condensation of 4,5-dimethoxy-2-mercaptobenzylam-
monium chloride with an aromatic aldehyde in the
presence of potassium carbonate14 and (ii) cycloaddition
of benzothiete with corresponding substituted imines.15
We have found no literature for the synthesis of
2,3,4,5-tetrahydro-1,3-benzo-
A Novel Dilith ia tion Ap p r oa ch to
3,4-Dih yd r o-2H-1,3-ben zoth ia zin es,
3,4-Dih yd r o-2H-1,3-ben zoxa zin es, a n d
2,3,4,5-Tetr a h yd r o-1,3-ben zoth ia zep in es
Alan R. Katritzky,* Yong-J iang Xu, and Ritu J ain
thiazepines.
Center for Heterocyclic Chemistry, Department of Chemistry,
University of Florida, Gainesville, Florida 32611-7200
Many reports on the synthesis of 3,4-dihydro-2H-1,3-
benzoxazines (Scheme 2, Supporting Information) de-
scribe (i) Mannich condensation of phenol and a primary
amine with formaldehyde,5b,16 (ii) condensation of o-
hydroxybenzylamine with an aldehyde,17 (iii) rearrange-
ment reactions of 2-(allyloxy)benzylamine with H2/CO in
the presence of rhodium catalysts,18 (iv) condensation of
a 4-substituted phenol with 1,3,5-trimethyl-hexahydro-
s-triazine in the presence of oxalyl chloride,19 (v) reaction
of 1-(bromomethyl)-2-(chloromethoxy)benzene with pri-
mary amines,20 and (vi) dehydration of N-(2-hydroxyben-
zyl)-3-aminopropanoic acid in the presence of sulfuric
acid.21
katritzky@chem.ufl.edu
Received March 13, 2002
Abstr a ct: 3,4-Dihydro-2H-1,3-benzothiazines 4, 3,4-dihy-
dro-2H-1,3-benzoxazines 9, and 2,3,4,5-tetrahydro-1,3-ben-
zothiazepines 6 were synthesized by directed ortho-lithiation
of thiophenols and phenols and by side-chain lithiation of
substituted thiophenols, respectively, in one-pot by reacting
with N,N-bis[(benzotriazol-1-yl)methyl]amines 3 as 1,3-
biselectrophile synthons.
Directed ortho-metalation methodology offers a pre-
dictable and widely applicable synthetic strategy for the
regiospecific construction of heterocyclic compounds.22
Directed ortho-lithiations of thiophenol and phenol have
been developed.23 We now show that such directed ortho-
lithiations of thiophenols and phenol provide a novel
benzotriazole-mediated approach to 3,4-dihydro-2H-1,3-
benzothiazines, 1,3-benzoxazines, and 2,3,4,5-tetrahydro-
1,3-Benzothiazines and 1,3-benzoxazines are of sig-
nificant pharmacological interest.1-7 Benzothiazepines
are also potent bradykinin agonists8 and have shown
activity as endogenous natriuretic factors,9 enzyme in-
hibitors,10 muscle relaxants, anticonvulsants,11 sedatives,
and hypnotics.12 Campiani and co-workers have devel-
oped novel pyrrolo[2,1-b][1,3]benzothiazepines as anti-
psychotic agents with serotonin and dopamine antagonist
properties.13
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10.1021/jo020176e CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
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J . Org. Chem. 2002, 67, 8234-8236