One-pot, three-component synthesis of 7H-[1,3,4]thiadiazolo[3,2-fl] pyridines from 2-phenacyl-[1,3,4]thiadiazole derivatives and arylmethylene-cyanoacetic acid derivatives

Article abstract of DOI:10.1515/znb-2007-1011

Generally, arylmethylene-cyanoacetic acid derivatives react with enols and aromatic or heteroaromatic hydroxy compounds to afford 2-amino-4H-pyran derivatives of type 6. In contrast, a ring closure with the nitrogen atom of the thiadiazole ring occurs when 2-phenacyl-1,3,4-thiadiazoles (1a-d) act on derivatives of arylmethylene-cyanoacetic acid giving rise to the formation of 777-[1,3,4]thiazolo[3,2-a]pyridine derivatives 5a -r. The same products are obtained if 2-phenacyl-1,3,4thiadiazoles react with aromatic or heteroaromatic aldehydes and cyanoacetic acid derivatives. The constitution of the novel compounds 5 has been confirmed by an X-ray analysis of 5a.

Full text of DOI:10.1515/znb-2007-1011

One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazo-
lo[3,2-a]pyridines from 2-Phenacyl-[1,3,4]thiadiazole Derivatives
and Arylmethylene-cyanoacetic Acid Derivatives
Imran Ali Hashmia, Wolfgang Freyb, Ivo C. Ivanovc, and Willi Kantlehnera,b
a Fakulta¨t Chemie/Organische Chemie, Hochschule Aalen,
Beethovenstr. 1, D-73430 Aalen, Germany
b Institut fu¨r Organische Chemie der Universita¨t Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
c Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Sofia,
Dunav 2, BG-1000 Sofia, Bulgaria
Reprint requests to Prof. Dr. Willi Kantlehner. Fax: +49(0)7361-5762250.
E-mail: willi.kantlehner@htw-aalen.de
Z. Naturforsch. 2007, 62b, 1298 – 1304; received March 20, 2007
Dedicated to Professor Horst Hartmann on the occasion of his 70th birthday
Generally, arylmethylene-cyanoacetic acid derivatives react with enols and aromatic or heteroaro-
matic hydroxy compounds to afford 2-amino-4H-pyran derivatives of type 6. In contrast, a ring
closure with the nitrogen atom of the thiadiazole ring occurs when 2-phenacyl-1,3,4-thiadiazoles
(1a – d) act on derivatives of arylmethylene-cyanoacetic acid giving rise to the formation of 7H-
[1,3,4]thiazolo[3,2-a]pyridine derivatives 5a – r. The same products are obtained if 2-phenacyl-1,3,4-
thiadiazoles react with aromatic or heteroaromatic aldehydes and cyanoacetic acid derivatives. The
constitution of the novel compounds 5 has been confirmed by an X-ray analysis of 5a.
Key words: 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines, 2-Methyl-5-phenacyl-1,3,4-thiadiazoles,
Aromatic Aldehydes, CH2-Acidic Compounds, Arylmethylene-cyanoacetic Acid
Derivatives
Introduction
The reaction of arylmethylene-malononitriles with
cyclohexanone [2a], α,β-unsaturated carbonyl com-
pounds [2b], β-dicarbonyl compounds [3], sodium
pyruvate [4] and acetylacetone [5], or with electro-
philic reagents such as α-naphthol [6], 6-bromo-2-
naphthol [7], hydroxyarenes [8], or with 4-hydroxy-2-
pyrones and 4-hydroxy-2-pyridones [9a], 4-hydroxy-
coumarins [9b], 1-acetylindol-3(2H)-one [10] and N-
acetonyl- or N-phenacyl-substituted heterocycles [11]
have all been reported to form 2-aminopyran deriva-
tives. Analogous 2-aminopyran derivatives were also
obtained by a three-component reaction involving the
enolisable β-dicarbonyl compound, an aldehyde and
malononitrile [12]. In some cases, however, it was
not pyran-2-amines but 2-aminopyridine derivatives
that were obtained. Thus, the reactions of arylidene-
malononitriles with enaminoketones and enhydrazino-
ketones gave rise mainly to the formation of 1,4-di-
hydropyridines [13] whereas by conjugate addition
of 2-(thienylcarbonyl)acetanilides to arylmethylene-
Methylene-cyanoacetates or methylene-malononitr-
iles show a reactivity pattern which is compatible with
that of the parent carbonyl compounds (aldehydes or
ketones). The compounds can electrophilically attack
hydroxyarenes, hydroxyhetarenes, and enols of car-
bonyl derivatives. The adducts thus formed can cy-
clize after tautomerization to give fused 2-aminopyr-
an derivatives, which are ketene-O,N-acetals, by ad-
dition of the hydroxy group to the nitrile group in
the presence of a catalytic amount of a base. Methy-
lene derivatives of nitroacetonitrile and (diethoxyphos-
phono)acetonitrile can also be used. By this reaction
principle, several hundred heterocyclic ketene-O,N-
acetals of a wide structural variety have been pre-
pared [1a]. More recently, reactions of this type have
been performed using microwaves, ultrasound [1b] and
ionic liquids as solvents [1c, d], with no influence on
the reaction outcome.
0932–0776 / 07 / 1000–1298 $ 06.00 © 2007 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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I. A. Hashmi et al. · One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines
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Scheme 1.
malononitriles some polyfunctionalized pyridines [14]
were prepared.
We wish to report here the one-pot synthesis of
some hitherto unknown 7H-[1,3,4]thiadiazolo[3,2-a]-
pyridines 5a – r (Scheme 1, Table 1) by reaction of the
CH-acidic phenacyl-thiadiazole derivatives 1a – d with
malononitrile 2a or of cyanoacetic acid esters 2b, c and
aromatic aldehydes 3a – f.
Results and Discussion
The synthesis of 2-methyl-5-phenacyl-1,3,4-thiadi-
azoles 1a – d was published recently [15] and it has
been shown that, as enolisable CH acids, these com-
pounds possess ambivalent reactivity. Because of the
presence of several tautomeric forms (Scheme 1), two
Fig. 1. ORTEP view of one of the two crystallographically
independent molecules of 5a in the crystal (displacement el-
lipsoids at the 50 % probability level).
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I. A. Hashmi et al. · One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines
Table 1. 7,8-Disubstituted 5-amino-2-methyl-7H-[1,3,4]thiadiazolo[3,2-a]pyridines 5a – ra.
Product Ar1
X
Ar2
Yield M. p.
Mol. formula
(mol. mass)
Elemental analysis
calcd./found
5
a
b
c
C6H5
CN
CN
CN
CN
CN
C6H5
88
86
86
83
55
83
213 (dec.) C21H16N4OS
(372.44)
C 67.72, H 4.33, N 15.04, S 8.61
C 67.59, H 4.71, N 14.99, S 8.55
C6H5
4-Cl–C6H4
4-CH3–C6H4
4-NO2–C6H4
2-furyl
194 – 197
197 – 199
204 – 207
C21H15N4OClS C 61.99, H 3.72, N 13.77, Cl 8.71, S 7.88
(406.89)
C22H18N4OS
(386.47)
C21H15N5O3S
(417.44)
C 61.90, H 3.81, N 13.96, Cl 8.89, S 7.60
C 68.37, H 4.69, N 14.50, S 8.30
C 68.17, H 4.76, N 14.25, S 8.32
C 60.42, H 3.62, N 16.78, S 7.68
C 60.33, H 3.69, N 16.94, S 7.65
C 62.97, H 3.89, N 15.46, S 8.85
C 62.63, H 4.01, N 15.31, S 8.79
C 65.17, H 4.72, N 10.36, S 7.91
C 65.06, H 4.92, N 10.37, S 7.45
C 63.43, H 4.86, N 9.65, S 7.36
C 63.29, H 5.01, N 9.85, S 7.23
C 65.85, H 5.05, N 10.02, S 7.64
C 65.85, H 5.07, N 10.09, S 7.84
C6H5
d
e
C6H5
C6H5
197 (dec.) C19H14N4O2S
(362.41)
f
C6H5
COOMe C6H5
200 – 203
C22H19N3O3S
(405.47)
g
h
i
C6H5
COOMe 4-CH3O–C6H4 68
195.5 – 196 C23H21N3O4S
(435.50)
C6H5
COOEt C6H5
84
80
54
87
94
91
89
96
88
88
88
193 – 196
171 – 173
150 – 153
199 – 202
211 – 215
209 – 211
208 – 210
227 – 230
212 – 215
C23H21N3O3S
(419.50)
C6H5
COOEt 4-Cl–C6H4
COOEt 4-CH3–C6H4
COOEt 4-NO2–C6H4
C23H20N3O3ClS C 60.86, H 4.44, N 9.26, Cl 7.81, S 7.06
(453.94)
C24H23N3O3S
(433.52)
C23H20N4O5S
(464.50)
C21H15N4OClS C 61.99, H 3.72, N 13.77, Cl 8.71, S 7.88
(406.89) C 61.80, H 3.90, N 13.57, Cl 9.28, S 7.83
C21H14N4OCl2S C 57.15, H 3.20, N 12.69, Cl 16.07, S 7.26
(441.33) C 56.90, H 3.37, N 12.83, Cl 15.96, S 6.98
C22H17N4OClS C 62.78, H 4.07, N 13.31, Cl 8.42, S 7.62
(420.92) C 62.67, H 4.76, N 13.04, Cl 8.37, S 7.46
C21H14N5O3ClS C 55.82, H 3.12, N 15.50, Cl 7.85, S 7.09
(451.89)
C22H18N4OS
(386.47)
C 60.80, H 4.50, N 9.34, Cl 7.88, S 6.97
C 66.49, H 5.35, N 9.69, S 7.40
C 66.30, H 5.35, N 9.86, S 7.51
C 59.47, H 4.34, N 12.06, S 6.90
C 59.29, H 4.38, N 12.32, S 6.63
j
C6H5
k
l
C6H5
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-CH3–C6H4
CN
CN
CN
CN
CN
Ph
m
n
o
p
q
r
4-Cl–C6H4
4-CH3–C6H4
4-NO2–C6H4
Ph
C 55.77, H 3.27, N 15.76, Cl 8.00, S 7.02
C 68.37, H 4.70, N 14.51, S 8.28
C 68.06, H 4.75, N 14.31, S 8.23
C 65.65, H 4.51, N 13.92, S 7.97
C 65.31, H 4.98, N 13.81, S 7.32
C 59.05, H 3.83, N 15.65, S 7.17
C 58.93, H 3.98, N 15.46, S 7.09
4-CH3O–C6H4 CN
4-CH3O–C6H4 CN
Ph
198 (dec.) C22H18N4O2S
(402.47)
214 (dec.) C22H17N5O4S
4-NO2–C6H4
(447.47)
a
All compounds recrystallized from ethanol as yellow crystals; yields in percent, m. p.’s in ◦C.
possible products 5 or 6 could be expected when at δ = 5.24 and δ = 4.88, respectively. The usual sig-
these compounds (1a, b) are treated with arylmethyl- nals due to one methyl and two phenyl groups were
ene-cyanoacetic acid derivatives of type 4 as Michael also present in the 1H and 13C NMR spectra. Further-
acceptors.
more, the IR spectrum displayed absorption bands for
In the first experiment, 5-methyl-2-phenacyl-1,3,4- a primary amino group at 3432 and 3313 cm−1 as
thiadiazole (1a) was allowed to react with one equiv- well as for a cyano and a carbonyl group at 2224 and
alent of benzylidene-malononitrile (4a) prepared ac- 1647 cm−1, respectively. Obviously, the 1H NMR and
cording to the literature [16]. A yellow solid of 5a IR spectral properties of the initially prepared com-
was obtained on cooling. The product 5a was isolated pound fit both isomeric structures 5a and 6a (X = CN,
in a rather high yield (88 %) in a one-pot reaction by Ar1 = Ar2 = phenyl). The problem of the structure as-
stirring the phenacyl-methyl-thiadiazole 1a with mal- signment has been solved, however, by means of an
ononitrile 2a and benzaldehyde 3a in ethanol for 2 h at X-ray structure determination (Fig. 1, Table 2) which
ambient temperature in the presence of triethylamine.
unambiguously confirmed the structure of 5a. Thus,
the fused bicyclic skeleton of 7H-[1,3,4]thiadiazolo-
[3,2-a]pyridine is present in all the new compounds
5a – r.
1
In the H NMR spectrum of this product, a broad-
ened signal for the primary amino group and a singlet
for the methine group adjacent to Ar2 were observed
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I. A. Hashmi et al. · One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines
1301
Table 2. Crystal structure data for 5aa.
The 7H-[1,3,4]thiadiazolo[3,2-a]pyridine deriva-
tives 5b – r were prepared at ambient temperature by
Formula
Mr
C21H16N4OS
372.44
the three-component procedure as mentioned above
Crystal size, mm3
Crystal system
Space group
0.4 × 0.1 × 0.05
for 5a. The IR, 1H NMR and 13C NMR spectral proper-
ties of the products 5b – r are fully in accordance with
those of 5a (see Experimental Section). For the reac-
tion products 5f – k obtained from the cyanoacetates
2b, c and 1a, no nitrile bands are present in the IR
spectra. Instead, a second carbonyl band appears in the
range 1619 – 1629 cm−1 for the vinylogous urethanes.
Yields, molecular formulae, some physical and ana-
lytical data for compounds 5a – r are summarized in
Table 1.
triclinic
¯
P1
˚
a, A
11.6762(9)
12.5076(6)
13.6080(10)
98.419(6)
103.528(6)
101.321(6)
1855.6(2)
4
1.333
1.695
776
+13, 13, 14
0.5616
˚
b, A
˚
c, A
α, deg
β, deg
γ, deg
3
˚
V, A
Z
Dcalcd, g cm−3
µ(CuKα ), mm−1
F(000), e
hkl range
Experimental Section
Compound 5a from 5-methyl-2-phenacyl[1,3,4]thiadiazole
(1a) and benzylidene-malononitrile (4a)
−1
˚
((sinθ)/λ)max, A
Refl. measured
Refl. unique
Rint
5494
5210
0.0461
A mixture of 21.8 g (0.1 mol) of the thiadiazole 1a [15]
and 15.4 g (0.1 mol) of benzylidene-malononitrile (4a) [16]
in 100 mL of ethanol was refluxed with stirring for 30 min.
The color of the mixture turned to dark brown. On cooling,
a yellow precipitate of 5a was formed, which was filtered,
washed with ethanol (5 × 20 mL) and air-dried. After con-
centrating the mother liquor in vacuo an additional amount of
product was obtained. The whole product was recrystallized
from ethanol. Yield: 31.2 g (85 %); yellow crystals of 6a (Ta-
ble 1). For crystallographic analysis, see Fig. 1 and Table 2;
for spectral data, see below (after the general procedure).
Param. refined
R(F)/wR(F2)
GoF (F2)
504
0.137/0.274
1.145
0.50/−0.44
−3
˚
∆ρfin (max/min), e A
CCDC 297331 contains the supplementary crystallographic data
of 5a for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac
.uk/data request/cif.
a
initial volume. The corresponding crude crystalline product
5a – r precipitated. It was filtered, washed with cold ethanol,
recrystallized from ethanol and air-dried.
General procedure for the preparation of the compounds
5a – r
5-Amino-8-benzoyl-2-methyl-7-phenyl-7H-[1,3,4]thiadi-
azolo[3,2-a]pyridine-6-carbonitrile (5a)
A mixture of 0.05 mol of the CH2-acidic component
2a – c, 0.05 mol of the corresponding aromatic aldehyde
3a – f, and 1.0 g (0.01 mol) of triethylamine in 50 mL of
ethanol was stirred at ambient temperature for a period of
15 min. Then, 0.05 mol of the corresponding 5-methyl-2-
phenacyl[1,3,4]thiadiazole derivative 1a – d was added with
stirring and the mixture was stirred for further 2 h at 20 –
25 ◦C. The completion of the reaction and the product purity
were monitored by means of TLC (silica gel pre-coated plas-
tic sheets Polygram SIL G/UV254, Macherey-Nagel GmbH;
solvent system: toluene-acetone (8 : 2); detection by UV irra-
diation at 254 nm). The mixture was concentrated in vacuo
on a rotatory evaporator to approximately one third of the
IR (ATR): ν = 3432 and 3313 (NH2), 2224 (CN), 1647
1
(C=O) cm−1. – H NMR (500 MHz, CDCl3): δ = 2.49 (s,
3 H, 2-CH3), 4.88 (s, 1 H, 7-H), 5.24 (br. s, 2 H, NH2),
6.82 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz, 2 Harom.), 7.1 – 7.4
(m, 8 Harom.). – 13C NMR (125.8 MHz, CDCl3): δ = 15.5
(2-CH3), 41.3 (C-7), 64.0 (C-6), 102.1 (C-8), 119.7 (CN),
146.8 (C-8a), 150.5 (C-2), 155.4 (C-5), 126.6 (4 Carom.
)
127.1, 128.2 (2 C), 128.7 (2 C), 130.1, 139.0, 145.1 (total
12 Carom.), 191.4 (8-C=O).
5-Amino-8-benzoyl-7-(4-chlorophenyl)-2-methyl-7H-
[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5b)
IR (ATR): ν = 3467 and 3318 (NH2), 2186 (CN), 1652
1
(C=O) cm−1. – H NMR (250 MHz, CDCl3): δ = 2.48 (s,
3 H, 2-CH3), 4.87 (s, 1 H, 7-H), 5.31 (br. s, 2 H, NH2), 6.72
(d, J = 8.5 Hz, 2 Harom.), 7.10 (d, J = 8.5 Hz, 2 Harom.), 7.30
(mc, 5 Harom.). – 13C NMR (62.9 MHz, CDCl3): δ = 15.5
(2-CH3), 40.9 (C-7), 63.5 (C-6), 150.6 (C-2), 155.5 (C-5),
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I. A. Hashmi et al. · One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines
101.7 (C-8), 119.5 (CN), 146.9 (C-8a), 126.5, 128.1, 128.3, 148.0 (C-8a), 150.4 (C-2), 155.1 (C-5), 169.1 (6-C=O), 191.3
128.8, 130.2, 132.8, 138.9, 143.6 (total 12 Carom.), 191.2 (8-C=O), 126.2, 126.8, 127.1, 128.0, 128.1, 130.0, 139.4,
(8-C=O).
146.7 (total 12 Carom.).
5-Amino-8-benzoyl-2-methyl-7-(4-methylphenyl)-7H-
Methyl 5-amino-8-benzoyl-7-(4-methoxyphenyl)-2-methyl-
[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5c)
7H-[1,3,4]thiadiazolo[3,2-a]pyridine-6-carboxylate (5g)
IR (ATR): ν = 3458 and 3303 (NH2), 2195 (CN), 1652
IR (ATR), ν = 3479 and 3301 (NH2), 1679 (C=O),
(C=O) cm−1. – H NMR (500 MHz, CDCl3): δ = 2.24 (s, 1627 (C=O, ester) cm−1. – 1H NMR (250 MHz, CDCl3):
3 H, Ar2CH3), 2.47 (s, 3 H, 2-CH3), 4.83 (s, 1 H, 7-H), 5.25 δ = 2.49 (s, 3 H, 2-CH3), 3.62 (s, 3 H, OCH3), 3.70 (s,
(br. s, 2 H, NH2), 6.72 (d, J = 8.0 Hz, 2 Harom.), 6.95 (d, 3 H, OCH3), 5.21 (s, 1 H, 7-H), 6.69 and 6.59 (2 × d, J =
J = 8.0 Hz, 2 Harom.), 7.2 – 7.5 (m, 5 Harom., PhC=O). – 8.8 Hz, 2 × 2 Harom., 7-C6H4), 7.41 (m, 5 Harom., PhC=O). –
13C NMR (125.8 MHz, CDCl3): δ = 15.5 (2-CH3), 21.0 13C NMR (62.9 MHz, CDCl3): δ = 15.7 (2-CH3), 38.5 (C-7),
(Ar2CH3), 40.8 (C-7), 64.1 (C-6), 102.1 (C-8), 119.8 (CN), 50.9 (OCH3), 55.1 (OCH3), 81.6 (C-6), 104.8 (C-8), 148.0
146.8 (C-8a), 150.4 (C-2), 155.3 (C-5), 126.4 (2 C), 126.7 (C-8a), 150.2 (C-2), 155.2 (C-5), 113.4, 127.2, 127.8, 128.2,
(2 C), 128.2 (2 C), 129.4 (2 C), 130.1, 136.7, 139.0, 142.3 129.9, 139.4, 139.5, 157.9 (total 12 Carom.), 169.5 (6-C=O),
1
(total 12 Carom.), 191.3 (8-C=O).
191.4 (8-C=O).
5-Amino-8-benzoyl-2-methyl-7-(4-nitrophenyl)-7H-[1,3,4]-
Ethyl 5-amino-8-benzoyl-2-methyl-7-phenyl-7H-[1,3,4]
thiadiazolo[3,2-a]pyridine-6-carbonitrile (5d)
thiadiazolo[3,2-a]pyridine-6-carboxylate (5h)
IR (ATR): ν = 3450 and 3341 (NH2), 2184 (CN), 1651
IR (ATR): ν = 3489 and 3301 (NH2), 1675 (C=O), 1626
1
(C=O) cm−1. – H NMR (250 MHz, CDCl3): δ = 2.52 (s, (C=O, ester) cm−1. – 1H NMR (250 MHz, CDCl3): δ =
3 H, 2-CH3), 5.06 (s, 1 H, 7-H), 5.39 (br. s, 2 H, NH2), 1.15 (t, 3 H, OCH2CH3), 2.48 (s, 3 H, 2-CH3), 4.10 (q, 2 H,
7.15, 7.30 (2 × m, 3 Harom. + 2 Harom.), 8.00 (d, J = 8.7 Hz, OCH2), 5.31 (s, 1 H, 7-H), 6.75, 7.04, 7.38 (3 × m, 2 H, 4 H,
2 Harom.), 6.59 (d, J = 8.7 Hz, 2 Harom.). – 13C NMR 4 H, 7-Ph, PhC=O). – 13C NMR (62.9 MHz, CDCl3): δ =
(62.9 MHz, CDCl3): δ = 15.5 (2-CH3), 41.5 (C-7), 63.0 14.2 (OCH2CH3), 15.6 (2-CH3), 39.4 (C-7), 59.5 (OCH2),
(C-6), 100.9 (C-8), 119.1 (CN), 147.1 (C-8a), 151.6 (C-2), 81.5 (C-6), 104.4 (C-8), 148.0 (C-8a), 150.4 (C-2), 155.1
155.8 (C-5), 124.0, 126.4, 127.6, 128.5, 130.4, 138.8, 146.8, (C-5), 126.2, 126.9, 127.2, 128.0, 128.1, 130.0, 139.5, 146.8
151.1 (total 12 Carom.), 191.0 (8-C=O).
(total 12 Carom.), 169.1 (6-C=O), 191.3 (8-C=O).
5-Amino-8-benzoyl-7-(2-furyl)-2-methyl-7H-thiadiazolo-
Ethyl 5-amino-8-benzoyl-7-(4-chlorophenyl)-2-methyl-
[3,2-a]pyridine-6-carbonitrile (5e)
7H-[1,3,4]thiadiazolo[3,2-a]pyridine-6-carboxylate (5i)
IR (ATR): ν = 3458 and 3433 (NH2), 2192 (CN), 1660
IR (ATR): ν = 3425 and 3302 (NH2), 1664 (C=O, ketone),
(C=O) cm−1 . – 1H NMR (250 MHz, CDCl3): δ= 2.49 (s, 1620 (C=O, ester) cm−1. – 1H NMR (500 MHz, CDCl3): δ =
3 H, 2-CH3), 4.99 (s, 1 H, 7-H), 5.34 (br. s, 2 H, NH2), 1.14 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.50 (s, 3 H, 2-CH3),
5.65 (d, J1 = 3.2 Hz, 1 Harom., furyl), 6.14 (dd, J1 = 3.2, 4.08 (q, J = 7.1 Hz, 2 H, OCH2), 5.28 (s, 1 H, 7-H), 7.00 (d,
J2 = 1.6 Hz, 1 Harom., furyl), 7.20 (d, J2 = 1.6 Hz, 1 Harom.
,
J = 8.5 Hz, 2 Harom.), 6.65 (d, J = 8.5 Hz, 2 Harom.), 7.35 (m,
furyl), 7.37 (mc, 5 Harom., PhC=O). – 13C NMR (62.9 MHz, 5 Harom.+ NH2). – 13C NMR (125.8 MHz, CDCl3): δ = 14.3
CDCl3): δ = 15.5 (2-CH3), 35.2 (C-7), 60.5 (C-6), 99.4 (OCH2CH3), 15.7 (2-CH3), 39.2 (C-6), 59.6 (OCH2), 81.2
(C-8), 105.4 (Carom., furyl), 110.2 (Carom., furyl), 119.5 (C-6), 104.1 (C-8), 147.9 (C-8a), 150.4 (C-2), 155.2 (C-5),
(CN), 126.8 (2 C), 128.4 (2 C), 130.3, 138.8 (total 6 Carom.
Ph), 148.1 (C-8a), 151.1 (C-2), 155.6 (C-5), 156.1 (Carom.
furyl), 142.2 (Carom., furyl), 190.9 (8-C=O).
,
,
127.0 (2 C), 128.0 (2 C), 128.3 (2 C), 128.4 (2 C), 130.1,
131.8, 139.3, 145.4 (total 12 Carom.), 168.9 (6-C=O), 191.3
(8-C=O).
Methyl 5-amino-8-benzoyl-2-methyl-7-phenyl-7H-[1,3,4]
Ethyl 5-amino-8-benzoyl-2-methyl-7-(4-methylphenyl)-7H-
thiadiazolo[3,2-a]pyridine-6-carboxylate (5f)
[1,3,4]thiadiazolo[3,2-a]pyridin-6-carboxylate (5j)
IR (ATR): ν = 3489 and 3306 (NH2), 1676 (C=O), 1622
IR (ATR): ν = 3426 and 3303 (NH2), 1664 (C=O, ketone),
(C=O, ester) cm−1. – 1H NMR (250 MHz, CDCl3): δ = 2.48 1619 (C=O, ester) cm−1. – 1H NMR (250 MHz, CDCl3): δ =
(s, 3 H, 2-CH3), 3.62 (s, 3 H, OCH3), 5.28 (s, 1 H, 7-H), 1.71 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.21 (s, 3 H, Ar2CH3),
6.77, 7.03 (2 × m, 2 Harom., 3 Harom., PhC=O), 7.35 (m, 2.49 (s, 3 H, 2-CH3), 4.10 (q, J = 7.1 Hz, 3 H, OCH2),
5 Harom., 7-Ph). – 13C NMR (62.9 MHz, CDCl3): δ = 15.6 5.29 (s, 1 H, 7-H), 6.66 (d, J = 7.9 Hz, 2 Harom.), 6.85 (d,
(2-CH3), 39.4 (C-7), 50.9 (OCH3), 81.5 (C-6), 104.4 (C-8), J = 7.9 Hz, 2 Harom.), 6.7 – 7.2 (br., 2 H, NH2), 7.38 (mc,
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I. A. Hashmi et al. · One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines
1303
5 Harom., PhC=O). – 13C NMR (62.9 MHz, CDCl3): δ = 14.3 J = 8.4 Hz, 2 Harom., Ar1), 7.15 (d, J = 8.4 Hz, 2 Harom., Ar2),
(OCH2CH3), 15.7 (2-CH3), 38.9 (C-7), 59.5 (OCH2), 81.6 7.25 (d, J = 8.4 Hz, 2 Harom., Ar2). – 13C NMR (62.9 MHz,
(C-6), 104.6 (C-8), 148.1 (C-8a), 150.3 (C-2), 155.1 (C-5), CDCl3): δ = 15.6 (2-CH3), 21.1 (PhCH3), 40.9 (C-7), 64.3
126.8, 127.3, 128.1, 128.7, 130.0, 135.6, 139.4, 143.9 (total (C-6), 101.9 (C-8), 119.7 (CN), 146.7 (C-8a), 151.0 (C-2),
12 Carom.), 169.1 (6-C=O), 191.4 (8-C=O).
155.5 (C-5), 126.5 (2 C), 128.3 (2 C), 128.5 (2 C), 129.6
(2 C), 136.2, 136.9, 137.5, 142.2 (total 12 Carom.), 189.9
(8-C=O).
Ethyl 5-amino-8-benzoyl-2-methyl-7-(4-nitrophenyl)-7H-
[1,3,4]thiadiazolo[3,2-a]pyridine-6-carboxylate (5k)
5-Amino-8-(4-chlorobenzoyl)-2-methyl-7-(4-nitrophenyl)-
IR (ATR): ν = 3392 and 3287 (NH2), 1671 (C=O, ketone),
1620 (C=O, ester) cm−1. – 1H NMR (250 MHz, CDCl3): δ =
1.13 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.53 (s, 3 H, 2-CH3),
4.07 (q, J = 7.1 Hz, 2 H, OCH2), 5.43 (s, 1 H, 7-H), 6.85
(d, J = 8.7 Hz, 2 Harom.), 7.90 (d, J = 8.7 Hz, 2 Harom.),
6.7 – 8.0 (br., 2 H, NH2), 7.2 – 7.5 (m, 5 Harom., PhC=O). –
13C NMR (62.9 MHz, CDCl3): δ = 14.3 (OCH2CH3), 15.7
(2-CH3), 40.0 (C-7), 59.8 (OCH2), 80.4 (C-6), 103.2 (C-8),
148.0 (C-8a), 151.0 (C-2), 155.5 (C-5), 123.3 (2 C), 126.9
(2 C), 127.9 (2 C), 128.5 (2 C), 130.4, 139.2, 146.2, 153.9
(total 12 Carom.), 168.6 (6-C=O), 191.0 (8-C=O).
7H-[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5o)
IR (ATR): ν = 3448 and 3338 (NH2), 2184 (CN), 1653
(C=O) cm−1. – 1H NMR (250 MHz, [D6]DMSO): δ = 2.55
(s, 3 H, 2-CH3), 5.05 (s, 1 H, 7-H), 7.05 (br. s, 2 H, NH2),
7.06 (d, J = 8.7 Hz, 2 Harom., Ar1), 7.25 (d, J = 8.4 Hz,
2 Harom., Ar2), 7.38 (d, J = 8.4 Hz, 2 Harom., Ar2), 8.04 (d, J =
8.7 Hz, 2 Harom., Ar1). – 13C NMR (62.9 MHz, [D6]DMSO):
δ = 15.1 (2-CH3), 41.2 (C-7), 60.3 (C-6), 100.0 (C-8), 119.6
(CN), 146.1 (C-8a), 152.6 (C-2), 155.1 (C-5), 123.8 (2 C),
127.8 (2 C), 128.2 (2 C), 128.4 (2 C), 134.6, 137.8, 146.1,
151.8 (total 12 Carom.), 188.2 (8-C=O).
5-Amino-8-(4-chlorobenzoyl)-2-methyl-7-phenyl-7H-
[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5l)
5-Amino-2-methyl-8-(4-methylbenzoyl)-7-phenyl-7H-[1,3,4]
thiadiazolo[3,2-a]pyridine-6-carbonitrile (5p)
IR (ATR): ν = 3466 and 3314 (NH2), 2187 (CN), 1652
IR (ATR): ν = 3465 and 3314 (NH2), 2187 (CN), 1651
(C=O, ketone) cm−1. – 1H NMR (250 MHz, CDCl3): δ =
2.35 (s, 3 H, Ar1CH3), 2.49 (s, 3 H, 2-CH3), 4.92 (s, 1 H,
7-H), 5.20 (br. s, 2 H, NH2), 7.20 (mc, 9 Harom., Ar1 + Ar2). –
13C NMR (62.9 MHz, CDCl3): δ = 15.5 (2-CH3), 21.5
(Ar1CH3), 41.2 (C-7), 63.8 (C-6), 102.1 (C-8), 119.7 (CN),
147.0 (C-8a), 150.3 (C-2), 155.4 (C-5), 126.6, 127.0, 127.1,
128.7, 128.9, 136.1, 140.57, 145.1 (total 12 Carom.), 191.2
(8-C=O).
1
(C=O) cm−1. – H NMR (250 MHz, CDCl3): δ = 2.53 (s,
3 H, 2-CH3), 4.82 (s, 1 H, 7-H), 5.21 (br. s, 2 H, NH2),
6.86 (mc, 2 Harom., Ph), 7.13 (d, J = 8.6 Hz, 2 Harom., Ar1),
7.13 – 7.27 (m, 3 Harom., Ph), 7.27 (d, J = 8.6 Hz, 2 Harom.
,
Ar1). – 13C NMR (62.9 MHz, CDCl3): δ = 15.5 (2-CH3),
41.3 (C-7), 64.3 (C-6), 101.7 (C-8), 119.5 (CN), 151.0 (C-2),
155.5 (C-5), 146.6 (C-8a), 126.6, 127.3, 128.2, 128.5, 128.9,
136.2, 137.4, 144.9 (total 12 Carom.), 190.0 (8-C=O).
5-Amino-8-(4-chlorobenzoyl)-7-(4-chlorophenyl)-2-methyl-
7H-[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5m)
5-Amino-8-(4-methoxybenzoyl)-2-methyl-7-phenyl-7H-
[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5q)
IR (ATR): ν = 3459 and 3301 (NH2), 2193 (CN), 1657
IR (ATR): ν = 3463 and 3321 (NH2), 2187 (CN), 1657
(C=O, ketone) cm−1. – 1H NMR (500 MHz, CDCl3): δ =
2.47 (s, 3 H, 2-CH3), 3.81 (s, 3 H, OMe), 4.97 (s, 1 H,
7-H), 5.28 (s, 2 H, NH2), 6.82 (d, J = 8.5 Hz, 2 Harom.),
6.91 (d, J = 7.2 Hz, 2 Harom.), 7.19 (mc, 3 Harom.), 7.29 (d,
J = 8.5 Hz, 2 Harom.). – 13C NMR (125,8 MHz, CDCl3):
δ = 15.2 (2-CH3), 41.3 (C-7), 55.4 (OMe), 63.4 (C-6), 102.1
(C-8), 119.9 (CN), 147.2 (C-8a), 150.4 (C-2), 155.4 (C-5),
113.6 (2 C), 126.5 (2 C), 127.1, 128.8 (2 C), 129.0 (2 C),
131.3, 145.1, 161.3 (total 12 Carom.), 190.3 (8-C=O).
1
(C=O) cm−1. – H NMR (250 MHz, CDCl3): δ = 2.50 (s,
3 H, 2-CH3), 4.82 (s, 1 H, 7-H), 5.33 (br. s, 2 H, NH2), 6.77
(d, J = 8.4 Hz, 2 Harom., Ar1), 7.14 (d, J = 8.4 Hz, 4 Harom.
,
Ar1 + Ar2), 7.29 (d, J = 8.4 Hz, 2 Harom., Ar2). – 13C NMR
(62.9 MHz, CDCl3): δ = 15.5 (2-CH3), 40.9 (C-7), 63.7
(C-6), 101.4 (C-8), 119.3 (CN), 151.1 (C-2), 155.6 (C-5),
146.7 (C-8a), 128.0 (2 C), 128.1 (2 C), 128.6 (2 C), 128.9
(2 C), 133.1, 136.3, 137.3, 143.5 (total 12 Carom.), 189.8
(8-C=O).
5-Amino-8-(4-chlorobenzoyl)-2-methyl-7-(4-methylphenyl)-
5-Amino-8-(4-methoxybenzoyl)-2-methyl-7-(4-nitrophenyl)-
7H-thiadiazolo[3,2-a]pyridine-6-carbonitrile (5n)
7H-[1,3,4]thiadiazolo[3,2-a]pyridine-6-carbonitrile (5r)
IR (ATR): ν = 3457 and 3301 (NH2), 2194 (CN), 1651
IR (ATR): ν = 3464 and 3322 (NH2), 2186 (CN), 1659
1
1
(C=O) cm−1. – H NMR (250 MHz, CDCl3): δ = 2.25 (s, (C=O) cm−1. – H NMR (250 MHz, CDCl3): δ = 2.53 (s,
3 H, Ar2CH3), 2.48 (s, 3 H, 2-CH3), 4.77 (s, 1 H, 7-H), 5.28 3 H, 2-CH3), 3.84 (s, 3 H, OMe), 5.17 (s, 1 H, 7-H), 5.28
(br. s, 2 H, NH2), 6.74 (d, J = 8.4 Hz, 2 Harom., Ar1), 6.98 (d, (br. s, 2 H, NH2), 6.85 (d, J = 8.8 Hz, 2 H, Ar1), 7.03 (d,
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1304
I. A. Hashmi et al. · One-pot, Three-component Synthesis of 7H-[1,3,4]Thiadiazolo[3,2-a]pyridines
J = 8.8 Hz, 2 H, Ar2), 7.26 (d, J = 8.8 Hz, 2 H, Ar1), 8.04 (C-8), 119.9 (CN), 147.2 (C-8a), 150.3 (C-2), 155.4 (C-5),
(d, J = 8.8 Hz, 2 H, Ar2). – 13C NMR (62.9 MHz, CDCl3): 113.6, 126.5, 127.1, 128.8, 129.0, 131.4, 145.1, 161.3 (total
δ = 15.5 (2-CH3), 41.3 (C-7), 55.3 (OMe), 63.4 (C-6), 102.1 12 Carom.), 190.3 (8-C=O).
[1] a) Review: W. Kantlehner, Science of Synthesis,
Vol. 24 (Ed.: A. de Meijere), Georg Thieme, Stuttgart,
2006, chapter 24.2.9.1, pp. 383 – 390; b) Y. Peng,
G. Song, R. Dou, Green Chem. 2006, 8, 573 – 575;
c) X. Fan, X. Hu, X. Zhang, J. Wang, Austr. J.
Chem. 2004, 57, 1067 – 1071; d) A. M. Shestopalov,
S. G. Zlotin, A. A. Shestopalov, V. Y. Mortikov, L. A.
Rodinovskaya, Russ. Chem. Bull. 2004, 53, 573 – 579,
Chem. Abstr. 2005, 142, 219167.
[2] a) M. G. Assy, M. M. Hassanien, S. A. Zaki, Pol. J.
Chem. 1995, 69, 371 – 375; b) H. Abdel-Ghany, A. A.
El-Seyed, A. A. Sultan, A. K. El-Shafei, Synth. Com-
mun. 1990, 20, 893 – 900.
[3] Z. E. Kandeel, A. M. Farag, M. R. Shaaban, M. H. El-
nagdi, J. Heteroarom. Chem. 1996, 7, 35 – 38.
[4] M. G. Assy, Sh. A. Youssif, N. H. Ouf, Pol. J. Chem.
1995, 69, 896 – 901.
[5] S. E. Zayed, E. I. A. Elmaged, S. A. Metwally, M. H.
Elnagdi, Collect. Czech. Chem. Commun. 1991, 56,
2175 – 2182.
Khodeir, M. H. Elnagdi, Bull. Chem. Soc. Jpn. 1993,
66, 464 – 468.
[9] a) E. V. Stoyanov, I. C. Ivanov, D. Heber, Molecules
2000, 5, 16 – 29; b) E. M. A. Yakout, N. M. Ibrahim,
K. M. Ghoneim, M. R. H. Mahran, J. Chem. Res.,
Synop. 1999, 652 – 653.
[10] A. M. Shestopalov, O. A. Naumov, V. N. Nesterov,
Russ. Chem. Bull. 2003, 52, 179 – 186, Chem. Abstr.
2003, 139, 36465.
[11] A. V. Samet, A. M. Shestopalov, M. I. Struchkova, V. N.
Nesterov, Yu. T. Struchkov, V. V. Semenov, Izv. Akad.
Nauk, Ser. Khim. 1996, 8, 2050 – 2055, Chem. Abstr.
1997, 126, 47161.
[12] a) F. F. Abdel-Latif, M. M. Mashaly, E. H. El-Gawish,
J. Chem. Res., Synop. 1995, 178 – 179; b) Y. Okamoto,
Y. Kaneda, Y. Tetsuo, T. Okawara, M. Furukawa,
J. Chem. Soc., Perkin Trans 1, 1997, 1323 – 1327;
c) D. Heber, E. V. Stoyanov, Synthesis 2003, 227 – 232;
d) R. Ballini, G. Bosica, M. L. Conforti, R. Maggi,
A. Mazzacani, P. Righi, G. Sartori, Tetrahedron 2001,
57, 1395 – 1398; e) F. F. Abdel-Latif, Z. Naturforsch.
1990, 45b, 1675 – 1678.
[13] B. V. Lichitsky, V. N. Yarovenko, I. V. Zavarzin, M. M.
Krayushkin, Russ. Chem. Bull. 2000, 49, 1251 – 1254,
Chem. Abstr. 2001, 134, 29286.
[14] K. Bogdanowicz-Szwed, M. Krasodomska, J. Chem.
Res., Synop. 2002, 149 – 150.
[6] a) A. E. A. Harb, A. M. El-Maghraby, S. A. Metwally,
Collect. Czech. Chem. Commun. 1992, 57, 1570 –
1574; b) A. M. El-Agrody, H. A. Emam, M. H. El-
Hakim, M. S. A. El-Latif, A. H. J. Fakery, Chem. Res.,
Synop. 1997, 320 – 321; c) J. Bioxham, C. P. Dell, C. W.
Smith, Heterocycles 1994, 38, 399 – 408; d) N. Martin,
A. Martinez-Grau, C. Seoane, J. L. Marco, A. Albert,
F. H. Cano, J. Heterocycl. Chem. 1996, 33, 27 – 31.
[7] A. Z. Sayed, N. A. El-Hady, A. M. El-Agrody, J. Chem.
Res., Synop. 2000, 164 – 166.
[15] W. Kantlehner, E. Haug, W. Kinzy, O. Scherr, I. C.
Ivanov, Z. Naturforsch. 2004, 59b, 366 – 374.
[16] Organikum, 22. Auflage, Wiley-VCH, Weinheim,
2004, p. 529.
[8] A. G. A. Elagamey, F. M. A. El-Taweel, M. N. M.
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