Transition metal-free protodecarboxylation of electron rich aromatic acids under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2017.10.036

A mild and practical method for the transition metal-free protodecarboxylation of aromatic acids using readily available and safe sodium persulfate as initiator was described. This environment-friendly decarboxylation approach was performed at 60 °C in ethanol and could easily scale up to the gram level with a good yield. In Particular, the tandem reactions of decarboxylation and halogenation were achieved by the addition of the corresponding halogenating reagents to the reaction system.

Full text of DOI:10.1016/j.tetlet.2017.10.036

Accepted Manuscript
Transition metal-free protodecarboxylation of electron rich aromatic acids under
mild conditions
Jingxian Fang, Dangui Wang, Guo-Jun Deng, Hang Gong
PII:
S0040-4039(17)31316-3
https://doi.org/10.1016/j.tetlet.2017.10.036
TETL 49398
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
11 August 2017
12 October 2017
14 October 2017
Please cite this article as: Fang, J., Wang, D., Deng, G-J., Gong, H., Transition metal-free protodecarboxylation of
electron rich aromatic acids under mild conditions, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.10.036
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Transition metal-free protodecarboxylation
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Jingxian Fang, Dangui Wang, Guo-Jun Deng, and Hang Gong*

1
Tetrahedron Letters
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Transition metal-free protodecarboxylation of electron rich aromatic acids under mild
conditions
Jingxian Fang+, Dangui Wang+, Guo-Jun Deng, and Hang Gong*
The Key Laboratory of Environmentally Friendly Chemistry and Application of the Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan
411105, China. E-mail: hgong@xtu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
A mild and practical method for the transition metal-free protodecarboxylation of aromatic acids
using readily available and safe sodium persulfate as initiator was described. This environment-
friendly decarboxylation approach was performed at 60 °C in ethanol and could easily scale up
to the gram level with a good yield. In Particular, the tandem reactions of decarboxylation and
halogenation were achieved by the addition of the corresponding halogenating reagents to the
reaction system.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Decarboxylation
Metal-free
Aromatic acid
Halogenation
1. Introduction
Scheme 1. Decarboxylative coupling/addition reactions.
Inexpensive and readily available carboxylic acids often act as
effective, green coupling partners to replace expensive and hard-
to-preserve organometallic reagents in C-C bond formation
reactions.1 In such reactions, aromatic synthons are formed after
decarboxylation and subsequently coupled with various coupling
partners.2 The decarboxylation of aromatic acids also plays a key
role in oxidative coupling reactions, such as Heck–type
reactions,3 C-H direct arylation,4 C-S formation,5 amination,6
allylation,7 conjugate addition,8 and other reactions.9
However, these decarboxylation reactions currently suffer
from the required harsh conditions because of the formation of
unstable intermediates. Metal-catalyzed/promoted reactions at
high temperature are the most common methods of aromatic acid
protocarboxylation (Scheme 2, A).10 Various transition metals,
such as Cu, Ag, and Au, are applied in these strategies, and a
reaction temperature exceeding 120 °C10a–d or even 160 °C10e-i is
required. These transformations are also achieved under
relatively mild reaction conditions in the presence of transition
Scheme 2. Methods for the protodecarboxylation of aromatic acids
and our strategy.
metals, such as Pd,11a,b Rh,11c Ag,11d,e Cu,11f Ir11g and Hg,11h,i
which can reduce the reaction temperature to 70 °C–120 °C
(Scheme 2, B). In particular, Hg-mediated decarboxylation can
be achieved under room temperature, but the requirement of
stoichiometric amounts of highly toxic mercury salts is extremely
harmful.11g,h Additionally, an increasing concern remains in
pharmaceuticals and materials because of the difficulty of
completely removing metal catalysts.12 The metal-free procedure
for this transformation is particularly advantageous (Scheme 2,
C). In 2016, Miyake reported the DBU-catalyzed
protodecarboxylation of aromatic acids, in which a high reaction
temperature reaching 190 °C–200 °C is required.13a Strong acids,
such as CF3CO2H, and Nafion-H, reportedly promote
protodecarboxylation, and the reaction requires a reaction

2
Tetrahedron Letters
Table 1. Selected optimization results.a
Table 2. Decarboxylative of benzoic acid derivatives.a
R
R
1equiv. Na2S2O8
C2H5OH, 60 oC, Air, 18h
CO2H
H
1
2
OEt
OnBu
OiPr
OMe
Entry
1
Solevent (mL)
CH3CN
H2O
T (oC)
60
60
60
60
60
60
60
60
60
60
60
50
70
60
60
Yield(%)
BuO
n
OnBu
PriO
OiPr
MeO
OMe
EtO
OEt
H
2a
85%
H
2d
86%
H
2c
80%
H
18
41
7
2b
87%
OEt
2
OMe
OMe
OBn
H
H
H
H
3
EtOAc
DCM
4
90
88
34
92
43
85
90
7
MeO
MeO
OMe
EtO
OMe
MeO
MeO
OMe
BnO
MeO
OMe
2e
73%
OMe
2f
70%
OiPr
2g
80%
2h
78%
5
toluene
acetone
EtOH
OCOCH3
6
7
OMe
OMe
MeO
OiPr
OMe
8b
9c
EtOH/H2O
EtOH
H
2j
82%
H
2k
30%
H
2i
85%
H
2l
0%
a Unless otherwise noted, all reactions were conducted on a 0.1 mmol scale
with Na2S2O8 (1 equiv.) in a sealed tube in C2H5OH (1 mL) under an
atmosphere of air for 18 h. The green star marked position is the original
location of carboxyl. The isolated yield were presented.
10d
11e
12
13
14f
15g
EtOH
EtOH
EtOH
7
amount of sodium persulfate. In particular, this transformation
could not be conducted in the absence of sodium persulfate (entry
11). Afterward, the reaction temperature was checked (entries 7,
12, and 13). The reaction was found to be sensitive to
temperature; a markedly low yield was obtained when the
reaction temperature was reduced or increased (entries 12 and
13). The reaction was finished within 18 h (entries 14 and 15).
EtOH
70
88
92(85)
EtOH
EtOH
a Unless otherwise noted, all reactions were conducted on a 0.1 mmol scale
with 1 equiv. Na2S2O8 in a sealed tube in 1 mL solvent under air at 60 oC for
24 h. Yields are detected by 1H NMR using CH3NO2 as internal standard.
b
c
EtOH:H2O = 1:1 (v:v). 0.5 equiv. Na2S2O8 is used. 1.5 equiv. Na2S2O8 is
d
e
used. Without Na2S2O8. f Reaction time is 12h. g Reaction time is 18h. The
isolated yield was given in brackets.
With the reliable protodecarboxylation of aromatic acids in
hand [sodium persulfate (1.0 equiv.) at 60 °C in ethanol (1 mL)
under air for 18 h], the substrate scope was then explored (Table
2). The reaction proceeded well when trimethoxy-substituted
aromatic acids were used as substrates. The desired products
were obtained at good to excellent yields (2a–j). However, this
transformation was highly dependent on the electronic degree of
the substrate. Even when a single methoxy group was changed to
acetoxy group, the yield sharply decreased to 30% (2k). With
2,6-dimethoxybenzoic acid as substrate, no corresponding
product could be found (2l). The results of other less electron-
rich aromatic acids are also given in Table S1. None of the
aromatic acids could achieve protodecarboxylation.
temperature of 162 °C and 100 °C, respectively.13b,c Moreover,
the corrosiveness of strong acid should not be ignored.
Interestingly, the enzyme-catalyzed decarboxylation of aromatic
acids was also reported by Nag.13d,e They conducted the reactions
in the juice of cucumber and fruits at room temperature
respectively, and several phenolic acids were converted to the
corresponding phenolic compounds. However, the substrate
limitation was significant, and only three to four phenolic acids
were achieved.
With this background, the development of metal-free
protodecarboxylation of aromatic acids under safe,
environmentally friendly, and mild conditions continues to attract
attention. In this paper, a persulfate-induced strategy for the
metal-free protodecarboxylation of aromatic acids in ethanol
under mild reaction conditions is described (Scheme 2, D).
This reaction could be easily scaled up to the half-gram level
using 1a (0.5 g, 2.36 mmol) as substrate, and Na2S2O8 (0.56 g,
1.0 equiv.) in ethanol (24 mL) was stirred in a sealed tube in air
atmosphere at 60 °C for 5 days. A good yield of 68% was
achieved (Scheme 3).
2. Results and discussion
The direct C-H trifluoromethylation of arene in water–
acetonitrile was recently reported by our group.14 When 2,4,6-
trimethoxybenzoic acid was used as substrate, no trifluoromethyl
group-substituted benzoic acid was detected, but the
protodecarboxylation product was found at excellent yield (GC
yield = 99%). Encouraged by this result, we immediately
investigated the protodecarboxylation of aromatic acid.
Scheme 3. Half-gram protodecarboxylation reaction of 1a.
This reaction was assumed to be a radical process. The radical
inhibition experiment was conducted. As shown in Scheme 4, the
First, various solvents were screened using 2,4,6-
trimethoxybenzoic acid as substrate and sodium persulfate (1.0
equiv) as initiator at 60 °C in an air atmosphere (Table 1, entries
1–8). Excellent yield was achieved when dichloromethane,
toluene, or ethanol was used as solvent (entries 4, 5, and 7).
Considering the environmental impact and price, ethanol was
selected as solvent in this conversion. The amount of sodium
persulfate was studied (entries 7, 9–11). A high yield of 85% still
could be obtained when 0.5 equiv. of sodium persulfate was
used. The result did not improve with further increase in the
reaction was almost terminated by adding
1 equiv. of
benzoquinone into the reaction system, and the yield of the
protodecarboxylation product sharply decreased to 24%. Based
on these results, this transformation proceeded via a radical
Scheme 4. Radical inhibition experiments.

3
Provincial Education Department (No. 15B232) and Hunan
2011 Collaborative Innovation Center of Chemical Engineering
& Technology with Environmental Benignity and Effective
Resource Utilization for their support of our research.
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5
Highlights
1. Scalable
2. ethanol as solvent
3. mild reaction conditions (60 oC)
4. transition metal-free, ligand-free

6
Tetrahedron
A mild, practical method for the catalyst-free
protodecarboxylation of aromatic acids by using
Na2S2O8 as initiator in ethanol was described.