Regiocontrolled synthesis of carbocycle-fused indoles via arylation of siyl enol ethers with o-nitrophenylphenyliodonium fluoride

Article abstract of DOI:10.1021/ol990759j

(Matrix presented) A new, regiocontrolled synthesis of carbocycle-fused indoles has been developed. The two-step procedure involves first the regiospecific arylation of silyl enol ethers with o-nitrophenylphenyliodonium fluoride (1). Reduction of the nitro group on the aromatic ring with TiCl₃ followed by spontaneous condensation of the aniline with the ketone then affords the indole products.

Full text of DOI:10.1021/ol990759j

ORGANIC
LETTERS
1999
Vol. 1, No. 4
673-676
Regiocontrolled Synthesis of
Carbocycle-Fused Indoles via Arylation
of Silyl Enol Ethers with
o-Nitrophenylphenyliodonium Fluoride
Tetsuo Iwama, Vladimir B. Birman, Sergey A. Kozmin, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
V-rawal@uchicago.edu
Received June 23, 1999
ABSTRACT
A new, regiocontrolled synthesis of carbocycle-fused indoles has been developed. The two-step procedure involves first the regiospecific
arylation of silyl enol ethers with o-nitrophenylphenyliodonium fluoride (1). Reduction of the nitro group on the aromatic ring with TiCl3
followed by spontaneous condensation of the aniline with the ketone then affords the indole products.
Indoles are among the most prevalent heterocycles. The
indole nucleus is found in numerous natural products and
constitutes the integral part of several families of alkaloids,
many with significant pharmacological activities.1 Conse-
quently, considerable effort has been directed toward devel-
oping new methods for the construction of the indole unit.2
One of the oldest and yet most widely used methods for
preparing indoles is the Fischer indole synthesis.3 A limitation
of this method, however, is the lack of regioselectivity with
unsymmetrical ketones having two enolizable sites. The
Fischer method produces the indole that arises from the
thermodynamically more stable enehydrazine. The regio-
selective4 synthesis of indoles from such ketones remains
an important and actively pursued problem. In connection
with our interest in the stereoselective synthesis of Aspi-
dosperma alkaloids,5 we have explored methods for the
regiocontrolled synthesis of the indole sector of tabersonine
and have developed a new, two-step synthesis of carbocycle-
fused indoles.
(1) Recent reviews: (a) Herbert, R. B. The Monoterpenoid Indole
Alkaloids, supplement to vol. 25, part 4 of The Chemistry of Heterocyclic
Compounds; Saxton J. E., Ed.; Wiley: Chichester, 1994. (b) Saxton, J. E.
Nat. Prod. Rep. 1997, 559-590. (c) Saxton, J. E. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1998; Vol. 50, Chapter 9. (d)
Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1998; Vol. 51, Chapter 1. (e) Toyota, M.; Ihara, M. Nat. Prod. Rep.
1998, 327-340, and references therein.
(2) (a) Gribble, G. W. Contemp. Org. Chem. 1994, 1, 145-172. (b)
Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996. (c)
Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford, 1996;
Vol. 2, pp 119-206. (d) Do¨pp, H.; Do¨pp, D.; Langer, U.; Gerding, B. In
Methoden der Organischen Chemie; Kreher, R., Ed.; Georg Thieme
Verlag: Stuttgart, 1994; Hetarene I, Teil 2, pp 546-1336, and references
therein.
Our method is based on the direct, regiospecific o-
nitrophenylation of an enol silyl ether (Scheme 1).5-7
Subsequent reduction of the nitro group on aryl ketone 3
followed by spontaneous cyclization affords the indole
(3) (a) Robinson, B. The Fischer Indole Synthesis; Wiley-Interscience:
New York, 1982. (b) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607-
632.
(4) (a) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468-
4475. (b) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791-3792, and references
therein.
(5) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998, 120, 13523-
13524.
10.1021/ol990759j CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/15/1999

On the basis of the work of Beringer et al.,13b the more
electron deficient o-nitrophenyl group was expected to
transfer during the arylation. The reaction conditions for the
o-nitrophenylation were optimized using the TMS ether of
cyclohexanone (Table 1, entry 1).14 A stirred solution of
NPIF (1) (345 mg, 1 mmol) in dry DMSO-CH2Cl2 (1.4-
2.1 mL) was treated dropwise with neat TMS ether 2 (1
mmol) at ca. -40 °C (CO2-MeCN). The mixture was stirred
at this temperature for 2 h and then allowed to warm to room
temperature gradually over 2-3 h. Standard extractive
workup and chromatographic purification yielded the arylated
ketone 3 in 89% yield (Table 1). As expected,13 no
2-phenylcyclohexanone had formed. The use of a polar
solvent was critical for successful arylation. The yield of
the arylated product was considerably lower (53%) when
using the tert-butyldimethylsilyl (TBS) enol ether 2a′ instead
of the TMS ether (entry 2).15 The example in entry 3
illustrates the regiocontrol possible using the present meth-
odology. Treatment of enol silyl ether 2b, obtained from the
kinetic enolate of 2-methylcyclohexanone,8 with NPIF gave
3b in good yield.16 The regiocontrol capability of the
nitrophenylation was further tested through the reaction of
substrate 2c, prepared by the reaction of 2-cyclohexenone
with dimethylcuprate followed by TMSCl.11a Despite the
greater steric crowding at the adjacent carbon, arylation of
2c gave the desired ketone in good yield as essentially a
single diastereomer (entry 4). Arylation of the methoxy-
substituted silyl ether 2e17 provided cyclohexanone 3e in 75%
yield (entry 6).
Scheme 1
products. The regiospecificity of this indole synthesis stems
from the starting silyl enol ethers, which can be easily
prepared in a highly or completely regiocontrolled manner
by, inter alia, (a) kinetic8 or thermodynamic9 enolization of
ketones, (b) Li/NH3 reduction of enones,10 and (c) 1,4-
addition of cuprates to enones.11
The required arylating reagent, o-nitrophenylphenyliodo-
nium fluoride (NPIF, 1),12 was conveniently prepared in two
steps (Scheme 2). The reaction of o-iodonitrobenzene with
Scheme 2
(12) Preparation of NPIF (1). (a) o-Nitrophenylphenyliodonium
Iodide. To a stirred solution of o-iodonitrobenzene (5.0 g, 20 mmol) in
H2SO4 (100 mL) was added K2S2O8 (6.0 g, 22 mmol) in small portions
followed by benzene (25 mL) at room temperature, and the mixture was
stirred vigorously for 1.5 h. The reaction mixture was poured into ice (total
volume 300 mL), and the insoluble material was removed by filtration.
The filtrate was treated with aqueous KI (5 g/20 mL of H2O), giving an
orange precipitate that was filtered and washed thoroughly with H2O (250
mL) followed by a small amount of acetone. The collected solid was dried
over P2O5 under reduced pressure to give 7.95 g (87%) of the iodonium
iodide. This procedure was developed from the method of Beringer et al.
(ref 13a, note the typographical error in their original procedure: o-
iodosonitrobenzene should be replaced with o-iodonitrobenzene). (b)
o-Nitrophenylphenyliodonium Fluoride. To a vigorously stirred solution
of AgF (1.0 g, 7.9 mmol) in H2O (30 mL) was added the iodonium iodide
(3.6 g, 7.9 mmol), and the mixture was stirred for several hours. After
removal of the insoluble material by filtration, the solution was concentrated
below 30 °C under reduced pressure (<5 Torr). The residue was diluted
with 8 mL of MeCN and crystallized at 0 °C to give NPIF (1, 1.80 g first
crop, 0.33 g second crop; total 2.13 g, 78%).
benzene under oxidizing conditions followed by treatment
with aqueous KI gave o-nitrophenylphenyliodonium iodide
as an orange solid.13 The exchange of iodide counterion with
fluoride gave the desired nitrophenylating reagent.
(6) Preparation of indoles via direct arylation of ketone enolates or their
equivalents has been previously investigated. For example, see: (a) Kuehne,
M. E. J. Am. Chem. Soc. 1962, 84, 837-847. (b) Gassman, P. G.;
Van Bergen, T. J. Organic Syntheses; Wiley: New York, 1988; Collect.
Vol. 6, pp 50-59. (c) RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T. J.
Am. Chem. Sco. 1985, 107, 5473-5483. (d) RajanBabu, T. V.; Chenard,
B. L.; Petti, M. A. J. Org. Chem. 1986, 51, 1704-1712.
(7) Phenylation of TMS enol ethers using diphenyl iodonium fluoride
has been reported: Chen, K.; Koser, G. F. J. Org. Chem. 1991, 56, 5764-
5767.
(8) (a) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. G. J. Org.
Chem. 1969, 34, 2324-2336. (b) Lessene, G.; Tripoli, R.; Cazeau, P.; Brian,
C.; Bordeau, M. Tetrahedron Lett. 1999, 40, 4037-4040.
(9) (a) Krafft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24, 1345-
1348. (b) Orban, J.; Turner, J. V.; Twitchin, B. Tetrahedron Lett. 1984,
25, 5099-5102.
(10) (a) Stork, G.; Singh, J. J. Am. Chem. Soc. 1974, 96, 6181-6182.
(b) Brown, P. A.; Jenkins, P. R. J. Chem. Soc., Perkin Trans. 1 1986, 1303-
1309.
(13) (a) Beringer, F. M.; Gindler, E. M.; Rapoport, M.; Taylor, R. J. J.
Am. Chem. Soc. 1959, 81, 351-361. (b) Beringer, F. M.; Forgione, P. S.;
Yudis, M. D. Tetrahedron 1960, 8, 49-63.
(14) General Procedure for Arylation Reaction. To a stirred solution
of NPIF (1) (345 mg, 1 mmol) in dry DMSO-CH2Cl2 (1.4-2.1 mL) was
added TMS ether 2 (1 mmol) dropwise at ca. -40 °C (CO2-MeCN) under
nitrogen. The mixture was stirred for 2 h at this temperature and allowed
to warm to room temperature gradually over 2-3 h. The reaction mixture
was poured into H2O (10 mL), and the whole was extracted with ether (10
mL × 3). The extracts were washed with brine, dried over MgSO4, and
concentrated. The residue was purified by flash column chromatography
on silica gel (EtOAc:hexanes ) 1:30-1:5) to give the aryl ketone (3). Aryl
1
ketones 3 were characterized from H and 13C NMR and IR spectra. See
Supporting Information for the spectral data as well as copies of actual
spectra.
(15) The modest yield for this example stands in contrast with the high
yield obtained for the o-nitrophenylation of a complex intermediate leading
to the natural product tabersonine (ref 5).
(11) (a) Binkley, E. S.; Heathcock, C. H. J. Org. Chem. 1975, 40, 2156-
2160. (b) Dieter, R. K.; Dieter, J. W. J. Chem. Soc., Chem. Commun. 1983,
1378-1380.
(16) Product 3b was obtained as an inseparable 12:1 mixture (by 1H
NMR) of cis-trans isomers.
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Org. Lett., Vol. 1, No. 4, 1999

Table 1. Regiocontrolled Synthesis of Indoles Via Arylation of Silyl Enol Ether Followed by TiCl3 Reduction
In comparison with the examples discussed above, the
TMS ethers of cyclopentanone and its derivatives were less
effective as substrates for the arylation reaction. The reaction
of 2f with NPIF in 1:1 DMSO-CH2Cl2 gave the arylated
cyclopentanone 3f in only moderate yield. The yield of 3f
improved to 56% by carrying out the reaction in 1:1 HMPA-
THF (entry 7, in parentheses). The methylcyclopentanone
derivative 3g was formed in 46% yield as an inseparable
mixture of cis:trans diastereomers (entry 8). Enol TMS ethers
of acyclic ketones, camphor, and cyclohexenone (kinetic
enolate) were poor substrates for this arylation reaction.
Nitrobenzene was the main byproduct in all arylation
reactions. A small amount of the enone corresponding to
the enol ether was also observed in the product mixture,
arising presumably from disproportionation competing with
radical coupling.7
The o-nitrophenyl-substituted ketones (3) were efficiently
converted into the corresponding indoles upon reduction with
TiCl3,18 a reagent that appears to be underutilized for the
reduction of nitro groups (Table 1). This reduction was
readily carried out by dropwise addition of a solution of the
nitrophenyl ketone (3) in acetone at room temperature to a
(17) Ghiron, C.; Piga, E.; Rossi, T.; Tamburini, B.; Thomas, R. J.
Tetrahedron Lett. 1996, 37, 3891-3894.
(18) (a) Ho, T.-L.; Wong, C. M. Synthesis 1974, 45. (b) Moody, C. J.;
Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1 1990, 673-679.
Org. Lett., Vol. 1, No. 4, 1999
675

vigorously stirred two-phase mixture containing aqueous
TiCl3, aqueous NH4OAc, and acetone.19 The reactions
proceeded smoothly, typically going to completion in just
15 min, and afforded the indole products (4) in good to high
yields. In the case of methoxy derivative 4e, an aqueous
solution of TiCl3 was added to a two-phase ammonium
acetate buffer solution of aryl ketone 3e in H2O-acetone in
order to avoid decomposition of the labile product (entry
6). We also utilized the arylation-reductive indolization
sequence for the regoicontrolled synthesis of a cholestene-
fused indole (entry 9). The steroidal enol silyl ether 2h,
prepared regioselectively from 4-cholesten-3-one by the
Birch reduction-silylation sequence,10 was treated with NPIF
to afford the arylated ketone. Direct reduction of the crude
ketone using TiCl3 gave indole 4h as the sole regioisomer,
albeit in low yield.
4c (eq 1).20 The recently developed palladium-catalyzed
annulation between 2-iodoaniline and 3-methylcyclohex-
anone is also reported to give 5 as the major product.21 By
contrast, using the present method, indole 4c can be obtained
as the sole regioisomer. Also worthy of note is the exclusive
formation of cholestene-fused indole 4h, a regioisomer that
is reportedly not formed from cholestan-3-one using the
palladium-catalyzed method.21
In summary, we have developed a new method for the
regiocontrolled synthesis of carbocycle-fused indoles. It is
a two-step procedure involving o-nitrophenylation of silyl
enol ethers using NPIF followed by reduction of the nitro
group with TiCl3, which yields the indole products.
The present method has allowed the synthesis of indoles
that would be difficult to obtain by conventional means. For
example, the Fischer indole synthesis using 3-methylcyclo-
hexanone is reported to afford a mixture of regioisomers,
with tetrahydrocarbazole 5 being formed in preference to
Acknowledgment. This work was supported in part by
the National Institutes of Health (R01-GM-55998). Pfizer
Inc. and Merck Research Laboratories are also thanked for
generous financial assistance.
(19) General Procedure for TiCl3 Reduction. Aqueous TiCl3 can be
purchased from Aldrich. Alternatively, it can be prepared inexpensively
by dissolving TiCl3‚1/3AlCl3 (available from Strem Chemicals, Inc.) in water
(CAUTION! Strong exotherm!) and filtering off the precipitate. The
concentration of the purple solution can be determined by titrating with
0.1 M KBrO3, wherein disappearance of the purple color indicates the
endpoint. To a purple solution of 1.44 M TiCl3 in H2O (0.56 mL, 0.8 mmol
of TiCl3) was added 2.5 M NH4OAc in H2O (1 mL) followed by acetone
(1 mL) at room temperature. The purple color turned dark brown, and the
mixture formed a two-phase system. A solution of a nitro ketone 3 (0.1
mmol) in acetone (1 mL) was added dropwise at room temperature with
vigorous stirring. After 15 min, the reaction mixture was diluted with H2O
(10 mL) and extracted with EtOAc (10 mL × 3). The extracts were washed
with a NaHCO3 aqueous solution followed by brine and then dried over
Na2SO4 and concentrated. The residue was purified by flash column
chromatography on silica gel (EtOAc:hexanes ) 1:60-1:50, containing a
small amount of Et3N) to give the indole product (4).
Supporting Information Available: 1H NMR and 13C
NMR of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL990759J
(20) Stoermer, D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 564-568.
(21) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J. J. Org. Chem. 1997, 62, 2676-2677.
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Org. Lett., Vol. 1, No. 4, 1999