Iodine-Promoted Deoxygenative Iodization/Olefination/Sulfenylation of Ketones with Sulfonyl Hydrazides: Access to β-Iodoalkenyl Sulfides

Article abstract of DOI:10.1021/acs.orglett.8b00511

A highly regio- and stereoselective synthesis of β-haloalkenyl sulfides using commercially available ketones and sulfonyl hydrazides as starting materials has been developed. This protocol obviates the need for alkynes and traditional sulfenylating agents

Full text of DOI:10.1021/acs.orglett.8b00511

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iodine-Promoted Deoxygenative Iodization/Olefination/
Sulfenylation of Ketones with Sulfonyl Hydrazides: Access to
β‑Iodoalkenyl Sulfides
Yishu Bao, Xiuqin Yang, Qingfa Zhou,* and Fulai Yang*
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P.
R. China
S
* Supporting Information
ABSTRACT: A highly regio- and stereoselective synthesis of β-
haloalkenyl sulfides using commercially available ketones and
sulfonyl hydrazides as starting materials has been developed. This
protocol obviates the need for alkynes and traditional sulfenylating
agents and therefore opens up a new door to construct β-
iodoalkenyl sulfides in a highly simple manner. This study reveals
that ketones could be used as vinyl iodide precursors in organic synthesis.
β-Haloalkenyl sulfides, including carbon−halogen bonds,
carbon−carbon double bonds, and carbon−sulfur bonds,
which are easily decorated into various alkenes and alkynyl
sulfides, can serve as key building blocks in the synthesis of
complex pharmaceutical drugs and biologically active mole-
cules.1 Consequently, developing effective methods to access β-
haloalkenyl sulfides represents a striking research field.
Traditionally, β-haloalkenyl sulfides are obtained by the
addition of sulfenylating agents, such as sulfenyl halides,2
sulfenamides,3 disulfides,4 thiols,4a and sodium arenesulfinates5
to alkynes (Scheme 1a). Nevertheless, these strategies endured
haloalkenyl sulfides from readily accessible substrates through
environmentally friendly reaction conditions.
In the course of exploring new methods to synthesize organic
sulfides, we found that sulfonyl hydrazides could serve as ideal
sulfenylating agents regarding stability, commercial availability,
and low toxicity.8 Later, many excellent and significant works
on the construction of the C−S bond using sulfonyl hydrazides
as sulfenylating agents have been reported by the groups of
Tian,9 Singh,10 Jiang,11 and others.12 In all these reports, the
reductive nature of the NHNH2 group is utilized to remove the
two oxygen atoms of the sulfonyl group to give sulfenylating
agents, water, and molecular nitrogen; however, none of these
reports takes advantage of the nucleophilicity of the NHNH2
group for chemical synthesis. In this context, we initiated a
research program with the aim of making full use of the
reductive nature and the nucleophilicity of the NHNH2 group
in the sulfonyl hydrazide. Ketones are stable and readily
accessible, and they have been widely employed to form
sulfonylhydrazones with sulfonyl hydrazides;13 consequently,
the use of ketones as electrophilic reagent was our first choice.
We envisioned that sulfonyl hydrazides reacted with ketones to
afford sulfonylhydrazones which might be oxidized by iodine
via single-electron transfer to afford vinyl iodides,14,15 and then
vinyl iodides reacted with the in situ generated sulfenyl iodides
from sulfonyl hydrazines or byproduct sulfonyl groups to afford
β-iodoalkenyl sulfides,8 wherein water and molecular nitrogen
are expected to be generated as byproducts (Scheme 1b). We
anticipated that the role of the iodine would be three-fold:
oxidizing sulfonylhydrazone, affording vinyl iodide, and
accelerating the decomposition of sulfonyl group to give
sulfenyl iodide. To the best of our knowledge, this three-
component reaction of ketones with sulfonyl hydrazides and
iodine to direct synthesis of β-iodoalkenyl sulfides has never
Scheme 1. Synthetic Strategy for the Formation of β-
Haloalkenyl Sulfides
three key challenges. First, many of the sulfenylating agents are
unstable to air and moisture, are expensive, or even possess
unpleasant odors.6 This is particularly problematic for large-
scale synthesis. In addition, most alkynes are noncommercial
and require several steps to prepare,7 thus complicating
synthetic operations and increase population. Furthermore,
these reactions frequently require metal catalysts, suffer from a
narrow substrate scope, or yield byproducts unfriendly to the
environment.2g,3−5 To address such challenges, it would be of
tremendous interest in developing new strategies to generate β-
Received: February 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00511
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
been documented, which represents a novel and important
reaction mode and extends the application of ketones.
Scheme 2. Scope of Ketones 1 for Synthesis of β-Iodoalkenyl
Sulfides 3
a
To test our hypothesis, the reaction of acetophenone (1a)
with p-toluenesulfonyl hydrazide (2a) and iodine was selected
as a prototype reaction (Table 1). When the reaction was
Table 1. Screening Reaction Conditions for Synthesis of β-
a
Iodoalkenyl Sulfides
b
c
entry
[ I ]
additive (equiv)
solvent
yield (%)
E/Z
1
2
3
4
5
6
7
8
9
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
NIS (1.0)
I2 (0.75)
I2 (0.4)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
CH2Cl2
CH2Cl2
DMF
12
30
trace
trace
12
36
19
26
48
72
58
40
51
64
52
0
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
KI (4)
NaI (4)
TBAI (4)
KI (2)
KI (6)
84:16
89:11
EtOH
CH3CN
toluene
CH3NO2
THF
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
90:10
92:8
d
10
d
11
91:9
d
d
d
d
d
d
d
,e
12
13
14
15
16
17
18
87:13
85:15
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), in n-hexane (1.0
b
c
d
mL), at 120 °C (oil bath), for 12 h. At 100 °C. Two hours. NIS (2
equiv), 2 h.
88:12
fluoro, chloro, bromo, iodo, and trifluoromethyl with a minor
steric effect. However, propiophenone (1p) gave 3p with lower
yield; it might be caused by steric effect of methyl group.
Acetylferrocene (1q) could also preform under the reaction
condition. To our delight, aliphatic ketones could also afford
corresponding β-iodoalkenyl sulfides (3r−3t) in moderate
yields, where it was notable that 1t gave a ring-opened product.
Furthermore, when 1-adamantyl methyl ketone (1u) was used
as substrate, the product more easily converted into alkenyl
disulfide 3u, albeit with lower yield.
Subsequently, the scope of sulfonyl hydrazides was tested
(Scheme 3). A range of aryl sulfonyl hydrazides that have
electron-donating and electron-withdrawing groups reacted
with ketones to give the corresponding β-iodoalkenyl sulfides
(4a−4h) in moderate to good yields. In addition, alkyl sulfonyl
hydrazides proved to be suitable reaction partners, giving
57
53
82:18
84:16
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), in solvent (1
b
c
mL), at 120 °C (oil bath), for 12 h. Yield of isolated product. E/Z
ratio determined by GC−MS. 2a (0.4 mmol). At 100 °C. NIS = N-
iomosuccinimide. TBAI = tetrabutylammonium iodide.
d
e
performed in CH2Cl2 at 120 °C, β-iodoalkenyl sulfide 3a was
obtained in 12% yield. The lower yield was ascribed to the
formation of a significant amount of dithioether. Surprisingly, in
the presence of additive KI, the amount of dithioether was
reduced and a moderate yield of 3a was obtained. Encouraged
by this result, various solvents were examined, and a good yield
was achieved when using n-hexane as solvent. Further
examination showed that the ratio of starting materials is
crucial, and the highest yield, 72%, was obtained when the ratio
of 1a, 2a, and I2 was adjusted to 2:4:1. Increasing the scale from
0.20 to 1.0 mmol gave a slightly lower yield (67%). Lowering
the reaction temperature to 100 °C led to a lower yield. NIS, in
place of I2, was also checked in the reaction, giving a moderate
yield. In addition, increasing and decreasing the amount of
iodine resulted in a much lower yield. Finally, screening
additives revealed that the additives have great impact on the
reaction. NaI could also be used as additive for the present
reaction; however, TBAI was not compatible with this reaction.
Thus, the optimal reaction conditions were 1 equiv of 1a, 2
equiv of 2a, 0.5 equiv of I2, and 4 equiv of KI in n-hexane at 120
°C.
Scheme 3. Scope of Sulfonyl Hydrazides 2 for Synthesis of β-
a
Iodoalkenyl Sulfides 4
Under the optimized reaction conditions, a series of ketones
were investigated for this reaction (Scheme 2). Various
substituted aryl methyl ketones (1a−1o) could react with
sulfonylhydrazides to give β-iodoalkenyl sulfides (3a−3o) in
moderate to good yields with high E/Z selectivity. Notably, the
reaction tolerated a variety of functional groups, such as alkoxy,
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), in n-hexane (1.0
b
c
mL), at 120 °C (oil bath), for 12 h. At 100 °C. Two hours.
B
DOI: 10.1021/acs.orglett.8b00511
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Letter
products 4i and 4j with similar efficiency. Notably, ternary ring
of 4j did not provide a ring-opened product, indicating that the
process might not involve sulfide radicals.16
Scheme 5. Plausible Reaction Mechanism
To gain insight into the reaction mechanism, a series of
control experiments with possible intermediates was performed
(Scheme 4). Initially, as the most possible two intermediates, 5
Scheme 4. Control Experiments
a
Scheme 6. Transformations of E-3a
and 6 were first synthesized and tested in the reaction. No
reaction was found when 5 was disposed with the standard
conditions, while 6 could be transformed into product 3a in the
yield of 48% (eqs 1 and 2). Vinyl iodide (7) and vinyl diiodide
(8) were found to be two critical intermediates during the
reaction, both of which could be directly transformed into final
product E-3a, in 60% and 22% yields, respectively (eqs 3 and
4). Sulfonyl hydrazide 2a easily decomposed to give disulfide 9,
sulfonothioate 10, and sulfinic acid 11 by previous study;8
however, none of them could afford the desired product under
the standard conditions, which substantially demonstrates that
the nucleophilicity of the NHNH2 group in the sulfonyl
hydrazide is essential (eq 5). The reaction was also examined in
the presence of base; however, no product was observed, which
suggests that the reaction may not proceed via diazo compound
intermediate (eq 6).13
On the basis of the results described above and previous
studies,8,14,15 a proposed pathway is illustrated (Scheme 5).
Initially, ketone 1 reacts with sulfonyl hydrazide 2 to give
sulfonylhydrazone I, which is oxidized by iodine via single
electron transfer to afford intermediate II.14 Isomerization of II
gives III, which reacts with iodine to afford intermediate IV,
and then IV releases N2 and tosyl group to give V, which
undergoes radical path with iodine to give VI. Under heating
conditions, VI loses HI to furnish the corresponding 7.15
Alternatively, sulfonyl hydrazide 2 reacts with iodine to yield
sulfenyl iodide 12. VII, tautomeric isomer of 7, reacts with 12
to give the target product 3a via path a, while a part of VII via
path b affords 8 and furnishes E-3a and Z-3a.
a
Reagents and conditions: (a) mCPBA (1 equiv), CH2Cl2, 40 °C, 4 h.
(b) mCPBA (2.5 equiv), CH2Cl2, 60 °C, 4 h. (c) p-MeC6H4B(OH)2
(2 equiv), Pd(OAc)2 (5 mol %), XPhos (10 mol %), K2CO3 (2 equiv),
toluene, 110 °C, 12 h. (d) p-MeC6H4CCH (1.2 equiv), Pd(PPh3)4 (5
mol %), CuI (5 mol %), Et3N (2 equiv), CH3CN, 70 °C, 3 h. (e)
TMSA (1.5 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N
(1.5 equiv), PPh3 (10 mol %), toluene, 70 °C, 2 h. (f) Pd(PPh3)4 (10
mol %), CuI (10 mol %), Et3N (1.5 equiv), THF, 120 °C, 18 h; the
yield of E-13f was calculated by sulfur atom. Tol = p-tolyl. TMSA =
trimethylsilylacetylene. XPhos = 2-dicyclohexylphosphino-2′,4′,6′-
triisopropylbiphenyl.
tolylboronic acid, via a Suzuki−Miyaura coupling reaction,
provided E-13c in 94% yield.18 E-3a with p-tolylacetylene
furnished E-13d in 91% yield by Sonogashira−Hagihara
coupling.19 Another conjugated enyne E-13e was obtained by
introducing trimethylsilylacetylene in 85% yield.20 Interestingly,
E-3a afforded E-13f under palladium catalysis, which can be
further oxidized to afford bis-sulfoxide ligands, a potent catalyst
precursor similar to White’s catalyst.21
To indicate the synthetic utility of the β-iodoalkenyl sulfides,
we undertook a series of reactions using the representative
product E-3a, and the results are summarized in Scheme 6.
With different equivalents of m-CPBA, E-3a could convert into
the corresponding oxidized products E-13a and E-13b, in yields
of 90% and 88%, respectively.17 Arylation of E-3a with p-
In conclusion, we have developed an unprecedented protocol
for the synthesis of β-iodoalkenyl sulfides through tandem
deoxygenative iodization/olefination/sulfenylation of ketones
C
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(5) Lin, Y.-M.; Lu, G.-P.; Cai, C.; Yi, W.-B. Org. Lett. 2015, 17,
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% iodine, a range of aryl- and alkylsulfonyl hydrazides smoothly
reacted with various ketones to give structurally diverse β-
iodoalkenyl sulfides with high regio- and stereoselectivity. This
protocol obviates the need for alkynes and traditional
sulfenylating agents and therefore opens up a new door to
construct β-haloalkenyl sulfides in a highly simple fashion. This
study paves the way for the use of ketones as precursor of vinyl
iodide in chemical synthesis. In addition, synthetic utility of the
iodide and sulfide revealed great potential value of β-
iodoalkenyl sulfides.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: zhouqingfa@cpu.edu.cn.
*E-mail: fly1986@ustc.edu.cn.
ORCID
Qingfa Zhou: 0000-0001-6360-2285
Fulai Yang: 0000-0002-1136-0867
Notes
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21502182, 21102179 and
21572271), Qing Lan Project of Jiangsu Province, National
Found for Fostering Talents of Basic Science (J1030830), the
Fundamental Research Funds for the Central Universities
(3010050077), and Postgraduate Scientific Research Innova-
tion Projects of Jiangsu Province (KYCX17_0664).
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