Single-step conversion of electron-deficient aldehydes into the corresponding esters in aqueous alcohols in the presence of iodine and sodium nitrite

Article abstract of DOI:10.1055/s-0029-1217121

The direct conversion of aldehydes into their corresponding esters in the presence of iodine and sodium nitrite in aqueous alcohols is reported. In all these reactions, alcohol serves as reactant and also as reaction medium. Almost quantitative yields were obtained with aldehydes containing electron-withdrawing substituents and heterocyclic aldehydes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217121

276
PAPER
Single-Step Conversion of Electron-Deficient Aldehydes into the Correspon-
ding Esters in Aqueous Alcohols in the Presence of Iodine and Sodium Nitrite
Conversion of
E
lec
.
tron-Deficie
B
nt
A
ldehydes int
.
o
the
C
orresp
K
onding Esters iran, Reiko Ikeda, Norio Sakai, Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science & Technology, Tokyo University of Science (RIKADAI), Noda,
Chiba 278-8510, Japan
E-mail: konaka@rs.noda.tus.ac.jp
Received 17 August 2009; revised 25 September 2009
O
I2, NaNO2
Abstract: The direct conversion of aldehydes into their corre-
Ar
ArCHO
sponding esters in the presence of iodine and sodium nitrite in aque-
ous alcohols is reported. In all these reactions, alcohol serves as
reactant and also as reaction medium. Almost quantitative yields
were obtained with aldehydes containing electron-withdrawing
substituents and heterocyclic aldehydes.
aq ROH
OR
1
2
Scheme 1
Key words: esterification, electron-deficient aldehydes, iodine,
sodium nitrite, nucleophilic addition
Generally, iodine is a good water purifier and is also nec-
essary to control thyroid disorders.8 Sodium nitrite, a nat-
urally occurring chemical, used as a meat preservative and
an antidote for cyanide poisoning, has many other medic-
inal applications.6,9 We report here the development of a
novel, low-cost, and green chemical method for the selec-
tive conversion of aldehydes into esters in the presence of
iodine and sodium nitrite.
Esters serve as equivalents for carbonyl and carboxyl
compounds. In addition, these compounds have many
commercial and biological applications.1 Esters can be
synthesized in a number of traditional ways.2 Unfortu-
nately, in many of these esterification reactions, the oxi-
dative pathway has restrictive requirements: dehydrating
agent, expensive metal catalysts,2b long reaction times,2c
oxidants in greater than stoichiometric amounts,2c,d anhy-
drous solvents,2c corrosive acids,2d and an inert atmo-
sphere.2h Also many reported procedures are
unsatisfactory for aldehydes containing electron-
withdrawing substituents.2h
We herein report an effective protocol that facilitates the
direct esterification of aldehydes, especially aromatic al-
dehydes with electron-withdrawing substituents; metha-
nol, ethanol, or a variety of alcohols including diols can be
used in the presence of iodine and sodium nitrite. This
method is robust, straightforward, and scalable. There is
no need for anhydrous solvents or an inert atmosphere to
be used. A simple chromatographic separation using a sil-
ica gel column (NH-type) is effective for the purification
of the esters. This purification procedure prevents the
product from undergoing partial deesterification and
deacetalization10 during workup and isolation.
A number of literature reports have shown iodine to be an
excellent catalyst for various transformations of carbonyl
compounds including aldehydes.3 For example, iodine in
the presence of an excess of base4 and with (diacetoxy-
iodo)benzene5 was used to convert aldehydes into the cor-
responding esters in alcohol.
We chose 4-nitrobenzaldehyde (1a) as a model substrate
to establish the reaction conditions in aqueous methanol
(Table 1). The best result was obtained when one equiva-
lent of iodine and one equivalent of sodium nitrite were
used at 70 °C for 18 hours; this furnished 2a as the sole
product in 99% yield (entry 4). The purity of the crude
Our successful regioselective iodination of phenols with
iodine and sodium nitrite [I2, NaNO2 (1:1), green reagent]
in aqueous methanol prompted us to study the application
of this reaction to aldehydes.6 Interestingly, the reaction of
aromatic aldehydes (1 equiv) with iodine and sodium ni-
trite in aqueous alcohol led to the formation of esters as
the final products, rather than the expected iodinated aro-
matic compounds. A blank reaction of an aldehyde and
aqueous alcohol with iodine at 70 °C and at room temper-
ature yielded the corresponding acetal.7 In the above reac-
tion, sodium nitrite alone fails to bring about either
esterification or acetalization, thus confirming the impor-
tance of the combination of iodine and sodium nitrite as a
reagent in esterification (Scheme 1).
1
product 2a thus obtained (entry 4) was confirmed by H
NMR analysis. Inspection of entries 1–4 in Table 1 re-
veals that esterification is dependent on the reaction tem-
perature and time sequence. In marked contrast, the
reaction proceeds well at room temperature, but gives a
low yield of 2a even after a long reaction time (entry 1),
and the use of less iodine and sodium nitrite results in low-
er yields of 2a (entries 5–8). In both cases it was found (by
TLC and 1H NMR analysis of the crude mixtures) that the
starting compound 1a remained in the reaction mixture.
Although our newly developed esterification reaction was
slow, as described above, the long reaction time was dras-
tically reduced when microwave irradiation was used
(70 °C, 4 min) (Table 1, entry 4). This effect may result
SYNTHESIS 2010, No. 2, pp 0276–0282
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217121; Art ID: F16609SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Conversion of Electron-Deficient Aldehydes into the Corresponding Esters
277
from a polar reaction mechanism,11 which will be shown
later.
Table 2 Esterification of Aromatic Aldehydes with Electron-
Withdrawing Substituents
O
O
I2, NaNO2
aq R2OH
70 °C
Table 1 Optimization of Reaction Conditions
R1
R1
OR2
H
O
O
H
I2, NaNO2
aq MeOH
O2N
1
2
O2N
OMe
Entry
1
R1
R2
Time (h)
2
Yielda (%)
1a
2a
1
2
1a
1a
1a
1a
1a
1b
1c
1d
1d
1e
1f
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
3-NO2
2-NO2
4-CN
Et
18
18
24
2b
2c
2d
2e
2f
96 (93)b
91
Entry I2 (equiv) NaNO2
(equiv)
Time (h) Temp (°C) Yielda (%)
n-Pr
i-Pr
1
2
3
4
1
1
1
1
1
1
1
1
24
6
r.t.
70
70
70
46
34
79
3
79
4
i-Bu 36
t-Bu 36
86
n.r.c
92
12
18
5
99
6
Me
Me
Me
Et
18
18
18
18
24
24
2g
2h
2i
(97)b
7
89
5
6
7
8
0.5
1
0.5
0.5
1
18
18
18
18
70
70
70
70
41
8
98 (94)b
94
28
9
4-CN
2j
0.5
0.05
47
10
11
4-Cl
Me
Me
2k
2l
89
0.05
trace
4-CO2H
7d
a Isolated yield.
a Isolated yield.
b The yield in parentheses is for a reaction conducted under micro-
wave irradiation for 4 min at 70 °C.
b The yields in parentheses are for reactions conducted under micro-
wave irradiation for 4 min at 70 °C.
c The starting material was quantitatively recovered; n.r. = no reac-
tion.
With these encouraging results in hand, the scope of the
iodine and sodium nitrite catalyzed esterification reaction
was examined with a series of aromatic or heterocyclic al-
dehydes and aliphatic aldehydes substituted with phenyl
groups in a variety of alcohols as solvents and reactants.
The results were dependent on the nature of the aldehyde
substituents, and excellent yields were obtained with elec-
tron-deficient substrates (Table 2).
d 1H NMR analysis of the crude reaction mixture indicated 67% con-
version of 1f into ester 2l.
the ester as in the case of isopropyl and isobutyl alcohol.
Surprisingly, in the presence of tert-butyl alcohol no reac-
tion was observed, and starting compound 1a was recov-
ered quantitatively (Table 2, entry 5). These results may
be attributed to steric hindrance of the alcohol.4,12,13 In ad-
dition, the higher yield in methanol compared to other al-
cohols is likely due to methanol (smaller size) being a
better nucleophile.13
Aromatic aldehydes with electron-withdrawing substitu-
ents were effectively converted into the corresponding es-
ters (Table 2, entries 1–4 and 6–10). The isolated yield of
2l is only 7%, but 1H NMR analysis of the crude reaction
mixture indicated 67% conversion of 1f into ester 2l
(Table 2, entry 11); this loss is due to the adsorption of
compound 2l onto the NH-type silica gel during purifica-
tion. 4-Nitro- and 4-cyanobenzaldehydes were neatly con-
verted into their pure methyl esters in nearly quantitative
yields when methanol was used as solvent and reactant
(Table 1, entry 4; Table 2, entry 8). In contrast, the ethyl
esters derived from 4-nitro- and 4-cyanobenzaldehyde
formed in slightly lower yields when ethanol was used as
solvent and reactant (Table 2, entries 1 and 9). These re-
sults encouraged us to examine the esterification of alde-
hydes in a variety of alcohols (Table 2, entries 2–5). The
results in Table 2 (entries 1–5, 8, and 9) clearly show that
the efficiency of the reaction decreases in the following
order: methanol > ethanol > propanol, and primary alco-
hol > secondary alcohol > tertiary alcohol. The branching
in the structure of the alcohol seems to reduce the yield of
The reaction of 4-methoxybenzaldehyde gave the corre-
sponding methyl ester in low yield (28%) after 36 hours
of reaction time (Table 3, entry 1). However, 4-methoxy-
benzaldehyde, 3-methoxybenzaldehyde, and 2-methoxy-
benzaldehyde were only mildly reactive in esterification,
even by microwave irradiation, for 12 min (entries 1–3).
Surprisingly, 4-methyl- and 3-methylbenzaldehyde were
unreactive, even after 24 hours at 70 °C (entries 4 and 5);
this is different from the reaction of 2-methylbenzalde-
hyde (entry 6). It appears that the applicability of iodine
and sodium nitrite in the reactions of aromatic aldehydes
with electron-donating substituents is limited under the
conditions developed by us. In addition, we did not ob-
serve any iodinated products;6 only the remaining un-
changed aldehyde along with the ester that forms in the
reaction were detected (Table 3).
Synthesis 2010, No. 2, 276–282 © Thieme Stuttgart · New York

278
Y. B. Kiran et al.
PAPER
Table 3 Esterification of Aromatic Aldehydes with Electron-
Donating Substituents
Table 4 Esterification of Simple Aromatic, Aliphatic, and Hetero-
cyclic Aldehydes
O
O
I2, NaNO2
O
O
I2, NaNO2
Ar
Ar
aq MeOH
70 °C
aq ROH
70 °C
R
R
OMe
H
OR
H
1
2
1
2
Entry
1
1
R
Time
2
Yielda (%)
2m 28
Entry
1
1
Ar
R
Time (h)
24
2
Yielda (%)
46b
1g
4-OMe
36 h
12 min
(48)b
2n (46)b
2o
(31)b
1m
Me 36
48
2s 54b
58
2
3
4
5
6
1h 3-OMe
12 min
12 min
24 h
24
Me
33b,c
1i
1j
2-OMe
4-Me
2
3
1n
1o
2t
36
40b,c
2p n.r.c
2q n.r.c
1k 3-Me
1l 2-Me
24 h
24
Et
29b,c
34c
39d
2u
24 h
2r
36
a Isolated yield.
b The yields in parentheses are for reactions conducted under micro-
wave irradiation at 70 °C (average of two runs).
c Determined by GC; starting material was quantitatively recovered;
n.r. = no reaction.
24
Me
23c
27c
4
1p
2v
36
d A mixture of acetal and ester formed.
Unsubstituted aromatic aldehydes 1m and 1n afforded the
corresponding esters in moderate yields (Table 4, entries
1 and 2). Aliphatic aldehydes 1o and 1p substituted with
phenyl groups were converted into the corresponding es-
ters at 70 °C (entries 3 and 4). In these cases, the yields
were slightly improved after longer reaction times (entries
1–4). However, TLC and NMR analyses of the crude
products indicated that a major portion of the correspond-
ing aldehydes remained in the reaction mixture along with
the newly formed esters even after long reaction times.
The efficacy of this methodology can also be extended to
heterocyclic aldehydes. Heterocyclic aldehydes 1q and 1r
could be smoothly converted into their methyl esters in
high yields (96–98%) (entries 5 and 6).
5
6
1q
1r
Me 14
Me 14
2w 98
2x 96
Br
N
N
a Isolated yield.
b Average of three runs.
c The starting material was quantitatively recovered.
Table 5 Esterification of 1a with Less Common Alcohols
I2, NaNO2
O
O
solvent
ROH
+
O2N
O2N
To further explore the scope of the iodine and sodium ni-
trite catalyzed esterification reaction, the esterification of
1a (1 equiv) in a variety of organic solvents was exam-
ined, with various alcohols (1.25 equiv) as a reactant
(Table 5). The results in Table 5 indicate the sensitivity of
our new reagent system for esterification. The esterifica-
tion of 1a proceeded quite well in polar solvents (entries
1 and 2).
(1.25 equiv)
H2O
70 °C, 18 h
H
OR
1a
2
Entry
Solvent
R
2
Yielda (%)
1
2
toluene
CH2Cl2
Me
Me
2a
2a
83
94
3
CH2Cl2
2y
75
In general, our new reagent (I2/NaNO2) is very effective in
the conversion of aldehydes substituted with electron-
withdrawing groups into the corresponding esters. The
use of microwave irradiation reduced the long reaction
time in our esterification procedure. The unique character-
istic of this method, using iodine and sodium nitrite in
aqueous alcohol, is that it selectively iodinates aromatic
rings of polyfunctionalized phenols,6 but in the case of
multifunctionalized aldehydes, iodine and sodium nitrite
chemoselectively convert the aldehydes into esters
(Tables 2– 5). Moreover, this procedure demonstrates that
H2N
HO
4
5
CH2Cl2
CH2Cl2
2z
83
81
2a¢
a Isolated yield.
esters do not result from oxidation of the aldehydes to car-
boxylic acids and subsequent Fischer-type esterification
in alcoholic solvents. This conclusion is supported by the
Synthesis 2010, No. 2, 276–282 © Thieme Stuttgart · New York

PAPER
Conversion of Electron-Deficient Aldehydes into the Corresponding Esters
279
observation that esterification of 4-formylbenzoic acid the alcohol more nucleophilic. This situation favors nu-
occurred at the formyl group, rather than at the carboxyl cleophilic addition of alcohols to the carbonyl carbon and,
group, and that benzoic acid was not esterified. Interest- subsequently, formation of the hemiacetals. In the pres-
ingly, attempts to obtain esters (2a or 2i) from the corre- ence of sodium nitrite, esters form from the hemiacetals
sponding acetals (3a or 3b) in aqueous methanol by using via a hemiacetal–iodate complex and an iodo–hemiacetal
sodium nitrite, iodine and sodium nitrite, or iodine were adduct.5 These two species form by hydrogen bonding be-
unsuccessful, even after 24 hours at room temperature or tween the oxoiodate(I) ion (IO–) and the hydroxy group of
at 70 °C; all starting materials were quantitatively recov- the hemiacetal and by bonding of the iodine cation (I+)
ered from these reactions (Scheme 2). These observations with the resulting hemiacetal anion; this is followed by
support the conclusion that under our reaction conditions facile a-hydrogen elimination, as hydrogen iodide, to
esters are not formed from acetals.
form the ester (Scheme 3). Obviously, the observed reac-
tivity of the aromatic aldehydes, which is limited to nu-
cleophilic addition of alcohols to form esters, is due to
variations in the degree of electrophilicity of the carbonyl
carbon, as determined by the resonance effects of the sub-
stituents.
NaNO2
OMe
OMe
R
I2, NaNO2
I2
aq MeOH
no reaction
3
3a R = NO2
3b R = CN
2 H+ + I– + IO–
I2 + H2O
NO+ + H2O + Na+
I+ + NOI
NaNO2 + 2 H+
I2 + NO+
Scheme 2
In addition, the blank reaction conditions discussed earlier
are good for the preparation of acetals (Table 6).10,12,13
Sun et al. also reported deprotection of acetals to give the
corresponding aldehydes in excellent yields within min-
utes under neutral conditions in the presence of a catalytic
amount of iodine at room temperature.14
(initiation of the reactions)
IO–
H+, ROH
Ar
OH
OR
Ar
H
Ar
O
OI
H
C
O
H
H
OR
– HOI
Table 6 Preparation of Acetals 3 from Benzaldehydes 1
O
Ar
O
I
I+
O–
OR
Ar
– HI
OMe
O
I2
Ar
H
H
OR
OR
aq MeOH
r.t.
R
R
OMe
H
Scheme 3 Proposed mechanism
1
3
Entry
1
R
Time (h)
1.5
3
Yielda (%)
If the iodo–hemiacetal adduct is generated by attack of
oxoiodate(I) anions (IO–) on the alkoxymethyl cation, an
ester will form even in the absence of sodium nitrite.
However, the formation of esters was not observed in the
absence of sodium nitrite (Scheme 4).
1
2
3
4
1a
1d
1e
1f
4-NO2
4-CN
4-Cl
3a
3b
3c
3d
97
95
95
98
2.0
2.5
4-CO2H
1.5
H+
+
–OI
HOI
OI
a Isolated yield.
O
Ph
H
OI
OR
Ph
H
Ph
OR
The experimental results support the following reaction
mechanism for esterification: aldehyde ↔ hemiacetal ↔
ester rather than through the commonly accepted alde-
hyde ↔ acid ↔ ester or aldehyde ↔ acetal ↔ ester mech-
anism.2d,15 When iodine dissolves in aqueous alcohol, the
solution becomes acidic (Scheme 3). Under mildly acidic
conditions, sodium nitrite (NaNO2) forms the nitrosyl ion
(NO+), which acts as a Lewis acid and converts iodine (I2)
into the iodine cation (I+) (Scheme 3).6,16 Iodine appears to
play a catalytic role in the conversion of aldehydes into
hemiacetals, as shown in Scheme 3; this is further facili-
tated by the oxoiodate(I) ion (IO–) generated in the medi-
um. Initially, the carbonyl oxygen atom is protonated,
rendering its carbon more electrophilic, and associates
with the alcoholic hydroxy group, leaving the oxygen of
OR
Scheme 4
In summary, although the literature enumerates a number
of reagents for esterification, the advantages of the proce-
dure described in this paper is that aldehydes with elec-
tron-withdrawing substituents and heterocyclic aldehydes
are chemoselectively converted into esters in nearly quan-
titative yields. Another advantage of our method is the use
of environmentally acceptable and less expensive re-
agents and the simplicity of the experimental procedure
and subsequent workup. The described methods can
readily be scaled up to multigram reactions. Additional
experiments that explore the scope and limitations of this
method are currently underway in our laboratory.
Synthesis 2010, No. 2, 276–282 © Thieme Stuttgart · New York

280
Y. B. Kiran et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 3.90 (s, 3 H), 8.11 (d, J = 8.5 Hz,
2 H), 8.19 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 52.7, 123.4, 130.6, 135.4, 150.4,
165.0.
All solvents and chemicals were purchased from TCI and used
without further purification. H2O was of Milli-Q grade with a spe-
cific resistance greater than 18 W·cm. A microwave synthesizer
(Green Motif I, IDX Corporation, Tokyo) was employed for micro-
wave-assisted synthesis. Reaction progress and compound purity
were monitored by TLC (hexane–EtOAc, 10:2); UV light at shorter
wavelengths was used for visualization. Flash chromatography was
performed on NH-type silica gel (particle size 100–200 mesh), and
for additional purification alumina (70–230 mesh ASTM) was used,
as needed. For the oxidation of aldehydes to acetals (shown in
Table 6), recycling preparative gel permeation chromatography
(GPC) (CHCl3) was used for purification. Melting points were de-
termined on a Yanaco micro-melting-point apparatus, and are un-
corrected. When necessary, a Shimadzu GC-9A gas chromatograph
(GC) was used to analyze reactions. 1H and 13C NMR spectra were
recorded using a JEOL ECP-500 (500 and 125 MHz, respectively)
and a JEOL ECP-300 (300 and 75 MHz, respectively) spectrometer.
The 1H and 13C chemical shifts were referenced to TMS (d = 0.00)
and the solvent residual peak. Mass spectra were recorded on a
JEOL JMS-MS700 mass spectrometer using xenon (6 kV, 10 mA)
as the FAB gas. IR spectra were obtained on a JASCO FT-IR 410
spectrophotometer.
MS–FAB: m/z (%) = 73 (100), 147 (60), 207 (10) [M + 3 H+ + Na+].
Ethyl 4-Nitrobenzoate (2b)18
White crystalline solid; mp 57.0–58.0 °C (Lit.18 54.9–55.1 °C).
1H NMR (500 MHz, CDCl3): d = 1.41 (t, J = 7.5 Hz, 3 H), 4.42 (q,
J = 6.5 Hz, 2 H), 8.20 (d, J = 9.0 Hz, 2 H), 8.28 (d, J = 9.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 14.2, 61.9, 123.4, 130.6, 135.8,
150.4, 164.6.
MS–FAB: m/z (%) = 150 (40), 196 (100) [ M + H+].
Propyl 4-Nitrobenzoate (2c)19
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 0.96 (t, J = 8.0 Hz, 3 H), 1.75 (q,
J = 6.0 Hz, 2 H), 4.25 (t, J = 7.0 Hz, 2 H), 8.12 (d, J = 8.0 Hz, 2 H),
8.19 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 10.2, 21.8, 67.3, 123.3, 130.4,
135.7, 150.3, 164.5.
Oxidation of Aldehydes 1 to Esters 2; General Procedure
Conventional heating: I2 (1 mmol) was added to a stirred soln of the
appropriate aldehyde (1 mmol) in the appropriate alcohol (4 mL) at
r.t. After the I2 had completely dissolved in the alcohol, NaNO2 (1
mmol) in H2O (1 mL) was added. The resulting reaction mixture
was stirred at r.t. for 10 min, and then the mixture was heated to
70 °C. The reaction progress was monitored by TLC (NH-type). Af-
ter completion of the reaction, the reaction mixture was slowly
cooled to r.t., then washed with 1 M aq Na2S2O3 (10 mL) to remove
the I2, and, subsequently, extracted with CHCl3 (3 × 10 mL). The
combined organic phase was dried (MgSO4), filtered, and concen-
trated under reduced pressure in a rotary evaporator and the result-
ing residue was purified by column chromatography (NH-type
silica gel).
Isopropyl 4-Nitrobenzoate (2d)2i
White crystalline solid; mp 104.0–106.0 °C (Lit.2i 106.0–108.0 °C).
1H NMR (500 MHz, CDCl3): d = 1.33 (d, J = 6.0 Hz, 6 H), 5.23 (m,
1 H), 8.13 (d, J = 8.5 Hz, 2 H), 8.21 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.8, 69.6, 123.4, 130.5, 136.2,
151.9, 164.1.
Isobutyl 4-Nitrobenzoate (2e)20
White crystalline solid; mp 68.0–69.0 °C (Lit.20 68.0–68.5 °C).
1H NMR (500 MHz, CDCl3): d = 1.05 (d, J = 6.5 Hz, 6 H), 2.11–
2.13 (m, 1 H), 4.17 (d, J = 6.5 Hz, 2 H), 8.23 (d, J = 9.0 Hz, 2 H),
8.30 (d, J = 9.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 19.0, 27.7, 71.8, 123.4, 130.5,
135.8, 150.4, 164.6.
Microwave heating: The microwave synthesizer was equipped with
a magnetic stirrer and a thermocouple to monitor the temperature,
which was set by varying the microwave power. For the esterifica-
tion reactions, 200 W energy was used to maintain the reaction tem-
perature at 70 °C. The volume and the composition of the reaction
mixture was the same as under conventional conditions.
Methyl 3-Nitrobenzoate (2g)17
Pale yellow solid; mp 79.0–80.0 °C (Lit.17 78.0–79.0 °C).
1H NMR (500 MHz, CDCl3): d = 3.91 (s, 3 H), 7.57 (t, J = 8.0 Hz,
1 H), 8.28 (d, J = 8.0 Hz, 1 H), 8.32 (d, J = 8.0 Hz, 1 H), 8.77 (s, 1
H).
13C NMR (125 MHz, CDCl3): d = 52.7, 124.5, 127.3, 129.5, 131.8,
135.1, 148.2, 164.8.
Esterification of 1a in organic solvents: A 25-mL reaction flask
equipped with a magnetic stirring bar was charged with 1a (1
mmol), NaNO2 (1 mmol) in H2O (1 mL), I2 (1 mmol), the appropri-
ate alcohol (1.25 mmol), and organic solvent (3 mL) (Table 5). The
mixture was vigorously stirred for 0.5 h at r.t. and then at 70 °C for
18 h and was then allowed to reach r.t.; then the reaction mixture
was washed with 1 M aq Na2S2O3 (10 mL) and subsequently ex-
tracted with CHCl3 (3 × 10 mL). The combined organic phase was
dried (MgSO4) for 2 h, filtered, and concentrated under reduced
pressure in a rotary evaporator. The crude compound was purified
by column chromatography (NH-type silica gel).
Methyl 2-Nitrobenzoate (2h)21
Colorless oil turning pale yellow.
1H NMR (500 MHz, CDCl3): d = 3.92 (s, 3 H), 7.64–7.68 (m, 2 H),
7.74 (d, J = 7.5 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 53.2, 123.8, 127.5, 129.8, 131.7,
132.8, 165.8.
Column chromatography: Compounds 2a (Table 1, entry 4) and 2i
(Table 2, entry 8) were obtained in pure form from the correspond-
ing aldehydes without any further purification. Purity was con-
firmed by 1H NMR analysis. All other compounds were obtained in
pure form by simply passing the product through a glass column (2
ft length and 0.5 ft diameter) filled with 100–200 mesh NH-type sil-
ica gel (2 g) and with hexane–EtOAc (9:1, 20 mL) as the eluent.
Compounds 2s and 2u were purified additionally on an alumina col-
umn.
Methyl 4-Cyanobenzoate (2i)2g
White crystalline solid; mp 69.0 °C (Lit.22 66.0–67.0 °C).
1H NMR (500 MHz, CDCl3): d = 3.96 (s, 3 H), 7.74 (d, J = 8.5 Hz,
2 H), 8.13 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 52.6, 116.4, 117.9, 130.0, 132.2,
133.9, 165.4.
Methyl 4-Nitrobenzoate (2a)2g
Ethyl 4-Cyanobenzoate (2j)18
White crystalline solid; mp 91.0–92.0 °C (Lit.17 94.0–95.0 °C).
White crystalline solid; mp 49.0–50.0 °C (Lit.23 51.0–53.0 °C).
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Conversion of Electron-Deficient Aldehydes into the Corresponding Esters
281
1H NMR (500 MHz, CDCl3): d = 1.32 (t, J = 7.5 Hz, 3 H), 4.31 (q,
J = 7.0 Hz, 2 H), 7.65 (d, J = 8.5 Hz, 2 H), 8.05 (d, J = 8.0 Hz, 2 H).
Methyl 2-Phenylpropanoate (2v)29
Colorless oil.
13C NMR (125 MHz, CDCl3): d = 14.1, 61.6, 116.1, 117.8, 129.9,
132.0, 134.2, 164.8.
1H NMR (500 MHz, CDCl3): d = 1.49 (d, J = 7.5 Hz, 3 H), 3.66 (s,
3 H), 3.72–3.73 (m, 1 H), 7.25–7.32 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 18.5, 45.4, 52.0, 127.1, 127.4,
Methyl 4-Chlorobenzoate (2k)2g
128.6, 140.5, 168.4.
Pale yellow crystals; mp 40.0–42.0 °C (Lit.17 44.0 °C).
MS–FAB: m/z (%) = 73 (100), 147 (40), 165 (70) [M + H+].
1H NMR (500 MHz, CDCl3): d = 3.91 (s, 3 H), 7.40 (d, J = 8.5 Hz,
2 H), 7.96 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 52.2, 128.1, 128.7, 130.9, 139.3,
166.2.
Methyl 6-Bromo-2-pyridinecarboxylate (2w)30
White crystalline solid; mp 94–96 °C.
1H NMR (500 MHz, CDCl3): d = 4.00 (s, 3 H), 7.70–7.73 (m, 2 H),
8.10 (d, J = 7.5 Hz, 1 H).
MS–FAB: m/z (%) = 155 (100) [M+ – CH3].
13C NMR (125 MHz, CDCl3): d = 53.0, 123.9, 131.7, 139.1, 141.9,
148.5, 164.2.
4-(Methoxycarbonyl)benzoic Acid (2l)24
White solid; mp 221–223 °C (Lit.24 219.0–222.0 °C).
1H NMR (500 MHz, CDCl3): d = 4.20 (s, 3 H), 7.61–7.70 (m, 4 H).
Methyl Isonicotinate (2x)31
Colorless oil
1H NMR (500 MHz, CDCl3): d = 3.88 (s, 3 H), 7.77 (s, 2 H), 8.70
(s, 2 H).
Methyl 4-Methoxybenzoate (2m)25
White solid; mp 48–50 °C (Lit.25 47–48 °C).
1H NMR (500 MHz, CDCl3): d = 3.85 (s, 3 H), 3.88 (s, 3 H), 6.92
(d, J = 9.5 Hz, 2 H), 8.00 (d, J = 9.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 52.5, 122.7, 137.1, 150.4, 165.4.
13C NMR (125 MHz, CDCl3): d = 51.8, 55.3, 113.5, 122.5, 131.5,
163.3, 166.8.
Isopentyl 4-Nitrobenzoate (2y)32
Yellow oil.
1H NMR (500 MHz, CDCl3): d = 0.90 (d, J = 6.5 Hz, 6 H), 1.60–
1.61 (m, 2 H), 1.71 (m, 1 H), 4.33 (t, J = 6.0 Hz, 2 H), 8.02 (d,
J = 8.5 Hz, 2 H), 8.20 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 22.3, 24.9, 37.1, 64.5, 123.4,
130.5, 135.7, 150.4, 164.6.
Methyl 3-Methoxybenzoate (2n)26
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 3.85 (s, 3 H), 3.90 (s, 3 H), 7.10
(d, J = 8.0 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.55–7.63 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 52.0, 55.2, 113.9, 119.3, 121.8,
129.2, 131.3, 159.4, 166.8.
2-Amino-1-methylethyl 4-Nitrobenzoate (2z)
White crystalline solid; mp 128.0–129.0 °C.
IR (neat): 721, 1078, 1335, 1518, 3108 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.35 (d, J = 6.0 Hz, 3 H), 3.21 (s,
2 H, NH2), 3.52–3.57 (m, 1 H), 4.06–4.11 (m, 1 H), 4.49 (s, 1 H),
8.02 (d, J = 9.0 Hz, 2 H), 8.21 (d, J = 9.0 Hz, 2 H).
Methyl 2-Methoxybenzoate (2o)27
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 3.29 (s, 3 H), 3.78 (s, 3 H), 6.81–
6.83 (m, 2 H), 7.18 (m, 1 H), 7.44 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 52.4, 56.8, 111.7, 119.2, 119.5,
130.9, 133.4, 158.4, 166.3.
13C NMR (125 MHz, CDCl3): d = 21.1, 62.1, 78.9, 124.6, 130.3,
134.5, 151.1, 164.2.
MS–FAB: m/z (%) = 167 (63), 207 (47), 225 (100) [M + H+].
Methyl Benzoate (2s)2g
Colorless oil.
HRMS (ESI): m/z calcd for C10H12N2O4: 223.0755 [M – H]; found:
1H NMR (500 MHz, CDCl3): d = 3.89 (s, 3 H), 7.40 (m, 2 H), 7.51
(d, J = 7.5 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 51.9, 128.2, 129.4, 130.0, 132.7,
166.9.
223.0748.
2-Hydroxyethyl 4-Nitrobenzoate (2a¢)33
White crystalline solid; mp 51.6 °C.
1H NMR (500 MHz, CDCl3): d = 2.27 (br s, 1 H, OH), 3.92 (s, 2 H),
4.44 (s, 2 H), 8.16 (d, J = 7.0 Hz, 2 H), 8.20 (d, J = 7.0 Hz, 2 H).
MS–FAB: m/z (%) = 55 (100), 69 (95), 95 (60), 137 (75) [M+ + H+].
13C NMR (125 MHz, CDCl3): d = 60.9, 67.2, 123.4, 130.7, 135.2,
150.5, 164.9.
Methyl 1-Naphthoate (2t)2g
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 3.93 (s, 3 H), 7.40–7.54 (m, 3 H),
7.80 (d, J = 8.5 Hz, 1 H), 7.94 (d, J = 8.5 Hz, 1 H), 8.10 (J = 7.5 Hz,
1 H), 8.82 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 52.1, 124.4, 125.8, 126.1, 127.0,
127.7, 128.5, 130.2, 131.3, 133.3, 133.8, 168.0.
Oxidation of Aldehydes 1 to Acetals 3; General Procedure
A reaction flask was charged with the appropriate aldehyde (1
mmol) and I2 (1 mmol), followed by MeOH (3 mL) and H2O (1
mL). The resultant reaction mixture was stirred at r.t. After comple-
tion of the reaction as indicated by TLC, the reaction mixture was
washed with Na2S2O3 and extracted with CHCl3 (3 × 10 mL). The
combined CHCl3 extract was dried (MgSO4) and the solvent was re-
moved under reduced pressure; this provided the corresponding
acetal. Acetals 3a and 3d were obtained in pure form and 3b and 3c
were further purified by column chromatography (NH-type silica
gel).
Ethyl 2-Phenylacetate (2u)28
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3 H), 3.59 (s,
2 H), 4.10 (q, J = 7.0 Hz, 2 H), 7.24–7.30 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 41.3, 60.6, 126.9, 128.4,
129.1, 134.0, 171.4.
Under similar conditions, 4-chlorobenzaldehyde (1e) yielded a mix-
ture of 1-chloro-4-(dimethoxymethyl)benzene (3c) (34%), 1-chlo-
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282
Y. B. Kiran et al.
PAPER
ro-4-(diethoxymethyl)benzene (3e) (30%), and 1-chloro-4-[eth-
oxy(methoxy)methyl]benzene (3f) (28%) when a MeOH–EtOH
mixture (1:1) was used as solvent and reactant in a reaction time of
2.5 h. These three compounds were separated by GPC from the
crude mixture.
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Compound 3f
Colorless oil.
IR (neat): 810, 1054, 1095, 2992 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.23 (t, J = 7.5 Hz, 3 H), 3.29 (s,
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MS–FAB: m/z (%) = 171 (100), 202 (55) [M+ + 2 H+].
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research from MEXT, a matching fund subsidy from MEXT
(2004–2006, No. 16550148 and 2009–2011, No. 21590025); a
grant for the ‘High-Tech Research Center’ Project for Private Uni-
versities, a matching fund subsidy from MEXT (2000–2004 and
2005–2007); a grant from the Japan Private School Promotion
Foundation (2008); a grant for the ‘Program for Development of
Strategic Research Center’ in Private Universities supported by
MEXT (2009–2013). Y.B.K. is grateful for the financial support of
a postdoctoral fellowship from the Tokyo University of Science.
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