Chlorocyclization has emerged as a powerful tool for the
construction of carbocycles and heterocycles. A combination
of a divalent palladium catalyst with superstoichiometric
amounts of lithium chloride or cupric chloride has been
predominantly employed.5,6 The process is proposed to
start from a chloropalladation of carbonÀcarbon multiple
bonds followed by an insertion to a CÀPd bond and end
with β-elimination or oxidative cleavage. However, recent
studies demonstrate that some chlorocyclization involving
allene and alkyne substrates tethered with O-, N-nucleo-
philes can be implemented on treatment with cupric chlor-
ide without any palladium catalyst, delivering chlorinated
heterocycles such as butenolides,7 isobenzofuran-1-
ones,8 isochromen-1-ones,9 1,3-oxazines,10 indoles,11 and
isoquinolines.12 The documented examples encourage us to
investigate the chlorocyclization of N-propargylaminoqui-
nones, a class of 1,5-enyne bearing an enamine nucleophile.
We initiated the study by choosing N-propargylamino-
quinone 1a as substrate (Table 1). After establishing
palladium acetate as a catalyst, a variety of conditions
were screened. No anticipated chlorocyclization was ob-
served in the presence of excess lithium chloride either at
room temperature or under heating conditions (Table 1,
entries 1À2). When cupric chloride was used instead, the
desired azaanthraquinone 2a was achieved in 51% yield
(Table 1, entry 3). The structure of 2a was confirmed by
X-ray crystallographic analysis13 (Figure 1). The yield
changed little when the amount of cupric chloride de-
creased from 4 to 3 equiv (Table 1, entry 4). To probe
the solvent effect, several solvents including DMA, aceto-
nitrile, 1,2-dichloroethane, and nitromethane were tested,
and it was found that the best yield was accessed in
nitromethane (Table 1, entries 5À8). Switching the catalyst
to palladium chloride was almost not detrimental to the
yield (Table 1, entry 9). A combination of palladium
chloride and ferric chloride proved to be futile, which drove
us to further examine the role of cupric chloride (Table 1,
entry 10). Control experiments showed that the transforma-
tion can be accomplished in higher efficiency only by cupric
chloride (Table 1, entry 11), and the amount of cupric
chloride can be reduced to 1 equiv without compromising
the yield under a prolonged reaction time (Table 1, entry
Table 1. Optimization of Reaction Conditions
entry
1
conditiona
yield (%)b
0
5 mol % Pd(OAc)2, 4.0 equiv of LiCl,
HOAc, rt, 4 h
2
5 mol % Pd(OAc)2, 4.0 equiv of LiCl,
HOAc, 80 °C, 4 h
0c
3
5 mol % Pd(OAc)2, 4.0 equiv of CuCl2,
51
50
17
60
60
66
62
0
HOAc, 80 °C, 1 h
4
5 mol % Pd(OAc)2, 3.0 equiv of CuCl2,
HOAc, 80 °C, 1 h
5
5 mol % Pd(OAc)2, 3.0 equiv of CuCl2,
DMA, 80 °C, 4 h
6
5 mol % Pd(OAc)2, 3.0 equiv of CuCl2,
CH3CN, 80 °C, 1 h
7
5 mol % Pd(OAc)2, 3.0 equiv of CuCl2,
(CH2Cl)2, 80 °C, 1 h
8
5 mol % Pd(OAc)2, 3.0 equiv of CuCl2,
CH3NO2, 80 °C, 1 h
9
5 mol % PdCl2, 3.0 equiv of CuCl2, CH3NO2,
80 °C, 1 h
10
5 mol % PdCl2, 3.0 equiv of FeCl3, CH3NO2,
80 °C, 4 h
11
12
13
3.0 equiv of CuCl2, CH3NO2, 80 °C, 1 h
1.0 equiv of CuCl2, CH3NO2, 80 °C, 4 h
3.0 equiv of FeCl3, CH3NO2, 80 °C, 4 h
85
86
0
a The reaction concentration is 0.05 M. b Isolated yield. c Consump-
tion of the substrate happened.
(4) For a review on naturally occurring organohalogen compounds,
see: Gribble, G. W. Acc. Chem. Res. 1998, 31, 141.
(5) (a) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (b) Zhu, G.; Ma, S.;
Lu, X.; Huang, Q. Chem. Commun. 1995, 271. (c) Lee, C.-Y.; Wu, M.-J. Eur.
J. Org. Chem. 2007, 3463. (d) Yin, G.; Liu, G. Angew. Chem., Int. Ed. 2008,
47, 5442. (e) Ye, S.; Gao, K.; Zhou, H.; Yang, X.; Wu, J. Chem. Commun.
2009, 5406. (f) Li, Y.; Jardine, K. J.; Tan, R.; Song, D.; Dong, V. M. Angew.
Chem., Int. Ed. 2009, 48, 784.
(6) For an account on chloropalladation, see: Lu, X.; Zhu, G.; Wang,
Z. Synlett 1998, 115.
(7) Ma, S. Acc. Chem. Res. 2003, 36, 701.
(8) Jithunsa, M.; Ueda, M.; Miyata, O. Org. Lett. 2011, 13, 518.
(9) Liang, Y.; Xie, Y.-X.; Li, J.-H. Synthesis 2007, 400.
(10) Hashmi, A. S. K.; Schuster, A. M.; Zimmer, M.; Rominger, F.
Chem.;Eur. J. 2011, 17, 5511.
(11) (a) Shen, Z.; Lu, X. Adv. Synth. Catal. 2009, 351, 3107. (b) Chen,
C.-C.; Chin, L.-Y.; Yang, S.-C.; Wu, M.-J. Org. Lett. 2010, 12, 5652.
(12) Yu, X.; Wu, J. J. Comb. Chem. 2009, 11, 895.
Figure 1. X-ray crystal structure of 1-azaanthraquinone 2a.
(13) CCDC 780630 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
uk/data_request/cif.
12). A parallel experiment revealed that ferric chloride did
not promote the transformation (Table 1, entry 13).
Org. Lett., Vol. 13, No. 16, 2011
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