Reactions of substituted oxazoles and thiazoles with acid chlorides: Carbon-carbon bond formation through cyclic ketene acetals

Article abstract of DOI:10.1055/s-0030-1258224

Reactions of 2,4,5-trimethyloxazole, 2,4,5-trimethylthiazole, 2-methylthiazole, and 2-ethyl-4,5-dimethylthiazole with different acid chlorides in the presence of different bases were explored. Arylvinyl esters of substituted benzoic acids containing subst

Full text of DOI:10.1055/s-0030-1258224

3384
PAPER
Reactions of Substituted Oxazoles and Thiazoles with Acid Chlorides:
Carbon–Carbon Bond Formation through Cyclic Ketene Acetals
Reactions of
S
a
ubstitute
d
O
b
xazoles and
o
T
hiazoles
w
r
ithAcid
n
Chloride
s
ie Chatterjee, Guozhong Ye, Yingquan Song, Bobby Lloyd Barker, Charles U. Pittman Jr. *
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Fax +1(662)3257611; E-mail: cpittman@chemistry.msstate.edu
Received 3 April 2010; revised 23 June 2010
O
X
Abstract: Reactions of 2,4,5-trimethyloxazole, 2,4,5-trimethylthi-
azole, 2-methylthiazole, and 2-ethyl-4,5-dimethylthiazole with dif-
ferent acid chlorides in the presence of different bases were
explored. Arylvinyl esters of substituted benzoic acids containing
substituted oxazoles or thiazoles were formed when aroyl chlorides
were used. Degrees of aroylation were different with different
bases. Reactions with alkyl acid chlorides were also explored. Most
of these reactions occurred through cyclic ketene acetal intermedi-
ates.
β
R
O
RCOCl, base
R = aryl, t-Bu
R
N
N
X
X = O, S
Scheme 2 Products obtained by reactions of 2-methyloxazoline and
2-methylthiazoline with excess of acid chlorides in the presence of a
base
Key words: carbon–carbon bond formation, oxazoles, thiazoles,
vinyl esters, in situ generated cyclic ketene acetal
O
O
O
base
R
N
X
R
N
X
N
X
– Cl–
Cyclic ketene O,O-, N,O- and -N,S-acetals have been
widely used in different cationic polymerizations1–10 and
nucleophilic reactions with various electrophiles.11–23 Cy-
clic ketene acetals are highly nucleophilic due to the pres-
ence of two electron-donating heteroatoms at one end of
the C=C bond. Resonance delocalization of lone-pair
electrons in response to electron demand enhances the
exocyclic carbon’s nucleophilicity (Scheme 1).
R
Cl
X = O, S
R = aryl, t-Bu
Scheme 3 Generation of N-acyl cyclic ketene acetals
Recently, reactions of 2-methylimidazoline, 2-methyl-
1,4,5,6-tetrahydropyrimidine, and 1,2-dimethyl-1,4,5,6-
tetrahydropyrimidine were reported to give various cyclic
and acyclic products via cyclic ketene N,N¢-acetals when
treated with aroyl chlorides in the presence of a base.27–29
Also, 2-methylimidazoline, 2-methylimidazole, and 2-
methylbenzimidazole formed both polycyclic and acyclic
products with diacid chlorides through cyclic ketene ace-
tal intermediates in the presence of a base.30,31 Thus, we
envisaged that analogous aromatic oxazoles and thiazoles
with a 2-methyl group might undergo similar reactions
with acid chlorides to those in Scheme 2.
X
Y
X
Y
X
Y
n
n
n
n = 0, 1
X, Y = NR, O, S
Scheme 1 Resonance structures of cyclic ketene acetals
Cyclic ketene acetals are readily protonated and then react
rapidly with water.4,6,13,14 Thus, they are often difficult to
isolate and use. Therefore, instead of isolating them
before use, in situ generation followed by reacting with
electrophiles is advantageous. For example, 2-methyl-
oxazolines and 2-methylthiazolines were reported to gen-
erate different N-acyl-b-keto cyclic ketene N,X-acetals
(X = O, S) with excess aroyl and 2,2-dimethylpropanoyl
chloride in the presence of a base (Scheme 2).24–26
Our intent was to react 2,4,5-trimethyloxazole and 2,4,5-
trimethylthiazole with excess aroyl chlorides and base to
generate the corresponding N-acyl-b-keto cyclic ketene
N,X-acetals (X = O, S) 2 (Scheme 4). However, the ex-
pected derivatives 2 were not formed, in sharp contrast to
what had been previously observed with 2-methyloxazo-
lines and thiazolines24,25 (Scheme 2). Instead, the
2-(oxazol-2-yl)-1-arylvinyl esters, 3a–f, from 2,4,5- tri-
methyloxazole and the corresponding 2-(thiazol-2-yl)-1-
arylvinyl esters, 4a–f, from 2,4,5-trimethylthiazole were
readily generated (Scheme 4). The reactions of these aro-
matic oxazole and thiazole derivatives must proceed
through five-membered cyclic ketene N,X-acetal (X = O,
S) intermediates formed after N-aroylation by deprotona-
tion of the aromatic (6p-electron) N-aroyl-2-methylox-
azolium (or thiazolium) chloride salts (Scheme 5). These
cyclic ketene N,X-acetals formally contain 7p electrons in
These products were reported to form through the in situ
formation of N-acyl cyclic ketene acetals (Scheme 3),
which further reacted via nucleophilic attack by the exo-
cyclic b-carbon on excess acid chloride.
SYNTHESIS 2010, No. 19, pp 3384–3394
x
x.
x
x
.
2
0
1
0
Advanced online publication: 20.08.2010
DOI: 10.1055/s-0030-1258224; Art ID: M02710SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reactions of Substituted Oxazoles and Thiazoles with Acid Chlorides
3385
O
O
their five-membered rings. Thus, the 6p-electron ring cat-
ions will lose a portion of their aromaticity upon proton
loss (Scheme 5).
O
O
Cl
Cl
NH
N
N
COOH
N
Et Et
Et
Et
Et3N, MeCN, reflux, 3 h
(reference 31)
O
O
O
O
Ar
O
N
O
N
Et
Et
Et
Cl
Cl
Ar
//
N
X
Et Et
NH
N
Et
Et3N, MeCN, reflux, 3 h
(reference 31)
O
O
2
Et3N
N
X
+
ArCOCl
Scheme 6 Reactions of 2-methylbenzimidazole and 2-methylimi-
dazole with diethylmalonyl chloride
reflux, 3 h
MeCN
O
Ar
1
azoles under these conditions (entries 15,16) and the
substituted oxazoles were recovered. The yield of 3a in
THF was lower than that in acetonitrile as illustrated by
the example in entry 1 versus entry 2 in Table 1. The high-
X = O, S
Ar
O
N
X
3a–f X = O
4a–f X = S
Table 1 Reactions of 2,4,5-Trimethyloxazole 1 (X = O) with Acid
Chlorides and Base in MeCN, THF, DMF, and DMACa
Scheme 4 Reactions of 2,4,5-trimethyloxazole with aroyl chlorides
Entry Acid chloride
Oxazole/
acid chloride (h)
(mol ratio)
Time
Product Yield
(%)b
H
H
N
H
X
H
N
H
O
O
1c
2c,d PhCOCl
PhCOCl
1: 3
1:3
1:6
1:1
1:3
1:3
1:3
1:3
1:3
1:3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
6
6
3a
3a
3a
3a
3a
54
33
68
21
64
0
base
Ar
X
Ar
3c
PhCOCl
PhCOCl
PhCOCl
PhCOCl
PhCOCl
6π–electron ring
7π–electron ring
4c
Scheme 5 Generation of nonaromatic cyclic ketene acetals
5e
2-Methylbenzoxazole and 2-methylbenzothiazole were
reported to give 2-(b-aryl-b-aryloxy)vinylbenzoxazoles
and 2-(b-aryl-b-aryloxy)vinylbenzothiazoles, respective-
ly, upon reactions with aroyl chlorides in presence of a
base.32 However, only very few examples were shown; no
mechanistic path was proposed and the analogous oxazole
and thiazole reactions (Scheme 4) have never been dem-
onstrated. We recently found that 2-methylbenzimidazole
does not form cyclic ketene N,N¢-acetal intermediates
when treated with diethylmalonyl chloride in the presence
of a base, whereas 2-methylimidazole readily generates
5,5,5,8-tetraethylimidazo[1,2,3-i,j][1,8]naphthyridine-
4,6,7,9-tetraone through cyclic ketene N,N¢-acetal inter-
mediate (Scheme 6).31 Thus, the corresponding oxazole
and thiazole reactions are of interest versus the behavior
of 2-methyl derivatives of benzoxazoles, benzothiazoles,
and benzimidazoles.
g
6c,f
7e,f
–
g
–
0
i
8c,h PhCOCl
9e,h PhCOCl
–
0
i
–
0
10c
11c
12c,j
13c
14c
15c
16k
4-ClC6H4COCl
2-MeC6H4COCl 1:3
3b
3c
3d
3e
3f
49
47
51
54
47
–
2-BrC6H4COCl
3-FC6H4COCl
1:3
1:3
4-O2NC6H4COCl 1:3
g
t-BuCOCl
1:3
1:3
–
g
MeCOCl
–
–
a The ratio of 1/base = 1:3.66.
Reactions of 2,4,5-trimethyloxazole with aroyl chlorides
with 3.66 equivalents of base (Table 1, entries 1–16) were
performed in acetonitrile, THF, DMF, and DMAC at dif-
ferent temperatures under nitrogen. Reactions in refluxing
acetonitrile generated 2-(oxazol-2-yl)-1-arylvinyl esters
of aryl carboxylic acids 3a–f in every case in moderate
yields.
b Isolated yields after column chromatography over silica gel.
c Et3N was used as the base.
d THF was used as the solvent.
e DIPEA was used as the base and the reaction was performed at
125 °C.
f DMF was used as the solvent.
g Starting oxazole recovered.
h DMAC was used as the solvent.
An X-ray crystal structure confirmed the structure of 3d
(Figure 1). Only the Z-isomers of 3a–f were formed. Ali-
phatic acid chlorides did not react with substituted ox-
i Complex product mixture.
j A crystal structure was obtained on the product.
k K2CO3 was used as the base; ratio of 1/K2CO3 = 1:3.66.
Synthesis 2010, No. 19, 3384–3394 © Thieme Stuttgart · New York

3386
S. Chatterjee et al.
PAPER
where both diisopropylethylamine (DIPEA) and triethyl-
amine were used as bases (Table 1, entries 6–9). None of
the reactions in DMA and DMAC gave the arylvinyl ester
3a. Complex mixtures of products were obtained. DMF
was reported to react with benzoyl chloride,33,34 and this
might have happened in our work.
Use of a large excess of benzoyl chloride increased the
yield of 3a to 68% (e.g., Table 1, entry 3). Substituents on
the aroyl chloride did not appear to affect the reaction and
similar yields were obtained in all reactions (entries 10–
16).
Two suggested mechanisms for this reaction are shown in
Scheme 7. This route is analogous to that described previ-
ously for the conversion of 2-methyloxazolines (and thia-
zolines)24,25 into N-acyl-b-keto cyclic ketene N,X-acetals
(Scheme 2) up to 1e. If the base deprotonates 1e to the
nonaromatic 1f, then 1f could be further converted into
1g.
Figure 1 X-ray crystal structure of compound 3d
An interesting feature of this mechanism is the loss of
aromaticity upon deprotonation of the two 6p-electron
oxazolium intermediates 1b and 1e to cyclic ketene N,O-
acetal, 7p-electron intermediates 1c and 1f, respectively.
er polarity and higher reflux temperature of acetonitrile
facilitated the reaction. Reactions were also attempted in
the highly polar, high boiling solvents, DMF and DMAC
O
Cl
H
H2C
O
O
O
NEt3
O
Cl
Ar
Ar
N
O
N
O
N
O
Ar
N
O
Ar
Ar
Cl
– Et3NH+Cl–
Cl
1
1a
aromatic
1b
aromatic
1c
aromatic
non-aromatic
O
NEt3
Ar
O
O
Cl
H
H
H
H
Ar
Ar
Ar
O
O
O
Ar
Ar
O
N
O
Ar
N
O
N
O
N
O
O
Ar
1f
non-aromatic
Cl
E-isomer
Z-isomer
1e
aromatic
1d
aromatic
Ar
H
Ar
Ar
H
Ar
NEt3
O
Cl
O
O
O
O
O
Ar
O
O
N
H
H
Ar
Ar
Ar
N
O
O
N
O
N
O
Cl
1g
aromatic
3a–f
aromatic
1e
aromatic
1h
aromatic
– Et3NH+Cl–
Ar
O
Ar
N
O
O
1g
aromatic
Scheme 7 Proposed mechanism for the formation of 3a–f
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Reactions of Substituted Oxazoles and Thiazoles with Acid Chlorides
3387
This feature is not present when either 2-methyloxazo- es of compounds might deprotonate rapidly from their 1e
lines or 2-methylthiazolines react with aroyl chlorides via analogues, because no aromaticity is lost in those cases.
cyclic ketene N,X-acetals (X = O, S) intermediates
(Scheme 3).
Intramolecular nucleophilic attack of the C-acyl carbonyl
oxygen on the N-acyl carbonyl carbon, only possible in
Initial nucleophilic acyl attack by the nitrogen of 2,4,5-tri- the E-isomer, generates zwitterionic aromatic 1g. Further,
methyloxazole on an acid chloride’s carbonyl carbon gen- opening of the six-membered ring in 1g results in the
erates zwitterionic intermediate 1a (Scheme 7). Ion pair products 3a–f. This is in contrast to 2-methyloxazoline or
1b is formed by the loss of chloride. Proton removal from thiazoline reactions where N to O aroyl transfer does not
1b by Et3N generates Et3NH+Cl– and N-acyl cyclic ketene occur.24,25 These reactions (Scheme 2) generate N-aroyl-
N,O-acetal 1c. Conversion of 1c into intermediate 1d by a b-keto cyclic ketene acetals where the rotation about the
second acylation at the b-carbon regenerates aromaticity. exo-double bond might also have a low barrier.24,25
Both nitrogen and oxygen in 1c activate the exocyclic
double bond of 1c to promote nucleophilic attack on a sec-
ond acid chloride. The high nucleophilicity of the exocy-
Reactions of 2,4,5-trimethylthiazole with aroyl chlorides
under similar conditions produced the corresponding
thiazole-based vinyl esters 4a–f (Scheme 9, R1 = H,
clic b-carbon promotes the second rapid aroylation,
explaining why 1c is not observed, even when a 1:1 sub-
strate to acid chloride is used (Table 1, entry 4). Loss of
chloride from 1d forms 1e, which might be deprotonated
by triethylamine generating 1f. The further conversion of
1f into 1g, and ultimately the Z-isomers 3a–f, requires the
E-isomer of 1f to be available. The Z-isomer is formed
with oxazolines and thiazolines (Scheme 2), so it would
likely be preferentially formed here also. A low rotational
barrier is postulated between the Z- and E-isomers of 1f,
made possible by the push-pull electronic structure which
reduces18,29,35 the exocyclic double bond’s order
(Scheme 8).
R2 = Me). For example, benzoyl chloride and 1 (X = S)
gave benzoic acid 2-(4,5-dimethylthiazol-2-yl)-1-phe-
nylvinyl ester (4a). The X-ray crystal structure of the 3-
bromobenzoyl analogue, 4d, is shown in Figure 2, con-
firming that the Z-isomer was formed. All yields in this
series were moderate.
O
O
Ar
Ar
O
O
Ar
N
O
Ar
N
O
non-aromatic
ring (Z)
aromatic
ring
Ar
O
O
O
Figure 2 X-ray crystal structure of compound 4d
N
O
N
Ar
Ar
O
2-Ethyl-4,5-dimethylthiazole produced the same type of
products 9a,b (Table 2, entries 7, 8). The X-ray crystal
structure of 9a is shown in Figure 3. Thus, an ethyl sub-
stituent at the 2-position does not affect the mechanistic
pathway. Again, the Z-isomer is exclusively formed for
4a–f and 9a,b (see Scheme 9). Reactions of 2-methylthia-
zole with aroyl chlorides and base also generated similar
Z-isomeric products 10a,b, in higher yields than the cor-
responding products from 2,4,5-trimethylthiazole.
(E)
90° rotation
angle
Scheme 8 Rotation through a push-pull electronic structure
We postulate that deprotonation of 1e to 1f might be slow
with oxazoles and thiazoles due to loss of aromaticity in
this process. Thus, 1e might react generating 1h by nu-
cleophilic attack of the carbonyl on the, now activated,
amide carbonyl carbon of 1e. Intermediate 1h would now
rapidly deprotonate to give 1g. This route establishes the
new double bond with only the Z-geometry. Ring-opening
of 1h between carbon and nitrogen must not occur prior to
deprotonation. If this happened, both the E- and Z-isomers
could form. This route offers a rational for why 3a–f form
with oxazoles and thiazoles, but the same route is not fol-
lowed by oxazolines or thiazolines. These latter two class-
Just like the case of 2,4,5-trimethyloxazole, reactions of
2,4,5-trimethylthiazole or 2-ethyl-4,5-dimethylthiazole
with the alkyl acid chlorides, 2,2-dimethylpropanoyl
chloride and acetyl chloride (Table 2, entries 12–14) re-
sulted only in the recovery of the reactants (Scheme 10).
In contrast, 2-methylthiazole reacted with 2,2-dimethyl-
propanoyl chloride in the presence of a base to form 2,2-
Synthesis 2010, No. 19, 3384–3394 © Thieme Stuttgart · New York

3388
S. Chatterjee et al.
PAPER
Table 2 Reactions of 2,4,5-Trimethylthiazole (1, X = S), 2-Ethyl-
4,5-dimethylthiazole (7), and 2-Methylthiazole (8) with Acid Chlo-
rides and Base in MeCNa
Entry Acid chloride
Thiazole/
Product Yield (%)b
acid chloride
(mol ratio)
1c
2c
3c
PhCOCl
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
4a
4b
44
48
44
43
47
46
52
46
76
62
59
–
4-ClC6H4COCl
2-MeC6H4COCl
4c
4c,d 3-BrC6H4COCl
4d
5c
6c
3-FC6H4COCl
4e
4-O2NC6H4COCl
4f
7d,e PhCOCl
9a
8e
9f
2-ClC6H4COCl
9b
Figure 3 X-ray crystal structure of compound 9a
PhCOCl
10a
10b
10c
O
Ar
N
10f
11f
12c
2-MeC6H4COCl
t-BuCOCl
R1
R1
Ar
O
Et3N
N
S + 2 ArCOCl
R2
S
g
MeCN
reflux, 3 h
t-BuCOCl
–
R2
R2
R2
13c,h MeCOCl
14e,h MeCOCl
–
–
g
1 R1 = H, R2 = Me
7 R1 = Me, R2 = Me
8 R1 = H, R2 = H
4a–f R1 = H, R2 = Me
9a,b R1 = Me, R2 = Me
10a,b R1 = H, R2 = H
g
–
–
a The ratio of 1/Et3N = 1:3.66; MeCN was used as solvent in all cases;
reflux time was 3 h in all cases.
Scheme 9 Reactions of 2,4,5-trimethylthiazole, 2-ethyl-4,5-di-
methylthiazole, and 2-methylthiazole with aroyl chlorides
b Isolated yields after column chromatography over silica gel.
c 2,4,5-Trimethylthiazole was the substrate.
d A crystal structure was obtained on the product.
e 2-Ethyl-4,5-dimethylthiazole was the substrate.
f 2-Methylthiazole was the substrate.
O
R
O
g Starting material was recovered.
h K2CO3 was used as the base, the ratio of 1/K2CO3 = 1:3.66.
N
X
Et3N
zole was quantitatively converted into its anion by
treatment with n-BuLi in THF and then reacted with aroyl
chlorides, triaroylated products were obtained. Treating
2,4,5-trimethylthiazole with n-BuLi followed by benzoyl
chloride generated benzoic acid 2-(4,5-dimethylthiazol-2-
yl)-3-oxo-1,3-diphenylpropenyl ester (11a) (Table 3, en-
try 1). 4-Chlorobenzoyl chloride gave 11b when reacted
with 2,4,5-trimethylthiazole under identical conditions.
The mole ratio of aroyl chloride to thiazole did not change
the product obtained. Tribenzoylated products were ob-
tained in lower yields at aroyl chloride/thiazole ratios of
2:1 and below without the isolation of mono- or diaroylat-
ed products (Table 3, entry 2). This observation implies
that each succeeding aroylation is faster than the preced-
ing aroylation step.
N
X
+
//
2 RCOCl
5 X = O, S
MeCN
reflux, 3 h
O
R
1 X = O,S
R
O
R = Me, t-Bu
N
X
6 X = O, S
O
R
O
Et3N
R
N
S
+
RCOCl
R = t-Bu
MeCN
reflux, 3 h
N
S
8
10c
Scheme 10 Reactions with aliphatic acid chlorides
Mechanistic studies are planned on this reaction. Finally,
triaroylation also occurred using the oxazole analogue,
2,4,5-trimethyloxazole, with n-BuLi followed by adding
benzoyl chloride under these conditions (Table 3, entry 5)
to give 12. In sharp contrast to aroyl chlorides, reacting
2,4,5-trimethylthiazole with n-BuLi followed by 2,2-di-
dimethylpropionic acid 2,2-dimethyl-1-thiazol-2-ylmeth-
ylenepropyl ester (10c) (Scheme 10) (Table 2, entry 11).
In all of these reactions, triaroylated products were never
obtained. In anticipation of obtaining a triaroylated prod-
uct, a stronger base was used. When 2,4,5-trimethylthia-
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Reactions of Substituted Oxazoles and Thiazoles with Acid Chlorides
3389
Table 3 Reactions of 2,4,5-Trimethylthiazole with Aryl and Alkyl Acid Chlorides with n-BuLi in THF
1) n-BuLi, THF, –78 °C
N
X
11a–c, 12
2) R2COCl, –78 °C to r.t.
R1
R1
X = O, S
R1 = Me, H
R
2 = aryl, alkyl
Entry
Substrate
Acid chloride
Substrate/
Product
Yield (%)
acid chloride
(mol ratio)
O
O
S
1
2
PhCOCl
PhCOCl
1:3
1:2
61
37
O
N
S
N
11a
Cl
O
O
S
3
4-ClC6H4COCl
1:3
63
O
N
S
N
Cl
Cl
11b
OH
N
t-Bu
4
t-BuCOCl
1:3
66
S
N
S
N
S
11c
O
O
O
5
PhCOCl
1:3
58
N
O
N
O
12
methylpropanoyl chloride generated 1,1-bis-(4,5-dimeth- reactions are being studied. Similar compounds have been
ylthiazol-2-yl)-2,2-dimethylpropan-1-ol (11c). Thus, reported to show insecticidal activities.36
nucleophilic attack of the 2,4,5-trimethylthiazole anion on
Possible cyclization reactions with diacid chlorides were
the acid chloride first generated the C-alkylated ketone,
explored based on previously demonstrated cyclization of
with which a second mole of anion reacted to give the Li+
2-methyloxazolines and thiazolines.26,29,30 Thus, 2,4,5-tri-
salt of the alcohol.
methylthiazole was reacted with diethylmalonyl chloride
All the aroylation reactions proceed through cyclic ketene and dimethylmalonyl chloride in the presence of a base
acetal intermediates and, unexpectedly, generated highly hoping to obtain the products shown in Scheme 11. How-
functionalized 2-(oxazol-2-yl)-1-arylvinyl esters of ben- ever, in all cases, the starting materials were recovered.
zoic acid and substituted benzoic acids and their 2-(thia- Similar reactions with 2,4,5-trimethyloxazole were also
zol-2-yl) analogues. Further applications of these unsuccessful. These cyclizations also did not occur when
the 2-methyloxazoles and thiazoles were first quantita-
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3390
S. Chatterjee et al.
PAPER
IR (neat): 3055, 2923, 1738, 1652, 1632, 1592, 1530, 1487, 1400,
1249 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (d, J = 7.6 Hz, OCOC6H4Cl
(arom ortho, 2 H), 7.46 (d, J = 7.5 Hz, OCOC6H4Cl arom meta, 2
H), 7.45 (m, C=CC6H4Cl arom ortho, 2 H), 7.28 (d, C=CC6H4Cl
O
N
R
O
R
Et3N or
n-BuLi
Cl
Cl
R
R
X
N
X
O
+
//
MeCN
reflux, 3 h
arom meta,
2 H), 6.68 (s, N=CCH=C, 1 H), 1.93 [s,
O
OC(CH3)C(CH3)N, 3 H], 1.89 [s, OC(CH3)C(CH3)N, 3 H].
X = O, S
R = Me, Et
13C NMR (75 MHz, CDCl3): d = 163.84 (OCOC6H4Cl), 155.59
(N=CCH=C), 148.54 (CH=CC6H4Cl), 143.81 (OCOC6H4Cl arom
para, Cl-bearing), 140.25 [OC(CH3)C(CH3)N], 135.71
(CH=CC6H4Cl arom para, Cl-bearing), 132.39 (CH=CC6H4Cl),
131.70 (OCOC6H4Cl arom ortho, 2 C), 129.16 (OCOC6H4Cl, 3 C),
128.96 (CH=CC6H4Cl arom meta 2 C), 127.93 (CH=CC6H4Cl arom
ortho, 2 C), 126.22 [OC(CH3)C(CH3)N], 103.68 (N=CCH=C),
11.05 [OC(CH3)C(CH3)N], 9.89 [OC(CH3)C(CH3)N].
Scheme 11 Unsuccessful reactions with dimethylmalonyl chloride
tively converted into their anions by n-BuLi and then re-
acted with these diacid chlorides.
The 1H and 13C NMR spectra were recorded on a Bruker Avance III
spectrometer operating at 300 MHz for H and 75 MHz for 13C.
1
2-Methylbenzoic Acid 2-(4,5-Dimethyloxazol-2-yl)-1-o-tolylvi-
Chemical shifts were reported in ppm downfield from TMS. CDCl3
was used as the solvent for all NMR samples. The FT-IR spectra
were recorded as films on KBr plates or on a diamond window. All
reactions were performed under N2. MeCN, THF, and Et3N were
dried by distillation over CaH2 under N2. CH2Cl2 was predried with
CaCl2 and then distilled from CaH2 under N2. DMF was predried
with anhyd MgSO4 and then distilled under reduced pressure. An-
hyd N,N-dimethylacetamide (DMAC) and all other chemicals were
obtained commercially and used as received. A mixture of dry ice
and acetone was used to achieve external bath temperature of
–78 °C. Melting points were obtained on a Mel-Temp instrument
with a heating rate of 5 °C/min and are uncorrected.
nyl Ester (3c)
Yield: 345 mg (47%); brown liquid; Rf = 0.45 (silica gel, 5:1 hex-
ane–EtOAc).
IR (KBr): 3065, 2925, 2300, 1740, 1636, 1456 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (m, OCOC6H4Me arom
ortho, 1 H), 7.53 (m, OCOC6H4Me arom para, 1 H), 7.46 (m,
OCOC6H4Me arom meta, 1 H), 7.62 (m, arom ortho and para of
C=CC6H4Me and arom ortho of both phenyl rings, 5 H), 6.34 (s,
N=CCH=C, 1 H), 2.59 (s, C=CC6H4CH3, 3 H), 2.53 (s,
OCOC6H4CH3, 3 H), 2.05 [s, OC(CH3)C(CH3)N, 6 H].
13C NMR (75 MHz, CDCl3): d = 164.78 (OCOC6H4Me), 155.83
(N=CCH=C), 151.03 (CH=CC6H4Me), 143.40 (OCOC6H4Me arom
ortho, Me-bearing), 141.17 [OC(CH3)C(CH3)N], 136.29
(CH=CC6H4Me), 135.17 (CH=CC6H4Mearom ortho, Me-bearing),
132.52 (OCOC6H4Me arom para), 131.88 (OCOC6H4Me), 131.66
(OCOC6H4Me arom ortho), 131.40 (CH=CC6H4Me arom meta),
131.02 (OCOC6H4Me arom meta), 129.31 (CH=CC6H4Me arom
para), 128.92 (CH=CC6H4Me arom ortho), 128.62 (CH=CC6H4Me
arom meta), 125.96 (OCOC6H4Me arom meta), 125.75
Benzoic Acid 2-(4,5-Dimethyloxazol-2-yl)-1-phenylvinyl Ester
(3a); Typical Procedure
To a solution of 2,4,5-trimethyloxazole [1 (X = O); 0.25 g, 2.1
mmol] in MeCN (15 mL) was added dropwise Et3N (0.784 g, 7.6
mmol). A solution of benzoyl chloride (0.903 g, 6.3 mmol) in
MeCN (15 mL) was added dropwise into the above solution under
N2 at r.t. The reaction mixture was refluxed for 3 h and then the sol-
vent was removed by rotary evaporation. Acetone (3 × 20 mL) was
added to the residue to give a solid/liquid mixture. The mixture was
filtered and the collected solid was thoroughly washed with acetone
(3 × 15mL). The filtrate was concentrated in vacuo and the residue
was purified by flash chromatography (silica gel, 5:1 hexane–
EtOAc) to give 3a (Table 1); yield: 366 mg (54%); sticky yellow
liquid; Rf = 0.6 (silica gel, 5:1 hexane–EtOAc).
[OC(CH3)C(CH3)N],
(CH=CC6H4CH3),
[OC(CH3)C(CH3)N], 9.85 [OC(CH3)C(CH3)N].
107.80
20.95
(N=CCH=C),
(OCOC6H4CH3),
21.72
11.09
2-Bromobenzoic Acid 1-(2-Bromophenyl)-2-(4,5-dimethyl-
oxazol-2-yl)vinyl Ester (3d)37
Yield: 514 mg (51%); yellow crystals; mp 92–93 °C; Rf = 0.65 (sil-
IR (KBr): 3063, 2923, 1920, 1740, 1634, 1600, 1449, 1313, 1240
cm–1.
ica gel, 5:1 hexane–EtOAc).
IR (neat): 3067, 2920, 2855, 1910, 1748, 1661, 1632, 1586, 1364
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 7.1 Hz, OCOC6H5
arom ortho, 2 H), 7.62 (m, OCOC6H5, 3 H), 7.51 (t, J = 7.7 Hz,
C=CC6H5 arom ortho, 2 H), 7.35 (m, C=CC6H5, 3 H), 6.83 (s,
N=CCH=C, 1 H), 1.99 [s, OC(CH3)C(CH3)N, 3 H], 1.89 [s,
OC(CH3)C(CH3)N, 3 H].
1H NMR (300 MHz, CDCl3): d = 8.30 (dd, J = 7.4 Hz, OCOC6H4Br
arom ortho, 1 H), 7.70 (dd, J = 7.7 Hz, OCOC6H4Br meta, next to
Br, 1 H), 7.64 (m, OCOC6H4Br arom ortho and para, 2 H), 7.40 (m,
C=CC6H4Br arom ortho, para, and meta, next to Br, 3 H), 7.23 (m,
C=CC6H4Br arom meta, 1 H), 6.55 (s, N=CCH=C, 1 H), 2.13 [s,
OC(CH3)C(CH3)N, 3 H], 2.07 [s, OC(CH3)C(CH3)N, 3 H].
13C NMR (75 MHz, CDCl3): d = 164.52 (OCOC6H5),
155.81(N=CCH=C),
149.76
(CH=CC6H5),
143.35
[OC(CH3)C(CH3)N], 133.85 (CH=CC6H5), 133.33 (OCOC6H5
arom para), 131.97 (OCOC6H5), 130.11 (OCOC6H5 arom ortho), 2
C), 129.47 (arom meta of both C6H5 groups, 4 C), 128.63
(OCOC6H5 arom para), 128.31 (OCOC6H5 arom ortho, 2 C),
124.84 [OC(CH3)C(CH3)N], 103.05 (N=CCH=C), 10.82
[OC(CH3)C(CH3)N], 9.49 [OC(CH3)C(CH3)N].
13C NMR (75 MHz,CDCl3): d = 162.80 (OCOC6H4Br), 155.07
(N=CCH=C), 148.57 (CH=CC6H4Br), 143.73 (CH=CC6H4Br),
135.78 [OC(CH3)C(CH3)N], 134.49 (OCOC6H4Br arom para),
133.54 (OCOC6H4Br), 133.13 (OCOC6H4Br arom ortho), 132.48
(OCOC6H4Br arom meta next to Br), 132.24 (CH=CC6H4Br arom
meta next to Br), 131.21 (CH=CC6H4Br arom para), 130.65
(CH=CC6H4Br arom ortho), 130.37 (OCOC6H4Br arom meta),
127.41 (OCOC6H4Br arom meta), 127.03 [OC(CH3)C(CH3)N],
122.53 (OCOC6H4Br arom ortho, Br-bearing), 121.70
(CH=CC6H4Br arom ortho, Br-bearing), 109.17 (N=CCH=C),
11.04 [OC(CH3)C(CH3)N], 9.94 [OC(CH3)C(CH3)N].
4-Chlorobenzoic Acid 1-(4-Chlorophenyl)-2-(4,5-dimethyl-
oxazol-2-yl)vinyl Ester (3b)
Yield: 403 mg (49%); white crystals; mp 123–125 °C; Rf = 0.6 (sil-
ica gel, 5:1 hexane–EtOAc).
Synthesis 2010, No. 19, 3384–3394 © Thieme Stuttgart · New York

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Reactions of Substituted Oxazoles and Thiazoles with Acid Chlorides
3391
3-Fluorobenzoic Acid 2-(4,5-Dimethyloxazol-2-yl)-1-(3-fluoro-
phenyl)vinyl Ester (3e)
Yield: 399 mg (54%); brown liquid; Rf = 0.6 (silica gel, 5:1 hexane–
EtOAc).
13C NMR (75 MHz, CDCl3): d = 163.75 (OCOC6H5), 156.84
(N=CCH=C), 148.90 [SC(CH3)C(CH3)N], 148.20 (CH=CC6H5),
133.94 (CH=CC6H5), 130.46 (OCOC6H5 arom para), 129.88
(OCOC6H5), 129.25 (OCOC6H5 arom ortho), 129.00 (OCOC6H5
arom meta), 128.79 (CH=CC6H5 arom meta), 128.18
[NC(CH3)C(CH3)S], 127.73 (CH=CC6H5 arom para), 124.74
(CH=CC6H5 arom ortho), 112.01 (N=CCH=C), 14.33
[SC(CH3)C(CH3)N], 11.23 [SC(CH3)C(CH3)N].
IR (KBr): 3076, 2937, 1733, 1661, 1591, 1455, 1416, 1380, 1273,
1224 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.05 (m, OCOC6H4F arom ortho,
1 H), 7.96 (m, OCOC6H4F arom ortho, 1 H), 7.51 (m, OCOC6H4F
arom meta, 1 H), 7.40 (m, arom ortho and meta of C=CC6H4F and
arom para of OCOC6H4F, 3 H), 7.06 (m, C=CC6H4F arom para, 1
H), 6.88 (s, N=CCH=C, 1 H), 2.02 [s, OC(CH3)C(CH3)N, 3 H], 1.96
[s, OC(CH3)C(CH3)N, 3 H].
4-Chlorobenzoic Acid 1-(4-Chlorophenyl)-2-(4,5-dimethylthia-
zol-2-yl)vinyl Ester (4b)
Yield: 378 mg (48%); yellow liquid; Rf = 0.45 (silica gel, 5:1 hex-
ane–EtOAc).
13C NMR (75 MHz, CDCl3): d = 164.55 (OCOC6H4F arom meta, F-
bearing), 163.44 (OCOC6H4F), 160.81 (CH=CC6H4F arom meta, F-
bearing), 155.40 (N=CCH=C), 148.30 (CH=CC6H4F), 143.89
[OC(CH3)C(CH3)N], 136.06 (CH=CC6H4F), 132.30 (OCOC6H4F),
131.50 (CH=CC6H4F arom meta), 131.40 (OCOC6H4F arom meta),
130.36 (OCOC6H4F arom ortho), 130.13 [OC(CH3)C(CH3)N],
126.00 (CH=CC6H4F arom ortho), 120.58 (OCOC6H4F arom para),
117.22 (OCOC6H4F arom ortho), 116.68 (CH=CC6H4F arom para),
111.76 (CH=CC6H4F arom ortho), 104.09 (N=CCH=C), 10.82
[OC(CH3)C(CH3)N], 9.63 [OC(CH3)C(CH3)N].
IR (neat): 2921, 1737, 1680, 1590, 1538, 1489, 1426, 1398, 1239,
1223, 1168 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.23 (d, J = 8.5 Hz, OCOC6H4Cl
arom ortho, 2 H), 7.56 (d, J = 8.5 Hz, OCOC6H4Cl arom meta, 2 H),
7.47 (d, J = 8.6 Hz, C=CC6H4Cl arom ortho, 2 H), 7.34 (d, J = 8.6
Hz, C=CC6H4Cl arom meta, 2 H), 6.68 (s, N=CCH=C, 1 H), 2.30
[s, SC(CH3)C(CH3)N, 3 H], 2.29 [s, SC(CH3)C(CH3)N, 3 H].
13C NMR (75 MHz, CDCl3): d = 156.17 (OCOC6H4Cl), 148.66
(N=CCH=C), 147.43 [SC(CH3)C(CH3)N], 140.78 (CH=CC6H4Cl),
135.28 (OCOC6H4Cl arom para, Cl-bearing), 132.47
(CH=CC6H4Cl arom para, Cl-bearing, 2 C), 129.24 (OCOC6H4Cl
arom ortho, 2 C), 129.13 (OCOC6H4Cl arom meta, 4 C), 128.16
(OCOC6H4Cl), 127.22 [SC(CH3)C(CH3)N], 125.96 (CH=CC6H4Cl
arom ortho, 2 C), 112.52 (N=CCH=C), 14.47 [SC(CH3)C(CH3)N],
11.34 [SC(CH3)C(CH3)N].
4-Nitrobenzoic Acid 2-(4,5-dimethyloxazol-2-yl)-1-(4-nitrophe-
nyl)vinyl Ester (3f)
Yield: 403 mg (47%); yellow solid; mp 207–209 °C; Rf = 0.45 (sil-
ica gel, 5:1 hexane–EtOAc).
IR (neat): 3113, 2923, 1733, 1625, 1594, 1522, 1410, 1341, 1245,
1121 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.42 (m, OCOC6H4NO2 arom-H,
4 H), 8.27 (m, C=CC6H4NO2 arom meta, 2 H), 7.75 (m,
C=CC6H4NO2 arom ortho, 2 H), 6.95 (s, N=CCH=C, 1 H), 2.03 [s,
OC(CH3)C(CH3)N, 3 H], 1.60 [s, OC(CH3)C(CH3)N, 3 H].
13C NMR (75 MHz,CDCl3): d = 162.64 (OCOC6H4NO2), 154.76
(OCOC6H4NO2 arom para), 151.16 (N=CCH=C), 148.07
(CH=CC6H4NO2), 146.70 (CH=CC6H4NO2 arom para), 144.47
2-Methylbenzoic Acid 2-(4,5-Dimethylthiazol-2-yl)-o-tolylvinyl
Ester (4c)
Yield: 297 mg (44%); yellow liquid; Rf = 0.65 (silica gel, 3:1 hex-
ane–EtOAc).
IR (neat): 3001, 2923, 1737, 1651, 1601, 1574, 1543, 1488, 1456,
1380, 1283, 1219, 1164 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.38 (m, OCOC6H4Me arom
ortho, 1 H), 7.50 (m, OCOC6H4Me arom para and meta, 2 H), 7.37
(m, OCOC6H4Me arom meta, 1 H), 7.23 (m, CH=CC6H4Me arom-
H, 4 H), 6.75 (s, N=CCH=C, 1 H), 2.58 [s, NC(CH3)C(CH3)S, 3 H],
2.54 (s, OCOC6H4CH3, 3 H), 2.30 (s, CH=CC6H4CH3, 3 H), 2.29 [s,
NC(CH3)C(CH3)S, 3 H].
(CH=CC6H4NO2),
139.67
[OC(CH3)C(CH3)N],
134.88
(OCOC6H4NO2), 133.50 (OCOC6H4NO2 arom ortho, 2 C), 131.62
(CH=CC6H4NO2 arom ortho, 2 C), 125.79 [OC(CH3)C(CH3)N],
124.42 (OCOC6H4NO2 arom meta), 123.98 (CH=CC6H4NO2 arom
meta), 106.60 (N=CCH=C), 11.14 (OC(CH3)C(CH3)N), 9.76
[OC(CH3)C(CH3)N].
13C NMR (75 MHz, CDCl3): d = 163.50 (OCOC6H4Me), 157.01
(N=CCH=C),
149.89
[SC(CH3)C(CH3)N],
147.88
Benzoic Acid 2-(4,5-Dimethylthiazol-2-yl)-1-phenylvinyl Ester
(4a); Typical Procedure
(CH=CC6H4Me), 142.29 (OCOC6H4Me arom ortho, Me-bearing),
140.70 (CH=CC6H4Me arom ortho, Me-bearing), 136.09
(CH=CC6H4Me), 135.08 (OCOC6H4Me arom para), 133.05
(OCOC6H4Me), 132.15 (OCOC6H4Me arom ortho), 131.65
(OCOC6H4Me arom meta), 130.89 (CH=CC6H4Me arom meta),
129.00 [SC(CH3)C(CH3)N], 128.54 (CH=CC6H4Me arom para),
127.58 (CH=CC6H4Me arom ortho), 127.48 (OCOC6H4Me arom
meta), 126.02 (CH=CC6H4Me arom meta), 115.63 (N=CCH=C),
To a solution of 2,4,5-trimethylthiazole [1 (X = S); 0.25 g, 1.9
mmol] in MeCN (15 mL) was added dropwise Et3N (0.712 g, 6.9
mmol). A solution of benzoyl chloride (0.817 g, 5.7 mmol) in
MeCN (15 mL) was added dropwise to the above solution under N2
at r.t. The reaction mixture was refluxed for 3 h and then the solvent
was removed by rotary evaporation. Acetone (3 × 20 mL) was add-
ed to the residue to give a solid/liquid mixture. The mixture was fil-
tered and the collected solid was thoroughly washed with acetone
(3 × 15 mL). The filtrate was concentrated in vacuo and the residue
was purified by flash chromatography (silica gel, 5:1 hexane–
EtOAc) to give 4a; yield: 287 mg (44%); yellow liquid; Rf = 0.40
(silica gel, 5:1 hexane–EtOAc).
22.11
(OCOC6H4CH3),
20.87
(CH=CC6H4CH3),14.38
[SC(CH3)C(CH3)N], 11.29 [SC(CH3)C(CH3)N].
3-Bromobenzoic Acid 1-(3-Bromophenyl)-2-(4,5-dimethylthia-
zole-2-yl)vinyl Ester (4d)37
Yield: 406 mg (43%); yellow crystals; mp 133–135 °C; Rf = 0.60
(silica gel, 3:1 hexane–EtOAc).
IR (KBr): 3063, 3043, 2949, 2917, 2854, 2479, 1910, 1740, 1699,
1538, 1492, 1314, 1235 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.32 (d, J = 7.8 Hz, OCOC6H5
arom ortho, 2 H), 7.69 (m, OCOC6H5 arom para, 1 H), 7.57 (m,
arom-H, 4 H), 7.35 (m, arom-H, 3 H), 7.30 (s, N=CCH=C, 1 H),
2.31 [s, NC(CH3)C(CH3)S, 3 H], 1.60 [s, NC(CH3)C(CH3)S, 3 H].
IR (neat): 3059, 2916, 1957, 1734, 1634, 1590, 1563, 1538, 1473,
1372, 1221, 1113 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.43 (s, OCOC6H4Br arom ortho,
next to Br, 1 H), 8.25 (s, OCOC6H4Br arom ortho, 1 H), 7.83 (m,
OCOC6H4Br arom para, 1 H), 7.69 (m, CH=CC6H4Br arom ortho,
Synthesis 2010, No. 19, 3384–3394 © Thieme Stuttgart · New York

3392
S. Chatterjee et al.
PAPER
next to Br, 1 H), 7.48 (m, arom-H, 3 H), 7.25 (m, arom-H and
CH=CC6H4Br, 2 H), 2.30 [s, NC(CH3)C(CH3)S, 6 H].
1H NMR (300 MHz, CDCl3): d = 8.21 (m, OCOC6H5 arom ortho, 2
H), 7.63 (m, OCOC6H5 arom para, 1 H), 7.54 (m, arom-H of two
aryl groups, 4 H), 7.37 (m, arom-H of two aryl groups, 3 H), 2.38
[d, J = 5.8 Hz, SC(CH3)C(CH3)N, 3 H], 2.30 [d, J = 5.5 Hz,
SC(CH3)C(CH3)N, 3 H], 2.26 [d, J = 5.5 Hz, N=CC(CH3)=C, 3 H].
13C NMR (75 MHz, CDCl3): d = 164.34 (OCOC6H5), 159.03
(N=CCH=C), 147.53 [SC(CH3)C(CH3)N], 145.64 (CH=CC6H5),
135.52 (CH=CC6H5), 133.62 (OCOC6H5 arom para), 130.43
13C NMR (75 MHz, CDCl3): d = 162.50 (OCOC6H4Br), 156.08
(N=CCH=C), 148.70 [SC(CH3)C(CH3)N], 146.95 (CH=CC6H4Br),
137.12 (CH=CC6H4Br), 136.01 (OCOC6H4Br arom para), 133.39
(OCOC6H4Br arom ortho, next to Br), 132.31 (OCOC6H4Br),
130.68 (CH=CC6H4Br arom para), 130.42 (OCOC6H4Br arom me-
ta), 130.39 (CH=CC6H4Br arom meta), 129.07 (CH=CC6H4Br arom
ortho, next to Br), 128.49 (OCOC6H4Br arom ortho), 127.76
[SC(CH3)C(CH3)N], 123.38 (CH=CC6H4Br aromatic ortho),
123.10 (OCOC6H4Br, Br-bearing), 122.91(CH=CC6H4Br, Br-
bearing), 112.99 (N=CCH=C), 14.36 [SC(CH3)C(CH3)N], 11.37
[SC(CH3)C(CH3)N].
(OCOC6H5), 129.60 (OCOC6H5 arom ortho,
2 C), 128.97
(OCOC6H5 arom meta, 2 C), 128.66 (CH=CC6H5 arom meta, 2 C),
128.56 [SC(CH3)C(CH3)N], 128.16 (CH=CC6H5 arom para),
127.35 (CH=CC6H5 arom ortho, 2 C), 120.39 [N=CC(CH3)=C],
14.5 [N=CC(CH3)=C], 14.68 [SC(CH3)C(CH3)N], 11.16
[SC(CH3)C(CH3)N].
3-Fluorobenzoic Acid 2-(4,5-Dimethylthiazol-2-yl)-1-(3-fluoro-
phenyl)vinyl Ester (4e)
Yield: 337 mg (47%); white crystals; mp 102–103 °C; Rf = 0.6 (sil-
2-Chlorobenzoic Acid 1-(2-Chlorophenyl)-2-(4,5-dimethylthia-
zol-2-yl)propenyl Ester (9b)
ica gel, 5:1 hexane–EtOAc).
Yield: 331 mg (46%); white crystals; mp 139–140 °C; Rf = 0.60
(silica gel, 5:1 hexane–EtOAc).
IR (neat): 2922, 1750, 1653, 1590, 1544, 1470, 1377, 1271 cm–1.
IR (KBr): 2976, 1730, 1586, 1538, 1482, 1445, 1333, 1253, 1230
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.11 (m, OCOC6H4F arom ortho,
1 H), 7.98 (m, OCOC6H4F arom ortho, 1 H), 7.57 (m, OCOC6H4F
arom meta), 1 H), 7.40 (m, arom ortho and meta of C=CC6H4F and
arom para of OCOC6H4CF, 3 H), 7.23 (m, C=CC6H4F arom para,
1 H), 7.05 (s, N=CCH=C, 1 H), 2.30 [s, SC(CH3)C(CH3)N, 6 H].
1H NMR (300 MHz, CDCl3): d = 8.19 (d, J = 7.5 Hz, OCOC6H5
arom ortho, 1 H), 7.67 (m, OCOC6H5 arom para, 1 H), 7.40 (m,
arom-H of two aryl groups,
7 H), 2.31 [d, J = 5.8 Hz,
SC(CH3)C(CH3)N, 3 H], 2.29 [d, J = 5.8 Hz, SC(CH3)C(CH3)N, 3
H], 2.16 [N=CC(CH3)=C, 3 H].
13C NMR (75 MHz, CDCl3): d = 164.59 (OCOC6H4F), 162.70
(OCOC6H4F arom meta, F-bearing), 161.32 (CH=CC6H4F arom
13C NMR (75 MHz, CDCl3): d = 152.28 (OCOC6H5), 147.81
(N=CCH=C), 142.60 [SC(CH3)C(CH3)N], 142.58 (CH=CC6H5),
134.97 (OCOC6H4Cl arom ortho, Cl-bearing), 134.05
(CH=CC6H4Cl), 133.68 (OCOC6H4Cl arom para), 133.41
(CH=CC6H4Cl arom ortho, Cl-bearing), 132.92 (OCOC6H4Cl arom
ortho), 132.82 (OCOC6H5), 131.45 (CH=CC6H4Cl arom para),
130.27 (OCOC6H5 meta position, next to Cl), 129.72 (CH=CC6H5
meta position, next to Cl), 127.82 [SC(CH3)C(CH3)N], 126.71
(CH=CC6H5 arom ortho), 126.68 (OCOC6H4Cl arom meta), 126.53
(CH=CC6H5 arom meta), 122.73 [N=CC(CH3)=C], 16.81
meta,
F-bearing),
156.06
(N=CCH=C),
148.67
[SC(CH3)C(CH3)N], 147.17 (CH=CC6H4F), 136.21 (CH=CC6H4F),
130.77 (OCOC6H4F), 130.59 (OCOC6H4F arom meta), 128.42
(CH=CC6H4F arom meta), 126.27 [SC(CH3)C(CH3)N], 126.23
(OCOC6H4F arom ortho), 121.43 (CH=CC6H4F arom ortho),
120.44 (OCOC6H4F arom para), 117.45 (OCOC6H4F arom ortho),
116.10 (CH=CC6H4F arom para), 112.97 (CH=CC6H4F arom
ortho), 111.88 (N=CCH=C), 14.35 [SC(CH3)C(CH3)N], 11.29
[SC(CH3)C(CH3)N].
[N=CC(CH3)=C],
14.68
[SC(CH3)C(CH3)N],
11.20
[SC(CH3)C(CH3)N].
4-Nitrobenzoic Acid 2-(4,5-Dimethylthiazol-2-yl)-1-(4-nitro-
phenyl)vinyl Ester (4f)
Yield: 376 mg (46%); yellow solid; mp 218–220 °C; Rf = 0.7 (silica
gel, 1:1 hexane–EtOAc).
Benzoic Acid 1-Phenyl-2-thiazol-2-ylvinyl Ester (10a)
Yield: 579 mg (76%); yellowish white crystals; mp 82–83 °C;
Rf = 0.65 (silica gel, 5:1 hexane–EtOAc).
IR (neat): 3114, 2980, 1741, 1686, 1597, 1526, 1428, 1374, 1311,
1228, 1079 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.49 (m, OCOC6H4NO2 arom-H,
4 H), 8.28 (m, C=CC6H4NO2 arom meta, 2 H), 7.73 (m,
C=CC6H4NO2 arom ortho, 2 H), 7.44 (s, N=CCH=C, 1 H), 2.32 [s,
SC(CH3)C(CH3)N, 3 H], 1.60 [s, SC(CH3)C(CH3)N, 3 H].
13C NMR (75 MHz,CDCl3): d = 163.19 (OCOC6H4NO2), 150.00
(OCOC6H4NO2 arom para), 149.81 (N=CCH=C), 138.92
(CH=CC6H4NO2), 131.67 (CH=CC6H4NO2 arom para), 131.26
IR (neat): 3062, 1735, 1642, 1598, 1474, 1448, 1226 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.32 (d, J = 7.3 Hz, OCOC6H5
arom ortho, 2 H), 7.78 (s, SCHCHN), 7.61 (arom-H and thiazole
ring H, 5 H), 7.31 (arom-H), 7.16 (s, N=CCH=C, 1 H).
13C NMR (75 MHz, CDCl3): d = 163.35 (OCOC6H5), 160.95
(N=CCH=C), 149.76 (CH=CC6H5), 142.47 (SCHCHN), 133.87
(CH=CC6H5), 133.42 (OCOC6H5 arom para), 130.13 (OCOC6H5),
129.31 (OCOC6H5 arom ortho, 2 C), 128.56 (arom meta of both
rings, 4 C), 128.42 (CH=CC6H5 arom para), 124.56 (CH=CC6H5
arom ortho, 2 C), 119.46 (SCHCHN), 111.72 (N=CCH=C).
(CH=CC6H4NO2),
130.63
[SC(CH3)C(CH3)N],
125.41
(OCOC6H4NO2), 124.27 (OCOC6H4NO2 arom ortho, 2 C), 124.04
(CH=CC6H4NO2 arom ortho), 2 C), 123.75 [SC(CH3)C(CH3)N],
123.20 (OCOC6H4NO2 arom meta), 121.99 (CH=CC6H4NO2 arom
meta), 104.55 (N=CCH=C), 11.82 [OC(CH3)C(CH3)N], 10.78
[SC(CH3)C(CH3)N].
2-Methylbenzoic Acid 2-Thiazol-2-yl-1-o-tolylvinyl Ester (10b)
Yield: 518 mg (62%); yellowish liquid; Rf = 0.60 (silica gel, 5:1
hexane–EtOAc).
IR (neat): 2927, 1738, 1653, 1574, 1488, 1381, 1218, 1033 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 7.7 Hz, OCOC6H4Me
arom ortho), 7.81(d, J = 3.2 Hz, SCHCHN, 1 H), 7.23 (m, arom-H
and thiazole ring H, 8 H), 6.91(s, N=CCH=C, 1 H), 2.65 (s,
CH3C6H4, 6 H).
Benzoic Acid 2-(4,5-Dimethylthiazol-2-yl)-1-phenylpropenyl
Ester (9a)37
Yield: 312 mg (52%); white crystals; mp 129–131 °C; Rf = 0.65
(silica gel, 5:1 hexane–EtOAc).
13C NMR (75 MHz, CDCl3): d = 163.23 (OCOC6H4Me), 151.12
(N=CCH=C), 142.33 (CH=CC6H4Me), 142.21 (SCHCHN), 135.97
(OCOC6H4Me arom ortho, Me-bearing), 134.75 (CH=CC6H4Me),
IR (neat): 3071, 2920, 1979, 1734, 1682, 1583, 1451, 1323, 1246
cm–1.
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PAPER
Reactions of Substituted Oxazoles and Thiazoles with Acid Chlorides
3393
133.12 (CH=CC6H4Me arom ortho, Me-bearing), 132.11
(OCOC6H4Me arom para), 131.50 (OCOC6H4Me), 130.83
(OCOC6H4Me arom ortho), 129.16 (arom meta of both rings, 2 C),
128.53 (CH=CC6H4Me arom para), 127.27 (CH=CC6H4Me arom
ortho), 125.95 (OCOC6H4Me arom meta), 125.90 (CH=CC6H4Me
arom meta), 119.51 (SCHCHN), 115.44 (N=CCH=C), 22.00
(CH=CC6H4CH3), 20.78 (OCOC6H4CH3).
ortho, 2 H), 7.54 (d, J = 8.58 Hz, OCOC6H4Cl arom meta, 2 H),
7.35 (m, N=CCCOC6H4Cl arom meta and C=CC6H4Cl arom meta,
4 H), 7.17 (d, J = 8.58 Hz, C=CC6H4Cl arom ortho, 2 H), 2.26 [s,
NC(CH3)C(CH3)S, 3 H], 2.08 [s, NC(CH3)C(CH3)S, 3 H].
13C NMR (75 MHz, CDCl3): d = 192.39 (N=CCCOC6H4Cl), 163.61
(OCOC6H4Cl), 154.52 (C=CC6H4Cl), 149.36 (N=CC=C), 146.29
[SC(CH3)C(CH3)N], 140.82 (N=CCCOC6H4Cl arom para, Cl-
bearing), 140.14 (OCOC6H4Cl arom para, Cl-bearing), 136.01
(N=CCCOC6H4Cl), 135.09 (C=CC6H4Cl arom para, Cl-bearing),
132.20 (C=CC6H4Cl), 131.89 (OCOC6H4Cl arom ortho), 2 C),
2,2-Dimethylpropionic Acid 2,2-Dimethyl-1-thiazol-2-ylmeth-
ylenepropyl Ester (10c)
Yield: 389 mg (59%); yellowish liquid; Rf = 0.75 (silica gel, 5:1
hexane–EtOAc).
IR (neat): 2970, 1751, 1648, 1479, 1394, 1264, 1091 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71 (s, SCHCHN, 1 H), 7.22 (s,
SCHCHN, 1 H), 6.59 (N=CCH=C, 1 H), 1.39 [s, OCOC(CH3)3, 9
H], 1.19 [s, CH=CC(CH3)3, 9 H].
131.18 (N=CCCOC6H4Cl arom ortho,
2
C), 129.31
(N=CCCOC6H4Cl arom meta, 2 C), 129.22 (OCOC6H4Cl arom
meta), 129.05 (C=CC6H4Cl arom meta, 2 C), 128.90 (OCOC6H4Cl),
128.59 [SC(CH3)C(CH3)N], 127.32 (C=CC6H4Cl arom ortho, 2 C),
125.39
(N=CC=C),
14.46
[SC(CH3)C(CH3)N],
11.12
[SC(CH3)C(CH3)N].
13C NMR (75 MHz, CDCl3): d = 174.83 [OCOC(CH3)3], 161.50
[CH=CC(CH3)3], 159.35 (N=CCH=C), 142.15 (SCHCHN), 118.05
(SCHCHN), 108.39 (N=CCH=C), 39.24 [OCOC(CH3)3], 37.29
[CH=CC(CH3)3], 27.73 [OCOC(CH3)3], 27.27 [CH=CC(CH3)3].
1,1-Bis(4,5-dimethylthiazol-2-yl)-2,2-dimethylpropan-1-ol
(11c)
Yield: 221 mg (66%); yellowish white crystals; mp 46–47 °C;
Rf = 0.60 (silica gel, 5:1 hexane–EtOAc).
IR (neat): 3316, 2959, 2921, 1558, 1469, 1307, 1259, 1179, 908
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.43 (s, OH, 1 H), 3.15 (s, CH2,
4 H), 2.23 [s, NC(CH3)C(CH3)S, 6 H], 2.16 [s, SC(CH3)C(CH3)N,
6 H], 0.99 [s, C(CH3)3 9 H].
13C NMR (75 MHz, CDCl3): d = 163.72 (N=CCH2, 2 C), 146.47
[SC(CH3)C(CH3)N, 2 C], 125.32 [SC(CH3)C(CH3)N, 2 C], 39.21
(COH), 37.71 (CCH3), 25.79 (CCH2, 2 C), 14.27 (CCH3, 3 C),
10.93 (=CCH3, 4 C).
Benzoic Acid 2-(4,5-Dimethylthiazol-2-yl)-3-oxo-1,3-diphenyl-
propenyl Ester (11a); Typical Procedure
A 2.5 M solution of n-BuLi in hexanes (1.1 mL, 2.7 mmol) was add-
ed using a syringe to a solution of 2,4,5-trimethylthiazole [1 (X =
S); 0.25g, 1.9 mmol] in THF (20 mL) at –78 °C under N2. The reac-
tion mixture turned yellow. The mixture was stirred at –78 °C for 1
h and then benzoyl chloride (0.817 g, 5.7 mmol) was added with a
syringe. The mixture was stirred for another 1 h and then warmed
gradually to r.t. The mixture was further stirred for another 3 h at r.t.
and then the solvent was removed by rotary evaporation. H2O (20
mL) was added to the residue followed by the extraction with
CH2Cl2 (3 × 40 mL). The organic layer was washed with 10% aq
NaHCO3 (2 × 20 mL) and H2O (2 × 20 mL), and dried (Na2SO4).
The solvent was removed by rotary evaporation and the residue was
purified by flash chromatography (silica gel, 5:1 hexane–EtOAc) to
give 11a; yield: 520 mg (61%); yellowish liquid; Rf = 0.45 (silica
gel, 5:1 hexane–EtOAc).
Benzoic Acid 2-(4,5-Dimethyloxazol-2-yl)-3-oxo-1,3-diphenyl-
propenyl Ester (12)
Yield: 522 mg (58%); yellow liquid; Rf = 0.40 (silica gel, 5:1 hex-
ane–EtOAc).
IR (neat): 2981, 1737, 1675, 1580, 1449, 1357, 1221 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24 (d, J = 8.26 Hz, OCOC6H5
arom ortho, 2 H), 8.12 (d, J = 8.21 Hz, N=CCCOC6H5 arom ortho,
2 H), 7.50 (m, arom-H, 8 H), 7.15 (m, arom-H, 3 H), 1.87 [s,
NC(CH3)C(CH3)S, 3 H], 1.83 [s, NC(CH3)C(CH3)S, 3 H].
13C NMR (75 MHz, CDCl3): d = 192.35 (N=CCCOC6H5), 165.21
(OCOC6H5), 154.36 (C=CC6H5), 149.64 (N=CC=C), 143.64
[OC(CH3)C(CH3)N], 136.30 (N=CCCOC6H5), 133.70 (C=CC6H5),
133.58 (N=CCCOC6H5 arom para), 133.53 (OCOC6H5 arom para),
132.31 (OCOC6H5), 130.15 (OCOC6H5 arom ortho, 2 C), 129.93
(N=CCCOC6H5 arom ortho, 2 C), 129.85 (N=CCCOC6H5 arom
meta, 2 C), 129.27 (C=CC6H5 arom meta and OCOC6H5 arom meta,
4 C), 128.41 (C=CC6H5 arom para), 128.25 (C=CC6H5 arom ortho,
2 C), 128.06 [OC(CH3)C(CH3)N], 118.78 (N=CC=C), 10.88
[OC(CH3)C(CH3)N], 9.46 [OC(CH3)C(CH3)N].
IR (neat): 2922, 1739, 1678, 1596, 1492, 1322, 1220 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.27 (d, J = 7.5 Hz, OCOC6H5
arom ortho, 2 H), 8.07 (d, J = 7.4 Hz, N=CCCOC6H5 arom ortho, 2
H), 7.67 (m, OCOC6H5 arom para, 1 H), 7.55 (m, OCOC6H5 arom
meta, 2 H), 7.43 (m, N=CCCOC6H5 arom meta and para, 3 H), 7.35
(m, C=CC6H5 arom ortho, 2 H), 7.16 (C=CC6H5 arom ortho and
para,
3 H), 2.22 [s, NC(CH3)C(CH3)S, 3 H], 2.07 [s,
NC(CH3)C(CH3)S, 3 H].
13C NMR (75 MHz, CDCl3): d = 193.85 (N=CCCOC6H5), 164.39
(OCOC6H5), 155.21 (C=CC6H5), 148.96 (N=CC=C), 147.75
[SC(CH3)C(CH3)N], 136.95 (N=CCCOC6H5), 133.99 (C=CC6H5),
133.94 (N=CCCOC6H5 arom para), 133.31 (OCOC6H5 arom para),
130.51 (OCOC6H5), 129.83 (OCOC6H5 arom ortho, 2 C), 129.63
(N=CCCOC6H5 arom ortho, 2 C), 129.14 (N=CCCOC6H5 arom
meta, 2 C), 128.70 (C=CC6H5 arom meta, 2 C), 128.44
[SC(CH3)C(CH3)N], 128.36 (OCOC6H5 arom meta, 2 C), 127.98
(C=CC6H5 arom para), 127.71 (C=CC6H5 arom ortho, 2 C), 125.71
(N=CC=C), 14.42 [SC(CH3)C(CH3)N], 11.02 [SC(CH3)C(CH3)N].
Acknowledgment
The authors acknowledge the educational and general funds of
Mississippi State University for partial financial support of this
work.
4-Chlorobenzoic Acid 1,3-Bis(4-chlorophenyl)-2-(4,5-dimeth-
ylthiazol-2-yl)-3-oxopropenyl Ester (11b)
Yield: 650 mg (63%); yellow crystals; mp 217–219 °C; Rf = 0.35
(silica gel, 5:1 hexane–EtOAc).
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Synthesis 2010, No. 19, 3384–3394 © Thieme Stuttgart · New York

3394
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Synthesis 2010, No. 19, 3384–3394 © Thieme Stuttgart · New York