CuCl2-promoted 6- endo-dig chlorocyclization and oxidative aromatization cascade: Efficient construction of 1-azaanthraquinones from N -propargylaminoquinones

Article abstract of DOI:10.1021/ol201542h

An efficient synthetic methodology was developed to assemble 1-azaanthraquinones from N-propargylaminoquinones by copper(II)-promoted sequential 6-endo-dig chlorocyclization and oxidative aromatization. The approach can be extended to preprare chlorinated

Full text of DOI:10.1021/ol201542h

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4208–4211
CuCl2-Promoted 6-endo-dig
Chlorocyclization and Oxidative
Aromatization Cascade: Efficient
Construction of 1-Azaanthraquinones
from N-Propargylaminoquinones
Na Fei,† Hao Yin,† Shaozhong Wang,*,† Huaqin Wang,‡ and Zhu-Jun Yao†
State Key Laboratory of Coordination Chemistry, Institute of Chemical Biology and
Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, P. R. China, and Modern Analytical Center of Nanjing University,
Nanjing 210093, P. R. China
wangsz@nju.edu.cn
Received June 9, 2011
ABSTRACT
An efficient synthetic methodology was developed to assemble 1-azaanthraquinones from N-propargylaminoquinones by copper(II)-promoted
sequential 6-endo-dig chlorocyclization and oxidative aromatization. The approach can be extended to preprare chlorinated alkaloids such as
cleistophine and sampangine. A possible mechanism involving carbonÀcarbon bond formation triggered by regioselective electrophilic
activation and carbonÀchlorine bond formation via reductive elimination was proposed.
1-Azaanthraquinone belongs to a featured scaffold em-
bedded in naturally occurring alkaloids such as cleisto-
phine, sampangine, and amphimedine.1 The pronounced
biological activities of these alkaloids together with their
analogs have attracted considerable attention, and differ-
ent methodologies have been developed to elaborate the
tricyclic skeleton. To date, a strategy based on an aza-
DielsÀAlder reaction starting from 1-azabutadiene and
quinone hasbeengenerally employed eventhoughintrinsic
limitations are still encountered.2 Our recent exploration in
electrophilic cyclization made us recognize the benign
nucleophilicity of aminoquinones.3 Since the incorpora-
tion of a chlorine atom on the azaanthraquinone ring
should potentiallyexpand the scopeof a structureÀactivity
relationship investigation,4 a strategy involving chlorocy-
clization of N-propargylaminoquinone was envisioned to
assemble a 1-azaanthraquinone framework (Scheme 1).
Scheme 1. Chlorocyclization Strategy
† State Key Laboratory of Coordination Chemistry, Institute of Chemical
Biology and Drug Innovation, School of Chemistry and Chemical Engineer-
ing, Nanjing University.
‡ Modern Analytical Center of Nanjing University.
(1) (a) Chaves, M. H.; Santos, L. A.; Lago, J. H. G.; Roque, N. F.
J. Nat. Prod. 2001, 64, 240. (b) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(c) Marshall, K. M.; Barrows, L. R. Nat. Prod. Rep. 2004, 21, 731.
(2) For reviews, see: (a) Pautet, F.; Nebois, P.; Bouaziz, Z.; Fillion, H.
Heterocycles 2001, 54, 1095. (b) Lazny, R.; Nodzewska, A. Chem. Rev.
2010, 110, 1386.
(3) (a) Jiang, C.; Xu, M.; Wang, S.; Wang, H.; Yao, Z.-J. J. Org.
Chem. 2010, 75, 4323. (b) Fei, N.;Hou, Q.; Wang, S.; Wang, H.; Yao, Z.-J.
Org. Biomol. Chem. 2010, 8, 4096.
r
10.1021/ol201542h
Published on Web 07/18/2011
2011 American Chemical Society

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
The Cambridge Crystallographic Data Center via www. Ccdc.cam.ac.
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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Table 2. Copper(II)-Promoted Chlorocyclization and Oxidative Aromatization of N-Propargylaminoquinonesa
a The concentration is 0.05 M. b 3-Unsubstituted azaanthraquinone was isolated.
With the optimal conditions in hand, the scope of the
chlorocyclization was next explored. A variety of N-pro-
pargylaminoquinones with aryl groups attached to the
alkyne moiety were first examined. Aminoquinone 1b
underwent the sequential chlorocyclization and oxidative
aromatization similarly to afford the 4-phenyl substituted
azaanthraquinone in 83% yield (Table 2, entry 1). In
comparison, electron-withdrawing groups (2-Br, 4-Cl,
4-NO2) on the phenyl ring were disadvantageous to the
conversion; the corresponding 1-azaanthraquinones 2cÀ2e
were isolated in decreased yields ranging from 42% to 66%
(Table 2, entries 2À4). An electron-donating group (4-
MeO) on the ring did not facilate the transformation due
to a competitive formation of 3-unsubstituted azaanthra-
quinone (Table 2, entry 5). On the other hand, when
N-propargylaminoquinones derived from aliphatic propar-
gylamines were performed, the 4-methyl, 4-propyl, and
4-butyl substituted 3-chloro-1-azaanthraquinones were ob-
tained in relatively higher yields (Table 2, entries 6À11). It is
worth mentioning that the approach not only can be
extended to prepare tricyclic alkaloid derivatives such as
3-chlorocleistophine 2g, 8-methoxy-3-chlorocleistophine
2h, and 5-hydroxy-3-chlorocleistophine 2i but also serves
as a key step to synthesize 3-chlorosampangine (Scheme 2).
Furthermore, the protocol can be applied to generate
2-alkylated 1-azaanthraquinones 2kÀ2l, which are difficult
to obtain in the aza-DielsÀAlder annulation. In addition,
when aminoquinone 1m containing a terminal alkyne moiety
was employed, the yield dropped to 58% (Table 2, entry 12).
Scheme 2. Sampangine Assembly from Methylated 1-Azaan-
thraquinone
A possible mechanism is outlined as follows (Scheme 3).
Cupric chloride selectively activates the triple bond by
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Org. Lett., Vol. 13, No. 16, 2011

coordination, and then an intramolecular nucleophilic
attack takes place in a 6-endo manner accompanied by
the formation of a carbonÀcarbon bond. The organocopper-
(II) intermediate undergoes a reductive elimination to afford
the chlorinated dihydroazaanthraquinone, which transforms
to the azaanthraquinone by oxidative aromatization (path a).
An alternative reductive elimination pathway to generate
the dihydroazaanthraquinone from an organocopper(III)
intermediate cannot be excluded since the conversion from
Cu(II) species to Cu(III) has been detected under certain
oxidative conditions (path b).14
8H-benzo[c]pyrido[4,3,2-mn]acridin-8-one proved to be
practical. As exemplified in Scheme 4, the pentacyclic
heterocycle was obtained in moderate yield starting
from N-propargylaminoquinone 4.
Scheme 4. Domino Cyclization of N-Propargylaminoquinone 4
Scheme 3. Proposed Mechanism
In conclusion, an efficient approach has been devel-
oped to assemble 1-azaanthraquinones by employing
a cupric chloride promoted 6-endo-dig chlorocycliza-
tion followed by oxidative aromatization. The protocol
features mild conditions and benign functional
group compatibility, which also allows for the con-
struction of tetracyclic and pentacyclic heterocycles.
Further applications of this transformation especially
in the preparation of pyridoacridine alkaloids are
underway.
Acknowledgment. The work was financially supported
by National Science Foundation of China (20802034,
21032002), Natural Science Foundation of Jiangsu Pro-
vince (BK 2009229), 973 Program (2007CB936404), and
the Fundamental Research Funds for the Central Univer-
sities (1082020502).
A domino process involving 6-endo-dig chlorocycli-
zation and intramolecular condensation to construct
Supporting Information Available. Experimental de-
1
tails for the synthesis and H and 13C NMR spectra of
(14) (a) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas,
X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068. (b) Castitas, A.;
King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem. Sci.
2010, 1, 326.
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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