"On water"-promoted direct coupling of indoles with 1,4-benzoquinones without catalyst

Article abstract of DOI:10.1002/ejoc.200500863

A highly efficient direct coupling of indole compounds with 1,4-benzoquinones was developed "on water" in the absence of any catalyst, organic co-solvent, or additives. The "on-water" conditions provided the best yields of the corresponding products and the only system to produce bis(coupling) products. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500863

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200500863
“On Water”-Promoted Direct Coupling of Indoles with 1,4-Benzoquinones
without Catalyst
Hai-Bo Zhang,[a] Li Liu,[a] Yong-Jun Chen,[a] Dong Wang,*[a] and Chao-Jun Li*[b]
Keywords: “On water” / Aqueous / No catalyst coupling / C–C bond formation
A highly efficient direct coupling of indole compounds with
1,4-benzoquinones was developed “on water” in the ab-
sence of any catalyst, organic co-solvent, or additives. The
sponding products and the only system to produce bis(cou-
pling) products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
“on-water” conditions provided the best yields of the corre- Germany, 2006)
[10]
Recently, organic reactions performed in water have at- acids [such as InBr3
and Bi(OTf)3[11]] in an organic sol-
tracted considerable attention[1] not only in light of growing vent, provided the most direct approach to 3Ј-indolylqui-
environmental concerns, but also with respect to the unique nones. However, the synthesis of bis(indolyl)-1,4-benzoqui-
properties of water in promoting reactions and enhancing none has been rarely reported. More recently, Pirrung re-
selectivities. In his pioneering work on aqueous Diels–Alder ported the synthesis of bis(indolyl)-1,4-benzoquinone under
reaction, Breslow[2] showed in 1980 that the reaction of cy- relatively intense reaction conditions: using Zn(OTf)2
clopentadiene with butenone in water was more than 700 (1 equiv.) as catalyst and THF as solvent, refluxing for 26 h
times faster than the same reaction in isooctane. In 2004, under nitrogen followed by oxidation with DDQ,[12] or by
Pirrung[3] reported that multicomponent reactions, such as coupling with mercury reagents catalyzed by PdII/Cu-
the Passerini and Ugi reactions were accelerated in water. (OAc)2.[13]
These water-accelerating effects have been attributed to the
hydrophobic effect in the aqueous phase. More recently,
Sharpless[4] reported that several cycloaddition reactions
and non-pericyclic reactions can proceed in pure water with
substantial rate acceleration even though water-insoluble
substrate was used in a suspension (denoted as “on water”
conditions).
On the other hand, 3-indolylquinone, especially bis(indol-
yl)quinone, is an important structural unit in many natural
products with biological and pharmaceutical activities.[5]
Among them, the asterriquinones found in fungi exhibit a
number of biological activities, including antitumor proper-
ties[6] and inhibition of HIV reverse transcriptase.[7] Re-
cently, demethylasterriquinone B1 was found to be a non-
protein, orally active insulin mimetic[8]. It is also interesting
to note that asterriquinone molecules consist of two prenyl-
ated indoles appended to a dihydroxyquinone core. There-
fore, the synthesis of bis(3-indolyl)quinones has attracted
considerable attention. The direct coupling of indole com-
pounds with 1,4-benzoquinones, which can be catalyzed by
protic acids (HCl, H2SO4 and CH3CO2H)[9] and Lewis
We report herein a highly efficient “on water”-promoted
direct coupling of indole compounds with 1,4-benzoqui-
nones (Scheme 1) without the use of any catalyst, additive,
or organic solvent. A notable water acceleration was ob-
served in these reactions, even though the reactants were in
a heterogeneous reaction system, which provided an ef-
ficient method for the synthesis of bis(indolyl)-1,4-qui-
nones.
[a] Center for Molecular Science, Institute of Chemistry, Chinese
Academy of Sciences,
Beijing 100080, P. R. China
[b] Department of Chemistry, McGill University,
Montreal, Quebec, Canada H3A 2K6, Canada
Scheme 1. “On water”-promoted direct coupling of indoles with
quinones.
Eur. J. Org. Chem. 2006, 869–873
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869

H.-B. Zhang, L. Liu, Y.-J. Chen, D. Wang, C.-J. Li
SHORT COMMUNICATION
Initially, the reaction of 2-methylindole (1a: R1, R3, R4 vent under the same conditions, the yield of 3a reached
= H, R2 = CH3) with 1,4-benzoquinone (2a; 1a/2a = 1:2) 82% (Entry 9), which is better than when any organic sol-
was carried out in various solvents at room temp. for 10 h vent was used (either polar, nonpolar, or aqueous organic
without using any catalyst (Scheme 2 and Table 1). In or- solvent). The reactants were insoluble in water, forming an
ganic solvents, such as dichloromethane, acetonitrile, THF, aqueous suspension by vigorous stirring. No molten starting
ethanol, and toluene, the yields of the coupled product, 2- materials were observed during the reaction when both re-
(2Ј-methylindol-3-yl)-1,4-benzoquinone (3a: R1, R3, R4, R5 actants are solid. To explain the experimental results in the
= H, R2 = CH3) were very poor (Entries 1–6), even though reaction on water, it is possible that one of the slightly solu-
the reaction system was completely homogeneous. When ble reagents reacts with the insoluble reagent on the surface
aqueous THF and ethanol were used as the reaction media, of its solid. The equilibrium was shifted to the product con-
the yields of 3a increased (Entries 7–8). Under solvent-free tinuously even when the product was also insoluble in
conditions, the yield of 3a was also low (Entry 11). It is water. Increasing the reaction temperature to 50 °C de-
interesting to note that when water alone was used as sol- creased the yield (Entry 10). The use of an aqueous LiCl
(2.5 ) or a solution of glucose (1  in water) as reaction
media neither changed the yield of 3a in an aqueous reac-
tion nor accelerated the reaction.[14]
Based on these results, various indole derivatives (1a–j)
reacted with 1,4-benzoquinones (2a–d) in neutral water (de-
ionized and redistilled three times) at room temperature
without using any catalysts or additives (Scheme 2). The re-
action proceeded smoothly to give the coupling products
(3a–p) in good yields (58–84%) (Table 2). The scale-up ex-
periment of the reaction of 1j with 2d was performed on a
600 mg scale to give the product 3p in quantitative yield. The
blue product floated on the colorless water phase, when the
reaction was complete and the stirring stopped. The nature
of the substituents on the indole ring strongly influences
the reactivity of indole substrates. The presence of a bulky
group at the 2-position of the indole ring reduced the reac-
tivity [compare methyl (1a), isopropyl (1b) and tert-butyl
(1e) substituents]. Having an electron-withdrawing group at
Scheme 2.
the 5-position of the indole ring also reduced the reactivity,
prolonged the reaction time to 16 h and generated a lower
yield of the coupled product (Entry 15). Interestingly, in the
Table 1. Reaction of 1a with 2a in various solvents.[a]
Entry
Solvent
Yield of 3a (%)[b]
reactions of 2d with 1a, 1g or 1h, bis(indolyl)quinones prod-
ucts 4a, 4b and 4c were obtained in 48–53% yields (En-
tries 7, 13 and 14), whereas the same reaction in an organic
solvent did not give bis(indolyl)quinone products at all. In
comparison, the reactions of 1a with 2d were carried out in
dichloromethane and THF under the same conditions at
room temp. for 12 h without any catalyst. In CH2Cl2, only
trace amounts of the monosubstituted product and no di-
substituted product were detected. In THF, neither the
mono- nor the disubstituted product was observed, and the
starting materials were recovered. Moreover, if the ratio of
1a/2a was changed from 1:2 to 1:1, the coupling reaction
(room temp., 28 h) provided bis(indolyl)-1,4-benzoquinone
1
2
3
CH2Cl2
CH3CN
Et2O
13
[c]
–
[c]
–
[c]
4
THF
–
5
6
7
8
9
10
11
toluene
C2H5OH
trace
38
55
51
82
39
20
THF/H2O (1:2)[d]
C2H5OH/H2O (10:1)[d]
H2O[d]
H2O[e]
[f]
–
[a] Room temperature for 10 h. [b] Isolated yield. [c] No product
was detected. [d] Aqueous suspension. [e] At 50 °C. [f] Solvent-free
conditions.
Scheme 3.
870
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Eur. J. Org. Chem. 2006, 869–873

“On Water” Coupling of Indoles with 1,4-Benzoquinones without Catalyst
Table 2. Reaction of indoles (1a–j) with quinones (2a–d) in water without catalyst.
SHORT COMMUNICATION
[a] Indole/quinone = 1:2. [b] Isolated yield. [c] Bis(indolyl)quinone products, see Table 3.
Eur. J. Org. Chem. 2006, 869–873
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871

H.-B. Zhang, L. Liu, Y.-J. Chen, D. Wang, C.-J. Li
SHORT COMMUNICATION
4a (53%) and bis(indolyl)-1,4-hydrobenzoquinone 5a
At first, the reactions of 1a with 3p (1a/3p = 1:2) were
(27%). Prolonging the reaction time to 48 h increased the carried out in various solvents without using any catalyst
yield of 4a to 73%, whereas the reaction of 1h with 2d (1h/ (Scheme 3). The results listed in Table 3 show that using
2d = 1:1) gave the homo-bis(indolyl)-1,4-quinone com- water as the reaction medium also provided the highest
pound 4c in 70% yield. The results indicate that the mono- yield (86%) of bis(indolyl)quinone product 4e. Homo-
indolylquinone intermediate formed during the course of bis(indolyl)quinones 4a–d and cross-bis(indolyl)quinones
the reaction exhibits a higher reactivity with another mole- 4e–o were synthesized in 68–90% and 72–92% yields
cule of indole substrate in water than in an organic solvent (Table 4), respectively, at room temperature for 24–30 h
and double coupling of indoles with 2,5-dichloro-1,4- without using a catalyst. The products, 2,5-dichloro-bis-
benzoquinone (2d) can be realized under “on water” condi- (indolyl)quinones 4f–g, were then converted into 2,5-dihy-
tions. Based on these observations, the synthesis of various droxybis(indolyl)quinones 6a–b in 62–70% yields by hy-
homo- and cross-bis(indolyl)quinones was investigated.
Table 3. Reaction of 1a with 3p in various solvents.[a]
Entry
Solvent
Yield of 4e (%)[b]
[c]
1
2
3
4
5
6
CH2Cl2
THF
C2H5OH
–
[c]
–
36
50
73
86
C2H5OH/H2O (1:1)
C2H5OH/H2O (1:10)[d]
H2O[d]
[a] At room temp. for 24 h. [b] Isolated yield. [c] No product was
detected. [d] Aqueous suspension.
Table 4. Synthesis of bis(indolyl)-1,4-quinones (4a–o) in water.
872
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Eur. J. Org. Chem. 2006, 869–873

“On Water” Coupling of Indoles with 1,4-Benzoquinones without Catalyst
Table 4. (Continued)
SHORT COMMUNICATION
[a] Indole/quinone = 1:2. [b] Isolated yield.
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In conclusion, a highly efficient direct coupling of indole
compounds with 1,4-benzoquinones was developed “on
water” without using any catalyst, organic co-solvent, or
additives. The “on water” conditions provided the best
yields of the corresponding products. Without using a cata-
lyst, “on water” is the only system that can provide the de-
sired bis(coupling) product. The scope and synthetic appli-
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Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China and the Chinese Academy of Sciences.
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Received: November 3, 2005
Published Online: December 20, 2005
444–445.
Eur. J. Org. Chem. 2006, 869–873
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