Facile one-pot palladium-catalyzed sequential coupling to diarylmethanes by using aryl methyl ketones as the methylene donors

Article abstract of DOI:10.1002/ejoc.201300594

A novel palladium-catalyzed coupling reaction of an aryl methyl ketone with two molecules of an aryl halide to yield symmetric diarylmethanes is described. In the facile one-pot reaction, the aryl methyl ketone acts as a formal methylene donor. The experimental facts, including TLC monitoring, speculated intermediates as the raw materials, analysis of the cesium benzoate coproduct by ex situ IR spectroscopy, and the cross-coupling reactions of two different aryl halides, indicate a mechanism involving a palladium-catalyzed sequential two-step coupling process, in which the presence of a trace amount of H ₂O is indispensable. The reaction is applicable to a broad spectrum of substrates and delivers the products in good to excellent yields. Access to unsymmetrical diarylmethanes with this method is also explored and various factors are discussed. An aryl methyl ketone is used as the methylene donor to couple with two molecules of an aryl halide for the synthesis of various symmetric diarylmethanes under palladium catalysis. The mechanism involves a two-step coupling process in which the presence of a trace amount of H ₂O is indispensable. The cross-coupling to unsymmetrical diarylmethanes with this method is also explored. Copyright

Full text of DOI:10.1002/ejoc.201300594

Job/Unit: O30594
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FULL PAPER
DOI: 10.1002/ejoc.201300594
Facile One-Pot Palladium-Catalyzed Sequential Coupling to Diarylmethanes
by Using Aryl Methyl Ketones as the Methylene Donors
Xing Wang,[a] Lian-Hua Liu,[a] Jin-Hua Shi,[a] Ji Peng,[a] Hai-Yang Tu,*[a] and
Ai-Dong Zhang*[a]
Keywords: Homogeneous catalysis / Palladium / Cross-coupling / C–C coupling / Reaction mechanisms
A novel palladium-catalyzed coupling reaction of an aryl
methyl ketone with two molecules of an aryl halide to yield
symmetric diarylmethanes is described. In the facile one-pot
reaction, the aryl methyl ketone acts as a formal methylene
donor. The experimental facts, including TLC monitoring,
speculated intermediates as the raw materials, analysis of the
cesium benzoate coproduct by ex situ IR spectroscopy, and
the cross-coupling reactions of two different aryl halides,
indicate a mechanism involving a palladium-catalyzed se-
quential two-step coupling process, in which the presence
of a trace amount of H2O is indispensable. The reaction is
applicable to a broad spectrum of substrates and delivers the
products in good to excellent yields. Access to unsymmetrical
diarylmethanes with this method is also explored and various
factors are discussed.
Introduction
Diphenylmethane is an important substructure unit that
is found not only in a number of natural products[1] (repre-
sentatives are shown in Scheme 1, a) but also in many syn-
thetic compounds of biological and pharmaceutical impor-
tance.[2] Significant efforts are devoted to the construction
of this motif and its derivatives, and diverse synthetic meth-
ods, roughly classified as conventional[3] and catalytic,[4]
have been reported so far. In the past decade, catalytic
methodologies have received great attention because of
their high efficiency and because they can be easily used for
the construction of generally inaccessible diphenylmethane
derivatives through C–C bond formation.[4a,4k,5–7] For ex-
ample, the palladium-catalyzed coupling of benzyl halides
with aryl nucleophiles[5] and the α-arylation of diphenyl-
ethanones with aryl bromides[6] are among the most effec-
tive methods used to prepare this distinct class of com-
pounds. Another interesting example was reported recently
in which air-stable diborylmethane was coupled with aryl
bromides (2 equiv.) by using palladium catalysis for the syn-
thesis of various diarylmethanes (Scheme 1, b).[7]
The common feature in the mechanism of the palladium-
catalyzed α-arylation of carbonyl compounds is a one-cycle
process involving successive oxidative addition, transmet-
alation, and reductive elimination,[8] and the equilibrium
Scheme 1. (a) Several naturally occurring compounds containing
the diphenylmethane unit. (b) Reported methods for constructing
diphenylmethane compounds and the method developed herein.
[a] Key Laboratory of Pesticide & Chemical Biology of Ministry
of Education, Central China Normal University,
Wuhan 430079, P. R. China
E-mail: adzhang@mail.ccnu.edu.cn
haiytu@mail.ccnu.edu.cn
http://english.ccnu.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300594.
between the Pd–O and Pd–C species in the transmetalation
step can be the rate-determining step.[9] Several factors de-
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termine the success of the reaction, including the ligand(s) ligand suppressed the reaction, and this is similar to the
of the palladium complex; the nature of the aryl halide, result obtained in the α-diarylation of ketones reported by
carbonyl compound, base, and solvent; the stoichiometry Palucki.[12] The catalytic system of Pd(OAc)2 (2 mol-%) and
of the reagents; and the reaction temperature.
PPh3 (8 mol-%) delivered the product in 82% yield (Table 1,
Most of the reported works are devoted to the design of entry 9), whereas the use of Pd2(dba)3 (dba = dibenz-
the palladium catalysts. Our initial effort was focused on the ylideneacetone) as the catalyst resulted in a decrease in the
direct coupling reaction of acetophenone with substituted yield to 56% (Table 1, entry 10). The yield decreased to
bromobenzene to yield various 1,2,2-triphenylethanones by 59% (Table 1, entry 1) if a larger amount of bromobenzene
using PdCl2 as the catalyst, which can usually be ac- was used and to 38% (Table 1, entry 9) if a higher catalyst
complished under anhydrous and inert atmosphere condi- loading was applied, probably because of over-reaction. In
tions.[10] On one occasion in which the reaction was con- the former case, triarylmethane[13] may be produced,
ducted without dry DMF or the protection of an inert at- whereas in the latter case, oxidation of diarylmethane to
mosphere, to our surprise, the direct α,α-diarylation of diarylmethanone[14] is possible. Therefore, the optimum re-
acetophenone to 1,2,2-triphenylethanone was not achieved, action conditions for the synthesis of diarylmethanes in-
but instead diphenylmethane was generated. Given that the volved the use of DMF as the solvent in the presence of
methylene group must come from acetophenone, aceto- Pd(OAc)2 (2 mol-%), PPh3 (8 mol-%), and Cs2CO3
phenone formally functions as the methylene donor, and (2.5 equiv.) under reflux (ca. 153 °C).
hence, the product, diphenylmethane, seems to be the result
of the cleavage of 1,2,2-triphenylethanone at the benzoyl
site in the presence of a trace amount of water in the reac-
tion medium. Remarkably, this kind of reaction has not
been reported to date. It may be viewed as a new method
for the synthesis of diarylmethanes, and the reaction scope
and mechanism deserve to be further investigated.
In this article, we report the investigation of this unusual
reaction by screening the optimal reaction conditions of the
direct coupling of acetophenone with 4-bromobenzene to
the symmetric diarylmethane product, bis(4-methylphenyl)-
methane, and then we expand the substrate scope and offer
insight into the mechanism. Finally, access to unsymmetri-
cal diarylmethanes with this method is also explored.
Table 1. Conditions for the synthesis of di-p-tolylmethane.[a]
Entry Catalyst[b]
Base[b]
Solvent
Yield[c] [%]
1
2
3
PdCl2
PdCl2
PdCl2
Cs2CO3
Cs2CO3
KOH, K2CO3, or DMF
DMF
DMF
63/80/59[d]
0/3[e]
0
NaOtBu
4
5
6
PdCl2
PdCl2
PdCl2
K3PO4·3H2O
DMF
DMF
THF or
toluene
H2O[g]
DMF
DMF
DMF
59
Cs2CO3
33/69/67[f]
0
Cs2CO3
7
8
9
10
PdCl2[h]
PdCl2
Pd(OAc)2
Pd2(dba)3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
23
10
13/82/38[i]
56
Results and Discussion
First, optimization of the reaction conditions was per-
formed on the model coupling reaction of 4-bromotoluene
with acetophenone for the synthesis of di-p-tolylmethane.
[a] Reactions were conducted with acetophenone (3.1 mmol) and
4-bromotoluene (6.2 mmol) in solvent (20 mL) for 8 h. All ratios
of the substrates were 1:2 unless otherwise noted. [b] Loading
Selected results are shown in Table 1. The isolated product based upon acetophenone. [c] Yield of isolated product. [d] Yield
obtained with a substrate ratio of 1:1, 1:2, and 1:3.4, respectively.
was obtained in up to 80% yield with an acetophenone/4-
[e] Yield obtained by conducting the reaction at 60 and 120 °C,
bromotoluene ratio of 1:2 under reflux and the catalysis
respectively. [f] Yield obtained by using 1.0, 2.0, and 3.0 equiv. of
of PdCl2 and PPh3 (Table 1, entry 1). Upon lowering the
Cs2CO3, respectively. [g] TBAB (1.55 mmol) was added. [h] Di-
temperature to 60 °C, no reaction occurred (Table 1, en-
try 2). No product was observed if KOH, K2CO3, or
NaOtBu was used as the base (Table 1, entry 3). Both
K3PO4·3H2O and Cs2CO3 promoted the reaction, but
Cs2CO3 was more efficient (Table 1, entries 1 and 4). Upon
cyclohexyl(2-mesityl-1H-inden-1-yl)phosphane was used as the li-
gand. [i] Yield obtained by using 1+4, 2+8, and 4+16 mol-% of
Pd(OAc)2 + PPh3, respectively.
To probe the substrate scope of the reaction, various aryl
conducting the reaction in the presence of 2.5 equiv. methyl ketones were used to react with a broad range of
Cs2CO3, the highest yield was obtained (Table 1, entries 1 aryl halides under the optimum conditions, and the results
and 5). However, changing the solvent from DMF to an- are listed in Table 2. Aryl methyl ketones, with little in-
other one, such as THF and toluene, shut down the reac- fluence from the substituent on the aryl group, efficiently
tion completely (Table 1, entry 6). In addition, the use of coupled with phenyl bromide (Table 2, entry 1). Among the
H2O as the solvent and tetrabutylammonium bromide phenyl halides tested, the bromide was the most efficient
(TBAB) as the phase-transfer agent decreased the reaction (Table 2, entries 1–3), which is consistent with the results of
yield dramatically (Table 1, entry 7). Moreover, by replacing the α,α-diarylation of acetophenones.[8d] The nature of the
PPh3 with dicyclohexyl(2-mesityl-1H-inden-1-yl)phosphane substituents on the aryl halide had a pronounced impact
as the spectator ligand,[11] the yield decreased to 10% on the yield, and electron-rich substituents (Table 2, en-
(Table 1, entry 8), which suggests that the bulky phosphane tries 4–11 and 13) performed better than electron-deficient
2
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Methylene Donation in Pd-Catalyzed Synthesis of Diarylmethanes
ones (Table 2, entries 14–19). For example, upon treatment Table 2. Substrate scope for the synthesis of diarylmethanes.[a]
of acetophenone with 3,5-bis(trifluoromethyl)phenyl brom-
ide, no desired product was observed (Table 2, entry 18),
whereas upon treatment with 4-trifluoromethylphenyl
bromide, a moderate yield was obtained (Table 2, entry 17).
For an aryl bromide with ortho steric hindrance or a para
long-chain substituent, the yield was 63 or 91%, respec-
tively (Table 2, entries 6 and 8). Furthermore, upon cou-
pling acetophenone with 4-bromochlorobenzene, selective
production of bis(4-chlorophenyl)methane was observed
(Table 2, entry 16). Importantly, some aryl halides with
functional groups were able to give the corresponding di-
arylmethanes in moderate yields (Table 2, entries 19 and
20). For example, 4-bromostyrene coupled with aceto-
phenone to produce bis(4-vinylphenyl)methane in 47%
yield, whereas tert-butyldimethylsilyl (TBS)-protected 3,5-di-
(hydroxymethyl)phenyl bromide reacted with acetophenone
to give bis[3,5-di(tert-butyldimethylsilyloxymethyl)phenyl]-
methane, which can be conveniently deprotected to give the
corresponding
polyhydroxy-bearing
diarylmethane
(Table 2, entry 20). However, for an aryl bromide with a 2-
methoxy group (Table 2, entry 12) or an active hydrogen
such as that in the amino and hydroxy groups (data not
shown), no coupling product was obtained. Interestingly, 3-
acetylpyridine, a heteroaryl methyl ketone, was also able to
function as the methylene donor to achieve diphenylmeth-
ane in good yield (Table 2, entry 21).
Notably, if the reaction of acetophenone with phenyl
bromide was carried out under anhydrous conditions, the
normal α-arylation product, diphenylethanone, was ob-
tained, as reported by Churruca,[15] without the formation
of diphenylmethane. It was speculated that the presence of
H2O was indispensable. To understand this reaction per-
formed without the use of dry DMF or the protection of
an inert atmosphere, the progress was first checked by TLC
monitoring. A major new spot appeared on the TLC plate
after a reaction time of 0.5 h, which gradually disappeared
as time progressed. Normal product 3a, resulting from the
α,α-diarylation of acetophenone, was obtained by quench-
ing the reaction after 0.5 h [Scheme 2, Eq. (1)]. Upon com-
pletion of the reaction, however, di-p-tolylmethane instead
of 3a was obtained. No di-p-tolylmethane was observed if
3a as the raw material was added to the reaction mixture
under the same conditions [Scheme 2, Eq. (2)], which sug-
gests that 3a was not the real intermediate and that the
spot that appeared on the TLC plate might come from an
unknown key intermediate, which may transform into 3a
during chromatography or upon quenching the reaction
with 1.4 m HCl after 0.5 h. However, if 1,2-diphenyl-
ethanone was used in the reaction with bromobenzene, the
desired diphenylmethane was obtained [Scheme 2, Eq. (3)],
and consequently, 1,2-diphenylethanone was another key
intermediate. 1,2-Diphenylethanone is a benzyl-type ketone,
and α-arylation has been reported, such as the palladium-
catalyzed α-arylation of benzyl ketone with iodobenzene[16]
and, more similarly, that of 1,2-diphenylethanone with vari-
ous aryl bromides for the synthesis of diarylmethanes in
aqueous media with microwave heating.[6]
[a] Conditions: Aryl methyl ketone (3.1 mmol), aryl halide
(6.2 mmol) for about 12 h. [b] Yield of isolated product. [c] 4-
Fluoroacetophenone, 4-methoxyacetophenone, or acetophenone
was used as the methylene donor, respectively. [d] 3-Acetylpyridine
was used as the methylene donor.
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ductive elimination occurs, which leads to cleavage of the
C–C bond and the formation of intermediate IV. A neces-
sary indicator of this process should be the concomitant
product ArCO2Cs. Intermediate IV undergoes reductive eli-
mination to generate the desired diarylmethane and the
active Pd0 species for the next catalytic cycle. The whole
mechanism involves a one-pot palladium-catalyzed sequen-
tial two-step coupling process.
Scheme 2. Reaction equations for mechanism exploration.
The above model reactions preliminarily demonstrated
that there may be two key intermediates involved in the
reaction: one is 1,2-diphenylethanone, whereas the another
remains unknown. In the α,α-diarylation of acetophenone
with aryl bromide to give 3a [Scheme 2, Eq. (1)], Churruca
et al. performed a detailed investigation and suggested a key
intermediate PdII complex bearing aryl and diarylethanon-
α-yl groups under the anhydrous conditions that transforms
Scheme 3. The proposed mechanism.
The indicator, the concomitant product ArCO2Cs (in this
into triarylethanone 3a after water workup.[10] As men- case, cesium benzoate), may be used to support this pro-
tioned above, 3a was unable to be transformed into diaryl- posed mechanism. Thus, the reaction mixture was acidified,
methane in our case, which demonstrates that the reaction extracted, and subjected to column chromatography, and
of this PdII complex to give 3a is an irreversible process. finally benzoic acid was indeed obtained and identified.
Given that the present reaction was conducted in wet DMF, With this knowledge, the reaction mixture was sampled at
a water-mediated process for the transformation of the PdII an interval of 1 h and the in situ formation of PhCO2Cs was
complex into the diarylmethane is possible. The process analyzed by IR spectroscopy by comparing the measured
may occur by water attack at the carbonyl of the diaryl- spectra to the standard spectrum of PhCO2Cs (Figure 1).
ethanon-α-yl group, and this would lead to the generation The characteristic bands of PhCO2Cs centered at approxi-
of an unreported intermediate and the release of a coprod- mately 1558 (C=O stretch of benzoate) and 715 cm–1 (one
uct, ArCO2Cs. Notably, this unreported intermediate is of the C–H out-of-plane bendings of monosubstituted
likely the phenylmethylene-bound Pd species with phenyl benzene) and their intensities increased as time progressed,
attached simultaneously. Then, this intermediate may fur- which is suggestive of the continuous generation of
ther transform into the diarylmethane by reductive elimi- PhCO2Cs in the reaction direction of the proposed mecha-
nation. The distinct feature of this transformation is the nism.
water-mediated C–C activation. Similarly, water-mediated
According to this mechanism, if two mixed aryl halides
C–C activation in the α-arylation of β-dicarbonyl com- were used simultaneously, three cross-coupling products
pounds to aryl ketones has been reported by Lei and col- could be possible (Scheme 4, a). For example, simultaneous
leagues.[17]
treatment of acetophenone with bromobenzene and 4-
Therefore, a complete mechanism involving a catalytic bromotoluene under our conditions resulted in the forma-
two-cycle process is proposed for the reaction and is shown tion of three different diarylmethanes, as recognized by
1
in Scheme 3. At first, the α-arylation of acetophenone with characteristic resonances for the methylene unit in the H
the palladium catalyst to give diarylethanone I is included NMR spectrum (Scheme 4, b, top). Two of the three diaryl-
in the first cycle, which has been well documented in a methanes were identified as diphenylmethane and di-p-
number of publications.[8,9] Next, diarylethanone I enolizes tolylmethane by comparing the characteristic chemical
and couples to PdII complex II generated from the Pd0 pre- shifts of the methylene group to the methylene signals of
catalyst by oxidative addition of ArX in the reaction to pure diphenylmethane (Table 2, entry 1) and di-p-tolylmeth-
form intermediate III. Intermediate III then undergoes re- ane (Table 2, entry 4). The remaining methylene signal at δ
ductive elimination, and after acidic aqueous workup, af- = 3.935 ppm, with the highest intensity lying in between
fords triphenylethanone 3a as the normal reported pro- the two known diarylmethanes, should be the characteristic
cess.[10] However, in our case, a trace amount of H2O may resonance for the methylene group of the unsymmetrical p-
attack the carbonyl group of intermediate III before re- tolylphenylmethane product.
4
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Methylene Donation in Pd-Catalyzed Synthesis of Diarylmethanes
three diarylmethanes (Scheme 4, b, middle and bottom),
and the compositions were also identified by the above
method. The different integration of the methylene reso-
nances is indicative of their relative abundance, which evi-
dences that 4-bromotoluene and 4-methoxyphenyl bromide
tend to undergo self-coupling, whereas 4-fluorophenyl
bromide tends to undergo cross-coupling. It is known that
electron-deficient aryl halides form diarylethanones more
easily,[8c] as intermediate I in the first cycle in our proposed
mechanism leads to a more stable enolate through stabiliza-
tion by the electron-deficient substituent. However, in the
second cycle, it is reasonable that the electron-rich aryl hal-
ide will tend to have higher reactivity in the oxidative ad-
dition to form intermediate II. Thus, the following trans-
metalation, water-mediated C–C cleavage, and reductive eli-
mination give high yields for the self-coupling product of
an electron-rich aryl halide and for the cross-coupling prod-
uct of an electron-rich aryl halide and an electron-deficient
one and a very low yield for the self-coupling product of an
electron-deficient aryl halide.
The above-obtained mixtures were subjected to column
chromatography. However, because of the small differences
in the polarities of the individual components, isolation of
the cross-coupling product derived from bromobenzene and
4-bromotoluene as well as that derived from 4-fluorophenyl
bromide and 4-bromotoluene failed. However, cross-cou-
pling 4-fluoro-4Ј-methoxydiphenylmethane product derived
from 4-fluorophenyl bromide and 4-methoxyphenyl brom-
ide was isolated in 40% yield, and its structural information
is described in the Experimental Section.
Figure 1. IR spectra of samples at different reaction times, together
with that of the solvent DMF and pure cesium benzoate.
Cross-coupling reactions for the synthesis of various un-
symmetrical diarylmethanes are also possible; nevertheless,
precaution should be taken. Given that the sequential two-
step coupling reaction is a successive process, a strategy
should be adapted to stop the reaction at the stage of the
formation of intermediate I after the first cycle so that the
first aryl halide will not participate in the second catalytic
cycle and that the second aryl halide will not participate in
the first catalytic cycle. In one of the above examples, by
making use of the different polarities and activities of the
substituents on the coupling aryl halide pair, it is possible
to obtain the cross-coupling product, although in relatively
low yield.
Conclusions
Scheme 4. (a) Predicted products for the one-pot cross-coupling re-
action. (b) 1H NMR spectra in the region of 4.06–3.75 ppm for the
mixtures obtained from the one-pot cross-coupling reactions.
In summary, we report the first examples of the synthesis
of symmetrical diarylmethanes by facile, one-pot, two-step,
palladium-catalyzed sequential coupling. The method is
also applicable to the synthesis of unsymmetrical diaryl-
To inspect the cross-coupling reactivity of different aryl methanes through a cross-coupling reaction. The major ad-
halides, two other cross-coupling reactions were conducted, vantage of this synthesis over the state-of-the-art methods
that is, the reaction of 4-fluorophenyl bromide with 4- is the utilization of aryl methyl ketones as the methylene
bromotoluene and the reaction of 4-fluorophenyl bromide donors, as they are cheap and widely available. The use of
with 4-methoxyphenyl bromide, and the pairs in these reac- a palladium catalyst without the need of a complex and
tions have relatively large differences in the electronegativity specially designed ligands is another valuable merit. A
of the substituent. Each reaction produced a mixture of plausible mechanism was outlined in detail, and it was sup-
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sion was stirred and heated to 153 °C, and the progress of the reac-
tion was monitored by TLC. Upon completion of the reaction, the
mixture was cooled. HCl (1.4 m in H2O, 50 mL) was added, and
the aqueous layer was extracted with CH2Cl2 (3ϫ 30 mL). The
combined organic extract was washed with saturated aqueous
NH4Cl (3ϫ 100 mL), dried with anhydrous sodium sulfate, and
concentrated in vacuo to give a residue. Then, the residue was puri-
fied by column chromatography on silica gel (petroleum ether or
petroleum ether/ethyl acetate) to give the product. All the as-syn-
thesized diarylmethanes are listed in Table 2.
ported by the following experimental facts: TLC monitor-
ing, intermediates possible as the raw materials, analysis of
the cesium benzoate coproduct by ex situ IR spectroscopy,
and the result of the cross-coupling model reaction.
Experimental Section
General Information: Unless otherwise noted, materials were used
as commercially supplied. All reactions were monitored by TLC
analysis on silica gel coated plates. Flash column chromatography
Diphenylmethane: The ketone (3.1 mmol; acetophenone, 0.37 g; 4-
methoxyacetophenone, 0.47 g; 4-fluoroacetophenone, 0.43 g; or 3-
acetylpyridine, 0.38 g) and an aryl halide (6.2 mmol; bromobenz-
ene, 0.97 g; iodobenzene, 1.27 g) were used. The product was ob-
tained as a colorless oil. The yields are indicated in Table 2, entry 1
(0.424 g, 80%; 0.435 g, 82%; 0.472 g, 89%) and entry 21 (0.435 g,
82%). 1H NMR (400 MHz, CDCl3): δ = 7.17–7.29 (m, 10 H), 3.97
(s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 141.08, 128.91,
128.43, 126.03, 41.92 ppm. MS: m/z = 168.1 [M]+. C13H12 (168.24):
calcd. C 92.81, H 7.19; found C 92.63, H 6.99.
1
was performed by using 200–300 mesh silica gel. H NMR spectra
were recorded with Varian Mercury 400 or 600 MHz spectrometers.
Chemical shifts (δ) are reported in ppm from tetramethylsilane (in-
ternal standard, 0.0 ppm). 13C NMR spectra were recorded with
the same spectrometers operating at 100 and 150 MHz, respec-
tively, with complete proton decoupling (internal standard CDCl3:
77.0 ppm). IR measurements were performed with a Bruker
TENSOR27 by using KBr pellets. Mass spectra were measured
with a Finnigan Trace MS spectrometer. Elementary analysis was
taken with a Vario EL III elementary analysis instrument.
Di-p-tolylmethane: Acetophenone (0.37 g, 3.1 mmol) and 4-bromo-
toluene (1.06 g, 6.2 mmol) were used. The product was obtained as
colorless oil (0.508 g, 82%). 1H NMR (600 MHz, CDCl3): δ = 7.06
(d, J = 9 Hz, 8 H), 3.89 (s, 2 H), 2.29 (s, 6 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 138.34, 135.38, 129.08, 128.72, 41.06,
20.98 ppm. MS: m/z = 196.1 [M]+. C15H16 (196.29): calcd. C 91.78,
H 8.22; found C 91.61, H 8.03.
Di-m-tolylmethane:[7] Acetophenone (0.37 g, 3.1 mmol) and 3-
bromotoluene (1.06 g, 6.2 mmol) were used. The product was ob-
tained as a colorless oil (0.464 g, 76%). 1H NMR (600 MHz,
CDCl3): δ = 7.15–7.18 (m, 2 H), 6.98–7.01 (m, 6 H), 3.89 (s, 2 H),
2.30 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.13,
137.97, 129.67, 128.29, 126.75, 125.94, 41.84, 21.40 ppm. MS: m/z
= 196.2 [M]+.
α,α-Bis(4-methoxyphenyl)acetophenone: DMF (20 mL) was added
to
a round-bottomed flask charged with Cs2CO3 (2.53 g,
7.75 mmol), PPh3 (65.05 mg, 0.248 mmol), PdCl2 (10.99 mg,
0.062 mmol), acetophenone (0.37 g, 3.1 mmol), and 4-bromotolu-
ene (1.06 g, 6.2 mmol) at room temperature. The resulting suspen-
sion was stirred and heated to 153 °C for 0.5 h. After cooling, HCl
(1.4 m in H2O, 50 mL) was added, and the aqueous layer was ex-
tracted with CH2Cl2 (3ϫ 30 mL). The combined organic extract
was washed with saturated aqueous NH4Cl (3ϫ 100 mL), dried
with anhydrous sodium sulfate, and concentrated in vacuo to give
a residue. The residue was purified by column chromatography on
1
silica gel (petroleum ether) to give the product as a yellow oil. H
NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.6 Hz, 2 H), 7.49 (t, J
= 7.6 Hz, 1 H), 7.37–9.41 (m, 2 H), 7.10–7.16 (m, 8 H), 5.96 (s, 1
H), 2.30 (s, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 198.43,
136.78, 136.61, 136.21, 132.84, 129.35, 128.88, 128.49, 128.24,
58.65, 21.01 ppm. C22H20O (300.40): calcd. C 87.96, H 6.71; found
C 87.71, H 6.64.
Di-o-tolylmethane: Acetophenone (0.37 g, 3.1 mmol) and 2-bromo-
toluene (1.06 g, 6.2 mmol) were used. The product was obtained as
a colorless oil (0.391 g, 63%). 1H NMR (600 MHz, CDCl3): δ =
7.20 (d, J = 6.6 Hz, 2 H), 7.14–7.16 (m, 2 H), 7.10–7.12 (m, 2 H),
6.89 (d, J = 6.6 Hz, 2 H), 3.92 (s, 2 H), 2.28 (s, 6 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 138.33, 136.49, 130.01, 129.09,
126.19, 126.00, 36.66, 19.54 ppm. MS: m/z = 196.2 [M]+. C15H16
(196.29): calcd. C 91.78, H 8.22; found C 91.59, H 8.00.
Benzoic Acid: DMF (20 mL) was added to a round-bottomed flask
charged with Cs2CO3 (2.53 g, 7.75 mmol), PPh3 (65.05 mg,
0.248 mmol), Pd(OAc)2 (13.92 mg, 0.062 mmol), acetophenone
(0.37 g, 3.1 mmol), and 4-bromotoluene (1.06 g, 6.2 mmol) at room
temperature. The resulting suspension was stirred and heated to
153 °C, and the progress of the reaction was monitored by TLC.
Upon completion of the reaction, the mixture was cooled. HCl
(1.4 m in H2O, 50 mL) was added, and the aqueous layer was ex-
tracted with CH2Cl2 (3ϫ 100 mL). The combined organic layer
was alkalified to pH 11 by using NaOH (aq.). The water phase was
separated and acidified to pH 3. The combined liquid layer was
extracted with CH2Cl2 (3ϫ 10 mL) and dried with anhydrous so-
dium sulfate, and the solvents were evaporated in vacuo to give a
residue. The residue was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate, 4:1) to give the product as
Bis(3,5-dimethylphenyl)methane: Acetophenone (0.37 g, 3.1 mmol)
and 3,5-dimethylbromobenzene (1.45 g, 6.2 mmol) were used. The
1
product was obtained as a colorless oil (0.618 g, 87%). H NMR
(600 MHz, CDCl3): δ = 6.82 (s, 2 H), 6.81 (s, 4 H), 3.81 (s, 2 H),
2.27 (s, 12 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 141.18,
137.83, 127.54, 126.64, 41.74, 21.73 ppm. MS: m/z = 224.2 [M]+.
C17H20 (224.35): calcd. C 91.01, H 8.99; found C 90.83, H 8.85.
Bis(4-pentylphenyl)methane: Acetophenone (0.37 g, 3.1 mmol) and
1-bromo-4-pentylbenzene (1.41 g, 6.2 mmol) were used. The prod-
uct was obtained as a colorless oil (0.892 g, 91%). 1H NMR
(600 MHz, CDCl3): δ = 7.08 (s, 8 H), 3.89 (s, 2 H), 2.55 (t, J =
11.4 Hz, 4 H), 1.56–1.62 (m, 4 H), 1.30–1.31 (m, 8 H), 0.88 (t, J =
10.8 Hz, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 140.52,
138.50, 128.63, 128.34, 41.13, 35.52, 31.55, 31.26, 22.56, 14.16 ppm.
MS: m/z = 308.3 [M]+. C23H32 (308.51): calcd. C 89.54, H 10.46;
found C 89.31, H 10.26.
1
a white solid. H NMR (400 MHz, CDCl3): δ = 11.3 (s, 1 H), 8.13
(d, J = 7.2 Hz, 2 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.47–7.51 (m, 2 H)
ppm.
General Procedure for the Synthesis of Diarylmethanes: DMF
(20 mL) was added to a round-bottomed flask charged with
Cs2CO3 (2.53 g, 7.75 mmol), PPh3 (65.05 mg, 0.248 mmol),
Bis(4-tert-butylphenyl)methane:[18]
Acetophenone
(0.37 g,
Pd(OAc)2 (13.92 mg, 0.062 mmol), one ketone (3.1 mmol), and an 3.1 mmol) and 1-bromo-4-tert-butylbenzene (0.32 g, 6.2 mmol)
aryl halide (6.2 mmol) at room temperature. The resulting suspen- were used. The product was obtained as a colorless oil (0.714 g,
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30594
/KAP1
Date: 10-09-13 16:35:27
Pages: 9
Methylene Donation in Pd-Catalyzed Synthesis of Diarylmethanes
83%). 1H NMR (600 MHz, CDCl3): δ = 7.30 (d, J = 7.2 Hz, 4 H), tained as a colorless oil (0.320 g, 47%). 1H NMR (400 MHz,
7.13 (d, J = 7.8 Hz, 4 H), 3.92 (s, 2 H), 1.29 (s, 18 H) ppm. 13C CDCl3): δ = 7.33 (d, J = 8.0 Hz, 4 H), 7.14 (d, J = 8.0 Hz, 4 H),
NMR (150 MHz, CDCl3): δ = 148.69, 138.23, 128.51, 125.30, 6.68 (q, J = 6.8 Hz, 2 H), 5.70 (d, J = 18 Hz, 2 H), 5.19 (d, J =
40.89, 34.34, 31.39 ppm. MS: m/z = 280.4 [M]+.
11.2 Hz, 2 H), 3.59 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 140.67, 136.55, 135.54, 129.05, 126.33, 113.23, 41.35 ppm. MS:
m/z = 220.3 [M]+. C17H16 (220.31): calcd. C 92.68, H 7.32; found
C 92.87, H 7.56.
Bis(4-methoxyphenyl)methane: Acetophenone (0.37 g, 3.1 mmol)
and 1-bromo-4-methoxybenzene (1.16 g, 6.2 mmol) were used. The
product was obtained as a yellow oil (0.634 g, 88%). 1H NMR
(600 MHz, CDCl3): δ = 7.08 (d, J = 7.8 Hz, 4 H), 6.82 (d, J =
8.4 Hz, 4 H), 3.86 (s, 2 H), 3.77 (s, 6 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 157.87, 133.69, 129.70, 113.82, 55.23, 40.09 ppm. MS:
m/z = 228.1. [M]+. C15H16O2 (228.29): calcd. C 78.92, H 7.06;
found C 79.09, H 6.93.
Bis[3,5-di(tert-butyldimethylsilyloxymethyl)phenyl]methane: Aceto-
phenone (0.37 g, 3.1 mmol) and 3,5-di(tert-butyldimethylsilyloxy-
methyl)phenyl bromide (2.58 g, 6.2 mmol) were used. The product
1
was obtained as a yellow oil (1.120 g, 49%). H NMR (600 MHz,
CDCl3): δ = 7.15 (s, 2 H), 6.98 (s, 4 H), 4.68 (s, 8 H), 3.94 (s, 2 H),
0.92 (s, 36 H), 0.07 (s, 24 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 141.46, 140.89, 125.24, 121.49, 64.96, 41.88, 25.97, 18.42,
–5.25 ppm. MS: m/z = 744.6 [M]+. C41H76O4Si4 (745.39): calcd. C
66.07, H 10.28; found C 65.94, H 10.06.
Bis(3-methoxyphenyl)methane:[7] Acetophenone (0.37 g, 3.1 mmol)
and 3-bromoanisole (1.16 g, 6.2 mmol) were used. The product was
obtained as a yellow oil (0.561 g, 79%). 1H NMR (400 MHz,
CDCl3): δ = 7.20 (t, J = 7.6 Hz, 2 H), 6.79 (d, J = 7.6 Hz, 2 H),
6.74 (d, J = 6.0 Hz, 4 H), 3.92 (s, 2 H), 3.77 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.68, 142.46, 129.38, 121.34,
114.74, 111.33, 55.12, 41.96 ppm. MS: m/z = 228.2 [M]+.
One-Pot Cross-Coupling to Diarylmethanes: Acetophenone
(3.1 mmol, 0.38 g) and bromobenzene (3.1 mmol, 0.49 g) and 1-
bromo-4-methylbenzene (3.1 mmol, 1.06 g) or 1-bromo-4-fluoro-
benzene (3.1 mmol, 0.54 g) and 1-bromo-4-methylbenzene
(3.1 mmol, 1.06 g) were used. After workup, the residue was sub-
jected to column chromatography, and the product mixture was
obtained as a colorless oil. For the product mixture of di-
phenylmethane, p-tolylphenylmethane, and di-p-tolylmethane: 1H
NMR (400 MHz, CDCl3): δ = 7.26–7.30 (m, 6.2 H), 7.18–7.22 (m,
8.6 H), 7.08 (s, 5.7 H), 3.98 (s, 1.6 H, CH2 of diphenylmethane),
3.94 (s, 2 H, CH2 of p-tolylphenylmethane), 3.89 (s, 0.4 H, CH2 of
di-p-tolylmethane), 2.38 (s, 1.1 H), 2.31 (s, 4.2 H) ppm. For the
product mixture of bis(4-fluorophenyl)methane, 4-fluoro-4Ј-
methyldiphenylmethane, and di-p-tolylmethane: 1H NMR
Bis(3,4-dimethoxyphenyl)methane:[6]
Acetophenone
(0.37 g,
3.1 mmol) and 1-bromo-3,4-dimethoxybenzene (1.34 g, 6.2 mmol)
were used. The product was obtained as a yellow oil (0.721 g, 81%).
1H NMR (600 MHz, CDCl3): δ = 6.79 (s, 2 H), 6.71 (d, J =
15.6 Hz, 4 H), 3.88 (s, 2 H), 3.86 (s, 6 H), 3.83 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 148.80, 147.27, 133.81, 120.64,
112.01, 111.08, 55.82, 55.72, 40.90 ppm. MS: m/z = 288.3 [M]+.
Bis(4-fluorophenyl)methane: Acetophenone (0.37 g, 3.1 mmol) and
1-bromo-4-fluorobenzene (1.09 g, 6.2 mmol) were used. The prod-
uct was obtained as a colorless oil (0.423 g, 65%). 1H NMR
(600 MHz, CDCl3): δ = 7.11 (t, J = 7.8 Hz, 4 H), 6.97 (t, J = 9 Hz, (400 MHz, CDCl3): δ = 7.04–7.13 (m, 14.2 H), 6.95–6.98 (t, J =
4 H), 3.91 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.21,
160.59, 136.55, 130.15, 115.33, 115.19, 40.18 ppm. MS: m/z = 204.1
[M]+. C13H10F2 (204.22): calcd. C 76.46, H 4.94; found C 76.28, H
4.87.
8.4 Hz, 5.9 H), 7.08 (s, 5.7 H), 3.94 [s, 0.3 H, CH2 of bis(4-
fluorophenyl)methane], 3.91 (s, 2 H, CH2 of 4-fluoro-4Ј-methyl-
diphenylmethane), 3.89 (s, 2.48 H, CH2 of di-p-tolylmethane), 2.31
(s, 1.98 H), 2.30 (s, 3.9 H) ppm.
4-Fluoro-4Ј-methoxydiphenylmethane:[7] Acetophenone (0.37 g,
3.1 mmol) and 1-bromo-4-methoxybenzene (0.58 g, 3.1 mmol) and
1-bromo-4-fluorobenzene (0.54 g, 3.1 mmol) were used. The prod-
uct was obtained as a colorless oil (0.268 g, 40%). 1H NMR
(600 MHz, CDCl3): δ = 7.10 (s, 2 H), 7.07 (d, J = 7.8 Hz, 2 H),
6.95 (t, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 3.88 (s, 2 H),
3.76 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.53,
160.11, 158.01, 137.22, 133.02, 130.14, 130.06, 129.73, 127.99,
115.22, 115.01, 114.21, 113.90, 55.21, 40.14 ppm. MS: m/z = 216.2
[M]+.
Bis(3-fluorophenyl)methane: Acetophenone (0.37 g, 3.1 mmol) and
1-bromo-4-fluorobenzene (1.09 g, 6.2 mmol) were used. The prod-
uct was obtained as a colorless oil (0.378 g, 60%). 1H NMR
(600 MHz, CDCl3): δ = 7.23 (t, J = 7.2 Hz, 2 H), 6.95 (d, J =
7.2 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 6.86 (t, J = 9.6 Hz, 2 H),
3.94 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.19,
161.74, 142.81, 142.74, 130.29, 129.92, 124.53, 124.50, 115.88,
115.66, 113.36, 113.15, 41.24 ppm. MS: m/z
C13H10F2 (204.22): calcd. C 76.46, H 4.94; found C 76.28, H 5.18.
=
204.2 [M]+.
Bis(4-chlorophenyl)methane: Acetophenone (0.38 g, 3.1 mmol) and
1-bromo-4-chlorobenzene (1.18 g, 6.2 mmol) were used. The prod-
uct was obtained as a colorless oil (0.533 g, 71%). 1H NMR
(600 MHz, CDCl3): δ = 7.24 (d, J = 8.4 Hz, 4 H), 7.07 (d, J =
7.8 Hz, 4 H), 3.89 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ
= 138.96, 132.07, 130.14, 128.63, 40.48 ppm. MS: m/z = 236.0
[M]+. C13H10Cl2 (237.13): calcd. C 65.85, H 4.25; found C 65.96,
H 4.14.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H NMR and 13C NMR spectra for all synthe-
sized compounds.
Acknowledgments
The authors gratefully acknowledge financial support from the
National Natural Science Foundation of China (NSFC) (project
numbers 21172087, 21172088, and 20972056) and in part from the
self-determined research funds of the Central China Normal Uni-
versity (CCNU) from the colleges’ basic research and operation of
the Ministry of Education (MOE), China.
Bis(4-trifluoromethylphenyl)methane:
Acetophenone
(0.38 g,
3.1 mmol) and 1-bromo-4-(trifluoromethyl)benzene (1.39 g,
6.2 mmol) were used. The product was obtained as a colorless oil
(0.490 g, 51%). 1H NMR (600 MHz, CDCl3): δ = 7.55 (d, J =
7.8 Hz, 4 H), 7.28 (d, J = 7.8 Hz, 4 H), 4.07 (s, 2 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 143.24, 129.23, 127.62, 125.93,
123.25, 41.43 ppm. MS: m/z = 304.0 [M]+.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30594
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Date: 10-09-13 16:35:27
Pages: 9
X. Wang, L.-H. Liu, J.-H. Shi, J. Peng, H.-Y. Tu, A.-D. Zhang
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Received: April 24, 2013
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30594
/KAP1
Date: 10-09-13 16:35:27
Pages: 9
Methylene Donation in Pd-Catalyzed Synthesis of Diarylmethanes
Palladium Catalysis
X. Wang, L.-H. Liu, J.-H. Shi, J. Peng,
H.-Y. Tu,* A.-D. Zhang* .................. 1–9
Facile
One-Pot
Palladium-Catalyzed
An aryl methyl ketone is used as the meth-
ylene donor to couple with two molecules
of an aryl halide for the synthesis of vari-
ous symmetric diarylmethanes under pal-
ladium catalysis. The mechanism involves
a two-step coupling process in which the
presence of a trace amount of H2O is indis-
pensable. The cross-coupling to unsym-
metrical diarylmethanes with this method
is also explored.
Sequential Coupling to Diarylmethanes by
Using Aryl Methyl Ketones as the Methyl-
ene Donors
Keywords: Homogeneous catalysis / Pal-
ladium / Cross-coupling / C–C coupling /
Reaction mechanisms
Eur. J. Org. Chem. 0000, 0–0
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