Catalytic regioselective synthesis of structurally diverse indene derivatives from N-benzylic sulfonamides and disubstituted alkynes

Article abstract of DOI:10.1021/ol101524w

An unprecedented protocol has been developed for the regioselective synthesis of structurally diverse indene derivatives from readily accessible N-benzylic sulfonamides and disubstituted alkynes through FeCl ₃-catalyzed cleavage of sp³ carbon-nitrogen bonds to generate benzyl cation intermediates. In the presence of 10 mol % of FeCl ₃, a broad range of N-benzylic sulfonamides smoothly react with internal alkynes, alkynylcarbonyl compounds, alkynyl chalcogenides, or alkynyl halides to afford various functionalized indene derivatives with extremely high regioselectivity.

Full text of DOI:10.1021/ol101524w

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3832-3835
Catalytic Regioselective Synthesis of
Structurally Diverse Indene Derivatives
from N-Benzylic Sulfonamides and
Disubstituted Alkynes
Cong-Rong Liu, Fu-Lai Yang, Yi-Zhou Jin, Xian-Tao Ma, Dao-Juan Cheng, Nan Li,
and Shi-Kai Tian*
Department of Chemistry, UniVersity of Science and Technology of China, Hefei,
Anhui 230026, China
tiansk@ustc.edu.cn
Received July 2, 2010
ABSTRACT
An unprecedented protocol has been developed for the regioselective synthesis of structurally diverse indene derivatives from readily accessible
N-benzylic sulfonamides and disubstituted alkynes through FeCl3-catalyzed cleavage of sp3 carbon-nitrogen bonds to generate benzyl cation
intermediates. In the presence of 10 mol % of FeCl3, a broad range of N-benzylic sulfonamides smoothly react with internal alkynes, alkynylcarbonyl
compounds, alkynyl chalcogenides, or alkynyl halides to afford various functionalized indene derivatives with extremely high regioselectivity.
The traditional cleavage of carbon-halogen bonds under
acidic conditions has been widely applied to the formation
of carbon-carbon bonds in chemical synthesis (e.g., the
Friedel-Crafts reaction). Nevertheless, strongly acidic hy-
drogen halides are inevitably generated as byproducts in the
reaction and are able to promote undesired side reactions
such as elimination and overalkylation.1 In this regard, the
acid-catalyzed cleavage of carbon-nitrogen bonds offers
opportunities to avoid such problems and consequently to
enhance reaction selectivity and efficiency. The employment
of N-sulfonyl groups in combination with either Brønsted2
or Lewis acids3 has recently emerged as a useful strategy to
cleave the carbon-nitrogen bonds of benzylic primary
amines to generate benzyl cations together with primary
sulfonamides as byproducts.
In the course of exploring the synthetic applications of
carbon-nitrogen bond cleavage,2d,3c,d,4 we utilized this
approach to generate benzyl cation intermediates in the
presence of carbon-carbon triple bonds to construct car-
bocycles. To our great delight, the reaction of N-benzylic
sulfonamides with alkynes under acidic conditions afforded
structurally diverse indene derivatives with extremely high
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C.-F.; Tian, S.-K. Org. Lett. 2009, 11, 2543. (e) He, Q.-L.; Sun, F.-L.; Zheng,
X.-J.; You, S.-L. Synlett 2009, 1111. (f) Sun, F.-L.; Zheng, X.-J.; Gu, Q.;
He, Q.-L.; You, S.-L. Eur. J. Org. Chem. 2010, 47
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Yang, C.-F.; Tian, S.-K. Chem. Commun. 2008, 1249. (d) Liu, C.-R.; Li,
(1) For a review, see: Olah, G. A.; Krishnamurti, R.; Surya, G. K. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
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5018
.
.
10.1021/ol101524w  2010 American Chemical Society
Published on Web 08/04/2010

regioselectivity. While recent years have witnessed a number
of reports on the construction of the indene ring system5,6
that is present in many biologically relevant molecules,7
chemical catalysts,8 and materials,9 these methods require
expensive reagents/catalysts and/or lengthy synthetic se-
quences and introduce very limited functional groups into
the indene ring system in a direct fashion. Herein, we wish
to report an unprecedented protocol for the regioselective
synthesis of various functionalized indene derivatives from
readily accessible N-benzylic sulfonamides and disubstituted
alkynes in the presence of an inexpensive and environmen-
tally benign iron Lewis acid catalyst.10
Gratifyingly, the yield was increased to 66% when the
reaction temperature was elevated to 80 °C despite the fact
that product 3a was partially consumed through its alkylation
with sulfonamide 1a (Table 1, entry 1).11,12 In addition, a
Table 1. FeCl3-Catalyzed Regioselective Synthesis of Indene
Derivatives from Sulfonamide 1a and Disubstituted Alkynesa
A number of Brønsted and Lewis acids (10 mol %) were
evaluated in the model reaction of N-(p-toluenesulfonyl)-
benzhydrylamine (1a) with diphenylacetylene (2a) in ni-
tromethane at room temperature for 24 h. While almost no
desired reaction took place in the presence of TsOH, H2SO4,
HCl, ZnCl2, CuCl2, Pd(OAc)2, AlCl3, or Bi2(SO4)3, the use
of FeCl3 resulted in the formation of 1,2,3-triphenyl-1H-
indene (3a) in 20% yield. The efforts to enhance yield proved
fruitless by replacing nitromethane with acetonitrile, dichlo-
romethane, acetone, ethyl acetate, or 1,2-dichloroethane.
entry
2
R1
R2
product time/h yieldb/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a Ph
2b 4-MeOC6H4 Ph
Ph
3a
3b
3c
3d
3e
3f
12
5
66
75
53
60
74
83
66
69
43
58
72
61
66
72
2c Ph
2d Ph
2e Ph
2f Ph
2g Ph
2h Ph
2i SPh
2j SePh
2k Br
2l Br
2m Cl
4-O2NC6H4
n-Pr
24
10
24
24
24
24
3
COOEt
COOH
COPh
COMe
Ph
3g
3h
3i
(5) For recent examples on indene synthesis via bimolecular cyclization,
see: (a) Wu, L.; Shi, M.; Li, Y. Chem.sEur. J. 2010, 16, 5163. (b) Sun,
Z.-M.; Chen, S.-P.; Zhao, P. Chem.sEur. J. 2010, 16, 2619. (c) Wang, S.;
Zhu, Y.; Wang, Y.; Lu, P. Org. Lett. 2009, 11, 2615. (d) Zhang, X.; Teo,
W. T.; Chan, P. W. H. Org. Lett. 2009, 11, 4990. (e) Zhou, F.; Yang, M.;
Lu, X. Org. Lett. 2009, 11, 1405. (f) Fukutani, T.; Umeda, N.; Hirano, K.;
Satoh, T.; Miura, M. Chem. Commun. 2009, 5141. (g) Park, E. J.; Kim,
S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 17268. (h) Chen, W.; Cao,
J.; Huang, X. Org. Lett. 2008, 10, 5537. (i) Miyamoto, M.; Harada, Y.;
Tobisu, M.; Chatani, N. Org. Lett. 2008, 10, 2975. (j) Liu, C.-C.; Korivi,
R. P.; Cheng, C.-H. Chem.sEur. J. 2008, 14, 9503. (k) Deng, R.; Sun, L.;
Li, Z. Org. Lett. 2007, 9, 5207. (l) Basavaiah, D.; Reddy, K. R. Org. Lett.
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Ph
Ph
3j
6
3k
3l
3m
3n
4
n-Bu
Ph
24
12
6
2n
I
Ph
a Reaction conditions: sulfonamide 1a (0.20 mmol), alkyne 2 (0.24
mmol), FeCl3 (10 mol %), nitromethane (2.0 mL), 80 °C. b Isolated yield.
gram-scale synthesis of indene derivative 3a (2.34 g, 68%
yield) was successfully performed according to this protocol.
In the presence of 10 mol % of FeCl3, the reaction of
sulfonamide 1a with a diphenylacetylene bearing either an
electron-donating or an electron-withdrawing group pro-
ceeded smoothly to afford the corresponding indene deriva-
tive with greater than 99:1 regioselectivity (Table 1, entries
2 and 3).13 Subsequently, an alkyl, an alkoxycarbonyl, a
carboxyl, and an acyl group were introduced exclusively into
the C-2 positions of indene derivatives by employing the
corresponding functionalized disubstituted alkynes (Table 1,
entries 4-8). Moreover, a range of alkynyl chalcogenides
and alkynyl halides served as suitable substrates to react with
sulfonamide 1a and consequently, provided a convenient
access to the indene derivatives bearing heretoatoms such
as sulfur, selenium, bromine, chlorine, and iodine at the C-3
Chem. 2007, 72, 251
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see :(a) Dai, L.-Z.; Shi, M. Chem.sEur. J. 2010, 16, 2496. (b) Kurouchi,
H.; Sugimoto, H.; Otani, Y.; Ohwada, T. J. Am. Chem. Soc. 2010, 132,
807. (c) Yang, S.; Li, Z.; Jian, X.; He, C. Angew. Chem., Int. Ed. 2009, 48,
3999. (d) Zhu, Z.-B.; Shi, M. Org. Lett. 2009, 11, 5278. (e) Khan, Z. A.;
Wirth, T. Org. Lett. 2009, 11, 229. (f) Womack, G. B.; Angeles, J. G.;
Fanelli, V. E.; Indradas, B.; Snowden, R. L.; Sonnay, P. J. Org. Chem.
2009, 74, 5738. (g) Tobisu, M.; Nakai, H.; Chatani, N. J. Org. Chem. 2009,
74, 5471. (h) Ye, S.; Gao, K.; Zhou, H.; Yang, X.; Wu, J. Chem. Commun.
2009, 5406. (i) Zhang, X.-M.; Tu, Y.-Q.; Jiang, Y.-J.; Zhang, Y.-Q.; Fan,
C.-A.; Zhang, F.-M. Chem. Commun. 2009, 4726. (j) Zhou, H.; Xie, Y.;
Ren, L.; Wang, K. AdV. Synth. Catal. 2009, 351, 1289. (k) Li, C.; Zeng,
Y.; Wang, J. Tetrahedron Lett. 2009, 50, 2956. (l) Wang, J.; Zhang, L.;
Jing, Y.; Huang, W.; Zhou, X. Tetrahedron Lett. 2009, 50, 4978. (m) Hu,
B.; Xing, S.; Wang, Z. Org. Lett. 2008, 10, 5481. (n) Zhou, X.; Zhang, H.;
Xie, X.; Li, Y. J. Org. Chem. 2008, 73, 3958. (o) Zhu, Z.-B.; Shi, M.
Chem.sEur. J. 2008, 14, 10219. (p) Sanz, R.; Miguel, D.; Rodr´ıguez, F.
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L.-B.; Liang, Y.-M. Org. Biomol. Chem. 2008, 6, 1040. (r) Guo, L.-N.;
Duan, X.-H.; Hu, J.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Eur. J. Org. Chem.
2008, 1418. (s) Yadav, V. K.; Kumar, N. V.; Parvez, M. Chem. Commun.
2007, 2281. (t) Tsukamoto, H.; Ueno, T.; Kondo, Y. Org. Lett. 2007, 9,
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117. (v) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J.
(11) The corresponding monoalkylation product was obtained in 19%
Org. Chem. 2007, 72, 1538
.
yield on the basis of sulfonamide 1a. It is noteworthy that no other byproduct
1
(7) For reviews, see: (a) Huffman, J. W.; Padgett, L. W. Curr. Med.
Chem. 2005, 12, 1395. (b) Gao, H.; Katzenellenbogen, J. A.; Garg, R.;
Hansch, C. Chem. ReV. 1999, 99, 723.
was detected by H NMR analysis of the crude product.
(12) The yield was not further improved at 80 °C when FeCl3 was
replaced with the previously examined catalysts and a few other iron salts.
Catalyst (yield): TsOH (62%), ZnCl2 (40%), CuCl2 (28%), Pd(OAc)2 (4%),
AlCl3 (3%), Bi2(SO4)3 (57%), BiCl3 (20%), SnCl4·5H2O (9%), FeCl3·6H2O
(4%), Fe2(SO4)3·5H2O (7%), Fe(NO3)3·9H2O (8%), FeCl2·4H2O (0%), and
(8) For reviews, see: (a) Wang, B. Coord. Chem. ReV. 2006, 250, 242.
(b) Alt, H. G.; Ko¨ppl, A. Chem. ReV. 2000, 100, 1205.
(9) For examples, see: (a) Barbera´, J.; Rakitin, O. A.; Ros, M. B.;
Torroba, T. Angew. Chem., Int. Ed. 1998, 37, 296. (b) Yang, J.; Lakshmi-
kantham, M. V.; Cava, M. P.; Lorcy, D.; Bethelot, J. R. J. Org. Chem.
2000, 65, 6739.
FeSO4·7H2O (0%)
.
1
(13) No regioisomer was detected by H and 13C NMR analysis of the
CH group at the C-1 position of an indene derivative. The product
regiochemistry was assigned by 2D NOSEY analysis and/or by analogy.
For details, see the Supporting Information.
(10) For a review on the iron Lewis acid catalysis, see: Bolm, C.; Legros,
J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217.
Org. Lett., Vol. 12, No. 17, 2010
3833

positions (Table 1, entries 9-14).14 It is noteworthy that no
rearrangement was observed with the carbon-carbon double
bonds under the reaction conditions, and the regioselective
introduction of such diverse functional groups greatly
facilitates the synthetic elaboration of indene derivatives.
A broad range of N-benzylic sulfonamides were found to
react with disubstituted alkynes in the presence of 10 mol
% of FeCl3 to yield structurally diverse indene derivatives
(Table 2). Notably, the phenyl group rather than the
4-chlorophenyl group in unsymmetric N-bisbenzylic sulf-
onamide 1b was found to form a new carbon-carbon bond
with a disubstituted alkyne in the reaction despite the fact
that a similar carbon-carbon bond-forming reaction occurred
with one of the two 4-chlorophenyl groups in symmetric
N-bisbenzylic sulfonamide 1c (Table 2, entries 1-3). This
protocol proved useful for the construction of indene-
containing polycarbocycles such as 3r-t (Table 2, entries
4-6). Moreover, the FeCl3-catalyzed indene synthesis pro-
ceeded smoothly with a wide variety of N-monobenzylic
sulfonamides and significantly, heteroatoms such as chlorine,
bromine, and oxygen were successfully introduced into the
C-5, C-6, and C-7 positions of indene derivatives (Table 2,
entries 7-16).
Table 2. FeCl3-Catalyzed Regioselective Synthesis of Indene
Derivatives from N-Benzylic Sulfonamides and Disubstituted
Alkynesa
The reaction of optically active sulfonamide (R)-1e (95%
ee) with alkyne 2a in the presence of 10 mol % of FeCl3
afforded indene derivative 3u in nearly racemic form (1%
ee). This result suggests that benzyl cation 4 is generated
from N-benzylic sulfonamide 1 through FeCl3-catalyzed sp3
carbon-nitrogen bond cleavage (Scheme 1).2d,3d The regi-
Scheme 1. Proposed Reaction Pathway
oselective attack of disubstituted alkyne 2 to benzyl cation
4 results in the formation of vinyl cation 5,15 which undergoes
cyclization and subsequent aromatization to afford indene
derivative 3.16 The formation of vinyl cation 5 was substantially
supported by the extremely high regioselectivity exhibited in
the reaction of N-benzylic sulfonamide 1 with disubstituted
alkyne 2, in which the R1 group is more capable of stabilizing
a positive charge relative to the R2 group. Moreover, this
mechanism accounts for the formation of alkyne 7, rather than
indene derivative 3ae, in the FeCl3-catalyzed reaction of
sulfonamide 1a with silylated alkyne 2o, during which vinyl
cation intermediate 5a is additionally stabilized by the ꢀ-trim-
ethylsilyl group that prefers to be eliminated to form a
carbon-carbon triple bond (Scheme 2).
(14) No indene derivative was obtained from terminal alkynes and
N-benzylic sulfonamides under similar reaction conditions.
(15) For reviews on vinyl carbocations, see: (a) Stang, P. J.; Rappopoat,
Z.; Hanack, M.; Subramanian, L. R. Vinyl Cations; Academic Press: New
York, 1979. (b) Dicoordinated Carbocations; Rappoport, Z., Stang, P. J.,
Eds; Wiley and Sons: Chichester, 1997.
a Reaction conditions: sulfonamide 1 (0.20 mmol), alkyne 2 (0.24 mmol),
FeCl3 (10 mol %), nitromethane (2.0 mL), 80 °C. b Isolated yield.
c 4-Chloro-1-methyl-2,3-diphenyl-1H-indene (3ab′) was obtained in 26%
yield as a minor regioisomer.
(16) For examples on the reaction of aromatic systems with vinyl cations,
see: (a) Stang, P. J.; Anderson, A. G. Tetrahedron Lett. 1977, 17, 1485. (b)
Stang, P. J.; Anderson, A. G. J. Am. Chem. Soc. 1978, 100, 1520.
3834
Org. Lett., Vol. 12, No. 17, 2010

internal alkynes, alkynylcarbonyl compounds, alkynyl chal-
cogenides, or alkynyl halides to afford various functionalized
indene derivatives with extremely high regioselectivity. The
regioselective introduction of diverse functional groups
greatly facilitates the synthetic elaboration of indene deriva-
tives for the discovery of new pharmaceutical agents and
chemical catalysts. Current efforts are directed toward further
methodological refinement and synthetic applications.
Scheme 2
.
Reaction of Sulfonamide 1a with Silylated Alkyne
2o
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (20972147 and 20732006), the National Basic Re-
search Program of China (973 Program 2010CB833300), the
Chinese Academy of Sciences, and the Graduate Innovation
Fund of USTC (C.-R. L.). We thank Professor Peter Stang
(University of Utah) for helpful discussions.
In summary, we have developed an unprecedented protocol
for the regioselective synthesis of structurally diverse indene
derivatives from readily accessible N-benzylic sulfonamides
and disubstituted alkynes through FeCl3-catalyzed cleavage
of sp3 carbon-nitrogen bonds to generate benzyl cation
intermediates. In the presence of 10 mol % of FeCl3, a broad
range of N-benzylic sulfonamides smoothly react with
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL101524W
Org. Lett., Vol. 12, No. 17, 2010
3835