N-Heterocyclic carbene catalysed aerobic oxidation of aromatic aldehydes to aryl esters using boronic acids

Article abstract of DOI:10.1039/c1ob06566a

The organocatalytic behavior of N-heterocyclic carbenes in the aerobic oxidation of aromatic aldehydes to esters with boronic acids has been explored. This transition metal-free protocol allows access to a wide variety of aromatic esters in good to excellent yields under mild reaction conditions.

Full text of DOI:10.1039/c1ob06566a

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PAPER
N-Heterocyclic carbene catalysed aerobic oxidation of aromatic aldehydes to
aryl esters using boronic acids†
Panjab Arde, B. T. Ramanjaneyulu, Virsinha Reddy, Apurv Saxena and R. Vijaya Anand*
Received 13th September 2011, Accepted 19th October 2011
DOI: 10.1039/c1ob06566a
The organocatalytic behavior of N-heterocyclic carbenes in the aerobic oxidation of aromatic aldehydes
to esters with boronic acids has been explored. This transition metal-free protocol allows access to a
wide variety of aromatic esters in good to excellent yields under mild reaction conditions.
Although the concept of organocatalysis has been utilised since
the beginnings of chemistry, the applications of organocatalysts
in organic transformations and asymmetric synthesis have been
realised to a great extent in the past two decades.1 N-Heterocyclic
carbenes (NHCs) have contributed in this revolution significantly
due to their unique reactivity towards carbonyl group activation.2
The umpolung reactivity of NHCs has been explored in many
organic transformations employing a variety of acyl anion
acceptors.3 Recently, the utility of NHCs has been extended to
some redox reactions4 and oxidation reactions where NHC was
used in combination with molecular oxygen5 or carbon dioxide6
or with an organic oxidant.7
We became interested in exploring the organocatalytic activity
of NHCs in this particular aerobic oxidation reaction using a
few commercially available N-heterocyclic carbene precursors 1–4
(Fig. 1).
Fig. 1 NHC precursors.
We began the optimisation studies using p-chlorobenzaldehyde
(5) and phenylboronic acid (6) as model substrates (Table 1).
The initial experiments on the reaction between 5 and 6 under
aerobic conditions were discouraging as no desired product (7)
was obtained using either 1 or 2 (10 mol%) at RT (Entries 1 and
2, Table 1). Surprisingly, when the same reaction was performed
at RT in toluene using 3 as a catalyst and Cs2CO3 as a base, 7 was
isolated in 64% yield (Entry 3).
Encouraged by this result, further optimisation experiments
were carried out by employing 10 mol% of 3 or 4 as a catalyst
(Entries 3–19). In all the cases, ester 7 was formed in moderate
to excellent yields and, in most of the cases, 4 was found to be
more active than 3. Use of a slight excess of aldehyde helped in
improving the yield of 7 considerably (Entries 17–19). No product
was obtained when the reaction was carried out in the absence of
NHC. It was also observed that 1.5 equivalent of base is essential
to carry out this transformation. Based on the above observations,
the optimal reaction was found to be the reaction where the ester
7 was obtained almost in quantitative yield using 1.3 equivalent
of 5 with respect to 6 in the presence of 10 mol% of 4 (Entry 17).
To generalise this synthetic methodology, the aerobic oxidative
esterification of 5 with a variety of boronic acids was evaluated
under the optimised reaction conditions and the results are
summarised in Table 2.
The ester functionality has been recognised as an important
synthetic target because it serves as a building block for a number
of natural products and active pharmaceutical ingredients (APIs).8
Traditional methods for the construction of the ester functional-
ity include acid catalysed esterification and transesterification.9
Alternative methods involve Lewis acid catalysed esterification,10
Baeyer–Villiger oxidation,11 esterification with hypervalent iodine
reagents,12 organocatalytic esterification13 and transition metal
catalysed coupling reactions.14 Recently, Wu’s group has reported
palladium catalysed aromatic esterification of aldehydes with
boronic acids and molecular oxygen.15 Though most of the
functional groups were tolerated, this methodology was performed
at harsh conditions (120 ◦C) and the products were obtained in low
yields (5–68%). Gois’ group has reported a modified procedure,
in which palladium was replaced with iron, and by using this
protocol a variety of aryl esters could be prepared in moderate
◦
to good yields at elevated temperature (90 C).16 However, since
NHC catalysed oxidative esterification of aryl aldehydes with alkyl
halides or alcohols has been well documented in the literature,5–7
we believed that NHC itself, without any assistance from a metal
catalyst, would promote the aerobic oxidation of aryl aldehydes in
the presence of boronic acids to furnish the corresponding esters.
Indian Institute of Science Education and Research (IISER) Mohali,
Sector 81, SAS Nagar, Manuali, (PO) 140 306, Punjab, India. E-mail:
rvijayan@iisermohali.ac.in; Fax: +91-172-2240266
† Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data. See DOI: 10.1039/c1ob06566a
It is apparent from Table 2 that boronic acids with various
substituents having different electronic and steric properties
reacted smoothly with 5 under the given reaction conditions and
produced the corresponding aryl esters in good to excellent yields.
848 | Org. Biomol. Chem., 2012, 10, 848–851
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Table 1 Optimisation of reaction conditionsa
Table 3 Substrate scope of the oxidative esterification reaction of alde-
hydes with phenylboronic acida
Entry
NHC
Base
Solvent
Time [h]
Yield [%]b
1
2
3
4
5
6
7
8
1
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
DBU
Toluene
Toluene
Toluene
Dioxane
THF
DCE
MeCN
DME
Toluene
Toluene
Toluene
THF
24
24
6
8
8
8
8
8
12
8
8
8
5
5
6
5
5
5
0
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOtBu
DBU
64
58
60
28
38
56
48
53
24
45
50
64
75
19
99
95
86
9
10
11
12
13
14
15
16
17c
18d
19e
NaH
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
Dioxane
Toluene
DMF
Toluene
Toluene
Toluene
5
a Reaction conditions: 5/6 = 1/1.1, 0.06 M of 5 in solvent, RT = 31 ◦C.
b Isolated yield. c 5/6 = 1.3/1. d 5/6 = 1.2/1. e 5/6 = 1.1/1.
Table 2 Oxidative esterification of 5 with boronic acidsa
a Reaction conditions: R–CHO/R–B(OH)2 = 1.3/1, 0.06 M of R–CHO in
toluene, RT = 31–33 ◦C. b Performed at 60 ◦C.
yields in the cases of other activated boronic acids (Examples 8c,
8f and 8h). Sterically hindered boronic acids (Examples 8a and
8j) also underwent smooth conversion under standard conditions.
It was observed that this transformation is applicable only for
aromatic boronic acids as cyclohexylboronic acid (Example 8o)
failed to react with 5 even at 80 ◦C.
In order to explore the significance of this transformation
further, phenylboronic acid (6) was treated with different aromatic
and heteroaromatic aldehydes under standard conditions and the
results are tabulated in Table 3.
Except in a few cases, aromatic esters were obtained in
modest to excellent yields. The reactivity of the aldehyde was
greatly influenced by the electronic and steric properties of the
substituents attached to it. Electron poor aldehydes reacted at a
faster rate when compared to electron rich aldehydes. For example,
p-cyanobenzaldehyde was converted to its corresponding ester 9i
in 93% yield in just 2 h. Other electron poor aldehydes such as
p-nitrobenzaldehyde and methyl-4-formyl benzoate reacted with
6 efficiently and provided esters 9d and 9f in 95% and 96%
yields respectively. But, electron rich aldehydes (Examples 9j–9l)
did not react with 6 at RT, but were converted to the esters in
◦
reasonably good yields at 60 C. Activated aldehydes such as p-
phenylbenzaldehyde and p-bromobenzaldehyde were oxidised to
their corresponding esters in excellent yields at RT (Examples 9b
and 9c). It is also evident from Table 3 that the substrate scope
was not limited to aromatic aldehydes as heteroaromatic aldehydes
(Examples 9g and 9h) could also be converted to esters in moderate
to good yields. Ferrocene carboxaldehyde reacted at a much slower
rate and the ester 9m was obtained in only 33% yield even at
a Reaction conditions: 5/R–B(OH)2 = 1.3/1, 0.06 M of 5 in toluene, RT =
31–33 ◦C. b Conversion started after 24 h. c Performed at 60 ◦C.
Electron rich boronic acids (Examples 8b, 8d, 8e, 8g and 8i) reacted
faster than electron deficient boronic acids (Examples 8k, 8l, 8m
and 8n) as expected. Interestingly, esters were obtained in excellent
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◦
60 C. In the case of cinnamaldehyde, a considerable amount of
cinnamic acid was formed during the reaction. As a result, ester
9n was isolated only in 25% yield. Since the reaction is carried out
under basic conditions, aliphatic aldehydes could not be used as
substrates. For example, cyclohexane carboxaldehyde did not give
9o but decomposed under the given reaction conditions.
Scheme 2 Isotopic labelling experiment using 18O2.
presence of the ester 10 (calcd for C13H9ClO18O 235.0412 [M +
H], found 235.0419). The EI MS spectrum also showed a strong
peak at m/z 234.91, which is attributed to the [M + H]+ ion of
ester 10. The fragmentation pattern showed the base peak at m/z
139.03 (100%), which could be attributed to the [ClC6H4CO]+
fragment. An additional peak appeared at m/z 141.00 (34% with
respect to the base peak), which could be due to the presence of
the chlorine isotope or oxygen isotope of [ClC6H4CO]+. But, we
strongly believe that the peak at m/z 141.00 does not correspond to
the [ClC6H4CO18]+ fragment because the peak (at m/z 143.00) for
the chlorine isotope of [ClC6H4CO18]+ was not at all observed in
the spectrum. So, it is conclusive from the mass spectral data that
the oxygen labelling did not take place at the carbonyl oxygen,
which sturdily supports the concerted mechanism operating in
the reaction (Scheme 1). The above experiment also indicates the
involvement of atmospheric oxygen in the esterification reaction.
To conclude, the studies described in this article have led
to the development of a mild and efficient method for the
oxidative esterification of aromatic aldehydes using NHC as an
organocatalyst under aerobic conditions. The practicability of this
methodology has been demonstrated using various boronic acids
and aldehydes.
In order to comprehend the mechanism in detail, the reaction
between 5 and 6 under standard reaction conditions was carefully
monitored by TLC at equal time intervals. Interestingly, phenol
was not detected during the course of the reaction, which is in
parallel with the findings reported by Gois’ group.16 Moreover,
phenol was not at all formed when the reaction was conducted
in the absence of aldehyde, without changing other parameters.
Although, NHC-metal catalysed oxidative esterification of alde-
hydes with phenol at elevated temperature has been reported
very recently,17 we strongly believe that phenol is not involved
as an intermediate in our methodology based on the above
experimental observations. To obtain a better understanding of
this transformation, an experiment was run using 5 and phenol
under optimal aerobic conditions, but the ester 7 was obtained
only in 18% yield even after stirring the reaction for a long period
(over 24 h). Addition of 1 equivalent of boric acid to the reaction
mixture helped in improving the yield of 7 but not significantly
(28% yield after 24 h).18 But, as discussed earlier, the reaction of
phenylboronic acid with 5 under the same conditions provided
7 in quantitative yield in less than 5 h (Entry 17, Table 1). This
clearly indicates a different kind of mechanism is operating in
the boronic acid case, without the involvement of phenol as an
intermediate. Based on the above experimental observations, a
plausible mechanism has been proposed (Scheme 1). We presume
that the intermediate II is formed by the reaction of I with oxygen
and boronic acid, and decomposes rapidly to III i.e., transfer of
the phenyl group to the peroxy linkage and formation of the borate
anion, both are probably occurring in a concerted manner. Finally,
intermediate III expels the NHC along with the ester and boric
acid.
Acknowledgements
The authors acknowledge IISER Mohali for providing financial
support and infrastructure. PA, VR and BTR thank CSIR for the
research fellowship. The NMR group of IISER Mohali is also
gratefully acknowledged.
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