A convenient synthesis of 2-substituted indoles by the reaction of 2-(chloromethyl)phenyl isocyanides with organolithiums

Article abstract of DOI:10.1016/j.tet.2009.06.127

The reaction of 2-(chloromethyl)phenyl isocyanides, readily available by dehydration of the respective N-[2-(chloromethyl)phenyl]formamides, with organolithiums produced 2-substituted indoles in satisfactory yields through addition of organolithiums to th

Full text of DOI:10.1016/j.tet.2009.06.127

Tetrahedron 65 (2009) 7523–7526
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A convenient synthesis of 2-substituted indoles by the reaction of
2-(chloromethyl)phenyl isocyanides with organolithiums
*
Kazuhiro Kobayashi , Daisuke Iitsuka, Shuhei Fukamachi, Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2009
Received in revised form 30 June 2009
Accepted 30 June 2009
Available online 4 July 2009
The reaction of 2-(chloromethyl)phenyl isocyanides, readily available by dehydration of the respective
N-[2-(chloromethyl)phenyl]formamides, with organolithiums produced 2-substituted indoles in satis-
factory yields through addition of organolithiums to the isocyano carbon followed by intramolecular
substitution reaction of the resulting imidoyl anion intermediates.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Isocyanides
Organolithiums
Intramolecular substitution
Imidoyl anion
1. Introduction
2. Results and discussion
Indoles are undoubtedly very important heterocycles in organic
synthesis. Therefore, development of new and efficient methods for
the general preparation of indoles has been the subject of intense
research.1 In this paper we wish to describe that a new and conve-
nient method for the preparation of 2-substituted indoles, which is
based on reactions of 2-(chloromethyl)phenyl isocyanides with
organolithiums, has been developed. The utility of ortho-function-
alized phenyl isocyanides in heterocycle synthesis is well estab-
lished.2–5 In particular, Fukuyama and Tokuyama have elegantly
demonstrated the utility of 2-isocyanosrtyrene derivatives in the
synthesis of indole derivatives including natural products.2 A syn-
thesis of 2,3-disubstituted quinolines through cyclization of
2-alkynylisocyanobenzenes has been reported by Ito and Sugi-
nome.3 Ichikawa has reported syntheses of 3-fluoroquinoline
Our preparation of 2-substituted indoles 3 was conducted as
illustrated in Scheme 1. The starting materials of the present syn-
thesis, N-(2-chlorophenyl)formamides 1, were easily prepared by
formylation of 2-aminobenzyl alcohols with ethyl or butyl formate
followed by chlorination with thionyl chloride. These formamides 1
were converted into 2-(chloromethyl)phenyl isocyanides 2 on
treatment with phosphorous oxychloride in the presence of tri-
ethylamine in THF.7 Because these isocyanides 2 were unstable
under purification conditions (distillation and chromatography on
silica gel), they were used in the next step without any purification
after the usual workup as soon as possible. Thus, crude isocyanides
2 were allowed to react with three molar amounts of organo-
lithiums in THF at ꢀ78 ꢁC. After stirring for 2 h, the usual workup
gave, after purification of preparative TLC on silica gel, the desired
products 3. The results are summarized in Scheme 1, which in-
dicates that overall yields of 3 from 1 are generally moderate-to-
fair. When 5-chloro-2-(chloromethyl)phenyl isocyanide (2b) was
used, somewhat higher yields of the corresponding desired indoles
3 were obtained, compared to those using other 2-(chloro-
methyl)phenyl isocyanides 2a and 2c. These results may be at-
tributed to higher reactivity of the isocyano carbon toward
nucleophiles due to the chloro substituent on the benzene ring.
The formation of 2-substituted indoles 3 is induced by attack of
an organolithium at the isocyano carbon of 2-(chloromethyl)phenyl
isocyanides 2 to generate the imidoyl anion intermediate 4, as
depicted in Scheme 2. This intermediate undergoes intramolecular
derivatives based on reactions utilizing
b-difluoro-2-iso-
cyanostyrenes.4 However, there have been few reports on utilization
of 2-(chloromethyl)phenyl isocyanides in organic synthesis so far,
though 2-(chloromethyl)phenyl isocyanide has been used in the
synthesis of 1- and 2-platinum(II)-substituted indole derivatives by
Michelin and colleagues.6 To the best of our knowledge, the present
report is the first example of the practical use of these isocyanide in
organic synthesis.
* Corresponding author. Tel./fax: þ81 857 31 5263.
E-mail address: kkoba@chem.tottori-u.ac.jp (K. Kobayashi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.127

7524
K. Kobayashi et al. / Tetrahedron 65 (2009) 7523–7526
R1
R2
R1
R2
3. Experimental
Cl
Cl
POCl3, Et3N, THF, 0°C
3.1. General
NHCHO
NC
1a R1 = R2 = H
2a R1 = R2 = H
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were
determined with a Shimadzu FTIR-8300 spectrophotometer. The
1H NMR spectra were determined in CDCl3 using TMS as an in-
ternal reference with a JEOL ECP500 FT NMR spectrometer oper-
ating at 500 MHz. The 13C NMR spectra were determined in CDCl3
using TMS as an internal reference with a JEOL ECP500 FT NMR
spectrometer operating at 125 MHz. Low- and high-resolution MS
spectra (EI, 70 eV) were measured by a JEOL JMS AX505 HA
1b R1 = H, R2 = Cl
1c R1 = Me, R2 = H
2b R1 = H, R2 = Cl
2c R1 = Me, R2 = H
R1
R2
R3Li, THF, - 78°C
R3
N
H
3a R1 = R2 = H, R3 = Ph 67%
3b R1 = R2 = H, R3 = p-Tol 54%
3c R1 = R2 = H, R3 = n-Bu 65%
spectrometer. TLC was carried out on a Merck Kieselgel 60 PF254
.
3d R1 = H, R2 = Cl, R3 = Ph 72%
3e R1 = H, R2 = Cl, R3 = o-Tol 53%
3f R1 = H, R2 = Cl, R3 = m-Tol 60%
Column chromatography was performed using Merck Kieselgel 60
(0.063–0.200 mm). All of the organic solvents used in this study
were dried over appropriate drying agents and distilled prior to
use.
3g R1 = H, R2 = Cl, R3 = 3-ClC6H4 63%
3h R1 = H, R2 = Cl, R3 = 4-ClC6H4 56%
3i R1 = H, R2 = Cl, R3 = 3-MeOC6H4 62%
3j R1 = H, R2 = Cl, R3 = 1-Naphthyl 49%
3k R1 = H, R2 = Cl, R3 = t-Bu 74%
3.2. Starting materials
3l R1 = Me, R2 = H, R3 = Ph 57%
N-[2-(Chloromethyl)phenyl]formamide (1a) was prepared by
the reported method1 from N-[2-(hydroxymethyl)phenyl]-
formamide,6 which was prepared by treating 2-aminobenzyl-
alcohol with refluxing ethyl formate. 2-Amino-4-chlorobenzyl
alcohol8 was prepared by the LAH reduction of ethyl 2-amino-4-
chlorobenzoate.9 All other chemicals used in this study were
commercially available.
Scheme 1.
Cl
R1
R2
R1
R2
R3Li
R3
Li
R2
2
N
N
5
4
3.2.1. 1-Chloromethyl-2-isocyanobenzene (2a)6,10
tautomerization
This compound was prepared from N-[2-(chloromethyl)-
phenyl]formamide6 by a modified procedure7a of Ugi’s method.7b
Thus, to a stirred solution of N-[2-(chloromethyl)phenyl]formamide
(0.30 g, 1.8 mmol) in THF (6 mL) containing Et3N (1.3 g, 12 mmol) at
0 ꢁC was added POCl3. After 10 min the mixture was treated with
saturated aqueous NaHCO3 (15 mL) and extracted with Et2O twice
(10 mL each). The combined extracts were washed with saturated
aqueous NaHCO3 and then brine, and dried over anhydrous K2CO3.
After evaporation of the solvent the residue (a brown liquid) was
used in the next step without any purification.
3
Scheme 2.
SN2 reaction to give the indolenine intermediate 5, which, probably,
tautomerized during workup and/or purification procedures to
afford 3. The possibility of lithiation of 5 to an indolyllithium in-
termediate with excess organolithium is excluded, because addi-
tion of iodomethane to the reaction mixture did not give the
corresponding N-methyl derivatives. The use of three molar
amounts of organolithiums is essential for the satisfactory pro-
duction of the desired products. With less than three molar
amounts of organolithiums the reaction sequence did not proceed
in a satisfactory manner and gave mixtures of only rather decreased
yields of the desired products and the starting materials. One of the
probable reasons for the modest yields of the products may be
ascribed to somewhat lower purity of 2-(chloromethyl)phenyl
isocyanides used without purification; no other products, whose
structures could be determined, were isolated. Although the reason
for the necessity of excess organolithiums in the present reaction is
not clear, the uses of excess nucleophiles have often be reported in
the heterocycle synthesis initiated by the attack of nucleophiles on
the isocyano carbon.4b,5f When the reaction sequence was carried
out in diethyl ether or 1,2-dimethoxyethane, an intractable mixture
of products including ones probably arising from deprotonation of
the benzyl proton of 2 was obtained in each case. No trace of 3 was
isolated from this mixture. Grignard reagents, such as phenyl-
magnesium bromide and ethylmagnesium bromide did not work
well in the present indole formation to give a complex reaction
mixture in each case.
3.2.2. N-[5-Chloro-2-(hydroxymethyl)phenyl]formamide
This compound was prepared by treating 2-amino-4-chloro-
benzyl alcohol with refluxing ethyl formate in 66% yield; a white
solid; mp 124–126 ꢁC (hexane–Et2O); IR (KBr) 3300, 1682 cmꢀ1; 1H
NMR
d 1.68 (br s, 1H), 4.72 and 4.73 (2s, combined 2H), 7.06–8.68
(m, 5H). Anal. Calcd for C8H8ClNO2: C, 51.77; H, 4.34; N, 7.55. Found:
C, 51.70; H, 4.39; N, 7.32.
3.2.3. N-[5-Chloro-2-(chloromethyl)phenyl]formamide (1b)
This compound was prepared by treating N-[5-chloro-2-
(hydroxymethyl)phenyl]formamide with SOCl2 according to the
reported procedure1 in 55% yield; mp 95–97 ꢁC (hexane–Et2O); IR
(KBr) 3279, 1665 cmꢀ1; 1H NMR
d 4.57 and 4.59 (2s, combined 2H),
7.14–8.61 (m, 5H). Anal. Calcd for C8H7C2NO: C, 47.09; H, 3.46; N,
6.86. Found: C, 46.93; H, 3.51; N, 6.61.
3.2.4. 1-Chloro-4-chloromethyl-3-isocyanobenzene (2b)
This compound was prepared from N-[5-chloro-2-(chloro-
methyl)phenyl]formamide by a similar procedure as described for
the preparation of 2a, and used in the next step without any pu-
rification after the usual workup; a brown liquid; IR (neat)
In conclusion, the results described above have shown that the
synthesis of 2-substituted indoles is conveniently accomplished
from readily available 2-(chloromethyl)phenyl isocyanides. We
believe that this procedure may be value in organic synthesis be-
cause of its simplicity.
2121 cmꢀ1; 1H NMR
d
4.67 (s, 2H), 7.42 (dd, J¼8.2, 2.3 Hz, 1H), 7.44
(d, J¼2.3 Hz, 1H), 7.47 (d, J¼8.2 Hz, 1H); MS m/z 185 (Mþ, 100).
HRMS Calcd for C8H5Cl2N: M, 184.9799. Found: m/z 184.9776.

K. Kobayashi et al. / Tetrahedron 65 (2009) 7523–7526
7525
3.2.5. N-[2-(Hydroxymethyl)-4-methylphenyl]formamide
3.3.6. 6-Chloro-2-(3-methylphenyl)indole (3f)
Colorless needles; mp 135–136 ꢁC (hexane–Et2O); IR (KBr) 3433,
1609 cmꢀ1; 1H NMR
(dd, J¼8.7, 1.8 Hz, 1H), 7.16 (d, J¼7.8 Hz, 1H), 7.34 (dd, J¼7.8, 7.3 Hz,
1H), 7.38 (s, 1H), 7.45 (d, J¼7.3 Hz, 1H), 7.47 (d, J¼1.8 Hz, 1H), 7.52 (d,
J¼8.7 Hz, 1H), 8.32 (br s, 1H); MS m/z 241 (Mþ, 100). Anal. Calcd for
C15H12ClN: C, 74.53; H, 5.00; N, 5.79. Found: C, 74.48; H, 5.24; N,
5.53.
This compound was prepared by treating 2-amino-5-methyl-
benzyl alcohol with refluxing butyl formate in 60% yield; aꢀw1 hite
d
2.43 (s, 3H), 6.78 (dd, J¼1.4, 0.9 Hz, 1H), 7.08
solid; mp 96–98 ꢁC (hexane–CHCl3); IR (KBr) 3231, 1657 cm
;
1H
NMR
d 2.08 and 2.20 (2br s, combined 1H), 2.31 and 2.33 (2s, com-
bined 3H), 4.69 and 4.70 (2s, combined 2H), 7.02–8.60 (m, 5H).
C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.39; H, 6.77; N, 8.44.
3.2.6. N-[2-(Chloromethyl)-4-methylphenyl]formamide (1c)
This compound was prepared by treating N-[2-(hydroxymethyl)-
4-methylphenyl]formamide with SOCl2 according to the reported
procedure1 in 48% yield; a white solid; mp 117–119 ꢁC (hexane–
3.3.7. 6-Chloro-2-(3-chlorophenyl)indole (3g)
Colorless crystals; mp 136–137 ꢁC (hexane–Et2O); IR (KBr) 3433,
1601 cmꢀ1; 1H NMR
d
6.81 (d, J¼1.8 Hz, 1H), 7.10 (dd, J¼8.7, 1.8 Hz,
Et2O); IR (KBr) 3231, 1661 cmꢀ1; 1H NMR
d
2.33 and 2.35 (2s, com-
1H), 7.31 (dt, J¼7.8, 0.9 Hz, 1H), 7.38 (t, J¼7.8 Hz, 1H), 7.40 (s, 1H),
7.52 (d, J¼7.8 Hz, 1H), 7.53 (d, J¼8.7 Hz, 1H), 7.63 (d, J¼1.8 Hz, 1H),
8.32 (br s, 1H); MS m/z 261 (Mþ, 100). Anal. Calcd for C14H9Cl2N: C,
64.15; H, 3.46; N, 5.34. Found: C, 63.96; H, 3.49; N, 5.22.
bined 3H), 4.57 and 4.59 (2s, combined 2H), 7.11–8.53 (m, 5H).
C9H10ClNO: C, 58.86; H, 5.49; N, 7.63. Found: C, 58.81; H, 5.51; N, 7.40.
3.2.7. 1-Chloromethyl-5-methyl-2-isocyanobenzene (2c)
This compound was prepared from N-[2-(chloromethyl)-4-
methylphenyl]formamide by a similar procedure as described for
the preparation of 2a, and used in the next step without any puri-
3.3.8. 6-Chloro-2-(4-chlorophenyl)indole (3h)
Colorless crystals; mp 164–165 ꢁC (hexane–Et2O); IR (KBr)
3381 cmꢀ1; 1H NMR
d
6.78 (d, J¼1.4 Hz, 1H), 7.10 (dd, J¼8.2, 1.8 Hz,
fication after the usual workup;
a
brown liquid; IR (neat)
1H), 7.39 (s, 1H), 7.42 (d, J¼8.7 Hz, 2H), 7.52 (d, J¼8.2 Hz, 1H), 7.57
2120 cmꢀ1; 1H NMR
d
2.39 (s, 3H), 4.67 (s, 2H), 7.16 (dd, J¼7.8,1.4 Hz,
(d, J¼8.7 Hz, 2H), 8.31 (br s, 1H); 13C NMR
d 100.39, 110.87, 121.23,
1H), 7.30 (d, J¼7.8 Hz, 1H), 7.31 (d, J¼1.4 Hz, 1H); MS m/z 165 (Mþ,
100). HRMS Calcd for C9H8ClN: M, 165.0345. Found: m/z 165.0337.
121.55, 126.31, 127.71, 128.34, 129.30, 130.43, 133.76, 137.20, 137.43;
MS m/z 261 (Mþ, 100). Anal. Calcd for C14H9Cl2N: C, 64.15; H, 3.46;
N, 5.34. Found: C, 63.97; H, 3.56; N, 5.09.
3.3. Typical procedure for the preparation of 2-substituted
indoles 3
3.3.9. 6-Chloro-2-(3-methoxyphenyl)indole (3i)
Colorless crystals; mp 105–107 ꢁC (hexane–Et2O); IR (KBr) 3451,
3.3.1. 2-Phenylindole (3a)11
1605 cmꢀ1; 1H NMR
d
3.88 (s, 3H), 6.79 (d, J¼1.4 Hz, 1H), 6.89 (dd,
To a stirred solution of 2a (0.15 g, 1.0 mmol) in THF (4 mL) at
ꢀ78 ꢁC was added dropwise PhLi (3.0 mmol; 1.04 M in cyclohexane–
Et2O); the mixture was stirred at the same temperature for 2 h.
The resulting mixture was diluted by adding 15 mL of Et2O, and
saturated aqueous NH4Cl (10 mL) and water (5 mL) was added.
The layers were separated, and the aqueous layer was extracted
with Et2O twice (5 mL each). The combined extracts were
washed with brine, dried over anhydrous Na2SO4, and the sol-
vent was evaporated. The residue was purified by preparative
TLC on silica gel (1:7 THF–hexane) to give 3a (0.13 g, 67%);
colorless needles; mp 189–190 ꢁC (hexane–Et2O). This product
was identified by a direct comparison with a commercially
available sample, purchased from Wako Pure Chemical In-
dustries, Ltd.
J¼8.7, 2.3 Hz, 1H), 7.09 (dd, J¼8.2, 1.8 Hz, 1H), 7.17 (dd, J¼2.3, 1.8 Hz,
1H), 7.23 (d, J¼7.8 Hz, 1H), 7.37 (dd, J¼8.2, 7.8 Hz, 1H), 7.39 (s, 1H),
7.52 (d, J¼8.7 Hz, 1H), 8.33 (br s, 1H); MS m/z 257 (Mþ, 100). Anal.
Calcd for C15H12ClNO: C, 69.91; H, 4.69; N, 5.43. Found: C, 69.65; H,
4.94; N, 5.44.
3.3.10. 6-Chloro-2-(naphthalene-1-yl)indole (3j)
A
white solid; mp 130–131 ꢁC (hexane–Et2O); IR (KBr)
3346 cmꢀ1; 1H NMR
d
6.78 (d, J¼1.4 Hz, 1H), 7.15 (dd, J¼8.2, 1.8 Hz,
1H), 7.45 (s, 1H), 7.52–7.56 (m, 3H), 7.61 (d, J¼8.2 Hz, 1H), 7.63 (dd,
J¼7.3, 1.4 Hz, 1H), 7.91 (d, J¼8.2 Hz, 1H), 7.93 (dd, J¼6.9, 2.3 Hz, 1H),
8.27 (dd, J¼6.9, 1.8 Hz, 1H), 8.33 (br s, 1H); 13C NMR
d 103.64, 110.78,
120.90, 121.41, 125.32, 125.44, 126.24, 126.80, 127.21, 127.42, 127.93,
128.54, 128.84, 130.56, 131.40, 133.91, 136.66, 137.44; MS m/z 277
(Mþ, 100). Anal. Calcd for C18H12ClN: C, 77.84; H, 4.35; N, 5.04.
Found: C, 77.59; H, 4.51; N, 4.91.
3.3.2. 2-(4-Methylphenyl)indole (3b)12
Colorless needles; mp 214–216 ꢁC (hexane–Et2O) (lit.,13 213–
214 ꢁC). The spectral data (IR and 1H NMR) were identical to those
reported previously.13
3.3.11. 6-Chloro-2-(1,1-dimethylethyl)indole (3k)
Colorless crystals; mp 94–95 ꢁC (hexane); IR (KBr) 3445,
1612 cmꢀ1; 1H NMR
d
1.38 (s, 9H), 6.22 (dd, J¼2.3, 0.9 Hz, 1H), 7.03
3.3.3. 2-Butylindole (3c)14
(dd, J¼8.2, 1.8 Hz, 1H), 7.23 (d, J¼1.8 Hz, 1H), 7.42 (d, J¼8.2 Hz, 1H),
A white solid; mp 35–36 ꢁC (hexane–Et2O) (lit.,14 36–37 ꢁC). The
spectral data (IR and 1H NMR) were identical to those reported
previously.15
7.92 (br s, 1H); 13C NMR
d 30.18, 31.84, 97.03, 110.32, 120.19, 120.71,
126.73, 127.06, 136.10, 149.55; MS m/z 207 (Mþ, 100), 192 (100).
Anal. Calcd for C12H14ClN: C, 69.39; H, 6.79; N, 6.74. Found: C, 69.49;
H, 6.94; N, 6.67.
3.3.4. 6-Chloro-2-phenylindole (3d)16
3.3.12. 5-Methyl-2-phenylindole (3l)18
Colorless needles; mp 180–181 ꢁC (hexane) (lit.,17 181–182 ꢁC).
The spectral data (IR and 1H NMR) were identical to those reported
previously.17
Colorless needles; mp 217–218 ꢁC (hexane) (lit.,19 216–217 ꢁC;
lit.,20 210–211 ꢁC). The spectral data (IR and 1H NMR) were identical
to those reported previously.19,20
3.3.5. 6-Chloro-2-(2-methylphenyl)indole (3e)
Colorless needles; mp 105–106 ꢁC (hexane); IR (KBr) 3373,
1602 cmꢀ1; 1H NMR
d
2.49 (s, 3H), 6.59 (dd, J¼1.4, 0.9 Hz, 1H), 7.11
Acknowledgements
(dd, J¼8.2, 1.8 Hz, 1H), 7.27–7.33 (m, 3H), 7.40 (t, J¼0.9 Hz, 1H), 7.46
(dd, J¼8.7, 3.2 Hz, 1H), 7.54 (d, J¼8.2 Hz, 1H), 8.14 (br s, 1H); MS m/z
241 (Mþ, 100). Anal. Calcd for C15H12ClN: C, 74.53; H, 5.00; N, 5.79.
Found: C, 74.49; H, 5.13; N, 5.77.
We thank Mrs. Miyuki Tanmatsu of this University for her as-
sistance in determining the mass spectra and performing com-
bustion analyses.

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O.; Konishi, H. Chem. Lett. 2003, 32, 76–77; (d) Kobayashi, K.; Yoneda, K.; Miz-
References and notes
umoto, T.; Umakoshi, H.; Morikawa, O.; Konishi, H. Tetrahedron Lett. 2003, 44,
4733–4736; (e) Kobayashi, K.; Takagoshi, K.; Kondo, S.; Morikawa, O.; Konishi, H.
Bull. Chem. Soc. Jpn. 2004, 77, 553–559; (f) Kobayashi, K.; Yoneda, K.; Miyamoto,
K.; Morikawa, O.; Konishi, H. Tetrahedron 2004, 60, 11639–11645; (g) Kobayashi,
K.; Izumi, Y.; Hayashi, K.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2005, 78,
2171–2174; (h) Kobayashi, K.; Hayashi, K.; Iitsuka, D.; Morikawa, O.; Konishi, H.
Synthesis 2006, 1077–1082. See also pertinent references cited in these papers.
6. Michelin, R. A.; Facchin, G.; Braga, D.; Sabatino, P. Organometallics 1986, 5,
2265–2274.
7. (a) Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. Soc. Jpn. 1984, 57, 73–
84; (b) Ugi, I.; Meyr, R. Org. Synth. 1973, Coll. Vol. V, 1060–1063.
8. Carling, R. W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.; Moyes, C. R.; Mawer,
I. M.; Thomas, S.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.;
Marshall, G. R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993, 36,
3397–3408.
1. For a recent excellent review: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873–2920; Recent general syntheses of indoles: (b) Tokuyama, H.; Makido, T.;
Han-ya, Y.; Fukuyama, T. Heterocycles 2007, 72, 191–197; (c) Nielsen, S. D.;
Ruhland, T.; Rasmussen, L. K. Synlett 2007, 443–446; (d) Xu, D.-Q.; Yang, W.-
L.; Luo, S.-P.; Wang, B.-T.; Wu, J.; Xu, Z.-Y. Eur. J. Org. Chem. 2007, 1007–
1021; (e) Schwarz, N.; Alex, K.; Ali Sayyed, I.; Khedkar, V.; Tillack, A.; Beller,
M. Synlett 2007, 1091–1095; (f) Della Rosa, C.; Kneeteman, M.; Mancini, P.
Tetrahedron Lett. 2007, 48, 1435–1438; (g) Sayyed, I. A.; Alex, K.; Tillack, A.;
Schwarz, N.; Michalik, D.; Beller, M. Eur. J. Org. Chem. 2008, 4525–4528; (h)
Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538–549; (i) Cucek, K.;
Vercek, B. Synthesis 2008, 1741–1746; (j) Sanz, R.; Guilarte, V.; Castroviejo,
E. P. Synlett 2008, 3006–3010; (k) Bondzic, B. P.; Farwick, A.; Liebich, J.;
Elibracht, P. Org. Biomol. Chem. 2008, 6, 3723–3731; (l) Stuart, D. R.; Ber-
trand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
16474–16475; (m) Donaldo, J. R.; Taylor, R. J. K. Synlett 2009, 59–62; (n)
Varma, P. P.; Sherigara, B. S.; Mahadevan, K. M.; Hulikal, V. Synth. Commun.
2009, 39, 158–165; (o) Nakamura, I.; Nemoto, T.; Shiraiwa, N.; Terada, M.
Org. Lett. 2009, 11, 1055–1058; (p) Lehmann, F.; Holm, M.; Laufer, S. Tet-
rahedron Lett. 2009, 50, 1708–1709.
9. Foggasy, K.; Kova´cs, K.; Keseru, G. N.; To˜ke, L.; Faigl, F. J. Chem. Soc., Perkin Trans.
1 2001, 1039–1043.
10. Michelin, R. A.; Facchin, G.; Uguagliati, P. Inorg. Chem. 1984, 23, 961–969.
11. Snyder, H. R.; Smith, C. W. J. Am. Chem. Soc. 1943, 65, 2452–2454.
12. Brown, F.; Mann, F. G. J. Chem. Soc., Chem. Commun. 1948, 847–858.
13. Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017–8028.
14. Piozzi, F.; Langella, M. R. Gazz. Chim. Ital. 1963, 40, 1382–1391.
15. Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215–2221.
16. Bazile, Y.; Bras, J. P.; De Cointet, P.; Nanthavong, S.; Pigerol, C.; Broll, M.; Eymard,
P.; Werbenec, J. P.; Fournier, J. Eur. J. Med. Chem. 1977, 12, 525–530.
17. Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull. 2003, 51,
1170–1173.
2. An excellent review: (a) Tokuyama, H.; Fukuyama, T. Chem. Rec. 2002, 2, 37–45;
See also: (b) Kotani, M.; Yamago, S.; Satoh, A.; Tokuyama, H.; Fukuyama, T.
Synlett 2005, 1893–1896 and references in these papers.
3. Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977–1979.
4. (a) Ichikawa, J.; Wada, Y.; Miyazaki, H.; Mori, T.; Kuroki, H. Org. Lett. 2003, 5,
1455–1458; (b) Ichikawa, J.; Mori, T.; Miyazaki, H.; Wada, Y. Synlett 2004, 1219–
1222; (c) Mori, T.; Ichikawa, J. Synlett 2007, 1169–1171.
5. Contributions from our laboratory: (a) Kobayashi, K.; Kitamura, T.; Yoneda, K.;
Morikawa, O.; Konishi, H. Chem. Lett. 2000, 798–799; (b) Kobayashi, K.; Irisawa,
S.; Matoba, T.; Matsumoto, T.; Yoneda, K.; Morikawa, O.; Konishi, H. Bull. Chem.
Soc. Jpn. 2001, 74, 1109–1114; (c) Kobayashi, K.; Yoneda, K.; Mano, M.; Morikawa,
18. Crowther, A. F.; Mann, F. G.; Purdie, D. J. Chem. Soc., Chem. Commun. 1943, 58–68.
19. Ito, Y.; Kobayashi, K.; Saegusa, T. J. Org. Chem. 1979, 44, 2030–2032.
20. Majumdar, K. C.; Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2008, 49,
7213–7216.