Mannich reaction in the synthesis of n,s-containing heterocycles. 14. unexpected formation of thiazolo[3,2-a]pyridines in the aminoalkylation of n-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates by isobutyraldehyde and primary amines

Article abstract of DOI:10.1007/s10593-012-1042-y

Treatment of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6- tetrahydropyridine-2-thiolates with an excess of isobutyraldehyde and primary aromatic amines in refluxing ethanol gives the corresponding 7-aryl-3-arylamino-2,2-dimethyl-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a] pyridine-8-carbonitriles in 18-38% yields.

Full text of DOI:10.1007/s10593-012-1042-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
MANNICH REACTION IN THE SYNTHESIS OF
N,S-CONTAINING HETEROCYCLES. 14*. UNEXPECTED
FORMATION OF THIAZOLO[3,2-a]PYRIDINES IN THE
AMINOALKYLATION OF N-METHYLMORPHOLINIUM
4-ARYL-3-CYANO-6-OXO-1,4,5,6-TETRAHYDROPYRIDINE-
2-THIOLATES BY ISOBUTYRALDEHYDE AND PRIMARY
AMINES
V. V. Dotsenko1* and S. G. Krivokolysko1
Treatment of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with
an excess of isobutyraldehyde and primary aromatic amines in refluxing ethanol gives the
corresponding 7-aryl-3-arylamino-2,2-dimethyl-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridine-
8-carbonitriles in 18-38% yields.
Keywords: isobutyraldehyde, N-methylmorpholinium 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates,
thiazolo[3,2-a]pyridines, aminoalkylation, Mannich reaction, three-component condensation.
We have previously shown that certain 2-mercaptopyridines (6-oxo-1,6-dihydropyridine-2-thiolates
[2, 3] and 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates 1 [4]) readily form condensed 1,3,5-thia-
diazines when treated with HCHO–RNH2. Continuing our studies in this area we have attempted to synthesize
novel pyrido[2,1-b][1,3,5]thiadiazines by treating the model tetrahydropyridine-2-thiolates 1 with isobutyr-
aldehyde and primary aromatic amines.
As expected, it was found that isobutyraldehyde was less active than HCHO in reaction with thiolates 1
and primary amines. Hence brief heating of isobutyraldehyde with pyridine-2-thiolates 1 and amines does not
give the products of aminoalkylation, whereas a mixture of the thiolate 1, HCHO, and an amine readily forms
high yields of pyrido[2,1-b][1,3,5]thiadiazines 2 [4] under the same conditions. Carrying out the reaction in
more rigorous conditions (refluxing for 4-5 h) led to an unexpected result. In place of pyrido[2,1-b]-
[1,3,5]thiadiazines 2, the only isolated products proved to be 7-aryl-3-arylamino-2-dimethyl-5-oxo-2,3,6,7-
tetrahydro-5H-thiazolo[3,2-a]pyridine-8-carbonitriles 3a-f. It should be noted that this reaction represents
_______
*For Communication 13, see [1].
**To whom correspondence should be addressed, e-mail: Victor_Dotsenko@bigmir.net.
1"ChemEx Laboratory", Vladimir Dal' East-Ukrainian National University, 20-A/7 Molodezhny Kv., Lugansk
91034, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 721-725, April, 2012. Original
article submitted September 5, 2011.
672
0009-3122/12/4804-0672©2012 Springer Science+Business Media, Inc.

a fundamentally novel route for constructing the thiazolo[3,2-a]pyridine system [5, 6]. In this reaction the
isobutyraldehyde behaves as a rather rare example of a two-carbon synthetic equivalent.
Me
Me
S
NC
Ar
R
N
Me
O
CN
S
N
O
Ar
Me
EtOH

Me
+
R
Me
O
N
H
6
2
O
5
Ar
NMMH+
7
N 4
H
N
H2N
1a–d
8
NC
3
S1
R
2
Me
3a–f
Me
1a, 3a,b Ar = 4-MeOC6H4; 1b, 3c Ar = 4-MeSC6H4; 1c, 3d Ar = 2-EtOC6H4;
1d, 3e,f Ar = 2-furyl; 3 a R = MeO; b–e R = Me; f R = АсNH; NMMH+ = N-methylmorpholinium
Compounds 3a-f are white or faintly colored, finely crystalline powders which are readily soluble in
acetone, ethyl acetate, and DMSO, moderately soluble in refluxing EtOH, and poorly soluble in cold EtOH. The
1
1
structure of compounds 3a-f was proved by their H NMR and IR spectra and by HPLC-MS analysis. The H
NMR spectra show two sets of signals for the 7-Ar and 3-NHC6H4R aromatic substituents and a characteristic ABX
pattern for the C(7)–C(6)H2 fragment together with the absence of signals for (CH3)2CH and CONH group
fragments. In place of the two doublets for the methyl groups and methine proton multiplet for the (CH3)2CH
fragment there were only two sharp singlets observed at high field. Two single-proton doublets were observed
in the range 5.71-6.28 ppm and these can be assigned to the signals of the C(3)H–NHAr fragment.
CN
NMMH+
Ar
S
4-RC6H4NH2
Me2CHCHO
Me
Me
1
N
3
O
4-RC6H4NH2
or
NH
RC6H4
4
– 4-RC6H4NH2
Me
N
Me
S
CN
NMMH+
Ar
NC
4-RC6H4NH2
O
Ar
S
Me
S
N
N
Me
O
CN
O
5
Me
Ar
6
Me
[ O ]
The spectrum of compound 3d shows signals for the individual diastereomers. The presence of the secondary
amino group in the compounds 3 was also confirmed from the narrow absorption bands within the range
3290-3335 cm-1 in the IR spectra. In addition, the IR spectra were characterized by the presence of absorption
673

bands for the conjugated nitrile and the lactam C=O groups. Peaks for [M+H]+ and also [M-ArNH2]+ and
[M-CH2CO-ArNH2]+ were seen in the mass spectra of compounds 3a-f.
The proposed reaction mechanism includes the N-aminoalkylation of the thiolates 1 in the first stage of
the process followed by desamination of the condensation product 4 to enamide 5 and oxidation to disulfide 6
by atmospheric oxygen. It should be noted that the possible formation of such bis(pyrid-2-yl)disulfides under
these conditions and also the ease of opening the S–S bond in the presence of different C-nucleophiles has
previously been confirmed experimentally [7]. Subsequent intramolecular thiolation of the enamide C=C bond
leads to the cleavage of a thiolate ion (compound 4 or 5) and formation of the final product 3. The low yields
(18-38%) of the target products 3 is likely a result of the multistage cascade process and nonoptimal reaction
conditions.
The proposed mechanism is also supported by the observation that bis(pyrid-2-yl)disulfide 7 (prepared
by oxidation of thiolate 1a) also gives the thiazolopyridine 3b (yield 56% calculated on disulfide 7) when
treated with excess of isobutyraldehyde and p-toluidine under analogous conditions.
MeO
4-MeC6H4NH2
Me2CHCHO
base, EtOH
CN
S
3b
– 1а
NH
2
O
7
Hence we have discovered a fundamentally novel route for preparation of thiazolo[3,2-a]pyridines
through a three-component condensation of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetra-
hydropyridine-2-thiolates, isobutyraldehyde, and primary aromatic amines.
EXPERIMENTAL
IR spectra were recorded on an IKS-29 spectrophotometer in nujol. 1H NMR spectra were recorded on a
Varian Unity Plus (400 MHz) instrument using DMSO-d6 with TMS as internal standard. HPLC-MS analysis was
performed on an Agilent 1100 liquid chromatograph fitted with DAD and Sedex 75 ELSD detectors and
combined with an Agilent LC/MSD VL mass spectrometer using electrospray ionization. Compound 3f was
analyzed on an Agilent 1200 chromatograph with a Rapid Resolution HT Cartridge analytical column (4.630 mm,
1.8 m, Zorbax SB-C18) and using electrospray ionization. HPLC-MS analysis for compound 7 was carried out
on a Shimadzu LC-10AD liquid chromatograph fitted with Shimadzu SP D-10A UV-Vis (254 nm) and Sedex
75 ELSD detectors combined with a PE SCIEX API 150EX mass spectrometer. Elemental analysis was
performed on a Carlo-Erba 1106 Elemental Analyzer instrument with a measurement accuracy of ±0.25%.
Monitoring of the purity of the compounds obtained was carried out by TLC on Silufol UV-254 plates with
acetone–hexane (1:1) eluent and visualization by UV light or iodine vapor. Melting points were measured on a
Koffler hot bench and are not corrected. The model thiolates 1a-d were prepared by condensation of the
corresponding aldehyde, cyanothioacetamide, Meldrum's acid, and N-methylmorpholine by a known method
[8-10].
7-Aryl-3-arylamino-2,2-dimethyl-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridine-8-carbonitri-
les (3a-f) (General Method). A mixture of the thiolate 1a-d (2.5 mmol), isobutyraldehyde (1.5 ml, 16.5 mmol),
and the primary amine (2.7 mmol) in ethanol (15 ml) was refluxed for 4-5 h in a flask fitted with a condenser.
The product was evaporated to two thirds of the initial volume and left for 72 h at 25ºC. The precipitate formed
was filtered off and washed with ethanol and petroleum ether to give analytically pure samples of the
thiazolopyridines 3a-f.
674

2,2-Dimethyl-7-(4-methoxyphenyl)-3-[(4-methoxyphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thia-
zolo[3,2-a]pyridine-8-carbonitrile (3a). Yield 0.28 g (26%), light-gray product, mp 205-207ºC. IR spectrum,
1
, cm-1: 3335 (NH), 2195 (C≡N), 1697 (C=O). H NMR spectrum, , ppm (J, Hz): 1.50 (3Н, s, 2-СН3); 1.61
(3Н, s, 2-СН3); 2.39-2.45 (1Н, m, cis-H-6); 3.23 (1Н, dd, 3J = 6.8, 2J = 15.6, trans-H-6); 3.64 (3Н, s, OCH3); 3.71
(3Н, s, OCH3); 3.90-3.94 (1H, m, Н-7); 5.85 (1Н, d, 3J = 9.3, Н-3); 6.09 (1Н, d, 3J = 9.3, NH); 6.71 (2H, d, 3J = 6.4,
H-3',5'); 6.78 (2H, d, 3J = 6.4, H-3'',5''); 6.95 (2H, d, 3J = 6.4, H-2',6'); 7.09 (2H, d, 3J = 6.4, H-2'',6''). Mass spectrum,
m/z (Irel, %): 436 [М+H]+ (24), 313 [М-ArNH2]+ (45), 271 [М-CH2CO-ArNH2]+ (100), 177 [ArN=СНМе2]+ (10).
Found, %: C 66.00; H 5.84; N 9.85. C24H25N3O3S. Calculated, %: C 66.18; H 5.79; N 9.65.
7-(4-Methoxyphenyl)-2,2-dimethyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazo-
lo[3,2-a]pyridine-8-carbonitrile (3b). Yield 0.23 g (22%), white finely crystalline powder, mp 195-197ºC. IR
1
spectrum, , cm-1: 3335 (NH), 2198 (C≡N), 1698 (C=O). H NMR spectrum, , ppm (J, Hz): 1.48 (3Н, s,
3
2
2-СН3); 1.62 (3Н, s, 2-СН3); 2.15 (3Н, s, ArСН3); 2.45 (1Н, dd, J = 2.4, J = 16.6, cis-H-6); 3.23 (1Н, dd,
2
3
3J = 7.8, J = 16.6, trans-H-6); 3.71 (3Н, s, OCH3); 3.92 (1H, dd, 3J = 7.8, 2J = 2.4, Н-7); 5.90 (1Н, d, J = 10.8,
Н-3); 6.28 (1Н, d, 3J = 10.8, NH); 6.77 (2H, d, 3J = 8.8, H-3',5'); 6.88-6.92 (4H, m, H Ar); 7.10 (2H, d, 3J = 8.8,
H-2',6'). Mass spectrum, m/z (Irel, %): 420 [М+H]+ (13), 313 [М-ArNH2]+ (36), 271 [М-CH2CO-ArNH2]+ (100).
Found, %: C 68.51; H 6.04; N 10.20. C24H25N3O2S. Calculated, %: C 68.71; H 6.01; N 10.02.
2,2-Dimethyl-3-[(4-methylphenyl)amino]-7-(4-methylsulfanylphenyl)-5-oxo-2,3,6,7-tetrahydro-
5H-thiazolo[3,2-a]pyridine-8-carbonitrile (3c). Yield 0.41 g (38%), white powder, mp 220-222ºC. IR
1
spectrum, , cm-1: 3320 (NH), 2195 (C≡N), 1697 (C=O). H NMR spectrum, , ppm (J, Hz): 1.51 (3Н, s,
2-СН3); 1.63 (3Н, s, 2- CH3); 2.18 (3Н, s, ArСН3); 2.43 (3H, s, SCH3); 2.50-2.52 (1Н, m, cis-H-6); 3.17-3.21
3
3
3
3
(1Н, m, trans-H-6); 3.91 (1Н, dd, J = 7.5, J = 1.8, Н-7); 5.86 (1Н, d, J = 10.9, Н-3); 6.18 (1Н, d, J = 10.9,
3
3
3
NH); 6.85 (2H, d, J = 8.5, H Ar); 6.88 (2H, d, J = 8.5, H Ar); 7.07 (2H, d, J = 8.5, H Ar); 7.10 (2H, d,
3J = 8.5, H Ar). Mass spectrum, m/z (Irel, %): 436 [M+H]+ (26), 329 [M-ArNH2]+ (52), 287 [M-CH2O-ArNH2]+
(100), 161 [ArN=CHMe2]+ (10). Found, %: C 65.90; H 5.81; N 9.78. C24H25N3OS2. Calculated, %: C 66.17;
H 5.78; N 9.65.
7-(2-Ethoxyphenyl)-2,2-dimethyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo-
[3,2-a]pyridine-8-carbonitrile (3d). Yield 0.30 g (28%), colorless needle crystals, mp 196-197ºC. IR spectrum,
1
3
, cm-1: 3290 (NH), 2195 (C≡N), 1675 (C=O). H NMR spectrum, , ppm (J, Hz): 1.42* (3H, t, J = 6.9,
CH2CH3); 1.50*2 (0.6H, s, 2-CH3); 1.53 (2.4H, s, 2-CH3); 1.64 (2.4H, s, 2-CH3); 1.66*2 (0.6H, s, 2-CH3); 2.19
(2.4H, s, ArCH3); 2.21*2 (0.6H, s, ArCH3); 2.58 (0.8H, br. pseudo doublet, 2J = 16.7, cis-H-6); 2.73*2 (0.2H, dd,
2J = 16.5, J = 6.8, cis-H-6); 2.84*2 (0.2H, dd, 2J = 16.5, 3J = 9.7, trans-H-6); 3.00 (0.8H, dd, J = 16.7, J = 8.0,
3
2
3
trans-H-6); 4.04-4.14* (2H, m, CH2CH3); 4.19-4.26* (1H, m, H-7); 5.71*2 (0.2H, d, 3J = 9.1, H-3); 5.83 (0.8H,
3
3
d, J = 10.9, H-3); 6.01-6.06* (1H, m, NH); 6.70-6.95* (6H, m, H Ar); 7.05 (0.8H, d, J = 7.3, H Ar); 7.14
(0.8H, dd, 3J = 7.3, 3J = 7.5, H Ar); 7.24*2 (0.2H, dd, 3J = 7.2, 3J = 7.7, H Ar). Mass spectrum, m/z (Irel, %): 472
[M+K]+ (8), 456 [M+Na]+ (11), 434 [M+H]+ (6), 327 [M-ArNH2]+ (85), 299 (17), 285 [M-CH2CO-ArNH2]+
(100), 179 [ArN=CHMe2+H+H2O]+ (11). Found, %: C 69.00; H 6.31; N 10.02. C25H27N3O2S. Calculated, %:
C 69.26; H 6.28; N 9.69.
7-(2-Furyl)-2,2-dimethyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]-
pyridine-8-carbonitrile (3e). Yield 0.26 g (27%), dark-beige powder, mp 229-231ºC (sublimes). IR spectrum,
1
, cm-1: 3330 (NH), 2195 (C≡N), 1695 (C=O). H NMR spectrum, , ppm (J, Hz): 1.47 (3Н, s, 2-СН3); 1.61
3
2
(3Н, s, 2-СН3); 2.18 (3Н, s, ArСН3); 2.66 (1Н, dd, J = 2.3, J = 16.8, cis-H-6); 3.16-3.20 (1Н, m, trans-H-6);
4.02-4.04 (1Н, m, Н-7); 5.82 (1Н, d, 3J = 10.9, Н-3); 6.00 (1Н, d, 3J = 10.9, NH); 6.12-6.13 (1Н, m, Н-3' furyl);
6.26-6.27 (1Н, m, Н-4' furyl); 6.84 (4H, dd, 3J = 8.2, 4-MeC6H4); 7.39-7.40 (1Н, m, Н-5' furyl). Mass spectrum,
m/z (Irel, %): 402 [M+Na]+ (10), 380 [М+H]+ (17), 273 [М-ArNH2]+ (26), 231 [М-CH2CO-ArNH2]+ (100).
Found, %: C 66.10; H 5.62; N 11.32. C21H21N3O2S. Calculated, %: C 66.47; H 5.58; N 11.07.
_______
* Overlapping of the signals of the major and minor isomers.
*2 Signals of the minor isomers. Ratio of minor and major isomers in compound 3d ~ 1:4.
675

N-{4-[(8-Cyano-7-(2-furyl)-2,2-dimethyl-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridin-3-yl)-
amino]phenyl}acetamide (3f). Yield 0.19 g (18%), beige powder, mp 223-225ºC (decomp.). IR spectrum, ,
cm-1: 3330 (NH), 2192 (C≡N), 1685 (C=O). 1H NMR spectrum, , ppm (J, Hz): 1.46 (3H, s, 2-CH3); 1.61 (3H,
3
2
s, 2-CH3); 1.98 (3H, s, COCH3); 2.58-2.68 (1H, m, cis-H-6); 3.20 (1H, dd, J = 7.5, J = 16.8, trans-H-6);
3
4.08-4.10 (1H, m, H-7); 5.87 (1H, d, J = 10.8, H-3); 6.15-6.18 (2H, m, NHAr, H-3' furyl); 6.32-6.33 (1H, m,
H-4' furyl); 6.87 (2H, d, 3J = 8.3, H Ar); 7.26 (2H, d, 3J = 8.3, H Ar); 7.48-7.49 (1H, m, H-5' furyl); 9.58 (1H, s,
AcNH). Mass spectrum, m/z (Irel, %): 423 [M+H]+ (100), 273 [M-ArNH2]+ (25), 231 [M-CH2CO-ArNH2]+ (21).
Found, %: C 62.30; H 5.22; N 13.33. C22H22N4O3S. Calculated, %: C 62.54; H 5.25; N 13.26.
Preparation of Thiazolo[3,2-a]pyridine (3b) from Disulfide 7. A mixture of disulfide 7 (0.973 g,
1.88 mmol), prepared from thiolate 1a using method described in [7], isobutyraldehyde (1.20 ml, 13.2 mmol), p-
toluidine (0.420 g, 3.92 mmol), and N-methylmorpholine (0.45 ml, 4.10 mmol) in ethanol (12 ml) was refluxed
in a flask fitted with a condenser. In about 30 min a precipitate began to form. The mixture was refluxed for a
further 4 h, evaporated to two thirds of the original volume, and left for 72 h at 25ºC. The precipitate was
filtered off and washed with ethanol and petroleum ether to give the thiazolopyridine 3b identical to that
obtained from thiolate 1a. Yield 0.434 g (56% calculated on the disulfide 7 or 28% calculated on thiolate 1a).
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