Efficient and convenient method for the synthesis of symmetrical triindolylmethanes catalyzed by iodine

Article abstract of DOI:10.1080/00397910601031652

Indoles reacted with triethyl orthoformate in the presence of a catalytic amount of iodine at room temperature to give the corresponding symmetrical triindolylmethanes (TIMs) in good to high yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601031652

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Efficient and Convenient Method for the
Synthesis of Symmetrical Triindolylmethanes
Catalyzed by Iodine
Zhan‐Hui Zhang a & Jin Lin a
a College of Chemistry and Material Science, Hebei Normal University,
Shijiazhuang, China
Version of record first published: 25 Jul 2007.
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Symmetrical Triindolylmethanes Catalyzed by Iodine, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:2, 209-215
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Synthetic Communicationsw, 37: 209–215, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601031652
Efficient and Convenient Method for
the Synthesis of Symmetrical
Triindolylmethanes Catalyzed by Iodine
Zhan-Hui Zhang and Jin Lin
College of Chemistry and Material Science, Hebei Normal University,
Shijiazhuang, China
Abstract: Indoles reacted with triethyl orthoformate in the presence of a catalytic
amount of iodine at room temperature to give the corresponding symmetrical triindo-
lylmethanes (TIMs) in good to high yields.
Keywords: indoles, iodine, triethyl orthoformate, triindolylmethanes
In recent years, the synthesis of indole derivatives continues to attract the
attention of the synthetic community because many of them are pharmacologi-
cally and biologically active compounds.[1] 1,1,1-tris(3,30,300-Indolyl)ethane
was found in bacterial metabolites,[2] and the triindolylmethanes (TIMs)
could be used as the acceptors of hydride ions[3] and dye materials.[4] They
are also effective frameworks for the construction of the very bulky and
p-acidic phosphine ligands.[5] Despite their importance from pharmacologi-
cal, industrial, and synthetic point of views, comparatively few methods for
the preparation of triindolylmethanes have been reported. TIMs were
usually synthesized by treatment of indole-3-carboxaldehyde with 2 equiva-
lents of indole in the presence of either protic or Lewis acids.[6] In 1971,
another synthetic method was developed by Bergman, in which TIMs were
prepared by treatment of 1- or 2-substitued indoles with acetic–formic
anhydride at 508C, and the yields were still not adequate.[7] Akgu¨n et al.[8]
reported that symmetric TIMs could be obtained by the condensation
Received in Japan March 7, 2005
Address correspondence to Zhan-Hui Zhang, College of Chemistry and Material
Science, Hebei Normal University, Shijiazhuang, China. E-mail: zhanhui@126.com
209

210
Z.-H. Zhang and J. Lin
reactions of indoles with orthoformate in the presence of p-TSA at 808C.
Chakrabarty and coworkers[9] have recently proposed a new useful variation
of this reaction by using acid-washed montmorillonite clay as catalyst in the
absence of solvent. Other synthetic approaches have also developed;[10]
however, many of these procedures suffered from long reaction times,
low yields, and complex handling. So, the development of new reagents
with great efficiency, convenient procedure, and better yields is of great
interest.
Recently, iodine has received considerable attention as an inexpensive
and easily available catalyst for various organic reactions including the
formation and cleavage of common protecting groups, oxidation, reduction,
cyclization, addition, substitution, and rearrangement.[11,12] As part of our
ongoing program in developing various new synthetic transformations using
cheap and ecofriendly materials as catalysts,[13] herein we introduce a
simple method for synthesis of symmetrical TIMs using a catalytic amount
of iodine at room temperature (Scheme 1).
The reaction was first carried out using a 1:0.33 molar ratio of indole (1a)
and orthoformate (2) along with 5 mol% of I2 in different solvents at room
temperature. The results are shown in Table 1. In CH2Cl2, the reaction
completed within 10 min to give tri(1H-indol-3-yl)methane (3a) in 92%
yield (Table 1, entry 1). The reaction in EtOH, MeOH, EtOAc, THF, DMF,
Et2O, and [bmim]BF4 required longer reaction times, and unreacted 1a
remained (Table 1, entries 2–8). No reaction took place in dimethyl/
sulfoxide (DMSO) and polyethylene glycol (PEG) 300 (Table 1, entries 9
and 10), whereas excellent yield was achieved in CH3CN (Table 1, entry
11). Lower catalyst loading can be used with only a marginal drop in
reaction rate (Table 1, entry 12).
Prompted by this success, we extended the reaction of orthoformate (2)
with a wide range of other substituted indole compounds under similar
conditions at room temperature, furnishing the symmetrical TIMs in good to
excellent yields (Table 2). In all cases, the reactions were clean without the
formation of any by-products. N-Alkylated indoles (Table 2, entries 2 and 3)
could also react with orthoformate (2) to obtain corresponding product in
good yields, but when a methyl was introduced onto C-2 of indole (Table 2,
entry 7), it would block the attack of indole, so the reaction time would get
longer and the yield was lower. When electron-withdrawing substituent such
as 2CO2Me onto C-2 (Table 2, entry 8) was introduced, indole’s reactivity
decreased so much that the reaction could not take place.
Scheme 1.

Symmetrical Triindolylmethanes
211
Table 1. Screening of the reaction conditions for the syn-
thesis 3aa
Time
(min)
Yield
(%)b
Entry
Solvent
CH2Cl2
EtOH
1
2
10
30
92
88
36
76
72
18
45
26
3
MeOH
EtOAc
THF
120
60
4
5
180
180
120
180
180
180
5
6
DMF
Et2O
7
8
[bmim]BF4
DMSO
PEG 300
CH3CN
CH3CN
c
9
—
—
c
10
11
12
95
92d
60
aThe reaction was carried out according to general experi-
mental procedure.
bIsolated yields.
cNo reaction.
d1% mmol catalyst was used.
The mechanism for this transformation is unclear. According to the litera-
ture,[12k] we think that iodine acts as a mild Lewis acid to catalyze this
reaction. A plausible mechanism is shown in Scheme 2. First, iodine
activated orthoformate to form a complex I, followed by indole attack to I
to give II. The second indole is added to II in the following step to form
the intermediate III, and subsequent loss of EtOH from III results in IV,
which is further activated by molecular iodine. The third indole is added to
IV to afford the TIM and iodine, which can catalyze the reaction.
In summary, we developed a simple, novel, and efficient procedure for the
preparation of symmetrical triindolylmethanes using a catalytic amount of
iodine. The mild reaction conditions, shorter reaction times, and application
of a cheap and commercially available catalyst make this method a valid con-
tribution to the existing methodologies.
EXPERIMENTAL
Melting points were measured using an X-4 apparatus and are uncorrected. NMR
spectra were taken with a Bruker 300 spectrometer in acetone-d6 or DMSO-d6
with tetramethylsilane as an internal standard. IR spectra were obtained using
Bruker-Tensor 27 instrument. Mass spectra were performed on a ThermoFinni-
gan LCQ Advantage instrument with an ESI source (4.5 KeV).

212
Z.-H. Zhang and J. Lin
Table 2. Synthesis of symmetrical triindolylmethanes catalyzed by iodine
Mp (8C)
Found Reported
Time Yield
Product (min) (%)a
Entry
1
Indole
3a
5
8
92 245–247 238–240[9]
2
3
3b
90 264–266 256–258[9]
3c
10
91 215–217 216–218[9]
4
5
6
3d
3e
3f
5
20
25
89 256–258 260–264[9]
86 221–223
83 320–322
325[14]
7
8
3g
3h
6 h
6 h
71 333–335
336[9]
b
—
aIsolated yield.
bNo reaction.
General Procedure for the Synthesis of Symmetrical
Triindolylmethanes
Iodine (0.05 mmol, 13 mg) was added to a mixture of indole (1 mmol) and
orthoformate (0.33 mmol) in acetontrile (2 mL) at room temperature. After
completion of the reaction (as monitored by thin-layer chromatography,
TLC), the solvent was removed under reduced pressure, and the residue was
directly charged on a chromatography column using n-hexane/EtOAc (8:2)
to give the pure product 3a.

Symmetrical Triindolylmethanes
213
Scheme 2.
Spectral Data of Selected Compounds
Tri(1H-indol-3-yl)methane (3a): IR (KBr): 3395, 3048, 1484, 1455, 1418,
1336, 1216, 1009, 801, 744 cm21 1H NMR (acetone-d6, 300 MHz) d
.
(ppm): 6.19 (s, 1H), 6.88 (t, J ¼ 7.8 Hz, 3H), 6.92 (s, 3H), 7.03
(t, J ¼ 7.8 Hz, 3H), 7.37 (d, J ¼ 7.8 Hz, 3H), 7.47 (d, J ¼ 7.8 Hz, 3H),
10.12 (br s, 3H, NH); 13C NMR (acetone-d6, 75 MHz) d (ppm): 31.5, 111.4,
118.4, 119.2, 119.7, 121.1, 123.5, 127.5, 137.4; ESI-MS (negative mode):
360 (M-1)2.
Tris(5-bromo-1H-indol-3-yl)methane (3d): IR (KBr): 3428, 2924, 1562,
1
1457, 1417, 1213, 1090, 868, 784 cm21. H NMR (DMSO-d6, 300 MHz)
d (ppm): 6.06 (s, 1H), 6.98 (s, 3H), 7.13 (d, J ¼ 8.4 Hz, 3H), 7.32
(d, J ¼ 8.4 Hz, 3H), 7.50 (s, 3H), 11.00 (br s, 3H, NH); 13C NMR
(DMSO-d6, 75 MHz) d (ppm): 30.9, 111.4, 114.2, 118.1, 122.0,
123.9, 125.6, 129.0, 135.9; ESI-MS (negative mode): 600, 598, 596, 594
(M-1)2.
Tris(5-methoxy-1H-indol-3-yl)methane (3e): IR (KBr): 3413, 2932, 1620,
1
1579, 1483, 1450, 1290, 1212, 1172, 1039, 842, 797, 772 cm21; H NMR
(acetone-d6, 300 MHz) d (ppm): 3.61 (s, 9H), 6.04 (s, 1H), 6.70 (dd,
J ¼ 8.7, 2.4 Hz, 3H), 6.94 (d, J ¼ 1.2 Hz, 3H), 6.97 (d, J ¼ 2.4 Hz, 3H),
7.27 (d, J ¼ 8.7 Hz, 3H), 9.97 (br s, 3H, NH); 13C NMR (acetone-d6,
75 MHz) d (ppm): 31.7, 55.1, 102.1, 111.0, 112.0, 118.8, 124.2, 127.9,
132.5, 153.4; ESI-MS (negative mode): 450 (M-1)2.
Tris(2-methyl-1H-indol-3-yl)methane (3g): IR (neat): 3393, 3051, 2908,
1618, 1461, 1427, 1340, 1297, 1218, 1010, 816, 747 cm21 1H NMR
.
(DMSO-d6, 300 MHz) d (ppm): 1.91 (s, 9H), 6.08 (s, 1H), 6.61
(t, J ¼ 8.1 Hz, 3H), 6.78 (d, J ¼ 8.1 Hz, 3H), 6.85 (t, J ¼ 8.1 Hz, 3H), 7.18
(d, J ¼ 8.1 Hz, 3H), 10.61 (br s, 3H, NH); ESI-MS (negative mode):
402 (M-1)2.

214
Z.-H. Zhang and J. Lin
ACKNOWLEDGMENT
We thank the Science Research Foundation of Hebei Normal University for
financial support of this work.
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