Synthesis of a C3-symmetric ferrocenylphosphine and its application to the Suzuki reaction of aryl chlorides

Article abstract of DOI:10.1016/S0040-4039(01)00568-8

(_pS,_pS,_pS)-Tris(2-methylferrocenyl)phosphine 1 was synthesised in 62% yield from (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline. In combination with Pd₂dba₃ this novel C₃-symmetric ligand generates a catalyst for the Suzuki reaction of aryl chloride substrates, these reactions proceed readily at 60°C in dioxane.

Full text of DOI:10.1016/S0040-4039(01)00568-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3767–3769
Synthesis of a C3-symmetric ferrocenylphosphine and its
application to the Suzuki reaction of aryl chlorides
Tom E. Pickett and Christopher J. Richards*
Department of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 28 March 2001; accepted 5 April 2001
Abstract—(pS,pS,pS)-Tris(2-methylferrocenyl)phosphine
1
was synthesised in 62% yield from (S)-2-ferrocenyl-4-(1-
methylethyl)oxazoline. In combination with Pd2dba3 this novel C3-symmetric ligand generates a catalyst for the Suzuki reaction
of aryl chloride substrates, these reactions proceed readily at 60°C in dioxane. © 2001 Elsevier Science Ltd. All rights reserved.
The recent development of methods for the utilisation
of aryl chlorides in CꢀC, CꢀN and CꢀO bond forming
reactions have largely focused on palladium catalysts
containing bulky, electron rich phosphine ligands. In
particular, tri-tert-butylphosphine,1 1,1%-bis(di-tert-
butylphosphino)ferrocene2 and biphenyls containing di-
tert-butylphosphino or dicyclohexylphosphino substi-
tuents3 have proved especially effective. Earlier work
with palladacycles derived from phosphines containing
2-methylphenyl substituents, such as tris(ortho-
tolyl)phosphine, had also demonstrated that cheaper
aryl chlorides could be used as alternatives to aryl
bromides and iodides, in this case for the Heck
reaction.4
are easily isolated.5 We therefore reasoned that phos-
phines containing 2-methylferrocenyl substituents may
be of use in palladium catalysed reactions of aryl
chloride substrates, and to fully test this hypothesis,
required access to a phosphine containing three such
substituents. An additional feature is the planar chiral-
ity displayed by ferrocenes containing two different
groups attached to one of the cyclopentadienyl rings.
As a consequence, one of the two possible diastereoiso-
mers of tris(2-methylferrocenyl)phosphine 1 displays
C3-symmetry, this class of monodentate ligand being
comparatively rare.6
As triarylphosphines may be synthesised by the addi-
tion of aryllithium precursors to phosphorous trichlo-
ride, a stereoselective synthesis of 1 using this method
required access to enantiomerically pure 2-lithio-1-
methylferrocene. We,7 and others,8 have previously
reported that planar chirality is conveniently generated
The ferrocenyl group is bulkier than a phenyl group,
and the electronic properties of this moiety are illus-
trated by its ability to stabilise an adjacent positive
charge, to the extent that a-ferrocenylcarbenium ions
O
O
O
NHTf
iii) Tf2O,
CH2Cl2
i) BuLi, Et2O
TMEDA
O
N
N
Br
Br
Fe
Fe
Fe
ii) C2Br2Cl4
iv) H2O
4
2
3
94% (from 2)
Me
Br
Me
P
OH
Et3SiH
TFA
i) BuLi, THF
DIBAL-H
Et2O
Br
Fe 3
Fe
Fe
ii) 0.33 eq. PCl3
pS-5
89% (from 4)
74%
pS-6
pS,pS,pS-1
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00568-8

3768
T. E. Pickett, C. J. Richards / Tetrahedron Letters 42 (2001) 3767–3769
by the diastereoselective lithiation of ferrocenyl oxazoli-
nes. Thus, addition of BuLi to 2 in the presence of
TMEDA8c followed by addition of dibromotetra-
chloroethane led to the formation of 3 without detec-
tion of the alternative diastereoisomer (Scheme 1). This
was cleanly and rapidly ring-opened by addition of
triflic anhydride at 0°C followed, after five minutes
stirring, by the addition of ice-water to give 4. Subse-
quent ester reduction with four equivalents of DIBAL-
H at room temperature gave alcohol 5 containing 17%
of 6, this mixture being completely converted to (pS)-2-
bromo-1-methylferrocene by further reduction with 2
equivalents of triethylsilane in TFA, also at room tem-
perature. Finally, bromo-lithium exchange at −78°C
was followed by addition of PCl3, warming of the
reaction mixture to room temperature and isolation of
1 as a yellow crystalline solid.9
irreversible formation of this material, and its inability
to react further with a final equivalent of 2-lithio-1-
methylferrocene would account for the absence of the
two possible tris(2-methylferrocenyl)phosphines.
To test the suitability of 1 for use with aryl chloride
substrates, we investigated the Suzuki cross-coupling
between para-chlorotoluene and phenylboronic acid
(Scheme 2). This reaction proceeded readily at 60°C,
the highest conversion after a 5 h reaction time being
obtained with two equivalents of Cs2CO3 as base
($CsF>KF>K2CO3) in dioxane (>THFꢀCH3CN)
with Pd2dba3 (>Pd(OAc)2), Table 1. Under the same
conditions both tris(ortho-tolyl)phosphine and tris(fer-
rocenyl)phosphine10 failed to give the cross-coupled
product, revealing the importance of both the ferro-
cenyl group and its 2-methyl substituent to the activity
observed with 1.
A synthesis of racemic 1 required racemic 2-bromo-1-
methylferrocene and a degree of selectivity in its trans-
A variety of other substrate combinations were exam-
ined under these optimised conditions, and as expected
the presence of an electron withdrawing substituent in
the aryl chloride promoted high conversion (Scheme 3,
Table 2, entry 1). Although the use of ortho-sub-
stituents reduced the effectiveness of the reaction
(entries 2 and 3), they did not prevent moderate conver-
sions from being achieved with sterically and electroni-
cally demanding substrate combinations (entries 4 and
5).
formation into 1, although the alternative S*,pS*,pR*
p
derivative was also of interest. The first requirement
was most conveniently met with the conversion of
2-ferrocenyl-4,4-dimethyloxazoline into rac-6 using the
same procedure just described (overall yield 70%).
However, following bromo-lithium exchange and addi-
tion of PCl3 as before, this reaction conspicuously
failed to give either of the two diastereomeric triferro-
cenyl phosphines. Examination of the crude reaction
mixture by 31P NMR revealed a major peak at 34.7
ppm which we have tentatively assigned to meso-
chlorodi(2-methylferrocenyl)phosphine. The rapid and
A feature of these reactions is the relatively high con-
versions observed after a short reaction time. For
0.036 eq.ligand
0.015 eq. Pd2dba3
+
Me
Cl
(HO)2B
Me
dioxane (1.6 ml)
2 eq. base
7 0.083 mmol
8 1.5 eq.
9
60 oC, 5 h.
Scheme 2.
Table 1. Results of the Suzuki cross-coupling of 7 with 8
Entry
Ligand
Base
Pd source
Solvent
Yield of 9a (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
Cs2CO3
CsF
KF
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd(OAc)2
Pd2dba3
Pd2dba3
Dioxane
Dioxane
Dioxane
Dioxane
THF
Dioxane
Dioxane
Dioxane
80 (86)b
76 (91)
63 (64)
50 (57)
11 (11)
41 (41)
B1
(o-tolyl)3P
Fc3P
B1
a As determined by GC.
b Yield after 24 h in parentheses.
0.036 eq.1
0.015 eq. Pd2dba3
Cl
+
(HO)2B
dioxane (1.6 ml)
2 eq. Cs2CO3
60 oC, 5 h.
R1
R
R
R1
Scheme 3.

T. E. Pickett, C. J. Richards / Tetrahedron Letters 42 (2001) 3767–3769
3769
Table 2. Results of Suzuki cross-couplings with 1
Chem., Int. Ed. Engl. 1998, 37, 3387; (c) Hartwig, J. F.;
Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575; (d)
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020.
Entry
R
R1
Yielda (%)
1
2
3
4
5
p-NO2
H
o-Me
o-Me
o-OMe
H
o-Me
H
o-Me
o-Me
90
57
49
46
36
2. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998,
120, 7369.
3. (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1999, 38, 2413; (b) Wolfe, J. P.; Singer, R. A.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 9550; (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.;
Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158; (d)
Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J.
Am. Chem. Soc. 2000, 122, 1360.
a As determined by GC.
example under the optimised conditions (Table 1, entry
1), 17% of 9 was present after only 10 minutes, and
51% after 1 h. Longer reaction times resulted in the
formation of palladium black in the reaction vessel, but
this did not effect the integrity of the ligand which
could be recovered in essentially quantitative yield.
Interestingly, despite the similarity of 1 to tris(ortho-
tolyl)phosphine, no palladacycles have yet been
observed.
4. Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Rier-
8
meier, T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3,
1357.
5. Allenmark, S. Tetrahedron Lett. 1974, 371.
6. Powell, M. T.; Porte, A. M.; Burgess, K. Chem. Commun.
1998, 2161.
In conclusion, we have demonstrated that a tris(2-
methylferrocenyl)phosphine is readily synthesised pro-
vided attention is paid to the absolute stereochemistry
of the 2-methylferrocenyl substituents. These result in
an efficient ligand promoting the Suzuki cross-coupling
of aryl chlorides under mild conditions, and both the
ferrocenyl group and the 2-methyl substituent are
required for activity. Given the recent interest in asym-
metric variants of this reaction,11 further work is on
going to explore the full utility of 1 and its derivatives.
7. Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse,
M. B. Synlett 1995, 74.
8. (a) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org.
Chem. 1995, 60, 10; (b) Nishibayashi, Y.; Uemura, S.
Synlett 1995, 79; (c) Sammakia, T.; Latham, H. A. J.
Org. Chem. 1995, 60, 6002.
9. Data for 1: mp 238–240°C (found: C, 62.19; H, 5.26.
C33H33Fe3P·1/2H2O requires C, 62.21; H, 5.38); [h]2D0 −72
(c 0.22, CH2Cl2); lH (400 MHz, CDCl3) 2.35 (3H, s, Me),
3.73 (5H, s, C5H5), 4.24 (2H, t, J 2.3 Hz, 2×Fc), 4.33 (1H,
d, J 1.54 Hz, Fc); lC (100 MHz, CDCl3) 15.24 (d, J 14.4
Hz, Me), 68.41 (Fc), 69.27 (C5H5), 70.60 (d, J 5.2 Hz,
Fc), 71.07 (d, J 5.8 Hz, Fc), 81.19 (d, J 6.3 Hz, Fc-ipso),
89.38 (d, J 36.3 Hz, Fc-ipso); lP (122 MHz, CDCl3)
−72.6; m/z (APCI), 628 (M+, 100), 429 (M−2−MeFc,
82%).
Acknowledgements
We wish to thank Lancaster Synthesis and Cardiff
University for the provision of a studentship (TEP).
10. Prepared by electrophilic substitution of ferrocene with
Me2NPCl2: Sollott, G. P.; Peterson, W. R. J. Organomet.
Chem. 1969, 19, 143.
11. (a) Cammidge, A. N.; Cre´py, K. V. L. Chem. Commun.
2000, 1723; (b) Yin, J.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 12051.
References
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