Preparation of tertiary amides from carbamoyl chlorides and organocuprates

Article abstract of DOI:10.1021/ol0487130

(Chemical Equation Presented) Reaction of carbamoyl chlorides with cyano-Gilman cuprates affords tertiary amides in good to excellent yields. The reaction is general due to the possibility of using reagents made either from organolithium or from Grignard compounds. The characterization of the main side products allowed for the suggestion of a possible mechanism.

Full text of DOI:10.1021/ol0487130

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3703-3706
Preparation of Tertiary Amides from
Carbamoyl Chlorides and
Organocuprates
Laurent Lemoucheux, Thomas Seitz, Jacques Rouden,* and Marie-Claire Lasne
Laboratoire de Chimie Mole´culaire et Thio-Organique, UMR CNRS 6507, ENSICaen,
UniVersite´ de Caen-Basse Normandie, 6 BouleVard du Mare´chal Juin,
14050 Caen Cedex, France
rouden@ensicaen.fr
Received July 7, 2004
ABSTRACT
Reaction of carbamoyl chlorides with cyano-Gilman cuprates affords tertiary amides in good to excellent yields. The reaction is general due
to the possibility of using reagents made either from organolithium or from Grignard compounds. The characterization of the main side
products allowed for the suggestion of a possible mechanism.
Despite numerous efforts to replace it, phosgene is still
widely used in organic chemistry, providing the carbonyl
part of many functional groups. Under basic conditions,1 it
reacts with secondary amines to afford carbamoyl chlorides,
which are often used in situ because of their high reactivity
toward nucleophiles. Thus, straightforward access to stable
carbamates and ureas is achieved with alcohols and amines,
respectively.2 Less common are their reactions with carb-
anions yielding amides. Indeed, unlike acid chlorides or
chloroformates, carbamoyl chlorides do not react properly
with Grignard reagents without a catalyst.3 Moreover, the
coupling is limited to alkyl and aryl Grignard reagents (not
vinyl). Their reactions with organolithium reagents are
mainly described with aromatic carbanions.4 Moreover, they
are carried out with an excess of carbamoyl chloride. A few
more reports described the Sonogashira5 or Stille6 type
couplings with carbamoyl chlorides. Only acetylenic, aryl,
or vinyl amides could be prepared by these methods.
Organopotassium,7 organozinc,8 and organotitanium9 were
used in specific cases for this transformation. Thus, there is
a need for a general method for making amides from
carbamoyl chlorides. In our continuing interest in synthesiz-
ing amides and lactams from carbamoyl chlorides3,10 we
report here an efficient method using organocuprates as
organometallic species. For our study we selected three
carbamoyl chlorides, 1 and 2, which are commercially
available, and 3, which is easily prepared1c (Figure 1).
First, we examined the reaction of 1 or 2 with the less
reactive organocopper reagents (MeCu‚LiI, MeCu‚MgICl,
n-BuCu‚LiBr‚Me2S, MeCu‚LiI‚2PBu3, n-BuCuCNLi).11 The
(1) (a) Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis 1996,
553-576. (b) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987,
26, 894-895. (c) Lemoucheux, L.; Rouden, J.; Ibazizene, M.; Sobrio, F.;
Lasne, M.-C. J. Org. Chem. 2003, 68, 7289-7297. (d) Gymer, G. E.;
Narayanaswani, S. N. In ComprehensiVe Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon Press: Oxford, 1995; Vol. 6, pp 442-443.
(2) Hegarty, A. F. In ComprehensiVe Organic Chemistry; Sutherland, I.
O., Ed.; Pergamon Press: Oxford, 1979; Vol. 2, Chapter 9.10.
(3) Lemoucheux, L.; Rouden, J.; Lasne, M.-C. Tetrahedron Lett. 2000,
41, 9997-10001.
(4) Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54, 4,
4372-4385.
(5) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977, 777-778.
(6) (a) Balas, L.; Jousseaume, B.; Shin, H.; Verhlac, J.-B.; Wallian, F.
Organometallics 1991, 10, 366-368. (b) Jousseaume, B.; Kwon, H.;
Verhlac, J.-B.; Denat, F.; Dubac, J. Synlett 1993, 2, 117-118.
(7) (a) Azzena, U.; Melloni, G.; Pisano, L. Tetrahedron Lett. 1993, 34,
5635-5638. (b) McNichols, A. T.; Stang, P. J.; Addington, D. M.
Tetrahedron Lett. 1994, 35, 437-440.
(8) Choi, S. K.; Jeong, Y.-T. Chem. Commun. 1988, 1478-1479.
(9) Szymoniak, J.; Felix, D.; Moise, C. Tetrahedron Lett. 1996, 37, 33-
36.
(10) Rouden, J.; Seitz, T.; Lemoucheux, L.; Lasne, M.-C. J. Org. Chem.
2004, 69, 3787-3793.
(11) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
10.1021/ol0487130 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/23/2004

Table 1. Amides from Carbamoyl Chlorides and
Cyano-Gilman Reagents
Figure 1. Selected carbamoyl chlorides.
reactions, attempted in THF or Et2O, did not afford a
conversion higher than 20% into the expected amides. Similar
results were obtained when the organometallic reagents were
used in combination with a catalyst: MeCu‚LiI and 5%
PdCl2(PPh3)2,12 n-BuCuCNLi and 5% NiCl2(PPh3)2, and
EtMgCl and 3% Li2CuCl4.13
Next, we turned our attention toward the reaction of
carbamoyl chloride 1 with Gilman and cyano-Gilman cu-
prates (RM).11 The results (Scheme 1) showed that the
Scheme 1. Lithiated Organocuprate Reaction with Carbamoyl
Chloride 1a
a Starting material. b Cyanocuprate reagents were prepared at -30 °C.
Reaction time: 2 h. c GC yields. Ratios of formamides, ureas, and
oxalamides are given in Supporting Information. d Also recovered was
5-10% starting material. e Also recovered was 10-20% starting material.
f Also recovered was 20-40% starting material.
a Ratios in % determined by GC-MS analysis.
highest yield of amide 4a was obtained using the cyano-
cuprate, with little or no formamide 5, urea 6, and oxalamide
7. Moreover, in the reaction of the Gilman reagent, GC-MS
analysis revealed also the presence of substantial amounts
of 5-nonanone and octane (3-4% of each). Therefore, we
selected copper(I) cyanide as the copper salt for the prepara-
tion of cuprate reagents.
side products deserve some comments. Formamides (5-
11%) are mainly produced in Et2O when using sec or tert-
butyl cuprates. A mechanism involving a copper(III) inter-
mediate14 followed by a â-elimination process is proposed
(Scheme 2).15 A radicalar decomposition of the same
intermediate (path a) could explain the formation of oxal-
amides (1-14%). Ureas (2-9%) were formed probably
according to path b. The reaction of 2 was also attempted
with alkyl cuprates in the presence of LiCl,16 R-methyl-
styrene,17 or p-trifluoromethylstyrene18 or in 2-methyl-
tetrahydrofuran,19 but none of these experiments improved
the previous results.
The scope of the reaction of carbamoyl chlorides 1-3 with
cyanocuprates generated from commercially available organo-
lithium solutions was studied next. The results are sum-
marized in Table 1. Aryl and alkyl amides were produced
in good to excellent yields with the exception of 8e (entry
10), and better results were obtained in THF compared to
Et2O. With branched alkyl cuprates (sec and tert-butyl),
moderate to good yields of amides were obtained considering
the steric demand of the organometallic reagent (entries 3,
6-8, 13).
(14) House, H. O.; Dubose, J. C. J. Org. Chem. 1975, 40, 788-790.
(15) We proposed the involvement of copper(III) and radical intermedi-
ates to explain the formation of the reaction products. For a complete
discussion, see: Bertz, S. H.; Dabbagh, G.; Mujsce, A. M. J. Am. Chem.
Soc. 1991, 113, 631-636.
(16) Nakamura, E.; Yamanaka, M.; Mori, S. J. Am. Chem. Soc. 2000,
122, 1826-1827.
(17) This reagent was used to trap free radicals; see ref 15.
(18) This reagent was used to accelerate reductive elimination and to
avoid â-elimination; see: Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 174-175 and references therein.
(19) Formamides were mainly produced in Et2O. We tried 2-Me-THF
as a better coordinating solvent than THF to completely suppress â-elimina-
tion and eventually to improve the overall yield (entries 7 and 8).
The side products formed beside the expected amides, i.e.,
formamides 5, 9, 13, ureas 6, 10, 14, and oxalamides 7, 11,
15, were independently synthesized for unambiguous char-
acterization and quantitation. The nature and the amount of
(12) Jabri, N.; Alexakis, A.; Normant, J. F. Tetrahedron 1986, 42, 1369-
1380.
(13) Cahiez, G.; Chaboche, C.; Je´ze´quel, M. Tetrahedron 2000, 56,
2733-2737 and references therein.
3704
Org. Lett., Vol. 6, No. 21, 2004

Scheme 2. Proposed Mechanism
Due to their unique reactivity,20 magnesiocuprates ap-
compared to our previous experiments with lithiocuprates.
The structure of the cyanocuprate reagents could explain such
differences. Whereas the lithiocuprates generated from copper
cyanide can be described as diorganocuprates with a di-
lithium cyanide countercation,22 their magnesium counter-
parts appear as monoalkyl-cyanocuprate magnesium com-
plexes with the cyanide still bound to the copper.23 The
second equivalent of organomagnesium remaining in the
solution could account for the formation of urea 10.3 Since
monoorganocyanocuprates are unable to react with carbam-
oyl chlorides,24 we cannot preclude the existence of the
diorganocuprate complex in small amounts, which may be
the reactive species.
peared as a viable alternative to lithiated cuprates because
of the diversity of commercially available organomagnesium
products or the easiness of their preparation.21 Reactions of
carbamoyl chloride 2 with cyano-Gilman magnesiocuprates
were carried out in Et2O or THF at room temperature over
15 h, and the most representative results are summarized in
Table 2. Et2O proved to be a better solvent than THF (entries
Table 2. Reaction of 2 with Cyano-Gilman Magnesiocuprates
entry
2 RMgX + CuCNa
amide
yieldb
1
2
3
4
5
6
7
8
9
n-BuMgBr
n-BuMgBrc
s-BuMgBr
t-BuMgCl
8a
8a
8b
8c
8d
8f
79
d
Finally, we used milder organometallic reagents compat-
ible with a wide range of functional groups. The reactions
of 2 with mixed copper-zinc reagents25 (RZn(Cu)X or
RCu(CN)ZnX‚2LiCl) and diorganozinc reagents (R2Zn) did
not provide amide 8 (even with catalytic Pd(PPh3)4), whereas
contrasting results were obtained with monoorganozinc
reagents (R3ZnX).26
75
56
70
62
51
51
69
45e
PhMgBr
c-HexMgCl
c-HexMgClc
allyl-MgBr
BnMgCl
8f
8g
8h
8i
In conclusion, we have disclosed an efficient method for
the synthesis of tertiary amides. It involved the coupling
reaction of carbamoyl chlorides with alkyl (including branched
alkyl), aryl, vinyl, allyl, and benzyl cyanocuprates. The nature
of the solvent was crucial to minimize the side reactions.
As precursors of cyanocuprates, organolithium and, more
advantageously, Grignard reagents were used. This reliable
methodology provides a viable alternative to carbon mon-
oxide and a new use for phosgene, or its substitutes, as a
carbonylating reagent to synthesize tertiary amides, mostly
when corresponding acids are not easily available. Due to
the peculiar reactivity of organocopper reagents,25 work is
now in progress to extend the scope of the reaction to
functionalized substrates or reagents.
10
Me2CdCHMgBr
a Cyanocuprate reagents (1.05 equiv compared to 2) were prepared in
Et2O at -30 °C. b Isolated yield. c Reactions carried out in THF. d Less
than 50% conversion. e Also recovered was 50% unreacted carbamoyl
chloride 2.
1-2 and 6-7), affording amides 8a and 8f in good yields.
Urea 10, the only byproduct, was formed in an amount not
exceeding 10% (data not shown in Table 2). All types of
carbon residues were coupled efficiently with carbamoyl
chloride 2: primary, secondary, and tertiary alkyl, phenyl,
benzyl, allyl, and vinyl. In the latter case, the reaction was
slow and only 50% conversion was observed after 15 h at
room temperature (entry 10), but we did not detect any 1,4-
addition product. The reactions were slower but cleaner
(22) Krause, N. Angew. Chem., Int. Ed. 1999, 38, 79-81.
(23) Huang, H. Ph.D. Dissertation, University of Michigan, Ann Arbor,
MI, 1997.
(24) We assume that RCuCNMgX reagents have a similar or lower
reactivity towards 2 than their lithiated counterparts.
(25) Knochel, P.; Betzemeier, B. In Modern Organocopper Chemistry;
Krause, N.; Wiley-VCH: Weinheim, 2002; pp 45-78.
(26) In refluxing toluene, low conversion occurred with n-BuZnCl and
72% yield of 8d was isolated with PhZnCl, where both reactions were
carried out with 5% Pd(PPh3)4.
(20) (a) Totani, K.; Nagatsuka, T.; Yamaguchi, S.; Takao, K.-I.; Ohba,
S.; Tadano, K.-I. J. Org. Chem. 2001, 66, 5965-5975. (b) Ito, M.;
Matsuumi, M.; Murugesh, M. G.; Kobayashi, Y. J. Org. Chem. 2001, 66,
5881-5889. (c) Oishi, S.; Kamano, T.; Niida, A.; Odagaki, Y.; Tamamura,
H.; Otaka, A.; Hamanaka, N.; Fujii, N. Org. Lett. 2002, 4, 1051-1054 and
1055-1058.
(21) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302-4320.
Org. Lett., Vol. 6, No. 21, 2004
3705

Acknowledgment. We gratefully acknowledge the French
Ministry of Research (fellowships to L.L.), “Poˆle Universi-
taire Normand de Chimie Organique”, CNRS, Re´gion Basse-
Normandie, and the European Union (FEDER funding) for
financial support. Special thanks are due to Professor James
Penner-Hahn, University of Michigan, for sending us Chapter
3 of Huang’s Ph.D. Thesis.
Supporting Information Available: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0487130
3706
Org. Lett., Vol. 6, No. 21, 2004