methylenation and formylation reactions. Further study of
their application in organic synthesis is currently underway.
This work was supported by National Natural Science
Foundation of China (90913023, 21121091) and the Fundamental
Research Funds for Central University (1082020502).
Notes and references
1 (a) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007,
36, 1173; (b) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem.
Rev., 2010, 110, 624; (c) T. Nishimura, H. Araki, Y. Maeda and
S. Uemura, Org. Lett., 2003, 5, 2997; (d) T. Seiser, T. Saget,
D. N. Tran and N. Cramer, Angew.Chem., Int. Ed., 2011,
50, 7740; (e) B. M. Trost and M. L. Crawley, Chem. Rev., 2003,
103, 2921; (f) J.-P. Chen, Q. Peng, B.-L. Lei, X.-L. Hou and
Y.-D. Wu, J. Am. Chem. Soc., 2011, 133, 14180.
2 (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215;
(b) Z. P. Li and C. J. Li, J. Am. Chem. Soc., 2005, 127, 3672;
(c) Z. P. Li, D. S. Bohle and C. J. Li, Proc. Natl. Acad. Sci.
U. S. A., 2006, 103, 8928.
3 (a) R. M. Laine, D. W. Thomas and L. W. Cary, J. Am. Chem.
Soc., 1982, 104, 1763; (b) L. J. L. Haeller, M. J. Page, S. Erhardt,
S. A. Macgregor, M. F. Mahon, M. Abu Naser, A. Velez and
M. K. Whittlesey, J. Am. Chem. Soc., 2010, 132, 18408;
(c) Y. Kuninobu, M. Nishi and K. Takai, Chem. Commun., 2010,
46, 8860.
4 (a) X. Xu, X. Li, L. Ma, N. Ye and B. Weng, J. Am. Chem. Soc.,
2008, 130, 14048; (b) H. Li, Z. He, X. Guo, W. Li, X. Zhao and
Z. Li, Org. Lett., 2009, 11, 4176; (c) M.-Z. Wang, C.-Y. Zhou,
M.-K. Wong and C.-M. Che, Chem–Eur. J., 2010, 16, 5723;
(d) K. Ramachandiran, D. Muralidharan and P. T. Perumal,
Tetrahedron Lett., 2011, 52, 3579; (e) W. Liu, J. Liu, D. Ogawa,
Y. Nishihara, X. Guo and Z. Li, Org. Lett., 2011, 13, 6272;
(f) W. Wu and W. Su, J. Am. Chem. Soc., 2011, 133, 11924;
(g) J.-C. Wu, R.-J. Song, Z.-Q. Wang, X.-C. Huang, Y.-X. Xie and
J.-H. Li, Angew. Chem., Int. Ed., 2012, 51, 3453.
5 (a) C. Pal, S. Dey, S. K. Mahato, J. Vinayagam, P. K. Pradhan,
V. S. Giri, P. Jaisankar, T. Hossain, S. Baruri, D. Ray and
S. M. Biswas, Bioorg. Med. Chem. Lett., 2007, 17, 4924;
(b) E. Ciska, R. Verkerk and J. Honke, J. Agric. Food Chem.,
2009, 57, 2334.
6 (a) R. B. Vanorder and H. G. Lindwall, J. Org. Chem., 1945,
10, 128; (b) M. Sisa, D. Pla, M. Altuna, A. Francesch, C. Cuevas,
F. Albericio and M. Alvarez, J. Med. Chem., 2009, 52, 6217;
(c) C.-Y. Wu, M. Hu, Y. Liu, R.-J. Song, Y. Lei, B.-X. Tang,
R.-J. Li and J.-H. Li, Chem. Commun., 2012, 48, 3197.
7 (a) J. T. Scanlan, J. Am. Chem. Soc., 1935, 57, 887; (b) A. Corma,
P. Botella and C. Mitchell, Chem. Commun., 2004, 2008.
8 (a) Z.-S. Deng, Y. Zhao, C.-C. He, J. Jin, Y.-M. He and J.-X. Li,
Org. Lett., 2008, 10, 3879; (b) Z.-S. Deng, J.-X. Li, P. Teng, P. Li
and X.-R. Sun, Org. Lett., 2008, 10, 1119; (c) J. Jin, M.-M. Cai and
J.-X. Li, Synlett, 2009, 2534.
Scheme 1 Proposed mechanism for methylenation and formylation.
the transformation. For example, m-methylaniline (5i) reacted
smoothly to furnish 6i in 95% yield. However, o-methylaniline
(5l) and p-methylaniline (5p) were completely inactive even at
o
140 C for 24 h. Fortunately, good yields were still achieved
from substrates with Bn, PMB, and allyl protected anilines
(6c–e). Furthermore, high yields for 6f and 6g indicated that
the sterically congested substrates were tolerated. Cyclic
amines such as 6m and 6n selectively underwent the target
coupling reaction in ideal yields.
To gain insight into the reaction pathway further experiments
were carried out. When hydroquinone monomethyl ether (MEHQ)
was used as a radical inhibitor, the yield of 3a remained almost
unchanged. H NMR study of the reaction mixture of 1a indicated
that TMEDA transformed into trimethylethylenediamine (2d)
when the MeCN-d3 was used as the solvent (Fig. S2, ESIw). To
exclude the possibility of 3-formylindole as an intermediate, 4a was
treated with indole 1j under standard conditions. Upon isolation
and GC-MS analysis, no heterobisindolylmethane was detected
(Fig. S3, ESIw). Therefore, a tentative mechanism was proposed
(Scheme 1). Initially, TMEDA coordinated with CuCl2 afforded
Cu(II)-TMEDA complex C;12 iminium ion (A) is generated by
selective oxidation of C–H bond of TMEDA. Following this,
nucleophilic addition of indole affords the oxidative Mannich-type
product B,2,13 which undergoes further oxidation to the second
iminium ion, followed by hydrolysis to generate 3-formylindole
(pathway A).4f In view of methylenation (pathway B), two
molecules of indoles react with one molecule of formaldehyde
that is generated in situ by metal-catalyzed oxidative
N-demethylation,4c,14 in the presence of Lewis acid, to afford
bisindolylmethane.5a,15 Pathways B and A presented in the
reaction system simultaneously, while the former could be
suppressed by adding base, such as K2CO3.
9 Other weaker bases such as NaHCO3, KOAc, and KH2PO4 gave
poor results.
10 (a) P. N. James and H. R. Snyder, Org. Synth., 1959, 39, 30;
(b) F. T. Tyson and J. T. Shaw, J. Am. Chem. Soc., 1952, 74, 2273.
11 (a) W. J. Boyd and W. Robson, Biochem. J., 1935, 29, 555;
(b) R. C. Blume and H. G. Lindwall, J. Org. Chem., 1945, 10, 255.
12 (a) D. S. Surry and S. L. Buchwald, Chem. Sci., 2010, 1, 13;
(b) J. P. Collman and M. Zhong, Org. Lett., 2000, 2, 1233.
13 (a) S. I. Murahashi, N. Komiya, H. Terai and T. Nakae, J. Am.
Chem. Soc., 2003, 125, 15312; (b) T. S. Dowers, D. A. Rock and
J. P. Jones, J. Am. Chem. Soc., 2004, 126, 8868.
14 (a) D. C. Heimbrook, R. I. Murray, K. D. Egeberg, S. G. Sligar,
M. W. Nee and T. C. Bruice, J. Am. Chem. Soc., 1984, 106, 1514;
(b) S. Murata, M. Miura and M. Nomura, J. Org. Chem., 1989,
54, 4700.
In summary, we have described a novel and base-switched
method for the synthesis of 3,30-bisindolylmethane, 3-formylindole
and 4,40-diaminodiphenylmethane using TMEDA as methylene
and formyl source catalyzed by CuCl2 under mild conditions, in the
presence of only atmospheric oxygen as an oxidant. The electronic
properties of the N-protecting groups and substituents as well
as substitute pattern play important roles in the reactivity of
15 A. Kumar, S. Sharma and R. A. Maurya, Tetrahedron Lett., 2009,
50, 5937.
c
5930 Chem. Commun., 2012, 48, 5928–5930
This journal is The Royal Society of Chemistry 2012