From isocyanides to trichloropyruvamides: Application to a new preparation of oxamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.08.169

Isocyanides react readily with trichloroacetic acid anhydride forming stable hydrates of trichloropyruvamides. These compounds are valuable intermediates for obtaining oxamides by reaction with TMSCl/NEt₃ followed by addition of an amine.

Full text of DOI:10.1016/j.tetlet.2004.08.169

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8047–8048
From isocyanides to trichloropyruvamides: application to a
new preparation of oxamide derivatives
Laurent El Kaim,* Laetitia Gaultier, Laurence Grimaud and Emilie Vieu
´ ´ ´ ´
Laboratoire Chimie et Procedes, Ecole Nationale Superieure de Techniques Avancees, 32 Bd Victor, 75015 Paris, France
Received 29 April 2004; revised 30 August 2004; accepted 31 August 2004
Available online 17 September 2004
Abstract—Isocyanides react readily with trichloroacetic acid anhydride forming stable hydrates of trichloropyruvamides. These
compounds are valuable intermediates for obtaining oxamides by reaction with TMSCl/NEt3 followed by addition of an amine.
Ó 2004 Elsevier Ltd. All rights reserved.
Since the discovery of the haloform reaction,1 the trihal-
omethyl group has been recognized as a potential leav-
ing group in synthesis and its elimination is usually
associated with the development of a negative charge
at a b-position. This is the case with the formation of
isocyanates after basic treatment of N-monoalkyltri-
chloroacetamides2 or in the addition–elimination proc-
ess between amines and trichloromethylketones.3
Following our studies on trifluoropyruvamides,4 we
wished to prepare the analogous chloro derivatives by
a similar addition of isocyanides to trichloroacetic acid
anhydride. As these pyruvamides had never been pre-
pared before, we were prompted to examine the behav-
iour of these compounds towards various nucleophiles.
soluble in hot toluene and almost insoluble at room tem-
perature, indicating a potential equilibrium between the
free ketone and its hydrate.
The highly electrophilic carbonyl function of chloro-
pyruvamides should promote easy additions of nucleo-
philes, and the stabilization of the tetrahedral adducts
should enhance, under basic conditions, the removal
of the trichloromethyl group.
The pharmacological interest in oxamides made us first
test the behaviour of these pyruvamides with amines. In-
deed, heating morpholine 3a and 2a in toluene brought
about the expected elimination of the trichloromethyl
group, but oxamide 4a was only formed in traces, the
acid 5 being obtained almost quantitatively. The starting
hydrate appears to be sensitive to the basic medium
leading to direct removal of CCl3 and formation of acid
5 (Scheme 2). A two-step procedure using silylation was
then adopted in order to suppress the acid formation:
TMSCl (2equiv) and triethylamine (2equiv) were added
When trichloroacetic anhydride was added to o-tolyliso-
cyanide 1a in dichloromethane and the mixture left at
room temperature, the new pyruvamide 2a was obtained
in a 85% isolated yield. The more complex 1b behaved
similarly (Scheme 1). As observed with the hydrates of
trifluoropyruvamides, the chloro analogues were highly
EtO2C
1) (CCl3CO)2O (1.2 eq), CH2Cl2
-20˚C then rt
O
NHR
OH
Me
R
NC
R=
Cl3C
2) H2O
OH
1
OMe
2
2a
2b
80%
85%
Scheme 1.
Keywords: Trichloromethyl; Amide; Pyruvamide; Isocyanides.
*
Corresponding author. Tel.: +33 14552557; fax: +33 145528322; e-mail: elkaim@ensta.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.169

8048
L. El Kaim et al. / Tetrahedron Letters 45 (2004) 8047–8048
O
O
O
O
3a
1) TMSCl, NEt3
OH
CCl3
N
N
H
N
N
H
toluene
∆
H
Me
O
HO OH
O
2)
NH rt
Me
Me
O
60%
5
2a
3a
4a
Scheme 2.
Table 1.
H
N
R = Ph : 3c
R = CO2Et : 3e
n = 1 : 3b
n = 2 : 3d
R
NH2
n
Starting 2a
Amine 3
Productb
Time (h)
Yield (%)
2a
2a
2a
2a
2a
2b
2b
3a
3b
3c
3d
3e
3b
3e
4a
4b
4c
4d
4e
4f
3
2
60
95
22
2
100
75
72
15
72
66
68
4g
72
a To a 0.3M solution of trichloroacetic anhydride (1.2equiv) in dry dichloromethane was added 1 at À20°C and the mixture stirred at rt for 16h
before adding water and aqueous NaHCO3. The crude mixture was purified by column chromatography on silica gel.
b To a 0.25M solution of 2 in dry THF was added TMSCl (2equiv) and NEt3 (2equiv). The resulting mixture was stirred for 2h at rt before adding
the amine. Stirring was continued at rt for the time given in the table.
O
O
1) TMSCl (2eq), NEt3 (2eq)
SC12H26
25%
CCl3
N
N
H
H
2) C1 2H26S (1.5 eq), DBU (1.5 eq)
rt
HO OH
Me
O
Me
2a
6
7
Scheme 3.
to pyruvamide 2a before adding the amine. The overall
process, conducted in THF at room temperature, leads
now to the formation of the expected oxamide in a
60% isolated yield (Scheme 2).
the mechanism involved are currently under study
(Scheme 3).
References and notes
Several secondary and primary amines behaved simi-
larly as shown by the results compiled in Table 1. Most
noteworthy is the quantitative formation of oxamide 4b
and 4c with pyrrolidine and benzylamine as well as the
successful addition of aminoester 3e to pyruvamides 2a
and 2b.
1. Fuson, R. C.; Bull, B. A. Chem. Rev. 1934, 15, 275–309.
2. Atanassova, I. A.; Petrov, J. S.; Moltov, N. M. Synthesis
1987, 8, 734–736; Braverman, S.; Cherkinsky, M.; Kedrova,
L.; Reiselman, A. Tetrahedron Lett. 1999, 40, 3235–3238.
3. Braverman, S.; Cherkinsky, M.; Kumar, E. V. K. S.;
Gottlieb, H. E. Tetrahedron 2000, 56, 4521–4530; Salim, J.
R.; Nome, F.; Rezende, M. C. Synth. Commun. 1989, 19,
1181–1188; Sukornick, B. In Organic Syntheses; Baumgar-
ten, H. E., Ed.; John Wiley & Sons: New York, 1973; Coll.
Vol. 5, pp 1074–1076.
Oxamides derivatives have already been prepared by
several routes. The most efficient involves addition of
amines to oxalyl chloride monoesters.5 Besides its inter-
est as an alternative procedure for the synthesis of
unsymmetrical oxamides, this new synthetic strategy
could be applied to additions of other nucleophiles such
as thiols; the new thioester 7 was thus obtained in a 25%
isolated yield from pyruvamide 2a and dodecanethiol 6.
The scope of these nucleophilic additions as well as
4. El Ka¨ım, L. Tetrahedron Lett. 1994, 35, 6669–6670; El
´
Ka¨ım, L.; Pinot-Perigord, E. Tetrahedron 1998, 54, 3799–
3806; El Ka¨ım, L.; Guyoton, S.; Meyer, C. Tetrahedron
Lett. 1996, 37, 375–378; El Ka¨ım, L.; Ollivier, C. Synlett
1997, 797.
5. Mulliez, M.; Royer, J. Tetrahedron 1984, 40, 5143–5152.