ChemComm
Communication
1a–j were reacted with the pinacolic ester of the cyclopropyl This method is efficient for numerous amides of medicinal
boronic acid 2 under a dry air atmosphere for 24 hours at reflux and agrochemical interest.
of toluene (Table 2). The N-cyclopropyl-benzanilides 3a–e were
obtained in good to excellent yields (72–95%) starting from
benzanilides substituted on the aryl ring at a of CQO. The
Notes and references
¨
1 S. Pataı, The Chemistry of the Cyclopropyl Group Part 2, John Wiley &
reaction tolerates para-fluoro or para-methoxy substituents
(Table 2, entries 2 and 3), and chloro substituents (entries 4
and 5) either at the para or the ortho position. When the aryl
group attached on the nitrogen of the benzanilides was sub-
stituted by a para- or a meta-fluoro atom, yields of the corre-
sponding products dropped (41–42%, Table 2, entries 6 and 7).
However, with ortho-fluoro, ortho-chloro or para-methoxy sub-
stituents, the yields were good to excellent (68–95%, Table 2,
entries 8–10).
In a second set of experiments, we used our method to react
a wide range of secondary acyclic and cyclic amides 4a–j bearing
aromatic and/or aliphatic groups (Table 3, entries 1–10). Reac-
tions with N-phenylacetamide 4a or N-(pyridine-3-yl)benzamide
4c afforded the desired products in good isolated yields
(Table 3, entries 1 and 3). In comparison, the catalytic systems
described in the literature do not permit the coupling of this
kind of acyclic secondary amides.8b On the other hand, reaction
with N-methylbenzamide 4b as a coupling partner gave a low
yield under our conditions (Table 3, entry 2). Three examples of
simple cyclic secondary amides were also described (Table 3,
entries 6–8). The desired products from pyrrolidinone 4f,
pyridin-2(1H)-one 4g and 3,4-dihydroquinolin-2(1H)-one 4h
were obtained, respectively, in 93, 90 and 92% yield. The
methodology was also suitable to react substituted N-phenyl-
acetamide 4j in 67% yield whereas other systems are inefficient
for this substrate (Table 3, entry 10).8c Finally, we applied the
system for the cyclopropylation of well-known bio-active mole-
cules having N-aryl secondary acyclic amide functions such
as fungicides fenfuram 4d (Table 3, entry 4),10 mepronil 4e
(entry 5)11 and oxycarboxine 4i (entry 9).12
Sons, New York, 1987, vol. 1.
2 C. L. Shaffer, S. Harriman, Y. M. Koen and R. P. Hanzlik, J. Am.
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3 N. A. Meanwell, J. Med. Chem., 2011, 54, 2529.
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5 (a) L. D. Julian, Z. Wang, T. Bostick, S. Caille, R. Choi, M. De
Graffenreid, Y. Di, X. He, R. W. Hungate, J. C. Jaen, J. Liu,
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G. Eiermann, H. He, B. Leiting, K. Lyons, A. Petrov, R. Sinha-Roy,
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(e) D. Angst, B. Bollbuck, P. Janser and J. Quancard, WO 072712 A1,
2010; ( f ) R. Angelaud, I. Davies, C. Maguire, S. Lau, P. O’Shea and
S. Schultz, WO 011584 A2, 2010; (g) C. Liu, K. Leftheris,
V. M. Vrudhula and J. Lin, WO 103839 A2, 2007.
6 (a) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009,
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Org. Lett., 2011, 13, 2818; (d) W. Deng, Y. F. Wang, Y. Zou, L. Liu and
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Chem., Int. Ed., 2012, 51, 2925.
7 In this communication we used the frequently encountered classi-
fication for amides RCONR0R00: R0 = R00 = H for primary amides, R0 =
H and R00 a H for secondary amides, R0 and R00 a H for tertiary
amides. It is worth noting that following the IUPAC rules all these
amide categories correspond in fact to primary amides differently
N,N-substituted, (RCO)2NR0 and (RCO)3N being, respectively,
secondary and tertiary amides.
´
8 (a) A. Gagnon, M. St-Onge, K. Little, M. Duplessis and F. Barabe, J. Am.
Note that we tested several oxidants other than the dioxygen
from dry air such as pyridine N-oxide (PINO) or 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO). No improvement was
observed. On the other hand, performing the reaction under
an inert atmosphere of N2 led to a dramatic decrease in the
yield. Several mechanistic studies and hypotheses were reported
in the literature for Chan–Lam’s reaction. The coupling product
(Ar–nucleophile) could be generated by reductive elimination
from a copper(III) intermediate (Ar–[Cu]III–Nu).13 The presence
of an oxidant is supposed to favor this step by in situ oxidation
Chem. Soc., 2007, 129, 44; (b) T. Tsuritani, N. A. Strotman, Y. Yamamoto,
M. Kawasaki, N. Yasuda and T. Mase, Org. Lett., 2008, 10, 1653;
´
(c) S. Benard, L. Neuville and J. Zhu, J. Org. Chem., 2008, 73, 6441;
´
(d) S. Benard, L. Neuville and J. Zhu, Chem. Commun., 2010, 46, 3393.
9 (a) J. X. Qiao and P. Y. S. Lam, Synthesis, 2011, 829; (b) K. S. Rao and
T.-S. Wu, Tetrahedron, 2012, 68, 7735; (c) D. M. T. Chan,
K. L. Monaco, R. P. Wang and M. P. Winters, Tetrahedron Lett.,
1998, 39, 2933; (d) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams,
M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998,
39, 2941.
10 A seed-treatment fungicide used to control bunts and smuts in
cereals. Mode of action of fenfuram: (a) P. J. Kuhn, Symp. Br. Mycol.
Soc., 1989, 9, 155; (b) D. L. Strider, Plant Dis., 1980, 64, 188.
of the corresponding Ar–[Cu]II–Nu. The oxidant could also 11 A fungicide used to control diseases caused by Basidomycetes
including Rhizoctonia and Puccinia spp. H. Terada, Biochim. Biophys.
Acta, 1981, 639, 225.
12 A fungicide for the control of rust diseases on ornamentals, cereals
regenerate the catalytically active species after the final reduc-
tive elimination step.9a
In summary, we have developed an efficient copper-
mediated system allowing the N-cyclopropylation of secondary
cyclic and acyclic amides, which are known to be poor nucleo-
philic partners, under Chan–Lam-type reaction conditions.
and nursery trees. Also used to control fairy rings on turf.
Also a pesticide transformation product: B. M. Spiegelman, WO
2006014529, 2006.
13 Modern arylation methods, ed. L. Ackerman, Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim, 2009, pp. 121–154.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.