O-Benzylation of Carboxylic Acids Using 2,4,6-Tris(benzyloxy)-1,3,5-triazine (TriBOT) under Acidic or Thermal Conditions

Article abstract of DOI:10.1002/ejoc.201501172

Two methods for the synthesis of benzyl esters from carboxylic acids using the O-benzylating reagent 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) have been developed. The reactions were conducted either in the presence of a catalytic amount of TfOH at room temperature (acidic conditions) or in the absence of TfOH at 180-230 C (thermal conditions). Interestingly, the O-benzylation of hydroxy carboxylic acids under the two conditions afforded different products: The dibenzylated product under acidic conditions and the hydroxy ester under thermal conditions. In addition to these results, other evidence indicated that the former reaction proceeds through an S_N1-type mechanism, and the latter by an S_N2-type mechanism. Two methods for the O-benzylation of carboxylic acids using TriBOT have been developed under either acidic or thermal conditions. The O-benzylation of hydroxy carboxylic acids afforded the dibenzylated product under acidic conditions and the hydroxy ester under thermal conditions. The former reaction proceeds through an S_N1-type mechanism and the latter by an S_N2-type mechanism.

Full text of DOI:10.1002/ejoc.201501172

FULL PAPER
DOI: 10.1002/ejoc.201501172
O-Benzylation of Carboxylic Acids Using 2,4,6-Tris(benzyloxy)-1,3,5-triazine
(TriBOT) under Acidic or Thermal Conditions
Kohei Yamada,[a] Saki Yoshida,[a] Hikaru Fujita,[a] Masanori Kitamura,[a] and
Munetaka Kunishima*[a]
Keywords: Synthetic methods / Alkylation / Carboxylic acids / Carbocations
Two methods for the synthesis of benzyl esters from carb-
oxylic acids using the O-benzylating reagent 2,4,6-tris-
(benzyloxy)-1,3,5-triazine (TriBOT) have been developed.
The reactions were conducted either in the presence of a
catalytic amount of TfOH at room temperature (acidic condi-
tions) or in the absence of TfOH at 180–230 °C (thermal con-
ditions). Interestingly, the O-benzylation of hydroxy carb-
oxylic acids under the two conditions afforded different prod-
ucts: The dibenzylated product under acidic conditions and
the hydroxy ester under thermal conditions. In addition to
these results, other evidence indicated that the former reac-
tion proceeds through an SN1-type mechanism, and the latter
by an SN2-type mechanism.
thesis of benzyl ethers using 2,4,6-tris(benzyloxy)-1,3,5-tri-
azine (TriBOT),[3] which has several advantages such as ex-
cellent stability, low cost, and high atom economy. We have
now adapted and modified our published protocol to allow
the synthesis of benzyl esters under either acidic or thermal
conditions (Figure 1). Moreover, we compared the reaction
mechanisms of the two strategies.
Introduction
The benzyl group is widely used for the protection of
carboxy groups because it is easily removed by metal-cata-
lyzed hydrogenolysis.[1] In general, benzyl esters can be pre-
pared from carboxylic acids by 1) SN2 reactions using a
benzyl halide and a base, 2) Fischer esterification in the
presence of an acid catalyst using an excess of benzyl
alcohol or azeotropic distillation at high temperature, or
3) esterification using a dehydrocondensation agent.[1] Acid-
catalyzed O-benzylation using benzyl 2,2,2-trichloroacet-
imidate (BTCAI) is also utilized because the reaction can
be conducted under mild acidic conditions at room tem-
perature.[2] We previously reported the acid-catalyzed syn-
Results and Discussion
When we attempted to conduct the O-benzylation of cy-
clohexanecarboxylic acid (1a) using TriBOT according to
the optimized procedure for the O-benzylation of alcohols
(Table 1, entry 1), the desired benzyl ester 2a was obtained
in only 32% yield along with N-benzylisocyanuric acid (3)
and N,NЈ-dibenzylisocyanuric acid (4) as byproducts (13
and 48% yields based on TriBOT, respectively). It appears
that these byproducts are formed by the competitive N-
benzylation of TriBOT and/or DiBOT and MonoBOT, gen-
erated by the acid-catalyzed debenzylation of TriBOT.[4]
The side-reactions occurred preferentially over the O-benz-
ylation of carboxylic acid 1a owing to the lower nucleophi-
licity of carboxylic acids relative to alcohols.[5] Thus, to sup-
press the production of 3 and 4, TriBOT and its intermedi-
ates should be kept in low concentrations during the reac-
tion. A solution of TriBOT in 1,4-dioxane was added drop-
wise to a solution of 1a in the presence of TfOH over 4 h
and the reaction was quenched after 1.5 h. As a result, the
yield of 2a improved dramatically to 89% (entry 2). More-
over, the use of 0.5 equiv. of TriBOT increased the yield to
95% (entry 3). 1,2-Dimethoxyethane (DME) could also be
used as a solvent, although a slightly lower yield was ob-
tained (entry 4).
Figure 1. O-Benzylation of alcohols and carboxylic acids using
TriBOT.
[a] Faculty of Pharmaceutical Sciences, Institute of Medical,
Pharmaceutical and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
E-mail: kunisima@p.kanazawa-u.ac.jp
http://www.p.kanazawa-u.ac.jp/e/lab/seibutsu.html
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
10.1002/ejoc.201501172.
Eur. J. Org. Chem. 2015, 7997–8002
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K. Yamada, S. Yoshida, H. Fujita, M. Kitamura, M. Kunishima
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Table 1. O-Benzylation of cyclohexanecarboxylic acid.
Table 2. O-Benzylation of various carboxylic acids under acidic
conditions.
Entry
Solvent
TriBOT Addition method
[equiv.]
Additional Yield[a]
reaction time
[h]
[%]
1
2
3
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
DME
0.4
0.4
0.5
0.5
one portion
5
1.5
1
32
89
95
71
dropwise over 4 h
dropwise over 4 h
dropwise over 4 h
1
[a] Isolated yield.
The O-benzylation of several carboxylic acids using
TriBOT and a catalytic amount of TfOH was investigated
(Table 2). The reactions of 3-phenylpropionic acid (1b) and
adamantane-1-carboxylic acid (1c) provided benzyl esters
2b and 2c in good-to-excellent yields (entries 1 and 2). Aro-
matic carboxylic acid 1d and α,β-unsaturated carboxylic
acid 1e were converted into the corresponding benzyl esters
2d and 2e in good yields (entries 3 and 4). Carboxylic acids
1f and 1g, which possess a base-labile bromoalkyl or carb-
onyl group, also afforded the products 2f and 2g, respec-
tively, in excellent yields (entries 5 and 6). The reaction with
N-(benzyloxycarbonyl)alanine (1h) was accomplished with-
out loss of enantiomeric purity (entry 7). The O-benz-
ylation of highly polar malonic acid (1i) using 0.85 equiv.
of TriBOT provided the corresponding dibenzyl ester 2i in
85% yield (entry 8). The selective O-benzylation of amino
acid 1j was achieved by using 1.2 equiv. of TfOH to sup-
press the N-benzylation of the amino group by temporarily
converting it into an ammonio group (entry 9).
It has been reported that the O-methylation of carboxylic
acids using 2,4,6-trimethoxy-1,3,5-triazine (6), a methyl an-
alogue of TriBOT, proceeded upon heating the mixture at
210 °C.[6] Thus, we next examined the O-benzylation under
thermal conditions without the addition of an acid catalyst
(Table 3). When the reaction of 1b with 1.0 equiv. of
TriBOT was conducted in 1,2-dichlorobenzene at a concen-
tration of 2.0 m at 160 °C for 6.5 h, the desired benzyl ester
2b was obtained in 70% yield (entry 1). However, the reac-
tion at a concentration of 0.2 m did not proceed at all (en-
try 2). Reactions at a higher temperature (180 °C) and with
1.5 equiv. of TriBOT improved the yield (entries 3 and 4).
Heating at 230 °C under microwave irradiation was found
to accelerate the reaction (entry 5). The reaction in diglyme
as a polar, high-boiling solvent resulted in a decrease in the
yield (trace to 78%, entries 6–8). Because the melting point
of TriBOT is 106 °C, we attempted the reaction without sol-
[a] The benzyl groups introduced in the reaction are indicated in
bold and italic face. [b] Isolated yield. [c] TriBOT solution was
added dropwise over 8 h. [d] TfOH (1.2 equiv.) was used. [e] Iso-
lated as the Boc-protected product 5.
increase in the yield (82%), probably due to the competitive
decomposition of TriBOT (entry 10).[7]
With these results in hand, we examined the O-benz-
vent; the ester was produced in 84% yield at 160 °C (en- ylation of several carboxylic acids using TriBOT under high
try 9). However, the reaction at 180 °C did not lead to an temperatures (Table 4). The O-benzylation of 1c proceeded
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O-Benzylation of Carboxylic Acids
Table 3. O-Benzylation of 3-phenylpropionic acid under thermal the carboxy group of salicylic acid (1l) was achieved to give
conditions.
benzyl salicylate (2l) in an excellent yield (entry 5).
To compare the two methods, namely, the reaction under
acidic and thermal conditions, we attempted to conduct the
reaction with aliphatic hydroxy carboxylic acid 1m
(Scheme 1). The reaction under acidic conditions afforded
the dibenzylated product 2m in 62% yield (Scheme 1, A).
However, the O-benzylation under thermal conditions pro-
ceeded chemoselectively at the carboxy group to give 2mЈ,
albeit in a low yield of 28%, along with several unknown
oligomeric compounds, which could be generated by trans-
esterification between 2mЈ and 1m (Scheme 1, B). When a
carboxylic acid possessing a sterically hindered tertiary hy-
droxy group (1n) was used as the starting material to sup-
press the transesterification, the reaction under thermal
conditions gave benzyl ester 2n in a good yield of 84%
(Scheme 1, C).
Entry Solvent
T [°C]
Time TriBOT Yield[a]
[equiv.]
[%]
1
1,2-dichlorobenzene
160
6.5 h
1.0
70
(b.p. 180 °C)
2
3
4
1,2-dichlorobenzene[b]
1,2-dichlorobenzene
1,2-dichlorobenzene
160
180
180
5 h
6.5 h
4 h
1.0
1.0
1.5
0
80
97
(97)[c]
96
5
1,2-dichlorobenzene
230 (MW) 30 min
160 6.5 h
230 (MW) 30 min
230 (MW)
160
1.5
1.5
1.5
1.5
1.5
1.5
6
diglyme (b.p. 162 °C)
trace
67
78
84
82
7
diglyme
8
diglyme
1 h
6.5 h
6.5 h
9
10
–
–
180
[a] NMR yield. [b] Concentration of 1b was 0.2 m. [c] Isolated yield.
to give benzyl ester 2c in excellent yield (entry 1). The yields
of the esters were good, even in the cases of carboxylic acids
bearing base-labile functionalities (entries 2 and 3). Benzoic
acid (1k) was converted into the corresponding benzyl
benzoate 2k in 90% yield (entry 4). As was the case in the
methylation using 6,[6] the chemoselective O-benzylation at
Table 4. O-Benzylation of several carboxylic acids under thermal
conditions.
Scheme 1. O-Benzylation of hydroxy carboxylic acids.
In contrast to the acid-catalyzed O-benzylation, which
would proceed via a benzyl cationic species as the reactive
intermediate (an SN1-type mechanism),[3a] the O-benz-
ylation under thermal conditions is considered to proceed
by a different reaction pathway for the following reasons:
1) Friedel–Crafts reaction at the aromatic ring was not ob-
served, 2) chemoselective O-benzylation at a carboxy group
in the presence of a hydroxy group, which is generally more
nucleophilic than a carboxy group,[5] occurred, 3) O-methyl-
ation of carboxylic acids using 6 proceeded under thermal
conditions[6] even though O-methylation of an alcohol un-
der acidic conditions did not occur,[3a] and 4) it has been
reported that an isourea obtained from optically pure sec-
ondary alcohols and dicyclohexylcarbodiimide (DCC),
which are considered the partial structures of TriBOT, re-
acts with carboxylic acids at high temperatures to give op-
tically pure esters with complete inversion of configura-
tion.[8] These results can be considered to be more consis-
tent with an SN2-type reaction, although kinetic studies
[a] The benzyl groups introduced in the reaction are indicated in
bold and italic face. [b] Isolated yield.
Scheme 2. Plausible reaction mechanism.
Eur. J. Org. Chem. 2015, 7997–8002
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K. Yamada, S. Yoshida, H. Fujita, M. Kitamura, M. Kunishima
FULL PAPER
reaction mixture was filtered through a pad of Celite, diluted with
Et2O (20 mL), and washed with satd. NaHCO3 (50 mL) and brine
(20 mL). The organic layer was dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane/EtOAc) to afford 2 in yields of
62–96%.
have not been conducted. The reaction would involve the
formation of a hydrogen bond between the proton of the
carboxylic acid and a nitrogen atom of TriBOT, which acti-
vates the two species and leads to an SN2-type reaction to
give benzyl esters (Scheme 2).[9]
General Procedure for Benzylation Under Thermal Conditions: A
solution of carboxylic acid 1 (1.0 mmol) and TriBOT (1.5 mmol)
in 1,2-dichlorobenzene (0.5 mL) was stirred at 180 °C (for the reac-
tions performed under microwave irradiation, the reaction mixture
was stirred at 230 °C). After stirring for 4–6.5 h, the reaction mix-
ture was directly purified by column chromatography (hexane/
EtOAc) to afford 2 in yields of 28–97%.
Benzyl Cyclohexanecarboxylate (2a):[10] Following the general pro-
cedure for benzylation under acidic conditions, the title compound
was obtained as a colorless oil (207 mg, 95%). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.29 (m, 5 H), 5.11 (s, 2 H), 2.41–2.30 (m, 1 H),
1.98–1.88 (m, 2 H), 1.82–1.70 (m, 2 H), 1.68–1.59 (m, 1 H), 1.54–
1.39 (m, 2 H), 1.35–1.16 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 176.1, 136.5, 128.7, 128.2, 128.1, 66.0, 43.4, 29.2, 25.9,
25.6 ppm. HRMS (DART): calcd. for C14H19O2 [M + H]+
219.1385; found 219.1410.
Conclusions
We have demonstrated the O-benzylation of carboxylic
acids using TriBOT. Two different methods have been devel-
oped, namely under acidic and thermal conditions. It is
worth noting that the O-benzylation of functionalized carb-
oxylic acids can be achieved in good yields under both con-
ditions, even though a strong acid or high-temperature
heating is employed. Moreover, the O-benzylation of hy-
droxy carboxylic acids under thermal conditions proceeded
chemoselectively to give hydroxy esters, whereas the reac-
tion under acidic conditions afforded the dibenzylated
product. These results and further evidence indicate that
the O-benzylation reaction under the different conditions
occurs by different reaction mechanisms: An SN1-type
mechanism under acidic conditions and an SN2-type
mechanism under thermal conditions. Chemists can choose
either method depending on the substrates.
Benzyl 3-Phenylpropionate (2b):[11] Following the general procedure
for benzylation under acidic conditions, the title compound was
1
obtained as a pale-yellow oil (190 mg, 79%). H NMR (400 MHz,
CDCl3): δ = 7.40–7.17 (m, 10 H), 5.12 (s, 2 H), 2.98 (t, J = 7.8 Hz,
2 H), 2.70 (t, J = 7.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.9, 140.5, 136.0, 128.68, 128.65, 128.45, 126.4, 66.4, 36.0,
31.1 ppm. HRMS (DART): calcd. for C16H17O2 [M + H]+
241.1229; found 241.1205.
Experimental Section
General Methods: 1H (400 or 600 MHz) and 13C NMR (100 or
125 MHz) spectra were recorded with a JEOL JNM-ECS400 and
JNM-ECS600 spectrometers. Chemical shifts are reported as δ val-
ues [ppm] relative to tetramethylsilane as the internal standard for
1H NMR and relative to the center line of the triplet of CDCl3 (δ
= 77.16 ppm) for 13C NMR; coupling constants are given in Hz.
The following abbreviations are used for spin multiplicity: s = sing-
let, d = doublet, t = triplet, m = multiplet, br. = broad. Mass
spectra were recorded with a Micromass Zq2000 (DART) spec-
trometer. The reactions under microwave irradiation were per-
formed with a Biotage Initiator. Chiral HPLC was performed with
a JASCO LC-2000 series instrument using a Daicel CHIRALPAK
IB-3 column. Analytical TLC was performed on Merck precoated
analytical plates (0.25 mm thick, silica gel 60 F254). Preparative
TLC separations were performed on Merck analytical plates (0.25
Benzyl Adamantane-1-carboxylate (2c):[12] Following the general
procedure for benzylation under acidic conditions, the title com-
1
pound was obtained as a pale-yellow oil (286 mg, 92%). H NMR
(400 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 5.10 (s, 2 H), 2.05–
1.98 (m, 3 H), 1.95–1.89 (m, 6 H), 1.78–1.65 (m, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 177.6, 136.7, 128.6, 128.1, 127.8,
65.9, 40.9, 39.0, 36.6, 28.1 ppm. HRMS (DART): calcd. for
C18H23O2 [M + H]+ 271.1698; found 271.1724.
Benzyl 4-Iodobenzoate (2d):[13] Following the general procedure for
benzylation under acidic conditions, the title compound was ob-
tained as a colorless crystalline solid (175 mg, 86%), m.p. 66.4 °C.
1H NMR (400 MHz, CDCl3): δ = 7.81–7.74 (m, 4 H), 7.46–7.30
(m, 5 H), 5.34 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.1, 137.9, 135.9, 131.3, 129.7, 128.8, 128.5, 128.4, 101.0,
67.1 ppm. HRMS (DART): calcd. for C14H12IO2 [M + H]+
338.9882; found 338.9887.
Benzyl (E)-Cinnamate (2e):[14] Following the general procedure for
benzylation under acidic conditions, the title compound was ob-
tained as a pale-yellow oil (233 mg, 91%). 1H NMR (600 MHz,
CDCl3): δ = 7.73 (d, J = 16.0 Hz, 1 H), 7.53–7.48 (m, 2 H), 7.43–
7.31 (m, 8 H), 6.48 (d, J = 16.0 Hz, 1 H), 5.25 (s, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 166.9, 145.3, 136.2, 134.4, 130.5,
129.0, 128.7, 128.39, 128.37, 128.2, 118.0, 66.5 ppm. HRMS
(DART): calcd. for C16H15O2 [M + H]+ 239.1072; found 239.1097.
Benzyl 6-Bromohexanoate (2f):[15] Following the general procedure
for benzylation under acidic conditions, the title compound was
obtained as a colorless oil (269 mg, 94%). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.30 (m, 5 H), 5.12 (s, 2 H), 3.39 (t, J = 7.0 Hz,
2 H), 2.38 (t, J = 7.7 Hz, 2 H), 1.87 (tt, J = 7.0, 7.0 Hz, 2 H),
1.68 (tt, J = 7.7, 7.7 Hz, 2 H), 1.52–1.42 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.4, 136.1, 128.7, 128.7, 128.4, 66.4, 34.2,
or 0.50 mm thick) precoated with silica gel 60 F254
. Flash
chromatography separations were performed on KANTO CHEMI-
CAL Silica Gel 60 N (spherical, neutral, 40–100 mesh) unless
otherwise noted. Recycling preparative HPLC was performed with
a Japan Analytical Industry LC-928 instrument equipped with Jai-
gel-1H and -2H GPC columns. Reagents were of commercial grade
and were used without any purification unless otherwise noted. De-
hydrated 1,4-dioxane and 1,2-dimethoxyethane (DME) were pur-
chased from commercial sources, and DME was distilled from cal-
cium hydride before use. All reactions sensitive to oxygen or moist-
ure were conducted under N2.
General Procedure for Benzylation Under Acidic Conditions: A solu-
tion of TriBOT (200 mg, 0.5 mmol) in 1,4-dioxane (2 mL, prepared
in a test tube) was added dropwise over 4–8 h to a solution of
carboxylic acid 1 (1.0 mmol) and trifluoromethanesulfonic acid
(17.6 μL, 0.2 mmol) in 1,4-dioxane (3 mL) in the presence of MS
(5 Å, 125 mg) at room temperature. After stirring for 0.5–6.5 h, the
8000
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O-Benzylation of Carboxylic Acids
33.6, 32.5, 27.8, 24.2 ppm. HRMS (DART): calcd. for C13H18BrO2
[M + H]+ 285.0490; found 285.0486.
1.0 mmol) and trifluoromethanesulfonic acid (105 μL, 1.2 mmol) in
1,4-dioxane (3 mL) in the presence of MS (5 Å, 125 mg) at room
temperature. After stirring for 2.5 h, NaHCO3 (210 mg, 2.5 mmol)
in water (2.5 mL) and (Boc)2O (276 μL, 1.2 mmol) was added. Af-
ter stirring for a further 14 h, the reaction mixture was filtered
through a pad of Celite, diluted with EtOAc (20 mL), and washed
with satd. NaHCO3 (50 mL) and brine (20 mL). The organic layer
was dried with MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(hexane/EtOAc, 10:1) and recycling preparative HPLC to afford
Boc-protected product 5 (283 mg) as a pale-yellow oil in 81% yield.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H), 5.11 (s, 2
H), 4.50 (br. s, 1 H), 3.09 (dt, J = 6.6, 6.6 Hz, 2 H), 2.34 (t, J =
6.6 Hz, 2 H), 1.68–1.57 (m, 2 H), 1.49–1.36 (m, 2 H), 1.44 (s, 9 H),
1.36–1.23 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.7,
156.1, 136.2, 128.7, 128.31, 128.29, 79.1, 66.2, 40.7, 34.4, 30.1, 29.1,
29.0, 28.6, 26.7, 25.1 ppm. C20H31NO4 (349.47): calcd. C 68.74, H
8.94, N 4.01; found C 68.64, H 9.01, N 3.95. HRMS (DART):
calcd. for C20H32NO4 [M + H]+ 350.2331; found 350.2304.
Benzyl 3-Benzoylpropionate (2g):[16] A solution of TriBOT (200 mg,
0.5 mmol) in 1,4-dioxane (2 mL, prepared in a test tube) was added
dropwise over 4 h to a solution of carboxylic acid 1g (178 mg,
1.0 mmol) and trifluoromethanesulfonic acid (17.6 μL, 0.2 mmol)
in 1,4-dioxane (3 mL) in the presence of MS (5 Å, 125 mg) at room
temperature. After stirring for 30 min, further TriBOT (20 mg,
0.05 mmol) was added. After stirring for an additional 1 h, the re-
action mixture was filtered through a pad of Celite, diluted with
Et2O (20 mL), and washed with satd. NaHCO3 (50 mL) and brine
(20 mL). The organic layer was dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (EtOAc) and recycling preparative HPLC
1
to afford 2g (257 mg) as a pale-yellow oil in 96% yield. H NMR
(600 MHz, CDCl3): δ = 8.00–7.95 (m, 2 H), 7.59–7.54 (m, 1 H),
7.49–7.44 (m, 2 H), 7.38–7.30 (m, 5 H), 5.15 (s, 2 H), 3.34 (t, J =
6.6 Hz, 2 H), 2.83 (t, J = 6.6 Hz, 2 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 198.2, 172.9, 136.7, 136.0, 133.4, 128.8, 128.7, 128.4,
128.3, 128.2, 66.7, 33.5, 28.4 ppm. HRMS (DART): calcd. for
C17H17O3 [M + H]+ 269.1178; found 269.1204.
Benzyl Benzoate (2k):[10] Following the general procedure for benz-
ylation under thermal conditions, the title compound was obtained
1
as a colorless oil (192 mg, 90%). H NMR (400 MHz, CDCl3): δ
Cbz-L
-alanine Benzyl Ester (2h):[17] A solution of TriBOT (200 mg,
= 8.10–8.05 (m, 2 H), 7.59–7.50 (m, 1 H), 7.48–7.30 (m, 7 H), 5.37
(s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.6, 136.2,
133.2, 130.2, 129.8, 128.7, 128.5, 128.4, 128.3, 66.8 ppm. HRMS
(DART): calcd. for C14H13O2 [M + H]+ 213.0916; found 213.0933.
0.5 mmol) in 1,4-dioxane (2 mL, prepared in a test tube) was added
dropwise over 4 h to a solution of carboxylic acid 1h (223 mg,
1.0 mmol) and trifluoromethanesulfonic acid (17.6 μL, 0.2 mmol)
in 1,4-dioxane (3 mL) in the presence of MS (5 Å, 125 mg) at room
temperature. After stirring for 1.5 h, further TriBOT (20 mg,
0.05 mmol) was added. After stirring for an additional 2 h, the re-
action mixture was filtered through a pad of Celite, diluted with
Et2O (20 mL), and washed with satd. NaHCO3 (50 mL) and brine
(20 mL). The organic layer was dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane/EtOAc, 10:1) to afford 2h
(204 mg) as a colorless oil in 65% yield. 1H NMR (600 MHz,
CDCl3): δ = 7.41–7.20 (m, 10 H), 5.40 (d, J = 6.8 Hz, 1 H), 5.18
(d, J = 12.1 Hz, 1 H), 5.14 (d, J = 12.1 Hz, 1 H), 5.11 (d, J =
12.1 Hz, 1 H), 5.08 (d, J = 12.1 Hz, 1 H), 4.43 (dq, J = 6.8, 6.9 Hz,
1 H), 1.40 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 172.9, 155.7, 136.4, 135.4, 129.0, 128.7, 128.6, 128.5, 128.22,
128.17, 67.2, 67.0, 49.8, 18.7 ppm. HRMS (DART): calcd. for
C18H20NO4 [M + H]+ 314.1392; found 314.1402.
Benzyl 2-Hydroxybenzoate (2l):[18] Following the general procedure
for benzylation under thermal conditions, the title compound was
1
obtained as a pale-yellow oil (213 mg, 93%). H NMR (400 MHz,
CDCl3): δ = 10.76 (s, 1 H), 7.89 (dd, J = 1.2, 8.8 Hz, 1 H), 7.50–
7.25 (m, 6 H), 6.98 (d, J = 8.8 Hz, 1 H), 6.87 (dd, J = 8.8, 8.8 Hz,
1 H), 5.39 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1,
161.9, 136.0, 135.4, 130.1, 128.8, 128.7, 128.4, 119.3, 117.7, 112.5,
67.1 ppm. HRMS (DART): calcd. for C14H13O3 [M + H]+
229.0865; found 229.0871.
Benzyl 3-(Benzyloxy)-2,2-dimethylpropanoate (2m): Following the
general procedure for benzylation under acidic conditions, the title
compound was obtained as a colorless oil (184 mg, 62%). 1H NMR
(600 MHz, CDCl3): δ = 7.33–7.22 (m, 10 H), 5.13 (s, 2 H), 4.49 (s,
2 H), 3.48 (s, 2 H), 1.24 (s, 6 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 176.5, 138.5, 136.5, 128.6, 128.4, 128.1, 127.8, 127.54,
127.47, 73.3, 66.3, 43.9, 22.6 ppm. C19H22O3: C 76.48, H 7.43;
found C 76.84, H 7.75. HRMS (DART): calcd. for C19H23O3 [M
+ H]+ 299.1647; found 299.1672.
Dibenzyl Malonate (2i):[11]
A solution of TriBOT (320 mg,
0.8 mmol) in 1,4-dioxane (2.5 mL, prepared in a test tube) was
added dropwise over 8 h to a solution of carboxylic acid 1i (104 mg,
1.0 mmol) and trifluoromethanesulfonic acid (17.6 μL, 0.2 mmol)
in 1,4-dioxane (2.5 mL) in the presence of MS (5 Å, 125 mg) at
room temperature. After stirring for 2.5 h, further TriBOT (20 mg,
0.05 mmol) was added. After stirring for an additional 1 h, the re-
action mixture was filtered through a pad of Celite, diluted with
Et2O (20 mL), and washed with satd. NaHCO3 (50 mL) and brine
(20 mL). The organic layer was dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane/EtOAc, 9:1) to afford 2i (242 mg)
Benzyl 3-Hydroxy-2,2-dimethylpropanoate (2mЈ):[19] Following the
general procedure for benzylation under thermal conditions, the
title compound was obtained as a pale-yellow oil (58 mg, 28%). 1H
NMR (600 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H), 5.15 (s, 2 H),
3.58 (d, J = 6.2 Hz, 1 H), 2.37 (t, J = 6.2 Hz, 1 H), 1.23 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.5, 136.1, 128.7,
128.4, 127.9, 69.8, 66.5, 44.4, 22.2 ppm. HRMS (DART): calcd. for
C12H17O3 [M + H]+ 209.1178; found 209.1168.
1
as a colorless oil in 85% yield. H NMR (400 MHz, CDCl3): δ =
Benzyl 2-Hydroxy-2-methylpropanoate (2n):[19] A solution of carb-
oxylic acid 1n (52 mg, 0.5 mmol) and TriBOT (300 mg, 0.75 mmol)
in 1,2-dichlorobenzene (0.25 mL) was stirred at 230 °C under mi-
crowave irradiation. After stirring for 30 min, the reaction mixture
was directly purified by column chromatography (hexane/CH2Cl2,
1:3, to hexane/EtOAc, 4:1, to EtOAc only) to afford 2n (82 mg) as
a colorless oil in 84% yield. 1H NMR (400 MHz, CDCl3): δ = 7.42–
7.31 (m, 5 H), 5.21 (s, 2 H), 3.09 (s, 1 H), 1.45 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 177.4, 135.5, 128.8, 128.6, 128.1,
7.35–7.25 (m, 10 H), 5.13 (s, 4 H), 3.42 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.4, 135.3, 128.7, 128.6, 128.5, 67.4,
41.7 ppm. HRMS (DART): calcd. for C17H17O4 [M + H]+
285.1127; found 285.1110.
Benzyl 8-Aminooctanoate (2j), Isolated as Benzyl 8-[(tert-Butoxy-
carbonyl)amino]octanoate (5): A solution of TriBOT (200 mg,
0.5 mmol) in 1,4-dioxane (2 mL, prepared in a test tube) was added
dropwise over 4 h to a solution of carboxylic acid 1j (160 mg,
Eur. J. Org. Chem. 2015, 7997–8002
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8001

K. Yamada, S. Yoshida, H. Fujita, M. Kitamura, M. Kunishima
FULL PAPER
[6] L. Paoloni, M. L. Tosato, Ric. Sci. 1967, 37, 258.
[7] The complete decomposition of TriBOT was observed when
only TriBOT was heated at 180 °C for 4 h.
[8] a) J. Kaulen, Angew. Chem. Int. Ed. Engl. 1987, 26, 773–774;
Angew. Chem. 1987, 99, 800; b) A. Chighine, S. Crosignani,
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72.2, 67.5, 27.3 ppm. HRMS (DART): calcd. for C11H15O3 [M +
H]+ 195.1021; found 195.1048.
Acknowledgments
This work was supported by the Japan Society for the Promotion
of Science (JSPS) KAKENHI (grant number 25460012) and by
Japan Science and Technology Agency (Adaptable and Seamless
Technology Transfer Program through Target-driven R&D,
AS242Z03610M).
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Received: September 9, 2015
Published Online: November 13, 2015
8002
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7997–8002