Water-mediated transition-metal-free Tsuji-Trost-type reaction

Article abstract of DOI:10.1016/j.tetlet.2003.09.038

The treatment of 1-acetoxy-1,3-diphenylpropene (1) by C-, O-, S- and N-nucleophiles in basic aqueous media produced the corresponding substitution products in the absence of a transition-metal catalyst. Mechanistic studies, using (S)-1 and p-MeC₆

Full text of DOI:10.1016/j.tetlet.2003.09.038

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8099–8102
Water-mediated transition-metal-free Tsuji–Trost-type reaction
Carole Chevrin, Jean Le Bras, Franc¸oise He´nin* and Jacques Muzart*
Unite´ Mixte de Recherche ‘Re´actions Se´lectives et Applications’, CNRS, Universite´ de Reims Champagne, Ardenne, BP 1039,
51687 Reims Cedex 2, France
Received 17 June 2003; revised 27 August 2003; accepted 5 September 2003
Abstract—The treatment of 1-acetoxy-1,3-diphenylpropene (1) by C-, O-, S- and N-nucleophiles in basic aqueous media produced
the corresponding substitution products in the absence of a transition-metal catalyst. Mechanistic studies, using (S)-1 and
p-MeC6H4CH(OAc)CHꢀCHPh as substrates, led to propose a BAL1 cleavage of the ester function leading to a stabilized allylic
carbocation as intermediate.
© 2003 Elsevier Ltd. All rights reserved.
Aqueous chemistry has received considerable attention
in synthetic organic chemistry for environmental, eco-
nomical, safety reasons and by showing unique reactiv-
ities and selectivities that are not attained in organic
solvents.1 One of the first illustrations of the potentials
of this ‘green chemistry’ was the positive effect of water
on rates and selectivities of Diels–Alder reactions
observed in the early 1980s by Breslow and Grieco.2
The role of water was explained by introducing the
concept of hydrophobic effects in organic reactions.3
Water has unique physical and chemical properties such
as high dielectric constant and cohesive energy density
compared to most organic solvents.3,4 By utilizing these
properties, it should be possible to observe reactivities
that cannot be attained in organic solvents.
air-sensitive phosphines. Surprisingly, we observed that
the reaction may occur in the absence of any transition
metal catalyst to afford substituted products with N, S,
O, or C-nucleophiles when carried out in the presence
of water which becomes an essential agent for the
success of the process (Eq. (1)).
(1)
We first studied the nucleophilic substitution of 1-ace-
toxy-1,3-diphenylpropene (1) with acetylacetone (2
equiv.) at 50°C in water9 in the presence of K2CO3 (2
equiv.) and 5% of both PdCl2(MeCN)2 and LH (Eq.
(1)). The reaction was very sluggish, 36% conversion of
1 in 6 days affording 17% of the expected substituted
product 2a. Therefore, the experiment was repeated in
using a range of co-solvents:10 2a was produced with
various yields, the nature of the co-solvent having a
dramatic effect on the efficiency and selectivity of the
reaction (Fig. 1). For example, only 63% conversion
and 36% 2a were obtained in 6 days in a 1/1 mixture of
water and THF while complete conversion of 1 was
attained in 1 day with methanol as co-solvent to afford
92% of 2a and traces of the dissymmetric ether 2e
(Table 1, entry 1). The reaction mixture in H2O/MeOH
was extracted by methylene chloride and, as expected,
we observed that the aqueous phase remained catalyti-
cally active, four successive reuses yielding 90–84% 2a.
For allylic substitution reactions, palladium methods
are probably the most widely employed5 and, some
years ago, Sinou et al. reported the Tsuji–Trost reaction
in a two-phase aqueous–organic medium using a sul-
fonated phosphine ligand, TPPTS, coordinated to
palladium.6,7
Recently, we have reported the use of the hydrophilic
ligand [(HOCH2CH2NHCOCH2)2NCH2]2 (LH) in cop-
per-catalyzed allylic oxidations in water and the
efficient recycling of the catalytic system.8 This led us to
study allylic substitutions with LH associated to palla-
dium salts to propose an alternative to the use of
Keywords: water chemistry; allylic acetate; substitution; palladium;
BAL1-SN1% mechanism.
* Corresponding authors. Fax: (+33)3 26 91 31 66; e-mail:
francoise.henin@univ-reims.fr; jacques.muzart@univ-reims.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.038

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C. Che6rin et al. / Tetrahedron Letters 44 (2003) 8099–8102
Figure 1. Substitution of 1 by acetylacetone in H2O/co-sol-
vent in the presence of PdCl2(MeCN)2-LH; experimental con-
ditions as in Table 1 (entry 1) except the reaction time, 144 h,
in H2O/MeCN and H2O/THF.
Figure 2. Substitution of 1 by acetylacetone in H2O/co-sol-
vent; experimental conditions as in Table 1 (entry 2).
a complete conversion of 1 was observed in MeOH
(entry 5); however, these conditions did not lead to 2a,
but afforded ether 2e and alcohol 2f, this latter, which
was not observed using H2O/MeOH as solvent (entry
2), being here the main product. Since K2CO3 is poorly
soluble in DMF, an organic base, DBU, was used.
Similar results were obtained: no reaction occurred in
DMF (entry 6) while 2a was isolated in 78% yield in
H2O/DMF (entry 7).
When the reaction in H2O/MeOH was performed in the
absence of any Pd and ligand, the quantitative conver-
sion of 1 was obtained in 24 h at 50°C to produce 40%
2a and 55% 2e (Table 1, entry 2). Compared to the
previous reaction (entry 1), the selectivity was different,
all the conditions, except the palladium-LH catalyst,
being the same. The surprising allylic alkylation of 1 in
the absence of a transition-metal11,12 led us to examine
the influence of other co-solvents on this Pd-uncata-
lyzed reaction (Fig. 2). The alkylation product was
obtained with fair selectivities in the other tested co-sol-
vents but high conversion was only attained in H2O/
DMF (entry 3); this differs from the Pd-catalyzed
reaction for which the best solvent was H2O/MeOH
(Fig. 1). It is important to note (i) the unreactivity of 1
when the experiment in DMF was carried out without
added water (entry 4) and (ii) the absence of hydrolysis
of 1 in basic H2O/DMF (entry 3). In contrast to DMF,
Repeating the reaction in H2O/DMF with new glass-
ware and stirring bar produced again 2a. Therefore, it
appeared that the formation of the CꢁC bond was
really transition-metal-free and that water activated the
substrate to the nucleophilic displacement. These results
led us to test three other types of nucleophiles, phenol/
K2CO3, sodium p-toluenesulfinate and morpholine, in
the presence and in the absence of palladium under the
above optimum aqueous conditions (entries 8–14). The
expected adducts 2b, 2c13 and 2d were isolated under
Table 1. Reactions of 1 (0.8 mmol) at 50°C for 24 h
Entry
Cat.a (equiv.)
Nucleophile (2 equiv.)
Base (2 equiv.) H2O (mL)
Solvent (1 mL) Conv. (%)
Products (%)
1
2
3
4
5
6
7
8
0.05
0
0
0
0
0
0
0.05
0
0
0.05
0
0.05
0
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Acetylacetone
Phenol
Phenol
Phenol
p-MeC6H4SO2Na
p-MeC6H4SO2Na
Morpholine
Morpholine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DBU
DBU
K2CO3
K2CO3
K2CO3
0
1
1
1
0
0
0
1
1
1
1
1
1
1
1
MeOH
MeOH
DMF
DMF
MeOH
DMF
DMF
MeOH
DMF
DMF
MeOH
DMF
MeOH
DMF
100
100
90
0
100
0
90
32
53
94
2a, 92+2e, traces
2a, 40+2e, 55
2a, 80
2e, 13+2f, 66
2a, 78
2b, traces+2e, 20
2b, 44
2b, 73
2c, 74+2e, traces
2c, 79
9
10b
11
12
13
14
100
82
100
100
0
0
0
2d, 95
2d, 96
a Cat: equimolecular quantities of PdCl2(MeCN)2 and LH.
b Reaction time: 84 h.

C. Che6rin et al. / Tetrahedron Letters 44 (2003) 8099–8102
8101
both conditions and it was of interest to point out that
the best yields were obtained without Pd-catalysis. Nev-
ertheless, the substitution by PhOH required a longer
reaction time to reach a high conversion (entries 9 and
10).
medium may induce the selective cleavage of either the
O-allyl or the O-acyl bond of the above allylic acetates.
The reversibility of the O-allyl bond cleavage in H2O/
DMF, as shown by the isomerization of 3 (Eq. (3)) and
the racemization of (S)-1, implies a competition
between AcO− and the other nucleophiles. This could
explain the rather long reaction times required for
efficient substitution by the nucleophiles especially with
phenol/K2CO3.
The transfer of the allyl group from acetate to nucle-
ophilic species formally corresponds to a nucleophilic
substitution with the acetate as the leaving group. In
order to approach the mechanism of these unusual
substitutions in the absence of a transition-metal cata-
lyst, experiments were performed with the dissymmetric
allylic acetate 314 and (S)-1.15
No reaction of 1 took place in a polar aprotic solvent
like DMF. It is known that ionization of neutral sub-
(2)
Subjecting 3 to the previous reagents in H2O/DMF at
50°C (Eq. (2)) led to a non-regioselective reaction
providing, in each case, a 1/1 mixture of 4 and 5
(4a+5a: 71%, 4b+5b: 38%, 4c+5c: 87%, 4d+5d: 76%) as
strates is promoted by protic solvents.4,16 Therefore, we
propose that addition of water to DMF favors the
formation of the cation by hydrogen bonding with
oxygen doublets of the substrate and then stabilization
of the ion pair.
1
indicated by H and 13C NMR analysis. In the absence
of reagents, 3 was unchanged when heated at 50°C for
24 h in DMF while a 1/1 mixture of 3 and its allylic
rearrangement product was recovered in H2O/DMF
(Eq. (3)).
In aprotic solvents, the substitution of allylic acetates is
often catalyzed by transition-metal complexes, in par-
ticular those of palladium which provide cationic h3-
(3)
The reaction of (S)-1 (95% e.e.) with acetyl acetone and
K2CO3 in H2O/DMF at 50°C for 24 h (conditions of
Table 1, entry 3) afforded racemic 2a (yield: 90%).
Using (S)-1 (99% e.e.) and a reaction time reduced to 1
h, the e.e. of the recovered substrate was lowered to
89%. The reaction of (S)-1 (92% e.e.) in MeOH under
conditions of Table 1, entry 7, provided alcohol (S)-2f
(92% e.e.).
allylpalladium intermediates.5 The present study shows
that the addition of water may induce the substitution
under transition-metal-free conditions, the process
involving the formation of stabilized carbocations
which react with different types of nucleophiles. Such a
reaction pathway may be preferred to the hydrolysis
which usually occurs in an aqueous basic medium.
Since (S)-2f is produced with retention of the e.e., its
formation in MeOH is due to a trans-esterification
involving the classical acyl-oxygen bond cleavage and
following the usual BAC mechanism.16 The addition of
water (entry 2) precludes this trans-esterification path-
way and induces the cleavage of the allyl-O bond. The
experiments from (S)-1 (no e.e. of the adduct, racem-
ization of the substrate) and 3 (no selectivity, isomeriza-
tion of the substrate) in H2O/DMF indicate that the
substitutions occurred on a stabilized allylic carboca-
tion, a BAL1-SN1% mechanism being involved.16 These
experiments led to conclude that the modification of the
Acknowledgements
We are grateful to ‘Re´gion Champagne-Ardenne’ for a
PhD studentship to C.C.
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