Utilization of methyl 3-Aryl-2-thiocyanatopropanoates in the synthesis of 2-(4-morpholinyl)- and 2-(piperazinyl)-5-(benzyl)thiazol-4-ones1

Article abstract of DOI:10.1080/10426500701242103

By the reaction of methyl acrylate with arenediazonium salts and KSCN in the presence of copper(II) acetate, the methyl 3-aryl-2-thiocyanatopropanoates 2 have been obtained. These compounds react with morpholine or monosubstituted piperazines in the prese

Full text of DOI:10.1080/10426500701242103

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Utilization of Methyl 3-Aryl-2-
thiocyanatopropanoates in the
Synthesis of 2-(4-Morpholinyl)-
and 2-(Piperazinyl)-5-
(benzyl)thiazol-4-ones1
Mykola D. Obushak a , Volodymyr V. Karpyak a , Yuri
V. Ostapiuk a & Vasyl S. Matiychuk a
a Department of Organic Chemistry, Ivan Franko
National University of Lviv, Lviv, Ukraine
Published online: 07 Jun 2007.
To cite this article: Mykola D. Obushak , Volodymyr V. Karpyak , Yuri V. Ostapiuk &
Vasyl S. Matiychuk (2007) Utilization of Methyl 3-Aryl-2-thiocyanatopropanoates in
the Synthesis of 2-(4-Morpholinyl)- and 2-(Piperazinyl)-5-(benzyl)thiazol-4-ones1 ,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:7, 1437-1445, DOI:
10.1080/10426500701242103
To link to this article: http://dx.doi.org/10.1080/10426500701242103
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Phosphorus, Sulfur, and Silicon, 182:1437–1445, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701242103
Utilization of Methyl 3-Aryl-2-thiocyanatopropanoates
in the Synthesis of 2-(4-Morpholinyl)- and
2-(Piperazinyl)-5-(benzyl)thiazol-4-ones1
Mykola D. Obushak
Volodymyr V. Karpyak
Yuri V. Ostapiuk
Vasyl S. Matiychuk
Department of Organic Chemistry, Ivan Franko National University of
Lviv, Lviv, Ukraine
By the reaction of methyl acrylate with arenediazonium salts and KSCN in the pres-
ence of copper(II) acetate, the methyl 3-aryl-2-thiocyanatopropanoates 2 have been
obtained. These compounds react with morpholine or monosubstituted piperazines
in the presence of acetic acid to form 2-(4-morpholinyl)- or 2-(4-R-piperazinyl)-5-
(Rꢀ-benzyl)thiazol-4-ones 4 and 5, respectively.
Keywords Arylation; cyclization; piperazines; thiocyanates; Thiazol-4-ones
INTRODUCTION
Thiazolidin-4-one and thiazol-4-one derivatives have been widely
employed in the investigation of biologically active heterocyclic
compounds.2−5 Therefore, the synthesis of combinatorial libraries of
these compounds was elaborated.6−9 In the recent past, 5-R-benzyl-
2,4-thiazolidinones have been investigated intensively, since series of
these compounds are already used as antidiabetic drugs.10−15 The 2-
amino(imino)-4-thiazolidinones have considerable interest for pharma-
cological investigations and for chemical modifications.2
A general synthesis of such compounds is based on the cycliza-
tion of thioureas or other S,N-nucleophiles with α-haloacids or their
esters.2,16 However, the ring closure takes place selectively, only in the
Received October 5, 2006; accepted December 4, 2006.
1Synthesis of Heterocycles on the Basis of Arylation Products of Unsaturated Com-
pounds, Communication 15.–Communication 14 see [1].
Address correspondence to Mykola D. Obushak, Department of Organic Chemistry,
Ivan Franko National University of Lviv, Kyryla & Mefodiya Str. 6, 79005 Lviv, Ukraine.
E-mail: obushak@in.lviv.ua.
1437

1438
M. D. Obushak et al.
case of considerable difference in the nucleophility of the N-atoms of
the reagents.17 Another strategy for the construction of thiazolidin-
4-ones or thiazol-4-ones avoids that complication. The method is
based on the reaction of α-thiocyanatocarboxylic acid derivatives
with amines.18−20 Through interaction with thiourea, the esters of α-
thiocyanatocarboxylic acid also experience ring closure. When using
substituted thioureas, however, there is no ring closure.2
In this article, we describe an approach to the synthesis of 2-amino-
5-benzylthiazol-4-ones from methyl 3-aryl-2-thiocyanatopropanoates 2
and secondary amines 3 (Scheme 1).
SCHEME 1
RESULTS AND DISCUSSION
Starting methyl 3-aryl-2-thiocyanatopropanoates 2a–d was obtained
from a one-pot procedure by the reaction of methylacrylates with arene-
diazonium tetrafluoroborates 1a–d and potassium thiocyanate in the
presence of copper(II) acetate as catalyst (Scheme 2).
SCHEME 2
Thiocyanatoarylation of unsaturated compounds is a convenient syn-
thetical modification of the Meerwein arylation reaction.21−23
Research showed that compounds 2a–d possess a low activity in
the reaction with secondary amines, such as morpholine 3a or substi-
tuted piperazines 3b–e. Under conditions cited in the paper,19 thiazol-
4-one ring was not formed. However, we found conditions to obtain
2-substituted 5-R1-benzylthiazol-4-ones 4a,b and 5a–j in reasonable
yields (Scheme 3). Reaction occurred after long-term heating of reagents

Benzyl Thiazolones
1439
in the presence of equimolar quantity of acetic acid in ethanol or 2-
propanol.
SCHEME 3
1
In the H-NMR spectra, the protons of the ArCH2CH fragment ap-
pear as an AMX spin system, i.e., as three doublets of doublets. In some
cases, these signals are broadened, evidently due to the fast modifica-
tion of the conformation of the morpholine or piperidine ring. In the
mass spectra of compounds 4, 5, the fragments [R2C6H4NCH2CH2]+,
[R1C6H4CH2]+, [R2C6H4N]+, and [NCH2CH2]+ became apparent.
Yields of compounds 4, 5 significantly depend on the form of amine
3. By using the free amine, or its salt with strong acid, the thiazol-4-
one derivatives form with low yields. The best results were obtained
using acetates or propionates of corresponding amines. Such results
showed that amines 3 enter into the reaction with compounds 2 as the
unprotonated base. But for successful reaction the acid was necessary.
Evidently, the acid promoted reaction of the nitrile group and thereby
catalyzed the reaction (Scheme 4).
Protonation of the N-atom of methyl 3-aryl-2-thiocyanato-
propanoates 2 caused the formation of carbocation 6, which was

1440
M. D. Obushak et al.
SCHEME 4
attacked by R2NH and generated intermediate cation 7. On proton
elimination, 7 was transformed to acyclic compound 8, which was sta-
bilized because of cyclization and formed thiazol-4-one 4, 5, following
the elimination of methanol.
Thus, by using of the methyl-3-aryl-2-thiocyanatopropanoates
2 a–d, we found a convenient method to synthesize 2-amino-5-R-
benzylthiazol-4-one.
EXPERIMENTAL
All melting points are uncorrected. The 1H-NMR spectra were recorded
on a Bruker AM300 (300 MHz) or Bruker DRX500 (500 MHz) spectrom-
eters in DMSO-d6 with Me4Si as internal standard. The mass spectra
were recorded on a Finnigan MAT-INKOS-50 chromatomass spectrom-
eter at 70 eV. The monosubstituted piperazines were obtained by known
methods.24
General Procedure for the Synthesis of Methyl
3-aryl-2-thiocyanatopropanoates (1a)
Arenediazonium tetrafluoroborate 1a–d had been prepared in the usual
manner from the appropriate aromatic amine (0.11 mol). The solid di-
azonium salt 1a–d was gradually added with stirring at 5◦ to the mix-
ture of acetone (75 ml), methyl acrylate (9.1 ml), and copper(II) sulphate
(0.01 mol). When the N2 evolution ceased, the mixture was diluted with
200 ml of water, extracted with CH2Cl2 (3 × 50 ml), the extracts were
dried (MgSO4), and concentrated. The residue was vacuum-distilled.
Compounds 2a–c have been described earlier.23

Benzyl Thiazolones
1441
Methyl 3-(3-chlorophenyl)-2-thiocyanatopropanoate (2d)
B.p. 154◦C/1.5 mm Hg; n2D0 1.5600; Yield 62%. Anal. requires for
C11H10ClNO2S (255.72) calcd./found: C 51.67/51.57; H 3.94/3.80; N
5.48/5.31.
General Procedure for Obtaining 5-R1-Benzyl-2-(4-
morpholinyl)-1,3-thiazol-4(5H)-ones (4a, b) and 5-R1-benzyl-2-
(4-phenyl-1-piperazinyl)-1,3-thiazol-4(5H)-ones (5 a–j)
The mixture of appropriate methyl 3-aryl-2-thiocyanatopropanoate 1a–
d (0.01 mol), amine 3a–e (0.01 mol), and AcOH (0.6 g) in ethanol or
2-propanol (10 ml) was refluxed for 15–30 h. The course of reaction was
monitored by TLC. After cooling of reaction mixture, the precipitate
was formed, filtered, and crystallized from the appropriate solvent.
5-Benzyl-2-(4-morpholinyl)-1,3-thiazol-4(5H)-one (4a)
m.p. 129–130◦C (hexane-benzene, 1:1) in 36% yield. 1H NMR ppm:
δ 2.88 (dd, J = 14.2/10.6, 1H); 3.43–3.51 (m, 3H); 3.66 (br. s, 4H);
3.78–3.85 (m, 2H); 4.60 (dd, J = 10.6/4.7, 1H); 7.19–7.31 (m, 5H).
Anal. requires for C14H16N2O2S (276.36) calcd./found: C, 60.85/60.77;
H, 5.84/5.92; N, 10.14/10.03.
5-(4-Methybenzyl)-2-(4-morpholinyl)-1,3-thiazol-4(5H)-one
(4b)
m.p. 117–118◦C (cyclohexane-benzene, 2:1) in 34% yield. 1H NMR ppm:
δ 2.28 (s, 3H); 2.82 (br. dd, 1H); 3.37–3.48 (m, 3H); 3.64 (br. s, 4H); 3.74–
3.83 (m, 2H); 4.57–4.63 (m, 1H); 7.07 (d, 2H); 7.12 (d, 2H). MS (m/z) (%):
290 (57, A+), 105 (100, [4-CH3C6H4CH2]), 86 (50, [C4H8NO]), 42 (67,
[NCH2CH2]). Anal. requires for C15H18N2O2S (290.39) calcd./found: C
62.04/61.85; H 6.25/6.23; N 9.65/9.47.
5-Benzyl-2-(4-phenyl-1-piperazinyl)-1,3-thiazol-4(5H)-one (5a)
1
m.p. 123–124◦C (pentane-benzene, 2:1) in 42% yield. H NMR ppm:
δ 2.89 (dd, J = 13.8/10.2, 1H); 3.18–3.27 (br. s, 4H); 3.49 (dd, J =
13.8/3.9, 1H); 3.61 (br. t, 2H); 3.98 (br. t, 2H); 4.58 (dd, J = 10.2/3.9,
1H); 6.83 (t, J = 7.2, 1H); 6.93 (d, J = 7.8, 2H), 7.17–7.32 (m, 7H).
Anal. requires for C20H21N3OS (351.47) calcd./found: C 68.35/68.12; H
6.02/5.97; N 11.96/11.85.

1442
M. D. Obushak et al.
5-Benzyl-2-(4-(3-methylphenyl)-1-piperazinyl)-1,3-
thiazol-4(5H)-one (5b)
m.p. 128–129◦C (ethanol) in 39% yield. 1H NMR ppm: δ 2.29 (s, 3H); 2.89
(br. dd, 1H); 3.22 (br. s, 4H); 3.50 (br. dd, 1H); 3.60 (br. t, 2H); 3.97 (br. t,
2H); 4.58 (br. dd, 1H); 6.60–6.80 (m, 3H); 7.09 (t, 1H); 7.15–7.36 (m, 5H).
Anal. requires for C21H23N3OS (365.50) calcd./found: C 69.01/68.88; H
6.34/6.23; N 11.50/11.42.
5-Benzyl-2-(4-(4-methylphenyl)-1-piperazinyl)-1,3-thiazol-
4(5H)-one (5c)
1
m.p. 115–116◦C (pentane-benzene, 2:1) in 35% yield. H NMR ppm:
δ 2.25 (s, 3H); 2.89 (dd, J = 14.4/13.8, 1H); 3.16 (br. s, 4H); 3.48 (dd,
J = 13.8/4.0, 1H); 3.60 (br. t, 2H); 3.97 (br. t, 2H); 4.57 (dd, J = 10.8/4.5,
1H); 6.83 (d, J = 8.7, 2H); 7.03 (d, J = 7.8, 2H); 7.18–7.34 (m, 5H).
Anal. requires for C21H23N3OS (365.50) Calcd./Found: C 69.01/68.82;
H 6.34/6.29; N 11.50/11.55.
5-(3-Methylbenzyl)-2-(4-phenyl-1-piperazinyl)-1,3-thiazol-
4(5H)-one (5d)
m.p. 173–174◦C (cyclohexane-benzene, 1:4) in 42% yield. 1H NMR ppm:
δ 2.30 (s, 3H); 2.83 (dd, J = 13.9/10.4, 1H); 3.43 (dd, J = 13.9/3.5, 1H);
3.18–3.29 (m, 4H); 3.61 (br. s, 2H); 3.96 (br. s, 2H); 4.61 (dd, J = 10.4/3.5
1H); 6.83 (t, J = 6.9, 1H); 6.95 (d, J = 8.1, 2H); 7.03 (t, J = 9.2, 2H);
7.07 (s, 1H); 7.17 (pseudo t, 1H); 7.20–7.26 (m, 2H). MS (m/z) (%):
365 (4, M+), 119 (25, [C6H5NCH2CH2]), 105 (39, [3-CH3C6H4CH2]), 91
(13, [C6H5N]), 77 (24, [C6H5]). Anal. requires for C21H23N3OS (365.50)
Calcd./Found: C 69.01/68.90; H 6.34/6.25; N 11.50/11.61.
5-(4-Methylbenzyl)-2-(4-phenyl-1-piperazinyl)-1,3-thiazol-
4(5H)-one (5e)
m.p. 182–183◦C (cyclohexane-benzene, 1:1) in 58% yield. 1H NMR
(DMSO-d6, 500 MHz) ppm: δ 2.25 (s, 3H); 2.86 (dd, J = 13.9/10.4, 1H);
3.40 (dd, J = 3.5/13.9, 1H); 3.17–3.29 (m, 4H); 3.59 (br. t, 2H); 3.91–
3.98 (m, 2H); 4.60 (dd, J = 10.4/3.5, 1H); 6.83 (t, J = 6.9, 1H); 6.94
(d, J = 8.1, 2H); 7.08 (d, J = 6.9, 2H); 7.13 (d, J = 6.9, 2H); 7.23 (t,
J = 8.1, 2H). MS (m/z) (%): 365 (4, M+), 119 (24, [C6H5NCH2CH2]), 105
(42, [4-CH3C6H4CH2]), 91 (13, [C6H5N]), 77 (23, [C6H5]). Anal. requires
for C21H23N3OS (365.50) Calcd./Found: C 69.01/69.12; H 6.34/6.40, N
11.50/11.38.

Benzyl Thiazolones
1443
5-(4-Methylbenzyl)-2-(4-(2-methylphenyl)-1-piperazinyl)-1,3-
thiazol-4(5H)-one (5f)
M.p. 144–145◦C (acetone-hexane, 4:1) in 41% yield. 1H NMR ppm:
δ 2.29 (s, 6H); 2.82–2.96 (m, 5H); 3.40 (dd, J = 14.1/3.8, 1H); 3.60
(br. t, 2H); 3.90–4.00 (m, 2H); 4.61 (dd, J = 3.8/10.4, 1H); 6.95–7.02
(m, 2H); 7.07–7.19 (m, 6H). MS (m/z) (%): 379 (2, M+), 146 (100, [4-
CH3C6H4CH2CHCO]), 133 (33, [2-CH3C6H4NCH2CH2]), 118 (38, [4-
CH3C6H4CH2CH]), 105 (24, [2-CH3C6H4N]), 91 (19, [2-CH3C6H4]).
Anal. requires for C22H25N3OS (379.53) Calcd./Found: C 69.62/69.49;
H 6.64/6.60; N 11.07/11.00.
5-(4-Methylbenzyl)-2-(4-(3-methylphenyl)-1-piperazinyl)-1,3-
thiazol-4(5H)-one (5g)
m.p. 160–161◦C (cyclohexane-benzene, 2:1) in 57% yield. 1H NMR ppm:
δ 2.26 (s, 3H); 2.28 (s, 3H); 2.86 (dd, J = 14.0/10.4, 1H); 3.16–3.26
(m, 4H); 3.40 (dd, J = 3.5/14.0, 1H); 3.58 (br. t, 2H); 3.93 (br. s, 2H);
4.60 (dd, J = 3.5/10.4, 1H); 6.65 (d, J = 8.1, 1H); 6.73 (d, J = 8.1, 1H);
6.76 (s, 1H); 7.06–7.16 (m, 5H). MS (m/z) (%): 379 (4, M+), 146 (100,
[4-CH3C6H4CH2CHCO]), 133 (31, [3-CH3C6H4NCH2CH2]), 118 (25,
[4-CH3C6H4CH2CH]), 105 (29, [3-CH3C6H4N]), 91 (26, [3-CH3C6H4]).
Anal. requires for C22H25N3OS (379.53) Calcd./Found: C 69.62/69.51; H
6.64/6.52; N 11.07/11.10.
5-(4-Methylbenzyl)-2-(4-(4-methylphenyl)-1-piperazinyl)-1,3-
thiazol-4(5H)-one (5h)
m.p. 167–168◦C (hexane-benzene, 1:2) in 55% yield. 1H NMR ppm:
δ 2.23 (s, 3H); 2.26 (s, 3H); 2.85 (dd, J = 14.2/9.8, 1H); 3.40 (dd,
J = 14.2/3.7, 1H); 3.05–3.15 (m, 4H); 3.57 (br. t, 2H); 3.93 (br. s, 2H);
4.60 (dd, J = 9.8/3.7, 1H); 6.84 (d, J = 8.1, 1H); 7.04 (d, J = 8.1, 1H);
7.08 (d, J = 8.1, 2H); 7.13 (d, J = 8.1, 2H). MS (m/z) (%): 379 (6, M+),
146 (100, [4-CH3C6H4CH2CHCO]), 133 (32, [4-CH3C6H4NCH2CH2]),
118 (27, [4-CH3C6H4CH2CH]), 105 (30, [4-CH3C6H4N]), 91 (27, [4-
CH3C6H4]). Anal. requires for C22H25N3OS (379.53) Calcd./Found: C
69.62/69.38, H 6.64/6.58, N 11.07/10.96.
5-(3-Chlorobenzyl)-2-(4-phenyl-1-piperazinyl)-1,3-thiazol-
4(5H)-one (5i)
m.p. 165–166◦C (acetone-hexane, 4:1) in 35% yield. 1H NMR ppm: δ 2.95
(dd, J = 14.2/9.3, 1H); 3.44 (dd, J = 14.2/4.6, 1H); 3.19–3.29 (m, 4H);

1444
M. D. Obushak et al.
3.61 (br. t, 2H); 3.95 (br. s, 2H); 4.70 (dd, J = 4.6/9.3, 1H); 6.83 (pseudo
t, 1H); 6.95 (d, J = 8.1, 2H); 7.20–7.27 (m, 4H); 7.32–7.34 (m, 2H). MS
(m/z) (%): 385 (2, M+), 119 (30, [C6H5NCH2CH2]), 91 (12, [C6H5N]), 77
(24, [C6H5]). Anal. requires for C20H20ClN3OS (385.92) Calcd./Found:
C 62.25/62.07; H 5.22/5.18; N 10.89/10.79.
5-(3-Chlorobenzyl)-2-(4-(4-methylphenyl)-1-piperazinyl)-1,3-
thiazol-4(5H)-one (5j)
m.p. 121–122◦C (propanol-2) in 30% yield. 1H NMR ppm: δ 2.25 (s,
3H); 2.93 (br. dd, 1H); 3.17 (br. s, 4H); 3.45 (br. dd, 1H); 3.61 (br. s,
2H); 3.96 (br. s, 2H); 4.62 (br. dd, 1H); 6.83 (d, J = 7.2, 2H); 7.03 (d,
J = 7.2, 2H); 7.17–7.34 (m, 4H). MS (m/z) (%) : 400 (5, M+), 133 (27, [4-
CH3C6H4NCH2CH2]), 105 (5, [4-CH3C6H4N]), 91 (20, [4-CH3C6H4]), 42
(4, [NC(O)]). Anal. requires for C21H22ClN3OS (399.95) Calcd./Found:
C 63.07/63.15; H 5.54/5.47, N 10.51/10.38.
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