Base-catalyzed selective esterification of alcohols with unactivated esters

Article abstract of DOI:10.1039/C8OB02411A

A practical and efficient base-catalyzed esterification has been developed for the facile synthesis of a broad range of esters from simple alcohols with unactivated tert-butyl esters. This protocol could be conducted at mild conditions, providing esters in high to excellent yields with good functional tolerance. Mechanistic studies provided evidence of an exchange of the tert-butyl alkoxide metal with the alcohol, producing a new alkoxide to participate in the transesterification reaction.

Full text of DOI:10.1039/C8OB02411A

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Base-catalyzed selective esterification of alcohols
with unactivated esters†
Cite this: Org. Biomol. Chem., 2018,
16, 8467
Chunyan Zhang, * Guoying Zhang, * Shizhong Luo, Chunfu Wang and
Huiping Li
Received 27th September 2018,
Accepted 17th October 2018
DOI: 10.1039/c8ob02411a
rsc.li/obc
A practical and efficient base-catalyzed esterification has been metric amounts of substrates or an in situ removal of the
developed for the facile synthesis of a broad range of esters from (by)products to prevent the reverse reaction from occurring
simple alcohols with unactivated tert-butyl esters. This protocol (Scheme 1, top).
could be conducted at mild conditions, providing esters in high to
One attractive method to solve this problem involves using
excellent yields with good functional tolerance. Mechanistic a tert-butyl ester as the starting ester, in which only a large
studies provided evidence of an exchange of the tert-butyl alkox- sterically bulky tert-butyl alcohol is produced as a by-product.
ide metal with the alcohol, producing a new alkoxide to participate Indeed, using tert-butyl esters as the starting ester, Gagné
in the transesterification reaction.
and co-workers have successfully developed an elegant
process for synthesizing esters from an ester-interchange
reaction with base as the catalyst.17 However, only low-
boiling-point esters would be in situ removed and hence toler-
ated in this system, thereby limiting the potential scope of
this environmentally friendly transformation. Inspired by
these results, we set out to exchange the initial metal alkoxide
with an alcohol, producing another metal alkoxide and large
sterically bulky tert-butyl alcohol. Once a tert-butyl ester is
introduced into the reaction system, the desired ester product
would be formed by carrying out a metathesis process and
the active catalyst t-BuO-M would be regenerated for the next
catalytic cycle. Herein we report a practical and efficient
approach to forming a broad range of esters from tert-butyl
esters and simple alcohols via base-catalyzed esterification
(Scheme 1, bottom).
Introduction
Substituted esters exist widely as pharmaceuticals, agrochem-
icals, natural products, and organic functional materials,
and are also useful intermediates as protecting groups for
alcohols in synthetic organic chemistry.1 As a result, con-
siderable effort has recently been focused on the develop-
ment of new synthetic methods for the generation of ester
motifs. Among them, the transesterification of carboxylic
esters with commercially available alcohols is not only an
indispensable synthetic method in organic chemistry but is
also of particular interest due to its sustainable and environ-
mentally friendly features.2 However, current transesterifica-
tions still often require the use of transition metal salt cata-
lysts (such as Sb,3 Ti,4 Sm,5 Sn,6 La,7 Y,8 Hf or Zr,9 Fe,10 Co,11
Al,12 Zn,13 etc.), I2,14 N-heterocyclic carbenes,15 phosphonium
or ammonium salt,16 resulting in the generation of undesired
waste and poor chemoselectivity. Moreover, many transesteri-
fication reactions generally require either extra-stoichio-
Key Laboratory of Sensor Analysis of Tumor Marker, Ministry of Education,
Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical
Chemistry for Life Science in Universities of Shandong, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China. E-mail: qustzcy@163.com, zhanggy@qust.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02411a
Scheme 1 Catalyzed transestrification of esters with alcohols.
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ditions, allowing the preparation of various ester derivatives.
As shown in Table 2, the reactions of alcohols 2 bearing an
Results and discussion
The reaction between 1-phenylethan-1-ol (2a) and tert-butyl electron-donating or electron-withdrawing group proceeded
acetate (1d) to form 1-phenylethnyl acetate (3aa) was smoothly to give the corresponding products 3aa–3ag in yields
thoroughly investigated to develop broadly applicable acetyl- higher than 89%. The attachment of halide groups remained
ation reaction conditions. After finding initial reaction con- particularly stable using the standard procedure, leading to
ditions for the esters, different functionalized esters were corresponding desired products 3ac–3ae, which can be used
tested to find the most active ester (Table 1, 1a–1j). The ester for further transformations involving oxidative addition to the
functionalized with the tert-butyl group (1d) gave the highest aryl–X bond (X = F, Cl). Alcohols carrying the heteroaromatic
yield of 3aa. Under these conditions, other functional groups groups 2h and 2i were linked successfully to 1d with this
of esters did not improve the reactivity. Further investigation catalytic system, giving transestrification products in 93% and
of the functionalized esters revealed that the reactivity was 88% yields, respectively. Furthermore, the methodology was
affected by the nature of the substituted group, and the equally effective for ethyl, butyl and phenyl-substituted benzyl
sequence of ester activity was tert-butyl > tert-pentyl > iso-
propyl > ethyl > methyl. Only moderate yields of the desired
product 3aa were obtained for esters functionalized with
benzyl, phenyl and vinyl groups. It was noteworthy that the
reaction still worked well with tert-butyl benzoate, and 4aa was
Table 2 Substrate scope of alcoholsa
obtained in high yield under the standard reaction conditions.
The best yield of 3aa was obtained after final optimization of
the reaction parameters (type of base, amount of base, type of
solvent, solvent amount, substrate ratio, reaction temperature
and reaction time; see ESI† for details) with 1d determined to
be the most active ester. Although some tert-butyl esters are
more difficult to synthesize than secondary alcohol esters, this
work provided, from a synthetic method development point of
view, an attractive method for the rapid preparation of various
esters from alcohols in a laboratory environment. Finally,
control reactions demonstrated that only a trace amount of the
acetylation product 3aa was obtained in the absence of base or
in the presence 10 mol% of H2O. Taken together, we con-
cluded that the desired transesterification product in the best
yield was obtained by stirring a toluene solution of tert-butyl
acetate, 1-phenylethan-1-ol and 2 mol% of t-BuONa at 100 °C
for an hour.
With the optimized conditions in hand, we could apply a
wide range of alcohol substrates using our optimized con-
Table 1 Investigated estersa
a General conditions: 1a–j (2 mmol), 2a (1 mmol), t-BuONa (2 mol%),
toluene (0.5 mL), 100 °C (external temperature), 1 h. Yield of 3aa or
4aa determined by performing GC analysis using n-dodecane as an
internal standard.
a General conditions: 1d (2 mmol) or 1j (1.2 mmol), 2 (1 mmol),
t-BuONa (2 mol%), toluene (0.5 mL), 100 °C (external temperature),
1 h. Isolated yield.
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secondary alcohols to give the corresponding products in order to further explore the synthetic potential of this process,
76–89% yields (3aj–3al) under the optimized conditons. a series of typical functional groups of the heteroaromatic
We next turned our attention to the more challenging ali- esters, such as furanyl and thienyl, were subjected to reaction
phatic alcohols. 1-Phenylpropan-2-ol (2m), hexan-2-ol (2n) and with 2g under the standard reaction conditions, and afforded
1-cyclopropylethan-1-ol (2o) were initially surveyed and their the corresponding products 4gi–4gj in excellent yields. Typical
reactions proceeded smoothly to give the desired adducts 3am, aliphatic functional groups on the esters, such as ethyl and
3an and 3ao in 92%, 85% and 88% yields, respectively. Notably, cyclopropnyl, also well tolerated the reaction conditions,
the reactions of hex-5-en-2-ol (2p) and 6-methylhept-5-en-2-ol thereby affording the corresponding desired adducts in
(2q) yielded the corresponding products 3ap and 3aq in 72% 88–91% yields. Moreover, similar results were obtained in the
and 93% yields, respectively, while the double bond remained reactions of primary alcohols to deliver the ester products
intact. In addition, similar results were obtained for the reac- 4dm–4jo efficiently in good yields.
tions of cyclic alcohols (2r–2t) and symmetrical alcohols (2u–
To validate the recyclability of current transesterification
2w), with these reactions delivering the desired adducts under lower catalyst loading, a reuse investigation was per-
efficiently in high yields. It is worth noting that the menthol formed in the model reaction of 1d with 2a in the presence of
derivative 2x could also be used in the present reaction, and 2 mol% of t-BuONa. After the completion of the reaction, a
afforded 3ax in a good isolated yield. We further demonstrated small aliquot of the reaction mixture was analyzed using GC
the robustness of our system: we were able to run experiments (Gas Chromatography) to monitor product formation. Then 1d
on the gram scale in the presence of 2 mol% of t-BuONa cata- and 2a were added to the reaction tube, and their reaction was
lyst to produce the ester 3aa in 83% yield.
allowed to continue for another hour at 100 °C. As shown in
Furthermore, the scope of the esters was also explored and Fig. 1, the current transesterification could be reused at least
the results are shown in Table 3. In all cases, tert-butyl aro- seven times: the seventh run gave an 89% yield of 3aa.
matic esters bearing both electron-donating and electron-with-
To gain insight into the transesterification mechanism,
drawing groups on the aromatic rings were all smoothly con- several experiments to form sodium alkoxide complexes were
verted to the corresponding aromatic esters in good to excel- conducted (Scheme 2). Initially, the desired sodium alkoxide
lent yields (74–94%). The aromatic esters having electron- complex Na-I ([Ph2CHONa]6) was isolated in moderate yield by
donating groups gave slightly higher yields than did those treating t-BuONa with 1.2 equiv. of 2l in toluene at 100 °C for
having electron-withdrawing groups (4gb–4gd vs. 4ge–4gh). In an hour (eqn (I)).18 However, only a trace amount of the
desired sodium alkoxide was detected when the same reaction
condition was used at room temperature for 12 hours (eqn
Table 3 Substrate scope of estersa
(II)). These results showed that a high temperature is required
for the exchange of alcohol with sodium alkoxide. Further
reaction of complex Na-I with 1d at the standard conditions
led to the formation of 3al in good yield (eqn (III)). In addition,
complex Na-I could catalyze the transesterification reaction
between 2l and 1d to give 3al in good yield under the standard
conditions (eqn (IV)), suggesting the plausible intermediacy of
complex Na-I in the catalytic cycle.
a General conditions: 1 (1.2 mmol), 2g (1 mmol), t-BuONa (2 mol%),
toluene (0.5 mL), 100 °C (external temperature), 1 h. Isolated yield.
b Yield of 4dn determined by GC analysis using n-dodecane as an
internal standard.
Fig. 1 Recyclability of a representative transesterification reaction.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This research was supported by the Shandong Provincial
Natural Science Foundation of China (No. ZR2017MB029,
ZR2017BB060), the Qingdao Source Innovation Program
Foundation (18-2-2-49-jch) and the Qingdao University of
Science and Technology Talent Startup Fund Foundation
(No. 010022797, 010022846) for financial support.
Scheme 2 Preliminary mechanistic studies.
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