Solvent-Controlled, Tunable Hydrosulfonylation of 3-Cyclopropylideneprop-2-en-1-ones

Article abstract of DOI:10.1021/acs.orglett.6b02047

An interesting and tunable hydrosulfonylation of 3-cyclopropylideneprop-2-en-1-ones with sodium sulfinates and acetic acid is described. The corresponding β- or ?3;-addition products can be produced in good to excellent yields with high selectivities, respectively. A rationale for these transformations is proposed base on the controlled experiments.

Full text of DOI:10.1021/acs.orglett.6b02047

Letter
pubs.acs.org/OrgLett
Solvent-Controlled, Tunable Hydrosulfonylation of
3‑Cyclopropylideneprop-2-en-1-ones
Maozhong Miao,* Yi Luo, Huaping Xu, Zhengkai Chen, Jianfeng Xu, and Hongjun Ren*
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P. R. China
S
* Supporting Information
ABSTRACT: An interesting and tunable hydrosulfonylation
of 3-cyclopropylideneprop-2-en-1-ones with sodium sulfinates
and acetic acid is described. The corresponding β- or γ-
addition products can be produced in good to excellent yields
with high selectivities, respectively. A rationale for these
transformations is proposed base on the controlled experi-
ments.
he functionalization of a carbon−carbon multiple bond
complete control of the regio- and stereoselective addition
remains a grand challenge and is still highly pursued.
T
constitutes highly synthetically versatile processes.1
Particularly, the nucleophilic additions to functionalized allenes
continue to attract the attention of chemists because they could
provide an efficient way to form a new C−C or C−heteroatom
bond in an inter- or intramolecular fashion with enormous
potential.2 Generally, the nucleophilic addition to acceptor
substituted allenes usually takes place at the β-position yielding
either the nonconjugated (kinetic control) or the conjugated
(thermodynamic control) products (Scheme 1a).3 However, a
On the other hand, the 3-cyclopropylideneprop-2-en-1-ones,
which contain the highly strained cyclopropyl ring and carbonyl
group adjacent to the two ends of cumulated double bonds, are
a class of thermally stable, yet activated allenic derivatives.7 The
versatile and unique reactivity makes these compounds highly
attractive synthetic building blocks in organic synthesis. Due to
interest in exploring the synthetic potential of these derivatives,
we have comprehensively studied the transition-metal-catalyzed
cycloisomerization of 3-cyclopropylideneprop-2-en-1-ones to
provide a facile synthesis of functionalized 2-alkylidenecyclo-
butanones, benzofuran-7(3aH)-ones, and furans.8 Moreover,
we have also reported a hydroxyphosphinylation of 3-
cyclopropylideneprop-2-en-1-ones, introducing the hydroxyl
and phosphonyl group simultaneously to afford highly
functionalized vinylcyclopropanol units in high yields.9
Recently, the incorporation of a sulfonyl group into organic
molecules has emerged as a significant research field of current
interest in organic chemistry as sulfones are commonly
encountered in agrochemicals,10 pharmaceuticals,11 and organic
materials.12 We thus envisioned that the hydrosulfonylation of
3-cyclopropylideneprop-2-en-1-ones would give valuable sulfo-
nylated entities, proceeding in a highly regio- and stereo-
selective manner. As a result, herein we report the solvent-
controlled13 switchable addition reactions of sodium sulfinates
to 3-cyclopropylideneprop-2-en-1-ones, which could give either
the β- or γ-sulfonylation products with high selectivities
(Scheme 1c). To our knowledge, such a facile and tunable
catalyst-free nucleophilic addition of activated allenes to give
both β- and γ-addition products of high selectivity has not been
observed before.
Scheme 1. Additions of Nucleophiles to Electron-Deficient
Allenes
troublesome feature of the reaction is the potential migration of
the CC bond that may lead to formation of a synthetically
useless mixture.4 The phosphine-catalyzed additions of
nucleophiles to electron-deficient allenes provide additional
selectivity, which enables the nucleophiles to add to the γ-
position to give allyl products (Scheme 1b).5 Nevertheless, the
formation of geometric isomers is often observed.6 Thus,
We initially studied the hydrosulfonylation reaction by
reacting 3-cyclopropylidene-1,2-diphenylprop-2-en-1-one (1a)
with PhSO2Na (2a) in acetone at room temperature employing
Received: July 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02047
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Letter
ab
,
acetic acid as the proton source. The nonconjugated β-addition
product 3a was produced with high selectivity in 85% yield as
expected (Table 1, entry 1). The use of strong organic acids as
Scheme 2. Scope of β-Adducts
a
Table 1. Examinations on Reaction Conditions
b
b
yield of 3a yield of 4aa
entry
acid
AcOH
solvent
acetone
t (h)
(%)
(%)
1
2
3
4
5
6
3
85
28
trace
84
84
86
94
91
76
84
89
71
−
−
−
−
−
−
trace
TsOH·H2O
TfOH
acetone
acetone
acetone
MeCN
THF
3
0.5
1.5
7
PhCO2H
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
7
c
7
MeOH
EtOH
0.1
0.1
12
10
12
12
8
−
trace
−
8
9
toluene
cyclohexane
DCM
10
11
12
13
14
15
trace
−
−
98
95
64
a
Conditions: 1 (0.2 mmol), 2 (0.4 mmol), AcOH (0.4 mmol) in 2 mL
dioxane
DMSO
DMF
b
c
of MeOH at rt in open air. Isolated yield. Large-scale reaction: 1a (5
mmol, 1.232 g), 2b (2 equiv), AcOH (2 equiv) to afford 3b (1.975 g).
24
24
trace
HMPA
−
products in high yield. In addition, a substrate bearing an alkyl
substituent at the 1-position, i.e., 1-cyclopropylidene-4-methyl-
2-phenylpent-1-en-3-one, also successfully gave the desired
product 3k cleanly, albeit in a somewhat low yield.
a
Conditions: 1a (0.1 mmol), 2a (0.2 mmol), AcOH (0.2 mmol) at rt
b
c
in open air. Isolated yield. The reaction generated a complex product
mixture when PhSO2H was directly used instead of PhSO2Na and
AcOH.
The selective addition of sodium sulfinates to 3-cyclo-
propylideneprop-2-en-1-ones to produce γ-adducts is partic-
ularly interesting, and our subsequent examination on the scope
of the reaction reveals that this transformation is quite general.
As shown in Scheme 3, a variety of sodium sulfinates are
applicable to produce the γ-adducts with excellent regioselec-
tivity and good to high geometric selectivity. Except in the case
of the sodium 4-acetamidobenzenesulfinate and sodium
thiophene-2-sulfinate, which gave the products 4af and 4am
in modest yields, the reactions of other sodium sulfinates with
1a all gave the desired products in high yields (81−98%).
Particularly, a sodium sulfinate bearing an isoxazol unit also
proved to be a good substrate to deliver the product 4an in
97% yield. Furthermore, the reaction could also be performed
with sodium alkylsulfinates, as exemplified by the successful
production of 4ao and 4ap from sodium methanesulfinate and
sodium cyclopropanesulfinate. Moreover, the generality of the
reaction with various 3-cyclopropylideneprop-2-en-1-ones 1
was also investigated. Substrates 1 bearing aryl groups at the 1-
position (R1 = aryl) gave the products in 64−97% yields.
Nevertheless, a low yield (43%) was observed in the case of the
isopropyl substituted substrate. The reaction of a vinyl substrate
(R1 = 2-methylpropenyl) afforded the desired product 4lb in
high yield. The substituent effect regarding R2 in 1 was also
briefly examined. As can be seen, substrates with both electron-
donating and -withdrawing aromatic groups are all good
substrates to afford the corresponding products 4mb−4rb in
good yields. Here it is worth noting that the reactions all
proceed with high geometric selectivity, giving the products
with an overwhelming E-selectivity referring to the double
bonds in the products.
the proton source gave terrible results (entries 2 and 3). In
contrast, the reaction of the weak acid PhCO2H also gave 3a in
high yield (entry 4). Reaction in other solvents such as MeCN,
THF, MeOH, EtOH, toluene, cyclohexane, DCM, and dioxane
favorably produced the β-addition product 3a with high
efficiency (entries 5−12), and MeOH gave the best perform-
ance (entry 7). When the reaction was examined by using
PhSO2H instead of PhSO2Na and AcOH in MeOH, it
generated a complex product mixture. Surprisingly, the
regioselectivity was reversed when DMSO was employed as
solvent for 8 h, offering the γ-addition product 4aa in 98% yield
with good geometric selectivity (entry 13). In addition,
selective production of 4aa was also obtained in the case of
polar aprotic solvent DMF or HMPA; nevertheless, a long
reaction time and slightly low yield was observed (entries 14
and 15).
Upon the identification of a set of reaction conditions, we
next explored the scope of the reactions. Scheme 2 lists some
typical results of the selective nucleophilic addition of 3-
cyclopropylideneprop-2-en-1-ones to afford β-adducts. A series
of sodium sulfinates bearing substituted phenyl rings could be
used to react with 1a affording the corresponding products 3a−
3e in good to excellent yields. A heterocyclic substrate i.e.,
sodium thiophene-2-sulfinate, also reacted smoothly with 1a to
give the adduct 3f in 98% yield. The reaction could also be
performed with sodium sulfinates bearing alkyl substituents.
For example, the reaction of sodium cyclopropanesulfinate and
(1S)-10-camphorsulfinate with 1a gave 3g and 3h in 81% and
97% yield, respectively. With respect to 3-cyclopropylidene-
prop-2-en-1-ones, typical substrates bearing substituted phenyls
at the 1- or 2-position were examined, which all delivered the
To obtain some information on the mechanism of the
selective γ-addition, several controlled experiments were
B
DOI: 10.1021/acs.orglett.6b02047
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a b
,
optimization study, we noted that the transformation was bad
even adding both PhSO2Na and AcOH (standard condition).
In contranst, the efficiency of the transformation improved
when the additive NaOAc was used, indicating that a basic
condition is crucial for the reaction. Furthermore, the yield of
4aa could be increased up to 89% when the additional
PhSO2Na was introduced to the reaction system (eq 1). The
involvement of the sodium sulfinate in the transformation of
the β-adduct to γ-adduct was further evident, as the reaction of
3a with p-ButC6H4SO2Na in the presence of NaOAc gave a
mixture of 4aa and 4ac with a ratio of 6/4 (eq 2). Finally, 3a
could be converted to the starting material 1a by using strong
base Cs2CO3 in acetone via an elimination reaction (eq 3).
Furthermore, it should be noted that the cyclopropyl group
in substrate 1 is quite critical for the current transformation of a
highly selective regio- and stereo-γ-addition (Scheme 5). As a
Scheme 3. Scope of γ-Adducts
Scheme 5. Hydrosulfonylation of Allenyl Ketones
matter of fact, when a dimethyl substituted allenyl ketone 5 was
subjected to the optimal conditions for 48 h, only the Micheal
addition-type product (β-adduct) was isolated. Although the
reaction of a simple allenyl ketone 7 also afforded the γ-adduct,
nevertheless an E/Z mixture with a 3/2 ratio was obtained. It is
reasonable that the release of the strain from the MCP unit of
the β-adducts should contribute to the tendency to form the γ-
adducts.
Based on the above results, a plausible mechanism is
proposed in Scheme 6. The nucleophilic addition of TsNa to
the α,β double bonds of 1 first takes place to give the β-adducts
3. The second nucleophilic addition of Ts− to the electron-
deficient double bond occurs to afford the double-addition
a
Conditions: 1a (0.2 mmol), 2 (0.4 mmol), AcOH (0.4 mmol) in 2
b
c
mL of DMSO at rt in open air. Isolated yield. Large-scale reaction:
1a (5 mmol, 1.240 g), 2a (2 equiv), AcOH (2 equiv) to afford 4aa
(1.956 g).
performed (Scheme 4). While the conversion of the product 3a
into 4aa was observed as monitored by TLC during the
Scheme 6. A Plausible Mechanism
Scheme 4. Controlled Experiments
C
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Letter
intermediate14 A when DMSO is used as a solvent. In the
presence of NaOAc which serves as a suitable base, A may lose
a proton to form two resonance structures, carbanion form B
and enolate B′ (note: it is reasonable that when R1 = alkyl
substituents, the reactions gave low yields due to the relatively
low stability of the corresponding intermediates like B′). Loss
of the Ts− from B′ by adopting a preferential conformer such as
B′-f finally gives the product 4 stereoselectively. The steric
repulsive effect between the sulfonylated cyclopropyl group and
enolate group may elevate the energy of the conformer B′-df.
In summary, we have reported a solvent-dependent hydro-
sulfonylation of 3-cyclopropylideneprop-2-en-1-ones with
sodium sulfinates. The β-adducts could be obtained in high
yields in MeOH with high efficiency. Particularly interesting is
that the reaction could also produce the γ-sulfonylation product
in DMSO with high geometric selectivity. Further investigation
into the reaction is underway.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02047.
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Experimental procedures and copies of 1H and 13C NMR
spectra for all new compounds (PDF)
Crystallographic information file for compound 3d (CIF)
Crystallographic information file for compound 4aa
(CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mmzok@zstu.edu.cn.
*E-mail: renhj@zstu.edu.cn.
Notes
́
(f) Stankovic, S.; Goossens, H.; Catak, S.; Tezcan, M.; Waroquier, M.;
Van Speybroeck, V.; D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2012,
77, 3181.
The authors declare no competing financial interest.
(14) (a) Hampton, C. S.; Harmata, M. J. Org. Chem. 2015, 80, 12151.
(b) Wang, Y.; Oriez, R.; Kuwano, S.; Yamaoka, Y.; Takasu, K.;
Yamada, K. J. Org. Chem. 2016, 81, 2652.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21302169, 21272003), the Natural Science Foundation
of Zhejiang Province (Grant No. LQ16B020001), the Science
Foundation of Zhejiang Sci-Tech University (Grant No.
13062121-Y), and the program for innovative research team
of Zhejiang Sci-Tech University (Grant No. 13060052-Y) for
financial support.
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DOI: 10.1021/acs.orglett.6b02047
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