3,5-Bis(trifluoromethyl)phenyl sulfones in the modified Julia olefination: Application to the synthesis of resveratrol

Article abstract of DOI:10.1016/j.tetlet.2003.10.196

The reaction between carbanions derived from alkyl 3,5-bis(trifluoromethyl) phenyl sulfones and aldehydes, affords with good yields and stereoselectivities the corresponding 1,2-disubstituted alkenes through the Julia-Kocienski olefination reaction. This one-pot protocol can be performed using KOH at room temperature or the phosphazene base P4-t-Bu at -78°C, and has been successfully used in a high yielding and stereoselective synthesis of various stilbenes such as resveratrol.

Full text of DOI:10.1016/j.tetlet.2003.10.196

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 573–577
3,5-Bis(trifluoromethyl)phenyl sulfones in the modified Julia
olefination: application to the synthesis of resveratrol
*
ꢀ
Diego A. Alonso, Carmen Najera and Montserrat Varea
Departamento de Quꢀımica Orgaꢀnica, Universidad de Alicante, Apartado. 99, 03080 Alicante, Spain
Received 26 September 2003; revised 21 October 2003; accepted 30 October 2003
Abstract—The reaction between carbanions derived from alkyl 3,5-bis(trifluoromethyl)phenyl sulfones and aldehydes, affords with
good yields and stereoselectivities the corresponding 1,2-disubstituted alkenes through the Julia–Kocienski olefination reaction. This
one-pot protocol can be performed using KOH at room temperature or the phosphazene base P4-t-Bu at )78 °C, and has been
successfully used in a high yielding and stereoselective synthesis of various stilbenes such as resveratrol.
Ó 2003 Elsevier Ltd. All rights reserved.
During several decades, a variety of fundamentally dif-
ferent approaches to the synthesis of olefins have been
developed, which attempt to address the regio- and
stereochemical demands that the synthesis of this moiety
makes. The most generally applicable methods remain
those involving direct olefination of carbonyl com-
pounds such as Wittig,1 Horner,2 Wadsworth-Em-
mons,3 Peterson,4 Johnson,5 and the classical Julia6
reactions. The classical Julia olefination, also known as
the Julia–Lythgoe olefination, was disclosed nearly
30 years ago and is based on a reductive elimination
process of b-acyloxy phenyl sulfones.7 Since its discov-
ery, significant advances have been made in the reaction
and it has become a crucial step in the synthesis of many
natural products.8 A new variant of the classical Julia
reaction, the Julia–Kocienski olefination also known as
the modified or one-pot Julia olefination,9 has recently
emerged as a powerful tool for olefin synthesis, and
basically consists of the replacement of the phenyl sul-
fone moiety traditionally used in the classical reaction,
with different heteroaryl sulfones, which allows the
direct olefination process. Principally, four heterocyclic
derivatives have been shown to give the highest yields
and levels of stereoselectivity: benzothiazol-2-yl (BT,
1),9a pyridin-2-yl (PYR, 2),10 1-phenyl-1H-tetrazol-5-yl
(PT, 3),11 and 1-tert-butyl-1H-tetrazol-5-yl (TBT, 4).12
The presence of an electrophilic imine-like moiety in the
sulfone is responsible for the different reactivity and
reaction pathway observed in the one-pot Julia olefin-
ation.
We have recently shown that the 3,5-bis(trifluoro-
methyl)phenylsulfonyl(BTFP-sulfonyl)group, is astrong
electron-withdrawing group and an excellent nucleofuge
in base-promoted b-elimination processes. Thus, a-aryl-
sulfonyl acetates 5 are very soft nucleophiles, which
can be easily dialkylated under very mild PTC condi-
tions. The reaction with ethyl bromoacetate, allows the
F3C
N
N
N
N
O
S
N
N
N
N
N
S
N
O
R
Ph
But
F3C
1, BT
2, PYR
3, PT
4, TBT
5, R = CH2CO2R'
6, R = CH2CH2OH
7, R = CH2R1
Keywords: Julia olefination; Sulfones; (Z/E)-Selectivity; Resveratrol.
* Corresponding author. Tel.: +34-96-5903728; fax: +34-96-5903549; e-mail: cnajera@ua.es
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.196

574
D. A. Alonso et al. / Tetrahedron Letters 45 (2004) 573–577
F3C
F3C
F3C
1. NaH, R1CH2Br, CH3CN, 1 d, rt
SH
SO2CH2R1
2. 30% H2O2, NaHCO3, MnSO4 (cat.),
CH3CN, 1 d, rt
F3C
7a, R1 = Ph (93%)
8
7b, R1 = 3,5-(MeO)2C6H3 (97%)
7c, R1 = Bun (86%)
Scheme 1.
direct synthesis of E-aconitates via an alkylation–elimi-
nation integrated process.13 On the other hand, b-aryl-
sulphonyl ethanol 6, is an efficient protecting group for
carboxylic acids, easily removed with aqueous
NaHCO3.14 We envisaged that the BTFP-sulfonyl group
could undergo the Smiles rearrangement15 necessary for
the modified Julia olefination. As part of a program
aimed at developing broadly useful applications of 3,5-
bis(trifluoromethyl)phenyl sulfones in organic synthesis,
herein we describe the use of alkyl BTFP-sulfones 7 in
the Julia–Kocienski olefination reaction as well as their
applications to the synthesis of stilbenes such as resve-
ratrol.
the BTFP-sulfonyl substituted carbanions even at rt.
Only in the case of using the combination system
KHMDS as base and DME as solvent, which has been
previously shown to give very good results in terms of
yield and stereoselectivity with other sulfones in the
modified Julia olefination,11;12 was the recovery unsat-
isfactory and some decomposition of the substrates
observed. This problem, which has also been observed
for phenyltetrazolyl sulfones (PT-sulfones) when
KHMDS is used as base,11 could be overcome in the
case of BTFP-sulfones using either KOH or P4-t-Bu as
base in THF (Table 1). Furthermore, the carbanions of
the BTFP-sulfones did not exhibit any propensity to
self-condense as is the case with BT-sulfones 112 and in
no case was self-condensation of the substrates detected
even when the deprotonation reactions were carried out
at rt. This allows the deprotonation step to be carried
out in the absence of the aldehyde, which extends the
scope of the olefination reaction to base-sensitive sub-
strates.
The p-deficient BTFP-sulfones 7 were prepared in high
yields by reaction of the arylthiolate from 8 with the
corresponding alkyl bromide using NaH as base in
CH3CN at room temperature, followed by oxidation
with 30% H2O2 in the presence of catalytic amounts of
MnSO4ÆH2O (1 mol %) and
NaHCO3 (Scheme 1).
a buffer solution of
16
The Julia–Kocienski olefination with BTFP-sulfones 7
was first evaluated through the coupling between benzyl
derivative 7a and PhCHO, employing different bases
such as KHMDS, KOH, and the phosphazene bases17
P2-Et and P4-t-Bu, either at rt (KOH) or at low tem-
peratures ()78 °C for P2-Et and P4-t-Bu and )60 °C for
KHMDS) in THF or DME as solvents (Scheme 2, Table
2). As shown in Table 2, entries 1–4, the yield of the
olefination reaction was usually good except when
KHMDS was used as base, as expected from the sta-
bility studies (see Table 1). With respect to the (E)-ste-
reoselectivity of the reaction, this was not overly
sensitive to changes of base and only in the presence of
KOH (Table 2, entry 2), was it slightly decreased com-
pared to the other bases, probably due to the rt condi-
tions. Both P2-Et (2.2 equiv) and P4-t-Bu18 (1.2 equiv) at
)78 °C in THF gave satisfactory results in terms of yield
and stereoselectivity (Table 2, entries 3 and 4). We also
studied the effect of employing HMPA as an additive on
In order to determine the stability of the sulfonyl car-
banions derived from the BTFP compounds 7, benzyl
sulfone 7a, and n-pentyl sulfone 7c were treated with
KOH in THF at rt, the phosphazene (triaminoimino-
phosphorane) base P4-t-Bu in THF at )78 °C and
KHMDS in DME at )60 °C to rt for 24 h, and the
reactions were then quenched with water. The sulfone
recovery (Table 1), clearly showed the high stability of
Table 1. Stability of BTFP-sulfones 7
Reaction conditions
Sulfone recovery (%)
7a
7c
KHMDS, DME, )60 °C to rt, 24 h
KOH, THF, rt, 24 h
50
95
88
28
98
77
P4-t-Bu, THF, )78 °C, 24 h
F3C
N
N
P
N
N
P
N
N
N
P
N
Base
SO2CH2R1
N
N
N
P
N
N
N
N
+ R2CHO
R1CH=CHR2
N
N
P
N
N
Solvent, T (ºC)
F3C
P
N
7
9
P2-Et
P4-t-Bu
Scheme 2.

D. A. Alonso et al. / Tetrahedron Letters 45 (2004) 573–577
Table 2. Modified Julia olefination with BTFP-sulfones 7
575
Entry
7
R2CHO
Reaction conditions
Base (equiv)
Solvent T (°C)
Alkene
R2
No
R1
Yield
(%)a
Z/Eb
1
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
KHMDS (1.1) DME
)60 to rt
rt
9a
9a
9a
9a
9a
9b
9c
9d
9d
9e
9e
9e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20c
78
67c
65c
78c
1/99
2
KOH (9)d
P2-Et (2.2)
P4-t-Bu (1.2)
THF
THF
THF
16/84
3/97
2/98
3
)78
)78
)78
)78
0
4
5
P4-t-Bu (1.2)e THF
5/95
6/94
6
4-MeOC6H4CHO P4-t-Bu (1.2)
4-NO2C6H4CHO P4-t-Bu (1.2)
THF
THF
THF
THF
THF
THFg
4-MeOC6H4 67f
7
4-NO2C6H4
C6H11
C6H11
76c
75
86
70/30
75/25
50/50
25/75
1/99
8
C6H11CHO
C6H11CHO
4-MeOC6H4CHO KOH (9)d
4-MeOC6H4CHO P4-t-Bu (1.2)
P2-Et (2.2)
P4-t-Bu (1.2)
rt
9
rt
10
11
12
rt
3,5-(MeO)2C6H3 4-MeOC6H4 81
3,5-(MeO)2C6H3 4-MeOC6H4 15c
3,5-(MeO)2C6H3 4-MeOC6H4 74c
)78
)78
4-MeOC6H4CHO P4-t-Bu (1.2)e THFg
2/98
13
14
7b
7b
KOH (9)d
P4-t-Bu (1.2)e THFg
THF
rt
9f
9f
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
81
73
15/85
10/90
CHO
)78
S
S
15
16
17
18
19
7c
7c
7c
7c
7c
PhCHO
PhCHO
KOH (9)d
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
9g
9g
9h
9h
9h
Bun
Bun
Bun
Bun
Bun
Ph
Ph
70
45
40
70
60
33/67
25/75
25/75
10/90
15/85
P4-t-Bu (1.2)
KOH (9)d
C6H11CHO
C6H11CHO
C6H11CHO
C6H11
C6H11
C6H11
P2-Et (2.2)
P4-t-Bu (2.2)
a Isolated yield after flash chromatography (hexane).
b Determined by GC over the crude reaction mixture.
c Isolated yield of (E)-isomer.
d 0.01 Equiv of TBAB were added to the reaction mixture.
e 1.2 Equiv of HMPA were added to the reaction mixture.
f Isolated yield of (Z)-isomer.
g The reaction was stirred for 48 h.
the scope of the reaction. The presence of this additive
(1.2 equiv) in the reaction medium when using P4-t-Bu
(1.2 equiv) as base involved a notable increase in the
reaction yield, still with a high (E)-selectivity (Table 2,
entry 5). The olefination reaction was also successful
when coupling the sulfone 7a, in the presence of the
system P4-t-Bu/THF, with para-substituted electron-
rich and electron-deficient benzaldehydes (Table 2,
entries 6 and 7). It is noteworthy that the olefination
reaction with p-nitrobenzaldehyde afforded the corre-
sponding alkene 9c with an opposite sense of stereo-
selectivity (Z/E ¼ 70/30). This behavior can be attributed
to a diastereomeric equilibration between the syn and
anti-b-alkoxysulfone intermediates via a retroaddition/
addition process. The lower energy barrier to Smiles
rearrangement for the syn isomer19 could then explain
the aforementioned (Z)-selectivity observed when an
electron-poor aldehyde is used in the one-pot Julia
olefination reaction. This result is also consistent with
the stereochemical trend observed by Julia in the reac-
tion of BT sulfones with different substituted benzalde-
hydes, which led him to postulate a plausible mechanism
for the reaction involving zwitterionic species.9b
With the aim of studying the applicability of BTFP-
sulfones to the synthesis of resveratrol,20 the benzylic
sulfone 7b was tested in the modified Julia olefination
(Table 2, entries 10–12). After an extensive study of
different bases, solvents, and temperatures, the reaction
between sulfone 7b and p-methoxybenzaldehyde with
KOH in the presence of TBAB yielded the corre-
sponding trimethoxyresveratrol 9e in an 81% yield with
a moderate (E)-selectivity21 (Z/E ¼ 25/75). In this case,
P4-t-Bu in THF, gave a very poor 15% yield in the
reaction, although with an excellent selectivity. How-
ever, when this reaction was carried out in the presence
of HMPA, trimethoxyresveratrol 9e was obtained with
an excellent yield and selectivity (Table 2, entry 12). This
strong positive effect of HMPA on the reaction22 is
probably due to interactions between the additive and
the P4-t-Bu-derived carbanion, which could modify its
structure and hence, the reactivity of the system.23 This
is, to the best of our knowledge, the first stereoselective
synthesis of resveratrol through a Julia–Kocienski olef-
ination protocol. Sulfone 7b also showed good reactivity
with other aromatic aldehydes such as thiophenecarb-
aldehyde, again when the reaction was carried out in
THF at )78 °C in the presence of P4-t-Bu as base and
HMPA as additive (Table 2, entry 14).24
With respect to aliphatic aldehydes, the BTFP-sulfone
7a condensed with cyclohexanecarbaldehyde in the
presence of the phosphazene bases at rt (Table 2, entries
8 and 9), to give alkene 9d with no or moderate (Z)-
stereoselectivity. In this particular case, P2-Et gave the
best result (75% yield, Z/E ¼ 75/25).
Finally, we also studied the reactivity of alkyl BTFP-
sulfone 7c towards benzaldehyde and cylohexanecarb-
aldehyde (Table 2, entries 15–19). The study was carried
out employing KOH, P2-Et, and P4-t-Bu as bases, due

576
D. A. Alonso et al. / Tetrahedron Letters 45 (2004) 573–577
R1
O2
O2
S
R1
R2
F3C
R1
S
O2S
F3C
F3C
R2
1. Base
2. R2CHO
O-
O
-
-O
CF3
CF3
CF3
R1
S
F3C
O-
O
R1CH=CHR2
R2
SO2
+
+
F3C
O
CF3
CF3
Scheme 3.
to the low stability of this sulfone towards KHMDS (see
Table 1). The (E)-selectivity of the olefination reaction
with sulfone 7c was in general lower than observed for
benzylic sulfones 7a and 7b, and the best result was
observed when the coupling with cyclohexanecarbalde-
hyde was carried out at rt in the presence of 2.2 equiv of
P2-Et (Table 2, entry 18).
Acknowledgements
This work was supported by the Direccion General de
ꢀ
Investigacion of the Spanish Ministerio de Ciencia y
ꢀ
Tecnologıa (MCyT) (BQU2001-0724-CO2-01). The
ꢀ
authors also thank Dr. Emilio Lorenzo for helpful
NMR assistance.
With respect to the reaction mechanism, we have
observed, after completion of the reaction, the forma-
tion of 3,5-bis(trifluoromethyl)phenol as a side product,
which supports the postulated pathway for the modified
Julia olefination (Scheme 3): addition of the sulfonyl
carbanion to the aldehyde, Smiles rearrangement, and
spontaneous sulfur dioxide and 3,5-bis(trifluoro-
methyl)phenolate eliminations.9c
References and Notes
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stilbenes, good yields and (E)-selectivities. Additionally,
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deprotonation step to take place prior to the addition of
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Typical experimental procedure: To a stirred solution,
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corresponding anhydrous solvent was added dropwise
the base (see Table 2). The mixture was then stirred for
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(1.2 mmol). After stirring for 18–48 h, the reaction
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NH4Cl (5 mL), extracted with EtOAc (10 mL), and the
organic phase was washed first with a saturated solution
of NaHCO3 (15 mL) and then with a saturated solution
of NaCl (15 mL). The organic phase was then dried
(Na2SO4), filtered and the solvent evaporated to afford
the corresponding crude olefin, which was purified by
flash chromatography (hexane) to afford pure com-
pounds 9.
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