The Mannich reaction in the synthesis of N,S-containing heterocycles 6. New approaches to the synthesis of pyrimido[4,3-b][1,3,5]thiadiazine derivatives

Article abstract of DOI:10.1007/s11172-007-0226-6

Aminomethylation of 2,6-diamino-4-aryl-4H-thiopyran-3,5-dicarbonitriles in the Mannich reaction with p-toluidine and formaldehyde unexpectedly gave pyrimido[4,3-b][1,3,5]thiadiazine derivatives. The same compounds were obtained in an independent way involving a multicomponent cascade condensation of aromatic aldehydes, cyanothioacetamide, p-toluidine, and formaldehyde.

Full text of DOI:10.1007/s11172-007-0226-6

Russian Chemical Bulletin, International Edition, Vol. 56, No. 7, pp. 1474—1476, July, 2007
1474
The Mannich reaction in the synthesis of N,Sꢀcontaining heterocycles
6.* New approaches to the synthesis
of pyrimido[4,3ꢀb][1,3,5]thiadiazine derivatives
V. V. Dotsenko,aꢀ S. G. Krivokolysko,a and V. P. Litvinovb†
aChemEx Laboratory, V. Dal´ EastꢀUkrainian National University,
20a Molodyozhny kv., 91034 Lugansk, the Ukraine.
Fax: + 380 (0642) 41 9151. Eꢀmail: Victor_Dotsenko@bigmir.net
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 8837
Aminomethylation of 2,6ꢀdiaminoꢀ4ꢀarylꢀ4Hꢀthiopyranꢀ3,5ꢀdicarbonitriles in the Mannich
reaction with pꢀtoluidine and formaldehyde unexpectedly gave pyrimido[4,3ꢀb][1,3,5]thiaꢀ
diazine derivatives. The same compounds were obtained in an independent way involving a
multicomponent cascade condensation of aromatic aldehydes, cyanothioacetamide, pꢀtoluꢀ
idine, and formaldehyde.
Key words: pyrimido[4,3ꢀb][1,3,5]thiadiazines, aminomethylation, the Mannich reaction,
multicomponent cascade synthesis, 2,6ꢀdiaminoꢀ4ꢀarylꢀ4Hꢀthiopyranꢀ3,5ꢀdicarbonitriles.
Proceeding further in our investigations of the
the corresponding fused systems.12—17 Nevertheless, the
transformation of thiopyrans 1 into compounds 2 we deꢀ
scribe here has no direct literature analogs and represents
a new type of the tandem reaction: crossꢀrecyclizaꢀ
tion—Mannich cascade cyclocondensation.
Mannich synthesis of fused Sꢀcontaining azines,1—4 we
studied aminomethylation of 2,6ꢀdiaminoꢀ4ꢀarylꢀ4Hꢀ
thiopyranꢀ3,5ꢀdicarbonitriles 1. Thiopyrans 1 are easily
accessible5—7 and have two amino groups and the nucleoꢀ
philic C(3) and C(5) centers, which makes them promisꢀ
ing objects for the Mannich aminomethylation. For inꢀ
stance, double aminomethylation of 3,5ꢀbinucleophilic
thiopyrans is known to be a convenient route to 3ꢀthiaꢀ7ꢀ
azabicyclo[3.3.1]nonane derivatives,8,9 which have reꢀ
vealed themselves as potent antiarrhythmic drugs.9—11
We found that treatment of thiopyran 1a (Ar = Ph)
with an equimolar amount of pꢀtoluidine and an excess of
formaldehyde does not lead to a bicyclic system (as could
be expected by analogy with related pyridine derivatives).4
Instead, pyrimido[4,3ꢀb][1,3,5]thiadiazine derivative 2a
was obtained in 7% yield as the sole product (Scheme 1).
When two, three, and four equivalents of the primary
amine were used, the yields of compound 2a were 11,
25, and 33%, respectively. An analogous reaction with
4 equivalents of pꢀtoluidine gave compound 2b in
40% yield. It should be noted that crossꢀrecyclization of
thiopyrans 1 under the action of nucleophilic agents in
basic media has been studied in detail and is a convenient
route to functionalized thiazoles and pyridines and
According to a plausible mechanism, this transformaꢀ
tion involves the retroꢀMichael reaction12—17 with elimiꢀ
nation of malononitrile and formation of unsaturated
thioamides 3. Their sequential aminomethylation leads,
via product 4 of the intramolecular Michael aza reaction,
to compounds 2. This scheme of transformations is supꢀ
ported by the previously reported18 formation of pyriꢀ
mido[4,3ꢀb][1.3.5]thiadiazines 2 from (E)ꢀ2ꢀ(het)arylꢀ2ꢀ
cyanopropꢀ2ꢀenethioamides 3 under the conditions of the
Mannich reaction. Since the reaction with thioamides 3
actually consumes two equivalents of the amine, one can
assume that the low yield of compound 2a in the thioꢀ
pyran : amine ratio = 1 : 2 is due to aminomethylation of
malononitrile as a side process leading to nonisolable
products. The structures of compounds 2a,b were conꢀ
firmed by spectroscopic data an independent synthesis:
multicomponent "one pot" cyclocondensation of an apꢀ
propriate aromatic aldehyde, cyanothioacetamide (5),
pꢀtoluidine, and formaldehyde (method B). In this case,
the yields of the target products were somewhat higher
(37—52%). The IR spectra of compounds 2a,b show an
absorption band at ν = 2165—2168 cm–1 due to the
stretching vibrations of the conjugated C≡N group. Among
the most characteristic signals in the 1H NMR spectra of
* For Part 5, see Izv. Akad. Nauk, Ser. Khim., 2007, 1384 [Russ.
Chem. Bull., Int. Ed., 2007, 56, 1437].
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1420—1422, July, 2007.
1066ꢀ5285/07/5607ꢀ1474 © 2007 Springer Science+Business Media, Inc.

Pyrimido[6,1ꢀb][1,3,5]thiadiazines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1475
Scheme 1
R = 4ꢀMeC6H4; Ar = Ph (a), 2ꢀClC6H4 (b)
the iodine vapor or under UV light. Melting points were deterꢀ
mined on a Kofler hot stage.
pyrimido[6,1ꢀb][1.3.5]thiadiazines 2, a broadened singlet
at δ 5.13—5.25 for the C(8)H proton is worth noting.
Signals for the C(2)H2, C(4)H2, and C(6)H2 protons apꢀ
pear as three doublets of doublets at δ 4.33—5.20.
To summarize, we proposed convenient routes to
pyrimido[4,3ꢀb][1.3.5]thiadiazines, a new heterocyclic
system, via a multicomponent "one pot" synthesis from
acyclic precursors and a new tandem (crossꢀrecycliꢀ
zation—cyclocondensation) reaction of 2,6ꢀdiaminoꢀ4ꢀ
arylꢀ4Hꢀthiopyranꢀ3,5ꢀdicarbonitriles.
Pyrimido[4,3ꢀb][1,3,5]thiadiazines (2a,b). Method A. A mixꢀ
ture of appropriate thiopyran 1a,b (2 mmol), pꢀtoluidine
(8 mmol), and an excess of 37% HCHO (2.5 mL) in EtOH
(15 mL) was refluxed for 3 min. The solution was filtered through
a paper filter and left at ~20 °C for 72 h. Crystals of compounds
2a,b were separated and recrystallized from an appropriate
solvent.
Method B. Three drops of Nꢀmethylmorpholine were added
to a mixture of cyanothioacetamide (5) (0.5 g, 5 mmol) and an
appropriate aromatic aldehyde (5 mmol) in EtOH (15 mL). The
mixture was stirred for 0.5 h and then pꢀtoluidine (1.07 g,
10 mmol) and an excess of 37% HCHO (5 mL) were added. The
reaction mixture was refluxed with stirring for 3 min and left at
~20 °C for 24 h. A colorless crystalline precipitate of pyrimidoꢀ
thiadiazine 2a,b was filtered off, washed with EtOH, and recrysꢀ
tallized from an appropriate solvent.
Experimental
1
H NMR spectra were recorded on a Varian Mercury VXꢀ200
instrument (199.97 MHz) in DMSOꢀd6 with Me4Si as the interꢀ
nal standard. IR spectra were recorded on an IKSꢀ29 spectroꢀ
photometer (in Nujol). Elemental analysis was carried out on a
Perkin—Elmer C,H,NꢀAnalyzer instrument. The purity of the
compounds obtained was checked by TLC on Silufol UV 254
plates in acetone—heptane (1 : 1). Spots were visualized with
3,7ꢀBis(4ꢀmethylphenyl)ꢀ8ꢀphenylꢀ3,4,7,8ꢀtetrahydroꢀ
2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitrile (2a).
The yield was 33 (method A) and 37% (method B). Colorless
crystals, m.p. 180—182 °C (from Me2CO—EtOH, 1 : 1).

1476
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Dotsenko et al.
Found (%): C, 74.06; H, 6.00; N, 12.74. C27H26N4S. Calcuꢀ
9. V. K. Yu, K. D. Praliev, E. E. Fomicheva, R. D.
Mukhasheva, and S. G. Klepikova, Khim. Geterotsikl. Soedin.,
2006, 585 [Chem. Heterocycl. Compd., 2006, 42, 512 (Engl.
Transl.)].
lated (%): C, 73.94; H, 5.98; N, 12.77. IR (Nujol), ν/cm–1
:
2168 (C≡N). 1H NMR (DMSOꢀd6), δ: 2.25, 2.23 (both s,
2
3 H each, 2 H3CC6H4); 4.33 (dd, 2 H, NCH2S, J = 13.0 Hz);
4.87 (dd, 2 H, NCH2N, 2J = 13.6 Hz); 5.13 (s, 1 H, C(8)H);
5.20 (dd, 2 H, NCH2N, 2J = 12.7 Hz); 7.00 (m, 8 H,
2 H3CC6H4); 7.32 (m, 5 H, Ph).
8ꢀ(2ꢀChlorophenyl)ꢀ3,7ꢀbis(4ꢀmethylphenyl)ꢀ3,4,7,8ꢀtetraꢀ
hydroꢀ2H,6Hꢀpyrimido[4,3ꢀb][1,3,5]thiadiazineꢀ9ꢀcarbonitrile
(2b). The yield was 40 (method A) and 52% (method B), colorꢀ
less crystals. The physical parameters, spectroscopic characterꢀ
istics, and elemental analysis data for compound 2b agree with
those for a sample obtained earlier.18
10. K. D. Berlin, B. J. Scherlag, C. R. Clarke, S. R. Otiv, S. A.
Zisman, S. Sangiah, and S. V. Mulekar, US Pat. 5 084 572;
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Received October 12, 2006;
in revised form June 21, 2007