High-pressure transesterification of sterically hindered esters

Article abstract of DOI:10.1016/j.tetlet.2012.07.094

A mild, rapid, and efficient method for the solvolysis of sterically hindered esters under high pressure is described. Transesterification is carried out in the presence of DBU at room temperature and at a pressure of 10 kbar to give quantitative conversions within short reaction times. The substrates examined included aromatic and aliphatic esters of sterically hindered alcohols and phenols. An optically pure benzyl ester of phenylalanine was chosen to study racemization of the amino acid esters under high-pressure reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.07.094

Tetrahedron Letters 53 (2012) 5287–5289
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
High-pressure transesterification of sterically hindered esters
⇑
Jan Romanski , Piotr Nowak, Krzysztof Kosinski, Janusz Jurczak
Department of Chemistry, Warsaw University, ul. Pasteura 1, 02-093 Warszawa, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, rapid, and efficient method for the solvolysis of sterically hindered esters under high pressure is
described. Transesterification is carried out in the presence of DBU at room temperature and at a pressure
of 10 kbar to give quantitative conversions within short reaction times. The substrates examined included
aromatic and aliphatic esters of sterically hindered alcohols and phenols. An optically pure benzyl ester of
phenylalanine was chosen to study racemization of the amino acid esters under high-pressure reaction
conditions.
Received 8 May 2012
Revised 6 July 2012
Accepted 19 July 2012
Available online 27 July 2012
Keywords:
Transesterification
High pressure
Ó 2012 Elsevier Ltd. All rights reserved.
Sterically hindered alcohols
Amino acid esters
Racemization
Transesterification is of significant importance in organic syn-
thesis as an equivalent of mild ester hydrolysis. This reaction is
well known and presents numerous preparative approaches.1–4
However, its application to sterically hindered esters is limited, be-
cause traditional methods require harsh reaction conditions when
applied to such substrates. This prevents its use in certain cases
where it would be a natural solution. One such example is the
cleavage of tert-butyl protecting groups from esters. The regular
procedure requires acidic conditions, which make it unsuitable
for acid-sensitive compounds. A frequently used alternative pro-
tection for esters are 2,6-dialkylphenyl groups. Their removal
requires the use of hot aqueous solutions of sodium hydroxide or
solutions of sodium methoxide in a mixture of toluene and
hexamethylphosphoramide.5,6
Efficient cleavage of sterically hindered esters is also desired in
syntheses involving alcohol-type chiral auxiliaries, such as men-
thol, borneol, and their derivatives. Near quantitative removal
would allow recycling of most of the auxiliaries. Additionally, the
chemical correlation method relies on the quantitative cleavage
to determine the obtained diastereomeric excesses.7
These examples indicate that a mild and efficient method for
cleavage of sterically hindered esters would solve many existing
synthetic problems. Both kinetic data (volume of activation ca.
12 cm3) and our earlier experience suggested that base-catalyzed
high-pressure transesterification might be such a method.9 More-
over, in the literature, there are several patents involving high-
pressure approaches to transesterifications.10,11
Table 1
Optimization of the reaction
O
O
MeOH
+
+
O
O
HO
Base
Amount (equiv)
Pressure (kbar)
Time (h)
Yield (%)
None
Et3N
Et3N
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
—
10
3
10
10
3
10
10
10
10
10
10
10
16
16
16
2
16
16
16
16
1
0
0
6
Many sterols are viable candidates as starting materials and chi-
ral pool compounds because of their natural abundance. However,
some are only available in acylated form, which usually necessi-
tates their transformation into the free alcohol form. Acylated
forms of sterols are also obtained in the later stages of multi-step
syntheses where the intended product is the free alcohol. Conven-
tional methods for ester cleavage and earlier proposed high-pres-
sure hydrolysis methods are not satisfactory in those cases.8
0.1
0.1
15
0.2
0.2
0.75
1
1
1
2
2
65
27
46
65
85
22
65
38
98a
2
1
2
⇑
Corresponding author. Tel.: +48 22 822 0211; fax: +48 22 822 5996.
E-mail address: jarom@chem.uw.edu.pl (J. Romanski).
a
100% conversion.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.094

5288
J. Romanski et al. / Tetrahedron Letters 53 (2012) 5287–5289
Table 2
methanol, which at the same time acted as the transesterifying
agent. Two commonly used Lewis bases chosen were: triethyl-
amine (Et3N) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
In the initial series of reactions, DBU appeared to be the more
efficient catalyst. The degree of conversion was found to increase
with pressure and time. Reaction time and economical consider-
ations suggested that further trials should be conducted under
10 kbar pressure, since this pressure afforded good conversions
while still being achievable in most commercial high-pressure
equipment. The optimal reaction conditions for the model com-
pound were 10 kbar pressure, 2 equiv of DBU, and a reaction time
of 2 h.12 The use of excess of the amine enabled quantitative con-
versions while maintaining short reaction times. In all cases, the
yields are based on the methyl esters formed. The results of the
optimization studies are shown in Table 1.
Scope of the reaction of benzoyl esters under the optimized conditions (2 equiv DBU,
2 h)
O
O
R
MeOH
ROH
+
+
O
O
Substrate
Yield (%)
2,6-Dimethylphenyl benzoate
2,6-Diisopropylphenyl benzoate
2-tert-Butylphenyl benzoate
tert-Butyl benzoate
Menthyl benzoate
Bornyl benzoate
95
97
98
97
98
98
97
neo-Pentyl benzoate
Next, 12 other sterically hindered esters were examined.
The results for the reaction of benzoic esters are summarized in
Table 2. In all cases, the reactions proceeded with quantitative
conversions.
Table 3
Scope of the reaction of lauroyl esters
Esters of lauric acids were also examined. For substrates giving
unsatisfactory conversions under the optimized conditions, addi-
tional reactions with larger excesses of DBU or longer reaction
times were performed; for detailed results, see Table 3.
In base-catalyzed transesterifications, an alkoxide ion attacks
the acyl group, therefore, bulky alkoxide ions should react less
readily due to the larger energy of activation required. Table 4 lists
the results obtained by varying the transesterifying agent in the
reaction with menthyl benzoate under the optimized conditions.
The results were in accordance with expectations.
To verify the advantages of the proposed method, two compar-
ative reactions with the model compound were performed. The
first used the conditions described by Seebach et al. (2 equiv
DBU, 8 equiv LiCl, rt).13 However, the reaction was incomplete even
after 7 days. The second involved using the optimized conditions,
but heating under reflux instead of high pressure. There was only
minor progress in the reaction after 20 h. Therefore we conclude
that the new approach is a substantial improvement over existing
methods.
O
O
R
MeOH
O
ROH
+
O
+
Substrate
Time (h)
DBU (equiv)
Yield (%)
2,6-Dimethylphenyl laurate
2,6-Diisopropylphenyl laurate
2-tert-Butylphenyl laurate
tert-Butyl laurate
Menthyl laurate
Menthyl laurate
2
3.5
2
2
2
2
2
2
2
2
2
2
2
3
2
3
98
96
98
98
67
76
72
94
Bornyl laurate
Bornyl laurate
Table 4
Reaction of menthyl benzoate with other alcohols
Alcohol
Solvent
Yield (%)
In order to check if racemization took place, L-phenylalanine
benzyl ester was selected as a substrate for transesterification.
An additional equivalent of DBU compared to the optimal condi-
Methanol
Ethanol
Propan-1-ol
Methanol
Ethanol
Propan-1-ol
Trifluoroethanol
Propan-2-ol
Dichloromethane
98
75
15
0
0
0
tions was added to neutralize the hydrochloride salt of L-phenylal-
Trifluoroethanol
Propan-2-ol
tert-Butanol (5 equiv)
anine benzyl ester. Quantitative conversions were achieved in each
case and it was found that, after 2 h, the obtained methyl ester of
phenylalanine was only slightly racemized (95% ee). Elongation
of the reaction time caused additional racemization, but reduction
of the DBU loading led to phenylalanine methyl ester with 99% ee
in 78% yield (Table 5).14
In summary, we have demonstrated that high pressure transe-
sterification represents a mild, rapid, and efficient method for
hydrolysis of sterically hindered esters. We have shown the
During the optimization study, menthyl benzoate was chosen as
the model compound due to the frequent use of menthol deriva-
tives as chiral auxiliaries and its bulkiness. Four parameters were
investigated: type and amount of amine catalyst, pressure and
duration of the reaction. The reactions were conducted in
Table 5
Phenylalanine benzyl ester transesterification
O
O
HO
MeOH
O
+
+
O
NH3+Cl-
NH2
Time (h)
DBU (equiv)
ee (%)
16
2
2
2
2
3
3
2
1.5
1.1
59
95
97
98
99

J. Romanski et al. / Tetrahedron Letters 53 (2012) 5287–5289
4. Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655.
5289
versatility of this transformation by applying the method to both
aromatic and aliphatic esters of a variety of sterically hindered
alcohols and phenols. We have also revealed that the method can
be used for optically active amino acid esters without leading to
racemization.
5. Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd ed.; John
Wiley & Sons: New York, 1991.
6. Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme: New York, 2005.
7. Romanski, J.; Chapuis, C.; Jurczak, J. Helv. Chim. Acta 2007, 90, 2116–2131.
8. Yamamoto, Y.; Furuta, T.; Matsuo, I.; Kurata, T. J. Org. Chem. 1991, 56,
5737–5738.
9. Kroszczyn´ ki, W.; Olszewska, E.; Sałan´ ski, P.; Jurczak, J. Helv. Chim. Acta 2004, 87,
1488–1492.
Acknowledgements
10. Pelousek, H.; Horbach, A.; Bottenbruch, L.; Binsack, R. DE 2340559, 1975; Chem.
Abstr. 1975, 83, 11167.
11. Martin, A.; Flynn, J.; Lange, H. US 2009/0163731, 2009; Chem. Abstr. 2009, 83,
11167.
This work was supported by Grant 501/86-DSM-100100 from
the Ministry of Science and Higher Education.
12. General procedure for the transesterification: 0.4 mmol of ester and 0.8 mmol
of DBU were placed in a 2 ml PTFE ampoule, filled with methanol, closed, and
transferred to a high-pressure vessel. The pressure was then slowly raised to
10 kbar at room temperature. After 2 h the chamber was decompressed. The
reaction mixture was concentrated under reduced pressure and the residue
was separated using flash column chromatography (SiO2; hexane/AcOEt in
various proportions). All products were analyzed by NMR spectroscopy and the
spectra were consistent with the structures of the desired products.
13. Seebach, D.; Thaler, A.; Blaser, D.; Ko, S. Y. Helv. Chim. Acta 1991, 74, 1102–
1118.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
094. These data include MOL files and InChiKeys of the most
important compounds described in this article.
14. The enantiomeric excess of phenylalanine methyl ester, after being derivatized
to N-benzyloxycarbonyl phenylalanine methyl ester with benzyl
chloroformate and diisopropylethylamine in CH2Cl2 at room temperature,
was determined using a Chiralcel-OD column, with 10:90 2-PrOH/hexane as
eluent, temp 25 °C, 1.0 mL/min flow rate, and 210 nm detection wavelength.
References and notes
1. Otera, J. Chem. Rev. 1993, 93, 1449–1470.
2. Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971–985.
3. Hoydonckx, H. E.; De Vos, D. E.; Chavan, S. A.; Jacobs, P. A. Top. Catal. 2004, 27,
83–96.