Regioselective synthesis of functionalized 3-(methylthio)phenols by the first formal [3+3] cyclocondensations of 1,3-bis(trimethylsilyloxy)-1,3- butadienes with 1,1-bis(methylthio)-1-en-3-ones

Article abstract of DOI:10.1055/s-2008-1077977

The [3+3] cyclocondensation of 1,3-bis(silyl enol ethers) with 1,1-bis(methylthio)-1-en-3-ones results in the regioselective formation of 3-(methylthio)phenols. The products represent useful synthetic building blocks, which are not readily available by ot

Full text of DOI:10.1055/s-2008-1077977

LETTER
2331
Regioselective Synthesis of Functionalized 3-(Methylthio)phenols by the First
Formal [3+3] Cyclocondensations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes
with 1,1-Bis(methylthio)-1-en-3-ones
S
ynthesis of Functiona
a
lized 3-(Me
t
thylthi
h
o)phenols ias Lubbe,a Renske Klassen,a Tiana Trabhardt,a Alexander Villinger,a Peter Langer*a,b
a
b
Received 21 April 2008
O
SMe
SMe
R2
2a–n
O
Abstract: The [3+3] cyclocondensation of 1,3-bis(silyl enol ethers)
with 1,1-bis(methylthio)-1-en-3-ones results in the regioselective
formation of 3-(methylthio)phenols. The products represent useful
synthetic building blocks, which are not readily available by other
methods.
i
R2
R1
R1
1a–n
Scheme 1 Synthesis of 1,1-bis(methylthio)-1-en-3-ones 2a–n.
Reagents and conditions: (i) 1. THF, KOt-Bu, 15 min, 20 °C; 2. THF,
CS2, MeI, 20 °C, 10 h.
Key words: arenes, cyclizations, regioselectivity, silyl enol ethers
arenes.18 For example, we have reported formal [3+3] cy-
clocondensations of 1,3-bis(silyl enol ethers) with
1,1,3,3-tetraalkoxypropanes.19 3-Alkoxy-1-aryl-2-en-1-
ones and 3-alkoxy-1-trifluoromethyl-2-en-1-ones have
also been successfully applied in [3+3] cyclocondensa-
tions with 1,3-bis(silyl enol ethers).20 In most reactions
developed so far, the products – functionalized phenols –
contain no functional group located at carbon atoms C-3
and C-5. This is a severe limitation to this methodology,
since most naturally occurring phenols do contain such a
functional group, since they are often derived from
polyketides. Recently, we reported a regioselective syn-
thesis of functionalized resorcins by cyclization of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes with 3,3-dimeth-
oxypentanoyl chloride.21 Herein, we report a new and
convenient synthesis of 3-(methylthio)phenols by what
are, to the best of our knowledge, the first cyclocondensa-
tions of 1,3-bis(silyl enol ethers) with 1,1-bis(methyl-
thio)-1-en-3-ones. Noteworthy, the functionalized 3-
(methylthio)phenols prepared are not readily available by
other methods.
Functionalized methylthio-substituted arenes, such as 2-
acyl-3-(methylthio)phenols, are of considerable impor-
tance as building blocks for the synthesis of pharmaceuti-
cals and fine chemicals. The methylthio group of these
compounds has been oxidized to sulfoxides1 and sul-
fones.2 Other synthetic transformations include Grignard
reactions3 and reductions with LiAlH4.4 2-(Methyl-
thio)benzoates have been transformed into thioindoxyls,
2-alkylidenebenzo[b]thiophen-3-ones (thioaurones), and
benzo[b]thiophenes. These transformations rely on the
deprotonation of the methylthio group and subsequent cy-
clization by attack of the carbanion onto a neighboring es-
ter or amide group.5,6 2-(Methylthio)benzoates have been
employed also as starting materials for the synthesis of
benzo[d]isothiazoles,7 3H-benzothiazol-2-ones,8 and 2-
(tert-butyl)-1,2-benzothiazol-3(2H)-ones.9 A 4-oxo-1,4-
dihydro-quinoline-3-carboxylate has been prepared by in-
tramolecular nucleophilic replacement of the thiomethyl
group, located at a benzene moiety, by an amino group.10
Thiochromen-4-ones have been prepared by cleavage of
the thiomethyl group and subsequent attack of the sulfur
atom onto an ynone.11 2-Acyl-3-(methylthio)phenols have
been prepared by Reformatzky reaction of ethyl bromo-
acetate with 1,1-bis(methylthio)-1-en-3-ones,12 based on
the directed ortho metalation (DoM) using n-BuLi,13 by n-
BuLi-mediated reaction of carbon dioxide with 1-meth-
oxy-3-(methylthio)benzene,14 and by [5+1] annulations of
nitro compounds.15
The required starting materials, 1,1-bis(methylthio)-1-en-
3-ones 2a–n, were prepared, following a known proce-
dure,22 by base-mediated reaction of ketones 1a–n with
carbon disulfide and methyl iodide (Scheme 1, Table 1).
The TiCl4-mediated cyclocondensation of 1,1-bis(meth-
ylthio)-1-en-3-ones 2a–n with 1,3-bis(silyl enol ethers)
3a–g afforded the 3-(methylthiophenols) 4a–z in 37–90%
yield (Scheme 2, Table 2).23 The best yields were ob-
tained for reactions of open-chain, alkyl-substituted 1,1-
bis(methylthio)-1-en-3-ones 2a–e with 1,3-bis(silyl enol
ethers) 3b–d derived from unsubstituted alkyl acetoace-
tates. The yields slightly dropped for the (less-reactive)
acetylacetone-derived diene 3e. The yields also dropped
for dienes 3a,f,g containing a terminal substituent. The
yields of cyclic and aryl-substituted 1,1-bis(methylthio)-
Chan and coworkers developed16 a convenient synthesis
of salicylates by cyclocondensation of 1,3-bis(silyl enol
ethers)17 with 3-silyloxy-2-en-1-ones. In recent years, we
have extended the scope of this chemistry and studied its
application to the synthesis of a variety of functionalized
SYNLETT 2008, No. 15, pp 2331–2333
1
5
.0
9
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077977; Art ID: D12608ST
© Georg Thieme Verlag Stuttgart · New York

2332
M. Lubbe et al.
LETTER
Table 1 Synthesis of 2a–n
Table 2 Synthesis of 3-(Methylthio)phenols 4a–z
2
R1
R2
H
Yield of 2 (%)a
2
3
4
R1
R2 R3
R4
Yieldof
4 (%)a
2a
2b
2c
2d
2e
2f
Me
Et
70
46
50
50
70
61
62
76
87
61
83
85
70
2a 3a 4a Me
2b 3b 4b Et
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OEt
65
89
90
80
Me
Me
Et
Me
Me
Me
Me
Et
n-Pr
Me
Me
t-Bu
2b 3c
4c
Et
OMe
OMe
2c
2c
3c
3d 4e
4d n-Pr
Me
H
n-Pr
O(CH2)2OMe 80
OEt 81
O(CH2)2OMe 76
2d 3b 4f
Me
2g
2h
2i
-(CH2)4-
-(CH2)5-
-(CH2)6-
2d 3d 4g Me
Et
2e
2e
2f
3e
3c
3e
4h Me
4i Me
4k t-Bu
Me
Me
H
Me
70
82
50
OMe
Me
2k
2l
Ph
H
H
H
Cl
4-ClC6H4
4-FC6H4
4-FC6H4
2g 3d 4l
2g 3b 4m
2h 3b 4n
-(CH2)4-
-(CH2)4-
-(CH2)5-
-(CH2)5-
-(CH2)6-
-(CH2)6-
O(CH2)2OMe 40
2m
2n
OEt
OEt
OMe
OEt
Me
55
70
62
61
50
60
45
37
50
76
62
62
88
63
a Yields of isolated products.
2h 3c
4o
TMSO
R3
OTMS
R4
2i
2i
3b 4p
OH
O
3e
4q
4r
4s
4t
R3
R1
3a–g
+
R4
SMe
i
2k 3c
Ph
H
H
H
H
H
H
OMe
OMe
O
SMe
SMe
R1
2l
2l
2l
3c
3f
4-ClC6H4
4-ClC6H4
R2
R2
2a–n
OMe OMe
4a–z
3b 4u 4-ClC6H4
4v 4-FC6H4
2m 3b 4w 4-FC6H4
H
H
H
OEt
MeSH
TiCl4
TMSCl
O
2m 3c
OMe
OEt
OH
O
TMSO
R3
R4
R3
R1
R4
SMe
SMe
2n 3a 4x 4-FC6H4 Cl Me
OMe
OMe
OEt
SMe
SMe
OTiCl3
R1
2n 3c
4y 4-FC6H4 Cl
H
R2
R2
2n 3g 4z
4-FC6H4 Cl Et
TMSOTiCl3
B
A
a Yields of isolated products.
Scheme 2 Synthesis of 3-(methylthio)phenols 4a–z. Reagents and
conditions: (i) 1. TiCl4, –78 °C to 20 °C, 14 h; 2. HCl (10%).
by extrusion of methylthiol (Scheme 2). Noteworthy, the
regioselectivity (initial 1,2-addition) is opposite to the one
observed for cyclocondensations of 1,3-bis(silyl enol
ethers) with 3-alkoxy- and 3-silyloxy-2en-1-ones (initial
1,4-addition).18
1-en-3-ones (2g–i and 2k–n) were lower than those of
open-chain, alkyl-substituted derivatives (except for 4y
which was isolated in 88% yield). The structures of the
products were elucidated by spectroscopic methods
(NOESY, HMQC, HMBC). The structure of 4m was in-
dependently confirmed by X-ray crystal structure analysis
(Figure 1).24
In conclusion, we reported a convenient synthesis of func-
tionalized 3-(methylthio)phenols by the first [3+3] cyclo-
condensations of 1,3-bis(silyl enol ethers) with 1,1-
bis(methylthio)-1-en-3-ones. The products represent use-
ful synthetic building blocks, which are not readily avail-
able by other methods.
The formation of the products can be explained by TiCl4-
mediated attack of the terminal carbon atom of 3 onto the
carbonyl group of 2 (intermediate A), cyclization by SN¢
reaction (intermediate B), and subsequent aromatization
Synlett 2008, No. 15, 2331–2333 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized 3-(Methylthio)phenols
2333
(13) Cipollina, J. A.; Ruediger, E. H.; New, J. S.; Wire, M. E.;
Shepherd, T. A.; Smith, D. W.; Yevich, J. P. J. Med. Chem.
1991, 34, 3316.
(14) Cabiddu, S.; Maccioni, A.; Piras, P. P.; Plumitallo, A. Gazz.
Chim. Ital. 1981, 111, 123.
(15) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am.
Chem. Soc. 2005, 127, 4578.
(16) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
(17) For a review of 1,3-bis(silyl enol ethers) in general, see:
Langer, P. Synthesis 2002, 441.
(18) For a review of [3+3] cyclocondensations of 1,3-bis(silyl
enol ethers) with 1,3-dielectrophiles, see: Feist, H.; Langer,
P. Synthesis 2007, 327.
(19) (a) Sher, M.; Ahmed, Z.; Rashid, M. A.; Fischer, C.; Langer,
P. J. Org. Chem. 2007, 72, 6284. (b) Mamat, C.; Büttner,
S.; Trabhardt, T.; Fischer, C.; Langer, P. J. Org. Chem. 2007,
72, 6273.
(20) Mamat, C.; Pundt, T.; Dang, T. H. T.; Klassen, R.; Reinke,
H.; Köckerling, M.; Langer, P. Eur. J. Org. Chem. 2008,
492.
Figure 1 Crystal structure of 4m
Acknowledgment
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
(21) Sher, M.; Langer, P. Synlett 2008, 1050.
(22) Potts, K. T.; Winslow, P. A. Synthesis 1987, 839.
(23) Typical Procedure: Synthesis of Ethyl 4-Ethyl-6-
hydroxy-3-methyl-2-(methylthio)benzoate (4b)
To a solution of 2b (0.190 g, 1.0 mmol) and 3b (0.549 g, 2.0
mmol) in CH2Cl2 (2 mL) was added TiCl4 (0.11 mL, 1.0
mmol) at –78 °C under argon. The temperature of the
reaction mixture was allowed to rise to 20 °C during 14 h,
and an aq HCl solution (10%, 10 mL) was added. The
organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in
vacuo. After column chromatography (SiO2, heptane–
EtOAc = 10:1), 4b was obtained as a colorless solid (227
mg, 89%); mp 120–121 °C; Rf = 0.39 (heptane–
EtOAc = 3:1). 1H NMR (250 MHz, CDCl3): d = 9.06 (s, 1 H,
OH), 6.78 (s, 1 H, ArH), 4.43 (q, 3J = 7.1 Hz, 2 H, OCH2),
2.60 (q, 3J = 7.5 Hz, 2 H, ArCH2), 2.45 (s, 3 H, ArCH3), 2.28
(s, 3 H, SCH3), 1.41 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 1.18 (t,
3J = 7.5 Hz, 3 H, ArCH2CH3). 13C NMR (300 MHz, CDCl3):
d = 170.2 (C=O), 156.9 (CO), 148.8, 136.2, 132.7, 117.3
(CAr), 116.9 (CHAr), 61.8 (OCH2), 27.6 (ArCH2), 20.0, 16.2,
14.0, 13.8 (CH3). IR (ATR): n = 3298 (OH), 1699 (C=O)
cm–1. MS (EI, 70 eV): m/z (%) = 254 (39) [M+], 209 (21),
208 (100), 193 (8), 180 (27), 165 (32). Anal. Calcd for
C13H18O3S (254.10): C, 61.39; H, 7.13. Found: C, 61.35; H,
7.27.
References and Notes
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(4) Ohkata, K.; Takee, K.; Akiba, K.-y. Bull. Chem. Soc. Jpn.
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(5) Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.; Demontis, S.;
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(24) CCDC-685823 contains all crystallographic details of this
publication and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(1223)336033; or
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deposit@ccdc.cam.ac.uk.
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