Synthesis of monodentate ferrocenylphosphines and their application to the palladium-catalyzed Suzuki reaction of aryl chlorides

Article abstract of DOI:10.1021/jo0265479

Racemic and enantiopure (_pS)-1-bromo-2-methylferrocene 6 were synthesized in 4 steps from 2-(4,4-dimethyloxazolinyl)ferrocene and (S)-2-(4-methylethyloxazolinyl)ferrocene, respectively (46 and 81% overall yield). Bromolithium exchange and addition of ClPR₂ gave the corresponding racemic or enantiopure 2-methylferrocenyl phosphine ligands 2-MeFcPR₂ 11 (R = Ph), 12 (R = Cy), and 13 (R = tBu) in 28-93% yield. Use of PCl₃ gave the C₃-symmetric phosphine (2-MeFc)₃P 5 from (_pS)-6 (72% yield) but racemic 6 did not lead to the formation of triferrocenyl phosphines. Combination of 5 and Pd₂(dba)₃ gave an active catalyst for the Suzuki reaction of aryl chlorides, for example, 4-chlorotoluene and phenylboronic acid reacted at only 60 °C in dioxane (86% yield). Other examples are reported together with the use of 12 in this same protocol. From the X-ray crystal structure of 5 the cone angle was determined as 211°. With this, and the electronic character of 11, 12, and other phosphines (derived from vco of trans-[(R₃P)₂Rh(CO)Cl]), an analysis is made of the steric and electronic influences on ligand activity in the Suzuki reaction.

Full text of DOI:10.1021/jo0265479

Syn th esis of Mon od en ta te F er r ocen ylp h osp h in es a n d Th eir
Ap p lica tion to th e P a lla d iu m -Ca ta lyzed Su zu k i Rea ction of Ar yl
Ch lor id es
Tom E. Pickett,‡ Francesc X. Roca,§ and Christopher J . Richards*,§
Department of Chemistry, Cardiff University, P.O. Box 912, Cardiff, CF10 3TB, UK, and
Department of Chemistry, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK
c.j.richards@qmul.ac.uk
Received October 10, 2002
Racemic and enantiopure (pS)-1-bromo-2-methylferrocene 6 were synthesized in 4 steps from 2-(4,4-
dimethyloxazolinyl)ferrocene and (S)-2-(4-methylethyloxazolinyl)ferrocene, respectively (46 and 81%
overall yield). Bromolithium exchange and addition of ClPR2 gave the corresponding racemic or
enantiopure 2-methylferrocenyl phosphine ligands 2-MeFcPR2 11 (R ) Ph), 12 (R ) Cy), and 13 (R
t
) Bu) in 28-93% yield. Use of PCl3 gave the C3-symmetric phosphine (2-MeFc)3P 5 from (pS)-6
(72% yield) but racemic 6 did not lead to the formation of triferrocenyl phosphines. Combination of
5 and Pd2(dba)3 gave an active catalyst for the Suzuki reaction of aryl chlorides, for example,
4-chlorotoluene and phenylboronic acid reacted at only 60 °C in dioxane (86% yield). Other examples
are reported together with the use of 12 in this same protocol. From the X-ray crystal structure of
5 the cone angle was determined as 211°. With this, and the electronic character of 11, 12, and
other phosphines (derived from νCO of trans-[(R3P)2Rh(CO)Cl]), an analysis is made of the steric
and electronic influences on ligand activity in the Suzuki reaction.
In tr od u ction
uents,2 and more recently pentaarylferrocene ligands 3.3
In conjunction with palladium these all generate cata-
lysts capable of transforming aryl halide substrates in a
variety of C-C coupling reactions (Suzuki,1c,j,2a,c,d,l,3e
Heck,1d,m,3b Stille,1i,n Sonogashira,1k Negishi,1l enolate
coupling,1h,2f,h,k,j,3c,d) in addition to C-O1e,g,2b,i,3a,e and
C-N1a,b,f,2c,e,3e bond formation. These results have trans-
formed the synthetic possibilities with low cost, low
molecular weight aryl chlorides, and reactions of these
substrates can often be carried out under very mild
conditions.
Electron-rich and bulky monodentate phosphine ligands
have recently been widely applied in palladium-catalyzed
reactions of aryl halides. Most attention has focused on
tri-tert-butylphosphine 1,1 biphenyls such as 2 containing
di-tert-butylphosphino or dicyclohexylphosphino substit-
‡ Cardiff University.
§ Queen Mary, University of London.
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Lett. 1998, 39, 2367. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
Engl. 1998, 37, 3387. (d) Littke, A. F.; Fu, G. C. J . Org. Chem. 1999,
64, 10. (e) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett.
1999, 40, 8837. (f) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.;
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10.1021/jo0265479 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/01/2003
2592
J . Org. Chem. 2003, 68, 2592-2599

Monodentate Ferrocenylphosphines
SCHEME 1
ladacycles generated from tris(o-tolyl)phosphine 4 and
related 2-methylphenyl-containing phosphines.4 These
results prompted a debate as to whether the structure
of the palladacycle was maintained during the catalytic
cycle, which would require the formation of palladium-
(IV) intermediates.4a,b,5 Evidence now favors the palla-
dacycles acting as sources of phosphine-ligated palladium-
(0).6
In light of these results we reasoned that tris(2-
methylferrocenyl)phosphine 5, the ferrocene equivalent
of tris(o-tolyl)phosphine, would be a superior ligand for
palladium-catalyzed transformations due to the greater
size of ferrocene compared to benzene, and the possibility
that ferrocene would have a favorable effect on the
electronic properties of the attached phosphorus atom.
This was reasoned from the ability of ferrocene to
stabilize an adjacent positive charge; R-ferrocenylcarbe-
nium ions are generally stable, isolable species.7 Fur-
thermore, one of the two possible diastereoisomers of 5
is C3-symmetric. Enantiopure C3-monodentate phosphine
ligands are few in number and have been little studied
in catalysis.8 In view of the recent interest in monoden-
tate phosphines,9 a C3-symmetric version is especially
desirable, particularly if its symmetry properties may be
combined with high activity in a resulting catalyst.
In this paper we report on the synthesis and applica-
tion of 5 and related ligands to the palladium-catalyzed
Suzuki reaction of aryl chlorides. The successful outcome
is rationalized through an examination of the steric and
electronic properties of the ligands, and contrasted to the
properties of 1 and other ligands which display similar
levels of reactivity. Parts of this work have been previ-
ously communicated.10
displays planar chirality. We11 and others12 have previ-
ously demonstrated the application of ferrocenyloxazo-
lines to the synthesis of related 1,2-disubstituted fer-
rocene derivatives. Thus (S)-valine-derived oxazoline
7a 11b was subjected to highly diastereoselective lithiation
(>100:1)12c followed by addition of dibromotetrachloro-
ethane (Scheme 1). The resulting 2-bromoferrocenylox-
azoline 8a was found to be relatively unstable and was
thus immediately ring-opened by treatment with triflic
anhydride followed, after 5 min, by the addition of ice-
water. The resulting ester 9a was isolated in excellent
overall yield with only a single diastereoisomer being
1
Resu lts a n d Discu ssion
observed by H NMR spectroscopy. We have previously
reported this ring-opening protocol for the synthesis of
1,1′,2,2′-tetrasubstituted ferrocenes.13 The high yields
obtained and the short reaction times make this method
significantly more convenient than previously reported
methods of ferrocenyloxazoline ring opening.14 Reduction
of 9a to alcohol 10 was carried out with DIBAL-H. Use
of lithium aluminum hydride resulted in partial removal
of bromine to give hydroxymethylferrocene as an insepa-
rable contaminant. Finally, ionic reduction15 gave (pS)-6
in 81% overall yield. Racemic 6 was similarly synthesized
from 7b16 (overall yield 46%).
Liga n d Syn th esis. The most convenient approach to
the desired ligand appeared to be from 1-bromo-2-
methylferrocene 6 utilizing bromine-lithium exchange
and addition of a phosphorus electrophile. As a conse-
quence of the two different substituents this compound
(4) (a) Herrmann W. A.; Brossmer, C.; O¨ fele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844. (b) Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele,
K.; Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848. (c)
Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Riermeier, T. H.;
O¨ fele, K.; Beller, M. Chem. Eur. J . 1997, 3, 1357.
Bromine-lithium exchange on (pS)-6 proceeded
smoothly, and following addition of 0.33 equiv of phos-
phorus trichloride, the novel C3-symmetric ligand
(pS,pS,pS)-5 was isolated as an air-stable yellow crystal-
line solid (Scheme 2). This we named TomPhos after its
first synthesizer. The identity of this new compound was
confirmed by determination of its X-ray crystal structure
(Figure 1). The unit cell contained two essentially identi-
cal C3-symmetric structures with P-C bond lengths of
1.820(2) and 1.831(2) Å. These are at angles of 115.79°
(5) (a) Shaw, B. L. New J . Chem. 1998, 77. (b) Shaw, B. L.; Perera,
S. D.; Staley, E. A. Chem. Commun. 1998, 1361. (c) Sundermann, A.;
Uzan, O.; Martin, J . M. L. Chem. Eur. J . 2001, 7, 1703.
(6) (a) Louie, J .; Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1996,
35, 2359. (b) Beller, M.; Riermeier, T. H. Eur. J . Inorg. Chem. 1998,
29. (c) Herrmann, W. A.; Bo¨hm, V. P. W.; Reisinger, C.-P. J . Organomet.
Chem. 1999, 576, 23. (d) Bohm, V. P. W.; Herrmann, W. A. Chem. Eur.
J . 2001, 7, 4191.
(7) Allenmark, S. Tetrahedron Lett. 1974, 371.
(8) (a) Bolm, C.; Davis, W. M.; Halterman, R. L.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1988, 27, 835. (b) Powell, M. T.; Porte,
A. M.; Burgess, K. Chem. Commun. 1998, 2161.
(9) Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40, 1197.
(10) (a) Abstracts of Papers; 221st National Meeting of the American
Chemical Society, San Diego, CA; American Chemical Society: Wash-
ington, DC, 2001; ORGN 276. (b) Pickett, T. E.; Richards, C. J .
Tetrahedron Lett. 2001, 42, 3767.
(11) (a) Richards, C. J .; Damalidis, T.; Hibbs, D. E.; Hursthouse,
M. B. Synlett 1995, 74. (b) Richards, C. J .; Mulvaney, A. W. Tetrahe-
dron: Asymmetry 1996, 7, 1419.
(12) (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.
(13) Locke, A. J .; Pickett, T. E.; Richards, C. J . Synlett 2001, 141.
(14) (a) Warshawsky, A. M.; Meyers, A. I. J . Am. Chem. Soc. 1990,
112, 8090. (b) Zhang, W.; Shimanuki, T.; Kida, T.; Nakatsuji, Y.; Ikeda,
I. J . Org. Chem. 1999, 64, 6247.
(15) West, C. T.; Donnelly, S. J .; Kooistra, D. A.; Doyle, M. P. J .
Org. Chem. 1973, 38, 2675.
(16) Bolm, C.; Mun˜iz-Ferna´ndez, K.; Seger, A.; Raabe, G.; Gu¨nther,
K. J . Org. Chem. 1998, 63, 7860.
J . Org. Chem, Vol. 68, No. 7, 2003 2593

Pickett et al.
SCHEME 3
SCHEME 4
TABLE 1. Com p a r ison of 5 a n d P tBu 3 in th e Su zu k i
Cr oss-cou p lin g of 14 a n d 15
entry
ligand
temp, °C
yielda
1
2
5
80
80
75 (75)b
80 (95)
PtBu3
F IGURE 1. Two views of the X-ray structure determination
of TomPhos 5.
3
5
60
81 (86)
SCHEME 2
4
5
6
PtBu3
P(o-tolyl)3
PFc3
60
60
60
74 (96)
<1
<1
a
b
Determined by GC. Yield after 24 h in parentheses
pS*,pS*-diastereoisomer, and its inability to react with
the final equivalent of 2-lithio-1-methylferrocene, would
account for the absence of both triferrocenyl phosphines.
Further monodentate ligands were generated from 6
by utilizing a series of commercially available chloro-
phosphines (Scheme 3). In this instance no significant
difference was observed in the use of pS- and rac-6,
indicating little differences in the reactivity of enan-
tiopure or racemic 2-lithio-1-methylferrocene intermedi-
ates.
and 116.73° to their respective C3-axes along which the
phosphorus lone pairs are oriented. Relative to these C3-
axes the planes of the methyl-substituted cyclopentadi-
enyl rings lie at angles of 10.46° and 9.18°. It is of note
1
Ap p lica t ion t o t h e Su zu k i R ea ct ion . To test our
hypothesis that ligand 5 would be effective in palladium-
catalyzed reactions, we examined the most widely used
of these, the Suzuki coupling between an aryl halide and
an aryl boronic acid. Fu and Littke had previously
reported that PtBu3/Pd2(dba)3 efficiently catalyzes the
cross-coupling reaction between 4-chlorotoluene 14 and
phenylboronic acid 15,1c and we initially chose to compare
5 with PtBu3 using these same conditions (Scheme 4,
Table 1, entries 1 and 2).
that in the H NMR of 5, the unsubstituted cyclopenta-
dienyl ring is observed at δ 3.73 ppm, 0.46 ppm upfield
of the corresponding value in ferrocene itself. This may
be attributed to a positive anisotropic effect from adjacent
methyl-substituted aromatic cyclopentadienyl rings.
Repeated attempts to use rac-6 under the same condi-
tions conspicuously did not result in the formation of pS*,
pS*,pS*-5 or the other possible diastereoisomer with a
pS*,pS*,pR* configuration. Examination of the crude
reaction mixture by 31P NMR revealed a peak at 34.7
ppm, which we tentatively assigned to meso-chlorodi(2-
methylferrocenyl)phosphine. The preferential and ir-
reversible formation of this rather than the alternative
This revealed 5 to be very similar to PtBu3 with use of
these previously optimized conditions. The only notable
difference was the lack of further product formation in
2594 J . Org. Chem., Vol. 68, No. 7, 2003

Monodentate Ferrocenylphosphines
TABLE 3. Ap p lica tion of Liga n d s 11-13 to th e Su zu k i
Cr oss-cou p lin g of 14 a n d 15a a t 60 °C
entry
ligandb
basec
solvent
% yieldd
1
2
3
4
5
6
11
12
13
12
12
12
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
dioxane
dioxane
dioxane
THF
dioxane
THF
2 (2)e
17 (31)
25 (29)
51 (64)
20 (33)
60 (69)
CsF
a
d
1.5 equiv. b 3.6 mol %. c Two equivalents. Determined by GC.
e Reaction time ) 5 h (yield after 24 h in parentheses).
Using these optimized conditions we next tested ligands
11-13 in this same reaction (Table 3). The diphe-
nylphosphine 11 was essentially inactive (entry 1),
ligands 12 and 13 providing a moderate yield of cross-
coupled material (entries 2 and 3). Due to the instability
of di-tert-butyl ligand 13, we instead used the very air-
stable dicyclohexylphosphine ligand 12 for a brief exami-
nation of the influence of base and solvent. In this
instance THF led to a significant increase in yield (entry
4), a trend mirrored when CsF was employed as base
(entries 5 and 6).
We next sought to use 5 and 12 with a wider range of
substrates, and in particular to delineate the limits of
their applicability with sterically and electronically de-
manding substrates (Table 4, entries 1-5). In addition,
coupling of 4-nitrochlorobenzene proceeded in high yield
(entry 6), and 5 again proved more effective than 12
(compare entries 3 with 4, and 6 with 7). However, 12
proved to be extremely effective with aryl bromide
substrates, two examples of which were coupled in
quantitative yield (entries 8 and 9).
Ra tion a liza tion of Liga n d Activity. In light of the
similar yields with PtBu3 and 5 in palladium-catalyzed
Suzuki reactions, we reasoned that comparing their steric
and electronic properties would help delineate the rela-
tive importance of these two factors for ligand activity.
The size of a ligand is most simply quantified through
measurement of the Tolman cone angle.18 Beginning with
the X-ray structures of 5, an additional atom was
introduced with a bond length to phosphorus of 2.28 Å.19
Measurement from the center of this new atom to the
edge of the van der Waals radii of the methyl groups
revealed the cone angles of the two structures to be 212°
and 210°. These contrast with the value of 182° previ-
ously determined for PtBu3.18 The cone angles of 11, 12,
and 13 were obtained by summation of the contributions
from the individual phosphorus substituents (Table 5).
The electronic characteristics of phosphorus ligands
have been extensively investigated by measurement of
carbonyl stretching frequencies in metal carbonyl ad-
ducts. Data are available for Ni(CO)3PR3 complexes
derived from nickel tetracarbonyl.20 Due to the toxicity
and limited availability of this compound we instead
began with [Rh(CO)2Cl]2 and synthesized trans-diphos-
phine adducts 17 which have also been used to study
ligand electronic characteristics (Scheme 5, Table 6).21
Use of PtBu3, 5, and 13 in this same test gave rise to
an anomalous figure of ∼1996 cm-1 in each case, and
F IGURE 2. Graphical comparison of PtBu3 1 and TomPhos
5 in the formation of 16 at 60 °C.
TABLE 2. An a lysis of th e Va r ia bles in th e Su zu k i
Cr oss-cou p lin g of 14 a n d 15a Em p loyin g Liga n d 5
entry mol % of 5 Pd sourceb
basec
solvent
% yieldd
1
2
3
4
5
6
7
8
3.6
6
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Cs2CO3
Cs2CO3
CsF
dioxane 83 (94)f
dioxane 89 (95)
dioxane 76 (91)
dioxane 66 (71)
dioxane 43 (51)
e
3.6
3.6
3.6
3.6
3.6
3.6
KF
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
dioxane 41 (41)
THF 30 (51)
11 (11)
g
Pd(OAc)2
Pd(OAc)2
g
a
b
1.5 equiv. 1.5 mol % unless otherwise stated. c Two equiva-
lents unless otherwise stated. Determined by GC. e Three equiva-
d
lents. f Reaction time ) 5 h (yield after 24 h in parentheses).
3
g
mol %.
the reaction containing 5 after 24 h. This indicated that
the catalyst generated from 5/Pd2(dba)3 is very active but
relatively short-lived, an observation consistent with the
formation of palladium black after ∼5 h. Lowering the
reaction temperature to 60 °C improved the percentage
conversion with 5. In contrast, conversion with PtBu3 is
initially slower but a higher yield was obtained after 24
h (entries 3 and 4, Figure 2). Significantly, tris(o-tolyl)-
phosphine 4 and tris(ferrocenyl)phosphine17 both failed
in this reaction, revealing the importance of the ferrocene
groups and the methyl substituents to the activity
observed with 5.
We next sought to investigate the yield of this reaction
as a function of the base, solvent, the source of palladium,
and the amount of ligand employed (Table 2).
Increasing the amount of base (entry 1) or ligand (entry
2) led to an improvement in yield. It is of note that the
ligand could be quantitatively recovered from these
reactions and we never observed the formation of a
palladacycle. Separate attempts to form a palladacycle
by heating just 5 with Pd(OAc)2 in toluene only led to
the deposition of palladium black.4c Cesium fluoride was
equally effective as a base (entry 3), potassium fluoride
less so (entry 4), and potassium carbonate gave only a
moderate yield (entry 5). Changing to THF as solvent led
to a dramatic decrease in yield (entry 6) as did employing
a palladium(II) salt (entry 7 and 8). The changes in yield
observed here as a function of these variables generally
mirror the results obtained with other monodentate
phosphine ligands employed for the Suzuki reaction. A
notable exception is the preferred use of Pd(OAc)2 in
conjunction with biaryl ligands of type 2.2
(18) Tolman, C. A. Chem. Rev. 1977, 77, 313.
(19) Chem-X; Chemical Design Ltd: Oxon, England.
(20) Tolman, C. A. J . Am. Chem. Soc. 1970, 92, 2953.
(21) Clarke, M. L.; Cole-Hamilton, D. J .; Slawin, A. M. Z.; Woollins,
J . D. Chem. Commun. 2000, 2065.
(17) Prepared by electrophilic substitution of ferrocene with Me2-
NPCl2: Sollett, G. P.; Peterson, W. R. J . Organomet. Chem. 1969, 19,
143.
J . Org. Chem, Vol. 68, No. 7, 2003 2595

Pickett et al.
TABLE 4. F u r th er Su zu k i Cr oss-cou p lin g Rea ction s w ith Liga n d s 5 a n d 12a
a
b
3.6 mol % of ligand, 1.5 mol % of Pd2dba3, 2 equiv of Cs2CO3, 60 °C, 5 h. Determined by GC.
TABLE 5. P h osp h in e Liga n d Con e An gles
TABLE 6. Ca r bon yl Str etch in g F r equ en cies of
Com p lexes 17
phosphine
cone angle (deg)
contribution of substituents
entry
ligand
PPh3
ν(CO) of 17a (cm-1
)
PPh3
PCy3
PtBu3
TomPhos 5
11
145a
170a
182a
211b
167
3 × 48.3
3 × 56.7
1
2
3
4
5
6
7
8
9
1976.0b
1974.9
1974.2
1973.0
1971.8
1967.1
1956.0
1952.8
1948.5
3 × 60.7
P(p-tol)3
11
Fc3P
3 × 70.3
2 × 48.3 + 70.3
56.7 × 2 + 70.3
60.7 × 2 + 70.3
12
13
184
192
P(o-tol)3
P(o-PhOMe)3
12
a
b
From ref 20. Average of the two values obtained.
PnBu3
PCy3
a
b
Determined in CH2Cl2. 1967 cm-1 after solvent evaporation
SCHEME 5
and redetermination as a Nujol mull (see ref 21).
as normally quoted). There is good agreement between
the two series in the relative order of substituent
contributions.
these data were not used in the subsequent analysis. It
has been shown that PtBu3 forms a Rh(I) complex 17
significantly distorted from the ideal square-planar ge-
ometry, preventing direct comparison of its carbonyl
stretching frequency.22
The contribution from each phosphine substituent was
calculated relative to the most basic phosphine in this
series, tricyclohexylphosphine (Table 7). For comparison,
previously reported values for Ni(CO)3PR3 complexes are
also given, adjusted relative to PCy3 (rather than PtBu3
These figures reveal the ferrocenyl phosphines to be
only slightly more electron rich than their phenyl ana-
logues, but significantly electron poorer than trialky-
lphosphines. The X-ray crystal structure of 5 reveals the
plane of the methyl-substituted cyclopentadienyl rings
to lie almost perpendicular to the orbital occupied by the
electron pair on phosphorus. Models reveal that this
conformation, which minimizes the influence of filled
metal-based orbitals (cf. the stabilization of R-ferroce-
nylcarbenium ions), is maintained in other ferrocenyl
phosphines, such as 11.
In Figure 3 the ligands used in this study are plotted
against the steric and electronic parameters discussed
(22) Harlow, R. L.; Westcott, S. A.; Thorn, D. L.; Baker, R. T. Inorg.
Chem. 1992, 31, 323.
2596 J . Org. Chem., Vol. 68, No. 7, 2003

Monodentate Ferrocenylphosphines
F IGURE 3. Analysis of ligand effectiveness in the Suzuki reaction of aryl chlorides as a function of size and electronic parameters.
Notations: (a) ν(CO) estimated as 1971 cm-1; (b) ν(CO) estimated as 1948 cm-1; (c) ν(CO) estimated as 1956 cm-1; (d) ν(CO)
estimated as 1956 cm-1; (e) cone angle determined as 170° by modification of the X-ray structure of 5.
TABLE 7. Con tr ibu tion of In d ivid u a l P h osp h in e
the former may be off set against further increases in
the size of the ligand, not withstanding the decrease in
catalyst stability revealed in this study. In support of this
analysis is the recent report on the use of the bulky
diarylferrocenylphosphine 18 for Suzuki coupling of aryl
chlorides at 70 °C.25
Su bstitu en ts to Meta l Ca r bon yl Str etch in g F r equ en cies
c
trans-(R3P)2Rh(CO)Cl
Ni(CO)3PR3
R
17 (cm-1
)
(cm-1
)
tBu
Cy
-0.1
0
1.3
0.9
0
nBu
0.7a
3.1a
3.7b
3.9a
4.1a
4.6a
o-PhOMe
2-MeFc
o-tol
Fc
Ph
3.5
4.3
a
b
[ν(CO) (R3P)2Rh(CO)Cl - 1948.5]/6. Average of the values
determined from 11 and 12. c From ref 20.
In addition, biaryl ligands 2 may also be analyzed by
this approach. Using the data above, the electronic
parameter is estimated as ca. 1957-1958 cm-1, and
molecular modeling19 reveals the cone angles of 2 (R )
tBu and Cy) to be approximately 225° and 217°, respec-
tively (the contribution from the 2-biphenyl unit being
104°). These fall into the zone of higher activity compared
to PtBu3 and 5, which correlates to the lower reaction
temperatures required for Pd/2-catalyzed Suzuki cou-
pling of aryl chlorides (room temperature for the reaction
between 14 and 152d).
above. On the basis of the similar outcome observed with
PtBu3 and 5, a line linking these two differing structures
denotes the characteristics of active ligands for the
palladium-catalyzed Suzuki reaction of aryl chlorides at
60 °C. Less effective ligands PCy31c and 12 fall in the zone
of reduced activity, while other ligands such as P(o-tol)3,
Fc3P, and PPh3 are in the zone of inactivity, as defined
by the mild conditions used in this study. That the di-
tert-butylferrocenylphosphine 13 was found to be less
active than 5 may be due to in situ decomposition of this
surprisingly unstable ligand. In addition, the simple
summation of cone angles used here may give an over-
estimate for the mixed substituent ligands 11-13. How-
ever, we have not yet been successful in obtaining X-ray
crystal structures to further examine this possibility.
These results support the contention that both elec-
tronic factors and size are important to ligand activity.
Oxidative addition to palladium is promoted by electron-
rich phosphine ligands,23 and increasing the steric bulk
around the metal should accelerate the rate of reductive
elimination.24 Furthermore, the line linking PtBu3 and 5
reveals that the very favorable electronic properties of
Con clu sion s
Enantiopure (pS)-1-bromo-2-methylferrocene 6 is readily
synthesized and is a key intermediate in the synthesis
of planar chiral monodentate phosphine ligands, notably
C3-symmetric (pS,pS,pS)-tris(2-methylferrocenyl)phos-
phine 5 (TomPhos). Combination with Pd2(dba)3 gener-
ates a very active catalyst for the Suzuki cross-coupling
reaction. From an X-ray crystal structure analysis, the
cone angle of 5 was determined as 211°. Analysis of
2-methylferrocenylphosphines 11 and 12 through forma-
tion of rhodium-carbonyl adducts, and comparison to
(23) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(24) Roy, A. H.; Hartwig, J . F. J . Am. Chem. Soc. 2001, 123, 1232.
(25) Liu, S.-Y.; Choi, M. J .; Fu, G. C. Chem. Commun. 2001, 2408.
J . Org. Chem, Vol. 68, No. 7, 2003 2597

Pickett et al.
4.4, 11.9 Hz), 4.73 (1 H, t, J ) 1.6 Hz), 4.85 (1 H, dd, J ) 1.6,
2.7 Hz), 5.49 (1 H, d, J ) 9.6 Hz). 13C{1H} (CDCl3) δ 19.4, 19.5,
30.9, 60.8, 64.7, 68.7, 70.3, 70.6, 72.9, 75.6, 78.7, 115.1, 118.3,
121.5, 124.7, 170.8. MS (m/z; APCI) 527 (M+, 100%), 525 (M+,
100%), 447 (20).
other triaryl and trialkyl phosphine adducts, revealed the
2-methylferrocenyl group to be a typical aryl substituent.
So the activity of the palladium(0) catalyst incorporating
5 is mainly a consequence of the ligand’s size. Further-
more, no palladacycle could be obtained from 5. This
supports other evidence that palladacycles derived from
2-methylphenylphosphines are not involved in the cata-
lytic cycles of the Suzuki reaction and related processes
(requiring Pd(IV) intermediates). Finally, the similar
activity of palladium catalysts containing PtBu3 and 5,
and their contrasting steric and electronic properties, was
used to construct a model of ligand effectiveness in the
Suzuki reaction. Using this approach we could rationalize
the higher activity associated with biphenyl ligands 2,
and we believe that this method of analysis will be useful
in explaining the characteristics of other ligands, aiding
their rational design.
2,2-Dim eth yl-2-tr iflu or om eth ylsu lfon am idoeth yl 1-br o-
m ofer r ocen e-2-ca r boxyla te (9b): A dark orange solution
of 7b16 (2.00 g, 7.1 mmol) in dry Et2O (18 mL) under nitrogen
was cooled to -78 °C. To this was added dropwise BuLi in
hexanes (5.65 mL, 14.1 mmol), the reaction mixture turning
red after the addition. The reaction mixture was allowed to
warm to room temperature, stirred for 3 h, then re-cooled to
-78 °C. A solution of 1,2-dibromotetrachloroethane (4.60 g,
14.1 mmol) in dry Et2O (25 mL) was then added via cannula
and the reaction mixture allowed to warm to room temperature
overnight. The resultant mixture was quenched with H2O,
partitioned, and further extracted with Et2O. The organic
extracts were combined, washed with brine, dried over Mg2-
SO4, and filtered, and the solvent was removed in vacuo to
give 8b as viscous brown oil: 1H NMR (CDCl3) δ 1.25 (6 H, s),
3.90 (1 H, d, J ) 13 Hz), 3.92 (1 H, d, J ) 13 Hz), 4.12 (5 H,
s), 4.16 (1 H, br s), 4.46 (1 H, br ), 4.63 (1 H, br s).
In our ongoing work we are applying the ligands
described herein to other reactions, particularly those in
which their nonracemic properties may find application.26
This was taken up in CH2Cl2 (50 mL) and cooled to 0 °C.
Trifluoromethane sulfonic anhydride (1.30 mL, 9.3 mmol) was
added via syringe and the resulting deep blue mixture was
stirred for 5 min. Ice-water (20 mL) was then added and the
mixture stirred for 10 min. After separation, the aqueous layer
was further extracted with CH2Cl2, the combined organic
extracts were washed with brine, dried (Mg2SO4), and filtered,
and the solvent was removed in vacuo. Column chromatogra-
phy (25% EtOAc/petroleum ether) followed by recrystallization
(EtOAc/hexane) gave 9b as an orange crystalline solid (2.246,
62%): Mp 82-83 °C. Anal. Calcd for C16H17BrF3FeNO4S: C,
37.52; H, 3.35; N, 2.74. Found: C, 37.87; H 3.39; N, 2.63. IR
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Dichloromethane and TMEDA
were distilled from calcium hydride and THF and Et2O were
distilled from sodium benzophenone ketyl, all under an
atmosphere of nitrogen. Petroleum ether refers to that fraction
boiling in the range 40-60 °C. Column chromatography was
performed on SiO2 (40-63 µm).
(S,p S)-2-Isop r op yl-2-t r iflu or om et h ylsu lfon a m id oet h -
yl 1-br om ofer r ocen e-2-ca r boxyla te (9a ): A dark orange
solution of 7a 11b (12.00 g, 40.4 mmol) and TMEDA (7.92 mL,
52.6 mmol) in dry Et2O (150 mL) under nitrogen was cooled
to -78 °C. To this mixture was added dropwise BuLi in
hexanes (22.15 mL, 52.5 mmol), the reaction mixture darken-
ing to red/brown. After stirring at -78 °C for 4 h, 1,2-
dibromotetrachloroethane (26.29 g, 80.7 mmol) in Et2O (50 mL)
was added via cannula and the reaction mixture allowed to
warm to room temperature overnight. The resultant mixture
was quenched with H2O, partitioned, and further extracted
with Et2O. The organic extracts were combined, washed with
brine, and dried (MgSO4) and the solvent was removed in
vacuo to give crude (S,pS)-2-(2′-(4′-isopropyl)oxazolinyl)-1-
bromoferrocene 8a as a brown amorphous solid: 1H NMR
(CDCl3) δ 0.97 (3 H, d, J ) 7 Hz), 1.04 (3 H, d, 3 H, J ) 7 Hz),
1.87 (1 H, sep, J ) 7 Hz), 4.00-4.17 (2 H, m), 4.25 (5 H, s),
4.27 (1 H, t, J ) 3 Hz), 4.28-4.35 (1 H, m), 4.59 (1 H, br s),
4.68 (1 H, br s).
1
(Nujol) νmax 3231 (NH), 1701 (CdO) cm-1. H NMR (CDCl3) δ
1.55 (3 H, s), 1.57 (3 H, s), 4.21-4.26 (2 H, m), 4.30 (5 H, s),
4.44 (1 H, t, J ) 2.7 Hz), 4.73 (1 H, br s), 4.88 (1 H, br s), 5.63
(1H, s). 13C{1H} (CDCl3) δ 25.0, 25.2, 59.2, 60.9, 68.8, 70.2,
70.4, 72.7, 75.5, 78.3, 112.6, 116.7, 121.9, 126.3, 170.4. MS (m/
z, FAB) 513 (M+, 100%), 511 (M+, 100%), 433 (38), 147 (75).
(pS)-1-Br om o-2-h ydr oxym eth ylfer r ocen e (10): DIBAL-H
(1 M) in hexanes (35.0 mL, 35 mmol) was added to a solution
of 9a (5.00 g, 9.5 mmol) in Et2O (100 mL) at 0 °C. After stirring
for 10 min, the reaction was quenched slowly with H2O (100
mL) and extracted with Et2O, the combined organic extracts
were filtered through a glass sinter, washed with brine, dried
(MgSO4), and filtered, and the solvent was removed in vacuo.
Recrystallization (EtOAc/petroleum ether) gave (pS)-10 as a
yellow crystalline solid (2.585 g, 92%): Mp 88-90 °C. Anal.
Calcd for C11H11BrFeO: C, 44.79; H, 3.76. Found: C, 44.66;
H, 3.62. [R]25 +8 (c 0.096, EtOH). IR (Nujol) νmax 3227 (OH)
D
This was taken up in CH2Cl2 (80 mL) and cooled to 0 °C.
Trifluoromethane sulfonic anhydride (7.47 mL, 53.5 mmol) was
added via syringe and the resulting deep blue mixture was
stirred for 5 min. Ice-water (100 mL) was added and the
mixture allowed to stand until the ice had melted. After
separation, the aqueous layer was further extracted with CH2-
Cl2, the combined organic extracts were washed with brine,
dried (Na2SO4), and filtered, and the solvent was removed in
vacuo. Column chromatography (30% EtOAc/petroleum ether)
followed by recrystallization (petroleum ether/EtOAc) gave 9a
as fine yellow needles (20.04 g, 94%): Mp 147-148 °C. Anal.
Calcd for C17H19BrF3FeNO4S: C, 38.80; H, 3.64; N, 2.66.
cm-1. H NMR (CDCl3) δ 1.65 (1 H, t, J ) 5.5 Hz), 4.15 (1 H,
1
t, J ) 2.3 Hz), 4.22 (5 H, s), 4.27 (1 H, br s), 4.41 (1 H, dd, J
) 5.2, 12.3 Hz), 4.49 (1 H, br s), 4.58 (1 H, dd, J ) 5.0, 12.3
Hz). 13C{1H} (CDCl3) δ 60.18, 66.99, 67.41, 71.04, 71.33, 79.90,
86.00. MS (m/z, FAB) 296 (M+, 5%), 294 (M+, 5%), 279 (100),
277 (100).
Using this procedure, 9b (8.30 g, 16.2 mmol) and DIBAL-H
(58.0 mL, 58 mmol) in Et2O (166 mL), workup, and column
chromatography (3% EtOAc/petroleum ether) gave rac-10 as
a yellow crystalline solid (4.68 g, 98%): Mp 63-64 °C.
(pS)-1-Br om o-2-m eth ylfer r ocen e (6): A solution of (pS)-
10 (5.00 g, 17.0 mmol) and triethylsilane (5.42 mL, 34.0 mmol)
in CH2Cl2 (25 mL) was cooled to 0 °C and TFA (5 mL, 65 mmol)
was added. After stirring for 5 min, the reaction was quenched
slowly with saturated aqueous NaHCO3 (50 mL). After separa-
tion, the organic layer was washed with saturated aqueous
NaHCO3 and brine, then dried (Na2SO4) and filtered, and the
solvent was removed in vacuo. Column chromatography (3%
EtOAc/petroleum ether) gave (pS)-6 as an orange crystalline
solid (4.45 g, 94%): Mp 82-83 °C. Anal. Calcd for C11H11BrFe:
C, 47.36; H, 3.98. Found: C, 47.58; H, 3.76. [R]25D -27 (c 0.11,
Found: C, 39.15; H, 3.64; N, 2.64. [R]25 +34 (c 0.105, EtOH).
D
IR (Nujol) νmax 3217 (NH), 1703 (CdO) cm-1. 1H NMR (CDCl3)
δ 1.10 (3 H, d, J ) 6.9 Hz), 1.12 (3 H, d, J ) 6.9 Hz), 2.05-
2.14 (1 H, m), 3.60-3.65 (1 H, m), 4.27 (5 H, s), 4.29 (1 H, dd,
J ) 3.8, 11.9 Hz), 4.43 (1 H, t, J ) 2.7 Hz), 4.53 (1 H, dd, J )
(26) For applications of chiral variants of 2 to asymmetric trans-
formations see: (a) Yin, J .; Buchwald, S. L. J . Am. Chem. Soc. 2000,
122, 12051. (b) Chieffi, A.; Kamikawa, K.; Åhman, J .; Fox, J . M.;
Buchwald, S. L. Org. Lett. 2001, 3, 1897.
2598 J . Org. Chem., Vol. 68, No. 7, 2003

Monodentate Ferrocenylphosphines
1
EtOH). H NMR (CDCl3) δ 2.06 (3 H, s), 3.99 (1 H, t, J ) 2.5
distilled by Kugelrohr (∼200 °C, 0.1 mmHg) to give (pS)-12 a
Hz), 4.04 (1 H, br s), 4.14 (5 H, s), 4.36 (1 H, br s). 13C{1H}
(CDCl3) δ 21.52, 65.97, 67.17, 69.96, 71.63, 79.9. MS (m/z,
APCI) 280 (M+, 100%), 278 (M+, 100%), 200 (90).
Using this procedure, rac-10 (1.50 g, 5.1 mmol), triethylsi-
lane (1.63 mL, 10.2 mmol), and TFA (1.5 mL, 19 mmol) in CH2-
Cl2 (8 mL) gave rac-6 as a yellow crystalline solid (1.08 g,
76%): Mp 52-55 °C.
yellow oil (1.60 g, 75%): [R]25 -148 (c 0.065, EtOH). 1H NMR
D
(CDCl3) δ 1.09-2.06 (21 H, m), 2.09 (3 H, s), 2.32-2.36 (1 H,
m), 4.00 (1 H, t, J ) 1.6 Hz), 4.06 (5 H, s), 4.12 (1 H, t, J ) 2.3
Hz), 4.24 (1 H, br s). 13C{1H} (CDCl3) δ 29.03, 29.84, 29.94,
30.20, 30.48, 31.88, 32.55, 33.91, 34.08, 35.71, 36.22, 38.06,
70.19, 71.53, 72.28, 73.49, 79.56, 91.79. 31P NMR (CDCl3) δ
-13.5. MS (m/z, APCI) 397 (MH+, 100%). High-resolution MS
(m/z; ES): found for MH+ 397.1747. C23H34FeP requires
397.1747.
(pS,pS,pS)-Tr is(2-m eth ylfer r ocen yl)p h osp h in e (5):
A
solution of (pS)-6 (1.00 g, 3.6 mmol) in THF (10 mL) was cooled
to -78 °C and BuLi (1.55 mL, 3.6 mmol) was added via
syringe. After stirring for 30 min, phosphorus trichloride (97
µl, 1.1 mmol) was added and the reaction mixture was allowed
to warm to room temperature. The solvent was removed in
vacuo and the residue was purified by column chromatography
(3%EtOAc/petroleum ether) to give (pS,pS,pS)-5 as a yellow
Meth od B. rac-6 (0.200 g, 0.72 mmol), BuLi (0.27 mL, 0.7
mmol), and chlorodicyclohexylphosphine (0.19 mL, 0.9 mmol)
in THF (4 mL) were manipulated as described above (for rac-
1
11) to give rac-12 (0.263 g, 93%). H and 31P NMR data were
essentially identical with those of (pS)-12.
(pS)-2-Meth yl-1-d i-ter t-bu tylp h osp h in ofer r ocen e (13):
Meth od A. A solution of (pS)-6 (0.500 g, 1.79 mmol) in THF
(5 mL) was cooled to -78 °C and BuLi (0.78 mL, 1.8 mmol)
was added via syringe. After stirring for 30 min, chlorodi-tert-
butylphosphine (0.38 mL, 2.0 mmol) was added and the
reaction mixture was allowed to warm to room temperature.
The solvent was removed in vacuo and the residue was taken
up in dry petroleum ether (10 mL) and filtered via cannula.
The solvent was removed and the residue distilled by Kugel-
rohr (∼250 °C, 0.1 mmHg) to give (pS)-13 as a very air-sensitive
brown/red oil (0.449 g, 73%): 1H NMR (CDCl3) δ 0.90 (9 H, d,
J ) 14.68 Hz), 1.47 (9 H, d, J ) 15.96 Hz), 2.07 (3 H, s), 4.10
(5 H, s), 4.16 (1 H, t, J ) 2.5 Hz), 4.30 (2 H, m). 31P NMR
(CDCl3) δ 16.69. MS (m/z, APCI) 345 (MH+, 100%). High-
solid (542 mg, 72%): Mp 238-240 °C. Anal. Calcd for C33H33
-
Fe3P‚1/2H2O: C, 62.21; H, 5.38. Found: C, 62.19; H, 5.26. [R]20
D
1
-72 (c 0.22, CH2Cl2). H NMR (CDCl3) δ 2.35 (3 H, s), 3.73 (5
H, s), 4.24 (2 H, t, J ) 2.3 Hz), 4.33 (1 H, d, J ) 1.5 Hz). 13C-
{1H} (CDCl3) δ 15.24 (d, J ) 14.4 Hz), 68.41, 69.27, 70.60 (d,
J ) 5.2 Hz), 71.07 (d, J ) 5.8 Hz), 81.19 (d, J ) 6.3 Hz), 89.38
(d, J ) 36.3 Hz). 31P NMR (CDCl3) δ -72.6. MS (m/z, APCI)
628 (M+, 100), 429 (M - 2-MeFc, 82%).
(pS)- a n d r a c-2-m eth yl-1-d ip h en ylp h osp h in ofer r ocen e
(11): Meth od A. A solution of (pS)-6 (0.500 g, 1.79 mmol) in
THF (5 mL) was cooled to -78 °C and BuLi (0.78 mL, 1.8
mmol) was added via syringe. After stirring for 30 min,
chlorodiphenylphosphine (0.35 mL, 1.9 mmol) was added and
the reaction mixture was allowed to warm to room tempera-
ture. The solvent was removed in vacuo and the residue was
taken up in dry petroleum ether (10 mL) and filtered via
cannula. The solvent was removed and the residue distilled
by Kugelrohr (∼150 °C, 0.1 mmHg) to give (pS)-11 as a yellow
resolution MS (m/z, ES) found for [M + OH]+ 361.1383. C19H30
FeOP requires 361.1384.
-
Using this procedure, rac-9 (0.200 g, 0.72 mmol), BuLi (0.27
mL, 0.7 mmol), and chlorodi-tert-butylphosphine (0.13 mL, 0.7
mmol) in THF (2 mL) gave rac-13 (0.07 g, 28%). 1H and 31P
NMR data were essentially identical with those of (pS)-13.
Method B was unsuccessful for the synthesis of 9.
Gen er a l P r oced u r e for Su zu k i Cr oss-cou p lin g Exp er i-
m en ts. All reactions were carried out using a Radleys Car-
ousel attached to a Schlenk line. A solution of aryl chloride
(0.63 mmol), boronic acid (0.95 mmol), Pd2dba3 (0.009 mmol),
base (1.26 mmol), and phosphine ligand (0.023 mmol) in
toluene, dioxane, or THF (2 mL) was stirred under nitrogen
at the required temperature. Samples were taken via syringe
(∼50 µL), diluted with CH2Cl2 (1 mL), and subjected to GC
analysis.
oil (600 mg, 87%): [R]25 -263 (c 0.099, EtOH). 1H NMR
D
(CDCl3) δ 2.04 (3 H, s), 3.57 (1 H, t, J ) 0.98 Hz), 4.04 (5 H,
s), 4.17 (1 H, t, J ) 2.4 Hz), 4.34 (1 H, t, J ) 1.6 Hz), 7.16-
7.19 (2 H, m), 7.25-7.27 (3 H, m), 7.37-7.39 (3 H, m), 7.51-
7.53 (2 H, m). 13C{1H} (CDCl3) δ 14.4, 68.7, 70.1, 70.8, 72.7,
76.1, 89.9, 128.2, 128.5, 128.6, 128.6, 129.4, 132.5, 132.7, 135.3,
135.5, 137.9, 140.1. 31P NMR (CDCl3) δ -21.1. MS (m/z, APCI)
385 (M+, 100%). High-resolution MS (m/z; ES): found for MH+
385.0808. C23H22FeP requires 385.0808.
Meth od B. rac-6 (0.200 g, 0.72 mmol), THF (2 mL), BuLi
(0.27 mL, 0.7 mmol), and chlorodiphenylphosphine (0.14 mL,
0.8 mmol) were manipulated as described above. Following
cannula filtration, the residue was column chromatographed
(3% EtOAc/petroleum ether) to give rac-11 as a yellow oil that
Ack n ow led gm en t. We thank Cardiff University
and Lancaster Synthesis (T.E.P.) and Queen Mary,
University of London (F.X.R.) for the provision of
studentships. In addition we thank Majid Motevalli
(Queen Mary) for the X-ray crystal structure determi-
nation and the EPSRC National Mass Spectrometry
Service Centre, University of Wales, Swansea.
1
crystallized on standing (0.200 g, 73%): Mp 159-160 °C. H
and 31P NMR data were essentially identical with those of (pS)-
11.
(p S )-2-Me t h y l-1-d ic y c lo h e x y lp h o s p h in o fe r r o c e n e
(12): Meth od A. A solution of (pS)-6 (1.50 g, 5.4 mmol) in
THF (15 mL) was cooled to -78 °C and BuLi (2.34 mL, 5.4
mmol) was added via syringe. After stirring for 30 min,
chlorodicyclohexylphosphine (1.31 mL, 5.9 mmol) was added
and the reaction mixture was allowed to warm to room
temperature. The solvent was removed in vacuo and the
residue was taken up in dry petroleum ether (20 mL) and
filtered via cannula. The solvent was removed and the residue
Su p p or tin g In for m a tion Ava ila ble: Details of the X-ray
structure determination of 5 and 1H and 31P NMR spectra of
11, 12, and 13. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0265479
J . Org. Chem, Vol. 68, No. 7, 2003 2599