A highly α-regioselective AgOTf-catalyzed nucleophilic substitution of the Baylis-Hillman acetates with indoles

Article abstract of DOI:10.1021/ol070878w

An efficient method for highly α-regioselective nucleophillc substitution of the Baylis-Hillman acetates with Indoles catalyzed by AgOTf in high yields (72-99%) has been developed. Reductive cyclization of the substitution products furnished the azepinoin

Full text of DOI:10.1021/ol070878w

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2525-2528
A Highly
AgOTf-Catalyzed Nucleophilic
r-Regioselective
Substitution of the Baylis−Hillman
Acetates with Indoles
Zahid Shafiq, Li Liu,* Zhe Liu, Dong Wang, and Yong-Jun Chen*
Beijing National Laboratory for Molecular Sciences (BNLMS), Laboratory for
Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100080, China
lliu@iccas.ac.cn; yjchen@iccas.ac.cn
Received April 16, 2007
ABSTRACT
An efficient method for highly
high yields (72
r
-regioselective nucleophilic substitution of the Baylis
−
Hillman acetates with indoles catalyzed by AgOTf in
−
99%) has been developed. Reductive cyclization of the substitution products furnished the azepinoindole derivatives in good
yields (up to 93%).
The Baylis-Hillman (B-H) reaction is one of the most
important C-C bond forming reactions and has received
considerable attention recently.1 The Baylis-Hillman ad-
ducts, which possess versatile functionalities bearing allylic
hydroxyl and Michael acceptor units, have been illustrated
as valuable synthons and starting materials for the synthesis
of heterocycles and many biologically active molecules.2
Regioselective introductions of nucleophiles at either the R-
or γ-position of the Baylis-Hillman adduct (Figure 1) have
become powerful tools in synthetic organic chemistry.1,2 In
most cases, a nucleophilic attack on the Baylis-Hillman
adducts takes place at the γ-carbon via a SN2′ reaction.1-3
More recently, direct nucleophilic substitutions at the R-posi-
tion of the Baylis-Hillman adduct were achieved by means
of a base-promoted SN2′-SN2′ reaction4,5 and through a Pd-
catalyzed coupling reaction.6
The allylic alkylation of indoles with allylic alcohols or
acetates is an important reaction in constructing indolic
(1) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811. (b) Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1997; Vol. 51, pp 201-350.
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Lett. 2005, 46, 5387. (d) Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem.
2004, 69, 555. (e) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem. Commun.
2004, 236. (f) Racker, R.; Doring, K.; Reiser, O. J. Org. Chem. 2000, 65,
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Figure 1.
10.1021/ol070878w CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/23/2007

alkaloids.7 The reaction of indoles with Baylis-Hillman
acetates8 could be catalyzed by indium tribromide to provide
the γ-allylic substitution products.9 However, direct substitu-
tion at the R position of Baylis-Hillman adducts is very
rare.8a Cyclic enones are important starting materials in the
Baylis-Hillman reaction,10 and its B-H adducts could be
applied in the synthesis of heterocycles such as quinolines10f-g
and 2H-indazole derivatives.10h In some Pd-catalyzed reac-
tions, cyclic B-H adducts (Figure 1, b) could favor
R-substitution which was different with acyclic B-H adducts
(Figure 1, a).6a Recently, a silver(I)-catalyzed reaction has
become an important method in organic synthesis in view
of the potential dual functions of Ag(I) as both a Lewis acid11
and a transition metal.12 Herein, we wish to report a highly
R-regioselective reaction of indoles with Baylis-Hillman
acetates derived from cyclic enones catalyzed by AgOTf for
direct nucleophilic substitution.
Initially, the reaction of indole 1 with 2-(acetoxyphenyl-
methyl)-cyclohex-2-enone 2a was investigated by using
palladium catalysts (Scheme 1, Table 1). Under the catalysis
Scheme 1
(3) (a) Basavaiah, D.; Satyanarayana, T. Org. Lett. 2001, 3, 3619. (b)
Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett. 2003, 5, 3803. (c)
Yadav, J. S.; Gupta, M. K.; Pandey, S. K.; Reddy, B. V. S.; Sarma, A. V.
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of Pd(acac)2/PPh3,8a the reaction of N-methylindole (1c)
provided substituted product 2-[(1-methylindolyl)phenyl-
(4) DABCO as promoter: (a) Singh, V.; Yadav, G. P.; Maulik, P. R.;
Batra, S. Tetrahedron 2006, 62, 8731. (b) Lee, K. Y.; Gowrisankar, S.;
Lee, Y. J.; Kim, J. N. Tetrahedron 2006, 62, 8798. (c) Li, J.; Wang, X.;
Zhang, Y. Tetrahedron Lett. 2005, 46, 5233. (d) Du, Y.; Han, X.; Lu, X.
Tetrahedron Lett. 2004, 45, 4967. (e) Chung, Y. M.; Gong, J. H.; Kim, T.
H.; Kim, J. N. Tetrahedron Lett. 2001, 42, 9023.
Table 1. Nucleophilic Substitution of B-H Acetate 2a with
1aa
(5) Phosphine catalysis: (a) Cho, C-W.; Krische, M. J. Angew. Chem.,
Int. Ed. 2004, 43, 6689. (b) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org.
Lett. 2004, 6, 1337.
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2005, 70, 9207. (b) Trost, B. M.; Tsui, H. C.; Toste, F. D. J. Am. Chem.
Soc. 2000, 122, 3534. (c) Roy, O.; Riahi, A.; Henin, F.; Muzart, J.
Tetrahedron 2000, 56, 8133. (d) Nemot, T.; Fukuyama, T.; Yamamoto, E.;
Tamura, S.; Fukuda, T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org.
Lett. 2007, 9, 927.
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(b) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-
Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424. (c) Kimura, M.; Futamata,
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Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793.
(g) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.; Kocovsky,
P. J. Org. Chem. 1999, 64, 2751-2764.
(8) (a) Ma, S.; Yu, S.; Guo, H. J. Org. Chem. 2006, 71, 9865. (b) Ma,
S.-M.; Yu, S.-C. Tetrahedron Lett. 2004, 45, 8419. (c) Ma, S.-M.; Yu, S.-
C.; Peng, Z.-H. Org. Biomol. Chem. 2005, 3, 1933. (d) Ma, S.-M.; Zhang,
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43, 3435.
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Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2005, 46, 639.
(10) (a) Narender, P.; Gangadasu, B.; Ravinder, M.; Srinivas, U.; Swamy,
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Porzelle, A.; Williams, C. M.; Schwartz, B. D.; Gentle, I. R. Synlett 2005,
2923. (c) Luo, S.; Mi, X. L.; Xu, H.; Wang, P. G.; Cheng, J. P. J. Org.
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Lett. 2005, 46, 5387.
entry catalyst
solvent
CH2Cl2
temp time (h) yield (%)b
1
2
3c
4
5
6
7
8
9
PdCl2
reflux
reflux
80 °C
24
24
1
NR
NR
65/30d
Pd(OAc)2 CH2Cl2
Pd(acac)2 HOAc
DABCOe THF/H2O (4:1) rt
FeCl3
Cu (OTf)2 CH2Cl2
Ag OTf
Ag OTf
-
24
48
24
48
6
NR
54
48
80
80
CH2Cl2
reflux
reflux
rt
reflux
reflux
CH2Cl2
CH2Cl2
CH2Cl2
24
NR
a
1a/2a ) 1:1. Catalyst: 10 mol %. b Isolated yield. c N-Methyl indole
d
(1c) was used, with 10 mol % of Pd (acac)2 and 20 mol % of PPh3. 3c/
2a′.
e
DABCO (1.1 equiv).
methyl]-cyclohex-2-enone 3c in 65% yield, together with an
isomerized elimination product of 2a, 2-benzylidene-cyclo-
hex-3-enone 2a′ in 30% yield (entry 3). When DABCO was
(11) For selected examples, see: (a) Momiyama, N.; Yamamoto, H. J.
Am. Chem. Soc. 2004, 126, 5360. (b) Josephohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734. (c) Wei, C.; Li, Z.; Li,
C.-J. Synlett 2004, 1472. (d) Josephohn, N. S.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 4018. (e) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (f) Yanagisawa, A.;
Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,
4723. (g) Yanagisawa, A. In Lewis acids in Organic Synthesis; Yamamoto,
H., Ed.; Wiley-VCH: Weinheim, Gemany, 2000; Vol. 2, Chapter 13.
(12) For examples, see: (a) Bates, R. W.; Satcharoen, V. Chem. Soc.
ReV. 2002, 31, 12. (b) Dias, H. V. R.; Browning, R. G.; Polach, S. A.;
Diyabalanage, H. V. K.; Lovely, C. J. J. Am. Chem. Soc. 2003, 125, 9270.
(c) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43, 4210. (d) Yao, X.; Li,
C.-J. J. Org. Chem. 2005, 70, 5752. (e) Youn, S. W.; Eom, J. I. J. Org.
Chem. 2006, 71, 6705.
2526
Org. Lett., Vol. 9, No. 13, 2007

(entry 4). Fortunately, some Lewis acids were found to
catalyze the reaction of 1a with 2a, and AgOTf exhibited
the best catalytic ability for the nucleophilic substitution in
80% yield of 3a with exclusive R-selection (Table 1, entry
7). No γ-product and isomerized elimination product (2a′)
were detected in the crude reaction mixture. Increasing the
temperature to reflux could shorten the reaction time (entry
7 vs 8). In the absence of the catalyst, the reaction could not
proceed at all (entry 9).
Table 2. Reaction of Indoles 1 with BH Acetates 2 Catalyzed
by AgOTf
To examine the effect of solvent, the reaction of 1a with
2a in the presence of AgOTf (10 mol %) was performed in
toluene, dichloromethane (DCM), 1,2-dichloroethane, and
CH3CN, respectively. The product 3a could be obtained in
35-80% yields. DCM was found to be the best solvent
(Table 1).
Subsequently, various indoles bearing an electron-with-
drawing or electron-donating group in either the 1-, 2-, 4-,
or 5-position of the indole ring (1a-f) were reacted with
B-H acetates (2a-h) to provide the R-substituted products
(3a-l) in good to excellent yields under the optimized
conditions (Scheme 1, Table 2). In all cases, the R-isomer
was obtained as a sole isomer, and no γ-products, isomerized
elimination products, or N-alkylation products were detected
in the reaction mixture. It can be found in Table 2 that when
the R4 group of the B-H acetate was a substituted phenyl
group, the reaction of the B-H acetates 2c-h with 2-meth-
ylindole 1a or 1f could also proceed smoothly to provide
their respective products 3g-l in excellent yields (73-99%)
(Table 2, entries 7-12). If an R4 group was a cyclohexyl
group (2b), the yield of the reaction product (3f) could still
be as high as 92% (entry 6). Furthermore, the B-H acetates
derived from chromone (2f-h) reacted with 2-methyl-4-
nitroindole 1f to generate the R-products 3j-l in excellent
yields (89-99%) (entries 10-12).
Although silver complexes have been used in many
organic reactions as powerful catalysts, to our knowledge,
Ag-catalyzed nucleophilic substitution of allylic compounds
was rare. 13 In cyclic B-H adducts 2, the R-position is close
to the carbonyl oxygen and the coordination of Ag(I) with
both carbonyl groups in the B-H adducts 2 may be
responsible for the highly catalytic ability and regioselectivity
for R-attack by indole nucleophiles. Meanwhile, the isomer-
ization-elimination reaction of the starting material (B-H
acetate) could be avoided.
The corresponding nucleophilic substitution products (3j-
l) of 2-methyl-4-nitroindole (1f) with B-H acetates (2f-h)
could be applied in the synthesis of novel azepinoindoles
via reduction of the nitro group, followed by a cyclization
(Scheme 2). The azepinoindole ring is a frequently encoun-
tered structural moiety in many alkaloids and pharmacologi-
cally relevant compounds.14 When the products 3j-l were
reduced in the presence of 10% Pd/C under a hydrogen
atmosphere at room temperature, azepinoindoles 4a-c were
obtained in good yields (63-93%) (Scheme 2). The reaction
is likely to proceed through the reduction of 3 and an in situ
a
Isolated yield.
used as a promoter, which was the normal method for the
R-substitution of B-H adducts (via SN2′-SN2′), no reaction
was observed after 24 h and starting materials were recovered
(13) Murai, T.; Yamamoto, M.; Kondo, S.; Kato, S. J. Org. Chem. 1993,
58, 7440.
Org. Lett., Vol. 9, No. 13, 2007
2527

products in good to excellent yields. An inert atmosphere
and strict anhydrous conditions were not required. Moreover,
the reaction products of the B-H acetates with 4-NO2-indole
derivatives could be applied in the synthesis of novel
azepino-[4, 3, 2-cd]-indoles via a one-pot reduction of a nitro
group, followed by an in situ aza-Michael addition.
Scheme 2
Acknowledgment. We thank The National Natural Sci-
ence Foundation of China and The Chinese Academy of
Sciences for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of the B-H acetates (2a-
h) and the products (3a-l and 4a-c). This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070878W
(14) (a) Matthews, J. M.; Greco, M. N.; Hecker, L. R.; Hoekstra, W. J.;
Andrade-Gordon, P.; de Garavilla, L.; Demarest, K. T.; Ericson, E.; Gunnet,
J. W.; Hageman, W.; Look, R.; Moore, J. B.; Maryanoff, B. E. Bioorg.
Med. Chem. Lett. 2003, 13, 753. (b) Hester, J. B. J. Org. Chem. 1967, 32,
4095. (c) Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K.
A.; Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang,
C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese, C.
R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L.-Z.; Calvert, A. H.;
Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber, S. E.; Hostomsky,
Z. J. Med. Chem. 2002, 45, 4961.
aza-Michael addition, followed by the cleavage of a hemi-
aminal in one pot to provide the azepino-[4, 3, 2-cd]-indoles
4.10f
In conclusion, a mild and efficient direct nucleophilic
substitution of the B-H acetates derived from cyclic enones
with indoles was developed by using 10 mol % of AgOTf
as a catalyst. The reaction provided highly R-regioselective
2528
Org. Lett., Vol. 9, No. 13, 2007