we observed the considerable effect of lithium salt. Sig-
nificantly, reactions using Mg(TMP)2 2LiCl8 gave the
cyclization product in quantitative yield and acceptable
3
D/H ratio (entry 3). It is also notable that Mg(TMP)-
6c
Cl LiCl9 and Mg(TMP)2 provided only a minute
3
amount of the desired products with recoveries of 89%
of starting 5a (entries 4 and 5). The reaction of a substrate
without a methoxy group was sluggish, indicating that the
methoxy group is necessary for the smooth metalation and
cyclization.10
Table 1. Optimization of Amide Basea
Figure 1. Highly substituted indoline and carbazole alkaloids.
Scheme 1. Our Initial Plan for the Benzyne-Mediated
CyclizationꢀFunctionalization Providing Indoline/Carbazole
entry
base
LiTMP
6 þ 7 (%)b
D/Hc
5a (%)
d
1
2
3
4
5
80
62:38
54:46
79:21
67:33
54:46
Mg(TMP)2 2LiBr
34
58
d
3
Mg(TMP)2 2LiCl
quant
3
Mg(TMP)Cl LiCl
9
8
89
89
3
Mg(TMP)2
a Conditions: Mg(TMP)2 2LiCl (5.0 equiv), THF, ꢀ78 to 0 °C, 1 h;
3
DCl/D2O, ꢀ78 to 0 °C, 1 h. b Isolated yield. c The ratio was determined
by 1H NMR. d Substrate 5a was completely consumed.
Having established optimal conditions for the benzyne-
mediated cyclization and trapping sequence, scope and
limitation of the protective group on the nitrogen and the
introducible substituent was investigated (Table 2). A
bromo group was introduced in good yield when the
reaction was terminated by addition of Br(CCl2)2Br11
(entry 1). Trisylamide 5balso served asa suitable substrate,
and the desired bromoindoline 8b was obtained in compar-
able yield to that of Boc carbamate 5a (entry 2). However,
the reaction of unprotected phenylethylamine 5c gave a
complex mixture (entry 3). Other substituents such as
iodine and chlorine atoms were installed using I(CH2)2I
and ClTf12 to give the 7-haloindolines in 47 and 83% yields
(8d,e) (entries 4 and 5).13 In addition to acetyl and cyano
crucial. Furthermore, the utility of this method is fully
demonstrated by a five-pot total synthesis of heptaphylline.
In order to explore a suitable base for the benzyne-
mediated sequential cyclization and trapping, a test substrate,
5a, was treated with various bases (Table 1). First, 5a was
treated with LiTMP (lithium 2,2,6,6-tetramethylpiperidide)5
at ꢀ78 to 0 °C. After recooling to ꢀ78 °C, the reaction was
terminated by addition of DCl/D2O. The desired com-
pounds 6 and 7 were obtained in good combined yields but
in a moderate D/H ratio (entry 1). We then tested Mg-
(TMP)2 2LiBr,6 which we previously found to be useful
3
for the benzyne generation.7 However, the desired pro-
ducts were isolated in low yields with recovery of the
starting material (entry 2). During further investigations,
(9) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
(10) If necessary, the methoxy group is directly removed by a nickel-
catalyzed reductive hydrogenation: (a) Sergeev, A. G.; Hartwig, J. F.
Science 2011, 332, 439. Reduction via aryl triflates: (b) Kotsuki, H.;
Datta, P. K.; Hayakawa, H.; Suenaga, H. Synthesis 1995, 1348. The
triflates are also transformed to alkyl, alkenyl, acyl groups: (c) James,
C. A.; Snieckus, V. J. Org. Chem. 2009, 74, 4080. (d) Danheiser, R. L.;
Casebier, D. S.; Firooznia, F. J. Org. Chem. 1995, 60, 8341.
(11) Beak, P.; Kempf, D. J.; Wilson, K. D. J. Am. Chem. Soc. 1985,
107, 4745.
(5) Olofson, R. A.; Dougherty, C. M. J. Am. Chem. Soc. 1973, 95,
582.
(6) (a) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989,
111, 8016. (b) Eaton, P. E.; Xiong, Y.; Gilardi, R. J. Am. Chem. Soc.
1993, 115, 10195. (c) Henderson, K. W.; Kerr, W. J. Chem.;Eur. J.
2001, 7, 3430. (d) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel,
P. Angew. Chem., Int. Ed. 2011, 50, 9794.
(12) Hakimelahi, G. H.; Just, G. Tetrahedron Lett. 1979, 20, 3643.
(13) 6-Methoxy-7-haloindoles (8a0, 8d0, and 8e0) were also isolated in
low yields. For a plausible mechanism for the formation of the indoles,
see the Supporting Information.
(14) (a) van Leusen, A. M.; Iedema, A. J. W.; Strating, J. Chem.
Commun. 1968, 440. (b) van Leusen, A. M.; Jagt, J. C. Tetrahedron Lett.
1970, 11, 967.
(7) (a) Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama, T.; Tokuyama,
H. Angew. Chem., Int. Ed. 2010, 49, 5925. (b) Tokuyama, H.; Okano, K.;
Fujiwara, H.; Noji, T.; Fukuyama, T. Chem. Asian J. 2011, 6, 560.
(8) (a) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew. Chem.,
Int. Ed. 2007, 46, 7681. (b) Rohbogner, C. J.; Clososki, G. C.; Knochel,
P. Angew. Chem., Int. Ed. 2008, 47, 1503. (c) Rohbogner, C. J.; Wagner,
A. J.; Clososki, G. C.; Knochel, P. Org. Synth. 2009, 86, 374.
Org. Lett., Vol. 15, No. 8, 2013
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