of SiO2 might be to drive the equilibrium between hemiaminal
I and aldimine III to the I side. From putative intermediate II,
further C–Br reductive elimination19 and oxidation of the C–O
bond by the Cu/O2 system20 deliver 4-bromoisoquinolone 3.
Nonetheless, CuBr plays multiple roles as the promoter of
N–C bond forming cyclization, the bromine carrier, and the
oxidant for the formation of the CQO bond under the present
aerobic conditions.21
(c) G. Zeni and R. C. Larock, Chem. Rev., 2004, 104, 2285;
(d) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104,
2127.
10 For selected reports, see: (a) N. Asao, Y. S. Salprima, T. Nogami
and Y. Yamamoto, Heterocycles, 2008, 76, 471; (b) S. Obika,
H. Kono, Y. Yasui, R. Yanada and Y. Takemoto, J. Org. Chem.,
2007, 72, 4462; (c) Q. Ding and J. Wu, Org. Lett., 2007, 9, 4959;
(d) N. Asao, S. Yudha, T. Nagomi and Y. Yamamoto, Angew.
Chem., Int. Ed., 2005, 44, 5526; (e) G. Dai and R. C. Larock,
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Chem., 2002, 67, 7042; (g) Q. Huang, J. A. Hunter and
R. C. Larock, J. Org. Chem., 2002, 67, 3437; (h) K. R. Roesch
and R. C. Larock, J. Org. Chem., 2002, 67, 86; (i) Q. Huang and
R. C. Larock, Tetrahedron Lett., 2002, 43, 3557; (j) G. Dai and
R. C. Larock, Org. Lett., 2001, 3, 4035; (k) Q. Huang, J. A. Hunter
and R. C. Larock, Org. Lett., 2001, 3, 2973.
11 (a) Y.-F. Wang, X. Zhu and S. Chiba, J. Am. Chem. Soc.,
2012, 134, 3679; (b) K. K. Toh, Y.-F. Wang, E. P. J. Ng and
S. Chiba, J. Am. Chem. Soc., 2011, 133, 13942; (c) L. Zhang,
J.-Y. Lee, N. Yamazaki and S. Chiba, Synlett, 2011, 2167;
(d) L. Zhang, G. Y. Ang and S. Chiba, Org. Lett., 2011,
13, 1622; (e) L. Zhang, G. Y. Ang and S. Chiba, Org. Lett.,
2010, 12, 3682; (f) S. Chiba, L. Zhang and J.-Y. Lee, J. Am. Chem.
Soc., 2010, 132, 7266.
In summary, a method for synthesis of 4-bromoisoquinolones
has been developed using 2-alkynylbenzaldehydes and primary
amines mediated by CuBr under an O2 atmosphere, where CuBr
plays multiple roles to facilitate the present reactions. Further
investigation of the scope and the reaction mechanism as well as
application of this strategy for synthesis of biologically active
molecules is currently underway.
This work was supported by funding from Nanyang
Technological University and Singapore Ministry of Education.
Notes and references
12 For recent reviews on copper-catalyzed aerobic oxidative transfor-
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13 Anderson et al. recently reported the effect of SiO2 as an additive
for aerobic oxidative transformation of alkynes, see: S. Z. Tasker,
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14 Oxidative dimerization of benzylamine (2a) to N-benzylbenzaldimine
was observed as a side reaction under the present reaction conditions.
To minimize this dimerization, 1 equiv. of benzylamine (2a) was
added three times at every 1 h interval. For a prior report of
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15 L. Yang, Z. Lu and S. S. Stahl, Chem. Commun., 2009, 6460.
16 It was found that CuCl and CuI also showed reactivity under the
present reaction conditions but gave 4-chloro- and 4-iodoiso-
quinolones, respectively, while the yields were lower (23 and
39%), see ESIw for more details.
17 The reactions with b-alanine ethyl ester and 3-phenylprop-2-yn-
1-amine were also examined, see ESIw for more details. The
reaction of b-alanine ethyl ester (2m) (as a hydrochloride salt)
with 1a under the standard reaction conditions provided the
corresponding 4-bromoisoquinoline 5 and protonated isoquinoline
6 in 42% and 28% yields, respectively, with certain C–N bond
cleavage, and the desired 4-bromoisoquinolone was not formed at
all (see ESIw for more details). Similarly, 3-phenylprop-2-yn-
1-amine (2n) also delivered the corresponding 4-bromoisoquinoline
5 without forming the desired 4-bromoisoquinolone 3. It is noted
that aromatic amines (anilines) did not work at all to provide any
cyclized product under the present reaction conditions.
4 G. Kohlhagen, K. Paull, M. Cushman, P. Nagafuji and
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18 In the present aerobic conditions, CuIBr might be oxidized by
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20 W. Xu, Y. Jiang and H. Fu, Synlett, 2012, 801.
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21 Pyridine might play the roles of base and ligand on the copper
species in the present 4-bromoisoquinoline formation.
c
7636 Chem. Commun., 2012, 48, 7634–7636
This journal is The Royal Society of Chemistry 2012