Methyl 3-(Dimethylamino)propionate1

[3853-06-3]  · C6H13NO2  · Methyl 3-(Dimethylamino)propionate  · (MW 131.20)

(masked acrylate synthetic equivalent; for preparation of a-methylene esters, acids, and lactones2)

Physical Data: bp 56 °C/15 mmHg.

Solubility: sol all common solvents.

Form Supplied in: colorless liquid.

Analysis of Reagent Purity: 1H and 13C NMR; GC.

Preparative Method: reaction of Methyl Acrylate with dimethylamine in ether at 0-25 °C.3

Purification: distillation at reduced pressure.

Handling, Storage, and Precautions: routine laboratory techniques; exhibits typical tendency of amines to undergo slow oxidation in the air. Use in a fume hood.

Preparation of 2-Substituted Acrylate Derivatives.

Methyl 3-(dimethylamino)propionate undergoes straightforward enolate formation upon treatment with Lithium Diisopropylamide. The resulting enolate undergoes high yield reactions with a number of alkylating agents. A representative reaction sequence is shown using a cyclic allylic halide (eq 1). The alkylation product is converted to the quaternary ammonium salt using Iodomethane followed by 1,5-Diazabicyclo[4.3.0]non-5-ene-induced elimination to give the 2-substituted acrylate derivative. Among the possible further reactions are iodo lactonization of the free acid and then either 1,8-Diazabicyclo[5.4.0]undec-7-ene-induced dehydroiodination or Tri-n-butylstannane-promoted reductive deiodination.

Alternative Reagents.

The primary motivation for the development of this reagent and a large number of related methods was the common natural occurrence of a-methylene lactones. Literally thousands of these compounds are known, and several of them possess antitumor activity.1 The other methods are too numerous to describe here,1 but a recent modification of the present method employs imines in place of alkyl halides in the reaction of the enolate; the ultimate products are a-alkylidene-b-lactam derivatives.4

Related Reagents.

Ethyl Acrylate; Formaldehyde; Methyl 3-Hydroxypropionate.

1. (a) Hoffmann, H. M. R.; Rabe, J. AG(E) 1985, 24, 94. (b) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. S 1986, 157.
2. (a) Yu, L.-C.; Helquist, P. TL 1978, 3423. (b) Yu, L.-C.; Helquist, P. SC 1981, 11, 591. (c) Yu, L.-C.; Helquist, P. JOC 1981, 46, 4536.
3. Rouvier, E.; Giacomoni, J.-C.; Cambon, A. BSF 1971, 1717.
4. Alcaide, B.; Plumet, J.; Rodriguez-López, J.; Sánchez-Cantalejo, Y. M. TL 1990, 31, 2493.

Paul Helquist

University of Notre Dame, IN, USA

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