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Synthesis 2008(23): 3707-3738  
DOI: 10.1055/s-0028-1083226
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

The Growing Synthetic Utility of the Weinreb Amide

Sivaraman Balasubramaniam, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
Fax: +91(44)22574202; e-Mail: isingh@iitm.ac.in;
Further Information

Publication History

Received 8 April 2008
Publication Date:
14 November 2008 (online)

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Abstract

N-Methoxy-N-methylamide, popularly addressed as the Weinreb amide, has surfaced as an amide with a difference. This amide has served as an excellent acylating agent for organolithium or organomagnesium reagents and as a robust equivalent for an aldehyde group. These two aspects have been exploited exhaustively in various synthetic endeavors. This review presents the growing synthetic utility of the Weinreb amide not only in academic circles, but also its popular use on kilogram scale by various pharmaceutical industries across the globe.

1 Introduction

1.1 Limitations

2 Methods for Preparation

3 Applications

3.1 Use in Heterocyclic Chemistry

3.2 Use in Total Synthesis

3.3 Use in Industry on Kilogram Scale

3.4 Synthetic Equivalents and Building Blocks

4 Miscellaneous

5 Conclusion

Key words

Weinreb amide - Grignard addition - ketones - aldehydes - acylation

10

Although apparently the main objective of the work described in some of the references 12 to 23 does not directly concern WA, buried in the contents of the work, whenever WA was needed from the corresponding acids or esters or lactones, the respective reagents were used and are mentioned in this review.

11

List of abbreviations: DECP = diethyl phosphoro-cyanimidate; EDCI = N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide; PPA = propylphosphonic anhydride; DCC = dicyclohexylcarbodiimide; HOBT = 1-hydroxy-benzotriazole; BOP˙PF6 = benzotriazol-1-yloxytris(di-methylamino)phosphonium hexafluorophosphate; CDI = N,N′-carbonyldiimidazole; TPP = triphenylphosphine.

24

TOTT = tetramethylurea S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; HOTT = tetramethyl-urea S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethyl uronium hexafluorophosphate; TODT = S-(1-oxido-2-pyridinyl)-1,3-dimethylpropyleneuronium tetrafluoroborate; HODT = S-(1-oxido-2-pyridinyl)-1,3-dimethylpropyleneuronium hexafluorophosphate; DMT-MM = 4-(4,6-dimeth-oxy[1,3,5]triazin-2-yl)-4- methylmorpholinium chloride; CDMT = 2-chloro-4,6-dimethoxy[1,3,5]triazine;
CPMA = (chlorophenylthiomethylene)dimethylammonium chloride.

72

The hydrobromide salts of N-methoxy-N-methyl-α-amino carboxamides were prepared from the corresponding Boc or CBz derivatives by deprotecting them using HBr/AcOH and precipitating their salts in diethyl ether; see reference 71a.

126

Aidhen, I. S. unpublished results.