π-Deficient α-arylsulfonyl esters as soft nucleophiles in organic synthesis

Article abstract of DOI:10.1016/S0040-4039(01)01920-7

Different π-deficient arylsulfonyl groups have been studied as candidates for the stabilization of α-sulfonyl esters. The 3,5-bis(trifluoromethyl)phenylsulfonyl group has been shown to be the best substituent for the stereoselective synthesis of E-aconitates by a dialkylation-dehydrosulfinylation integrated process under PTC conditions using K₂CO₃ as base.

Full text of DOI:10.1016/S0040-4039(01)01920-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8845–8848
p-Deficient a-arylsulfonyl esters as soft nucleophiles
in organic synthesis
Diego A. Alonso, Carmen Na´jera* and Montserrat Varea
Departamento de Qu´ımica Orga´nica, Universidad de Alicante, Apartado. 99, 03080 Alicante, Spain
Received 6 September 2001; revised 10 October 2001; accepted 14 October 2001
Abstract—Different p-deficient arylsulfonyl groups have been studied as candidates for the stabilization of a-sulfonyl esters. The
3,5-bis(trifluoromethyl)phenylsulfonyl group has been shown to be the best substituent for the stereoselective synthesis of
E-aconitates by a dialkylation–dehydrosulfinylation integrated process under PTC conditions using K2CO3 as base. © 2001
Elsevier Science Ltd. All rights reserved.
The use of sulfones in organic synthesis has become a
classic strategy in the preparation of complex molecules.1
The sulfonyl group can be easily introduced in an
intermediate molecule for the construction of car-
bonꢀcarbon bonds, mainly as a carbanion-stabilizing
group.2 The desulfonylation is the last step to achieve the
target compound, generally by a reductive process or via
abase-promotedb-elimination.3 Thepresenceofelectron-
withdrawing substituents at the arylsulfonyl moiety
should facilitate the deprotonation at the a-position and
the subsequent desulfonylation step. Some representative
examples are the p-nitro, p-bromo and p-methylsulfonyl
substituted (phenylsulfonyl)ethoxycarbonyl groups (Nsc,
Bsc and Mpc) 1, which are base-labile amino-protective
groups4 for peptide synthesis as an alternative to the most
popular 9-fluorenylmethoxycarbonyl (Fmoc).5 More
recently, the (2,4-dinitrophenylsulfonyl)ethoxycarbonyl
group has also been described.6 p-Fluorophenyl and
2-naphthyl sulfones increase the rate and the yield of the
desulfonylation reaction by sodium amalgam.7 In addi-
tion, the radical-mediated cleavage of a-fluoro-a-(aryl-
sulfonyl)esters by means of tributyltin hydride takes
place faster with a-pyrimidin-2-yl sulfones 2.8 b-Acetalic
carbanions substituted with an electron-withdrawing
group can be mainly dialkylated in the case of the
(nitrophenyl)sulfonyl systems 3.9 In the total synthesis of
Rhizoxin D, a natural macrolactone with potent anti-
tumor and antifungal activity, the 3,4-(dichlorophenyl)-
sulfonyl group has been introduced to improve the yield
in the alkylation of the LDA-generated carbanion
derived from compound 4 and for the dehydrosulfinyla-
tion step (DBU, 105°C) in comparison with the phenyl-
sulfonyl moiety.10 Triflones can be used alternatively as
electron-deficient sulfones for the stabilization of carban-
ions, as olefins in Michael additions and in cyclo-
addition reactions.11 However, they have to be prepared
from non-commercially available sodium triflinate12
and have a great tendency to decompose by sulfur
dioxide extrusion.3 In this paper we report our studies
on the double effect of different p-deficient arylsulfones
on the stabilization of carbanions derived from a-sulfo-
nyl acetates and to assist the desulfonylation by a
successive b-elimination reaction in an integrated pro-
cess.13
O
N
O
S
EWG
SO2CH2CH2OCO-
N
CO2Et
R
F
1 (EWG = NO2, Br, MeSO2)
2
OTHP
O
O
O
Cl
S
O
O
EWG
Cl
O
3 (EWG = CO2Me, SO2Ph,
4
SO2-C6H4-p-NO2, SO2-C6H4-o-NO2)
Keywords: sulfones; PTC; aconitate; dialkylation.
* Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01920-7

8846
D. A. Alonso et al. / Tetrahedron Letters 42 (2001) 8845–8848
The p-deficient a-(arylsulfonyl)acetates 5 were prepared
by reaction of arylthiolates with alkyl a-bromoacetates
by using NaH or TEA as base in acetonitrile at rt,
followed by oxidation with oxone® in methanol/water
or with MCPBA in dichloromethane at room tempera-
ture (Scheme 1 and Table 1). The alkylation reaction
was studied treating the different a-arylsulfonyl esters 5
with benzyl bromide by using K2CO3 as base and
tetra-n-butylammonium bromide (TBAB) as phase-
transfer catalyst in acetonitrile for 1 day at room
temperature. (Scheme 1, Table 1). In all cases studied,
the dialkylation process took place easily to afford
quaternary compounds 6 in moderate yields except for
2-pyridine-1-oxide derivative 6ca, which decomposed.
In the case of the pentafluorophenyl sulfone 6ha, sec-
ondary products resulting from aromatic nucleophilic
substitution were also formed. When the dialkylation
reaction was carried out with ethyl a-bromoacetate as
electrophile under the same PTC conditions as
described above, only a-sulfonyl esters 5a,d,e,f, gave
cleanly the dialkylation–elimination process to provide
stereoselectively (E)-aconitate 7a (R=Bn) (Scheme 2,
Table 2).14 The 3,5-bis(trifluoromethyl)phenylsulfonyl
group showed a strong electron-withdrawing effect and
sulfone 5f gave aconitate 7a after 3 days reaction at rt
with the higher yield. In order to accelerate this inte-
grated process, the reaction was carried out with the
isopropyl a-(arylsulfonyl)acetate 5g to avoid hydrolysis
of the ester moiety. Aconitate 7b was obtained in 71%
yield after 3 days at rt and 60% when the reaction was
warmed up to 60°C in 1 day reaction time (Table 2).
The dialkylation reaction was studied with the 3,5-
bis(trifluoromethyl)phenyl sulfonyl ester 5f under PTC
conditions with different alkyl halides and 1,4-dihalides
to furnish products 6f in good yields after 1 day at rt.
Cyclopentenyl derivative 6ff with a phenylsulfonyl
group has been used as starting material for the genera-
tion of 3-(ethoxycarbonyl)cyclopentadienone, a very
reactive dienophile.16 In the case of ethyl acrylate,
Michael diaddition took place by using substoichiomet-
ric amounts of DBU (0.2 equiv.) at 60°C in acetonitrile
over 1 day (Scheme 3, Table 3).
O
O
O
1. ArSH, NaH or TEA
2. Oxone or MCPBA
PhCH2Br, K2CO3, TBAB
CH3CN, rt
ArO2S
OR
Br
ArO2S
OR
OR
Ph Ph
5
6
Scheme 1.
Table 1. Synthesis and dibenzylation of a-(arylsulfonyl)acetates
R
Ar
Base
Oxidant (time)
Product 5a
Product 6a
No.
Yield (%)b
Rfc
No.
Yield (%)b
Rfc
Bn
Bn
Bn
4-NO2-C6H4
2-Pyridyl
NaH
TEA
TEA
Oxone (1 day)
MCPBA (3 h)
Oxone (1 day)
5a
5b
5c
47
56
30
0.28
0.33
0.20
6aa
6ba
6ca
66
64
Dec.
0.39
0.26
–
+
N
-
O
Bn
Bn
Bn
Pri
Bn
2-Pyrimidyl
3-CF3-C6H4
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
C6F5
TEA
NaH
NaH
NaH
NaH
MCPBA (1 day)
Oxone (1 day)
Oxone (1 day)
Oxone (1 day)
Oxone (1 day)
5d
5e
5f
5g
5h
62
83
75
92
68
0.24
0.38
0.58
0.54
0.58
6da
6ea
6fa
6ga
6ha
58
30
58
71
28
0.28
0.33
0.60
0.57
0.74
a All products gaved satisfactory IR, 1H, 13C NMR spectral data and elemental analysis.
b Isolated yield after flash chromatography.
c Hexane/AcOEt: 2/1.
CO2Et
CO2R
O
BrCH2CO2Et
ArO2S
EtO2C
K2CO3, TBAB, CH3CN
OR
5
7
Scheme 2.

D. A. Alonso et al. / Tetrahedron Letters 42 (2001) 8845–8848
8847
Table 2. Synthesis of aconitates 7
Starting ester
R
Ar
T (°C)
Time (days)
No.
Yield (%)a
Rfb
5a
5d
5e
5f
5g
5g
Bn
Bn
Bn
Bn
Pri
Pri
4-NO2-C6H4
2-Pyrimidyl
3-CF3-C6H4
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
Rt
Rt
Rt
Rt
Rt
60
3
7
4
3
3
1
7a
7a
7a
7a
7b
7b
20
30
50
64
71
60
0.60
0.59
0.60
0.60
0.57
0.57
a Based on a-arylsulfonyl ester 5, after flash chromatography.
b Hexane/AcOEt: 2:1.
F3C
F3C
RHal, K2CO3
O O
S
TBAB, CH3CN
SO2CH2CO2Bn
CO2Et
CO2Bn
R
F3C
F3C
DBU (0.2 equiv.)
60 ºC
R
5f
6
Scheme 3.
Table 3. Dialkylation of sulfonyl ester 5f
Electrophile
Base
Product
No.
R
Yield (%)a
Rfb
PhCH2Br
MeI
CH2ꢁCHCH2Br
HCꢂCCH2Br
I(CH2)4I
PTC
PTC
PTC
PTC
PTC
PTC
PTC
6fa
6fb
6fc
6fd
6fe
6ff
PhCH2
Me
CH2ꢁCHCH2
HCꢂCCH2
(CH2)4
58
89
74
67
73
92
57
0.31
0.33
0.33
0.38
0.29
0.38
0.35
(Z)-BrCH2CHꢁCHCH2Br
(Z)-CH2CHꢁCHCH2
6fg
Br
Br
CH2ꢁCHCO2Et
DBU
6fh
CH2CH2CO2Et
54
0.31
a Based on sulfone 5f after flash chromatography.
b Hexane/AcOEt: 3/1.
Finally, the reduction of dibenzylated ester 6ga was
carried out with Zn in the presence of ammonium
chloride under refluxing THF for 1 day, to give ester 8
in 70% yield (Scheme 4).17
sulfinylation process under very mild reaction
conditions.18
References
In conclusion, the 3,5-bis(trifluorophenyl)sulfonyl
group is an excellent substituent for the deprotonation
of a-arylsulfonyl esters which allows the quaternization
of the corresponding enolates as well as the dehydro-
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F3C
Ph
OPri
O O
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S
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6ga
8
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2000, 56, 2339–2358.
Scheme 4.

8848
D. A. Alonso et al. / Tetrahedron Letters 42 (2001) 8845–8848
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80°C for 145 h in 67% yield.15
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D.A.A. thanks MEC for a contract under the program
Acciones para la Incorporacio´n a Espan˜a de Doctores y
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13. A preliminary account of this work was presented at the