Pd-catalyzed chemoselective threefold cross-coupling of triarylbismuths with benzylic bromides

Article abstract of DOI:10.1039/c3ra40413g

An efficient palladium-catalyzed protocol was demonstrated for the chemoselective cross-coupling of functionalized benzylic bromides with triarylbismuth reagents. Under the established conditions, catalyzed by palladium in the presence of K₃PO<

Full text of DOI:10.1039/c3ra40413g

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Pd-catalyzed chemoselective threefold cross-coupling of
triarylbismuths with benzylic bromides3
Cite this: DOI: 10.1039/c3ra40413g
Maddali L. N. Rao* and Ritesh J. Dhanorkar
Received 24th January 2013,
Accepted 7th March 2013
DOI: 10.1039/c3ra40413g
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frequently found skeletons entering Phase I clinical trials and
beyond.15 This encouraged us to explore the synthesis of
diarylmethane skeletons through the hitherto unexplored cou-
pling reactivity of triarylbismuths with benzylic systems.13 This
was done with the aim to develop a viable threefold arylation
strategy for the synthesis of functionalized diarylmethanes (Fig. 1).
As described herein, these efforts led to the development of an
efficient chemoselective palladium-catalyzed protocol for the
threefold coupling of triarylbismuths with benzylic bromides in
a one-pot operation.
An efficient palladium-catalyzed protocol was demonstrated for
the chemoselective cross-coupling of functionalized benzylic
bromides with triarylbismuth reagents. Under the established
conditions, catalyzed by palladium in the presence of K3PO4 base
in DMA at 90 uC for
1 h, the threefold arylations using
triarylbismuth reagents proceeded smoothly with electronically
diverse benzylic bromides. All the coupling reactions furnished
the corresponding functionalized diarylmethanes in high yields.
Cross-coupling studies with further development in terms of new
reagents and/or protocol conditions are vital to realize hitherto
unknown capabilities of reactivity and selectivity of these reactions
in organic synthesis. Recent developments in the utilization of
new reagents, such as organotrifluoroborates1 and organosilicon,2
are a step forward in this direction. Diarylmethanes are ubiquitous
in nature with a range of biological and pharmacological proper-
ties. Typically, diarylmethanes are constructed either through the
coupling of benzylic metal reagents and aryl electrophiles or aryl
metal reagents and benzylic electrophiles.3–10 The methods
involving benzylic derivatives in combination with aryl metal
reagents demonstrated a varied reactivity under different metal
catalyzed protocol conditions. Usually, cross-coupling reactions
are dominated by reagents which deliver one organic group at
the expense of one equivalent organometallic reagent for each
C–C coupling. Development of new organometallic reagents
which can serve more than one organic group for example, such
as triarylindium11 and triarylbismuth reagents,12,13 would add
more value to the coupling with sub-stoichiometric loadings of
organometallic reagents. Importantly, triarylbismuths14 are
compatible with three C–C couplings without losing stoichio-
metry in a facile manner.12
Triarylbismuth compounds usually give homo-coupled biaryls
under palladium catalytic conditions.14 To develop an efficient
cross-coupling protocol with benzylic bromides
a suitable
combination of reagents is necessary. Hence, this investigation
was carried out under various conditions (Table 1).
The cross-coupling of 4-acetylbenzyl bromide with BiPh3 was
initially investigated in the presence of Pd(PPh3)4 and K3PO4 base
(6 equiv.) in DMF solvent. This reaction afforded the cross-coupled
4-acetyldiphenylmethane, 2.1, in 54% yield (entry 1). However,
these
couplings
in
N-methyl-2-pyrrolidone
(NMP),
N,N-dimethylacetamide (DMA), acetonitrile and 1,2-dimethox-
yethane (DME) solvents furnished 53–71% yields (entries 2–5).
From these, DMA was found to be suitable with high product yield
(entry 3). Further screening was carried out with K2CO3, Na2CO3
and Cs2CO3 bases. This attempt using different bases delivered
moderate product yields (entries 6–8). Additionally, increase of the
reaction time to 2 h furnished 71% yield (entry 9), whereas
coupling with 4 equiv. of benzyl bromide furnished 74% yield
(entry 10). Lowering the reaction temperature did not show any
positive effect (entry 11). Optimization with lowering the base
equivalents (entries 12–15) and the amount of catalyst (entries 16
and 17) also lowered the yields. Thus, this investigation using
Interestingly, the cross-coupling study of triarylbismuth
reagents with benzylic systems has not been described in the
literature. In addition, the diarylmethane core is one of the most
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016,
India. E-mail: maddali@iitk.ac.in; Fax: +91 5122597532
Electronic supplementary information (ESI) available: Detailed cross-coupling
3
representative procedure along with characterization data of all the products
(including 1H NMR, 13C NMR and mass spectra). See DOI: 10.1039/c3ra40413g
Fig. 1 Chemoselective benzylic arylation.
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Table 1 Screening conditionsa,b,c
Table 2 Couplings with BiAr3 reagentsa,b
Entry
1
BiAr3
Diarylmethanes
Yield (%)
71
Entry
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Na2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
No base
K3PO4
K3PO4
DMF
NMP
DMA
MeCN
DME
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
54
54
71
53
63
49
55
50
2
3
4
75
65
70
9
71d
74e
64f
64g
54h
40i
42
10
11
12
13
14
15
16
17
58j
0k
5
6
63
69
a
Reaction conditions: 4-acetylbenzyl bromide (0.875 mmol, 3.5
equiv.), BiPh3 (0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09
equiv.), base (1.5 mmol, 6 equiv.), solvent (3 mL), 90 uC, 1 h.
b
c
Isolated yields. Homo-coupled biphenyl formed in minor
d
e
f
amounts. For 2 h. With 4 equiv. of bromide. Reaction at 60 uC.
g
h
i
With 4 equiv. of base. With 2 equiv. of base. With 1 equiv. of
j
k
base. With 0.06 equiv. of catalyst. Without catalyst.
7
8
9
63
60
61
various bases, solvents, temperature and time conditions,
delivered the combination of Pd(PPh3)4 (0.09 equiv.) and K3PO4
(6 equiv.) in DMA at 90 uC for 1 h as the optimum protocol to
obtain high yields of cross-coupling products, involving the
threefold coupling of triphenylbismuth reagent in a one-pot
operation. This catalytic protocol is more efficient as three phenyl
couplings occurred in
advantageous from a synthetic point of view in comparison to
similar couplings known for boron and other reagents.10a
1 h reaction time. This is more
10
53
At this stage, the study was further extended to different
triarylbismuth reagents. These results are given in Table 2. In
summary, the cross-coupling ability of various triarylbismuths was
tested with 4-acetylbenzyl bromide under the established condi-
tions. This study revealed the atom-economic threefold arylation
of 3 equivalents of benzylic bromide with various triarylbismuths
to afford high yields. The reactivity of various electronically
different BiAr3 reagents in coupling with 4-acetylbenzyl bromide
was found to be very facile in a one-pot operation.
Further coupling of different benzylic bromides were tested
with triarylbismuth reagents and these results are given in Table 3.
In this study, electronically different, functionalized benzylic
bromides with substituents such as benzoyl, cyano, methyl,
methoxy and carboxylic ester groups were coupled elegantly to
afford high product yields. The simple unsubstitued benzyl
bromide also reacted smoothly with high yields. It is noteworthy
that the protocol is very efficient in furnishing uninterrupted
a
Reaction conditions: 4-acetylbenzyl bromide (0.875 mmol, 3.5
equiv.), BiAr3 (0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09
equiv.), K3PO4 (1.5 mmol, 6 equiv.), DMA (3 mL), 90 uC, 1 h. Isolated
yields based on three aryl couplings from BiAr3 with 0.75 mmol of
b
product as 100% yield. Homo-coupled biaryls from the BiAr3
reagents formed in minor amounts.
threefold aryl couplings from triarylbismuths with both functio-
nalized or unfunctionalized benzylic bromides. Electronically
diverse triarylbismuths containing electron-rich or -deficient aryl
groups reacted with equal ease in high yields. The reactivity of
sterically congested tri(2-methoxyphenyl)bismuth reagent also
furnished moderate coupling yields. The observed variation in
the relative reactivity in some cases is well known with
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Table 3 Couplings with different benzylic bromidesa,b
a
Reaction conditions: benzylic bromide (0.875 mmol, 3.5 equiv.), BiAr3 (0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09 equiv.), K3PO4
(1.5 mmol, 6 equiv.), DMA (3 mL), 90 uC, 1 h. Isolated yields based on three aryl couplings from BiAr3 with 0.75 mmol of product as 100%
b
yield. Homo-coupled biaryls formed in minor amounts.
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chemoselective coupling at the benzylic terminus, thus furnishing
regio-isomeric bromo-substituted diarylmethanes in high yields.
The coupling of o-chloro benzylic bromide also proved to be
chemoselective affording high yields.
electronically different organometallic reagents in such cou-
plings.16,17
This made us look into chemoselective couplings with benzylic
substrates. The optional challenge was to check the competitive
reactivity of aryl halide versus benzylic bromide embedded in the
same molecular skeleton. Importantly, the coupling reactivity of
aryl halides was well studied and nurtured under the Suzuki and
other coupling conditions.18 Again, the proposed chemoselective
coupling is substrate dependent and often problematic.19 Hence,
examples of such chemoselective couplings are scarce in the
literature. Expectedly, these chemoselective couplings are advanta-
geous as this allows further core functionalization in a desired
manner. So, we tested these chemoselective benzylic couplings
despite the known facile reactivity of aryl halides under palladium
conditions20 (Table 4).
The chemoselective benzylic coupling made us curious to
check the cross-coupling of bromo substituted diarylmethanes
under the known aryl bromide palladium coupling conditions.20
This was to explore the viability of core expansion of o-, m- and
p-bromo diarylmethanes through sequential couplings. This brief
study amply demonstrated this feasibility and led to the
corresponding aryl–aryl coupling in good yields (Table 5). This
study thus unequivocally established the wide synthetic utility and
the facile coupling ability of triarylbismuths in both benzylic and
aryl coupling under palladium coupling conditions.
It is well known that the diarylmethane core was subjected to a
variety of medicinal studies as reported in the literature.21 In
addition to various methods given in the introduction,3–10 these
skeletons can also be synthesized through the coupling of benzylic
manganese halide,22 organo-indium23 and -magnesium,24 and
aryltrifluoroborate17 reagents in addition to other methods.25
Close examination of these coupling methods for the synthesis of
diarylmethanes clearly indicated that the present method is more
advantageous in terms of (a) higher reactivity of triarylbismuths in
threefold arylations with benzylic bromides (b) chemoselective
compatibility (c) atom-economic couplings with high yields (d)
threefold couplings in a one-pot operation in 1 h reaction time. In
this way, the threefold reaction using triarylbismuths with
It was heartening to see that the present palladium protocol
was chemoselective and led to the desired site-selective benzylic
coupling, leaving the aryl halide terminus intact. Encouragingly,
investigations using various o-, m- and p-bromo substituted
benzylic bromides revealed a smooth site-selectivity with a
Table 4 Chemoselective couplingsa,b
Table 5 Aryl couplingsa,b
a
Reaction conditions: benzylic bromide (0.875 mmol, 3.5 equiv.),
a
BiAr3 (0.25 mmol, 1 equiv.), Pd(PPh3)4 (0.0225 mmol, 0.09 equiv.),
K3PO4 (1.5 mmol, 6 equiv.), DMA (3 mL), 90 uC, 1 h. Isolated yields
based on three aryl couplings from BiAr3 with 0.75 mmol of product
Reaction conditions: 4-bromo diarylmethane (3.3 equiv.), BiAr3 (1
equiv.), Cs2CO3 (4 equiv.), PdCl2 (0.09 equiv.), PPh3 (0.18 equiv.)
DMA, 90 uC, 2 h. Isolated yields based on three aryl couplings from
BiAr3.
b
b
as 100% yield. Homo-coupled biaryls formed in minor amounts.
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additional chemoselectivity is an advantageous process and not
many reagents match this reactivity coupled with high synthetic
utility and yields.
In summary, the hitherto unexplored reactivity of triarylbis-
muths as threefold arylating agents for benzylic coupling was
demonstrated under palladium conditions. Additional chemose-
lective coupling studies of o-, m- and p-bromo or o-chloro benzylic
bromides also afforded high product yields involving benzylic
couplings. Further arylations at the aryl bromide terminus of
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Acknowledgements
R. J. D. acknowledges the research fellowship from the Council
for Scientific and Industrial Research (CSIR), New Delhi. We
also acknowledge the initial experiments carried out by V.
Venkatesh. We thank the Department of Science and
Technology (DST) for supporting this work under the Green
Chemistry Program (SR/S5/GC-11/2008).
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