mannich reaction (1)
TRANSCRIPT
The Mannich Reaction
Rahul PatelM.S. IInd sem.
Department of medicinal chemistry
Contents
Background Reaction Mechanism Limitations Modifications Applications Conclusions
Carl Ulrich Franz Mannich (March 8, 1877 in Breslau-March 5, 1947 in Karlsruhe) was a German Chemist
From 1927 to 1943 he was Professor for pharmaceutical chemistry at the University of Berlin
His areas of expertise were Keto bases, Alcohol bases, Piperidine-Derivatives, Papaverine, Lactone and also Digitalis-Glycoside
Background
The Mannich reaction is the aminoalkylation reaction, involving the condensation of an enolizable carbonyl compound with a nonenolizable aldehyde (like formaldehyde) and ammonia, or a primary or a secondary amine to furnish a β-aminocarbonyl compound, also known as Mannich base
Background
Li, J.J. Name Reactions. 2. Springer 2003.
Mechanism
Li, J.J. Name Reactions. 2. Springer 2003.
O
R2R1
H
B:
Enolate
formation
O-
R1 R2
NR
R
N
R
RR2
R1
O
Li, J.J. Name Reactions. 2. Springer 2003.
MechanismBase Catalyzed Mannich reaction
Limitations
Thus the range of application is limited (e.g. confined toaminomethylation)
In many cases undesired side products are formed
The ability to control regio- and stereoselectivity is generallyunsatisfactory
ModificationsPreformed Mannich reagents
Higher concentration of the electrophile, leading to lower reaction temperatures and much shorter reaction times
Many undesired side reactions, which so often cause problems in the Mannich reaction, are avoided, even with sensitive substrates
Carbonyl component can be replaced with much more reactive synthetic equivalents such as enolates
Extended spectrum of application for the reaction
NR
R1
NR2R2N
R1
NR2R2O
R1
NN
N
R1NR2
NR2
R1 X
Imines Aminals N,O-acetals
benzotriazole aminals Iminium Salts
Modifications(cont.)
Preformed Mannich reagents
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Intermolecular amino -alkylation: Regioselective synthesis of Novel b-Amino Ketones and Aldehydes
Modifications(cont.)
Carbonyl Compounds (With Iminium salts)
H2C NMe2 ClO
PhO
Ph NMe2 HCl
Enolates (With N,O acetals)
OLi
+ N
OTiCl3Ph
O N
PhO N
Ph
+
anti syn: = 78:22
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Modifications(cont.)
OBBu2
PhPh
Me2N
NMe2+
O
Ph Ph
NMe2
+
O
Ph Ph
NMe2
anti syn
Boron enol ethers (With aminals)
Silyl enol ethers (With methelene iminium salts)
OSiMe3 NMe2CH2 I
OSiMe3
NMe2 HI
O
NMe2
1) HCl2) OH-
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Intramolecular Mannich ReactionsModifications(cont.)
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Modifications(cont.)
OH
R1NR
R
O
R1 NR2
NTMSO O
N
Vinylogous Mannich Reactions
Chem. Ber. 1979, 112, 1913.Tet.Lett. 1980, 21, 805.
Asymmetric mannich reaction
Angew. Chem. Int. Ed. 1998, 37. 1044-1070Angew. Chem. Int. Ed. 2004, 43. 5138-5175
Asymmetric mannich reaction
Org. Lett. 2010, 12, 708-711.
Applications
J. Pharm. Sci. 1996, 4, 715-733.
Applications
OHCHOMe2NH
HCl
O
N
F
F
F
O
HN
fluoxetin
HN
NH
O
O
HNR1
R2
HCHOHN
NH
O
O
NR1
R2
J. Med. Chem. 1976, 19, 345-350.J. Org. Chem. 1959, 24, 1069-1076.
Chem. Pharm. Bull. 1994, 8, 1676-1685.
O
(CH2O)n/AcOHN
H
O
N HCLHClHO
O
N
Tramadol
MedicinalCompoundsSynthesis
ApplicationsNatural Product Synthesis
NHOOC
COOMe
O
Bn
COCl2
BnN
MeOOC
COMe
HN
NHOOC
Bnn
O BnN
COCl2
O HNO
NHOOC
COOMeBn
OCOCl
2
BnN
COMe
COOMe
BnN
N
Cl
Epibatidine
Ferruginine
Anatoxin
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Natural Product SynthesisApplications
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
SummaryNucleophilic addition of an enol to an iminium ion formed by the reaction of formaldehyde with a secondary amine
Multi-component condensation
Amino-methylation
Modifications like preformed mannich bases and use of different reagents like enolate s, silyl enol ethers etc. gives wide range of the synthesis and amino-alkylation
Wide synthetic applicationsorganic synthesis of natural compounds such as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone)
Agro chemicals such as plant growth regulators, paint- and polymer chemistry, catalysts and crosslinking
Medicinal compounds e.g. rolitetracycline (Antibiotic), fluoxetine (antidepressant), tramadol, and tolmetin (anti-inflammatory drug)
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