A new approach to 3-substituted indoles through palladium-catalyzed C-H activation followed by intramolecular amination reaction of enamines

Article abstract of DOI:10.1055/s-0028-1087413

Palladium-catalyzed C-H activation followed by intramolecular amination reaction of enamine compounds was achieved using a Pd(OAc)₂ (10 mol%)/Cu(OAc)₂ (100 mol%) catalyst system in DMSO. This work introduces an entirely new approach to 3-substituted indoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087413

LETTER
3157
A New Approach to 3-Substituted Indoles through Palladium-Catalyzed C–H
Activation Followed by Intramolecular Amination Reaction of Enamines
P
alladium-Catalyz
i
e
d
C–H
y
Amination
o
for Indoles
S
f
ynthesisumi Inamoto,* Tadataka Saito, Kou Hiroya, Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)7956864; E-mail: inamoto@mail.pharm.tohoku.ac.jp; E-mail: doi_taka@mail.pharm.tohoku.ac.jp
Received 4 September 2008
R4
Abstract: Palladium-catalyzed C–H activation followed by in-
tramolecular amination reaction of enamine compounds was
achieved using a Pd(OAc)2 (10 mol%)/Cu(OAc)2 (100 mol%) cata-
lyst system in DMSO. This work introduces an entirely new ap-
proach to 3-substituted indoles.
R5
R2
X
N
R1
a
b
c
N
R3
a
Key words: palladium, catalysis, C–H activation, indoles, amina-
tions
b
c
R2
R2
X
a,c
N
R1
d
NHR1
R2
NHR1
The indole scaffold occurs frequently in numerous biolog-
ically active compounds, ranging from natural products1
to designed medicinal agents.2 Therefore, the develop-
ment of more practical and efficient procedures for syn-
thesizing indoles, especially using catalytic approaches
with transition metals, remains an area of intensive re-
search.3
d
+
+
R3
R3X
R3
H
R2
NHR1
this work
Among the transition-metal sources, the palladium (Pd)
catalyst is one of the most widely studied and used metals
for the construction of indoles;4–13 Scheme 1 shows some
of the representative procedures. Arguably, cycloaddi-
tions of 2-haloanilines with terminal or internal alkynes
(disconnections a and c)4 and intermolecular reactions of
2-alkynyl anilides with electrophiles (R3X; disconnection
c)5 are the most frequently used methods for the synthesis
of indoles with substituent(s) at 2- and/or 3-position(s).
Several efficient approaches through tandem-type cou-
pling reactions have also been reported recently.9–12
Scheme 1 Representative Pd-catalyzed approaches to indoles
(entries 1–9). We were pleased to find that the use of 100
mol% of Cu(OAc)2 enabled this process to be performed
in fairly good yield (entry 9). Dimethyl sulfoxide is cru-
cial for this transformation.17 The use of a higher catalyst
loading improved the yield (entry 11), whereas increasing
reaction temperature to 120 °C resulted in a slightly lower
yield (entry 12). Unfortunately, no further improvement
in yield was obtained from the screening of additional Pd
sources (Table 1, entries 13–19).18,19
Herein, we describe an entirely new approach to indoles
using a Pd-catalyzed C–H activation–intramolecular ami-
nation sequence (C–H amination) using enamine com-
pounds as starting materials (Scheme 1, disconnection d).
We next examined the scope of the above-optimized cat-
alyst system using several kinds of enamines 5, which
were prepared by the Wittig reaction of benzophenones 3
followed by one-pot conversion of enol ethers 4 into 5
(Table 2). Both of the reactions proceeded generally in
high yields.20
The amount of 10 mol% of Pd(OAc)2, along with the re-
oxidant Cu(OAc)2, effectively catalyzed this process, pro-
ducing 3-substituted indoles with good functional group
compatibility (e.g., alkoxycarbonyl and cyano groups).13
Indeed, the method developed in this manuscript repre-
sents one of the rare examples of Pd-catalyzed C–H ami-
nation reactions.14,15
In the reactions of enamines 5a–c possessing two substit-
uents symmetrically at the 4- and 4¢-positions on the ben-
zene rings, the desired indoles 6a–c were obtained
generally in good yields at 120 °C (Table 3, entries 2, 4,
and 6). Low conversion was observed in the reaction of
enamine 5d (entries 7 and 8). Substrate 5e, which has two
methoxy groups at the 3- and 3¢-positions, also underwent
this cyclization under the same reaction conditions, albeit
in relatively low conversion and yield (entries 9 and 10).
In this reaction, indole 6e was obtained as the sole prod-
uct; no regioisomer, such as 7-methoxy-3-(3-methoxy-
phenyl)indole, was observed.
We began our study by examining the reaction of enamine
116 to indole 2 to obtain the optimal reaction conditions
(Table 1). The effect of reoxidant was initially screened in
the presence of 10 mol% of Pd(OAc)2 in DMSO at 80 °C
SYNLETT 2008, No. 20, pp 3157–3162
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087413; Art ID: U09308ST
© Georg Thieme Verlag Stuttgart · New York

3158
K. Inamoto et al.
LETTER
Table 1 Optimization of Reaction Conditions
Ph
Ph
'Pd' (10 mol%)
oxidant (100 mol%)
DMSO (0.05 M)
80 °C, 24 h
NHTs
N
Ts
1
2
Entry
1
‘Pd’
Oxidant
Yield of 2a (%)
Yield of recovered 1a (%)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
PhI(TFA)2
benzoquinone
CAN
0
15
8
0
61
0
2
3
4
CuCl
0
39
34
27
76
74
0
5
CuCl2
0
6
Cu(acac)2
Cu(OMs)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
31
8
7
8
9
9
53
60
84
47
47
48
43
10
0
10b,c
11d
12e
13
14
15
16
17
18
19
0
0
0
0
0
[Pd(allyl)Cl]2
PdCl2[P(2-Tol)3]2
PdI2
27
53
0
f
Pd2(dba)3
37
15
35
22
Pd(PPh3)4
a Isolated yield from reaction on 0.14 mmol scale.
b Under microwave condition (180 °C, 10 min).
c Cu(OAc)2 (200 mol%) was used.
d Pd(OAc)2 (30 mol%) was used.
e Conditions: 120 °C, 6 h.
f Ph3P (10 mol%) was added.
OMe
Pd(OAc)2 (10 mol%)
Cu(OAc)2 (100 mol%)
MeO
MeO
+
DMSO (0.05 M)
80 °C, 24 h
NHTs
N
N
Ts
Ts
6f-A
6f-B
5f (single isomer)
38% (4.8:1)
Scheme 2 Palladium-catalyzed cyclization of dissymmetric substrate 5f
Although the reaction of the substrate 5f, which has one ed another insight into the reaction mechanism. Namely,
methoxy group on the benzene ring (a dissymmetric sub- despite the starting 5f being a single isomer,21 the cyclized
strate), produced a relatively low yield, this result provid- product obtained was a mixture of two indoles, 6f-A and
Synlett 2008, No. 20, 3157–3162 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed C–H Amination for Indoles Synthesis
3159
Table 2 Synthesis of Enamine 5
R2
R2
R2
BuLi
MeOCH2PPh3Cl
TsNH2
TFAA, TFA
dioxane
r.t., 2–17 h
CH2Cl2
reflux, 14–20 h
R1
O
R1
R1
OMe
NTs
3a–f
4a–f
5a–f
Entry
3
R1
R2
Yield of 4a (%)
4a 67
Yield of 5a (%)
5a 79
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
4-MeO
4-F
4-MeO
4-F
4b 82
5b 79
4-EtO2C
4-NC
4-EtO2C
4-NC
3-MeO
H
4c 64
5c 37b
4d 54
5d 86
3-MeO
3-MeO
4e 94
5e 67
4f 83
5f 65
a Isolated yield.
b Compound 5c was prepared stepwise from 4c (hydration of 4c followed by enamine formation); yield over 2 steps.
Table 3 Palladium-Catalyzed Synthesis of Indoles 6a–e
4
3
R2
R2
Pd(OAc)2 (10 mol%)
Cu(OAc)2 (100 mol%)
R1
R1
NHTs
DMSO (0.05 M)
conditions
4
N
Ts
3
5a–e
6a–e
Conditions
80 °C, 17 h
120 °C, 5 h
80 °C, 24 h
120 °C, 6 h
80 °C, 22 h
120 °C, 6 h
80 °C, 22 h
150 °C, 6 h
80 °C, 22 h
120 °C, 6 h
Entry
Enamine 5 (R1, R2)
5a (4-MeO, 4-MeO)
Indole 6
Yield of 6a,b (%)
41 (41)
Yield of recovered 5 (%)
1
2
6a
0
0
55 (55)
3
5b (4-F, 4-F)
6b
6c
6d
6e
42 (42)
0
4
59 (51)
13
0
5
5c (4-EtO2C, 4-EtO2C)
5d (4-NC, 4-NC)
5e (3-MeO, 3-MeO)
OMe
60 (60)
6
71 (68)
4
7
81 (29)
64
53
10
0
8
89 (42)
9
50 (45)
10
30 (30)
F
CO2Et
CN
OMe
MeO
N
F
N
N
N
N
Ts
MeO
EtO2C
NC
Ts
Ts
Ts
Ts
6a
6b
6c
6d
6e
a Conversion yield based on recovered starting material.
b Isolated yield in parentheses.
Synlett 2008, No. 20, 3157–3162 © Thieme Stuttgart · New York

3160
K. Inamoto et al.
LETTER
(8) (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew.
Chem. Int. Ed. 2000, 39, 2501. (b) Brown, J. A.
6f-B, suggesting that the E/Z isomerization of the enamine
occurs rapidly during this process (Scheme 2).22
Tetrahedron Lett. 2000, 41, 1623. (c) Peat, A. J.; Buchwald,
S. L. J. Am. Chem. Soc. 1996, 118, 1028.
(9) Jensen, T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.;
Jørgensen, M. Angew. Chem. Int. Ed. 2008, 47, 888.
(10) Ackermann, L.; Althammer, A. Angew. Chem. Int. Ed. 2007,
46, 1627.
(11) Ackermann, L. Org. Lett. 2005, 7, 439.
(12) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes, I. P.
Adv. Synth. Catal. 2006, 348, 851.
(13) Similar Pd-mediated synthesis of indoles in the presence of
0.5 equiv Pd(OAc)2 and 3.0 equiv Cu(OAc)2 was previously
reported, see: (a) Queiroz, M.-J. R. P.; Abreu, A. S.;
Castanheira, E. M. S.; Ferreira, P. M. T. Tetrahedron 2007,
63, 2215. (b) Abreu, A. S.; Ferreira, P. M. T.; Queiroz,
M.-J. R. P.; Ferreira, I. C. F. R.; Calhelha, R. C.; Estevinho,
L. M. Eur. J. Org. Chem. 2005, 2951. (c) Abreu, A. S.;
Silva, N. O.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.;
Venanzi, M. Eur. J. Org. Chem. 2003, 4792. (d) Abreu,
A. S.; Silva, N. O.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.
Tetrahedron Lett. 2003, 44, 3377.
(14) Only a few examples of Pd-catalyzed C–H amination have
been reported to date, see: (a) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.
(b) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc.
2006, 128, 9048.
In conclusion, we have developed a new approach to in-
doles through Pd-catalyzed C–H activation followed by
intramolecular amination of enamine compounds. Al-
though the yields were moderate under our conditions,
this method can be employed complementarily with pre-
viously reported techniques to obtain a variety of indoles.
Furthermore, our atom-economical and straightforward
procedure represents one of the rare examples of Pd-cata-
lyzed C–H amination reactions. Studies to expand the
substrate scope, increase yields, and apply this reaction to
other nitrogen-based heterocycles are currently under
way.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Young Sci-
entists (B) from the Japan Society for the Promotion of Science
(JSPS).
References and Notes
(1) For selected recent reviews, see: (a) Higuchi, K.; Kawasaki,
T. Nat. Prod. Rep. 2007, 24, 843. (b) Brancale, A.;
Silvestri, R. Med. Res. Rev. 2007, 27, 209. (c) O’Connor,
S. E.; Maresh, J. Nat. Prod. Rep. 2006, 23, 532.
(15) We have already reported the synthesis of indazoles using a
Pd-catalyzed intramolecular C–H amination process, see:
Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya,
K. Org. Lett. 2007, 9, 2931.
(2) For selected recent examples, see: (a) Peifer, C.; Selig, R.;
Kinkel, K.; Ott, D.; Totzke, F.; Schächtele, C.; Heidenreich,
R.; Röcken, M.; Schollmeyer, D.; Laufer, S. J. Med. Chem.
2008, 51, 3814. (b) Romagnoli, R.; Baraldi, P. G.; Sarkar,
T.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Preti, D.;
Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Cristina, A. D.;
Zonta, N.; Balzarini, J.; Brancale, A.; Hsieh, H.-P.; Hamel,
E. J. Med. Chem. 2008, 51, 1464. (c) McKew, J. C.; Lee,
K. L.; Shen, M. W. H.; Thakker, P.; Foley, M. A.; Behnke,
M. L.; Hu, B.; Sum, F.-W.; Tam, S.; Hu, Y.; Chen, L.;
Kirincich, S. J.; Michalak, R.; Thomason, J.; Ipek, M.; Wu,
K.; Wooder, L.; Ramarao, M. K.; Murphy, E. A.; Goodwin,
D. G.; Albert, L.; Xu, X.; Donahue, F.; Ku, M. S.; Keith, J.;
Nickerson-Nutter, C. L.; Abraham, W. M.; Williams, C.;
Hegen, M.; Clark, J. D. J. Med. Chem. 2008, 51, 3388.
(3) For selected recent reviews, see: (a)Patil, N. T.;Yamamoto,
Y. Chem. Rev. 2008, 108, 3395. (b) Ackermann, L. Synlett
2007, 507. (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875. (d) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873.
(4) (a) Gathergood, N.; Scammells, P. J. Org. Lett. 2003, 5, 921.
(b) Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4,
3339. (c) Zhang, H.-C.; Moretto, A. F.; Brumfield, K. K.;
Maryanoff, B. E. Org. Lett. 2000, 2, 89. (d) Roesch, K. R.;
Larock, R. C. Org. Lett. 1999, 1, 1551.
(5) (a) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63,
1001. (b) Arcadi, A.; Cacchi, S.; Marineli, F. Tetrahedron
Lett. 1992, 33, 3915. (c) Iritani, K.; Matsubara, S.; Utimoto,
K. Tetrahedron Lett. 1988, 29, 1799.
(16) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003,
44, 1231.
(17) Use of solvents such as DMF, NMP, MeCN, dioxane,
toluene, and DCE resulted in decreased yields.
(18) We also examined the effect of a variety of additives such as
phosphines, N-heterocyclic carbenes, tetraalkylammonium
salts, inorganic bases, lithium and silver salts, and so on, all
of which led to unsatisfactory results.
(19) Typical Procedure for the Pd-Catalyzed C–H Amination
of Enamines (Table 1, entry 9)
A mixture of 1 (50.0 mg, 0.14 mmol), Pd(OAc)2 (3.2 mg,
0.014 mmol), and Cu(OAc)2 (26.0 mg, 0.14 mmol) in
DMSO (2.9 mL) was stirred at 80 °C for 24 h. The reaction
mixture was extracted with EtOAc (3 × 5 mL) and the
combined organic layer was washed with brine (10 mL), and
dried over MgSO4. The solvent was evaporated and the
residue was purified by silica gel column chromatography
(hexane–EtOAc, 9:1) to give indole 2 (26.2 mg, 53%) as a
colorless solid.
1-(4-Methylphenylsulfonyl)-3-phenylindole (2)
Mp 151–152 °C (colorless needles from hexane–EtOAc). IR
(film): 2924, 1597, 1447, 1371, 1175, 669 cm–1. 1H NMR
(400 MHz, CDCl3): d = 2.34 (3 H, s), 7.22 (2 H, d, J = 8.2
Hz), 7.26–7.30 (1 H, m), 7.34–7.38 (2 H, m), 7.46 (2 H, t,
J = 7.8 Hz), 7.59–7.61 (2 H, m), 7.69 (1 H, s), 7.77 (1 H, d,
J = 7.8 Hz), 7.80 (2 H, d, J = 8.4 Hz), 8.05 (1 H, d, J = 8.4
Hz). 13C NMR (100 MHz, CDCl3): d = 21.5, 113.7, 120.3,
122.8, 123.4, 123.8, 124.8, 126.7, 127.4, 127.8, 128.8,
129.1, 129.8, 132.9, 135.0, 135.4, 144.9. MS: m/z = 347
(50.2) [M+], 192 (100). HRMS: m/z calcd for C21H17NO2S:
347.0980; found: 347.0967. Anal. Calcd for C21H17NO2S: C,
72.60; H, 4.93; N, 4.03. Found C, 72.63; H, 5.08; N, 3.99.
(20) Typical Procedure for the Synthesis of Enol Ether (4a,
Table 2, entry 1)
(6) (a) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H.
Synthesis 1990, 215. (b) Larock, R. C.; Babu, S.
Tetrahedron Lett. 1987, 28, 5291. (c) Kasahara, A.; Izumi,
T.; Murakami, S.; Yanai, H.; Takatori, M. Bull. Chem. Soc.
Jpn. 1986, 59, 927. (d) Mori, M.; Chiba, K.; Ban, Y.
Tetrahedron Lett. 1977, 29, 1037.
To a solution of(methoxymethyl)triphenylphosphinium
chloride (1.1 g, 3.1 mmol) in anhyd dioxane (5 mL) was
(7) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc.
2000, 122, 5662.
Synlett 2008, No. 20, 3157–3162 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed C–H Amination for Indoles Synthesis
3161
slowly added BuLi (1.53 M solution in hexane, 2.3 mL, 3.1
reflux for 13.5 h. The mixture was poured into cold H2O and
extracted with CH2Cl2 (3 × 5 mL), and dried over MgSO4.
The solvent was evaporated, and the residue was purified by
silica gel column chromatography (hexane–EtOAc, 9:1) to
give 5a (58.5 mg, 79%) as a colorless amorphous solid.
N-[2,2-Bis(4-methoxyphenyl)vinyl] 4-Methylphenyl-
sulfonamide (5a)
mmol) at 0 °C and stirred for 30 min at the same temperature.
A solution of 3a (0.50 g, 2.1 mmol) in anhyd dioxane (10
mL) was then slowly added at 0 °C, and the mixture was
heated under reflux for 10 h. The reaction mixture was
treated with sat. aq NH4Cl soln (5 mL), and the aqueous
phase was extracted with EtOAc (3 × 10 mL). The combined
organic layer was washed with brine (5 mL) and dried over
MgSO4. The solvent was evaporated, and the residue was
purified by silica gel column chromatography (hexane–
EtOAc, 9:1) to give 4a (0.4 g, 67%) as a colorless oil.
1,1-Bis(4-methoxyphenyl)-2-methoxyethene (4a)
IR (film): 2359, 1341, 1508, 1244 cm–1. 1H NMR (400 MHz,
CDCl3): d = 3.73 (3 H, s), 3.80 (6 H, s), 6.32 (1 H, s), 6.82
(2 H, d, J = 8.8 Hz), 6.85 (2 H, d, J = 8.8 Hz), 7.13 (2 H, d,
J = 8.8 Hz), 7.31 (2 H, d, J = 8.8 Hz). 13C NMR (100 MHz,
CDCl3). d = 55.1, 55.2, 60.3, 113.2, 113.5, 119.5, 129.2,
130.2, 130.7, 133.0, 133.6, 157.9, 158.2. MS: m/z = 270
(100) [M+].
IR (film): 3273, 1607, 1512, 1352, 1246, 1165 cm–1. 1H
NMR (400 MHz, CDCl3): d = 2.44 (3 H, s), 3.77 (3 H, s),
3.82 (3 H, s), 6.22 (1 H, d, J = 11.4 Hz), 6.65 (1 H, d,
J = 11.4 Hz), 6.76–6.86 (6 H, m), 7.02 (2 H, d, J = 8.8 Hz),
7.33 (2 H, d, J = 8.4 Hz), 7.71 (2 H, d, J = 8.4 Hz). 13C NMR
(100 MHz, CDCl3): d = 21.6, 55.28, 55.30, 113.7, 114.6,
118.5, 125.8, 126.7, 127.6, 128.5, 129.8, 130.6, 132.2,
136.6, 143.7, 158.7, 159.1. MS: m/z (%) = 409 (33.4) [M+],
254 (100). HRMS: m/z calcd for C23H23NO4S: 409.1348;
found: 409.1341.
N-[2,2-Bis(4-fluorophenyl)vinyl] 4-Methylphenyl-
sulfonamide (5b)
1,1-Bis(4-fluorophenyl)-2-methoxyethene (4b)
Mp 144–145 °C (colorless plates from hexane–EtOAc). IR
(film): 3267, 2361, 1638, 1601, 1510, 1167 cm–1. 1H NMR
(400 MHz, CDCl3): d = 2.46 (3 H, s), 6.25 (1 H, d, J = 11.4
Hz), 6.71 (1 H, d, J = 11.4 Hz), 6.87–6.95 (4 H, m), 7.01–
7.06 (4 H, m), 7.35 (2 H, d, J = 8.4 Hz), 7.72 (2 H, d, J = 8.4
Hz). MS m/z (%) = 385 (41.0), 230 (100). HRMS: m/z calcd
for C21H17F2NO2S: 385.0948; found: 385.0930. Anal. Calcd
for C21H17F2NO2S: C, 65.44; H, 4.45; N, 3.63. Found: C,
65.38; H, 4.50; N, 3.62.
IR (film): 2934, 2361, 1636, 1508, 1229, 1109, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.76 (3 H, s), 6.37 (1 H, s),
6.95–7.02 (4 H, m), 7.14 (2 H, dd, J = 8.8, 5.6 Hz), 7.32
(2 H, dd, J = 8.8, 5.6 Hz). MS: m/z = 246 (100) [M+].
HRMS: m/z calcd for C15H12F2O: 246.0856; found:
246.0841.
1,1-Bis(4-ethoxycarbonylphenyl)-2-methoxyethene (4c)
IR (film): 3477, 2981, 1717, 1277 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.39 (6 H, t, J = 7.2 Hz), 3.82 (3 H, s), 4.37 (4 H,
q, J = 7.2 Hz), 6.61 (1 H, s), 7.24 (2 H, d, J = 8.0 Hz), 7.42
(2 H, d, J = 8.4 Hz), 7.96 (2 H, d, J = 8.4 Hz), 8.00 (2 H, d,
J = 8.0 Hz). MS: m/z = 355 (4.58) [M+ + 1], 177 (100).
HRMS: m/z calcd for C21H22O5: 354.1467; found: 354.1438.
1,1-Bis(4-cyanophenyl)-2-methoxyethene (4d)
N-[2,2-Bis(4-ethoxycarbonylphenyl)vinyl] 4-Methyl-
phenylsulfonamide (5c)
Compound 4c (0.91 g, 2.6 mmol) was dissolved in a solution
of 10% H2SO4 in AcOH (20 mL) and stirred for 18 h at r.t.
The reaction mixture was extracted with EtOAc (3 × 10 mL)
and the combined organic layer was washed with brine (5
mL) and dried over MgSO4. The solvent was evaporated to
give 2,2-bis(4-ethoxycarbonylphenyl)acetaldehyde, which
was used to the next reaction without further purification. A
solution of the above aldehyde (0.87 g, 2.6 mmol) and TFAA
(0.54 g, 2.6 mmol) in CH2Cl2 (20 mL) was added to a
solution of 4-toluenesulfonamide (0.20 g, 1.2 mmol) in
CH2Cl2 (10 mL) and heated under reflux for 20.5 h. The
reaction mixture was extracted with CH2Cl2 (3 × 10 mL) and
the combined organic layer was washed with brine (10 mL)
and dried over MgSO4. The solvent was evaporated and the
residue was purified by silica gel column chromatography
(hexane–EtOAc, 9:1) to give 5c (0.47 g, 37%) as a colorless
amorphous solid. IR (film): 3238, 2361, 1717, 1601, 1275,
1167, 1103 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.36–
1.43 (6 H, m), 2.47 (3 H, s), 4.33–4.44 (4 H, m), 6.34 (1 H,
d, J = 12.2 Hz), 6.94 (1 H, d, J = 12.2 Hz), 7.03 (2 H, d,
J = 8.4 Hz), 7.12 (2 H, d, J = 8.0 Hz), 7.36 (2 H, d, J = 8.4
Hz), 7.73 (2 H, d, J = 8.4 Hz), 7.91 (2 H, d, J = 8.0 Hz), 8.04
(2 H, d, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3): d = 14.2,
21.5, 60.8, 61.1, 122.8, 123.1, 126.1, 126.5, 127.0, 128.7,
129.5, 129.6, 129.8, 129.9, 130.4, 136.6, 140.6, 143.4,
144.0, 165.6, 165.9. MS: m/z (%) = 493 (100) [M+], 292
(48.5). HRMS: m/z calcd for C27H27NO6S: 493.1559; found:
493.1549.
IR (film): 2922, 2849, 2226, 1628, 1601, 1240, 1103 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.86 (3 H, s), 6.64 (1 H, s),
7.26 (2 H, d, J = 8.2 Hz), 7.44 (2 H, d, J = 8.4 Hz), 7.58 (2
H, d, J = 8.2 Hz), 7.61 (2 H, d, J = 8.4 Hz). 13C NMR (100
MHz, CDCl3): d = 61.3, 110.2, 110.3, 117.7, 118.7, 118.8,
128.3, 130.2, 131.8, 132.2, 141.1, 143.9, 149.7. MS: m/z (%)
= 260 (100) [M+]. HRMS: m/z calcd for C17H12N2O:
260.0950; found: 260.0965.
1,1-Bis(3-methoxyphenyl)-2-methoxyethene (4e)
IR (film): 2999, 2936, 2833, 1597, 1576, 1485, 1285, 1252,
1229, 1105, 1049 cm–1. 1H NMR (400 MHz, CDCl3):
d = 3.75 (3 H, s), 3.761 (3 H, s), 3.764 (3 H, s), 6.46 (1 H, s),
6.76–6.81 (4 H, m), 6.93–6.97 (2 H, m), 7.17 (1 H, d, J = 8.0
Hz), 7.21 (1 H, d, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3):
d = 55.17, 55.21, 111.7, 112.0, 113.9, 115.5, 120.2, 120.7,
122.3, 128.7, 129.0, 138.7, 141.6, 146.5, 146.5, 159.1,
159.4. MS: m/z = 270 (100) [M+], 135 (17.5). HRMS: m/z
calcd for C17H18O3: 270.1256; found: 270.1248.
1-Phenyl-1-(3-methoxyphenyl)-2-methoxyethene (4f)
Obtained as a mixture of E- and Z-isomers (1.2:1). IR (film):
2932, 2835, 1634, 1597, 1236, 1107, 696 cm–1. 1H NMR
(400 MHz, CDCl3): d = 3.75–3.76 (6 H, m), 6.44 (0.55 H, s),
6.47 (0.45 H, s), 6.76–6.81 (2 H, m), 6.93–6.96 (1 H, m),
7.19–7.38 (6 H, m). MS: m/z (%) = 240 (100) [M+], 197
(26.2). HRMS: m/z calcd for C16H16O2: 240.1150; found:
240.1134.
N-[2,2-Bis(4-cyanophenyl)vinyl] 4-Methylphenyl-
sulfonamide (5d)
Typical Procedure for the Synthesis of Enamines (5a,
Table 2, Entry 1)
A solution of 4a (48.9 mg, 0.18 mmol) in CH2Cl2 (2 mL) was
added to a solution of 4-toluenesulfonamide (34.1 mg, 0.20
mmol) in CH2Cl2 (2 mL). Then, TFAA (42.0 mg, 0.20
mmol) and TFA (22.8 mg, 0.20 mmol) were added to the
reaction mixture at r.t., and the mixture was heated under
Mp 232–233 °C (colorless plates from hexane–CHCl3). IR
(film): 3261, 2226, 1634, 1599, 1339, 1165 cm–1. 1H NMR
(400 MHz, CDCl3): d = 2.47 (3 H, s), 6.82 (1 H, d, J = 11.8
Hz), 6.96 (1 H, d, J = 11.8 Hz), 7.12 (2 H, d, J = 8.0 Hz),
7.13 (2 H, d, J = 8.4 Hz), 7.37 (2 H, d, J = 8.4 Hz), 7.53 (2 H,
d, J = 8.0 Hz), 7.65 (2 H, d, J = 8.0 Hz), 7.72 (2 H, d, J = 8.0
Hz). 13C NMR (100 MHz, CDCl3): d = 21.7, 110.5, 112.3,
Synlett 2008, No. 20, 3157–3162 © Thieme Stuttgart · New York

3162
K. Inamoto et al.
LETTER
IR (film): 2982, 1715, 1375, 1279, 1177, 1163 cm–1.
117.9, 118.5, 121.2, 124.3, 126.6, 126.8, 130.1, 130.6,
132.3, 133.3, 136.3, 140.3, 143.1, 144.6. MS: m/z (%) = 399
(45.0) [M+], 244 (100). HRMS: m/z calcd for C23H17N3O2S:
399.1042; found: 399.1025.
N-[2,2-Bis(3-methoxyphenyl)vinyl] 4-Methylphenyl-
sulfonamide (5e)
1H NMR (400 MHz, CDCl3): d = 1.41–1.47 (6 H, m), 2.36
(3 H, s), 4.39–4.47 (4 H, m), 7.27 (2 H, d, J = 8.6 Hz), 7.66
(2 H, d, J = 8.0 Hz), 7.80 (2 H, d, J = 8.6 Hz), 7.85 (1 H, d,
J = 8.6 Hz), 7.90 (1 H, s), 7.99 (1 H, d, J = 8.6 Hz), 8.14 (2
H, d, J = 8.0 Hz), 8.74 (1 H, s). 13C NMR (100 MHz,
CDCl3): d = 14.4, 14.5, 21.7, 61.1, 61.2, 115.5, 119.9, 122.6,
124.7, 126.3, 127.0, 127.3, 127.5, 129.6, 130.1, 130.2,
132.1, 134.7, 134.8, 137.0, 145.5, 166.1, 166.4. MS: m/z (%)
= 491 (81.9) [M+], 336 (100). HRMS: m/z calcd for
C27H25NO6S: 491.1403; found: 491.1409.
IR (film): 3265, 2937, 2835, 1597, 1578, 1350, 1286, 1161,
1090 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.44 (3 H, s),
3.71 (3 H, s), 3.74 (3 H, s), 6.30 (1 H, d, J = 12.0 Hz), 6.46
(1 H, s), 6.49 (1 H, d, J = 8.1 Hz), 6.63–6.64 (1 H, m), 6.72
(1 H, dt, J = 8.1, 0.8 Hz), 6.75 (1 H, dd, J = 8.1, 2.8 Hz), 6.79
(1 H, d, J = 12.0 Hz), 6.86 (1 H, dd, J = 8.1, 2.8 Hz), 7.16 (1
H, t, J = 8.1 Hz), 7.25 (1 H, t, J = 8.1 Hz), 7.32 (2 H, d,
J = 8.2 Hz), 7.71 (2 H, d, J = 8.2 Hz). 13C NMR (100 MHz,
CDCl3): d = 21.7, 55.21, 55.24, 112.1, 112.5, 113.8, 114.8,
119.0, 120.4, 121.6, 125.7, 126.7, 129.2, 129.8, 130.4,
136.6, 137.4, 140.6, 143.9, 159.5, 160.2. MS: m/z (%) = 409
(49.0) [M+], 254 (100). HRMS: m/z calcd for C23H23NO4S:
409.1348; found: 409.1331. Anal. Calcd for C23H23NO4S: C,
67.46; H, 5.66; N, 3.42. Found: C, 67.51; H, 5.69; N, 3.44.
N-[2-(3-Methoxyphenyl)-2-phenylvinyl] 4-Methyl-
phenylsulfonamide (5f)
Obtained as a mixture of E- and Z-isomers (1.1:1).
Recrystallization gave the single isomer. Mp 150–151 °C
(colorless needles from hexane–EtOAc). 1H NMR (400
MHz, CDCl3): d = 2.44 (3 H, s), 3.72 (3 H, s), 6.33 (1 H, d,
J = 11.6 Hz), 6.47 (1 H, s), 6.50 (1 H, d, J = 7.7 Hz), 6.78 (1
H, d, J = 11.6 Hz), 6.86 (1 H, dd, J = 7.7, 2.6 Hz), 7.12 (2 H,
d, J = 8.2 Hz), 7.20–7.28 (4 H, m), 7.33 (2 H, d, J = 8.2 Hz),
7.71 (2 H, d, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3):
d = 21.5, 55.2, 113.8, 115.0, 120.3, 121.7, 125.9, 126.5,
126.8, 127.1, 128.4, 129.9, 130.5, 136.9, 137.7, 139.2,
144.0, 160.4. MS: m/z (%) = 379 (55.3) [M+], 224 (100).
HRMS:
6-Cyano-3-(4-cyanophenyl)-1-(4-methylphenylsulfonyl)-
indole (6d)
Mp 238–239 °C (colorless prisms from hexane–EtOAc). IR
(film): 2922, 2228, 1611, 1431, 1379, 1175 cm–1. 1H NMR
(400 MHz, CDCl3): d = 2.40 (3 H, s), 7.32 (2 H, d, J = 8.4
Hz), 7.56 (1 H, dd, J = 8.4, 1.2 Hz), 7.67 (2 H, d, J = 8.0 Hz),
7.77 (2 H, d, J = 8.0 Hz), 7.82 (1 H, d, J = 8.4 Hz), 7.84 (2
H, d, J = 8.4 Hz), 7.95 (1 H, s), 8.38 (1 H, s). 13C NMR (100
MHz, CDCl3): d = 21.8, 108.4, 109.7, 111.6, 118.2, 118.4,
119.0, 120.9, 121.7, 126.8, 127.0, 127.1, 128.3, 130.4,
131.3, 132.8, 134.3, 136.6, 146.2. MS: m/z (%) = 397 (100)
[M+]. HRMS: m/z calcd for C23H15N3O2S: 397.0885; found:
397.0873.
5-Methoxy-3-(3-methoxyphenyl)-1-(4-methylphenyl-
sulfonyl) indole (6e)
IR (film): 2934, 2835, 1597, 1472, 1371, 1219, 1173, 1132,
667 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.33 (3 H, s),
3.81 (3 H, s), 3.86 (3 H, s), 6.91 (1 H, dd, J = 8.1, 2.4 Hz),
6.97 (1 H, dd, J = 9.2, 2.4 Hz), 7.10 (1 H, s), 7.16 (1 H, d,
J = 8.1 Hz), 7.19–7.22 (3 H, m), 7.37 (1 H, t, J = 8.1 Hz),
7.64 (1 H, s), 7.76 (2 H, d, J = 8.1 Hz), 7.93 (1 H, d, J = 9.2
Hz). 13C NMR (100 MHz, CDCl3): d = 21.6, 55.3, 55.7,
102.9, 113.0, 113.3, 113.8, 114.7, 120.1, 123.83, 123.85,
126.7, 129.8, 129.9, 130.1, 130.2, 134.4, 135.0, 144.8,
156.6, 159.9. MS: m/z (%) = 407 (59.9) [M+], 252 (100).
HRMS: m/z calcd for C23H21NO4S: 407.1191; found:
407.1178. Anal. Calcd for C23H21NO4S: C, 67.79; H, 5.19;
N, 3.44. Found C, 67.86; H, 5.33; N, 3.44.
m/z calcd for C22H21NO3S: 379.1242; found: 379.1230.
Anal. Calcd for C22H21NO3S: C, 69.63; H, 5.58; N, 3.69.
Found: C, 69.37; H, 5.65; N, 3.71.
6-Methoxy-3-(4-methoxyphenyl)-1-(4-methylphenyl-
sulfonyl) indole (6a)
IR (film): 2934, 2837, 1597, 1508, 1369, 1252, 1173, 1115,
1032 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.35 (3 H, s),
2.86 (3 H, s), 2.90 (3 H, s), 6.89 (1 H, dd, J = 8.8, 2.6 Hz),
6.96 (1 H, d, J = 8.8 Hz), 6.98 (1 H, d, J = 8.8 Hz), 7.22 (1
H, d, J = 7.6 Hz), 7.49–7.51 (3 H, m), 7.585 (1 H, s), 7.593
(1 H, d, J = 7.6 Hz), 7.78–7.80 (3 H, m). 13C NMR (100
MHz, CDCl3): d = 21.6, 55.3, 55.8, 98.1, 112.5, 114.2,
120.8, 123.2, 123.6, 125.5, 126.7, 128.8, 129.8, 135.1,
136.5, 144.8, 157.9, 159.0. MS: m/z (%) = 407 (31.0) [M+],
252 (100). HRMS: m/z calcd for C23H21NO4S: 407.1191;
found: 407.1184.
5-Methoxy-1-(4-methylphenylsulfonyl)-3-phenylindole
(6f-A) and 3-(3-Methoxyphenyl)-1-(4-methylphenyl-
sulfonyl) indole (6f-B)
IR (film): 2926, 2361, 1597, 1470, 1371, 1173, 1134, 669
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.33 (3 H, s), 3.80
(2.49 H, s), 3.86 (0.51 H, s), 6.91 (0.17 H, ddd, J = 8.2, 2.5,
1.3 Hz), 6.97 (0.83 H, dd, J = 9.2, 2.4 Hz), 7.13 (0.17 H, dd,
J = 2.5, 1.3 Hz), 7.18–7.25 (3 H, m), 7.28 (0.17 H, d, J = 7.6
Hz), 7.34–7.38 (1.17 H, m), 7.45 (1.66 H, dd, J = 8.0, 7.2
Hz), 7.56 (1.66 H, dd, J = 8.2, 1.4 Hz), 7.63 (0.83 H, s), 7.69
(0.17 H, s), 7.76 (1.66 H, d, J = 8.4 Hz), 7.78–7.80 (0.51 H,
m), 7.94 (0.83 H, d, J = 8.8 Hz), 8.04 (0.17 H, d, J = 8.4 Hz).
13C NMR (100 MHz, CDCl3): d = 21.5, 55.7, 103.0, 113.8,
114.8, 123.8, 124.1, 126.8, 127.5, 127.8, 128.9, 129.87,
129.92, 130.3, 133.2, 135.2, 144.9, 156.8. MS: m/z (%) =
377 (60.4) [M+], 222 (100). HRMS: m/z calcd for
C22H19NO3S: 377.1086; found: 377.1068.
6-Fluoro-3-(4-fluorophenyl)-1-(4-methylphenylsulfonyl)
indole (6b)
IR (film): 3111, 2926, 1504, 1375, 1188, 1175, 1107, 679
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.36 (3 H, s), 7.00–
7.06 (1 H, m), 7.12–7.16 (2 H, m), 7.26 (2 H, d, J = 8.0 Hz),
7.49–7.53 (2 H, m), 7.59–7.63 (1 H, m), 7.61 (1 H, s), 7.76–
7.81 (3 H, m). MS: m/z = 383 (40.0) [M+], 319 (9.0), 228
(100). HRMS: m/z calcd for C21H15F2NO2S: 383.0781;
found: 383.0782.
(21) Geometry of enamine 5f was determined by NOESY.
(22) Regioisomeric products 6f-A and 6f-B could not be
separated from one another; their ratio was determined by 1H
NMR spectroscopy.
6-Ethoxycarbonyl-3-(4-ethoxycarbonylphenyl)-1-(4-
methylphenylsulfonyl) indole (6c)
Synlett 2008, No. 20, 3157–3162 © Thieme Stuttgart · New York

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