Efficient one-pot synthesis of alkyl 2-(dialkylamino)-4-phenylthiazole-5- carboxylates and single-crystal x-ray structure of methyl 2-(diisopropylamino)- 4-phenylthiazole-5-carboxylate

Article abstract of DOI:10.1002/hlca.201100322

The reaction between secondary amines, benzoyl isothiocyanate, and dialkyl acetylenedicarboxylates (=dialkyl but-2-ynedioates) in the presence of silica gel (SiO₂) led to alkyl 2-(dialkylamino)-4-phenylthiazole-5- carboxylates in fairly high yi

Full text of DOI:10.1002/hlca.201100322

Helvetica Chimica Acta – Vol. 95 (2012)
339
Efficient One-Pot Synthesis of Alkyl 2-(Dialkylamino)-4-phenylthiazole-5-
carboxylates and Single-Crystal X-Ray Structure of Methyl 2-
(Diisopropylamino)-4-phenylthiazole-5-carboxylate
a
b
c
d
d
´
by Ali Souldozi* ), Ali Ramazani* ), Ali Reza Dadrass ), Katarzyna Slepokura ), and Tadeusz Lis )
a) Department of Chemistry, Urmia Branch, Islamic Azad University, P.O. Box 969, Urmia, Iran
(fax: þ 98-441-3453371; e-mail: alisouldozi@yahoo.com)
b) Department of Chemistry, Zanjan Branch, Islamic Azad University, P.O. Box 49195-467, Zanjan, Iran
(fax: þ 98-241-4261221; e-mail: aliramazani@gmail.com)
c) Department of Chemistry, Faculty of Science, Urmia University, P.O. Box 57159-165, Urmia, Iran
d) Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., PL-50-383 Wrocław
The reaction between secondary amines, benzoyl isothiocyanate, and dialkyl acetylenedicarbox-
ylates (¼dialkyl but-2-ynedioates) in the presence of silica gel (SiO2) led to alkyl 2-(dialkylamino)-4-
phenylthiazole-5-carboxylates in fairly high yields. The structures of the products were confirmed by their
IR, 1H- and 13C-NMR, and mass spectra, and by a single-crystal X-ray structure determination.
Introduction. – The thiazoles and their derivatives have attracted the attention of
chemists for many years [1][2]. Thiazole derivatives occur widely in a range of natural
products. For example, the thiazolium ring present in vitamin B1 serves as an electron
sink, and its coenzyme form is important for the decarboxylation of a-keto acids [3].
Thiazoles and their derivatives are known to exhibit pharmacological activity. Among
them, antimicrobial, antihistaminic, antiparasitic, antihelminthic, antipyretic, and
antiviral activities were found [4 – 9]. Aryl-substituted thiazoles are also important
organic functional materials such as fluorescent dyes and liquid crystals. Thiazole
orange is used as a fluorescent intercalator for determining DNA binding affinity and
sequence selectivity of small molecules [10]. Due to their broad utility in the
pharmaceutical industry [11 – 17], the development of novel methods for the synthesis
of thiazol-2-amines would provide additional lead molecules for drug discovery.
Thiazoles have traditionally been synthesized by the Hantzsch synthesis [18][19], but
its multi-step character and need to isolate the intermediate such as bromo ketones
possessing lacrimatory properties are some of its disadvantages. Recently, powerful
methods involving Pd mediated coupling processes have emerged [20 – 24]; the
disadvantages of the methods are the use of toxic and hazardous Pd compounds.
Herein, we report a hitherto unknown, one-pot, three-component reaction, which,
starting from readily available benzoyl isothiocyanate (1), secondary amines 2, and
acetylenedicarboxylates 4, afforded the alkyl 2-(dialkylamino)-4-phenylthiazole-5-
carboxylates 8a – 8l, wherein the catalytic role of SiO2 powder in the conversion of S-
vinylated N-benzoylisothiourea derivatives 5 to 8a – 8l under solvent-free thermal
conditions in fairly high yields was a crucial factor.
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

340
Helvetica Chimica Acta – Vol. 95 (2012)
Results and Discussion. – Our new synthetic method that led to the title compounds
is shown in the Scheme. The reaction of N-benzoylthiourea derivatives 3, which were
derived from the addition of secondary amines 2 to benzoyl isothiocyanate (1), with
acetylenedicarboxylates (¼ but-2-ynedioates) 4 proceeded in CH2Cl2 at room temper-
ature to give compound 5. SiO2 Powder was found to catalyze the conversion of 5 to the
alkyl 2-(dialkylamino)-4-phenylthiazole-5-carboxylates 8 under solvent-free conditions
at 908 in fairly good yields without the formation of by-products (Table 1).
Scheme. Proposed Mechanism for the Formation of Alkyl 2-(Dialkylamino)-4-phenylthiazole-5-
carboxylate Derivatives
Table 1. Synthesis of Alkyl 2-(Dialkylamino)-4-phenylthiazole-5-carboxylates 8 (see Scheme)
8
R
R’
R’’
Yield [%]a)
a
b
c
d
e
f
g
h
i
Et
Et
i-Pr
i-Pr
Et
Et
i-Pr
i-Pr
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
86
85
85
83
81
79
84
80
80
77
78
75
(CH2)5
(CH2)5
(CH2)2O(CH2)2
(CH2)2O(CH2)2
Bn
Bn
Bn
Bn
Me
Me
Bn
Bn
j
k
l
a) Yield of isolated products.
Although the mechanistic details of the reaction are not known, a plausible
rationalization may be advanced to explain the product formation (Scheme).

Helvetica Chimica Acta – Vol. 95 (2012)
341
Presumably, the initial event is the reaction of the secondary amine 2 and benzoyl
isothiocyanate (1) which leads to a thiourea derivative 3. After addition of 3 to the
acetylenedicarboxylate 4, the benzoyl O-atom of intermediate 5 attacks the vinyl
moiety to give 6, which undergoes intramolecular nucleophilic attack to produce fused
bicyclic compound 7, which eliminates 9 to give 8.
To confirm our proposed mechanism, the four intermediates 3a, 3g, 3i, and 3k were
isolated and characterized (Table 2). The latter were then treated with compound 4 to
give intermediates 5a, 5g, 5i, and 5k which were also isolated and characterized
(Table 3). The spectroscopic data confirmed the molecular structures of 3a, 3g, 3i, 3k,
5a, 5g, 5i, and 5k, and TLC monitoring indicated that 5a, 5g, 5i, and 5k were converted
to the corresponding final products 8a, 8g, 8i, and 8k in the presence of SiO2 at 908 after
1 h. In this last step, we also used MgO, ZnO, or CuO, MnO2, Al2(SO4)3, Al2O3,
Cu(NO3)2, Na2CO3, NaHCO3, NaHSO4, FeSO4, Mn(NO3)2, or Cu(NO3)2 powder
instead of SiO2 but no corresponding product 8 was observed.
Table 2. Synthesis of Some Intermediates 3 by the Two-Component Reaction of 1 and 2 (see Scheme)
3
R
R’
Yield [%]a)
3
R
R’
Yield [%]a)
a
g
Et
Et
97
96
i
k
Bn
Bn
Me
Bn
94
94
(CH2)2O(CH2)2
a) Yield of isolated products.
Table 3. Synthesis of Some Intermediates 5 from Two-Component Reaction of Isolated Intermediates 3
and 4 (see Scheme)
5
R
R’
R’’
5
R
R’
R’’
a
g
Et
Et
Me
Me
i
k
Bn
Bn
Me
Bn
Me
Me
(CH2)2O(CH2)2
1
The structures of products 8 were confirmed by their IR and H- and 13C-NMR
spectra, and by a single-crystal X-ray structure determination of 8c. The mass spectra
of these compounds displayed molecular-ion peaks at the appropriate m/z values. The
1H-NMR spectrum (CDCl3) of 8c consisted of a d for the two Me2CH groups (d(H)
3
1.42, J(H,H) ¼ 6.9 Hz), a s for the MeO group (d(H) 3.74), a m for the two Me2CH
groups (d(H) 3.92 – 3.96), and two m for the aromatic H-atoms (d(H) 7.39 – 7.42 and
7.81 – 7.84). The 1H-decoupled 13C-NMR spectrum of 8c showed 11 distinct resonances;
1
a partial assignment of these resonances is given in the Exper. Part. The H- and
13C-NMR spectra of compounds 8a – 8l were similar to those of 8c, except for the
resonances of the R, R’, R’’ groups which exhibited characteristic signals with
appropriate chemical shifts.
In the X-ray crystal structure of compound 8c (Fig. 1., and Table 4), the COOMe
group is planar and is almost coplanar with the plane of the thiazole ring. As seen from
the value of the torsion angle S(1)ꢀC(3)ꢀC(4)ꢀO(2) (Table 5), the molecule has the
C¼O,S anti-periplanar conformation. Similarly, the exocyclic N(2)-atom and C(12) and
C(15) attached to it, which form a roughly planar moiety, are coplanar with the thiazole
ring, due to the conjugation of the N-atom lone pair with the thiazole system, resulting

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 1. X-Ray crystal structure of compound 8c, showing intramolecular CꢀH ··· O/N/S H-bonds forming
S(7), S(6), and S(5) motifs, respectively (dotted lines). Arbitrary atom numbering; 50% probability
ellipsoids.
Table 4. Crystallographic Data of Compound 8c
Crystallized from
Empirical formula
Mr
Crystal color, habit
Crystal dimensions [mm]
Radiation type, l [ꢂ]
Temperature [K]
Crystal system
Space group
Z
hexane
C17H22N2O2S
318.43
colorless, block
0.55 ꢂ 0.47 ꢂ 0.41
MoKa, 0.71073
100(2)
monoclinic
P21/c
Scan type
q Range [8]
Index range
w and f
4.24 – 35.00
ꢀ 10 ꢁ h ꢁ 11
ꢀ 22 ꢁ k ꢁ 22
ꢀ 27 ꢁ l ꢁ 26
26825
7301
6143
0.023
F2
Measured reflections
Independent reflections
Reflections with I > 2s(I)
Rint
4
Refinement on
Unit cell parameters:
a [ꢂ]
b [ꢂ]
Data, restraints, parameters
7301, 0, 287
R1 ¼ 0.033a)
wR2 ¼ 0.098a)
R1 ¼ 0.040
wR2 ¼ 0.100
1.07
0.0692/0.0428
0.66; ꢀ 0.29
7.239(3)
13.813(5)
16.780(6)
97.31(3)
1664.2(11)
1.271
R (Fo2 > 2s(Fo2))
c [ꢂ]
b [8]
V [ꢂ3]
R (all data)
Goodness-of-fit ¼ S
Dx (calc.) [g cmꢀ3
]
Weighting parameter a/b
m [mmꢀ1
]
0.203
680
D1 (max; min) [e ꢂꢀ3
]
F(000) [e]
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
P
P
P
P
a) R1 ¼ jjFoj ꢀ jFcjj= jFoj; wR2 ¼
½wðFo2 ꢀ Fc2Þ ꢃ= ½wðFo2Þ ꢃ. Weighting scheme: w ¼ 1/
2
2
[s(F2o ) þ (aP)2 þ bP] where P ¼ (Fo2 þ 2F2c )/3.
in formal N-sp2 hybridization (see also the N(2)ꢀC(1) bond length in Table 5). The
N(2)-atom deviates little (0.086 ꢂ) from the plane defined by C(1), C(12), and C(15),
and this plane is inclined only slightly (at 5.4(1)8) to the thiazole-ring plane. In contrast,

Helvetica Chimica Acta – Vol. 95 (2012)
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Table 5. Selected Interatomic Distances, Bond Angles, and Torsion Angles of 8c
Bond lengths [ꢂ]
S(1)ꢀC(1)
S(1)ꢀC(3)
N(1)ꢀC(1)
N(1)ꢀC(2)
1.7553(8)
1.7454(9)
1.3293(9)
1.3721(10)
N(2)ꢀC(1)
N(2)ꢀC(12)
N(2)ꢀC(15)
C(2)ꢀC(3)
1.3466(10)
1.4867(10)
1.4779(10)
1.3842(10)
Bond angles [8]
C(1)ꢀS(1)ꢀC(3)
C(1)ꢀN(1)ꢀC(2)
C(1)ꢀN(2)ꢀC(15)
C(1)ꢀN(2)ꢀC(12)
89.14(4)
111.31(6)
119.35(6)
121.11(6)
C(15)ꢀN(2)ꢀC(12)
O(1)ꢀC(4)ꢀC(3)
O(2)ꢀC(4)ꢀC(3)
118.46(6)
109.64(6)
127.54(7)
Torsion angles [8]
C(2)ꢀN(1)ꢀC(1)ꢀN(2)
C(12)ꢀN(2)ꢀC(1)ꢀN(1)
C(15)ꢀN(2)ꢀC(1)ꢀN(1)
C(12)ꢀN(2)ꢀC(1)ꢀS(1)
C(15)ꢀN(2)ꢀC(1)ꢀS(1)
C(5)ꢀO(1)ꢀC(4)ꢀC(3)
S(1)ꢀC(3)ꢀC(4)ꢀO(2)
N(1)ꢀC(2)ꢀC(6)ꢀC(11)
179.87(6)
ꢀ 10.00(10)
ꢀ 177.96(6)
169.65(5)
1.69(9)
ꢀ 177.69(6)
173.95(6)
138.98(7)
C(1)ꢀN(2)ꢀC(12)ꢀC(14)
C(15)ꢀN(2)ꢀC(12)ꢀC(14)
C(1)ꢀN(2)ꢀC(12)ꢀC(13)
C(15)ꢀN(2)ꢀC(12)ꢀC(13)
C(1)ꢀN(2)ꢀC(15)ꢀC(16)
C(12)ꢀN(2)ꢀC(15)ꢀC(16)
C(1)ꢀN(2)ꢀC(15)ꢀC(17)
C(12)ꢀN(2)ꢀC(15)ꢀC(17)
66.76(9)
ꢀ 125.18(7)
ꢀ 61.14(9)
106.92(8)
95.43(8)
ꢀ 72.85(8)
ꢀ 137.81(7)
53.92(8)
the benzene-ring plane is inclined to a much larger extent (at an angle of 38.9(1)8) to
the thiazole-ring plane. The orientation of the isopropyl groups (towards the N(1)- and
away from the S(1)-atom) is accompanied by the intramolecular CꢀH ··· N/S contacts,
as shown in Fig. 1.
The crystal structure of 8c is stabilized by weak CꢀH ··· S and CꢀH ··· p interactions
involving the benzene ring (Fig. 2 and Table 6). The adjacent molecules located down
Fig. 2. Arrangement of the molecules within the layers parallel to the (001) plane in the crystal of 8c.
Intermolecular CꢀH ··· S and CꢀH ··· p contacts are shown with dashed lines. Intramolecular interactions
are omitted for clarity. Symmetry codes are given in Table 6.

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 6. Geometry of Proposed CꢀH ··· p Close Contacts for 8c
DꢀH ··· Aa)
DꢀH [ꢂ]
H ··· A [ꢂ]
D ··· A [ꢂ]
DꢀH ··· A [8]
C(9)ꢀH(9) ··· S(1)i
0.98(2)
0.97(2)
0.99(2)
0.98(2)
1.00(2)
0.99(2)
2.90(2)
2.48(2)
2.58(2)
2.52(2)
2.39(2)
2.91(2)
3.869(2)
2.949(2)
3.134(2)
3.067(2)
2.984(2)
3.614(2)
170(1)
110(1)
115(1)
115(1)
118(1)
129(1)
C(11)ꢀH(11) ··· O(2)
C(13)ꢀH(13C) ··· N(1)
C(14)ꢀH(14A) ··· N(1)
C(15)ꢀH(15) ··· S(1)
C(10)ꢀH(10) ··· Cg(1)ii
a) Symmetry codes: i: ꢀ x, y ꢀ 1/2, ꢀ z þ 1/2; ii: x ꢀ 1, y, z; Cg(1) is the centroid of the thiazole ring
S(1)ꢀC(1)ꢀN(1)ꢀC(2)ꢀC(3).
the a-axis are joined with each other via C(10)ꢀH(10) ··· p[Cg(1)]ii contacts. At the
same time, the benzene moiety forms a C(9)ꢀH(9) ··· S(1)i contact with the neighbor-
ing, 21-screw-axis-related molecule, giving rise to layers parallel to the (001) plane, as
shown in Fig. 2.
Conclusions. – In summary, the reported method offers a mild, simple and efficient
route for the preparation of alkyl 2-(dialkylamino)-4-phenylthiazole-5-carboxylates.
The easy workup, high yield, and fairly mild reaction conditions, make it a useful
addition to modern synthetic methodologies. Other aspects of this process are under
investigation.
Experimental Part
General. Starting materials and solvents were obtained from Merck (Germany) and Fluka
(Switzerland) and were used without further purification. Flash chromatography (FC): preparation of
columns with Merck silica gel (SiO2) powder. M.p.: Electrothermal-9100 apparatus; uncorrected. IR
Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker-DRX-300-Avance
spectrometer; at 300.13 (1H) and 75.467 MHz (13C); in CDCl3; d in ppm rel. to Me4Si as internal standard,
J in Hz. MS: Finnigan-MAT-8430 mass spectrometer; ionization potential 20 eV. Elemental analyses:
Heraeus-CHN-O-Rapid analyzer.
X-Ray Crystal-Structure Determination of 8c (Table 4 and Fig. 1)1). Single crystals of 8c were
prepared in hexane at 408 during two weeks by using the branch-tube method. The white crystals were
filtered off, washed with cold hexane, and dried at r.t. (m.p. 105.48). The crystallographic measurement
was performed on a k-geometry Xcalibur-PX automated four-circle diffractometer with graphite-
monochromatized MoKa radiation (l 0.71073 ꢂ). The data for the crystal were collected at 100(2) K by
using an Oxford-Cryosystems cooler. Data collection, cell refinement, and data reduction and analysis
were carried out with the Xcalibur-PX software (Oxford Diffraction Ltd.): CrysAlis CCD and CrysAlis
RED, resp. [25]. The data were corrected for Lorentz and polarization effects. The structure was solved
by direct methods with the SHELXS-97 program [26] and refined by a full-matrix least-squares
technique by using SHELXL-97 [26] with anisotropic thermal parameters for all non-H-atoms. All H-
atoms were found in difference Fourier maps and were refined isotropically. All figures were made with
the XP program [27]. A summary of the conditions for the data collection and the structure-refinement
parameters are given in Table 4.
1
)
CCDC-812743 contains the supplementary crystallographic data for 8c. These data can be obtained
free of charge via http://www.ccdc.cam.ac.uk.

Helvetica Chimica Acta – Vol. 95 (2012)
345
Compounds 3a, 3g, 3i, and 3k: General Procedure. To a magnetically stirred soln. of benzoyl
isothiocyanate (1; 0.163 g, 1 mmol) in dry CH2Cl2 (5 ml) was added dropwise a soln. of secondary amine 2
(1 mmol) in dry CH2Cl2 (3 ml) at r.t. over 2 min. The mixture was stirred for 15 min at r.t. The solvent
evaporated and the viscous residue purified by FC (SiO2, petroleum ether/AcOEt 10 :1): product 3.
N’-Benzoyl-N,N-diethylthiourea (¼ N-[(Diethylamino)thioxomethyl]benzamide; 3a): Yield 230 mg
(97%). White crystals. M.p. 96.8 – 97.68. IR (KBr): 3209, 3031, 2971, 2930, 1681, 1227. 1H-NMR: 1.33 (br.
s, 2 Me); 3.62 (br. s, 2 CH2); 4.02 (br. s, NH); 7.45 – 7.50 (m, 2 arom. H); 7.55 – 7.60 (m, 1 arom. H); 7.84 –
7.86 (m, 2 arom. H). 13C-NMR: 11.51, 13.25 (2 Me); 47.69, 47.78 (2 CH2); 127.84, 128.82, 132.866 (5 arom.
C); 132.75 (C); 164.05 (C¼S); 179.61 (C¼O).
N’-(Morpholinocarbonothioyl)benzamide (¼ [(Morpholin-4-yl)thioxomethyl]benzamide; 3g): Yield
241 mg (96%). White crystals. M.p. 129.1 – 129.88. IR (KBr): 3243, 3035, 2969, 2923, 1666, 1524, 1268,
1241, 1223, 1114. 1H-NMR: 3.68 – 3.98 (m, 4 CH2); 4.23 (br. s, NH); 7.47 – 7.52 (m, 2 arom. H); 7.58 – 7.63
(m, 1 arom. H); 7.83 – 7.86 (m, 2 arom. H). 13C-NMR: 43.28 ((CH2)2N); 63.79 ((CH2)2O); 127.79, 128.97,
133.18 (5 arom. C); 132.31 (C); 163.23 (C¼S); 179.24 (C¼O).
N’-Benzoyl-N-benzyl-N-methylthiourea (¼ N-{[Methyl(phenylmethyl)amino]thioxomethyl}benza-
mide; 3i): Yield 268 mg (94%). White crystals. M.p. 126.7 – 127.48. IR (KBr): 3182, 3062, 3028, 2915,
1688, 1543, 1256, 1215, 1183. 1H-NMR: 3.18 (s, Me); 4.81 (br. s, NH); 5.30 (s, CH2); 7.33 – 7.60 (m, 8 arom.
H); 7.87 (br. s, 2 arom. H). 13C-NMR: 40.35 (Me); 59.63 (CH2); 127.91, 128.82, 128.91, 133.10 (10 arom.
C); 130.27, 132.51 (2 C); 163.53 (C¼S); 181.52 (C¼O).
N’-Benzoyl-N,N-dibenzylthiourea (¼ N-{[Bis(phenylmethyl)amino]thioxomethyl}benzamide; 3k):
Yield 341 mg (94%). White crystals. M.p. 142.0 – 142.98. IR (KBr): 3329, 3085, 3059, 2952, 2919, 1689,
1515, 1266, 1277, 1192. 1H-NMR: 4.54 (br. s, NH); 4.75 (br, 2 CH2); 7.35 – 7.50 (m, 9 arom. H); 7.57 – 7.61
(m, 3 arom. H); 7.82 – 7.84 (m, 3 arom. H). 13C-NMR: 55.82, 56.46 (2 CH2); 127.77, 127.95, 128.88, 133.08
(15 arom. C); 132.51, 134.72, 135.38 (3C); 164.24 (C¼S); 182.20 (C¼O).
Compounds 5a, 5g, 5i, and 5k: General Procedure. To a magnetically stirred soln. of thiourea
derivative 3 (1 mmol) in dry CH2Cl2 (5 ml) was added dropwise a soln. of dimethyl but-2-ynedioate 4
(0.142 g,1 mmol) in dry CH2Cl2 (3 ml) at r.t. over 2 min. The mixture was stirred for 1h at r.t. The solvent
was evaporated and the viscous residue purified by FC (SiO2, petroleum ether/AcOEt 10 :2): product 5.
Dimethyl (2Z)-2-{[(Benzoylimino)(diethylamino)methyl]thio}but-2-enedioate (5a): Viscous oil. IR
1
(KBr): 3059, 2876, 2949, 1727, 1628, 1546, 1314, 1249, 1203. H-NMR: 1.26 – 1.35 (m, 2 MeCH2); 3.58,
3.79 (2 s, 2 MeO); 3.68 – 3.79 (m, 2 MeCH2); 6.77 (s, 1 olef. H); 7.36 – 7.44 (m, 2 arom. H); 7.73 – 7.74 (m, 1
arom. H); 7.96 – 7.98 (m, 2 arom. H). 13C-NMR: 12.45, 13.22 (2 MeCH2, Et2N); 45.61, 45.77 (2 MeCH2);
52.23, 53.23 (2 MeO); 127.51 (olef. ¼CH); 127.67, 129.304, 131.41 (5 arom. C); 136.79, 139.74, 159.66
(3 C); 163.89, 164.59 (2 C¼O, ester); 172.01 (C¼O, ketone).
Dimethyl (2Z)-2-{[(Benzoylimino)(morpholin-4-yl)methyl]thio}but-2-enedioate (5g): Viscous oil.
1
IR (KBr): 3059, 2654, 2856, 1726, 1545, 1253, 1203. H-NMR: 3.64, 3.79 (2 s, 2 MeO); 3.74 – 3.84 (m,
4 CH2); 6.78 (s, 1 olef. H); 7.35 – 7.40 (m, 2 arom. H); 7.45 – 7.50 (m, 2 arom. H); 7.95 – 7.98 (m, 1 arom. H).
13C-NMR: 48.89 ((CH2)2N); 52.30, 53.40 (2 MeO); 66.36 ((CH2)2O); 127.88, 129.43, 131.99 (5 arom. C);
127.98 (olef. ¼CH); 135.91, 140.56, 158.51 (3 C); 163.80, 164.64 (2 C¼O, ester); 173.72 (C¼O, ketone).
Dimethyl (2Z)-2-{{(Benzoylimino)[methyl(phenylmethyl)amino]methyl}thio)}but-2-enedioate (5i):
Viscous oil. IR (KBr): 3060, 3029, 2950, 2855, 1728, 1612, 1548, 1328, 1250, 1200. 1H-NMR: 3.20 (s, MeN);
3.62, 3.80 (2 s, 2 MeO); 4.91 (s, CH2); 6.82 (s, 1 olef. H); 7.36 – 7.45 (m, 8 arom. H); 7.96 – 7.99 (m, 2 arom.
H). 13C-NMR: 38.22 (MeN); 52.26, 53.37 (2 MeO); 56.33 (CH2); 127.78, 128.86, 129.44, 129.85, 131.61 (10
arom. C); 127.93 (olef. ¼CH); 135.56, 136.44, 139.88, 161.23 (4 C); 163.96, 164.57 (2 C¼O, ester); 172.48
(C¼O, ketone).
Dimethyl (2Z)-2-{{(Benzoylimino)[bis(phenylmethyl)amino]methyl}thio}but-2-enedioate (5k): Vis-
1
cous oil. IR (KBr): 3060, 3030, 2948, 2926, 1724, 1631, 1534, 1313, 1252, 1199. H-NMR: 3.61, 3.81 (2 s,
2 MeO); 4.85, 4.89(2 s, 2 CH2); 6.84 (s, 1 olef. H); 7.34 – 7.45 (m, 12 arom. H); 7.89 – 7.92 (m, 3 arom. H).
13C-NMR: 52.30, 53.40 (2 Me); 52.99, 53.12 (2 CH2); 127.75, 128.95, 129.43, 129.65, 131.99 (15 arom. C);
127.86 (olef. ¼CH); 134.90, 135.58, 136.34, 139.36, 160.69 (5 C); 163.81, 164.50 (2 C¼O, ester); 172.72
(C¼O, ketone).
Compounds 8a – 8l: General Procedure. To a stirred soln. of benzoyl isothiocyanate (1; 0.163 g,
1 mmol) and secondary amine 2 (1 mmol) in dry CH2Cl2 (5 ml) was added dropwise a mixture of dialkyl

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Helvetica Chimica Acta – Vol. 95 (2012)
but-2-ynedioate 4 (1 mmol) in dry CH2Cl2 (3 ml) at r.t. over 2 min. Then, after 0.5 h, SiO2 powder (2 g)
was added, and the solvent was evaporated. The dry materials were heated for 1 h at 908 and then placed
on top of a column of SiO2 (10 g). The column was washed with AcOEt/light petroleum ether 2 :10. The
solvent was then evaporated: product 8.
Methyl 2-(Diethylamino)-4-phenylthiazole-5-carboxylate (8a): Yield 250 mg (86%). White crystals.
M.p. 81.48. IR (KBr): 3054, 3025, 2974, 2934, 1710, 1600, 1511, 1481, 1331, 1263. 1H-NMR: 1.26 (t, 3J ¼ 6.9,
2 MeCH2); 3.54 – 3.57 (m, 2 MeCH2); 3.73 (s, MeO); 7.39 (br., 3 arom. H); 7.75 (br., 2 arom. H).
13C-NMR: 12.49 (2 MeCH2); 45.46 (2 MeCH2); 51.61 (MeO); 127.51, 128.88, 129.80 (5 arom. C); 133.15,
134.99, 160.56, 162.47 (4 C); 169.45 (C¼O). EI-MS: 290 (50, Mþ), 275 (12), 261 (39), 247 (77), 229 (15),
215 (23), 201 (13), 149 (21), 133 (32), 103 (28), 89 (39), 57 (42), 42 (100). Anal. calc. for C15H18N2O2S
(290.38): C 62.04, H 6.25, N 9.65; found: C 61.24, H 6.14, N 8.86.
Ethyl 2-(Diethylamino)-4-phenylthiazole-5-carboxylate (8b): Yield 259 mg (85%). White crystals.
M.p. 90.18. IR (KBr): 3051, 2975, 2929, 1698, 1551, 1330, 1258. 1H-NMR: 1.23 – 1.31 (m, 3 MeCH2); 3.56
(q, 3J ¼ 7.2, 2 MeCH2N); 4.20 (q, 3J ¼ 7.2, MeCH2O); 7.38 – 7.40 (m, 3 arom. H); 7.75 – 7.76 (m, 2 arom. H).
13C-NMR: 12.49 (2 MeCH2N); 14.28 (MeCH2O); 45.41 (2 MeCH2N); 60.38 (MeCH2O); 127.44, 128.77,
129.84 (5 arom. C); 133.44, 135.14, 160.19, 162.10 (4 C); 169.41 (C¼O). EI-MS: 304 (100, Mþ), 289 (12),
275 (35), 261 (80), 247 (17), 232 (27), 215 (17), 202 (12), 188 (14), 133 (23), 103 (18), 89 (33), 71 (14).
Anal. calc. for C16H20N2O2S (304.41): C 63.13, H 6.62, N 9.20; found: C 63.4, H 6.56, N 8.93.
Methyl 2-[Bis(1-methylethyl)amino]-4-phenylthiazole-5-carboxylate (8c): Yield 271 mg (85%).
1
White crystals. M.p. 105.48. IR (KBr): 3020, 2965, 2929, 1706, 1600, 1526, 13331, 1258. H-NMR: 1.42
(d, 3J ¼ 6.9, 2 MeCH2); 3.74 (s, MeO); 3.91 – 3.96 (m, 2 (Me)2CH); 7.37 – 7.45 (m, 3 arom. H); 7.81 – 7.84
(m, 2 arom. H). 13C-NMR: 20.02 (Me2CH); 51.15 (MeO); 51.44 (2 Me2CH); 127.38, 128.78, 129.95 (5
arom. C); 130.86, 135.13, 160.05, 162.62 (4 C); 168.01 (C¼O). EI-MS: 318 (44, Mþ), 261 (28), 234 (100),
57 (38), 41 (55). Anal. calc. for C17H22N2O2S (318.43): C 64.12, H 6.96, N 8.80; found: C 63.87, H 6.71, N
8.65.
Ethyl 2-[Bis(1-methylethyl)amino]-4-phenylthiazole-5-carboxylate (8d): Yield 278 mg (83%). White
1
3
crystals. M.p. 90.58. IR (KBr): 3080, 3047, 2966, 2930, 1700, 1603, 1529, 1260. H-NMR: 1.27 (t, J ¼ 7.1,
MeCH2); 1.42 (d, 3J ¼ 6.9, Me2CH); 3.91 – 3.95 (m, 2 Me2CH); 4.21 (q, 3J ¼ 7.1, MeCH2); 7.38 – 7.41 (m, 3
arom. H); 7.81 – 7.84 (m, 2 arom. H). 13C-NMR: 14.34 (MeCH2); 20.04 (2 Me2CH); 51.14 (MeCH2); 60.31
(2 Me2CH); 127.32, 128.68, 129.99 (5 arom. C); 130.87, 135.28, 159.76, 162.25 (4 C); 167.98 (C¼O). EI-
MS: 332 (58, Mþ), 289 (100), 275 (86), 261 (18), 247 (21), 229 (15), 174 (15), 148 (35), 129 (17), 103 (28),
39 (21), 43 (24). Anal. calc. for C18H24N2O2S (332.46): C 65.03, H 7.28, N 8.43; found: C 64.21, H 6.46, N
8.01.
Methyl 4-Phenyl-2-(piperidin-1-yl)thiazole-5-carboxylate (8e): Yield 244 mg (81%). White crystals.
1
M.p. 90.78. IR (KBr): 3065, 2997, 2962, 2946, 1715, 1531, 1482, 1340, 1303, 1245, 1145. H-NMR: 1.67 –
1.72 (m, 3 CH2 (pip)); 3.57 – 3.59 (m, 2 CH2 (pip)); 3.74 (s, Me); 7.39 – 7.41 (m, 3 arom. H); 7.74 – 7.77
(m, 2 arom. H). 13C-NMR: 23.99, 25.12, 49.17 (5 CH2); 51.53 (MeO); 127.54, 128.90, 129.76 (5 arom. C);
130.86, 134.91, 160.38, 162.44 (5 C); 170.90 (C¼O). EI-MS: 302 (25, Mþ), 273 (14), 246 (17), 167 (17),
149 (39), 84 (21), 58 (41), 43(100). Anal. calc. for C16H18N2O2S (302.39): C 63.55, H 6.00, N 9.26; found:
C 62.10, H 5.82, N 9.00.
Ethyl 4-Phenyl-2-(piperidin-4-yl)thiazole-5-carboxylate (8f): Yield 249 mg (79%). Viscous oil. IR
(KBr): 3056, 2936, 2855, 1708, 1677, 1532, 1243. 1H-NMR: 1.25 (t, 3J ¼ 7.0, MeCH2); 1.66 – 1.71 (m, 3 CH2
(pip)); 3.58 – 3.57 (m, 2 CH2 (pip)); 4.20 (q, 3J ¼ 7.0, MeCH2); 7.38 – 7.40 (m, 3 arom. H); 7.73 – 7.76 (m, 2
arom. H). 13C-NMR: 14.25 (MeCH2); 23.76, 25.13, 49.17 (5 CH2 (pip)); 60.46 (MeCH2); 127.49, 128.82,
129.79 (5 arom. C); 130.86, 134.10, 159.99, 162.05 (4 C); 170.84 (C¼O). EI-MS: 318 (60, Mþ), 275 (100) ,
261 (96) , 299 (20) , 201 (13) , 174 (15), 129 (15), 104 (13), 89 (18) , 43 (32). Anal. calc. for C17H20N2O2S
(316.42): C 64.53, H 6.37, N 8.85; found: C 64.26, H 6.21, N 8.73.
Methyl 2-(Morpholin-4-yl-4-phenylthiazole-5-carboxylate (8g): Yield 255 mg (84%). White crystals.
M.p. 130.08. IR (KBr): 3065, 2955, 2924, 1735, 1534, 1483, 1237, 1114. 1H-NMR: 3.59 – 3.62 (m, (CH2)2N);
3.75 (s, Me); 3.82 – 3.83 (m, (CH2)2O); 7.39 (br, 3 arom. H); 7.72 (br, 2 arom. H). 13C-NMR: 51.74 (Me);
47.99 ((CH2)2N); 66.04 ((CH2)2O); 127.63, 129.15, 129.760 (5 arom. C); 133.48, 135.01, 160.74, 162.74
(4 C); 170.02 (C¼O). EI-MS: 304 (100, Mþ), 285 (6), 273 (20), 259 (18), 247 (70), 231 (13), 215 (28), 201

Helvetica Chimica Acta – Vol. 95 (2012)
347
(8), 133 (23), 89 (28), 76 (10). Anal. calc. for C15H16N2O3S (304.36): C 59.19, H 5.30, N 9.20; found: C
59.02, H 5.16, N 9.17.
Ethyl 2-(Morpholin-4-yl)-4-phenylthiazole-5-carboxylate (8h): Yield 254 mg (80%). White crystals.
1
3
M.p. 90.0 – 91.08. IR (KBr): 3053, 2980, 2924, 1708, 1528, 1482, 1368, 1250. H-NMR: 1.27 (t, J ¼ 7.2,
MeCH2); 3.59 – 3.62 (m, (CH2)2N); 3.81 – 3.85 (m, (CH2)2O); 4.21 (q, 3J ¼ 7.2, MeCH2); 7.39 – 7.41 (m, 3
arom. H); 7.72 – 7.74 (m, 2 arom. H). 13C-NMR: 14.21 (MeCH2); 47.98 ((CH2)2N); 60.70 (MeCH2); 66.05
((CH2)2O); 127.56, 129.02, 129.78 (5 arom. H); 133.56, 135.31, 160.85, 162.90 (4 C); 170.41 (C¼O). EI-
MS: 318 (100, Mþ), 304 (7), 289 (9), 273 (27), 260 (73), 246 (24), 232 (32), 215 (29), 188 (41), 133 (71),
105 (52), 39 (85), 77 (29), 56 (40). Anal. calc. for C16H18N2O3S (318.39): C 60.36, H 5.70, N 8.80; found: C
60.27, H 5.61, N 8.73.
Methyl 2-[Methyl(phenylmethyl)amino]-4-phenylthiazole-5-carboxylate (8i): Yield 270 mg (80%).
1
White crystals. M.p. 77.28. IR (KBr): 3025, 2984, 2943, 1710, 1604, 1550, 1330, 1244. H-NMR: 3.11 (s,
MeN); 3.75 (s, MeO); 4.79 (s, CH2N); 7.33 – 7.42 (m, 8 arom. H); 7.79 – 7.80 (m, 2 arom. H). 13C-NMR:
37.88 (MeN); 51.61 (MeO); 55.97 (CH2N); 127.57, 127.74, 127.86, 128.81, 129.87 (10 arom. C); 129.01,
134.77, 136.01, 160.41, 162.38 (5 C); 170.96 (C¼O). EI-MS: 338 (85, Mþ), 329 (47), 309 (37), 247 (11), 215
(24), 188 (14), 146 (18), 120 (15), 103 (13), 91 (100), 77 (13), 65 (17). Anal. calc. for C19H18N2O2S
(338.42): C 67.43, H 5.36, N 8.28; found: C 67.36, H 5.30, N 8.10.
Ethyl 2-[Methyl(phenylmethyl)amino]-4-phenylthiazole-5-carboxylate (8j): Yield 271 mg (77%).
White crystals. M.p. 73.28. IR (KBr): 3059, 2983, 2926, 1702, 1605, 1550, 1331, 1242. 1H-NMR: 1.25 (t, 3J ¼
7.0, MeCH2, EtO); 3.10 (s, MeN); 4.211 (q, 3J ¼ 7.0, MeCH2); 7.32 – 7.39 (m, 8 arom. H); 7.78 – 7.79 (m, 2
arom. H). 13C-NMR: 14.29 (MeCH2); 37.89 (MeN); 55.93 (CH2N); 60.55 (MeCH2); 127.52, 127.73,
127.83, 128.79, 129.90 (10 arom. C); 128.93, 134.89, 136.07, 160.07, 162.17 (5 C); 170.90 (C¼O). EI-MS:
352 (27, Mþ), 327 (13), 323 (14), 279 (8), 215 (10), 167 (26), 149 (86), 104 (100), 91 (58), 70 (54), 57 (34),
43 (48). Anal. calc. for C20H20N2O2S (352.45): C 68.16, H 5.72, N 7.95; found: C 68.02, H 5.64, N 7.81.
Methyl 2-[Bis(phenylmethyl)amino]-4-phenylthiazole-5-carboxylate (8k): Yield 322 mg (77%).
1
White crystals. M.p. 107.68. IR (KBr): 3061, 32029, 2936, 1677, 1604, 1528, 1310, 1263. H-NMR: 3.73
(s, Me); 4.72(s, 2 CH2); 7.29 – 7.40 (m, 12 arom. H); 7.80 – 7.3 (m, 3 arom. H). 13C-NMR: 51.59 (Me); 53.40
(2 CH2); 127.55, 127.89, 128.81, 129.94 (15 arom. C); 129.05, 134.68, 135.75, 160.10, 162.31 (6 C); 171.12
(C¼O). EI-MS: 414 (20, Mþ), 323 (82), 291 (8), 149 (4), 133 (7), 105 (6), 91 (100), 65 (12). Anal. calc. for
C25H22N2O2S (414.52): C 72.44, H 5.35, N 6.76; found: C 68.02, H 5.64, N 7.81.
Ethyl 2-[Bis(phenylmethyl)amino]-4-phenylthiazole-5-carboxylate (8l): Yield 321 mg (75%). White
crystals. M.p. 73.18. IR (KBr): 3060, 3028, 2978, 2912, 1708, 1534, 1481, 1331, 1237. 1H-NMR: 1.25 (t, 3J ¼
3
7.1, MeCH2); 4.21 (q, J ¼ 7.1, MeCH2); 4.73 (s, (CH2)2N); 7.27 – 7.40 (m, 12 arom. H); 7.82 – 7.83 (m, 3
arom. H). 13C-NMR: 14.28 (MeCH2); 53.32 (CH2)2N); 60.57 (MeCH2); 127.50, 127.87, 127.89, 128.80,
129.98 (15 arom. C); 128.97, 134.81, 135.82, 159.78, 161.96 (6 C); 171.10 (C¼O). EI-MS: 428 (3, Mþ), 337
(7), 279 (4), 206 (8), 191 (15), 167 (20), 149 (66), 105 (91), 91 (73), 70 (98), 59 (97), 48 (100). Anal. calc.
for C26H24N2O2S (428.55): C 72.87, H 5.64, N 6.54; found: C 72.75, H 5.56, N 6.41.
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Received August 14, 2011