Palladium-catalyzed synthesis of diarylmethanes: Exploitation of carbanionic leaving groups

Article abstract of DOI:10.1021/ol900874z

A novel route to the synthesis of diarylmethanes via a Pd-catalyzed α-arylation of benzyl ketones is rseported. By harnessing the inherent reactivity of enolates, it is possible to circumvent the need for a transmetalating reagent such as boron for the co

Full text of DOI:10.1021/ol900874z

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2575-2578
Palladium-Catalyzed Synthesis of
Diarylmethanes: Exploitation of
Carbanionic Leaving Groups
Jason R. Schmink and Nicholas E. Leadbeater*
Department of Chemistry, UniVersity of Connecticut, 55 North EagleVille Road,
Storrs, Connecticut 06269-3060
nicholas.leadbeater@uconn.edu
Received April 21, 2009
ABSTRACT
A novel route to the synthesis of diarylmethanes via a Pd-catalyzed r-arylation of benzyl ketones is reported. By harnessing the inherent
reactivity of enolates, it is possible to circumvent the need for a transmetalating reagent such as boron for the coupling. Additionally, the two
phenyl rings of the intermediate are exploited to stabilize the high-energy carbanionic leaving group in a straightforward synthesis.
Palladium-catalyzed carbon-carbon bond formation contin-
ues to be a powerful synthetic organic tool.1 Thus, it is no
surprise that the palladium-catalyzed synthesis of diaryl-
methanes has received much attention recently. The cross-
coupling of arylboronic acids with benzyl halides2,3 or benzyl
phosphates,4 coupling of aryltrifluoroborates with benzyl
halides,5 and the coupling of benzyl indium reagents with
aryl iodides6 illustrate a few recent approaches in the
synthesis of diarylmethanes. Although the use of transmet-
allating reagents in palladium-catalyzed carbon-carbon bond
formation continues to be a powerful synthetic technique,
these reagents are often synthesized from the corresponding
halides and thus reduce overall atom economy for the
transformation. As a result, the development of selective
cross-coupling reactions that avoid a transmetalating event
is highly desirable. Given that the diarylmethane motif is
found in a range of biologically active compounds and
pharmaceuticals, in our laboratory we have been seeking
approaches to their synthesis that avoid a transmetallating
reagent and employ ligand-free palladium catalysts at low
loadings (i.e., e 0.1 mol %).
The simultaneous publications by Buchwald7 and Hartwig8
in 1997 describing palladium-catalyzed R-arylation of ke-
tones illustrate an attractive approach to carbon-carbon bond
formation, as it takes advantage of the inherent reactivity of
enolates and avoids a transmetalating reagent. Despite the
many advantages and further development of this chemistry
over the past decade,9 to our knowledge there is no report
that avoids the use of either activating phosphine or N-
heterocylic carbene ligands to affect this reaction. Thus, we
wanted to probe the feasability of performing the R-arylation
(1) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol. 1.
(2) For the first reported example of a Suzuki-Miyaura coupling with
a benzyl halide, see: Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994,
59, 6501
.
(7) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(8) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(9) For representative examples, see: (a) Culkin, D. A.; Hartwig, J. F.
Acc. Chem. Res. 2003, 36, 234. (b) Viciu, M. S.; Germaneau, R. F.; Nolan,
S. P Org. Lett. 2002, 4, 4053. (c) Grasa, G. A.; Colacot, T. J. Org. Lett.
2007, 9, 5489. (d) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545. (e)
Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc. 2008, 130,
10510.
(3) For recent examples, see: (a) Nobre, S. M.; Montiero, A. L.
Tetrahedron Lett. 2004, 45, 8225. (b) Burns, M. J.; Fairlamb, I. J. S.; Kapdi,
A. R.; Sehnal, P.; Taylor, R. J. K. Org. Lett. 2007, 9, 5397
(4) McLaughlin, M. Org. Lett. 2005, 7, 4875.
.
(5) Molander, G. A.; Elia, M. D. J. Org. Chem. 2006, 71, 9198.
(6) Chupak, L. S.; Wolkowski, J. P.; Chantigny, Y. A. J. Org. Chem.
2009, 74, 1388.
10.1021/ol900874z CCC: $40.75
Published on Web 05/20/2009
 2009 American Chemical Society

of ketones using simple ligandless palladium catalysts.
Application of microwave heating in Suzuki and Heck
couplings has allowed us to affect these similar palladium-
catalyzed transformations rapidly and with extremely low
loadings of ligandless palladium in aqueous reaction me-
dia.10-12
Table 2. Electronic Studies into the Diarylation of
Acetophenonea
We began our studies by investigating the coupling of
acetophenone with 2 equiv of 4-bromoanisole to form 1a.
We chose to perform the reactions under phase-transfer
conditions in a water-sodium hydroxide-tetrabutylammonium
bromide (TBAB) mix and using a commercially available
palladium ICP standard solution as a convenient ligandless
palladium source (0.1 mol %). Immediately, we noticed that
whereas we were able to isolate diarylated product 1a in
moderate yield after 20 min of heating at 150 °C (Table 1,
entry
R
conversionb to 1 (%)
conversion to 2 (%)b
A
B
C
D
-OCH3
-H
-CH3
>95
91
89
tr
9
11
48
-F
52
a Conditions: 1.0 mmol of acetophenone, 2.1 mmol of aryl bromide,
0.5 mmol of TBAB, 2.0 mL of 2.0 M NaOH(aq), 0.025 mol % PdCl2 (based
on aryl bromide), 100 °C, 20 h. b Ratios of 1:2 as determined by 1H NMR;
in all cases consumption of aryl bromide starting material was complete.
Table 1. Optimization of Conditions for the Diarylation of
Acetophenone with 4-Bromoanisolea
entry a), when electron-neutral or electron-poor systems were
used, the conversion to the diarylated products dropped
significantly (Table 2, entries b-d). Of interest, however,
was the observation of diarylmethanes as byproduct. Indeed,
in the case of 1-bromo-4-fluorobenzene, a significant amount
of 4,4′-difluorodiphenylmethane (2d) was isolated. This
electron-poor system is likely better able to stabilize the
carbanionic diarylmethane leaving group. This observation
helped to explain why yields suffered initially when the
reaction between acetophenone and 4-bromoanisole was
performed at higher temperatures. While there are limited
examples of isolating diarylmethanes from the corresponding
ketone intermediates for characterization purposes,13 the
authors are not aware of any systematic approach employing
this methodology in order to synthesize these moieties. As
a result, we felt that this mechanistically interesting route to
diarylmethanes warranted further exploration.
entry
time (h)
tempb
Pd (mol %)c
yield (%)d
1
2
3
4
5
6
7
8
0.33
0.5
1
0.5
7
20
20
20
150
150
150
130
110
100
100
100
0.1
0.1
0.1
0.05
0.05
0.05
0.025
0.005
73
63
64
81
90
95
95
58/28/14e
a Conditions: 1.0 mmol of acetophenone, 2.1 mmol of 4-bromoanisole,
0.5 mmol of TBAB, 2.0 mL of 2.0 M NaOH(aq). b Entries 1-5 performed
using microwave heating, entries 6-9 carried out in a thermostatted oil
bath. c Loading based upon aryl bromide. d Isolated yields. e Relative ratio
of diarylated product:monoarylated product:acetophenone.
We moved from acetophenone to deoxybenzoin as the
ketone coupling partner in order to optimize conditions for
generating benzylated coupling product 3a. We reasoned that
additional equivalents of NaOH should not only accelerate
the rate of the reaction but would be necessary because of
entry 1), extending the reaction time to 30 or 60 min resulted
in a decrease in yield (Table 1, entries 2 and 3). Reducing
the reaction temperature and catalyst loading while extending
the time did, however, show an overall increase in isolated
yields, leading to an optimized set of reaction conditions of
0.025 mol % Pd, 100 °C for 20 h, which provided a 95%
isolated yield of the diarylated product (Table 1, entry 7).
Although the reaction progresses at even lower catalyst
loadings, it was deemed unreasonably sluggish (Table 1,
entry 8).
Table 3. Optimization of the Formation of
4-Methoxy-diphenylmethane from Deoxybenzoin and
4-Bromoanisolea
Our next step was to perform a small screen of three
additional substrates to probe the effects of changing the aryl
bromide coupling partner. While the optimized conditions
worked well for the electron-rich 4-bromoanisole (Table 2,
entry
reaction time and temperature
conversion (%)c
1
2
3
150 °C, 60 min
150 °C, 90 min
130 °C, 30 min; 160 °C, 30 min
90b
65
>95 (91)d
(10) For a review see: Leadbeater, N. E. Chem. Commun. 2005, 2881
(11) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.;
Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161
(12) Arvela, R. K.; Leadbeater, N. E. J. Org. Chem. 2005, 70, 1786
.
a Conditions: 1.1 mmol of deoxybenzoin, 1.0 mmol of 4-bromoanisole,
2.5 mL of 3.0 M NaOH(aq), 0.1 mol % PdCl2. b 0.2 mol % PdCl2.
c Conversion to desired product relative to arylated intermediate determined
by 1H NMR; consumption of 4-bromoanisole was complete. d Isolated yield.
.
.
(13) (a) Lagrave, R. Ann. Chim. 1927, 8, 363. (b) Koelsch, C. F. J. Am.
Chem. Soc. 1931, 53, 1147
.
2576
Org. Lett., Vol. 11, No. 12, 2009

With optimized conditions in hand, we screened a number
of aryl bromides to probe the scope and limitations of this
new methodology. A wide range of substrates could be used
in the coupling with success, the notable exception being
4-bromoaniline (Table 4, entry j), which afforded no product
nor any arylated intermediate, instead returning only starting
materials. The methodology allowed for the chemoselective
coupling of 1-bromo-4-chlorobenzene (Table 4, entry e), just
the bromo functionality being involved in the reaction,
although with slightly attenuated reactivity. Moderate con-
version was achieved using 1-bromonaphthlene (Table 4,
entry k), though there was no reaction with the more
sterically demanding 2-bromo-toluene (Table 4, entry l).14
The reaction could be extended to use a vinyl bromide
coupling partner. Using ꢀ-bromostyrene afforded the desired
ꢀ-benzylstyrene (3n) in moderate yield. However, due to
competitive decomposition of the ꢀ-bromostyrene, 2.4 equiv
of the vinyl bromide had to be used in order to ensure
complete consumption of the deoxybenzoin starting material.
In order to gain further insight into the reaction, we sought
to couple aryl bromides with substituted deoxybenzoins. It
became apparent that the nature of the substituent on the
deoxybenzoin had a more pronounced impact upon the rate
of the reaction than that of the aryl bromide. Only the
couplings with the electronically similar R-(4′-methylphe-
nyl)acetophenone (Table 5, entries 1-3) resulted in complete
Table 4. Synthesis of Diarylmethanes from Deoxybenzoina
Table 5. Synthesis of Substituted Diarylmethanesa
entry
R
R′
product
yield (%)b
50c d
,
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
Cl
Cl
Cl
Cl
OCH3
OCH3
4-Cl
4-Ph
4-OCH3
4-F
4-CH3
3-Cl
OCH3
4-Cl
3,5-(OCH3)2
4a
4b
4c
4d
4a
4e
4f
87c
83
80
95
62
82
(15/10/75)e
(-/10/90)e
a Conditions: 1.0 mmol of aryl bromide, 1.1 mmol of deoxybenzoin,
0.5 mmol of TBAB, 2.5 mL of 3.0 M NaOH(aq), 0.1 mol % PdCl2,
microwave heating, 130 °C for 30 min followed by 160 °C for 30 min.
b Isolated yields. c Additionally, 32 mg of 4,4′-bis(trifluoromethyl)biphenyl
was isolated. d 60 min at 130 °C followed by 30 min at 160 °C. e 0.5 mmol
dibromobenzene. f 1.0 mmol of deoxybenzoin, 2.4 mmol of ꢀ-bromostyrene,
E/Z ratio assigned by 1H NMR integrations of the ꢀ-bromostyrene and the
isolated product.
4f
4g
a Conditions: identical to Table 4, but 130 °C for 1 h followed by 160
°C for 1 h. b Isolated yields. c 130 °C for 30 min followed by 160 °C for
30 min. d 15 mg of the symmetric 4,4′-dichlorobiphenyl side product was
isolated. e Relative conversion of product:arylated intermediate:starting
1
deoxybenzoin as determined by H NMR of the crude product mixture.
consumption of the starting aryl bromide after 60 min. All
other reactions required longer reaction times and were run
at 130 °C for 1 h followed by an additional 1 h at 160 °C in
order to consume all of the starting aryl bromide. The
attenuated reactivity of a slightly electron-rich deoxybenzoin
versus a slightly electron-poor one can be seen in the two
the equivalent of benzoic acid that is generated as the reaction
progresses. We undertook a screen of reaction conditions
using 1 equiv of 4-bromoanisole and 3.0 M aqueous sodium
hydroxide as solvent (Table 3). Our optimal conditions
involved a two-stage process, namely, heating the reaction
mixture to 130 °C and holding at this temperature for 30
min before increasing to 160 °C for a further 30 min (Table
3, entry 3).
(14) A trace of the arylated intermediate, 2-(2-methyl-phenyl)deoxy-
1
benzoin, in the crude mixture was detected by H NMR.
Org. Lett., Vol. 11, No. 12, 2009
2577

orthogonal syntheses of 4f (Table 5, entries 7 and 8). Placing
the chlorine moiety on the deoxybenzoin and reacting with
4-bromoanisole (Table 5, entry 7) affords 4f in a moderate
82% isolated yield, but reversal of the substitution pattern
(Table 5, entry 8) reduces the reactivity dramatically, and
after 2 h the crude reaction mixture contains only ap-
proximately 15% of 4f. Similar effects are seen in the two
syntheses of 4a. Reacting 4-bromotoluene with the chlori-
nated deoxybenzoin (Table 5, entry 5) affords the product
in 95% isolated yield, but upon reversal of the substitution
pattern (Table 5, entry 1) only 50% of 4a is isolated.
In conclusion, we have reported a novel, ligand-free,
palladium-catalyzed route to the synthesis of diarylmethanes
carried out in water. This route takes advantage of the
inherent reactivity of enolates toward palladium-catalyed
coupling, hence eliminating the need for a transmetalating
reagent. The use of microwave heating facilitates the
methodology and enables facile access to the elevated
temperatures required. Computational and kinetic investiga-
tions are currently underway to explore this mechanism in
greater detail, and the results will be reported in due course.
Acknowledgment. The authors thank CEM Corp. for
microwave equipment support. ACS-PRF 45433-AC1 is
thanked for funding.
Supporting Information Available: Experimental pro-
cedures and NMR spectral data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL900874Z
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Org. Lett., Vol. 11, No. 12, 2009