Pd-catalyzed synthesis of α-aryl ketones through couplings of α-arylacetyl chlorides with triarylbismuths as multi-coupling nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2009.08.074

The cross-coupling reaction of α-arylacetyl chlorides with triarylbismuths was studied under Pd-catalyzed conditions. The reaction was found to be facile under the established protocol and furnished high yields of α-aryl ketones in short reaction times. T

Full text of DOI:10.1016/j.tetlet.2009.08.074

Tetrahedron Letters 50 (2009) 6133–6138
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Pd-catalyzed synthesis of a-aryl ketones through couplings of a-arylacetyl
chlorides with triarylbismuths as multi-coupling nucleophiles
*
Maddali L. N. Rao , Somnath Giri, Deepak N. Jadhav
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The cross-coupling reaction of
a-arylacetyl chlorides with triarylbismuths was studied under Pd-cata-
Received 24 June 2009
Revised 17 August 2009
Accepted 21 August 2009
Available online 26 August 2009
lyzed conditions. The reaction was found to be facile under the established protocol and furnished high
yields of -aryl ketones in short reaction times. This work also demonstrated a facile synthesis of various
regio-isomeric mono-, di- and tri-substituted -aryl ketones in high yields. Triarylbismuths were
a
a
employed as sub-stoichiometric multi-coupling organometallic nucleophiles in this coupling protocol.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Catalysis
Triarylbismuths
a
a
-Arylacetyl chlorides
-Aryl ketones
Cross-coupling
With the advent of new organometallic nucleophiles and organ-
of
catalytic conditions were limited to a few substrates. We envi-
sioned that the development of an efficient protocol using -ary-
lacetyl chlorides would make the process more versatile for the
synthesis of -aryl ketones. Given the known complexity of
general methods as cited before, we intended to develop a facile
metal-catalyzed method using -arylacetyl chlorides and triaryl-
bismuth11 nucleophiles for
-aryl ketones synthesis. Triarylbis-
a-arylacetyl chlorides with organometallic nucleophiles under
ic electrophiles, the versatility of cross-coupling methodology is
further expanding in organic synthesis.1,2 Some of these reactions
are currently being used in industry for the synthesis of active
a
pharmaceutical ingredients (APIs).3 Direct
a
-arylations of ketones
have been the subject of several recent studies for the synthesis
of
-aryl ketones.4,5 Some of the methods reported for the purpose
include (i) nucleophilic acylation of o-quinone methides using
a
a
a
a
umpolung,4a (ii) hydration of alkynes,4b,5c (iii)
a-arylation of ke-
muth compounds1d,12 have been demonstrated to possess
additional multi-coupling ability unlike some of the well-known
organometallic nucleophiles.2 In continuation of our interest in
organobismuth chemistry, we report here an efficient palladium
tones using organometallic reagents,4c or aryl halides,4d,5a,b,e (iv)
coupling of aryl bromides with an acyl anion equivalent,4e (v) addi-
tion reaction of arylboronic acid to nitriles4f (vi) Heck arylation of
2-substituted enol ethers,4g (vii) homologation of aldehydes5d
,
protocol for the coupling of
muth nucleophiles.
a-arylacetyl chloride with triarylbis-
etc. Although Friedel–Crafts acylation reaction also provides an-
other option, this method lacks the flexibility to synthesize regio-
isomeric compounds.6
The reaction of a-phenylacetyl chloride with triphenylbismuth
was initially studied by Barton et al. with Pd catalyst in hexameth-
ylphosphoramide (HMPA) as a solvent.12h This methodology how-
ever suffers from drawbacks such as the use of a highly toxic and
polluting solvent. So, in the search for a novel protocol, we have
a-Aryl ketones attracted attention due to their role as useful
precursors for a variety of transformations including the synthesis
of heterocyclic compounds in organic chemistry.7 The cross-cou-
pling of acyl chloride with organometallic nucleophile is a novel
route for the synthesis of ketones.8,1d However, the reactivity of
these acid chlorides varies under different cross-coupling reaction
conditions.
carried out a systematic investigation using
a-phenylacetyl chlo-
ride and triphenylbismuth under different catalytic conditions. As
illustrated in Table 1, reaction with Pd(OAc)2 as a catalyst precur-
sor in THF provided 57% conversion to cross-coupling product
Although many coupling methods have been reported using
a-phenylaceto phenone in 51% isolated yield (Table 1, entry 1)
aryl and aliphatic acid chlorides,8,9 reactivity studies involving
a
along with homo-coupling biphenyl as a minor side product.
Homo-coupling of triarylbismuths usually gives bi-aryls under
Pd-catalyzed conditions.12h,11b Hence, to drive the reaction toward
cross-coupling further screening was carried out using different
catalysts, solvents, and reaction conditions.
-arylacetyl chlorides are scarce.10,12h Thus, coupling reactions
* Corresponding author. Tel./fax: +91 512 2597532.
E-mail address: maddali@iitk.ac.in (M.L.N. Rao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.074

6134
M. L. N. Rao et al. / Tetrahedron Letters 50 (2009) 6133–6138
Table 1
The reaction was studied employing PdCl2(PPh3)2 catalyst in
Screening conditionsa,b,c,d
different solvents such as 1,4-dioxane, 1,2-dimethoxyethane
(DME), and acetonitrile. These combinations yielded mixed con-
version to the desired product (Table 1, entries 2–4). The catalytic
efficiency of other Pd sources was checked using Pd(PPh3)4,
PdCl2(MeCN)2, and PdCl2(PhCN)2, and these catalytic systems
showed poor reactivity (Table 1, entries 5–7). Encouragingly, the
efficiency of PdCl2(PPh3)2 or PdCl2/2PPh3 catalysts was found to
be promising to accomplish high product conversion in THF sol-
vent (Table 1, entries 8 and 9). Under similar conditions, the reac-
tions which have been carried out for 2 h and 1 h afforded
moderate yield of product (Table 1, entries 10 and 11). This also
indicated that 3 h time is essential for the reaction to reach com-
pletion (Table 1, entries 9–11). Additional study by varying tem-
perature did not improve the product yield (Table 1, entries 12
and 13). Notably, the absence of Et3N has lowered the product con-
version and the respective isolated yield (Table 1, entry 14). Impor-
Cl
[Pd]
+
Bi
(1 equiv)
O
O
3
NEt3
Solvent
(3 equiv)
(3 equiv)
Entry
Catalyst
Solvent
Temp (°C), time (h)
Conv (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Pd(OAc)2/2PPh3
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
PdCl2(MeCN)2
PdCl2(PhCN)2
PdCl2(PPh3)2
PdCl2/2PPh3
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
—
THF
80, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 2 h
80, 1 h
60, 3 h
40, 3 h
80, 3 h
80, 3 h
80, 3 h
80, 3 h
57 (51)
56
50
35
32
Dioxane
DME
MeCN
Dioxane
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
15
27
74 (72)
76 (69)
65 (63)
57 (50)
70 (61)
54 (47)
55 (50)e
85 (83)f
52 (44)g
20
tantly, in these screening studies, we have used 3.3 equiv of
a-
phenylacetyl chloride with 1 equiv of triphenylbismuth and this
resulted in 72% yield of the product (Table 1, entry 8). Gratifyingly,
the reaction with 4 equiv of acid chloride furnished increased iso-
lated product yield up to 83% (Table 1, entry 15). Although 3 equiv
of acid chloride is enough to cross-couple 1 equiv of triphenylbis-
muth, additional 1 equiv acid chloride has been employed to fur-
ther drive the reaction toward cross-coupling and to suppress the
competitive homo-coupling from triphenylbismuth. Further, the
reaction with low Pd catalyst (0.01 equiv) loading afforded 44%
yield of product (Table 1, entry 16). It is noteworthy that
PdCl2(PPh3)2 has served as an efficient catalyst to furnish high yield
a
Reaction conditions: BiPh3 (0.25 mmol, 1 equiv),
(0.825 mmol, 3.3 equiv), Pd (0.0225 mmol, 0.09 equiv), Et3N (0.25 mmol, 1 equiv),
solvent (3 mL), 80 °C.
a
-phenylacetyl chloride
b
Conversions are based on GC analysis with reference to BiPh3.
Isolated yields are given in parentheses.
Homo-coupling biphenyl formed as a minor side product.
Without triethylamine.
c
d
e
of a-phenylacetophenone product in short reaction time as its ab-
sence afforded only poor conversion in a control experiment that
f
With 4 equiv of
a
-phenylacetyl chloride.
g
With Pd (0.0025 mmol, 0.01 equiv).
has been carried out without Pd catalyst (Table 1, entry 17). From
Table 2
Coupling of
a
-arylacetyl chlorides with triarylbismuthsa,b,c,d
R1
R1
R4
R2
R3
(3 equiv)
R2
R3
Cl
[Pd]
+
Bi
3
O
O
R4
(1 equiv)
(3 equiv)
Entry
1
BiAr3
a
-Arylacetyl chloride
Ketone
Yieldb (%)
83
Cl
O
Bi
3
O
Me
OMe
Cl
Cl
O
Bi
Bi
Bi
Bi
Me
2
3
4
5
6
84
64
71
81
65
3
O
O
O
Cl
O
OMe
3
Cl
O
Cl
3
F
Cl
O
F
3
O
O
Cl
Cl
O
Cl
Bi
3

M. L. N. Rao et al. / Tetrahedron Letters 50 (2009) 6133–6138
6135
Table 2 (continued)
Entry
BiAr3
a
-Arylacetyl chloride
Ketone
Yieldb (%)
Me
Cl
O
7
8
66
72
Me
Bi
O
O
3
OMe
Cl
O
OMe
Bi
Bi
3
O
Me
Me
Me
Me
Cl
O
9
10
11
O
91
75
86
3
O
O
Me
Cl
Me
Me
Bi
Bi
3
O
Me
Me
Cl
Me
3
O
O
CF3
Me
Cl
Me
Me
12
13
14
50
65
74
CF3
Cl
Bi
O
O
O
3
Cl
Me
Cl
Bi
Bi
O
3
3
Cl
O
Me
O
O
Me
Me
Cl
Bi
Bi
Bi
Me
15
16
17
75
70
66
O
3
Me
Me
Cl
O
3
MeO
O
MeO
OMe
Cl
OMe
O
3
MeO
Cl
O
MeO
Cl
Cl
Cl
Bi
Bi
18
19
74
71
3
O
O
O
O
Me
Cl
Cl
Cl
Cl
Me
3
OMe
Cl
Cl
Cl
Cl
Bi
Bi
OMe
20
21
72
3
O
O
O
O
Cl
65
Cl
3
(continued on next page)

6136
M. L. N. Rao et al. / Tetrahedron Letters 50 (2009) 6133–6138
Table 2 (continued)
Entry
BiAr3
a
-Arylacetyl chloride
Ketone
Yieldb (%)
76
Cl
Cl
Cl
Bi
22
S
S
3
O
O
Cl
O
Bi
Bi
23
24
76
65
3
Cl
Cl
O
Cl
Cl
Me
Cl
Me
O
3
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Bi
Bi
Bi
25
26
27
71
71
63
3
O
O
O
Cl
Cl
Cl
Cl
Cl
Me
Cl
Cl
Cl
Me
3
O
O
OMe
OMe
3
Cl
Cl
Cl
Cl
S
Bi
Bi
28
29
75
71
S
3
O
O
O
O
Cl
Cl
Cl
Cl
3
Cl
Cl
Cl
Me
Cl
Cl
Cl
Cl
Bi
Bi
Me
30
31
61
74
O
O
Cl
Cl
3
O
O
OMe
Cl
Cl
OMe
3
Cl
F
Cl
Cl
Cl
Cl
Bi
Bi
Cl
32
33
60
73
O
O
Cl
Cl
3
O
O
Cl
Cl
Cl
Cl
F
3
Cl
Cl
Me
Cl
Cl
34
35
75
68
O
O
Me
Cl
Bi
Bi
Cl
Cl
O
O
3
Cl
Cl
Cl
Cl
Cl
3
a
Conditions: BiAr3 (1 equiv, 0.25 mmol),
a
-arylacetyl chloride (4 equiv, 1 mmol), PdCl2(PPh3)2 (0.09 equiv, 0.0225 mmol), NEt3 (1 equiv, 0.25 mmol), THF (3 mL), 80 °C, 3 h.
b
Isolated yields were reported. Product yields were calculated considering all the three aryl groups for coupling from triarylbismuth. Thus, 3 equiv of cross-coupling
product (0.75 mmol) corresponds to 100% yield.
c
All the products were characterized by 1H NMR, 13C NMR, IR, and ESI-MS spectroscopic studies and in comparison with known literature data.
In general, varied minor amounts of homo-coupling bi-aryls from triarylbismuths were formed as side products.
d

M. L. N. Rao et al. / Tetrahedron Letters 50 (2009) 6133–6138
6137
this study, the coupling reaction was demonstrated to be facile
using catalytic Pd with Et3N (1 equiv) in THF to furnish the high
yield of product at 80 °C in short reaction time (Table 1, entry 15).
Hence, it was decided to study the scope of cross-coupling of
stoichiometric multi-coupling reagents. This study demonstrated
the efficient synthesis of various regio-isomeric mono-, di- and
tri-substituted
coupling reaction has been found to be facile for the synthesis of
a variety of -aryl mixed ketones with both electronically diver-
gent -arylacetyl chlorides as electrophiles and triarylbismuths
as nucleophiles. The coupling ability of triarylbismuths with
3 equiv of -arylacetyl chloride is an added advantage associated
a-arylketones under the Pd-catalytic protocol. The
a-arylacetyl chlorides with triarylbismuths to generalize the reac-
a
tion. Firstly, the reactivity of -phenylacetyl chloride with a variety
a
a
of triarylbismuths was checked using the optimized protocol
(Table 2).13,14
a
As illustrated, both electron-deficient and electron-rich triarylbis-
with this class of compounds in comparison with some of the
known organometallic nucleophiles used for such coupling
reactions.
muths have fared well in furnishing the corresponding
tophenones in good to high yields (Table 2, entries 1–9). The
overall reactivity of -phenylacetyl chloride with electronically
divergent triarylbismuths was facile under the present protocol.
Further, various functionalized -arylacetyl chlorides were studied
a-arylace-
a
Acknowledgments
a
with different triarylbismuth nucleophiles (Table 2, entries 10–35).
These reactions furnished moderate to high yields of correspond-
We thank the Department of Science and Technology (DST),
New Delhi, for funding this work under green chemistry program
(SR/S5/GC-11/2008). S.G. and D.N.J. thank the Council of Scientific
and Industrial Research (CSIR), New Delhi, for their research
fellowships.
ing
tyl chlorides with ortho, meta, and para substitutions reacted
efficiently giving high yields of regio-isomeric -arylacetophenon-
a-arylacetophenones. The mono- and di-substituted a-arylace-
a
es. The reactions carried out with trithiophen-2-ylbismuth also
afforded high yields of corresponding coupling products (Table 2,
entries 22 and 28). At large, the coupling ability of various triaryl-
bismuths was found to be efficient with electronically divergent
References and notes
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chloride also afforded high yields of products. Notably, in all reac-
tions homo-coupling bi-aryl products from triarylbismuths12h,11b
were formed in minor amounts. However, higher amounts of bi-ar-
yls were formed in reactions with moderate cross-coupling yields.
In addition, the moderate cross-coupling yields in some cases may
also be due to electronics of the triarylbismuth nucleophiles to
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substituted a-arylketones in high yields. It is noteworthy that syn-
4.
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Crafts condition would be difficult.
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similar to the one proposed by Barton et al. for acid chloride cou-
plings.12h The initial oxidative addition of arylacetyl chloride A to
in situ generated-Pd(0) provides Pd(II) species B. This intermediate
upon transmetalation with triarylbismuth reagent further provides
C which undergoes reductive elimination to give the product D. Par-
ticipation of other species such as Ar2BiX/ArBiX2 or Ar3Bi (formed
through disproportionative regeneration of Ar2BiX or Ar2BiX)12h is
also possible during transmetalation. This way, triarylbismuths
would function as multi-coupling organometallic nucleophile with
the transfer of three aryl groups for coupling reaction. However,
homo-coupling of triarylbismuths in the presence of Pd catalyst is
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products.12h,11b
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In summary, we have disclosed an efficient cross-coupling of
a-arylacetyl chlorides with triarylbismuth nucleophiles as sub-
Oxidative
Transmetalation
(II)
Pd
Cl
addition
Ar1
(B)
BiAr3
Cl
Ar1
(A)
O
Ar2BiX
Ar
O
(II)
Pd
Pd(0)
Ar1
(C)
O
Reductive
elimination
Ar
Ar1
(D)
O
Scheme 1. Proposed catalytic cycle.

6138
M. L. N. Rao et al. / Tetrahedron Letters 50 (2009) 6133–6138
13. General procedure: In
a
hot oven-dried Schlenk tube under nitrogen
a-aryl acetyl chloride (1 mmol, 4 equiv), Ar3Bi
over anhydrous MgSO4. The solvent was removed on rotator evaporator under
reduced pressure. The crude product was subjected to column chromatography
on silica gel (100–200 mesh) using ethyl acetate:petroleum ether (3:97) as
atmosphere were taken
(0.25 mmol, 1 equiv), PdCl2(PPh3)2 (0.0225 mmol, 0.09 equiv), and Et3N
(0.25 mmol, 1 equiv) followed by 3 mL of dry THF solvent. The contents were
stirred at 80 °C in an oil bath for 3 h. After the reaction time, the contents were
cooled to room temperature, quenched with dil HCl (10 mL), and extracted
using ethyl acetate (20 mL Â 3). The combined organic extract was treated
with saturated NaHCO3 solution (20 mL Â 2) and brine (20 mL Â 3), and dried
eluent to obtain
a-aryl ketone as a pure product. The product was
characterized by 1H NMR, 13C NMR, IR, and ESI-MS spectroscopic studies.
14. For all reactions, yields were calculated considering three aryl groups from
triarylbismuth for coupling. Thus, 1 equiv of BiAr3 is equal to 3 equiv of Bi–Ar.
So, 3 equiv of cross-coupling product (0.75 mmol) corresponds to 100% yield.