Iodine-catalyzed highly efficient synthesis of 3-alkylated/3-alkenylated indoles from 1,3-dicarbonyl compounds

Article abstract of DOI:10.1055/s-0032-1316684

Molecular iodine has been found to be an efficient and inexpensive catalyst for the synthesis of 3-alkylated/3-alkenylated indoles in excellent yields by using different indoles and 1,3-dicarbonyl compounds at room temperature. Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/s-0032-1316684

2116▌
LETTER
lIeottedr ine-Catalyzed Highly Efficient Synthesis of 3-Alkylated/3-Alkenylated
Indoles from 1,3-Dicarbonyl Compounds
Synthesis of 3-Alkylated/3-Alkenylated Indoles
Neetu Singh, Krishna Nand Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
Fax +91(542)2368127; E-mail: knsinghbhu@yahoo.co.in
Received: 26.05.2012; Accepted after revision: 10.06.2012
doles at room temperature using different indoles and 1,3-
Abstract: Molecular iodine has been found to be an efficient and
dicarbonyl compounds (Scheme 1).
inexpensive catalyst for the synthesis of 3-alkylated/3-alkenylated
indoles in excellent yields by using different indoles and 1,3-dicar-
bonyl compounds at room temperature.
Table 1 Optimization of Reaction Conditions for 3a
O
Key words: iodine, 3-alkenylated indoles, 1,3-dicarbonyl com-
pounds, solvent-free, bis(indolyl)carbonyl compounds
O
O
catalyst
neat, r.t.
+
The indole nucleus is a ubiquitous heterocycle in nature
and represents a ‘privileged’ structural moiety with a
broad spectrum of pharmaceutical and biological activi-
ties.1 Among different substitution patterns, 3-substituted
indoles are of special interest as important building blocks
for the synthesis of therapeutic agents and display physi-
ological properties such as anticancer, antimigraine, anti-
depressant, anti-inflammatory, antiestrogen, and
antagonist activity.2 The synthesis and selective function-
alization of indoles at the C-3 position have been the focal
point of active research over a prolonged period.3 3-Al-
kylated indoles are central compounds in pharmaceutical
chemistry, and their direct synthesis involves the conju-
gate addition of indoles to α,β-unsaturated compounds in
the presence of protic and Lewis acids.4 While these meth-
ods for preparing 3-alkylated indoles are well established,
there exist only a few reports for the alternative prepara-
tion of 3-alkenylated indoles using gold(III) chloride,5
ionic liquid,6 and iron(III) chloride.7 These methods, how-
ever, suffer from one or other drawbacks, such as the use
of strongly acidic conditions, moisture-sensitive catalysts,
or expensive reagents. Therefore, there remains the de-
mand for the development of a mild and efficient method
for the preparation of 3-alkenylated indoles.
N
H
3a
N
H
1a
2a
Entry
Catalyst
(mol%)
Solvent
Time
(h)
Yield
(%)a
1
2
–
–
10
10
10
3
n.r.b
n.r.b
n.r.b
75
[bmim]BF4 (10)
[bmim]PF6 (10)
ZnCl2 (10)
MnCl2·6H2O (10)
AlCl3 (10)
NiCl2·6H2O (10)
CuCl2 (10)
LiClO4 (10)
NH2·SO3H (10)
I2 (10)
–
3
–
4
–
5
–
3
60
6
–
3
65
7
–
3
70
8
–
3
72
9
–
3
50
10
11
12
13
14
15
16
17
18
19
–
4
55
–
2
90
I2 (10)
CH2Cl2
MeCN
THF
EtOH
MeOH
–
2
90
I2 (10)
2
78
As molecular iodine (I2) has received considerable atten-
tion as an inexpensive, easily available, and mild Lewis
acid catalyst for various organic transformations,8 it was
thought worthwhile to explore the catalytic potential of I2
and other unexplored catalysts for this particular conver-
sion.
I2 (10)
2
75
I2 (10)
2
78
I2 (10)
2
75
I2 (5)
5
70
In view of the above and as a part of our ongoing program
to develop viable protocols,9 we report herein an iodine
(10 mol%) catalyzed, mild, simple, and efficient proce-
dure for the construction of 3-alkylated/3-alkenylated in-
I2 (15)
–
2
89
I2 (20)
–
2
90
a Using an equimolar ratio of 1a and 2a.
b n.r. = no reaction.
SYNLETT 2012, 23, 2116–2120
Advanced online publication: 03.08.2012
DOI: 10.1055/s-0032-1316684; Art ID: ST-2012-D0457-L
© Georg Thieme Verlag Stuttgart · New York
In order to optimize the reaction conditions, the effect of
different catalysts and solvents was investigated in detail
for a typical reaction of 2-methyl indole (1a), and acetyl-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of 3-Alkylated/3-Alkenylated Indoles
2117
O
R4
R1 = Me, Ph
R2
R3
75–90%
N
H
R1
R2
O
O
I2 (10 mol%)
3a–g
R3
2a–c
R4
R1
neat, r.t., 2–3 h
N
H
1a–e
R4
R2
R2
R3
O
2a R3 = Me, R4 = Me
2b R3 = Me, R4 = OEt
2c R3,R4 = -(CH2)-
R1 = H
N
H
N
78–84%
H
4a–f
Scheme 1 C-3 Alkylation/alkenylation of indoles
acetone (2a). As solvent-free synthesis has gained much 1, entries 18 and 19). In order to screen the effect of sol-
current interest, it was considered worthwhile to investi- vent, the model reaction was undertaken at room temper-
gate the reaction under these conditions as well. The out- ature using 10 mol% of iodine in different solvents (Table
come is presented in Table 1 where it is evident that no 1, entries 12–16). The best conversion was finally
conversion into the product was obtained in the absence of achieved either under solvent-free conditions or in dichlo-
catalyst even after a prolonged reaction time of ten hours romethane at room temperature (Table 1, entries 11 and
(Table 1, entry 1) and so a number of catalysts was then 12). To refrain from the use of dichloromethane, iodine
screened. Due to their intrinsic advantages as green cata- (10 mol%) under solvent-free conditions at room temper-
lysts, attempts were made to study the model reaction us- ature was chosen as the optimum condition and was sub-
ing some common ionic liquids such as [bmim]BF4 and sequently applied to the reaction of 2-methylindole (1a),
[bmim]PF6, which resulted in no net reaction (Table 1, en- and 2-phenylindole (1b) with 1,3-dicarbonyl compounds
tries 2 and 3). However, many other catalysts such as such as acetylacetone (2a), ethyl acetoacetate (2b), and
ZnCl2, MnCl2·6H2O, AlCl3, NiCl2·6H2O, and CuCl2 pro- dimedone (2c) to afford a variety of 3-alkenylated indole
moted the reaction to some extent (Table 1, entries 4–8); derivatives 3a–g in excellent yields with complete E se-
whereas catalysts such as lithium perchlorate and sulfam- lectivity (Table 2). It is worth mentioning that no side
ic acid provided relatively low product yields (Table 1, product was obtained under these conditions, albeit some
entries 9 and 10). Out of all the catalysts monitored, iodine of the reactions did not proceed smoothly under solvent-
was concluded to be the best at room temperature under free conditions, thereby making the use of dichlorometh-
solvent-free conditions to afford the product 3a in 90% ane necessary to achieve desirable conversion (Table 2,
yield (Table 1, entry 11). In terms of catalyst concentra- entries 3, 6, and 7). It is interesting to note that when 2-un-
tion, 10 mol% of iodine was optimum for the effective substituted indoles such as indole (1c), 5-bromoindole
completion of the reaction (Table 1, entry 11), as the reac- (1d), and 5-methoxyindole (1e), were reacted with 1,3-di-
tion remained incomplete when 5 mol% of the catalyst carbonyl compounds, we were confronted with the forma-
were used (Table 1, entry 17). No further improvement tion of bis(indolyl)carbonyl compounds 4a–f (Table 2,
was observed with 15 mol% or 20 mol% of iodine (Table entries 8–13) rather than the desired adducts.
Table 2 Alkylation/Alkenylation of Indoles with 1,3-Dicarbonyl Compounds9
Entry
Indole
1,3-Dicarbonyl
Product
Time (h)
Yield (%)a
O
O
O
1
2
90
N
H
N
H
2a
1a
3a
3b
O
OEt
O
O
N
H
2
OEt
3
76
N
H
2b
1a
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2116–2120

2118
N. Singh, K. N. Singh
LETTER
Table 2 Alkylation/Alkenylation of Indoles with 1,3-Dicarbonyl Compounds9 (continued)
Entry
Indole
1,3-Dicarbonyl
Product
Time (h)
Yield (%)a
O
O
O
3
3
82b
N
H
N
H
1a
2c
3c
3d
3e
O
O
O
N
H
Ph
4
5
2
3
80
78
N
H
Ph
2a
1b
1b
O
OEt
O
O
N
H
Ph
OEt
N
H
Ph
2b
O
O
O
N
H
Ph
6
7
2.5
81b
N
H
Ph
1b
2c
3f
O
O
O
N
H
2
75b
N
H
1c
1c
2c
2a
3g
O
O
O
N
H
8
9
2.5
80
83
80
N
H
N
H
4a
OEt
O
O
O
N
H
3
OEt
N
H
N
H
2b
2a
1c
4b
Br
Br
Br
O
O
O
10
3
N
H
N
H
N
H
1d
4c
Synlett 2012, 23, 2116–2120
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Alkylated/3-Alkenylated Indoles
2119
Table 2 Alkylation/Alkenylation of Indoles with 1,3-Dicarbonyl Compounds9 (continued)
Entry
11
Indole
1,3-Dicarbonyl
Product
Time (h)
Yield (%)a
OEt
O
Br
Br
Br
O
O
2.5
78
OEt
N
H
N
H
N
H
2b
2a
1d
4d
OMe
MeO
MeO
O
O
O
12
2
3
82
84
N
H
N
H
N
H
1e
4e
OEt
OMe
MeO
MeO
O
O
O
13
N
H
OEt
N
H
N
H
2b
1e
4f
a Isolated yield.
b Using CH2Cl2 as a solvent.
(4) (a) Reddy, A. V.; Ravinder, K.; Niranjan Reddy, V. L.;
Gound, T. V.; Ravikanth, V.; Venkateswarlu, Y. Synth.
Commun. 2003, 33, 3687. (b) Chen, D.; Yu, L.; Wang, P. G.
Tetrahedron Lett. 1996, 37, 4467. (c) Sharma, G. V. M.;
Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R. Tetrahedron Lett.
2004, 45, 7729. (d) Kumar, A. V.; Rao, K. R. Tetrahedron
Lett. 2011, 52, 5188. (e) Bandini, M.; Cozzi, P. G.;
Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A.
J. Org. Chem. 2002, 67, 3700. (f) Bartoli, G.; Bartolacci, M.;
Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2003, 68, 4594. (g) Rajabi,
F.; Razavia, S.; Luque, R. Green Chem. 2010, 12, 786.
(h) Hou, X.; Hemit, H.; Yong, J.; Nie, L.; Aisa, H. A. Synth.
Commun. 2010, 40, 973. (i) Ekbote, S. S.; Panda, A. G.;
Malhari, D.; Bhor, M. D.; Bhanage, B. M. Catal. Commun.
2009, 10, 1569. (j) King, H. D.; Meng, Z.; Denhart, D.;
Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.; Macor, J. E. Org.
Lett. 2005, 7, 3437.
In conclusion, we have demonstrated the use of iodine as
an efficient, inexpensive, and easy-to-handle catalyst for
C-3 alkylation/alkenylation of various indoles with 1,3-
dicarbonyl compounds at room temperature, for the most
part under solvent-free conditions. Due to the mild and
metal-free nature of the reaction, we believe that this pro-
cess is a useful addition to the available synthetic method-
ologies.
Acknowledgment
We are grateful to the Council of Scientific and Industrial Research,
New Delhi for financial assistance.
References and Notes
(5) (a) Arcadi, A.; Alfonsi, M.; Bianchi, G.; D’Anniballe, G.;
Marinelli, F. Adv. Synth. Catal. 2006, 348, 331.
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52, 3825. (b) Rad-Moghadam, K.; Sharifi-Kiasaraie, M.
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(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic
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2004, 449. (b) Gribble, G. W. In Comprehensive
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New York, 1996, 211. (c) Andreani, A.; Burnelli, S.;
Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
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Kunkel, M. W. J. Med. Chem. 2008, 51, 4563.
(8) (a) Kumar, K. P.; Satyanarayana, S.; Reddy, P. L.;
Narasimhulu, G.; Ravirala, N.; Reddy, B. V. S. Tetrahedron
Lett. 2012, 53, 1738. (b) Gao, S.; Tzeng, T.; Sastry, M. N.
V.; Chu, C.; Liu, J.; Lin, C.; Yao, C. Tetrahedron Lett. 2006,
47, 1889. (c) Varala, R.; Nuvula, S.; Adapa, S. R. J. Org.
Chem. 2006, 71, 8283. (d) More, S. V.; Sastry, M. N. V.;
Wang, C. C.; Yao, C. F. Tetrahedron Lett. 2005, 46, 6345.
(e) Li, X.; Mao, Z.; Wang, Y.; Chen, W.; Lin, X.
(d) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17,
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(f) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1.
Tetrahedron 2011, 67, 3858. (f) Reddy, B. V. S.; Grewal, H.
Tetrahedron Lett. 2011, 52, 761. (g) Kavala, V.; Lin, C.;
Kuo, C.-W.; Fang, H.; Yao, C.-F. Tetrahedron 2012, 68,
1321. (h) Datta, B.; Madhusudana Reddy, M. B.; Pasha,
(3) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2116–2120

2120
N. Singh, K. N. Singh
LETTER
M. A. Synth. Commun. 2011, 41, 2331. (i) Verma, A. K.;
Aggarwal, T.; Rustagia, V.; Larock, R. C. Chem. Commun.
2010, 46, 4064. (j) Lamar, A. A.; Nicholas, K. M. J. Org.
Chem. 2010, 75, 7644. (k) Togo, H.; Iida, S. Synlett 2006,
2159.
Ethyl 3,3-Bis(1H-3-indolyl)butanoate (4b)
IR (KBr): 3406, 3351, 3056, 2938, 1724 cm–1. 1H NMR (300
MHz, CDCl3): δ = 7.95 (br s, 2 H), 7.35–7.28 (m, 4 H), 7.10–
7.03 (m, 4 H), 6.88 (t, 2 H, J = 7.5 Hz), 3.86 (q, 2 H, J = 7.2
Hz), 3.37 (s, 2 H), 2.08 (s, 3 H), 0.86 (t, 3 H, J = 7.2 Hz).
Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09.
Found: C, 76.21; H, 6.25; N, 8.01.
(9) (a) Raghuvanshi, D. S.; Singh, K. N. Synlett 2011, 373.
(b) Singh, N.; Singh, S. K.; Khanna, R. S.; Singh, K. N.
Tetrahedron Lett. 2011, 52, 2419. (c) Raghuvanshi, D. S.;
Singh, K. N. Tetrahedron Lett. 2011, 52, 5702. (d) Kumari,
K.; Raghuvanshi, D. S.; Jouikov, V.; Singh, K. N.
4,4-Bis(5-bromo-1H-3-indolyl)pentan-2-one (4c)
IR: 3342, 3321, 2966, 1680 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.08 (br s, 2 H), 7.37 (m, 2 H), 7.20–7.13 (m, 6
H), 3.42 (s, 2 H), 1.95 (s, 3 H), 1.60 (s, 3 H). Anal. Calcd for
C21H18Br2N2O: C, 53.19; H, 3.83; N, 5.91. Found: C, 53.11;
H, 3.70; N, 5.84.
Tetrahedron Lett. 2012, 53, 1130. (e) Allam, B. K.; Singh,
K. N. Tetrahedron Lett. 2011, 52, 5851
General Experimental Procedure for the 3-
Alkenylation/3-Alkylation of Indoles (Table 2)
Ethyl 3,3-Bis(5-bromo-1H-3-indolyl)butanoate (4d)
IR (KBr): 3423, 3360, 2976, 1713 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.06 (br s, 2 H), 7.37 (m, 2 H), 7.20–7.14 (m, 6
H), 3.89 (q, 2 H, J = 7.2 Hz), 3.28 (s, 2 H), 2.02 (s, 3 H), 0.91
(t, 3 H, J = 7.2 Hz). Anal. Calcd for C22H20Br2N2O2: C,
52.41; H, 4.00; N, 5.56. Found: C, 53.33; H, 4.05; N, 5.51.
4,4-Bis(5-methoxy-1H-3-indolyl)pentan-2-one (4e)
IR (KBr): 3408, 3360, 2934, 1695 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.90 (br s, 2 H), 7.22–7.07 (m, 4 H), 6.76–6.73
(m, 4 H), 3.61 (s, 6 H), 3.46 (s, 2 H), 1.95 (s, 3 H), 1.57 (s, 3
H). Anal. Calcd for C23H24N2O3: C, 73.38; H, 6.43; N, 7.44.
Found: C, 73.22; H, 6.43; N, 7.35.
Ethyl 3,3-Bis(5-methoxy-1H-3-indolyl)butanoate (4f)
IR (KBr): 3409, 3365, 2978, 1719 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.87(br s, 2 H), 7.19–7.10 (m, 4 H), 6.74–6.71
(m, 4 H), 3.89 (q, 2 H, J = 7.2 Hz), 3.61 (s, 6 H), 3.33 (s, 2
H), 2.04 (s, 3 H), 0.90 (t, 3 H, J = 7.2 Hz). Anal. Calcd for
C24H26N2O4: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.83; H,
6.28; N, 6.78.
A mixture of indole (1 mmol), 1,3-dicarbonyl compound (1
mmol) and I2 (10 mol%) was taken in a round-bottom flask
and stirred at r.t. for the appropriate time (Table 2). After the
completion of reaction as indicated by TLC, a sat. aq
solution of Na2S2O3 (2 × 5 mL) was added, and the mixture
was extracted with EtOAc (3 × 5 mL). The combined
organic phases were dried over anhyd Na2SO4, filtered, and
evaporated under reduced pressure to furnish the crude
product which was purified by column chromatography.
Spectral Data of some Representative Products
(E)-Ethyl-3-(2-methyl-1H-3-indolyl)-2-butenoate (3b)
IR (KBr): 3411, 2933, 1718 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.99 (br s, 1 H), 7.65 (d, 1 H, J = 7.5 Hz), 7.29–
7.25 (m, 1 H), 7.17–7.09 (m, 2 H), 5.92 (s, 1 H), 4.25 (q, 2
H, J = 7.2 Hz), 2.66 (s, 3 H), 2.51 (s, 3 H), 1.35 (t, 3 H, J =
7.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 167.3, 152.0,
135.0, 132.7, 127.0, 121.7, 120.3, 119.5, 117.1, 116.8,
110.4, 59.5, 20.4, 14.4,13.4. Anal. Calcd for C15H17NO2: C,
74.05; H, 7.04; N, 5.76. Found: C, 73.99; H, 7.06; N, 5.68.
Synlett 2012, 23, 2116–2120
© Georg Thieme Verlag Stuttgart · New York

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