Threefold and chemoselective couplings of triarylbismuths with benzylic chlorides and iodides using palladium catalysis

Article abstract of DOI:10.1039/c3ra46672h

This paper describes the palladium-catalyzed studies on threefold coupling of triarylbismuth reagents with benzylic chlorides and iodides. The optimized protocol conditions are operationally simple, delivering threefold coupling of a variety of triarylbismuths in combination with benzylic chlorides and iodides. The two optimized protocols allowed the synthesis of a diverse range of unsymmetrical diarylmethanes in an efficient manner. As part of this study, chemoselective transformation of benzylic chlorides and iodides was also achieved. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra46672h

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Threefold and chemoselective couplings of
triarylbismuths with benzylic chlorides and iodides
Cite this: RSC Adv., 2014, 4, 13134
using palladium catalysis†
*
Maddali L. N. Rao and Ritesh J. Dhanorkar
This paper describes the palladium-catalyzed studies on threefold coupling of triarylbismuth reagents with
benzylic chlorides and iodides. The optimized protocol conditions are operationally simple, delivering
threefold coupling of a variety of triarylbismuths in combination with benzylic chlorides and iodides. The
two optimized protocols allowed the synthesis of a diverse range of unsymmetrical diarylmethanes in an
efficient manner. As part of this study, chemoselective transformation of benzylic chlorides and iodides
was also achieved.
Received 13th November 2013
Accepted 27th January 2014
DOI: 10.1039/c3ra46672h
www.rsc.org/advances
Thus, new ways of synthesizing diarylmethane skeletons
through simple and more adaptive means are highly useful.
Introduction
This gives an additional advantage when one of the reactants
offers multi-fold couplings in one-pot operation with addi-
tional, functional group tolerance and chemoselectivity. To the
best of our knowledge, the coupling studies of triarylbismuths
in combination with benzylic chlorides and iodides are not
reported so far.5,7 In continuation, we report here our studies on
the couplings of triarylbismuth reagents with benzylic chlorides
and iodides using palladium-catalyzed conditions.
Bismuth compounds are user friendly reagents with high
reactivity and selectivity for various transformations in organic
synthesis.1,2 The emphasis and utilization of bismuth reagents
in organic synthesis is highly benecial, as bismuth compounds
are non-toxic and are used in medicinal and other applications.3
Our focussed efforts in the utilization of triarylbismuths as
threefold coupling reagents is conceptually novel and synthet-
ically useful as this approach allows threefold coupling in
one-pot operation with 1/3 loading of aryl organometallic
nuclephiles.4 As part of these efforts, we recently demonstrated
the facile coupling reactivity of triarylbismuth reagents with
benzylic bromides under Pd-catalyzed conditions.5
Results and discussion
To start the process, the cross-coupling reactivity study of
benzylic chloride and BiPh3 was checked under our earlier
conditions developed for benzylic bromides5 (Table 1). This
study with 4-acetylbenzyl chloride utilizing Pd(PPh3)4 catalyst
using N,N-dimethylacetamide (DMA) solvent in the presence of
K3PO4 base provided 57% yield of the cross-coupled product 2.1
in one hour reaction time (entry 1). Increasing the reaction time
to two hours did not provide high product yield (entry 2).
Evaluation of different solvents such as N,N-dimethylforma-
mide (DMF) and N-methyl-2-pyrrolidone (NMP) offered 69%
and 53% yields (entries 3 and 4). Different bases in DMF solvent
also proved to be benecial, in particular K2CO3 and Na2CO3
delivered 91% and 93% yields (entries 6 and 7); while Cs2CO3
gave 2.1 in 41% yield (entry 5). Other palladium precursors such
as PdCl2(PPh3)2 and Pd2(dba)3 proved to be ineffective with low
cross-coupled yields (entries 8 and 9). Further checks to nd the
optimum amount required for threefold coupling gave mixed
results with varied amounts of base (entries 10–15). The cross-
coupling was ineffective without base (entry 15), while reactions
with increasing amounts of base furnished improved yields
between 40 and 84% (entries 10–14) and a high outcome was
achieved with 6 equiv. of base giving 93% yield (entry 7). The
Importance of benzylic couplings originates from the fact
that diarylmethanes are signicant skeletons of biological and
medicinal importance. For example, sergliozin, dapagliozin
and tofogliozin (Fig. 1) are recently investigated for Selective
Sodium Glucose Cotransporter 2 (SGLT2) inhibition studies for
type 2 diabetes applications.6
Fig. 1 A few examples of SGLT2 inhibitors.
Indian Institute of Technology Kanpur, Department of Chemistry, Kanpur, U.P., India.
E-mail: maddali@iitk.ac.in
† Electronic supplementary information (ESI) available: Spectra for all the
literature unknown products (including 1H NMR, 13C NMR and mass spectra).
See DOI: 10.1039/c3ra46672h
13134 | RSC Adv., 2014, 4, 13134–13144
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 1 Screening for benzylic chloride couplingsa,b,c
substituted with p-methyl, p-methoxy, m-methoxy, o-methoxy,
m-methyl, p-uoro, p-chloro, m-triuoromethyl, p-isopropoxy
and p-allyloxy groups. In this evaluation, the general coupling
ability was proved to be effective and the desired unsymmetrical
diarylmethanes (2.1–2.13) were formed in 52–93% yields.
Simultaneously, this has also demonstrated the facile threefold
coupling nature of numerous aryl bismuth reagents in one-pot
operation. This study also indicated the effective functional
group tolerance in the formation of diverse unsymmetrical
diarylmethanes in a short reaction time.
Further investigation under the optimized protocol condi-
tions proved to be capable of efficient couplings with diverse
benzylic chlorides (Table 3). This was achieved with benzyl
chlorides comprising electronically different functional groups
and in conjunction with a variety of triarylbismuth reagents. It
was interesting to note that electron-rich or -poor benzyl chlo-
rides in general furnished excellent yields indicating the
synthetic efficiency of these couplings. Functional group toler-
ance that was observed further demonstrates the general
coupling ability and compatibility of our protocol conditions.
This elegance of aryl bismuth reagents with threefold coupling
in combination with electronically different benzyl chlorides
provided a diverse range of unsymmetrical diarylmethanes
under simple protocol conditions. This is a novel and facile
reactivity and the corresponding products were isolated
between 49 and 98% yields (3.1–3.29). Notably, sterically
Entry
Catalyst (equiv.)
Base (equiv.)
Solvent
Yieldb [%]
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
No catalyst
K3PO4 (6)
K3PO4 (6)
K3PO4 (6)
K3PO4 (6)
DMA
DMA
DMF
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
57d
60
69
53
41
91
93
7
Cs2CO3 (6)
K2CO3 (6)
Na2CO3 (6)
Na2CO3 (6)
Na2CO3 (6)
Na2CO3 (5)
Na2CO3 (4)
Na2CO3 (3)
Na2CO3 (2)
Na2CO3 (1)
No base
Na2CO3 (6)
Na2CO3 (6)
Na2CO3 (6)
Na2CO3 (6)
Na2CO3 (6)
Na2CO3 (6)
9
33
84
82
64
40
44
—
50e
59f
10
11
12
13
14
15
16
17
18
19
20
21
g
—
52h
55i
—
a
Conditions: 4-acetylbenzyl chloride (0.875 mmol, 3.5 equiv.), BiPh3
(0.25 mmol, 1 equiv.), Pd-catalyst (0.0225 mmol, 0.09 equiv.), base (1.5
b
mmol, 6 equiv.), solvent (3 mL), 90 ꢀC, 2 h. Isolated yields reported.
Table 2 Couplings with different BiAr3 reagentsa,b
c
e
Homo-coupled biphenyl formed in minor amounts. d For 1 h. At 80
f
g
h
i
ꢀC. At 60 ꢀC. At 40 ꢀC. With 0.06 equiv. of catalyst. With 0.03
equiv. of catalyst.
couplings conducted at different temperaꢀture conditions were
ꢀ
informative. For example, reactions at 80 C or 60 C provided
moderate yields (entries 16 and 17) and found to be ineffective
at 40 ꢀC (entry 18). Screenings with lowered amounts of catalysts
provided moderate yields (entries 19 and 20) and the desired
coupling did not occur in the absence of catalyst (entry 21). As is
known in these couplings,2 invariably homo-coupled biphenyl
was formed in varied amounts during screening reactions.
However, it was easy to separate it from the desired cross-
coupling product during chromatographic separation. Aer this
investigation, it was clear that the cross-coupling is high
yielding with the protocol consisting of Pd(PPh3)4 (0.09 equiv.)
and Na2CO3 (6 equiv.) in DMF solvent at 90 ꢀC for 2 hours (entry
7); and it was considered as our optimum condition. It should
be mentioned that the optimized palladium protocol is effective
with the delivery of threefold coupling of triphenylbismuth in
reactions with three equivalents of functionalized benzyl chlo-
ride for 2 hours reaction time. This is very fast and appreciable
reactivity of this coupling method.
To demonstrate the generality, various bismuth reagents
were tested in threefold coupling with 4-acetylbenzyl chloride
under the optimized conditions. For this, electronically
different aryl bismuth reagents were employed (Table 2)
a
Reaction conditions: 4-acetylbenzyl chloride (0.875 mmol, 3.5 equiv.),
BiAr3 (0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09 equiv.),
Na2CO3 (1.5 mmol, 6 equiv.), DMF (3 mL), 90 ꢀC, 2 h. Isolated yields
reported. b Homo-coupled biaryls formed in minor amounts.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 13134–13144 | 13135

View Article Online
RSC Advances
Paper
Table 3 Couplings with different benzylic chloridesa,b
The comprehensive couplings carried out with p-bromo, m-
bromo, and o-bromo benzyl chlorides underwent selective
benzylic couplings and delivered the corresponding bromo
substituted unsymmetrical diarylmethanes (4.1–4.13) in 71–
95% yields. Similar couplings with p-chloro, m-chloro, and o-
chloro benzyl chlorides also furnished chemoselective
couplings and the respective chloro diarylmethanes (4.14–4.19)
were obtained in 67–94% yields. Thus, this protocol allowed the
synthesis of regio-isomerically substituted bromo or chloro
derivatives of diarylmethanes in good to high yields. More
importantly, the presence of reactive bromide and chloride
groups in diarylmethane core products is synthetically useful
for further modications under metal catalyzed conditions.
At this stage of study, we considered the couplings with
benzylic iodides as they are expected to be more reactive under
metal catalysis. This led us to test the couplings of 4-ace-
tylbenzyl iodide as given in Table 5. The initial screening of the
model reaction with our benzylic bromide condition5 employ-
ing Pd(PPh3)4 and K3PO4 base in N,N-dimethylacetamide (DMA)
at 90 ꢀC furnished 2.1 in 42% yield (entry 1). This reaction with
the condition established above for chloride couplings showed
poor reactivity with 17% yield (entry 2).
Table 4 Chemoselective benzylic chloride couplingsa,b
a
Reaction conditions: benzylic chloride (0.875 mmol, 3.5 equiv.), BiAr3
(0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09 equiv.), Na2CO3
(1.5 mmol, 6 equiv.), DMF (3 mL), 90 ꢀC, 2 h. Isolated yields reported.
b
Homo-coupled biaryls formed in minor amounts. c 5 hours. d 4 hours.
congested ortho substituted triarylbismuth reagent and benzyl
chlorides provided moderate to high yields of diarylmethanes
(3.8, 3.18, 3.25–3.27) under the established conditions. In some
of the cases where moderate yields are given, unreacted benzyl
halide and its conversion to diarylethanes or benzyl alcohol in
minor amounts were observed along with the usual formation
of biaryl from triarylbismuth in minor amounts. Formation of
these side products is well known under metal-catalyzed
conditions.
Next, our investigation was focussed on chemoselective
couplings of functionalized benzylic chlorides with bismuth
reagents (Table 4). It was amazing to see that the relatively more
labile bromide did not participate in aryl couplings8 thus
furnishing chemoselective benzylic reactivity under the present
protocol conditions.
a
Reaction conditions: benzylic chloride (0.875 mmol, 3.5 equiv.), BiAr3
(0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09 equiv.), Na2CO3 (1.5
mmol, 6 equiv.), DMF (3 mL), 90 ꢀC, 2 h. Isolated yields reported.
b
Homo-coupled biaryls formed in minor amounts.
13136 | RSC Adv., 2014, 4, 13134–13144
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 5 Screening for benzylic iodide couplingsa,b,c
reagents were subjected to this protocol with 4-acetylbenzyl
iodide (Table 6). This effort gave a signicant general reactivity
of triarylbismuths in benzylic iodide couplings furnishing good
to high cross-coupled yields. This also revealed the minimum
dependence on electronic impact of aryl bismuth reagents in
threefold coupling with benzylic iodides under the established
protocol. This has provided various unsymmetrical diaryl-
methanes in 55–85% yields (2.1–2.9).
Entry Base (equiv.) Solvent
Temp (ꢀC) Time (h) Yield (%)
Further evaluation of the established protocol was carried
out with different benzylic iodides and bismuth reagents (Table
7). In these couplings, a variety of functional benzylic iodides
fared well in effective couplings with aryl bismuth reagents. In
these cases, the corresponding unsymmetrical diarylmethanes
were formed in 51–83% yields.
To further investigate, chemoselective couplings were
carried out with functionalized benzylic iodides as given in
Table 8. These reactions with bromo and chloro substituted
benzyl iodides demonstrated preferential couplings at the
benzylic terminus furnishing the corresponding chemoselective
products in 55–70% yields. The reactivity of various benzylic
iodides were fast and are effective in threefold coupling with
bismuth reagents even with low catalyst loadings (0.06 equiv.)
1
2
3
4
5
6
7
8
K3PO4 (6)
Na2CO3 (6)
K3PO4 (6)
K3PO4 (6)
K3PO4 (6)
Cs2CO3 (6)
K2CO3 (6)
K3PO4 (5)
K3PO4 (4)
K3PO4 (3)
K3PO4 (6)
K3PO4 (6)
K3PO4 (6)
K3PO4 (6)
K3PO4 (6)
No base
DMA
DMF
DMF
NMP
1,4-Dioxane 90
DME
THF
1,4-Dioxane 90
1,4-Dioxane 90
1,4-Dioxane 90
1,4-Dioxane 60
1,4-Dioxane 40
1,4-Dioxane 90
1,4-Dioxane 90
1,4-Dioxane 90
1,4-Dioxane 90
1,4-Dioxane 90
90
90
90
90
1
2
1
1
1
1
1
1
1
1
1
1
0.5
0.5
0.5
0.5
0.5
42
17
15
32
88
36
33
79
79
58
49
35
84
85d
66e
—
90
90
9
10
11
12
13
14
15
16
17
f
K3PO4 (6)
—
a
Conditions: 4-acetylbenzyl iodide (0.875 mmol, 3.5 equiv.), BiPh3 (0.25
mmol, 1 equiv.), Pd(PPh3)4b(0.0225 mmol, 0.09 equiv.), base (1.5 mmol, 6
Table 6 Couplings with different BiAr3 reagentsa,b
c
equiv.), solvent (3 mL). Isolated yields reported. Homo-coupled
d
biphenyl formed in minor amounts. With 0.06 equiv. of Pd(PPh3)4.
e
With 0.03 equiv. of Pd(PPh3)4. f Without catalyst.
To circumvent this, further screening was continued to nd
the right condition for iodide couplings. Initially, different
solvents and bases were tested to check their suitability and
this gave mixed results (entries 3–7). This study revealed that
1,4-dioxane in combination with K3PO4 was a more suitable
combination with 88% yield (entry 5). N,N-dimethylforma-
mide (DMF), N-methyl-2-pyrrolidone (NMP), 1,2-dimethoxy-
ethane (DME) and tetrahydrofuran (THF) solvents furnished
yields in the range of 15–36% with different base combina-
tions. Further checks carried out with K3PO4 base in 3–5
equivalents (entries 8–10) revealed that 6 equiv. was the most
suitable to provide a high yield (entry 5). Couplings at different
temperature conditions also indicated that the desired
coupling is more effective at 90 ꢀC (entry 5) while reactions
under 40–60 ꢀC conditions gave 35–49% yields (entries 11 and
12). Further optimization with 0.5 hour reaction time fur-
nished 84% yield (entry 13). Screening with catalyst loading of
0.06 equiv. also furnished 2.1 in 85% yield (entry 14) whereas,
0.03 equiv. delivered only 66% yield (entry 15). Coupling
reactions without base or catalyst proved to be ineffective
(entries 16 and 17). Overall, this search thus furnished
the condition with Pd(PPh3)4 (0.06 equiv.) and K3PO4 (6 equiv.)
in 1,4-dioxane at 90 ꢀC in 0.5 hour reaction time as the
optimum condition for efficient coupling with benzylic iodide
substrate (entry 14).
Entry
BiAr3
Diarylmethanes
Yield (%)
1
2
85
83
3
4
5
72
85
78
6
7
55
76
81
8
a
Conditions: 4-acetylbenzyl iodide (0.875 mmol, 3.5 equiv.), BiAr3 (0.25
mmol, 1 equiv.), Pd(PPh3)4 (0.015 mmol, 0.06 equiv.), K3PO4 (1.5 mmol,
6 equiv.), 1,4-dioxane (3 mL), 90 ꢀC, 0.5 h. Isolated yields reported.
Having established the optimum conditions for benzyl
iodide couplings with triphenylbismuth, various other bismuth
b
Homo-coupled biaryls formed in minor amounts.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 13134–13144 | 13137

View Article Online
RSC Advances
Paper
Table 7 Couplings with different benzylic iodidesa,b
It is to be highlighted that these chemoselective benzylic
couplings are useful for further structural elaborations.5,9 The
present chemoselective study has clearly demonstrated the
amenable reactivity of various halo substituted benzylic systems
in reaction with triarylbismuth reagents under simple palla-
dium protocol conditions.
The overall threefold coupling reactivity of triarylbismuth
reagents with benzylic halides is given in Scheme 1. As stated,
we have earlier demonstrated the coupling reactivity with
benzylic bromides under palladium conditions.5 The present
study dealt with the couplings of benzyl chlorides and iodides.
It is evident that this investigation revealed the exemplary
reactivity of these substrates with functional group (FG) toler-
ance and chemoselectivity. For general reactivity comparison,
benzylic iodides reacted with low catalyst loadings and 0.5 hour
short reaction time condition. Benzylic chlorides needed 2
hours while our earlier benzylic bromide couplings required 1
hour time to obtain high yields. Thus, the present investigation
shed light on the relative reactivity of various benzylic halides in
couplings with triarylbismuth reagents (Scheme 1).
The versatile couplings of various functionalized benzylic
chlorides and iodides, in addition to chemoselective investiga-
tion carried out here hence expanded the scope and generality
of triarylbismuth reagents as threefold coupling reagents in
benzylic couplings. In comparison, the three palladium
protocol conditions indicated that base and solvent have crucial
roles in reactions with different benzylic halides. In fact, the
change of base and solvent evolved through systematic
screening and has delivered facile coupling reactivity with
different benzylic bromides, chlorides, and iodides (Scheme 1).
An additional advantage of the present study is that benzylic
chlorides, that are otherwise supposed to be less reactive,
showed excellent coupling reactivity in tune with that of
benzylic bromides.5 Reactions with electronically rich benzyl
chlorides also showed better couplings under our coupling
conditions. This was not the case with literature known exam-
ples using other organometallic reagents.7d The couplings with
benzylic iodides using bismuth reagents is notable as these
a
Conditions: benzylic iodide (0.875 mmol, 3.5 equiv.), BiAr3 (0.25
mmol, 1 equiv.), Pd(PPh3)4 (0.015 mmol, 0.06 equiv.), K3PO4 (1.5
mmol, 6 equiv.), 1,4-dioxane (3 mL), 90 ꢀC, 0.5 h. Isolated yields
reported. b Homo-coupled biaryls formed in minor amounts.
Table 8 Chemoselective benzylic iodide couplingsa,b
a
Conditions: benzylic iodide (0.875 mmol, 3.5 equiv.), BiAr3 (0.25
mmol, 1 equiv.), Pd(PPh3)4 (0.015 mmol, 0.06 equiv.), K3PO4 (1.5
mmol, 6 equiv.), 1,4-dioxane (3 mL), 90 ꢀC, 0.5 h. Isolated yields
reported. b Homo-coupled biaryls formed in minor amounts.
and short reaction time in comparison to the couplings given
above with benzylic chlorides involving 2 hours or earlier results
with benzylic bromides using 1 hour reaction conditions.5
Scheme 1 Benzylic halide couplings with BiAr3 reagents.
13138 | RSC Adv., 2014, 4, 13134–13144
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
substrates are not popularly studied in a similar manner7h and benzylpalladium(II) chloride was performed with tri(p-anisyl)
this could be partly due to stability related issues known with bismuth under standardized conditions (eqn (1)).
these compounds. This demonstration of versatile, general and
chemoselective reactivity of benzyl chlorides and iodides as
electrophilic coupling partners is a rst time elaboration with
triarylbismuth reagents. Importantly, this was achieved using
routinely used palladium catalyzed conditions. As similar
comprehensive investigations are not available with bismuth
reagents in benzylic couplings,5,10,11 the present study is a
notable contribution.
(1)
(2)
(3)
(4)
Some methods are known in the literature using benzylic
halides as coupling partners with other organometallic
reagents.7 For example, the known benzyl chloride coupling
with aryltriuoroborate utilizes dppf ligand under palladium
conditions with longer reaction times delivering one C–C cou-
pling.7a Similar reactions with aryl boronic acids employing
specialized phosphine7d or pincer7b ligands in the palladium
protocol need a longer reaction course or higher reaction
temperature delivering one C–C coupling. The corresponding
benzylic iodide couplings are scarcely studied in the literature.7h
In that context, this study reveals a new scope of these couplings
with triarylbismuth reagents with efficient reactivity, selectivity,
short reaction times and good to high yields involving threefold
couplings from bismuth reagents in one-pot operation. Of note
is that in the literature not many organometallic reagents are
known which can serve as threefold coupling partners for
similar coupling reactions.10 The structural importance of dia-
rylmethanes in synthetic, medicinal, biological and other
applications adds further credence to the importance of this
method in the synthesis of various functionalized unsymmet-
rical diarylmethanes.
In this attempt, the benzylpalladium(II) chloride prepared
using benzyl chloride with Pd2(dba)3/PPh3 was directly used for
couplings aer removing the solvent under vacuum13 and with the
addition of DMF solvent and other reagents (eqn (1)). This reac-
tion gave the cross-coupled diarylmethane product namely,
1-benzyl-4-methoxybenzene in 45% yield. This utilization of pre-
formed Pd(II) intermediate (2a) and its reactivity is in tune with the
proposed oxidative addition step and its subsequent involvement
in the catalytic cycle (Fig. 2). Further investigations using the above
prepared benzylpalladium(II) chloride precatalyst in coupling
reactions with different benzyl chlorides furnished 31% and 39%
yields, respectively (eqn (2) and (3)). This additionally supports the
facile participation and catalytic reactivity of the preformed Pd(II)
intermediate. Further couplings with the direct use of Pd2(dba)3/
PPh3 replacing Pd(PPh3)4 in the standardized protocol also deliv-
ered the cross-coupled 1-benzyl-4-methoxybenzene in 40% yield
(eqn (4)). It should also be noted that the GC-MS analyses of the
crude reaction mixtures indicated the formation of biaryl homo-
coupling product from bismuth reagent in eqn (1)–(4) along with
unreacted benzyl chloride in eqn (2)–(4). Based on these investi-
gations, it is most likely that the cross-coupling follows the
proposed catalytic cycle to deliver the diarylmethane product. The
threefold coupling reactivity of triarylbismuth reagents can also be
envisaged through the repetitive participation of aryl bismuth
species4c in the catalytic cycle as the high yields of coupled yields
were seen usually under standardized conditions.
The mechanistic aspect of benzylic couplings under metal
catalyzed couplings with organometallic nucleophiles is well
documented in the literature. The oxidative addition of benzylic
halide to palladium(0) to give 2a (ref. 13) and its involvement in
transmetallation with organometallic reagent to give 2b was
proposed earlier.12 The reductive elimination of 2b further
generates benzyl coupled diarylmethane product as proposed in
catalytic cycle (Fig. 2).
To check this, we carried out a few investigations as outlined
below. Firstly, the coupling reaction of in situ generated
Conclusions
In conclusion, a diverse range of functionalized unsymmetrical
diarylmethane compounds have been synthesized using cross-
Fig. 2 Proposed catalytic cycle.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 13134–13144 | 13139

View Article Online
RSC Advances
Paper
coupling methodology involving the rst time couplings of 3H), 7.07 (d, J ¼ 7.45 Hz, 1H), 6.90–6.85 (m, 2H), 4.01 (s, 2H),
benzylic chlorides and iodides with triarylbismuths as threefold 3.79 (s, 3H), 2.55 (s, 3H). 13C NMR (125 MHz, CDCl3): d ¼ 197.88,
coupling partners. The two palladium protocol conditions 157.28, 146.98, 134.96, 130.34, 128.99, 128.74, 128.41, 127.82,
established in this study involve routinely used palladium 120.53, 110.48, 55.29, 36.07, 26.53. IR (neat, cmꢂ1): 3002, 2937,
catalysts under convenient reaction conditions. This study also 2836, 1681, 1606, 1493, 1463, 1438, 1357, 1267, 1245. EI (m/z)
delivered the functionalized unsymmetrical diarylmethanes in calcd for C16H16O2 [M]+ 240.1150; found 240.1154.
high product yields. The optimized protocols also delivered
chemoselective couplings both with benzyl chlorides and
iodides.
1-(4-(3-Fluorobenzyl)phenyl)ethanone (2.10)
Colorless liquid (114 mg, 67%), Rf (5% EtOAc–hexane) 0.32; 1H
NMR (500 MHz, CDCl3): d ¼ 7.88 (d, J ¼ 8.3 Hz, 2H), 7.26–7.23
(m, 3H), 6.94 (d, J ¼ 7.45 Hz, 1H), 6.90 (dt, J ¼ 8.9, 2.3 Hz, 1H),
6.84 (d, J ¼ 9.75, 1H), 4.00 (s, 2H), 2.56 (s, 3H). 13C NMR (125
MHz, CDCl3): d ¼ 197.82, 163.75 (d, JC–F ¼ 245.61 Hz), 145.96,
135.56, 130.14 (d, JC–F ¼ 8.35 Hz), 129.20, 128.82, 124.65, 115.90
(d, JC–F ¼ 21.46 Hz), 113.53, 113.37, 41.63, 26.66. IR (neat,
cmꢂ1): 2925, 1682, 1589, 1486, 1358, 1267, 785. EI (m/z) calcd for
Experimental
General
All reactions were performed according to standard procedures
in a oven-dried Schlenk tube under inert nitrogen atmosphere.
Triarylbismuths were prepared using the literature procedures.2
Benzylic chlorides and benzylic iodides were prepared using the
known methods.14,15 JEOL-Lambda (500 MHz and 400 MHz)
spectrometers was used for NMR measurements using CDCl3 as
solvent. Waters CAB155 GCT Premier analyzer was used for
HRMS spectral measurements.
C
15H13FO [M]+ 228.0950; found 228.0950.
1-(4-(4-Isopropoxybenzyl)phenyl)ethanone (2.12)
Pale brown liquid (with benzyl chloride or iodide, 157 mg, 78%),
Rf (5% EtOAc–hexane) 0.25; 1H NMR (500 MHz, CDCl3): d ¼ 7.87
(d, J ¼ 8 Hz, 2H), 7.26 (d, J ¼ 8 Hz, 2H), 7.06 (d, J ¼ 8.3 Hz, 2H),
6.81 (d, J ¼ 8.6 Hz, 2H), 4.52–4.47 (m, 1H), 3.95 (s, 2H), 2.56 (s,
Representative coupling procedure for 4-acetylbenzyl chloride
To an oven dried Schlenk tube, 4-acetylbenzyl chloride (0.875
mmol, 0.147.5 g), triphenylbismuth (0.25 mmol, 0.11 g), Na2CO3
(1.5 mmol, 0.159 g), Pd(PPh3)4 (0.0225 mmol, 0.026 g) and dry
DMF (3 mL) were added in the order specied under nitrogen
atmosphere. The contents were stirred at 90 ꢀC for 2 h using an
oil bath. Aer the specied time, the reaction mixture was
quenched with water and extracted with ethyl acetate (2 ꢁ 20
mL). The organic extract aer treating with brine was dried over
anhydrous MgSO4 and concentrated using a rotatory evapo-
rator. The crude product was subjected to silica gel column
chromatography (1% EtOAc–hexane) to obtain 1-(4-benzyl-
phenyl)ethanone as a colourless oil (0.146 g, 93%). The yield
was calculated considering 0.75 mmol of the product as 100%.
Note: in the case of products 3.27–3.29, p-methoxybenzyl
chloride was added aer addition of the solvent with a slight
change in the representative procedure. This was done as a
vigorous color change, heat generation and decomposition were
observed when p-methoxybenzyl chloride was added to the solid
mixture before addition of the solvent.
3H), 1.31 (d, J ¼ 6.3 Hz, 6H). 13C NMR (125 MHz, CDCl3): dC
¼
197.85, 156.40, 147.32, 135.08, 131.88, 129.85, 128.97, 128.58,
115.93, 69.81, 40.98, 26.57, 22.03. IR (neat, cmꢂ1): 2980, 2926,
1511, 1681, 1607, 1510, 1412, 1358, 1267, 1245, 1077, 1115.
HRMS (ES+): calcd for C18H21O2 [M + H]+ 269.1542; found
269.1542.
1-(4-(4-(Allyloxy)benzyl)phenyl)ethanone (2.13)
Colorless liquid (133 mg, 67%), Rf (5% EtOAc–hexane) 0.28; 1H
NMR (500 MHz, CDCl3): d ¼ 7.86 (d, J ¼ 8.3 Hz, 2H), 7.25 (d, J ¼
8.35 Hz, 2H), 7.06 (d, J ¼ 8.9 Hz, 2H), 6.84 (d, J ¼ 8.6 Hz, 2H),
6.07–5.99 (m, 1H), 5.39 (dd, J ¼ 1.45 Hz, 17.4 Hz, 1H), 5.26 (dd, J
¼ 1.45 Hz, 10.6 Hz, 1H), 4.50 (d, J ¼ 5.45 Hz, 2H), 3.95 (s, 2H),
2.56 (s, 3H). 13C NMR (125 MHz, CDCl3): d ¼ 197.81, 157.16,
147.24, 135.13, 133.28, 132.27, 129.84, 128.96, 128.59, 117.62,
114.82, 68.80, 40.98, 26.55. IR (neat, cmꢂ1): 2980, 2926, 1511,
1681, 1607, 1510, 1412, 1358, 1267, 1245, 1077, 1115, 1047, 810,
680, 602. HRMS (ES+): calcd for C18H19O2 [M + H]+ 267.1385;
found 267.1382.
Coupling conditions for benzylic iodide couplings
The above procedure was also used for benzylic iodide
couplings with the following conditions. Benzyl iodide (0.875
mmol, 3.5 equiv.), BiAr3 (0.25 mmol, 1 equiv.), K3PO4 (1.5 mmol,
6 equiv.), Pd(PPh3)4 (0.015 mmol, 0.06 equiv.), dry 1,4-dioxane (3
mL), 90 ꢀC, 0.5 h. The yield was calculated considering 0.75
mmol of the product as 100%.
4-(3,4-Dimethoxybenzyl)benzonitrile (3.5)
White solid (172 mg, 91%); m.p. 58–60 ꢀC, Rf (5% EtOAc–
hexane) 0.35. 1H NMR (500 MHz, CDCl3): d ¼ 7.56 (d, J ¼ 8.0 Hz,
2H), 7.27 (d, J ¼ 8.0 Hz, 2H), 6.81 (d, J ¼ 8.30 Hz, 1H), 6.69 (d, J ¼
8.05 Hz, 1H), 6.65 (s, 1H), 3.97 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H).
13C NMR (125 MHz, CDCl3): d ¼ 149.11, 147.81, 147.00, 132.24,
131.75, 129.45, 121.01, 118.96, 112.13, 111.32, 109.96, 55.88,
55.82, 41.48. IR (KBr, cmꢂ1): 3037, 2834, 2225, 1603, 1517, 1260,
All the products were identied by spectroscopic means and
in comparison with the literature data wherever available.
1-(4-(2-Methoxybenzyl)phenyl)ethanone (2.6)
Colorless liquid (145 mg, 80%), Rf (5% EtOAc–hexane) 0.22; 1H 1240, 1171, 1158, 1027, 811, 561. HRMS (ES+): calcd for
NMR (500 MHz, CDCl3): d ¼ 7.85–7.84 (m, 2H), 7.29–7.21 (m,
13140 | RSC Adv., 2014, 4, 13134–13144
C
16H16NO2 [M + H]+ 254.1181; found 254.1188.
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
(500 MHz, CDCl3): d ¼ 7.10–7.05 (m, 6H), 6.81 (d, J ¼ 8.55 Hz,
2H), 4.99 (q, J ¼ 7.15 Hz, 2H), 3.88 (s, 2H), 2.31 (s, 3H), 1.39 (t, J
¼ 6.85 Hz, 3H). 13C NMR (125 MHz, CDCl3): d ¼ 157.21, 138.54,
135.39, 133.38, 129.74, 129.07, 128.66, 114.39, 63.36, 40.57,
20.98, 14.87. IR (KBr, cmꢂ1): 2836, 2226, 1610, 1511, 1301, 1247,
1117, 1110, 1034, 810, 761, 572. HRMS (ES+): calcd for
4-(4-Chlorobenzyl)benzonitrile (3.7)
White solid (with benzyl chloride, 149 mg, 87%; with benzyl
iodide, 99 mg, 57%), m.p. 53–55 ꢀC, Rf (5% EtOAc–hexane) 0.59;
1H NMR (500 MHz, CDCl3): d ¼ 7.57 (d, J ¼ 8.05 Hz, 2H), 7.27–
7.24 (m, 4H), 7.07 (d, J ¼ 8.3 Hz, 2H), 3.98 (s, 2H). 13C NMR (125
MHz, CDCl3): d ¼ 146.07, 137.74, 132.56, 132.37, 130.26, 129.54,
128.87, 118.83, 110.28, 41.22. IR (KBr, cmꢂ1): 2223, 1603, 1488,
1405, 1176, 1088, 1014, 870, 819, 795. HRMS (ES+): calcd for
C
16H18ONa [M + Na]+ 249.1255; found 249.1253.
C
14H11ClN [M + H]+ 228.0580; found 228.0584.
1-Isopropoxy-4-(4-methylbenzyl)benzene (3.14)
1
Colorless liquid (169 mg, 93%), Rf (hexane) 0.67; H NMR (500
MHz, CDCl3): d ¼ 7.11–7.07 (m, 6H), 6.81 (d, J ¼ 8.6 Hz, 2H),
4.52–4.47 (m, 1H), 3.88 (s, 2H), 2.32 (s, 3H), 1.32 (d, J ¼ 6.3 Hz,
6H). 13C NMR (125 MHz, CDCl3): d ¼ 156.12, 138.53, 135.38,
133.35, 129.74, 129.06, 128.68, 115.84, 69.81, 40.58, 22.06,
20.09. IR (neat, cmꢂ1): 2836, 2226, 1610, 1511, 1301, 1247, 1117,
1110, 1034, 810, 761, 572. HRMS (ES+): calcd for C17H19O [M ꢂ
H]+ 239.1436; found 239.1431.
4-(2-Methoxybenzyl)benzonitrile (3.8)7e
Colorless liquid (142 mg, 85%), Rf (5% EtOAc–hexane) 0.45; 1H
NMR (500 MHz, CDCl3): d ¼ 7.53 (d, J ¼ 8.35 Hz, 2H), 7.29 (d, J ¼
8.30 Hz, 2H), 7.26–7.22 (m, 1H), 7.09 (d, J ¼ 5.7 Hz, 1H), 6.92–
6.87 (m, 2H), 4.00 (s, 2H), 3.79 (s, 3H). 13C NMR (125 MHz,
CDCl3): d ¼ 157.23, 146.90, 132.03, 130.40, 129.49, 128.13,
127.82, 120.60, 119.20, 110.55, 109.54, 55.27, 36.32. IR (neat,
cmꢂ1): 2838, 2216, 1612, 1511, 1300, 1247, 1117, 1110. EI (m/z)
calcd for C15H13NO [M]+ 223.0997; found 223.0999.
1-Methoxy-4-(4-uorobenzyl)benzene (3.15)7h
1
Colorless liquid (154 mg, 95%), Rf (hexane) 0.65; H NMR (500
MHz, CDCl3): d ¼ 7.12–7.06 (m, 4H), 6.95 (t, J ¼ 8.75 Hz, 2H),
6.83 (d, J ¼ 8.55 Hz, 2H), 3.88 (s, 2H), 3.77 (s, 3H). 13C NMR (125
MHz, CDCl3): d ¼ 161.33 (d, JC–F ¼ 242.02 Hz), 158.00, 137.21,
133.03, 130.11 (d, JC–F ¼ 8.33 Hz), 129.74, 115.13 (d, JC–F ¼ 21.42
Hz), 113.90, 55.23, 40.14. IR (KBr, cmꢂ1): EI (m/z) calcd for
Methyl 4-benzylbenzoate (3.9)16
Colorless liquid (with benzyl chloride or iodide, 110 mg, 65%),
Rf (5% EtOAc–hexane) 0.55; 1H NMR (500 MHz, CDCl3): d ¼ 7.95
(d, J ¼ 8.3 Hz, 2H), 7.30–7.20 (m, 5H), 7.17 (d, J ¼ 7.15 Hz, 2H),
4.02 (s, 2H), 3.89 (s, 3H). 13C NMR (125 MHz, CDCl3): d ¼ 167.05,
146.49, 140.09, 129.79, 128.92, 128.58, 128.05, 126.35, 52.00,
41.88. IR (neat, cmꢂ1): 2950, 1610, 1721, 1611, 1452, 1281, 1178,
1108, 805, 742. HRMS (ES+): calcd for C15H15O2 [M]+ 227.1072;
found 227.1071.
C
14H13FO [M]+ 216.0950; found 216.0950.
1-Ethoxy-4-(4-uorobenzyl)benzene (3.16)
1
Colorless liquid (162 mg, 94%), Rf (hexane) 0.67; H NMR (500
MHz, CDCl3): d ¼ 7.12–7.10 (m, 2H), 7.06 (d, J ¼ 8.85 Hz, 2H),
6.94 (t, J ¼ 8.72 Hz, 2H), 6.82 (d, J ¼ 8.6 Hz, 2H), 4.00 (q, J ¼ 6.85
Hz, 2H), 3.88 (s, 2H), 1.39 (t, J ¼ 6.85 Hz, 3H). 13C NMR (125
MHz, CDCl3): d ¼ 161.32 (d, JC–F ¼ 243.22 Hz), 157.37, 137.23,
132.88, 130.12 (d, JC–F ¼ 8.35 Hz), 129.72, 115.11 (d, JC–F ¼ 21.46
Hz), 114.48, 63.38, 40.16, 14.85. IR (neat, cmꢂ1): 2980, 1609,
1509, 1245, 1048, 816. EI (m/z) calcd for C15H15FO [M]+
230.1107; found 230.1108.
Methyl 4-(4-methylbenzyl)benzoate (3.10)7i
White solid (117 mg, 65%), m.p. 59–62 ꢀC Rf (5% EtOAc–hexane)
1
0.59; H NMR (500 MHz, CDCl3): d ¼ 7.94 (d, J ¼ 8.3 Hz, 2H),
7.24 (d, J ¼ 8.3 Hz, 2H), 7.10 (d, J ¼ 8 Hz, 2H), 7.05 (d, J ¼ 8 Hz,
2H), 3.98 (s, 2H), 3.88 (s, 3H), 2.31 (s, 3H). 13C NMR (125 MHz,
CDCl3): d ¼ 167.07, 146.82, 137.04, 135.89, 129.77, 129.27,
128.85, 128.80, 127.96, 51.98, 41.47, 20.99. IR (KBr, cmꢂ1): 2950,
1721, 1610, 1513, 1434, 1280, 1177, 1109, 1020, 819, 739. HRMS
(ES+): calcd for C16H17O2 [M + H]+ 241.1229; found 241.1227.
1-Isopropoxy-4-(4-uorobenzyl)benzene (3.17)
1
Colorless liquid (175 mg, 96%), Rf (hexane) 0.69; H NMR (500
MHz, CDCl3): d ¼ 7.13–7.10 (m, 2H), 7.04 (d, J ¼ 8.55 Hz, 2H),
6.95 (t, J ¼ 8.9 Hz, 2H), 6.80 (d, J ¼ 8.6 Hz, 2H), 4.51–4.47 (m,
1H), 3.87 (s, 2H), 1.30 (d, J ¼ 6 Hz, 6H). 13C NMR (125 MHz,
CDCl3): d ¼ 161.33 (d, JC–F ¼ 242.02 Hz), 156.30, 137.21, 132.85,
130.14 (d, JC–F ¼ 7.16 Hz), 129.73, 115.91, 115.11 (d, JC–F ¼ 21.46
Hz), 69.87, 40.17, 22.06. IR (neat, cmꢂ1): 2977, 1608, 1507, 1241,
1119, 956, 811. HRMS (ES+): calcd for C16H16FO [M ꢂ H]+
243.1185; found 243.1182.
Methyl 4-(4-methoxybenzyl)benzoate (3.11)17
Colorless liquid (with benzyl chloride, 142 mg, 74%; with benzyl
iodide, 125 mg, 65%), Rf (5% EtOAc–hexane) 0.43; 1H NMR (500
MHz, CDCl3): d ¼ 7.94 (d, J ¼ 8.3 Hz, 2H), 7.23 (d, J ¼ 8 Hz, 2H),
7.08 (d, J ¼ 8.3 Hz, 2H), 6.83 (d, J ¼ 8.55 Hz, 2H), 3.96 (s, 2H),
3.88 (s, 3H), 3.77 (s, 3H). 13C NMR (125 MHz, CDCl3): d ¼ 167.07,
158.12, 147.00, 132.18, 129.88, 129.77, 128.79, 127.95, 113.97,
55.23, 51.99, 40.99. IR (neat, cmꢂ1): 2951, 1720, 1611, 1511,
1435, 1282, 1247, 1178, 1109, 1035. HRMS (ES+): calcd for
1-(4-Fluorobenzyl)-2-methoxybenzene (3.18)
C
16H17O3 [M + H]+ 257.1178; found 257.1177.
1
Colorless liquid (105 mg, 65%), Rf (hexane) 0.65; H NMR (500
MHz, CDCl3): d ¼ 7.22–7.14 (m, 3H), 7.05 (d, J ¼ 7.45 Hz, 1H),
1-Ethoxy-4-(4-methylbenzyl)benzene (3.13)
6.96–6.92 (m, 2H), 6.90–6.86 (m, 2H), 3.93 (s, 2H), 3.81 (s, 3H).
White solid (with benzyl chloride, 167 mg, 98%; with benzyl 13C NMR (125 MHz, CDCl3): d ¼ 161.22 (d, JC–F ¼ 242.36 Hz),
iodide, 101 mg, 60%), m.p. 68–70 ꢀC, Rf (hexane) 0.65; 1H NMR 157.22, 136.61, 130.20 (d, JC–F ¼ 8.38 Hz), 129.46, 127.54, 120.48,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 13134–13144 | 13141

View Article Online
RSC Advances
Paper
114.92 (d, JC–F ¼ 21.60 Hz), 110.40, 55.30, 35.12. IR (neat, cmꢂ1):
3005, 2900, 2841, 1589, 1500, 1439, 1222, 1177. EI (m/z) calcd for
4-(4-Bromobenzyl)-1,2-dimethoxybenzene (4.5)
Brown liquid (195 mg, 85%), Rf (hexane) 0.45; 1H NMR (500
MHz, CDCl3): d ¼ 7.39 (d, J ¼ 8.3 Hz, 2H), 7.04 (d, J ¼ 8.6 Hz,
2H), 6.78 (d, J ¼ 8.30 Hz, 1H), 6.69–6.67 (m, 1H), 6.65 (d, J ¼ 2
Hz, 1H), 3.86 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H). 13C NMR (125
MHz, CDCl3): d ¼ 148.96, 147.52, 140.34, 132.92, 131.46, 130.49,
120.83, 119.85, 112.05, 111.17, 55.88, 55.79, 40.82. IR (neat,
cmꢂ1): 2950, 1721, 1610, 1513, 1434, 1280, 1177, 1109, 1020,
819, 739. HRMS (ES+): calcd for C15H16BrO2 [M + H]+ 307.0334;
found 307.0339.
C
14H13FO [M]+ 216.0950; found 216.0957.
1-Benzyl-4-methoxybenzene (3.19)18
1
Colorless liquid (140 mg, 94%), Rf (hexane) 0.65; H NMR (500
MHz, CDCl3): d ¼ 7.29–7.25 (m, 2H), 7.19–7.17 (m, 3H), 7.12–
7.09 (m, 2H), 6.84–6.82 (m, 2H), 3.93 (s, 2H), 3.78 (s, 3H). 13C
NMR (125 MHz, CDCl3): d ¼ 157.94, 141.56, 133.23, 129.84,
128.79, 128.41, 125.95, 113.84, 55.23, 41.01. IR (neat, cmꢂ1):
3026, 2906, 2834, 1610, 1511, 1493, 1453, 1300, 1246, 1116,
1035. EI (m/z) calcd for C14H14O [M]+ 198.1045; found 198.1042.
1-(Allyloxy)-4-(4-bromobenzyl)benzene (4.9)
1
Colorless liquid (177 mg, 78%), Rf (hexane) 0.25; H NMR (500
MHz, CDCl3): d ¼ 7.38 (d, J ¼ 8.3 Hz, 2H), 7.06–7.02 (m, 4H),
6.83 (d, J ¼ 8.6 Hz, 2H), 6.07–6.0 (m, 1H), 5.39 (dd, J ¼ 17.45 Hz,
1.45 Hz, 1H), 5.27 (dd, J ¼ 10.6 Hz, 1.45 Hz, 1H), 4.50 (d, J ¼ 5.45
Hz, 2H), 3.85 (s, 2H). 13C NMR (125 MHz, CDCl3): d ¼ 157.11,
140.50, 133.33, 132.70, 131.44, 130.53, 129.77, 119.79, 117.61,
114.78, 68.82, 40.38. IR (neat, cmꢂ1): 2980, 2926, 1511, 1681,
1607, 1510, 1412, 1358, 1267, 1245, 1077, 1115, 1047, 810, 680,
602. HRMS (ES+): calcd for C16H16BrO [M + H]+ 302.0306; found
302.0301.
(4-Chlorophenyl)(4-(4-chlorobenzyl)phenyl)methanone (3.24)
White solid (207 mg, 81%), m.p. 90–91 ꢀC Rf (5% EtOAc–hexane)
1
0.25; H NMR (500 MHz, CDCl3): d ¼ 7.73 (d, J ¼ 8.55 Hz, 2H),
7.70 (d, J ¼ 7.95 Hz, 2H), 7.44 (d, J ¼ 8.55 Hz, 2H), 7.27–7.25 (m,
4H), 7.12 (d, J ¼ 8.55 Hz, 2H), 4.01 (s, 2H). 13C NMR (125 MHz,
CDCl3): d ¼ 195.06, 145.79, 138.77, 138.42, 135.92, 135.32,
132.31, 131.35, 130.39, 130.29, 128.85, 128.76, 128.59, 41.20. IR
(KBr, cmꢂ1): 2909, 1647, 1604, 1310, 1280, 1112, 1088, 1012, 929,
792, 766, 737, 500, 471. EI (m/z) calcd for C20H14Cl2O [M]+
340.0422; found 340.0421.
1-Bromo-3-(3-methoxybenzyl)benzene (4.11)
1
Colorless liquid (155 mg, 75%), Rf (hexane) 0.50. H NMR (500
1-(4-Ethoxybenzyl)-2-methylbenzene (3.25)
MHz, CDCl3): d ¼ 7.33–7.32 (m, 2H), 7.22 (t, J ¼ 7.95 Hz, 1H),
7.16–7.10 (m, 2H), 6.77–6.76 (m, 2H), 6.71 (s, 1H), 3.91 (s, 2H),
3.78 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d ¼ 159.74,
143.22, 141.70, 131.86, 129.97, 129.55, 129.23, 127.52, 122.51,
121.30, 114.80, 111.48, 55.14, 41.51 ppm. IR (neat, cmꢂ1): 3001,
2934, 2834, 1593, 1567, 1488, 1475, 1454, 1258, 1050. EI (m/z)
calcd for C14H13BrO [M]+ 276.0150; found 276.0157.
1
Colorless liquid (126 mg, 74%), Rf (hexane) 0.35; H NMR (400
MHz, CDCl3): d ¼ 7.17–7.15 (m, 3H), 7.11 (d, J ¼ 4.85 Hz, 1H),
7.05 (d, J ¼ 8.72 Hz, 2H), 6.83 (d, J ¼ 8.24 Hz, 2H), 4.02 (q, J ¼
7.32 Hz, 2H), 3.94 (s, 2H), 2.26 (s, 3H), 1.42 (t, J ¼ 6.88 Hz, 3H).
13C NMR (100 MHz, CDCl3): d ¼ 157.14, 139.35, 136.53, 132.22,
130.19, 129.73, 129.60, 126.29, 125.90, 114.33, 63.33, 38.52,
19.61, 14.86. EI (m/z) calcd for C16H18O [M]+ 226.1358; found
226.1353.
1-Bromo-2-(4-ethoxybenzyl)benzene (4.12)
1
Colorless liquid (163 mg, 75%), Rf (hexane) 0.55. H NMR (500
1-Methoxy-2-(2-methylbenzyl)benzene (3.26)19
MHz, CDCl3): d 7.55 (d, J ¼ 6.75 Hz, 1H), 7.23–7.20 (m, 1H),
7.12–7.05 (m, 4H), 6.82 (d, J ¼ 8.55 Hz, 2H), 4.04 (s, 2H), 3.99 (q,
J ¼ 7.05 Hz, 2H), 1.39 (t, J ¼ 7.05 Hz, 3H) ppm. 13C NMR (125
MHz, CDCl3): d 157.40, 140.81, 132.78, 131.35, 130.93, 129.93,
127.74, 127.41, 124.78, 114.43, 63.36, 40.87, 14.86 ppm. IR (neat,
cmꢂ1): 3031, 2979, 2925, 1612, 1592, 1567, 1510, 1425, 1392,
1245, 1176, 1070. EI (m/z) calcd for C15H15BrO [M]+ 290.0306;
found 290.0307.
1
Colorless liquid (78 mg, 49%), Rf (hexane) 0.35; H NMR (400
MHz, CDCl3): d ¼ 7.23–7.13 (m, 4H), 7.06 (d, J ¼ 6.4 Hz, 1H),
6.89 (d, J ¼ 8.24 Hz, 1H), 6.85 (d, J ¼ 4.6 Hz, 1H), 3.96 (s, 2H),
3.85 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 157.32,
138.65, 136.77, 130.00, 129.74, 129.61, 128.74, 127.12, 126.11,
125.85, 120.38, 109.99, 55.29, 33.01, 19.49. EI (m/z) calcd for
C
15H16O [M]+ 212.1201; found 212.1201.
1-Methoxy-2-(4-methoxybenzyl)benzene (3.27)
1-Bromo-2-(3-methoxybenzyl)benzene (4.13)
1
Colorless liquid (100 mg, 58%), Rf (2.5% EtOAc–hexane) 0.50; Colorless liquid (147 mg, 71%), Rf (hexane) 0.55. H NMR (500
1H NMR (400 MHz, CDCl3): d ¼ 7.21–7.17 (m, 1H), 7.14 (d, J ¼ MHz, CDCl3): d ¼ 7.56 (d, J ¼ 7.95 Hz, 1H), 7.23–7.19 (m, 2H),
8.24 Hz, 2H), 7.05 (d, J ¼ 7.32 Hz, 1H), 6.89–6.86 (m, 2H), 6.82 7.14–7.13 (m, 1H), 7.09–7.06 (m, 1H), 6.79–6.74 (m, 3H), 4.09 (s,
(d, J ¼ 8.68 Hz, 2H), 3.92 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H). 13C 2H), 3.77 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d ¼ 159.69,
NMR (100 MHz, CDCl3): d ¼ 157.71, 157.23, 133.04, 130.11, 141.07, 140.16, 132.81, 131.05, 129.39, 127.90, 127.46, 124.84,
130.07, 129.84, 127.25, 120.41, 113.65, 110.32, 55.31, 55.20, 121.40, 114.85, 111.44, 55.12, 41.70 ppm. IR (neat, cmꢂ1): 3001,
34.90. EI (m/z) calcd for C15H16O2 [M]+ 228.1150; found 2934, 2834, 1593, 1567, 1488, 1475, 1454. EI (m/z) calcd for
228.1156.
C
14H13BrO [M]+ 276.0150; found 276.0151.
13142 | RSC Adv., 2014, 4, 13134–13144
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
1-Chloro-4-(4-ethoxybenzyl)benzene (4.14)
Ethyl 3-(4-methoxybenzyl)benzoate (7.2)20
White solid (with benzyl chloride, 174 mg, 94%; with benzyl Colorless liquid (136 mg, 68%), Rf (5% EtOAc–hexane) 0.52; 1H
iodide, 129 mg, 70%), m.p. 47–49 ꢀC, Rf (hexane) 0.59; 1H NMR NMR (500 MHz, CDCl3): d ¼ 7.89 (s, 2H), 7.35–7.33 (m, 2H), 7.10
(500 MHz, CDCl3): d ¼ 7.24–7.23 (m, 2H), 7.09 (d, J ¼ 8.55 Hz, (d, J ¼ 8.55 Hz, 2H), 6.83 (d, J ¼ 8.55 Hz, 2H), 4.36 (q, J ¼ 7.20 Hz,
2H), 7.06 (d, J ¼ 8.85 Hz, 2H), 6.83–6.81 (m, 2H), 4.00 (q, J ¼ 6.70 2H), 3.96 (s, 2H), 3.78 (s, 3H), 1.38 (t, J ¼ 7.30 Hz, 3H). 13C NMR
Hz, 2H), 3.88 (s, 2H), 1.40 (t, J ¼ 6.70 Hz, 3H). 13C NMR (125 (125 MHz, CDCl3): d ¼ 166.70, 158.07, 141.83, 133.30, 132.64,
MHz, CDCl3): d ¼ 157.44, 140.08, 132.49, 131.73, 130.11, 129.77, 130.62, 129.86, 129.80, 128.44, 127.28, 113.95, 60.92, 55.23,
128.48, 114.53, 63.40, 40.33, 14.84. IR (KBr, cmꢂ1): 3030, 2979, 40.80, 14.32. IR (neat, cmꢂ1): 2981, 2933, 2835, 1717, 1611, 1585,
2908, 1612, 1582, 1510, 1489, 1477, 1244, 1175. EI (m/z) calcd for 1160, 1246, 1104, 1034. EI (m/z) calcd for C17H18O3 [M]+
C
15H15ClO [M]+ 246.0811; found 246.0810.
270.1256; found 270.1254.
1-(4-Chlorobenzyl)-3-methoxybenzene (4.15)
Ethyl 3-(3-methoxybenzyl)benzoate (7.3)
Colorless liquid (127 mg, 63%), Rf (5% EtOAc–hexane) 0.48; 1H
NMR (500 MHz, CDCl3): d ¼ 7.90–7.87 (m, 2H), 7.37–7.32 (m,
2H), 7.21–7.18 (m, 1H), 6.78–6.71 (m, 3H), 4.35 (q, J ¼ 7.30 Hz,
2H), 3.99 (s, 2H), 3.76 (s, 3H), 1.38 (t, J ¼ 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3): d ¼ 166.67, 159.75, 142.08, 141.16, 133.41,
130.66, 129.98, 129.51, 128.47, 127.42, 121.27, 114.75, 111.44,
60.93, 55.13, 41.70, 14.32. IR (neat, cmꢂ1): 2980, 2935, 2836,
1717, 1599, 1585, 1465, 1454, 1439, 1279, 1194, 1105. EI (m/z)
calcd for C17H18O3 [M]+ 270.1256; found 270.1255.
Colorless liquid (with benzyl chloride, 145 mg, 83%; with benzyl
iodide, 117 mg, 67%), Rf (hexane) 0.55; 1H NMR (500 MHz,
CDCl3): d ¼ 7.25–7.19 (m, 3H), 7.12 (d, J ¼ 8.55 Hz, 2H), 6.76–
6.74 (m, 2H), 6.70 (s, 1H), 3.91 (s, 2H), 3.77 (s, 3H). 13C NMR (125
MHz, CDCl3): d ¼ 159.75, 142.10, 139.36, 131.87, 130.22, 129.51,
128.53, 121.25, 114.75, 111.43, 55.13, 41.22. IR (neat, cmꢂ1):
3001, 2935, 2835, 1599, 1584, 1489, 1454, 1436, 1406, 1257,
1149. EI (m/z) calcd for C14H13ClO [M]+ 232.0655; found
232.0658.
1-Chloro-3-(4-ethoxybenzyl)benzene (4.16)
Ethyl 3-benzylbenzoate (7.4)11c
Colorless liquid (with benzyl chloride, 172 mg, 93%, with benzyl
iodide, 124 mg, 66%), Rf (hexane) 0.55. 1H NMR (500 MHz,
CDCl3): d ¼ 7.21–7.15 (m, 3H), 7.08–7.04 (m, 3H), 6.83 (d, J ¼
8.85 Hz, 2H), 4.01 (q, J ¼ 7.05 Hz, 2H), 3.88 (s, 2H), 1.40 (t, J ¼ 7.0
Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): d ¼ 157.50, 143.66,
134.17, 132.11, 129.85, 129.62, 128.87, 126.96, 126.15, 114.55,
63.39, 40.65, 14.85 ppm. IR (neat, cmꢂ1): 3032, 2980, 2925, 1613,
1596, 1583, 1572, 1511, 1475, 1245, 1176. EI (m/z) calcd for
Colorless liquid (139 mg, 77%), Rf (5% EtOAc–hexane) 0.59; 1H
NMR (500 MHz, CDCl3): d ¼ 7.91–7.88 (m, 2H), 7.38–7.33 (m,
2H), 7.30–7.26 (m, 2H), 7.22–7.17 (m, 2H), 4.36 (q, J ¼ 7.05 Hz,
2H) 4.03 (s, 2H), 1.38 (t, J ¼ 7.35 Hz, 3H). 13C NMR (125 MHz,
CDCl3): d ¼ 166.68, 141.35, 133.43, 133.10, 130.64, 129.98,
128.85, 128.54, 128.47, 127.37, 126.25, 60.94, 41.68, 14.32. IR
(neat, cmꢂ1): 2982, 1615, 1366, 1277, 1177, 1104, 1021. EI (m/z)
calcd for C16H16O2 [M]+ 240.1150; found 240.1155.
C
15H15ClO [M]+ 246.0811; found 246.0813.
Ethyl 3-(4-methylbenzyl)benzoate (7.5)
1-Chloro-3-(3-methoxybenzyl)benzene (4.17)
Colorless liquid (124 mg, 65%), Rf (5% EtOAc–hexane) 0.65; 1H
NMR (500 MHz, CDCl3): d ¼ 7.90–7.87 (m, 2H), 7.35–7.33 (m,
2H), 7.11–7.06 (m, 4H), 4.36 (q, J ¼ 7.05 Hz, 2H), 3.98 (s, 2H),
2.31 (s, 3H), 1.38 (t, J ¼ 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d ¼ 166.70, 141.66, 137.48, 135.76, 133.37, 130.60, 129.92,
129.23, 128.71, 128.44, 127.28, 60.91, 41.27, 20.99, 14.32. IR
(neat, cmꢂ1): 2981, 1610, 1513, 1276, 1176, 1106, 1021, 739. EI
(m/z) calcd for C17H18O2 [M]+ 254.1307; found 254.1306.
Colorless liquid (with benzyl chloride, 135 mg, 77%; with benzyl
iodide, 97 mg, 55%), Rf (hexane) 0.57. 1H NMR (500 MHz,
CDCl3): d ¼ 7.23–7.16 (m, 4H), 7.07 (d, J ¼ 7.35 Hz, 1H), 6.77–
6.75 (m, 2H), 6.71 (s, 1H), 3.92 (s, 2H), 3.78 (s, 3H) ppm. 13C
NMR (125 MHz, CDCl3): d ¼ 159.75, 142.92, 141.73, 134.20,
129.65, 129.55, 128.96, 127.06, 126.31, 121.31, 114.81, 111.49,
55.14, 41.55 ppm. IR (neat, cmꢂ1): 3001, 2935, 2835, 1595, 1585,
1573, 1488, 1454, 1434, 1258, 1163, 1050. EI (m/z) calcd for
C
14H13ClO [M]+ 232.0655; found 232.0658.
Ethyl 3-(4-uorobenzyl)benzoate (7.6)
1-Chloro-2-(3-methoxybenzyl)benzene (4.19)
Colorless liquid (117 mg, 61%), Rf (5% EtOAc–hexane) 0.62; 1H
1
Colorless liquid (117 mg, 67%), Rf (hexane) 0.55. H NMR (500 NMR (500 MHz, CDCl3): d ¼ 7.89 (d, J ¼ 8.85 Hz, 2H), 7.37–7.32
MHz, CDCl3): d ¼ 7.38–7.36 (m, 1H), 7.23–7.20 (m, 1H), 7.18– (m, 2H), 7.14–7.12 (m, 2H), 6.99–6.95 (m, 2H), 4.36 (q, J ¼ 7.0
7.14 (m, 3H), 6.80–6.75 (m, 3H), 4.08 (s, 2H), 3.77 (s, 3H) ppm. Hz, 2H), 3.99 (s, 2H), 1.38 (t, J ¼ 7.05 Hz, 3H). 13C NMR (125
13C NMR (125 MHz, CDCl3): d ¼ 159.66, 141.09, 138.46, 134.17, MHz, CDCl3): d ¼ 166.60, 161.5 (d, JC–F ¼ 242.37 Hz), 141.20,
130.98, 129.49, 129.39, 127.66, 126.81, 121.34, 114.79, 111.39, 136.18, 133.28, 130.78, 130.45 (d, JC–F ¼ 8.38 Hz), 129.88, 128.56,
55.11, 39.14 ppm. IR (neat, cmꢂ1): 2935, 2834, 1600, 1584, 1488, 127.49, 115.33 (d, JC–F ¼ 21.6 Hz), 60.97, 40.84, 14.32. IR (neat,
1469, 1453, 1441, 1256, 1051. EI (m/z) calcd for C14H13ClO [M]+ cmꢂ1): 2987, 1718, 1619, 1509, 1277, 1105, 1021, 781. EI (m/z)
232.0655; found 232.0650.
calcd for C16H15FO2 [M]+ 258.1056; found 258.1058.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 13134–13144 | 13143

View Article Online
RSC Advances
Paper
I. Moreno, R. SanMartin and E. Dominguez, J. Org. Chem.,
2008, 73, 8448–8451; (c) M. Amatore and C. Gosmini,
Chem. Commun., 2008, 5019–5021; (d) S. M. Nobre and
A. L. Monteiro, Tetrahedron Lett., 2004, 45, 8225–8228; (e)
L. Chahen, H. Doucet and M. Santelli, Synlett, 2003, 11,
1668–1672; (f) A. C. Frisch, N. Shaikh, A. Zapf and
M. Beller, Angew. Chem., Int. Ed., 2002, 41, 4056–4059; (g)
A. Bej, D. Srimani and A. Sarkar, Green Chem., 2012, 14,
661–667; (h) D. Srimani, A. Bej and A. Sarkar, J. Org. Chem.,
2010, 75, 4296–4299; (i) R. B. Bedford, M. Huwe and
M. C. Wilkinson, Chem. Commun., 2009, 600–602; (j)
T. Z. Nichele and A. L. Monteiro, Tetrahedron Lett., 2007,
48, 7472–7475; (k) S. Chowdhury and P. E. Georghiou,
Tetrahedron Lett., 1999, 40, 7599–7603.
8 Aryl couplings: (a) M. L. N. Rao, D. N. Jadhav and
D. Banerjee, Tetrahedron, 2008, 64, 5762–5772; (b)
M. L. N. Rao, D. Banerjee and D. N. Jadhav, Tetrahedron
Lett., 2007, 48, 6644–6647; (c) M. L. N. Rao, D. Banerjee
and D. N. Jadhav, Tetrahedron Lett., 2007, 48, 2707–2711.
9 (a) M. Rottlander and P. Knochel, Tetrahedron Lett., 1997, 38,
1749–1752; (b) S. Langle, M. Abarbri and A. Duchene,
Tetrahedron Lett., 2003, 44, 9255–9258.
Ethyl 3-(4-chlorobenzyl)benzoate (7.7)
Colorless liquid (102 mg, 51%), Rf (5% EtOAc–hexane) 0.58; 1H
NMR (500 MHz, CDCl3): d ¼ 7.90–7.87 (m, 2H), 7.37–7.32 (m,
2H), 7.26–7.24 (m, 2H), 7.10 (d, J ¼ 8.25 Hz, 2H), 4.36 (q, J ¼ 7.0
Hz, 2H), 3.99 (s, 2H), 1.38 (t, J ¼ 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): d ¼ 166.57, 140.81, 138.96, 133.31, 132.10, 130.77,
130.18, 129.90, 128.66, 128.60, 127.57, 61.00, 40.98, 14.32. IR
(neat, cmꢂ1): 3033, 1716, 1610, 1491, 1277, 1177, 1105, 1016. EI
(m/z) calcd for C16H15ClO2 [M]+ 274.0761; found 274.0763.
Acknowledgements
R. J. D. thanks Council for Scientic and Industrial Research
(CSIR), New Delhi for a research fellowship. It is our pleasure to
thank the Department of Science and Technology (DST) for
supporting this work under Green Chemistry special initiative
(SR/S5/GC-11/2008).
Notes and references
1 S. Shimada and M. L. N. Rao, Top. Curr. Chem., 2012, 311,
199–228.
´
10 I. Perez, J. P. Sestelo and L. A. Sarandeses, J. Am. Chem. Soc.,
2 Organobismuth Chemistry, ed. H. Suzuki and Y. Matano,
Elsevier, Amsterdam, 2001.
3 G. G. Briand and N. Burford, Chem. Rev., 1999, 99, 2601–
3657.
4 (a) M. L. N. Rao, D. N. Jadhav and P. Dasgupta, Eur. J. Org.
Chem., 2013, 781–788; (b) M. L. N. Rao and S. Giri, RSC
Adv., 2012, 2, 12739–12750; (c) M. L. N. Rao, D. N. Jadhav
and P. Dasgupta, Org. Lett., 2010, 12, 2048–2051.
5 M. L. N. Rao and R. J. Dhanorkar, RSC Adv., 2013, 3, 6794–
6798.
2001, 123, 4155–4160.
11 Other benzylic couplings (a) R. Kuwano and M. Yokogi,
Chem. Commun., 2005, 5899–5901; (b) R. Kuwano and
M. Yokogi, Org. Lett., 2005, 7, 945–947; (c) C. C. Konk and
P. Knochel, Org. Lett., 2006, 8, 4121–4124; (d)
M. McLaughlin, Org. Lett., 2005, 7, 4875–4878; (e)
C. Vanier, F. Lorge, A. Wagner and C. Mioskowski, Angew.
Chem., Int. Ed., 2000, 39, 1679–1683; (f) X. Li, Y. Feng,
L. Lin and G. Zou, J. Org. Chem., 2012, 77, 10991–10995.
12 B. Liegault, J.-L. Renaud and C. Bruneau, Chem. Soc. Rev.,
2008, 37, 290–299.
6 Selected examples: (a) W. N. Washburn, J. Med. Chem., 2009,
52, 1785–1794; (b) N. C. Goodwin, R. Mabon, B. A. Harrison, 13 (a) W.-Y. Yu, Y.-T. Tsoi, Z. Zhou and A. S. C. Chan, Org. Lett.,
M. K. Shadoan, Z. Y. Almstead, Y. Xie, J. Healy, L. M. Buhring,
C. M. DaCosta, J. Bardenhagen, F. Mseeh, Q. Liu,
A. Nouraldeen, A. G. E. Wilson, S. D. Kimball, D. R. Powell
2009, 11, 469–472; (b) C. M. Crawforth, S. Burling,
I. J. S. Fairlamb, A. R. Kapdi, R. J. K. Taylor and
A. C. Whitwood, Tetrahedron, 2005, 61, 9736–9751.
and D. B. Rawlins, J. Med. Chem., 2009, 52, 6201–6204; (c) 14 S. Yu, X. Zhang, Y. Yan, C. Cai, L. Dai and X. Zhang, Chem. –
W. Meng, B. A. Ellsworth, A. A. Nirschl, P. J. McCann, Eur. J., 2010, 16, 4938–4943.
M. Patel, R. N. Girotra, G. Wu, P. M. Sher, E. P. Morrison, 15 C. T. Hoang, F. Bouillere, S. Jahannesen, A. Zulauf, C. Panel,
S. A. Biller, R. Zahler, P. P. Deshpande, A. Pullockaran,
D. L. Hagan, N. Morgan, J. R. Taylor, M. T. Obermeier,
A. Pouilhes, D. Gori, V. Alezra and C. Kouklovasky, J. Org.
Chem., 2009, 74, 4177–4187.
W. G. Humphreys, A. Khanna, L. Discenza, J. G. Robertson, 16 A. Flaherty, A. Trunkeld and W. Barton, Org. Lett., 2005, 7,
A. Wang, S. Han, J. R. Wetterau, E. B. Janovitz, O. P. Flint,
4975–4978.
J. M. Whaley and W. N. Washburn, J. Med. Chem., 2008, 51, 17 S. W. McDaniel, C. M. Keyari, K. C. Rider, N. R. Natale and
1145–1149; (d) Y. Ohtake, T. Sato, T. Kobayashi, P. Diaz, Tetrahedron Lett., 2011, 52, 5656–5658.
M. Nishimoto, N. Taka, K. Takano, K. Yamamoto, 18 M. Amatore and C. Gosmini, Chem. Commun., 2008, 5019–
M. Ohmori, M. Yamaguchi, K. Takami, S.-Y. Yeu, 5021.
K.-H. Ahn, H. Matsuoka, K. Morikawa, M. Suzuki, 19 S. Podder, J. Choudhury, U. K. Roy and S. Roy, J. Org. Chem.,
H. Hagita, K. Ozawa, K. Yamaguchi, M. Kato and S. Ikeda,
J. Med. Chem., 2012, 55, 7828–7840.
7 Selected benzylic halide couplings (a) G. A. Molander and
M. D. Elia, J. Org. Chem., 2006, 71, 9198–9202; (b) B. Ines,
2007, 72, 3100–3103.
20 F. M. Piller, A. Metzger, M. A. Schade, B. A. Baag,
A. Gavryushin and P. Knochel, Chem. – Eur. J., 2009, 15,
7192–7202.
13144 | RSC Adv., 2014, 4, 13134–13144
This journal is © The Royal Society of Chemistry 2014