N-Heterocyclic carbene catalyzed esterification of aromatic aldehydes with alcohols under aerobic conditions

Article abstract of DOI:10.1039/c2ra22718e

A simple, organocatalytic procedure for the direct oxidative esterification of a variety of aromatic aldehydes with alcohols has been described that affords the corresponding aromatic esters in high yields. The method employs N-heterocyclic carbenes as catalysts and molecular O₂ as an oxidant under ambient conditions.

Full text of DOI:10.1039/c2ra22718e

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N-Heterocyclic carbene catalyzed esterification of
aromatic aldehydes with alcohols under aerobic
Cite this: RSC Advances, 2013, 3, 1695
conditions3
Received 1st November 2012,
Accepted 4th December 2012
I. N. Chaithanya Kiran, Komal Lalwani and Arumugam Sudalai*
DOI: 10.1039/c2ra22718e
www.rsc.org/advances
A simple, organocatalytic procedure for the direct oxidative
esterification of a variety of aromatic aldehydes with alcohols
has been described that affords the corresponding aromatic esters
in high yields. The method employs N-heterocyclic carbenes as
catalysts and molecular O2 as an oxidant under ambient condi-
tions.
NHC catalyzed oxidative esterification of aldehydes with alco-
hols,14 alkyl halides15 and boronic acids16 has been reported.
However, the use of heavy metals (Pd, Mn, Fe, etc.) as oxidants, the
use of excess alkyl halides and bases and higher reaction
temperatures are some of the drawbacks associated with
them.14,15 Herein, we report the NHC catalyzed direct esterification
of aromatic aldehydes (2) with a variety of alcohols using a
catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
low to high yields under ambient conditions (Scheme 1).
Fig. 1 shows the NHC precatalysts 1a–f that were examined for
the oxidative esterification of aldehydes. Catalysts 1a–d and 1f
were prepared following a modified procedure17 while 1e was
purchased from Aldrich, USA.
When 4-nitrobenzaldehyde was subjected to oxidative ester-
ification with MeOH (1 equiv.) in the presence of 1a (10 mol%)
and DBU (20 mol%) as a base in THF under an N2 atmosphere at
room temperature, no trace of ester 3f was formed. When the
same reaction was conducted in open air, 3f was indeed isolated
in low yields (45%). However, a dramatic increase in yield (70%)
was realized when the experiment was carried out under an O2
atmosphere (O2 balloon, 1 atm). Out of several NHC catalysts
screened, imidazolium salt 1a showed higher catalytic activity,18
providing the desired product 3f in 70% yield, while 1b and 1c
gave 3f in moderate yields (Table 1). However, other catalysts 1d,
1e and 1f were found to be less effective for the esterification
reaction. Also, either increasing the NHC catalyst quantity from 10
mol% up to 20 mol% or increasing the temperature from 25 uC to
50 uC did not improve the yield of the product. Surprisingly,
increasing the amount of alcohol from 1 equiv. to 1.2 equiv.
resulted in an improved yield (76%) of the ester product. However,
Aromatic esters are important and useful structural elements
finding tremendous applications in a wide range of fields
encompassing solvents, lubricants, plasticizing agents, perfumes,
pharmaceuticals, agrochemicals, etc.1 Aromatic esters are generally
prepared using one of these methods: Fischer esterification,2
Mitsunobu reaction,3 Favorskii rearrangement,4 Baeyer–Villiger
oxidation5 and Pinner reaction.6 In addition, the halogen–metal
exchange of aryl halides with either carbon monoxide,7 ethyl
chloroformate8 or DMF9 has emerged as an alternative method of
synthesis. However, these methods have several limitations such
as the reversibility of the conventional esterification reaction, the
use of expensive Pd catalysts, the handling of toxic CO gas and
variable yields often obtained in some cases. In this respect, a new
strategy involving the direct oxidative esterification of aromatic
aldehydes to aromatic esters under mild conditions has assumed
special importance in the synthesis of natural products.10 This
useful transformation generally involves an oxidative pathway,
often requiring more than stoichiometric amounts of oxidants
(e.g., oxone,11a SnO2/SBA–H2O2,11b hypervalent iodine,11c pyridi-
11e
nium bromide perbromide,11d V2O5–H2O2 and acetone cyano-
hydrin/base11f) and long reaction times. In addition, some of these
reagents are less effective for substrates with electron-withdrawing
groups.
In recent years, N-heterocyclic carbenes (NHCs) have emerged
as an important and powerful class of organocatalysts12 with
tremendous applications in a variety of synthetic transformations
and as versatile ligands13 in transition metal catalysis. Recently,
Chemical Engineering and Process Development Division, National Chemical
Laboratory, Pashan Road, Pune 411008, India. E-mail: a.sudalai@ncl.res.in;
Fax: (+)91-02025902675
Scheme 1 NHC catalyzed direct esterification of aromatic aldehydes with
Electronic supplementary information (ESI) available: Experimental details and
3
alcohols.
spectral data of all the new compounds. See DOI: 10.1039/c2ra22718e
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Table 2 Oxidative esterification of aryl aldehydes: substrate scopea
Entry
Substrate, Ar 2a–p
Time (h)
Yield of 3a–p (%)b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
m-Tolualdehyde
10
30
36
36
28
4
10
14
18
18
14
10
7
78
72
70
65
68
76
82
78
72
79
70
76
69
72
76
63
4-OMe-benzaldehyde
3,4-(OMe)2-benzaldehyde
3,4,5-(OMe)3-benzaldehyde
4-SMe-benzaldehyde
4-NO2-benzaldehyde
3-NO2-benzaldehyde
4-Br-benzaldehyde
3-Br-benzaldehyde
4-Cl-benzaldehyde
3-Cl-benzaldehyde
4-F-benzaldehyde
Fig. 1 N-Heterocyclic carbene precatalysts screened for the oxidative esterification.
further increase in the amount of alcohol (3 equiv.) had no effect
on the yield. Among several solvents and bases screened for the
reaction, THF and DBU were found to be the most effective
(Table 1).
4-CF3-benzaldehyde
4-CN-benzaldehyde
3-Pyridinecarboxaldehyde
Furfural
In order to gauge the scope and generality of the reaction, a
variety of aromatic aldehydes having both electron-donating and
withdrawing groups were screened.20 The results of such studies
are presented in Table 2. As can be seen, several aromatic
aldehydes underwent oxidative esterification with methanol
smoothly under mild conditions. Remarkably, substrates with
electron-withdrawing groups showed higher reactivity than those
with electron-releasing substituents. Heteroaromatic aldehydes
such as 3-pyridine carboxaldehyde and furfural also gave the
corresponding esters in high yields. In the case of cinnamalde-
hydes, an inseparable mixture of saturated and unsaturated
methyl esters were obtained,19 while aliphatic aldehydes failed to
undergo this reaction, which may be a limitation.
6
20
24
a
Reaction conditions: aldehyde (5 mmol), methanol (6 mmol), NHC
b
1a (10 mol%), base (20 mol%), 25 uC, O2 (1 atm). Isolated yield
after column chromatographic purification.
A wide range of alcohols were then examined for oxidative
esterification with 4-nitrobenzaldehyde as the substrate; the
results are summarized in Table 3.
Both primary and secondary alcohols including allylic,
propargylic and benzylic alcohols underwent this reaction to give
the corresponding esters in excellent yields.
In order to gain insight into the mechanistic details of the
reaction, the following experiments were conducted: (i) for 2f, no
esterification took place under an N2 atmosphere while at the
same time a low yield (45%) was obtained in air, suggesting the
necessity of O2 for realizing higher yields; (ii) the esterification
reaction between p-nitrobenzoic acid and methanol did not
proceed under the reaction conditions, confirming the absence
of carboxylic acid as the intermediate; (iii) when (S) or (R)-
tetrahydrofuran-3-ol was used as the alcohol partner, the retention
of the configuration was obtained, thereby confirming the
incorporation of alcohol oxygen into the ester moiety; (iv) when
Table 1 Oxidative esterification of 4-nitrobenzaldehyde: optimization studiesa
Entry Catalyst (10 mol%) Base (20 mol%) Solvent Yield of 3f (%)b
1
2
No catalyst
1a
DBU
DBU
DBU
DBU
DBU
DBU
K2CO3
Et3N
nBuLi
KOtBu
DBU
DBU
DBU
DBU
DBU
THF
THF
CH2Cl2 60
CH3CN 58
DMSO 27
Toluene 60
THF
THF
THF
THF
THF
THF
THF
THF
THF
—
76 (45)c
Table 3 Oxidative esterification of 4-nitrobenzaldehyde: alcohol scopea
Entry
Alcohol components
Time (h)
Yield of ester (%)b
3
1a
56
40
16
12
36
54
14
27
26
1
2
3
4
5
6
Ethanol
2-Propanol
Benzyl alcohol
Allyl alcohol
4
7
4
4
5
80
76
80
76
4
5
6
7
8
1b
1c
1d
1e
1f
Propargyl alcohol
82
(S)-Tetrahydrofuran-3-olc
16
66 (99% ee)
a
Reaction conditions: 4-nitrobenzaldehyde (5 mmol), alcohol (6
a
mmol), NHC 1a (10 mol%), DBU (20 mol%), 25 uC, O2 (1 atm).
Reaction conditions: 4-nitrobenzaldehyde (5 mmol), methanol (6
b
c
Isolated yield after column chromatographic purification. The (R)-
mmol), NHC catalyst (10 mol%), base (20 mol%), 25 uC, O2 (1 atm),
b
c
tetrahydrofuran-3-ol gave the corresponding ester in 64% yield and
99% ee.
4 h. Isolated yield after column chromatographic purification. In
air.
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Scheme 2 Probable mechanistic pathway for the oxidative esterification.
1 equiv. of sodium methoxide was used as the alcohol component,
the corresponding methyl ester was obtained in 46% yield,
suggesting the possibility of alkoxide anion formation as the
intermediate. Based on this result and on precedents set by
the literature,16,18 we have proposed a catalytic cycle in which the
peroxy anion II16 formed from the reaction between the Breslow
intermediate I and O2 is depicted as the key intermediate in the
esterification process (Scheme 2). Upon decomposition this results
in the formation of the acyl intermediate III.16b Subsequently, the
alkoxide ion18 formed from the alcohol reacts with III to give the
corresponding ester with the liberation of NHC.
In conclusion, we have developed a simple organocatalytic
procedure for the direct oxidative esterification of aromatic
aldehydes with alcohols employing NHC as a catalyst and oxygen
as an oxidant at ambient conditions. The reaction is simple to
carry out and the products are obtained in high yields and purity
from stoichiometric amounts of alcohol and catalytic amounts of
organic base.
Acknowledgements
INCK and KL thank CSIR, New Delhi for the award of a
research fellowship and DST (No. SR/S1/OC-67/2010) New
Delhi, for financial support. The authors are thankful to Dr V.
V. Ranade, Head, CEPD, for his constant support and
encouragement.
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The resultant reaction mixture was kept stirring at 25 uC for 45
min. To this mixture was added aromatic aldehydes 2a–p (5
mmol) and alcohol (6 mmol) successively. It was allowed to stir
at 25 uC. After completion of the reaction (monitored by TLC),
THF was evaporated, H2O (50 mL) was added and the mixture
was extracted with EtOAc (3 6 50 ml). The combined organic
layers were dried over anhyd. Na2SO4 and concentrated to give
crude ester, which was purified by silica gel-packed column
chromatography to obtain pure esters, 3a–p. Spectral data for
(S)-tetrahydrofuran-3-yl 4-nitrobenzoate: Yield: 66%; colorless
25
25
gum; [a]D 231.24 (c 1.2, CH2Cl2) (ref. 19 [a]D +31.26 (c 1,
CH2Cl2) for the corresponding (R)-enantiomer); IR (CHCl3): 720,
18 E. M. Phillips, M. Riedrich and K. A. Scheidt, J. Am. Chem. Soc.,
2010, 132, 13179.
878, 1086, 1106, 1122, 1529, 1604, 1718, 2877, 2933, 3076 cm21
;
19 B. E. Maki, A. Chan and K. A. Scheidt, Synlett, 2008, 1306.
20 General experimental procedure for esterification of aromatic
aldehydes: to a flame-dried round bottom flask equipped with a
magnetic stir bar was added imidazolium salt 1a (10 mol%),
DBU (20 mol%) and THF (10 mL). The flask was evacuated and
the contents were covered with molecular oxygen in a balloon.
1H NMR (200 MHz, CDCl3): d 2.14–2.21 (m, 1H), 2.29–2.43 (m,
1H), 3.91–4.07 (m, 4H), 5.57–5.60 (m, 1H), 8.21 (d, J = 8.8 Hz,
2H), 8.30 (d, J = 8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3): d 32.8,
66.9, 72.9, 76.4, 123.5, 130.7, 135.2, 150.7, 164.1; Analysis:
C11H11NO5 requires C 55.70, H 4.67, N 5.90%, found C 55.62, H
4.51, N 5.79%.
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