Potassium hydrogen sulfate-catalyzed reactions of indoles: A mild, expedient synthesis of bis-indolylmethanes

Article abstract of DOI:10.1246/cl.2004.288

Biologically important bis-indolylmethanes and their derivatives were prepared in good yields by the electrophilic substitution of indole with aldehydes catalyzed by potassium hydrogen sulfate.

Full text of DOI:10.1246/cl.2004.288

288
Chemistry Letters Vol.33, No.3 (2004)
Potassium Hydrogen Sulfate-Catalyzed Reactions of Indoles:
A Mild, Expedient Synthesis of Bis-indolylmethanes
Rajagopal Nagarajan and Paramasivan T. Perumalꢀ
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai-600020, India
(Received November 6, 2003; CL-031062)
Biologically important bis-indolylmethanes and their deriv-
hydes. The lower yield of the vibridole A is due to the self con-
atives were prepared in good yields by the electrophilic substitu-
tion of indole with aldehydes catalyzed by potassium hydrogen
sulfate.
densation of acetaldehyde under acidic condition. The catalyst is
not affected by the presence of water was evidenced by the reac-
tion of aqueous formaldehyde with indole (Scheme 1, Entry 1).
R
Bis-indolylmethanes and their derivatives constitute an im-
portant group of bioactive metabolites of terrestrial and marine
origin.1 A large number of bis-indolylmethanes have since been
reported to be isolated from terrestrial and marine natural
sources, viz. parasitic bacteria, tunicates and sponges,1 and some
of these possess significant biological activities.
KHSO4
+
RCHO
CH3OH, rt
N
H
N
H
N
H
1, R = H, 2.5 hrs, 83%
2, R = CH3, 2.0 hrs, 43%
3, R = C3H7, 3.0 hrs, 79%
4, R = C5H11, 3.5 hrs, 73%
R
1: R = H
2: R = CH
3: R = CH OAc
3
2
4: R = CH(OH)CH OH
2
N
H
N
Scheme 1.
H
Three toxic indolic metabolites were isolated from the fun-
gus, Balansia epichloe, a parasite to pasture grasses which were
known to elicit ergot-type syndrome in cattle grazing on these
infected grasses.1a One of these compounds is 3,30-bis(30-indo-
lyl)propane-1,2-diol 4, the first diindolylmethane reported from
a natural source. Streptindole 3 is the first bacterial diindolylme-
thane metabolite possessing genotoxicity and DNA-damaging
activities which are reparable in Basillus subtilis cells.1b The
diindolylmethane, vibrindole A 2 was demonstrated for the first
time to exihibit antibacterial activity against Staphylococcus
aureus, S. albus, and B. subtilis, where gentamycin is used as
the standard drug. 3,30-Diindolylmethane 1 has been gaining in-
creasing importance in recent years because of its potent anti-
carcinogenic properties.2
R2
R1
CHO
KHSO4
+
CH3OH, rt
1.5−2.0 hrs
N
H
R1
N
H
N
H
R2
5
6
Scheme 2.
Table 1. Synthesis of bis-indolyl(aryl)methanes catalyzed by
KHSO4
The principal synthetic avenues to the bis-indolylmethanes
comprise the protic or Lewis acid-catalyzed reaction of indoles
or indolyl Grignard reagents with aldehydes, ketones, ꢀ-keto
acids, imines, iminium salts, or nitrones.3 Most of these methods
suffer from various disadvantages such as long reaction time
(e.g. 10 days4), use of expensive Lewis acids (e.g. dysprosium
triflate5) or preformed reagents (e.g. oxazolidines/tetrahydroox-
azines,6a,b nitrones7) etc., yet furnishing the bis-indolymethanes
in extremely low (e.g. 2%1b) or unspecified6b yields in some cas-
es. Recently several efficient methods were developed using In-
Cl3,8 I2,9 NBS,10 Montmorillonite,11 and LiClO4.12
In this report we wish to introduce KHSO4 as a mild and ef-
ficient catalyst for the synthesis of bis-indolylmethanes in high
yields for the first time. The method is highly efficient and free
from aforesaid drawbacks. The electrophilic substitution reac-
tions of indole with aldehydes proceeded smoothly at room tem-
perature to afford the corresponding bis-indolylmethanes13 in
high yields in shorter reaction times. The reaction is general
and applicable to various aromatic as well as aliphatic alde-
Entry
Substituents
Time
/h
Yielda,b
/%
R1
R2
1
2
3
4
5
6
H
OCH3
H
H
OH
Cl
2.5
1.5
2.0
2.0
2.0
2.0
90
87
92
93
95
96
H
H
H
CH3
OCH3
NO2
aAll the products were thoroughly characterized by IR, NMR,
Mass, and elemental analysis.
bYield is based on isolation by column chromatography.
In conclusion, we have developed a mild, expedient, KHSO4
catalyzed synthesis of diindolylmethane derivatives. The cata-
lyst is mild and better dehydrating agent may be due to the slow
and controlled release of sulfuric acid generated in situ in protic
solvent such as methanol. Direct use of sulfuric acid leads to oli-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.3 (2004)
289
gomerisation of indole as reported in the literature. Even though
Lewis acids and other protic acids are known to catalyze this re-
action, this is the first report using a mineral salt. The use of other
mineral salts is yet to be explored. The catalyst is mild, cheap,
commercially available and also offers several advantages in-
cluding cleaner reactions, higher yields of the products as well
as simple experimental and isolation procedures which makes
it a useful and attractive process for the synthesis of bis-indolyl-
methanes.
(2000).
8
9
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References and Notes
1
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13 To a mixture of indole (2.5 mmol) and substituted benzalde-
hydes (1.25 mmol) in methanol (10 mL), KHSO4 (1.25 mol)
was added and stirred at room temperature for the appropri-
ate time. When the reaction was complete, water (10 mL)
was added to quench the reaction and extracted with CH2Cl2
(3 ꢁ 10 mL). The combined organic layers were dried using
anhydrous Na2SO4, filtered and the solvent evaporated. The
crude products were purified by column chromatography and
eluted with ethyl acetate and petroleum ether mixture to af-
ford the products. 3,30-Bis-indolyl(phenyl)methane 6a: Pink
coloured solid; mp 125–126 ꢂC (Lit.,14 124–125 ꢂC); IR
2
3
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4
5
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(KBr) 3416, 1634, 1378, 737 cmꢃ1 1H NMR (300 MHz,
;
CDCl3) ꢁ 7.58 (brs, 2H), 7.45–7.18 (m, 13 H), 6.51 (s,
2H), 5.91 (s, 1H); 13C NMR (75 MHz, CDCl3) ꢁ 137.1,
134.3, 133.7, 130.2, 130.1, 130.0, 127.1, 125.1, 123.0,
119.4, 118.9, 114.3, 21.5; MS m/z 322 (Mþ); Anal Calcd.
for C23H18N2: C, 85.68; H, 5.63; N, 8.69; Found : C,
85.59; H, 5.68; N, 8.54%.
6
7
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Published on the web (Advance View) February 9, 2004; DOI 10.1246/cl.2004.288