Novel synthesis of 2-aryl and 2,3-disubstituted indoles by modified double elimination protocol

Article abstract of DOI:10.1021/ol051826e

(Chemical Equation Presented) Syntheses of 2-aryl and 2,3-substituted indoles were realized by modified double elimination protocol. Under basic conditions, vinyl sulfones derived from the reaction of 2-aminobenzyl sulfone with benzaldehydes underwent cyclization and alkylation followed by elimination of sulfinic acid to afford 2,3-substituted indoles.

Full text of DOI:10.1021/ol051826e

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4641-4643
Novel Synthesis of 2-Aryl and
2,3-Disubstituted Indoles by Modified
Double Elimination Protocol
Govindarajulu Babu, Akihiro Orita, and Junzo Otera*
Department of Applied Chemistry, Okayama UniVersity of Science, Ridai-cho,
Okayama 700-0005, Japan
otera@high.ous.ac.jp
Received July 31, 2005
ABSTRACT
Syntheses of 2-aryl and 2,3-substituted indoles were realized by modified double elimination protocol. Under basic conditions, vinyl sulfones
derived from the reaction of 2-aminobenzyl sulfone with benzaldehydes underwent cyclization and alkylation followed by elimination of sulfinic
acid to afford 2,3-substituted indoles.
The indole nucleus is widely prevalent in many biologically
active natural and unnatural products.1 Numerous methods
have been reported in the literature for the construction of
the indole skeleton.2 Apart from classical methods such as
Fischer, Reissert, and Madelung protocols,2a,3-5 many transi-
tion metal-assisted intermolecular annulation6 and intramo-
lecular cyclization7 methods have been developed in the last
two decades which provide indole derivatives efficiently and
with different functional group compatibility. We have long
been involved in the project on synthesis of polyenes and
acetylenes by taking advantage of the double elimination
reactions of â-substituted sulfones in which vinyl sulfones
are readily generated as intermediates (Scheme 1).8 In this
context, we postulated that incorporation of an amino group
to the ortho position of arylvinyl sulfones would lead to a
(1) (a) Mckay, M. J.; Carroll, A. R.; Quinn, R. J.; Hooper, J. N. A. J.
Nat. Prod. 2002, 65, 595. (b) Verpoorte, R. Alkaloids 1998, 397. (c)
Sundberg, R. J. Prog. Heterocycl. Chem. 1989, 1, 111. (d) Saxon, J. E.
Nat. Prod. Rep. 1986, 3, 357.
(2) For reviews, see: (a) Sundberg, R. J. Indoles. In Best Synthetic
Methods; Academic Press; San Diego, CA, 1996. (b) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045.
(3) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry; Pyrroles
and their Benzoderivatives: Synthesis and Applications, Vol. 4; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, UK, 1984; p 313.
(4) For solid-phase synthesis see: (a) Ohno, H.; Tanaka, H.; Takahashi,
T. Synlett 2005, 1191. (b) Mun, H. S.; Ham, W.-H.; Jeong, J.-H. J. Comb.
Chem. 2005, 7, 130.
(5) For Fischer indole synthesis in ionic liquid see: Calderon M. R.;
Tambyrajah, V.; Jenkins, P. R.; Davies, D. L.; Abbott, A. P. Chem. Commun.
2004, 158.
(6) (a) Hopkins, C. R.; Collar, N. Tetrahedron Lett. 2004, 45, 8631. (b)
Hiroya, K.; Matsumoto, S.; Sakamoto, T. Org. Lett. 2004, 6, 2953. (c) Shen,
M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, V.; Senanayake,
C. H. Org. Lett. 2004, 6, 4129.
(7) For representative recent papers: (a) Alfonsi, M.; Arcadi, A.; Aschi,
M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265. (b) Shimada,
T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (c)
Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (d) Pal,
M.; Subramanian, V.; Batchu, V. R.; Dager, I. Synlett 2004, 1965. (e) Shen,
M.; Li, B. Z.; Hossain, A.; Roshangar, F.; Farina, V.; Senanayake, C. H.
Org. Lett. 2004, 6, 4129.
(8) (a) Orita, A.; Yamashita, Y.; Toh, A.; Otera, J. Angew. Chem., Int.
Ed. Engl. 1997, 36, 779. (b) Orita, A.; Yoshioka, N.; Struwe, P.; Braier,
A.; Beckmann, A.; Otera, J. Chem. Eur. J. 1999, 5, 1355. (c) Orita, A.;
Alonso, E.; Yaruva, J.; Otera, J. Synlett 2000, 1333. (d) Orita, A.; Hasegawa,
D.; Nakano, T.; Otera, J. Chem. Eur. J. 2002, 8, 2000. (e) Ye, F.; Orita,
A.; Doumoto, A.; Otera, J. Tetrahedron 2003, 59, 5635. (f) Orita, A.;
Miyamoto, K.; Nakashima, M.; Ye, F.; Otera, J. AdV. Synth. Catal. 2004,
346, 767.
10.1021/ol051826e CCC: $30.25
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Published on Web 09/21/2005

vinyl sulfone 3a. The cleavage of the amino protecting group
with potassium carbonate was accompanied by spontaneous
cyclization to afford 2-phenyl indole 4a in excellent yield.
The reaction proceeded well with other aromatic aldehydes
in good to moderate yields, thus providing a general method
to synthesize 2-aryl indoles.
Scheme 1
Next, we turned our attention to 2,3-disubstituted indoles
through one-pot incorporation of a substituent at the 3-posi-
tion. The synthetic route for requisite o-amino vinyl sulfone
10 is depicted in Scheme 4. The N-methyl group is the
new protocol for arylindole synthesis (Scheme 2). To our
knowledge, no such cyclization mode has been exploited
although the endo-mode cyclization of sulfonylallenes to
Scheme 4
Scheme 2
construct nitrogen heterocycles9 and intramolecular addition
of amines to vinylsulfoxides leading to isoquinoline deriva-
tives10 are known. Furthermore, it is of practical use that
the double elimination reaction is conducted by an orga-
noalkali metal promoter while many intramolecular cycliza-
tions so far known have recourse to transition metal catalysts,
which are occasionally toxic.11 In this letter, we wish to report
a new strategy for synthesis of indoles consisting of two one-
pot procedures for preparing o-amino vinyl sulfone and
subsequent Michael addition of in situ-generated amino
anion.12
a One isomer (geometry not determined).
protection of choice because this group can survive under
the double elimination conditions and, more preferably, there
are many biologically important 1-methylindoles. The key
sulfone 9 was prepared straightforwardly from commercially
available N-methyl anthranillic acid methyl ester 5. Then, 9
was converted to vinyl sulfone 10 by a one-pot sequence of
reactions with benzaldehyde, diethyl chlorophosphate, and
t-BuOK followed by cleavage of the BOC group by 12 N
HCl/EtOAc. Remarkably, these four sequential reactions
gave rise to a 92% overall yield. Treatment of vinyl sulfone
10 with lithium hexamethyldisilazide (LHMDS) and subse-
quent trapping of the carbanion generated after the Michael-
type cyclization with methyl iodide afforded 1,3-dimethyl-
2-phenyl indole 11a in good yield (Table 1). The reaction
went smoothly with many electrophiles as summarized in
the table. In addition to simple alkyl and allyl iodides,
First, we examined the synthesis of 2-phenylindole starting
from sulfone 2 (Scheme 3). The anion of benzyl sulfone 2
Scheme 3
(9) Mukai, C.; Kobayashi, M.; Kubota, S.; Takahashi, Y.; Kitagaki, S.
J. Org. Chem. 2004, 69, 2128.
(10) Pyne, G. S. Tetrahedron Lett. 1987, 28, 4737.
(11) Indole synthesis with the aid of lithium reagents: (a) Miyagi, T.;
Hari, Y.; Aoyama, T. Tetrahedron Lett. 2004, 45, 6303. (b) Coleman, M.
C.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054.
a One isomer (geometry not determined).
(12) R-Amino benzyl sulfones were converted to the corresponding Schiff
bases, whose benzylic anions underwent intramolcular addition to the Cd
N bond at the ortho position to afford 2-arylindoles: Wojciechowski, K.;
Makosza, M. Bull. Soc. Chim. Belg. 1986, 95, 671.
reacted with benzaldehyde at -78 °C, and the trapping of
the resulting aldolate with diethyl chlorophosphate followed
by the elimination of the phosphate with t-BuOK provided
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Org. Lett., Vol. 7, No. 21, 2005

modified double elimination protocol. Upon treatment of the
amino anion generated from 12 with LHMDS in the presence
of chloroacetamide 13,14 the intramolecular Michael-type
addition and in situ alkylation of the resulting carbanion
occurred smoothly to provide compound 14 in good yield.15
In conclusion we have shown a novel route to synthesize
indole derivatives from easily accessible sulfones by a
sequence of two one-pot procedures. The overall yields are
high, in general, and the products are free from the residues
of transition metal catalysts, offering a practical means for
the indole synthesis. Efforts to synthesize other heterocycles
are currently in progress.
Table 1. Synthesis of 2,3-Disubstituted Indoles
yield
electrophile
MeI (3 equiv)
R
product (%)a
CH3
11a
11b
11c
11d
11e
11f
82
86
84
84
81
86
85
C2H5I (4 equiv)
C3H7I (4 equiv)
C2H5
C3H7
Supporting Information Available: Experimental details
and characterizaton data. This material is available free of
charge via the Internet at http://pubs.acs.org.
allyl iodide (4 equiv)
BrCH2CO2C2H5 (4 equiv)
CH2CHdCH2
CH2CO2C2H5
ClCH2CON(C2H5)2 (4 equiv) CH2CON(C2H5)2
benzoyl chlorideb (5 equiv)
COPh
11g
OL051826E
a Isolated yield. b Reagents and conditions: (i) LHMDS (1.5 equiv), 0
°C, 1 h to room temperature, 10 min, (ii) PhCOCl (5 equiv), rt, 1 h, (iii)
LHMDS (5 equiv), rt, 1 h.
(13) Kozikowski, A. P.; Ma, D.; Brewer, J.; Sun, S.; Costa, E.; Romeo,
E.; Guidotti, A. J. Med. Chem. 1993, 36, 2908.
(14) Seguin H.; Gardette, D.; Moreau, M. F.; Madelmont, J. C.; Gramai,
J. C. Synth. Commun. 1998, 28, 4257.
(15) Synthesis of 12: BuLi (1.33 M in hexane, 1.45 mL, 1.93 mmol)
was added to a THF solution (20 mL) of sulfone 9 (0.636 g, 1.76 mmol)
at -78 °C, and the mixture was stirred for 30 min. 4-Chlorobenzaldehyde
(0.296 g, 2.11 mmol) in THF (8 mL) was added dropwise at this
temperature. After an additional 1 h, ClP(O)(OEt)2 (0.305 mL, 2.11 mmol)
was added at -78 °C and the mixture was stirred at room temperature for
2 h. Potassium tert-butoxide (0.645 g, 5.28 mmol) was added at 0 °C. After
the mixture had been stirred at the same temperature for 1 h, the solvent
was evaporated and the residue was dissolved in a premixed solution of
ethyl acetate (29.4 mL)/12 M HCl (12.6 mL) and stirred at room temperature
for 2 h. The reaction mixture was neutralized with solid NaHCO3, extracted
with ethyl acetate, dried over MgSO4, and filtered. The solvent was
evaporated and the residue was chromatographed (2.5:7.5 ethyl acetate/
hexane) to give 0.614 g of 12 (91%) as a yellow solid: 1H NMR (500
MHz, CDCl3) δ 7.99 (s, 1H), 7.65 (dd, 2H, J ) 8.5, 1.5 Hz), 7.57 (m, 1H),
7.42 (t, 2H, J ) 8.5 Hz), 7.28 (m, 1H), 7.18 (d, 2H, J ) 8.5 Hz), 7.10 (d,
2H, J ) 8.5 Hz), 6.58 (d, 1H, J ) 8.0 Hz), 6.55 (dt, 1H, J ) 7.0, 1.0 Hz),
alkylation reagents with an ester or amide function were
employable as well. It is to be noted that acylation also works
smoothly because 3-acyl derivatives constitute an important
class of the indole derivatives.
To exemplify the usefulness of the present protocol, we
have chosen compound 14, which is one of the better ligands
for the antineophonic mitochondrial DBI receptor complex13
(Scheme 5). Thus, the vinyl sulfone 12 was synthesized
starting from 9 and 4-chlorobenzaldehyde according to our
6.47 (dd, 1H, J ) 7.0, 1.0 Hz), 3.97 (br, 1H), 2.57 (d, 3H, J ) 5.0 Hz); 13
C
Scheme 5
NMR (125 MHz, CDCl3) δ 147.9, 139.0, 138.2, 138.0, 136.5, 133.3, 131.4,
131.2, 131.1, 131.0, 128.9, 128.8, 128.6, 116.8, 115.0, 110.4, 30.4. Synthesis
of 14:13 A 50 mL flask was charged with 12 (0.306 g, 0.79 mmol) in THF
(15 mL) and cooled to 0 °C. LHMDS (1 M in THF, 1.20 mL, 1.19 mmol)
was added slowly. After the mixture had been stirred at 0 °C for 1 h, and
then at room temperature for 10 min, 13 (0.566 g, 3.18 mmol) was added.
After the mixture had been stirred at room temperature for 1 h, the reaction
was quenched by the addition of aqueous NH4Cl and extracted with ethyl
acetate. The extract was dried over MgSO4 and filtered. The solvent was
evaporated and chromatographed (3:7 ethyl acetate/hexane) to give 0.244
g of 14 (80%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 7.68 (d,
1H, J ) 7.5 Hz), 7.47 (d, 2H, J ) 8.5 Hz), 7.40 (d, 2H, J ) 8.5 Hz), 7.33
(d, 1H, J ) 8.5 Hz), 7.25 (m, 1H), 7.14 (t, 1H, J ) 8.0 Hz), 3.68 (s, 2H),
3.60 (s, 3H), 3.26 (t, 2H, J ) 7.5 Hz), 3.10 (t, 2H, J ) 7.5 Hz), 1.53 (m,
4H), 0.83 (t, 3H, J ) 7.5 Hz), 0.74 (t, 3H, J ) 7.5 Hz); 13C NMR (125
MHz, CDCl3) δ 170.7, 137.3, 137.1, 134.3, 131.8, 129.9, 128.6, 127.6,
122.0, 119.6, 119.4, 109.3, 107.6, 49.6, 47.8, 30.9, 30.5, 22.1, 20.8, 11.3,
11.0.
a One isomer (geometry not determined).
Org. Lett., Vol. 7, No. 21, 2005
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