A convenient synthesis of (E)-conjugated polyene sulfonyl derivatives with excellent stereospecificity

Article abstract of DOI:10.1016/j.tetlet.2018.05.060

A highly selective synthesis of conjugated polyene sulfonyl derivatives is described via the elimination of disulfonyl chloride with readily accessible raw material dihaloalkane. The protocol offers a convenient way to form sulfonamides, sulfonates and even sulfones. Furthermore, this method was manipulated under mild condition with simple operation in high yield to afford only trans products.

Full text of DOI:10.1016/j.tetlet.2018.05.060

Accepted Manuscript
A convenient synthesis of (E)-conjugated polyene sulfonyl derivatives with ex-
cellent stereospecificity
Chunyan Yu, Zhongwen Lv, Sheng Xu, Jun Zhang
PII:
S0040-4039(18)30677-4
https://doi.org/10.1016/j.tetlet.2018.05.060
TETL 50007
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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11 April 2018
16 May 2018
22 May 2018
Please cite this article as: Yu, C., Lv, Z., Xu, S., Zhang, J., A convenient synthesis of (E)-conjugated polyene sulfonyl
derivatives with excellent stereospecificity, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.05.060
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A convenient synthesis of (E)-conjugated
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Chunyan Yu, Zhongwen Lv, Sheng Xu and Jun Zhang

1
Tetrahedron Letters
A convenient synthesis of (E)-conjugated polyene sulfonyl derivatives with excellent
stereospecificity
Chunyan Yu, Zhongwen Lv, Sheng Xu and Jun Zhang
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and
Technology, 130 Mei Long Road, Shanghai 200237, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly selective synthesis of conjugated polyene sulfonyl derivatives is described via the
elimination of disulfonyl chloride with readily accessible raw material dihaloalkane. The
protocol offers a convenient way to form sulfonamides, sulfonates and even sulfones.
Furthermore, this method was manipulated under mild condition with simple operation in high
yield to afford only trans products.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Dihaloalkane
Disulfonyl chloride
Elimination
Polyene sulfonyl derivatives
Scheme 1. Synthetic routes of conjugated polyene-sulfonyl
compounds
 Corresponding author. e-mail: xusheng@ecust.edu.cn

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Alkene sulfonyl compounds bearing unique bifunctional
moiety have been reported to exhibit a diverse range of biological
and pharmaceutical activities1, serve as important synthetic
intermediates and building block in organic and medicinal
chemistry2, and represent click function in Click chemistry3. For
instance, Cruz etc. recently reported vinyl sulfonates were
utilized as efficient tools for “coupling-and-decoupling” (CAD)
chemistry, in which the coupling step relied on Michael addition
of various nucleophiles to vinyl sulfonates and decoupling step
based on cleavage of the resulting sulfonates adducts4. The
antimigraine drug Naratriptan was synthesized industrially by the
Heck reaction of vinyl sulfonamide with substituted 5-
bromoindole as a key step5. Vinyl- and 1,3-butadiene-sulfonyl
compounds represents an important class of dienophile or diene
in Diels-Alder reaction6, Liang etc. reported the Himandrine core
was synthesized through the intramolecular Diels-Alder reaction
of dienic sulfonamide as diene with dienone6c. In addition,
divinyl sulfones have been explored as thiol-terminated acrylate
polymers’ catchers to generate semitelechelic vinyl sulfone
polymers capable of reacting with free cysteines7a. Very recently,
the utilization of butadiene sulfonyl compound as a novel ligand
was successfully applied in Ru based complex to catalyzed
benzophenone hydrogenation8.
Prior research has thoroughly investigated the synthesis of
vinyl sulfonyl compounds9, however, the convenient formation of
conjugated diene- and triene-sulfonyl compounds has been much
less recognized10. As depicted in Scheme 1, the conversion of 3-
sulfolene into 1,3-butadiene-1-sulfonyl compound in the presenc-
-e of n-BuLi and NCS or haloalkane has a good yield, but this
method generally obtains multiple products due to poor regio-
and stereo-selectivity (Method A)10a
. Then Madden etc.
developed a Pd-catalyzed Matsuda-Heck reaction to give 1,3-
butadiene mesylate with a poor yield (18% yield, Method B)11.
Scheme 2. Synthetic routes of substrates

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In hence, considering the broad applications of the conjugated
Table 1. Preparation of monoene- and (E)-conjugated
diene-sulfonamide and -sulfonate
polyene sulfonyl compounds in organic chemistry, it is highly
desirable to develop a general strategy to synthesize this class of
building blocks with high yields in stereroselective manner.
It has been reported that the sulfonyl functionality could act as
a leaving group in organic synthsis12, Furthermore, taking
advantage of the molecule’s symmetry into consideration, the
disulfonyl chloride (2) can be easily synthesized by sulfonation
of dihaloalkane (1) with anhydrous sodium sulfite followed by
chlorination with PCl5, SOCl2 or oxalyl chloride (Scheme 2)13.
Herein, we employ compounds 2 as the starting material, one
sulfonyl chloride could act as a leaving group to form a double
bond and the other sulfonyl chloride could react with the
nucleophile to offer a functional moiety such as sulfonamide,
sulfonate and sulfone. Comparing with the previously reported
methods, this strategy provides a general method for the
syntheses of conjugated polyene-sulfonyl derivatives including
monoene, diene and triene. It is noteworthy that the reaction
featured with excellent stereospecificity (Scheme 1).
Entrya
1
NuH
Productb
3a (80%)
3b (90%)
3c (93%)
3d (89%)
Et2NH
2
3
4
5
n-BuNH2
The reaction optimization commended with the treatment of
2-butene-1,4-disulfonyl chloride (2a) as the model substrate with
various nucleophilic reagent. Firstly, our synthetic strategy was
examined for the formation of alkene sulfonamide and sulfonate.
As expected, N,N-diethyl-1,3-butadiene-1-sulfonamide (3a) and
isopropyl-1,3-butadiene-1-sulfonate (4a) were successfully
synthesized from E-2a with Et2NH and isopropanol, and
moreover, only E-3a and E-4a were obtained (Table 1, entry 1
and entry 6). It was found that the use of two equivalents Et2NH
maximized the yield of compound 3a. With increasing the
amount of Et2NH, the yield of polyene-sulfonamide 3a decreased
since the excess Et2NH would further undergo the undesired
Michael addition reaction with the product 3a2b,9. It is worth
noting that the formation of polyene-sulfonate was not affected
even the alcoholic nucleophile was used as the solvent, no
Michael addition side reaction was observed in the reaction
mixture. In addition, compound 4a could be synthesized
regardless of the addition of base (Table 1, entry 6).
3e (82%)
6c
i-PrOH
4a (90%, 91%a,d)
4b (65%)
7c
MeOH
EtOH
8c
4c (76%)
9c
n-PrOH
4d (82%)
10c
11c
4e (88%)
With this simple procedure in hand, the scopes of amines and
alcohols were investigated carefully. As shown in Table 1, both
anilines containing electron-withdrawing or electron-donating
group (entries 3 and 4), cyclic amine (entry 5) and linear amines
(entries 1 and 2) all generated corresponding E-conjugated diene
sulfonamides with 80-93% yields although the yield of secondary
amines were slightly lower than that of primary amines. The
saturated linear alcohols (entries 6-9), cyclic alcohols (entries 10
and 11) even alcohols containing the alkene and terminal alkyne
functionalities (entries 13 and 14) are suitable for this method,
affording the corresponding sulfonate with 65-90% yield.
Unfortunately, tert-Butanol was failed to add into the sulfonyl
chloride group probably due to the disfavored steric hindrance.
Subsequently, the monoene-sulfonamide and -sulfonate
(compounds 3f and 4j) were given under similarly reaction
condition with satisfactory yield (entries 15 and 16).
4f (89%)
4g (80%)
4h (73%)
4i (72%)
12c
13c
14c
15c
n-BuNH2
3f (85%)
4j (81%)
16c
For the purpose of comparison with this method, we attempted
to synthesize compound 3a used traditional method that
corresponding 1,3-butadiene-1-sulfonyl chloride reacted with
Et2NH (Scheme 3). Actually, the 53% yield of latter method was
far lower than that of one-pot procedure. These results clearly
demonstrate the current method has unique advantages over the
known strategy.
aReaction condition: 1.0 mmol compound 2a or 2b as substrate, 2.0
equiv amine or 5-10 mL alcohol, 10-20 mL DCM as solvent, room
temperature, 5-15 min. bIsolated yield. csolvent-free, 35oC, 3-10 h. d1.0
equiv TEA and 1.0 equiv isopropanol.
Encouraged by above results and inspired the extensive
applications of sulfone in organic chemistry14, we tried to
investigate the synthesis of conjugated alkene sulfones
Scheme 3. Direct comparison of two methods

4
Table 2. Preparation of monoene- and (E)-conjugated
Table 3. Preparation of (E, E)-conjugated triene-
diene-sulfone
sulfonyl derivatives
Entrya
1
NuH
Productb
Entrya
1
R4MgX
Productb
Et2NH
3g (67%)
5a (78%)
2
3
2
3
i-PrMgBr
PhMgBr
3h (89%)
3i ( 64%)
5b (81%)
4c
i-PrOH
5c (75%)
5d (83%)
4
5
4k (80%)
4l (71%)
5c
6c
PhMgBr
5e (85%)
aReaction condition: 1 mmol of compound 2a or 2b, 2.0 equiv
Grignard reagent and 10-20 mL anhydrous THF under an Ar
atmosphere in ice bath. bIsolated yield.
4m (75%)
5f (60%)
7d
8d
(compound 5) to establish the generality and versatility of this
protocol. The Grignard reagent was easily accessible and widely
applied in modern organic synthesis, we next studied the
feasibility of formation the conjugated polyene sulfone using the
Grignard reagent as a nucleophile, though it may undergo the
competing addition way15. To our delight, the (E)-conjugated
olefin sulfones were successfully obtained from compound 2 in
high efficiency without any undesired side adducts formation
(Table 2). In this protocol, three representative Grignard reagents
containing alkenyl, alkyl and aryl group were selected to
synthesize monoene, (E)-conjugated diene-sulfone with 75-85%
yield. It is particularly to point out, bilateral polyene sulfones
(5a, 5d) were furnished when vinyl Grignard reagent was used
(entries 1 and 4). It's reasonable to predict that the diversity of
Grignard reagents could provide more variability with this
methodology. Eventually, the generality of this protocol was
further approved through the application of the synthesis of
various sulfones.
PhMgBr
5g (62%)
aReaction condition: 1.0 mmol compound 2c, 2.0 equiv amine or
Grignard reagent, 10-20 mL DCM as solvent, room temperature, 5-15
min. Isolated yield. solvent-free, 5-10 mL alcohol, 35oC, 3-8 h. 10-
b
c
d
20 mL anhydrous THF as solvent.
Scheme 4. Stereo-selectivity of the reaction
Subsequently, this strategy was used to synthesize a series of
(E)-conjugated triene sulfonyl compounds under this similar
reaction conditions. As excepted, conjugated triene sulfonyl
derivatives were successfully obtained with
a
sole
stereospecificity, and the results were shown in Table 3. Notably,
the bi-polyene sulfone 5f could also be prepared through this
methodology.
chloride group was expelled as the leaving group and new double
bond was formed. Finally, nucleophiles attacked the intermediate
again to afford target conjugated alkene sulfonyl compound.
The results that all above products were trans suggested that
this method should have excellent stereoselectivity, then the E/Z-
2a were exploited as substrates for further study. As shown in
Scheme 4, only E-product were obtained as the sole product
regardless of E/Z-2a was used as the starting material, suggesting
the strategy has an excellent stereospecificity.
Conclusion
In summary, we have developed a convenient and general
method for the synthesis of conjugated polyene-sulfonyl
compounds including sulfonamides, sulfonates and sulfones from
cheap and simple starting materials dihaloalkane under mild
conditions with great yield and excellent stereospecificity. In
particular, the synthesis of the conjugated triene products and the
successful applications of Grignard reagents demonstrated the
universality of this strategy, and the application of those
The plausible reaction mechanism was deduced through E1cb
elimination mechanism by an example of compound 2a (Scheme
5)16. Initially, the α-H was attacked by the nucleophile and a
carbon anion was generated, then the lone pair of electrons on the
carbon anion resonated to the neighboring atom, thus sulfonyl

5
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 A highly selective synthesis of (E)-conjugated
polyene sulfonyl derivatives.
 The convenient protocol has a great generality.
 The reaction was manipulated under mild
condition with high yield.