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PRESENTED BY
PRASANNA R. ANGANE. M.Pharm. I-sem (Pharmaceutical chemistry) GUIDED BY
Dr. S. G. WALODE. Head of The Department (Pharmaceutical Chemistry) SINHGAD INSTITUTE OF PHARMACEUTICAL SCIENCES, LONAVALA, PUNE. 1
INTRODUCTION HISTORY
GENERAL REACTION MECHANISM
OF THE REACTION STEREOCHEMISTRY APPLICATION REFERENCES 2
INTRODUCTION 2 The 1,4-reduction of aromatic rings to the corresponding unconjugated Cyclohexadienes by alkali metals (Li, Na, K) dissolved in liquid ammonia. In the presence of an alcohol is called the Birch Reduction. Heterocycles, such as pyridines, pyrroles, and furans are also reduced under this condition.
When the aromatic compound is substituted, the regioselectivity of the reduction depends on the nature of the substituent
3
The Birch Reduction was reported in 1944 by the Australian chemist Arthur Birch (1915–1995) working in the Dyson Perrins Laboratory in the University of Oxford.
The original reaction reported by Arthur Birch in 1944 utilized sodium and ethanol. Subsequently A. L. Wilds noted that better yields result with lithium. 4
Benzene
1,4-dihydro cyclohexadiene
5
Step 1: Electron transfer from sodium H H
H H Benzene
H H + • Na
H
H
H
–
•
H
••
H
+
Na+
H Benzene anion radical 6
Step 2: Proton transfer from methanol
H H H
–
•
H
••
H
H
H •• OCH3 ••
7
Step 2: Proton transfer from methanol
H H
H
•
H H
H
Cyclohexadienyl radical
H
H
H
H – •• •• OCH3 ••
–
•
H
••
H
H
H •• OCH3 ••
8
Step 3: Electron transfer from sodium
H H
H + • Na
•
H
H H
H
Cyclohexadienyl radical 9
Step 3: Electron transfer from sodium
H H
H
•
H H
H
H + • Na
H
H
H
–
H +
••
Na+
H H
H
Cyclohexadienyl anion 10
Step 4: Proton transfer from methanol
H H
–
•• •• OCH3 H H
••
H
H H
H
11
Step 4: Proton transfer from methanol
H
H
– •• •• OCH •• 3
H
H
H
H
H
H
H
H
H
–
•• •• OCH3 H H
••
H H
H
1,4-Cyclohexadiene 12
STEREOCHEMISTRY 5,6,7
13
Regioselectivity OMe
OMe H
-
t BuOH Na or Li in Liq NH 3
COOH -
t BuOH
H
H
H
H
COOH
Na or Li in Liq NH 3 H
H 14
APPLICATION 2,8,9,10 Et
1)
CO 2Me
Me
OMe
N
N
K,NH3, t-BuOH
N
H
OMe
Chiral benzamide 2)
Apovincamine
R H3C
CN
Li,NH3, EtOH
H N H
H
H MOMO
H
HCL / MeOH
H H
HO OMOM
H O
Galbulimima alkaloid 15
3) OMe OMe
Me NaNH 3/THF, -78 C /THF, -78 C
Me
Me STEPS
then add Mel 93% then add Mel 93%
N
HOOC
N
O O
H
CH 2 OMe
O
Me O
COOH O Me
CH 2
Me
OMe
Nemorensic acid
16
4) Useful in synthesis of steroids. A) Synthesis of 19-nor testosterone
5) The synthesis and CNS depressant activity of 3-aminocyclohexa-1,4-diene-1-carboxylic acid and 3-[5-substituted1,3,4-thiadiazole-2-yl]-2-styryl 5,8 dihydroquinazoline-4 (3H)-ones 6)
Asymmetric Synthesis of the Core Structure of the Melodinus Alkaloids 17
7
Benzoyl-CoA reductase: a biological birch reduction
8
Synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2] tridecanes—a new class of peroxides
18
REFERENCES 1) Carey.F.; Sundberg. R. Advanced Organic Chemistry, Part B : Reactions and Synthesis.; Springer publications.; Fifth edition.; pp- 445-448. 2) Kurti L.; Czako B. Strategic applications of named reactions in organic Synthesis.; Elsevier academic press.; pp- 60-61.
3) Sanyal S. Reaction Rearrangement and Reagent.; Bhararti Bhavan Publishers and Distributers.; fourth edition.; pp- 96-97. 4) March J. Advanced Organic Chemistry Reaction Mechanism And Structure.; fourth edition.; John Wiley and Sons.; pp- 779-783. 5) Kalasi P. Organic reaction & their mechanisms.; New age International publishers.; Second edition.; Pp-471-472.
19
6) Nasipuri D., Stereochemistry of Organic Compounds: Principles and Applications In asymmetrical synthesis, New age international publishers, second edition, pp. 395-397. 7) http://en.wikipedia.org/wiki/birch_reduction
8) Charbe N.B., Mehere A.P., Shende S.G. Study of new developments in birch reduction process and their applications for the synthesis and CNS depressant activity of 3- aminocyclohexa-1,4-diene-1-carboxylic acid and 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl 5,8 dihydroquinazoline-4 (3H)-ones International Journal of Drug Discovery, Volume 2, 2010, pp.17-25. 9) Arthur G. S. and Mingshi D. Asymmetric Synthesis of the Core Structure of the Melodinus Alkaloids Tetrahedron Letters volume 40,1999, pp.645-648.
20
10) Kumar D. N., Sudhakar N., Venkateswara B. Synthesis of trans-1,8,12,13tetraoxadispiro[4.1.4.2]-tridecanesa new class of peroxides Tetrahedron Letters volume 47 2006 pp.771–774 11) ACD/chemsketch(Free ware),File version-12.10 31258
21
22
PRASANNA R. ANGANE. M.Pharm. I-sem (Pharmaceutical chemistry) GUIDED BY
Dr. S. G. WALODE. Head of The Department (Pharmaceutical Chemistry) SINHGAD INSTITUTE OF PHARMACEUTICAL SCIENCES, LONAVALA, PUNE. 1
INTRODUCTION HISTORY
GENERAL REACTION MECHANISM
OF THE REACTION STEREOCHEMISTRY APPLICATION REFERENCES 2
INTRODUCTION 2 The 1,4-reduction of aromatic rings to the corresponding unconjugated Cyclohexadienes by alkali metals (Li, Na, K) dissolved in liquid ammonia. In the presence of an alcohol is called the Birch Reduction. Heterocycles, such as pyridines, pyrroles, and furans are also reduced under this condition.
When the aromatic compound is substituted, the regioselectivity of the reduction depends on the nature of the substituent
3
The Birch Reduction was reported in 1944 by the Australian chemist Arthur Birch (1915–1995) working in the Dyson Perrins Laboratory in the University of Oxford.
The original reaction reported by Arthur Birch in 1944 utilized sodium and ethanol. Subsequently A. L. Wilds noted that better yields result with lithium. 4
Benzene
1,4-dihydro cyclohexadiene
5
Step 1: Electron transfer from sodium H H
H H Benzene
H H + • Na
H
H
H
–
•
H
••
H
+
Na+
H Benzene anion radical 6
Step 2: Proton transfer from methanol
H H H
–
•
H
••
H
H
H •• OCH3 ••
7
Step 2: Proton transfer from methanol
H H
H
•
H H
H
Cyclohexadienyl radical
H
H
H
H – •• •• OCH3 ••
–
•
H
••
H
H
H •• OCH3 ••
8
Step 3: Electron transfer from sodium
H H
H + • Na
•
H
H H
H
Cyclohexadienyl radical 9
Step 3: Electron transfer from sodium
H H
H
•
H H
H
H + • Na
H
H
H
–
H +
••
Na+
H H
H
Cyclohexadienyl anion 10
Step 4: Proton transfer from methanol
H H
–
•• •• OCH3 H H
••
H
H H
H
11
Step 4: Proton transfer from methanol
H
H
– •• •• OCH •• 3
H
H
H
H
H
H
H
H
H
–
•• •• OCH3 H H
••
H H
H
1,4-Cyclohexadiene 12
STEREOCHEMISTRY 5,6,7
13
Regioselectivity OMe
OMe H
-
t BuOH Na or Li in Liq NH 3
COOH -
t BuOH
H
H
H
H
COOH
Na or Li in Liq NH 3 H
H 14
APPLICATION 2,8,9,10 Et
1)
CO 2Me
Me
OMe
N
N
K,NH3, t-BuOH
N
H
OMe
Chiral benzamide 2)
Apovincamine
R H3C
CN
Li,NH3, EtOH
H N H
H
H MOMO
H
HCL / MeOH
H H
HO OMOM
H O
Galbulimima alkaloid 15
3) OMe OMe
Me NaNH 3/THF, -78 C /THF, -78 C
Me
Me STEPS
then add Mel 93% then add Mel 93%
N
HOOC
N
O O
H
CH 2 OMe
O
Me O
COOH O Me
CH 2
Me
OMe
Nemorensic acid
16
4) Useful in synthesis of steroids. A) Synthesis of 19-nor testosterone
5) The synthesis and CNS depressant activity of 3-aminocyclohexa-1,4-diene-1-carboxylic acid and 3-[5-substituted1,3,4-thiadiazole-2-yl]-2-styryl 5,8 dihydroquinazoline-4 (3H)-ones 6)
Asymmetric Synthesis of the Core Structure of the Melodinus Alkaloids 17
7
Benzoyl-CoA reductase: a biological birch reduction
8
Synthesis of trans-1,8,12,13-tetraoxadispiro[4.1.4.2] tridecanes—a new class of peroxides
18
REFERENCES 1) Carey.F.; Sundberg. R. Advanced Organic Chemistry, Part B : Reactions and Synthesis.; Springer publications.; Fifth edition.; pp- 445-448. 2) Kurti L.; Czako B. Strategic applications of named reactions in organic Synthesis.; Elsevier academic press.; pp- 60-61.
3) Sanyal S. Reaction Rearrangement and Reagent.; Bhararti Bhavan Publishers and Distributers.; fourth edition.; pp- 96-97. 4) March J. Advanced Organic Chemistry Reaction Mechanism And Structure.; fourth edition.; John Wiley and Sons.; pp- 779-783. 5) Kalasi P. Organic reaction & their mechanisms.; New age International publishers.; Second edition.; Pp-471-472.
19
6) Nasipuri D., Stereochemistry of Organic Compounds: Principles and Applications In asymmetrical synthesis, New age international publishers, second edition, pp. 395-397. 7) http://en.wikipedia.org/wiki/birch_reduction
8) Charbe N.B., Mehere A.P., Shende S.G. Study of new developments in birch reduction process and their applications for the synthesis and CNS depressant activity of 3- aminocyclohexa-1,4-diene-1-carboxylic acid and 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl 5,8 dihydroquinazoline-4 (3H)-ones International Journal of Drug Discovery, Volume 2, 2010, pp.17-25. 9) Arthur G. S. and Mingshi D. Asymmetric Synthesis of the Core Structure of the Melodinus Alkaloids Tetrahedron Letters volume 40,1999, pp.645-648.
20
10) Kumar D. N., Sudhakar N., Venkateswara B. Synthesis of trans-1,8,12,13tetraoxadispiro[4.1.4.2]-tridecanesa new class of peroxides Tetrahedron Letters volume 47 2006 pp.771–774 11) ACD/chemsketch(Free ware),File version-12.10 31258
21
22
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