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Cycloaddition versus amidation in reactions of 2-amino-2-oxoethyl-phenanthrolinium ylides to activated alkynes and alkenes

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C. R. Chimie 21 (2018) 27e31Contents lists avaiComptes Rendus Chimie
www.sciencedirect.comFull paper/MemoireDirect carboxylation of aromatic compounds using the
sodium hydrogen carbonate/triphenylphosphine ditriflate
system
Mohammad M. Khodaei*, Abdolhamid Alizadeh**, Hadis A. Hezarkhani
Department of Organic Chemistry, Razi University, Kermanshah 67149-67346, Irana r t i c l e i n f o
Article history:
Received 11 August 2017
Accepted 30 October 2017
Available online 6 December 2017
Keywords:
Triphenylphosphine ditriflate
Carboxylic acids
Arenes
Sodium hydrogen carbonate
Electrophilic substitution* Corresponding author.
** Corresponding author.
E-mail address: mmkhoda@razi.ac.ir (M.M. Khod
https://doi.org/10.1016/j.crci.2017.10.008
1631-0748/© 2017 Académie des sciences. Publishea b s t r a c t
A new procedure was developed for the highly regioselective synthesis of aromatic car-
boxylic acids using the sodium hydrogen carbonate/triphenylphosphine ditriflate system
in ethanol at room temperature. This metal-free system was used for the carboxylation of
thiophenol with unexpected products in terms of selectivity. The simplicity of the pro-
cedure, readily available aromatic compounds, short reaction times, and mild reaction
conditions are other advantages of this protocol.
© 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.1. Introduction
Breaking and functionalization of a CeH bond leading to
a new CeC bond formation is a challenging area in organic
chemistry [1]. Traditionally, the carbonecarbon bond for-
mation in preparation of aromatic carboxylic acids involves
treatment of strongly organometallic compounds such as
aryl palladium or aryl magnesium reagent [2] with CO [3] or
CO2 [4]. The use of other substrates such as aryl halides has
been reported in carboxylation reactions [5]. Arenes have
also been used to produce aromatic carboxylic acids via
direct carboxylation of the CeH bond. Carboxylation of
arenes with formic acid was developed [6]. It was reported
thatN-heterocyclic carbenemetal complexes can efficiently
catalyze carboxylation of heteroaromatic compounds [7].
Carboxylationof benzoxazole andbenzothiazolederivatives
with CO2 by heterocyclic copper complexes was reported
[8]. Consequently, the introduction of a simple and efficientaei).
d by Elsevier Masson SAS. Amethod without using transition metal and gaseous carbon
dioxide or carbon monoxide is desirable, especially using
reagents, which are more favorable to handle.
Trifluoromethanesulfonic anhydride, Tf2O, is a good
reagent for the conversion of an OH group into an OTf
leaving group [9]. Triphenylphosphine ditriflate (TPPD) was
prepared exothermically as a white precipitate from the
reaction of Tf2O with Ph3PO in CH2Cl2 [10]. This salt was
presented as a powerful dehydrating agent and promoter
(Scheme 1) [11].
As part of our ongoing efforts to develop electrophilic
aromatic substitution [12], we have examined direct
carboxylation of arenes using sodium hydrogen carbonate
as a carboxylating agent, TPPD as a promoter, and ethanol
as a solvent at room temperature under transition metal-
free conditions (Scheme 2).
2. Experimental section
2.1. General information
All the chemicals were obtained from Merck, and used
as received. All products are known and characterized by all rights reserved.
Scheme 1. Synthesis of TPPD.
Scheme 2. Synthesis of carboxylic acids.
M.M. Khodaei et al. / C. R. Chimie 21 (2018) 27e3128comparison of their spectra (1H NMR, 13C NMR) with those
reported in the literature. All yields refer to the isolated
products. NMR spectra were recorded on a Bruker Avance
spectrophotometer (400 MHz) in CDCl3 and used as an
internal standard.Table 1
Effect of the solvent on the carboxylation reaction of arenes.a
Entry Solvent Time (min) Yield (%)b
1 H2Oeethanol (1:1) 120 37
2 H2Oeethanol (1:2) 95 67
3 H2Oeethanol (2:1) 120 30
4 Ethanol 60 89
5 H2O 120 0
6 CH2Cl2 120 0
7 MeCN 120 0
8 CHCl3 120 0
9 n-hexane 120 0
a Mesitylene (1 mmol), sodium hydrogen carbonate (1 mmol), and
TPPD (1.2 mmol) in EtOH at room temperature.
b Isolated yield.2.2. General procedure for the carboxylation of arenes
The fresh obtained TPPD (0.672 g, 1.2 mmol) was dis-
solved in 3 mL of ethanol, and then sodium hydrogen car-
bonate (0.084 g, 1 mmol) was added into the solution. The
resulting mixture was stirred for 30 min at room temper-
ature. Then, mesitylene (0.14 mL, 1 mmol) was added into
the solution and the stirring continued for 60 min at room
temperature. The reaction completion was monitored by
thin layer chromatography. After the completion of reac-
tion, the solvent was removed under reduced pressure, and
the saturated sodium bicarbonate solution (10 mL) was
added to the medium. The product was extracted with
chloroform (3  5 mL) and the organic layer washed with
water and dried over anhydrous MgSO4. The filtrate was
evaporated and the crude product was purified by silica gel
column chromatography using ethyl acetate/n-hexane
(3:7) as eluent to afford 2,4,6-trimethylbenzoic acid
(0.131 g, 89%).
3. Results and discussion
The initial study was directed toward exploring the re-
action conditions for the carboxylation of mesitylene using
NaHCO3/TPPD system. We first tested the suitability of
several different solvents for the carboxylation of mesity-
lene with NaHCO3 promoted by TPPD. It was observed that
the nature of the solvent has a considerable effect on the
reaction rate and the yield of product, and EtOH was found
to be the most effective solvent (Table 1, entry 4). Other
solvents including H2O-EtOH (1:1), H2O-EtOH (1:2), H2O-
EtOH (2:1), CH2Cl2, CH3CN, and CHCl3 were substantiallyless effective. Water was not effective at all due to the low
solubility of arenes at the reaction temperature. To study
the effect of the amount of TPPD, different amounts of the
promoter (0.5, 1.0, 1.2, 1.4, and 2.0 mmol) were chosen. The
results show that 1.2 mmol of the promoter per millimoles
of mesitylene afforded the best results. An increase in the
amount of TPPD to 2 mmol shows no significant difference
with respect to the yield. The reaction was not complete
when less than 1.2 mmol of the promoter was used. An
increase in the temperature from room temperature to
reflux condition indicates that the yield was almost unaf-
fected. As a result, the optimized reaction conditions are
TPPD (1.2 equiv) in EtOH at room temperature. The pres-
ence of the promoter is essential to the reaction, because no
reaction occurs in the absence of it.
To examine the generality of this procedure, we inves-
tigated the reactions using a wide range of arenes as sub-
strates under the present reaction conditions. The results
are summarized in Table 2. The carboxylation reaction can
be carried out with aromatic compounds without consid-
eration of the type of substituent. Aromatic compounds
with both electron releasing and electron withdrawing
groups afforded the corresponding products in moderate to
Table 2
Synthesis of aromatic carboxylic acids from sodium hydrogen carbonate
using TPPD.
Entry ArH Product Time (min) Yield (%)a
1 CH3 CH3
HOOC
90 65
2 Cl Cl
HOOC
95 60
3 Br Br
HOOC
90 60
4 OH OH
HOOC
70 65
5 OCH3 OCH3
HOOC
70 60
6 F F
HOOC
120 40
7 SH
SH
COOH 70b 67
8 NO2 NO2
COOH
120 25
9
N N
COOH 120 38
10 CH3
CH3
CH3
COOH
CH3
70 67
11 Cl
Cl
Cl
COOHCl
95 57
12 CH3
CH3
CH3
COOHH3C
65 75
13
CH3
CH3 CH3
H3C
COOH
65 70
14 CH3
CH3H33C CH3H3C
CH3
COOH
60 89
15 NO2
NO2 NO2
O2N COOH 120 20
16 COOH 90 53
a Isolated yield.
b Trace amount of p-isomer.
M.M. Khodaei et al. / C. R. Chimie 21 (2018) 27e31 29good yields. Of course, the arenes with electron donating
groups reacted faster than those with electron acceptor
groups and afforded better yields. Naphthalene was con-
verted to 1-naphthoic acid with high regioselectivity in 53%
yield (Table 2, entry 16). The carboxylation of nitrobenzene
with electron acceptor group occurred in 25% yield (Table 2,
entry 8).m-Dinitrobenzene and dichlorobenzene were also
reacted and produced the corresponding carboxylic acids in20% and 57% yields, respectively (Table 2, entries 11 and 15).
Notably, not only carboxylation of nitrobenzene with
strong electron withdrawing group occurred, but also m-
dinitrobenzene can be carboxylated.
Of course, the yields of their products were low due to
their strong electron withdrawing groups and incom-
pletion of the reaction. Carboxylation of pyridine occurred
and pyridine-3-carboxylic acid was obtained in 38% yield
(Table 2, entry 9).
The carboxylation reactions of toluene, chlorobenzene,
bromobenzene, anisole, and fluorobenzene were carried
out with high regioselectivity and afforded their corre-
sponding products in 65%, 60%, 60%, 60%, and 40% yields,
respectively (Table 2, entries 1, 2, 3, 5, and 6). The excellent
regioselectivity of these reactions under the present reac-
tion conditions is considerable. It seems that steric effect
has an important role in the reactions. The high selectivity
of these reactions might be because of the presence of the
highly hindered carboxylating reagent, which does not
permit ortho position to carboxylate.
Interestingly, thiophenol was reacted under the reaction
conditions and 2-sulfanylbenzoic acid was obtained as the
productwithhigh regioselectivity,whereasphenol afforded
p-hydroxybenzoic acid. The result of thiophenol carboxyl-
ation reaction is unexpected. It was reported that electro-
philic reagents generally attack the sulfur atom of
thiophenol and ring substitution is rarelyoccurred [13]. This
selectivity might be due to an intramolecular rearrange-
ment similar to the Fries rearrangement [14]. It was re-
ported that Fries rearrangements of formyl groups can also
be induced by trifluoromethanesulfonic acid [15]. In addi-
tion, triphenylphosphine oxide released during the reaction
may act as a Lewis acid for the Fries rearrangement.
The intermediate 2 was isolated and identified by NMR.
The peaks of protons at 1.2 and 3.9 ppm observed as a
triplet and quartet in the 1H NMR spectrum ascribed to CH3
and CH2 of the ethyl group. The peaks at 7.2e8.6 ppm
related to aromatic CeH bonds. The 13C NMR spectrum of
intermediate 2 shows the presence of an ethyl group by the
peaks of carbons at 21.6 and 55.4 ppm. The carbon atoms of
aromatic rings can be confirmed by the peaks at 116e
147 ppm. These data indicate that the intermediate 2 was
produced during the reaction.
Our attempts to isolate the intermediate 3 [(PPh3-OCO-
OH)þ OTf] from the sodium triflate salt were not suc-
cessful. Hence, the FT-IR and NMR spectra of the mixture of
these two salts were taken (see Supplementary Material).
The presence of intermediate 3 during the process of the
carboxylation reaction might be confirmed by the obser-
vation peak at 2500e3010 cm1 related to the stretching
vibrations of the hydroxy group and the broad peak at
1680 cm1 corresponding to the carbonyl group, which are
the characteristic peaks of the carboxyl group. In the 1H
NMR spectrum of the mixture, the peaks of protons of CeH
bonds ascribed to aromatic CeH bonds, and the peak
related to OeH bond of the carboxyl group were observed
at about 7e8 and 13.2 ppm, respectively, and confirmed the
presence of phenyl and carboxyl groups in the intermediate
3. Furthermore, the 13C NMR spectrum indicates the pres-
ence of carboxylating agent 3 by the peaks of carbons of
aromatic rings at 118e138 ppm and a carbonyl group at
Scheme 3. Proposed reaction mechanism for the synthesis of aromatic carboxylic acids.
M.M. Khodaei et al. / C. R. Chimie 21 (2018) 27e3130188 ppm. It seems that the intermediate 3 was formed
during the process of the reaction.
The intermediates 1 and 3 as highly electrophile species
reacted with highly nucleophilic ethanol. The feasibility of
these reactions can be concluded when the reaction of
mesitylene with sodium hydrogen carbonate under the
same reaction conditions in a less polar solvent such as
chloroform, acetonitrile, and dichloromethane and n-hex-
ane as a nonpolar solvent did not proceed. These results
showed that ethanol has an important role in the carbox-
ylation reaction. TPPD (intermediate 1) reacted with
ethanol and afforded ethoxytriphenylphosphonium tri-
flate, 2. The ethoxy group in compound 2was protonated in
the presence of produced TfOH and became a good leaving
group when it was attacked by sodium hydrogen carbonate
as a nucleophile and the intermediate 3 was obtained.
Ethanol attacked to CO group of the intermediate 3. In this
case, EtO-CO-OH (4), Ph3P¼O, and TfOH were obtained as
products and mesitylene attacked to the carbonyl group of
unstable intermediate 4 in the presence of TfOH to produce
the corresponding carboxylated products. The other pos-
sibility is attack of EtOH to phosphorous of phosphonium
ion in the intermediate 3 to obtain intermediate 2, carbon
dioxide, and water. It seems that this reaction does not
occur because no CO2 bubbling was observed during the
reaction. In addition, we expected to obtain the ethylated
aromatic compound as a product but this arene was not
produced.
As a result of this observation, the following mechanism
indicated in Scheme 3 was proposed for the synthesis ofaromatic carboxylic acids promoted by TPPD. The resulting
reagent was used for successful carboxylation of broad
range of arenes via an ordinary electrophilic aromatic
substitution reaction.
4. Conclusion
We have developed a novel approach for direct
carboxylation of a wide range of aromatic compounds in
moderate to good yields with high regioselectivity using
NaHCO3/TPPD system in EtOH. This metal-free protocol
does not need to use carbon monoxide or carbon dioxide
gases. The unreactive aromatic compounds such as m-
dinitrobenzene can also be carboxylated under the reaction
conditions. The o-carboxylation of thiophenol was unex-
pected due to its regioselectivity. Readily available aromatic
compounds, toleration of various functional groups, short
reaction times, and performance at room temperature are
other advantages of this method [16].Acknowledgments
The authors thank the Razi University for providing the
generous financial support to this work.
Appendix A. Supplementary data
Supplementary data related to this article can be found
at https://doi.org/10.1016/j.crci.2017.10.008.
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