Synthesis of 2,3-disubstituted indoles by palladium-mediated coupling of 2-iodoindoles

Article abstract of DOI:10.1055/s-2000-6354

N-Unprotected 2-iodoindoles are synthesized by treatment of 2- stannylindoles with iodine, which in turn are prepared by tin-mediated radical cyclization of 2-alkenylphenylisocyanides. Palladium-catalyzed coupling reactions of N-unprotected 2-iodoindoles

Full text of DOI:10.1055/s-2000-6354

PAPER
429
Synthesis of 2,3-Disubstituted Indoles by Palladium-Mediated Coupling of 2-
Iodoindoles
Hidetoshi Tokuyama, Yosuke Kaburagi, Xiaoqi Chen,1 Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The University of Tokyo CREST, The Japan Science and Technology Corporation, 7-3-1
Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 3 November 1999
Following our protocol, we prepared 2-stannylindole by
Abstract: N-Unprotected 2-iodoindoles are synthesized by treat-
radical cyclization of 2-isocyanocinnamate 5 (Scheme 2).
Upon treatment of 2-stannylindole 6 with iodine, 2-iodo-
indole 7 could be isolated in 91% overall yield from 5.
ment of 2-stannylindoles with iodine, which in turn are prepared by
tin-mediated radical cyclization of 2-alkenylphenylisocyanides.
Palladium-catalyzed coupling reactions of N-unprotected 2-iodoin-
doles with terminal acetylenes, terminal olefins, carbonylation, and Compound 7 proved to be relatively stable, and could be
the Suzuki coupling reaction with phenyl borate proceed smoothly
to furnish the corresponding 2,3-disubstituted indoles in good to ex-
cellent yields.
stored in a freezer for several weeks without appreciable
decomposition. While 2-iodoindole 9 was prepared in
moderate yield from 8, the subsequent conversion to 2,3-
disubstituted indole proceeded in good yields (vide infra).
Key words: 2-iodoindole, 2-stannylindole, isonitrile, radical cy-
clization, palladium-mediated coupling
The indole nucleus is present in a wide range of natural
products, and the synthesis of this important heterocycle
has been a topic of interest for many years.2 Although nu-
merous methods for the synthesis of indoles have been de-
veloped to date,3 few practical and mild procedures are
available for the construction of 2,3-disubstituted in-
doles.4 One of the most commonly employed protocols
for synthesis of 2,3-disubstituted indoles is introduction
of substituents at the C2 position using 2-lithioindoles.
This sequence, however, requires protection and depro-
tection steps of the indole nitrogen.
In our earlier studies we reported the formation of 2-stan-
nylindoles 3 by means of radical cyclization of 2-alk-
enylphenyl isocyanides 1 (Scheme 1), and 3 could be
readily converted to either 3-substituted or 2,3-disubsti-
Scheme 2
tuted indoles 4 by an acidic workup or palladium mediat-
ed coupling reaction, respectively, in
a one-pot
procedure.5 Since it is known that the tin-carbon bond is
readily oxidized by iodine, we considered that the 2-stan-
nylindole intermediate 3 might be converted to the corre-
sponding 2-iodoindole, which would serve as a substrate
for palladium-mediated cross-coupling reactions to fur-
nish a variety of 2,3-disubstituted indoles.
With the desired 2-iodoindoles in hand, we then examined
palladium-mediated cross-coupling reaction with various
substrates. The 2-iodoindole underwent smooth palladi-
um-catalyzed coupling reactions with methyl acrylate,
terminal acetylene and vinyltin reagents to give excellent
yields of the desired coupling products (Table, entries 1−
5). It is noteworthy that the cross-coupling reaction can
also be conveniently performed in a one-pot procedure
without isolating the 2-iodoindole intermediate (Table,
entries 4, 5). When the reaction was carried out under an
atmosphere of carbon monoxide, carbonylation proceed-
ed smoothly, and subsequent reaction with vinylstannane,
methanol, or tri-n-butyltin hydride gave the correspond-
ing a,b-unsaturated ketone, methyl ester, or aldehyde, re-
spectively (entries 6−8). In the case of the carbonylation
reactions, PdCl2(dppf) gave the best results. In addition,
treatment of 2-iodoindole with KCN in the presence of
Scheme 1
Synthesis 2000, No. 3, 429–434 ISSN 0039-7881 © Thieme Stuttgart · New York

430
H. Tokuyama et al.
PAPER
Table Synthesis of 2,3-Disubstituted Indoles (4) by Palladium-Mediated Cross-Coupling Reaction of 2-Iodoindoles
En- Sub-
Coupling Partner
HC∫CH-n-Bu
Equiv Conditions
Time (h) Prod-
uct
R
R’
Yield
(%)
try
strate
1
7
5.0
2.0
Pd(PPh3)2Cl2 (5 mol%)
CuI (10 mol%), Et2NH, r.t.
8
4a
CO2Me
-C∫C-n-Bu
89
2
9
CH2=CHCO2Me
Pd(OAc)2 (5 mol%)
Et3N (1.1)
4
4b
CH2OTHP -CH=CHCO2Me
83a
P(o-tol)3 (10 mol%)
CH3CN, 100°C
3
4
9
5
HC∫CH-n-Bu
5.0
3.0
Pd(PPh3)2Cl2 (5 mol%)
CuI (10 mol%), Et2NH, r.t.
8
8
4c
CH2OTHP -C∫C-n-Bu
93
CH2=CHCO2Me
Bu3SnH (1.1), AIBN (0.04)
100 °C, CH3CN; I2 (1.1);
Pd(OAc)2 (3 mol%)
4d
CO2Me
-CH=CHCO2Me
81b,c
P(o-tol)3 (12 mol%)
Et3N (2.1), 80 °C
5
5
trans-
Bu3SnCH=CH-n-Bu
2.0
Bu3SnH (1.1), AIBN (0.04) 10
100 °C, CH3CN; I2 (1.1);
Pd(PPh3)4 (5 mol%)
4e
CO2Me
-CH=CH-n-Bu
66a,b
CuI (1.0), 70 °C
6
7
7
7
trans-
Bu3SnCH=CH-n-Bu
1.5
PdCl2(dppf) (5 mol%)
BHT (trace), CO (1 atm)
DMF, 80°C
12
5
4f
CO2Me
CO2Me
-(C=O)CH=CH-n-Bu 78 c
–
–
PdCl2(dppf) (5 mol%)
CO (1 atm), Et3N (1.5)
MeOH, 80 °C
4g
CO2Me
89
8
9
7
7
7
Bu3SnH
KCN
1.6
1.2
1.1
PdCl2(dppf) (5 mol%)
CO (1 atm), DMF, 80 °C
3
6
4h
4i
CO2Me
CO2Me
CO2Me
CHO
CN
Ph
85
79
94
Pd(PPh3)4 (5 mol%)
THF, reflux
10
PhB(OH)2
Pd(OAc)2 (5 mol%)
K2CO3 (2.5)
0.5
4j
acetone/H2O (1:1)
65 °C
a trans only.
b One-pot procedure.
c trans:cis = 2.7:1.
Pd(PPh3)4 furnished 2-cyanoinodole in high yield.6 Final- reaction, this synthesis along with the previously reported
ly, Suzuki coupling with phenylboronic acid took place protocol constitutes a facile and versatile method for the
nicely to afford 2-phenylindole in good yield.7
construction of 2,3-disubstituted indoles.
In conclusion, we have developed a preparation of N-un-
protected 2-iodoindoles by tin-mediated indole synthesis
and subsequent oxidation of the 2-stannylindole interme-
All non-aqueous reactions were carried out in oven-dried glass
tubes under slight positive pressure of Ar unless otherwise noted.
diate with iodine. Furthermore, 2-iodoindoles have been Toluene and CH2Cl2 were distilled from calcium hydride. THF was
distilled from Na/benzophenone ketyl under Ar. All other reagents
shown amenable to palladium-mediated coupling reac-
were commercially available and used without further purification.
tions with a variety of substrates. Our newly developed
Preparative flash chromatography was performed using Silica Gel
method compliments the previously reported procedure
60 (spherical, 40−100 mm) purchased from Kanto Chemical Co.,
for the synthesis of 2,3-disubstituted indoles by palladi-
um-mediated coupling reaction of 2-stannylindoles.5a Be-
cause a wide variety of functional groups are known to
tolerate both radical cyclization and palladium-mediated
Inc. All products were characterized by 1H NMR, 13C NMR, and IR
spectroscopy. NMR spectra were obtained in CDCl3 on a JEOL LA-
400 MHz spectrometer. All 1H NMR spectra are reported in ppm (d)
relative to TMS. All 13C NMR spectra are reported in ppm relative
to the central line of the triplet for CDCl3 at 77 ppm. IR spectra were
Synthesis 2000, No. 3, 429–434 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Disubstituted Indoles by Palladium-Mediated Coupling of 2-Iodoindoles
431
recorded on a JASCO FT/IR-410, absorptions are reported in cm−1.
High resolution mass spectra were obtained on a JEOL JMS-GC-
mate MS-DIP20 quadrupole at 70 eV using direct probe insertion at
temperatures of 70−330 °C. Mps were determined using a Yanako
MP-500V melting point apparatus and are uncorrected.
fied by flash column chromatography on silica gel eluting with
Et2O/hexane (3:2) to give 7 (308 mg, 91%) as a colorless oil.
IR (film): ν = 3350, 3050, 3000, 2950, 2850, 1730, 1440, 1340,
1270, 1200, 1170, 1010, 940, 750 cm−1.
1H NMR (CDCl3): d = 3.70 (s, 3H), 3.74 (s, 2H), 7.13 (m, 2H), 7.26
(m, 1H), 7.54 (m, 1H), 8.22 (s, 1H).
13C NMR (CDCl3): d = 32.9, 52.1, 79.9, 110.5, 114.7, 118.0, 120.3,
122.3, 127.2, 138.6, 171.7.
EI-LRMS: m/z (%) = 315 (M+, 69), 256 (86), 188 (12), 145 (13),
129 (99), 117 (14), 102 (56), 75 (22), 59 (9).
EI-HRMS: m/z calc for C11H10NO2I1 (M+) 314.9756. Found:
314.9755.
Methyl o-(N-Formylamino)cinnamate
A mixture of o-iodo-N-formylaniline (161 mg, 0.65 mmol), methyl
acrylate (70 mL, 0.78 mmol), Pd(OAc)2 (1.5 mg, 0.0070 mmol),
Et3N (100 mL, 0.72 mmol), and P(o-tol)3 (4 mg, 0.01 mmol) in an-
hyd CH3CN (2 mL) was heated at 100 °C for 2.5 h in a tightly
capped culture tube under Ar atm. The mixture was partitioned be-
tween Et2O and a 1:1 mixture of 3 N HCl and brine. The extracts
were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered,
and evaporated to dryness in vacuo. The crude product was purified
by flash column chromatography on silica gel eluting with Et2O/
hexane (3:2) to give methyl o-(N-formylamino)cinnamate (141 mg,
91%) as a white solid: mp 99−100 °C.
Isonitrile 8 was prepared from o-iodo-N-formanilide in a two-step
sequence.
(1) Sonogashira-Coupling Reaction of o-Iodo-N-formanilide
with Propargyl Alcohol THP Ether
IR (film): ν = 3310, 3070, 3050, 3020, 2970, 2890, 1700, 1640,
1580, 1530, 1450, 1400, 1330, 1270, 1200, 1180, 1040, 980, 870,
770 cm−1.
1H NMR (CDCl3), observed as a mixture of two amide rotamers:
δ = 3.71 (s, 3H), 3.74 (s, 3H), 6.36 (d, 1H, J = 15.8 Hz), 6.39 (d, 1H,
J = 15.8 Hz), 7.10−7.41 (m, 8H), 7.55 (m, 2H), 7.88 (m, 2H), 8.43
(m, 1H), 8.63 (s, 1H).
13C NMR (CDCl3), observed as a mixture of two amide rotamers:
d = 51.7, 119.7, 120.4, 122.8, 124.4, 125.6, 126.8, 127.6, 130.8,
131.1, 135.0, 139.0, 139.4, 163.9, 166.8, 167.4, 168.7, 168.9.
A
mixture of o-iodo-N-formanilide (4.17 g, 16.8 mmol),
Pd(PPh3)2Cl2 (236 mg, 0.34 mmol), CuI (257 mg, 1.35 mmol), and
propargyl alcohol THP ether (4.26 g, 30.4 mmol) in anhyd Et2NH
(20 mL) was stirred for 8 h at r.t., under Ar. The mixture was then
partitioned between Et2O and 3 N HCl. The extracts were washed
with sat. NaHCO3 and then with brine, dried (Na2SO4), filtered, and
evaporated to dryness in vacuo. The crude product was purified by
flash column chromatography on silica gel eluting with Et2O/hex-
ane (1:4) to give 3-(o-(N-formylamino)phenyl)propargyl alcohol
THP ether (3.98 g, 91%) as a yellow oil.
EI-LRMS: m/z (%) = 205 (M+, 22), 146 (79), 128 (63), 118 (95),
117 (99), 91 (31), 90 (37), 89 (36), 39 (19).
EI-HRMS: m/z calc for C11H11NO3 (M+) 205.0739. Found:
IR (film): ν = 3300, 2950, 2870, 2860, 2230, 1700, 1580, 1520,
1450, 1400, 1350, 1300, 1270, 1200, 1120, 1090, 1160, 1030, 900,
870, 820, 760 cm−1.
1H NMR (CDCl3), observed as a mixture of two amide rotamers:
d = 1.56−1.90 (m, 4H), 3.60 (m, 2H), 3.91 (m, 2H), 4.56 (m, 2H),
4.90 (m, 1H), 7.06 (m, 1H), 7.22−7.48 (m, 3H), 7.28 (s, 1H), 8.42
(d, 1H, J = 8.3 Hz), 8.47 (d, 1H, J = 1.6 Hz), 8.82 (d, 1H, J = 11.3
Hz).
13C NMR (CDCl3), observed as a mixture of two amide rotamers:
d = 18.9, 25.2, 29.6, 30.3, 54.9, 55.4, 62.2, 80.9, 92.9, 97.5, 97.9,
113.3, 115.8, 119.8, 123.7, 124.3, 129.8, 131.7, 133.1, 138.6, 159.1,
161.2.
EI-LRMS: m/z (%) = 259 (M+, 3), 243 (2), 175 (45), 158 (34), 146
(10), 130 (99), 102 (23), 101 (23), 77 (23), 55 (22), 41 (39).
EI-HRMS: m/z calc for C15H17NO3 (M+) 259.1208. Found:
259.1206.
205.0734.
Methyl o-Isocyanocinnamate (5)
To a solution of methyl o-(N-formylamino)cinnamate (141 mg,
0.680 mmol) and Et3N (287 mL, 2.06 mmol) in CH2Cl2 at 0 °C was
added dropwise a solution of phosgene in CH2Cl2. The reaction was
monitored closely by TLC until completion. The mixture was parti-
tioned between Et2O and sat. NaHCO3, and then brine. The com-
bined extracts were dried (Na2SO4), filtered, and evaporated to
dryness in vacuo. The crude product was purified by flash column
chromatography on silica gel eluting with Et2O/hexane (1:4) to give
5 (106 mg, 87%) as a white solid: mp 57−59 °C.
IR (KBr): ν = 3430, 3050, 3010, 2960, 2120, 1750, 1640, 1480,
1430, 1330, 1290, 1200, 1040, 990, 780 cm−1.
1H NMR (CDCl3): d = 3.84 (s, 3H), 6.55 (d, 1H, J = 16.0 Hz), 7.46
(m, 2H), 7.67 (m, 2H), 7.98 (d, 1H, J = 16.0 Hz).
13C NMR (CDCl3): d = 51.9, 121.9, 125.8, 126.8, 127.6, 129.6,
130.4, 130.7, 137.8, 166.3, 168.7
EI-LRMS: m/z (%) = 187 (M+, 6), 156 (30), 143 (14), 142 (13), 139
(99), 138 (99), 101 (61), 75 (43), 51 (30), 28 (31).
EI-HRMS: m/z calc for C11H9NO2 (M+) 187.0633. Found:
187.0635.
(2) Conversion to Isonitrile (8)
A mixture of 3-(o-(N-formylamino)phenyl)propargyl alcohol THP
ether (3.98 g, 15.3 mmol), and Pd/BaSO4 (200 mg) in EtOH (40
mL) was stirred for 2.5 h at r.t., under atmospheric pressure of H2.
The reaction was monitored closely by TLC until completion. The
reaction mixture was passed through a pad of Celite, and evaporated
to dryness in vacuo. The crude product was purified by flash column
chromatography on silica gel eluting with Et2O/hexane (3:7) to give
cis-3-(o-(N-formylamino)phenyl)propen-1-ol THP ether (2.53 g,
63%) as a dark yellow oil. To a mixture of cis-3-(o-(N-formylami-
no)phenyl)propen-1-ol THP ether (2.53 g, 9.68 mmol), and Et3N
(4.07 mL, 29.3 mmol) in CH2Cl2 at 0 °C was added drop-wise a so-
lution of phosgene in CH2Cl2. The reaction was monitored closely
by TLC until completion. The mixture was partitioned between
Et2O and sat. NaHCO3, and washed with brine. The combined ex-
tracts were dried (Na2SO4), filtered, and evaporated to dryness in
vacuo. The crude product was purified by flash column chromatog-
raphy on silica gel eluting with Et2O/hexane (1:9) to give 8 (2.27 g,
97%) as a colorless oil:
Methyl 2-(2-Iodo-1H-indol-3-yl)acetate (7)
A mixture of isonitrile (5, 202 mg, 1.08 mmol), n-Bu3SnH (320 mL,
1.19 mmol), and AIBN (2,2′-azobisisobutyronitrile) (9 mg, 0.05
mmol) in anhyd CH3CN (6 mL) was heated at 100 °C for 1 h in a
tightly capped culture tube under Ar. After the mixture was cooled
to r.t., I2 (302 mg, 1.19 mmol) was added in one portion. The mix-
ture was stirred at r.t. for 10 min before the mixture was partitioned
twice between hexane and CH3CN. The combined CH3CN extracts
were evaporated to dryness in vacuo. The crude product was puri-
Synthesis 2000, No. 3, 429–434 ISSN 0039-7881 © Thieme Stuttgart · New York

432
H. Tokuyama et al.
PAPER
IR (film): ν = 3040, 2950, 2860, 2140, 1730, 1450, 1375, 1340,
2-(2-(2-Carbomethoxy)vinyl-1H-indol-3-yl)ethanol THP Ether
(4b)
1270, 1200, 1130, 1030, 970, 900, 770 cm−1.
A mixture of iodoindole (9, 42 mg, 0.11 mmol), methyl acrylate (21
mL, 0.23 mmol), Pd(OAc)2 (1 mg, 0.005 mmol), Et3N (17 mL, 0.12
mmol), and (o-tol)3P (4 mg, 0.01 mmol) in anhyd CH3CN (2 mL)
was heated at 100 °C for 4 h in a tightly capped culture tube under
Ar. After cooling to r.t., the mixture was partitioned between Et2O
and a 1:1 mixture of 3 N HCl and brine. The combined extracts were
washed with sat. NaHCO3 and then with brine, dried (Na2SO4), fil-
tered, and evaporated to dryness in vacuo. The crude product was
purified by preparative TLC (silica gel) eluting with Et2O/hexane
(2:3) to give 4b (31 mg, 83%) as a light yellow solid: mp 121−
122 °C.
1H NMR (CDCl3): d = 1.45−1.88 (m, 4H), 3.49 (m, 1H), 3.86 (m,
1H), 4.18 (dd, 2H, J = 6.5, 12.9 Hz), 4.43 (dd, 2H, J = 6.5, 12.9 Hz),
4.65 (t, 1H, J = 3.0 Hz), 6.12 (dt, 1H, J = 6.5, 11.9 Hz), 6.74 (d, 1H,
J = 11.9 Hz), 7.30 (m, 4H).
13C NMR (CDCl3): d = 19.3, 25.3, 30.6, 62.2, 63.9, 98.4, 126.1,
126.8, 128.1, 128.9, 129.8, 132.4, 133.3.
EI-LRMS: m/z (%) = 243 (M+, 1), 214 (2), 200 (4), 199 (30), 143
(55), 142 (99), 130 (36), 115 (82), 85 (96), 43 (57), 41 (62).
EI-HRMS: m/z calc for C15H17NO2 (M+) 243.1259. Found:
243.1259.
IR (film): ν = 3350, 3060, 2950, 2880, 1700, 1620, 1460, 1440,
1330, 1290, 1200, 1180, 1040, 980, 920, 740 cm−1.
2-(2-Iodo-1H-indol-3-yl)ethanol THP Ether (9)
1H NMR (CDCl3): d = 1.49 (m, 4H), 1.79 (m, 2H), 3.17 (t, 2H,
J = 6.8 Hz), 3.46 (m, 1H), 3.60 (q, 1H, J = 7.0 Hz), 3.77 (m, 1H),
3.81 (s, 3H), 3.97 (q, 1H, J = 7.0 Hz), 4.58 (t, 1H, J = 2.5 Hz), 6.19
(d, 1H, J = 15.9 Hz), 7.08 (t, 1H, J = 7.5 Hz), 7.26 (m, 1H), 7.27 (d,
1H, J = 7.5 Hz), 7.61 (d, 1H, J = 7.5 Hz), 7.85 (d, 1H, J = 15.9 Hz),
8.61 (s, 1H).
13C NMR (CDCl3): d = 19.3, 24.9, 25.3, 30.5, 51.6, 62.0, 67.5, 98.8,
110.9, 113.5, 119.8, 119.9, 124.8, 128.3, 130.5, 132.7, 137.3, 167.6.
EI-LRMS: m/z (%) = 329 (M+, 21), 227 (29), 214 (33), 201 (99),
167 (69), 154 (75), 128 (6), 115 (6), 85 (67), 67 (19), 57 (19), 28
(23).
A mixture of isonitrile (8, 216 mg, 0.90 mmol), n-Bu3SnH (264 mL,
0.98 mmol), and AIBN (7 mg, 0.04 mmol) in anhyd CH3CN (6 mL)
was heated at 100 °C for 1 h in a tightly capped culture tube under
Ar. After cooling to r.t., pyridine (80 mL, 0.99 mmol) and I2 (249
mg, 0.98 mmol) were added to the mixture. The mixture was stirred
for 10 min at r.t., then partitioned twice between hexane and
CH3CN. The combined CH3CN extracts were evaporated to dryness
in vacuo. The crude product was purified by flash column chroma-
tography on silica gel eluting with Et2O/hexane (2:3) to give 9 (156
mg, 47%) as a colorless oil.
IR (film): ν = 3390, 3250, 3050, 2940, 2860, 1450, 1350, 1280,
1200, 1140, 1120, 1070, 1020, 900, 870, 800, 740 cm−1.
EI-HRMS: m/z calc for C19H23NO4 (M+) 329.1627. Found:
329.1630.
1H NMR (CDCl3): d = 1.25−1.89 (m, 6H), 3.02 (t, 2H, J = 7.4 Hz),
3.47 (m, 1H), 3.61 (q, 1H, J = 9.6 Hz), 3.81 (m, 1H), 3.93 (q, 1H,
J = 9.6 Hz), 4.64 (t, 1H, J = 3.2 Hz) 7.07 (t, 1H, J = 7.4 Hz), 7.12 (t,
1H, J = 7.0 Hz), 7.27 (d, 1H, J = 7.0 Hz), 7.58 (d, 1H, J = 7.4 Hz),
8.20 (s, 1H).
13C NMR (CDCl3): d = 19.4, 25.4, 27.6, 30.6, 62.1, 66.9, 78.5, 98.6,
110.2, 118.2, 119.0, 119.6, 122.1, 127.6, 138.8.
EI-LRMS: m/z (%) = 371 (M+, 1), 256 (8), 193 (22), 176 (14), 165
(13), 158 (17), 148 (55), 130 (33), 85 (99), 55 (99), 39 (29).
EI-HRMS: m/z calc for C15H18NO2I1 (M+) 371.0382. Found:
371.0381.
(2-(Hex-1-ynyl-1H-indol-3-yl)ethanol THP Ether (4c)
A mixture of iodoindole (9, 45 mg, 0.12 mmol), Pd(PPh3)2Cl2 (4
mg, 0.006 mmol), CuI (2 mg, 0.01 mmol), and hex-1-yne (70 mL,
0.61 mmol) in anhyd Et2NH in (1 mL) was stirred for 8 h at r.t., un-
der Ar. Then, the mixture was partitioned between Et2O and 3 N
HCl. The combined extracts were washed with sat. NaHCO3 and
then with brine, dried (Na2SO4), filtered, and evaporated to dryness
in vacuo. The crude product was purified by preparative TLC (silica
gel) eluting with Et2O/hexane (1:4) to give 4c (37 mg, 93%) as a
light yellow oil.
IR (film): ν = 3410, 3290, 3060, 2940, 2860, 2220, 1620, 1580,
Methyl (2-(Hex-1-ynyl-1H-indol-3-yl)acetate (4a)
1460, 1350, 1300, 1200, 1120, 1070, 1020, 900, 870, 810, 740 cm−1.
To a mixture of iodoindole (7; 50 mg, 0.16 mmol), Pd(PPh3)2Cl2 (6
mg, 0.01 mmol), and CuI (3 mg, 0.02 mmol) in anhyd Et2NH (2 mL)
was added hex-1-yne (92 mL, 0.80 mmol) at r.t. under Ar. The reac-
tion mixture was stirred for 8 h and then partitioned between Et2O
and 3 N HCl. The combined extracts were washed with sat.
NaHCO3 and then with brine, dried (Na2SO4), filtered, and evapo-
rated to dryness in vacuo. The crude product was purified by prepar-
ative TLC (silica gel) eluting with Et2O/hexane (2:3) to give 4a (38
mg, 89%) as a light yellow oil.
1H NMR (CDCl3): d = 0.96 (t, 3H, J = 7.2 Hz), 1.45−1.89 (m, 10H),
2.47 (t, 2H, J = 6.8 Hz), 3.15 (t, 2H, J = 7.6 Hz), 3.50 (m, 1H,), 3.70
(q, 1H, J = 9.3 Hz), 3.86 (m, 1H), 4.02 (q, 1H, J = 9.3 Hz), 4.68 (t,
1H, J = 3.8 Hz), 7.06 (m, 2H), 7.22 (m, 1H), 7.61 (d, 1H, J = 7.7
Hz), 8.27 (s, 1H).
13C NMR (CDCl3): d = 13.5, 19.2, 19.4, 21.9, 25.4, 25.6, 30.6, 62.1,
67.3, 72.2, 96.0, 98.6, 110.5, 117.3, 117.5, 117.8, 119.1, 119.5,
122.8, 127.4, 135.4.
IR (film): ν = 3350, 3050, 2950, 2920, 2870, 2320, 1730, 1460,
EI-LRMS: m/z (%) = 325 (M+, 38), 283 (3), 223 (51), 210 (99), 197
(62), 170 (50), 168 (21), 167 (21), 155 (14), 85 (5).
EI-HRMS: m/z calc for C21H27NO2 (M+) 325.2042. Found:
325.2041.
1430, 1350, 1300, 1270, 1250, 1170, 1010, 750 cm−1.
1H NMR (CDCl3): d = 0.98 (t, 3H, J = 7.2 Hz), 1.46−1.66 (m, 4H),
2.49 (t, 2H, J = 6.7 Hz), 3.70 (s, 3H), 3.87 (s, 2H), 7.14 (m, 2H),
7.23 (m, 1H), 7.56 (d, 1H, J = 7.6 Hz), 8.18 (s, 1H).
13C NMR (CDCl3): d = 13.6, 19.3, 21.9, 30.6, 31.0, 51.9, 71.5, 96.9,
Methyl 2-(2-(2-Carbomethoxy)vinyl-1H-indol-3-yl)acetate (4d)
A mixture of isonitrile (5; 52 mg, 0.28 mmol), n-Bu3SnH (82 mL,
0.30 mmol), and AIBN (2 mg, 0.01 mmol) in anhyd CH3CN (2 mL)
was heated at 100 °C for 1.5 h in a tightly capped culture tube under
Ar. After cooling to r.t., the mixture was treated with I2 (78 mg, 0.31
mmol) in one portion. The mixture was stirred at r.t. for 10 min prior
to the addition of methyl acrylate (75 mL 0.84 mmol), Pd(OAc)2 (2
mg, 0.01 mmol), Et3N (84 mL, 0.60 mmol), and (o-tol)3P (10 mg,
0.03 mmol). After heating at 80 °C for 8 h under Ar, the mixture
110.7, 112.8, 118.8, 119.0, 120.1, 123.1, 127.0, 135.3, 172.0.
EI-LRMS: m/z (%) = 269 (M+, 53), 210 (99), 170 (13), 167 (25),
154 (16), 139 (10), 49 (4).
EI-HRMS: m/z calc for C17H19NO2 (M+) 269.1416. Found:
269.1418.
Synthesis 2000, No. 3, 429–434 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Disubstituted Indoles by Palladium-Mediated Coupling of 2-Iodoindoles
433
was partitioned between Et2O and a 1:1 mixture of 3 N HCl and
brine. The combined extracts were washed with sat. NaHCO3 and
brine, dried (Na2SO4), filtered, and evaporated to dryness in vacuo.
The crude product was purified by preparative TLC (silica gel) elut-
ing with Et2O/hexane (2:3) to give cis-4d (17 mg, 22%) as a light
yellow oil and trans-4d (45 mg, 59%) as white crystals.
Methyl 2-(2-(trans-1-Oxo-2-heptenyl)-1H-indole-3-yl)acetate
(4f)
A mixture of iodoindole (7, 62 mg, 0.20 mmol), 1-tri-n-butylstan-
nylhexene (131 mg, 0.30 mmol), PdCl2(dppf)•CH2Cl2 (7 mg, 0.01
mmol), and a trace amount of 2,6-di-t-butyl-4-methylphenol (BHT)
in dry DMF (1 mL) was heated at 70 °C under atmospheric pressure
of CO. The mixture was stirred for 12 h, then partitioned between
Et2O and a one third sat. KF. The combined extracts were washed
with diluted brine, dried (Na2SO4), filtered, and evaporated to dry-
ness in vacuo. The crude product was purified by preparative TLC
(silica gel) eluting with Et2O/hexane (2:3) to give 4f (46 mg, 78%)
as a light yellow solid: mp 78−79 °C.
cis-4d
IR (film): ν = 3300, 3050, 3030, 3010, 2970, 1740, 1700, 1600,
1530, 1500, 1450, 1430, 1340, 1270, 1200, 1030, 1010, 830, 750
cm−1.
1H NMR (CDCl3): d = 3.66 (s, 3H), 3.83 (s, 3H), 3.89 (s, 2H), 5.86
(d, 1H, J = 12.9 Hz), 7.09 (d, 1H, J = 12.9 Hz), 7.12 (t, 1H, J = 8.1
Hz), 7.29 (t, 1H, J = 8.1 Hz), 7.43 (d, 1H, J = 8.1 Hz), 7.65 (d, 1H,
J = 8.1 Hz), 11.99 (s, 1H).
13C NMR (CDCl3): d = 30.4, 52.0, 52.1, 112.0, 112.7, 114.8, 119.7,
120.1, 125.2, 127.2, 130.9, 132.0, 136.4, 169.0, 171.4.
EI-LRMS: m/z (%) = 273 (M+, 31), 241 (5), 214 (18), 182 (26), 154
IR (film): ν = 3320, 3050, 2950, 2920, 2860, 1730, 1650, 1600,
1540, 1430, 1340, 1250, 1210, 1170, 1020, 930, 740 cm−1.
1H NMR (CDCl3): d = 0.93 (t, 3H, J = 7.1 Hz), 1.42 (m, 4H), 2.27
(q, 2H, J = 6.6 Hz), 3.75 (s, 3H), 4.16 (s, 2H), 6.83 (d, 1H, J = 15.3
Hz), 7.03 (t, 1H, J = 6.7 Hz), 7.13 (m, 1H), 7.32 (m, 2H), 7.66 (d,
1H, J = 8.1 Hz), 9.58 (s, 1H).
13C NMR (CDCl3): d = 13.8, 22.2, 27.8, 30.0, 31.2, 32.4, 52.1,
112.2, 114.2, 120.6, 126.1, 126.5, 129.4, 133.2, 136.1, 148.2, 171.8,
182.8.
(99), 127 (10), 77 (5), 44 (14).
EI-HRMS: m/z calc for C15H15NO4 (M+) 273.1001. Found:
273.1001.
EI-LRMS: m/z (%) = 299 (M+, 22), 242 (38), 240 (55), 226 (19),
210 (22), 196 (45), 182 (99), 168 (60), 156 (34), 128 (34), 101 (9).
EI-HRMS: m/z calc for C18H21NO3 (M+) 299.1521. Found:
299.1519.
trans-4d: mp 145−146 °C.
IR (film): ν = 3350, 3070, 3050, 3010, 2960, 2850, 1720, 1690,
1630, 1620, 1460, 1440, 1320, 1290, 1200, 1150, 1030, 970, 850,
750 cm−1.
1H NMR (CDCl3): d = 3.71 (s, 3H), 3.80 (s, 3H), 3.88 (s, 2H), 6.12
(dd, 1H, J = 1.1, 15.8 Hz), 7.09 (t, 1H, J = 6.1 Hz), 7.28 (m, 2H),
7.58 (d, 1H, J = 8.0 Hz), 7.70 (dd, 1H, J = 2.3, 15.8 Hz), 8.65 (s,
1H).
13C NMR (CDCl3): d = 30.1, 51.8, 52.3, 111.2, 114.1, 114.9, 119.8,
120.5, 125.1, 128.2, 130.9, 131.7, 137.2, 167.3, 173.8.
EI-LRMS: m/z (%) = 273 (M+, 36), 241 (8), 214 (61), 182 (29), 154
(99), 127 (13), 77 (11), 44 (6), 28 (14).
EI-HRMS: m/z calc for C15H15NO4 (M+) 273.1001. Found:
273.1003.
Methyl 2-(2-Methoxycarbonyl-1H-indol-3-yl)acetate (4g)
A mixture of iodoindole (7; 109.9 mg, 0.349 mmol) and PdCl2(dp-
pf)•CH2Cl2 (14.2 mg, 0.0174 mmol) in MeOH (1.7 mL) in a culture
tube equipped with septum was bubbled with CO for 3 min. After
bubbling, Et3N (73 mL, 0.524 mmol) was added, and then the tube
was capped, and heated at 80 °C for 5 h under atmospheric pressure
of CO. The reaction mixture was partitioned between Et2O and a 1:2
mixture of 3 N HCl and brine. The organic layer was washed with
1:1 mixture of sat. NaHCO3 and brine, and with brine, dried
(MgSO4), filtered, and evaporated to dryness in vacuo. The crude
product was purified by preparative TLC (silica gel) eluting with
EtOAc/hexane (3:7) to give 4g (76.9 mg, 89%) as a white solid: mp
130−131 °C.
Methyl [2-(trans-Hex-1-enyl)-1H-indol-3-yl]acetate (4e)
To a mixture containing 2-iodoindole prepared as above from isoni-
trile (5, 52 mg, 0.28 mmol), n-Bu3SnH (82 mL, 0.30 mmol), AIBN
(2 mg, 0.01 mmol), and I2 (78 mg, 0.31 mmol) were added 1-tri-n-
butylstannylhexene (247 mg, 0.56 mmol), Pd(PPh3)4 (16 mg, 0.01
mmol), and CuI (53 mg, 0.28 mmol). The mixture was heated at
80 °C for 10 h under Ar, and then partitioned between Et2O and a
1:1 mixture of 3 N HCl and brine. The combined extracts were
washed with sat. KF and then with brine, dried (Na2SO4), filtered,
and evaporated to dryness in vacuo. The crude product was purified
by preparative TLC (silica gel) eluting with Et2O/hexane (3:7) to
give 4e (50 mg, 66%) as a light yellow oil.
IR (neat): ν = 3343, 1714, 1559, 1457, 1330, 1256 cm−1.
1H NMR (CDCl3): d = 3.70 (s, 3H), 3.94 (s, 3H), 4.12 (s, 2H), 7.17
(t, 1H, J = 7.2 Hz), 7.32−7.41 (m, 2H), 7.65 (d, 1H, J = 7.6 Hz),
8.85 (br s, 1H).
13C NMR (CDCl3): d = 30.4, 51.8, 52.0, 111.9, 115.8, 120.5, 120.6,
124.1, 125.7, 127.7, 135.8, 162.3, 171.8.
EI-LRMS: m/z = 247 (M+).
FAB-HRMS: m/z calc for C13H13NO4 (M+) 247.0844. Found:
247.0844.
IR (film): ν = 3400, 3030, 2950, 2930, 2860, 1730, 1450, 1310,
Anal. Calcd for C13H13NO4: C, 63.15, H, 5.30, N, 5.67. Found C,
62.89, H, 5.33, N, 5.62.
1270, 1160, 1020, 960, 740 cm−1.
1H NMR (CDCl3): d = 0.94 (t, 3H, J = 7.0 Hz), 1.42 (m, 4H), 2.27
(dd, 2H, J = 6.6, 6.9 Hz), 3.66 (s, 3H), 3.77 (s, 2H), 6.03 (dt, 1H,
J = 6.9, 16.0 Hz), 6.52 (d, 1H, J = 16.0 Hz), 7.08 (t, 1H, J = 6.9 Hz),
7.16 (t, 1H, J = 7.0 Hz), 7.27 (d, 1H, J = 7.0 Hz), 7.55 (d, 1H,
J = 7.1 Hz), 8.06 (s, 1H).
13C NMR (CDCl3): d = 13.9, 22.2, 30.1, 31.4, 32.9, 52.0, 106.0,
110.4, 118.4, 118.7, 119.7, 122.5, 128.7, 130.8, 133.7, 135.7, 172.2.
EI-LRMS: m/z (%) = 271 (M+, 71), 228 (11), 212 (99), 198 (13),
182 (11), 168 (94), 154 (31), 130 (23), 28 (46).
EI-HRMS: m/z calc for C17H21NO2 (M+) 271.1572. Found:
271.1574.
Methyl 2-(2-Formyl-1H-indol-3-yl)acetate (4h)
A mixture of iodoindole (7; 150.3 mg, 0.477 mmol) and PdCl2(dp-
pf)•CH2Cl2 (19.5 mg, 0.0239 mmol) in DMF (3.4 mL) was heated
at 80 °C for 15 min under atmospheric pressure of CO, and then n-
Bu3SnH (156 mL, 0.770 mmol) was added dropwise over 3 h using
a syringe pump. The mixture was evaporated and partitioned be-
tween Et2O and 1 N HCl. The combined organic extracts were
washed with sat. KF, sat. NaHCO3, and brine, dried (MgSO4), fil-
tered, and evaporated to dryness in vacuo. The crude product was
purified by preparative TLC (silica gel) eluting with EtOAc/ben-
zene (1:19) to give 4h (88.2 mg, 85%) as a white solid: mp 122.7−
123.1 °C.
Synthesis 2000, No. 3, 429–434 ISSN 0039-7881 © Thieme Stuttgart · New York

434
H. Tokuyama et al.
PAPER
IR (neat): ν = 3318, 1737, 1657 cm−1.
IR (film): ν = 3480, 3050, 2950, 2860, 1730, 1610, 1450, 1320,
1270, 1170, 1010, 750, 700 cm−1.
1H NMR (CDCl3): d = 3.72 (s, 3H), 4.11 (s, 2H), 7.18−7.22 (m, 1H),
7.41 (d, 2H, J = 4.0 Hz), 7.76 (d, 1H, J = 8.8 Hz), 8.97 (br s, 1H),
10.07 (s, 1H).
13C NMR (CDCl3): d = 29.7, 52.5, 112.5, 119.5, 121.1, 121.3,
127.4, 127.6, 132.6, 137.2, 170.9, 180.8.
EI-LRMS: m/z = 217 (M+).
FAB-HRMS: m/z calc for C12H11NO3 (M+) 217.0739. Found:
1H NMR (CDCl3): d = 3.75 (s, 3H), 3.91 (s, 2H), 7.21 (t, 1H, J = 5.8
Hz), 7.26 (t, 1H, J = 5.8 Hz), 7.36 (d, 1H, J = 8.8 Hz), 7.45 (t, 1H,
J = 7.3 Hz), 7.51 (t, 2H, J = 6.8 Hz), 7.67 (d, 2H, J = 7.5 Hz), 7.72
(d, 1H, J = 6.8 Hz), 8.32 (s, 1H).
13C NMR (CDCl3): d = 30.9, 52.0, 105.3, 110.9, 119.1, 120.0,
122.5, 128.0, 128.2, 128.8, 129.0, 132.2, 135.7, 136.1, 172.8.
EI-LRMS: m/z (%) = 265 (M+, 19), 206 (99), 178 (19), 102 (4), 59
(5).
EI-HRMS: m/z calc for C17H15NO2 (M+) 265.1103. Found:
265.1102.
271.0740.
Anal: Calcd. for C12H11NO3: C; 66.35, H; 5.10, N; 6.45. Found: C;
66.07, H; 5.27, N; 6.40.
Methyl 2-(2-Cyano-1H-indol-3-yl)acetate (4i)
A mixture of iodoindole (7; 115.3 mg, 0.366 mmol), pulverized
KCN (28.1 mg, 0.432 mmol), and Pd(PPh3)4 (21.0 mg, 0.0182
mmol) in THF (1.2 mL) was refluxed for 6 h under Ar. After cool-
ing to r.t., the mixture was filtered and evaporated to dryness. The
crude product was purified by preparative TLC (silica gel) eluting
with MeOH/CH2Cl2/hexane (7:63:30) to give 4i (59.2 mg, 79%) as
a light orange solid: mp 81.0−82.0 °C.
Acknowledgement
The authors thank the Ministry of Education, Sports, and Culture
Japan for their partial financial support of this work.
References
(1) Present address: Tularik Inc., Two Corporate Drive, South
San Francisco, CA 94080, USA.
(2) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1.
Saxton, J. E. Indoles, Part Four; Wiley-Interscience: New
York, 1983.
(3) Sundberg, R. J. Indoles; Academic Press: London, 1996, and
references cited therein.
(4) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, Jr, B.
W. J. Am. Chem. Soc. 1974, 96, 5495.
IR (neat): ν = 3324, 2953, 2224, 1728, 1437, 1347, 1213, 1174, 746.
1H NMR (CDCl3): d = 3.73 (s, 3H), 3.95 (s, 2H), 7.21−7.25 (m, 1H),
7.39 (m, 2H), 7.66 (d, 1H, J = 7.6 Hz), 8.60 (br s, 1H).
13C NMR (CDCl3): d = 30.7, 52.4, 106.0, 111.9, 113.4, 120.4,
120.9, 121.6, 125.8, 126.5, 136.8, 170.5.
EI-LRMS: m/z = 214 (M+).
FAB-HRMS: m/z calc for C12H10N2O2 (M+) 214.0742. Found:
214.0744.
Fürstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468.
(5) a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994,
116, 3127.
Anal. Calcd for C12H10N2O2: C, 67.28, H, 4.71, N, 13.08. Found C,
67.07, H, 4.72, N, 13.03.
b) Kobayashi, Y.; Fukuyama, T. J. Heterocycl. Chem. 1998,
35, 1043.
Methyl 2-(2-Phenyl-1H-indol-3-yl)acetate (4j)
(6) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Ohno, A.; Oka, S.;
Hayama, N. Bull. Chem. Soc. Jpn. 1975, 48, 3298.
(7) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034.
A mixture of iodoindole (7, 100 mg, 0.318 mmol), PhB(OH)2 (42.2
mg, 0.346 mmol), K2CO3 (110 mg, 0.798 mmol), and Pd(OAc)2
(3.5 mg, 0.016 mmol) in a 1:1 mixture of acetone/H2O (1.6 mL) was
stirred at 65 °C for 30 min under Ar. After cooling to r.t., the mix-
ture was partitioned between Et2O and 1 N HCl. The organic layers
were washed with sat. NaHCO3, and then with brine, dried
(MgSO4), filtered, and evaporated to dryness in vacuo. The crude
product was purified by preparative TLC (silica gel) eluting with
MeOH/CH2Cl2/hexane (4:36:60) to give 4j (79.6 mg, 94%) as a
light yellow foam: mp 106−107 °C.
Article Identifier:
1437-210X,E;2000,0,03,0429,0434,ftx,en;Z08399SS.pdf
Synthesis 2000, No. 3, 429–434 ISSN 0039-7881 © Thieme Stuttgart · New York