Stereoselective one-pot synthesis of substituted (4Z)-2-alkyl-4- benzylidene-4H-1,3-benzothiazines

Article abstract of DOI:10.1021/jo049777r

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 propanethioate with substituted benzyl ni

Full text of DOI:10.1021/jo049777r

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).
rma@quim.ucm.es
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.
(
1) Masaki, M.; Miyake, N.; Tendo, A.; Ishida, M.; Shinozaki, A.;
Nomura, Y.; Goto, Y. WO 26,959, 1995; Chem. Abstr. 1996, 124,
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2) Levi, S.; Benedini, F.; Bertolini, G.; Dona, G.; Gromo, G.; Sala,
A. WO 25,542, 1993; Chem. Abstr. 1994, 120, 245128x.
3) Oyama, H.; Ono, T.; Tsujimoto, K.; Wada, T. J P 61 106,562;
Chem. Abstr. 1986, 105, 226603x.
4) Levi, S.; Benedi, F.; Bertolini, G.; Gromo, G.; Mizrhai, J .; Sala,
A. WO 04,048, 1995; Chem. Abstr. 1995, 123, 9449u.
5) (a) Cecchetti, V.; Cruciani, G.; Filiponi, E.; Fravolini, A.; Tabar-
rini, O.; Xin, T. Bioorg. Med. Chem. 1997, 5, 1339. (b) CIBA ltd. Fr.
,555,544, 1969; Chem. Abstr. 1970, 72, 55468a.
6) Lopatina, K. I.; Artemenko, G. N.; Sokolova, T. V.; Salimov, R.
V.; Vikhlayaev, Yu. I.; Zagorevskii, V. A. Khim.-Farm. Zh. 1978, 12,
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J . Med. Sci. 1993, 18, 209; Chem. Abstr. 1994, 120, 129372y.
8) (a) Hari, A.; Miller, B. L.Organic Lett. 2000, 2, 3667. (b)
Fernandes, M. A.; Reid, D. H. Synlett 2003, 2231.
(10) Benedini, F.; Bertolini, G.; Ferrario, F.; Guindani, R.; Sala, A.
J . Heterocycl. Chem. 1994, 31, 1589.
(11) Kajino, M.; Kawada, A.; Nakayama, Y.; Kimura, H. WO
2003020719: Chem. Abstr. 2003, 138, 238199.
(12) Szab o´ , J .; Bani-Akoto, E.; Szent-Gy o¨ rgi, A.; Fodor, L.; Soh a´ r,
P. J . Heterocycl. Chem. 1992, 29, 1513.
(13) Fodor, L.; Bern a´ th, G.; Sinkkonnen J .; Pihlaja, K. J . Heterocycl.
Chem. 2002, 39, 927.
(14) Schmidt, M.; Meier H.; Saleh, S. A. J . Heterocycl. Chem. 1991,
28, 573.
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40, 3363.
(16) Katritzky, A. R.; Xu, Y.-J .; J ain, R. J . Org. Chem. 2002, 67,
8234.
(17) Zhu, X.; Yu, Qian-sheng.; Greig, N. H.; Flippen-Anderson, J .
L.; Brossi, A. Heterocycles 2003, 59, 115.
(18) Garc ´ı a Mart ´ı nez, A.; Herrera Fern a´ ndez, A.; Moreno J im e´ nez,
F.; Garc ´ı a Fraile, A.; Subramanian, L. R.; Hanack, M. J . Org. Chem.
1992, 57, 1627.
1
(
(
(
(
1
(
6
(
(
1
0.1021/jo049777r CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/22/2004
J . Org. Chem. 2004, 69, 4545-4547
4545

SCHEME 1. Rea ction of S-Alk yl a n d S-Ar yl
SCHEME 3. P ostu la ted Mech a n ism for th e
Th ioester s w ith Aceton itr ile a n d Tr iflic An h yd r id e
F or m a tion of th e (4Z)-Ben zylid en e-2-m eth yl-
4
H-1,3-ben zoth ia zin e 1a
SCHEME 2. Rea ction of S-P h en yl Th ioester s 4, 7
w ith Su bstitu ted Ben zyl Nitr iles 8 a n d th e
Ben zoth ia zin es 1 a n d 2 Th a t Wer e P r ep a r ed
the presence of triflic anhydride to form 4-alkylthio- or
-arylthiopyrimidines 5 and 6, respectively.2 However,
when the reaction was carried out with benzyl nitriles
8) only substituted 4-benzylidene-2-methyl-4H-1,3-ben-
1
4
(
zothiazines (1) were isolated and benzyl pyrimidines (9)
were not observed. Moreover, Z isomers of compounds 1
were exclusively obtained. The change of the reaction
pathway to form 1 can be explained by the nature of
possible intermediates involved in the mechanism pro-
posed for this reaction18 (Scheme 3).
In the proposed mechanism, S-phenyl ethanethioate
4
reacts with triflic anhydride forming the trifliloxycar-
benium ion 10 which undergoes a nucleophilic attack by
a nitrile molecule leading the immonium stabilized
nitrilium ion 11.18 A ring closure through an intramo-
lecular aromatic substitution takes place on the activated
ortho position of the S-phenyl ring of 11 affording the
intermediate 12.
The easy elimination of the triflate group from 12
affords the allylic-type cation 13 (Scheme 3). Proton
elimination from 13 leads to stereoselective formation of
R-haloketones and aliphatic esters leads to 5-halopyri-
midines19 and 4-alkoxypyrimidines, respectively. Re-
cently, we reported a new synthetic procedure for the
preparation of 4-alkylthio- (5) and 4-arylthiopyrimidines
20
(6) based on the reaction of S-alkyl and S-arylthioesters
(
3 and 4) with alkyl or arylnitriles and triflic anhydride21
(Scheme 1).
In the present work, we wish to report that the reaction
of S-phenyl ethanethioate (4) and S-phenyl propane-
thioate (7) with substituted benzyl nitriles (8) in the
presence of triflic anhydride produces substituted (4Z)-
1
a in synthetically useful yields. A side reaction leading
to tris(thiophenyl) orthoacetate CH C(SC . (14) and
(15) was observed
3
6 5 3
H )
21,22
(
phenyldithio)benzene C
Supporting Information).
To test other nitriles bearing a methylene group
6 5 6 5
H SSC H
2
-alkyl-4-benzylidene-4H-1,3-benzothiazines (1, 2) in mod-
(
erate yields (35-60%). Surprisingly, the formation of 2,6-
dibenzyl-4-phenylthiopyrimidines (9) was not observed
bonded to a cyano function we investigated the reaction
(Scheme 2).
of S-phenyl ethanethioate 4 with propanenitrile (Scheme
Syn th esis of Su bstitu ted 2-Alk yl-4-ben zylid en e-
1
4
). In the H NMR spectra of the crude reaction mixture,
4
H-1,3-ben zoth ia zin es. S-Phenyl ethanethioate (4) is
a sharp singlet at around 6.4 ppm ruled out formation
of benzothiazine structure 16, which has been expected
to display a quartet at this approximate chemical shift.
After the corresponding workup, only pyrimidine 17 was
isolated. This fact clearly indicates that the formation of
known to react with 2 equiv of alkyl or aryl nitriles in
(
19) Garc ´ı a Mart ´ı nez, A.; Herrera Fern a´ ndez, A.; Molero Vilchez,
D.; Subramanian, L. R.; Hanack, M. Synthesis 1992, 1053.
20) Garc ´ı a Mart ´ı nez, A.; Herrera Fern a´ ndez, A.; Mart ´ı nez-Alvarez,
R.; Molero Vilchez, D.; Subramanian, L. R. Tetrahedron 1999, 55, 4825.
21) Herrera, A.; Mart ´ı nez-Alvarez, R.; Ramiro, P. Tetrahedron 2003,
9, 7331.
(
(
(22) Billard, T.; Langlois, B. R.; Large, S.; Anker, D.; Roidor, N.;
Roure, P. J . Org. Chem. 1996, 61, 7545.
5
4
546 J . Org. Chem., Vol. 69, No. 13, 2004

TABLE 1. Hea ts of F or m a tion (∆Hf in k J m ol-1) of
Con for m er s 18 a n d 19
SCHEME 4. Rea ction of S-P h en yl Eth a n eth ioa te 4
w ith P r op a n en itr ile a n d Tf
2
O
conformer
∆Hf (AM1)
∆Hf (PM3)
1
1
8
9
-1240.45
-1490.17
-1239.53
-1448.45
and the hydrogen to be eliminated which present the
phenyl ring and the nitrogen atom in gauche disposition
1
8 are much more stable than 19 (Scheme 6 and Table
1
). Energy difference values between conformers are in
agreement with the observed stereoselectivity of the
process.
In summary, a novel approach to substituted 2-alkyl-
(
4Z)-benzylidene-4H-1,3-benzothiazines was successfully
SCHEME 5. NOESY Exp er im en ts w ith th e Mod el
Com p ou n d 1a
achieved by direct one-pot reaction of aryl thioesters with
substituted benzyl nitriles and triflic anhydride. The
reaction is stereoselective, forming only the corresponding
Z isomer. The methodology was applied for a wide range
of substituted benzyl nitriles.
Εxp er im en ta l section
Triflic anhydride was prepared from TfOH and distilled twice
over P O before use.
2 5
Syn th esis of Su bstitu ted 2-Alk yl-(4Z)-4-ben zylid en e-4H-
,3-ben zoth ia zin e 1, 2. To a solution of S-phenyl ethanethioate
or S-phenyl propanethioate 7 (6.5 mmol) and the corresponding
SCHEME 6. Con for m er s for th e P r oton
Elim in a tion fr om 13
1
4
substituted phenylacetonitrile 8 (33.6 mmol) in dry CH
2
Cl
2
was
added triflic anhydride (3.55 g, 12.6 mmol) in CH Cl
2
2
(20 mL)
dropwise at -78 °C. The mixture was stirred for 1 h at this
temperature and allowed to stand at 0 °C during 3 days. The
progress of the reaction was monitored by TLC. The reac-
tion mixture was hydrolyzed by careful addition of saturated
NaHCO
and dried over MgSO
3
. The organic layer was separated, washed with brine,
. The solvent was evaporated in vacuo,
4
and the residue was purified by column chromatography (eluent
EtOAc/hexanes ) 1/99).
benzothiazines is made possible by the benzyl group of
the nitrile.
The corresponding E isomers of 1 and 2 were not
detected in any of the examples studied. The complete
assignment of the structure of 1 and 2 was achieved from
(
4Z)-4-(3,4-Dich lor ob en zylid en e)-2-m et h yl-4H -1,3-b en -
zoth ia zin e (1i): yellow needles (from EtOH); yield 41%; mp
1
9
(
3
0-91 °C; H NMR δ 2.52 (s, 3H, CH ), 6.30 (s, 1H, dCH), 7.16
dd, J ) 7.8, 1.2 Hz, 1H, H-8), 7.31 (td, J ) 7.8, 1.2 Hz, 1H,
H-6), 7.37 (td, J ) 7.8, 1.2 Hz, 1H, H-7), 7.40 (d, J ) 8.4 Hz, 1H,
2
D HMBC and HMQC spectra. NOESY spectra revealed
H-5′), 7.67 (dd, J ) 7.8, 1.2 Hz, 1H, H-5), 7.69 (dd, J ) 8.4, 1.9
1
3
Hz, 1H, H-6′), 8.13 (d, J ) 1.9 Hz, 1H, H-2′); C NMR δ 27.6
cross-peaks between the olefinic proton which appears
as a singlet at around 6.45 ppm and the aromatic proton
attached to C-5 (Scheme 5). Moreover, there are cross-
peaks observed between the olefinic proton and the ortho
(
(
(
(
3
CH ), 116.1 (dCH), 125.3 (C-5), 125.7 (C-8), 126.0 (C-8a), 128.4
C-6), 128.4 (C-7), 129.3 (C-6′), 129.4 (C-4a), 129.8 (C-5′), 130.1
C-1′), 131.6 (C-2′), 132.0 (C-3′), 136.8 (C-4′), 141.0 (C-4), 157.4
+•
C-2); MS (EI) m/z (%B) 319 (M , 100), 304 (M - CH
3
, 29), 278
(H-2′ and H-6′) positions of the phenyl ring of the
(M - CH
3
CN, 65), 208 (278 - 2Cl, 43); IR (KBr) ν 1603, 1474,
-
1
benzylidene group. The total assignment of the protons
of the phenyl rings was carried out by selective irradia-
tions. Structure elucidation of 1i was confirmed by an
X-ray crystallographic determination (Supporting Infor-
mation).
Differences in the stabilities of isomeric Z- and E-
benzothiazines 1, 2 (Scheme S8 and Table S1, Supporting
Information) are not significant enough to explain the
observed stereoselectivity. Thus, the observed stereose-
lectivity seems to be controlled by the steric require-
ments for the proton elimination from 13 (Scheme 3).
According to this hypothesis, we have calculated the
relative stabilities of the conformers of 13 around the
1150, 766 cm . Anal. Calcd for C16H11Cl NS: C,60.01; H, 3.46;
2
Cl, 22.14; N, 4.37; S, 10.01. Found: C, 59.79; H, 3.15; Cl, 21.69;
N, 3.89; S, 9.88.
Ack n ow led gm en t. We thank the DGESIC (Spain,
Grant No. BQU2002-00406) for financial support and
the CAIs of the UCM (Madrid, Spain) for determining
spectra and CHN analyses We thank also Dr. J . Almy
(CSU, Stanislaus, CA) for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Schemes S1-S8,
Experimental Section, characterization data for compounds 1,
1
2, 14, 15, and 17, crystallographic data for compound 1i, H
and 13C NMR spectra for compounds 1a -m , 14, 15, and 17,
and 2D NMR spectra for compound 1i. This material is
available free of charge via the Internet at http://pubs.acs.org.
2 6 5
C4-CH C H bond using molecular mechanics (AM1 and
PM3) as implemented in Hyperchem 7.0 program. Thus,
conformers with an anti disposition of the empty p-orbital
J O049777R
J . Org. Chem, Vol. 69, No. 13, 2004 4547