Heck arylation of allylic alcohols in molten salts

Article abstract of DOI:10.1016/S0022-328X(01)01149-4

The Heck coupling of ArX (X=I, Br) with allylic alcohols, carried out at 80-120°C in molten n-Bu₄NBr using NaHCO₃ as base and PdCl₂ as catalyst without extra ligands, leads to the corresponding β-arylated carbonyl compounds. After extraction of the organic materials with diethyl ether, the ionic layer can be reused directly.

Full text of DOI:10.1016/S0022-328X(01)01149-4

Journal of Organometallic Chemistry 634 (2001) 153–156
www.elsevier.com/locate/jorganchem
Heck arylation of allylic alcohols in molten salts
Sandrine Bouquillon, Benjamin Ganchegui, Boris Estrine, Franc¸oise He´nin,
Jacques Muzart *
Unite´ Mixte de Recherche ‘Re´actions Se´lecti6es et Applications’, Faculte´ des Sciences, CNRS—Uni6ersite´ de Reims Champagne-Ardenne,
B.P. 1039, 51687 Reims Cedex 2, France
Received 18 May 2001; accepted 30 July 2001
Abstract
The Heck coupling of ArX (X=I, Br) with allylic alcohols, carried out at 80–120 °C in molten n-Bu4NBr using NaHCO3 as
base and PdCl2 as catalyst without extra ligands, leads to the corresponding b-arylated carbonyl compounds. After extraction of
the organic materials with diethyl ether, the ionic layer can be reused directly. © 2001 Published by Elsevier Science B.V.
Keywords: Heck reactions; Allylic alcohols; Molten ammonium salts; Recycling
1. Introduction
(1)
In the course of our studies devoted to Pd-catalyzed
oxidations of alcohols [1–4], we have recently disclosed
that anionic catalysts, [Pd2X6][n-Bu4N]2, can be ob-
tained from PdCl2 and n-Bu4NX (X: Cl, Br) [5]. This
2. Results and discussion
led us to envisage the arylation of allylic alcohols
through Heck reactions using such a catalyst in molten
Initial experimentation was undertaken in tetra-n-bu-
n-Bu4NBr. Indeed, Heck reactions may involve PdII/
tyl ammonium bromide using 3-methyl-3-buten-2-ol
PdIV catalytic cycles when particular PdII-catalysts are
(1a, R1=H, R2=R3=Me), iodobenzene, sodium bi-
used [6–12], and the formation of b-arylated ketones
carbonate and catalytic amounts of palladium chloride,
from allylic alcohols [13,14] seems to be promoted by
the mixture being heated at 80 °C for 6 h (Eq. (1),
the presence of an ammonium salt as additive [15–22].
Table 1, run 1A). Although the melting point of n-
Furthermore, the use of ionic liquids as solvents is
Bu4NBr is 103 °C, a melt was thus obtained. After
presently undergoing a new springtime although they
cooling to room temperature, the resulting solid was
have been known since the beginning of the last cen-
carefully triturated with hexane to extract the organic
tury.1 Recent reports concerning Heck reactions with
compounds from which ketone 2a (R1=H, R2=R3=
a,b-unsaturated esters, styrene and vinyl ethers in phos-
Me) was isolated in 74% yield after evaporation of the
phonium, 1-butyl-3-methylimidazolium or other ammo-
solvent and chromatography. The phenylation was re-
nium salts [28–35] urge us to present the results we
have obtained with allylic alcohols (Eq. (1)).
peated with the recovered solid and a fresh mixture of
1a and iodobenzene: a lower conversion was obtained
and the yield of 2a dropped to 50%. Further recycling
led to a dramatic decrease in the conversion (run 3A).
We noted that the extraction of 2a from the mixture
was more effective when using diethyl ether as solvent
rather than hexane (run 1B). The recycling process was
then examined by adding a batch of NaHCO3 for each
new run: better results were obtained but, nevertheless,
* Corresponding author. Tel.: +33-3-2691-3237; fax: +33-3-2691-
3166.
E-mail address: jacques.muzart@univ-reims.fr (J. Muzart).
1 For recent reviews, see Refs. [23–27].
0022-328X/01/$ - see front matter © 2001 Published by Elsevier Science B.V.
PII: S0022-328X(01)01149-4

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S. Bouquillon et al. / Journal of Organometallic Chemistry 634 (2001) 153–156
Table 1
Use and reuse of PdCl2 and n-Bu4NBr in the reaction of iodobenzene with 1a a
a
Protocol
Run 1
Run 2
Run 3
Run 4
C (%) b
Y (%) c
C (%) b
Y (%) c
C (%) b
Y (%) c
C (%) b
Y (%) c
A
B
C
100
100
100
74
89
90
65
89
95
50
61
68
25
75
93
12
58
63
–
–
92
–
–
63
a A: run 1 was carried out at 80 °C for 6 h using 1a (1 mmol), iodobenzene (1 mmol), NaHCO3 (1.2 mmol), PdCl2 (0.1 mmol) and n-Bu4NBr
(1.5 g); runs 2–4 were carried out with the recovered solid without additive. B: run 1 as under A conditions; addition of NaHCO3 (1.2 mmol) for
runs 2–4. C: as under B conditions except for the reaction temperature and the reaction time which were 120 °C and 24 h, respectively. A: hexane
was used for extractions; B and C: diethyl ether was used for extractions.
b C: conversion of 1a.
c Y: isolated yield of 2a.
Table 2
Use and reuse of PdCl2 and n-Bu4NBr in the reaction of iodobenzene with 1b–1h under conditions of protocol C (see Table 1)
the conversion dropped with each cycle (runs 2B and
3B). However, an increase in both the reaction time and
temperature led to improved results (runs 2C–4C).
Since the chemical yields of 2a thus obtained were
superior to those previously reported under conven-
tional Heck conditions, i.e. in DMF as solvent [36],
Protocol C was extended to alcohols 1b–1h (Table 2).
Alcohols 1b–1f were regioselectively b-phenylated giv-
ing carbonyl compounds 2b–2f with fair yields. The
reaction with 1g and 1h was in contrast less selective.
Indeed, the isomerization of the double bond of 1g
leading to the corresponding ketone (2b) was a compet-
itive reaction while 1h underwent non-regioselective
phenylation. The formation of 3h indicates that the
HPdX species, which were produced in situ by b-H
elimination, added back to the initially formed a-ad-
duct (A) rather than reacting with the base; this addi-
tion followed by a second b-H elimination results in the
isomerization to the enol (B) giving then the aldehyde
(Scheme 1) [13,14,37]. The formation of 2b from 1g
could also be due to a 1,2-addition/elimination se-
quence of HPdX on 1g.
Since iodobenzene is relatively expensive, we exam-
ined the treatment of 1a with bromobenzene and
chlorobenzene. No reaction was observed with PhCl at
120 °C and increasing the temperature to 150 °C pro-
duced a complex mixture. With PhBr, 1a yielded 65%
of 2a in 4 h at 120 °C; interestingly, the decrease of the
amount of PdCl2 to 0.05 equivalents led to the same
chemical yield (reaction time: 6 h). The use of solely

S. Bouquillon et al. / Journal of Organometallic Chemistry 634 (2001) 153–156
155
Scheme 1.
0.01 equivalents of the catalyst required a long reaction
time (24 h, 56% yield).
obtained in a Bruker AC 250 spectrometer using TMS
as internal standard and CDCl3 as solvent.
A drawback of the above procedures is the formation
of sodium halides which remain trapped in the ammo-
nium salt. This led us to employ benzoic anhydride
instead of phenyl halides because (i) this arylating agent
does not require the presence of a base [38] and (ii) we
expected an easy removal of the byproduct, PhCO2H,
from the ammonium salt [30]. Furthermore, it has been
shown that the Heck reaction of double bonds with
benzoic anhydride under classical conditions requires
the addition of halide salts such as n-Bu4NBr [38].
However, this protocol was unsuccessful: a mixture of
1a, (PhCO)2O, n-Bu4NBr and catalytic amounts of
PdCl2 reacted slowly at 120 °C giving 20% conversion
of 1a after 72 h with the appearance of small amounts
of 2, butyl benzoate and 3-(2-methyl-1-butenyl) ben-
zoate. In fact, these two esters were also produced when
the experiment was repeated in the absence of the
Pd-catalyst.
4.1. Typical procedure
Palladium chloride (18 mg, 0.1 mmol) and tetra-n-
butylammonium bromide (1.5 g) were heated at 120 °C
for 10 min in a round-bottomed flask under an Ar
atmosphere. To this homogeneous mixture, cooled to
around 80 °C, was successively added the allylic alco-
hol (1 mmol), the aryl halide (1 mmol) and NaHCO3
(101 mg, 1.2 mmol). After 24 h at 120 °C, the mixture
was cooled and extracted with Et2O (3×10 ml). The
solid phase is thus ready for use in a new run. The
organic phase was evaporated under reduced pressure
and the residue was purified by chromatography.
The NMR data of the isolated compounds—2b [42],
2c [43], 2d [44], 2e [45], 2f [44], 2g [44], 2h [43], 3h [46],
butyl benzoate [47] and 3-(2-methyl-1-butenyl) benzoate
[48]—were in agreement with literature.
The success of the reaction with PhBr prompted us to
attempt the single-step synthesis of nabumethone (5), a
nonsteroidal antiinflammatory drug [39,40] (Eq. (2)).
Using a 1:1 ratio of 1b and 2-bromo-6-methoxynaph-
thalene (4), 5 was isolated in 74% yield.
Acknowledgements
This work was supported by the European Commu-
nity (COST D12/0028/99) and in part by Europol’Agro
(Glycoval). We are grateful to both ‘Ministe`re de la
Recherche et de la Technologie’ and ‘Re´gion Cham-
pagne-Ardenne’ for PhD studentships to B.G. and
B.E., respectively. We thank Engelhard Company for
generous gifts of palladium salts and Dr G. Bird (As-
traZeneca, Reims) for help with the text of the
manuscript.
(2)
3. Conclusions
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