Catalytic conversion of ketones to esters: Via C(O)-C bond cleavage under transition-metal free conditions

Article abstract of DOI:10.1039/d0cc03312j

The catalytic conversion of ketones to esters via C(O)-C bond cleavage under transition-metal free conditions is reported. This catalytic process proceeds under solvent-free conditions and offers an easy operational procedure, broad substrate scope with excellent selectivity, and reaction scalability. This journal is

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DOI: 10.1039/D0CC03312J
Authors:
Murugan Subaramanian,a Palmurukan M. Ramar,a Jagannath Rana,a Virendra Kumar Gupta,*,b and
Ekambaram Balaraman*,a
a
Address: Department of Chemistry, Indian Institute of Science Education and Research (IISER)
Tirupati, Tirupati - 517507, India. E-mail: eb.raman@iisertirupati.ac.in
b
Polymer Synthesis and Catalysis Group, Reliance Re-search and Development Center, Reliance
Industries Lim-ited, Ghansoli, Navi Mumbai-400701, India. E-mail: virendrakumar.gupta@ril.com
Acknowledgements:
This research work was supported by IISER Tirupati, and SERB, India (Grant No:
CRG/2018/002480/OC). MS thanks the UGC for fellowship.

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DOI: 10.1039/D0CC03312J
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Catalytic Conversion of Ketones to Esters via C(O)-C Bond
Cleavage under Transition-Metal free Conditions†
Murugan Subaramanian,a Palmurukan M. Ramar,a Jagannath Rana,a Virendra Kumar Gupta,b* and
Ekambaram Balaramana*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The catalytic conversion of ketones to esters via C(O)-C bond content, KOtBu plays a vital role in numerous organic
cleavage under transition-metal free conditions is reported. This transformations, including various C-C/C-N bond coupling
catalytic process proceeds under solvent-free conditions and reactions, silylation reaction of C-H bonds,9 and various single
offers an easy operational procedure, broad substrate scope with electron transfer (SET) reactions.10 Of late, the research group
excellent selectivity, and reaction scalability.
of Jiang has reported K2CO3 mediated aerobic oxidative
carbon–carbon bond cleavage and esterification of acyclic
α
-
hydroxy ketones.11 Herein, we report a mild and benign
strategy of readily available KOtBu catalyzed direct conversion
of ketone derivatives to esters via C(O)-C bond cleavage
(Scheme 1). This catalytic process proceeds under solvent-free
conditions and offers an easy operational procedure, broad
substrate scope with excellent selectivity, and reaction
scalability.
The carbonyl group is one of the most prevalent functional
groups found in various organic chemical reactions such as
condensation, reduction, addition, cyclization, and α-
functionalization reactions.1 In particular, the direct
transformation of ketones into esters via C(O)-C bond cleavage
has been paid more attention in synthetic organic chemistry
and catalysis; however, its applicability is still limited and rarely
reported.2 This is due to high activation energy is required to
cleave the strong C(O)-C σ-bond. Conventionally, conversion of
ketones to esters by the direct insertion of an oxygen atom
into the C(O)-C σ-bonds using peroxide is known as Baeyer–
Villiger reaction.3
In recent years, activation of unstrained C-C bonds has been
attracted much interest and widely documented using
transition-metal based catalysts.4 Recently, Jiao and co-
workers reported an aerobic oxidation and oxygenation of
ketones transformed to esters under Cu-catalysis.5 An iron-
catalyzed aerobic oxidative C-CN bond cleavage of aryl
acetonitriles to esters via benzoyl cyanide intermediate is also
reported.6 In general, these protocols involve the oxidative
cleavage of carbon-carbon bonds,7 and the requirement of
toxic reagents8 and expensive metal catalysts. That may
Scheme 1. Esterification via C(O)-C bond cleavage.
produce
a large amount of by-product and limits its
applications. Therefore, the development of a transition
metal-free method to achieve carbon–carbon bond cleavage is
still desirable for these synthetic transformations. In this
We
began
our
investigation
using
3-oxo-3-
phenylpropanenitrile (1a) as a model substrate. Thus, in the
presence of KOtBu (1 equiv.) at 140 C in methanol for 12 h, a
o
quantitative conversion of starting material with a selective
formation of product 2a was observed (Table 1, entry 1).
Interestingly, changing the bases from KOtBu to various bases
such as NaOtBu, LiOtBu, K2CO3, Na2CO3, KOH, NaOMe, Cs2CO3,
and KHMDS resulted the product 2a in poor yields (Table 1,
entries 2-9). Notably, reaction temperature plays a significant
role in the present transformation. Thus, decreasing the
aDepartment of Chemistry, Indian Institute of Science Education and Research
(IISER) Tirupati, Tirupati - 517507, India. E-mail: eb.raman@iisertirupati.ac.in
bPolymer Synthesis and Catalysis Group, Reliance Research and Development
Center, Reliance Industries Limited, Ghansoli, Navi Mumbai - 400701, India. E-mail:
virendrakumar.gupta@ril.com
†Electronic Supplementary Information (ESI) available: [Experimental procedures
analytical data]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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o
temperature from 140 C to 120 C offered only 64% of the and offered the corresponding esters in good Vtieow AertxiccleeOllnelinnet
DOI: 10.1039/D0CC03312J
product 2a (Table 1, entry 10), and further lowering the yields (Table 3).
temperature to 100 oC resulted ~15% of 2a (Table 1, entry 11).
Table 2. KOtBu catalyzed conversion of Ketones to Esters: Scope of 3-
In the absence of KOtBu, virtually no ester is formed (Table 1,
oxopropanenitrilea
entry 12). A decrease in the amount of KOtBu (10 mol%) led to
the same reactivity and gave 2a in 88% of isolated yield (Table
1, entries 13-14). The present KOtBu catalyzed direct
conversion of 1a to 2a via C(O)-C bond cleavage gives
acetonitrile as the only by-product (see ESI).
Table 1. Optimization of reaction conditionsa
aReaction conditions: 1 (0.5 mmol), KOtBu (10 mol%), MeOH (1 mL) heated for 12 h at
140 oC (oil-bath temperature) under closed condition and the calculated yields are
isolated yields. bYield determined by 1H NMR using mesitylene as an internal standard.
To our delight, aliphatic alcohols ranging from ethanol to
decanol afforded the corresponding esters in very good yields
(products 3a-3f, 66-84% yields). Notably, aliphatic secondary
aReaction conditions: 1a (0.5 mmol), base (1 equiv.), MeOH (1 mL) heated for 12 h at
140 oC (oil-bath temperature) under closed condition, and the yield was determined by
alcohols such as 2-heptanol and 2-octanol yielded the
corresponding products in lower yields (products 3g in 47%,
and 3h in 51% isolated yields). Similarly, aliphatic cyclic
secondary alcohol such as cyclopentanol, cyclohexanol,
cycloheptanol, and cyclooctanol also proceeded the reaction
under standard reaction conditions and yielded the
corresponding alkylated esters (3i-3n) in moderate yields (48-
61%). Besides, cyclohexyl methanol, and cyclopropylmethanol
gave the desired products 3o in 70%, and 3p in 59% isolated
yields, respectively. Aromatic alcohols such as benzyl alcohol,
2-phenyl ethanol, 1-phenyl ethanol, and 1-phenyl propanol
were successfully applied in our standard reaction conditions
and offered the corresponding esters 3q-3t in moderate to
good isolated yields (up to 82%). Indeed, aromatic alcohols
containing electron-realising substituents (–Me, –OMe, and
OBn), electron-withdrawing substituent (–NO2), and halo-
substituents (-Cl, and -Br) gave the corresponding ester
derivatives in moderate to good yields (46-81% isolated
yields). Moreover, sulphur containing heterocyclic alcohol
afforded the corresponding ester 3ac in 79% isolated yield.
Notably, conjugated cinnamyl alcohol resulted the product
cinnamyl benzoate 3ae in 63% isolated yield under standard
reaction conditions. We have also successfully shown the
scalability of this catalytic protocol under standard conditions
NMR using mesitylene as an internal standard. bIsolated yield. n.d = not detected.
Having optimized reaction conditions in hand, we next
investigated the scope of diverse 3-oxopropanenitrile
derivatives under the optimized reaction conditions (Table 2).
Initially, 3-oxo-3-phenylpropanenitrile containing electron-
donating group methyl
(1b), and methoxy (1c) were
successfully converted to the corresponding esters to give the
product 2b, and 2c in 82%, and 91%, respectively. Similarly, the
halide functionality such as fluoro, chloro, and bromo-
containing 3-oxopropanenitrile derivatives yielded the
corresponding methyl ester products in good to excellent
yields (products 2d-2g, 70-93% isolated yields). Importantly,
heterocyclic 3-(furan-2-yl)-3-oxopropanenitrile, and 3-oxo-3-
(thiophen-2-yl)propanenitrile were selectively converted to
the corresponding methyl ester derivatives 2h and 2i in 47%
and 36% yields, respectively. Interestingly, aliphatic 4,4-
dimethyl-3-oxopentanenitrile yielded 51% of the product 2j
under our KOtBu catalyzed conditions. However, 2-
phenylacetonitrile, 2-(phenylsulfonyl) acetonitrile, 4-oxo-4H-
chromene-3-carbonitrile, and, 2-(1H-benzo[d]imidazol-2-
yl)acetonitrile were incompatible under standard reaction
conditions.
Next, we have examined the reaction of 3-oxopropanenitrile
(Table 3, products 3a, 3d, 3q, and 3s). Thus, the present
(1a) with various alcohols under the optimized reaction
transition-metal free protocol is convenient and a wide range
of substrates, including primary and secondary alcohols as well
as aliphatic alcohols, are reactive, underscoring the great value
of this reaction for the synthesis of a variety of esters.
conditions. Thus, alcohols such as unactivated aliphatic
alcohols as well as aromatic primary and secondary alcohols
smoothly reacted with 1a under KOtBu catalyzed conditions,
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cleavage smoothly and gave the corresponding mixture of
esters and ketones under KO Bu catalyzed conditions (Table 4
and Scheme 2).
Table 3. KOtBu catalyzed conversion of Ketones to Esters: Scope of alcoholsa
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DOI: 10.1039/D0CC03312J
t
Table 4. KOtBu catalyzed C(O)-C bond cleavage: Effect of carbonyl derivativesa
aReaction conditions: 4a-k (0.5 mmol), KOtBu (10 mol%), MeOH (1 mL) heated at 140 oC
(oil-bath temperature) under closed condition and the yield was determined by 1H
NMR using mesitylene as an internal standard.
99%
100
90
80
70
60
50
40
30
20
10
0
89%
76%
33%
20%
15% 15%
5%
0%
0%
0% 0%
(R)
Figure 1. Comparison of reactivity of various carbonyl compounds under KOtBu
catalyzed conditions.
aReaction conditions: 1a (0.5 mmol), KOtBu (10 mol%), ROH (3a-3c 0.5 mL, 3d-3ae 4
eq.) heated for 12 h at 140 oC (oil-bath temperature) under closed condition and the
calculated yields are isolated yields. b 5 mmol scale after 24 h.
We extended our strategy to the C(O)-C bond cleavage of
various 1,3 diketone derivatives (Scheme 2). Pleasingly, cyclic
1,3 diketone (cyclohexane-1,3-dione;
5) under standard
reaction conditions gave the expected methyl 5-oxohexanoate
5a in 58% of yield. Similarly, other acyclic 1,3-diones, for
Next, we extended our transition-metal free strategy to
various C(O)-C containing carbonyl compounds (Table 4). Thus,
the reaction of benzoyl cyanide (4a), and 2,2,2-trifluoro-1-
phenylethanone (4b) with methanol using catalytic amount of
KOtBu (10 mol%) gave the product 2a in 33%, and 15% yields,
example
tetramethylheptane-3,5-dione (
4i), 4,4,4-trifluoro-1-phenylbutane-1,3-dione
1,1,1-trifluoropentane-2,4-dione
), 1-phenylbutane-1,3-dione
4j), 1,3-
(6), 2,2,6,6-
7
(
(
diphenylpropane-1,3-dione (4k) gave the corresponding C(O)-C
bond cleaved products (a mixture of esters and ketones) with
good conversion. It was observed that that the strong electron
withdrawing group (-CN, -NO2, and -C(O)R) at α-position of the
carbonyl carbon is crucial for this unprecedented
respectively. In the case of acetophenone
propiophenone 4d), no ester product formation was
observed. It is important to note that, acetophenone
containing strong electron-withdrawing groups (e.g –NO2; 4e
at the -position of carbonyl moiety underwent C(O)-C bond
(4c), and
(
)
α
transformation.
However,
other
electron-donating
cleavage and afforded the expected product methyl benzoate
2a in 76% isolated yield. However, acetophenone containing
substituents (-CH3, -OH, -Br, and -Cl) at the α-carbon are
inactive under our standard reaction conditions (Figure. 1).
In order to get insights of the present KOtBu catalysis, a series
of control experiments were carried out under the optimal
reaction conditions (Scheme 3). The reaction of deuterated
methanol under standard conditions resulted 72% yield of 2a-
strong electron-donating (-OH; 4f
functionality (-Cl; 4h), and –Br; 4g) at the
)
as well as halide
-position failed to
α
yield the desired product under the optimized reaction
conditions. Moreover, in the presence of another carbonyl
moiety at the
4,4,4-trifluoro-1-phenylbutane-1,3-dione
diphenylpropane-1,3-dione 4k underwent C(O)-C bond
α
-carbon such as 1-phenylbutane-1,3-dione (4i),
D
which confirms the reaction proceeds via C(O)-C bond
(
4j), 1,3-
cleavage of 3-oxopropanenitrile (Scheme 3a).
(
)
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Scheme 2. KOtBu catalyzed C(O)-C bond cleavage of 1,3 diketones (Standard conditions:
5-7 and 4i-4k (0.5 mmol), KOtBu (10 mol%), MeOH (1 mL) heated for 12 h at 140 oC (oil-
bath temperature) under closed condition and the yield was determined by 1H NMR
using mesitylene as an internal standard.
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3b). This result suggests that a single-electron transfer (SET)
may be operative in the present catalytic transformation.
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In summary, KOtBu catalyzed direct conversion of ketones to
esters via C(O)−C bond cleavage is reported. This catalytic
process proceeds under solvent-free conditions and offers an
easy operational procedure, broad substrate scope with
excellent selectivity. In addition, 1,3-diketones are selectively
converted to the corresponding esters and mono-ketones.
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Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
This research work was supported by IISER Tirupati, and SERB, India
(CRG/2018/002480/OC). MS thanks the UGC for fellowship.
Notes and references
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