Replacing a stoichiometric silver oxidant with air: Ligated Pd(II)-catalysis to β-aryl carbonyl derivatives with improved chemoselectivity

Article abstract of DOI:10.1039/c3gc42504e

Air was employed as a green reoxidant of Pd(0), replacing stoichiometric and toxic silver salt, in the chelation-controlled Pd(II)-modulated arylative enolization of prop-2-en-1-ols to acquire synthetically-important β-aryl carbonyl derivatives. This green approach, which didn't require acid or base, allowed the compatibility of a range of functionalities (inclusive of -I, -Br & -Cl), resulting in the construction of structurally-diverse dihydrochalcones, α-benzyl-α′-alkyl acetones, α-benzyl β-keto esters and dihydrocinnamaldehydes. In addition to organoboronic acids, efficient coupling was also achieved with boronic esters and trifluoroborate salts. A deuterium labelling experiment revealed an interesting 1,2-hydrogen shift after β-arylation in the catalytic process. the Partner Organisations 2014.

Full text of DOI:10.1039/c3gc42504e

Green Chemistry
View Article Online
View Journal | View Issue
PAPER
Replacing a stoichiometric silver oxidant with air:
ligated Pd(II)-catalysis to β-aryl carbonyl
derivatives with improved chemoselectivity†
Cite this: Green Chem., 2014, 16,
2788
Mari Vellakkaran,a Murugaiah M. S. Andappanb and Nagaiah Kommu*a
Air was employed as a green reoxidant of Pd(0), replacing stoichiometric and toxic silver salt, in the chela-
tion-controlled Pd(II)-modulated arylative enolization of prop-2-en-1-ols to acquire synthetically-impor-
tant β-aryl carbonyl derivatives. This green approach, which didn’t require acid or base, allowed the
compatibility of a range of functionalities (inclusive of –I, –Br & –Cl), resulting in the construction of
structurally-diverse dihydrochalcones, α-benzyl-α’-alkyl acetones, α-benzyl β-keto esters and dihydro-
cinnamaldehydes. In addition to organoboronic acids, efficient coupling was also achieved with boronic
esters and trifluoroborate salts. A deuterium labelling experiment revealed an interesting 1,2-hydrogen
shift after β-arylation in the catalytic process.
Received 10th December 2013,
Accepted 13th February 2014
DOI: 10.1039/c3gc42504e
www.rsc.org/greenchem
its widespread prevalence in natural products of medicinal
importance, and it is also present in marketed drugs (Fig. 1).4
Introduction
Due to highly-attractive green and sustainable advantages,
Because of their above-mentioned significance, several syn-
molecular oxygen finds increasing use in both the commodity thetic routes have been pursued to construct these useful
chemical industry and academic labs. Dioxygen is an inexpen- motifs in recent years. Of these, arylative transformation of
sive and abundantly-available oxidant, which doesn’t leave allyl alcohols in a single step through cross-coupling with aryl
behind any solid waste. In contrast, transition metal oxidants halides in the presence of Pd(0) represents a shortcut strategy
(being required in stoichiometric quantities) are toxic, leave to synthesize β-aryl propanals or propanones, taking advantage
behind hazardous solid waste, and are known for promoting of the commercial availability/ready-accessibility of the allyl
undesirable side reactions.1 Hence, replacement of metal oxi- alcohols.5 However, when using this versatile process, limit-
dants in transition-metal catalyzed organic transformations ations are encountered such as a decrease in chemoselectivity
would serve as an environmentally-conscious strategy. In (aryl carbonyl vs. aryl allyl alcohol), decrease in regioselectivity
recent years, Pd(II)-catalysis has found widespread utility in (β-arylation vs. α-arylation) and a necessity for high tempera-
C–C bond formation2 (e.g., oxidative-Heck), C–H functionali- tures and a base.
zation, oxidation (alcohol oxidation, Wacker oxidation
&
Oxidative Pd(II)-mediated coupling of allyl alcohols with
Saegusa oxidation), etc. Sustainability of the catalysis in these transmetallation substrates presents a promising alternative
transformations is accomplished by the oxidation of Pd(0)
(produced at the terminal phase of the catalytic cycle) to Pd(II)
by an oxidant.
β-Aryl alkyl carbonyl intermediates have found extensive
use as versatile synthetic building blocks in medicinal chem-
istry to construct diverse scaffolds or drug-like compounds for
a plethora of therapeutic targets, and also in agricultural and
materials chemistry.3 The “β-aryl carbonyl” motif is known for
aOrganic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad, 500007, India. E-mail: nagaiah@iict.res.in
bSyngene, Biocon Park, Bengaluru, 560009, India.
E-mail: murugaiah.andappan@gmail.com
†Electronic supplementary information (ESI) available: Experimental procedures
Fig. 1 Compounds of pharmaceutical importance, encoded with β-aryl
and analytical data. See DOI: 10.1039/c3gc42504e
carbonyl skeleton.
2788 | Green Chem., 2014, 16, 2788–2797
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Paper
Table 1 Optimization protocol for arylative enolizationa
approach to synthesize β-aryl aldehydes and ketones, consider-
ing key advantages. For example, the reaction can be per-
formed at low temperatures. Surprisingly, only a few methods
for the oxidative coupling of allyl alcohols with organometallic
reagents as an aryl source have been reported in the literature.6
However, these reactions suffer from limitations like the toxic
nature of the aryl metallic reagents (e.g., aryl mercuric salts
and aryl antimony halides), incompatibility of acid-sensitive
functionalities due to the use of acetic acid as a co-solvent6c
and poor yields (<20%).7 We recently reported the first ligand-
modulated and regioselective Pd(II)-catalysis method to syn-
thesize β-aryl aldehydes and ketones, thereby enhancing the
scope of these reactions from the development of selective
applications in organic synthesis.8 However, this method still
suffers from the use of hazardous silver salt as a stoichio-
metric oxidant and limited compatibility of halogen function-
alities. This article illustrates the utility of oxygen as an
environmentally-friendly alternative to silver salt in the ligated
regioselective coupling of allylic alcohols with arylboronic
acids as arylpalladium(II) precursors and enhanced chemo-
selective coupling with iodo-containing arylboronic acids.
Pd
Ligand
Additive
Yieldb
Entry (0.1 equiv.)
(0.2 equiv.) (0.05 equiv.) Solvent (%)
1c
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd2(dba)2
Pd(MeCN)2Cl2 Dmphen
Dmphend
Dmphen
Dmphen
Dmphen
—
CH3CN
CH3CN 31
0
2c
CuCl
CuCl
CuCl
CuCl
CuCl2
CuBr
CuBr2
CuI
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
50
28
15
33
15
20
5
4
5c
6c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
Bphend
Phend
7
8c
9c
10c
11c
12c
13c
14
CuSO4·5H2O DMSO
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
—
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
5
10
10
48
65
43
45
21
10
93
93
9
0
0
0
50
62
10
10
57
85
15
16c
17c
18c
19c
20
Bpyd
Pyridine
PPh3
DPPPd
Results and discussion
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
—
Dmphen
Dmphen
Dmphen
Dmphen
Dmphen
21e
22c, f
23c
24c
25c,g
26
We began our investigation by replacing the Ag2CO3 oxidant
used in our earlier procedure8 with air. We examined the coup-
ling of 1-(4-methyl)phenylprop-2-en-1-ol (Ia) and PhB(OH)2
(IIa) as the model substrates. The secondary alcohol (Ia) was
selected as the model olefin instead of a primary alcohol,
taking into account the stability of the corresponding products
(ketone vs. aldehyde). Disappointingly, no product was
obtained (Table 1, entry 1). However, we were encouraged to
note that the addition of catalytic CuCl additive (0.05 equiv.)
led to product formation, albeit, in a low yield (entry 2).9
Subsequently, identification of the optimum conditions for
regioselective vinylative enolization was undertaken in a com-
binatorial fashion by varying conditions such as the palladium
source, ligand, additive and solvent with air/oxygen.
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
27
28c
29c
30h
31i
DMF
DMAc
DMSO
DMSO
a Unless specified, the reaction was carried out with Ia (1.0 mmol), IIa
(1.5 mmol), Pd (0.1 equiv.), ligand (0.2 equiv.), additive (0.05 equiv.)
under an air balloon (1 atm) at 50 °C in a solvent (3.0 mL) for 12.0 h.
b Isolated yield (average of two runs). c The starting material was not
consumed fully. d Dmphen
=
2,9-dimethyl-1,10-phenanthroline,
Bphen = 4,7-diphenyl-1,10-phenanthroline, Phen = 1,10-phenanthroline,
Bpy
= 2,2′-bipyridyl, DPPP = 1,3-bis(diphenylphosphino)propane.
e Oxygen was used instead of air. f Nitrogen was used instead of air.
g Stoichiometric CuCl was used. h CuCl (1.0 equiv.) with N2 atmosphere.
i CuCl (2.0 equiv.) with N2 atmosphere.
The oxo-palladium source, Pd(OAc)2, proved to be more
efficient than other Pd(II) precursors (entries 3–5 & 20).9 No
product was obtained in the absence of a Pd(II) metal source
with either catalytic or stoichiometric CuCl additives (entries
24 & 25). Pyridine, which is an example of a monodentate realized through the reduced productivity in the absence of
ligand, gave a moderate yield (entry 17). Dmphen, which is the Dmphen ligand (entry 26). A catalytic amount of copper
a bidentate nitrogenous ligand and is routinely used in salt was deemed necessary for promoting the coupling (entries
palladium(II)-mediated oxidative Heck transformations, turned 20 & 23).6c Cuprous salt performed better than cupric salt, as
out to be an efficient ligand (entry 20).10 Other nitrogen-chelat- evident from CuCl vs. CuCl2 and CuBr vs. CuBr2 (entries 6–13).
ing ligands like Bphen, Phen, and Bpy gave moderate yields Replacement of DMSO with other polar aprotic solvents like
(entries 14–16). The phosphine ligands, TPP (monodentate) DMF and DMAc was found to be counterproductive (entries
and DPPP (the oft-used bis-phosphine ligand to generate the 28–29). The less-polar solvent, 1,2-dichloroethane, gave a mod-
cationic Pd(II) complex) were found to be unsuitable (entries erate yield (entry 27). As there was no advantageous effect on
18–19). Superiority of the nitrogen ligands over the phosphines the reaction output on replacing air with oxygen (entries 20 &
is presumably due to the higher stability of the former under 21), inexpensive and safer air was subsequently chosen as the
oxidative Pd(II)-mediated transformations than the oxidation- oxidant of choice for preparative reactions. The yield dramati-
vulnerable phosphines. The importance of ligand control was cally reduced on replacing an air atmosphere with a nitrogen
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 2788–2797 | 2789

View Article Online
Paper
Green Chemistry
atmosphere, which clearly underscored the necessity of dioxy-
gen for promoting the reaction (entries 20 & 22).
α-Arylation products (α-1 & α-2) were not isolated from the
reaction under the optimized conditions (Scheme 1). The fact
that the addition of the aryl moiety exclusively occurs at the
terminal carbon of the double bond indicates the β-regioselec-
tivity of the insertion. Nevertheless, β-arylation delivered the
β-aryl keto compound (β-2) as the exclusive product. The oxi-
dative Heck product, β-aryl allyl alcohol (β-1) (arising from
β-hydride elimination) was not detected under the present con-
ditions.5e The side reactions like isomerization of the alkenol
starting material and allylation of the arylboronic acid,11
which were evident in the Pd(II)–Ag2CO3 system,8 were not
noticed in the present procedure.
The optimized conditions from Table 1 (entry 20) were
employed as standard protocol to investigate the impact of
electronic and steric modulation of both the allyl alcohols and
the arylboronic acids on the reaction outcomes. Though the
electron-poor arylboronic acids were known to be less pro-
ductive in chelation-controlled Pd(II)-catalysis (because of the
presumed sluggish transmetallation), they underwent efficient
coupling (Scheme 2). Nevertheless, the electronic disparity
between electron-rich and electron-poor arylboronic acids had
no impact on the reaction outcome (2–6). Satisfactory yields
were observed, even with sterically-demanding arylboronic
acids (7–8). The β-aryl ketones, bearing halogen handles, were
also obtained in excellent yields (9–12). Relatively-deactivated
aryl ring systems, like naphthyl and biphenyl, also underwent
smooth coupling (13–14).
Scheme 2 Scope
dihydrochalcones.
of
the
arylboronic
acids:
synthesis
of
The scopes and limitations of several different allyl alcohol
derivatives were investigated (Schemes 3–6). 1-Arylpropenols
with differently-activated aryl ring systems of electron-with-
drawing, electron-donating and halogen groups reacted
efficiently (15–18). An aryl propenol, bearing an unprotected
phenolic OH group, a heteroaryl propenol and a fused ring
propenol also furnished the corresponding coupling products
in good yields (19–21) (Scheme 3), indicating the generality of
the method.
The propenols, bearing linear and branched alkyl substitu-
ents at the allylic position, furnished excellent yields
(Scheme 4, 22–24). The olefins, derived from carbohydrate-
based chiral synthons like the protected (S)-glyceraldehyde
(25 & 26) and protected xylose-5-carboxaldehyde (27), under-
Scheme 3 Scope of the substituted aryl vinyl carbinols: synthesis of
dihydrochalcones.
went efficient arylation. This is an indication of the compat-
ibility of this methodology with acid-labile functionalities.
Cyclohex-2-en-1-ol (28), which is an example of an internal
olefin and a challenging substrate for oxidative coupling, was
also arylated successfully. This example opens up an opportu-
nity to develop an asymmetric arylative enolization by repla-
cing achiral ligands with chiral ligands.12
α-Benzyl-β-keto ester derivatives are important building
blocks with extensive value in constructing pharmaceutically-
relevant heterocyclic compounds.13 Though synthesis of the
α-benzyl-β-keto esters from Morita–Baylis–Hillman adducts
Scheme 1 Scope of regioselectivity and chemoselectivity in the aryl
insertion and dehydropalladation steps.
2790 | Green Chem., 2014, 16, 2788–2797
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Paper
Scheme 6 Scope of the primary allyl alcohols: synthesis of substituted
dihydrocinnamaldehydes.
ducts arising from decarboxylation, β-elimination and Pd(0)-
directed oxidative addition were not observed.
The simple allyl alcohol with a primary hydroxy group
(prop-2-en-1-ol) underwent C–C bond formation effectively
with a range of arylboronic acids of varying electronic and
steric character (Scheme 6, 36–41). As seen before with the sec-
ondary alcohol, iodo, bromo, and chloro functionalities were
intact. Thus, this method was superior over the previous pro-
cedure, in which the C–iodo bond was found to be less-compa-
tible with the formation of a Heck-type product as the side
product. Prop-2-en-1-ol is known to undergo Pd(II)-mediated
oxidative Heck coupling to afford the corresponding cinnamyl
alcohol through the competitive β-hydride elimination
pathway.7 However, we observed dihydrocinnamaldehyde as
the exclusive product, indicating the high regioselective
outcome of this methodology through the allylic hydride elim-
ination pathway. 3-Aryl propionaldehydes are known to be sus-
ceptible to aldol condensation at high temperatures and/or in
the presence of a base. This methodology, which obviates the
need for high temperatures and a base, provides facile and
chemoselective access to generate dihydrocinnamaldehydes.
To expand the scope of this catalysis further, two different
derivatives of phenylboronic acid were considered for coupling
(Scheme 7). The pinacolboronic ester of phenylboronic acid
(IIb) and the potassium salt of phenyl trifluoroborate (IIc)
underwent smooth coupling to afford the corresponding aryla-
tive enolization product (1). While boronic esters demonstrate
higher solubility in organic solvents, trifluoroborate salts are
endowed with higher degrees of nucleophilic character com-
pared to free boronic acids.
Scheme 4 Scope of the alkyl vinyl carbinols: synthesis of α,α’-dialkyl-
ketone derivatives.
Scheme 5 Scope of the Morita–Baylis–Hillman adducts: synthesis of
α-benzyl-β-keto esters.
through classical Heck-type coupling with aryl bromides is
known, this coupling requires high temperatures and is known
for the formation of a mixture of products.14 1,3-Dicarbonyl
compounds are known to be susceptible to decarboxylation
under elevated temperatures. Keeping this in mind, we investi-
gated the coupling of arylboronic acids with highly-functiona-
lized acrylic esters to further expand the scope, taking
advantage of (a) the requirement of a lower temperature for
the present procedure than that of a classical Heck-type coup-
ling; (b) the high regioselectivity of arylation and (c) the
chemoselectivity of the product formation. These adducts,
differing in aryl substitution (electron-donating, electron-with-
drawing and halogen groups (iodo and bromo)) underwent
efficient coupling regioselectively (Scheme 5, 29–35). Side pro-
The mild and neutral nature of the reaction conditions
allowed robust functional group tolerance (–NO2, –CN, –CO–,
–NHAc, ketal, –I, –Br, & –Cl). Compatibility of the halogens
under the present conditions has facilitated access to diverse
halogen-intact β-aryl carbonyl derivatives with complete
chemoselectivity. Even though the aryl–halogen bonds (Ar–I,
Ar–Br, and Ar–Cl) were expected to be susceptible to the oxi-
dative addition with Pd(0) species (generated in the penulti-
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 2788–2797 | 2791

View Article Online
Paper
Green Chemistry
Table 3 Competitive coupling: formation of a Heck-type product, indi-
cating the generation of Pd(0) in the catalytic cyclea
Scheme 7 Scope of the phenylboronic reagents with pinacol ester and
potassium trifluoroborate head groups.
Entryb
Oxidative (PdII) product 16
Heck (Pd0) product 16a
1
85%
71%
0%
0%
15%
51%
mate step through dehydropalladation) in the catalytic cycle,
no competitive Heck, Suzuki and dehalogenation products
were observed. Halogens are strategically employed in the aryl
ring by medicinal chemists as handles for diversification
during lead-optimization. Thus, this method offers chemo-
selective access to halogen-appended β-aryl carbonyl com-
pounds, which are of limited scope in Pd(0)-mediated
coupling of allyl alcohols with aryl halides. Importantly, this
methodology can be considered to be an alternative to Rh-cata-
lyzed Michael addition of arylboronic acids to α,β-unsaturated
enones.15 Allyl alcohols provide the advantages of higher
stability, and easy availability over the enal and the enone
counterparts.
To investigate the influence of the oxidant on the chemo-
selective compatibility of the iodo group, reactions were per-
formed with four structurally-different propenols and iodo-
bearing arylboronic acids following the previously reported Pd
(II)–Ag2CO3 procedure for comparison. The results (Table 2)
indicated clearly that oxygen was superior as the oxidant in
terms of productivity. Diminished productivity, achieved in the
case of the Ag2CO3 oxidant, was due to the promotion of side
reactions involving iodo functionality.8
2c
3d,e
a Isolated yield (average of two runs). b Standard condition. c 100 °C.
d Triethylamine (2.0 equiv.), 100 °C, nitrogen atmosphere. e The
starting material was not consumed fully.
temperature, and presence of an efficient oxidant might have
suppressed the oxidative addition of 4-methyliodobenzene
with the transient Pd(0), and hence the formation of a Heck-
type product. Considering the requirement of a higher acti-
vation energy for the oxidative addition of aryl halides to Pd(0)
compared to the transmetallation of arylboronic acids, the
reaction was performed at an elevated temperature (100 °C).
This resulted in the formation of a Heck-type Pd(0) product
(16a) in a 15% yield, in addition to the formation of an oxi-
dative Pd(II)-arylation product (16) in a 71% yield (entry 2). The
yield of the Heck-type product was further enhanced by the
addition of a soluble (tertiary amine) base and by replacing
the O2 atmosphere with a N2 atmosphere (thereby reducing
the rate of oxidation of Pd(0)), which resulted in the require-
ment of a base in the reductive elimination step to convert the
palladium(II) hydride complex to Pd(0) in the Heck catalytic
pathway. The formation of the Heck-type product supports the
mechanism, which involves the generation of Pd(0) in the cata-
lytic cycle.
A reduction in the reaction rate is expected, if the arylpalla-
dium(II) complex (obtained after the transmetallation with
ArB(OH)2) is stabilized. A detrimental effect on the reaction
rate was observed on the addition of LiCl to the reaction
mixture (reaction A, Scheme 8).2q,r,16 This indicated the invol-
vement of a cationic complex in the catalytic cycle. The halide
coordination might neutralize the cationic (N,N)Pd(II)-complex,
thereby blocking the vacant site, which is required for the
olefin to form the metal–olefin π-complex. This prohibits the
forward catalytic step, thereby halting the reaction.
An intermolecular competition experiment was performed
to understand the kinetic and mechanistic aspects using
4-methyliodobenzene (1.5 equiv.), phenylboronic acid (1.5
equiv.) and the alkenol Ib (1.0 equiv.) (Table 3) under the stan-
dard conditions. The arylboronic acid-derived product (16) was
exclusively obtained with no concomitant formation of Heck
and Suzuki products (entry 1). The absence of a base, low
Table 2 Enhanced chemoselectivity with the (N,N)Pd(II)–O2 system
over the previous (N,N)Pd(II)–Ag+ systema
c
Entry
Compound
(N,N)Pd(II)–oxygenb
(N,N)Pd(II)–Ag2CO3
1
2
3
4
11
23
35
41
89%
95%
87%
94%
41%
38%
43%
51%
To investigate the elimination pathway after migratory
insertion of the allyl alcohol into the arylpalladium(II) precur-
sor, the substituted cinnamyl alcohol, Ic (the presumptive
β-dehydropalladation product), was synthesized, as this inter-
mediate was not detected under the present protocol. When Ic
a Isolated yield (average of two runs). b Standard conditions. c Olefin
(1.0 mmol), PhB(OH)2 (2.0 mmol), Pd(OAc)2 (0.1 equiv.), Dmphen (0.2
equiv.), Ag2CO3 (2.0 equiv.) at 60 °C in CH3CN (3.0 mL) for 24.0 h.
2792 | Green Chem., 2014, 16, 2788–2797
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Paper
sient species in the catalytic cycle and subsequent isomerisa-
tion of 1c to the β-ketoaryl product (16).
The complete absence of the α-aryl keto product (or exclu-
sive formation of the β-aryl ketone) can be explained by a
mechanism involving a π-allylpalladium complex (Scheme 8,
reaction C). The product Id can be envisaged to arise from the
activation of the hydroxyl group by PhB(OH)2, subsequent for-
mation of the π-allylpalladium complex by the oxidative
addition of (N,N)Pd(0), transmetallation of the π-allylpalladium
complex with PhB(OH)2 and the final reductive elimination.11
The resultant compound Id can undergo Wacker-type oxi-
dation [Pd(II)/CuCl/O2]17 to afford the β-arylketone (16).
However, we didn’t observe the intermediate Id under the
present conditions. To eliminate the possibility of the transi-
ent formation of Id and subsequent oxidation, we prepared the
aryl–allyl product Id and subjected it to the standard con-
ditions, but could not observe the Wacker oxidation of Id. This
unambiguously ruled out the feasibility of the allylation mech-
anism that would involve the π-allylpalladium complex.
The methyl ether derivative, 1e, did not afford the β-aryl
ketone under the standard conditions but gave the oxidative
Heck product (16c) and allylation product (1d) in a 4 : 1 ratio.
This suggests that on masking the hydroxyl group, the catalytic
route deviates from the normal pathway through (a) β-hydride
elimination after aryl insertion and subsequent termination
and (b) the formation of the π-allylpalladium(II) complex, aryla-
tion and elimination. This strongly suggested the necessity of
a free hydroxyl group for the operation of the allylic hydride
elimination pathway.
To further probe the hydride elimination, the deuterium-
labelled propenol (Ib-d1), was synthesized and reacted with
PhB(OH)2 under the standard conditions. The deuterium-
installed
1-(4-methoxyphenyl)-3-phenyl-2(2H1)-propan-1-one
(16-d1) was obtained exclusively (reaction A, Scheme 9). This
critical observation indicates that the propenol (Ib-d1), after
Scheme 8 Control experiments: diminished productivity with lithium
salts as additives, implying a cationic pathway (reaction A); ruling out
cascaded β-arylation, β-elimination & isomerisation as the mechanism
(reaction B); ruling out sequential formation of π-allylic species
&
Wacker type oxidation as the mechanism (reaction C) and absence of
the allylic hydrogen elimination pathway with protected OH group
(reaction D).
was subjected to the standard conditions (reaction B,
Scheme 8),5e,7 the expected allylic isomerisation of 2-en-1-ol
(Ic) to deliver the corresponding product (16) did not take
place and only a small amount of the product of alcohol oxi-
dation was isolated (16b). This ruled out the possibility of the
generation of a cinnamyl-type β-aryl allyl alcohol (Ic) as a tran-
Scheme 9 Migration of allylic deuterium to the adjacent position
during the arylation.
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 2788–2797 | 2793

View Article Online
Paper
Green Chemistry
Table 4 Different Lewis acids promoting efficient (N,N)Pd(II)-catalysisa
carbopalladation with (N,N)ArPd(II), undergoes a 1,2-hydrogen
shift.5,6 The isotopically-unmodified product (16), was not
detected (reaction B, Scheme 9). Nevertheless, the insertion of
any deuterium atom by the addition of deuterated water to the
reaction of Ib with PhB(OH)2 under the standard protocol was
not evident. This probably rules out the pathway involving the
formation of an α,β-unsaturated ketone (III) through the oxi-
dation of the alcohol (Ib) and the subsequent insertion of a
phenyl palladium(II) precursor into the α,β-unsaturated ketone
(III), followed by protonolysis of the σ-alkyl complex (IV).18
This is further corroborated by the fact that the intermediate,
III, was not observed in the experiment.
Experimental observations from Table 1 indicated the
necessity of Cu(I) for the successful outcome of the reaction,
and the higher performance of the Cu(I) oxidation state over
that of Cu(II). To investigate further, control experiments were
performed with 0.05, 1.0 and 2.0 equiv. of CuCl in an oxygen-
free nitrogen atmosphere (Table 1, entries 22, 30 and 31). The
formation of the desired arylation product (9%, 57%, and
85%) is evidence that the role of the copper(I) salt is as an elec-
tron-transfer mediator for the reoxidation of Pd(0). In the
present procedure, Cu(I) can potentially play dual roles as both
a co-oxidant for the reoxidation of Pd(0) with the oxygen as the
terminal oxidant, and as a Lewis acid, coordinating to the allyl
hydroxyl group to facilitate selective allylic hydride elimination
after carbopalladation. Molecular oxygen was used as the sole
oxidant with no necessity for copper salt as the co-catalyst in
a number of recent Pd(II)-catalyzed oxidative transformations
(e.g., direct O2-coupled Wacker oxidation), when nitrogenous
ligands were employed.2i Dioxygen reacts readily with a (batho-
cuproine)Pd(0) complex to afford a Pd(II)peroxo complex,
which can be protonated with AcOH (2.0 equiv.) to afford
(bathocuproine)Pd(OAc)2 and H2O2.19 Hence, the other role of
catalytic copper(I) salts, behaving like Lewis acids in the
present procedure, which was modulated by the bidentate neo-
cuproine ligand, could not be ruled out. Control experiments
were undertaken with a range of Lewis acids (CuCl, ZnCl2,
ZnBr2, and InBr3) in the presence of stoichiometric Pd(OAc)2
in an oxygen-free nitrogen atmosphere (Table 4, entries 2–5).
Similar yields were obtained as with that of CuCl, which would
substantiate the role of Cu(I) as a Lewis acid.
Entry
Ib/IIa (equiv.)
Additive
16b (%)
1
2
3
4
5
1.0/1.5
1.0/1.5
1.0/1.5
1.0/1.5
1.0/1.5
No additive
CuCl
ZnCl2
ZnBr2
InBr3
<5
91
92
92
93
a Pd(OAc)2 (1.0 equiv.), Dmphen (2.0 equiv.), additive (1.0 equiv.) in
DMSO at 50 °C under N2 atm for 12.0 h. b Isolated yield (average of two
runs).
Fig. 2 Proposed catalytic cycle of aerobic cationic Pd(II) mediated ary-
lation; Dmphen = 2,9-dimethyl-1,10-phenanthroline.
Based on the results from the above mechanistic investi-
gations, a plausible catalytic cycle can be depicted (Fig. 2). The
foremost step of the catalysis might involve the transmetalla- The complex (E) spontaneously undergoes insertion, resulting
tion of arylboronic acid with the Dmphen-chelated palladium(II) in the formation of the σ-alkylpalladium complex with the
complex (A)20 to form the cationic arylpalladium(II) complex transfer of deuterium to the α-carbon (F). The resulting
(B).2q,r Subsequently, the olefin (Ib-d1) coordinates to the metal palladium(II) complex finally undergoes elimination to form the
centre of the Pd(II)-aryl species through the vacant site to form β-aryl keto compound (16-d1) and the cationic (neocuproine)pal-
the π-complex (C). The latter complex then undergoes ladium hydride (G). The palladium hydride subsequently
migratory insertion to form the σ-alkylpalladium complex (D). decomposes to (neocuproine)Pd(0) (H), which is then oxidised
This is followed by β-hydride elimination involving allylic by molecular oxygen and/or Cu(I), thereby regenerating the
hydrogen to form the enol-bound palladium(II) deuteride active Pd(II) catalyst and initiating the new catalytic cycle. Cu(I)
complex (E). The coordination of the copper(I) salt to the could potentially coordinate to the hydroxyl group through 2–5
hydroxyl group of the allyl alcohol could potentially increase steps to enable the elimination of allylic hydrogen and extru-
the acidic character of allylic hydrogen, which could poten- sion of β-aryl ketone, and could act as the co-oxidant in the
tially contribute to the regioselective β-hydride elimination. final step, similar to Tsuji–Wacker oxidation [Pd(II)/CuCl/O2].17
2794 | Green Chem., 2014, 16, 2788–2797
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Paper
silica gel and a gradient of hexane and ethyl acetate (eluent) to
afford the pure product.
Conclusions
Air was shown to be an eco-friendly oxidant to enhance the
sustainability of Pd(II)-directed arylation of prop-2-en-1-ols
with arylboronic acids as the arylpalladium precursors, which
eliminated the use of non-green silver salts and the generation
Acknowledgements
of solid waste. This green approach proceeds with very high We thank the Director of CSIR-Indian Institute of Chemical
regioselectivity and chemoselectivity and does not require a Technology for the generous support and CSIR, New Delhi for
base or an acid (as co-solvent) or high temperature, thereby funding through the programme ORIGIN XII FVP
offering mild conditions. This allowed the tolerance of a wide (CSC0108). V. M. thanks CSIR, New Delhi for the Senior
range of functionalities compared to what was previously poss- Research Fellowship.
ible. Hence, this method provided expeditious access to func-
tionalized β-aryl aldehydes and ketones, and β-keto esters. The
incorporation of ligands has now made asymmetric arylation
feasible and this is under investigation. A mechanistic investi-
Notes and references
gation has shed light on the involvement of the cationic
palladium(II) species, generation of Pd(0) in the catalytic cycle,
and migration of the allylic hydrogen in the catalytic cycle
after arylative insertion.
1 (a) X. Mi, M. Huang, H. Guo and Y. Wu, Tetrahedron, 2013,
69, 5123; (b) E. Song, J. Park, K. Oh, H. M. Jung and S. Lee,
Bull. Korean Chem. Soc., 2010, 31, 1789; (c) Z. He,
S. Kirchberg, R. Frchlich and A. Studer, Angew. Chem., Int.
Ed., 2012, 51, 3699; (d) D. Kim, K. Ham and S. Hong, Org.
Biomol. Chem., 2012, 10, 7305; (e) P. Sun, Y. Zhu, H. Yang,
H. Yan, L. Lu, X. Zhang and J. Mao, Org. Biomol. Chem.,
2012, 10, 4512.
Experimental section
General experimental details
2 (a) S. S. Stahl, Science, 2005, 309, 1824; (b) S. S. Stahl,
Angew. Chem., Int. Ed., 2004, 43, 3400; (c) B. M. Stoltz,
Chem. Lett., 2004, 33, 362; (d) M. J. Schultz and
M. S. Sigman, Tetrahedron, 2006, 62, 8227; (e) J. Muzart,
Chem.–Asian J., 2006, 1, 508; (f) M. S. Sigman and
D. R. Jensen, Acc. Chem. Res., 2006, 39, 221;
(g) E. M. Beccalli, G. Broggini, M. Martinelli and
S. Sottocornola, Chem. Rev., 2007, 107, 5318; (h) J. Piera
and J. E. Backvall, Angew. Chem., Int. Ed., 2008, 47, 3506;
(i) K. M. Gligorich and M. S. Sigman, Chem. Commun.,
2009, 3854; ( j) R. M. Trend, Y. K. Ramtohul, E. M. Ferreira
and B. M. Stoltz, Angew. Chem., Int. Ed., 2003, 42, 2892;
(k) R. M. Trend, Y. K. Ramtohul and B. M. Stoltz, J. Am.
Chem. Soc., 2005, 127, 17778; (l) K. T. Yip, M. Yang,
K. L. Law, N. Y. Zhu and D. J. Yang, J. Am. Chem. Soc., 2006,
128, 3130; (m) W. He, K. T. Yip, N. Y. Zhu and D. Yang, Org.
Lett., 2009, 11, 5626; (n) C. C. Scarborough, A. Bergant,
G. T. Sazama, I. A. Guzei, L. C. Spencer and S. S. Stahl,
Tetrahedron, 2009, 65, 5084; (o) F. Jiang, Z. Wu and
W. Zhang, Tetrahedron Lett., 2010, 51, 5124; (p) Z. Shi,
C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41,
3381; (q) M. M. S. Andappan, P. Nilsson, H. Schenck and
M. Larhed, J. Org. Chem., 2004, 69, 5212; (r) P. Enquist,
P. Nilsson, P. Sjoberg and M. Larhed, J. Org. Chem., 2006,
71, 8779.
All solvents and reagents were used as received from the sup-
pliers. TLC was performed using Merck Kiesel gel 60, F254
plates with a layer thickness of 0.25 mm. Column chromato-
graphy was performed on silica gel (100–200 mesh) using a
gradient of ethyl acetate and hexane as the mobile phase.
Melting points were determined using a Fisher Johns melting
point apparatus and were uncorrected. IR spectra were
recorded using a Perkin-Elmer RX-1 FT-IR system. 1H NMR
spectral data were collected at 300 (AVANCE & JCAMP), 400
(INOVA) and 500 (AVANCE & INOVA) MHz, while 13C NMR were
recorded at 75, 100 and 125 MHz. 1H NMR spectral data are
given as chemical shifts in ppm followed by the multiplicity (s
– singlet; d – doublet; dd – doublet of doublet; t – triplet; q –
quartet; m – multiplet), number of protons and coupling con-
stants. 13C NMR chemical shifts are expressed in ppm. HRMS
(ESI) spectral data were collected using Q-star & ORBITRAP
high resolution mass spectrometers.
General procedure for the synthesis of β-aryl carbonyl
compounds from allyl alcohols
A mixture of arylboronic acid (1.5 mmol), Pd(OAc)2 (0.022 g,
0.1 mmol), 2,9-dimethyl-1,10-phenanthroline (0.042 g,
0.20 mmol), CuCl (0.005 g, 0.05 mmol) and allyl alcohol
(1.0 mmol) was dissolved in DMSO (3 mL) in a 10.0 mL RB
flask. The flask was then fitted to an air balloon (1 atm
pressure). The mixture was vigorously stirred at 50 °C for 12 h.
After cooling to room temperature, the reaction mixture was
partitioned between ethyl acetate (25.0 mL) and water
(25.0 mL) and the contents were transferred to a separatory
funnel. The organic layer was washed with water and brine,
dried over anhydrous Na2SO4 (s) and concentrated in vacuo.
The residue was purified by column chromatography using
3 (a) G. Rassias, N. G. Stevenson, N. R. Curtis, J. M. Northall,
M. Gray, J. Prodger and A. J. Walker, Org. Process Res. Dev.,
2010, 14, 92; (b) C. S. N. Krishnamurthy, T. Kashyap
and J. Singh, PCT Int. Appl., WO 2010064109 A2, 2010;
(c) J. Liu, S. He, T. Jian, P. H. Dobbelaar, I. K. Sebhat,
L. S. Lin, A. Goodman, C. Guo, P. R. Guzzo and M. Hadden,
Bioorg. Med. Chem. Lett., 2010, 20, 2074; (d) P. D. A. Amaral,
J. Petrignet, N. Gouault, T. Agustini, F. Lohezic-Ledevehat,
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 2788–2797 | 2795

View Article Online
Paper
Green Chemistry
A. Cariou, R. Gree, V. L. Eifler-Lima and M. David, J. Braz.
F. Henin and J. Muzart, J. Organomet. Chem., 2001, 634,
153.
Chem. Soc., 2009, 20, 1687; (e) M. R. Gesinski, K. Tadpetch
and S. D. Rychnovsky, Org. Lett., 2009, 11, 5342;
(f) D. C. K. Rathwell, Y. Sung-Hyun, K. T. Tsang and
M. A. Brimble, Angew. Chem., Int. Ed., 2009, 48, 7996;
(g) Y. Hiraiwa, A. Morinaka, T. Fukushima and T. Kudo,
Bioorg. Med. Chem. Lett., 2009, 19, 5162; (h) E. E. Boros,
C. E. Edwards, S. A. Foster, M. Fuji, T. Fujiwara,
E. P. Garvey, P. L. Golden, R. J. Hazen, J. L. Jeffrey and
B. A. Johns, J. Med. Chem., 2009, 52, 2754; (i) A. Heim-
Riether, Synthesis, 2008, 883; ( j) O. Benavente-García and
J. Castillo, J. Agric. Food Chem., 2008, 56, 6185;
(k) L. H. Cazarolli, L. Zanatta, E. H. Alberton,
M. S. Figueiredo, P. Folador, R. G. Damazio,
M. G. Pizzolatti and F. R. Silva, Mini Rev. Med. Chem., 2008,
8, 1429; (l) L. Marzocchella, M. Fantini, M. Benvenuto,
L. Masuelli, I. Tresoldi, A. Modesti and R. Bei, Recent Pat.
6 (a) R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5518;
(b) K. Matoba, S. I. Motofusa, C. S. Cho, K. Ohe and
S. Uemura, J. Organomet. Chem., 1999, 574, 3; (c) M. Chen,
J. Wang, Z. Chai, C. You and A. Lei, Adv. Synth. Catal.,
2012, 354, 341; (d) L. Huang, Q. Ji, H. Kefan and H. Jiang,
Org. Lett., 2013, 15, 2330.
7 L. Yuting, Y. Fan, W. Kun and W. Yangjie, Tetrahedron,
2010, 66, 1244.
8 V. Mari, A. M. S. Murugaiah and K. Nagaiah, Eur. J. Org.
Chem., 2012, 4694.
9 As suggested by the referee, two reactions were performed
by replacing CuCl (5 mol%) with Ag2CO3 (5 mol%) in
MeCN and DMSO (Table 1, entries 2 and 20). While 28%
yield was obtained with MeCN as solvent, no product was
obtained with DMSO.
Inflammation Allergy Drug Discovery, 2011, 5, 200; 10 (a) A. Nordqvist, C. Bjorkelid, M. Andaloussi,
(m) M. Kobori, H. Shinmoto, T. Tsushida and K. Shinohara,
Cancer Lett., 1997, 119, 207; (n) L. Mathiesen,
K. E. Malterud and R. B. Sund, Free Radicals Biol. Med.,
A. M. Jansson, S. L. Mowbray, A. Karlen and M. Larhed,
J. Org. Chem., 2011, 76, 8986; (b) K. S. Yoo, C. H. Yoon and
K. W. Jung, J. Am. Chem. Soc., 2006, 128, 16384.
1997, 22, 307; (o) D. H. S. Silva, S. C. Davino, 11 H. Tsukamoto, T. Uchiyama, T. Suzuki and Y. Kondo, Org.
B. M. S. Barros and M. Yoshida, J. Nat. Prod., 1999, 62, Biomol. Chem., 2008, 6, 3005.
1475; (p) B. M. Rezk, G. R. M. M. Haenen, W. J. F. Van der 12 K. S. Yoo, C. P. Park, C. H. Yoon, S. Sakaguchi, J. O’Neill
Vijah and A. Bast, Biochem. Biophys. Res. Commun., 2002, and K. W. Jung, Org. Lett., 2007, 9, 3933.
295, 9; (q) R. M. Horowitz and B. Gentili, J. Agric. Food 13 (a) A. N. Shestopalov, A. A. Shestopalov and
Chem., 1969, 17, 696; (r) G. E. DuBois, G. A. Crosby and
P. Saffron, Science, 1977, 195, 397; (s) G. E. DuBois,
G. A. Crosby and R. A. Stephenson, J. Med. Chem., 1981, 24,
408; (t) M. L. Whitelaw, H. J. Chung and J. R. Daniel,
J. Agric. Food Chem., 1991, 39, 663; (u) A. Bakal, Alternative
Sweeteners, Dekker, New York, 2nd edn, 1991;
(v) B. O. Garcia, J. Castillo, M. J. Del Bano and J. Lorente,
J. Agric. Food Chem., 2001, 49, 189.
L. A. Rodinovskaya, Synlett, 2008, 1; (b) C. Simon,
T. Constantieux and J. Rodriguez, Eur. J. Org. Chem., 2004,
4957; (c) H. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem.
Soc., 2004, 126, 9906; (d) J. Luo, L.-W. Xu, R. A. S. Hay and
Y. Lu, Org. Lett., 2008, 11, 437; (e) P. Maity and
S. D. Lepore, J. Org. Chem., 2009, 74, 158; (f) A. R. Katritzky,
Z. Wang, M. Wang, C. R. Wilkerson, C. D. Hall and
N. G. Akhmedov, J. Org. Chem., 2004, 69, 6617;
(g) N. Ismabery and R. Lavila, Chem.–Eur. J., 2008, 14, 8444.
4 (a) S. D. Roughly and A. M. Jordan, J. Med. Chem., 2011,
54, 3451; (b) S. W. Martin, P. Glunz, B. R. Beno, 14 (a) D. Basavaiah and K. Muthukumaran, Tetrahedron, 1998,
C. Bergstrom, J. L. Romine, E. S. Priestley, M. Newman,
M. Gao, S. Roberts, K. Rigat, R. Fridell, D. Qiu,
G. Knobloh and Y. K. Wang, Bioorg. Med. Chem. Lett.,
2011, 21, 2869.
5 (a) G. Satyanarayana and M. Maier, Tetrahedron, 2008, 64,
356; (b) I. Ambrogio, S. Cacchi, G. Fabrizi, A. Goggiamani
and S. Galla, Synlett, 2009, 620; (c) J. M. Kim, K. H. Kim,
T. H. Kim and J. N. Kim, Tetrahedron Lett., 2008, 49, 3248;
54, 4943; (b) J. L. Bras and J. Muzart, Synthesis, 2011, 3581;
(c) J. Muzart, Tetrahedron, 2005, 61, 4179;
(d) R. Kumareswaran and Y. D. Vankar, Synth. Commun.,
1998, 28, 2291; (e) F. Coelho, B. R. V. Ferreira, R. V. Pirovani
and L. G. Souza-Filho, Tetrahedron, 2009, 65, 7712;
(f) O. A. C. Antunes, R. Perez, D. Veronese and F. Coelho,
Tetrahedron Lett., 2006, 47, 1325; (g) N. Sunder and
S. V. Bhat, Synth. Commun., 1998, 28, 2311.
(d) P. Colbon, J. Ruan, M. Purdie, K. Mulholland and 15 (a) A. Segura and G. C. Aurelio, Org. Lett., 2007, 9, 3667;
J. Xiao, Org. Lett., 2011, 13, 5456; (e) E. Alacid and
C. Najera, Adv. Synth. Catal., 2007, 349, 2572; (f) J. Mo,
L. Xu, J. Ruan, S. Liu and J. Xiao, Chem. Commun., 2006,
3591; (g) V. Calo, A. Nacci, A. Monopoli and V. Ferola,
(b) M. Pucheault, S. Darses and J. P. Genet, Tetrahedron
Lett., 2002, 43, 6155; (c) Y. Ma, C. Song, C. Ma, Z. Sun,
Q. Chai and M. B. Andrus, Angew. Chem., Int. Ed., 2003, 42,
5871.
J. Org. Chem., 2007, 72, 2596; (h) A. Briot, C. Baehr, 16 As suggested by the referee, LiOAc (5.0 equiv.) was
R. Brouillard, A. Wagner and C. Mioskowski, J. Org. Chem.,
2004, 69, 1374; (i) X. Fang, X. Yang, X. Yang, M. Zhao,
G. Chen and F. Wu, Tetrahedron Lett., 2006, 47, 8231;
( j) G. Satyanarayana and M. Maier, Tetrahedron, 2012, 68,
1745; (k) J. B. Melpolder and R. F. Heck, J. Org. Chem.,
1976, 41, 265; (l) S. Bouquillon, B. Ganchegui, B. Estrine,
employed instead of LiCl. The referee reasoned that the
detrimental effect of LiCl could be attributed to the fact
that it generates in situ PdCl2, a precursor ineffective for
the reaction. LiOAc had similar detrimental effect on reac-
tion outcome (8% yield). This further corroborates the
involvement of cationic Pd(II) species in the catalytic cycle.
2796 | Green Chem., 2014, 16, 2788–2797
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Paper
17 (a) J. Tsuji, Palladium Reagents and Catalysts, Wiley, Chiche-
ster, 2004; (b) P. M. Henry, Handbook of Organopalladium
2012, 77, 8541; (c) L. Zhao and X. Lu, Org. Lett., 2002, 4,
3903; (d) S. Lin and X. Lu, Org. Lett., 2010, 12, 2536.
Chemistry for Organic Synthesis, ed. E. Negishi, Wiley, 19 N. R. Conley, L. A. Labios, D. M. Pearson,
New York, 2002, vol. 2, p. 2119; (c) J. Tsuji, Synthesis, 1984,
369.
C. C. L. McCroy and R. M. Waymouth, Organometallics,
2007, 26, 5447.
18 (a) H. Peng and G. Liu, Org. Lett., 2011, 13, 772; (b) J. Chen, 20 I. W. C. E. Arends, G. J. Ten Brink and R. A. Shledon,
X. Lu, W. Lou, Y. Ye, H. Jiang and W. Zeng, J. Org. Chem.,
J. Mol. Catal. A: Chem., 2006, 251, 246.
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 2788–2797 | 2797