Acid fluorides as acyl electrophiles in suzuki–miyaura coupling

Article abstract of DOI:10.1002/ejoc.201700917

The first palladium-catalyzed construction of ketones through Suzuki–Miyaura reaction by using acid fluorides is described. In contrast to typical acyl electrophiles such as acid chlorides, acid fluorides are uncommon acyl electrophiles to use in boron-based coupling reactions, probably due to a high level of stability toward nucleophiles. This first attempt to use acid fluorides as a coupling partner with boronic acids allowed highly functional group tolerance and a wide substrate scope while affording various ketones in effective yields.

Full text of DOI:10.1002/ejoc.201700917

A Journal of
Accepted Article
Title: Acid Fluorides as Acyl Electrophiles in Suzuki-Miyaura Coupling
Authors: Yohei Ogiwara, Daisuke Sakino, Yuka Sakurai, and Norio
Sakai
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700917
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700917
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700917
COMMUNICATION
Acid Fluorides as Acyl Electrophiles in Suzuki–Miyaura Coupling
Yohei Ogiwara,* Daisuke Sakino, Yuka Sakurai, and Norio Sakai*
Abstract: The first palladium-catalyzed construction of ketones via
Suzuki–Miyaura reaction using acid fluorides is described. In
contrast to typical acyl electrophiles such as acid chlorides, acid
fluorides are uncommon acyl electrophiles to use in boron-based
coupling probably due to a high level of stability toward nucleophiles.
This first attempt to use acid fluorides as a coupling partner with
boronic acid allowed highly functional group tolerance and a wide
substrate scope, and afforded various ketones in effective yields.
the versatility and utility of both fragments in cross-coupling, an
acyl electrophile and a carbon nucleophile. Herein, we describe
the use of acyl fluorides as novel building blocks for the
synthesis of ketones in a palladium-catalyzed coupling with
boronic acids, which exhibits highly functional group tolerance
and a wide substrate scope while providing various symmetrical
and unsymmetrical ketones (Scheme 1c).
a) using organozinc reagents
O
Ni(cod) /pyphos
O
O
O
2
+
R' Zn
2
Introduction
4-fluorostyrene
THF
R
F
R
Ar
R
R'
Ar'
R'
b) using organosilicon reagents
O
Carboxylic acid derivatives have been regarded as
a
significant acylation reagent in synthetic chemistry. In particular,
the efficient construction of a ketone skeleton can be achieved
via acyl carbon–carbon bond formation, when the acyl fragment
can be transferred into carbon nucleophiles by transition metal
catalysts. Since the organoboron compounds that are utilized in
Suzuki–Miyaura reactions have been recognized as one of the
most representative and useful carbon nucleophiles, boron-
based coupling for ketones has been widely investigated. A
large variety of carboxylic acid derivatives are currently utilized
t
Pd(OAc) /P
Bu3
2
+
Ar'SiF
3
CsF, xylene
Ar
F
c) using organoboron reagents (this work)
Pd(OAc)2
P(4-MeOC H )
O
6
4 3
+
R'B(OH)
2
KF, toluene
R
F
Scheme 1. Cross coupling of acyl fluorides and organometallic reagents.
[
1]
[2−4]
as coupling partners: acid chlorides,
anhydrides,
[
5]
[6]
thioesters,
activated esters,
esters bearing chelating
[
7]
[8]
[9]
groups, aryl esters, and carboxamides.
Results and Discussion
Among these carboxylic acid derivatives, acyl fluorides are
generally considered inactive and easily handled electrophiles.
Compared with acid chlorides, these show greater stability
toward nucleophiles such as water, and they can be easily
prepared from either corresponding carboxylic acids or acyl
Initially, the optimization of the reaction conditions for the
coupling of benzoyl fluoride (1a) with 4-methylphenylboronic
acid (2a) was investigated as model substrates (Table 1). During
the screening of several reaction parameters, such as a ligand
[
10]
and
quantitatively to give the corresponding diaryl ketone 3 under the
following standard conditions: 2a (1.5 equiv), Pd(OAc) (1
mol %), P(4-MeOC (L1) (4 mol %), and KF (1.5 equiv) in
a base, the expected coupling reaction proceeded
chlorides.
The use of these acyl fluorides as versatile acyl
electrophiles in cross-coupling, therefore, provides an alternative
and attractive synthetic route to a ketone framework. In 2004,
Rovis and co-worker reported pioneering work in the transition
metal-catalyzed cross coupling of acyl fluorides with
organometallic reagents. In that reaction, organozinc reagents
were available as coupling partners of acyl fluorides in the
2
6
4 3
H )
toluene (1 mL) at 120 °C for 16 h (entry 1). The selected results
of the effects of each phosphorous ligand are described in
entries 2−11. The yield of product 3 was also excellent when
[
11]
PPh
deficient phosphine, P(4-CF
entries 2 and 3). Both reactions with triarylphosphines bearing
3
was used as a ligand, whereas the use of an electron-
presence of a nickel (0) catalyst (Scheme 1a). Recently, our
research group developed a palladium-catalyzed coupling of
acid halides with organosilicon compounds leading to ketones,
wherein the acid fluorides acted as acyl electrophiles as well as
3
6 4 3
C H )
, decreased the yield to 48%
(
methyl substituents at their 4- and 3-positions resulted in 78 and
69% yields, respectively, but substitution with 2-methyl was not
effective as a ligand for this coupling (entries 4−6). When
trialkylphosphines and dialkylbiarylphosphines were employed,
[
12]
typical acid chlorides (Scheme 1b). Although these two kinds
of organometallic reagents have been already revealed to be
available for the cross-coupling with acyl fluorides, the boron-
[
13]
though PCy
3
(L2) gave good result in 92% yield of 3, the other
, XPhos, and JohnPhos, provided the product in
−21% yields (entries 7−10). In the absence of a ligand, no yield
based alternatives have been unexplored even now,
despite
t
ones, P Bu
3
0
of ketone 3 was generated (entry 11). The screening of several
bases was next investigated (entries 12−16). To clarify the
difference in the effect of bases, decreasing amounts of boronic
acid 2a and a base (1.2 equiv each) were used under a milder
reaction temperature (80 °C). With respect to KF, however, a
sufficient yield of 3 was generated regardless of the conditions
[*]
Dr. Y. Ogiwara, D. Sakino, Y. Sakurai, Prof. Dr. N. Sakai
Department of Pure and Applied Chemistry, Faculty of Science and
Technology, Tokyo University of Science
Noda, Chiba 278-8510 (Japan)
E-mail: yoheiogiwara@rs.tus.ac.jp, sakachem@rs.noda.tus.ac.jp
Supporting information for this article is given via a link at the end of
the document.
(
3 4 2 3
entry 12). Other bases, such as CsF, K PO , K CO , and
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European Journal of Organic Chemistry
10.1002/ejoc.201700917
COMMUNICATION
Na
2
CO
3
, led to no yields higher than that of KF (entries 13−16).
coupling and provided the corresponding benzophenones 15−17,
albeit in slightly decreased yields (entries 13−15). Boronic acids
bearing 2-naphthyl, 3-furyl, and 2-thienyl moieties 2p−2r were
also applicable to the coupling with 1a, to afford the coupling
products 18−20 (entries 16−18). When alkenylboronic acids 2s
and 2t were used, the expected enone products 21 and 22 were
obtained in 34 and 42% yields, respectively (entries 19 and 20).
This coupling proceeded smoothly, and afforded 3 in a 93%
yield after 5 h (entry 17).
Table 1. Optimization of the coupling reaction.
Pd(OAc)2 (1 mol %)
P(4-MeOC H ) (L1)
(4 mol %) (1:4 Pd/P)
O
6
4 3
O
(HO)
2
B
+
Ph
[
a]
KF (1.5 equiv)
toluene, 120 °C
16 h
Table 2. Substrate scope for boronic acids 2.
Pd(OAc) (1 mol %)
2
Ph
F
1a
2a (1.5 equiv)
3
O
L1 (4 mol %)
O
[
a]
[b]
+
(HO) B
R
2
Entry
Variation of the standard conditions
none
Yield of 3 [%]
KF (1.5 equiv)
toluene, 120 °C, 5 h
Ph
F
Ph
R
1
2
3
4
5
6
7
8
9
99
96
48
78
69
0
1a
2 (1.5 equiv)
[
b]
PPh
3
instead of L1
Entry
2
R
ketone
Yield [%]
P(4-CF
3
C
6
H
4
)
3
instead of L1
instead of L1
instead of L1
instead of L1
1
2
2a
2b
2c
2d
2e
2f
4-MeC
3-MeC
2-MeC
6
6
6
H
H
H
4
4
4
3
4
89
78
86
P(4-MeC
P(3-MeC
P(2-MeC
6
6
6
H
H
H
4
4
4
)
)
)
3
3
3
3
5
[
c]
4
4-EtC
6
H
4
6
58
47
52
78
81
70
55
60
48
44
33
45
56
45
90
34
42
n
[c]
PCy
3
(L2) instead of L1
instead of L1
92
21
5
5
4- PrC
6
H
4
7
t
n
[c]
P Bu
3
6
4- BuC
6
H
4
8
t
[c,d]
XPhos instead of L1
JohnPhos instead of L1
without L1
7
2g
2h
2i
4- BuC
6
H
4
9
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
0
8
Ph
10
[
[
[
[
[
[
[
[
[
c]
0
9
4-MeOC
3,4-(MeO)
4-PhC
4-Me SiC
4-FC
4-ClC
6
H
4
11
12
13
14
15
16
17
18
19
20
21
22
c]
2a (1.2 equiv), KF (1.2 equiv), 80 °C
2a (1.2 equiv), CsF (1.2 equiv), 80 °C
93
48
24
78
0
10
11
12
13
14
15
2j
2 6 3
C H
c]
2k
2l
6 4
H
c,e]
c,e,f]
c]
2a (1.2 equiv), K
2a (1.2 equiv), K
3
2
PO
4
(1.2 equiv), 80 °C
(1.2 equiv), 80 °C
3
6 4
H
CO
3
2m
2n
2o
2p
2q
2r
6 4
H
2a (1.2 equiv), Na
2
CO
3
(1.2 equiv), 80 °C
6 4
H
c,e]
c]
5 h
93
4-MeOC(O)C
2-naphthyl
3-furyl
6 4
H
1
1
1
1
2
6
7
8
9
0
[
(
a] Standard reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), Pd(OAc)
0.005 mmol), P(4-MeOC (L1) (0.02 mmol), and KF (0.75 mmol) in
toluene (1 mL) at 120 °C for 16 h. [b] GC yield.
2
6 4 3
H )
c]
2-thienyl
[
[
c,e]
c]
2s
2t
PhCH=CH
The coupling of benzoyl fluoride (1a) with boronic acids 2
3 2 2
CH CH CH CH=CH
was then conducted under the present catalytic conditions,
Pd(OAc)
yields of the products were improved by switching the ligand
from L1 to PCy (L2) (Table 2). The reactions of alkyl-substituted
2 6 4 3
/P(4-MeOC H ) (L1) system. In some cases, the
[
a] Reaction conditions: 1a (1.0 mmol), 2 (1.5 mmol), Pd(OAc)
P(4-MeOC (L1) (0.04 mmol), and KF (1.5 mmol) in toluene (2 mL) at
120 °C for 5 h. [b] Isolated yield. [c] 16 h. [d] 1.2 equiv each of 2 (1.2 mmol)
2
(0.01 mmol),
6
4 3
H )
3
arylboronic acids 2a−2g, phenylboronic acid (2h), the methoxy
substituted ones 2i and 2j, and phenyl- or trimethylsilyl-
substituted arylboronic acids 2k and 2l, afforded the various
symmetrical and unsymmetrical diaryl ketones 3−14 in good
yields (entries 1−12). Electron-withdrawing substituents such as
a halogen atom, 2m and 2n, and a methoxycarbonyl group, 2o,
at the 4-positions on the benzene ring, were also suitable for the
and KF (1.2 mmol). [e] PCy
mmol) and KF (2 mmol).
3
(L2) instead of L1. [f] 2 equiv each of 2 (2
The generality of acid fluorides 1 was next investigated for
coupling with phenylboronic acid (2h). A variety of acid fluorides
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European Journal of Organic Chemistry
10.1002/ejoc.201700917
COMMUNICATION
were available as acyl electrophiles in the present reaction Conclusions
(
Scheme 2). The 4-substituted benzoyl fluoride derivatives 1b
and 1c possess either an electron-donating methoxy group or an
electron-withdrawing trifluoromethyl group underwent coupling
with phenylboronic acid (2h) to provide asymmetric diaryl
ketones 11 and 23 in 72 and 41% isolated yields, respectively.
The coupling of methyl-substituted versions 1d−1g, such as 4-
methyl, 3-methyl, 2-methyl, and 3,5-dimethyl groups, with 2h
formed the corresponding ketones 3−5 and 24 in good yields.
Fused aromatic- and heteroaromatic acid fluorides 1h−1j were
also available as an aroyl source in this transformation to form
In summary, we developed a palladium/phosphine-catalyzed
cross-coupling between acid fluorides and boronic acids. A
striking feature of the description is that acid fluorides can act as
a novel acyl electrophile for the boron-based coupling. Various
symmetrical and unsymmetrical ketones were synthesized using
this method, regardless of their carbon structures and functional
groups. Acid fluorides would potentially be applicable as an acyl
electrophile in many other transition metal-catalyzed
transformations. Further investigations and applications of the
axis of the features of acyl fluorides are now underway by our
research group.
1
8, 25, and 26. Reactions of acyl fluorides containing an alkenyl-
and an alkyl skeleton, cinnamoyl fluoride (1k) and 3-
phenylpropanoyl fluoride (1l), proceeded with 2h to give the
coupling products 21 and 27, in 76 and 56% yields, respectively.
Finally, the construction of several ketones with diverse carbon
skeletons was demonstrated using this method [Eqs (1) and (2)].
Coupling between acid fluoride 1k with boronic acid 2t afforded
unsymmetrical vinyl ketone 28. Alkyl heteroaryl ketone 29 was
also obtained from 1l and 2r.
Experimental Section
To a screw-capped vial in a glovebox, Pd(OAc)
.01 mmol), P(4-MeOC (L1) (14.0 mg, 0.04 mmol) or PCy
L2) (11.2 mg, 0.04 mmol), KF (87.1 mg, 1.5 mmol), a boronic
2
(2.2 mg,
0
6
H
4
)
3
3
(
Pd(OAc)2 (1 mol %)
L1 or L2 (4 mol %)
acid (1.5 mmol) and toluene (2 mL) were added. The vial was
then sealed and removed from the glovebox, and an acyl
fluoride (1 mmol) was successively added to the vial. The
O
O
+
(HO) B
Ph
2
KF (1.5 equiv)
toluene, 120 °C, 16 h
R
F
R
Ph
mixture was heated at 120 °C for 5−16 h. After the reaction, H
was added to the mixture, which was then extracted with EtOAc.
The organic layer was dried over Na SO , and the volatile
2
O
1
2h (1.5 equiv)
O
O
O
2
4
materials were removed by rotary evaporation. The crude
material was purified by silica gel column chromatography.
F
F
F
MeO
(
F3C
1c
(23, 41%)
Me
1
b
1d
(3, 73%)
[
a]
[a]
[a]
11, 72%)
O
O
Me
O
O
Acknowledgements
Me
Me
F
F
F
F
This work was partially supported by JSPS KAKENHI Grant
Number JP16K21400 and by a Research Grant from Shorai
Foundation for Science and Technology, a grant from Central
Glass Co., Ltd. Award in Synthetic Organic Chemistry, Japan,
and a Research Grant from Takahashi Industrial and Economic
Research Foundation.
Me
1g
(24, 88%)
1
e
1f
(5, 75%)
1h
(18, 84%)
[
b]
[b]
[b,c]
[b,c]
(
4, 88%)
O
O
O
O
F
F
NH
Ph
F
Ph
F
1
i
1j
(26, 20%)
1k
(21, 76%)
1l
Keywords: Cross-coupling • Ketones • Acyl fluorides • Boronic
[
b]
[a]
[b]
[a,d]
(
25, 42%)
(27, 56%)
acids • Palladium catalyst
Scheme 2. Substrate scope for acid fluorides 1. Reaction conditions: 1 (1.0
mmol), 2h (1.5 mmol), Pd(OAc) (0.01 mmol), ligand (L1 or L2) (0.04 mmol),
and KF (1.5 mmol) in toluene (2 mL) at 120 °C for 16 h. Isolated yields of
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2
ketones are shown. [a] P(4-MeOC
6
H
4
)
3
(L1). [b] PCy
3
(L2). [c] 2 equiv each of
3
109; d) G. W. Kabalka, R. R. Malladi, D. Tejedor, S. Kelley,
2
h (2 mmol) and KF (2 mmol). [d] 5 h.
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Pd(OAc)2 (1 mol %)
O
L1 (4 mol %)
1
k
+
+
2t
(1)
KF (1.5 equiv)
.5 equiv toluene, 120 °C, 16 h
Ph
1
2
8, 25%
Pd(OAc)2 (5 mol %)
L1 (20 mol %)
O
S
1l
2r
(2)
Ph
KF (2 equiv)
2
equiv
toluene, 120 °C, 16 h
2
9, 45%
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European Journal of Organic Chemistry
10.1002/ejoc.201700917
COMMUNICATION
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6]
a) L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 11260; b) Y.
Yu, L. S. Liebeskind, J. Org. Chem. 2004, 69, 3554; c) H. Yang, H. Li,
R. Wittenberg, M. Egi, W. Huang, L. S. Liebeskind, J. Am. Chem. Soc.
n
n
4
ketone was very low (4% yield of PhCO Bu from PhCOF with LiB Bu ).
The relative reactivities of benzoyl halides toward a borate are also
described in the following order: PhCOBr > PhCOCl >> PhCOF, see:
E.-i. Negishi, K.-W. Chiu, T. Yoshida, J. Org. Chem. 1975, 40, 1676.
2
007, 129, 1132; d) H. Prokopcová, C. O. Kappe, Angew. Chem., Int.
Ed. 2009, 48, 2276.
[
a) R. Kakino, I. Shimizu, A. Yamamoto, Bull. Chem. Soc. Jpn. 2001, 74,
3
71; b) L. J. Gooβen, K. Ghosh, Chem. Commun. 2001, 2084; c) K.-C.
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European Journal of Organic Chemistry
10.1002/ejoc.201700917
COMMUNICATION
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COMMUNICATION
Acyl fluorides as Suzuki
Y. Ogiwara,* D. Sakino, Y. Sakurai, N.
Sakai*
electrophiles: Acyl fluorides
functioned as a coupling partner in a
Suzuki–Miyaura reaction. This
transformation effectively provided a
wide range of symmetrical, and
unsymmetrical ketones including aryl-,
heteroaryl-, alkenyl-, as well as also
alkyl frameworks.
Page No. – Page No.
Acid Fluorides as Acyl Electrophiles
in Suzuki–Miyaura Coupling
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