Cooperation of the Neutral and the Cationic Leaving Group Pathways in Acid-Catalyzed O-Benzylation of TriBOT

Article abstract of DOI:10.1021/acs.joc.8b01505

The reaction profile of acid-catalyzed O-benzylation with 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) was analyzed to study the reaction kinetics. The first-order kinetic constant for the formation of benzyl cation species from N-protonated TriBOT (neutral leaving group pathway) was estimated and compared with that of the model compound for TriBOT. Since rapid consumption of TriBOT in the late stage could not be explained solely by this pathway, cooperation of another reaction mechanism, the cationic leaving group pathway, was proposed to rationalize the rate acceleration.

Full text of DOI:10.1021/acs.joc.8b01505

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Cooperation of the Neutral and the Cationic Leaving Group
Pathways in Acid-Catalyzed O‑Benzylation of TriBOT
Hikaru Fujita, Naoko Hayakawa, and Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
S
* Supporting Information
ABSTRACT: The reaction profile of acid-catalyzed O-benzylation
with 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) was analyzed to
study the reaction kinetics. The first-order kinetic constant for the
formation of benzyl cation species from N-protonated TriBOT
(neutral leaving group pathway) was estimated and compared with
that of the model compound for TriBOT. Since rapid consumption
of TriBOT in the late stage could not be explained solely by this
pathway, cooperation of another reaction mechanism, the cationic
leaving group pathway, was proposed to rationalize the rate
acceleration.
n 2012, we developed 2,4,6-tris(benzyloxy)-1,3,5-triazine
(TriBOT, Scheme 1) as an acid-catalyzed benzylating
where resulting coproducts like DiBOT and 2 have no
charge.11
Herein we analyze the reaction profile of TriBOT (80 mM)
with TfOH (40 mM), at 25 °C, to study the kinetics of
TriBOT, which is still not clearly understood (Scheme 2). The
I
Scheme 1. Neutral LG Pathway of Triazine-Based
Benzylating Reagents
Scheme 2. Acid-Catalyzed O-Benzylation with TriBOT in
the Presence of TfOH (40 mM, 50 mol %)
reagent, which was designed to be the formal trimer of the
smallest unit of alkyl imidate.1,2 This versatile concept has been
applied to the introduction of p-methoxybenzyl,3 fluorous
benzyl,4 tert-butyl,5 allyl, and substituted allyl groups.6 After we
reported TriBOT, it was utilized for the synthesis of sugar
derivatives,7a−c natural products,8a,b and other compounds.9a−c
The standard reaction conditions of TriBOT employ
trifluoromethanesulfonic acid (TfOH) as a catalyst (40 mM,
50 mol % based on 80 mM TriBOT) in 1,4-dioxane at room
temperature in the presence of a nucleophile (200 mM) such
as an alcohol. Powdered molecular sieves (5 Å) are added as a
dehydrating agent to remove residual moisture. The
protonated TriBOT (TriBOT-H+) formed in situ generates
benzyl cation species, most likely benzyl trifluoromethanesul-
fonate, and DiBOT as a leaving group (LG). The nucleophile
is benzylated by the benzyl cation species and regenerates the
acid catalyst. We previously carried out a kinetic study for the
model compound of TriBOT, 2-benzyloxy-4,6-dimethoxy-
1,3,5-triazine (1, Scheme 1), whose protonated form (1-H+)
gave the benzyl cation species and LG 2 following first-order
kinetics.10 We refer to this kind of reaction mechanism for
triazine-based alkylating reagents as a neutral LG pathway,
final product from TriBOT is isocyanuric acid, formed due to
the intermediates, DiBOT and MonoBOT (Scheme 2), also
generating the benzyl cation species in the presence of TfOH.
In this study, a nucleophile (3-phenylpropanol, 3) was used in
excess (1200 mM) to suppress the known side reaction, which
affords N-benzylisocyanuric acid (<5%). p-Nitrotoluene was
added as an internal standard for HPLC analysis. After we
determine the first-order kinetic constant of the neutral LG
pathway of TriBOT (kn) by an approximate calculation, the
cooperation of another reaction pathway will be discussed to
rationalize the late-stage kinetics of TriBOT.
Interestingly, the decrease in [TriBOT]obs was able to be
closely approximated by a straight line (Figure 1, red line, r2 =
0.999) from the beginning to the end (2−232 min). Here,
[TriBOT]obs is the concentration of TriBOT observed in the
Received: June 14, 2018
Published: July 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 1. Time course of [TriBOT]obs, [TriBOT-H+], [DiBOT]obs, and [TriBOT]obs + [DiBOT]obs in O-benzylation of 3 (1200 mM) with
TriBOT (80 mM) and TfOH (40 mM).
HPLC analysis after quenching by neutralization and
represents the sum of [TriBOT] and [TriBOT-H+] in the
reaction mixture. Previously, a similar linear decrease in
TriBOT was also observed under the standard conditions with
200 mM of 3.10 On the basis of our previous model studies,10
the basicity order of the compounds in the reaction mixture is
considered to be DiBOT > TriBOT ≈ MonoBOT >
isocyanuric acid, an alcohol, and 1,4-dioxane. TriBOT and
DiBOT will behave as dominant bases because the
concentration of MonoBOT was too low to detect during
the reaction. Therefore, [TriBOT-H+] was estimated to be
statistically faster than that of 1 owing to its three benzyl
groups. Another factor may be derived from the inductive
effect of the substituents enhancing the LG ability. According
to Taft’s δI constants for the strength of inductive effects,13
which were obtained from ionization constants of acetic acid
derivatives, a benzyl group has a slightly stronger inductive
effect (δI = 0.03) compared to a methyl group (δI = −0.01),
which hence helps to explain why the reactivity of TriBOT
could be higher than 1.
As shown in Figure 1, [DiBOT]obs was observed to be nearly
constant (9.1
[TriBOT]obs + [DiBOT]obs was plotted as a straight line (blue
line, r2 = 0.998) in this region, showing that [TriBOT]obs
1.5 mM) for 30−240 min. Consequently,
[H+]total − [DiBOT]obs in the region of [TriBOT]obs
>
[TriBOT-H+], where [H+]total represents the sum of acidic
protons in the reaction mixture. Since the reaction between the
benzyl cation species and 3 produces H+ rapidly, [H+]total will
be constant and equal to the amount of TfOH (40 mM) used
during the reaction. As a result, [TriBOT-H+] was almost
constant during 30−120 min (purple dashed line, 31.4 1.0
mM). Consequently, the decrease in [TriBOT]obs in this
region, virtually followed pseudozero-order kinetics if TriBOT
was consumed via the neutral LG pathway. The kinetic
constant kn was estimated to be 10.3 × 10−3 min−1 (25 °C),
from the calculation using [TriBOT-H+] = 31.4 mM and the
slope of [TriBOT]obs in Figure 1.
+
[DiBOT]obs fell below [H+]total (40 mM) at 137.9 min.
[TriBOT-H+] was calculated to be 30.7 mM at this time point
as indicated by the cross mark. It was assumed that [TriBOT-
H+] was equal to [TriBOT]obs after 137.9 min because
TriBOT was completely protonated in the reaction mixture.
Therefore, [TriBOT]obs was expected to follow first-order
kinetics (curve A, green curve, Figure 2) if TriBOT was
consumed only via the neutral LG pathway. However,
interestingly, TriBOT decreased more rapidly than expected
as shown in Figure 2, implying possible rate acceleration
caused by the excess H+. We recently reported a new reaction
It is worth comparing kn with the corresponding kinetic
constant of 1 under the analogous conditions since 1 was
prepared as a model of TriBOT. As expected, first-order
kinetics were observed in the reaction of 1 (42.4 mM) with
TfOH (40 mM, 95 mol % based on 1) in the presence of
excess 3 (1200 mM) at 25 °C (Scheme 3). The rate constant
for the neutral LG pathway of 1 was obtained as k′n = 1.88 ×
10−3 min−1, which was 5.5 times smaller than kn.12 A plausible
factor for this difference is the number of benzyl groups in the
molecules. The reaction of TriBOT is expected to be
Scheme 3. Acid-Catalyzed O-Benzylation with 1 in the
Presence of TfOH (40 mM, 95 mol %)
Figure 2. Late-stage kinetics of TriBOT in O-benzylation of 3 (1200
mM) with TriBOT (80 mM) and TfOH (40 mM).
B
DOI: 10.1021/acs.joc.8b01505
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mechanism of triazine-based alkylating reagents, a cationic LG
pathway (Scheme 4) where the carbocation species were
ability for “spontaneous in situ rate acceleration” as observed
for TriBOT. This property is unique and advantageous over
most organic reactions, which require extended reaction times
due to the slowdown of the reaction in the late stage.
Scheme 4. Cationic LG Pathway of Triazine-Based
Benzylating Reagents
EXPERIMENTAL SECTION
■
General Information. Reagents were commercial grade and were
used without any purification. Known compounds (TriBOT,1
DiBOT,10 MonoBOT,10 and 110) were prepared as described in the
literature. HPLC analysis was carried out using Mightysil RP-18Gp
Aqua at a flow rate of 1.0 mL/min with UV detection at 254 nm.
Concentrations of compounds were determined using calibration
curves generated with p-nitrotoluene as an internal standard and with
samples of known concentrations. The calibration curves for HPLC
analysis were previously reported.10
generated rapidly from N,N′-diprotonated triazines formed in
the presence of excess H+ with a small equilibrium
concentration.11 We also provided the rate law for this
pathway in the O-benzylation reaction on the basis of kinetic
studies using a model compound. Using the rate law, the
decrease in [TriBOT]obs ([TriBOT-H+]) after 137.9 min can
be given by eq 1 if both the neutral and the cationic LG
pathways were operative.
General Procedure for HPLC Monitoring of Acid-Catalyzed
O-Benzylation. TfOH (40−80 mM) was added to a solution of 3
(40−1200 mM), a triazine-based benzylating reagent [TriBOT (67−
80 mM) or 1 (42.4 mM)], p-nitrotoluene (15−30 mM), and
powdered MS5A (5.0 mg/mL) in 1,4-dioxane at 25 0.5 °C or at
room temperature. Aliquots were withdrawn from the reaction
mixture at recorded intervals, diluted 50 times with a pyridine solution
(2.0 mM) in H2O/MeCN (1:1), and filtered. HPLC analysis was
performed using p-nitrotoluene as an internal standard. HPLC
conditions of the reaction with TriBOT: gradient of 0.1% TFA in
H2O (solvent A) and 0.1% TFA in MeCN (solvent B), 80% A + 20%
B to 65% A + 35% B (0−10 min), 65% A + 35% B (10−20 min), 65%
A + 35% B to 40% A + 60% B (20−25 min), 40% A + 60% B (25−40
min), 40% A + 60% B to 20% A + 80% B (40−45 min). HPLC
conditions of the reaction with 1: gradient of 80% H2O + 20% MeCN
to 65% H2O + 35% MeCN (0−10 min), 65% H2O + 35% MeCN to
30% H2O + 70% MeCN (10−25 min), 30% H2O + 70% MeCN to
10% H2O + 90% MeCN (25−26 min).
d[TriBOT]obs
−
= (kn + kc[excess H+]2)[TriBOT]obs
dt
(1)
Here, kc is the observed first-order kinetic constant for the
cationic LG pathways of TriBOT, while [excess H+] after
137.9 min is described to be 40 − ([TriBOT]obs
+
[DiBOT]obs) (black dashed line, Figure 2). Curve fitting
using the resulting equation for [TriBOT]obs obtained curve B
(red curve, r2 = 0.999) with kc = 7.71 × 10−5 min−1 mM−2 at
25 °C. (The details can be found in the Supporting
Information.)
To demonstrate the cationic LG pathways of TriBOT under
typical conditions, we carried out acid-catalyzed O-benzylation
reactions for 3 (200 mM) using TriBOT (67 mM) and TfOH
(Table 1). When 40 mM of TfOH (60 mol % based on
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01505.
■
S
Table 1. Effect of the TfOH Concentration on the Reaction
Rate of TriBOT
Kinetic study of O-benzylation with 1 and curve fitting
for the late-stage kinetics of TriBOT (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: kunisima@p.kanazawa-u.ac.jp.
■
TfOH (mol % based on
TriBOT)
time of TriBOT disappearance
ORCID
a
entry
(min)
Hikaru Fujita: 0000-0002-0430-9705
Munetaka Kunishima: 0000-0002-3296-490X
Notes
1
2
60
120
60−65
<6
a
TriBOT disappearance (<1%) was monitored by HPLC analysis.
The authors declare no competing financial interest.
TriBOT) was used, TriBOT was consumed in 60−65 min
(entry 1). In contrast, TriBOT disappeared within only 6 min
in the presence of 80 mM of TfOH (120 mol % based on
TriBOT).14 The cationic LG pathway accounts for this
considerable rate acceleration caused by the excess H+.
In summary, our study on the reaction profile of TriBOT
provided a deeper understanding of the reaction mechanisms
and the kinetics. We obtained an estimated value for the
kinetic constant of the neutral LG pathway of TriBOT and
evaluated it by comparison to the model compound. The
cooperation of the cationic LG pathway was proposed to
explain the sharp decrease in TriBOT in the late stage of the
reaction. Additionally, since the cationic LG pathway also
works for other alkylation reactions,8 trialkoxytriazine-based
reagents for TfOH-catalyzed alkylation potentially have the
ACKNOWLEDGMENTS
■
This work was supported by the Japan Society for the
Promotion of Science (JSPS) in the form of a Research
Fellowship for Young Scientists (to H.F.) and partially
supported by the JSPS Grants-in-Aid for Scientific Research
program (KAKENHI; 17H03970, 26293003, and 26670001).
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DOI: 10.1021/acs.joc.8b01505
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The Journal of Organic Chemistry
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sensitivity to the excess H+ depending on the isomeric core triazine
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one in DiBOT.
D
DOI: 10.1021/acs.joc.8b01505
J. Org. Chem. XXXX, XXX, XXX−XXX