Practical selective monohydrolysis of bulky symmetric diesters

Article abstract of DOI:10.1016/j.tetlet.2017.12.061

The highly efficient selective monohydrolysis reaction we previously reported has been applied to monohydrolysis of several bulkyl symmetric diesters, including diethyl esters, dipropyl esters, and dibutyl esters. A greater proportion of a polar aprotic co-solvent, DMSO, and aqueous KOH appear to help improve the reactivity of bulky diesters compared to the corresponding dimethyl esters. The procedure is mild and practical, yielding the corresponding half-esters in high yields under simple conditions.

Full text of DOI:10.1016/j.tetlet.2017.12.061

Accepted Manuscript
Practical Selective Monohydrolysis of Bulky Symmetric Diesters
Jianjun Shi, Satomi Niwayama
PII:
S0040-4039(17)31580-0
https://doi.org/10.1016/j.tetlet.2017.12.061
TETL 49563
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 November 2017
15 December 2017
19 December 2017
Please cite this article as: Shi, J., Niwayama, S., Practical Selective Monohydrolysis of Bulky Symmetric Diesters,
Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.061
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.

Practical Selective Monohydrolysis of Bulky Symmetric Diesters
Jianjun Shia and Satomi Niwayamaa,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 highly efficient selective monohydrolsis reaction we previously reported has been
applied to monohydrolysis of several bulkyl symmetric diesters, including diethyl esters,
dipropyl esters, and dibutyl esters. A greater proportion of a polar aprotic co-solvent, DMSO,
and aqueous KOH appear to help improve the reactivity of bulky diesters compared to the
corresponding dimethyl esters. The procedure is mild and practical, yielding the corresponding
half-esters in high yields under simple conditions.
Key Words: hydrolysis, symmetric diester, half-ester, solvent effect, cost-effective synthesis
Half-esters are among the most important building blocks for organic synthesis of a
variety of compounds including natural products, drugs, polymers, and dendrimers.1 Most
typically, they are prepared by monohydrolysis of symmetric diesters. However, the classical
monosaponification of symmetric diesters tends to produce complex mixtures consisting of
starting diesters, half-esters, and diacids in which both the ester groups are hydrolyzed, and a
1

small percentage of the corresponding half-esters, typically as yellowish material. For example,
in our experiments, monosaponification of dimethyl bicyclo[2.2.1]hept-2,5-diene-2,3-
dicarboxylate, 1, resulted in a complex mixture, and less than 10% of the half-ester was obtained
as a yellowish paste-like solid (Scheme 1).2 Enzymatic monohydrolysis of symmetric diesters
requires random screening, as it provides no basis for prediction of the reactivity.
Scheme 1. Classical monosaponification of a symmetric diester
Earlier, we reported highly efficient selective monohydrolysis of symmetric diesters.3
This reaction selectively monohydrolyzes a series of symmetric diesters under mild and practical
conditions with high yields. The reaction mixtures are clean, and only the half-esters, and
diacids as well as the starting diesters, if they exist, are observable, unlike the
monosaponification reactions. In many cases, the yields are near quantitative (Scheme 2).
Scheme 2. Selective monohydrolysis of symmetric diesters
2

However, when the starting diesters have relatively bulky ester groups, the reactions
sometimes require an extended period of time or greater amounts of a base for completion of the
reactions within a shorter reaction time. The amount of base and the reaction time tend to
increase as the bulkiness of the ester group increases depending on the starting diesters.4 For
example, while the dimethyl ester, 1, is monohydrolyzed in about one hour with about 2
equivalents of a base, monohydrolysis of the corresponding diethyl ester, 2, needs about three to
four times the equivalent of the base or a longer reaction time,3 and the same monohydrolysis of
diisopropyl ester, 3, requires about 19 hours (Scheme 3).5
Scheme 3. Examples of selective monohydrolysis
3

This trend is consistent with our observation reported before that the monohydrolysis
occurs at the interface between the aqueous face and the diester, hence reflecting the reduced
contact of the more hydrophobic ester groups with the aqueous phase. The drawback in this
trend is occasional decrease of the yields of half-esters due to the prolonged reaction time. A
long reaction time while maintaining 0 oC may also be difficult. Therefore, here we attempted to
improve the selectivity of monohydrolysis of bulky symmetric diesters.
We initially applied ultrasound in order to accelerate the reaction rate,6 because
ultrasound-assisted reactions are known to enhance rates of many two-phase reactions.7
However, ultrasound-assisted conditions did not improve the selectivity or reactivity of the
diisopropyl ester, 3. At the best result, the half-ester was obtained only in 60% yield with the use
of 6 equivalents of aqueous KOH after 3 hours with recovery of 12% of the starting diester, 3.6
We next tried to adjust reaction conditions without a special device. According to our
hypothesis, once one of the two ester groups is monohydrolyzed, the intermediary
monocarboxylates form micellar aggregates in which the remaining hydrophobic portions point
inside and the hydrophilic carboxylate groups point outside, prohibiting further hydrolysis and
keeping the remaining ester group intact. Consistent with this hypothesis, we observed that a
water–miscible polar aprotic co-solvent such as THF and CH3CN increases the reaction rate and
selectivity while a protic co-solvent such as an alcohol decreases the selectivity, perhaps by
dissociating the micellar aggregates.8 We also previously reported that use of DMSO improved
exo-selectivity of various dialkyl bicycle[2.2.1]heptane-2,3-carboxylates by accelerating the
monohydrolysis of the sterically less hindered exo-ester groups.9,10
Furthermore, we found that KOH often improves selectivity and reactivity compared to
NaOH, which is perhaps due to stronger affinity of K+ with carbonyl oxygen, leading to the
4

enhanced electrophilic character of the starting ester group.11 We reported that aqueous KOH
improved selectivity in various diesters including dialkyl malonates.11-13
Here we report various selective monohydrolysis of symmetric bulky diesters by tuning
the reaction conditions based on our previous findings and mechanistic hypothesis.
We first screened the selective monohydrolysis of dialkyl bicyclo[2.2.1]hept-2,5-diene-
2,3-dicarboxylates.14 All these diesters were synthesized in high yields by simple Diels-Alder
reactions of cyclopentadiene and the corresponding dialkyl acetylenedicarboxylates.15 The
results are summarized in Table 1.
5

Table 1.
Selective monohydrolysis of dialkyl bicycle[2.2.1]hept-2,5-diene-2,3-
dicarboxylates
6

As for the dimethyl ester, 1, the reaction is known to proceed quite efficiently regardless
of the kinds of base or co-solvent.3,8,11 Therefore, in all the cases, the reaction produced near-
quantitative yields of the corresponding half-ester, 1a, although we noticed, judging from the
reaction time, that DMSO and KOH somewhat enhanced the reaction rate, which is consistent
with our previous observation. The volume percentage of the co-solvent is the same as what we
reported before (7%), which was found to be optimal for this dimethyl ester, 1.
The diethyl ester, 2, required about 3-4 times as much base in the conditions we reported
before.3 However, the selectivities increased as the amount of THF increased even with the use
of 1.7 equivalents of the base. The maximal conditions appear to exist when the volume
percentage of THF is between 13% and 67%. The aqueous KOH also appears to be better than
aqueous NaOH, as reported previously. However, DMSO improved the selectivity rather
significantly, and the best and comparable results to the dimethyl ester, 1, were obtained when
44-67% of DMSO and aqueous KOH were used. These conditions worked out for the diipropyl
ester, 3, and di-n-propyl ester, 4, but the better results were obtained when the greater amount of
DMSO was used. Therefore, it appears that use of a larger amount of DMSO help improve the
selectivity as the bulkiness increases. A greater proportion of THF or DMSO was applied for
monohydrolysis of di-n-butyl ester, 5, and the effect of DMSO became clearer for this
monohydrolysis. The reaction times have also been shortened significantly even with the use of
1.7 equivalents of the base, while we sometimes needed more than a day for selective
monohydrolysis of some dipropyl esters with the conditions reported previously.3,12
It appears that the maximal volume percentage of the co-solvent tends to increase as the
size of the ester group increases, which is also consistent with the smaller optimal amount of co-
solvents for the less bulky dimethyl ester, 1, as mentioned above. This greater proportion of
polar aprotic co-solvent is likely to help increase the contact of the hydrophobic ester groups and
7

the aqueous face, increasing the chance for the hydrolysis of one of the two ester groups. The
co-solvent may also help protect the potential micellar aggregates formed from the intermediary
carboxylates of bulky half-esters described above, and thereby prohibiting further hydrolysis.
The unsuccessful results with the ultrasound-assisted conditions mentioned above may also be
attributed to potential dissociation of the aggregates by sonication.
From a technical point of view, use of a larger proportion of THF also sometimes formed
hydrates, hampering the stirring of the reaction mixture, which was not the case with DMSO.
Although DMSO is less volatile than THF or CH3CN and may take a longer time to completely
evaporate, the product half-esters all show high purities.
Applying the proportions that turned out to be the best in each reaction above, we next
tried selective monohydrolysis of several bulky dialkyl phthalates. The starting symmetric
diesters, dialkyl phthalates, are all readily available inexpensively. The product half-esters,
monoalkyl phthalates, exhibit widespread applications to various industrial products such as
plasticizers and adhesives, as well as to synthesis of a variety of pharmaceuticals and
polymers,16,17 but they are rather costly. Therefore, methods for their cost-effective production
have been actively investigated.18
The results are summarized in Table 2. Again, the effect of DMSO is more prominent.
The yields of the corresponding half-esters are significantly higher with DMSO than with THF.
Although only about 1.7 equivalents of the base were used for each run, the reaction time was
significantly shorter than with THF. Here again, the maximal percentages of the co-solvent tend
to increase as the bulkiness of the ester groups increases. The increased volume percentages of
the co-solvent also appear to help enhance the contact between the hydrophobic ester groups and
the aqueous phase.
Table 2. Selective monohydrolysis of dialkyl phthalates
8

In summary, we found that a larger proportion of a water-miscible polar aprotic co-
solvent, DMSO, and aqueous KOH helps accelerate the selective monohydrolysis reaction of
several bulky symmetric diesters, and consequently enhances the selectivity, producing the
9

corresponding half-esters in high yields. We found that 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, and/or greater amounts of an aqueous
base when the reactivity is low.19 The conditions reported here are practical without requiring
expensive reagents or equipment and consistent with our mechanistic hypothesis and previous
observations. All the half-esters here show excellent purities and stability over a period of time.20
Acknowledgements:
We thank Kajima Foundation Research Grant for the financial support.
References and Notes:
1.
For example, (a) Kumar, A.; Khan, S.; Ahmed, Q. N. Org. Lett. 2017, 19, 4730-4733.
(b) Chudasama, N. A.; Prasad, K.; Siddhanta, A. K. Carbohydr. Polym. 2016, 151, 735-
742.
(c) Cavusoglu, J.; Cayli, G. J. Appl. Polym. Sci. 2015, 132, 41457/1-41457/6.
(d) Yuan, H.-N.; Li, S.; Nie, J.; Zheng, Y.; Ma, J.-A. Chem. Eur. J. 2013, 19, 15856-
15860.
(e) Singhal, R.; Mishra, A.; Nagpal, A. K.; Mathur, G. N. J. Polym. Mater. 2009, 26,
239-250.
(f) Yamada, S.; Mrozek, T.; Rager, T.; Owens, J.; Rangel, J.; Wilson, C. G.; Byers, J.
Macromolecules 2004, 37(2), 377-384.
(g) Gao, F.; Schricker, S. R.; Tong, Y.; Culbertson, B. M. Polym. Mater. Sci. Eng. 2002,
86, 247-248.
10

(h) Gao, F.; Schricker, S. R.; Tong, Y.; Culbertson, B. M. J. Macromol. Sci. Pure Appl.
Chem. 2002, A39, 267-286.
(i) Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu J.; Cacchio, T. Tetrahedron Lett. 2000, 41,
5647-5651.
(j) Sano, S.; Ushirogochi, H.; Morimoto, K.; Tamai, S.; Nagao, Y.Chem. Commun. 1996,
1775-1776. and references cited therein.
2.
3.
4.
5.
6.
7.
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.
Cho, H.; Niwayama, S. unpublished results.
Zhao, T. Master’s thesis, Texas Tech University, August 2011, p19-43
For example, (a) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443-451.
(b) Vidal, M.; Garcia-Arriagada, M; Rezende, M. C.; Dominguez, M. Synthesis, 2016, 48,
4246-4252.
(c) Qin, B.; Schneider, U. J. Am. Chem. Soc. 2016, 138, 13119-13122.
(d) Jaita, S.; Phakhodee, W.; Pattarawarapam, M. Synlett 2015, 26, 2006-2008.
(e) Soengas, R. G.; Silva, A. M. S. Synlett 2012, 23, 873-876.
Niwayama, S.; Wang, H.; Hiraga, Y.; Clayton, J. C. Tetrahedron Lett. 2007, 48, 8508-
8510.
8.
9.
Niwayama, S.; Cho, H.; Zabet-Moghaddam, M.; Whittlesey, B. R. J. Org. Chem. 2010,
75, 3775-3780.
10.
Enhancement of the reaction rates for ester hydrolyses with DMSO over ethanol has also
been reported. Roberts, D. D. J. Org. Chem. 1966, 31, 4037-4041 and references cited
therein.
11

11.
12.
13.
14.
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.
The experimental procedures are as follows: 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 is consumed according to TLC. The reaction mixture was acidified with 1.0 M
o
HCl 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.
Huntress, E. H.; Lesslie, T. H.; Bornstein, J. Org. Syn. 1963, Coll. Vol. 4, 329-330.
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.
15.
16.
(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.
12

(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.
17.
The experimental procedures are as follows: 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 is 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.
For example, (a) Meng, Q.-Y.; Wang, S.; König, B. Angew. Chem. Int. Ed. 2017, 56,
13426-13430.
18.
(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.
13

(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.
It is recommended that the maximal amount of the co-solvent be adjusted depending on
the starting diesters.
19.
20. The structures of all the half-esters reported here were determined by 1H NMR, 13C NMR,
and elemental analysis or HRMS. The spectral data are as follows:
Half-ester 1a. White solid. 1H NMR (500 MHz, CDCl3) = 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) = 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). HRMS Calcd for C10H11O4 (M+H)+: 195.0675.
Found: 195.0651.
1
Half-ester 2a. Oil. H 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
13
(2H, m); C NMR (125 MHz, CDCl3) δ= 14.08, 53.51, 54.88, 63.49, 72.83, 141.878,
142.90, 151.50, 162.34, 162.81, 167.91. HRMS Calcd for C11H13O4 (M+H)+: 209.0813.
Found: 209.0818.
1
Half-ester 3a. Oil. H NMR (500 MHz, CDCl3) = 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) =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.
1
Half-ester 4a. Oil. H 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,
14

13
br. s), 6.90 (2H, m); C 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.
Half-ester 5a. Oil. 1H NMR (500 MHz, CDCl3) = 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,
13
br. s), 4.31 (2H, m), 6.90 (2H, m); C NMR (125 MHz, CDCl3) = 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.
1
Half-ester 6a. White solid. H NMR (500 MHz, CDCl3) = 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) = 53.03,
128.87, 130.00, 130.11, 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 7a. Oil. 1H NMR (500 MHz, CDCl3) = 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) = 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.
Half-ester 8a. White solid. 1H NMR (500 MHz, CDCl3) = 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) = 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) HRMS Calcd for C11H13O4 (M+H)+: 209.0813.
Found: 209.0805.
Half-ester 9a. Oil. 1H NMR (500 MHz, CDCl3) = 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) = 10.55, 21.87, 67.73, 128.87, 129.89, 130.08, 130.89,
15

132.31, 133.66, 168.35, 172.83. HRMS Calcd for C11H13O4 (M+H)+: 209.0813. Found:
209.0819.
Half-ester 10a. White solid. 1H NMR (500 MHz, CDCl3) = 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) = 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). 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.
Half-ester 11a. White solid. 1H NMR (500 MHz, CDCl3) = 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) = 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)
HRMS Calcd for C12H15O4 (M+H)+: 223.0970. Found: 223.0965.
16

Table 1.
Selective monohydrolysis of dialkyl bicycle[2.2.1]hept-2,5-diene-2,3-
dicarboxylates
reaction
time
yield
（%）
>99
Run
R
co-solvent
co-solvent (v/v): H2O (mL)
aqueous base
1
2
3
1: Me
THF
2 mL (7%): 20 mL
2 mL (7%): 20 mL
2 mL (7%): 20 mL
0.25 M NaOH 8 mL
0.25 M NaOH 8 mL
0.25 M KOH 8 mL
45 min
40 min
30 min
DMSO
DMSO
>99
>99
4
5
6
7
8
9
2: Et
THF
THF
4 mL (13%): 24mL
16 mL (44%): 16mL
24 mL (67%): 8mL
4 mL (13%): 24mL
16 mL (44%): 16mL
24 mL (67%): 8mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
5h 30min
3h
95
93
THF
1h 50min
3h
95
DMSO
DMSO
DMSO
84
2h
92
1h 30min
>99
10
11
12
3: iPr
4: nPr
5:nBu
THF
22 mL (73%): 4mL
24 mL (67%): 8mL
22 mL (73%): 4mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
12h
4h 30min
3h
71
87
93
DMSO
DMSO
13
14
15
THF
22 mL (73%): 4mL
24 mL (67%): 8mL
22 mL (73%): 4mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
0.5 M KOH 4 mL
12h
4h
78
91
96
DMSO
DMSO
3h
16
THF
32 mL (84%): 2mL
0.5 M KOH 4 mL
18h
63
17

17
DMSO
32 mL (84%): 2mL
0.5 M KOH 4 mL
6h
84
18

Table 2. Selective monohydrolysis of dialkyl phthalates
Run
1
R
co-solvent
THF
co-solvent (v/v):H2O (mL)
2 mL (7%): 20 mL
reaction time
2h
yield（%）
6: Me
88 a
94
2
DMSO
2 mL (8%): 20 mL
40 min
3
4
7: Et
THF
24 mL (67%): 8mL
24 mL (67%): 8mL
8h
2h
66
93
DMSO
5
6
8: iPr
THF
22 mL (73%): 4mL
22 mL (73%): 4mL
14h
4h
46
81
DMSO
19

7
8
9: nPr
10:iBu
11:nBu
THF
22 mL (73%): 4mL
22 mL (73%): 4mL
14h
55
85
DMSO
3h 30min
9
THF
32 mL (84%): 2mL
32 mL (84%): 2mL
18h
10h
34
77
10
DMSO
11
12
THF
32 mL (84%): 2mL
32 mL (84%): 2mL
18h
8h
40
81
DMSO
a: The conditions we previously reported were applied with 0.25M NaOH (8 mL)3,6
20

• Practical reactions for selective monohydrolysis of symmetric diesters
• Highly versatile reactions requiring only readily accessible inexpensive reagents
• Efficient production of costly bulky half-esters without a special device
21

CO2R
CO2H
CO2R
CO2H
1) co-solvent, H2O
aqueous base, 0 oC
CO2R
CO2R
2) H3O+
CO2R
CO2R
R= Me, Et, iPr, nPr, iBu, nBu