Cesium-Catalyzed Regioselective Synthesis of Trisubstituted Heteroatom Alkenes: A New Strategy for the Preparation of Functional Alkenes

Article abstract of DOI:10.1021/acs.orglett.5b00751

A highly chemo-, regio-, and stereoselective method for the synthesis of (Z)-vinylic selenosulfides and (Z)-vinylic tellurosulfides in a one-pot reaction of terminal alkynes, diaryl disulfides, and diaryl diselenides (ditellurides) catalyzed by simple bas

Full text of DOI:10.1021/acs.orglett.5b00751

Letter
pubs.acs.org/OrgLett
Cesium-Catalyzed Regioselective Synthesis of Trisubstituted
Heteroatom Alkenes: A New Strategy for the Preparation of
Functional Alkenes
Jinyang Chen, Zhi Tang, Renhua Qiu,* Yunhua He, Xie Wang, Ningbo Li, Haibo Yi,* Chak-Tong Au,
Shuang-Feng Yin, and Xinhua Xu*
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha, 410082, P. R. China
S
* Supporting Information
ABSTRACT: A highly chemo-, regio-, and stereoselective
method for the synthesis of (Z)-vinylic selenosulfides and (Z)-
vinylic tellurosulfides in a one-pot reaction of terminal alkynes,
diaryl disulfides, and diaryl diselenides (ditellurides) catalyzed
by simple base cesium hydroxide monohydrate is described.
Due to the different activities of the carbon−chalcogen bonds, the target products cleave selectively and act as a kind of readily
available platform molecule for the synthesis of tetrasubstituted alkenes. The mechanism of thioselenation was studied by
experimental and theoretical methods.
selenosulfides and tellurosulfides, efforts are devoted toward
their generation.12
Thioselenation of alkynes is one of the simplest, most efficient
methods for the preparation of vinylic selenosulfides wherein
alkynes, diaryl disulfides, and diaryl diselenides are reacted in one
pot. In such a reaction, there are a total of eight products: Z1, Z2,
Z3, Z4, and their relative E-stereoisomers (Scheme 1). Thus, the
ince the report by Georg Witting on the transformation of
1
Sketone to olefin in 1953,
the use of alkenes for the
construction of complex molecules has become strategically
important.2 For example, tri- and tetra-substituted alkenes are
used in the syntheses of natural products such as Nileprost
analogues3 and Ratjadone,4 as well as drugs such as Tamoxifen5
and Roaccutane.6 In addition, it is envisaged that there are
potential uses of alkenes in polymer chemistry7 and biochem-
istry.8 But there are challenges, especially in terms of stereo-
selective synthesis of alkenes.
Scheme 1. Possible Products of Thioselenation
In general, it is difficult to attach reagents to double bonds due
to the congested nature and eclipsing interactions of the
products.9 The carbon metalation of alkynes could be the most
efficient method for the preparation of tri- and tetrasubstituted
alkenes,10 but the regio- and stereoselectivity of products is
difficult to control. Recently, by using directing groups10a or
employing symmetrical alkynes as substrates,10f the issue of
regioselectivity is addressed partially, especially when sym-
metrical alkynes are used as substrates.10g However, the problem
of structural flexibility still exists.
(Z)-Vinylic selenosulfides and (Z)-vinylic tellurosulfides are
important platform molecules for stereoselective synthesis of tri-
and tetrasubstituted alkenes (Figure 1). It is because the C−S,
C−Se, and C−Te bonds can be readily cleaved in high
selectivity.11,10b Due to the important functionality of (Z)-vinylic
control of chemo- and regioselectivity of products is essential.
Until now, the only two examples for such control are by means
of photoirradiation12a and Rh catalysis12b (Scheme 2, a and b),
but the approaches are limited for special or narrow substrates,
and the chemo- and regioselectivity of products are poor.
Therefore, it is necessary to develop a new method that can
synthesize (Z)-vinylic selenosulfides regio-, chemo-, and stereo-
selectively under mild reaction conditions.
Herein, we demonstrate a highly chemo-, regio-, and
stereoselective method for the synthesis of (Z)-vinylic
selenosulfides using simple cesium hydroxide monohydrate
(CsOH·H2O) as a catalyst. First, propargyl alcohol was treated
with a binary system of diphenyl disulfide and diphenyl
diselenide, and a 71% yield of the desire product was obtained
in Z2-form (Scheme 3, 4a). There is no detection of (E)-isomers
Figure 1. Preparation of tetrasubstituted alkenes using (Z)-
diorganochalcogen alkenes as platform molecules.
Received: March 15, 2015
Published: April 17, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00751
Org. Lett. 2015, 17, 2162−2165

Organic Letters
Letter
different diaryl disulfides (2) and diaryl diselenides (3). The
results are summarized in Scheme 3.
Scheme 2. Thioselenation of Alkynes via Three Main Routes
As shown in Scheme 3, both propargylic alcohols and ethers
and aromatic alkynes give the desired products in good to
excellent yields. And the steric hindrance of the proparyl alcohols
affects the stereoselectivity slightly (4a, 71%; 4d, 76%). When the
hydroxyl of proparyl alcohols is substituted by methoxyl,
phenoxyl, and naphthoxyl, there is still a good yield for (Z)-
vinylic selenosulfides (4i−4p, 62%−78%). The efficiency may be
related to the electrostatic interaction of the cesium ion with the
O-atom of alcohols and ethers and the promotion effect of the
benzene ring on the reactions.
In addition, the reactions show good tolerance toward various
phenyl acetylenes with electron-donating (e.g., p-methyl, p-(n-
Pr), p-OMe, m-NH2, except for p-NH2) and -withdrawing groups
(e.g., fluoro), leading to corresponding products in excellent
yields (4z−4ah, 85%−92%). But it is not suitable for the phenyl
acetylenes with a strong electron-withdrawing group (eg., p-
NO2, p-CN). The thioselenation of 2-ethynylpyridine with
diphenyl diselenide and diphenyl disulfide also gives the desired
product in moderate yield (4aj, 61%). Furthermore, there is also
tolerance toward different functional groups in disulfides (2) and
diselenides (3). For example, in the case of diaryl diselenide with
an electron-donating group (e.g., methoxyl), the desire product is
obtained in 65% yield (4t). For diaryl disulfides, the attachment
of an electron-withdrawing group to the phenyl ring results in a
good yield and regioselectivity (4s, 78%), and the same applies to
the attachment of electron-donating groups to the ring (4r, 89%
and 4x, 90%, 4y, 84%). The attachment of a NO2 group to the
phenyl ring of disulfides (2) gives the desired products in poor
yields (4u−4w, 11−25%), and the yields of (Z)-vinylic disulfides
increase, plausibly because of the high reactivity of the disulfides.
As for 1-hexyne, the generation of desired products as detected in
TLC analysis is low, and most of the reactants can be recovered.
We extended the procedure for the synthesis of (Z)-vinylic
tellurosulfides and telluroselenides (Scheme 4). It was found that
Scheme 3. Thioselenation of Alkynes with a Binary System of
Diaryl Disulfides and Diaryl Diselenides
ab
,
Scheme 4. Thiotelluration of Alkynes with a Binary System of
a b
,
Diaryl Disulfides and Diaryl Ditellurides
a
Reaction conditions: alkynes (1) (0.2 mmol), diaryl disulfides (2)
(0.1 mmol), diaryl diselenides (3) (0.1 mmol), CsOH·H2O (25 mol
b
%), DMF (2 mL), rt, N2, 20 h. Isolated yields.
a
Reaction conditions: alkynes (1) (0.2 mmol), diaryl disulfides (2)
(0.1 mmol), diaryl ditellurides (5) (0.1 mmol), CsOH·H2O (25 mol
b
%), DMF (2 mL), rt, N2, 20 h. Isolated yields.
in 1H NMR analysis of the crude product, exemplifying the idea
of atom and step economy. After optimization of reaction
conditions (Table S1), the most suitable parameters are alkynes,
diaryl diselenides (0.5 equiv), diaryl disulfides (0.5 equiv),
cesium hydroxide monohydrate (0.25 equiv), DMF, rt (25 °C),
20 h, and under N2.
the method is not suitable for the synthesis of (Z)-vinylic
telluroselenides mainly because the two heteroatoms Se and Te
are rather similar in chemical and physical features. In the case
when S and Te are heteroatoms, (Z)-vinylic telluroselenides are
obtained in excellent yield (6d, 90%). Furthermore, both
electron-donating (6b, 90%, 6d, 90% and 6e, 91%, 6f, 85%, 6h,
To demonstrate the efficiency and generality of the reaction,
we applied the method to various terminal alkynes (1) and
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Letter
89%) and -withdrawing groups (6c, 84%) in the phenyl ring of
diaryl disulfides lead to excellent yields of the corresponding
products. Similar to thioselenation, thiotelluration works well
with various phenyl acetylenes with an electron-donating group
(e.g., p-OMe, m-NH2) (6i and 6j, 87% and 86%). The reaction
gives the corresponding product in a moderate yield when 2-
ethynylpyridine is used as a substrate (6l, 65%).
We also investigated the use of the products in the synthesis of
tetrasubstituted alkenes. Recently, a number of methods for
stereoselective synthesis of tetrasubstituted alkenes were
reported,13 but chemo- and regioselectivity are hard to control
in some of these methods.13b,d,e Due to the different activities of
C−S, C−Se, and C−Te bonds and the retention of configuration
feature of the chalcogen atoms (S, Se, Te), the carbon−
chalcogen bonds of (Z)-vinylic dichalcogenides can be cleaved
readily with high stereoselectivity.11,12d,14 For example, with 6h
and 4k, we can easily obtain (Z)-vinylic monchalcogenides (7a,
62%; 9a, 93%) through cleaving the C−Te bond11a and the
transformation of the C−S bond,15 respectively. Thus, the
products can be efficiently transformed to the desired
tetrasubstituted alkenes using the methods reported in the
references (Scheme 5).16−20
should be unsymmetrical diorganoyl dichalcogenides (RSSeR′)
rather than diaryl disulfides or diselenides. An acetylenic anion is
easily reacted with unsymmetrical diorganoyl dichalcogenides
(RSSeR′) to form an acetylenic selenide intermediate, due to the
stronger electronegativity of the S-atom then that of the Se-atom.
The E/Z diastereoselectivity of the products is mainly driven
by the addition reaction of an arylthio anion (ArS−) with the
acetylenic selenide intermediate. Various cesium intermediates
(I1−I7) should be formed during the addition. The structures and
relative energies of the cesium intermediates at the B3LYP/6-
311G(d,p) and B3LYP/6-311++G(d,p) level using the Gaussian
09 B.01 package21 show that the I1 intermediate is more stable
than the other isomers (I2−I7), because of the lower relative
energies (Figure 2). The stability of the I1-form structure may be
Scheme 5. Possible Ways for the Synthesis of Tetrasubstituted
Alkenes
To shed light on the mechanism of thioselenation, we treated
2-methylbut-3-yn-2-ol with a binary system of diphenyl
diselenide and di(4-methylphenyl) disulfide in dry DMF/D2O
(eq 1) and obtained (Z)-vinylic selenosulfide (12). The result
Figure 2. Structures and relative energies of the various isomers of the
cesium intermediates at B3LYP/6-311++G(d,p)//B3LYP/6-311G-
(d,p) level.
indicates that the first step of thioselenation is the removal of acid
hydrogen from terminal alkyne. We also found that cesium
hydroxide monohydrate catalyzes the thioselenation of unsym-
metrical diorganoyl dichalcogenide (RSSeR′) with a terminal
alkyne for exclusive generation of (Z)-vinylic selenosulfide (13)
(eq 2); the result suggests that unsymmetrical diorganoyl
dichalcogenides (RSSeR′) have an active role to play in
thioselenation. When diphenyl diselenide is treated with di(4-
methoxyphenyl) disulfide in DMF-d7 (eq 3), selenosulfide (14)
is obtained in 20% yield, and a similar result is observed when
diphenyl ditelluride is treated with di(4-methoxyphenyl)
disulfide. In contrast, we do not obtain telluroselenide
(RSeTeR′) when diphenyl diselenide is treated with diphenyl
ditelluride in DMF-d7 in the presence or absence of CsOH·H2O.
The overall results imply that the active species for thioselenation
a result of the cation interaction between Cs+ and the benzene
ring as well as interaction between the O- and Cs-atoms (see
Figure S9 of SI). In addition, the Se-atom can also stabilize the
carbanions bonding to it, which contributes to the stability of the
I1 intermediate.22
On the basis of the calculation and experimental results, a
plausible mechanism is brought forward (Figure 3a). First, there
is the removal of acid hydrogen from terminal alkyne 1 giving the
cesium intermediate a as a result. Second, selenosulfides
(tellurosulfides) 15 obtained via the exchange reaction of 2
and 3(5) react readily with cesium intermediate a, giving species
b and c. Finally, there is nucleophilic addition of species c with b
to give cesium intermediate d and hydrogen addition by water to
give the desired products 4 or 6. The configuration is confirmed
by X-ray (Figure 3b) and NOE analyses (see Figures S2 and S3).
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ASSOCIATED CONTENT
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Experimental procedure, characterization data, and copies of 1H,
13C, and HPLC spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: renhuaqiu@hnu.edu.cn (R.Q.).
*E-mail: hbyi@hnu.edu.cn (H.Y.).
*E-mail: xhx1581@hnu.edu.cn (X.X.).
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A.; Gibb, A.; Junker, E. M.; Lieberman, D. J. Am. Chem. Soc. 2015, 137,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21273068 and 21373003), the
National Natural Science Foundation of Hunan Province
(14JJ7027), and the Fundamental Research Funds for the
Central University, Hunan University. All authors thank Prof.
Nobuaki Kambe of Osaka University, Prof. Akihiro Orita of
Okayama University of Science, and Dr. Li-Biao Han of AIST for
helpful advice. C.-T.A. thanks HNU for an adjunct professorship.
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