Pd(DPEPhos)Cl2-catalyzed Negishi cross-couplings for the formation of biaryl and diarylmethane phloroglucinol adducts

Article abstract of DOI:10.1016/j.tet.2011.01.030

Several functionalized biaryls and diarylmethanes containing the phloroglucinol subunit were synthesized in 55-85% yields using Negishi cross-couplings of 2,4,6-trimethoxyphenylzinc chloride with aryl and benzyl halides in the presence of catalytic quantities of Pd(DPEPhos)Cl₂. These simple to prepare couplings were generally complete in 1-24 h depending on the halide, and were applicable to aryl and benzyl halides containing both electron-donating and electron-withdrawing groups.

Full text of DOI:10.1016/j.tet.2011.01.030

Tetrahedron 67 (2011) 2125e2131
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(DPEPhos)Cl2-catalyzed Negishi cross-couplings for the formation of biaryl and
diarylmethane phloroglucinol adducts
,
b
,
,
Eric G. Dennis a 1, David W. Jeffery b, Michael V. Perkins a, Paul A. Smith b
*
a School of Chemical and Physical Sciences, Flinders University, GPO Box 2100, Adelaide 5001, South Australia, Australia
b The Australian Wine Research Institute, PO Box 197, Glen Osmond 5064, South Australia, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Several functionalized biaryls and diarylmethanes containing the phloroglucinol subunit were synthe-
sized in 55e85% yields using Negishi cross-couplings of 2,4,6-trimethoxyphenylzinc chloride with aryl
and benzyl halides in the presence of catalytic quantities of Pd(DPEPhos)Cl2. These simple to prepare
couplings were generally complete in 1e24 h depending on the halide, and were applicable to aryl and
benzyl halides containing both electron-donating and electron-withdrawing groups.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 September 2010
Received in revised form 16 December 2010
Accepted 11 January 2011
Available online 15 January 2011
Keywords:
Negishi cross-coupling
Biaryls
Diarylmethanes
Organozinc
Phloroglucinol
Catechin
1. Introduction
Biaryls and diarylmethanes continue to be seen as fundamental
motifs in organic synthesis,1 industrial processes1a,2 and medicinal
chemistry.3 Given their significance, the synthesis of such com-
pounds has received great attention.1,4 The palladium-catalyzed
cross-coupling of aryl or benzyl halides with arylmetallic species
has become an increasingly important and popular method for the
synthesis of these structural motifs (Scheme 1). The Suzuki
method,5 involving the use of arylboronic acids and/or boronate
esters, is perhaps the most popular method and has been widely
used for both biaryl6 and diarylmethane7 syntheses. Stille8 and
Negishi9 protocols have also been applied to the formation of both
substructures. More recently, numerous syntheses of diaryl-
methanes involving the coupling of aryl halides with benzyl halides
using zinc powder/dust in the presence of palladium or cobalt
catalysts have been reported.10 However, no literature method for
the convenient synthesis of both biaryls and diarylmethanes was
identified. As such, a single method for both structural arrays was
targeted for further development.
Scheme 1. Palladium-catalyzed cross-couplings of arylorganometallic derivatives with
aryl and benzyl halides.
Of particular interest was the synthesis of biaryl and diaryl-
methane derivatives containing the 1,3,5-trimethoxyphenyl (TMP)
subunit. This subunit is a useful protected precursor to phlor-
oglucinol 1 (Fig. 1), a commonly occurring unit in many natural
products,11 including tannins or proanthocyanidins.12 One
subgroup of such proanthocyanidins are the C8-substituted cate-
chin derivatives 2 (Fig. 1). Access to substituted catechins has re-
ceived increased attention over the last decade in order to gain
some insight into structureeactivity relationships of these com-
pounds.13 In particular, the biological properties of these molecules,
which include antioxidant14 and anticancer15 activities, have been
of great interest in this field of study.
* Corresponding author. Tel.: þ61 8 83136619; fax: þ61 8 83136601; e-mail
address: paul.smith@awri.com.au (P.A. Smith).
1
Present address: CSIRO Plant Industry, PO Box 350, Glen Osmond 5064, South
Australia, Australia.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.030

2126
E.G. Dennis et al. / Tetrahedron 67 (2011) 2125e2131
attempted through the coupling of these organometallics with
benzyl bromide (BnBr) in the presence of Pd(PPh3)2Cl2 (Scheme 3).
2.1. Attempted Suzuki couplings of boronic acid 9a with
benzyl bromide
As a well-utilized coupling method, Suzuki cross-couplings in-
volving boronic acid 9a were attempted first. Initially, boronic acid
9a was synthesized from 7 using a modification to the method
reported by Chaumeil et al.17 Directed ortho-lithiation of 7 using
n-BuLi furnished an organolithium intermediate, which was then
treated with excess B(OMe)3. Aqueous quenching of the resulting
boronate salt provided the desired boronic acid 9a, which was
readily purified by crystallization (Scheme 4). Reaction scale for this
transformation was very important; using ca. 1 g or fewer of 7,
yields of 9a were typically 20e30%. Increasing the reaction scale
resulted in much higher conversions to the point where 9a was
consistently obtained in 70e75% yields after purification when
conducting the reaction with 10e15 g of 7.
With 9a available, Pd(PPh3)Cl2-mediated Suzuki couplings to
benzyl bromide were attempted using either NaOH or K2CO3 as the
base in aqueous, and anhydrous, THF (Scheme 4). Under the
aqueous conditions, the desired diarylmethane 10 was obtained in
very poor yields (10e20%) following isolation by silica chroma-
tography. The major compound recovered for these couplings was
7, presumably formed from protonolysis of 9a. In the case of the
anhydrous couplings, no product was detected by 1H NMR analysis
of crude reaction mixtures. In these cases, only benzyl bromide and
7 were recovered after aqueous quenching.
Fig. 1. Phloroglucinol 1 and C8-substituted (þ)-catechin 2.
Access to a variety of protected C8-phenyl- and C8-benzyl-
substituted catechin derivatives 3 using a C8-metallated moiety 4
in Pd-catalyzed cross-coupling procedures presented an interesting
pathway towards the synthesis of these compounds. Given the
complexity of the catechin derivative, cross-couplings of the 1,3,5-
trimethoxyphenyl subunit were screened as a model system to
establish the potential of such a pathway (Scheme 2). Accordingly,
the synthesis of phenyl- and benzyl-substituted trimethox-
ybenzenes 5 was targeted through the development of suitable
cross-couplings of metallated 2,4,6-trimethoxyphenyl derivatives 6
with aryl and benzyl halides.
The reasons for the poor Suzuki coupling results were not en-
tirely clear. As protonolysis of 9a to 7 was identified as the major
reaction pathway under both aqueous and anhydrous conditions, it
was likely that the boronic acid was the problematic coupling
partner. Both K2CO3 and NaOH showed poor solubility in anhydrous
THF, so in these cases there may not have been any base available in
solution to activate boronic acid 9a. This activation step has been
reported to be crucial in successful transmetallation of boronic
acids to a Pd catalyst.18 If 9a could not be activated by the base or if
there was minimal activation, then the coupling to benzyl bromide
would not proceed. In the aqueous base couplings, boronic acid 9a
may have deboronated under the aqueous conditions to provide 7
at a faster rate than the transmetallation of the activated boronic
acid to the Pd catalyst. As a result, 7 formed as the major product of
the coupling and only a small proportion of the desired diaryl-
methane 10 was produced.
Scheme 2. Pd-catalyzed cross-coupling pathway to C8-susbtituted catechins 3 from
C8-metallated catechins 4 and the synthesis of model trimethoxyphenyl adducts 5.
2.2. Development of Negishi cross-coupling system utilizing
organozinc 9b
2. Results and discussion
To test the initial scope of the designed synthetic pathway,
1,3,5-trimethoxybenzene (7) or its mono-brominated analogue 816
were converted to either boronic acid 9a (M¼B(OH)2) or organozinc
9b (M¼ZnCl). The formation of diarylmethane 10 was then
Given the poor compatibility of boronic acid 9a under the basic
and/or aqueous conditions and subsequent poor Suzuki coupling
results, the organozinc derivative of trimethoxybenzene 9b was
investigated as the organometallic coupling partner. Formation of
Scheme 3. Proposed synthetic method for diarylmethane 10 from organometallics 9a or 9b.

E.G. Dennis et al. / Tetrahedron 67 (2011) 2125e2131
2127
Scheme 4. Synthesis of boronic acid 9a and attempted Suzuki couplings to benzyl bromide.
organozinc 9b was achieved using
a
low temperature lith-
a yellow suspension upon addition to the reaction mixture; heating
to approximately 30 ꢀC was required to ensure complete dissolu-
tion of the catalyst. Interestingly, no distinguishable differences
between the reactivity of benzyl chloride and benzyl bromide were
observed. Both halides showed similar coupling yields and reaction
times using either Pd(PPh3)2Cl2 or Pd(DPEPhos)Cl2 as the pre-
iumehalogen exchange of bromide 8 using n-BuLi in THF, followed
by addition of anhydrous ZnCl2 as a solution in THF.19 The pre-
sumably formed organozinc species was then immediately coupled
to benzyl bromide in the presence of precatalyst Pd(PPh3)2Cl2
(Scheme 5).20
Scheme 5. Formation of organozinc 9b and its Pd-catalyzed coupling to benzyl bromide.
Using these conditions, the desired diarylmethane 10 was con-
sistently isolated in 50e60% yield when organozinc 9b was
employed in slight excess (1.5 mol equiv) with stirring for 16e20 h
at 70 ꢀC in the presence of 1 mol % of the precatalyst.
Table 1
Catalyst screening for the Negishi cross-coupling of 9b with BnBr or BnCl
Entry Catalyst
Loading Electrophile Temp Time Yielda
(mol %)
(ꢀC)
(h)
(%)
It is worthwhile to note at this point that generation of the
intermediate organolithium species prior to addition of ZnCl2 could
also have been achieved through directed ortho-lithiation of 7 as
used for the synthesis of boronic 9a. In the case of organozinc 9b
formation, this transformation was typically carried out using
approximately 1.5 mmol of 8. At this scale, coupling yields using
organozinc 9b derived from directed ortho-lithiation of 7 varied
widely. In contrast, the organolithium derived from lithiumehal-
ogen exchange of bromide 8 reacted smoothly upon addition of
ZnCl2, and the presumably formed organozinc 9b coupled to benzyl
bromide to provide highly consistent yields of diarylmethane 10.
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
1
1
4
1
1
5
5
3
BnBr
BnCl
BnBr
BnBr
BnCl
BnCl
BnBr
BnBr
70
70
70
70
70
20
70
70
20
20
24
1.5
1.5
48
2.5
48
60
61
55
84
85
19
64
52
b
Pd(DPEPhos)Cl2
Pd(DPEPhos)Cl2
Pd(DPEPhos)Cl2
Pd(dba)2/DPEPhosc
d
Pd(dppf)Cl2$CH2$Cl2
a
b
c
Isolated yield after silica gel purification.
DPEPhos¼bis(o-diphenylphosphinophenyl) ether.
dba¼dibenzylideneacetone.
d
dppf¼1,10-bis(diphenylphosphino)ferrocene.
catalyst (compare entries 1 with 2 and 4 with 5). Comparison of the
results of entry 1 with entry 3 and entry 4 with entry 7, clearly show
that Pd(II) precatalysts were more effective than their Pd(0)
counterparts for this coupling procedure.
Notably, bibenzyl 11 (Fig. 2) was formed as a homocoupling
byproduct in approximately 10% yields (with respect to the halide)
when Pd(PPh3)2Cl2 was employed as the precatalyst in the coupling
reaction. In contrast, this byproduct was not detected when the
coupling was carried out using Pd(DPEPhos)Cl2. This accounted for
the higher observed coupling yields obtained using Pd(DPEPhos)Cl2
versus Pd(PPh3)2Cl2. In the Pd(DPEPhos)Cl2-catalyzed couplings the
halide was not being consumed in this homocoupling side reaction,
2.3. Catalyst screening for the developed Negishi coupling
method
In an effort to improve the isolated yield of diarylmethane 10,
numerous Pd(0) catalysts and their Pd(II) precatalyst analogues
were employed at various loadings and temperatures using either
benzyl bromide or benzyl chloride (BnCl) as the electrophilic
partners in the developed Negishi cross-coupling (Table 1). Re-
actions were carried out in THF, monitored by TLC for the con-
sumption of the halide and were stopped after a maximum of 48 h.
It was found that the bidentate ligand precatalyst Pd(DPEPhos)
21
Cl2 was by far the most effective Pd reagent employed in the
transformation, showing relatively higher yields (84e85%), faster
coupling rates and requiring only low catalyst loading (ca. 1 mol %)
at 70 ꢀC (entries 4 and 5) compared to other catalytic systems
attempted. The effect of temperature for this catalyst was also ex-
amined. When the coupling was carried out at 20 ꢀC (entry 6)
diarylmethane 10 was produced in very poor yield (19%) despite
the use of higher catalyst loading (5 mol %) and a longer reaction
time. This low coupling yield was attributed to the poor catalyst
solubility at 20 ꢀC, apparent because the catalyst remained as
Fig. 2. Bibenzyl 11, obtained as a byproduct in the Pd(PPh3)2Cl2-catalyzed cross-
couplings.

2128
E.G. Dennis et al. / Tetrahedron 67 (2011) 2125e2131
so a greater quantity of halide was available to participate in the
cross-coupling with organozinc 9b.
A variety of cross-coupling products were constructed in
acceptable to very good yields using low precatalyst loading
(ca. 1 mol %) in reasonable reaction times. Entries 1 and 2 show
benzyl bromides and chlorides containing either electron donating
or electron withdrawing substituents can be coupled to organozinc
9b using the developed catalytic system. In order to establish the
selectivity of cross-couplings of benzyl bromides in comparison
with aryl bromides, the reactivity of bromide 12b in the coupling
system was explored (entry 2). Reduction of the reaction temper-
ature to 40 ꢀC resulted in the selective coupling of the benzylic
bromide (at 70 ꢀC, mixtures of aryl, benzyl and bis coupled products
were obtained). This strongly suggested under these reaction
conditions, oxidative addition of the Pd catalyst into the benzyl
carbonebromine bond was much faster in comparison to the aryl
bromide. The reduced reaction temperature resulted in a decreased
coupling yield compared to that obtained for the couplings of other
benzyl halides. The 55% isolated yield of diarylmethane 13b, how-
ever, was acceptable when the difficult nature of the coupling was
taken into consideration. Furthermore, this selective coupling
provides opportunities for iterative syntheses of larger and more
elaborate motifs, as the remaining aryl bromide could be coupled to
other organometallic reagents in a subsequent step.
The coupling was also attempted using another bidentate ligand
precatalyst, Pd(dppf)Cl2.CH2Cl2 (entry 8) at 70 ꢀC. The coupling us-
ing this catalyst was very sluggish, with TLC analysis showing benzyl
bromide was still present even after 48 h, and 52% was the highest
coupling yield obtained using this catalyst. It was noted that this
catalyst did not appear to dissolve completely in the reaction mix-
ture. This provided some explanation for the sluggish reaction rate
as the actual catalyst loading present in solution was likely much
lower than that added to the reaction mixture (3 mol %).
2.4. Extension of Negishi coupling system to other
electrophiles
In order to further investigate the scope of this methodology,
the optimized Pd(DPEPhos)Cl2-catalyzed coupling procedure was
expanded to the coupling of organozinc 9b with numerous benzyl
and aryl halides containing a variety of functional groups to furnish
substituted diarylmethanes and biaryls containing the 1,3,5-tri-
methoxyphenyl subunit (Table 2).
Aryl halides 12cef (entries 3e6) also readily coupled to orga-
nozinc 9b under the conditions developed to provide the corre-
sponding biaryls 13cee. Notably, biaryl 13c was obtained in
comparable yields using either iodobenzene 12c (entry 3) or bro-
mobenzene 12d (entry 4) as the coupling electrophile. A much
longer reaction time was required, however, to achieve complete
coupling of 12d. Additionally, chlorobenzene 12g could not be
coupled under the developed conditions (entry 7). This suggested
that the nature of the aryl halide (Cl, Br or I) played an important
role in the rate of the coupling reaction, which contrasted to the
earlier results observed for the coupling rates of benzyl halides. The
coupling system was also extended to incorporate aryl iodides
containing either electron withdrawing (entry 5) or electron do-
nating (entry 6) substituents. Comparison of the coupling yields
and times of these aryl iodides suggested that the yield was not
greatly affected by the substituent, but the coupling rate increased
slightly in the presence of the strongly electron withdrawing nitro
group. The synthesis of biaryls 13c and 13e also supported the
experimental and theoretical results reported recently by Liu
et al.22 This report concluded that the best results for synthesis of
ortho-substituted biaryls using Negishi methods requires the cou-
pling of a more ortho-substituted arylzinc species with a less
substituted aryl iodide. This was indeed the case for biaryls 13c and
13e, which were synthesized in good yield (81% and 74%,
respectively) through the coupling of the more substituted orga-
nozinc 9b with the less substituted iodides 12c and 12f.
Table 2
Pd(DPEPhos)Cl2-mediated cross-couplings of 9b with benzyl and aryl halides
Entry
Halide
Rxn timea
(h)
Productb
Yieldc
(%)
1
4
68
55
2
3d
3
4
5
5
24
4
81
77
80
3. Conclusions
In summary, various biaryls and diarylmethanes containing the
highly electron rich 1,3,5-trimethoxyphenyl subunit were synthe-
sized in moderate to very good yields utilizing a single, easy to
prepare and conduct Pd(DPEPhos)Cl2-catalyzed Negishi coupling
protocol. Importantly, this method was applicable to the coupling
of both benzyl and aryl halides containing electron withdrawing
and electron donating substituents. To the best of our knowledge,
this is the first report of a single method, that is, conveniently
applicable to both biaryl and diarylmethane synthesis. Extension
of these methods to other aromatic and aliphatic electrophiles
is currently underway in order to access additional products
containing the phloroglucinol subunit. The application of similar
Pd-catalyzed coupling procedures towards the synthesis of C8-
subsituted catechin derivatives is also under investigation.
6
6
74
0
7
48
a
Reaction conditions: halide (1 equiv), 9b (1.5 equiv), THF, Pd(DPEPhos)Cl2
(w1 mol %), 70 ꢀC. Reactions were monitored by TLC for consumption of halide.
b
R¼2,4,6-trimethoxyphenyl.
c
Isolated yields following silica chromatography.
d
Conducted at 40 ꢀC.

E.G. Dennis et al. / Tetrahedron 67 (2011) 2125e2131
2129
4. Experimental
minimal boiling CHCl3 and a roughly equal portion of hot Et2O was
added. The mixture was cooled to room temperature and placed in
a ꢁ20 ꢀC freezer overnight to allow crystallization of the product.
The resulting white crystals were isolated by suction, washed with
cold Et2O (10 mL) and allowed to dry to provide 10.1 g (71%) of the
4.1. General methods
4.1.1. Materials. Commercial reagents were purchased from Sig-
maeAldrich and used without further purification unless noted.
THF was distilled from sodium/benzophenone ketyl under an
atmosphere of nitrogen prior to use. All Pd catalysts other than Pd
(DPEPhos)Cl2 were purchased from SigmaeAldrich, used as
received and stored under nitrogen in fridge at 4 ꢀC between uses.
N-Bromosuccinimide (NBS) was recrystallised from hot water prior
to use. n-BuLi was used as received as a solution in hexanes and
titrated according to the method of Suffert23 either prior to use or
on a weekly basis when in regular use. 1-Bromo-2,4,6-trimethox-
ybenzene (8) was prepared according to the literature procedure of
Mondal et al.16
desired boronic acid 9a. 1H NMR (400 MHz, CDCl3)
d 7.00 (s, 2H),
6.14 (s, 2H), 3.87 (s, 6H), 3.83 (s, 3H). NMR data for the synthesized
compound corresponded to those reported for the title compound
by Chaumeil et al.17
4.3. 1,3,5-Trimethoxy-(2-phenylmethyl)benzene (10). General
procedure for the coupling of boronic acid 9a with benzyl
bromide
A 25 mL round bottom flask was charged with 9a (ca. 320 mg,
1.51 mmol), either anhydrous NaOH or K2CO3 (ca. 3 mmol) and Pd
(PPh3)2Cl2 (1 mol %). THF (10 mL) was then added and the mixture
was stirred until the boronic acid and catalyst dissolved. The
resulting mixture was degassed with an Argon sparge for 30 min.
4.1.2. Experimental procedures. All reactions were conducted using
anhydrous solvents under an argon atmosphere and performed in
oven dried round bottom or vial flasks fitted with a rubber suba seal
unless stated. Organic solutions were concentrated via rotary
evaporation under reduced pressure. Thin layer chromatography
(TLC) was performed using the indicated solvent systems on
E. Merck silica gel 60 F254 plates (0.25 mm). Compounds were
Neat BnBr (120 mL, 1 mmol) was added via syringe, followed by
water (2 mL) for the aqueous reactions. The resulting mixtures
were stirred for 24 h at 70 ꢀC, then cooled to room temperature and
quenched by the addition of satd aq NH4Cl (10 mL). The resulting
mixture was extracted with CH2Cl2 (2ꢂ20 mL) and the combined
organics were dried (Na2SO4), filtered and concentrated in vacuo.
The title product 10 was obtained in w10% isolated yield using
aqueous K2CO3 as the base and w20% using aqueous NaOH as the
base. In both cases the product was isolated as a white, powdery
solid following silica gel chromatography (CH2Cl2/hexanes, 1:1) of
visualized via exposure to a UV lamp (
l
¼254 nm) and developed by
dipping in a KMnO4 solution followed by brief heating using a heat
gun. Silica gel chromatography was conducted using E. Merck silica
gel (230e400 mesh).
4.1.3. Spectral and structural analysis. 1H and 13C NMR spectra were
recorded on a Bruker Avance III 400 MHz spectrometer. 1H NMR
(400 MHz) chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane and referenced to residual pro-
the crude mixtures. 1H NMR (400 MHz, CDCl3)
6.15 (s, 2H), 3.93 (s, 2H), 3.80 (s, 3H), 3.77 (s, 6H). 13C NMR
d 7.24e7.07 (m, 5H),
(100 MHz, CDCl3) d 159.5,159.1,142.5,128.6,128.1,125.4,110.6, 90.9,
55.9, 55.5, 28.5. Mp 93e94 ꢀC (lit. Mp 93e95 ꢀC). NMR and mp data
for the synthesized compound corresponded to those reported by
Katritzky et al.24 for the title compound.
tonium in the NMR solvent (CHCl3,
d¼7.26). Data are reported as
the following: chemical shift, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet, b¼broad, app¼apparent), cou-
pling constant J hertz (Hz), and integration. 13C NMR chemical shifts
(100 MHz) are reported in ppm downfield from tetramethylsilane
and referenced to the carbon resonances in the NMR solvent (CDCl3,
4.4. 1,3,5-Trimethoxy-(2-phenylmethyl)benzene (10). Table 1:
representative procedure for the Pd(PPh3)2Cl2-catalyzed
cross-coupling of 9b with benzyl bromide
d¼77.0). High resolution mass spectra (HRMS) were performed at
the Monash University Mass Spectrometry Unit and were recorded
using a Bruker 4.7 T FTMS Ultra High Resolution spectrometer using
Electrospray Ionisation (ESI). Melting points were recorded using
a Reichert hot stage apparatus and are uncorrected. FTIR spectra
were recorded using a Lambda Scientific FTIR-7600 instrument in
ATR mode using a solid sample. FTIR absorbances are reported as
wavenumbers (cmꢁ1).
To a stirring solution of 1-bromo-2,4,6-trimethoxybenzene 8
(0.32 g, 1.29 mmol) in anhydrous THF (4 mL) at ꢁ78 ꢀC, n-BuLi
(1.00 mL, 1.40 M, 1.40 mmol) was added dropwise over 1 min and
stirring was continued until a white precipitate formed (ca.
10e15 min). To this mixture, a solution of ZnCl2 (1.40 mL, 1.00 M in
THF, 1.40 mmol), was added dropwise and the resulting clear, col-
ourless solution was stirred at ꢁ78 ꢀC for 15 min and then slowly
warmed to 0 ꢀC over 30 min. Neat BnBr (100
mL, 0.84 mmol) was
4.2. 2,4,6-Trimethoxyphenylboronic acid (9a)
added at 0 ꢀC, followed immediately by solid Pd(PPh3)2Cl2 (6 mg,
1 mol %) and the resulting mixture was warmed to 70 ꢀC and stirred
for 20 h. The mixture was cooled to room temperature and dilute
HCl (2 M, 10 mL) was added, followed by CH2Cl2 (20 mL) and the
mixture was rapidly stirred for 10 min. The phases were then
separated and the aqueous phase was extracted with CH2Cl2
(2ꢂ10 mL). The combined organics were dried (Na2SO4), filtered
and concentrated in vacuo. Purification of the yellow residue by
silica gel chromatography (CH2Cl2/hexanes 1:1) provided 131 mg
(60%) of the title compound as a white powdery solid.
The title compound was prepared using an adapted procedure
for the same compound reported by Chaumeil et al.17 To a stirring
solution of 1,3,5-trimethoxybenzene 7 (11.3 g, 67.2 mmol) in THF
(200 mL) at 0 ꢀC, n-BuLi (45 mL, 1.60 M, 72.0 mmol) was added
dropwise over 10 min. The resulting white suspension was stirred
at this temperature for 2 h and then cooled to ꢁ78 ꢀC. B(OMe)3
(15.0 mL, 135 mmol) in THF (15 mL) was added dropwise over 1 h
and the resulting mixture was stirred at ꢁ78 ꢀC for 1 h before being
allowed to slowly warm in the cold bath to room temperature
overnight. The resulting cloudy, white mixture was cooled to 0 ꢀC
and water (100 mL) was added dropwise with stirring over 30 min.
The mixture was poured into water (200 mL) and CH2Cl2 (300 mL)
and stirred vigorously for 15 min. The phases were separated and
the aqueous phase was extracted with CH2Cl2 (4ꢂ50 mL), and the
combined organics were dried (Na2SO4), filtered and concentrated
to provide a white powdery solid. The solid was dissolved in
4.5. [Bis(o-diphenylphosphinophenyl)ether]palladium(II)
chloride (Pd(DPEPhos)Cl2)
The title compound was prepared using an adapted procedure as
reported by Kranenburg et al.25 A suspension of bis(triphenylphos-
phino)palladium(II) chloride (Pd(PPh3)2Cl2, 0.32 g, 0.46 mmol) and
bis(o-diphenylphosphinophenyl)ether (DPEPhos, 0.30 g, 0.56 mmol)

2130
E.G. Dennis et al. / Tetrahedron 67 (2011) 2125e2131
inTHF (20 mL) was stirred at room temperature for 24 h. The THF was
removed in vacuo and the remaining solids were filtered by suction,
and washed with several portions of Et2O. The residual solid was
collected and dried in vacuo to afford 0.31 g (95%) of the desired
product as a dull yellow solid. The catalyst was used without further
purification and stored in fridge at 4 ꢀC under nitrogen between uses.
4.9. 2,4,6-Trimethoxy-40-nitrobiphenyl (13d, Table 2, entry 5)
The title compound was prepared by the general Table 2 pro-
cedure using 12e as the halide. Purification by silica gel chroma-
tography (EtOAc/hexanes, 1:9) afforded the product (80%) as an
orange solid. 1H NMR (400 MHz, CDCl3)
d
8.19 (d, J¼9.0 Hz, 2H), 7.50
(d, J¼9.0 Hz, 2H), 6.23 (s, 2H), 3.86 (s, 3H), 3.72 (s, 6H). Mp
167e169 ꢀC (lit. Mp 170 ꢀC). NMR and mp data for the prepared
compound corresponded to those reported by Abramovitch et al.28
for the title compound.
4.6. 1,3,5-Trimethoxy-2-[(4-methoxyphenyl)methyl]benzene
(13a, Table 2, entry 1). Representative procedure for Table 2
couplings
4.10. 2,4,6-Trimethoxy-20-methylbiphenyl (13e, Table 2, entry 6)
To a stirring solution of 1-bromo-2,4,6-trimethoxybenzene 8
(0.29 g, 1.17 mmol) in anhydrous THF (4 mL) at ꢁ78 ꢀC, n-BuLi
(1.00 mL, 1.25 M, 1.25 mmol) was added dropwise over 1 min and
stirring was continued until a white precipitate formed (ca.
10e15 min). To this mixture, a solution of ZnCl2 (1.20 mL, 1.00 M in
THF, 1.20 mmol), was added dropwise and the resulting clear, col-
ourless solution was stirred at ꢁ78 ꢀC for 15 min and then slowly
warmed to 0 ꢀC over 30 min. Neat 4-methoxy-benzyl chloride (12a,
The title compound was prepared by the general Table 2 pro-
cedure using 12f as the halide. Purification by silica gel chroma-
tography (EtOAc/hexanes, 1:9) afforded the product (74%) as
a white solid. 1H NMR (400 MHz, CDCl3)
d
7.29e7.15 (m, 4H), 6.27
(s 2H), 3.91 (s, 3H), 3.73 (s, 6H), 2.12 (s, 3H). 13C NMR (100 MHz,
CDCl3) 160.8, 158.5, 138.0, 134.4, 131.5, 129.7, 127.2, 125.4, 112.1,
d
91.0, 56.0, 55.5, 20.0. HRMS (ESI): calculated for C16H18O3,
[MþH]þ¼259.1329, found 259.1336. Mp 91e93 ꢀC. FTIR (solid):
3017, 2956, 2936, 2846, 1607, 1585, 1456, 1410, 1338, 1223, 1207,
110 m
L, 0.81 mmol) was added at 0 ꢀC, followed immediately by
solid Pd(DPEPhos)Cl2 (7 mg, 1 mol %) and the resulting mixture was
warmed to 70 ꢀC and stirred for 4 h. The mixture was cooled to
room temperature and dilute HCl (2 M, 10 mL) was added, followed
by CH2Cl2 (20 mL) and the mixture was rapidly stirred for 10 min.
The phases were then separated and the aqueous phase was
extracted with CH2Cl2 (2ꢂ10 mL). The combined organics were
dried (Na2SO4), filtered and concentrated in vacuo. Purification of
the yellow residue by silica gel chromatography (CH2Cl2/hexanes
1:1) provided 160 mg (68%) of the title compound as a white
1153, 1124, 1058, 1003, 807, 768, 731 cmꢁ1
.
Acknowledgements
This work was financially supported by Australia’s grapegrowers
and winemakers through their investment body the Grape and
Wine Research and Development Corporation, with matching
funds from the Australian Government, and by the Commonwealth
Cooperative Research Centres Program.
powdery solid. 1H NMR (400 MHz, CDCl3)
6.76 (d, J¼8.8 Hz, 2H), 6.15 (s, 2H), 3.88 (s, 2H), 3.80 (s, 3H), 3.79 (s,
d
7.16 (d, J¼8.8 Hz, 2H),
6H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
159.8, 159.0, 157.6,
Supplementary data
134.7, 129.5, 113.6, 111.0, 90.9, 55.9, 55.5, 55.4, 27.6. Mp 73e77 ꢀC
(lit. Mp 77e78 ꢀC). NMR and mp data for the synthesized com-
pound corresponded to those reported by Hofmann et al.26 for the
title compound.
Characterization data, 1H and 13C NMR and HRMS for new
compounds 13b and 13e are available. Supplementary data associ-
ated with this article can be found in online version at doi:10.1016/
j.tet.2011.01.030. These data include MOL files and InChIKeys of the
most important compounds described in this article.
4.7. 1,3,5-Trimethoxy-2-[(3-bromophenyl)methyl]benzene
(13b, Table 2, entry 2)
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