Facile synthesis of 5-acyl-2-amino-1,3-thiazole by the reaction of thiaazadienes with α-halo ketones

Article abstract of DOI:10.3987/COM-04-10231

The reaction of thiaazadienes (1a-e) with α-halo ketones (2a-d) gives 5-acyl-2-amino-1,3-thiazole (3a-q) in high yields.

Full text of DOI:10.3987/COM-04-10231

HETEROCYCLES, Vol. 63, No. 12, 2004, pp. 2805 - 2812
Received, 16th September, 2004, Accepted, 21st October, 2004, Published online, 26th October, 2004
FACILE SYNTHESIS OF 5-ACYL-2-AMINO-1,3-THIAZOLE BY THE
REACTION OF THIAAZADIENES WITH a-HALO KETONES
Ramadas Sathunuru and Ed Biehl*
Department of Chemistry, Southern Methodist University, Dallas, TX,
75275 U. S. A. ebiehl@smu.edu
Abstract – The reaction of thiaazadienes (1a–e) with a-halo ketones (2a–d)
gives 5-acyl-2-amino-1,3-thiazole (3a–q) in high yields.
INTRODUCTION
Substituted 1,3-thiazoles are ubiquitous structural motifs found in several compounds of biological
interest. For example, 2-dialkyl-1,3-thiazoles serve as key intermediates in the synthesis of biologically
interesting and pharmaceutically useful molecules such as dipeptidyl peptidase IV (DPP-IV) inhibitors,
agonists of peroxisome proliferation-activated receptors (PPARs), subtype selective N-methyl-R-aspartate
antagonists, glucose and lipid lowering agents and antifungal agents.1-3 Consequently, several methods for
the preparation of substituted 1,3-thiazoles have been developed.4-6 Although these methods allow ready
accessibility to this class of compounds, their ability to prepare thiazoles with specific substitution
patterns is limited and usually requires the design of new synthetic strategies.
Recently, the synthesis of sulfur heterocycles has been extensively studied using the carbon-sulfur double
bond as 2p dienophile intermediates for [4+2] cycloadditions. For example, a,b-unsaturated
thiaaldehydes and thiaketones selectively under go ‘head-to-head’ [4+2] dimerization to give six-
membered cyclic dithianides.7 Furthermore, the reaction of N-thiaazadienes with dimethyl
acetylenedicarboxylate (DMAD) affords six-membered ring 4H-thiazine that gets converted to a 4H-
thianopyran by cycloreversion and recycloaddition with excess DMAD.8 Recently, Noack and Hartman9
prepared a series of 5-acyl-2-amino-1,3-thiazoles by allowing suitably substituted thiaazadines and
haloacetophenones to react in a polar solvent such as acetonitrile or methanol to give vinanidinium salts
which were converted in situ to by the addition of a suitable base (TEA or MeOK) and refluxing. During
the course of our study on the biological activity of certain 1,3-thiazoles, we needed a supply of 5-acyl-2-

amino-1,3-thiazoles for testing purposes. We initially used the aforementioned method.9 However, we
were able to modify the procedure with improved results which we report herein.10
RESULTS AND DISCUSSION
Five thiaazadienes (thiaacylamides) (1a-e), which were on hand from a previous study,11 were treated
with bromoacetophenones (2a-c) and chloroacetone (2d). We noted early on that the initially formed
vinanidinium salts could simply be quench with water to give the desired products (3). By eliminating the
base/refluxing step, 3 were obtained in almost quantitative yields. The results are shown in Scheme 1.
O
R
S
1
Br
N
+
N
R
2
N Me
Me
R
3
1
2
a) R =H
3
a) R =R = -(CH ) , R =H
1
2
2 5
3
b) R = Cl
3
b) R =R =-CH ) -O-(CH ) , R =H
1
2
2 2
2 2
3
1. anhydrous THF
reflux, 2h
c) R =R = Me, R =H
c) R = OMe
1
2
3
3
d) R =R = Et, R =H
1
2
3
2. H O
2
e) R =R = -CH-(CH ) -CH-, R =H
1
2
2 4
3
O
R
1
N
S
N
R
2
R
3
3a-q
Yield (%)
Yield (%)
97
a) R =R = -(CH ) , R =H
i) R =R = Et, R =Cl
99
98
1
2
2 5
3
1
2
3
j) R =R = -CH-(CH ) -CH-, R =Cl
b) R =R =-CH ) -O-(CH ) , R =H
97
1
2
2 4
3
1
2
2 2
2 2
3
k) R =R = -(CH ) , R =OMe
98
96
98
c) R =R =Me, R =H
1
2
2 5
3
1
2
3
d) R =R = Et, R =H
l) R =R = -(CH ) -O-(CH ) , R =OMe
96
1
2
3
1
2
2 2
2 2
3
e) R =R = -CH-(CH ) -CH-, R =H
96
93
n) R =R = Me, R =OMe
89
96
1
2
2 4
3
1
2
3
f) R =R = -(CH ) , R =Cl
m) R =R = Et, R =OMe
1 2 3
1
2
2 5
3
g) R =R =-(CH ) -O-(CH ) , R =Cl 97
o) R =R = -CH-(CH ) -CH-, R =OMe
93
1
2
2 2
2 2
3
1
2
2 4
3
98
h) R =R = Me, R =Cl
1
2
3
1. anhydrous THF
reflux, 2 h
O
O
R
1
N
S
Cl
+ 1c,1d
Me
Me
2. H O
2
N
R
2
2d
3p,3q
p) R =R = Me, 98
97
1
2
q) R =R = Et
1
2
Scheme 1

Accordingly, the reaction of bromoacetophenones (2a-c) with 1a-e gave the 2-amino derivatives of 5-
benzoyl-1,3-thiazoles (3a-o) in 89–99% yields and the reaction of chloroacetone (2d) with 1c,d afforded
5-acyl-1,3-thiazoles (p,q) in 97–98% yields. Interestingly, the yields of 3c (98%) and 3p (98%) obtained
in this study are significantly higher than the yields of 3c (29%) and 3p (13%) reported previously.9
The structures of 3a-q were confirmed by GCMS, 1H NMR, 13C NMR spectroscopy, and elemental
analysis. In addition, the structures of 3a–c were determined using X-Ray diffraction analysis (Figures
1–3). The X-Ray structure of 3c was particularly important since its melting point reported here is much
higher than that previously reported.9
Figure 1. ORTEP of compound (3a)
Figure 2. ORTEP of compound (3b)
Figure 3. ORTEP of compound (3c)
A possible mechanism for the formation of compounds (3a–q) is described in Scheme 2. The first step
involves a SN2 reaction involving the attack of the sulfur atom of a sulfuracylamidine (1) onto the α-

position of carbonyl carbon of 2 with the concomitant loss of Br-. The resulting adduct (4) then cyclizes to
5 from which dimethyl amine is eliminated to give the 5-acyl-2-amino-1,3-thiazole derivative (3).
H O
2
O
R
3
H
H
+
R
R
S
-H O
1
N
2
Br
3
R
R
S
1
N
2
R
3
O
_
N
2
Br
N
:
Me
N
Me
N Me
Me
1
4
O
O
H
S
R
1
S
R
1
N
N
_
R
N
2
R
NHMe
3
R
N
2
N
Me
2
Me
R
3
3
5
Scheme 2
Conclusions
In this study, 2-amino-5-benzoyl-1,3-thiazoles and 5-acyl-2-amino-1,3-thiazoles were prepared in
high yields by a one-pot reaction of thiaazadienes and the appropriate α−halo ketones. The yields of the
previously reported synthesis of 1,3-thiazoles were lower (significantly lower in some cases) than those
reported here presumably due to the use of an additional base-mediated refluxing step in the latter. In that
second step, undesired side reactions of starting materials, intermediates, or products presumably occur.
EXPERIMENTAL
General Data Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected with
1
respect to stem correction. H NMR and 13C NMR spectra were recorded on a 400 MHz Bruker
AVANCE DRX-400 Multi-nuclear NMR spectrometer. Chemical shifts are reported in reference to TMS
as internal standard. Elemental analyses were carried out in the SMU Analytical Laboratory. The
°
glassware was heated overnight in an oven at 125 C prior to use. All the reactions were done under an
atmosphere of dry O2 –free Ar via balloon.
General Procedure for the Synthesis of 5-Benzoyl-2-(piperidin-1-yl)-1,3-thiazole (3a)
2-Bromoacetophenone (2a) (0.75g, 3.8 mmol) was added to a stirred solution of N1,N1-dimethyl-N2-
piperidinothiacarbonylformamidine (0.53 g, 2.5 mmol) in anhydrous tetrahydrofuran (50 mL) at rt under
argon. The reaction mixture was refluxed for 2 h then cooled to rt during which time a solid appeared.

After the solvent was removed by distillation, the remaining solid was dissolved in water and stirred for 5
min. The mixture was extracted with ethyl acetate (2 X 50 mL) and the combined ethyl acetate extracts
were washed with water (50 mL). The organic layer was separated, dried (Na2SO4) and evaporated to
dryness. The residue was purified by flash chromatography on silica gel with cyclohexane: ethyl acetate
(6:4) to give 5-benzoyl-2-(piperidine-1-yl)-1,3-thiazole (3a) (0.70g, 97%) as white crystals, mp
117–118 °C. 1H NMR (400 MHz, CDCl3) δ 1.73 (m, 6H), 3.65 (m, 4H), 7.49 (m, 2H), 7.55 (m, 1H), 7.72
13
(s, 1H), 7.79 (m, 2H). C NMR (100 MHz, CDCl3) δ 24.3 (t), 25.5 (t), 50.0 (t), 128.3 (s), 128.8 (d),
128.9 (d), 132.0 (d), 139.0 (s), 151.3 (d), 175.7 (s), 187.0 (s). Anal. Calcd for C15H16N2O: C, 66.15; H,
5.92; N, 10.29. Found: C, 66.39; H, 5.81; N, 10.30.
5-Benzoyl-2-(morpholin-1-yl)-1,3-thiazole (3b)
Colorless crystals, mp 144–145 °C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.66 (m, 4H), 3.85 (m,
4H), 7.51 (m, 2H), 7.57 (m, 1H), 7.75 (s, 1H), 7.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 48.6 (t), 66.3
(t), 128.8 (d), 129.0 (d), 129.4 (s), 132.2 (d), 138.7 (s), 150.6 (d), 173.6 (s), 187.1 (s). Anal. Calcd for
C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21. Found: C, 61.59; H, 5.14; N;10.17.
5-Benzoyl-2-N,N-dimethylamino-1,3-thiazole (3c)
Light brown crystals, mp 72–73 °C (hexane/ CHCl3) (lit.,9 38–40 °C). 1H NMR (400 MHz, CDCl3) δ 3.25
(s, 6H), 7.49 (m, 2H), 7.57 (m, 1H), 7.75 (s, 1H), 7.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 40.7 (q),
128.8 (d), 128.9 (d), 129.1 (s), 132.0 (d), 138.9 (s), 151.3 (d), 174.2 (s), 187.0 (s). Anal. Calcd for
C12H12N2OS: C, 62.04; H, 5.21; N, 12.06. Found: C, 62.01; H, 5.18; N, 11.87.
5-Benzoyl-2-N,N-diethylamino-1,3-thiazole (3d)
Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 6H), 3.61 (q, J = 6.7 Hz, 4H), 7.48 (m,
2H), 7.56 (m, 1H), 7.73 (s, 1H), 7.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 12.8 (q), 46.4 (t), 128.2 (d),
128.8 (d), 128.9 (d), 131.9 (s), 139.1 (s), 151.5 (d), 174.5 (s), 186.9 (s). Anal. Calcd for C14H16N2OS: C,
64.58; H, 6.19; N, 10.76. Found: C, 64.30; H, 6.24; N, 10.46.
5-Benzoyl-2-N,N-diisopropylamino-1,3-thiazole (3e)
°
Light yellow crystals, mp 82–84 C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.50 (t, J = 6.7 Hz,
13
12H), 4.03 (dd, J = 13.1, 6.6 Hz, 2H), 7.47 (m, 2H), 7.55 (m, 1H), 7.74 (s, 1H), 7.79 (m, 2H). C NMR
(100 MHz, CDCl3) δ 20.2 (q), 52.0 (d), 126.9 (s), 128.7 (d), 128.8 (d), 131.8 (d), 139.3 (s), 151.4 (d),
173.4 (s), 186.9 (s). Anal. Calcd for C16H20N2OS: C, 66.63; H, 6.99; N, 9.71. Found: C, 66.76; H, 7.04;
N, 9.63.
5-(4’-Chlorobenzoyl)-2-piperidin-1,3-thiazole (3f)
°
1
Colorless crystals, mp 158–159 C (hexane/ CHCl3). H NMR (400 MHz, CDCl3) δ 1.66 (m, 6H), 3.65
(m,4H), 7.46 (d, J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CD24.2
(t),

25.5 (t) 50.0 (t), 127.9 (s), 129.0 (d), 130.3 (d), 137.3 (s), 138.1(s), 151.3 (d), 175.6 (s), 185.3 (s). Cl3) δ
Anal. Calcd for C15H15N2O2ClS: C, 58.72; H, 4.93; N, 9.13. Found: C, 58.61; H, 4.92; N, 8.95.
5-(4’-Chlorobenzoyl)-2-(morpholin-1-yl)-1,3-thiazole (3g)
Colorless crystals, mp 180–181°C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.66 (m, 4H), 3.85 (m,
4H), 7.48 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 48.7 ,
66.3, 129.0, 129.2, 130.3, 137.0, 138.7, 150.6, 175.9, 185.6. Anal. Calcd for C14H13N2O2Cl S: C, 54.46; H,
4.24; N, 9.07. Found: C, 54.61; H, 4.26; N, 9.09.
5-(4’-Chlorobenzoyl)-2-N,N-dimethylamino-1,3-thiazole (3h)
•
Colorless crystals, mp 124–125 C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.25 (s, 6H), 7.47 (d,
J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3). δ 40.6 (q), 128.6 (s),
129.0 (d), 130.2 (d), 137.2 (s), 138.0 (s), 151.2 (d), 175.7 (s), 185.1 (s). Anal. Calcd for C12H11N2OClS: C,
54.03; H, 4.16; N, 10.50. Found: C, 54.45; H, 4.12; N, 10.50.
5-(4’-Chlorobenzoyl)-2-N,N-diethylamino-1,3-thiazole (3i)
Colorless crystals, mp 85–86 °C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J = 7.1 Hz, 6H),
13
3.60 (q, J = 6.9 Hz, 4H), 7.46 (d, J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H). C NMR (100
MHz, CDCl3). δ 12.7 (q), 46.4 (t), 127.7 (s), 129.0 (d), 130.2 (d), 137.3 (s), 138.0 (s), 151.4 (d) , 174.4 (s),
185.1 (s). Anal. Calcd for C14H15N2OClS: C, 57.04; H, 5.13; N, 9.50. Found: C, 57.56; H, 4.9; N, 9.47.
5-(4’-Chlorobenzoyl)-2-N,N-diisopropylamino-1,3-thiazole (3j)
Light yellow crystals, mp 109–110 °C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.51 (t, J = 6.7 Hz,
12H), 4.03 (dd, J = 13.1, 6.6 Hz, 2H), 7.45 (d, J = 8.3Hz, 2H), 7.71 (s, 1H), 7.74 (d, J = 8.3Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 20. (q), 52.1 (d), 126.5 (s), 128.9 (d), 130.2 (d), 137.5 (s), 137.8 (s), 151.3 (d),
173.4 (s), 185.1 (s). Anal. Calcd for C16H19N2OClS: C, 59.52; H, 5.93; N, 8.68. Found: C, 59.88; H, 5.94;
N, 8.64.
5-(4’-Methoxybenzoyl)-2-(piperidine-yl)-1,3-thiazole (3k)
Colorless crystals, mp 131–132 °C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.73 (m, 6H), 3.64 (m,
4H), 3.89 (s, 3H), 6.98 (d, J = 8.6 Hz, 2H), 7.73 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 24.3 (d), 25.5 (d), 49.9 (d), 55.7 (q), 114.0 (d), 128.4 (s), 131.0 (d), 131.5 (s), 150.2 (d), 162.9
(s), 175.3 (s), 185.6 (s). Anal. Calcd for C16 H18N2 O2S: C, 63.55; H, 6.00; N, 9.26. Found: C, 63.56; H,
6.03; N, 9.23.
5-(4’-Methoxybenzoyl)-2-(morpholin-1-yl)-1,3-thiazole (3l)
°
Colorless crystals, mp 166–167 C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.65 (m, 4H), 3.85
(m, 4H), 3.91 (s, 3H), 6.99 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.83 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 48.6 (d), 55.8 (q) , 66.3 (t), 114.1 (d), 129.6 (s), 131.2 (d), 149.4 (d), 163.1 (s), 175.5 (s), 185.8
(s). Anal Calcd for C15H16N2O3S: C, 59.19; H, 5.30; N, 9.20. Found: C, 59.21; H, 5.30; N, 9.08.

5-(4’-Methoxybenzoyl)-2-N,N-dimethylamino-1,3-thiazole (3m)
Colorless crystals, mp 105-106 °C (hexane/ CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.24 (s, 6H), 3.90 (s,
3H), 6.98 (d, J = 6.8 Hz, 2H), 7.76 (s, 1H), 7.82 (d, J = 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 40.6
(q), 55.8 (q), 114.1 (d), 129.3 (s), 131.1 (d), 131.5 (s), 150.2 (d), 163.0 (s), 175.5 (s), 185.8 (s). Anal.
Calcd for C13H14N2O2S: C, 59.52; H, 5.38; N, 10.68. Found C, 59.76; H, 5.42, N; 10.57.
5-(4’-Methoxybenzoyl)-2-N,N-diethylamino-1,3-thiazole (3n)
Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J = 7.0 Hz, 6H), 3.60 (q, J = 6.8 Hz, 4H), 3.89 (s,
3H), 6.98 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 12.7
((q), 46.4 (t), 55.8 (q), 114.0 (d), 128.3 (s), 131.0 (d), 131.6 (s), 150.4 (d), 162.9 (s), 174.1(s), 185.7 (s).
Anal. Calcd for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.51; H, 6.25; N, 9.36.
5-(4’-Methoxybenzoyl)-2-N,N-diisopropylamino-1,3-thiazole (3o)
Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.43 (t, J = 6.8 Hz, 12H), 3.89 (s, 3H), 4.03 (dd, J = 13.2,
6.6 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 7.74 (s, 1H), 7.81 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3).
δ 20.2 (q), 51.9 (d), 55.8 (q), 114.0 (d), 127.0 (s), 131.0 (d), 131.8 (s), 150.3 (d), 162.8 (s), 173.1(s), 185.8
(s). Anal. Calcd for C17H22N2O2S: C, 64.12; H, 6.96; N, 8.80. Found: C, 64.44; H, 6.85; N, 8.31.
5-Acetyl-2-N,N-dimethylamino-1,3-thiazole (3p)
Light brown crystals, mp 98 °C (hexane/ CHCl3) (lit.,9 96–98 °C). 1H NMR (400 MHz, CDCl3) δ 2.42
(s, 3H), 3.20 (s, 6H), 7.82 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 26.1 (q), 40.6 (q), 129.5 (s), 148.8 (d),
175.8 (s), 189.2 (s). Anal. Calcd for C7H10N2OS: C, 49.39; H, 5.92; N, 16.46. Found: C, 50.08; H, 5.98;
N, 16.38.
5-Acetyl-2-N,N-diethylamino-1,3-thiazole (3q)
Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 6H), 2.44 (s, 3H), 3.55 (q, J = 6.8 Hz,
4H), 7.81 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 12.6 (q), 26.0 (q), 46.3 (t), 128.5 (s), 149.0 (d), 174.4 (s),
189.1 (s). Anal. Calcd for C9H14N2OS: C, 54.52; H, 7.12; N, 14.13. Found: C, 53.23; H, 7.09; N,13.49.
ACKNOWLEDGEMENTS
This work was supported in part by grant from Welch Foundation, Houston, TX.
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