3,5-Bis(trifluoromethyl)phenyl sulfones for the highly stereoselective Julia-Kocienski synthesis of α,β-unsaturated esters and weinreb amides

Article abstract of DOI:10.1002/ejoc.200800041

The 3,5-bis(trifluoromethyl)phenyl (BTFP) sulfones tert-butyl α-(BTFPsulfonyl)acetate (4) and Weinreb α-(BTFPsulfonyl)-acetamide (5) have successfully been employed in the Julia-Kocienski olefination of aldehydes with K₂CO₃ as the base at 120°C in DMF under solid/liquid phase-transfer catalysis conditions to afford α,β- unsaturated esters and Weinreb amides, respectively. The corresponding products were obtained in good yields and with high E stereoselectivities (E/Z up to >99:1), especially in the case of the amides. A detailed computational study of the Julia-Kocienski olefination with BTFP sulfone 4 was carried out and confirmed the existence of an equilibrium in the initial addition of the sulfone enolate to the aldehyde and, in contrast to other proposed mechanisms, a non-concerted final elimination of SO₂ and 3,5-bis-(trifluoromethyl) phenoxide. A plausible explanation for the high E diastereoselectivity observed in the reaction has been suggested based on kinetic considerations at spirocyclic TS2 and thermodynamic factors during the elimination after TS2. ESI-MS studies carried out during the olefination reaction of benzaldehyde with BTFP sulfone 4 were used to characterize the sulfone enolate and the intermediate assumed for the reaction mechanism. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800041

FULL PAPER
DOI: 10.1002/ejoc.200800041
3,5-Bis(trifluoromethyl)phenyl Sulfones for the Highly Stereoselective
Julia–Kocienski Synthesis of α,β-Unsaturated Esters and Weinreb Amides
Diego A. Alonso,*[a] Mónica Fuensanta,[a] Enrique Gómez-Bengoa,[b] and Carmen Nájera*[a]
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Keywords: Olefination / Esters / Amides / Sulfones
The 3,5-bis(trifluoromethyl)phenyl (BTFP) sulfones tert-butyl
α-(BTFPsulfonyl)acetate (4) and Weinreb α-(BTFPsulfonyl)-
acetamide (5) have successfully been employed in the Julia–
Kocienski olefination of aldehydes with K2CO3 as the base
at 120 °C in DMF under solid/liquid phase-transfer catalysis
conditions to afford α,β-unsaturated esters and Weinreb
amides, respectively. The corresponding products were ob-
tained in good yields and with high E stereoselectivities (E/Z
up to Ͼ99:1), especially in the case of the amides. A detailed
computational study of the Julia–Kocienski olefination with
BTFP sulfone 4 was carried out and confirmed the existence
of an equilibrium in the initial addition of the sulfone enolate
to the aldehyde and, in contrast to other proposed mecha-
nisms, a non-concerted final elimination of SO2 and 3,5-bis-
(trifluoromethyl)phenoxide. A plausible explanation for the
high E diastereoselectivity observed in the reaction has been
suggested based on kinetic considerations at spirocyclic TS2
and thermodynamic factors during the elimination after TS2.
ESI-MS studies carried out during the olefination reaction of
benzaldehyde with BTFP sulfone 4 were used to characterize
the sulfone enolate and the intermediate assumed for the re-
action mechanism.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
and versatility in organic synthesis as they serve as impor-
tant synthetic intermediates. Very recently, BT sulfones 1a
and 1b were reported as effective reagents for the one-pot
Julia olefination of aldehydes in the synthesis of α,β-unsatu-
rated esters[12] and Weinreb amides[13] employing DBU and
NaH as the base, respectively (Figure 1). π-Deficient
4-nitrophenyl (NP) sulfone 2 (Figure 1) has also shown
moderate reactivity towards the alkenylation of aromatic al-
dehydes with Cs2CO3 as the base.[14]
Introduction
For several decades, a wide variety of approaches have
been developed for the regio- and stereoselective synthesis
of alkenes, the most generally applicable methods being
those that involve the direct olefination of carbonyl com-
pounds,[1] as in the Wittig,[2] Horner,[3] Wadsworth–
Emmons,[4] Peterson,[5] Johnson[6] and classic Julia[7] reac-
tions. A new variant of the classic Julia reaction, the Julia–
Kocienski olefination, also called the modified or one-pot
Julia olefination,[8] has recently emerged as a powerful tool
in olefin synthesis. The process involves the replacement of
the aryl sulfone moiety, traditionally used in the classic re-
action, with different heteroaryl[8,9] sulfones, such as benzo-
thiazol-2-yl sulfones (BT sulfones), 2-pyridyl sulfones (PYR
sulfones), 1-phenyl-1H-tetrazol-5-yl sulfones (PT sulfones)
and 1-tert-butyl-1H-tetrazol-5-yl sulfones (TBT sulfones),
thus allowing direct olefination. The α,β-unsaturated es-
ter[10] and Weinreb amide[11] functions are of great utility
[a] Departamento de Química Orgánica and Instituto de Síntesis
Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante,
Apartado 99, 03080 Alicante, Spain
E-mail: diego.alonso@ua.es
cnajera@ua.es
[b] Departamento de Química Orgánica I, Facultad de Química,
Universidad del País Vasco,
Apdo. 1072, 20080 San Sebastián, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. BT, NP and BTFP sulfones.
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D. A. Alonso, M. Fuensanta, E. Gómez-Bengoa, C. Nájera
FULL PAPER
We have recently demonstrated that the 3,5-bis(trifluoro- (Scheme 2, R = Ph, and Table 1). The reaction was per-
methyl)phenyl (BTFP) sulfone group is an excellent nucleo- formed by the addition of a base to a mixture of sulfone 4
fuge in base-promoted β-elimination processes.[15] On the (2 equiv.) and benzaldehyde (Barbier conditions). Under
other hand, 3,5-bis(trifluoromethyl)phenyl sulfones (BTFP the conditions previously employed for the Julia–Kocienski
sulfones) 3 (Figure 1) can undergo the Smiles rearrange- olefination of aldehydes with BT sulfone 1a[12] and DBU as
ment[8b] that is involved in the Julia–Kocienski olefination. the base in CH2Cl2, sulfone 4 failed to react. However, in
Thus, they have been employed as excellent π-deficient part- DMF at 120 °C over 48 h, 8a was obtained in 15% yield
ners for the stereoselective synthesis of di-, tri- and tetra- and excellent selectivity (Z/E = 1:99) (Table 1, entries 1 and
substituted olefins by the Julia–Kocienski olefination of ali- 2). The yield of the reaction was improved to 36% by using
phatic and aromatic aldehydes as well as ketones under very the phosphazene base P4-tBu in DMF at the same tempera-
simple reaction conditions by using KOH and phos- ture (Table 1, entry 3). By employing NaH as the base un-
phazenes as bases.[16] Herein we report the synthesis of tert- der THF reflux, sulfone 4 failed to react with benzaldehyde
butyl α-(BTFPsulfonyl)acetate (4) (Figure 1) and Weinreb to any significant extent (Table 1, entry 4). The inorganic
α-(BTFPsulfonyl)acetamide (5) (Figure 1) and their appli- bases tBuOK and KOH gave modest yields of 8a in DMF,
cation as efficient reagents for the stereoselective synthesis even on heating at 120 °C. When the reaction was per-
of α,β-unsaturated esters and Weinreb amides by the Julia– formed in the same solvent with a large excess (18 equiv.)
Kocienski olefination of aldehydes.
of weaker ionic bases such as Cs2CO3 and K2CO3 at 120 °C
under solid/liquid phase transfer catalysis (PTC) conditions
(TBAB, 10 mol-%), tert-butyl cinnamate (8a) was obtained
in high yields and excellent stereoselectivities (Table 1, en-
tries 7 and 8). By using K2CO3 as the base and different
solvents, such as DMSO, DMAc, acetonitrile, THF and tol-
uene, lower yields than in DMF were obtained (Table 1,
entries 8–13). When the amount of K2CO3 was decreased
to 10 equiv., a lower yield of 49% was obtained (Table 1,
entry 14). Finally, and to try to decrease the reaction time,
the olefination was carried out under microwave irradiation
(Table 1, entry 15). Unfortunately, BTFP methyl sulfone (3,
Results and Discussion
Commercially available 3,5-bis(trifluoromethyl)thio-
phenol[17] was S-alkylated with tert-butyl bromoacetate and
pre-prepared 2-bromo-N-methoxy-N-methylacetamide[18]
using triethylamine as base to afford sulfides 6 and 7 in
89 and 92% yields, respectively, after flash chromatography
(Scheme 1). These compounds were submitted to oxidation
without purification to yield the corresponding BTFP sul-
fones 4 and 5, respectively. Oxidation with 30% H2O2/
NaHCO3/MnSO4·H2O[19] led to sulfones 4 and 5 in 83 and
81% overall yields, respectively. For multigram-scale syn-
thesis, the oxidation of sulfides 6 and 7 was performed with
Oxone® to provide the corresponding sulfones in 86 and
78% overall yields, respectively (Scheme 1).
Scheme 2. Synthesis of α,β-unsaturated esters by Julia–Kocienski
olefination.
Table 1. Synthesis of tert-butyl cinnamate (8a) by Julia–Kocienski
olefination.[a]
Entry Base (equiv.) Solvent
T [°C]
t [h] % Yield[b] Z/E[c]
1
2
3
4
5
6
7
8
DBU (2.4)
DBU (2.4)
P4-tBu (2.4)
NaH (3)
CH2Cl2 Room temp. 48
Ͻ5
15
36
Ͻ5
22
26
71
95
83
65
n.d.
1:99
4:96
n.d.
n.d.
n.d.
3:97
4:96
5:95
5:95
n.d.
n.d.
n.d.
1:99
–
DMF
DMF
THF
120
120
76
48
18
48
48
18
48
18
18
18
18
18
18
18
0.5
tBuOK (4)
DMF
DMF
120
120
120
120
120
120
76
KOH (9)[d]
Cs2CO3 (18)[d] DMF
K2CO3 (18)[d] DMF
K2CO3 (18)[d] DMSO
K2CO3 (18)[d] DMAc
K2CO3 (18)[d] MeCN
K2CO3 (18)[d] THF
K2CO3 (18)[d] PhMe
K2CO3 (10)[d] DMF
K2CO3 (18)[d] DMF
9
10
11
12
13
14
15
Ͻ5
Ͻ5
Ͻ5
49
76
110
120
80[e]
Scheme 1. Synthesis of BTFP sulfones 4 and 5.
45[f]
[a] The reaction was carried out under Barbier-type conditions [ad-
dition of the base to a solution of benzaldehyde and BTFP sulfone
4 (1:2)]. [b] Isolated yield after flash chromatography. [c] Deter-
With the olefination reagents in hand, we then focused
on the stereoselective synthesis of α,β-unsaturated esters by
Julia–Kocienski olefination of aldehydes with sulfone 4.
The synthesis of tert-butyl cinnamate (8a, R = Ph) was se-
1
mined by H NMR of the crude reaction mixture. [d] The reaction
was performed in the presence of TBAB (0.1 equiv.). [e] The reac-
tion was performed under microwave irradiation (80 W). [f] Yield
lected in order to identify the optimal reaction conditions of BTFP methyl sulfone (3, R = RЈ = H).
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Julia–Kocienski Olefination
R = RЈ = H) was the only product formed in 45% yield cinnamate (8a) in 45% yield. The formation of 8a can be
under these conditions as a consequence of the hydrolysis explained by an oxidative coupling between the BTFP sul-
and decarboxylation of the starting tert-butyl ester.[20]
fone 4 and aldehyde enolates[21] and β-elimination of BTFP
The scope of the olefination reaction with sulfone 4 sulfinate from the resulting 1,4-dicarbonyl intermediate un-
(2 equiv.) with a range of different aldehydes was examined der the basic reaction conditions (Scheme 3).
under the optimized reaction conditions, K2CO3 (18 equiv.)
as base in DMF at 120 °C for 18 h under Barbier conditions
(Scheme 2 and Table 2). All the aromatic and heteroarom-
atic aldehydes tested gave moderate-to-high yields of the
corresponding olefins after flash chromatography (Table 2,
entries 1–10). The diastereoselectivity of the process was ex-
cellent (Z/E up to Ͼ 1:99) irrespective of the steric demand
and electronic character of the electrophile, except in the
case of the alkenylation of 2-thiophenecarbaldehyde in
which olefin 8i was obtained with Z/E = 15:85 (Table 2,
entry 9). In general, better yields were observed with elec-
tron-poor electrophiles such as 4-halobenzaldehydes and
4-trifluoromethylbenzaldehyde (Table 2, entries 2–4), the
highest yield being obtained for the olefination of benzalde-
hyde and 4-pyridinecarbaldehyde (Table 2, entries 1 and
10).
Scheme 3. Formation of tert-butyl cinnamate (8a) from phenyl-
acetaldehyde and 4.
On the other hand, when the reaction was carried out
Table 2. Synthesis of α,β-unsaturated esters 8 by Julia–Kocienski
under kinetic conditions employing LDA as the base at a
olefination.[a]
low temperature under Grignard conditions (addition of
Entry RCHO
α,β-Unsaturated esters 8
the electrophile to the previously generated sulfone enolate),
the starting sulfone was mainly obtained, compound 9 also
being isolated in a low yield of 17% (Scheme 4). The ther-
modynamically less stable β,γ-unsaturated ester 9 was
formed as a result of the aldol reaction between the α-sulfo-
nyl carbanion of 4 and phenylacetaldehyde followed by
double bond isomerization.[22]
% yield[b]
Z/E[c]
1
2
C6H5CHO
4-ClC6H4CHO
8a
8b
8c
8d
8e
8f
95
56
62
74
45
52
48
31
46
96
14
15
4:96
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
5:95
3
4
5
6
4-BrC6H4CHO
4-CF3C6H4CHO
4-MeOC6H4CHO
2-ClC6H4CHO
7
8
9
10
11
12
2-naphthaldehyde
6-MeO-2-naphthaldehyde
2-thiophenecarbaldeyde
4-pyridinecarbaldehyde
nC9H19CHO
8g
8h
8i
5:95
15:85
4:96
8j
8k
8l
32:68
25:75
cC6H11CHO
[a] Reactions were performed under Barbier-type conditions: To a
DMF solution of BTFP sulfone 4 (2 equiv.) and the corresponding
aldehyde (1 equiv.), TBAB (10 mol-%) and K2CO3 (18 equiv.) were
added and the resulting mixture was stirred at 120 °C for 18 h. [b]
Isolated yield after flash chromatography. [c] Determined by 1H
NMR of the crude reaction mixture.
Scheme 4. Synthesis of the α-sulfonyl ester 9 from BTFP sulfone 4
and phenylacetaldehyde.
Finally, alkene formation from a representative α,β-un-
saturated aldehyde such as trans-cinnamaldehyde with sul-
fone 4 afforded a complex mixture of products in which
The results obtained with BTFP sulfone 4 in the one-pot tert-butyl cinnamate (8a) was characterized as the major
Julia olefination of aromatic aldehydes are comparable, in product and was isolated in a yield of 20%. In this case,
terms of yield and selectivity, with those obtained with BT the formation of 8a could be a consequence of the Julia–
sulfone 1a[12] even though this heteroaromatic sulfone reacts Kocienski reaction between 4 and benzaldehyde, the latter
at room temp. with DBU as the base in CH2Cl2. In con- obtained from trans-cinnamaldehyde by a retro-aldol pro-
trast, when compared with other non-heteroaromatic sul- cess.
fones such as 2 (Cs2CO3, DMF, room temp. or 60 °C),[14]
BTFP sulfone 4 affords higher yields in much shorter reac- alkenylation of aldehydes with BTFP sulfone 5 was next
tion times. investigated under the optimized reaction conditions
The synthesis of α,β-unsaturated Weinreb amides by the
The stabilized α-sulfonyl carbanion of BTFP sulfone 4 (Scheme 5 and Table 3). Sulfone 5 reacted with aryl and
showed very low reactivity in the alkenylation of aliphatic heteroaryl aldehydes in moderate-to-good yields to give the
aldehydes such as decanal and cyclohexanecarbaldehyde, corresponding diastereomerically pure E α,β-unsaturated
providing the corresponding olefins 8k and 8l in very low Weinreb amides 10. The stereochemistry was again indepen-
yields and with modest selectivities (Table 2, entries 11 and dent of the electronic character or the steric demand of the
12). The olefination reaction of phenylacetaldehyde unex- aldehyde (Table 3, entries 1–10). However, the yield of the
pectedly led to the stereoselective formation of tert-butyl process was lower for electron-rich aldehydes, even with
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longer reaction times, as in the case of 4-methoxybenzalde- the formation of a high-energy alkoxide intermediate (II).
hyde, 2-naphthaldehyde and 6-methoxy-2-naphthaldehyde A second transition state (TS2) was located thereafter that
(Table 3, entries 5, 7 and 8).
corresponds to the nucleophilic aromatic substitution of the
sulfonyl group by the incoming alkoxide. A preliminary ex-
tensive conformational search for TS1- and II-type struc-
tures was conducted at the B3LYP/6-31G* level of theory
including all the possible gauche conformations around the
forming C–C bond and all the different orientations of the
ester and sulfonyl moieties. Two related lowest-lying transi-
tion-state structures (TS1-syn and TS1-anti) and two abso-
lute minima (II-syn and II-anti) were located and reopti-
mized at the B3LYP/6-31++G** level of theory. The sum
of the absolute free energies of anion I + benzaldehyde was
taken as G = 0 and H = 0 for the gas-phase and solution-
phase calculations. Thus, the activation barriers to TS1
were measured as the difference between the energies of
TS1 and the separate starting reactants (G = H = 0),
whereas the activation barriers to TS2 were measured as
the difference between the energies of TS2 and the II-type
intermediates (∆G‡ = GTS2 – GII, ∆H‡ = HTS2 – HII). The
solution-phase energies were treated in the same manner.
Scheme 5. Synthesis of α,β-unsaturated Weinreb amides by Julia–
Kocienski olefination.
Table 3. Synthesis of α,β-unsaturated Weinreb amides 10 by Julia–
Kocienski olefination.[a]
Entry RCHO
Weinreb amides 10
% yield[b] Z/E[c]
1
2
3
PhCHO
4-ClC6H4CHO
4-BrC6H4CHO
10a
10b
10c
10d
10e
10f
10g
10h
10i
66
47
51
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
Ͼ1:99
4
5
6
4-CF3C6H4CHO
4-MeOC6H4CHO
2-ClC6H4CHO
82
20[d]
84
7
8
9
10
2-naphthaldehyde
6-MeO-2-naphthaldehyde
2-thiophenecarbaldehyde
2-furancarbaldehyde
30
25
49
50
10j
[a] The reaction was carried out under Barbier-type conditions with
2 equiv. of sulfone 5. [b] Isolated yield after flash chromatography.
1
[c] Determined by H NMR of the crude reaction mixture. [d] Re-
action time was 48 h.
In terms of yield and selectivity, BTFP sulfone 5 com-
petes with other sulfones recently employed in the synthesis
of α,β-unsaturated Weinreb amides from aromatic alde-
hydes by the one-pot Julia olefination, for example, BT sul-
fone 1b (NaH, THF, room temp.),[13] the main advantage of
the protocol presented here being the absence of anhydrous
conditions, which is essential when using sulfone 1b. On the
other hand, 1b has been shown to be an effective reagent
for the olefination of aliphatic aldehydes, derivatives which
are not reactive with BTFP sulfone 5 under the optimized
reaction conditions.
With respect to the reaction mechanism, we have pre-
viously demonstrated that the Julia–Kocienski olefination
of aromatic aldehydes employing stabilized benzyl BTFP
sulfones may involve zwitterionic intermediates.[16b] How-
ever, the formation of zwitterionic betaine intermediates
should not be so favoured for stabilized sulfones such as 4
and 5. To add further insight into the reaction mechanism
we computationally studied the reaction between tert-butyl
ester 4 and benzaldehyde.
Scheme 6. Mechanism for the Julia–Kocienski olefination of benz-
aldehyde with BTFP sulfone
311++G** level of theory.
4 computed at the B3LYP/6-
In order to ascertain the origin of the selectivity of the
reaction, two diastereomeric pathways (syn and anti) were
The initial nucleophilic addition of sulfone anion I to
computed separately (Scheme 6). The reaction proceeds benzaldehyde occurs through TS1-type transition states;
through a two-step mechanism. The first one (TS1) involves diastereomeric TS1-syn and TS1-anti were found to be the
the nucleophilic addition of enolate I to benzaldehyde with lowest-energy structures. In both cases, the phenyl ring of
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Julia–Kocienski Olefination
the benzaldehyde appears anti to the sterically demanding matic ring, were not located. Furthermore, IRC calculations
arylsulfonyl moiety, whereas the developing alkoxide is situ- show that the TS2 transition states are undoubtedly con-
ated gauche to the electron-deficient BTFP aromatic ring. nected to the final products (E)-8a and (Z)-8a as well as to
Thus, the reaction seems to be faster for the anti attack and the intermediates II-anti and II-syn. The final products are
the activation energies for TS1-anti and TS1-syn in the gas- 61.3 (syn) and 59.3 kcal/mol (anti) lower in energy than
phase differ by around 2 kcal/mol (∆∆H‡ = 2.1 kcal/mol TS2, and thus the second step (Smiles rearrangement) leads
and ∆∆G‡ = 1.4 kcal/mol). The nucleophilic attack gener- to the irreversible formation of the final products without
ates a pair of alkoxide intermediates (II-anti or II-syn) that the generation of intermediates. The IRC calculations also
lie very close in energy to the corresponding transition show that after TS2, the elimination of SO2 and ArO– is
states. The high energy of the II-type intermediates and the not a concerted process. A fast elimination of SO2 occurs
small barrier for the retro-addition reaction (GTS1-syn
–
first, producing an anionic enolate species III that is not a
GII-syn = 1.5 kcal/mol and GTS1-anti – GII-anti = 0.4 kcal/mol) minimum along the reaction coordinate. Thus, this species
suggest the existence of an equilibrium in the first step that could not be detected and subsequent barrierless elimi-
is strongly displaced towards the starting materials. Inter- nation of ArO– leads directly to the final products. Note,
estingly, the very small energy difference in favour of II-anti elimination from TS2-syn leads to the E product, whereas
over II-syn in both the gas phase and the solvent phase the Z product is observed from TS2-anti.
(∆∆G° = 0.3 kcal/mol, ∆∆G°DMF = 0.4 kcal/mol) is not
Thus, in contrast to other proposed mechanisms,[24] the
enough to explain the high selectivity experimentally en- elimination of SO2 and BTF-phenol is not a concerted pro-
countered in this particular reaction. The nucleophilic aro- cess and does not occur in an anti fashion in our reaction
matic displacement of the sulfonyl group by the alkoxide II- system. The fact that a significant activation energy differ-
type intermediates leads to a second transition state (TS2), ence was computed in favour of TS2-syn over TS2-anti
which represents the highest-lying point along the reaction (∆∆G‡ = 3.7 kcal/mol, ∆∆G‡
= 3.0 kcal/mol), leading
DMF
coordinate (GTS2-anti = 35.0 kcal/mol, GTS2-syn = 31.6 kcal/ to the formation of the experimentally encountered E iso-
mol). The mechanism of related nucleophilic displacements mer, suggests that TS2 is the selectivity-determining step of
has been theoretically studied and is well established.[23] In this reaction. In addition, the introduction of solvent effects
our case, the high relative energy of the II-type inter- does not alter the overall picture described above. As found
mediates induces a fairly low activation barrier to TS2 by others in related aromatic substitution reactions,[23] po-
(∆G‡
= 5.1 kcal/mol, ∆G‡
= 8.8 kcal/mol). lar solvents (DMF in this study) induce a relative stabiliza-
TS2-syn
TS2-anti
These data correspond to a significant energy difference in tion of the charged species, especially II-type intermediates,
favour of the less sterically demanding TS2-syn dia- and hence, the TS2 barriers are higher in the solvent-phase
stereomeric structure in which the ester and phenyl moieties than in the gas-phase calculations.
are located in an anti relationship.
We also considered the possibility that after elimination
Both of the TS2 transition states are very asynchronous of SO2 and prior to the elimination of ArO– a fast rotation
(Figure 2); the partial formation of the C–O bond (ca. around the newly formed C–C bond could lead to equili-
1.9 Å) precedes the rupture of the C–S bond (ca. 1.7 Å), bration of the III-type enolate species. The fact that they
which means that during the formation of the transition are not localizable stationary points along the reaction co-
state significant charge injection into the aromatic ring oc- ordinate precludes a direct comparison of their energies,
curs that is facilitated by the highly electron-withdrawing which were estimated by fixing the C–O bond at 1.45 Å to
CF3 groups. Nonetheless, in accordance with previous re- avoid elimination of ArO– during the optimization. Thus,
lated theoretical studies on aromatic substitution,[23] the we could have an indirect measure of the relative energies
corresponding Meisenheimer intermediates, in which both of III-type species and the rotation barrier between them.
atoms (sulfur and oxygen) are covalently bound to the aro- Eventually, these could lead to the thermodynamic conver-
Figure 2. Transition-state structures for the nucleophilic aromatic substitution step (second step) of the reaction between benzaldehyde
and BTFP sulfone 4.
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D. A. Alonso, M. Fuensanta, E. Gómez-Bengoa, C. Nájera
FULL PAPER
(0.040–0.063 mm) was employed. Reactions under inert atmo-
sphere (argon) were performed in oven-dried glassware sealed with
a rubber septum using anhydrous solvents.
gence of both pathways to the more stable E isomer
through III-syn, which is 6.4 kcal/mol more stable than its
isomer III-anti. The rotational barrier is 11.5 kcal/mol,
which suggests that the rotation might be too slow in com-
parison to the barrierless elimination of phenoxide. The
lack of detectable intermediates after TS2 does not allow
direct evaluation of its significance in the mechanism.
Nonetheless, both kinetic considerations at TS2 and
thermodynamic factors during elimination after TS2 merge
at the formation of the same isomer [(E)-8a] and account
for the high E diastereoselectivity observed in the process.
The formation of the enolate from sulfone 4 was con-
With respect to the computational studies, all stationary points
along the reaction coordinate were optimized using the B3LYP
functional[25] and the 6-311++G** basis set as implemented in
Gaussian 03.[26] Use of the large basis set was described as being
important for the correct energetic description of anionic species
in computational studies of related reactions. All energy minima
and transition states were characterized by frequency analysis. The
energies reported in this work include unscaled electronic and ther-
mal corrections to the enthalpy and Gibbs free energy. The station-
ary points were characterized by frequency calculations in order to
firmed by ESI-MS experiments (see the Supporting Infor- verify that they have the right number of negative eigenvalues. The
intrinsic reaction coordinate[27] (IRC) was followed to verify the
energy profiles connecting each transition state to the correct local
minima. DMF solvent effects have been considered by B3LYP/6-
311++G** single-point calculations on the previously gas-phase-
mation). Under typical reaction conditions, enolate I (m/z
= 391.0, Scheme 6) was detected after stirring sulfone 4
(0.05 mmol), K2CO3 (62 mg, 0.45 mmol) and TBAB
(1.5 mg, 10 mol-%) in DMF (300 µL) for 10 min at room
optimized structures with the self-consistent reaction field (SCRF)
temp. Benzaldehyde (3 µL, 0.025 mmol) was then added to
based on the polarizable continuum model PCM[28] (ε = 36.7, sol-
this solution and the mixture was heated at 120 °C for 1 h.
vent radius = 3.48 Å).
An aliquot of the reaction mixture was then dissolved in
Products 8a,[29] 8b,[30] 8c,[30] 8d,[30] 8e,[30] 8f,[31] 8g,[32] 8h,[33] 8i,[34]
MeOH and injected after 0.2 min. The formation of inter-
8j,[35] 8k,[29] 8l,[29,36] 10a,[37] 10b,[38] 10c,[39] 10d,[40] 10e,[38] 10f,[41]
mediate II (Scheme 6) was detected in the mixture by ESI-
MS.
10g,[42] 10h,[43] 10i,[43] and 10j[43] have been described previously
and gave satisfactory spectroscopic and physical data. Products 8a,
10a and 10d are also commercially available.
General Procedure for the Synthesis of BTFP Sulfides 6 and 7: 3,5-
Bis(trifluoromethyl)thiophenol (835 µL, 5 mmol) was added at
room temperature to a solution of TEA (1.4 mL, 10 mmol) in
MeCN (15 mL) under argon. After stirring for 15 min, the corre-
sponding alkyl bromide (5.5 mmol) was added to the reaction and
the resulting mixture was stirred at room temp. for 1 d. After
quenching with H2O (20 mL), the mixture was extracted with
EtOAc (2ϫ20 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated to afford the corresponding 3,5-
bis(trifluoromethyl)phenyl sulfides, which were used in the next
step without further purification. They were purified by flash
chromatography for characterization purposes.
Conclusions
We have shown that BTFP sulfones 4 and 5 are efficient
reagents for the stereoselective synthesis of (E)-α,β-unsatu-
rated esters and Weinreb amides by the Julia–Kocienski ole-
fination of aromatic aldehydes under very convenient solid/
liquid phase-transfer catalysis conditions employing K2CO3
as the base and TBAB in DMF at 120 °C. According to
computational studies, the reaction mechanism, which in-
volves two transition states, ends with a non-concerted eli-
mination of SO2 and 3,5-bis(trifluoromethyl)phenoxide, in
contrast to other proposed mechanisms, with the generation
of TS2 being the selectivity-determining step in a step
closely related to the Smiles rearrangement. Additional ap-
plications of BTFP sulfones in olefination and other reac-
tions are currently under investigation.
tert-Butyl 2-[3,5-Bis(trifluoromethyl)phenylsulfanyl]acetate (6):
Yield 1.6 g, 89%, colourless oil; Rf (hexane/EtOAc, 4:1) = 0.68.
IR: ν = 2984, 2936, 1731, 1617, 1354, 1277, 1133 cm1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.81 (s, 2 H, ArH), 7.68 (s, 1 H, ArH),
3.69 (s, 2 H, CH2S), 1.43 [s, 9 H, C(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.5 (CO), 139.6 (ArC), 132.0 (q, JCF
=
33.3 Hz, 2 CCF3), 127.7 (ArCH), 122.9 (q, JCF = 272.9 Hz, 2 CF3),
119.5 (ArCH), 82.5 [C(CH3)3], 36.1 (CH2S), 27.4 (3 CH3) ppm.
MS: m/z (%) = 360 (19) [M]+, 304 (20), 285 (32), 260 (21), 259 (93),
239 (35), 57 (100). HRMS: calcd. for C14H14F6O2S [M]+ 360.0619;
found 360.0613.
Experimental Section
General: Melting points were obtained with a Reichert Thermovar
apparatus and are not corrected. IR data were collected with a
Nicolet Impact 400D FTIR apparatus. Only the structurally most
important IR peaks have been listed. NMR spectra were recorded
with a Bruker AC-300 spectrometer (300 MHz for H1 NMR and
75 MHz for 13C NMR) using CDCl3 as the solvent and TMS as the
internal standard unless otherwise noted. Low-resolution electron
impact (EI) mass spectra were obtained at 70 eV with Shimadzu
QP-5000 and Agilent 5973 spectrometers. HRMS were recorded
with a Finnigan MAT 95S spectrometer. ESI-MS experiments were
carried out with an Agilent 1100 Series LC/MSD Trap “SL” mass
spectrometer equipped with an ESI source. Analytical TLC was
visualized with UV light at 254 nm or with KMnO4. Thin-layer
chromatography was carried out with TLC aluminium sheets with
silica gel 60 F254 (Merck). For flash chromatography, silica gel 60
2-[3,5-Bis(trifluoromethyl)phenylsulfanyl]-N-methoxy-N-methylacet-
amide (7): Yield 1.1 g, 92%, yellow oil; Rf (hexane/EtOAc, 4:1) =
0.18. IR: ν = 1670, 1354, 1278, 1181, 1132 cm1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.87 (s, 2 H, ArH), 7.66 (s, 1 H, ArH),
3.96 (s, 2 H, CH2S), 3.78 (s, 3 H, OCH3), 3.23 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.6, 139.6 (ArC), 131.8 (q, JCF
= 33.2 Hz, 2 CCF3), 127.9 (ArCH), 122.8 (q, JCF = 272.6 Hz, 2
CF3), 119.4 (ArCH), 61.3 (OCH3), 33.7 (CH2S), 32.1 (CH3) ppm.
MS: m/z (%) = 347 (34) [M]+, 260 (18), 259 (100), 239 (62), 195 (14),
61 (89). HRMS: calcd. for C12H11F6NO2S [M]+ 347.0415; found
347.0415.
General Procedure for the Synthesis of BTFP Sulfones 4 and 5: Oxi-
dation reaction employing H2O2/NaHCO3/MnSO4·H2O: An aque-
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2915–2922

Julia–Kocienski Olefination
ous mixture of 30% H2O2 (5 mmol, 515 µL) and a 0.2  buffer
with EtOAc (2ϫ15 mL) and the organic phase was dried (MgSO4),
solution of NaHCO3 (17 mL), prepared at 0 °C, was slowly added filtered, the solvent evaporated and the residue purified by flash
to solution of the corresponding crude sulfide 6 or 7 (1 mmol) and
MnSO4 monohydrate (2 mg, 1 mol-%) in MeCN (23 mL) stirred a
room temp. After stirring for 1 d at room temp., the reaction was
quenched with a saturated aqueous solution of NaCl (30 mL), ex-
tracted with EtOAc (2ϫ20 mL) and dried (MgSO4). Final evapo-
ration of the solvents (15 Torr) afforded the corresponding pure
crude sulfones 4 or 5, which were recrystallized from diethyl ether/
hexane.
Oxidation reaction employing Oxone®: Oxone® (50 mmol, 31 g)
was slowly added to a 0 °C stirred solution of the corresponding
sulfide 6 or 7 (5 mmol) in a 1:1 mixture of MeOH/H2O (44 mL).
The reaction was stirred at room temp. for 1 d. After this time,
MeOH was evaporated and the residue was dissolved in CH2Cl2
(50 mL) and filtered through Celite. Water was added to the filtrate
and the mixture was extracted with CH2Cl2 (2ϫ25 mL) and
washed with a saturated aqueous solution of NaCl (3ϫ50 mL).
The organic phase was then dried (MgSO4), filtered and evaporated
to afford the corresponding crude sulfones 4 and 5 which were
recrystallized from diethyl ether/hexane.
chromatography to afford 24.5 mg of the title compound (17%
yield). White solid; m.p. 71–72 °C (EtOAc/hexane). IR: ν 2982,
˜
1731, 1358, 1279, 1144, 1100 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.28 (s, 2 H, ArCH), 8.16 (s, 1 H, ArCH), 7.40–7.28 (m, 5 H,
ArCH), 6.72 (d, 3JH,H = 15.9 Hz, 1 H, CH=CHPh), 6.00 (dd, 3JH,H
3
= 15.9, 9.2 Hz, 1 H, CH=CHPh), 4.67 (d, JH,H = 9.4 Hz, 1 H,
CH), 1.46 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ
= 162.3 (CO), 139.6 (CH=CHPh), 138.5, 133.8 (ArC), 131.5 (q,
JC–F = 33.7 Hz, 2 CCF3), 129.46, 129.43, 128.3, 127.8, 125.9
(ArCH), 122.6 (2 CF3), 113.7 (CH=CHPh), 83.7 [C(CH3)3], 74.1
(CH), 26.6 [C(CH3)3] ppm. MS: m/z (%) = 494 (0.04) [M]+, 217
(20), 213 (10), 162 (10), 161 (95), 144 (15), 133 (44), 117 (22), 116
(24), 115 (100), 57 (44). HRMS: calcd. for C22H20F6O4S [M]+
494.0986, [M – tBuO]+ 421.0330; found 421.0325.
Supporting Information (see also the footnote on the first page of
this article): Cartesian coordinates for transition states and reactant
complexes as well as ESI-MS(–) spectra.
Acknowledgments
tert-Butyl 2-{[3,5-Bis(trifluoromethyl)phenyl]sulfonyl}acetate (4):
White solid; m.p. 70–71 °C. IR: ν = 3104, 3082, 2984, 2940, 1734,
˜
This work was supported by the Dirección General de Investiga-
ción of the Ministerio de Educación y Ciencia (Grants CTQ2004-
00808/BQU, CTQ2007-62771/BQU, Consolider INGENIO 2010
CSD2007-00006), by the Generalitat Valenciana (CTIOIB/2002/
320, GRUPOS03/134, GRUPOS05/11, GV05/157 and GV/2007/
142) and the University of Alicante. We also thank SGI/IZO-
SGIker UPV/EHU for allocation of computational resources and
Dr. Pablo Candela from the Servicios Técnicos de Investigación
(Universidad de Alicante) for the ESI-MS measurements.
1
1282, 1164, 1133 cm–1. H NMR (300 MHz, CDCl3): δ = 8.41 (s,
2 H, ArCH), 8.18 (s, 1 H, ArCH), 4.13 (s, 2 H, SCH2), 1.19 [s, 9
H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 160.6 (CO),
141.4 (ArC), 133.0 (q, JC–F = 35.2 Hz, 2 CCF3), 129.2, 127.7
(ArCH), 122.3 (q, JC–F = 274.5 Hz, 2 CF3), 84.6 [C(CH3)3], 61.7
(CH2S), 27.5 [C(CH3)3] ppm. MS: m/z (%) = 377 (15) [M – CH3]+,
317 (35), 277 (42), 213 (75), 57 (100). HRMS: calcd. for
C14H14F6O4S [M]+ 392.0517, [M – CO2tBu]+ 276.9758; found
276.9757.
2-{[3,5-Bis(trifluoromethyl)phenyl]sulfonyl}-N-methoxy-N-methyl-
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General Procedure for the Julia–Kocienski Olefination of Aldehydes
with BTFP Sulfones 4 or 5: K2CO3 (250 mg, 1.8 mmol) and TBAB
(6 mg, 0.02 mmol) were added portionwise to a solution of sulfone
4 or 5 (0.2 mmol) and aldehyde (0.10 mmol) in DMF (4 mL) stirred
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night at 120 °C and then quenched with a saturated aqueous solu-
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by flash chromatography (see Tables 1, 2 and 3).
Synthesis of tert-Butyl (E)-2-{[3,5-Bis(trifluoromethyl)phenyl]-
sulfonyl}-4-phenylbut-3-enoate (9): Freshly prepared LDA
(0.3 mmol) was added dropwise to a solution of sulfone 4
(0.3 mmol) in anhydrous THF (6 mL) stirred at –78 °C under ar-
gon. The mixture was then stirred for 30 min at –78 °C and then
phenylacetaldehyde (35 µL, 0.3 mmol) was added and the tempera-
ture allowed to rise to room temp. The resulting mixture was stirred
overnight at room temperature and quenched with a saturated
aqueous solution of NH4Cl (10 mL). The mixture was extracted
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2921

D. A. Alonso, M. Fuensanta, E. Gómez-Bengoa, C. Nájera
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Received: January 14, 2008
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Published Online: April 23, 2008
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2915–2922