Regioselective synthesis of 2-arylthio-4-methoxybenzoates by formal [3+3] cyclocondensations of 3-arylthio-1-trimethylsilyloxybuta-1,3-dienes with 3-oxo-orthoesters

Article abstract of DOI:10.1055/s-0029-1217177

A variety of 2-arylthio-4-methoxybenzoates are regioselectively prepared by the first formal [3+3] cyclocondensations of 3-arylthio-1- trimethylsilyloxybuta-1,3-dienes with 3-oxo-orthoesters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217177

LETTER
1477
Regioselective Synthesis of 2-Arylthio-4-methoxybenzoates by Formal [3+3]
Cyclocondensations of 3-Arylthio-1-trimethylsilyloxybuta-1,3-dienes with
3-Oxo-orthoesters
S
ynthesis of 2-Arylthio
u
-4-methoxy
h
s
ammad Imran,a Inam Iqbal,a Peter Langer*a,b
a
b
Received 11 December 2008
cyclization–homo-Michael’ reaction of 3-arylthio-1-tri-
methylsilyloxybuta-1,3-dienes with 1,1-diacylcyclopro-
panes.14 Recently, we have studied the synthesis of 4-
methoxysalicylates by cyclization of 1,3-bis(silyloxy)buta-
1,3-dienes with 3-oxo-orthoesters.15 Herein, we report a
convenient synthesis of 2-arylthio-4-methoxybenzoates
by what are, to the best of our knowledge, the first [3+3]
cyclocondensations of 3-oxo-orthoesters with 3-arylthio-
1-trimethylsilyloxybuta-1,3-dienes. This method provides
a regioselective approach to a wide range of novel diaryl
sulfides which are not readily available by other methods.
In contrast to the C–S coupling reactions outlined above,
our method relies on the assembly of one of the two arene
moieties.
Abstract: A variety of 2-arylthio-4-methoxybenzoates are regio-
selectively prepared by the first formal [3+3] cyclocondensations of
3-arylthio-1-trimethylsilyloxybuta-1,3-dienes with 3-oxo-ortho-
esters.
Key Words: arenes, cyclizations, diaryl sulfides, regioselectivity,
silyl enol ethers
Diaryl sulfides are of pharmacological importance and are
found in many natural products. This includes, for exam-
ple, the lissoclibadins, dibenzothiophenes, cyclic sulfides,
varacins (lissoclinotoxins), and related natural products.1
Diaryl sulfides are available by reaction of arenes with
sulfur2 or sulfur dichloride,3 by condensation of organo-
metallic reagents with chlorophenylsulfides4 or by base-
mediated reactions of thiophenols with chloroarenes.5
However, the competing formation of polysulfides and
the (in several cases) low regioselectivities are severe
drawbacks of these classic synthetic approaches. In recent
years, a number of transition-metal-catalyzed6 and metal-
free7 carbon–sulfur coupling reactions have been devel-
oped which allow the formation of diaryl sulfides under
mild conditions. However, reactions of sterically encum-
bered substrates are often difficult or not possible at all. In
addition, the synthesis of the starting materials, substitut-
ed aryl halides or triflates, can be a difficult and tedious
task.
The known 3-oxo-orthoesters 1a,b were prepared, follow-
ing literature procedures, by condensation of 1,1-dichloro-
ethene with acetyl and propionyl chloride, respectively,
and subsequent reaction of the 3,3,3-trichloro-ketones
thus formed with methanol.16 The known 3-arylthio-1-tri-
methylsilyloxybuta-1,3-dienes 2a–i were prepared, again
according to the literature, from methyl acetoacetate,
methyl 3-oxopentanoate, and various thiophenols in two
steps.13,17
The TiCl4-mediated cyclization of 1a with 3-phenylthio-
1-trimethylsilyloxybuta-1,3-diene 2a resulted in regiose-
lective formation of the 2-phenylthio-4-methoxybenzoate
3a (Scheme 1).18 The formation of 2-phenylthio-6-meth-
oxybenzoate, a regioisomer of 3a, was not observed. The
best yields were obtained when a stoichiometric ratio of
2a/1a/TiCl4 = 1.0:1.5:1.5 was used, and when the reac-
tion was carried out in a fairly concentrated solution [c (1a)
= 0.33 M].
An alternative approach to diaryl sulfides is based on the
use of sulfur-containing building blocks in cyclization
reactions. Hilt and coworkers reported a convenient ap-
proach to diaryl sulfides by cobalt(I)-catalyzed [4+2] cy-
cloaddition of alkynyl sulfides with 1,3-butadienes.8
Recently, we have studied9 the synthesis of 3- and 5-
(arylthio)salicylates by TiCl4-mediated formal [3+3]
cyclizations10 of 1,3-bis(silyloxy)buta-1,3-dienes11 with
3-silyloxy-2-en-1-ones.12 Chan et al. reported the synthe-
sis of 2-(phenylthio)benzoates by TiCl4-mediated [3+3]
cyclization of 3-silyloxy-2-en-1-ones with 1-methoxy-3-
phenylthio-1-trimethylsilyloxybuta-1,3-diene.13 We have
recently reported the synthesis of 5-chloroethyl-2-
(arylthio)benzoates by TiCl4-mediated domino ‘[3+3]
The formation of 3a can be explained by TiCl4-mediated
attack of the terminal carbon atom of diene 2a onto the
orthoester to give intermediate A, subsequent cyclization
by attack of the central carbon atom of 2a onto the carbo-
nyl group (intermediate B), aromatization (intermediates
C and D) and hydrolysis upon aqueous workup. Alterna-
tively, the cyclization might proceed by TiCl4-mediated
extrusion of methanol from 1a to give 4,4-dimethoxybut-
3-en-2-one. Attack of the terminal carbon atom of 2a onto
the latter (conjugate addition) and subsequent cyclization
would lead to the final product. This process would follow
a mechanism earlier suggested for the cyclization of
SYNLETT 2009, No. 9, pp 1477–1479
x
x.
x
x.
2
0
0
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Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217177; Art ID: D41208ST
© Georg Thieme Verlag Stuttgart · New York

1478
M. Imran et al.
LETTER
PhS
OTMS
OMe
Table 1 Synthesis of 3a–l
SPh
O
1
2
3
R1
R2
Ar
Yield of 3
2a
+
(%)a
OMe
TiCl4
i
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
2
3a
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
Ph
55
50
46
51
45
40
46
37
35
37
38
40
OMe
O
MeO
Me
MeO
MeO
2b
2c
2d
2e
2f
H
3-MeC6H4
3-ClC6H4
4-MeC6H4
4-EtC6H4
4-FC6H4
4-ClC6H4
Ph
3a (55%)
Me
1a
H
– TiOCl2
– HCl
+ H2O
TiCl4,
TMSOMe
2a
H
(HO)Cl3Ti
SPh
H
O
PhS
O
H
OMe
OMe
Me
MeO
MeO
2g
2h
2i
3g
3h
3i
H
MeO
Me
TiCl4
O
D
A
Me
Me
H
4-EtC6H4
3-ClC6H4
4-MeC6H4
4-ClC6H4
[HCl]
SPh
HCl
O
2c
2d
2g
3j
O
SPh
3k
3l
Et
H
[HCl]
OMe
Me
OTiCl3
OMe
Me
Et
H
MeO
MeO
MeO
MeOH
a Isolated yields.
OTiCl3
B
C
Scheme 1 Possible mechanism of the formation of arene 3a.
Reagents and conditions: i: 1) TiCl4 (1.0 equiv), CH2Cl2, –78 °C to 20
°C, 20 h; 2) HCl (10%).
orthoesters. The scope and applications of this methodol-
ogy are currently studied in our laboratory.
Acknowledgment
1,3-bis(trimethylsilyloxy)buta-1,3-dienes with 3-alkoxy-
and 3-silyloxy-2-en-1-ones.10,12
Financial support by the State of Pakistan (scholarship for I.I.) and
by the State of Mecklenburg-Vorpommern (scholarship for M.I.) is
gratefully acknowledged.
The TiCl4-mediated cyclization of 3-oxo-orthoesters 1a,b
with 3-arylthio-1-trimethylsilyloxybuta-1,3-dienes 2a–i
afforded the novel 2-arylthio-4-methoxybenzoates 3a–l
(Scheme 2, Table 1). A wide range of products could be
successfully prepared. Various substituents can be intro-
duced at carbon atoms C3 and C6 of the benzoate moiety
(substituents R1 and R2) and at the arylthio group. The
moderate yields can be explained by partial hydrolysis of
the starting materials and TiCl4-mediated oxidative
dimerization of the diene. In some reactions a small
amount of hydrolyzed starting material was recovered.
References and Notes
(1) (a) Behar, V.; Danishefsky, S. J. J. Am. Chem. Soc. 1993,
115, 7017. (b) Toste, F. D.; Still, I. W. J. J. Am. Chem. Soc.
1995, 117, 7261. (c) Davidson, B. S.; Molinski, T. F.;
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M. L.; Reents, W. D. Tetrahedron Lett. 1982, 23, 373.
(h) Hosoya, Y.; Adachi, H.; Nakamura, H.; Nishimura, Y.;
Naganawa, H. Tetrahedron Lett. 1996, 37, 9227.
ArS
OTMS
OMe
R2
SAr
O
2a–i
R2
i
OMe
+
MeO
R1
O
OMe
(2) See, for example: (a) Glass, H. B.; Reid, E. E. J. Am. Chem.
Soc. 1929, 51, 3428. (b) Dougherty, G.; Hammond, P. D.
J. Am. Chem. Soc. 1935, 57, 117. (c) For the
3a–l
R1
MeO
MeO
1a,b
trifluoromethanesulfonic acid catalyzed sulfurization of
cycloalkanes, see:Olah, G. A.; Wang, Q.; Prakash, G. K. S.
J. Am. Chem. Soc. 1990, 112, 3697.
Scheme 2 Synthesis of arenes 3a–l. Reagents and conditions: i: 1)
TiCl4 (1.0 equiv), CH2Cl2, –78 °C to 20 °C, 20 h; 2) HCl (10%).
(3) Kemp, D. S.; Carey, R. I.; Dewan, J. C.; Galakatos, N. G.;
Kerkman, D.; Leung, S.-L. J. Org. Chem. 1989, 54, 1589;
and references cited therein.
(4) Chua, M.; Hoyer, H. Z. Naturforsch., B: J. Chem. Sci. 1965,
20, 416.
In conclusion, we have reported a convenient and regio-
selective synthesis of a variety of 2-arylthio-4-methoxy-
benzoates by formal [3+3] cyclocondensations of 3-
arylthio-1-trimethylsilyloxybuta-1,3-dienes with 3-oxo-
Synlett 2009, No. 9, 1477–1479 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Arylthio-4-methoxybenzoates
1479
(5) (a) Baxter, I.; Ben-Haida, A.; Colquhoun, H. M.; Hodge, P.;
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Lüers, S.; Harms, K. J. Org. Chem. 2004, 69, 624.
(9) (a) Rashid, M. A.; Reinke, H.; Langer, P. Tetrahedron Lett.
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Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2008, 64,
3782.
(10) For a review of [3+3] cyclizations, see: Feist, H.; Langer, P.
Synthesis 2007, 327.
(11) For a review of 1,3-bis(silyloxy)buta-1,3-dienes, see:
Langer, P. Synthesis 2002, 441.
(12) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
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52, 110.
(17) Iqbal, I.; Imran, M.; Villinger, A.; Langer, P. Synthesis 2009,
297.
(18) General Experimental Procedure
To a CH2Cl2 soln (3 mL/mmol of 1) of 2 (1.5 mmol) and 1
(2.25 mmol) was added TiCl4 (2.25 mmol) at –78 °C. The
solution was allowed to warm to 20 °C within 20 h. To the
solution was added HCl (10%, 25 mL). The organic and the
aqueous layer were separated and the latter was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
dried (Na2SO4), filtered, and the filtrate was concentrated in
vacuo, and the residue was purified by chromatography
(SiO2, EtOAc–n-heptane = 1:9).
4-Methoxy-6-methyl-2-(3-tolylsulfanyl)benzoic Acid
Methyl Ester (3b)
Starting with 1a (2.25 mmol), 2b (1.5 mmol), and TiCl4
(2.25 mmol), 3b was isolated as a yellow oil (226 mg, 50%).
1H NMR (250 MHz, CDCl3): d = 2.25 (s, 3 H, CH3), 2.30 (s,
3 H, CH3), 3.69 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 6.57–
7.39 (m, 6 H, Ar). 13C NMR (63 MHz, CDCl3): d = 20.4
(CH3), 21.2 (CH3), 51.9 (OCH3), 55.2 (CH3O), 114.1, 114.5,
(CHAr), 126.9, 128.3 (C), 129.4, 131.5, 132.1, 133.0 (CHAr),
138.3, 139.1, 140.1, 146.9, 168.8 (C). IR (KBr): n = 2998
(w), 2947 (w), 2834 (w), 2735 (w), 2570 (w), 1724 (s), 1589
(s), 1564 (m), 15560 (m), 1471 (m), 1426 (m), 1380 (w),
1302 (m), 1264 (s), 1217 (s), 1187 (m), 1136 (s), 1090 (s),
1047 (s), 998 (m), 960 (m), 776 (s), 691 (s), 608 (m). MS
(EI): m/z (%) = 302 (100) [M+], 272 (11), 271 (61), 270 (21),
269 (86), 256 (18), 255 (49),228 (17), 227 (13), 184 (15),
121 (3), 91 (4), 65 (5). HRMS (EI): m/z calcd for
C17H18O2O3S [M+]: 302.09712; found: 302.097152.
(14) Rashid, M. A.; Rasool, N.; Iqbal, I.; Imran, M.; Langer, P.
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2008, 2671.
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Jones, E. R. H.; Julia, M. J. Chem. Soc. 1949, 1434.
(c) Searles, S.; Sanchez, R. A.; Soulen, R. L.; Kundinger,
Synlett 2009, No. 9, 1477–1479 © Thieme Stuttgart · New York

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