A straightforward synthesis of benzothiazines

Article abstract of DOI:10.1021/ol802346r

(Chemical Equation Presented) A series of 4H-3,1-benzothiazines have been successfully synthesized through a three-step sequence starting from commercially available 2-iodoaniline. The key step consists of the cyclization of compounds 6 via an intramolecu

Full text of DOI:10.1021/ol802346r

ORGANIC
LETTERS
2009
Vol. 11, No. 2
269-271
A Straightforward Synthesis of
Benzothiazines
Carolina Gimbert and Adelina Vallribera*
Department of Chemistry, UniVersitat Auto`noma de Barcelona, Cerdanyola del Valle`s,
08193 Barcelona, Spain
adelina.Vallribera@uab.es
Received October 10, 2008
ABSTRACT
A series of 4H-3,1-benzothiazines have been successfully synthesized through a three-step sequence starting from commercially available 2-iodoaniline.
The key step consists of the cyclization of compounds 6 via an intramolecular S-conjugate addition. The synthesis is straightforward, gives good
yields and offers a broad range of possibilities since R can be many alkyl or aryl groups and Z a suitable electron-withdrawing functionalization.
Heterocycles having the 4H-3,1-benzothiazine nucleus are
systems of great interest because of their biological activity,1
as well as their applications in recording and photographic
materials.2 Several synthetic routes have been described in
the literature to obtain 4H-3,1-benzothiazines. The most used
route involves the condensation between 2-aminobenzyl
chloride and thioamides, a reaction that also works with other
substrates such as thioureas or benzopyran-2-thiones as sulfur
sources.3 A related process uses 2-aminobenzyl or 2-(N-
acylamino)benzyl alcohols as starting materials.1a,c,4 Another
strategy is to use the cycloaddition of thiones to conveniently
functionalized ketenimines.5 A minor amount of benzothi-
azine has also been isolated as a byproduct of the
Willgerodt-Kindler reaction, which involves a similar
cycloaddition reaction.6 Moreover, various isothiocyanates
have been used as starting materials to obtain this heterocycle
through other cyclization processes.1f,7 Direct thionation of
quinazolines or benzoxazines derivatives has also been
described.8 Finally, other approaches to 4H-3,1-benzothiaz-
ines are limited to a restricted range of products.9
Our recent studies demonstrated that under phosphine
organocatalysis10 thioamides can effectively react with
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J. A.; Asselin, A. A. Can. Patent 1212396, 1986; Chem. Abstr. 1987, 106,
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1977; Chem. Abstr. 1977, 87, 144134. (d) Usui, H.; Ishige, S.; Saeki, K.
Ger. Patent 2,658,246, 1977; Chem. Abstr. 1977, 87, 137318.
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J. Heterocycl. Chem. 2001, 38, 343. (b) Dean, V. L.; Lindamood, B. S.;
Papadopoulos, E. P. Synthesis 1984, 68. (c) Dean, W. D.; Papadopoulos,
E. P. J. Heterocycl. Chem. 1982, 19, 1117. (d) Abaev, V. T.; Tsiunchik,
F. A.; Gutnov, A. V.; Butin, A. V. Tetrahedron Lett. 2006, 47, 4029. (e)
Butin, A. V.; Abaev, V. T.; Stroganova, T. A.; Gutnov, A. V. Molecules
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.
10.1021/ol802346r CCC: $40.75
Published on Web 12/11/2008
2009 American Chemical Society

electron-poor olefins generating not only the expected
in 4 would definitely favor the desired S-adduct, allowing
us to obtain a new family of 4H-3,1-benzothiazines.
Our synthetic proposal conveniently starts with 2-iodoaniline
(Scheme 2). After condensation, Mizoroki-Heck reaction, and
thionation of the amide group by Lawesson’s reagent (LR), the
cyclization would take place. The stabilization of the zwitteri-
onic resonance structure A or tautomer B of thioamide 3 would
favor the cyclization without requiring a catalyst (Scheme 2).
This synthesis is very simple, gives good yields, and makes it
possible to obtain a broad diversity of 4H-3,1-benzothiazines
by varying the R and the Z substituents.
N-adduct 1 but also the S-adduct derivative 2 (Scheme 1).10a
Scheme 1
The results obtained for the synthesis of precursors 6 are
depicted in Table 1. o-Iodoaniline reacted successfully with
Table 1. Synthesis of Amides 5 (Step 1, Scheme 2)a and
Precursors 6 (Step 2, Scheme 2)b
yield (%)c
entry
R
Z
compounds 5
compounds 6
This result can be explained by the ability of the sulfur atom
of thioamides to stabilize the negative charge induced by
the conjugation of the neighboring nitrogen atom.
These results prompted us to investigate a new family of
substrates that would favor the S-addition over the N-addition
reaction. For this reason we focused on thioamides 3 in
Scheme 2, which would be expected to undergo intramo-
lecular cyclization. The formation of the six-membered ring
1
2
3
4
5
6
7
8
9
CH3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
5a (85)
5b (79)
5c (75)
5d (43)d
5e (73)
5f (80)
5a (85)
5b (79)
5e (73)
6a (95)
6b (91)
6c (83)
6d (96)
6e (99)
6f (87)
6g (84)e
6h (48)f
6i (77)f
tBu
Ad
NO2C6H4
BuOC6H4
C3F7
CH3
tBu
CN
CN
BuOC6H4
a Reactions performed in diethyl ether at room temperature, using 1.1
equiv of acyl chloride and 1.1 equiv of Et3N. b Reactions performed in
refluxing THF, using 2-10% mol of Pd(OAc)2, 1 equiv of Bu3N, and 2
equiv of olefin. c Isolated yields. d Reaction performed in refuxing CHCl3.
e DMF at 80 °C was used. f CH3CN at 80 °C was used.
Scheme 2
different acyl chlorides in the presence of triethylamine in
diethyl ether at room temperature, affording amides 5 in good
yields (73-85%). Only the 4-nitroaniline derivative required
changing conditions (CHCl3, reflux)11 to obtain a moderate yield
of the product (43%).
Amides 5 were then treated with ethyl acrylate in the
presence of Pd(OAc)2 and tributylamine in refluxing THF,
giving 6 with excellent yields (83-99%, Table 1). Mizoroki-
Heck reactions using acrylonitrile (Table 1, entries 7-9) were
performed in CH3CN or DMF at 80 °C because conversions
were <100% when THF was used. As commonly occurs
using the nitrile derivative, the products were obtained as a
mixture of Z/E isomers.12
Finally, compounds of type 6 were cyclized by reaction with
Lawesson’s reagent in refluxing toluene, using different molar
ratios depending on the substrate (Table 2). For instance,
benzothiazines 4a and 4g were obtained in good yields using
only 0.5 equiv of LR. However, more hindered compounds such
as tert-butyl or adamantyl derivatives required 1 and 3 equiv,
respectively, as well as longer reaction times (entries 2, 3, 8).
The fact that the Lawesson’s reagent has a specific order of
reactivity toward different functional groups,13 i.e., R-OH >
PdO > R-CO-NHR′ > R-CO-R′ > R-CO-OR′, allowed us to
perform chemoselective processes in the presence of esters
(entries 1-6, Table 2).
270
Org. Lett., Vol. 11, No. 2, 2009

3 equiv of LR. The reactivity of perfluoroalkyl derivative 6f
was much lower than the one observed for the alkyl or aryl
compounds.
Benzothiazine 4f was detected in reactions using a large
amount of LR (up to 6 equiv) and high temperatures (up to
150 °C). However isolation was difficult as a result of the
presence of starting material (low reaction conversions) and
dithionated compound 7f (Table 2, entry 6).
Table 2. Synthesis of 4H-3,1-Benzothiazines 4 (Step 3, Scheme
2)a
Some attempts were carried out to cyclize compounds of
type 6 with Z ) COCH3, but complex mixtures of the desired
product and byproducts were obtained. This result can be
explained by the higher reactivity of ketones compared to
that of esters, which would favor the formation of dithionated
products equivalent to 7f (entry 6, Table 2).13
4H-3,1-Benzothiazines 4a-4i are easily identified by their
1
characteristic R- and ꢀ-carbonyl(cyano) signals in the H
NMR spectra (ca. 2.6 and ca. 4.5 ppm, respectively).
Noteworthy is the observed diastereotopic relationship
between the -CH2- protons of the ester group in compounds
4a-f, indicative of a restricted movement of this side chain
(see Supporting Information).
In conclusion, we have designed a new, rapid, and high-
yielding synthetic approach to 4H-3,1-benzothiazines that has
as a key step a noncatalyzed intramolecular S-conjugate
addition of a thioamide. Another advantage is the versatility
due to the broad range of acyl chlorides and electronically
poor olefins that can be used.
Acknowledgment. Financial support from Ministerio de
Ciencia e Innovacio´n (Projects CTQ2005-04968-C02-01 and
Consolider Ingenio 2010 CSD2007-00006) and Generalitat
de Catalunya (SGR2005-00305 and predoctoral scholarship to
C.G.) are gratefully acknowledged.
Supporting Information Available: Experimental details,
product characterization and full spectroscopic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
OL802346R
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Compounds containing aromatic substituents were synthe-
sized successfully using the same reaction conditions (entries
4, 5, 9). Substrates with an electron-rich group such as 6e and
6i were more reactive than the equivalent with an electron-
poor derivative, 6d, the former requiring 1 equiv and the latter
Org. Lett., Vol. 11, No. 2, 2009
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