The mannich reaction in the synthesis of N,S-containing heterocycles 11.* Synthesis of 3,3?-(1,4-phenylene)-bis(8-aryl-6-oxo-3,4,7,8- tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles)

Article abstract of DOI:10.1007/s11172-012-0018-5

N-Methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2- thiolates readily undergo the Mannich reaction with p-phenylenediamines and excess formaldehyde in the absence of a catalyst to form 3,3?-(1,4- phenylene)-bis(8-aryl-6-oxo-3,4,7,8-tet

Full text of DOI:10.1007/s11172-012-0018-5

Russian Chemical Bulletin, International Edition, Vol. 61, No. 1, pp. 131—135, January, 2012
131
The Mannich reaction in the synthesis of N,Sꢀcontaining heterocycles
11.* Synthesis of 3,3´ꢀ(1,4ꢀphenylene)ꢀbis(8ꢀarylꢀ6ꢀoxoꢀ3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀ
pyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitriles)
V. V. Dotsenko,a,b S. G. Krivokolysko,a and V. P. Litvinovc†
a"ChemEx" Laboratory Vladimir Dal´ EastꢀUkrainian National University,
20 a kv. Molodezhnyi, 91034 Lugansk, Ukraine.
Eꢀmail: Victor_Dotsenko@bigmir.net
bPhysicoꢀchemical Department, State Enterprise "Luganskstandartmetrology",
50 ul. Timiryazeva, 91021 Lugansk, Ukraine
cN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation
NꢀMethylmorpholinium 4ꢀarylꢀ3ꢀcyanoꢀ6ꢀoxoꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolates
readily undergo the Mannich reaction with pꢀphenylenediamines and excess formaldehyde in
the absence of a catalyst to form 3,3´ꢀ(1,4ꢀphenylene)ꢀbis(8ꢀarylꢀ6ꢀoxoꢀ3,4,7,8ꢀtetrahydroꢀ
2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitriles) in moderate yields (24—56%).
Key words: the Mannich reaction, tetrahydropyridineꢀ2ꢀthiolates, aminomethylation,
pyrido[2,1ꢀb][1,3,5]thiadiazines, threeꢀcomponent reaction.
One of the most convenient methods for the preparaꢀ
tion of 1,3,5ꢀthiadiazine fused ring derivatives is the
"double" Mannich reaction of 2ꢀmercaptoazoles (ꢀazines)
with formaldehyde and primary amines.1 Such an apꢀ
proach was used for the synthesis of substituted pyridoꢀ
[2,1ꢀb][1,3,5]thiadiazines2, bis(pyrido[2,1ꢀb][1,3,5]thiaꢀ
diazinꢀ7ꢀyl)methanes,3 1,2,4ꢀtriazolo[3,4ꢀb][1,3,5]thiaꢀ
diazines,4 imidazo[2,1ꢀb][1,3,5]thiadiazines,5,6 1,2,4ꢀtriꢀ
azino[3,2ꢀb][1,3,5]thiadiazines,5 thiazolo[3´,4´:1,5][1,2,4]ꢀ
triazolo[3,4ꢀb][1,3,5]thiadiazines,7 1,3,5ꢀthiadiazinoꢀ
[3,2ꢀa]benzimidazoles,8 cyclopenta[g]pyrido[2,1ꢀb][1,3,5]ꢀ
thiadiazines,9 pyrimido[2,1ꢀb][1,3,5]thiadiazines,10 and
pyrimido[4,3ꢀb][1,3,5]thiadiazines.11
In continuation of the works in the field of chemistry
of partially hydrogenated pyridineꢀ2ꢀchalcogenones,12 we
studied reactions of Nꢀmethylmorpholinium 4ꢀarylꢀ3ꢀ
cyanoꢀ6ꢀoxoꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolates (1)
with formaldehyde and pꢀphenylenediamine. The Manꢀ
nich reaction involving pꢀphenylenediamine and cyclic
S,Nꢀbinucleophiles has been studied earlier using 2ꢀmerꢀ
captobenzimidazole,13 2ꢀthioxoꢀ1,3,4ꢀoxadiazoles,14 and
4ꢀmercaptoquinazoline15 as examples. It was noted that
in all the cases, only one nucleophilic center of the subꢀ
strate was involved to form the products of normal aminoꢀ
methylation at the nitrogen13,14 or sulfur atom.15
We found that a threeꢀcomponent reaction of tetrahyꢀ
dropyridineꢀ2ꢀthiolates 1a—f with 0.5 equiv. of pꢀphenylꢀ
enediamine and excess of formaldehyde leads to the prodꢀ
ucts of a "double" S,Nꢀaminomethylation, i.e., 3,3´ꢀ(1,4ꢀ
phenylene)ꢀbis(8ꢀarylꢀ6ꢀoxoꢀ3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀ
pyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitriles) (2a—f) in
24—56% yields (Scheme 1). The starting tetrahydropyriꢀ
dineꢀ2ꢀthiolates 1a—f were synthesized by the condensaꢀ
tion of the corresponding aromatic aldehyde, cyanothioꢀ
acetamide (3), and the Meldrum´s acid (4) with subseꢀ
quent cyclization of the stable Michael adduct 5.
It is necessary to note that, in contrast to the most
reactions of the "double" aminomethylation of 2ꢀmercaptoꢀ
azoles and ꢀazines, the synthesis of compounds 2 does not
require acid catalysis. Products 2 are beige or slightly yelꢀ
lowish finely crystalline compounds, virtually insoluble in
EtOH and acetone and soluble in warm DMF or DMSO.
Compounds 2 were characterized by IR and 1H and
13C NMR spectroscopy. The 1H NMR spectra are distinꢀ
guished by a double set of signals for the pyrido[2,1ꢀb]ꢀ
[1,3,5]thiadiazine fragment. This fact indicates that the
compounds obtained are mixtures of stereoisomers. In fact,
as it has been shown earlier,16 the starting tetrahydroꢀ
pyridineꢀ2ꢀthiolates 1 and their derivatives are mixtures of
(4R)ꢀ and (4S)ꢀenantiomers in the ratio close to 1 : 1. Due
to the presence of the equivalent chiral centers C(8) and
C(8´), bisꢀpyrido[2,1ꢀb][1,3,5]thiadiazines 2 can exist as
a mixture of stereoisomers: an enantiomeric pair (8S,8´S)/
(8R,8´R) (the structures A and B) and the (8S,8´R)ꢀmesoꢀ
* For Part 10, see V. V. Dotsenko, K. A. Frolov, S. G. Kriꢀ
vokolysko, V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim., 2009,
1436 [Russ. Chem. Bull., Int. Ed., 2009, 58, 1479].
† Deceased.
1
form C. Thus, the double set of signals in the H NMR
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 129—133, January, 2012.
1066ꢀ5285/12/6101ꢀ131 © 2012 Springer Science+Business Media, Inc.

132
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
Dotsenko et al.
Scheme 1
B = Nꢀmethylmorpholine; Ar = 1ꢀnaphthyl (a), 2ꢀMeOC6H4 (b), 2ꢀClꢀ6ꢀFC6H3 (c), 2ꢀNO2C6H4 (d), 4ꢀFC6H4 (e), 2,4ꢀ(MeO)2C6H3 (f)
spectra of compounds 2 is related to the resonances of the
protons of the enantiomeric pair A+B and the mesoꢀform C
(the ratio ~1 : 1).
with respect to C(8)H, 2J = 16.0—23.0 Hz, 3J = 7.0—8.5 Hz),
as well as a multiplet (pseudotriplet) for the protons C(8)H
and C(8´)H at  3.88—4.85 (ABX system). The protons of
the 1,3,5ꢀthiadiazine fragment produce a complicated patꢀ
tern in the region  5.24—5.65 because of the overlap
of the double doublets for the diastereotopic protons
N—C(4)H2—N, N—C(4´)H2—N, the pair of double douꢀ
blets for the protons N—C(2)H2—S, N—C(2´)H2—S, and
the total doubling the number of peaks, corresponding to
the signals of the enantiomeric pair A+B and mesoꢀform C.
It should be noted that chemical shifts of the signals for
the protons N—C(4)H2—N—C(2)H2—S are in good
1
agreement with the H NMR spectroscopic data for the
related pyrido[2,1ꢀb][1,3,5]thiadiazine structures.2,3,9 The
protons of the 1,4ꢀphenylene spacer (AA´BB´ system) resꢀ
onate either as a broad singlet, or as a pseudodoublet due
to the overlap of two unresolved peaks for the protons
(A+B)/C in the region  7.07—7.19. The IR spectra of
compounds 2a—f are characterized the presence of the
strong absorption bands related to the stretching vibraꢀ
tions of the conjugated cyano group ( = 2188—2196 cm–1
)
and the C=O group ( = 1685—1707 cm–1).
In conclusion, Nꢀmethylmorpholinium 4ꢀarylꢀ3ꢀcyꢀ
anoꢀ6ꢀoxoꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolates under
the action of pꢀphenylenediamine and formaldehyde in
the absence of a catalyst readily undergo S,Nꢀdiaminomeꢀ
thylation to be converted to 3,3´ꢀ(1,4ꢀphenylene)ꢀbis(8ꢀ
arylꢀ6ꢀoxoꢀ3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]ꢀ
thiadiazineꢀ9ꢀcarbonitriles), which exist as mixtures of
(8S,8´S)ꢀ, (8R,8´R)ꢀ, and (8S,8´R)ꢀstereoisomers.
The 1H NMR spectra of bisꢀpyrido[2,1ꢀb][1,3,5]ꢀ
thiadiazines 2a—f exhibit two doublets of doublets for the
diastereotopic protons C(7)H2 and C(7´)H2 at  2.62—2.84
(cisꢀarrangement with respect to C(8)H, 2J = 16.0—23.0 Hz,
3J = 3.0—7.5 Hz) and  2.90—3.29 (transꢀarrangement
Experimental
1
H NMR spectra of compounds 1d—f and 2a—d were reꢀ
corded on a Bruker DRXꢀ500 spectrometer (500.07 MHz) in

Pyrido[2,1ꢀb][1,3,5]thiadiazines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
133
DMSOꢀd6, of compounds 2e,f on a Bruker Avance II 400 spectroꢀ
meter (400.13 MHz), 13C NMR spectrum of compound 2c on
a Bruker DRXꢀ500 spectrometer (125.76 MHz) in DMSOꢀd6,
using Me4Si as an internal standard. IR spectra were recorded
on a IKSꢀ29 spectrophotometer in Nujol. Elemental analysis
were performed on a Perkin—Elmer C,H,NꢀAnalyzer. Purity of
compounds was monitored by TLC on Silufol UVꢀ254 plates,
using acetone—hexane (1 : 1) as an eluent and visualizing in
iodine vapors or under UV light. Melting points of compounds
were measured on a Kofler hotꢀstage microscope and were not
corrected. All the solvents (reagent grade) were used without
additional purification. The starting Nꢀmethylmorpholinium
tetrahydropyridineꢀ2ꢀthiolates 1a—c were synthesized accordꢀ
ing to the known procedures.17—19 Cyanothioacetamide (3) was
obtained by the reaction of malononitrile with hydrogen sulfide
following the Brunskill method.20 The Meldrum´s acid (2,2ꢀdiꢀ
methylꢀ1,3ꢀdioxaneꢀ4,6ꢀdione, 4) was synthesized according to
the procedure described earlier.21
NꢀMethylmorpholinium (4R/4S)ꢀ4ꢀarylꢀ3ꢀcyanoꢀ6ꢀoxoꢀ
1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolates 1d—f were obtained acꢀ
cording to a modified procedure19 as follows: Nꢀmethylmorpholine
(5 drops) was added to a mixture of the corresponding aromꢀ
atic aldehyde (20 mmol) and cyanothioacetamide (3) (2.0 g,
20 mmol) in EtOH (25—30 mL) with stirring. The reaction mixꢀ
ture was stirred for 1 h at 20 C, followed by addition of the
Meldrum´s acid (4) (3.0 g, 20.8 mmol) and Nꢀmethylmorpholine
(3.3 mL, 30 mmol). From the pale yellow solution formed,
a white precipitate of the Michael adduct, Nꢀmethylmorpholinꢀ
ium 5ꢀ(3ꢀaminoꢀ1ꢀarylꢀ2ꢀcyanoꢀ3ꢀthioxopropyl)ꢀ2,2ꢀdimethylꢀ
4ꢀoxoꢀ4Hꢀ1,3ꢀdioxinꢀ6ꢀolate (5), was formed within 5—10 min.
A suspension obtained was refluxed for 3—4 h with stirring (acꢀ
companied by the adduct dissolution and CO2 evolution), an
orange solution was half concentrated, a crystalline precipitate
formed upon cooling and stirring was filtered off, washed with
EtOH and acetone. The obtained thiolates 1d—f were used in
the reactions without additional purification.
system); 3.79 (m, 4 H, CH2OCH2); 7.11—7.23 (m, 4 H, Ar);
8.66 (s, 1 H, NH); 9.63 (br.s, 1 H, NH+).
NꢀMethylmorpholinium (4R/4S)ꢀ3ꢀcyanoꢀ4ꢀ(2,4ꢀdimethoxyꢀ
phenyl)ꢀ6ꢀoxoꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolate (1f). Pinkꢀ
ish yellow finely crystalline powder, the yield was 82%, m.p.
144—147 C. Found (%): C, 58.69; H, 6.50; N, 10.88.
C19H25N3O4S (M = 391.50). Calculated (%): C, 58.29; H, 6.44;
N, 10.73. IR, /cm–1: 3150, 3080 (NH, NH+); 2193 (CN); 1683
1
(C=O); 1618 (C=C). H NMR (DMSOꢀd6), : 2.27 (dd, 1 H,
3
C(5)H, ABX system, 2J = 16.1 Hz, J = 2.5 Hz); 2.65 (dd, 1 H,
2
3
C(5)H, ABX system, J = 16.1 Hz, J = 7.3 Hz); 2.77 (s, 3 H,
NCH3); 3.15 (m, 4 H, CH2NCH2); 3.74, 3.78 (both s, 3 H each,
2 MeO); 3.75—3.82 (m, 5 H, the overlap of the signals CH2OCH2
and C(4)H); 6.47 (br.d, 1 H, C(5)HAr, 3J = 8.3 Hz); 6.54 (s, 1 H,
3
C(3)HAr); 6.93 (br.d, 1 H, C(6)HAr, J = 8.3 Hz); 8.61 (s, 1 H,
NH); 9.63 (br.s, 1 H, NH+).
Synthesis of 3,3´ꢀ(1,4ꢀphenylene)ꢀbis(8ꢀarylꢀ6ꢀoxoꢀ3,4,7,8ꢀ
tetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarboꢀ
nitriles) 2a—f (general procedure). pꢀPhenylenediamine (65 mg,
0.6 mmol) and excess of 37% aqueous HCHO (1.5 mL, 20 mmol,
free of the paraformaldehyde impurities) were added to a susꢀ
pension of tetrahydropyridineꢀ2ꢀthiolate 1a—f (1.2 mmol) in
EtOH (8—10 mL). The mixture obtained was heated until the
homogeneity was reached, refluxed for 3—5 min with vigorous
stirring (the product may start to crystallize at this step), stirred
for 3 h at 20 C, and kept for 24—72 h. The crystals were filꢀ
tered off, sequentially washed with EtOH, acetone, and light
petroleum. Compounds 2a—f were obtained in the analytically
pure form.
3,3´ꢀ(1,4ꢀPhenylene)ꢀbis[8ꢀ(1ꢀnaphthyl)ꢀ6ꢀoxoꢀ3,4,7,8ꢀtetraꢀ
hydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitrile]
(2a). Beige finely crystalline powder, the yield was 24%, m.p.
248—251 C (decomp.). Found (%): C, 69.90; H, 4.48; N, 11.80.
C42H32N6O2S2 (M = 716.89). Calculated (%): C, 70.37; H, 4.50;
N, 11.72. IR, /cm–1: 2196 (CN); 1693 (C=O). 1H NMR, :
2.70 (m, the overlap of two dd for stereoisomers (A+B)/C,
2 H each, C(7)H + C(7´)H, ABX system, 2J = 16.0 Hz,
3Jcis = 3.0 Hz); 3.29 (m, the overlap of two dd for stereoisomers
(A+B)/C, 2 H each, C(7)H + C(7´)H, ABX system, 2J = 16.0 Hz,
3Jtrans = 7.0 Hz); 4.85 (m, the overlap of two dd for stereoꢀ
isomers (A+B)/C, 2 H each, C(8)H + C(8´)H, ABX system);
5.43—5.58 (m, the overlap of four dd for stereoisomers (A+B)/C,
2 H each, N—C(4)H2—N, N—C(4´)H2—N, N—C(2)H2—S,
N—C(2´)H2—S); 7.07, 7.09 (both d, 1 H each, C(2)H +
+ C(2´)Hnaphthyl stereoisomers (A+B)/C, 3J = 7.5 Hz); 7.182,
7.189 (both s, 4 H each, phenylene of stereoisomers (A+B)/C);
7.34 (dd, 2 H, C(3)Hnaphthyl, 3J = 7.5 Hz); 7.59 (m, 4 H, C(6)H
+ C(6´)Hnaphthyl, C(7)H + C(7´)Hnaphthyl); 7.87 (m, the overlap
of two d for stereoisomers (A+B)/C, 2 H each, C(4)H +
NꢀMethylmorpholinium (4R/4S)ꢀ3ꢀcyanoꢀ6ꢀoxoꢀ4ꢀ(2ꢀnitroꢀ
phenyl)ꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolate (1d). Yellow fineꢀ
ly crystalline powder, the yield was 57%, m.p. 146—148 C.
Found (%): C, 54.66; H, 5.37; N, 14.98. C17H20N4O4S (M =
= 376.44). Calculated (%): C, 54.24; H, 5.36; N, 14.88. IR, /cm–1
:
3160, 3075 (NH, NH+); 2178 (CN); 1695 (C=O); 1612 (C=C).
2
1H NMR, : 2.35 (dd, 1 H, C(5)H, ABX system, J = 16.0 Hz,
3J = 4.0 Hz); 2.80 (s, 3 H, NMe); 2.89 (dd, 1 H, C(5)H, ABX
2
3
system, J = 16.0 Hz, J = 8.0 Hz); 3.19 (m, 4 H, CH2NCH2);
3.78 (m, 4 H, CH2OCH2); 4.06 (m, the overlap of two d, 1 H,
C(4)H, ABX system); 7.44 (br.d, 1 H, C(6)HAr,
3J = 8.0 Hz);
7.51 (pseudot, the overlap of two d, 1 H, C(4)HAr, 3J = 8.0 Hz);
7.72 (pseudot, the overlap of two d, 1 H, C(5)HAr, 3J = 8.0 Hz);
3
7.92 (br.d, 1 H, C(3)HAr, J = 8.0 Hz); 8.95 (s, 1 H, NH); 9.65
+ C(4´)Hnaphthyl
, ,
3J = 8.0 Hz); 7.98 (d, 2 H, C(5)Hnaphthyl
(br.s, 1 H, NH+).
3J = 7.5 Hz); 8.10 (d, 2 H, C(8)Hnaphthyl, 3J = 8.0 Hz).
NꢀMethylmorpholinium (4R/4S)ꢀ3ꢀcyanoꢀ4ꢀ(4ꢀfluoropheꢀ
nyl)ꢀ6ꢀoxoꢀ1,4,5,6ꢀtetrahydropyridineꢀ2ꢀthiolate (1e). Light yelꢀ
low finely crystalline powder, the yield was 71%, m.p. 138—142 C.
Found (%): C, 58.06; H, 5.79; N, 12.18. C17H20FN3O2S
(M = 349.43). Calculated (%): C, 58.43; H, 5.77; N, 12.03. IR,
/cm–1: 3155, 3075 (NH, NH+); 2168 (CN); 1698 (C=O); 1602
(C=C). 1H NMR, : 2.35 (dd, 1 H, C(5)H, ABX system,
3,3´ꢀ(1,4ꢀPhenylene)ꢀbis[8ꢀ(2ꢀmethoxyphenyl)ꢀ6ꢀoxoꢀ
3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀ
carbonitrile] (2b). Beige finely crystalline powder, the yield was
43%, m.p. 241—243 C (decomp.). Found (%): C, 63.40; H, 4.80;
N, 12.55. C36H32N6O4S2 (M = 676.82). Calculated (%):
C, 63.89; H, 4.77; N, 12.42. IR, /cm–1: 2195 (CN); 1690 (C=O).
1H NMR, : 2.62 (m, the overlap of two dd for stereoisomers
(A+B)/C, 2 H each, C(7)H + C(7´)H, ABX system, 2J = 16.0 Hz,
3Jcis = 3.5 Hz); 3.08 (m, the overlap of two dd for stereoisomers
(A+B)/C, 2 H each, C(7)H + C(7´)H, ABX system, 2J = 16.0 Hz,
3
2J = 16.0 Hz, J = 3.8 Hz); 2.74 (dd, 1 H, C(5)H, ABX system,
2J = 16.0 Hz, 3J = 7.5 Hz); 2.81 (s, 3 H, NCH3); 3.21 (m, 4 H,
CH2NCH2); 3.67 (m, the overlap of two d, 1 H, C(4)H, ABX

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Dotsenko et al.
3Jtrans = 7.5 Hz); 3.783, 3.787 (both s, 3 H each, MeO of stereoꢀ
isomers (A+B)/C); 4.07 (m, the overlap of two dd for stereoꢀ
isomers (A+B)/C, 2 H each, C(8)H + C(8´)H, ABX system);
5.34—5.55 (m, the overlap of four dd for stereoisomers (A+B)/C,
2 H each, N—C(4)H2—N, N—C(4´)H2—N, N—C(2)H2—S,
N—C(2´)H2—S); 6.80—6.89 (m, 4 H, C(3)H + C(3´)HAr, C(5)H +
two dd for stereoisomers (A+B)/C, 2 H each, N—C(4)H2—N,
N—C(4´)H2—N or N—C(2)H2—S, N—C(2´)H2—S, 3J = 12.6 Hz);
5.43 (m, the overlap of two dd for stereoisomers (A+B)/C,
2 H each, N—C(2)H2—S, N—C(2´)H2—S or N—C(4)H2—N,
N—C(4´)H2—N, 3J = 13.8 Hz); 6.99—7.15 (m, 8 H, 2 Ar);
7.063, 7.068 (both s, 4 H each, phenylene of stereoisomers
(A+B)/C).
+ C(5´)HAr); 7.03 (dd, 2 H, C(4)H + C(4´)HAr,
3J = 7.5 Hz,
3J = 8.0 Hz); 7.10 (pseudos, 4 H, phenylene); 7.28 (m, the
overlap of the signals for stereoisomers (A+B)/C, 2 H, C(6)H +
+ C(6´)HAr).
3,3´ꢀ(1,4ꢀPhenylene)ꢀbis[8ꢀ(2,4ꢀdimethoxyphenyl)ꢀ6ꢀoxoꢀ
3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀ
carbonitrile] (2f). Beige crystals, the yield was 52%, m.p.
255—258 C (decomp.). Found (%): C, 62.22; H, 4.96; N, 11.51.
C38H36N6O6S2 (M = 736.88). Calculated (%): C, 61.94; H, 4.92;
N, 11.40. IR, /cm–1: 2196 (CN); 1707 (C=O). 1H NMR,
: 2.62 (m, the overlap of two dd for stereoisomers (A+B)/C,
3,3´ꢀ(1,4ꢀPhenylene)ꢀbis[8ꢀ(2ꢀchloroꢀ6ꢀfluorophenyl)ꢀ6ꢀ
oxoꢀ3,4,7,8ꢀtetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ
9ꢀcarbonitrile] (2c). Beige finely crystalline powder, the yield
was 53%, m.p. 275—277 C (decomp.). Found (%): C, 56.25;
H, 3.38; N, 11.73. C34H24Cl2F2N6O2S2 (M = 721.64). Calculatꢀ
ed (%): C, 56.59; H, 3.35; N, 11.65. IR, /cm–1: 2190 (CN);
1695 (C=O). 1H NMR, : 2.84 (m, the overlap of two dd for
stereoisomers (A+B)/C, 2 H each, C(7)H + C(7´)H, ABX sysꢀ
tem, 2J = 16.8 Hz, 3Jcis = 7.5 Hz); 3.08 (m, the overlap of two dd
for stereoisomers (A+B)/C, 2 H each, C(7)H + C(7´)H, ABX
2
3
2 H each, C(7)H + C(7´)H, ABX system, J = 16.4 Hz, Jcis
=
= 3.2 Hz); 2.89 (m, the overlap of two dd for stereoisomers
(A+B)/C, 2 H each, C(7)H + C(7´)H, ABX system, 2J = 16.4 Hz,
3Jtrans = 6.8 Hz); 3.760, 3.769 (both s, 3 H each, 2 MeO of
stereoisomers (A+B)/C); 3.80 (m, the overlap of two s for stereoꢀ
isomers (A+B)/C, 3 H each, 2 MeO); 3.95 (m, the overlap of
two dd for stereoisomers (A+B)/C, 2 H each, C(8)H + C(8´)H,
ABX system, 3Jcis = 3.2 Hz, 3Jtrans = 6.8 Hz); 5.32 (m, the overꢀ
lap of two dd for stereoisomers (A+B)/C, 2 H each, N—C(4)H2—N,
N—C(4´)H2—N or N—C(2)H2—S, N—C(2´)H2—S, 3J = 12.4 Hz);
5.41 (m, the overlap of two dd for stereoisomers (A+B)/C,
2 H each, N—C(2)H2—S, N—C(2´)H2—S or N—C(4)H2—N,
N—C(4´)H2—N, 3J = 13.6 Hz); 6.29 (m, the overlap of two d
2
3
system, J = 16.8 Hz, Jtrans = 8.5 Hz); 4.63 (m, the overlap of
two dd for stereoisomers (A+B)/C, 2 H each, C(8)H + C(8´)H,
ABX system); 5.34—5.53 (m, the overlap of four dd for stereoꢀ
isomers (A+B)/C, 2 H each, N—C(4)H2—N, N—C(4´)H2—N,
N—C(2)H2—S, N—C(2´)H2—S); 7.12 (pseudos, 4 H, phenylꢀ
ene); 7.25 (dd, 2 H, C(4)H + C(4´)HAr, 3J = 8.3 Hz, 3J = 8.5 Hz);
7.37 (m, 4 H, C(3)H + C(3´)HAr, C(5)H + C(5´)HAr). 13C NMR,
: 32.31; 34.84; 53.44; 58.62; 86.57; 115.79; 115.97; 117.26;
118.41; 125.71; 125.85; 126.61; 130.96; 134.18; 138.82; 149.71;
160.87; 162.85; 167.13.
for stereoisomers (A+B)/C, 2 H each, C(5)H + C(5´)HAr
,
3J = 8.6 Hz); 6.46 (br.pseudos, 2 H, C(3)H + C(3´)HAr); 6.66
(m, the overlap of two d for stereoisomers (A+B)/C, 2 H each,
C(6)H + C(6´)HAr, 3J = 8.6 Hz); 7.08 (pseudos, 4 H, phenylene).
3,3´ꢀ(1,4ꢀPhenylene)ꢀbis[8ꢀ(2ꢀnitrophenyl)ꢀ6ꢀoxoꢀ3,4,7,8ꢀ
tetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarboꢀ
nitrile] (2d). Sandꢀcolored powder, the yield was 28%, m.p.
265—268 C (decomp.). Found (%): C, 57.50; H, 3.74; N, 16.02.
C34H26N8O6S2 (M = 706.76). Calculated (%): C, 57.78; H, 3.71;
References
1
N, 15.85. IR, /cm–1: 2188 (CN), 1698 (C=O). H NMR, :
1. C. J. Moody, in Comprehensive Heterocyclic Chemistry, Vol. 3,
Eds A. R. Katritzky, C. W. Rees, Pergamon, Oxford, UK,
1984, p. 1039; R. K. Smalley, in Comprehensive Heterocyclic
Chemistry II, Vol. 6. SixꢀMembered Rings With Two Or More
Heteroatoms and Fused Carbocyclic Derivatives, Ed. A. J.
Boulton, Elsevier, Oxford, UK, 1996, p. 783; N. Shobana,
P. Farid, in Comprehensive Heterocyclic Chemistry III, Vol. 9,
Eds A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor, Elsevier, Oxford, UK, 2008, p. 457.
2. V. V. Dotsenko, S. G. Krivokolysko, A. N. Chernega, V. P.
Litvinov, Dokl. Akad. Nauk, 2003, 389, 763 [Dokl. Chem.
(Engl. Transl.), 2003, 389 Nos 4—6, 92].
3. V. V. Dotsenko, S. G. Krivokolysko, V. P. Litvinov, Monatsh.
Chem., 2008, 139, 657.
2.81 (m, the overlap of two dd for stereoisomers (A+B)/C, 2 H each,
3
C(7)H + C(7´)H, ABX system, 2J = 23.0 Hz, Jcis = 6.5 Hz);
3.15 (m, the overlap of two dd for stereoisomers (A+B)/C,
2 H each, C(7)H + C(7´)H, ABX system, 2J = 23.0 Hz, 3Jtrans
=
= 7.5 Hz); 4.39 (pseudot, 2 H, C(8)H + C(8´)H, ABX system,
3
3Jcis = 6.5 Hz, Jtrans = 7.5 Hz); 5.32—5.65 (m, the overlap of
four dd for stereoisomers (A+B)/C, 2 H each, N—C(4)H2—N,
N—C(4´)H2—N, N—C(2)H2—S, N—C(2´)H2—S); 7.135, 7.140
(both s, 4 H each, phenylene of stereoisomers (A+B)/C); 7.26,
7.31 (both d, 2 H each, C(6)H + C(6´)HAr of stereoisomers
(A+B)/C, 3J = 7.5 Hz, 3J = 6.5 Hz); 7.55—7.61 (m, 4 H,
C(4)H + C(4´)HAr, C(5)H + C(5´)HAr); 7.98 (br.d, 2 H,
C(3)H + C(3´)HAr, 3J = 7.0 Hz).
3,3´ꢀ(1,4ꢀPhenylene)ꢀbis[8ꢀ(4ꢀfluorophenyl)ꢀ6ꢀoxoꢀ3,4,7,8ꢀ
tetrahydroꢀ2H,6Hꢀpyrido[2,1ꢀb][1,3,5]thiadiazineꢀ9ꢀcarboꢀ
nitrile] (2e). Greyish beige powder, the yield was 56%, m.p.
252—255 C (decomp.). Found (%): C, 62.10; H, 4.04; N, 13.02.
C34H26F2N6O2S2 (M = 652.75). Calculated (%): C, 62.56;
H, 4.01; N, 12.87. IR, /cm–1: 2193 (CN); 1685 (C=O). 1H NMR,
: 2.67 (m, the overlap of two dd for stereoisomers (A+B)/C,
4. Z. Y. Wang, H. X. Shi, H. J. Shi, Synth. Commun., 2001, 31,
2841; Z. Y. Wang, T. P. You, H. J. Shi, H. X. Shi, Molecules,
1996, 1, 89; Avail. URL: http://www.mdpi.net/molecules/
list96.htm; Z. Y. Wang, T. P. You, H. J. Shi, H. X. Shi,
Gaodeng Xuexiao Huaxue Xuebao, 1997, 18, 550; Chem.
Abstr., 1997, 127, 95265t; H. X. Shi, H. J. Shi, Z. Y. Wang,
Youji Huaxue, 2000, 20, 344; Chem. Abstr., 2000, 133,
120280c; Z. A. Hozein, A. A. O. Sarhan, H. A. H.
El—Sherief, A. M. Mahmoud, Z. Naturforsch. Teil B, 1997,
52, 1401; Chem. Abstr., 1998, 128, 88906v; H. J. Shi, H. X.
Shi, Z. Y. Wang, J. Heterocycl. Chem., 2001, 38, 929; H. J.
Shi, Z. Y. Wang, H. X. Shi, Chimia, 1997, 51, 529; RZhKhim.,
2
3
2 H each, C(7)H + C(7´)H, ABX system, J = 16.2 Hz, Jcis
=
= 4.6 Hz); 3.00 (m, the overlap of two dd for stereoisomers
(A+B)/C, 2 H each, C(7)H + C(7´)H, ABX system, 2J = 16.2 Hz,
3Jtrans = 7.0 Hz); 3.88 (pseudot, 2 H, C(8)H + C(8´)H, ABX
3
system, 3Jcis = 4.6 Hz, Jtrans = 7.0 Hz); 5.34 (m, the overlap of

Pyrido[2,1ꢀb][1,3,5]thiadiazines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
135
1998, 13 Zh 272; H. J. Shi, Z. Y. Wang, H. X. Shi, Synth.
Commun., 1999, 29, 2027; T. B. Sarfraz, S. A. Husain,
N. Murtaza, B. S. Siddiqui, Pakistan J. Sci. Ind. Res., 2000,
43, 334.
5. Z. A. Hozein, J. Chem. Res. Synop., 2000, No. 3, 99.
6. K. A. Frolov, V. V. Dotsenko, S. G. Krivokolysko, V. P.
Litvinov, Izv. Akad. Nauk, Ser. Khim., 2005, 2158 [Russ.
Chem. Bull., Int. Ed., 2005, 54, 2226].
7. L. D. S. Yadav, A. Vaish, S. Sharma, J. Agric. Food Chem.,
1994, 42, 811.
8. A. A. O. Sarhan, S. H. AbdelꢀHafez, H. ElꢀSherief, T. Aboelꢀ
Fadl, Synth. Commun., 2006, 36, 987.
14. V. J. Ram, H. N. Pandey, Eur. J. Med. Chem., 1977, 12, 537;
R. B. Pathak, U. Srivastava, S. C. Bahel, J. Ind. Chem. Soc.,
1982, 59, 776.
15. A. J. Beher, US Pat. 2594381, 1952. Avail. URL: www.espaꢀ
cenet.com
16. Y. Wang, C. Duraiswami, K. P. Madauss, T. B. Tran, S. P.
Williams, S.ꢀJ. Deng, T. L. Graybill, M. Hammond, D. G.
Jones, E. T. Grygielko, J. D. Bray, S. K. Thompson, Bioorg.
Med. Chem. Lett., 2009, 19, 4916.
17. V. V. Dotsenko, S. G. Krivokolysko, A. N. Chernega, V. P.
Litvinov, Izv. Akad. Nauk, Ser. Khim., 2003, 918 [Russ. Chem.
Bull., Int. Ed., 2003, 52, 969].
9. V. V. Dotsenko, S. G. Krivokolysko, V. P. Litvinov, Monatsh.
Chem., 2008, 139, 271.
10. V. V. Dotsenko, S. G. Krivokolysko, E. B. Rusanov, V. P.
Litvinov, Izv. Akad. Nauk, Ser. Khim., 2007, 1384 [Russ.
Chem. Bull., Int. Ed., 2007, 56, 1437].
11. V. V. Dotsenko, K. A. Frolov, S. G. Krivokolysko, V. P.
Litvinov, Izv. Akad. Nauk, Ser. Khim., 2009, 1436 [Russ.
Chem. Bull., Int. Ed., 2009, 58, 1479]; V. V. Dotsenko, K. A.
Frolov, S. G. Krivokolysko, A. N. Chernega, V. P. Litvinov,
Monatsh. Chem., 2006, 137, 1089; V. V. Dotsenko, S. G.
Krivokolysko, V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim.,
2007, 1420 [Russ. Chem. Bull., Int. Ed., 2007, 56, 1474].
12. V. P. Litvinov, Phosphorus, Sulfur, Silicon, Relat. Elem., 1993,
74, 139; V. P. Litvinov, S. G. Krivokolysko, V. D. Dyaꢀ
chenko, Khim. Geterotsikl. Soedin., 1999, 579 [Chem. Heteroꢀ
cycl. Compd. (Engl. Transl.), 1999, 35, 509].
18. S. G. Krivokolysko, V. D. Dyachenko, V. P. Litvinov, Izv.
Akad. Nauk, Ser. Khim., 2000, 485 [Russ. Chem. Bull., Int.
Ed., 2000, 49, 487].
19. V. D. Dyachenko, S. G. Krivokolysko, V. P. Litvinov, Izv.
Akad. Nauk, Ser. Khim., 1997, 1852 [Russ. Chem. Bull.
(Engl. Transl.), 1997, 46, 1758].
20. J. S. A. Brunskill, A. De, D. F. Ewing, J. Chem. Soc., Perkin
Trans 1, 1978, 629.
21. I. N. Nesterova, A. K. Shakhnazarov, A. M. Poznyak, M. I.
Lakoza, B. V. Shemeryankin, V. G. Granik, Khim. Farm.
Zh., 1994, 28 No. 8, 41 [Pharm. Chem. J. (Engl. Transl.),
1994, 28, 583].
13. A. A. Hassan, Phosphorus, Sulfur, Silicon, Relat. Elem., 1995,
106, 55.
Received November 12, 2010;
in revised form August 10, 2011