Cross-coupling reactions of carbamoyl chlorides and Grignard reagents: A new rapid synthesis of tertiary amides

Article abstract of DOI:10.1016/S0040-4039(00)01783-4

Tributyl phosphine or nickel catalysts allow the cross-coupling reaction between N,N-dialkylcarbamoyl chlorides and alkyl or aryl Grignard reagents. This convenient and simple method affords tertiary amides with moderate to excellent yields in short reaction times. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01783-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9997–10001
Cross-coupling reactions of carbamoyl chlorides and
Grignard reagents: a new rapid synthesis of tertiary amides
†
Laurent Lemoucheux, Jacques Rouden* and Marie-Claire Lasne
Laboratoire de Chimie Mol e´ culaire et Thioorganique, CNRS, ISMRA, Universit e´ de Caen-Basse Normandie,
6
Bd du Mar e´ chal Juin, 14050 Caen, France
Received 1 August 2000; accepted 10 October 2000
Abstract
Tributyl phosphine or nickel catalysts allow the cross-coupling reaction between N,N-dialkylcarbamoyl
chlorides and alkyl or aryl Grignard reagents. This convenient and simple method affords tertiary amides
with moderate to excellent yields in short reaction times. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amide; coupling reaction; carbamoyl chloride; nickel catalyst; Grignard; trialkyl phosphine.
Amides are usually synthesized as a two-component reaction from amines and acids via their
1
activated form. Another strategy is based on the reaction of an amine, a carbonyl equivalent
2
3
and a halogenated sp and sp carbon (electrophilic character). Carbon monoxide has been
largely used as a carbonyl source and this three-component one-step reaction is catalyzed by
2
transition metal complexes. This procedure was shown to be valuable in the restricted field of
3
4
5
6,7
radiochemistry. Carbon dioxide, carbamates, and phosgene are also used but more rarely.
Recently our laboratory reported the successful application of this methodology for the
1
1
4
preparation of radiolabeled amides using [ C] carbon dioxide. Due to the short half-life of this
positron emitter (20 min), and the limited number of available sources of carbon-11 (CO , CO
2
or CH ) from a cyclotron, there is still a need for a rapid synthesis of amides, especially when
4
the acid cannot be synthesized easily. Therefore we focussed our efforts on phosgene—easily
prepared from methane in carbon-11 chemistry—to introduce the carbonyl part of the amide
(
Scheme 1).
*
Corresponding author. Tel: (33) 2 31 45 28 93; fax: (33) 2 31 45 28 77; e-mail: rouden@ismra.fr
Preliminary communication at the 10th OMCOS, July 18–22, 1999, Versailles, France, poster P-402.
†
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01783-4

9998
O
3
+
CO2
R3
R -MgX
1 2
R R NH
R1
R2
R1
R2
OMgBr
O
O
O
1
2
N
N
+
R R NH
Cl
Cl
R3
Cl
R-X
+
CO
1
2
R R NH
Scheme 1.
8
By analogy with the formation of ketones from acid chlorides, we anticipated the possibility
of synthesizing amides from carbamoyl chlorides. In stable isotope chemistry, these latter
compounds are obtained in high yields by reaction of secondary amines in pyridine with
9
triphosgene [bis(trichloromethyl)carbonate]. Their reactions with an organometallic reagent to
yield amides is then the critical step. A few examples of amide formation using this strategy have
been reported. Ivanov reagent C H CH(MgCl)CO MgCl with diethyl- or diphenycarbamoyl
6
4
2
10
chlorides was reported to afford the corresponding amides in 71 and 47% yields. Carbamoyl
chlorides (in large excess, dimethyl carbamoyl chloride, the most often) were used to trap
lithiated species at low temperature as amides. The reaction of organotin reagents with
7
chlorocarbamates (1:1 ratio) in the presence of a palladium catalyst (5%) gave the corresponding
6
amides in moderate to good yields. However, the reaction was limited to aryl and vinylstan-
nanes. Moreover, it required high temperature, then the removal of often toxic tin derivatives.
We wish to describe herein our preliminary results on the rapid synthesis of amides from
commercially available carbamoyl chlorides 1 or 2 (Table 1) and Grignard reagents 3 (Scheme
2
).
First, we examined the reaction of 1 with a stoichiometric amount of n-butylmagnesium
bromide 3b at rt. After 21 h, the ratio of the expected amide 4b to the starting material 1 was
.85/1. This ratio was not improved with a longer reaction time. Difficulties encountered to
0
reproduce the reaction led us to envisage replacement of the CꢀCl bond of the carbamoyl
chloride. Tributyl phosphine, known to enhance the reactivity of acid chlorides in their
1
1
transformation into ketones and esters were allowed to react neat for 5 min with the
carbamoyl chlorides 1 or 2. Using a stoichiometric amount of reagents the corresponding
acylphosphonium salts 7 or 8 were isolated in quantitative yields. To the best of our knowledge
1
2
these salts have never been described. Triphenylphosphine and triethylphosphite failed to give
the phosphonium salt and the phosphonate, respectively, with 1 or 2. The reaction of salts 7 and
8
with Grignard reagents 3a–f in THF proceeded quickly (<30 min) to afford the desired amides
in 38–96% yields (Table 1, method A). Amides 4c or 5c were not isolated when using
trimethylsilylmethylmagnesium chloride.
As a promising alternative to this carbonꢀchloride bond replacement, we turned our attention
13
to nickel catalysis, often used in cross-coupling reactions with Grignard reagents. When
diethylcarbamoyl chloride 1 was allowed to react with ethylmagnesium bromide 3a in the
presence of NiCl dppe [dppe: 1,2-bis(diphenylphosphino)ethane], under the conditions described
2
1
4
to prepare thioamides from dialkylthiocarbamoyl chlorides and Grignard reagents, we
observed a complete conversion of 1 into the amide 4a after 1 h. Therefore we compared the
efficiency of a few nickel catalysts using the same reaction model. Using NiCl dppe, NiCl dppp
2
2
[
dppp: 1,3-bis(diphenylphosphino)propane] or NiCl (PPh ) similar conversions were obtained in
2
3 2
1
5 min (88, 83, and 84%, respectively). We then decided to employ NiCl (PPh ) , a cheap and
2
3 2
1
5
easily synthesized catalyst. The results (method B) are presented in Table 1 and compared with
those observed previously (method A).

9999
Table 1
Reaction of carbamoyl chlorides 1 and 2 with Grignard reagents 3
O
R
R
O
R'MgX 3
O
R
R
N
R,
R
N
N
N
Ni0
R'
Cl
O
O
Et, Et
1
2
4
5
6
(
O
(
CH2)2
R
O
R,
R
CH2)2
N
Et, Et
7
8
PBu3
R
PBu3 Cl
R' MgX
(
O
(
CH2)2
CH2)2
Scheme 2. Synthesis of amides from carbamoyl chlorides
Amides 4a–g and 5a–g were obtained in moderate to excellent yields, method B gave good
results with aryl Grignard reagents (entries 10–12) and with TMSCH MgCl (entries 5 and 6).
2
When a branched Grignard reagent was used, the phosphonium method appeared superior
(
entries 7 and 8). Vinylmagnesium bromide gave no reaction in both methods and the starting

10000
chlorocarbamates was almost recovered quantitatively (entry 13). In method B, the use of a
limited excess of organomagnesium reagent was necessary to avoid the formation of the
corresponding urea. This side product, not observed in method A, was formed in 5–15% yield
when morpholine chlorocarbamate 2 was allowed to react with ethylmagnesium bromide 3a,
n-butylmagnesium chloride 3b or with cyclohexylmagnesium chloride 3d (entries 2, 4, and 8).
We did not observe any decomposition of diethyl and morpholino chlorocarbamate under the
reaction conditions. Palladium complexes showed either a lower [Pd(PPh ) ] or a similar
3
4
[
PdCl (PPh ) ] reactivity than nickel catalysts in reaction of 1 with 3b.
2
3 2
General procedure: Method A: Under a nitrogen atmosphere, tri-n-butylphosphine (14.5
mmol, 1 equiv.) was added to the carbamoyl chloride (14.5 mmol). The reaction mixture was
heated with a heat gun until crystallization occurred (5 min, quantitative yield). After cooling,
the flask was charged with THF (10 mL) and a titrated solution of the Grignard reagent (15.95
mmol, 1.1 equiv.) was added dropwise at rt. The mixture turned yellow and was hydrolyzed with
water (3 mL) after 20 min. The solution was then washed with HCl (6N, 10 mL) to remove most
1
6
of the phosphine. The solution was washed successively with a saturated solution of Na CO3
2
and brine. Kugelrohr distillation or flash chromatography afforded the desired tertiary amide.
Method B: Under a nitrogen atmosphere, 1 (3.6 mmol) and NiCl (PPh ) (0.18 mmol, 0.05
2
3 2
equiv.) were mixed in THF (20 mL). The solution was stirred for a few minutes, and a titrated
THF solution of n-BuMgCl (2 mL, 2 M, 4 mmol, 1.1 equiv.) was carefully added dropwise at
rt. The solution turned dark brown and after 2 h it was quenched with a saturated NH Cl
4
solution (10 mL) and extracted with CH Cl (2×50 mL). The organic layers were dried over
2
2
Na SO and concentrated. Kugelrohr distillation afforded the amide 4b (2.5 mmol) in 68% yield.
2
4
The structures of amides 4a–f and 5a–f were assigned from their analytical and spectroscopic
1
7
data.
In summary, these two methods provide a useful tool for the preparation of tertiary amides
in rapid and convenient processes. The yields are similar to those obtained in carbonylations of
1
8,19
the corresponding amines.
Thus, carbamoyl chlorides afford a good carbonyl source usable
20
on a large scale avoiding double carbonylation. They also could be a good alternative to
carbon monoxide in carbon-11 chemistry. Indeed, the low reactivity and solubility of this
reagent require special equipment (recirculation flow or autoclave) in order for the reactions to
occur. The cross-coupling reaction of carbamoyl chlorides was achieved with either alkyl or aryl
Grignard complementing the procedure described with organotin compounds. Further studies
are underway with other organometallics and polymer-supported phosphines to expand the
scope of the reaction. Investigations for the synthesis of lactams as well as application to the
1
1
synthesis of C-amides will be reported in due course.
Acknowledgements
This work was supported by the ‘R e´ seau Interr e´ gional de Chimie Organique Fine’ Action 7
(
Contrat de Plan Etat Bassin Parisien-R e´ gions Haute Normandie, Basse Normandie). The
authors thank Jean Christophe Plaquevent and Dominique Cahard (Rouen) for the helpful
discussions.

10001
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(
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13
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.