Reactions of keto-enol tautomers of 2-thiazolyl-, 2-oxazolyl-, 2-benzoxazolyl-, or 2-benzothiazolyl-1-phenylethenols with α,β- alkynyl esters: Syntheses of highly functionalized fused-ring heterocycles

Article abstract of DOI:10.1055/s-0032-1316790

2-Methyl-1,3-thiazole, 2,4-dimethyl-1,3-thiazole, 2,4,5-trimethyl-1,3- thiazole, 2,4,5-trimethyl-1,3-oxazole, 2-methyl-1,3-benzoxazole and 2-methyl-1,3-benzothiazole were each treated with benzoyl chloride in acetonitrile containing triethylamine to give

Full text of DOI:10.1055/s-0032-1316790

PAPER
▌3337
paper
Reactions of Keto–Enol Tautomers of 2-Thiazolyl-, 2-Oxazolyl-, 2-Benz-
oxazolyl-, or 2-Benzothiazolyl-1-phenylethenols with α,β-Alkynyl Esters:
Syntheses of Highly Functionalized Fused-Ring Heterocycles
Highly Functionalized Fused-Ring Heterocycles
Hondamuni I. De Silva,* William P. Henry, Charles U. Pittman, Jr*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Fax +1(662)3251618; E-mail: cpittman@chemistry.msstate.edu; E-mail: hicdesilva@gmail.com
Received: 03.07.2012; Accepted after revision: 10.09.2012
O
O
Ph
N
Abstract: 2-Methyl-1,3-thiazole, 2,4-dimethyl-1,3-thiazole, 2,4,5-
trimethyl-1,3-thiazole, 2,4,5-trimethyl-1,3-oxazole, 2-methyl-1,3-
benzoxazole and 2-methyl-1,3-benzothiazole were each treated
with benzoyl chloride in acetonitrile containing triethylamine to
give the corresponding (Z)-2-(heterocyclic)-1-phenylvinyl benzo-
ates. Base hydrolysis of these vinyl benzoates gave the correspond-
ing 2-(heterocyclic)-1-phenylethenols, which exist in both keto and
enol tautomeric forms. These tautomers were used as starting mate-
rials for the syntheses of fused-ring heterocycles. The reactivity of
the keto–enol tautomers depends on the nature of the heteroatom
and the substituents that are present on the ring. Each tautomeric
pair reacts with dimethyl acetylenedicarboxylate (DMAD) in meth-
anol to give the 5,6-ring-fused 8-benzoyl-5-oxo-5H-thiazolo- and
Ph
Cl
H
X
Ph
O
MeCN, Et3N
reflux
N
X
R
R
R
R
1: X = S; R = H
2: X = S; R = Me
3: X = O; R = Me
4: X = S; R = H
5: X = S; R = Me
6: X = O; R = Me
Scheme 1 Reactions of heterocycles 1–3 with benzoyl chloride5
phenylethenols (11a), which exists in both keto and enol
tautomeric forms 11a and 11b, respectively (Scheme 2).7
The 5,6-ring-fused products 12 and 13 were obtained
when the tautomeric pair was treated with methyl propio-
late or dimethyl acetylenedicarboxylate (DMAD), respec-
tively (Scheme 2).7
8-benzoyl-5-oxo-5H-oxazolopyridinecarboxylate,
4-benzoyl-1-
oxo-1H-pyrido[2,1-b]benzoxazolecarboxylate and 4-benzoyl-1-
oxo-1H-pyrido[2,1-b]benzothiazolecarboxylate derivatives. Two
novel 5,7-ring-fused compounds, tetramethyl 9-benzoyl-2,3-di-
methyl-5,6-dihydrothiazolo[3,2-a]azepine-5,6,7,8-tetracarboxylate
and its oxazole analogue, were also obtained when the tautomers
formed from 2,4,5-trimethyl-1,3-thiazole and 2,4,5-trimethyl-1,3-
oxazole, respectively, were treated with DMAD. Reactions of the
tautomers with methyl propiolate did not, however, give satisfacto-
ry results.
Ph
O
O
Ph
O
PhCOCl, Et3N
MeCN
concd HCl, reflux
NaHCO3
HN
N
Ph
10
N
N
Key words: tautomerism, heterocycles, polycycles, Michael addi-
tions, cyclocondensations
9
Ph
R
O
Ph
H
O
HO
R
CO2Me
Ph
O
MeOH, r.t., 24 h
Derivatives of thiazole, oxazole, benzoxazole, and benzo-
thiazole form an important class of heterocyclic units that
are found in antiviral, antifungal, antibacterial, anti-in-
flammatory, and anticancer agents.1–4 This wide range of
biological activities justifies the syntheses of novel het-
erocyclic compounds that contain such ring structures.
HN
N
N
NH
HN
11b
N
11a
12: R = H
13: R = CO2Me
Scheme 2 Synthesis of 5,6-ring-fused products 12 and 137
We hypothesized that hydrolysis of (Z)-2-(heterocyclic)-
1-phenylvinyl benzoates of thiazoles, oxazoles, benzoxa-
zoles, or benzothiazoles followed by reaction of the resul-
tant 2-(heterocyclic)-1-phenylethenols with α,β-alkynyl
esters might give highly functionalized fused-ring hetero-
cycles, in a similar manner to the syntheses of 12 and 13
(Scheme 2). In this manner, we were able to prepare six
novel 5,6-ring-fused and two novel 5,7-ring-fused com-
pounds.
We have previously reported reactions of 2-methyl-1,3-
thiazole (1), 2,4,5-trimethyl-1,3-thiazole (2), and 2,4,5-
trimethyl-1,3-oxazole (3) with benzoyl chlorides in the
presence of a base to give the corresponding (Z)-2-(het-
erocyclic)-1-phenylvinyl benzoates 4–6 (Scheme 1).5 2-
Methyl-1,3-benzoxazole (7) and 2-methyl-1,3-benzothia-
zole (8) have also been reported to give similar vinyl ben-
zoates.6
Acid hydrolysis of (Z)-2-(1-benzoyl-1H-imidazol-2-yl)-
1-phenylvinyl benzoate (10), prepared from 2-methyl-
1H-imidazole (9), gave (Z)-2-(1H-imidazol-2-yl)-1-
Treatment of 2-methyl-1,3-thiazole (1), 2,4-dimethyl-1,3-
thiazole (14), 2,4,5-trimethyl-1,3-thiazole (2), 2,4,5-tri-
methyl-1,3-oxazole (3), 2-methyl-1,3-benzoxazole (7), or
2-methyl-1,3-benzothiazole (8) with benzoyl chloride in
the presence of triethylamine in refluxing acetonitrile
gave the corresponding (Z)-2-(heterocyclic)-1-phenylvi-
nyl benzoates 4–6 and 15–17 (shown in Table 1). Com-
SYNTHESIS 2012, 44, 3337–3352
Advanced online publication: 09.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316790; Art ID: SS-2012-M0562-OP
© Georg Thieme Verlag Stuttgart · New York

3338
H. I. De Silva et al.
PAPER
pounds 4–6, 16, and 17 followed from our earlier work,5
and the new preparation of 15 from thiazole 14 provided
a sixth model vinyl benzoate.
Table 1 Keto–Enol Tautomeric Ratios of 18a,b–23a,b in Chloro-
form-d1 Solution at 20 °C, and Their Isolated Yields
Entrya Substrate
Product
Enol/ Yield
keto
(%)c
Benzoates 4–6 and 15–17 (Table 1) were hydrolyzed with
a solution of potassium hydroxide in anhydrous methanol
to give the equilibrated 2-(heterocyclic)-1-phenylethenols
18a–23a and their corresponding keto tautomers 18b–23b
in good yields.8 All the hydrolyzed products showed two
ratiob
Ph
N
Ph
HO
O
Ph
H
H
S
H
S
H
S
O
Ph
O
1
sets of resonances in their H and 13C NMR spectra in
1
2
1:2.0 90
N
N
4
chloroform-d1 at 20 °C. The presence of a methylene pro-
ton and the 13C signals at δ = 4.38–4.81 and 43.81–38.81
ppm confirmed that each hydrolyzed product contained
the appropriate keto tautomer 18b–23b. This was further
confirmed by the presence of distinct carbonyl carbon sig-
nals between δ = 192.38 and δ = 194.79 ppm. Vinyl proton
signals of the enol forms (δ = 5.98–6.35 ppm) were also
observed for each hydrolyzed product. The 1H NMR spec-
tra of the hydrolyzed products of 4, 5, 15, 16, and 17 each
showed a broad downfield signal (δ = 12.62–13.91 ppm)
from the strong intramolecularly hydrogen-bonded enol
hydroxy proton, except in the case of the hydrolyzed prod-
uct from 6. Hydrolysis of 4, 15, 5, and 6 afforded the keto
forms 18b–21b, respectively, as the major tautomers (Ta-
ble 1, entries 1–4). In contrast, hydrolysis of the benzoxa-
zole and benzothiazole derivatives 16 and 17 gave the
corresponding enol forms 22a and 23a as the major tauto-
mers.
18a
18b
O
Ph
Ph
Ph
H
S
H
H
S
H
S
Ph
O
O
HO
1:1.32 67
N
N
N
15
19a
19b
O
Ph
Ph
Ph
H
S
H
H
S
H
S
Ph
O
O
HO
3
4
1:1.41 85
N
N
N
5
20a
20b
O
Ph
Ph
Ph
H
O
H
H
H
O
Ph
O
O
HO
N
1:3.57 74
The 13C NMR carbonyl resonances were used to confirm
the presence of enol tautomers rather than enaminones.
The enaminone carbonyl carbon of 23 appears 12.9 ppm
upfield from the keto tautomer 23b, which appears at δ =
192.4 ppm.9 Enolic carbons (=C–OH) of the intramolecu-
larly hydrogen-bonded enol tautomers 22a and 23a ap-
peared even further upfield (δ = 166.3 and 163.5 ppm,
respectively) than the enaminone carbonyl carbons.9,10
The absence of 13C NMR responses in the δ = 170–190
ppm region for the hydrolysis products of 16 and 17 ex-
cluded the presence of the corresponding enaminones and
confirmed the presence of the enol forms 22a and 23a, re-
spectively. Hydrolysis products of 4–6 and 15 also
showed no 13C peaks in the δ = 170–190 ppm region, con-
firming that only keto and enol tautomers were present in
chloroform-d1.
N
O
N
21a
21b
6
O
Ph
Ph
N
Ph
N
H
O
H
H
H
O
Ph
O
O
HO
N
O
5
1.06:1 73
22a
22b
16
Ph
Ph
O
Ph
H
H
H
S
H
S
O
HO
Ph
O
N
S
N
N
6
1.63:1 92
The equilibrating tautomers 18a,b–23a,b were then treat-
ed with dimethyl acetylenedicarboxylate in anhydrous
methanol at either room temperature or at reflux. The
products and their isolated yields are shown in Tables 2–
4, together with the appropriate reaction conditions.
17
23a
23b
a Reactions were carried out in anhyd MeOH for 24 h at r.t.
b Ratios were determined by NMR spectral integrations. The total
concentrations of the enol and keto tautomers in CDCl3 were between
0.184 M and 0.0186 M. Enol/keto ratios were calculated based on the
=CH peak area of the enol and the methylene protons of the keto tau-
tomer. The keto/enol ratios in the solid state are not known and might
be significantly different from the solution values given in this table.
c Isolated yields were calculated by considering 4–6 and 15–17 as the
limiting reagents.
Tautomers 18a,b gave the 5,6-ring-fused product methyl
8-benzoyl-5-oxo-5H-thiazolo[3,2-a]pyridine-7-carboxyl-
ate (25) in moderate-to-good yields (42–70%) under vari-
ous reaction conditions (Table 2, entries 1–3). The open-
chain product 24, a possible intermediate in the formation
of 25, was also isolated in 9–26% yield under all three sets
of conditions. The isolated yield of 24 was higher when
Synthesis 2012, 44, 3337–3352
© Georg Thieme Verlag Stuttgart · New York

PAPER
Highly Functionalized Fused-Ring Heterocycles
3339
Table 2 Reactions of Tautomeric Pairs 18a,b and 19a,b with Dimethyl Acetylenedicarboxylate in Anhydrous Methanol for 24 Hours under
Various Conditions
CO2Me
CO2Me
CO2Me
Ph
N
O
Ph
N
O
O
H
H
S
CO2Me
H
O
HO
MeO
O
H
Ph
Ph
MeOH
r.t. or reflux
H
H
N
S
N
S
S
+
R
R
R
R
18b, 19b
24, 26
18a, 19a
25, 27
18a,b: R = H
19a,b: R = Me
25: R = H
27: R = Me
24: R = H
26: R = Me
Entry Substrate
Tautomeric pair /DMAD ratio [molarities (M)] Temp
Yielda (%)
24
25
26
27
1b
2
18a,b
R = H
1:1.1 [0.18:0.16]
1:1.5 [0.18:0.26]
1:2.5 [0.18:0.44]
1:2.5 [0.18:0.44]
1:1 [0.08:0.08]
r.t.
26
42
18a,b
R = H
reflux
reflux
reflux
reflux
9
70
51
3c
4d
5e
18a,b
R = H
13
19a,b
R = Me
12
25
65
32
19a,b
R = Me
a Yields of isolated products were calculated by considering the sum of both tautomers as the limiting reagent.
b 10% of the starting equilibrating tautomers were recovered at a 18a/18b ratio of 1:1.89, as determined by NMR in CDCl3.
c 0.135 g of a solid byproduct was isolated but not identified.
d Traces of both dimethyl (E)-2-methoxymaleate (28) and dimethyl (Z)-2-methoxymaleate (29) were also isolated.11
e 15% of the starting equilibrating tautomeric pair were recovered in a 19a/19b ratio of 1:1.25, as determined by NMR in CDCl3.
the reaction was carried out at 20–25 °C, whereas forma- to 33, 34, and 35. The yield of both 32 and 35 increased
tion of 25 was favored in refluxing methanol (Table 1, en- when more than two equivalents of dimethyl acetylenedi-
tries 1 vs. 2).
carboxylate were used (Table 3, entries 2 vs. 1 and 3 vs.
4).
When 2.5 equivalents of dimethyl acetylenedicarboxylate
were refluxed with tautomeric pair 19a,b in methanol, The yields of isolated products from reactions of dimethyl
methyl 8-benzoyl-3-methyl-5-oxo-5H-[1,3]thiazolo[3,2- acetylenedicarboxylate with benzoxazole- and benzothia-
a]pyridine-7-carboxylate (27), an analogue of 25, was iso- zole-derived tautomeric pairs 22a,b and 23a,b in anhy-
lated in moderate yield (65%), along with a small amount drous methanol are summarized in Table 4. Tautomeric
(12%) of the open-chain product 26 (Table 2, entry 4). pair 22a,b with 1.5 equivalents of dimethyl acetylenedi-
The use of lower concentrations of 19a,b and dimethyl carboxylate in refluxing methanol gave the 5,6-ring-fused
acetylenedicarboxylate in methanol resulted in an in- product methyl
4-benzoyl-1-oxo-1H-pyrido[2,1-
creased yield of 26 but a lower yield of 27 and a lower b][1,3]benzoxazole-3-carboxylate (38) in excellent yield
combined yield of both products (Table 2, entry 5).
(Table 4, entry 1). The yield of 38 decreased from 93% to
11%, whereas that of the open-chain product 37 increased
from 2% to 35% at lower concentrations of the tautomeric
pair and dimethyl acetylenedicarboxylate (Table 4,
Entries 1 and 2). The 5,6-ring-fused product methyl 4-
benzoyl-1-oxo-1H-pyrido[2,1-b][1,3]benzothiazole-3-
carboxylate (40) was isolated exclusively on treating
23a,b with dimethyl acetylenedicarboxylate (entries 3 and
4). The open-chain product 39, a probable precursor of 40,
was not observed, even when the tautomeric pair 23a,b
was treated with dimethyl acetylenedicarboxylate at low
concentrations at room temperature.
Tautomeric pairs 20a,b and 21a,b reacted with dimethyl
acetylenedicarboxylate in methanol in a different manner
to 18a,b or 19a,b (Table 3). Interestingly, the novel, high-
ly functionalized, 5,7-ring-fused compounds 32 and 35
were isolated in addition to the open-chain products 30
and 33 and the 5,6-ring-fused products 31 and 34. The low
isolated yields of 31 and 34 suggest that the C-4 and C-5
methyl groups of the thiazole and oxazole rings slow the
cyclization of 30 to 31 and of 33 to 34. This allows 30 and
32 to add a second equivalent of dimethyl acetylenedicar-
boxylate before cyclizing, resulting in 5,7-ring fusion. A
trace (1%) of a new compound 36 was isolated in addition
© Georg Thieme Verlag Stuttgart · New York
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3340
H. I. De Silva et al.
PAPER
Table 3 Reactions of Tautomers 20a,b and 21a,b with Dimethyl Acetylenedicarboxylate in Anhydrous Methanol for 24 Hours under Various
Conditions
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O
MeO2C
MeO2C
CO2Me
O
Ph
N
Ph
N
MeO2C
H
O
O
H
H
X
H
O
CO2Me
MeOH
MeO
HO
O
H
Ph
Ph
+
Ph
Ph
MeO2C
H
H
r.t. or reflux
+
N
X
H
N
X
N
X
X
+
N
X
MeO2C
32, 35
31, 34
30, 33
20a, 21a
36
20b, 21b
31: X = S
34: X = O
20a,b: X = S
21a,b: X = O
30: X = S
33: X = O
32: X = S
35: X = O
36: X = O
Entry Substrate
Tautomeric pair/DMAD ratio [molarities (M)] Temp
Yielda (%)
30
31
32
33
34
35
36
1
20a,b (X = S)
20a,b (X = S)
1:1.5 [0.22:0.15]
1:2.5 [0.15:0.44]
1:2.5 [0.15:0.44]
1:1 [0.17:0.17]
reflux
reflux
reflux
r.t.
46
21
16
7
2b
3b
4c
32b
23
21a,b (X = O)
21a,b (X = O)
36b
44c
4
–
47
20
1
–
a Yields of isolated products were calculated by considering the sum of both tautomers as the limiting reagent.
b Traces of both dimethyl (E)-2-methoxymaleate (28) and dimethyl (Z)-2-methoxymaleate (29) were also isolated.11
c 17% of the starting equilibrating tautomeric pair was recovered in a 21a/21b ratio of 1:2.73, as determined by NMR in CDCl3.
Table 4 Reactions of Tautomers 22a,b and 23a,b with Dimethyl Acetylenedicarboxylate in Anhydrous Methanol for 24 Hours under Various
Conditions
CO2Me
CO2Me
CO2Me
O
Ph
N
Ph
N
O
O
H
CO2Me
H
X
H
O
MeO
HO
O
H
Ph
Ph
MeOH
r.t. or reflux
H
H
N
X
N
X
X
+
22a, 23a
37, 39
38, 40
22b, 23b
22a,b: X = O
37: X = O
39: X = S
38: X = O
40: X = S
23a,b: X = S
Entry
Substrate
Tautomeric pair/DMAD ratio [molarities (M)]
Temp
Yielda (%)
37
38
39
40
1
22a,b (X = O)
22a,b (X = O)
23a,b (X = S)
23a,b (X = S)
1:1.5 [0.14:0.22]
1:1.5 [0.05:0.08]
1:2.5 [0.18:0.44]
1:1 [0.08:0.08]
reflux
reflux
reflux
r.t.
2
93
11
2b
3c
4d
35
–
–
85
65
a Yields of isolated products were calculated by considering the sum of both tautomers as the limiting reagent.
b 41% of the starting tautomers were recovered at a 22a/22b ratio of 1.11:1, as determined by NMR in CDCl3.
c Traces of both dimethyl (E)-2-methoxymaleate (28) and dimethyl (Z)-2-methoxymaleate (29) were also isolated.11
d 22% of the starting tautomeric pair was recovered at a 23a/23b ratio of 1.62:1, as determined by NMR in CDCl3.
Synthesis 2012, 44, 3337–3352
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PAPER
Highly Functionalized Fused-Ring Heterocycles
3341
The presence of a single vinyl proton and one ester
1
methoxy group in the H NMR spectra and of three car-
bonyl carbons (corresponding to the ketone, ester, and
amide functions) in the 13C NMR spectra were character-
istic of each of the 5,6-ring-fused structures 25, 27, 31, 34,
38, and 40. The IR spectra of each of these compounds
showed three distinct absorptions for unsaturated ester,
amide, and unsaturated aromatic ketone carbonyl groups.
X-ray crystal structures were obtained for compounds 25,
34, and 38 (Figures 1–3), thereby completing the defini-
tive identification of these structures.
Figure 3 The X-ray crystal structure of 38 (CCDC 888333)
necessary to permit cyclization to the 5,6-ring-fused struc-
tures 34, 38, 25, 27, 31, and 40, respectively. If these dou-
ble bonds had the opposite geometries, then cyclization at
the nitrogen would only be possible for the ester carbonyl
carbon substituting this double bond, which would lead to
5,5-ring fusion.
Figure 1 The X-ray crystal structure of 25 (CCDC 888329)
CO2Me
H
CO2Me
CO2Me
O
O
O
(E)
H
H
H
H
Ph
Ph
Ph
MeO2C
MeO2C
MeO2C
S
S
N
S
N
HN
42
24
41
isolated
not Isolated
Scheme 3 Two possible tautomers of 24
Figure 2 The X-ray crystal structure of 34 (CCDC 888334)
The presence of a methylene proton and of 13C signals at
δ = 4.38–4.12 and 43.81–38.81 ppm in the NMR spectra
of all the open-chain products 24, 26, 30, 33, and 37 (Ta-
bles 2–4) excluded the two other possible tautomeric
structures (41 and 42, Scheme 3). The X-ray crystal struc-
ture of the oxazole derivative 33 confirmed the Z-geome-
try of the C4–C5 double bond (Figure 4) in the solid state.
The existence of the Z-geometrical isomers of 33 and 37
and the analogous E-geometries in 24, 26, 30, and 39 are
Figure 4 The X-ray crystal structure of 33 (CCDC 888330)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3337–3352

3342
H. I. De Silva et al.
PAPER
1
The H NMR spectra of the highly functionalized 5,7- electrophilic than the α,β-unsaturated ester carbonyl of 45
ring-fused compounds 32 and 35 (Table 3) showed the in Path A, but the ring nitrogen of 33 is less nucleophilic,
presence of four ester methoxy groups and two methyl because it is conjugated. Cyclocondensation of 33 through
groups on the C4 and C5 atoms of the thiazole and oxazole nitrogen nucleophilic attack gives 48, which loses a meth-
rings. Two downfield doublets (J = 5.2 Hz in 32 and oxy group to form 49. Subsequent loss of the acidic proton
J = 4.9 Hz in 35) appeared, each of which integrated as gives 34.
one proton. The X-ray crystal structure of 35 confirmed
this structure (Figure 5). The two ester groups on the two
The path to 5,7-ring fusion starts with removal of the acid-
ic methylene proton of 45 with inter- or intramolecular
adjacent tertiary ring carbons are oriented trans to one an-
base catalysis to form the zwitterionic intermediate 50.
other. The structures of 32 and 35 indicate that two equiv-
Alternatively, tautomerization of 45 to 33, also with inter-
alents of dimethyl acetylenedicarboxylate had reacted
or intramolecular base catalysis, is followed by deproton-
with one equivalent of the tautomeric pairs 20a,b and
ation of 33 to form zwitterion 50. If 50 undergoes Michael
21a,b, respectively.
addition to a second molecule of dimethyl acetylenedicar-
boxylate to give 51, in competition with cyclization of 33
or 45 (leading to 5,6-ring fusion), the formation of the 5,7-
ring-fused products become possible. Proton transfer
from 51, followed by keto–enol tautomerization of 52, re-
sults in the formation of the enetetracarboxylate 53. This
can undergo intramolecular cyclization through a third
Michael addition to give the fused derivative 54. Proton-
ation of 54 followed by keto–enol tautomerization of the
product 55 gives the 5,7-ring-fused compound 35.
Isolations of the open-chain products 24, 26, 30, 33, and
37 confirmed that the β-carbons of the starting tautomers
can undergo Michael additions to dimethyl acetylenedi-
carboxylate (Scheme 5). We needed to determine whether
24, 26, 30, 33, 37, and 39 are the actual precursors to the
5,6-ring-fused products 25, 27, 31, 34, 38 and 40, respec-
tively. To answer this question, we refluxed 37 in anhy-
drous methanol (Scheme 5). The fused product 38 was
observed exclusively on a thin-layer chromatogram after
refluxing 37 for 15 hours, and 38 was isolated in 99%
yield, thereby confirming our hypothesis.
Figure 5 X-ray crystal structure of 35. This crystal structure con-
tains a 1:1 ratio of two slightly different geometries of 35 (see Sup-
porting Information). Solvent molecules (acetone) are omitted for
clarity (CCDC 888332).
We envisioned that reactions of isolated open-chain prod-
ucts, such as 24, with a base might facilitate the cyclocon-
densation (Scheme 6). To test this hypothesis, the isolated
intermediates 24, 30, 33, and 37 were refluxed in tetrahy-
drofuran containing the strong base sodium hydride,
which should convert these intermediates quantitatively
into their enolate anions (Table 5).
Possible reaction paths for the 5,6- and 5,7-ring fusion
processes are shown in Scheme 4. The formation of com-
pounds 34 and 35 from the tautomeric pair 21a,b is used
as an example. All the steps to 45 are common for paths
to the open-chain and the 5,6- and 5,7-ring-fused prod-
ucts. Enol 21a, or the corresponding enolate anion in-
duced by the action of the oxazole nitrogen as a base,
undergoes Michael addition to dimethyl acetylenedicar-
boxylate to give the allenic intermediate 43. Protonation
of the central carbon of the allene group of 43 results in
the formation of enedioate 44, which can have either an E-
or a Z-geometry at the C=C bond. The Z-isomer cannot
give the observed 5,6-ring-fused compound. Therefore, if
the Z-isomer is present, it isomerizes to the E-isomer 45
before undergoing 5,6-ring fusion. Two possible path-
ways (A and B) starting from 45 can lead to the desired
cyclocondensation. Nucleophilic attack by nitrogen on the
terminal ester carbonyl carbon of 45 (path A) gives the
zwitterionic intermediate 46, which then expels a meth-
oxy group to give oxazolium cation 47. Finally, 47 is con-
verted into the fused product 34 by loss of the acidic β-
proton. In the alternative path B, E-isomer 45 first tautom-
erizes to give 33, the isolated open-chain product men-
tioned in Table 3. The ester carbonyl of 33 is more
Intermediates 24, 30, and 37 were converted entirely into
the corresponding 5,6-ring-fused compounds 25, 31, and
38, respectively, when treated with sodium hydride in re-
fluxing tetrahydrofuran for seven to eight hours (Table 5,
entries 1, 2, and 5). No other products were observed by
thin-layer chromatography (TLC). The reported yields are
the isolated yields after workup, including column chro-
matography. Compound 33 was only partially converted
into 34 after refluxing for 24 hours in tetrahydrofuran (Ta-
ble 5, entry 3). Only a 40% yield of 34 was isolated, along
with 39% of the unreacted starting intermediate 33. Reac-
tion in refluxing 1,4-dioxane (boiling point 101 °C) in-
stead of tetrahydrofuran (boiling point 66 °C) gave only a
7% yield of 34, along with 32% of unreacted 33, after 24
hours (entry 4). Increasing the temperature may have de-
stroyed the starting material 33, the 5,6-ring-fused prod-
Synthesis 2012, 44, 3337–3352
© Georg Thieme Verlag Stuttgart · New York

PAPER
Highly Functionalized Fused-Ring Heterocycles
3343
O
C
O
C
C
OMe
Ph
N
Ph
N
H
Ph
Ph
N
H
H
H
OMe
H
H
C
O
C
O
O
O
H
C
CO2Me
H
MeO
C
OMe
MeOH
CO2Me
O
O
O
N
O
O
O
44
E and/or Z geometries
43
21a
21b
rotation and E/Z
isomerization
O
OMe
H
CO2Me
C
CO2Me
CO2Me
H
CO2Me
H
CO2Me
O
CO2Me
C
O
H
O
2nd Michael
O
O
O
removal of acidic
MeO2C
MeO2C
C
H
C
N
(E)
C
C
H
Ph
H
H
C
N
proton by inter- or
intramolecular
base catalysis
addition
DMAD
H
H
O
Ph
MeO2C
MeO2C
Ph
Ph
– H
Ph
Ph
path A
C
N
O
H
O
O
O
C
O
O
O
N
O
N
O
N
MeO
MeO
C
50
OMe
O
46
45
path B
51
47
34
tautomerization
proton transfer
removal of acidic
CO2Me
CO2Me
proton by inter- or
intramolecular
base catalysis
CO2Me
CO2Me
C
O
O
H
H
H
O
O
H
H
(Z)
H
MeO2C
C
Ph
H
Ph
OMe
C
Ph
Ph
MeO2C
C
O
O
O
N
O
N
O
MeO
N
O
O
N
C
C
OMe
49
48
OMe
HO
52
33
CO2Me
O
CO2Me
C
CO2Me
CO2Me
MeO
O
MeO2C
MeO
MeO2C
MeO2C
H
H
MeO2C
O
MeO2C
MeO
HO
O
H
MeO2C
3rd Michael
addition
Ph
Ph
Ph
Ph
MeO2C
+ H
O
N
O
N
O
N
O
N
O
H
H
O
H
MeO2C
MeO2C
CO2Me
53
35
54
55
Scheme 4 Plausible mechanisms for the formation of 5,6- and 5,7-ring-fused compounds 34 and 35, respectively
uct 34, or both, thereby reducing the yield of 34. Neither dependently treated with 2.5 equivalents of dimethyl acet-
33 nor 34 was refluxed in 1,4-dioxane in the absence of ylenedicarboxylate in methanol containing 0.32 or 0.28
sodium hydride to test their thermal stability in this sol- equivalents of sodium methoxide, respectively (Scheme
vent.
7). The yields of 31 and 34 did increase (to 44 and 36%,
respectively) compared with those reported in Table 3.
The amount of 36 increased from 1 to 17%, and product
59 was observed for the first time. The 5,7-ring-fused
compounds 32 or 35 were not detected by TLC.
CO2Me
CO2Me
O
O
O
H
O
MeO
Ph
Ph
reflux, 15 h
MeOH
H
H
N
O
O
N
CO2Me
CO2Me
CO2Me
99%
isolated yield
B :
O
O
O
H
H
H
H
Ph
Ph
37
38
Ph
MeO2C
MeO2C
O
C
N
S
N
S
N
S
Scheme 5 Conversion of the open-chain product 37 into fused-ring
product 38
MeO
24
56
57
CO2Me
CO2Me
In an attempt to increase the yields of the 5,6-ring-fused
compounds 31 and 34 and those of the 5,7-ring-fused
compounds 32 and 35, we added a stronger base (sodium
methoxide) at the start of the reaction with the starting tau-
tomers (Scheme 7). We speculated that this might en-
hance the rate of both the initial Michael addition to
dimethyl acetylenedicarboxylate and of the cyclization
step in a manner analogous to the conversion of 24 into 25
in Scheme 6. Tautomeric pairs 20a,b and 21a,b were in-
O
O
H
H
Ph
Ph
O
MeO
N
S
O
N
S
58
25
Scheme 6 Conversion of 24 into 25 in the presence of sodium hydride
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3337–3352

3344
H. I. De Silva et al.
PAPER
Table 5 Synthesis of 5,6-Ring-Fused Heterocycles 25, 31, 34, and
38 Starting from 24, 30, 33, and 37, Respectively, in the Presence of
Sodium Hydride
We also speculated that the reaction of intermediate 33
with dimethyl acetylenedicarboxylate in the presence of a
base might increase the yield of the 5,7-ring-fused com-
pound 35. We therefore treated 33 with 1.1 equivalents of
dimethyl acetylenedicarboxylate in the presence of small
amount of sodium methoxide in refluxing methanol for 24
hours (Scheme 8). However, no 35 was detected and the
5,6-ring-fused products 34 (65%) and 36 (4%), together
with unreacted 33 (18%), were isolated after workup. This
absence of the 5,7-ring-fused product 35 is consistent with
the results summarized in Scheme 7, starting from tauto-
mers 21a,b and 2.5 equivalents of dimethyl acetylenedi-
carboxylate.
Entry Substrate
Time Product
(h)
Yielda
(%)
CO2Me
CO2Me
O
O
O
H
O
MeO
Ph
Ph
1
7
8
76
61
H
H
N
S
S
N
25
24
O
CO2Me
CO2Me
O
O
H
O
MeO
Ph
Ph
CO2Me
H
H
N
2
CO2Me
S
S
N
O
O
CO2Me
MeO
Ph
NaOMe (0.01 equiv)
MeOH, reflux, 24 h
H
H
30
O
31
N
O
CO2Me
CO2Me
O
O
H
O
33
CO2Me
MeO
Ph
Ph
CO2Me
O
3b
4c
24
24
40
7
CO2Me
H
H
N
MeO2C
CO2Me
MeO2C
H
O
N
O
O
H
Ph
MeO2C
Ph
Ph
MeO2C
+
N
O
H
O
N
O
N
O
33
34
MeO2C
CO2Me
CO2Me
O
O
O
34
65%
isolated
35
not formed
36
4%
isolated
H
O
MeO
Ph
Ph
H
H
N
O
N
O
5
8
79
Scheme 8 Reaction of 33 with dimethyl acetylenedicarboxylate in
the presence of sodium methoxide
37
38
This led us to postulate that the methoxide ion might in-
duce reopening of the seven-membered ring of 35 to form
the corresponding open-chain enolate anion 60, which
might then reclose by an aldol condensation to give the ar-
yloxazole 36 (Scheme 9). To test this hypothesis, we treat-
ed 35 with ~0.9 equivalents of sodium methoxide in
methanol at room temperature and we monitored the reac-
tion by TLC. The TLC spot for 35 disappeared after only
15 min and a new spot appeared and was identified as
aryloxazole 36, which was isolated in 37% yield. This
showed that if 35 had formed from 21a,b (Scheme 7) or
from 33 (Scheme 8) in the presence of methoxide, it might
have been converted into to 36.
a Isolated yields were calculated by assuming 100% conversion of the
open-chain product into the corresponding 5,6-ring-fused compound.
b 39% of 33 was recovered.
c 32% of 33 was recovered.
CO2Me
CO2Me
Ph
N
Ph
N
O
H
H
O
H
X
CO2Me
NaOMe
HO
O
H
Ph
MeOH, reflux, 24 h
X
N
X
31: X = S (44%)
34: X = O (36%)
20a,b: X = S
21a,b: X = O
Methyl propiolate is an α,β-alkynyl monoester analogous
to dimethyl acetylenedicarboxylate. It was used in an at-
tempt to extend the successful preparation of the 5,6-ring-
fused compounds 25, 27, 31, 34, 38, and 40 from tauto-
meric pairs 18a,b–23a,b and dimethyl acetylenedicarbox-
ylate. Methyl propiolate is a weaker electrophile than
dimethyl acetylenedicarboxylate. When tautomeric pairs
18a,b, 21a,b, or 23a,b were treated with methyl propio-
late in methanol (Scheme 10), the expected 5,6-ring-fused
compounds 62, 63, and 64 were not obtained.
CO2Me
CO2Me
O
MeO2C
H
MeO2C
CO2Me
Ph
MeO2C
MeO2C
Ph
N
X
H
MeO2C
N
X
32: X = S
35: X = O
59: X = S (9%)
36: X = O (17%)
not formed
Scheme 7 Reactions of the tautomeric pairs 20a,b and 21a,b with di-
methyl acetylenedicarboxylate in the presence of sodium methoxide
Synthesis 2012, 44, 3337–3352
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PAPER
Highly Functionalized Fused-Ring Heterocycles
3345
CO2Me
the carbon next to the nitrogen of the side-chain alkene.
This might be due to a low rotational barrier about the
exocyclic double bond, which could prevent observation
of an NOE interaction. Therefore, the geometry of the
exo-ring double bond at the β-carbon of 65 is unknown.
MeO2C
MeO2C
CO2Me
CO2Me
O
MeO2O
MeO2O
O
Ph
OMe
MeO2C
H
Ph
Ph
MeO2C
MeO2C
O
N
O
H
N
O
H
MeO2C
MeO2C
N
O
35
60
H
60
(1.5 equiv)
Ph
N
Ph
N
O
O
H
CO2Me
H
O
CO2Me
H
N
CO2Me
HO
O
H
H
Ph
MeOH, reflux
24 h
MeO2C
MeO2C
CO2Me
MeO2C
CO2Me
H
MeO2C
O
4%
H
Ph
OH
Ph
MeO2C
– H2O
N
O
21b
65
21a
N
O
O
H
H
MeO2C
(1 equiv)
61
36
Ph
16%
H
CO2Me
HN
O
Scheme 9 Possible mechanism for the formation of aryloxazole 36
by ring opening of 35 with sodium methoxide in methanol
MeOH, reflux
r.t., 18 h
66
O
O
O
H
N
H
MeO2C
H
H
H
Ph
Ph
N
N
Ph
N
O
H
N
O
(1.5 equiv)
CO2Me
MeOH, reflux, 24 h
H
H
H
X
H
O
HO
O
H
no 66 or
O
Ph
Ph
68
X
X
R
67
R
R
R
R
R
Scheme 11 Reactions of the tautomeric pair 21a,b with methyl pro-
piolate in methanol at the reflux or at room temperature
18a: X = S; R = H
21a: X = O; R = Me
18b: X = S; R = H
21b: X = O; R = Me
62: X = S; R = H
63: X = O; R = Me
H
Ph
Ph
H
H
N
O
S
When tautomeric pair 21a,b was treated with a single
equivalent of methyl propiolate in methanol at room tem-
perature, a new compound 68 was isolated in 16% yield,
along with the recovered tautomers 21a,b (39%). The
structure of 68 was confirmed by X-ray crystallography
(Figure 6).
(1.5 equiv)
H
H
HO
O
H
Ph
CO2Me
MeOH, reflux, 23 h
O
N
S
N
S
23a
23b
64
Scheme 10 Attempted reactions of the tautomeric pairs 18a,b,
21a,b, and 23a,b with methyl propiolate
Unreacted tautomers were isolated along with unidenti-
fied byproducts when the thiazole-based tautomeric pair
18a,b or the benzothiazole-based tautomeric pair 23a,b
was treated with 1.5 equivalents of methyl propiolate in
refluxing methanol for 24 or 23 hours, respectively (see
Supporting Information). No attempt was made at further
purification or analysis of these unidentified fractions.
One new compound 65 was isolated in 4% yield when the
oxazole-based tautomeric pair 21a,b was treated with 1.5
equivalents of methyl propiolate in refluxing methanol for
Figure 6 The X-ray crystal structure of 68. This crystal structure
contains two independent enantiomeric molecules (see Supporting In-
formation) (CCDC 888331).
1
24 hours (Scheme 11). The H NMR spectrum of 65
showed the presence of one ester methoxy group, three vi-
nyl protons, five phenyl protons, and six methyl protons.
Two vinyl protons were doublets with a 15-Hz coupling
constant, consistent with vicinal trans vinyl proton cou-
pling. This ruled out structure 67. The presence of nine
carbon signals in the DEPT 135 spectrum (see Supporting
Information) excluded the other possible structure 66, as
only eight signals should be seen for 66. The NOESY
spectrum of 65 did not show clear evidence for an NOE
interaction between the vinyl protons on the β-carbon and
In conclusion, we prepared the (Z)-2-(heterocyclic)-1-
phenylvinyl benzoates 4, 15, 5, 6, 16, and 17 by treating
the appropriate methylated heterocycles with benzoyl
chloride. Hydrolysis of 4, 15, 5, 6, 16 and 17 with metha-
nolic potassium hydroxide gave the corresponding 2-(het-
erocyclic)-1-phenylethenols 18a–23a and their tautomers
18b–23b These tautomeric pairs afforded a wide variety
of products, including highly functionalized 5,6- and 5,7-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3337–3352

3346
H. I. De Silva et al.
PAPER
13C NMR (150 MHz, CDCl3): δ = 163.68, 161.42, 150.18, 142.77,
134.13, 133.85, 130.57, 129.63, 128.89, 128.85, 128.82, 124.96,
119.66, 112.08.
ring-fused heterocycles, when treated with dimethyl acet-
ylenedicarboxylate. The reactivity of the keto–enol tauto-
meric pairs 18a,b–23a,b depends on the nature of their
heteroatoms and the substituents present on the ring.
However, the corresponding 5,6-ring-fused heterocycles
were not isolated when methyl propiolate, a weaker elec-
trophile than dimethyl acetylenedicarboxylate, was used
as a dielectrophile.
(Z)-2-(4,5-Dimethylthiazol-2-yl)-1-phenylvinyl Benzoate (5)5
By following the typical procedure, starting from thiazole 2 (0.636
g, 5 mmol, 1 equiv), Et3N (1.84 g, 18 mmol, 3.6 equiv), and BzCl
(2.13 g, 15 mmol, 3 equiv), benzoate 5 was isolated as a yellow sol-
id; yield: 1.11 g (66%); mp 156–158 °C; Rf = 0.50 (EtOAc–hexane
1:3).
The scope of this work is not limited to 2-(heterocyclic)-
1-phenylethenols and their keto tautomers, such as 11,
18–23, etc. We have previously shown5 that aroyl chlo-
rides, in general, can be used to prepare aryl derivatives of
compounds 4–6. Therefore, these aryl derivatives and
their benzoxazole and benzothiazole analogues could be
synthesized6 and hydrolyzed to give the corresponding
aryl-substituted keto and enol tautomeric analogues of 11
and 18–23, thereby extending the scope of this synthetic
route. However, aliphatic acid chlorides, with the excep-
tion of 2,2-dimethylpropanoyl chloride, failed in these re-
actions.5
IR (neat): 3066, 3045, 2951, 2915, 1741, 1655, 1537, 1450, 1432,
1227, 1076, 1050, 1023, 885, 767, 694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.33 (d, J = 7.55 Hz, 2 H), 7.72 (t,
J = 7.40 Hz, 1 H), 7.62–7.56 and 7.38–7.35 (m, 7 H), 7.23 (s, 1 H),
2.31 (s, 3 H), 2.28 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 163.84, 156.69, 148.75, 148.38,
134.03, 134.01, 130.54, 129.29, 129.00, 128.85, 128.79, 127.80,
124.73, 112.24, 14.54, 11.35.
(Z)-2-(4,5-Dimethyloxazol-2-yl)-1-phenylvinyl Benzoate (6)5
By following the typical procedure, starting from oxazole 3 (0.585
g, 5 mmol, 1 equiv), Et3N (1.87 g, 18.5 mmol, 3.7 equiv), and BzCl
(2.15 g, 15.1 mmol, 3 equiv), benzoate 6 was isolated as a sticky oil;
yield: 1.26 g (79%); Rf = 0.54 (EtOAc–hexane, 1:3).
Future efforts in this research area will involve attempts to
optimize the reaction conditions for using methyl propio-
late. Furthermore, this work could be extended to α,β-un-
saturated esters, nitriles, ketones, or aldehydes, to explore
the synthesis of new fused-ring heterocycles.
IR (neat): 3062, 2978, 2953, 2923, 2858, 1738, 1633, 1449, 1236,
1175, 1082, 1064, 1024, 1000, 760, 705, 689 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 7.47 Hz, 2 H), 7.69–
7.37 (m, 8 H), 6.83 (s, 1 H), 2.01 (s, 3 H), 1.92 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 164.62, 155.83, 149.71, 143.42,
133.82, 133.42, 132.00, 130.16, 129.54, 129.73, 128.69, 128.37,
124.86, 103.10, 10.92, 9.59.
Chemicals and solvents were purchased from commercial suppliers
and used as received, except for MeCN and Et3N, which were dis-
tilled from CaH2 under N2. All reactions were carried out under N2.
Silica gel (230–400 mesh; pore size 60 Ǻ; Sorbent Technologies)
was used as the stationary phase for flash chromatography. 1H NMR
and 13C NMR spectra were recorded on a Bruker AVANCE III-300
or -600 spectrometer operating at 300 MHz or 600 MHz for protons,
and at 75 MHz or 150 MHz for carbon-13. Chemical shifts are re-
ported relative to the TMS as an internal standard for 1H (δ = 0 ppm)
and to the centerline of the deuterated solvent for 13C (CDCl3:
δ = 77.0 ppm; DMSO-d6: δ = 39.43 ppm). High-resolution mass
spectra were recorded on a Bruker UHPLC-micro-Q/T MS/MS
spectrometer in the ESI mode. Melting points were recorded with a
Mel-Temp apparatus and are uncorrected. IR spectra were recorded
on a Nicolet 6700 FT-IR spectrometer. A Bruker AXS Smart 1000
diffractometer, upgraded with an APEX II detector and software
that incorporates SHELX components,12 was employed for crystal-
structure determinations at –173 °C.
(Z)-2-(4-Methylthiazol-2-yl)-1-phenylvinyl Benzoate (15)
By following the typical procedure, starting from thiazole 14 (2.29
g, 20 mmol, 1 equiv), Et3N (7.29 g, 72 mmol, 3.6 equiv), and BzCl
(8.54 g, 61 mmol, 3 equiv), benzoate 15 was isolated as a yellow
solid; yield: 3.95 g (62%); mp 125–126 °C; Rf = 0.40 (EtOAc–hex-
ane, 1:4).
IR (neat): 3107, 3073, 2971, 2929, 1731, 1635, 1599, 1510, 1448,
1421, 1232, 1079, 1059, 1025, 1000, 968, 871, 765, 750, 692 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.33 (d, J = 7.19 Hz, 2 H), 7.71 (t,
J = 7.42 Hz, 1 H), 7.62–7.57 and 7.42–7.36 (m, 7 H), 7.30 (s, 1 H),
6.80 (s, 1 H), 2.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.73, 160.64, 152.69, 149.87,
134.06, 133.88, 130.50, 129.52, 128.88, 128.78, 124.84, 114.63,
111.95, 16.90.
HRMS (ESI): m/z [M + H]+ calcd for C19H16NO2S: 322.0900;
found: 322.0880.
(Z)-1-Phenyl-2-(thiazol-2-yl)vinyl Benzoate5 (4): Typical Proce-
dure
(Z)-2-(Benzoxazol-2-yl)-1-phenylvinyl Benzoate (16)
By following the typical procedure, starting from benzoxazole 7
(2.69 g, 20 mmol, 1 equiv), Et3N (7.48 g, 74 mmol, 3.7 equiv), and
BzCl (8.51 g, 60.5 mmol, 3 equiv), benzoate 16 was isolated as a
white crystalline solid; yield: 2.94 g (43%); mp 97–98 °C; Rf = 0.58
(EtOAc–hexane, 1:4).
Et3N (1.83 g, 18.1 mmol, 3.6 equiv) was added to a stirred soln of
thiazole 1 (0.496 g, 5 mmol, 1 equiv) in MeCN (25 mL) at r.t. under
N2. BzCl (2.13 g, 15 mmol, 3 equiv) in MeCN (20 mL) was added
dropwise at r.t. under N2. The resulting soln was refluxed for 7 h,
then cooled to r.t. MeCN was removed by rotary evaporation and
the residue was dissolved in CH2Cl2 (30 mL), washed with sat. aq
NaHCO3 (2 × 30 mL), dried (Na2SO4), filtered, and concentrated by
rotary evaporation. The crude product was purified by column chro-
matography [silica gel, EtOAc–hexane (1:3)] to give a yellow solid;
yield: 1.364 g (89%); mp 105–106 °C; Rf = 0.39 (EtOAc–hexane,
1:3).
IR (neat): 3078, 1731, 1644, 1605, 1540, 1451, 1234, 1181, 1152,
1084, 1067, 1027, 946, 848, 790, 746, 701, 687 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.32 (d, J = 7.68 Hz, 2 H), 7.71–
7.67, 7.60–7.54, 7.41–7.40 and 7.24–7.18 (m, 11 H), 7.11 (d,
J = 8.04 Hz, 1 H), 7.04 (s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 164.47, 159.75, 154.09, 150.06,
141.57, 133.67, 133.58, 130.45, 130.41, 129.37, 128.87, 128.56,
125.48, 125.19, 124.39, 119.95 and 110.12, 103.22.
IR (neat): 3116, 3069, 3032, 2981, 1732, 1642, 1599, 1448, 1235,
1175, 1076, 1058, 1023, 762, 707, 692 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.33 (d, J = 7.48 Hz, 2 H), 7.82 (d,
J = 3.0 Hz, 1 H), 7.71 (t, J = 7.40 Hz, 1 H), 7.63–7.55 and 7.37–7.40
(m, 8 H), 7.25 (d, J = 3.0 Hz, 1 H).
Synthesis 2012, 44, 3337–3352
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Highly Functionalized Fused-Ring Heterocycles
3347
(Z)-2-(Benzothiazol-2-yl)-1-phenylvinyl Benzoate (17)
By following the typical procedure, starting from benzothiazole 8
(1.51 g, 10 mmol, 1 equiv), Et3N (3.71 g, 36.7 mmol, 3.7 equiv), and
BzCl (4.26 g, 30 mmol, 3 equiv), benzoate 17 was isolated as yellow
solid; yield: 1.89 g (53%); mp 146–148 °C; Rf = 0.54 (EtOAc–hex-
ane, 1:4).
Rf = 0.44 (EtOAc–hexane, 1:6). In CDCl3, the ratio of 20a to 20b
was 1:1.41.
IR (neat): 3089, 3055, 3038, 2980, 2918, 1630, 1573, 1555, 1492,
1454, 1268, 1146, 1060, 817, 770, 747, 687, 648 cm–1.
1H NMR (300 MHz, CDCl3): δ = 13.52 (br s, 1 H), 8.04 (d, J = 7.66
Hz, 2 H), 7.79 (d, J = 7.41 Hz, 2 H), 7.58 (t, J = 7.38 Hz, 1 H), 7.48
(t, J = 7.57 Hz, 2 H), 7.41–7.35 (m, 3 H), 6.19 (s, 1 H), 4.61 (s, 2 H),
2.32, 2.31, 2.30 (s, 12 H).
13C NMR (75 MHz, CDCl3): δ = 194.79, 164.01, 160.45, 157.33,
147.50, 145.00, 135.86, 135.10, 133.57, 129.32, 128.69, 128.52,
128.33, 127.27, 125.25, 121.56, 90.64, 42.92, 14.52, 14.24, 11.14.
IR (neat): 3061, 2981, 1739, 1641, 1596, 1452, 1445, 1432, 1227,
1209, 1175, 1080, 1055, 1023, 1000, 850, 754, 656 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.36 (d, J = 7.80 Hz, 2 H), 7.97 (d,
J = 8.19 Hz, 1 H), 7.73 (dd, J = 7.80, 7.61 Hz, 2 H), 7.65 (d,
J = 7.65 Hz, 2 H), 7.60 (dd, J = 7.65, 7.56 Hz, 2 H), 7.45–7.39 (m,
5 H), 7.31 (t, J = 7.56 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 163.71, 161.38, 152.57, 152.48,
135.05, 134.20, 133.73, 130.63, 130.05, 128.95, 128.88, 128.80,
126.25, 125.32, 125.21, 123.00, 121.29, 112.44.
(Z)-2-(4,5-Dimethyloxazol-2-yl)-1-phenylethenol (21a) and 2-
(4,5-Dimethyloxazol-2-yl)-1-phenylethanone (21b)
By following the typical procedure, starting from benzoate 6 (1.6 g,
5.1 mmol, 1 equiv) in anhyd MeOH (15 mL) and KOH (0.578 g,
10.3 mmol, 2 equiv) in MeOH (10 mL), tautomers 21a,b were iso-
lated as a dark-green oil; yield: 0.811 g (74%); Rf = 0.57 (EtOAc–
hexane, 1:6). In CDCl3, the ratio of 21a to 21b was 1:3.57.
(Z)-1-Phenyl-2-(thiazol-2-yl)ethenol (18a) and 1-Phenyl-2-(thia-
zol-2-yl)ethanone (18b): Typical Procedure
A soln of KOH (0.788 g, 14.04 mmol, 2 equiv) in MeOH (10 mL)
was added dropwise to a soln of benzoate 4 (2.144 g, 6.98 mmol, 1
equiv) in anhyd MeOH (15 mL), and the mixture was stirred for 24
h at r.t. MeOH was then removed by rotary evaporation and the res-
idue was dissolved in H2O (30 mL). The soln was neutralized with
1 M H2SO4 and extracted with CH2Cl2 (2 × 25 mL). The organic
layer was washed with H2O (30 mL), dried (Na2SO4), filtered, and
concentrated by rotary evaporation. The crude product was purified
by column chromatography [silica gel, EtOAc–hexane (1:4)] to
give a dark-green oil; yield: 1.273 g (90%); Rf = 0.48 (EtOAc–hex-
IR (neat): 3059, 2980, 2953, 2924, 2882, 1693, 1633, 1598, 1578,
1532, 1496, 1449, 1293, 1201, 1066, 1012, 756, 713, 688, 639, 618
cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.94 (d, J = 7.66 Hz, 2 H), 7.71 (d,
J = 7.72 Hz, 2 H), 7.51 (m, 5 H), 7.32 (t, J = 7.56 Hz, 1 H), 5.91 (s,
1 H), 4.37 (s, 2 H), 2.17 (s, 3 H), 2.14 (s, 3 H), 2.03 (s, 3 H), 2.02 (s,
3 H); OH peak not seen.
13C NMR (75 MHz, CDCl3): δ = 193.28, 161.23, 160.92, 155.28,
143.98, 140.21, 135.63, 134.42, 133.49, 130.61, 129.41, 128.88,
128.57, 128.36, 128.22, 125.08, 84.01, 38.81, 10.88, 10.73, 9.75,
9.63.
1
ane, 1:3). H and 13C NMR in CDCl3 confirmed that the isolated
product consists of the tautomers 18a and 18b in a 1:2.0 ratio.
IR (neat): 3117, 3084, 3060, 1687, 1622, 1598, 1576, 1494, 1483,
1449, 1263, 1210, 1100, 1070, 752, 686, 632 cm–1.
(Z)-2-(Benzo[d]oxazol-2-yl)-1-phenylethenol (22a) and 2-(Ben-
zo[d]oxazol-2-yl)-1-phenylethanone (22b)
1H NMR (600 MHz, CDCl3): δ = 13.18 (br s, 1 H), 7.99 (d, J = 7.56
Hz, 2 H), 7.74 (d, J = 7.95 Hz, 2 H), 7.70 (d, J = 3.25 Hz, 1 H), 7.61
(d, J = 3.32 Hz, 1 H), 7.53 (t, J = 7.37 Hz, 2 H), 7.42 (t, J = 7.70 Hz,
2 H), 7.35–7.31 (m, 2 H), 7.26 (d, J = 3.25 Hz, 1 H), 7.00 (d,
J = 3.32 Hz, 1 H), 6.28 (s, 1 H), 4.69 (s, 2 H).
13C NMR (150 MHz, CDCl3): δ = 194.46, 168.35, 162.15, 160.64,
142.10, 140.11, 135.71, 134.60, 133.71, 129.63, 128.74, 128.52,
128.34, 125.42, 120.04, 114.39, 90.99, 42.65.
By following the typical procedure, starting from benzoate 16
(0.844 g, 2.47 mmol, 1 equiv) in anhyd MeOH (15 mL) and KOH
(0.28 g, 5.2 mmol, 2.1 equiv) in MeOH (10 mL), tautomers 22a,b
were isolated as a greenish-white solid; yield: 0.541 g (92%); mp
87–89 °C; Rf = 0.64 (EtOAc–hexane, 1:5). In CDCl3, the ratio of
22a to 22b was 1.06:1.
IR (neat): 3065, 3032, 3044, 2979, 1625, 1576, 1530, 1453, 1277,
1250, 1164, 1064, 850, 792, 743, 762, 702, 685 cm–1.
1H NMR (600 MHz, CDCl3): δ = 12.62 (br s, 1 H), 8.05 (d, J = 7.74
Hz, 2 H), 7.88 (m, 2 H), 7.72 (m, 1 H), 7.61 (m, 2 H), 7.52–7.45 (m,
7 H), 7.34–7.31 (m, 3 H), 7.28 (t, J = 7.66 Hz, 1 H), 6.21 (s, 1 H),
4.64 (s, 2 H).
13C NMR (150 MHz, CDCl3): δ = 192.38, 166.19, 165.68, 160.41,
151.24, 148.69, 141.26, 139.85, 135.66, 134.03, 133.91, 130.56,
128.85, 128.53, 128.53, 125.82, 124.98, 124.61, 124.32, 124.08,
119.95, 117.85, 110.61, 110.19, 83.66, 39.56.
(Z)-2-(4-Methylthiazol-2-yl)-1-phenylethenol (19a) and 2-(4-
Methylthiazol-2-yl)-1-phenylethanone (19b)
By following the typical procedure, starting from benzoate 15
(1.045 g, 3.25 mmol, 1 equiv) in anhyd MeOH (15 mL) and KOH
(0.365 g, 6.51 mmol) in MeOH (10 mL), tautomers 19a,b were iso-
lated as a yellow solid; yield: 0.473 g (66.9%); mp 96–97 °C;
Rf = 0.42 (EtOAc–hexane, 1:7). In CDCl3, the ratio of 19a to 19b
was 1:1.32.
IR (neat): 3106, 3053, 2956, 2918, 1608, 1574, 1519, 1492, 1454,
1259, 1035, 836, 758 cm–1.
(Z)-2-(Benzo[d]thiazol-2-yl)-1-phenylethenol (23a) and 2-(Ben-
zo[d]thiazol-2-yl)-1-phenylethanone (23b)
1H NMR (300 MHz, CDCl3): δ = 13.44 (br s, 1 H), 7.98 (d, J = 7.23
Hz, 2 H), 7.74–7.72 (d, J = 7.73 Hz, 2 H), 7.52 (t, J = 6.90 Hz, 1 H),
7.42 (t, J = 7.79 Hz, 2 H), 7.37–7.42 (m, 3 H), 6.79 (d, J = 0.71 Hz,
1 H), 6.53 (d, J = 0.74 Hz, 1 H), 6.21 (s, 1 H), 4.63 (s, 2 H), 2.37 (s,
J = 0.75 Hz, 3 H), 2.35 (d, J = 0.78 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 194.58, 167.58, 161.37, 160.52,
152.02, 150.11, 135.61, 134.67, 133.70, 129.53 128.27, 128.44,
128.37, 125.30, 114.56, 108.92, 91.06, 42.68, 16.95, 16.68.
By following the typical procedure, starting from benzoate 17
(1.008 g, 2.82 mmol, 1 equiv) in anhyd MeOH (15 mL) and KOH
(0.316 g, 5.63 mmol, 2 equiv) in MeOH (10 mL), tautomers 23a,b
were isolated as a yellowish-green solid; yield: 0.516 g (73%); mp
111–112 °C; Rf = 0.64 (EtOAc–hexane, 1:5). In CDCl3, the ratio of
23a to 23b was 1.63:1.
IR (neat): 3057, 2922, 1610, 1596, 1573, 1494, 1473, 1436, 1378,
1264, 1249, 1136, 1057, 751, 729, 687, 668 cm–1.
(Z)-2-(4,5-Dimethylthiazol-2-yl)-1-phenylethenol (20a) and 2-
(4,5-Dimethylthiazol-2-yl)-1-phenylethanone (20b)
By following the typical procedure, starting from benzoate 5 (0.502
g, 1.50 mmol, 1 equiv) in anhyd MeOH (10 mL) and KOH (0.168
g, 2.99 mmol, 2 equiv) in MeOH (10 mL), tautomers 20a,b were
isolated as a yellow solid; yield: 0.308 g (85%); mp 80–81 °C;
1H NMR (600 MHz, CDCl3): δ = 13.91 (br s, 1 H), 8.07 (d, J = 7.68
Hz, 2 H), 7.99 (d, J = 8.13 Hz, 1 H), 7.85–7.87 (m, 3 H), 7.80 (d,
J = 8.10 Hz, 1 H), 7.76 (d, J = 7.93 Hz, 1 H), 7.58 (dd, J = 8.13,
7.91 Hz, 1 H), 7.48 (dd, J = 7.68, 7.53 Hz, 2 H), 7.41–7.46 (m, 5 H),
7.36 (t, J = 7.53 Hz, 1 H), 7.27 (t, J = 7.53 Hz, 1 H), 6.35 (s, 1 H),
4.81 (s, 2 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3337–3352

3348
H. I. De Silva et al.
PAPER
13C NMR (150 MHz, CDCl3): δ = 194.05, 168.07, 165.46 163.44,
152.68, 150.38, 135.88, 135.78, 134.74, 133.82, 131.37, 130.28,
128.81, 128.64, 128.48, 126.46, 125.96, 125.89, 125.05, 124.11,
122.85, 121.51, 121.37, 119.95, 90.83, 43.81.
Dimethyl (2E)-2-[1-(4-Methyl-1,3-thiazol-2-yl)-2-oxo-2-phenyl-
ethylidene]succinate (26)
Yellow solid; yield: 0.073 g (12%); mp 114–115 °C; Rf = 0.47
(EtOAc–hexane, 1:2).
IR (neat): 3100, 2997, 2949, 2933, 1733, 1711, 1679, 1604, 1505,
1446, 1257, 1231, 1198, 1172 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.07 (d, J = 6.74 Hz, 2 H), 7.54 (t,
J = 6.39 Hz, 1 H), 7.45 (dd, J = 6.74, 6.39 Hz, 2 H), 7.26 (s, 1 H),
4.12 (s, 2 H), 3.80 (s, 3 H), 3.57 (s, 3 H), 2.47 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 194.52, 171.19, 166.23, 159.22,
155.04, 143.81, 135.54, 133.42, 128.86, 128.69, 126.30, 117.87,
52.42, 51.98, 35.15, 17.02.
Reaction of Tautomers 18a,b with Dimethyl Acetylenedicar-
boxylate: Typical Procedure
A soln of DMAD (0.63 g, 4.4 mmol, 2.5 equiv) in anhyd MeOH (5
mL) was added dropwise to a stirred soln of the tautomers 18a,b
(0.357 g, 1.76 mmol, 1 equiv) in anhyd MeOH (5 mL) at r.t. under
N2. (The molarities of DMAD and tautomers 18a,b were 0.44 M
and 0.18 M, respectively.) The soln was refluxed for 24 h under N2
and then MeOH was removed by rotary evaporation. The residue
was dissolved in CH2Cl2 (40 mL), washed with H2O (2 × 40 mL),
and dried (Na2SO4). CH2Cl2 was removed by rotary evaporation to
give a crude product that was purified by column chromatography
[silica gel, EtOAc–hexane (1:3 then 3:1)]. The open-chain interme-
diate product 24 eluted first and was followed by the 5,6-ring-fused
product 25. An orange-colored solid (0.135 g) was also isolated but
not identified.
HRMS (ESI): m/z [M + H]+ calcd for C18H18NO5S: 360.0906;
found: 360.0908.
Methyl 8-Benzoyl-3-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyri-
dine-7-carboxylate (27)
Yellow solid; yield: 0.379 g (65%); mp 203–204 °C; Rf = 0.53
(EtOAc–hexane, 1:1).
Dimethyl (2E)-2-[2-Oxo-2-phenyl-1-(1,3-thiazol-2-yl)ethyli-
dene]succinate (24)
Yellow solid; yield: 0.079 g, 13%; mp 130–131 °C; Rf = 0.42
(EtOAc–hexane, 1:2).
IR (neat): 3128, 3066, 2981, 2951, 1723, 1667, 1625, 1594, 1475,
1435, 1406, 1304, 1255, 1144, 1126 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.57 (d, J = 7.14 Hz, 2 H), 7.51 (t,
J = 7.38 Hz, 1 H), 7.44 (dd, J = 7.38, 7.14 Hz, 2 H), 6.74 (s, 1 H),
6.53 (s, 1 H), 3.16 (s, 3 H), 2.92 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 190.97, 166.35, 161.18, 157.55,
142.18, 139.56, 138.93, 131.64, 128.42, 127.78, 112.36, 111.34,
107.46, 52.26, 18.25.
IR (neat): 3134, 3112, 3096, 3040, 3001, 2951, 2843, 1733, 1712,
1679, 1663, 1612, 1448, 1256, 1198, 1176, 1113, 1102 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.08 (d, J = 7.73 Hz, 2 H), 7.96
(d, J = 2.64 Hz, 1 H), 7.55 (t, J = 7.26 Hz, 1 H), 7.45 (m, 3 H), 4.12
(s, 2 H), 3.79 (s, 3 H), 3.57 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 194.59, 171.01, 166.17, 160.50,
144.62, 143.84, 135.55, 133.55, 128.97, 128.80, 127.17, 122.73,
52.54, 52.54, 35.11.
HRMS (ESI): m/z [M + H]+ calcd for C17H13NO4S: 328.0663;
found: 328.0644.
Reaction of Tautomers 20a,b with Dimethyl Acetylenedicar-
boxylate
HRMS (ESI): m/z [M + H]+ calcd for C17H16NO5S: 346.0749;
found: 346.0740.
The open-chain product 30, the 5,6-ring-fused product 31, and the
5,7-ring-fused product 32 were prepared by treating DMAD (0.638
g, 4.44 mmol, 2.49 equiv) in anhyd MeOH (5 mL) with tautomers
20a,b (0.337 g, 1.46 mmol) in MeOH (5 mL) in accordance with the
typical procedure described above. The molarities of DMAD and
tautomers 20a,b were 0.44 M and 0.15 M, respectively.
Methyl 8-Benzoyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyridine-7-car-
boxylate (25)
Yellow solid; yield: 0.278 g (51%); mp 145–146 °C; Rf = 0.42
(EtOAc–hexane, 1:1).
IR (neat): 3158, 3125, 3091, 3062, 3030, 3008, 2953, 1725, 1681,
1663, 1619, 1595, 1472, 1439, 1409, 1331, 1252, 1159, 1096, 1077
cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.36 (d, J = 4.27 Hz, 1 H), 7.59
(d, J = 7.95 Hz, 2 H), 7.53 (t, J = 7.28 Hz, 1 H), 7.46 (m, 2 H), 7.31
(d, J = 4.27 Hz, 1 H), 6.67 (s, 1 H), 3.18 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 191.20, 166.43, 158.12, 154.89,
42.89, 139.37, 131.86, 128.54, 127.85, 124.14, 117.00, 109.81,
108.09, 52.39.
Dimethyl (2E)-2-[1-(4,5-Dimethyl-1,3-thiazol-2-yl)-2-oxo-2-
phenylethylidene]succinate (30)
Brown sticky oil; yield: 0.175 g (32%); Rf = 0.50 (EtOAc–hexane,
2:1).
IR (neat): 3060, 3023, 2997, 2981, 2951, 2925, 2847, 1736, 1714,
1672, 1628, 1294, 1254, 1491, 1407, 1205, 1170, 1121, 939, 785,
729, 689 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.06 (d, J = 7.50 Hz, 2 H), 7.55 (t,
J = 7.21 Hz, 1 H), 7.45 (dd, J = 7.50, 7.21 Hz, 2 H), 4.12 (s, 2 H),
3.79 (s, 3 H), 3.55 (s, 3 H), 2.33 (s, 3 H), 2.30 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 195.67, 171.33, 166.34, 154.98,
151.20, 144.00, 135.61, 133.32, 131.79, 128.83, 128.66, 129.95,
52.35, 51.94, 35.10, 14.70, 11.17.
HRMS (ESI): m/z [M + H]+ calcd for C16H12NO4S: 314.0487;
found: 314.0455.
Single crystals for X-ray crystallography were grown by the vapor-
diffusion method by diffusing hexane into a soln of ester 25 in
CHCl3.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO5S: 374.1062;
found: 374.1074.
Reaction of Tautomers 19a,b with Dimethyl Acetylenedicar-
boxylate
Methyl 8-Benzoyl-2,3-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-
a]pyridine-7-carboxylate (31)
Yellow solid; yield: 0.08 g (16%); mp 172–174 °C; Rf = 0.58
(EtOAc–hexane, 1:1).
The open-chain product 26 and the 5,6-ring-fused product 27 were
prepared by treating DMAD (0.638 g, 4.44 mmol, 2.49 equiv) in an-
hyd MeOH (5 mL) with the tautomers 19a,b (0.386 g, 1.78 mmol)
in MeOH (5 mL) in accordance with the typical procedure de-
scribed above. The molarities of DMAD and tautomers 19a,b were
0.44 M and 0.18 M, respectively.
IR (neat): 3081, 3030, 2970, 2981, 2951, 2936, 1733, 1683, 1608,
1598, 1539, 1480, 1443, 1413, 1323, 1310, 1280, 1249, 1174, 1123,
981, 947, 847, 780, 694 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.56 (d, J = 7.84 Hz, 2 H), 7.51 (t,
J = 7.02 Hz, 1 H), 7.44 (dd, J = 7.84, 7.02 Hz, 2 H), 6.53 (s, 1 H),
3.15 (s, 3 H), 2.82 (s, 3 H), 2.35 (s, 3 H).
Synthesis 2012, 44, 3337–3352
© Georg Thieme Verlag Stuttgart · New York

PAPER
Highly Functionalized Fused-Ring Heterocycles
3349
13C NMR (150 MHz, CDCl3): δ = 191.07, 166.55, 161.06, 155.57,
141.50, 139.73, 133.24, 131.61, 128.44, 127.85, 122.59, 111.68,
107.19, 52.25, 15.11, 11.61.
Single crystals for X-ray crystallography were grown by the vapor-
diffusion method by diffusing hexane into a soln of compound 34 in
CHCl3.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO4S: 342.0800;
found: 342.0773.
Tetramethyl (5S*,6S*)-9-Benzoyl-2,3-dimethyl-5,6-di-
hydro[1,3]oxazolo[3,2-a]azepine-5,6,7,8-tetracarboxylate (35)
Intense yellow solid; yield: 0.392 g (47%); mp 170 °C (dec);
Rf = 0.35 (EtOAc–hexane, 4:1).
Tetramethyl (5S*,6S*)-9-Benzoyl-2,3-dimethyl-5,6-di-
hydro[1,3]thiazolo[3,2-a]azepine-5,6,7,8-tetracarboxylate (32)
Yellowish-orange solid; yield: 0.173 g (23%); mp 216–218 °C:
Rf = 0.45 (EtOAc–hexane, 3:1).
IR (neat): 2997, 2991, 2980, 2930, 1729, 1683, 1657, 1570, 1515,
1430, 1232, 1227, 1225, 1170, 1120, 1097, 1000, 855, 768, 716,
695 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.60 (d, J = 7.58 Hz, 2 H), 7.39 (t,
J = 7.25 Hz, 1 H), 7.31 (dd, J = 7.58, 7.25 Hz, 2 H), 5.42 (d, J = 4.9
Hz, 1 H), 5.26 (d, J = 4.9 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.69
(s, 3 H), 3.65 (s, 3 H), 2.05 (s, 3 H), 1.83 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.37, 170.38, 168.76, 167.08,
166.58, 158.96, 144.31, 141.85, 138.12, 130.69, 128.40, 127.71,
121.44, 110.70, 89.79, 60.29, 53.28, 53.16, 52.32, 52.25, 44.93,
9.59, 7.59.
IR (neat): 1996, 2949, 2840, 1738, 1709, 1549, 1449, 1333, 1348,
1213, 1137, 997, 786, 740, 700, 662 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.53 (d, J = 7.16 Hz, 2 H), 7.38 (t,
J = 7.34 Hz, 1 H), 7.31 (dd, J = 7.34, 7.16 Hz, 2 H), 5.76 (d, J = 5.2
Hz, 1 H), 4.98 (d, J = 5.2 Hz, 1 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.67
(s, 3 H), 3.03 (s, 3 H), 2.24 (s, 3 H), 2.21 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 189.64, 169.06, 167.73, 167.70,
167.08, 160.25, 142.15, 140.86, 132.81, 130.45, 129.34, 127.53,
119.90, 116.90, 97.59, 64.12, 53.16, 53.07, 52.35, 51.93, 46.32,
12.51, 11.43.
HRMS (ESI): m/z [M + H]+ calcd for C25H26NO10: 500.1557; found:
500.1530.
HRMS (ESI): m/z [M + H]+ calcd for C25H26NO9S: 516.1328;
found: 516.1286.
Single crystals for X-ray crystallography were grown by the vapor-
diffusion method by diffusing hexane into a soln of compound 35 in
acetone.
Reaction of Tautomeric Pair 21a,b with Dimethyl Acetylenedi-
carboxylate
The open-chain product 33, the 5,6-ring-fused product 34, and the
5,7-ring-fused product 35 were prepared by treating DMAD (0.601
g, 4.19 mmol, 2.51 equiv) in anhyd MeOH (5 mL) with tautomers
21a,b (0.360 g, 1.67 mmol, 1 equiv) in MeOH (5 mL) in accordance
with the typical procedure described above. The molarities of
DMAD and tautomers 21a,b were 0.42 M and 0.17 M, respectively.
Tetramethyl 6-(4,5-Dimethyl-1,3-oxazol-2-yl)biphenyl-2,3,4,5-
tetracarboxylate (36)
Off-white solid; yield: 0.011 g (1%); mp 124–126 °C; Rf = 0.35
(EtOAc–hexane, 2:3).
IR (neat): 3023, 3018, 3001, 2981, 2956, 2928, 1735, 1438, 1335,
1209, 1187, 1176, 1153, 1094, 924, 857, 715 cm–1.
Dimethyl (2Z)-2-[1-(4,5-Dimethyl-1,3-oxazol-2-yl)-2-oxo-2-
phenylethylidene]succinate (33)
Yield: 0.212 g (36%); yellow solid; mp 110–111 °C; Rf = 0.65
(EtOAc–hexane, 1:1).
1H NMR (600 MHz, CDCl3): δ = 7.29 (m, 3 H), 7.06 (d, J = 7.19
Hz, 2 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.76 (s, 3 H), 3.50 (s, 3 H),
1.99 (s, 3 H), 1.92 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.71, 166.42, 165.85, 165.82,
154.26, 144.52, 142.90, 136.44, 135.98, 135.27, 131.75, 131.48,
130.99, 129.89, 53.24, 53.20, 52.88, 52.51, 11.08, 9.57.
IR (neat): 3084, 3066, 3029, 2959, 2935, 2850, 1736, 1708, 1601,
1434, 1361, 1335, 1279, 1248, 1216, 1195, 1174, 1120, 942, 968,
896, 866 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.02 (d, J = 7.92 Hz, 2 H), 7.55 (t,
J = 7.30 Hz, 1 H), 7.46 (dd, J = 7.92, 7.30 Hz, 2 H), 4.22 (s, 2 H),
3.78 (s, 3 H), 3.55 (s, 3 H), 2.16 (s, 3 H), 2.07 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 192.63, 171.13, 166.14, 154.61,
145.93, 138.17, 136.16, 134.06, 133.22, 128.77, 128.65, 126.95,
52.44, 52.09, 34.94, 11.19, 10.05.
HRMS (ESI): m/z [M + H]+ calcd for C25H24NO9: 482.1451; found:
482.1435.
Reaction of Tautomeric Pair 22a,b with Dimethyl Acetylenedi-
carboxylate
The open-chain product 37 and the 5,6-ring-fused product 38 were
prepared by treating DMAD (0.308 g, 2.15 mmol, 1.5 equiv) in an-
hyd MeOH (5 mL) with tautomers 22a,b (0.339 g, 1.43 mmol, 1
equiv) in MeOH (5 mL) in accordance with the typical procedure.
The molarities of DMAD and tautomers 22a,b were 0.22 M and
0.14 M, respectively.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO6: 358.1291; found:
358.1261.
Single crystals for X-ray crystallography were grown by the vapor-
diffusion method by diffusing hexane into a soln of compound 33 in
CHCl3.
Dimethyl (2Z)-2-[1-(1,3-Benzoxazol-2-yl)-2-oxo-2-phenylethyli-
dene]succinate (37)
Yellow solid; yield: 0.01 g (2%); mp 130–132 °C; Rf = 0.48
(EtOAc–hexane, 1:2).
Methyl 8-Benzoyl-2,3-dimethyl-5-oxo-5H-[1,3]oxazolo[3,2-
a]pyridine-7-carboxylate (34)
Yellow solid; yield: 0.023 g (4%); mp 162–164 °C; Rf = 0.44
(EtOAc–hexane, 2:1).
IR (neat): 3086, 3067, 2981, 2952, 2923, 2849, 1743, 1720, 1694,
1596, 1534, 1449, 1434, 1296, 1243, 1209, 1181, 1001, 944, 753,
725, 692 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.08 (d, J = 8.53 Hz, 2 H), 7.77–
7.73 (m, 1 H), 7.57 (t, J = 7.93 Hz, 1 H), 7.50–7.47 (m, 3 H), 7.37–
7.33 (m, 2 H), 4.38 (s, 2 H), 3.81 (s, 3 H), 3.61 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.12, 170.72, 165.75, 158.21,
150.05, 141.13, 138.43, 135.96, 133.64, 132.39, 128.93, 128.90,
126.92, 125.25, 121.12, 111.10, 52.86, 52.47, 35.45.
IR (neat): 3079, 2993, 2973, 2950, 2933, 1733, 1706, 1663, 1640,
1444, 1428, 1270, 1154, 971 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.56 (d, J = 8.42 Hz, 2 H), 7.50 (t,
J = 7.38 Hz, 1 H), 7.44 (dd, J = 8.42, 7.38 Hz, 2 H), 6.54 (s, 1 H),
3.16 (s, 3 H), 2.83 (s, 3 H), 2.35 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 189.57, 166.08, 158.48, 153.22,
142.76, 142.10, 138.43, 132.84, 128.69, 128.45, 119.38, 109.85,
97.77, 52.62, 9.95, 9.79.
HRMS (ESI): m/z [M + H]+ calcd for C21H18NO6: 380.1134; found:
380.1115.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO5: 326.1028; found:
326.0998.
© Georg Thieme Verlag Stuttgart · New York
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3350
H. I. De Silva et al.
PAPER
Methyl 4-Benzoyl-1-oxo-1H-pyrido[2,1-b][1,3]benzoxazole-3-
carboxylate (38)
Pale-yellow solid; yield: 0.46 g (93%); mp 193–195 °C; Rf = 0.48
(EtOAc–hexane, 1:1).
Synthesis of Other 5,6-Ring-Fused Products from Open-Chain
Products by Treatment With Sodium Hydride
By following the typical procedure, refluxing 31 (0.114 g, 0.31
mmol, 1 equiv) and NaH (0.02 g, 0.5 mmol, 1.6 equiv) in THF (20
mL) for 8 h gave 30; yield: 0.064 g (61%).
IR (neat): 3081, 3040, 3006, 2952, 1739, 1687, 1648, 1634, 1599,
1516, 1441, 1418, 1297, 1250, 1164, 1050, 1000, 850, 790, 782,
757, 623 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.64 (d, J = 7.49 Hz, 2 H), 7.85
(d, J = 7.74 Hz, 1 H), 7.61 (t, J = 7.31 Hz, 1 H), 7.50–7.44 (m, 5 H),
6.89 (s, 1 H), 3.61 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 189.40, 165.57, 158.07, 152.87,
147.03, 143.08, 137.96, 133.34, 128.99, 128.69, 127.72, 126.44,
125.56, 117.37, 112.76, 110.96, 98.16, 52.94.
By following the typical procedure, refluxing 33 (0.203 g, 0.57
mmol) and NaH (0.034 g, 0.85 mmol, 1.5 equiv) in THF (20 mL)
for 24 h gave 34; yield: 0.073 g (40%). Unreacted 33 (38.6%) was
also recovered. On refluxing 33 (0.208 g, 0.58 mmol) and NaH
(0.035 g, 0.88 mmol, 1.5 equiv) in 1,4-dioxane (20 mL) for 24 h, 34
was obtained in 7% yield (0.013 g) with 31.6% recovery of 33.
By following the typical procedure, refluxing 37 (0.121 g, 0.32
mmol) and NaH (0.02 g, 0.5 mmol, 1.6 equiv) in THF (20 mL) for
8 h gave 38: yield: 0.088 g (79%).
HRMS (ESI): m/z [M + H]+ calcd for C20H14NO5: 348.0872; found:
348.0829.
Tetramethyl 6-(4,5-Dimethyl-1,3-thiazol-2-yl)biphenyl-2,3,4,5-
tetracarboxylate (59)
Single crystals for X-ray crystallography were grown by the vapor-
diffusion method by diffusing hexane into a soln of compound 38 in
CHCl3.
A soln of DMAD (0.523 g, 3.64 mmol, 2.5 equiv) in anhyd MeOH
(5 mL) was added dropwise to a soln of the tautomers 20a,b (0.337
g, 1.46 mmol) in anhyd MeOH (5 mL) at r.t. under N2. A 25 wt%
soln of NaOMe in MeOH (0.1 mL, 0.5 mmol, 0.32 equiv) was then
added and the mixture was refluxed for 24 h under N2. MeOH was
removed by rotary evaporation, and the residue was dissolved in
CH2Cl2 (40 mL), washed with H2O (2 × 40 mL), dried (Na2SO4),
and concentrated by rotary evaporation. The crude product was pu-
rified by column chromatography [silica gel, EtOAc–hexane (1:2)].
The 5,6-ring-fused product 31 [yield: 0.221 g (44%)] eluted first,
and this was followed by the open-chain product 59 as an off-white
solid; yield: 0.067 g (9%); mp 165–166 °C; Rf = 0.50 (EtOAc–
hexane, 1:2).
Reaction of Tautomeric Pair 23a,b with Dimethyl Acetylenedi-
carboxylate
The 5,6-ring-fused product 40 was synthesized by treating DMAD
(0.226 g, 1.57 mmol, 1.5 equiv) in anhyd MeOH (5 mL) with tauto-
mers 23a,b (0.261g, 1.03 mmol, 1 equiv) in MeOH (15 mL) in ac-
cordance with the typical procedure. The molarities of tautomers
23a,b and DMAD were 0.05 M and 0.08 M, respectively.
Methyl 4-Benzoyl-1-oxo-1H-pyrido[2,1-b][1,3]benzothiazole-3-
carboxylate (40)
Intense-yellow solid; yield: 0.317 g (85%); mp 234–236 °C;
Rf = 0.43 (EtOAc–hexane, 1:2).
IR (neat): 3081, 3030, 2981, 2951, 2936, 1733, 1683, 1608, 1598,
1539, 1480, 1443, 1310, 1413, 1323, 1280, 1249, 947, 789, 747,
726, 694 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.36–7.29 (m, 3 H), 7.11 (d,
J = 7.68 Hz, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.72 (s, 3 H), 3.47 (s,
3 H), 2.26 (s, 3 H), 2.20 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.95, 166.81, 166.08, 165.78,
156.93, 148.01, 141.68, 135.96, 135.81, 135.28, 134.94, 131.41,
130.18, 130.99, 129.50, 128.55, 128.14, 53.15, 53.10, 52.49, 52.40,
14.41, 11.18.
IR (neat): 3126, 3094, 3068, 3013, 2981, 2952, 1719, 1672, 1621,
1559, 1492, 1434, 1409, 1289, 1264, 1244, 1196, 1120, 1066, 996,
945, 858, 805, 762, 679, 620 cm–1.
1H NMR (600 MHz, CDCl3): δ = 9.32 (d, J = 8.14 Hz, 2 H), 7.81
(d, J = 7.32 Hz, 1 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.60–7.53 (m, 3 H),
7.47 (dd, J = 8.14, 7.50 Hz, 2 H), 6.83 (s, 1 H), 3.23 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 191.72, 166.09, 161.13, 154.90,
141.70, 139.25, 137.20, 132.12, 128.61, 128.35, 127.98, 127.48,
127.06, 121.66, 120.34, 113.92, 108.16, 52.46.
HRMS (ESI): m/z [M + H]+ calcd for C25H24NO8S: 498.1223;
found: 498.1182.
HRMS (ESI): m/z [M + H]+ calcd for C20H14NO4S: 364.0644;
found: 364.0600.
Reaction of the Tautomeric Pair 21a,b with Dimethyl Acetyl-
enedicarboxylate in the Presence of Sodium Methoxide in
Methanol
The reaction of DMAD (0.599 g, 4.17 mmol, 2.5 equiv) with tauto-
mers 21a,b (0.359 g, 1.67 mmol) in the presence of NaOMe (0.1
mL, 0.5 mmol, 0.28 equiv) in MeOH (10 mL) for 24 h gave the 5,6-
ring-fused product 34 [yield: 0.286 g (36%)] and tetracarboxylate
36 yield: 0.089 g (17%).
Conversion of the Open-Chain Product 37 into the 5,6-Ring-
Fused Product 38
A soln of open-chain product 37 (0.20 g, 0.53 mmol) in anhyd
MeOH (3 mL) was refluxed and the reaction was monitored by
TLC. When the spot for 37 disappeared after 15 h, the MeOH was
removed by rotary evaporation and the residue was dissolved in
CH2Cl2 (10 mL) and washed with H2O (2 × 10 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated; yield: 0.182 g
(99%).
Reaction of Succinate 33 with Dimethyl Acetylenedicarboxylate
in the Presence of Sodium Methoxide
A soln of DMAD (0.112 g, 0.78 mmol, 1.1 equiv) in anhyd MeOH
(2 mL) was added dropwise to a soln of succinate 33 (0.255 g, 0.71
mmol) in anhyd MeOH (2 mL) at r.t. under N2. A 25 wt% soln of
NaOMe in MeOH (1.5 μL, 0.01 equiv) was added and the resulting
soln was refluxed for 24 h under N2. MeOH was removed by rotary
evaporation, and the residue was dissolved in CH2Cl2 (40 mL),
washed with H2O (2 × 40 mL), dried (Na2SO4), and concentrated by
rotary evaporation. The crude product was purified by column chro-
matography [silica gel, EtOAc–hexane (1:2)]. The 5,7-ring-fused
product 35 was not detected by TLC but, instead, the 5,6-ring-fused
product 34 [yield: 0.15 g (65%)] and the tetracarboxylate 36 [yield:
0.012 g (4%)] were obtained. In addition, 18% of the starting succi-
nate 33 was also recovered.
Synthesis of the 5,6-Fused-Ring Product 25 from the Open-
Chain Product 24 by Treatment with Sodium Hydride: Typical
Procedure
A soln of the open-chain product 24 (0.301 g, 0.84 mmol) in THF
(10 mL) was added to a mixture of a 60% suspension of NaH in
mineral oil (0.051 g, 1.28 mmol, 1.5 equiv) and THF (10 mL) at r.t.
under N2. Bubbles of H2 evolved. When the mixture had been re-
fluxed for 7 h and unreacted 24 was no longer observed by TLC, the
THF was removed by rotary evaporation. The residue was dissolved
in CH2Cl2 (30 mL), washed with H2O (2 × 20 mL), dried (Na2SO4),
and concentrated by rotary evaporation. The crude product was pu-
rified by column chromatography [silica gel, EtOAc–hexane (1:1)];
yield: 0.086 g (76%).
Synthesis 2012, 44, 3337–3352
© Georg Thieme Verlag Stuttgart · New York

PAPER
Highly Functionalized Fused-Ring Heterocycles
3351
Reaction of 5,7-Ring-Fused Product 35 with Sodium Methoxide
in Methanol
The reaction of 21a,b (0.269 g, 1.25 mmol, 1 equiv) with methyl
propiolate (0.109 g, 1.28 mmol, 1 equiv) in MeOH (20 mL) at r.t.
for 24 h gave 68 in 13% (0.036 g) yield.
A soln of NaOMe in MeOH (0.09 mL, 0.4 mmol, 0.9 equiv) was
added to a soln of 35 (0.2 g, 0.4 mmol) in MeOH at r.t. The intense
yellow color of the 35 in MeOH changed to a dark brown. After stir-
ring for 15 min at r.t., the soln was analyzed by TLC. The spot for
the starting 5,7-ring-fused 35 had disappeared while a new spot ap-
peared on the TLC plate and was identified as corresponding to tet-
racarboxylate 36. After 15 min, MeOH was removed by rotary
evaporation and the products were purified according to the general
workup procedure and by column chromatography [silica gel,
EtOAc–hexane (1:1) to give tetracarboxylate 36; yield: 0.072 g
(37.1%).
2-Acetyl-2-methyl-6-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one
(68)
Pale-yellow solid; yield: 0.042 g (16%); mp 142–144 °C; Rf = 0.45
(EtOAc–hexane, 1:2).
IR (neat): 3168, 3055, 2895, 1727, 1652, 1451, 1394, 1197, 1108,
1053, 1021, 952, 900, 825, 769, 684, 664 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.37 (s, 1 H), 7.78 (d, J = 7.37 Hz,
2 H), 7.54–7.44 (m, 3 H), 5.83 (s, 1 H), 2.33 (s, 3 H), 1.79 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 205.48, 165.55, 164.12, 131.67,
131.45, 128.76, 126.56, 96.55, 91.09, 24.80, 22.09.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO3: 232.0974; found:
232.0992.
Reaction of Tautomeric Pair 21a,b with Methyl Propiolate in
Refluxing Methanol
A soln of methyl propiolate (0.264 g, 3.11 mmol, 1.51 equiv) in an-
hyd MeOH (15 mL) was added dropwise to a stirred soln of tauto-
mers 21a,b (0.444 g, 2.06 mmol, 1 equiv) in anhyd MeOH (10 mL)
at r.t. under N2. The molarities of methyl propiolate and tautomers
21a,b were 0.21 M and 0.14 M, respectively. The resulting soln was
refluxed for 24 h under N2, and then MeOH was removed by rotary
evaporation. In addition to a spot for the unreacted 21a,b, two new
spots were detected by TLC (EtOAc–hexane, 1:2). The products
were isolated and purified by following the general workup proce-
dure. The crude product was further purified by column chromatog-
raphy [silica gel, EtOAc–hexane (1:3 then 1:1)]. Unreacted 21a,b
[0.291g (66%)] was eluted first (21a/21b ratio 1:3.03 in CDCl3),
followed by oxazole 65; yield: 0.022 g (4%). A more polar intense-
yellow solid (0.026 g), corresponding to the third spot on the TLC,
was also isolated; Rf = 0.29 (EtOAc–hexane, 1:2).
Single crystals for X-ray crystallography were grown by the vapor-
diffusion method by diffusing hexane into a soln of compound 68 in
CHCl3.
Crystallographic data for compounds 25, 33, 34, 35 38, and 68 have
been deposited with the accession numbers CCDC 88832, CCDC
888330, CCDC 888334, CCDC 888332, CCDC 888333, and
CCDC 888331, respectively, and can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: depos-
it@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/conts/retriev-
ing.html.
Repetition of this reaction with 21a,b (0.37 g, 1.7 mmol, 1 equiv)
and methyl propiolate (0.222 g, 2.61 mmol, 1.52 equiv) in refluxing
MeOH (10 mL) for 27 h gave the unreacted starting tautomers 21a,b
[0.15 g (41%)], 65 [yield: 0.03 g (6%)], and the same unidentified
intense-yellow solid (0.058 g).
Acknowledgment
The authors acknowledge the educational and general funds of Mis-
sissippi State University for partial financial support of this work.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. This con-
tains details of the experimental procedures discussed in this article,
along with detailed peak assignments for 1H and 13C NMR spectra
Methyl (2E)-3-[4,5-Dimethyl-2-(2-oxo-2-phenylethylidene)-1,3-
oxazol-3(2H)-yl]acrylate (65)
Yellow solid; yield: 0.022 g (4%); mp 150–152 °C; Rf = 0.40
(EtOAc–hexane, 1:2).
IR (neat, cm–1): 3084, 3001, 2951, 2850, 1699, 1635, 1597, 1573,
1450, 1351, 1326, 1289, 1239, 1222, 1152, 1123, 1064, 978, 924,
861, 834, 763, 680.
1H NMR (600 MHz, CDCl3): δ = 8.09 (d, J = 14.95 Hz, 1 H), 7.46
(m, 5 H), 6.70 (s, 1 H), 5.32 (d, J = 14.95 Hz, 1 H), 3.75 (s, 3 H),
2.03 (s, 3 H), 1.72 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 203.52, 168.84, 167.46, 162.13,
134.10, 131.51, 129.44, 129.39, 127.24, 120.34, 99.73, 75.44,
51.57, 23.39, 18.21.
HRMS (ESI): m/z [M + 2H]+ calcd for C17H19NO4: 301.1314;
found: 301.1407.
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References
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A soln of methyl propiolate (0.097 g, 1.1 mmol, 1 equiv) in anhyd
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Synthesis 2012, 44, 3337–3352
© Georg Thieme Verlag Stuttgart · New York