Novel heteroannulation through copper catalysis: A highly regio- and stereoselective synthesis of 2-substituted 3,1-benzoxathiinones

Article abstract of DOI:10.1055/s-2001-11402

A highly regio- and stereoselective method, comprising a cuprous iodide-catalysed cyclisation as a key step, gives an easy access to (E)-2-(2-arylvinyl)-3,1-benzoxathiin-4-ones 16-22.

Full text of DOI:10.1055/s-2001-11402

LETTER
415
Novel Heteroannulation through Copper Catalysis: a Highly Regio- and
Stereoselective Synthesis of 2-Substituted 3,1-Benzoxathiinones
Nitya G. Kundu,* Bidisha Nandi
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta, 700 032, India
Fax +91(33)473 2805; E-mail: ocngk@mahendra.iacs.res.in
Received 4 January 2001
atoms, e.g. substituted benzodioxans, benzoxazines,6b
benzodioxepinones and benzoxazepinones.6c In continua-
tion of these studies, we recently found that 3-(2-ami-
nophenylthio)prop-1-yne could successfully be arylated
with aryl iodides under palladium-copper catalysis to the
corresponding disubstituted alkynes which, however, un-
derwent a novel cyclisation with cuprous iodide to 2-sub-
stituted benzothiazolines.7
6a
Abstract: A highly regio- and stereoselective method, comprising
a cuprous iodide-catalysed cyclisation as a key step, gives an easy
access to (E)-2-(2-arylvinyl)-3,1-benzoxathiin-4-ones 16-22.
Key words: copper catalysis, 3,1-benzoxathiinones
Palladium-catalysed reactions1,2 have been of great signif-
icance in C-C bond formation and extensively used in the
In order to explore further the scope of copper mediated
cyclisation in the heteroannulation processes, we have re-
cently reacted 3-(2-carbomethoxyphenylthio)prop-1-yne
1 with aryliodides 2-8 under palladium-copper catalysis to
generate the disubstituted alkynes 9-15 in excellent yields
(70-84%). The alkynes were then hydrolysed to the corre-
sponding acids, which on cyclisation with cuprous iodide
(20 mol%), Et3N (2 equiv.) in THF under reflux for 24
hours yielded the (E)-2-(2-arylvinyl)-3,1-benzoxathiin-4-
ones 16-22 in good yields (61-70%) instead of the expect-
ed 3-alkyl (aryl)idene-4,1-benzoxathiepin-5-ones 23. No
last
few
decades
for
carboannulation3
and
heteroannulation4 processes. We have utilised the palladi-
um-catalysed reactions of aryl halides with a nucleophilic
group at the ortho-position and terminal alkynes to gener-
ate various benzofused heterocyclic structures.5 In a dif-
ferent strategy, by using prop-2-ynyloxy or prop-2-
ynylamino aromatic compounds with an ortho-nucleo-
philic group and aryl iodides under palladium-copper-ca-
talysed conditions and subsequent cyclisation of the
disubstituted alkynes generated, we could easily synthe-
sise benzo-fused heterocyclic structures with two hetero-
Reagents (i) (PPh3)2PdCl2 (3.5 mol%); CuI (6 mol%); Et3N; CH3CN (ii) 5 mol dm-3 methanolic KOH (iii) HCl (1:1) (iv) CuI (20 mol%),
Et3N, THF.
Scheme
Synlett 2001 No. 3, 415–417 ISSN 0936-5214 © Thieme Stuttgart · New York

416
N. G. Kundu, B. Nandi
LETTER
Table Palladium-catalysed arylation of 1 and the subsequent cop-
per-catalysed cyclisation leading to 2-(2-arylvinyl)-3,1-benzoxathi-
in-4-ones 16-22
compounds of (Z)-configuration or 7-membered hetero-
cycles were obtained. The structures were established
from spectroscopic data [see under Table; compound 16,
H 6.36 (dd, 1H, J 15.9 Hz, 6.3 Hz, CH=CHAr), 6.92 (d,
1H, J 15.9 Hz, CH=CH-Ar)]. Both cuprous iodide and tri-
ethylamine were found to be essential reagents needed for
the cyclisation step. Absence of either of them did not
yield any benzoxathiinones. Also, 20 mol% of CuI (entry
1) was found to be the optimum amount needed for the cy-
clisation. Any less or more amount of the catalyst led to
decline in yields (entries 2-5). Similarly, 2 equivalents of
Et3N was found to be the optimum (entries 1 and 6) for the
reaction.
Mechanistically, it appears that the disubstituted alkynes
underwent rearrangement to the allenic intermediates8 24.
A nucleophilic attack by the carboxylate ion generated on
the terminal carbon (next to the sulfur atom) of the allenic
group9 gives rise to the (E)-2-(2-arylvinyl)-3,1-benzox-
athiin-4-ones 16-22. Thus, we have described a very gen-
eral and highly regio- and stereoselective procedure for
the synthesis of 2-substituted-3,1-benzoxathiin-4-ones. In
the literature10 only a few methods are available for the
synthesis of these interesting heterocyclic structures. Al-
so, 2-(2-arylvinyl)-3,1-benzoxathiinones are of potential
biological interest (e.g. as possible enzyme inhibitors) be-
cause of the presence of various active functionalities (e.g.
vinyl, lactone and sulfur moieties) in the molecular do-
main. Thus, we believe the procedure we have described
will be of considerable interest to many organic and me-
dicinal chemists.
aTypical reaction for arylation, e.g. synthesis of compound 9. A mix-
ture of p-iodotoluene (2.4 mmol) and 3-(2-carbomethoxyphe-
nylthio)prop-1-yne 1 (2.4 mmol) was stirred with (PPh3)2PdCl2 (0.08
mmol), CuI (0.14 mmol) and triethylamine (9.6 mmol) in acetonitrile
(10 ml) at room temperature for 20 h in an argon atmosphere. After
the removal of solvent and triethylamine, the residue was treated
with water (5 ml) followed by extraction with CHCl3 (3 20 ml).
The organic layer was washed with water (5 ml), dried (anh. Na2SO4)
and the crude product was purified by column chromatography on si-
lica gel (60-120 mesh) with the eluent being CHCl3/ light petroleum
(60-800C) (1:1; v/v) to furnish 9 as a light yellow solid.
References and Notes
bSynthesis of 2-(2-arylvinyl)-3,1-benzoxathiin-4-ones, e.g. synthesis
of compound 16; the disubstituted alkyne 9 (1.0 mmol) was stirred
with a methanolic solution of potassium hydroxide (5 mol dm-3; 20
ml) at room temperature for 2 h. After the removal of methanol under
reduced pressure, the residue was diluted with water (5 ml), acidified
with dilute HCl (1:1) and extracted with diethyl ether (3 20 ml).
The combined organic layer was washed with water (5 ml) and dried
(anh. Na2 SO4). The crude product obtained was then heated under re-
flux with CuI (0.2 mmol) and Et3N (2.24 mmol) in THF (15 ml) in
an argon atmosphere for 24 h. After removal of solvent and Et3N, the
residue was purified by column chromatography on silica gel (60-
120 mesh) with the eluent being CHCl3/light petroleum(60-800C)
(1:1) to furnish 16 as a pale yellow solid.
(1) References on Palladium-catalysed reactions, see: (a). Heck,
R.F. Palladium Reagents in Organic Synthesis, Academic
Press: London 1985. (b) Davies, G.D Jr.; Hallberg, A. Chem.
Rev. 1989, 89, 1433. (c) Tsuji, J. Palladium Reagents and
Catalysts, Wiley: Chichester 1995.
(2) References on palladium-catalysed reactions of terminal
alkynes, see:
(a) Cassar, L.J. Organomet. Chem. 1975, 93, 253. (b) Dieck,
H.A.; Heck, R.F. J. Organomet. Chem. 1975, 93, 256. (c)
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467. (d). Torii, S.; Xu, L.H.; Okumoto, H. Synlett
1992, 575.
cCuI (zero mol%), Et3N (2 equiv.) in cyclisation step iv.
(3) References on carboannulation, see: (a) Trost, B.M.; Tanoury,
G.J.; Lautens, M.; Chan, C.; McPherson, D.T. J. Am. Chem.
Soc. 1994, 116, 4255. (b) Ma, S.; Negishi, E.-i. J. Am. Chem.
Soc. 1995, 117, 6345. (c) Tietze, L.F.; Nobel, T.; Spescha, M.
J. Am. Chem. Soc. 1998, 120, 8971.
(4) References on heteroannulation, see: (a) Arcadi, A.; Cacchi,
S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581. (b)
Bouyssi, D.; Caviechioli, M.; Balme, G. Synlett 1997, 944.
(c) Frederickson, M.; Grigg, R.; Markandu, J.; Thornton-Pett,
M.; Redpath, J. Tetrahedron 1997, 53, 15051. (d) Roesch,
K.R.; Larock, R.C. Org. Lett. 1999, 4, 553. Larock, R.C.
J.Organomet. Chem. 1999, 576, 111.
(5) (a) Kundu, N.G.; Pal, M.; Mahanty, J.S.; Dasgupta, S.K. J.
Chem. Soc., Chem. Commun. 1992, 41. Kundu, N.G.; Pal, M.
Mahanty, J.S.; De, M. J. Chem. Soc., Perkin Trans. I 1997,
2815. (b) Kundu, N.G.; Pal, M. J. Chem. Soc., Chem.
Commun. 1993, 86. Kundu, N.G.; Pal, M.; Nandi, B. J. Chem.
dCuI (10 mol%), Et3N (2 equiv.).
eCuI (30 mol%), Et3N (2 equiv.).
f CuI (40 mol%), Et3N (2 equiv.).
g CuI (20 mol%), Et3N (2.5 equiv.).
hSatisfactory spectroscopic data (IR and 1H NMR) were obtained for
all the compounds synthesised : typical data, 9, mp 92 °C; IR
max
1
1705, 1585.4, 1566.1, 1508.2 cm-1, H NMR (300 MHz, CDCl3)
H
2.3 (s, 1H, ArCH3), 3.88 (s, 2H, S-CH2), 3.9 (s, 3H, COOCH3), 7.05
(d, 2H, J 8.1 Hz, ArH), 7.16-7.26 (m, 3H, ArH), 7.45-7.55 (m, 2H,
ArH), 7.98 (d, 1H, J 7.5 Hz, 1.2 Hz, ArH). 16, light yellow solid, mp
1
89 °C; IR
1728.1, 1589.2, 1512.2 cm-1. H NMR (300 MHz,
max
CDCl3) H 2.35 (s, 3H, ArCH3), 6.22 (d, 1H, J = 6.3 Hz, S-CH), 6.36
(dd, 1H, J1 = 15.9 Hz, J2 = 6.3 Hz, CH=CHAr), 6.92 (d, 1H, J = 15.9
Hz, CH=CHAr), 7.16 (d, 2H, J = 7.8 Hz, ArH), 7.31-7.37 (m, 4H,
ArH), 7.5 (td, 1H, J1 = 9 Hz, J2 = 1.2 Hz, ArH), 8.2 (d, 1H, J 8.1 Hz,
ArH). Elemental analyses were satisfactory.
Synlett 2001, No. 3, 415–417 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Soc., Perkin Trans. I 1998, 561. (c) Kundu, N.G.; Mahanty,
Novel Heteroannulation through Copper Catalysis
417
7.77-7.81 (m, 3H, ArH), 8.08(dd, 1H, J1 = 7.6 Hz, J2 = 1.5 Hz,
ArH). 13C NMR (75 MHz, CDCl3) C 89.59, 97.98, 124.99,
125.24, 126.44, 126.76, 126.9, 127.02, 127.99, 128.1, 128.17,
128.78, 130.69, 132.16, 132.78, 133.27, 133.89,, 141.57,
J.S.; Das, P.; Das, B. Tetrahedron Lett. 1993, 34, 1625.
Mahanty, J.S.; De, M.; Das, P.; Kundu, N.G. Tetrahedron
1997, 53, 13397. (d) Khan, M.W.; Kundu, N.G. Synlett 1997,
1435. Khan, M.W.; Kundu, N.G. Synlett 1999, 435.
(6) (a) Chowdhury, C.; Kundu, N.G. Chem. Commun. 1996,
1067; Chowdhury, C.; Chaudhuri, G.; Guha, S.; Mukherjee,
A.K.; Kundu, N.G. J. Org. Chem. 1998, 63, 1863. (b)
Chaudhuri, G.; Chowdhury, C.; Kundu, N.G. Synlett 1998,
1273. (c) Chaudhuri, G.; Kundu, N.G. J. Chem. Soc., Perkin
Trans. I, 2000, 775.
(7) Nandi B. and Kundu, N.G. Org. Lett. 2000, 2, 235.
(8) Allenic intermediates 24 were formed in all cases due to
alkaline hydrolysis of 9-15. The crude allenes were used for
cyclisation to benzoxathiinones 16-12. An allenic compound
24 (Ar = 2-naphthyl) was isolated and characterised fully
168.67, 209.36. 13C NMR (75 MHz, CDCl3, DEPT 135)
C
89.3, 97.69, 124.7, 124.95, 126.15, 126.47, 126.61, 126.72,
127.81, 127.88, 128.5, 131.87, 132.5
(9) The nucleophilic attack by the carboxylate ion is assisted by
coordination of the Cu+ with the allenic bond; for addition of
carboxylates to allenes see: (a) Marshall, J.A.; Wolf, M.A.:
Wallace, E. J. Org. Chem. 1997, 62, 367. (b) Zimmer, R.;
Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000,
100(8), 3067.
(10) Landquist, J.K. Six-membered Ring Systems in
Comprehensive Organic Chemistry, 1st ed., Vol. 4; D. Barton,
W.D. Ollis, Eds.; Pergamon Press: Oxford, 1979; pp 1051-
1056.
from the alkaline hydrolysis of 12, mp 154 °C. IR. (KBr)
max
1932.5, 1678, 1596.9, 1585.4 cm-1; 1H NMR (300 MHz,
CDCl3) H 6.49(d, 1H, J = 6 Hz, S-CH=C=CH), 6.62 (d, 1H,
J = 6Hz, S-CH=C=CH) 7.24 (td, 1H, J1 = 7.2 Hz, J2 = 1.2
Hz,ArH), 7.44-7.53 (m, 4H, ArH), 7.66-7.71 (m, 2H, ArH),
Article Identifier:
1437-2096,E;2001,0,03,0415,0417,ftx,en;L22100ST.pdf
Synlett 2001, No. 3, 415–417 ISSN 0936-5214 © Thieme Stuttgart · New York