Synopsis For Ph.d Thesis

SYNOPSIS OF THE Ph.D THESIS “A SYSTEMATIC INVESTIGATION FOR THE PREPARATION OF TRICYCLIC [6:6:5] OXAZOLO DERIVATIVES BY REDUCTIVE CYCLIZATION WITH LAH”

by VENUGOPAL RAO VEERAMANENI, M.Sc.

Research Supervisor: Dr. Venkateswarlu Akella (Dr. Reddy’s Research Foundation, Hyderabad) Research Co-Supervisor: Dr. Pramod Kumar Dubey (J.N.T. Univ., Hyderabad)

Submitted to

JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD, (A.P) INDIA JANUARY - 2004

Oxazole (LXXXVIII) is a five membered heterocycle, which contains one oxygen and one nitrogen as heteroatoms in 1 and 3 positions. 2 3N

O1

4

5

(LXXXVIII)

The oxazolo moiety is frequently found to be an integral part of many biologically active molecules and natural products. Oxazole moiety may also be found in fusion with other heterocycles such as pyridines, piperidines, indoles, quinolines, benzoxazines, pyrimidines, naphthyridines, quinazolines etc. The oxazole ring is an integral part of bioactive compounds such as HIV-1 inhibitors, antitumor agents, antihypertensive agents, antibacterial agents, gastric antisecretory agents, compounds used in the treatment of congenital disorders and other interesting synthetic compounds. The present work involves studies on reductive cyclization using lithium aluminumhydride with various carboxamido esters yielding oxazolo compounds. The thesis consists of five Chapters; first one being introductory chapter deals with Literature Survey describing synthesis of oxazolo derivatives by known methods and the remaining four are Experimental Chapters. CHAPTER – I: INTRODUCTION AND LITERATURE SURVEY This chapter deals with the introductory aspects, Literature Survey and use of Lithium aluminum hydride as a reducing agent an fused oxazoles several of which are biologically important molecules. CHAPTER – II: STUDIES ON SYNTHESIS OF OXAZOLO THIAZINES This chapter describes facile synthesis of substituted tricyclic-6.6.5-oxazolo thiazines (16). This was achieved as follows:Commercially available 2-aminothiophenol (1) was treated with chloroacetic acid in the presence of sodium hydroxide to obtain 1,4-benzothiazine-3(4H)-one (2). The latter on treatment with ethyl 2-bromoacetate in the presence of potassium hydroxide in acetone at 60 °C for 30 min. gave a product which was found to be 3. Treatment of 3 with 1.1 eq. of LAH in THF followed by simple processing gave the oxazolothiazines 16.

KOH, BrR2CHCO2Et, Acetone, 60 °C, 30 - 45 min

BrRR1CCO2Et, NaOH, H2O 80 0C, 1 h, 68 - 93 % SH

S

NH2

N H

BrRR1CCO2Et, NaOH, H2O MW, 4 - 5 min, 70 - 90 %

(1)

R

S

R1

N

O K2CO3, BrR2CHCO2Et, Acetone, 60 °C, 6 - 12 hrs

(2)

R

R1

O

S

LAH THF, 0 °C - r.t 1 hr

OEt

R2

R1

O

R2 (16)

O

(3)

N

R

(R = H, Me, Et, Pr, iPr, Hexyl, Aryl; R1 = H, Me; R2 = H, Me, Et, Pr, iPr, Hexyl, Phenyl) Structures of oxazolothiazines 16 prepared were confirmed by analytical & spectral data. Reaction conditions were optimized by differing equivalents of LAH and various other reducing reagents. CHAPTER – III: STUDIES ON SYNTHESIS OF OXAZOLO OXAZINES This chapter describes facile synthesis of substituted tricyclic 6,6,5 oxazolo oxazines (42). This was carried as follows:o-Nitrophenol (36) was treated with ethyl 2-bromoacetate in the presence of potassium carbonate as a base to obtain ethyl 2-(2-nitrophenoxy)acetate (37), which on reduction with hydrogen in the presence of 10 % Pd- C gave 38. The latter on treatment with ethyl 2-bromoacetate in the presence of potassium carbonate in DMF at 80 °C gave 3,4 dihydro-3-oxo-2H-1,4-benzoxazine –4acetic acid ethyl esters (41). Treatment of 41 with 1.1 eq. of LAH in THF followed by usual workup gave the requisite substituted tricyclic[6.6.5]oxazolooxazines (42). 1) BrCH2CO2Et, K2CO3, DMF R OH 80 °C, 4.0 h

R 1

R

(36)

NO2

2) 10 % Pd-C, R1 AcOH 60 PSI, H2. 6 h

(38)

O

BrCHR2CO2Et, K2CO3, DMF R 80 °C, 4.0 h

O

N H

O

R1

N

(41)

LAH THF

R

1h, r.t R1 O OEt

R2

O

(42)

N

O

R2

O

(R = H, F, Me, SMe, SO2Me; R1 = H, F, Me; R2 = H, Aryl; R3 = H, Me, Et, Pr, Hex and Substituted Aryls) In this chapter is explained the effect of substitution on the aromatic ring during reductive cyclization and the structure was confirmed by single crystal XRD.

CHAPTER – IV: STUDIES ON SYNTHESIS OF OXAZOLO QUINOXALINES Studies on synthesis of tricyclic oxazolo[3.2-a]quinoxalines (59) are described in this chapter. o-phenylenediamine (55) was treated with ethyl 2-bromo acetate in DMF in the presence of microwave irradiation for 5.0 min to obtain substituted 3,4-Dihydro-1H-quinoxalin-2-ones (56). The latter on treatment with alkyl/aryl bromides in the presence of sodium carbonate in aq.ethanol gave 4benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57), which was alkylated with ethyl 2-bromoacetate in the presence of K2CO3 as base in DMF at 80 0C for 12.0 hrs to yield ethyl 2-(4-benzyl-2-oxo-1,2,3,4tetrahydro-1-quinoxalinyl)acetate (58). Treatment of 58 with 1.1 eq. of LAH in THF followed by simple processing gave the oxazoloquinoxalines 59. BrRCHCO2Et, NaOH Water, 80 °C, 1.0 hr NH2

(55)

H N

NH2 BrRCHCO2Et, NaOH Water, MW, 5 min

(56)

N H

R

2 O 2) BrCH(R )CO2Et, K2CO3, DMF

R1

R1

1) R1Br, Na2CO3 aq. EtOH, 12 hrs

R

N

LAH, THF 0 °C - r.t, O 1.0 hr OEt

N (58) R2

N

R

N

O

(59) R2

O

R = H, DiMe, Ph; R1 = Et, Bn; R2 = H, Me, Et, Pr, Hex and Substituted Aryls)

CHAPTER – V: STUDIES ON SYNTHESIS OF OXAZOLO QUINOLINES This chapter deals with the studies on synthesis of tricyclic oxazolo[3.2-a]quinolines (80). This was carried out as described below;2-Nitrobenzaldehyde (75) was reacted with arylacetic acid in the presence of triethylamine and acetic anhydride to obtain 3-(2-Nitrophenyl)acrylic acids 77, which by reductive cyclization with Pd-C in the presence of hydrogen gas afforded 3,4-dihydro-1H-quinolin-2-ones (78). The latter on treatment with ethyl 2-bromo acetate in the presence of potassium carbonate gave 79, which with lithium aluminumhydride yielded the expected oxazolo[3.2-a]quinolines 80. CHO

(75)

1) Ac2O, Et3N RCH2CO2H

NO2 2) 10 % Pd-C H2, 60 PSI

R

(78)

N H

O

R

BrR1CHCO2Et K2CO3 (79) R1

O

N

O

R

LAH, THF 0 0C - r.t, 1.0 hr

O

(R = H and Substituted Aryls; R1 = H, Me, Et, Hexyl and Aryl)

N (80) R1

O

SOME OTHER APPLICATIONS OF REDUCTIVE CYCLIZATION: OXAZINOTRI [6.6.6] RING SYSTEMS. R

X

R2

R1

N H

O

BrCH2CH2CO2Et K2CO3, DMF, 80 0C

R

X

R

R1

N

THF O CO2Et

LAH

R

X

R2

R1

N

O

X = C, NBn, O, S

OXAZEPINES (TETRA CYCLIC [6.6.7.6] RING SYSTEMS) Br

K2CO3, DMF, 80 0C

OEt

X

R

N

O

O

LAH

O

N

O

X = C, NBn, O, S

O N H

R

THF

R

X

X

O

OXAZOLO TRICYCLIC [6.7.5] RING SYSTEMS BrCH2CO2Et NaH, r.t

LAH THF N

N H

N O

O

O

OEt O

BENZO [b] FURO THIAZINES NaHCO3, Ethanil, 30 min Neat 190 - 210 0C

S

N H

O

SH

CO2Et

Br

Diethyl maleate

O

O

NH2 Neat, MW, 3.0 min

NaOH, water, MW, 3.0 min

BnBr, K2CO3 DMF

N Bn

CO2Et O

O

BnBr, K2CO3 DMF OH

LAH, THF

LAH, THF 0 0C - r.t, 1.0 h

N H

S

S

S

OH

S

N Bn

O

0 0C - r.t, 1.0 h

N Bn

O