Bismuth triflate catalyzed conjugate addition of indoles to α,β-enones

Article abstract of DOI:10.1016/S0040-4039(03)01555-7

Reaction of indoles with electron deficient olefins under the influence of bismuth triflate has been studied at ambient temperature and affords the corresponding 3-alkylated indoles in excellent yields.

Full text of DOI:10.1016/S0040-4039(03)01555-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6257–6260
Bismuth triflate catalyzed conjugate addition of indoles to
a,b-enonesꢀ
A. Vijender Reddy, K. Ravinder, T. Venkateshwar Goud, P. Krishnaiah, T. V. Raju and
Y. Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 20 February 2003; revised 12 June 2003; accepted 20 June 2003
Dedicated to Prof. Goverdhan Mehta on his 60th birthday
Abstract—Reaction of indoles with electron deficient olefins under the influence of bismuth triflate has been studied at ambient
temperature and affords the corresponding 3-alkylated indoles in excellent yields.
© 2003 Elsevier Ltd. All rights reserved.
The development of synthetic methods leading to
indole derivatives has attracted much attention in
organic synthesis because of their biological activities.1
Various indoles are components of drugs and are com-
monly found in molecules of pharmaceutical interest in
a variety of therapeutic areas. Generally, 3-substituted
indoles exhibit numerous biological activities.2 Since the
3-position in indoles is the preferred site for elec-
trophilic substitution, 3-alkyl or acyl indoles are ver-
satile intermediates for the synthesis of a wide range of
indole derivatives. In fact, the 3-substituted ketones are
highly interesting building blocks for the synthesis of
biologically active compounds as well as natural
products.3
methods for the synthesis of 3-alkylated indoles involve
the conjugate addition of indoles to a,b-enones in the
presence of protic4 or Lewis acids.5 However, several of
these procedures suffer from drawbacks, such as the
need for strongly acidic conditions, expensive reagents,
long reaction times, and low yields of products due to
dimerisation of the indoles or polymerization of the
vinyl ketones.
Thus, an efficient Lewis acid catalyst is desirable for
conjugate addition of indoles to a,b-enones. In this
connection we describe the use of bismuth triflate as a
Lewis acid catalyst for these reactions. Previously, bis-
muth triflate has been used as a catalyst for Friedel–
Crafts acylations,7 sulfonylation of arenes,8 Diels–Alder
reactions,9 aza-Diels–Alder reactions,10 rearrangements
of epoxides,11 formation of acylals12 and deprotection
of acetals.13 We have a special interest in bismuth
triflate because it is inexpensive14 and can easily be
prepared.15
Over the past few years a variety of methods has been
reported for the preparation of 3-substituted indoles.4,5
Acid catalyzed electrophilic substitution of indoles
requires careful control of acidity to prevent side reac-
tions such as dimerisation and polymerization.6 Other
Scheme 1.
Keywords: bismuth triflate; indole; a,b-enones; addition reactions.
ꢀ IICT communication No. 030101.
* Corresponding author. Tel.: +91-40-27193167; fax: +91-40-27160757; e-mail: luchem@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01555-7

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A. V. Reddy et al. / Tetrahedron Letters 44 (2003) 6257–6260
Table 1. Conjugate addition of indoles to a,b-enones

A. V. Reddy et al. / Tetrahedron Letters 44 (2003) 6257–6260
6259
The reaction of indole with methyl vinyl ketone in the
presence of a catalytic amount of bismuth triflate in
acetonitrile gave 1-(3%-indolyl)butan-3-one, 1 in 95%
yield (Scheme 1).16 Similarly, various a,b-unsaturated
ketones such as cyclic enones, acyclic enones such as
chalcones and naphthoquinone were reacted with
indole, 2-methylindole and 5-methoxyindole to give the
corresponding Michael adducts in excellent yields. In
all cases the reactions proceeded smoothly at ambient
temperature with high selectivity (Table 1).
4. (a) Iqbal, Z.; Jackson, A. H.; Rao, K. R. N. Tetrahedron
Lett. 1998, 29, 2577; (b) Dujardin, G.; Poirier, J. M. Bull.
Soc. Chim. Fr. 1994, 131, 900; (c) Harrington, P. E.;
Kerr, M. A. Synlett. 1996, 1047; (d) Manabe, K.;
Aoyama, N.; Kobayashi, S. Adv. Synth. Catal. 2001, 343,
174; (e) Yadav, J. S.; Reddy, B. V. S.; Abraham, S.;
Sabitha, G. Synthesis 2001, 2165; (f) Bandini, M.; Cozzi,
P. G.; Giacomini, M.; Melchiorre, P.; Selva, S.; Ronchi,
A. U. J. Org. Chem. 2002, 67, 3700.
5. For a comprehensive review focused on the asymmetric
catalytic arylation reaction, see: Bolm, C.; Hildebrand, J.
P.; Muniz, K.; Hermanns, N. Angew. Chem., Int. Ed.
2001, 40, 3284.
The products were characterized by 1H NMR, 13C
NMR, IR and mass spectroscopy. In the case of entries
4 and 5, the reaction of indole with 1,5-diphenyl-1,4-
pentadien-3-one and 2-benzylidenecyclohexanone gave
1:1 and 7:3 diastereomeric mixtures of the products 4
and 5, respectively. Interestingly, when indole reacts
with 2-methyl-1,4-naphthoquinone, it attacks at the
more hindered position and gave exclusively 6 (entry 6).
The product 6 was characterized by the presence of
methylene signals at l 3.30 (1H, d, J=16 Hz) and 3.64
(1H, d, J=16 Hz) and a tertiary methyl at l 1.79 (s,
6. Houlihan, W. J. Indoles; John Wiley & Sons Inc: New
York, 1972; Vol. I, p. 71.
7. (a) Labrouillere, M.; Le Roux, C.; Gaspard, H.; Lapor-
terie, A.; Dubac, J. Tetrahedron Lett. 1997, 38, 8871; (b)
Repichet, S.; Le Roux, C.; Dubac, J.; Desmurs, J. R. Eur.
J. Org. Chem. 1998, 2743.
8. Repichet, S.; Le Roux, C.; Hernandez, P.; Dubac, J. J.
Org. Chem. 1999, 64, 6479.
9. (a) Garrigues, B.; Gonzaga, F.; Robert, H.; Dubac, J. J.
Org. Chem. 1997, 62, 4880; (b) Robert, H.; Garrigues, B.;
Dubac, J. Tetrahedron Lett. 1998, 39, 1161.
1
3H) in its H NMR spectrum. However, in the case of
2-methylindole attack at the less hindered position was
observed to give product 7, which was characterized by
the presence of two vinylic methyls at l 2.08 (3H, s)
10. Laurent-Robert, H.; Garrigues, B.; Dubac, J. Synlett.
2000, 1160.
11. Bhatia, K. A.; Eash, K. J.; Leonard, N. M.; Oswald, M.
C.; Mohan, R. S. Tetrahedron Lett. 2001, 42, 8129.
12. Carrigan, M. D.; Eash, K. J.; Oswald, M. C.; Mohan, R.
S. Tetrahedron Lett. 2001, 42, 8133.
13. Wieland, L. C.; Carrigan, M. C.; Sarapa, D.; Smith, R.
S.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027.
14. Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. Angew.
Chem., Int. Ed. 2000, 39, 2877.
1
and l 2.14 (3H, s) in its H NMR spectrum. Under
similar conditions, 5-methoxyindole adds to the 2- and
3-positions of 2-methyl-1,4-naphthoquinone to give 8a
and 8b in a 1:1 ratio. The reaction is highly efficient and
3 mol% of bismuth triflate was sufficient to catalyze the
reaction which proceeded smoothly at ambient temper-
ature with high yields.
15. Labrouillere, M.; Le Roux, C.; Gaspard, H.; Laporterie,
A.; Dubac, J.; Desmurs, J. R. Tetrahedron Lett. 1999, 40,
285. Bismuth triflate synthesized by this procedure is
reported to be mainly the tetrahydrate. Recently, another
procedure for the synthesis of bismuth triflate has been
reported: Repichet. S.; Zwick. A.; Vendier, L.; Le Roux.
C.; Dubac, J. Tetrahedron Lett. 2002, 43, 993.
In summary, we have demonstrated that bismuth tri-
flate is a catalyst for alkylation of indoles.
Acknowledgements
16. Typical experimental procedure: To a solution of indole (5
mmol), and the vinyl ketone (5 mmol) in CH3CN (10 ml)
was added bismuth triflate (3 mol%) and the mixture was
stirred for the appropriate time (see Table 1). After
completion of the reaction, as indicated by TLC, the
catalyst was filtered. The filtrate was concentrated under
reduced pressure to give the crude product, which was
purified by silica gel column chromatography to afford
the pure product.
The authors thank CSIR, New Delhi for providing
fellowships.
References
1. (a) Sakagami, M.; Muratake, H.; Natsume, M. Chem.
Pharm. Bull. 1994, 42, 1393; (b) Fukuyama, T.; Chen, X.
J. Am. Chem. Soc. 1994, 116, 3125; (c) Vaillancouirt, V.;
Albizati, K. F. J. Am. Chem. Soc. 1993, 115, 3499; (d)
Murakatake, H.; Kumagami, H.; Natsume, M. Tetra-
hedron 1990, 46, 6351; (e) Murakatake, H.; Natsume, M.
Tetrahedron Lett. 1990, 46, 6351.
5: Solid, m.p. 154–155°C; IR (KBr) wmax (cm−1): 2937,
1
1703, 1453, 1231 and 751; H NMR (300 MHz, CDCl3)
l: 1.26 (1H, m), 1.68 (2H, m), 1.88 (2H, m), 2.26 (1H, m),
2.30 (2H, m), 3.72, (1H, m), 4.60 (1H, d, J=7.8 Hz), 7.02
(2H, t, J=7.2 Hz), 7.13 (2H, t, J=7.2 Hz), 7.20 (2H, d,
J=7.8 Hz), 7.26 (1H, d, J=7.8 Hz), 7.32 (2H, d, J=8.0
Hz), 7.72 (1H, d, J=7.8 Hz) and 7.80 (1H, bs); 13C NMR
(75 MHz, CDCl3) l: 12.60, 24.15, 29.27, 33.61, 41.99,
42.28, 53.96, 110.55, 113.30, 118.79, 119.03, 120.87,
125.90, 127.49, 128.31, 131.72, 135.22, 143.16 and 212.96.
EIMS m/z (%): 303 (M+, 8), 221 (100), 205 (12), 178 (14),
155 (8), 141 (16), 119 (12), 91 (25) and 43 (75). Anal.
calcd for C21H21NO: C, 83.13; H, 6.98; N, 4.62; O, 5.27.
Found: C, 83.32; H, 6.66; N, 4.66; O, 5.36.
2. Sundberg, R. J. The Chemistry of Indoles; Academic
Press: New York, 1996; p. 113.
3. (a) Moore, R. E.; Cheuk, C.; Yang, X. Q.; Patterson, G.
M. L.; Bonjouklian, R.; Smita, T. A.; Mynderse, J.;
Foster, R. S.; Jones, N. D.; Skiartzendruber, J. K.;
Deeter, J. B. J. Org. Chem. 1987, 52, 1036; (b) Garnick,
R. L.; Levery, S. B.; LeQuesne, U. P. J. Org. Chem. 1978,
43, 1226; (c) Moore, R. E.; Cheuk, C.; Patterson, G. M.
L. J. Am. Chem. Soc. 1984, 106, 6456.

6260
A. V. Reddy et al. / Tetrahedron Letters 44 (2003) 6257–6260
6: Solid, m.p.163–164°C; IR (KBr) wmax (cm−1): 3375,
2929, 1629 and 1594; 1H NMR (300 MHz, CDCl3) l:
1.79 (3H, s), 3.30 (1H, d, J=16.3 Hz), 3.64 (1H, d,
J=16.3 Hz), 7.06 (1H, d, J=2.6 Hz), 7.12 (2H, t, J=6.0
Hz), 7.24 (1H, dd, J=7.6, 1.2 Hz), 7.58 (2H, t, J=7.0
Hz), 7.70 (1H, dd, J=7.6, 1.2 Hz), 7.92 (1H, dd, J=7.8,
2.2 Hz) and 7.98 (1H, dd, J=7.8, 2.2 Hz); 13C NMR (75
MHz, CDCl3) l: 24.62, 49.30, 50.84, 111.30, 117.51,
119.90, 120.44, 121.36, 122.32, 125.35, 125.70, 127.72,
133.51, 134.23, 134.32, 134.44, 136.60, 196.60 and 198.42;
EIMS m/z (%): 289 (M+, 98), 274 (100), 246 (50), 218
(10), 141 (16), 115 (12), 104 (12) and 76 (12). Anal. calcd
for C19H15NO2: C, 78.87; H, 5.23; N, 4.84; O, 11.06.
Found: C, 79.15; H, 4.74; N, 4.87; O, 11.24.
8a: Solid, m.p. 137–139°C; IR (KBr) wmax (cm−1): 3366,
2929, 1697, 1512 and 1288; H NMR (300 MHz, CDCl3)
1
l: 1.72 (3H, s), 3.40 (1H, d, J=16.0 Hz), 3.60 (1H, d,
J=16.0 Hz), 3.82 (3H, s), 6.67 (1H, d, J=2.0 Hz), 7.10
(3H, m), 7.60 (2H, t, J=7.2 Hz), 7.90 (1H, dd, J=2.0, 7.8
Hz), 7.96 (1H, dd, J=2.0, 7.8 Hz) and 9.8 (1H, brs, NH);
13C NMR (75 MHz, CDCl3) l: 24.02, 49.30, 51.04, 56.20,
102.20, 111.40, 117.62, 118.40, 122.00, 126.40, 127.21,
128.46, 129.24, 132.04, 133.12, 154.04, 196.52 and 198.20;
EIMS m/z (%): 319 (M+, 100), 304 (80), 276 (46), 174 (8),
102 (10) and 76 (12). Anal. calcd for C20H17NO3: C,
75.22; H, 5.37; N, 4.39; O,15.03. Found: C, 75.26; H,
5.40; N, 4.34; O 15.00.
8b: Solid, m.p. 125–126°C; IR (KBr) wmax (cm−1): 3665,
7: Solid, m.p. 115–117°C; IR (KBr) wmax (cm−1): 3393,
1654, 1457 and 1287; 1H NMR (300 MHz, CDCl3) l:
2.08 (3H, s), 2.14 (3H, s), 7.14 (4H, m), 7.70 (1H, dd,
J=2.1, 8.2 Hz), 7.73 (1H, dd, J=2.1, 8.2 Hz), 8.14 (1H,
1
1695, 1593, 1484 and 1244; H NMR (300 MHz, CDCl3)
l: 2.18 (3H, s), 3.78 (3H, s), 6.62 (1H, d, J=2.0 Hz), 6.84
(1H, dd, J=7.8, 2.0 Hz), 7.23 (1H, d, J=7.8 Hz), 7.38
(1H, d, J=2.2 Hz), 7.75 (2H, t, J=7.8 Hz), 8.18 (2H, m)
and 8.43 (1H, brs, NH); 13C NMR (75 MHz, CDCl3) l:
16.50, 56.02, 102.20, 108.42, 112.35, 120.01, 122.36,
123.42, 130.60, 131.74, 132.27, 132.63, 132.80, 140.02,
135.04, 135.06, 143.20, 151.24, 184.82 and 186.04; EIMS
m/z (%): 317 (M+, 80), 303 (78), 285 (8), 258 (4), 217 (10).
178 (12), 136 (24), 104 (42) and 76 (50). Anal. calcd for
C20H15NO3: C, 75.70; H, 4.76; N, 4.41; O, 15.12. Found:
C, 75.54; H, 4.72; N, 4.59; O, 15.15.
dd, J=2.0, 7.8 Hz) and 8.18 (1H, dd, J=2.0, 7.8 Hz); 13
C
NMR (75 MHz, CDCl3) l: 12.98, 15.18, 106.24, 110.80,
118.92, 120.00 121.37, 126.17, 126.66, 127.84, 132.34,
132.46, 133.44, 134.95, 135.46. 140.99, 145.58, 184.14 and
185.78; EIMS m/z (%): 301 (M+, 100), 300 (20), 286 (80),
284 (18), 168 (10), 141 (14), 141(16), 130 (4), 104 (4), 83
(25) and 76 (12). Anal. calcd for C20H15NO2: C, 79.72; H,
5.02; N, 4.65; O, 10.62. Found: C, 78.31; H, 4.62; N, 4.56,
O, 10.51.