Synthesis of 2-aminothiazole derivatives

Full text of DOI:10.1023/A:1010477022450

Pharmaceutical Chemistry Journal
Vol. 35, No. 2, 2001
SYNTHESIS OF 2-AMINOTHIAZOLE DERIVATIVES
S. I. Zav’yalov,1 O. V. Dorofeeva,1 E. E. Rumyantseva,1 L. B. Kulikova,1 G. I. Ezhova,1
N. E. Kravchenko,1 and A. G. Zavozin1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 2, pp. 35 – 36, February, 2001.
Original article submitted June 22, 2000.
2-Aminothiazole derivatives were reported to possess
antibacterial [1], antiviral [2], and psychotropic activity [3].
These compounds are usually obtained using a two-stage
scheme, including bromination of the initial ketones in ether
in the presence of AlCl3 [4] or in a MeOH–(MeO)3 mixture
[5] followed by cyclocondensation of the intermediate
a-bromoketones with thiourea (I) in ethanol or methanol
[4, 6, 7]. It was also reported that 2-aminothiazole deriva-
tives can be synthesized via a single-stage interaction of ke-
tones with a mixture of N-bromosuccinimide, thiourea, and
benzoyl peroxide in boiling benzene [8].
of urea and DMF followed by cyclocondensation of the inter-
mediate bromoketones in situ with thiourea (I) or
allylthiourea (II).
O
C
O
C
CH3
CH2Br
I or II
Br2
R
R
III, IV
V, VI
N
The two-stage character and the need to isolate the inter-
mediate a-bromoketones possessing lacrimatory properties
are obvious drawbacks of the first method. The disadvan-
tages of the second method are the use of toxic and explosive
solvent (benzene) and the absence of data concerning the
synthesis of 2-aminothiazole derivatives from allylthiourea
(II) and related compounds.
R
NHR'
S
VII – X
R = H (III, V, VII, VIII), Br (IV, IV, IX, X)
R¢ = H (VII, IX), CH2–CH=CH2 (VIII, X)
This process yields 2-aminothiazole derivatives in the form
of hydrobromides, which convert into free bases when
treated with an aqueous K2CO3 solution.
In the search for a simple and effective means of obtain-
ing 2-aminothiazole derivatives, we have studied the possi-
bility of selective monobromination of ketones in a mixture
of urea and DMF, followed by cyclocondensation of the
monobromoketones in the same solvent. An indication of the
possibility to ensure the selective monobromination of ke-
tones in the presence of urea and DMF was the fact that
carboxylic acid amides are capable of forming complexes
with Br2, thus inhibiting the undesired dibromination process
[9, 10].
Using the method outlined above and proceeding from
the initial ketones III and IV and thioureas I and II, we ob-
tained the following 2-aminothiazole derivatives:
2-amino-4-phenylthiazole (VII), 2-allylamino-4-phenylthia-
zole (VIII), 2-amino-4-( p-bromophenyl)thiazole (IX), and
2-allylamino-4-( p-bromophenyl)thiazole (X). The reaction
pathways are depicted in the scheme below; the yield and
characteristics of the products are listed in Table 1.
Indeed, it was established that acetophenone (III) and
p-bromoacetophenone (IV) are subject to selective
monobromination in a mixture of urea and DMF to form
phenacyl bromide (V) and p-bromophenacyl bromide (VI)
with a yield above 70%.
Using the same scheme to brominate ethyl acetoacetate
(EAA), we obtained an a-bromine derivative (XI) that re-
acted with I and II to yield 2-amino-4-methyl-5-ethoxycarbo-
nylthiazole (XII) and 2-allylamino-4-methyl-5-ethoxy-
carbonylthiazole (XIII). By the same token, bromination of
compound X in an ether solution led to an isomer bromide
XIV which reacted with thiourea to yield 2-amino-4-(ethoxy-
carbonylmethyl)thiazole (XV) [8, 13].
Our experiments showed that the target 2-aminothiazole
derivatives can be obtained “in one flask,” by initially con-
ducting monobromination of the initial ketones in a mixture
1
Our experience showed that this scheme can also be used
for the synthesis of 2-amino-4,5-tetramethylenethiazole
Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Moscow, Russia.
96
0091-150X/01/3502-0096$25.00 © 2001 Plenum Publishing Corporation

Synthesis of 2-Aminothiazole Derivatives
97
(XVI) from cyclohexanone (XVII), but more stable results in
this case are obtained when DMF is replaced by methanol.
m.p., 57 – 59°C. When necessary, bromoketone V can be
distilled under reduced pressure (water-jet pump) [5].
Bromophenacyl bromide (VI). Compound VI was ob-
tained using a procedure analogous to that described above.
Yield, 71%; m.p., 107 – 108°C (ethanol) [5].
Br2
CH3COCH2COOEt
EAA
Ether
Br2
[CH3COCHBrCOOEt]
XI
DMF,
urea
2-Aminothiazole derivatives (VII – X). To a solution of
0.1 mole of acetophenone or p-bromoacetophenone and
0.1 mole urea in 60 ml of DMF was gradually added, with
stirring and cooling in ice, 0.1 mole of bromine. The mixture
was allowed to stand at ~20°C until complete discoloration
of bromine (~24 h). Then 0.1 mole of thiourea or allylthiour-
ea were added and the mixture was stirred for 24 h at ~20°C
and 2 h at 70 – 80°C (here and below, on a bath). Upon cool-
ing, the mixture was treated with an excess of aqueous
K2CO3 solution. The precipitate was separated by filtration
and washed with water to obtain 2-amino-4-phenylthiazole
(VII), 2-allylamino-4-phenylthiazole (VIII), 2-amino-4-( p-
bromophenyl)thiazole (IX), and 2-allylamino-4-( p-bromo-
phenyl)thiazole (X).
I or II
BrCH2COCH2COOEt
XIV
I
H3C
N
NHR
S
EtOOCCH2
N
EtOOC
NH2
XII, XIII
S
R = H (XII); CH2CH=CH2 (XIII)
XV
This synthesis is also conducted in one flask without isolat-
ing intermediate bromocyclohexanone (XVIII).
O
O
Br
N
S
2-Amino-4-methyl-5-ethoxycarbonylthiazole (XII).
To a mixture of 1.3 g (10 mmole) of ethyl acetoacetate and
0.6 g (10 mmole) urea in 4 ml of DMF was gradually added,
with stirring and cooling in ice, 1.6 g (10 mmole) of bro-
mine. Upon complete discoloration of bromine (~5 min),
0.76 g (10 mmole) of thiourea was added and the mixture
was stirred for 24 h at ~20°C. Then the process was termi-
nated by diluting the reaction mixture with ethyl acetate. The
precipitate was separated by filtration and washed with ethyl
Br2
I
NH2
MeOH,
urea
XVI
XVII
XVIII
The synthesized 2-aminothiazole derivatives were identi-
fied by comparing their melting points and TLC patterns
1
with those of known samples. For compound XII, the H
NMR spectra were compared as well (see the experimental
part below).
1
acetate to obtain the salt XII × HBr; H NMR spectrum (d,
ppm): 1.23 (t, 3H, J 7.2 Hz), 2.45 (s, 3H, CH3), 4.21 (q, 2H, J
7.2 Hz, CH2), 7.20 (bs, 2H, NH2).
In order to obtain compound XII in the base form, the re-
action mixture upon treatment with thiourea has to be diluted
with an excess of aqueous K2CO3 solution (instead of ethyl
acetate), after which the precipitated product is separated by
filtration and washed with water.
Being relatively simple and offering satisfactory yields,
the proposed method may compete with those described pre-
viously for the synthesis of 2-aminothiazole derivatives
[4 – 8].
EXPERIMENTAL PART
The 1H NMR spectra were measured on a Bruker
AM-300 spectrometer using samples dissolved in DMSO-d6.
The course of reactions was monitored and purity of the re-
action products was checked by TLC on Silufol UV-254
plates eluted in a benzene – ethyl acetate (1 : 1) system; the
spots were visualized under UV illumination. The yields and
physicochemical characteristics of the synthesized com-
pounds are listed in Table 1. When necessary, the obtained
2-aminothiazole derivatives can be purified by
recrystallization from aqueous ethanol.
TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds VII – X, XII, XIII and XVI
Initial
compounds
Target
Yield,
%
M.p.,
°C
Empirical
formula
Ref.
compound
Thiou
rea
Ketone
III
I
II
I
VII
VIII
73 148 – 150 C9H8N2S
75 72 – 73 C12H12N2S
[6]
[11]
[6]
III
Phenacyl bromide (V). To a mixture of 12 g (0.1 mole)
of acetophenone and 6 g urea in 60 ml of DMF was gradu-
ally (over ~15 min) added, with stirring and cooling in ice,
16 g (0.1 mole) of bromine. Upon termination of the
bromination process (20 – 30 h at ~20°C), the reaction mix-
ture was diluted with water. The precipitated oily product ex-
hibited crystallization within a short period of time, after
which the crystalline deposit was separated by filtration and
washed with water to obtain 17 g (85%) of compound V;
IV
IX
77 180 – 182 C9H7BrN2S
71 108 – 110 C12H11BrN2S
80 174 – 176 C7H10N2O2S
IV
II
I
X
[12]
[8]
EAA
EAA
XII
I
70 225 – 228
(decomp.)
[8]
XII × HBr
C7H10N2O2S × HBr
EAA
XVII
XVII
II
I
XIII
XVI × HBr
XVI
55
70 – 73 C10H14N2O2S
[14]
[15]
[15]
53 234 – 236
C7H10N2S × HBr
I
42
86 – 87 C7H10N2S

98
S. I. Zav’yalov et al.
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2-Allylamino-4-methyl-5-ethoxycarbonylthiazole (XIII).
Compound XIII was obtained using a procedure analogous
to that described above for XII in the base form. Upon add-
ing allylthiourea, the reaction mixture was kept for 12 h at
~20°C and heated for 3 h at 70 – 80°C.
2-Amino-4,5-tetramethylenethiazole (XVI). To a mix-
ture of 10 g (0.1 mole) of cyclohexanone and 12 g (0.2 mole)
of urea in 25 ml of MeOH was gradually (over ~10 min)
added, with stirring and cooling in ice, 16 g (0.1 mole) of
bromine. Upon termination of the bromination process
(10 – 15 min at ~20°C), thiourea (7.8 g, 0.1 mole) was added
immediately and the reaction mixture was allowed to stand
for 72 h at ~20°C with periodic stirring. The precipitated
hydrobromide was filtered and washed with methanol.
In order to obtain compound XVI in the free base form,
the hydrobromide was treated with an excess of aqueous
K2CO3 solution, after which the precipitated product was
separated by filtration and washed with water.
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