An improved method for the synthesis of phenylacetic acid derivatives via carbonylation

Article abstract of DOI:10.1177/1747519819876202

2,4-Dichlorophenylacetic acid is synthesized in high yield via the carbonylation of 2,4-dichlorobenzyl chloride, and various experimental conditions are evaluated. Xylene, bistriphenylphosphine palladium dichloride, tetraethylammonium chloride and sodium hydroxide in solution are added to the reaction system and held at 80 °C under a CO atmosphere. 2,4-Dichlorophenylacetic acid is obtained in a maximum yield of 95percent, and a mechanism for 2,4-dichlorobenzyl chloride carbonylation is proposed. The reaction system provides a mild, effective and novel means by which to prepare phenylacetic acid derivatives from their corresponding benzyl chloride derivatives.

Full text of DOI:10.1177/1747519819876202

876202CHL0010.1177/1747519819876202Journal of Chemical ResearchLi et al.
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An improved method for the synthesis of
phenylacetic acid derivatives via carbonylation
https://doi.org/10.1177/1747519819876202
DOI: 10.1177/1747519819876202
journals.sagepub.com/home/chl
He Li , Yijun Zhang, Dinghua Liu and Xiaoqin Liu
Abstract
2,4-Dichlorophenylacetic acid is synthesized in high yield via the carbonylation of 2,4-dichlorobenzyl chloride, and
various experimental conditions are evaluated. Xylene, bistriphenylphosphine palladium dichloride, tetraethylammonium
chloride and sodium hydroxide in solution are added to the reaction system and held at 80°C under a CO atmosphere.
2,4-Dichlorophenylacetic acid is obtained in a maximum yield of 95%, and a mechanism for 2,4-dichlorobenzyl chloride
carbonylation is proposed. The reaction system provides a mild, effective and novel means by which to prepare
phenylacetic acid derivatives from their corresponding benzyl chloride derivatives.
Keywords
benzyl chloride derivatives, carbonylation, palladium catalyst, phase-transfer catalysis, phenylacetic acid derivatives
Date received: 01 May 2019; accepted: 21 August 2019
products in good yields (Scheme 1). Carbonylation with a
Introduction
small amount of CO and a tetraalkylammonium (TAA) salt
Phenylacetic acid and its derivatives comprise an important
produced a higher yield of 2,4-dichlorophenylacetic acid
class of organic carboxylic acids. They are fundamental
(2,4-DCPA) than previously reported methods.
building blocks of many pharmaceutical intermediates such
as ibuprofen, carbenicillin, diclofenac and spirodiclofen.1,2
Carbonylation and carboxylation are the most widely Results and discussion
investigated reactions for the synthesis of phenylacetic acid
derivatives. Benzyl halides and their derivatives are used as
Effect of the solvents
raw materials, and either sodium cyanide (NaCN) or CO2 is Various solvents were evaluated as the reaction medium for the
utilized as a C1 source.3–9 However, NaCN is a nitrile and synthesis of 2,4-DCPAvia carbonylation of 2,4-dichlorobenzyl
is highly toxic to humans, while the experimental process chloride (2,4-DCBC) using the bistriphenylphosphine palla-
involving CO2 places a relatively high demand on the elec- dium dichloride (Pd(PPh3)2Cl2) and tetraethylammonium chlo-
trochemical reactor. The synthesis of phenylacetic acid via ride (TEAC) catalytic system. The results are summarized in
direct, metal-catalysed hydrocarboxylation of styrene Table 1. Polar N,N-dimethylformamide (DMF) was not an
derivatives has recently been reported.10–12 The disadvan- effective solvent for carbonylation, as 2,4-DCPA was obtained
tage of using highly reactive metal compounds like in a yield of only 35% (Table 1, entry 5). However, the reaction
Grignard reagents is the need for an anhydrous environ-
ment. Currently, the most promising carbonylation method
for industrial applications combines the use of a transition
metal and phase-transfer catalysis (TM-PTC) chemistry.13
State Key Laboratory of Materials-Oriented Chemical Engineering,
College of Chemical Engineering, Nanjing Tech University, Nanjing,
China
Herein, a new carbonylation process for the synthesis of
phenylacetic acid derivatives from their corresponding
benzyl chloride derivatives is reported. A water-soluble
palladium catalyst was employed in the presence of a base.
The method was facile, mild, and provided carbonylated
Corresponding author:
Dinghua Liu, State Key Laboratory of Materials-Oriented Chemical
Engineering, College of Chemical Engineering, Nanjing Tech University,
Nanjing 211816, China.
Email: ncldh@njtech.edu.cn

2
Journal of Chemical Research 00(0)
Scheme 1. Synthesis of phenylacetic acid derivatives.
Table 1. Effect of the solvents.a
Entry
Solvents
ε (C2/(N*M2))
Conversion (%)
Yield (%)
1
2
3
4
5
DMB
2.27
2.68
13.4
14.7
36.7
99
94
71
66
46
95
62
49
43
35
Diphenyl ether
Butyraldehyde
Isoamyl alcohol
DMF
DMF: N,N-dimethylformamide.
aReaction conditions: 2,4-DCBC (0.01 mol), solvent (10 mL), NaOH (4 M, 8 mL), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), CO (1.5 MPa), 80°C,
20 h.
produced 2,4-DCPA in maximum yields of up to 95% in a
non-polar xylene (DMB) solvent system (Table 1, entry 1).14
As the results in Table 1 show, less polar solvents lead to better
conversions and yields of the carbonylation product (Table 1,
entries 1–5).
Table 2. Effect of temperature.a
Entry
T (°C)
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
60
70
80
91
94
99
96
92
71
46
79
83
95
86
83
66
36
Effect of temperature
90
100
110
120
The reaction yield depended greatly on temperature. As
the reaction temperature increased, the extent of conver-
sion clearly increased. However, the catalyst and TAA
salt decomposed rapidly at high temperatures, which was aReaction conditions: 2,4-DCBC (0.01 mol), DMB (10 mL), NaOH (4 M,
detrimental to carbonylation. Therefore, it was necessary
8 mL), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), CO (1.5 MPa), 20 h.
to investigate the effect of temperature on the reaction.
The results are shown in Table 2. At 60°C, 2,4-DCPA
to high (Table 3, entries 1–5). Under the CO atmosphere,
was obtained in a moderate yield of 79% (Table 2, entry 1).
Pd(II) was readily reduced to Pd(0). Thus, only a moder-
When the temperature was increased from 60°C to 80°C,
ate yield of 2,4-DCPA was obtained from the reaction per-
both the conversion of 2,4-DCBC and the yield of 2,4-
formed with ligand-free palladium chloride (Table 3,
DCPA increased (Table 2, entries 1–3). This was due to the
entries 6 and 7).
higher probability of collision between the reactant mole-
As reported previously, nanoscale Pd colloids can be
cules. As the reaction temperature increased from 80°C to
stabilized by quaternary ammonium salts, which prevent
120°C, the yield decreased from 95% to 36%. This was
attributed to the decomposition of Pd(PPh3)2Cl2 and dena-
turation of TEAC (Table 2, entries 4–7). Thus, the optimal
reaction temperature was 80°C.
undesired agglomeration and promotes carbonylation.15–22
In this work, Pd ions played the role of a Pd colloid. The
activities of Co(CH3COO)2/PPh3 (0.13mmol) and CoCl2/
PPh3 (0.13mmol) were evaluated for comparison. 2,4-
DCPA yields of only 22% and 18% were obtained with
Co(CH3COO)2/PPh3 and CoCl2/PPh3, respectively (Table
3, entries 8 and 9). The results indicated that the catalytic
effect of Pd catalysts was superior to that of Co catalysts in
the carbonylation reaction, and Pd(PPh3)2Cl2 had the high-
est catalytic activity.
Effect of the catalysts
The Pd(PPh3)2Cl2 and TEAC catalytic system exhibited
the highest activity for 2,4-DCBC carbonylation. The pal-
ladium complex contained phosphine ligands, and its cat-
alytic activity in the carbonylation reaction was moderate

Li et al.
3
Table 3. Effect of the catalysts.a
Table 5. Effect of the base.a
Entry Catalysts (mmol)
Conversion (%) Yield (%) Entry Base
Concentration n(material)
:
Conversion Yield
(mol L−1)
n(base)
(%)
(%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2 (0.13)
Pd(PPh3)2Cl2 (0.04)
Pd(PPh3)2Cl2 (0.09)
Pd(PPh3)2Cl2 (0.11)
Pd(PPh3)2Cl2 (0.17)
PdCl2 (0.13)
PdCl2/PPh3 (0.13)
Co(CH3COO)2/PPh3 (0.13) 64
CoCl2/PPh3 (0.13) 48
99
50
65
94
99
82
90
95
38
43
74
82
55
67
22
18
1
2
3
4
5
6
7
NaOH
NaOH
NaOH
NaOH
KOH
3
4
5
6
4
4
4
1:2.4
1:3.2
1:4.0
1:4.8
1:3.2
1:3.2
1:3.2
84
99
95
99
83
20
31
27
95
84
78
67
19
30
Na2CO3
K2CO3
aReaction conditions: 2,4-DCBC (0.01 mol), DMB (10 mL), base (8 mL),
Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), CO (1.5 MPa), 80°C, 20 h.
aReaction conditions: 2,4-DCBC (0.01 mol), DMB (10 mL), NaOH (4 M,
8 mL),TEAC (0.18 mmol), CO (1.5 MPa), 80°C, 20 h.
sharply to 95% (Table 5, entries 1 and 2). Increasing the
NaOH concentration further to 6M decreased the yield of
2,4-DCPA (Table 5, entries 3 and 4). Potassium hydroxide
was also effective, as indicated by a 67% yield of 2,4-
DCPA. However, sodium carbonate and potassium carbon-
ate were not efficient bases for carbonylation. Thus,
2,4-DCPA was obtained in low yields of 19% and 30% with
Na2CO3 and K2CO3, respectively (Table 5, entries 6 and 7).
An excess of base was needed for the carbonylation reac-
tion. When the molar ratio of 2,4-DCBC and NaOH was
greater than 1:2, 1:3.2 in particular, a portion of the OH−
provided by NaOH was consumed in the synthesis of the
products. The remaining OH− reacted with the TAA salt and
produced intermediates for the carbonylation reaction.25
Table 4. Effect of the TAA salts.a
Entry TAA salts R
X Conversion (%) Yield (%)
1
2
3
4
5
6
7
TEAC
TMAB
TPAB
DMBAC PhCh2(Me)3
TEBAC
DTAC
Et4
Me4
Cl 99
Br 99
95
87
81
81
82
65
58
(CH3CH2CH2)4 Br 99
Cl 99
Cl 96
Cl 82
Cl 88
PhCh2(Et)3
C12H25(Me)3
HTMAC C16H33(Me)3
TEAC: tetraethylammonium chloride;TMAB: tetramethylammonium
bromide;TPAB: tetrapropylammonium bromide; DMBAC:
benzyltrimethylammonium chloride;TEBAC: benzyltriethylammonium
chloride; DTAC: dodecyltrimethylammonium chloride; HTMAC:
hexadecyltrimethylammonium chloride.
aReaction conditions: 2,4-DCBC (0.01 mol), DMB (10 mL), NaOH (4 M,
8 mL), Pd(PPh3)2Cl2 (0.13 mmol),TAA salts (0.18 mmol), CO (1.5 MPa),
80°C, 20 h.
Evaluation of scope
Under the optimized conditions, the generality of the cata-
lytic system was determined by carbonylating several dif-
ferent benzyl chlorides. The various benzyl chloride
derivatives were converted to their corresponding pheny-
lacetic acid derivatives in good yields (Table 6, entries 1–13,
Supplemental material). It was noted that only the benzylic
position was carbonylated, while the aryl chlorines remained
in their original positions. The results indicated the carbon-
ylation reaction was highly regioselective. This arose from
the reactivity of the benzylic chlorine atom, which was
higher than that of chlorine substituents on the benzene ring.
Effect of theTAA salts
TAA salts played an important role in the organic reac-
tion,23 and the effect of the salt (R4N+X−) on carbonylation
was investigated. The results are shown in Table 4. The
short-chain TAA salts had higher catalytic efficiencies than
the long-chain TAA salts. For example, 2,4-DCPA was
obtained in a 95% yield with TEAC, a short-chain TAA salt
(Table 4, entry 1). In the presence of hexadecyltrimethyl-
ammonium chloride (HTMAC), a long-chain TAA salt,
2,4-DCPA was obtained in a yield of only 58% (Table 4,
entry 7). This was because the long-chain TAA salts could
be carbonylated by the Pd catalyst. Carbonylation of the
long-chain TAA salts competed with 2,4-DCBC carbonyla-
tion and reduced the yield of 2,4-DCPA.24 In addition, the
catalytic activity of chloride salts in the carbonylation reac-
tion was higher than that of the bromide salts (Table 4,
entries 1 and 2). Most importantly, these results demon-
strated that 2,4-DCPA could be produced in excellent yield
via carbonylation in the presence of TEAC.
Reaction mechanism
The mechanism of palladium-catalysed carbonylation of
benzyl chlorides is shown in Scheme 2. RX was first trans-
formed into R–Pd–X (A) via the insertion of the Pd com-
plex. R–CO–Pd–X (B) was readily produced from A
through oxidative addition in the CO atmosphere. Under
+
−
−
′
basic conditions, ion exchange between X in R4N X
and OH− yielded complex C. This was a reversible process
and required a large excess of OH− ions. Under the optimal
reaction conditions at 80°C, the OH− ion carried by com-
+
′
plex C attacked B to form a new complex, R − COO − NR4
Effect of the base
(D). This was accompanied by the regeneration of the Pd
As shown in Table 5, the yield of 2,4-DCPA was 27% at a
NaOH concentration of 3M. When the NaOH concentra-
tion was increased to 4M, the yield of 2,4-DCPA increased
catalyst. Complex D was subsequently resolved to an ionic
+
−
liquid comprising
of sodium hydroxide. Finally, the phenylacetic acid
and R–COO− in the presence
′
R4 N X

4
Journal of Chemical Research 00(0)
Table 6. Evaluation of scope.a
role in the carbonylation process. In summary, this carbon-
ylation system enables the carbonylation of substituted
benzyl chlorides and provides a new alternative for prepar-
ing the corresponding substituted phenylacetic acids.
Entry
1
Benzyl chlorides
Phenylacetic acids
Yield (%)
85
Experimental
2
85
86
93
88
83
86
81
85
83
86
82
84
Materials and instruments
All reagents were used without further purification.
Toluene, DMF, isoamyl alcohol, butyraldehyde, diphenyl
ether and DMB were obtained from Sinopharm Chemical
Reagent Co., Ltd (Shanghai, China). All reagents were of
analytical reagent (AR)-grade. Catalysts (Reagent Grade
[RG]) and PPh3 (RG) in Table 3 were purchased from Xi’an
Kaili Catalyst and New Materials Co., Ltd (Xi’an, China).
TAA salts (98%) listed in Table 4 were purchased from
Shanghai Aladdin Bio-Chem Technology Co., Ltd
(Shanghai, China). CO (99.99%) was purchased from a
local manufacturer. AR-grade bases (Table 5) and benzyl
chlorides (Table 6) were obtained from Sinopharm
Chemical Reagent Co., Ltd.
The reaction mixtures were analysed qualitatively via
gas chromatography (GC) and compared with standard
samples. The analyses were performed on a 7890A
GC (Agilent) equipped with a flame ionization detector
(FID) and an Agilent DB-1ms capillary column
(30m×0.25mm×0.25μm). Nitrogen was used as the car-
rier gas at a flow rate of 0.9mLmin−1. High performance
liquid chromatography (HPLC) was used to quantitatively
analyse the reaction mixtures. Analysis was carried out
with a Prominence LC-20A HPLC (Shimadzu) equipped
with a Shimadzu Shim-pack VP-ODS C18 column
(250mm×4.6mm, 5μm) and ultraviolet detector (UVD)
using o-dichlorobenzene as an internal standard. Fourier
transform infrared (FTIR) measurements were conducted
with a Nicolet IS10 spectrometer (Thermo Fisher Scientific,
Waltham, MA, USA) using the KBr pellet technique. The
spectra were recorded with a resolution of 16cm−1. Nuclear
magnetic resonance (NMR) spectroscopy was conducted
with an AV400 NMR spectrometer (Bruker, Billerica, MA,
USA). The samples were dissolved in dimethyl sulfoxide-
d6 (DMSO-d6), and tetramethylsilane (TMS) was used as
the internal standard.
3
4
5
6
7
8
9
10
11
12
13
aReaction conditions: material (0.01 mol), DMB (10 mL), NaOH (4 M, 8
mL), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), CO (1.5 MPa), 80°C,
20 h.
Catalytic experiments
derivative R–COOH was obtained upon addition of a strong
acid (HCl).26
The carbonylation reaction was performed in a 150mL pol-
ytetrafluoroethylene (PTFE)-lined autoclave equipped with
a magnetic stir bar. In a typical experiment, the substituted
benzyl chloride (0.01mol), Pd(PPh3)2Cl2 (0.13mmol),
TEAC (0.18mmol), NaOH (4M, 8mL) and DMB (10mL)
were placed in the autoclave. The autoclave was purged
three times with N2 and three times with CO, and then
heated to 80°C. During the reaction, the CO pressure was
maintained at 1.5MPa. When the reaction was complete,
the autoclave was cooled to room temperature in ice water,
and the CO was discharged to atmospheric pressure. The
mixture was then adjusted to pH 2 with HCl (12M), and the
solid was collected via filtration and air-dried. The crude
Conclusion
A mild, effective and novel method for the synthesis of 2,4-
DCPA was developed using 2,4-DCBC as the starting
material, CO as the carbon source and Pd(PPh3)2Cl2 as the
catalyst. Results obtained under various experimental con-
ditions showed that carbonylation at 80°C using xylene
(DMB) as the solvent and sodium hydroxide as the base
with a Pd(PPh3)2Cl2 dosage of 0.13mmol produced the
highest yield of 2,4-DCPA, which reached 95%. The mech-
anism demonstrated that R–CO–Pd–X played an important

Li et al.
5
Scheme 2. Mechanism of palladium-catalysed carbonylation.
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product was recrystallised in MeOH/H2O (1:1, v/v) to
obtain 2,4-DCPA. The remaining commercially available
catalysts were evaluated under the same conditions. The
percent conversion and yield were quantified by the method
reported by Lei et al.27
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2,4-Dichlorophenylacetic acid (1b). a white solid; m.p. 128–
130°C (lit.28 132–133°C); IR (KBr) 770, 822, 870, 906,
1040, 1100, 1230, 1290, 1330, 1400, 1470, 1560, 1590,
1730, 3090cm−1; 1H NMR (400MHz; DMSO-d6) δ 12.54 (s,
1H), 7.61 (d, J=2.1Hz, 1H), 7.49–7.33 (m, 2H), 3.72 (s, 2H)
ppm; 13C NMR (100MHz; DMSO-d6) δ 171.66, 135.17,
133.89, 133.05, 132.81, 128.92, 127.71, 38.52ppm.
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Declaration of conflicting interests
10: 615.
The author(s) declared no potential conflicts of interest with
respect to the research, authorship and/or publication of this
article.
15. Veisi H and Mirzaee N. Appl Organomet Chem 2017; 2:
4067.
16. Veisi H, Kordestani D and Faraji AR. J Porous Mat 2014; 2:
141.
Funding
17. Wang B, Wang YY, Li JZ, et al. Catal Sci Technol 2018; 8:
3357.
18. Wang YW, Zeng YY, Wu XC, et al. Mater Lett 2018; 220:
321.
The author(s) received no financial support for the research,
authorship and/or publication of this article.
ORCID iD
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He Li
https://orcid.org/0000-0002-9547-3163
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Supplemental material
Analytical data, FTIR, 1H NMR and 13C NMR spectra.
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