Stereoselective: Z -halosulfonylation of terminal alkynes using sulfonohydrazides and CuX (X = Cl, Br, I)

Article abstract of DOI:10.1039/c6ra13737g

The Z-selective halosulfonylation of terminal alkynes has been achieved via the halosulfonylation of terminal alkynes by using sulfonohydrazides and copper(i) halides (CuI, CuBr and CuCl), which enables the generally applicable synthesis of halogenated vi

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DOI: 10.1039/C6RA13737G
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Stereoselective Z-halosulfonylation of terminal alkynes using
sulfonohydrazides and CuX (X = Cl, Br, I)
Jie-Ping Wan,a,* Deqing Hu,a Feicheng Bai,a Li Weia and Yunyun Liua,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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The Z-selective halosulfonylation of terminal alkynes has been presence of copper catalyst, stoichiometical Me2S ligand with
o
achieved via the halosulfonylation of terminal alkynes by using 110 C heating.5d On the other hand, the reactions employing
sulfonohydrazides and copper (I) halides (CuI, CuBr and CuCl), stable sulfonohydrazides as partners are known to provide
which enables the generally applicable synthesis of halogenated selectively E-configurated products (Scheme 1).8 Additionally,
vinyl sulfones with satisfactory efficiency.
another challenge in the difunctionalization-based synthesis of
halogenated vinyl sulfones is that almost no method showing
general applicability to the synthesis of chloro-, bromo- and
iodo-vinyl sulfones is present available because of either the
limited tolerance of the catalytic conditions or the
unavailability of related halogen sources. In this regard,
developing alkyne halosulfonylation reactions of Z-selectivity
and/or general application to the synthesis of Cl, Br and I
functionalized vinyl sulfones is presently an issue of urgent
significance. Upon our recent research interest in the
sulfonohydrazide-based synthesis9 and related reactions
The difunctionalization of alkynes is a crucial strategy in
modern organic synthesis by providing straightforward and
flexible accesses to poly functionalized alkene derivatives.1
Among the various known patterns of alkyne
difunctionalization, the halosulfonylation which provides
halogenated vinyl sulfones has received extensive attention in
recent years because of the prevalent presence of sulfonylated
vinyl substructure in biologically functional molecules as well
as their valuable application in organic synthesis.2 There have
been longstanding efforts made by chemists for the synthesis
of these halogenated vinyl sulfones during the past decades,
the survey on related literature shows that these halogenated
vinyl sulfones can be synthesized by the electrophilic
halogenation of sulfonylated vinyl zirconium,3 the oxidation of
β-halogenated vinyl sulfides,4 and more universally, the
difunctionalization of alkynes using various sulfonyl reagents.
Generally, the halosulfonylation using sulfonyl halides,5
sodium sulfinates/halogen source,6 sulfinic acid/iodine7 and
sulfonohydrazides have all been known as practical routes to
halogenated vinyl sulfones.8 While these known protocols
provide enriched options in the synthesis of these
functionalized compounds, an amazing fact was that almost all
these known methods give vinyl sulfone products with E-
selectivity, and the only known example of Z-selective alkyne
Scheme 1 Stereoselective halosulfonylation of alkynes
difunctionalization toward the β-halo vinyl sulfone synthesis
has been reported by Liang and co-workers wherein sulfonyl
chloride is used as the difunctionalizing reagents in the
involving efficient C-S bond formation,10 we report herein an
unprecedented and generally applicable Z-selective
halosulfonylation reactions of alkynes using CuX (X = Cl, Br, I)
as halogen sources as well as the switchable alkyne
hydrosulfonylation reactions (Scheme 1).
Originally, the reaction between phenylacetylene 1a and tosyl
hydrazine 2a was conducted in the presence of CuI, BPO
(benzoyl peroxide), and CuI/BPO, respectively. The results
indicated that the presence of both CuI and BPO enabled the
a.College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China.
b.Email: wanjieping@jxnu.edu.cn chemliuyunyun@jxnu.edu.cn
Electronic Supplementary Information (ESI) available: [general experimental
information, procedure for the synthesis of
3 and 4,
1H and 13C NMR spectra of all
products and the crystallographic data of 3i]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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production of (Z)-iodosulfonylated styrene 3a with moderate To examine the application scope, the synthesis VoiefwdAirvticelersOenliZne-
DOI: 10.1039/C6RA13737G
yield (entries 1-3, Table 1). While CuI was a mandatory halogenated vinyl sulfones
component acting as both the catalyst and iodine source in the variety of different terminal alkynes
reaction, we then examined the effect of peroxide to the As shown in Table 2, under the optimized conditions, a
reaction. It was found that peroxides such as hydrogen number of Z-alkene products were smoothly synthesized
3 was conducted by employing a
1
and sulfonohydrazides 2.
3
peroxide and TBHP (t-butyl hydrogen peroxide) was not with generally good to excellent yields. Aryl terminal alkynes
practical for the target transformation. Interestingly, the and sulfonohydrazides containing various functional groups
variation on the reaction medium with various organic such as alkyl, alkoxyl, halogen et al were all well tolerated.
solvents, including DMF, ethyl lactate (EL), EtOH, water, Considerably lower yield of related product was acquired
dichloromethane and toluene suggested that none of these when phenylacetylene containing strong electron withdrawing
solvent could mediate the reaction, implying the specific group was used (3ai, Table 2). A highly notable fact of the
function of DMSO for this reaction probably by acting as a present protocol lied in its universal applicability not only for
ligand to stabilize the copper catalyst (entries 6-11, Table 1). the synthesis of iodinated products (3a-3s, Table 2), but also
While the entry increasing the amount of CuI did not improve
Table 2 Scope of the Z-selective alkyne halosulfonylationa
the yield of 3a (entry 12, Table 1), increasing the loading of 2a
to 1.5 eq led to evident improvement on the yield of 3a
(entries 13-14, Table 1). Finally, the variation on the amount of
BPO was not able to further improve the reaction (entries 15-
16, Table 1). An additional entry employing molecular iodine as
the halogen source in the presence of catalytic amount of CuI
resulted in the production of complex mixture (entry 17, Table
1). The Z-configuration of 3a was clearly assigned by full
spectroscopic analysis and the comparison of related data with
those of E-isomer reported in literature.4c The X-ray analysis on
the single crystal of the synthesized product 3i was a further
confirmation on the assignment (Fig. 1).
R
Ar
X
Product
Yield (%)b
H
H
4-CH3
3-CH3
3-F
4-CH3C6H4
Ph
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
85
71
86
74
65
63
81
83
79
73
80
68
66
71
56
69
65
58
61
83
72
64
78
73
75
62
59
76
71
70
68
59
62
62
30
Ph
Ph
Ph
Ph
Ph
Ph
Table 1 Optimization on the reaction conditions for the Z-selective iodosulfonylation a
2-F
4-Cl
4-Br
4-CH3O
4-Cl
4-Br
4-CH3
4-Cl
4-CH3
4-Cl
4-CH3
4-CH3
4-Cl
4-CH3
4-CH3
4-CH3O
4-Cl
3-CH3
H
4-CH3
4-Cl
4-Br
4-CH3
4-Cl
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
4-CNC6H4
4-NO2C6H4
2-CH3C6H4
2-FC6H4
Ph
Entry
1c
2
3
4
5
6
7
8
Oxidant
BPO
no
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
EL
EtOH
H2O
CH2Cl2
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Yield(%)b
nr
trace
57
BPO
TBHP
H2O2
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
BPO
21
I
I
trace
trace
nr
nr
nr
nr
nr
59
85
82
70
75
nr
3s
3t
3u
3v
3w
3x
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
I
Ph
Ph
Ph
9
10
11
12d
13e
14f
15g
16h
17i
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
2-naphthyl
2-naphthyl
Ph
3y
3z
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
H
4-CH3
4-Cl
4-Br
4-Br
4-CN
Ph
Ph
Ph
aGeneral conditions: 1a (0.2 mmol), 2a (0.2 mmol), CuI (0.2 mmol), oxidant (0.2
mmol), stirred at rt for 12 h in 2.0 mL solvent, nr = no reaction; EL = ethyl lactate.
c
bYield of isolated product based on 1a. No CuI was employed. dThe CuI loading
4-CH3C6H4
4-CH3C6H4
was 0.3 mmol. eThe loading of 2a was 0.3 mmol. fThe loading of 2a was 0.4 mmol.
i
gThe loading of BPO was 0.1 mmol. hThe loading of BPO was 0.3 mmol. Catalytic
aGeneral conditions: 1 (0.2 mmol), 2 (0.3 mmol), CuX (0.2 mmol) and BPO (0.2
mmol) in DMSO (2 mL), stirred at room temperature for 12 h. bYield of isolated
product based on 1.
amount of CuI (10 mol%) in the presence of 1 eq mole of I2 (0.2 mmol), and
complex mixture was formed.
2 | J. Name., 2012, 00, 1-3
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the brominated (3t
products (3ad
-
3z
,
3aa
-
3ac, Table 2) and chlorinated formation. Subsequently, the reductive eliminViaewtiAornticleoOfnlin8e
DOI: 10.1039/C6RA13737G
-
3ah, Table 2). Therefore, along with the hardly provides Z-halogenated vinyl sulfone products 3.
accessible Z-selectivity,11 the general application scope to
different halogen sources remarks another desirable feature of
the present alkyne halosulfonylation protocol.12 No expect
halosulfonylation was observed when 1,2-diphenylethyne, a
typical internal alkyne, aliphatic terminal alkyne or
phenylacetylenes containing sensitive groups (3-hydroxyl
phenylacetylene, 3-aminophenylacetylene and 2-formyl
phenylacetylene, respectively) were subjected with tosyl
hydrazine and CuI and standard reaction conditions. In
addition, the reactions employing methanesulfonohydrazide
didn’t provide expect transformation, either.
Scheme 2 The proposed reaction mechanism
Conclusions
In conclusion, by employing Cu(I) halides as the halogen
sources and sulfonohydrazides as reaction partners, the hardly
accessible Z-selective halosulfonylation of terminal alkynes has
been successfully achieved in the presence of BPO at room
temperature. The novel Z-stereoselectivty, mild reaction
conditions and the general tolerance to halogen sources (Cl, Br,
I) have featured the high potential of the present method in
the synthesis of diverse halogenated vinyl sulfones.
Figure 1 X-Ray single crystal structure of 3i
Considering the rare availability of these Z-halogenated vinyl
sulfones determined by the lack of synthetic methodology,
primary investigation on their synthetic applications of the Z-
vinyl sulfone was then conducted. For example, products 3a
could undergo Sonogashira coupling reaction with terminal
Acknowledgments
This work is financially supported by the National Natural
Science Foundation of China (21562025) and Natural Science
Foundation of Jiangxi Province (20151BAB203008).
alkyne 1b to provide corresponding conjugate Z-enyne
In addition, the copper-catalyzed C(sp2)-I hydroxylation of 3a
could provide efficiently α-tosyl phenylacetone (eq 2).
4 (Eq1).
5
Notes and references
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To illustrate the possible routes of transformation, the
mechanism has been proposed on the basis of the outcomes
obtained in our work and related literatures (Scheme 2).5d,8a In
known reports of alkyne difunctionalization involving the
sulfonyl reagents, the sulfone radical is a generally recognized
intermediate. As proposed in the previous E-selective
halosulfonylation of alkynes using sulfonohydrazides in the
presence of a peroxide and FeX3 (X = Cl, Br),8a the sulfonyl
2
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3
4
radical
sulfonohydrazide in the presence of peroxide (BPO). With the
activation CuX, the reaction of alkyne with sulfonyl radical
provides vinyl sulfone radical . The incorporation of to CuX
may then results in the formation of Cu(II)-species via
oxidative addition. The Cu---O interaction forming cyclic
structure in accounts for the Z-selectivity of this vinyl sulfone
6
is proposed to be produced from the
6
7
7
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11 CCDC 1474142
(3i
)
contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
12 According to the TLC analysis, small amount of E-isomers
were observed in some entries, but none of them were
isolable by column chromatography (very low yield) in the
present scale of experiment.
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DOI: 10.1039/C6RA13737G
Stereoselective Z-halosulfonylation of terminal alkynes using
sulfonohydrazides and CuX (X = Cl, Br, I)
Jie-Ping Wan,*,a Deqing Hu,a Feicheng Bai,a Li Weia and Yunyun Liu*,a
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, 330022
China.
Email: wanjieping@jxnu.edu.cn; chemliuyunyun@jxnu.edu.cn
The unconventional Z-selective halosulfonylation of terminal alkynes has been
achieved by using CuX (X= Cl, Br, I)/sulfonohydrazides at rt. Providing a practical
and new route for the synthesis of diverse halogenated vinyl sulfones.