Synthesis of aryl-substituted 1,4-benzoquinone via water-promoted and In(OTf)3-catalyzed in situ conjugate addition-dehydrogenation of aromatic compounds to 1,4-benzoquinone in water

Article abstract of DOI:10.1002/adsc.200505248

Mono- and diaryl-substituted 1,4-quinones were synthesized by the In(OTf)₃-catalyzed conjugate addition of aromatic C-nucleophiles to 1,4-quinone derivatives followed by in situ dehydrogenation in water. Water was found to be beneficial to the reaction. The regioselectivity of the addition reaction in water was also examined.

Full text of DOI:10.1002/adsc.200505248

FULL PAPERS
DOI: 10.1002/adsc.200505248
Synthesis of Aryl-Substituted 1,4-Benzoquinone via
Water-Promoted and In(OTf)3-Catalyzed in situ Conjugate
Addition-Dehydrogenation of Aromatic Compounds to
1,4-Benzoquinone in Water
Hai-Bo Zhang,a Li Liu,a Yong-Jun Chen,a Dong Wang,a,* Chao-Jun Lib,*
a
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, People)s Republic of
China
Fax: (þ86)-10-6255-4449, e-mail: dwang210@iccas.ac.cn
b
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec, Canada H3A2K6
Fax: (þ1)-514-398-3797, e-mail: cj.li@mcgill.ca
Received: June 16, 2005; Accepted: November 4, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Mono- and diaryl-substituted 1,4-quinones The regioselectivityof the addition reaction in water
were synthesized by the In(OTf)3-catalyzed conjugate was also examined.
addition of aromatic C-nucleophiles to 1,4-quinone
À
derivatives followed by in situ dehydrogenation in wa- Keywords: arylation; benzoquinone; C C bond for-
ter. Water was found to be beneficial to the reaction. mation; homogeneous catalysis; indium; water as sol-
vent
Introduction
hand, Chan and co-workers[13] reported the synthesis
of 4-hydroxycoumarin derivatives by the reaction of 4-
Substituted 1,4-benzoquinone derivatives exist widely hydroxycoumarins with p-benzoquinone. Although
in nature and exhibit various important biological activ- conjugate additions of simple non-conjugated carbonyl
ities,[1] including antitumor and antibiotic activities,[2] in- compounds byusing aromatic compounds as C-nucleo-
hibition of HIV-1 reverse transcriptase,[3] antidiabetic philes have been studied extensively, there were few ex-
activities,[4] and others. Among these derivatives, aryl- amples of conjugate addition of aromatic C-nucleo-
substituted 1,4-quinones are found in manynatural
philes to benzoquinones for the synthesis of aryl-substi-
products. For example, belamcandaquinones A and B tuted benzoquinone compounds.[14] Recently, aqueous
isolated from the seed of a medicinal plant, Belamcanda organic reactions have received considerable attention
chinests, were used as a specific cyclooxygenase inhibi- in view of their synthetic efficiency and environmental
tor.[5] Common synthetic methods for aryl-substituted friendliness.[15] As part of our continuing interest in per-
1,4-quinone compounds include the Meerwein arylation forming In(OTf)3-catalyzed addition reactions of aro-
reaction of quinone with diazonium salts,[6] oxidation of matic C-nucleophiles in water,[16] herein we report an
aromatic compounds,[7] transition metal-catalyzed cou- In(OTf)3-catalyzed conjugate addition of aromatic com-
pling reactions,[8] and photochemical reactions of acety- pounds to 1,4-benzoquinones followed by in situ dehy-
lenes with Fe(CO)5.[9] All these methods have certain drogenation in water to give aryl-substituted benzoqui-
limitations, such as the need for precious metals to act none compounds.
as catalysts, the use of a great amount of reagents, or pol-
ymerizations and low yields as a result of performing the
reaction under intensive reaction conditions. Recently, Results and Discussion
it was reported byYadav [10] and Pirrung[11] that a Lewis
acid can catalyze the conjugate addition reaction of When 3-methoxy-N,N-dimethylaniline (1a) was reacted
indole compounds with 1,4-benzoquinone to give 3- with 1,4-benzoquinone (2a) (1a/2a¼1:2) in the pres-
indolylquinone compounds. Such a reaction can also ence of a catalytic amount of In(OTf)3 (5 mol %) in or-
be catalyzed by some Brønsted acids.[12] On the other ganic solvents such as CH3CN, CH2Cl2 or THF, the yields
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Hai-Bo Zhang et al.
Yield [%][b]
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Table 1. In(OTf)3-catalyzed reactions of 1a with 2a in various solvents.
Entry
1a:2a
Catalyst[a]
Solvent
Reaction time [h]
3a
4a
1
2
3
4
5
6
7
8
9
10
11
12
13
1: 2
1: 2
1: 2
1: 2
1: 2
1: 2
1: 2
1: 2
1: 1
1: 1
1: 1
1: 1
1: 1
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
HOTf
H2O
2
24
24
24
24
24
2
93
25
37
10
7
Trace
86
31
8
trace
–
–
–
–
–
–
–
79
–
CH3CN
CH3CN/H2O (2: 1)
CH2Cl2
THF
THF/H2O (1: 4)
H2O
H2O
H2O
CH3CN
CH2Cl2
THF
[c]
–
2
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
HOTf
24
24
24
24
24
10
12
4
–
–
–
H2O
52
[a]
Catalyst loading: 5 mol %.
Isolated yield.
Without using catalyst.
[b]
[c]
of the product 3a were poor (trace À25%) (Scheme 1,
Table 1). Several reports have shown that, aside from
potential environmental benefit, the use of water as a re-
action medium sometimes provides special effects for
chemical reactions.[17] In a mixed solvent, CH3CN/H2O
(2:1), the reaction yield increased to 37% (entry 3);
however, the use of aqueous THF as reaction media
did not improve the yield at all (entry 6). Interestingly,
if the reaction of 1a with 2a was carried out at room tem-
perature in air and water, the reaction time was short-
ened from 24 h to 2 h and the yield of 3a increased re-
markablyto 93% (entry1). When the ratio of 1a/2a
was changed to 1:1, the solvent effect was more obvious:
the aqueous reaction gave diaryl-substituted benzoqui-
Scheme 1.
none (4a) in 79% yield (yield is based on the aromatic sulting from the aromatic C-nucleophilic attack on the
starting material, entry9), while the reaction in organic a,b-unsaturated carbonyl unit of 1,4-benzoquinone.
solvent did not produce 4a at all (entries 10–12). Al- However, when methylaniline (1e) was used, an N-nu-
though trifluoromethanesulfonic acid (HOTf) could cleophilic addition product 3g was obtained in 63% yield
also catalyze the reaction (entry 7), no diaryl-substitut- (Table 2, entry8). Oxygen-containing aromatic com-
ed product 4a was detected in the product mixture pounds 1f and 1g were also effective as aromatic C-nu-
(with 1a/2a¼1:1) (entry13). [Note: similarly, the reac-
cleophiles in the reaction. The reaction of 1,3-dimethoxy-
tion between 1,3-dimethoxybenzene (1f) and 2a (1:1) benzene (1f) produced a mixture of mono-substituted
did not afford diaryl-substituted quinone (4 h) at all in (3h) and di-substituted benzoquinone derivatives 4h,
the presence of HOTf; whereas byusing In(OTf) 3 as a while the use of 2-methylfuran (1g) generated product
catalyst, 4 h was obtained in 79% yield (Table 3, 3j in 64% yield (Table 2, entry 9), with the 5-position
entry8)]. In the absence of a catalyst, 3a was obtained of furyl group linked to the benzoquinone moiety. On
in 31% yield when the reaction was carried out in water the other hand, 45% of the starting material 1,4-benzo-
(Table 1, entry8).
quinone (2a) was recovered from the reaction of 1a with
Subsequently, various aniline derivatives 1a–d were 2a (1a/2a¼1:2) after the reaction had gone to comple-
used in the reaction with 1,4-benzoquinone compounds tion. In the reactions of both 1d with 2a and 1a with 2c
2a–c in water and in the presence of catalyst In(OTf)3. (Table 2, entries 4 and 6), aryl-substituted 1,4-hydroqui-
The reactions were carried out under the same condi- none compounds could be obtained. When the reaction
tions, giving the aryl-substituted benzoquinone products time was prolonged to 24 h, the ratio of benzoquinone
3a–f in good to high yields (Table 2). All the products (3f) to hydrobenzoquinone 3f-1 increased noticeably
exhibited a para-amino-arylbenzoquinone structure, re- (Table 2, entry7). Based on these results, the mecha-
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Scheme 2.
nism of the reaction can be hypothesized[18] as follows: at tures of the 2,5-addition products were confirmed by
first, the conjugate addition of the aromatic nucleophile X-ray analyses of the single crystals of (2,5)-4c and
to 1,4-benzoquinone produced a mono-aryl-substituted (2,5)-4e. For the amino-substituted 1,4-benzoquinone,
hydroquinone intermediate 5. Then one half of 1,4-ben- the conjugate addition of 2-arylamino-1,4-quinone 3g
zoquinone 2a was incorporated into the product and the with C-nucleophile 1a also exhibited exclusive 2,5-selec-
other half of 2a oxidized the 1,4-hydroquinone inter- tivity(entry12). However, when 2-methyl-1,4-benzo-
mediate 5 into the mono-substituted 1,4-benzoquinone quinone (2e) was used, verypoor regioselectivity(2,5-/
1
3. At the same time, 2a was re-generated bythe oxida-
2,6-¼1:1.1) was observed by H NMR of the product
tion of the 1,4-hydrobenzoquinone 6 under an air atmos- mixture (entry5). [19] Changing the methyl group to a t-
phere in water. In the case of 1a, due to the high reactiv- butyl group (2f) increased the 2,6-selectivity(2,6-/2.5-
ityin water during the course of the reaction ( 1a/2a¼ isomer¼7.3:1) (entry6). [20] 2,6-Regioselectivitywas
1:1), it could react with the mono-substituted benzoqui- observed in a one-pot reaction of aromatic compounds
none 3 (generated in situ) to produce diaryl-substituted 1a or 1f with quinone (2a). When the ratio of 1a or 1f
hydrobenzoquinone 7, which was oxidized to give the fi- to 2a was 1:1, (2,6)-substituted 1,4-benzoquinones
nal product, diaryl-substituted 1,4-benzoquinone (4a) (2,6)-4a and 4h were obtained exclusivelyin 79% yield
(Scheme 2).
(Table 3, entries 7 and 8). The 2,6-selectivitywas also
When mono-substituted benzoquinone was used as a confirmed bythe X-rayanalysis of the single crystals
substrate in this reaction, there was an issue of regiose- of (2,6)-4a and 4h. In terms of the mechanism of the
lectivity: the addition could occur at either the 5- or 6- one-pot reaction, it can be hypothesized that the
position of 1,4-benzoquinone, leading to 2,5- or 2,6-re- mono-substituted benzoquinone 3a or 3h, generated in
gioisomers, respectively(Scheme 3). The regioselectivi-
tywas found to be highlydependent upon the substitu-
situ from the initial reaction, underwenta subsequent re-
action with the same aromatic C-nucleophile to give the
ent on the 1,4-benzoquinone ring. As shown in Table 3, homo-(2,6)-diaryl-substituted benzoquinones. This
for 2-methoxy-1,4-benzoquinone (2d), (2,5)-addition hypothesis was confirmed by stepwise experiments in
products 4b–e were obtained exclusivelyin 76–89%
which the reaction of preformed 3a with 1a also gave
yields, either through C-nucleophilic (Table 3, entries the identical homo-diaryl-substituted 1,4-quinone,
1–3) or N-nucleophilic additions (entry4). The struc-
(2,6)-4a, in 64% yield (Table 3, entry 9). In contrast,
when N-methylaniline 1e was reacted with 2a (1e/2a¼
1:1), (2,5)-homo-diarylamino-substituted benzoqui-
none (2,5)-4i was obtained in 65% yield (Table 3, en-
try10). The stepwise reaction could be used to generate
the cross-2,6-diaryl-substituted 1,4-quinone (2,6)-4j
(Table 3, entry11). In the case of an N-nucleophile,
which is more reactive than aromatic C-nucleophiles,
(2,6)-selectivitywas also observed (Table 3, entry13).
Byusing the stepwise reactions two isomers, (2,6)- 4k
Scheme 3.
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Hai-Bo Zhang et al.
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[a]
À
Table 2. Reactions of Ar H with quinones catalyzed by In(OTf)3 in water.
[a]
Catalyst loading: 5 mol %.
[b]
Ar-H/quinine¼1: 2.
[c]
Isolated yield.
[d]
Di-substituted quinine 4h, see Table 3, entry8.
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Conjugate Addition-Dehydrogenation of Arenes to 1,4-Benzoquinone
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Table 3. Regioselectivityof the In(OTf) -catalyzed[a] reactions of Ar H with quinones in water.
À
3
[a]
[b]
[c]
[d]
1
Catalyst loading: 5 mol %.
Isolated yield.
Determined by H and 13C NMR of the product mixture.
With mono-substituted product 3h (13% yield).

Hai-Bo Zhang et al.
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Experimental Section
General Remarks
IR spectra were recorded on a Bruker Tensor 27 infra-red spec-
trometer. 1H and 13C NMR spectra were measured on a Bruker
AV-300 spectrometer in CDCl3 with tetramethylsilane as an in-
ternal standard. Mass spectra were recorded on a GCT-MS Mi-
cromass spectrometer. Elemental analyses were performed on
a Carlo Flash 1112 Element Analysis instrument. Melting
points were measured bya Beijing-Tike X-4 apparatus and
are uncorrected. The X-raycrystal structures were measured
on Rigaku R-axis RAPID IP. Common reagents and materials
were purchased from commercial sources and purified before
used.
Figure 1.
and (2,5)-4k, could be obtained respectively(entries 12
and 13).
The regioselectivities are attributed to the different
coordinating sites of benzoquinones to In(OTf)3 (Fig-
ure 1). For 2-methoxy-1,4-benzoquinone, a chelation
between In(III) with oxygen atoms in the methoxy and
1-carbonyl groups (A) would occur during the reaction,
which resulted in the 2,5-selectivity; whereas in the case
of the alkyl substituents (R¼methyl and t-butyl), no
chelation was possible and both carbonyl groups of
1,4-benzoquinone ring could coordinate with the Lewis
acid, depending on the steric effect of the R group. The
smaller methyl group led to the coordination of a Lewis
acid to both carbonyl groups with no significant selectiv-
ity(a mixture of almost equal amounts of B and B ’) of
the addition reaction; however, the bulky t-butyl group
prevented the coordination of its neighboring carbonyl
and favored the B’ coordination mode, resulting in the
2,6-selectivitypredominantly. In the case of heteroaro-
matic-substituted 1,4-benzoquinones (such as 3a and
Typical Experimental Procedure
A mixture of N,N-dimethyl-3-methoxyaniline (1a, 15.1 mg,
0.1 mmol), 1,4-benzoquinone (2a, 21.6 mg, 0.2 mmol), and
In(OTf)3 (2.8 mg, 0.005 mmol) in water (2 mL) was stirred at
room temperature. The reaction was monitored byTLC. After
1a had disappeared, the reaction mixture was extracted with di-
chloromethane (10 mLꢀ3). The combined organic layer was
dried over Na2SO4 and evaporated to remove the solvent.
The crude product was purified byflash chromatographyon
silica gel (eluent: petroleum ether/ethyl acetate¼6:1) to give
3a as a blue solid; yield: 24 mg (93%).
Synthesis of Diaryl-Substituted 1,4-Quinones with a
One-Pot Reaction
A mixture of 1a (30.2 mg, 0.2 mmol), 2a (21.6 mg, 0.2 mmol)
and In(OTf)3 (5.6 mg, 0.01 mmol) in water (2 mL) was stirred
at room temperature for 24 h. The reaction was monitored by
3b), although nitrogen- and oxygen-containing groups TLC. After 1a had disappeared, the reaction mixture was ex-
tracted bydichloromethane (6 mL ꢀ3). The combined organic
were present on the phenyl ring, no chelation between
In(OTf)3 and the carbonyl group occurred. Thus, the
B’ coordination mode was also predominant, resulting
in the 2,6-regioselectivity.
layer was dried over Na2SO4 and evaporated to remove the sol-
vent. The crude product was purified byflash chromatography
on silica gel (eluent: petroleum ether/ethyl acetate¼6:1) to
give (2,6)-4a as a red solid; yield: 32 mg (79%).
Characterization data for all products can be found in the
Supporting Information file. Crystallographic data (excluding
structure factors) for 4a, 4c, 4e, and 4 h have been deposited
with the Cambridge Crystallographic Data Centre with the fol-
Conclusion
A convenient and efficient method for the synthesis of
lowing supplementarypublication nos.: (2,6)- 4a: CCDC
aryl-substituted 1,4-quinones through a In(OTf)3-cata- 288003, (2,5)-4c: CCDC 288004, (2,5)-4e: CCDC 288005,
(2,6)-4 h: CCDC 288006. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cam-
bridge CB21EZ, UK [fax.: (internat.) þ44 1223/336-033; e-
mail: deposit@ccdc.cam.ac.uk].
lyzed conjugate addition reaction followed by an in
situ dehydrogenation was developed in water. Water
not onlyserves as the reaction media but also promotes
the reaction. (2,6)-Regioselectivitywas observed for the
bis-arylation reaction and the regioselectivity was con-
firmed in the reactions of mono-substituted 1,4-qui-
nones without the chelating group, byusing either a C-
nucleophile or N-nucleophile.
Acknowledgements
We thank the National Natural Science Foundation of China
and The Chinese Academy of Sciences for financial support.
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[10] a) J. S.Yadav, B. V. S. Reddy, T. Swamy,Tetrahedron Lett.
2003, 44, 9121; b) J. S. Yadav, B. V. S. Reddy, R. T. Swa-
my, Synthesis 2004, 106.
[11] M. C. Pirrung, Y. Liu, L. Deng, D. K. Halstead, Z. Li,
J. F. May, M. Wedel, D. A. Austin, N. J. G. Webster, J.
Am. Chem. Soc. 2005, 127, 4609.
[12] a) M. C. Pirrung, K. Park, Z. Li, Org. Lett. 2001, 3, 365;
b) M. C. Pirrung, L. Deng, Z. Li, K. Park, J. Org.
Chem. 2002, 67, 8374.
[13] S.-L. Zhang, Z.-S. Huang, L.-K. An, X.-Z. Bu, L. Ma, Y.-
M. Li, A. S. C. Chan, L.-Q. Gu, Org. Lett. 2004, 6, 4853.
[14] Conjugate addition reactions of aromatic C-nucleophiles
to a,b-unsaturated carbonyl compounds, see: K. B. Jen-
sen, J. Thorhauge, R. G. Hazell, K. A. Jørgensen, Angew.
Chem. Int. Ed. 2001, 40, 160.
[15] a) C. J. Li, T. H. Chan, Organic Reactions in Aqueous
Media, John Wiley, New York, 1997; b) Organic Syn-
thesis in Water; (Ed.: P. A. Grieco), Blackie Academic
and Professional, London, 1998; c) A. Lubineau, J.
Auge, in: Modern Solvent in Organic Synthesis, (Ed.: P.
Knochel), Springer Verlag, Berlin, 1999; d) C. J. Li,
Chem. Rev. 2005, 105, 3095; e) C. J. Li, Chem. Rev.
1993, 93, 2023.
References and Notes
[1] R. H. Thomson, Naturally Occurring Quinones IV,
Blackie Academic & Professional, London, 1997.
[2] For example, see: a) R. S. Coleman, F.-X. Felpin, W.
Chen, J. Org. Chem. 2004, 69, 7309; b) W. T. Bradner,
Cancer Treat. Rev. 2001, 27, 35; c) W. Wang, T. Li, R. Mil-
burn, J. Yates, E. Hinnant, M. J. Luzzio, S. A. Noble, G.
Attardo, Bioorg. Med. Chem. Lett. 1998, 8, 1579.
[3] a) K. Arai, S. Shimizu, Y. Taguchi, Y. Yamamoto, Chem.
Pharm. Bull. 1981, 29, 991; b) S. Shimizu, Y. Yamamoto,
S. Koshimura, Chem. Pharm. Bull. 1982, 30, 1896; c) A.
Kaji, R. Saito, Y. Hata, N. Kiriyama, S. Wakusawa, K.
Miyamoto, Chem. Pharm. Bull. 1994, 42, 1682.
[4] B. Zhang, G. Salituro, D. Szalkowski, Z. Li, Y. Zhang, I.
Royo, D. Vitella, M. T. Diez, F. Pelaez, C. Ruby, R. L.
Kendall, X. Mao, P. Griffin, J. Calaycay, J. R. Zierath,
J. V. Heck, R. G. Smith, D. E. Moller, Science, 1999,
284, 974.
[5] a) Y. Fukuyama, J. Okino, M. Kodama, Chem. Pharm.
Bull. 1991, 39, 1877; b) Y. Fukuyama, Y. Kiriyama, J.
Okino, M. Kodama, Tetrahedron Lett. 1993, 34, 7633.
[6] a) D. E. Kvalnes, J. Am. Chem. Soc. 1934, 56, 2478; b) I.
Takahashi, O. Muramatsu, J. Fukuhara, H. Kitajima,
Chem. Lett. 1994, 465.
[16] R. Ding, H. B. Zhang, Y. J. Chen, L. Liu, D. Wang, C.-J.
Li, Synlett 2004, 555.
[7] a) B. Errazuriz, R. Tapia, J. A. Valderrama, Tetrahedron [17] a) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751; b) C. J.
Lett. 1985, 26, 819; b) T. Higuchi, C. Satake, M. Hirobe,
J. Am. Chem. Soc. 1995, 117, 8879.
Li; D. Wang, CHEMTRACTS Org. Chem. 2003, 16, 59.
[18] Regarding the mechanism of the Lewis acid-catalyzed
reaction of C-nucleophiles to benzoquinone, see ref.[10]
[19] The ratio of 2,5- to 2,6-isomers was determined bythe ra-
[8] a) T. Itahara, J. Org. Chem. 1985, 50, 5546; b) P. K. Singh,
B. K. Rohtagi, R. N. Khanna, Synth. Commun. 1992, 22,
987; c) L. S. Liebeskind, S. W. Riesinger, J. Org. Chem.
1993, 58, 408; d) R. A. Oliveira, F. Carazza, M. O. Per-
eira, Synth. Commun. 2000, 30, 4563.
1
tio of the H NMR peaks of the reaction mixture at d¼
2.12 and 2.08 ppm.
[20] The ratio of 2,5- to 2,6-isomers was determined bythe ra-
1
[9] K. Maruyama, T. Shio, Y. Yamamoto, Bull. Chem. Soc.
Jpn. 1979, 52, 1877.
tio of the H NMR peaks of the reaction mixture at d¼
6.57, 6.68 and 6.64, 6.71 ppm.
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