Practical selective monohydrolysis of bulky symmetric diesters: Comparing with sonochemistry

Article abstract of DOI:10.1016/j.tet.2018.09.051

The conditions of the practical selective monohydrolysis of symmetric diesters we previously reported have been modified and applied to selective monohydrolysis of bulky symmetric diesters. While ultrasound is generally considered effective for two-phase reactions, its effect actually turned out to be rather marginal. Instead, use of a larger proportion of a polar aprotic co-solvent, DMSO, and aqueous KOH helped enhance the reaction rates and improve the yields of the half-esters. The reactions are simple, mild and practical without special devices.

Full text of DOI:10.1016/j.tet.2018.09.051

Accepted Manuscript
Practical selective monohydrolysis of bulky symmetric diesters: Comparing with
sonochemistry
Jianjun Shi, Tian Zhao, Satomi Niwayama
PII:
S0040-4020(18)31147-5
10.1016/j.tet.2018.09.051
TET 29823
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 July 2018
Revised Date: 25 September 2018
Accepted Date: 26 September 2018
Please cite this article as: Shi J, Zhao T, Niwayama S, Practical selective monohydrolysis of bulky
symmetric diesters: Comparing with sonochemistry, Tetrahedron (2018), doi: https://doi.org/10.1016/
j.tet.2018.09.051.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Practical Selective Monohydrolysis of Bulky Symmetric Diesters: Comparing with
Sonochemistry
Jianjun Shi,a,† Tian Zhao,b,‡ and Satomi Niwayama*,a,b
a: Graduate School of Engineering, Muroran Institute of Technology,
27-1, Mizumoto-cho, Muroran, Hokkaido, 050-8585, Japan
b: Department of Chemistry and Biochemistry,
Texas Tech University, Lubbock, TX 79409-1061, U. S. A.
Abstract: The conditions of the practical selective monohydrolysis of symmetric diesters we
previously reported have been modified and applied to selective monohydrolysis of bulky symmetric
diesters. While ultrasound is generally considered effective for two-phase reactions, its effect actually
turned out to be rather marginal. Instead, use of a larger proportion of a polar aprotic co-solvent,
DMSO, and aqueous KOH helped enhance the reaction rates and improve the yields of the half-esters.
The reactions are simple, mild and practical without special devices.
Key Words: selective monohydrolysis; half-ester, symmetric diester; sonochemistry; practical
synthesis
1. Introduction
Half-esters have been important building blocks for synthesis of various classes of compounds
such as polymers, natural products, and pharmaceuticals.1 Among the most typical methods for their
preparation is monohydrolysis of one of the two identical ester groups in symmetric diesters. The
challenge in this method, however, is to distinguish two identical groups. Consequently, classical
1

ACCEPTED MANUSCRIPT
saponification typically leads to complex mixtures of the starting diester, the corresponding diacid,
and a small amount of half-esters.2
Previously we reported selective monohydrolysis of symmetric diesters. This reaction allows
selective monohydrolysis of symmetric diesters in high yields under practical conditions (Scheme 1).3
Scheme 1 Selective monohydrolysis of symmetric diesters
However, in this reaction, monohydrolysis of relatively bulky symmetric diesters typically
takes a long time, or needs greater amounts of a base in order to consume the starting diesters.
Scheme 2 shows some examples for diesters with the same norbornadiene skeleton.3 The
monohydrolysis of dimethyl ester, needs approximately one hour with about 2 equivalents of the base.
As the size of the ester groups increase, the reaction time and the amount of the base also increases.4
Scheme 2 Some examples of selective monohydrolysis
2

ACCEPTED MANUSCRIPT
This trend is reflective of our previous observation that the monohydrolysis occurs at the
interface between the aqueous phase and the diester, which means that bulky alkyl groups reduce the
contact with the aqueous phase. The problem is that the extended reaction time tends to reduce the
yields of the half-esters. Therefore, we attempted to improve the selectivity of the reactions by
adjusting the reaction conditions.
Regarding the mechanisms of this selectivity, we hypothesize that after one of the two
identical ester groups is monohydrolyzed, the resultant intermediary carboxylates form micellar
aggregates in which the remaining hydrophobic parts are directed inside with the hydrophilic
carboxylate groups being outside. Such aggregates may potentially prohibit further hydrolysis with
the remaining ester groups intact. In fact, in consonant with this hypothesis, we observed that a water-
miscible polar aprotic co-solvent such as THF, CH3CN, and DMSO increases the reaction rate and
selectivity, while a protic co-solvent such as an alcohol decreases the selectivity.5,6 This decrease of
the reaction rate is likely to be attributed to dissociation of the micellar aggregates. In addition, we
reported that KOH often improves selectivities compared to NaOH, perhaps due to stronger affinity of
the K+ cation with carbonyl oxygen, leading to the enhanced electrophilicity of the starting ester
group.7 We demonstrated that improvement of the selectivities is possible for various symmetric
diesters including dialkyl malonates.8,9
Therefore, based on this hypothesis and supporting observations, we tried to improve the
selectivities of various bulky symmetric diesters.
2. Results and discussion
We first applied ultrasound to the monohydrolysis, as ultrasound-assisted reactions are known
to increase reaction rates of heterogeneous reactions including two-phase reactions.10 The results are
summarized in Table 1.
3

ACCEPTED MANUSCRIPT
Table 1. Effects of ultrasounds in selective monohydrolysis of dialkyl bicycle[2.2.1]hept-2,5-
diene-2,3-dicarboxylates
We first tried to monohydrolyze diester 1. Indeed the acceleration of the reaction was
observed with a comparable yield (Run 2), as the reaction time for the monohydrolysis was shortened
from 1 hour to 15 minutes by sonication. The amount of co-solvent is 7% as we reported previously.3
However, in the case of the corresponding diisopropyl ester, the situation was different.
The
monohydrolysis was completed in about 19 hours without ultrasound (Run 3). With the same
equivalent of the base, KOH, using DMSO as a co-solvent, which was previously observed to enhance
the reaction rates,6 only 19% of the half-ester was obtained after 8 h sonication (Run 5). Runs 6-8
show that greater yields of the half-ester can be obtained with the increased base within shorter
reaction times with DMSO. However, no significant improvement in the yields was achieved beyond
the addition of 3.0 equivalents of the base. Therefore, it is questionable whether the reaction rate was
accelerated by ultrasound or by increased amounts of the base.
Somewhat interesting results were selective monohydrolysis of dipropyl phenyl malonate, 4.
We had reported that this monohydrolysis reaction took 33 hours with 0.8 equivalents of aqueous
4

8
ACCEPTED MANUSCRIPT
KOH, yielding about 77% of half-ester, 4a. We attempted to improve the results by applying
ultrasound with DMSO and aqueous KOH. The results are shown in Table 2.
Table 2 Effects of ultrasounds in selective monohydrolysis of dipropyl phenyl malonate
As can be seen from this table, when ultrasound was applied to the conditions we reported
before,8 only 6% of the half-ester was obtained even after 10 hours, which is the maximum amount of
the processing time of the sonicator with recovery of 76% of the starting diester (Run 1), which means
that ultrasound did not help accelerate the reaction. As the amount of the base increases, the yield of
half-ester 4a also increases with shorter sonication time. When 3 equivalents of the base were used
with ultrasound, 83% of the half-ester was obtained with only 2 hours (Run 4). In order to confirm
that this acceleration was due to ultrasound instead of the greater amount of the base, the same
reaction condition was performed without ultrasound. The yield of the half-ester was only 10% with
recovery of 81% diester after 2.5 hours (Run 5). Therefore, it appears that the ultrasound helped
accelerate the selective monohydrolysis of dipropyl phenyl malonate.
From these results, we conclude that it may be possible by ultrasound to increase the reaction
rate of some small-sized diesters such as a dimethyl ester without decreasing the selectivity. Some
bulkier diesters may need additional amounts of base as a trigger of the ultrasonic effect in the
5

ACCEPTED MANUSCRIPT
monohydrolysis. It is noteworthy that long duration processing by ultrasound tends to overheat the
reaction vessel, requiring special precaution for cooling.
We next tried to modify the reaction conditions based on our proposed mechanistic hypothesis
without relying on a special device.11 We first screened the selective monohydrolysis of dialkyl
bicycle[2.2.1]hept-2,5-diene-2,3-dicarboxylates, which were synthesized in high yields by simple
Diels-Alder reactions of cyclopentadiene and the corresponding acetylene dicarboxylates.12 The
results are summarized in Table 3.
Table 3 Selective monohydrolysis of dialkyl bicycle[2.2.1]hept-2,5-diene-2,3-dicarboxylates
6

ACCEPTED MANUSCRIPT
Again monohydrolysis of dimethyl ester, 1, proceeded quite efficiently regardless of the type
of the co-solvent or base, producing the half-ester in almost quantitative yields, although DMSO and
KOH again appeared to have somewhat enhanced the reaction rate, consistently with our previous
observations. The volume percentage of the co-solvent is the same as reported before (7%), which
was found to be optimal for this diester.3
7

3
ACCEPTED MANUSCRIPT
As we reported before, diethyl ester 2 needed about 3-4 times as much base. KOH also
worked better than NaOH. It became noticeable that the selectivities increased as the amount of THF
increased even with the use of 1.7 equivalents of the base, and the optimal conditions existed when
THF was between 13% and 67%. However, selectivity was rather significantly improved when
DMSO was employed as a co-solvent, and the best and comparable results to the dimethyl ester, 1,
were obtained when 44-67% of DMSO was used in combination with aqueous KOH. These
conditions were also effective for the diipropyl ester, 3, and di-n-propyl ester, 5, but the increased
selectivities and reaction rates were achieved when a greater amount of DMSO was used. Therefore,
it appears that use of a larger amount of DMSO helps improve the selectivity as the bulkiness of the
diesters increases. A greater proportion of THF or DMSO was applied for monohydrolysis of di-n-
butyl ester, 6, and the effect of DMSO instead of THF became clearer for this monohydrolysis. The
reaction times have also been shortened significantly even with the use of 1.7 equivalents of the base.
From these results, it appears that the optimal volume percentage of the co-solvent tends to
increase with the increase of the size of the ester group. This greater proportion of polar aprotic co-
solvent is likely to help increase the contact of the hydrophobic ester groups and the aqueous phase,
which can increase the chance for hydrolysis of one of the two ester groups. The co-solvent is also
likely to help protect the potential micellar aggregates formed from the intermediary carboxylates of
bulky half-esters described above, and thereby prohibit further hydrolysis. The unsuccessful results
with the ultrasound-assisted conditions described above may also be due to potential dissociation of
the aggregates by sonication.
Gratifyingly, when monohydrolysis of diisopropyl phenyl malonate, 4, was performed with the
use of DMSO as a co-solvent, significant enhancement of the reaction rate was again observed, while
we needed 33 hours with the conditions reported previously.9 The starting diester was consumed in 6
hours under these conditions. Although this reaction time is slightly longer than with the ultrasound,
when the same equivalent of the base (3.0 eq) was used, the yield has been improved to 86%, which is
better than the ultrasound-assisted conditions described above.
8

ACCEPTED MANUSCRIPT
Table 4 Selective monohydrolysis of propyl phenyl malonate
o
From a technical point of view, use of a larger proportion of THF at 0 C also sometimes
formed hydrates,13 hampering the stirring of the reaction mixture, but this was not the case with
DMSO. The product half-esters also all show high purities, despite the fact that DMSO is less volatile
than THF or CH3CN and may take a longer time to completely evaporate. As we reported before,8,9
the corresponding diacids, if extant, remained in the aqueous phase and were not isolated or only a
trace amount was isolated after the reaction mixture was worked up.
Based on the proportions that turned out to be the best in each reaction in Table 3, we next
tried selective monohydrolysis of several bulky dialkyl phthalates, all of which are readily available
inexpensively. The product half-esters, monoalkyl phthalates, exhibit a wide range of applications to
various industrial products such as plasticizers and adhesives, as well as to synthesis of a variety of
pharmaceuticals and polymers,14 but they are rather expensive. Therefore, methods for their cost-
effective production have been under close scrutiny.15
The results are summarized in Table 5. Here again, the effect of DMSO as a co-solvent is
more remarkable. In all the cases, the yields of the corresponding half-esters are significantly higher
with DMSO than with THF. The equivalent of the base applied in each run was only about 1.7
9

ACCEPTED MANUSCRIPT
equivalent, but the reaction rate was significantly faster with DMSO than with THF. Again, the
optimal percentage of the co-solvent tends to increase as the size of the ester groups increases.
Table 5 Selective monohydrolysis of dialkyl phthalates
10

ACCEPTED MANUSCRIPT
3. Conclusions
In summary, we found that the use of a larger proportion of a water-miscible polar aprotic co-
solvent, DMSO, and aqueous KOH can accelerate the selective monohydrolysis of a series of bulky
symmetric diesters, leading to enhancement of the selectivity, producing the corresponding half-esters
in high yields. This additional factor helps improve the results of the monohydrolysis reaction for
bulky diesters in addition to a longer reaction time, use of other polar aprotic co-solvents such as THF
or CH3CN,16 and/or greater amounts of an aqueous base when the reactivity is low. Although
ultrasound-assisted conditions are generally perceived to enhance reaction rates of water-mediated
reactions, these conditions turned out to have marginal effects for these monohydrolysis. Instead,
conditions applying greater proportions of a polar aprotic solvent, DMSO, are practical and do not
require a special device or expensive reagents. These conditions are also consistent with our
mechanistic hypothesis and previous observations. All the half-esters synthesized by this method are
stable and exhibit excellent purities.
4. Experimental section
General procedure for ultrasound-assisted selective monohydrolysis of symmetric diesters
A diester (0.60 mmol) was dissolved in 1 mL of DMSO or THF and 14-X (X:volume of the aqueous
KOH) mL of water was added. The probe of the sonicator (VCX 750 sonicator, Sonics & Materials
o
Inc., USA) was immersed in the reaction mixture. The reaction mixture was cooled to 0 C, and the
sonicator was turned on. To this mixture was added the indicated equivalent of a 0.5M aqueous KOH
solution dropwise. The reaction mixture was irradiated under 20kHz ultrasound (750W, tip diameters
of 13 mm) until the starting diester was consumed according to TLC or until the maximum amount of
the processing time of the sonicator (10 hours) was elapsed, acidified with 1.0 M HCl, saturated with
NaCl, extracted with ethyl acetate, washed with brine, and dried over Na2SO4. The extract was
concentrated in vacuo and purified by silica gel column chromatography with hexane:ethyl acetate and
ethyl acetate to afford monopropyl ethyl malonate.
11

ACCEPTED MANUSCRIPT
General procedure for selective monohydrolysis of norbornadiene without sonication
A diester (1.2 mmol) was dissolved in the specified amount of THF or DMSO, and the specified
amount of water was added. The reaction mixture was immersed in an ice-water bath and cooled to 0
oC. To this reaction mixture was added the aqueous base in small portions with stirring until the
starting diester was consumed according to TLC. The reaction mixture was acidified with 1.0 M HCl
o
at the same temperature (0 C), saturated with NaCl, extracted with ethyl acetate three to four times,
and dried over Na2SO4. The extracts were evaporated in vacuo and purified by silica gel column
chromatography to afford the desirable half-ester.
General procedure for selective monohydrolysis of diisopropyl phenyl malonate without
sonication
Dipropyl phenyl malonate (316 mg, 1.2 mmol) was dissolved in the specified amount of DMSO and
o
the specified amount of water was added, and the reaction mixture was cooled to 0 C. To this
mixture was added 0.5M KOH in small portions with stirring until the starting diester was consumed
according to TLC. The reaction mixture was acidified with 1.0 M HCl at the same temperature (0 oC),
saturated with NaCl, extracted with ethyl acetate three to four times, and dried over Na2SO4. The
extract was concentrated in vacuo and purified by silica gel column chromatography with
hexane:ethyl acetate and ethyl acetate to afford monopropyl ethyl malonate.
General procedure for selective monohydrolysis of dialkyl phthalate without sonication
A diester (1.2 mmol) was dissolved in the specified amount of THF or DMSO, and the specified
amount of water was added. The reaction mixture was immersed in an ice-water bath and cooled to
0
. To this reaction mixture, 4mL of 0.5 M KOH was added in small portions with stirring until the
starting diester was consumed according to TLC. The reaction was stirred at the same temperature. It
was then acidified with 1.0 M HCl at 0 , saturated with NaCl, extracted with ethyl acetate three to
four times, and dried over Na2SO4. The extracts were evaporated in vacuo and purified by silica gel
column chromatography to afford the desirable half-ester.
The spectral data for all the half-esters reported here are as follows:
12

1
ACCEPTED MANUSCRIPT
Half-ester 1a. White solid. H NMR (500 MHz, CDCl3) δ= 2.13 (1H, d, J = 7.0 Hz), 2.23 (1H, d, J =
7.0 Hz), 3.94 (3H, s), 4.10 (1H, br. s), 4.25 (1H, br. s), 6.90 (2H, m);13C NMR (125 MHz, CDCl3) δ=
53.52, 53.89, 54.88, 72.83, 141.87, 142.83, 151.14, 162.55, 162.66, 168.31; mp 107-108 °C (lit.108-
109 °C).17 HRMS Calcd for C10H11O4 (M+H)+: 195.0675. Found: 195.0651.
Half-ester 2a. Oil. 1H NMR (500 MHz, CDCl3) δ= 1.40 (3H, t, J = 7.5 Hz), 2.13 (1H, d, J = 7.0 Hz),
2.24 (1H, d, J = 7.0 Hz), 4.10 (1H, br.s), 4.28 (1H, br. s), 4.38 (2H, m), 6.91 (2H, m); 13C NMR (125
MHz, CDCl3) δ= 14.08, 53.51, 54.88, 63.49, 72.83, 141.88, 142.90, 151.50, 162.34, 162.81, 167.91.
HRMS Calcd for C11H13O4 (M+H)+: 209.0813. Found: 209.0818.
Half-ester 3a. Oil. 1H NMR (500 MHz, CDCl3) δ= 1.38 (6H, dd, J = 6.0 Hz, J = 6.5 Hz), 2.12 (1H, d,
J = 7.0 Hz), 2.23 (1H, d, J = 7.0 Hz), 4.08 (1H, br. s), 4.25 (1H, br. s), 5.18 (1H, m), 6.91 (2H, m); 13C
NMR (125 MHz, CDCl3) δ=21.76, 53.51, 54.86, 71.87, 72.74, 141.86, 142.94, 151.96, 162.02, 162.96,
167.43. HRMS Calcd for C12H15O4 (M+H)+: 223.0970. Found: 223.0961.
Half-ester4a:
Oil. 1H NMR (500 MHz, CDCl3) δ= 0.91 (3H, t, J = 7.5), 1.64 (2H, m, J = 7.5), 4.07 (2H, m), 4.64
(1H, s), 7.31 (5H, m); 13C NMR (125 MHz, CDCl3) δ= 10.33, 21.92, 58.13, 67.39, 128.25, 128.64,
129.38, 132.98, 168.34, 171.76.HRMS Calcd for C12H15O4 (M+H)+: 223.0970. Found: 223.0962.
Half-ester 5a. Oil. 1H NMR (500 MHz, CDCl3) δ= 1.01 (3H, t, J = 7.5 Hz), 1.79 (2H, m), 2.13 (1H, d,
J = 7.5 Hz), 2.24 (1H, d, J = 7.5 Hz), 4.10 (1H, br. s), 4.27 (2H, m), 4.32 (1H, br. s), 6.90 (2H, m); 13C
NMR (125 MHz, CDCl3) δ=10.42, 21.80, 53.49, 54.84, 68.84, 72.76, 141.83, 142.93, 151.55, 162.28,
162.81, 167.93. HRMS Calcd for C12H15O4 (M+H)+: 223.0970. Found: 223.0979.
1
Half-ester 6a. Oil. H NMR (500 MHz, CDCl3) δ= 0.97 (3H, t, J = 7.5 Hz), 1.44 (2H, m), 1.74 (2H,
m), 2.12 (1H, d, J = 7.0 Hz), 2.23 (1H, d, J = 7.0 Hz), 4.09 (1H, br. s), 4.24 (1H, br. s), 4.31 (2H, m),
6.90 (2H, m); 13C NMR (125 MHz, CDCl3) δ= 13.78, 19.20, 30.36, 53.50, 54.84, 67.25, 72.76, 141.84,
142.92, 151.55, 162.25, 162.81, 167.94 HRMS Calcd for C13H17O4 (M+H)+: 237.1126. Found:
237.1136.
Half-ester 7a. White solid. 1H NMR (500 MHz, CDCl3) δ= 3.93 (3H, s), 7.59 (2H, m), 7.69 (1H, d, J =
7.8 Hz), 7.93(1H, d, J = 8.0 Hz). 13C NMR (125 MHz, CDCl3) δ= 53.03, 128.87, 130.00, 130.11,
13

17
ACCEPTED MANUSCRIPT
131.04, 132.44 , 133.40 , 168.82, 172.23. mp 82–83 °C.(lit. 82-84 °C) HRMS Calcd for C9H9O4
(M+H)+: 181.0500. Found: 181.0507.
Half-ester 8a. Oil. 1H NMR (500 MHz, CDCl3) δ= 1.37 (3H, t, J = 7.0 Hz), 4.39 (2H, q, J = 7.3 Hz),
7.59 (2H, m), 7.70 (1H, d, J = 7.0 Hz), 7.91 (1H, d, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3) δ=
13.99, 62.07, 128.82, 129.88, 130.04, 130.88, 132.30, 133.64, 168.28, 172.71 HRMS Calcd for
C10H11O4 (M+H)+: 195.0657. Found: 195.0649.
1
Half-ester 9a. White solid. H NMR (500 MHz, CDCl3) δ= 1.35 (6H, d, J = 6.5 Hz), 5.28 (1H, m),
7.57 (2H, m), 7.68 (1H, d, J = 7.5 Hz), 7.90 (1H, d, J = 7.5 Hz). 13C NMR (125 MHz, CDCl3) δ=
21.67, 69.83, 128.90, 129.94, 130.66, 130.78, 132.32, 134.05, 167.77, 172.73. mp 78-80 °C. (lit.79-
81.5 °C)18 HRMS Calcd for C11H13O4 (M+H)+: 209.0813. Found: 209.0805.
Half-ester 10a. Oil. 1H NMR (500 MHz, CDCl3) δ= 1.00 (3H, t, J = 7.5 Hz), 1.77 (2H, m), 4.29 (2H, t,
J = 7.0 Hz), 7.59 (2H, m), 7.71 (1H, d, J = 7.0 Hz), 7.91 (1H, d, J = 7.2 Hz). 13C NMR (125 MHz,
CDCl3) δ= 10.55, 21.87, 67.73, 128.87, 129.89, 130.08, 130.89, 132.31, 133.66, 168.35, 172.83.
HRMS Calcd for C11H13O4 (M+H)+: 209.0813. Found: 209.0819.
1
Half-ester 11a. White solid. H NMR (500 MHz, CDCl3) δ= 0.99 (6H, d, J = 7.0 Hz), 2.05 (1H, m),
4.11 (2H, d, J = 7.0 Hz), 7.59 (2H, m), 7.72 (1H, d, J = 7.0 Hz), 7.91 (1H, d, J = 7.5 Hz). 13C NMR
(125 MHz, CDCl3) δ= 19.26, 27.78, 72.59, 128.93, 129.95, 130.17, 130.95, 132.32, 133.64, 168.35,
172.54. mp 77.8-78.2 °C. (lit. 78-80 °C).19 Anal calcd for C12H14O4 : C, 64.85; H, 6.35. Found: C,
64.72; H, 6.36. HRMS Calcd for C12H15O4 (M+H)+: 223.0970. Found: 223.0977.
1
Half-ester 12a. White solid. H NMR (500 MHz, CDCl3) δ= 0.94 (3H, t, J = 7.5 Hz), 1.44 (2H, m),
1.73 (2H, m), 4.34 (2H, t, J = 6.5 Hz), 7.59 (2H, m), 7.70 (1H, d, J = 7.5 Hz), 7.91 (1H, d, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3) δ= 13.81, 19.29, 30.54, 66.02, 128.90, 129.94, 130.11, 130.91, 132.32,
133.68, 168.37, 172.69. mp 73-74 °C. (lit. 73°C)20 HRMS Calcd for C12H15O4 (M+H)+: 223.0970.
Found: 223.0965.
1
Half-ester 13a. Oil. H NMR (500 MHz, CDCl3) δ= 1.27 (1H, m), 1.41 (2H, m), 1.54 (3H, m), 1.75
(2H, m), 1.98 (2H, m), 5.04 (1H, m), 7.56 (2H, m), 7.70 (1H, dd, J=1.5Hz, J=1.5Hz), 7.88 (1H, dd,
J=1.5Hz, J=1.5Hz); 13C NMR (125 MHz, CDCl3) δ= 23.84, 25.44, 31.37, 74.61, 128.90, 129.73,
14

+
ACCEPTED MANUSCRIPT
130.28, 130.77, 132.09, 133.81, 167.65, 172.48. HRMS Calcd for C12H15O4 (M+H) : 249.1127.
Found: 249.1126.
Acknowledgements
We thank Kajima Foundation Research Grant and the National Science Foundation-CAREER
grant (CHE-0443265) for the financial support. We also thank Dr. Hanjoung Cho (Texas Tech
University) for his technical assistance.
Supplementary Data
Supplementary Data related to this article can be found online.
† Current address: College of Chemistry and Chemical Engineering, Hainan Normal University,
Haikou 571158, China
‡ Current address: OncoNano Medicine Inc. 550 Reserve St., Suite 190, Southlake, TX 76092, U.S.A.
References
1.
For example, (a) Kumar, A.; Khan, S.; Ahmed, Q. N. Org. Lett. 2017, 19, 4730-4733.
(b) Lakic, M.; Sabo, L.; Ristic, S.; Savic, A.; Petricevic, S.; Nikolic, N.; Vukadinovic, A.;
Jankovic, D.; Sabo, T. J.; Vranjes-Duric, S. Appl. Organomet. Chem. 2016, 30(2), 81-88.
(c) Chudasama, N. A.; Prasad, K.; Siddhanta, A. K. Carbohydr. Polym. 2016, 151, 735-742.
(d) Cavusoglu, J.; Cayli, G. J. Appl. Polym. Sci. 2015, 132, 41457/1-41457/6.
(e) Chudasama, N. A.; Siddhanta, A. K. Carbohydr. Res. 2015, 417, 57-65
(f) Yuan, H.-N.; Li, S.; Nie, J.; Zheng, Y.; Ma, J.-A. Chem. Eur. J. 2013, 19, 15856-15860.
(g) Singhal, R.; Mishra, A.; Nagpal, A. K.; Mathur, G. N. J. Polym. Mater. 2009, 26, 239-250.
15

ACCEPTED MANUSCRIPT
(h) Yamada, S.; Mrozek, T.; Rager, T.; Owens, J.; Rangel, J.; Wilson, C. G.; Byers, J.
Macromolecules 2004, 37(2), 377-384.
(i) Gao, F.; Schricker, S. R.; Tong, Y.; Culbertson, B. M. Polym. Mater. Sci. Eng. 2002, 86,
247-248.
(j) Gao, F.; Schricker, S. R.; Tong, Y.; Culbertson, B. M. J. Macromol. Sci. Pure Appl. Chem.
2002, A39, 267-286.
(k) Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu J.; Cacchio, T. Tetrahedron Lett. 2000, 41, 5647-
5651.
(l) Sano, S.; Ushirogochi, H.; Morimoto, K.; Tamai, S.; Nagao, Y. Chem. Commun. 1996,
1775-1776. and references cited therein.
2.
3.
4.
5.
6.
Niwayama, S. J. Synth. Org. Chem. Jpn. 2008, 66, 983-994.
Niwayama, S. J. Org. Chem. 2000, 65, 5834-5836.
Niwayama, S. Tetrahedron Lett. 2000, 41, 10163-10166.
Niwayama, S.; Wang, H.; Hiraga, Y.; Clayton, J. C. Tetrahedron Lett. 2007, 48, 8508-8510.
Niwayama, S.; Cho, H.; Zabet-Moghaddam, M.; Whittlesey, B. R. J. Org. Chem. 2010, 75,
3775-3780.
7.
Niwayama, S.; Rimkus, A. Bull. Chem. Soc. Jpn. 2005, 78, 498-500.
Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49, 4434-4436.
Niwayama, S.; Cho, H. Chem. Pharm. Bull. 2009, 57, 508-510.
For example, (a) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443-451.
(b)Yim, B.; Yoo, Y.; Nagata, Y.; Maeda, Y. Chem. Lett. 2001, 938-939.
(c) Vidal, M.; Garcia-Arriagada, M; Rezende, M. C.; Dominguez, M. Synthesis, 2016, 48,
4246-4252.
8.
9.
10.
(d) Qin, B.; Schneider, U. J. Am. Chem. Soc. 2016, 138, 13119-13122.
(e) Jaita, S.; Phakhodee, W.; Pattarawarapam, M. Synlett 2015, 26, 2006-2008.
(f) Soengas, R. G.; Silva, A. M. S. Synlett 2012, 23, 873-876.
11.
Shi, J.; Niwayama, S. Tetrahedron Lett. 2018, 59, 799-802.
16

ACCEPTED MANUSCRIPT
Huntress, E. H.; Lesslie, T. H.; Bornstein, J. Org. Syn. 1963, Coll. Vol. 4, 329-330.
12.
13.
For example, (a) Iida, T.; Mori, H.; Mochizuki, T.; Mori, Y. H. Chem. Eng. Sci. 2001, 56,
4747-4758; (b) Makino, T.; Sugahara, T.; Ohgaki, K. J. Chem. Eng. Data 2005, 50, 2058-
2060; (c) Gao, S.; Chapman, W. G.; House, W. Ind. Eng. Chem. Res. 2005, 44, 7373-7379.
For example, (a) Thum, S.; Kokornaczyk, A. K.; Seki, T.; Maria, M. D.; Zacarias, N. V. O.; de
Vrues, H.; Weiss, C.; Koch, M; Schepmann, D.; Kitamura, M.; Tschammer, N.; Heitman, L.
H.; Junker, A. Münsch, B. Eur. J. Med. Chem. 2017, 135, 401-413.
(b) Kuduk, S. D.; Skudlarek, J. W.; DiMarco, C. N.; Bruno, J. G.; Pausch, M. H.; O’Brien, J.
A.; Cabalu, T. D.; Stevens, J.; Brunner, J.; Tannenbraum, P. L. Garson, S. L.; Savitz, A. T.;
Harrell, C. M.; Cotter, A. L.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Bioorg. Med. Chem.
Lett. 2015, 25, 2488-2492.
14.
(c) Aguilar, N.; Moyano, A.; Petricas, M. A.; Riera, A. J. Org. Chem. 1998, 63, 3560-3567.
(d) Shao, C.; Lu, A.; Wang, X.; Zhou, B.; Guan, X.; Zhang, Y. Org. Biomol. Chem. 2017, 15,
5033-5040.
(e) Raposo, M. M. M.; Sampaio, A. M. B. A.; Kirsch, G. J. Heterocylic Chem. 2005, 42, 1245-
1251.
(f) Hradil, P.; Melnicky, R.; Grepl, M.; Koristek, K.; Hlavac, J.; Bertolasi, V. Heterocycles,
2006, 68, 1845-1859.
(g) Yang, D.; Ding, S.; Huang, J.; Zhao, K. Chem. Commun. 2013, 49, 1211-1213.
(h) Moy, T. M.; DePorter, C. D.; McGrath, J. E. Polymer 1993, 34, 819-24.
(i) Hu, L.; Wang, D.; Chen, X.; Yu, L.; Yu, Y.; Tan, Z.; Zhu, G. Org. Biomol. Chem. 2017, 15,
5674-5679.
(j) Del, B. M.; Ancillotti, C.; Checchini, L.; Fibbi, D.; Rossini, D.; Ciofi, L.; Rivoira, L.;
Profeti, C.; Orlandini, S.; Furlanetto, S. J. Pharm. Biomed. Anal. 2018, 148, 6-16.
For example, (a) Meng, Q.-Y.; Wang, S.; König, B. Angew. Chem. Int. Ed. 2017, 56, 13426-
13430.
15.
17

ACCEPTED MANUSCRIPT
(b) Ebert, G. W.; Juda, W. L.; Kosakowski, R. H.; Ma, B.; Dong, L.; Cummings, K. E.; Phelps,
M. V. B.; Mostafa, A. E.; Luo, J. J. Org. Chem. 2005, 70, 4314-4317.
(c) Rekha, V. V.; Ramani, M. V.; Ratnamala, A.; Rupakalpana, V.; Subbaraju, G. V.;
Satyanarayana, C.; Rao, C. S. Org. Process. Rev. Dev. 2009, 13, 769-773.
(d) Sabitha, G.; Srividya, R.; Yadav, J. S. Tetrahedron, 1999, 55, 4015-4018.
(e) Jiang, D.; Wang, Y. Y.; Xu, Y. N.; Dai, L. Y. J. Chem. Res. 2009, 3, 167-169.
(f) Udayakumar, S.; Pandurangan, A.; Sinha, P. K. J. Mol. Catal. A: Chem. 2005, 240 139-154.
(g) Yadav, G. D.; Rahuman, M. S. M. M. Org. Process. Rev. Dev. 2002, 6, 706-713.
(h) Dubey, P. K.; Mohiuddin, S. M. G.; Ramesh, D. Asian J. Chem. 1997, 9, 379-387.
(i) Ogawa, H.; Ichimura, Y.; Chihara, T.; Teratani, S.; Taya, K. Bull. Chem. Soc. Jpn. 1986, 59,
2481-2483.
(j) Kim, S. S.; Mah, Y. J.; Lee, H. J.; Park, S. K. J. Photosci. 2003, 10, 241-243.
We also tried other kinds of polar-aprotic solvents such as dioxane, DMF, pyridine, and DME
as a co-solvent, but all these co-solvents turned out to be inferior to DMSO. For example, in
the selective monohydrolysis of diisopropyl ester 3, under the same conditions as run 12 in
Table 3, yields of the half-ester, 3a, were 39%(dioxane), 23%(DMF), 42%(pyridine), and
32%(DME) respectively after 3.5-hour reaction time.
16.
17. Metz P. Tetrahedron 1989, 45, 7311-7316.
18. Mislow, K.; O’Brien, R. E.; Schaefer, H. J. Am. Chem. Soc. 1962, 84, 1940-1944.
19. https://www.chemicalbook.com/ChemicalProductProperty_US_CB1899322.aspx
20.
Consden, R.; Duveen, D. I.; Kenyon, J. J. Chem. Soc. 1938, 2104-2106.
18

ACCEPTED MANUSCRIPT
•
•
•
Practical selective monohydrolysis of symmetric diesters without a special
device
Highly efficient reactions starting from only readily available inexpensive
reagents
Production of costly half-esters under simple conditions from inexpensive starting
diesters