Direct Iodosulfonylation of Alkylynones with Sulfonylhydrazides and Iodine Pentoxide Leading to Multisubstituted α,β-Enones

Article abstract of DOI:10.1055/s-0036-1589160

A facile and efficient method has been developed for the construction of multisubstituted α,β-enones through the direct selective iodosulfonylation of alkylynones with sulfonylhydrazides and iodine pentoxide. The present methodology offers a simple and attractive approach to various multisubstituted α,β-enones in moderate to good yields with excellent stereo- and regioselectivities under the metal- and peroxide-free conditions.

Full text of DOI:10.1055/s-0036-1589160

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
Date, Signature
st-2017-w0771-l.fm
letter
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1/10/18
H. Cui et al.
Letter
Synlett
Direct Iodosulfonylation of Alkylynones with Sulfonylhydrazides
and Iodine Pentoxide Leading to Multisubstituted α,β-Enones
Huanhuan Cuia§
Metal-free
Peroxide-free
O
I
Chenglong Hea§
Daoshan Yanga
Huilan Yueb
O
O
S
+ I2O5
+
Ar
NHNH2
DME, 80 °C
air, 9–12h
R2
R1
R1
O
S
O
O
Ar
Wei Wei*a,b
Hua Wang*a
R2
18 examples
up to 97% yields
a Institute of Medicine and Material Applied Technologies,
Key Laboratory of Pharmaceutical Intermediates and
Analysis of Natural Medicine, School of Chemistry and
Chemical Engineering, Qufu Normal University, Qufu
273165, Shandong, P. R. of China
huawangqfnu@126.com
b Key Laboratory of Tibetan Medicine Research, Northwest
Institute of Plateau Biology, Chinese Academy of Sciences,
Qinghai 810008, P. R. of China
weiweiqfnu@163.com
§ These authors contributed equally to this work
Received: 17.10.2017
Accepted after revision: 06.12.2017
Published online:
ods for the preparation of multifunctionalized α,β-enones
with defined substitution patterns are relatively rare, and
they usually involve harsh reaction conditions and multiple
steps.6
DOI: 10.1055/s-0036-1589160; Art ID: st-2017-w0771-l
Abstract A facile and efficient method has been developed for the
construction of multisubstituted α,β-enones through the direct selec-
tive iodosulfonylation of alkylynones with sulfonylhydrazides and iodine
pentoxide. The present methodology offers a simple and attractive ap-
proach to various multisubstituted α,β-enones in moderate to good
yields with excellent stereo- and regioselectivities under the metal- and
peroxide-free conditions.
Sulfone groups are extremely valuable functionalities
that are frequently found in various natural products, bio-
logically active compounds, and materials.7 Thus, the incor-
poration of sulfone groups into organic frameworks to con-
struct various organic sulfones has attracted increasing at-
tention from chemists.8 Over the past several years, the
halosulfonylations of alkynes have been developed to ac-
cess β-halovinyl sulfones,9,10 in which both halogen and sul-
fone groups could be simultaneously introduced into or-
ganic molecules. However, most of these methods are re-
stricted to terminal alkynes, and only a few successful
strategies have been developed for the halosulfonylation of
internal alkynes in a highly regioselective manner because
of steric and electronic issues.11,12 With our continued in-
terests in the construction of sulfone-containing com-
pounds,13 herein, we wish to describe a convenient and effi-
cient synthetic method for the construction of multifunc-
tionalized α,β-enones through selective iodosulfonylation
of alkylynones with iodine pentoxide and sulfonylhydra-
zides (Scheme 1). This protocol provides an attractive ap-
proach to various multisubstituted α,β-enones in moderate
to good yields with excellent stereo- and regioselectivities
under the metal- and peroxide-free conditions.
Key words multifunctionalized α,β-enones, iodosulfonylation, alkyly-
nones, sulfonylhydrazides, iodine pentoxide
α,β-Enones represent a common structural motif in
many useful reactions.1 Furthermore, they frequently serve
as important bifurcations for the construction of drug-like
heterocyclic libraries.2 In particular, functionalized α,β-
enones have drawn particular interest from chemists be-
cause of their widespread applications in synthetic and me-
dicinal chemistry. To date, various approaches towards the
synthesis of α,β-enones have been developed, such as aldol
condensation,3 dehydration of α-hydroxy carbonyl com-
pounds,4a isomerization of propargylic alcohols,4b and
Horner–Wadsworth–Emmons (HWE) reaction.5 Neverthe-
less, most of these methods mainly focus on the synthesis
of unfunctionalized α,β-enones. Direct and efficient meth-
O
I
O
O
DME, 80 °C
air, 9–12 h
+
Ar
S
NHNH2 + I2O5
R2
R1
R1
O
S
O
O
Ar
R2
Scheme 1 Iodosulfonylation of alkylynones with sulfonylhydrazides and I2O5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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H. Cui et al.
Letter
Synlett
In an initial experiment, we started our investigation by
choosing 1,3-diphenylprop-2-yn-1-one (1a) and benzene-
sulfono-hydrazide (2a) as model substrates to optimize the
reaction conditions in the presence of I2O5 (1 equiv) (Table
1). When the model reaction was carried out in 1,2-dime-
thoxyethane (DME) at room temperature, the desired prod-
uct 4aa was obtained in only 10% yield (entry 1). To our de-
light, the efficiency of the reaction clearly improved with an
increase in the reaction temperature (entries 2–4), and a
good yield (83%) was obtained when the reaction was car-
ried out at 80 °C (entry 3). The structure of 4aa was further
unambiguously confirmed by single-crystal X-ray analysis
(Figure 1). Solvent screening studies established that the
use of 1,2-dichloroethane (DCE) also resulted in good yield
(81%) ((entry 5), and other solvents such as THF, CH3CN, tol-
uene, MeOH, and H2O gave low to moderate yields (entries
6–10). No transformation was observed when either DMF
or DMSO was used as solvent (entries 11 and 12, respec-
tively). Furthermore, replacing I2O5 with other iodine re-
agents such as I2, KI, NaI, or TBAI all resulted in low reaction
efficiency (entries 13–16), indicating the important role of
I2O5 in the present reaction system. Either reducing or in-
creasing the amount of I2O5 slightly decreased the yields
(entries 17 and 18). In addition, the substrate ratio was also
examined, and the appropriate proportion of 1a, benzene-
sulfono-hydrazide 2a, and I2O5 was 1:3:1 (entries 19 and 20).
Table 1 Optimization of Reaction Conditionsa
O
I
O
S
O
Solvent
T (°C)
Ph
Ph
+
Ph
NHNH2
+
Iodine reagents
Ph
O
S
O
O
Ph
1a
Ph
4aa
2a
3
Entry
Iodine reagents (equiv) Solvent
Temp. (°C) Yield (%)b
1
2
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2O5 (1)
I2 (1)
DME
DME
DME
DME
DCE
25
60
80
100
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
10
77
83
82
81
62
40
27
10
20
0
3
4
5
6
THF
7
CH3CN
toluene
MeOH
H2O
8
9
10
11
12
13
14
15
16
17
18
19
20
DMF
DMSO
DME
DME
DME
DME
DME
DME
DME
DME
0
10
35
24
15
49
77
30c
57d
KI (1)
NaI (1)
TBAI (1)
I2O5 (0.5)
I2O5 (1.5)
I2O5 (1)
I2O5 (1)
a Reaction conditions: 1a (0.125 mmol), 2a (0.375 mmol), iodine reagent
(0.125 mmol), solvent (2 mL), 25–80 °C, under air, 12 h.
b Isolated yield based on 1a.
c 1a (0.125 mmol), 2a (0.125 mmol).
d 1a (0.125 mmol), 2a (0.25 mmol).
tron-donating group or an electron-withdrawing group all
reacted with sulfonylhydrazide to give the corresponding
products 4aa–ga in good yields.
In general, electron-donating group substituted alkyly-
nones (1b, 1d) showed higher activity than those bearing
electron-withdrawing groups (1e–g). Furthermore, the re-
action efficiency was also affected by steric effects; sub-
strates bearing a methyl group in the meta-position of the
phenyl ring resulted in slightly lower yield than those sub-
stituted on the para-position of the phenyl ring (4ab vs.
4ac). Moreover, haslide substituents such as F, Cl, and Br
groups were compatible with this reaction, leading to the
corresponding products 3ea–ga, which could be used for
further structural modifications. Subsequently, the impact
of alkyne end substitution on the reaction was studied.
Similarly, arylynones including an electron-donating group
Figure 1 The crystal structure of 4aa. ORTEP drawing of C21H15IO3S
with 50% probability ellipsoids, showing the atomic numbering
scheme.
After establishing the optimal reaction conditions for
the iodosulfonylation of alkylynones, the scope of the reac-
tion with various alkylynones and sulfonylhydrazides was
examined. Firstly, the impact of substitution variation at
the keto terminal of the ynone was investigated. As shown
in Scheme 2, aromatic ynones containing either an elec-
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H. Cui et al.
Letter
Synlett
O
I
O
O
S
DME, 80 °C
R1
R2
+ I2O5
Ar
NHNH2
+
R1
O
S
O
O
R2
Ar
4
2
3
1
MeO
F
O
O
S
O
I
O
O
S
O
O
O
S
O
I
O
O
S
O
O
O
S
O
I
I
I
4aa ( 83%)
4ba (90%)
4ca (75%)
4da (92%)
4ea (75%)
Cl
Br
F
O
O
S
O
I
O
O
S
O
O
O
S
O
I
O
O
S
O
I
O
O
S
O
I
I
4fa (68%)
4ga (75%)
4ha (97%)
4ia (72%)
4ja (73%)
F
Br
Cl
O
O
S
O
I
O
O
S
O
I
O
O
S
O
I
O
O
S
O
I
O
S
O
I
H
4ka (86%)
4la (63%)
4ma (84%)
4ab (92%)
4ac(82%)
Br
Me
O
O
S
O
I
O
O
S
O
O
O
S
O
I
I
4ad (52%)
4ae (0%)
4af (0%)
Scheme 2 Results for the reactions of iodosulfonylation of alkylynones with sulfonohydrazides and I2O5. Reagents and conditions: 1 (0.125 mmol), 2
(0.375 mmol), 3 I2O5 (0.125 mmol), DME (2 mL), 80 °C, under air, 9–12 h (isolated yields based on 1).
or an electron-withdrawing group were all suitable for this
reaction, and the corresponding products 4ha–la were ob-
tained in good to excellent yield. In addition, compounds
with a terminal alkyne such as phenylacetylene was also
compatible with this reaction, leading to the corresponding
product 4ma in 84% yield. Finally, with respect to sulfono-
hydrazides, in addition to benzenesulfonohydrazide 2a, a
series of arylsulfonohydrazides bearing both electron-do-
nating groups (Me) and electron-withdrawing groups (F,
Br) could also be smoothly transformed into the corre-
sponding products 4ab–ad. However, none of desired prod-
ucts were detected when a more sterically hindered sulfo-
nylhydrazide such as 2,4,6-triisopropylbenzenesulfonohy-
drazide or a alkylsulfonohydrazide such as methane-
sulfonohydrazide were employed in the present reaction
system.
To gain further insight into the mechanism, a radical
capture experiment was carried out. As shown in Scheme 3,
when 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was
added into the reaction system, the model reaction was ex-
tremely inhibited and only a trace amount of desired prod-
uct 4aa was detected, suggesting that a radical pathway
might be involved in this transformation.
O
I
O
O
S
TEMPO (2 equiv)
DME, 80 °C
Ph
Ph
+
+ I2O5
NHNH2
Ph
Ph
O
S
O
O
Ph
Ph
4aa (0%)
3
1a
2a
Scheme 3 Preliminary mechanistic study
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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H. Cui et al.
Letter
Synlett
Based on the above results and on previous reports,9–12,14
a possible reaction pathway is proposed as shown in
Scheme 4. Initially, sulfonyl radical 5 and I2 are generated
from the single-electron oxidation of sulfonylhydrazide 2
by I2O5.14 Subsequently, the selective addition of sulfonyl
radical 5 to alkylynone 1 gives vinyl radical 6. Finally, the
interaction of radical 6 with molecular iodine would lead to
the formation of the desired product 4.
(2) (a) Marzinzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63, 723.
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I2O5
O
O
S
O
S
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Ar
NHNH2
R2
O
S
O
O
O
N2
Ar
6
5
2
I2 + H2O
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2015, 80, 2281. (b) Ciesielski, J.; Canterbury, D. P.; Frontier, A. J.
Org. Lett. 2001, 3, 823. (c) Bertozzi, F.; Gustafsson, M.; Olsson, R.
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Murray, W. V. J. Org. Chem. 2016, 81, 3464.
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Organic Synthesis; Pergamon Press: Oxford, 1993. (b) Wolf, W.
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Carter, M.; Cockerill, G. S.; Dickerson, S.; Gauthier, C. A.; Guo, Y.;
Mook, R. A.; Rusnak, D. W.; Walker, A. L.; Wood, E. R.; Lackey, K.
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O
I
R2
R1
O
S O
Ar
4
Scheme 4 Postulated reaction pathway
In summary, a new and efficient iodosulfonylation of al-
kylynones with iodine pentoxide and sulfonylhydrazides
leading to multisubstituted α,β-enones has been devel-
oped.15 The present protocol, which utilizes simple and
readily available starting materials, as well as metal- and
peroxide-free conditions, provides an attractive approach
to various multisubstituted α,β-enones in moderate to
good yields with excellent stereo- and regioselectivities.
Further studies on the scope and application of this reac-
tion are under way in our laboratory.
Funding Information
This work was supported by the National Natural Science Foundation
of China (No. 21302109, 21302110, 21375075, and 21675099), the
Natural Science Foundation of Shandong Province (ZR2015JL004 and
ZR2016JL012), and the Open Projects Program of the Key Laboratory
of Tibetan Medicine Research, Chinese Academy of Sciences, National
Training Programs of Innovation and Entrepreneurship for Under-
graduates (201610446026).
N
oaitn
a
l
N
a
utra
l
Secince
F
o
u
n
doaitn
of
C
h
n
i
a
2(
1
3
0
2
1
0
9
N)
a
utarl
Secince
F
o
u
n
doaitn
of
S
h
a
n
d
o
n
g
Provn
i
ce
Z(
R
2
0
1
5LJ0
0
4)
Z(
R
2
0
1
6LJ0
1
2)
(10) (a) Katrum, P.; Chiamapanichayakul, S.; Korworapan, K.;
Pohmakotr, M.; Reutrkul, V.; Jaipetch, T.; Kuhakarn, C. Eur. J.
Org. Chem. 2010, 5633. (b) Wei, W.; Wen, J.; Yang, D.; Jing, H.;
You, J.; Wang, H. RSC Adv. 2015, 5, 4416. (c) Liu, X.; Duan, X.;
Pan, Z.; Han, Y.; Liang, Y. Synlett 2005, 1752. (d) Fang, Y.; Luo, Z.;
Xu, X. RSC Adv. 2016, 6, 59661. (e) Wan, J.-P.; Hu, D.; Bai, F.; Wei,
L.; Liu, Y. RSC Adv. 2016, 6, 73132.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589160.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
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(12) After performing the experiments and while preparing this
manuscript, Reddy and co-workers reported iodosulfonylation
of internal alkynes to synthesize highly substituted multifunc-
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M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, 315.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E