Efficient synthesis of 2-aminothiazole-4-phenyl-5-acetamides via the open chain tautomers of γ-keto amides

Article abstract of DOI:10.1080/00397910500385001

A simple and efficient method is described for the synthesis of new functionalized 2-aminothiazoles, the 2-aminothiazole-4-phenyl-5-acetamides 5, in 67-96% yields based on an application of the Hantzsch synthesis. The method involves the reaction of thiou

Full text of DOI:10.1080/00397910500385001

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Efficient Synthesis of
2‐Aminothiazole‐4‐phenyl‐5‐acetamides via
the Open Chain Tautomers of γ‐Keto Amides
Georgia Tsolomiti a & Athanase Tsolomitis a
a Laboratory of Organic Chemistry, School of Chemical Engineering ,
National Technical University of Athens , Athens, Greece
Published online: 19 Aug 2006.
To cite this article: Georgia Tsolomiti & Athanase Tsolomitis (2006) Efficient Synthesis of
2‐Aminothiazole‐4‐phenyl‐5‐acetamides via the Open Chain Tautomers of γ‐Keto Amides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:4,
501-507, DOI: 10.1080/00397910500385001
To link to this article: http://dx.doi.org/10.1080/00397910500385001
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Synthetic Communicationsw, 36: 501–507, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500385001
Efficient Synthesis of 2-Aminothiazole-4-
phenyl-5-acetamides via the Open Chain
Tautomers of g-Keto Amides
Georgia Tsolomiti and Athanase Tsolomitis
Laboratory of Organic Chemistry, School of Chemical Engineering,
National Technical University of Athens, Athens, Greece
Abstract: A simple and efficient method is described for the synthesis of new functio-
nalized 2-aminothiazoles, the 2-aminothiazole-4-phenyl-5-acetamides 5, in 67–96%
yields based on an application of the Hantzsch synthesis. The method involves the
reaction of thiourea with 3-benzoyl-3-bromo-propionamides 4 prepared from the cor-
responding 3-benzoylpropionamides 3. The tautomeric structure of the g-keto amides 3
and 6 is directly related to the present study, because 2-aminothiazoles 5 are readily
obtained from the corresponding open chain g-keto amides 3.
Keywords: 2-Aminothiazole-4-phenyl-5-acetamides, 3-benzoylpropion-amides,
3-benzoyl-3-bromopropionamides
The 2-aminothiazole ring system is a useful structural element in medicinal
chemistry and has found broad application in drug development for the
treatment, among other diseases, of allergies[1] and bacterial[2] and HIV infec-
tions.[3] Given this proven utility, it seems reasonable that the development of
libraries of 2-aminothiazoles might provide additional lead molecules for use
in drug discovery.
2-Aminothiazoles are prepared by the condensation of a-halo ketones
with an appropriate thiourea, a specific case of the well-established and
extremely versatile Hantzsch syntesis of the C–C þ S–C–N route.[4,5]
Received in Poland May 24, 2005
Address correspondence to Athanase Tsolomitis, Laboratory of Organic Chemistry,
School of Chemical Engineering, National Technical University of Athens, Athens 157
80, Greece. E-mail: tsolom@chemeng.ntua.gr
501

502
G. Tsolomiti and A. Tsolomitis
Many preparations of 2-aminothiazoles by conventional procedures have been
reviewed[6–8] and tabulated recently.
Herein we report a facile synthesis of the titled compounds. Our synthesis
of 2-aminothiazole-4-phenyl-5-acetamides 5 entails the use of the readily
prepared 3-benzoyl-3-bromopropionamides 4 (Scheme 1). Treatment of 4
with thiourea in refluxing ethanol for 1 h cleanly afforded 2-aminothiazole-
4-phenyl-5-acetamides 5, which were isolated, as their hydrobromides, in
67–96% yields. However, it was first necessary to synthesize 3-benzoylpro-
pionamides 3; thus we applied a described method[9,10] for the synthesis of
g-keto amides 3a and 3b from 3-benzoylpropionic acid 1 with the reaction
sequence that appears in Scheme 1, with a modification[11] in the preparation
of 5-phenylfuran-2(3H)-one 2.
g-Keto amides of the general formula 3 (R155H) are known to exhibit the
ring-chain tautomerism[9,10,12a]–d (Scheme 1). The tautomeric structure of the
1
g-keto amides 3a–3d has been studied spectroscopically (IR, H and 13C
NMR), and these compounds were assigned the open chain amide structure 3.
The tautomerism of the g-keto amides is directly related to the present
study, because the synthesis of the titled compounds 5 are readily obtained
from the corresponding open chain g-keto amides 3, as described in
following sections.
In conclusion, we have prepared a new series of functionalized
2-aminothiazoles in good yields and with high degrees of purity from
thiourea and 3-benzoyl-3-bromopropionamides, with an application of the
well-known Hantzsch synthesis. The key to this method is the preparation
Scheme 1.

2-Aminothiazole-4-phenyl-5-acetamides
503
of the open chain tautomers 3-benzoylpropionamides and their conversion to
the corresponding (open chain) 3-benzoyl-3-bromopropionamides. Given that
the 2-aminothiazole ring system is a useful structural element in medicinal
chemistry, these new functionalized 2-aminothiazoles could be considered
to be of interest as potential drugs.
EXPERIMENTAL
General
NMR spectra were recorded at ambient temperature using a Varian Gemini
2000 300-MHz spectrometer. The data are reported as follows: chemical
shift quoted in ppm on the d scale, multiplicity (br ¼ broad, s ¼ singlet,
d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), and coupling constants
given in (Hz). Micro analyses were performed by microanalytical laboratory
of CNRS (France). Melting points are reported uncorrected. IR spectra were
obtained at a Nicolet Magna 560 spectrometer (as nujol mulls).
5-Phenylfuran-2(3H)-one (2) was prepared from b-benzoylpropionic acid
and acetyl chloride at reflux conditions.[11]
3-Benzoylpropionamide-N-phenyl (3a)
A mixture of 8 g (49.95 mmol) of 5-phenylfuran-2(3H)-one and 4.9 g
(52.45 mmol) of fresh distilled aniline was heated on a steam bath for 3.5 h.
The solid product after recrystallization from ethanol gave 10 g (79%) of a
solid, mp 148–1498C, lit.[13] 1498C. IR (Nujol mull, cm21): 3290, 1678, 1658,
1
1597, and 1529. H NMR (CDCl3): 2.77 (t, J ¼ 6.2 Hz, 2H, .NCOCH2–),
3.88 (t, J ¼ 6.2 Hz, 2H, –CH2COPh), 7.00–8.18 (m, 10H, arom.), 10.10
(br s, 1H, –NHCO–). 13C NMR (CDCl3): 30.30, 33.40, 120.01, 124.27,
127.42, 128.25, 128.68, 129.17, 133.35, 138.28, 172.36, and 199.46.
3-Benzoylpropionamide-N-benzyl (3b)
A mixture of 8.00 g (49.95 mmol) of 5-phenylfuran-2(3H)-one and 5.62 g
(52.45 mmol) of benzylamine was heated on a steam bath for 10 min.
The solid product after recrystallization from ethanol gave 11.50 g (86%) of
a solid, mp 110–1128C, lit.[10] 110–1118C. IR (Nujol mull, cm21): 3257,
1681, 1634, and 1550. 1H NMR (CDCl3): 2.70 (t, J ¼ 6.2 Hz, 2H,
.NCOCH2–), 3.45 (t, J ¼ 6.2 Hz, 2H, –CH2COPh), 4.53 (d, J ¼ 6.5 Hz,
2H, .NCH2Ph), 6.38 (br m, 1H, –NHCO–), 7.35–8.30 (m, 10 H, arom.).
13C NMR (CDCl3): 30.13, 34.03, 43.61, 127.52, 127.88, 128.26, 128.80,
133.45, 136.76, 138.63, 172.32, 199.51.

504
G. Tsolomiti and A. Tsolomitis
3-Benzoylpropionamide-N,N-diphenyl (3c)
A mixture of 18.68 g (116.77 mmol) of 5-phenylfuran-2(3H)-one and 20.75 g
(122.60 mmol) of diphenylamine was heated on an oil bath at 1208C for 4.5 h.
The dark colored retinous product after recrystallization from ethanol gave
25.72 g (67%) of a solid, mp 147–1498C. Anal. calcd. for C22H!9NO2: C,
80.22; H, 5.81; N, 4.25. Found: C, 79.94; H, 5.94; N, 4.11. IR (Nujol mull,
1
cm21): 1673, 1647, 1593, and 1583. H NMR (CDCl3): 2.69 (t, J ¼ 6.2 Hz,
2H, .NCOCH2–), 3.39 (t, J ¼ 6.2 Hz, 2H, –CH2COPh), 7.00–8.36
(m, with as at 7.37 ppm, 15 H, arom.). 13C NMR (CDCl3): 30.11, 33.50,
121.31, 124.35, 127,31, 127.49, 128.41, 128.51, 128.71, 128.95, 129.22,
129.31, 133.33, 133.45, 171.73, 199.41.
3-Benzoylpropionamide-N,N-dibenzyl (3d)
A mixture of 8.00 g (49.95 mmol) of 5-phenylfuran-2(3H)-one and 10.35 g
(52.44 mmol) of dibenzylamine was heated on a steam bath for 2 h. The
solid product after recrystallization from ethanol gave 16 g (90%) of a solid
mp 84–868C. lit.[14] 84–858C. Anal. calcd. for C24H23NO2: C, 80.64; H,
6.48; N, 3.92. Found: C, 80.48; H, 6.27; N, 3.69. IR (Nujol mull, cm21):
1
1687, 1644, 1605, 1594, and 1581. H NMR (CDCl3): 2,80 (t, J ¼ 6.2 Hz,
2H, .NCOCH2–), 3.36 (t, J ¼ 6.2 Hz, 2H, –CH2COPh), 4.58 (s, 4H,
benzylic protons), 7.13–8.36 (m, 15H, arom.). 13C NMR (CDCl3): 27.37,
33.89, 48,47, 50.03, 126.82, 127.61, 127.87, 128.38, 128.47, 128.81,
128.86, 129.23, 136,73, 137.13, 137.57, 172.69, 199.49.
General Procedure for the Preparation of 3-Benzoyl-3-
bromopropion-amides (4a–4d)
A solution of bromine 9.6 mmol in 20 ml of dichloromethane was added
slowly to a solution of 3-benzoylpropionamide (3a–3d) (8 mmol) in 30–
80 ml of dichloromethane, depending on the solubility. Then the solution
was refluxed with stirring for 5–20 min until the bromine color disappeared.
The solution was concentrated under vacuum, at moderate temperature,
and the solid or retinous concentrate recrystallized from ethanol to give an
analytical sample of the 3-benzoyl-3-bromopropionamide (4a–4d).
Data
3-Benzoyl-3-bromopropionamide-N-phenyl (4a): Yield 85%, mp
110–1118C, lit.[15] 106–1118C. Anal. calcd for C16H14BrNO2: C, 57.85; H,
4.25; Br, 24.05; N, 4.22. Found: C, 57.67; H, 4.11; Br, 24.25; N, 3.99.

2-Aminothiazole-4-phenyl-5-acetamides
505
IR (Nujol mull, cm21): 3273, 1688, 1680, 1655, 1595, 1587, 1580, and 1528.
1H NMR (CDCl3): 2.80–3.87 (m, 2H, –CH2–), 5.68 (dd, J ¼ 7.1 Hz, 1H,
.CH–), 7.03–7.47 (m, 10H, arom.), 7.82–8.13 (br m, 1H, –NHCO–). 13C
NMR (CDCl3): 40.41, 40.87, 121.31, 125.35, 127.52, 128.34, 128.74,
129.26, 133.44, 138.72, 169.58, 193.44.
3-Benzoyl-3-bromopropionamide-N-benzyl (4b): Yield 78%, mp 118–
1198C. Anal. calcd. for C17H16BrNO2: C, 58.97; H, 4.66; Br, 23.08; N,
4.04. Found: C, 59.12; H, 4.73; Br, 23.11; N, 3.88. IR (Nujol mull, cm21):
3320, 1690, 1680, 1636, 1596, 1577, and 1549. 1H NMR (CDCl3):
2.75–3.66 (m, 2H, –CH2–), 5.70 (dd, J ¼ 7.2 Hz, 1H, .CH–), 4.43
(d, J ¼ 6.2 Hz, 2H, –CH2Ph), 6.29 (br m, 1H, –NHCO–), 7.27–8.25
(m, 10H, arom.). 13C NMR (CDCl3): 40.74, 40.97, 43.85, 127.90, 128.04,
129.02, 129.09, 129.40, 134.10, 134.25, 138.04, 169.48, 193.28.
3-Benzoyl-3-bromopropionamide-N,N-diphenyl (4c): Yield 81%, mp
121–1228C. Anal. calcd. for C22H18BrNO2: C, 64.72; H, 4.44; Br, 19.57;
N, 3.43. Found: C, 64.50; H, 4.31; Br, 19.64; N, 3.52. IR (Nujol mull,
cm21): 1680, 1664, 1592, and 1578. 1H NMR (CDCl3): 2.73–3.46
(m, 2H, –CH2–), 5.65 and 5.80 (dd, J ¼ 5.2 Hz, 1H, .CH–), 7.08–8.31
(m, 15H, arom.). 13C NMR (CDCl3): 40.62, 40.90, 124.05, 125.44, 127.61,
127.93, 128.31, 128.62, 128.97, 129.45, 133.12, 136.03, 136.45, 138.41,
169.42, 193.34.
3-Benzoyl-3-bromopropionamide-N,N-dibenzyl (4d): Yield 83%, mp
104–1068C. Anal. calcd. for C24H22BrNO2: C, 66.06; H, 5.08; Br, 18.31;
N, 3.21. Found: C, 65.87; H, 4.83; Br, 18.44; N, 3.30. IR (Nujol mull,
1
cm21): 1693, 1682, 1648, 1594, 1575, and 1550. H NMR (CDCl3): 3.01–
4.07 (m, 2H, –CH2–), 4.50 (s, 4H, benzylic protons), 5.75 and 5.90 (dd,
J ¼ 5.2 Hz, 1H, .CH–), 7.01–8.31 (m, 15H, arom.). 13C NMR (CDCl3):
40.31, 40.87, 49.41, 50.32, 126.74, 127.50, 127.61, 128.04, 128.11, 128.41,
128.45, 129.31, 136.90, 137.61, 138.90, 169.61, 193.72.
General Procedure for the Preparation of 2-Aminothiazole-4-
Phenyl-5-Acetamides (5a–5d)
A mixture of the 3-benzoyl-3-bromopropionamide (4a–4d) (5 mmol) and
thiourea (7 mmol) in 7–15 ml of ethanol was refluxed for 1 h. After cooling
the crystalline solid was filtered and recrystallized from ethanol to give an
analytical sample.
Data
2-Aminothiazole-4-phenyl-5-acetamide-N-phenyl, hydrobromide (5a):
Yield 74%, mp 224–2258C. Anal. calcd. for C17H16BrN3OS: C, 52.31;

506
G. Tsolomiti and A. Tsolomitis
H, 4.13; Br, 20.47; N, 10.76. Found: C, 52.13; H, 3.87; Br, 20.51; N, 10.59. IR
(Nujol mull, cm21): 3286, 3163, 3136, 3105, 1642, 1594, 1536, 1487, 1399,
1
and 1071. H NMR (CDCl3/DMSO-d6): 3.91 (s, 2H, –CH2–), 7.29–7.83
(m, 10H, arom.), 9.00 (br m, 3H, –NþH3), 10.50 (s, 1H, –NHCO–).
2-Aminothiazole-4-phenyl-5-acetamide-N-benzyl, hydrobromide (5b):
Yield 67%, mp 105–1068C. Anal. calcd. for C18H18BrN3OS: C, 53.47;
H, 4.49; Br, 19.76; N, 10.39. Found: C, 53.23; H, 4.21; Br, 19.95; N, 10.11.
IR (Nujol mull, cm21): 3365, 3265, 3077, 1642, 1627, 1598, 1585, 1541,
1
1491, 1415, and 1081. H NMR (CDCl3/DMSO-d6): 3.71 (s, 2H, –CH2–),
4.38 (d, J ¼ 6.2 Hz, 2H, –CH2Ph), 7.20–7.72 (m, 10H, arom.), 8.62 (br m,
1H, –NHCO–), 8.96 (br m, 3H, –NþH3).
2-Aminothiazole-4-phenyl-5-acetamide-N,N-diphenyl, hydrobromide (5c):
Yield 88%, mp 233–2348C. Anal. calcd. for C23H20BrN3OS: C, 59.23;
H, 4.32; Br, 17.13; N, 9.01. Found: C, 58.98; H, 4.11; Br, 17.25; N, 8.83.
IR (Nujol mull, cm21): 3272, 3158, 1648, 1631, 1594, 1572, 1491, 1400,
1
and 1074. H NMR (CDCl3/DMSO-d6): 3.71 (s, 2H, –CH2–), 7.05–7.73
(m, 15H, arom.), 9.13 (br m, 3H, –NþH3).
2-Aminothiazole-4-phenyl-5-acetamide-N,N-dibenzyl, hydrobromide (5d):
Yield 96%, mp 177–1788C. Anal. calcd. for C25H24BrN3OS: C, 60.73; H,
4.89; Br, 16.16; N, 8.50. Found: C, 60.48; H, 4.69; Br, 16.34; N, 8.37. IR
(Nujol mull, cm21): 3340, 3239, 3194, 1642, 1620, 1603, 1578, 1495, 1406,
1
and 1075. H NMR (CDCl3/DMSO-d6): 3.89 (s, 2H, –CH2–), 4.48 and
4.67 (two s, 4H, benzylic protons), 6.88–7.53 (m, 15H, arom.), 9.14 (br m,
3H, –NþH3).
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