Efficient synthesis of new chiral 1,2-benzothiazin-3-one 1,1-dioxide derivatives via lateral lithiation of 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2008.01.015

Chiral 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones 4a-e derived from (l)- and (d)-amino acids 1a-e undergo lateral lithiation with lithium diisopropylamide and TMEDA in anhydrous THF to provide new optically-active 1,2-benzothiazin-3-one 1,1-dioxide deri

Full text of DOI:10.1016/j.tetlet.2008.01.015

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1473–1475
Efficient synthesis of new chiral 1,2-benzothiazin-3-one
1,1-dioxide derivatives via lateral lithiation of
3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones
*
´
Ahmed Ould Aliyenne, Jamil Kraıem, Yakdhane Kacem, Bechir Ben Hassine
¨
` `
Laboratoire de Synthese Organique Asymetrique et Catalyse Homogene (01UR 1201), Faculte des Sciences de Monastir,
´ ´
Avenue de l’Environnement, 5019 Monastir, Tunisia
Received 1 October 2007; revised 17 December 2007; accepted 2 January 2008
Available online 8 January 2008
Abstract
Chiral 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones 4a–e derived from (L)- and (D)-amino acids 1a–e undergo lateral lithiation with
lithium diisopropylamide and TMEDA in anhydrous THF to provide new optically-active 1,2-benzothiazin-3-one 1,1-dioxide derivatives
5a–e with yields ranging from 63% to 79%.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Oxazolidinones; Directed lateral lithiation; Benzothiazin-3-one 1,1-dioxides
Benzothiazinone 1,1-dioxides represent a class of hetero-
cycles that have received continuing attention in pharma-
ceutical research. Examples of such compounds include
non-steroidal anti-inflammatory drugs (NSAIDs) widely
used in the treatment of rheumatoid arthritis and other
inflammatory diseases.1,2 Furthermore, six-membered
heterocycles containing the sulfamyl group have also been
utilized as therapeutic agents to treat several diseases.3,4
Owing to these important biological benefits, several
synthetic approaches to 1,2-benzothiazinone 1,1-dioxides
have been described in the literature. Almost all of these
are based on the cyclization of an ortho-substituted sulfon-
amide to form the thiazine ring.5 The first example was
reported by Lombardino6 and involved the lithiation of
N-benzyl-o-toluenesulfonamide with n-BuLi, followed by
the treatment of the dilithio intermediate with CO2 and
then cyclodehydration, leading to the desired product. Bar-
reiro and co-workers have described the synthesis of benzo-
thiazin-3-one 1,1-dioxide starting from natural safrole.7,8
No examples of chiral 1,2-benzothiazin-3-one 1,1-dioxides
were known when our work was initiated.
Following our investigations on developing synthetically
useful anionic aromatic reactions for the synthesis of bio-
logically active compounds,9–11 we report lateral lithiation
of 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones as a prac-
tical and efficient synthesis of new chiral 1,2-benzothia-
zin-3-one 1,1-dioxides 5a–e. These heterocycles have
potentially great pharmaceutical importance and are
required for the evaluation of biological activities and as
starting materials to prepare new drugs.
Table 1
Entry
R
Mp (°C)
[a]D (c 1, CHCl3)
Yield (%)a
4a
4b
4c
4d
4e
a
i-Pr
sec-Bu
i-Bu
Bn
191–192
84–86
143–145
113–115
93–95
+175
+95
+105
+135
À192
90
88
86
86
82
Ph
*
Corresponding author. Tel.: +216 73500279; fax: +216 73500278.
Yield from 3a–e.
E-mail address: bechirbenhassine@yahoo.fr (B. Ben Hassine).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.015

1474
A. Ould Aliyenne et al. / Tetrahedron Letters 49 (2008) 1473–1475
O
O
R
EtNiPr2/ NaOH
OH
R
SO2Cl
+
OH
NH
O
acetone
S
NH2
1a-e
O
2a-e
R
R
OH
O
O
N
LiAlH4
THF
S
BTC / Et3N
CH2Cl2
NH
O
S
O
O
O
3a-e
4a-e
Scheme 1.
Table 2
The starting compounds, (4S)-alkyl-3-N-mesitylene-
sulfonyl-1,3-oxazolidin-2-ones 4a–d and (4R)-phenyl-3-N-
mesitylenesulfonyl-1,3-oxazolidin-2-one 4e (Table 1), were
prepared in three steps starting from the corresponding
(L)- and (D)-amino acids 1a–e according to our previously
described procedures12 (Scheme 1).
The utility of directed lateral metalation (DreM)–
cyclization reactions in organic synthesis has been widely
demonstrated by Snieckus and others.13–17 Also, lateral
metalation18,19 has been reported for o-tolylsulfonamide,
p-tolylcarbamide,20 p-tolylsulfonates21 and p-tolylsulfon-
amide22 which undergo benzylic deprotonation. We have
found that the lithiation of 3-N-mesitylenesulfonyl-1,3-
oxazolidin-2-ones 4a–e constitutes a mild method for the
preparation of novel chiral 1,2-benzothiazin-3-one 1,1-
dioxide derivatives 5a–e (Scheme 2).
Pre-cyclization Producta
product
R
Mp
(°C)
[a]D (c, CHCl3) Yield
(%)
4a
4b
4c
4d
4e
a
5a
5b
5c
5d
5e
i-Pr
53–55 +40 (0.2)
76
69
70
79
63
sec-Bu 73–75 À25 (0.2)
i-Bu
Bn
Ph
—
+40 (0.2)
94–96 +30 (0.5)
78–80 +45 (0.2)
Identification of products was accomplished from 1H, 13C and C–H
correlation NMR spectra and by FTIR spectroscopy. Satisfactory
elemental analytical data were obtained.25
the reaction. We then resorted to the optimized conditions
of Lohse and co-workers.17 Thus, the treatment of com-
pounds 4a–e with 2.5 equiv of LDA–TMEDA resulted in
lateral metalation–cyclization to provide 1,2-benzothia-
zin-3-one 1,1-dioxides but in low conversions. Increasing
the equivalents of LDA–TMEDA improved the yields;
however, prolonging the reaction time led to the formation
of side products. Finally, we found that the use of 6 equiv
of LDA–TMEDA at À20 °C, possibly for the deprotonation
of the three methyls of the aromatic ring (Fig. 1) was effi-
cient, leading after 30 min to the desired 1,2-benzothia-
zin-3-one 1,1-dioxides 5a–e in good yields23 (Table 2).
This process was possibly driven by complex-induced prox-
imity effects.13,24
Initially, an investigation of the optimum reaction
conditions for the synthesis of compounds 5a–e was under-
taken. Thus, the treatment of N-mesitylenesulfonyloxazol-
idin-2-ones 4a–e with various equivalents of LDA at low
and room temperatures failed, in all cases, to bring about
R
R
*
O
O
O
O
1. LDA / TMEDA
S
*
S
OH
N
N
THF / -20 °C
2. NH4Cl
O
In summary, the efficient four-step process described in
this Letter has enabled us to prepare chiral 1,2-benzothia-
zin-3-one 1,1-dioxides from inexpensive and readily avail-
able amino acids. The anti-inflammatory activity of these
new products is under test in our laboratory.
O
O
5a-e
4a-e
Scheme 2.
R
Li
H2C
R
O
O
O
Acknowledgements
O
OLi
S
O
N
O
LiH2C
S
N
´ ´
The authors thank the DGRSRT (Direction Generale
de la Recherche Scientifique et de la Renovation Techno-
logique) of the Tunisian Ministry of Higher Education
and Scientific research and Technology for financial sup-
port of this research.
O
LiCH2
´
CH2
Li
LiH2C
Fig. 1.

A. Ould Aliyenne et al. / Tetrahedron Letters 49 (2008) 1473–1475
1475
(90:10) mp = 94–96 °C; [a]D +30, (c 0.5, CHCl3); IR (cmÀ1):
CO = 1712, mOH = 3242, 3582. 1H NMR (300 MHz, CDCl3): d 2.33
References and notes
m
(s, 3H, Ar-CH3), 2.39 (s, 3H, Ar-CH3), 2.45 (s, 1H, –OH), 2.95–3.20
(ABX system, J = 6, 9, 12 Hz, 2H, –CH2–), 3.75–4.15 (AB system,
J = 18 Hz, 2H, Ar-CH2–), 3.90–4.20 (ABX system, J = 6, 9, 12 Hz,
2H, –CH2–OH), 4.90 (s, 1H, N–CH–), 6.86–6.97 (m, 7H, ArH). 13C
NMR (75 MHz, CDCl3): d = 20.25, 21.61, 34.36, 41.34, 61.55, 64.00,
126.68, 127.38, 128.36, 129.31, 131.95, 132.17, 132.78, 135.73, 137.60,
143.51, 170.95 (C@O). Anal. Calcd for C19H21NO4S, 359.11: C, 63.49;
H, 5.89; N, 3.90. Found: C, 63.51; H, 6.13; N, 3.97.
1. Flower, R. J. Pharmacol. Rev. 1974, 26, 33–67.
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3. Aran, V. J.; Goya, P.; Ochoa, C. Adv. Heterocycl. Chem. 1988, 44, 81–
197.
4. Stegelmeier, E.; Niemers, E.; Rosentreter, U.; Knorr, A.; Garthoff, B.
German Patent 3,309,655, 1984; Chem. Abstr. 1985, 102, P24633.
5. Lombardino, J. G.; Kuhla, D. E. Adv. Heterocycl. Chem. 1981, 28,
73–126.
6. Lombardino, J. G.; Wiesman, E. H. J. Med. Chem. 1971, 14, 973–977.
7. Carlos, A. M. F.; Barreiro, E. J. J. Heterocycl. Chem. 1992, 1667–
1669.
8. Teixeita, L. H. P.; Carlos, A. M. F.; Barreiro, E. J. J. Braz. Chem.
Soc. 1998, 9, 120–130.
9. Ould Aliyenne, A.; Khiari, J. E.; Kacem, J.; Kra¨ıem, Y.; Ben Hassine,
B. Tetrahedron Lett. 2006, 47, 6405–6408.
10. Kacem, Y.; Bouroui, A.; Ratovelomanana-Vidal, V.; Geneˆt, J. P.;
Ben Hassine, B. C.R. Chimie 2002, 5, 611–621.
11. Kacem, Y.; Kra¨ıem, J.; Kerkeni, E.; Bouraoui, A.; Ben Hassine, B.
Eur. J. Pharm. Sci. 2002, 16, 221–228.
12. Ould Aliyenne, A.; Kacem, J.; Kra¨ıem, Y.; Ben Hassine, B. C.R.
Chimie 2007, 10, 251–258.
13. Whistler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206–2225.
14. McNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. J.; Snieckus, V. Synlett
1998, 419–421.
15. Fouche, J.; Leger, A. German Patent 2,202,486, 1972; Chem. Abstr.
1972, 77, 152012.
16. Fouche, J.; Leger, A., German Patent 2,039,396, 1972; Chem. Abstr.
1972, 77, 5379.
17. Lohse, O.; Beutler, U.; Funfschilling, P.; Furet, P.; France, J.; Penn,
D.; Kaufmann, G.; Zaugg, W. Tetrahedron Lett. 2001, 42, 385–
389.
18. Watanabe, H.; Mao, C. L.; Barnish, I. T.; Hauser, C. R. J. Org.
Chem. 1969, 34, 1786–1791.
19. Clark, R. D. J. Org. React. 1995, 47, 1–314.
20. Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34–46.
21. Alo, B. I.; Familoni, O. B.; Marsais, F.; Quequiner, G. J. J. Chem.
Soc., Perkin Trans. 1 1990, 1611–1614.
24. Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
25. Selected data: Compound 4a: Yield = 90%; mp: 192–194 °C; [a]D
+175 (c 1, CHCl3); IR (cmÀ1): mCO = 1765. 1H NMR (300 MHz,
CDCl3): 0.99 (d, 3H, J = 6 Hz, –CH3); 1.09 (d, 3H, J = 9 Hz, –CH3);
2.30 (s, 3H, Ar-CH3); 2.54–2.63 (m, 1H, –CH–); 2.66 (s, 6H, Ar-CH3);
4.22–4.45 (m, 3H, –CH–, –CH2–); 6.98 (s, 2H, Ar-H). 13C NMR
(75 MHz, CDCl3): d = 14.68; 17.97; 21.18; 22.76; 30.99; 62.56; 63.75;
131.63; 132.16; 141.20; 144.29, 152.44 (C@O). Anal. Calcd for
C
15H21NO4S, 311.40: C, 57.86; H, 6.80; N, 4.50. Found: C, 58.12;
H, 6.92; N, 4.55.
Compound 5a: Yield = 76%, mp = 53–55 °C, [a]D +40; (c 0.2,
CHCl3), 1H NMR (300 MHz, CDCl3): d 0.66 (d, 3H, J = 6 Hz, –
CH3); 0.94 (d, 3H, J = 6 Hz, –CH3); 2.29 (s, 3H, Ar-CH3); 2.35–2.38
(m, 1H); 2.55 (s, 3H, Ar-CH3); 3.20 (s, 1H, –OH); 3.77–4.07 (ABX
system, J = 3, 6, 12 Hz, 2H, –CH2–OH); 3.88–4.05 (AB system, 2H,
J = 18 Hz, Ar-CH2–); 4.15 (s, 1H, N–CH–); 6.92 (s, 1H, ArH); 6.97 (s,
1H, ArH). 13C NMR (75 MHz, CDCl3): d = 20.50; 21.70; 23.48;
27.29; 30.10; 41.20; 62.91; 66.22; 127.71; 132.33; 132.80; 136.08;
139.08; 144.00; 170.71 (C=O). Anal. Calcd for C15H21NO4S, 311.40:
C, 57.86; H, 6.80; N, 4.50. Found: C, 57.80; H, 6.90; N, 4.37.
Compound 5b: Yield = 69%; mp = 73–75 °C; [a]D À25; (c 0.2,
CHCl3). 1H NMR (300 MHz, CDCl3): d 0.76 (t, 3H, J = 6, 9 Hz,
–CH3); 0.97 (d, 3H, J = 6 Hz, –CH3); 1.09–1.34 (m, 3H, –CH–,
–CH2–); 2.36 (s, 3H, Ar-CH3); 2.63 (s, 3H, Ar-CH3); 3.38 (s, 1H,
–OH); 3.84–4.12 (m, 4H, 2H at –CH2–OH and 2H at –CH2-Ar); 4.20–
4.42 (m, 1H, –CH–); 6.98 (s, 1H, Ar-H); 7.04 (s, 1H, Ar-H). 13C NMR
(75 MHz, CDCl3): d = 10.71; 16.38; 20.51; 21.72; 26.23; 41.25; 63.11;
64.73; 127.73; 132.48; 132.81; 136.05; 144.00; 170.78 (C@O). Anal.
Calcd for C16H23NO4S,325.43: C, 59.05; H, 7.12; N, 4.30. Found: C,
59.10; H, 7.05; N, 4.22.
Compound 5c: Yield = 70%; [a]D +40; (c 0.2, CHCl3); 1H NMR
(300 MHz, CDCl3): d 0.75–0.90 (2d, 6H, J = 6 Hz, 2CH3); 1.20–1.29
(m, 1H, –CH–); 1.43–1.47 (m, 2H, –CH2–); 2.36 (s, 3H, Ar-CH3); 2.64
(s, 3H, Ar-CH3); 3.25 (s, 1H, –OH); 3.38–4.05 (m, 4H, 2H at –CH2–
OH and 2H at –CH2-Ar); 4.78 (m, 1H, N–CH–); 6.95 (s, 1H, ArH);
6.97 (s, 1H, ArH). 13C NMR (75 MHz, CDCl3): d = 20.52; 21.72;
22.24; 23.38; 25.46; 41.28; 58.12; 64.15; 127.70; 132.46; 132.81; 135.97;
143.99; 169.91 (C@O). Anal. Calcd for C16H23NO4S, 325.43: C, 59.05;
H, 7.12; N, 4.30. Found: C, 59.38; H, 7.10; N, 4.25.
22. MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001, 66,
3662–3670.
23. Typical cyclization procedure:
A solution of diisopropylamine
(450 lL, 2.88 mmol) and tetramethylethylenediamine (450 lL,
2.88 mmol) in anhydrous THF (4 mL) was cooled to À30 °C and n-
BuLi in hexanes (2.5 M, 1.15 mL, 1.44 mmol) was added dropwise.
The resulting solution was stirred for 45 min, and then warmed to
À20 °C before the dropwise addition of a solution of 3-N-mesityl-
sulfonyl-4-benzyloxazolidin-2-one 4d (150 mg, 0.48 mmol) in THF
(3 mL). The reaction mixture was stirred for 30 min. After warming to
room temperature, 5 mL of saturated ammonium chloride solution
and 10 mL of ether were added. The layers were separated and the
aqueous layer was extracted with ether (3 Â 5 mL). The combined
ether extracts were washed with brine, dried over MgSO4, filtered and
concentrated in vacuum and the residue was purified by column
chromatography on silica gel (20% ethyl acetate: 80% cyclohexane) to
afford 2-[(1S)-2-hydroxy-1-benzylethyl]-6,8-dimethyl-[1,2]-benzothia-
zin-3-one 5d, which was recrystallized from hexane/ethyl acetate
Compound 5e: Yield = 63%; mp = 78–80 °C; [a]D +45; (c 0.2,
CHCl3). 1H NMR (300 MHz, CDCl3): d 2.29 (s, 3H, Ar-CH3); 2.58
(s, 3H, Ar-CH3); 1.90 (s, 1H, –OH); 3.91–4.03 (AB system, 2H,
J = 18 Hz, –CH2-Ar); 4.17–5.75 (ABX system, J = 9, 10, 12 Hz, 3H, –
CH–CH2–OH); 6.89 (s, 1H, ArH); 6.97 (s, 1H, ArH); 7.12–7.28 (m,
5H, ArH). 13C NMR (75 MHz, CDCl3): d = 20.57; 21.72; 41.23;
60.65; 62.36; 127.78; 128.16; 128.34; 128.87; 132.51; 136.11; 136.43;
144.11; 169.57 (C@O). Anal. Calcd for C18H19NO4S, 345.42: C, 62.59;
H, 5.54; N, 4.06. Found: C, 62.45; H, 5.68; N, 4.07.