One-pot chemoenzymatic multicomponent synthesis of thiazole derivatives

Article abstract of DOI:10.3390/molecules181113425

A novel chemoenzymatic one-pot multicomponent synthesis of thiazole derivatives was developed. A series of thiazole derivatives were synthesized with high yields up to 94% under mild enzyme-catalyzed conditions. The blank and control experiments reveal that trypsin from porcine pancreas (PPT) displayed great catalytic activity to promote this reaction and showed a wide tolerance range towards different substrate amines. This trypsin-catalyzed multicomponent conversion method provides a novel strategy to synthesize thiazole derivatives and expands the application of enzymes in organic synthesis.

Full text of DOI:10.3390/molecules181113425

Molecules 2013, 18, 13425-13433; doi:10.3390/molecules181113425
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
One-Pot Chemoenzymatic Multicomponent Synthesis of
Thiazole Derivatives
Hui Zheng *, Yi-Jia Mei, Kui Du, Xian-Ting Cao and Peng-Fei Zhang
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University,
Hangzhou 310036, Zhejing, China
* Author to whom correspondence should be addressed; E-Mail: huizheng@hznu.edu.cn;
Tel./Fax: +86-571-2886-2867.
Received: 19 August 2013; in revised form: 20 October 2013 / Accepted: 21 October 2013 /
Published: 30 October 2013
Abstract: A novel chemoenzymatic one-pot multicomponent synthesis of thiazole
derivatives was developed. A series of thiazole derivatives were synthesized with high
yields up to 94% under mild enzyme-catalyzed conditions. The blank and control
experiments reveal that trypsin from porcine pancreas (PPT) displayed great catalytic
activity to promote this reaction and showed a wide tolerance range towards different
substrate amines. This trypsin-catalyzed multicomponent conversion method provides a
novel strategy to synthesize thiazole derivatives and expands the application of enzymes in
organic synthesis.
Keywords: heterocycles; multicomponent; chemoenzymatic; catalysis; thiazole
1. Introduction
Thiazoles and their derivatives are an important class of heterocyclic compounds which possess
broad biological activities, such as antimicrobial [1], antipyretic [2], antiparasitic [3], antihistaminic [4],
and antiviral properties [5]. Aryl-substituted thiazoles are also important functional materials in
applications such as fluorescent dyes and liquid crystals [6]. Thiazoles have traditionally been
synthesized by the Hantzsch synthesis [7,8], which suffers from some disadvantages such as long
reaction times, low yields and harsh reaction conditions. Although there are some reports using
microwave irradiation in the Hantzsch reaction to overcome these disadvantages [9,10], the
development of novel methods for the preparation of thiazoles derivatives is still in demand.

Molecules 2013, 18
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We have been interested in the study of chemoenzymatic organic reactions and especially the
enzymatic synthesis of heterocyclic compounds [11,12]. Several enzymes have exhibited great
advantages in organic transformations like Michael additions [13–15], aldol reactions [16,17], Mannich
reactiona [18] and Knoevenagel reactiona [19]. As far as we know, natural enzymes which are capable
of catalyzing multicomponent reactions, are very rare. As a continuation of our work studying
chemoenzymatic organic reactions, we report herein a novel strategy for the high yielding
chemoenzymatic one-pot multicomponent synthesis under mild conditions of thiazole derivatives from
secondary amines, benzoyl isothiocyanate, and dialkyl acetylenedicarboxylates as starting materials.
2. Results and Discussion
Benzoyl isothiocyanate (1a), secondary amine 2a, and dimethyl acetylenedicarboxylate (3a) were
selected as model substrates to prepare the thiazole 4a via reactions catalyzed by different enzymes in
EtOH solvent. The model reaction and yields are shown in Scheme 1 and Table 1. Eight candidates such as
trypsin from porcine pancreas (PPT), α-amylase from hog pancreas, diastase from Aspergillus oryzae,
α-amylase from Aspergillus oryzae, lipase AT30, Amano lipase M from Mucor javanicus, and bovine
serum albumin (BSA) were screened (Table 1, entries 1–8). The yield of product was the monitored
parameter to evaluate the catalytic activity of enzymes. The experimental results revealed that trypsin
from porcine pancreas had a good catalytic ability affording 90% yields. Other enzymes (Table 1,
entries 2–8) showed medium to low catalytic activity in this reaction. Moreover, the reaction catalyzed
by the non-enzyme protein bovine serum albumin (BSA) gave the product in 50% yield (Table 1, entry 8),
which showed that non-enzyme proteins also have the ability to catalyze this reaction, but the yield is
much lower than that catalyzed by PPT. These results implied that the reaction take place in a specific
fashion on the catalytic site of PPT, so we selected PPT as the optimum catalyst in this reaction.
Scheme 1. Model one-pot multicomponent synthesis of thiazole derivatives.
OCH3
O
O
enzyme
S
N
O
O
NCS
H
+
N
+
N
H3CO
OCH3
3a
1a
2a
4a
Additionally, the blank experimental without enzyme and the control experiment with denatured
PPT were performed to confirm the catalytic ability of PPT. It was found that only trace products were
detected (Table 1, entries 9 and 10) in these experiments. Therefore, trypsin from porcine pancreas
plays a key catalytic role in this chemoenzymatic one-pot synthesis of thiazole derivatives.
In order to optimize the reaction conditions, the effects of solvents, temperature and PPT concentration
were investigated. Various organic solvents were screened using PPT as catalyst (Table 2). The results
revealed that solvent shows great effect on the catalytic activity of PPT. It was found that ethanol was the
most efficient solvent to promote the reaction, with a yield of 90% by GC (Table 2, entry 1). Other
solvents, such as 1,4-dioxane, acetone, and THF only gave traces of products (Table 2, entries 7–9).

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Table 1. Optimization of catalyst a.
Entry
Catalyst
Time (h)
Yield (%) b
1
2
3
4
5
6
7
8
9
Trypsin from porcine pancreas (PPT)
α-Amylase from hog pancreas
Diastase from Aspergillus oryzae
α-Amylase from Aspergillus oryzae
Lipase AT30
7
7
7
7
7
7
7
7
7
7
90
60
67
53
61
Amano lipase M from Mucor javanicus
Lipase from porcine pancreas
Bovine serum albumin (BSA)
Blank (no enzyme)
40
63
50
Trace
Trace
10
Denatured typsin from porcine pancreas c
a
Reaction conditions: diethylamine (1 mmol), benzoyl isothiocyanate (1 mmol), and dimethyl
but-2-ynedioate (1 mmol), Trypsin from porcine pancreas (20 mg), ethanol (5 mL), shaken at 160 rpm at
b
c
45 °C; GC yields are based on tridecane as an internal standard; Trypsin from porcine pancreas was
denatured according to the literature [18].
Table 2. The different screened solvents a.
Entry
Solvent
Ethanol
CH2Cl2
T/°C
45
Yield (%) b
1
2
3
4
5
6
7
8
9
90
75
45
n-Hexane
CH3CN
Methanol
Acetone
1,4-Dioxane
THF
45
33
45
32
45
31
45
10
45
Trace
Trace
Trace
45
Water
45
a
Reaction conditions: diethylamine (1 mmol), benzoyl isothiocyanate (1 mmol), and dimethyl
but-2-ynedioate (1 mmol), Trypsin from porcine pancreas (20 mg), solvents (5 mL), shaken at 160 rpm at 45 °C;
b GC yields are based on tridecane as an internal standard.
Other influence factors such as temperature, concentration of PPT, and reaction time also have been
investigated (Table 3). It was found that when the temperatures ranged from 20 °C to 45 °C, the yield
of the products increased (Table 3, entries 1–5), whereas when the temperature exceeded 45 °C, the
yield decreased from 90% to 82% (Table 3, entries 5–7). This was probably due to the inactivation of
the enzyme at the higher temperature. The results of screened PPT amount revealed that the amount of
20 mg enzyme was the optimal proportion to promote this reaction under the same conditions
(Table 3, entries 8–12). The reaction time was also screened and found 7 h is suitable. So the optimum
reaction conditions are 20 mg PPT, 45 °C and 7 h.

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Table 3. Optimization of the reaction conditions a.
Entry
1
PPT amount (mg)
Temp (°C)
Time (h)
Yield (%) b
20
20
20
20
20
20
20
10
20
30
40
50
20
20
20
20
30
35
40
45
50
55
45
45
45
45
45
45
45
45
7
7
7
7
7
7
7
7
7
7
7
7
6
7
8
46
59
73
80
90
85
82
70
88
80
77
71
75
90
88
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
Reaction conditions: diethylamine (1 mmol), benzoyl isothiocyanate (1 mmol), and dimethyl
b
but-2-ynedioate (1 mmol), ethanol (5 mL), shaken at 160 rpm; GC yields are based on tridecane as an
internal standard.
Table 4. Chemoenzymatic one-pot multicomponent synthesis of thiazole derivatives a.
Entry
Products
R1
R2
R3
Yield (%)
90 b (82) c
69 (62)
1
2
3
4
4a
4b
4c
4d
C2H5-
C2H5-
CH3-
CH3-
C2H5-
C2H5-
CH3-
CH3-
CH3-
C2H5-
CH3-
C2H5-
93 (83)
79 (70)
5
6
4e
4f
CH3-
94 (85)
88 (79)
C2H5-
7
8
4g
4h
4i
-CH2CH2OCH2CH2-
CH3-
C2H5-
CH3-
C2H5-
80 (72)
63 (52)
85 (73)
74 (61)
-CH2CH2OCH2CH2-
-CH2CH2CH2CH2-
-CH2CH2CH2CH2-
9
10
4j
11
4k
H
CH3-
(75)
a
Reaction conditions: secondary amines (1 mmol), benzoyl isothiocyanate (1 mmol), and dimethyl
but-2-ynedioate (1 mmol), Trypsin from porcine pancreas (20 mg), ethanol (5 mL), shaken at 160 rpm at
45 °C; b GC yields are based on tridecane as an internal standard; c Isolated yield.

Molecules 2013, 18
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After we established the optimal reaction conditions, we employed various different secondary
amines and dialkyl acetylenedicarboxylates to investigate the substrate scope for this novel
chemoenzymatic one-pot multicomponent synthetic method. The results are summarized in Table 4.
Interestingly, the experiments demonstrated that diethyl acetylenedicarboxylate offered a lower yield
compared to that with dimethyl acetylenedicarboxylate, which is probably attributable to the steric
effect. Furthermore, the result showed that PPT has a wide tolerance range towards secondary amines in
this reaction. Especially, it was found that the glucosamine could be well applied in this reaction
(Table 4, entry 11), which is a new approach to synthesize some glucosamine thiazole derivatives with
potential bioactivities.
The plausible reaction mechanism for this process is proposed in Scheme 2. The reaction of
N-benzoylthiourea derivatives 5 which were derived from the addition of secondary amines 2 to
benzoyl isothiocyanate 1, reacts with acetylenedicarboxylates 3 to give compound 6. The trypsin
activates carbonyl of compound 6 and transforms it to intermediate 7 and 8, and then the final product 4
is formed in good yields without by-products [7].
Scheme 2. The plausible reaction mechanism of this one-pot multicomponent synthesis of
thiazole derivatives catalyzed by enzyme.
3. Experimental
3.1. General
1
All reagents were purchased without further purification. H-NMR was recorded on a Bruker
Avance 400 spectometer at 400 MHz in CDCl3 using TMS as internal standard. IR spectra were
recorded on a Bruker Equinox-55 spectrophotometer using KBr discs in the 4000–400 cm−1 region. A
Hewlett-Packard model 6890 gas chromatograph with a capillary column (HP-5) and flame-ionization
detector was used to analyze the yields of products using tridecane as an internal standard. Melting
points were recorded on an X4-Data microscopic melting point apparatus and were uncorrected.
Elemental analyses were performed on an EA-1110 instrument. All the enzymes were purchased from
Acros, Alfa, Aldrich and TCI.

Molecules 2013, 18
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3.2. General Procedure for the Synthesis of Thiazole Derivatives
A mixture of secondary amine (1.0 mmol), benzoyl isothiocyanate (1.0 mmol), dialkyl
acetylenedicarboxylate (1.0 mmol), trypsin from porcine pancreas (PPT, 20 mg) and ethanol (5 mL),
was introduced to a test tube (10 mL), then the mixture was placed on a shaker under 160 rpm
end-over-end rotation at 45 °C for 7 h. The reaction mixture was monitored by TLC to the endpoint.
The solution was then filtered through paper and the solvent was evaporated. The residue was purified
on silica gel (hexane/EtOAc = 4:1 as eluent) to afford the target compounds. The compounds 4a–j are
known [7,20] and compounds 4c and 4k are new, and were additionally characterized by elemental
analysis. The compounds were identified as follows:
Methyl 2-(diethylamino)-4-phenylthiazole-5-carboxylate (4a): Solid. Mp 81–83 °C. IR (KBr): 3054,
1
3025, 2974, 2934, 1710, 1600, 1511, 1481, 1331, 1263 cm−1. H-NMR (CDCl3, δ, ppm): 1.28
(t, J = 6.8 Hz, 6H, 2CH3-); 3.56 (q, J = 6.8 Hz, J = 14.0 Hz, 4H, 2-CH2-); 3.73 (s, 3H, CH3O-);
7.39–7.77 (m, 5H, Ph-H). MS(EI): m/z(%) = 290 (M+).
Ethyl 2-(diethylamino)-4-phenylthiazole-5-carboxylate (4b): Solid. Mp 90–92 °C. IR (KBr): 3051,
1
2975, 2929, 1698, 1551, 1330, 1258 cm−1. H-NMR (CDCl3, δ, ppm): 1.24 (t, J = 6.8 Hz, 3H, CH3-);
1.28 (t, J = 7.2 Hz, 6H, 2CH3-); 3.56 (q, J = 7.2 Hz, J = 14.4 Hz, 4H, 2-CH2-); 4.20 (q, J = 7.2 Hz,
J = 14.4 Hz, 2H, -CH2O-); 7.38–7.76 (m, 5H, Ph-H). MS(EI): m/z(%) = 304 (M+).
Methyl 2-[methyl(phenylmethyl)amino]-4-phenylthiazole-5-carboxylate (4c): Solid. Mp 77–79 °C. IR
(KBr): 3025, 2984, 2943, 1710, 1604, 1550, 1330, 1244 cm−1. 1H-NMR (CDCl3, δ, ppm): 3.11 (s, 3H,
-CH3-); 3.75 (s, 3H, CH3O-); 4.79 (s, 2H, -CH2-); 7.33–7.42 (m, 8H, Ph-H); 7.79–7.80 (m, 2H, Ph-H).
MS(EI): m/z(%) = 262 (M+). Anal. Calcd for C13H14N2O2S: C, 59.52; H, 5.38; N, 10.68; Found:
C, 59.60; H, 5.36; N, 10.71%.
Ethyl 2-[methyl(phenylmethyl)amino]-4-phenylthiazole-5-carboxylate (4d): Solid. Mp 73–75 °C.
1
IR (KBr): 3059, 2983, 2926, 1702, 1605, 1550, 1331, 1242 cm−1. H-NMR (CDCl3, δ, ppm): 1.25
(t, J = 6.8 Hz, 3H, CH3-); 3.11 (s, 3H, CH3-); 4.22 (q, J = 7.2 Hz, J = 14.4 Hz, 2H, -CH2O-); 7.31–7.41
(m, 8H, Ph-H); 7.78–7.79 (m, 2H, Ph-H). MS(EI): m/z(%) = 276 (M+).
Methyl 2-[diisopropylamine]-4-phenylthiazole-5-carboxylate (4e): Solid. Mp 85–86 °C. IR (KBr):
1
3054, 3025, 2988, 2934, 1710, 1605, 1520, 1501, 1481, 1331, 1175 cm−1; H-NMR (CDCl3, δ, ppm):
1.42 (d, J = 6.4 Hz, 12H, 4CH3-); 3.74 (s, 3H, CH3O-); 3.93(t, J = 6.4 Hz, 2H, 2-CH-); 7.39–7.80
(m, 5H, Ph-H). MS(EI): m/z(%) = 318 (M+).
Ethyl 2-[diisopropylamine]-4-phenylthiazole-5-carboxylate (4f): Solid. Mp 83–85 °C. IR (KBr): 3025,
2974, 2943, 1710, 1600, 1545, 1330, 1250 cm−1; 1H-NMR (CDCl3, δ, ppm) :1.27 (t, J = 7.1 Hz, 3H, CH3-);
1.42 (d, J = 6.9 Hz, 12H, 4CH3-); 3.93 (d, J = 6.9 Hz, 2H, 2-CH2-); 4.21 (q, J = 7.1Hz, J = 14.0 Hz, 2H,
-CH2O-); 7.81–7.84 (m, 2H, Ph-H); 7.38–7.41 (m, 3H, Ph-H). MS(EI): m/z(%) = 332 (M+).
Methyl 2-morpholin-4-yl-4-phenylthiazole-5-carboxylate (4g): Solid. Mp 130–133 °C. IR (KBr): 3065,
1
2955, 2924, 1735, 1534, 1483, 1237, 1114 cm−1. H-NMR (CDCl3, δ, ppm): 3.61 (t, J = 4.8 Hz, 4H,

Molecules 2013, 18
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2-CH2-); 3.75 (s, 3H, CH3-); 3.82 (t, J = 4.8 Hz, 4H, 2-CH2-); 7.39–7.42 (m, 3H, Ph-H); 7.73–7.75
(m, 2H, Ph-H). MS(EI): m/z(%) = 304 (M+).
Ethyl 2-morpholin-4-yl-4-phenylthiazole-5-carboxylate (4h): Solid. Mp 90–95 °C. IR (KBr): 3053, 2980,
2924, 1708, 1528, 1482, 1368, 1250 cm−1. 1H-NMR (CDCl3, δ, ppm): 1.27 (t, J = 7.2 Hz, 3H, CH3-); 3.61
(t, J = 4.8 Hz, 4H, 2-CH2-); 3.84 (t, J = 4.8 Hz, 4H, 2-CH2-); 4.21 (q, J = 7.2 Hz, J = 14.4 Hz, 2H,
-CH2O-); 7.39–7.41 (m, 3H, Ph-H); 7.72–7.74 (m, 2H, Ph-H). MS(EI): m/z(%) = 318 (M+).
Methyl 2-pyrrolidine-4-phenylthiazole-5-carboxylate (4i): Solid. Mp 120–123 °C. IR (KBr): 3066,
1
2978, 2924, 1725, 1530, 1483, 1240, 1114 cm−1; H-NMR: 1.81–1.83 (m, 4H, 2-CH2-); 2.76
(t, J = 7.2 Hz, 4H, 2-CH2-); 3.75(s, 3H, CH3O-); 7.40–7.43 (m, 3H, Ph-H); 7.75–7.79 (m, 2H, Ph-H).
MS(EI): m/z(%) = 288 (M+).
Ethyl 2-pyrrolidine-4-phenylthiazole-5-carboxylate (4j): Solid. Mp 112–126 °C. IR (KBr): 3052, 2978,
2923, 1700, 1520, 1482, 1360, 1210 cm−1; 1H-NMR (CDCl3, δ, ppm): 1.27 (t, J = 7.2 Hz, 3H, CH3-);
1.80–1.83 (m, 4H, 2-CH2-); 2.75 (t, J = 7.2 Hz, 4H, 2-CH2-); 4.21 (q, J = 7.2 Hz, J = 14.4 Hz, 2H,
-CH2O-); 7.39–7.41 (m, 3H, Ph-H); 7.72–7.74 (m, 2H, Ph-H). MS(EI): m/z(%) = 302 (M+).
2-(5-methoxycarbonyl-4-phenylthiazol-2-amino)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl
tris(2,2-dimethylpropanoate) (4k): Solid. Mp 150–153 °C. IR (KBr): 2976, 2802, 1744, 1590, 1535,
1
1482, 1349, 1283, 1242 cm−1; H-NMR (CDCl3, δ, ppm): 1.12–1.15 (m, 36H, 12CH3-); 3.83 (d,
J = 8 Hz, 2H, -CH2-); 4.11 (s, 1H, -NH-); 4.15 (s, 3H, CH3O-); 4.68 (q, J = 7.2 Hz, J = 14.4 Hz, 1H,
-CH-); 4.95 (t, J = 9.6 Hz 1H, -CH-); 5.06 (t, J = 9.6 Hz 1H, -CH-); 5.14 (t, J = 9.6 Hz 1H, -CH-); 5.41
(t, J = 9.6 Hz 1H, -CH-); 7.39–7.77(m, 5H, Ph-H). MS(EI): m/z(%) = 733 (M+). Anal. Calcd for
C37H52N2O11S: C, 60.64; H, 7.15; N, 3.82; Found: C, 60.70; H, 7.19; N, 3.78%.
4. Conclusions
In conclusion, we report herein a novel chemoenzymatic one-pot multicomponent synthesis of
thiazole derivatives catalyzed by trypsin from porcine pancreas. The optimum reaction conditions
of 20 mg PPT, 45 °C and 7 h were identified. Blank and control experiments were performed and
proved that PPT plays a key catalytic role in this reaction. The substrate evaluation showed that PPT
has a wide range of tolerance towards secondary amines. This easy workup, high yield, and mild
reaction conditions, make it a useful tool to synthesize thiazole derivatives and expand the applications
of chemoenzymatic synthesis.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (No. 21106026), Key Sci-tech
Innovation Team of Zhejiang Province (No. 2010R50017-7) and PCSIRT (IRT 1231) for providing
financial support.
Conflicts of Interest
The authors declare no conflict of interest.

Molecules 2013, 18
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