α-arylation of ketones using highly active, air-stable (DtBPF)PdX2 (X = Cl, Br) catalysts

Article abstract of DOI:10.1021/ol702430a

α-Arylation of various ketones with aryl chlorides and bromides using the well-defined and air-stable (DtBPF)PdX₂ (X = Cl, Br) catalysts gave 80-100% yield of the coupled products under relatively mild conditions at low catalyst loadings. The X

Full text of DOI:10.1021/ol702430a

ORGANIC
LETTERS
2
007
Vol. 9, No. 26
489-5492
r
-Arylation of Ketones Using Highly
5
Active, Air-Stable (DtBPF)PdX (X
) Cl,
2
Br) Catalysts
Gabriela A. Grasa and Thomas J. Colacot*
Johnson Matthey Catalysis and Chiral Technologies, 2001 Nolte DriVe,
West Deptford, New Jersey 08066
colactj@jmusa.com
Received October 4, 2007
ABSTRACT
r
-Arylation of various ketones with aryl chlorides and bromides using the well-defined and air-stable (DtBPF)PdX
2
(X
)
Cl, Br) catalysts gave
revealed
-catalyzed reaction of
-chlorotoluene with propiophenone indicated that DtBPF remained coordinated in a bidentate mode during the catalytic cycle.
80
−
100% yield of the coupled products under relatively mild conditions at low catalyst loadings. The X-ray structure of (DtBPF)PdCl
2
31
the largest P−Pd−P bite angle (104.2°) for a ferrocenyl bisphosphine ligand. P NMR monitoring of (DtBPF)PdCl
2
4
Toward the end of the last century, there was a paradigm
studied the applications of Pd-based N-heterocyclic carbenes
shift in the area of C-C bond forming reactions, in designing
and diaminochlorophosphines, respectively, for R-arylation
1
6a
6b
complex organic molecules via Pd-catalyzed coupling.
of ketone enolates, while Chan and Buchwald have
independently reported asymmetric R-arylation using chiral
atropoisomeric bisphosphine-based nickel catalysts.
Among the various cross-coupling reactions, such as Heck,
Suzuki, Stille, Sonogashira, Negishi, and Kumada, Pd-
catalyzed R-arylation of carbonyl compounds has emerged
as a powerful new C-C bond forming method. Seminal work
By virtue of their adjustable electronic, steric, and bite
angle properties, bidentate ferrocenylphosphines have be-
come a very important class of ligands in transition-metal-
2
3
from the groups of Hartwig and Buchwald identified
palladium precursors such as Pd(OAc) and Pd (dba) in
7
2
2
3
catalyzed reactions in organic synthesis. 1,1′-Bis-substituted
conjunction with bulky, electron-rich monodentate or biden-
tate phosphines as viable catalytic systems for such trans-
formations. Nolan and Ackerman have also effectively
ferrocenylphosphines have been particularly successful for
a wide range of Pd-catalyzed C-C and C-heteroatom cross-
4
5
8
coupling reactions. Recently, our group has reported the
superior catalytic activity of the air-stable, preformed catalyst
1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichlo-
(
1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; De Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
4
4, 4442. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(4) (a) Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M.;
Nolan, S. P. Org. Lett. 2003, 5, 1479. (b) Viciu, M. S.; Germaneau, R.;
Nolan, S. P. Org. Lett. 2002, 4, 4053. (c) Navarro, O.; Marion, N.; Oonishi,
Y.; Kelly, R. A.; Nolan, S. P. J. Org. Chem. 2006, 71, 685.
(5) Ackermann, L.; Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer,
A. Angew. Chem., Int. Ed. 2006, 45, 7627.
(d) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; VCH: Weinheim, Germany, 1998. (e) Corbet, J.-P.; Mignani, G.
Chem. ReV. 2006, 106, 2651.
(2) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234 (see
references therein). (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
1
1
1
999, 121, 1473. (c) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
997, 119, 12382. (d) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
999, 121, 1473.
(6) (a) Chen, G.; Kwong, F.; Chan, H. O.; Yu, W.-Y.; Chan, A. S. C.
Chem. Commun. 2006, 1413. (b) Spielvogel, D. J.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 3500.
(7) (a) Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH: Weinheim,
Germany, 1995. (b) Stepnicka, P. Ferrocenes: From Materials and
Chemistry to Biology; Wiley: Chichester, UK, in press.
(
3) (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,
25, 11818.
(
1
1
0.1021/ol702430a CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/22/2007

ride (DtBPF)PdCl
2
in Suzuki coupling of a wide variety of
The X-ray structure determination of (DtBPF)PdCl
ure 2) has been useful in explaining the structure-activity
2
(Fig-
aryl chlorides.9 In continuation of our studies toward
developing simple and elegant catalytic processes for C-C
bond forming reactions, we report herein the application
2
studies of (DtBPF)PdCl and its analogous bromide complex
in the R-arylation of ketone enolates with aryl bromides and
chlorides. We also report the X-ray crystal structure of
2
(DtBPF)PdCl with a view to understand its unique catalytic
activity in comparison to the respective in situ catalytic
systems and other examples of palladium complexes of 1,1′-
bis-substituted, bidentate ferrocenylphosphines.
Figure 1 illustrates the various Pd complexes of ferroce-
Figure 2. (DtBPF)PdCl
angles (deg): Pd-P1 2.3466(16), Pd-P2 2.3503(15), Pd-Cl1
2
complex. Selected bond lengths (Å) and
2
Figure 1. Bis(phosphino)ferrocene-PdX complexes.
2
.3607(15), Pd-Cl2 2.3532(15); P1-Pd-P2 104.22(5), Cl1-Pd-
Cl2 83.66(5), P1-Pd-Cl2 159.98(6), P2-Pd-Cl2 88.17(5), P1-
Pd-Cl1 88.74(5), P2-Pd-Cl1 160.82(5).
nylphosphines employed in this study, while Table 1 shows
their relative reactivity in the arylation of a model system
relationship of the catalyst. As shown in Figure 2, Pd has a
distorted square planar geometry with the two phosphorus
atoms in a cis configuration. Notably, the P-Pd-P bite angle
Table 1. Performance of Pd-Bisphosphinoferrocene-Based
Catalysts in the Arylation of Propiophenone with
of the bidentate ligand in (DtBPF)PdCl
2
is the largest
4
-Chlorotoluenea
(
104.22°) in the series of bisphosphinoferrocene complexes
b
8a,11
entry
precatalyst
conv (%)
of PdCl
2
.
This is in agreement with the X-ray structure
of an oxidative addition product, (DtBPF)Pd(Br)(4-CN-
1
2
3
4
5
6
7
(DPPF)PdCl2
(DiPPF)PdCl2
(DCPF)PdCl2
(DtBPF)PdCl2
(DtBPF)PdBr2
(DtBPF)Pdl2
NR
14
42
88
89
1
2
C
6
H
5
) (104.28°), reported by Hartwig et al. Although the
reported bite angle of the isopropyl analogue (DiPPF)PdCl
2
1
1a
is 103.95°, this catalyst has not been very active for
9
R-arylation and aryl chloride Suzuki coupling. This suggests
12
NR
that, in addition to the larger bite angle, the bulky, electron
rich t-Bu groups on the phosphorus atoms play a crucial role
in providing the apt electronic and steric balance necessary
to facilitate the oxidative addition and subsequent reductive
elimination steps during the coupling of challenging sub-
strates, such as aryl chlorides.
Pd2(dba)3/DtBPF
a
Reaction conditions: 3 mmol of 4-chlorotoluene, 3.3 mmol of
propiophenone, 0.06 mmol of catalyst, 3.3 mmol of NaO Bu, 3 mL of THF,
0 °C, 3 h reaction time. Conversion was determined by GC.
t
b
6
2 3
The in situ catalyst system generated from Pd (dba) and
(
1
propiophenone with electron neutral para-chlorotoluene) at
M substrate concentration in THF solvent at 60 °C for a
reaction period of 3 h. Both (DtBPF)PdCl and (DtBPF)-
PdBr led to high conversions, while the Pd dba /DtBPF in
DtBPF ligand in 1:1 molar ratio has shown no activity in
the model reaction after 3 h (Table 1, entry 7), although there
are reports on the use of DtBPF ligand in conjunction with
2
2
2
3
1
3
14
Pd precursors in Suzuki, Buchwald-Hartwig amination,
situ generated catalyst gave no activity under identical
conditions (Table 1, entries 4 and 5 vs entry 7). Among the
preformed catalysts, the activity increased in the order Ph
(9) Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731.
(10) Hagopian, L. E.; Campbell, A. N.; Golen, J. A.; Rheingold, A. L.;
Nataro, C. J. Organomet. Chem. 2006, 691, 4890.
<
i-Pr < Cy < t-Bu. This observation was similar to our
(
11) (a) (DiPrPF)PdCl2: P-Pd-P ) 103.59°: Elsagir, A. R.; Gassner,
9
earlier observation on Suzuki coupling of aryl chlorides and
F.; Gorls, H.; Dinjus, E. J. Organomet. Chem. 2000, 597, 139. (b) (DCyPF)-
PdCl2: P-Pd-P ) 102.45°: see ref 10. (c) (DMPF)PdCl2: P-Pd-P )
9.3°: Bianchini, C.; Meli, A.; Oberhauser, W.; Parisel, S.; Passaglia, E.;
10
Buchwald-Hartwig aminations. Surprisingly, (DtBPF)PdI
catalyst gave only 12% conversion.
2
9
Ciardelli, F.; Gusev, O. V.; Kal’sin, A. M.; Vologdin, N. V. Organometallics
2
005, 24, 1018. (d) (DPPF)PdCl2: P-Pd-P ) 97.98°: Butler, I. R.; Cullen,
(
8) (a) Colacot, T. J.; Parisel, S. Ferrocenes: From Materials and
W. R.; Kim, T. J.; Rettig, S. J.; Trotter, J. Organometallics 1985, 4, 972.
(12) Mann, G.; Shelby, Q.; Roy, A. H.; Hartwig, J. F. Organometallics
2003, 22, 2775.
Chemistry to Biology; Wiley: Chichester, UK, in press. (b) Colacot, T. J.
Chem ReV. 2003, 103, 3101 (see 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.
(13) Itoh, T.; Mase, T. Tetrahedron Lett. 2003, 46, 3573.
(14) Hamann, B. C.; Hartwig, J. F. J. Am. Chem Soc. 1998, 120, 7369.
5490
Org. Lett., Vol. 9, No. 26, 2007

2b
15
ketone R-arylation, and Heck coupling. This observation
prompted us to have a closer look at the influence of
stoichiometry of Pd:DtBPF in the ketone R-arylation reac-
tions (Table 2). A control experiment performed in the
Scheme 1
Table 2. Effect of Pd:L Ratio and Concentration on the
Activity
[
S]
Pd:DtBPF
mole ratio
conva
(%)
entry
Pd precursor
(mmol/mL)
1
2
3
4
5
a
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1
1
0.5
0.33
1
no ligand
1:0.5
1:1
1:1
1:1
NR
70
35
31
80
peak characteristic of (DtBPF)PdCl
completely disappeared during the catalytic cycle with the
2
complex (∼63 ppm)
formation of a new singlet at ∼54 ppm. This singlet could
(DtBPF)PdCl2
2b,12
be attributed to an active catalytic species, (DtBPF)Pd(0).
2b
Conversion was determined by GC.
The absence of a peak at ca. 25 ppm, characteristic of a
mono-uncoordinated bidentate ligand, unlike in the case of
the stoichiometric reaction, indicates that DtBPF ligand
possibly retains its bidentate coordination mode during
catalysis, under these conditions. The fact that no transient
species are detected in the NMR time scale suggests that
2
absence of DtBPF gave no reaction. Interestingly, when Pd -
(dba)
3
and DtBPF were employed in a 1:0.5 molar ratio at
1
M substrate concentration, 70% conversion to the desired
product was observed (Table 2, entry 2 vs Table 1, entry 7).
However, at lower substrate/catalyst concentrations, a Pd:
DtBPF ratio of 1:1 gave modest to moderate conversions
2
18
(
η -DtBPF)Pd(0) could be the ground state of the reaction.
The identification of the pre-isolated complexes (DtBPF)-
PdCl and (DtBPF)PdBr as efficient catalysts in the R-ary-
2
2
(
Table 2, entries 4 and 5). Very interestingly, the preformed
complex, (DtBPF)PdCl , with a formal Pd:DtBPF ratio of
:1 gave the highest conversion within 3 h at 1 mol %
catalyst loading, even at high substrate concentration (Table
, entry 6). The above results indicate that, for the in situ
lation of propiophenone with 4-chlorotoluene prompted us
to investigate their generality with respect to various other
2
1
2
substrates. Catalysis using (DtBPF)PdCl led to high conver-
sions at room temperature in the arylation of propiophenone
2
1
6
systems, the optimum Pd:DtBPF ratio is 1:0.5. This
difference in reactivity behavior could be explained based
Table 3. Room Temperature (DtBPF)PdCl
R-Arylation of Aryl Bromides
2
-Catalyzed
n
on the formation of Pd(0)(DtBPF) and differential release
of the ligand to form the active species at various ligand
ratios and concentrations. This is in agreement with Buch-
wald’s observations on the influence of Pd:L ratios in
1
7
amination using Pd(dba)
Hartwig also observed that a Pd(dba)
2
/XantPhos in situ systems.
/DtBPF molar ratio
2
2b
31
of 1:0.5 is optimal in the R-arylation of ketones. Using P
NMR spectroscopy, his group monitored the stoichiometric
reaction of the oxidative addition product and postulated that
one of the phosphorus atoms may decoordinate to form a
tricoordinate palladium center upon enolate coordination. To
test this hypothesis, we also monitored the fate of the
preformed (DtBPF)PdCl
Scheme 1).
While reacting 4-chlorotoluene with propiophenone in
THF-d at 1 M substrate concentration, in the presence of
NaO Bu base and 5 mol % of (DtBPF)PdCl loading, 24%
conversion was observed after 2 h at rt. Furthermore, the
2
catalyst in R-arylation by NMR
(
8
t
2
(
15) (a) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
999, 121, 2123. (b) Boyles, A. L.; Butler, I. R.; Quayle, S. C. Tetrahedron
Lett. 1998, 39, 7766.
16) A reviewer suggested that free dba ligand released from the reaction
a
Conversion was determined by GC. Isolated yields reported in
1
parentheses. b With 0.1 mol % of (DtBPF)PdCl2, 100 °C, dioxane.
(
of Pd2(dba)3 with DtBPF might inhibit the catalysis. We are also currently
studying the reaction of Pd2(dba)3 with DtBPF at different stoichiometries.
with challenging aryl bromides (Table 3). Electron-rich
substrates as well as sterically hindered substrates were
(17) Klingensmith, L. M.; Streiter, E. R.; Barder, T. E.; Buchwald, S.
L. Organometallics 2006, 25, 82.
Org. Lett., Vol. 9, No. 26, 2007
5491

efficiently converted to the desired product under mild
reaction conditions (Table 3, entries 2-6 and 8). However,
highly sterically hindered substrates, such as 2,6-diisopro-
pylbromobenzene, gave very low conversions. This method
Table 5. Effect of the Ketone Substrate in the
(
DtBPF)PdCl -Catalyzed R-Arylation
2
(room temperature) also allowed us to carry out selective
arylation using a dihalogenated arene substrate, where
coupling occurred only at the C-Br center (Table 3, entry
2
1). (DtBPF)PdCl was tested at low loadings (S/C 1000/1)
for an unactivated bromide with high conversion (Table 3,
entry 3).
The activity of (DtBPF)PdCl catalyst in the ketone
2
R-arylation was tested using very challenging aryl chloride
substrates (Table 4). While sterically hindered aryl chlorides,
Table 4. Effect of the Aryl Chloride Substrate in the
(
DtBPF)PdCl -Catalyzed R-Arylation of Propiophenone
2
a
Conversion was determined by GC. Isolated yields reported in
a
b
Conversion was determined by GC. Isolated yields reported in
parentheses. The reaction was performed using dioxane at 100 °C.
parentheses. b 47% bisarylation product determined by GC.
such as 2-chloro-m-xylene and chloromesitylene, proceeded
smoothly at 60 °C in high conversions (Table 4, entries 1-6),
the electron-rich 4-chloroanisole required higher temperature
to reach full conversion (Table 4, entry 7). Inversely, the
effect of the ketone substrate was also studied using difficult
aryl chlorides, such as 2-chloro-m-xylene and 4-chloroanisole
In conclusion, we have identified well-defined and air-
stable (DtBPF)PdX (X ) Cl, Br) catalysts for the arylation
2
of various ketones with aryl chlorides and bromides in
excellent yields, under mild reaction conditions, and low
catalyst loadings (S/C loading up to 1000/1) with very good
reproducibility, in comparison to the respective in situ
systems. Preliminary NMR investigation of the Pd:DtBPF
ratios of the preformed and in situ systems in catalysis
(
Table 5). Various acetophenone derivatives reacted effi-
ciently with sterically hindered 2-chloro-m-xylene to give the
products in excellent isolated yields (Table 5, entries 1-6).
We also tried to understand the effect of substrate, base,
and stoichiometry on monoarylation versus diarylation.
Sterically crowded aryl halides (e.g., 2-chloro-m-xylene) gave
only monoarylation products, while sterically less hindered
substrates such as 4-chloroanisole led to both mono- and
bisarylation products even when stoichiometric amounts of
the reagents were used (Table 4, entry 7). The selectivity
toward the monoarylated product was, however, increased
by increasing the amount of base, while the selectivity of
the bisarylated product was improved by using excess of
indicates that the well-defined catalyst (DtBPF)PdCl
preferred choice. The mechanistic and structural studies to
understand the lower activity of (DtBPF)PdI , in comparison
2
is a
2
to that of its analogous chloride and bromide counterparts,
are in progress.
Acknowledgment. We thank Dr. Glenn Yap of Univer-
sity of Delaware for X-ray structure determination. Fred
Hancock and Bill Tamblyn, Johnson Matthey CCT, are
acknowledged for useful discussion and encouragement.
Supporting Information Available: Experimental pro-
cedures, characterization data, and a X-ray crystallographic
4-chloroanisole (Table 5, entry 8).
t
2
data of (DtBPF)PdCl . This material is available free of
charge via the Internet at http://pubs.acs.org.
(
18) No free ArP Bu2 due to DtBPF cleavage under catalytic R-arylation
conditions was observed. For DtBPF cleavage under O-arylation conditions,
see: Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem Soc.
2
000, 122, 10718.
OL702430A
5492
Org. Lett., Vol. 9, No. 26, 2007