Kraus and Guo
JOCArticle
SCHEME 7
3-methylquinoxazoline.25 The indole 10 can be generated
from aldehyde 11 and commercial available phosphonium
salt 4 in 81% yield (Scheme 7).
7.53 (d, J=6.8 Hz, 2H), 7.19-7.45 (m, 5H), 7.08-7.09 (d, J=2.0
Hz, 1H), 6.90-6.92 (m, 1H), 6.72-6.74 (d, J=8.4 Hz, 1H), 3.83
(s, 3H);13C NMR (100 MHz, CDCl3) δ 146.5, 145.7, 135.9, 135.4,
134.2, 130.3, 128.9, 128.7, 126.3, 126.1, 122.5, 120.7, 120.4, 119.6,
114.5, 114.3, 111.1, 111.0, 55.98; HRMS electrospray (m/z) calcd
for C21H17NO2 315.1259, found 315.1264.
Conclusions
4-(3-Phenylindol-2-yl)benzoate (6g). The product was purified
by short chromatography on silica gel (Rf 0.30 in 90% hexanes/
10% EtOAc). The product was obtained by recrystallization
from the mixture of CH2Cl2 and hexane as a white solid (74 mg,
45% yield): mp 192-193 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.76 (s, 1H), 7.91-7.93 (d, J = 8.4 Hz, 2H), 7.58-7.60 (d, J =
8.4 Hz, 2H), 7.49-7.51 (d, J = 8.4 Hz, 2H), 7.29-7.43 (m, 5H),
7.19-7.23 (m, 1H), 7.05-7.08 (t, J =7.6 Hz, 1H), 3.84 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ 166.4, 137.6, 137.0, 135.3,
133.1, 130.3, 129.8, 128.6, 128.4, 126.9, 123.2, 120.5, 119.4,
115.5, 112.2, 52.6; HRMS electrospray (m/z) calcd for
C22H17NO2 327.1259, found 327.1263.
In conclusion, we have developed a very efficient synthesis
of 2,3-disubstituted indoles by a two-step approach in one
pot involving imine formation and six-electron ring closure,
followed by a 1,5-hydrogen shift. These reactions proceed
under very mild conditions and remarkably short reaction
times. A wide range of aryl or R,β-unsaturated aldehydes
undergo this process in excellent yield. The adduct from
4-oxo-3,4-dihydroquinazoline-2-carboxaldehyde is an ad-
vanced intermediate in the synthesis of several rutaecarpine
analogues.
3-Phenyl-2,30-biindole (6i). The product was purified by short
chromatography on silica gel (Rf 0.15 in 75% hexanes/25%
EtOAc). The product was obtained as a yellow solid (117 mg,
76% yield): mp 202-204 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.40 (s, 1H), 11.30 (s, 1H), 7.59-7.61 (d, J=8.0 Hz, 1H), 7.39-
7.50 (m, 5H), 7.29-7.33 (t, J=7.6 Hz, 2H), 7.05-7.20 (m, 5H),
6.83-6.87 (t, J=7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 136.7, 136.6, 130.8, 129.6, 128.9, 128.3, 125.9, 125.7, 125.5,
122.1, 121.6, 120.4, 120.0, 119.8, 118.4, 112.6, 112.2, 111.7,
108.2; HRMS electrospray (m/z) calcd for C22H16N2 308.1313,
found 308.1319.
Experimental Section
General Procedure for the Synthesis of 2,3-Disubstituted In-
doles from Substituted 2-Aminobenzyl Phosphonium Salts. In a
10 mL microwave reaction vessel (CEM Discover System)
equipped with a magnetic stir bar, phosphonium salt 5a
(262 mg, 0.5 mmol), the aldehyde (0.5 mmol), and glacial acetic
acid (11.4 μL, 0.2 mmol) were added to 3 mL of distilled
methanol. The vial was capped properly and placed in the
microwave. Microwave irradiator was carried out at 80 °C for
10 min (temperature fixed). After the vial was cooled to room
temperature, methanol was removed under vacuum. All metha-
nol must be removed before the next step. THF (4 mL) was
added to the mixture and 0.8 mL of a 1 M t-BuOK solution in
THF was added dropwise. The resulting mixture was stirred
at 25 °C under argon for 1 h. The saturated NH4Cl solution
(10 mL) was added to quench the reaction. The aqueous layer
was extracted with ethyl acetate (3ꢀ10 mL). The organic layers
were combined and washed with brine (2 ꢀ 10 mL). The organic
layer was separated, dried with MgSO4, and filtered. The filtrate
was concentrated under vacuum and the residue was purified by
silica gel column chromatography by using a mixture of ethyl
acetate and hexanes as the eluent.
5-Chloro-3-phenyl-2,30-biindole (6v). The product was puri-
fied by short chromatography on silica gel (Rf 0.15 in 60%
hexanes/40% EtOAc). The product was obtained as a light
1
yellow solid (159 mg, 93% yield): mp 220-221 °C; H NMR
(400 MHz, DMSO-d6) δ 11.6 (s, 1H), 11.5 (s, 1H), 7.43-7.59
(m, 6H), 7.32-7.36 (d, J =7.6 Hz, 2H), 7.10-7.24 (m, 4H),
6.88-6.92 (t, J=7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 136.8, 136.0, 135.1, 133.0, 129.7, 129.6, 129.0, 126.2, 126.1,
125.7, 124.6, 122.1, 121.4, 120.5, 119.8, 117.5, 113.2, 112.3,
112.2, 107.6; HRMS electrospray (m/z) calcd for C22H15ClN2
342.0924, found 342.0928.
2-(3-Hydroxyphenyl-4-methoxy)-3-phenylindole (6f). The pro-
duct was purified by short chromatography on silica gel (Rf 0.35
in 80% hexanes/20% EtOAc). The product was obtained as a
yellow solid (157 mg, 100% yield): mp 72-74 °C; 1H NMR (400
MHz, CDCl3) δ 8.33 (s, 1H), 7.34-7.54(d, J=8.0 Hz, 1H), 7.51-
Acknowledgment. We thank the Iowa State University
Department of Chemistry for support of this work.
Supporting Information Available: General experimental pro-
cedures and spectral data for all starting materials and products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(25) Khalil, Z. H.; Koraiem, A. I. M.; El-Maghraby, M. A.; Abu-El-
Hamd, R. M. J. Chem. Tech. Biotech. 1986, 36, 379.
J. Org. Chem. Vol. 74, No. 15, 2009 5341