LETTER
Synthesis of Indoles Using Cyclization of Imidoyl Radicals
1907
tion was stirred for 2 h at r.t., H2O and CH2Cl2 added and separated.
The CH2Cl2 solution was dried and evaporated to dryness. The res-
idue was purified by flash silica column chromatography to yield
the imidoyl selanide 6a (R = p-tol) as a yellow oil (1.24 g, 64%). IR
(neat): 3056, 2976, 1707, 1628, 1592, 1474, 1314, 1267, 1172,
1
1092, 910 cm–1. H NMR (250 MHz, CDCl3): d = 1.32 (t, J = 7.2
Hz, 3 H, Me), 2.29 (s, 3 H, Me), 4.26 (q, J = 7.2 Hz, 2 H, CH2O),
6.38 (d, J = 15.9 Hz, 1 H, CHCO2Et), 6.89 (d, J = 7.9 Hz, 1 H, Ar-
H), 7.53–7.01 (m, 9 H, Ar-H), 7.59 (d, J = 8.1 Hz, 2 H, Ar-H), 7.86
(d, J = 16.1 Hz, 1 H, CH=CHCO2Et). 13C NMR (100 MHz, CDCl3):
d = 14.3 (Me), 21.3 (Me), 60.2 (CH2), 118.7 (CHCO2Et), 119.8 (Ar-
CH), 124.6 (Ar-C), 124.7 (Ar-CH), 127.2 (Ar-CH), 127.7 (Ar-CH),
128.7 (Ar-CH), 128.8 (Ar-CH), 128.9 (Ar-C), 129.1 (Ar-CH), 130.5
(Ar-CH), 135.2 (Ar-CH), 135.5 (Ar-C), 140.7 (Ar-C), 140.8
(ArCH=CH), 150.3 (Ar-C-N), 165.2 (C=O or C=N), 167.0 (C=O or
C=N). HRMS (FAB): C25H13NO2Se + H requires: 450.0972; found:
450.0970; m/z (%) = 450 (10) [M + H]+, 366 (4), 292 (42), 248 (42),
220 (90), 128 (19), 119 (100), 91 (25), 77 (15), 65 (5).
Scheme 3 Mechanism of the cyclization of imidoyl selanide 6 to
yield 5-exo and 6-endo products
hydridized bond, which suggests reversibility is unlikely,
but cannot be ruled out.
Cyclization Reactions. (2-p-Tolyl-1H-indol-3-yl)acetic Acid
Ethyl Ester [11a (R = p-tol)].
The reaction was carried out under an atmosphere of nitrogen. A
deoxygenated solution of Bu3SnH in toluene (20 mL) was added us-
ing a syringe pump over 5 h to a solution of 3-{2-[(phenylselanyl-
p-tolylmethylene)amino]-phenyl}acrylic acid ethyl ester [6a
(R = p-tol), 0.469 g, 1.046 mmol] in anhyd toluene (100 mL) under
reflux. AIBN (0.086 g, 0.523 mmol) was added portion-wise over 5
No quinoline products were observed for the ester- and
aryl-substituted alkenes 6a and 6c, respectively. In the
former, the 5-exo radical 9a is electrophilic and will react
rapidly with the nucleophilic Bu3SnH. Compound 9a will
also react very slowly via 3-exo cyclization onto the elec-
trophilic a-carbon atom of the imine required for a neo- h. The reaction mixture was refluxed for a further hour, cooled and
evaporated to dryness. The crude mixture was purified by flash sil-
phyl rearrangement, thereby preventing rearrangement. In
ica column chromatography using light petroleum:EtOAc (6:1) as
the aryl substituted reaction, a benzylically stabilized 5-
eluant to yield the indole 11a (R = p-tol) as a pale yellow oil (0.290
g, 95%). IR (thin film): 3373, 3053, 3024, 2976, 2921, 2869, 1718,
exo radical 9c results and hence there is no driving force
for a neophyl rearrangement.
1506, 1457, 1342, 1306, 1176, 1029, 822 cm–1. 1H NMR (250 MHz,
CDCl3): d = 1.23 (t, J = 7.1 Hz, 3 H, Me), 2.38 (s, 3 H, Me), 3.80 (s,
2 H, CH2CO2Et), 4.14 (q, J = 7.1 Hz, 2 H, CH2O), 7.30–7.12 (m, 5
H, Ar-H), 7.52–7.49 (m 2 H, Ar-H), 7.66–7.64 (m, 1 H, Ar-H), 8.18
(br s, 1 H, NH). 13C NMR (100 MHz, CDCl3): d = 14.2 (Me), 21.2
(Me), 31.2 (CH2), 60.8 (OCH2), 105.3 (Ar-C), 110.8 (Ar-CH),
119.2 (Ar-CH), 119.9 (Ar-CH), 122.3 (Ar-CH), 128.1 (Ar-CH),
129.1 (Ar-C), 129.5 (Ar-C), 129.6 (Ar-CH), 135.7 (Ar-C), 136.3
In the reactions of 6b at low [Bu3SnH], a number of un-
identified products also were observed. Overall, the yields
were less favorable, indicating a number of different side
reactions. Surprisingly, aromatization of the 6-endo radi-
cal 14 (R = p-tol) has sufficient driving force to eliminate
propyl radicals to yield 17b (R = p-tol). The aromatiza-
tion by loss of hydrogen [H] to yield the aromatic 2,3-di- (Ar-C), 137.9 (Ar-C), 172.3 (C=O). HRMS (EI): C19H19NO2 re-
quires: 293.1415; found: 293.1419; m/z (%) = 292 (40) [M+], 269
substituted quinolines 17a is a now well-known
phenomenon in Bu3SnH-facilitated reactions.15
(20), 220 (100), 204 (22), 177 (5), 155 (4), 91 (4).
Our preliminary results indicate that imidoyl selanides are
Acknowledgment
good easily accessible precursors for generating imidoyl
radicals and provide a useful protocol for the synthesis of
2,3-disubstituted indoles. We are extending our studies to
more complex systems and cascade reactions for the syn-
thesis of natural products.
We thank GlaxoSmithKline and Loughborough University for a
postgraduate studentship (JMP), EPSRC for a research associate
(AJF), GlaxoSmithKline for generous support and the EPSRC Mass
Spectrometry Unit, Swansea University, Wales for mass spectra.
References
Preparation of Imidoyl Phenyl Selanides. 3-{2-[(Phenylselanyl-
p-tolyl-methylene)-amino]-phenyl}acrylic Acid Ethyl Ester [6a,
(R = p-tol)].
(1) A good selection of groups is detailed in this reference:
Motherwell, W. B.; Crich, D. Free Radical Reactions in
Organic Synthesis; Academic Press: London, 1991.
(2) Bachi, M. D.; Bosch, E.; Denenmark, D.; Girsh, D. J. Org.
Chem. 1992, 57, 6803.
(3) (a) Tokuyama, H.; Yamashita, Y.; Reding, M. T.; Kaburagi,
Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791.
(b) Reding, M. T.; Fukuyama, T. Org. Lett. 1999, 1, 973.
(c) Reding, M. T.; Kaburagi, Y.; Tokuyama, H.; Fukuyama,
T. Heterocycles 2002, 56, 313.
Phosgene [20% w/w toluene solution] (6.39 mL, 12.13 mmol) and
DMF (5 drops) were added to a solution of 3-[2-(4-methyl-benzoyl-
amino)phenyl]acrylic acid ethyl ester 4a (R = p-tol) (1.50 g, 4.85
mmol) in anhyd CH2Cl2 (40 mL). The reaction mixture was stirred
at r.t. for 4 h. The solution of the imidoyl chloride was evaporated
to dryness and the product re-dissolved in anhyd THF (50 mL). A
solution of ‘potassium phenylselanate’ was prepared by adding K-
Selectride® (1 M THF solution; 4.60 mL, 4.60 mmol) to diphenyl
diselanide (0.68 g, 2.18 mmol) in anhyd THF (50 mL). This solution
was added to the solution of the imidoyl chloride in THF. The reac-
(4) Du, W.; Curran, D. P. Org. Lett. 2003, 5, 1765.
Synlett 2004, No. 11, 1905–1908 © Thieme Stuttgart · New York