A ferrocene based palladacyclic precatalyst for the Suzuki cross-coupling of aryl chlorides

Article abstract of DOI:10.1039/b310526a

Addition of palladium acetate to 2-(dicyclohexylphosphino)-phenylferrocene gave palladacycle 16 that is a very effective precatalyst for the Suzuki cross-coupling of aryl chlorides at room temperature (1 mol% 16) or 60°C (≥ 0.01 mol% 16).

Full text of DOI:10.1039/b310526a

A ferrocene based palladacyclic precatalyst for the Suzuki cross-coupling
of aryl chlorides
Francesc X. Roca and Christopher J. Richards*
Department of Chemistry, Queen Mary, University of London, Mile End Road, London, UK E1 4NS.
E-mail: c.j.richards@qmul.ac.uk; Fax: +44(0)20 7882 7427; Tel: +44(0)20 7882 3271
Received (in Cambridge, UK) 29th August 2003, Accepted 16th October 2003
First published as an Advance Article on the web 7th November 2003
Addition of palladium acetate to 2-(dicyclohexylphosphino)-
phenylferrocene gave palladacycle 16 that is a very effective
precatalyst for the Suzuki cross-coupling of aryl chlorides at
room temperature (1 mol% 16) or 60 °C (4 0.01 mol% 16).
acid 7 with a range of aryl halides (Scheme 2, Table 1). Aryl
bromides 8–10 were converted in high yield to the correspond-
ing cross-coupled products at room temperature (entries 1–3).
Under the same conditions 4-chlorotoluene 11 reacted partially
(entry 4), a higher conversion resulting with a reaction
temperature of 60 °C (entry 5). At this higher temperature aryl
chlorides 12, 14 and 15 were also tested, the conversions
obtained also being very similar to those arising from ligand 1a
(entries 6–8).
We next chose to investigate the reaction between 4 and
Pd(OAc)2 by mixing these two in toluene-d8 and studying the
resulting mixture by 31P NMR. Within ten minutes the signal for
4 (211.7 ppm) had essentially disappeared and been replaced
Recent developments in the application of electron rich and/or
bulky phosphine ligands to palladium catalysis have trans-
formed the synthetic utility of the Suzuki reaction.1 Both
sterically encumbered and electronically demanding substrates
such as aryl chlorides may now be transformed under relatively
mild conditions. Prominent in this recent work are reports on the
application of biphenyl ligands 1 such as 2-(dicyclohexyl-
phosphinyl)biphenyl 1a.2 Ferrocene based ligands have also
received significant attention,3 including use of this metallocene
as a replacement for the phosphine substituted ring of 1, and
application of the resulting planar chiral ligands 2 to asym-
metric Suzuki cross-coupling.3f Various observations and
comments have been made in connection with the very high
activity associated with palladium catalysts derived from 1.
These include comparison of the steric and electronic properties
2
of 1 to other phosphine ligands,3d the isolation of an h -aryl
t
Scheme 1 Reagents and conditions: i, BuLi, THF; ii, ZnCl2, THF; iii)
palladium(0) complex from a related phenanthrene based
ligand,4 and the possible intermediacy in the catalytic cycle of
a Ca-Pd species similar to binaphthyl 3.5 In view of the
significant differences between a benzene ring and the cyclo-
pentadienyl rings of ferrocene,6 we reasoned that replacement
of the non-phosphorus substituted ring of 1a with ferrocene to
give 4 would: a) generate a new and potentially highly active
ligand for Suzuki cross-coupling and b) shed some light on the
factors responsible for this activity. Our preliminary results of
this study are reported in this Communication.
1,2-Br2C6H4, 5% PdCl2(PPh3)2/DIBAL-H, THF, D (27% yield for 3 steps);
iv, BuLi, THF; v, ClPCy2 (74%).
Scheme 2 Reagents and conditions: i, 1.0 eq. aryl halide, 1.5 eq. 7, 3 eq. KF,
1 mol% Pd(OAc)2, 2 mol% 4, THF (1 ml/mmol aryl halide), 24 h.
Table 1 Suzuki cross-coupling with ligand 4
Entry
ArX
Temperature
Conversion (%)a
1
2
3
4
5
6
7
8
8
9
RT
RT
RT
RT
60 °C
60 °C
60 °C
60 °C
> 95
> 95
> 95b
65
10
11
11
12
14
15
83c
45d
> 95e
> 95e
a Determined by 1H NMR spectroscopy. b Toluene as solvent. c Conversion
88% with ligand 1a under identical conditions. d Conversion 65% with 1a.
e Conversion > 95% with 1a.
The main synthetic challenge presented by 4 was the
monoarylation of ferrocene itself. This stems from the difficulty
of selectively generating ferrocenyllithium, a necessary first
step in any cross-coupling methodology since ferrocene cannot
be directly halogenated. Use of the Kagan lithiation protocol,7
and subsequent transmetallation with anhydrous zinc chloride,
was followed by the addition of a palladium catalyst generated
in situ from the DIBAL-H reduction of PdCl2(PPh3)2 (Scheme
1).8 Heating this mixture at reflux with 1,2-dibromobenzene led
to the formation of 2-bromophenylferrocene 6 that was readily
separated from unreacted starting materials. Bromo-lithium
exchange and subsequent addition of ClPCy2 cleanly gave
ligand 4 as an air-stable yellow/orange crystalline solid.
We first sought to examine the effectiveness of 4 in the
palladium catalysed Suzuki cross-coupling of phenylboronic
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CHEM. COMMUN., 2003, 3002–3003
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by a new signal at 45.1 ppm. Repetition of this procedure on a
mmol scale resulted in a high yield of a new complex identified
as palladacycle 16† (Scheme 3).
A report recently appeared on the synthesis of a related
palladacycle obtained from 1b after a 16 h. reaction with
palladium acetate in toluene at room temperature.10 Thus the
expected differences between a benzene ring and the cyclo-
pentadienyl rings of ferrocene are manifested in the ease of
palladacycle formation, a consequence of the greater propensity
of this metallocene to undergo electrophilic aromatic substitu-
tion.6,11 Palladacycles have recently received a lot of attention
for the catalysis of carbon-carbon bond forming reactions,
including the Suzuki reaction. Accumulating evidence points to
such Pd(II) species requiring an in situ transformation into a
Pd(0) species for entry into the catalytic manifold.12 Thus 16, an
easily synthesised, air-stable and easily handled complex, is
most likely acting as a precatalyst for the Suzuki reaction of aryl
chlorides. It is competitive with the mildest conditions for this
reaction yet reported and may also be used at very low loadings.
In our ongoing work we are seeking to determine the nature of
the Pd(0) species arising from 16, and to explore the application
of this and related systems in other palladium catalysed
reactions.
Addition of 1 mol%9 of 16 to a mixture of phenylboronic acid
7, potassium fluoride and an aryl chloride resulted in good to
excellent levels of conversion to the corresponding cross-
coupled product at room temperature (Scheme 4, Table 2,
entries 1, 4 and 5). Use of preformed 16 resulted in higher
conversions than obtained previously with 4, and even the
demanding substrates 4- and 2-chloroanisole also underwent a
fair level of conversion under the standard conditions employed
(entries 2 and 3).
Very similar yields and levels of conversion were obtained
when these reactions were carried out under otherwise identical
conditions at 60 °C for 24 h. The effect of higher temperature
only became apparent with lower loadings of the palladacycle
(Scheme 4, Table 3). For substrates 11 and 14 some conversion
took place with 0.1 mol% of 16 at room temperature (entries 1
and 2). In contrast, essentially quantitative levels of conversion
resulted on repetition of these reactions at 60 °C (entries 3 and
4), and dropping the loading of 16 to 0.01 mol% also resulted in
successful cross-coupling (entries 5 and 6).
We wish to thank the Department of Chemistry, Queen Mary,
for the provision of a studentship (FXR).
Notes and references
† 16: mp 215 °C (Found: C, 58.00; H, 5.75%. C60H74Fe2O4P2Pd2 requires
C, 57.85; H, 5.99%); nmax/cm21 (KBr) 1574 (CO); dH (271.6 MHz, CDCl3);
0.78–2.55 (44H, m, Cy), 2.17 (6H, s, COCH3), 4.13 (10H, s, C5H5), 4.38
(2H, t, J 3, Fc), 4.56 (2H, br s, Fc), 4.75 (2H, br s, Fc), 7.17 (2H, t, J 8, Ar),
7.33 (2H, t, J 8, Ar) 7.38 (2H, t, J 8, Ar), 7.62 (2H, dd, J 8, 4, Ar); dC (68
MHz, CDCl3), 24.44 (COCH3), 25.86–27.13 (m), 27.94 (CH2), 28.78
(CH2), 29.57 (CH2), 31.01 (CH2), 33.04 (d, J 29, CH), 37.65 (d, J 28, CH),
66.90 (Fc), 70.19 (Fc), 70.57 (C5H5), 73.49 (Fc), 78.99 (d, J 20, Fc-ipso),
81.38 (d, J 13, Fc-ipso), 116.47 (d, J 51, Ar-ipso), 124.48 (d, J 8, Ar), 127.03
(d, J 8, Ar), 130.17 (Ar), 131.02 (Ar), 149.31 (d, J 11, Ar-ipso) 188.64 (CO);
dP 31P (109.3 MHz, CDCl3), 45.1 (PdPCy2); m/z (FAB) 1198 (3%, M 2 48),
Scheme 3 Reagents and conditions: i, Pd(OAc)2, toluene, RT, 1 h.
1
622 (6, 2M), 457 (100).
1 (a) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed. Engl., 2002, 41,
4176; (b) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58,
9633.
2 J. P. Wolfe, R. A. Singer, B. H. Yang and S. L. Buchwald, J. Am. Chem.
Soc., 1999, 121, 9550.
Scheme 4 Reagents and conditions: i, 1.0 eq. aryl halide, 1.5 eq. 7, 3 eq. KF,
16, THF (1 ml/mmol aryl halide), 24 h.
3 (a) T. E. Pickett and C. J. Richards, Tetrahedron Lett., 2001, 42, 3767;
(b) S.-Y. Liu, M. J. Choi and G. C. Fu, Chem. Commun., 2001, 2408; (c)
N. Kataoka, Q. Shelby, J. P. Stambuli and J. F. Hartwig, J. Org. Chem.,
2002, 67, 5553; (d) T. E. Pickett, F. X. Roca and C. J. Richards, J. Org.
Chem., 2003, 68, 2592; (e) Q.-S. Hu, Y. Lu, Z.-Y. Tang and H.-B. Yu,
J. Am. Chem. Soc., 2003, 125, 2856; (f) J. F. Jensen and M. Johannsen,
Org. Lett., 2003, 5, 3025.
4 J. Yin, M. P. Rainka, X.-X. Zhang and S. L. Buchwald, J. Am. Chem.
Soc., 2002, 124, 1162.
5 P. Kocˆovsky, S. Vyskocˆil, I. Cisaˆrová, J. Sejbal, I. Tisˆlerová, M.
Smrcˆina, G. C. Lloyd-Jones, S. C. Stephen, C. P. Butts, M. Murray and
V. Langer, J. Am. Chem. Soc., 1999, 121, 7714.
Table 2 Room-temperature Suzuki cross-coupling with palladacycle 16a
Entry
ArCl
Conversion (%)b
Yield (%)c
1
2
3
4
5
11
12
13
14
15
82
56
58
> 95
> 95
65
40
48
77
55
a 1 mol%. b Determined by 1H NMR spectroscopy. c Unoptimised isolated
yield after column chromatography.
6 For example, ferrocene displays significantly enhanced reactivity in
electrophilic aromatic substitution reactions, W. E. Watts, in Compre-
hensive Organometallic Chemistry, Eds. G. Wilkinson, F. G. A. Stone
and E. W. Abel, Pergamon: Oxford, 1982; Vol. 8, pp. 1013–1024.
7 F. Rebiere, O. Samuel and H. B. Kagan, Tetrahedron Lett., 1990, 31,
3121.
Table 3 Suzuki cross-coupling with 0.1 and 0.01 mol% of 16
Entry
ArCl
mol% 16
Temp.
Conversion (%)a
1
2
3
4
5
6
11
14
11
14
11
14
0.1
0.1
0.1
0.1
0.01
0.01
RT
RT
60 °C
60 °C
60 °C
60 °C
20
60
> 95
> 95
> 95
> 95
8 R. Arnold, S. A. Matchett and M. Rosenblum, Organometallics, 1988,
7, 2261.
9 Alternatively, this may be expressed as 0.5 mol% of the palladacycle
dimer.
10 D. Zim and S. L. Buchwald, Org. Lett., 2003, 5, 2413.
11 M. Gómez, J. Granell and M. Martinez, Eur. J. Inorg. Chem., 2000,
217.
a Determined by 1H NMR spectroscopy.
12 R. B. Bedford, Chem. Commun., 2003, 1787.
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