Facile Coupling of Aldehydes with Alcohols: An Evolved Tishchenko Process for the Preparation of Unsymmetrical Esters

Article abstract of DOI:10.1002/ejoc.201700756

A facile coupling process between aldehydes and alcohols to afford unsymmetrical esters is presented herein. This transformation is complementary to the Tishchenko reaction and provides access to unsymmetrical esters under very mild conditions. Various aldehydes and alcohols are suitable in this reaction, and the addition of a sacrificial trifluoromethyl ketone allows the process to take place in a highly selective manner. A plausible mechanism based on details obtained by monitoring the reaction progress and deuterium-labeling studies has been proposed.

Full text of DOI:10.1002/ejoc.201700756

A Journal of
Accepted Article
Title: Facile Coupling Aldehydes with Alcohols: An Evolved Tishchenko
Process in Preparing Unsymmetrical Esters
Authors: Moris S. Eisen and Heng Liu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700756
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700756
Supported by

10.1002/ejoc.201700756
European Journal of Organic Chemistry
FULL PAPER
Facile Coupling Aldehydes with Alcohols: An Evolved
Tishchenko Process in Preparing Unsymmetrical Esters
Heng Liu,[a] and Moris S. Eisen*[a]
Abstract: A facile coupling process between aldehydes and alcohols
to afford unsymmetrical ester compounds is presented herein. This
reaction is complementary to the Tishchenko reaction and provides
an evolved procedure to access unsymmetrical esters under very mild
conditions. Various aldehydes and alcohols are suitable for this
transformation. Using the sacrificial trifluoromethyl ketones renders
the reaction to proceed in a highly selective way. A plausible
mechanism is proposed based on the reaction progress monitoring
and deuterium labeling studies.
consecutively (Scheme 1(3)). We envisage that, if an external
alcohol is also present, in addition to the aldehydes, a proton-
transfer process between the metal alkoxide M-OCH2R1 and the
alcohol R2OH might take place, which thereafter lead to a
different metal alkoxide compound M-OR2 (Scheme 1(4)). This
newly formed M-OR2 species shows high similarity to the
previous M-OCH2R1, and will subsequently undergo insertion
and hydride transfer steps with aldehydes R1CHO, furnishing the
unsymmetrical ester R1COOR2 as the final product. If our
proposed scenario is operative, the present esterification process
can be viewed as an evolved process of the Tishchenko reaction,
because in both of the processes it has a similar metal alkoxide
as an active species. Comparing with other esterification
strategies between aldehyde and alcohols, such as oxidative
esterification, dehydrogenative esterification, etc., no external
strong oxidants are necessary herein, revealing an advanced
methodology towards the synthesis of unsymmetrical esters
under very mild conditions.24-37
Introduction
The Tishchenko reaction, i.e., the dimerization of aldehyde
to produce the corresponding esters (Scheme 1(1)), has been
known for more than a century, and served as a highly efficient
and waste-free strategy for the production of ester compounds.1-
11
Nevertheless, it has not been accepted as a common
methodology for ester synthesis due to the selectivity-controlling
difficulties in preparing unsymmetrical esters.12 In the cross
coupling of two different aldehydes, it is a great challenge to
selectively obtain one single unsymmetrical ester from the four
possible esters (Scheme 1(2)).13-18 Previously, endeavors
employed steric/electronic discrepancies, or reaction rate
differences, or special ortho-substituents to promote the crossed
Tishchenko reactions between two different aldehydes.19-23 For
instance, by using Ni(0)/NHC complexes, the reaction of CyCHO
with PhCHO could give rise to the cross-coupled unsymmetrical
ester product CyCOOCH2Ph in high yields under mild conditions.
However, one limitation of this reaction is that it only works
between aliphatic and aromatic aldehydes, selectively cross-
coupling between two different aliphatic or aromatic aldehydes
has not been shown to be feasible.19 Some recent progresses
was made by Connon et al., in which selectively intermolecular
crossed Tishchenko reaction in producing asymmetric esters
between two different aromatic aldehydes was achieved by
incorporating special ortho substitutents (usually bromo-) to
benzaldehyde, and a wide range of aromatic aldehydes are
tolerated during this process.20
Tishchenko reaction:
(1)
O
O
2
R1
R1
O
R1
reaction:
Crossed Tishchenko
(2)
O
O
O
O
O
O
+
+
+
+
R1
O
R1
R2
O
R2
R1
R2
R1
O
R2 R2
O
R1
reaction:
Scheme for Tishchenko
(3)
R1
CH2R1
O
H
O
O
H
CH2R1
[M]
R1
O
R1
O
O
R1
R1
CH2R1
O
[M]
precatalyst
O
O
[M]
CH2
R1
O
R1
proton-transfer
Mechanistically, the Tishchenko reaction involves a hydride
transfer step from the hemiacetal intermediate, produced from the
coupling of a metal alkoxide and an aldehyde, to a coordinated
carbonyl group, of an incoming aldehyde, which subsequently
gives back the metal alkoxide intermediate and releases the ester
product. During this catalytic cycle, the metal alkoxide species
serves as the active species, which is consumed and regenerated
into Tishchenko
reaction:
R2
Schematic combination of
(4)
O
O
[M]
R2OH
R1
O
CH2R1
R1CH2OH
R2OH
R1CH2OH
R1
O
R2
O
H
O
O
O
[M]
precatalyst
H
R2
[M]
R1
[a]
Dr. H. Liu, Prof. Dr. M. S. Eisen
Schulich Faculty of Chemistry,
Technion – Israel Institute of Technology,
Haifa City, 32000 (Israel).
R1
O
R1
R2
O
O
[M]
R1
E-mail: chmoris@tx.technion.ac.il
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Schemes for traditional Tishchenko reaction between aldehydes (1-
3) and evolved Tishchenko reaction between alcohol and aldehyde (4).
1 / 8
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10.1002/ejoc.201700756
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Reactions of benzaldehyde with various alcohols were also
conducted. Besides methanol, ethanol and isopropanol were also
suitable for this transformation, but with decreased yields, 52%
and 12% conversions were obtained for 3ab and 3ac, respectively.
Reacting ethanol and 2-propanol with an activated aldehyde, 3-
nitrobenzaldehyde, showed a significant improvement on the
yields, demonstrating again the enhanced activities of aldehydes
promoted by electron-withdrawing groups. Interestingly, no
detectable conversion was observed during the reaction between
benzaldehyde and tert-butanol, however, reacting 3-
nitrobenzaldehyde with benzyl alcohol afforded product 3de in
moderate yields. It is worth of noting that the chemoselective
coupling of benzaldehyde and 3-nitrobenzaldeyde to produce 3de
is very challenging, and the present strategy provides an
alternative method, which is complementary to the conventional
Tishchenko reactions.
Based on the above assumptions, the esterification
between benzaldehyde and methanol was established as a model
reaction under different conditions. To avoid the homocoupled
Tishchenko of benzaldehydes at the beginning of the reaction, the
following addition order was employed: MeOH, catalyst, and lastly
PhCHO. When Na[N(SiMe3)2] was used as the precatalyst,
increasing the benzaldehyde equivalents enhanced the yield of
asymmetric ester 3aa significantly, up to 81% was obtained
(Table 1, entries 1-3). In this reaction, besides target compound
3aa, benzyl benzoate (4) and benzyl alcohol were also detected
as byproducts, for instance, 34% benzyl benzoate was observed
when reacting methanol with 3 equivalents of benzaldehyde.
Increasing the methanol stoichiometry, however, was detrimental
for the yield of 3aa, leading to decreased yields from 49% to 13%
(Table 1, entries 4-5); in spite of this, it is noteworthy that no
symmetric ester benzyl benzoate was formed when 3 equivalents
of methanol was applied, demonstrating a selective esterification
method to produce 3aa. Several main group, transition metal, and
lanthanide complexes were also employed to evaluate the
influence of metal centers on reactivities, and except for Ti and Hf
compounds, all other homoleptic amido complexes served as
highly efficient precursors during the esterification, affording the
corresponding methyl benzoate in high yields. Metal alkoxides,
NaOMe and La(OiPr)3, showed quite similar behaviors as their
corresponding amido counterparts, inferring the a similar catalytic
species is present in both circumstances.
Table 2. Esterification between various aldehydes and alcohols. [a]
O
O
R2
]
Na[N(SiMe3)2
+
HO R2
R1
O
R1
H
3
( )
1
2
( )
( )
Entry
R1
R2
Yield (%)
Product
1
2
4-ClPh
4-NO2Ph
3-NO2Ph
4-CNPh
4-CF3Ph
4-MePh
4-MeOPh
2-pyridyl
2-thiophen
2-furyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
85%
90%
94%
93%
88%
71%
13%
90%
78%
44%
67%
81%
52%
12%
89%
78%
60%
3ba
3ca
3da
3ea
3fa
3
4
5
Table 1. Esterification between benzaldehyde and methanol under different
conditions. [a]
6
3ga
3ha
3ia
7
O
O
O
Cat.
8
+
+
HO
CH3
)
H
O
O
70o
C
9
3ja
10
11
12
13
14
15
16
17
3ka
3la
3aa
4
1a
2a
(
)
( )
(
)
(
1-naphthyl
2-naphthyl
Ph
[PhCHO]/
[MeOH]
Time
(h)
3aa
(%)[b]
4
3ma
3ab
3ac
3db
3dc
3de
Entry
Cat.
(%)[c]
1
2
NaN(SiMe3)2.
NaN(SiMe3)2.
NaN(SiMe3)2.
NaN(SiMe3)2.
NaN(SiMe3)2.
LiN(SiMe3)2.
KN(SiMe3)2.
1/1
2/1
3/1
1/2
1/3
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
6h
6h
49
68
81
23
13
85
80
73
68
3
15
31
34
6
Ph
iPr
3-NO2Ph
3-NO2Ph
3-NO2Ph
Et
3
6h
iPr
4
6h
Bn
5
6h
-
[a] Conditions: 0.007mmol catalysts, [Cat.]/[CHO]/[OH]= 1/150/50, 700 μL
C6D6, 70oC, 6h; substrates were added in the order of alcohols, catalyst,
aldehyde; yield was determined by 1H NMR spectroscopy of the crude
reaction mixture basing on alcohols.
6
12h
6h
35
28
20
6
7
8
Mg[N(SiMe3)2.]2
Zn[N(SiMe3)2.]2
Ti(NMe2)4
6h
9
12h
24h
24h
4h
10
11
12
13
14
15
16
-
Hf(Bn)4
31
87
74
86
79
81
3
Y[N(SiMe3)2.]3
Gd[N(SiMe3)2.]3
La[N(SiMe3)2.]3
NaOCH3
30
43
37
30
21
6h
6h
6h
La(OiPr)3
12h
[a] Conditions: 0.007mmol catalysts, [Cat.]/[OH]= 1/50, 700 μL C6D6, 70oC;
substrates were added in the order of alcohols, catalyst, aldehyde. [b] Yield
[c]
was determined by 1H NMR spectroscopye based on MeOH.
determined by 1H NMR spectroscopy based on PhCHO.
Yield
2 / 8
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10.1002/ejoc.201700756
European Journal of Organic Chemistry
FULL PAPER
1
( )
R1CH2OH
[M]
R2OH
R2OH
R1CHO
Symmetrical R1CHO
esters
Unsymmetrical
esters
OCH2R1
OCH2R1
OR2
[M]
R
1CH2OH
O
O
Route 1
Route 2
R2
Table 3. Esterification of benzaldehyde with methanol in the presence of
trifluoromethyl ketones using Na[N(SiMe3)2] [a]
[M]
R1
O
R1
R1
O
R1CH2OH
R1CO
OR2
R1COO
CH2R1
(%)[d]
2
( )
R3
R3CO
CF3
[R3COCF3]
/[OH]
Entry
R1CHO
R2OH
OH
R1
(%)[c]
O
R
F C
R2OH
3
R3
O
F3C
H
O
[M]
O
R
2
[M]
1
2
Ph
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Ph
1/1
3/1
1/1
1/1
76
97
60
71
3
-
R3
F3C
[M]
O
O
R3
ROH
R2
OH
R1
O
3[b]
4
Ph
2
-
F3C
3-MePh
Scheme 2. (1), Competitive routes for metal alkoxide species; (2),
plausible procedure for hydride transfer when using
trifluoromethyl ketone as an acceptor.
2-
5
Me
Ph
1/1
59
-
naphthyl
6
8
9
Ph
Ph
Ph
Et
Ph
1/1
3/1
3/1
30
93
86
-
-
-
During the above esterification studies, in the later stage of
the reaction, two undesired byproducts starts to accumulate, i.e.,
the symmetrically coupled Tishchenko ester and the substituted
benzyl alcohol, which were generated from the Tishchenko cycle
and proton transfer step, respectively (Scheme 2 (1)). Therefore,
it is demanding to circumvent these byproducts and make the
reaction proceed in a selective way. From Scheme 2 (1), we can
observe that for the metal alkoxide species, two competitive
routes are available, which give rise to the symmetrical ester
(route 1) and the unsymmetrical ester (route 2), respectively. We
envisage that increasing the alcohol concentration will facilitate
the proton transfer step and thus benefit the formation of the
unsymmetrical ester. This hypothesis was confirmed by our
above optimization studies, in which 3 equivalents of methanol
caused the reaction to proceed only via route 2, and furnishing
the target unsymmetrical ester as the sole product (table 1, entry
5). Another hypothesis towards the reactions amends the use of
ketones that can only serve as “hydrogen acceptor” during the six-
membered rate determining step (vide infra). The ketones will be
reduced into secondary alcohols,17, 18, 38, 39 and in view of our
aforementioned results, in which secondary alcohols performed
by far with inferior nucleophilicity than the primary alcohols, most
of them will be left unreacted in the reaction mixture. Therefore,
using the appropriate ketone will supitpress the Tishchenko cycle
and render the reaction to proceed in a “sacrificial fashion”
selectively towards the unsymmetrical ester (Scheme 2 (2)).
Based on these considerations, α,α,α-trifluoroacetophenone
(PhCOCF3) was employed as the “hydride acceptor” and the
results are summarized in Table 3. As expected, the presence of
PhCOCF3 suppresses route 1 efficiently, and only ~3% of the
homocoupled symmetrical ester was obtained for the reaction
between benzaldehyde and methanol. Using three equivalents of
PhCOCF3 is enough to completely shut off the symmetrically
coupling cycle, and yield the unsymmetrical ester as the sole ester
compounds. Similar results were also observed for other
aldehydes and alcohol substrates, indicating that PhCOCF3 acts
as an effective “hydride acceptor” during the six-membered
transition state, affording the unsymmetrical ester target in a
selective way. Two other types of trifluromethyl ketones were also
investigated as well, and both of them afforded similar results as
PhCOCF3. It is important to mention that no coupling products
between the aldehyde and PhCOCF3 were observed in these
studies.
Me
Me
4-BrPh
4-MePh
[a]
Conditions: 0.007mmol catalysts, [Cat.]/[CHO]/[OH]= 1/150/50, 700 μL C6D6,
70oC; substrates were added in the order of alcohols, catalyst, aldehyde, ketone.
[b] [Cat.]/[CHO]/[OH]= 1/50/50. [c] Yield was determined by 1H NMR spectroscopy
of the crude reaction mixture based on MeOH. [d] Yield was based on aldehyde.
Figure 1. Reaction progress monitoring for PhCHO/CH3OH/ Na[N(SiMe3)2]
system.
The progress of the catalytic reaction between
PhCHO/MeOH and Na[N(SiMe3)2] was followed by 1H NMR
spectroscopy and presented in Figure 1. By tracking the reaction
spectroscopically, it is shown that the substituted benzyl alcohol
is produced concomitantly with the unsymmetrical ester 3aa from
the beginning of the reaction, with a roughly 1/1 ratio. The benzyl
benzoate can be observed only at later stages of the reaction,
when most of the MeOH was consumed, and the Tishchenko
reaction became predominant. These observations indicates that
there is no transesterification between benzyl benzoate and
sodium methoxide as an additional pathway in the synthesis of
the unsymmetrical ester.
3 / 8
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10.1002/ejoc.201700756
European Journal of Organic Chemistry
FULL PAPER
O
with a KIE (kMeOH/kMeOD) value of 1.05 (Figure 2), suggesting a
ester
byproduct
Symmetrical
R1
R1
O
rapid proton transfer step between metal alkoxide species and
alcohols. On the contrary, reaction of MeOH with benzaldehyde-
d (PhCDO) were slower as compared to the PhCHO/MeOH
G
R
1CH2OH
O
R2
systems revealing a primary kinetic isotope effect (kPhCHO/kPhCDO=
R1
O
O
[M]
R
2OH
F
3.1). This result indicates that the hydride transfer is the rate-
determining step.
R1
CH2
E
R
1CH2OH
R
2OH
R1
O
R2
R
2OH
O
R
1CH2OH
H
MN''
O
O
[M]
Conclusions
H
A
R2
B
[M]
HN''
R1
In summary, an evolved Tishchenko reaction towards the
coupling of aldehydes and alcohols is disclosed herein for the
production of asymmetrical ester in high yields and under very
mild condistions. The reaction is applicable to wide range of
aldehyde and alcohol substrates. The use of sacrificial
trifluoromethyl ketones affords the asymmetrical ester in a
selective manner. An plausible mechanism for the present
reaction was proposed based on reaction progress monitoring
and deuterium labeling studies.
D
R1
O
R1
R2
O
O
O
[M]
R1
C
Scheme 3. Proposed schemes for coupling reation betweena
aldehydes and alcohols.
0.4
PhCHO+CH3OH
0.35
Experimental Section
y = 0.000112 x - 0.012037
R² = 0.998231
0.3
General considerations
PhCHO+CH3OD
0.25
0.2
All manipulations of air-sensitive materials were performed with the
rigorous exclusion of oxygen and moisture in flamed Schlenk-type
glassware or J-Young Teflon valve-sealed NMR tubes on a dual manifold
Schlenk line interfaced to a high vacuum (10-5 Torr) line, or in a nitrogen-
y = 0.000107 x - 0.027438
R² = 0.990212
0.15
0.1
PhCDO+CH3OH
filled Innovative Technologies glovebox with
a medium-capacity
y = 0.000037 x - 0.005170
R² = 0.998737
recirculator (1 – 2 ppm of O2). Argon and nitrogen were purified by
passage through MnO oxygen-removal column and a Davison 4Å
molecular sieve column. Hydrocarbon solvents benzene-d6 (Cambridge
Isotopes), toluene (Bio-Lab), were distilled under vacuum from Na/K alloy.
Liquid aldehydes were distilled over sodium bicarbonate and stored in a
glovebox prior to use, solid aldehydes were recrystallized twice and then
dried for 12 h on a high vacuum line (10-5 Torr) and stored in a glovebox
prior to use. Methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol
was dried using sodium (Na) metal (or CaH2), distilled, and stored over 4
0.05
0
0
1000
2000
3000
4000
5000
6000
7000
Time （s)
Figure 2. Initial reaction progress of the reaction of precatalyst
NaN(SiMe3)2, PhCHO (or PhCDO), CH3OH (MeOD).
On the basis of the above experimental results, a plausible
reaction mechanism is proposed (Scheme 3). In the first step, the
metal amido precatalyst is protonolyzed with the alcohols,
affording the metal alkoxide species B. Subsequent insertion of
an aldehyde into this alkoxide compound will yield the
intermediate complex C, which undergoes a hydride transfer with
an additional aldehyde (D) and furnishes the unsymetrical ester F
and the alkoxo intermediate complex E. A proton transfer between
complex E and the alcohol regenerates the initial metal alkoxide
complex B and start a new cycle. As the reaction progresses,
alcohols will be consumed gradually, which slow down the proton
transfer process, and the metal alkoxide species E will start
coupling two molecules of aldehyde, giving rise to the symmetrical
ester byproduct G. In the presence of the sacrificial trifluoromethyl
ketones, they will outcompete with the aldehyde for the metal
hemiacetal complex C, and the the hydride transfer will give rise
to trifluoromethylbenzylalcoholate metal compounds, which will
undergo a rapid proton tranfer with alcohols to regenerate the
initial active species B. To understand the turnover limiting step,
reactions with deuterated substrates were carried out. When
reacting benzaldehyde with MeOD using Na[N(SiMe3)2], a similar
rate constant as with the PhCHO/MeOH system was obtained
Å
molecular sieves. LiN(SiMe3)2, NaN(SiMe3)2, KN(SiMe3)2,
Mg[N(SiMe3)2]2, Zn[N(SiMe3)2]2, Y[N(SiMe3)2]3, Gd[N(SiMe3)2]3 were
prepared according to published procedures.40-45 All the aforementioned
reagents were stored in an inert atmosphere glovebox prior to use. O-
deuterated methanol was purchased from Sigma Aldrich, and dried
according the above procedure, and storing over 4 Å molecular sieves.
Deuterated benzaldehyde PhCDO was prepared according to previous
reports, storing over 4 Å molecular sieves after being dried.46 NMR spectra
were recorded on Bruker Avance 300, Bruker Avance III 400
spectrometers on crude reaction mixtures. Chemical shifts for 1H and 13
C
NMR are referenced to internal protiosolvent and reported relative to
tetramethylsilane.
General procedures for coupling aldehydes with alcohols
In a typical experiment, into a J. Young Teflon sealed NMR tube was
added desired amount of catalyst in C6D6, followed by adding alcohol (50
equiv.) and aldehyde (150 equiv.) respectively (trifluoromethyl ketone was
added when necessary). Samples were then sealed and placed in an oil
bath preheated to 70 °C, and the reaction progress monitored at regular
1
intervals using H NMR spectroscopy. The yield was calculated from the
ratio of esters and alcohols from the crude 1H NMR spectra (see examples
in Figure 1). After completion of the reaction, all the ester pure product was
4 / 8
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10.1002/ejoc.201700756
European Journal of Organic Chemistry
FULL PAPER
obtained by flash column chromatography on silica gel (n-hexane : EtOAc
δ 8.14 (d, J = 8.1 Hz, 1H, HAr), 7.69 (d, J = 8.1 Hz, 1H, HAr), 3.94 (s, 1H,
CH3). MS (APCI): m/z 205.0433(M+H)*.
= 20:1) and compared with previous reports.
Deuterium labeling studies.
Methyl 4-methylbenzoate49 (3ga): reaction of 4-methylbenzaldehyde
(1.044mmol, 123.1 µL) with methanol (0.348mmol, 14.1µL) was carried
out following the general procedure described above, affording 3ga with
yield of 71% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave colorless oil
(isolated yield: 28 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 7.92 – 7.84 (m,
2H, HAr), 7.19 – 7.14 (m, 2H, HAr), 3.87 (s, 3H, CH3), 2.38 (s, 3H, CH3).
13C NMR (75 MHz, CDCl3) δ 167.10, 143.46, 129.48, 128.97, 127.28,
51.39, 21.29. MS (APCI): m/z 151.0758 (M+H)*.
Into a J. Young Teflon sealed NMR tube was added desired amount
of catalyst in C6D6, followed by adding methanol (50 equiv.) (or MeOD)
and aldehyde (150 equiv.) (or PhCDO) respectively. Take the tube out of
the glove box and freeze it in ice bath until the 1H NMR experiment began.
All the experiments were done by changing one substrate or catalyst while
keeping the other reagents constant, and the data was collected every two
minutes up to 6 hours. The reaction progresses were shown in Figure 2.
Methyl benzoate47 (3aa): reaction of benzaldehyde (1.044mmol, 106.4
µL) with methanol (0.348mmol, 14.1µL) was carried out following the
general procedure described above, affording 3aa with yield of 81%
(based on methanol) from 1H NMR. Purification by flash chromatography
on silica gel (n-hexane/EtOAc 20/1) gave colorless oil (isolated yield: 34
mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.13 – 7.86 (m, 2H, HAr), 7.67 –
7.33 (m, 3H, HAr), 3.94 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3) δ 167.13,
132.92, 130.13, 129.57, 128.36, 52.12. MS (APCI): m/z 137.0607(M+H)*.
Methyl 4-chlorobenzoate48 (3ba): reaction of 4-chlorobenzaldehyde
(1.044mmol, 146.8mg) with methanol (0.348mmol, 14.1µL) was carried
out following the general procedure described above, affording 3ba with
yield of 85% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave off-white solid
(isolated yield: 49 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.05 – 7.84 (m,
2H, HAr), 7.50 – 7.31 (m, 2H, HAr), 3.89 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 166.15, 139.26, 130.86, 128.61, 128.45, 51.92. MS (APCI): m/z
171.0204 (M+H)*.
Methyl 4-nitrobenzoate49 (3ca): reaction of 4-nitrobenzaldehyde
(1.044mmol, 157.8mg) with methanol (0.348mmol, 14.1µL) was carried
out following the general procedure described above, affording 3ca with
yield of 90% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave off-white solid
(isolated yield: 51 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 8.41 – 8.22 (m,
2H, HAr), 8.17 (m, 2H, HAr), 3.98 – 3.86 (m, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 165.07, 150.35, 135.35, 130.60, 123.44, 52.74. MS (APCI): m/z
182.0476(M+H)*.
Methyl anisate49 (3ha): reaction of 4-anisaldehyde (1.044mmol, 126.8µL)
with methanol (0.348mmol, 14.1µL) was carried out following the general
procedure described above, affording 3ha with yield of 13% (based on
methanol) from 1H NMR. Purification by flash chromatography on silica gel
1
(n-hexane/EtOAc 20/1) gave colorless oil (isolated yield: 6 mg, 10%). H
NMR (300 MHz, CDCl3) δ 8.03 – 7.87 (m, 2H, HAr), 6.95 – 6.73 (m, 2H,
H
Ar), 3.87 – 3.86 (m, 3H, CH3), 3.85 – 3.83 (m, 2H, CH3). 13C NMR (75
MHz, CDCl3) δ 166.78, 163.22, 131.48, 122.53, 113.32, 55.21, 51.71. MS
(APCI): m/z 166.01 (M+H)*.
Methyl picolinate52 (3ia): reaction of 2-pyridinecarboxaldehyde
(1.044mmol, 99.3 µL) with methanol (0.348mmol, 14.1µL) was carried out
following the general procedure described above, affording 3ia with yield
of 90% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave colorless oil
(isolated yield: 40 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.81 – 8.63 (m,
1H, HAr), 8.28 – 7.96 (m, 1H, HAr), 7.88 – 7.64 (m, 1H, HAr), 7.54 – 7.36
(m, 1H, HAr), 3.99 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 165.59,
149.69, 147.82, 136.92, 126.83, 125.01, 52.78. MS (APCI): m/z 138.0572
(M+H)*.
Methyl thenoate53 (3ja): reaction of 2-thenaldehyde (1.044mmol, 97.6 µL)
with methanol (0.348mmol, 14.1µL) was carried out following the general
procedure described above, affording 3ja with yield of 78% (based on
methanol) from 1H NMR. Purification by flash chromatography on silica gel
(n-hexane/EtOAc 20/1) gave colorless oil (isolated yield: 29 mg, 60%). 1H
NMR (300 MHz, CDCl3) δ 7.80 – 7.77 (m, 1H, HAr), 7.55 – 7.52 (m, 1H,
H
Ar), 7.11 – 7.06 (m, 1H, HAr), 3.87 (s, 3H, CH3). 13C NMR (75 MHz,
Methyl 3-nitrobenzoate50 (3da): reaction of 3-nitrobenzaldehyde
(1.044mmol, 157.8mg) with methanol (0.348mmol, 14.1µL) was carried
out following the general procedure described above, affording 3da with
yield of 94% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave off-white solid
(isolated yield: 55 mg, 87%) 1H NMR (300 MHz, CDCl3) δ 8.91 – 8.76 (m,
1H, HAr), 8.50 – 8.25 (m, 2H, HAr), 7.74 – 7.50 (m, 1H, HAr), 3.98 (s, 3H,
CH3). 13C NMR (75 MHz, CDCl3) δ 164.86, 148.14, 135.18, 131.73,
129.54, 127.30, 124.51, 52.72. MS (APCI): m/z 182.0411(M+H)*.
Methyl 4-cyanobenzoate49 (3ea) reaction of 4-cyanobenzaldehyde
(1.044mmol, 136.9mg) with methanol (0.348mmol, 14.1µL) was carried
out following the general procedure described above, affording 3ea with
yield of 93% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave off-white solid
(isolated yield: 49 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 8.15 – 8.00 (m,
2H, HAr), 7.80 – 7.55 (m, 2H, HAr), 3.93 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 165.33, 133.79, 132.12, 129.99, 117.87, 116.27, 52.64. MS
(APCI): m/z 162.0563 (M+H)*.
CDCl3) δ 162.83, 133.71, 133.38, 132.22, 127.65, 51.96. MS (APCI): m/z
143.0174 (M+H)*
Methyl 2-furoate53 (3ka): reaction of 2-furaldehyde (1.044mmol, 87µL)
with methanol (0.348mmol, 14.1µL) was carried out following the general
procedure described above, affording 3ka with yield of 44% (based on
methanol) from 1H NMR. Purification by flash chromatography on silica gel
(n-hexane/EtOAc 20/1) gave colorless oil (isolated yield: 15 mg, 34%). 1H
NMR (300 MHz, CDCl3) δ 7.59 – 7.53 (m, 1H, HAr), 7.19 – 7.13 (m, 1H,
H
Ar), 6.54 – 6.46 (m, 1H, HAr), 3.88 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 158.95, 146.15, 143.41, 117.80, 111.71, 51.79. MS (APCI): m/z
127.0411 (M+H)*.
Methyl naphthalene-1-carboxylate49 (3la): reaction of 1-naphthaldehyde
(1.044mmol, 141.8µL) with methanol (0.348mmol, 14.1µL) was carried out
following the general procedure described above, affording 3la with yield
of 67% (based on methanol) from 1H NMR. Purification by flash
chromatography on silica gel (n-hexane/EtOAc 20/1) gave off-white solid
(isolated yield: 41 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 8.92 – 8.83 (m,
1H, HAr), 8.20 – 8.11 (m, 1H, HAr), 8.01 (d, J = 8.2 Hz, 1H, HAr), 7.91 –
7.80 (m, 1H, HAr), 7.64 – 7.56 (m, 1H, HAr), 7.56 – 7.43 (m, 2H, HAr), 3.99
(s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 167.95, 133.71, 133.27, 131.20,
130.11, 128.43, 127.66, 126.95, 126.10, 125.68, 124.39, 51.71. MS
(APCI): m/z 187.0838 (M+H)*.
Methyl
4-trifluoromethylbenzoate51
(3fa):
reaction
of
4-
trifluorobenzadehyde (1.044mmol, 140.0µL) with methanol (0.348mmol,
14.1µL) was carried out following the general procedure described above,
affording 3fa with yield of 88% (based on methanol) from 1H NMR.
Purification by flash chromatography on silica gel (n-hexane/EtOAc 20/1)
gave colorless oil (isolated yield: 51 mg, 72%). 1H NMR (300 MHz, CDCl3)
Methyl
naphthalene-2-carboxylate49 (3ma):
reaction
of
2-
naphthaldehyde (1.044mmol, 163.5mg) with methanol (0.348mmol,
5 / 8
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10.1002/ejoc.201700756
European Journal of Organic Chemistry
FULL PAPER
14.1µL) was carried out following the general procedure described above,
affording 3ma with yield of 81% (based on methanol) from 1H NMR.
Purification by flash chromatography on silica gel (n-hexane/EtOAc 20/1)
gave off-white solid (isolated yield: 49 mg, 76%). 1H NMR (300 MHz,
CDCl3) δ 8.60 (s, 1H, HAr), 8.05 (d, J = 8.6 Hz, 1H, HAr), 7.98 – 7.91 (m,
1H, HAr), 7.90 – 7.82 (m, 2H, HAr), 7.61 – 7.48 (m, 2H, HAr), 3.97 (s, 3H,
CH3). 13C NMR (75 MHz, CDCl3) δ 167.17, 135.39, 132.36, 130.96,
129.25, 128.13, 128.05, 127.65, 127.26, 126.53, 125.11, 52.03. MS
(APCI): m/z 187.0762 (M+H)*.
Supporting Information
1H and 13C NMR of the products (34 pages)
Acknowledgements
This work was supported by the Israel Science Foundation
administered by the Israel Academy of Science and Humanities under
Contract No. 78/14; and by the PAZY Foundation Fund (2015)
administered by the Israel Atomic Energy Commission. H.L. thanks
the Technion-Guangdong Fellowship Program.
Methyl benzoate53 (3ab): reaction of benzaldehyde (1.044mmol, 106.4
µL) with ethanol (0.348mmol, 20.3 µL) was carried out following the
general procedure described above, affording 3ab with yield of 52%
(based on methanol) from 1H NMR. Purification by flash chromatography
on silica gel (n-hexane/EtOAc 20/1) gave colorless oil (isolated yield: 21
mg, 41%). 1H NMR (300 MHz, CDCl3) δ 8.07 – 7.95 (m, 2H, HAr), 7.57 –
7.45 (m, 1H, HAr), 7.45 – 7.34 (m, 2H, HAr), 4.51 – 4.19 (q, J = 7.2 Hz, 2H,
CH2), 1.36 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 166.43,
132.68, 130.37, 129.22, 128.07, 60.57, 14.19. MS (APCI): m/z 151.0748
(M+H)*.
Keywords: Alcohols • Aldehydes • Esterification • Selective •
Tishchenko reaction
REFERENCES
Isopropyl benzoate54 (3ac): reaction of benzaldehyde (1.044mmol, 106.4
µL) with isopropanol (0.348mmol, 26.6µL) was carried out following the
general procedure described above, affording 3ac with yield of 12%
(based on methanol) from 1H NMR. Purification by flash chromatography
on silica gel (n-hexane/EtOAc 20/1) gave colorless oil (isolated yield: 6 mg,
10%). 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.2 Hz, 2 H, HAr), 7.55 (t,
J = 7.6 Hz, 1 H, HAr), 7.44 (t, J = 7.6 Hz, 2 H, HAr), 4.38 (q, J = 5.6 Hz, 2
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69.38, 21.76. MS (APCI): m/z 209.0431.
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European Journal of Organic Chemistry
FULL PAPER
Table of Contents
New Esterificationmethod*
reaction
Evolved Tishchenko
O
O
CF3
R3
Heng Liu, Moris S. Eisen*
O
esters
Asymmetric
R1
+
R1 OH
R2
O
R2
H
Page No. – Page No.
Selective esterification
Title: Facile Coupling Aldehydes with
Alcohols: An Evolved Tishchenko
Process in Preparing Unsymmetrical
Esters
Table of Contents
An evolved Tishchenko reaction betweeen alcohols and aldehydes to afford unsymmetrical ester compounds is reported
herein. The presence of sacrifical trifluoromethyl ketones are able to render the reaction process in the highly selective
fashion.
8 / 8
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