An active ferrocenyl triarylphosphine for palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl halides

Article abstract of DOI:10.1039/b407661c

Pd-catalyzed Suzuki-Miyaura reaction of aryl chlorides was accomplished through the use of an active ferrocene-based triarylphosphine ligand. This air- and moisture-stable ligand was found to be effective for the cross-coupling of aryl halides at room temperature to 115 °C.

Full text of DOI:10.1039/b407661c

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An active ferrocenyl triarylphosphine for palladium-catalyzed Suzuki–
Miyaura cross-coupling of aryl halides{
Fuk Yee Kwong,*a Kin Shing Chan,b Chi Hung Yeunga and Albert S. C. Chan*a
a Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and
Synthesis, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Hong Kong. E-mail: bcfyk@inet.polyu.edu.hk; bcachan@polyu.edu.hk
b Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
Received (in Cambridge, UK) 24th May 2004, Accepted 29th July 2004
First published as an Advance Article on the web 21st September 2004
Pd-catalyzed Suzuki–Miyaura reaction of aryl chlorides was
Lithiation with n-BuLi and subsequent reaction with ClPPh2
cleanly gave air-stable ligand 7 in good yield (Scheme 1).
To test the effectiveness of this new ligand 7, we used it in
comparison with various commercially available triarylphosphine
ligands in the Suzuki–Miyaura coupling of an ortho-substituted
aryl bromide (eqn. (1) and Table 1). While rac-BINAP and tri-o-
tolylphosphine gave moderate conversions, the new monodentate
ferrocenyl triarylphosphine 7 showed superior results in Suzuki
coupling of sterically hindered aryl bromide at room temperature.
In addition, the triarylphosphine 7 has the highest activity over the
other triarylphosphines in Suzuki coupling of aryl chloride
(eqn. (2), Table 1).
This interesting finding led us to the exploration of using 7 in the
coupling of various substituted aryl bromides (Table 2). ortho-
Phenyl substituted aryl bromide was coupled with phenyl boronic
acid in excellent yield (Table 2, entry 2). Highly substituted aryl
bromides, such as 2,6-diisopropyl or 2-tert-butyl-6-methoxy
substituted bromobenzene required slightly higher temperature
(30 uC) (Table 2, entries 4 and 5).
The combination of variety of solvents and bases were screened
for coupling of aryl chlorides. Potassium phosphate monohydrate
was found to be superior in toluene. Functional groups such as
aldehyde, keto, nitrile and ester were found to be compatible under
these reaction conditions (Table 3). Electron-deficient aryl chloride
can be coupled with arylboronic acid at room temperature
(Table 3, entry 4). The coupling of deactivated aryl chlorides with
ortho-substituted arylboronic acids required slightly higher catalyst
loading (Table 3, entry 6). Interestingly, about 2% of diarylmetha-
nol was observed from GC-MS (Table 3, entry 2), possibly
resulting from the addition of arylboronic acid to the carbonyl
group.12 Aryl-aryl exchange reactions between Pd-Ar and P-Ar are
typical side reactions encountered when triarylphosphine ligands
are employed in coupling reactions,13 however, no such side
products were formed from under these reaction conditions when
ligand 7 was employed in Suzuki–Miyaura coupling.14
accomplished through the use of an active ferrocene-based
triarylphosphine ligand. This air- and moisture-stable ligand
was found to be effective for the cross-coupling of aryl
halides at room temperature to 115 uC.
Recent advances in cross-coupling methodologies have made
significant contribution to organic synthesis as well as pharma-
ceutical and agricultural chemistry.1 Suzuki–Miyaura cross-
coupling is one of the most attractive and practical protocols for
carbon-carbon bond formation due to its tolerance of a wide range
of functional groups and the simple separation of products.2
Recently, improved catalyst systems for Suzuki–Miyaura couplings
have been described, such as Pd-complexes of trialkylphosphines,3
ortho-biaryl or ferrocenyl dialkylphosphines,4,5 and other ligands,6
that allow couplings to be carried out under mild conditions for the
preparation of substituted biaryl compounds from relatively
inexpensive aryl chlorides.7 Despite the intensive attention this
area has received, few examples are known where triarylphosphines
were used in Suzuki–Miyaura couplings employing aryl chlor-
ides.8,9 Since triarylphosphines are usually prepared from relatively
inexpensive chlorodiphenylphosphine with Grignard or organo-
lithium reagents, it would add a further attractive feature if these
modified triarylphosphines are active and similar to some results of
Pd-trialkylphosphine or -dialkylarylphosphine catalyzed reactions.
We report a simple and active ferrocenyl triarylphosphine for
Suzuki–Miyaura cross-coupling of sterically hindered aryl bromides
at room temperature and aryl chlorides at elevated temperatures.10
In view of the electronic and steric differences between a benzene
ring and the cyclopentadienyl ring of ferrocene, we envisioned that
the replacement of a benzene ring with ferrocene would generate a
new class of potentially active ligand for cross-coupling reactions.
To our delight, the active ligand 7 demonstrated that even Pd-
triarylphosphine moiety could catalyze Suzuki–Miyaura coupling
using aryl chloride as the substrates.
Triarylphosphine 7 was prepared from commercially available
ferrocene in two steps (Scheme 1). Since ferrocene cannot be
directly halogenated, the use of the Kagan lithiation protocol is
necessary.11 Ferrocene was lithiated with t-BuLi in THF to afford
ferrocenyllithium and subsequent transmetallation with ZnCl2 to
obtain the Negishi coupling precursor (Scheme 1). Heating the
mixtures in the presence of 3% Pd(PPh3)4 and ortho-bromoiodo-
benzene led to the formation of 2-bromophenylferrocene.
Table 1 Triarylphosphine ligands screening in Pd-catalyzed Suzuki–
Miyaura cross-coupling of aryl bromide and chloride
Entry Ligand L
GC yield (%), eqn. (1) GC yield (%), eqn. (2)
1
2
3
4
5
6
7
No ligand 8
rac-BINAP 32
0
5
4
5
15
9
DPPF
7
7
55
18
98
Scheme 1 Synthesis of ferrocenyl triarylphosphine ligand.
Xantphos
(o-tolyl)3P
Ph3P
{ Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b4/b407661c/
Ligand 7
92
2 3 3 6
C h e m . C o m m u n . , 2 0 0 4 , 2 3 3 6 – 2 3 3 7
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Suzuki–Miyaura coupling of sterically hindered ArBr at RTa
Table 3 Pd-catalyzed Suzuki coupling of ArCl with Fc-ligand 7a
a Reaction conditions: ArBr (1.0 mmol), Ar’B(OH)2 (1.5 mmol),
Pd2(dba)3 (0.5 mol%), ligand 7 (1.2 mol%), KF (3.0 mmol) and THF
(2.0 mL) were charged in a Schlenk flask under N2 and stirred at
RT. b Isolated yields. c Reactions were conducted at 30 uC for 72 h.
Heteroaryl and alkenyl chlorides were effective substrates.
(Table 3, entries 8–9). Additionally, the cross-coupling of aryl
chlorides with alkylboronic acids are rare.15 Gratifyingly, a
preliminary study of the couplings of alkylboronic acids with
both electron-poor and rich aryl chlorides was found to be
successful (Table 3, entries 10–11).
In summary, we have developed a new, air-stable and active
ferrocenyl triarylphosphine and have established its effectiveness in
the palladium-catalyzed Suzuki–Miyaura coupling of aryl halides.
The capability of this system to achieve cross-coupling of activated
aryl chloride at room temperature is noteworthy. In light of the fact
that 7 is a triarylphosphine, the high reactivity of Pd-7 is
unexpected. In view of the ease with which the structure of 7
can be modified, we anticipate that further enhancements in
reactivity as well as the design of versatile ligands for asymmetric
catalysis will be a fruitful pursuit.
a Reaction conditions: ArCl (1.0 mmol), Ar’B(OH)2 (1.5 mmol),
Pd2(dba)3 (0.5 mol%), ligand 7 (1.2 mol%), K3PO4 . H2O (3.0 mmol)
and toluene (2.0 mL) were stirred at 110 uC under N2 for 24 h; entry
3, 70 uC; entry 7, 90 uC. b Isolated yields. c Reactions were conducted
with Pd2(dba)3 (2 mol%), ligand 7 (8 mol%), 115 uC, 28 h. d Pd2dba3
(2 mol%), ligand 7 (4 mol%), rt, 48 h. e K3PO4 (3.0 mmol) was used.
J. P. Stambuli and J. F. Hartwig, J. Org. Chem., 2002, 67, 5553;
(b) J. F. Jensen and M. Johannsen, Org. Lett., 2003, 5, 3025.
6 For review of phosphinite ligands, see: (a) R. B. Bedford, Chem.
Commun., 2003, 1787. For the Suzuki reaction using phosphine oxide
ligand, see: ; (b) G. Y. Li, Angew. Chem., Int. Ed. Engl., 2001, 40, 1513.
7 A. F. Littke and G. C. Fu, Angew Chem., Int. Ed. Engl., 2002, 41, 4176.
8 For one example of Suzuki coupling of an activated aryl chloride by a
We thank the University Grants Committee Area of Excellence
Scheme in Hong Kong (Project No. AoE/P-10/01) and the Hong
Kong Polytechnic University Area of Strategic Development Fund
for financial support of this study.
ˇ
Pd-triarylphosphine catalyst, see: P. Kocovsky´, S. Vyskocil, I. C´ısarova´,
J. Sejbal, I. Tiˇslerova´, M. Smrcina, G. C. Lloyd-Jones, S. C. Stephen,
ˇ
ˇ
ˇ
C. P. Butts, M. Murray and V. Langer, J. Am. Chem. Soc., 1999, 121,
7714. For Suzuki coupling of mainly activated ArCl by a Pd-PPh(2-
ClC6H4)2 catalyst, see: M. R. Pramick, S. M. Rosemeier, M. T. Beranek,
S. B. Nickse, J. J. Stone, R. A. Stockland, Jr., S. M. Baldwin and
M. E. Kastner, Organometallics, 2003, 22, 523.
9 ForAr3Pwith–PPh2moietyattachedtoCpring,see: (a)S.-Y.Liu,M.Choi
and G. C. Fu, Chem. Commun., 2001, 2408. For Fc3P: ; (b) T. E. Pickett
and C. J. Richards, Tetrahedron Lett., 2001, 42, 3767; (c) T. E. Pickett,
F. X. Roca and C. J. Richards, J. Org. Chem., 2003, 68, 2592.
10 During the preparation of the manuscript, a similar ferrocenyl
dicyclohexylphosphine was reported, F. X. Roca and C. J. Richards,
Chem Commun., 2003, 3002.
11 F. Rebiere, O. Samuel and H. B. Kagan, Tetrahedron Lett., 1990, 31, 3121.
12 For Rh-catalyzed addition of ArB(OH)2 acids to aldehyde: M. Sakai,
M. Euda and N. Miyaura, Angew. Chem., Int. Ed. Engl., 1998, 37, 3279.
13 (a) K. C. Kong and C. H. Cheng, J. Am. Chem. Soc., 1991, 113, 6313;
(b) F. E. Goodson, T. I. Wallow and B. M. Novak, J. Am. Chem. Soc.,
1997, 119, 12441; (c) F. Y. Kwong, C. W. Lai and K. S. Chan, J. Am.
Chem. Soc., 2001, 123, 8864.
Notes and references
1 (a) O. Baudoin, M. Cesario, D. Gue´nard and F. Gue´ritte, J. Org. Chem.,
ˇ
2002, 67, 1199; (b) M. Hocek, A. Holy´, I. Votruba and H. Dvora´kova´,
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4020; (b) A. F. Littke and G. C. Fu, Angew Chem., Int. Ed. Engl., 1998,
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4 For dialkyl biphenyl-based phosphine ligands, see: (a) D. W. Old,
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(b) J. P. Wolfe and S. L. Buchwald, Angew Chem., Int. Ed. Engl., 1999,
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14 For aryl-aryl exchange side reactions in Suzuki–Miyaura coupling using
triarylphosphines:
(a) D. F. O’Keefe, M. C. Dannock and
S. M. Marcuccio, Tetrahedron Lett., 1992, 33, 6679; (b) F. E. Goodson,
T. I. Wallow and B. M. Novak, Macromolecules, 1998, 31, 2047.
15 For coupling of alkylboronic acid with ArCl using dialkylphosphine
ligands, see ref. 5a and, most recent, ref. 4f.
5 For dialkyl ferrocenyl-based ligands, see: (a) N. Kataoka, Q. Shelby,
C h e m . C o m m u n . , 2 0 0 4 , 2 3 3 6 – 2 3 3 7
2 3 3 7