A simple synthesis of ketone from carboxylic acid using tosyl chloride as an activator

Article abstract of DOI:10.1016/j.tetlet.2019.151084

An effective process for the conversion of carboxylic acid to ketone has been discovered. In this process, carboxylic acid has been activated using p-toluene sulphonyl group. Under the optimized condition, aromatic, aliphatic heteroaromatic carboxylic acids have been proved to be good substrates for this methodology. The byproduct of this reaction can be removed very easily during work up process. Also, one equivalent of organometallic reagent is sufficient to complete this transformation.

Full text of DOI:10.1016/j.tetlet.2019.151084

Tetrahedron Letters xxx (xxxx) xxx
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A simple synthesis of ketone from carboxylic acid using tosyl chloride as
an activator
⇑
Debasis Sahoo, Sohini Sarkar, Samaresh Jana
Department of Chemistry, School of Applied Sciences, Kalinga Institute of Industrial Technology (KIIT)-Deemed to be University, Bhubaneswar 751024, Odisha, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective process for the conversion of carboxylic acid to ketone has been discovered. In this process,
carboxylic acid has been activated using p-toluene sulphonyl group. Under the optimized condition, aro-
matic, aliphatic heteroaromatic carboxylic acids have been proved to be good substrates for this method-
ology. The byproduct of this reaction can be removed very easily during work up process. Also, one
equivalent of organometallic reagent is sufficient to complete this transformation.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 8 June 2019
Revised 23 August 2019
Accepted 26 August 2019
Available online xxxx
Keywords:
Carboxylic acid
Ketone
Tosyl chloride
Organometallic reagent
Being a ubiquitous moiety, carbonyl group particularly ketone
has been considered as one of the most important functionalities
in organic chemistry [1]. Therefore, accessibility of ketone based
on a simple chemical reaction is still demanding. Till now, efforts
have been made to access ketone from different starting materials
such as alcohol, aldehyde, amide etc [2]. One notable method
which has been studied extensively, involves the conversion of car-
boxylic acid to ketone [3]. Easy accessibility and stable nature of
the carboxylic acid have attracted the curiosity of organic chemists
for this purpose. Generally, acids are transformed to the desired
ketones by using a suitable organometallic reagent via Wenreib
amide intermediate [4]. Other metal catalyzed processes are also
well known for this conversion [5].
To overcome the drawbacks associated with some metal cat-
alyzed reactions, recently we have reported a convenient way for
the conversion of carboxylic acid to ketone in a one pot fashion
using DCC as a carboxylic acid activator [6]. In that methodology,
a problem related to byproduct separation made the process less
viable in organic synthesis (Scheme 1). Therefore, attention was
paid on searching for an activating agent which after reaction,
can be separated easily from the product. Consequently, our efforts
for this transformation have been discussed herein.
intermediate A (Fig. 1) in mind, we anticipated to generate a sim-
ilar type intermediate such as B (Fig. 1) which might fulfill our pur-
pose. The intermediate B could be obtained during the reaction
between organometallic compound (R0-M, Scheme 1) and mixed
anhydride 4 (Scheme 1) at low temperature.
With this intention, p-toluenesulfonyl chloride (tosyl chloride,
TsCl) has been selected for this task. Sulphonyl chlorides are fre-
quently used for various transformations in synthetic chemistry
as for example, protection of alcohol and amine, synthesis of
amide, ester from carboxylic acid etc. [7]. To explore the versatility
of this reagent in organic synthesis, we thought to utilize in the
conversion of carboxylic acid to ketone, which was unexplored till
date [8]. We envisioned that as tosyl protected alcohol 8 can be
easily converted to the product 10, if treated with a carbon or het-
eroatom based nucleophile [9], therefore tosyl protected acid 9
could be converted to the ketone 11 in a more facile manner based
on a similar type of reaction (Scheme 2).
This difference in reactivity, between 8 and 9 can be rational-
ized based on the electrophilic character of the carbon which is
attached with the O-protected tosyl group (Scheme 2). To ensure
these assumptions, we started the investigation using benzoic acid
as initial substrate.
So far, Wenreib amide concept has been widely accepted among
synthetic community for the conversion of carboxylic acid to
ketone. In this aspect, intermediate A (Fig. 1) plays a crucial role
to produce ketone at low temperature. Keeping the image of the
Thus, a reaction was carried out using commercially available
benzoic acid (1a, Table 1, 0.5 mmol) and TsCl (0.5 mmol) in pres-
ence of 4-(dimethylamino)pyridine (DMAP, 0.5 mmol) in THF
(2.5 mL) at room temperature under N2 atmosphere. After 1 h, a
new compound formation has been observed (monitored by TLC)
along with the formation of pyridinium salt. Into it, n-BuLi
(1 mmol, 1.6 M in hexanes) was added dropwise at low
⇑
Corresponding author.
E-mail address: samareshfch@kiit.ac.in (S. Jana).
https://doi.org/10.1016/j.tetlet.2019.151084
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: D. Sahoo, S. Sarkar and S. Jana, A simple synthesis of ketone from carboxylic acid using tosyl chloride as an activator, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.151084

2
D. Sahoo et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Substrate scope of ketone synthesis using TsCl: Reactions were carried out in
0.5–1 mmol scale under N2 atmosphere; Yields refer to the isolated yield; aFor this
n-BuLi was used, bFor this MeMgBr was used.
Entry
1
Substrate
Product
Yield (%)
75a
Scheme 1. Ketone synthesis: A comparative study.
2
3
71a
63a
4
60a
Fig. 1. Intermediate formed during the interaction of Wenreib amide and
organometallic reagent.
5
6
56a
55a
7
8
58a
80b
9
75b
70b
10
Scheme 2. Activation of carboxylic acid using tosyl chloride.
temperature (-20 °C) and satisfyingly the desired ketone 5a was
obtained which was confirmed by using 1H NMR spectroscopy.
Based on this preliminary result, we concentrated to optimize
the reaction conditions on benzoic acid in presence of n-BuLi. A
few reactions were performed to get the best yield of the desired
ketone 5a in THF solvent. After varying the reaction conditions,
best yield of 5a was obtained when one equivalent of TsCl was
added to the equimolar amount of carboxylic acid in THF at room
temperature for 2 h, followed by slow addition of n-BuLi (2 equiv-
alents) at ꢀ20 °C. Further, we determined to reduce the amount of
organometallic reagent during the reaction. After careful thinking
about the reaction mechanism, a process has been developed,
where the pyridinium salt (12, Scheme 3) has been filtered from
the medium before adding the nucleophile. Thus we optimized
the reaction conditions [10] with one equivalent of organometallic
reagent and various aliphatic, aromatic and heteroaromatic car-
boxylic acids were converted to the corresponding ketones in good
yields under this condition. Aromatic carboxylic acids containing
electron poor as well as electron rich ring systems found as excel-
lent substrates. Pleasingly, chloro functionality (Entry 2, Table 1),
ether group (Entry 3 Table 1) are stable enough under optimum
conditions. Moreover, heteroaromatic acids (Entry 4 and 5, Table 1)
yielded the desired ketones in reasonable amounts. Experiment
with aliphatic acids (Entry 6 and 7, Table 1) was satisfactory to pro-
duce the desired ketone. Next, to explore the potentiality of this
11
78b
Scheme 3. A proposed mechanistic pathway.
methodology, we decided to perform the reaction using organo-
magnesium reagent. Few reactions have been performed using
methyl magnesium bromide as a nucleophile (Entry 8, 9, 10 and
11, Table 1). Gratifyingly, acteophenone and 4-chloroacetophenone
Please cite this article as: D. Sahoo, S. Sarkar and S. Jana, A simple synthesis of ketone from carboxylic acid using tosyl chloride as an activator, Tetrahedron
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D. Sahoo et al. / Tetrahedron Letters xxx (xxxx) xxx
3
were isolated in excellent amount from the reaction mixture under
References
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A probable mechanism of the reaction has been shown in
Scheme 3. Carboxylic acid 1 in presence of a base reacts with tosyl
chloride at room temperature, to form a mixed anhydride 4, [8,11]
which can be separated through simple filtration technique under
inert condition. Then slow addition of nucleophile at ꢀ20 °C into 4
leads to the formation of an intermediate C (Scheme 3). This inter-
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along with p-toluene sulphonic acid 6. During the work up process,
ketone 5 could be accessed easily, as the by-product 6 can be
removed by washing with bicarbonate solution and water.
In conclusion, a simple and effective method for the synthesis of
ketone from carboxylic acid has been developed. In this process,
aromatic, aliphatic and heteroaromatic carboxylic acids were
reacted with tosyl chloride in the presence of DMAP, which upon
addition of an organometallic compound provided the desired
ketones in exclusive manner. The key advantage of this process
is: the ketone has been accessed from acid using one equivalent
of organometallic reagent. Also the byproduct of this reaction can
be removed easily during the work-up process. Detail studies on
this transformation using soft nucleophiles and using aliphatic
acids are under investigation in our laboratory and will be
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[10] Experimental procedure: To a stirred solution of carboxylic acid 1 (1 mmol)
and TsCl (1 mmol) in THF (5 mL), DMAP (1 mmol) was added at room
temperature under N2 atmosphere. After 2h (to ensure the complete
conversion, checked by TLC), the mixture was filtered under N2 atmosphere
and the filtrate was cooled to ꢀ20 °C. Then, R-M (1 mmol) was added dropwise
to the reaction mixture at that temperature. After 15 min. the reaction was
quenched with saturated aqueous NH4Cl solution (5 mL) at ꢀ20 °C. The
mixture was warmed to room temperature and extracted with diethyl ether
(50 mL ꢁ 3). The combined organic layers were washed with 10% NaHCO3
solution (20 mL ꢁ 3), water (20 mL ꢁ 3), brine (20 mL) and finally dried over
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mass which was then purified by column chromatography on silica gel to
obtain pure ketone 5.
Acknowledgments
Financial support of DST-SERB (Ref. No. SB/FT/CS-049/2013) is
acknowledged. The authors thank KIIT, Deemed to be University
for providing the basic research facility. We acknowledge the sup-
port of Mr. H. G. Mekonnen for running few experiments.
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Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151084.
Please cite this article as: D. Sahoo, S. Sarkar and S. Jana, A simple synthesis of ketone from carboxylic acid using tosyl chloride as an activator, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.151084