Copper-mediated intramolecular oxidative C-H/C-H cross-coupling of α-oxo ketene N, S -acetals for indole synthesis

Article abstract of DOI:10.1021/jo5014542

CuCl₂-mediated intramolecular C-H/C-H cross-dehydrogenative coupling (CDC) of thioalkyl-substituted α-acetyl or α-aroyl ketene N,S-acetals afforded 2-thioalkyl indoles. Tunable C-S bond transformations of the resultant indoles led to highly fun

Full text of DOI:10.1021/jo5014542

Note
pubs.acs.org/joc
Copper-Mediated Intramolecular Oxidative C−H/C−H
Cross-Coupling of α‑Oxo Ketene N,S‑Acetals for Indole Synthesis
Fei Huang,† Ping Wu,† Liandi Wang,† Jiping Chen,† Chenglin Sun,† and Zhengkun Yu*,†,‡
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023,
People’s Republic of China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: CuCl2-mediated intramolecular C−H/C−H cross-dehydro-
genative coupling (CDC) of thioalkyl-substituted α-acetyl or α-aroyl ketene
N,S-acetals afforded 2-thioalkyl indoles. Tunable C−S bond transformations
of the resultant indoles led to highly functionalized N-heterocyclic com-
pounds. A β-thioalkyl is necessary to activate the N,S-acetal substrate and
enable the CDC reaction to occur, and the relevant mechanism studies
revealed that the CDC reaction follows a radical pathway.
Scheme 1. Indole Synthesis via CDC Reactions of N-Aryl
ndole motifs are abundant in natural products and are
Ialso featured in many pharmaceuticals. Diverse synthetic
methods have been developed to access indole derivatives since
the Fischer indole synthesis was reported in 1883.1 Unfortu-
nately, functionalized indoles can only be prepared through
specific synthetic methods2 or by functionalization of struc-
turally simple indoles.3 As cross-coupling via transition-metal-
catalyzed C−H activation has recently become a promising
straightforward route to form carbon−carbon and carbon−
heteroatom bonds, catalytic C−H/C−halo cross-coupling4 and
C−H amination5 have been reported for the direct synthesis of
indoles. Palladium-catalyzed cyclization of 2-alkynylanilid(n)es6
or N-alkynylanilines7 and Rh(III)-promoted reactions of ani-
lides with alkenes8 have been applied for the construction of
indole nuclei. On the basis of the pioneering work of Åkermark
Enamines13−16
Electron-withdrawing group (EWG)-substituted (α-oxo)
ketene S,S-acetals20 and N,O-acetals21 are versatile building
blocks in organic synthesis. However, their analogues, that is,
α-oxo ketene N,S-acetals, have been paid much less attention.22
We recently found that olefinic C−H and C−S bonds of α-oxo
ketene S,S-acetals could be activated by palladium catalysts to
participate in various cross-coupling reactions.23 Keeping the
knowledge of indole synthesis13−19 in mind, we reasonably en-
visioned that α-oxo ketene N,S-acetals might be utilized for
direct indole synthesis through their intramolecular C−H/C−H
CDC reactions. Herein we report a thioalkyl-dependent, copper-
(II)-mediated CDC reaction of α-oxo ketene N,S-acetals for the
synthesis of highly functionalized indoles.
and Knolker on palladium-promoted intramolecular C−H/C−H
̈
cross-coupling of ArXAr′ (X = O, NY) for the synthesis of
carbazoles and dibenzofurans,9 intramolecular cross-dehydrogen-
ative coupling (CDC)10 has become a promising protocol for
the synthesis of indoles from enamines and imines,11 although
photoredox-catalyzed intramolecular C−H/C−H cross-coupling12a
and the Larock protocol12b can also be utilized for the same
purpose. Palladium(II)-catalyzed, copper(II)-mediated cycliza-
tion of the enamine methyl (Z)-3-(phenylamino)but-2-enoate
and its analogues formed indoles,13 and Cu(I)-catalyzed oxida-
tive cyclization of N-aryl enaminones afforded multisubstituted
indoles.14 Iron(III)-catalyzed, Cu(II)-mediated CDC reactions
of methyl 3-(arylamino)but-2-enoates also gave indole deriva-
tives,15 and a process involving PhI(OAc)2 was also reported
for the construction of functionalized indoles16 (Scheme 1).
Pd(II)-catalyzed aerobic oxidative cyclization of N-aryl imines
produced 2-substituted indoles,17 and a combination of I2
and NBS was also effective for the same purpose.18 It is noted
that 2,3-disubstituted indoles have been obtained from
N-substituted anilines under palladium catalysis.6d,19
Initially, the reaction of α-acetyl ketene N,S-acetal 1a was
performed under the known CDC conditions.13−17 With the
protocols developed by Åkermark and Knolker [10 mol %
̈
Pd(OAc)2/HOAc/O2/95 °C],9 Glorius [10 mol % Pd(OAc)2/
Cu(OAc)2/K2CO3/DMF/140 °C],13 or Zhao [PhI(OAc)2/
DCE/60 °C],16 1a reacted to afford acetanilide (MeCONHPh)
as the product in 45−56% yield without the formation of
the desired product, 2-thiomethyl-3-acetylindole (2a). Under
Received: July 1, 2014
© XXXX American Chemical Society
A
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Note
Cacchi’s (5 mol % CuI/phen/Li2CO3/DMF/air/100 °C)14 or
Yoshikai’s [10 mol % Pd(OAc)2/Bu4NBr/DMSO/O2/60 °C]17
conditions, no reaction occurred. Using Liang’s procedure
[10 mol % FeCl3/Cu(OAc)2·CuCl2/K2CO3/DMF/120 °C]15
led to a mixture of 2a and acetanilide. These results reveal that
both metallic and organic acetates easily cleave the olefinic
C−N bond in 1a to form acetanilide and that neither Pd(II)/
oxidant nor Cu(I)/air promoted the intramolecular CDC reac-
tion of 1a. Intramolecular hydrogen bonding between the N−H
moiety and the carbonyl oxygen seems to activate the β-olefinic
C−N bond of 1a, allowing nucleophilic attack of stoichiometric
AcO− anion at the β-carbon followed by attack of the nitrogen
atom at the acetyl carbon in the β-C-attached OAc, resulting in
acetanilide. Such a reactivity difference between 1a and the re-
ported N-aryl enamines and imines13−17 is presumably attri-
buted to the stronger push−pull electronic effect in the α-oxo
ketene N,S-acetal substrate enhanced by the β-thioalkyl func-
tionality. To our delight, stoichiometric CuCl2 mediated the
intramolecular CDC reaction of 1a to yield 2a without using an
additional transition-metal catalyst.
The reaction of 1a was then conducted to screen the reaction
conditions. In the presence of both CuCl2 and K2CO3 (3 equiv
each) under an argon atmosphere, 1a reacted to give indole 2a
in 31% yield in DMSO at 120 °C within 2 h (Table 1, entry 1).
Using DMF as the solvent obviously improved the reaction
efficiency, and a mixture of DMF and DMSO (7:1 v/v) acted as
the most suitable reaction medium, enhancing the yield of 2a to
88% (Table 1, entries 2−4). Using K3PO4 as the base further
improved the formation of 2a (94% isolated yield; Table 1,
entries 4−8). Elevating the temperature to 140 °C did not fur-
ther improve the reaction efficiency, while using a lower tem-
perature (100 °C) deteriorated the product yield (Table 1,
entries 9 and 10). It was found that employing an air atmo-
sphere dramatically lessened the yield of 2a to 68% and that an
oxygen atmosphere nearly prohibited the reaction (Table 1,
entries 11 and 12). Using a smaller amount of CuCl2 obvi-
ously reduced the formation of 2a (Table 1, entries 13 and 14).
CuCl2·2H2O was not an effective promoter, whereas CuBr2
behaved as efficiently as CuCl2 did (Table 1, entries 15 and 16).
It should be noted that enamine 1a′ did not undergo the same
CDC reaction, demonstrating that the compatible push−pull
effect of the electron-donating/withdrawing functionalities
on the CC backbone of 1a is crucial for the intramolecular
C−H/C−H CDC reaction to occur.
a
Table 1. Screening of the Reaction Conditions
T
b
entry
[Cu]
CuCl2
base
solvent (v:v)
DMSO
(°C) yield (%)
1
2
3
K2CO3
K2CO3
K2CO3
120
120
120
31
c
CuCl2
CuCl2
DMF
76 (72)
DMF/DMSO
(5:1)
83
88
4
5
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
K2CO3
Li2CO3
K3PO4
DMF/DMSO
(7:1)
120
120
120
120
120
140
100
120
120
120
120
120
120
DMF/DMSO
(7:1)
87
c
6
DMF/DMSO
(7:1)
97 (94)
d
7
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF/DMSO
(7:1)
83
e
8
DMF/DMSO
(7:1)
73
c
9
DMF/DMSO
(7:1)
96 (94)
10
DMF/DMSO
(7:1)
81
68
7
f
11
DMF/DMSO
(7:1)
g
12
DMF/DMSO
(7:1)
d
13
14
15
16
CuCl2
CuCl2
DMF/DMSO
(7:1)
52
6
e
DMF/DMSO
(7:1)
CuCl2·2H2O
DMF/DMSO
(7:1)
76
95
CuBr2
DMF/DMSO
(7:1)
a
Conditions: 1a (0.2 mmol), [Cu] (0.6 mmol), base (0.6 mmol),
solvent (2 mL), Ar (0.1 MPa), 2 h. GC yields with mesitylene as the
internal standard. The isolated yield is given in parentheses. 2 equiv.
b
c
d
e
f
g
1 equiv. In air. In O2 (1 atm).
indole products 2 could be further functionalized by
Liebeskind−Srogl cross-coupling20b or nucleophilic condensa-
tion (Scheme 2). These transformations render our method an
alternative route that provides access to diverse indole deriva-
tives. It is noteworthy that indoles 2d, 2x, and 3b were structur-
ally characterized by X-ray crystallography (see the Supporting
Information).
In order to probe into the reaction mechanism, kinetic iso-
tope effect (KIE) experiments on 1r[D5] were performed (eq 1).
At 0.5 h, kH/kD = 1.07 was observed, suggesting that C−H bond
cleavage in the N-aryl moiety of 1 is not involved in the rate-
determining step.24 At the present time, 1r[D7] was not success-
fully prepared for KIE experiments relevant to the olefinic C−D/
C−H bonds. On the basis of the observation that both air and
oxygen atmospheres deteriorated the reaction efficiency of 1a
(Table 1), radicals are considered to be involved in the C−H/
C−H CDC reactions of 1.
Next, the generality of the protocol was explored by using
various α-oxo ketene N,S-acetals 1 as the substrates (Table 2).
Substituents such as p-Me, o-Me, p-OMe, and p-OEt on the
NAr functionality were tolerated, efficiently giving the desired
products 2b and 2d−2f, respectively (90−96%). Two isomeric
products, 2c (55%) and 2c′ (28%), were obtained when two
reactive sites were present in the NAr group of 1c. A 2-methoxy
group exhibited a negative steric effect on the formation of 2g
(65%). Electron-withdrawing chloro and fluoro substituents
lessened the yields of 2h−j to 68−78%. Increased bulkiness in
the N-aryl moiety deteriorated the reaction efficiency in the
formation of 2k (73%) and 2l (79%). The corresponding
thioethyl-bearing analogues (i.e., 1m−q) also efficiently reacted
to form the target products 2m−q (81−96%). In a similar
fashion, α-aroyl ketene N,S-acetals reacted to afford 2r−x in
65−89% yield, demonstrating an obvious steric effect of the
aroyl moiety.
Addition of the radical scavenger 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) (1 or 2 equiv) resulted in complete
inhibition of the reaction of 1a (see the Experimental Section),
suggesting involvement of radicals in the reaction. N-2′,6′-
Dimethylphenyl ketene N,S-acetal 1y could not undergo the
reaction to form the chlorinated product 1y′, and substrate 1i
In contrast to the indole derivatives obtained by the synthetic
protocols depicted in Scheme 1, the 2-positions of the target
B
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Note
ab
,
Table 2. CDC Reactions of α-Acetyl/Aroyl Ketene N,S-Acetals (1) To Form Indoles (2)
a
b
Conditions: 1 (0.5 mmol), CuCl2 (1.5 mmol), K3PO4 (1.5 mmol), DMF/DMSO (7:1 v/v, 5 mL), Ar (0.1 MPa), 120 °C, 2 h. Yields refer to the
isolated products.
Scheme 2. Functionalization of 2-Thioalkylindoles 2
during the reaction, so intramolecular C−H/C−Cl cross-coupling
can be excluded from the reaction pathway of 1 (Scheme 3).
Consequently, a plausible mechanism involving radicals and
single-electron transfer (SET) is proposed (Scheme 4).
In summary, CuCl2-mediated intramolecular C−H/C−H
CDC reactions of α-acetyl/aroyl ketene N,S-acetals afford
could not be converted into 2a. These results revealed that
chlorinated intermediate of the type 1y′ cannot be generated
2-thioalkylindoles. Readily tunable C−S bond transformations of
the resultant products render the present method a promising
C
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Note
(E)-4-(Thiomethyl)-4-(p-tolylamino)but-3-en-2-one (1b). 1.44 g,
yield 65%; white solid, mp 43−45 °C; 1H NMR (400 MHz, CDCl3) δ
12.82 (s, 1H), 7.13 (s, 4H), 5.15 (s, 1H), 2.33 (s, 3H), 2.29 (s, 3H),
2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 166.4, 136.4,
135.5, 129.6, 125.5, 91.2, 29.2, 21.0, 14.5; HRMS (EI) calcd for
C12H15NOS 221.0874, found 221.0874.
Scheme 3. Exclusion of Intramolecular C−H/C−Cl
Cross-Coupling
(E)-4-(Thiomethyl)-4-(m-tolylamino)but-3-en-2-one (1c). 1.44 g,
1
yield 65%; yellow liquid; H NMR (400 MHz, CDCl3) δ 12.91 (s,
1H), 7.20 (t, J = 8.1 Hz, 1H), 7.05 (d, J = 6.6 Hz, 2H), 7.01 (d, J =
7.7 Hz, 1H), 5.16 (s, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 165.9, 138.9, 138.0, 128.7,
127.0, 125.8, 122.2, 91.4, 29.2, 21.3, 14.5; HRMS (EI) calcd for
C12H15NOS 221.0874, found 221.0877.
(E)-4-(Thiomethyl)-4-(o-tolylamino)but-3-en-2-one (1d). 1.37 g,
yield 62%; white solid, mp 75−77 °C; 1H NMR (400 MHz, CDCl3) δ
12.72 (s, 1H), 7.24 and 7.18 (m each, 2:2H), 5.17 (s, 1H), 2.29
(s, 6H), 2.15 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.0,
167.2, 137.0, 134.7, 130.8, 127.3, 127.1, 126.3, 90.9, 29.2, 18.0, 14.5;
HRMS (EI) calcd for C12H15NOS 221.0874, found 221.0878.
(E)-4-(4-Methoxyphenylamino)-4-(thiomethyl)but-3-en-2-one
(1e). 1.59 g, yield 67%; yellow liquid; 1H NMR (400 MHz, CDCl3) δ
12.66 (s, 1H), 7.14 and 6.85 (d each, J = 8.8 Hz, 2:2H), 5.13 (s, 1H),
3.78 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.9, 167.1, 158.2, 130.9, 127.5, 114.2, 90.9, 55.5, 29.3,
14.5; HRMS (EI) calcd for C12H15NO2S 237.0823, found 237.0829.
(E)-4-(4-Ethoxyphenylamino)-4-(thiomethyl)but-3-en-2-one (1f).
Scheme 4. Proposed Mechanism
1
1.73 g, yield 69%; yellow solid, mp 62−65 °C; H NMR (400 MHz,
CDCl3) δ 12.66 (s, 1H), 7.13 and 6.84 (d each, J = 8.8 Hz, 2:2H), 5.13
(s, 1H), 4.00 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 2.12 (s, 3H), 1.39 (t,
J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.9, 167.2,
157.8, 130.8, 127.5, 114.7, 90.9, 63.7, 29.3, 14.9, 14.6; HRMS (EI)
calcd for C13H17NO2S 251.0980, found 251.0988.
(E)-4-(2-Methoxyphenylamino)-4-(thiomethyl)but-3-en-2-one
(1g). 1.52 g, yield 64%; yellow solid, mp 51−53 °C; 1H NMR (400 MHz,
CDCl3) δ 12.75 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz,
1H), 6.90 (t, J = 7.3 Hz, 2H), 5.19 (s, 1H), 3.84 (s, 3H), 2.31 (s, 3H),
2.14 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.9, 165.7, 152.9,
127.5, 127.0, 125.6, 120.0, 111.3, 92.1, 55.8, 29.3, 14.8; HRMS (EI) calcd
for C12H15NO2S 237.0823, found 237.0826.
alternative route to access highly functionalized indole deriv-
atives.
EXPERIMENTAL SECTION
■
General Considerations. The solvents were dried and distilled by
1
literature methods prior to use. H and 13C{1H} NMR spectra were
(E)-4-(4-Chlorophenylamino)-4-(thiomethyl)but-3-en-2-one (1h).
1
1.69 g, yield 70%; white solid, mp 60−62 °C; H NMR (400 MHz,
recorded on a 400 and 100 MHz FT-NMR spectrometer, and all
chemical shift values refer to δTMS = 0.00 ppm or to CDCl3 [δ(1H) =
7.26 ppm; δ(13C) = 77.16 ppm] or DMSO-d6 [δ(1H) = 2.50 ppm;
δ(13C) = 39.52 ppm]. HRMS (EI) analysis was performed on a Waters
GC-TOF mass spectrometer. All of the chemical reagents were pur-
chased from commercial sources and used as received, unless other-
wise indicated. (E)-4-Thiomethyl-4-(phenylamino)but-3-en-2-one
(1a),25a (E)-3-thiomethyl-1-phenyl-3-(phenylamino)prop-2-en-1-one
(1r),25a (E)-3-thiomethyl-3-phenylamino-1-(p-tolyl)prop-2-en-1-one
(1s),25b and (E)-1-(4-chlorophenyl)-3-thiomethyl-3-(phenylamino)-
prop-2-en-1-one (1u)25b are known compounds and were prepared
by the literature methods. 2-Thiomethyl-3-acetyl-1H-indole (2a) and
2-thiomethyl-3-benzoyl-1H-indole (2r) are known compounds and
were identified by comparison of their NMR features with the reported
data for the authentic samples.25c
CDCl3) δ 12.92 (s, 1H), 7.28 and 7.18 (d each, J = 8.6 Hz, 2:2H), 5.20
(s, 1H), 2.31 (s, 3H), 2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 193.2, 165.4, 136.8, 131.6, 129.0, 126.4, 92.1, 29.2, 14.5; HRMS (EI)
calcd for C11H12NOSCl 241.0328, found 241.0335.
(E)-4-(2-Chlorophenylamino)-4-(thiomethyl)but-3-en-2-one (1i).
1
1.52 g, yield 63%; white solid, mp 87−90 °C; H NMR (400 MHz,
CDCl3) δ 12.89 (br, 1H), 7.40 (m), 7.20 (m), and 7.12 (m) (2:1:1H),
5.22 (s, 1H), 2.29 (s, 3H), 2.13 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 193.5, 165.4, 135.9, 129.8, 130.0, 127.3, 137.0, 92.8, 29.3,
14.7; HRMS (EI) calcd for C11H12NOSCl 241.0328, found 241.0333.
(E)-4-(4-Fluorophenylamino)-4-(thiomethyl)but-3-en-2-one (1j).
1
1.53 g, yield 68%; white solid, mp 73−75 °C; H NMR (400 MHz,
CDCl3) δ 12.77 (s, 1H), 7.18 and 7.00 (m each, 2:2H), 5.16 (s, 1H),
2.29 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.3,
166.4, 161 (d and Cq, J = 246.4 Hz), 134.2, 127.6 (d, J = 8.3 Hz),
115.8 (d, J = 22.7 Hz), 91.5, 29.3, 14.5; HRMS (EI) calcd for
C11H12NOSF 225.0624, found 225.0628.
Typical Procedure for the Synthesis of 1: Synthesis of 1a. To
a stirred solution of the ketene S,S-acetal 4,4-bis(methylthio)but-3-en-
2-one (1.62 g, 10 mmol) and aniline (1.40 mL, 15 mmol) in toluene
(30 mL) was added BF3·Et2O (0.13 mL, 1.0 mmol), and the resulting
mixture was heated to reflux. When TLC monitoring on silica gel indi-
cated complete consumption of the acetal, the mixture was cooled to
ambient temperature, and all of the volatiles were evaporated under
reduced pressure. The resulting residue was purified by silica gel col-
umn chromatography [eluent: petroleum ether (60−90 °C)/AcOEt =
30:1 v/v], affording N,S-acetal 1a (1.30 g, 63%) as a yellow liquid.
(E)-4-(Thiomethyl)-4-(phenylamino)but-3-en-2-one (1a). 1.30 g,
(E)-4-(3,5-Dimethylphenylamino)-4-(thiomethyl)but-3-en-2-one
(1k). 1.43 g, yield 61%; white solid, mp 60−62 °C; 1H NMR (400 MHz,
CDCl3) δ 12.87 (s, 1H), 6.87 and 6.85 (s each, 2:1H), 5.16 (s, 1H), 2.31
(s, 3H), 2.30 (s, 6H), 2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 192.8, 166.1, 138.7, 138.0, 128.0, 123.0, 91.3, 29.3, 21.3, 14.6; HRMS
(EI) calcd for C13H17NOS 235.1031, found 235.1031.
(E)-4-(Thiomethyl)-4-(naphthalen-1-ylamino)but-3-en-2-one (1l).
1
1.26 g, yield 49%; white solid, mp 96−98 °C; H NMR (400 MHz,
1
CDCl3) δ 13.29 (s, 1H), 8.07 and 7.78 (d each, J = 7.8 Hz, 1:1H), 7.87
and 7.49 (d each, J = 7.6 Hz, 1:1H), 7.54 and 7.44 (m each, 2:1H),
5.30 (s, 1H), 2.26 (d, J = 1.8 Hz, 3H), 2.24 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 193.3, 167.7, 134.3, 134.2, 129.7, 128.2, 127.5,
yield 63%; yellow liquid; H NMR (400 MHz, CDCl3) δ 12.95 (s,
1H), 7.26 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.12 (m, 1H),
5.13 (s, 1H), 2.21 (d, 3H), 2.08 (d, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.6, 165.5, 137.9, 128.7, 125.9, 124.8, 91.4, 29.0, 14.2.
D
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Note
126.9, 126.6, 125.0, 124.1, 122.8, 91.6, 29.3, 14.5; HRMS (EI) calcd
for C15H15NOS 257.0874, found 257.0873.
(s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 167.5, 140.3,
138.3, 138.1, 131.8, 129.1, 128.3, 127.8, 126.4, 125.3, 124.2, 88.9, 21.6,
14.9; HRMS (EI) calcd for C17H17NOS 283.1031, found 283.1039.
(E)-1-(4-Chlorophenyl)-3-(thiomethyl)-3-(phenylamino)prop-2-
(E)-4-(Thioethyl)-4-(o-tolylamino)but-3-en-2-one (1m). 1.88 g,
yield 80%; yellow solid, mp 48−51 °C; 1H NMR (400 MHz,
CDCl3) δ 12.89 (s, 1H), 7.33 and 7.26 (m each, 2:2H), 5.33 (s, 1H),
2.91 (q, J = 7.4 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.38 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 166.2, 136.9, 134.5,
130.7, 127.1, 127.0, 126.2, 91.5, 29.1, 25.6, 18.0, 13.3; HRMS (EI)
calcd for C13H17NOS 235.1031, found 235.1037.
(E)-4-(Thioethyl)-4-(p-tolylamino)but-3-en-2-one (1n). 2.10 g,
yield 89%; yellow solid, mp 39−42 °C; 1H NMR (400 MHz,
CDCl3) δ 12.88 (s, 1H), 7.10 (s, 4H), 5.20 (s, 1H), 2.79 (q, J = 7.4 Hz,
2H), 2.30 (s, 3H), 2.10 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 192.6, 165.2, 136.0, 135.5, 129.4, 125.2,
91.8, 29.0, 25.6, 20.9, 13.2; HRMS (EI) calcd for C13H17NOS
235.1031, found 235.1038.
(E)-4-(Thioethyl)-4-(4-methoxyphenylamino)but-3-en-2-one
(1o). 1.56 g, yield 62%; yellow liquid; 1H NMR (400 MHz, CDCl3) δ
12.72 (br, 1H), 7.16 and 6.87 (d each, J = 8.8 Hz, 2:2H), 5.18 (s, 1H),
3.80 (s, 3H), 2.83 (q, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.30 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 166.3, 158.3, 131.0,
127.5, 114.2, 91.6, 55.5, 29.2, 25.8, 13.4; HRMS (EI) calcd for
C13H17NO2S 251.0980, found 251.0986.
1
en-1-one (1u). 2.51 g, yield 83%; yellow solid, mp 84 °C; H NMR
(400 MHz, CDCl3) δ 13.49 (s, 1H), 7.83 and 7.39 (d each, J = 8.2 Hz,
2:2H), 7.36 and 7.31 (d each, J = 7.7 and 7.6 Hz, 2:2H), 7.24 (t, J =
7.2 Hz, 1H), 5.81 (s, 1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 184.6, 168.2, 138.6, 138.1, 137.1, 129.2, 128.6, 128.5, 126.7,
125.4, 88.3, 14.9.
(E)-1-(3-Chlorophenyl)-3-(thiomethyl)-3-(phenylamino)prop-2-
1
en-1-one (1v). 2.56 g, yield 85%; yellow solid, mp 56−58 °C; H
NMR (400 MHz, CDCl3) δ 13.49 (s, 1H), 7.86 (t, J = 1.7 Hz), 7.76
(d, J = 7.7 Hz), 7.41 (m), and 7.24 (t, J = 7.2 Hz) (1:1:1:1H), 7.39−
7.27 (m, 5H), 5.79 (s, 1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 184.3, 168.5, 142.1, 138.0, 134.5, 130.8, 129.7, 129.2, 127.3,
126.7, 125.4, 125.2, 88.4, 14.9; HRMS (EI) calcd for C16H14NOSCl
303.0485, found 303.0494.
(E)-1-(3-Bromophenyl)-3-(thiomethyl)-3-(phenylamino)prop-2-
1
en-1-one (1w). 2.32 g, yield 67%; red liquid; H NMR (400 MHz,
CDCl3) δ 13.51 (s, 1H), 8.01 (t, J = 1.5 Hz), 7.78 (d, J = 7.8 Hz), 7.52
(m), 7.32 (m), 7.27 (m), 7.21 (m) (1:1:1:2:2:2H), 5.76 (s, 1H), 2.35
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.8, 168.3, 142.1,
137.8, 133.5, 130.0, 129.8, 129.0, 126.5, 125.5, 125.1, 122.6, 88.3, 14.7;
HRMS (ESI) calcd for C16H14NOSBrNa [M + Na]+ 369.9877, found
369.9883.
(E)-4-(4-Ethoxyphenylamino)-4-(thioethyl)but-3-en-2-one (1p).
1
1.62 g, yield 61%; yellow solid, mp 88−91 °C; H NMR (400 MHz,
CDCl3) δ 12.71 (s, 1H), 7.14 and 6.85 (d each, J = 8.6 Hz, 2:2H), 5.18
(s, 1H), 4.01 (q, J = 6.9 Hz, 2H), 2.82 (q, J = 7.4 Hz, 2H), 2.12 (s,
3H), 1.40 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 192.8, 166.1, 157.7, 130.9, 127.4, 114.7, 91.6,
63.7, 29.3, 25.8, 14.9, 13.4; HRMS (EI) calcd for C14H19NO2S
265.1136, found 265.1139.
(E)-3-(4-Ethoxyphenylamino)-3-(thioethyl)-1-phenylprop-2-en-1-
1
one (1x). 1.58 g, yield 48%; yellow solid, mp 86−88 °C; H NMR
(400 MHz, CDCl3) δ 13.36 (s, 1H), 7.90 and 7.45 (m each, 2:3H),
7.22 and 6.89 (d each, J = 8.8 Hz, 2:2H), 5.90 (s, 1H), 4.02 (q, J =
7.0 Hz, 2H), 2.94 (q, J = 7.4 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H), 1.36 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.8, 167.8,
157.7, 140.4, 130.7, 130.8, 128.3, 127.2, 127.0, 114.7, 88.6, 63.6, 26.0,
14.9, 13.4; HRMS (EI) calcd for C19H21NO2S 327.1293, found
327.1304.
(E)-4-(2-Chlorophenylamino)-4-(thioethyl)but-3-en-2-one (1q).
1
1.60 g, yield 63%; white solid, mp 66−69 °C; H NMR (400 MHz,
CDCl3) δ 12.90 (br, 1H), 7.43 (t, J = 8.3 Hz), 7.23 (m), and 7.15 (m)
(2:1:1H), 5.29 (s, 1H), 2.83 (q, J = 7.4 Hz, 2H), 2.15 (s, 3H), 1.30 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 164.3,
136.1, 130.0, 127.4, 127.3, 126.9, 129.9, 93.8, 29.0, 26.1, 13.3; HRMS
(EI) calcd for C12H14NOSCl 255.0485, found 255.0489.
(E)-3-(2,6-Dimethylphenylamino)-3-(thiomethyl)-1-phenylprop-
1
2-en-1-one (1y). 1.37 g, yield 46%; white solid, mp 130−132 °C; H
NMR (400 MHz, CDCl3) δ 12.98 (s, 1H), 7.98 (dd, J = 7.4 and 1.9 Hz)
and 7.13 (d, J = 7.4 Hz) (2:2H), 7.46 and 7.19 (m each, 3:1H), 5.91 (s,
1H), 2.40 (s, 3H), 2.32 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
186.0, 170.2, 140.4, 136.8, 136.0, 130.8, 128.3, 128.2, 128.1, 127.1, 86.9,
18.2, 14.3; HRMS (EI) calcd for C18H20NOS 298.1266, found
298.1269.
(E)-3-(Thiomethyl)-1-phenyl-3-(phenylamino)prop-2-en-1-one
1
(1r). 2.15 g, yield 80%; yellow solid, mp 58 °C; H NMR (400 MHz,
CDCl3) δ 13.58 (s, 1H), 7.96 and 7.48 (m each, 2:3H), 7.39 and 7.28
(m each, 4:1H), 5.93 (s, 1H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 186.1, 167.6, 140.3, 138.3, 131.0, 129.1, 128.4, 127.1, 126.4,
125.3, 88.8, 14.8.
Typical Procedure for the Synthesis of Indoles 2: Synthesis
of 2a. Under an argon atmosphere, a mixture of ketene N,S-acetal 1a
(104 mg, 0.5 mmol), CuCl2 (202 mg, 1.5 mmol), and K3PO4 (318 mg,
1.5 mmol) in 5 mL of DMF/DMSO (7:1 v/v) was stirred at 120 °C
for 2 h. The resulting mixture was cooled to ambient temperature, fil-
tered through a short pad of Celite, rinsed with 20 mL of AcOEt, and
washed with 10% aqueous NH3·H2O (2 × 10 mL) and brine (10 mL).
The organic phase was dried over anhydrous Na2SO4 and filtered. All
of the volatiles were evaporated under reduced pressure. The resultant
residue was purified by silica gel column chromatography [eluent:
petroleum ether (60−90 °C)/AcOEt = 10:1 v/v] to afford 2a as a
white solid (96 mg, 94%).
Synthesis of (E)-3-(Thiomethyl)-1-phenyl-3-(D5-phenylamino)-
prop-2-en-1-one (1r[D5]). To a stirred solution of ketene S,S-acetal
3,3-bis(methylthio)-1-phenylprop-2-en-1-one (1.12 g, 5 mmol) and
aniline-d7 (0.50 mL, 5.5 mmol) in toluene (10 mL) was added BF3·
Et2O (65 mL, 0.05 mmol), and the resulting mixture was heated to
reflux. When TLC monitoring on silica gel indicated complete con-
sumption of the acetal, the mixture was cooled to ambient tempera-
ture, and all of the volatiles were evaporated under reduced pressure.
The resulting residue was purified by silica gel column chromatog-
raphy (eluent: petroleum ether (60−90 °C)/AcOEt = 30:1 v/v) to
afford ketene N,S-acetal 1r[D5] (0.99 g, 72%, 98% D) as a yellow solid.
1
2-(Thiomethyl)-3-acetyl-1H-indole (2a). 96 mg, yield 94%; yellow
Mp 51−53 °C; H NMR (400 MHz, CDCl3) δ 13.57 (s, 1H), 7.93
1
solid, mp 170 °C; H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H),
and 7.38 (m each, 2:3H), 5.91 (s, 1H), 2.42 (d, J = 1.7 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.1, 167.6, 140.3, 138.1, 130.9,
7.83, 7.45, and 7.15 (m each, 1:1:2H), 2.62 (s, 3H), 2.54 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 191.2, 145.0, 136.9, 126.6,
121.6, 121.4, 119.3, 111.3, 113.7, 30.3, 14.4; HRMS (EI) calcd for
C11H11NOS 205.0561, found 205.0569.
2-(Thiomethyl)-3-acetyl-5-methyl-1H-indole (2b). 104 mg, yield
95%; white solid, mp 212−215 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.66 (s, 1H), 7.67 (s), 7.36 (d, J = 6.4 Hz), and 7.01 (d, J = 5.5 Hz)
(1:1:1H), 2.64, 2.56, and 2.44 (s each, 9H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 191.1, 144.8, 135.2, 130.3, 126.8, 122.8, 119.2, 113.4,
110.9, 30.3, 21.5, 14.3; HRMS (EI) calcd for C12H13NOS 219.0718,
found 219.0709.
128.4, 127.1, 128.8, 128.6, 125.1, 124.8, 124.6, 88.8, 14.8; HRMS (EI)
calcd for C16H11D5NOS [M + H]+ 275.1266, found 275.1278.
(E)-3-(Thiomethyl)-3-(phenylamino)-1-(p-tolyl)prop-2-en-1-one
(1s). 2.49 g, yield 88%; yellow solid, mp 61−64 °C; 1H NMR (400 MHz,
CDCl3) δ 13.56 (s, 1H), 7.87 (d, J = 8.1 Hz) and 7.27 (d, J = 7.8 Hz)
(2:3H), 7.47−7.32 (m, 4H), 5.93 (s, 1H), 2.46 (s, 3H), 2.44 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.1, 167.2, 141.4, 138.4, 137.5,
129.1, 127.2, 126.4, 125.3, 88.6, 21.6, 14.8.
(E)-3-(Thiomethyl)-3-(phenylamino)-1-(m-tolyl)prop-2-en-1-one
1
(1t). 2.66 g, yield 94%; yellow liquid; H NMR (400 MHz, CDCl3) δ
13.57 (s, 1H), 7.75 (s), 7.71 (d, J = 7.4 Hz), 7.30 (d, J = 7.6 Hz), and
7.26 (m) (1:1:1:1H), 7.39 and 7.34 (m each, 2:3H), 5.89 (s, 1H), 2.44
2-(Thiomethyl)-3-acetyl-6-methyl-1H-indole (2c). 60 mg, yield
55%; white solid, mp 216−218 °C; 1H NMR (400 MHz, DMSO-d6) δ
E
dx.doi.org/10.1021/jo5014542 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
11.60 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H), 6.96 (d, J =
8.1 Hz, 1H), 2.59 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 191.1, 143.9, 137.2, 130.6, 124.4, 123.0,
119.1, 111.1, 113.7, 30.2, 21.2, 14.5; HRMS (EI) calcd for C12H13NOS
219.0718, found 219.0710.
2-(Thiomethyl)-3-acetyl-4-methyl-1H-indole (2c′). 31 mg, yield
28%; yellow solid, mp 141−143 °C; 1H NMR (400 MHz, DMSO-d6)
δ 11.76 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.87
(d, J = 7.2 Hz, 1H), 2.62 (s, 3H), 2.60 (s, 3H), 2.44 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 195.3, 137.0, 136.6, 129.7, 125.0,
123.1, 122.5, 108.7, 119.4, 32.0, 21.9, 17.0; HRMS (EI) calcd for
C12H13NOS 219.0718, found 219.0713.
2-(Thiomethyl)-3-acetyl-7-methyl-1H-indole (2d). 99 mg, yield
90%; white solid, mp 186−189 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.18 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.95
(d, J = 7.2 Hz, 1H), 2.69 (s, 3H), 2.58 (s, 3H), 2.52 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 191.9, 142.8, 136.0, 126.5, 123.0,
121.8, 117.5, 120.7, 115.7, 30.5, 17.1, 15.7; HRMS (EI) calcd for
C12H13NOS 219.0718, found 219.0714.
2-(Thiomethyl)-3-acetyl-5-methoxy-1H-indole (2e). 109 mg, yield
93%; white solid, mp 192−194 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.61 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.79 (dd, J = 8.7 and 2.0 Hz,
1H), 3.79 (s, 3H), 2.61 (s, 3H), 2.53 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 191.1, 155.1, 144.6, 131.8, 127.4, 113.8, 111.8, 110.4,
102.5, 55.3, 30.3, 14.5; HRMS (EI) calcd for C12H13NO2S 235.0667,
found 235.0668.
2-(Thiomethyl)-3-acetyl-5-ethoxy-1H-indole (2f). 120 mg, yield
96%; white solid, mp 152−154 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.60 (s, 1H), 7.33 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 4.03 (q, J = 6.9 Hz,
2H), 2.60 (s, 3H), 2.51 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 191.2, 154.4, 144.7, 131.8, 127.4, 113.8, 111.8,
110.8, 103.4, 63.4, 30.3, 14.9, 14.5; HRMS (EI) calcd for C13H15NO2S
249.0823, found 249.0826.
2-(Thiomethyl)-3-acetyl-7-methoxy-1H-indole (2g). 76 mg, yield
65%; white solid, mp 197−200 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.66 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.76
(d, J = 7.9 Hz, 1H), 3.94 (s, 3H), 2.67 (s, 3H), 2.55 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 191.8, 145.4, 143.2, 128.1, 126.6,
122.4, 112.4, 103.0, 115.5, 55.3, 30.5, 15.3; HRMS (EI) calcd for
C12H13NO2S 235.0667, found 235.0674.
2-(Thiomethyl)-3-acetyl-5-chloro-1H-indole (2h). 86 mg, yield
72%; yellow solid, mp 232−234 °C; 1H NMR (400 MHz, DMSO-d6)
δ 11.87 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.14
(dd, J = 8.5 and 1.8 Hz, 1H), 2.63 (s, 3H), 2.52 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 191.1, 146.5, 135.3, 127.8, 126.3,
121.4, 118.6, 112.6, 113.3, 30.3, 14.4; HRMS (EI) calcd for
C11H10NOSCl 239.0172, found 239.0178.
δ 12.23 (s, 1H), 8.61 and 7.94 (d each, J = 7.8 Hz, 1:1H), 8.14 (d, J =
8.5 Hz, 1H), 7.61 (m, 2H), 7.46 (t, J = 6.8 Hz, 1H), 2.74 (s, 3H), 2.67
(s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 192.8, 138.9, 131.3,
129.8, 120.9, 122.9, 128.3, 125.8, 124.5, 122.4, 121.4, 120.0, 117.6,
30.6, 16.9; HRMS (EI) calcd for C15H13NOS 255.0718, found
255.0728.
2-(Thioethyl)-3-acetyl-7-methyl-1H-indole (2m). 107 mg, yield
92%; white solid, mp 114−116 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.57 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.00
(d, J = 7.1 Hz, 1H), 3.25 (q, J = 7.3 Hz, 2H), 2.66 (s, 3H), 2.55 (s,
3H), 1.28 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
192.7, 138.8, 136.0, 126.5, 123.4, 121.8, 118.2, 120.7, 117.7, 30.7, 27.9,
17.0, 14.4; HRMS (EI) calcd for C13H15NOS 233.0874, found
233.0878.
2-(Thioethyl)-3-acetyl-5-methyl-1H-indole (2n). 106 mg, yield
1
91%; white solid, mp 186−188 °C; H NMR (400 MHz, DMSO-
d6) δ 11.70 (s, 1H), 7.71 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.97 (d, J =
8.2 Hz, 1H), 3.13 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 2.40 (s, 3H), 1.30
(t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 191.5,
142.1, 135.3, 130.2, 126.8, 123.0, 119.5, 111.0, 114.4, 30.5, 25.8, 21.5,
14.3; HRMS (EI) calcd for C13H15NOS 233.0874, found 233.0880.
2-(Thioethyl)-3-acetyl-5-methoxy-1H-indole (2o). 117 mg, yield
94%; white solid, mp 148−150 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.72 (s, 1H), 7.44 (s) and 7.32 and 6.80 (d each, J = 8.6 Hz)
(1:1:1H), 3.78 (s, 3H), 3.13 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.29 (t,
J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 191.7, 155.2,
141.6, 131.7, 127.4, 115.0, 111.8, 111.0, 102.7, 55.3, 30.4, 26.1, 14.3;
HRMS (EI) calcd for C13H15NO2S 249.0823, found 249.0826.
2-(Thioethyl)-3-acetyl-5-ethoxy-1H-indole (2p). 126 mg, yield 96%;
1
white solid, mp 157−160 °C; H NMR (400 MHz, DMSO-d6) δ 11.70
(s, 1H), 7.41 (s), 7.31 (d, J = 8.7 Hz), and 6.78 (d, J = 7.7 Hz) (1:1:1H),
4.03 (q, J = 6.8 Hz, 2H), 3.13 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.34 and
1.29 (t each, J = 6.9 and 7.3 Hz, 3:3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 191.6, 154.4, 141.7, 131.7, 127.4, 114.9, 111.8, 111.4, 103.5,
63.3, 30.4, 26.0, 14.9, 14.3; HRMS (EI) calcd for C14H17NO2S 263.0980,
found 263.0982.
2-(Thioethyl)-3-acetyl-7-chloro-1H-indole (2q). 102 mg, yield
1
81%; white solid, mp 135−137 °C; H NMR (400 MHz, DMSO-
d6) δ 12.02 (s, 1H), 8.01 (d, J = 7.7 Hz), 7.26 (d, J = 7.6 Hz), and 7.16
(t, J = 7.9 Hz) (1:1:1H), 3.27 (q, J = 7.3 Hz, 2H), 2.63 (s, 3H), 1.23 (t,
J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 192.8, 140.8,
133.6, 128.5, 122.7, 122.4, 119.5, 118.2, 115.5, 30.8, 27.9, 14.3; HRMS
(EI) calcd for C12H12NOSCl 253.0328, found 253.0330.
2-(Thiomethyl)-3-benzoyl-1H-indole (2r). 95 mg, yield 71%; yellow
1
solid, mp 159−161 °C; H NMR (400 MHz, DMSO-d6) δ 12.00 (s,
1H), 7.58 (s) and 7.52−7.43 (m) (1:3H), 7.56 (t, J = 3.3 Hz), 7.08
(dt, J = 8.2 and 4.2 Hz), and 6.94 (d, J = 4.0 Hz) (2:1:2H), 2.60 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 190.2, 146.2, 141.3,
137.2, 131.3, 128.7, 128.1, 122.0, 121.5, 119.2, 111.6, 127.1, 113.3,
14.9; HRMS (EI) calcd for C16H13NOS 267.0718, found 267.0727.
2-(Thiomethyl)-3-benzoyl-4,5,6,7-D4-1H-indole (2r[D4]). 91 mg,
yield 67%; yellow solid, mp 164−166 °C; 1H NMR (400 MHz,
DMSO-d6) δ 11.93 (s, 1H), 7.58 and 7.50 (m each, 3:2H), 2.62 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 189.6, 145.7, 141.1,
136.8, 126.7, 113.0, 137.4, 129.7, 128.6, 127.6, 131.0, 128.3, 127.8,
14.6; HRMS (ESI) calcd for C16H10D4NOS [M + H]+ 272.1047,
found 272.1046.
2-(Thiomethyl)-3-acetyl-7-chloro-1H-indole (2i). 93 mg, yield
1
78%; yellow solid, mp 168−171 °C; H NMR (400 MHz, DMSO-
d6) δ 11.69 (s, 1H), 7.92 (m, 1H), 7.25 (m, 1H), 7.17 (d, J = 7.9 Hz,
1H), 2.73 (s, 3H), 2.59 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 192.1, 144.5, 133.6, 128.5, 122.8, 121.9, 118.9, 116.2, 115.5, 30.6,
15.8; HRMS (EI) calcd for C11H10NOSCl 239.0172, found 239.0172.
2-(Thiomethyl)-3-acetyl-5-fluoro-1H-indole (2j). 76 mg, yield 68%;
pale-yellow solid, mp 202−204 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.69 (s, 1H), 7.45, 7.31, and 6.86 (m each, 1:1:1H), 2.51 (s, 3H),
2.40 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 191.1, 158.5 (d
and Cq, J = 233.7 Hz), 146.5, 133.4, 127.3 (d and Cq, J = 10.8 Hz),
113.8 (d and Cq, J = 3.9 Hz), 112.1 (d, J = 9.9 Hz), 109.1 (d, J =
25.7 Hz), 104.8 (d, J = 25.4 Hz), 30.1, 14.4; HRMS (EI) calcd for
C11H10NOSF 223.0467, found 223.0474.
2-(Thiomethyl)-3-(4-methylbenzoyl)-1H-indole (2s). 103 mg, yield
1
73%; white solid, mp 170−172 °C; H NMR (400 MHz, DMSO-d6)
δ 11.92 (s, 1H), 7.52 and 7.30 (d each, J = 7.9 Hz, 2:2H), 7.45 (d, J =
8.0 Hz), 7.10 (t, J = 7.5 Hz), 7.04 (d, J = 7.9 Hz), and 6.97 (t, J = 7.5 Hz)
(1:1:1:1H), 2.61 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 189.5, 145.1, 141.1, 138.2, 136.8, 128.9, 128.3, 121.6, 121.1,
119.0, 111.2, 126.8, 113.3, 21.1, 14.7; HRMS (EI) calcd for C17H15NOS
281.0874, found 281.0879.
2-(Thiomethyl)-3-acetyl-4,6-dimethyl-1H-indole (2k). 85 mg, yield
1
73%; pale-red solid, mp 149−151 °C; H NMR (400 MHz, DMSO-
d6) δ 11.62 (s, 1H), 7.01 and 6.71 (s each, 1:1H), 2.59 (s, 3H), 2.58 (s,
3H), 2.40 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 195.2, 137.5, 135.6, 131.7, 129.5, 123.0, 124.9, 108.6, 119.5, 31.9,
21.8, 21.0, 17.3; HRMS (EI) calcd for C13H15NOS 233.0874, found
233.0874.
2-(Thiomethyl)-3-(3-methylbenzoyl)-1H-indole (2t). 101 mg, yield
72%; yellow solid, mp 105−108 °C; 1H NMR (400 MHz, DMSO-d6)
δ 11.93 (s, 1H), 7.45 (d, J = 8.0 Hz), 7.08 (m), and 6.96 (m)
(1:1:2H), 7.39 (d, J = 8.3 Hz, 4H), 2.62 (s, 3H), 2.36 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 189.8, 145.6, 141.2, 137.6,
2-(Thiomethyl)-3-acetyl-1H-benzo[g]indole (2l). 101 mg, yield
79%; brown solid, mp 206−208 °C; 1H NMR (400 MHz, DMSO-d6)
F
dx.doi.org/10.1021/jo5014542 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
136.9, 131.6, 128.3, 128.2, 125.1, 121.6, 121.1, 118.9, 111.3, 126.9,
113.1, 20.9, 14.7; HRMS (EI) calcd for C17H15NOS 281.0874, found
281.0879.
2-(Thiomethyl)-3-(4-chlorobenzoyl)-1H-indole (2u). 101 mg, yield
67%; yellow solid, mp 199−201 °C; 1H NMR (400 MHz, DMSO-d6)
δ 12.00 (s, 1H), 7.62 and 7.56 (d each, J = 8.4 Hz, 2:2H), 7.46 (d),
7.11 (m), and 7.01 (m) (1:1:2H), 2.63 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 188.3, 146.1, 139.7, 136.9, 135.8, 129.9,
128.5, 121.8, 121.4, 118.9, 111.4, 126.7, 112.8, 14.7; HRMS (EI) calcd
for C16H12NOSCl 301.0328, found 301.0334.
2-(Thiomethyl)-3-(3-chlorobenzoyl)-1H-indole (2v). 98 mg, yield
65%; yellow solid, mp 168−170 °C; 1H NMR (400 MHz, DMSO-d6)
δ 12.02 (s, 1H), 7.64 (m), 7.54 (d, J = 4.8 Hz), and 7.47 (d, J =
8.0 Hz) (1:2:1H), 7.59 (s), 7.11 (m), and 7.00 (d, J = 3.5 Hz)
(1:1:2H), 2.63 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
187.8, 146.5, 143.1, 137.0, 133.2, 130.7, 130.4, 127.5, 126.4, 121.8,
121.4, 118.8, 111.4, 126.7, 112.6, 14.7; HRMS (EI) calcd for
C16H12NOSCl 301.0328, found 301.0326.
2-(Thiomethyl)-3-(3-bromobenzoyl)-1H-indole (2w). 114 mg,
yield 66%; white solid, mp 168−170 °C; 1H NMR (400 MHz,
DMSO-d6) δ 12.03 (s, 1H), 7.77 (d, J = 7.9 Hz), 7.58 (d, J = 7.6 Hz),
and 7.46 (m) (1:1:2H), 7.72 (s) and 7.12 and 7.10 (m each) (1:1:2H),
2.63 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 187.8, 146.6,
143.3, 137.0, 133.6, 130.8, 130.4, 126.8, 121.9, 121.5, 118.8, 111.4,
126.7, 121.7, 112.6, 14.7; HRMS (ESI) calcd for C16H12NOSBrNa
[M + Na]+ 367.9721, found 367.9729.
2-(4-Methylphenyl)-3-benzoyl-5-ethoxy-1H-indole (3d). 112 mg,
yield 63%; white solid, mp 182−184 °C; 1H NMR (400 MHz, DMSO-
d6) δ 11.98 (s, 1H), 7.51 and 7.35 (m each, 2:1H), 7.39 and 6.87
(d each, J = 8.8 Hz, 1:1H), 7.22 (m, 5H), 7.03 (d, J = 7.9 Hz, 2H),
3.95 (q, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.31 (t, J = 6.9 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 192.1, 154.2, 144.6, 140.0, 137.8,
130.8, 129.0, 128.8, 111.8, 131.1, 129.3, 128.9, 128.5, 127.7, 113.1,
112.5, 103.4, 63.3, 20.7, 14.8; HRMS (EI) calcd for C24H22NO2
[M + H]+ 356.1651, found 356.1641.
Typical Procedure for the Reactions of 2 with Hydroxyl-
amine Hydrochloride: Synthesis of 4a. A mixture of 2c (110 mg,
0.50 mmol), hydroxylamine hydrochloride (52 mg, 0.75 mmol),
and potassium hydroxide (42 mg, 0.75 mmol) in ethanol (5 mL) was
stirred at 100 °C for 18 h. After the reaction was complete as deter-
mined by TLC monitoring on silica gel, the mixture was cooled to
ambient temperature, and all of the volatiles were removed under
reduced pressure. The resultant residue was dissolved in 15 mL of
water, and the solution was extracted with CH2Cl2 (2 × 10 mL). The
combined organic phases were washed with water (2 × 10 mL) and
dried over anhydrous Na2SO4, and all of the volatiles were evaporated
under reduced pressure. Purification by silica gel column chromatog-
raphy [eluent: petroleum ether (60−90 °C)/AcOEt = 50:1 v/v]
afforded 4a as a white solid (67 mg, 72%).
3,6-Dimethyl-8H-isoxazolo[5,4-b]indole (4a). 67 mg, yield 72%;
white solid, mp 141−144 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.60
(s, 1H), 7.72 and 7.01 (d each, J = 8.0 Hz, 1:1H), 7.32 (s, 1H), 2.66
(d, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 158.4,
156.6, 144.4, 132.5, 125.0, 118.1, 121.5, 118.4, 112.2, 21.5, 18.5;
HRMS (EI) calcd for C11H11N2O [M + H]+ 187.0871, found
187.0876.
2-(Thioethyl)-3-benzoyl-5-ethoxy-1H-indole (2x). 145 mg, yield
89%; white solid, mp 151−153 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.87 (s, 1H), 7.58 and 7.50 (m each, 3:2H), 7.32 (d, J = 8.7 Hz), 6.74
(dd, J = 8.7 and 2.3 Hz), and 6.51 (d, J = 2.1 Hz) (1:1:1H), 3.75 (q,
J = 6.9 Hz, 2H), 3.10 (q, J = 7.3 Hz, 2H), 1.25 and 1.22 (t each, J = 6.9
and 7.3 Hz, 3:3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 189.9,
153.8, 142.8, 141.1, 131.8, 131.0, 128.3, 128.0, 111.9, 111.5, 102.7,
127.6, 114.0, 63.0, 25.9, 14.7, 14.2; HRMS (EI) calcd for C19H19NO2S
325.1136, found 325.1144.
3,7-Dimethyl-8H-isoxazolo[5,4-b]indole (4b). 60 mg, yield 64%;
white solid, mp 212−215 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.85
(s, 1H), 7.70 and 7.11 (m each, 1:2H), 2.69 (s, 3H), 2.51 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 158.3, 156.9, 143.2, 125.4,
121.0, 119.8, 123.7, 120.1, 116.3, 18.4, 16.7; HRMS (EI) calcd for
C11H11N2O [M + H]+ 187.0871, found 187.0879.
Typical Procedure for the Reactions of 2 with Arylboronic
Acids: Synthesis of 3a. Under a nitrogen atmosphere, a mixture of
2b (110 mg, 0.5 mmol), phenylboronic acid (92 mg, 0.75 mmol),
Pd(PPh3)4 (43 mg, 0.0375 mmol), CuTC (191 mg, 1.0 mmol), and
Cs2CO3 (326 mg, 1.0 mmol) in 5 mL of THF was stirred at 50 °C for
48 h. The resulting mixture was cooled to ambient temperature, fil-
tered through a short pad of Celite, and rinsed with 10 mL of CH2Cl2.
All of the volatiles were evaporated from the combined filtrate under
reduced pressure. The resultant residue was purified by silica gel col-
umn chromatography [eluent: petroleum ether (60−90 °C)/AcOEt =
30:1 v/v] to afford 3a as a white solid (99 mg, 79%).
2-Phenyl-3-acetyl-5-methyl-1H-indole (3a). 99 mg, yield 79%;
white solid, mp 231−233 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.97
(s, 1H), 8.03 (s, 1H), 7.62 and 7.53 (m each, 2:3H), 7.32 and 7.05 (d
each, J = 8.2 Hz, 1:1H), 2.42 (s, 3H), 2.06 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 193.6, 144.9, 133.8, 132.9, 130.5, 127.3,
114.0, 130.0, 129.3, 128.4, 124.3, 121.3, 111.3, 30.1, 21.5; HRMS
(ESI) calcd for C17H15NONa [M + Na]+ 272.1051, found 272.1042.
2-Phenyl-3-acetyl-6-methyl-1H-indole (3b). 90 mg, yield 72%;
white solid, mp 219−222 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.94
(s, 1H), 8.09 and 7.04 (d each, J = 8.2 Hz, 1:1H), 7.62 and 7.53
(m each, 2:3H), 7.23 (s, 1H), 2.42 (s, 3H), 2.08 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 193.5, 144.4, 135.9, 132.9, 132.1,
124.9, 114.2, 130.0, 129.2, 128.4, 123.4, 121.3, 111.3, 30.02, 21.28;
HRMS (ESI) calcd for C17H15NONa [M + Na]+ 272.1051, found
272.1047.
KIE Experiments. The deuterated derivative of 1r, that is, 1r[D5],
was prepared using aniline-d7 as the starting material in a fashion
similar to the preparation of 1r. Two sets of reactions of 1r[D5] and 1r
were carried out on a 0.3 mmol scale in a parallel manner under the
optimized conditions shown in Table 2. The reactions were monitored
by GC analysis, and the yields were carefully checked by integration of
the signals of the desired products using mesitylene as the internal
standard. At 20 min, a sample of the reaction mixture was withdrawn
for GC analysis, and yields of 63% and 66% were measured for 2r[D4]
and 2r, respectively; at 0.5 h, the yields increased to 67% for 2r[D4]
and 72% for 2r. The corresponding kH/kD values of 1.05 (0.66/0.63)
at 20 min and 1.07 (0.72/0.67) at 0.5 h were thus obtained.
Radical Trapping Study. Under an argon atmosphere, a mixture
of ketene N,S-acetal 1a (104 mg, 0.5 mmol), CuCl2 (202 mg, 1.5 mmol),
TEMPO (0.5 or 1.0 mmol), and K3PO4 (318 mg, 1.5 mmol) in 5 mL of
DMF/DMSO (7:1 v/v) was stirred at 120 °C for 2 h. The resultant
mixture was cooled to ambient temperature and subjected to GC analysis
using mesitylene as the internal standard. The desired product 2a was
not detected in the reaction mixture.
2-(4-Chlorophenyl)-3-acetyl-7-methyl-1H-indole (3c). 93 mg,
yield 66%; white solid, mp 174−175 °C; 1H NMR (400 MHz,
CDCl3) δ 8.83 (s, 1H), 7.37 (s, 4H), 7.22 (d, J = 8.0 Hz, 1H), 7.16
(t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 2.54 (s, 3H), 2.25
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.9, 138.4, 136.0,
135.5, 131.8, 130.8, 125.5, 118.4, 130.1, 129.3, 123.9, 109.0, 32.7,
21.4; HRMS (EI) calcd for C17H15NOCl [M + H]+ 284.0842, found
284.0832.
ASSOCIATED CONTENT
■
S
* Supporting Information
Optimization of the reaction conditions, H and 13C NMR
1
spectra of all of the compounds, and X-ray structural infor-
mation for 2d, 2x, and 3b (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
G
dx.doi.org/10.1021/jo5014542 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
H. F.; Jin, W. W.; Sun, C. L.; Chen, J. P.; Du, W. M.; He, S. B.; Yu, Z.
K. Angew. Chem., Int. Ed. 2010, 49, 5792.
AUTHOR INFORMATION
■
Corresponding Author
* E-mail: zkyu@dicp.ac.cn.
(24) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(25) (a) Surmont, R.; Verniest, G.; Schrijver, D. M.; Thuring, J. W.;
Holte, P. T.; Deroose, F.; Kimpe, D. N. J. Org. Chem. 2011, 76, 4105.
(b) Zhang, T.; Jia, Y.-M.; Yan, S.-J.; Yu, C.-Y.; Huang, Z.-T. ARKIVOC
2009, 2009 (xiv), 156. (c) Fukamachi, S.; Konishi, H.; Kobayashi, K.
Synthesis 2009, 1786.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Basic
Research Program of China (2015CB856600) and the National
Natural Science Foundation of China (21472185).
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dx.doi.org/10.1021/jo5014542 | J. Org. Chem. XXXX, XXX, XXX−XXX