Ferrocenyl monophosphine ligands: Synthesis and applications in the Suzuki-Miyaura coupling of aryl chlorides

Article abstract of DOI:10.1021/jo048963u

Ferrocenyl monophosphine ligands have been developed by a method based on palladium-catalyzed Suzuki-Miyaura coupling. The modular procedure creates a rapid synthesis of phosphines with diverse properties. The electron-rich phosphines have been successfully applied to the Suzuki-Miyaura coupling of activated and deactivated aryl chlorides, with low catalyst loading being feasible in the synthesis of tris-ortho-substituted biaryls.

Full text of DOI:10.1021/jo048963u

Recently, there has been a noteworthy emergence of
ferrocenyl phosphines, providing suitable ligands for the
palladium-catalyzed Suzuki-Miyaura coupling.7 In our
effort toward developing catalytic methods for phosphine
synthesis,9 we thought that ortho-arylated ferrocenyl
phosphines 1 would provide good ligands for the Suzuki-
Miyaura reactions on the basis of their similarity to
Buchwald’s biphenyl-based ligands.3 Ligands 1 could be
easily synthesized by an ortho-lithiation, an iodination,
and a Suzuki-Miyaura coupling sequence starting with
readily available ferrocenyl phosphine oxides. Some
chiral analogues of 1 have recently been synthesized by
J ohannsen and a co-worker, starting with an optically
pure ferrocenyl sulfoxide; the planar chiral dicyclohexyl-
phosphines were shown to be effective in the Suzuki-
Miyaura coupling of aryl chlorides at 2 mol % palladium
loading and give moderate enantiomeric excesses in the
asymmetric coupling of aryl bromides.7a
F er r ocen yl Mon op h osp h in e Liga n d s:
Syn th esis a n d Ap p lica tion s in th e
Su zu k i-Miya u r a Cou p lin g of Ar yl
Ch lor id es
Colin Baillie, Lixin Zhang, and J ianliang Xiao*
Department of Chemistry, University of Liverpool,
Liverpool L69 7ZD, U.K.
j.xiao@liv.ac.uk
Received J une 21, 2004
Abstr a ct: Ferrocenyl monophosphine ligands have been
developed by a method based on palladium-catalyzed Su-
zuki-Miyaura coupling. The modular procedure creates a
rapid synthesis of phosphines with diverse properties. The
electron-rich phosphines have been successfully applied to
the Suzuki-Miyaura coupling of activated and deactivated
aryl chlorides, with low catalyst loading being feasible in
the synthesis of tris-ortho-substituted biaryls.
Palladium-catalyzed cross-coupling reactions have been
extensively studied, dominating the catalytic transforma-
tions for C-C and C-heteroatom bond formation.1 The
efficient activation of aryl chlorides remains the goal in
this area of study, due to their inexpensive costs and
convenient availability.2 In the specific case of Suzuki-
Miyaura coupling, several classes of ligands have been
developed that effect the coupling of activated and
deactivated aryl chlorides; these include, for example, the
electron-rich biaryl dialkylphosphines,3 trialkylphos-
phines,4 palladacycles,5 carbenes,6 and ferrocenylphos-
phines.7 However, there are still few ligands available
that allow for the coupling of deactivated aryl chlorides
and boronic acids, both bearing ortho substituents, at a
low catalyst loading.3a,4b,5e Herein, we report easy access
to a class of monodentate ferrocenyl phosphine ligands,
which are effective for the Suzuki-Miyaura coupling of
deactivated aryl chlorides, including sterically hindered
coupling partners, at a catalyst loading of 0.1 mol %.8
Ligands 1 can be synthesized in three steps from
ferrocenyl phosphine oxides 2, which were prepared by
established methods (Scheme 1).10 The first step is the
ortho-lithiation of 2 to access the iodo-substituted phos-
phine oxides 3. Price and Simpkins have previously
(5) (a) Bedford, R. B.; Cazin, C. S. J . Chem. Commun. 2002, 2610.
(b) Bedford, R. B.; Cazin, C. S. J . Chem. Commun. 2001, 1540. (c) Zim,
D.; Gruber, A. S.; Ebeling, G.; Dupont, J .; Monteiro, A. L. Org. Lett.
2000, 2, 2881. (d) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaster,
H.-U. Angew. Chem., Int. Ed. 2002, 41, 4668. (e) Bedford, R. B.; Cazin,
C. S. J .; Coles, S. J .; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.;
Light, M. E. Organometallics 2003, 22, 987.
(6) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b)
Navarro, O.; Kelly, R. A., III; Nolan, S. P. J . Am. Chem. Soc. 2003,
125, 16194. (c) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius,
F. Angew. Chem., Int. Ed. 2003, 42, 3690. (d) Navarro, O.; Kaur, H.;
Mahjoor, P.; Nolan, S. P. J . Org. Chem. 2004, 69, 3173. (e) Gurbuz,
N.; Ozdemir, I.; Demir, S. J . Mol. Catal. A 2004, 209, 23.
(7) (a) J ensen, J . F.; J ohannsen, M. Org. Lett. 2003, 5, 3025. (b)
Pickett, T. E.; Roca, F. X.; Richards, C. J . J . Org. Chem. 2003, 68, 2592.
(c) Roca, F. X.; Richards, C. J . Chem. Commun. 2003, 3002. (d) Hierso,
J .-C.; Fihri, A.; Amardeil, A.; Meunier, P.; Doucet, H.; Santelli, M.;
Donnadieu, B. Organometallics 2003, 22, 4490. (e) Kataoka, N.; Shelby,
J . P.; Hartwig, J . F. J . Org. Chem. 2002, 67, 5553. (f) Lin, S.-Y.; Choi,
M. J .; Fu, G. C. Chem. Commun. 2001, 2408.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH: New York, 1998. (b) Applied Homoge-
neous Catalysis with Organometallic Reagents; Cornils, B., Herrmann,
W. A., Eds.; VCH: Weinheim, Germany, 1996. (c) Tsuji, J . Palladium
Reagents and Catalysts, Innovations in Organic Synthesis; Wiley: New
York, 1995.
(2) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(b) Whitcombe, N. J .; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57,
7449.
(3) For examples of biphenyl-based ligands in C-C coupling reac-
tions, see: (a) Yin, J .; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J .
Am. Chem. Soc. 2002, 124, 1162. (b) Wolfe, J . P.; Buchwald, S. L.
Angew. Chem., Int. Ed. 1999, 38, 2413. (c) Wolfe, J . P.; Singer, R. A.;
Yang, B. H.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 9550. For
C-N coupling reactions, see: (d) Wolfe, J . P.; Tomori, H.; Sadighi, J .
P.; Yin, J . J .; Buchwald, S. L. J . Org. Chem. 2000, 65, 1158. (e) Old,
D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 9722.
For C-O coupling reactions, see: (f) Palucki, M.; Buchwald, S. L. J
Am. Chem. Soc. 1997, 119, 11108.
(4) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
(b) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122, 4020.
(c) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153.
(8) This work was initially presented at the EuropaCat-VI, Inns-
bruck, Austria, September 2002; poster A1.111.
(9) (a) Chen, W.; Xu, L.; Xiao, J . Org. Lett. 2000, 2, 2675. (b) Chen,
W.; Xiao, J . Tetrahedron Lett. 2000, 41, 3697. (c) Hu, Y.; Chen, W.;
Xu, L.; Xiao, J . Organometallics 2001, 20, 3206. (d) Baillie, C.; Chen,
W.; Xiao, J . Tetrahedron Lett. 2001, 42, 9085. (e) Chen, W.; Xu, L.;
Hu, Y.; Banet, A. M.; Xiao, J . Tetrahedron 2002, 58, 3889. (f) Xu, L.;
Mo, J .; Baillie, C.; Xiao, J . J . Organomet. Chem. 2003, 687, 310. (g)
Baillie, C.; Xiao, J . Tetrahedron 2004, 60, 4159.
(10) (a) Sollott, G. P.; Mertwoy, H. E.; Portnoy, S.; Snead, J . L. J .
Org. Chem. 1963, 28, 1090. (b) The synthesis of 3c has previously been
reported, see: Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J . F. J .
Am. Chem. Soc. 2000, 122, 10718. (c) Guillaneux, D.; Kagan, H. B. J .
Org. Chem. 1995, 60, 2502. (d) 2c was prepared from cyclohexylmag-
nesium chloride and phosphorus trichloride and used without further
purification. This procedure was described for the synthesis of biaryl-
based dicyclohexylphosphines, see: Tomori, H.; Fox, J . M.; Buchwald,
S. L. J . Org. Chem. 2000, 65, 5334.
10.1021/jo048963u CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/07/2004
J . Org. Chem. 2004, 69, 7779-7782
7779

SCHEME 1. Mod u la r Syn th esis of Mon oa r ylfer r ocen ylp h osp h in es
TABLE 1. Su zu k i-Miya u r a Cou p lin g of
4-Ch lor oa cetop h en on e w ith P h en ylbor on ic Acid a
reported the asymmetric ortho-lithiation of 2a in the
synthesis of a silylated ferrocenylphosphine oxide.11
Using a combination of nBuLi and TMEDA, 3a was
obtained in 62% isolated yield. These conditions also
allowed 3c to be accessed, although the compound could
not be isolated in an analytically pure form, as it did not
appear to be stable to standard chromatographic purifi-
cation. Compound 3b required the alternative ortho-
lithiation conditions developed by Snieckus and co-
entry
ligand
T (°C)
conversion (%)b
1
2
3
4
5
6
7
8
9
1a x
1a z
1bx
1by
1bz
1a x
1a z
1bx
1by
1bz
22
22
22
22
22
65
65
65
65
65
40
50
8
11
61
22
43
86
96
100
t
workers,12 which utilize BuLi as the source of lithium.
Again, the iodo-substituted product could not be isolated
in an analytically pure form. Because of their instability,
compounds 3 were used without further purification.
The Suzuki-Miyaura reactions between compounds 3
and three arylboronic acids afforded the coupled oxides
4a x,a z, 4bx-bz, and 4cx-cz in good yields. The condi-
tions were identical for each coupling reaction in that
PdCl2(PPh3)2 was used as the catalyst, with aqueous
NaOH as the choice of base. With various arylboronic
acids generally commercially available, the method should
allow other ortho-arylated ferrocenyl phosphines or their
oxides to be easily accessible, as we have previously
demonstrated for biphenyl-based phosphines.9d,g
Free phosphines 1a ,b were easily obtained from oxides
4a ,b by reduction with trichlorosilane. By simply heating
a mixture of 4a ,b, 5.0 equiv of HSiCl3, and 5.5 equiv of
NEt3 in toluene at 90 °C, we obtained 1a ,b in analytically
pure form in ca. 30% overall isolated yield. Unfortunately,
we were unable to access (di-tert-butyl)phosphine 1c
using these conditions. Other attempts, including the
choice of LiAlH4 as the reducing agent, borane protection,
and the use of higher temperatures, also proved unsuc-
cessful.
10
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.5 equiv of
b
arylboronic acid, 22 °C for 24 h or 65 °C for 11 h. Conversion
based on 1H NMR.
with 1b at a reduced reaction time, however. This is in
line with the literature where ferrocenyl ligands gener-
ally require heating to effect the Suzuki-Miyaura cou-
pling of aryl chlorides.7 In contrast, an adverse effect was
observed with ligands 1a (entries 6 and 7), indicating
early catalyst decomposition. This preliminary screening
established the more electron-rich phosphines 1b to be
superior to 1a for coupling at high temperatures. J o-
hannsen has reported that 1bz delivers a >99% conver-
sion at room temperature for the same coupling at 5 mol
% palladium loading in wet THF with K3PO4 as the base
in 24 h.7a
Ligands 1b were then screened for the more demand-
ing reaction between the deactivated 4-chlorotoluene and
phenylboronic acid. Under conditions similar to those
described above, using either KF or K3PO4 as a base,
lower conversions resulted (Table 2, entries 1-6). How-
ever, switching to dioxane resulted in total or nearly total
conversion with both bases when employing the more
electron-rich and more sterically demanding 1b y and
1bz (entries 7-12). Two equivalents of ligand appears
necessary since using 1 equiv resulted in a reduced
conversion (entry 13). This may be attributed to part of
the phosphine being consumed in the reduction of Pd(II)
to Pd(0).13
With the ligands in hand, we began to examine their
potential in coupling reactions. Ligands 1 were initially
screened in the Suzuki-Miyaura coupling of an activated
aryl chloride (4-chloroacetophenone) with phenylboronic
acid. The analogous biphenylphosphines have previously
been shown to be capable of activating Ar-Cl bonds at
ambient temperatures.3b Using 1 mol % Pd(OAc)2 and 2
mol % 1 at room temperature for 24 h, we were disap-
pointed when a maximum of 61% conversion was ob-
tained (Table 1, entries 1-5). At the elevated tempera-
ture of 65 °C, much improved conversions were observed,
(11) Price, D.; Simpkins, N. S. Tetrahedron Lett. 1995, 36, 6135.
(12) Gray, M.; Chappell, B. J .; Felding, J .; Taylor, N. J .; Snieckus,
V. Synlett 1998, 4, 422.
With the apparent improvement in performance with
increased temperature, we decided to investigate the use
7780 J . Org. Chem., Vol. 69, No. 22, 2004

TABLE 2. Su zu k i-Miya u r a Cou p lin g of
TABLE 3. Su zu k i-Miya u r a Cou p lin g of Ar yl Ch lor id es
4-Ch lor otolu en e a n d P h en ylbor on ic Acid a
w ith Low Ca ta lyst Loa d in gsa
conversion
(%)b
entry
ligand
solvent
base
KF
K3PO4
KF
K3PO4
KF
K3PO4
KF
K3PO4
KF
K3PO4
KF
K3PO4
K3PO4
1
2
3
4
5
6
7
8
9
10
11
12
13
1bx
1bx
1by
1by
1bz
1bz
1bx
1bx
1by
1by
1bz
1bz
1by
THF
THF
THF
THF
THF
THF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
64
17
71
73
61
33
59
62
99
99
92
100
86c
a
Reaction conditions: 1.0 equiv of aryl chloride and 1.5 equiv
of arylboronic acid. Conversion based on 1H NMR. c With 1 mol
b
% 1by, 24 h.
of lower catalyst concentrations. We were pleased to
discover that 0.1 mol % Pd(OAc)2 could be used at 95 °C
to complete the same coupling using either 1by or 1bz.
The scope of the reaction was successfully expanded to a
range of aryl chlorides. As can be seen from Table 3,
phenylboronic acid coupled with the activated 4′-chloro-
acetophenone and deactivated chlorotoluene and the
anisole derivatives affording the corresponding biphenyls
in excellent isolated yields regardless of the substitution
pattern in the chlorides (entries 1-7). ortho-Substituted
arylboronic acids coupled equally well with the deacti-
vated chlorides (entries 9-12). The Suzuki-Miyaura
coupling of aryl chlorides to access sterically bulky biaryls
usually requires relatively high catalyst concentra-
tions.3a,4b,6b,c,7a,b,e However, under the established condi-
tions, bis-ortho-substituted biaryls could be made avail-
able in 89-90% yield (entries 8 and 13). Even a tris-ortho-
substituted biaryl was accessed in 88% yield with the
Suzuki-Miyaura coupling between 2-chloro-m-xylene
and o-tolylboronic acid under these conditions (entry 14).
However, some difficulty was encountered in accessing
the same tris-ortho-substituted biaryl from 2-chlorotolu-
ene and 2,6-dimethylphenylboronic acid, with a lower
conversion observed, indicating the transmetalation step
is more sensitive to the steric hindrance arising from the
boronic acids (entry 15). Buchwald’s bulky biaryl phos-
phines,3a Fu’s PCy3-based catalyst,4b and Glorius’ flexible
N-heterocyclic carbene6c appear to be the only known
ligands capable of coupling in this manner (i.e., allowing
bis-ortho-substituted arylboronic acids to be used) at
catalyst loadings >1 mol %.
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.5 equiv of
arylboronic acid, 0.1 mol % Pd(OAc)2, 0.2 mol % 1bz, 3 equiv of
K3PO4, dioxane, 95 °C, 24 h. Reaction times were not minimized.
b Isolated yield. c Reaction conducted for 8 h. With 0.4 mol % 1bz.
d
e With 0.2 mol % 1by used as the ligand. f Reaction in toluene.
Encouraged, we decided to lower the catalyst concen-
tration further to 0.01 mol % Pd(OAc)2. However, for the
reaction between 4-chlorotoluene and phenylboronic acid,
the highest conversion obtained was 67%. This may be
due to palladium decomposition before the palladium-
phosphine catalyst is formed in situ in solution. In this
g
h
Reaction at 100 °C. With 2.5 equiv of arylboronic acid.
sense, it is noted that the preformed palladacycle cata-
lysts developed by Bedford are extremely effective for the
Suzuki-Miyaura coupling of aryl chlorides with phenyl-
boronic acid at very low catalyst loadings.5a,b
Ligands 1b are also effective for the Buchwald-
Hartwig amination, a reaction that has become powerful
(13) (a) Amatore, C.; Carre´, E.; J utand, A.; M’Barki, M. A. Orga-
nometallics 1995, 14, 1818. (b) Ozawa, F.; Kubo, A.; Hayashi, T. Chem.
Lett. 1992, 2177.
J . Org. Chem, Vol. 69, No. 22, 2004 7781

SCHEME 2. Am in a tion of Ar yl Ch lor id es w ith
Low Ca ta lyst Loa d in gsa
ligands for the palladium-catalyzed Suzuki-Miyaura
coupling of aryl chlorides.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Su zu k i Cou p lin g of Ar ylbo-
r on ic Acid s w ith Iod o-Su bstitu ted F er r ocen ylp h osp h in e
Oxid es 3. To a Schlenk tube were added 3 (R ) Ph, 2.0 mmol),
arylboronic acid (4.0 mmol), and PdCl2(PPh3)2 (70.2 mg, 0.10
mmol); the mixture was degassed. NaOH (1.67 mL, 3 M) and
degassed DME (25 mL) were introduced, and the resulting
mixture was heated at 90 °C for 24 h. After the mixture was
cooled to ambient temperature, it was diluted with H2O (25 mL)
and extracted with CHCl3 (3 × 25 mL). The organic layers were
dried (MgSO4) and concentrated in vacuo. Flash chromatography
(EtOAc/hexane, 2:1) yielded the coupled products 4 in 49-86%
yields.
Gen er a l P r oced u r e for th e Su zu k i Cou p lin g of Ar yl
Ch lor id es a t 0.1 m ol % Ca ta lyst Loa d in g. An oven-dried
carousel reaction tube was charged with boronic acid (1.5 mmol),
K3PO4 (3 mmol), and phosphine 1 (2 × 10-3 mmol). The reaction
vessel was evacuated and backfilled with N2; this process was
repeated five times. Through a rubber septum, aryl chloride in
dioxane (1.0 mL, 1.0 M, 1.0 mmol), Pd(OAc)2 in dioxane (0.5 mL,
2 × 10-3 M, 1 × 10-3 mmol), and dioxane (3.5 mL) were added
to the reaction tube. The resulting mixture was heated at 95 °C
for 24 h before being cooled to ambient temperature for analysis.
Conversions were calculated from crude 1H NMR, and isolated
yields were obtained after a standard workup and purification
by flash chromatography (hexane, 100%).
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of
morpholine, and 1.4 equiv of NaOtBu. Isolated yield.
b
for the preparation of substituted anilines.2,14 Bulky,
electron-rich phosphine and carbene ligands have fre-
quently been employed for the less-reactive aryl chlo-
rides.15 We have found that 1bz promotes the amination
of aryl chlorides with morpholine at a low palladium
loading of 0.1 mol %, furnishing the aniline derivatives
in >80% isolated yields (Scheme 2).
To summarize, we have synthesized monoarylferroce-
nylphosphines via the Suzuki-Miyaura coupling of fer-
rocenyl phosphine oxides. This represents a simplified
procedure for accessing such phosphines in that the easily
accessible phosphine oxide itself serves as a directing
group for ortho-lithiation rather than a more-expensive
group that has to be cleaved afterward. The electron-rich
phosphines 1b have been demonstrated to be effective
Ack n ow led gm en t. We thank the EPSRC (C.B.) and
Johnson Matthey Synetix (J.X.) for support, and Johnson
Matthey for the loan of palladium.
(14) (a) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J . F. Angew. Chem., Int.
Ed. 1998, 37, 2046.
(15) For some recent examples, see: (a) Anderson, K. W.; Mendez-
Perez, M.; Priego, J .; Buchwald, S. L. J . Org. Chem. 2003, 68, 9563.
(b) Hooper, M. W.; Utsunomiya, M.; Hartwig, J . F. J . Org. Chem. 2003,
68, 2861. (c) Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer,
M.; Nolan, S. P. Org. Lett. 2003, 5, 1479. (d) J i, J .; Li, T.; Bunnelle, W.
H. Org. Lett. 2003, 5, 4611. (e) Strieter, E. R.; Blackmond, D. G.;
Buchwald, S. L. J . Am. Chem. Soc. 2003, 125, 13978. (f) Urgaonkar,
S.; Nagarajan, M.; Verkade, J . G. Org. Lett. 2003, 5, 815.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the syntheses of 1-4, procedures for the Suzuki-
Miyaura coupling, and analytical data for the ligands. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O048963U
7782 J . Org. Chem., Vol. 69, No. 22, 2004