Condensation of thiourea derivatives with carbonyl compounds: One-pot synthesis of N-alkyl-1, 3-thiazol-2-amines and of 3-alkyl-1, 3-thiazolimines

Article abstract of DOI:10.1039/a809086f

The reactions of ketones and AT-substituted thioureas, in the presence of HC1 (or HBr) and DMSO afford mixtures of the title compounds which are easily separated on a silica gel column. This method avoids the classical use of a-haloketones. The mechanism of these reactions involves the enolization of ketones and the activation of thiourea sulfur, probably by oxygen transfer from DMSO.

Full text of DOI:10.1039/a809086f

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Condensation of thiourea derivatives with carbonyl compounds:
one-pot synthesis of N-alkyl-1,3-thiazol-2-amines and of 3-alkyl-
1,3-thiazolimines
Carla Boga,a Luciano Forlani,*a Cristian Silvestroni,a Anna Bonamartini Corradib and
Paolo Sgarabottoc
a Dipartimento di Chimica Organica “A. Mangini” viale Risorgimento 4, 40136 Bologna, Italy
b Dipartimento di Chimica, Facoltà d’Ingegneria, Università di Modena, via Campi 183,
41100 Modena, Italy
c Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica,
Università di Parma, Centro di Studio per la Strutturistica Diffrattometrica del CNR,
viale delle Scienze 43100 Parma, Italy
Received (in Cambridge) 20th November 1998, Accepted 23rd March 1999
The reactions of ketones and N-substituted thioureas, in the presence of HCl (or HBr) and DMSO afford mixtures
of the title compounds which are easily separated on a silica gel column. This method avoids the classical use of
α-haloketones. The mechanism of these reactions involves the enolization of ketones and the activation of thiourea
sulfur, probably by oxygen transfer from DMSO.
Bn
X
S
Introduction
N
C
We have reported1 that mixtures of DMSO–Hϩ–halides pro-
duce an easy cyclization reaction of substituted thioamides or
thioureas, affording 1,2,4-thiadiazole derivatives. These hetero-
cyclic derivatives are interesting potential biocides2 of low
environmental impact. During our experiments we observed
that some mixtures of N-substituted thioureas with HBr and
DMSO, in acetone, afford 1,3-thiazole derivatives in high
yields.
NH2
2 X = Cl
3 X = Br
N
S
BnNH
NH
N
Bn
Usually, thiazol-2-amines are obtained3 from thioureas or
related compounds,4 and α-haloketones, as indicated in Scheme
1, and 3-alkyl-1,3-thiazolimines are obtained from the corre-
sponding thiazolamines and alkyl halides.3
4
Compound 3 may be one of the possible intermediates of the
cyclization reaction of thiourea derivatives (and of thioamides)
that give the thiadiazole derivatives.1
S
The same solids 2 and 3 were also obtained (in acetone) from
1b and N-chloro- and N-bromo-succinimide, respectively. H
O
C
S
1
RHN
C
+
H3C
NHR
H3C
CH2
X
N
NMR spectra (in DMSO-d6) of 2, 3 are very complicated and
NH2
1
1
poorly reproducible, while H NMR spectra in CD3OD repro-
duce the spectrum of N-benzylthiourea 1b. Aqueous solutions
of both 2 and 3 liberate I2 from KI solution and N-benzylthio-
urea is recovered. Addition of sodium carbonate to a solution
of 2 or 3 in water quantitatively afforded 1b. When 2 is dis-
solved in acetone and it is stirred at 40 ЊC for 10 days, the
presence of 5b and 6b was not detected in the reaction mixtures
(by TLC, eluant: Et2O). In DMSO–acetone, both 2 and 3 give
(after 8 days) traces of 5b and 6b. Probably 2 and 3 arise from
reversible side reactions.
X = Cl, Br
Scheme 1
We report some results on the cyclization of ketones and
substituted thioureas in the presence of DMSO and hydrogen
halides to give the title compounds without employment of
α-haloketones.
After further vigorous stirring of the original mixture con-
taining 2 (or 3), acetone and DMSO at 40 ЊC, 2 (or 3) slowly
dissolves, and a further crystalline solid 5 precipitates; the solu-
tion contains isomers 5 and 6 (Scheme 2). The structures of 5
and 6 were assigned on the basis of 1H and 13C NMR spectral
data and by comparison (in some cases) with authentic samples
prepared by literature procedures (see Experimental section). In
particular, the NMR signal of H-5 of the thiazole moiety is
representative of two isomers.5 In addition, all products con-
taining –NH–CH2–Ar groups (as well as the –NH-2-butyl
group) show the CH2 signal as a broad singlet/doublet which
becomes a sharp singlet after addition of deuterium oxide.5 The
structure of compound 5b was ascertained by X-ray diffraction
of 5b hydrochloride (5g).
Results
Condensation of substituted thioureas with acetone
When the mixture of 2 equivalents of HCl (36%) (or HBr 48%)
and DMSO (2 equivalents) is added to a solution in acetone of
1 equivalent of N-alkylthiourea, immediately a whitish solid
separates. In the case of N-benzylthiourea 1b, it was possible to
collect and analyze this solid to which was tentatively assigned
the structure of an N-chlorinated (or N-brominated) N-benzyl-
thiourea (labelled as 2, or 3 respectively, see Experimental
section). Compound 3 is unreactive toward the acetone, also in
the presence of HBr. When 3 is dissolved in DMSO and the
solution is stirred at 40 ЊC for 20 h the thiadiazole derivative
4 is isolated in 95% yield.
J. Chem. Soc., Perkin Trans. 1, 1999, 1363–1368
1363

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Table 1 Condensation reactions between N-benzylthioureaa and
S
S
acetone at 30 ЊC
H3C
NH
N
DMSO,
HCl (36%)
Yield (%)
5b
S
O
C
R
5
+
Reaction
time
+
RHN
C
Reagent/mmol
HX/mmol
6b
H3C
CH3
NH2
1
DMSO
(6.0)
DMSO
(6.0)
HCl 37%
(6.0)
—
4 d
4 d
70
25
H3C
NHR
n.r.b
n.r.
47
n.r.
n.r.
47
N
6
—
HCl 37%
(6.0)
MeSO3H
(6.0)
5 d
Yield (%)
DMSO
(6.0)
7 h
Compound
series
R
5
6
NCS
(3.6)
NBS
(3.6)
—
10 d
2 d
13
10
a
b
c
d
e
f
2-Butyl
Benzyl
p-Methylbenzyl
p-Methoxybenzyl
p-Chlorobenzyl
Methyl
0
70
76
74
25
20
70
23
6
—
30
40
a 3.0 mmol of N-benzylthiourea. b n.r. = no reactions were observed.
undetected
60
40
Scheme 2
It is of interest to emphasize that in 5, the more substituted
nitrogen (which is the more hindered nitrogen) becomes
included in the ring, while the unsubstituted amino group ends
up in the exocyclic position. Usually in cyclization reactions the
less hindered nitrogen is involved in the formation of the ring.
In order to investigate whether 5 and 6 are formed from the
cyclization reaction or if they are from some isomerization
reactions (5 ↔ 6) we checked the stability of 5 and 6 separately
in the reaction medium. No conversion 5↔ 6 was observed
even after long reaction times (1 week) in DMSO–HCl
mixtures.
Reaction between thiourea and acetone afforded, in the pres-
ence of the DMSO–HCl mixture, the 4-methylthiazol-2-amine
(7) in low yields (15%).
S
NH2
N
H3C
7
Fig. 1 Molecular structure of 5g with labelling scheme. Displacement
ellipsoids are plotted at the 50% probability level. H atoms are drawn as
small circles of arbitrary radius.
The condensation reaction between N-phenylthiourea and
acetone afforded in high yields thiadiazole derivative 81
(Scheme 3).
the literature.7 In particular the S–C bonds [S(1)–C(2) 1.718(2),
S(1)–C(5) 1.727(3) Å] are intermediate between 1.808 Å for a
single and 1.556 Å for a double bond. Also the N–C bonds
[N(3)–C(2) 1.339(2), N(21)–C(2) 1.319(3) Å] are intermediate
between single (1.47 Å) and double (1.29 Å) and are indicative
of a high degree of π-delocalized bonding involving the S and
N lone pairs. The N(21), C(31) and C(41) atoms are practically
coplanar with the thiazole ring, the distances from the mean
plane being 0.025(3), Ϫ0.045(2) and Ϫ0.0016(3) Å, respectively.
The N(21)ϩ iminium ion is involved in hydrogen bonds with
ClϪ ion through its two hydrogen atoms, one intramolecular
[N(21)] ؒ ؒ ؒ Cl(1) 3.120(3), H(21) ؒ ؒ ؒ Cl(1) 2.22(3) Å; N(21)–
H(21) ؒ ؒ ؒ Cl(1) 173(2)Њ] and the other intermolecular with
ClϪ in the Ϫx, Ϫy, 1 Ϫ z position [N(21) ؒ ؒ ؒ Cl(1) 3.178(3),
H(22) ؒ ؒ ؒ Cl(1) 2.42(3) Å; N(21)–H(22) ؒ ؒ ؒ Cl(1) 165(3)Њ]. Other
contacts are consistent with van der Waals interactions.
N
S
+ 1/8 S8
NH
DMSO/HCl
PhNHCSNH2 + CH3COCH3
PhNH
N
Ph
8 (90%)
Scheme 3
Table 1 collects data of some reactions between N-benzylthio-
urea 1b and acetone under different experimental conditions.
It is worthy of consideration that the mixture DMSO–HCl
may be substituted by other reagents6 (N-bromosuccinimide,
N-chlorosuccinimide) but this gives lower conversion. The
formation of 5b and 6b also in the presence of DMSO–
MeSO3H, and in the absence of halide ions (see Table 1), con-
firms that 2 and 3 are from a side reaction, while the acid
catalysis is important.
The structure of Fig. 1 confirms8 that (in the solid state) the
exocyclic nitrogen is more basic than the endocyclic nitrogen
since it is the only protonated nitrogen.
X-Ray diffraction analysis of 5g
The molecular structure is shown in Fig. 1. The thiazole ring
is planar and its displacement of bond distances and angles
compares well with that of analogous compounds reported in
Condensation of 1b with other ketones
In order to obtain information on the reaction mechanism of
1364
J. Chem. Soc., Perkin Trans. 1, 1999, 1363–1368

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Scheme 2, we carried out some reactions with structurally
different methyl ketones.
Condensation of N-benzylthiourea 1b and butan-2-one
Cl
O
DMSO,
S
HCl 37%
+ BnNHCONH2
NHBn
1b +
H3C
CHCl2
H3C
30 °C
3-4 d
N
affords the two thiazole derivatives 9 and 10 (Scheme 4).
16 (20%)
(20%)
H3C
S
Scheme 6
1-Chloroacetone (in H2O or in acetone) with 1b (without
DMSO and in the absence or in the presence of acid) affords
the thiazole 6b in almost quantitative yields. 1-Chloroacetone in
acetone and in the presence of DMSO–HCl affords a mixture
of isomers 5b and 6b (Scheme 7).
H3C
NH
N
Bn
DMSO,
O
9 (53%)
HCl 37%
1b +
+
40 °C 1d
CH3 CH2
CH3
H3C
S
S
NH
H3C
NHBn
N
N
H3C
10 (18%)
Bn
5b (59%)
Scheme 4
O
(acetone)
1b +
+
DMSO/HCl 37%
H3C
CH2Cl
The condensation of 1b with 3-methylbutan-2-one only
affords thiazoline 11. Structure 11 was assigned on the basis of
1H and 13C NMR and mass spectral data. These results indicate
that the thiazole ring is formed by the attack of the S atom of
the thiourea on the more substituted α carbon of the ketone.
S
NHBn
N
H3C
6b (31%)
Scheme 7
H3C
The major product is the N-alkylthiazole derivative 5b, which
cannot arise from chloroacetone. This fact indicates that the
only role for the chloroacetone could be in the synthesis of 6b,
but 6b could also be synthesised from actone.
H3C
H3C
S
N
N
Bn
11 40%
Discussion
Thus, the ring closure occurs by the formation of an S–C5
bond between sulfur and C3 of butanone, and of an N–C4
bond between the nitrogen atom and the carbonyl carbon.
The reaction of 1b with acetylacetone affords isomers 12
and 13. In this case also, the more substituted α carbon of
the ketone participates in the ring formation.
In the mixtures of ketone and thiourea different reactions take
place, affording several products which, in principle, may be
considered intermediates toward compounds 5 and 6. In
particular, N-halogenothioureas 2 or 3 may be on the reaction
pathway to give a thiazole ring, but attempts to obtain thiazole
from 3 failed: probably, 2 and 3 are products of side reactions.
However, 2 and 3 are on the reaction pathway to obtain 1,2,4-
thiadiazole derivatives in a reaction pathway which competes
with that previously proposed.1
Also the formation of alkyldimethylsulfonium halides (such
as 15) may be considered a side reaction which takes place when
other reactions are slow.
Data reported here strongly indicate the possibility that in
our reaction mixtures the formation of a species involving posi-
tive halogen occurs, as tested by the formation of N-halogeno
derivatives 2 and 3.
O
O
H3C
H3C
H3C
H3C
S
S
NH
NHBn
N
N
Bn
12 (46%)
13 (16%)
The reaction between 1b and acetophenone is depicted in
Scheme 5. In this case the side reaction of formation of
Recently,9 the mixture DMSO–Hϩ–BrϪ has been indicated to
be capable of brominating several substrates. Probably, the
DMSO acts as an oxidizing reagent (in the acidic medium) to
afford positive halonium ion. The possible presence of positive
halonium ion (or molecular halogen) indicates that α-halo-
ketones may be formed in the reaction mixtures, but from
α-haloketones only the compounds 6 are obtained.1,10
The reaction also occurs in the presence of methansulfonic
acid (without the presence of halides). Probably the first step is
the activation of the thiourea by the DMSO in the presence of
an acid as catalyst.
S
Ph
O
NHBn
N
14 (5%)
+
O
DMSO,
HBr 48%
1b +
Ph
CH3
40 °C
13 h
CH3
Ph
CH2 +S
Br–
CH3
15 (90%)
Scheme 5
The formation of compounds 9, 10, 11, 12, 13 and 16
strongly indicates that the formation of the thiazole ring occurs
between the sulfur atom and the α-carbon atom of the carbonyl
group, and between the nitrogen atom and the carbonyl group
in a situation in which the steric hindrance is insignificant. A
possible reaction pathway is depicted in Scheme 8.
The reaction between the electrophilic sulfur atom (probably
as an S-oxide11) and the α carbon of the enol form of the
ketone produces an intermediate to 19. This pathway explains
the preference of the halogenated carbon (Scheme 6) or of the
sulfonium bromide 15 predominates over the formation of the
thiazole ring. Compound 15 is unable to yield thiazole
derivatives.
The reaction between 1,1-dichloroacetone and 1b affords
thiazole derivative 16 in low yield. In this case the reaction of
substitution of the thiourea sulfur by oxygen competes with the
thiazole formation (Scheme 6). The benzylurea is obtained in
low yield.
J. Chem. Soc., Perkin Trans. 1, 1999, 1363–1368
1365

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tions of 3.0 mmol of 1b and 6.0 mmol of DMSO in acetone
S
SO
H+
(5 mL) a whitish solid precipitates. This solid, probably, is
N-chloro-N-benzylthiourea 2. In the same way (from DMSO–
HBr mixtures), N-bromo-N-benzylthiourea 3 is obtained.
Compounds 2 and 3 are collected by filtration. All attempts to
recrystallize these materials failed.
NHRCNH2 + Me2SO
NHRCNH2 + Me2S
17
MeCOCH3
MeCOHCH2
18
Compound 2. Mp 159–162 ЊC. Anal. calc. for C8H9N2SCl: C,
47.88; H, 4.52; N, 13.96; S, 15.98; Cl, 17.67%. Found: C, 47.59;
H, 4.50; N, 13.76; S, 15.88; Cl, 17.55%.
O–
H
OH
H
H
H
H+
C
S
NH2
NHR
H
C
S
NH2
17 + 18
C
C
C
C
+
H3C
H3C
NHR
OH
O
Compound 3. Mp 189–191 ЊC. Anal. calc. for C8H9N2SBr: C,
39.20; H, 3.70; N, 11.43; S, 13.08; Br, 32.6%. Found: C, 39.37;
H, 3.64; N, 11.29; S, 12.97; Br, 32.53%.
+OH2
H
H
H
C
H
+
S
H
+
C
S
NH2
C
NH2
S
NH2
–H2O
C
C
C
C
C
C
O
H3C
H3C
H3C
NHR
NHR
NHR
O
O
Condensation reactions to give thiazole derivatives: typical
procedure
–H+
A mixture of DMSO–HCl (2 equivalents, 1:1 molar ratio) and
1b (1 equivalent) in acetone (2 mL per mmol of 1) was vigor-
ously stirred at 40 ЊC for 4 days, showing (TLC analysis, eluant
Et2O) the disappearance of the starting thiourea. Most of com-
pound 5b spontaneously precipitated (as the hydrochloride)
and was filtered off. The remaining solution was concentrated
(under vacuum) and poured into aqueous 10% KOH. The mix-
ture was extracted with 20 mL of CH2Cl2, dried and the solvent
was evaporated. The residue contains both 5b and 6b isomers
which were separated on a silica gel column (eluant Et2O–
MeOH, 95:5).
H
C
H
H
H
S
NH2
C
S
R
C
C
N
N
C
O
C
H
H3C
H3C
O
N
H
R
19
H
H
H
H
C
S
C
S
H3C
HO
C
C
H3C
HO
C
C
NH
NHR
N
N
Crystal structure of 5g†
R
A summary of the crystallographic work is given in Table 2.
The intensities Ihkl were determined by analysing the reflection
profiles by the Lehmann and Larsen procedure.14 Corrections
for Lorentz and polarization effects were performed; there were
no corrections for polarization effects.
Atomic scattering factors were from International Tables for
X-ray Crystallography.15 Bibliographic searches were carried
out using the Cambridge Structural database Files through the
Servizio Italiano di Diffusione Dati Cristallografici, Parma,
Italy.
–H2O
–H2O
H
C
H
S
C
S
C
C
C
C
H3C
NH
H3C
NHR
N
N
R
5
6
Scheme 8
carbon with electron-withdrawing substituents (such as in the
formation of 12 and 13) to form the C–S bond. The tautomer-
ism of ketones12 explains the regioselectivity of the attack. The
sulfur attack on the enol is possible if the sulfur is in an electro-
philic form (such as in the S-oxide derivative).
In principle, both nitrogen atoms can attack the carbonyl
group, but the substituted nitrogen is slightly more reactive
than the unsubstituted nitrogen in forming the thiazole ring.
It is known that the sp2 nitrogen atom is a better base and
nucleophile than the sp3 nitrogen atom.8,13 Probably, the ring
closure occurs in a fast step, in which the steric requirements
of nitrogen atoms are not very important, as in 19.
N-(sec-Butyl)-4-methyl-1,3-thiazol-2-amine19 (6a)
Oil, mp (picrate) 185–187 ЊC; δH(200 MHz; CDCl3) 6.01 (1 H,
q, J 1.1 Hz), 5.6 (1H, br s), 3.30–3.45 (1H, m), 2.21 (3H, d, J 1.1
Hz), 1.50–1.70 (2H, m), 1.24 (3H, d, J 6.4 Hz), 0.95 (3H, t, J 7.4
Hz); δC(50.3 MHz; CDCl3) 170.2, 147.9, 100.1, 54.4, 29.9, 20.4,
17.0, 10.5; m/z 170 (Mϩ, 37%), 155 (14), 141 (100), 114 (77), 72
(16), 71 (14), 45 (13); HRMS: C8H14N2S requires 170.0878,
found 170.0875. Found: C, 56.50; H, 8.33; N, 16.60; S, 18.74%.
C8H14N2S requires C, 56.43; H, 8.29; N, 16.45; S, 18.83%.
3-Benzyl-4-methyl-2,3-dihydro-1,3-thiazol-2-iminium chloride
(5g)
Experimental
General
1H and 13C NMR spectra were recorded at 200 or 300 MHz and
50.3 or 75.46 MHz, respectively. Chemical shifts were measured
in δ (ppm) and referenced to TMS. All compounds containing
NH protons show a disappearance of the relevant signals in the
1H NMR spectra, after addition of D2O.
Mp 254–256 ЊC (MeOH); δH(200 MHz; DMSO-d6) 9.82 (2H, br
s), 7.5–7.1 (5H, m), 6.79 (1H, s), 5.36 (2H, s) 2.14 (3H, s);
δC (50.3 MHz; DMSO-d6) 169.4, 137.9, 133.7, 129.4, 128.5,
128.2, 102.7, 48.2, 13.4; m/z 204 (Mϩ, 49%), 189 (2), 127 (3), 113
(13), 106 (7), 100 (5), 91 (100), 65 (20), 36 (18). Found: C, 54.75;
H, 5.50; N, 11.70; S, 13.28%. C11H13ClN2S requires: C, 54.88;
H, 5.44; N, 11.64; S, 13.32; Cl, 14.73%.
Solvents and reagents (Carlo Erba) were reagent grade.
N-Substituted thioureas were prepared by the usual procedures.
Reported yields (in mol%) are from weight determinations of
the separate compounds. Melting points are uncorrected.
3-Benzyl-4-methyl-1,3-thiazol-2(3H)-imine20 (5b)
δH(200 MHz; CDCl3) 7.12–7.35 (5H, m), 5.42 (1H, q, J 1.4 Hz)
4.96 (2H, s), 1.93 (3H, d, J 1.4 Hz); δC(50.3 MHz; CDCl3) 166.2,
137.3, 135.3, 128.9, 127.4, 126.5, 92.6, 46.3, 15.2.
Halogenated N-benzylthioureas 2 and 3
When 6.0 mmol of HCl (37%) were added dropwise to solu-
† CCDC reference number 207/313.
1366
J. Chem. Soc., Perkin Trans. 1, 1999, 1363–1368

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Table 2 Experimental data for the X-ray diffraction studies on crystal-
line compound 5g
30), 106 (8), 105 (100), 79 (7), 77 (9); HRMS: C12H14N2S
requires 218.0878, found 218.0880. Found: C, 65.90; H, 6.56; N,
12.78; S, 14.63%. C12H14N2S requires C, 66.02; H, 6.46; N,
12.83; S, 14.69%.
Formula
C11H13N2SϩClϪ
prism
colourless
240.7 504
monoclinic
P21/c
Cryst. habit
Cryst. colour
FW F(000)
Cryst. system
Space group
Cell parameters at 295 K
a/Å
N-(4-Methoxybenzyl)-4-methyl-1,3-thiazol-2-amine (6d)
Mp 88–91 ЊC (MeOH); δH(200 MHz; CDCl3) 7.28 (2H, d,
J 8.7 Hz), 6.87 (2H, d, J 8.7 Hz), 6.15 (1H, br s), 6.02 (1H, q,
J 1.0 Hz), 4.36 (2H, s), 3.79 (3H, s), 2.17 (3H, d, J 1.0 Hz);
δC(50.3 MHz; CDCl3) 170.4, 159.7, 149.3, 130.2, 129.9, 114.5,
101.1, 55.6, 49.6, 17.5; m/z 234 (Mϩ, 13%), 137 (13), 122 (9),
121 (100), 78 (6), 77 (9), 43 (5); HRMS: C12H14N2OS requires
234.0827, found 234.0831. Found: C, 61.40; H, 6.09; N, 12.04%.
C12H14N2OS requires C, 61.51; H, 6.02; N, 11.96%.
8.466(2)
b/Å
c/Å
10.733(3)
13.599(3)
α (Њ)
β (Њ)
90
98.5(1)
γ (Њ)
90
1222.1(6)
V/Å3
Z
4
1.31
dcalc/g cmϪ3
3-(4-Chlorobenzyl)-4-methyl-1,3-thiazol-2(3H)-imine (5e)
Cryst. dimensions/mm
Linear abs. coeff./cmϪ1
Diffractometer
Scan type
Scan width (Њ)
Radiation
0.43 × 0.29 × 0.34
41.1
Siemens AED
ω–2θ
b
Mp 200–202 ЊC (hydrochloride, MeOH); δH(300 MHz; CDCl3)
7.31 (2H, d, J 8.5), 7.18 (2H, d, J 8.5), 5.48 (1H, s), 4.97 (s, 2H),
1.98 (3H, s); δC(75.46 MHz; CDCl3) 165.8, 135.8, 134.8, 133.2,
129.0, 127.9, 92.7, 45.7, 15.1; m/z 240 (Mϩ, 13%), 238 (34), 127
(33), 125 (100), 113 (16), 89 (15); HRMS: C11H11N2SCl requires
238.0331, found 238.0334. Found: C, 55.23; H, 4.60; N, 11.66;
S, 13.30%. C11H11ClN2S requires C, 55.34; H, 4.64; N, 11.73; S,
13.43%.
c
2θ range collection (Њ)
hkl range
6–170
h,k,l
2623
I > 2σ(I)
1946
188
10.4
d
Unique total data
Criterion of observation
Unique obs. data (NO)
No. of refined par (NV)
Overdetermn ratio (NO/NV)
Absorption
Solution
H atoms
R
Rw
GOF
N-(4-Chlorobenzyl)-4-methyl-1,3-thiazol-2-amine (6e)
Mp 139–141 ЊC (MeOH); δH(200 MHz; CDCl3) 7.2–7.4 (4H,
m), 6.06 (1H, q, J 1.1 Hz) 5.8 (1H, br s), 4.43 (2H, s), 2.21 (3H,
d, J 1.1); δC(75.46 MHz; CDCl3) 170.0, 148.8, 136.5, 133.5,
129.0, 100.8, 49.2, 17.4; m/z 240 (Mϩ, 12%), 238 (36), 140 (7),
127 (33), 125 (100), 113 (8), 89 (10); HRMS: C11H11N2SCl
requires 238.0331, found 238.0340. Found: C, 55.23; H, 4.57;
N, 11.63; S, 13.28%. C11H11ClN2S requires C, 55.34; H, 4.64;
N, 11.73; S, 13.43%.
e
f
0.035
0.040
0.826
0.3
0.2
g
Largest shift/esd
Largest peak/e ÅϪ3
Computer and programs
a Unit cell parameters were obtained by least-squares analysis of the
setting angles of 30 carefully centred reflections chosen from diverse
regions of reciprocal space. b From (θ–0.6)Њ to [θ ϩ (0.6 ϩ ∆θ)]Њ; ∆θ =
(λα2 Ϫ λα1)/λ]tanθ. c Ni-filtered Cu-Kα, λ = 1.54178 Å. d No. correction
applied. e Direct methods. f Located in ∆F map and isotropically
refined. g ENCORE e91, SHELX86,16 SHELX76,17 PARST.18 R =
3,4-Dimethyl-1,3-thiazol-2(3H)-imine (5f)
Mp 45–47 ЊC (lit.,22 43–46 ЊC), mp 196–197 ЊC (picrate) (lit.,21
200 ЊC); δH(300 MHz; CDCl3) 5.44 (1H, q, J 1.3 Hz), 3.25 (3H,
s), 2.07 (3H, d, J 1.3 Hz); δC(75.46 MHz, CDCl3) 166.5, 135.1,
92.1, 30.0, 15.3; m/z 128 (Mϩ, 38%), 86 (64), 84 (100), 71 (6), 56
(34); HRMS: C5H8N2S requires 128.0408, found 128.0411.
¹
2 2
Σ|∆F|/Σ|Fo|, Rw = [Σw(∆F ) /Σw(Fo ) ] , GOF = [Σw|∆F|2/(NO Ϫ
2
2
²
¹
²
NV)] .
N-Benzyl-4-methyl-1,3-thiazol-2-amine21 (6b)
N,4-Dimethyl-1,3-thiazol-2-amine (6f)
Mp 226–228 ЊC (hydrochloride) (lit.,23 226–227 ЊC); δH(300
MHz; CDCl3) 6.05 (1H, q, J 1.1 Hz), 2.94 (3H, s), 2.22 (3H, d,
J 1.1 Hz); δC(75.46 MHz; CDCl3) 171.0, 149.0, 100.8, 32.3, 17.5;
m/z 128 (Mϩ, 100%), 100(49), 86 (16), 84 (26), 72 (31), 71 (40),
57 (17); HRMS: C5H8N2S requires 128.0408, found 128.0410.
Mp 91–93 ЊC (MeOH); δH(200 MHz; CDCl3) 7.25–7.40 (5H,
m), 6.3 (1H, br s), 6.02 (1H, q, J 1.1 Hz), 4.44 (2H, s), 2.17 (3H,
d, J 1.1 Hz); δC(50.3 MHz; CDCl3) 170.3, 148.9, 137.9, 128.8,
127.7, 127.6, 100.6, 49.9, 17.4; m/z 204 (Mϩ, 39%), 127 (3), 113
(5), 106 (8), 100 (6), 91 (100), 65 (12). Found: C, 64.60; H, 5.87;
N, 13.68; S, 15.80%. C11H12N2S requires C, 64.67; H, 5.92; N,
13.71; S, 15.69%.
4-Methyl-1,3-thiazol-2-amine (7)
Mp 44–45 ЊC (lit.,24 44–45 ЊC) (MeOH); δH(300 MHz; CDCl3)
6.05 (1H, q, J 1.1 Hz), 5.3 (2H, br s), 2.20 (3H, d, J 1.1 Hz);
m/z 114 (Mϩ, 100%), 72 (40), 71 (55), 45 (35), 42 (22).
3-(4-Methylbenzyl)-4-methyl-1,3-thiazol-2(3H)-imine (5c)
Oil, mp (picrate) 174–176 ЊC; δH(200 MHz; CDCl3) 7.05–7.15
(4H, m), 5.7 (1H, br s), 5.51 (1H, q, J 1.2 Hz), 4.96 (2H, s), 2.30
(3H, s), 1.97 (3H, d, J 1.2 Hz); δC(50.3 MHz; CDCl3) 166.4,
138.9, 135.3, 133.6, 129.4, 126.2, 93.2, 46.2, 21.0, 14.9; m/z 218
(Mϩ, 31%), 105 (100), 86 (23), 84 (37), 78 (23), 63 (27); HRMS:
C12H14N2S requires 218.0878, found 218.0875. Found: C, 65.91;
H, 6.42; N, 12.79; S, 14.71%. C12H14N2S requires C, 66.02; H,
6.46; N, 12.83; S, 14.69%.
3-Benzyl-4,5-dimethyl-1,3-thiazol-2(3H)-imine21 (9)
Mp 147–149 ЊC (EtOH); δH(300 MHz; CDCl3) 7.2–7.4 (5H, m),
6.0 (1H, br s), 4.96 (2H, s), 2.00 (3H, br s), 1.87 (3H, br s);
δC(75.46 MHz; CDCl3) 165.5, 143.0, 137.2, 128.8, 127.3, 126.3,
113.0, 46.9, 29.8, 11.86; m/z 218 (Mϩ, 30%), 127 (16), 106 (15),
91 (100), 65 (12); HRMS: C12H14N2S requires 218.0878, found
218.0880. Found: C, 66.22; H, 6.56; N, 12.74; S, 14.59%.
C12H14N2S requires C, 66.02; H, 6.46; N, 12.83; S, 14.69%.
4-Methyl-N-(4-methylbenzyl)-1,3-thiazol-2-amine (6c)
Mp 120–121 ЊC (MeOH); δH(200 MHz; CDCl3) 7.1–7.3 (4H,
m), 6.1 (1H, br s), 6.03 (1H, q, J 1.1 Hz), 4.39 (2H, s), 2.34 (3H,
s), 2.19 (3H, d, J 1.1 Hz); δC(50.3 MHz; CDCl3) 170.3, 149.4,
137.9, 135.1, 129.9, 128.0, 101.1, 49.9, 21.3 17.5; m/z 218 (Mϩ,
N-Benzyl-4,5-dimethyl-1,3-thiazol-2-amine (10)
Mp 114–116 ЊC (cyclohexane); δH(200 MHz; CDCl3) 7.25–7.40
(5H, m), 5.25 (1H, br s), 4.42 (2H, s), 2.17 (3H, br s), 2.12 (3H,
J. Chem. Soc., Perkin Trans. 1, 1999, 1363–1368
1367

View Article Online
br s); δC(75.46 MHz; CDCl3) 166.2, 143.1, 138.0, 128.8, 127.7,
127.6, 113.5, 50.6, 14.2, 10.8; m/z 218 (Mϩ, 80%), 127 (21), 106
(18), 91 (100), 85 (17), 65 (12); HRMS: C12H14N2S requires
218.0878, found 218.0880. Found: C, 65.88; H, 6.54; N, 12.80%.
C12H14N2S requires C, 66.02; H, 6.46; N, 12.83%.
Acknowledgements
The authors thank the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica, the Consiglio Nazionale delle
Ricerche (CNR, Roma) and the University of Bologna (funds
for selected research topics 1997–1999).
N-Benzyl-N-[4,5,5-trimethyl-1,3-thiazol-2(5H)-ylidene]amine
(11)
References
Oil; δH(300 MHz; CDCl3) 7.2–7.5 (5H, m), 4.46 (2H, s), 2.28
(3H, s) 1.65 (6H, s); δC(75.46 MHz; CDCl3) 191.8, 169.3, 139.6,
128.8, 128.2, 127.2, 67.4, 60.0, 28.5, 16.1; m/z 232 (Mϩ, 39%),
217 (62), 148 (15), 91 (100), 85 (17), 65 (15); HRMS: C13H16N2S
requires 232.1034, found 232.1039. Found: C, 67.0; H, 6.88; N,
11.96; S, 13.75%. C13H16N2S requires C, 67.2; H, 6.94; N, 12.06;
S, 13.80%.
1 L. Forlani, A. Lugli, C. Boga, A. C. Bonamartini and P. Sgarabotto,
submitted for publication in J. Heterocycl. Chem.
2 A. B. George, E. M. Craig, US Patent, 4209522, 1980; T. Teraji,
K. Sakane and J. Gota, E. P. Application, 27599, 1981; K. Srivstava
and N. S. Pandeya, Indian J. Heterocycl. Chem., 1991, 1, 29; P. R.
Naik, N. S. Pandeya and P. N. Singh, Pharmakeutike, 1991, 4, 44.
3 G. Vernin, Thiazole and its Derivatives, Part 1, ed. J. V. Metzger,
John Wiley & Sons, New York, 1979, ch. 2.
4 J. G. Schantland and I. M. Lagoja, Synth. Commun., 1998, 28, 1451.
5 L. M. Werbel, Chem. Ind., 1996, 1634; L. Forlani, Gazz. Chim. Ital.,
1981, 111, 159; L. Forlani, M. Sintoni and P. E. Todesco, Gazz.
Chim. Ital., 1981, 116, 229.
1-(3-Benzyl-2-imino-4-methyl-2,3-dihydro-1,3-thiazol-5-
yl)ethan-1-one (12)
6 K. W. Ratts and A. N. Yao , J. Org. Chem., 1966, 31, 1185.
7 R. J. S. Beer, D. McMonagle, M. S. S. Siddiqui, A. Hordvik and
K. Jynge, Tetrahedron, 1979, 35, 1199; M. Ghosh, A. K. Basak,
P. N. Roy, S. K. Mazumdar and B. Sheldrick, Acta Crystallogr.,
1987, C43, 732.
8 L. Forlani, P. De Maria and A. Fini, J. Chem. Soc., Perkin Trans. 2,
1980, 1156.
9 S. K. Srivastava, P. M. S. Chauhan and A. P. Bhaduri, Chem.
Commun., 1996, 2679; G. Majetich, R. Hicks and S. Reister, J. Org.
Chem., 1997, 62, 4321.
10 R. M. Dodson and L. C. King, J. Am. Chem. Soc., 1945, 67, 2242;
1946, 68, 871.
11 B. Zwanenburg, Recl. Trav. Chim. Pays-Bas, 1982, 101, 1 and
references cited therein.
12 J. Toullec, The Chemistry of Enols, ed. Z. Rappoport, John Wiley &
Sons, Chichester, 1990, p. 323; J. R. Keeffe and A. J. Kresge,
The Chemistry of the Enols, ed. Z. Rappoport, John Wiley & Sons,
Chichester, 1990, p. 399.
13 L. Forlani and P. De Maria, J. Chem. Soc., Perkin Trans. 2, 1982,
535; L. Forlani, G. Guastadisegni, L. Raffellini, P. E. Todesco and
E. Foresti, Gazz. Chim. Ital., 1990, 120, 493.
14 M. S. Lehmann and F. K. Larsen, Acta Crystallogr., Sect. A, 1974, 30,
580.
15 International Tables for X-Ray Crystallography, Kynoch Press,
Birmingham, vol. IV, 1974.
16 G. M. Sheldrick, SHELX-86, Program for the Solution of Crystal
Structures, University of Göttingen, Germany, 1986.
17 G. M. Sheldrick, SHELX-76, System of Computer Programs for
Crystal Structure Determinations, University of Cambridge, 1976.
18 M. Nardelli, Comput. Chem., 1983, 7, 95.
19 S. I. Burmistrov and V. A. Krasovkii, Zh. Obshch. Khim., 1984, 34,
685 (Chem. Abstr., 1984, 60, 13235).
20 G. M. Clarke and P. Sykes, J. Chem. Soc. C., 1967, 14, 1269.
21 A. K. Bhattacharya, J. Indian Chem. Soc., 1967, 44, 57.
22 S. E. Bramley, V. Duplin, D. G. C. Goberdhan and G. D. Meakins,
J. Chem. Soc., Perkin Trans. 1, 1987, 639.
Mp 93–95 ЊC (CH2Cl2); δH(300 MHz; CDCl3) 7.1–7.4 (5H, m),
6.3 (1H, br s), 5.10 (2H, s), 2.43 (3H, s), 2.28 (3H, s); δC(75.46
MHz; CDCl3) 188.8, 162.6, 146.2, 135.8, 129.0, 127.7, 126.4,
110.3, 46.5, 30.1, 14.4; m/z 246 (Mϩ, 25%) 231 (2), 203 (3), 155
(3), 91 (100), 65 (11), 43 (5); HRMS: C13H14N2OS requires
246.0827, found 246.0831. Found: C, 63.23; H, 5.70; N, 11.42%;
C13H14N2OS requires C, 63.39; H, 5.73; N, 11.37%.
1-[2-(Benzylamino)-4-methyl-1,3-thiazol-5-yl]ethan-1-one (13)
Mp 118–120 ЊC (lit.,21 112 ЊC) (CH2Cl2); δH(300 MHz; CDCl3)
7.3–7.4 (5H, m), 7.0 (1H, br s), 4.47 (2H, s), 2.47 (3H, s), 2.39
(3H, s); δC(75.46; CDCl3) 188.0, 171.8, 157.9, 136.4, 128.9,
128.0, 127.5, 122.0, 48.9, 29.8, 18.4; m/z 246 (Mϩ, 45%), 231 (5),
149 (5), 106 (7), 91 (100), 65 (8), 43 (14); HRMS: C13H14N2OS
requires 246.0827, found 246.0825. Found: C, 63.30; H, 5.70; N,
11.23%; C13H14N2OS requires C, 63.39; H, 5.73; N, 11.37%.
N-Benzyl-4-phenyl-1,3-thiazol-2-amine (14)
Mp 100–102 ЊC (MeOH); δH(300 MHz; CDCl3) 10.2 (1H, br s),
7.65–7.75 (3H, m), 7.3–7.5 (7H, m), 6.56 (1H, s), 4.57 (2H, d,
J 5.8 Hz). Found: C, 72.00; H, 5.27; N, 10.45%; C16H14N2S
requires C, 72.15; H, 5.30; N, 10.52%.
Phenacyldimethylsulfonium bromide (15)
Mp 136–138 ЊC (lit.,25 133–134 ЊC); δH(300 MHz; CDCl3) 8.1–
7.6 (5H, m), 5.60 (2H, s), 3.02 (6H, s); δC(75.46 MHz; CDCl3)
191.5, 133.9, 135.2, 129.3, 128.8, 52.3, 24.7; m/z 200 (Mϩ, for
C8H7OBr, 5%), 198 (5), 120 (3), 105 (100), 91 (10), 77 (38), 62
(23).
23 W. Wilson and R. Woodger, J. Chem. Soc., 1955, 2943.
24 R. Barone, M. Chanon and R. Gallo, Thiazole and its Derivatives,
Part 2, ed. J. V. Metzger, John Wiley & Sons, New York, 1979,
ch. VI.
25 T. Hashimoto, H. Kitano and K. Fukui, Nippon Kagaku Zasshi,
1968, 89, 83.
N-Benzyl-5-chloro-4-methyl-1,3-thiazol-2-amine (16)
Oil; δH(300 MHz; CDCl3) 7.3–7.4 (5H, m), 4.40 (2H, s), 2.13
(3H, s); δC(75.46 MHz; CDCl3) 165.5, 144.5, 137.1, 128.8,
127.9, 127.6, 106.0, 49.4, 14.4; (m/z) 238 (Mϩ, 15%), 132 (5),
91 (100), 65 (10). Found: C, 55.18; H, 4.61; N, 11.65; S, 13.37;
Cl, 14.78%; C11H11ClN2S requires C, 55.34; H, 4.64; N, 11.73;
S, 13.43; Cl, 14.85%.
Paper 8/09086F
1368
J. Chem. Soc., Perkin Trans. 1, 1999, 1363–1368