Copper-Catalyzed Radical C-C Bond Cleavage and [4+1] Annulation Cascade of Cycloketone Oxime Esters with Enaminothiones

Article abstract of DOI:10.1021/acs.joc.8b03175

Carbon-carbon bond formation is among the most important reactions in organic synthesis. Reconstruction of a carbon-carbon bond through ring-opening C-C bond cleavage of a strained carbocycle usually occurs via a thermodynamically preferable pathway. However, carbon-carbon bond formation through thermodynamically less favorable C-C bond cleavage has seldom been documented. Herein, we disclose an unusual C-C bond cleavage of cycloketone oxime esters for [4+1] annulation. Under anaerobic copper(I) catalysis, cycloketone oxime esters underwent regioselective, thermodynamically less favorable radical C-C bond cleavage followed by annulation with enaminothiones; that is, α-thioxo ketene N,S-acetals efficiently affording 2-cyanoalkyl-aminothiophene derivatives. Cyclobutanone, -pentanone, -hexanone, and -heptanone oxime esters could act as the effective C1 building blocks in the annulation reaction. An iminyl radical mechanism is proposed for the rare C-C bond cleavage/[4+1] annulation cascade.

Full text of DOI:10.1021/acs.joc.8b03175

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Article
Copper-Catalyzed Radical C-C Bond Cleavage and [4+1] Annulation
Cascade of Cycloketone Oxime Esters with Enaminothiones
Yuan He, Jiang Lou, Kaikai Wu, Hongmei Wang, and Zhengkun Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03175 • Publication Date (Web): 11 Jan 2019
Downloaded from http://pubs.acs.org on January 11, 2019
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Copper-Catalyzed Radical CC Bond Cleavage and [4+1]
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Annulation Cascade of Cycloketone Oxime Esters with Enaminothiones
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Yuan He,†,‡ Jiang Lou,†,‡ Kaikai Wu,† Hongmei Wang,*,§ and Zhengkun Yu*,†,¶
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†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023,
People’s Republic of China
‡University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
§State Key Laboratory of NBC Protection for Civilian, Beijing 102205, P. R. China
¶tate Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, People’s Republic of China
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
_____________________________________________________________________
OR1
R4
R'
CN
R2
R3
R5
10 mol% CuCl
NaOAc
N
R'
S
S
R2
R3
+
()n-1
()n
DMF, 70 o
n = 1~4
C
NHR''
R4 R5
NHR''
up to 84% yields
MeS
ABSTRACT: Carboncarbon bond formation is among the most important reactions
in organic synthesis. Reconstruction of a carboncarbon bond through ring-opening
CC bond cleavage of a strained carbocycle usually occurs via a thermodynamically
preferable pathway. However, carboncarbon bond formation through
thermodynamically less favorable CC bond cleavage has been seldomly documented.
Herein, we disclose an unusual CC bond cleavage of cycloketone oxime esters for
[4+1] annulation. Under anaerobic copper(I) catalysis, cycloketone oxime esters
underwent regioselective, thermodynamically less favorable radical CC bond
cleavage followed by annulation with enaminothiones, that is, α-thioxo ketene
N,S-acetals, efficiently affording 2-cyanoalkyl-aminothiophene derivatives.
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Cyclobutanone, -pentanone, -hexanone, and -heptanone oxime esters could act as the
effective C1 building blocks in the annulation reaction. An iminyl radical mechanism
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is proposed for the rare CC bond cleavage/[4+1] annulation cascade.
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____________________________________________________________________
INTRODUCTION
Regioselective CC bond cleavage has been a challenge in the construction of CC
and C-heteroatom bonds.1 Continuous efforts have been devoted to ring-opening CC
bond cleavage of strained carbocycles.2 In this regard, the ring-opening reactions of
cycloketone oxime esters have recently been paid considerable attention because
cyanoalkylation can be established via nitrogen-centered-radicals (NCRs), that is,
iminyl radicals,3 by means of organotin hydride,4 or under transition-metal catalysis,5
photo-induction,6 and microwave irradiation.7 Oxime esters have been used as the
diverse reagents for CC and C-heteroatom bond formation as well as for
N-heterocycle synthesis.8 In the reaction of a cycloketone oxime ester, an iminyl
radical is initially generated by a single-electron-transfer (SET) process to undergo
regioselective CC bond cleavage through -elimination, producing the
thermodynamically preferable alkyl radical which is then trapped to form the
corresponding cyanoalkylation product (Scheme 1a). Cycloketone oxime esters have
been well investigated in the reactions with terminal alkenes or their surrogates,
affording Heck-type cyanoalkylation products (Scheme 1b),5a,5e,5f,5h,6b,6e or
cyanoalkylation-cyclization com-pounds.5c,5d,6a A visible light-driven, copper-
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catalyzed three-component radical cross-coupling of cyclobutanone oxime esters,
styrenes, and boronic acids,9a photoredox-catalyzed reactions of cycloketone oxime
esters with styrenes in DMSO,9b and transition-metal-free CC cleavage/borylation of
cyclobutanone oxime esters, B2(OH)4, and pinacol10 were achieved to give the
corresponding cyanoalkylation/arylation, acylation, and cyanoalkylation/borylation
products, respectively. The direct CH cyanoalkylation of quinoxalin-2-(1H)-ones5b
and heteroaromatic N-oxides5e was reported to yield the cyanoalkylation and
cyanoalkyl-arylation products. The iminyl radicals generated in situ from cycloketone
oxime esters could also be trapped by other reagents to produce the cyanoalkylation
products with their alkyl-chains functionalized by acyloxy, aloxy, hydroxyl,5g,6d PhX
(X = S, Se, Te),5i fluoro,6c or TEMPO.7 The radical CC bond cleavage reaction of
2,4-unsubstituted cyclobutanone oxime esters has recently been employed to
synthesize polycyclic N-heterocycles from the aerobic cyclization with
1-(2-aminophenyl)pyrroles.11 In all these reactions, the regioselective ring-opening
CC bond cleavage occurred between the iminyl carbon and the vicinal sterically
hindered carbon atoms in the cycloketone oxime esters (Scheme 1a and 1b). However,
the ring-opening CC bond cleavage between the iminyl carbon and the less sterically
hindered carbon atoms is thermodynamically less favorable. To date, only two such
examples have been documented in the intramolecular ring-opening reactions of
strained cyclobutanone oxime esters, that is, the reaction of 2,2a,7,7a-
tetrahydrocyclobuta[a]inden-1-one oxime ester with stoichiometric nBu3SnH/AIBN
leading to a thermodynamically less favorable nitrile (3%) as the byproduct,12a and
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palladium(0)-catalyzed ring-opening transformation of bicyclo[4.2.0]octan-7-one
oxime ester under basic conditions to form 2-methylene-cyclohexane-carbonitrile via
-H elimination.12b Occurrence of such thermodynamically less favorable CC bond
cleavage in these 2-substituted cyclobutanone oxime esters is very dependent on the
nature of the products or substituents on the cyclobutanone backbone.12
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_____________________________________________________________________
Scheme 1. Cyanoalkylation by Means of Cycloketone Oxime Esters
(a) Generation and trapping of NCRs from cycloketone oxime esters
OR1
radical
SET
C-C
N
N
CN
R
CN
trapping
process
cleavage
R2
R2
R2
R2
R3
R3
R3
R3
(b) Previous work: thermodynamically preferable C-C bond cleavage
OR1
N
R5 R2 CN
R5
transition-metal cat.
or photoredox
+
()n
R4
R2
()n
R4
R6
R6
R3
R3
R2
N
OR1
EWG
R2
photoredox
+
CN
EWG
R
R
X
OR1
N
Cu(II) cat.
X
N
N
+
NMP, 80 o
O2
C
NH2
X = C, N
N
CN
R3
R3
R2
R2
(c) This work: thermodynamically unfavorable C-C bond cleavage
OR1
R4
CN
R2
R3
10 mol% CuCl
N
R5
R'
S
NHR''
NaOAc
S
R2
R3
+
()n-1
()n
DMF, 70 o
n = 1~4
C
R'
SMe
R4 R5
NHR''
_____________________________________________________________________
The thiophene ring ubiquitously exists in natural products, pharmaceuticals, and
functional polymers,13 and thiophene derivatives can function as versatile building
blocks in organic synthesis and manufacture of functional materials.14 Cyanoalkyl
moiety is also one of the important structural motifs which are widely present in
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natural products and pharmaceutical drugs.15 Synthesis of functionalized thiophenes
are often achieved by modification of an existing thiophene ring or through
ring-closure reactions.16-18 In this area, considerable advance has been made in the
establishment of amino-substituted thiophenes.19,20 Base-promoted multiple-
component Gewald reactions21 and those of -ketothio-amides22 have been employed
for the synthesis of 2-aminothiophenes. 3-Aminothiophenes are also considered as the
important small molecules for drug development,23 but only a few methods have been
reported for their synthesis.24,25 Enaminothiones,26 that is, α-thioxo ketene N,S-acetals,
have been known to react with activated methylene compounds in the presence of
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stoichiometric Hg(OAc)2 or with diazo compounds under Rh(II) catalysis,28
affording 3-aminothio-phenes.
Recently, we found that enaminothiones, which can be conveniently prepared from
readily available α-oxo ketene N,S-acetals,29 could be used for the construction of
S-heterocycles by Cu(II) catalysis26 or under transition-metal-free conditions30 by
using N-tosylhydrazones as the C1 building blocks. A copper-catalyzed
three-component reaction of acyclic methyl aryl ketoxime acetate, aryl aldehyde, and
elemental sulfur was used to furnish a fused thieno[3,2-d]thiazole core.31 Intrigued by
the regioselective reactivity of cycloketone oxime esters, we conceived that
cycloketone oxime esters might be utilized as the C1 building blocks for the synthesis
of aromatic S-heterocycles. Unexpectedly, our initial attempt revealed that
2-substituted cyclobutanone oxime esters could undergo annulation with
enaminothiones through thermodynamically less favorable radical ring-opening CC
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bond cleavage, furnishing a thiophene ring (Scheme 1c). Herein, we disclose the
unusual [4+1] annulation of cycloketone oxime esters with enaminothiones for the
synthesis of 2-cyanoalkyl-3-aminothiophene derivatives.
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RESULTS AND DISCUSSION
Initially, the reaction of cyclobutanone oxime ester 1a with enaminothione 2a was
conducted to screen the reaction conditions (Table 1). With 10 mol% CuCl2 as the
catalyst and Na2CO3 (1 equiv) as the base, the reaction underwent in DMF at 80 C
for 12 h to form the target 2-cyanoalkylthiophene product 3a in 53% yield, while
CuCl facilitated the reaction more efficiently (entries 1 and 2). Copper salts CuBr2,
Cu(OAc)2, CuBr, CuI, and CuOAc were also screened as the catalysts to render the
formation of 3a in 43-51% yields, exhibiting a lower catalytic activity than CuCl.
Among the screened bases Na2CO3, K2CO3, KOAc, NaOAC, and CsOAc, NaOAc
was found to be the most effective promoter (entries 2-6). DMSO was a less effective
solvent than DMF (entry 7). The best yield was obtained at 70 C, resulting in 3a in
79% isolated yield (entries 5, 8, and 9). Variation of the substrate ratios by using
excess of 1a or equimolar amount of 2a did not improve the reaction efficiency
(entries 10 and 11). An air atmosphere deteriorated the reaction, and the reaction
could not occur without the catalyst or base promoter (entries 12-14). The analogs of
1a, that is, cyclobutanone O-acetyl (1A), O-(3-methylbenzoyl) (1B),
O-4-(trifluoromethyl)benzoyl (1C), and O-(perfluorobenzoyl) (1D) oxime esters,
were also tested in the reaction with 2a, producing 3a in <1%, 49%, 61%, and 27%
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yields, respectively, revealing that cyclobutanone oxime esters 1A-D could not be
used as the effective C1 building blocks for the synthesis of 3a. The molecular
structure of compound 3a was further confirmed by the X-ray single crystallographic
determination (see the Supporting Information for details).
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_____________________________________________________________________
Table 1. Optimiation of Reaction Conditionsa
Ph
OBz
CN
S
N
S
NHBn
SMe
conditions
+
Ph
NHBn
1a
2a
3a
temp
(oC)
yieldsb
(%)
entry
catalyst
base
solvent
CuCl2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
53
57
1
2
Na2CO3
Na2CO3
K2CO3
KOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
80
80
80
80
80
70
60
70
70
70
70
70
46
3
65
4
75
5
NaOAc
CsOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
59
6
63
7
77 (79)c
62
8
9
10d
11e
12f
13
14
69
71
10
0
trace
CuCl
a
Conditions: 1a (0.30 mmol), 2a (0.33 mmol), catalyst (0.03 mmol), base (0.30
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mmol), solvent (2 mL), 0.1 MPa N2, 12 h. b Determined by 1H NMR analysis using
c
1,3,5-trimethoxylbenzene as the internal standard.
Isolated yield given in
d
e
f
parentheses. 1a (0.33 mmol), 2a (0.30 mmol). 2a (0.30 mmol). Under air
7
8
atmosphere.
F
9
CF3
F
F
F
10
11
12
13
14
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O
N
Me
O
N
O
N
O
N
Me
O
O
O
O
F
1A
1B
, 49%
1C
, 61%
1D
, 27%
, <1%
_____________________________________________________________________
Under the optimal conditions, the scope of enaminothiones 2 was investigated by
reacting with 1a (Table 2). Electron-donating substituents such as methyl and
methoxy on the aryl group of the thioaroyl moiety in 2 did not facilitate formation of
the target products 3b-e (64-75%) in comparison to the formation of compound 3a
(79%). The substituent effects of the electron-withdrawing trifluoromethyl and fluoro
groups varied to render the formation of 3f-h (70-80%). 4-Bromo-substituted
enaminothione 2i reacted with 1a to give 3i in 72% yield. Substituted
benzylamino-based enaminothiones were also reacted to give the target products 3j-m
in good yields (63-75%). 2-Furylmethylamino-derived enaminothiothione 2n reacted
with 1a to afford 3n in 68% yield. Other aliphatic non- benzylamine derived
enaminothiones 2o-t efficiently reacted with 1a, producing the target products 3o-t in
65-80% yields. However, cyclopropylamine-derived enaminothione failed to react
with 1a to give the corresponding product. Anilide-based enaminothione 2u also
reacted with 1a to form product 3u (68%). It is noteworthy that 2-thienyl, styryl, and
methyl- functionalized enaminothiones 2v-x exhibited a good reactivity to 1a, and
their reactions afforded 3v-x in 61-75% yields.
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Table 2. The Scope of Enaminothiones (2)a
6
7
8
R1
OBz
CN
S
NHR2
SMe
N
S
conditions
+
R1
NHR2
9
1a
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
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Me
MeO
F3C
Br
Ph
CN
S
CN
CN
S
S
NHBn
, 79%
NHBn
NHBn
b
3a
3b
, 71%
3c
, 64%
Me
CN
S
CN
S
CN
S
MeO
NHBn
NHBn
NHBn
b
b
b
3d
, 75%
3e
3f
, 71%
, 68%
F3C
CN
CN
S
S
CN
CN
S
F
NHBn
NHBn
, 80%
NHBn
3g
, 70%
3h
3i
, 72%
Ph
Ph
CN
S
S
Ph
CN
S
HN
HN
HN
OMe
CN
OMe
F
b
b
b
3j
3k
3l,
75%
, 71%
, 65%
Ph
Ph
CN
Cl
S
S
Ph
CN
S
HN
HN
HN
O
Ph
b
3m
, 63%
3n
3o
, 75%
, 68%
Ph
CN
S
Ph
Ph
CN
CN
S
S
HN
NH
HN
HN
Me
Et
b
3p
, 80%
3q
, 71%
3r
, 65%
S
Ph
CN
S
Ph
Ph
CN
CN
S
HN
NHnBu
NHPh
b
3s
, 70%
3t
3u
, 68%
, 76%
Me
CN
S
CN
S
Me
S
CN
S
NHBn
NHBn
NHPh
b
3v
, 75%
3w
3x
, 75%
, 61%
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a Conditions: 1a (0.30 mmol), 2 (0.33 mmol), CuCl (0.03 mmol), NaOAc
(0.30 mmol), DMF (2 mL), 70 oC, 0.1 MPa N2, 12 h. b 80 oC,18 h.
6
7
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Next, the generality of cycloketone oxime esters 1 was examined as the C1
building blocks in the [4+1] annulation with enaminothiones 2 (Table 3).
3-Substituted cyclobutanone oxime esters 1b-g efficiently reacted with various
enaminothiones to give the target 3-aminothiophene products 4a-g (70-81%).
Functional groups such as benzyl, CO2tBu, 4-tBu-phenyl, phenyl, methyl, and
functionalized alkyl could be tolerated as the 3-substituents on the cyclobutanone ring.
It should be noted the 3,3-disubstituted 3-methyl-3-phenylcyclobutanone oxime ester
(1f) did not exhibit an obvious steric effect on the generation of 4g (76%).
Unexpectedly, when 2-substituted cyclobutanone oxime esters were used as the C1
synthons, the CC bond cleavage occurred between the iminyl carbon and the vicinal
less sterically hindered 4-carbon atoms, affording 4h-j in 68-79% yields. Such
transformations unambiguously proceeded through a thermodynamically less
favorable ring-opening CC bond cleavage pathway. However, the previously known
CC bond cleavage usually occurs between the iminyl carbon and the vicinal more
sterically hindered 2-carbon atoms for 2-substituted cyclobutanone oxime esters and
their analogs (Scheme 1a and 1b).4-7,9,10 Unsubstituted cyclopentanone oxime ester 1j
also reacted well with 2a to afford the ring-opening CC cleavage/cyanoalkylation
product 4k (69%) by extending one carbon of the cyanoalkyl chain at 2-position of
the thiophene ring. 2,2-Dimethylcyclopentanone oxime ester 1k reacted more
efficiently with 2a and its analogs than unsubstituted 1j did, giving products 4l-n in
10
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Table 3. The Scope of Cycloketone Oxime Esters (1)a
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7
8
9
OBz
R5
CN
R3
R4
10 mol% CuCl
NaOAc
N
R6
R1
S
NHR2
SMe
S
R3
R4
+
()n-1
()n
DMF, 70 oC, N2
n = 1~4
R1
R5 R6
NHR2
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1
2
4
Ph
Ph
Ph
CN
CN
S
S
CN
S
S
Bn
CO2tBu
CO2tBu
NHBn
NHBn
NHBn
4c
, 81%
4a
4b
, 81%
, 78%
Ph
CN
S
CN
S
Ph
CN
CO2Me
S
NH
BnHN
Me Me
BnHN
tBu
O
tBu
4d
4e
4f
, 73%
, 76%
, 70%
S
Me
Bn
Ph
CN
Ph
S
Ph
Ph
CN
CN
S
Me
BnHN
NHBn
4h,
NHBn
4g
4i
, 79%
, 76%
72%
CN
CN
Me
Ph
Ph
S
S
Ph
CN
S
Me
NHBn
4k,
NHBn
4l,
NHBn
4j,
68%
69%
76%
Me
CN
Me
CN
Me
Me
CN
CN
Ph
S
Ph
S
S
Me
F
NHPh
NHBn
, 84%
NHBn
4o,
b
4m
4n,
80%
Ph
61%
Ph
CN
Ph
CN
S
Ph
Ph
S
S
NH
NHBn
NHBn
4r
Ph
4q
, 55%
b
4p
, 51%
, 45%
a
Conditions: 1 (0.30 mmol), 2 (0.33 mmol), CuCl (0.03 mmol), NaOAc (0.30
mmol), DMF (2 mL), 70 oC, 0.1 MPa N2, 12 h. b 80 oC,18 h.
_____________________________________________________________________
76-84% yields without exhibiting a negative steric impact on the reaction efficiency.
The six-membered cycloketone oxime esters, that is, 2-methyl and
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2-phenylcyclohexanone oxime esters showed a reactivity lower than those of the
cyclobutanone and cyclopentanone oxime esters, leading to 4o-q in 51-61% yields.
This phenomenon is attributed to the lower ring tension of the six-membered
carbocycle than those of the strained four- and five-membered carbocyclic rings.
Interestingly, cyclohepentanone oxime ester could also undergo the annulation
reaction with 2a through the ring-opening CC bond cleavage, forming 4r (45%) by
elevating the reaction temperature and prolonging the reaction time.
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_____________________________________________________________________
OBz
Me
Me
N
Me
CN
Ph
S
NHBn
SMe
S
standard conditions
(1)
+
Ph
NHBn
1o
2a
4s
, 50%
OBz
Ph
CN
S
N
X
S
NHBn
SMe
standard conditions
X
(2)
+
Ph
NHBn
(X = O), trace
4u
2a
1p
1q
4t
(X = O)
(X = NCHPh2)
(X = NCHPh2), trace
Ph
OBz
+
CN
S
S
NHPh
R
N
standard conditions
(3)
Ph
R
1a
2aa
2ab
2ac
3u (R = NHPh), 65%
3u' (R = OEt), 0%
3u'' (R = Me), 0%
(R = NHPh)
(R = OEt)
(R = Me)
_____________________________________________________________________
Bicyclic oxime ester 1o derived from camphor reacted with enaminothione 2a to
yield the target product 4s in 50% yield (eq 1). However, oxetan-3-one and
1-Cbz-3-azetidinone derived oxime esters 1p and 1q hardly reacted with 2a under the
standard conditions (eq 2). -Thioxo ketene N,N-acetal 2aa reacted with 1a to afford
3-arylaminothiophene 3u (65%), whereas the corresponding ketene N,O-acetal (2ab)
and enamine (2ac) exhibited no reactivity to 1a (eq 3). These results have suggested
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that the alkylthio functionality in enaminothiones 2 plays a crucial role in executing
the [4+1] annulation reaction.
8
9
To demonstrate the applicability of the present synthetic protocol, gram-scale
preparation experiments were carried out by means of the reactions of 1a with 2a, and
1c with 2v, respectively (eq 4). Under the standard conditions, the target products 3a
and 4c were obtained in 86% and 82% yields, respectively. It should be noted that 3a
and 4c were more efficiently obtained from the larger scale preparation, which has
demonstrated the potential application of the synthetic protocol for the synthesis of
2-cyanoalkyl-3-aminothiophene derivatives.
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OBz
N
R'
CN
S
S
NHBn
SMe
standard conditions
+
(4)
R
R'
NHBn
R
5 mmol
5.5 mmol
1a
1c
2a
2v
3a
4c
(R = H)
(R' = Ph)
, 1.37 g, 86%
(R = CO2tBu)
(R' = 2-thienyl)
, 1.74 g, 82%
standard
conditions
Ph
OBz
CN
S
N
S
NHBn
SMe
+
(5)
N
NC
O
Ph
NHBn
1a
2a
3a
5
detected by HRMS
2.0 equiv TEMPO
2.0 equiv BHT
21%
trace
_____________________________________________________________________
Control experiments were conducted to probe into the reaction mechanism. The
reaction of 1a with 2a was performed in the presence of two equivalents of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) under the standard conditions,
1
forming 3a in 21% yield by H NMR analysis of the reaction mixture, while
2,6-di-tert-butyl-4-methylphenyl (BHT) completely inhibited the reaction (eq 5). The
adduct of the possible cyanoalkyl radical intermediate with TEMPO, that is,
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compound 5, was detected in the reaction mixture by high resolution mass
spectrometry. These radical scavengers obviously inhibited the reaction, which
implicates that the reaction may proceed through a radical pathway.7
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A plausible mechanism is proposed in Scheme 2 by simplifying the core structure
of the cycloketone oxime esters. The reaction is initiated by a single-electron-transfer
(SET) process from cycloketone oxime ester 1 in the presence of a Cu(I) catalyst,
generating cyclobutylidene iminyl radical A and a Cu(II) species. Iminyl radical A
undergoes regioselec-tive CC bond cleavage via -elimination to form the
thermo-dynamically less favorable alkyl radical B12 which is then added to
enaminothione 2 to result in radical C. A second SET process occurs to generate
cation D/iminium D which undergo hydrogen abstration by the carboxylate anion to
_____________________________________________________________________
Scheme 2. Proposed Reaction Mechanism
S
NHR2
OBz
2
N
N
CN
R1
SMe
-PhCOO-
SET
C-C cleavage
R'
R'
R'
R''
B
R''
A
R''
1
CuX2
CuX
R'
R''
R'
R''
R'
R''
CN
CN
CN
SET
H
R2
H
R2
R2
H
N
S
N
S
N
S
R1
R1
SMe
R1
SMe
SMe
D'
D
C
PhCOO-
R'
R'
H
NaOAc
R1
R1
CN
S
CN
S
R''
SMe
R''
NHR2
PhCOOH
R2HN
HOAc
MeSNa
E
3
4
or
_____________________________________________________________________
furnish the five-membered S-heterocycle E with regeneration of the Cu(I) catalyst.
Base-assisted aromatization through elimination of MeSH affords the target
2-cyanoalkyl- 3-aminothiophene product 3 or 4. Although generation of primary alkyl
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radical B is thermodynamically less favorable, production of the stable aromatic
thiophene products of types is kinetically preferred.
8
9
In conclusion, efficient copper(I)-catalyzed [4+1] annulation of enaminothiones
(α-thioxo ketene N,S-acetals) with cycloketone oxime esters has been achieved to
synthesize diverse 2-cyanoalkyl-3-aminothiophene derivatives. A rare thermodyna-
mically less favorable CC bond cleavage method has been developed for CC bond
construction with 2-substituted cycloketone oxime esters. Due to easy manipulations,
readily available reactants, excellent regioselectivity, and mild reaction conditions, the
present work offers a promising protocol to access a cyanoalkyl-thiophene motif.
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EXPERIMENTAL SECTION
General Considerations. The solvents were dried and distilled prior to use by the
1
literature methods. H and 13C{1H} NMR spectra were recorded on a Bruker
DRX-400 spectrometer and all chemical shift values refer to δTMS = 0.00 ppm or
CDCl3 (δ(1H), 7.26 ppm and δ(13C), 77.16 ppm). The HRMS (ESI) analysis was
obtained on a Waters GC-TOF CA156 mass spectrometer. X-Ray crystallographic
analysis was achieved by the Analysis Center, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences. All the chemical reagents were purchased from
commercial sources and used as received unless otherwise indicated. The starting
cycloketone oxime esters 1A,32a 1C,6b 1D, 1a, 1b, and 1e-i,5h 1j and 1n,32b -oxo
ketene N,S-acetals,32c,32d α-thioxo ketene N,S-acetals 2a,30 2c,26 2f, 2h-k, 2m, 2n, 2p,
and 2q,30 2r,26 2t-x and 2aa-ac,30 were prepared by the literature procedures and their
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spectroscopic features are in good agreement with those reported in the literatures.
Preparation of cycloketone oxime esters (1)
8
9
Cycloketone oxime esters 1a and 1g-q were prepared from the corresponding
cycloketones by a two-step procedure. The cycloketones were commercially available
or manufactured by the reduction of α,α-dichlorocyclobutanones synthesized from the
corresponding alkenes by the reported procedure.5h,6b
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A typical procedure for the preparation of 1a and 1g-q  Synthesis of
cyclobutanone oxime ester 1a: A mixture of cyclobutanone (350 mg, 5.0 mmol),
hydroxylamine hydrochloride (695 mg, 10.0 mmol), and saturated aqueous sodium
o
carbonate (10 mL) was stirred at 40 C for 5 h. After cooled to ambient temperature,
the mixture was extracted with diethyl ether (310 mL). The combined organic phase
was dried over anhydrous Na2SO4, filtered, and evaporated all the volatiles under
reduced pressure to give a crude oxime product which was directly used in the next
step reaction without further purification.
To a mixture of the crude cyclobutanone oxime, triethylamine (1.01 g, 10.0 mmol)
and 10 mL dichloromethane was added benzoyl chloride (1.05 g, 7.5 mmol) at 0 °C.
After the reaction was continued at 0-25 °C for 6 h, diethyl ether and water (20 mL
each) were added. The organic layer was separated, washed with water (20 mL), dried
over anhydrous MgSO4, and filtered. The resultant residue was purified by silica gel
column chromatography (eluent: petroleum ether (60-90 oC)/ethyl acetate = 30:1, v/v)
to afford cyclobutanone oxime ester 1a as a white solid (747 mg, 79%).
Cycloketone oxime esters 1b-f were prepared from the corresponding alkenes by a
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four-step procedure as follows.
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A typical procedure for the preparation of 1b-f  Synthesis of
3-benzylcyclobutanone O-benzoyl oxime (1b): Under an argon atmosphere, to a
stirred mixture of allylbenzene (591 mg, 5.0 mmol) and zinc-copper couple (960 mg,
15.0 mmol) in anhydrous diethyl ether (10 mL) was added a solution of
trichloroacetyl chloride (1.81 g, 10.0 mmol) and phosphorus oxychloride (843 mg, 5.5
mmol) in diethyl ether (10 mL) over 1 h. The suspension was stirred at reflux
overnight. After cooled to ambient temperature, the mixture was filtered through a
short pad of celite and rinsed with diethyl ether (20 mL). The combined filtrate was
successively washed with water, saturated aqueous NaHCO3, and brine (30 mL each),
dried over anhydrous MgSO4, filtered, and removed all the volatiles under reduced
pressure. The resultant crude product was directly used in the next step reaction
without further purification.
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A mixture of the crude 3-benzyl-2,2-dichlorocyclobutanone and zinc dust (1.30 g,
20.0 mmol) in acetic acid (10 mL) was stirred at ambient temperature for 2 h and then
heated at 80 °C for 5 h. The resulting mixture was allowed to cool to ambient
temperature, diluted with water (30 mL), and extracted with diethyl ether (320 mL).
The combined organic phase was successively washed with saturated aqueous
NaHCO3 (330 mL), water (30 mL), and brine (30 mL), dried over anhydrous MgSO4,
and concentrated in vacuum to remove all the volatiles. The resultant residue was
purified by flash silica gel column chromatography (eluent: petroleum ether (60-90
C)/ethyl acetate, v/v = 20:1) to afford 3-benzylcyclobutanone.
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To a stirred solution of 3-benzylcyclobutanone in 10 mL pyridine was added
hydroxylamine hydrochloride (695 mg, 10.0 mmol) at ambient temperature. After
stirring for 2 h, pyridine was removed under reduced pressure. The residue was
diluted with water (20 mL) and extracted with EtOAc (20 mL). The aqueous phase
was extracted with EtOAc (10 mL) and the combined organic extracts were washed
with brine (20 mL), dried over anhydrous MgSO4, and evaporated under reduced
pressure to give the crude material, which was used in the next step reaction without
further purification.
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To a mixture of the resultant 3-benzylcyclobutanone oxime and triethylamine
(1.01 g, 10.0 mmol) in 10 mL dichloromethane was added benzoyl chloride (1.05 g,
7.5 mmol) at 0 °C. After stirring at 0-25 °C for 6 h, water and diethyl ether (20 mL
each) were added. The organic layer was separated and washed with water (20 mL),
dried over anhydrous Na2SO4, filtered, and evaporated all the volatiles under reduced
pressure. The resultant residue was purified by silica gel column chromatography
(eluent: petroleum ether (60-90 oC)/ethyl acetate, v/v = 30:1) to afford
3-benzylcyclobutanone oxime ester 1b as a white solid (768 mg, 55%).
Cyclobutanone O-(3-methylbenzoyl) oxime (1B): 720 mg, yield 71%, yellow solid,
o
m.p.: 294-295 C (recrystallized from petroleum ether and ethyl acetate). Rf
(petroleum ether/ethyl acetate = 4:1, v/v) = 0.33. 1H NMR (400 MHz, CDCl3) δ 7.81,
7.34 (m each, 2:2 H), 3.12 (t, J = 8.0 Hz, 4 H), 2.40 (s, 3 H), 2.11 (m, 2 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 169.1, 164.0, 138.1, 133.8, 129.9, 128.7, 128.2, 126.4,
31.7, 31.6, 21.0, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H14NO2:
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204.1025; Found: 204.1024.
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tert-Butyl 3-((benzoyloxy)imino)cyclobutanecarboxylate (1c): 796 mg, yield 55%,
8
9
o
yellow solid, m.p.: 84-85 C (recrystallized from petroleum ether and ethyl acetate).
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Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.38. 1H NMR (400 MHz, CDCl3) δ
8.01, 7.58 (m each, 2:1 H), 7.46 (t, J = 7.7 Hz, 2 H), 3.35 (m, 4 H ), 3.19 (m, 1 H),
13
1.49 (s, 9 H). C{1H} NMR (100 MHz, CDCl3) δ 172.5, 164.9, 163.9, 133.4, 129.7,
128.9, 128.6, 81.7, 35.8, 35.6, 32.1, 28.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C16H20NO4: 290.1392; Found: 290.1391.
3-(4-(tert-Butyl)phenyl)cyclobutanone O-benzoyl oxime (1d): 820 mg, yield 51%,
yellow solid, m.p.: 130-131 oC (recrystallized from petroleum ether and ethyl acetate).
Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.45. 1H NMR (400 MHz, CDCl3) δ
7.98 (dd, J = 8.3 and 1.2 Hz, 2 H), 7.50, 7.31 (m each, 1:2 H), 7.39 (t, J = 7.9 Hz, 2
H), 7.15 (d, J = 8.2 Hz, 2 H), 3.56, 3.16 (m each, 3:2 H), 1.25 (s, 9 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 166.3, 164.0, 149.9, 140.0, 133.3, 129.6, 129.0, 128.5, 126.1,
125.6, 39.6, 39.5, 34.5, 32.1, 31.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C21H24NO2: 322.1807; Found: 322.1807.
(E)-2,2-Dimethylcyclopentanone O-benzoyl oxime (1k): 867 mg, yield 75%,
o
yellow solid, m.p.: 74-75 C (recrystallized from petroleum ether and ethyl acetate).
Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.35. 1H NMR (400 MHz, CDCl3) δ
8.03, 7.57, 7.42 (m each, 2:1:2 H), 2.76 (t, J = 7.5 Hz, 2 H), 1.83, 1.70 (m each, 2:2
13
H), 1.30 (s, 6 H). C{1H} NMR (100 MHz, CDCl3) δ 180.8, 164.0, 133.1, 129.6,
128.5, 43.4, 41.1, 29.0, 26.4, 20.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
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C14H18NO2: 232.1338; Found: 232.1338.
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(E)-2-Methylcyclohexanone O-benzoyl oxime (1l): 821 mg, yield 71%, yellow
8
9
o
solid, m.p.: 69-70 C (recrystallized from petroleum ether and ethyl acetate). Rf
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(petroleum ether/ethyl acetate = 4:1, v/v) = 0.60. 1H NMR (400 MHz, CDCl3) δ 7.95,
7.46, 7.35 (m each, 2:1:2 H), 2.79, 2.55, 2.31, 1.84, 1.67, 1.49 (m each, 1:1:1:1:2:3 H),
13
1.17 (d, J = 6.8 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 172.7, 164.4, 133.1,
129.7, 129.6, 128.6, 37.2, 35.0, 26.4, 25.8, 23.4, 17.2. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C14H18NO2: 232.1338; Found: 232.1335.
(E)-2-Phenylcyclohexanone O-benzoyl oxime (1m): 997 mg, yield 68%, yellow
1
liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.53. H NMR (400 MHz,
CDCl3) δ 8.00, 7.50, 7.38, 7.29, 7.17 (m each, 2:1:2:4:1 H), 3.94 (t, J = 4.9 Hz, 1 H),
2.91, 2.44, 2.23, 1.99, 1.65 (m each, 1:1:1:1:4 H). 13C{1H} NMR (100 MHz, CDCl3) δ
171.5, 164.3, 139.1, 133.2, 129.7, 129.5, 128.7, 128.6, 127.8, 126.8, 45.5, 31.1, 26.5,
25.4, 22.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H20NO2: 294.1494; Found:
294.1494.
(1S,4R,E)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-one O-benzoyl oxime (1o): 841
mg, yield 62%, yellow solid, m.p.: 74-75 oC (recrystallized from petroleum ether and
ethyl acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.65. 1H NMR (400 MHz,
CDCl3) δ 7.97, 7.47, 7.36 (m each, 2:1:2 H), 2.68, 1.89, 1.75, 1.52, 1.21 (m each,
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1:1:2:1:1 H), 2.19 (d, J = 18.1 Hz, 1 H), 1.11, 0.88, 0.79 (s each, 3:3:3 H). C{1H}
NMR (100 MHz, CDCl3) δ 178.9, 164.1, 133.1, 129.6, 129.5, 128.5, 53.3, 48.8, 43.6,
35.0, 32.5, 27.2, 19.6, 18.5, 11.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
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C17H22NO2: 272.1651; Found: 272.1651.
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Preparation of enaminothiones (2)
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A typical procedure for the preparation of 2  Synthesis of (E)-3-
(benzylamino)-3-(methylthio)-1-phenylprop-2-ene-1-thione (2a): A mixture of α-oxo
ketene N,S-acetal, that is, (E)-3-(benzylamino)-3-(methylthio)-1-phenylprop-2-en-
1-one (567 mg, 2.0 mmol), Lawesson’s reagent (404 mg, 2.0 mmol) in 5 mL toluene
was stirred at 110 oC for 10 minutes. After cooled to ambient temperature, the mixture
was evaporated all the volatiles under reduced pressure. The resultant residue was
purified by silica gel column chromatography (eluent: petroleum ether (60-90
oC)/ethyl acetate, v/v = 50:1) to afford 2a as a yellow solid (509 mg, 85%).
(E)-3-(Benzylamino)-3-(methylthio)-1-(p-tolyl)prop-2-ene-1-thione (2b): 552 mg,
yield 88%, yellow solid, m.p.: 85-86 oC (recrystallized from petroleum ether and ethyl
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acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.45. H NMR (400 MHz,
CDCl3) δ 14.86 (br, 1 H), 7.62 (d, J = 8.1 Hz, 2 H), 7.37 (m, 5 H), 7.15 (d, J = 8.1 Hz,
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2 H), 6.56 (s, 1 H), 4.72 (d, J = 5.4 Hz, 2 H), 2.50 (s, 3 H), 2.36 (s, 3 H). C{1H}
NMR (100 MHz, CDCl3) δ 198.2, 171.4, 146.5, 139.5, 135.6, 129.0, 128.8, 128.1,
127.8, 127.0, 106.8, 48.5, 21.3, 14.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C18H20NS2: 314.1037; Found: 314.1038.
(E)-3-(Benzylamino)-3-(methylthio)-1-(m-tolyl)prop-2-ene-1-thione (2d): 533
o
mg, 85% yield, yellow solid; m.p. 87-88 C (recrystallized from petroleum ether and
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ethyl acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.32. H NMR (400
MHz, CDCl3) δ 14.91 (br, 1 H), 7.58 (s, 1 H), 7.43 (m, 6 H), 7.27 (t, J = 6.7 Hz, 1 H),
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7.21 (d, J = 7.5 Hz, 1 H), 6.59 (s, 1 H), 4.75 (s, 2 H), 2.52 (s, 3 H), 2.43 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 198.5, 171.5, 149.3, 137.7, 135.5, 129.9, 128.9,
127.9, 127.8, 123.8, 107.2, 48.4, 21.5, 14.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C18H20NS2: 314.1037; Found: 314.1037.
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(E)-3-(Benzylamino)-1-(2-methoxyphenyl)-3-(methylthio)prop-2-ene-1-thione
(2e): 586 mg, yield 89%, yellow solid, m.p.: 77-78 oC (recrystallized from petroleum
ether and ethyl acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.33. 1H NMR
(400 MHz, CDCl3) δ 14.85 (br, 1 H), 7.57 (dd, J = 7.6 and 1.5 Hz, 1 H), 7.47 (d, J =
7.2 Hz, 2 H), 7.42 (t, J = 7.4 Hz, 2 H), 7.36 (t, J = 7.1 Hz, 1 H), 7.30 (m, 1 H), 7.02 (t,
J = 7.5 Hz, 1 H), 6.95 (d, J = 8.3 Hz, 1 H), 6.58 (s, 1 H), 4.72 (s, 2 H), 3.85 (s, 3 H),
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2.40 (s, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 196.1, 171.0, 153.9, 139.4, 135.6,
130.2, 129.3, 129.0, 128.1, 127.9, 120.8, 111.6, 110.5, 56.0, 48.6, 14.7. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C18H20NOS2: 330.0986; Found: 330.0986.
(E)-3-(Benzylamino)-3-(methylthio)-1-(3-(trifluoromethyl)phenyl)prop-2-ene-1-t
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hione (2g): 514 mg, yield 70%, yellow solid, m.p.: 105-106 C (recrystallized from
petroleum ether and ethyl acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.43.
1H NMR (400 MHz, CDCl3) δ 14.86 (br, 1 H), 7.95 (s, 1 H), 7.86 (d, J = 7.8 Hz, 1 H),
7.60 (d, J = 7.7 Hz, 1 H), 7.51-7.29 (m, 6 H), 6.55 (s, 1 H), 4.73 (d, J = 5.8 Hz, 2 H),
2.50 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 172.2, 149.6, 135.2, 130.4 (J
= 32.2 Hz), 130.1, 129.0, 128.6, 128.2, 127.7, 125.5 (q, J = 3.5 Hz), 123.7 (q, J = 3.9
Hz), 122.8 (q, J = 272.5 Hz), 107.4, 48.5, 14.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C18H17F3NS2: 368.0755; Found: 368.0757.
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(E)-3-((4-Fluorobenzyl)amino)-3-(methylthio)-1-phenylprop-2-ene-1-thione (2l):
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502 mg, yield 79%, yellow solid, m.p.: 106-107 C (recrystallized from petroleum
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ether and ethyl acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.42. 1H NMR
(400 MHz, CDCl3) δ 14.87 (br, 1 H), 7.70, 7.40, 7.08 (m each, 2:5:2 H), 6.57 (s, 1 H),
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4.68 (d, J = 4.1 Hz, 2 H), 2.50 (s, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 198.5,
171.5, 162.5 (d, J = 245.3 Hz), 149.1, 131.3 (d, J = 3.3 Hz), 129.6 (d, J = 8.2 Hz),
129.2, 128.1, 126.9, 115.9 (d, J = 21.7 Hz), 107.2, 47.7, 14.7. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C17H17FNS2: 318.0786; Found: 318.0786.
(E)-3-(Methylthio)-3-(phenethylamino)-1-phenylprop-2-ene-1-thione (2o): 508
o
mg, yield 81%, yellow solid, m.p.: 108-109 C (recrystallized from petroleum ether
and ethyl acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.45. 1H NMR (400
MHz, CDCl3) δ 14.49 (br, 1 H), 7.61 (m, 2 H), 7.35–7.08 (m, 8 H), 6.44 (s, 1 H), 3.67
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(m, 2 H), 3.01 (m, 2 H), 2.41 (s, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 197.5,
171.4, 149.3, 137.8, 129.1, 129.0, 128.9, 128.1, 127.0, 127.0, 107.1, 46.5, 35.4, 14.7.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H20NS2: 314.1037; Found: 314.1038.
(E)-3-(Butylamino)-3-(methylthio)-1-phenylprop-2-ene-1-thione (2s): 377 mg,
yield 71%, yellow solid, m.p.: 88-89 oC (recrystallized from petroleum ether and ethyl
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acetate). Rf (petroleum ether/ethyl acetate = 6:1, v/v) = 0.55. H NMR (400 MHz,
CDCl3) δ 14.52 (br, 1 H), 7.79-7.62 (m, 2 H), 7.44-7.31 (m, 3 H), 6.54 (s, 1 H), 3.52
(m, 2 H), 2.52 (s, 3 H), 1.80 (m, 2 H), 1.56 (m, 2 H), 1.02 (t, J = 7.4 Hz, 3 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 196.5, 171.4, 149.3, 129.0, 128.1, 126.9, 107.0, 44.6, 30.7,
20.3, 14.6, 13.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H20NS2: 266.1037;
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Found: 266.1035.
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A typical procedure for the synthesis of thiophenes 3 and 4  Synthesis of
3-(3-(benzylamino)-5-phenylthiophen-2-yl)propanenitrile (3a): Under a nitrogen
atmosphere, a mixture of 1a (57 mg, 0.3 mmol), 2a (99 mg, 0.33 mmol), CuCl (3.0
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mg, 0.03 mmol), and NaOAc (24 mg, 0.3 mmol) in 2 mL DMF was stirred at 70 C
for 12 h. After cooled to ambient temperature, the resultant mixture was purified by
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silica gel column chromatography (eluent: petroleum ether (60-90 C)/ethyl acetate,
v/v = 30:1) to afford 3a as a yellow solid (75 mg, 79%).
3-(3-(Benzylamino)-5-phenylthiophen-2-yl)propanenitrile (3a): 76 mg, 79%;
yellow solid, m.p.: 104-105 oC (recrystallized from petroleum ether and ethyl acetate).
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Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.38. H NMR (400 MHz, CDCl3) δ
7.55 (m, 2 H), 7.50-7.24 (m, 8 H), 6.99 (s, 1 H), 4.44 (s, 2 H) 3.54 (br, 1 H), 2.99 (t, J
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= 7.4 Hz, 2 H), 2.59 (t, J = 7.4 Hz, 2 H). C{1H} NMR (100 MHz, CDCl3) δ 145.4,
140.8, 139.7, 134.3, 129.0, 128.8, 127.8, 127.6, 126.9, 125.4, 119.3, 115.6, 112.4,
51.5, 23.1, 18.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H19N2S: 319.1269;
Found: 319.1267.
3-(3-(Benzylamino)-5-(p-tolyl)thiophen-2-yl)propanenitrile (3b): 71 mg, 71%;
yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.45. 1H NMR (400 MHz,
CDCl3) δ 7.43-7.29 (m, 7 H), 7.15 (d, J = 7.9 Hz, 2 H), 6.91 (s, 1 H), 4.36 (s, 2 H),
2.97 (t, J = 7.4 Hz, 2 H), 2.57 (t, J = 7.4 Hz, 2 H), 2.35 (s, 3 H). 13C{1H} NMR (100
MHz, CDCl3) δ 145.4, 140.9, 139.7, 137.5, 131.6, 129.6, 128.8, 127.8, 127.5, 125.3,
119.3, 115.1, 111.9, 51.6, 23.1, 21.3, 18.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
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C21H21N2S: 333.1425; Found: 333.1417.
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3-(3-(Benzylamino)-5-(4-methoxyphenyl)thiophen-2-yl)propanenitrile (3c): 67
mg, 64%; yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.31. 1H NMR
(400 MHz, CDCl3) δ 7.32 (d, J = 8.9 Hz, 2 H), 7.25, 7.17 (m, 4:1 H), 6.76 (d, J = 8.9
Hz, 2 H), 6.72 (s, 1 H), 4.23 (s, 2 H), 3.69 (s, 3 H), 3.26 (br, 1 H), 2.81 (t, J = 7.4 Hz,
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2 H), 2.41 (t, J = 7.4 Hz, 2 H). C{1H} NMR (100 MHz, CDCl3) δ 159.2, 145.3,
140.6, 139.7, 128.7, 127.7, 127.4, 127.2, 126.6, 119.3, 114.6, 114.3, 111.2, 55.4, 51.4,
23.0, 18.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H21N2OS: 349.1375; Found:
349.1357.
3-(3-(Benzylamino)-5-(m-tolyl)thiophen-2-yl)propanenitrile (3d): 75 mg, 75%;
yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.25. 1H NMR (400 MHz,
CDCl3) δ 7.28, 7.23, 7.14 (m each, 4:3:1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.85 (s, 1 H),
4.27 (s, 2 H), 2.85 (t, J = 7.4 Hz, 2 H), 2.46 (t, J = 7.4 Hz, 2 H), 2.28 (s, 3 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 145.4, 141.0, 139.7, 138.6, 134.2, 128.8, 128.4, 127.8,
127.6, 126.1, 122.6, 119.3, 115.5, 112.3, 51.6, 23.2, 21.5, 18.7. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C21H21N2S: 333.1425; Found: 333.1425.
3-(3-(Benzylamino)-5-(2-methoxyphenyl)thiophen-2-yl)propanenitrile (3e): 71
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mg, 68%; yellow solid, m.p.: 102-103 C (recrystallized from petroleum ether and
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ethyl acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.28. H NMR (400
MHz, CDCl3) δ 7.36-7.14 (m, 6 H), 6.99 (m, 2 H), 6.83 (s, 1 H), 6.79-6.65 (m, 1 H),
4.28 (s, 2 H), 3.75 (s, 3 H), 2.88 (t, J = 7.4 Hz, 2 H), 2.49 (t, J = 7.4 Hz, 2 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 160.0, 145.4, 140.5, 139.6, 135.6, 129.9, 128.8, 127.7,
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127.5, 119.3, 118.0, 115.8, 113.0, 112.5, 111.1, 55.4, 51.5, 23.1, 18.6. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C21H21N2OS: 349.1375; Found: 349.1373.
3-(3-(Benzylamino)-5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)propanenitrile
(3f): 82 mg, 71%; yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.33.
1H NMR (400 MHz, CDCl3) δ 7.49 (s, 4 H), 7.28 (m, 5 H), 6.91 (s, 1 H), 4.28 (s, 2 H),
2.89 (t, J = 7.3 Hz, 2 H), 2.50 (t, J = 7.3 Hz, 2 H). 13C{1H} NMR (100 MHz, CDCl3)
δ 145.8, 139.5, 138.9, 137.7, 129.2 (q, J = 32.6 Hz), 128.9, 127.7, 127.6, 125.9 (q, J =
3.8 Hz), 125.4, 124.2 (q, J = 270.2 Hz), 119.1, 116.6, 113.8, 51.4, 23.1, 18.6. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C21H18F3N2S: 387.1143; Found: 387.1142.
3-(3-(Benzylamino)-5-(3-(trifluoromethyl)phenyl)thiophen-2-yl)propanenitrile
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(3g): 81 mg, 70%; yellow solid, m.p.: 68-69 C (recrystallized from petroleum ether
and ethyl acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.42. 1H NMR (400
MHz, CDCl3) δ 7.64 (s, 1 H), 7.56 (d, J = 7.6 Hz, 1 H, 7.40 (m, 2 H), 7.35-7.12 (m, 5
H), 6.91 (s, 1 H), 4.29 (s, 2 H), 2.90 (t, J = 7.3 Hz, 2 H), 2.50 (t, J = 7.3 Hz, 2 H).
13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 139.5, 139.0, 135.2, 131.4 (q, J = 32.5 Hz),
129.5, 128.9, 128.5 (q, J = 3.7 Hz), 127.8, 127.7, 124.0 (q, J = 270.6 Hz), 123.9 (q, J
= 3.7 Hz), 122.0 (q, J = 3.7 Hz), 119.1, 116.5, 113.5, 51.6, 23.2, 18.7. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C21H18F3N2S: 387.1143; Found: 387.1144.
3-(3-(Benzylamino)-5-(2-fluorophenyl)thiophen-2-yl)propanenitrile (3h): 81 mg,
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80%; yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.35. H NMR
(400 MHz, CDCl3) δ 7.44 (m, 1 H), 7.35-7.15 (m, 5 H), 7.17-6.94 (m, 4 H), 4.27 (s, 2
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H), 2.89 (t, J = 7.4 Hz, 2 H), 2.48 (t, J = 7.4 Hz, 2 H). C{1H} NMR (100 MHz,
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CDCl3) 159.1 (d, J = 248.5 Hz), 145.2, 139.7, 133.7 (d, J = 31.8 Hz), 128.8, 128.6 (d,
J = 8.4 Hz), 128.2 (d, J = 3.3 Hz), 127.8, 127.6, 124.5 (d, J = 3.4 Hz), 122.2 (d, J =
123.1 Hz), 119.2, 118.9 (d, J = 71.4 Hz), 116.5 (d, J = 222.7 Hz), 113.5 (d, J = 41.5
Hz), 51.6, 23.1, 18.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H18FN2S:
337.1175; Found: 337.1173.
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3-(3-(Benzylamino)-5-(4-bromophenyl)thiophen-2-yl)propanenitrile (3i): 86 mg,
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72%; yellow solid, m.p.: 97-98 C (recrystallized from petroleum ether and ethyl
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acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.30. H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 8.5 Hz, 2 H), 7.34 (m, 7 H), 6.92 (s, 1 H), 4.36 (s, 2 H), 3.38 (br,
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1 H), 2.96 (t, J = 7.3 Hz, 2 H), 2.57 (t, J = 7.3 Hz, 2 H). C{1H} NMR (100 MHz,
CDCl3) δ 145.6, 141.3, 139.4, 132.0, 131.3, 128.8, 127.7, 127.6, 126.8, 121.3, 119.2,
115.8, 112.8, 51.4, 23.1, 18.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H18BrN2S:
397.0374; Found: 397.0373.
3-(3-((4-Methoxybenzyl)amino)-5-phenylthiophen-2-yl)propanenitrile (3j): 74
mg, 71%; yellow solid, m.p.: 80-81 oC (recrystallized from petroleum ether and ethyl
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acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.42. H NMR (400 MHz,
CDCl3) δ 7.56, 7.33, 6.91 (m each, 2:5:2 H), 6.99 (s, 1 H), 4.32 (s, 2 H), 3.84 (s, 3 H),
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2.97 (m, 3 H), 2.58 (t, J = 7.4 Hz, 2 H). C{1H} NMR (100 MHz, CDCl3) δ 159.1,
145.5, 140.7, 134.3, 131.7, 129.0, 128.9, 127.5, 125.3, 119.3, 115.6, 114.2, 112.3,
55.4, 51.0, 23.1, 18.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H21N2OS:
349.1375; Found: 349.1384.
3-(3-((3-Methoxybenzyl)amino)-5-phenylthiophen-2-yl)propanenitrile (3k): 68
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mg, 65%; yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.30. 1H NMR
(400 MHz, CDCl3) δ 7.54, 7.34, 7.00, 6.86 (m each, 2:4:3:1 H), 4.37 (s, 2 H), 3.84 (s,
3 H), 3.53 (br, 1 H), 3.00 (t, J = 7.4 Hz, 2 H), 2.60 (t, J = 7.4 Hz, 2 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 160.0, 145.4, 141.4, 140.7, 134.3, 129.8, 128.9, 127.5, 125.4,
119.9, 119.3, 115.5, 113.3, 112.9, 112.3, 55.3, 51.4, 23.1, 18.7. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C21H21N2OS: 349.1375; Found: 349.1378.
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3-(3-((4-Fluorobenzyl)amino)-5-phenylthiophen-2-yl)propanenitrile (3l): 76 mg,
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75%; yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.25. H NMR
(400 MHz, CDCl3) δ 7.40, 7.24, 7.16, 6.95 (m each, 2:4:1:2: H), 6.81 (s, 1 H), 4.23 (s,
2 H), 3.06 (br, 1 H), 2.87 (t, J = 7.3 Hz, 2 H), 2.49 (t, J = 7.3 Hz, 2 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 162.2 (d, J = 243.9 Hz,), 145.3, 140.8, 134.2, 135.4 (d, J = 31.4
Hz), 129.3 (d, J = 8.0 Hz), 128.9, 127.6, 125.4, 119.3, 115.7, 115.4 (d, J = 6.9 Hz),
112.6, 50.7, 23.1, 18.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H18FN2S:
337.1175; Found: 337.1175.
3-(3-((2-Chlorobenzyl)amino)-5-phenylthiophen-2-yl)propanenitrile (3m): 67
mg, 63%; yellow solid, m.p.: 65-66 oC (recrystallized from petroleum ether and ethyl
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acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.35. H NMR (400 MHz,
CDCl3) δ 7.40, 7.30, 7.09 (m each, 2:2:3 H), 7.23 (t, J = 7.6 Hz, 2 H), 6.80 (s, 1 H),
4.34 (s, 2 H), 3.40 (br, 1 H), 2.86 (t, J = 7.4 Hz, 2 H), 2.45 (t, J = 7.4 Hz, 2 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 144.9, 140.8, 137.0, 134.2, 133.4, 129.7, 129.6, 128.9,
128.8, 127.6, 127.2, 125.3, 119.2, 115.6, 113.1, 49.1, 23.1, 18.7. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C20H18ClN2S: 353.0879; Found: 353.0879.
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3-(3-((Furan-2-ylmethyl)amino)-5-phenylthiophen-2-yl)propanenitrile (3n): 63
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mg, 68%; yellow solid, m.p.: 68-69 oC (recrystallized from petroleum ether and ethyl
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acetate). Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.24. H NMR (400 MHz,
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CDCl3) δ 7.42 (d, J = 7.4 Hz, 2 H), 7.27 (m, 3 H), 7.16 (m, 1 H), 6.88 (s, 1 H), 6.23
(dd, J = 2.8, 2.0 Hz, 1 H), 6.13 (d, J = 3.1 Hz, 1H), 4.22 (s, 2 H), 3.37 (br, 1 H), 2.86
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(t, J = 7.4 Hz, 2 H), 2.46 (t, J = 7.4 Hz, 2 H). C{1H} NMR (100 MHz, CDCl3) δ
153.1, 144.7, 140.7, 134.3, 142.1, 128.9, 127.6, 125.4, 119.2, 115.9, 114.0, 110.5,
107.3, 44.5, 23.0, 18.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17N2OS:
309.1062; Found: 309.1059.
3-(3-(Phenethylamino)-5-phenylthiophen-2-yl)propanenitrile (3o): 75 mg, 75%;
yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.40. 1H NMR (400 MHz,
CDCl3) δ 7.44, 7.25, 7.14 (m each, 2:4:4 H), 6.85 (s, 1 H), 3.54 (br, 1 H), 3.35 (t, J =
6.9 Hz, 2 H), 2.80 (t, J = 6.9 Hz, 2 H), 2.73 (t, J = 7.4 Hz, 2 H), 2.38 (t, J = 7.4 Hz, 2
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H). C{1H} NMR (100 MHz, CDCl3) δ 145.1, 140.8, 139.2, 134.3, 128.9, 128.9,
128.8, 127.5, 126.6, 125.3, 119.1, 115.3, 112.0, 48.2, 36.2, 23.1, 18.7. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C21H21N2S: 333.1425; Found: 333.1427.
3-(3-((2-(1H-indol-3-yl)ethyl)amino)-5-phenylthiophen-2-yl)propanenitrile (3p):
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89 mg, 80%; yellow liquid. Rf (petroleum ether/ethyl acetate = 4:1, v/v) = 0.15. H
NMR (400 MHz, CDCl3) δ 8.02 (br, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.42, 7.28, 7.17,
7.06 (m each, 2:3:2:1 H), 6.98 (d, J = 2.3 Hz, 1 H), 6.98 (s, 1 H), 3.44 (t, J = 6.5 Hz, 2
H), 3.01 (t, J = 6.4 Hz, 2 H), 2.67 (t, J = 7.4 Hz, 3 H), 2.30 (t, J = 7.4 Hz, 2 H).
13C{1H} NMR (100 MHz, CDCl3) δ 145.5, 140.7, 136.6, 134.4, 128.9, 127.5, 127.5,
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