Unmasked acyl anion equivalent from acid chloride with indium: Reversed-polarity synthesis of unsymmetric aryl aryl and alkenyl aryl ketone through palladium-catalyzed cross-coupling reaction

Article abstract of DOI:10.1021/ol500003g

A reversed-polarity synthetic method of a range of unsymmetric aryl aryl and alkenyl aryl ketones has been developed through Pd-catalyzed cross-coupling reaction of acylindium reagents generated in situ from easily available acid chlorides and indium with various electrophiles such as aryl iodide and triflate and alkenyl triflate.

Full text of DOI:10.1021/ol500003g

Letter
pubs.acs.org/OrgLett
Unmasked Acyl Anion Equivalent from Acid Chloride with Indium:
Reversed-Polarity Synthesis of Unsymmetric Aryl Aryl and Alkenyl
Aryl Ketone through Palladium-Catalyzed Cross-Coupling Reaction†
Dohyung Lee, Taekyu Ryu, Youngchul Park, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: A reversed-polarity synthetic method of a range of unsymmetric aryl aryl and alkenyl aryl ketones has been
developed through Pd-catalyzed cross-coupling reaction of acylindium reagents generated in situ from easily available acid
chlorides and indium with various electrophiles such as aryl iodide and triflate and alkenyl triflate.
ransition-metal-catalyzed cross-coupling reaction of a
nanes, -zirconocenes, and -silanes have been generally used as
Tnumber of electrophilic coupling partners with organo- acyl anion equivalents (Scheme 2). Although acylstannanes and
metallic reagents is one of the most straightforward methods
for C−C bond formation.1 To date, Pd catalysis has been
Scheme 2. Synthesis of Ketones Using Cross-Coupling
Reaction of Acyl Organometallic Reagents
applied widely in the synthesis of a variety of ketones
constituting aryl aryl, alkyl aryl, and alkyl alkyl groups. Synthetic
strategies of ketones through Pd catalysis could be generally
classified into three categories: substitution and cross-coupling
reaction of electrophilic acid derivatives with organometallic
reagents (eq 1),2 carbonylative cross-coupling reaction of aryl
halides with organometallic reagents under CO atmosphere (eq
2),3 and cross-coupling reaction of acyl anion equivalents with
electrophiles (eq 3) (Scheme 1).
Scheme 1. Synthetic Methods for Ketone Synthesis
-zirconocenes were reacted with aryl halide to afford one
example each of ketone in low yield,4 acylsilanes in reaction
with a range of aryl bromides gave diaryl ketones in variable
yields (eq 4).5 These reagents were reacted with allylic halides
and esters to afford β,γ-unsaturated ketones (eq 5).4,6
Acylstannane and -zirconocene reagents produced unsymmetric
1,2-diketones in reaction with acid chlorides (eq 6).4,7
Aldehydes, imines, or hydrazones were also arylated with aryl
iodides and tins or potassium aryl(trifluoro)borates through Pd
catalysis.8 Pd-catalyzed arylation of electron-rich olefins by aryl
halides followed by acidic hydrolysis was reported in the
formation of diaryl ketones.9
The first two methods have been commonly used in the
formation of ketones. However, the last one has been limited in
application due to difficult preparation of acyl anion
equivalents. Although acyl anion equivalents in cross-coupling
reaction have been used with some limitations, the use of acyl
organometallic reagents provides an effective method for the
polarity-reversed synthesis of ketones. Up to now, acylstan-
However, these methods require additional and tedious
synthetic steps under harsh conditions for the preparation of
the unmasked acyl anion equivalents. Also, we are not aware of
Received: January 1, 2014
Published: February 7, 2014
© 2014 American Chemical Society
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Letter
any reported synthetic examples of acyl anion equivalent
generated in situ from easily available acid chloride. In our
continuing efforts to develop Pd-catalyzed cross-coupling
reactions using organoindium reagents,10 we have been
interested in development of a novel synthetic route to acyl
anion equivalents using indium and then envisioned a cross-
coupling reaction of electrophilic coupling partners with acyl
anion equivalents generated in situ from indium and acid
halides. Herein, we report the challenging reversed-polarity
synthetic method of a diversity of ketones via Pd-catalyzed
cross-coupling reaction of acylindium reagents generated in situ
from easily accessible acid chlorides and indium at room
temperature (Scheme 3).
Among the solvents (THF, DMF, DMSO, NMP, THF−NMP,
TH−DMF, and TH−DMSO) tested, NMP gave the best result
(see the Supporting Information). The best result was obtained
from the reaction of 2a with acylindium reagent, which was
generated in situ from 1a (1.5 equiv) and indium (3 equiv)
with lithium chloride (3 equiv), TMSCl (6 mol %), and 1,2-
dibromoethane (15 mol %) at 40 °C for 3 h, in the presence of
Pd2(dba)3 (2 mol %) in NMP at room temperature after 3 h,
producing 3a in 86% yield (entry 4). The use of a wide array of
ligands [Xantphos, DPEphos, Ph3P, Cy3P, Cy2(Biphenyl)P,
(furyl)3P, and (o-tolyl)3P] did not increase the yield (see the
Supporting Information). Other palladium catalysts such as
Pd(OAc)2, Pd(Ph3P)2Cl2, and Pd(Ph3P)4 were totally
ineffective (entries 5, 6, and 8). A number of additives such
as LiBr, LiI, KBr, and KI failed to give the coupling product in
good yield (see the Supporting Information). Control experi-
ments in the reaction of 4-iodoacetophenone with benzoyl
chloride and indium suggest that use of TMSCl as well as
dibromoethane is essential for giving successful results (see the
Supporting Information). Commercially available indium does
not react with benzoyl chloride. However, when LiCl was
added to indium powder that had been activated with 1,2-
dibromoethane and TMSCl, an efficient insertion oc-
curred.10−12 Ethyl 4-iodobenzoate pretreated with indium,
lithium chloride, TMSCl, and dibromoethane in NMP was
reacted with benzoyl chloride in the presence of Pd2(dba)3 to
produce 3a (12%) and 4 (52%), indicating that 4-
ethoxycarbonylphenylindium was not involved in this reac-
tion.11 Because benzoyltrimethylsilane was not detected in the
treatment of 1a with In, LiCl, and TMSCl, the coupling
reaction via the formation of benzoyltrimethylsilane ruled out.5
Next, we applied this catalytic system to various electrophiles
to demonstrate the efficiency and scope of the present method
(Scheme 4). Phenyl iodide was reacted with acylindium to
produce benzophenone 3b in 78% yield. The presence of an
electron-donating group on the phenyl ring lowered the
product yield. 3- and 4-Iodotoluene were converted to the
corresponding ketones 3c and 3d in 58% and 47% yields,
respectively, under modified conditions [4 mol % of (Ph3P)4Pd,
60 °C]. However, 3- and 4-iodobenzotrifluoride having an
electron-withdrawing trifluoromethyl group gave the corre-
sponding 3- and 4-trifluoromethylphenyl phenyl ketones 3e
(71%) and 3f (63%). When 3-iodobenzaldehyde having an
electrophilic labile formyl group was subjected to the standard
conditions, the desired product 3g was obtained in 77% yield.
Treatment of 3- and 4-iodoacetophenone with acylindium
reagent also provided the desired ketones 3h and 3i in 71% and
78% yields, respectively. Aryl iodide having an ethoxycarbonyl
group furnished the desired ketone 3j in 88% yield. 4-
Iodobenzonitrile was reacted with acylindium, affording 4-
cyanophenyl phenyl ketone 3k in 67% yield. The tolerance of
the formyl, ketone, ester, and nitrile group is especially
significant, as successive functional group transformations are
hopeful. As an extension of this work, we applied this catalytic
system in aryl and alkenyl triflate. The reactivity of aryl triflate
derived from ethyl 4-hydroxybenzoate is similar to that of ethyl
4-iodobenzoate, providing 3a in 81% yield in the presence of 4
mol % of Pd2(dba)3. Subjecting alkenyl triflate to generated in
situ acylindium produced the corresponding alkenyl aryl ketone
3l in 67% yield.
Scheme 3. Reversed-Polarity Synthesis of Ketones via Cross-
Coupling Reaction with Acylindium Reagents
To access unmasked acyl anion equivalents from acid
chlorides, we studied the reactions of ethyl 4-iodobenzoate
(2a) with organoindium reagents generated in situ from
benzoyl chloride (1a) and indium in the presence of palladium
catalyst and additive (Table 1). After 1a was treated with
Table 1. Reaction Optimization of Reversed-Polarity Ketone
a
Synthesis
b
entry
cat.
solvent temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
Pd2 (dba)3
DMF
DMSO
NMP
NMP
NMP
NMP
NMP
NMP
90
90
60
25
60
60
60
60
2
12
5
31 (27)
Pd2 (dba)3
0
Pd2 (dba)3
77 (11)
Pd2 (dba)3
Pd (OAc)2
3
86
12
12
12
12
0
Pd (Ph3P)2Cl2
Pd2 (dba)3CHCl3
Pd (Ph3P)4
0
48 (15)
0
a
1a (1.5 equiv) and 2a (1 equiv) were used in the presence of In (3
equiv), LiCl (3 equiv), TMSCl (6 mol %), and (BrCH2)2 (15 mol %)
in NMP. Indium reagent was prepared at 50 °C (entries 1−3) and 40
°C (entries 4−8) for 3 h. In the case of Pd(OAc)2 and Pd(Ph3P)4, 4
b
mol % of catalyst was used. Numbers in parentheses is isolated yield
of 4,4′-diethoxycarbonyl-1,1′-biphenyl (4).
indium in the presence of LiCl, TMSCl, and 1,2-dibromo-
ethane in DMF (50 °C, 3 h), the reaction mixture was
subjected to 2a in the presence of Pd2(dba)3, producing ethyl
4-benzoyl benzoate 3a in 31% yield together with 4,4′-
diethoxycarbonyl-1,1′-biphenyl (27%, 4) (entry 1). However,
the reaction did not proceed in DMSO (entry 2). Surprisingly,
NMP as a solvent increased yield of 3a to 77% (entry 3).
Therefore, the formation of acyl anion equivalent was assumed.
Encouraged by these results, we investigated the coupling
reaction of acyl anion equivalents having useful functional
groups with a variety of aryl iodides 2 (Scheme 5). Acylindium
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Letter
reagent generated in situ from 3-methylbenzoyl chloride 1b and
indium under the standard conditions was reacted with 3-
iodobenzotrifluororide, 3-iodoacetophenone, ethyl 4-iodoben-
zoate, and 3-iodobenzonitrile to produce the corresponding
unsymmetric aryl aryl ketones 3m, 3n, 3o, and 3p in good
yields. Reaction of 4-tert-butylbenzoyl chloride 1c with indium
delivered also an acyl anion equivalent that coupled with aryl
iodides having labile acetyl, ethoxycarbonyl, and nitrile group to
provide the desired unsymmetric ketones 3q, 3r, and 3s.
Acylindium reagent derived from 4-methoxybenzoyl chloride
1d worked equally well with electron-deficient aryl iodide.
However, preparation of acylindium reagent from 4-chlor-
obenzoyl chloride 1e and indium is not effective.
Scheme 4. Preparation of Ketones from Coupling of
Acylindium with Electrophiles
a
To prove the mechanism of the present reaction, we
conducted the reaction of acylindium reagent generated in
situ from benzoyl chloride with 4-iodoacetophenone under the
standard conditions in the presence of radical inhibitor. As
expected, adding 2,2,6,6-tetramethylpiperidine-1-oxy
(TEMPO) did not retard or suppress the reaction (eq 7).
These results indicate that the present reaction does not seem
to proceed through a radical process promoted by indium.13
a
1a (1.5 equiv) and 2 (1 equiv) were used in the presence of In (3
equiv), LiCl (3 equiv), TMSCl (6 mol %), (BrCH2)2 (15 mol %), and
b
To prove the anion character of acylindium reagent
generated in situ from benzoyl chloride and indium, the
prepared reagent was quenched with 10% HCl and 10% DCl to
afford benzaldehyde (70%) and benzaldehyde-d1 (60%),
respectively (eq 8). These results indicate that a variety of
Pd2(dba)3 (2 mol %) in NMP unless otherwise noted. 4 mol % of
c
(Ph3P)4Pd was used. Coupling was carried out at 60 °C. Coupling
d
was carried out at 10 °C. Triflate was used. 4 mol % of Pd2(dba)3 was
used.
Scheme 5. Preparation of Unsymmetric Aryl Aryl Ketones
a
from Coupling of Acylindium
organoindium reagents obtained from the present reactions
have anion character, and the possibility of a radical
intermediate rules out the mechanism. The elucidation of the
detailed reaction mechanism must wait further study.
In conclusion, we have developed a reversed-polarity
synthetic method for a diversity of unsymmetric aryl aryl and
aryl alkenyl ketones via Pd-catalyzed cross-coupling reaction of
acylindium reagents generated in situ from acid chlorides and
indium. Because the direct synthetic method of unmasked acyl
anion equivalents from easily available acid chlorides with
indium has been developed for the first time under mild
conditions, the present reaction is highly useful and promising.
The tolerance of formyl, ketone, ester, and nitrile groups is
especially practical, providing an opportunity for further
functionalization.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
a
1 (1.5 equiv) and 2 (1 equiv) were used in the presence of In (3
AUTHOR INFORMATION
equiv), LiCl (3 equiv), TMSCl (6 mol %), (BrCH2)2 (15 mol %), and
Pd2(dba)3 (2 mol %) in NMP unless otherwise noted.
■
Corresponding Author
*E-mail: phlee@kangwon.ac.kr.
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Letter
X.-G.; Li, J.-H. Org. Lett. 2011, 13, 2184. (l) Pucheault, M.; Darses, S.;
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (No. 2011-0018355).
DEDICATION
■
†This paper is dedicated to Professor T. Livinghouse (Montana
State University) on the occasion of his 60th birthday.
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