Expeditious one-pot synthesis of highly substituted thiazolo[3,2-a]pyridines involving chromones

Article abstract of DOI:10.1016/j.tet.2009.11.096

The 1,4-zwitterion derived from 4,5-dimethylthiazole and acetylenedicarboxylates has been shown to react at low temperature readily with 3-formylchromones (chromone-3-carboxaldehydes) resulting, after an unusual rearrangement, in the facile synthesis of thiazolo[3,2-a]pyridine derivatives; in the case of electron-donating substituents in the chromone ring tetracyclic chromenothiazolopyridines are isolated as the main reaction products. However, at higher temperature after an unexpected 1,2-aroyl migration 8-formyl-5H-[1,3]thiazolo[3,2-a]pyridines are formed as a mixture of two rotamers. Structural assignments of the new compounds as well as complete assignment of ¹H and ¹³C NMR signals were based on the analysis of their ¹H and ¹³C NMR (1D and 2D), IR, MS and elemental analysis data. Plausible mechanisms are proposed.

Full text of DOI:10.1016/j.tet.2009.11.096

Tetrahedron 66 (2010) 947–954
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expeditious one-pot synthesis of highly substituted thiazolo[3,2-a]pyridines
involving chromones
,
a
,
b
Michael A. Terzidis a, Julia Stephanidou-Stephanatou a , Constantinos A. Tsoleridis , Aristides Terzis ,
*
*
Catherine P. Raptopoulou b, Vassilis Psycharis b
a Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
b X-Ray Laboratory, NCR ‘‘Democritos’’, Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,4-zwitterion derived from 4,5-dimethylthiazole and acetylenedicarboxylates has been shown to
react at low temperature readily with 3-formylchromones (chromone-3-carboxaldehydes) resulting,
after an unusual rearrangement, in the facile synthesis of thiazolo[3,2-a]pyridine derivatives; in the case
of electron-donating substituents in the chromone ring tetracyclic chromenothiazolopyridines are iso-
lated as the main reaction products. However, at higher temperature after an unexpected 1,2-aroyl
migration 8-formyl-5H-[1,3]thiazolo[3,2-a]pyridines are formed as a mixture of two rotamers. Structural
assignments of the new compounds as well as complete assignment of 1H and 13C NMR signals were
based on the analysis of their 1H and 13C NMR (1D and 2D), IR, MS and elemental analysis data. Plausible
mechanisms are proposed.
Received 28 August 2009
Received in revised form
2 November 2009
Accepted 20 November 2009
Available online 29 November 2009
Keywords:
Acetylenedicarboxylates
3-Formylchromones
Ó 2009 Elsevier Ltd. All rights reserved.
Chromenothiazolopyridines
Chromone-3-carboxaldehydes
Multicomponent reactions
Thiazolopyridines
1. Introduction
formation of either thiazolopyridines or chromenylthiazolooxazines.
The use of 3-formylchromones and thiazole would give to the re-
The thiazolopyridine ring system is found in a broad range of
biologically active compounds.1 Specifically, thiazolo[3,2-a]pyridine
derivatives are found to exhibit a broad spectrum of potent anti-
cancer activity and are useful for chemotherapy of various cancers,
such as leukemia, lung cancer, and melanoma.2 Due to their bi-
ological importance, thiazolo[3,2-a]pyridine derivatives have be-
come synthetic targets for many organic and medicinal chemists.3,4
On the other hand, the rich and fascinating chemistry that stems
from the addition of nucleophiles to activated acetylenic compounds
has evoked considerable interest.5 N-Heterocycles are known to
form zwitterions with activated acetylenic compounds, which can be
trapped by a variety of electrophiles and proton donors leading thus
to the facile synthesis of heterocyclic compounds.6 In the light of our
interest on the development of new routes toward heterocyclic
systems,7 we have exploited the reactivity profile of a thiazole-di-
methyl acetylenedicarboxylate (DMAD) zwitterion in bringing about
three-component reactions with 3-formylchromones speculating
action a new perspective, since 3-formylchromones represent a very
reactive system owing to the presence of an unsaturated keto func-
tion, a conjugated second carbonyl group at C-3 and, above all, a very
reactive electrophilic center at C-2 and the thiazole ring is liable to
molecular rearrangement.8
2. Results and discussion
Our studies were initiated by the reaction of DMAD with 3-
formylchromone 1a and 4,5-dimethylthiazole at ꢀ10 ꢁC to rt to
afford the thiazolo[3,2-a]pyridinedicarboxylate 5a in 45% yield,9
instead of the expected chromenylthiazolooxazine 7a or thiazolo-
pyridine 8a (and/or 9a) (Scheme 1). A minor product, identified as
chromenothiazolopyridinedicarboxylate 6a (w4% yield), was also
detected. The reaction appears to be general with a number of
substituted 3-formylchromones affording thiazolo[3,2-a]pyr-
idinedicarboxylates 5 in moderate yield. However, in the case of
3-formylchromones 1b and 1c with electron-donating substituents
in 6-position, the tetracyclic derivatives 6 were the main reaction
products, whereas 5 were formed as minor products in w5% yield
(Table 1).
* Corresponding authors. Tel.: þ30 2310 997831; fax: þ30 2310 997679.
E-mail addresses: ioulia@chem.auth.gr (J. Stephanidou-Stephanatou), tsolerid@
chem.auth.gr (C.A. Tsoleridis).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.096

948
M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
Scheme 1. Reaction of 3-formylchromones 1 with acetylenedicarboxylates 2 and thiazole 3 to afford compounds 4, 5, and 6.
Table 1
Synthesis of thiazolopydines 4, 5, and benzopyranothiazolopydines 6
Chromone
Ester
Products
R1
R2
R3
E
4a (%)
Rotameric ratio A:B
5b (%)
6b (%)
1a
1b
1c
1d
1e
1f
1g
1a
1d
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Br
H
H
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
4a (45)
4b (50)
4c (45)
4d (41)
4e (37)
4f (23)
4g (38)
4h (45)
4i (41)
1.4:1.0
1.9:1.0
2.5:1.0
2.2:1.0
2.4:1.0
2.6:1.0
2.5:1.0
1.6:1.0
2.3:1.0
5a (45)
5b (5)d
5c (10)d
5d (41)
5e (37)
5f (23)
5g (38)
d
6a (4)c
6b (38)
6c (32)
Me
i-Pr
Cl
Cl
NO2
Br
6e (5)c
d
d
H
Cl
d
COOEt
d
d
a
Reaction conditions: 85 ꢁC in DME (reflux).
Reaction conditions: ꢀ10 ꢁC to rt in DME.
As an inseparable mixture with 5.
b
c
d
As an inseparable mixture with 6.
Unexpectedly, when the reaction was repeated in boiling
formation of the non interconvertible rotamers, most probably,
during the [1,3]H shift (17–4, Scheme 2) syn hydride migration
leading to the major rotamer appears to be more favorable com-
pared to the anti leading to the minor rotamer, on account of
dimethoxyethane (DME), 8-formyl-5H-thiazolo[3,2-a]pyridines 4
were isolated, as the only reaction products, as a mixture of two
rotamers in moderate yields (23–50%). The rotameric ratio, as
expected, was greatly dependent on the size of the R1 chromone
substituents varying from 1.4:1 in the unsubstituted derivative 4a
to 2.6:1 in the nitro-substituted 4f (Table 1 and Fig. 2). The same
products 4 were also isolated, when the reaction was carried out
with diethyl acetylenedicarboxylate. A MO reaction path calcula-
tion for the estimation of the rotational energy barrier of the
benzoyl group, with the assumption that the hydrogen bond of the
salicylate moiety is preserved, gave comparable results by both
AM1 and PM3 methods.10 In Figure 1 the calculated sinusoid-like
curve (PM3) for compound 4b for the variation of relative energy of
formation (DDHf) versus the dihedral angle between the atoms in
group C14-C8-C7-C6 (Fig. 4) showing two energy barriers of 26.8
and 31.4 kcal (PM3) for a full rotation, is depicted. The minima of
energy at 90ꢁ and 270ꢁ correspond to the major and minor
rotamers, respectively. Moreover, as already mentioned, the rota-
meric ratio greatly depends on the size of the chromone 50-sub-
stituents. This ratio remains unchanged even by refluxing in DME
for 4 h, because the rotational restriction energy is relatively high,
as was also confirmed by computation. Concerning the initial
Figure 1. Variation of relative energy of formation (DDHf) versus the dihedral angle
between C14-C8-C7-C6 atoms (Fig. 4) as the salicylate group is rotating in compound
4b (PM3).

M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
949
Figure 4. Crystal structure of compound 4g cocrystallized with CHCl3 (major
component).
(instead of the expected aldehyde carbon)6,13 giving intermediate
11, which, by chromone ring opening (path a) leads initially to 12
and then by ring closure and formation of a new six-member ring to
13. Deformylation of 13 followed by 1,5-sigmatropic shift results in
5 through the intermediacy of the vinyl sulfide zwitterion 15
bearing an aromatic pyridine ring. However, when R1 is an elec-
tron-donating substituent, the ether bond of the chromone moiety
in intermediate 11 is stabilized resulting, before deformylation, in
the formation of the cyclohexene ring, through path b, leading thus
stereoselectively to compound 6. Nevertheless, 6c was completely
transformed to 5c during column purification. Finally, when the
reaction is carried out at higher temperature 1,2-aroyl migration in
intermediate 13 seems to be more favorable to deformylation
leading through 16 to the isolated products 4.
Figure 2. Global lower energy conformations of 4b major (a) and minor (b) rotamers
calculated by DFT (B3LYP/6-31G(d)).
2.1. Structure assignments of the new compounds
The assigned molecular structures of the new compounds 4, 5,
and 6 were based on rigorous spectroscopic analysis including IR,
NMR (1H, 13C, COSY, NOESY, HETCOR, and COLOC), MS and ele-
mental analysis data.
Concerning the structural assignment of the major and minor
rotamers of compounds 4 a substantial difference was observed in
the 1H NMR chemical shift of the C-60 proton, being always shifted
downfield, approximately 0.5 ppm, in the major rotamer. This dif-
ference can be attributed to the influence of the 5-ester moiety
being in close proximity compared to the minor rotamer, as is
depicted in Figure 2.
However, in order to eliminate any ambiguity about the struc-
ture of compounds 4, the structures of the major rotamers of 4b and
4g were independently confirmed by crystal structure analysis14
(Fig. 3 and Fig. 4). In both structures the salicylate carbonyl is in anti
configuration with the 5-carboxymethylo group. The thiazolo ring
is planar and the dihydropyridine ring has the boat conformation.
The dihedral angle between oxadiazole plane and C9-C8-C14-C13 is
about 30ꢁ and the salicylate moiety is almost perpendicular to the
plane of atoms C9-C8-C14 (Fig. 3).
Concerning the structure of 6b COLOC correlations in conjunc-
tion with the NOESY correlations (Fig. 5) confirmed the structure
and the syn-approximation of protons 6a-H and 12b-H. In Figure 5
the COLOC correlations of protons with carbons via 2J and 3J cou-
pling for compounds 4c, 5a, and 6b are depicted.
Figure 3. Crystal structure of compound 4b (major component).
stereochemical interactions, irrespective of the initial configuration
of salicyloyl moiety. In Figure 2 the global lower energy confor-
mations of 4b rotamers calculated by DFT (B3LYP/6-31G(d))11,12 are
depicted. The two rotamers could also be regarded as di-
astereomers, since there is a chiral center at C5 and the inability of
free rotation of salicyloyl moiety at C7 can be considered to create
a second chiral center. However, for the sake of clarity, the isomers
will be referred to as rotamers throughout this work.
The following mechanistic postulate (Scheme 2) may be invoked
to rationalize the reaction. The Huisgen zwitterion 10 formed from
thiazole and DMAD attacks initially the C-2 chromone carbon
The global lower energy conformation of 6b, in accordance with
COLOC and NOESY data, calculated by DFT (B3LYP/6-31G(d)) is
depicted in Figure 6.

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M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
Scheme 2. Proposed plausible mechanism for the formation of compounds 4, 5, and 6.
2
3
Figure 5. Diagnostic COLOC correlations between protons and carbons (via JC-H and JC-H) in compounds 4c, 5a, and 6b. In 6b some important diagnostic NOESY correlations (in
blue color) are also included.
obtained along with promising new tetracyclic chromenothiazolo-
pyridines (6), since they combine two biologically active ring sys-
tems 1,4-chromenone with [1,3]thiazolo[3,2-a]pyridine,2 whereas
at higher temperature through an unexpected 1,2-aroyl migration
8-formyl-5H-[1,3]thiazolo[3,2-a]pyridines (4) were isolated as
a mixture of two non interconvertible rotamers. Moreover, the
present work demonstrates the versatility of chromones in bringing
about one-pot synthetic procedures.
4. Experimental
4.1. General
Melting points were measured on a Kofler hot-stage and are
uncorrected. Column chromatography was carried out using Merck
silica gel. TLC was performed using precoated silica gel glass plates
Figure 6. Global lower energy conformation of 6b calculated by DFT (B3LYP/6-31G(d)).
0.25 mm containing fluorescent indicator UV254 purchased from
Macherey–Nagel using a 3:1 mixture of petroleum ether/ethyl ac-
3. Conclusions
etate. Petroleum ether refers to the fraction boiling between 60 and
80 ꢁC. NMR spectra were recorded at room temperature (rt) on
a Bruker AM 300 spectrometer at 300 MHz for 1H and 75 MHz for
13C, respectively, using CDCl3 as solvent. Chemical shifts are
In conclusion, we have devised the first three-component re-
action involving a thiazole-DMAD zwitterion for the synthesis of
novel thiazolo- and chromenothiazolopyridines. The outcome of the
reaction was found to be temperature depended. So, at ꢀ10 ꢁC to rt,
through an unusual rearrangement of the thiazole ring, salicylate
derivatives of [1,3]thiazolo[3,2-a]pyridines (5) were mainly
expressed in d values (ppm) relative to TMS as internal standard for
1H and relative to TMS (0.00 ppm) or to CDCl3 (77.05 ppm) for 13C
NMR spectra. Coupling constants nJ are reported in Hertz. Second
order 1H spectra in the aromatic region, where it was possible, were

M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
951
analyzed by simulation.15 IR spectra were recorded on a Perkin–
Elmer 297 spectrometer or on a Perkin–Elmer 1600 series FTIR
spectrometer and are reported in wave numbers (cmꢀ1). Low-res-
olution electron impact mass spectra were recorded on a 6890 N
GC/MS system (Agilent Technology) and elemental analyses per-
formed with a Perkin–Elmer 2400-II CHN analyzer.
(C-10), 120.5 (C-2), 128.4 (C-30), 132.1 (C-3), 131.4 (C-60), 138.1 (C-40),
145.2 (C-6), 157.7 (C-8a), 160.0 (C-20), 164.6 (5-C]O), 168.6 (6-
C]O), 180.1 (8-C]O), 199.7 (7-C]O).
4.2.3. 5,6-Dimethoxycarbonyl-2,3-dimethyl-8-formyl-7-(20-hydroxy-
50-isopropylbenzoyl)-5H-[1,3]thiazolo[3,2-a]pyridine (4c). Yellow crys-
tals, as a 2.5:1 inseparable mixture of rotamers (0.212 g, 45%), mp
212–214 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax: 3448 (br), 1734,
4.2. General procedure for the reaction of
3-formylchromones (1a–1g) with acetylenedicarboxylates and
4,5-dimethylthiazole at 85 8C
ꢂ
1696 cmꢀ1. MS (LCMS) m/z (%) 472 (100, Mþ þ1). Anal. Calcd for
C24H25NO7S(471.52):C,61.13;H,5.34;N, 2.97. Found:C,61.01;H, 5.48;
N, 3.13.
1
To a stirred solution of 3-formylchromone 1 (1.0 mmol) and 4,5-
dimethylthiazole (1 mmol) in DME (20 mL) kept at ꢀ10 ꢁC under ar-
gon, methyl (or ethyl) acetylene (1.2 mmol) was added. The system
was then allowed to attain room temperature and was refluxed for
12 h. The solvent was distilled off and the resulting residue was sub-
jected to columnchromatographyon silicagel using petroleumether/
AcOEt (7:1) as eluent, slowly increasing the polarity up to 3:1 to give.
Major rotamer: H NMR: 1.178 (d, J¼6.9 Hz, 3H, 50-CH(CH3)2),
1.183 (d, J¼6.9 Hz, 3H, 50-CH(CH3)2), 2.35 (s, 6H, 2-CH3, 3-CH3), 2.78
(sept, J¼6.9 Hz,1H, 50-CH), 3.61 (s, 3H, 5-OCH3), 3.79 (s, 3H, 6-OCH3),
6.21 (s, 1H, 5-H), 6.98 (d, J¼8.6 Hz, 1H, 30-H), 7.39 (dd, J¼8.6, 2.3 Hz,
1H, 40-H), 7.49 (d, J¼2.3 Hz, 1H, 60-H), 8.99 (s, 1H, CHO), 11.46 (s, 1H,
OH). 13C NMR: 10.9 (3-CH3), 11.8 (2-CH3), 23.7, and 24.05 (CHMe2),
33.2 (CHMe2), 51.9 (5-OCH3), 53.5 (6-OCH3), 57.2 (C-5), 98.4 (C-7),
104.5 (C-8), 118.0 (C-30), 120.4 (C-2), 120.5 (C-10), 129.0 (C-60), 132.0
(C-3),135.4 (C-40),139.7 (C-50),146.3 (C-6),157.9 (C-8a),159.9 (C-20),
164.4 (5-C]O), 168.9 (6-C]O), 180.2 (8-C]O), 200.6 (7-C]O).
4.2.1. 5,6-Dimethoxycarbonyl-2,3-dimethyl-8-formyl-7-(20-hydroxy-
benzoyl)-5H-[1,3]thiazolo[3,2-a]pyridine (4a). Yellow crystals as
1.4:1 inseparable mixture of rotamers (0.193 g, 45%), mp 227–230 ꢁC
1
Minor rotamer: H NMR: 1.08 (d, J¼6.9 Hz, 3H, 50-CH3), 1.09 (d,
(CH2Cl2/pet. ether); IR (KBr) nmax: 3444 (br), 1736, 1695, 1632 cmꢀ1
.
J¼6.9 Hz, 3H, 50-CH3), 2.33 (s, 3H, 2-CH3, 3-CH3), 2.69 (sept,
J¼6.9 Hz, 1H, 50-CH), 3.55 (s, 3H, 5-OCH3), 3.76 (s, 3H, 6-OCH3), 6.29
(s, 1H, 5-H), 6.96 (d, J¼8.6 Hz, 1H, 30-H), 6.97 (d, J¼2.3 Hz, 1H, 60-H),
7.34 (dd, J¼8.6, 2.3 Hz, 1H, 40-H), 9.04 (s, 1H, CHO), 11.50 (s, 1H, OH).
13C NMR: 10.9 (3-CH3), 11.8 (2-CH3), 23.83, and 24.05 (CHMe2), 33.0
(CHMe2), 51.8 (5-OCH3), 53.6 (6-OCH3), 57.4 (C-5), 98.2 (C-7), 103.1
(C-8), 118.3 (C-30), 120.5 (C-2), 120.5 (C-10), 128.5 (C-60), 132.3 (C-3),
134.8 (C-40), 139.6 (C-50), 145.1 (C-6), 157.7 (C-8a), 160.3 (C-20), 164.6
(5-C]O), 168.6 (6-C]O), 180.1 (8-C]O), 199.7 (7-C]O).
ꢂ
MS (LCMS) m/z (%) 452 (100, Mþ þNa). Anal. Calcd for C21H19NO7S
(429.44): C, 58.73; H, 4.46; N, 3.26. Found: C, 58.56; H, 4.50; N, 3.33.
Major rotamer: 1H NMR: 2.34 (s, 3H, 2-CH3), 2.36 (s, 3H, 3-CH3),
3.61 (s, 3H, 5-OCH3), 3.82 (s, 3H, 6-OCH3), 6.19 (s, 1H, 5-H), 6.87
(ddd, J¼8.2, 7.5, 1.1 Hz, 1H, 50-H), 7.05 (dd, J¼8.0, 1.1 Hz, 1H, 30-H),
7.50 (ddd, J¼8.0, 7.5, 1.5 Hz, 1H, 40-H), 7.67 (dd, J¼8.3, 1.5 Hz, 1H, 60-
H), 9.00 (s, 1H, CHO), 11.61 (s, 1H, OH). 13C NMR: 11.0 (3-CH3), 11.9
(2-CH3), 51.8 (5-OCH3), 53.5 (6-OCH3), 57.2 (C-5), 98.4 (C-7), 104.4
(C-8), 118.3 (C-30), 119.7 (C-50), 120.6 (C-2), 120.8 (C-10), 131.7 (C-60),
132.1 (C-3), 136.9 (C-40), 146.1 (C-6), 157.8 (C-8a), 161.8 (C-20), 164.4
(5-C]O), 168.9 (6-C]O), 180.1 (8-C]O) 200.7 (7-C]O).
4.2.4. 7-(50-Chloro-20-hydroxybenzoyl)-5,6-dimethoxycarbonyl-2,3-
dimethyl-8-formyl-5H-[1,3]thiazolo[3,2-a]pyridine (4d). Yellow crys-
tals, as a 2.2:1 inseparable mixture of rotamers (0.190 g, 41%), mp
273–276 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax: 3448 (br), 1736, 1693,
Minor rotamer: 1H NMR: 2.34 (s, 3H, 2-CH3), 2.35 (s, 3H, 3-CH3),
3.57 (s, 3H, 5-OCH3), 3.77 (s, 3H, 6-OCH3), 6.27 (s, 1H, 5-H), 6.73
(ddd, J¼8.3, 7.5, 1.1 Hz, 1H, 50-H), 7.02 (dd, J¼8.0, 1.1 Hz, 1H, 30-H),
7.20 (dd, J¼8.3, 1.5 Hz, 1H, 60-H), 7.43 (ddd, J¼8.0, 7.5, 1.5 Hz, 1H, 40-
H), 9.05 (s, 1H, CHO), 11.61 (s, 1H, OH). 13C NMR: 11.0 (3-CH3), 11.9
(2-CH3), 52.0 (5-OCH3), 53.7 (6-OCH3), 57.4 (C-5), 98.6 (C-7), 103.1
(C-8), 118.4 (C-30), 119.4 (C-50), 119.7 (C-10), 120.5 (C-2), 131.3 (C-60),
132.3 (C-3), 136.7 (C-40), 145.1 (C-6), 157.6 (C-8a), 162.0 (C-20), 164.4
(5-C]O), 168.6 (6-C]O), 180.1 (8-C]O) 199.8 (7-C]O).
ꢂ
1640 cmꢀ1. MS (LCMS) m/z (%) 462/464 (100, Mþ ꢀ1). Anal. Calcd for
C21H18ClNO7S (463.89): C, 54.37; H, 3.91; N, 3.02. Found: C, 54.46; H,
3.84; N, 3.09.
Major rotamer: 1H NMR: 2.35 (s, 3H, 2-CH3), 2.38 (s, 3H, 3-CH3),
3.65 (s, 3H, 5-OCH3), 3.89 (s, 3H, 6-OCH3), 6.18 (s, 1H, 5-H), 7.02 (d,
J¼8.5 Hz,1H, 30-H), 7.44 (dd, J¼8.5, 2.5 Hz,1H, 40-H), 7.62 (d, J¼2.5 Hz,
1H, 60-H), 8.98 (s, 1H, CHO), 11.52 (s, 1H, OH). 13C NMR: 11.0 (3-CH3),
11.9 (2-CH3), 52.1 (5-OCH3), 53.8 (6-OCH3), 57.2 (C-5), 98.2 (C-7),
104.5 (C-8), 120.1 (C-30), 120.9 (C-2), 121.4 (C-10), 124.0 (C-50), 130.7
(C-60), 132.4 (C-3), 136.7 (C-40), 145.4 (C-6), 157.8 (C-8a), 160.3 (C-20),
164.2 (5-C]O), 168.7 (6-C]O), 179.8 (8-C]O), 200.0 (7-C]O).
Minor rotamer: 1H NMR: 2.34 (s, 3H, 2-CH3), 2.36 (s, 3H, 3-CH3),
3.62 (s, 3H, 5-OCH3), 3.77 (s, 3H, 6-OCH3), 6.24 (s, 1H, 5-H), 7.00 (d,
J¼8.5 Hz, 1H, 30-H), 7.15 (d, J¼2.5 Hz, 1H, 60-H), 7.38 (dd, J¼8.5,
2.5 Hz, 1H, 40-H), 9.02 (s, 1H, CHO), 11.57 (s, 1H, OH). 13C NMR: 11.0
(3-CH3), 11.9 (2-CH3), 52.1 (5-OCH3), 53.7 (6-OCH3), 57.4 (C-5), 98.2
(C-7), 103.0 (C-8), 120.2 (C-30), 120.4 (C-10), 120.9 (C-2), 124.0 (C-50),
129.9 (C-60), 132.4 (C-3), 136.7 (C-40), 144.7 (C-6), 157.8 (C-8a), 160.5
(C-20), 164.2 (5-C]O), 168.4 (6-C]O), 179.6 (8-C]O), 199.1
(7-C]O).
4.2.2. 5,6-Dimethoxycarbonyl-2,3-dimethyl-8-formyl-7-(20-hydroxy-
50-methyl-benzoyl)-5H-[1,3]thiazolo[3,2-a]pyridine (4b). Yellow cry-
stals as an inseparable mixture of rotamers in a 1.9:1 ratio (0.222 g,
50%), mp 238–240 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax: 3447 (br),
ꢂ
1736, 1699, 1637 cmꢀ1. MS (LCMS) m/z (%) 466 (100, Mþ þNa), 444
ꢂ
(25, Mþ þ1). Anal. Calcd for C22H21NO7S (443.47): C, 59.58; H, 4.77;
N, 3.16. Found: C, 59.46; H, 4.68; N, 3.23.
Major rotamer: 1H NMR: 2.24 (s, 3H, 50-CH3), 2.34 (s, 3H, 2-CH3),
2.36 (s, 3H, 3-CH3), 3.63 (s, 3H, 5-OCH3), 3.83 (s, 3H, 6-OCH3), 6.20
(s, 1H, 5-H), 6.96 (d, J¼8.5 Hz, 1H, 30-H), 7.32 (dd, J¼8.5, 2.2 Hz, 1H,
40-H), 7.41 (d, J¼2.2 Hz,1H, 60-H), 9.00 (s,1H, CHO),11.45 (s,1H, OH).
13C NMR: 11.0 (3-CH3), 11.9 (2-CH3), 52.0 (5-OCH3), 53.5 (6-OCH3),
57.2 (C-5), 98.2 (C-7), 104.5 (C-8), 118.1 (C-30), 120.4 (C-2), 120.5 (C-
10), 128.4 (C-50), 131.4 (C-60), 132.1 (C-3), 138.0 (C-40), 146.2 (C-6),
157.9 (C-8a), 159.8 (C-20), 164.4 (5-C]O), 168.9 (6-C]O), 180.3 (8-
C]O) 200.5 (7-C]O).
4.2.5. 7-(50-Chloro-20-hydroxy-40-methylbenzoyl)-5,6-dimethoxy-
carbonyl-2,3-dimethyl-8-formyl-5H-[1,3]thiazolo[3,2-a]pyridine
(4e). Yellow crystals as a 2.4:1 inseparable mixture of rotamers
Minor rotamer: 1H NMR: 2.15 (s, 3H, 5-CH3), 2.35 (s, 3H, 2-CH3),
2.35 (s, 3H, 3-CH3), 3.58 (s, 3H, 5-OCH3), 3.77 (s, 3H, 6-OCH3), 6.28
(s, 1H, 5-H), 6.92 (d, J¼8.5 Hz, 1H, 30-H), 6.93 (d, 2.2 Hz, 1H, 60-H),
7.25 (dd, J¼8.5, 2.2 Hz, 1H, 40-H), 9.03 (s, 1H, CHO), 11.51 (s, 1H, OH).
13C NMR: 11.0 (3-CH3), 11.9 (2-CH3), 20.4 (5-CH3), 52.0 (5-OCH3),
53.5(6-OCH3), 57.5 (C-5), 98.1 (C-7), 103.2 (C-8), 118.2 (C-50), 119.3
(0.177 g, 37%), mp 262–266 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax
:
3448 (br), 1739, 1695, 1638 cmꢀ1. MS (LCMS) m/z (%) 500/502 (100,
ꢂ
M
þ þNa). Anal. Calcd for C22H20ClNO7S (477.91): C, 55.29; H, 4.22;
N, 2.93. Found: C, 55.40; H, 4.14; N, 3.01.
Major rotamer: 1H NMR: 2.34 (s, 3H, 40-CH3), 2.36 (s, 3H, 2-CH3),
2.39 (s, 3H, 3-CH3), 3.64 (s, 3H, 5-OCH3), 3.89 (s, 3H, 6-OCH3), 6.18

952
M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
(s, 1H, 5-H), 6.95 (s, 1H, 30-H), 7.59 (s, 1H, 60-H), 8.98 (s, 1H, CHO),
11.47 (s, 1H, OH). 13C NMR: 10.9 (3-CH3), 11.9 (2-CH3), 20.9 (40-CH3),
52.1 (5-OCH3), 53.8 (6-OCH3), 57.2 (C-5), 98.1 (C-7), 104.4 (C-8),
119.8 (C-10), 120.4 (C-30), 120.5 (C-2), 124.6 (C-50), 131.0 (C-60), 132.3
(C-3), 145.5 (C-40), 146.2 (C-6), 157.8 (C-8a), 160.1 (C-20), 164.2 (5-
C]O), 168.8 (6-C]O), 179.9 (8-C]O), 199.3 (7-C]O).
inseparable mixture of rotamers 1.6:1 (0.206 g, 45%), mp 186–189 ꢁC
(CH2Cl2/pet. ether); IR (KBr) nmax: 3447 (br), 1749, 1730. 1696 cmꢀ1
.
ꢂ
MS (LCMS) m/z (%) 480 (100, Mþ þNa). Anal. Calcd for C23H23NO7S
(457.50): C, 60.38; H, 5.07; N, 3.06. Found: C, 60.15; H, 4.92; N, 3.15.
Major rotamer: 1H NMR: 0.99 (t, J¼7.1 Hz, 3H, 5-CH2CH3), 1.29 (t,
J¼7.1 Hz, 3H, 6-CH2CH3), 2.33 (s, 3H, 2-CH3), 2.35 (s, 3H, 3-CH3),
4.06 (q, J¼7.0 Hz, 2H, 5-OCH2CH3), 4.21 (q, J¼7.1 Hz, 1H, 6-
OCH2CH3), 4.30 (q, J¼7.1 Hz, 1H, 6-OCH2CH3), 6.19 (s, 1H, 5-H), 6.85
(ddd, J¼8.3, 7.0, 1.2 Hz, 1H, 50-H), 7.04 (dd, J¼8.1, 1.2 Hz, 1H, 30-H),
7.50 (ddd, J¼8.1, 7.0, 1.5 Hz, 1H, 40-H), 7.71 (dd, J¼8.3, 1.5 Hz, 1H, 60-
H), 8.99 (s, 1H, CHO), 11.66 (s, 1H, OH). 13C NMR: 10.9 (3-CH3), 11.8
(2-CH3), 13.5 (5-OCH2CH3), 14.1 (6-OCH2CH3), 57.4 (C-5), 61.1 (5-
OCH2), 62.8 (6-OCH2), 99.1 (C-7), 104.3 (C-8), 118.2 (C-30), 119.3 (C-
50), 120.3 (C-2), 121.0 (C-10), 131.9 (C-60), 132.2 (C-3), 136.9 (C-40),
145.2 (C-6), 157.8 (C-8a), 161.8 (C-20), 164.1 (5-C]O), 168.4 (6-
C]O), 180.0 (8-C]O) 200.8 (7-C]O).
Minor rotamer: 1H NMR: 2.36 (s, 3H, 2-CH3), 2.37 (s, 3H, 40-CH3),
2.39 (s, 3H, 3-CH3), 3.62 (s, 3H, 5-OCH3), 3.76 (s, 3H, 6-OCH3), 6.25
(s, 1H, 5-H), 6.92 (s, 1H, 30-H), 7.13 (s, 1H, 60-H), 9.02 (s, 1H, CHO),
11.52 (s, 1H, OH). 13C NMR: 11.0 (3-CH3), 11.8 (2-CH3), 20.9 (40-CH3),
52.0 (5-OCH3), 53.7 (6-OCH3), 57.4 (C-5), 98.2 (C-7), 103.0 (C-8),
118.8 (C-10), 120.5 (C-30), 120.7 (C-2), 124.6 (C-50), 130.3 (C-60), 132.4
(C-3), 144.8 (C-40), 146.1 (C-6), 157.7 (C-8a), 160.4 (C-20), 164.3 (5-
C]O), 168.5 (6-C]O), 179.7 (8-C]O), 198.5 (7-C]O).
4.2.6. 5,6-Dimethoxycarbonyl-2,3-dimethyl-8-formyl-7-(20-hydroxy-
50-nitrobenzoyl)-5H-[1,3]thiazolo[3,2-a]pyridine (4f). Orange crys-
tals as an inseparable mixture of rotamers 2.6:1 (0.109 g, 23%), mp
273–276 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax: 3448 (br), 1736, 1694,
Minor rotamer: 1H NMR: 0.94 (t, J¼7.4 Hz, 3H, 5-CH2CH3), 1.25 (t,
J¼7.1 Hz, 3H, 6-CH2CH3), 2.33 (s, 3H, 2-CH3), 2.34 (s, 3H, 3-CH3),
4.02 (q, J¼7.0 Hz, 2H, 5-OCH2CH3), 4.20 (q, J¼7.1 Hz, 1H, 6-
OCH2CH3), 4.33 (q, J¼7.1 Hz, 1H, 6-OCH2CH3), 6.26 (s, 1H, 5-H), 6.74
(ddd, J¼8.3, 7.0, 1.2 Hz, 1H, 50-H), 7.00 (dd, J¼8.1, 1.2 Hz, 1H, 30-H),
7.24 (dd, J¼8.3, 1.5 Hz, 1H, 60-H), 7.43 (ddd, J¼8.1, 7.0, 1.5 Hz, 1H, 40-
H), 9.05 (s, 1H, CHO), 11.67 (s, 1H, OH). 13C NMR: 10.9 (3-CH3), 11.8
(2-CH3), 13.4 (5-OCH2CH3), 14.0 (6-OCH2CH3), 57.4 (C-5), 61.1 (5-
OCH2), 62.8 (6-OCH2), 98.9 (C-7), 103.0 (C-8), 118.3 (C-30), 119.3 (C-
50), 119.9 (C-10), 120.3 (C-2), 131.5 (C-60), 132.2 (C-3), 136.7 (C-40),
144.3 (C-6), 157.6 (C-8a), 162.1 (C-20), 164.2 (5-C]O), 168.0 (6-
C]O), 180.0 (8-C]O) 199.8 (7-C]O).
ꢂ
1692 cmꢀ1. MS (LCMS) m/z (%) 475 (100, Mþ þ1). Anal. Calcd for
C21H18N2O9S (474.44): C, 53.16; H, 3.82; N, 5.90. Found: C, 53.32; H,
3.84; N, 6.03.
Major rotamer: 1H NMR: 2.36 (s, 3H, 2-CH3), 2.38 (s, 3H, 3-CH3),
3.67 (s, 3H, 5-OCH3), 3.93 (s, 3H, 6-OCH3), 6.19 (s, 1H, 5-H), 7.18 (d,
J¼9.3 Hz, 1H, 30-H), 8.38 (dd, J¼9.3, 2.7 Hz, 1H, 40-H), 8.60 (d,
J¼2.7 Hz, 1H, 60-H), 8.97 (s, 1H, CHO), 12.25 (s, 1H, OH). 13C NMR:
11.0 (3-CH3), 11.9 (2-CH3), 52.3 (5-OCH3), 54.4 (6-OCH3), 57.3 (C-5),
98.4 (C-7),104.6 (C-8),119.6 (C-30),119.9 (C-2), 121.2 (C-10), 127.8 (C-
60), 131.3 (C-40), 132.5 (C-3), 140.2 (C-50), 144.9 (C-6), 158.1 (C-8a),
164.2 (C-20), 166.3 (5-C]O), 168.6 (6-C]O), 179.3 (8-C]O), 200.6
(7-C]O).
4.2.9. 7-(50-Chloro-20-hydroxybenzoyl)-5,6-diethoxycarbonyl-2,3-di-
methyl-8-formyl-5H-[1,3]thiazolo[3,2-a]pyridine (4i). Yellow crys-
tals as an inseparable mixture of rotamers 2.3:1 (0.202 g, 41%), mp
175–178 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax: 3448 (br), 1732, 1690,
Minor rotamer: 1H NMR: 2.37 (s, 3H, 2-CH3), 2.38 (s, 3H, 3-CH3),
3.65 (s, 3H, 5-OCH3), 3.78 (s, 3H, 6-OCH3), 6.23 (s, 1H, 5-H), 7.15 (d,
J¼9.3 Hz, 30-H), 8.13 (d, J¼2.7 Hz, 1H, 60-H), 8.32 (dd, J¼9.3, 2.7 Hz,
1H, 40-H), 9.01 (s, 1H, CHO), 12.30 (s, 1H, OH). 13C NMR: 11.1 (3-CH3),
11.9 (2-CH3), 52.3 (5-OCH3), 53.8 (6-OCH3), 57.5 (C-5), 98.5 (C-7),
104.5 (C-8), 119.7 (C-30), 119.9 (C-2), 121.4 (C-10), 127.4 (C-60), 131.2
(C-40), 132.5 (C-3), 140.2 (C-50), 144.9 (C-6), 158.2 (C-8a), 164.1 (C-
20), 166.6 (5-C]O), 168.3 (6-C]O), 179.1 (8-C]O), 200.7 (7-C]O).
ꢂ
1637 cmꢀ1. MS (LCMS) m/z (%) 514 (100, Mþ þNa). Anal. Calcd for
C23H22ClNO7S (491.94): C, 56.15; H, 4.51; N, 2.85. Found: C, 56.26; H,
4.54; N, 3.01.
Major rotamer: 1H NMR: 1.06 (t, J¼7.1 Hz, 3H, 5-OCH2CH3), 1.31
(t, J¼7.1 Hz, 3H, 6-OCH2CH3), 2.34 (s, 3H, 2-CH3), 2.36 (s, 3H, 3-CH3),
4.10 (q, J¼7.1 Hz, 2H, 5-OCH2), 4.32 (q, J¼7.1 Hz, 2H, 6-OCH2), 6.19 (s,
1H, 5-H), 7.02 (d, J¼9.0 Hz, 1H, 30-H), 7.45 (dd, J¼9.0, 2.7 Hz, 1H, 40-
H), 7.63 (d, J¼2.7 Hz, 1H, 60-H), 8.96 (s, 1H, CHO), 11.60 (s, 1H, OH).
13C NMR: 11.0 (3-CH3), 11.8 (2-CH3), 13.7 (5-OCH2CH3), 14.2 (6-
OCH2CH3), 57.4 (C-5), 61.2 (5-OCH2), 63.1 (6-OCH2), 99.1 (C-7),104.2
(C-8), 120.0 (C-30), 120.6 (C-2), 121.6 (C-10), 124.0 (C-50), 130.6 (C-60),
132.4 (C-3), 136.7 (C-40), 144.5 (C-6), 157.8 (C-8a), 160.3 (C-20), 163.9
(5-C]O), 168.2 (6-C]O), 179.6 (8-C]O), 200.1 (7-C]O).
Minor rotamer: 1H NMR: 1.01 (t, J¼7.1 Hz, 3H, 5-OCH2CH3), 1.25
(t, J¼7.3 Hz, 3H, 6-OCH2CH3), 2.36 (s, 6H, 2-CH3, 3-CH3), 4.09 (q,
J¼7.1 Hz, 2H, 5-OCH2), 4.20 (q, J¼7.3 Hz, 2H, 6-OCH2), 6.24 (s, 1H, 5-
H), 6.98 (d, J¼9.0 Hz, 30-H), 7.19 (d, J¼2.7 Hz, 1H, 60-H), 7.39 (dd,
J¼9.0, 2.7 Hz,1H, 40-H), 9.01 (s, 1H, CHO),11.63 (s, 1H, OH). 13C NMR:
11.0 (3-CH3), 11.8 (2-CH3), 13.6 (5-OCH2CH3), 14.0 (6-OCH2CH3), 57.4
(C-5), 61.2 (5-OCH2), 62.8 (6-OCH2), 98.9 (C-7),102.8 (C-8), 120.1 (C-
30), 120.7 (C-2), 121.6 (C-10), 123.95 (C-50), 130.0 (C-60), 132.5 (C-3),
136.6 (C-40), 143.9 (C-6), 157.6 (C-8a), 160.6 (C-20), 163.9 (5-C]O),
167.9 (6-C]O), 179.5 (8-C]O), 199.1 (7-C]O).
4.2.7. 7-(30,50-Dibromo-20-hydroxybenzoyl)-5,6-dimethoxycarbonyl-
2,3-dimethyl-8-formyl-5H-[1,3]thiazolo[3,2-a]pyridine (4g). Yellow
crystals, as an inseparable mixture of rotamers 2.5:1 (0.223 g, 38%),
mp 236–237 ꢁC (CH2Cl2/pet. ether); IR (KBr) nmax: 3445 (br), 1740,
ꢂ
1690, 1636 cmꢀ1. MS (LCMS) m/z (%) 586/588/590 (100, Mþ þ1).
Anal. Calcd for C21H17Br2NO7S (587.24): C, 42.95; H, 2.92; N, 2.39.
Found: C, 42.81; H, 2.84; N, 2.31.
Major rotamer: 1H NMR: 2.35 (s, 3H, 2-CH3), 2.38 (s, 3H, 3-CH3),
3.66 (s, 3H, 5-OCH3), 3.89 (s, 3H, 6-OCH3), 6.17 (s, 1H, 5-H), 7.76 (d,
J¼3.0 Hz, 60-H), 7.87 (d, J¼3.0 Hz, 40-H), 8.94 (s, 1H, CHO), 12.20 (s,
1H, OH). 13C NMR: 11.0 (3-CH3), 11.9 (2-CH3), 52.1 (5-OCH3), 53.8 (6-
OCH3), 57.2 (C-5), 98.3 (C-7), 104.5 (C-8), 111.0 (C-30), 113.1 (C-50),
121.1 (C-2), 122.3 (C-10), 132.4 (C-3), 132.9 (C-60), 141.8 (C-40), 145.0
(C-6),157.4 (C-20),157.6 (C-8a),164.1 (5-C]O),168.6 (6-C]O),179.5
(8-C]O), 199.8 (7-C]O).
Minor rotamer: 1H NMR: 2.36 (s, 3H, 2-CH3), 2.37 (s, 3H, 3-CH3),
3.64 (s, 3H, 5-OCH3), 3.77 (s, 3H, 6-OCH3), 6.22 (s, 1H, 5-H), 7.28 (d,
J¼3.0 Hz, 1H, 60-H), 7.82 (d, J¼3.0 Hz, 1H, 40-H), 8.98 (s, 1H, CHO),
12.27 (s,1H, OH). 13C NMR: 11.0 (3-CH3),11.9 (2-CH3), 52.1 (5-OCH3),
53.8 (6-OCH3), 57.2 (C-5), 98.4 (C-7), 103.0 (C-8), 111.0 (C-30), 113.3
(C-50), 121.3 (C-2), 121.3 (C-10), 132.5 (C-3), 132.1 (C-60), 141.8 (C-40),
144.4 (C-6), 157.6 (C-8a), 157.8 (C-20), 164.1 (5-C]O), 168.3 (6-
C]O), 179.3 (8-C]O), 198.9 (7-C]O).
4.3. General procedure for the reaction of
3-formylchromones (1a–1g) with DMAD and 4,5-
dimethylthiazole at L10 8C
DMAD (1.2 mmol) was added to a stirred solution of 3-for-
mylchromone 1 (1.0 mmol) and 4,5-dimethylthiazole (1 mmol) in
DME (20 mL) kept at ꢀ10 ꢁC under argon. The system was then
allowed to attain room temperature and was stirred for 12 h. The
solvent was distilled off and the resulting residue was subjected to
4.2.8. 5,6-Diethoxycarbonyl-2,3-dimethyl-8-formyl-7-(20-hydroxy-
benzoyl)-5H-[1,3]thiazolo[3,2-a]pyridine (4h). Yellow crystals as an

M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
953
column chromatography on silica gel using petroleum ether/AcOEt
(7:1) as eluent, slowly increasing the polarity up to 3:1 to give in
elution order.
(8-C]O), 169.3 (8a-C]O), 192.9 (6-C]O). MS (LCMS) m/z (%) 466
ꢂ
(100, Mþ þNa), 444 (70, Mþþ1). Anal. Calcd for C23H25NO6S
(443.51): C, 62.29; H, 5.68, N, 3.16. Found: C, 62.53; H, 5.52; N, 3.21.
4.3.1. From compound 1a. 4.3.1.1. 8,8a-Dimethoxycarbonyl-2,3-di-
methyl-6-(20-hydroxybenzoyl)-8aH-[1,3]thiazolo[3,2-a]pyridine
(5a). Orange crystals, (0.180 g, 45%), mp 208–209 ꢁC (CH2Cl2/Et2O);
4.3.3.2. 12a,12b-Dihydro-5,6-dimethoxycarbonyl-12a-formyl-10-
isopropyl-12-oxo-2,3-dimethyl-6aH,12H-chromeno[3,2-c][1,3]thia-
zolo[3,2-a]pyridine (6c). Oil, 32% yield, estimated from the 1H NMR
of the mixture with 5c. From a 1:3 mixture of 5c:6c the NMR data
IR (Nujol) nmax: 3458, 1738, 1698 cmꢀ1 1H NMR
. d: 2.02 (s, 3H,
2-CH3), 2.03 (s, 3H, 3-CH3), 3.75 (s, 3H, 8a-OCH3), 3.84 (s, 3H, 8-
OCH3), 6.91 (ddd, J¼7.6, 7.4, 1.1 Hz, 1H, 50-H), 7.03 (dd, J¼8.3, 1.1 Hz,
1H, 30-H), 7.45 (ddd, J¼8.3, 7.4, 1.75 Hz, 1H, 40-H), 7.50 (dd, J¼7.6,
1.75 Hz, 1H, 60-H), 7.90 (d, J¼1.0 Hz, 1H, 5-H), 7.98 (d, J¼1.0 Hz, 1H,
were deduced. 1H NMR
d
: 1.23 (d, J¼6.9 Hz, 6H, 50-CH(CH3)2), 1.84
(q, J¼1.0 Hz, 3H, 3-CH3), 1.93 (q, J¼1.0 Hz, 3H, 2-CH3), 2.90 (sept, 1H,
50-CH), 3.78 (s, 3H, 6-OCH3), 3.89 (s, 3H, 5-OCH3), 5.61 (s, 1H, 6a-H),
5.65 (s, 1H, 12b-H), 6.95 (d, J¼8.5 Hz, 1H, 8-H), 7.43 (dd, J¼8.5,
2.2 Hz, 1H, 9-H), 7.72 (d, J¼2.2 Hz, 1H, 11-H), 10.17 (s, 1H, 12a-CHO).
7-H), 11.63 (s, 1H, OH). 13C NMR
d: 11.2 (3-CH3), 12.7 (2-CH3), 52.1
(8-OCH3), 53.7 (8a-OCH3), 72.8 (C-8a),109.5 (C-6),118.3 (C-30),118.6
(C-50), 119.1 (C-2), 120.1 (C-10), 125.5 (C-3), 130.9 (C-60), 132.1 (C-7),
134.9 (C-40), 141.6 (C-5), 161.9 (C-20), 165.2 (8-C]O), 169.3 (8a-
13C NMR
d: 11.6 (3-CH3), 13.6 (2-CH3), 23.8 (10-CH(CH3)2), 33.4 (10-
CH), 52.3 (6-OCH3), 53.2 (5-OCH3), 58.6 (C-12a), 63.0 (C-6a), 71.1 (C-
12b), 114.2 (C-2), 118.3 (C-6), 118.4 (C-8), 119.8 (C-11a), 126.2 (C-11),
127.4 (C-3), 138.5 (C-9), 144.1 (C-5), 147.8 (C-10), 159.3 (C-7a), 164.2
(5-C]O), 165.7 (6-C]O), 187.4 (C-12), 196.8 (12a-C]O).
ꢂ
C]O), 192.8 (6-C]O). MS (LCMS) m/z (%) 402 (100, Mþ þ1). Anal.
Calcd for C20H19NO6S (401.43): C, 59.84; H, 4.77, N, 3.49. Found: C,
59.93; H, 4.83; N, 3.40.
4.3.4. From compound 1d. 4.3.4.1. 6-(50-Chloro-20-hydroxybenzoyl)-
8,8a-dimethoxycarbonyl-2,3-dimethyl-8aH-[1,3]thiazolo[3,2-a]pyri-
dine (5d). Orange crystals (0.178 g, 41%), mp 182–183 ꢁC (CH2Cl2/
4.3.1.2. 12a,12b-Dihydro-5,6-dimethoxycarbonyl-2,3-dimethyl-
12a-formyl-12-oxo-6aH,12H-chromeno[3,2-c][1,3]thiazolo[3,2-a]pyr-
idine (6a). From a 5:1 mixture of 5a:6a some 1H NMR data were
Et2O); IR (Nujol) nmax: 3448, 1736, 1695 cmꢀ1. 1H NMR
d: 2.03 (s, 3H,
deduced. 1H NMR
d: 1.83 (s, 3H, CH3), 1.94 (s, 3H, CH3), 3.75 (s, 3H,
3-CH3), 2.06 (s, 3H, 2-CH3), 3.76 (s, 3H, 8a-OCH3), 3.85 (s, 3H, 8-
OCH3), 6.99 (d, J¼8.8 Hz, 1H, 30-H), 7.39 (dd, J¼8.8, 2.5 Hz, 1H, 40-H),
7.45 (d, J¼2.5 Hz, 1H, 60-H), 7.91 (d, J¼1.1 Hz, 1H, 5-H), 7.94 (d,
6-OCH3), 3.89 (s, 3H, 5-OCH3), 5.61 (s, 1H, 6a-H), 5.68 (s, 1H, 12b-H),
7.02 (dd, J¼8.4, 1.0 Hz, 1H, 8-H), 7.08 (ddd, J¼8.0, 7.2, 1.0 Hz, 1H, 10-
H), 7.55 (ddd, J¼8.4, 7.2, 1.75 Hz, 1H, 9-H), 7.89 (dd, J¼8.0, 1.75 Hz,
1H, 11-H), 10.16 (s, 1H, CHO).
J¼1.1 Hz,1H, 7-H),11.48 (s,1H, OH). 13C NMR
d: 11.2 (3-CH3), 12.8 (2-
CH3), 52.2 (8-OCH3), 53.9 (8a-OCH3), 72.8 (C-8a), 107.9 (C-8), 109.0
(C-6), 119.1 (C-2), 119.8 (C-30), 120.9 (C-10), 123.3 (C-50), 125.5 (C-3),
129.9 (C-60), 131.7 (C-7), 134.5 (C-40), 141.8 (C-5), 160.2 (C-20), 165.0
(8-C]O), 169.0 (8a-C]O), 191.3 (6-C]O). MS (LCMS) m/z (%) 436/
4.3.2. From compound 1b. 4.3.2.1. 8,8a-Dimethoxycarbonyl-2,3-di-
methyl-6-(20-hydroxy-50-methylbenzoyl)-8aH-[1,3]thiazolo[3,2-
a]pyridine (5b). From a 1:2 mixture of 5b:6b some 1H NMR data
ꢂ
438 (100, Mþ þ1). Anal. Calcd for C20H18ClNO6S (435.88): C, 55.11;
were deduced. 1H NMR
d
: 2.02 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.32 (s,
H, 4.16, N, 3.21. Found: C, 54.98; H, 4.13; N, 3.30.
3H, 50-CH3), 3.76 (s, 3H, 8a-OCH3), 3.84 (s, 3H, 8-OCH3), 6.93 (d,
J¼8.0 Hz, 1H, 30-H), 7.26 (dd, J¼8.0, 2.0 Hz, 1H, 40-H), 7.89 (d,
J¼1.0 Hz, 1H, 5-H), 7.98 (d, J¼1.0 Hz, 1H, 7-H), 11.36 (s, 1H, OH).
4.3.5. From compound 1e. 4.3.5.1. 6-(50-Chloro-20-hydroxy-40-methyl-
benzoyl)-8,8a-dimethoxycarbonyl-2,3-dimethyl-8aH-[1,3]thiazolo[3,2-
a]pyridine (5e). Yellow crystals (0.167 g, 37%), mp 215–217 ꢁC
4.3.2.2. 12a,12b-Dihydro-5,6-dimethoxycarbonyl-12a-formyl-12-
oxo-2,3,10-trimethyl-6aH,12H-chromeno[3,2-c][1,3]thiazolo[3,2-
a]pyridine (6b). Orange crystals, (0.169 g, 38%), mp 189–192 ꢁC
(CH2Cl2/Et2O); IR (Nujol) nmax: 3437, 1734, 1693 cmꢀ1 1H NMR
. d:
2.03 (s, 3H, 3-CH3), 2.05 (s, 3H, 2-CH3), 2.39 (s, 3H, 40-CH3), 3.77 (s,
3H, 8a-OCH3), 3.85 (s, 3H, 8-OCH3), 6.92 (d, J¼0.6 Hz,1H, 30-H), 7.45
(d, J¼0.6 Hz, 1H, 60-H), 7.89 (d, J¼1.0 Hz, 1H, 5-H), 7.94 (d, J¼1.0 Hz,
(CH2Cl2/Et2O); IR (Nujol) nmax: 1735, 1708, 1662 cmꢀ1 1H NMR
. d:
1.83 (q, J¼1.0 Hz, 3H, 3-CH3), 1.93 (q, J¼1.0 Hz, 3H, 2-CH3), 2.32 (s,
3H, 10-CH3), 3.78 (s, 3H, 6-OCH3), 3.89 (s, 3H, 5-OCH3), 5.60 (s, 1H,
6a-H), 5.64 (s, 1H, 12b-H), 6.92 (d, J¼8.5 Hz, 1H, 8-H), 7.36 (dd,
J¼8.5, 2.2 Hz, 1H, 9-H), 7.67 (d, J¼2.2 Hz, 1H, 11-H), 10.16 (s, 1H, 12a-
1H, 7-H), 11.56 (s, 1H, OH). 13C NMR
d: 11.3 (3-CH3), 12.8 (2-CH3),
20.7 (40-CH3), 52.2 (8-OCH3), 53.8 (8a-OCH3), 72.8 (C-8a), 107.7 (C-
8), 109.1 (C-6), 118.9 (C-2), 119.5 (C-10), 120.4 (C-30), 123.8 (C-50),
125.5 (C-3), 130.4 (C-60), 131.8 (C-7), 141.6 (C-5), 143.7 (C-40), 160.3
(C-20), 165.1 (8-C]O), 169.1 (8a-C]O), 191.2 (6-C]O). MS (LCMS)
CHO). 13C NMR
d: 11.9 (3-CH3), 13.6 (2-CH3), 20.5 (10-CH3), 52.0 (6-
ꢂ
OCH3), 53.2 (5-OCH3), 58.7 (C-12a), 63.0 (C-6a), 71.1 (C-12b), 114.2
(C-2), 117.6 (C-6), 118.3 (C-8), 119.8 (C-11a), 126.8 (C-11), 127.4 (C-3),
132.1 (C-10), 138.5 (C-9), 144.1 (C-5), 159.1 (C-7a), 164.2 (5-C]O),
165.7 (6-C]O), 187.4 (C-12), 196.8 (12a-C]O). MS (LCMS) m/z (%)
m/z (%) 450/452 (100, Mþ þ1). Anal. Calcd for C21H20ClNO6S
(449.90): C, 56.06; H, 4.48, N, 3.11. Found: C, 56.13; H, 4.53; N, 3.24.
4.3.5.2. 10-Chloro-12a,12b-dihydro-5,6-dimethoxycarbonyl-12a-
formyl-12-oxo-2,3,9-trimethyl-6aH,12H-chromeno[3,2-c][1,3]thia-
zolo[3,2-a]pyridine (6e). From a 2:1 mixture of 5e:6e some 1H NMR
ꢂ
444 (100, Mþ þ1), 416 (91). Anal. Calcd for C22H21NO7S (443.47): C,
59.58; H, 4.77, N, 3.16. Found: C, 59.43; H, 4.68; N, 3.22.
data were deduced. 1H NMR
d: 1.83 (s, 3H, 3-CH3), 1.93 (s, 3H, 2-
4.3.3. From compound 1c. 4.3.3.1. 8,8a-Dimethoxycarbonyl-2,3-di-
methyl-6-(20-hydroxy-50-isopropylbenzoyl)-8aH-[1,3]thiazolo[3,2-
a]pyridine (5c). Yellow crystals (0.044 g, 10%), mp 178–180 ꢁC
CH3), 2.39 (s, 3H, 9-CH3), 3.79 (s, 3H, 6-OCH3), 3.89 (s, 3H, 5-OCH3),
5.56 (s, 1H, 6a-H), 5.64 (s, 1H, 12b-H), 6.91 (s, 1H, 8-H), 7.82 (s, 1H,
11-H), 10.13 (s, 1H, 12a-CHO).
(CH2Cl2/Et2O); IR (KBr) nmax: 3448, 1735, 1701 cmꢀ1. 1H NMR
d: 1.23
(d, J¼6.9 Hz, 3H, 50-CHCH3),1.26 (d, J¼6.9 Hz, 3H, 50-CHCH3), 2.02 (s,
6H, 2-CH3, 3-CH3), 2.88 (sept, J¼6.9 Hz, 1H, 50-CH), 3.75 (s, 3H, 8a-
OCH3), 3.84 (s, 3H, 8-OCH3), 6.96 (d, J¼8.0 Hz, 1H, 30-H), 7.32 (dd,
J¼8.0, 2.0 Hz,1H, 40-H), 7.36 (d, J¼2.0 Hz,1H, 60-H), 7.86 (d, J¼1.0 Hz,
4.3.6. From compound 1f. 4.3.6.1. 8,8a-Dimethoxycarbonyl-2,3-di-
methyl-6-(20-hydroxy-50-nitrobenzoyl)-8aH-[1,3]thiazolo[3,2-a]pyri-
dine (5f). Yellow crystals (0.103 g, 23%), mp 187–189 ꢁC (CH2Cl2/
Et2O); IR (Nujol) nmax: 3449, 1740, 1698 cmꢀ1. 1H NMR
d: 2.05 (s, 3H,
1H, 5-H), 8.00 (d, J¼1.0 Hz, 1H, 7-H), 11.36 (s, 1H, OH). 13C NMR
d:
3-CH3), 2.07 (s, 3H, 2-CH3), 3.79 (s, 3H, 8a-OCH3), 3.86 (s, 3H, 8-
OCH3), 7.13 (d, J¼9.2 Hz, 1H, 30-H), 7.94 (d, J¼1.0 Hz, 1H, 5-H), 7.99
(d, J¼1.0 Hz, 1H, 7-H), 8.33 (dd, J¼9.2, 2.7 Hz, 1H, 40-H), 8.51 (d,
11.2 (3-CH3), 12.7 (2-CH3), 24.0, and 24.2 (50-CH(CH3)2), 33.2 (50-
CH), 52.0 (8-OCH3), 53.7 (8a-OCH3), 72.7 (C-8a), 107.5 (C-8), 109.5
(C-6), 117.8 (C-30), 119.0 (C-2), 119.8 (C-10), 125.4 (C-3), 128.3 (C-60),
132.2 (C-7), 133.6 (C-40), 138.8 (C-50), 141.7 (C-5), 159.7 (C-20), 165.2
J¼2.7 Hz, 1H, 60-H), 12.62 (br s, 1H, OH). 13C NMR
d: 11.3 (3-CH3),
12.9 (2-CH3), 52.3 (8-OCH3), 54.0 (8a-OCH3), 65.9 (C-8a), 108.47 (C-

954
M.A. Terzidis et al. / Tetrahedron 66 (2010) 947–954
8), 108.54 (C-6), 118.9 (C-2), 119.2 (C-30), 121.0 (C-10), 125.4 (C-3),
126.9 (C-60), 129.6 (C-40), 131.3 (C-7), 139.3 (C-50), 142.0 (C-5), 164.9
(8-C]O), 167.2 (8a-C]O), 167.9 (C-20), 190.7 (6-C]O). MS (LCMS)
4. (a) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res.
2006, 39, 520–530; (b) Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M.
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Biju, A. T.; Rath, N. P. Tetrahedron Lett. 2003, 44, 729–732.
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Yavari, I.; Hossaini, Z.; Sabbaghan, M.; Ghanzanfarpour-Darzani, M. Monatsh.
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2001, 3, 3495–3497; (d) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2002, 4,
2807–2807.
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2006, 62, 3435–3438.
7. (a) Terzidis, M.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J. Tetrahedron Lett.
2005, 46, 7239–7242; (b) Terzidis, M.; Tsoleridis, C. A.; Stephanidou-Stepha-
natou, J. Tetrahedron 2007, 63, 7828–7832.
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Soc., Perkin Trans. 1 1975, 155–156; (b) Maeda, M.; Ito, S.; Kojima, M. Tetrahedron
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9. Terzidis, M. A.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A. Tetrahedron Lett.
2009, 50, 1196–1198.
10. Mopac2000 Ver 1.11. Fujitsu in Chem3D Ultra 7.0.
11. (a) Becke, A. D. J. Chem. Phys. 1993, 5648–5652; (b) Lee, C.; Yang, W.; Parr, R. G.
Phys. Rev. B 1988, 37, 785–789.
12. Frisch, M. J. T.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03,
revision B.02; Gaussian,: Pittsburgh PA, 2003.
ꢂ
m/z (%) 446 (30, Mþ ), 374 (100). Anal. Calcd for C20H18N2O8S
(446.43): C, 53.81; H, 4.06, N, 6.27. Found: C, 53.73; H, 4.00; N, 6.40.
4.3.7. From compound 1g. 4.3.7.1. 6-(30,50-Dibromo-20-hydroxy-
benzoyl)-8,8a-dimethoxycarbonyl-2,3-dimethyl-8aH-[1,3]thia-
zolo[3,2-a]pyridine (5g). Yellow crystals (0.212 g, 38%), mp 233–
235 ꢁC (CH2Cl2/Et2O); IR (Nujol) nmax: 3450, 1735, 1680 cmꢀ1 1H
.
NMR d: 2.03 (s, 3H, 3-CH3), 2.05 (s, 3H, 2-CH3), 3.77 (s, 3H, 8a-
OCH3), 3.85 (s, 3H, 8-OCH3), 7.56 (d, J¼2.3 Hz, 1H, 60-H), 7.83 (d,
J¼2.3 Hz, 1H, 40-H), 7.90 (d, J¼1.0 Hz, 1H, 5-H), 7.92 (d, J¼1.0 Hz, 1H,
7-H), 11.56 (s, 1H, OH). 13C NMR
d: 11.2 (3-CH3), 12.8 (2-CH3), 52.2
(8-OCH3), 53.9 (8a-OCH3), 73.0 (C-8a), 108.3 (C-8), 108.7 (C-6), 110.1
(C-50), 113.1 (C-30), 120.6 (C-2), 122.0 (C-10), 125.4 (C-3), 131.5 (C-60),
132.2 (C-7), 139.7 (C-5), 142.1 (C-40), 157.4 (C-20), 164.9 (8-C]O),
168.9 (8a-C]O), 190.5 (6-C]O). Anal. Calcd for C20H17Br2NO6S
(559.23): C, 42.95; H, 3.06, N, 2.50. Found: C, 43.11; H, 3.09; N, 2.41.
References and notes
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Elmore, N. F. Adv. Heterocycl. Chem. 1978, 23, 263–482; (c) El-Gaby, M. S. A.;
Al-Sehemi, A. G.; Mohamed, Y. A.; Ammar, Y. A. Phosphorous, Sulfur, Sil-
icon 2006, 181, 631–674.
2. Isobe, Y.; Goto, J.; Chiba, S.; Matsuda, Y. Jpn. Kokai Tokkyo Koho JP 08, 157, 363
[96, 157, 363] Cl. A61 K31/435, 18 June 1996, Appl. 94/329, 388, 2 Dec. 1994;
Chem. Abstr. 1996, 125, 195649y.
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Builla, J. J. Org. Chem. 2001, 66, 8528–8536; (b) Dombrowski, A.; Nieger, M.;
Niecke, E. Chem. Commun. 1996, 1705–1710; (c) Potts, K. T.; Rochanapruk, T.;
Coats, S. J.; Hadjiarapoglou, L.; Padwa, A. J. Org. Chem. 1993, 58, 5040–5042; (d)
Potts, K. T.; Dery, M. O. J. Org. Chem. 1990, 55, 2884–2894; (e) Gotthardt, H.;
Riegels, M. Chem. Ber. 1988, 121, 1143–1146; (f) Ungureanu, I.; Klotz, P.; Shoe-
nfelder, A.; Mann, A. Chem. Commun. 2001, 958–959; (g) Rigby, J. H. Synlett
2000, 1–12; (h) Tejeda, J.; Reau, R.; Dahan, F.; Bertrand, G. J. Am. Chem. Soc. 1993,
115, 7880–7881; (i) Facklam, T.; Wagner, O.; Heydt, H.; Regitz, M. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 314–315.
13. (a) Yavari, I.; Sabbaghan, M.; Hossaini, Z. Synlett 2006, 2501–2503; (b) Nair, V.;
Devipriya, S.; Eringathodi, S. Tetrahedron Lett. 2007, 48, 3667–3670.
14. Complete crystallographic data for compounds 4b and 4g have been deposited
with the Cambridge Crystallographic Data Center as supplementary publication
No. CCDC 694985 and CCDC 694986. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax (int.
code): þ44 1223 336 033, e-mail: deposit@ccdc.cam.ac.uk).
15. Simulated with SpinWorks simulation program, version 2.5, available from
http://davinci.chem.umanitoba.ca/pub/marat/SpinWorks/.