Sulfur as a bridge: Synthesis of medium rings via a bicyclic sulfonium ion

Article abstract of DOI:10.1002/adsc.201100502

A facile and efficient synthesis of medium rings via a bicyclic sulfonium ion was developed. Spectroscopic evidence for the formation of an intermediate sulfonium moiety is provided. The sulfur atom served as a "bridge" to access the medium ring system and could be removed after use via a Ramberg-Baecklund process. As a result of the readily available starting materials, simple operation, and mild conditions, these reactions should be an appealing strategy in organic synthesis. Copyright

Full text of DOI:10.1002/adsc.201100502

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DOI: 10.1002/adsc.201100502
Sulfur as a Bridge: Synthesis of Medium Rings via a Bicyclic
Sulfonium Ion
Hongwei Zhou,a,* Yanpeng Xing,a Le Liu,a and Junjie Honga
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310007, Peopleꢀs Republic of China
Fax : (+ 86)-571-8892-0271; e-mail: zhouhw@zju.edu.cn
Received: June 29, 2011; Published online: November 16, 2011
This paper is dedicated to the memory of Prof. Xian Huang.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100502.
Abstract:
A
facile and efficient synthesis of
for the formation of a bicyclic sulfonium ion in a 4-
thio-substituted tetrahydropyran acetal system, in
which the bridged sulfonium ion experienced a ring-
openning even at low temperature.[4] This knowledge
stimulated us to propose a bicyclic sulfonium species
A, in which the central carbon-sulfur bond could be
broken to release a medium ring (Scheme 1).
The formation of the bicyclic sulfonium A might be
not difficult because it is a five- or six-membered ring
closure strategy. If this proposal could work, the
sulfur atom would behave like a bridge to make the
distant span close.
On the basis of this proposal and our previous un-
derstanding of sulfur participation,[5,6] we were stimu-
lated to choose [2-(2-methyl-1,3-dithian-2-yl)phenyl]-
methanol (1a) as the starting material, which could be
synthesized via the reaction of [2-(2-methyl-1,3-dithi-
medium rings via a bicyclic sulfonium ion was de-
veloped. Spectroscopic evidence for the formation
of an intermediate sulfonium moiety is provided.
The sulfur atom served as a “bridge” to access the
medium ring system and could be removed after
use via a Ramberg–Bꢁcklund process. As a result of
the readily available starting materials, simple oper-
ation, and mild conditions, these reactions should
be an appealing strategy in organic synthesis.
Keywords: bicyclic sulfonium species; cyclization;
medium ring synthesis; medium rings; sulfur partici-
pation
an-2-yl)phenyl]lithium
with
paraformaldehyde
Cyclic structures of various ring sizes are quite signifi- (Scheme 2).
cant in organic and bioorganic chemistry as they are
the structural core of a large number of biologically
important natural products and are often incorporat-
ed into drugs.[1] While five- and six-membered carbo-
cycles are most common, seven-, eight-, nine- and
ten-membered or larger cycles occupy an important
fraction of these compounds.[2] The synthetic proto-
cols to five- and six- membered cycles via the differ-
ent types of cyclizations are familiar to the organic
community, but the construction of eight-, nine- and
ten-membered or larger ring compounds are not as
abundant. This may be ascribed to the fact that tradi-
tional ring-closure strategies are effective for five- or
six- membered systems, but problematic for medium
or larger ring systems owing to the high transannular
interactions and an unfavorable entropy factor. In
brief, to bring the two ends of a reactant together is
difficult for medium ring-closure.[3] Recently, an excel-
Scheme 1. Proposal of synthesis of medium rings.
lent report by Woerpel gave spectroscopic evidence Scheme 2. Synthesis of the substrate 1a.
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Sulfur as a Bridge: Synthesis of Medium Rings via a Bicyclic Sulfonium Ion
Scheme 3. Synthesis of 2a.
Using 1a as the starting material, we examined the
cyclization reaction in the presence of triflic anhy-
dride and pyridine in dichloromethane at À788C. We
observed the complete consumption of 1a on TLC in
15 min, but did not observe the expected product. We
chose a stronger base triethylamine and kept the reac-
Figure 1. 1H NMR of 1a about Ha and Hb.
tion mixture at 358C for 48 h. As expected, 6-methyl-
ene-3,4,6,9-tetrahydro-2H-benzo[g][1,5]dithionine
AHCTUNGTRENNUNG
(2a) was isolated in 90% yield (Scheme 3).
During this examination, we found that the hy-
pothesized bicyclic sulfonium is quite stable before
the addition of triethylamine. Thus, after the treat-
ment of 1a with triflic anhydride and pyridine-d5 in di-
chloromethane at À788C, we removed the volatile di-
chloromethane in vacuum at room temperature and
charged CDCl3 for the NMR experiments. The
1H NMR spectroscopy of the reaction mixture con-
firmed that the bridged bicyclic sulfonium was
formed. Downfield shifts were observed for the pro-
tons adjacent to the sulfur atom (Ha to Ha’), demon-
strating the presence of an electron-withdrawing func-
tionality on sulfur. Also, the single peak of the meth-
ylene group adjacent to the benzene ring of 1a was
changed to two double peaks of the intermediate (Hb
to Hb’), showing an obvious AB system. In addition,
on the 13C NMR spectroscopy of reaction mixture, a
downfield shift was observed for the quaternary
carbon (C1 to C1’) and an upfield shift for the meth-
ylene carbon adjacent to the benzene ring (C2 to
C2’), consistent with the formation of bicyclic sulfoni-
um (Table 1, Figure 1, Figure 2, Figure 3 and
Figure 4).
Figure 2. 1H NMR of bicyclic sulfonium about Ha’ and Hb’.
Based on these results, we propose a plausible path-
way as shown in Scheme 4. Treatment of 1a with trifl-
ic anhydride and pyridine gave a trifluoromethanesul-
fonate and the sulfur atom attacked the trifluorome-
thanesulfonate to afford a bridged bicyclic sulfonium
A. The bicyclic sulfonium A offered the nine-mem-
Table 1. NMR shifts from 1a to bicyclic sulfonium.
Figure 3. 13C NMR of 1a about C1 and C2.
Compounds
1H NMR [ppm]
13C NMR [ppm]
1a
Ha (2.79, 2.98); Hb (5.14) C1 (52.5); C2
(62.8)
bered product 2a via an E2 process in the presence of
triethylamine.
With this result in hand, we examined the scope of
the reaction and obtained a series of medium rings in
Bicyclic sulfo- Ha’ (2.86, 4.15); Hb’
nium (4.79, 5.14)
C1’ (71.7); C2’
(45.4)
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Hongwei Zhou et al.
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Figure 4. 13C NMR of bicyclic sulfonium about C1’ and C2’.
Scheme 5. Synthesis of 13-membered ring.
[2-(2-Methyl-1,3-oxathian-2-yl)phenyl]methanol (5a),
in which one of the two sulfur atoms of 1a was re-
placed by an oxygen, could be thought of as a promis-
ing expansion of 1a, and reasonably, one of the two
sulfur atoms of the substrate might also be replaced
by a carbon (Table 3).
The sulfur atom, which serves as a bridge in these
reactions, is also a very useful part of the products
prepared by the above protocols and could be used as
a convenient handle for further generation of chemi-
cal diversity. We treated 6d with m-CPBA in dichloro-
methane followed by a Ramberg–Bꢁcklund process[7]
and obtained 1-phenylcyclohepta-1,3-diene (7) in
58% yield. This result demonstrates that the bridge of
sulfur could be removed after use to give a new ring
system without a sulfur atom (Scheme 6).
Scheme 4. Plausible mechanism.
In summary, we have developed a facile and effi-
cient synthesis of medium rings via bicyclic sulfonium
moderate to good yields under mild conditions species. Spectroscopic evidence for the formation of
(Table 2). an intermediate sulfonium ion is provided. The sulfur
The formation of the carbon-carbon double bond atom served as a “bridge” to access the medium ring
via the E2 process is highly stereoselective and the system and could be removed after used via a Ram-
stereochemistry of the products 2b and 2g was estab- berg–Bꢁcklund process. As a result of the readily
lished by NOESY experiments.
available starting materials, simple operation, and
It is noteworthy that the product 2i (entry 9, mild conditions, these reactions should be an appeal-
Table 1), containing a latent hydroxy group, might be ing strategy in organic synthesis.
transformed to the precursor of a new substrate
which could undergo another “bicyclic sulfonium-
open” process. Thus, we treated 2i with TsOH/metha-
nol at room temperature affording 4-(6-methylene-
Experimental Section
3,4,6,9-tetrahydro-2H-benzo[g]
ACHTUNGTRENNUNG
ACHTUNGTNER[NUNG 1,5]dithionin-1-yl)but-
General Procedure for Synthesis of 2a
To a stirred solution of 1a (0.5 mmol) in 5 mL of dry pyri-
dine/dichloromethane (1:20) was added trifluoromethanesul-
fonic anhydride (0.15 mL) by syringe at À788C under an N2
atmosphere. After stirring for 15 min at À788C, the reaction
mixture was allowed to stir for 30 min at room temperature.
Then triethylamine (0.8 mL) was added and the reaction
mixture was stirred at 358C for 48 h. The reaction mixture
was diluted by 10 mL dichloromethane, washed successively
with 2N hydrochloric acid (2ꢃ10 mL) and water (1ꢃ
tion under similar conditions. As expected, (E)-
6-methylene-3,4,6,11,12,13-hexahydro-2H-benzo[g]-
ACHTUNGTRENNUNG[1,5]dithiacyclotridecine (4) was obtained in 53%
yield. This result means that the sulfur atom was used
as the “bridge” again. Theoretically, the bridge of
sulfur could be used for many times to afford large
rings provided that a suitable substrate was pre-de-
signed (Scheme 5).
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Adv. Synth. Catal. 2011, 353, 3146 – 3150

Sulfur as a Bridge: Synthesis of Medium Rings via a Bicyclic Sulfonium Ion
Table 2. Synthesis of medium rings.[a]
Entry
Substrate
Product
Yield [%]
90
1
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2
46
77
58
51
3
4
5[b]
6
7
8
1f
1g
1h
2f
2g
2h
87
90
61
9
1i
2i
60
[a]
All reactions were run under the following conditions, unless otherwise specified: 0.5 mmol of 1, 5 mL of pyridine/DCM
(1:20) and 0.15 mL of Tf2O at À788C for 15 min followed by warming to room temperature, then charged 0.8 mL of tri-
ACHTUNGTRENNUNGethylamine at 358C for 48 h under a N2 atmosphere.
[b]
Stirring at 358C for 60 h.
10 mL), then dried with anhydrous Na2SO4. After evapora-
tion, chromatography on silica gel (hexane/dichlorome-
thane: 15/1) of the reaction mixture afforded 2a; yield:
100 mg (90%). 1H NMR (400 MHz, CDCl3): d=7.30–7.23
(m, 3H), 7.18–7.16 (m, 1H), 5.65 (s, 1H), 5.09 (s, 1H), 3.83
(s, 2H), 3.04–3.01 (t, J=5.6 Hz, 2H), 2.42–2.39 (t, J=5.8 Hz,
2H), 1.84–1.78 (m, 2H); 13C NMR (CDCl3, 100 MHz): d=
145.5, 141.1, 138.0, 129.0, 128.9, 128.7, 126.8, 114.6, 37.2,
33.8, 33.6, 28.7; IR (neat): n=2921, 1594, 1482, 1067, 757
cmÀ1
222.0537.
;
HR-MS;: m/z=222.0532, calcd. for C12H14S2:
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Hongwei Zhou et al.
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Table 3. Synthesis of medium rings containing one sulfur
References
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Entry
Substrate
Product
Yield [%]
58
1
5a
5b
5c
6a
6b
6c
2
69
52
3
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4[b]
5d
5e
6d
6e
93
45
5[c,d]
[a]
All reactions were run under the following conditions,
unless otherwise specified: 0.5 mmol of 5, 5 mL of pyri-
dine/DCM (1:20) and 0.15 mL of Tf2O at À788C for
15 min followed by warming to room temperature, then
treated with 0.8 mL of triethylamine at 358C for 48 h
under an N2 atmosphere.
The stereochemistry of 6d was established by a NOESY
experiment.
0.8 mL of DBU instead of Et3N was added and stirring
was at 358C for 72 h.
[b]
[c]
[d]
An E/Z ratio (13:87) was observed and the stereochemis-
try of 6e was established by a NOESY experiment.
[7] L. J. Baird, M. S. M. Timmer, P. H. Teesdale-Spittle, J. E.
Harvey, J. Org. Chem. 2009, 74, 2271.
Scheme 6. Removal of the bridge of sulfur.
Acknowledgements
Financial support was received from the National Natural
Science Foundation of China (Nos. 20702046, 20972134).
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Adv. Synth. Catal. 2011, 353, 3146 – 3150