A Facile and Efficient Synthesis of 2,2-Bis(3′/2′ -indolyl)ethylamines and Three Bisindolic Natural Products

Article abstract of DOI:10.1081/SCC-120027281

A simple and efficient synthesis of bis(indolyl)ethylamines and three bisindolic natural products, viz. hallucinogenic 6, genotoxic 7 and the alkanoic acid 8 has been developed by the reaction of indoles with appropriate carbonyl compounds on montmorillonite K10 clay.

Full text of DOI:10.1081/SCC-120027281

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 3, pp. 421–434, 2004
A Facile and Efficient Synthesis of
2,2-Bis(30/20-indolyl)ethylamines and
Three Bisindolic Natural Products
1
1
Manas Chakrabarty,1, Nandita Ghosh, Ramkrishna Basak,
*
and Yoshihiro Harigaya2
1Department of Chemistry, Bose Institute, Kolkata, India
2School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
ABSTRACT
A simple and efficient synthesis of bis(indolyl)ethylamines and three
bisindolic natural products, viz. hallucinogenic 6, genotoxic 7 and the
alkanoic acid 8 has been developed by the reaction of indoles with
appropriate carbonyl compounds on montmorillonite K10 clay.
Key Words: Synthesis; Bis(indolyl)ethylamines; Bisindolic natural
products; Streptindole.
*
Correspondence: Manas Chakrabarty, Department of Chemistry, Bose Institute, 93/1,
A.P.C. Road, Kolkata 700009, India; Fax: þ91(33) 2350 6790; E-mail: chakmanas@
yahoo.co.in.
421
DOI: 10.1081/SCC-120027281
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Chakrabarty et al.
The diindolylalkanes and their derivatives, viz. -alkanols, -alkanals,
-alkanoic acids and -alkylamines, collectively abbreviated as DIAs, constitute
an important group of bisindoles because of their diverse syntheses and
significant biological activities.[1] The bis(3-indolyl)ethylamines and -propyl-
amines (1), a particular type of DIAs, assumed importance because some of
them displayed strong coronary dilatory activity comparable to that of
papaverine as well as antagonistic activity on the arterial tension of dogs.[2]
However, the recent isolation of a few bis(indolyl)ethylamines from a marine
tunicate[3] and a sponge[4] has made this class of compounds even more
important since some of them showed antagonistic activity in antiserotoni-
nergic activity assays and inhibition of specific ligand-binding in neuropeptide
receptor-binding assays. The bis(indolyl)alkylamines (1) were first synthes-
ised (i) by the acid-catalysed condensation of indoles with N,N-dialkyl-
aminoalkanals or their diethylacetals and also (ii) by the hydride reduction of
bis(indolyl)acetamides, prepared from the corresponding bis(indolyl)acetic
acids and haloalkylamines.[2]
But these procedures often required long reaction time (12–60 h) and
furnished the target molecules in wide ranging yields (7–92%). Recently,
three 2,2-bis(30-indolyl)ethylamines (BIEAs) were prepared by the addition of
indoles to appropriate nitrones or 3-indolylhydroxylamines using trimethylsi-
lyl chloride as an activator.[5,6] But this method too sometimes required a very
long reaction period (e.g. 54 h), furnished the BIEAs in only (31–55)% yields
and additionally necessitated the preformation of nitrones and indolyl-
hydroxylamines.
Therefore, in search of an alternate, efficient synthesis of BIEAs, a
microwave-assisted, solvent-free synthesis of 2,2-bis(30-indolyl)nitroethanes
(BINEs) was recently reported by us.[7] But all subsequent attempts to reduce
the BINEs to BIEAs by a number of reductants failed.[8] The need to develop
an efficient synthesis of BIEAs thus still remained. We have now developed
one such method, in which we employed our recently developed solvent-free
method of synthesis of DIAs by the reaction of indoles with aldehydes or
ketones using montmorillonite K10 clay as a solid acidic catalyst.[9] Since
phthalimidoacetaldehyde diethylacetal (2), a masked acetaldehyde, is com-
mercially available, we utilized our clay-mediated protocol for the reaction of
indoles (3) with 2 to generate N-[2,2-bis(30/20-indolyl)ethyl]phthalimides
(BIEPs; 4), which were cleaved by the Ing–Manske procedure[10,11] to furnish

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Synthesis of 2,2,Bis(30/20-indolyl)ethylamines
423
BIEAs, isolated as their N-acetyl derivatives (5). The successful outcome of
our approach has been presented in this communication.
Thus, when indole (3a) was treated with 0.5 equivalent of 2 on m. K10
clay (2 g/1 mM of indole), the reaction was complete in 8 h at room
temperature. Mere leaching of the clay with dichloromethane furnished the
BIEP 4a in excellent yield. The reaction of 2 was next extended to other
indoles (3b–i) when the BIEPs 4b–i were obtained in (80–98)% yields in (5–
16) h at rt (Sch. 1, Table 1), except for 5-nitroindole (3g) which required
heating at 608C. The appearance of 1H NMR signals at d 4.909–5.349 (1H, t)
and d 4.252–4.768 (2H, d, J ¼ 6.5–8.0 Hz) and 13C NMR signals at d 32.5–
34.2 (CH) and d 41.4–43.7 (CH2; DEPT 135) demonstrated the presence of
the Ar2CHCH2Phthal. group in the BIEPs 4a–i (vide Experimental).
The following observations need to be highlighted in this connection. The
indoles 3d, e, i required longer reaction periods (14–16 h) probably due to the
steric crowding in the resulting BIEPs (4d, e, i). Based on our previous
experience[9] that the use of a larger amount of clay (with consequently a
larger surface area) vastly expedites the clay-mediated reactions, the reaction
of 2 with indole itself (for generalization) and with each of these three indoles
(3d, e, i) was repeated using twice the amount (4 g) of clay. The reactions were
complete in half the original time periods, furnishing the BIEPs in practically
the same yields. The BIEP 4f had to be purified by preparative TLC, and the
BIEP 4h was sensitive to temperature (undergoing decomposition), which
Scheme 1.

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Chakrabarty et al.
Table 1. Reaction of 2 (0.5 mM) with 3a-i (1 mM) on m. K10 clay (2 g) at rt.
Indoles
R
R0
R00
Reaction time (h)
BIEPs
Yields (%)
3a
3b
3c
3d
3e
3f
H
Me
H
H
H
H
H
8 (4)a
4a
4b
4c
4d
4e
4f
97 (97)a
98
6
H
Br
H
6
91
H
2-Me
3-Me
H
14 (8)a
85 (86)a
91 (92)a
82
H
H
14 (7.5)a
H
OMe
NO2
NO2
H
5
8b
3g
3h
3i
H
H
4g
4h
4i
87
80
92 (93)a
Me
Me
H
Me
8
16 (8)a
aUsing 4 g clay.
bThe reaction was carried out at 608C.
probably accounts for their comparatively low isolated yields. The reaction
with 5-nitroindole (3g) was extremely slow clearly because of the nitro group,
which necessitated carrying out the reaction at 608. In 3h, however, the
additional presence of the N-methyl group must have counteracted the rate-
inhibitory effect of the nitro group, thus completing the reaction in the usual
time span at rt.
The BIEPs (4a-i) were then cleaved to the corresponding BIEAs by the
Ing–Manske procedure,[10,11] i.e. by refluxing with ethanolic hydrazine
hydrate. After the reaction was complete, the precipitated 1,4-dihydrox-
yphthalazine was filtered off and the filtrates were evaporated to residues. But
in each case, an attempt to crystallize the residue led to gradual
decomposition. For structural verification, the 1H NMR spectrum of only
one BIEA, viz. the one derived from the BIEP 4a was recorded, and the data
were in full agreement with the assigned structure. In general, however, the
residues were left overnight in pyridine and acetic anhydride and, after usual
work-up, the N-acetyl-BIEAs (5a–i) were isolated in (79–95)% yields in
(2.5–8) h, except for 4i which required 16 h for completion (Sch. 2, Table 2).
The presence of the Ar2CHCH2NHCOCH3 skeleton in 5a–i was demon-
strated, as in the case of the BIEPs, by the appearance of signals at d 4.501–
4.841 (1H, t) and d 3.691–4.02 (2H, dd, Jvic ꢀ 5.5–7.7 Hz) in their 1H NMR
spectra and the signals at d 33.7–35.5 (CH) and d 42.7–45.2 (CH2; DEPT
135) in their 13C NMR spectra (vide Experimental).
We have thus developed an efficient, facile and three-step synthetic route
to N-acetyl-BIEAs, furnishing the same in (65–92)% overall yields from
indoles.

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Synthesis of 2,2,Bis(30/20-indolyl)ethylamines
425
Scheme 2.
Table 2. Cleavage of BIEPs (0.3 mM) to BIEAs and subsequent N-acetylationa to
N-acetyl-BIEAs.
BIEPs
Cleavage time (h)
N-acetyl-BIEAs
Yields (%) Overall Yields (%)b
4a
4b
4c
4d
4e
4f
2.5
6
5a
5b
5cc
5d
5e
5f
95
92
87
84
80
79
90
82
92
92
90
79
71
73
65
78
66
90
3
5
5.5
5
4g
4h
4i
7
5g
5h
5i
8
16
aThroughout: pyridine, Ac2O, rt, overnight.
bRounded off to nearest integers.
cPertinently, the BIEA corresponding to 5c is a structural analogue of 2,2-
bis(60-bromo-30-indolyl)ethylamine (6-bromo instead of 5-bromo in 5c).[3,4]
We next extended our clay-mediated protocol for the preparation of three
important DIAs, viz. 3,3-bis(30-indolyl)propane-1,2-diol (6), steptindole (7)
and 2,2-bis(30-indolyl)propionic acid (8).

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Chakrabarty et al.
Scheme 3.
The toxic DIA 6 had earlier been reported to be isolated from a fungus,
¨
Balansia epichloe (Weese), a parasite to pasture grasses which were known to
elicit ergot-type syndrome in cattle grazing on these infected grasses.[12] It was
also reported therein to be synthesized by the acid-catalysed condensation of
indole with glyceraldehyde in 52% yield. The DIA 6 had previously been
prepared in 16.3% yield by the reaction of indole with glyceraldehyde
diethylacetal in presence of hydrochloric acid.[13] We, therefore, carried out a
similar but a solvent-free reaction using montmorillonite K10 clay as the
acidic catalyst (Sch. 3), when 6 was obtained in 80% yield. Ours is thus the
first solvent-free and only efficient synthesis of 6.
The first genotoxic (DNA-damaging) DIA, streptindole (7), was isolated
from the culture of human intestinal bacteria, Streptococcus faecium IB 37.[14]
These workers also prepared 7 by the reaction of indole with glycolaldehyde
acetate in presence of para-toluene sulphonic acid (TsOH) as catalyst, but the
yield of 7 was merely 2%. Subsequently, three more syntheses of 7 were
reported from the reaction of indole separately with glycolic acid (four-step
procedure),[15] a terahydrooxazine as a carbon-transfer reagent[16,17] and a
nitrone (three-step route),[5,6] furnishing 7 in 42%, unstated and 72% yields,
respectively. The drawbacks of the extants methods, viz. extremely low yield
or unstated yields, multi-step procedure and the need to use expensive and/or
preformed reagents and very low temperature (245 8C)[16,17] prompted us to
develop a new, simple and efficient synthesis of 7. Thus, when indole was
treated with glycolaldehyde dimethylacetal, a commercial product, on m. K10
clay under solvent-free conditions, the diindolylalkanol 9 was smoothly and
promptly formed. It was identified by spectroscopic analyses (vide Experi-
mental). Usual acetylation of 9 then furnished 7 in nearly 76% overall yield
(Sch. 4).
The superiority of our method to the extant methods of synthesis of
streptindole (7) becomes obvious when the reagents, the conditions, the
number of steps and the yields of 7 in the various methods are compared, as
shown in Table 3.
In 2000, the diindolylpropionic acid 8 along with the corresponding
isocaproic acid was isolated from the indole-supplemented supernatants of
E. coli and was also synthesized in unspecified yield by the overnight reaction
of indole with pyruvic acid in aqueous medium at 378C,[18] followed

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Synthesis of 2,2,Bis(30/20-indolyl)ethylamines
427
Scheme 4.
by neutralization, solvent extraction and purification by HPLC. We carried out
the same reaction, conceivably the simplest route, but in a solvent-free manner
on m. K10 clay following our protocol. The reaction was complete within
minutes (,5 min) and the product 8 could be isolated in 67% yield by merely
leaching the clay with a suitable solvent (Sch. 5). Our conditions were clearly
much better than the only previously reported synthesis.[18]
To conclude, we have utilised our clay-mediated protocol for the
synthesis of the DIAs as the critical or sole step in developing a new, facile and
efficient general synthesis of 2,2-bis(30/20-indolyl)ethylamines (5a–i) and the
improved synthesis of three naturally occurring DIAs (6–8), two of which are
bioactive.
Table 3. Comparison of different synthetic routes to streptindole (7) starting from
indole.
Sl.
No.
No. of Yield (%)
steps
Whether
eco-friendly Lit. ref.
Reagents
of 7
1
2
CHOCH2OAc, TsOH, rt, 5 h
CHOCO2H; SOCl2; LAH;
Ac2O, KOAc, 17 h
1
4
2
41.7
No
No
14
15
3
4
A tetrahydrooxazine,a TFA, rt,
20–25 h
1
3
Not stated
No
No
16,17
5,6
A nitrone,a Me3SiCl, rt, 15.5 h;
H2, Pd(OH)2/C, AcOH, 18 h;
Ac2O, NaOAc, 17 h
72 (from
nitrone)
5
CH2OHCH(OMe)2, clay, rt,
1.5 h; Ac2O, NaOAc, 17 h
2
76
Yes
(1st step)
Our
method
aThese reagents had to be preformed in a number of steps.

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Chakrabarty et al.
Scheme 5.
EXPERIMENTAL
General
Melting points (in Celsius) were determined on a Toshniwal apparatus
and are uncorrected. IR spectra (nujol) were recorded in a Nicolet Impact 410
spectrophotometer, LR EI-MS on JEOL-JMS AX 505HA and HR FAB-MS
(m-nitrobenzyl alcohol as liquid matrix) on JEOL JMS-700 Mstation mass
1
spectrometers, and H and 13C NMR spectra, both 1D and 2D, on a Bruker
DRX 500 NMR spectrometer. TLCs, both analytical and preparative, were
carried out on silica gel G (Merck, India) plates and spots were visualized by
iodine vapour or 0.5% KMnO4 in aq. 1(N) NaOH. Elemental analyses were
performed in a Dr. Hans Hoesli Analyser (Type A1; No. 1058).
Preparation of BIEPs (4a–i). In a typical experiment, a solution of indole
(3a; 1 mM) and 2 (0.5 mM) in CH2Cl2 (2 mL) was adsorbed on m. K10 clay
(2 g) and the solvent was allowed to evaporate off at rt. After completion of the
reaction (TLC; 8 h), the clay was leached with CH2Cl2 (3 ꢀ 15 mL), solvent
removed from the pooled filtrates, and the residue was crystallized from pet.
ether-CH2Cl2 to furnish 4a (195 mg) as yellow needles, m.p. 208–2108C; IR:
3420, 1762, 1707, 1401, 744 cm21; MS: m/z 405 (Mþ), 257, 245 (100%), 217,
189, 160; 1H (CDCl3): d 7.943 (2H, br s), 7.759 (2H, d, J ¼ 8 Hz), 7.724 and
7.607 (2H, dd each, J ¼ 5, 3 Hz), 7.291 (2H, d, J ¼ 8 Hz), 7.133 and 7.039
(2H, t each, J ¼ 7.5 Hz), 7.074 (2H, s), 5.314 (1H, t, J ¼ 7.5 Hz), 4.381 (2H, d,
J ¼ 7.5 Hz); 13C: d 169.0 (CO), 136.8, 132.4, 127.5, 117.1 (all Ar-C), 134.2,
123.4, 122.7, 122.4, 119.9, 119.8, 111.4 (all Ar-CH), 43.0 (CH2), 32.9 (CH).
Anal. Calcd for C26H19N3O2: C, 77.03; H, 4.69; N, 10.37. Found: C, 77.16; H,
4.67; N, 10.33.
The other BIEPs, prepared in a similar manner, were crystallized from
pet. ether-CH2Cl2, unless otherwise stated.
4b. Yield: 212 mg; yellow needles, m.p. 180–1828C; IR: 1768, 1704,
1464, 1375, 751 cm21; MS: m/z 433 (Mþ), 302, 273 (100%), 257, 242, 160;
1H (CDCl3): d 7.810 (2H, d, J ¼ 7.8 Hz), 7.756 and 7.629 (2H, dd each, J ¼ 5,
3 Hz), 7.270 (2H, d, J ¼ 8 Hz), 7.202 (2H, t, J ¼ 7.8 Hz), 7.077 (2H, t,
J ¼ 7.5 Hz), 7.004 (2H, s), 5.349 (1H, t, J ¼ 7.5 Hz), 4.386 (2H, d,
J ¼ 7.5 Hz), 3.715 (6H, s); 13C: d 169.0 (CO), 137.6, 132.5, 127.9, 115.7

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Synthesis of 2,2,Bis(30/20-indolyl)ethylamines
429
(all Ar-C), 134.1, 127.4, 123.4, 121.9, 120.0, 119.2, 109.5 (all Ar-CH), 43.3
(CH2), 33.1 (CH3), 32.8 (CH). Anal. Calcd for C28H23N3O2: C, 77.59; H, 5.31;
N, 9.69. Found: C, 77.73; H, 5.29; N, 9.65.
4c. Yield: 255 mg; white needles, m.p. 178–1808C; IR: 3355, 1702,
1697, 1454, 718 cm21; 1H (CDCl3): d 11.067 (2H, br s), 7.759 (4H, s), 7.573
(2H, s), 7.345 (2H, d, J ¼ 2 Hz), 7.261 (2H, d, J ¼ 8.5 Hz), 7.088 (2H, dd,
J ¼ 8.5, 1.5 Hz), 4.909 (1H, t, J ¼ 7.75 Hz), 4.252 (2H, d, J ¼ 7.75 Hz); 13C:
d 168.6 (CO), 135.9, 132.1, 129.2, 115.4, 111.8 (all Ar-C), 135.2, 125.3,
124.2, 123.8, 121.6, 114.3 (all Ar-CH), 43.2 (CH2), 32.9 (CH); MS: m/z 565
(Mþ), 563, 561, 405, 403 (100%), 401, 368, 366, 325, 323, 321, 278, 243, 242;
HR MS: obs.: m/z 560.9703; Calcd for C26H17N3O729Br2: 560.9688.
4d. Yield: 184 mg; yellow needles, m.p. 262–2648C; IR: 3407, 3362,
1779, 1772, 1613, 743 cm21; MS: m/z 433 (Mþ), 302 (100%), 273, 257, 155,
130; 1H (DMSO-d6): d 10.648 (2H, s), 7.734 (4H, s), 7.387 and 7.166 (2H, d
each, J ¼ 8 Hz), 6.887 and 6.782 (2H, t each, J ¼ 7.5 Hz), 4.968 (1H, t,
J ¼ 8 Hz), 4.570 (2H, d, J ¼ 8 Hz), 2.238 (6H, s); 13C: d 168.4 (CO), 135.8,
132.6, 132.1, 128.7, 111.2 (all Ar-C), 135.1, 123.7, 120.5, 119.0, 118.9, 111.3
(all Ar-CH), 42.5 (CH2), 33.5 (CH), 13.0 (CH3). Anal. Calcd for C28H23N3O2:
C, 77.59; H, 5.31; N, 9.69. Found: C, 77.41; H, 5.33; N, 9.73.
4e. Yield: 196 mg; yellow needles, m.p. 116–1188C; IR: 3381, 1768,
1709, 1379, 743 cm21; MS: m/z 433 (Mþ), 318, 302, 273 (100%), 257, 243,
1
147; H (DMSO-d6): d 10.813 (2H, s), 7.895–7.610 (4H, m), 7.317 (4H, d,
J ¼ 7 Hz), 7.011 and 6.90 (2H, t each, J ¼ 6.5 Hz), 5.201 (1H, t, J ¼ 7.5 Hz),
4.379 (2H, d, J ¼ 7.5 Hz), 2.131 (6H, s); 13C: d 168.3 (CO), 136.4, 133.2,
132.0, 128.8, 107.5 (all Ar-C), 135.4, 123.9, 121.7, 119.1, 118.8, 111.7 (all Ar-
CH), 41.4 (CH2), 33.1 (CH), 9.0 (CH3). Anal. Calcd for C28H23N3O2: C,
77.59; H, 5.31; N, 9.69. Found: C, 77.35; H, 5.29; N, 9.66.
4f. Yield: 191 mg; white needles, m.p. 226–2288C; IR: 3347, 1768,
1703, 1697, 1573, 1394, 731 cm21; MS: m/z 465 (Mþ), 318 (100%), 305, 275,
171, 147; 1H (DMSO-d6): d 10.648 (2H, s), 7.789–7.696 (4H, m), 7.195 and
6.978 (2H, d each, J ¼ 2 Hz), 7.174 (2H, d, J ¼ 8.5 Hz), 6.645 (2H, dd,
J ¼ 8.5, 2 Hz), 4.940 (1H, t, J ¼ 7.8 Hz), 4.260 (2H, d, J ¼ 7.8 Hz), 3.629
(6H, s); 13C: d 168.7 (CO), 153.6, 132.3, 132.2, 127.9, 115.7 (all Ar-C), 135.2,
124.1, 123.8, 112.9, 111.6, 101.5 (all Ar-CH), 56.0 (CH3), 43.3 (CH2), 33.0
(CH). Anal. Calcd for C28H23N3O4: C, 72.26; H, 4.95; N, 9.03. Found: C,
72.47; H, 4.93; N, 9.00.
4g. Yield: 216 mg; yellow needles, m.p. 326–3288C (pet. ether-EtOAc);
IR: 3415, 3332, 1761, 1696, 1689, 1517, 1320, 738 cm21; MS: m/z 495 (Mþ),
478, 348, 335 (100%), 319, 289, 272; 1H (DMSO-d6): d 11.697 and 8.435 (2H,
s each), 7.889 (2H, d, J ¼ 8 Hz), 7.820-7.682 (4H, m), 7.646 (2H, s), 7.469
(2H, d, J ¼ 8.5 Hz), 5.135 (1H, t, J ¼ 6.5 Hz), 4.348 (2H, d, J ¼ 6.5 Hz); 13C:
d 168.5 (CO), 141.0, 140.4, 132.0, 126.6, 118.2 (all Ar-C), 135.1, 127.8,

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Chakrabarty et al.
123.8, 117.3, 116.6, 112.8 (all Ar-CH), 43.2 (CH2), 33.0 (CH). Anal. Calcd for
C26H17N5O6: C, 63.03; H, 3.43; N, 14.14. Found: C, 63.25; H, 3.42; N, 14.09.
4h. Yield: 209 mg; yellow needles, m.p. 263–2658C (pet. ether-EtOAc);
IR: 1772, 1705, 1613, 1508, 1321, 742 cm21; 1H (DMSO-d6): d 8.486 (2H, s),
7.934 and 7.544 (2H, d each, J ¼ 9 Hz), 7.719 (4H, s), 7.570 (2H, s), 5.150
(1H, t, J ¼ 7.5 Hz), 4.256 (2H, d, J ¼ 7.5 Hz), 3.793 (6H, s); 13C: d 168.6
(CO), 141.1, 140.4, 132.0, 126.8, 117.8 (all Ar-C), 135.2, 132.1, 123.8, 117.3,
116.7, 111.3 (all Ar-CH), 43.7 (CH2), 33.8 (CH3), 32.5 (CH). Anal. Calcd for
C28H21N5O6: C, 64.24; H, 4.02; N, 13.38. Found: C, 64.04; H, 4.03; N, 13.40.
4i. Yield: 213 mg; yellow needles, m.p. 262–2648C; IR: 1765, 1707,
1
1395, 1370, 741 cm21; H (CDCl3): d 7.705 (2H, d, J ¼ 8 Hz), 7.654 and
7.578 (2H, dd each, J ¼ 5.5, 3 Hz), 7.170 (2H, d, J ¼ 8 Hz), 7.053 and 6.950
(2H, t each, J ¼ 7.5 Hz), 5.224 (1H, t, J ¼ 8 Hz), 4.768 (2H, d, J ¼ 8 Hz),
3.545 and 2.236 (6H, s each); 13C: d 168.6 (CO), 136.8, 133.9, 132.3, 127.8,
111.5 (all Ar-C), 134.2, 123.3, 120.4, 119.5, 119.2, 108.9 (all Ar-CH), 42.8
(CH2), 34.2 (CH), 29.8, 11.2 (all CH3). Anal. Calcd for C30H27N3O2: C, 78.09;
H, 5.86; N, 9.11. Found: C, 77.85; H, 5.88; N, 9.14. Conversion of BIEPs to
N-acetyl-BIEAs (5a–i). General Procedure: The BIEP (0.3 mM) and
NH2NH2.H2O (0.02 mL; 0.4 mM) in methanol (15 mL) was refluxed on
water bath until the reaction was complete. The solution was then cooled to rt,
the resulting white precipitate was filtered off under suction and the filtrate was
concentrated to 5 mL, poured into excess water, extracted with EtOAc
(3 ꢀ 15 mL), dried (Na2SO4) and filtered. Solvent was removed from the
filtrate to furnish a residue which was dissolved in required minimum of
pyridine (0.2–0.4 mL), treated with Ac2O (0.4–0.8 mL) and kept overnight at
rt. The solution was then poured into water, extracted with EtOAc (3 ꢀ 15 mL).
Usual work-up furnished a residue, which was crystallized from pet. ether-
CH2Cl2 (unless otherwise stated) to furnish the N-acetyl-BIEAs.
BIEA derived from 4a. Yield: 79 mg (83%); brown solid, m.p. 96–988C;
1H (CDCl3): d 8.045 (2H, br s), 7.599 and 7.352 (2H, d each, J ¼ 8 Hz), 7.164
and 7.045 (2H, t each, J ¼ 7.5 Hz), 7.035 (2H, s), 4.578 (1H, t, J ¼ 7 Hz),
3.468 (2H, d, J ¼ 7 Hz), 2.127 (2H, br s).
5a. Yield: 90 mg; white needles, m.p. 114–1168C; IR: 3416, 3317, 1659,
1650, 1460, 751 cm21; MS: m/z 317 (Mþ), 284, 272, 258, 245 (100%), 243,
217; 1H (CDCl3): d 8.140 (2H, br s), 7.583 and 7.339 (2H, d each, J ¼ 8 Hz),
7.165 and 7.041 (2H, t each, J ¼ 7.5 Hz), 6.963 (2H, s), 5.60 (1H, t, J ¼ 6 Hz),
4.714 (1H, t, J ¼ 7 Hz), 4.020 (2H, dd, J ¼ 7, 6 Hz), 1.859 (3H, s); 13C:
d 170.7 (CO), 137.0, 127.2, 117.2 (all Ar-C), 122.54, 122.53, 119.9, 119.8,
111.6 (all Ar-CH), 44.2 (CH2), 34.6 (CH), 23.8 (CH3). Anal. Calcd for
C20H19N3O: C, 75.71; H, 5.99; N, 13.25. Found: C, 75.87; H, 5.97; N, 13.21.
5b. Yield: 95 mg; white needles, m.p. 112–1148C; IR: 1710, 1659, 1612,
1
1455, 740 cm21; MS: m/z 345 (Mþ), 286, 273 (100%), 257, 214, 158; H

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431
(DMSO-d6): d 7.896 (1H, t, J ¼ 5.5 Hz), 7.512 (2H, d, J ¼ 8 Hz), 7.329 (2H, t,
J ¼ 8 Hz), 7.119 (2H, s), 7.078 and 6.925 (2H, t each, J ¼ 7.5 Hz), 4.606 (1H,
t, J ¼ 7 Hz), 3.721 (2H, dd, J1 ¼ J2 ¼ 6.5 Hz), 3.693 (6H, s), 1.728 (3H, s);
13C: d 170.2 (CO), 137.6, 128.0, 116.6 (all Ar-C), 127.6, 121.8, 119.8, 119.0,
110.4 (all Ar-CH), 44.9 (CH2), 34.3 (CH), 33.1, 23.5 (all CH3). Anal. Calcd
for C22H23N3O: C, 76.52; H, 6.67; N, 12.17. Found: C, 76.47; H, 6.69; N,
12.14.
5c. Yield: 123 mg; white needles, m.p. 172–1748C; IR: 3414, 3266,
1648, 1642, 1526, 730 cm21; 1H (DMSO-d6): d 11.047 (2H, s), 7.905 (1H, t,
J ¼ 7 Hz), 7.574 (2H, s), 7.281 and 7.109 (2H, d each, J ¼ 8.5 Hz), 7.245 (2H,
s), 4.534 (1H, t, J ¼ 7 Hz), 3.691 (2H, dd, J1 ¼ J2 ¼ 5.75 Hz), 1.728 (3H, s);
13C: d 170.9 (CO), 135.6, 128.8, 116.4, 113.1 (all Ar-C), 125.4, 123.7, 122.2,
113.3 (all Ar-CH), 44.1 (CH2), 34.4 (CH), 23.8 (CH3); MS: m/z 477 (Mþ),
475, 473, 418, 416, 414, 405, 403 (100%), 401, 323, 278, 242; HR MS: obs.:
m/z 472.9723; Calcd for C20H17N3O79Br2: 472.9738.
5d. Yield: 87 mg; yellow micro needles, m.p. 168–1708C; IR: 3382,
3277, 1706, 1646, 1375, 747 cm21; MS: m/z 345 (Mþ), 302, 273, 257, 214,
1
130 (100%); H (DMSO-d6): d 10.675 (2H, br s), 7.789 (1H, t, J ¼ 7 Hz),
7.363 and 7.190 (2H, d each, J ¼ 7.5 Hz), 6.898 and 6.793 (2H, t each,
J ¼ 7 Hz), 4.606 (1H, t, J ¼ 7 Hz), 3.933 (2H, dd, J1 ¼ J2 ¼ 7.7 Hz), 2.325
(6H, s), 1.743 (3H, s); 13C: d 170.1 (CO), 136.0, 132.4, 128.7, 112.4 (all Ar-C),
120.3, 119.2, 118.8, 111.2 (all Ar-CH), 44.0 (CH2), 34.9 (CH), 23.4, 13.1 (all
CH3). Anal. Calcd for C22H23N3O: C, 76.52; H, 6.67; N, 12.17. Found: C,
76.44; H, 6.70; N, 12.20.
5e. Yield: 83 mg; yellow micro needles, m.p. 102–1048C; IR: 3299,
1656, 1650, 1643, 1487, 742 cm21; MS: m/z 345 (Mþ), 315, 286, 273 (100%),
1
257, 158, 130; H (DMSO-d6): d 10.558 (2H, br s), 7.980 (1H, t, J ¼ 7 Hz),
7.375 (2H, d, J ¼ 7.5 Hz), 7.292 (2H, d, J ¼ 8 Hz), 7.004 and 6.927 (2H, t
each, J ¼ 7.5 Hz), 4.841 (1H, t, J ¼ 7.5 Hz), 3.790 (2H, dd, J1 ¼ J2 ¼ 6.5 Hz),
2.195 (6H, s), 1.725 (3H, s); 13C: d 170.5 (CO), 136.2, 134.8, 129.2, 107.0 (all
Ar-C), 121.4, 119.0, 118.6, 111.6 (all Ar-CH), 42.7 (CH2), 34.9 (CH), 23.3,
9.2 (all CH3). Anal. Calcd for C22H23N3O: C, 76.52; H, 6.67; N, 12.17. Found:
C, 76.65; H, 6.65; N, 12.13.
5f. Yield: 89 mg; white needles, m.p. 196–1988C; IR: 3338, 3270, 1621,
1585, 1537, 738 cm21; MS: m/z 377 (Mþ), 319, 305 (100%), 273, 230, 147;
1H (DMSO-d6): d 10.605 (2H, s), 7.871 (1H, t, J ¼ 5.5 Hz), 7.194 (2H, d,
J ¼ 8.5 Hz), 7.096 and 7.010 (2H, d each, J ¼ 2 Hz), 6.666 (2H, dd, J ¼ 8.5,
2 Hz), 4.501 (1H, t, J ¼ 7.5 Hz), 3.735 (2H, dd, J ¼ 7.5, 5.5 Hz), 3.661 (6H, s),
1.743 (3H, s); 13C: d 170.1 (CO), 153.5, 132.5, 128.0, 116.9 (all Ar-C), 123.9,
112.7, 111.4, 102.0 (all Ar-CH), 44.5 (CH2), 34.8 (CH), 56.1, 23.5 (all CH3).
Anal. Calcd for C22H23N3O3: C, 70.03; H, 6.10; N, 11.14. Found: C, 70.25; H,
6.12; N, 11.10.

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Chakrabarty et al.
5g. Yield: 110 mg; yellow needles; m.p. 158–1608C (pet. ether-EtOAc);
IR: 3372, 1708, 1647, 1623, 1517, 1465, 740 cm21; 1H (DMSO-d6): d 11.669
(2H, s), 8.427 (2H, s), 8.010 (2H, t, J ¼ 8 Hz), 7.932 (2H, d, J ¼ 8 Hz), 7.527
(2H, s), 7.497 (2H, d, J ¼ 8.5 Hz), 4.805 (1H, t, J ¼ 7.5 Hz), 3.776 (2H, dd,
J1 ¼ J2 ¼ 7.5 Hz), 1.736 (3H, s); 13C: d 170.3 (CO), 141.0, 140.5, 126.8,
119.5 (all Ar-C), 127.5, 117.3, 116.7, 112.8 (all Ar-CH), 44.7 (CH2), 34.2
(CH), 23.4 (CH3). Anal. Calcd for C20H17N5O5: C, 58.97; H, 4.18; N, 17.19.
Found: C, 58.79; H, 4.17; N, 17.13.
5h. Yield: 107 mg; yellow needles; m.p. 226–2288C (pet. ether-EtOAc);
IR: 1712, 1615, 1512, 1331, 738 cm21; MS: m/z 435 (Mþ), 417, 376, 363
1
(100%), 333, 317, 259, 232; H (DMSO-d6): d 8.511 (2H, s), 8.007 (3H, s),
7.581 and 7.467 (2H, s each), 4.834 (1H, s), 3.90-3.60 (8H, m) 1.730 (3H, s);
13C: d 170.3 (CO), 141.1, 140.5, 127.0, 119.0 (all Ar-C), 131.8, 117.3, 116.6,
111.2 (all Ar-CH), 45.2 (CH2), 33.7 (CH), 33.8, 23.4 (all CH3). Anal. Calcd
for C22H21N5O5: C, 60.69; H, 4.83; N, 16.09. Found: C, 60.51; H, 4.81; N,
16.14.
5i. Yield: 84 mg; brown micro needles, 88–908C; IR: 1654, 1647, 739
cm21; 1H (DMSO-d6): d 7.782 (1H, t, J ¼ 6.5 Hz), 7.445 and 7.30 (2H, d each,
J ¼ 8 Hz), 6.979 and 6.841 (2H, t each, J ¼ 7.5 Hz), 4.641 (1H, t, J ¼ 7.5 Hz),
3.947 (2H, dd, J1 ¼ J2 ¼ 6.5 Hz), 3.593 and 2.308 (6H, s each), 1.721 (3H, s);
13C: d 170.1 (CO), 137.1, 134.3, 127.5 112.5 (all Ar-C), 120.4, 119.5, 119.1,
109.8 (all Ar-CH), 44.2 (CH2), 35.5 (CH), 30.1, 23.4, 11.3 (all CH3). Anal.
Calcd for C24H27N3O: C, 77.21; H, 7.24; N, 11.26. Found: C, 77.43; H, 7.27;
N, 11.22.
Preparation of 6. A solution of indole (3a; 1 mM) in 1.8 mL MeOH was
mixed with a solution of glyceraldehyde (45 mg, 0.5 mM) in 0.2 mL water.
The resulting clear solution was adsorbed on m. K10 clay (2 g). This wet clay
was kept fitted to a water pump. In 0.5 h, the off-white colour of the clay turned
into red, when the reaction was found to be complete (TLC). The clay was
leached with EtOAc (3 ꢀ 15 mL), solvent distilled off from the filtrate and the
residue crystallized from pet. ether-EtOAc to furnish 6 (123 mg; 80%) as
1
white needles, m.p. 88–908C (Lit[13] m.p. 90–918C); IR and H NMR: as
reported earlier; 13C (DMSO-d6): d 136.9, 136.7, 128.7, 127.7, 118.1, 116.0
(all Ar-C), 124.2, 123.7, 121.3, 121.1, 120.0, 119.7, 118.7, 118.6, 112.0, 111.8
(all Ar-CH), 75.1, 36.7 (CH), 65.5 (CH2).
Preparation of streptindole (7). A solution of indole (3a; 1 mM) in
CH2Cl2 (2 mL) containing glycolaldehyde dimethylacetal (53 mg, 0.5 mM)
was adsorbed on m. K10 clay (2 g) and the solvent was allowed to evaporate
off at rt. After the reaction was complete (TLC) in 1.5 h, the clay was leached
with CH2Cl2 (3 ꢀ 15 mL), followed by filtration, removal of solvent from the
pooled filtrates and crystallization of the resulting residue from pet. ether-
CH2Cl2 to give 9 (121 mg; 88%); m.p. 47–498C (Lit[15] m.p. 508C); IR and 1H

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Synthesis of 2,2,Bis(30/20-indolyl)ethylamines
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NMR: as reported earlier;[16,17] 13C (DMSO-d6): d 137.2, 127.8, 117.2 (all Ar-
C), 123.3, 121.4, 119.8, 118.7, 112.1 (all Ar-CH), 37.8 (CH), 66.0 (CH2).
Acetylation of 9. A solution of 9 (50 mg) in Ac2O (2 mL) containing
fused NaOAc (60 mg) was stirred for 17 h. EtOAc (1.4 mL) and EtOH
(0.2 mL) were then added, and the resulting mixture was stirred for another
8 h. The reaction mixture was washed successively with water, aq. NaHCO3
and brine. The organic layer was dried, filtered and solvent removed to give
pure 7 (50 mg; 86%) as a waxy residue; IR and 1H NMR: as reported
earlier;[14] 13C (CDCl3): d 171.8 (CO), 136.8, 127.4, 116.5 (all Ar-C), 122.6,
122.4, 119.9, 119.7, 111.6 (all Ar-CH), 67.9 (CH2), 33.9 (CH), 21.5 (CH3).
Preparation of 8. A solution of indole (3a; 1 mM) in CH2Cl2 (1.8 mL)
was mixed with a solution of pyruvic acid (0.03 mL, 0.5 mM) in MeOH
(0.2 mL). The resulting clear solution was adsorbed on m. K10 clay (2 g) and
the solvent was allowed to evaporate off at rt. The reaction was complete
(TLC) in 5 min. The clay was leached with CH2Cl2 (3 ꢀ 20 mL) and the
residue obtained from the pooled filtrates was crystallized from pet. ether-
CH2Cl2 to furnish 8 (93 mg; 67%) as red prisms, m.p. 108–1118C (Lit[18] m.p.
1
109–1148C). Its IR, H, 13C NMR and MS data agreed with those reported
earlier.
ACKNOWLEDGMENTS
The authors sincerely thank the Director, Bose Institute for laboratory
facilities, the C.S.I.R., Govt. of India for providing fellowships (N.G.,
R.K.B.), Mr. B. Majumder, NMR Laboratory, B.I. and Mr. P. Dey,
Microanalytical Laboratory, B.I. for recording the spectra.
REFERENCES
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4. Bifulco, G.; Bruno, I.; Riccio, R.; Lavayre, J.; Bourdy, G. J. Nat. Prod.
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6. Chalaye-Mauger, H.; Denis, J.-N.; Averbuch-Pouchot, M.-T.; Vallee, Y.
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8. Chakrabarty, M.; Basak, R., unpublished results.

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9. Chakrabarty, M.; Ghosh, N.; Basak, R.; Harigaya, Y. Tetrahedron Lett.
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Received in India June 24, 2003

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