Iron-catalyzed direct difunctionalization of alkenes with dioxygen and sulfinic acids: A highly efficient and green approach to β-ketosulfones

Article abstract of DOI:10.1039/c4ob01369g

A novel iron-catalyzed direct difunctionalization of alkenes with sulfinic acids and dioxygen for the synthesis of β-ketosulfones has been developed under mild conditions. The present protocol, which utilizes an inexpensive iron salt as the catalyst, readily available benzenesulfinic acids as the sulfonylating reagents, and dioxygen as the oxidant and oxygen source, provides a cost-effective and environmentally benign approach to access various β-ketosulfones.

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Iron-catalyzed direct difunctionalization of alkenes with dioxygen and
sulfinic acids: a highly efficient and green approach to β-ketosulfones†
Wei Weia, Jiangwei Wena, Daoshan Yanga, Min Wua, Jinmao Youa, Hua Wang*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5 DOI: 10.1039/b000000x
Jiao et al13 and our group14 presented independently the
A novel iron-catalyzed direct difunctionalization of alkenes
arylsulfonylation of activated alkenes with sulfinic acids to access
50 sulfonated oxindoles (Scheme 1, path C). Also, Lei’s group15
reported a aerobic oxysulfonylation of alkenes with arylsulfinic
acids leading to β-hydroxysulfones in the presence of
stoichiometric amounts of pyridine and PPh3 (Scheme 1, path D).
To the best of our knowledge, however, there is no example
55 describing the direct aerobic oxidative difunctionalization of
alkenes catalyzed by eco-friendly iron salt using sulfinic acids as
sulfonylating reagents to access β-ketosulfones, the key structural
motifs of many natural products, biological active molecules,
clinical pharmaceuticals and synthetic intermediates.16
with sulfinic acids and dioxygen for the synthesis of β-
ketosulfones has been developed under mild conditions. The
present protocol, which utilizes inexpensive iron salt as the
10 catalyst, readily available benzenesulfinic acids as the
sulfonylating reagents, and dioxygen as the oxidant and
oxygen source, provides a cost-effective and environmentally
benign approach to access various β-ketosulfones.
As an important class of biological molecules, sulfone-containing
15 organic compounds are widely used in the organic synthesis,
materials, and pharmaceuticals.1 The introduction of sulfone
functionality into organic frameworks via C-S bond formation
has thereby drawn great attentions of chemists in view of their
important biological properties and widespread synthetic
20 applications.2 In the past few decades, various functionalized
sulfonyl precursors such as sulfonyl halides,3 sulfonyl selenides,4
sulfonyl cyanides,5 sulfonylazides,6 sulfonyl hydrazides,7
thiophenols,8 sulfinates9 and dimethyl sulfoxide10 have emerged
for the synthesis of organic sulfone compounds. Nevertheless,
25 most sulfonylation reactions usually suffer from low atom-
efficiency, relatively complex reaction conditions, stoichiometric
amount of oxidants such as TBHP, H2O2, K2S2O8, copper(II),
manganese(III) and cerium(IV) salts, and undesired side-
products.3-9 The development of convenient, efficient, atom-
30 economic, and, especially, environmentally-benign methods
using simple sulfonylating agents to access sulfone-containing
compounds still remains a highly desirable but challenging task
in the modern organic chemistry.
Recently, sulfinic acids as simple, stable and readily available
35 solid sulfonylating source have been empolyed for constructing
sulfone-containing compounds via functionation of alkynes or
alkenes with high atom-efficiency.11-15 In 2013, Lei and co-
workers reported an elegant work for the aerobic oxidaitve
synthesis of β-ketosulfones from alkynes and sulfinic acids in the
40 presence of pyridine (Scheme 1, Path A).11 Copper-catalyzed
direct hydrosulfonylation of alkynes with arylsulnic acids was
achieved in our group for the construction of (E)-vinyl sulfones
with a high atom economy 12 (Scheme 1, path B). Very recently,
60
Scheme 1. Methods for the synthesis of sulfone-containing compounds
from sulfinic acids.
With continuous efforts to the copper-catalyzed synthesis of
sulfone-containing organic compounds,12,17 here, we report
65 alternatively a more atom-economic and highly efficient iron-
catalyzed direct oxysulfonylation of alkenes with sulfinic acids
towards β-ketosulfones via cascade C–S and C=O bond formation
simply by using dioxgyen as the oxidant and oxygen source
(Scheme 1, path E). The present synthesis methodology provides
70 a desirably convenient and green approach to a diverse range of
β-ketosulfones in moderate to excellent yields with high-atom
efficiency and the sole byproduct of water.
a
The Key Laboratory of Life-Organic Analysis and Key Laboratory of
45 Pharmaceutical Intermediates and Analysis of Natural Medicine, School
of Chemistry and Chemical Engineering, Qufu Normal University, Qufu
273165, Shandong, China. E-mail: huawang_qfnu@126.com
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Table 1 Optimization of the reaction conditionsa
Table 2 Results for iron-catalyzed difunctionalization of alkenes with
35 dioxygen and sulfinic acidsab,
Entry
1
2
3
4
5
6
7
8
Catalyst
Cu(OAc)2
CuBr
CuBr2
CuCl2
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
1,4-dioxane
THF
Yield (%)b
47
41
47
53
61
49
41
60
72
77
92
67
trace
87
59
61
35
CuI
Cu(OTf)2
Fe(NO3)3
Fe(acac)2
FeSO4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
FeBr3
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
--
DME
DMSO
DMF
CH3CN
Toluene
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
50
33
36
47c
54d
88e
42
FeCl2·4H2O
tracef
a
Reaction conditions: 1a (0. 5 mmol), 2a (1 mmol), catalyst (5 mol %),
solvent (2 mL), O2 (balloon), 16. b Isolated yields based on 1a. c catalyst
5 (1 mol %). d catalyst (2 mol %). e catalyst (10 mol %). f N2.
For purpose of comparison to the copper-catalyzed
oxysulfonylation of alkenes with sulfonylhydrazides,16 initially,
the reactions of styrene 1a and benzenesulfinic acid 2a catalyzed
by various Cu salts (5 mol%) were performed in EtOH at 70oC
10 under dioxygen. Low to moderate yields were obtained for the
desired products (Table 1, entries 1-6). Instead, iron salts were
introduced as the catalysts into these reactions. To our delight,
significantly improved reaction efficiencies were obtained, and
FeCl2·4H2O was found to be the best catalyst to afford the desired
15 product 3aa in 92% yield (Table 1, entries 7-11). Furthermore, a
range of reaction solvents were screened, with EtOH being the
superior for the formation of product 3aa (Table 1, entries 12-20).
The effects of catalyst loadings were also examined and 5 mol%
of catalyst was found to the best choice (Table 1, entries 21-23).
20 Notably, the desired product could be obtained in 42% yield
when the reaction was conducted in the absence of catalyst (Table
1, entry 24). In contrast, only a trace amount of 3aa was detected
when the reaction occurred in the absence of dioxygen. It
indicates that dioxygen could play the key role in the formation
25 of β-ketosulfone (Table 1, entry 25).
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), FeCl2·4H2O (5 mol %),
EtOH (2 mL), 16-24 h, O2 (balloon). b Isolated yields based on 1.
40 in further modifications. It is noteworthy that internal alkenes
such as (E)-prop-1-enylbenzene and (E)-1,2-diphenylethene)
could be compatible with this protocol, with the desired products
(3ka and 3la) in 53% and 12% yields, respectively.
Heteroaromatic alkene (i.e., 4-vinylpyridine) could also be used
45 in the reaction to give the product 3ma in 42% yield. Moreover,
investigations of different arylsulfinic acids showed that the
substrates bearing with electron-rich and electron-deficient
groups were all suitable for this reaction to give the
corresponding products in good yields (3ab-3ag). Notably, the
50 transformation could be sterically dependent, as confirmed by the
moderate yield obtained when 2-bromobenzenesulfinic acid was
employed as the substrate (3af). Interestingly, naphthalene-2-
sulfinic acid could be used in the reaction to give the desired
product 3ah in 90% yield.
55 To gain further insights into this reaction, several control
experiments were conducted as shown in eqns 1-3. It is well
known that sulfonyl radical species are easily formed from
sulfinic acids in the presence of dioxygen or transition metals.10-14
Therefore, a radical pathway might also be involved in this
60 reaction system. As shown in eqn (1), when TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy, a well-known radical scavenger)
was added into the reaction system, the present reaction was
With the optimized conditions in hand, the scope of the
reaction with respect to various alkenes and sulfinic acids were
investigated (Table 2). Generally, aromatic alkenes containing
electron-donating or withdrawing groups on the aryl rings were
30 also suitable for this process, with the corresponding products in
moderate to good yields (3aa-3ja). Also, functional groups such
as halogen, chloromethyl, and cyano groups (3ea-3ka) were all
well tolerated, which corresponding products could be applied
2
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completely inhibited. Accordingly, this transformation reaction is 35 catalyst, operation simplicity, high atom efficiency, clean
thought to involve a radical pathway. Furthermore, 18O-labeling
experiment was performed to elucidate the origination of the
carbonyl oxygen atom of β-ketosulfones. Considering that H2O
5 would be formed in the present reaction system to exert the
reaction byproduct (water), and environmently-benign
conditions, this synthesis system is expected to provide an
alternative and green approach to a series of β-ketosulfones.
Further studies of the detailed reaction mechanism and the
possible effect on the judgement of the origin of carbonyl oxygen 40 synthetic application are ongoing.
atom of β-ketosulfone, 4 Å MS was added into the reaction of 1a
This work was supported by the National Natural Science
and 2a under 18O2 to eliminate water generated in the this reaction
system. As demonstrated in eqn (2), the experimental result
10 showed that the carbonyl oxygen atom of β-ketosulfone came
from dioxygen (HRMS spectrum see ESI.†). In addition, when
the reaction with β-hydroxysulfone 8aa was performed under the
standard conditions, the desired product 3aa could not be
obtained (eqn (3)), indicating that β-hydroxysulfone might not be
15 an intermediate in the present reaction system.
Foundation of China (No. 21302109, 21302110, and 21375075),
the Taishan Scholar Foundation of Shandong Province, the
Excellent Middle-Aged and Young Scientist Award Foundation
45 of Shandong Province (BS2013YY019), and the Scientific
Research Foundation of Qufu Normal University (BSQD
2012020).
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•
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via direct difunctionalization of alkenes with sulfinic acids
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95
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