Microwave-accelerated samarium triiodide catalyzed conjugate addition of indoles with electron-deficient olefins

Article abstract of DOI:10.1055/s-2005-869849

A fast, efficient, environmentally benign, solvent-free procedure under microwave irradiation, using silica gel supported reagents, for the samarium triiodide catalyzed conjugated addition of indoles with electron-deficient olefins has been developed. Geo

Full text of DOI:10.1055/s-2005-869849

LETTER
1551
Microwave-Accelerated Samarium Triiodide Catalyzed Conjugate Addition
of Indoles with Electron-Deficient Olefins
Conjugate
Addi
h
tion of Indol
u
es
w
ithElec
a
tron-Deficie
n
nt
O
lefins g-Ping Zhan,* Kai Lang
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, P. R. China
Fax +86(592)2185780; E-mail: zpzhan@xmu.edu.cn
Received 4 April 2005
In the past few decades, many lanthanide salts have been
Abstract: A fast, efficient, environmentally benign, solvent-free
proved to be extraordinarily effective Lewis acids in var-
procedure under microwave irradiation, using silica gel supported
reagents, for the samarium triiodide catalyzed conjugated addition
ious chemical transformations.8,9b Though samarium diio-
dide as a one-electron reducing agent has played an
important role in organic synthesis,9 little work has been
carried out on samarium triiodide used as a Lewis acid
catalyst.10 This promoted us to investigate the use of
samarium triiodide as a Lewis acid for conjugate addition
of indoles to electron-deficient olefins.
of indoles with electron-deficient olefins has been developed.
Key words: microwave irradiation, samarium triiodide, indoles,
a,b-unsaturated compounds, Michael reaction
The work of how to more efficiently synthesize a variety
of indole derivatives continues to receive much interest
because indole fragments are featured in many pharmaco-
logically and biologically active compounds.1,2 Among
various indole derivatives, 3-substituted indoles are im-
portant building blocks in the synthesis of natural prod-
ucts and in the design of therapeutic agents.3 Therefore, a
variety of methods have been reported for the preparations
of this class of compounds.4,5 The simple and direct meth-
od for the synthesis of 3-alkylated indoles involves the
conjugate addition of indoles to a,b-unsaturated com-
pounds in the presence of either protic4 or Lewis acid.5
However, the acid-catalyzed conjugate addition of indoles
requires careful control of acidity to prevent side reactions
such as dimerization or polymerization. Furthermore,
many of these procedures involved strong acidic condi-
tions, expensive reagents, low yields of products, complex
handling, and long reaction times. Thus, a fast and effi-
cient method using a new Lewis acid as a catalyst is desir-
able for conjugate addition of indoles to electron-deficient
olefins.
Herein, we present an efficient approach to 3-alkylated in-
doles via samarium triiodide catalyzed conjugate addition
of indoles with electron-deficient olefins using silica gel
supported reagents under microwave irradiation
(Scheme 1).
R4
O
O
10 mol% SmI3
R3
+
R3
R2
R4
MW, 2–15 min,
N
silica gel support
N
R1
R2
R1
R3 = Ph, CH3, Ph–CH=CH
R4 = Ph, H
R1 = H, PhCH2
R2 = H, CH3, Ph
R3 = R4 = –(CH2)3–
Scheme 1
Our first aim was to testify the catalytic activity of SmI3 in
conjugate addition of indoles with electron-deficient ole-
fins under microwave irradiation. Under MW conditions,
we carried out the reaction of indole with chalcone in the
presence of catalytic amount of SmI3 (10 mol%) absorbed
on the silica gel and obtained the corresponding 3-alkylat-
ed indole in 83% yield (Table 1, product a). By monitor-
ing the reaction mixture at different intervals by TLC, we
found that this reaction only needed 15 minutes to com-
plete. As a control, the same reaction proceeded under
MW in the absence of catalyst, only trace of product was
found. The result indicated that SmI3 exhibited a high cat-
alytic activity.
The application of microwave (MW) irradiation as an un-
conventional energy source for activation of reactions, in
general and on inorganic solid supports in particular, have
gained popularity over the usual homogeneous and het-
erogeneous reactions, as they can be performed rapidly to
give pure products in high yields under solvent-free con-
ditions with several eco-friendly advantages in the context
of green chemistry.6,7 Even though MW has been used ex-
tensively in organic synthesis, it has not been employed to
promote conjugated addition of indoles with electron-de-
ficient olefins.
After this success, various a,b-unsaturated compounds re-
acted with indole, 2-methylindole and 2-phenylindole to
give the corresponding 3-alkylated products.11 The results
were summarized in Table 1. Electron-deficient olefins
such as methyl vinyl ketone, chalcone, benzalacetone, cy-
clohexenone, dibenzylidene acetone and b-nitrostyrene
afforded the desired products in good to excellent yields.
With the methyl vinyl ketone, the Michael reactions com-
pleted in two minutes to provide the products in 90–92%
SYNLETT 2005, No. 10, pp 1551–1554
1
7
.0
6
.2
0
0
5
Advanced online publication: 12.05.2005
DOI: 10.1055/s-2005-869849; Art ID: U09905ST
© Georg Thieme Verlag Stuttgart · New York

1552
Z.-P. Zhan, K. Lang
LETTER
yields (entries 6–8). In cases of more hindered a,b-enones, 2-phenylindole was more hindered, its 3-position alkyl-
the reaction times were prolonged to 15 minutes. In previ- ation proceeded in good to excellent yields (entries 8, 10,
ous reports, Lewis acid-catalyzed conjugate addition of 11). The reactions were clean and the products were ob-
indoles with electron-deficient olefins usually required a tained in high yields without the formation of any side
long time (1–24 h). Though ultrasound also accelerated products such as N-alkylation product. This important re-
the conjugate addition, it needed three to four hours to sult provided a remarkable contrast to similar reactions
complete.5h By comparison, our reactions proceeded far under palladium catalysis, where N-alkylation was pre-
more rapidly (2 min or 15 min), which showed that MW dominant.12 Furthermore, the indole nitrogen did not re-
had more efficient promoting effect. The treatment of b- quire prior protection and the avoidance of strong bases
nitrostyrene with indole produced the corresponding 3- for deprotection permitted compatibility with a wide
alkylated indole in 94–96% yields (entries 12, 13). In range of functional groups.
comparison with InCl3-catalyzed reaction which provided
78% of product l,5e our procedure was more efficient for
the Michael addition of indole to b-nitrostyrene. Though
Table 1 Samarium Triiodide Catalyzed Conjugate Addition of Indoles with Electron-Deficient Olefins Using Silica Gel Supported Reagents
under MW
Entry Nucleophile
1
Electrophile
Product
Time (min)
15
Isolated yield (%)
83
O
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
Ph
Ph
Ph
Ph
N
H
N
H
a
b
c
2
15
15
15
15
95
76
95
80
O
Ph
Ph
N
H
N
H
3
O
Ph
Ph
Ph
N
H
N
H
4
O
O
Ph
Ph
Ph
Ph
N
H
N
H
d
5
N
CH2Ph
N
CH2Ph
e
f
6
2
2
90
92
O
O
O
O
N
H
N
H
7
N
H
N
H
g
Synlett 2005, No. 10, 1551–1554 © Thieme Stuttgart · New York

LETTER
Conjugate Addition of Indoles with Electron-Deficient Olefins
1553
Table 1 Samarium Triiodide Catalyzed Conjugate Addition of Indoles with Electron-Deficient Olefins Using Silica Gel Supported Reagents
under MW (continued)
Entry Nucleophile
8
Electrophile
Product
Time (min)
2
Isolated yield (%)
91
O
O
N
H
Ph
N
Ph
H
h
9
15
15
97
95
O
O
N
H
N
H
i
10
O
O
N
H
Ph
N
H
Ph
j
11
15
2
70
96
94
95
O
Ph
O
Ph
N
H
Ph
N
H
Ph
Ph
k
l
12
NO2
Ph
NO2
NO2
NO2
N
H
N
H
13
2
NO2
p-MeO-
Ph
p-MeOPh
N
H
N
H
m
14
2
NO2
p-MeO-
Ph
p-MeOPh
N
CH2Ph
N
CH2Ph
n
In conclusion, we have developed a new fast and efficient
microwave-assisted procedure for the synthesis of 3-sub-
stituted indoles using samarium triiodide as a catalyst.
Short reaction times, high yields, operational simplicity
and solvent-free conditions are some of the relevant ad-
vantages that make this procedure a more desirable alter-
native to conventional chemical synthesis.
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Acknowledgment
The financial support is provided by FuJian Provincial Department
of Science and Technology (2003J019). We thank Professor Min
Lin for technical assistance.
Synlett 2005, No. 10, 1551–1554 © Thieme Stuttgart · New York

1554
Z.-P. Zhan, K. Lang
LETTER
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corresponding 3-alkylated indole.
Procedure for the Reactions with Methyl Vinyl Ketone.
To a solution of SmI3 (0.1 mmol) in MeCN (1 mL) was
added indole (1 mmol) or 2-methylindole (1 mmol) or 2-
phenylindole (1 mmol), and silica gel (0.25 g). Then the
mixture was mixed thoroughly and dried under reduced
pressure, followed by the addition of methyl vinyl ketone
(1 mmol) in CH2Cl2 (0.5 mL) while stirring. The following
work up was the same to typical experimental procedure.
All new compounds were fully characterized by 1H NMR,
13C NMR, MS, IR and elemental analysis.
3-(1-Benzyl-1H-indol-3-yl)-1,3-diphenylpropan-1-one
(e): Yield: 332 mg (80%). IR (film): nmax = 3034, 1680,
1598, 1493 cm–1. 1H NMR (500 MHz, CDCl3): d = 3.72 (dd,
J = 7, 16.5 Hz, 1 H), 3.81 (dd, J = 7, 16.5 Hz, 1 H), 5.09 (t,
J = 7 Hz, 1 H), 5.26 (s, 2 H), 6.90–7.07 (m, 4 H), 7.10–7.21
(m, 3 H), 7.23–7.30 (m, 5 H), 7.33–7.47 (m, 5 H), 7.50–7.55
(m, 1 H), 7.88–7.93 (m, 2 H). 13C NMR (125 MHz, CDCl3):
d = 38.3, 45.3, 49.9, 109.7, 118.4, 119.1, 119.8, 121.9,
125.6, 126.3, 126.6, 127.3, 127.5, 127.8, 128.1, 128.4,
128.5, 128.7, 132.9, 137.0, 137.2, 137.6, 144.3, 198.6. ESI-
MS: m/z (%) = 416 (88)[M + H+], 438 (100) [M + Na+].
Anal. Calcd for C30H25NO: C, 86.72; H, 6.06; N, 3.37.
Found: C, 86.84; H, 6.05; N, 3.43.
3-[1-(4-methoxyphenyl)-2-nitroethyl]-1H-indole (m):
Yield: 278 mg (94%). IR (film): nmax = 3412, 3058, 1610,
1548, 1509, 1373 cm–1. 1H NMR (500 MHz, CDCl3):
d = 3.79 (s, 3 H), 4.91 (dd, J = 7.5, 12.5 Hz, 1 H), 5.06 (dd,
J = 7.5, 12.5 Hz, 1 H), 5.15 (t, J = 7.5 Hz, 1 H), 6.86 (d,
J = 8.5 Hz, 2 H), 7.03 (s, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.21
(t, J = 7.5 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.36 (d, J = 7.5
Hz, 1 H), 7.45 (d, J = 7.5 Hz, 1 H), 8.10 (s, 1 H). 13C NMR
(125 MHz, CDCl3): d = 40.9, 55.2, 79.7, 111.3, 114.3, 114.8,
119.0, 119.9, 121.4, 122.7, 126.1, 128.8, 131.2, 136.5,
158.9. ESI-MS: m/z (%) = 297 (15) [M + H+], 319 (100)
[M + Na+]. Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44;
N, 9.45. Found: C, 68.80; H, 5.32; N, 9.46.
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1-Benzyl-3-[1-(4-methoxyphenyl)-2-nitroethyl]-1H-
indole (n): Yield: 367 mg (95%). IR (film): nmax = 3027,
1606, 1548, 1501, 1373 cm–1. 1H NMR (500 MHz, CDCl3):
d = 3.53 (s, 3 H), 4.66 (dd, J = 7, 11 Hz, 1 H), 4.79 (dd, J = 7,
11 Hz, 1 H), 4.93 (t, J = 7 Hz, 1 H), 5.00 (s, 2 H), 6.64–6.71
(m, 2 H), 6.76–6.80 (m, 1 H), 6.86–6.93 (m, 3 H), 6.96–7.02
(m, 1 H), 7.04–7.16 (m, 6 H), 7.26–7.34 (m, 1 H). 13C NMR
(125 MHz, CDCl3): d = 40.6, 49.6, 54.8, 79.5, 109.8, 113.6,
114.0, 119.0, 119.4, 122.2, 125.4, 126.4, 126.6, 127.4,
128.5, 128.6, 131.2, 136.7, 137.1, 158.6. ESI-MS: m/z
(%) = 387 (100) [M + H+], 409 (91) [M + Na+]. Anal. Calcd
for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25. Found: C, 74.46;
H, 5.73; N, 7.13.
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(11) Typical Experimental Procedure.
To a solution of SmI3 (0.1 mmol) in MeCN (1 mL) was
added indole (1 mmol) or 2-methylindole (1 mmol) or 2-
phenylindole (1 mmol), electron-deficient olefin (1 mmol)
and silica gel (0.25 g). Then the mixture was mixed
thoroughly and dried under reduced pressure. The contents
were taken in a 5-mL conical flask and was placed in a
microwave oven (cooking type, Galanz WP 700P 21-6) and
irradiated for 2 min or 15 min at 680 W. After completion of
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Synlett 2005, No. 10, 1551–1554 © Thieme Stuttgart · New York