Transesterifications mediated by t-BuNH2

Article abstract of DOI:10.1016/j.tetlet.2007.12.013

A mild protocol for transesterification of simple esters is described. The method is based on the use of t-BuNH₂/ROH (R = Me, Et, i-Pr, t-Bu) with or without LiBr. The scope of the procedure was explored for aliphatic and aromatic esters. The protocol is particularly useful when going from higher to lower hindered esters and harsh reaction conditions are needed for the reversal process. A rationalization of the mechanism is presented. The scope and limitation of this transformation are also described.

Full text of DOI:10.1016/j.tetlet.2007.12.013

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 996–999
Transesterifications mediated by t-BuNH2
*
´
´
Oscar R. Suarez-Castillo , Luis Alberto Montiel-Ortega, Manuel Jonathan Fragoso-Vazquez,
´
´
´
Myriam Melendez-Rodrıguez, Maricruz Sanchez-Zavala
Centro de Investigaciones Quı´micas, Universidad Auto´noma del Estado de Hidalgo, Apartado 1-328, Pachuca, Hidalgo 42001, Mexico
Received 17 November 2007; accepted 4 December 2007
Available online 8 December 2007
Abstract
A mild protocol for transesterification of simple esters is described. The method is based on the use of t-BuNH2/ROH (R = Me, Et,
i-Pr, t-Bu) with or without LiBr. The scope of the procedure was explored for aliphatic and aromatic esters. The protocol is particularly
useful when going from higher to lower hindered esters and harsh reaction conditions are needed for the reversal process. A rationali-
zation of the mechanism is presented. The scope and limitation of this transformation are also described.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Transesterification; tert-Butylamine; Lithium bromide; Aliphatic esters; Aromatic esters
The ester formation is an important and commonly used
transformation in organic synthesis, in industrial as well as
in academic laboratories. Esters are some of the most com-
mon functional groups in organic transformations, playing
an important role in synthetic chemistry serving as key
intermediates or protecting groups in the multiple-step
synthesis of many natural products.1 Ester syntheses are
generally accomplished either from coupling of carboxylic
acids with alcohols in a variety of conditions2 and/or by
transesterification of an ester with an alcohol (alcoholy-
sis).1,2b,3 For alcoholysis, a number of useful and reliable
procedures catalyzed by a variety of protic and Lewis acids,
organic and inorganic bases, enzymes and antibodies have
been developed.3,4 The alkoxy groups commonly used in
the new ester formation are methoxy, ethoxy, t-butoxy,
allyloxy and benzyloxy groups,1,4a,b,5 and less frequently
i-propoxy,6 and prenyloxy7 groups. Even though numerous
methods of transesterification have been reported in the
literature including variation and improvements of well
established procedures there is still a constant need to
discover and apply new protocols, which require mild con-
ditions especially for compounds with acid and base
sensitive functionalities.
In the course of our studies on the use of t-BuNH2/
MeOH mediated deprotection of carbamates,8 we found
that esters suffer rapid transesterification in the presence
of this base. A number of organic bases, for example,
Et3N, 2-(dimethylamino)ethanol (DMAE) and Et3N/
DMF have been used for transesterifications in peptide-
(polystyrene resin) cleavage9a–c and in the synthesis of
artificial b-sheets.9d The diamino alcohol 2-{[2(dimethyl-
amino)ethyl]methylamino}ethanol (DAEMAE) has been
used for transesterification of glycidyl methylacrylate.10a,b
N,N-Dimethyltrimethylenediamine (DMTMD), 4-methyl-
piperidine (4-MP), Et2NH and tetramethyldiaminoethane
(TEMED) have been used in biodiesel-transesterification
of biological oils.11 The more complex bases benzoyl-
quinine (BQ) and a thiourea-amine system have been used
in the preparation of b-amino acids12a and for selective
transesterification of lactide.12b N,N-Diethylaminopro-
pylated silica gel (NDEAP)13a and 4-(N,N-dimethyl-
amino)pyridine (DMAP)1 have been used for transesteri-
fication of b-ketoesters. DMAP has also been used for
transesterification of trihaloethyl esters.13b DBU has been
used for transesterification of p-nitrophenyl phospho-
nates14a and the DBU/LiBr system14b has been used for
*
Corresponding author. Tel.: +52 771 71 72000x2206; fax: +52 771 71
72000x6502.
´
E-mail address: osuarez@uaeh.edu.mx (O. R. Suarez-Castillo).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.013

O. R. Sua´rez-Castillo et al. / Tetrahedron Letters 49 (2008) 996–999
997
transesterification of simple esters and peptides. The latest
author claims that no reaction occurs in the absence of
LiBr. More recently, amino hemiacetals/hemiketals have
been used for transesterification of p-nitrophenyl esters.15
As can be seen, a number of organic bases are used in
transesterifications; however, the main drawback of most
of them is their narrow range of applicability. Here we wish
to report our results on a systematic investigation involving
the soft nucleophile t-BuNH2/ROH (R = Me, Et, i-Pr,
t-Bu, Bn) system as an efficient promoter for transesteri-
fication. We also found that significant improvements
in reaction times can be achieved by including lithium
bromide (LiBr) in the transesterification.
We initially investigated the transesterification reaction
using phenyl acetates 1a–d. As indicated in Table 1 excel-
lent yields have been achieved including reactions involving
sterically hindered esters. In a typical experimental proce-
dure, ester 1a was refluxed for 8 h with MeOH in the pres-
ence of 5 equiv of t-BuNH2 (entry 1). The reaction progress
was monitored by TLC and/or 1H NMR analysis and after
completion the excess t-BuNH2/MeOH mixture was
removed from the reaction simply by evaporation under
vacuum or by fractional distillation to recover t-BuNH2.
The procedure gave the desired methyl ester 2 in very high
yield and neither column chromatography nor aqueous
work-up was necessary to afford pure ester 2. Although
the reaction proceeds well with only 1 equiv of t-BuNH2,
the reaction is quite slow. Under similar conditions esters
1b and 1c afforded product 2 in quantitative yield but they
needed harsh reaction conditions, that is, high temperature
and pressure (entries 4 and 6).
The reaction times for the conversion of 1a into 2 were
substantially reduced when an excess of the amine was used
(entries 2 and 3). Accordingly, we decided to use as an opti-
mum reaction conditions 20 equiv of t-BuNH2. Under
these reaction conditions the transesterification of 1a–c
into 2 was completed in 2, 21, and 2 h, respectively (entries
3, 5, and 7). In the case of 1d (entry 8) only 15% of 2 was
1
observed in the H NMR spectrum of the reaction crude.
As is shown in Table 1 the steric effect of the alkoxy group
of esters 1a–d influences the rate of transesterification in the
order OEt ꢀ OBn > Oi-Pr ꢁ Ot-Bu.
To ensure that t-BuNH2 facilitated the transesterifica-
tion process, ester 1a was heated under reflux of MeOH
in the absence of the base but no ester 2 was detected even
under forcing conditions after 24 h of reaction (entry 9).
The result of this experiment confirmed that the alcohol
alone does not directly provide the alkoxyl group for
transesterification and t-BuNH2 is indeed necessary for this
transformation.
On the basis of these results, we decided to pursue the
use of t-BuNH2/MeOH system together with LiBr for
further transesterification. Remarkably, stirring 1a with
20 equiv of t-BuNH2 and 5 equiv of LiBr at room temper-
ature for 3 h led to homologue 2 in quantitative yield (entry
10). Encouraged by this result, we screened the reaction of
Table 1
t-BuNH2 transesterification with MeOH
t
-BuNH2
MeOH
CO2R
CO2Me
1a-d
Equiv of LiBr
2
Entry
Compound
Equiv of t-BuNH2
Reaction conditions
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
a
1a: R = Et
1a
1a
—
—
—
—
—
—
—
—
—
5
5
5
1
5
5
1
5
5
5
15
20
5
20
5
20
20
—
20
5
Reflux
Reflux
Reflux
Sealed tube
Reflux
Sealed tube
Reflux
Reflux
Reflux
rt
8
3
2
175
21
24
2
35
24
3
13
15
25
1
4
8
Quant
Quant
Quant
Quant
Quant
Quant
Quant
15a
—
Quant
98
98
Quant
99
1b: R = i-Pr
1b
1c: R = Bn
1c
1d: R = t-Bu
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
rt
rt
rt
1
1
5
1
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Sealed tube
Quant
Quant
29a
1
—
5 mL
5
5
5
24
24
32
0.25
39
b
—
5
5
5
99
Quant
20a
Calculated by 1H NMR analysis of the crude material.
The reaction was carried out without MeOH.
b

998
O. R. Sua´rez-Castillo et al. / Tetrahedron Letters 49 (2008) 996–999
1a varying the equivalents of t-BuNH2, LiBr, and reaction
time (entries 11–16). As indicated in entries 10-13, reducing
the amounts of LiBr or t-BuNH2 still afforded excellent
yields of 2 albeit in longer reaction times. With the objec-
tive of achieving high conversion in short reaction time,
we further explore the transesterification under reflux
(entries 14–16). The best reaction conditions for the trans-
formation of 1a into 2, namely in the presence of 5 equiv of
t-BuNH2 and 5 equiv of LiBr under reflux, occurred in 1 h
(entry 14).
Compound 1a was also utilized in a control experiment
to assess the role of LiBr and reveal its participation in the
observed increased rate of transesterification. The reaction
occurred with LiBr/MeOH in the absence of t-BuNH2 but
only with 29% yield after 24 h (entry 17). On the other
hand, the reaction of 1a with LiBr/t-BuNH2 in the absence
of MeOH (entry 18) did not produce the corresponding
amide even in traces as judged by a careful 1H NMR spec-
tral analysis of the crude material. These results indicate
that for the reaction to proceed faster the t-BuNH2 and
MeOH must be present in the reaction mixture and Li+
should activate the carbonyl ester group to improve base
catalyzed O-nucleophilic attack by the MeOH.16 Despite
the greater nucleophilicity of t-BuNH2 relative to MeOH,17
steric hindrance in this base should prevent nucleophilic
attack at the carbonyl ester group.
More sterically congested esters 1b–d (entries 19–21)
were also found to react under these conditions to afford
2 in excellent yields. In the cases of 1b and 1d longer reac-
tion times were necessary and for 1d harsh reaction condi-
tions were also required.
Methyl phenyl acetate (2) underwent transesterification
to higher homologues with t-BuNH2, EtOH, and i-PrOH
to afford the corresponding esters 1a and 1b (Table 2,
entries 1 and 2). As is shown in Table 2, methyl ester 2
required fairly harsh reaction conditions to undergo tran-
sesterification to higher homologues. When t-BuNH2/
alcohol/LiBr system was used, better results were obtained.
Thus, reactions carried out under reflux afforded esters 1a
and 1b in excellent yields (entries 4–6). Ester 1d was not
obtained either in the absence or presence of LiBr even
under longer reaction times (entries 3 and 7).
We next turn our attention on the transesterification of
aromatic esters 3a–c (Table 3). The reactions are very clean
Table 2
t-BuNH2 transesterification with EtOH, i-PrOH, and t-BuOH
t-BuNH2
CO2Me
CO2R
ROH
2
1a-d
Entry
Equiv of LiBr
Equiv of t-BuNH2
Reaction conditions
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
a
—
—
—
5
5
5
20
20
20
5
5
15
5
Reflux
24
24
24
6
32
33
24
1a: R = Et
1b: R = i-Pr
1d: R = t-Bu
1a
1b
1b
1d
66b
6b
—
Quant
77b
Sealed tube
Sealed tube
Reflux
Reflux
Reflux
a
99
a
5
Reflux
—
Starting material was recovered.
Calculated by 1H NMR analysis of the crude material.
b
Table 3
t-BuNH2 transesterification of aromatic esters
CO2Me
CO2R1
t-BuNH2
R1OH
R
R2
3a-c
4a-e
Entrya
Compound
Equiv of LiBr
Reaction conditions
Time (h)
Product
Yield (%)
33a,c
1
2
3
4
5
6
7
a
3a: R = H
3b: R = N(Me)2
3c: R = NO2
3c
3c
3c
3c
—
—
—
—
—
5
Reflux
Reflux
Reflux
Reflux
Sealed tube
Reflux
Reflux
46
24
10
34
32
1
4a: R1 = Et, R2 = H
4b: R1 = Et, R2 = N(Me)2
4c: R1 = Et, R2 = NO2
4d: R1 = i-Pr, R2 = NO2
4e: R1 = t-Bu, R2 = NO2
4c
a
—
Quanta
55a,c
a
—
99b
96b
5
11
4d
Reactions were carried out with 20 equiv of t-BuNH2.
Reactions were carried out with 5 equiv of t-BuNH2.
Calculated by 1H NMR analysis of the crude material.
b
c

O. R. Sua´rez-Castillo et al. / Tetrahedron Letters 49 (2008) 996–999
999
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donating group retards the reaction rate, while the presence
of an electron withdrawing group does the contrary, as it is
evident in entries 2 and 3. These results, together with those
obtained by the treatment of 1 or 2 with different alcohols
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direct nucleophilic attack at the carbonyl ester group by the
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´
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´
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In conclusion, the present procedure using t-BuNH2/
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sterification. Various types of carboxylic esters including
aliphatic and aromatic compounds have been subjected
to transesterification using a variety of alcohols according
to this procedure.18 The reactions are, in general, very clean
and give very high yields. Besides, the simplicity of this
approach and the low cost of the reagents enhance its
attractiveness. The method is especially well applicable
when going from higher to lower hindered esters but harsh
reaction conditions are needed for the reversal process.
Works on other reactions catalyzed by t-BuNH2/MeOH
are currently underway in our laboratory.
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Acknowledgement
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We are pleased to acknowledge the financial support
from UAEH-PAI 2006-28B for this investigation.
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18. Typical experimental procedure:
To the appropriate ester (0.6 mmol) in the corresponding alcohol
(5 mL) was added t-BuNH2 (20 equiv, 1.26 mL) or t-BuNH2 (5 equiv,
0.315 mL)/LiBr (5 equiv, 0.261 g), and the mixture was stirred under
reflux for the appropriate time (Tables). After complete conversion, as
indicated by TLC or 1H NMR spectroscopy, the volatile reagents
were evaporated to afford the pure transesterified product in the case
of esters treated only with t-BuNH2/ROH. For esters treated with
t-BuNH2/ROH/LiBr the residue was diluted with EtOAc (50 mL),
washed with saturated aqueous NH4Cl solution (2 Â 15 mL), dried
over anhydrous Na2SO4 and evaporated to give the pure transe-
sterified product.
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The identity and the purity of the reaction products were estab-
lished by their 1H NMR data by direct comparison with authentic
samples.