Author Topic: High yielding R-CO2H to R-C(O)NEt2 reference.  (Read 1817 times)

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somuchclass

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High yielding R-CO2H to R-C(O)NEt2 reference.
« on: October 07, 2004, 08:37:00 AM »
Excerpted from _Organic Syntheses_, Collective Volume 9, 559. 

Submitted by X. Wang, S.O. de Silva, J.N. Reed, R. Billadeau, E.J. Griffen, A. Chan, and V. Snieckus.  Checked by Chris Lumberakis and Stephen F. Martin.

From the Discussion section:

The present procedure uses a readily available and inexpensive material, benzoic acid, proceeds in reproducible, high yields, and *does not require chromatographic separation.*

Procedure:

A.  N,N-diethyl-2-methoxybenzamide:  An oven-dried, two-necked, 500 mL flask equipped with a septum cap, nitrogen bubbler, and magnetic stir bar is charged with
2-methoxybenzoic acid (20 g, 0.13 mol; see Note 1) under nitrogen.  Thionyl chloride (135 mL, 220 g, 1.85 mol; see Note 2) is added with stirring, resulting in a slow effervescence.  Dimethylformamide (DMF, 0.34 mol, 320 mg, 4.4 mol; see Notes 3 and 4) is added dropwise via a syringe after which the effervescence becomes much more vigorous (CAUTION:  sulfur dioxide and hydrogen chloride are evolved).  The solution is stirred for 30 minutes, at which time no further effervescence is visible.  Half of the thionyl chloride is removed under reduced pressure on a rotary evaporator, toluene (100 mL) is added, and the mixture is evaporated to dryness.  A further 100 mL of toluene is added and the process of evaporation is repeated twice more to ensure complete removal of all excess thionyl chloride (see Note 5).  The colorless oil is dissolved in dry tetrahydrofuran (THF, 150 mL; see Note 6), and the resulting solution is cooled in an ice water bath, and treated slowly with diethylamine (50 mL, 35.3 g, 0.48 mol; see Note 7), with stirring to prevent the reaction from becoming too vigorous.  A copious white precipitate forms.

     When all the diethylamine has been added the mixture is stirred for a further 10 minutes and then concentrated under reduced pressure.  The residue is dissolved in methylene chloride (200 mL), washed with water (2 x 200 mL) and saturated brine (2 x 50 mL), and concentrated under reduced pressure to give an orange oil.  The oil is distilled at reduced pressure to give 23.5 g to 24.5 g (86% to 90%) of N,N-diethyl-2-methoxybenzamide (118-120 degrees Celsius at 0.1 mm Hg pressure) as a straw-colored liquid.

Notes:

1.  2-Methoxybenzoic acid was used as received.
2.  Thionyl chloride was used as received.
3.  Dimethylformamide was distilled from calcium hydride and stored over 4 Angstrom molecular sieves under nitrogen.
4.  The use of DMF to accelerate the formation of acid chlorides from carboxylic acids has been reviewed previously, and is believed to occur via an imidoyl chloride intermediate.
5.  The removal of excess thionyl chloride by formation of an azeotrope with benzene was used in a previous Org Syn procedure; however, toluene is much less toxic than benzene and is thus recommended.
6.  Tetrahydrofuran was freshly distilled from sodium/benzophenone ketyl at atmospheric pressure under nitrogen.
7.  The use of acid chlorides in the preparation of amides has been reviewed.  The diethylamine was distilled from calcium hydride prior to use.
10.  Reagent grade methylene chloride was distilled before use.

(Pardon my error if this thread should have been posted in the tryptamine/ergoline section.)