Dimedone-catalyzed addition of amines into cyano group: Facile synthesis of thiazol-2-yl substituted E-acrylonitriles

Article abstract of DOI:10.1002/cjoc.201100719

An efficient dimedone-catalyzed synthesis of highly functionalized thiazol-2-yl substituted E-acrylonitrile derivatives has been established through two-step reaction of α-thiocyanate ketones with malononitrile and amines. The α-thiocyanate ketones were s

Full text of DOI:10.1002/cjoc.201100719

FULL PAPER
DOI: 10.1002/cjoc.201100719
Dimedone-catalyzed Addition of Amines into Cyano Group:
Facile Synthesis of Thiazol-2-yl Substituted E-Acrylonitriles
Zhu, Weijunb(朱伟军)
Tu, Xingchaoa(屠兴超)
Feng, Huia(冯惠)
Tu, Mansua(屠蔓苏)
Jiang, Bo*,a(姜波)
Wu, Feiyuea(吴飞跃)
Tu, Shujiang*,a(屠树江)
a School of Chemistry and Chemical Engineering, Laboratory of Green Synthetic Chemistry for Functional Materi-
als, Xuzhou Normal University, Xuzhou, Jiangsu 221116, China
b School of Chemical Engineering and Technology, Xuzhou College of Industrial Technology, Xuzhou, Jiangsu
221000, China
An efficient dimedone-catalyzed synthesis of highly functionalized thiazol-2-yl substituted E-acrylonitrile de-
rivatives has been established through two-step reaction of α-thiocyanate ketones with malononitrile and amines.
The α-thiocyanate ketones were subjected with malononitrile to provide thiazol-2-ylidenemalononitrile derivatives,
followed with various amines in the presence of dimedone to yield the final thiazol-2-yl substituted acrylonitrile de-
rivatives.
Keywords dimedone-catalyzed synthesis, E-acrylonitriles, addition reaction, microwave heating, heterocycles
Introduction
macological activities.[6] They were also widely used in
the preparation of antibiotics and antiphlogistics,[7] such
as penicillin and vitamin B1. The thiazole motif is one
of the significant core structures among the most exten-
sively natural and unnatural heterocyclic compounds
with remarkable medicinal activities such as anti-
inflammatory,[8] antinociceptive activity,[9] and antican-
cer.[10] However, (Z)-3-amino-2-(thiazol-2-yl)-acrylo-
nitriles (II) as important intermediates in organic syn-
thesis were nearly neglected or not explored thoroughly
so far (Scheme 1).
Organic functional group transformations (OFGTs)
continue to be an area of vital concernment in the fields
of organic synthesis and chemical biology.[1] The aim of
OFGTs was to realize the collections of functionally and
regiochemically diverse small molecules, particularly
those possessing skeletons found in natural products or
drug-like molecules.[2] Further chemical modifications
of the natural product frameworks or drug-like molecule
units such as direct functional groups transformations
have allowed expansion of the research of structure-
activity relationships, affording new insights into the
molecular interactions. In the other hand, the OFGTs on
the specific position of bioactive molecules will lead to
great improvements of their biological and pharmacol-
ogical activities.[3] Thus, the organic functional group
transformations have been attracted much attention.[4]
As one of the most important functional groups, a cyano
group was usually converted into amines, imines, am-
ides, amidines, imidates and carboxylic acids etc.[3]
Among them, the preparation of enamines was through
the addition of amines into cyano group catalyzed by
metal catalyst[5a-5c] or stronger bases[5d] or N-trimethyl-
silylamines.[5e] However, to the best of our knowledge,
facile transformation of cycno group to enamines cata-
lyzed by easily available and cheap dimedone was not
reported so far.
Scheme 1
N
S
H2N
CN
N
S
N
O
Thiazole (I)
2-(thiazol-2-yl)acrylonitrile (II)
Over the past several years, our group have devel-
oped various domino reactions that can offer easy ac-
cess to useful functionalized multiple ring structures of
chemical and pharmaceutical interest.[11,12] For example,
a new four-component domino reaction was established
as to provide an easy access to the synthesis of multi-
functionalized quinazoline[11a] and tricyclo[6.2.2.0[1,6]]-
dodecanes derivatives.[11b] Recently, we have also found
Thiazoles (I) and its derivatives exist widely in bio-
active molecules because of its physiological and phar-
*
E-mail: jiangchem@xznu.edu.cn (B. Jiang); laotu@xznu.edu.cn (S-J. Tu); Fax: 86(516) 83500065
Received December 19, 2011; accepted February 15, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100719 or from the author.
Chin. J. Chem. 2012, XX, 1—7
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Zhu et al.
FULL PAPER
that the domino reaction of Meldrum’s acid, aromatic
aldehydes and electron-rich heteroaryl-amines in aque-
ous phase under microwave (MW) irradiation led to the
multifunctionalized spiro{[1,3]dioxanes-pyridine}-4,6-
dione with high chemo-, regio- and stereoselectivity and
good yields.[11c]
As a part of our continuing interest in the develop-
ment of new domino reaction and new organocata-
lysts[11] in heterocyclic compounds, in this paper, we
would like to report a new route to a set of thiazol-2-yl
substituted E-acrylonitrile derivatives that are of chemi-
cal and biomedical importance using readily available
α-thiocyanate ketones, malononitrile and amines as
starting materials. This reaction was achieved through
two-step strategy which was shown in Scheme 2. Inter-
estingly, during second-step reaction process dimedone
as a new and efficient catalyst provided a series of thia-
zol-2-yl substituted E-acrylonitrile derivatives 5 with
good yields.
tion conditions. Experiments were carried out in various
bases such as K2CO3, Et3N, and DMAP. The incomplete
reactions were observed using these bases. Next, the
similar reaction was conducted in the presence of 1.0
equiv. of different cyclic-1,3-dicarbonyls with high re-
activity, such as tetronic acid, Meldrum's acid, 1,3-
cyclo-hexanedione, and dimedone. As shown in Table 1,
the use of dimedone allowed the direct conversion of
thiazol-2-ylidenemalononitriles 3a into the corresponding
thiazol-2-yl substituted acrylonitrile 5a in a yield of
52% at 90 ℃ for 25 min under microwave irradiation
condition (Table 1, Entry 4). Other cyclic-1,3-dicar-
bonyls gave much lower yields of 40%—47% (Table 1,
Entries 1—3). Subsequently, the reaction was per-
formed in EtOH and repeated many times at different
temperatures in a sealed vessel under microwave irra-
Scheme 3
H
N
Ar
O
Ar
CN
CN
CN
20% KOH EtOH
r.t.
+
Scheme 2
SCN
CN
S
1a
3a
2
Ar
Ar
Ar
O
CN
20% KOH EtOH
r.t.
HN
NC
S
+
O
S
HN
NC
CN
SCN
CN
1
O
2
3
HN
O
H2N
O
O
Ar
+
3a
6a
EtOH, MW
O
N
S
R2
NH2
20 mol% Dimedone
Ar
N
N
S
H2N
R1
3
HN
+
EtOH, 130 oC
Sealed MW
CN
R1
N
NC
4
R2
5a
5
Ar = 4-Nitrophenyl
Results and Discussion
The α-thiocyanate ketones, possessing four high re-
activity centers including two electrophilic centers and
two nucleophilic centers, have proven to be important
building blocks for the construction of important hetero-
cyclic frameworks.[12] Our strategy of synthesizing the
highly multifunctionalized thiazol-2-yl substituted
E-acrylonitrile was through the reaction of a preformed
thiazol-2-ylidenemalononitriles with an amine. The
preparation of thiazol-2-ylidenemalononitriles was
commonly achieved in the presence of potassium hy-
droxide at room temperature for 2 h.[12b] We then started
this synthesis by conducting the reaction of thiazol-2-
ylidenemalononitriles (3a) with dimedone in the pres-
ence of morpholine in EtOH. The expected compound
6a was not obtained (Scheme 3). All of the analytical
data showed that morpholine unit was introduced in the
final product, and dimedone did not take part in this
reaction. Thus a new thiazol-2-yl substituted E-acrylo-
nitrile 5a was produced and its structure was further
confirmed by single crystal X-ray (Figure 1).[13]
Figure 1 X-ray crystallography structure of compound 5a.
Table 1 Catalyst optimization for the synthesis of 5a under
MW
Entry Catalyst
T/℃ Time/min Yielda/%
1
2
3
4
5
6
7
8
Tetronic acid
1.0 90
1.0 90
1.0 90
1.0 90
0.6 130
0.4 130
0.2 130
0.1 130
43
40
47
52
76
76
78
65
Meldrum's acid
1,3-Cyclohexanedione
Dimedone
Dimedone
Dimedone
Dimedone
Encouraged by the above interesting results, we de-
voted our efforts to the study of the reaction of 3a with
morpholine 4a as a model reaction to optimize the reac-
Dimedone
a Isolated yield.
2
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—7

Facile Synthesis of Thiazol-2-yl Substituted E-Acrylonitriles
diation for 25 min. The yield of product 5a was in-
creased from 52% to 78% as the temperature varied
from 90 to 130 ℃. When 0.2 equiv. of dimedone was
employed as a promoter in this reaction, the yield of
product 5a was slightly raised to 78% at 130 ℃ (Table
1, Entry 7).
With this result in hand, we went on to study the
scope of the methodology. Using the optimized reaction
conditions, a variety of structurally diverse thiazol-2-
ylidenemalononitriles were investigated, and a series of
new thiazol-2-yl substituted E-acrylonitriles were syn-
thesized in good yields. As shown in Table 2, at the be-
ginning, we made a search for the thiazol-2-ylidene-
malononitriles scope, morpholine 4a was used as model
substrate (Table 2), and the results indicated that sub-
strates 3 bearing either electron donating or electron
withdrawing functional groups such as nitro, chloro, or
methoxyl were able to affect the synthesis of compound
5.
To further expand the scope of amine substrates,
different substrates 3 were subjected to examine various
amines including secondary amines 4b—4f (piperidine
4b, 4-methylpiperidine 4c, dimethylamine 4d, diethyl-
amine 4e, piperazine 4f) and aromatic amines 4g—4i
Table 2 Synthesis of compounds 5 under microwave irradiation
Entry
Product
Ar'
Amine
Time/min Yield/%
1
2
4-Nitrophenyl
3-Nitrophenyl
3-Chlorophenyl
Phenyl
Morpholine
Morpholine
Morpholine
Morpholine
25
25
30
35
35
35
35
40
40
40
78
75
73
74
76
72
70
69
70
65
5a
5b
5c
5d
5e
5f
CN
N
S
N
O
Ar
3
H2N
4
5a—5e
5
4-Methoxyphenyl Morpholine
6
4-Nitrophenyl
3-Nitrophenyl
3-Chlorophenyl
Phenyl
Piperidine
Piperidine
Piperidine
Piperidine
CN
S
7
5g
5h
5i
N
N
Ar
8
H2N
9
5f—5j
10
4-Methoxyphenyl Piperidine
5j
CN
S
N
N
Ar
11
4-Nitrophenyl
4-Methylpiperidine
35
67
5k
H2N
5k
12
13
4-Nitrophenyl
3-Nitrophenyl
Dimethylamine
Dimethylamine
30
30
74
72
5l
CN
S
Me
Me
5m
N
N
Ar
H2N
14
15
Phenyl
Dimethylamine
32
35
69
71
5n
5o
5l—5o
4-Methoxyphenyl Dimethylamine
4-Nitrophenyl Diethylamine
CN
S
N
Et
16
35
72
5p
N
Ar
H2N
Et
17
18
19
4-Methoxyphenyl Diethylamine
35
30
33
68
69
67
5q
5r
5s
5p—5q
3-Nitrophenyl
Piperazine
Piperazine
CN
S
N
NH2
Ar
N
N
N
Ar
3-Chlorophenyl
H2N
S
NC
20
4-Methoxyphenyl Piperazine
35
71
5t
5r—5t
CN
21
22
3-Nitrophenyl
3-Nitrophenyl
4-Chlorobenzenamine
27
28
75
71
S
N
5u
5v
X
H
N
4-Bromobenzenamine
Ar
H2N
23
Phenyl
4-Methlybenzenamine
30
74
5w
5u—5w
Chin. J. Chem. 2012, XX, 1—7
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Zhu et al.
FULL PAPER
－
1
1
(4-chlorobenzenamine 4g, 4-bromobenzenamine 4h,
4-methoxybenzenamine 4i). In all these cases, the reac-
tions proceeded smoothly to give the corresponding
thiazol-2-yl substituted E-acrylonitriles in good yields of
67%—76% (Table 2, Entries 6—23). Indeed, the proto-
col provides a straightforward pathway to construct
highly functionalized thiazol-2-yl substituted E-crylo-
nitrile. The structures of products 5 were deduced from
their IR, 1H NMR, 13C NMR and HRMS.
A reasonable mechanism for formation of 5 was
proposed in Scheme 4. The formation of 5 is expected to
proceed via initial condensation of α-thiocyanate ke-
tones 1 and malononitrile 2 to afford 2-(4-aryl-3H-thia-
zol-2-ylidene)-malononitrile (3). And then the nucleo-
philic addition between dimedone and cyano group of
substrate 3 occurred, providing intermediate A which
underwent nucleophilic addition with amine and subse-
quent isomerization to afford the products 5.
ported in cm . H NMR spectra were measured on a
Bruker DPX 400 MHz spectrometer in DMSO-d6 (100
MHz, 13C NMR) with chemical shift (δ) relative to TMS
as internal standard. HRMS (ESI) was determined by
using microTOF-QII HRMS/MS instrument (BRUKER).
X-ray crystallographic analysis was performed with a
Siemens SMART CCD and a Siemens P4 diffractome-
ter.
General procedure for the synthesis of compounds 5
Preparation of compounds 3 α-Thiocyanate ke-
tones and malononitrile in an ethanolic aqueous solution
of 20% potassium hydroxide at room temperature for 2
h produced a sole product 3.
Preparation of compounds 5 Typically, in a
10-mL Biotage microwave vial, the thiazol-2-ylidene-
malononitriles 3 (1 mmol), morpholine (1 mmol), di-
medone (0.2 equiv.) and EtOH (2 mL) were capped and
pre-stirred for 20 s. The mixture was subjected to mi-
crowave irradiation at 130 ℃ for a given time. Upon
completion, monitored by TLC, the reaction mixture
was cooled to room temperature, filtered to give the
crude product, which was further purified by recrystal-
lization from acetone to give the corresponding products
5 with good yields.
Scheme 4 The reasonable mechanism for the formations of
thiazol-2-yl substituted E-acrylonitriles 5
Ar
O
CN
+
CN
2
SCN
1
EtOH
N
20% KOH
(E)-3-Amino-3-morpholin-4-yl-2-[4-(4-nitro-
phenyl)-thiazol-2-yl]-acrylonitrile (5a) Yellow solid,
S
Ar
S
CN
HN
H2N
1
m.p. 294—295 ℃; H NMR (400 MHz, DMSO-d6) δ:
N
CN
O
Ar
H
8.30 (d, J＝8.8 Hz, 2H, ArH), 8.14 (d, J＝8.8 Hz, 2H,
ArH), 8.02 (s, 1H, ＝CH), 3.70—3.68 (m, 4H, CH2),
3.51—3.49 (m, 4H, CH2); IR (KBr) ν: 3319, 3108, 2956,
2178, 1644, 1598, 1528, 1513, 1453, 1378, 1340, 1271,
1204, 1149, 1117, 1066, 1023, 967, 854, 838, 741, 618
3
O
O
A
Ar
NHR1R2
Ar
－
－
1
O
cm ; HRMS (ESI) calcd for C16H15N5O3S [M－H]
N
S
S
HN
H2N
356.0812, found 356.0795.
H2N
R1
CN
NR1R2
O
(E)-3-Amino-3-morpholin-4-yl-2-[4-(3-nitro-
phenyl)-thiazol-2-yl]-acrylonitrile (5b) Yellow solid,
CN
N
R2
1
O
m.p. 214—216 ℃; H NMR (400 MHz, DMSO-d6) δ:
5
8.63 (s, 1H, ArH), 8.32 (d, J＝8.0 Hz, 1H, ArH), 8.19—
8.16 (m, 1H, ArH), 7.94 (s, 1H, ＝CH), 7.72 (t, J＝8.0
Hz, 1H, ArH), 3.71—3.69 (m, 4H, CH2), 3.51—3.49 (m,
4H, CH2); 13C NMR (100 MHz, DMSO-d6) δ: 169.0,
163.0, 150.0, 148.3, 135.5, 131.9, 130.3, 122.3, 122.1,
120.0, 109.7, 65.9, 60.1, 48.6; IR (KBr) ν: 3371, 3109,
2960, 2174, 1635, 1537, 1528, 1450, 1376, 1351, 1264,
Conclusions
In summary, a new dimedone-mediated addition of
amines to cyano group has been established to afford a
series of thiazol-2-yl substituted E-acrylonitriles that
serve as versatile building block. The reactions showed
high chemoselectivity and a broad scope of substrates
which can employ a wide range of common commercial
starting materials. A new mechanism has been proposed
to explain the reaction process.
－
1
1200, 1136, 1117, 1063, 1024, 975, 897, 719, 596 cm ;
－
HRMS (ESI) calcd for C16H15N5O3S [M － H]
356.0812, found 356.0804.
(E)-3-Amino-2-[4-(3-chlorophenyl)-thiazol-2-yl]-
3-morpholin-4-yl-acrylonitrile (5c)
Yellow solid,
1
m.p. 207—208 ℃; H NMR (400 MHz, DMSO-d6) δ:
7.87 (s, 1H, ArH), 7.79 (d, J＝7.6 Hz, 1H, ArH), 7.74 (s,
1H, ＝CH), 7.42 (t, J＝7.6 Hz, 1H, ArH), 7.34 (d, J＝
8.0 Hz, 1H, ArH), 3.64—3.63 (m, 4H, CH2), 3.44 (s, 4H,
CH2); 13C NMR (100 MHz, DMSO-d6) δ: 168.7, 163.1,
150.8, 136.0, 133.6, 130.6, 127.5, 125.4, 124.3, 122.2,
112.7, 108.6, 65.9, 60.1, 48.5; IR (KBr) ν: 3329, 3109,
2855, 2176, 1639, 1598, 1541, 1494, 1447, 1404, 1379,
Experimental
Microwave irradiation was carried out with Initiator
2.5 Microwave Synthesizers from Biotage, Uppsala,
Sweden. Melting points were determined in open capil-
laries and were uncorrected. IR spectra were taken on a
FT-IR-Tensor 27 spectrometer in KBr pellets and re-
4
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—7

Facile Synthesis of Thiazol-2-yl Substituted E-Acrylonitriles
1318, 1257, 1177, 1150, 1118, 1064, 1026, 975, 908,
59.7, 49.2, 25.5, 23.7; IR (KBr) ν: 3333, 3147, 2932,
2178, 1643, 1596, 1548, 1491, 1452, 1407, 1390, 1360,
1314, 1255, 1214, 1159, 1126, 1060, 968, 906, 776, 740,
－
1
871, 787, 742, 720, 591 cm ; HRMS (ESI) calcd for
C16H15ClN4OS [M－H]－ 345.0571, found 345.0580.
(E)-3-Amino-3-morpholin-4-yl-2-(4-phenylthiazol-
2-yl)-acrylonitrile (5d) Yellow solid, m.p. 205—206
－
1
709 cm ; HRMS (ESI) calcd for C17H17ClN4S [M－
H]－ 343.0777, found 343.0770.
1
℃; H NMR (400 MHz, DMSO-d6) δ: 7.86 (d, J＝7.6
(E)-3-Amino-2-(4-phenylthiazol-2-yl)-3-piperidin-
1-yl-acrylonitrile (5i) Yellow solid, m.p. 200—201
Hz, 2H, ArH), 7.64 (s, 1H, ＝CH), 7.44 (t, J＝7.6 Hz,
2H, ArH), 7.34 (t, J＝7.2 Hz, 1H, ArH), 3.69 (t, J＝4.4
Hz, 4H, CH2), 3.49 (t, J＝4.8 Hz, 4H, CH2); 13C NMR
(100 MHz, DMSO-d6) δ: 168.5, 163.2, 152.4, 134.0,
128.7, 127.8, 125.7, 122.2, 107.1, 65.9, 60.3, 48.6; IR
(KBr) ν: 3339, 2966, 2175, 1636, 1520, 1499, 1444,
1377, 1337, 1242, 1148, 1117, 1061, 1019, 971, 895,
1
℃; H NMR (400 MHz, DMSO-d6) δ: 7.85 (d, J＝7.2
Hz, 2H, ArH), 7.61 (s, 1H, ＝CH), 7.43 (t, J＝7.6 Hz,
2H, ArH), 7.33 (t, J＝7.2 Hz, 1H, ArH), 3.45 (s, 4H,
CH2), 1.62 (s, 6H, CH2); IR (KBr) ν: 3311, 3146, 3119,
2935, 2855, 2181, 1644, 1598, 1544, 1503, 1470, 1435,
1391, 1362, 1328, 1262, 1214, 1177, 1125, 1105, 965,
－
－
1
1
835, 721, 690 cm ; HRMS (ESI) calcd for C16H16N4OS
709, 599 cm ; HRMS (ESI) calcd for C17H18N4S [M－
[M－H]－ 311.0961, found 311.0954.
H]－ 309.1168, found 309.1168.
(E)-3-Amino-2-[4-(4-methoxyphenyl)-thiazol-2-
yl]-3-morpholin-4-yl-acrylonitrile (5e) Yellow solid,
m.p. 238—239 ℃; H NMR (400 MHz, DMSO-d6) δ:
(E)-3-Amino-2-[4-(4-methoxyphenyl)-thiazol-2-
yl]-3-piperidin-1-yl-acrylonitrile (5j) Yellow solid,
m.p. 200—202 ℃; H NMR (400 MHz, DMSO-d6) δ:
1
1
7.79 (d, J＝8.8 Hz, 2H, ArH), 7.46 (s, 1H, ＝CH), 6.99
(d, J＝8.4 Hz, 2H, ArH), 3.79 (s, 3H, OCH3), 3.69 (t,
7.77 (d, J＝8.8 Hz, 2H, ArH), 7.43 (s, 1H, ＝CH), 6.99
(d, J＝8.4 Hz, 2H, ArH), 3.79 (s, 3H, OCH3), 3.44 (s,
4H, CH2), 1.61 (s, 6H, CH2); 13C NMR (100 MHz,
DMSO-d6) δ: 168.7, 163.1, 159.0, 152.1, 127.0, 122.4,
114.1, 104.7, 59.9, 55.2, 49.2, 25.5, 23.7; IR (KBr) ν:
3332, 3137, 2937, 2853, 2179, 1633, 1610, 1531, 1508,
1465, 1453, 1417, 1386, 1301, 1284, 1247, 1175, 1103,
J＝4.0 Hz, 4H, CH2), 3.48 (t, J＝4.0 Hz, 4H, CH2); 13
C
NMR (100 MHz, DMSO-d6) δ: 168.2, 163.2, 159.0,
152.3, 127.1, 126.9, 122.2, 114.1, 105.1, 65.9, 60.3,
55.2, 48.6; IR (KBr) ν: 3312, 3146, 3111, 2960, 2184,
1649, 1610, 1537, 1525, 1506, 1457, 1377, 1361, 1322,
－
－
1
1
1304, 1244, 1177, 1121, 1031, 971, 841, 617 cm ;
HRMS (ESI) calcd for C17H18N4O2S C17H18N4O2S [M
－H]－ 341.1066, found 341.1055.
1058, 1032, 966, 835, 741 cm ; HRMS (ESI) calcd for
C18H20N4OS [M－H]－ 339.1274, found 339.1288.
(E)-3-Amino-3-(4-methylpiperidin-1-yl)-2-[4-(4-
nitrophenyl)-thiazol-2-yl]-acrylonitrile (5k) Yellow
(E)-3-Amino-2-[4-(4-nitrophenyl)-thiazol-2-yl]-3-
piperidin-1-yl-acrylonitrile (5f) Yellow solid, m.p.
1
solid, m.p. 292—293 ℃; H NMR (400 MHz, DMSO-
1
288—290 ℃; H NMR (400 MHz, DMSO-d6) δ: 8.29
d6) δ: 8.29 (d, J＝8.8 Hz, 2H, ArH), 8.12 (d, J＝8.8 Hz,
2H, ArH), 7.96 (s, 1H, ＝CH), 3.90 (d, J＝13.6 Hz, 2H,
CH2), 3.04 (t, J＝12.0 Hz, 2H, CH2), 1.71 (d, J＝13.2
Hz, 2H, CH2), 1.24—1.16 (m, 2H, CH2), 0.94 (d, J＝6.4
Hz, 3H, CH3); IR (KBr) ν: 3335, 3143, 2931, 2178,
1640, 1591, 1548, 1491, 1452, 1403, 1390, 1364, 1314,
1250, 1211, 1159, 1126, 1061, 968, 906, 773, 740, 705
(d, J＝9.2 Hz, 2H, ArH), 8.12 (d, J＝8.8 Hz, 2H, ArH),
7.98 (s, 1H, ＝CH), 3.46 (s, 4H, CH2), 1.62 (s, 6H,
CH2); 13C NMR (100 MHz, DMSO-d6) δ: 169.6, 162.9,
150.3, 146.4, 140.0, 126.6, 124.1, 112.7, 111.3, 59.8,
49.3, 25.5, 23.7; IR (KBr) ν: 3309, 3137, 3109, 2938,
2176, 1643, 1598, 1531, 1496, 1453, 1410, 1383, 1340,
1282, 1259, 1201, 1123, 1063, 962, 852, 737, 657, 618
－
－
1
cm ; HRMS (ESI) calcd for C18H19N5O2S [M－H]
－
－
1
cm ; HRMS (ESI) calcd for C17H17N5O2S [M－H]
368.1175, found 368.1156.
354.1019, found 354.1017.
(E)-3-Amino-3-dimethylamino-2-[4-(4-nitro-
phenyl)-thiazol-2-yl]-acrylonitrile (5l) Yellow solid,
m.p. 277—278 ℃; H NMR (400 MHz, DMSO-d6) δ:
8.29 (d, J＝8.8 Hz, 2H, ArH), 8.11 (d, J＝8.8 Hz, 2H,
ArH), 7.95 (s, 1H, ＝CH), 3.10 (s, 6H, CH3); IR (KBr)
ν: 3343, 3164, 2173, 1645, 1598, 1565, 1539, 1515,
(E)-3-Amino-2-[4-(3-nitrophenyl)-thiazol-2-yl]-3-
piperidin-1-yl-acrylonitrile (5g) Yellow solid, m.p.
1
1
230—231 ℃; H NMR (400 MHz, DMSO-d6) δ: 8.63
(s, 1H, ArH), 8.31 (d, J＝8.0 Hz, 1H, ArH), 8.19—8.16
(m, 1H, ArH), 7.91 (s, 1H, ＝CH), 7.73 (t, J＝8.0 Hz,
1H, ArH), 3.46 (s, 4H, CH2), 1.62 (s, 6H, CH2); IR (KBr)
ν: 3318, 2945, 2175, 1644, 1539, 1513, 1455, 1437,
1463, 1441, 1409, 1373, 1339, 1270, 1197, 1115, 1065,
－
1028, 984, 619 cm 1; HRMS (ESI) calcd for
1380, 1344, 1300, 1216, 1160, 1120, 1104, 1031, 971,
C14H13N5O2S [M－H]－ 314.0706, found 314.0706.
(E)-3-Amino-3-dimethylamino-2-[4-(3-nitro-
phenyl)-thiazol-2-yl]-acrylonitrile (5m) Yellow solid,
－
917, 736, 619 cm 1; HRMS (ESI) calcd for
C17H17N5O2S [M－H]－ 354.1019, found 354.1019.
(E)-3-Amino-2-[4-(3-chlorophenyl)-thiazol-2-yl]-
3-piperidin-1-yl-acrylonitrile (5h) Yellow solid, m.p.
1
m.p. 204—205 ℃; H NMR (400 MHz, DMSO-d6) δ:
8.62 (s, 1H, ArH), 8.31 (d, J＝8.0 Hz, 1H, ArH), 8.17
(dd, J＝1.6, 8.0 Hz, 1H, ArH), 7.89 (s, 1H, ＝CH), 7.73
(t, J＝8.0 Hz, 1H, ArH), 3.10 (s, 6H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ: 170.0, 162.3, 149.8, 148.3,
135.6, 131.9, 130.3, 122.3, 119.9, 114.9, 112.7, 109.0,
58.4; IR (KBr) ν: 3334, 3105, 2170, 1647, 1553, 1513,
1497, 1462, 1421, 1344, 1321, 1253, 1196, 1104, 1060,
1
195—196 ℃; H NMR (400 MHz, DMSO-d6) δ: 7.90
(s, 1H, ArH), 7.82 (d, J＝7.6 Hz, 1H, ArH), 7.74 (s, 1H,
＝CH), 7.46 (t, J＝8.0 Hz, 1H, ArH), 7.38 (d, J＝7.6 Hz,
1H, ArH), 3.45 (s, 4H, CH2), 1.62 (s, 6H, CH2); 13C
NMR (100 MHz, DMSO-d6) δ: 169.1, 163.0, 150.7,
136.0, 133.6, 130.6, 127.5, 125.4, 124.3, 122.4, 108.2,
Chin. J. Chem. 2012, XX, 1—7
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Zhu et al.
FULL PAPER
981, 897, 800, 733 cm－ 1; HRMS (ESI) calcd for
C14H13N5O2S [M－H]－ 314.0706, found 314.0723.
(E)-3-Amino-3-dimethylamino-2-(4-phenylthiazol-
2-yl)-acrylonitrile (5n) Yellow solid, m.p. 181—182
3333, 3115, 2176, 1659, 1633, 1536, 1513, 1496, 1452,
－
1
1377, 1344, 1261, 1199, 1116, 983, 730, 617 cm ;
HRMS (ESI) calcd for C28H22N10O4S2 [M － H] －
625.1183, found 625.1196.
1
℃; H NMR (400 MHz, DMSO-d6) δ: 7.84 (d, J＝7.6
(E)-3-Amino-3-(4-{(E)-1-amino-2-[4-(3-chloro-
phenyl)-thiazol-2-yl]-2-cyano-vinyl}-piperazin-1-yl)-
2-[4-(3-chloro-phenyl)-thiazol-2-yl]-acrylonitrile (5s)
Hz, 2H, ArH), 7.57 (s, 1H, ＝CH), 7.43 (t, J＝7.2 Hz,
2H, ArH), 7.33 (t, J＝7.2 Hz, 1H, ArH), 3.09 (s, 6H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ: 169.4, 162.4,
152.1, 134.0, 128.7, 127.8, 125.7, 122.9, 112.7, 106.4,
58.4; IR (KBr) ν: 3336, 3118, 2175, 1643, 1562, 1496,
1462, 1439, 1416, 1335, 1257, 1188, 1063, 1026, 972,
898, 846, 776, 709, 667 cm ; HRMS (ESI) calcd for
C14H14N4S [M－H]－ 269.0855, found 269.0854.
(E)-3-Amino-3-dimethylamino-2-[4-(4-methoxy-
phenyl)-thiazol-2-yl]-acrylonitrile (5o) Yellow solid,
1
Yellow solid, m.p. ＞300 ℃; H NMR (400 MHz,
DMSO-d6) δ: 7.93 (s, 2H, ArH), 7.85 (d, J＝7.6 Hz, 2H,
ArH), 7.81 (s, 2H, ＝CH), 7.47 (t, J＝8.0 Hz, 2H, ArH),
7.40 (d, J＝7.6 Hz, 2H, ArH), 3.66 (s, 8H, CH2), 3.30 (s,
4H, NH2); 13C NMR (100 MHz, DMSO-d6) δ: 188.0,
164.5, 131.7, 131.5, 131.3, 130.2, 128.2, 122.6, 114.4,
112.8, 112.7, 55.8, 37.5, 34.4, 15.0; IR (KBr) ν: 3328,
3118, 2175, 1631, 1595, 1523, 1501, 1446, 1380, 1295,
－
1
－
1
1
m.p. 240—241 ℃; H NMR (400 MHz, DMSO-d6) δ:
1143, 983, 802, 750, 731, 600 cm ; HRMS (ESI) calcd
－
7.77 (d, J＝8.8 Hz, 2H, ArH), 7.40 (s, 1H, ＝CH), 6.99
(d, J＝8.8 Hz, 2H, ArH), 3.79 (s, 3H, OCH3), 3.08 (s,
6H, CH3); IR (KBr) ν: 3344, 3163, 2173, 1644, 1573,
1499, 1460, 1440, 1417, 1319, 1283, 1249, 1174, 1113,
for C28H22Cl2N8S2 [M － H]
603.0724.
(E)-3-Amino-3-(4-{(E)-1-amino-2-cyano-2-[4-(4-
methoxyphenyl)-thiazol-2-yl]-vinyl}-piperazin-1-yl)-
2-[4-(4-methoxy-phenyl)-thiazol-2-yl]-acrylonitrile
603.0702, found
－
1
981, 837, 741, 701, 618 cm ; HRMS (ESI) calcd for
C15H16N4OS [M－H]－299.0961, found 299.0945.
(E)-3-Amino-3-diethylamino-2-[4-(4-nitrophenyl)-
thiazol-2-yl]-acrylonitrile (5p) Yellow solid, m.p.
1
(5t) Yellow solid, m.p. ＞300 ℃; H NMR (400
MHz, DMSO-d6) δ: 7.80 (d, J＝8.8 Hz, 4H, ArH), 7.48
(s, 2H, ＝CH), 7.00 (d, J＝8.4 Hz, 4H, ArH), 3.80 (s,
6H, OCH3), 3.65 (s, 8H, CH2); IR (KBr) ν: 3332, 3121,
2904, 2175, 1631, 1529, 1501, 1447, 1381, 1287, 1249,
1173, 1142, 1059, 1031, 980, 837, 740, 703, 583 cm ;
HRMS (ESI) calcd for C30H28N8O2S2 [M － H]
1
251—252 ℃; H NMR (400 MHz, DMSO-d6) δ: 8.29
(d, J＝8.8 Hz, 2H, ArH), 8.10 (d, J＝9.2 Hz, 2H, ArH),
7.96 (s, 1H, ＝CH), 3.52 (dd, J＝6.8, 13.6 Hz, 4H,
CH2), 1.20 (t, J＝7.2 Hz, 6H, CH3); 13C NMR (100
MHz, DMSO-d6) δ: 170.5, 163.4, 160.4, 146.4, 139.9,
126.5, 124.1, 111.2, 61.7, 58.3, 43.9, 13.1; IR (KBr) ν:
3370, 3112, 2165, 1646, 1598, 1547, 1510, 1456, 1385,
－
1
－
595.1698, found 595.1663.
(E)-3-Amino-3-(4-chloro-phenylamino)-2-[4-(3-
nitrophenyl)-thiazol-2-yl]-acrylonitrile (5u) Yellow
solid, m.p. 228 — 230 ℃ ; 1H NMR (400 MHz,
DMSO-d6) δ: 9.27 (s, 1H, NH), 8.61 (s, 1H, ArH), 8.32
(d, J＝7.2 Hz, 1H, ArH), 8.18 (d, J＝7.2 Hz, 1H, ArH),
7.99 (s, 1H, ＝CH), 7.73 (t, J＝8.0 Hz, 1H, ArH), 7.47
(d, J＝7.6 Hz, 2H, ArH), 7.34 (s, 2H, ArH); IR (KBr) ν:
3476, 3344, 3230, 3115, 2183, 1663, 1619, 1574, 1541,
－
1
1340, 1244, 1114, 983, 854, 838, 714, 618 cm ; HRMS
(ESI) calcd for C16H17N5O2S [M－H]－ 342.1019, found
342.1004.
(E)-3-Amino-3-diethylamino-2-[4-(4-methoxy-
phenyl)-thiazol-2-yl]-acrylonitrile (5q) Yellow solid,
1
m.p. 172—173 ℃; H NMR (400 MHz, DMSO-d6) δ:
7.77 (d, J＝8.0 Hz, 2H, ArH), 7.40 (s, 1H, ＝CH), 6.99
(d, J＝8.0 Hz, 2H, ArH), 3.79 (s, 3H, OCH3), 3.50 (d,
1517, 1493, 1422, 1395, 1348, 1276, 1162, 1116, 996,
－
828, 729, 620 cm 1; HRMS (ESI) calcd for
J＝6.4 Hz, 4H, CH2), 1.20 (t, J＝5.6 Hz, 6H, CH3); 13
C
C18H12ClN5O2S [M－H]－ 396.0317, found 396.0333.
(E)-3-Amino-3-(4-bromo-phenylamino)-2-[4-(3-
nitrophenyl)-thiazol-2-yl]-acrylonitrile (5v) Yellow
solid, m.p. 236 — 237 ℃ ; 1H NMR (400 MHz,
DMSO-d6) δ: 9.26 (s, 1H, NH), 8.61 (s, 1H, ArH), 8.31
(d, J＝7.6 Hz, 1H, ArH), 8.18 (d, J＝8.4 Hz, 1H, ArH),
7.99 (s, 1H, ＝CH), 7.73 (t, J＝8.0 Hz, 1H, ArH), 7.59
(d, J＝6.4 Hz, 2H, ArH), 7.29—7.27 (m, 2H, ArH); 13C
NMR (100 MHz, DMSO-d6) δ: 183.0, 168.3, 148.3,
143.1, 136.6, 132.2, 132.1, 131.9, 130.4, 125.5, 122.4,
120.6, 120.0, 112.7, 56.0, 18.5; IR (KBr) ν: 3467, 3352,
3228, 2181, 1663, 1619, 1572, 1540, 1515, 1489, 1420,
1390, 1346, 1274, 1173, 1116, 1064, 1009, 974, 828,
NMR (100 MHz, DMSO-d6) δ: 169.7, 160.5, 159.0,
151.9, 127.0, 126.9, 123.1, 114.1, 104.4, 58.3, 55.2,
43.8, 13.2; IR (KBr) ν: 3353, 3117, 2170, 1643, 1608,
1558, 1532, 1493, 1461, 1434, 1415, 1360, 1318, 1281,
1249, 1176, 1112, 1086, 1028, 895, 837, 810, 744, 709
－
－
1
cm ; HRMS (ESI) calcd for C17H20N4OS [M－H]
327.1274, found 327.1291.
(E)-3-Amino-3-(4-{(E)-1-amino-2-cyano-2-[4-(3-
nitrophenyl)-thiazol-2-yl]-vinyl}-piperazin-1-yl)-2-[4-
(3-nitro-phenyl)-thiazol-2-yl]-acrylonitrile
(5r)
1
Yellow solid, m.p. ＞300 ℃; H NMR (400 MHz,
DMSO-d6) δ: 8.66 (s, 2H, ArH), 8.34 (d, J＝7.6 Hz, 2H,
ArH), 8.19 (d, J＝8.0 Hz, 2H, ArH), 7.97 (s, 2H,
＝CH), 7.74 (t, J＝8.0 Hz, 2H, ArH), 3.68 (s, 8H, CH2),
3.51 (s, 2H, NH2), 2.89 (s, 2H, NH2); 13C NMR (100
MHz, DMSO-d6) δ: 158.7, 154.6, 151.6, 148.7, 147.9,
141.5, 131.4, 130.7, 128.6, 127.8, 126.4, 122.1, 121.7,
113.9, 111.0, 101.2, 55.5, 33.9, 25.0, 25.0; IR (KBr) ν:
－
1
728 cm ; HRMS (ESI) calcd for C18H12BrN5O2S [M－
H]－ 439.9811, found 439.9811.
(E)-3-Amino-3-(4-methylphenylamino)-2-(4-
phenylthiazol-2-yl)-acrylonitrile (5w) Yellow solid,
1
m.p. 209—211 ℃; H NMR (400 MHz, DMSO-d6) δ:
9.03 (s, 1H, NH), 7.84 (d, J＝6.4 Hz, 2H, ArH), 7.63 (s,
6
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—7

Facile Synthesis of Thiazol-2-yl Substituted E-Acrylonitriles
Kornienko, A.; Magedov, I. V. Org. Lett. 2011, 13, 1118; (e) Okabe,
F.; Nakamura, S.; Yamagata, K. J. Heterocycl. Chem. 2007, 44, 227.
[6] Lewis, J. R. Nat. Prod. Rep. 1999, 16, 389.
1H, ＝CH), 7.42 (t, J＝7.2 Hz, 2H, ArH), 7.34—7.22
(m, 5H, ArH), 2.33 (s, 3H, OCH3); IR (KBr) ν: 3437,
3306, 3206, 2191, 1645, 1603, 1573, 1514, 1480, 1442,
1419, 1396, 1289, 1265, 1253, 1176, 1060, 1027, 965,
[7] (a) Lin, G.; Li, D.; de Carvalho, L. P. S.; Deng, H.; Tao, H.; Vogt, G.;
Wu, K.; Schneider, J.; Chidawanyika, T.; Warren, J. D.; Li, H.; Na-
than, C. Nature 2009, 461, 621; (b) Barroso, I.; Gurnell, M.; Crow-
ley, V. E.; Agostini, M.; Schwabe, J. W.; Soos, M. A.; Maslen, G. L.;
Williams, T. D.; Lewis, H.; Schafer, A. J.; Chatterjee, V. K.; O'Ra-
hilly, S. Nature 1999, 402, 880; (c) Shao, D.; Rangwala, S. M.; Bai-
ley, S. T.; Krakow, S. L.; Reginato, M. J.; Lazar, M. A. Nature 1998,
396, 377; (d) Jiang, C.; Ting, A. T.; Seed, B. Nature 1998, 391, 82.
[8] Van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga, R. C.; von
Kuenzel, J. F.; de Groote, M.; Visser, S.; IJzerman, A. P. J. Med.
Chem. 2001, 44, 749.
－
1
894, 819, 776, 723, 706 cm ; HRMS (ESI) calcd for
C19H16N4S [M－H]－ 332.1090, found 332.1017.
Acknowledgement
We are grateful for financial support from the Na-
tional Science Foundation of China (Nos. 21072163,
21102124), PAPD of Jiangsu Higher Education Institu-
tions, Jiangsu Science and Technology Support Program
(No. BE2011045), Science Foundation in Interdiscipli-
nary Major Research Project of Xuzhou Normal Uni-
versity (No. 09XKXK01), and the NSF of Jiangsu Edu-
cation Committee (No. 11KJB150016).
[9] Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W. Med. Chem. Res.
2010, 19, 1245.
[10] Kukaniev, M. A.; Salimov, T. M.; Murvatulloeva, M. S.; Imatshoev,
I. K. Pharm. Chem. J. 2006, 40, 421.
[11] (a) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc.
2009, 131, 11660; (b) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.;
Wever, W.; Li, G. J. Org. Chem. 2010, 75, 2962; (c) Ma, N.; Jiang,
B.; Zhang, G.; Tu, S.-J.; Wever, W.; Li, G. Green Chem. 2010, 12,
1357.
[12] (a) Tu, S.; Wu, S.; Han, Z.; Hao, W. Chin. J. Chem. 2009, 27, 1148;
(b) Peng, J.; Hao, W.; Wang, X.; Tu, S.; Ma, N.; Zhang, G. Chin. J.
Chem. 2009, 27, 1707; (c) Peng, J.; Jia, R.; Xu, Y.; Tu, S.; Ma, N.;
Zhang, G. Chin. J. Chem. 2009, 27, 2392; (d) Wang, S.; Cheng, C.;
Gong, F.; Wu, F.; Jiang, B.; Zhou, J.; Tu, S. Chin. J. Chem. 2011, 29,
2101; (e) Wang, S.; Wang, X.; Tu, M.; Jiang, B.; Tu, S. Chin. J.
Chem. 2011, 29, 2411.
References and Note
[1] Jones, K., Comprehensive Organic Functional Group Transforma-
tions II, Volume 3, Elsevier Ltd., Oxford, 2005.
[2] Jereb, M.; Vrazic, D.; Zupan, M. Tetrahedron 2011, 67, 1355.
[3] (a) Li, J.; Corey, E. J. Name Reactions for Functional Group
Transformations, Wiley-Interscience, Hoboken, N. J., 2007; (b) Breit,
B.; Schmidt, Y. Chem. Rev. 2008, 108, 2928; (c) Yamaguchi, K.;
Mizuno, N. Synlett 2010, 2365
[4] (a) Zhang, Z.-Y.; Wallace, M. B.; Feng, J.; Stafford, J. A.; Skene, R.
J.; Shi, L.-H.; Lee, B.-S.; Aertgeerts, K.; Jennings, A.; Xu, R.-D.;
Kassel, D. B.; Kaldor, S. W.; Navre, M.; Webb, D. R.; Gwaltney, S.
L. II. J. Med. Chem. 2011, 54, 510; (b) Collier, S. J.; Langer, P. In
Science of Synthesis, Ed.: Thomas, E. J., Georg Thieme Verlag,
Stuttgart, Germany, 2004, pp. 403—425.
[5] (a) Li, W.; Yu, A.; Higgins, D. C.; Llanos, B. G.; Chen, Z. J. Am.
Chem. Soc. 2010, 132, 17056; (b) Demir, A. S.; Emrullahoglu, M.;
Buran, K. Chem. Commun. 2010, 8032; (c) Haddadin, M. J.; Zerdan,
R. M. B.; Kurth, M. J.; Fettinger, J. C. Org. Lett. 2010, 12, 5502; (d)
Frolova, L. V.; Evdokimov, N. M.; Hayden, K.; Malik, I.; Rogelj, S.;
[13] (a) Bisogno, F. R.; Cuetos, A. Green Chem. 2009, 11, 452; (b)
El-Din, A. S. Sulfur Lett. 2003, 26, 35.
[14] The single-crystal growth was carried out in DMF at room tempera-
ture. Crystal data for 5a: Empirical formula C16H15N5O3S, Formula
weight 357.39, crystal dimension 0.17 mm×0.08 mm×0.06 mm,
Monoclinic, space group P2(1)/c, a＝7.2560(8) Å, b＝14.7641(15)
Å, c＝16.1849(16) Å, α＝90°, β＝97.9370(10)°, γ＝90°, μ＝0.214
mm－1, V＝1717.3(3) Å3, Z＝4, Dc＝1.382 Mg/m3, F(000)＝744, S
＝0.924, R1＝0.0712, wR2＝0.0740.
(Cheng, F.)
Chin. J. Chem. 2012, XX, 1—7
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7