Metal-free aerobic oxidative esterification of aldehydes in the presence of cyanide

Article abstract of DOI:10.1002/bkcs.10398

A metal-free aerobic oxidative esterification of aldehydes in the presence of cyanide is described. Various aromatic aldehydes and sterically congested alcohols were amenable to this protocol. In addition, this method could be extended to the preparation of thioesters with a thiol in place of an alcohol. Furthermore, the cyanide-mediated aerobic oxidation of aldehydes was applied to the synthesis of lactones via intramolecular esterification in the absence of an alcohol.

Full text of DOI:10.1002/bkcs.10398

Article
DOI: 10.1002/bkcs.10398
BULLETIN OF THE
Y.-J. Kim and C.-H. Cheon
KOREAN CHEMICAL SOCIETY
Metal-Free Aerobic Oxidative Esterification of Aldehydes in the
Presence of Cyanide
*
Yoo-Jin Kim and Cheol-Hong Cheon
Department of Chemistry, Korea University, Seoul 136701, Republic of Korea. *E-mail: cheon@korea.ac.kr
Received March 31, 2015, Accepted April 22, 2015, Published online July 24, 2015
A metal-free aerobic oxidative esterification of aldehydes in the presence of cyanide is described. Various aro-
matic aldehydes and sterically congested alcohols were amenable to this protocol. In addition, this method
could be extended to the preparation of thioesters with a thiol in place of an alcohol. Furthermore, the
cyanide-mediated aerobic oxidation of aldehydes was applied to the synthesis of lactones via intramolecular
esterification in the absence of an alcohol.
Keywords: Aerobic oxidative esterification, Aldehydes, Cyanide, Oxidative lactonization, Thioester
benzoin
condensation
previous work
Introduction
O
R
O
R
k1
R
O
condensation
OH
The similarity in the reactivity between N-heterocyclic car-
benes (NHCs) and cyanide has been extensively studied and
exploited in several organic reactions.1 For example, both
NHCs and cyanide are known to be efficient catalysts for
the benzoin reaction, and a number of protocols for the synthe-
sis of benzoin products have been developed in the presence of
either NHCs or cyanide.2 Apart from the benzoin reaction,
there have been various examples of oxidative esterification
of aldehydes3 using NHCs as catalysts including aerobic oxi-
dative esterification,4–6 and thus it is not be surprising to find
examples of oxidative esterification of aldehydes in the pres-
ence of cyanide.7,8 Indeed, several examples of oxidative
esterification of aldehydes in the presence of cyanide have
been reported8 since the seminal report on the oxidative ester-
ification ofaldehydes with cyanide in combination with MnO2
as an oxidant.7 However, it is rather surprising that there have
not been as many examples of oxidative esterification of alde-
hydes with cyanide as those with NHCs. Even more surpris-
ingly, aerobic oxidative esterification of aldehydes in the
presence of cyanide has been rarely investigated even with
the aid of any metal catalysts/co-oxidants.9
We recently reported the unusual trimerizationof aldehydes
in the presence of cyanide in an open flask without any other
additives under ambient conditions.10 Mechanistic studies
suggested that a trimeric compound 2 was formed via the
condensation between the cyanide-catalyzed benzoin conden-
sationproduct 4andbenzoylcyanide 5generated bythemetal-
free aerobic oxidation of aldehyde. Considering the proposed
reaction mechanism, it was hypothesized that suppression
or negligible progress of benzoin condensation relative to
aerobic oxidation, i.e. k1 << k2, should lead to complete con-
version of the cyanohydrin intermediateI tobenzoylcyanide 5
without the concomitant formation of benzoin product 4, and
the subsequent reaction of the resulting benzoyl cyanide 5
with an external alcohol would generate the corresponding
ester 3 (Scheme 1).
R
4
O
O
R
O
NaCN
2
R
H
R
CN
H
1
I
O
this work
k2
O
R
CN
R' OH
metal-free
aerobic
oxidation
5
R
OR'
esterification
3
Scheme 1. Working hypothesis for cyanide-mediated aerobic oxida-
tive esterification of aldehyde 1. If k2 >> k1, 1 could be converted into
ester 3 through benzoyl cyanide 5 without concomitant formation of
trimer 2.
Based on this working hypothesis, we successfully demon-
strated the cyanide-mediated aerobic oxidative esterification
of aldehydes without the aid of any metal catalysts and/or
co-oxidants. Here we describe the direct synthesis of ester
compounds from aldehydes in the presence of cyanide via
metal-free aerobic oxidative esterification in a mixture of
DMF/ethanol. Various aromatic aldehydes and sterically con-
gested secondary alcohols were amenable to this protocol. In
addition, this protocol could be extended to the synthesis of
thioesters from aldehydes using a thiol in lieu of an alcohol.11
Furthermore, the extension of this protocol to the synthesis of
lactones was achieved via the intramolecular esterification in
the absence of an alcohol.12
Experimental
All reactions were carried out in oven-dried glassware in an
open flask unless otherwise noted. Except otherwise indi-
cated, all reactions were magnetically stirred and monitored
by analytical thin-layer chromatography (TLC, Merck,
Germany) using precoated silica gel glass plates (0.25 mm)
with F254 indicator. Visualization was accomplished by
UV light (254 nm), with a combination of potassium
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BULLETIN OF THE
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Metal-Free Aerobic Oxidative Esterification of Aldehydes
KOREAN CHEMICAL SOCIETY
permanganate and/or phosphomolybdic acid solution as an
indicator. Flash column chromatography was performed
according to the method of Still using silica gel
60 (230–400 mesh). Yields refer to chromatographically and
spectrographically pure compounds, unless otherwise noted.
Commercial grade reagents and solvents were used without
further purification. Liquid aldehydes were freshly distilled
under an atmosphere of dry argon, and solid aldehydes were
Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H),
1.39 (t, J = 7.1 Hz, 3H). The corresponding carboxylic acid
(6f) was obtained in 24% yield (37 mg).
Ethyl 4-bromobenzoate (3e)15 Yield: 160 mg (70%); col-
orless oil. 1H NMR (CDCl3, 300 MHz) δ 7.91 (d, J = 8.5 Hz,
2H), 7.58 (d, J = 8.5 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t,
J = 7.1 Hz, 3H). The corresponding carboxylic acid (6g) was
obtained in 24% yield (48 mg).
1
purified by flash chromatography on silica gel. H NMR
Methyl ethyl terephthalate (3f )14 Yield: 102 mg (49%);
and 13C NMR spectra were recorded on 300/400 MHz and
100 MHz NMR spectrometers, respectively. Tetramethylsi-
lane and CDCl3 were used as internal standards for 1H
NMR(δ:0.0 ppm)and13CNMR(δ:77.16 ppm), respectively.
The proton spectra are reported as δ (position of proton, mul-
tiplicity, coupling constant J, number of protons). Multiplici-
ties are indicated by s (singlet), d (doublet), t (triplet), q
(quartet), p (quintet), h (septet), m (multiplet), and br (broad).
High-resolution mass spectra (HRMS) were obtained using
a Quadrupole instrument (Agilent, Santa Clara, CA, USA)
using electron ionization (EI) as the ionization method.
General Procedure for Metal-Free Aerobic Oxidative
Esterification (Tables 2 and 3). Aldehyde 1 (1.0 mmol;
1.0 equiv.) and 4 Å molecular sieves (300 mg) were added
to a mixture of DMF (3.0 mL) and an appropriate alcohol
(or a thiol) (3.0 mL). To the above solution was added sodium
cyanide (1.5 mmol; 1.5 equiv). The reaction mixture was stir-
red in an open flask at 50 ꢀC and monitored by TLC. After the
complete consumption of 1, the mixture was poured into water
(25 mL) and extracted with diethyl ether (5 × 10 mL). The
organic layers were combined, dried over anhydrous magne-
sium sulfate, and concentrated. The crude mixture was further
purified by column chromatography on silica gel using ethyl
acetate/hexane as the eluent to furnish the desired ester com-
pound 3. The aqueous layer was acidified with HCl, extracted
with ether, and concentrated to yield the corresponding car-
boxylic acid 6, which was sufficiently pure needing no further
purification.
white solid. H NMR (CDCl3, 300 MHz) δ 8.11 (m, 4H),
1
4.41 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 1.42 (t, J = 7.1 Hz,
3H). The corresponding carboxylic acid (6h) was obtained
in 28% yield (50 mg).
Ethyl 4-nitrobenzoate (3g)14 Yield: 78 mg (40%);
1
yellow solid. H NMR (CDCl3, 300 MHz) δ 8.21–8.31 (m,
4H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). The cor-
responding carboxylic acid (6i) was obtained in 54% yield
(90 mg).
Ethyl4-methoxybenzoate (3h)14 Yield: 85 mg (47%); col-
orless liquid. 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J = 8.8
Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H),
3.86 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). The corresponding car-
boxylic acid (6c) was obtained in 10% yield (15 mg).
Ethyl 4-methylbenzoate (3i)14 Yield: 139 mg (85%); col-
orless liquid. 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, J = 8.0
Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H),
2.41 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). The corresponding car-
boxylic acid (6d) was obtained in 10% yield (14 mg).
Ethyl 3-methoxybenzoate (3j)14 Yield: 140 mg (78%);
colorless liquid. 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, J =
7.7 Hz, 1H), 7.57 (s, 1H), 7.32–7. 37 (m, 1H), 7.08–7.12
(m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.39 (t, J =
7.1 Hz, 3H). The corresponding carboxylic acid (6j) was
obtained in 11% yield (17 mg).
Ethyl 3-methylbenzoate (3k)14 Yield: 148 mg (90%); col-
1
orless liquid. H NMR (CDCl3, 300 MHz) δ 7.83–7.86 (m,
2H), 7.30–7.38 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 2.40 (s,
3H), 1.40 (t, J = 7.1 Hz, 3H). The corresponding carboxylic
acid (6k) was obtained in 6% yield (8 mg).
Ethyl 2-naphthoate (3a)13 Yield: 170 mg (85%); yellow
liquid. 1H NMR (CDCl3, 300 MHz) δ 8.61 (s, 1H),
8.06–8.09 (m, 1H), 7.95–7.97 (m, 1H), 7.86–7.89 (m, 2H),
7.52–7.61 (m, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1
Hz, 3H). The corresponding carboxylic acid (6a) was obtained
in 9% yield (15 mg).
Ethyl 3-chlorobenzoate (3l)16 Yield: 121 mg (66%); col-
1
orless liquid. H NMR (CDCl3, 300 MHz) δ 8.02 (s, 1H),
7.94 (d, J = 7.7 Hz, 1H), 7.51–7.54 (m, 1H), 7.35–7.41 (m,
1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). The cor-
responding carboxylic acid (6l) was obtained in 33% yield
(51 mg).
Ethyl 1-naphthoate (3b)14 Yield: 132 mg (66%); colorless
liquid. 1H NMR (CDCl3, 300 MHz) δ 8.90 (d, J = 8.5 Hz, 1H),
8.18 (d, J = 7.1 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.88 (d, J =
8.2 Hz, 1H), 7.47–7.64 (m, 3H), 4.48 (q, J = 7.1 Hz, 2H), 1.46
(t, J = 7.1 Hz, 3H). The corresponding carboxylic acid (6b)
was obtained in 20% yield (34 mg).
Ethyl 3,4-dichlorobenzoate (3m)17 Yield: 133 mg (61%);
yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.12 – 8.13 (m,
1H), 7.86–7.89 (m, 1H), 7.51–7.54 (m, 1H), 4.38 (q, J = 7.1
Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). The corresponding car-
boxylic acid (6m) was obtained in 32% yield (61 mg).
Ethyl 3,5-dimethoxybenzoate (3n)18 Yield: 160 mg
(76%); colorless liquid. 1H NMR (CDCl3, 300 MHz) δ 7.20
(d, J = 2.47 Hz, 2H), 6.64–6.66 (m, 1H), 4.36 (q, J = 7.14
Hz, 2H), 3.84 (s, 6H), 1.39 (t, J = 7.14 Hz, 3H). The corre-
sponding carboxylic acid (6n) was obtained in 9% yield
(16 mg).
Ethyl benzoate (3c)14 Yield: 99 mg (66%); colorless liq-
uid. 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J = 7.1 Hz, 2H),
7.53–7.58 (m, 1H), 7.41–7.46 (m, 2H), 4.38 (q, J = 7.1 Hz,
2H), 1.40 (t, J = 7.1 Hz, 3H). The corresponding carboxylic
acid (6e) was obtained in 30% yield (37 mg).
Ethyl 4-chlorobenzoate (3d)14 Yield: 123 mg (67%); col-
orless liquid. 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J = 8.5
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Metal-Free Aerobic Oxidative Esterification of Aldehydes
KOREAN CHEMICAL SOCIETY
Ethyl2-methylbenzoate(3o)14 Yield:79 mg(59%);color-
31.0, 23.0, 13.5. HRMS (EI) calcd. for C14H14OS
230.0765, found 230.0767.
less liquid. 1H NMR (CDCl3, 300 MHz) δ 7.89–7.92 (m, 1H),
7.36–7.41 (m, 1H), 7.23–7.25 (m, 2H), 4.36 (q, J = 7.1 Hz,
2H), 2.60 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). The corresponding
carboxylic acid (6o) was obtained in 22% yield (30 mg).
Ethyl 2-chlorobenzoate (3p)19 Yield: 133 mg (72%); col-
orless liquid. 1H NMR (CDCl3, 300 MHz) δ 7.81 (d, J = 8.0
Hz, 1H), 7.29–7.46 (m, 3H), 4.40 (q, J = 7.1 Hz, 2H), 1.40
(t, J = 7.1 Hz, 3H). The corresponding carboxylic acid (6p)
was obtained in 25% yield (39 mg).
2H-benzo[e][1,4]dioxepin-5(3H)-one (8)12 Yield: 56 mg
1
(34 %); colorless liquid. H NMR (DMSO-d6, 300 MHz) δ
7.75 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.0 Hz, 1H), 7.17 (t,
J = 7.4 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.50 (s, 4H).
Results and Discussion
Based on the working hypothesis shown in Scheme 1, initial
efforts were directed at establishing the optimal reaction con-
ditions for this metal-free aerobic oxidative esterification by
decreasing the rate of benzoin condensation reaction (k1) with-
out a significant decrease in the aerobic oxidation (k2) through
modification of the reaction conditions10 previously used for
the trimerization of aldehydes. Since the benzoin reaction is
known to proceed much more slowly in ethanol than in
DMSO,23 it was anticipated that the use of a mixture of DMSO
and ethanol would retard the rate of the benzoin condensation
reaction. Under such circumstances, if there were no signifi-
cant decrease in the rate of aerobic oxidation, ester 3a would
be formed from the reaction of the resulting benzoyl cyanide
5 with ethanol.
Withthese anticipations in mind, themetal-free aerobic oxi-
dative esterification of aldehyde in the presence of a stoichio-
metric amount of cyanide was explored in a mixture of DMSO
and ethanol using 2-naphthaldehyde 1a as a model compound
(Table 1). To our delight, the use of a mixture of DMSO and
ethanol turned out to have a beneficial effect on the oxidative
esterification; only trimeric compound 2a was obtained in
DMSO, while the reaction in a mixture of DMSO and ethanol
provided the corresponding ester 3a albeit in moderate yield
(entries 1 and 2). Since our prior study in the trimerization
of aldehydes showed that this aerobic oxidation took place
in either DMSO or DMF,10 this aerobic oxidative esterifica-
tion was performed using a mixture of ethanol and DMF
instead of DMSO. Although the reaction in a DMF/ethanol
mixture afforded ester 3a in a similar yield as that in a
DMSO/ethanol mixture (entries 2 and 3), a mixture of DMF
and ethanol was chosen for further investigation because of
the easy removal of DMF from the reaction mixture compared
to DMSO.
Next, the optimum proportion of ethanol in the reaction
medium for the maximum efficiency of this aerobic oxidative
esterification was investigated (entries 3–7). The ratio of eth-
anol to DMF in the reaction media turned out to affect this
transformation. The yield of 3a increased until the ratio of eth-
anol in DMF reached 50% (entries 3–5). However, with a high
proportion of ethanol, there was no further improvement in the
yield of 3a; instead, both the oxidative esterification and tri-
merization were significantly slowed down and no formation
of trimer 2a was observed in the entire ethanol solvent, and 1a
remained unreacted in the reaction mixture (entries 6 and 7).
The best result was obtained using a 1:1 mixture of ethanol
and DMF, and 3a was obtained in 67% yield (entry 5). Subse-
quent evaluation of the effect of the amount of cyanide
Ethyl 2-furoate (3q)15 Yield: 99 mg (70%); yellow liquid.
1H NMR (CDCl3, 300 MHz) δ 7.57 (m, 1H), 7.17 (d, J = 3.3
Hz, 1H), 6.50–6.51 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t,
J = 7.1 Hz, 3H). The corresponding carboxylic acid (6q) was
obtained in 12% yield (13 mg).
Ethyl 2-thienoate (3r)14 Yield: 119 mg (76%); yellow liq-
uid. 1H NMR (CDCl3, 300 MHz) δ 7.79–7.81 (m, 1H),
7.53–7.55 (m, 2H), 7.08–7.11 (m, 1H), 4.35 (q, J = 7.1 Hz,
2H), 1.38 (t, J = 7.1 Hz, 3H). The corresponding carboxylic
acid (6r) was obtained in 5% yield (6 mg).
Ethyl 2-picolinate (3s)15 Yield: 118 mg (78%); yellow liq-
uid. 1H NMR (CDCl3, 300 MHz) δ 8.76–8.78 (m, 1H),
8.13–8.16 (m, 1H), 7.83–7.88 (m, 1H), 7.47–7.51 (m, 1H),
4.49 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). The corre-
sponding carboxylic acid (6s) was obtained in 3% yield
(4 mg).
Ethyl cinnamate (3t)20 Yield: 116 mg (66%); yellow liq-
uid. 1H NMR (CDCl3, 300 MHz) δ 7.66–7.72 (m, 1H),
7.52–7.54 (m, 2H), 7.39–7.40 (m, 3H), 6.42- 6.47 (m, 1H),
4.27 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). The corre-
sponding carboxylic acid (6 t) was obtained in 22% yield
(33 mg).
Methyl 2-naphthoate (3a-Me)7(a) Yield: 182 mg (98%);
1
white solid. H NMR (CDCl3, 300 MHz) δ 8.61 (s, 1H),
7.87–8.08 (m, 4H), 7.52–7.62 (m, 2H), 3.99 (s, 3H).
Benzyl 2-naphthoate (3a-Bn)21 Yield: 244 mg (93%); col-
orless liquid. 1H NMR (CDCl3, 300 MHz) δ 8.65 (s, 1H), 8.10
(d, J = 7.7 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.5
Hz, 2H), 7.33–7.60 (m, 7H), 5.44 (s, 2H).
Allyl 2-naphthoate (3a-Allyl)22 Yield: 174 mg (82%); yel-
1
low liquid. H NMR (CDCl3, 300 MHz) δ 8.64 (s, 1H),
8.07–8.10 (m, 1H), 7.88–7.98 (m, 3H), 7.53–7.62 (m, 2H),
6.04–6.15 (m, 1H), 5.43–5.49 (m, 1H), 5.32 (d, J = 10.16
Hz, 1H), 4.90 (d, J = 5.77 Hz, 2H). The corresponding car-
boxylic acid (6a) was obtained in 14% yield (24 mg).
Isopropyl 2-naphthoate (3a-iPr)13 Yield: 141 mg (66%);
1
yellow liquid. H NMR (CDCl3, 300 MHz) δ 8.60 (s, 1H),
7.86–8.08 (m, 4H), 7.52–7.61 (m, 2H), 5.30–5.35 (m, 1H),
1.43 (d, J = 6.0 Hz, 6H). The corresponding carboxylic acid
(6a) was obtained in 33% yield (57 mg).
n-Propyl 2-naphthothioate (3a-SPr) Yield: 191 mg
(83%); colorless liquid. 1H NMR (CDCl3, 300 MHz) δ 8.54
(s, 1H), 7.87–8.02 (m, 4H), 7.53–7.62 (m, 2H), 3.12 (t, J =
7.1 Hz, 2H), 1.75 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.1 Hz,
3H). 13C NMR (400 MHz, CDCl3) δ 192.0, 135.7, 134.5,
132.4, 129.5, 128.5, 128.4, 128.3, 127.8, 126.8, 123.2,
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BULLETIN OF THE
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Metal-Free Aerobic Oxidative Esterification of Aldehydes
KOREAN CHEMICAL SOCIETY
Table 1. Optimization of reaction conditions.
Table 2. Substrate scope of aldehydes.
NaCN (x equiv)
NaCN (1.5 equiv)
DMF:EtOH=1:1
O
O
O
O
O
O
DMF/EtOH (y vol%)
O
Ar
+
Ar
H
Ar
OEt
3a
Ar
+
R
H
R
OEt
R
OH
4A MS, rt, time (h)
4A MS, 50 °C
open flask
Ar
O
1a
2a
1
6
3
open flask
Ar = 2-naphthyl
Entry
Product
R
Time
Yielda (%)
NaCN
(equiv)
%
EtOH
Time
(h)
Conversiona Yieldb
1
2
3
4
5
6
7
8c
9d
10
11d
12
13
14
15e
16
17
18
19
20
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
2-Naphthyl
1-Naphthyl
C6H5
4-ClC6H4
4-BrC6H4
4-(MeO2C)C6H4
4-NO2C6H4
4-(MeO)C6H4
4-MeC6H4
3-(MeO)C6H4
3-MeC6H4
3-ClC6H4
3,4-Cl2C6H3
3,5-(MeO)2C6H3
2-MeC6H4
2-ClC6H4
12 h
24 h
24 h
5 h
3 h
2 h
10 min
24 h
24 h
24 h
24 h
1 h
85
66 (20)b
66 (30)b
67 (24)b
70 (24)b
49 (28)b
40 (54)b
47
Entry
(%)
(%)
1c
2c
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
2.0
1.5
0
25
25
33
50
66
100
50
50
50
50
12
12
12
12
12
24
24
12
12
12
12
100
100
100
100
100
95
— (71)d
45 (29)d
46 (27)d
56 (21)d
67 (11)d
65 (10)d
42 (0)
45
85
78
90
46
45 (N.D.e)
72 (N.D.e)
65 (N.D.e)
85 (N.D.e)
100
100
100
10
11f
66 (33)b
61 (32)b
76
1 h
5 h
a Determined by the amount of 1a remaining in the reaction mixture using
1H NMR analysis.
24 h
4 h
24 h
24 h
24 h
8 h
59 (22)b
72
b Isolated yield.
c DMSO was used in place of DMF.
d The number in parentheses indicates the isolated yield of 2a.
e N.D. means not determined.
2-Furyl
2-Thienyl
2-Pyridyl
C6H4CH CH
70
76
78
f Reaction was performed at 50 ꢀC.
3t
66 (22)b
a Isolated yield.
revealed that the amount of cyanide also played an important
role in this transformation (entries 5, 8–10). The yield of 3a
improved to 72% as the amount of cyanide increased to 1.5
equiv of cyanide and dropped to 65% with 2.0 equiv. There-
fore, the use of 1.5 equiv of cyanide was selected for further
investigation (entry 9). Finally, an elevated reaction tempera-
ture turned out to have a beneficial effect on this oxidative
esterification; when the reaction was performed at 50 ꢀC,
the yield of 3a could be further increased to 85% (entry 11).
Under these optimized conditions, the substrate scope of
aldehydes for this transformation was investigated
(Table 2). Similar to previous examples of the aerobic oxida-
tive esterification of aldehydes,4,5 the electronic nature of the
aldehydes exerted a strong influence on this transformation
(entries 3–9). Electron-neutral aldehydes smoothly underwent
the aerobic oxidative esterification to provide esters 3 in good
yields (entry 3). However, with electron-deficient aldehydes,
esters 3 were obtained in moderate to good yields, and a sig-
nificant amount of the corresponding carboxylic acids 6 were
simultaneously obtained even though the oxidation reaction
proceeded rapidly (entries 4–7).24
b The numbers in parenthesis indicate the isolated yields of the
corresponding acids 6.
c Reaction was performed at 90 ꢀC.
d Reaction was performed at 80 ꢀC.
e Reaction was performed at 100 ꢀC.
newly developed protocol was attempted to be applied to
the oxidative esterification of electron-rich aldehydes (entries
8 and 9). Rather disappointingly, under the optimized condi-
tions (at 50 ꢀC), electron-rich aldehyde 1c provided the corre-
sponding ester 3c in low yield, and the benzoin product 4c and
trimeric compound 2c were formed at the same time. This
result implied that the aerobic oxidation of an electron-rich
aldehyde proceeded much more slowly than that of
electron-neutral and electron-deficient aldehydes. During
the optimization for this transformation, an elevated reaction
temperature was found to have a beneficial effect on the aer-
obic oxidation of aldehydes, and thus the reaction was exe-
cuted at a slightly higher temperature. Gratifyingly,
electron-rich aldehydes underwent aerobic oxidative esterifi-
cation at a slightly elevated temperature to afford the ester
compounds in moderate to good yields (entries 8 and 9).
Furthermore, sterically congested aromatic aldehydes
could be applied to this protocol (entries 2, 15–16). For exam-
ple, aromatic aldehydes bearing a substituent at the ortho posi-
tion provided the desired ester compounds in good yields.
Then the protocol was further extended to more challenging
substrates. Despite several reports of aerobic oxidative ester-
ification of aldehydes,4,5 in most cases the substrate scope was
limited to electron-neutral and electron-deficient aldehydes,
and only a few examples of aerobic oxidative esterification
of electron-rich aldehydes have been reported.25 Thus, the
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Metal-Free Aerobic Oxidative Esterification of Aldehydes
KOREAN CHEMICAL SOCIETY
Heteroaromatic aldehydes and α,β-unsaturated aldehydes
were also amenable to this protocol to afford the desired ester
compounds in good yields (entries 17–20).
corresponding ester 3a even after a long reaction time, which
led us to exclude this possibility (Eq. (1)).
NaCN (1.5 equiv)
O
O
Under these optimized reaction conditions, the generality
and limitation of alcohols in this metal-free aerobic oxidative
esterification were evaluated (Table 3). The steric bulk of the
alcohol had a strong effect on the efficiency of this transforma-
tion; as the alkyl group in an alcohol became bulkier, the yield
of the corresponding ester compound significantly decreased.
For example, primary alcohols afforded the corresponding
esters in high yields (entries 1–4), whereas secondary alco-
hols, such as isopropyl alcohol (IPA), afforded the desired
ester compound in good yield along with concomitant forma-
tion of the corresponding carboxylic acid 6a (entry 5). How-
ever, a tertiary alcohol was not tolerated in this protocol; the
trimeric compound was obtained as the major product and a
significant amount of aldehyde 1a remained unreacted (entry
6). Furthermore, this aerobic oxidative protocol could be fur-
ther extended to the synthesis of thioesters with a thiol without
any significant decrease in the efficiency (entry 7).11
DMF/EtOH (1:1)
4A MS, 50 oC, 48 h
O
Ar
Ar
Ar
OEt (1)
(3.0 equiv)
Ar
O
open flask
2a
3a
No Reaction
Ar = 2-naphthyl
In addition, because carboxylic acid 6 was also observed
during this oxidative esterification, the esterification of the
resulting carboxylic acid with an alcohol under the optimized
conditions was examined (Eq. (2)). When carboxylic acid 6a
was treated with NaCN under standard conditions, however,
no formation of ester 3a was observed; instead, only rapid pro-
ton transfer from 6a to cyanide took place leading to the exclu-
sive formation the sodium salt 6a-Na of 6a. This result also
forced us to eliminate this possibility.
NaCN (1.5 equiv)
O
O
O
DMF/EtOH (1:1)
With these results in hand, we attempted to elucidate the
reaction mechanism for this cyanide-mediated metal-free aer-
obic oxidative esterification of aldehydes. Since it was
reported that the trimeric compound 2 could be the key inter-
mediate in aerobic oxidative esterification in the presence of
an NHC catalyst,26 and we frequently observed the concomi-
tant formation of 2 during this aerobic oxidative esterification,
we first explored the possibility of this oxidative esterification
through the formation of the trimeric compound 2 followed by
ethanolysis of the resulting trimeric compound 2 in a high con-
centration of ethanol.
Ar
+
Ar
6a-Na
quantitative
OEt
ONa (2)
Ar
4A MS, 50 °C, 1 h
OH
3a
6a
open f lask
not observed
Ar = 2-naphthyl
Based on these experimental results, in conjuntion with our
previous trimerization of aldehydes, it is highly plausible that
the aerobic oxidative esterification10 may proceed through
benzoyl cyanide 5 as the key intermediate generated by the
hydride transfer of cyanohydrin I, as shown in Scheme 1. Sub-
sequent reaction with an alcohol provides the desired ester
compound 3. Based on this mechanism, the concomitant for-
mation of carboxylic acid 6 during the reaction could be
explained by the hydrolysis of the resulting benzoyl cyanide 5.
To further demonstrate the synthetic utility of this protocol,
we attempted to extend the method for the synthesis of lac-
tones.12 When aldehyde 7 was subjected to the cyanide-
mediated aerobic oxidation conditions in the absence of an
alcohol, to our delight, the lactone 8 was obtained even under
the unoptimized reaction conditions, although the yield of
8 was moderate (Scheme 2).
When trimeric compound 2a was subjected to the standard
conditions, however, 2a was not converted into the
Table 3. Effect of alcohols on metal-free aerobic oxidative
esterification.
O
O
O
NaCN (1.5 equiv)
OR
+
OH
H
DMF:ROH = 1:1
4A MS, 50 °C
open flask
3a-X
6a
1a
O
O
NaCN (1.5 equiv)
OH
DMF, 4A MS, 100 oC, 24 h
O
open flask
Entry
3a-X
R–OH
Time (h)
Yielda (%)
O
O
7
8
34% yield
1
2
3
4
3a
EtOH
MeOH
BnOH
12
12
24
24
85
99
93
82
3a-Me
3a-Bn
3a-Allyl
Scheme 2. Extension to lactonization.
Conclusion
5
6
7
3a-iPr
3a-tBu
3a-SPr
i-PrOH
t-BuOH
n-PrSH
24
24
24
66 (33)b
N.R.c
83
In conclusion, we have developed a new protocol for the syn-
thesis of esters from aldehydes via the metal-free aerobic oxi-
dative esterification in the presence of cyanide. Various types
of aromatic aldehydes including electron-rich aromatic alde-
hydes were well tolerated in this newly developed method.
a Isolated yield.
b The number in parenthesis indicates the isolated yield of 6a.
c No formation of 3a-tBu was observed.
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Metal-Free Aerobic Oxidative Esterification of Aldehydes
KOREAN CHEMICAL SOCIETY
P. M. P. Gois, Org. Biomol. Chem. 2011, 9, 3126;
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6. For excellent examples of metal/additive-free aerobic oxidative
In addition, several different types of alcohols were utilized in
this oxidative esterification to afford the corresponding esters
in good to excellent yields. Moreover, this protocol could be
extended to the synthesis of thioesters using a thiol as an acyl
transfer nucleophile. Furthermore, the synthesis of lactones
via intramolecular metal-free aerobic oxidative esterification
was achieved based on this protocol in the absence of an
alcohol.
Although the similarity in reactivity between NHCs and
cyanide has been well-appreciated in carbon–carbon bond for-
mation reactions, there have not been as many examples of the
oxidative esterification of aldehydes with cyanide as those
with NHCs, which suggested that oxidative esterification of
aldehydes with cyanide might be relatively unexplored so
far. This study demonstrated that the cyanide-mediated
metal-free aerobic oxidative esterification of aldehydes was
not an unusual and isolated example, but a general and predict-
able protocol.
esterification of aldehydes with
a NHC catalyst, see:
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Acknowledgment.
We acknowledge the National
Research Foundation of Korea (NRF) grants (NRF-
2014M2A8A4021398 and NRF-20100020209).
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
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2011, 32, 2070.
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Metal-Free Aerobic Oxidative Esterification of Aldehydes
KOREAN CHEMICAL SOCIETY
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