A palladium catalysed cyclisation-carbonylation of bromodienes: Control in carbonylation over facile β-hydride elimination

Article abstract of DOI:10.1039/b201311h

Conditions have been found for the efficient palladium mediated cyclisation-carbonylation of bromodienes to give γ,δ-unsaturated acids.

Full text of DOI:10.1039/b201311h

A palladium catalysed cyclisation–carbonylation of bromodienes: control
in carbonylation over facile b-hydride elimination†
Varinder K. Aggarwal,*a Paul W. Daviesa and William O. Mossb
a School of Chemistry, Bristol University, Cantock’s Close, Bristol, UK BS8 1TS.
E-mail: v.aggarwal@bristol.ac.uk; Fax: +44 (0)117 929 8611; Tel: +44 (0)117 954 6315
b AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, UK LE11 5RH
Received (in Cambridge, UK) 6th February 2002, Accepted 26th February 2002
First published as an Advance Article on the web 4th April 2002
Conditions have been found for the efficient palladium
mediated cyclisation–carbonylation of bromodienes to give
g,d-unsaturated acids.
Palladium mediated cascade processes as developed by Trost,1
Negishi,2 Overman3 and Grigg4 often allow simple substrates to
be converted directly into polycyclic functionalised products
and as such the processes have been widely employed in highly
efficient natural product synthesis. However, to ensure high
yields, the substrates and trapping agents are usually designed/
chosen so that only a single reaction pathway can be followed.
Clearly it would be more useful if the particular reaction
manifold could be controlled by choice of the palladium
catalyst/co-catalyst/conditions rather than substrate structure as
this would provide greater versatility in synthesis.
We chose to study the cyclisation–carbonylation of vinyl
bromide 1 with the aim of producing the g,d-unsaturated acid 2
(Scheme 1).5 Related work by Negishi6 showed that whilst
disubstituted alkenes provided high yields of unsaturated ester,
monosubstituted alkenes only gave a mixture of dienes (Scheme
2).
Scheme 3 Possible reaction routes, (a) Pd(0) (b) carbopalladation (c)
carbonylation (d) b-hydride elimination.
b-hydride elimination;9 the latter being the main reaction
pathway in the related Negishi work.6,9 Unfortunately the
simple expedient of increasing the CO pressure to promote
carbonylation over b-hydride elimination cannot be employed
as this would result in trapping the vinyl palladium species 6.
Instead, we considered the possibility of tuning the reactivity of
alkyl palladium 9 through choice of phosphine ligand. We
reasoned that the rate of carbonylation could be increased by
using electron rich phosphines, which should favour binding of
CO to palladium because it is a strong p-acceptor. Thus, we
should be able to control the course of the reaction towards the
desired product through the correct choice of phosphine.
Treating bromodiene 1a with a palladium catalyst under an
atmosphere of carbon monoxide led to the formation of a
mixture of products consisting of the g,d-unsaturated acid 2a,
the a,b-unsaturated acid 8a and the diene 11a. Brief optimisa-
tion of solvent, base, temperature and pressure led us to the
following standard conditions: Pd2(dba)3·CHCl3 (2.5 mol%),
NaOAc (2 eq.) dry DMF (0.2 M) at 80 °C under 2 atmospheres
of CO10 for 24 h with a phosphine co-catalyst (0.4 eq.).11
We then varied the phosphine ligand and analysed the ratio of
products obtained (Table 1) and we were pleased to note that our
analysis was broadly correct: highly electron rich phosphines
promoted carbonylation. However, carbonylation was so fast
with the electron rich alkyl phosphines (entries 1–3) that this
process competed with carbopalladation leading to significant
amounts of the linear acid. It transpired that aryl phosphines
possessed the right balance between promoting carbonylation,
but not too fast so that none of the linear acid was detected, and
inhibiting the rate of b-hydride elimination (entries 4 and 5). Of
the aryl phosphines, P(2-furyl)3 gave more of the carbonylated
product 2 over the b-hydride eliminated diene 3. The bi-
sphosphine dppb was also tested but gave large amounts of
diene 11.
Evidently in the case where b-hydride elimination can occur,
it does so exclusively even in preference to an otherwise fast
carbonylative process.7 No doubt b-hydride elimination is
facilitated by the presence of the alkene moiety which weakens
the allylic C–H bond.8 Our proposed palladium-mediated
cascade process 1 ? 2 is challenging as after oxidative addition,
each of the proposed intermediates has at least one alternative
pathway it can follow (Scheme 3). Our key concern was
whether we could find conditions under which the alkyl
palladium species 9 was trapped by CO faster than it underwent
Scheme 1 Desired process.
Scheme 2 Negishi’s cyclisation–carbonylation protocol. Reagents and
conditions: CO (1 atm) 5% Cl2Pd(PPh3)2, NEt3 (4 eq.), MeOH–DMF (1+2),
85 °C.
Having achieved good yields and high selectivity in favour of
the cyclised acid, we decide to investigate alternative substrates
using the two optimum phosphines from our screening studies
(Table 2).
† Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b2/b201311h/
972
CHEM. COMMUN., 2002, 972–973
This journal is © The Royal Society of Chemistry 2002

Table 1 Effect of phosphines on the reaction distribution (Scheme 4)
Entry
Phosphine
Yield (%)a
Ratiob 2a+8a
1
2
3
4
5
6
7
PtBu3
65
48
42
65
79
26
42e
1+3+7
2.1+1
PtBu2BiPh
PCy2BiPh
PPh3
1.9+1
> 20+1
> 20+1
> 20+1
2.4+1
P(2-furyl)3
dppbc
Scheme 5
d
PtBu3
a Isolated yields of acids, the remainder of materials is diene 11.
Table 3 Effects of solvent on product distribution (Scheme 5)
1
b Determined from H NMR. c 0.2 eq. d 1 atm CO. e Purified by column
chromatography.
Yield of esters (acids)(%)b
Entry
Substrate
Conditionsa
2
8
1
2
3
4
5
1b
1b
1c
1c
1c
A
B
A
B
C
69
(74)
36
(29)
48
—
(7)
21
(23)
23
a All reactions were run at 85 °C for 24 h under 2 atm of CO pressure in the
presence of NEt3 (4 eq.), A = 5% Cl2Pd(PPh3)2, PPh3 (0.2 eq.), MeOH–
DMF–H2O (1+2+0.1), B = 5% Cl2Pd(PPh3)2, PPh3 (0.2 eq.), DMF–H2O
(20+1), C = 5% PdCl2, P(2-furyl)3 (0.3 eq.), MeOH–DMF–H2O (1+2+0.1).
b Isolated yield of acid or ester mixtures after column chromatography.
Scheme 4 Reagents and conditions: substrate (0.25 mmol, 1 eq.),
Pd2dba3.CHCl3 (2.5 mol%), phosphine (0.4 eq.), NaOAc (2 eq.), dry DMF
(0.2 M), 80 °C, CO (2 atm), 24 h.
Table 2 Effect of substituents on product distribution (Scheme 5, R =
H)
on monosubstituted alkenes. These substrates are particularly
difficult as the alkyl palladium intermediate is prone to
undergoing facile b-hydride elimination. We have been able to
achieve moderate to good yields of cyclic g,d-unsaturated esters
and acids even from substrates that do not have an inherent
proclivity towards cyclisation.
The authors would like to thank the EPSRC National Mass
Spectrometry Service Centre at Swansea and AstraZeneca plc
for support of a studentship (PD).
Entry
X
Phosphinea Yield (%)b
Ratio 2+8c
1
2
3
4
5
6
(EtO2C)2C
(EtO2C)2C
TsN
TsN
O
A
B
A
B
A
B
68
52
62
50
69
37
> 20+1
> 20+1
1+1d
9+1
1+6
O
0+1e
Reagents and conditions: substrate (0.25 mmol, 1 eq.), Pd2dba3·CHCl3 (2.5
mol%), phosphine (0.3 eq.), NaOAc (2 eq.), dry DMF (0.2 M), 80 °C, CO (2
atm), 24 h.a A = P(2-furyl)3, B = PPh3. b Isolated yield of acid mixtures
purified by column chromatography. c Determined by 1H NMR. d Ratio of
isolated products and 1H NMR. e Direct capture product only.
Notes and references
1 B. M. Trost and J. Dumas, J. Am. Chem. Soc., 1992, 114, 1924.
2 C. Copéret and E. Negishi, Org. Lett., 1999, 1, 165; E. Negishi, C.
Copéret, S. Ma, S. Liou and F. Liu, Chem. Rev., 1996, 96, 365.
3 L. E. Overman, D. J. Ricca and Y. D. Tran, J. Am. Chem. Soc., 1993,
115, 2042.
4 R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65.
5 This process has previously been described using; (a) stoichiometric
Ni(COD)2 leading to the cyclised methyl esters when using N-tethered
halodienes: D. Solé, Y. Cancho, A. Llebaria, J. M. Moretó and A.
Delgado, J. Org. Chem., 1996, 61, 5895; (b) stoichiometric Ni(CO)4
requires sterically bulky alcohols to prevent predominant formation of
the linear esters: A. Llebaria, F. Camps and J. M. Moretó, Tetrahedron
Lett., 1992, 33, 3683.
The sulfonamide linked substrate 1b gave a 1+1 mixture of
cyclised+linear acids 2b+8b using P(2-furyl)3 but a much
improved 9+1 ratio with PPh3 (Table 2, entries 3 and 4). The
ether linked substrates were much poorer and provided mostly
the linear acids. The ratio of linear+cyclised acids for the
different substrates reflects their relative rates of cyclisation
which is increased with increasing substitution in the linking
chain.12
The yield of the cyclised acid was especially low for substrate
1c bearing the oxygen linker which is undoubtedly the most
challenging substrate. If we could increase the yield for 1c this
would provide a general solution to the cyclisation–carbonyla-
tion of essentially any related bromodiene. Having explored
how variation in the phosphine altered the course of the reaction
we decided to investigate solvent effects. As a starting point we
chose Negishi’s solvent system [DMF–MeOH–H2O
(20+10+1)], which was effective in cyclisation of 3a to give 4,
and chose to initially study substrate 1b where improved yields
and selectivity were desirable. Although some product was
obtained using these conditions, we found that with added PPh3
and at the higher pressure of 2 atm of CO, a good yield of the
cyclised methyl ester was achieved (Table 3, entry 1). The
reaction could also be conducted in DMF–H2O and an even
higher yield of the cyclised acid was obtained (entry 2). Using
these conditions, improved yields of cyclised esters/acids were
also obtained with the most difficult oxygen linker 1c (entries 3
and 4). In particular, use of P(2-furyl)3 gave a 48% isolated
yield of the cyclic ester 2c (entry 5).
6 E. Negishi, S. Ma, J. Amanfu, C. Copéret, J. A. Miller and J. M. Tour,
J. Am. Chem. Soc., 1996, 118, 5919.
7 There are a number of examples where b-hydride elimination is
suppressed: (a) through proposed chelation of the palladium inter-
mediate 9 with donating groups on the substrate: C. Lee, K. S. Oh, K. S.
Kim and K. H. Ahn, Org. Lett., 2000, 2, 1213; see also ref. 6. (b)
Palladium catalysed reactions where intramolecular carbopalladation is
favoured over b-hydride elimination: (1) C. H. Oh, C. Y. Rhim, J. H.
Kang, A. Kim, B. S. Park and Y. Seo, Tetrahedron Lett., 1996, 37, 887;
(2) S. Schweizer, Z. Song, F. E. Meyer, P. J. Parsons and A. de Meijere,
Angew. Chem., Int. Ed. Engl., 1999, 38, 1452.
8 R. Grigg, P. Stevenson and T. Worakun, Tetrahedron, 1988, 44,
2033.
9 Alkyl palladium 9 is the intermediate in cycloisomerisation of enynes
and undergoes rapid b-hydride elimination,B. M. Trost, D. L. Romero
and F. Rise, J. Am. Chem. Soc., 1994, 116, 4268.
10 The reaction vessel was pressurised to 2 atm at ambient temperature.
11 A large amount of phosphine was required to prevent catalyst
degradation/aggregation to palladium black. We later found that 0.3 eq.
would suffice but any less resulted in lower yields.
In summary, we have found conditions under which a
cascade cyclisation–carbonylation can be efficiently conducted
12 M. Jung, Synlett., 1999, S1, 843.
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