Facile synthesis of substituted diaryl sulfones: Via a [3 + 3] benzannulation strategy

Article abstract of DOI:10.1039/c8ob00662h

A base-mediated [3 + 3] benzannulation strategy for the conversion of 1,3-bis(sulfonyl)propenes and β,γ-unsaturated α-ketoesters to diaryl sulfones has been developed. This method provides facile, metal-free and efficient access to highly substituted diaryl sulfones in good to excellent yields. In addition, the sulfonyl group could be easily removed or converted to other functional groups via an organostannane intermediate.

Full text of DOI:10.1039/c8ob00662h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C8OB00662H
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Facile Synthesis of Substituted Diaryl Sulfones via a [3+3]
Benzannulation Strategy
Received 00th January 20xx,
Accepted 00th January 20xx
Xiang-zheng Tang, Lang Tong, Hua-ju Liang, Jie Liang, Yong Zou, Xue-jing Zhang*, Ming Yan* and
Albert S. C. Chan
DOI: 10.1039/x0xx00000x
www.rsc.org/
A base-mediated [3+3] benzannulation strategy for the conversion aryl sulfones. Over the past decades, various types of
of 1,3-bis(sulfonyl)propenes and β,γ-unsaturated α-ketoesters to benzannulations have been developed for the construction of
diaryl sulfones has been developed. This method provides facile, substituted benzenes.10 Among these reactions, [3+3]
metal-free and efficient access to highly substituted diaryl benzannulations have received much attention.11 This kind of
sulfones in good to excellent yields. In addition, the sulfonyl group reaction allow the formation of several chemical bonds in a
could be easily removed or converted to other functional groups single operation, and enable facile access to substituted
via an organostannane intermediate.
benzenes from acyclic precursors under mild conditions.12
In 2015, Menon group reported a regioselective, oxidative
[3 + 3] benzannulation reaction of 4-sulfonylcrotonates (or 1,3-
bissulfonylpropene) with α,β-unsaturated aldehydes and
ketones.12c A series of highly substituted 3-sulfonyl benzoic
ester derivatives was prepared. Our group have been exploring
the synthetic potentials of β,γ-unsaturated α-ketoesters as the
electrophiles in conjugate additions and annulation
reactions.13 We speculated that the arylsulfones can be
obtained by the benzannulation reaction of 1,3-
bis(phenylsulfonyl)propenes and β,γ-unsaturated α-ketoesters.
Herein, we report a DBU-mediated [3+3] benzannulation
reaction for the synthesis of highly substituted diaryl sulfones
via cascade conjugate addition/intramolecular carbonyl
addition/desulfonative aromatization.
We initiated our study by exploring the reaction between
1,3-bis(p-tolylsulfonyl)propene 1a with β,γ-unsaturated α-
ketoester 2a in DMF with different bases. To our delight, 3a
was obtained in 77% yield in the presence of DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) at room temperature (Table 1,
entry 1). The structure of 3a was determined by a combination
of NMR spectroscopy and HRMS analysis (see supporting
information for the details). Other organic bases like TEA,
Aryl sulfones are useful building blocks in organic synthesis,1
and are widely present in biologically active compounds. For
example, sulfonyl-substituted benzenes have been shown to
display antibacterial (Dapsone),2 antidepressant (CX157),3 and
anti-inflammatory (Rofecoxib) activities (Fig. 1).4 Furthermore,
aryl sulfones are important synthetic targets due to their
broad synthetic possibilities and photoelectric properties.5 A
variety of methods had been developed for the construction of
substituted aryl sulfones. Classical approaches include the
oxidation of the corresponding aryl sulfides,6 Friedel-Crafts-
type sulfonylation of arenes,7 and the coupling of
arenesulfinates with aryl halides or boronic acids.8 The
majority of these processes have the limitations such as harsh
reaction conditions, poor regioselectivities, and unsatisfactory
yields.9 In addition, these traditional reactions are less
effective for synthesizing sterically hindered aryl sulfones and
thus are of limited practical applications.
To overcome these limitations, benzannulation reaction is
proved to be an alternative method for building substituted
DABCO
(1,4-diazabicyclo[2.2.2]octane),
TMG
(1,1,3,3-
tetramethylguanidine) and DMAP (4-dimethylaminopyridine)
gave lower yields in comparison with DBU (entries 2-5).
Inorganic base NaHCO3 provided a moderate yield of 3a (entry
6), whereas Na2CO3, K2CO3, Cs2CO3 and Na3PO4 were
inefficient in this reaction (entries 7-10). Furthermore, DBU
was employed as the base for the investigation of solvent
effect. The reaction solvent was found to affect the chemical
yield significantly. CH3CN and toluene gave the desired
Figure 1 Representative biologically active aryl sulfones.
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China.
E-mail: zhangxj33@mail.sysu.edu.cn; yanming@mail.sysu.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data of new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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products in lower yields (entries 11-12). THF provided a better reaction conditions, providing phenylethyl VieswuAbrtsictlietOuntleinde
yield compared with DMF (entry 13). The chlorinated solvents
arylsulfone 7
in a 96% yield (Scheme 1). DOI: 10.1039/C8OB00662H
Table 1 Optimization of the reaction conditionsa
Table 2 Scope of the benzannulation reactiona
Entry
1
2
3
4
5
6
7
8
S
olvent
Base
DBU
TEA
DABCO
TMG
DMAP
NaHCO3
Na2CO3
K2CO3
Cs2CO3
Na3PO4
DBU
Yield (%)b
77
27
33
47
27
61
37
19
11
18
60
72
82
90
87
96
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Entry
1
2
3
4
5
6
7
8
1
Ar
Ph
Ph
Ph
Ph
Ph
R2
3
Yield (%)b
96 (93)c
97
93
92
95
98
98
96
97
97
99
98
97
95
99
91
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
CH3
CH3
CH3
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
i-Pr
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-CH3C6H4
3-CH3OC6H4
3-BrC6H4
3,4-CH3OC6H3
2-CH3OC6H4
2-BrC6H4
2-naphthyl
2-thienyl
2-furyl
9
DMF
DMF
10
11
12
13
14
15
16
CH3CN
Toluene
THF
CH2Cl2
ClCH2CH2Cl
CHCl3
9
DBU
DBU
DBU
DBU
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
DBU
aAll reactions were carried out with 1a (0.21 mmol), 2a (0.20 mmol) and base
(0.24 mmol) in solvent (4 mL) under an argon atmosphere for 48 h at room
temperature. b Isolated yield of 3
a.
89
94
95
98
like CH2Cl2, ClCH2CH2Cl and CHCl3 improved the yield
dramatically (entries 14-16), and the reaction in CHCl3 afforded
the best yield (96%).
aReactions were carried out with 1a-1c (0.21 mmol), 2a-2r (0.20 mmol) and
DBU (0.24 mmol) in CHCl3 (4 mL) under an argon atmosphere for 48 h at
room temperature. b Isolated yields. c Gram-scale reaction.
With the optimized reaction conditions in hand, the reaction
scope was then explored. The results are summarized in Table
2. The reactions worked well with differently substituted 1,3-
bis(sulfonyl)propenes 1a-1c. When R1 were 4-methylphenyl, 4-
chlorophenyl or phenyl groups respectively, the reactions gave
products 3a-3c in excellent yields (entries 1-3). Changing the
size of the ester groups on α-ketoesters (R2) exerted negligible
effect on the yields (entries 4–5). The electronic properties and
the position of substituents on aromatic rings of α-ketoesters
had little effect on the efficiency of this process. With regard
to para- and meta-substituents, both electron-withdrawing
and electron-donating groups afforded the products in
excellent yields (entries 6-15). However, increased steric
hindrance was found to negatively influence the yields (entries
16-17). Naphthyl and heteroaryl substrates (thienyl and furyl)
also showed favorable reactivity (entries 18-20). To evaluate
the practicality of this cascade process, a gram-scale reaction
with 1a (4.0 mmol) and 2a (3.8 mmol) was carried out under
the standard conditions. The desired product 3a was obtained
in 93% yield, which was comparable with that obtained in the
small-scale reaction.
Treatment of the benzannulation product 3a with
Bu3SnH/AIBN afforded organostannane
(Scheme 2), which is valuable for further transformations. The
stannyl group of could be easily removed by the acidification
with TFA to furnish biphenyl derivative in a 96% yield. The
treatment of with iodine gave the iodinated product 10 in a
87% yield. In addition, the cross coupling of with methyl 4-
8 in a 72% yield
8
9
8
8
iodobenzoate proceeded smoothly through Stille coupling
(CuCl/Pd(0)/LiCl) to give the product 11 in a 78% yield.14
Based on the above experimental results and the related
literature,12c
benzannulation process is proposed in Scheme 3. In the
presence of DBU, 1,3-bis(sulfonyl)propene is deprotonated
into sulfone-stabilized allylic carbanion , which may undergo
a
possible reaction mechanism for the
1
A
a conjugate addition with β,γ-unsaturated α-ketoester yielding
While β,γ-unsaturated α-ketoester
double bond was used, the alkenylated arylsulfone
isolated in a 82% yield. The corresponding double bond
saturated substrate was also applicable under the standard
4
with an extended
5
was
6
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diaryl sulfones. The new synthetic applications of 1,3-
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DOI: 10.1039/C8OB00662H
bis(arylsulfonyl)propenes as C3 synthons are ongoing in our
group.
Conflicts of interest
There are no conflicts to declare.
Scheme 1 Synthesis of alkenylated and phenylethyl substituted arylsulfones.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 21472248), the Innovative Scientific Research Team
Introducing Project of Zhongshan City (No. 2015-224) and the
National Science and Technology Major Project of the Ministry
of Science and Technology of China (2017ZX09305010) for the
financial support of this study.
Notes and references
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00662H
A metal-free and efficient synthesis of highly substituted diaryl sulfones via a
base-mediated [3+3] benzannulation strategy.