Uncatalyzed Michael addition of indoles: synthesis of some novel 3-alkylated indoles via a three-component reaction in solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.01.105

Synthesis of some novel 3-alkylated indoles via an uncatalyzed Michael addition of indoles using three components in one-pot solvent-free conditions is reported. The mechanism was established by performing the reaction in two steps. The reaction was also studied in different solvents and an important solvent effect was noticed.

Full text of DOI:10.1016/j.tetlet.2007.01.105

Tetrahedron Letters 48 (2007) 2159–2163
Uncatalyzed Michael addition of indoles: synthesis of some novel
3-alkylated indoles via a three-component reaction in
solvent-free conditions
Mohit L. Deb and Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785 006, Assam, India
Received 15 December 2006; revised 11 January 2007; accepted 18 January 2007
Available online 24 January 2007
Abstract—Synthesis of some novel 3-alkylated indoles via an uncatalyzed Michael addition of indoles using three components in
one-pot solvent-free conditions is reported. The mechanism was established by performing the reaction in two steps. The reaction
was also studied in different solvents and an important solvent effect was noticed.
Ó 2007 Elsevier Ltd. All rights reserved.
The importance of indoles is well recognized by synthetic
as well as biological chemists.1 The most ubiquitous of
the known bioactive alkaloids are based on the indole
moiety.2 Medicinal chemists repeatedly turn to indole-
based compounds as a target pharmacophore for the
development of therapeutic agents.3 The prevalence of
this motif in natural and bioactive products continues
to be a vector in the development of new methodology
to find useful compounds.4 Michael addition of indoles
to a,b-unsaturated systems is an efficient approach to
indole-containing molelcules.5 Owing to the total atom
efficiency these reactions are inherently green.6 The
regioselectivity in the addition of indoles to electron-
deficient alkenes is strongly controlled by the reaction
conditions: N-alkylation under alkaline conditions and
C-3-substitution in acid-catalyzed reactions. Besides
protic acids, a number of Lewis acid catalyzed metho-
dologies for the C-3 alkylation of indoles by Michael
addition have been reported7 and the use of lanthanide
triflates8 represents an attractive alternative to their
classical competitors such as AlCl3 and SnCl4. Unfortu-
nately, lanthanide triflates are rather expensive and their
use in large-scale synthetic methodology is very limited.
Recently CeCl3Æ7H2O–NaI supported on silica gel was
successfully utilized for the Michael addition of indoles
to an a,b-unsaturated system.9
Barbituric acids are an important class of compounds
that constitute the basic moiety of a number of clinically
used hypnotic drugs of the barbiturate class (5-alkylated
barbituric acids), for example, Veronal, Seconal, Pheno-
barbital and Luminal.10
Development of new solid-phase (solvent-free) reactions
and transferring solution-phase reactions to solid-phase
are subjects of recent interest in the context of
generating libraries of molecules for the discovery of
biologically active leads and also for the optimization
of drug candidates.11 One-pot multi-component reac-
tions (MCRs), by virtue of their convergence, ease of
execution and generally high yields of products have at-
tracted considerable attention.12 In the past decade there
have been tremendous developments in three- and four-
component reactions and great efforts have been and
continue to be made to find and develop new MCRs.13
In our continued interest in the synthesis of diverse
heterocyclic compounds of biological importance,14 we
report here the synthesis of some novel 3-alkylated
indoles via a three-component reaction in solvent-free
conditions. The reaction, which gave access to 5-alkyl-
ated barbituric acids also demonstrated an uncatalyzed
Michael addition of indoles to an a,b-unsaturated sys-
tem (Scheme 1).
Keywords: Indoles; Michael addition; Pyrimidines; Solvent-free reac-
tion; Multicomponent reaction.
Utilizing equimolar amounts of indole 1a benzaldehyde
2a and N,N-dimethylbarbituric acid 3a in the absence of
solvents at 95 °C for 15 min afforded15 after work-up,
*
Corresponding author. Fax: +376 2370011; e-mail: pulak_ jyoti@
yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.105

2160
M. L. Deb, P. J. Bhuyan / Tetrahedron Letters 48 (2007) 2159–2163
R3
O
N
R2
O
N
R3
O
R1
O
4a-p
N
H
R3
O
R2
H
N
R1
+
+
+
N
H
N
R3
O
O
R2
1a-b
2a-g
R2 = C6H5
3a-b
R1 =H
=CH3
R3 = Me
= H
R1
R1
N
H
N
H
=
=
=
p-CH3OC6H4
p-CH3C6H4
p-ClC6H4
5a-p
= p-O2NC6H4
= CH3
= H
Scheme 1.
67% of 3-alkylated indole 4a as a crystalline compound,
the structure confirmed from the spectroscopic data and
elemental analysis. In addition to the Michael adduct,
we isolated 15% of 3,30-bisindolylmethane 5a, with
physical and spectroscopic data comparable in all
respects to those of an authentic sample.16 Similarly
compounds 4b–p and 5b–p were synthesized from 1–3
and characterized. The reaction is equally applicable
to aliphatic aldehydes. The three-component reactions
and our observations are recorded in Table 1. 2-Methyl-
indole was found to be highly reactive and the forma-
tion of compounds 4 and 5 to depend on the reaction
time. Thus, we obtained a maximum yield of compound
4 in 10 min, while a reaction time above 15 min maxi-
mized the yield of bisindolylmethanes 5. However, we
obtained 4 as a minor compound and 5 as a major com-
pound when 3b was utilized in the three-component
reactions.
formation of Knoevenagel product [A] from 2 and 3
under thermal condition which then suffers a nucleophilic
attack by indole 1 to give Michael adduct 4. The forma-
tion of minor bisindolylmethane 5 can be explained by
the formation of small amount of [B] from product 4
with the elimination of barbituric acid 3 under thermal
conditions.17 The intermediate [B] then adds a second
indole to give 5. Comparatively easy formation of inter-
mediate [B] might be the reason for small yields of the
compounds 4n–p and hence the maximum formation
of bisindolylmethanes 5n–p.
We confirmed the mechanism by performing the trans-
formations in two steps. First we synthesized the a,b-
unsaturated system [A] by condensing aldehydes 2 with
barbituric acids 3 following our own method18 and
then reacted [A] with indole at 85 °C for 10–25 min
in the absence of solvent.19 As expected we obtained
3-alkylated indoles 4 as a major product and bis-
indolylalkanes 5 as a minor product (Table 2). The
small amounts of barbituric acids 3 eliminated during
the process were isolated and characterized. However,
A reasonable mechanism for the formation of 3-alkyl-
ated indoles from the three-component reaction is out-
lined in Scheme 2. The sequence starts with the
Table 1. Three-component reactions of 1–3 in solvent-free conditions and synthesis of 3-alkylated indoles 4 and bisindolylmethanes 5
R1 of 1
R2 of 2
R3
Time (min)
Temperature (°C)
Product 4
Yield (%)
Product 5
Yield (%)
H
H
H
H
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
15
15
15
15
15
12
10
10
15
15
25
25
20
25
25
25
95
85
85
85
110
80
80
80
80
80
4a
4b
4c
4d
4e
4f
67
65
68
61
70
73
70
74
74
74
64
74
75
22
24
23
5a
5b
5c
5d
5e
5f
15
12
10
14
12
10
12
10
10
11
15
10
8
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-O2N–C6H4
CH3
H
CH3
CH3
CH3
CH3
CH3
H
H
CH3
H
4g
4h
4i
5g
5h
5i
4j
5j
80
4k
4l
5k
5l
H
H
C6H5
C6H5
100
120
120
150
150
150
4m
4n
4o
4p
5m
5a
5f
59
65
62
CH3
H
H
H
4-MeC6H4
5b

M. L. Deb, P. J. Bhuyan / Tetrahedron Letters 48 (2007) 2159–2163
2161
O
R2
O
R3
O
R3
N
N
+
R2
H
N
O
O
N
O
O
R3
R3
2
[A]
3
R3
O
N
R2
R2
O
O
R3
N
N
R3
R1
O
R1
N
H
N
R3
O
O
N
H
[A]
4
1
R2
R2
O
O
R3
R3
O
N
N
R1
+
R1
O
N
N
N
N
O
O
R3
R3
H
4
[B]
3
R2
R2
R1
R1
R1
R1
N
N
N
N
H
H
H
[B]
1
5
Scheme 2.
Table 2. Two-component reactions of 1 & [A] in solvent-free/in solvent (acetonitrile) and synthesis 4 and 5
Entry
Solvent free/(in solvent) Time (min/h),
Product 4
mp (°C)
Yield (%)
Product 5
Yield (%)
Temperature (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
15 min, 85 (11 h), (rt)
15 min, 85 (11 h), (rt)
15 min, 85 (10 h), (rt)
15 min, 85 (11 h), (rt)
15 min, 80 (9 h), (rt)
5 min, 80 (9 h), (rt)
5 min, 80 (9 h), (rt)
7 min, 80 (9 h), (rt)
8 min, 85 (10 h), (rt)
5 min, 85 (10 h), (rt)
40 min, 85 (13 h), (rt)
30 min, 85 (9 h), (rt)
30 min, 85 (9 h), (rt)
40 min, 85 (13 h), (rt)
30 min, 85 (9 h), (rt)
30 min, 85 (9 h), (rt)
4a
4b
4c
4d
4e
4f
175–176
156–158
171–173
161–162
148–150
177–178
171–173
103–106
179–181
189–190
163–164
175–176
173–174
163–164
175–176
173–174
65 (64)
72 (75)
74 (71)
70 (70)
65 (70)
70 (72)
72 (70)
68 (72)
68 (70)
55 (52)
63 (65)
74 (75)
67 (72)
23 (22)
26 (19)
21 (20)
5a
5b
5c
5d
5e
5f
10 (8)
7 (5)
5 (4)
8 (5)
11 (7)
10 (8)
10 (7)
12 (5)
12 (10)
20 (12)
8 (5)
—
—
60 (55)
69 (62)
58 (55)
4g
4h
4i
5g
5h
5i
4j
5j
4k
4l
5k
5l
4m
4n
4o
4p
5m
5a
5f
5b
in the case of formaldehyde, 3-alkylated indoles were
obtained as the sole product. The reason is that unlike
aromatic and aliphatic aldehydes containing an a-
hydrogen, the intermediate is not stabilized by either
resonance or hyperconjugation.
ditions. However, in protic solvents we observed the for-
mation of bisindolyl-methanes 5 as the sole products,
which can be reasonably explained by our recent
study.14b We also studied the two-component reactions
in various solvents. Accordingly, when equimolar
amounts of indoles and intermediates [A] were reacted
in acetonitrile at room temperature for 9–13 h, we ob-
tained (19–75%) of the Michael addition products 4
and (4–62%) of bisindolylmethanes 5, while in refluxing
The reaction was now studied in acetonitrile, dioxane,
methanol and ethanol, and in all the cases the desired
compounds 4 were not formed even under refluxing con-

2162
M. L. Deb, P. J. Bhuyan / Tetrahedron Letters 48 (2007) 2159–2163
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R
H
O
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O
R2
R2
O
R3
R3
N
3. Gribble, G. W. In Comprehensive Heterocyclic Chemistry,
2nd ed.; Pergamon Press: New York, 1996; Vol. 2, pp 211–
213.
N
+
R1
O
O
N
N
R1
N
O
N
O
H
4. (a) Kam, T. S. In Alkaloids, Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: Amsterdam,
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R3
3
R3
R
O
[B]
H
R2
R2
R1
R1
R1
N
H
R1
N
N
H
N
H
H
5
O
1
R
Scheme 3.
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acetonitrile these reactions required 1 h to give similar
results (Table 2).20 As in the three-component reactions,
in entries 14–16 we obtained 4 as minor and 5 as major
products. However, in EtOH or MeOH, we obtained
bisindolylmethanes 5 as major products (70–75%) and
Michael adducts 4 as minor compounds, as rationalized
by the mechanism shown in Scheme 3. The protic sol-
vents help the elimination of 3 and thus enhance the for-
mation of intermediate [B]. This was further confirmed
by refluxing Michael adduct 4 with an equimolar
amount of indole 1 in MeOH for 0.5 h which afforded
80% of bisindolyl methane 5. In the case of formalde-
hyde, when the Michael adduct and indole were heated
in methanol, bisindolylmethane was not formed. Thus,
the non-formation of intermediate [A] in the three-com-
ponent reactions in different solvents is the reason for
the non-formation of product 4.
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In conclusion we have reported the synthesis of some
novel 3-alkylated indoles via three-component reactions
in solvent-free conditions. Moreover, the results demon-
strated a novel uncatalyzed Michael addition of indoles
to an a,b-unsaturated system in a one-pot three-compo-
nent reaction under solvent-free conditions. The mecha-
nism of the three-component reaction was established by
synthesizing the proposed intermediate and by perform-
ing the overall transformation in two steps.
Acknowledgements
We thank the DST, New Delhi, for financial support.
M.L.D. thanks the CSIR (India), for the award of a
Senior Research Fellowship.
References and notes
1. (a) Sundberg, R. J. In The Chemistry of Indoles; Academic
Press: New York, 1970; pp 78–83; (b) Marion, L. In The
Alkaloids. Chemistry and Physiology; Academic Press:
New York, 1952; Vol. 2, pp 371–481.
15. An equimolar amount indole 1a (117 mg, 1 mmol),
benzaldehyde 2a (106 mg, 1 mmol) and N,N-dimethylbar-

M. L. Deb, P. J. Bhuyan / Tetrahedron Letters 48 (2007) 2159–2163
2163
bituric acid 3a (156 mg, 1 mmol) were heated at 95 °C for
15 min. The reaction mixture was cooled to rt and
petroleum ether:ethanol (4:1) (5 ml) added. After few
minutes a solid appeared and was filtered off and
recrystallized from ethanol:chloroform (3:1) (241 mg,
67%) m.p = 175–176 °C. IR (KBr): 3436 (NH stretch),
3148 (w), 3048 (w), 2956 (w), 1748 (w), 1693 (s), 1677 (s),
19. Equimolar amounts of indole 1a (117 mg, 1 mmol) and [A]
(244 mg, 1 mmol) were mixed till homogeneous and
heated at 85 °C for 15 min. The reaction mixture was
cooled to rt and added petroleum ether:chloroform (4:1)
(5 ml). The solid obtained was filtered off and recrystal-
lized from a mixture of ethanol:chloroform (3:1). The
compound was identified as 4a from the spectroscopic
data and elemental analysis. Yield = 234 mg (65%). The
filtrate was evaporated to dryness and bisindolylmethane
5a isolated from the residue by column chromatography
on silica gel column (eluent:hexane) and characterized.
20. Equimolar amounts of indole 1a (117 mg, 1 mmol) and [A]
(244 mg, 1 mmol) in acetonitrile (15 ml) were stirred for
11 h (or refluxed for 1 h). The solvent was removed under
reduced pressure and added petroleum ether:chloroform
(4:1) (5 ml). The solid obtained was filtered off and
1665 (s), 1378 (m), 740 (m) cmꢀ1 1H NMR (300 MHz,
.
CDCl3 + CD3COCD3) d 3.00 (s, 3H, NMe), 3.11 (s, 3H,
NMe), 4.36 (d, 1H, J = 2.85 Hz), 5.24 (d, 1H, J = 2.7 Hz),
6.98–7.41 (m, 10H), 8.21 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3 + CD3COCD3) d 28.6, 28.7, 48.8, 55.0, 111.6,
114.6, 119.5, 120.0, 122.7, 124.2, 126.9, 128.3, 128.4, 128.8,
136.5, 138.8, 151.4, 168.2, 169.2: m/z 362 (M+H)+. Anal.
Calcd for C21H19N3O3: C, 69.80; H, 5.26; N, 11.63.
Found: C, 70.25; H, 5.17; N, 11.52.
16. Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Tetrahedron
2004, 60, 2051–2155.
17. Bhuyan, P. J.; Boruah, R. C.; Sandhu, J. S. J. Org. Chem.
1990, 55, 568–571.
18. Deb, M. L.; Bhuyan, P. J. Tetrahedron Lett. 2005, 46,
6453–6456.
recrystallized from a mixture of ethanol:chloroform
(3:1). The compound was identified as 4a by spectroscopic
and elemental analyzes. Yield = 230 mg (64%). The filtrate
was evaporated to dryness and the bisindolylmethane 5a
isolated from the residue by column chromatography on
silica gel column (eluent:hexane) and characterized.