Ster eoselective On e-P ot Syn th esis of
CHART 1. Su bstitu ted (4Z)-2-Alk yl-4-ben zylid en e-
H-1,3-ben zoth ia zin es 1 (R1 ) CH
CH CH ) a n d Th eir Nu m ber in g System
1
4
3
) a n d 2 (R )
Su bstitu ted (4Z)-2-Alk yl-4-ben zylid en e-
H-1,3-ben zoth ia zin es†
2
3
4
‡
,‡
Antonio Herrera, Roberto Mart ´ı nez-Alvarez,*
‡
§
|
Pedro Ramiro, Angel S a´ nchez, and Rosario Torres
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias
Qu ı´ micas, Universidad Complutense, E-28040 Madrid,
Spain, CAI de Resonancia Magn e´ tica Nuclear, Facultad de
Ciencias Qu ı´ micas, Universidad Complutense, E-28040
Madrid, Spain, and Laboratorio de Difracci o´ n de Rayos X,
Facultad de Ciencias Qu ´ı micas, Universidad Complutense,
E-28040 Madrid, Spain
of hypertension.10 2-Heterocyclyl-1,3-benzothiazinone de-
rivatives are inhibitors of apoptosis and are cytoprotec-
tive agents (Chart 1).
11
Synthetic approaches to 4H-1,3-benzothiazine deriva-
tives include ring-closure reactions of substituted N-(3,4-
dialcoxyphenylthiomethyl)-2-substituted benzamides with
Received February 9, 2004
Abstr a ct: Substituted (4Z)-4-benzylidene-2-methyl-4H-1,3-
benzothiazines (1) and (4Z)-2-ethyl-4-benzylidene-4H-1,3-
benzothiazines (2) were synthesized by direct stereoselective
reactions of S-phenyl ethanethioate or S-phenyl propane-
thioate with substituted benzyl nitriles in the presence of
triflic anhydride.
phosphoryl chloride, to yield derivatives of 1,3-benzo-
thiazines12,13 (Scheme S1, Supporting Information). Treat-
ment of thiosalicylic acid with nitrooxyethylamine nitrate
8
produces 1,3-benzothiazine-2,4-dione derivatives (Scheme
S2, Supporting Information). The reaction of benzothiete
with tosylnitrile affords derivatives of the 4H-1,3-ben-
zothiazine through a hetero-Diels-Alder [8 + 2] cycload-
dition14 (Scheme S3, Supporting Information). Pyrrolo-
[1,3]benzothiazines can be prepared by intramolecular
R-amidoalkylation cyclizations with internal sulfur atom
Since they were first reported in 1947, benzothiazines
have attracted significant interest for their interesting
pharmacological properties.1 The synthetic and biologi-
cal chemistry of the 3,1-benzothiazine nucleus is a
relatively unexplored class of compounds from the stand-
point of both synthetic chemistry and biological chemis-
-7
1
5
as nucleophile from o-(benzylthio)benzyl alcohol (Scheme
S4, Supporting Information). The photocyclization of
1,2,4-triazole-3-thiones leads to triazolo-4H-1,3-benzo-
8
9
try. Other benzothiazines rings such as 1,2-, 2,1-, 1,4-,
thiazines (Scheme S5, Supporting Information).
and 1,3- have been extensively studied. In particular, 1,3-
benzothiazines are of significant interest. Thus, triazolo-
Only a few examples of non-multistep reactions are
reported for the preparation of benzothiazine derivatives
from easily available starting materials. Among these,
we find the dilithiation of thiophenols and subsequent
1
,3-benzothiazines were evaluated for their ability to
displace (3H)-funitrezepam from bovine brain mem-
branes while IDPH-791, an analogue of triazolobenzo-
thiazine, is a well-known centrally acting muscle relax-
1
6
reaction with N,N-bis[(benzotriazol-1-yl)methyl]amines
(Scheme S6, Supporting Information) and the treatment
of thiosalicylic acid with ethyl chloroformiate and ben-
zylamine17 (Scheme S7, Supporting Information).
The reaction of ketones with aliphatic and aromatic
nitriles in the presence of triflic anhydride affords alkyl-
9
ant. Benzothiazines bearing a nitrooxyethyl group show
anti-ischemic properties for heart diseases and for control
*
To whom correspondence should be addressed. Tel: 34 913944325.
Fax: 34 913944103.
18
and arylpyrimidines. Application of this reaction to
†
This work is dedicated to the memory of Dr. J . C. del Amo Aguado,
victim of the terrorism on March 11, 2004.
‡
Departamento de Qu ´ı mica Org a´ nica.
CAI de Resonancia Magn e´ tica Nuclear.
(9) (a) Senthilvelan, A.; Ramakrishnan V. T. Tetrahedron 2002, 43,
5119. (b) Senthilvelan, A.; Thirumalai, D.; Ramakrishan, V. T.
Tetrahedron 2004, 60, 851.
§
|
Laboratorio de Difracci o´ n de Rayos X.
(
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0.1021/jo049777r CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/22/2004
J . Org. Chem. 2004, 69, 4545-4547
4545