The alkylation of thione 1 by the ethyl 2,3-dibromopropionate 2 in the presence of an equimolar amount
of sodium methylate or piperidine at room temperature gives a complex mixture of products but the action of
two equivalents of sodium methylate on a mixture of 1 and 2 gives the methylamide of 5-amino-
6-cyano-2-methoxymethyl-3-oxo-7-phenyl-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carboxylic acid (3) in
73% yield. The alkylation of thione 1 by ester 2 apparently initially gives the ethyl ester of 3-bromo-2-(3,4-
dihydropyridyl-2-sulfanyl)propionic acid (the alkylation of thione 1 with the ethyl bromoacetate gives the ethyl
ester of 2-(3,4-dihydropyridyl-2-sulfanyl)acetic acid [2]), which cyclizes losing ethanol and then reacts with a
second molecule of sodium methylate to give 2-methoxymethyl-3-oxo-2,3-dihydro-7H-thiazolo[3,2-a]pyridine 3.
The structure of pyridine 3 was solved spectroscopically and supported by elemental analysis. The
carbonyl group stretching bands at 1667 and 1718 cm-1 and cyano group stretching band at 2178 cm-1 are the
1
most characteristic IR bands. The H NMR spectra show signals for H-7 at 4.59 and 4.62 ppm and for the
OCH3 group at 3.28 and 3.32 ppm as two singlets, indicating the formation of methylamide 3 as two
diastereomers. The signals for the CHCH2O system protons form two ABX multiplets at 4.33-4.39 (CH protons)
and 3.63-3.88 ppm (OCH2 protons). The 13C NMR chemical shifts at 72.1 and 72.0 ppm, characteristic for the
OCH2 fragment but not for the SCH2 fragment support the structure of 2-methoxymethyl-3-oxo-2,3-dihydro-
7H-thiazolo[3,2-a]pyridine-8-carboxylic acid 3 and exclude alternative structures, namely, 3-methoxy-
4-oxo-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazine-9-carboxylic acid 4, whose formation is possible in the
case of alternative alkylation, and the methyl ester of 2,3-dihydro-7H-thiazolo[3,2-a]pyridine-3-carboxylic
acid 5, whose formation is possible in the case of cyclocondensation with the loss of hydrogen bromide and
transformation of the ethyl ester into a methyl ester. The skeleton of the structure of methylamide 3 and the
1
assignment of the H and 13C NMR signals were also indicated by the NOESY, TOCSY, HSQC, and
HMBC 2D spectra. The mass spectrum of compound 3 shows a molecular ion peak at m/z 370.
1
The H and 13C NMR spectra were obtained on a Varian Inova were taken at 600 and 150 MHz,
respectively, in DMSO-d6 with TMS as the internal standard. The two-dimensional 1H-1H TOCSY,
1H-1H NOESY spectra as well as the 13C-1H HMBC and 13C-1H HSQC spectra were taken at 25°C using the
pulse gradient technique. The mixing time was 1 sec in the 2D-NOESY spectrum but 70 msec in the TOCSY
spectrum. The 13C-HMBC spectra were taken with 62.5 msec evolution period for generation of long-range
correlations. A 4098×1024 data matrix was used to record all the 2D spectra, which provides for
1
τ
2max = 250 msec for H in recording along the F2 axis and τ1max = 100 msec for 1H or τ1max = 50 msec for 13C in
recording along the F1 axis. Prior to the Fourier transformation, the data matrix was supplemented twice with
zeros and multiplied by the cosine function in order to improve the signal-to-noise ratio. The chemical shifts of
the hydrogen and carbon atoms are given relative to the residual signals of the solvent: 2.5 and 39.5 ppm,
respectively, in DMSO. The IR spectra were taken on a Specord IR-75 spectrometer for vaseline mulls, while
the mass spectra were taken on an AEI MS-905 spectrometer at 70 eV.
Methylamide of 5-Amino-6-cyano-2-methoxymethyl-3-oxo-7-phenyl-2,3-dihydro-7H-thiazolo-
[3,2-a]pyridine-8-carboxylic Acid (3) was obtained in 73% yield; mp 220-222°C (ethanol). IR spectrum,
ν, cm-1: 1667, 1718 (C=O), 2178 (C≡N), 3316, 3390, 3425 (NH, NH2). 1H NMR spectrum, δ, ppm (J, Hz): 2.47
and 2.50 (3H, two d, J = 4.4, NHCH3); 3.28 and 3.32 (3H, two s, OCH3); 3.63-3.88 (2H, m, OCH2); 4.33-4.39
(1H, m, 2-CH); 4.59 and 4.62 (1H, two s, H-7); 7.19-7.51 (7H, m, 7-C6H5 and NH2); 7.51 and 7.50 (1H, two q,
13
J = 4.4, NHCH3). C NMR spectrum, δ, ppm: 26.0 and 26.1 (NMe); 38.7 and 38.8 (C-7); 46.7 and 47.0 (C-2);
58.7 and 58.9 (OMe); 65.8 and 65.9 (C-6); 72.0 and 72.2 (OCH2); 105.0 and 105.2 (C-8); 119.4 and 119.5
(C≡N); 126.9 and 127.0 (Co-Ph); 127.1 and 127.2 (Cp-Ph); 128.5 and 128.6 (Cm-Ph); 141.2 and 141.8 (Ci-Ph);
144.0 and 144.1 (C-5); 147.9 and 148.1 (C-8a); 165.3 and 165.4 (8-C=O); 174.2 and 174.4 (3-C=O). Mass
spectrum, m/z (Irel, %): 370 (24), 338 (63), 310 (26), 309 (31), 284 (62), 261 (78), 253 (64), 207 (49), 69 (20), 43
(20). Found, %: C 58.16; H 4.97; N 14.93; S 8.60. C18H18N4O3S. Calculated, %: C 58.36; H 4.90; N 15.12;
S 8.65.
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