Esterification with aromatic acyl-1,2,4-triazole Catalyzed by weak base at the rate comparable to acyl chloride

Article abstract of DOI:10.1246/cl.170975

Benzoyl-1,2,4-triazole underwent esterification with a primary alcohol in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) catalyst at the rate comparable to benzoyl chloride. The kinetic study concluded that the reaction proceeds in a similar mechanism to carboxylic acid anhydride and is thus sensitive to the steric hindrance of alcohol. As the esterification of benzoyl-1,2,4-triazole did not afford acidic by-product and require an equimolar or more amount of base, it is effective for the protection of acid-sensitive alcohol and polyester synthesis.

Full text of DOI:10.1246/cl.170975

Advance Publication Cover Page
Esterification with Aromatic Acyl-1,2,4-triazole Catalyzed by Weak Base at the Rate
Comparable to Acyl Chloride
Yasuhiro Kohsaka,* Kazumasa Homma, Susumu Sugiyama, and Yoshikazu Kimura
Advance Publication on the web November 11, 2017
doi:10.1246/cl.170975
©
2017 The Chemical Society of Japan
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Publication manuscripts.

1
Esterification with Aromatic Acyl-1,2,4-triazole Catalyzed by Weak Base at the Rate
Comparable to Acyl Chloride
1
1
2
2
Yasuhiro Kohsaka, * Kazumasa Homma, Susumu Sugiyama, and Yoshikazu Kimura
1
Faculty of Textile Science and Technology, Shinshu University, 3-15-1 Tokida, Ueda, Nagano 386-8567, Japan
Iharanikkei Chemical Industry Co., Ltd., 5700-1, Kambara, Shimizu-ku, Shizuoka, Shizuoka 421-3203, Japan
2
E-mail: kohsaka@shinshu-u.ac.jp
Benzoyl-1,2,4-triazole underwent the esterification with
investigated the kinetics of acyl azoles with various weak
base catalyst in low-polar solvents as the alternative
conditions and found that esterification of benzoyl 1,2,4-
triazole with 4-N,N- (dimethylamino)pyridine (DMAP)
proceeds in high selectivity to primary alcohol and a similar
rate constant comparable to that of benzoyl chloride.
a
primary alcohol in the presence of 4-(N,N-
dimethylamino)pyridine (DMAP) catalyst at the rate
comparable to benzoyl chloride. The kinetic study concluded
that the reaction proceeds in a similar mechanism to
carboxylic acid anhydride and thus sensitive to the steric
hindrance of alcohol. As the esterification of benzoyl-1,2,4-
triazole did not afford acidic byproduct and require an
equimolar or more amount of base, it is effective for
protection of acid-sensitive alcohol and polyester synthesis.
Benzoyl-1,2,4-triazole (1b) was prepared from the
1
3
respective chloride (1a). The esterification of 1b was
conducted with alcohol (50 equiv.) in CH Cl in the presence
of base catalyst (10 mol%) and monitored by gas
2
2
1
4
chromatography (Scheme 1). Similar experiments were
Acylazoles are known as acylating reagents alternative
15
also conducted with 1a and its imidazole derivative (1c).
1
-3
of acyl chlorides. For example, acylimidazole prepared
from carboxylic acid and carbonyl diimidazole is often used
O
R OH
(
50 equiv.)
O
4
,5
in peptide synthesis. 1,2,4-Triazole that has higher acidity
than imidazole is a more excellent leaving group, and thus
the acyl derivatives can undergo esterification with primary
alcohols in polar solvents with a strong base catalyst that
R N
mol%)
X
3
(10
OR
CH Cl2
2
=
=
1
a: X
Cl
N
2
1
,6
generate alkoxide. In addition, the esterification can be
achieved without catalyst if much excess amount of alcohol
1b
:
X
N
N
3
is used. Recently, we have prepared bifunctional acyl-1,2,4-
N
triazoles that functioned as alternative monomers of
7
,8
dicarbonyl chlorides for polyester synthesis.
=
1
c: X
N
Base-catalyzed esterification with carboxylic acid
anhydrides are important tools for the protection of hydroxy
9
group and kinetic resolution of alcohols and carboxylic
Scheme 1. Esterification of benzoyl chloride and its derivatives
1
0
acids. In particular, benzoates are often used as protecting
groups, as the selective deprotection could be achieved in
moderate conditions.9 Compared with carboxylic acid
anhydrides, the esterification with acyl-1,2,4-triazoles and
acylimidazoles does not require an excess amount of
auxiliary base that regenerate the base catalyst in situ. In
addition, such acyl azoles can be prepared from the acyl
chloride in a facile procedure and stored in bulk. The
liberated azoles are nontoxic and can be removed from the
product by washing with water. In spite of such attractive
features, however, the kinetics of the esterification with
benzoyl azole in the presence of weak base have not been
reported. The knowledge is important to selective protection
of primary alcohols, kinetic resolution, and polycondensation
catalyzed by base.
1
R OH
O
R N
3
O
X
R OH
NR3
2
NR3
– R N
3
X
–
HX
3
4
Scheme 2. Reaction mechanism of the esterification.
The pathway of the esterification of carboxylic acid
anhydride has been proposed by the quantum calculation
with polarizable continuum model-united atom for Hartree-
Fock (PCM-UAHF). Similar mechanism can be applied for
the case of acylazole 1 (Scheme 2). Since the alcohol
associate with the intermediate, quaternary amide 4, the
reaction rate should be discussed according to the following
7
,8
with aromatic bifunctional acylazoles. It should be noted
that the esterification with benzoyl 1,2,4-triazole in polar
solvents in the presence of strong base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) proceeds almost
1
6
1
0,11
quantitatively.
However, the conditions are not suitable
for the polycondensation of aromatic bifunctional acylazoles
because of the poor solubility of the resulting polymer in
polar solvents and the transesterification between the ester
backbone and hydroxy groups at the chain end that catalyzed
1
6,17
equation
;
(
1)
8
by strong base. In this report, therefore, we have

2
The first and second members are for the uncatalyzed and the
catalyzed pathway, respectively. k and k are rate constant.
carboxylic acid anhydride, because it provides a stable
quaternary amide as an intermediate. Similarly, DMAP was
found effective against 1b and 1c (Entries 11 and 12). It is
1
2
Since much excess amount of alcohol was used, [alcohol]
can be treated as a constant. In the case of 1a, the base
catalyst became hydrochloric salt and did not regenerated,
and thus the second member should be ignored in the late
stage of esterification ([base] = 0). For others, base is catalyst
and thus [base] is constant. Consequently, equation (1) can
be rewrite as follows;
−5
−1
notable that the k
’ of 1a (50.8 × 10 s ). 4-Pyrrolidinopyridine (PPY) is
known as a more effective catalyst than DMAP for
2
’ of 1b (56.1 × 10 s ) is comparable to
−5
−1
k
1
1
8
2
acylation. Remarkably, the k ’ of 1b catalyzed by PPY (134
−5
−1
−5 −1
× 10 s ) was almost twice of that of 1a (61.5 × 10 s ).
That is, 1b is more reactive acylating agent than 1a in the
presence of suitable catalyst.
Table 1. Pseudo-first-order kinetic constant in the esterification of
Although the reactivity order among the three
benzoyl chloride and its derivatives with various alcohols.
1
compounds, i.e. 1a > 1b > 1c, are reported, the detailed
b
b
mechanism has not been discussed. If the elimination of
azole from the intermediate 3 is the rate-determining step,
k
1
’
2
k ’
a
Entry
Alcohol
Base
1
−5 −1
−5 −1
[
10 s ]
[10 s ]
a
the pK of the liberated azole should be suitable to explain
the reactivity of 1b and 1c. However, they exhibit higher
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
iPrOH
iPrOH
tBuOH
tBuOH
-
-
-
1a
1b
1c
1a
1b
1c
1a
1b
1c
1a
1b
1c
1a
1b
1c
1b
1c
1b
1c
63.2
-
No reaction
No reaction
63.1
reactivity than phenyl ester that undergoes esterification in
pyridine
pyridine
pyridine
-
19
equilibrium even in the presence of catalyst. The pK
a
of
-
2.18
phenol is 9.95, while those of 1,2,4-triazole and imidazole
are 10.3 and 14.5. Therefore, pK of azole is not suitable to
No reaction
52.8
-
-
50.8
-
a
Et
Et
Et
3
3
3
N
N
N
-
explain the reactivity. Staab has reported that the reaction
rate of the aminolysis of acylazole obey the two-molecules
4.43
1.71
-
56.1
5.68
1
1
0
1
2
3
4
5
6
7
8
9
DMAP
DMAP
DMAP
PPY
PPY
PPY
DMAP
DMAP
DMAP
DMAP
(addition-elimination) model. Moreover, the recent reports
1
1
1
1
1
1
1
1
1
16
on the esterification of carboxylic acid theoretically and
16,17
experimentally
supported the two-molecules model.
61.5
-
Therefore, the reaction rate orders of 1 should be discussed
on the basis of two-molecules model. In order to support this
presumption, the structures of 1 were optimized by DFT
calculation under B3LYP/6-31G*. In the optimized
conformation (Figure 1), the dihedral angle of the carbonyl
group of 1b and the phenyl group is 18°, whereas that in 1c
is 36°. That is, 1c has more twisted structure due to the steric
repulsion of 2-CH of the imidazole ring and 2’-CH of the
benzene ring. The twisted structure of 1c was also implied by
-
-
-
134
5.34
2.05
No reaction
No reaction
No reaction
a) [Acylating agent]
0
= 1.0 M, [alcohol]
0 0 0
/[acylating agent] /[base]
=
50/1/0.10, CH
2
Cl , 25 °C. b) Determined by GC.
2
(
2)
1
H NMR spectrum (Figure 2). The 2’-CH signal of the
In order to estimate k
1
’, the rate constant for
phenyl group of 1b (signal a, 8.24-8.21 ppm) was observed
in much lower magnet field than that of 1c (7.80 ppm). Since
uncatalyzed pathway, esterification of 1 with ethanol were
conducted in the absence of base (Table 1, Entries 1-3). k
for 1a was determined from the pseudo-first-order kinetic
plots as 63.2 × 10 s , while 1b and 1c did not afford the
ester. This is contractive to the esterification in polar solvents,
where 1b yielded esters even in the absence of catalyst. In
the presence of pyridine, 1a and 1b afforded the ester
Entries 4 and 5). In the case of 1a, the pseudo-first-order
kinetic plot should give k ’ as mentioned before, and the
1
’
1
b has planner structure, the resonance of the carbonyl group
and benzene ring would strongly affect the chemical shift of
’-CH. As well known, a nucleophile attack to carbonyl
−
5
−1
2
group at an angle ca. 45° against the carbonyl planner. The
twisted structure of 1c, therefore, has much steric hindrance
to the nucleophile, DMAP, and the reaction rate would
become much slower than 1b.
3
(
1
−5
−1
determined value (63.1 × 10 s ) was actually similar to
that of Entry 1. Since 1b did not yield the ester in the
absence of pyridine (Entry 2), k
ignored and the pseudo-first-order kinetic plot for the current
experiment should give k ’. In fact, the plot obeyed liner
relationship and the determined k
which was less than 1/10 of k ’ for 1a. Et
1
’ for 1b is enough low to be
2
−5
−1
2
’ was 2.18 × 10 s ,
N accelerated the
1
3
reaction more efficiently (Entry 8), and 1c also afforded the
ester although the reaction was slower (Entry 9).
2
Since the values of k ’ were dependent on the acylating
agent, 1b or 1c, and on the basicity of catalyst, the rate-
determining step is the formation of quaternary amide 4 as
expected. 4-(N,N-Dimethyl)aminopyridine (DMAP) is an
effective catalyst for the esterification of active ester and

3
the esterification with 1b may proceed in a similar pathway
to that of carboxylic acid anhydride.
In conclusion, 1b has a similar reactivity to carboxylic
anhydride and afforded the ester with primary alcohol in the
presence of DMAP at the rate comparable to acyl chloride.
Since the reaction proceeds under ambient conditions and the
byproduct, 1,2,4-trizole, is non-toxic and water soluble, the
esterification with acylazole might be a strong tool for the
selective functionalization or protection of primary alcohol.
In fact, we have succeeded the polyester synthesis with
bifunctional acylazoles. The detail will be reported in our
next paper.
Supporting
Information
is
available
on
http://dx.doi.org/10.1246/cl.******.
References and Notes
Figure 1. Optimized structure of (a) 1b and (b) 1c by DFT
1
2
3
4
H. A. Staab, Angew. Chem. Int. Ed. 1956, 1, 351.
S. Ohta, M. Okamoto, J. Synth. Org. Chem., Jpn. 1983, 41, 38.
S. Murata, Bull. Chem. Soc. Jpn. 1984, 57, 3597.
calculation (B3LYP/6-31G*).
A. G. Christian, N. Montalbetti, F. Virginie, Tetrahedron, 2005,
1, 10827.
6
5
6
V. Eric, B. Mark, Chem. Soc. Rev. 2009, 38, 606.
G. Cai, N. Bozhkova, J. Odingo, N. Berova, K. Nakanishi, J. Am.
Chem. Soc. 1993, 115, 7192.
7
8
9
Y. Kimura, Jpn. Kokai Tokkyo Koho 2013-231027A;
JP6088890B, 2017; Chem. Abstr. 2013, 159, 742826.
Y. Kohsaka, K. Homma, S. Sugiyama, Y. Kimura, Chem. Lett.
submitted.
a) T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd ed., Wiley-Interscience, New York, 1999, Chap. 2,
1
73-176.; b) P. G. M. Wuts, Greene’s Protective Groups in
Organic Synthesis, 5th ed., Wiley, Hoboken, New Jersey, 2014,
Chap. 2, 315-322.
1
1
0
1
E. Vedejs, M. Jure, Angew.Chem. Int. Ed. 2005, 44, 3971.
W. Adam, H.-U. Humpf, M. N. Korb, P. Schreier, Tetrahedron
Asymmetry, 1997, 8, 3555.
W. Adam, Z. Lukacs, K. Viebach, H.-U. Humpf, C. R. Saha-
Möller, P. Schreier, J. Org. Chem. 2000, 65, 186.
1
2
1
3
Synthesis of 1b: Benzoyl chloride (1.25 g, 8.89 mmol) was added
dropwise to a solution of 1,2,4-triazole (1.23 g, 17.8 mmol) in
N,N-dimethylformamide (25 mL) and dichloromethane (10 mL).
The reaction mixture was stirred for 3 h, and the resulting
precipitate was removed by filtration. The filtrate was washed
with cold water (≤ 5 °C, 10 mL × 3) and concentrated under
reduced pressure. The residue was purified by bulb-to-bulb
distillation (heater temperature: 160 °C, 80 mmHg) to yield 1b
1
Figure 2. H NMR spectra of (bottom) 1b and (top) 1c (400 MHz,
3 3
CDCl , 26 °C). *: Signal of CHCl .
Esterification with sterically hindered alcohol, i.e.
iPrOH and tBuOH were also investigated. 1b reacted with
iPrOH in the presence of DMAP (Entry 16). Since the k
1
(
1.20 g, 78% yield) as colorless liquid. H NMR (400 MHz,
CDCl , 26 °C) δ/ppm 9.10 (s, 1H, f), 8.24-8.21 (m, 2H, a), 8.13(s,
H, e), 7.69 (tt, J = 7.5 Hz, J = 1.3 Hz, 1H, c), 7.57-7.53 (m, 2H,
b). See Figure 2(a).
3
1
1
2
2
’
against iPrOH was ca. 30times smaller than that against
EtOH. 1b did not react with tBuOH (Entry 18).
Consequently, 1b can esterify the primary alcohol in high
selectivity. 1c did not yield the esters under the same
condition (Entry 17 and 19). These results indicated that the
rate-determining step in the esterification is not a simple
1
1
4
5
See Supporting Information for the experimental detail.
Synthesis of 1c: Benzoyl chloride (4.99 g, 35.5 mmol) was added
dropwise to a solution of imidazole (4.83 g, 7.1. mmol) in
dichloromethane (25 mL). The reaction mixture was stirred for 3
h, and the resulting precipitate was removed by filtration. The
filtrate was washed with cold water (≤ 5 °C, 10 mL × 3) and
concentrated under reduced pressure. The residue was purified by
bulb-to-bulb distillation (heater temperature: 160 °C, 80 mmHg)
2
reaction between 1 and DMAP, otherwise k ’ should be
agreed with that with EtOH. Zipse et al. have reported
similar phenomena on the esterification of carboxylic acid
anhydride, where the hydrogen bond of alcohol molecules to
1
to yield 1c (4.33 g, 71% yield) as colorless liquid. H NMR (400
MHz, CDCl
m, 2H, a), 7.69 (tt, J
3H, b and d), 7.16 (dd, J
(b).
3
, 26 °C) δ/ppm 8.07 (t, J = 1.0 Hz, 1H, f), 7.81-7.79
= 7.4 Hz, J = 1.8 Hz, 1H, c), 7.58-7.54 (m,
= 1.8 Hz, J = 1.0 Hz, 1H, e). See Figure
(
1
2
1
6
1
2
DMAP has an important role to determine the reaction rate
and thus the reaction rate is sensitive to the steric hindrances
2
1
1
6
7
S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich, H. Zipse, Chem.
Eur. J. 2005, 11, 4751.
C. B. Fisher, S. Xu, H. Zipse, Chem. Eur. J. 2006, 12, 5779.
1
7
of both alcohol and carboxylic acid anhydride. Therefore,

4
1
8
G. Höfle, W. Steglich, H. Vorbrüggen, Angew. Chem. Int. Ed.
1
978, 17, 569.
1
9
L. B. Jackson , A. J. Waring, J. Chem. Soc., Perkin Trans. 2:
Phys. Org. Chem. 1990, 1893.