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Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
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A New Synthesis of β-Keto

Amides via Reaction of
Ketone Lithium Enolates with
Isocyanates
a a
Shivakumar B. Hendi , Mukta S. Hendi & James F.
a
Wolfe
a
Department of Chemistry , Virginia Polytechnic
Institute and State University , Blacksburg, VA,
24061
Published online: 05 Dec 2006.

To cite this article: Shivakumar B. Hendi , Mukta S. Hendi & James F. Wolfe
(1987) A New Synthesis of β-Keto Amides via Reaction of Ketone Lithium
Enolates with Isocyanates, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 17:1, 13-18, DOI:
10.1080/00397918708063898

To link to this article: http://dx.doi.org/10.1080/00397918708063898

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 SYNTHETIC COMMUNICATIONS, 17(1), 13-18 (1987)

A NEW SYNTHESIS OF 0-KETO AMIDES VIA

REACTION OF KETONE LITHIUM ENOLATES
WITH ISOCYANATES
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Shivakumar B. Hendi, Mukta S. Hendi, and James F. Wolfe*

Department of Chemistry
Virginia Polytechnic Institute and State University
Blacksburg, VA 24061

ABSTRACT: A series of R-ketoamides was prepared by a convenient new method

involving addition of various isocyanates to the lithium enolates of acetophenone
propiophenone and pinacolone.

In connection with the synthesis of new compounds having potential

anticonvulsant activity, we needed to prepare R-keto amides 3a-1 (Table) as
synthetic intermediates. Traditional procedures for the preparation of R-keto
amides involve reactions of amines with 8-keto acids,2 R-keto esters? or d i k e t e ~ ~ e . ~
More recently, reactions of isocyanates with en01 ethers: silyl enol ethers?
enamines,6 and a-acylphosphonium ylides’ have been used to prepare R-keto
amides. In view of the electrophilicreactivity of isocyanates toward these reagents,
it occurred to us that 3a-I might be synthesized in one step via reactions of
acetophenone, propiophenone and pinacolone lithium enolates (la-c) with

* To whom correspondence should be addressed.

13

Copyright 0 1987 by Marcel Dekker, Inc.

 14 HENDI, HENDI, AND WOLFE

Table I
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la-c 2a-d 3a-1

Product No. R1 R2 R3 Yield, %

3a Ph H Ph 98
3b Ph H 3-Cl-Ph 87
3c Ph H 4-C1-Ph 85
3d Ph H cyclo-CgH11 96

3e Ph Me Ph 97
3f Ph Me 3-C1-Ph 83

3g Ph Me 4-C1-Ph 90
3h Ph Me CyClO-c6H11 96

3i ~-Bu H Ph 85

3j ~ B u H 3-C1-Ph 76
3k ~-Bu H 4-C1-Ph 81
31 ~-Bu H CyClO-c6H11 93
 REACTION OF KETONE LITHIUM ENOLATES 15

isocyanates 2a-d. We now wish to report that this approach works smoothly to
afford the desired products in good to excellent yields (Table).8
The present method is operationally simple and more efficient than earlier
isocyanate-based procedures, in that it does not require initial synthesis and
purification of en01 ethers, enamines, or a-acylphosphoranes prior to reaction with
Downloaded by [University of Huddersfield] at 01:41 15 January 2015

the appropriate isocyanate.

EXPERIMENTALg
General Method for the €'reoarah'on of R-Keto AmideL
A 125-mL three-neck round bottomed flask was maintained under a positive
pressure of nitrogen. A solution of LDA in ether was prepared at -78'C by adding
sequentially to the flask 40 mL of ether, 1.40 mL (10 mmol) of diisopropylamine,
10 mmol of n-BuLi (dropwise) and finally, 20 mL of ether. After stirring for 5 min,
a solution of the appropriate ketone (10 mmol) in 10 mL of ether was added
dropwise and the resulting solution was stirred for 15-20 min. A solution of the
isocyanate (10 mmol) in 10 mL of ether was added dropwise and allowed to s t i r for
2 h, during which time the reaction mixture was allowed to attain room temperature.

The reaction mixture was then quenched with saturated NH4Cl solution and

extracted with CH2C12. The extracts were washed with water, dried (Na2SO4) and

evaporated to afford the R-keto amide. In experiments employing 3-chlorophenyl-

and 4-~hlorophenylisocyanates,
the product R-keto amides were accompanied by ca.
10-20% of the corresponding N-aryl-N',N'-diisopropylurea,
and repeated
recrystallizations were required to give pure R-keto amides in the yields reported in
Table I. Known compounds 3a,1° 3b,11 3c,lo 3d,12 3e? 3i-k13 had melting
 16 HENDI, HENDI, AND WOLFE

points and lH NMR spectra consistent with the assigned structures. The following
new compounds were prepared in this manner:

mp 125'C from CH2C12-hexanes;lH Nh4R (-13) , 1.65 (d, 3H), 4.5 (9,
lH), 7.0-8.1 (m, 9 ArH), 8.8 (broad,NH).
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Anal. Calcd for c16H14cwo2: C, 66.78; H, 4.87; N, 4.87. Found: C,

66.78; H, 4.90; N, 4.85.

N-(CC-vlI _ _0x0-3-b
-2-methvl3 w d e f3g):

mp 151°Cfrom CH2C12-hexanes;lH N M R (CDCl3) , 1.65 (d, 3H), 4.5 (4,

lH), 7.2-8.2 (m, 9 ArH), 8.8 (broad, NH).

Anal. Calcd for C16H14ClNO2: C, 66.78; H, 4.87; N, 4.87. Found C,

66.7 1;H, 4.94; N, 4.84.

__ __ __
PJ-Cvclohexvl2 methvl3 0x0 3: -

mp 152°Cfrom CH2C12-hexanes;lH Nh4R (CDCl3) ,0.8-2.1 (m,

cyclohexyl CH2), 1.5 (d, 3H), 3.7 (broad, m, cyclohexyl CH), 4.3 (1, lH), 6.2

(broad,NH),7.2-8.1 (m, 5 ArH).

Anal. Calcdfor C16H21N02: C, 74.13; H, 8.11; N, 5.40. Found: C, 73.66;

H, 8.15; N, 5.35.
- -O X 0-4.4:--
N-CvclohmyI3

mp 76°C from CH2C12-hexanes; lH Nh4R (CDCl3) , 1.2 (s, 9H), 1.2-2.0

(m, cyclohexyl CH2),3.45 (s, 2H), 3.75 (broad, m, CH),7.15 (broad, NHJ.

Anal. Calcd for C13H23N02: C, 69.33; H, 10.22; N, 6.22. Found C,

69.17; H, 10.32; N, 6.18.

 R E A C T I O N OF KETONE L I T H I U M E N O L A T E S 17

Acknowledeements: The authors are pleased to acknowledge the National

Institutes of Health for financial support of this work through Grant no. NS 10197.

REFERENCES
1. For preliminary report of this work see: Wolfe, J. F.; Hendi, S. B.; Hendi, M.
Downloaded by [University of Huddersfield] at 01:41 15 January 2015

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Ether was distilled from lithium aluminum hydride. n-Butyllithium and
isocyanates were obtained from Aldrich Chemical Co., Milwaukee, WI, and
were used as such. Elemental analyses were carried out by Atlantic Microlab
Inc., Atlanta, GA.
 18 HENDI, HENDI, AND WOLFE

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