Reaction of 1-tosyl-2,2-dichloroenamines with the Lawesson's reagent

Article abstract of DOI:10.1134/S1070363212050076

In the reaction of the available 1-tosyl-2,2-dihlorenamides with the Lawesson's reagent the derivatives of 4-tosyl-1,3-thiazole were shown to form containing a labile chlorine atom at the C⁵ position. This fact was used for the synthesis of a number of the previously unknown bifunctionally substituted 4,5-thiazoles.

Full text of DOI:10.1134/S1070363212050076

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 5, pp. 848–852. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © K.V. Turov, T.K. Vinogradova, E.B. Rusanov, V.S. Brovarets, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 5,
pp. 741–746.
Reaction of 1-Tosyl-2,2-dichloroenamines
with the Lawesson’s Reagent
K. V. Turova, T. K. Vinogradovaa, E. B. Rusanovb, and V. S. Brovaretsa
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Murmanskaya ul. 1, Kiev-94, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received March 10, 2011
Abstract—In the reaction of the available 1-tosyl-2,2-dihlorenamides with the Lawesson’s reagent the
derivatives of 4-tosyl-1,3-thiazole were shown to form containing a labile chlorine atom at the C5 position. This
fact was used for the synthesis of a number of the previously unknown bifunctionally substituted 4,5-thiazoles.
DOI: 10.1134/S1070363212050076
Previously we studied the reaction of the enamides
of type I with the highly basic amines [1] and sodium
hydrosulfide [2], which leads to the derivatives of 5-
amino-5-mercaptooxazole, the agonists of 5-NT6
receptors [3].
center of the heterocycle. In this case, a possible
mechanism involves a sequence of reactions: addition
of the nucleophile to the activated double bond of the
heterocycle (A), prototropic transformation (B), and
cleavage of the chloride anion (C) and proton (D).
In this work we for the first time studied the
interaction of the enamides I with the Lawesson’s
reagent leading to the 2-R-4-tosyl-5-chloro-1,3-thiazole
derivatives III. The chlorine atom in compounds III
shows significant lability towards the action of the
highly basic amines, sodium phenolate, and thiophen-
oxides, undoubtedly due to the influence of electron-
acceptor groups in the vicinal position to the halogen
atom. The nature of the agent used as a rule does not
affect the course of this reaction, the reaction products
IV–VI can be isolated in a high yield (Scheme 1).
The choice between two alternative structures (D
and E) by means of NMR spectroscopy is difficult. We
failed to accomplish identification also using the
nuclear Overhauser effect, because the spatial arrange-
ment of the tozyl group in the 4 and 5 sites and the rest
of the nucleophile does not lead to the interaction
between them in the NOE experiment, no effect was
observed. Therefore, to prove the structure of the
compounds IV–VI unambiguously, one of them (Va)
was studied by the method of X-ray diffraction. The
general view of the molecule Va and its main
geometric parameters are shown in the figure.
Note that at the interaction of the thiazole IIIa
unsubstituted in 2 position with the secondary amines
and sodium tiophenoxides the replacement of the
halogen atom occurs under the milder conditions and
in a shorter time, but with lower yields. The interaction
of compound IIIa with the highly basic primary
amines is also complicated. The result of these
reactions is apparently due not only to the nucleophilic
substitution of the chlorine atom. The reaction includes
obviously some other processes that in the case of
primary amines result in a mixture of unidentified
products, so this reaction requires more detailed study.
In addition, analysis of the published data [4] suggests
that in such systems a nucleophile can attack the C2
Bond lengths in the central thiazole heterocycle are
close to usual for such compounds. Thus, the CS bonds
distances are equal, and the length of the C1N1 bond is
close to that of the standard C=N double bond 1.28 Å,
despite the conjugation in the heterocycle. The C–S1
bonds are equal within experimental error, while the
bonds C–S3 are markedly not equivalent (see caption
to the figure), apparently, because of a more efficient
conjugation of the lone electron pair of the S3 atom
with the aromatic π-system of the thiazole ring. The
thiazole ring is planar within 0.004 Å, and the atoms S1
and S3 deviate from this plane at –0.059 and –0.023 Å,
respectively. Phenyl rings C4–9 and C11–16 are turned by
848

REACTION OF 1-TOSYL-2,2-DICHLOROENAMINES
849
Scheme 1.
Cl
Cl
Ts
HN
Cl
Cl
Ts
HN
LR
O
R
S
R
Ia_Id
IIa_IId
Ts
2R1R2NH
Ar2ONa
N
R
Cl
S
IIIa_IIId
Ar1SNa
Ts
Ts
Ts
N
N
N
R1R2N
Ar1S
Me
S
VIa, VIb
Ar2O
R
R
S
Va_Vd
S
IVa_IVg
R = H (Ia, IIIa, IVa, IVb, Va, Vb), Me (Ib, IIIb, IVc_IVg, Vc, Vd), Ph (Ic, IIIc),
(Id, IIId); Ar1 = Ph (Va, Vc), 4-MeC6H4 (Vb, Vd),
O
2
1 2
O
N (IVa, IVc),
Ar = Ph (VIa), 4-MeC6H4 (VIb); R R N =
N (IVd),
N (IVb, IVe), PhCH2NH (IVf),
S
S
O
N
(CH2)2NH (IVg); LR = MeO
OMe.
Ts
P
P
S
S
Ts
Ts
N
NH
N
H
H
NuH
Cl
H
H
Nu
Nu
S
Cl
S
III
_HCl
Cl
S
A
H
B
_Cl_
NuH
Ts
Ts
Ts
N
N
N
H
_H+
+
Nu
Nu
Nu
H
H
S
S
S
E
D
C
96.6° and 95.4°, respectively, with respect to the thia-
zole mean plane. No other special features were found
in the structure of the molecule.
thiazole derivative VII, which is regioselectively
alkylated at the sulfur atom to form thiazoles VIII.
The structure of the compounds shown in Schemes 1
and 2 not only directly follow from the method of their
synthesis, but also were confirmed by elemental
For the introduction of alkylthio group to the 5
position of the thiazole ring it is more convenient to
use the approach shown by Scheme 2. Thus, initially
compound IIIb under the action of excess sodium
hydrogen sulfide is transformed into 5-mercapto-
1
analysis (Table 1), and H NMR spectra (Table 2).
Thus, the reaction of compounds I with the Lawes-
son’s reagent actually proceeds with the participation
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 5 2012

850
TUROV et al.
General view of the molecule Va and selected bond lengths and angles: C1S2 1.723(3), C3S2 1.723(2), C1N1 1.299(3), C2N1 1.385(3),
C2C3 1.371(3), C2S1 1.754(2), C4S1 1.759(2), C3S2 1.723(2), C11S3 1.779(3) Å; C1S2C3 89.75(13), N1C1S2 115.9(2), C3C2N1 117.0(2),
C1N1C2 109.0(2), C2C3S2 108.24(18), C2S1C4 103.21(11), C3S3C11 101.47(12)°.
of acylamino residues, as evidenced by the disappe-
arance of the NH group signal characteristic of the
starting materials. In addition, the data of the elemental
analysis on sulfur, chlorine and nitrogen are indicative.
Also compound IIIc was synthesized previously by
another method [5], which leaves no doubt in its
structure. Introduction of R1R2N, ArS, AlkS, and ArO
to the C5 center of the thiazole ring at the formation of
compounds IV–VIII is confirmed by the presence in
Thus, the method we developed for the synthesis of
substituted thiazoles III–VIII not only supplements,
but also simplifies the well-known one [5, 6], which
involves the use of 1-aryl-3-tosyl-1,4,4-trichloro-2-
aza-1,3-dienes less accessible than compounds I and
does not allow the introduction of a hydrogen atom,
alkyl, and heterocyclic substituents in 2 position of the
thiazole ring. Another recent publication [7] on the
synthesis of 4-tosyl-5-chloro-1,3-thiazoles also concerns
only the compounds with aryl substituents at the 2
position of the thiazole ring.
1
the H NMR spectra of appropriate signals with the
corresponding integral intensity.
Table 1. Yields, constants, and elemental analysis data of compounds III–VIII
Found, %
Calculated, %
Cl(N)
Comp. no. Yield, %
mp, °С a
Formula
Cl(N)
12.91
12.37
10.01
10.32
(8.73)
(8.89)
(8.11)
(8.24)
(8.57)
(7.65)
(10.89)
(3.97)
(3.76)
(3.65)
(3.61)
(3.79)
(3.79)
(4.83)
(3.59)
(3.32)
S
S
76
82
87
79
63
65
59
70
68
60
64
62
64
59
61
68
75
54
85
87
164–165
130–131
150–151b
142–143
174–175
158–159
140–141
138–140
136–138
113–115
145–146
145–146
179–180
120–121
138–139
101–103
118–119
100–104c
158–159
145–106
23.35
22.12
18.26
18.63
19.64
20.72
18.79
19.12
19.73
17.75
16.76
27.54
26.58
26.57
25.65
18.22
17.79
33.91
25.24
24.43
C10H8ClNO2S2
C11H10ClNO2S2
C16H12ClNO2S2
C14H10ClNO3S2
C14H16N2O3S2
C14H16N2O2S2
C15H18N2O3S2
C16H20N2O2S2
C15H18N2O2S2
C18H18N2O2S2
C17H23N3O3S2
C16H13NO2S3
C17H15NO2S3
C17H15NO2S3
C18H17NO2S3
C17H15NO3S2
C18H17NO3S2
C11H11NO2S3
C18H17NO2S3
C19H19NO2S3
12.95
12.32
10.13
10.43
(8.63)
(9.08)
(8.28)
(8.33)
(8.69)
(7.81)
(11.01)
(4.03)
(3.87)
(3.87)
(3.73)
(4.05)
(3.90)
(4.91)
(3.73)
(3.60)
23.42
22.28
18.33
18.87
19.77
20.79
18.95
19.06
19.89
17.89
16.81
27.68
26.61
26.61
25.61
18.56
17.84
33.70
25.61
24.69
IIIa
IIIb
IIIc
IIId
IVа
IVb
IVc
IVd
IVe
IVf
IVg
Vа
Vb
Vc
Vd
VIa
VIb
VII
VIIIa
VIIIb
a After recrystallization from ethanol. b Corresponds to published data [5]. c Without further purification.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 5 2012

REACTION OF 1-TOSYL-2,2-DICHLOROENAMINES
Table 2. 1H NMR spectra of the synthesized compounds III–VIII
851
Comp.
no.
δ, ppm (CDCl3)
2.45 s (3H, CH3); 7.37 d, 7.99 d (4H, C6H4, JHH 8.0 Hz), 8.63 s (1H, CHthiaz.
)
IIIa
IIIb
IIId
IVa
IVb
IVc
IVd
2.45 s (3H, CH3), 2.63 s (3H, CH3); 7.36 d, 7.98 d (4H, C6H4, JHH 8.0 Hz)
2.44 s (3H, CH3), 6.54 s (1Hfuran), 7.10 d (1Hfuran, JHH 4.0 Hz); 7.36 d, 8.00 d (4H C6H4, JHH 8.5 Hz), 7.50 s (1Hfuran
2.44 s (3H, CH3), 3.19 s (4H, 2CH2), 3.90 s (4H, 2CH2); 7.33 d, 7.94 d (4H, C6H4, JHH 7.0 Hz), 8.33 s (1H, CHthiaz.
)
)
2.04 s (4H, 2CH2), 2.43 s (3H, CH3), 3.57 s (4H, 2CH2), 7.32 d, 7.89 d (4H, C6H4, JHH 8.0 Hz), 7.85 s (1H, CHthiaz.
)
2.43 s (3H, CH3), 2.58 s (3H, CH3), 3.05 s (4H, 2CH2), 3.85 s (4H, 2CH2); 7.31 d, 7.95 d (4H, C6H4, JHH 8.0 Hz)
1.57 m (2H, CH2), 1.73 m (4H, 2CH2), 2.42 s (3H, CH3), 2.57 s (3H, CH3), 2.98 m (4H, 2CH2); 7.30 d, 7.95 d (4H, C6H4, JHH 8.0
Hz)
1.99 s (4H, 2CH2), 2.42 s (3H, CH3), 2.46 s (3H, CH3), 3.48 s (4H, 2CH2); 7.29 d, 7.88 d (4H, C6H4, JHH 8.0 Hz)
IVe
IVf
IVg
2.42 s (3H, CH3), 2.56 s (3H, CH3), 4.38–4.40 m (2H, CH2), 7.18–7.84 m (9H, C6H5,C6H4)
2.42 s (3H, CH3), 2.46 s (3H, CH3), 2.57–2.78 m (6H, 3CH2), 3.27 s (2H CH2, 3.80 s (4H, 2CH2); 7.30 d, 7.88 d (4H, C6H4, JHH
8.0 Hz)
2.45 s (3H, CH3), 7.36–7.38 m (2Harom.), 7.42–7.50 m (3Harom.); 7.60 d, 8.04 d (4H, C6H4, JHH 8.0 Hz), 8.45 s (1H, CHthiaz.
)
Va
Vb
2.41 s (3H, CH3), 2.46 s (3H, CH3); 7.25 d, 7.37 d, (4H, C6H4, JHH 8.0 Hz) 7.50 d, 8.05 d (4H, C6H4, JHH 8.0 Hz), 8.41 s
(1H,CHthiaz.
)
2.45 s (3H, CH3), 2.50 s (3H, CH3), 7.36–8.04 m (9H, C6H5, C6H4)
Vc
2.40 s (3H, CH3), 2.45 s (3H, CH3), 2.48 s (3H, CH3), 7.22–8.04 m (8H, 2C6H4, JHH 8.0 Hz)
2.44 s (3H, CH3), 2.56 s (3H, CH3), 7.30–7.38 m (5Harom.); 7.32 d, 7.97 d (4H, C6H4, JHH 8.0 Hz)
Vd
VIа
VIb
VIIIа
VIIIb
2.36 s (3H, CH3), 2.44 s (3H, CH3), 2.56 s (3H, CH3); 7.00 d, 7.16 d (4H, C6H4, JHH 8.0 Hz), 7.32 d, 7.97 d (4H, C6H4, JHH 8.0 Hz)
2.44 s (3H, CH3), 2.56 s (3H, CH3), 4.18 c (2H, CH2), 7.29–7.98 m (9H, C6H5,C6H4)
2.29 s (3H, CH3), 2.39 s (3H, CH3), 2.55 s (3H, CH3), 4.29 s (2H, CH2), 7.11–7.80 m (9H, C6H5, C6H4)
EXPERIMENTAL
tion was introduced with the program SADABS by the
multi-scanning method (Tmin/Tmax = 0.8955/0.9734). Hydro-
gen atoms were revealed and refined isotropically,
except for the hydrogen atoms in the C10 methyl, which
were localizd geometrically and their positions were
refined by a rider model together with the carbon atom.
In the refinement 2828 reflections were used with I >
2σ(I), (256 refined parameters, number of reflections
per parameter 11.0, a weight scheme was used, ω =
1/[σ2(Fo2) + (0.0420P)2 + 0.5034P] where P = (Fo2 +
2Fc2)/3, the ratio of maximum (average) shift to the error
in the final cycle is 0.001(0.000). The final divergence
factors R1(F) = 0.0484, wR2(F2) = 0.1002 for reflec-
tions with I > 2σ(I), R1(F) = 0.0863, wR2(F2) = 0.1151,
GOF = 1.031 for all independent reflections. Residual
electron density from the difference Fourier series after
the final refinement cycle is 0.40 and –0.39 e Å–3.
1
The H NMR spectra were recorded on a Varian
Mercury-400 spectrometer from CDCl3 solution with
internal reference TMS.
The X-ray diffraction study of a single crystal of
compound Va with linear dimensions 0.06×0.23×
0.25 mm was carried out at room temperature on a
Bruker Smart Apex II diffractometer (λMoKa radia-
tion, graphite monochromator, θmax 28.66°, a segment
of the sphere –16 ≤ h ≤ 16, –10 ≤ k ≤ 10 , –21 ≤ l ≤
22). Totally 16933 reflections were collected, of which
4267 were independent (the averaging R-factor is
0.0658). The structure was solved by the direct method
and refined by full-matrix least-squares in an aniso-
tropic approximation using the programs SHELXS97
and SHELXL97 [8,9]. The correction for the extinct-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 5 2012

852
TUROV et al.
A complete set of X-ray data for compound Va is
by recrystallization.
deposited in the Cambridge Structural Database
(CCDC 812149).
2-Methyl-5-phenoxy(or p-tolyloxy)-4-tosyl-1,3-thi-
azoles (VIa, VIb). To a solution of 0.0035 mol of com-
pound IIIb in 20 ml of THF was added 0.0039 mol of
the corresponding sodium phenolate and the mixture
was heated for 15 h at 60°C. Then the solvent was
removed in a vacuum and to the residue was added 10 ml
of water. The precipitste of a compound VIa or VIb formed
was filtered off and purified by recrystallization.
4-Tosyl-5-chloro-1,3-thiazole (IIIa). To a solution
of 0.0035 mol of compound Ia [1] in 50 ml of dioxane
was added 0.0035 mol of Lawesson’s reagent. The
mixture was heated for 8 h at 100°C, the solvent was
removed in a vacuum, to the residue was added 100 ml
of saturated solution of sodium hydrogen carbonate,
and the mixture was kept for 3 h at 20°C. The preci-
pitated compound IIIa was filtered off and purified by
recrystallization.
2-Methyl-5-mercapto-4-tosyl-1,3-thiazole (VII).
To a solution of 0.0035 mol of compound IIIb in 20 ml
of methanol was added 0.007 mol of sodium hydrogen
sulfide and the mixture was heated for 3 h at 60°C.
Then the solvent was removed in a vacuum, and 10 ml
of water was added to the residue; the mixture was
acidified with concentrated hydrochloric acid to pH
~2. The precipitate formed (compound VII) was
filtered off and used for further transformations
without purification.
2-Methyl(phenyl, furan-2-yl)-4-tosyl-5-chloro-1,3-
thiazoles IIIb–IIId were obtained like IIIa from the
corresponding enamides Ib–Id.
5-Morpholino(pyrrolidino)-4-tosyl-1,3-thiazoles
(IVa, IVb). To a solution of 0.001 mol of compound
IIIa in 20 ml of THF was added 0.003 mol of
morpholine (or pyrrolidine), the mixture was heated
for 2 h at 60°C, the solvent was removed in a vacuum,
to the residue was added 10 ml of water and the
precipitated compound IVa or IVb was filtered off and
purified by recrystallization.
5-[Benzyl(or 3-methylbenzyl)sulfanyl]-2-methyl-
4-tosyl-1,3-thiazoles (VIIIa, VIIIb). To a solution of
0.0035 mol of compound VII in 20 ml of methanol was
added 0.0035 mol of sodium methilate and 0.0038 mol
of the corresponding benzyl chloride. The mixture was
stirred for 3 h at 20°C, then the solvent was removed
in a vacuum and 10 ml of water was added to the
residue. The precipitate formed (compounds VIIIa, VIIIb)
was filtered off and purified by recrystallization.
2-Methyl-5-morpholino[piperidino, pyrrolidino,
benzylamino, (4-morpholino)-2-ethylamino]-4-tosyl-
1,3-thiazoles (IVc–IVg). To a solution of 0.001 mol of
compound IIIb in 20 ml of n-butanol was added
0.005 mol of the corresponding nitrogen base, and the
mixture was heated for 24 h at 120°C. Then the solvent
was removed in a vacuum, to the residue 10 ml of water
was added, the precipitate was filtered off. Compounds
IVc–IVg were purified by recrystallization.
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(Va, Vb). To a solution of 0.001 mol of compound
IIIa in 20 ml of THF was added 0.0011 mol of the
corresponding sodium thiophenolate, and the mixture
was left for 3 h at 20–25°C. Then the solvent was
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compound IIIb in 20 ml of THF was added
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solvent was removed in a vacuum and 10 ml of water
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