Synthesis of 2,3-disubstituted indole using palladium(II)-catalyzed cyclization with alkenylation reaction.

Article abstract of DOI:10.1248/cpb.50.235

The reaction of ethyl 2-ethynylphenylcarbamate derivative with alkenes in the presence of a palladium(II) catalyst, copper dichloride and tetrabutylammonium fluoride (TBAF) produced 2-substituted 3-ethenylindoles during refluxing. The intramolecular cycli

Full text of DOI:10.1248/cpb.50.235

February 2002
Chem. Pharm. Bull. 50(2) 235—238 (2002)
235
Synthesis of 2,3-Disubstituted Indole Using Palladium(II)-Catalyzed
Cyclization with Alkenylation Reaction
Akito YASUHARA,* Yousuke TAKEDA, Naoyuki SUZUKI, and Takao SAKAMOTO
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980–8578, Japan.
Received September 12, 2001; accepted October 31, 2001
The reaction of ethyl 2-ethynylphenylcarbamate derivative with alkenes in the presence of a palladium(II)
catalyst, copper dichloride and tetrabutylammonium fluoride (TBAF) produced 2-substituted 3-ethenylindoles
during refluxing. The intramolecular cyclization reaction of ethyl 2-ethynylphenylcarbamates, which have an
ethenyl part in the ethynyl group, was also used to produce carbazole derivatives.
Key words palladium-catalyzed cyclization; indole; carbazole; tetrabutylammonium fluoride
Heterocyclic compounds, especially indoles, widely occur influenced the yields of the cyclization. A stoichiometric
in natural products and have unique biological activities.1) amount of TBAF was required (runs 1, 2), but the cy-
Many synthetic methods for producing the indole structure clization reaction under dry conditions using anhydrous
have been reported.2) The cyclization of the 2-ethynylanilines CuCl2 instead of CuCl2·H2O in dry tetrahydrofuran (THF)
is one of the most useful methods for the synthesis of multi- occurred with only a low yield (run 8). Differences in the re-
substituted indoles, because 2-ethynylanilines can be easily action solvent did not significantly influence the yields (runs
prepared from 2-haloanilines with terminal acetylenes by the 4—7). For the cyclization reaction, Cu(OAc)2, 2,3-dichloro-
Sonogashira reaction,3) and many synthetic methods of the 2- 5,6-dicyanobenzoquinone (DDQ), and pyridine 1-oxide did
haloanilines have been reported. For example, the prepara- not work at all as a re-oxidant (runs 9—11). As a result, the
tion for 2-haloanilines is easily achieved by the ortho-lithia- reaction using TBAF (1.2 eq), palladium dichloride and
tion of N-protected anilines with alkyllithium.4) In our pre- CuCl2·H2O as a re-oxidant in THF at refluxing temperature
vious paper, we reported the tetrabutylammonium fluoride gave 2a in 64% yield (run 5). The cyclization of 1a with
(TBAF)-promoted cyclization of 2-alkynylanilines to prepare ethyl acrylate under the previous conditions (PdCl2, CuCl2,
the 2-substituted indoles.5) The method under mild condi- K2CO3 and NaOAc in acetonitrile at 50 °C) proceeded in
tions is useful for the synthesis of substituted indoles except only 34% yield.6)
for the 3-substituted indoles. On the other hand, we reported
Under the same reaction conditions, the cyclization of
the palladium(II) catalyzed cyclization of 2-ethynylanilines various 2-ethynylanilines with alkenes was investigated. As
in the presence of alkenes to give the 2,3-disubstituted in- shown in Table 2, the synthesis of 2-aryl- (e.g., run 2) and 2-
doles via the Heck reaction of the indolylpalladium interme- alkyl-3-alkenylindoles (run 6) could be achieved in 42—68%
diate with alkenes (Chart 1).6) However, this cyclization has using the corresponding alkenes and 2-ethynylanilines, which
the following limitations; 1) the alkenes must have an elec- were prepared by the Sonogashira reaction of the 2-iodoani-
tron-withdrawing group, and 2) the mesyl group as a protect- lines with the terminal alkynes. The cyclization reaction in
ing group for the primary amino groups of anilines is re- the presence of alkenes having either an electron-withdraw-
quired for the cyclization.
ing (runs 1, 2, 6—11) or electron-donating group (runs 3, 4)
Moreover, we reported that the palladium-catalyzed cross- occurred. The synthesis of the 2,3-disubstituted indoles with
coupling reaction of N-(2-iodophenyl)methanesulfonamide a functional group like cyano (run 8), chloro (runs 7, 9), or
with terminal alkynes produced the 2-substituted indoles in- methoxy group (run 5) in benzene can be achieved under the
stead of the corresponding 2-ethynylanilnes.7) In short, the same conditions using the corresponding ethynylanilines
Sonogashira reaction of N-(2-alkynylphenyl)methanesulfon-
amides with terminal acetylenes under the general conditions
produces the corresponding indoles instead of 2-ethynylani-
lines, and only the N-(2-alkynylphenyl)methanesulfonamides
are available for the palladium-cyclization reaction with the
alkenylation reaction under the previously reported condi-
tions.6) These facts show the limitation of the synthetic route
for 2-ethynylanilines as a starting material for the palladium
catalyzed cyclization with alkenylation reaction.
Based on the background described above, we now report
the cyclization reaction of ethyl 2-alkynylphenylcarbamates
in the presence of alkenes using a palladium(II) catalyst and
TBAF to produce 2,3-disubstituted indoles.
The reaction conditions for the cyclization reaction of
alkynylanilines (1) to form 2,3-disubutituted indoles (2) were
examined using ethyl 2-phenylethynylphenylcarbamate and
Chart 1
methyl acrylate as shown in Table 1. The amount of TBAF
To whom correspondence should be addressed. e-mail: yasuhara@mail.pharm.tohoku.ac.jp
© 2002 Pharmaceutical Society of Japan

236
Vol. 50, No. 2
Table 1. The Cyclization Reaction in Presence of Methyl Acrylate under Verious Conditions
Run
TBAF
COOMe
Solvent
Oxidant
Time (h)
2a
3a
1
2
3
4
5
6
7
8
9
1.0
0.25
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
THF
THF
THF
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2
18
2
17
4
52
22
63
64
60
52
54
17
0
0
42
11
17
19
9
15
0
0
THF
MeCN
THF–H2O
MeCN–H2O
Dry THF
THF
2
20
47
24
24
24
24
Cu(OAc)2
DDQ
pyridine 1-oxide
10
11
THF
THF
0
0
0
0
Table 2. The Cyclizaiton Reaction of Various 2-Ethynylanilines in Presence of Alkenes
Run
R1
R2
R3
R6
Time (h)
2
3
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
COOEt
Boc
Ms
Ph
Ph
Bu
Ph
Ph
Bu
Ph
Ph
Ph
Ph
tBu
COOMe
COOMe
COOMe
Bu
H
H
H
H
MeO
H
Cl
CN
Cl
H
4
4
1
3
8
6
6
22
4.5
16
25
64
57
58
68
42
42
66
66
31
51
22
17
19
39
0
0
34
0
0
0
9
16
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Bu
COOMe
COOMe
COOMe
CN
Ac
Ac
10
11
j
k
H
Chart 2
with the functional groups as the starting materials.
um chlorochromate, and the Horner–Emmons reaction with
When the reaction of the 2-ethynylaniline derivative with trimethyl phosphonoacetate as shown in Chart 2. The cy-
an internal alkene occurs, it can construct another carbo- clization reaction of 7 proceeded, but it gave a mixture of the
cycle. We first tried the cyclization of methyl 8-[2-(ethoxy- corresponding carbazole (8) and unknown compound, which
carbonylamino)phenyl]oct-2-en-7-ynoate (7). According to could not be completely separated by column chromatogra-
Grissom’s synthetic method,8) 7 was prepared from ethyl 2- phy. In order to confirm the structure of 8, we tried the de-
iodophenylcarbamate in 71% overall yield via three steps, protection of the N-ethoxycarbonyl group with sodium
i.e., the Sonogashira reaction, the oxidation with pyridini- methoxide in THF to get methyl 2-(1,2,3,4-trihydrocarbazol-

February 2002
237
Chart 3
4-ylidene)acetate (9) in 39% yield (2 steps). Compound 9 Colorless viscous oil. IR (KBr) cmϪ1: 1734, 1632. 1H-NMR (CDCl3) d: 1.23
(9H, s), 3.75 (3H, s), 6.54 (2H, d, Jϭ16.2 Hz), 7.33—7.49 (7H, m), 7.54
(1H, d, Jϭ16.2 Hz), 7.92 (1H, d, Jϭ7.1 Hz), 8.31 (1H, d, Jϭ7.1 Hz). High
resolution (HR)-MS m/z: 377.1627 (Calcd for C23H23NO4: 377.1622).
had an E-configuration in the double bond, which was de-
termined from the nuclear Overhauser effect spectroscopy
(NOESY) spectrum. The H-10 (d 6.40) proton of 9 has a
1-tert-Butoxycarbonyl-2-phenylindole (3b): Colorless scales from
1
hexane–Et2O; mp 76—77 °C (lit.10) 76—77 °C). IR (KBr) cmϪ1: 1720. H-
NMR (CDCl3) d: 1.30 (9H, s), 6.65 (1H, s), 7.23—7.42 (7H, m), 7.54 (1H,
d, Jϭ8.2 Hz), 8.22 (1H, d, Jϭ8.2 Hz). MS m/z 293 (Mϩ).
NOESY correlation to the H-5 (d 7.90—7.93) proton.
We investigated the intramolecular reaction of ethyl 2-[2-
(2-propenyl)phenylalkynyl]phenylcarbamate (11) which was
also easily prepared by the Sonogashira reaction of 1-bromo-
2-(2-propenyl)benzene with a terminal acetylene. We pro-
posed that the alkene moiety in 11 connects to the benzene
ring which is an electron withdrawing group, and the carbon-
carbon bond formation occurred on the terminal carbon atom
of the alkene to give 3-methyl-9-ethoxycarbonylbenzo[a]car-
bazole (12).
The results of this study show that the palladium(II)-cat-
alyzed cyclization reaction of the ethynylphenylcarbamates
with TBAF in the presence of not only alkenes with electron-
withdrawing groups, but also alkenes such as hexene, gave
the corresponding 2,3-disubstituted indoles, and the in-
Methyl (E)-3-(1-Methylesulfonyl-2-butylindol-3-yl)propenoate (3c): Col-
orless needles form hexane–Et2O; mp 128—129 °C. IR (KBr) cmϪ1: 1710,
1377. 1H-NMR (CDCl3) d: 0.96 (3H, t, Jϭ7.4 Hz), 1.41—1.48 (2H, m),
1.65—1.72 (2H, m), 3.09 (3H, s), 3.15 (2H, t, Jϭ7.4 Hz), 3.85 (3H, s), 6.58
(1H, d, Jϭ16.0 Hz), 7.34—7.40 (2H, m), 7.84—7.87 (1H, m), 7.89 (1H,
d, Jϭ16.0 Hz), 8.06—8.10 (1H, m). HR-MS m/z: 335.1197 (Calcd for
C17H21NO4S: 335.1191). Anal. Calcd for C17H21NO4S·1/4H2O: C, 60.07; H,
6.37; N, 4.12; S, 9.43. Found: C, 60.10; H, 6.29; N, 4.13; S, 9.61.
1-Methylesulfonyl-2-phenylindole (3c): Colorless needles from hex-
1
ane–Et2O; mp 115—116 °C (lit.5) 116—117 °C). IR (KBr) cmϪ1: 1370. H-
NMR (CDCl3) d: 2.74 (3H, s), 6.73 (1H, s), 7.35—7.45 (5H, m), 7.56—7.63
(3H, m), 8.15 (1H, d, Jϭ7.1 Hz). MS m/z: 271 (Mϩ).
1-Ethyoxycarbonyl-2-phenyl-3-[(1E)-hexenyl]indole (2d): Colorless vis-
cous oil; IR (neat) cmϪ1: 1729. 1H-NMR (CDCl3) d: 0.89 (3H, t, Jϭ6.3 Hz),
0.98 (3H, t, Jϭ7.1 Hz), 1.29—1.41 (4H, m), 2.14 (2H, q, Jϭ6.3 Hz), 4.15
tramolecular cyclization also gave the corresponding car- (2H, q, Jϭ7.1 Hz), 6.17 (1H, d, Jϭ17.0 Hz), 6.27 (1H, dt, Jϭ17.0, 6.3 Hz),
7.29—7.43 (7H, m), 7.88 (1H, d, Jϭ8.2 Hz), 8.26 (1H, d, Jϭ8.2 Hz). HR-
MS m/z: 347.1901 (Calcd for C23H25NO2: 347.1886).
bazoles, although some problems still remain with respect to
the cyclization reaction yields.
1-Ethoxycarbonyl-2-phenyl-3-[(1E)-hexenyl]-6-methoxyindole (2e): Col-
orless viscous oil. IR (neat) cmϪ1: 1730. 1H-NMR (CDCl3) d: 0.94 (6H, m),
Experimental
1.37 (4H, m), 2.14 (2H, q, Jϭ6.9 Hz), 3.91 (3H, s), 4.12 (2H, q, Jϭ7.1 Hz),
General All melting points and boiling points are uncorrected. IR spec- 6.15 (1H, d, Jϭ16.2 Hz), 6.26 (1H, dt, Jϭ16.2, 6.5 Hz), 6.95 (1H, dd, Jϭ8.8,
tra were taken on a JASCO IR-810 and Shimadzu FT-IR 8400 spec- 2.5 Hz), 7.30—7.44 (5H, m), 7.75 (1H, d, Jϭ8.8 Hz), 7.87 (1H, d, Jϭ
trophotometer. 1H-NMR spectra were recorded on Varian Gemini 200 2.5 Hz). HR-MS m/z: 377.1968 (Calcd for C24H27NO3: 377.1990).
(300 MHz) spectrometers. Chemical shifts are expressed in d (ppm) values
Methyl (E)-3-(1-Ethoxycarbonyl-2-butylindol-3-yl)propenoate (2f): Col-
with tetramethylsilane (TMS) as the internal reference, and coupling con- orless viscous oil. IR (neat) cmϪ1: 1736, 1628. 1H-NMR (CDCl3) d: 0.98
stants are expresses in herts (Hz). Mass spectra (MS) and high resolution (3H, t, 7.4), 1.39—1.65 (7H, m), 3.20 (2H, t, 7.4), 3.84 (3H, s), 4.56 (2H, q,
mass spectra were recorded on JMS-DX303 and JMS-AX500 instruments. 7.1), 6.57 (1H, d, 16.0), 7.30—7.34 (2H, m), 7.82—7.85 (1H, m), 7.93 (1H,
Column chromatography was carried out with silica gel [Silica gel 60 N d, 16.0), 8.14—8.17 (1H, m). HR-MS m/z: 329.1642 (Calcd for C19H23NO4:
(Kanto chemical)]
329.1627).
General Procedure A mixture of 2-ethynyl anilines (1 mmol), alkenes
(1.5 mmol), PdCl2 (5 mol%), CuCl2·2H2O, 1 M TBAF–THF solution (1.2 ml)
1-Ethoxycarbonyl-2-butylindole (3f): White solid. bp 180—190 °C/3
1
mmHg, mp 35 °C (lit.5) 35 °C). IR (KBr) cmϪ1: 1730. H-NMR (CDCl3) d:
and THF (20 ml) was refluxed. Water was added to the mixture and the mix- 0.97 (3H, t, Jϭ7.4 Hz), 1.49—1.51 (5H, m), 1.64—1.74 (2H, m), 3.01 (2H,
ture was extracted with AcOEt. The residue obtained from the extract was t, Jϭ6.8 Hz), 4.52 (2H, q, Jϭ7.4 Hz), 6.37 (1H, s), 7.17—7.24 (2H, m), 7.44
purified by silica gel column chromatography. The product was purified by (1H, d, Jϭ5.9 Hz), 8.11 (1H, d, Jϭ8.2 Hz). MS m/z 245 (Mϩ).
distillation or recrystallization.
Methyl (E)-3-(1-Ethoxycarbonyl-2-phenyl-6-chloroindol-3-yl)propenoate
(2g): Colorless needles from acetone–hexane. mp 172—173 °C. IR (KBr)
Methyl (E)-3-(1-Ethoxycarbonyl-2-phenylindol-3-yl)propenoate (2a):
1
Colorless prisms from hexane–acetone; mp 115—116 °C. IR (KBr) cmϪ1
:
cmϪ1: 1745, 1722, 1634. H-NMR (CDCl3) d: 0.94 (3H, t, Jϭ7.2 Hz), 3.75
1732, 1699. 1H-NMR (CDCl3) d: 0.98 (3H, t, Jϭ7.1 Hz), 3.75 (3H, s), 4.16 (3H, s), 4.18 (2H, q, Jϭ7.2 Hz), 6.48 (1H, d, Jϭ16.2 Hz), 7.32—7.48 (6H,
(2H, q, Jϭ7.1 Hz), 6.57 (1H, d, Jϭ16.5 Hz), 7.31—7.48 (7H, m), 7.55 (1H,
d, Jϭ16.2 Hz), 7.93 (1H, d, Jϭ7.4 Hz), 8.29 (1H, d, Jϭ7.4 Hz). MS m/z 349
m), 7.50 (1H, d, Jϭ16.2 Hz), 7.82 (1H, d, Jϭ8.7 Hz), 8.32 (1H, d,
Jϭ1.8 Hz). HR-MS m/z: 383.0912 (Calcd for C21H18ClNO4: 383.0923).
(Mϩ). Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, Anal. Calcd for C21H18ClNO4: C, 65.71; H, 4.73; N, 3.65. Found: C, 65.79;
72.23; H, 5.55; N, 3.97.
H, 4.84; N, 3.58.
1-Ethoxycarbonyl-2-phenylindole (3a)5): Colorless viscous oil. IR (neat)
Methyl (E)-3-(1-Ethoxycarbonyl-2-phenyl-6-cyanoindol-3-yl)propenoate
cmϪ1: 1736. 1H-NMR (CDCl3) d: 1.09 (3H, t, Jϭ7.1 Hz), 4.24 (2H, q, (2h): Colorless needles from acetone–hexane. mp 237—239 °C. IR (KBr)
Jϭ7.1 Hz), 6.60 (1H, s), 7.24—7.46 (7H, m), 7.56 (1H, d, Jϭ7.3 Hz), 8.20 cmϪ1: 2222, 1753, 1722, 1637. 1H-NMR (CDCl3) d: 1.00 (3H, t, Jϭ7.1 Hz),
(1H, d, Jϭ8.2 Hz). MS m/z 265 (Mϩ).
Methyl (E)-3-(1-tert-Butoxycarbonyl-2-phenylindol-3-yl)propenoate (2b):
3.76 (3H, s), 4.21 (2H, q, Jϭ7.1 Hz), 6.47 (1H, d, Jϭ16.5 Hz), 7.33—7.53
(6H, m), 7.64 (1H, d, Jϭ8.5 Hz), 7.98 (1H, d, Jϭ8.5 Hz), 8.65 (1H, s). HR-

238
Vol. 50, No. 2
MS m/z: 374.1257 (Calcd for C22H18N2O4: 374.1265). Anal. Calcd for 1.80 mmol) and THF (30 ml) were added to the residue obtained from the
C22H18N2O4·1/4H2O: C, 69.74; H, 4.92; N, 7.39. Found: C, 70.00; H, 5.03;
N, 7.31.
AcOEt extract. After the mixture had been refluxed for 5 h, the mixture was
concentrated under reduced pressure. The residue was dissolved with AcOEt
(E)-3-(1-Ethoxycarbonyl-2-phenyl-6-chloroindol-3-yl)propenitrile (2i): (50 ml) and the AcOEt solution was washed with brine (50 mlϫ2). The
1
Pale yellow viscous oil. IR (neat) cmϪ1: 2216, 1742. H-NMR (CDCl3) d: residue obtained from the AcOEt extract purified by silica gel column chro-
0.98 (3H, t, Jϭ7.1 Hz), 4.16 (2H, q, Jϭ7.1 Hz), 5.84 (1H, d, Jϭ16.8 Hz), matography using AcOEt–hexane (1 : 15) as an eluent. The product was pu-
7.15 (1H, d, Jϭ16.8 Hz), 7.30—7.52 (6H, m), 7.67 (1H, d, Jϭ8.5 Hz), 8.34 rified by recrystallization from acetone–hexane. Colorless prisms (152 mg,
1
(1H, s). HR-MS m/z: 350.0833 (Calcd for C20H15ClN2O2: 350.0822).
39%), mp 176—178 °C. IR (nujol) cmϪ1: 3277, 1682. H-NMR (CDCl3) d:
1-Ethoxycarbonyl-2-phenyl-3-[3-oxo-(1E)-butenyl]indole (2j): Pale yel- 2.03 (2H, quintet, 6.3), 2.87 (2H, t, 6.3), 3.26—3.30 (2H, m), 3.75 (3H, s),
low viscous oil. IR (neat) cmϪ1: 1740, 1688, 1660. 1H-NMR (CDCl3) d: 6.40 (1H, s), 7.20—7.23 (2H, m), 7.32—7.35 (1H, m), 7.90—7.94 (1H, m),
1.00 (3H, t, Jϭ7.1 Hz) 2.33 (3H, s), 4.19 (2H, q, Jϭ7.1 Hz), 6.85 (1H, d, 8.25 (1H, br). HR-MS m/z: 241.1120 (Calcd for C15H15NO2: 241.1102).
Jϭ16.5 Hz), 7.33—7.51 (8H, m), 7.95 (1H, d, Jϭ7.8 Hz), 8.29 (1H, d,
Jϭ7.9 Hz). HR-MS m/z: 333.1380 (Calcd for C21H19NO3: 333.1364).
1-Ethoxycarbonyl-2-tert-butyl-3-[3-oxo-(1E)-butenyl]indole (2k): Col-
Anal. Calcd for C15H15NO2•1/8H2O: C, 74.02; H, 6.25; N, 5.53. Found: C,
73.98; H, 6.31; N, 5.75.
Ethyl 2-(2-(2-Propenylphenyl)ethynyl)phenylcarbamete (11) After
orelss viscous oil. IR (CHCl3) cmϪ1: 1743, 1685, 1599. 1H-NMR (CDCl3) d: ethyl 2-ethynylphenylcarbamate (421 mg, 2.23 mmol) in N,N-dimethylfor-
1.48 (3H, t, Jϭ7.2 Hz), 1.58 (9H, s), 2.41 (3H, s), 4.50 (2H, q, Jϭ7.2 Hz), mamide (DMF) (5 ml) was dropped into a mixture of 1-bromo-2-(2-
6.69 (1H, d, Jϭ16.2 Hz), 7.20—7.33 (2H, m), 7.68—7.74 (2H, m), 8.00
(1H, d, Jϭ16.2 Hz). HR-MS m/z: 313.1702 (Calcd for C19H23NO3: CuI (18 mg, 0.93 mmol), diisopropylamine (3 ml), and DMF (5 ml) at reflux-
313.1678). ing temperature during 1 h, the resultant mixture was refluxed for 2 h. Water
propenyl)benzene (364 mg, 1.86 mmol), PdCl2(PPh3)2 (65 mg, 0.93 mmol),
1-Ehoxycarbonyl-2-tert-butylindole (3k): Pale yellow viscous oil. IR (50 ml) was added to the mixture and extracted with Et2O (50 mlϫ3). The
(KBr) cmϪ1: 1740. 1H-NMR (CDCl3) d: 1.51 (9H, s), 1.52 (3H, t, Jϭ ethereal layer was washed with brine (50 mlϫ3). The residue obtained from
7.2 Hz), 4.53 (2H, q, Jϭ7.2 Hz), 6.51 (1H, s), 7.17 (1H, t, Jϭ7.1 Hz), 7.20 the ethereal extract purified by silica gel column chromatography using
(1H, t, Jϭ7.1 Hz), 7.45 (1H, d, Jϭ7.1 Hz), 7.92 (1H, d, Jϭ7.1 Hz). HR-MS AcOEt–hexane (1 : 20) as an eluent. Colorless viscous oil (377 mg, 67%). IR
m/z: 245.1394 (Calcd for C15H19NO2: 245.3169).
6-[(2-Ethoxycarbonylamino)phenyl]hex-5-yn-1-ol (5) A mixture of
(CHCl3) cmϪ1: 1740. 1H-NMR (CDCl3) d: 1.36 (3H, t, Jϭ7.1 Hz), 2.21 (3H,
s), 4.29 (2H, q, Jϭ7.1 Hz), 5.23 (1H, s), 5.40 (1H, s), 7.00 (1H, dt, Jϭ1.1,
ethyl 2-iodophenylcarbamate (522 mg, 1.80 mmol), 5-hexynyl-1-ol (212 mg, 7.4 Hz), 7.24—7.35 (4H, m), 7.45 (1H, d, Jϭ6.9 Hz), 7.55—7.57 (2H, m),
2.16 mmol), PdCl2(PPh3)2 (63 mg, 0.90 mmol), CuI (35 mg, 1.80 mmol), and 8.21 (1H, d, Jϭ8.5 Hz). HR-MS m/z: 305.1394 (Calcd for C20H19NO2:
Et3N (20 ml) was stirred at room temperature for 3 h. Water (50 ml) was 305.1415).
added to the mixture and extracted with AcOEt (30 mlϫ3). The AcOEt layer
5-Methyl-11-ethoxycarbonylbenzo[a]carbazole (12) According to the
was washed with water (50 mlϫ2). The residue obtained from the AcOEt synthetic procedure for 8, 12 was obtained from the reaction using 11
extract was purified by silica gel column chromatography using AcOEt– (71 mg, 0.23 mmol). Colorless viscous oil (35 mg, 49%). IR (CHCl3) cmϪ1
:
hexane (1 : 10) as an eluent. The product was purified by distillation. Pale 1732. 1H-NMR (CDCl3) d: 1.47 (3H, t, Jϭ7.1 Hz), 2.81 (3H. s), 4.59 (2H, q,
yellow liquid (451 mg, 96%). bp 180—190 °C (45 mmHg). IR (CHCl3) Jϭ7.1 Hz), 7.39 (1H, t, Jϭ8.0 Hz), 7.47 (1H, t, Jϭ8.0 Hz), 7.54—7.57 (2H,
1
cmϪ1: 3400, 1740. H-NMR (CDCl3) d: 1.33 (3H, t, Jϭ6.0 Hz), 1.67—1.77 m), 7.88 (1H, s), 7.99 (1H, d, Jϭ7.4 Hz), 8.09—8.13 (1H, m), 8.21 (1H,
(5H, m), 2.56 (2H, t, Jϭ6.6 Hz), 3.72—3.75 (2H, m), 4.25 (2H, q, d, Jϭ7.4 Hz), 8.27—8.31 (1H, m). HR-MS m/z: 303.1284 (Calcd for
Jϭ7.1 Hz), 6.95 (2H, t, Jϭ7.7 Hz), 7.27—7.34 (2H, m), 8.10 (1H, d, C20H17NO2: 303.1260).
Jϭ8.2 Hz). HR-MS m/z: 261.1327 (Calcd for C15H19NO3: 261.1364).
6-[(2-Ethoxycarbonylamino)phenyl]hex-5-ynal (6) Pyridinium chloro-
5-Methylbenzo[a]carbazole (13) A mixture of 14 (100 mg, 0.33 mmol),
3 N KOH (0.17 ml), and methanol (5 ml) was refluxed for 1 h. The methanol
chromate (6.0 g, 28 mmol) was added to a mixture of 5 (4.0 g, 14 mmol), was removed under reduced pressure. Water (100 ml) was added to the
Celite® (1.0 g), and CH2Cl2 (50 ml). After stirring for 2 h at room tempera- residue and extracted with CHCl3 (50 mlϫ3). The residue obtained from the
ture, the mixture was concentrated under reduced pressure. The residue was CHCl3 extract was purified by silica gel column chromatography using
dissolved to CHCl3. The solution was filtered through Celite® pad and con- AcOEt–hexane (1 : 20) as an eluent. The product was purified by recrystal-
centrated under reduced pressure. The residue was purified by silica gel col- lization from acetone–hexane. Colorless prisms (62 mg, 82%). mp 183—
umn chromatography using AcOEt–hexane (1 : 3) as an eluent. The product 185 °C. IR (KBr) cmϪ1: 3412. 1H-NMR (CDCl3) d: 2.81 (3H, s), 7.26—7.31
was purified by distillation. Pale yellow liquid (3.4 g, 94%), bp 130—145 °C (1H, m), 7.39—7.45 (1H, m), 7.55—7.62 (3H, m), 7.98 (1H, s), 8.09—8.15
(45 mmHg). IR (CHCl3) cmϪ1: 3400, 1730, 1720. 1H-NMR (CDCl3) d: 1.32 (3H, m), 8.72 (1H, bs). 13C (CDCl3) d: 19.4, 110.6, 117.6, 119.2, 119.4,
(3H, t, Jϭ7.3 Hz), 2.00 (2H, quintet, Jϭ6.9 Hz), 2.58 (2H, t, Jϭ6.9 Hz), 119.5, 120.5, 120.9, 123.8, 124.3, 124.7, 124.9, 125.2, 125.6, 131.3, 133.6,
2.68 (2H, t, Jϭ7.1 Hz), 4.24 (2H, q, Jϭ7.1 Hz), 6.97 (1H, d, Jϭ8.7 Hz), 138.1. MS m/z: 231 (Mϩ). Anal. Calcd for C17H13N: C, 88.28; H, 5.67; N,
7.26—7.35 (2H, m), 8.10 (1H, d, Jϭ8.5 Hz), 9.58 (1H, s). HR-MS m/z: 6.06. Found: C, 88.37; H, 5.94; N, 5.97.
259.1195 (Calcd for C15H17NO3: 259.1207).
Methyl (E)-8-[2-(Ethoxycarbonylamino)phenyl]oct-2-en-7-ynoate (7)
Acknowledgement The authors thank Mr. Masashi Kaneko for assis-
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (2.65 g, 17.4 mmol) in dry tance with some of these experiments.
MeCN (30 ml) was added to a mixture of trimethyl phosphonoacetate
(3.17 g, 17.4 mmol), LiCl (983 mg, 23.2 mmol), and dry MeCN (30 ml) References
under Ar atmosphere. After stirring for 30 min at room temperature, 6
(566 mg, 2.3 mmol) in MeCN (10 ml) was added to the mixture. The mixture
was stirred at room temperature for 1 h and concentrated under reduced
pressure. Water (100 ml) was added to the residue and extracted with CHCl3
(100 mlϫ3). The residue obtained from the CHCl3 extract was purified by
silica gel column chromatography using AcOEt–hexane (1 : 3) as an eluent.
The product was purified by distillation. Colorless liquid (2.9 g, 79%), bp
162—180 °C (45 mmHg). IR (CHCl3) cmϪ1: 3400, 1730, 1210. 1H-NMR
(CDCl3) d: 1.33 (3H, t, Jϭ7.1 Hz), 1.81 (2H, quintet, Jϭ7.4 Hz), 2.40 (2H,
q, Jϭ6.0 Hz), 2.54 (2H, t, Jϭ7.1 Hz), 3.73 (3H, s), 4.25 (2H, q, Jϭ7.1 Hz),
5.90 (1H, d, Jϭ18.9 Hz), 6.93—7.04 (2H, m), 7.25—7.35 (3H, m), 8.12
(1H, d, Jϭ8.5 Hz). HR-MS m/z: 315.1452 (Calcd for C18H21NO4: 315.1469).
Methyl (E)-2-(1,2,3,4-Trihydrocarbazol-4-ylidene)acetate (9) After 7
(510 mg, 1.62 mmol) was dropped into a mixture of PdCl2 (57 mg, 0.34
mmol), CuCl2·2H2O (552 mg, 3.24 mmol), 1 M TABF in THF (1.90 ml,
1.90 mmol), and THF (30 ml) at refluxing temperature during 30 min, the re-
sultant mixture was refluxed for 1 h. The mixture was filtrated and THF was
removed under reduced pressure. Water (50 ml) was added to the residue and
the mixture was extracted with AcOEt (30 mlϫ3). The AcOEt layer was
washed with brine (50 mlϫ2). One molar TBAF in THF (1.80 ml,
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