syn-2,3-Disubstituted-2,3-dihydro-1,4-benzoxathiin rings: Preparation from quinone ketals and 2-mercaptoethanols

Article abstract of DOI:10.1016/j.tetlet.2004.05.047

A general method for the preparation of syn-2,3-disubstituted-2,3-dihydro- 1,4-benzoxathiin rings from 2-mercaptoethanols and quinone ketals is presented. This ring system is produced by Michael addition of a 2-mercaptoethanol to a quinone ketal, followed by cyclization of the initial Michael adduct, and subsequent aromatization to afford a syn-2,3-disubstituted-1,4-benzoxathiin in fair to good chemical yield. Several chiral syn-2,3-disubstituted-2,3-dihydro-1, 4-benzoxathiin rings were prepared with this method from enantioenriched 2-mercaptoethanols. No loss of enantiopurity was observed.

Full text of DOI:10.1016/j.tetlet.2004.05.047

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5429–5432
syn-2,3-Disubstituted-2,3-dihydro-1,4-benzoxathiin rings:
preparation from quinone ketals and 2-mercaptoethanolsq
a,
a
b
Peter G. Dormer,a,* Amude M. Kassim, Johnnie L. Leazer, Jr., Fengrui Lang,
*
Feng Xu,a Kimberly A. Savary,a Edward G. Corley,a Lisa DiMichele,a Jimmy O. DaSilva,a
Anthony O. King,a David M. Tschaena and Robert D. Larsena
aDepartment of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Process Research, Merck Research Laboratories, 466 Devon Park Dr. Wayne, PA 19087, USA
Received 11 March 2004; revised 9 May 2004; accepted 11 May 2004
Abstract—A general method for the preparation of syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings from 2-mercapto-
ethanols and quinone ketals is presented. This ring system is produced by Michael addition of a 2-mercaptoethanol to a quinone
ketal, followed by cyclization of the initial Michael adduct, and subsequent aromatization to afford a syn-2,3-disubstituted-1,4-
benzoxathiin in fair to good chemical yield. Several chiral syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings were prepared
with this method from enantioenriched 2-mercaptoethanols. No loss of enantiopurity was observed.
Ó 2004 Elsevier Ltd. All rights reserved.
The 2,3-dihydro-1,4-benzoxathiin ring system 1 is a
useful scaffold for the synthesis of selective estrogen
receptor modulators (SERM).1 Derivatives of this ring
core are of interest for treatment of disorders such as
hypertension, hot flashes, osteoporosis, endometriosis,
vaginal dryness, breast cancer, and uterine cancer in
post-menopausal women.1;2 Few examples, which report
the preparation of 2,3-dihydro-1,4-benzoxathiins have
appeared in the literature. Most deal with unsubsti-
tuted,3 monosubstituted,4;5d or 2,3-anti-disubstituted-
2,3-dihydro-1,4-benzoxathiins.5 Relatively few examples
for the preparation of syn-2,3-disubstituted-2,3-dihydro-
1,4-benzoxathiins have appeared in the open litera-
ture.1a;5d;6
approach is often problematic.6a Recently, Kim et al.1a
and Dininno et al.1b;c reported the dehydrative reductive
cyclization of alpha-thioketones to provide 2,3-syn-di-
hydro-1,4-benzoxathiins in good yield and selectivity.
As part of a program directed toward the synthesis of a
novel SERM, we required a practical route to syn-2,3-
dihydro-1,4-benzoxathiins 1. Herein, we report a novel
methodology to prepare syn-2,3-dihydro-1,4-benzoxa-
thiins and demonstrate its synthetic utility in the prep-
aration of racemic and chiral dihydrobenzoxathiins
1a–f. Retrosynthetically, 1 might arise from enone
2 after aromatization (Scheme 1). Enone 2 could in turn
arise from 4 and 5 through Michael addition and
cyclization, respectively.
Preparation of the syn-isomer is typically accomplished
via a Diels–Alder cyclization of an ortho-thioquinone
with an olefin, however regioisomer formation in this
Condensation of 4a7 with dimethyl ketal 5a (R@H)8 in
methanol (Scheme 2) with catalytic triethylamine affor-
ded a ꢀ1.6:1 mixture of diastereomers 6 and 7, which
could be separated by chromatography (55%). To our
disappointment, when this mixture was treated with
trifluoroacetic acid (TFA), only a small amount of 1a
was produced. Independent treatment of the major
Michael diastereomer 6 with TFA afforded only small
amount of 1a along with ketals 8 and 9 (>20:1); these
could be isolated from the reaction mixture by silica gel
chromatography.
Keywords: Quinone ketal; 2-Mercaptoethanol; Michael addition; 2,3-
Dihydro-1,4-benzoxathiin.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.047
* Corresponding authors. Tel.: +1-732-594-0201; fax: +1-732-594-9456
(P.G.D.); tel.: +1-732-594-1873; fax: +1-732-594-1499 (A.M.K.);
e-mail addresses: peter_dormer@merck.com; amude_kassim@
merck.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.047

5430
P. G. Dormer et al. / Tetrahedron Letters 45 (2004) 5429–5432
Table 1. Synthesis of syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxa-
thiins
HO
R
S
Ar1
Ar2
O
S
Ar1
Ar2
O
R3
O
O
R
SH
MeO
HO
R
S
Ar1
Ar2
1
2
+
Ar2
MeO
MeO
Ar1
O
Ar1
S
Ar2
OH
OH
O
OH
4a-e
R
H
Ar1
5a
R=H
5b R=Bn
1a-f
O
+
Ar2
SH
OMe
OMe
1f Ar1=Ar2=Ph, R=Bn
4
MeO
OMe
OBn
I
Entrya
1
Yieldb
3
5a R=H
5b R=Bn
Ar1=
4a Ar1=Ar2=Ph
4b Ar1=
4d
Assayc
Isolated
OMe
Ar2=
1
4a
4a
4b
4c
4d
4e
4a
5a
5a
5a
5a
5a
5a
5b
5a
5b
5a
1a
1a
50
50
n/a
50
50
30
77
n/a
85
47
44
30
18
29
41
15
61
27
63
40
OMe
Ar2=
2d
3d
4d
5
4e Ar1=H, Ar2=Ph
OTf
1b
1c
OTf
4c Ar1=
Ar2=
1d
1e
Scheme 1.
6
7
1f
8e
9e
10e
(+)-4a
())-4a
(+)-4d
(+)-1a
())-1f
(+)-1d
Of interest, in the presence of TFA only the minor ketal
9 converted (overnight) to 1a, while the major ketal 8
proved resistant to aromatization. The addition of
trimethysilyl triflate (TMSOTf) to the reaction mixture
was necessary to effect aromatization of the ketal 8.9 In
contrast to 6, exposure of the minor Michael diaste-
reomer 7 to TFA resulted in rapid and clean conversion
to 1a.
a Cyclization/aromatization using BF3-TMSOTf except where noted.
See supplementary section for representative procedure.
b Three-step overall yield from the starting 2-mercaptoethanol 4.
c Assay yield from HPLC monitoring of reaction.
d TFA-TMSOTf used for cyclization/aromatization steps. See supple-
mentary section for representative procedure.
e Enantiomeric excesses (ee) were measured by chiral supercritical fluid
chromatography (SFC). See supplementary materials for details. For
(+)-1a, ())-1f, (+)-4a, ())-4a, ee were P99%. For (+)-4d and (+)-1d,
ee were 89% and 87%, respectively.
Addition of catalytic TMSOTf to the toluene/TFA
reaction mixture accelerated the aromatization of ketals
8–10 significantly (60–90 min, Table 1, entry 2). Boron
trifluoride–etherate could be used in place of TFA with
similar results, however the use of TMSOTf was still
required to effect aromatization of the major ketal 8
(Table 1, entry 1). Repeating the cyclization/aromati-
zation sequence for the diastereomeric mixture of 6 and
7 with an optimized process10 afforded 1a (50% HPLC
assay, 44% isolated). Also observed were small amounts
of stilbene (<5%) and methyl ether 12 (<10%). The
formation of undesired 12 was minimized by running
both the cyclization and aromatization steps in toluene
and at a reduced pressure to remove any excess metha-
nol. Presumably, 12 resulted from ketalization of 8 prior
to elimination of methanol.
H
O
O
S
Ph
Ph
TMSOTf
Ph
S
Ph
O
MeO
H
O
OH
8 (major)
TFA or
BF3
OMe
+
H
S
Ph
Ph
OMe
Ph
Ph
6 (major)
HS
OH
4
Et3N
O
MeO
+
+
RO
S
Ph
Ph
MeOH
9 (minor)
R
Ph
Ph
O
O
R=H
R=Me
H
1a
12
H
S
O
S
Ph
OMe
O
OH
TFA or
BF3
OMe
OMe
O
Ph
MeO
10 (major)
5a
5b
R=H
R=Bn
OMe
7 (minor)
+
Ph
Ph
H
O
S
Ph
Ph
O
S
OH
13
O
O
MeO
11 (not observed)
Scheme 2.

P. G. Dormer et al. / Tetrahedron Letters 45 (2004) 5429–5432
5431
The relative stereochemistries were assigned for the
major and minor ketals 8 and 9 using gradient NOE.11
Characterization and assignment of the relative stereo-
chemistry for ketal 10 was achieved from in situ moni-
toring (NMR) of the BF3 promoted cyclization (toluene-
d8) of the minor Michael adduct 7. Of interest, dihy-
droquinone 13 was also observed to slowly form
()20 °C, 5 h, <15%) in the NMR tube during this reac-
tion presumably due to hydrolysis of dimethylketal 7.
Upon gradual warming the reaction mixture from )20
to +67 °C, both ketal 10 and quinone 13 were converted
to the aromatized material 1a.
adducts from (+)-4a (>99% ee) and 5a (entry 8) were
cyclized with BF3 etherate and then aromatized with
TMSOTf, product (+)-1a was obtained with no loss of
enantiopurity. Similar results were obtained with enan-
tioenriched 2-mercaptoethanols ())-4a and (+)-4d (en-
tries 9 and 10), with no loss of enantiopurity upon
conversion to ())-1f and (+)-1d, respectively. Analogs of
the quinone ketal could also be utilized (entries 7 and 9).
The benzyl-substituted analog 5b, 2-benzyl-4,4-dimeth-
oxycyclohexa-2,5-dien-1-one, when reacted with 2-mer-
capto-1,2-diphenylethanol 4a (entry 7) afforded the
Michael adduct, which was cyclized and then aroma-
tized to produce 1f in 61% yield.
While only the syn isomer of 1a was observed in the
cyclization/aromatization sequence of the initial Michael
adduct (Table 1, entry 1), the presence of an electron
donating group (e.g., OMe) in the para-position of the
D-aromatic ring gave a mixture of syn and anti isomers
(Scheme 3). For example, with Ar1 ¼ 3-methoxyphenyl
and Ar2 ¼ 4-methoxyphenyl (4b, Table 1, entry 3)
cyclization of the initial Michael adducts (from 4b and
5a) and subsequent aromatization, using the TFA/tol-
uene/TMSOTf conditions, afforded a 1:1.6 syn:anti
mixture 1b. Formation of the anti isomer of 1b might
occur as proposed in Scheme 3. Ring opening of syn-1b
would afford the intermediate quinone 14. Bond rota-
tion, followed by 1,6-addition of the phenoxide to the
quinone would then produce anti isomer 1b. This
pathway can be suppressed by destabilizing quinone 14
through replacement of the para-methoxy group in the
D-ring with a less electron donating group. The use of
triflate on both the aryl rings of the mercaptoethanol
(4c, Table 1, entry 4) afforded only the syn isomer 1c
(50% assay, 29% isolated) upon treatment of the Mi-
chael adduct with TFA/toluene/)20 °C followed by
TMSOTf/)40 °C. Substitution of a halide for methoxy
in the para position of the D-ring (4d, Table 1, entry 5)
afforded only the syn-2,3-dihydro-1,4-benzo-ben-
zoxathiin 1d.
In conclusion, a novel, convenient, and effective syn-
thetic route to syn-2,3-disubstituted-2,3-dihydro-1,4-
benzoxathiins was developed. The starting materials are
readily available. The method lends itself to the prepa-
ration of a plethora of derivatives in good chemical yield
and high enantiopurity. Most importantly, chiral syn-
2,3-disubstituted-2,3-dihydro-1,4-benzoxathiins can be
readily prepared from enantioenriched mercaptoetha-
nols without any loss of optical activity.
Supplementary material
Representative experimental procedures for the prepa-
ration of 2-mercaptoethanols (4d) and for the Michael
addition, cyclization, and aromatization reactions
(4d+5a!1d). Also included is characterization data for
compounds 1a–f, 4a–e, 5a–b, 8–10.
Acknowledgements
We would like to thank Ms. Mirlinda Biba for the chiral
SFC and HPLC method development and enantiopurity
determinations. Also, we would like to thank Dr. Tho-
mas J. Novak for obtaining high resolution mass spec-
troscopic data.
As demonstrated above, the method works well for
disubstituted 2-mercaptoethanols (Table 1, entries 1–5).
It is possible to utilize mono-substituted 2-mercapto-
ethanols. For example, 4e (Table 1, entry 6) afforded 1e
in modest yield. Importantly, enantioenriched 2-mer-
captoethanols12;13 may also be used (Table 1, entries 8–
10) with no erosion of stereochemistry in the cyclization/
aromatization sequence. For example, when the Michael
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OMe
O
OMe
O
O
-
syn-1b
14
O
+
bond rotation
then ring
closure
C
D
HO
S
B
O
OMe
OMe
A
anti-1b
Scheme 3.

5432
P. G. Dormer et al. / Tetrahedron Letters 45 (2004) 5429–5432
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H
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*
O
S
O
S
Ph
3.9%
Ph
Ph
3.9%
Ph
O
O
O
*
* <1%
O
H
H
*
1.7%
Me
Me
3.1%
8
9
.
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12. Resolved using semi-preparative chiral SFC. See supple-
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)40 °C, add TMSOTf and age for 60 min.
11. Gradient 1D NOESY using Gaussian excitation pulse and
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