A fast and practical synthesis of tert-butyl esters from 2-tert-butoxypyridine using boron trifluoride·diethyl etherate under mild conditions

Article abstract of DOI:10.1016/j.tet.2018.05.050

A practical direct preparation of tert-butyl esters from 2-tert-butoxypyridine has been developed. This system features the use of boron trifluoride·diethyl etherate in toluene solvent to rapidly achieve the reaction at room temperature. Using this reaction protocol, a variety of tert-butyl esters were synthesized from several different carboxylic acids at high yields. This practical procedure provides a promising and effective approach to the protection of carboxylic acids with a tert-butyl group.

Full text of DOI:10.1016/j.tet.2018.05.050

Accepted Manuscript
A fast and practical synthesis of tert-butyl esters from 2-tert-butoxypyridine using
boron Trifluoride·Diethyl etherate under mild conditions
Minh Thanh La, Hee-Kwon Kim
PII:
S0040-4020(18)30598-2
10.1016/j.tet.2018.05.050
TET 29557
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 March 2018
Revised Date: 15 May 2018
Accepted Date: 18 May 2018
Please cite this article as: La MT, Kim H-K, A fast and practical synthesis of tert-butyl esters from 2-tert-
butoxypyridine using boron Trifluoride·Diethyl etherate under mild conditions, Tetrahedron (2018), doi:
10.1016/j.tet.2018.05.050.
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A Fast and Practical Synthesis of tert-Butyl
Esters from 2-tert-Butoxypyridine using
Boron Trifluoride·Diethyl Etherate under
Mild Conditions
Leave this area blank for abstract info.
Minh Thanh La a, b and Hee-Kwon Kima, b, *
a
Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk
National University Medical School and Hospital, Jeonju, 54907, Republic of Korea
b
Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of
Chonbuk National University Hospital, Jeonju, 54907, Republic of Korea
O
BF3 OEt2
O
+
O
R
OH
R
Toluene, rt.
30 min
O
N
52-98% yield
26 examples
Fast tert-butyl esterification
at ambient temperature

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A Fast and Practical Synthesis of tert-Butyl Esters from 2-tert-Butoxypyridine using
Boron Trifluoride·Diethyl Etherate under Mild Conditions
Minh Thanh La a, b and Hee-Kwon Kim a, b,
a
Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital,
Jeonju, 54907, Republic of Korea
Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju,
b
54907, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A practical direct preparation of tert-butyl esters from 2-tert-butoxypyridine has been
developed. This system features the use of boron trifluoride·diethyl etherate in toluene solvent to
rapidly achieve the reaction at room temperature. Using this reaction protocol, a variety of tert-
butyl esters were synthesized from several different carboxylic acids at high yields. This
practical procedure provides a promising and effective approach to the protection of carboxylic
acids with a tert-butyl group.
Available online
Keywords:
Esterification
2009 Elsevier Ltd. All rights reserved
.
Tert-butyl ester
Carboxylic acid
Boron Trifluoride·Diethyl Etherate
Protecting groups
1. Introduction
Several synthetic methods for the preparation of tert-butyl
esters have been reported (Scheme 1). Wright and co-workers
reported a procedure to prepare tert-butyl esters promoted by
reaction of an excess of tert-butyl alcohol and sulfuric acid in the
presence of anhydrous magnesium sulfate.13 Alternatively,
isobutylene with concentrated H2SO4 in Et2O has been shown to
protect carboxylic acids with the tert-butyl group.14 These
methods use strong concentrated acid, which can obstruct the
esterification of acid-sensitive functionalities. Also, isobutylene
gas poses safety concerns for large-scale applications because of
its high flammability and risk of explosion. Some methods of
preparing tert-butyl esters have been reported that do not require
strong acid or isobutylene gas such as the reaction of a carboxylic
acid, N,N'-carbonyldiimidazole, and t-BuOH with DBU,15 or
reaction of an acid chloride, tert-BuOH, and AgCN in benzene.16
However, these reactions still use expensive catalysts. Therefore,
developing a new method that uses inexpensive starting materials
as well as a short reaction time and mild conditions is an
important challenge. In particular, discovery of new types of
efficient reagents for the preparation of tert-butyl esters would be
a valuable addition to organic chemistry. Lewis acids are
potentially useful agents in the preparation of tert-butyl esters
because they play an important role in various organic
reactions.17,18 Thus, we hypothesized that Lewis acids could be
used for the high-yield synthesis of tert-butyl esters. Herein, we
report a novel facile synthesis of tert-butyl esters from 2-tert-
Carboxylic acids are common structures in organic synthesis
and pharmaceutical development. Protection and deprotection of
this functional group are commonly performed during multistep
syntheses. Esters, carboxylic acid derivatives, are widely used as
carboxyl protecting groups. The conversion of carboxylic acid to
tert-butyl ester is a particularly useful synthetic method because
of the stability of the ester against nucleophilic attack and its easy
cleavage. Several methods have been developed to remove the
tert-butyl group from an ester. Traditional and simple strategies
using strong acids such as CF3COOH,1 H2SO4,2 and HNO3 have
3
been reported. Some Lewis acids such as MgI2,4 TiCl4,5 and
6,7
ZnBr2 have also been used for the deprotection of tert-butyl
esters. Heating at 190–200 °C is a non-chemical method of
cleaving the tert-butyl group.8 Having various options for tert-
butyl group removal provides advantages in multistep organic
syntheses. The tert-butyl group has also been used in a wide
range of organic reactions to protect carboxylic acids in the
synthesis of bioactive compounds such as inhibitors of hepatitis
C virus NS3 protease,9 inhibitors of MMP-3, -6 and -9 subclasses
of matrix metalloproteinases, which are related to dermal
ulcers,10 GABA-T inhibitors,11 and HIV-gp120 discontinuous
epitope mimics for the development of synthetic vaccines.12
———
Corresponding author. Tel.: +82 63 250 2768; fax: +82 63 255 1172; e-mail: hkkim717@jbnu.ac.kr (H. Kim)

2
Tetrahedron
ACCEPTED MANUSCRIPT
butoxypyridine and various carboxylic acids using the Lewis
results are shown in Table 1. No change in the starting material
acid boron trifluoride·diethyl etherate under mild conditions in a
short reaction time.
was observed after 30 min when K2CO3, Et3N, NaHCO3, or DBU
were used. Thus, we concluded that basic reagents were not a
proper choice for this reaction. The addition of Lewis acids such
as SnCl4 resulted in small increased reaction yield for tert-butyl
esterification, whereas none of the desired product was observed
when the reaction was carried out with TiCl4 or AlCl3. Finally,
the possibility of tert-butyl esterification using BF3·OEt2 was
investigated. A yield of 94% of the desired product was observed,
suggesting BF3·OEt2 as the most effective reagent for tert-butyl
esterification.
1. Previous studies:
O
O
O
O
HO
acid-sensitive functionalities problem
- acid-sensitive functionalities problem
R
R
OH
OH
R
R
O
O
H2SO4 / MgSO4
- high flammability and risk of dangerous explosion
of gas
H2SO4 conc.
O
O
HO
- usage of costly catalysts
- usage of unstable starting material
R
Cl
R
O
AgCN, C6H6
Next, screening for a reaction solvent effect was carried out.
As shown in Table 2, reactions performed with BF3ꢀOEt2 in THF,
1,4-dioxane, and chlorinated solvents (dichloromethane and
dichloroethane) led to low yields of tert-butyl ester. When the
reaction was carried out in MeCN, the desired product yield
increased to 47%. Surprisingly, employing toluene as a solvent
led to an accelerated reaction and gave significantly increased
yield of the desired tert-butyl ester. The solvent screening study
suggested that toluene was the best solvent for the reaction.
2. This work:
O
O
- short-time reaction
- mild reaction conditions
- inexpensive reagents
N
O
R
OH
R
O
BF3 OEt2 / Toluene
Scheme 1. Synthetic strategies of tert-butyl esters.
2. Result and Discussion
To provide a better understanding of the effect of BF3·OEt2 on
the reaction, we investigated the use of different amounts of
BF3·OEt2 (0.1 equiv, 0.5 equiv, 1.0 equiv, 1.35 equiv, and 2.0
equiv) in the tert-butyl esterification. As shown in Table 2, ester
product yield increased in proportion to the amount of reagent
(i.e., 3% for 0.1 equiv of BF3·OEt2, 21% for 0.5 equiv of
BF3·OEt2). The highest yield of tert-butyl ester was observed in
the presence of 1.35 equiv and 2.0 equiv of BF3·OEt2 for 30 min
(94% yield for both 1.35 and 2.0 equiv of BF3·OEt2). There was
no significant difference in yield when employing 1.35 equiv or
2.0 equiv of BF3·OEt2. These results demonstrate that the
synthetic yield of tert-butyl ester significantly depends on the
amount of BF3·OEt2. Based on these results, 1.35 equiv. of
BF3·OEt2 reagent was selected for further investigation in the
tert-butyl ester synthesis.
Dudley and co-workers first prepared benzyl esters from 2-
benzyloxy-1-methylpyridine.19 In the method, treatment of 2-
benzyloxy-1-methylpyridine with MeOTf produced 2-benzyloxy-
1-methylpyridinium triflate salt, one of the oxypyridinium salts
and a key intermediate to achieve the desired reactions. This
method was also employed to prepare allyl ester.20 From the
results of these reactions, we hypothesized that 2-tert-
butoxypyridine could be used in the synthesis of tert-butyl esters.
Tert-butyl esters were prepared from potassium tert-butoxide
in 2 steps, as shown in Scheme 2. In the reaction, potassium tert-
butoxide was converted to 2-tert-butoxypyridine by previously
reported method.21 Treatment of potassium tert-butoxide with 2-
chloropyridine in the presence of 18-crown-6 in toluene at
110 °C for 15 h generated 2-tert-butoxypyridine (compound 2) in
54% yield. The purification of compound 2 was easily achieved
via silica gel chromatography. Next, we employed the reported
synthetic protocol using oxypyridinium salt to prepare tert-butyl
ester.19 Compound 2 was treated with carboxylic acid and MeOTf
at room temperature. However, tert-butyl esterification at room
temperature was inadequate (32% esterification after 20 h).
Having determined the optimal conditions, we carried out
esterification reactions with a variety of carboxylic acids
including saturated or unsaturated ones, bulky ones, heterocyclic
carboxylic acids, and aromatic carboxylic acids with electron-
donating or electron-withdrawing groups. 1.00 equiv. of
carboxylic acid substrate was treated with 1.35 equiv. of 2-tert-
butoxypyridine and 1.35 equiv. of BF3·OEt2 in anhydrous toluene
at room temperature. All tert-butyl esterification yields from
carboxylic acids were determined after 30 min reaction time. As
shown in Table 3, aromatic carboxylic acids containing electron-
donating groups afforded the corresponding tert-butyl ester in
very good yields ranging from 80 to 98% (Table 3, entries 2-5).
Changing the substituents to electron-withdrawing groups led to
similar results under the same conditions (Table 3, entries 6-10),
suggesting that reactions using BF3·OEt2 with most substituted
aromatic carboxylic acids will successfully produce the
corresponding tert-butyl ester in excellent yield.
O
OH
R
O
N
4
MeOTf
OTf
base
Cl
N
3
O
KOH, 18-C-6
110 oC, 15h
O
O
R
K
O
N
O
BF3.OEt2
5
2
1
OH
R
4
Scheme2. Synthesis of tert-butyl esters.
Thus, various reaction conditions for compound 2 were
examined to yield tert-butyl esters (compound 5). In an initial
investigation, we carried out the esterification reaction with
various commercially available reagents such as Lewis acids
(TiCl4, AlCl3, SnCl4, and BF3·OEt2) and bases (K2CO3, Et3N,
NaHCO3, and DBU) to identify better reagents for tert-butyl ester
formation. Benzoic acid was selected as a model substrate in our
study. To a mixture of 1.35 equiv. of Lewis acid or base and 1.00
equiv. of benzoic acid in toluene, a 1.35 equiv. solution of
compound 2 in toluene was added. After a 30-min reaction at
room temperature, the yield of the desired product obtained after
purification by flash column chromatography was calculated to
determine the effect of each reagent on the esterification. The
Furthermore, esterification of alkyl substituted carboxylic
acids produced their corresponding tert-butyl esters in excellent
yields. It is noteworthy that aliphatic acids were reactive in the
esterification (Table 3, entries 11-12). Cyclohexane carboxylic
acid as a cyclic substrate or aromatic substituted aliphatic acids
also gave greater than 93% conversion yields in the reaction
(Table 3, entries 13-15). The scope of this synthetic method was
extended to unsaturated carboxylic acids containing sensitive and
reactive π-bonds. Surprisingly, alkenyl and alkynyl substituted
carboxylic acids converted to tert-butyl esters in high yields
without any side reactions observed at the double or triple bond
(84% yield for compound 5q and 92% yield for compound 5r).

3
Table 1. Screening of Lewis acids and bases for the tert-butyl
To demonstrate the efficiency of this method, we performed
ACCEPTED MANUSCRIPT
esterification reactiona
esterification reactions on carboxylic acids with bulky substituent
groups for which steric effects usually obstruct the reaction. 3,5-
dimethylbenzoic acid and 2,4,6-trimethylbenzoic acid, despite
their bulky aromatic substrates, were converted to the desired
products 5u and 5v in 81% and 82% yields, respectively (Table 3,
entries 21-22). Moreover, diphenylacetic acid with its two bulky
benzene groups, adamantine carboxylic acid, and 3-hydroxy-2,2-
dimethylpropanoic acid were all utilized to form their
corresponding esters in high yield under the same conditions
(Table 3, entries 19, 20 and 23). These results indicated the
importance of BF3ꢀOEt2 as a useful reagent for the synthesis of
tert-butyl esters from bulky carboxylic acids during this mild
reaction process with 2-tert-butoxypyridine.
Base
or
Lewis acid
O
O
OH
+
O
O
N
Toluene, rt
2
4
3
Entry
Base or Lewis acid
Time
(min)
30
Temp.
Yieldb
(%)
NRc
NRc
NRc
NRc
NRc
NRc
4
1
2
3
4
5
6
7
8
9
K2CO3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
Trimethylamine
NaHCO3
DBU
30
30
Moreover, 2-furoic acid, a heterocyclic acid containing an
oxygen, was investigated in our protocol to further expand the
scope of the reaction utilizing BF3·OEt2. It has been previously
noted that the furan compound is not stable under acidic
conditions and easily decomposes. In our investigation,
remarkably, the treatment of 2-furoic acid with 2-tert-
30
TiCl4
30
AlCl3
30
SnCl4
30
butoxypyridine readily achieved
a
94% yield of the
BF3·OEt2
None
30
94
NRc
corresponding tert-butyl ester 5x in 30 min without any observed
by-products (Table 3, entry 24), demonstrating that BF3·OEt2 is
suitable for the synthesis of tert-butyl esters from different types
of carboxylic acids under mild conditions.
30
aReaction conditions: 1.35 mmol of compound 2, 1.0 mmol of
carboxylic acid, 1.35 mmol of base or Lewis acid, toluene (2 mL),
room temperature, 30 min
Amino acids such as tyrosine and Boc-protected tyrosine were
also utilized for tert-butyl esterification. The reaction of Boc-
protected tyrosine produced its corresponding tert-butyl ester
under the same conditions (Table 3, entry 25), while reaction of
tyrosine with unprotected NH2 produced tert-butyl protected
amine compound as a main product. The results suggest that the
new reaction method is more efficient at synthesis of tert-butyl
ester from carboxylic acid than the class of reactions acting
through the hydroxyl group. In this particular case, however,
amine reacted with 2-tert-butoxypyridine more rapidly than
carboxylic acid.
bProduct yield after purification by flash column
chromatography.
cNo reaction.
Table 2. Screening of solvents in the esterification reaction of
benzoic acid and compound 2a
O
O
BF3 OEt2
OH
+
O
O
N
Solvent, rt, 30min
2
4
5
To further assess the utility of this synthetic procedure, 18β-
glycyrrhetinic acid, a more complex bioactive compound, was
used for the synthesis of tert-butyl ester. The desired tert-butyl
ester was successfully obtained under the described reaction
conditions while using an increased volume of toluene (Scheme
3).
Entry
Lewis acids
(equiv)
Solvent
Temp Yieldb
(%)
.
1
BF3·OEt2 (1.35)
BF3·OEt2 (1.35)
BF3·OEt2 (1.35)
BF3·OEt2 (1.35)
BF3·OEt2 (1.35)
BF3·OEt2 (1.35)
BF3·OEt2 (2.0)
BF3·OEt2 (1.0)
BF3·OEt2 (0.5)
BF3·OEt2 (0.1)
None
THF
r.t.
r.t
4
2
MeCN
47
NRc
25
20
94
94
67
21
3
O
O
H3C
H3C
OH
O
3
1,4-dioxane
DCE
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
2
H
H
O
N
O
O
BF3 OEt2
CH3 CH3
CH3
CH3 CH3
CH3
4
Toluene, rt, 30min
82%
H
H
CH3
H
H
CH3
5
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
HO
HO
7
6
6
7
Scheme 3. Protection of a bioactive compound with tert-butyl
8
ester
9d
10d
11
It has been reported that BF3-pyridine complex can be
prepared from the reaction of pyridine with BF3·OEt2,22 and that a
BF3-2-methoxypyridine complex was formed by interaction of
NRc
BF3 and 2-methoxypyridine.23 Thus,
a proposed reaction
mechanism for this tert-butyl esterification based on our results
and previous reports is shown in Scheme 4. The initial addition
of BF3·OEt2 to 2-tert-butoxypyridine 2 generates a BF3-2-tert-
butoxypyridine complex intermediate, which undergoes
nucleophilic attack by the carboxylic acid to yield the tert-butyl
ester product.
aReaction conditions: 1.35 mmol of compound 2, 1.0 mmol of
carboxylic acid, solvent (2 mL), room temperature, 30 min
bProduct yield after purification by flash column
chromatography.
cNo reaction.
dReaction performed for 6 h.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 3. Scope of tert-butyl esterification of carboxylic acid using 2-tert-butoxypyridinea
O
N
2
O
O
BF3 OEt2
Toluene, rt, 30 min
O
R
OH
R
4
5
Entry Carboxylic acid
Product
Yieldb (%)
Entry Carboxylic acid
Product
Yieldb (%)
O
O
O
O
O
O
OH
O
OH
95
14
94
1
2
3
5n
5a
4n
4a
O
O
O
O
OH
O
OH
93
92
15
84
98
5o
4o
5b
4b
O
O
O
O
O
OH
O
OH
16
5p
4p
4c
5c
O
O
O
O
O
O
O
OH
OH
O
4
80
17
84
O
O
5d
5q
4q
4d
O
O
O
O
O
O
OH
OH
5
6
95
94
18
92
85
5e
4e
5r
4r
O
O
O
O
O
OH
O
OH
19c
Cl
Cl
4s
5s
5f
O
4f
O
O
O
Cl
Cl
O
OH
83
HO
O
7
HO
OH
20c
84
81
5g
4g
5t
4t
O
O
O
O
O
Br
Br
O
OH
OH
8
92
93
95
21
5h
O
5u
4h
4u
O
O
O
O
OH
OH
O
22c
9
82
O2N
O2N
5i
O
O
4v
4i
5v
O
O
O
OH
10
OH
O
90
23
O
O
5j
O
4j
4w
5w
O
O
11
91
87
96
O
O
OH
O
O
24
25
O
94
52
OH
4k
5k
O
O
5x
4x
OH
4
O
O
4
12
13
O
O
5l
4l
OH
NHBoc
NHBoc
HO
O
O
O
HO
4y
OH
5y
5m
4m
aReaction conditions: 1.35 mmol of compound 2, 1.00 mmol of carboxylic acid, 1.35 mmol of BF3·OEt2, toluene (2 mL), room
temperature, 30 min
bProduct yield after purification by flash column chromatography.
cReaction conditions: room temperature, 2h

5
by flash column chromatography on silica gel with 0:4 to 1:4
ACCEPTED MANUSCRIPT
F
B
O
F
F
O
R
dichloromethane/hexane as eluent to yield the desired product 5a
F
B
H
O
F
F
R
O
O
as a colorless oil.
+
O
N
+
F
B
F
F
4.3.1. Tert-butyl benzoate (5a)
O
N
O
N
Colorless oil. 1H NMR (400 MHz, CDCl3) 8.02 (m, J = 8.0 Hz,
1.2 Hz, 2H), 7.53 (m, J = 7.2 Hz, 1.6 Hz, 1H), 7.44 (t, J = 7.6 Hz,
2H), 1.63 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 165.8, 132.4,
132.0, 129.4 (2C), 128.1 (2C), 80.9, 28.2 (3C). HRMS (ESI) m/z
(M+H)+ calcd for C11H15O2 = 179.1072; found 179.1075.
Scheme 4. Proposed esterification mechanism using 2-tert-
butoxypyridine with BF3ꢀOEt2.
3. Conclusion
4.3.2. Tert-butyl 4-methylbenzoate (5b)
Colorless oil. 1H NMR (400 MHz, CDCl3) 7.90 (d, J = 7.6 Hz,
2H), 7.23 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H), 1.61 (s, 9H). 13C
NMR (100 MHz, CDCl3) δ 165.9, 142.9, 129.4 (2C), 129.3,
128.8 (2C), 80.6, 28.2 (3C), 21.6. HRMS (ESI) m/z (M+H)+
calcd for C12H17O2 = 193.1229; found 193.1227.
In conclusion, rapid and practical tert-butyl esterification of
diverse carboxylic acids has been successfully achieved via
reaction with 2-tert-butoxypyridine in the presence of BF3ꢀOEt2.
This synthetic method provides a new reaction system for
protection of various carboxylic acids and has been shown to be
effective for the preparation of tert-butyl esters at high yields
under mild reaction conditions. We believe this novel, efficient,
and readily applicable protocol will be useful for a broad range of
carboxylic acid protections in a variety of organic syntheses.
4.3.3. Tert-butyl 2-methylbenzoate (5c)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6
Hz, 1H), 7.38 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7,24 (t, J = 7.6 Hz,
2H), 2.60 (s, 3H), 1.63 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
167.2, 139.2, 131.8, 131.5, 131.3, 130.3, 125.3, 81.0, 28.3 (3C),
21.7; HRMS (ESI) m/z (M+H)+ calcd for C12H17O2 = 193.1229;
found 193.1231.
4. Experimental
4.1. General information
Reagents and solvents were commercially available and used
as received. Column chromatography was performed using silica
gel 60 (0.040-0.063 mm) and eluted with proper mixture
(CH2Cl2/hexane). All of the new compounds were identified by
400 MHz 1H and 100 MHz 13C NMR spectra in deuterated
chloroform (CDCl3) with tetramethylsilane (TMS) as an internal
reference, and high resolution mass spectroscopy. The identity of
the known compounds was established by the comparison of
their 1H and 13C NMR peaks with the authentic values.
4.3.4. Tert-butyl 4-methoxybenzoate (5d)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8
Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 1.60 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 165.6, 162.9, 131.3 (2C), 124.5,
113.4 (2C), 81.4, 55.4, 28.3 (3C); HRMS (ESI) m/z (M+H)+
calcd for C12H17O3 = 209.1178; found 209.1182.
4.3.5. Tert-butyl 3-methoxybenzoate (5e)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 8.0,
1.2 Hz, 1H), 7.55 (dd, J = 2.8, 1.2 Hz, 1H), 7.34 (t, J = 8.0 Hz,
1H), 7.10 (ddd, J = 8.0, 2.8, 0.8 Hz, 1H), 3.87 (s, 3H), 1.62 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 165.6, 159.5, 133.4, 129.2,
121.8, 118.8, 114.0, 81.1, 55.4, 28.2 (3C); HRMS (ESI) m/z
(M+H)+ calcd for C12H17O3 = 209.1178; found 209.1180.
4.2. Procedure for the preparation of 2-tert-butoxypyridine
A mixture of potassium tert-butoxide (9.88 g, 88.07 mmol)
and 2-chloropyridine (5 g, 44.04 mmol) was added to toluene
(100 mL), followed by 18-crown-6 (0.58 g, 2.20 mmol). The
reaction mixture was heated at 110 °C for 15 h. After cooling to
room temperature, the reaction mixture was diluted with ethyl
acetate (200 mL), then washed with water (150 mL), followed by
brine (150 mL). The organic layer was dried over anhydrous
sodium sulfate and carefully concentrated under reduced pressure.
The resulting residue was then purified by flash column
chromatography on silica gel with 0:5 to 1:5 ethyl acetate/hexane
as eluent to yield the desired product 2 as a colorless oil (3.59 g,
54%). 1H NMR (400 MHz, CDCl3) 8.15 (ddd, J =4.8 Hz, 2.0 Hz,
0.4 Hz, 1H), 7.52 (ddd, J = 9.2 Hz, 6.8 Hz, 1.6 Hz, 1H), 6.81
(ddd, J = 6.8 Hz, 5.2 Hz, 1.2 Hz, 1H), 6.67 (dt, J = 8.4 Hz, 0.8 Hz,
1H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 163.9, 146.5,
138.1, 116.2, 113.4, 79.4, 28.7 (3C). HRMS (ESI) m/z (M+H)+
calcd for C9H14NO = 152.1075, found 152.1077.
4.3.6. Tert-butyl 4-chlorobenzoate (5f)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.8
Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 1.61 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 164.8, 138.8, 130.8 (2C), 130.5, 128.4 (2C), 81.4,
28.2 (3C); HRMS (ESI) m/z (M+H)+ calcd for C11H14ClO2 =
213.0682; found 213.0685.
4.3.7. Tert-butyl 3-chlorobenzoate (5g)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 7.97 (t, J = 1.2
Hz, 1H), 7.90 (dt, J = 8.0, 1.2 Hz, 1H), 7.51 (ddd, J = 8.0, 2.0,
1.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 1.61 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 164.4, 134.3, 133.8, 132.4, 129.5 (2C), 127.5,
81.7, 28.1 (3C); HRMS (ESI) m/z (M+H)+ calcd for C11H14ClO2
= 213.0682; found 213.0686.
4.3. General procedure for the preparation of tert-butyl ester
compounds (5a-5v)
4.3.8. Tert-butyl 3-bromobenzoate (5h)
Carboxylic acid (0.2 g, 1.64 mmol), tert-butoxypyridine (0.33
g, 2.21 mmol) and boron trifluoride diethyl etherate (0.31 g, 2.21
mmol) in dry PhCH3 (2 mL) were added to a 20-ml vial. The
reaction mixture was then allowed to stir at room temperature for
30 min before quenching with anhydrous NaHCO3. The reaction
mixture was diluted with ethyl acetate (30 mL), then washed with
water (20 mL), followed by brine (20 mL). The organic layer was
dried over anhydrous sodium sulfate and carefully concentrated
under reduced pressure. The resulting residue was then purified
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 8.13 (t, J = 1.6
Hz, 1H), 7.93 (dt, J = 8.0, 1.2 Hz, 1H), 7.66 (ddd, J = 8.0, 2.0,
1.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 1.61 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 164.3, 135.3, 134.0, 132.4, 129.7, 128.0, 122.3,
81.7, 28.1 (3C); HRMS (ESI) m/z (M+H)+ calcd for C11H14BrO2
= 257.0177; found 257.0179.
4.3.9. Tert-butyl 4-nitrobenzoate (5i)

6
Tetrahedron
White solid; m.p. 116 - 118 °C; 1H NMR (400 MHz, CDCl3)
(3C); HRMS (ESI) m/z (M+H)+ calcd for C13H17O2 = 205.1229;
ACCEPTED MANUSCRIPT
δ 8.27 (d, J = 9.2 Hz, 2H), 8.16 (d, J = 8.8 Hz, 2H), 1.64 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 163.7, 150.3, 137.4, 130.5 (2C),
123.3 (2C), 82.6, 28.1 (3C); HRMS (ESI) m/z (M+H)+ calcd for
C11H14NO4 = 224.0923; found 224.0935.
found 205.1231.
4.3.18. Tert-butyl 3-phenylpropiolate (5r)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 6.8,
1.6 Hz, 2H), 7.42 (tt, J = 7.2, 2.0 Hz, 1H), 7.38 (tt, J = 6.8, 1.6
Hz, 2H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.1,
132.8 (2C), 130.3, 128.5 (2C), 120.0, 83.8, 83.5, 82.0, 28.1 (3C);
HRMS (ESI) m/z (M+H)+ calcd for C13H15O2 = 203.1072; found
20.1075.
4.3.10. Tert-butyl 4-acetylbenzoate (5j)
1
White solid; m.p. 39-41°C; H NMR (400 MHz, CDCl3) δ
8.07 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 7.6 Hz, 2H), 2.65 (s, 3H),
1.62 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 197.6, 164.8, 139.8,
135.8, 129.6 (2C), 128.0 (2C), 81.7, 28.1 (3C), 26.8; HRMS
(ESI) m/z (M+H)+ calcd for C13H17O3 = 221.1178; found
221.1180.
4.3.19. Tert-butyl adamantane-1-carboxylate (5s)
1
White solid; m.p. 42 - 44 °C; H NMR (400 MHz, CDCl3) δ
2.01 (s, 3H), 1.86 (d, J = 6.8 Hz, 6H), 1.75-1.65 (m, 6H), 1.44 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 177.2, 79.3, 41.1, 38.9 (3C),
36.6 (3C), 28.1 (3C), 28.0 (3C). HRMS (ESI) m/z (M+H)+ calcd
for C15H25O2 = 237.1855; found 237.1859.
4.3.11. Tert-butyl heptanoate (5k)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 2.22 (t, J = 7.6
Hz, 2H), 1.59 (t, J = 7.6 Hz, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 6H),
0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.3,
79.8, 35.6, 31.5, 28.7, 28.1 (3C), 25.1, 22.5, 14.0; HRMS (ESI)
m/z (M+H)+ calcd for C11H23O2 = 187.1698; found 187.1697.
4.3.20. Tert-butyl 3-hydroxy-2,2-dimethylpropanoate (5t)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 3.52 (s, 2H), 2.57
(br s, 1H), 1.47 (s, 9H), 1.65 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 177.1, 80.8, 69.7, 44.4, 28.0 (3C), 22.2 (2C); HRMS
(ESI) m/z (M+H)+ calcd for C9H19O3 = 175.1334; found
175.1337.
4.3.12. Tert-butyl undecanoate (5l)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 2.22 (t, J = 7.2
Hz, 2H), 1.59 (t, J = 7.6 Hz, 2H), 1.46 (s, 9H), 1.35-1.23 (m,
14H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.3, 79.8, 35.6, 31.9, 29.6, 29.5, 29.3 (2C), 29.1, 28.1 (3C),
25.1, 22.7, 14.1; HRMS (ESI) m/z (M+H)+ calcd for C15H31O2 =
243.2324; found 243.2328.
4.3.21. Tert-butyl 3,5-dimethylbenzoate (5u)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 2H), 7.17
(s, 1H), 2.38 (s, 6H), 1.62 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
166.1, 137.8, 134.0 (2C), 131.9, 127.1 (2C), 80.7, 28.2 (3C), 21.2
(2C); HRMS (ESI) m/z (M+H)+ calcd for C13H19O2 = 207.1385;
found 207.1387.
4.3.13. Tert-butyl 2-phenylacetate (5m)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m,
5H), 3.56 (s. 2H), 1.64 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
170.9, 134.7, 129.2 (2C), 128.4 (2C), 126.8, 80.8, 42.7, 28.0
(3C); HRMS (ESI) m/z (M+H)+ calcd for C12H17O2 = 193.1229;
found 193.1232.
4.3.22. Tert-butyl 2,4,6-trimethylbenzoate (5v)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 2H), 2.34
(s, 6H), 2.30 (s, 3H), 1.63 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
169.4, 138.6, 134.4 (2C), 132.6, 128.3 (2C), 81.4, 28.3 (3C), 21.1,
4.3.14. Tert-butyl 3-phenylpropanoate (5n)
19.5 (2C); HRMS (ESI) m/z (M+H)+ calcd for C14H21O2
221.1542; found 221.1545.
=
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m,
2H), 7.26-7.20 (m, 3H), 2.94 (t, J = 8.0 Hz, 2 H), 2.57 (t, J = 8.0
Hz, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.3,
140.8, 128.4 (2C), 128.3 (2C), 126.1, 80.3, 37.1, 31.1, 28.1 (3C);
HRMS (ESI) m/z (M+H)+ calcd for C13H19O2 = 207.1385; found
207.1388.
4.3.23. Tert-butyl 2,2-diphenylacetate (5w)
1
White solid; m.p. 81 - 83 °C; H NMR (400 MHz, CDCl3) δ
7.36-7.31 (m, 8H), 7.31-7.25 (m, 2H), 4.95 (s, 1H), 1.48 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 171.7, 139.3 (2C), 128.6 (4C),
128.5 (4C), 127.0 (2C), 81.3, 58.1, 28.0 (3C); HRMS (ESI) m/z
(M+H)+ calcd for C18H21O2 = 269.1542; found 269.1546.
4.3.15. Tert-butyl cyclohexanecarboxylate (5o)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 2.19 (tt, J = 10.8,
3.6 Hz, 1H), 1.90-1.83 (m, 2H), 1.80-1.70 (m, 2H), 1.66-1.60 (m,
1H), 1.45-1.34 (m, 11H), 1.34-1.20 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.6, 79.5, 44.1, 29.1 (2C), 28.1 (3C), 25.8, 25.5 (2C);
HRMS (ESI) m/z (M+H)+ calcd for C11H21O2 = 185.1542; found
185.1545.
4.3.24. Tert-butyl furan-2-carboxylate (5x)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 1.6,
0.8 Hz, 1H), 7.09 (dd, J = 3.2, 0.8 Hz, 1H), 6.48 (dd, J = 4.0, 2.0
Hz, 1H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.1,
146.0, 145.7, 116.9, 111.5, 81.9, 28.2 (3C); HRMS (ESI) m/z
(M+H)+ calcd for C9H13O3 = 169.0865, found 169.0869.
4.3.16. Tert-butyl 2-ethylhexanoate (5p)
4.3.25. (R)-tert-butyl
hydroxyphenyl)propanoate (5y)
2-(tert-butoxycarbonylamino)
-3-(4-
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 2.17-2.10 (m,
1H), 1.63-1.50 (m, 2H), 1.50-1.40 (m, 11H), 1.35-1.25 (m, 4H),
0.90 (td, J = 7.6, 2.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
175.8, 79.7, 48.2, 31.9, 29.6, 28.1 (3C), 25.7, 22.6, 13.9, 11.8;
HRMS (ESI) m/z (M+H)+ calcd for C12H25O2 = 201.1855; found
201.1857.
Colorless solid; m.p. 100-102 °C; 1H NMR (400 MHz,
CDCl3) δ 7.02 (d, J = 8.0 Hz, 2H, 2-CH= tyrosine), 6.75 (d, J =
8.0 Hz, 2H, 2-CH= tyrosine), 6.22 (br s, OH phenol), 5.05 (d, J =
8.4 Hz, 1H, NH), 4.42 (d, J = 7.2 Hz, 1H, -CH-NH), 3.05-2.95
(m, 2H, -CH2-), 1.44 (s, 9H, -C(CH3)3 Boc), 1.43 (s, 9H, -
C(CH3)3 ester); 13C NMR (100 MHz, CDCl3) δ 171.1, 155.3,
155.0, 130.6 (2C), 127.8, 115.3 (2C), 82.2, 80.0, 55.1, 37.7, 28.3
(3C), 28.0 (3C); HRMS (ESI) m/z (M+H)+ calcd for C18H28NO5
= 338.1967; found 338.1970.
4.3.17. Tert-butyl cinnamate (5q)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 16.0
Hz, 1H), 7.55-7.50 (m, 2H), 7.42-7.37 (m, 3H), 6.40 (d, J =16.0
Hz, 1H), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.3,
143.5, 134.7, 129.9, 128.8 (2C), 127.9 (2C), 120.2, 80.5, 28.2
4.3.26. Tert-butyl 18β-glycyrrhetinate (7)

7
White solid. m.p. 229 - 231 °C; 1H NMR (400 MHz, CDCl3) δ
15. Ohta S, Shimabayashi A, Aona M, Okamoto M. Synthesis
ACCEPTED MANUSCRIPT
5.65 (s, 1H), 3.25 (dd, J = 10.8, 5.6 Hz, 1H), 2.80 (dt, J = 13.2,
3.2 Hz, 1H), 2.36 (s, 1H), 2.19-2.11 (m, 1H), 2.09-1.99 (m, 1H),
1.98-1.91 (m, 1H), 1.90-1.79 (m, 2H), 1.72-1.57 (m, 4H), 1.53-
1.43 (m, 11H), 1.43-1.34 (m, 6H), 1.33-1.24 (m, 2H), 1.24-1.08
1982: 833-834.
16. Takimoto S, Inanaga J, Katsuki T, Yamaguchi M. Bull.
Chem. Soc. Jpn. 1976; 49: 2335-2336.
(m, 10H), 1.07-0.94 (m, 5H), 0.82 (s, 6H), 0.75-0.68 (m, 1H); 13
C
17. Kishii N, Negishi S, Yamada T, Sugimura H. Tetrahedron
Lett. 2015; 56: 2813-2816.
NMR (100 MHz, CDCl3) δ 200.23, 175.7, 169.6, 128.4, 80.1,
78.8, 61.8, 54.9, 48.5, 45.4, 44.3, 43.2, 41.3, 39.1 (2C), 37.8, 37.1,
32.8, 31.8, 31.2, 28.8, 28.3, 28.1 (4C), 27.3, 26.5, 26.4, 23.4, 18.7,
17.5, 16.4, 15.6; HRMS (ESI) m/z (M+H)+ calcd for C34H55O4 =
527.4100; found 527.4102.
18. Zhou Y, Tang Z, Song Q. Adv.Synth. Catal. 2017; 359:
952-958.
19. Tummatorn J, Albiniak PA, Dudley GB. J. Org. Chem.
2007; 72: 8962-8964.
Conflicts of interest
20. Strayer TA, Culy CC, Bunner MH, Frank AR, Albiniak
There are no conflicts to declare..
Acknowledgements
PA. Tetrahedron Lett. 2015; 56: 6807-6809.
21. Salvati AE, Hubley CT, Albiniak PA. Tetrahedron Lett.
2014; 55: 7133-7135.
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
22. Chenard E, Sutrisno A, Zhu L, Assary RS, Kowalski JA,
Barton JL, Bertke JA, Gray DL, Brushett FR, Curtiss LA,
Moore JS. J. Phys. Chem. C. 2016; 120: 8461-8471.
(NRF)
funded
by
the
Ministry
of
Education
(2014R1A1A2057943). Minh Thanh La was supported by the
BK21 Plus program in the Chonbuk National University Medical
School.
23. Singh A, Dhau JS, Sharma N, Singh A. Inorganica Chim.
Acta. 2015; 432: 109-114.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/
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