Direct construction of imino-pyrrolidine-thione scaffold via isocyanide-based multicomponent reaction

Article abstract of DOI:10.1021/cc100014g

A novel and efficient method has been developed for the direct construction of imino-pyrrolidine-thione scaffold via the coupling of isocyanides, heterocyclic thiols, and gem-dicyano olefins. Smiles rearrangement followed by intramolecular cyclization leads directly to formation of the core structure. A water-acceleration effect is observed, promoting most of the reactions to go to completion within a short reaction time.

Full text of DOI:10.1021/cc100014g

822
J. Comb. Chem. 2010, 12, 822–828
Direct Construction of Imino-pyrrolidine-thione Scaffold via
Isocyanide-Based Multicomponent Reaction
Xu Zhu, Xiao-Ping Xu, Chang Sun, Hai-Ying Wang, Kai Zhao, and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu ProVince, College of Chemistry, Chemical Engineering
and Materials Science, Soochow UniVersity, Suzhou 215123, China
ReceiVed January 25, 2010
A novel and efficient method has been developed for the direct construction of imino-pyrrolidine-thione
scaffold via the coupling of isocyanides, heterocyclic thiols, and gem-dicyano olefins. Smiles rearrangement
followed by intramolecular cyclization leads directly to formation of the core structure. A water-acceleration
effect is observed, promoting most of the reactions to go to completion within a short reaction time.
reactions,13 especially in I-MCRs,14 focuses in the introduc-
Introduction
tion of such substrates into the modified U-4CR reactions.
The pyrrolidine moiety is widely featured in a myriad of
pharmacologically and biologically active compounds.1 Pyr-
rolidine derivatives of thioxopyrrolidine and iminopyrrolidine
have been demonstrated to be useful functional scaffolds in
biologic and organic syntheses. For example, 3-hydroxym-
ethylene-2-thioxopyrrolidine was found out to show good
activity in inhibiting the growth of mutant streptococci.2 In
addition, the unique scaffold and good reactivity of thiox-
opyrrolidines lead to useful building blocks in the synthesis
of natural cyclic tetrapyrroles.3 On the other hand, iminopy-
rrolidine derivatives display biological activity as nitric oxide
synthase inhibitors.4 Nowadays, the combination of several
functional groups in one molecule appears as an efficient
strategy to optimize properties of pharmaceutical and bio-
active compounds. Therefore, explorations on the synthesis
and application of such highly functionalized compounds
have drawn a great deal of attention from many chemists.
Multicomponent reactions (MCRs), where several different
starting materials can be combined in one reaction, are
capable of efficiently generating hundreds to millions of small
organic molecules, many of which possess highly compli-
cated structures.5 MCRs, especially involved in isocyanides,
are expected to offer great opportunities both in discovering
new reactions and in synthesizing complex molecules.
Among them, the Ugi four-component reaction (U-4CR) is
one of the most important isocyanide-based multicomponent
reactions (I-MCRs).6 The U-4CR containing aldehydes,
amides, isocyanides and nucleophiles undergoes a Ugi-Smiles
coupling to yield various drug backbones effectively.7 It
should be noted that various nucleophiles, such as carboxylic
acids, nitrophenol,8 heterocyclic thiols,9a and even water,10
can be all utilized in the reaction. Since Saegusa and co-
workers11 developed the first reaction between isocyanides
and olefins bearing electron-withdrawing groups over thirty
years ago, only couples of I-MCRs involving olefins have
been reported.12 Our continuing interest in multicomponent
Inspired by our previous works as well as the Ugi-Smiles
coupling, we report here a novel reaction to synthesize imino-
pyrrolidine-thione derivatives using a one-pot condensation
of gem-dicyano olefin 1, isocyanide 2, and 2-mercaptoben-
zothiazole 3a (Scheme 1). The reactions proceeded efficiently
in the presence of pyridine and aqueous MeCN to afford
products in a good yield at ambient temperature.
Results and Discussion
Initially, 4-cholorobenzylidenemalonitrile (1a), tert-butyl
isocyanide (2a), and 2-mercapto-benzothiazole (3a) were
stirred in a mixture of MeCN and H2O (VMeCN/VH O ) 3:1)
2
at room temperature for 5 h (Table 1, entry 1).15 After
standard workup and purification of the reaction mixture via
silica gel column chromatography, product 4d was obtained
1
in 59% yield. Full characterization involving IR, H NMR,
13C NMR, and HRMS proved the identity of 4d, and the
structure was further confirmed unambiguously by single-
crystal X-ray analysis (Figure 1).
It is worthwhile to note that the reaction proceeded
selectively to generate the imino-pyrrolidine-thione as a
single trans diastereomer.
Encouraged by this interesting result, we continued to
focus on the optimization of reaction conditions. To activate
the thiol, one equivalent of base was added to the reaction
system.12c The results are summarized in Table 1.
As shown in Table 1, various bases were screened for their
efficiency in the reaction. Among them, pyridine was proven
superior to other bases, and the yield of the desired product
Scheme 1. Construction of Imino-pyrrolidine-thione
Derivatives 4 via a One-Pot Condensation of gem-Dicyano
Olefin 1, Isocyanide 2 and 2-Mercaptobenzothiazole 3a
* To whom correspondence should be addressed. E-mail: chemjsj@
suda.edu.cn.
10.1021/cc100014g  2010 American Chemical Society
Published on Web 08/30/2010

Imino-pyrrolidine-thione Scaffold
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 823
Table 1. Optimization of the Reaction Conditionsa
Table 2. Substrate Scope Study Using Different gem-Dicyano
Olefins and Isocyanidesa
entry
base
MgCO3
Na2CO3
K2CO3
solvent
yield (%)b
entry
Ar
R
time (h)
products
yield (%)b
1
2
3
4
5
6
7
8
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 3:1
MeCN/H2O ) 1:3
MeCN/H2O ) 1:1
H2O
59
48
38
33
37
41
22
52
59
43
60
69
68
54
0
1
2
3
4
5
6
7
8
4-NO2C6H4
3-NO2C6H4
4-FC6H4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
1
1
4
3
2
2
1
4
2
3
2
8
5
24
3
3
10
3
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
92
87
63
69
84
89
92
93
89
81
96
70
73
trace
62
50
72
78
57
4-ClC6H4
3-ClC6H4
2-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
3-BrC6H4
2-BrC6H4
2-naphthyl
1-naphthyl
C6H5
4-OCH3C6H4
4-NO2C6H4
3-NO2C6H4
2,4-Cl2C6H3
3-BrC6H4
2-naphthyl
NaOH
KOH
piperidine
Et3N
quinoline
diisopropylamine
HMPA
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
9
9
10
11
12
13
14
15
16
17
10
11
12
13
14
15
16
17
18
19
c-hexyl
c-hexyl
c-hexyl
c-hexyl
c-hexyl
MeCN
MeCN
45
71c
a Unless otherwise noted, the reactions were carried out at room
temperature for using 4-cholorobenzylidenemalonitrile 1a (0.5
5
h
a The reactions were carried out at room temperature for a specific
mmol), tert-butyl isocyanide 2a (0.6 mmol), 2-mercaptobenzothiazole 3a
(0.5 mmol), base (0.5 mmol), and solvent (2.0 mL). b Isolated yield.
c Reaction time: 16 h.
time using 1 (0.5 mmol), 2 (0.6 mmol), 3a (0.5 mmol), pyridine (0.5
mmol), solvent (2.0 mL, VMeCN:VH O ) 3:1). b Isolated yield.
2
groups gave good yields within a short reaction time (entries
1-10) and olefins containing naphthyl and phenyl group
could also react well to produce the desired products in good
to excellent yields (entries 11-13). Unfortunately, the
electron-donating counterparts were not good substrates even
upon prolonging the reaction time to 24 h (entry 14). When
cyclohexyl isocyanide was used instead of tert-butyl iso-
cyanide, the reactions could also proceed well to give the
desired products in good yields (entries 15-19).
To further explore the generality of this novel multicom-
ponent reaction, we continued to study the use of other
heterocyclic thiols (Table 3). As shown in Table 3, moderate
to good yields were also obtained when thiols including
2-mercaptobenzoxazole, 2-mercaptopyrimidine, and 2-thia-
zoline-2-thiol were used. Random combination of the three
starting materials could give the final products with up to
94% yield.
Figure 1. Crystal structure of 4d.
4d could be increased to 69% (entry 12). The influence of
volume ratio of MeCN and H2O on the reaction was also
investigated. A 3:1 ratio of VMeCN/VH O proved to be optimal
Therefore, we have discovered a novel I-MCR leading to
highly substituted thioxopyrrolidines. Since the first Ugi-
Smiles conversion of thiols was observed in 2006 by Kaim
and co-workers,9a few such processes have been explored.9b-k
On the basis of the above results, a plausible mechanism
was proposed for the formation of the thioxopyrrolidine
derivatives (Scheme 2) by analogy with the Ugi multicom-
ponent condensation. The first step probably involves the
reaction of gem-dicyano olefin with isocyanide, followed by
attack of thiol on the resulting intermediate. Subsequent Ugi-
Smiles-type rearrangement followed by nucleophilic addition
of the amino group onto the cyano group affords the final
product. According to the molecular structure of 4d, presence
of the C-S double bond and benzothiazole group indicated
the possible involvement of a Ugi-Smiles-type coupling.
Formation of the imino fragment might be the result of the
2
(entries 12-14). However, the reaction could hardly occur
in pure water (entry 15), and a much longer reaction time
was needed when the reaction was carried out in pure MeCN
(entries 16-17). This indicated that a certain amount of water
could accelerate this reaction well, which might be explained
through the properties of water as a solvent and especially
the direct involvement of water in a bond-making step.16a,b
This acceleration may be attributed to many factors, including
the hydrophobic effect,16c,d enhanced hydrogen bonding in
the transition state,16e and the high cohesive energy density
of water (550.2 cal/mL at 25 °C).16f,g
With the optimized reaction conditions in hand, we
continued to examine the substrate scope of the reaction using
a wide variety of gem-dicyano olefins. As shown in Table
2, the gem-dicyano olefins bearing electron-withdrawing

824 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Table 3. Substrate Scope Study Using Various Thiols
Zhu et al.
Scheme 2. Possible Mechanism for the Formation of Product 4d
nucleophilic addition of an amino group to the activated
cyano group. To verify the hypothesis we brought forward,
another experiment was carried out. When the model reaction
was terminated after it had proceeded for 30 min, a Ugi-
Smiles-type coupling product, which was proposed to be a
key intermediate (A) of this reaction was isolated (16% yield)
and fully characterized. Once intermediate A is formed in
the reaction mixture, the simultaneous presence of an
activated cyano group and thio-amide functional group in
the intermediate triggered an intramolecular cyclization to
furnish the final product. To identify the hypothesis, the
intermediate A was stirred in the same reaction condition
and the product 4d was obtained in 70% yield after 3 h.
of imino-pyrrolidine-thiones via a Ugi-Smiles-type strategy.
In addition, this reaction is 100% atom economic that makes
the whole reaction highly efficient. Further studies are
underway to examine more thoroughly the scope and
limitations of this three-component reaction system.
Experimental Section
Typical Experimental Procedure for the Synthesis of
Imino-pyrrolidine-thione Derivatives 4a-s, 5a-g and
the Intermediate A. To a mixture of gem-dicyano olefin 1
(0.5 mmol) and heterocyclic thiol 3 (0.5 mmol) in the mixed
solvent of MeCN and H2O (3:1, v/v) was added isocyanide
2 (0.6 mmol) and pyridine (0.5 mmol). The solution was
stirred at room temperature for a specific as shown in Tables
2 and 3. The progress of the reaction was monitored by TLC.
After completion of the reaction, 30 mL of H2O was added
to the reaction mixture and then extracted by CH2Cl2 (10
mL × 3). The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. The organic layer
was evaporated under reduced pressure, and the residue was
subjected to silica gel column chromatography using petro-
leum ether and ethyl acetate as eluant to afford the desired
Conclusion
In summary, we have developed a novel and highly
efficient three-component reaction involving isocyanides,
various thiols and gem-dicyano olefins bearing electron-
withdrawing groups to produce the corresponding imino-
pyrrolidine-thiones. Most of the reactions are completed
within short time. This is a novel and direct route for the
construction of biologically relevant heterocyclic scaffolds

Imino-pyrrolidine-thione Scaffold
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 825
products of 4a-s and 5a-g. The intermediate A was
obtained when the reaction proceeded for 30 min.
MHz, CDCl3) δ ) 203.7, 153.0, 138.7, 135.6, 135.5, 131.0,
130.5, 130.0, 129.4, 127.7, 127.3, 126.9, 125.7, 124.7, 122.4,
115.1, 66.4, 65.1, 58.3, 28.7 ppm; HRMS (m/z) calcd for
C22H19ClN4S2 (M+) 438.0740, found 438.0742; Anal. Calcd
for C22H19ClN4S2 C 60.19, H 4.36, N 12.76; found C 60.48,
H 4.38, N 13.00.
4f: Yellow solid; mp 145-147 °C; IR (KBr) ν 3227 (NH),
2978, 1686 (CdN), 1502, 1359 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.93 (s, 9H, 3CH3), 5.23 (s, 1H, CH), 7.10-7.12
(m, 1H, ArH), 7.33-7.36 (m, 2H, ArH), 7.46-7.60 (m, 3H,
ArH), 7.95 (d, J ) 8.1 Hz, 1H, ArH), 8.10 (d, J ) 7.8 Hz,
1H, ArH), 9.23 (br s, 1H, NH) ppm; 13C NMR (75 MHz,
CDCl3) δ ) 197.9, 158.2, 156.6, 147.3, 130.3, 130.1, 129.6,
125.2, 124.9, 123.0, 122.7, 122.0, 121.5, 119.0, 116.7, 109.4,
59.6, 58.3, 52.9, 23.1 ppm; HRMS (m/z) calcd for
C22H19ClN4S2 (M+) 438.0740, found 438.0794; Anal. Calcd
for C22H19ClN4S2 C 60.19, H 4.36, N 12.76; found C 60.28,
H 4.38, N 12.89.
4g: Yellow solid; mp 161-162 °C; IR (KBr) ν 3258 (NH),
2971, 1671 (CdN), 1478, 1350 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.90 (s, 9H, 3CH3), 5.47 (s, 1H, CH), 7.04 (d,
J ) 8.4 Hz, 1H, ArH), 7.32 (d, J ) 8.1 Hz, 1H, ArH),
7.48-7.60 (m, 3H, ArH), 7.94 (d, J ) 7.8 Hz, 1H, ArH),
8.10 (d, J ) 8.1 Hz, 1H, ArH), 9.31 (s, 1H, NH) ppm; 13C
NMR (75 MHz, CDCl3) δ ) 202.7, 163.2, 161.6, 152.7,
136.4, 136.0, 135.5, 133.6, 130.1, 129.4, 128.5, 127.4, 127.0,
124.5, 122.1, 114.7, 65.0, 63.0, 57.9, 28.4 ppm; HRMS (m/
z) calcd for C22H18Cl2N4S2 (MH+) 473.0423, found 473.0415;
Anal. Calcd for C22H18Cl2N4S2 C 55.81, H 3.83, N 11.83;
found C 56.17, H 3.97, N 11.73.
4h: Yellow solid; mp 174-176 °C; IR (KBr) ν 3248 (NH),
2976, 1673 (CdN), 1488 cm-1; 1H NMR (300 MHz, CDCl3)
δ ) 1.90(s, 9H, 3CH3), 5.01 (s, 1H, CH), 7.14 (d, J ) 6.9
Hz, 2H, ArH), 7.49-7.62 (m, 4H, ArH), 7.94 (d, J ) 7.8
Hz, 1H, ArH), 8.12 (d, J ) 8.1 Hz, 1H, ArH), 9.29 (br s,
1H, NH) ppm; 13C NMR (100 MHz, CDCl3) δ ) 203.7,
164.0, 161.8, 153.0, 139.0, 132.8, 132.4, 131.3, 127.7, 127.3,
124.7, 123.6, 122.4, 115.0, 66.4, 65.2, 58.4, 28.7 ppm;
HRMS (m/z) calcd for C22H19BrN4S2 (M+) 482.0235, found
482.0230; Anal. Calcd for C22H19BrN4S2 C 54.66, H 3.96,
N 11.59; found C 54.94, H 4.02, N 11.58.
4a: Yellow solid; mp 187-189 °C; IR (KBr) ν 3244 (NH),
2978, 1677 (CdN), 1522, 1349 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.91 (s, 9H, 3CH3), 5.24 (s, 1H, CH), 7.46 (d,
J ) 8.4 Hz, 2H, ArH), 7.52-7.64 (m, 2H, ArH), 7.96 (d, J
) 7.8 Hz, 1H, ArH), 8.13 (d, J ) 7.8 Hz, 1H, ArH), 8.28
(d, J ) 8.7 Hz, 2H, ArH), 9.33 (br s, 1H, NH) ppm; 13C
NMR (75 MHz, CDCl3) δ ) 202.5, 163.3, 160.9, 152.7,
148.4, 143.3, 135.3, 130.2, 127.7, 127.2, 124.6, 124.5, 122.2,
114.7, 65.8, 65.1, 57.7, 28.4 ppm; HRMS (m/z) calcd for
C22H19N5O2S2 (M+) 449.0980, found 449.0985; Anal. Calcd
for C22H19N5O2S2 C 58.78, H 4.26, N 15.58; found C 59.10,
H 4.31, N 15.87.
4b: Yellow solid; mp 132-134 °C; IR (KBr) ν 3259 (NH),
2979, 1672 (CdN), 1531, 1349 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.92 (s, 9H, 3CH3), 5.23 (s, 1H, CH), 7.51-7.62
(m, 4H, ArH), 7.96 (d, J ) 8.1 Hz, 1H, ArH), 8.15(t, J )
7.8 Hz, 2H, ArH), 8.25-8.29 (m, 1H, ArH), 9.31 (br s, 1H,
NH) ppm; 13C NMR (75 MHz, CDCl3) δ ) 199.7, 160.4,
158.1, 150.1, 145.8, 135.6, 132.5, 132.1, 127.8, 124.9, 124.4,
121.7, 121.6, 121.5, 119.4, 111.9, 62.9, 62.4, 54.9, 25.6 ppm;
HRMS (m/z) calcd for C22H19N5O2S2 (M+) 449.0980, found
449.0978; Anal. Calcd for C22H19N5O2S2 C 58.78, H 4.26,
N 15.58; found C 58.73, H 4.29, N 15.52.
4c: Yellow solid; mp 123-125 °C; IR (KBr) ν 3259 (NH),
2974, 1676 (CdN), 1509, 1356 cm-1; 1H NMR (400 MHz,
CDCl3) δ ) 1.90 (s, 9H, 3CH3), 5.01 (s, 1H, CH), 7.09 (t,
J ) 8.4 Hz, 2H, ArH), 7.22-7.25 (m, 2H, ArH), 7.50 (t, J
) 7.6 Hz, 1H, ArH), 7.58 (t, J ) 8.0 Hz, 1H, ArH), 7.93 (d,
J ) 8.0 Hz, 1H, ArH), 8.11 (d, J ) 8.4 Hz, 1H, ArH), 9.31
(br s, 1H, NH) ppm; 13C NMR (100 MHz, CDCl3) δ ) 204.4,
164.7, 162.2, 153.0, 135.5, 132.8, 132.8, 130.9, 130.8, 127.2
(d, J ) 35.0 Hz, C), 124.6, 122.4, 116.9 (d, J ) 16.4 Hz,
CH), 115.2, 66.3, 65.0, 58.6, 28.7 ppm; Assignment of CH
and C in 13C NMR has been confirmed by a DEPT (see
Supporting Information); HRMS (m/z) calcd for C22H19FN4S2
(M+) 422.1035, found 422.1040; Anal. Calcd for
C22H19FN4S2 C 62.53, H 4.53, N 13.26; found C 62.60, H
4.64, N 13.45.
4d: Yellow solid; mp 163-165 °C; IR (KBr) ν 3249 (NH),
2980, 1674 (CdN), 1491, 1349 cm-1; 1H NMR (400 MHz,
CDCl3) δ ) 1.90 (s, 9H, 3CH3), 5.00 (s, 1H, CH), 7.19 (d,
J ) 6.0 Hz, 2H, ArH), 7.38 (d, J ) 8.4 Hz, 2H, ArH), 7.51
(t, J ) 7.6 Hz, 1H, ArH), 7.59 (t, J ) 7.6 Hz, 1H, ArH),
7.94 (d, J ) 8.0 Hz, 1H, ArH), 8.11 (d, J ) 8.4 Hz, 1H,
ArH), 9.31 (br s, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6) δ ) 197.3, 151.8, 136.2, 134.8, 133.6, 130.4,
129.1, 128.0, 127.2, 126.6, 123.4, 122.9, 114.9, 114.9, 65.7,
63.8, 57.2, 27.7 ppm; HRMS (m/z) calcd for C22H19ClN4S2
(M+) 438.0740, found 438.0741; Anal. Calcd for
C22H19ClN4S2 C 60.19, H 4.36, N 12.76; found C 60.24, H
4.50, N 12.99.
4i: Yellow solid; mp 148-150 °C; IR (KBr) ν 3247 (NH),
2924, 1675 (CdN), 1568, 1348 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.91 (s, 9H, 3CH3), 5.01 (s, 1H, CH), 7.18 (d,
J ) 7.2 Hz, 1H, ArH), 7.31 (d, J ) 7.8 Hz, 1H, ArH), 7.42
(s, 1H, ArH), 7.50-7.62 (m, 3H, ArH), 7.95 (d, J ) 7.8 Hz,
1H, ArH), 8.01 (d, J ) 8.1 Hz, 1H, ArH), 9.29 (br s, 1H,
NH) ppm; 13C NMR (75 MHz, CDCl3) δ ) 203.5, 163.8,
161.6, 152.7, 138.7, 135.3, 132.6, 132.1, 131.1, 127.5, 127.1,
124.6, 124.5, 123.4, 122.2, 114.8, 66.2, 65.0, 58.2, 28.5 ppm;
HRMS (m/z) calcd for C22H19BrN4S2 (M+) 482.0235, found
482.0237; Anal. Calcd for C22H19BrN4S2 C 54.66, H 3.96,
N 11.59; found C 54.84, H 3.94, N 11.42.
4e: Yellow solid; mp 136-137 °C; IR (KBr) ν 3245 (NH),
2975, 1674 (CdN), 1349 cm-1; 1H NMR (300 MHz, CDCl3)
δ ) 1.90 (s, 9H, 3CH3), 5.01 (s, 1H, CH), 7.13 (d, J ) 6.3
Hz, 1H, ArH), 7.35 (d, J ) 6.3 Hz, 2H, ArH), 7.49-7.62
(m, 3H, ArH), 7.94 (d, J ) 7.8 Hz, 1H, ArH), 8.11 (d, J )
7.8 Hz, 1H, ArH), 9.30 (br s, 1H, NH) ppm; 13C NMR (100
4j: Yellow solid; mp 138-140 °C; IR (KBr) ν 3278 (NH),
2978, 1669 (CdN), 1494, 1359 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.93 (s, 9H, 3CH3), 5.53 (s, 1H, CH), 7.10 (d,
J ) 7.8 Hz, 1H, ArH), 7.26 (t, J ) 7.7 Hz, 1H, ArH), 7.38
(t, J ) 7.5 Hz, 1H, ArH), 7.48-7.60 (m, 2H, ArH), 7.69 (d,
J ) 8.1 Hz, 1H, ArH), 7.94 (d, J ) 7.8 Hz, 1H, ArH), 8.10

826 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Zhu et al.
(d, J ) 7.8 Hz, 1H, ArH), 9.32 (s, 1H, NH) ppm; 13C NMR
(75 MHz, CDCl3) δ ) 198.0, 158.1, 156.6, 147.3, 131.5,
130.1, 128.2, 125.5, 123.4, 123.1, 122.0, 121.5, 121.2, 119.0,
116.7, 109.4, 60.8, 60.0, 52.9, 23.0 ppm; HRMS (m/z) calcd
for C22H19BrN4S2 (MH+) 483.0307, found 483.0305; Anal.
Calcd for C22H19BrN4S2 C 54.66, H 3.96, N 11.59; found C
54.54, H 3.90, N 11.70.
4k: Yellow solid; mp 199-200 °C; IR (KBr) ν 3256 (NH),
2978, 2226, 1678 (CdN), 1586, 1349 cm-1; 1H NMR (300
MHz, CDCl3) δ ) 1.98 (s, 9H, 3CH3), 5.20 (s, 1H, CH),
7.33 (d, J ) 8.1 Hz, 1H, ArH), 7.52-7.64 (m, 4H, ArH),
7.80-7.97 (m, 5H, ArH), 8.16 (d, J ) 7.5 Hz, 1H, ArH),
9.37 (s, 1H, NH) ppm; 13C NMR (75 MHz, CDCl3) δ )
204.5, 164.2, 162.1, 152.8, 135.4, 134.0, 133.6, 133.5, 129.7,
129.1, 128.5, 128.1, 127.5, 127.1, 127.0, 126.9, 125.0, 124.5,
122.2, 115.1, 67.2, 64.9, 58.4, 28.6 ppm; HRMS (m/z) calcd
for C26H22N4S2 (M+) 454.1286, found 454.1285; Anal. Calcd
for C26H22N4S2 C 68.69, H 4.88, N 12.32; found C 68.94, H
4.95, N 11.90.
4l. Yellow solid; mp 178-179 °C; IR (KBr) ν 3219 (NH),
2986, 1683 (CdN), 1450, 1358 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.96 (s, 9H, 3CH3), 6.00(s, 1H, CH), 7.27 (s,
1H, ArH), 7.44-7.64 (m, 5H, ArH), 7.90-7.97 (m, 3H,
ArH), 8.08 (d, J ) 8.1 Hz, 1H, ArH), 8.18 (d, J ) 8.1 Hz,
1H, ArH), 9.28 (br s, 1H, NH) ppm; 13C NMR (100 MHz,
CDCl3) δ ) 205.5, 153.1, 135.7, 134.4, 134.0, 132.7, 130.3,
129.7, 127.7, 127.7, 127.2, 126.8, 126.0, 125.4, 124.8, 123.1,
122.4, 121.8, 115.3, 112.5, 65.1, 62.3, 59.1, 28.8 ppm;
HRMS (m/z) calcd for C26H22N4S2 (M+) 454.1286, found
454.1285; Anal. Calcd for C26H22N4S2 C 68.69, H 4.88, N
12.32; found C 68.30, H 4.85, N 12.10.
4m: Yellow solid; mp 146-147 °C; IR (KBr) ν 3264
(NH), 2966, 1674 (CdN), 1492, 1350 cm-1; 1H NMR (300
MHz, CDCl3) δ ) 1.91 (s, 9H, 3CH3), 5.26 (s, 1H, CH),
7.26 (s, 2H, ArH), 7.39 (d, J ) 1.5 Hz, 3H, ArH), 7.48-7.60
(m, 2H, ArH), 7.93 (d, J ) 7.5 Hz, 1H, ArH), 8.10 (d, J )
8.1 Hz. 1H, ArH), 9.10 (br s, 1H, NH) ppm; 13C NMR (100
MHz, CDCl3) δ ) 204.8, 164.1, 162.3, 153.0, 137.0, 135.6,
129.8, 129.7, 128.8, 127.6, 127.2, 124.6, 122.3, 115.2, 67.3,
64.9, 58.8, 28.7 ppm; HRMS (m/z) calcd for C22H20N4S2
(M+) 404.1129, found 404.1126; Anal. Calcd for C22H20N4S2
C 65.32, H 4.98, N 13.85; found C 65.57, H 4.93, N 13.46.
4o: White solid; mp 176-177 °C; IR (KBr) ν 3243 (NH),
2928, 1675 (CdN), 1522, 1386 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.28-1.45 (m, 3H, CH2), 1.70-1.73 (m, 2H,
CH), 1.86-1.96 (m, 3H, CH2), 2.46-2.62 (m, 2H, CH2),
5.02-5.11 (m, 1H, CH), 5.36 (s, 1H, CH), 7.47 (d, J ) 8.7
Hz, 2H, ArH), 7.50-7.63 (m, 2H, ArH), 7.95 (d, J ) 7.8
Hz, 1H, ArH), 8.12 (d, J ) 8.1 Hz, 1H, ArH), 8.29 (d, J )
8.7 Hz, 2H, ArH), 9.05 (br s, 1H, NH) ppm; 13C NMR (100
MHz, DMSO-d6) δ ) 202.7, 165.3, 151.8, 142.0, 141.0,
135.3, 127.2, 126.8, 123.6, 122.4, 114.0, 106.4, 55.4, 55.0,
52.6, 25.5, 25.4, 24.8, 24.8, 23.2 ppm; HRMS (m/z) calcd
for C24H21N5O2S2 (M+) 475.1137, found 475.1140; Anal.
Calcd for C24H21N5O2S2 C 60.61, H 4.45, N 14.73; found C
60.64, H 4.53, N 15.11.
CH), 1.86-1.96 (m, 3H, CH2), 2.47-2.63 (m, 2H, CH2),
5.07 (t, J ) 12.2 Hz, 1H, CH), 5.36 (s, 1H, CH), 7.53 (t, J
) 7.5 Hz,1H, ArH), 7.61-7.66 (m, 3H, ArH), 7.94 (d, J )
7.8 Hz, 1H, ArH), 8.12 (d, J ) 8.4 Hz, 1H, ArH), 8.16 (s,
1H, ArH), 8.26-8.29 (m, 1H, ArH), 9.05 (br s, 1H, NH)
ppm; 13C NMR (100 MHz, CDCl3) δ ) 202.1, 162.2, 161.5,
152.9, 148.7, 137.8, 135.0, 130.7, 127.7, 127.2, 124.6, 124.5,
122.2, 114.7, 65.2, 59.2, 56.0, 27.9, 26.8, 26.2, 26.0, 25.3
ppm; HRMS (m/z) calcd for C24H21N5O2S2 (M+) 475.1137,
found 475.1142; Anal. Calcd for C24H21N5O2S2 C 60.61, H
4.45, N 14.73; found C 60.22, H 4.06, N 14.50.
4q: Yellow solid; mp 172-174 °C; IR (KBr) ν 3292 (NH),
2932, 1673 (CdN), 1393 cm-1; 1H NMR (300 MHz, CDCl3)
δ ) 1.29-1.44 (m, 3H, CH2), 1.71-1.74 (m, 2H, CH), 1.91
(s, 3H, CH2), 2.57-2.62 (m, 2H, CH2), 5.12 (s, 1H, CH),
5.63 (s, 1H, CH), 7.05-7.08 (m, 1H, ArH), 7.33 (s, 1H,
ArH), 7.52-7.60 (m, 3H, ArH), 7.94 (t, J ) 5.7 Hz, 1H,
ArH), 8.11 (d, J ) 6.9 Hz, 1H, ArH), 8.99 (br s, 1H, NH)
ppm; 13C NMR (75 MHz, CDCl3) δ ) 202.6, 162.6, 152.9,
136.2, 135.3, 133.1, 130.2, 129.3, 128.5, 127.5, 127.0, 124.5,
122.1, 114.7, 62.6, 59.2, 56.0, 28.2, 26.6, 26.2, 26.0, 25.3
ppm; HRMS (m/z) calcd for C24H20Cl2N4S2 (M+) 498.0506,
found 498.0506; Anal. Calcd for C24H20Cl2N4S2 C 57.71, H
4.04, N 11.22; found C 57.56, H 4.12, N 11.35.
4r: White solid; mp 179-181 °C; IR (KBr) ν 3263 (NH),
2931, 2853, 1670 (CdN), 1375 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.33-1.45 (m, 3H, CH2), 1.70-1.73 (m, 2H,
CH), 1.85-1.95 (m, 3H, CH2), 2.47-2.62 (m, 2H, CH2),
5.02-5.11 (m, 1H, CH), 5.13 (s, 1H, CH), 7.18 (d, J ) 7.8
Hz, 1H, ArH), 7.30 (t, J ) 7.8 Hz, 1H, ArH), 7.42 (s, 1H,
ArH), 7.49-7.62 (m, 3H, ArH), 7.93 (d, J ) 7.8 Hz, 1H,
ArH), 8.10 (d, J ) 8.4 Hz, 1H, ArH), 9.02 (br s, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6) δ ) 203.3, 152.0,
139.1, 135.4, 134.8, 132.0, 131.7, 131.5, 127.2, 126.8, 126.5,
123.4, 122.8, 122.1, 65.0, 57.8, 55.4, 27.3, 26.0, 25.6, 25.3,
24.8 ppm; HRMS (m/z) calcd for C24H21BrN4S2 (M+)
508.0391, found 508.0391; Anal. Calcd for C24H21BrN4S2
C 56.58, H 4.15, N 11.00; found C 57.33, H 4.26, N 11.11.
4s: Yellow solid; mp 153-154 °C; IR (KBr) ν 3230 (NH),
2929, 1669 (CdN), 1374 cm-1; 1H NMR (300 MHz, CDCl3)
δ ) 1.31-1.47 (m, 3H, CH2), 1.72-1.76 (m, 2H, CH),
1.87-1.97 (m, 3H, CH2), 2.53-2.70 (m, 2H, CH2), 5.09-5.17
(m, 1H, CH), 5.31 (s, 1H, CH), 7.30 (s, 1H, ArH), 7.49-7.62
(m, 4H, ArH), 7.78 (s, 1H, ArH), 7.82-7.93 (m, 4H, ArH),
8.13 (d, J ) 8.1 Hz, 1H, ArH), 9.07 (br s, 1H, NH) ppm;
13C NMR (100 MHz, DMSO-d6) δ ) 203.9, 161.3, 152.0,
134.8, 134.1, 132.8, 132.8, 129.1, 128.4, 128.1, 127.7, 127.2,
126.9, 126.9, 126.5, 124.7, 123.4, 122.9, 66.3, 57.9, 55.6,
27.4, 26.0, 25.6, 25.4, 24.8 ppm; HRMS (m/z) calcd for
C28H24N4S2 (M+) 480.1442, found 480.1443; Anal. Calcd
for C28H24N4S2 C 69.97, H 5.03, N 11.66; found C 69.93, H
5.35, N 11.29.
5a: Yellow solid; mp 159-160 °C; IR (KBr) ν 3233 (NH),
2979, 1684 (CdN), 1565, 1452, 1347 cm-1; 1H NMR (300
MHz, CDCl3) δ ) 1.90 (s, 9H, 3CH3), 5.01 (s, 1H, CH),
7.20 (d, J ) 7.8 Hz, 1H, ArH), 7.32 (d, J ) 7.8 Hz, 1H,
ArH), 7.45-7.56 (m, 4H, ArH), 7.63 (d, J ) 7.8 Hz, 1H,
ArH), 7.83 (d, J ) 6.9 Hz, 1H, ArH), 9.44 (s, 1H, NH) ppm;
13C NMR (100 MHz, CDCl3) δ ) 203.2, 162.0, 151.9, 140.7,
4p: Brown solid; mp 95-98 °C; IR (KBr) ν 3230 (NH),
2932, 1670 (CdN), 1513, 1370 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.24-1.46 (m, 3H, CH2), 1.70-1.74 (m, 2H,

Imino-pyrrolidine-thione Scaffold
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 827
138.5, 133.0, 132.5, 131.3, 130.5, 127.4, 126.2, 125.9, 123.6,
121.6, 113.4, 111.7, 65.3, 64.3, 54.3, 28.7 ppm; HRMS (m/
z) calcd for C22H19BrN4OS (M+) 466.0463, found 466.0464;
Anal. Calcd for C22H19BrN4OS C 56.54, H 4.10, N 11.99;
found C 56.46, H 3.95, N 11.97.
(100 MHz, CDCl3) δ ) 204.1, 164.0, 161.8, 158.8, 153.0,
135.8, 135.5, 135.4, 132.3, 130.4, 130.0, 127.8, 127.3, 124.7,
122.4, 115.2, 66.4, 65.2, 58.5, 28.7 ppm; HRMS (m/z) calcd
for C22H22N4S2 (M+) 406.1286, found 406.1285; Anal. Calcd
for C22H22N4S2 C 64.99, H 5.45, N 13.78; found C 64.86, H
5.46, N 13.65.
5b: Yellow solid; mp 110-111 °C; IR (KBr) ν 3252 (NH),
2929, 1672 (CdN), 1368 cm-1; 1H NMR (300 MHz, CDCl3)
δ ) 1.24-1.44 (m, 3H, CH2), 1.62-1.73 (m, 2H, CH),
1.86-1.95 (m, 3H, CH2), 2.47-2.70 (m, 2H, CH2), 5.02-5.10
(m, 1H, CH), 5.19 (s, 1H, CH), 7.20 (d, J ) 7.5 Hz, 1H,
ArH), 7.31 (t, J ) 7.8 Hz, 1H, ArH), 7.42-7.51 (m, 3H,
ArH), 7.55 (d, J ) 7.8 Hz, 1H, ArH), 7.63 (d, J ) 8.1 Hz,
1H, ArH), 7.82 (d, J ) 6.9 Hz, 1H, ArH), 9.21 (s, 1H, NH)
ppm; 13C NMR (75 MHz, CDCl3): δ ) 202.6, 151.7, 140.3,
137.7, 132.9, 132.1, 131.1, 127.2, 127.2, 126.0, 123.5, 121.4,
113.1, 111.6, 63.1, 59.1, 52.3, 27.8, 26.9, 26.2, 26.0, 25.3
ppm; HRMS (m/z) calcd for C24H21BrN4OS (M+) 492.0619,
found 492.0618; Anal. Calcd for C24H21BrN4OS C 58.42, H
4.29, N 11.35; found C 58.06, H 4.30, N 11.26.
5c: Yellow solid; mp 195-196 °C; IR (KBr) ν 3231 (NH),
2977, 1679 (CdN), 1523, 1350 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.91 (s, 9H, 3CH3), 5.51 (s, 1H, CH), 7.51 (d,
J ) 7.5 Hz, 4H, ArH), 7.65 (d, J ) 6.9 Hz, 1H, ArH), 7.85
(d, J ) 6.9 Hz, 1H, ArH), 8.29 (d, J ) 8.7 Hz, 2H, ArH),
9.49 (s, 1H, NH) ppm; 13C NMR (100 MHz, CDCl3) δ )
202.3, 170.8, 151.9, 148.7, 143.1, 140.6, 130.5, 127.6, 126.3,
124.8, 121.6, 113.2, 111.7, 105.4, 65.4, 63.9, 53.8, 28.6 ppm;
HRMS (m/z) calcd for C22H19N5O3S (M+) 433.1209, found
433.1211; Anal. Calcd for C22H19N5O3S C 60.96, H 4.42, N
16.16; found C 60.94, H 4.43, N 16.16.
5d: Yellow solid; mp 191-193 °C; IR (KBr) ν 3234 (NH),
2935, 1675 (CdN), 1561, 1344 cm-1; 1H NMR (300 MHz,
CDCl3) δ ) 1.89 (s, 9H, 3CH3), 5.03 (s, 1H, CH), 7.22(d, J
) 8.4 Hz, 2H, ArH), 7.40 (d, J ) 8.4 Hz, 2H, ArH),
7.45-7.49 (m, 2H, ArH), 7.63 (d, J ) 8.4 Hz, 1H, ArH),
7.82 (d, J ) 6.6 Hz, 1H, ArH), 9.35 (br s, 1H, NH) ppm;
13C NMR (75 MHz, CDCl3) δ ) 203.7, 164.0, 161.8, 153.0,
139.0, 132.8, 132.4, 131.3, 127.7, 127.3, 124.7, 123.6, 122.4,
115.0, 66.4, 65.2, 58.4, 28.7 ppm; HRMS (m/z) calcd for
C22H19ClN4OS (M+) 422.0968, found 422.0965; Anal. Calcd
for C22H19ClN4OS C 62.48, H 4.53, N 13.25; found C 62.50,
H 4.68, N 13.46.
5e: Yellow solid; mp 161-163 °C; IR (KBr) ν 3257 (NH),
2964, 1676 (CdN), 1566, 1491, 1408 cm-1; 1H NMR (300
MHz, CDCl3): δ ) 1.86 (s, 9H, 3CH3), 5.06 (s, 1H, CH)
7.21 (d, J ) 8.1 Hz, 2H, ArH), 7.37 (d, J ) 8.1 Hz, 2H,
ArH), 7.43 (t, J ) 5.0 Hz, 1H, ArH), 8.86 (d, J ) 4.8 Hz,
2H, ArH), 9.31 (br s, 1H, NH) ppm; 13C NMR (100 MHz,
CDCl3) δ ) 205.5, 163.0, 158.9, 136.2, 135.4, 132.3, 130.5,
129.9, 121.9, 116.0, 65.0, 64.7, 61.5, 28.8 ppm; HRMS (m/
z) calcd for C19H18ClN5S (M+) 383.0971, found 383.0970;
Anal. Calcd for C19H18ClN5S C 59.44, H 4.73, N 18.24;
found C 59.60, H 4.86, N 18.45.
5g: Yellow solid; mp 226-227 °C; IR (KBr) ν 3310 (NH),
2938, 2185, 1658 (CdN), 1603, 1528 cm-1; 1H NMR (300
MHz, CDCl3) δ ) 1.19-1.27 (m, 1H, CH2), 1.44-1.46 (m,
2H, CH2), 1.78-1.96 (m, 7H, CH2), 3.36 (s, 2H, CH2), 4.38
(s, 2H, CH2), 5.17 (br s, 1H, NH), 5.57 (s, 2H, CH),
7.53-7.58 (m, 1H, ArH), 7.87 (s, 1H, ArH), 8.20 (d, J )
6.9 Hz, 1H, ArH), 8.35 (s, 1H, ArH); 13C NMR (100 MHz,
DMSO-d6) δ ) 203.1, 168.9, 147.1, 140.6, 135.5, 129.4,
123.5, 122.8, 116.9, 112.3, 79.2, 64.4, 33.6, 26.9, 26.9, 25.7,
25.5, 25.4 ppm; HRMS (m/z) calcd for C20H21N5O2S2 (M+)
427.1137, found 427.1134; Anal. Calcd for C20H21N5O2S2
C 56.18, H 4.95, N 16.38; found C 56.35, H 4.66, N 16.60.
A: Yellow solid; mp 177-178 °C; IR (KBr) ν 3250 (NH),
1
2950, 2245(CN), 1560, 1491, 1350 cm-1; H NMR (300
MHz, CDCl3) δ ) 1.90 (s, 9H, CH3), 5.02 (s, 1H, CH), 7.19
(d, J ) 8.4 Hz, 2H, ArH), 7.38 (d, J ) 8.7 Hz, 2H, ArH),
7.49-7.62 (m, 3H, ArH and NH), 7.94 (d, J ) 8.1 Hz, 1H,
ArH), 8.11 (d, J ) 8.1 Hz, 1H, ArH) ppm; 13C NMR (75
MHz, CDCl3) δ ) 204.0, 153.0, 150.8, 135.8, 133.0, 130.6,
127.7, 127.3, 124.7, 124.0, 122.4, 115.1, 102.1, 66.5, 65.1,
58.4, 28.7 ppm; HRMS (m/z) calcd for C22H19ClN4S2 (M+)
438.0740, found 438.0740; Anal. Calcd for C22H19ClN4S2
C 60.19, H 4.36, N 12.76; found C 60.45, H 4.21, N 12.89.
Acknowledgment. The work was partially supported by
the National Natural Science Foundation of China (No.
20672079, 20910102041), Natural Science Foundation of
Jiangsu Province (No. BK 2006048), Nature Science Key
Basic Research of Jiangsu Province for Higher Education
(No. 06KJ A15007), the Specialized Research Fund for the
Doctoral Program of Higher Education (No. 20060285001),
and Key Project in Science and Technology Innovation
Cultivation Program of Soochow University.
Supporting Information Available. Detailed experimen-
1
tal procedure, compound characterization data, H and 13C
NMR spectra, and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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828 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
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