Highly adequate oxidative esterification of α-carbonyl aldehydes with alkyl halides in TBAI/TBHP mediated system

Article abstract of DOI:10.1080/00397911.2019.1600193

An efficient and viable synthesis of α-ketoesters from alkyl halides and α-carbonyl aldehydes has been reported under metal-free conditions. The present method involves oxidative esterification of α-carbonyl aldehydes with alkyl halide using TBAI as a promoter and TBHP as an oxidant to form α-ketoesters in good to excellent yields with versatile structural diversity. Use of commercially accessible and inexpensive substrates, broad substrate scope and good functional group tolerance are the key features of this protocol.

Full text of DOI:10.1080/00397911.2019.1600193

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Highly adequate oxidative esterification of α-
carbonyl aldehydes with alkyl halides in TBAI/
TBHP mediated system
Pooja L. Bhargude, Jatin J. Lade, Bhausaheb N. Patil, Kamlesh S.
Vadagaonkar & Atul C. Chaskar
To cite this article: Pooja L. Bhargude, Jatin J. Lade, Bhausaheb N. Patil, Kamlesh S.
Vadagaonkar & Atul C. Chaskar (2019): Highly adequate oxidative esterification of α-carbonyl
aldehydes with alkyl halides in TBAI/TBHP mediated system, Synthetic Communications, DOI:
10.1080/00397911.2019.1600193
To link to this article: https://doi.org/10.1080/00397911.2019.1600193
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https://doi.org/10.1080/00397911.2019.1600193
Highly adequate oxidative esterification of a-carbonyl
aldehydes with alkyl halides in TBAI/TBHP mediated system
a
a
a
ꢀ
ꢀ
Pooja L. Bhargude , Jatin J. Lade , Bhausaheb N. Patil ,
Kamlesh S. Vadagaonkarb, and Atul C. Chaskara
aNational Centre for Nanosciences and Nanotechnology, University of Mumbai, Mumbai, India;
bDepartment of Dyestuff Technology, Institute of Chemical Technology, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 5 March 2019
An efficient and viable synthesis of a-ketoesters from alkyl halides
and a-carbonyl aldehydes has been reported under metal-free condi-
tions. The present method involves oxidative esterification of a-car-
bonyl aldehydes with alkyl halide using TBAI as a promoter and
TBHP as an oxidant to form a-ketoesters in good to excellent yields
with versatile structural diversity. Use of commercially accessible and
inexpensive substrates, broad substrate scope and good functional
group tolerance are the key features of this protocol.
KEYWORDS
a-Ketoester; metal-free
synthesis; oxidative
esterification; TBHP;
a-carbonyl aldehyde
GRAPHICAL ABSTRACT
Introduction
The ester is a beloved functional group of organic chemists and is frequently used in
organic synthesis owing to its further easy synthetic manipulations in the architecture
of various natural and pharmaceutical molecules, agrochemicals, artificial fragrances,
and polymers.[1,2] Consequently, several methods have been reported for the synthesis
of esters in the literature. Amongst them, a-ketoesters have been fetching significant
attention due to their use as synthetic ancestors for several organic conversions[3] and
enantioselective synthesis.[4] Many biologically and pharmacologically active compounds
consisting a-ketoester as a core structural unit are known to exhibit wide range of bio-
activities.[5] a-ketoesters have been employed as important starting materials for the
preparation of various bioactive molecules like inhibitors of proteolytic enzymes,[6]
CONTACT Bhausaheb N. Patil
Nanotechnology, University of Mumbai, Mumbai 400098, India; Kamlesh S. Vadagaonkar
Department of Dyestuff Technology, Institute of Chemical Technology, Mumbai 400019, India; Atul C. Chaskar
manishpatil241187@gmail.com
National Centre for Nanosciences and
vadgaonkarks@gmail.com
achaskar25@gmail.com
National Centre for Nanosciences and Nanotechnology, University of Mumbai, Mumbai
400098, India.
ꢀ
Authors contributed equally to this work.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
P. L. BHARGUDE ET AL.
leukotriene A4 hydrolase inhibitors,[7] and photo polymerization initiators.[8] As a
result, numerous synthetic methodologies have been developed for the synthesis
of a-ketoesters.
Friedal-crafts acylation of aromatic compounds using alkyl oxalyl chlorides is a well-
known method to prepare a-ketoesters.[9] a-Hydroxy esters are oxidized in the presence
of CrO3 in pyridine[10a] and Dess-Martin periodinane[10b] to form a-ketoesters. Cyano
keto phosphoranes on oxidative cleavage with ozone forms a,b-diketonitriles which
upon reaction with alcohols gives a-ketoesters.[11] Further, chemoselective cross-cou-
pling of organocopper compounds occurs easily with esters of dicarboxylic acid chlor-
ides to furnish a-ketoesters.[12] a-Aryl halogen esters undergoes aerobic oxidation in
presence of catalytic amounts of Ru(bpy)3Cl2 and 4-methoxypyridine using Li2CO3 as a
base to afford a-ketoesters.[13] a-ketoesters are also prepared by hydrolysis of acyl cya-
nides in aq. H2SO4 by using NaBr as a catalyst followed by esterification with alcohol.[8]
The reaction of dialkyl oxalates with aryllithiums generated from aryl halides and n-
BuLi in a flow microreactor results in the formation of a-ketoesters.[14] 1,3-Diones[15]
and acetophenones[16] on reaction with alcohols undergo oxidative esterification in the
presence of a copper catalyst to yield a-ketoesters. a-Carbonyl aldehydes couple with
alcohols under aerobic conditions using a copper catalyst,[17a] whereas b-ketoesters in
the presence of oxone and AlCl3 undergo oxidative cleavage to produce a-ketoesters
under aqueous conditions.[17b] Moreover, a-ketoesters have been synthesized via palla-
dium-catalyzed double carbonylation of aryl halides with alcohols by using NEt3.[18a]
Furthermore, an electrochemical synthesis of a-ketoesters has been described by
Wang et al.[18b] from acetophenones and alcohols by using KI and 2,2,6,6-
tetramethylpiperidine(TMP). Moreover, Sharada et al.[18c] reported an coupling of
a-carbonyl aldehydes with alcohols to form a-ketoesters employing I2 as a promoter in
presence of base K2CO3, while Bhahwal Ali Shah et al.[18d] used the combination of
TBAI and TBHP for this transformation. Furthermore, b-ketonitriles[18e] and nitro-
methyl aryl ketones[18f] have also been utilized as synthetic precursors for the synthesis
of a-ketoesters. Recently, we have proposed metal-free and efficient protocol for the
conversion of a-ketoesters through oxidative cross-coupling of a-carbonyl aldehydes
and alcohols.[19]
Although, these methods provide useful access to the desired a-ketoesters, several key
problems like the use of expensive metal catalyst, water sensitive reagents, prolonged
reaction time, restricted yield and high temperature of the reaction, hinder the further
applicability of the developed protocols. Keeping this in mind and in continuation of
our research and interest to discover environmentally benign protocols,[20] we herein
report the TBHP mediated oxidative esterification of a-carbonyl aldehydes with alkyl
halides in presence of tetra-n-butylammonium iodide (TBAI) as a promoter. To the
best of our knowledge herein, we first report the oxidative esterification of a-carbonyl
aldehydes with alkyl halides (Scheme 1).
Scheme 1. Metal-free protocol for the synthesis of a-ketoesters.

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3
Result and discussion
The optimization study was initiated by the reaction of a-carbonyl aldehyde 1a and
methyl bromide 2a using I2 (1.0 eq.) as a promoter and TBHP (2.0 eq.) as an oxidant at
ꢁ
60 C for 2 h, which interestingly produced a-ketoester 3aa in 45% yield (Table 1, entry
1). Use of CuI and KI as promoters afforded the desired product in trace amount
(Table 1, entries 2 and 3). To our delight, the reaction with 1.0 eq. TBAI as a promoter
and 2.0 eq. TBHP as an oxidant offered a-ketoester 3aa in 89% yield (Table 1, entry 4).
To study the effect of temperature, we perform the same reaction at room temperature
ꢁ
as well as 80 C which furnished the desired product in 37% and 85% yields, respect-
ively (Table 1, entries 5 and 6). In order to optimize the time required for the comple-
tion of reaction, we performed the reaction for 1 h and 3 h. These reactions revealed
that decrease in reaction time lowers the yield while increase in time does not improve
the yield of the product (Table 1, entries 7 and 8). The reaction with 1.0 eq. of TBHP
formed a-ketoester 3aa in moderate yield (63%) (Table 1, entry 9). Use of hydrogen
peroxide (H2O2) as an oxidant gave product 3aa in 57% yield, while per acetic acid
failed to form a-ketoester 3aa (Table 1, entries 10 and 11).
With the optimized conditions in hand, the scope of this protocol was explored by
using variously substituted a-carbonyl aldehydes and alkyl halides (Table 2). We
observed that various functional groups were found to be suited under the optimized
conditions and derived corresponding a-ketoesters in good to excellent yields.
a-Carbonyl aldehydes on reaction with variety of alkyl halides, 2-bromoethyl benzene,
benzyl bromide, and allyl bromide offered corresponding a-ketoesters 3aa–3ah in yields
ranging from 77–91%. The reaction of a-carbonyl aldehydes bearing halogen substitu-
ents such as 3-chloro and 4-bromo proceeded efficiently with various alkyl halides as
well as benzyl halides to afford 3ba–3cf in 81–91% yields. a-Carbonyl aldehydes with
electron donating and electron withdrawing substituents reacted smoothly with different
alkyl and benzyl halides to give corresponding a-ketoesters 3da–3fb in 80–87% yields.
Likewise, 2-naphthylglyoxal on reaction with methyl and benzyl bromide offered
respective products 3ga and 3gb in 87% and 84% yields.
Table 1. Optimization of reaction conditionsa.
Entry
Promoter (1.0 eq.)
Oxidant (eq.)
Time (h)
Temp. (oC)
Yieldb (%)
1
2
3
4
5
6
7
8
I2
CuI
KI
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (1.0)
H2O2 (2.0)
CH3COOOH (2.0)
2
2
2
2
2
2
1
3
2
2
2
60
60
60
60
rt
80
60
60
60
60
60
45
trace
trace
89
37
85
54
81
63
57
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
9
10
11
nd
aReaction conditions: a-carbonyl aldehyde 1a (1.0 eq.), alkyl halide 2a (1.0 eq.), promoter (1.0 eq.) and oxidant (1.0-2.0
eq.) was heated at rt-80 ꢁC for 1-3 h in a sealed tube. bThe yield was determined by GC-MS.

4
P. L. BHARGUDE ET AL.
Table 2. Substrate Scope with various a-carbonyl aldehydes and alkyl halides.a,b
aReaction conditions: a-carbonyl aldehyde 1 (1.0 eq.), alkyl halide 2 (1.0 eq.) TBAI (1.0 eq.), TBHP (2.0 eq.) were heated
at 60 ꢁC for 2 h in a sealed tube.
bIsolated yields.
Based on the above results and literature reports,[18d,21] a plausible mechanism for
t
this conversion is depicted in Scheme 2. Initially, the reaction of BuOOH with Bu4NI
results in formation of tert-butoxyl radical and tert-butylperoxy radical (Scheme 2).
Further, tert-butoxyl radical on reaction with 1a generates tert-butyl alcohol and 2-oxo
acyl radical which couples with tert-butylperoxy radical to form per-ketoester intermedi-
t
ate A. This per-ketoester intermediate in the presence of BuOOH and Bu4NI produces
a a-ketoacid B and tert-butoxyl radical. a-ketoacid B is further converted into respective
carboxylate anion followed by nucleophilic substitution with alkyl halide affords
a-ketoester 3aa.
The following control experiment supports the formation of a-ketoester via radical
pathway using radical trapping agent (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)
which obstruct the formation of 3aa (Scheme 3). This result indicated that the 2-oxo
acyl radical is formed as a reaction intermediate under the reaction conditions.

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SYNTHETIC COMMUNICATIONSV
5
Scheme 2. Proposed reaction pathway.
Scheme 3. Control experiment.
Conclusion
In summary, we have developed a metal-free synthetic approach for an efficient synthe-
sis of a-ketoesters through oxidative esterification of a-carbonyl aldehydes and alkyl hal-
ides in combination of TBAI and TBHP. This operationally simple and functional
group compatible process involves the use of soft reaction environment, requires less
reaction time, and provides notable yield of the products.
Experimental
General information
a-Carboxy aldehydes were synthesized according to a literature procedure.[22] Chemical
reagents were obtained from commercial suppliers. All reactions were done in a sealed
tube and monitored using TLC performed on aluminum plates (0.25 mm, E. Merck)
precoated with silica gel (Merck 60 F-254). Developed TLC plates were visualized under
a short-wavelength UV lamp. Reactions were conducted under open air atmosphere in
TBHP as a solvent. Yields refer to spectroscopically (1H, 13C NMR) homogeneous

6
P. L. BHARGUDE ET AL.
material obtained after column chromatography performed on silica gel (100:200 mesh
1
size) supplied by S. D. Fine Chemicals Limited, India. H and 13C NMR were recorded
in CDCl3 as well as DMSO solution on a Bruker 300 MHz spectrometer. Chemical
shifts (d) are quoted in ppm, relative to SiMe4 (d ¼ 0.0) as an internal standard. The
number of protons (n) for a given resonance is indicated by nH. Peak multiplicities are
designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, doublet of doublet; dt, doublet of triplet; J, coupling constant in Hz. IR
spectra were recorded on a JASCO-FT/IR-4100 LE with attenuated total reflection
(ATR) method and PerkinElmer FTIR spectrophotometers. Melting points were
recorded on a standard melting point apparatus from Sunder Industrial Product,
Mumbai and are uncorrected.
Experimental procedure for the synthesis of 3aa
A sealed tube equipped with a magnetic stirring bar is charged with a-carbonyl alde-
hyde 1a (1.0 eq.) and alkyl halide 2a (1.0 eq.) in TBHP (2.0 eq.) along with TBAI (1.0
ꢁ
eq.). The resulting mixture was stirred at 60 C for 2 h. After completion of the reaction
(monitored using TLC), 10 mL of saturated Na2S2O3 solution and ethyl acetate (10 mL)
were added to the reaction mixture. The organic layer after separation was washed with
water (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on 100:200 mesh silica gel by
using n-hexane:ethyl acetate (95:5) as an eluent to obtain the corresponding
a-ketoester 3aa.
Spectral data for the compound 3aa
Methyl 2-oxo-2-phenylacetate (3aa). Yellow oil; 1H NMR (300 MHz, CDCl3): d
8.03–8.00 (m, 2H), 7.68–7.64 (m, 1H), 7.55-7.49 (m, 2H), 3.98 (s, 3H); 13C NMR (75
MHz, CDCl3): d 186.1, 164.1, 135.0, 132.4, 130.1, 128.9, 52.8; IR (ATR) (cmꢂ1): 2957,
1737, 1691, 1595, 1451, 1324, 1206, 1173, 1003, 748, 677.
1
1
Full experimental details, H NMR, 13C NMR, and IR data, copies of H NMR and
13C NMR spectra can be found via the “Supplementary Content” section of this article’s
webpage.
Funding
P.L.B., K.S.V., and A.C.C. thank DST-SERB, India (sanction no. SB/FT/CS-147/2013) for financial
support. J.J.L. and B.N.P. thank University Grants Commission (UGC), New Delhi, India for pro-
viding fellowships. A.C.C. thanks DRDO, India (sanction no. ERIP/ER/1503212/M/01/1666) for
financial support.
ORCID
Atul C. Chaskar
http://orcid.org/0000-0001-8773-9526

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