First isolation of both indolylcarbinols and diindolylalkanes from microwave-assisted acid (clay)-catalysed reaction of indoles with diethyl ketomalonate

Article abstract of DOI:10.3987/COM-04-10200

Indoles (1a-f) react with diethyl ketomalonate on montmorillonite K10 clay under microwave irradiation to furnish expeditiously (1-4 min) the corresponding indol-3′-ylcarbinols (2a-f; 20-45%) and the respective diindolylalkanes (3a-f; 5-35%), which constitute the first direct evidence for the intermediacy of indolylcarbinols in the formation of diindolylalkanes from the acid-catalysed reaction of indoles with aldehydes and ketones.

Full text of DOI:10.3987/COM-04-10200

HETEROCYCLES, Vol. 65, No. 1, 2005
37
HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 37 - 48
Received, 16th August, 2004, Accepted, 1st November, 2004, Published online, 2nd November, 2004
FIRST ISOLATION OF BOTH INDOLYLCARBINOLS AND
DIINDOLYLALKANES FROM MICROWAVE-ASSISTED ACID
(CLAY)-CATALYSED REACTION OF INDOLES WITH DIETHYL
KETOMALONATE
Manas Chakrabarty,a* Sulakshana Karmakara and Yoshihiro Harigayab
aDepartment of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700009,
India
E-mail: chakmanas@yahoo.co.in
bSchool of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo
108, Japan
Abstract- Indoles (1a-f) react with diethyl ketomalonate on montmorillonite
K10 clay under microwave irradiation to furnish expeditiously (1-4 min) the
corresponding indol-3'-ylcarbinols (2a-f; 20-45%) and the respective
diindolylalkanes (3a-f; 5-35%), which constitute the first direct evidence for
the intermediacy of indolylcarbinols in the formation of diindolylalkanes from
the acid-catalysed reaction of indoles with aldehydes and ketones.
Diindolylalkanes (DIAs) in general and bis(1H-3'-indolyl)alkanes in particular of both synthetic and
natural origins are an old1 and well studied group of compounds, whose synthesis and bioactivity have
been recently reviewed.2 The recent isolation of several DIAs from natural sources2,3 and their reported
significant bioactivities2,4 render this class of compounds important synthetic targets. As a result, although
a wide variety of synthetic routes to the DIAs are available,2 newer synthetic avenues to these bisindolic
compounds continue to be developed.5 The reaction of indoles with aldehydes or ketones using protic or
Lewis acids as catalysts is by far the most widely used route to the DIAs.6 We have recently
demonstrated7 that montmorillonite K10 clay, possessing both Brønsted and Lewis acidic sites,8 is also
effective for an expedient and efficient synthesis of DIAs by this route. It is well accepted that the DIAs
are formed in this type of reactions through the corresponding indolylcarbinols. Although indolylcarbinols
along with the corresponding DIAs have previously been reported from the reaction of indolyl Grignard

38
HETEROCYCLES, Vol. 65, No. 1, 2005
reagents with, for example, pyridine 2- and 4-carboxaldehydes,9 indolylcarbinols have never been isolated
from any acid-catalysed reaction since in the acidic conditions they dehydrate to the corresponding
alkylidene indoleninium cations. The latter, though isolated in some cases,10,11 are usually immediately
attacked by a second molecule of the indole, resulting in the formation of DIAs.12 In continuation of our
interest13 in the clay-mediated reactions of indoles, we recently undertook the study of the microwave-
assisted solvent-free14 reaction of indoles (1a-f) with diethyl ketomalonate (DEKM) on K10 clay. As a
result, both indolylcarbinols (2a-f) and the respective DIAs (3a-f) were formed as (except for 1d) the
major and the minor products, respectively, though only in moderate overall yields (28-78%). Our work
thus assumes considerable importance from mechanistic viewpoint. We, therefore, present our findings
herein.
Initially, indole itself (1a) and an equimolar amount of DEKM, adsorbed on the aforesaid clay, was
subjected to microwave irradiation,15 when indole was consumed in a minute to result in the formation of
two products (TLC). These were leached from the clay by a suitable solvent, separated into its
components by preparative TLC and identified spectroscopically. The major product (20%), analysing for
C15H17NO5 (also, MS: M+ 291), recorded in its IR, 1H and 13C NMR and MS spectra the presence of a 3-
substituted indolyl moiety and two ethoxycarbonyl groups in addition to a hydroxyl group (IR: 3429 cm-1;
1H NMR: δ 4.33, 1H, s) and an oxygenated quaternary (DEPT 135) carbon (δ 78.1). It was thus identified
as diethyl 2-hydroxy-2-(3'-indolyl)malonate (2a), i.e. an indol-3'-ylcarbinol.
The minor product (8%) also showed the presence of a 3-substituted indolyl moiety and only one
1
13
ethoxycarbonyl group in its H and C NMR spectra. But from the additional presence of a quaternary
carbon (DEPT 135) at δ 58.9 together with its moleculer formula, C23H22N2O4 (also, M+ 390), and the
appearance of two (indolic) N-H stretchings (3417, 3362 cm-1) in its IR spectrum, it was identified as
diethyl 2,2-bis(3'-indolyl)malonate (3a), i.e. the DIA generated via 2a. The isolation of 2a constitutes, to
our knowledge, the first isolation of an indolylcarbinol from an acid (clay in this case)-catalysed reaction
of an indole with a carbonyl compound.
This significant outcome of our experiment with indole itself prompted us to extend this reaction to a
number of substituted indoles in order to check the generality of this observation. Accordingly, each of 1-
methyl (1b), 2-methyl (1c), 1,2-dimethyl (1d), 5-methoxy (1e) and 5-bromo (1f) derivatives of indole was
separately but similarly treated with an equimolar amount of DEKM on clay under microwave irradiation
until (1-4 min) the reactions were complete. In each case, two products were formed. As in the case of 1a,
1
both the types of products, 2a-f (20-45%) and 3a-f (5-35%), were identified spectroscopically (IR, H
and 13C NMR spectra including DEPT 135, MS, elemental analysis and/or HR MS) as the corresponding

HETEROCYCLES, Vol. 65, No. 1, 2005
39
indol-3'-ylcarbinols (2b-f) and the DIAs (3b-f), respectively (Scheme 1). Pertinently, N-methylindole (1b)
has earlier been reported to react with DEKM in toluene under reflux to furnish 2b as the sole product.
When, however, the same reaction was carried out in presence of the Lewis acid, lithium aluminium
dichloride, the corresponding DIA (3b) was the only product (38%).16
2
EtO C
CO Et
2
2
4'
R"
R"
3'
OH
mont. K10 clay (4 g)
MW, 1-4 min
+
R'
CO(CO Et)
2
2
2'
N
R
R'
N
7'
R
DEKM
(1 mmol)
1a-g (1 mmol)
2a-f (20-45%)
+
EtO C
CO Et
2
2
2
4'
R"
3'
)
2
:
for 1-3
R'
R = H (a, c, e, f), Me (b, d)
R' = H (a, b, e, f), Me (c, d)
R'' = H (a-d), OMe (e), Br (f)
N
R
7'
3a-f (5-35%)
Scheme 1
The two types of products displayed distinguishing spectral behaviour. Thus, in MS spectrum, while each
of 3a-f recorded the base peak at M+-73 m.u. (i.e. M+-•CO2Et), the same appeared at M+-147 m.u. (i.e.
M+-HCO2Et, -•CO2Et) in the case of 2a-f. In 13C NMR spectroscopy, C-2 appeared at δ 78/79 in the case
1
of 2a-f and at δ 58 for 3a-f. In H NMR spectroscopy, although the protons of the two ethoxycarbonyl
groups displayed expected splitting patterns in the case of 3a-f (see EXPERIMENTAL), the two
methylene protons of each ethoxycarbonyl group in 2a-f transpired to be chemical shift non-equivalent,
appearing as two signals (2H, dq each, J=7, 10.5/11 Hz) with the six methyl protons appearing as a 6H,
1
13
dd, J1=J2=7 Hz. The individual H and C NMR spectral assignments of one indolylcarbinol (2c) were
ascertained by analysing its HMQC and HMBC spectra.
Since the acid-catalysed conversion of indolylcarbinols to the corresponding DIAs is well documented,17
the isolation of the DIAs (2a-f) along with the indolylcarbinols (3a-f), from which the former are
generated, provides the first direct evidence in support of the widely believed intermediacy of
indolylcarbinols in the acid-catalysed conversion of indoles to DIAs.
In order to ascertain the influence of electronic factors on the relative yields of the two types of products,

40
HETEROCYCLES, Vol. 65, No. 1, 2005
each of skatole (4) and 5-nitroindole (1g) was separately treated with equimolar amounts of DEKM on
clay under microwave irradiation in a similar manner. From 4, the corresponding indol-2'-ylcarbinol (5;
35%) was formed as practically the sole product (Scheme 2) with only traces of the corresponding DIA
having been formed. But from 1g, the corresponding DIA (3g; 58%) was practically the sole product,
which was quite surprising.
3'
Me
Me
CO(CO Et)
clay, MW
3 min; 35 %
2
2
OH
CO Et
2
N
H
N
2
H
EtO C
2
4
5
Scheme 2
Pertinently, the reactions were also carried out successfully at room temperature or, when necessitated, by
heating at 60 °C in an oven. Expectedly, the reactions took longer time for completion, 1g requiring an
appreciably longer period and skatole never going to completion even after exposure to both forms of
heating for considerable periods. Clearly, the electron-withdrawing effect of the nitro group in 1g and the
well known reduced nucleophilicity of 3-substituted indoles (4) at C-2 are responsible for these
observations. The overall findings from our experiments are presented in Table 1.
In order to account for the formation of the indol-3'/2'-ylcarbinols, the first of its kind from such reactions,
the fate of the clay-mediated reactions of indoles across the series: acetone7 to pyruvic acid18 to DEKM
(present work) needed to be considered. In the first two cases, the corresponding DIAs were the sole
products. But in the case of DEKM, the DIAs were only either minor products (3a-c, e, f) or not formed
at all (from 4), with the indolylcarbinols as the major (2a-c, e, f) or the sole (5) product(s). The modified
carbonyl character of DEKM in comparison to those of acetone and pyruvic acid must be the clue to the
contrasting courses of the reactions of these two sets of carbonyl compounds. Since the carbocations are
in general electron-deficient,19 we believe, the destabilizing effect of the two electron-withdrawing
carbethoxy groups on the carbocations of type (6), through which the DIAs (3a-f) are believed to be
formed from 2a-f, largely inhibits the formation of these carbocations in the first place, thereby rendering
the formation of the DIAs as only the minor products (except for 3d). Nevertheless, we are baffled at the
formation of 3g as practically the only product from 1g.
The intermediacy of the indolylcarbinols in the formation of the DIAs received additional support from

HETEROCYCLES, Vol. 65, No. 1, 2005
41
the fact that when the indole (1c) was treated with an equimolar amount of the corresponding
indolylcarbinol (2c) on clay at room temperature, the corresponding DIA (3c) was obtained as the only
Table 1. Reaction of indolesa with DEKMa on clayb under MW irradiation / at room temperature / 60 °C
Entry
No.
Indoles
R
Time (min)
Productsc
(Yield, %)
Overall
yield
(%)
R′
R′′
MW
rt
10
10
20
15
10
60
120
⎯
60°C
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
Me
H
H
H
H
1
1
2a
(20)
2b
3a
(8)
3b
28
33
66
65
28
78
35
58
⎯
⎯
H
(20)
2c
(13)
3c
Me
H
1
⎯
(35)
2d
(31)
3d
Me
H
Me
H
1
⎯
(30)
2e
(35)
3e
H
OMe
Br
1
⎯
(23)
2f
(5)
3f
H
H
3-Methyl
H
4
15
(45)
(33)
⎯
4
3
30
5
(35)d
⎯
1g
H
NO2
18
3.5 h
3g
(58)
aOne mmol of each reactant was used.
bFor 1 mmol of each reactant, 4 g of montmorillonite K10 clay was used.
cFully identified by IR, 1H and 13C NMR, MS spectra and elemental analysis.
dThe yield of 5 was calculated on the basis of 4 that was consumed.
EtO C
CO Et
2
2
(3'/2'-Indolyl)
6
product (52%). Notably, the reaction was not complete even after being kept overnight at room
temperature, which suggested that the second step in the formation of the DIAs is considerably slower
than the first step.
In order to check the recyclability of clay, the clay left after the reaction of 1c with DEKM was
thoroughly washed, dried and then reused in the same reaction in the same scale. The same two products,
2c and 3c, were obtained, 2c in a similar yield (32%) and 3c in only 12% yield, compared to those using

42
HETEROCYCLES, Vol. 65, No. 1, 2005
fresh clay (2c: 35%; 3c: 31%) in the same time period. The recyclability of clay for at least the second
cycle in this type of reactions was thus demonstrated, which adds to the usefulness of these reactions.
In conclusion, we have isolated the hitherto elusive indolylcarbinols (along with the corresponding DIAs)
from the acid (clay in this case)-catalysed reaction of indoles with carbonyl compounds, diethyl
ketomalonate in the present case. The instability of the crucial carbocations (6), hence a right choice of
the carbonyl compound appears to be the clue to the successful isolation of the indolylcarbinol
intermediates.
EXPERIMENTAL
Mps were determined on a Toshniwal apparatus and are uncorrected. IR (Nujol) spectra were recorded on
a Nicolet Impact 410 spectrophotometer, LR EI-MS in AEI MS 30 and JEOL JMS-AX505HA, HR FAB-
MS (using m-nitrobenzyl alcohol as liquid matrix) in JEOL JMS-700 MStation mass spectrometers and
1H (500 MHz) and 13C (125 MHz) NMR spectra, both 1D and 2D, including DEPT 135, in a Bruker DRX
1
500 NMR spectrometer. Individual H and 13C NMR assignments of 2c were based on HMQC and
HMBC spectral analyses. TLC was carried out on silica gel G (Merck, India) plates. PE refers to
petroleum ether boiling at 60-80 °C. Diethyl ketomalonate was purchased from Lancaster and
montmorillonite K10 clay from Fluka.
Diethyl 2-hydroxy-2-(3'/2'-indolyl)malonates (2a-f, 5) and Diethyl 2,2-bis(3'-indolyl)malonates (3a-
g). General Procedure
A solution of the indole (1 mmol) in CH2Cl2 (2-3 mL) (except for 1g) was mixed with a solution (1 mL)
of DEKM (from a stock solution of 0.76 mL, 5 mmol in CH2Cl2, made up to 5 mL) and adsorbed on clay
(4 g), and the solvent was allowed to evaporate off at rt. The reactants-on-clay were then subjected in
separate lots to MW irradiation (power: 50% for 1a-e; 70% for 1f; 80% for 1g and 4; each pulse was for 3
min or less) or kept at room temperature or heated in an oven at 60 °C until the indole was consumed
(TLC). The clay was then leached with 2% MeOH-EtOAc (3×15 mL), the solvent distilled off from the
pooled extracts and the resulting residue separated into its components by preperative TLC in PE-C6H6-
EtOAc (1:2:1). The resulting products were finally purified by crystallisation from PE-CH2Cl2, unless
stated otherwise.
Only for 1g, 3% MeOH-CH2Cl2 was required to dissolve it, and the products had to be leached with 5%
MeOH-EtOAc. In the case of 4, the reaction did not go to completion even after long exposure to either of
the conditions (MW, rt or 60 °C). The reaction was, therefore, terminated at a stage when a maximum
amount of the product appeared (TLC; thereafter decomposition started) to be formed. The indole (4) was

HETEROCYCLES, Vol. 65, No. 1, 2005
43
recovered from this reaction in 34% yield.
Diethyl 2-hydroxy-2-(3'-indolyl)malonate (2a): Yield: 58 mg (20%); colourless rods; mp 82 °C; IR:
1
3429, 3343, 1745, 1712, 751 cm-1; H NMR (CDCl3): δ 8.25 (1H, s), 7.71 (1H, d, J=8 Hz), 7.37 (1H, d,
J=2 Hz), 7.28 (1H, d, J=8 Hz), 7.16 and 7.10 (1H, t each, J=7.5 Hz), 4.34 (1H, s), 4.33 and 4.25 (2H, dq
13
each, J1=11 Hz, J2=7 Hz), 1.26 (6H, dd, J1=J2=7 Hz); C NMR (CDCl3): δ 170.6, 136.9, 125.7, 112.4,
78.1 (all C), 124.4, 122.6, 121.2, 120.3, 111.7 (all CH), 63.2 (CH2), 14.3 (CH3); EI-MS: m/z (%) 291 (M+
,
17), 218 (63), 144 (100), 116 (13); Anal. Calcd for C15H17NO5: C, 61.86; H, 5.84; N, 4.81. Found: C,
61.66; H, 5.85; N, 4.80.
Diethyl 2-hydroxy-2-(1'-methyl-3'-indolyl)malonate (2b): Yield: 61 mg (20%); pale yellow prisms; mp
84-86 °C (lit.,16 78 °C); IR: 3468, 1753, 1724, 735 cm-1; 1H NMR (CDCl3): δ 7.70 (1H, d, J=8 Hz), 7.36
(1H, s), 7.28 (1H, d, J=8 Hz), 7.21 and 7.10 (1H, t each, J=7.5 Hz), 4.34 and 4.25 (2H, dq each, J1=10.5
13
Hz, J2=7 Hz), 4.29 (1H, s), 3.75 (3H, s), 1.27 (6H, dd, J1=J2=7 Hz); C NMR (CDCl3): δ 170.6, 137.7,
126.3, 110.7, 78.0 (all C), 128.8, 122.2, 121.4, 120.0, 109.7 (all CH), 63.1 (CH2), 33.3, 14.4 (both CH3);
EI-MS: m/z (%) 305 (M+ 15), 232 (59), 158 (100), 149 (16), 130 (9); FAB-MS (m-NBA): m/z 328
,
(M++Na); Anal. Calcd for C16H19NO5: C, 62.95; H, 6.23; N, 4.59. Found: C, 62.86; H, 6.25; N, 4.60.
Diethyl 2-hydroxy-2-(2'-methyl-3'-indolyl)malonate (2c): Yield: 107 mg (35%); colourless prisms; mp
1
142 °C (PE-EtOAc); IR: 3443, 3390, 1745, 1725, 754 cm-1; H NMR (DMSO-d6): δ 10.93 (1H, s, NH),
7.36 (1H, d, J=8 Hz, H-4'), 7.20 (1H, d, J=8 Hz, H-7'), 6.94 (1H, t, J=7.5 Hz, H-6'), 6.86 (1H, t, J=7.5 Hz,
H-5'), 6.58 (1H, s, H-2'), 4.17 and 4.09 (2H, dq each, J1=11 Hz, J2=7 Hz, 2×CO2CH2CH3), 2.28 (3H, s, 2'-
CH3), 1.14 (6H, dd, J1=J2=7 Hz, 2×CO2CH2CH3); 13C NMR (DMSO-d6): δ 171.1 (2×CO2Et), 135.4 (C-
7'a), 134.4 (C-2'a), 127.8 (C-3'a), 108.5 (C-3'), 79.4 (C-2), 120.8 (CH-6'), 120.5 (CH-4'), 119.2 (CH-5'),
111.2 (CH-7'), 62.0 (2×CH2), 14.7 (2×CH3), 13.8 (2'-CH3); EI-MS: m/z (%) 305 (M+ 35), 232 (79), 158
,
(100), 149 (14), 130 (20); FAB-MS (m-NBA): m/z 328 (M++Na); Anal. Calcd for C16H19NO5: C, 62.95;
H, 6.23; N, 4.59. Found: C, 62.80; H, 6.21; N, 4.61.
Diethyl 2-hydroxy-2-(1',2'-dimethyl-3'-indolyl)malonate (2d): Yield: 96 mg (30%); colorless prisms;
mp 104-106 °C; IR: 3476, 1737, 1712, 737 cm-1; 1H NMR (CDCl3): δ 7.50 and 7.24 (1H, d each, J=8 Hz),
7.13 and 7.04 (1H,teach, J=7.5 Hz), 4.38 and 4.25 (2H, dq each, J1=10.5 Hz, J2=7 Hz), 4.26 (1H, s), 3.64
and 2.41 (3H, s each), 1.27 (6H, dd, J1=J2=7 Hz); 13C NMR (CDCl3): δ 171.4, 136.8, 135.9, 126.4, 107.0,
79.0 (all C), 121.2, 120.0, 119.9, 109.2 (all CH), 63.2 (CH2), 29.8, 14.3, 12.2 (all CH3); EI-MS: m/z (%)
319 (M+ 42), 249 (95), 172 (100), 40 (45); Anal. Calcd for C17H21NO5: C, 63.95; H, 6.58; N, 4.39.
,

44
HETEROCYCLES, Vol. 65, No. 1, 2005
Found: C, 64.17; H, 6.60; N, 4.38.
Diethyl 2-hydroxy-2-(5'-methoxy-3'-indolyl)malonate (2e): Yield: 74 mg (23%); white needles; mp 71
1
°C; IR: 3423, 3344, 1749, 1730, 1273, 1260, 1215, 1063, 804 cm-1; H NMR (CDCl3): δ 8.19 (1H, s),
7.38 (1H, d, J=2.5 Hz), 7.19 (1H, d, J=9 Hz), 7.18 (1H, s), 6.85 (1H, dd, J1=9 Hz, J2=2.5 Hz), 4.35 and
4.27 (2H, dq each, J1=10.5 Hz, J2=7 Hz), 4.31 (1H, s), 3.83 (3H, s), 1.29 (6H, dd, J1=J2=7 Hz); 13C NMR
(CDCl3): δ 170.5, 154.6, 132.0, 126.2, 112.0, 78.1 (all C), 125.0, 113.1, 112.3, 103.0 (all CH), 63.2 (CH2),
56.2 (OCH3), 14.4 (CH3); EI-MS: m/z (%) 321 (M+ 18), 248 (49), 232 (13), 174 (100); FAB-MS (m-
,
NBA): m/z 344 (M++Na); Anal. Calcd for C16H19NO6: C, 59.81; H, 5.92; N, 4.36. Found: C, 59.89; H,
5.90; N, 4.37.
Diethyl 2-hydroxy-2-(5'-bromo-3'-indolyl)malonate (2f): Yield: 166 mg (45%); brown amorphous
solid; mp 99-101 °C; IR: 3436, 3317, 1739, 1717, 1021, 807, 792 cm-1; 1H NMR (CDCl3): δ 8.34 (1H, br
s), 7.89 (1H, s), 7.37 (1H, d, J=2.5 Hz), 7.24 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.14 (1H, d, J=8.5 Hz),
4.344 and 4.27 (2H, dq each, J1=10.5 Hz, J2=7 Hz), 4.34 (1H, s), 1.29 (6H, dd, J1=J2=7 Hz); 13C NMR
(CDCl3): δ 170.3, 135.5, 127.4, 113.7, 112.1, 78.0 (all C), 125.59, 125.56, 124.1, 113.1 (all CH), 63.4
(CH2), 14.3 (CH3); EI-MS: m/z (%) 371 (M++2, 21), 369 (M+ 21), 298 (70), 296 (70), 224 (100), 222
,
(100), 196 (7), 194 (7), 143 (20), 115 (10); Anal. Calcd for C15H16NO5Br: C, 48.65; H, 4.32; N, 3.78.
Found: C, 48.54; H, 4.30; N, 3.76.
Diethyl 2-hydroxy-2-(3'-methyl-2'-indolyl)malonate (5): Yield: 72 mg (35%); yellow needles; mp 93-
95 °C; IR: 3456, 3410, 1739, 738 cm-1; 1H NMR (CDCl3): δ 8.92 (1H, s), 7.56 and 7.33 (1H, d each, J=8
Hz), 7.19 and 7.10 (1H, t each, J=7.5 Hz), 4.53 (1H, s), 4.35 and 4.27 (2H, dq each, J1=11 Hz, J2=7 Hz),
13
2.31 (3H, s), 1.29 (6H, dd, J1=J2=7 Hz); C NMR (CDCl3): δ 168.7, 133.9, 129.0, 126.5, 110.0, 77.95
(all C), 122.0, 118.7, 118.3, 110.6 (all CH), 62.8 (CH2), 13.4, 8.8 (both CH3); EI-MS: m/z (%) 305 (M+
,
37), 232 (73), 158 (100); Anal. Calcd for C16H19NO5: C, 62.95; H, 6.23; N, 4.59. Found: C, 62.80; H,
6.22; N, 4.61.
Diethyl 2,2-bis(3'-indolyl)malonate (3a): Yield: 12 mg (8%); light brown prisms; mp 184-186 °C; IR:
3417, 3362, 1759, 1728, 744 cm-1; 1H NMR (CDCl3): δ 9.04 (2H, s), 7.43 and 7.31 (2H, d each, J=8 Hz),
7.27 (2H, d, J=2 Hz), 7.08 and 6.93 (2H, t each, J=7.5 Hz), 4.22 (4H, q, J=7 Hz), 1.18 (6H, t, J=7 Hz);
13C NMR (CDCl3): δ170.4, 136.9, 126.6, 112.9, 58.9 (all C), 125.8, 121.81, 121.80, 119.4, 111.6 (all CH),
61.8 (CH2), 14.3 (CH3); EI-MS: m/z (%) 390 (M+ 21), 317 (100), 289 (9), 243 (13); Anal. Calcd for
,
C23H22N2O4: C, 70.77; H, 5.64; N, 7.18. Found: C, 70.60; H, 5.62; N, 7.21.

HETEROCYCLES, Vol. 65, No. 1, 2005
45
Diethyl 2,2-bis(1'-methyl-3'-indolyl)malonate (3b): Yield: 21 mg (13%); pink needles; mp 145 °C
(lit.,16 mp 172 °C); IR: 1743, 1722, 739 cm-1; 1H NMR (CDCl3): δ 7.47 and 7.27 (2H, d each, J=8.5 Hz),
7.21 (2H, s), 7.17 and 6.99 (2H, t each, J=7.5 Hz), 4.22 (4H, q, J=7 Hz), 3.71 (6H, s), 1.19 (6H, t, J=7
13
Hz); C NMR (CDCl3): δ 170.5, 137.6, 127.1, 111.7, 58.8 (all C), 130.1, 122.1, 121.7, 119.4, 109.5 (all
CH), 62.0 (CH2), 33.2, 14.4 (both CH3); EI-MS: m/z (%) 418 (M+ 70), 345 (100), 317 (31), 273 (20), 257
,
(10), 158 (15), 136 (23); FAB-MS (m-NBA): m/z 441 (M++Na); Anal. Calcd for C25H26N2O4: C, 71.77; H,
6.22; N, 6.70. Found: C, 71.57; H, 6.20; N, 6.68.
Diethyl 2,2-bis(2'-methyl-3'-indolyl)malonate (3c): Yield: 42 mg (31%); white needles; mp 228 °C
(decomp); IR: 3363,1718, 1699, 794, 731 cm-1; 1H NMR (DMSO-d6): δ 10.95 (2H, s), 7.21 and 6.98 (2H,
d each, J=8 Hz), 6.90 and 6.71 (2H, t each, J=7.5 Hz), 3.99 (4H, q, J=7 Hz), 2.08 (6H, s), 0.93 (6H, t, J=7
13
Hz); C NMR (DMSO-d6): δ 169.2, 135.7, 135.6, 128.2, 107.9, 58.7 (all C), 121.2, 120.6, 118.8, 111.1
(all CH), 61.2 (CH2), 14.53, 14.50 (both CH3); EI-MS: m/z (%) 418 (M+ 31), 345 (100), 271 (15), 256
,
(13), 158 (5), 130 (7); FAB-MS (m-NBA): m/z 441 (M++Na); Anal. Calcd for C25H26N2O4: C, 71.77; H,
6.22; N, 6.70. Found: C, 71.90; H, 6.23; N, 6.72.
Diethyl 2,2-bis(1',2'-dimethyl-3'-indolyl)malonate (3d): Yield: 54 mg (35%); colorless prisms; mp 214-
1
216 °C; IR: 1732, 750 cm-1; H NMR (CDCl3+DMSO-d6): δ 7.24 and 7.20 (2H, d each, J=8.5 Hz), 7.07
and 6.86 (2H, t each, J=7.5 Hz), 4.08 (4H, q, J=7 Hz), 3.65 and 2.16 (6H, s each), 1.02 (6H, t, J=7 Hz);
13C NMR (CDCl3+DMSO-d6): δ 169.5, 136.8, 136.7, 127.1, 108.2, 58.8 (all C), 121.5, 120.5, 119.0,
108.6 (all CH), 61.2 (CH2), 29.8, 14.1, 12.7 (all CH3); EI-MS: m/z (%) 446 (M+ 41), 373 (100), 144 (51),
,
143 (48); Anal. Calcd for C27H30N2O4: C, 72.64; H, 6.73; N, 6.28. Found: C, 72.44; H, 6.71; N, 6.30.
Diethyl 2,2-bis(5'-methoxy-3'-indolyl)malonate (3e): Yield: 9 mg (5%); brown amorphous solid; mp
121 °C; IR: 3385, 1722, 1210, 1029, 801, 724 cm-1; 1H NMR (CDCl3): δ 8.05 (2H, s), 7.26 (2H, d, J=2.5
Hz), 7.18 (2H, d, J=8.5 Hz), 6.88 (2H, d, J=2 Hz), 6.78 (2H, dd, J1=8.5 Hz, J2=2.5 Hz), 4.23 (4H, q, J=7
Hz), 3.66 (6H, s), 1.21 (6H, t, J=7 Hz); 13C NMR (CDCl3): δ 170.3, 154.1, 131.9, 127.1, 112.9, 58.8 (all
C), 126.2, 112.5, 112.0, 103.7 (all CH), 62.0 (CH2), 56.1 (OCH3), 14.5 (CH3); EI-MS: m/z (%) 450 (M+
,
27), 377 (100), 349 (6), 305 (6), 248 (11), 174 (30); Anal. Calcd for C25H26N2O6: C, 66.67; H, 5.78; N,
6.22. Found: C, 66.45; H, 5.80; N, 6.23.
Diethyl 2,2-bis(5'-bromo-3'-indolyl)malonate (3f): Yield: 49 mg (33%); brown amorphous solid; mp
82-84 °C; IR: 3383, 1721, 884, 797, 724 cm-1; 1H NMR (CDCl3): δ 8.22 (2H, br s), 7.57 (2H, s), 7.22 (2H,
d, J=2.5 Hz), 7.20 (2H, dd, J1=8.5 Hz, J2=1.5 Hz), 7.15 (2H, d, J=8.5 Hz), 4.24 (4H, q, J=7 Hz), 1.22 (6H,

46
HETEROCYCLES, Vol. 65, No. 1, 2005
t, J=7 Hz); 13C NMR (CDCl3): δ 170.0, 135.4, 128.1, 113.3, 112.6, 58.7 (all C), 126.8, 125.3, 124.3, 113.1
(all CH), 62.5 (CH2), 14.3 (CH3); EI-MS: m/z (%) 550 (M++4, 34), 548 (M++2, 63), 546 (M+, 33), 477 (94),
475 (100), 473 (95), 449 (14), 447 (28), 445 (15), 355 (29), 353 (29), 282 (61), 280 (61), 236 (16), 224
(26), 214 (17); Anal. Calcd for C23H20N2O4Br2: C, 50.36; H, 3.65; N, 5.11. Found: C, 50.20; H, 3.67; N,
5.09.
Diethyl 2,2-bis(5'-nitro-3'-indolyl)malonate (3g): Yield: 139 mg (58%); yellow needles; mp 242-244
°C (decomp) (C6H6-MeOH); IR: 3429, 3350, 3284, 1732, 1513, 1328, 747 cm-1; 1H NMR (DMSO-d6): δ
11.89 (2H, s), 8.08 (2H, d, J=2 Hz), 7.92 (2H, dd, J1=9 Hz, J2=2 Hz), 7.59 (2H, s), 7.55 (2H, d, J=9 Hz),
13
4.19 (4H, q, J=7 Hz), 1.11 (6H, t, J=7 Hz); C NMR (DMSO-d6): δ 169.6, 141.2, 140.6, 125.9, 114.4,
58.6 (all C), 130.1, 118.1, 117.4, 113.3 (all CH), 62.8 (CH2), 14.5 (CH3); EI-MS: m/z (%) 480 (M+ 23),
,
407 (100), 391 (11), 279 (27), 335 (6), 189 (10); Anal. Calcd for C23H20N4O8: C, 57.58; H, 4.17; N, 11.67.
Found: C, 57.71; H, 4.19; N, 11.63.
Reaction of 1c with 2c on clay
A solution of the indole (1c) (131 mg, 1 mmol) in CH2Cl2 (3 mL) was mixed with a solution of the
corresponding indolylcarbinol (2c) (305 mg, 1 mmol) in EtOAc (3 mL), adsorbed on K10 clay (4 g) and
kept at room temperature, but the reaction was not complete even after 2 h. It was, therefore, left
overnight at rt. But small amounts of both the reactants were found to be still present. The clay was
leached with 2% MeOH-EtOAc (3×15 mL) and the product purified from the remaining 1c and 2c by
preparative TLC to furnish the corresponding DIA (3c) in 52% yield (214 mg), identified by usual
comparisons (TLC, co-TLC and mixed mp) with a sample of 3c obtained from 1c and DEKM.
Reaction of 1c with DEKM on recovered clay
The clay left after leaching of the products from the reaction between 1 mmol each of 1c and DEKM
(Entry 3, Table 1) was washed thoroughly with 5% MeOH-EtOAc, dried in a water pump and then heated
in an oven at 110°C for 7 h. The indole (1c) (131 mg, 1 mmol) was then treated with DEKM (1 mmol, i.e.
1 mL of the stock solution stated earlier) on this recovered clay (4 g) at rt. After 1c was found to be
consumed (20 min), the two products (TLC) formed were leached with 2% MeOH-EtOAc (3×15 mL) and
separated by preparative TLC to furnish 2c and 3c in 32% and 12% yields, respectively. The products
were identified by usual comparisons (TLC, co-TLC and mixed mp) with those obtained from the main
experiments.
ACKNOWLEDGEMENTS

HETEROCYCLES, Vol. 65, No. 1, 2005
47
The authors express their sincere thanks to Dr. M. Siddiqi, the Director of Bose Institute, for providing
laboratory facilities, to Mr. Pranab Dey, Microanalytical Lab., B.I. and Mr. Barun Majumdar, NMR Lab.,
B.I. for recording the spectra and to the C.S.I.R., Govt. of India for a Fellowship (S.K.).
REFERENCES AND NOTES
1. E. Fischer, Ber., 1886, 19, 2988; W. E. Noland, Tetrahedron, 1958, 14, 68.
2. M. Chakrabarty, R. Basak, and Y. Harigaya, Heterocycles, 2001, 55, 2431.
3. T. S. Kam, In ‘Alkaloids, Chemical and Biological Perspectives,’ Vol. 4, ed. by S. W. Pelletier,
Pergamon, Amsterdam, 1999, 285.
4. S. A. Morris and R. J. Anderson, Tetrahedron, 1990, 46, 715; K. Umezawa, T. Ohse, T.
Yamamoto, T. Koyano, and Y. Takahashi, Anticancer Res., 1994, 14, 2413; N. Animo, T. Ohse, T.
Koyano, and K. Umezawa, Anticancer Res., 1996, 16, 55; K. Umezawa, T. Taniguchi, M. Tou, T.
Ohse, T. Isutsumi, T. Yamamoto, T. Koyano, and M. Ishizuka, Drugs Exp. Clin. Res., 1996, 22, 35; T.
Irie, K. Kubushirs, K. Suzuki, K. Tsukazaki, K. Umezawa, and S. Nozawa, Anticancer Res., 1999, 8,
49.
5. R. Nagarajan and P. T. Perumal, Tetrahedron, 2002, 58, 1229; S.-J. Ji, M.-F. Zhon, D.-G. Gu, S. Y.
Wang, and T.-P. Loh, Synlett, 2003, 2077; C. Ramesh, J. Banerjee, R. Pal, and B. Das, Adv. Synth.
Commun., 2003, 345, 557; A. Mahadevan, H. Sard, M. Gonzalez, and J. C. Mckew, Tetrahedron Lett.,
2003, 44, 4589; A. V. Reddy, K. Ravinder, V. L. N. Reddy, T. V. Goud, V. Ravikanth, and Y.
Venkateswarlu, Synth. Commun., 2003, 33, 3687; B. P. Bandgar and K. A. Shaikh, Tetrahedron Lett.,
2003, 44, 1959; J .S . Yadav, B. V. S. Reddy, and S. Sunitha, Adv. Synth. Catal., 2003, 345, 349; G.
Bartoli, M. Bosco, G. Foglia, A. Giuliani, E. Marcantoni, and L. Sambri, Synthesis, 2004, 895.
6. R. J. Sundberg, ‘The Chemistry of Indoles,’ Academic Press, New York, 1970, 39; J. Bergman, S.
Hogeberg, and J.-O. Lindström, Tetrahedron, 1970, 26, 3347; J. Bergman and R. J. Carlsson, J.
Heterocycl. Chem., 1972, 9, 833; J. K. Porter, C. W. Bacon, J. D. Robbins, D. S. Himmelsbach, and H.
C. Higman, J. Agric. Food Chem., 1977, 25, 88; T. Osawa and M. Namiki, Tetrahedron Lett., 1983,
24, 4719; D. Chen, L. Yu, and P. G. Wang, Tetrahedron Lett., 1996, 37, 4467; G. Babu, N. Sridhar,
and P. T. Perumal, Synth. Commun., 2000, 30, 1614; J. S. Yadav, B. V. S. Reddy, Ch. V. S. R. Murthy,
G. M. Kumar, and Ch. Madan, Synthesis, 2001, 787.
7. M. Chakrabarty, N. Ghosh, R. Basak, and Y. Harigaya, Tetrahedron Lett., 2002, 43, 4075; M.
Chakrabarty, N. Ghosh, R. Basak, and Y. Harigaya, Synth. Commun., 2004, 34, 421.
8. P. Laszlo, Science, 1987, 235, 1473.
9. H. Bader and W. Oroshnik, J. Am. Chem. Soc., 1959, 81, 163.
10. G. O. Burr and R. A. Gortner, J. Am. Chem. Soc., 1924, 46, 1224.

48
HETEROCYCLES, Vol. 65, No. 1, 2005
11. A. H. Cook and J. R. Majer, J. Chem. Soc., 1944, 486; U. Pindur and C. Flo, Monatsh. Chem., 1986,
117, 375.
12. J. A. Joule and K. Mills, ‘Heterocyclic Chemistry,’ 4th edn, Blackwell Science Ltd., Oxford, 2000,
p. 331.
13. M. Chakrabarty and S. Sarkar, Tetrahedron Lett., 2002, 43, 1351; M. Chakrabarty and S. Sarkar,
Tetrahedron Lett., 2003, 44, 8131; M. Chakrabarty, S. Sarkar, A. Linden, and B. K. Stein, Synth.
Commun., 2004, 34, 1801.
14. The term ‘solvent-free’ refers only to reaction conditions. Minimal amounts of solvents had to be
used for pre-adsorption of reactants on clay and for leaching the products from clay, which is
accepted in the field of solvent-free synthesis.20
15. BPL-SANYO Domestic Oven, 800 Watt, 2450 MHz.
16. U. Pindur and M.-H. Kim, Tetrahedron, 1989, 45, 6427.
17. E. Leete, J. Am. Chem. Soc., 1959, 81, 6023.
18. G. Bifulco, I. Bruno, R. Riccio, J. Lavayre, and G. Bourdy, J. Nat. Prod., 1995, 58, 1254.
19. T. W. G. Solomons, ‘Organic Chemistry,’ 6th edn, Wiley, New York, 1996, p. 94.
20. K. Tanaka, ‘Solvent-free Organic Synthesis,’ Wiley-VCH, Weinheim, 2003, p. V.