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Table 3 Scope of aminesa,b
Scheme 3 Plausible mechanism.
One of the nitrogen atoms of the substrate coordinated to the
copper atom in complex A and formed intermediate B, which
facilitated the attack of secondary amine on the carbon atom of
isocyanide to give rise to the diaminocarbene intermediate C.22 The
subsequent insertion reaction and reductive elimination of CuH
led to intermediate E,23 which then afforded the urea product 4d
through a thermolytically induced 1,3-O - N acyl transfer.24
In conclusion, we have successfully revealed the first copper-
mediated multi-component reaction through sequential isocyanide
insertions into N–H bonds of less active secondary arylamines,
reductive elimination of CuH, and [1,3]-acyl transfer processes. This
approach features a new mode of insertion for isocyanides and
provides an efficient access to unsymmetrical tetrasubstituted
ureas with operational simplicity and a wide substrate scope.
Further insight into the mechanism, reaction scope and synthetic
applications are under investigation.
a
Reaction conditions: amine (0.5 mmol), 2a (3.0 equiv.), Cu(OAc)2ÁH2O
b
(2.0 equiv.), 110 1C, air, toluene (3.0 mL). Isolated yield.
We thank the National Natural Science Foundation of China
(No. 21272149) and Innovation Program of Shanghai Municipal
Education Commission (No. 14ZZ094) for financial support and
Prof. Hongmei Deng (Laboratory for Microstructures, SHU) for
assistance with spectral measurements.
Scheme 2 Mechanistic studies.
was used, and this result implied that incorporation of a nitrogen
atom into the substituent of poorly nucleophilic amine is crucial
for this transformation (eqn (1)). When the complex of 1d and
Cu(OAc)2ÁH2O was treated with tert-butyl isocyanide, the reaction
afforded only a trace amount of the desired urea 4d (eqn (2)).
Evidently, the complexation effect of copper did not take place in
the initial step with the substrate. However, when a Cu(II) acetate–
isocyanide complex, generated from Cu(OAc)2ÁH2O and tert-butyl iso-
cyanide, was treated with 1d, the urea product could be obtained in
89% yield under the standard conditions (eqn (3)), which is comparable
with the result of the one-step procedure giving 90% yield (Table 2).
Furthermore, the reaction of 1d with the synthesized acetate–isocyanide
complex [AcOCu(I)Á(CRN-Bu-t)]19 could give urea 4d in comparable
yields under an air or nitrogen atmosphere (eqn (4)). These results
indicated that the Cu(I) complex might be the key intermediate during
the reaction, and the incorporated nitrogen atom of the amine
facilitated the subsequent insertion by its coordination effect to the
copper atom. The addition of TEMPO as a radical scavenger had no
significant effect on this reaction which evidenced that the radical
mechanism through the imidoyl radical could be ruled out.20
Notes and references
1 For reviews, see: (a) M. Tobisu and N. Chatani, Chem. Lett., 2011, 40, 330;
(b) R. M. Wilson, J. L. Stockdill, X. Wu, X. Li, P. A. Vadola, P. K. Park,
P. Wang and S. J. Danishefsky, Angew. Chem., Int. Ed., 2012, 51, 2834.
¨
2 For reviews, see: (a) A. Domling, Chem. Rev., 2006, 106, 17; (b) A. V. Lygin
and A. de Meijere, Angew. Chem., Int. Ed., 2010, 49, 9094.
3 Progress in Inorganic Chemistry, ed. F. A. Cotton, Interscience,
New York, 1959, pp. 284–379.
4 For reviews, see: (a) S. Lang, Chem. Soc. Rev., 2013, 42, 4867; (b) G. Qiu,
Q. Ding and J. Wu, Chem. Soc. Rev., 2013, 42, 5257; (c) T. Vlaar, E. Ruijter,
B. U. W. Maes and R. V. A. Orru, Angew. Chem., Int. Ed., 2013, 52, 7084.
5 For selected examples, see: (a) J. Ping, L. Liu, Z. Hu, J. Huang and
Q. Zhu, Chem. Commun., 2012, 48, 3772; (b) G. Qiu, G. Liu, S. Pu and
J. Wu, Chem. Commun., 2012, 48, 2903.
6 Isocyanide Chemistry Applications in Synthesis and Material Science,
ed. V.Nenajdenko, WILEY-VCH, Weinheim, 2012, pp. 35–73.
7 (a) T. Saegusa, Y. Ito, S. Kobayashi, K. Hirota and H. Yoshioka,
Tetrahedron Lett., 1966, 7, 6121; (b) T. Saegusa, Y. Ito, S. Kobayashi,
K. Hirota and H. Yoshioka, Bull. Chem. Soc. Jpn., 1969, 42, 3310.
8 (a) R. Smith and T. Livinghouse, J. Org. Chem., 1983, 48, 1554;
(b) J. Zakrazewski, J. Jezierska and J. Hupko, Org. Lett., 2004, 6, 695;
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9 For recent reviews, see: (a) P. Dydio, D. Lichosyt and J. Jurczak,
Chem. Soc. Rev., 2011, 40, 2971; (b) N. Volz and J. Clayden, Angew.
Chem., Int. Ed., 2011, 50, 12148.
Although the detailed reaction mechanism remains to be
clarified, a plausible mechanism for this reaction was proposed
on the basis of the above results (Scheme 3). Initially, Cu(I) acetate–
isocyanide complex A was formed possibly by disproportionation of
Cu(II)21 or through reduction of Cu(II) reagents by isocyanide.3,7b
10 For reviews see: (a) F. Biggi, R. Maggi and G. Sartori, Green Chem.,
´
2000, 2, 140; (b) D. J. Dıaz, A. K. Darko and L. McElwee-White, Eur.
J. Org. Chem., 2007, 4453; (c) F. Ragaini, Dalton Trans., 2009, 6251.
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