4-Dimethylamino-pyridine (DMAP)

Introduction

In 1969 Steglich and Höfle reported 4-(dimethylamino)-pyridine (DMAP) (1) as a very effective acylation catalyst. [1] Independently, the Russian group of Litvinenko and Kirichenko discovered that pyridine replaced by DMAP accelerates the reaction rate by ca. 10 [4] for the benzoylation of m-chloroaniline. [2] As a result of many investigations based on the fundamental work by Steglich et al., DMAP has been used in a large range of applications as a catalyst for acylation of alcohols, amines, phenols and enolates, [3-5] in particular for the acylation of sterically hindered secondary or tertiary alcohols. For example, 1-methyl-1-cyclohexanol is not acylated under basic conditions (pyridine, Ac₂O), whereas in the presence of 4.1 mol% of DMAP a yield of 86% is achieved after 14 hours at room temperature. [1] It should be mentioned that DMAP shows good catalytic activity under certain conditions. Non-polar solvents like pyridine and Ac₂O (rather than acid chlorides) are suitable.

The catalytic efficiency is probably due to the stabilization of an acylpyridinium ion, which plays an important role in the catalytic cycle (Scheme 1). Steric effects, the donor ability of the amine substituent, and the good nucleophilic properties of DMAP additionally affect the reactivity of DMAP. Hassner et al. pointed out that 2-dialkylamino-pyridines have no catalytic activity for steric reasons. [6]

Scheme 1

It is well known that DMAP does not only serve as a catalyst for acylation reactions and (trans-) esterifications [7] but also for various organic transformations like the Baylis-Hillman reaction, [8] the Dakin-West reaction, [9] the protection of amines, [10] C-acylations, [11] silylations, [5] applications in natural products chemistry, [12] and many others. [5]

References

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• 2 Litvinenko LM. Kirichenko AI. Dokl. Akad. Nauk  1967,  176:  97 
• 3 Höfle G. Steglich W. Vorbrüggen H. Angew. Chem., Int. Ed. Engl.  1978,  17:  569 
• 4 Scriven EFV. Chem. Soc. Rev.  1983,  12:  129 
• 5 Murugan R. Scriven EFV. Aldrichimica Acta  2003,  36:  21 
• 6 Hassner A. Krepski LR. Tetrahedron  1978,  34:  2069 
• 7 Neises B. Steglich W. Angew. Chem., Int. Ed. Engl.  1978,  17:  522 
• 8 Rezgui F. El Gaied MM. Tetrahedron Lett.  1998,  39:  5965 
• 9 Buchanan GL. Chem. Soc. Rev.  1988,  17:  91 
• 10 Regnarsson U. Grehn L. Acc. Chem. Res.  1998,  31:  494 
• 11 Mermerian AH. Fu GC. J. Am. Chem. Soc.  2003,  125:  4050 
• 12 Müller M. Lamottke K. Löw E. Mayer-Veenstra E. Steglich W. J. Chem. Soc., Perkin Trans. 1  2000,  2483 
• 13 Spivey AC. Fekner T. Spey SE. J. Org. Chem.  2000,  65:  3154 
• 14 Priem G. Pelotier B. Macdonald SJF. Anson MS. Campbell IB. J. Org. Chem.  2003,  68:  3844 
• 15 Arai S. Bellemin-Laponnaz S. Fu GC. Angew. Chem. Int. Ed.  2001,  40:  234