Direct formation of 1-vinyl-1H-isochromene derivatives via a palladium-catalysed coupling reaction

Article abstract of DOI:10.1039/b005519k

The palladium-catalysed reaction of the tert-butyldimethylsilyl ether of a 3-(o-bromophenyl)allylic alcohol with a methyl ketone leads directly to a 1-vinyl-1H-isochromene via a tandem ketone arylation-allylic cyclisation reaction.

Full text of DOI:10.1039/b005519k

Direct formation of 1-vinyl-1H-isochromene derivatives via a
palladium-catalysed coupling reaction
Roger Mutter, Eva M. Martin de la Neva† and Martin Wills*
Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL. E-mail: m.wills@warwick.ac.uk
Received (in Liverpool, UK) 6th July 2000, Accepted 26th July 2000
The palladium-catalysed reaction of the tert-butyldime-
thylsilyl ether of a 3-(o-bromophenyl)allylic alcohol with a
methyl ketone leads directly to a 1-vinyl-1H-isochromene via
a tandem ketone arylation–allylic cyclisation reaction.
isochromene 1‡ was formed as the major product. Subsequent
optimisation of this tandem arylation–allylic substitution reac-
tion improved the yield of this product to 71%.§ As far as we are
aware, this represents the first observation of such a tandem
enolate arylation–allylic cyclisation reaction. Notable in this
process is the involvement of a silyloxy leaving group, which
would normally not be considered to be a suitable group for
allylic activation. Presumably this reacts because of the high
reaction temperature. Related intramolecular reactions of b-
keto ester enolates and diketones have been reported to form
five-membered rings in palladium-catalysed intramolecular
cyclisations.4
As a part of a wider project concerned with the synthesis of
biologically active molecules, we wished to prepare 1-vinyl-
1H-isochromenes 1. We felt that we could achieve this end in
two stages. The first stage (for the example shown in Scheme 1)
would require the coupling reaction of an appropriate aryl
During this work it appeared that a lithium base and a co-
ordinating solvent must be employed to make the reaction work.
Trost has reported a similar requirement for a lithium base in an
allylic alkylation reaction.2d A series of phosphine ligands and
ketones were also investigated (Table 1) and it was found that a
Table 1 Palladium-catalysed ketone arylation–allylic cyclisation reactions
Aryl
Yield
Product (%)
bromide Ketone
Solvent
Ligand
2
2
2
6
7
2
2
2
2
2
3
3
3
3
3
3
3
3
Toluene/THF dppf
Dioxane/THF dppf
1
1
—
1
—
67
71
0
54
0
15a
61
27b
28
36c
Toluene
dppf
Toluene/THF dppf
Toluene/THF dppf
Scheme 1 Intramolecular cyclisation reaction to form 1-vinyl-1H-iso-
chromenes. Reagents and conditions: (i) ligand, base, solvent, [Pd2(dba)3],
85 °C (See Table 1).
Dioxane
L-S-ESPHOS 1
Toluene/THF (o-Tol)3P
Toluene/THF (t-Bu)3P
1
1
8
9
Acetophenone Toluene/THF dppf
Propiophenone Toluene/THF dppf
bromide 2 with a ketone 3 to give 4.1 The second stage would
involve replacement of the TBS with an acetyl group and
subsequent cyclisation of the ketone enolate onto the allylic
system. For the first step, we were confident that a palladium-
catalysed ketone arylation reaction would be effective. The
reason for the choice of a non-activating silyl group in 2 was
simply to prevent the allylic substitution from outpacing the aryl
coupling at the high reaction temperatures required ( > 80 °C).
Allylic acetates, for example, are known to react with ketones
under palladium-catalysed reactions at rt.2
We first examined the coupling of the tert-butyldimethyl-
silyl-protected allylic alcohol substrate 2 with pinacolone
(Scheme 1). Starting material 2 was prepared from readily
available 2-bromobenzaldehyde in three steps in 90% overall
yield following a literature procedure to the alcohol which was
then silyated.3 Initial attempts to couple 2 to pinacolone
following the procedure of Hartwig et al.1 (NaOt-Bu, Pd/DPPF,
toluene, 100 °C) led mainly to the debrominated cinnamyl ether
5; no coupling product was observed. Investigation of several
a Side-products: 4; 21%, 5: 6% b Side-products; 4: 30%, 5: 6%. Side-
product; 10 6%.
c
substantial amount of the intermediate 4 could be isolated when
either tri-tert-butylphosphine or the bis(diazaphospholidine)
ligand semi-ESPHOS5 were used. This intermediate, 4, was
then exposed to the reaction conditions in the absence of
palladium and ligands. No cyclisation occurred after several
hours, indicating that the cyclisation step was also palladium
catalysed. Tri-o-tolylphosphine also proved to be a good ligand
for isochromene formation. The isolation of 4 from certain
experiments suggests that it may be possible to ‘tune’ the
reaction conditions towards the formation of either cyclic or
acyclic products. We are currently investigating this issue.
Changing the protecting group on the bromide in 2 from
TBS- to the TBDPS- (i.e. 6) did not effect the tandem reaction.
Substitution at the allylic ether carbon with a phenyl group (i.e.
7) led to an unreactive substrate. Aromatic ketones such as
acetophenone and propiophenone also proved compatible with
the reaction conditions. In each case the desired cyclic products
8 and 9 respectively were formed, although the non-optimised
yields were low to moderate in both cases. In the case of
propiophenone a small amount (6%) of non-cyclised material
10 was also formed.
We wished to confirm that the choice of a trialkylsilyloxy-
allylic substrate was essential for a successful reaction. This was
achieved through the attempted reaction of acetate 11 with both
bases (NaOt-Bu, Na2CO3, Cs2CO3 LHMDS) gave none of the
expected product 4. In the case of LiHMDS, however, the 1H-
DOI: 10.1039/b005519k
Chem. Commun., 2000, 1675–1676
This journal is © The Royal Society of Chemistry 2000
1675

Notes and references
† Visitor from University of Salamanca, Summer 1999. Current address:
Departamento de Quimica Organica, Facultad de Quimica, Plaza de los
Caidos 1-5, 37008-Salamanca, Spain.
‡ Characterisation data for 1-vinyl-3-tert-butyl-1H-isochromene 1.
nmax(NaCl)/cm21 2954, 1638, 1085, 914, 750; dH(300 MHz, CDCl3) 1.16
(9H, s, C(CH3)3), 5.16 (1H, dt, J 17.1 and 1.3, CHNCH2), 5.23 (1H, dt, J
10.4 and 1.3, CHNCH2), 5.46 (1H, d, J 6.6, ArCH(OR)CHNCH2), 5.67 (1H,
s, ArCHNC(OR)), 6.15 (1H, ddd, J 17.1, 10.4 and 6.6, CH(OR)CHNCH2),
6.90–7.30 (4H, m, ArH); dC(75 MHz, CDCl3) 28.3, 35.5, 79.3, 97.7, 118.2,
123.8, 124.9, 126.2, 128.5, 129.4, 132.0, 136.7, 164.2; m/z (EI) 214 [M]+,
187, 129 (Found: [M]+, 214.136173. C15H18O requires m/z, 214.135765).
§ General experimental procedure for the synthesis of 1-vinyl-3-tert-butyl-
1H-isochromene 1. To a solution of LiHMDS (1 M in THF, 3 eq.) was
slowly added a solution of the pinacolone (2 eq.) in solvent at 5 °C. A
solution of Pd2(dba)3 (5% mol) and ligand (10% mol) in solvent was added
at room temperature, followed by a solution of tert-butyldimethyl
[3-(2-bromophenyl)allyloxy]silane 2 (1 eq.). The reaction mixture was
heated to 100 °C overnight, allowed to cool and then quenched with 1 M
HCl solution at room temperature. The mixture was twice extracted with
dichloromethane and the combined organic layers were dried and the
solvent was evaporated under reduced pressure yielding the crude product.
The crude product was purified by flash chromatography.
pinacolone and acetophenone under our reaction conditions for
cyclisation. In the former case the result was a complex mixture,
in the latter case the deacetylated alcohol was the major product
of the reaction, together with a small amount of ketone 12. The
latter result serves to confirm the ability of the silyloxy group to
delay the allylic reaction conveniently until after the arylation
process has been completed.
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In conclusion, we have demonstrated that, through the careful
choice of ether protecting group, a tandem enolate-arylation–
allylic cyclisation process may be ‘fine-tuned’ in order for the
steps to take place in a desired order. The overall result is a
convenient and rapid synthesis of vinyl-1H-isochromenes,
which represent valuable synthetic building blocks for further
reactions. The results of our studies on these products, together
with further details of the coupling–cyclisation process, will be
reported in full in due course.
We thank the CVCP for an Overseas Research Studentship
(ORS) award (to R. M.) and Professor D. Games, Dr J.
Ballantine and Dr B. Stein of the EPSRC Mass Spectrometry
Service at Swansea for carrying out analyses of certain
compounds.
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Chem. Commun., 2000, 1675–1676