Novel Bronsted acid catalyzed three-component alkylations of indoles with N-phenylselenophthalimide and styrenes

Article abstract of DOI:10.1021/ol7024795

(Chemical Equation Presented) Novel and efficient Bronsted acid (p-TsOH) catalyzed inter- and intramolecular Friedel-Crafts alkylations have been developed to synthesize selenated three-component coupling and selenation-cyclization indole derivatives. Chemical removal of the phenylseleno moiety was investigated, and the reaction mechanisms were discussed.

Full text of DOI:10.1021/ol7024795

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5263-5266
Novel Brønsted Acid Catalyzed
Three-Component Alkylations of Indoles
with N-Phenylselenophthalimide and
Styrenes
Xiaodan Zhao, Zhengkun Yu,* Tongyu Xu, Ping Wu, and Haifeng Yu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS),
457 Zhongshan Road, Dalian, Liaoning 116023, PR China
zkyu@dicp.ac.cn
Received October 11, 2007
ABSTRACT
Novel and efficient Brønsted acid (p-TsOH) catalyzed inter- and intramolecular Friedel−Crafts alkylations have been developed to synthesize
selenated three-component coupling and selenation−cyclization indole derivatives. Chemical removal of the phenylseleno moiety was investigated,
and the reaction mechanisms were discussed.
Functionalization of indoles has received more and more
attention because the indole moiety is an important structural
unit in many bioactive compounds, and indoles have also
been used as synthons of complex molecules.1 Recently,
much work has been directed to catalytic Friedel-Crafts
reactions of indoles with active carbonyl compounds,2
epoxides,3 olefins,4-6 imines,7 and allyl compounds,8 etc.
Three-component aza-Friedel-Crafts reactions of indoles,
aldehydes, and amines have also been documented to prepare
3-substituted indole derivatives.2,9 Organoselenium com-
pounds are potentially bioactive and have demonstrated
versatile utility in main group chemistry,10 where phenylse-
leno compounds can be used as valuable synthetic intermedi-
ates.11 A phenylseleno group can be introduced to unsaturated
substrates by means of N-phenylselenophthalimide (N-PSP)
or other phenylseleno reagents, and removal of such a
phenylseleno moiety results in a saturated or unsaturated
functional group in the product.12-16 Lewis and Brønsted
(1) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-
VCH: Weinheim, Germany, 2003.
(2) Li, H.-M.; Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063.
(3) Kantam, M. L.; Laha, S.; Yadav, J.; Sreedhar, B. Tetrahedron Lett.
2006, 47, 6213.
(4) Blay, G.; Fernandez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9,
2601.
(5) (a) Liu, C.; Han, X. Q.; Wang, X.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2004, 126, 3700. (b) Zhang, Z. B.; Wang, X.; Widenhoefer, R. A.
Chem. Commun. 2006, 3717.
(6) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292.
(7) (a) Wang, Y. Q.; Song, J.; Hong, R.; Li, H. M.; Deng, L. J. Am.
Chem. Soc. 2006, 28, 8156. (b) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am.
Chem. Soc. 2007, 129, 1485.
(8) (a) Westermaier, M.; Mayr, H. Org. Lett. 2006, 8, 4791. (b) Trost,
B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
(9) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8, 4939.
(10) (a) Back, T. G. Organoselenium Chemistry-A Practical Approach;
Oxford University Press: Oxford, 1999. (b) Nogueira, C. W.; Zeni, G.;
Rocha, J. B. T. Chem. ReV. 2004, 104, 6255.
(11) (a) Tojino, M.; Otsuka, N.; Fukuyama, T.; Matsubara, H.; Ryu, I.
J. Am. Chem. Soc. 2006, 128, 7712. (b) Clive, D. L. J.; Pham, M. P.; Subedi,
R. J. Am. Chem. Soc. 2007, 129, 2713.
(12) Liotta, D. Acc. Chem. Res. 1984, 17, 28.
10.1021/ol7024795 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/10/2007

acids BF3,17a SnCl4,17b CSA,17c and p-TsOH17c,d have been
known to promote reactions of phenylseleno reagents with
some carbon-carbon unsaturated substrates. Although sulfe-
nylation of indoles has recently been realized by MgBr2-
catalyzed reactions of indoles with N-phenylthiophthalimide
(N-PTP),18 reactions of indoles with organoselenium reagents
have seldom been investigated.19 Herein, we report a novel
and efficient catalytic route to PhSe-functionalized indoles
by catalytic three-component reactions of indoles, N-PSP,
and styrenes.
Table 1. Three-Component Alkylation of Indoles, 2, and
Styrenes
yieldb
(%)
entrya
R1
R2
R3
Ar
product
The reaction of indole (1a), N-PSP (2), and styrene (3a)
was initially carried out with 10 mol % of p-TsOH as catalyst
in CH2Cl2 at 23 °C (eq 1). The three-component reaction
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
82
66
69
68
99
97
88
83
63
99
89
91
95
83
80
82
82
93
81
4-MeC6H4
2-MeC6H4
4-ClC6H4
Ph
4-MeC6H4
2-MeC6H4
4-ClC6H4
2-ClC6H4
Ph
4-MeC6H4
2-MeC6H4
4-ClC6H4
Ph
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
allyl
H
Ph
Ph
Ph
Ph
Et
H
Bn
H
Br
Br
NO2
Ph
proceeded rapidly to afford 3-alkylation product 4a in 80%
isolated yield within 10 min. The catalyst loading varied from
5 to 100 mol % to give 4a in similar yields, but the reaction
did not efficiently proceed with <5 mol % of catalyst. With
5 mol % of p-TsOH as catalyst, the reaction also efficiently
occurred in CH3CN or DCE, while in THF or Et2O, 3-phenyl-
selenoindole (5a) was formed as the major product. Without
a catalyst, the reaction of 1a, 2, and styrene proceeded to
form 5a in 82% yield with styrene unreacted (vide infra).
The methodology was extended to substituted and func-
tionalized indoles (Table 1). The reactions of indoles, 2, and
styrenes gave the desired products 4a-d in 66-82% yields
(entries 1-4), while the reactions of N-methyl and N-
benzylindoles, 2, and styrenes afforded 4e-g and 4j-m in
excellent yields (88-99%, entries 5-7 and 10-13), and only
in the cases using 4- and 2-chlorostyrenes, 4h and 4i were
obtained in good to moderate yields (83 and 63%, entries 8
and 9). From the reactions of functionalized indoles, 2, and
styrene, the desired products 4n-s were produced in 80-
93% yields (entries 14-19), in which allyl, bromo, and nitro
groups can withstand the reaction conditions. Compounds 4
a Conditions: indole, 0.5 mmol; indole/N-PSP/styrene ) 1:1.2:1.5;
p-TsOH, 5 mol %; CH2Cl2, 3 mL; 23 °C, 10 min. b Isolated yields.
1
were characterized by H, 13C{1H} NMR, and HRMS or
elemental analysis, and their molecular structures were
further confirmed by the X-ray single-crystal structure of
4r (Figure 1). In compound 4r, the PhSe and aryl groups
are arranged anti to each other. The three-component
(13) Nicolaou, K. C. Tetrahedron 1981, 37, 4097.
(14) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Org. Chem. 1974, 39,
2133.
(15) Uemura, S.; Fukuzawa, S. I.; Toshimitsu, A. J. Chem. Soc., Chem.
Commun. 1983, 1501.
(16) Woo, S. H. Tetrahedron Lett. 1993, 34, 7587.
(17) (a) Back, T. G.; Collins, S. J. Org. Chem. 1981, 46, 3249. (b)
Chretien, F.; Chapleur, Y. J. Org. Chem. 1988, 53, 3615. (c) Herna´ndez,
R.; Leo´n, E. I.; Salazar, J. A.; Sua´rez, E. J. Chem. Soc., Chem. Commun.
1987, 312. (d) Cossy, J.; Furet, N. Tetrahedron Lett. 1993, 34, 7755.
(18) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R. Org. Lett.
2006, 8, 565.
(19) (a) Crich, D.; Huang, X. H. J. Org. Chem. 1999, 64, 7218. (b) Crich,
D.; Davies, J. W. Tetrahedron Lett. 1989, 30, 4307. (c) Barton, D. H. R.;
Lusinchi, X.; Milliet, P. Tetrahedron 1985, 41, 4727.
Figure 1. Molecular structure of 4r.
5264
Org. Lett., Vol. 9, No. 25, 2007

coupling can also take place at the 2-position of 3-substituted
indoles. Treatment of 3-methylindoles 6a and 6b with 2 and
styrene produced 2-alkylation products 7a and 7b in 66-
68% yields, respectively (Scheme 1). Without a catalyst, the
3-Alkenyl indole 9 and 2 efficiently underwent intramo-
lecular selenation-cyclization, generating ring-closure prod-
ucts 10 (67%) and 11 (24%) (Scheme 3). In a similar fashion,
reaction of 2-alkenyl indole 13 with 2 exclusively afforded
the six-membered ring-closure product 15 in 88% yield. It
was found that intermediate 14 was initially formed during
the reaction by TLC monitoring and then quickly converted
to 15. Thus 14 was isolated in 84% yield after the reaction
was carried out for 10 min, and it was also transformed to
15 in 87% yield (Scheme 3). The selenation-cyclization
products were additionally characterized by 2D NMR
analysis (see the Supporting Information).
Scheme 1. Three-Component Alkylation at the 2-Position of
Indoles
The mechanisms are proposed for formation of the
selenation-alkylation products (Scheme 4). As shown in path
a, the in situ generated cation PhSe+ from the reaction of
catalyst p-TsOH and 2 instantly reacts with styrene 3 to form
cation A12-17 which electrophilically attacks indole 1 at
its 3-position, producing intermediate B, and B releases a
proton to form the product 4. Compounds 7, 10, and 11
are considered to be formed in the same way, and species
C-E may be involved in the formation of 10 and 11
(path b). Compound 15 is presumably formed via a dif-
ferent route (path c). The initially generated intermediate 14
reacts with PhSe+ to form F which further undergoes
intramolecular cyclization to form G instead of sterically
hindered H. A PhSe group is deleted from G to afford 15.
This type of organocatalytic intramolecular cyclization of
indoles is obviously different from those catalyzed by
metals5,20 but similar to those sulfenium ion-promoted
cyclizations.21
three-component reaction did not occur, but the direct
coupling of indoles and 2 afforded 3- and 2-phenylselenoin-
Scheme 2. Noncatalytic Coupling of Indoles and 2
Treatment of 10, 15, 4a, 4e, and 4j with Bu3SnH/AIBN
in toluene at the refluxing temperature for 1.5 h efficiently
produced alkyl-functionalized indoles 12, 16, and 17 in 83-
99% yields (Schemes 3 and 5). Oxidation of 4e with 30%
H2O2 in THF afforded vinylindole 18 and PhSe-functional-
ized vinylindole 19 in 44 and 16% yields, respectively, while
doles 5 and 8, respectively (Scheme 2). In these two-
component coupling reactions, the 2-position of an indole
substrate demonstrated much lower reactivity than its 3-posi-
tion. It should be noted that indole can couple with
phenylselenic anhydride or phenylselenic acid to form
3-phenylselenoindole.19c
Scheme 3. Intramolecular Selenated Alkylation of Indoles
Org. Lett., Vol. 9, No. 25, 2007
5265

Scheme 4. The Proposed Mechanisms
treatment of 4e with m-CPBA in CH2Cl2 exclusively gener-
ated 19 in 44% yield. It is noteworthy that m-CPBA usually
and formation of 19 is a rare example in the oxidation of
phenylseleno derivatives by m-CPBA.22
In conclusion, we have developed a novel and efficient
organocatalytic route to phenylseleno-functionalized indoles
by inter- and intramolecular three-component Friedel-Crafts
alkylations.
Scheme 5. Chemical Removal of a Phenylseleno Group
Acknowledgment. We are grateful to the “Hundred
Talented Program” Funding of CAS for support of this
research.
Supporting Information Available: Experimental pro-
cedures, analytical data, copies of NMR spectra, and X-ray
crystallographic data of 4r. This material is available free
of charge via the Internet at http://pubs.acs.org.
oxidizes PhSe compounds into phenylselenoxide deriva-
tives.15,21 19 can be considered as the intermediate to 18,
OL7024795
(21) Edstrom, E. D.; Livinghouse, T. J. Am. Chem. Soc. 1986, 108,
1334.
(22) Saluzzo, C.; Alvernhe, G.; Anker, D.; Haufe, G. Tetrahedron Lett.
1990, 31, 2127.
(20) (a) Kong, A. D.; Han, X. L.; Lu, X. Y. Org. Lett. 2006, 8, 1339.
(b) Han, X. Q.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801. (c) Liu, C.;
Widenhoefer, R. A. Org. Lett. 2007, 9, 1935.
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