Rapid and efficient synthesis of 2-amino-4H-benzothiazines

Article abstract of DOI:10.1021/ol006580m

(matrix presented) The benzothiazine nucleus is a relatively unexplored class of compounds, from the standpoint of both synthetic chemistry and biological activity. We have developed a rapid, high-yielding synthesis of benzothiazines in which a precursor

Full text of DOI:10.1021/ol006580m

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3667-3670
Rapid and Efficient Synthesis of
2-Amino-4H-benzothiazines
Anitha Hari and Benjamin L. Miller*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
miller@miller1.chem.rochester.edu
Received September 12, 2000
ABSTRACT
The benzothiazine nucleus is a relatively unexplored class of compounds, from the standpoint of both synthetic chemistry and biological
activity. We have developed a rapid, high-yielding synthesis of benzothiazines in which a precursor aryl thiourea is prepared on solid phase.
Addition of trifluoroacetic acid catalyzes a conjugate addition reaction to form the desired heterocycle and releases it from the resin.
The synthesis of heterocyclic systems is of continuing interest
in the field of organic chemistry, at least in part as a result
of the large number of biologically active molecules that
contain heterocyclic rings.1 A heterocyclic ring system that
has been relatively unexplored, with respect to both its
synthesis and its biological activity, is the 4-alkyl-4H-
benzothiazine nucleus (1).2 As part of a continuing program
demonstrated in our previous work, treatment of this resin-
in the development of novel synthetic methodology for the
immobilized nitroarene (2 or 3) with catalytic CrCl2 in the
preparation of biologically active substances, we recently
presence of excess Mn metal and TMSCl in DMF would
disclosed a highly selective method for the catalytic reduction
provide a hexamethyldisilazane (4 or 5), which could
of nitroarenes.3 It occurred to us during the course of that
subsequently be converted to the aniline (6 or 7) by stirring
work that we could potentially employ this reduction as the
in aqueous DMF. Addition of an isothiocyanate would then
first step toward the synthesis of a variety of benzo-fused
provide a thiourea (8 or 9). Treatment of 8 or 9 with
heterocycles. In this communication, we report the synthesis
trifluoroacetic acid (TFA) in methylene chloride would
of a series of 2-anilino-4-alkyl-4H-benzothiazines, which
trigger nucleophilic attack of the thiourea on the R,â-
employs the acid-catalyzed intramolecular conjugate addition
unsaturated carbonyl system, as well as releasing the final
of a thiourea to an R,â-unsaturated carbonyl compound as a
cyclized product 10 or 11 from the resin.
key step.
Our results are summarized in Tables 1 and 2. The solid-
As shown in Scheme 1, our plan was to first immobilize
supported aminocinnamic acids were condensed with phen-
a 2-nitrocinnamic acid on Wang4 or Rink amide5 resin. As
ylisothiocyanate (12), p-tolylisothiocyanate (13), p-methoxy
(1) For recent reviews of heterocycle synthesis, see: (a) Nefzi, A.;
Ostresh, J. M.; Houghten, R. A. Chem. ReV. 1997, 97, 449-472. (b) Franze´n,
cyanate (15), or cyclohexylisothiocyanate (16). For both
R. G. J. Comb. Chem. 2000, 2, 195-214.
phenylisothiocyanate (14), m-trifluoromethyl phenylisothio-
Wang (Table 1) and Rink amide (Table 2) resins, products
were obtained in moderate to excellent yield, particularly
when one considers that this sequence concatenates six
transformations (resin loading, nitro group reduction, hex-
amethyldisilazane hydrolysis, isothiocyanate addition, cy-
clization, and cleavage) into four chromatography-free steps.
(2) For syntheses of 4-aryl and unsubstituted 4H-3,1-benzothiazines,
see: (a) Nishio, T. J. Org. Chem. 1997, 62, 1106-1111. (b) El-Desoky, S.
I.; Kandeel, E. M.; Abd-el-Rahman, A. H.; Schmidt, R. R. J. Herocycl.Chem.
1999, 36, 153-160.
(3) (a) Hari, A.; Miller, B. L. Angew. Chem., Int. Ed. Engl. 1999, 38,
2777-2779. (b) Hari, A.; Miller, B. L. Org. Lett. 2000, 2, 691-693.
(4) Wang, S. J. Am. Chem. Soc. 1973, 95, 1328-1333.
(5) Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790.
10.1021/ol006580m CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Scheme 1
Table 1. Preparation of Benzothiazines on Wang Resin
Best yields were obtained with alkoxy-substituted 2-nitro-
cinnamic acid and aryl isothiocyanates (Table 1, entries 6-9
and 11-14).6
a Conversion based on 1H NMR. b Crude yield (75-95% pure by HPLC).
Most products were obtained in reasonably high purity,
as judged by HPLC and H NMR analysis of the crude
c Isolated yield.
1
products (Figure 1). Assignment of product structures as
2-amino-4H-benzothiazines rather than the isomeric quinazo-
line-2-thione was based primarily on the chemical shift of
the C-4 proton (δ ) 4.5-4.7 ppm), a value inconsistent with
published values for quinazoline-2-thiones.9 Reaction with
cyclohexyl isothiocyanate was unsuccessful, providing com-
plex mixtures of materials that could not be separated
(6) Representative Experimental Procedure. 4,5-Dimethoxy 2-nitro-
cinnamate was loaded onto 50 mg of Wang resin (Advanced Chemtech,
1.2 mmol/g) and reduced using catalytic CrCl2 in the presence of Mn metal
and TMSCl as reported previously. After separation of the resin from Mn
and transfer to a second reaction vessel (Bio-Rad Bio-Spin 1.5 mL
polyethylene chromatography column fitted with a porous polymer frit), it
was treated with 1.0 mL of 50% aqueous DMF for 12 h at room temperature.
The aqueous DMF solution was then removed, and the resin was washed
with DMF and CH2Cl2. After drying the resin thoroughly on an aspirator,
29 µL (0.24 mmol, 4 equiv) of phenyl isothiocyanate (Aldrich) was then
shaken with the resin in 1.0 mL of DMF for 12 h. The resin was then
thoroughly washed with DMF, CH3OH, and CH2Cl2. Cyclization and
product release was accomplished by treatment of the resin with 1.0 mL of
50% trifluoroacetic acid in CH2Cl2 for 30 min. This solution was drained
off, and the resin washed with 1 mL of CH2Cl2. The CH2Cl2 solutions were
combined, and solvent was removed in vacuo. Purification of the crude
sample by preparative reverse-phase HPLC (C18 column, 10-100% 0.1%
TFA/CH3CN in 0.1% TFA/H2O) provided the desired benzothiazine
essentially pure as a white solid (14 mg, 65%).
(7) Analytical HPLC was performed on a Hewlett-Packard series 1050
quaternary HPLC system, equipped with a Hamilton PRP-1 0.3 cm × 15
cm reverse-phase column. A linear gradient of 10-100% CH3CN (0.1%
CF3CO2H) in H2O (0.1% CF3CO2H) was performed over 30 min at a flow
rate of 300 µL/min.
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Org. Lett., Vol. 2, No. 23, 2000

cyclohexyl isothiocyanate in DMF produced a complex
mixture of products.
Table 2. Preparation of Benzothiazines on Rink Amide Resin
This methodology is complementary to solution-phase
methods reported recently by Xin and co-workers for the
synthesis of dihydroquinazolines (eq 1)8 and the solution-
phase dihydroquinazoline-2-thione and 4H-3,1-benzothi-
azine-2-thione preparation reported by Ta´rraga, Molina, and
Lo´pez (eq 2).9 Both of these processes are essentially base-
driven, providing significantly different products than are
obtained with our acid-mediated process.
a Conversion based on 1H NMR. b Crude yield (75-95% pure by HPLC).
c Isolated yield.
chromatographically (Table 1, entries 5 and 10). We suspect
the reaction fails in this case at the isothiocyanate addition
stage. Although it is difficult to test this directly on the resin,
we found that treatment of methyl 2-aminocinnamate with
Curious as to the comparative reactivity of solid-supported
urea derivatives under acidic conditions, we derivatized a
Figure 1. Representative analytical HPLC trace (λ ) 254 nm)7 and NMR spectrum (1H, 400 MHz, CDCl3/CH3OD) of the crude product
from Table 1, entry 7 (top) and Table 1, entry 8 (bottom).
Org. Lett., Vol. 2, No. 23, 2000
3669

resin-loaded o-amino cinnamate with phenyl isocyanate as
shown in Scheme 2. Treatment of this resin with CF3CO2H
compound that was verified to be 18.10 Presumably, cycliza-
tion does not occur in this case as a result of the lower
nucleophilicity of the urea oxygen relative to the thiourea
sulfur atom.
Scheme 2
In summary, we have developed a method for the synthesis
of 2-amino-4H-benzothiazines, which takes advantage of an
acid-catalyzed intramolecular cyclization of thioureas pre-
pared on solid support. Efforts to examine the bioactivity of
combinatorial libraries of this relatively unexplored class of
heterocycles are underway in our laboratory.
Acknowledgment. This research was supported by the
Eastman Kodak Corporation.
Supporting Information Available: Full spectroscopic
data is provided for selected compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL006580M
(8) Xin, Z.; Pei, Z.; von Geldem, T.; Jirousek, M. Tetrahedron Lett. 2000,
41, 1147-1150.
(9) Ta´rraga, A.; Molina, P.; Lo´pez, J. L. Tetrahedron Lett. 2000, 41,
4895-4899.
(10) For alternative solid-supported preparations of ureas, see: (a)
Gordeev, M. F.; Hui, H. C.; Gordon, E. M.; Patel, D. V. Tetrahedron Lett.
1997, 38, 1729-1732. (b) Wang, G. T.; Chen, Y.; Wang, S.; Sciotti, R.;
Sowin, T. Tetrahedron Lett. 1997, 38, 1895-1898.
1
in CH2Cl2 yielded a product that appeared to be 17 by H
NMR but could not be isolated chromatographically. Sub-
sequent esterification of this crude product provided a
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Org. Lett., Vol. 2, No. 23, 2000