Oxidative decarboxylation of arylacetic acids in water: One-pot transition-metal-free synthesis of aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2017.06.013

One-pot transition-metal-free synthesis of aromatic aldehydes and ketones via oxidative decarboxylation of arylacetic acids in water is developed. Protocol relies on the direct decarboxylation of sp³-hybridized carbon in water without any over oxidation into carboxylic acids with minimal waste. Reaction mechanism is investigated and application of this protocol is demonstrated on a gram scale.

Full text of DOI:10.1016/j.tetlet.2017.06.013

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative decarboxylation of arylacetic acids in water: One-pot
transition-metal-free synthesis of aldehydes and ketones
⇑
Trimbak B. Mete, Tushar M. Khopade, Ramakrishna G. Bhat
Department of Chemistry, Indian Institute of Science Education & Research (IISER), Pune 411008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot transition-metal-free synthesis of aromatic aldehydes and ketones via oxidative decarboxylation
of arylacetic acids in water is developed. Protocol relies on the direct decarboxylation of sp -hybridized
carbon in water without any over oxidation into carboxylic acids with minimal waste. Reaction mecha-
Received 13 May 2017
Accepted 4 June 2017
Available online xxxx
3
nism is investigated and application of this protocol is demonstrated on a gram scale
.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Transition-metal-free
Water
Persulfate
One-pot synthesis
Decarboxylation
Introduction
carbon-heteroatom bonds starting from carboxylic acids and by
cleaving the CAC bond to carboxylate group. Also, decarboxyla-
9
Aldehydes and ketones are very important class of compounds
and they have been used extensively in wide areas of chemical syn-
thesis. Evidently, the effort towards the quick and short synthesis
tion reaction procedures are usually done at neutral reaction con-
ditions and importantly carbon dioxide liberated as a sole non-
toxic by-product. Transition metal catalyzed decarboxylation at
1
2
-
of aldehydes and ketones always has been desirable. Traditional
synthesis of aldehydes and ketones rely on activating the car-
sp hybridized carbon is mostly explored in the literature and
3
-
more strikingly, decarboxylation at sp hybridized carbon to intro-
2
3
10
boxylic acid into a Weinreb amide or into an acyl halide with
subsequent nucleophilic attack with hydrides or organometallic
species. One-step synthesis of ketones starting from carboxylic
acids can be achieved using excess of organolithium reagents;
duce a functional group is relatively rare and challenging. Transi-
tion metal catalyzed synthesis of aldehydes, ketones and amides
via oxidative decarboxylation has been explored very recently.1
Reactivity of cuprous salt was explored for the novel synthesis of
1,12
4
13
however formation of tertiary alcohols is unavoidable. These
aldehydes from methyl ketones in presence of oxygen. Recently,
harsh conditions can lead to the erosion of stereochemical purity
thus leading to partial racemization.5 Nevertheless, efforts have
been made to improvise the existing methods. Cyanocuprates have
been explored to convert the carboxylic acids directly into
Song and co-workers demonstrated the ability of cupric salts for
3-
the aerobic oxidative decarboxylation at sp hybridized carbon to
1
1
12
afford aldehydes, ketones and amides at high temperatures.
Decarboxylative non-aerobic oxidation of phenyl acetic acid to
benzaldehyde was described by using cupric salts at high temper-
ature and pressure thus mimicking the geochemically relevant
6
ketones. Quick and efficient cleavage of carbon-carbon bond is
7
one of the most important challenges in organic synthesis. The
1
4
selective cleavage of CAC
r
bond has greatly attracted the atten-
conditions. All of these protocols rely on transition metal, viz.
1
5
tion of researchers in the recent times due to its inert nature.
Undoubtedly, development of an efficient protocol for the selective
copper for catalyzing the transformation. However, there are
only countable protocols for the oxidative decarboxylation of aryl
carboxylic acids under transition-metal-free conditions. Earlier,
decarboxylation of carboxylic acids to aldehydes and ketones were
achieved by using tetrabutylammonium periodate in 1,4-dioxane
under refluxing condition, combination of iron(III)/manganese(III)
tetraphenylprorphyrins and tetrabutylammonium periodate, and
cleavage of CAC
r bond is a great challenge and still much to be
explored. Transition metal catalyzed decarboxylation via CAC
bond cleavage has been gaining a great importance due its signif-
8
icant role in decaboxylative reactions. Elegant and valuable proto-
cols are developed in this area for making carbon-carbon and
1
6,17
(
diacetoxyiodo)benzene/NaN
3
.
Thus development of more
easier, practical and non-hazardous protocol for the synthesis of
aldehydes and ketones via oxidative decarboxylation under
⇑
Corresponding author.
E-mail address: rgb@iiserpune.ac.in (R.G. Bhat).
http://dx.doi.org/10.1016/j.tetlet.2017.06.013
040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
T.B. Mete et al. / Tetrahedron Letters xxx (2017) xxx–xxx
transition-metal-free conditions is highly desirable. There are
ambiguities in defining a true ‘green method’. However, some of
the most accepted guiding principles such as minimal waste,
higher mass productivity lower E-factor, non-toxicity etc define
the greener methods. Practical, efficient and highly selective tran-
sition-metal-free transformations using environmentally benign,
less expensive and readily available reagents are gaining a great
importance for the last few years.1 As a part of our ongoing efforts
to develop transition metal free protocols,19 we herein, report an
oxidative decarboxylative strategy for the direct and clean synthe-
sis of aldehydes and ketones without over oxidation into car-
boxylic acids in water with a minimal waste and lower E-factor.
This simple protocol uses potassium persulfate as a reagent and
makes the novel use of it for the synthesis of aldehydes and
ketones starting from arylacetic acids.
incomplete conversion of the starting material (entry 13). Reac-
tions under oxygen or open air atmosphere did not change the
course of the reaction and also did not have any significant effect
on yield or reaction time (entries 9, 14). Reaction did not work in
the absence of potassium persulfate (entry 15). After extensive
screening of solvents and temperature optimum reaction condition
2 2 8
was emerged as 4-methylphenyl acetic acid 1a (1 equiv.), K S O
8
(2 equiv.) at 90 °C in water under aerial atmosphere (entry 9,
Table 1) in 12 h. It is also important to note that persulfates are
very popular for their ability to oxidize variety of contaminants
in ground water via ‘in situ chemical oxidation’ (ISCO).20 Persul-
fates are known to be benign, eco-friendly or green and low cost
2
1
reagent.
Encouraged by the initial success and with an optimized reac-
tion condition in hand; we explored the substrate scope of the
method. Under optimal reaction conditions arylacetic acids (1a–
1o) possessing the electron-donating group as well as electron
withdrawing groups reacted smoothly by affording the corre-
sponding aldehydes (2a–2o) in moderate to good yields
(Scheme 1). 1-Naphthylacetic acid 1p reacted smoothly and gave
the corresponding naphthaldehyde 2p in 80% yield. Similarly, the
heteroaromatic acid such as 2-thienyl acetic acid 1q under reaction
We commenced our initial work with 4-methyl phenylacetic
acid 1a with K
tion of 1a with K
2
S
2
O
8
as a model reaction (Table 1). Attempted reac-
(2 equiv.) in CH CN/H O (1:1) at room tem-
2
S
2
O
8
3
2
perature (both in air and inert condition) did not work even after
prolonged reaction condition (entry 1, Table 1). Interestingly, when
the reaction was carried at elevated temperature (80 °C), to our
delight, the desired product, 4-methylbenzaldehyde 2a was
formed in 75% isolated yield (Table 1, entry 2) in 12 h. With this
result in hand, further the reaction was screened in different sol-
conditions afforded the 2-thienyl carboxylaldehyde (2q). a-Substi-
tuted phenyl acetic acids (1r–1w) under optimal reaction condi-
tions afforded the corresponding ketones (2r–2w) in excellent
yields (86–92%). The anti-inflammatory drug, ibuprofen 1u
vent conditions. However, the reaction was sluggish in CH
and DCE (entries 4, 6) and afforded only trace amount of desired
product 2a. However, the reaction in DCE/H O at 80 °C afforded
3
CN
2
2
2
afforded the corresponding ketone 2u in excellent yield as well.
Interestingly, the amino acid phenyl glycine 1x afforded benzalde-
hyde 2d instead of anticipated amide. Probably, imine might have
formed during the course of reaction, which upon hydrolysis
resulted in 2d. The position of the substituents on the ring had
no significant and noticeable effect on reaction rate and yields.
Functional group such as hydroxyl, chloro, bromo, methoxy and
nitro were well tolerated. However, unfortunately, attempted reac-
the desired product in 60% yield (entry 7). Interestingly, the model
reaction worked efficiently only in water at 80 °C affording the
desired product 4-methyl benzaldehyde 2a in 75% yield (entry 8).
Gratifyingly, with the elevated temperature (90 °C) under aerial
condition reaction afforded the compound 2a in excellent yield
of 85% (entry 9). PIDA, PIFA and Oxone were found to be ineffective
reagents for the desired transformation (entries 10–12). Attempts
to lower the reaction temperature resulted in lower yield with
Table 1
a
Optimization of the reaction conditions.
Entry
Reagent
Solvent
Temp (°C)
Atm
Yieldb (%)
1
2
3
4
5
6
7
8
9
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
S
S
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
8
CH
CH
CH
CH
MeOH
DCE
3
3
3
3
CN/H
CN/H
CN
2
O (1:1)
O (1:1)
rt
80
Reflux
Reflux
Reflux
90
80
80
90
90
90
90
50
90
90
Air
Air
Air
O
2
Air
NR
75
Trace
12
NR
Trace
60
75
85
27
21
2
CN
O
2
DCE/ H
2
O (1:1)
Air
Air
Air
Air
Air
Air
Air
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
c
10
11
12
13
14
15
PIDA
PIFA
Oxone
c
c
15
20
83
–
K
K
–
2
S
S
2
O
O
8
2
2
8
O
2
Air
Bold values correspond to the optimum reaction conditions.
a
Reaction conditions: 4-methylphenyl acetic acid 1a (1 equiv.), potassium persulfate (2 equiv.), solvent (2 mL) under corresponding atmosphere for 12 h.
Isolated yield after purification by column chromatography.
Reactions did not work at rt.
b
c
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T.B. Mete et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Scheme 2. Control experiments for understanding the mechanism.
Scheme 3. Plausible mechanism for the formation of aldehyde and ketones.
experiment indicates that oxygen did not have any role in the reac-
tion mechanism. Interestingly, reaction did not work in the
absence of water. To validate the role of water in the reaction, com-
2 2 8
pound 1r was treated with K S O (2 equiv.) in labeled water
1
8
(
H
2
O, 97%) under inert condition for 12 h. To our delight we iso-
0
lated the corresponding 2r in excellent yield (81%, eq. i, Scheme 2).
Presence of O was confirmed by the HRMS and GC-mass spec-
trometry ( O content 96.3%, see ESI). It is very significant to note
1
8
1
8
1
8
that this protocol gives a direct access to prepare O-labeled alde-
hydes and ketones quantitatively without resorting to an exchange
experiment. Later, to gain further insight into the mechanism,
diphenyl acetic acid 1r was treated with TEMPO (2,2,6,6-tetram-
ethyl-1-piperidinyloxyl) under standard optimal conditions. The
result showed that reaction did not proceed even after prolonged
reaction time indicating that TEMPO inhibited the radical pathway
Scheme 1. Oxidative decarboxylation of arylacetic acids to aldehydes and ketones.
a
Reaction conditions: arylacetic acid 1 (1 equiv.), potassium persulfate (2 equiv.),
b
water (2 mL) open atmosphere; reaction was monitored by TLC. Isolated yield after
purification by column chromatography.
(
eq. ii, Scheme 2).
tions of aliphatic acids such as 3-butenoic acid, tert-butyl acetic
acid and valeric acid did not afford the desired products.
Based on our investigations and previous literature25 we pro-
Åꢀ
pose that sulfate radical anion (SO
tion of potassium persulfate) upon reaction with phenyl acetic acid
1
4
) (produced by the decomposi-
To make the protocol more general and for the wider applicabil-
ity we demonstrated the synthesis of benzaldehyde 2d (83%) and
benzophenone 2r (93%) on a gram scale starting from the corre-
sponding arylacetic acids 1d and 1r respectively under optimum
conditions. During the optimization we observed that reaction
worked efficiently in water under atmosphere of air as well as oxy-
gen. Effective minimization of reagents in this protocol led to a
minimal waste (free from halogen and transition metal), thus pro-
ducing only 3.5 g of waste for every 1 g of the product formed. It is
also gratifying to note that this one pot reaction with E (environ-
Åꢀ
d generates benzyl radical I by extrusion of carbon dioxide. SO
4
further oxidizes the benzyl radical to the corresponding benzyl car-
bocation II via one electron oxidation. This reactive species reacts
with water to form the corresponding benzyl alcohol III. Persulfate
further oxidizes benzyl alcohol to the corresponding intermediates
IV and V. Ultimately, the loss of proton from V would afford the
desired product, benzaldehyde 2d. Alternatively, intermediate IV
would directly afford benzaldehyde 2d by the loss of hydrogen rad-
ical (Scheme 3).
2
3
mental) factor of 3.49 and mass productivity of 23% (mass inten-
2
3
24
sity 4.5) satisfies the defined metrics for the cleaner and
greener chemical processes.
Conclusions
In order to investigate and elucidate the reaction mechanism
few control experiments were carried out. Compound 1a when
In conclusion, we have demonstrated a one-pot protocol for the
direct and clean transformation of arylacetic acids to aldehydes
and ketones in water with minimal waste. Protocol employs envi-
treated with K
2 2 8
S O (2 equiv.) in water under inert conditions
afforded the corresponding aldehyde 2a in good yield (80%). This
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4
T.B. Mete et al. / Tetrahedron Letters xxx (2017) xxx–xxx
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R.G.B. thanks DST-SERB (EMR/2015/000909), Govt. of India for
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