 5.6) The structure of 77c was confirmed by its analytical and spectral data. Thus, its IR showed peak at 1686 cm-1 due to the carbonyl stretching. Its 1

H NMR (in DMSO d6) showed signals at 8.17 (s, 1H, Ar H), 8.10 – 8.08 (dd, J = 2.42 &

5.37 Hz, 1H, Ar H), 7.37 - 7.33 (m, 2H, ArH), 7.07 (d, J = 8.86 Hz, 2H, ArH), 6.99 – 6.95 (m, 1H, Ar H), 6.76 (d, J = 8.60 Hz, 2H, ArH), 3.76 (s, 3H). Its mass spectrum showed peak at 300 (M+1, 100 %). OMe

CO2H Ac2O, Et3N

CHO +

CO H NO2 2

NO2 OMe (75)

(77c)

(13)

Equation – 5.6 Ethyl (E)-3-(2-nitrophenyl)-2-propenoate (77 a) was reduced with hydrogen gas over 10 % palladium on charcoal in acetic acid at room temperature11 to give 1,2,3,4tetrahydro-2-quinolinone (78a) in 97.0 % yield, (Equation – 5.7) which was characterized by analytical and spectral data. Thus, its IR (KBr) spectrum showed (Fig 5.4) a peak at 3440 cm-1 which may be assigned to –NH- stretching vibration, and a strong peak at 1680 cm –1 in the carbonyl region which may be assigned to the amide carbonyl grouping. Its 1

H NMR (in CDCl3) showed (Fig 5.5) three aromatic signals at δ 8.79 (bs, 1H, D2O

exchangeable), 7.14 (d, J = 7.0 Hz, 2H), 6.99 (d, J = 7.0 Hz, 1H), 6.81 (d, J = 7.0 Hz,

145

1H), and other signals at 2.97 (t, J = 7.0 Hz, 2H), 2.68 (d, J = 7.0 Hz, 2H). Its mass spectrum (Fig 5.6) showed peaks at m/z 148 (M+ +1, 100 %). 10 % Pd-C CO Et NO2 2

N H

H2, 60 PSI

(77a)

O

(78a)

Equation – 5.7 Substituted 2-quinolinones (78 b and c) were prepared in the similar manner as above.12 The structures for these products were assigned on the basis of analogy and on the basis of analytical and spectral data. (Table –5.2) R

R 10 % Pd-C CO H NO2 2

N O H (78b-c)

H2, 60 PSI

(77b-c)

Equation – 5.8 Table 5.2: Synthesis of 78 from 77 and their spectral Data: Sub.

Pdt.

R

Yield %

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr) / cm-1.

77b

78b

H

65.0

IR (KBr): 3210 cm-1 (amide –NH- band), 1680 cm-1 (amide carbonyl stretching);

1

H NMR (DMSO d6, 200 MHz):

δ10.31 (bs, 1H, D2O exchangeable, NH), 7.23 – 7.14 (m, 7H, Ar H), 6.90 – 6.87 (m, 2H, Ar H), 3.80 (t, J = 7.3 Hz, 1H, PhCH), 3.15 (d, J = 7.30 Hz, 2H, Ph CH2); Mass: m/z 224 (M+1, 100 %). 77c

78c

OMe 67.0

IR (KBr): 3208 cm-1 (amide –NH- band), 1678 cm-1 (amide carbonyl stretching); 1H NMR (DMSO d6, 200 MHz): δ 8.39 (bs, 1H, D2O exchangeable, NH), 7.18 – 7.15 (m, 5H, Ar H),7.03 – 6.95 (m, 1H), 6.87 – 6.75 (m, 2H, Ar H), 3.85 – 3.72 (m, 1H, PhCH), 3.77 (s, 3H, OMe), 3.23 (d, J = 7.70

146

Hz, 2H, Ph CH2); Mass: m/z 254 (M+1, 100 %). 1,2,3,4-tetrahydro-2-quinolinone (78a) was treated with ethyl 2-bromoacetate in the presence of potassium carbonate in DMF at 80 °C for 9 hrs. Processing of the reaction mixture gave a product (68 %) which was found to be 79a in 50 % yield (Equation 5.9) it was characterized by spectral methods. Thus, its IR spectrum showed no absorption above 3000 cm-1 indicating absence of any –NH- grouping. However, the IR spectrum (Fig 5.7) showed two strong sharp bands, one at 1743 cm-1 and the other at1688 cm-1. The former has been assigned to ester carbonyl grouping and other assigned to amide carbonyl grouping. Thus, its 1H NMR spectrum (Fig 5.8) displayed signals at δ 7.2117(m, 2H, Ar - H), 7.03 (d, J = 7.3 Hz, 1H, Ar-H), 6.75 (d, J = 7.3 Hz, 1H), 4.66 (s, 2H, N-CH2), 4.27 – 4.16 (q, J = 7.30 Hz, 2H, O – CH2CH3), 2.95 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H, O – CH2CH3) while the mass spectrum (Fig 5.9) showed m/z 234 (M+ +1, 100 %). BrR1CHCO2Et N H

O

N

K2CO3 (79a)

(78a)

O CO2Et

Equation – 5.9

147

Substituted 1,2,3,4-tetrhydro-2-oxo-quinolinone-1-acetic acid ethyl esters (79a-k) could also be prepared using the above method. Structures of all products 79a – k (Equation 5.10) have been assigned on the basis of analogy and on the basis of spectral & analytical data (Table – 5.3). R N H

R BrR1CHCO2Et

O

K2CO3

N R1

O CO2Et

(79a-k)

(78a-c)

Equation – 5.10 Table 5.3 Synthesis of 79 (a-k) from 78 (a-c) and data: Sub.

Pdt.

R

R1

Yield %

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr) / cm-1.

78b

79b

Ph

H

54

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1748 cm-1 and amide carbonyl appeared at 1681 cm-1; 1

H NMR (CDCl3): δ 7.26 (s, 5H), 7.17 (d, J = 10 Hz,

2H), 7.01 (t, J = 7.32 Hz, 1H), 6.80 (d, J = 8.10 Hz, 1H), 4.84 – 4.61 (q, J = 17.46 Hz, 2H), 4.28 – 4.18 (q, J = 7.25 Hz, 2H), 3.96 (t, J = 6.72 Hz, 1H), 1.25 (t, J = 7.25 Hz, 3H); Mass: m/z 310 (M+ +1, 100 %). 78b

79c

Ph

Me

49

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1742 cm-1 and amide carbonyl appeared at 1677 cm-1; 1

H NMR (CDCl3): δ 7.30 – 6.79 (m, 9H), 5.07 – 4.97

(m, 1H), 4.26 – 4.08 (m, 2H), 3.80 – 3.74 (m, 1H), 3.39 – 3.20 (m, 1H), 3.18 – 3.04 (m, 1H), 1.57 – 1.43 (m, 3H), 1.28 – 1.12 (m, 3H); Mass: m/z 324 (M+1, 100 %). 78b

79d

Ph

Et

51

IR (KBr): no absorption above 3000 cm-1 indicating

150

absence of –NH- grouping. Ester carbonyl appeared at 1738 cm-1 and amide carbonyl appeared at 1676 cm-1; 1

H NMR (CDCl3): δ 7.28 – 6.78(m, 9H), 5.15 – 5.08

(m, 1H), 4.28 – 4.10 (m, 2H), 3.91 – 3.83 (m, 1H), 3.33 – 2.88 (m, 1H), 2.35 – 2.19 (m, 1H), 2.15 – 2.00 (m, 1H), 1.28 – 1.20 (m, 3H), 1.10 – 0.97 (m, 3H); Mass: m/z 338 (M+ +1, 100 %). 78c

79f

Ar

H

57

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1735 cm-1 and amide carbonyl appeared at 1678 cm-1; 1

H NMR (CDCl3): δ 7.26 – 7.16 (m, 5H, ArH), 7.05 –

7.01 (m, 1H), 6.85 – 6.77 (m, 2H), 4.84– 4.59 (q, J = 17.46 Hz, 2H, NCH2), 4.28 – 4.17 (q, J = 6.98 Hz, 2H, O – CH2CH3), 3.95 – 3.88 (m, 1H), 3.75 (s, 3H, OCH2), 3.25 – 3.20 (m, 2H), 1.25 (t, J = 6.98 Hz, 3H, O – CH2CH3); Mass: m/z 340 (M+, 100 %). 78c

79g

Ar

Me

56

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1739 cm-1 and amide carbonyl appeared at 1670 cm-1; 1

H NMR (CDCl3): δ 7.26 – 7.08 (m, 5H, ArH), 7.03 –

6.74 (m, 4H), 5.38 – 5.31 (m, 1H), 4.27 – 4.10 (m, 2H, O – CH2CH3), 3.95 – 3.89 (m, 1H), 3.73 (s, 3H, OCH2), 3.35 – 3.03 (m, 2H), 1.69 – 1.62 (m, 3H), 1.26 (t, J = 7.33 Hz, 3H, O – CH2CH3); Mass: m/z 354 (M+, 100 %). 78c

79h

Ar

Et

62

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1737 cm-1 and amide carbonyl appeared at 1676cm-1; 1

H NMR (CDCl3): δ 7.26 – 7.12 (m, 4H, ArH), 7.06 –

151

7.02 (m,1H), 6.98 – 6.74 (m, 3H), 5.47 – 5.12 (m, 1H), 4.28 – 4.10 (m, 2H), 3.99 – 3.81 (m, 1H), 3.73 (s, 3H, OCH2), 3.35 – 3.08 (m, 2H), 2.35 – 2.04 (m, 2H), 1.20 (t, J = 6.98 Hz, 3H, O – CH2CH3), 0.88 (t, J = 7.3 Hz, 3H); Mass: m/z 368 (M+, 100 %). 78c

79i

Ar

Pr

49

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1737 cm-1 and amide carbonyl appeared at 1676cm-1; 1

H NMR (CDCl3): δ 7.26 – 7.12 (m, 4H, ArH), 7.05 –

7.02 (m,1H), 6.98 – 6.74 (m, 3H), 5.47 – 5.12 (m, 1H), 4.28 – 4.10 (m, 2H), 3.99 – 3.81 (m, 1H), 3.73 (s, 3H, OCH2), 3.35 – 3.08 (m, 2H), 2.35 – 2.04 (m, 2H), 1.21 – 1.18 (t, J = 6.98 Hz, 3H, O – CH2CH3), 0.92 – 0.85 (m, 3H); Mass: m/z 411 (M+, 100 %). 78c

79j

Ar

Hex

46

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1737 cm-1 and amide carbonyl appeared at 1677cm-1; 1

H NMR (CDCl3): δ 7.26 – 7.10 (m, 4H, ArH), 7.05 –

7.02 (m,1H), 6.91 – 6.74 (m, 3H), 5.53 – 5.46 (m, 1H), 4.27 – 4.10 (m, 2H, O – CH2CH3), 3.98 – 3.81 (m, 1H), 3.73 (s, 3H, OCH2), 3.36– 3.12 (m, 2H), 2.34 – 2.05 (m, 2H), 1.23 – 1.14 (m, 11), 0.98 – 0.84 (m, 3H); Mass: m/z 424 (M+, 100 %). 78c

79k

Ar

Ph

49

IR (KBr): no absorption above 3000 cm-1 indicating absence of –NH- grouping. Ester carbonyl appeared at 1747 cm-1 and amide carbonyl appeared at 1667 cm-1; 1

H NMR (CDCl3): δ 7.34 – 7.26 (m, 5H, ArH), 7.22 –

7.06 (m, 4H, ArH), 7.02 – 6.86 (m, 2H, ArH), 6.83 – 6.72 (m, 2H, ArH), 3.86 – 3.83 (m, 1H), 3.80 (s, 3H),

152

3.75 (s, 3H), 3.40 – 3.20 (m, 2H). Mass: m/z 402 (M+ 100 %), 369 (20 %), 342 (20 %) Ar = 4-methoxyphenyl

153

Reductions with Lithium Aluminum Hydride (LAH): Treatment of 79a with 1.1 eq. of LAH in THF followed by simple processing gave a product, which was obtained as a syrupy liquid. The compound was found to be homogenous on TLC. Its IR spectrum (Neat) did not show any diagnostic peaks due to of –NH- and -CO- groups (Fig 5.10). Its 1H NMR (400 MHz, in CDCl3) showed (Fig 5.11) signals at δ 7.12 – 7.10 (m, 1H), 7.08 – 6.99 (m, H), 6.68 – 6.64 (m, 1H), 6.52 – 6.50 (d, J = 7. 0 Hz, 1 H), 4.850 – 4.82 (dd, J = 1.9 & 7.9 Hz, 1H), 4.22 – 4.17 (m, 1H), 4.01 – 3.95 (m, 1H), 3.51 – 3.46 (m, 1H), 3.38 – 3.34 (m, 1H), 2.84 – 2.74 (m, 1H), 2.29 – 2.23 (m, 1H), 1.69 – 1.43 (m, 2H). Its mass spectrum showed (Fig 5.12) peaks at m/z 175 (M+, 30 %), 174 (40 %), 149 (70 %), 135 (40 %), 125 (75 %), 97 (100 %). Based on this data, the product was assigned as 1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2a]quinoline (80a). (Equation – 5.11) LAH, THF N (79a)

O

0 °C - r.t, 1.0 hr

CO2Et

N

O

(80a)

Equation – 5.11 The above reaction of 79a yielding 80a seems to be general one. It has been extended to other substituted 1,2,3,4-tetrhydro-2-oxo-quinolinone-1-acetic acid ethyl esters (79a-k) yielding 80a-k. (Equation – 5.12) R N R1

O

R

LAH, THF 0 °C - r.t, 1.0 hr

CO2Et

N

O

R1 (80a-k)

(79a-k)

Equation – 5.12

154

Table 5.3 Synthesis of 80 (a-k) from 79 (a-k) by reduction with LAH and their spectral characteristics. Sub.

Pdt.

R

R1

Yield %

Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm-1.

79c

80c

Ph

Me

65

IR: Did not show any diagnostic peaks due to –NHand -CO- groups. 1H NMR (CDCl3): δ 7.43 – 7.21 (m, 5H, ArH), 7.17 – 6.99 (m, 2H, ArH), 6.70 (t, J = 7.32 Hz, 1H, ArH), 6.56 (d, J = 7.81 Hz, 1H, ArH), 4.92 (d, J = 8.79 Hz, 1H), 4.27 (t, J = 6.83 Hz, 1H), 4.03 – 3.90 (m, 1H), 3.57 (t, J = 5.86 Hz, 1H), 3.43 (t, J = 7.81 Hz, 1H), 3.19 – 2.93 (m, 1H), 2.87 – 2.69 (m, 1H), 1.44 (s, 3H); Mass: m/z 266 (M+, 100 %).

79d

80d

Ph

Et

52

IR: Did not show any diagnostic peaks due to –NHand -CO- groups. 1H NMR (CDCl3): δ 7.37 – 7.26 (m, 5H), 7.16 – 7.01 (m, 2H), 6.98 – 6.83 (m, 1H), 6.67 – 6.59 (m, 1H), 5.00 – 4.87 (m, 1H), 4.26 – 4.22 (m, 1H), 3.85 – 3.81 (m, 1H), 3.65 – 3.61 (m, 1H), 3.38 (m, 1H), 3.07 – 3.00 (m, 1H), 2.88 – 2.75 (m, 1H), 1.89 – 1.86 (m, 1H), 1.64 – 1.61 (m, 1H), 1.00 – 0.85 (m, 3H); Mass: m/z 280 (M+, 100 %).

79f

80f

Ar

H

58

IR: Did not show any diagnostic peaks due to –NHand -CO- groups. 1H NMR (CDCl3): δ 7.26 – 7.17 (m, 4H), 7.07 (d, J = 7.52 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.69 (t, J = 7.30 Hz, 1H), 6.55 (d, J = 7.82 Hz, 1H), 4.86 (d, J = 8.79 Hz, 1H), 4.31 – 4.23 (m, 1H), 3.99 – 3.90 (m, 1H), 3.82 (s, 3H), 3.57 – 3.52 (m, 1H), 3.46 – 3.34 (m, 1H), 3.5 (d, J = 13.70 Hz, 1H), 2.91 (d, J = 3.90 Hz, 1H), 2.75 – 2.64 (m, 1H); Mass: m/z 282 (M+, 100 %), 270 (30 %), 240 (20 %)

155

and 216 (30 %). 79g

80g

Ar

Me

49

IR: Did not show any diagnostic peaks due to –NHand -CO- groups. 1H NMR (CDCl3): δ 7.30 – 7.17 (m, 4H), 7.09 – 7.02 (m, 1H), 6.95 – 6.78 (m, 2H), 6.72 – 6.57 (m, 1H), 4.97 – 4.92 (d, J = 9.80 Hz, 1H), 4.32 (t, J = 7.4 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.94 – 3.88 (m, 1H), 3.82 (s, 3H), 3.55 – 3.57 (m, 1H), 3.34 – 3.23 (m, 1H), 3.09 – 3.01 (m, 1H), 2.98 – 280 (m, 1H), 2.77 – 2.65 (m, 1H), 1.41 – 1.27 (m, 3H); Mass: m/z 296 (M+, 100 %).

79h

80h

Ar

Et

52

IR: Did not show any diagnostic peaks due to –NHand -CO- groups. 1H NMR (CDCl3): δ 7.34 – 7.14 (m, 4H), 7.09 – 7.03 (m, 1H), 6.96 – 6.84 (m, 2H), 6.73 – 6.60 (m, 1H), 4.96 – 4.80 (m, 2H), 4.28 (t, J = 7.8 Hz, 1H), 4.03 – 3.87 (m, 1H), 3.82 (s, 3H), 3.77 – 3.59 (m, 1H), 3.48 – 3.38 (m, 1H), 3.09 – 3.01 (m, 1H), 2.99 – 266 (m, 2H), 1.98 – 1.81 (m, 1H), 1.77 – 1.46 (m, 1H), 1.02 – 0.95 (m, 3H); Mass: m/z 310 (M+, 100 %).

79j

80j

Ar

Hex

45

IR: Did not show any diagnostic peaks due to –NHand -CO- groups. 1H NMR (CDCl3): δ 7.34 – 7.18 (m, 4H), 7.14 – 7.05 (m, 1H), 7.02 – 6.80 (m, 2H), 6.72 – 6.59 (m, 1H), 4.95 – 4.85 (m, 2H), 4.26 – 4.23 (m, 1H), 3.81 (s, 3H), 3.61 (t, J = 7.8 Hz, 1H), 3.42 – 3.34 (m, 1H), 3.27 – 3.04 (m, 1H), 2.97 – 271 (m, 2H), 1.86 – 1.79 (m, 1H), 1.58 – 1.55 (m, 1H), 1.34 (m, 6H), 0.93 – 0.81 (m, 3H); Mass: m/z 366 (M+, 100 %).

Ar = 4-methoxyphenyl

156

157

5.4 Experimental procedure: i) Preparation of 77a: A mixture of 2-nitrobenzaldehyde (75, 5.0 gms, 33 mmol) and triphenylphosphine ylid (76, 13.8 gms, 39 mmol) in benzene (150 mL) was refluxed for 24 hours at 80 °C. Then the mixture was cooled to r.t, adsorbed over silica gel and purified through column chromatography to give pure 77a as thick liquid (5 gms, 71 %).

ii) Preparation of 77b and c (General procedure): A mixture of 2-nitrobenzaldehyde (75, 20.0 gms, 131.11 mmol), phenylacetic acid (197.35 mmol of 4 or 13), acetic anhydride (67.0 mL, 657 mmol) and triethylamine (18.0 mL, 131.11) were refluxed at 90 °

C for 15 min. The solution was cooled, the separated solid was filtered and washed with

mixture of water-acetic acid to give 77a & b, yield of 77a 28 gms (79 %); yield of 77b 32 gms (82 %)

iii) Preparation of 78a-c (General procedure): 10 % palladium carbon (1.0 gm/10.0 gms of substrate) was charged in hydrogenation flask, made wet with acetic acid (10 mL/1.0 gm of substrate) and to this 78a-c (1.0 gm, in10 mL of acetic acid) was added at room temperature. Then the flask was arranged for parr hydrogenation for 6 hrs at 60 psi H2 pressure.

The reaction mixture was filtered through a pad of Celite to remove

palladium carbon and the filter bed washed with acetic acid. The filtrate was stirred with water (100 ml/1.0 gm substrate) and the separated white solid was filtered, washed with water and dried to give 78a-c. (Table-5.1)

iv) Preparation of 79a-k (General procedure): To a solution of 78 a – c (1.0 eq) and potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2alkyl acetate (1.2 eq) drop wise at room temperature. After 24.0 hrs stirring, the mixture was poured in to water and the separated solid was filtered, washed with water and dried to give 79a-k. (Table-5.2)

158

v) Preparation Of 80a – k (General procedure): To a solution of 79a – k (2.0 mmol) in dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The reaction mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was filtered and the filtrate concentrated.

The crude product was purified by column

chromatography using ethyl acetate and pet. Ether (5:95) to give 80a – k (Table-5.3).

5.5 References: 01. (a) Pellettier, S. W., Walter A. Jacobs. J. Amer. Chem. Soc. 1954, 76, 4496. (b) Pellettier, S. W., David M. Locke. J. Amer. Chem. Soc. 1965, 87 (4) 761. (c) Pellettier, S. W., Parthasarathi, P. C. J. Amer. Chem. Soc. 1965, 87 (4) 777. (d) Pellettier, S. W., Naresh V. M., Haridutt K. D., Janet Finer-Moore, Jacek Nowacki, and Balawant S. J., J. Org. Chem., 1983, 48 (11), 1787. (e) Naresh V. M., Pellettier, S. W., Tetrahedron; 1978, 34, 2421.(f) Pellettier, S. W. and Walter A. J., J. Amer. Chem. Soc. 1956, 78, 4144. 02. Crist N. Filer, Felix E. Granchelli, Albert H. Soloway and John L. Neumeyer.

J. Org. Chem., 1978, 43 (4), 672.

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03. (a) Spath, E.; Dengel, F. Chem. Ber., 1938, 71B, 113. (b) Masatoshi, Y.; Kuniko, H.; Shigetaka, I. and Nazmul, Q. Tetrahedron Letters; 1988, 29 (52), 6949. 04. (a) Trevor, A. Crabb and Asmita V. Patel. Heterocycles. 1994, 37 (1), 431. (b) Marie-Christine Lallemand; Mathieu Gaillard; Nicole Kunesch and HenriPhilippe Husson. Heterocycles. 1998, 47 (2), 747. (c) Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A. I. Arkivoc, 2003, xiii, 166. 05. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A. I. Arkivoc, 2003, xiii, 166. 06. (a) Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (b) Lue Guerrier, Jacques Royer, David S. Grierson and Henri-Philippe Husson. . J. Amer. Chem. Soc. 1983, 105, 7754. (c) Mercedes Amat, Nuria Llor, Carmen Escolano, Marta Huguet, Maria Perez, Elies Molins and Joan Bosch. Tetrahedron Asymmetry; 2003, 14, 293. (d) Teran, J. L. Gnecco, D. Galindo, A. Juarez, J. Bernes, S. and Enriquez, R. G. Tetrahedron Asymmetry; 2001, 12, 357. 07. (a) Mercedes, A.; Nuria, L.; Carmen, E.; Marta, H.; Maria, P.; Elies, M and Joan, B.; Tetrahedron Asymmetry; 2003, 14, 293. (b) Jean-Charles, Q.; David S. G.; Jacques, R and Henri-Philippe H.; Tetrahedron Letters; 1988, 29 (27), 3311. (c) Lue, G.; Jacques, R.; David S. G and Henri-Philippe Husson. . J. Amer.

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CONCLUSIONS & HIGHLITS A simple method has been developed for the synthesis of Novel tricyclic oxazolo or oxazine derivatives, This method represents a good example of reductive cyclization with lithium aluminumhydride. The oxazolo compounds are structural mimics of some known biologically active molecules. Preparation of starting materials (benzothiazin-3-ones and quinoxaline-2-ones) in this work was made by the method of high-speed parallel synthesizer using microwaves and water as solvent. Intense use has been made of chromatographic methods to isolate products in a state of high purity. Intense use has been made of spectroscopic methods and X-ray diffraction technique to assign structures for products to the highest accuracy and detail.

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APPENDIX – LIST OF PUBLICATIONS 1. Novel Method for the preparation of Tricyclic [6:6:5] systems by Reductive Cyclization with Lithium Aluminum Hydride (LAH). B. B. Lohray, V. B. Lohray, A. Sekar Reddy, V. Venugopal Rao.

Indian .J. Chem., Vol. 39B, April 2000, pp. 297 – 299. 2.

7-nitro-1,2,3a,4-tetrahyfrobenzo[b][1,3]oxazolo[3,2-d]oxazine: A new heterocycle. S. Vishnuvardhan Reddy, A. Sivalaxmi Devi, K. Vyas. Venugopal Rao

Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey.

32nd National Seminar on Crystallography, October 24 – 26, 2002. Jammu, INDIA. (Poster Presentation) 3. 7-nitro-1,2,3a,4-tetrahyfrobenzo[b][1,3]oxazolo[3,2-d]oxazine: A new heterocycle. S. Vishnuvardhan Reddy, A. Sivalaxmi Devi, K. Vyas.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey.

Acta Cyrstallographia E, 2003, E359 4. One pot and High-Speed Parallel Synthesis of Substituted 3,4-dihydro-2Hbenzo[b][1,4]thiazine-3-ones And 1,2,3,4-tetrahydro-2-quinoxalinones.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey.

Pharmacophore, January 16-17, 2004, Hyderabad. INDIA. (Poster Presentation) 5. Novel method for the preparation of poly cyclic [6:6:5], [6:6:6] and [6:6:7:6] systems by reductive cyclization with LAH.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey.

IUPAC – BNP – 2004. January 26 – 31, 2004, New Delhi, INDIA.

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(Poster Presentation) 6. One pot and High-Speed Parallel Synthesis of Substituted 3,4-dihydro-2Hbenzo[b][1,4]thiazine-3-ones And 1,2,3,4-tetrahydro-2-quinoxalinones.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey. (J. Org. Chem., Will be communicated) 7. Novel method for the preparation of tri cyclic [6:6:5] oxazolooxazines, oxazolothiazines, oxazoloquinoxalines and oxazoloquinolines by reductive cyclization with LAH.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey. (J. Org. Chem., Will be communicated) 8. Novel method for the preparation of poly cyclic [6:6:6] [6:7:5]and [6:6:7:6] systems by reductive cyclization with LAH.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and Pramod Kumar Dubey. (J. Org. Chem., Will be communicated)

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