Synthesis of 2-(2-R1)-hydrazino)-5-(R2-benzyl)-2- thiazolines on the basis of meerweins arylation products of allyl isothiocyanate

Article abstract of DOI:10.3390/80200263

3-Aryl-2-chloropropylisothiocyanates (1) are formed by interaction of arene-diazonium chlorides with allyl isothiocyanate. Adducts 1 react with monoacylhydrazines to form 1-acyl-4-(3-aryl-2-chloropropyl)thiosemicarbazides (2a-d). Thiosemicarbazides 2a-d in the presence of bases selectively transform into 2-(2-R¹-hydrazino)-5-(R²-benzyl)-2-thiazolines (3a-d).

Full text of DOI:10.3390/80200263

Molecules 2003, 8, 263-268
molecules
ISSN 1420-3049
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Synthesis of 2-(2-R1-Hydrazino)-5-(R2-benzyl)-2-thiazolines on
the Basis of Meerweins Arylation Products of Allyl
Isothiocyanate
Volodymyr V. Karpyak, Mykola D. Obushak* and Mykola I. Ganushchak
Department of Organic Chemistry, Ivan Franko Lviv National University, Kyryla & Mefodiya St. 6, Lviv
79005, Ukraine.
* Author to whom correspondence should be addressed. Tel.: +38 (0322) 728062, e-mail:
obushak@in.lviv.ua
Received: 12 July 2002; in revised form: 20 February 2003 / Accepted: 21 February 2003 / Published:
28 February 2003
Abstract: 3-Aryl-2-chloropropylisothiocyanates (1) are formed by interaction of arene-
diazonium chlorides with allyl isothiocyanate. Adducts 1 react with monoacylhydrazines to form
1-acyl-4-(3-aryl-2-chloropropyl)thiosemicarbazides (2a–d). Thiosemicarbazides 2a–d in the
presence of bases selectively transform into 2-(2-R1-hydrazino)-5-(R2-benzyl)-2-thiazolines
(3a–d).
Keywords: Arylation, allyl isothiocyanate, thiosemicarbazides, 2-thiazolines, cyclizations.
Introduction
There are different approaches to the synthesis of 2-thiazoline derivatives [1, 2]. One of the most
convenient methods is cyclization of compounds containing the CH(X)CH NHC(S) fragment that take place
2
when they are heated or when they are subjected to base-catalysis. Another well-known method involves an
addition of an electrophilic reagent to the double bond of the allylic fragment of the thiourea or a related
compound.

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To obtain five- or six-membered heterocycles, allyl isothiocyanate or its dibromo-derivative [3] were used
as starting materials. We now offer a new approach to the synthesis of such compounds by the use of chloro-
or bromoarylation products of allyl isothiocyanate in reaction with arenediazonium halides. Taking into account
that Ar and Hal add to the double bond as the result of catalytic dediazoniation of arenediazonium halides in
the presence of unsaturated compounds [4], we used this approach with allyl isothiocyanate to obtain suitable
reagents for the synthesis of 2-thiazolines [5, 6].
Results and Discussion
It had been shown before that allyl isothiocyanate takes part in a catalytic reaction with arenediazonium
chlorides [4, 5]. The result is formation of the addition products of an aryl group and a chlorine atom to the
C=C double bond (Meerwein reaction).
Scheme 1.
CuCl2
-
+
NCS
RC6H4N 2Cl +
RC6H4
NCS
– N
2
Cl
1a, b
R = H (1a) and 3-Cl (1b).
Compounds 1a,b are suitable reagents for obtaining five-membered heterocycles. Specifically, these
compounds react with primary and secondary amines to form 1,3-disubstituted thioureas, which were
converted to 2-thiazoline-derivatives in the presence of bases [5, 6]. In this work the interaction of
chloroarylation products of allyl isothiocyanate 1a,b with some monoacylhydrazines was investigated. It was
shown that the result of this reaction was formation of 1,4-disubstituted thiosemicarbazides 2a–d.
Scheme 2.
S
H
O
N
R2
R1C6H4
N=C=S
+ R2
R1C6H4
N
H
N
H
NHNH2
Cl
Cl
O
1a, b
2a–d
2a
2b
2c
2d
R1
R2
H
H
3-Cl
C5H11
3-Cl
Ph
C5H11
Ph

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Thiosemicarbazides 2a–d contain in the side chain the chlorine atom and several other nucleophilic
centers. For this reason the can be used for intramolecular cyclisations with subsequent formation of
heterocycles. Actually, compounds 2a–d cyclize in the presence of bases to form 2-thiazoline derivatives 3a–
d, which contain hydrazino groups in the 2 position of the ring (pathway a). It has been noted that other
variants of this cyclization – formation of imidazolidine-2-thione derivatives (pathway b), or hexahydro-1,2,4-
thiazine-3-thione derivatives (pathway c) do not take place. This may be caused by the high nucleophility of
the sulfur atom relative to the nitrogen atoms:
Scheme 3.
N
H
(a)
R1C6H4
N
R2
N
H
S
3a–d
O
H
N
R1C6H4
NH
H
S
(b)
R2
:B
R1C6H4
O
Cl
N
N
S
N
R2
H
NH
NH
O
2a–d
(c)
R1C6H4
R2
N
N
H
S
O
The heterocyclization reactions of thiosemicarbazides 2a–d were carried out in acetone, in the presence of
organic bases (triethylamine or N-methylmorpholine). It is important to note that 2-thiazoline derivatives 3a–d,
which contain the hydrazino group in the 2 position of the ring, are difficult to obtain by other methods. The
1
structure of the synthesized compounds has been confirmed by H-NMR-spectroscopy. The spectra of the
compounds 2a–d and 3a–d (see Experimental) contain two ABX spin systems (CH2CHXCH2). It is
significant that the chemical shifts of the proton in the CHCl group (thiosemicarbazides 2a–d) and those of the
protons in the CHS group (thiazolines 3a–d) differ by ~ 0.5 ppm. The protons of the NHC(S)NH fragments
in compounds 2a–d and the NHNH in thiazolines 3a–d do not give sharp signals in the 1H-NMR spectra.
Conclusions
We have presented a facile route for the formation of 1-acyl-4-(3-aryl-2-chloropropyl)-thiosemicarbazides
and 2-(2-R1-hydrazino)-5-(R2-benzyl)-2-thiazolines.

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Experimental
General
1
All melting points are uncorrected. H-NMR spectra were obtained using a Bruker AC-200 spectrometer
and were recorded at 200 MHz in DMSO-d6. Chemical shifts are reported in ppm relative to the residual
signal of the solvent. When the signals of the CH2N or CH2Ar groups in compounds 2a–d and 3a–d were
not sharp, coupling constants were not determined. For narrow multiplets the centres of the signals is
indicated. The chloroarylation of allyl isothiocyanate was carried by the method described in [4]. The data of
3-phenyl-2-chloropropylisothiocyanate (1a) are presented there.
20
3-(3-Chlorophenyl)-2-chloropropylisothiocyanate (1b); yield 27%, b.p. 108–110°C (0.5 mm), n
D
1.6066; Found: C, 48.58; H, 3.77; S, 13.25. C H9Cl2NS requires C, 48.79; H, 3.69; S, 13.03%;
10
1H-NMR: d 2.98 (dd, 1H, CH Ar, J13 8.0 Hz, J12 14.2 Hz), 3.19 (dd, 1H, CH2Ar, J13 5.0 Hz), 3.89 (dd,
2
1H, CH2N, J13 5.8 Hz, J12 15.2 Hz), 4.04 (dd, 2H, CH2N, J13 4.0 Hz), 4.53 (m, 1H, CH), 7.20–7.60 (m,
4H, C6H4).
1-Acyl-4-(3-aryl-2-chloropropyl)thiosemicarbazides (2a-d). A mixture of 3-aryl-2-chloropropyl-
isothiocyanate (1, 5 mmole) and the corresponding monoacylhydrazine (5 mmole) was boiled in benzene (5
mL) for 1 hour. The precipitates obtained were filtered and recrystallized from the solvent indicated.
1-Caproyl-4-(3-phenyl-2-chloropropyl)thiosemicarbazide (2a); yield 61%, m.p. 170–171°C (from
dioxane); Found: C, 56.14; H, 7.22; S, 9.21; C H24ClN3OS requires C, 56.21; H, 7.08; S, 9.38%;
16
1H-NMR: 0.90 (t, 3H, CH ), 1.24–1.36 (m, 4H, CH CH CH ), 1.50–1.64 (m, 2H, CH CH C=O), 2.22
d
3
2
2
3
2
2
(t, 2H, CH C=O), 3.01(dd, 1H, CH2Ar), 3.17 (dd, 1H, CH Ar), 3.78 (dd, 1H, CH N), 4.03 (dd, 1H,
2
2
2
CH2N), 4.49 (m, 1H, CH), 7.26 (m, 5H, C6H5), 10.98 (s, 1H, NHC=O).
1-Benzoyl-4-(3-phenyl-2-chloropropyl)thiosemicarbazide (2b); yield 72%, m.p. 172–173°C (from
toluene); Found: C, 58.81; H, 5.32; S, 9.43; C H18ClN3OS requires C, 58.69; H, 5.21; S, 9.22%;
17
1H-NMR: d 3.05 (dd, 1H, CH Ar), 3.19 (dd, 1H, CH Ar), 3.77 (m, 1H, CH2N), 4.02 (m, 1H, CH2N),
2
2
4.50 (m, 1H, CH), 7.04–7.36 (m, 5H, C6H5), 7.44–7.63 (m, 3H, C6H5), 7.98–8.08 (m, 2H, C6H5 – o-H),
11.69 (s, 1H, NHC=O).
1-Caproyl-4-[3-(3-chlorophenyl)-2-chloropropyl]thiosemicarbazide (2c); yield 53%, m.p. 161–162°C
(from toluene); Found: C, 50.89; H, 6.04; S, 8.64; C16H23Cl2N3OS requires C, 51.06; H, 6.16; S, 8.52%);
1H-NMR: d 0.88 (t, 3H, CH3), 1.20–1.40 (m, 4H, CH2CH2CH3), 1.48–1.67 (m, 2H, CH2CH2C=O), 2.23
(t, 2H, CH C=O), 3.01 (dd, 1H, CH2Ar, J13 8.6 Hz, J12 13.6 Hz), 3.19 (dd, 2H, CH2Ar, J13 7.0 Hz), 3.80
2

Molecules 2003, 8
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(dd, 1H, CH2N), 4.06 (dd, 1H, CH2N), 4.50 (m, 1H, CH), 7.20–7.45 (m, 4H, CH4), 11.00 (s, 1H,
6
NHC=O).
1-Benzoyl-4-[3-(3-chlorophenyl)-2-chloropropyl]thiosemicarbazide (2d); yield 46%, m.p. 188–189°C
(from benzene); Found: C, 53.57; H, 4.31; S, 8.23; C17H17Cl N3OS requires C, 53.41; H, 4.48; S, 8.39%;
2
1H-NMR: d 3.09 (dd, 1H, CH Ar, J13 8.0 Hz, J12 14.4 Hz), 3.21 (dd, 1H, CH2Ar, J13 6.4 Hz), 3.80 (dd,
2
1H, CH2N), 4.04 (dd, 1H, CH N), 4.55 (m, 1H, CH), 7.20–7.40 (m, 4H, Ar), 7.56 (m, 3H, Ar), 8.04 (m,
2
2H, C6H5 – o-H), 11.64 (s, 1H, NHC=O).
2-(2-Acylhydrazino)-5-benzyl-2-thiazolines (3a–d). Triethylamine (or N-methylmorpholine) (5 mmoles)
was added to a solution of the corresponding thiosemicarbazide 2a–d (2 mmoles) in acetone (5 mL) and the
mixture was boiled for 30 min. After cooling water (15 mL) was added to the mixture. The precipitate was
filtered, air dried and recrystallized from the appropriate solvent.
2-(2-Caproylhydrazino)-5-benzyl-2-thiazoline (3a); yield 86%, m.p. 156–157°C (from benzene –
cyclohexane, 3:1); Found: C, 62.80; H, 7.70; S, 10.61; C H23N3OS requires C, 62.92; H, 7.59; S,
16
1
10.50%); H-NMR: d 0.90 (t, 3H, CH3), 1.18–1.38 (m, 4H, CH2CH2CH3), 1.42–1.60 (m, 2H,
CH2CH2C=O), 2.02 (t, 2H, CH2C=O), 2.92 (dd, 1H, CH2Ar, J 9.2 Hz, J 14.4 Hz), 3.04 (dd, 1H,
13
12
CH2Ar, J 6.8 Hz), 3.37 (dd, 1H, CH2N, J13 6.6 Hz, J12 8.0 Hz), 3.62 (dd, 1H, CH2N, J13 6.4 Hz), 3.94
13
(m, 1H, CH), 7.19–7.35 (m, 5H, C6H5).
2-(2-Benzoylhydrazino)-5-benzyl-2-thiazoline (3b); yield 56%, m.p. 143–144°C (from toluene); Found:
1
C, 65.41; H, 5.35; S 10.11; C17H17N3OS requires C, 65.57; H, 5.50; S, 10.30%); H-NMR: d 2.93 (dd,
1H, CH2Ar, J13 8.6 Hz, J12 14.0 Hz), 3.06 (dd, 1H, CH2Ar, J13 6.0 Hz), 3.40 (dd, 1H, CH N, J13 6.4 Hz, J12
2
11.2 Hz), 3.66 (dd, 1H, CH2N, J13 7.0 Hz), 3.98 (m, 1H, CH), 7.10–7.33 (m, 5H, C6H5), 7.38–7.48 (m,
3H, C6H5), 7.77–7.87 (m, 2H, C6H5 – o-H).
2-(2-Caproylhydrazino)-5-(3-chlorobenzyl)-2-thiazoline (3c); yield 69%, m.p. 149–150°C (from
petroleum ether – benzene, 1:5); Found: C, 56.74; H, 6.68; S, 9.33; C16H22ClN3OS requires C, 56.54; H,
1
6.52; S, 9.43%); H-NMR: d 0.89 (t, 3H, CH3), 1.21–1.37 (m, 4H, CH2CH2CH3), 1.45–1.60 (m, 2H,
CH2CH2C=O), 2.03 (t, 2H, CH2C=O), 2.88 (dd, 1H, CH2Ar, J 8.2 Hz, J 13.6 Hz), 3.05 (dd, 1H,
13
12
CH2Ar, J13 6.4 Hz), 3.38 (dd, 1H, CH2N, J13 5.4 Hz, J12 10.4 Hz), 3.63 (dd, 2H, CH2N, J13 6.6 Hz), 3.97
(m, 1H, CH), 7.16–7.36 (m, 4H, C6H4).
2-(2-Benzoylhydrazino)-5-(3-chlorobenzyl)-2-thiazoline (3d); yield 56%, m.p. 176–177°C (from
toluene); Found : C, 59.21; H, 4.44; S, 9.37; C H16ClN3OS requires C, 59.04; H, 4.66; S, 9.27%);
17
1H-NMR: d 2.92 (dd, 1H, CH Ar, J13 8.0 Hz, J12 14.4 Hz), 3.08 (dd, 2H, CH2Ar, J13 6.2 Hz), 3.41 (dd,
2

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1H, CH2N, J13 5.6 Hz, J12 10.2 Hz), 3.66 (dd, 1H, CH2N, J13 5.8 Hz), 4.01 (m, 1H, CH), 7.15–7.50 (m,
7H, Ar), 7.78–7.88 (m, 2H, C6H5 – o-H).
References and Notes
1. Heterocyclic Compounds; Elderfield, R. C., ed.; Moscow, 1961; Vol. 5, pp 531-544.
2. Staninets, V. I.; Shilov, Ye. A. Addition Reactions with intramolecular ring closure. Uspekhi Khimii
(Chem. Rev. USSR) 1971, 40, 491-512.
3. Tkachenko, S. E.; Pushin, A. N.; Fedoseev, V. M. Course of the addition of amines to 2,3-
dibromopropyl isothiocyanate. J. Gen. Chem. USSR 1987, 57, 2146-2147.
4. Obushak, N. D.; Karpyak, V. V.; Ganushchak, N. I.; Koval’chuk, E. P.; Tikhonov, V. P.
Chloroarylation of allyl compounds. Russ. J. Org. Chem. 1993, 29, 1149-1156.
5. Obushak, M. D.; Karpyak, V. V.; Ganushchak, M. I. Synthesis of Heterocycles on the Basis of
Anionoarylation Products of Unsaturated Compounds. 6. Halogenoarylation of Allyl Isothiocyanate:
Synthesis of 2,5-Disubstituted 2-Thiazolines. Heteroatom Chem. 1999, 10, 517-525.
6. Karpyak, V. V.; Obushak, N. D.; Ganushchak, N. I. Preparation of 2,5-disubstituted 2-thiazolines.
Chem. Heterocycl. Compds. 1997, 1278-1279.
Sample Availability: Compounds 1-3 are available from the authors.
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