SCHEME 1
Syn th esis of
3,4-Dih yd r o-2H-1,3,5-th ia d ia zin es
Alan R. Katritzky,*,‡ Anatoliy V. Vakulenko,‡
Yong-J iang Xu,‡ and Peter J . Steel§
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, and
Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
katritzky@chem.ufl.edu
Received J anuary 16, 2002
Abstr a ct: 3,4-Dihydro-2H-1,3,5-thiadiazines substituted at
the 3 and 6 positions were synthesized by treatment of
N-substituted N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-
amines with thioamides and zinc bromide in dry CH2Cl2 at
room temperature for 48-60 h in 48-80% yields.
1,3,5-Thiadiazines are useful as herbicides,1 antimi-
crobial drugs,2 insecticides,3 and miticides.4 Most reported
3,4-dihydro-2H-1,3,5-thiadiazines contain ring carbonyl
or thiocarbonyl groups: such compounds were previously
synthesized (see Scheme 1) by (i) treatment of heterocy-
clic primary thioamides with phenoxycarbonyl isocya-
nate2a; (ii) cyclization of perchloroethyl isocyanate with
thioamides;5 (iii) reaction of thiobenzoyl isocyanates with
CdN bonds in arylhydrazones,6 benzaldazines,7 carbo-
diimides,8 or anils;9 (iv) [4 + 2] cycloaddition of 1-thia-
3-azadienes with electron-deficient nitriles;10 (v) dimer-
ization ofthiocarbamoylisothiocyanates;11 or (vi)dimerization
of carbamoyl isothiocyanates.12 Previously reported com-
pounds of type 5 were made by thermolysis of 4-substi-
tuted and 2,4-disubstituted 6H-1,3,5-oxathiazines fol-
lowed by dimerization13 (Scheme 1, vii). We now report
an alternative and convenient route to 3,4-dihydro-2H-
1,3,5-thiadiazines 5 using benzotriazole methodology.
previously used for the preparation of 5-alkyldihydro-4H-
1,3,5-dithiazines,14 substituted piperidines,15 3-arylpyr-
rolidines,16 and also for tertiary amines.17 We now employ
intramolecular cyclization involving compounds 1a -e to
access the thiadiazines 5.
Resu lts a n d Discu ssion
Reactions of aliphatic amines with 2 equiv of 1-hy-
droxymethylbenzotriazole or Mannich reactions of ben-
zotriazole with formaldehyde and primary aliphatic
amines (1:2:2) form N-alkyl-N,N-bis(1H-1,2,3-benzotri-
azol-1-ylmethyl)amines 1a -d as single isomers in high
yields.14,18 Condensations of benzotriazole with formal-
dehyde and aromatic amines often give mixtures of
benzotriazol-1-yl- and benzotriazol-2-yl-substituted iso-
meric products.19 We used N,N-bis(1H-1,2,3-benzotriazol-
1-ylmethyl)-4-methoxyaniline to carry out Lewis acid-
catalyzed condensation with thioamides because this
compound could be easily obtained as a single isomer;19
N-Substituted N,N-bis(1H-1,2,3-benzotriazol-1-ylmeth-
yl)amines 1 containing two leaving groups have been
‡ University of Florida.
§ University of Canterbury.
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10.1021/jo020033s CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/17/2002
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J . Org. Chem. 2002, 67, 4960-4962