Copper(I) bromide-mediated synthesis of novel 2-arylthiazole-5-carboxylates from α-diazo-β-keto esters and aromatic thioamides

Article abstract of DOI:10.1055/s-2001-17697

Starting from readily available α-diazo-β-keto esters 8 and aromatic primary thioamides 9 and 14, a simple synthesis of 2-aryl 4-substituted thiazole-5-carboxylate derivatives of type 10 and 16 has been accomplished. The method is based on the efficient catalysis of CuBr, which promotes the formation of the corresponding carbenoids 11 from diazo derivatives 8. These Cu-carbenoids 11 react with the thiocarbonyl group of the primary thioamides to afford presumably intermediates of the general type 12, which by subsequent cyclocondensation furnish the title thiazole derivatives.

Full text of DOI:10.1055/s-2001-17697

PAPER
2021
Copper(I) Bromide-Mediated Synthesis of Novel 2-Arylthiazole-5-
carboxylates from -Diazo- -Keto Esters and Aromatic Thioamides
Synthesis of
N
ove
a
l
2-Arylthia
v
zole-5-carbo
i
xylateser Fontrodona,a,1 Santiago Díaz,a,2 Anthony Linden,b José M. Villalgordo*a
a
Departament de Química, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain
Fax +34(972)418150; E-mail: jose.villalgordo@udg.es
b
Organisch-Chemisches Institut , Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
Received 22 May 2001; revised 10 July 2001
In addition to their intrinsic theoretical interest, these re-
actions between thiocarbonyl groups and diazo com-
pounds have also found useful preparative applications in
the synthesis of several complex natural products like the
Abstract: Starting from readily available -diazo- -keto esters 8
and aromatic primary thioamides 9 and 14, a simple synthesis of 2-
aryl 4-substituted thiazole-5-carboxylate derivatives of type 10 and
16 has been accomplished. The method is based on the efficient ca-
talysis of CuBr, which promotes the formation of the corresponding antibiotic indolizomycin,24,25 the alkaloids chilenine and
cephalotaxine.26 In these cases, the formation of the corre-
carbenoids 11 from diazo derivatives 8. These Cu-carbenoids 11 re-
act with the thiocarbonyl group of the primary thioamides to afford
sponding thiocarbonyl ylides served as the key intermedi-
presumably intermediates of the general type 12, which by subse-
ates for the successful accomplishment of their total
quent cyclocondensation furnish the title thiazole derivatives.
syntheses.
Key words: thiazoles, primary aromatic thioamides, CuBr cataly-
During the course of our ongoing studies on the develop-
ment of efficient methodologies that could readily be
adapted for combinatorial and/or parallel synthesis of rel-
evant core structures in solution or on solid supports,27–31
we became interested in exploring the synthetic possibili-
ties offered by thiocarbonyl ylides specifically generated
from primary thioamides, as useful reactive intermediates
toward the preparation of different heterocyclic systems.32
sis -diazo- -keto esters, carbenoid formation
It is well known that the thiocarbonyl group (C=S) is a
very reactive dipolarophile. The reaction between thioke-
tones (“superdipolarophiles”)3,4 and diazo compounds
was first studied many years ago by Staudinger.5 From
this seminal work and through the fundamental studies
carried out by Schönberg,6,7 Huisgen8–10 and others,11 it
was shown that thiocarbonyl compounds 1 react very ef-
ficiently with diazo derivatives 2 to give 2,5-dihydro-
1,3,4-thiadiazoles of type 3.12 Most of these adducts 3, are
rather unstable at ambient temperature and eliminate N2
spontaneously or after slight warming to give reactive
thiocarbonyl ylides of type 4, which depending on the
substitution pattern and/or on the reaction conditions, can
undergo various reactions such as 1,3-dipolar cycloaddi-
tions,13–16 ring closure to thiiranes,17–19 dimerization to
1,4-dithianes,20,21 1,4-shifts22 and 1,5-dipolar electro-
cyclizations23 (Scheme 1).
There are many reports in the literature regarding the use
in organic synthesis of thiocarbonyl ylides generated by
the reaction of diazo compounds with thioketones,33 thi-
olactones,34,35 and thiolactams,36 however, the analogous
reaction with thioamides has received considerably less
attention. Only recently has it been reported that when 2-
diazo-1,3-diketones are allowed to react with thioamides
at high temperatures, the corresponding condensation
products of the 1,3-oxazinone type are formed in good
yields together with small amounts of 5-acylthiazoles.
The same reaction under photochemical conditions was
reported to produce only the corresponding 5-acylthiazole
derivatives albeit in low yields.37
R2
R1
R3
R4
N
N
Herein, we report our findings from an investigation of the
reaction between -diazo- -keto esters and primary thio-
amides and its application toward the synthesis of novel
thiazole derivatives. We prepared a number of -diazo- -
keto esters of type 8 using known procedures. These were
formed in high yields by the reaction of tosyl azide with
-keto esters 7 in the presence of a suitable base.38 (Cau-
tion! we have routinely worked with derivatives of type 8
in scales up to 5 g and although in our hands no hazard oc-
curred, -diazo carbonyl compounds are toxic and poten-
tially explosive. Accordingly, they should be handled
with care). In turn, commercially unavailable -keto es-
ters 7 were also prepared easily in high yields by follow-
ing a one-pot, two-step procedure based on the
condensation of different acid chlorides 5 with Meldrum’s
acid 6 and subsequent alcoholysis39 (Scheme 2).
R4
R3
R2
R1
+
S
S
N2
1
2
3
R2
S
R4
-N2
Products
R1
R3
4
Scheme 1
Synthesis 2001, No. 13, 08 10 2001. Article Identifier:
1437-210X,E;2001,0,13,2021,2027,ftx,en;E03901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2022
X. Fontrodona et al.
PAPER
Table 1 2-Arylthiazole-5-carboxylates 10a–d Prepared
O
O
O
R
O
O
Producta Ar
R
R1
Et
Yield (%) Mp (°C)
+
Cl
R
OR1
Ref. 39
O
O
10a
10b
10c
10d
Ph
Ph
78
62
66
65
101–102
85–86
Ph
PhCH2CH2 Et
5
6
7
Ph
Pr
Et
Et
105–106
94–95
O
O
4-MeC6H4
Ph
R
OR1
a Satisfactory microanalyses obtained: C 0.29, H 0.33, N
0.27, S 0.25.
Ref. 38
N2
8a-i
Scheme 2
When the diazo derivatives 8 were allowed to react with
aromatic primary thioamides 9a,b in refluxing toluene in
the presence of 1 equivalent of CuBr for 2 hours, the cor-
responding thiazole derivatives 10a–d were obtained in
good yields (62–78%) (Scheme 3, Tables 1 and 2).
O
O
S
OR1
+
R
Ar
NH2
Apparently, this transformation takes place via the effi-
cient catalytic effect of copper(I), which generates the
corresponding carbenoids 11 from 8. These Cu-car-
benoids 11 react with the thiocarbonyl group of 9 to give
an intermediate 12, which, after cyclocondensation, af-
fords trisubstituted thiazoles 10 (Scheme 4).
N2
9a Ar = Ph
8a-c
9b Ar = 4-Me-C6H4
R
N
OR1
CuBr (1 eq.)
The use of other metals as catalysts, such as Rh2(OAc)4,
led to untreatable reaction mixtures in which the presence
of thiazoles of type 10 could only be detected in trace
amounts. CuCl also promoted the formation of the corre-
sponding thiazole derivatives 10, albeit in 10–15% lower
yields. Furthermore, the presence of an aromatic ring ad-
Ar
S
toluene / ∆ / 2 h
O
60-72%
10a-d
Scheme 3
Table 2 MS, IR and NMR Data of Thiazoles 10a–d
Product MS
m/z (%)
IR (KBr)
(cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
10a
311 ([M + 2]+, 8), 310 ([M + 1]+, 25), 2972, 1721, 1520, 1482,
309 ([M]+·, 100), 281 (18), 280 (73), 1425, 1323, 1256, 1235,
1.34 (t, J = 7, 3 H), 4.35 (q, 14.1 (q, CH3), 61.5 (t, CH2), 122.4
J = 7, 2 H), 7.5–7.55 (m, 6 (s, Carom), 126.9, 127.7, 129.0,
264 (52), 237 (70), 134 (75), 133
(74), 105 (24), 89 (89)
1139, 1084, 1018, 758,
682, 604
H), 7.85–7.90 (m, 2 H),
8.05–8.1 (m, 2 H)
129.1, 129.9, 131.1, (d, CHarom),
132.9, 134.2, 160.8, 161.6 (s, Car-
om), 169.8 (s, CO)
10b
339 ([M + 2]+, 8), 338 ([M + 1]+, 25), 3061, 3026, 2986, 2932,
337 ([M]+·, 86), 336 (14), 309 (13), 1707, 1520, 1450, 1420,
308 (100), 292 (17), 290 (19), 265 1239, 1253, 1169, 1091,
(16), 264 (80), 218 (81), 190 (18), 764, 696
160 (30), 128 (31), 116 (29), 145
1.41 (t, J = 7.2, 3 H), 3.1– 14.3 (q, CH3), 32.9, 35.4, 61.2 (t,
3.2 (m, 2 H), 3.5–3.6 (m, 2 CH2), 125.9, 126.9, 128.3, 128.5,
H), 4.38 (q, J = 7.2, 2 H),
129.0, 130.9 (d, CHarom), 133.1,
7.25–7.35 (m, 5 H), 7.5–
141.5, 162.0, 164.2 (s, Carom), 170.0
7.55 (m, 3 H), 8.0–8.05 (m, (s, CO)
2 H)
(43), 104 (55), 91 (96)
10c
10d
277 ([M + 2]+, 4), 276 ([M + 1]+, 11), 2962, 2932, 2871, 1712,
275 ([M]+·, 50), 260 (31), 248 (40), 1519, 1454, 1423, 1368,
1.05–1.1 (m, 3 H, CH3),
1.41 (t, J = 7.2, 3 H, CH3), (t, CH2), 121.7 (s, Carom), 126.8,
14.0, 14.2 (q, CH3), 22.7, 32.8, 61.1
247 (80), 246 (71), 232 (39), 230
1329, 1299, 1262, 1170,
1.75–1.95 (m, 2 H, CH2),
3.15–3.25 (m, 2 H, CH2),
4.38 (q, J = 7.2, 2 H), 7.45– CO)
7.55 (m, 3 H), 7.95–8.05
(m, 2 H)
129.2, 130.8 (d, CHarom), 133.0,
162.1, 165.4 (s, Carom), 169.8 (s,
(42), 218 (31), 202 (60), 176 (36), 1099, 1022, 765, 686
175 (100), 121 (40), 104 (74), 97
(63)
325 ([M + 2]+, 12), 324 ([M + 1]+, 3048, 2972, 2923, 1712,
40), 323 ([M]+·, 100), 295 (26), 294 1519, 1482, 1440, 1328,
(81), 278 (67), 252 (25), 251 (83), 1259, 1233, 1139, 1082,
1.34 (t, J = 7.2, 3 H), 2.45 (s, 14.1, 21.5 (q, CH3), 61.4 (t, CH2),
3 H, CH3), 4.33 (q, J = 7.2, 121.9 (s, Carom), 126.8, 127.7,
2 H), 7.25–7.30 (m, 2 H),
7.45–7.50 (m, 3 H), 7.85– 130.2, 134.3, 141.6, 161.0, 161.6
8.00 (m, 4 H) (s, Carom), 170.0 (s, CO)
129.1, 129.7, 129.9 (d, CHarom),
250 (20), 145 (19), 135 (26), 134
(82), 133 (93), 119 (28), 90 (38), 89
(93)
1018, 817, 757, 699
Synthesis 2001, No. 13, 2021–2027 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel 2-Arylthiazole-5-carboxylates
2023
O
S
O
O
O
O
CuBr
NH2
NH2
NH2
NH2
Lawesson`s
THF, r.t.
CuBr
OR1
R
OR1
R
∆ / −Ν2
N2
68%
8
11
13
14
O
O
Ar
H2N
O
S
R
OR1
NH2
Ar
S
O
OR1
9
N2
8b-h
10
S
OR1
NH
O
R
CuBr / toluene / ∆
NH
O
R
12
15
Scheme 4
R
N
CO2R1
Table 3 2-Arylthiazoles 16a–h Prepared
S
Producta
16a
R
R1
Yield (%)
Mp (°C)
100–101
93–94
38-48%
NH2
16a-h
PhCH2CH2
Pr
Et
48
42
42
47
40
41
38
44
16b
16c
Et
Scheme 5
PhCH2
i-Pr
Et
141–142
95–96
responding thiazoles 10. When aliphatic thioamides like
thioacetamide or thiourea were subjected to analogous re-
action conditions, the reaction did not result in the forma-
tion of any thiazoles. In these cases, we only could
observe the decomposition of the diazo compounds 8 to
give the parent -keto esters 7, plus the formation of stable
Cu(I) complexes of the type CuBr[RC(=S)NH2]4, which
were detected by cyclic voltammetric methods.40,41
16d
16e
Et
Me
Me
Me
Me
Me
115–116
101–102
117–118
77–78
16f
Me
16g
Chxb
i-Pr
16h
a Satisfactory microanalyses obtained: C 0.27, H 0.33, N 0.25, S
With the aim of further extending the scope of the suc-
cessful methodology developed herein toward the synthe-
sis of 2-arylthiazoles 10, we wished to use additionally
functionalised aromatic thioamides that could further en-
hance the potential introduction of a higher degree of mo-
lecular diversity. For that purpose, we initially selected
the anthranilic thioamide 14, easily available in 72% from
anthranilic amide 13 and Lawesson’s reagent. This thioa-
mide 14, once transformed into the corresponding thiaz-
ole, would enable the introduction of additional diversity
through suitable manipulations at the nitrogen atom of the
aniline moiety. Thus, when a mixture of 14 and different
-diazo- -keto esters of type 8 were prompted to react in
the presence of 1 equivalent of CuBr in refluxing toluene,
the corresponding thiazole derivatives 16a–h were also
obtained although in moderate yields (38–48%)
(Scheme 5, Tables 3 and 4).
0.29.
b Chx = cyclohexane.
The presence of an additional nitrogen atom on the aro-
matic moiety could deactivate the copper catalyst to some
extent through partial complexation, but the addition of
additional amounts of CuBr did not improve the yields.
The structural elucidation of the novel thiazole derivatives
16a–h was accomplished by the usual spectroscopic
methods, and in addition, 16b was subjected to an X-ray
crystal structure analysis, which unambiguously con-
firmed the structure (Figure).
Figure ORTEP plot42 of the molecular structure of 16b with 50%
probability ellipsoids
jacent to the thiocarbonyl group seemed to be essential in
order to drive the reaction toward the formation of the cor-
Synthesis 2001, No. 13, 2021–2027 ISSN 0039-7881 © Thieme Stuttgart · New York

2024
X. Fontrodona et al.
PAPER
Table 4 MS, IR and NMR Data of Thiazoles 16a–g
Prod-
uct
MS
m/z (%)
IR (KBr)
(cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
16a
16b
16c
354 ([M + 2]+, 8), 353 ([M + 3431, 3316, 2956, 1690, 1.42 (t, J = 7.2, 3 H), 3.10–3.15 14.3 (q, CH3), 32.4, 35.2, 61.1 (t,
1]+, 23), 352 ([M]+·, 100),
1618, 1477, 1412, 1278, (m, 2 H), 3.45–3.6 (m, 2 H),
CH2), 114.8 (s, Carom), 116.8, 117 (d,
324 (18), 323 (79), 233 (42), 1103, 735
160 (11), 120 (10), 119 (22),
118 (23), 115 (18), 91 (60),
71 (14), 65 (25)
4.38 (q, J = 7.2, 2 H), 6.11 (br s, CHarom), 119.4 (s, Carom), 125.9, 128.3,
2 H, NH2), 6.7–6.8 (m, 2 H),
7.2–7.4 (m, 6 H), 7.6–7.65 (m, 146.5, 162.1, 162.9 (s, Carom), 171.5 (s,
1 H) CO)
128.4, 129.3, 131.7 (d, CHarom), 141.3,
292 ([M + 2]+, 6), 291 ([M + 3359, 3233, 2954, 2868, 1.0–1.1 (m, 3 H), 1.4–1.45 (m, 13.9, 14.3 (q, CH3), 22.4, 32.7, 61.1 (t,
1]+, 18), 290 ([M]+·, 100),
1708, 1619, 1524, 1262, 3 H), 1.8–1.9 (m, 2 H), 3.15–
CH2), 114.9 (s, Carom), 116.9, 117.1 (d,
CHarom), 119.1 (s, Carom), 129.3, 131.7
262 (45), 261 (26), 247 (10), 1103, 734
217 (10), 190 (71), 120 (10),
119 (31), 118 (51), 71 (20),
65 (14)
3.2 (m, 2 H), 4.38 (q, J = 7, 2
H), 6.3 (br s, 2 H, NH2), 6.7–6.8 (d, CHarom), 146.5, 162.3, 164.1 (s, Car-
(m, 2 H), 7.2–7.3 (m, 1 H), 7.6– om), 171.4 (s, CO)
7.7 (m, 1 H)
340 ([M + 2]+, 6), 339 ([M + 3440, 3323, 2925, 1698, 1.43 (t, J = 7.2, 3 H), 4.41 (q, J 14.3 (q, CH3), 36.6, 61.3 (t, CH2),
1]+, 23), 338 ([M]+·, 100),
1619, 1476, 1410, 1270, = 7.2, 2 H), 4.57 (s, 2 H), 6.17 114.7 (s, Carom), 116.9, 117.1 (d,
309 (16), 292 (17), 266 (13), 1103, 1020, 728
265 (34), 148 (12), 147 (22),
(br s, 2 H, NH2), 6.7–6.75 (m, 2 CHarom), 119.6 (s, Carom), 126.2, 128.4,
H), 7.2–7.4 (m, 6 H), 7.6–7.65 129.1, 129.2, 131.8 (d, CHarom), 139.0,
146 (14), 136 (15), 118 (24),
103 (23), 102 (13), 91 (15)
(m, 1 H)
146.6, 161.6, 162.2 (s, Carom), 171.7 (s,
CO)
16d
16e
16f
292 ([M + 2]+, 4), 291 ([M + 3448, 3312, 2974, 2928, 1.3–1.5 (m, 9 H), 4.05 (sept, J = 14.3, 22.1 (q, CH3), 29.0 (d, CH), 61.1
1]+, 19), 290 ([M]+·, 100),
1688, 1619, 1525, 1474, 6.8, 1 H), 4.4 (m, q, J = 7.2, 2 (t, CH2), 115.1 (s, Carom), 117.0, 117.1
262 (12), 261 (27), 247 (16), 1405, 1316, 1267, 1148, H), 6.3 (br s, 2 H, NH2), 6.7–6.8 (d, CHarom), 117.9 (s, Carom), 129.3,
143 (13), 119 (12), 118 (27), 1112, 790, 776
99 (19), 98 (19)
(m, 2 H), 7.2–7.3 (m, 1 H),
7.65–7.7 (m, 1 H)
131.7 (d, CHarom), 146.6, 162.2, 169.3
(s, Carom), 171.6 (s, CO)
264 ([M + 2]+, 4), 263 ([M + 3477, 3442, 3303, 1692, 1.42 (t, J = 7.2, 3 H), 2.79 (s, 3 14.3, 17.5 (q, CH3), 61.1 (t, CH2),
1]+, 19), 262 ([M]+·, 100),
1614, 1490, 1473, 1373, H), 4.38 (q, J = 7.2, 2 H), 6.21 114.7 (s, Carom), 116.8, 117.0 (d,
234 (47), 216 (14), 190 (12), 1330, 1296, 1104, 768
120 (62), 119 (22), 118 (97),
(br s, 2 H, NH2), 6.7–6.8 (m, 2 CHarom), 119.1 (s, Carom), 129.2, 131.6
H), 7.2–7.25 (m, 1 H), 7.65–7.7 (d, CHarom), 146.5, 159.8, 162.3 (s, Car-
91 (19), 71 (27)
(m, 1 H)
om), 171.3 (s, CO)
250 ([M + 2]+, 17), 249 ([M 3430, 3295, 2952, 2926, 2.80 (s, 3 H, CH3), 3.93 (s, 3 H, 17.5, 52.1 (q, CH3), 114.6 (s, Carom),
+ 1]+, 73), 248 ([M]+·, 66),
154 (100), 152 (10), 149
1685, 1618, 1618, 1600, CH3), 6.26 (br s, 2 H, NH2),
1475, 1416, 1334, 1283, 6.7–6.8 (m, 2 H), 7.2–7.3 (m, 1 om), 129.3, 131.8 (d, CHarom), 146.5,
117.0, 117.1 (d, CHarom), 118.6 (s, Car-
(17), 139 (16), 138 (36), 137 1104, 738
(71), 136 (87)
H), 7.6–7.65 (m, 1 H)
160.2, 162.8 (s, Carom), 174.3 (s, CO)
16g
16h
318 ([M + 2]+, 22), 317 ([M 3366, 3260, 2922, 2846, 1.25–1.95 (m, 10 H), 3.65–3.75 26.0, 26.41, 32.4 (t, CH2), 39.0 (d,
+ 1]+, 100), 316 ([M]+·, 26), 1717, 1619, 1509, 1410, (m, 1 H), 3.91 (s, 3 H, CH3),
315 (13), 261 (11), 149 (57), 1302, 1264, 1251, 1094, 6.27 (br s, 2 H, NH2), 6.7–6.8
CH), 52.0 (q, CH3), 115.0 (s, Carom),
117.0, 117.1 (d, CHarom), 117.3 (s, Car-
om), 129.2, 131.7 (d, CHarom), 146.5,
162.5, 169.0 (s, Carom), 171.6 (s, CO)
109 (96)
734
(m, 2 H), 7.2–7.25 (m, 1 H),
7.6–7.65 (m, 1 H)
278 ([M + 2]+, 12), 277 ([M 3432, 3307, 3210, 2969, 1.37 (d, J = 3.5, 6 H), 3.9 (s, 3 22.1 (q, CH3), 28.9 (d, CH), 52.0 (q,
+ 1]+, 35), 276 ([M]+·, 100), 2932, 2870, 1688, 1619, H), 4.0–4.1 (m, 1 H), 5.88 (br s, CH3), 115.1, 117.1 (s, Carom), 117.2,
262 (18), 261 (77)
1559, 1514, 1482, 1436, 2 H), 6.7–6.8 (m, 2 H), 7.2–7.3 129.2, 131.6 (d, CHarom), 145.9 (s, Car-
1413, 1336, 1317, 1284, (m, 1 H), 7.6–7.65 (m, 1 H)
1230, 1190, 1092, 1031,
763, 740
om), 146.0 (d, CHarom), 162.4, 169.5 (s,
Carom), 171.6 (s, C=O)
Table 5 2-Arylthiazoles 17a,b and 18a,b Prepared
Finally, and just to show that our initial working hypothe-
sis regarding the introduction of further diversity through
the aniline moiety was feasible, compounds 16g and 16h
were sulfonylated with TsCl in CH2Cl2–pyridine to give
17a,b in high yields. Saponification of the ester moiety
with 1 N NaOH/MeOH afforded the corresponding car-
boxylic acids 18a,b, also in good yields (Scheme 6,
Tables 5 and 6).
Producta
17a
R
Yield (%)
Mp (°C)
152–153
139–140
228–229
237–238
Chx
i-Pr
Chx
i-Pr
69
70
94
93
17b
18a
18b
In summary, we have developed a simple methodology
that allows novel trisubstituted thiazoles 10 and 16 to be
a Satisfactory microanalyses obtained: C 0.34, H 0.29, N 0.28,
0.31.
S
Synthesis 2001, No. 13, 2021–2027 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel 2-Arylthiazole-5-carboxylates
2025
Table 6 MS, IR and NMR Data of Thiazoles 17a,b and 18a,b
Product MS m/z (%)
IR (KBr) (cm–1)
1H NMR (CDCl3/TMS) , J (Hz)
13C NMR (CDCl3/TMS)
17a
17b
18a
472 ([M + 2]+, 4), 471 ([M 2927, 2849, 1718, 1.45–1.95 (m, 10 H), 2.35 (s, 3 H), 20.5 (q, CH3), 24.9, 25.5, 31.5 (t, CH2),
+ 1]+, 9), 470 ([M]+ , 30), 1512, 1438, 1344, 3.65–3.75 (m, 1 H), 3.94 (s, 3 H),
415 (5), 402 (6), 316 (20), 1263, 1161, 1093, 7.05–7.80 (m, 8 H)
38.1 (d, CH), 51.3 (q, CH3), 118.4, 118.6
(s, Carom), 119.0, 122.5, 126.0, 127.8,
128.5, 130.9 (d, CHarom), 135.5, 136.0,
142.6, 161.0, 167.5 (s, Carom), 169.0 (s,
CO)
315 (100), 283 (20), 260
(20), 255 (12), 247 (15),
227 (6), 217 (5)
913, 812, 758,
662
432 ([M + 2]+, 9), 431
2972, 2928, 2869, 1.46 (d, J = 6.8, 6 H), 2.35 (s, 3 H), 21.4, 22.2 (q, CH3), 29.0 (d, CH), 52.3 (q,
CH3), 119.3, 119.4 (s, Carom), 119.7,
1319, 1254, 1162, 7.05–7.20 (m, 3 H), 7.35–7.40 (m, 1 123.4, 127.0, 128.8, 129.5, 131.9 (d,
([M+1]+, 17), 430 ([M]+ , 1715, 1461, 1343, 3.94 (s, 3 H), 4.00–4.10 (m, 1 H),
70), 366 (27), 276 (28),
275 (100), 260 (18), 243
(68), 215 (34), 91 (73), 65 663
(31)
1093, 920, 764,
H), 7.65–7.80 (m, 4 H)
CHarom), 136.5, 137.0, 143.6, 161.9,
169.0 (s, Carom), 170.1 (s, CO)
414 ([M – CO2 + 2]+, 3),
413 ([M – CO2 + 1]+, 6),
2926, 2852, 1706, 1.30–2.05 (m, 10 H), 2.39 (s, 3 H), 20.9 (q, CH3), 25.6, 26.0, 32.0 (t, CH2),
1633, 1520, 1345, 3.70–3.80 (m, 1 H), 7.25–7.40 (m, 3 35.7 (d, CH), 120.1, (s, Carom), 120.2 (d,
412 ([M – CO2]+, 22), 348 1302, 1263, 1161, H), 7.50–7.70 (m, 4 H), 7.90–7.95
CHarom), 121.8, (s, Carom), 124.6, 126.6,
129.3, 129.8, 132.1 (d, CHarom), 135.7,
135.8, 144.0, 162.3, 166.0 (s, Carom),
168.3 (s, CO)a
(3), 258 (19), 257 (100),
202 (10), 189 (11), 136
(5), 119 (6), 118 (5), 97
(8), 91 (21)
1093, 919, 755,
668
(m, 1 H), 12.16 (s, 1 H)a
18b
374 ([M – CO2 + 2]+, 4),
373 ([M – CO2 + 1]+, 8),
2979, 2940, 2877, 1.37 (d, J = 6.8, 6 H), 2.30 (s, 3 H), 20.9, 22.0 (q, CH3), 28.1 (d, CH), 119.8
1670, 1517, 1412, 3.95–4.05 (m, 1 H), 7.15–7.85 (m, 8 (s, Carom), 119.9 (d, CHarom), 121.6 (s, Car-
372 ([M – CO2]+, 37), 308 1320, 1270, 1159, H)
(11), 218 (15), 217 (100), 907, 760
202 (17), 201 (10), 149
om), 124.5, 126.6, 129.3, 129.9, 132.1 (d,
CHarom), 135.7, 135.8, 144.0, 162.3 (s,
Carom), 166.8 (s, CO), 168.5 (s, Carom
)
(5), 91 (16), 85 (7)
a NMR spectra were recorded in DMSO-d6.
ole derivatives 10 and 16. The easy access to the corre-
sponding starting materials 8, 9 and 14 permits the
potential introduction of a wide range of structural varia-
tions and therefore makes this method an attractive alter-
native route for the synthesis of novel thiazole derivatives
with a high degree of molecular diversity. The limitation
imposed by the fact that only aromatic thioamides can un-
dergo this type of transformation (no restrictions were
found within the diazo carbonyl ester derivatives) should
be considered as a disadvantage. Nevertheless, due to the
importance of the thiazole nucleus in medicinal chemistry
(the thiazole ring is a pharmacophore widely distributed in
many biologically active molecules43–46), the develop-
ment of new synthetic repertoires for the preparation of
novel members of this important class of heterocycles is
of current interest.
R
N
R
CO2Me
S
N
Ts-Cl
CO2Me
CH2Cl2 / Py
69-70%
S
NH
S
O
NH2
O
Me
16g R = Chx
16h R = i-Pr
17a R = Chx
17b R = i-Pr
R
N
CO2H
S
NaOH 1N
NH
S
MeOH
O
93-94%
All commercially available chemicals were used as purchased.
CH2Cl2 was dried over CaH2 and kept over activated molecular
sieves (4Å). Toluene and THF were dried over Na/benzophenone
prior to use. All reactions were run under a positive pressure of dry
N2. Melting points (capillary tube) were measured with an electro-
thermal digital melting point apparatus, IA 9100 and are uncorrect-
ed. IR spectra were recorded on a Mattson-Galaxy Satellite FT-IR
spectrometer. 1H and 13C NMR spectra were recorded at 200 and 50
MHz, respectively, on a Brucker DPX200 Advance instrument with
TMS as the internal standard. MS spectra were recorded on a VG
Quattro instrument in the positive ionisation FAB mode, using 3-
NBA or 1-thioglycerol as the matrix. Elemental analyses were per-
formed on an apparatus from Thermo instruments, model EA1110-
O
Me
18a R = Chx
18b R = i-Pr
Scheme 6
synthesized from easily available starting materials. The
method is based on the key role played by Cu(I) which
presumably catalyses the formation of intermediates 12
from carbenoids 11 and leads to the corresponding thiaz-
Synthesis 2001, No. 13, 2021–2027 ISSN 0039-7881 © Thieme Stuttgart · New York

2026
X. Fontrodona et al.
PAPER
CHNS. Analytical TLC was performed on precoated TLC plates,
silica gel 60 F254 (Merck). Flash-chromatography purifications were
performed on silica gel 60 (230–400 mesh, Merck).
orated and the residue purified by flash-chromatography (hexane–
EtOAc) to afford pure 10a–d and 16a–h (Tables 1– 4).
Crystal Data for Compound 16b47
Thioamide 9b
C15H18N2O2S, Mr = 290.38, monoclinic, space group C2/c,
a = 27.880(3), b = 4.864(4), c = 23.585(2) Å, = 109.614(8)°,
V = 3013(2) Å3, Z = 8, Dc = 1.280 g cm–3, crystal dimensions: 0.17
0.22 0.48 mm, T = –100 °C, Rigaku AFC5R diffractometer, Mo
To a solution of 4-Methylbenzonitrile (2.9 g, 25 mmol) in a mixture
of absolute EtOH (13 mL) and 25% aq NaOH (2 mL) was added
35% H2O2 (10 mL). The mixture was stirred at r.t. for 0.5 h. Addi-
tional 25% aq NaOH (2 mL) and 35% H2O2 (5 mL) were added and
the mixture stirred at r.t. for 2 h. Then 50% H2SO4, was added until
pH 3–4. EtOH was distilled off, and the resulting residue was parti-
tioned between H2O (10 mL) and EtOAc (30 mL). To the aqueous
layer, aq 25% NaOH was added until pH 7–8 and extracted with
EtOAc (30 mL). The combined organic layers were dried (MgSO4),
filtered, and evaporated to give the corresponding 4-methylbenza-
mide as a colourless solid (3.34 g, 99%), pure enough to be used in
the next step; mp 158–159 °C.
K
2
radiation, = 0.71069 Å, = 0.218 mm–1, –2 scans,
max = 55°, 3959 measured reflections of which 3471 were unique.
The intensities were corrected for Lorentz and polarization effects.
An empirical absorption correction based on -scans48 was applied.
The structure was solved by direct methods using SIR9249 and re-
fined on F by full-matrix least-squares methods using teXsan.50 The
positions of the amine H-atoms were refined isotropically, while all
other H-atoms were in calculated positions. The refinement of 189
parameters using 2161 observed reflections with I > 2 (I) gave
R1 = 0.0501, wR2 = 0.0426, S = 1.792, and max = 0.28 e Å–3.
IR (KBr): 3342, 3164, 1670, 1616, 1567, 1412, 1386, 1178, 1144,
1119, 840, 792, 728, 670, 629, 587, 528, 456 cm–1.
MS: m/z (%) = 136 ([M + 1]+, 10), 135 ([M]+·, 90), 119 (100), 92
Tosyl Thiazole Derivatives 17a,b; General Procedure
To a solution of 16g,h (0.39 mmol) in anhyd CH2Cl2 (2 mL) was
added pyridine (0.03 mL, 0.39 mmol) and a solution of p-toluene-
sulfonyl chloride (0.077g, 0.39 mmol) in anhyd CH2Cl2 (2 mL). The
mixture was stirred at r.t. for 48 h, then diluted with CH2Cl2 (10 mL)
and washed with 0.1 N HCl (3 20 mL). The separated organic lay-
er was dried (MgSO4), filtered and concentrated. The resulting
crude material was purified by flash column chromatography (hex-
ane–EtOAc, 10:1 as eluent) (Tables 5 and 6).
(12), 91 (90), 90 (10), 89 (21), 65 (45), 63 (16).
To a solution of the above 4-methylbenzamide (1 g, 7.4 mmol) in
THF (30 mL) was added the Lawesson’s reagent (1.64 g. 4.1
mmol). The mixture was stirred under N2 at r.t. for 24 h. The solvent
was evaporated, and the residue partitioned between CHCl3 (30
mL), and aq 10% NaHCO3 (30 mL). The organic layer was separat-
ed, dried (MgSO4) and filtered. The solvent was evaporated and the
resulting solid residue recrystallised from MeCN to afford pure 9b
as a yellow solid; yield: 0.81 g (72%); mp 166–167 °C.
Thiazole Carboxylic Acid Derivatives 18a,b; General
Procedure
1H NMR (200 MHz, CDCl3): = 1.64 (br s, 2 H, NH2), 2.43 (s, 3 H,
CH3), 7.2–7.3 (m, 2 Harom), 7.8–7.85 (m, 2 Harom
To a solution of 17a,b (0.5 mmol) in MeOH (1 mL) was added aq 1
N NaOH (1 mL). The mixture was stirred at r.t. for 24 h. 1 N HCl
was added until pH 3 was reached and then extracted with CH2Cl2
(3 10 mL). The organic layer was dried (MgSO4), filtered and
evaporated under reduced pressure to afford pure 18a,b as colour-
less solids (Tables 5 and 6).
)
IR (KBr): 3376, 3276, 3157, 1622, 1413, 1321, 1270, 1181, 1132,
879, 821, 791, 711, 595, 475 cm–1.
MS: m/z (%) = 153 ([M + 2]+, 8), 152 ([M + 1]+, 18), 151 ([M]+·,
83), 117 (100), 116 (65), 90 (47).
2-Aminothiobenzamide (14)
Acknowledgements
To a solution of 13 (2 g, 14.7 mmol) in THF (73 mL) was added the
Lawesson’s reagent (3.23 g. 8 mmol). The mixture was stirred un-
der N2 at r.t. for 24 h. The solvent was evaporated, and the residue
partitioned between EtOAc (50 mL), and 1 N HCl (30 mL). To the
aqueous layer was added aq sat. NaHCO3 until pH 8–9. The basic
solution extracted with EtOAc (2 30 mL). The combined organic
layers were dried (MgSO4) and filtered. The solvent was evaporated
and the resulting solid residue recrystallised from toluene to afford
pure 14 as a yellow solid; yield: 1.62 g (72%); mp 116–117 °C.
1H NMR (200 MHz, CDCl3): = 5.47 (br s, 2 H, NH2), 6.7–6.8 (m,
2 Harom), 7.2–7.4 (m, 2 Harom + NH2).
13C NMR (50 MHz, DMSO–d6): = 115.2, 116.2, (d, CHarom),
123.7 (s, Carom), 127.0, 130.8 (d, CHarom), 147.2 (s, Carom), 200.2 (s,
C=S).
Fruitful discussions with Dr. Victor Sipido (Janssen Research Foun-
dation, Belgium) are gratefully acknowledged. We are indebted to
Dirección General de Enseñanza Superior e Investigación Científi-
ca (DGESIC, Spain) through project PB98-0451, Universitat de Gi-
rona through project UdG98-452, Janssen-Cilag (Toledo),
Medichem S.A. (Barcelona) and Roviall Química S.L. (Murcia) for
generous financial support. One of us, SD, thanks Janssen-Cilag
(Toledo) for a predoctoral fellowship. Thanks are also due to Dr.
Llüisa Matas (Servei d´Análisi, Universitat de Girona) for recording
the NMR spectra and performing the microanalyses and to Dr. M.
Maestro and Dr. J. Mahía (Servicios Xerais de Apoio á Investiga-
ción, Universidade da Coruña) for recording the mass spectra.
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IR (KBr): 3409, 3286, 3070, 1650, 1604, 1582, 1489, 1454, 1410,
1328, 1287, 908, 754 cm–1.
MS: m/z (%) = 152 ([M]+·, 83), 119 (100), 118 (60), 92 (41), 91
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Synthesis 2001, No. 13, 2021–2027 ISSN 0039-7881 © Thieme Stuttgart · New York