Parallel synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives on traceless solid support

Article abstract of DOI:10.1016/j.tet.2014.10.030

A parallel solid-phase synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives was developed. The polymer-supported synthetic route progressed using the sulfide linker via a traceless strategy. The initial synthesis utilized the Thorpe-Zieg

Full text of DOI:10.1016/j.tet.2014.10.030

Tetrahedron 70 (2014) 9183e9190
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Parallel synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile
derivatives on traceless solid support
,
,
Suyoun Lee a y, Doohyun Lee a y, Kyung-Sik Song a, Kwang-Hyeon Liu a,
Young-Dae Gong b , Taeho Lee
a College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701,
,
a,
*
*
Republic of Korea
b Center for Innovative Drug Library Research, Department of Chemistry, College of Natural Science, Dongguk University-Seoul, 26 Pildong 3-ga,
Jung-gu, Seoul 100-715, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A parallel solid-phase synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives was de-
Received 13 September 2014
Received in revised form 10 October 2014
Accepted 14 October 2014
veloped. The polymer-supported synthetic route progressed using the sulfide linker via a traceless
strategy. The initial synthesis utilized the ThorpeeZiegler type cyclization of a-haloketone and polymer-
supported 2,2-dicyanoethene-1,1-bis(thiolate), which was derived from the Merrifield resin. The re-
sulting thiophene resin was introduced to one substitution by N-arylation. After oxidation of sulfides to
sulfones in the thiophene resins for subsequent cleavage, nucleophilic desulfonative substitution with
amines and thiols afforded the desired thiophene-3-carbonitrile derivatives in good overall yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 18 October 2014
Keywords:
Thiophene-3-carbonitrile
Solid-phase synthesis
Combinatorial chemistry
Heterocycles
1. Introduction
efficient synthesis of multi-substituted thiophene derivatives has
attracted much attention.
Multi-substituted thiophenes 1, which are bioisosteres of arene
derivatives and congeners of thiazole derivatives, are useful scaf-
folds with diverse important biological activities (Fig. 1).1,2 For ex-
amples, biological activities of multi-substituted thiophenes 1 have
shown activity as dual inhibitor of the cancer-related cysteine
isopeptidase human ubiquitin-specific proteases 7 (USP7) and 47
(USP47),2a as protein farnesyltransferase (FTase),2b,c as antitumor
and antioxidant agents,2d,e and as selective phosphoinositide 3-
kinase (PI3K) inhibitors.2f Owing to these properties, they serve
as attractive targets for combinatorial library construction and the
The combinatorial synthetic methods in the solution-phase for
thiophenes and their relative derivatives have been well docu-
mented.2,3 However, to the best of our knowledge, there is one
report, which describes the synthesis of 2,4,5-trisubstituted thio-
phene-3-carbonitrile 1 (R1¼CN) on solid support.4 The known
solid-phase process lacks the amine diversity elements
(R4¼secondary amines) and has no R3 substituent in 1. Similarly,
the solid-phase synthesis of thiophene-2-carboxylic acids and their
derivatives have been reported.2c,5 The carboxylic acid moiety of
thiophene was used as a solid support linker with Wang resin or
trityl resin.
As part of a recent drug discovery project, we required efficient
solid-phase synthetic methods for a multi-substituted thiophene
library. Herein, we described our recent progress on this study,
including the solid-phase synthetic protocol for thiophene-3-
carbonitrile derivatives 1 (R1¼CN), using previously synthetic
methods for thiazole and its fused ring library on the traceless solid
linker.6
HN R3
R2
R1 HN R3
H
N
N
R3
R1
R4
R4
R2
S
S
R2
1
Fig. 1. Structures of thiophene 1 and its related skeletons.
2. Result and discussion
* Corresponding authors. Tel.: þ82 53 9508573; fax: þ82 53 9508557 (T.L.);
In preliminary studies on solid support, the divergent synthesis
e-mail addresses: ydgong@dongguk.edu (Y.-D. Gong), tlee@knu.ac.kr (T. Lee).
These authors contributed equally to this work.
of the 2-amino-thiophene-3-carbonitrile derivatives 1A (R1¼CN,
y
http://dx.doi.org/10.1016/j.tet.2014.10.030
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

9184
S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
R3¼H) was developed from Merrifield resin 2 as the starting ma-
terial and solid support (Scheme 1). The solid-phase synthetic route
for the preparation of 2-amino-thiophene-3-carbonitrile de-
rivatives 1A utilizes appropriate a-haloacetophenones derivatives 3
and various nucleophiles 4 as key building blocks and diversity
elements. The sequence began with the formation of the polymer-
supported 2,2-dicyanoethene-1,1-bis(thiolate) 5 through the well-
known
reaction
of
dipotassium
2,2-dicyanoethene-1,1-
bis(thiolate) (6)3a,c with Merrifield resin 2. The reaction progress
was monitored using attenuated total reflection Fourier transform
infrared (ATR-FTIR) spectroscopy.
NC
S
CN
SK
NC
KS
CN
SK
Cl
+
Fig. 3. ATR-FTIR spectra of Merrifield resin 2 and resins 5, 7, and 8 (R2¼COPh).
DMF, rt
Merrifield
resin (2)
5
6
X-CH2R2 (3), Et3N
MeO
acetone, rt
NH2
NH2
NH
NH
O
NH
NC
S
NH2
NC
NH2
R2
1
2
3
4
5
mCPBA
CH2Cl2, rt
NH2
R2
S
SH
SH
NH2
S
S
O O
6
7
8
9
7
8
R4-H (4), Et3N
Fig. 4. Diversity reagents 4{1e9}.
CHCl3, 45 oC
NC
R4
NH2
This new solid-phase synthetic route facilitated the preparation
of a number of 2-amino-thiophene-3-carbonitrile derivatives 1A, as
displayed in Table 1, starting from Merrifield resin 2 and appro-
R2 & R4 : see the text and table 1
X = Br or Cl
R2
S
priate a
-halo components 3{1e6} (R1CH2X; Fig. 3) and nucleophiles
1A
4{1e9}(R4eH; Fig. 4). All reactions were performed in duplicated
under the same conditions.
Scheme 1. Solid-phase synthesis of 2-amino-thiophene-3-carbonitriles 1A.
When the benzoyl group was the substituent at the R2 position
of resin 8, 2-amino-thiophene-3-carbonitrile derivatives 1A{1,1e9}
were obtained in high yields (85e57%, Table 1, entries 1e9), except
of 1A{1,7}. Reaction of resins 8{2e3} (ester and ketone) with nu-
cleophiles 4 afforded the 1A{2e3, 1e9} in good yields (entries
10e27), except of 1A{2,5 and 2,7} and 1A{3,7}. The desulfonative
nucleophilic substitution was sensitive to the nucleophilicity of
nucleophiles 4{1e9}, because thiols 4{8e9} are more nucleophilic
than amines 4{1e6} (entries 1e6 and entries 8e9). In the case of
sterically hindered nucleophile 4{7}, the yields of 1A{1e3,7} was
either low (entry 7) or traces (entries 16 and 25). Furthermore, in
the cases of the reaction of the intermediate resins 8{4e6} with
nucleophile 5{1}, no products 1A{4e6,1} were obtained on solid-
phase (entries 28e30). The isolated overall yields for 2-amino-
thiophene-3-carbonitrile derivatives ranged from 27 to 90% for the
four-step linear pathway (average yield for each step was 72e97%)
from the Merrifield resin 2. Moreover, the target compounds were
furnished in high purities [>95% as judged from the LCeMS traces
(integration of photodiode array 200e400 nm traces)] and were
characterized by using MS as well as 1H and 13C NMR spectroscopy.
On the basis of these successful solid-phase reaction conditions
of 2-amino-thiophene-3-carbonitrile derivatives 1A, we in-
vestigated the further diversity elements in thiophene-3-
carbonitrile derivatives 1 (e.g., the R1 and R3 positions). First, po-
tassium bis(thiolate) 9 (R1¼CO2Me or Ph) was prepared from nitrile
10 and carbon disulfide and applied to the solid-phase synthesis of
2-amino-thiophene-3-carbonitrile derivatives 1A for the expansion
of R1 diversity point in 1 (Scheme 2). However, this process did not
lead to target product 11 upon reaction with the high-yielding di-
versity elements 3{1} and 4{9} under various reaction conditions.
Second, various N-substitution reactions, such as acylation, al-
kylation, sulfonylation, and arylation of resin 7 were attempted for
the introduction of R3 diversity elements into thiophene-3-
carbonitrile derivatives 1 (R1¼CN) (Scheme 3).
Resin 5 was first swollen in acetone and then treated with a-
bromoacetophenone 3 (the first diversity element; see Fig. 2) and
triethylamine at room temperature to afford the corresponding 2-
amino-thiophene resin 7 via the ThorpeeZiegler cyclization.3e,7
The reaction progress (R2¼COPh) was monitored by ATR-FTIR,
which showed the disappearance of the conjugated nitrile stretch-
ing band at 2186 cmꢀ1 and the appearance of the ketone carbonyl
stretching band at 1585 cmꢀ1 and the NH2 stretching bands at 3446
and 3306 cmꢀ1 (Fig. 3). Treatment of 2-amino-thiophene resin 7
with mCPBA in CH2Cl2 provided the resin-bound sulfone in-
termediate 8. Although this reaction was not amenable to ATR-FTIR
monitoring, similar protocols of solid-thiazole synthetic studies5b,6
and solution-phase thiophene synthetic studies8 are well known.
OEt
Br
Cl
Br
O
O
O
2
1
3
Br
Cl
CN
Br
NO2
4
5
6
NO2
Fig. 2. Diversity reagents 3{1e6}.
The sulfone group in resin 8 was displaced by a nucleophilic
desulfonative substitution reaction with the corresponding nucle-
ophiles 4 (R4eH, benzylamine for 1A{1,1}; see Fig. 4), which served
as the second diversity element, in CHCl3. This process, which is
accompanied by concurrent cleavage from the resin, furnished the
final 2-amino-thiophene-3-carbonitrile derivatives 1A{1,1} (79%
over four steps, from Merrifield resin 2), which was then purified by
column chromatography.

S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
9185
Table 1
R1
S
CN
SK
Cl
2-Amino-thiophene-3-carbonitrile derivatives 1A using the solid-phase synthetic
R1
CN
SK
CS2, KOH
EtOH, rt
2
routea
R1
CN
DMF, rt
KS
10
9
3{1}, Et3N
acetone, rt
R1
NH2
R1
NH2
O
1. mCPBA
CH2Cl2, rt
Entry
Products
R2
R4
Yield (%)b
Ph
Ph
S
X
1
2
1A{1,1}
1A{1,2}
eCOPh
eCOPh
BnNH
4-MeOeBnNH
79
68
S
S
2. 4{9}, Et3N
CHCl3, 45 oC
S
O
11
3
4
5
1A{1,3}
eCOPh
eCOPh
eCOPh
85
82
57
N
R1 = CO2Me or Ph
1A{1,4}3e
1A{1,5}3e
Scheme 2. Solid-phase synthesis of 2-amino-thiophenes 11.
N
NC
S
HN R3
R2
O
N
NC
S
NH2
R2
R3-X (12)
6
7
8
9
10
11
1A{1,6}
1A{1,7}
1A{1,8}
1A{1,9}
1A{2,1}
1A{2,2}
eCOPh
eCOPh
eCOPh
eCOPh
eCO2Et
eCO2Et
n-BuNH
i-PrNH
PhS
n-PrS
BnNH
81
27
80
83
27
39
S
see text
S
7
13
mCPBA
CH2Cl2, rt
4-MeOeBnNH
12
13
14
1A{2,3}3d
eCO2Et
eCO2Et
eCO2Et
90
N
NC
HN R3
NC
R4
HN R3
R2
R4-H (4), Et3N
1A{2,4}
56
N
R2
S
CHCl3, 45 oC
S
O O
S
1A{2,5}3d
N.R.c
14
O
N
1
Scheme 3. Solid-phase synthesis of thiophene-3-carbonitriles 1 with N-substitution
reaction.
15
16
17
18
19
20
1A{2,6}
1A{2,7}
1A{2,8}
1A{2,9}
1A{3,1}
1A{3,2}
eCO2Et
eCO2Et
eCO2Et
eCO2Et
eCOMe
eCOMe
n-BuNH
i-PrNH
PhS
n-PrS
BnNH
46
N.R.c
90
O
O
88
44
44
Cl
OH
Br
4-MeOeBnNH
3
1
2
21
22
23
1A{3,3}
1A{3,4}
1A{3,5}3e
eCOMe
eCOMe
eCOMe
36
41
48
N
O O
S
N
Cl
OH
O
F
6
5
4
O
N
F
F
24
25
26
27
28
29
30
1A{3,6}
1A{3,7}
1A{3,8}
1A{3,9}
1A{4,1}
1A{5,1}
1A{6,1}
eCOMe
eCOMe
eCOMe
eCOMe
eCN
n-BuNH
i-PrNH
PhS
n-PrS
BnNH
BnNH
BnNH
44
N.R.c
65
MeO2C
O2N
NC
9
7
8
69
N.R.c
N.R.c
N.R.c
Fig. 5. Diversity reagents 12{1e9}.
eNO2
e4-NO2ePh
the overall peak intensity relative to that of resin 7{1} (see the
Supplementary data).
By employing the optimized solid-phase synthetic route (see
Scheme 3), 2,4,5-trisubstituted thiophene-3-carbonitrile de-
rivatives 1 could be prepared from Merrifield resin 2 and appro-
a
All reactions were performed in duplicate on 200e300 mg scale based on
resin 8.
b
Four-step overall average isolated yield from Merrifield resin
2 (loading
capacity¼1.29 mmol/g).
c
No reaction or traces.
priate
a-halo compounds 3{1e3}, N-substitution agents 12
{1,3,6e7}, and nucleophiles 4{1e9} as the diversity elements. The
substances generated in this way and the isolated yields obtained
after passing the reaction mixture through a short plug of silica are
given in Table 3.
In the cases of N-acylation, alkylation, and sulfonylation (Table
3, entries 1e3), thiophene-3-carbonitriles 1 were not obtained as
a result of the test reactions. However, the corresponding desired
thiophene-3-carbonitrile derivatives 1 were formed in the case of
N-arylation (R3¼4-NO2ePh) using 12{7}, except some cases. When
the R2 is benzoyl or ester, the desired thiophene-3-carbonitrile
derivatives 1 were obtained in moderate yields (43e8%, Table 2,
entries 1e18), except in some cases. The methyl ketone derivatives
Attempts to promote the reaction of N-substitution source 12
(Fig. 5) with 2-amino-thiophene resin 7{1} to generate di-
substituted thiophene resin 13 under various reaction conditions
were unsuccessful (Table 2).9 In contrast, the N-arylation of 7{1}
with 1-fluoro-4-nitrobenzene (12{7}) took place efficiently when
sodium hydride was used as the base and DMF as the solvent at
room temperature. The reaction progress (R2¼COPh) was moni-
tored by ATR-FTIR, which indicated the disappearance of the NH2
stretching bands at 3451 and 3302 cmꢀ1 and a general decline in

9186
S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
Table 2
Table 3
N-Substitution of 7{1} on solid supporta
2,4,5-Trisubstituted thiophene-3-carbonitriles 1 using the solid-phase synthetic
routea
Entry
Products
R2
R3
R4
Yield (%)b
Entry
Reaction type
Acylation
Reagent
Reaction condition
Yield (%)b
N.R.c
N.R.c
N.R.c
N.R.c,d
N.R.c,d
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c
N.R.c,d
30
1
2
3
4
5
1{1,1,1}
1{1,3,1}
1{1,6,1}
1{1,7,1}
1{1,7,2}
eCOPh
eCOPh
eCOPh
eCOPh
eCOPh
Bz
Bn
BnNH
BnNH
BnNH
BnNH
N.R.c
N.R.c
N.R.c
N.R.c
12
1
2
3
4
5
6
7
8
12{1}
12{1}
12{1}
12{1}
12{1}
12{2}
12{2}
12{3}
12{4}
12{5}
12{6}
12{6}
12{7}
12{8}
12{9}
Pyridine, CH2Cl2
Et3N, DMAP, CH2Cl2
Et3N, MeCN
4-MeePhSO2
4-NO2ePh
4-NO2ePh
DBU, CH2Cl2
4-MeOeBnNH
t-BuOLi, CH2Cl2
POCl3, pyridine
DCC, DMAP, CH2Cl2
NaH, DMF
DEAD, PPh3, THF
NaBH(OAc)3, DCE
NaH, DMF
t-BuOLi, CH2Cl2
NaH, DMF
NaH, DMF
6
7
8
1{1,7,3}
1{1,7,4}
1{1,7,5}
eCOPh
eCOPh
eCOPh
4-NO2ePh
4-NO2ePh
4-NO2ePh
16
20
8
N
Alkylation
9
N
10
11
12
13
14
15
Sulfonylation
Arylation
O
N
N.R.c
N.R.c
9
1{1,7,6}
1{1,7,7}
1{1,7,8}
1{1,7,9}
1{2,7,1}
1{2,7,2}
eCOPh
eCOPh
eCOPh
eCOPh
eCO2Et
eCO2Et
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
n-BuNH
i-PrNH
PhS
16
NaH, DMF
10
11
12
13
14
N.R.c
25
a
All reactions were performed on 200e300 mg scale based on resin 7{1} at room
temperature to 80 ꢂC over 1 day.
n-PrS
BnNH
30
b
N.R.c
12
Isolated yield from Merrifield resin 2 (loading capacity¼1.29 mmol/g) after the
additional reactions (oxidation and nucleophilic desulfonative substitution with 4
{9}) were progressed.
4-MeOeBnNH
c
15
16
17
1{2,7,3}
1{2,7,4}
1{2,7,5}
eCO2Et
eCO2Et
eCO2Et
4-NO2ePh
4-NO2ePh
4-NO2ePh
21
No reaction or traces.
In solution model system, the corresponding products were obtained (see
N
d
Supplementary data).
16
N
1{3,7,1e9} were synthesized in relatively low yields or traces (en-
tries 19e27). Among the nucleophiles 4{1e9}, amines (4{1e7})
afforded the desired thiophene-3-carbonitrile derivatives 1 in low
yields or traces (entries 1e7, 10e16, and 19e25). When the nucle-
ophiles 4{8e9}, such as thiols, were used for desulfonative sub-
stitution, thiophene-3-carbonitrile derivatives 1 were formed in
moderated overall yields (entries 8e9, 17e18, and 26e27; 15e43%
yields).
N.R.c
O
N
18
19
20
21
22
23
1{2,7,6}
1{2,7,7}
1{2,7,8}
1{2,7,9}
1{3,7,1}
1{3,7,2}
eCO2Et
eCO2Et
eCO2Et
eCO2Et
eCOMe
eCOMe
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
n-BuNH
i-PrNH
PhS
22
N.R.c
34
n-PrS
BnNH
43
N.R.c
N.R.c
4-MeOeBnNH
The isolated overall yields for the desired 2,4,5-trisubstituted
thiophene-3-carbonitriles ranged from 6 to 43% for the five-step
linear pathway from the Merrifield resin 2, indicating that the av-
erage yield for each step is 57e95%. The target compounds 1 were
obtained with high purities following column chromatography
[>95% as judged from LCeMS traces (integration of photodiode
array 200e400 nm traces)] and were characterized by using MS
and 1H NMR spectroscopy.
24
25
26
1{3,7,3}
1{3,7,4}
1{3,7,5}
eCOMe
eCOMe
eCOMe
4-NO2ePh
4-NO2ePh
4-NO2ePh
10
N
N.R.c
N.R.c
N
O
N
27
28
29
30
1{3,7,6}
1{3,7,7}
1{3,7,8}
1{3,7,9}
eCOMe
eCOMe
eCOMe
eCOMe
4-NO2ePh
4-NO2ePh
4-NO2ePh
4-NO2ePh
n-BuNH
i-PrNH
PhS
6
N.R.c
16
15
3. Conclusion
n-PrS
In summary, a traceless solid-phase synthetic route for efficient
generation of multi-substituted thiophene-3-carbonitriles, which
are bioisosteres of arene derivatives and the congeners of thiazoles,
was successfully developed. The sequence contained three di-
a
All reactions were performed on 200e300 mg scale based on resin 14 and the R3
substitution reaction of 7{1e3} was progressed with 12{1,3,6e7} and NaH at room
temperature.
b
Four-step overall isolated yield from Merrifield resin
capacity¼1.29 mmol/g).
2
(loading
versity sites that were introduced in reactions involving
a-halo
c
No reaction and traces.
components (R1), an N-substitution source (R3), and nucleophiles
(R4). This strategy enables the construction of a large library and is
potentially applicable for the preparation of other drug-like thio-
phene-fused ring systems. Further studies in this area are un-
derway and the results, of which will be reported in due course.
ATR-FTIR analysis using Agilent Technologies Cary 630 FTIR spec-
trometer. The crude products were purified by parallel chroma-
tography using a CombiFlashÔ. 1H NMR and l3C NMR spectra were
4. Experimental
4.1. General
recorded in d units relative to the deuterated solvent (CDCl3, DMSO-
d6, etc.) as the internal reference using a Bruker 500 MHz NMR
instrument. LCeMS analysis was performed on ESI mass spec-
trometer equipped PDA detection. LCeMS area% purities of all the
products were determined by LC peak area analysis (XDB C18 col-
umn, 4.6 mmꢁ100 mm; PDA detector at 200e400 nm; isocratic,
5 mM ammonium formate/CH3CN (30:70)).
All chemicals were reagent grade and used as purchased. The
Merrifield resin (loading capacity 1.29 mmol/g, 100e200 mesh)
was purchased from BeadTech. All the reactions were monitored by

S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
9187
4.2. General procedure for the preparation of 2-amino-thio-
phene-3-carbonitrile 1A on solid-phase
500 MHz):
d 7.72e7.66 (m, 2H), 7.48e7.40 (m, 3H), 7.05 (br s, 2H),
3.71e3.58 (m, 4H), 2.11e2.05 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d
185.2, 164.0, 158.7, 141.2, 130.6, 128.5, 127.3, 116.0, 95.5, 76.5, 51.6,
A typical procedure for the preparation of 2-amino-thiophene-
3-carbonitrile, as exemplified for 4-amino-5-benzoyl-2-(benzyla-
mino)thiophene-3-carbonitrile (1A{1,1}; R2¼COPh, R4¼NHBn) is as
follows.
25.8; LCeMS (ESI) m/z 298.1 ([Mþ1]þ).
4.3.4. 4-Amino-5-benzoyl-2-(piperidin-1-yl)thiophene-3-
carbonitrile (1A{1,4}).3e Isolated yield: 82%. 1H NMR (CDCl3,
500 MHz):
d 7.73e7.63 (m, 2H), 7.51e7.38 (m, 3H), 7.05 (br s, 2H),
4.2.1. Preparation of 2,2-dicyanoethene-1,1-bis(thiolate) resin
5. Merrifield resin 2 (60.0 g, 77.4 mmol, 1.29 mmol/g) was treated
with potassium 2,2-dicyanoethene-1,1-bis(thiolate) (6)3a,c (50.0 g,
232.2 mmol) in DMF (600 mL). The reaction mixture was shaken at
room temperature for 12 h, and then filtered, washed several times
with H2O, DMF, MeOH, and CH2Cl2, and dried in a vacuum oven to
give 2,2-dicyanoethene-1,1-bis(thiolate) resin 5 (75.0 g): On-bead
ATR-FTIR (neat) 2185, 1337, 977 (cmꢀ1).
3.70e3.58 (m, 4H), 1.76e1.65 (m, 6H); 13C NMR (CDCl3, 125 MHz):
d
185.6, 167.3, 158.7, 141.2, 130.7, 128.5, 127.4, 115.8, 95.1, 77.7, 52.0,
25.4, 23.6; LCeMS (ESI) m/z 312.2 ([Mþ1]þ).
4.3.5. 4-Amino-5-benzoyl-2-morpholinothiophene-3-carbonitrile
(1A{1,5}).3e Isolated yield: 57%. 1H NMR (CDCl3, 500 MHz):
d
7.70e7.64 (m, 2H), 7.50e7.40 (m, 3H), 7.01 (br s, 2H), 3.85e3.79
(m, 4H), 3.67e3.60 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d
186.1,
167.8, 158.0, 140.9, 131.0, 128.6, 127.4, 115.3, 96.0, 79.1, 65.9, 50.2;
4.2.2. Preparation of thiophene resin 7 (R2¼COPh). A mixture of
resin 5 (5.00 g, theoretically 5.68 mmol), 2-bromoacetophenone (6)
(3.50 g, 17.04 mmol), and triethylamine (3.90 mL, 28.40 mmol) in
acetone (50 mL) was shaken at room temperature for 24 h and then
filtered, washed several times with H2O, MeOH, and CH2Cl2, and
dried in a vacuum oven to give thiophene resin 7{1} (6.20 g): On-
bead ATR-FTIR (neat) 3446, 3306, 1585, 1307 (cmꢀ1).
LCeMS (ESI) m/z 314.1 ([Mþ1]þ).
4.3.6. 4-Amino-5-benzoyl-2-(butylamino)thiophene-3-carbonitrile
(1A{1,6}). Isolated yield: 81%. 1H NMR (CDCl3, 500 MHz):
d
7.74e7.64 (m, 2H), 7.51e7.41 (m, 3H), 6.97 (br s, 2H), 5.57 (br s,
1H), 3.26e3.18 (m, 2H), 1.70e1.61 (m, 2H), 1.45e1.35 (m, 2H), 0.95
(t, 3H, J¼7.4 Hz); 13C NMR (CDCl3, 125 MHz):
d 185.9, 168.7, 157.2,
141.1, 130.8, 128.5, 127.3, 114.1, 95.8, 77.7, 47.2, 30.9, 20.0, 13.7;
4.2.3. Preparation of sulfonyl thiophene resin
8
(R2¼COPh). To
LCeMS (ESI) m/z 300.1 ([Mþ1]þ).
a mixture of sulfanyl resin 7{1} (4.00 g, theoretically 4.00 mmol) in
CH2Cl2 (30 mL) was added m-chloroperbenzoic acid (4.50 g,
20.0 mmol, 77% max) at 0 ꢂC. The reaction mixture was shaken at
room temperature for 12 h, and then quenched with saturated
NaHCO3 solution, filtered, washed several times with H2O, MeOH, and
CH2Cl2, and dried in avacuum oven to give sulfonyl resin 8{1} (3.90g):
On-bead ATR-FTIR (neat) 3460, 3335, 1591, 1448, 1125 (cmꢀ1).
4.3.7. 4-Amino-5-benzoyl-2-(isopropylamino)thiophene-3-
carbonitrile (1A{1,7}). Isolated yield: 27%. 1H NMR (CDCl3,
500 MHz):
d 7.73e7.63 (m, 2H), 7.51e7.40 (m, 3H), 6.97 (br s, 2H),
5.58 (br s, 1H), 3.62e3.47 (m, 1H), 1.30 (d, 6H, J¼6.4 Hz); 13C NMR
(CDCl3, 125 MHz):
d 185.9, 167.3, 157.0, 141.1, 130.8, 128.5, 127.4,
114.0, 95.7, 77.9, 50.2, 22.6; LCeMS (ESI) m/z 286.1 ([Mþ1]þ).
4.2.4. Preparation of 2-amino-thiophene-3-carbonitrile derivatives
1A{1,1} (R2¼COPh, R4¼NHBn). The sulfonyl resin 8{1} (250 mg, the-
oretically 0.24 mmol) in CHCl3 (5 mL) was treated with benzylamine
(4{1};0.13 mL,1.20mmol)andtriethylamine(0.17 mL,1.20mmol). The
reaction mixture was shaken at 45 ꢂC for 48 h. The reaction mixture
was filtered, washed several times with MeOH and CH2Cl2, and con-
centrated under reduced pressure in a centrifugal vacuum evaporator.
The residue was purified by silica gel column chromatography to give
4.3.8. 4-Amino-5-benzoyl-2-(phenylthio)thiophene-3-carbonitrile
(1A{1,8}). Isolated yield: 80%. 1H NMR (CDCl3, 500 MHz):
d
7.67e7.61 (m, 2H), 7.61e7.53 (m, 2H), 7.52e7.36 (m, 6H), 6.76 (br s,
2H); 13C NMR (CDCl3, 125 MHz):
d
187.4, 159.2, 155.8, 139.9, 134.2,
131.7, 130.6, 130.2, 129.8, 128.7, 127.7, 112.3, 109.6, 101.3; LCeMS
(ESI) m/z 337.1 ([Mþ1]þ).
4.3.9. 4-Amino-5-benzoyl-2-(propylthio)thiophene-3-carbonitrile
the
desired
4-amino-5-benzoyl-2-(benzylamino)thiophene-3-
(1A{1,9}). Isolated yield: 83%. 1H NMR (CDCl3, 500 MHz):
carbonitrile 1A{1,1} (Average 79% yield from Merrifield resin 2; first-
try reaction¼82% (66 mg) and second-try reaction¼75% (60 mg)).
d 7.78e7.66 (m, 2H), 7.58e7.41 (m, 3H), 6.82 (br s, 2H), 3.05 (t, 2H,
J¼7.2 Hz), 1.82e1.72 (m, 2H), 1.05 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3,
125 MHz): d 187.0,159.4,155.9,140.1,131.6, 128.7, 127.6,112.5, 108.5,
4.3. Characterization data of 2-amino-thiophene-3-
carbonitrile 1A
100.3, 37.7, 22.4, 13.3; LCeMS (ESI) m/z 303.1 ([Mþ1]þ).
4.3.10. Ethyl 3-amino-5-(benzylamino)-4-cyanothiophene-2-
4.3.1. 4-Amino-5-benzoyl-2-(benzylamino)thiophene-3-carbonitrile
carboxylate (1A{2,1}). Isolated yield: 27%. 1H NMR (DMSO-d6,
(1A{1,1}). Isolated yield: 79%.1H NMR (CDCl3, 500 MHz):
d
7.72e7.65
500 MHz): d 7.45e7.30 (m, 5H), 5.80 (br s, 2H), 5.72 (br s, 1H), 4.41
(m, 2H), 7.52e7.34 (m, 6H), 7.32e7.28 (m, 2H), 6.96 (br s, 2H), 5.94 (t,
(d, 2H, J¼5.5 Hz), 4.29e4.17 (m, 2H), 1.30 (t, 3H, J¼7.0 Hz); 13C NMR
1H, J¼4.5 Hz), 4.38 (d, 2H, J¼5.4 Hz); 13C NMR (CDCl3, 125 MHz):
(DMSO-d6, 125 MHz): d 166.7, 162.8, 155.0, 137.0, 128.5, 127.4, 127.3,
d
186.2, 168.0, 156.8, 140.9, 135.2, 130.9, 129.3, 128.8, 128.6, 128.0,
114.2, 80.6, 76.3, 59.0, 49.5, 14.5; LCeMS (ESI) m/z 302.1 ([Mþ1]þ).
127.4, 113.7, 96.1, 78.7, 51.3; LCeMS (ESI) m/z 334.1 ([Mþ1]þ).
4.3.11. Ethyl
phene-2-carboxylate (1A{2,2}). Isolated yield: 39%. 1H NMR (CDCl3,
500 MHz):
7.25 (d, 2H, J¼8.4 Hz), 6.90 (d, 2H, J¼8.5 Hz), 5.88 (br s,
3-amino-4-cyano-5-((4-methoxybenzyl)amino)thio-
4.3.2. 4-Amino-5-benzoyl-2-((4-methoxybenzyl)amino)thiophene-3-
carbonitrile (1A{1,2}). Isolated yield: 68%. 1H NMR (CDCl3,
d
500 MHz):
2H), 6.92e6.88 (m, 2H), 5.74 (t, 2H, J¼4.8 Hz), 4.32 (d, 2H, J¼5.4 Hz),
3.82 (s, 3H); 13C NMR (CDCl3, 125 MHz):
186.1, 167.8, 160.1, 156.8,
d
7.73e7.65 (m, 2H), 7.50e7.40 (m, 3H), 7.25e7.19 (m,
1H), 5.81 (br s, 2H), 4.32 (d, 2H, J¼5.4 Hz), 4.26e4.19 (m, 2H), 3.81
(s, 3H), 1.30 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3, 125 MHz):
d 166.4,
d
164.0, 159.9, 153.8, 129.4, 127.6, 114.5, 114.2, 84.2, 78.3, 60.0, 55.5,
141.0, 130.9, 129.5, 128.6, 127.4, 127.2, 114.7, 113.8, 96.1, 78.5, 55.5,
50.5, 14.7; LCeMS (ESI) m/z 332.1 ([Mþ1]þ).
50.8; LCeMS (ESI) m/z 364.1 ([Mþ1]þ).
4.3.12. Ethyl 3-amino-4-cyano-5-(pyrrolidin-1-yl)thiophene-2-
4.3.3. 4-Amino-5-benzoyl-2-(pyrrolidin-1-yl)thiophene-3-
carboxylate (1A{2,3}).3d Isolated yield: 90%. 1H NMR (CDCl3,
carbonitrile (1A{1,3}). Isolated yield: 85%. 1H NMR (CDCl3,
500 MHz):
d
5.85 (br s, 2H), 4.23 (q, 2H, J¼7.1 Hz), 3.67e3.58 (m,

9188
S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
4H), 2.13e2.02 (m, 4H), 1.31 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3,
NMR (CDCl3, 125 MHz): d 188.1, 166.3, 155.7, 115.3, 96.8, 79.4, 65.9,
125 MHz):
d
163.9, 162.8, 155.6, 116.5, 83.2, 76.3, 59.8, 51.4, 25.9,
50.2, 28.1; LCeMS (ESI) m/z 252.1 ([Mþ1]þ).
14.8; LCeMS (ESI) m/z 266.1 ([Mþ1]þ).
4.3.22. 5-Acetyl-4-amino-2-(butylamino)thiophene-3-carbonitrile
4.3.13. Ethyl 3-amino-4-cyano-5-(piperidin-1-yl)thiophene-2-
(1A{3,6}). Isolated yield: 44%. 1H NMR (CDCl3, 500 MHz):
d 6.65 (br
carboxylate (1A{2,4}). Isolated yield: 56%. 1H NMR (CDCl3,
s, 2H), 5.72 (br s, 1H), 3.26 (q, 2H, J¼7.0 Hz), 2.19 (s, 3H), 1.72e1.64
500 MHz):
d
5.82 (br s, 2H), 4.22 (q, 2H, J¼7.0 Hz), 3.62e3.57 (m,
(m, 2H), 1.47e1.39 (m, 2H), 0.98 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3,
4H), 1.75e1.64 (m, 6H), 1.30 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3,
125 MHz): d 187.8, 166.9, 154.9,114.0, 96.4, 77.8, 47.2, 31.0, 27.9, 20.1,
125 MHz):
d
166.3, 163.8, 155.4, 116.1, 83.6, 77.9, 59.9, 51.8, 25.3,
13.7; LCeMS (ESI) m/z 238.1 ([Mþ1]þ).
23.7, 14.7; LCeMS (ESI) m/z 280.1 ([Mþ1]þ).
4.3.23. 5-Acetyl-4-amino-2-(phenylthio)thiophene-3-carbonitrile
4.3.14. Ethyl 3-amino-5-(butylamino)-4-cyanothiophene-2-
(1A{3,8}). Isolated yield: 65%. 1H NMR (CDCl3, 500 MHz):
carboxylate (1A{2,6}). Isolated yield: 46%. 1H NMR (CDCl3,
d 7.64e7.59 (m, 2H), 7.54e7.45 (m, 3H), 6.48 (br s, 2H), 2.20 (s, 3H);
500 MHz):
d
5.82 (br s, 2H), 5.49 (br s, 1H), 4.23 (d, 2H, J¼6.6 Hz),
13C NMR (CDCl3, 125 MHz):
d 189.5, 157.9, 153.9, 134.5, 130.8, 130.3,
3.23 (q, 2H, J¼7.1 Hz), 1.70e1.62 (m, 2H), 1.46e1.37 (m, 2H), 1.31 (t,
129.6, 112.3, 110.4, 100.6, 28.4; LCeMS (ESI) m/z 275.0 ([Mþ1]þ).
3H, J¼7.1 Hz), 0.96 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3, 125 MHz):
d
167.0, 164.0, 154.0, 114.3, 83.7, 77.6, 59.9, 47.0, 31.0, 20.1, 14.8, 13.8;
4.3.24. 5-Acetyl-4-amino-2-(propylthio)thiophene-3-carbonitrile
LCeMS (ESI) m/z 268.1 ([Mþ1]þ).
(1A{3,9}). Isolated yield: 69%. 1H NMR (CDCl3, 500 MHz):
d 6.48 (br
s, 2H), 3.08 (t, 2H, J¼7.2 Hz), 2.32 (s, 3H), 1.86e1.76 (m, 2H), 1.08 (t,
4.3.15. Ethyl 3-amino-4-cyano-5-(phenylthio)thiophene-2-
3H, J¼7.4 Hz); 13C NMR (CDCl3,125 MHz):
d 189.1,157.0, 153.9,112.5,
carboxylate (1A{2,8}). Isolated yield: 90%. 1H NMR (CDCl3,
109.8, 100.8, 37.9, 28.4, 22.5, 13.3; LCeMS (ESI) m/z 241.0 ([Mþ1]þ).
500 MHz):
d 7.63e7.55 (m, 2H), 7.52e7.40 (m, 3H), 5.76 (br s, 2H),
4.23 (q, 2H, J¼7.1 Hz), 1.28 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3,
4.4. General procedure for the preparation of thiophene-3-
carbonitrile 1 on solid-phase
125 MHz): d 162.9,156.6,153.3,134.1,130.4,130.3,130.1,112.5,101.3,
101.0, 60.8, 14.5; LCeMS (ESI) m/z 305.1 ([Mþ1]þ).
A
typical procedure for the preparation of thiophene-3-
4.3.16. Ethyl 3-amino-4-cyano-5-(propylthio)thiophene-2-
carbonitrile, as exemplified for 5-benzoyl-2-((4-methoxybenzyl)
carboxylate (1A{2,9}). Isolated yield: 88%. 1H NMR (CDCl3,
amino)-4-((4-nitrophenyl)amino)thiophene-3-carbonitrile
(1
500 MHz):
d
5.76 (br s, 2H), 4.28 (q, 2H, J¼7.1 Hz), 3.04 (t, 2H,
{1,7,2}; R2¼COPh, R3¼4-NO2ePh, R4¼NHe4-MeOeBn) is as follows.
J¼7.2 Hz), 1.87e1.69 (m, 2H), 1.33 (t, 3H, J¼7.1 Hz), 1.06 (t, 3H,
J¼7.3 Hz); 13C NMR (CDCl3, 125 MHz):
d
162.8, 156.4, 153.3, 112.8,
4.4.1. Preparation of ((4-nitrophenyl)amino)thiophene resin 13
(R2¼COPh, R3¼4-NO2ePh). To a mixture of thiophene resin 7
(4.00 g, theoretically 4.00 mmol) in DMF (80 mL) was added so-
dium hydride (400 mg, 10.0 mmol) at 0 ꢂC. The reaction mixture
was shaken for 1 h, followed by adding 1-fluoro-4-nitrobenzene (12
{7}; 1.28 mL, 12.0 mmol) at room temperature. The reaction mix-
ture was shaken at room temperature for 22 h, and then filtered,
washed several times with H2O, MeOH, and CH2Cl2, and dried in
a vacuum oven to give 4-nitrophenyl substituted resin 13{1,7}
(75.0 g): On-bead ATR-FTIR (neat) 1597, 1510, 1334 (cmꢀ1).
101.0, 99.9, 60.8, 37.9, 22.5, 14.6, 13.3; LCeMS (ESI) m/z 271.0
([Mþ1]þ).
4.3.17. 5-Acetyl-4-amino-2-(benzylamino)thiophene-3-carbonitrile
(1A{3,1}). Isolated yield: 44%. 1H NMR (DMSO-d6, 500 MHz):
d
9.19
(br s, 1H), 7.58 (br s, 2H), 7.39e7.33 (m, 4H), 7.32e7.27 (m, 1H), 4.41
(s, 2H), 2.01 (s, 3H); 13C NMR (DMSO-d6, 125 MHz):
185.7, 166.6,
d
155.9, 136.9, 128.5, 127.5, 127.3, 114.0, 93.8, 76.2, 49.7, 27.6; LCeMS
(ESI) m/z 272.1 ([Mþ1]þ).
4.3.18. 5-Acetyl-4-amino-2-((4-methoxybenzyl)amino)thiophene-3-
4.4.2. Preparation of sulfonyl thiophene resin 14 (R2¼COPh, R3¼4-
NO2ePh). To a mixture of 4-nitrophenyl substituted resin 13{1,7}
(4.00 g, theoretically 3.57 mmol) in CH2Cl2 (80 mL) was added m-
chloroperbenzoic acid (4.00 g, 17.8 mmol, 77% max) at 0 ꢂC The
reaction mixture was shaken at room temperature for 24 h, and
then filtered, washed several times with H2O, MeOH, and CH2Cl2,
and dried in a vacuum oven to give sulfonyl resin 14{1,7} (3.90 g):
On-bead ATR-FTIR (neat) 1598, 1524, 1339 (cmꢀ1).
carbonitrile (1A{3,2}). Isolated yield: 44%. 1H NMR (CDCl3,
500 MHz):
2H), 5.78 (br s, 1H), 4.36 (d, 2H, J¼5.4 Hz), 3.83 (s, 3H), 2.19 (s, 3H);
13C NMR (CDCl3, 125 MHz):
188.0, 166.2, 160.0, 154.7, 129.4, 127.2,
d
7.28e7.24 (m, 2H), 6.92 (d, 2H, J¼8.6 Hz), 6.63 (br s,
d
114.6, 113.9, 96.8, 78.4, 55.5, 50.7, 28.0; LCeMS (ESI) m/z 302.1
([Mþ1]þ).
4.3.19. 5-Acetyl-4-amino-2-(pyrrolidin-1-yl)thiophene-3-
carbonitrile (1A{3,3}). Isolated yield: 36%. 1H NMR (DMSO-d6,
4.4.3. Preparation of thiophene-3-carbonitrile derivatives
1
500 MHz):
d
7.55 (br s, 2H), 3.66e3.50 (m, 4H), 2.07 (s, 3H),
185.6, 161.9,
(R2¼COPh, R3¼4-NO2ePh, R4¼NH-4-MeOeBn). The sulfonyl resin 14
{1,7} (250 mg, theoretically 0.21 mmol) in CHCl3 (5 mL) was treated
with 4-methoxybenzylamine (4{2}; 0.11 mL, 0.86 mmol) and trie-
thylamine (0.09 mL, 0.65 mmol). The reaction mixture was shaken at
45 ꢂC for 48h. Thereactionmixturewasfiltered, washed several times
with MeOH and CH2Cl2, and concentrated under reduced pressure
using a centrifugal vacuum evaporator. The residue was purified by
silica gel column chromatography to give the desired 5-benzoyl-2-
((4-methoxybenzyl)amino)-4-((4-nitrophenyl)amino)thiophene-3-
carbonitrile 1{1,7,2} (13 mg, 12% from Merrifield resin 2).
2.03e1.91 (m, 4H); 13C NMR (DMSO-d6, 125 MHz):
d
156.9, 115.8, 94.0, 75.0, 51.5, 27.8, 25.3; LCeMS (ESI) m/z 236.1
([Mþ1]þ).
4.3.20. 5-Acetyl-4-amino-2-(piperidin-1-yl)thiophene-3-carbonitrile
(1A{3,4}). Isolated yield: 41%. 1H NMR (DMSO-d6, 500 MHz):
d
7.50
(br s, 2H), 3.69e3.57 (m, 4H), 2.08 (s, 3H), 1.70e1.58 (m, 6H); 13C
NMR (DMSO-d6, 125 MHz):
d 186.0, 165.3, 156.7, 115.4, 90.5, 76.4,
51.4, 27.8, 24.8, 22.9; LCeMS (ESI) m/z 250.1 ([Mþ1]þ).
4.3.21. 5-Acetyl-4-amino-2-morpholinothiophene-3-carbonitrile (1A
4.5. Characterization data of thiophene-3-carbonitrile 1
{3,5}).3e Isolated yield: 48%. 1H NMR (DMSO-d6, 500 MHz):
d
7.50
(br s, 2H), 3.78e3.72 (m, 4H), 3.63e3.57 (m, 4H), 2.11 (s, 3H); 13C
4.5.1. 5-Benzoyl-2-((4-methoxybenzyl)amino)-4-((4-nitrophenyl)
amino)thiophene-3-carbonitrile (1{1,7,2}). Isolated yield: 12%. 1H

S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
9189
NMR (CDCl3, 500 MHz):
d
11.26 (br s,1H), 8.24 (d, 2H, J¼8.9 Hz), 7.73
119.9, 114.7, 113.9, 92.6, 79.9, 60.9, 55.5, 50.7, 14.6; LCeMS (ESI) m/z
453.1 ([Mþ1]þ).
(d, 2H, J¼7.3 Hz), 7.59e7.44 (m, 3H), 7.30 (d, 2H, J¼8.9 Hz), 7.21 (d,
2H, J¼8.5 Hz), 6.90 (d, 2H, J¼8.5 Hz), 6.15 (t, 1H, J¼4.8 Hz), 4.33 (d,
2H, J¼5.3 Hz), 3.82 (s, 3H); 13C NMR (CDCl3, 125 MHz):
d
187.06,
4.5.9. Ethyl 4-cyano-3-((4-nitrophenyl)amino)-5-(pyrrolidin-1-yl)
169.24, 160.16, 151.44, 145.03, 144.22, 140.22, 131.60, 129.51, 128.76,
127.71, 126.61, 125.16, 122.08, 114.72, 113.61, 100.92, 79.23, 55.53,
50.85; LCeMS (ESI) m/z 485.1 ([Mþ1]þ).
thiophene-2-carboxylate (1{2,7,3}). Isolated yield: 21%. 1H NMR
(CDCl3, 500 MH):
d
8.77 (br s, 1H), 8.18 (d, 2H, J¼9.0 Hz), 7.12 (d, 2H,
J¼9.0 Hz), 4.27 (q, 2H, J¼7.1 Hz), 3.73e3.61 (m, 4H), 2.17e2.06 (m,
4H), 1.33 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3, 125 MHz):
d 163.9, 163.4,
4.5.2. 5-Benzoyl-4-((4-nitrophenyl)amino)-2-(pyrrolidin-1-yl)thio-
149.2, 147.0, 142.6, 125.4, 118.7, 115.7, 93.7, 79.2, 60.8, 52.0, 25.9,
phene-3-carbonitrile (1{1,7,3}). Isolated yield: 16%. 1H NMR (CDCl3,
14.6; LCeMS (ESI) m/z 387.1 ([Mþ1]þ).
500 MHz):
7.56e7.51 (m, 1H), 7.51e7.43 (m, 2H), 7.30e7.26 (m, 2H), 3.75e3.63
(m, 4H), 2.15e2.07 (m, 4H); 13C NMR (CDCl3, 125 MHz):
186.6,
d 11.12 (br s, 1H), 8.28e8.19 (m, 2H), 7.76e7.68 (m, 2H),
4.5.10. Ethyl 4-cyano-3-((4-nitrophenyl)amino)-5-(piperidin-1-yl)
d
thiophene-2-carboxylate (1{2,7,4}). Isolated yield: 16%. 1H NMR
165.6, 153.3, 145.8, 143.6, 140.4, 131.5, 128.7, 127.8, 125.2, 120.9,
(CDCl3, 500 MHz):
d
8.72 (br s, 1H), 8.19 (d, 2H, J¼9.0 Hz), 7.14e7.06
115.4, 101.7, 78.7, 52.3, 25.9; LCeMS (ESI) m/z 419.1 ([Mþ1]þ).
(m, 2H), 4.27 (q, 2H, J¼7.1 Hz), 3.69e3.63 (m, 4H), 1.80e1.70 (m,
6H), 1.33 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3, 125 MHz):
d 167.9, 163.3,
4.5.3. 5-Benzoyl-4-((4-nitrophenyl)amino)-2-(piperidin-1-yl)thio-
149.1, 147.0, 142.7, 125.4, 118.6, 115.3, 94.3, 81.4, 60.9, 52.3, 25.4,
phene-3-carbonitrile (1{1,7,4}). Isolated yield: 20%. 1H NMR (CDCl3,
23.6, 14.6; LCeMS (ESI) m/z 401.1 ([Mþ1]þ).
500 MHz):
7.56e7.51 (m, 1H), 7.51e7.43 (m, 2H), 7.27e7.21 (m, 2H), 3.72e3.64
(m, 4H), 1.80e1.69 (m, 6H); 13C NMR (CDCl3, 125 MHz):
186.9,
d 11.02 (br s, 1H), 8.28e8.17 (m, 2H), 7.77e7.68 (m, 2H),
4.5.11. Ethyl 5-(butylamino)-4-cyano-3-((4-nitrophenyl)amino)thio-
d
phene-2-carboxylate (1{2,7,6}). Isolated yield: 22%. 1H NMR
169.4, 153.1, 145.9, 143.5, 140.3, 131.6, 128.7, 127.8, 125.2, 120.6,
(CDCl3, 500 MHz):
d
8.97 (br s, 1H), 8.20 (d, 2H, J¼9.0 Hz),
115.0, 101.7, 80.4, 52.6, 25.5, 23.6; LCeMS (ESI) m/z 433.2 ([Mþ1]þ).
7.20e7.10 (m, 2H), 5.73 (br t, 1H, J¼5.3 Hz), 4.28 (q, 2H, J¼7.1 Hz),
3.26 (q, 2H, J¼7.0 Hz), 1.71e1.63 (m, 2H), 1.47e1.38 (m, 2H), 1.34
(t, 3H, J¼7.1 Hz), 0.96 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3,
4.5.4. 5-Benzoyl-2-morpholino-4-((4-nitrophenyl)amino)thiophene-
3-carbonitrile (1{1,7,5}). Isolated yield: 8%. 1H NMR (CDCl3,
125 MHz): d 168.1, 163.9, 147.8, 146.1, 143.3, 125.4, 119.9, 114.0,
500 MHz):
d
10.90 (br s, 1H), 8.24 (d, 2H, J¼9.0 Hz), 7.74 (d, 2H,
92.0, 79.2, 60.8, 47.2, 30.8, 20.1, 14.6, 13.7; LCeMS (ESI) m/z 389.1
J¼7.2 Hz), 7.58e7.52 (m, 1H), 7.51e7.43 (m, 2H), 7.28e7.24 (m, 2H),
([Mþ1]þ).
3.89e3.82 (m, 4H), 3.71e3.63 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d
187.3, 169.9, 152.5, 145.7, 143.7, 140.0, 131.9, 128.8, 127.9, 125.3,
4.5.12. Ethyl 4-cyano-3-((4-nitrophenyl)amino)-5-(phenylthio)thio-
120.8, 114.6, 102.8, 82.0, 65.9, 50.7; LCeMS (ESI) m/z 435.1
phene-2-carboxylate (1{2,7,8}). Isolated yield: 34%. 1H NMR (CDCl3,
([Mþ1]þ).
500 MHz):
d
8.65 (br s, 1H), 8.22 (d, 2H, J¼9.0 Hz), 7.69e7.62 (m,
2H), 7.57e7.49 (m, 3H), 7.12 (d, 2H, J¼9.0 Hz), 4.27 (q, 2H, J¼7.1 Hz),
4.5.5. 5-Benzoyl-2-(butylamino)-4-((4-nitrophenyl)amino)thio-
1.29 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3, 125 MHz):
d 162.5, 160.4,
phene-3-carbonitrile (1{1,7,6}). Isolated yield: 16%. 1H NMR (CDCl3,
147.7, 146.0,143.4,134.8, 131.1, 130.5, 129.3,125.5,119.5, 112.2, 109.8,
500 MHz):
d
11.30 (br s, 1H), 8.25 (d, 2H, J¼9.0 Hz), 7.77e7.70 (m,
102.2, 61.7, 14.3; LCeMS (ESI) m/z 426.1 ([Mþ1]þ).
2H), 7.59e7.44 (m, 3H), 7.31 (d, 2H, J¼9.0 Hz), 5.98 (t, 1H, J¼5.3 Hz),
3.23 (q, 2H, J¼7.0 Hz), 1.67e1.60 (m, 2H), 1.43e1.33 (m, 2H), 0.93 (t,
4.5.13. Ethyl 4-cyano-3-((4-nitrophenyl)amino)-5-(propylthio)thio-
3H, J¼7.4 Hz); 13C NMR (CDCl3, 125 MHz):
d
187.0, 170.0, 151.7, 145.1,
phene-2-carboxylate (1{2,7,9}). Isolated yield: 43%. 1H NMR (CDCl3,
144.2, 140.3, 131.5, 128.8, 127.7, 125.1, 122.1, 113.7, 100.6, 78.6, 47.4,
500 MHz):
d
8.67 (br s,1H), 8.27e8.15 (m, 2H), 7.11 (d, 2H, J¼9.0 Hz),
30.7, 20.0, 13.7; LCeMS (ESI) m/z 421.1 ([Mþ1]þ).
4.34 (q, 2H, J¼7.1 Hz), 3.12 (t, 2H, J¼7.2 Hz), 1.90e1.79 (m, 2H), 1.37
(t, 3H, J¼7.1 Hz), 1.10 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3, 125 MHz):
4.5.6. 5-Benzoyl-4-((4-nitrophenyl)amino)-2-(phenylthio)thio-
d 162.4, 159.0, 147.7, 146.0, 143.4, 125.5, 119.4, 112.3, 109.0, 102.6,
phene-3-carbonitrile (1{1,7,8}). Isolated yield: 25%. 1H NMR (CDCl3,
61.7, 37.8, 22.4, 14.4, 13.3; LCeMS (ESI) m/z 392.1 ([Mþ1]þ).
500 MHz):
d
10.40 (br s, 1H), 8.25 (d, 2H, J¼9.0 Hz), 7.69 (d, 2H,
J¼7.3 Hz), 7.65e7.60 (m, 2H), 7.56e7.41 (m, 6H), 7.25 (d, 2H,
4.5.14. 5-Acetyl-4-((4-nitrophenyl)amino)-2-(pyrrolidin-1-yl)thio-
J¼9.2 Hz); 13C NMR (CDCl3, 125 MHz):
d
187.9, 162.8, 150.1, 145.2,
phene-3-carbonitrile (1{3,7,3}). Isolated yield: 10%. 1H NMR (CDCl3,
144.0, 139.0, 134.7, 132.6, 131.2, 130.5, 128.9, 128.8, 128.2, 125.4,
500 MHz):
d 10.54 (br s, 1H), 8.24e8.15 (m, 2H), 7.23e7.15 (m, 2H),
121.0, 116.3, 112.0, 101.7; LCeMS (ESI) m/z 458.1 ([Mþ1]þ).
3.75e3.65 (m, 4H), 2.29 (s, 3H), 2.16e2.10 (m, 4H); 13C NMR (CDCl3,
125 MHz): d 188.8,164.0,151.1,145.9,143.4,125.1,120.6,115.4,102.6,
4.5.7. 5-Benzoyl-4-((4-nitrophenyl)amino)-2-(propylthio)thiophene-
78.4, 52.3, 28.6, 25.9; LCeMS (ESI) m/z 357.1 ([Mþ1]þ).
3-carbonitrile (1{1,7,9}). Isolated yield: 30%. 1H NMR (CDCl3,
500 MHz):
d
10.47 (br s, 1H), 8.29e8.20 (m, 2H), 7.84e7.76 (m, 2H),
4.5.15. 5-Acetyl-2-(butylamino)-4-((4-nitrophenyl)amino)thio-
7.61 (t, 1H, J¼7.4 Hz), 7.53 (t, 2H, J¼7.6 Hz), 7.30e7.22 (m, 2H), 3.11
phene-3-carbonitrile (1{3,7,6}). Isolated yield: 10%. 1H NMR (CDCl3,
(t, 2H, J¼7.2 Hz), 1.88e1.78 (m, 2H), 1.08 (t, 3H, J¼7.4 Hz); 13C NMR
500 MHz):
d
10.75 (br s, 1H), 8.23 (d, 2H, J¼8.9 Hz), 7.24 (d, 2H,
(CDCl3, 125 MHz):
d
187.7, 162.0, 150.3, 145.2, 144.1, 139.2, 132.6,
J¼8.9 Hz), 5.73 (s, 1H), 3.30 (q, 2H, J¼6.9 Hz), 2.31 (s, 3H),
129.0, 128.2, 125.3, 121.1, 115.3, 112.2, 101.4, 37.7, 22.2, 13.4; LCeMS
1.75e1.65 (m, 2H), 1.49e1.39 (m, 2H), 0.99 (t, 3H, J¼7.4 Hz); 13C
(ESI) m/z 424.1 ([Mþ1]þ).
NMR (CDCl3, 125 MHz):
d 189.0, 168.2, 149.6, 145.1, 144.2, 125.1,
121.9, 113.7, 101.3, 78.6, 47.4, 30.9, 28.4, 20.1, 13.7; LCeMS (ESI) m/z
4.5.8. Ethyl 4-cyano-5-((4-methoxybenzyl)amino)-3-((4-
359.1 ([Mþ1]þ).
nitrophenyl)amino)thiophene-2-carboxylate
(1{2,7,2}). Isolated
yield: 12%. 1H NMR (CDCl3, 500 MHz):
d
8.97 (br s, 1H), 8.20 (d, 2H,
4.5.16. 5-Acetyl-4-((4-nitrophenyl)amino)-2-(phenylthio)thiophene-
J¼8.7 Hz), 7.31e7.22 (m, 2H), 7.15 (d, 2H, J¼8.7 Hz), 6.92 (d, 2H,
J¼8.2 Hz), 5.98 (br s, 1H), 4.36 (d, 2H, J¼5.1 Hz), 4.28 (q, 2H,
J¼7.0 Hz), 3.83 (s, 3H), 1.34 (t, 3H, J¼7.0 Hz); 13C NMR (CDCl3,
3-carbonitrile (1{3,7,8}). Isolated yield: 16%. 1H NMR (CDCl3,
500 MHz):
d
10.03 (br s, 1H), 8.24 (d, 2H, J¼9.0 Hz), 7.67 (d, 2H,
J¼7.1 Hz), 7.61e7.50 (m, 3H), 7.21 (d, 2H, J¼8.9 Hz), 2.31 (s, 3H); 13
C
125 MHz):
d
167.4,163.8,160.1, 147.6,146.1,143.3,129.5,127.0,125.4,
NMR (CDCl3, 125 MHz): d 190.3, 161.7, 148.7, 145.0, 144.2, 135.0,

9190
S. Lee et al. / Tetrahedron 70 (2014) 9183e9190
2. (a) Weinstock, J.; Wu, J.; Cao, P.; Kingsbury, W. D.; McDermott, J. L.; Kodrasov,
M. P.; McKelvey, D. M.; Kumar, K. G. S.; Goldenberg, S. J.; Mattern, M. R.;
Nicholson, B. ACS Med. Chem. Lett. 2012, 3, 789e792; (b) Lethu, S.; Dubois, J.
Eur. J. Org. Chem. 2011, 3920e3931; (c) Lethu, S.; Bosc, D.; Mouray, E.; Grellier,
P.; Dubois, J. J. Enzyme Inhib. Med. Chem. 2013, 28, 163e171; (d) Gouda, M. A.;
Berghot, M. A.; Baz, E. A.; Hamama, W. S. Med. Chem. Res. 2012, 21,
1062e1070; (e) Fadda, A. A.; Berghot, M. A.; Amer, F. A.; Badawy, D. S.;
Bayoumy, N. M. Arch. Pharm. 2012, 345, 378e385; (f) Huang, Q.; Richardson,
P. F.; Sach, N. W.; Zhu, J.; Liu, K. K.-C.; Smith, Q. H. Org. Process Res. Dev. 2011,
15, 556e564.
131.4, 130.6,128.9,125.3,121.3,116.7,112.0,100.9, 28.9; LCeMS (ESI)
m/z 396.0 ([Mþ1]þ).
4.5.17. 5-Acetyl-4-((4-nitrophenyl)amino)-2-(propylthio)thiophene-
3-carbonitrile (1{3,7,9}). Isolated yield: 15%. 1H NMR (CDCl3,
500 MHz):
d 10.07 (br s, 1H), 8.29e8.18 (m, 2H), 7.24e7.15 (m, 2H),
3.14 (t, 2H, J¼7.2 Hz), 2.45 (s, 3H), 1.91e1.82 (m, 2H), 1.12 (t, 3H,
J¼7.4 Hz); 13C NMR (CDCl3, 125 MHz):
d 190.0, 159.9, 148.8, 145.1,
144.2, 125.3, 121.3, 116.1, 112.2, 101.5, 37.9, 28.9, 22.3, 13.4; LCeMS
3. (a) Zubarev, A. A.; Larionova, N. A.; Rodinovskaya, L. A.; Mortikov, V. Y.; Shes-
topalov, A. M. ACS Comb. Sci. 2013, 15, 546e550; (b) Shestopalov, A. M.; Lar-
ionova, N. A.; Fedorov, A. E.; Rodinovskaya, L. A.; Mortikov, V. Y.; Zubarev, A. A.;
Bushmarinov, I. S. ACS Comb. Sci. 2013, 15, 541e545; (c) Zubarev, A. A.; Shesto-
palov, A. M.; Larionova, N. A.; Rodinovskaya, L. A.; Shestopalov, A. A. Tetrahedron
2013, 69, 9648e9655; (d) Thomae, D.; Perspicace, E.; Henryon, D.; Xu, Z.;
Schneider, S.; Hesse, S.; Kirsch, G.; Seck, P. Tetrahedron 2009, 65, 10453e10458;
(ESI) m/z 362.1 ([Mþ1]þ).
Acknowledgements
€
(e) Gruner, M.; Bottcher, G.; Gewald, K. J. Heterocycl. Chem. 2008, 45, 1071e1076;
This research was supported by the National Research Founda-
tion of Korea (NRF) grants (NRF-2014R1A1A1037635) from the
Basic Science Research Program, the Ministry of Education, Science
and Technology, Korea; and by a grant from the Korea Health
Technology R&D Project, Ministry of Health & Welfare, Korea
(A111345).
(f) Liu, M.-G.; Hu, Y.-G.; Ding, M.-W. Tetrahedron 2008, 64, 9052e9059; (g) Be-
gouin, A.; Hesse, S.; Queiroz, M.-J. R. P.; Kirsch, G. Eur. J. Org. Chem. 2007,
1678e1682; (h) Le Foulon, F.-X.; Braud, E.; Fabis, F.; Lancelot, J. C.; Rault, S. J.
Comb. Chem. 2005, 7, 253e257.
4. Stephensen, H.; Zaragoza, F. J. Org. Chem. 1997, 62, 6096e6097.
5. (a) Traversone, A.; Brill, W. K.-D. Tetrahedron Lett. 2007, 48, 3535e3538; (b)
Zaragoza, F. Tetrahedron Lett. 1996, 37, 6213e6216.
6. (a) Lee, T.; Lee, D.; Lee, I. Y.; Gong, Y.-D. J. Comb. Chem. 2010, 12, 95e99; (b) Lee,
T.; Park, J.-H.; Lee, D.-H.; Gong, Y.-D. J. Comb. Chem. 2009, 11, 495e499; (c) Lee, T.;
Park, J.-H.; Jeon, M.-K.; Gong, Y.-D. J. Comb. Chem. 2009, 11, 288e293.
7. (a) Luo, L.; Meng, L.; Sun, Q.; Ge, Z.; Li, R. Tetrahedron Lett. 2014, 55, 259e263; (b)
Shestopalov, A. M.; Rodinovskaya, L. A.; Shestopalov, A. A. J. Comb. Chem. 2010,
12, 9e12.
8. (a) Sasikumar, T. K.; Qiang, L.; Burnett, D. A.; Greenlee, W. J.; Li, C.; Grilli, M.;
Bertorelli, R.; Lozza, G.; Reggiani, A. Bioorg. Med. Chem. Lett. 2010, 20, 2474e2477;
(b) Briel, D. Pharmazie 1998, 53, 775e781.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.030.
References and notes
9. In solution model system, acylation and sulfonylation products were obtained in
moderate yields (see Supplementary data).
1. Selected reviews: (a) Lima, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23e49;
(b) Olesen, P. H. Curr. Opin. Drug Discovery Dev. 2001, 4, 471e478; (c) Patani, G. A.;
Edmond, J.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147e3176.