Azaanthraquinone assembly from N -propargylamino quinone via a Au(I)-catalyzed 6- endo - Dig cycloisomerization

Article abstract of DOI:10.1021/jo1006637

A methodology to assemble the azaanthraquinone skeleton from N-propargylamino quinone by a Au(I)-catalyzed 6-endo-dig cycloisomerization was developed. The catalytic process was applied to the synthesis of alkaloid cleistopholine and its analogues. A mechanism involving benign nucleophilicity of the aminoquinone was proposed.

Full text of DOI:10.1021/jo1006637

pubs.acs.org/joc
Azaanthraquinone Assembly from
N-Propargylamino Quinone via a Au(I)-Catalyzed
6-endo-dig Cycloisomerization
Chunhui Jiang,† Min Xu,† Shaozhong Wang,*,†
Huaqin Wang,‡ and Zhu-Jun Yao†
†School of Chemistry and Chemical Engineering, State Key
Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210093, P. R. China, and Modern Analytical Center
FIGURE 1. Azaanthraquinone and related alkaloids.
‡
of Nanjing University, Nanjing 210093, P. R. China
wangsz@nju.edu.cn
Received April 7, 2010
FIGURE 2. Strategies to assemble azaanthraquinone.
from the initial Diels-Alder adduct would react with the
quinone dienophiles, thus substantially decreasing the reac-
tion efficiency, and (ii) low regioselectivities were encountered
with unsymmetric dienophiles, and product purification was
difficult.
Our interest in alkaloid synthesis prompted us to consider
whether the azaanthraquinone skeleton could be assembled
through a cycloisomerization of N-propargylamino quinone
(Figure 2, route II). Notably such enyne substrates can be
easily prepared. Meanwhile, the nucleophilicity of electron-
rich double bonds such as enamine, enaminone, and enamide
in transtion-metal-catalyzed cycloisomerization has been
disclosed recently by different groups.6 For instance, Arcadi
and Cacchi independently reported enamines/enaminones
tethered by alkyne units proceeded cycloisomerization effi-
ciently to afford pyridine derivatives when catalyzed by
NaAuCl4 or CuBr salts.6a,i Dake found that cyclic enamides
appended by alkyne units underwent PtCl2-catalyzed cyclo-
isomerization to afford azahydrindans and spiro-fused hete-
rocycles regioselectively.6c-f Inspired by the findings, we
envisioned a gold-catalyzed annulation of the azaanthra-
quinone ring.7 As shown in Scheme 1, a gold complex
selectively activates the C-C triple bond, promoting nucleo-
philic attack by the double bond of aminoquinone via a
6-endo-dig cyclization, and then the cyclized intermediate
would undergo tautomerization and aromatization, afford-
ing the azaanthraquinone skeleton.
A methodology to assemble the azaanthraquinone skele-
ton from N-propargylamino quinone by a Au(I)-catalyzed
6-endo-dig cycloisomerization was developed. The cata-
lytic process was applied to the synthesis of alkaloid cleisto-
pholine and its analogues. A mechanism involving benign
nucleophilicity of the aminoquinone was proposed.
Naturally occurring tricyclic quinone alkaloids possess
extensive biological properties ranging from antimicrobial
capacity to cytotoxicity.1,2 Among them, cleistopholine along
with its hydroxy/methoxy-substituted counterparts were iso-
lated from Porcelia macrocarpa and feature a 4-methyl-
substituted azaanthraquinone ring.1c Ring structures related
to azaanthraquinone can also be found in polycyclic alkaloids
such as sampangine and meridine (Figure 1).3
The classical strategy to construct an azaanthraquinone
framework involves a hetero-Diels-Alder reaction between
R,β-unsaturated N,N-dimethylhydrazone and quinone (Figure 2,
route I).4 Although this method has been applied extensively,
there are still drawbacks:5 (i) the dimethylamine liberated
(6) (a) Abbiati, G.; Acradi, A.; Bianchi, G.; Giuseppe, S. D.; Marinelli, F.;
Rossi, E. J. Org. Chem. 2003, 68, 6959. (b) Binder, J. T.; Crone, B.; Haug,
T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025. (c) Kozak, J. A.;
Dodd, J. M.; Harrison, T. J.; Jardine, K. J.; Patrick, B. O.; Dake, G. R.
J. Org. Chem. 2009, 74, 6929. (d) Kozak, J. A.; Dake, G. R. Angew. Chem.,
Int. Ed. 2008, 47, 4221. (e) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org.
Lett. 2007, 9, 367. (f) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023.
(g) Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791.
(h) Minnihan, E. C.; Colletti, S. L.; Toste, F. D.; Shen, H. C. J. Org. Chem.
2007, 72, 6287. (i) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629.
(7) For selected reviews on homogeneous gold catalysis, see: (a) Arcadi,
A. Chem. Rew. 2008, 108, 3266. (b) Li, Z.; Brouwer, C.; He, C. Chem. Rev.
2008, 108, 3239. (c) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008,
108, 3351. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395.
(e) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326.
(f) Furstner, A.; Davis, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(g) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(1) (a) Konoshima, T.; Kozuka, M.; Koyama, J.; Tagahara, T. O.;
Tokuda, H. J. Nat. Prod. 1989, 52, 987. (b) Soonthornchareonnon, N.;
Suwanborirux, K.; Bavovada, R.; Patarapanich, C.; Cassady, J. M. J. Nat.
Prod. 1999, 62, 1390. (c) Chaves, M. H.; Santos, L. A.; Lago, J. H. G.; Roque,
N. F. J. Nat. Prod. 2001, 64, 240. (d) Gandy, M. N.; Piggott, M. J. J. Nat.
Prod. 2008, 71, 866.
(2) (a) Omura, S.; Nakagawa, A.; Aoyama, H.; Hinotozawa, K.; Sano, H.
Tetrahedron Lett. 1983, 24, 3643. (b) Forbis, R. M.; Rinehart, R. L., Jr.
J. Am. Chem. Soc. 1973, 95, 5003.
(3) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(4) Serckx-Poncin, B.; Hebain-Frisque, A.-M.; Ghosez, L. Tetrahedron
Lett. 1982, 23, 3261.
(5) For a review, see: Pautet, F.; Nebois, P.; Bouaziz, Z.; Fillion, H.
Heterocycles 2001, 54, 1095.
DOI: 10.1021/jo1006637
r
Published on Web 05/21/2010
J. Org. Chem. 2010, 75, 4323–4325 4323
2010 American Chemical Society

Jiang et al.
JOCNote
SCHEME 1. Proposed Synthesis of Azaanthraquinone via
a 6-endo-dig Cycloisomerization
TABLE 2. Azaanthraquinone Assembly via a AuI-Catalyzed
6-endo-dig Cycloisomerizationa
TABLE 1. Optimization of Reaction Conditions
entry
conditiona
yield (%)
1
2
3
4
5
6
7
8
10 mol % Ph3PAuOTf, (ClCH2)2, 80 °C, 6 h
10 mol % Ph3PAuOTf, PhCH3, 100 °C, 6 h
10 mol % Ph3PAuOTf, Dioxane, 100 °C, 12 h
10 mol % Ph3PAuOTf, THF, 60 °C, 12 h
10 mol % Ph3PAuOTf, HOAc, 100 °C, 1 h
5 mol % Ph3PAuOTf, HOAc, 100 °C, 6 h
10 mol % PtCl2, HOAc, 100 °C, 2 h
64
82
55
19
85
25
49
34
14
0b
10 mol % NaAuCl4 2H2O, HOAc, 100 °C, 4 h
3
9
10 mol % CuBr, HOAc, 100 °C, 4 h
10 mol % AgOTf, HOAc, 80 °C, 12 h
HOAc, 80 °C, 12 h
10
11
12
13c
0b
10 mol % Ph3PAuCl, HOAc, 100 °C, 4 h
10 mol % Ph3PAuOAc, toluene, 100 °C, 6 h
19
<5
aThe reaction was open in air. bNo azaanthraquinone detected.
cThe catalyst was generated in situ from 10 mol % Ph3PAuCl and AgOAc.
aAll reactions performed at 0.05 M. bReaction time 0.5 h.
We initiated the study by using enyne 1a as substrate. As
shown in Table 1, when 10 mol % of Ph3PAuOTf, generated
in situ from Ph3PAuCl and AgOTf, was employed, the antici-
pated 1-azaanthraquinone 2a was indeed formed. However,
except for the unreacted starting material, no dihydroazaan-
thraquinone intermediate was isolated. The structure of 2a
was confirmed by X-ray crystallography.8 Different solvents
including dichloroethane, toluene, dioxane, THF, and HOAc
were screened (entries 1-5), and both acetic acid and toluene
led to good yields, although the reaction in the former solvent
completed in just 1 h. The amount of Ph3PAuOTf was neces-
sary as prelonged reaction and a much lower yield was obser-
ved in the presence of 5 mol % of the catalyst (entry 6). In
The scope of the transformation was next investigated accor-
ding to the optimized reaction conditions (Table 1, entry 5).
Enynes with various substituted aryl groups at the alkyne
terminus were examined. As shown in Table 2, a p-MeO
group faciliated the reaction, and azaanthraquinone 2b was
formed in 95% yield after 0.5 h (entry 1). In contrast, electron-
withdrawing substitutents such as p-NO2 and o-NO2 hindered
the reaction, and the 4-nitrophenyl and 2-nitrophenyl azaan-
thraquinones 2c-d were obtained in only 52% and 57%
yield, respectively (entries 2 and 3). For a Ph group, the
reaction yield was moderate (entry 4). Different from the
electronic effect, the steric effect was minimal as substitutents
such as o-Br and o-CO2Me were tolerated without compro-
mising the yields (entries 5 and 6). In addition, enynes con-
taining alkyl substituent and terminal alkynes also underwent
the cycloisomerization smoothly to afford azaanthraquinone
2 h-i in 84% and 64% yield (entries 7 and 8).
addition, other metal salts such as PtCl2, NaAuCl4 2H2O,
3
and CuBr also catalyzed this transformation albeit with
much lower efficiency (entries 7-9). Control experiments
indicated that the gold complex was necessary for the observed
reaction (entries 10-13).
Since a characteristic 4-methyl group is found on the
azaanthraquinone moiety of natural alkaloids such as cleisto-
pholine, our attention was then turned to the 6-endo-dig
cycloisomerization of enynes derived from 2-butynylamine
(8) CCDC 748374 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
4324 J. Org. Chem. Vol. 75, No. 12, 2010

Jiang et al.
JOCNote
TABLE 3. 4-Methyl-azaanthraquinone Assembly via a AuI-Catalyzed
and pyridone units were readily tolerated to deliver 1,5-
diazaanthraquinone and 1,8-diazaanthraquinone, suggest-
ing the generality of this cycloisomerization (entries 5-7).
In conclusion, an anternative approach to attain azaan-
thraquinones from N-propargylamino quinones was deve-
loped by employing a Au(I)-catalyzed 6-endo-dig cycloiso-
merization. Synthesis of alkaloid cleistopholine and its hydroxy/
methoxy-substituted counterparts was easily achieved using
this gold catalysis.
6-endo-dig Cycloisomerizationa
Experimental Section
General Procedure for the Au(I)-Catalyzed 6-endo-dig Cyclo-
isomerization. Chloro(triphenylphosphine)gold(I) (14.9 mg,
0.03 mmol) was added to a stirred solution of AgOTf (7.8 mg,
0.03 mmol) in acetic acid (6.0 mL) at room temperature. After
5 min, N-propargylamino quinone (0.3 mmol) was put in one
portion. Then the reaction was heated at 100 °C for 1 h. After
cooling, the solvent was distilled under vacuum pressure. The
residue was dissolved in CH2Cl2 (20 mL), and then the organic
layer was washed with saturated NaHCO3 solution (10 mL), water
(10 mL), and brine (10 mL) successively. The organic layer was
dried with anhydrous MgSO4, filtered, and concentrated. The
residue was purified by flash chromatography to get pure product.
4-(4-Methylphenyl)-benzo[g]quinoline-5,10-dione (2a). Yellow
needle, mp 243-245 °C (EtOH); IR (KBr) νmax 1684, 1592,
1
1571, 1300, 1287, 955, 823, 725 cm-1; H NMR (300 MHz,
CDCl3) δ 9.04 (d, J=5.1 Hz, 1H), 8.41-8.38 (m, 1H), 8.16-8.13
(m, 1H), 7.85-7.77 (m, 2H), 7.52(d, J=4.8 Hz, 1H), 7.31 (d, J=
8.1 Hz, 2H), 7.25-7.22 (m, 2H), 2.47 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 182.9, 181.6, 153.3, 152.7, 150.0, 138.3, 136.0, 134.6,
134.2, 133.8, 132.5, 130.6, 128.9, 128.2, 127.6, 127.33, 127.26,
21.3; MS (EI) m/z 299 (Mþ, 17), 298 (M - 1, 54), 284 (100). Anal.
Calcd for C20H13NO2: C, 80.25; H, 4.38; N, 4.68. Found: C,
80.35; H, 4.37; N, 4.67.
Acknowledgment. This work was financially supported by
National Science Foundation of China (20802034), Natural
Science Foundation of Jiangsu Province (BK 2009229) and
973 Program (2007CB936404). We thank Prof. Liming Zhang
for helpful discussions.
a[3] = 0.05 M.
and different quinones (Table 3). Hence, starting from enyne
3a, cleistopholine was directly prepared in one step in 60%
yield (entry 1), demonstrating the synthetic power of this new
approach. Similarly, 8-methoxycleistopholine, 8-hydroxy-
cleistopholine, and 6,7-dimethoxycleistopholine were syn-
thesized smoothly in fairly good yields from enynes 3b-d
(entries 2-4). Furthermore, enynes 3e-g containing pyridine
Supporting Information Available: Experimental details
for the synthesis and 1H and 13C NMR spectra of compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4325