Palladium-catalyzed cross-coupling of aroyl chlorides with aryl stannanes in the presence of triethylsilane: Efficient access to aromatic ketones

Article abstract of DOI:10.1016/j.tetlet.2020.152466

Herein, we report the development of a palladium-catalyzed cross-coupling reaction that focuses on the preparation of aromatic ketones. Aroyl chlorides react quickly at 120 °C with aryl stannanes in the presence of Pd(PPh₃)₄ and Et₃SiH to efficiently give the corresponding ketones without the formation of significant decarbonylated byproducts. In other words, the decarbonylative side reaction is practically suppressed by simply adding Et₃SiH to the reaction mixture, which reduces the amount of biaryl impurities in the products.

Full text of DOI:10.1016/j.tetlet.2020.152466

Journal Pre-proofs
Palladium-catalyzed cross-coupling of aroyl chlorides with aryl stannanes in
the presence of triethylsilane: Efficient access to aromatic ketones
Shoko Higashi, Sota Uno, Yui Ohsuga, Maiko Noumi, Ryota Saito
PII:
S0040-4039(20)30947-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152466
TETL 152466
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Tetrahedron Letters
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Revised Date:
Accepted Date:
26 July 2020
11 September 2020
14 September 2020
Please cite this article as: Higashi, S., Uno, S., Ohsuga, Y., Noumi, M., Saito, R., Palladium-catalyzed cross-
coupling of aroyl chlorides with aryl stannanes in the presence of triethylsilane: Efficient access to aromatic
ketones, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152466
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Graphical Abstract
Palladium-catalyzed Cross-coupling of Aroyl
Chlorides with Aryl Stannanes in the
Presence of Triethylsilane: Efficient Access
to Aromatic Ketones
Leave this area blank for abstract info.
Shoko Higashi, Sota Uno, Yui Ohsuga, Maiko Noumi, and Ryota Saito*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Palladium-catalyzed Cross-coupling of Aroyl Chlorides with Aryl Stannanes in the
Presence of Triethylsilane: Efficient Access to Aromatic Ketones
Shoko Higashia, Sota Unoa, Yui Ohsugaa, Maiko Noumia, and Ryota Saitoa,b 
a
Department of Chemistry, Faculty of Science, Toho University, Funabashi, Chiba 274-8510, Japan
Research Center for Materials with Integrated Properties, Toho University, Funabashi, Chiba 274-8510, Japan
b
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +81-47-472-1926; fax: +81-47-472-1926; e-mail: saito@chem.sci.toho-u.ac.jp
Article history:
Received
Herein, we report the development of a palladium-catalyzed cross-coupling reaction that focuses
on the preparation of aromatic ketones. Aroyl chlorides react quickly at 120 °C with aryl
Received in revised form
Accepted
Available online
stannanes in the presence of Pd(PPh3)4 and Et3SiH to efficiently give the corresponding ketones
without the formation of significant decarbonylated byproducts. In other words, the
decarbonylative side reaction is practically suppressed by simply adding Et3SiH to the reaction
mixture, which reduces the amount of biaryl impurities in the products.
Keywords:
Stille coupling reaction
Diaryl ketones
2009 Elsevier Ltd. All rights reserved.
Triethylsilane
Suppression of decarbonylation
Introduction
analogs that are expected to be drug candidates for diabetic
complications (Scheme 1).20, 21
Among a number methods for the syntheses of targeted
compounds, four general popular strategies exist for preparing
aromatic ketones: (i) the reactions of aroyl halides with
organometallics such as organolithiums1 or Grignard reagents,2
which are well-known classical methods; (ii) the Friedel–Crafts
acylation of aromatic compounds activated by aluminum
chloride;3 (iii) CO insertion into aryl halides or their equivalents
catalyzed by organometallic complexes,4, 5 which is an efficient
process with high atom economy that has remarkably advanced
in recent years; and (iv) the Stille and Suzuki–Miyaura cross-
coupling reactions of aroyl halides with aryl partners (aryl
stannanes and aryl boronic acids, respectively) promoted by
palladium catalysts.6-15 Compared with the other three methods,
the Stille and Suzuki–Miyaura cross-coupling strategies are
advantageous for the fine syntheses of asymmetric aromatic
ketones with diverse structures. These cross-coupling reactions
are mostly very chemoselective and can be applied to a range of
substrates.7-15 Moreover, methods for the synthesis of aryl
stannanes and aryl boronic acids have already been developed
through the pioneering efforts of a number of researchers,16-19 and
has provided a large number of substrates to choose from. In
addition, aroyl halides are also readily prepared from benzoic
acids; hence, CO gas or CO-metal complexes are not required in
subsequent ketone-forming coupling reactions. Furthermore, the
oxidative additions of palladium catalysts to aroyl halides are
faster than those involving aryl halides, which enables the use of
molecules that possess both aroyl halide and aryl halide
HO
MeO
O
N
SnBu3
N
O
N
N
N
N
Cl
Cl
HO
Scheme 1. A Pathway for the Synthesis of Botryllazine B
During this study, we encountered a serious problem: the
Stille-coupling products from the reactions of some substituted
aryl chlorides contained considerable amounts of byproducts that
had lost their carbonyl moieties. While decarbonylative cross-
coupling reactions using aroyl halides instead of aryl halides
have been studied intensively in recent years,22-24 we needed to
suppress this side reaction in order to obtain our target ketones.
Herein, we report the unprecedented and surprising ability of
triethylsilane to suppress decarbonylation.
Results and Discussion
4-Methoxybenzoyl chloride (1a) was coupled with aryl
stannane 2a in the presence of 3 mol% Pd(PPh)3 at 120 °C for 3 h
to afford the botryllazine B building block 3aa in good yield
without the decarbonylated byproduct 4aa (Table 1, entry 1). In
contrast, 3-methoxybenzoyl chloride (1b) gave a non-negligible
amount of 4ba under the same reaction conditions (entry 2).
Decreasing the reaction temperature to 60 °C led to the formation
of less 4ba; however, significantly long reaction times were
required for reaction completion (entry 5). For us, the reaction
14
functionalities as starting materials.11,
Based on this
background, we used the Stille coupling strategy with aroyl
chlorides and heteroaryl stannanes to synthesize botryllazine B

2
Tetrahedron
condition dependence on the structure of the aroyl chloride is
inconvenient because we wanted to synthesize as many
botrillazine B analogs as possible in order to create a chemical
library for thorough structure-activity relationship studies. For
that reason, we explored more-efficient and versatile reaction
conditions that are applicable to aroyl chlorides in general and
that do not generate decarbonylated byproducts. We first
explored the use of CO-rich conditions to suppress
decarbonylation, since this process involves an equilibrium
between CO migration and insertion at the palladium-acyl
intermediate stage of the catalytic reaction cycle. Hence, we
chose reactions that use the safe and readily available CO sources
reported by Manabe et al.25 for the acylation of aryl halides to
avoid the direct use of toxic CO gas (Table 2).
decarbonylation (entry 17). Finally, we chose to use 1.3
equivalents of Et3SiH because of its availability and low cost.
Table 2. Reactions using CO sources and Et3SiHa
OMe
OMe
Pd(PPh3)4 (3 mol%)
CO source / base
Additive
O
N
+
1b
2a
+
toluene, 120 oC, 2.5 h
N
N
N
O
Cl
Cl
Cl
Cl
O
O
O
S
3ba
4ba
3
H
O
H
Cl
O
5b
5a
CO sources
entry CO
source
base
Additive
(equiv.)
yield (%)b
3ba 4ba
Table 1. Coupling Reactions of Benzoyl chlorides with 2aa
R
R
(equiv.)
O
SnBu3
Pd(PPh3)4
(3 mol%)
O
N
Cl
1
5a
Na2CO3 (1.6) Et3SiH (1.3) 85
Na2CO3 (1.6) Et3SiH (1.3) 69
3
N
R
+
+
N
toluene
2
3
4
5b
5a
–
2
Cl
N
N
2a
1a: R = 4-OMe
1b: R = 3-OMe
N
Na2CO3 (1.6)
–
–
77
29
Cl
Cl
3
4
Et3SiH (1.3) 94
3
entry substrate
temp.
(°C)
time Product (yield/%)b
(h)
aReaction conditions: 1b (3.0 mmol), 2a (1.0 mmol), Pd(PPh3)4 (0.03 mmol),
CO source (1.5 mmol), Na2CO3 (1.6 mmol), Et3SiH (1.3 mmol), and toluene
(20 mL) at 120 °C for 2.5 h under Ar. bDetermined by 1H NMR spectroscopy
of a mixture of 3 and 4 obtained after silica-gel column chromatography.
1
1a
1b
1b
1b
1b
120
120
90
60
60
2.5
2.5
2.5
2.5
48
3aa (81)
3ba (76)
3ba (84)
3ba (19)
3ba (89)
4aa (0)
2
3
4
5
4ba (20)
4ba (9)
4ba (0)
4ba (2)
Table 3. Optimizing the Reaction Conditionsa
aReaction conditions: 1 (3.0 mmol), 2a (1.0 mmol), Pd(PPh3)4 (0.03 mmol),
and toluene (20 mL) at 60–120 °C for 2.5 h. bDetermined by 1H NMR
spectroscopy of a mixture of 3 and 4 obtained after silica-gel column
chromatography.
entry 1b
/
2a Additive (equiv.) yield (%)b
(equiv.)
3ba
4ba
16
23
1
1
1 : 1
6 : 1
1 : 1
6 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
–
63
66
50
86
82
92
88
60
76
71
Improved ratios of ketone 3ba to biaryl 4ba were obtained in the
presence of 5a or 5b, Na2CO3, and Et3SiH (entries 1 and 2). The
results were quite satisfactory; the CO sources were apparently
effective at suppressing decarbonylation. At this point, we
considered that Et3SiH, which was used as a hydride source in
the original reaction to afford aldehydes, was unnecessary in the
present reaction; hence the same reaction was carried out in the
absence of Et3SiH (entry 3). However, contrary to expectation,
the yields of 3ba and 4ba were almost the same as those from the
reaction in the absence of the CO source (Table 1, entry 2). The
same reaction was then performed in the absence of the CO
source but in the presence of Et3SiH (entry 4). Surprisingly, an
unexpected and desirable effect, which gave the required ketone
in excellent yield, was observed, clearly demonstrating that the
addition of only Et3SiH to the reaction mixture effectively
suppressed decarbonylation.
2
–
3
Et3SiH (1.3)
Et3SiH (1.3)
Et3SiH (0.5)
Et3SiH (1.0)
Et3SiH (2.6)
iPr3SiH (1.3)
Ph3SiH (1.3)
(EtO)3SiH (1.3)
Ph2SiH2 (1.3)
PhSiH3 (1.3)
Et2MeSiH (1.3)
EtMe2SiH (1.3)
Et3SiCl (1.3)
Bu3SnH (1.3)
Et3GeH (1.3)
4
3
5
10
4
6
7
3
8
24
20
23
1
9
10
11
12
13
14
15
16
17
73
75
87
85
62
75
87
0
We next explored the silane scope of this reaction (Table 3).
Increasing or decreasing of the equivalents of aroyl chloride 1b
did not improve the yield of 3ba (entries 1, 2), while the
generation of 4ba was clearly suppressed in the presence of
Et3SiH (entries 3, 4). Using 0.5 or 2.6 equivalents of Et3SiH was
less effective than 1.0 or 1.3 equivalents (entries 5-7). Bulky
silanes, such as triisopropyl, triphenyl, and triethoxysilane, were
less effective than Et3SiH (entries 8-10). Meanwhile, compact
silanes, such as diphenyl, phenyl, and diethylmethyl silane, were
effective at reducing decarbonylation rates (entries 11-14).
Chlorotriethylsilane and tributylstannane were inactive in this
reaction (entries 15-16). Et3GeH proved to be most effective
among the tested additives, completely suppressing
3
9
23
21
0
aGeneral Reaction conditions: 1b (3.0 mmol), 2a (1.0 mmol), additive (1.3
mmol), Pd(PPh3)4 (0.03 mmol), and toluene (20 mL) at 120 °C for 2.5 h
b
1
under Ar. Determined by H NMR spectroscopy of a mixture of 3ba and
4ba obtained after silica-gel column chromatography.
With the optimized reaction conditions in hand, we
investigated the effect of Et3SiH on the cross-couplings of

3
27
insertion of metal alkyl carbonyl complexes,26,
we
various aroyl chlorides with aryl stannanes (Scheme 2).
Improved yields of ketones (3ca, 3da, 3ea, and 3fa) and reduced
amounts of decarbonylated byproducts (4ca, 4da, 4ea, and 4fa)
were observed in all cases when Et3SiH was added to the reaction
system; pleasingly, these products are important precursors of
considered that Et3SiH behave as a Lewis acid and stabilize
the palladium-acyl complexes. And thus we propose the
reaction cycle shown in Scheme 4.
Scheme 3. Reaction Pathway Studiesa
botryllazine
B
analogs. The reaction of 1b with
O
SnBu3
chlorophenylstannane 2b also proceeded smoothly under the
same conditions to afford the corresponding ketone in 82% yield
accompanied by a small amount of 4bb. Furthermore, when
either an electron-donating or -withdrawing substituted
phenylstannane (2c or 2d) was used as the starting material, the
ratio of the produced ketone dramatically changed to a desired
value, which clearly demonstrates that the addition of Et3SiH to
the Stille acylation reaction mixture suppresses the
decarbonylative side reaction remarkably, irrespective of the
substrate.
MeO
Et3SiH (1.3 eq.)
Cl
N
(1)
+
+
1b
2a
N
toluene, 120 oC, 2.5 h
Cl
quant. quant.
1b
2a
OMe
OMe
Pd(PPh3)4 (3 mol%)
Et3SiH (0 or 1.3 eq.)
O
N
+
+
(2)b
3ba
4ba
N
N
toluene, 120 oC, 2.5 h
( 19 : 3 )
N
Cl
Cl
3ba
4ba
Scheme 2. Substrate scopea
( 19 : 3 )
R1
R1
SnBu3
Pd(PPh3)4
(3 mol%)
Et3SiH
O
Pd(PPh3)4 (3 mol%)
Et3SiH (1.3 eq.)
SnBu3
O
X
N
Cl
X
2e
(3)
(4)
R1
+
+
toluene, 120 oC, 2.5 h
quant.
X
toluene
X
X
120 oC, 2.5 h
R2
2e
X
3
1
2
R2
R2
3
4
O
SnBu3
Pd(PPh3)4 (3 mol%)
Et3SiH (0 or 1.3 eq.)
MeO
OMe
OMe
H
N
+
+
3ba
4ba
MeO
CF3
N
O
N
toluene, 120 oC, 2.5 h
0%
0%
Cl
O
O
O
N
O
N
6
2a
MeO
a General reaction conditions: 1b or 6 (3.0 mmol), 2 (1.0 mmol), Pd(PPh3)4
(0.03 mmol), Et3SiH (1.3 mmol), and toluene (20 mL) at 120 °C for 2.5 h
under Ar. Yields were determined by 1H NMR spectroscopy. bReaction
conditions: 3ba containing 4ba (total 62 mg), Pd(PPh3)4 (0.03 mmol), Et3SiH
(0 or 1.3 mmol), and toluene (20 mL) at 120 °C for 2.5 h under Ar. Final and
initial ratios were determined by 1H NMR spectroscopy against an internal
standard (triphenylmethane).
N
N
N
N
N
Cl
Cl
Cl
Cl
3ca, 73% (72%)
4ca, 3% (12%)
3da, 71% (62%)
4da, 9% (22%)
3ea, 84% (66%)
4ea, 5% (29%)
3fa, 77% (56%)
4fa, 21% (30%)
OMe
OMe
OMe
O
O
O
Scheme 4. Proposed reaction mechanism
N
N
R
Cl
N
Cl
N
R
Cl
O
acylated
product
decarbonylated
product
NO2
OMe
3bb, 82% (54%)
4bb, 9% (36%)
3bc, 64% (28%)
4bc, 10% (43%)
3bd, 59% (35%)
4bd, 4% (32%)
N
N
O
aGeneral reaction conditions: 1 (3.0 mmol), 2 (1.0 mmol), Et3SiH (1.3 mmol),
Pd(PPh3)4 (0.03 mmol), and toluene (20 mL) at 120 °C for 2.5 h under Ar.
Yields were determined by 1H NMR spectroscopy of a mixture of 3 and 4
obtained after silica-gel column chromatography. Yields in the absence of
Et3SiH are shown in parentheses. Isolated yields are shown.
N
N
PdII
Ln
Cl
Products made out of
R
R
PdII
Ln
Cl
Bu3SnCl+Et3SiH
O
L
nPd0
(L: phospine ligand)
Bu3SnCl
Cl
R
R
N
Et3
Si
N
Cl
N
SnBu3
O
H
O
Cl
N
SnBu3
CO
LnPdII
Cl
R
LnPdII
Cl
R
LnPdII
LnPdII
Cl
R
Cl
CO migration
CO
We also studied the behavior of Et3SiH in the reaction
pathway (Scheme 3). As might be expected, no coupling
products were observed in the presence of Et3SiH but the
absence Pd(PPh3)4 (eq. 1). The ketone and biaryl products
did not interconvert under the same Pd-catalyzed reaction
conditions with/without Et3SiH (eq. 2). In order to examine
whether or not the SnBu3 moiety can be replaced by Et3SiH,
2e was mixed with Et3SiH in the presence of Pd(PPh3)4 (eq.
3), which resulted in the complete recovery of the starting
aryl stannane. Aldehyde 6, which might be generated by Pd-
catalyzed reaction of benzoyl halide with Et3SiH, also failed
to give 3ba and 4ba (eq. 4). Even though further details on
the behavior of Et3SiH remain unknown, these observations
suggested that the metal-reactive functional groups of the
starting materials remain unchanged in the presence of
Et3SiH. Although we were unable to determine the critical
factors responsible for Et3SiH behavior at this point, based
on previous reports that Lewis acids promote CO migratory
Et3SiH
Conclusion
In summary, we developed a Pd-catalyzed method for cross-
coupling aroyl chlorides with aryl stannanes in the presence of
Et3SiH to produce aromatic ketones. The addition of Et3SiH to
the reaction mixture suppresses decarbonylative side reactions
and improves the yields of the desired ketones, irrespective of the
substrate. We believe that this discovery will be helpful for the
future synthesis of a wide range of aromatic ketones.
Declaration of Competing Interest
The authors declare no competing financial interests or
personal relationships that could have appeared to influence the
work reported in this paper

4
Tetrahedron
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This research was supported by JSPS KAKENHI Grant
Number 19K0569. Partial financial support to RS by a Faculty of
Science Special Grant for Promoting Scientific Research at Toho
University is also appreciated. The authors thank Prof. Toshiya
Komatsu, Teikyo Heisei University, Japan, and Dr. Kaname
Sasaki, Toho University, Japan, for fruitful discussions. The
authors also acknowledge Editage (www.editage.jp) for English
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Supplementary data to this article can be found online
athttps://doi.org/10.1016/j.tetlet.xxxx.xxxxxx.