A highly practical and general route for α-arylations of ketones using bis-phosphinoferrocene-based palladium catalysts

Article abstract of DOI:10.1021/op7002503

Well-defined, air-stable Pd complexes of bis-phosphinoferrocene family of catalysts have been studied in the arylation of various ketones with aryl chlorides and aryl bromides. Bis(di-tert-butyl)phosphinoferrocene (DtBPF)-based catalysts such as (DtBPF) P

Full text of DOI:10.1021/op7002503

Organic Process Research & Development 2008, 12, 522–529
A Highly Practical and General Route for r-Arylations of Ketones Using
Bis-phosphinoferrocene-Based Palladium Catalysts
Gabriela A. Grasa* and Thomas J. Colacot
Johnson Matthey Catalysis and Chiral Technolgies, 2001 Nolte DriVe, West Deptford, New Jersey 08066, U.S.A.
Abstract:
forming reactions, mainly because of the pioneering work
of Hartwig3 and Buchwald.4 Subsequent contributions
from Nolan,5 Ackerman,6 and Chan7 are also significant.
Our laboratory has been involved in designing practical,
elegant, and simple catalytic solutions to various name reactions
in the area of cross-coupling. In this context, we identified
bidentate phosphines featuring the ferrocene backbone as an
interesting class of ligands in a variety of transition metal-
catalysed reactions in organic synthesis.8 Palladium complexes
of 1,1′-bis-substituted ferrocenylphosphines have been utilized
efficiently as practical commercial catalysts for a number of
cross-coupling reactions.9 Recent work from our group suc-
cessfully demonstrated the application of an air-stable, yet highly
active, preformed catalyst: 1,1′-bis(di-tert-butylphosphino)fer-
rocene palladium dichloride (DtBPF)PdCl2 in the Suzuki
coupling of a wide variety of unactivated aryl halides.10 Very
recently, we also successfully explored the suitability of
(DtBPF)PdCl2 catalyst in the R-arylation of ketone enolates
with aryl chlorides.11 As a continuation of our studies toward
developing simple, elegant, and general catalytic processes for
C-C bond-forming reactions, we present herein a detailed study
on the use of bis-phosphinoferrocene-based Pd(II) complexes
as preformed catalysts (Figure 1) in the R-arylation of ketone
enolates with aryl-bromides and -chlorides. From an organic
process development point of view, there are several parameters
Well-defined, air-stable Pd complexes of bis-phosphinoferrocene
family of catalysts have been studied in the arylation of various
ketones with aryl chlorides and aryl bromides. Bis(di-tert-bu-
tyl)phosphinoferrocene (DtBPF)-based catalysts such as (DtBPF)
PdCl2 and (DtBPF)PdBr2 have been identified as two of the most
active catalysts for the r-arylation of a model reaction involving
propiophenone and 4-chlorotoluene. The scope of the (DtBPF)-
PdCl2 catalyst has been efficiently expanded to the arylation of
various ketones with aryl chlorides and bromides with up to 97%
isolated yields, under relatively mild reaction conditions at low
catalyst loadings. The efficacy of the (DtBPF)PdCl2 catalyst was
demonstrated at very low catalyst loadings with S/C 10,000 for
the difficult aryl bromide, 4-bromoanisole, and 2000 for the
electron-neutral aryl chloride, 4-chlorotoluene, on ∼10-g scale with
excellent isolated yields and lower Pd in the product (6 and 48
ppm, respectively). Comparative studies on the Pd:DtBPF molar
ratios between in situ catalysts and preisolated catalysts revealed
that preisolated (DtBPF)PdX2 (X ) Cl, Br) are the catalysts of
choice due to various practical reasons.
Introduction
The R-aryl carbonyl moiety is ubiquitous in many
organic compounds with interesting pharmacological and
biological properties.1 Stoichiometric reactions between
a stabilized ketone enolate carbanion and an aryl electro-
phile serve as a classical C-C bond-forming technology
toward the synthesis of R-aryl carbonyl compounds.2
However, these transformations suffer from many practical
drawbacks, such as functional group compatibility and air
and moisture sensitivity, in addition to the toxicity of the
reagents. To alleviate some of these limitations, recently
metal-catalysed R-arylation of carbonyl compounds has
been developed as a new and novel class of C-C bond-
(3) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. and
references therein. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473. (c) Hamann, B. C.; Hartwig, J. F. 1997, 119,
12382. (d) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 1473. (e) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 4976. (f) Beare, N. A.; Hartwig, J. F. J. Org. Chem.
2002, 67, 541.
(4) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818. (c) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 3500. (d) Moradi, W. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7996.
(5) (a) Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M.;
Nolan, S. P. Org. Let. 2003, 5, 1479. (b) Viciu, M. S.; Germaneau,
R.; Nolan, S. P. Org. Let. 2002, 4, 4053. (c) Navarro, O.; Marion, N.;
Oonishi, Y.; Kelly, R. A.; Nolan, S. P. J. Org. Chem. 2006, 71, 685.
(6) Ackermann, L.; Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer, A.
Angew. Chem., Int. Ed. 2006, 45, 7627.
* Corresponding author. Telephone: 856-384-7039. Fax: 856-384-7035.
E-mail: grasag@jmusa.com.
(1) (a) Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta, D. C.
J. Org. Chem. 2001, 66, 3653. (b) Shen, T. Y. Angew. Chem., Int.
Ed. Engl. 1972, 11, 460. (c) Wright, W. B.; Press, J. B.; Chan, P. S.;
Marsico, J. W.; Haug, M. F.; Lucas, J.; Tauber, J.; Tomcufcik, A. S.
J. Med. Chem. 1986, 29, 523. (d) Goehring, R. R.; Sachdeva, Y. P.;
Pisipati, J. S.; Sleevi, M. C.; Wolfe, J. F. J. Am. Chem. Soc. 1985,
107, 435. (e) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.;
Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147.
(7) Chen, G.; Kwong, F.; Chan, H. O.; Yu, W.-Y.; Chan, A. S. C. Chem
Commun. 2006, 1413.
(8) (a) Togni, A., Hayashi, T., Eds. Ferrocenes; VCH Verlagsgesellschaft:
Weinheim, 1995. (b) Stepnicka, P. Ferrocenes: From Materials and
Chemistry to Biology; Wiley: Chicester, 2008. In press.
(9) (a) Colacot, T. J.; Parisel, S. In Ferrocenes: From Materials and
Chemistry to Biology, Wiley: Chicester, 2008; pp 117–140. (b) Colacot,
T. J Chem. ReV. 2003, 103, 3101 and references therein. (c) Colacot,
T. J. Platinum Met. ReV. 2001, 45, 22. (d) Colacot, T. J.; Quian, H.;
Cea-Olivares, R.; Hernandez-Ortega, S. J. Organomet. Chem. 2001,
637–639, 691.
(2) (a) Elliot, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5863. (b)
Abramovitch, R. A.; Barton, D. H. R.; Finet, J. P. Tetrahedron 1988,
44, 3039. (c) Kozyrod, R. P.; Pinhey, J. T. Tetrehedron Lett. 1983,
24, 1301. (d) Donnely, D. M. X.; Finet, J. P.; Guiry, P. J.; Nesbitt, K.
Tetrahedron 2001, 57, 413. (e) Fraboni, A.; Fagnoni, M.; Albini, A.
J. Org. Chem. 2003, 68, 4886. (f) Stewart, J. D.; Fields, S. C.; Kochhar,
K. S.; Pinnick, H. J. Org. Chem. 1987, 52, 2110.
(10) Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731.
(11) Grasa, G. A.; Colacot, T. J Org. Lett. 2007, 9, 5489.
522
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Vol. 12, No. 3, 2008 / Organic Process Research & Development
10.1021/op7002503 CCC: $40.75
2008 American Chemical Society
Published on Web 04/25/2008

Figure 1. Palladium catalysts.
Figure 2. Bite angle variation for bis-phosphinoferrocene PdCl2
Table 1. Performance of Pd-bis-phosphinoferrocene-based
catalysts in the arylation of propiophenone with
4-chlorotoluenea
complexes.9a,12
gave no activity under identical conditions (Table 1, entry
1 vs entries 2 and 3). In order to further understand its
superior activity, we have determined the X-ray molecular
structure of (DtBPF)PdCl2 complex11 and compared its
bonding characteristics with other similar complexes
(Figure 2). Notably, the P-Pd-P bite angle of the
bidentate ligand in (DtBPF)PdCl2 is the largest (104.22
°) in the series of bis-phosphinoferrocene complexes of
PdCl2 (Figure 2).9a,12 Interestingly, the bite angle of the
isopropyl analog, (DiPPF)PdCl2 (103.95 °) is close to that
of (DtBPF)PdCl2.12a However, (DiPPF)PdCl2 catalyst has
not been very active either in the R-arylation (Table 1,
entry 6) or Suzuki coupling involving arylchlorides.10 The
unique activity of (DtBPF)PdCl2 could be due to its larger
bite angle, coupled with the steric and electronic effects
of the tert-butyl group. Surprisingly, among the (DtBPF)-
PdX2 series, (DtBPF)PdI2 catalyst gave only 12% conver-
sion. Current study is in progress to understand its
structure–activity relationship in catalysis.
Effect of Solvent and Base in the r-Arylation of Pro-
piophenone. The catalysts such as (DtBPF)PdCl2, (DtBPF)-
PdBr2 and (DCPF)PdCl2, which gave reasonably good conver-
sions, were selected for further optimization in terms of under-
standing the solvent and base effect at 1% catalyst loading
(Chart 1). Both (DtBPF)PdCl2 and (DtBPF)PdBr2 showed high
conversion in dioxane solvent, while the (DCPF)PdCl2 catalyst,
inversely, led to increased conversions in the following or-
der: THF < dioxane < Toluene ≈ MTBE. This difference in
behavior indicates that solvent–catalyst combination is indeed
important even when the structural differences of the catalysts
are very subtle.
entry
precatalyst
conv (%)b
1
2
3
4
5
6
7
Pd2(dba)3/DtBPF
(DtBPF)PdCl2
(DtBPF)PdBr2
(DtBPF)Pdl2
(DCPF)PdCl2
(DiPPF)PdCl2
(DPPF)PdCl2
NR
88
89
12
42
14
NR
a Reaction conditions: 3 mmol of 4-chlorotoluene, 3.3 mmol of propiophenone,
0.06 mmol of catalyst, 3.3 mmol of NaOtBu, 3 mL of THF, 60 °C, 3 h reaction
time. b Conversion was determined by GC.
in a cross-coupling reaction such as palladium precursor, ligand,
additive, solvent, temperature, in situ vs fully formed catalyst,
etc., and there are, correspondingly, a large number of protocols
for accomplishing the transformation, the choice of which
depends on the electronic and steric match between the catalysts
and the reactants. In this study, we investigated the role of these
parameters and protocols, with a view to develop economically
viable and environmentally friendly processes relevant to the
fine chemical and pharmaceutical industries. The results of the
study are discussed below.
Results
Figure 1 shows the various preformed Pd complexes of bis-
phosphinoferrocenes employed in the study. All these catalysts
have been isolated in very good yield and purity and are
commercially available through Johnson Matthey Catalysis and
Chiral Technologies. Based on our experience in catalysis, in
general, we prefer preformed catalysts, as Pd-catalysts generated
in situ require high catalyst loadings and therefore may suffer
from reproducibility issues. In addition, certain free ligands such
as tris- tert- butylphosphine employed in coupling are often air
sensitive or even pyrophoric.
Effect of the Catalyst on the r-Arylation of Propiophe-
none with 4-Chlorotoluene. The structure–activity relation-
ship of the catalysts (1,1′-bis(phosphinoferrocene)palla-
diumdihalide)wasstudiedintheR-arylationofpropiophenone
with an electron-neutral substrate, 4-chlorotoluene, in the
presence of NaOtBu base at 60 °C with 1 M sub-
strate concentration in THF. Table 1 summarizes the
relative activities of both isolated as well as in situ
catalysts. As expected, among the preisolated catalysts,
the activity increased in the order: Ph < i-Pr < Cy <
t-Bu. This observation was similar to our earlier observa-
tion on Suzuki coupling of aryl chlorides.10 The DtBFP-
based catalysts (DtBPF)PdX2 (X ) Br, Cl) gave moderate
to high conversions within 3 h (Table 1, entries 2 and 3),
while the corresponding in situ system, Pd2(dba)3/DtBPF
The type of the base and its ratio to the substrates are also
important factors in the R-arylation of ketone enolates. Inves-
tigation of different alkoxide bases in the model reaction showed
that NaOtBu was the best base of choice (Table 2, entries 1–5).
Although bis-silylamides have been previously shown to work
in the R-arylation of ketones with aryl bromides and iodides,3c
in our model reaction involving an aryl chloride substrate in
the presence of (DtBPF)PdCl2 catalyst, KN(Me3Si)2 has led to
modest conversion (Table 2, entry 7). Other inorganic bases
(e.g., hydroxides, carbonates, or phosphates) have given no
arylation products, presumably due to their poor basicity to
(12) (a) (DiPrPF)PdCl2: P-Pd-P ) 103.59. Elsagir, A. R.; Gassner, F.;
Gorls, H.; Dinjus, E. J. Organomet. Chem. 2000, 597, 139. (b)
(DCPF)PdCl2: P-Pd-P ) 102.45; see ref 23. (c) (DMPF)PdCl2: P-
Pd-P ) 99.3; Bianchini, C.; Meli, A.; Oberhauser, W.; Parisel, S.;
Passaglia, E.; Ciardelli, F.; Gusev, O. V.; Kal’sin, A. M.; Vologdin,
N. V. Organometallics 2005, 24, 1018. (d) (DPPF)PdCl2: P-Pd-P )
97.98; Butler, I. R.; Cullen, W. R.; Kim, T. J.; Rettig, S. J.; Trotter,
J. Organometallics 1985, 4, 972.
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523

Chart 1. Solvent effect in the
bis(phosphinoferrocene)palladium dichloride-catalysed
arylations
eroaryl halides is known to pose problems, due to the base
sensitivity of these substrates. Therefore, we investigated the
effect of the base in the arylation of propiophenone with
2-bromopyridine, under various reaction conditions (Table 2,
entries 8–17) using (DtBPF)PdCl2 catalyst. Although the
reaction proceeded at room temperature with the full consump-
tion of 2-bromopyridine in the presence of NaOtBu base, only
46% of the coupled product was observed. The remaining
starting material was consumed by the base concomitantly,
therefore limiting the complete formation of the desired product.
In an attempt to limit the residence time of the unreacted
2-bromopyridine with the base, controlled addition of the
substrate or base was performed in a dropwise manner. The
results shown in Table 2, entries 9 and 10 suggest that even
when the reagent addition is controlled, the reaction of the
substrate with the base competes with the coupling reaction,
leading again to the moderate formation of the arylated product.
When weaker bases, such as NaN(Me3Si)2 and KN(Me3Si)2,
were investigated at rt, only 30–40% conversion to the desired
product was observed. Notably, in the case of these bases, the
starting material 2-bromopyridine was not fully consumed by
the base even after 24 h of reaction time. Decreasing the
substrate concentration or increasing the amount of base did
not have any effect on the product conversion (Table 2, entries
14 and 15), while increasing the temperature to 60 °C gave
moderate conversion (Table 2, entry 16). Interestingly, under
similar conditions, 2-chloropyridine also gave 60% conversion
(Table 2, entry 18). We have not yet made any attempts to
further optimize the reaction by increasing the reaction tem-
perature, changing the solvent, and changing the substrate
concentration. Although Buchwald demonstrated an efficient
R-arylation of ketones with halonitroarenes by using Pd-based
bulky monodentate phosphines in the presence of K3PO4 in
conjunction with 20% p-methoxyphenol as additive,14 we
observed no reaction under similar conditions in the (DtBPF)-
PdCl2-catalysed R-arylation of propiophenone with 2-bromopy-
ridine (Table 2, entry 17).
Table 2. Base effect in the (DtBPF)PdCl2-catalysed
r-arylation
catalyst
conv
entry
base
(mol %) solvent time (h) T (°C) (%)a
4-chlorotoluene
THF
1
2
3
4
5
6
7
NaOtBu
1
1
1
1
1
1
1
3
3
3
3
3
3
3
60 80
60 68
KOtBu
THF
NaOiPr
KOMe
NaOMe
LiN(Me3Si)2
KN(Me3Si)2
THF
60
9
THF
60 15
60 33
60 NR
60 24
THF
THF
THF
Scope of (DtBPF)PdCl2-Catalysed r-Arylation. The iden-
tification of the preisolated complexes (DtBPF)PdCl2 and
(DtBPF)PdBr2 as efficient catalysts in the R-arylation of
propiophenone with 4-chlorotoluene prompted us to investigate
their generality with respect to both aryl halides and ketones.
Catalysis using (DtBPF)PdCl2 led to high conversions in the
arylation of various ketones with challenging aryl halides (Table
3). Electron rich and neutral aryl bromides were efficiently
converted to the desired product at room temperature (Table 3,
entries 1 and 3). This methodology (room temperature) also
allowed us to carryout selective arylation using a bromochlo-
roarene substrate, where C-C bond formation occurred only
at the C-Br center (Table 3, entry 2). While electron neutral
aryl chlorides such as 4-chlorotoluene and chlorobenzene
proceeded smoothly at 60 °C in high conversions (Table 3,
entries 9 and 10), the electron rich 4-chloroanisole required
higher temperature to reach high conversion in the reactions
with both aromatic and cyclic ketones such as tetralones (Table
3, entries 6–8).
2-bromopyridine
8
9
NaOtBu
2
2
2
2
2
2
2
2
2
2
THF
24
4
24
3
25 46
110 48
110 48
25 17
25 39
25 33
25 30
25 23
60 50
KOtAmb,c
toluene
toluene
THF
10 KOtAmb,d
11 LiN(Me3Si)2
12 NaN(Me3Si)2
13 KN(Me3Si)2
THF
3
THF
3
e
14 KN(Me3Si)2
THF
3
f
15 KN(Me3Si)2
THF
3
16 KN(Me3Si)2
THF
6
g
17 K3PO4
THF
24
60
6
2-chloropyridine
18 KN(Me3Si)2
2
THF
6
60 62
a Conversion was determined by GC. b 25% solution in toluene. c Base solution
added dropwise over 4 h. d 2-Br-pyridine added slowly over approximately 3 h.
e 0.5 M substrate concentration. f 1.5 equiv KN(Me3Si)2 relative to substrate. g 20
mol % p-methoxyphenol relative to the substrate was added.
generate the ketone enolate, necessary to facilitate the “trans-
metalation” step.
We also decided to study the arylation of heterocyclic halides
due to their importance in the production of pharmaceutically
active ingredients.13 However, the use of a strong base/
nucleophile in the R-arylation using nitrogen-containing het-
(13) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127.
(14) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 15168.
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Table 3. (DtBPF)PdCl2-catalysed r-arylation of aryl bromides and chlorides with various ketones
a Conversion was determined by GC. Isolated yields reported in parentheses. b 47% bis-arylation product. c 2 equiv 4-chloroanisole and 2.2 equiv NaOtBu were used;
bis-arylation product was formed exclusively.
We also tried to understand the effect of substrate, base and
stoichiometry on monoarylation versus diarylation. Sterically
less hindered substrates such as 4-chloroanisole led to both
mono- and bisarylation products even when stoichiometric
amount of the reagents was used (Table 3, entry 4). The
selectivity towards the monoarylated product was however
increased by increasing the amount of base, while the selectivity
to the bisarylated product was improved by using excess of
4-cholroanisole (Table 3, entry 5). 2-Chlorothiophene, a fairly
difficult substrate in coupling reactions, was reacted with
propiophenone at 100 °C in the presence of 2 mol %
(DtBPF)PdCl2 and gave 48% conversion to the desired product
(Table 3, entry 11).
dioxane). The arylation of propiophenone with 4-chloro-
toluene in dioxane (1 M substrate concentration) at 100
°C showed high conversion in the case of both catalysts
at substrate to catalyst ratios (S/C) of 1000 in less than
3 h. Lowering further the catalyst loading to S/C 2000
still gave high conversion in the case of (DtBPF)PdCl2
catalyst, while (DtBPF)PdBr2 catalyst reached 78% con-
version after 24 h (Table 5, entries 4 and 8). Similar
activity tests were also performed using 4-bromoanisole
at much lower catalyst loadings (S/C 10,000), with ca.
90% conversion (Table 5, entries 11 and 14). To our
knowledge this is the lowest catalyst loading that has ever
been reported in an arylation of a ketone.
The versatility of (DtBPF)PdCl2 catalyst has also been tested
in the arylation of various ketones with sterically hindered
substrates (Table 4). While sterically hindered and electron rich
aryl bromides such as 2-methyl-4-bromoanisole proceeded
smoothly at room temperature (Table 4, entries 4–6), highly
sterically hindered substrates such as, 2,6-diisopropyl-bro-
mobenzene gave very low conversions. The effect of the ketone
substrate was also studied by using various acetophenone
derivatives, which reacted efficiently with sterically hindered
aryl halides to give the products in excellent isolated yields,
without the formation of the bisarylated byproducts.
Catalyst Loading Optimization, Scale-Up at Low Cata-
lyst Loadings, Workup and Palladium Removal. The
comparative catalytic activities of (DtBPF)PdCl2 and
(DtBPF)PdBr2 catalysts were tested at lower catalyst
loadings using both aryl chloride and challenging aryl
bromide substrates (Table 5, entries corresponding to fresh
In our preliminary catalyst loading optimization studies
involving an undegassed bottle of a previously opened dioxane,
much lower conversions were observed in comparison to the
freshly opened bottle of solvent (see Table 5). This might be
due to the hygroscopic nature of the dioxane, coupled with the
potential formation of peroxide. It is fairly established that
moisture content in the solvent can affect the enolate formation
in the R-arylation of enolates, while peroxide can poison the
catalyst. Interestingly, when a fresh bottle of anhydrous dioxane
was used, significantly higher conversions were consistently
observed with excellent reproducibility on both 5mmol and
40mmol scale of reactions. This indicates that subtle changes
are important in the process optimization of a catalytic reaction
such as this.
The best reaction conditions were reproduced successfully
on 9-g scale synthesis using (DtBPF)PdCl2 catalyst at S/C 2000
in the case of 4-chlorotoluene substrate (Scheme 1), when the
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525

Table 4. (DtBPF)PdCl2-catalysed r-arylation of ketones with sterically hindered aryl halides
a Conversion was determined by GC. Isolated yields reported in parentheses.
starting materials were consumed within 6 h. A simple workup
procedure involving filtration through a silica pad to remove
solids afforded 96% recovery of the product in >98.5% purity.
The high conversion at low catalyst loading not only enabled
the high yield recovery of the product Via simple filtration but
also facilitated lower residual Pd and Fe contents (48 ppm Pd
and 34 ppm Fe) in the product.15 In the case of 4-bromoanisole
even at much lower catalyst loading (S/C 10000), 95%
conversion was observed within 24 h of the reaction period
(Scheme 2). The unreacted starting materials in this case have
been removed by recrystallization of the crude product from
MTBE/hexane, affording the product in 88% isolated yield,
>99.8% purity, and 6 ppm residual Pd.
Effect Pd/DtBPF Ratio on the r-Arylation of Propiophe-
none with 4-Chlorotoluene. In our preliminary catalyst testing,
we observed that the in situ generated catalyst using Pd2(dba)3
and DtBPF ligand showed no conversion in the model reaction,
where the Pd:DtBPF molar ratio is 1:1, although there are
reports on the use of DtBPF ligand in conjunction with Pd
precursors in Suzuki,16 Buchwald-Hartwig amination,17 ketone
R-arylation,3b and Heck coupling.18 This observation prompted
us to look more closely at the influence of this parameter in
the ketone R-arylation reactions (Table 6). A control experiment
in the absence of DtBPF was performed to ensure no conversion
in the absence of a ligand. When Pd2(dba)3 and DtBPF were
employed in 1:0.5 molar ratio at 1 M substrate concentration,
(15) The same-scale reaction was complete in less than 1 h at S/C 200. In
this case, the higher residual metal content (theoretical, Pd ) 2378
ppm, Fe ) 1250 ppm) was reduced by recrystallization of the crude
product from MTBE/hexane (83% recovery of the product in >99%
purity, found: Pd ) 600 ppm, Fe ) 200 ppm).
(16) Itoh, T.; Mase, T. Tetrahedron Lett. 2003, 46, 3573.
(17) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369.
(18) (a) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2123. (b) Boyles, A. L.; Butler, I. R.; Quayle, S. C.
Tetrahedron Lett. 1998, 39, 7766.
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Table 5. Effect of substrate to catalyst (S/C) ratio and
solvent purity on the activity
Discussion
Scheme 3 represents the catalytic cycle involving a bidentate
fully formed complex. However, complication can occur due
to ꢀ-hydrogen elimination, mono- vs diarylation, and thermo-
dynamic stability of Pd-O coordinated species vs Pd-C
coordinated species in the reductive elimination step.
While much progress has been achieved in the Pd-catalysed
cross couplings of aryl halides and pesudohalides with various
coupling partners, this area is still very much open to the role
of reaction conditions in finding an optimal and practical
“catalyst system”. An ideal catalyst system may be the result
of the apt metal to ligand ratio in addition to the fine balance
of several factors: nature of ancillary ligands (electronic and
steric factors), Pd precursor, solvent, base, additive, and
counterion (from the Pd precursor, base, or aryl electrophile
substrate). The results presented in this study clearly illustrate
the role of these parameters in devising a practical catalyst
system for the arylation of ketones.
As shown in the mechanism, a preformed complex is indeed
superior to the in situ catalyst system, when DtBPF ligand is
used. This is due to the formation of a well-defined species,
and therefore more control in activity and selectivity during the
scale-up. This study also indicates that bis-phosphinoferrocene
PdCl2 catalyst family follows the general trends: electron-rich
substituents favor the oxidative addition of aryl chlorides, while
the steric bulk and bite angle play an active role in the reductive
elimination step (Table 1 and Figure 2). Although theoretically
catalyst activation of the (DtBPF)PdX2 series may lead to the
same active (DtBPF)Pd(0) species, this study suggests that
catalyst activity has been also influenced by the nature of the
halide counterion (Table 1). We are currently studying the
relationship between the nature of the palladium precursor and
activity in coupling reactions (for both preisolated and in situ
systems). We believe that this factor has an important influence
on the precatalyst activation in generating the active Pd(0)
species and, hence, influencing the difference in activity.
fresh dioxane
conv
old dioxane
conv
entry
Pd catalyst
S/C time (h) (%)a time (h) (%)a
4-cholorotolueneb
1
2
3
4
5
6
7
8
(DtBPF)PdCl2
(DtBPF)PdCl2
(DtBPF)PdCl2 1000
(DtBPF)PdCl2 2000
(DtBPF)PdBr2
(DtBPF)PdBr2
(DtBPF)PdBr2 1000
(DtBPF)PdBr2 2000
200
400
1
3
98
99
96
90
97
94
94
78
24
90
24
60
3
24
52
3
NAd
24
NA
100
77
200
400
1
1
24
24
NA
3
42
NA
24
4-bromoanisolec
9
(DtBPF)PdCl2 1000
1
3
24
1
3
24
96
95
91
96
89
80
24
24
24
24
24
24
78
71
51
61
60
49
10 (DtBPF)PdCl2 2000
11 (DtBPF)PdCl2 10000
12 (DtBPF)PdBr2 1000
13 (DtBPF)PdBr2 2000
14 (DtBPF)PdBr2 10000
a Conversion was determined by GC; average of two runs. b 4-chlorotoluene (3
mmol, 355 µL), propiophenone (3.3 mmol, 440 µL), (DtBPF)PdX2 catalyst,
NaOtBu (3.3 mmol, 317 mg), dioxane (3 mL), 100 °C. c 4-bromoanisole (5 mmol,
626 µL), propiophenone (5.5 mmol, 730 µL), (DtBPF)PdX2 catalyst, NaOtBu (5.5
mmol, 530 mg), dioxane (5 mL), 100 °C. d NA ) not available.
Scheme 1. Nine-gram scale r-arylation of 4-chlorotoluene
at S/C 2000
70% conversion to the desired product was observed, while no
conversion was observed when the Pd:L mole ratio was 1:1
(Table 6, entry 2 vs entry 3). A similar behavior was observed
for other Pd precursors such as Pd(OAc)2 and Pd(acac)2 (Table
6, entry 4 vs entry 5 and entry 6 vs entry 7). Interestingly, at
lower substrate concentrations, and hence lower catalyst con-
centrations, a Pd:DtBPF ratio of 1:1 led to modest to moderate
conversions (Table 6, entries 8 and 9). Very interestingly, the
use of the preisolated catalyst (DtBPF)PdCl2 with a formal Pd:
DtBPF ratio of 1:1 led to the highest conversion within 3 h at
1 mol % catalyst loading and 1 M substrate concentration at
60 °C (Table 6, entry 10).
The results in Table 6 suggest that in situ generated catalysts
are highly dependent on the reaction conditions. At high
substrate concentration, the optimum Pd:DtBPF ratio is 1:0.5,
while the activity of the 1:1 Pd:DtBPF system slightly increased
with lowering the substrate concentration. This behavior could
be correlated with the formation of a Pd(0)(DtBPF)2 species
and slow release of the active species Pd(0)(DtBPF) at lower
concentration.11 A similar observation has been made by
Buchwald on the influence of Pd:L ratios in an amination
reaction involving Pd(dba)2/XantPhos under in situ conditions.19
Conclusions
A general protocol for the efficient R-arylation of aryl
chlorides and bromides without the need of special handling
of catalyst, solvent, and reagents was devised efficiently,
although the reactions were performed under inert conditions.
Air-stable (DtBPF)PdX2 (X ) Cl, Br) catalysts were identified
for the arylation of various ketones with a variety of aryl
chlorides and aryl bromides, with excellent yields and selectiv-
ity. This study gives the lowest catalyst loadings (S/C loading
up to 10,000/1) that have been reported for an R-arylation
reaction with very good reproducibility. We have been able to
perform scale up on two substrates and isolated the products in
high yields and purity, with low residual metal in the product
using simple work up procedures. Therefore, our current
technology might be useful for plant scale up involving similar
substrates. Investigation of the Pd:DtBPF ratios of the preformed
and in situ systems in catalysis indicated that the well-defined
catalyst (DtBPF)PdCl2 is a preferred catalyst of choice. The
investigation of this catalyst family in other coupling reactions
Vol. 12, No. 3, 2008 / Organic Process Research & Development
•
527

Scheme 2. Nine-gram scale r-arylation of 4-bromoanisole at S/C 10000
Table 6. Effect of Pd:L ratio and concentration on the
activity
Experimental Section
General. All solvents and reagents were purchased from
commercial sources and used as received. All catalysts, ligands,
or precious metal precursors are commercially available from
Johnson Matthey, Catalysis and Chiral Technologies. Flash
chromatography was performed on silica gel 60, 0.040–0.063
mm (230–400 mesh) (Alfa Aesar) using hexane/methyl-tert-
[S]
Pd:DtBPF
entry
Pd precursor
(mmol/mL) molarratio conv (%)a
1
butyl ether. H and 13C NMR and spectra were recorded on
1
2
3
4
5
6
7
8
9
10
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1
no ligand
1:0.5
1:1
1:1
1:0.5
1:1
1:0.5
1:1
1:1
1:1
NR
70
NR
NR
40
1
Bruker-400 MHz spectrometer at ambient temperature in CDCl3
(Alfa Aesar). GC analyses were performed on a Perkin-Elmer
Autosystem XL gas chromatograph equipped with a Varian CP
SIL 5CB capillary column. All reactions were carried out under
inert atmosphere in 12-place Radleys carousels or in Schlenk
tubes with magnetic stirring, unless otherwise indicated. The
purity of the isolated products was >95% as determined by
1HNMR, GC, and/or elemental analysis. Elemental analyses
were performed by Robertson Microlit Laboratories, Inc.,
Madison, NJ 07904.
1
b
Pd(OAc)2
1
Pd(OAc)2
1
b
Pd(acac)2
1
NR
56
Pd(acac)2
1
Pd2(dba)3
Pd2(dba)3
0.5
0.33
1
35
31
(DtBPF)PdCl2
80
a Conversion was determined by GC. b 2 mol % Pd precursor was used.
Scheme 3. Proposed catalytic cycle for ketone r-arylation
using bis-phosphinoferrocene PdX2 catalysts
General Procedure for r-Arylation of Ketones with Aryl
Halides. (DtBPF)PdCl2 (2 mol %, 0.04 mmol, 26 mg) and
NaOtBu (2.2 mmol, 212 mg) were loaded in a 25 mL Schlenk
tube. The tube was evacuated by performing three vacuum/
nitrogen refill cycles, and 2 mL of anhydrous, degassed THF
or dioxane was injected, followed by the addition of the aryl
halide (2 mmol) and ketone (2 mmol). The resulting mixture
was stirred at the indicated temperature, and conversion was
monitored by GC. The reaction mixture was purified directly
by flash chromatography using 5–10% methyl-tert-butyl ether
(MTBE)/hexane. 2-(2,6-Dimethylphenyl)-1-(3-methoxyphe-
nyl)ethanone (Table 4, entry 15). The general procedure
afforded the title compound in 91% isolated yield (439 mg,
white solid). 1H NMR(CDCl3): δ 7.72 (d, J ) 7.6, 1H, ArH),
7.6 (m, J ) 7.6, 1H, ArH), 7.45 (t, J ) 8.2, 1H, ArH), 7.1 (m,
4H, ArH), 4.39 (s, 2H, CH2(CO)), 3.4 (s, 3H, OCH3), 2.25 (s,
6H, CH3). 13C NMR(CDCl3): δ 197, 160, 138, 137, 132, 130,
128, 127, 120, 119, 113, 55, 40, 20. Elemental analysis: Calcd
C, 80.28; H, 7.13; Found C, 80.41; H, 7.19.
General Procedure for r-Arylation of 4-Chlorotoluene
at Low Catalyst Loadings (Table 5, entries 1–8). (DtBPF)-
PdX2 (X ) Cl, Br) and NaOtBu (3.3 mmol, 317 mg) were
loaded in a Radleys carousel tube. The tube was evacuated by
performing three vacuum/nitrogen refill cycles, and anhydrous
dioxane (3 mL), 4-chlorotoluene (3 mmol, 0.355 mL), and
propiophenone (3.3 mmol, 0.44 mL) were injected. The
resulting mixture was degassed by performing three vacuum/
nitrogen refill cycles, stirred at 100 °C, and conversion
monitored by GC.
as well as the mechanistic and structural studies to understand
the lower activity of (DtBPF)PdI2 in comparison to its analogous
chloride and bromide counterparts are currently under inves-
tigation.
(19) Klingensmith, L. M.; Streiter, E. R.; Barder, T. E.; Buchwald, S. L.
Organometallics 2006, 25, 82.
528
•
Vol. 12, No. 3, 2008 / Organic Process Research & Development

General Procedure for r-Arylation of 4-Bromoanisole
at Low Catalyst Loadings (Table 5, entries 9–15). (DtBPF)-
PdX2 (X ) Cl, Br) and NaOtBu (5.5 mmol, 530 mg) were
loaded in a Radley carousel tube. The tube was evacuated by
performing three vacuum/nitrogen refill cycles and anhydrous
dioxane (5 mL), 4-bromoanisole (5 mmol, 0.626 mL) and
propiophenone (5.5 mmol, 0.73 mL) were injected. The
resulting mixture was degassed by performing three vacuum/
nitrogen refill cycles, stirred at 100 °C, and conversion
monitored by GC.
three vacuum/nitrogen refill cycles and anhydrous dioxane (30
mL), 4-bromoanisole (40 mmol, 5 mL), and propiophenone
(40.4 mmol, 5.4 mL) were injected. The resulting mixture was
degassed by performing three vacuum/nitrogen refill cycles,
lowered in a preheated oil bath at 100 °C, stirred, and conversion
was monitored by GC. After 24 h, the reaction reached 95%
conversion. The flask was cooled down, the resulting mixture
was filtered through a silica pad (10 g), and the silca pad was
washed with 250 mL of MTBE. The filtrate was evaporated
and the resulting sticky white solid was dried under high
vacuum. The GC analysis of the crude solid showed 94%
product, 3% 4-bromoanisole, and 3% propiophenone. The crude
solid was recrystallized from MTBE/hexane (10 mL/200 mL)
at –60 °C, filtered, and dried under high vacuum (8.4 g of white
solid, 35 mmol, 88% isolated yield, >99.5% by GC). 2(4-
methoxyphenyl)-1-phenylpropan-1-one: Elemental analysis:
Calcd. C, 82.05; H, 6.68; Found C, 79.74; H, 6.75. Residual
Pd and Fe content: Theoretical Pd, 44 ppm; Fe, 23 ppm; Found
Pd, 6 ppm; Fe, 13 ppm. 1H NMR(CDCl3): δ 7.95 (d, J ) 7.6,
2H, ArH), 7.45 (t, J ) 7.2, 1H, ArH), 7.36 (t, J ) 7.6, 2H,
ArH), 7.2 (d, J ) 8.4, 2H, ArH),), 6.82 (d, J ) 8.4, 2H, ArH),
4.64 (q, J ) 6.9, 1H, CH(CO)), 3.73 (s, 3H, CH3),1.51 (d, J )
6.8, 3H, CH3). 13C NMR(CDCl3): δ 200, 159,133, 129, 128.8,
128.5, 114, 55, 47, 20.
Scale-up and Isolation of r-Arylation of 4-Chlorotoluene
at S/C 2000. (DtBPF)PdCl2 (S/C 2000, 0.1 mol %, 0.02 mmol,
13 mg) and NaOtBu (40.4 mmol, 4g) were loaded in a 100 mL
Schlenk flask. The flask was evacuated by performing three
vacuum/nitrogen refill cycles, and anhydrous dioxane (30 mL),
4-chlorotoluene (40 mmol, 4.7 mL), and propiophenone (40.4
mmol, 5.4 mL) were injected. The resulting mixture was
degassed by performing three vacuum/nitrogen refill cycles,
lowered in a preheated oil bath at 100 °C and stirred, and
conversion was monitored by GC. After 6 h, the reaction
reached 99% conversion. The flask was cooled down, the
resulting mixture filtered through a silica pad (30 g), and the
silca pad washed with 250 mL MTBE. The filtrate was
evaporated, and the resulting off-white solid was dried under
high vacuum (8.36 g, 37.4 mmol, 96% isolated yield, >98.5%
by GC). 1-Phenyl-2-p-tolylpropan-1-one: Elemental analysis:
Calcd C, 85.79; H, 7.19; Found C, 85.46; H, 7.28. Residual Pd
and Fe content: Theoretical Pd, 238 ppm; Fe, 125 ppm; Found
Acknowledgment
We thank Bill Carole for his assistance in some lab work
on the influence of ketone substrates. Fred Hancock, Johnson
Matthey CCT, is acknowledged for useful discussion and
encouragement of this work.
1
Pd, 48 ppm; Fe, 34 ppm. H NMR (CDCl3): δ 8.07 (d, J )
7.2, 2H, ArH), 7.46 (t, J ) 7.6, 1H, ArH), 7.38 (t, J ) 7.6, 2H,
ArH), 7.23 (d, J ) 8, 2H, ArH),), 7.13 (d, J ) 8, 2H, ArH),
4.7 (q, J ) 6.8, 1H, CH(CO)), 2.3 (s, 3H, CH3),1.57 (d, J )
6.8, 3H, CH3). 13C NMR (CDCl3): δ 200, 139, 136.7, 136.5,
133, 130, 129, 128.5, 128, 47.6, 21, 20.
Supporting Information Available
Copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scale-up and Isolation of r-Arylation of 4-Bromoanisole
at S/C 10000. (DtBPF)PdCl2 (S/C 10000, 0.01 mol %, 0.004
mmol, 2.6 mg) and NaOtBu (40.4 mmol, 4 g) were loaded in
a 100 mL Schlenk flask. The flask was evacuated by performing
Received for review November 1, 2007.
OP7002503
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