[1122-58-3]  · C7H10N2  · 4-Dimethylaminopyridine  · (MW 122.19)

(catalyst for acylation of alcohols or amines,1-11 especially for acylations of tertiary or hindered alcohols or phenols12 and for macrolactonizations;13-15 catalyst for direct esterification of carboxylic acids and alcohols in the presence of dicyclohexylcarbodiimide (Steglich-Hassner esterification);5 catalyst for silylation or tritylation of alcohols,9,10 and for the Dakin-West reaction20)

Alternate Name: DMAP.

Physical Data: colorless solid; mp 108-110 °C; pKa 9.7.

Solubility: sol MeOH, CHCl3, CH2Cl2, acetone, THF, pyridine, HOAc, EtOAc; partly sol cold hexane or water.

Form Supplied in: colorless solid; commercially available.

Preparative Methods: prepared by heating 4-pyridone with HMPA at 220 °C, or from a number of 4-substituted (Cl, OPh, SO3H, OSiMe3) pyridines by heating with DMA.2 Prepared commercially from the 4-pyridylpyridinium salt (obtained from pyridine and SOCl2) by heating with DMF at 155 °C.1,2

Purification: can be recrystallized from EtOAc.

Handling, Storage, and Precautions: skin irritant; corrosive, toxic solid.

Acylation of Alcohols.

Several 4-aminopyridines speed up esterification of hindered alcohols with acid anhydrides by as much as 10 000 fold; of these, DMAP is the most commonly used but 4-pyrrolidinopyridine (PPY) and 4-tetramethylguanidinopyridine are somewhat more effective.11 DMAP is usually employed in 0.05-0.2 mol equiv amounts.

DMAP catalyzes the acetylation of hindered 11b- or 12a-hydroxy steroids. The alkynic tertiary alcohol acetal in eq 1 is acetylated at rt within 20 min in the presence of excess DMAP.3

Esterifications mediated by 2-Chloro-1-methylpyridinium Iodide also benefit from the presence of DMAP.22

DMAP acts as an efficient acyl transfer agent, so that alcohols resistant to acetylation by Acetic Anhydride-Pyridine usually react well in the presence of DMAP.4a Sterically hindered phenols can be converted into salicylaldehydes via a benzofurandione prepared by DMAP catalysis (eq 2).4b

Direct Esterification of Alcohols and Carboxylic Acids.

Instead of using acid anhydrides for the esterification of alcohols, it is possible to carry out the reaction in one pot at rt by employing a carboxylic acid, an alcohol, 1,3-Dicyclohexylcarbodiimide, and DMAP.5,6 In this manner, N-protected amino acids and even hindered carboxylic acids can be directly esterified at rt using DCC and DMAP or 4-pyrrolidinopyridine (eq 3).5

DCC-DMAP has been used in the synthesis of depsipeptides.6b Macrocyclic lactones have been prepared by cyclization of hydroxy carboxylic acids with DCC-DMAP. The presence of salts of DMAP,13a such as its trifluoroacetate, is beneficial in such cyclizations, as shown for the synthesis of a (9S)-dihydroerythronolide.13b Other macrolactonizations have been achieved using 2,4,6-Trichlorobenzoyl Chloride and DMAP in Triethylamine at rt14 or Di-2-pyridyl Carbonate (6 equiv) with 2 equiv of DMAP at 73 °C.15

Acylation of Amines.

Acylation of amines is also faster in the presence of DMAP,7 as is acylation of indoles,8a phosphorylation of amines or hydrazines,2,8 and conversion of carboxylic acids into anilides by means of Phenyl Isocyanate.1 b-Lactam formation from b-amino acids has been carried out with DCC-DMAP, but epimerization occurs.8b

Silylation, Tritylation, and Sulfinylation of Alcohols.

Tritylation, including selective tritylation of a primary alcohol in the presence of a secondary one,9 silylation of tertiary alcohols, selective silylation to t-butyldimethylsilyl ethers,6 and sulfonylation or sulfinylation10 of alcohols proceed more readily in the presence of DMAP. Silylation of b-hydroxy ketones with Chlorodiisopropylsilane in the presence of DMAP followed by treatment with a Lewis acid gives diols (eq 4).16

Miscellaneous Reactions.

Alcohols, including tertiary ones, can be converted to their acetoacetates by reaction with Diketene in the presence of DMAP at rt.17 Decarboxylation of b-keto esters has been carried out at pH 5-7 using 1 equiv of DMAP in refluxing wet toluene (eq 5).18

Elimination of water from a t-alcohol in a b-hydroxy aldehyde was carried out using an excess of Methanesulfonyl Chloride-DMAP-H2O at 25 °C.23

Glycosidic or allylic alcohols (even when s-) can be converted in a 80-95% yield to alkyl chlorides by means of p-Toluenesulfonyl Chloride-DMAP. Simply primary alcohols react slower and secondary ones are converted to tosylates.24

Aldehydes and some ketones can be converted to enol acetates by heating in the presence of TEA, Ac2O, and DMAP.2 DMAP catalyzes condensation of malonic acid monoesters with unsaturated aldehydes at 60 °C to afford dienoic esters (eq 6).19

The conversion of a-amino acids into a-amino ketones by means of acid anhydrides (Dakin-West reaction)20 also proceeds faster in the presence of DMAP (eq 7).

Ketoximes can be converted to nitrimines which react with Ac2O-DMAP to provide alkynes (eq 8).21

For the catalysis by DMAP of the t-butoxylcarbonylation of alcohols, amides, carbamates, NH-pyrroles, etc., see Di-t-butyl Dicarbonate.

1. Hoefle, G.; Steglich, W.; Vorbrueggen, H. AG(E) 1978, 17, 569.
2. Scriven, E. F. V. CSR 1983, 12, 129.
3. (a) Steglich, W.; Hoefle, G. AG(E) 1969, 8, 981. (b) Hoefle, G.; Steglich, W. S 1972, 619.
4. (a) Salomon, R. G., Salomon, M. F.; Zagorski, M. G.; Reuter, J. M.; Coughlin, D. J. JACS 1982, 104, 1008. (b) Zwanenburg, D. J.; Reynen, W. A. P. S 1976, 624.
5. (a) Neises, B.; Steglich, W. AG(E) 1978, 17, 522. (b) Hassner, A.; Alexanian, V. TL 1978, 4475.
6. (a) Ziegler, F. E.; Berger, G. D. SC 1979, 539. (b) Gilon, C.; Klausner, Y.; Hassner, A. TL 1979, 3811.
7. Litvinenko, L. M., Kirichenko, A. C.; DOK 1967, 176, 97. (b) Kirichenko, A. C.; Litvinenko, L. M.; Dotsenko, I. N.; Kotenko, N. G.; Nikkel'sen, E.; Berestetskaya, V. D. DOK 1969, 244, 1125 (CA 1979, 90, 157 601).
8. (a) Nickisch, K.; Klose, W.; Bohlmann, F. CB 1980, 113, 2036. (b) Kametami, T.; Nagahara, T.; Suzuki, Y.; Yokohama, S.; Huang, S.-P.; Ihara, M. T 1981, 37, 715.
9. (a) Chaudhary, S. K.; Hernandez, O. TL 1979, 95, 99. (b) Hernandez, O.; Chaudhary, S. K.; Cox, R. H.; Porter, J. TL 1981, 22, 1491.
10. Guibe-Jampel, E.; Wakselman, M.; Raulais, D. CC 1980, 993.
11. Hassner, A.; Krepski, L. R.; Alexanian, V. T 1978, 34, 2069.
12. Vorbrueggen, H. (Schering AG) Ger. Offen. 2 517 774, 1976 (CA 1977, 86, 55 293).
13. (a) Boden, E. P.; Keck, G. E. JOC 1985, 50, 2394. (b) Stork, G.; Rychnovsky, S. D. JACS 1987, 109, 1565.
14. Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. JOC 1990, 55, 7.
15. (a) Kim, S.; Lee, J. I.; Ko, Y. K. TL 1984, 25, 4943. (b) Denis, J.-N.; Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.; Mangatal, L.; Potier, P. JACS 1988, 110, 5917.
16. Anwar, S.; Davis, A. P. T 1988, 44, 3761.
17. Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. S 1989, 387.
18. Taber, D. F.; Amedio J. C., Jr.; Gulino, F. JOC 1989, 54, 3474.
19. Rodriguez, J.; Waegell, B. S 1988, 534.
20. (a) Buchanan, G. L. CSR 1988, 17, 91. (b) McMurry, J. JOC 1985, 50, 1112. (c) Hoefle, G., Steglich, W. CB 1971, 104, 1408.
21. Buechi, G.; Wuest, H. JOC 1979, 44, 4116.
22. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. JACS 1994, 116, 8402.
23. Furukawa, J.; Morisaki, N.; Kobayashi, H.; Iwasaki, S.; Nozoe, S.; Okuda, S. CPB 1985, 33, 440.
24. Hwang, C. K.; Li, W. S.; Nicolaou, K. C. TL 1984, 25, 2295.

Alfred Hassner

Bar-Ilan University, Ramat Gan, Israel

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