Synthesis of 3-Iodoindoles
time, and the resulting solution was filtered, washed with a saturated
aq NaCl solution, and extracted with diethyl ether (2 × 10 mL).
The combined ether fractions were dried over Na2SO4 and
concentrated under vacuum to yield the crude product. The crude
product was purified by flash chromatography on silica gel using
ethyl acetate/hexane as the eluent.
N,N-Dimethyl-2-(phenylethynyl)aniline (2). The product was
obtained as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 3.01 (s,
6H), 6.88-6.94 (m, 2H), 7.25 (t, J ) 6.3 Hz, 1H), 7.31-7.37 (m,
3H), 7.49 (d, J ) 5.7 Hz, 1H), 7.54 (d, J ) 7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 43.8, 89.1, 95.0, 115.3, 117.2, 120.7, 124.1,
128.2, 128.5, 129.5, 131.5, 134.6, 155.0; IR (neat, cm-1) 3059,
2943, 2833, 2785, 2209. HRMS calcd for C16H15N, 221.120 45;
found, 221.120 76.
dole were added 5.0 mmol of Na2CO3 and 1.25 mmol of NaBPh4,
and the reaction mixture was stirred for 2 min. Pd(OAc)2 (5 mol
%) was then added, and the flask was flushed with Ar, sealed, and
allowed to stir at 100 °C for 2 h. The resulting reaction mixture
was extracted with diethyl ether (2 × 10 mL). The combined ether
layers were dried over anhydrous Na2SO4 and concentrated under
vacuum to afford a white solid. Recrystallization afforded a 92%
yield of a crystalline solid. The product was obtained as white
needles: mp 113-114 °C; 1H NMR (300 MHz, CDCl3) δ 3.67 (s,
3H), 7.16-7.39 (m, 13H), 7.80 (d, J ) 10.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 31.1, 109.8, 115.3, 119.8, 120.4, 122.4, 125.7,
127.2, 128.2, 128.4, 128.6, 130.1, 131.4, 132.1, 135.4, 137.5, 137.9;
IR (neat, cm-1) 3058, 2923, 2849. HRMS calcd for C21H17N,
283.136 10; found, 283.136 90.
General Procedure for Iodocyclization. To a solution of 0.25
mmol of N,N-dialkyl-2-(1-alkynyl)aniline and 3 mL of CH2Cl2 was
added gradually 2 equiv of I2 dissolved in 2 mL of CH2Cl2. The
reaction mixture was flushed with Ar and allowed to stir at room
temperature for the desired time. The excess I2 was removed by
washing with a saturated aq solution of Na2S2O3. The aq solution
was then extracted with diethyl ether (2 × 10 mL). The combined
ether layers were dried over anhydrous Na2SO4 and concentrated
under vacuum to yield the crude product, which was purified by
flash chromatography on silica gel using ethyl acetate/hexanes as
the eluent.
3-Iodo-1-methyl-2-phenylindole (29). The product was obtained
as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 3.63 (s, 3H), 7.21-
7.28 (m, 3H), 7.43-7.51 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
32.2, 59.0, 110.0, 120.9, 121.6, 123.1, 128.6, 129.0, 130.5, 131.1,
131.8, 137.9, 141.9; IR (neat, cm-1) 3054, 2937. HRMS calcd for
C15H12IN, 333.001 45; found, 333.001 94.
1-Methyl-2-phenyl-3-(phenylethynyl)indole (53). This indole
was prepared by the following procedure. Into a well-mixed Et3N
solution (5 mL) containing 5.0 mmol of 3-iodo-1-methyl-2-
phenylindole, 6.0 mmol of phenylacetylene, and PdCl2(PPh3)2 (5
mol %) was added CuI (2.5 mol %), and the flask was flushed
with Ar, sealed, and allowed to stir at room temperature for 2 h.
The resulting precipitate was filtered off and washed with diethyl
ether (10 mL). The combined ether layers were dried over
anhydrous Na2SO4 and concentrated under vacuum to afford a
yellow oil: 1H NMR (300 MHz, CDCl3) δ 3.69 (s, 3H), 7.21-
7.32 (m, 6H), 7.41-7.44 (m, 3H), 7.49 (t, J ) 7.2 Hz, 2H), 7.65
(dd, J ) 10.8, 2.0 Hz, 2H), 7.85 (dd, J ) 10.4, 2.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 31.8, 84.5, 91.9, 110.0, 120.2, 121.0,
123.1, 124.7, 127.4, 128.1, 128.4, 128.5, 128.7, 129.0, 130.4, 131.0,
131.3, 137.4, 144.0; IR (neat, cm-1) 3004, 2962, 2923, 2204. HRMS
calcd for C23H17N, 307.136 10; found, 307.136 98.
n-Butyl (E)-3-[1-Methyl-2-phenylindol-3-yl]propenoate (55).
This indole was prepared by the following procedure. Into 1 mL
of DMF containing 0.25 mmol of 3-iodo-1-methyl-2-phenylindole
and 0.25 mmol of Na2CO3 were added 0.25 mmol of n-Bu4NCl
and 0.525 mmol of n-butyl acrylate, and the reaction mixture was
stirred for 2 min. Pd(OAc)2 (5 mol %) was then added, and the
flask was flushed with Ar, sealed, and allowed to stir at 80 °C for
24 h.23 The resulting reaction mixture was extracted with diethyl
ether (2 × 10 mL). The combined ether layers were dried over
anhydrous Na2SO4 and concentrated under vacuum to afford a pale
yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.94 (t, J ) 7.5 Hz,
3H), 1.37-1.44 (m, 2H), 1.62-1.67 (m, 2H), 3.61 (s, 3H), 4.15 (t,
J ) 6.6 Hz, 2H), 6.48 (d, J ) 15.9 Hz, 1H), 7.32-7.40 (m, 5H),
7.50-7.53 (m, 3H), 7.72 (d, J ) 16.2 Hz, 1H), 8.01 (d, J ) 7.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 19.4, 31.1, 31.3, 64.0,
110.2, 110.6, 113.1, 120.9, 121.9, 123.2, 125.8, 128.8, 129.4, 130.2,
131.1, 138.1, 139.0, 145.6, 168.8; IR (neat, cm-1) 3004, 2963, 2925,
1711. HRMS calcd for C22H23NO2, 333.172 88; found, 333.173 70.
Acknowledgment. We gratefully acknowledge partial fi-
nancial support from the National Institute of General Medical
Sciences (GM070620) and National Institutes of Health Kansas
University Chemical Methodologies and Library Development
Center of Excellence (P50 GM069663). We thank Johnson
Matthey, Inc., and Kawaken Fine Chemicals Co., Ltd., for
providing the palladium salts.
Supporting Information Available: General experimental
procedures and spectral data for all previously unreported starting
materials and products. This material is available free of charge
JO051549P
1-Methyl-2,3-diphenylindole (54). This indole was prepared
according to a literature procedure.22 To 10 mL of a 2:1 DMF/
H2O solution containing 5.0 mmol of 3-iodo-1-methyl-2-phenylin-
(22) Bumagin, N.; Bykov, V. V. Tetrahedron 1997, 53, 14437.
(23) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
J. Org. Chem, Vol. 71, No. 1, 2006 69