Synthesis of 3-substituted-3,4-dihydro-2H-1,3-benzothiazin-2-ones via a highly regioselective palladium-catalyzed carbonylation of 2-substituted-2,3- dihydro-1,2-benzisothiazoles

Article abstract of DOI:10.1021/jo702146n

(Chemical Equation Presented) A novel synthesis of 3-substituted-3,4- dihydro-2H-1,3-benzothiazin-2-ones is described herein. The strategy relies on a highly regioselective palladium-catalyzed carbonylation of 2-substituted-2,3- dihydro-1,2-benzisothiazol

Full text of DOI:10.1021/jo702146n

groups have demonstrated that the insertion of carbon monoxide
into the carbon-heteroatom bond of cyclic compounds contain-
ing one heteroatom (usually N, S, or O) can be effectively used
to synthesize the aforementioned heterocyclic structures.8 In
contrast with these studies, little attention has been paid to the
carbonylative insertion reaction of substrates containing two
adjacent heteroatoms.9
Synthesis of
3-Substituted-3,4-dihydro-2H-1,3-benzothiazin-
2-ones via a Highly Regioselective
Palladium-Catalyzed Carbonylation of
2-Substituted-2,3-dihydro-1,2-benzisothiazoles
Gwenaella Rescourio and Howard Alper*
Our research group has recently reported several examples
that illustrate the applicability of this methodology.10 In
particular, we found that the carbonylative ring expansion of
N-alkylisothiazolidines10a and 1,3-thiazolidines10c could take
place with a rhodium-based catalyst (chloro(1,5-cyclooctadiene)-
rhodium(I) dimer) and elevated pressures and temperatures
(typically 1000 psi of CO and 130 or 180 °C depending on the
substrate used). Despite the severity of the conditions required
for this transformation to occur, the corresponding tetrahydro-
2H-1,3-thiazin-2-ones could be isolated in modest to good yields
(35-88% yield).
Centre for Catalysis Research and InnoVation, Department of
Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa,
Ontario K1N 6N5, Canada
halper@science.uottawa.ca
ReceiVed October 3, 2007
Due to the intrinsic value of developing alternative strategies
for the synthesis of this valuable class of compounds, we decided
to expand our studies in this area. We were particularly
interested in the possibility of applying a metal-catalyzed
carbonylation reaction to benzisothiazole substrates in order to
directly access the corresponding benzothiazin-2-ones. We felt
that this methodology could be distinctively useful due to the
limited availability of synthetic methods to elaborate these
structures. To our knowledge, only one example has been
reported in the literature thus far for the preparation of this class
of functionalized heterocycles (Scheme 1). The strategy relied
on the reaction of benzenethiol derivatives 3a-d with phosgene,
a transformation that generally proceeds in poor to modest yields
(33-62%).11
A novel synthesis of 3-substituted-3,4-dihydro-2H-1,3-ben-
zothiazin-2-ones is described herein. The strategy relies on
a highly regioselective palladium-catalyzed carbonylation of
2-substituted-2,3-dihydro-1,2-benzisothiazoles to give the
corresponding 3,4-dihydro-2H-1,3-benzothiazin-2-one de-
rivatives in good to excellent yields.
Transition-metal-catalyzed carbonylation reactions have be-
come an invaluable tool in organic synthesis in both industry
and academia.1-4 These reactions provide access to a broad
range of structurally diverse organic compounds, including
functionalized heterocyclic structures such as lactams, lactones,
or thiolactones.5-7
SCHEME 1. Synthetic Approach Followed by Szabo´ et al.
From a practical point of view, one of the main advantages
of this methodology is the possibility of accessing functionalized
heterocycles in a single reaction step. Thus, a number of research
(1) (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453. (b)
Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. Curr. Org. Chem.
2004, 8, 919. (c) Vizer, S. A.; Yerzhanov, K. B.; Al Aziz Al Quntar, A.;
Dembitsky, V. M. Tetrahedron 2004, 60, 5499. (d) Morimoto, T.; Kakiuchi,
K. Angew. Chem., Int. Ed. 2004, 43, 5580.
(2) (a) El Ali, B.; Alper, H. Synlett 2000, 2, 161. (b) Vasapollo, G.;
Mele, G. Targets Heterocycl. Syst. 2002, 6, 197. (c) Mahadevan, V.; Getzler,
Y. D. Y. L.; Coates, G. W. Angew. Chem., Int. Ed. 2002, 41, 2781.
(3) (a) Nagy, E.; Benedek, C.; Heil, B.; To˜ro¨s, S. Appl. Organomet.
Chem. 2002, 16, 628. (b) To˜ro¨s, S.; Gemes-Pecsi, I.; Heil, B.; Mahob, S.;
Tuba, Z. J. Chem. Soc., Chem. Commun. 1992, 11, 859.
(4) (a) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773. (b)
Larksarp, C.; Alper, H. Org. Lett. 1999, 1, 1619. (c) Dhawan, R.; Dghaym,
R. D.; Arndtsen, B. A. J. Am. Chem. Soc. 2003, 125, 1474. (d) Boeckman,
R. K., Jr.; Reed, J. E.; Ge, P. Org. Lett. 2001, 3, 3651. (e) Dghaym, R. D.;
Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2001, 40, 3228.
(5) (a) Davoli, P.; Moretti, I.; Prati, F.; Alper, H. J. Org. Chem. 1999,
64, 518. (b) Van den Hoven, B. G.; Alper, H. J. Am. Chem. Soc. 2001,
123, 10214.
(6) (a) Van den Hoven, B. G.; El Ali, B.; Alper, H. J. Org. Chem. 2000,
65, 4131. (b) Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441. (c) Consorti, C. S.; Ebeling, G.;
Dupont, J. Tetrahedron Lett. 2002, 43, 753.
To test the viability of utilizing a metal-catalyzed carbony-
lation approach toward the synthesis of benzothiazin-2-ones,
we needed to access precursor 1. Thus, we envisioned a strategy
in which benzisothiazole 1 would be derived from an amino
intermediate 5 (Figure 1). This key intermediate would be
subjected to a tandem oxidation-[2,3]-sigmatropic rearrange-
ment reaction with concomitant nucleophilic attack to give 1.
The key amino derivative 5 would be obtained via reductive
amination of aldehyde 6, which in turn would be synthesized
(8) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414.
(9) (a) Soma, Y.; Yamamoto, N.; Sano, H.; Yamauchi, K.; Tamaoki,
K.; Tanaka, K.; Yabushita, T. Agency of industrial Sciences and Technology.
Jpn. Patent 01,299,285; Chem. Abstr. 1990, 112, 216979e. (b) Souma Y.
Agency of industrial Science and Technology. U.S. Patent 4,990,629.
(10) (a) Dong, C.; Alper, H. Org. Lett. 2004, 6, 3489. (b) Khumtaveeporn,
K.; Alper, H. J. Org. Chem. 1995, 60, 8142. (c) Khumtaveeporn, K.; Alper,
H. J. Am. Chem. Soc. 1994, 116, 5662. (d) Alper, H.; Delledone, D.;
Kameyama, M.; Roberto, D. Organometallics 1990, 9, 762.
(11) Sza´bo, J.; Varga, I.; Fodor, L.; Berna´th, G.; Soha´r, P. Acta Chim.
Hung. 1984, 115, 429.
(7) Wang, M.-D.; Calet, S.; Alper, H. J. Org. Chem. 1989, 54, 20.
10.1021/jo702146n CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/11/2008
1612
J. Org. Chem. 2008, 73, 1612-1615

With these precursors in hand, the carbonylation reaction of
a series of 2-substituted-2,3-dihydro-1,2-benzisothiazoles 1a-g
was performed using 5% of tetrakis(triphenylphosphine)-
palladium(0) in dry pyridine and 300 psi of carbon monoxide
at 80 °C for 24 h.17 Column chromatography of the resulting
crude reaction mixture allowed the isolation of the corresponding
3-substituted-3,4-dihydro-2H-1,3-benzothiazin-2-ones in good
to excellent yields and as the only products. Table 1 summarizes
the outcome of this study. The reaction is compatible with a
number of substituents, including primary and secondary alkyl
groups (entries 1 to 4) and benzylic (entries 5 to 6) and the
naphthylmethyl (entry 7) functionalities. Comparison of the first
four entries of the table shows that the yield is clearly dependent
on the size of the substituent attached to the nitrogen atom.
When the steric hindrance decreases (n-Bu< i-Bu < i-Pr ≈
cyclohexyl), the yield of the carbonylation reaction increases
(n-Bu > i-Bu > i-Pr ≈ cyclohexyl). Entries 5 and 7 show that
both benzylic and naphthylmethyl groups are well tolerated,
whereas a diminution of yield is noticed when a methoxy group
is introduced in the para position of the aromatic ring. In all
the cases, we observed that the conversion is complete and that
the carbonylative insertion occurs with complete regioselectivity
in the N-S bond under these reactions conditions. In addition,
it is worth noting that the conditions are somewhat milder than
those used for the carbonylative insertion of other heterocycles
such as isoxazolidines and N-alkylisothiazolidines.10a,c
FIGURE 1. Retrosynthetic analysis.
from readily available 2-mercapto benzoic acid 7 via a three-
step sequence (reduction-allylation-oxidation).
The synthesis of the benzisothiazole precursor 1 started with
the lithium aluminum hydride reduction of commercially
available 2-mercapto benzoic acid 7 to give the alcohol 8
(Scheme 2).12 Allylation of 2-(mercaptophenyl)methanol 8 with
allylbromide in the presence of potassium carbonate13 and
subsequent oxidation of the alcohol moiety with sulfur trioxide-
pyridine complex14 afforded the aldehyde 6 in 94% overall yield.
At this stage, the amination of 6 was carried out with a number
of different amines and the in situ reduction of the corresponding
imines was performed with sodium borohydride. The resulting
secondary amines were then converted into their hydrobromic
salts 9a-g in good yields. The sulfur atom of these last
intermediates 9a-g was oxidized with sodium metaperiodate
to produce the sulfoxide derivatives 10a-g.15 The latter
spontaneously underwent a [2,3]-sigmatropic rearrangement16
to form the corresponding sulfenates 11a-g followed by a
concomitant intramolecular thiophilic substitution.15
TABLE 1. Palladium-Catalyzed Carbonylation of
2-Substituted-2,3-dihydro-1,2-benzisothiazolesa
entry
reactants
products
yield (%)b
1, R ) Bu
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
92
2, R ) i-Bu
82c
56c
62c
95
3, R ) i-Pr
4, R ) cyclohexyl
5, R ) Bn
6, R ) PMB
75, 86d
91
SCHEME 2. Synthesis of
7, R ) naphthylmethyl
1g
2g
2-Substituted-2,3-dihydro-1,2-benzisothiazoles
a Reaction conditions: 1 (0.5 mmol), Pd(PPh3)4 (0.025 mmol), pyridine
(1 mL), and CO (300 psi) at 80 °C for 24 h. b Isolated yield. c Reactant not
pure, yield calculated as if it was pure. d Reaction conditions: 1f (2 mmol),
Pd(PPh3)4 (0.1 mmol), pyridine (4 mL), and CO (300 psi) at 80 °C for
24 h.
The structures of the products 2a-g were assigned based on
analysis of the spectroscopic data (see the Experimental Section).
(12) Roberts, C. F.; Hartley, R. C. J. Org. Chem. 2004, 69, 6145.
(13) Burkhard, C. A.; Schmitz, J. V.; Burnett, R. E. J. Am. Chem. Soc.
1953, 75, 5957.
(14) Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004,
126, 613.
(15) (a) Hoffmann, R. W.; Goldmann, S. Chem. Ber. 1978, 111, 2716.
(b) Antonjuk, D. J.; Ridley, D. D.; Smal, M. A. Aust. J. Chem. 1980, 33,
2635. (c) It must be noted that the efficiency of this process is highly
dependent on the nature of the alkyl amine. With some of the substrates
the overall yields were acceptable (48-55%) but with some other alkyl
amines, this tandem oxidation-[2,3]-sigmatropic rearrangement-nucleo-
philic substitution process was low yielding (see the Experimental Section).
A possible solution to this problem could be to follow a different approach,
see ref 15d. However, we decided to employ this strategy for all our
substrates due to the inherent convenience of utilizing the “one-pot” reaction
sequence. (d) Kanakarajan, K.; Meier, H. Angew. Chem. 1984, 96, 220.
(16) (a) Miller, E. G.; Rayner, D. R.; Thomas, H. T.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4861. (b) Bickart, P.; Carson, F. W.; Jacobus, J.;
Miller, E. G.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4869. (c) Tang, R.;
Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100. (d) Evans, D. A.; Andrews,
G. C. Acc. Chem. Res. 1974, 7, 147.
J. Org. Chem, Vol. 73, No. 4, 2008 1613

Thus, we observed that the 13C NMR spectra show a signal at
165.3-166.4 ppm corresponding to the carbonyl group in the
benzothiazin-2-one adducts 2a-g and that the infrared spectra
ents, including primary and secondary alkyl groups and benzylic
and naphthylmethyl functionalities.
display a thiourethane γCdO bond at 1635, 1643, or 1647 cm-1
.
Experimental Section
In addition, the structure of 2e was also confirmed by X-ray
The synthesis and purification of the substrates 1a-g are
described in the Supporting Information. Anhydrous pyridine was
purchased from Aldrich and was used without further purification.
Tetrakis(triphenylphosphine)palladium(0) was purchased from Strem
Chemicals.
crystallographic analysis (see Figure 2).
3-Butyl-3,4-dihydro-2H-1,3-benzothiazin-2-one (2a): Typical
Procedure for the Palladium-Catalyzed Carbonylation Reaction
of 2-Substituted-2,3-dihydro-1,2-benzisothiazoles 1a-g. Based
on the method of Kuniyasu et al.,17 into a 50 mL stainless steel
autoclave containing a glass liner and stirring bar were added freshly
prepared 2-substituted-2,3-dihydro-1,2-benzisothiazole (1a) (97 mg,
0.5 mmol), anydrous pyridine (1 mL), and Pd(PPh3)4 (29 mg, 0.025
mmol) under an argon atmosphere. The autoclave was then purged
three times with carbon monoxide and pressured to 300 psi. The
reaction mixture was stirred at 80 °C for 24 h, cooled to room
temperature, and diluted with a 1:1 mixture of hexanes-diethyl
ether (ca. 25 mL). The precipitate was filtered through Celite and
washed several times with hexanes-diethyl ether (1:1). The filtrate
was concentrated in vacuo and the crude mixture was purified by
flash chromatography on silica using a mixture of hexanes-
methylene chloride (polarity increasing from 3.5:1.5 to 1:1) as
eluent. 2a (102 mg, 92%) was isolated as a yellow oil: 1H NMR
(300 MHz, CDCl3 with TMS) δ 7.29-7.22 (m, 4 H), 4.39 (s, 2H),
3.53 (t, J ) 6.4 Hz, 2H), 1.64-1.54 (m, 2H), 1.38-1.25 (m, 2H),
0.92 (t, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3 with TMS)
δ 165.3 (s), 132.9 (s), 131.3 (s), 128.3 (d), 126.6 (d), 126.1 (d),
126.0 (d), 52.8 (t), 49.0 (t), 29.9 (t), 19.9 (t), 13.8 (q); EI-HMRS
calcd for C12H15NOS [M]+ 221.0874, found 221.0881.
FIGURE 2. ORTEP view of compound 2e.
A plausible mechanism for the palladium-catalyzed carbo-
nylation of 2-substituted-2,3-dihydro-1,2-benzisothiazoles is
proposed in Scheme 3. After the loss of phosphine ligands, the
resulting coordinatively unsaturated Pd(0) complex inserts into
the N-S bond of 1 via oxidative addition generating a Pd(II)
species 12. Insertion of carbon monoxide into the S-Pd bond
or the N-Pd bond in 12 produces a transient palladium-
carbonyl intermediate 13, which affords the desired product 2
and regenerates the catalyst via reductive elimination. This
mechanism is also consistent with the trend in yields observed
in our experiments, since it is well-known that Pd reactions are
particularly sensitive to steric factors.
3-Isobutyl-3,4-dihydro-2H-1,3-benzothiazin-2-one (2b): 1H
NMR (300 MHz, CDCl3 with TMS) δ 7.29-7.22 (m, 4H), 4.39
(s, 2H), 3.36 (d, J ) 8.7 Hz, 2H), 2.06-1.92 (m, 1H), 0.89 (d, J
) 7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3 with TMS) δ 165.6
(s), 133.0 (s), 131.4 (s), 128.3 (d), 126.6 (d), 126.1 (d), 126.0 (d),
56.5 (t), 53.5 (t), 27.6 (d), 19.9 (2q); EI-HMRS calcd for C12H15-
NOS [M]+ 221.0874, found 221.0868.
SCHEME 3. Proposed Mechanism for the
Palladium-Catalyzed Carbonylation of 1
1
3-Isopropyl-3,4-dihydro-2H-1,3-benzothiazin-2-one (2c): H
NMR (300 MHz, CDCl3 with TMS) δ 7.30-7.19 (m, 4H), 4.84-
4.70 (m, 1H), 4.25 (s, 2H), 1.21 (d, J ) 6.8 Hz, 6H); 13C NMR
(75 MHz, CDCl3 with TMS) δ 165.6 (s), 133.2 (s), 132.0 (s), 128.3
(d), 126.6 (d), 126.0 (d), 125.9 (d), 46.8 (d), 45.7 (t), 19.9 (2q);
EI-HMRS calcd for C11H13NOS [M]+ 207.0718, found 207.0696.
3-Cyclohexyl-3,4-dihydro-2H-1,3-benzothiazin-2-one (2d): 1H
NMR (300 MHz, CDCl3 with TMS) δ 7.30-7.21 (m, 4H), 4.40-
4.30 (m, 1H), 4.27 (s, 2H), 1.85-1.67 (m, 5H), 1.55-1.31 (m,
4H), 1.21-1.06 (m, 1H); 13C NMR (75 MHz, CDCl3 with TMS)
δ 165.8 (s), 133.3 (s), 132.2 (s), 128.2 (d), 126.6 (d), 126.0 (d),
125.8 (d), 55.0 (d), 46.8 (t), 30.3 (2t), 25.5 (2t), 25.4 (t); EI-HMRS
calcd for C14H17NOS [M]+ 247.1031, found 247.1009.
3-Benzyl-3,4-dihydro-2H-1,3-benzothiazin-2-one (2e): 1H NMR
(300 MHz, CDCl3 with TMS) δ 7.36-7.26 (m, 7H), 7.20-7.14
(m, 1H), 7.07-7.04 (m, 1H), 4.73 (s, 2H), 4.29 (s, 2H); 13C NMR
(75 MHz, CDCl3 with TMS) δ 166.1 (s), 135.9 (s), 132.4 (s), 130.9
(s), 128.8 (2d), 128.3 (d), 128.0 (2d), 127.8 (d), 126.6 (d), 126.2
(d), 125.9 (d), 51.9 (2t); EI-HMRS calcd for C15H13NOS [M]+
255.0718, found 255.0739.
3-(4-Methoxybenzyl)-3,4-dihydro-2H-1,3-benzothiazin-2-
one (2f): 1H NMR (300 MHz, CDCl3 with TMS) δ 7.25-7.24 (m,
2H), 7.21-7.18 (m, 2H), 7.16-7.12 (m, 1H), 7.06-7.03 (m, 1H),
6.86-6.81 (m, 2H), 4.64 (s, 2H), 4.25 (s, 2H), 3.77 (s, 3H); 13C
NMR (75 MHz, CDCl3 with TMS) δ 166.4 (s), 159.7 (s), 132.9
(s), 131.4 (s), 129.9 (2d), 128.7 (d), 128.4 (s), 127.0 (d), 126.7 (d),
126.4 (d), 114.6 (2d), 55.7 (q), 52.1 (t), 51.8 (t); EI-HMRS calcd
for C16H15NO2S [M]+ 285.0823, found 285.0803.
In conclusion, we have described a novel approach toward
the synthesis of 3-substituted-3,4-dihydro-2H-1,3-benzothiazin-
2-ones that relies on the palladium-catalyzed carbonylation
reaction of 2-substituted-2,3-dihydro-1,2-benzisothiazoles. This
carbonylative insertion process occurs in good to excellent yields
with total regioselectivity at the N-S bond of the benzisothia-
zole precursor and the reaction tolerates a number of substitu-
(17) (a) Kuniyasu H.; Hiraike H.; Morita M.; Tanaka A.; Sugoh K.;
Kurosawa H. J. Org. Chem. 1999, 64, 7305. For some other examples on
Pd-mediated carbonylation of the N-S bond, see: (b) Knapton, D. J.;
Meyer, T. Y. J. Org. Chem. 2005, 70, 785. (c) Kuniyasu, H.; Kato, T.;
Asano, S.; Ye, J. H.; Ohmori, T.; Morita, M.; Hiraike, H.; Fujiwara, S. I.;
Terao, J.; Kurosawa, H.; Kambe, N. Tetrahedron Lett., 2006, 47, 1141.
1614 J. Org. Chem., Vol. 73, No. 4, 2008

3-(1-Naphthylmethyl)-3,4-dihydro-2H-1,3-benzothiazin-2-
one (2g): H NMR (300 MHz, CDCl3 with TMS) δ 7.98-7.95
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support.
1
(m, 1H), 7.83-7.76 (m, 2H), 7.47-7.32 (m, 4H), 7.21-7.14 (m,
2H), 7.03 (td, J ) 7.0, 1.9 Hz, 1H), 6.85-6.83 (m, 1H), 5.14 (s,
2H), 4.23 (s, 2H); 13C NMR (75 MHz, CDCl3 with TMS) δ 165.8
(s), 133.7 (s), 132.2 (s), 131.4 (s), 131.1 (s), 130.8 (s), 128.8 (d),
128.7 (d), 128.2 (d), 126.8 (d), 126.7 (d), 126.5 (d), 126.2 (d), 126.1
(d), 125.8 (d), 125.1 (d), 123.3 (d), 51.2 (t), 49.7 (t); EI-HMRS
calcd for C19H15NOS [M]+ 305.0874, found 305.0902.
Supporting Information Available: Experimental procedures,
full characterization data, and 1H and 13C NMR spectra of all
compounds, as well as X-ray crystallographic data of compound
2e. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702146N
J. Org. Chem, Vol. 73, No. 4, 2008 1615