Palladium-catalyzed silver-mediated α-arylation of acetic acid: A new approach for the α-arylation of carbonyl compounds

Article abstract of DOI:10.1002/cctc.201402061

A new approach for the α-arylation of acetic acid through Pd-catalyzed silver-mediated direct C-H arylation of acetic acid with aryl iodides was developed. This protocol provided a straightforward method for the synthesis of a diverse set of α-phenylacetic acids. Palladium served on a silver platter: A new approach for the α-arylation of acetic acid through Pd-catalyzed silver-mediated direct C-H arylation of acetic acid with aryl iodides is presented. This protocol provides a straightforward method for the synthesis of a diverse set of α-phenylacetic acids. Deuteration experiments are performed to help elucidate the reaction mechanism.

Full text of DOI:10.1002/cctc.201402061

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DOI: 10.1002/cctc.201402061
Palladium-Catalyzed Silver-Mediated a-Arylation of Acetic
Acid: A New Approach for the a-Arylation of Carbonyl
Compounds
Guo-Jie Wu,[a, b] Jing Guan,[b] Fu-She Han,*[b] and Yu-Long Zhao*[a]
A new approach for the a-arylation of acetic acid through Pd-
catalyzed silver-mediated direct CÀH arylation of acetic acid
with aryl iodides was developed. This protocol provided
a straightforward method for the synthesis of a diverse set of
a-phenylacetic acids.
tractive, as such a protocol would provide the most straightfor-
ward pathway to access synthetically and biologically useful
a-arylacetic acids given that both the aryl compounds and the
carboxylic acids are readily affordable chemical substrates. For
the synthesis of a-arylacetic acid derivatives, a number of pro-
tocols have been developed. Conventional methods have
relied mainly on the nucleophilic substitution of MCN (M=
metal) followed by hydrolysis or transition-metal-catalyzed car-
bonylation of CO with benzylic (pseudo)halides.[5] In addition,
the transition-metal-catalyzed cross-coupling of aryl halides
with enolates, malonates, and acetoacetates has also been fre-
quently investigated.[6] Improved methods include the cross-
coupling of boron compounds with a-haloacetate esters[7] and
amides[8] [Eq. (2)], direct benzylic CÀH carbonylation[9] [Eq. (3)],
and the decarboxylative coupling of benzylic alcohols with ox-
alate esters[10] [Eq. (4)] in the presence of a suitable metal cata-
lyst. Finally, a few recent reports have shown that a-arylacetic
acid derivatives could also be synthesized through the reaction
of a-diazoacetate esters with boroxines[11] [Eq. (5)] or acetylace-
tates with sulfonium ylides[12] [Eq. (6)] under metal-free condi-
tions.
Recently, the direct CÀH arylation of a-carbonyl compounds
has emerged as a rapidly growing field in the area of transi-
tion-metal-catalyzed sp2–sp3 bond-forming reactions.[1] This is
attributed not only to the numerous advantages of direct CÀH
functionalization reactions, but also to the prevalence of a-aryl
carbonyl scaffolds in agrochemicals and drugs.[2] Following the
pioneering work of Miura,[3a] Buchwald,[3b] and Hartwig,[3c] the
direct CÀH arylation of a variety of carbonyl derivatives such as
aldehydes, ketones, esters, and amides has been intensively in-
vestigated.[1] These reactions are generally performed with the
assistance of a base to promote the enolization of the carbonyl
substrates. However, such conditions are inapplicable for the
arylation of carboxylic acids, because after the formation of
carboxylic anion A [(Eq. (1)], it is extremely difficult to form car-
boxylic dianion B under basic conditions. This is attributed to
the rather weak acidity of the a-proton in carboxylic anion A.[4]
As a result, the a-arylation of carboxylic acids remains largely
unexplored.
Thus, the development of a new protocol that allows the
direct CÀH a-arylation of carboxylic acids is considerably at-
[a] G.-J. Wu, Dr. Y.-L. Zhao
Department of Chemistry
Northeast Normal University
Changchun, Jilin 130024 (P.R. China)
E-mail: zhaoyl351@nenu.edu.cn
Although these protocols provide flexible options for the
synthesis of a-phenylacetic acid derivatives, most of them
cannot access a-phenylacetic acid directly, as extra steps for
the preparation of the starting materials or the conversion of
the reaction products into the desired acids are often required.
With our interest in the transition-metal-catalyzed direct CÀH
functionalization of arenes,[13] we recently investigated the
[b] G.-J. Wu, J. Guan, Prof. F.-S. Han
Changchun Institute of Applied Chemistry
Chinese Academy of Sciences
5625 Renmin Street, Changchun, Jilin 130022 (P.R. China)
Fax: (+86)0431-85262926
E-mail: fshan@ciac.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402061.
CÀH arylation of phosphinate
1 with aryl iodide 2a
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additive to tune the acidity of the reaction system. Accordingly,
a range of alkali salts were examined.[17] The results revealed
that addition of NaOAc or KOAc improved the yield of 4b to
higher than 50% (Table 1, entries 5–7). In addition, only a slight-
ly increased yield was observed if the reaction was performed
under a nitrogen atmosphere as opposed to an oxygen atmos-
phere (data not shown). Finally, by optimizing the number of
equivalents of the catalyst and additives (Table 1, entries 8–10),
we obtained product 4b in 55% yield in the presence of PdCl2
(10 mol%), AgOAc (1.5 equiv.), and NaOAc (5.0 equiv.; Table 1,
entry 9). Further extensive efforts toward improving the reac-
tion efficiency were futile, because the homocoupling of 2b
was observed as a major side reaction and it could not be suc-
cessfully suppressed under various conditions.
Scheme 1. Reaction of phosphinate 1 with aryl iodide 2a in acetic acid.
(Scheme 1). In the presence of Pd(OAc)2 and Ag2CO3, arylated
product 3 was obtained in 52% yield based on 1. In addition,
tolylacetic acid (4a) was isolated as a byproduct in approxi-
mately 6% yield based on iodotoluene (2a). A literature survey
showed that in a 2007 report by Daugulis,[14] the same side re-
action was observed in their study on the Pd-catalyzed aryla-
tion of benzoic acids in acetic acid solvent. Motivated by these
observations, we envisioned that the reaction of carboxylic
acids with aryl halides under acidic conditions would offer
a new opportunity to realize the a-arylation of carboxylic acids
[Eq. (7)]. The successful demonstration of this method and
a preliminary mechanistic inspection will be presented herein.
Thus, we examined the scope and limitations of the reaction
by varying the aryl iodides (Table 2). The results show that for
aryl iodides with an unsubstituted phenyl ring or with
a phenyl ring substituted with a weak electron-donating Me
group, the a-arylacetic acids were obtained in moderately high
yields (see 4a–4d). However, the yield was somewhat dimin-
ished if the Me group was replaced by a stronger electron-do-
nating OMe group (see 4 f). In contrast, for aryl iodides bearing
electron-withdrawing groups, the reactions proceeded more
efficiently than those with electron-donating groups. Generally,
moderately high yields of approximately 60–70% were ob-
served for substrates modified by a rich variety of electron-de-
ficient groups such as F (see 4g and 4h), Cl (see 4j and 4k), Br
(see 4l and 4m), CO2Me (see 4n and 4o), CF3 (see 4p and
4q), and NO2 (see 4r). 4’-Iodoacetophenone afforded a some-
what diminished yield (see 4s). Moreover, the reaction exhibit-
ed good chemoselectivity, as the F, Cl, and Br groups remained
intact (see 4g–4m) during the reaction. Finally, the yields were
lower for ortho-substituted aryl iodides 4e and 4i. These re-
sults indicate that the reaction is sensitive to steric hindrance.
Notably, for most of the reactions, products resulting from the
homocoupling of the aryl iodides were observed as major by-
products.
The optimization of the reaction parameters was performed
through the reaction of iodobenzene (2b) in neat acetic acid.
Representative data are summarized in Table 1. Extensive
screening of various Pd catalysts[15] showed that Pd(OAc)2, Pd-
(CF3CO2)2, and PdCl2 in the presence of silver salts such as
silver acetate (AgOAc) or silver trifluoromethanesulfonate
(AgOTf)[16] were promising combinations that could afford ary-
lated product 4b in approximately 40% yield (Table 1, en-
tries 1–3 and 7). We then investigated the effect of a weak
base on this transformation, which was assumed to act as an
Next, to gain some mechanistic information for this new
transformation, a series of control experiments were per-
formed. Upon treatment of aryl iodide 2o with CD3CO2D under
standard conditions (Table 3, entry 1), analysis of product 4o-D
Table 1. Optimization of the reaction conditions.[a]
1
by H NMR spectroscopy revealed that the deuterated and un-
deuterated ratio for the H-a proton was approximately D-a/
H-a=5.45:1, which indicated the generation of 15.5% undeu-
terated H-a. This is understandable because both AgOAc and
NaOAc may also serve as the acetic acid sources to participate
in competitive arylation with CD3CO2D. However, an interesting
observation was that the H-b and H-c protons in the phenyl
ring were partially deuterated. The deuterated ratio for
H-b and H-c was approximately D-b/H-b=4.56:1 and D-c/
H-c=1:5.06, respectively. The data showed that the ortho
H-b proton could be deuterated much more easily than the
meta H-c proton. A similar trend was also observed by replac-
ing CD3CO2D with CH3CO2D (Table 3, entry 2). These experi-
ments imply that proton exchange of H-a, H-b, and H-c with
D+ takes place during the arylation reaction. A similar deutera-
tion reaction was also reported very recently by Yu.[18]
Entry
Pd catalyst
Pd(OAc)2
Silver salt [equiv.] Additive [equiv.] Yield [%][b]
1
2
3
4
5
6
7
8
9
10
AgOAc (2.0)
–
–
42
42
Pd(O2CCF3)2 AgOAc (2.0)
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
AgOAc (2.0)
–
–
–
43
trace
50
53
50
53
55
45
AgOAc (2.0)
AgOAc (2.0)
AgOTf (2.0)
AgOAc (2.0)
AgOAc (1.5)
AgOAc (1.0)
KOAc (5.0)
NaOAc (5.0)
NaOAc (5.0)
NaOAc (10.0)
NaOAc (5.0)
NaOAc (5.0)
[a] Reaction conditions: 2b (1.0 mmol), Pd catalyst (10 mol%), AcOH
(3.0 mL), 1308C, 24 h. [b] The yield was determined by 1H NMR spectros-
copy owing to contamination by trace diarylacetic acid 5b after isolation.
The structure of 5b was determined by analysis of the mixture of 4b and
5b by HRMS and 1H NMR and 13C NMR spectroscopy.
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The above results raised an interesting question of
how the proton exchange takes place. Clarification of
this issue would provide more useful information for
a better understanding of the arylation mechanism.
Thus, we investigated the role of each reagent such
as the palladium catalyst and the AgOAc and NaOAc
additives on the proton exchange (Table 4). Heating
4o in CH3CO2D in the absence of PdCl2, AgOAc, and
NaOAc led to approximately 28% deuteration of H-a,
but H-b and H-c remained intact (Table 4, entry 1).
This observation suggests that H/D exchange for
H-a could proceed automatically in the absence of
a Pd catalyst or AgOAc and NaOAc as additives. How-
ever, the presence of AgOAc or NaOAc largely accel-
erated the exchange rate of H-a (Table 4, compare
entry 1 vs. entries2 and 3). AgOAc is relatively more
effective than NaOAc in promoting the deuteration
reaction (Table 4, entry 2 vs. 3). Somewhat surprising-
ly, the deuteration of H-a was slightly retarded by the
Pd catalyst (Table 4, entry 1 vs. 4). This observation
ruled out the CÀH activation process of the a-proton
by the Pd catalyst. Finally, a combination of PdCl2
and AgOAc was essential for the H/D exchange of
H-b and H-c (Table 4, entry 5), as deuterium incorpo-
ration was not observed if both (Table 4, entries 1
and 3) or either of the two reagents was absent
(Table 4, entries 2 and 4). The results provide a way
for the selective incorporation of D at H-a.
Table 2. Palladium-catalyzed a-arylation of acetic acid with various aryl iodides.[a]
On the basis of the above control experiments and
Yu’s recent report on the deuteration of arenes,[18] we
reasoned that the deuteration of H-a should proceed
through a different model to that of H-b and H-c.
Namely, H/D exchange of H-a may occur through
Ag+- and/or Na+-aided tautomerization between the
[a] Reaction conditions: 2 (1.0 mmol), Pd catalyst (10 mol%), AcOH (3.0 mL), 1308C,
24 h. [b] The yield was determined by 1H NMR spectroscopy owing to the contamina-
1
tion by trace diarylacetic acid 5a. [c] The yield was determined by H NMR spectrosco-
py owing to the contamination by trace diarylacetic acid 5b.
enolate and the carboxylate rather than a CÀH activation pro-
cess, as Pd-catalyzed CÀH-a activation was not observed.
Whereas that of H-b and H-c should take place by Pd-catalyzed
Table 3. a-Arylation of deuterated acetic acid with aryl iodide 2o.[a]
Table 4. Deuteration experiments of 4o.[a]
Entry Acetic
acid
Yield of
4o-
D [%][b]
D-a/H-a[c]
(IA[d] of H-
a [%])
D-b/H-b
(IA[d] of H-
b [%])
D-c/H-c
(IA[d] of H-
c [%])
Entry
PdCl2
AgOAc
NaOAc
IA [%][b]
H-a (D-a)
1
2
CD3CO2D 53
CH3CO2D 57
5.45:1
(15.5)
1.78:1
(36.0)
4.56:1
(18.0)
1.27:1
(44.0)
1:5.06
(83.5)
1:10.76
(91.5)
H-b
H-c
[c]
1
2
3
4
5
À
À
À
À
+
À
À
72.0 (28.0)
21.0 (79.0)
35.5 (64.5)
86.0 (14.0)
18.5 (81.5)
100.0
100.0
100.0
100.0
67.0
100.0
100.0
100.0
100.0
96.0
[d]
À
À
+
+
+
À
À
+
[a] Reaction conditions: Aryl iodide 2o (0.5 mmol), PdCl2 (10 mol%),
AgOAc (0.75 mmol), NaOAc (2.5 mmol), [Dn]acetic acid (1.0 mL) at 1308C
for 12 h under an atmosphere of N2. [b] Yield of isolated product. [c] The
deuterated ratio for D-a/H-a, D-b/H-b, and D-c/H-c was deduced from the
integration area of the signal of the corresponding H-a, H-b, and
H-c proton in the 1H NMR spectrum. [d] IA=percentage of integration
area of H-a, H-b, and H-c in the isolated product.
[a] Reaction conditions: Arylacetic acid 4o (0.5 mmol), PdCl2 (10 mol%),
AgOAc (0.75 mmol), NaOAc (2.5 mmol), CH3CO2D (1.0 mL) at 1308C for
12 h under an atmosphere of N2. [b] IA=percentage of integration area
of H-a, H-b, and H-c in the isolated product. [c] À: Absence of reagent.
[d]+: Presence of reagent.
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pletion of the reaction as monitored by TLC, the reaction mixture
was poured into 2n HCl (20 mL) and then extracted with CH2Cl2
(4ꢁ20 mL). The combined organic layer was washed with brine,
dried with anhydrous Na2SO4, filtered, and concentrated to dryness.
The crude material was purified by flash chromatography on silica
gel (hexane/acetone+trace AcOH) to give the desired products.
Ag-promoted aryl CÀH activation followed by protonolysis of
the aryl–PdII intermediate with D+. Thus, although we were
unable to provide more evidence as a result of difficulties in
detecting the possible intermediates formed from acetic acid
and the catalyst or additives, we could tentatively speculate
that the a-arylation of acetic acid should proceed more plausi-
bly through
a Heck-type cross-coupling. As shown in
Scheme 2, oxidative addition of aryl iodide 2 to Pd0 forms PdII
Acknowledgements
Financial support from Hundred Talent Program of the Chinese
Academy of Sciences is acknowledged.
Keywords: arylation
palladium · silver
· carboxylic acids · cross-coupling ·
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Experimental Section
General procedure for the a-arylation of acetic acid with
aryl iodides
A Schlenk tube was equipped with a magnetic stir bar and
charged with PdCl2 (10 mol%), AgOAc (1.5 mmol), and NaOAc
(5.0 mmol). The tube was then evacuated under vacuum and back-
filled with N2. Then, the aryl iodide (1.0 mmol) and AcOH (3.0 mL)
were added by syringe (aryl iodides that were solids at room tem-
perature were added together with the catalyst, AgOAc, and
NaOAc), and the reaction mixture was stirred at 1308C. Upon com-
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[15] Pd catalysts being screened: Pd(OAc)2, Pd(O2CCF3)2, PdCl2, Pd(acac)2,
PdCl2(PPh3)2, Pd(dba)2, Pd(PPh3)4.
[18] S. Ma, G. Villa, P. S. Thuy-Boun, A. Homs, J.-Q. Yu, Angew. Chem. Int. Ed.
2014, 53, 734–737; Angew. Chem. 2014, 126, 753–756; and references
cited therein.
[16] Among several silver salts such as AgOAc, AgoTf, Ag2O, AgClO4, and
Ag2CO3, AgOAc and AgOTf afforded a higher yield.
[17] NaOAc, KOAc, CsOAc, CsF, Cs2CO3, MgSO4, K3PO4, and K2HPO4 were
screened.
Received: February 19, 2014
Revised: March 6, 2014
Published online on April 24, 2014
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