Study of the Reactivities of Acid-Catalyzed O-Benzylating Reagents Based on Structural Isomers of 1,3,5-Triazine

Article abstract of DOI:10.1021/acs.joc.5b02059

We have demonstrated O-benzylating abilities of both 4,6-bis(benzyloxy)-1,3,5-triazin-2(1H)-one (DiBOT) and 6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione (MonoBOT), which have been previously suggested as reaction intermediates of the acid-catalyzed benzylation of 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT). We studied the effect on the reactivity of acid-catalyzed O-benzylation caused by the isomeric core triazine structures in these compounds by carrying out a kinetic study and estimating relative basicities using model compounds. Since MonoBOT showed superior reactivity, 1,3,5-triazine-2,4(1H,3H)-dione is a promising core structure for acid-catalyzed alkylating reagents.

Full text of DOI:10.1021/acs.joc.5b02059

Note
pubs.acs.org/joc
Study of the Reactivities of Acid-Catalyzed O‑Benzylating Reagents
Based on Structural Isomers of 1,3,5-Triazine
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: We have demonstrated O-benzylating abilities of both
4,6-bis(benzyloxy)-1,3,5-triazin-2(1H)-one (DiBOT) and 6-(benzyl-
oxy)-1,3,5-triazine-2,4(1H,3H)-dione (MonoBOT), which have been
previously suggested as reaction intermediates of the acid-catalyzed
benzylation of 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT). We
studied the effect on the reactivity of acid-catalyzed O-benzylation
caused by the isomeric core triazine structures in these compounds by
carrying out a kinetic study and estimating relative basicities using
model compounds. Since MonoBOT showed superior reactivity, 1,3,5-
triazine-2,4(1H,3H)-dione is a promising core structure for acid-
catalyzed alkylating reagents.
ecently, we developed a novel acid-catalyzed benzylating
reagent, 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT, Fig-
tion. This provides further mechanistic insights into the
reaction of TriBOT and reveals the effect of the core structures
of the benzylating reagents on acid-catalyzed O-benzylation.
DiBOT and MonoBOT were synthesized from 2,4-bis-
(benzyloxy)-6-chloro-1,3,5-triazine and 2-benzyloxy-4,6-di-
chloro-1,3,5-triazine in good yields (93% and 84%, respec-
tively).6 Both DiBOT and MonoBOT are crystalline solids and
stable in air at room temperature.
To evaluate the O-benzylating abilities of DiBOT and
MonoBOT by comparing them with that of TriBOT, we
treated 3-phenylpropanol (1) with TriBOT (0.4 equiv),
DiBOT (0.6 equiv), or MonoBOT (1.2 equiv) in the presence
of TfOH (0.2 equiv). The mole equivalents of the benzyl group
available for the reaction are identical (1.2 equiv) in these
conditions. As a result, benzyl 3-phenylpropyl ether (2) was
obtained at 95% yield with TriBOT (Table 1, entry 1), while
relatively lower 85% yield with increased byproducts, N-
benzylisocyanuric acid (3) and N,N′-dibenzylisocyanuric acid
(4) (entry 2), was observed when using DiBOT. When
MonoBOT was used, the reaction proceeded with an excellent
98% yield (entry 3). MonoBOT was therefore a promising
benzylating reagent.
R
ure 1), which is an inexpensive stable crystalline solid with high
atom economy.1 TriBOT was designed based on the concept of
the formal trimerization of the smallest unit of benzyl imidate.
This concept has also been applied to acid-catalyzed p-
methoxybenzylation.2 Various alcohols react with TriBOT at
room temperature, in the presence of an acid catalyst such as
trifluoromethanesulfonic acid (TfOH), to afford the corre-
sponding benzyl ethers.
Since all the three benzyl groups in TriBOT can be used for
the reaction, and isocyanuric acid is formed as a coproduct, the
reaction using TriBOT is considered to involve 4,6-bis-
(benzyloxy)-1,3,5-triazin-2(1H)-one (DiBOT)3 and 6-(benzyl-
oxy)-1,3,5-triazine-2,4(1H,3H)-dione (MonoBOT) as reaction
intermediates (Figure 1). Although the reactivities of the acid-
catalyzed O-benzylation of DiBOT and MonoBOT have not
been investigated, we presume that TriBOT, DiBOT, and
MonoBOT (henceforth referred to as BOTs) are activated by
protonation with TfOH to release a benzyl cation species,
probably benzyl trifluoromethanesulfonate, via steps 1−3,
respectively. These species react with alcohols to give the
benzyl ethers and regenerate TfOH. The final O-benzylation
step will be very fast at room temperature.4 Therefore, the
generation of the benzyl cation species from the protonated
forms (PFs) of BOTs, whose concentrations in the reaction
system depend on their basicities, is the rate-determining step
in a series of reaction steps. The reaction rates of steps 1−3 as
well as the basicities of BOTs are not expected to be mutually
identical in view of the isomeric core structures of BOTs (1,3,5-
triazine in TriBOT; 1,3,5-triazin-2(1H)-one in DiBOT; and
1,3,5-triazine-2,4(1H,3H)-dione in MonoBOT).5
To observe the time course of the reaction intermediates and
products of the acid-catalyzed O-benzylation with TriBOT, we
monitored the reaction between alcohol 1 (200 mM) and
TriBOT (80 mM) in the presence of a catalytic amount of
TfOH (40 mM). As shown in Figure 2, DiBOT was observed
to increase while TriBOT remained in the reaction mixture (0−
90 min). After TriBOT disappeared completely, DiBOT began
to decrease and finally disappeared (90−120 min). These
Herein, we report the comparison of the reactivities of
BOTs-based benzylating reagents in acid-catalyzed O-benzyla-
Received: September 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02059
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The Journal of Organic Chemistry
Note
Figure 1. Acid-catalyzed O-benzylation with TriBOT.
Table 1. Acid-Catalyzed O-Benzylation of 1 with BOTs
a
a
a
a
entry
BOT (equiv)
time (h)
recovered 1 (%)
2 (%)
3 (%)
4 (%)
b
c
c
b
b
b
c
c
c
1
2
3
TriBOT (0.4)
DiBOT (0.6)
3.5
3
4
95
85
29 (11)
0
6
1
(0)
(7)
(3)
b
12
25 (15)
b
c
MonoBOT (1.2)
1.5
1
98
6 (7)
a
b
c
Yields were calculated by 1H NMR analysis using an internal standard. Yields based on BOTs. Yields based on the benzyl groups (total 1.2 equiv
= 120%).
as observed in Table 1. Byproduct 3 seems to be formed via N-
benzylated DiBOT (5) because 5 formed competitively in the
early stage of the reaction and appeared earlier than 3.
Since the benzyl cation species would be generated from the
PFs of BOTs, the basicities of BOTs are meaningful factors in
characterizing their reactivities as benzylating reagents. To
estimate the relative basicities between BOTs, isocyanuric acid,
and the alcohol, we conducted 1H NMR analysis (NoD NMR)
in competitive protonation among model compounds of BOTs
(1.0 equiv, respectively) with TfOH (0.95 equiv) in 1,4-
dioxane. The model compounds we employed were 2,4,6-
trimethoxy-1,3,5-triazine (6), 4,6-bis(cyclohexylmethoxy)-1,3,5-
triazin-2(1H)-one (7), 6-(3-phenylpropoxy)-1,3,5-triazine-2,4-
(1H,3H)-dione (8), 3, and p-bromobenzyl alcohol (9) for
TriBOT, DiBOT, MonoBOT, isocyanuric acid, and the alcohol,
respectively. These compounds were adopted because of their
structural similarity, high solubility in 1,4-dioxane, inertness
under acidic conditions and easy detection of NMR signals.
When TfOH was added to a mixture composed of all the model
compounds, only the methylene signal of 7 showed a downfield
shift (Figure 3a,b), indicating that 7 is the most basic among all
the model compounds. The downfield shift of the methyl signal
of 6 and the relatively small downfield shift of the methylene
signal of 8 were observed in the absence of 7 (Figure 3c). The
only downfield shift of 8 (Figure 3d) in a mixture of 8, 3, and 9
shows that 8 has a stronger basicity than 3 and 9. Thus, the
order of the basicities is 7 > 6 ≈ 8 > 3 and 9. On the basis of
these model studies, it is presumed that BOTs are sufficiently
more basic than isocyanuric acid and the alcohol in 1,4-dioxane,
to give the corresponding PFs. Also, DiBOT is the most basic
among the BOTs.
Figure 2. Time course of the reaction intermediates and products of
the acid-catalyzed O-benzylation of 1 with TriBOT. The reaction was
conducted in 1,4-dioxane at room temperature, and the concentration
of each compound was determined by HPLC analysis.
To estimate the reaction rate constants of each step in the
acid-catalyzed O-benzylation of TriBOT (steps 1−3, Figure 1)
individually, we measured the reaction rates of the acid-
results suggest that DiBOT was formed from TriBOT as a
reaction intermediate. In contrast to DiBOT, MonoBOT could
not be detected during the reaction, implying its high reactivity
B
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Note
Figure 3. NMR spectroscopic analysis of competitive protonation among the model compounds.
Figure 4. Acid-catalyzed O-benzylation with (a) 10 and (b) 11.
catalyzed O-benzylation with 2-(benzyloxy)-4,6-dimethoxy-
1,3,5-triazine (10), 4-(benzyloxy)-6-methoxy-1,3,5-triazin-
2(1H)-one (11), and MonoBOT as shown in Figure 4.
Compounds 10 and 11 are model compounds for TriBOT and
DiBOT, respectively, whose benzyl group(s) is(are) partially
replaced by a nonreactive methyl group(s). The reaction rate
for the formation of 2 from these compounds can be compared
under the same conditions because they all afford only 1 equiv
of benzyl cation species. If the rate-limiting steps are the
formation of the benzyl cation species from the PFs of 10, 11,
and MonoBOT (steps 1′ and 2′ for 10 and 11 in Figure 4,
respectively, and step 3 for MonoBOT in Figure 1), the
reactions should follow first-order kinetics in the concentrations
of their PFs. As a result, the reaction of 10 and 11 followed
first-order kinetics in the estimated [PF] in the observed region
with k1′ = 16.5 × 10−3 min−1 for 10 and k2′ = 14.8 × 10−3 min−1
for 11 at 25 °C (Figure S1 in the Supporting Information).7,8
Unfortunately, the disappearance of MonoBOT was too fast to
measure the rate constant (the residual MonoBOT was less
than 3% at 5 min). Thus, the order of the rates for the
formation of the benzyl cation species is MonoBOT > 10 ≈ 11.
These results can be considered based on the relative free
energies of 10, 11, MonoBOT, and their PFs. The higher the
exothermicity of the formation of the leaving group, the faster
the reaction will proceed. However, when the PF as a reactant
is stable, the reaction will be slow. It is reported that the
enthalpies of the sequential tautomerization reaction of
cyanuric acid (2,4,6-trihydroxy-1,3,5-triazine) to 4,6-dihy-
droxy-1,3,5-triazin-2(1H)-one, 6-hydroxy-1,3,5-triazine-2,4-
(1H,3H)-dione, and isocyanuric acid were calculated to be
−4.0, −43.6, −68.2 kJ/mol (B3LYP/6-31++G(d,p) level of
theory)9a and −1.9, −41.2, −66.1 kJ/mol (B3LYP/aug-cc-
pVDZ level of theory)9b for each step, respectively. Owing to
their structural similarity, the order of the exothermicities is
presumed to be as follows: from MonoBOT to isocyanuric acid
> from 11 to 6-(methoxy)-1,3,5-triazine-2,4(1H,3H)-dione
(13) > from 10 to 4,6-dimethoxy-1,3,5-triazin-2(1H)-one
(12). In addition, on the basis of the study of the basicities
of the model compounds, the order of stability of the PFs
would be 11 > 10 ≈ MonoBOT. Thus, the fast reaction of
MonoBOT can be attributed to the instability of the protonated
MonoBOT and the high exothermicity of the formation of
C
DOI: 10.1021/acs.joc.5b02059
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Note
(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).
General Procedure for NMR Analysis in Competitive
Protonation among the Model Compounds. 1,4-Dioxane (153
μL); 1,4-dioxane solutions of 6, 8, 3, and 9 (60.0 μL of 0.10 M stock
solution); 7 (150 μL of 0.040 M stock solution); and TfOH (57.0 μL
of 0.10 M stock solution) were mixed in an NMR tube. A NoD NMR
spectrum was recorded at 21 °C.
isocyanuric acid. It is interesting that 10 and 11 have the
comparable rate constants. This indicate that steps 1′ and 2′
have similar activation energies despite the expected much
higher exothermicity of the reaction of 11 to 13 than that of 10
to 12. Although the origin of their comparable reactivities is not
clear at present, the stability of the PF of 11 may contribute to
some extent to increase in the activation energy.
In summary, acid-catalyzed O-benzylation proceeded with
DiBOT and MonoBOT, which clearly indicates that they are
reaction intermediates of TriBOT. We have studied the kinetics
of acid-catalyzed O-benzylation and relative basicities using
several compounds possessing 1,3,5-triazine; 1,3,5-triazin-
2(1H)-one and 1,3,5-triazine-2,4(1H,3H)-dione structures,
and shown the effect of the isomeric core structures of
benzylating reagents on the reactivity of acid-catalyzed O-
benzylation. We found that MonoBOT, which contains the
1,3,5-triazine-2,4(1H,3H)-dione structure, has a superior
reactivity in acid-catalyzed O-benzylation. This characteristic
heterocyclic structure contained in MonoBOT will be applied
to the development of new acid-catalyzed alkylating reagents.
General Procedure for the Kinetic Study of O-Benzylation
with 10, 11 and MonoBOT. To a solution of 10 (98.9 mg, 0.400
mmol), 11 (93.3 mg, 0.400 mmol) or MonoBOT (87.7 mg, 0.40
mmol), and 1 (54.5 μL, 0.400 mmol); p-nitrotoluene (16.5 mg, 0.120
mmol); and MS5A (20.0 mg) in 1,4-dioxane (4.0 mL) was added
trifluoromethanesulfonic acid (33.4 μL, 0.381 mmol) at 25 0.5 °C.
Aliquots (40 μL) were taken from the reaction mixture at intervals,
diluted with pyridine solution (4.0 mM, 2.0 mL) in H2O−MeCN
(1:1), and filtered. HPLC analysis was performed using p-nitrotoluene
as an internal standard. HPLC conditions of the kinetic study with 10:
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). HPLC conditions of the kinetic study with 11 and MonoBOT:
gradient of 0.1% TFA in H2O (solvent A) and 0.1% TFA in MeCN
(solvent B), 85% A + 15% B (0−5 min), 85% A + 15% B to 15% A +
85% B (5−15 min).
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR spectra were
recorded on 400 and 600 MHz spectrometers. Chemical shifts for
1H NMR are reported in parts per million (δ) relative to
tetramethylsilane as the internal standard. Coupling constant (J) are
reported in hertz (Hz). The following abbreviations are used for spin
multiplicity: s = singlet, d = doublet, t = triplet, m = multiplet, br =
broad. 13C NMR spectra were recorded on 100 and 150 MHz
spectrometers. Chemical shifts for 13C NMR are reported in parts per
million (δ) relative to the solvent (CDCl3, δ 77.16; DMSO-d6, 39.52;
acetone-d6, 29.84). Analytical thin layer chromatography (TLC) was
performed using glass plates precoated with 0.25 mm silica gel
impregnated with a fluorescent indicator (254 nm). Flash chromatog-
raphy was performed using silica gel (spherical, neutral, 40−100
mesh). TriBOT was prepared by the procedure reported in the
literature.1 Trifluoromethanesulfonic acid (>98.0% purity), dehydrated
1,4-dioxane, CH2Cl2, THF, and MeOH were purchased from
commercial sources and used without further purification. Xylene
was distilled over sodium before use. All reactions sensitive to oxygen
or moisture were conducted under a nitrogen atmosphere. 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 samples with known
concentrations.
2,4-Bis(benzyloxy)-6-chloro-1,3,5-triazine.10 To a solution of
cyanuric chloride (92.2 mg, 0.500 mmol) and benzyl alcohol (156
μL, 1.50 mmol) in CH2Cl2 (1.0 mL) was added ethyldiisopropylamine
(261 μL, 1.50 mmol) at −40 °C. After it stirred for 1.5 h, the mixture
was allowed to warm to rt and stirred for 30 h. The mixture was
washed with sat. aqueous NH4Cl (2 mL) and brine (2 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (hexane−EtOAc, 10:1) to afford title compound (156.6 mg,
96%) as colorless crystals. Mp 72−73 °C.
4,6-Bis(benzyloxy)-1,3,5-triazin-2(1H)-one (DiBOT).3 To a
solution of N-methylmorpholine (220 μL, 2.00 mmol) and acetic
acid (57.2 μL, 1.00 mmol) in MeOH was added 2,4-bis(benzyloxy)-6-
chloro-1,3,5-triazine (163.9 mg, 0.500 mmol) at 0 °C. After it stirred
for 30 min, the mixture was allowed to warm to rt. After it stirred for
an additional 1.5 h, acetic acid (57 μL, 1.0 mmol) was wadded. The
mixture was concentrated under reduced pressure and CHCl3 (5 mL)
was added to the residue. The mixture was washed with 1 M aqueous
HCl (5 mL) and brine (5 mL). The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (CHCl3−EtOAc, 4:1)
to afford DiBOT (143.1 mg, 93%) as a white solid. Mp 170 °C
(decomp.).
General Procedure for O-Benzylation of 1 with BOTs. To a
solution of 1 (40.1 μL, 0.30 mmol), DiBOT (55.7 mg, 0.18 mmol),
and MS5A (7.5 mg) in 1,4-dioxane (1.50 mL) was added
trifluoromethanesulfonic acid (5.3 μL, 0.060 mmol) at rt. After it
stirred for 3 h, the reaction mixture was quenched with pyridine (24
μL, 0.30 mmol), concentrated under reduced pressure, and MeOH
was added to the residue. The resulting mixture was filtered and
concentrated under reduced pressure. The yields of 1−4 were
2-(Benzyloxy)-4,6-dichloro-1,3,5-triazine. To a solution of
cyanuric chloride (7.38 g, 40.0 mmol) in CH2Cl2 (70.0 mL) was
added a solution of benzyl alcohol (4.12 mL, 40.0 mmol) and
ethyldiisopropylamine (7.70 mL, 44.0 mmol) in CH2Cl2 (35.0 mL)
prepared in a flask at 0 °C. The residual benzyl alcohol and
ethyldiisopropylamine in the flask were rinsed with CH2Cl2 (5.0 mL)
into the mixture. After it stirred for 1 h, the mixture was allowed to
warm to rt. After it stirred for an additional 1.5 h, the mixture was
washed with 1 M aqueous HCl (110 mL) and brine (50 mL). The
organic layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (hexane−CHCl3, 1:1) and recrystallization from hexane to
afford title compound (9.45g, 92%) as colorless crystals. Mp 86−88
°C; 1H NMR (400 MHz, CDCl3): δ 7.49−7.33 (m, 5H), 5.53 (s, 2H).
13C NMR (100 MHz, CDCl3): δ 172.7, 171.0, 133.8, 129.2, 128.9,
1
determined using H NMR measurements (CD3OD) of the crude
product, which contained (E)-N,N-dimethylcinnamamide as an
internal standard. In the case of the reaction with MonoBOT, 2.60
mL of 1,4-dioxane was used as the reaction solvent.
HPLC Monitoring of O-Benzylation with TriBOT. To a solution
of 1 (136 μL, 1.00 mmol), TriBOT (159.8 mg, 0.40 mmol), p-
nitrotoluene (13.7 mg, 0.10 mmol), and MS5A (25.0 mg) in 1,4-
dioxane (5.0 mL) was added trifluoromethanesulfonic acid (17.6 μL,
0.20 mmol) at rt. Aliquots (20 μL) were taken from the reaction
mixture at intervals, diluted with pyridine solution (2.0 mM, 1.98 mL)
in H2O−MeCN (1:1), and filtered. HPLC analysis was performed
using p-nitrotoluene as an internal standard. HPLC conditions:
gradient of 0.1% TFA in H2O (solvent A) and 0.1% TFA in MeCN
128.8, 71.9. Anal. Calcd for C10H7Cl2N3O: C, 46.90; H, 2.76; N, 16.41.
Found: C, 47.13; H, 2.92; N, 16.32. HRMS (DART-TOF) m/z: [M +
H]+ Calcd for C10H8Cl2N3O 256.0044. Found: 256.0016. IR (KBr):
1541, 1508, 1429, 1362, 1300, 1255, 1057 cm−1.
D
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Note
6-(Benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione (MonoBOT).
To a biphasic solution of sodium acetate (2.051 g, 25.0 mmol) and
N-methylmorpholine (110 μL, 1.00 mmol) in THF (10.0 mL) and
H2O (10.0 mL) was added 2-(benzyloxy)-4,6-dichloro-1,3,5-triazine
(1.280 g, 5.00 mmol) at 0 °C. After it stirred for 1 h, the mixture was
allowed to warm to rt. After it stirred for an additional 19 h, 1 M
aqueous HCl (1.0 mL) was added to the mixture. After careful
evaporation of THF, a precipitate was corrected and recrystallized
from EtOH to afford MonoBOT (923.4 mg, 84%) as colorless crystals.
Calcd for C17H28N3O3 322.2131. Found: 322.2145. IR (KBr): 2924,
2852, 1674, 1610, 1558, 1423, 1358, 1331 cm−1.
2,4-Dichloro-6-(3-phenylpropoxy)-1,3,5-triazine. To a solu-
tion of cyanuric chloride (1.00 g, 5.42 mmol) and ethyldiisopropyl-
amine (1.04 mL, 5.97 mmol) in CH2Cl2 was added 1 (739 μL, 5.42
mmol) at −20 °C. The mixture was stirred at −20 °C for 3 h, at 0 °C
for 7 h, and at rt for 1 h. Ethyldiisopropylamine (378 μL, 2.17 mmol)
was added at rt. After it stirred for an additional 6 h, the mixture was
diluted with CHCl3, washed with 1 M aqueous HCl (15 × 2 mL), and
brine. The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane−EtOAc, 20:1) followed by
recrystallization from hexane to afford title compound (1.07 g, 70%)
as colorless crystals. Mp 53.6−54.8 °C; 1H NMR (600 MHz, CDCl3):
δ 7.32−7.27 (m, 2H), 7.24−7.17 (m, 3H), 4.49 (t, J = 6.3 Hz, 2H),
2.80 (t, J = 7.6 Hz, 2H), 2.19−2.11 (m, 2H). 13C NMR (150 MHz,
CDCl3): δ 172.7, 171.2, 140.6, 128.7, 128.5, 126.4, 69.8, 31.8, 30.0.
Anal. Calcd for C12H11Cl2N3O: C, 50.72; H, 3.90; N, 14.79. Found: C,
50.81; H, 4.00; N, 14.78. HRMS (DART-TOF) m/z: [M + H]+ Calcd
for C12H12Cl2N3O 284.0357. Found: 284.0368. IR (KBr): 3030, 1541,
1506, 1308, 1255, 1038 cm−1.
6-(3-Phenylpropoxy)-1,3,5-triazine-2,4(1H,3H)-dione (8). To
a solution of sodium acetate (430.7 mg, 5.25 mmol) and N-
methylmorpholine (38.5 μL, 0.35 mmol) in MeOH (17.5 mL) was
added 2,4-dichloro-6-(3-phenylpropoxy)-1,3,5-triazine (497.2 mg, 1.75
mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h, at rt for 13 h,
and at 40 °C for 25 h. The mixture was concentrated under reduced
pressure, and CHCl3 was added to the residue. The mixture was
washed with sat. aqueous NH4Cl (20 mL), brine (20 mL), 1 M
aqueous HCl (10 mL) and concentrated under reduced pressure. The
residue was purified by column chromatography (CHCl3−MeOH,
19:1) followed by recrystallization from hexane−THF to afford 8
(271.4 mg, 63%) as colorless crystals. Mp 200 °C (decomp.); 1H
NMR (600 MHz, DMSO-d6): δ 12.16 (br s, 1H), 11.01 (br s, 1H),
7.32−7.27 (m, 2H), 7.25−7.16 (m, 2H), 4.27 (t, J = 6.6 Hz, 2H), 2.68
(t, J = 7.7 Hz, 2H), 2.02−1.94 (m, 2H). 13C NMR (150 MHz, DMSO-
d6): δ 161.4, 140.9, 128.4, 128.3, 125.9, 67.6, 31.0, 29.4. Anal. Calcd for
C12H13N3O3: C, 58.29; H, 5.30; N, 17.00. Found: C, 58.07; H, 5.25;
N, 16.93. HRMS (DART-TOF) m/z: [M + H]+ Calcd for
C12H14N3O3 248.1035. Found: 248.1033. IR (KBr): 3084, 2817,
1751, 1685, 1577, 1417, 1317 cm−1.
1
Mp 200 °C (decomp); H NMR (600 MHz, DMSO-d6): δ 12.24 (br
s, 1H), 11.07 (br s, 1H), 7.48−7.34 (m, 5H), 5.35 (s, 2H). 13C NMR
(100 MHz, DMSO-d6): δ 162.3, 153.9 (br s), 135.1, 128.49, 128.45,
128.42, 69.2. Anal. Calcd for C10H9N3O3: C, 54.79; H, 4.14; N, 19.17.
Found: C, 54.71; H, 4.12; N, 19.10. HRMS (DART-TOF) m/z: [M +
H]+ Calcd for C10H10N3O3 220.0722. Found: 220.0708. IR (KBr):
3076, 1751, 1736, 1684, 1577, 1313 cm−1.
1-Benzyl-4,6-bis(benzyloxy)-1,3,5-triazin-2(1H)-one (5). To a
mixture of DiBOT (154.7 mg, 0.500 mmol), cesium carbonate (177.2
mg, 0.544 mmol) and DMSO (1.0 mL) was added benzyl bromide
(62.4 μL, 0.525 mmol) at rt. After it stirred for 30 min, the mixture
was diluted with Et2O (4 mL) and washed with H2O (10 mL) and
brine (4 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (CH2Cl2−EtOAc, 19:1) to afford 5 (130.8
1
mg, 65%) as a clear colorless oil. H NMR (400 MHz, CDCl3): δ
7.49−7.43 (m, 2H), 7.42−7.21 (m, 13H), 5.43 (s, 2H), 5.42 (s, 2H),
5.11 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 168.9, 163.1, 156.9,
135.5, 135.3, 133.7, 129.3, 128.91, 128.87, 128.85, 128.77, 128.7,
128.6, 128.2, 72.0, 70.5, 45.7. Anal. Calcd for C24H21N3O3: C, 72.16;
H, 5.30; N, 10.52. Found: C, 72.54; H, 5.50; N, 10.44. HRMS (DART-
TOF) m/z: [M + H]+ Calcd for C24H22N3O3 400.1661. Found:
400.1685. IR (CHCl3): 1705, 1603, 1533, 1423, 1348, 1176 cm−1.
2,4,6-Trimethoxy-1,3,5-triazine (6).1,11 To a suspension of
NaHCO3 (205.8 mg, 2.45 mmol) in MeOH (2.80 mL) was added
cyanuric chloride (129.1 mg, 0.700 mmol) at rt. After it stirred for 2 h,
the mixture was warmed to 50 °C. After it stirred an additional 22 h,
the mixture was cooled to rt and concentrated under reduced pressure.
The residue was purified by column chromatography (hexane−EtOAc,
1:1) to afford 6 (110.1 mg, 92%) as colorless crystals. Mp 143.6−144.6
°C.
2-Chloro-4,6-bis(cyclohexylmethoxy)-1,3,5-triazine. A solu-
tion of cyanuric chloride (2.634 g, 15.0 mmol), cyclohexylmethanol
(4.59 mL, 37.5 mmol) and 1,10-phenanthroline (8.109 g, 45.0 mmol)
in xylene (50.0 mL) was heated to reflux for 20 h. After it cooled to rt,
the mixture was filtered through a Celite pad and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (hexane−EtOAc, 30:1) followed by recrystallization from
hexane to afford title compound (4.392 g, 86%) as colorless crystals.
2-(Benzyloxy)-4-chloro-6-methoxy-1,3,5-triazine. A solution
of 2-(benzyloxy)-4,6-dichloro-1,3,5-triazine (200.0 mg, 0.781 mmol)
and 1,10-phenanthroline (154.8 mg, 0.859 mmol) in MeOH (1.56
mL) was stirred at 50 °C for 7.5 h. After it cooled to rt, the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography (hexane−EtOAc, 4:1) to afford title
compound (161.7 mg, 82%) as colorless crystals. Mp 64.9−66.2 °C;
1H NMR (400 MHz, CDCl3): δ 7.50−7.42 (m, 2H), 7.42−7.31 (m,
3H), 5.48 (s, 2H), 4.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
172.9, 172.7, 172.1, 134.7, 128.84, 128.76, 128.6, 70.8, 56.2. Anal.
Calcd for C11H10ClN3O2: C, 52.50; H, 4.01; N, 16.70. Found: C,
52.63; H, 3.80; N, 16.75. HRMS (DART-TOF) m/z: [M + H]+ Calcd
for C11H11ClN3O2 252.0534. Found: 252.0515. IR (KBr): 1570, 1541,
1429, 1346, 1236, 1122 cm−1.
1
Mp 75.8−76.2 °C; H NMR (600 MHz, CDCl3): δ 4.22 (d, J = 6.2
Hz, 4H), 1.89−1.63 (m, 12H), 1.34−1.13 (m, 6H), 1.12−0.99 (m,
4H). 13C NMR (150 MHz, CDCl3): δ 172.6, 172.4, 74.5, 37.2, 29.8,
29.6, 26.4, 25.7. Anal. Calcd for C17H26ClN3O2: C, 60.08; H, 7.71; N,
12.36. Found: C, 60.35; H, 7.49; N, 12.28. HRMS (DART-TOF) m/z:
[M + H]+ Calcd for C17H27ClN3O2 340.1792. Found: 340.1820. IR
(KBr): 2927, 2854, 1576, 1522, 1508, 1342, 1072, 1007 cm−1.
4,6-Bis(cyclohexylmethoxy)-1,3,5-triazin-2(1H)-one (7). To a
solution of acetic acid (46 μL, 0.80 mmol) and N-methylmorpholine
(176 μL, 1.60 mmol) in MeOH (2.0 mL) was added 2-chloro-4,6-
bis(cyclohexylmethoxy)-1,3,5-triazine (135.9 mg, 0.400 mmol) at 0
°C. After it stirred for 1.5 h, the mixture was allowed to warm to rt.
After it stirred for an additional 1.5 h, 6 M aqueous HCl (0.13 mL)
was added to the mixture and concentrated under reduced pressure.
The residue was purified by column chromatography (CH2Cl2−
MeOH, 30:1) to afford 7 (121.3 mg, 94%) as a white solid. Mp 200.2−
202.4 °C; 1H NMR (600 MHz, CDCl3): δ 12.16 (br s, 1H), 4.23 (d, J
= 6.3 Hz, 4H), 1.90−1.63 (m, 12H), 1.32−1.12 (m, 6H), 1.06−0.93
(m, 4H). 13C NMR (150 MHz, CDCl3): δ 160.1, 74.7, 36.9, 29.6, 26.4,
25.6. Anal. Calcd for C17H27N3O3: C, 63.53; H, 8.47; N, 13.07. Found:
C, 63.45; H, 8.41; N, 13.13. HRMS (DART-TOF) m/z: [M + H]+
2-(Benzyloxy)-4,6-dimethoxy-1,3,5-triazine (10). A solution of
2-(benzyloxy)-4-chloro-6-methoxy-1,3,5-triazine (200.0 mg, 0.795
mmol) and 1,10-phenanthroline (286.4 mg, 1.59 mmol) in MeOH
(1.6 mL) was heated to reflux. After it stirred for 77 h, MeOH (1.6
mL) was added and the mixture was stirred at reflux for an additional
83 h. After the solution cooled to rt, the solvent was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy (CHCl3−MeOH, 100:1) to afford 10 (113.3 mg, 58%) as
1
colorless crystals. Mp 65.0−66.6 °C; H NMR (400 MHz, CDCl3): δ
7.49−7.42 (m, 2H), 7.41−7.29 (m, 3H), 5.45 (s, 2H), 4.03 (s, 6H).
13C NMR (100 MHz, CDCl3): δ 173.7, 173.1, 135.5, 128.7, 128.6,
128.5, 70.0, 55.5. Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N,
16.99. Found: C, 58.15; H, 5.36; N, 16.88. HRMS (DART-TOF) m/z:
[M + H]+ Calcd for C12H14N3O3 248.1035. Found: 248.1023. IR
(KBr): 2951, 1558, 1348, 1130 cm−1.
E
DOI: 10.1021/acs.joc.5b02059
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6-(Benzyloxy)-4-methoxy-1,3,5-triazin-2(1H)-one (11). To a
solution of acetic acid (57.2 μL, 1.00 mmol) and N-methylmorpholine
(220 μL, 2.00 mmol) in MeOH (2.50 mL) was added 2-(benzyloxy)-
4-chloro-6-methoxy-1,3,5-triazine (128.5 mg, 0.500 mmol) at 0 °C.
After it stirred for 30 min, the mixture was allowed to warm to rt and
stir for an additional 1.5 h. Acetic acid (57 μL, 1.0 mmol) was added to
the mixture and concentrated under reduced pressure. CHCl3 (5 mL)
was added to the residue, and the mixture was washed with 1 M
aqueous HCl (5 mL) and brine (5 mL). The organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (CHCl3−EtOAc, 4:1)
to afford 11 (104.1 mg, 89%) as colorless crystals. Mp 130 °C
of TfOH (95 mM) in 1,4-dioxane at 25 °C (see Experimental
Section). Since TfOH, which is a super acid (pKa = −12 in H2O, see
below), would ionize completely in the reaction mixture, and 10
should be more basic than 1, it is considered that [10]0 was 5 mM and
the [PF of 10]0 was 95 mM. The leaving group, 4,6-dimethoxy-1,3,5-
triazin-2(1H)-one (12), which is generated from the PF of 10 and
would be sufficiently more basic than 10, was protonated with
regenerated TfOH and thus [10] was considered to be constantly 5
mM. Therefore, it is estimated that [PF of 10] = [10]obs − 5, where
[10]obs is the concentration of 10 observed in HPLC analysis, and
represents the sum of [10] and the [PF of 10]. For pKa value of
TfOH, see: Raamat, E.; Kaupmees, K.; Ovsjannikov, G.; Trummal, A.;
1
(decomp.); H NMR (400 MHz, CDCl3): δ 12.35 (br s, 1H), 7.48−
Kutt, A.; Saame, J.; Koppel, I.; Kaljurand, I.; Lipping, L.; Rodima, T.;
̈
7.31 (m, 5H), 5.46 (s, 2H), 4.04 (2, 3H). 13C NMR (100 MHz,
CDCl3): δ 160.2, 134.4, 129.0, 128.9, 128.8, 71.0, 56.2. Anal. Calcd for
C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.45; H, 4.78;
N, 17.95. HRMS (DART-TOF) m/z: [M + H]+ Calcd for
C11H12N3O3 234.0879. Found: 234.0874. IR (KBr): 2962, 1684,
1610, 1576, 1471, 1362, 1325 cm−1.
Pihl, V.; Koppel, I. A.; Leito, I. J. Phys. Org. Chem. 2013, 26, 162−170.
(8) The basicity of 11 would be sufficiently higher than that of 1 and
the leaving group, 6-methoxy-1,3,5-triazine-2,4(1H,3H)-dione (13).
For this reason, it is considered that [11]0 was 5 mM and the [PF of
11]0 was 95 mM. Also, when the sum of [11] and the [PF of 11] was
95 mM or less, [11] was virtually 0 mM because 11 was completely
protonated by 95 mM of TfOH. Therefore, when the sum of [11] and
the [PF of 11] was 95 mM or less, it was estimated that [PF of 11] =
[11]obs, where [11]obs is the concentration of 11 observed in HPLC
analysis, and represents the sum of [11] and the [PF of 11].
(9) (a) Liang, X.; Zheng, W.; Wong, N.-B.; Li, J.; Tian, A. J. Mol.
Struct.: THEOCHEM 2004, 672, 151−159. (b) Liang, X.; Pu, X.;
Zhou, H.; Wong, N.-B.; Tian, A. J. Mol. Struct.: THEOCHEM 2007,
816, 125−136.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02059.
■
S
Kinetic study of O-benzylation with 10 and 11,
1
calibration curves for HPLC analysis, and H and 13C
(10) Jastrzabek, K.; Kolesinska, B.; Sabatino, G.; Rizzolo, F.; Papini,
A. M.; Kaminski, Z. J. Int. J. Pept. Res. Ther. 2007, 13, 229−236.
(11) Dudley, J. R.; Thurston, J. T.; Schaefer, F. C.; Holm-Hansen, D.;
Hull, C. J.; Adams, P. J. Am. Chem. Soc. 1951, 73, 2986−2990.
NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*Tel and Fax: (+81) 76-264-6201. E-mail: kunisima@p.
kanazawa-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS Research Fellowship for
Young Scientists (to H.F.).
■
REFERENCES
■
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F
DOI: 10.1021/acs.joc.5b02059
J. Org. Chem. XXXX, XXX, XXX−XXX