Palladium-catalyzed decarboxylative, decarbonylative and dehydrogenative C(sp2)-H acylation at room temperature

Article abstract of DOI:10.1039/c7ob01466j

Over the past few decades, an impressive array of C-H activation methodology has been developed for organic synthesis. However, due to the inherent inertness of the C-H bonds (e.g. ～110 kcal mol^-1 for the cleavage of C(aryl)-H bonds) harsh reaction conditions have been realized to overcome high energetic transition states resulting in a limited substrate scope and functional group tolerance. Therefore, the development of mild C-H functionalization protocols is in high demand to exploit the full potential of the C-H activation strategy in the synthesis of a complex molecular framework. Although, electron-rich substrates undergo electrophilic metalation under relatively mild conditions, electron-deficient substrates proceed through a rate-limiting C-H insertion under forcing conditions at high temperature. In addition, a stoichiometric amount of toxic silver salt is frequently used in palladium catalysis to facilitate the C-H activation process which is not acceptable from the environmental and industrial standpoint. We report herein, a Pd(ii)-catalyzed decarboxylative C-H acylation of 2-arylpyridines with α-ketocarboxylic acids under mild conditions. The present protocol does not require stoichiometric silver(i) salts as additives and proceeds smoothly at ambient temperature. A novel decarbonylative C-H acylation reaction has also been accomplished using aryl glyoxals as acyl surrogates. Finally, a practical C-H acylation via a dehydrogenative pathway has been demonstrated using commercially available benzaldehydes and aqueous hydroperoxides. We also disclose that acetonitrile solvent is optimal for the acylation reaction at room temperature and has a prominent role in the reaction outcome. Control experiments suggest that the acylation reaction via decarboxylative, decarbonylative and dehydrogenative proceeds through a radical pathway. Thus we disclose a practical protocol for the sp² C-H acylation reaction.

Full text of DOI:10.1039/c7ob01466j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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ARTICLE
Palladium-Catalyzed Decarboxylative, Decarbonylative and
Dehydrogenative C(sp2)-H Acylation at Room Temperature
Asik Hossian,a,b Manash Kumar Manna,a,b Kartic Manna a,b and Ranjan Jana*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
Over the past decades, an impressive array of C-H activation methodology have been developed for organic synthesis.
However, due to the inherent inertness of the C-H bonds (e. g. ~ 110 kcal/mol for the cleavage of C(aryl)–H bonds) harsh
reaction conditions have been realized to overcome high energetic transition states resulting in limited substrate scope
and functional group tolerance. Therefore, development of mild C-H functionalization protocols are in high demand to
exploit the full potential of C-H activation strategy in the synthesis of complex molecular framework. Although, electron-
rich substrates undergo eletrophilic metalation under relatively mild conditions, eletron-deficient substrates procceds
through a rate-limiting C-H insertion under forcing conditions at high temperature. In addition, stoichiometric amount of
toxic silver salt is frequently used in palladium catalysis to facilitate the C-H activation process which is not acceptable
from environmental and industrial standpoint. We report herein, a Pd(II)-catalyzed decarboxylative C-H acylation of 2-
arylpyridines with α-ketocarboxylic acids under mild conditions. The present protocol does not require stoichiometric
silver(I) salts as additives and proceeds smoothly at ambient temperature. A novel decarbonylative C-H acylation reaction
has also been accomplished using aryl glyoxals as acyl surrogate. Finally, a practical C-H acylation via dehydrogenative
pathway has been demonstrated using commercially available benzaldehydes and aqueous hydroperoxide. We also
disclose that acetonitrile solvent is optimal for the acylation reaction at room temperature and has a prominent role on
the reaction outcome. Control experiments suggest that the acylation reaction via decarboxylative, decarbonylative and
dehdrogenative proceeds through radical pathway. Thus we disclose a practical protocol for the sp2 C-H acylation reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
palladium-catalyzed
Liebeskind-Srogl
cross-coupling.5
However, the reaction requires stoichiometric amount of
copper complex as additive. Carbonylation of aryl halides with
hazardous carbon monoxide requires special handling skills
and laboratory set up.6 Therefore, considering the stringent
environmental factors (E factors) in chemical processes there is
an urgent need for the development of practical and
Introduction
Owing to the prevalence of benzophenones in natural
products, pharmaceuticals and functionalized materials, the
synthesis of functionalized carbonyl compounds is a sustained
exertion in organic synthesis (Figure 1).1 Typically, Lewis-acid
promoted Friedel-Crafts acylation via electrophilic aromatic
substitution generates isomeric mixtures and requires
stroichiometric metal salts.2 The reaction of Weinreb amides
with Grignard reagents yields the carbonyl compounds with
limited functional group tolerance.3 Whereas, transition metal
catalyzed cross-couplings are reported with relatively less
nucleophilic organometallic reagents such as organozinc
reagents and boronic acids.4 As an alternative to air and
moisture sensitive acyl chlorides which generate
stoichiometric metal halide waste, thioesters is used in
environmentally benign acylation reactions.
O
O
O
I
N
N
O
OH
nBu
Amiodarone
O
S
HO
I
Raloxifene
selective estrogen
receptor modulator
anti-arrhythmic
O
O
O
HO
CO2H
O
HO
Cl
O
NO2
Tolcapone
O
Ketoprofen
Fenofibrate
anti-hypercholesterolemia
NSAID
For Perkinson's Disease
Figure 1 Some benzophenone containing drugs
Beyond typical cross-coupling approaches, the C-H
activation strategy offers a unique opportunity to access
carbonyl compounds without prefunctionalization steps.7
Although an enormous effort has been dedicated for the
development of C-H activation processes, significant
challenges still remain unsolved. The harsh reaction
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conditions, use of stoichiometric toxic silver(I) salts, high agent via decarbonylative and dehydrogenative manifolds
reaction temperature etc. limits their application in the respectively.
synthesis of complex molecular architecture and industrial
processes. Thus, developments of mild acylation reaction via
C-H activation processes are in high demand.8
Results and discussion
In recent years, decarboxylative cross-coupling has also
been established as a modern strategy for C-C and C-
heteroatom bond formation.9 Inexpensive and readily
available carboxylic acids are used as an alternative to
expensive organometallic reagents and halides. Combining
these two promising technologies, decarboxylative C-H
Initially, we started optimization for the decarboxylative
acylation reaction at room temperature. A mixture of 2-
phenylpyridine (1a) and phenylglyoxylic acid (2a) was stirred in
the presence of 10 mol % palladium(II)acetate and 2.0 equiv of
potassium persulfate (K2S2O8) in diglyme solvent.10k The
expected monoacylated product (3a) was obtained in 20%
yield without any silver(I) salt added (entry 1, Table 1). Further
screening of solvents showed that acetonitrile is superior to
other solvents such as DMF, DMSO, toluene, acetic acid, 1,4-
dioxane and DCE (entry 2-7, Table 1). Typically, silver salt is
used in palladium catalysis for facile decarboxylation,
carbonate or carboxylate anion source, halide scavenger and
terminal oxidant for catalytic turnover.19 However, contrary to
our expectations, no desired product was isolated using silver
salts such as Ag2CO3, Ag2O etc. at room temperature although
it is used as additive for this transformation at high
temperature15a (entry 9-10, Table 1). Other common oxidants
such as ammonium persulfate, (diacetoxyiodo)benzene (PIDA),
tert-butyl hydroperoxide (in decane) and also molecular
oxygen etc. were found to be inferior for this coupling reaction
(entry 11-14, Table 1). Owing to the facile electrophilic
palladation of cationic palladium salts, several Pd-complexes,
functionalization has emerged as
a fascinating field of
research.10 However, like C-H insertion, decarboxylative
metalation is also a high energetic process and proceeds at
elevated temperatures.11 α-Oxocarboxylic acids undergo
transition metal-catalyzed decarboxylation to provide acyl
anion equivalent which been utilized in cross-coupling12 and C-
H acylation reaction to provide diaryl ketones.13 Although
decarboxylative C-H acylation of electron rich aniline
derivatives or oximes proceed at ambient temperature
through a facile electrophilic ortho metalation,14 electron-
deficient substrates require high temperature (110-140 oC) and
stoichiometric silver(I) salt which is not acceptable from
environmental and industrial viewpoint.15 To the best of our
knowledge, silver free decarboxylative acylation of electron-
deficient 2-arylpyridine at room temperature has not been
reported so far. As a part of our continuing research program
for the development of cross-coupling reactions at mild
conditions, we have reported decarboxylative Heck coupling at
room temperature16 and divergent synthesis of 2-arylindol and
indolines via C-H activation.17 Herein for the first time, we
report a palladium-catalyzed decarboxylative C-H acylation of
electron-deficient 2-
such as Pd(TFA)2, Pd(MeCN)2Cl2,
Pd(MeCN)2(OTs)2, and
Pd(MeCN)4(BF4)2 were examined but provided lower yield
(entry 15-18, Table 1). We also observed that silver nitrate as a
catalyst was inactive for this transformation (entry 19, Table
1). Finally, in combination of 10 mol % Pd(OAc)2 and 2.0 equiv
of K2S2O8 as oxidant using acetonitrile as a solvent provided
excellent yield after stirring 16 h at room temperature (entry 8,
Table 1). It is important to note that both Pd(OAc)2 and K2S2O8
are essential for this coupling reaction since no desired
product was isolated while they were used separately (entry
20-21, Table 1). The yield of the acylation product was
decreased to some extent under air (entry 22, Table 1) and no
product was formed with oxygen purging (entry 23, Table 1).
During optimization, it was found that moisture has negative
impact on the reaction outcome presumably due to the
formation of decarboxylative protonation product from
phenylglyoxylic acid.
Next we explored the substrate scope under the optimized
reaction conditions. A wide variety of phenylglyoxylic acids
Scheme 1 C(sp2)-H Acylation Reaction
having
electron-withdrawing
and
electron-donating
substituents underwent decarboxylative coupling providing
high to excellent yield (Scheme 2). Besides methoxy, alkyl, and
arylpyridines system at room temperature. The present
protocol does not require stoichiometric silver(I) salt and
a
dramatic influence of solvent was observed where acetonitrile
was found to be optimal for this acylation reaction at ambient
condition.18 This room temperature acylation reaction was also
demonstrated using phenylglyoxals and aldehydes as acylating
2 | J. Name., 2012, 00, 1-3
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Table 1. Optimization of the reaction conditionsa,b
ARTICLE
entry catalyst
(10 mol %)
Pd(OAc)2
oxidant
(2.0 equiv)
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
solvent
yield
(%)b
20
1
diglyme
DMF
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
50
DMSO
Toluene
AcOH
1,4-
52
trace
25
14
dioxane
DCE
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
K2S2O8
Ag2CO3
Ag2O
40
76
0
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
0
(NH4)2S2O8
PIDA
50
26
0
TBHP
(in decane)
O2
14
15
16
17
18
19
20
21
22c
23d
Pd(OAc)2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
Pd(TFA)2
K2S2O8
K2S2O8
70
8
Pd(MeCN)2Cl2
Pd(MeCN)2(OTs)2 K2S2O8
Pd(MeCN)4(BF4)2 K2S2O8
65
57
0
AgNO3
Pd(OAc)2
-
K2S2O8
-
0
K2S2O8
K2S2O8
K2S2O8
0
Pd(OAc)2
Pd(OAc)2
67
0
aAll reactions were carried out in 0.1 mmol scale, 1a (1.0 equiv)
and 2a (1.5 equiv). bYields refer to here are overall isolated
Scheme
2
Substrate scope of 2-phenylpyridines and α-
ketocarboxylic acids. The reaction was carried out in 0.2 mmol
scale, (1.0 equiv) and (1.5-2.0 equiv). The yield referred to
yields. Reaction was run under air. dReaction was run under
c
1
2
O2.
here is the average isolated yield of at least two experiments.
aDiacylation occurred.
aryl groups, halogens such as bromo (3i, 3l, 3v, Scheme 2),
chloro (3h, Scheme 2), and fluoro (3g, Scheme 2) were also
well tolerated in the reaction condition which are useful for
acid also afforded the desired product in good yield (3w
,
Scheme 2). Unfortunately, electron deficient groups like acyl,
trifluromethyl on 2-phenylpyridine moiety did not furnish any
acylated products. Other nitrogen directing groups like 2-
phenoxypyridine, 1-phenyl-1H-pyrazole, acetophenone O-
methyl oxime, and also 2-phenylbenzo[d]thiazole did not
provide desired acylation products at room temperature.
However, 2-phenylpyrimidine furnished a mixture of mono
and diacylation product which was separated through column
further cross-coupling reactions.
A
strong electron-
withdrawing group on α-keto acid afforded the acylated
product in good yield (3j, Scheme 3). Interestingly, the α-keto
acid with a naphthyl moiety furnished the desired product in
good yield (3k, Scheme 2). The ortho substituted α-keto acid
participated in the reaction with excellent yield (3l, Scheme 2).
Disubstituted α-keto acids also participated in the reaction
providing good yield
(3m-3n, scheme 2). No significant
chromatography (mono:di
= 2.5:1). To demonstrate the
influence of the electronic nature of the substituents on α-
keto acids was observed on the reaction outcome. Similarly,
practical utility of this present protocol the reaction was
performed in gram-scale providing the acylation product in
comparable yields (3a, Scheme 2).
substitutions on the 2-phenylpyridine moiety such as alkyl (3o
-
3q, Scheme 2), methoxy (3s-3v, Scheme 2) were tolerated in
In recent years, decarbonylative cross-coupling reaction
from carbonyl or carboxylic acid derivatives has emerged as a
the reaction condition. In addition, aliphatic α- oxocarboxylic
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promising strategy in organic synthesis.20 Initially, the to here is the average isolated yield of at least two
transition metal undergoes oxidative addition to the activated experiments.
carboxylic acid derivatives such as acid chlorides,21
anhydrides,22 esters23 etc. to generate an acyl-metal species.
Subsequently, aryl-metal species is formed through the
extrusion of carbon monoxide. Unlike redox-neutral
decarboxylative cross-coupling, no stoichiometric oxidant is
required in the decarbonylative cross-coupling process.
Although transition metal-catalyzed decarbonylative cross-
coupling for arylation has been explored24 but decarbonylative
C-H acylation is not known. We hypothesized that glyoxals can
be utilized in palladium-catalyzed decarbonylative C-H
acylation reaction. To test, a mixture of 2-phenylpyridine, (1a
)
and phenylglyoxal (4a) was subjected under the optimized
reaction conditions of decarboxylative acylation. Gratifyingly,
the corresponding acylation product was isolated in 70% yield
(
3a, Scheme 3). However, the reaction under oxygen did not
furnish any acylation product although dioxygen-mediated
generation of alkyl radical from corresponding aldehydes is
known at elevated temperature.25 Other oxidants such as aq.
TBHP or TBHP in decane even (NH4)2S2O8 were ineffective for
this transformation. Surprisingly, a trace amount of acylation
product was isolated in other solvents like DMSO, DMF, DCE
and toluene. Therefore, we proceeded to examine the
substrate scope under this condition. To our delight, a number
of 2-phenylpyridine as well as phenylglyoxal with different
substituents provided the corresponding acylated product with
moderate to good yield (Scheme 3). It is noteworthy that
halogenated and ortho-substituted 2-phynylpyridines also
provided moderate yield of the acylation products which were
ineffective under decarboxylative acylation protocol.
Scheme 4 Substrate scope of 2-phenylpyridines and aldehydes.
The reaction was carried out in 0.2 mmol scale, (1.0 equiv)
and (1.5 equiv). The yield referred to here is the average
1
5
a
isolated yield of at least two experiments. The reaction was
run for 72 h.
Next we turned our attention to achieve acylation reaction
with commercially available and inexpensive aldehydes as
acylation agent. From literature, palladium-catalyzed C-H
acylation of 2-phenylpyridine with aryl and alkyl aldehydes is
Scheme 3 Substrate scope of 2-phenylpyridines and 2-oxo-2-
phenylacetaldehydes. The reaction was carried out in 0.2
mmol scale, 1 (1.0 equiv) and 4 (1.5 equiv). The yield referred
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known at high temperature.26 However, aldehydes are alcohol, benzyl amine, styrene and toluene did not furnish any
converted to the corresponding acids by oxygen rapidly at high acylated product with 2-phenylpyridine under the reaction
temperature and the yield is decreased.26b,27 In addition, the conditions.
oxidant TBHP is explosive at high temperature particularly in
industrial-scale.28 Keeping this in mind we intended to develop
Investigation of the reaction mechanism
an acylation reaction with aldehydes at room temperature.
Our initial trial reaction between 2-phenylpyridine (1a) and
benzaldehyde (5a) under the previous optimized reaction
conditions afforded acylated product in 35% yield (3a, Scheme
4). Considering the unique ability of tert-butylhydroperoxide
(TBHP) to generate acyl radical from aldehydes,29 we decided
to use TBHP as oxidant in lieu of K2S208. Surprisingly, the yield
was improved to 55% with inexpensive aq. TBHP. Finally an
excellent yield of the acylated product (3a) in 87% was isolated
To gain insight into the reaction mechanism, we performed
several
control
experiments.
To
check
whether
decarboxylative acylation reaction with phenylglyoxylic acid
proceeds through radical or anionic pathway, radical scavenger
2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) experiment was
performed. It was observed that the acylation reaction
completely suppressed with 1.0 equiv of TEMPO. The TEMPO-
acyl adduct, 2,2,6,6-tetramethylpiperidin-1-yl benzoate (6a
)
after stirring the reaction mixture for 36
temperature with the combination of 10 mol % Pd(OAc)2 and
3.0 equiv of aq. TBHP from 1.0 equiv of 2-phenylpyridine (1a
h at room
was detected in electrospray ionization (ESI) mass
spectrometry of the crude reaction mixture. Further, it was
isolated in 74% yield and well-charcterized by NMR and HRMS
spectroscopy (Scheme 5a) (see the ESI). Thus the
decarboxylative acylation reaction may proceed through
radical pathway and the acyl radical may generate from the
corresponding phenylglyoxylic acids with K2S2O8 at room
temperature. Similarly, acylation reaction with phenylglyoxal
was also completely suppressed with 1.0 equiv of TEMPO and
the TEMPO-acyl adduct (6a) was isolated in 56% yield (Scheme
5a). In addition, phenylglyoxal did not oxidized to the
phenylglyoxylic acid under the reaction condition and
remained intact (Scheme 5b). Therefore, the possibility of
oxidation to the corresponding acid followed by
decarboxylative acylation was ruled out rather an acyl radical
may generate in the course of the reaction through
decarbonylation of the arylglyoxal. Finally, dehydrogenative
acylation reaction with benzaldehyde was also supressed
substantially with 1.0 and 1.5 equiv of TEMPO and completely
suppressed with 2.0 equiv of TEMPO. The TEMPO-acyl adduct
)
and 1.5 equiv of benzaldehyde (5a). However, 30% aq. H2O2 in
lieu of aq. TBHP did not furnish any acylation product. To note,
the reaction under air or oxygen provided lower (37%) or no
yield thus the reaction vessel was purged with nitrogen. The
reaction under neat condition also furnished inferior result
(38%).
Subsequently, we explored the substrate scope under the
optimized reaction conditions. A wide variety of functional
groups on 2-phenylpyridine as well as on aldehyde were found
to be compatible under this mild reaction protocol. Besides
methoxy, alkyl, and aryl groups, halogens such as chloro (3ah
Scheme 4), ester (3ad, Scheme 4), cyano (3ae, Scheme 4), nitro
3af, Scheme 4) remain intact which are useful for further
,
(
organic transformation. Interestingly, the acyl group on
aldehyde (3ac, Scheme 4) is well-tolerated under the reaction
conditions which demonstrate the mild nature of the
conditions. Interestingly, the aldehyde with a naphthyl moiety
furnished the desired product in good yields (3ag, Scheme 4).
The electron deficient group like acyl on 2-phenylpyridine
afforded the moderate yield (3an, Scheme 4) which was
inferior in the decarboxylative acylation reaction. The reaction
with 2-phenylquinoline afforded the acylation product in
moderate yield (3ao, Scheme 4). Interestingly, the heterocyclic
aldehydes, such as furan-2-carbaldehyde and thiophene-3-
carbaldehyde provided moderate yield of the desired product
(
6a) was also isolated in 71% yield for further confirmation
(Scheme 5a). Thus, dehydrogenative acylation may also
proceed through radical pathway and the acyl radical
intermediate may form from the corresponding benzaldehyde
via TBHP oxidation. In the absence of K2S2O8 no
decarboxylative acylation product was isolated with 10 mol %
or even with 1.0 equiv of Pd(OAc)2 indicating that combination
of palladium and K2S2O8 is essential for the reaction to occur
(Scheme 5c). Since palladium(II) acetate is known to form a
dimeric complex with 2-phenylpyridine through C-H
insertion,30 a palladium dimer complex (7a) was prepared
separately and subjected to the reaction conditions (Scheme
5d). Only a trace amount of product was detected suggesting
that dimeric palladium species with 2-phenylpyridine may not
(
3ap
afforded the acylation product in moderate to excellent yield
3w 3as Scheme 4). It is important to note that,
-3aq, Scheme 4). In addition, aliphatic aldehydes also
(
-
,
benzo[h]quinoline worked extremely well in the reaction
conditions to give the corresponding acylation product in
excellent yield (3at, Scheme 4). Although, 2-phenoxypyridine,
1-phenyl-1H-pyrazole provided lower yield and unreacted
form under the present reaction conditions whereas
monomeric palladium species may be involved.
a
starting material was recovered (3au-3av, Scheme 4) but 2-
phenylpyrimidine furnished good yield (3x, Scheme 4) of the
mono-acylation product. Finally, the reaction was reproduced
in gram-scale providing comparable yield (3a, Scheme 4).
Other in situ convertible acylating agents such as benzyl
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Scheme 6 Plausible mechanism of C(sp2)-H acylation
Conclusions
In conclusions, we have developed a mild reaction protocol
for Pd(II)-catalyzed C(sp2)-H acylation using α-ketocarboxylic
acids, phenylglyoxals and commercially available, inexpensive
aldehydes via decarboxylative, decarbonylative and
dehydrogenative manifolds respectively. The major
advantages of the present protocol are- a) the reaction
operates under mild conditions at room temperature; b) it
does not require stoichiometric amount of toxic silver(I) salt
for decarboxylation of the α-ketocarboxylic acid or as oxidant;
c) acetonitrile was optimal for the acylation; d) gaseous CO2,
CO or water is formed as by-products avoiding rigorous
separation technique; e) the present acylation reaction
proceeds through radical pathway to provide mono acylation
product at the ortho position selectively. This room
temperature acylation reaction is scalable, energy efficient and
avoids the accidental hazard due to explosion of peroxides at
elevated temperature. Thus, we anticipate that this mild C-H
acylation protocol will find its place in industrial application.
Scheme 5 Control experiments
From the control experiments and previous reported
literatures,29,31,32 we propose the reaction mechanism which
has shown in Scheme 6. The pyridine-assisted cyclopalladation
with Pd(II) via electrophilic palladation may generates the 5-
membered palladacycle intermediate
undergoes oxidative addition with acyl radical to yield
cyclopalladated Pd(III) intermediate (Scheme 6). Under
A (Scheme 6), which
B
visible light photoredox and palladium dual catalysis condition
this putative Pd(III) is further oxidized to Pd(IV) with
photoredox catalyst and/or oxidant.8f,14b,32c,32d,33 However in
these catalytic systems, the role of K2S2O8 or TBHP in
Pd(III)/Pd(IV) oxidation is not clear at this moment and
Experimental section
General information
warrants further investigation. The desired acylation product
may form through the facile reductive elimination of the
intermediate (Scheme 6) and the generation of Pd(II) catalyst
3
Melting points were determined in open end-capillary tubes
and are uncorrected. TLC was performed on silica gel plates
(silica gel 60, f254), and the spots were visualized with UV light
B
for the subsequent runs.
1
(254 and 365 nm) and KMnO4 stain. H and 13C NMR spectra
were recorded in CDCl3 using TMS as the internal standard.
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HRMS (m/z) were measured using EI (magnetic sector, positive Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 7.03-
ion) and ESI (Q-TOF, positive ion) techniques. Infrared (IR) 7.06 (m, 1H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 197.9,
spectra were recorded on Fourier transform infrared 156.9, 149.1, 143.1, 139.7, 139.5, 136.2, 135.3, 130.0, 129.7,
spectroscopy; only intense peaks were reported.
128.92, 128.90, 128.8, 128.4, 122.8, 121.9, 21.6; IR (neat): υmax
General experimental procedure for the decarboxylative 1662, 1604, 1433, 1284, 929, 751 cm-1; HRMS (ESI, m/z) calcd.
acylation reaction between 2-phenylpyridines and α- for C19H15NONa [M + Na]+: 296.1051; found: 296.1049.
ketocarboxylic acids
,
Scheme 2
.
(4-(tert-Butyl)phenyl)(2-(pyridin-2-yl)phenyl)methanone, 3c,
To an oven-dried 10 mL sealed tube, a mixture of 2- Scheme 2.34 The same general procedure was followed by
phenylpyridines (0.2 mmol, 1.0 equiv), α-ketocarboxylic acids using 2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-(4-
(0.3-0.4 mmol, 1.5-2.0 equiv), potassium persulfate (108 mg, (tert-butyl)phenyl)-2-oxoacetic acid (62 mg, 0.3 mmol, 1.5
0.4 mmol, 2.0 equiv) and palladium(II)acetate (4.6 mg, 0.02 equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv)
mmol, 0.1 equiv) was taken and dry MeCN (3.0 mL) was added and palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv).
to it. After flushing with nitrogen for 30 seconds, immediately Column chromatography (SiO2, eluting with 7:3 hexane/ethyl
the vessel was sealed with a screw cap. The reaction mixture acetate) afforded the desired product as a yellowish oil, (46.0
1
was allowed to stir for 16 h at room temperature. After that mg, 73%). H NMR (300 MHz, CDCl3): δ 8.40 (d, J = 4.2 Hz, 1H),
the reaction mixture was quenched with NaHCO3 to remove 7.76 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.46-7.62 (m,
the unreacted acids. Then the reaction mixture was poured 5H), 7.30 (d, J = 8.4 Hz, 2H), 7.00-7.04 (m, 1H), 1.27 (s, 9H); 13
C
into water (40 mL) and extracted with ethyl acetate (40 mL). NMR (150 MHz, CDCl3): δ 197.9, 157.0, 156.0, 149.1, 139.7,
The organic layer was washed with water (10 mL) and brine 139.6, 136.2, 135.1, 130.0, 129.6, 129.0, 128.9, 128.2, 125.0,
(10 mL), dried over anhydrous Na2SO4 and the solvent was 122.9, 121.8, 35.0, 31.0; IR (neat): υmax 2961, 1666, 1598, 1466,
evaporated under reduced pressure. The crude product was 1277, 753 cm-1; HRMS (ESI, m/z) calcd. for C22H21NONa [M +
purified
by
column
chromatography
using
ethyl Na]+: 338.1521; found: 338.1523.
acetate/hexane as eluent to afford the desired product.
(4-isoButylphenyl)(2-(pyridin-2-yl)phenyl)methanone,
3d,
To note: During optimization, it was found that α- Scheme 2. The same general procedure was followed by using
ketocarboxylic acids are hygroscopic in nature thus water or 2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-(4-
moisture is detrimental to the reaction outcome. Therefore, so isobutylphenyl)-2-oxoacetic acid (62 mg, 0.3 mmol, 1.5 equiv),
after flushing with nitrogen the reaction vessel was potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) and
immediately sealed with a screw cap.
palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). Column
Phenyl(2-(pyridin-2-yl)phenyl)methanone, 3a, Scheme 2.7d chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
The same general procedure was followed by using 2- afforded the desired product as a colourless oil, (45.0 mg,
phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-oxo-2- 71%). 1H NMR (600 MHz, CDCl3): δ 8.39 (d, J = 4.2 Hz, 1H), 7.76
phenylacetic acid (45 mg, 0.3 mmol, 1.5 equiv), potassium (d, J = 7.8 Hz, 1H), 7.51-7.62 (m, 6H), 7.45 (d, J = 7.8 Hz, 1H),
persulfate (108 mg, 0.4 mmol, 2.0 equiv) and palladium(II) 7.03 (d, J = 8.4 Hz, 2H), 7.00-7.02 (m, 1H), 2.43 (d, J = 7.2 H,
acetate (4.5 mg, 0.02 mmol, 0.1 equiv). Column 2H), 1.78-1.85 (m,1H), 0.84 (d, J = 6.6 Hz, 6H); 13C NMR (150
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) MHz, CDCl3): δ 198.0, 157.0, 149.0, 146.8, 139.7, 139.6, 136.1,
afforded the desired product as a white solid, (39.5 mg, 76%), 135.5, 130.1, 129.5, 129.1, 128.9, 128.7, 128.4, 123.0, 121.8,
mp 105-107 oC. 1H NMR (600 MHz, CDCl3): δ 8.36 (d, J = 4.2 Hz, 45.3, 30.1, 22.2; IR (neat): υmax 2957, 1664, 1602, 1281, 930,
1H), 7.78 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 751 cm-1; HRMS (ESI, m/z) calcd. for C22H21NONa [M + Na]+:
7.2 Hz, 1H), 7.50-7.56 (m, 4H), 7.39 (t, J = 7.2 Hz, 1H), 7.27 (t, J 338.1521; found: 338.1520.
= 7.2 Hz, 2H), 7.01 (t, J = 4.8 Hz, 1H); 13C NMR (150 MHz, (4-Methoxyphenyl)(2-(pyridin-2-yl)phenyl)methanone,
3e,
CDCl3): δ 198.2, 156.7, 149.0, 139.6, 139.5, 137.9, 136.3, 132.3, Scheme 2.7d The same general procedure was followed by
130.2, 129.4, 129.1, 128.7, 128.5, 128.0, 122.6, 121.9; IR using 2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-(4-
(neat): υmax 1665, 1587, 1279, 929, 751, 703 cm-1; HRMS (EI, methoxyphenyl)-2-oxoacetic acid (54 mg, 0.3 mmol, 1.5 equiv),
m/z) calcd. for C18H13NO [M]+: 259.0997; found: 259.0979.
potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) and
(2-(Pyridin-2-yl)phenyl)(p-tolyl)methanone, 3b, Scheme 2.7d palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). Column
The same general procedure was followed by using 2- chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-oxo-2-(p- afforded the desired product as a yellowish oil, (35.0 mg, 60%).
tolyl)acetic acid (49 mg, 0.3 mmol, 1.5 equiv), potassium 1H NMR (600 MHz, CDCl3): δ 8.44 (d, J = 4.8 Hz, 1H), 7.78 (d, J =
persulfate (108 mg, 0.4 mmol, 2.0 equiv) and palladium(II) 7.8 Hz, 1H), 7.68-7.70 (m, 2H), 7.56-7.62 (m, 2H), 7.52 (d, J =
acetate (4.5 mg, 0.02 mmol, 0.1 equiv). Column 4.2 Hz, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.05-7.07 (m, 1H), 6.76-
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) 6.79 (m,2H), 3.81 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 197.0,
afforded the desired product as a white solid, (39.0 mg, 72%), 163.0, 157.0, 149.1, 139.6, 139.5, 136.2, 131.9, 130.7, 129.9,
o
1
mp 97-99 C. H NMR (600 MHz, CDCl3): δ 8.41 (d, J = 4.2 Hz, 129.0, 128.8, 128.3, 123.0, 121.9, 113.3, 55.3; IR (neat): υmax
1H), 7.78 (d, J = 7.2 Hz, 1H), 7.56-7.62 (m, 4H), 7.52 (d, J = 4.2
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1658, 1597, 1464, 1256, 1027, 753 cm-1; HRMS (ESI, m/z) calcd. (4-Fluorophenyl)(5-methoxy-2-(pyridin-2
for C19H15NO2Na [M + Na]+: 312.1000; found: 312.0997.
yl)phenyl)methanone, 3u, Scheme 2. The same general
(2,4-Dimethylphenyl)(2-(pyridin-2-yl)phenyl)methanone, 3m, procedure was followed by using 2-(4-methoxyphenyl)pyridine
Scheme 2. The same general procedure was followed by using (37.0 mg, 0.2 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-oxoacetic
2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-(2,4- acid (67 mg, 0.4 mmol, 2.0 equiv), potassium persulfate (108
dimethylphenyl)-2-oxoacetic acid (53.5 mg, 0.3 mmol, 1.5 mg, 0.4 mmol, 2.0 equiv) and palladium(II) acetate (4.5 mg,
equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) 0.02 mmol, 0.1 equiv). Column chromatography (SiO2, eluting
and palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). with 7:3 hexane/ethyl acetate) afforded the desired product as
Column chromatography (SiO2, eluting with 7:3 hexane/ethyl a white solid, (39.0 mg, 64%), mp 74-76 oC. 1H NMR (600 MHz,
acetate) afforded the desired product as a light yellow oil, CDCl3): δ 8.31 (d, J = 4.8 Hz, 1H), 7.70-7.73 (m, 3H), 7.55 (td, J =
(40.0 mg, 70%). 1H NMR (600 MHz, CDCl3): δ 8.46-8.47 (m, 1H), 7.8 Hz, 1.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 8.4 Hz,
7.66-7.67 (m, 1H), 7.56-7.60 (m, 3H), 7.49-7.52 (m, 1H), 7.42 2.4 Hz, 1H), 7.4 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 7.2 Hz, 4.8
(d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.03-7.05 (m, 1H), Hz,1H), 6.93 (t, J = 8.4 Hz, 2H), 3.89 (s, 3H); 13C NMR (150 MHz,
6.92 (s, 1H), 6.76 (d, J = 7.8 Hz, 1H), 2.56 (s, 3H), 2.24 (s, 3H); CDCl3): δ 196.3, 165.1 (d, J = 252.0 Hz), 159.9, 156.1, 148.8,
13C NMR (150 MHz, CDCl3): δ 199.5, 157.4, 148.7, 141.5, 141.0, 140.5, 136.3, 134.2 (d, J = 3.0 Hz), 131.8 (d, J = 9.0 Hz), 129.9,
139.8, 139.4, 136.3, 135.2, 132.1, 131.2, 130.3, 129.6, 129.2, 121.9, 121.4, 116.1, 115.1 (d, J = 21.0 Hz), 113.9, 55.6; IR
128.4, 125.5, 122.8, 121.8, 21.3, 21.0; IR (neat): υmax 2924, (neat): υmax 1668, 1596, 1464, 1289, 1230, 850 cm-1; HRMS
1663, 1601, 1436, 1299, 753 cm-1; HRMS (EI, m/z) calcd. for (ESI, m/z) calcd. for C19H14FNO2Na [M + Na]+: 330.0906; found:
C20H17NO [M]+: 287.1310; found: 287.1305.
330.0872.
(3,5-Dimethoxyphenyl)(2-(pyridin-2-yl)phenyl)methanone,
(4-Bromophenyl)(5-methoxy-2-(pyridin-2-
3n, Scheme 2. The same general procedure was followed by yl)phenyl)methanone, 3v, Scheme 2. The same general
using 2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), 2-(3,5- procedure was followed by using 2-(4-methoxyphenyl)pyridine
dimethoxyphenyl)-2-oxoacetic acid (63 mg, 0.3 mmol, 1.5 (37.0 mg, 0.2 mmol, 1.0 equiv), 2-(4-bromophenyl)-2-oxoacetic
equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) acid (92 mg, 0.4 mmol, 2.0 equiv), potassium persulfate (108
and palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). mg, 0.4 mmol, 2.0 equiv) and palladium(II) acetate (4.5 mg,
Column chromatography (SiO2, eluting with 7:3 hexane/ethyl 0.02 mmol, 0.1 equiv). Column chromatography (SiO2, eluting
acetate) afforded the desired product as a colourless oil, (37.0 with 7:3 hexane/ethyl acetate) afforded the desired product as
1
mg, 58%). H NMR (600 MHz, CDCl3): δ 8.40 (d, J = 4.8 Hz, 1H), a yellowish solid, (49.0 mg, 67%), mp 107-109 oC. 1H NMR (600
7.77 (d, J = 7.8 Hz, 1H), 7.58-7.61 (m, 2H), 7.50-7.54 (m, 3H), MHz, CDCl3): δ 8.28 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H),
7.04-7.06 (m, 1H), 6.96 (d, J = 1.8 Hz, 2H), 6.50 (t, J = 2.4 Hz, 7.55-7.57 (m, 3H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 9.0 Hz,
1H), 3.73 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 197.6, 160.3, 2H), 7.13 (dd, J = 9.0 Hz, 3.0 Hz, 1H), 7.03 (d, J = 3.0 Hz, 1H),
156.7, 149.0, 139.8, 139.5, 139.3, 136.3, 130.2, 129.1, 128.7, 6.98 (dd, J = 7.2 Hz, 4.8 Hz, 1H), 3.88 (s, 3H); 13C NMR (150
128.4, 122.4, 122.0, 107.3, 105.0, 55.5; IR (neat): υmax 1670, MHz, CDCl3): δ 196.8, 159.9, 155.8, 148.7, 140.3, 136.7, 136.4,
1594, 1462, 1302, 1156, 1062, 753 cm-1; HRMS (ESI, m/z) calcd. 131.7, 131.3, 130.7, 129.8, 127.2, 121.7, 121.5, 116.2, 113.9,
for C20H17NO3Na [M + Na]+: 342.1106; found: 342.1007.
55.6; IR (neat): υmax 1669, 1586, 1464, 1230, 841, 757 cm-1;
(5-Methoxy-2-(pyridin-2-yl)phenyl)(phenyl)methanone,
Scheme 2.26b The same general procedure was followed by found: 390.0104.
3t, HRMS (ESI, m/z) calcd. for C19H14BrNO2Na [M + Na]+: 390.0106;
using 2-(4-methoxyphenyl)pyridine (37.0 mg, 0.2 mmol, 1.0 For the spectroscopy data of compounds 3f, 3g, 3h, 3i, 3j, 3k,
equiv), 2-oxo-2-phenylacetic acid (60 mg, 0.4 mmol, 2.0 equiv), 3l, 3o, 3p, 3q, 3r, 3s, 3w and 3x see the ESI.
potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) and General experimental procedure for the decarbonylative
palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). Column acylation reaction between 2-phenylpyridines and
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) phenylglyoxals
, Scheme 3.
afforded the desired product as a white solid, (46.0 mg, 80%). To an oven-dried 10 mL sealed tube, a mixture of 2-
o
1
mp 98-100 C. H NMR (600 MHz, CDCl3): δ 8.32 (d, J = 4.8 Hz, phenylpyridines (0.2 mmol, 1.0 equiv), phenylglyoxals (0.3
1H), 7.73 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.53 (td, J = mmol, 1.5 equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0
7.8 Hz, 1.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.2 Hz, equiv) and palladium(II)acetate (4.6 mg, 0.02 mmol, 0.1 equiv)
1H), 7.26-7.28 (m, 2H), 7.14 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.06 (d, was taken and dry MeCN (3.0 mL) was added to it. After
J = 2.4 Hz, 1H), 6.95-6.97 (m, 1H), 3.89 (s, 3H); 13C NMR (150 flushing with nitrogen, immediately the vessel was sealed with
MHz, CDCl3): δ 197.9, 159.8, 156.3, 148.8, 140.8, 137.7, 136.2, a screw cap. The reaction mixture was allowed to stir for 16 h
132.3, 132.0, 129.9, 129.3, 128.0, 122.0, 121.3, 116.1, 114.0, at room temperature. After that the reaction mixture was
55.6; IR (neat): υmax 1666, 1595, 1462, 1286, 1230, 741, 700 quenched with NaHCO3. Then the reaction mixture was poured
cm-1; HRMS (ESI, m/z) calcd. for C19H15NO2Na [M + Na]+: into water (40 mL) and extracted with ethyl acetate (40 mL).
312.1000; found: 312.1003.
The organic layer was washed with water (10 mL) and brine
(10 mL), dried over anhydrous Na2SO4 and the solvent was
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evaporated under reduced pressure. The crude product was 1458, 1275, 786 cm-1; HRMS (ESI, m/z) calcd. for C18H12BrNONa
purified by column chromatography using
ethyl [M + Na]+: 360.0000, 361.9979; found: 359.9971, 361.9979.
acetate/hexane as eluent to afford the desired product.
(3-methyl-2-(pyridin-2-yl)phenyl)(phenyl)methanone,
3ab,
(5-fluoro-2-(pyridin-2-yl)phenyl)(phenyl)methanone,
3y, Scheme 3.26b The same general procedure was followed by
Scheme 3.26b The same general procedure was followed by using 2-(o-tolyl)pyridine (34.0 mg, 0.2 mmol, 1.0 equiv), 2-oxo-
using 2-(4-fluorophenyl)pyridine (35.0 mg, 0.2 mmol, 1.0 2-phenylacetaldehyde (40 mg, 0.3 mmol, 1.5 equiv), potassium
equiv), 2-oxo-2-phenylacetaldehyde (40 mg, 0.3 mmol, 1.5 persulfate (108 mg, 0.4 mmol, 2.0 equiv) and palladium(II)
equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). Column
and palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
Column chromatography (SiO2, eluting with 7:3 hexane/ethyl afforded the desired product as a colourless oil, (27.0 mg,
acetate) afforded the desired product as a white solid, (26.5 50%). 1H NMR (600 MHz, CDCl3): δ 8.49 (d, J = 4.2 Hz, 1H), 7.65
mg, 48%), mp 149-151 oC. 1H NMR (600 MHz, CDCl3): δ 8.36 (d, (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 7.2 Hz,
J = 4.8 Hz, 1H), 7.78 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.69 (d, J = 7.8 1H), 7.40-7.43 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.28-7.31 (m,
Hz, 2H), 7.58 (td, J = 7.8 Hz, 1.2 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 3H), 7.08 (dd, J = 6.6 Hz, 5.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (150
7.42 (t, J = 7.2 Hz, 1H), 7.25-7.33 (m, 4H), 7.03 (dd, J = 6.6 Hz, MHz, CDCl3): δ 198.2, 157.3, 148.7, 140.0, 137.6, 136.8, 136.1,
5.4 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ 196.4, 162.6 (d, J = 132.6, 132.5, 129.9, 129.8, 128.0, 127.9, 126.2, 125.3, 121.9,
249.0 Hz), 155.6, 148.9, 141.4 (d, J = 4.5 Hz), 137.2, 136.5, 20.1; IR (neat): υmax 1666, 1589, 1282, 752, 707 cm-1; HRMS
135.5 (d, J = 1.5 Hz), 132.6, 130.6 (d, J = 7.5 Hz), 129.3, 128.1, (ESI, m/z) calcd. for C19H15NONa [M + Na]+: 296.1051; found:
122.4, 122.0, 117.1 (d, J = 21.0 Hz), 116.1 (d, J = 22.5 Hz); IR 296.1062.
(neat): υmax 1661, 1588, 1279, 846, 789 cm-1; HRMS (ESI, m/z) General experimental procedure for the dehydrogenative
calcd. for C18H12FNONa [M + Na]+: 300.0801; found: 300.0802.
acylation reaction between 2-phenylpyridines and aldehydes,
(5-chloro-2-(pyridin-2-yl)phenyl)(phenyl)methanone,
3z, Scheme 4
.
Scheme 3.15b The same general procedure was followed by To an oven-dried
7 mL clear vial, a mixture of 2-
using 2-(4-chlorophenyl)pyridine (38.0 mg, 0.2 mmol, 1.0 phenylpyridines (0.2 mmol, 1.0 equiv) and palladium(II)acetate
equiv), 2-oxo-2-phenylacetaldehyde (40 mg, 0.3 mmol, 1.5 (4.6 mg, 0.02 mmol, 0.1 equiv) was taken and dry MeCN (3.0
equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) mL) was added to it. The corresponding aldehydes (0.3 mmol
and palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). 1.5 equiv) were added to the reaction mixture. After flushing
Column chromatography (SiO2, eluting with 7:3 hexane/ethyl with nitrogen for 30 seconds, immediately the vessel was
acetate) afforded the desired product as a white solid, (33.0 sealed with a screw cap. Then aq. TBHP (82 µL, 0.6 mmol, 3.0
mg, 56%), mp 113-115 oC. 1H NMR (600 MHz, CDCl3): δ 8.36 (d, equiv) was added to the reaction mixture via micro-litter
J = 4.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4 Hz, 1.2 syringe. The reaction mixture was allowed to stir for 36 h at
Hz, 2H), 7.57-7.61 (m, 2H), 7.52 (d, J = 1.8 Hz, 1H), 7.50 (d, J = room temperature. After completion (as indicated by TLC), the
8.4 Hz, 1H), 7.40-7.43 (m, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.04-7.06 reaction mixture was quenched with NaHCO3. Then the
(m, 1H); 13C NMR (150 MHz, CDCl3): δ 195.8, 155.4, 148.9, reaction mixture was poured into water (40 mL) and extracted
141.0, 137.7, 137.2, 136.6, 134.9, 132.6, 130.2, 129.9, 129.3, with ethyl acetate (40 mL). The organic layer was washed with
129.0, 128.2, 122.4, 122.2; IR (neat): υmax 1688, 1588, 1458, water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4
1276, 786 cm-1; HRMS (ESI, m/z) calcd. for C18H12ClNONa [M + and the solvent was evaporated under reduced pressure. The
Na]+: 316.0505; found: 316.0502.
crude product was purified by column chromatography using
(5-bromo-2-(pyridin-2-yl)phenyl)(phenyl)methanone,
3aa, ethyl acetate/hexane as eluent to afford the desired product.
Scheme 3.29a The same general procedure was followed by Methyl 4-(2-(pyridin-2-yl)benzoyl)benzoate, 3ad, Scheme
using 2-(4-bromophenyl)pyridine (47.0 mg, 0.2 mmol, 1.0 4.31a The same general procedure was followed by using 2-
equiv), 2-oxo-2-phenylacetaldehyde (40 mg, 0.3 mmol, 1.5 phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), palladium(II)
equiv), potassium persulfate (108 mg, 0.4 mmol, 2.0 equiv) acetate (4.5 mg, 0.02 mmol, 0.1 equiv), methyl 4-
and palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv). formylbenzoate (49 mg, 0.3 mmol, 1.5 equiv), and aq. tert-
Column chromatography (SiO2, eluting with 7:3 hexane/ethyl butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column
acetate) afforded the desired product as a white solid, (28.5 chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
mg, 42%), mp 109-111 oC. 1H NMR (600 MHz, CDCl3): δ 8.36 (d, afforded the desired product as a white solid, (45.5 mg, 72%).
J = 4.2 Hz, 1H), 7.74 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 7.66-7.69 (m, mp 100-102 oC. 1H NMR (600 MHz, CDCl3): δ 8.28-8.29 (m, 1H),
4H), 7.59 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.4
7.42 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.04 (dd, J = 6.6 Hz, 2H), 7.61-7.64 (m, 1H), 7.54-7.59 (m, 4H), 6.98-7.00 (m,
Hz, 4.8 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ 196.2, 155.5, 1H), 3.89 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 197.4, 166.3,
149.0, 141.1, 138.2, 137.2, 136.6, 133.1, 132.6, 131.8, 130.1, 156.1, 148.8, 141.6, 139.4, 139.0, 136.5, 132.8, 130.5, 129.2,
129.4, 128.2, 123.0, 122.4, 122.3; IR (neat): υmax 1668, 1587, 128.9, 128.8, 128.4, 122.2, 122.1, 52.3; IR (neat): υmax 1717,
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1664, 1281, 1107, 743 cm-1; HRMS (EI, m/z) calcd. for (4-Methoxy-2-(pyridin-2-yl)phenyl)(p-tolyl)methanone, 3ak,
C20H15NO3 [M]+: 317.1052; found: 317.1053.
Scheme 4. The same general procedure was followed by using
(3,4-Dichlorophenyl)(2-(pyridin-2-yl)phenyl)methanone, 3ah, 2-(3-methoxyphenyl)pyridine (37.0 mg, 0.2 mmol, 1.0 equiv),
Scheme 4. The same general procedure was followed by using palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 4-
2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), palladium(II) methylbenzaldehyde (36 µL, 0.3 mmol, 1.5 equiv), and aq. tert-
acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 3,4- butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column
dichlorobenzaldehyde (52.5 mg, 0.3 mmol, 1.5 equiv), and aq. chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
tert-butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column afforded the desired product as a colourless oil, (36.5 mg,
1
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) 60%). H NMR (600 MHz, CDCl3): δ 8.43-8.44 (m, 1H), 7.58 (d, J
afforded the desired product as a white solid, (31.5 mg, 48%), = 8.4 Hz, 2H), 7.52-7.55 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.27
mp 135-137 oC. 1H NMR (600 MHz, CDCl3): δ 8.33 (d, J = 4.2 Hz, (d, J = 7.8 Hz, 1H), 7.02-7.07 (m, 4H), 3.93 (s, 3H), 2.31 (s, 3H);
1H), 7.80 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.63-7.66 13C NMR (150 MHz, CDCl3): δ 197.3, 161.0, 157.2, 149.1, 142.9,
(m, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.49- 142.1, 136.1, 135.6, 132.0, 131.3, 129.8, 128.7, 123.4, 122.0,
7.53 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.06-7.08 (m, 1H); 13C 114.6, 113.7, 55.5, 21.5; IR (neat): υmax 2926, 1659, 1603, 1467,
NMR (150 MHz, CDCl3): δ 195.7, 156.0, 148.8, 139.3, 138.5, 1284, 1223, 1032, 758 cm-1; HRMS (EI, m/z) calcd. for
137.8, 136.6, 136.4, 132.5, 130.9, 130.6, 130.1, 129.0, 128.8, C20H17NO2 [M]+: 303.1259; found: 303.1256.
128.4, 128.2, 122.2, 122.1; IR (neat): υmax 1666, 1580, 1434, (4-(Pyridin-2-yl)-[1,1'-biphenyl]-3-yl)(p-tolyl)methanone,
1380, 1275, 955, 747 cm-1; HRMS (ESI, m/z) calcd. for 3am, Scheme 4. The same general procedure was followed by
C18H11Cl2NONa [M + Na]+: 350.0115; found: 350.0117.
using 2-([1,1'-biphenyl]-4-yl)pyridine (46.5 mg, 0.2 mmol, 1.0
equiv), palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 4-
(3,4-Dimethoxyphenyl)(2-(pyridin-2-yl)phenyl)methanone,
3ai, Scheme 4. The same general procedure was followed by methylbenzaldehyde (36 µL, 0.3 mmol, 1.5 equiv), and aq. tert-
using 2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column
palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 3,4- chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
dimethoxybenzaldehyde (50 mg, 0.3 mmol, 1.5 equiv), and aq. afforded the desired product as a white solid, (38.5 mg, 55%),
tert-butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column mp 145-147 oC. 1H NMR (600 MHz, CDCl3): δ 8.42 (d, J = 4.2 Hz,
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.84 (dd, J = 7.8 Hz, 1.8 Hz, 1H),
afforded the desired product as a white solid, (48.0 mg, 75%). 7.76 (d, J = 1.8 Hz, 1H), 7.67-7.69 (m, 4H), 7.59 (td, J = 7.8 Hz,
mp 108-110 oC. 1H NMR (600 MHz, CDCl3): δ 8.42-8.43 (m, 1H), 1.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.39
7.77 (d, J = 7.8 Hz, 1H), 7.58-7.60 (m, 1H), 7.56 (td, J = 7.8 Hz, (t, J = 7.2 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.04-7.06 (m, 1H),
1.8 Hz, 1H), 7.49-7.52 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.44 (d, J 2.34 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 197.9, 156.5, 149.1,
= 1.8 Hz, 1H), 7.16 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.03-7.05 (m, 143.2, 141.2, 140.2, 139.7, 138.3, 136.3, 135.2, 129.8, 129.3,
1H), 6.66 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 3H); 13C NMR 128.9, 128.8, 128.5, 127.9, 127.5, 127.1, 122.6, 121.9, 21.6; IR
(150 MHz, CDCl3): δ 197.0, 157.0, 152.7, 149.2, 148.6, 139.51, (neat): υmax 1662, 1596, 1462, 1245, 758 cm-1; HRMS (ESI, m/z)
139.48, 136.2, 130.8, 130.0, 129.0, 128.9, 128.3, 125.2, 122.9, calcd. for C25H19NONa [M + Na]+: 372.1364; found: 372.1364.
121.9, 110.9, 109.6, 55.91, 55.89; IR (neat): υmax 1656, 1588, 1-(3-(4-Methylbenzoyl)-4-(pyridin-2-yl)phenyl)ethanone, 3an,
1511, 1269, 1128, 753 cm-1; HRMS (ESI, m/z) calcd. for Scheme 4. The same general procedure was followed by using
C20H17NO3Na [M + Na]+: 342.1106; found: 342.1112.
1-(4-(pyridin-2-yl)phenyl)ethanone (39.5 mg, 0.2 mmol, 1.0
(4-Methyl-2-(pyridin-2-yl)phenyl)(p-tolyl)methanone,
3aj, equiv), palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 4-
Scheme 4. The same general procedure was followed by using methylbenzaldehyde (36 µL, 0.3 mmol, 1.5 equiv), and aq. tert-
2-(m-tolyl)pyridine (34.0 mg, 0.2 mmol, 1.0 equiv), butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column
palladium(II) acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 4- chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
methylbenzaldehyde (36 µL, 0.3 mmol, 1.5 equiv), and aq. tert- afforded the desired product as a white solid, (28.0 mg, 45%),
o
1
butyl hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column mp 89-91 C. H NMR (600 MHz, CDCl3): δ 8.41-8.42 (m, 1H),
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate) 8.19 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.89 (d,
afforded the desired product as a white solid, (46.0 mg, 80%), J = 8.4 Hz, 1H), 7.59-7.64 (m, 3H), 7.55 (d, J = 7.8 Hz, 1H), 7.08-
mp 128-130 oC. 1H NMR (600 MHz, CDCl3): δ 8.42 (d, J = 4.2 Hz, 7.11 (m, 3H), 2.66 (s, 3H), 2.34 (s, 3H); 13C NMR (150 MHz,
1H), 7.58-7.61 (m, 3H), 7.53 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.43 (t, CDCl3): δ 197.1, 197.0, 155.6, 149.2, 143.6, 143.5, 140.0, 136.6,
J = 7.2 Hz, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 136.5, 134.8, 129.6, 129.5, 129.2, 128.9, 122.9, 122.6, 26.8,
7.01-7.03 (m, 1H), 2.50 (s, 3H), 2.31 (s, 3H); 13C NMR (150 MHz, 21.6; IR (neat): υmax 2925, 1682, 1599, 1300, 1243, 756 cm-1;
CDCl3): δ 198.0, 157.2, 149.1, 143.0, 140.3, 139.8, 136.8, 136.1, HRMS (EI, m/z) calcd. for C21H17NO2 [M]+: 315.1259; found:
135.4, 129.8, 129.7, 129.2, 129.0, 128.7, 123.1, 121.8, 21.6, 315.1248.
21.4; IR (neat): υmax 1661, 1605, 1467, 1286, 931, 756 cm-1; (2-(Pyridin-2-yl)phenyl)(thiophen-3-yl)methanone,
HRMS (ESI, m/z) calcd. for C20H17NONa [M + Na]+: 310.1208; Scheme 4. The same general procedure was followed by using
3ap,
found: 310.1217.
2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), palladium(II)
10 | J. Name., 2012, 00, 1-3
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acetate (4.5 mg, 0.02 mmol, 0.1 equiv), thiophene-3-
carbaldehyde (26 µL, 0.3 mmol, 1.5 equiv), and aq. tert-butyl
hydroperoxide (82 µL, 0.6 mmol, 3.0 equiv). Column
chromatography (SiO2, eluting with 7:3 hexane/ethyl acetate)
afforded the desired product as a colourless oil, (30.0 mg,
56%). 1H NMR (600 MHz, CDCl3): δ 8.46 (d, J = 4.2 Hz, 1H), 7.77
(d, J = 7.2 Hz, 1H), 7.58-7.62 (m, 4H), 7.52 (t, J = 7.2 Hz, 1H),
7.49 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.15-7.16 (m,
1H), 7.07-7.09 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 191.8,
157.0, 149.2, 142.8, 140.0, 139.4, 136.3, 133.9, 130.3, 129.2,
128.7, 128.4, 127.6, 125.8, 122.9, 121.9; IR (neat): υmax 1656,
1586, 1428, 1273, 858, 752 cm-1; HRMS (ESI, m/z) calcd. for
C16H11NSONa [M + Na]+: 288.0459; found: 288.0460.
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Ghosh and B. C. Ranu, Adv. Synth. Catal. 2016, 358, 283-295.
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4924-4927. (d) B. Zhao, M. Yu, H. Liu, Y. Chen, Y. Yuan and X.
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Lett., 2012, 14, 4358-4361. (g) J. Park, E. Park, A. Kim, Y. Lee,
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3-Methyl-1-(2-(pyridin-2-yl)phenyl)but-2-en-1-one,
3as,
Scheme 4. The same general procedure was followed by using
2-phenylpyridine (31.0 mg, 0.2 mmol, 1.0 equiv), palladium(II)
acetate (4.5 mg, 0.02 mmol, 0.1 equiv), 3-methylbut-2-enal (29
µL, 0.3 mmol, 1.5 equiv), and aq. tert-butyl hydroperoxide (82
µL, 0.6 mmol, 3.0 equiv). Column chromatography (SiO2,
eluting with 7:3 hexane/ethyl acetate) afforded the desired
1
product as a colourless oil, (15.0 mg, 76%). H NMR (600 MHz,
A. Tazawa, K. Honda and F. Kakiuchi, Chem. Lett. 2011, 40,
CDCl3): δ 8.64 (d, J = 4.8 Hz, 1H), 7.72 (td, J = 7.8 Hz, 1.8 Hz,
1H), 7.62 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.52-7.54
(m, 1H), 7.46-7.48 (m, 2H), 7.22-7.24 (m, 1H), 6.03 (s, 1H), 2.08
(s, 3H), 1.72 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 196.0, 158.1,
154.8, 149.2, 142.1, 139.4, 136.1, 130.1, 129.5, 128.4, 128.1,
125.3, 123.5, 122.0, 27.5, 20.7; IR (neat): υmax 2926, 1666,
1615, 1434, 1236, 1012, 752 cm-1; HRMS (ESI, m/z) calcd. for
C16H15NONa [M + Na]+: 260.1051; found: 260.1057.
1018-1020.
8
For selected reviews, see: (a) T. Gensch, M. N. Hopkinson, F.
Glorius and J. Wencel-Delord, Chem. Soc. Rev., 2016, 45
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2900-2936. (b) O. Tischler, B. Tóth and Z. Novák, Chem. Rec.,
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F. Glorius, Chem. Soc. Rev., 2011, 40, 4740-4761. For
selected examples, see: (d) N. Xu, P. Li, Z. Xie and L. Wang,
Chem. Eur. J., 2016, 22, 2236-2242. (e) M. Shang, S.-H. Zeng,
S.-Z. Sun, H.-X. Dai and J.-Q. Yu, Org. Lett., 2013, 15, 5286-
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Houlden, C. D. Bailey, J. G. Ford, M. R. Gagné, G. C. Lloyd-
For the spectroscopy data of compounds 3ac, 3ae, 3af, 3ag,
3al, 3ao, 3aq, 3ar, 3at, 3au and 3av see the ESI.
Acknowledgements
Jones, K. I. Booker-Milburn, J. Am. Chem. Soc., 2008, 130
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10066-10067.
RJ thanks DST, SERB, Govt. of India for Ramanujan fellowship;
award no. SR/S2/RJN-97/2012 and extra mural research grant
no. EMR/2014/000469 for financial support. AH, KM and MKM
thank CSIR and UGC respectively for their fellowships.
9
For selected reviews, see: (a) W. I. Dzik, P. P. Lange and L. J.
Gooßen, Chem. Sci., 2012, , 2671-2678. (b) J. Cornella, I.
3
Larrosa, Synthesis, 2012, 44, 653-676 (c) N. Rodríguez and L.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01466J
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01466J
Palladium-Catalyzed Decarboxylative, Decarbonylative and
Dehydrogenative C(sp2)-H Acylation at Room Temperature
Asik Hossian, Manash Kumar Manna, Kartic Manna and Ranjan Jana*
A practical and environmentally benign protocol for C(sp2)-H acylation at room temperature has been achieved
via entropically favourable decarboxylative, decarbonylative and cross-dehydrogenative manifolds.