N,N′-Dimethylated Benzyloxytriazinedione: A Stable Solid Reagent for Acid-Catalyzed O-Benzylation

Article abstract of DOI:10.1002/ejoc.201601387

N,N′-Dimethylated 6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione (DMBOT) has been developed as a triazinedione-based, stable solid reagent for acid-catalyzed O-benzylation. The conceptual basis of the design was to fix the core triazinedione skeleton, and

Full text of DOI:10.1002/ejoc.201601387

A Journal of
Accepted Article
Title: N,N'-Dimethylated Benzyloxytriazinedione; A Stable Solid
Reagent for Acid-Catalyzed O-Benzylation
Authors: Hikaru Fujita, Satoshi Kakuyama, and Munetaka Kunishima
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601387
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10.1002/ejoc.201601387
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N,N'-Dimethylated Benzyloxytriazinedione: A Stable Solid
Reagent for Acid-Catalyzed O-Benzylation
Hikaru Fujita, Satoshi Kakuyama, and Munetaka Kunishima*[a]
Abstract:
N,N'-Dimethylated
6-(benzyloxy)-1,3,5-triazine-
(Bn+),
indicating
that
1,3,5-triazine-2,4(1H,3H)-dione
2,4(1H,3H)-dione (DMBOT) has been developed as a triazinedione-
based, stable solid reagent for acid-catalyzed O-benzylation. The
N,N'-dimethyl groups were introduced on the basis of the design
concept to fix the core triazinedione skeleton. The coproduct of
DMBOT can be easily removed by simple washing. Various acid- and
base-labile alcohols were O-benzylated using DMBOT in the
presence of an acid catalyst. In particular, 2,6-di-tert-butylpyridinium
(triazinedione) is a promising core skeleton. On the basis of these
findings, in this paper, we report the development of a new, highly
reactive acid-catalyzed O-benzylating reagent based on the
triazinedione skeleton.
trifluoromethanesulfonate, which is
a mild, stable, and non-
hygroscopic acid catalyst, can be utilized for the reaction of DMBOT.
Compared to other reported methods, DMBOT afforded better results
in several challenging O-benzylation under non-basic conditions.
Introduction
Owing to its stability and mild deprotection conditions, the benzyl
group is one of the most widely used alcohol-protecting groups.[1]
Since typical Williamson ether synthesis requires strongly basic
conditions,
trichloroacetimidate
several
reagents[2-4]
(BTCAI)[2]
such
and
as
benzyl
2-benzyloxy-1-
methylpyridinium trifluoromethanesulfonate (Dudley reagent)[3]
have been developed for O-benzylation under non-basic
conditions. However, the handling of BTCAI is not satisfactory
because it is a moisture- and heat-sensitive liquid.[5] Although
Dudley reagent is stable enough to use in air, its reaction requires
high temperatures (83−120 °C) to proceed. Therefore, the
development of a milder O-benzylation method using an easy-to-
handle reagent is still desirable.[6]
We previously reported a new acid-catalyzed O-benzylating
reagents, 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT, Figure 1),
which is a stable solid, and thus easy to handle.[7] The reaction
using TriBOT involves 4,6-bis(benzyloxy)-1,3,5-triazin-2(1H)-one
Figure 1. Desirable and undesirable pathways of acid-catalyzed O-benzylation
using MonoBOT.
Results and Discussion
(DiBOT)
and
6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
O-Benzylation of 3-phenyl-1-propanol (1a) proceeded with 98%
yield using MonoBOT (1.2 equiv) and TfOH (20 mol%) as an acid
catalyst (entry 1 in Table 1, the desirable pathway in Figure 1).[8]
Unfortunately, however, the use of milder acid catalysts resulted
in lower yields of the corresponding benzyl ether 2a (entries 2–5,
58–82%) with increased N-benzylated byproducts 3 and 4 (~28%
and ~39% based on MonoBOT, respectively). When we
monitored the time course of the reaction between 1a and
MonoBOT in the presence of TfOH (20 mol%), we found that
about 20% of MonoBOT was converted to DiBOT rapidly in the
early stage of the reaction (the undesirable pathway in Figure 1,
details in Figure S1 in Supporting information). This conversion
should be avoided because the reactivity of triazinone-based
DiBOT is lower than that of MonoBOT. Moreover, non-reactive
byproducts 3 and 4 can be formed via N-benzylated DiBOT (5).
(MonoBOT) as reaction intermediates, and both of which are also
capable of O-benzylation of alcohols.[8] Our recent study on the
reactivity of TriBOT, DiBOT, and MonoBOT, whose triazine core
skeletons are different from each other, revealed that MonoBOT
has the highest ability of the generation of benzyl cation species
[a]
Dr. H. Fujita, S. Kakuyama, Prof. Dr. M. Kunishima
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 for this article is given via a link at the end of
the document.
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Since the use of milder acid catalysts increases the side reaction,
O-benzylation with MonoBOT requires 20 mol% or more of TfOH.
However, if the skeleton of MonoBOT can be firmly fixed as the
triazinedione, the high reactivity of MonoBOT will be fully
exhibited. On the basis of this concept, we newly designed N,N'-
dimethylated benzyloxytriazinedione (DMBOT, Scheme 1). The
N,N'-dimethyl groups of DMBOT play the role of "an anchor" to fix
the core triazinedione scaffold, and thus they will block the
undesirable conversion of the core skeleton into the triazinone
caused by the two acidic protons of MonoBOT.
Initially, O-benzylation of 1a with DMBOT (1.2 equiv) was carried
out at room temperature in 1,4-dioxane (0.1 M) in the presence of
molecular sieves 5A (MS5A)[10] using TfOH as an acid catalyst
(Table 2). Product 2a was obtained in high yields in the presence
of 20, 10, and 5 mol% of TfOH (entries 1−3, 93−97%). These
results indicate that the N,N'-dimethyl groups of DMBOT
effectively suppressed the side reaction observed in the reaction
with MonoBOT. A similar result was observed when the substrate
concentration was increased from 0.1 M to 0.3 M (entry 2 vs 4,
respectively). Moreover, O-benzylation in the presence of only 1
mol% of TfOH at 60 °C was completed within 1.5 h (entry 5, 95%).
The use of other ethereal solvents (entry 6, DME; entry 7, a 1:1
mixture of Et2O/CH2Cl2) or other acid catalysts [entries 8−12,
TMSOTf, HBF4·Et2O, BF3·Et2O, Sc(OTf)3, and Cu(OTf)2,
respectively] were also effective (86−96%). It is worth noting that
Table 1. Acid-catalyzed O-benzylation of 1a using MonoBOT.
2,6-di-tert-butylpyridinium trifluoromethanesulfonate (6),
a
Entry
Acid catalyst
[mol%]
Time [h]
2a [%][a]
3 [%][a,b]
4 [%][a,b]
compound that can be considered as partially neutralized TfOH,
was also an efficient acid catalyst for DMBOT (entry 13, 97%). To
the best of our knowledge, although 6 is a stable, non-hygroscopic,
and easy-to-handle solid,[11] it has never been used as an acid
catalyst for O-benzylation of alcohols to date. In contrast to
DMBOT, TriBOT was inert to 6 (entry 14), suggesting a higher
reactivity of DMBOT when compared to that of TriBOT.
1[c]
2
TfOH [20]
1.5
5
98
82
79
73
58
7
3
[d]
[d]
TfOH [10]
−
−
3
TfOH [5]
9
15
28
13
8
4
Sc(OTf)3 [20]
BF3·Et2O [20]
24
4
13
39
5
Table 2. Screening of reaction conditions.
[a] Calculated from 1H NMR analysis using an internal standard. [b] Yields
based on benzyl groups (total 1.2 equiv = 120%). [c] Data from ref. 8. [d] Not
determined.
Entry
1
Acid catalyst [mol%]
TfOH [20]
Solvent
Time [h]
Yield [%][a]
1,4-dioxane[b]
1,4-dioxane[b]
1,4-dioxane[b]
1,4-dioxane[c]
1,4-dioxane[c]
DME[b]
1.5
5
96
2
TfOH [10]
93
3
TfOH [5]
9
97
4
TfOH [10]
4
97 (90)[d]
95
5[e]
6
TfOH [1]
1.5
6
TfOH [10]
92
[c]
7
TfOH [10]
Et2O/CH2Cl2
1,4-dioxane[b]
1,4-dioxane[c]
1,4-dioxane[c]
1,4-dioxane[c]
1,4-dioxane[c]
1,4-dioxane[c]
1,4-dioxane[c]
17
8
90
8
TMSOTf [10]
HBF4·Et2O [10]
BF3·Et2O [10]
Sc(OTf)3 [5]
Cu(OTf)2 [5]
6 [10]
96
9
9
91
10
11[e]
12[e]
13
14[f]
24
3
86
Scheme 1. Synthesis of DMBOT.
93
3
91
The N,N'-dimethylation of MonoBOT afforded DMBOT (Scheme
1, 90% yield). More conveniently, the one-pot MonoBOT
synthesis,[8] followed by N,N'-dimethylation, provided DMBOT
(72% yield) from inexpensive cyanuric chloride. DMBOT is a
stable crystalline solid, and thus it can be easily handled in air at
room temperature. MonoBOT has limitation of the reaction
solvents and the concentration, because its solubilities in aprotic
solvents were low probably due to the hydrogen-bonding ability
similar to isocyanuric acid.[9] In contrast, the solubilities of DMBOT
were successfully much improved (details in Table S1 in
Supporting Information).
6
97
6 [10]
6
<1
[a] Calculated from 1H NMR analysis using an internal standard. [b] The
substrate concentration was 0.1 M. [c] The substrate concentration was 0.3
M. [d] Isolated yield. [e] The reaction was conducted at 60 °C. [f] TriBOT (0.4
equiv) was used instead of DMBOT.
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A coproduct, N,N'-dimethylisocyanuric acid (7, Table 3), is formed
from DMBOT in a reaction[12] similar to that for trichloroacetamide
(8) from BTCAI, and N-methylpyridone from Dudley reagent.
Coproduct 7 can be removed by simple washing with a basic
aqueous solution, because unlike N-methylpyridone, 7 has an
acidic proton, with an acidity higher than that of 8.[13] When a
solution of 7 and 2a (0.5 mmol each) in EtOAc (20 mL) was
washed with saturated NaHCO3 (Table 3, entry 1) or 1% K2CO3
(entry 2), almost all of 7 (97% or >98%, respectively) was
successfully removed from 2a. In contrast, 8 could not be
removed by washing with these solutions (entries 3 and 4, 3% and
6%, respectively).[14] The easy removal of 7 greatly facilitates the
purification of the product.[15]
1
2
3.5
4
94
90
3
4
5
93
8.5
87[b]
5
16
96
Table 3. Removal of coproducts by washing.
6
7
15
13
91
90
Entry
Coproduct
Basic aqueous
solution
Recovered
2a [%][a]
Removed
coproduct [%]
1
2
3
4
7
7
8
8
sat. NaHCO3
1% K2CO3
99
99
98
98
97[b]
>98[b]
3[c]
8[c]
3
3
83
89
sat. NaHCO3
1% K2CO3
6[c]
9[c,d]
2i
[a] Calculated from 1H NMR analysis using an internal standard. [b]
Calculated based on yields of recovered 7 determined from 1H NMR analysis
using an internal standard. [c] Calculated based on isolated yields of
recovered 8.
[a] Isolated yield. [b] No racemization was observed. [c] The reaction was
conducted at 50 °C using DMBOT (1.5 equiv). [d] Acid catalyst 6 (10 mol%)
was used instead of TfOH.
To evaluate the usefulness of DMBOT, we conducted an O-
benzylation reactions between DMBOT and several alcohols
(Table 5).[16] These reactions did not proceed with high yields
when BTCAI or Dudley reagent was used. O-Benzylation of chiral
lactate ester 1j proceeded with 62−70% yield when BTCAI and
TfOH (entry 1, reported method) were utilized.[20,21] Furthermore,
triethyl citrate (1k) underwent O-benzylation with only 5% yield
when BTCAI and TfOH were used (entry 2, reported method). In
contrast, the reaction of 1j and 1k using DMBOT and TfOH,
proceeded to afford 88% (entry 1, without racemization) and 55%
(entry 2)[22] yields, respectively. No evidence of the desired
product (2l) was observed in the reaction of 1l with BTCAI and
TfOH (entry 3, reported method). However, 2l was successfully
obtained with 73% yield when DMBOT was used with 6 (entry
3).[23] The use of Dudley reagent for the O-benzylation of the acid-
labile tertiary alcohols 1m and 1n resulted in 59% and 44% yields
of 2m and 2n, respectively (entries 4 and 5, respectively; reported
method). Moreover, when DMBOT and 6 were used, the yields of
both 2m and 2n improved significantly (entries 4 and 5, 70% and
65% yields, respectively).
As shown in Table 4,[16] the reactions between primary alcohols
1b-e and DMBOT under the conditions of entry 4 in Table 2
provided benzyl ethers 2b-e in high yields (entries 1−4, 87−94%).
Neither the chloroalkyl group of 1c nor the ester moieties of 1d
and 1e were affected by the reaction. No racemization was
observed during the reaction of 1e. O-Benzylation of secondary
alcohols 1f and 1g and tertiary alcohols 1h and 1i resulted in good
yields (entries 5−8, 83−96%).[17] Interestingly, the use of 6 as a
catalyst slightly improved the yield from 83% to 89% in the
reaction with 1i (entry 8 vs 9), which tends to undergo an
elimination reaction under acidic conditions. This result suggests
that 6 is more suitable than TfOH for the O-benzylation of an acid-
labile alcohol.
Table 4. Acid-catalyzed O-benzylation using DMBOT.
Entry
Product
Time [h]
Yield [%][a]
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Table 5. Comparison of challenging O-benzylation using DMBOT, BTCAI, or Dudley Reagent.
Entry
1
Product
DMBOT [equiv]
1.2
Acid catalyst
TfOH
T [°C]
Time [h]
4
Yield [%][a]
88[b]
Reported method
50
BTCAI (1.2 equiv), TfOH (15 mol%),
cyclohexane/CH2Cl2, RT, 18 h, 62%[c]; BTCAI
(1.2
equiv),
TfOH
(20
mol%),
cyclohexane/CH2Cl2, RT, 2.5 h, 70%[d]
2
1.2
TfOH
50
11
55
BTCAI (1.2 equiv), TfOH (15 mol%),
cyclohexane/CH2Cl2, RT to 38 °C, 2.5 h, 5%[e]
3
4
2
2
6
6
RT
50
12
73
70
BTCAI (2 equiv), TfOH (50 mol%), RT, 2 h,
decomposition[f]
5.5
Dudley reagent (2 equiv), MgO (2 equiv),
PhCF3, 120 °C (MW), 20 min, 59%[g]
5
2
6
50
3
65
Dudley reagent (2 equiv), MgO (2 equiv),
PhCF3, 83 °C, 24 h, 44%[f]
[a] Isolated yield. [b] No racemization was observed. [c] Data from ref. 18. [d] Data from ref. 19. [e] Data from ref. 2c. [f] Data from ref. 3b. [g] Data from ref. 3f.
multiplicity: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad.
Chemical shifts for 13C NMR are reported in parts per million (δ) relative to
the solvent [CDCl3, δ 77.16; (CD3)2SO, δ 39.52]. IR spectra were recorded
on a Horiba FT-720 FREEXACT-II spectrophotometer and were reported
in wavenumbers (cm−1). Mass spectra were measured on JMS-T100TD
Conclusions
In conclusion, we have designed and synthesized DMBOT on the
basis of the concept of the triazinedione fixation with N,N'-
dimethyl groups. Owing to the fixed triazinedione skeleton,
DMBOT successfully showed high reactivity and suppressed
byproducts formation. Various alcohols with acid- and base-labile
functionalities were O-benzylated using DMBOT in the presence
of TfOH. Furthermore, an easy-to-handle organic salt 6, whose
acidity is weaker than TfOH, was also an effective acid catalyst
for DMBOT. In the challenging O-benzylation processes of
several alcohols, DMBOT gave better results than those of BTCAI
and Dudley reagent. DMBOT has high practicability because of
its favorable physical properties (i.e. high stability and solubility)
and the coproduct removability.
(DART-MS) and Micromass Zq2000 spectrometer (ESI-MS). Analytical
TLC was performed on Merck precoated analytical plates, 0.25 mm, silica
gel 60 F254. Preparative TLC separations were performed on Merck
analytical plates (0.50 or 1.0 mm) precoated with silica gel 60 F254. Flash
chromatography separations were performed on Kanto Chemical Silica
Gel 60 N (spherical, neutral, 40–100 mesh) unless otherwise noted.
Recycling preparative HPLC was performed with Japan Analytical Industry
LC-928 equipped with GPC columns Jaigel-1H and 2H. Reagents were
commercial grades and were used without any purification unless
otherwise noted. Dehydrated Et2O, DMSO and CH2Cl2 were purchased
from commercial sources. DME and 1,4-dioxane was purchased from
commercial sources and distilled over sodium metal before use.
MonoBOT[8] and 6[24] were prepared according to the reported procedure.
All reactions sensitive to oxygen or moisture were conducted under a
nitrogen atmosphere.
6-(Benzyloxy)-1,3-dimethyl-1,3,5-triazine-2,4(1H,3H)-dione (DMBOT)
Experimental Section
Synthesis from cyanuric chloride: To a solution of cyanuric chloride (368.8
mg, 2.00 mmol) and benzyl alcohol (0.31 mL, 3.0 mmol) in CH2Cl2 (4.00
mL) was added ethyldiisopropylamine (359 L, 2.06 mmol) at 0 °C. After
stirred for 1 h, the mixture was allowed to warm to RT. After stirred for
additional 1 h, the mixture was cooled to 0 °C. Sodium acetate (492.2 mg,
6.00 mmol), isopropyl alcohol (4.00 mL), and N-methylmorpholine (110 L,
General methods: NMR spectra were determined on a JEOL JNM-
ECS400 spectrometer [1H NMR (400 MHz), 13C NMR (100 MHz)] or a
JEOL JNM-ECA600 [1H NMR (600 MHz), 13C NMR (150 MHz)]. 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
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1.00 mmol) was added at 0 °C. The mixture was stirred for 1 h at 0 °C and
for 1 h at RT. After aqueous HCl (6 M, 0.33 mL) was added at 0 °C, the
mixture was concentrated under reduced pressure. The residue was
washed with cold water. Cesium carbonate (1.95 g, 6.00 mmol), DMSO
(4.00 mL), and methyl iodide (374 L, 6.00 mmol) was added at RT. After
stirred for 40 min, the mixture was diluted with EtOAc (20 mL) and washed
with water (40 mL) and brine (20 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/acetone = 2:1)
to afford DMBOT (358.0 mg, 72%) as a crystalline solid.
1H NMR (400 MHz, CDCl3):  = 7.37–7.25 (m, 5H), 4.58 (s, 2H), 3.77 (t, J
= 6.0 Hz, 2H), 3.72–3.67 (m, 2H), 3.66–3.61 (m, 4H); 13C NMR (100 MHz,
CDCl3):  = 138.2, 128.5, 127.9, 127.8, 73.5, 71.5, 70.9, 69.5, 42.9 LRMS
(DART): m/z 215 ([M+H]+).
1-Acetoxy-10-(benzyloxy)decane (2d):[7a] To a solution of 1d (86.5 mg,
0.400 mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (6.7 mg) in 1,4-
dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol) at RT.
After stirred for 5 h, the reaction mixture was diluted with EtOAc (10 mL),
filtered to remove MS5A. The filtrate was washed with sat. aqueous
NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column
Synthesis from MonoBOT: To a suspension of MonoBOT (109.6 mg, 0.500
mmol) and cesium carbonate (358 mg, 1.10 mmol) in DMSO (1.00 mL)
was added methyl iodide (68.5 L, 1.10 mmol) at RT. After stirred for 40
min, the reaction mixture was diluted with EtOAc (10 mL) and washed with
water (30 mL × 2) and brine (30 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/EtOAc = 1:1) to
afford DMBOT (111.2 mg, 90%) as a crystalline solid. M.p. 109–110 °C;
1H NMR (400 MHz, CDCl3):  = 7.47–7.37 (m, 5H), 5.49 (s, 2H), 3.37 (s,
3H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3):  = 158.9, 154.6, 151.2,
134.0, 129.2, 128.9, 128.8, 71.8, 29.4, 29.3; IR (KBr): 3060, 2956, 1739,
1671, 1616, 1600, 1583, 1500, 1435, 1225; HRMS (DART): m/z: Calcd for
C12H14N3O3 ([M+H]+): 248.1035, Found: 248.1051; elemental analysis
calcd (%) for C12H13N3O3: C 58.29, H 5.30, N 17.00; found: C 58.23, H
5.48, N 17.02.
chromatography (hexane/EtOAc
=
9:1) and preparative TLC
(hexane/EtOAc= 9:1) to afford 2d (114.1 mg, 93%) as a clear colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.40–7.23 (m, 5H), 4.50 (s, 2H), 4.05 (t, J
= 6.6 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.05 (s, 3H), 1.67–1.55 (m, 4H),
1.40–1.23 (m, 12H); 13C NMR (100 MHz, CDCl3):  = 171.4, 138.8, 128.5,
127.8, 127.6, 73.0, 70.6, 64.8, 29.9, 29.62, 29.58, 29.4, 28.7, 26.3, 26.0,
21.2; LRMS (DART): m/z 307 ([M+H]+).
Methyl (2R)-3-(benzyloxy)-2-methylpropionate (2e):[27] To a solution of
1e (44.2 μL, 0.400 mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (6.7
mg) in 1,4-dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol)
at RT. After stirred for 8.5 h, the reaction mixture was diluted with EtOAc
(10 mL), filtered to remove MS5A. The filtrate was washed with sat.
aqueous NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/EtOAc = 19:1) to afford 2e (72.4 mg,
Benzyl 3-phenylpropyl ether (2a):[25] To a mixture of 1a (54.5 L, 0.400
mmol), DMBOT (118.7 mg, 0.480 mmol), and MS5A (6.7 mg) in 1,4-
dioxane (1.33 mL) was added TfOH (3.5 L, 0.040 mmol) at RT. After
stirred for 4 h, the reaction mixture was quenched with pyridine (32.0 L),
diluted with EtOAc (20 mL), and filtered to remove MS5A. The filtrate was
washed with 1% (w/w) aqueous K2CO3 (10 mL) and brine (10 mL), dried
over Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/EtOAc = 9:1)
followed by recycling preparative HPLC to afford 2a (81.0 mg, 90%) as a
clear colorless oil. 1H NMR (400 MHz, CDCl3):  = 7.39–7.12 (m, 10H),
4.51 (s, 2H), 3.49 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 7.8 Hz, 2H), 1.94 (tt, J =
6.4, 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):  = 142.1, 138.7, 128.6,
128.5, 128.4, 127.8, 127.7, 125.9, 73.1, 69.6, 32.5, 31.5; LRMS (DART):
m/z 227 ([M+H]+).
1
87%) as a clear colorless oil. H NMR (400 MHz, CDCl3):  = 7.37–7.23
(m, 5H), 4.52 (s, 2H), 3.70 (s, 3H), 3.66 (dd, J = 7.3, 9.2 Hz, 2H), 3.49 (dd,
J = 5.5, 9.2 Hz, 1H), 2.85–2.73 (m, 1H), 1.18 (d, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3):  = 175.5, 138.3, 128.5, 127.74, 127.71, 73.2, 72.1,
51.9, 40.3, 14.1; LRMS (DART): m/z 209 ([M+H]+).
(1R, 2S, 5R)-(−)-O-Benzylmenthol (2f):[28] To a solution of 1f (62.5 mg,
0.400 mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (6.7 mg) in 1,4-
dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol) at RT.
After stirred for 16 h, the reaction mixture was quenched with pyridine (16.0
µL), diluted with EtOAc (10 mL) and filtered to remove MS5A. The filtrate
was washed with sat. aqueous NaHCO3 (10 mL) and brine (10 mL), dried
over Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/CHCl3 = 3:1) to
Benzyl 2-(2-methoxyethoxy)ethyl ether (2b):[26] To a solution of 1b (47.1
µL, 0.400 mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (6.7 mg) in
1,4-dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol) at RT.
After stirred for 3.5 h, the reaction mixture was quenched with pyridine
(32.0 µL), diluted with EtOAc (10 mL) and filtered to remove MS5A. The
filtrate was washed with water (10 mL) and brine (10 mL), dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/acetone = 4:1) to
afford 2b (79.0 mg, 94%) as a clear colorless oil. 1H NMR (400 MHz,
CDCl3):  = 7.40–7.20 (m, 5H), 4.57 (s, 2H), 3.70–3.60 (m, 6H), 3.58–3.53
(m, 2H), 3.39 (s, 3H);13C NMR (100 MHz, CDCl3):  = 138.4, 128.5, 127.9,
127.7, 73.4, 72.1, 70.8, 70.7, 69.6, 59.2; LRMS (DART): m/z 211 ([M+H]+).
afford 2f (94.5 mg, 96%) as a clear colorless oil. H NMR (400 MHz,
1
CDCl3):  = 7.46–7.15 (m, 5 H), 4.66 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5
Hz, 1H), 3.17 (td, J = 4.1, 10.6 Hz, 1H), 2.40–2.24 (m, 1H), 2.24–2.11 (m,
1H), 1.72–1.58 (m, 2H), 1.45–1.22 (m, 2H), 1.11–0.77 (m, 1H), 0.93 (d, J
= 6.9 Hz, 3H), 0.89 (d, J = 7.3 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3):  = 139.3, 128.4, 128.0, 127.5, 78.9, 70.6, 48.5, 40.4,
34.7, 31.7, 25.6, 23.2, 22.5, 21.2, 16.2; LRMS (DART): m/z 247 ([M+H]+).
Benzyl 1-phenylethyl ether (2g):[7a] To a solution of 1g (48.4 μL, 0.400
mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (33.3 mg) in 1,4-
dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol) at RT.
After stirred for 15 h, the reaction mixture was quenched with pyridine (32.0
µL), diluted with EtOAc (10 mL) and filtered to remove MS5A. The filtrate
was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/Et2O/EtOAc = 47:2:1) and recycling
preparative HPLC to afford 2g (77.2 mg, 91%) as a clear colorless oil. 1H
NMR (400 MHz, CDCl3):  = 7.40–7.23 (m, 10H), 4.50 (q, J = 6.4 Hz, 1H),
4.45 (d, J = 11.9 Hz, 2H), 4.30 (d, J = 11.9 Hz, 2H), 1.48 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3):  = 143.8, 138.8, 128.6, 128.5, 127.9,
127.7, 127.6, 126.5, 77.4, 70.4, 24.4; LRMS (DART): m/z 213 ([M+H]+).
Benzyl 2-(2-chloroethoxy)ethyl ether (2c):[7a,26] To a solution of 1c (42.2
μL, 0.400 mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (6.7 mg) in
1,4-dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol) at RT.
After stirred for 4 h, the reaction mixture was diluted with EtOAc (10 mL),
and filtered to remove MS5A. The filtrate was washed with sat. aqueous
NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc
=
17:3) and preparative TLC
(hexane/EtOAc = 4:1) to afford 2c (76.9 mg, 90%) as a clear colorless oil.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601387
European Journal of Organic Chemistry
FULL PAPER
1-Adamantyl benzyl ether (2h):[3b] To a solution of 1h (60.9 mg, 0.400
mmol), DMBOT (118.7 mg, 0.480 mmol) and MS5A (33.3 mg) in 1,4-
dioxane (1.33 mL, 0.3 M) was added TfOH (3.5 µL, 0.040 mmol) at RT.
After stirred for 13 h, the reaction mixture was quenched with pyridine (32.0
µL), diluted with EtOAc (10 mL) and filtered to remove MS5A. The filtrate
was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/acetone = 97:3) and preparative TLC
(hexane/acetone = 30:1) to afford 2h (87.2 mg, 90%) as a colorless oil. 1H
NMR (400 MHz, CDCl3):  = 7.40–7.16 (m, 5H), 4.51 (s, 2H), 2.18 (s, 3H),
1.91–1.80 (m, 6H), 1.71-1.59 (m, 6H); 13C NMR (100 MHz, CDCl3):  =
140.3, 128.4, 127.6, 127.2, 72.9, 62.4, 41.9, 36.6, 30.7 LRMS (DART): m/z
243 ([M+H]+).
diluted with EtOAc (5 mL) and filtered to remove MS5A. The filtrate was
washed with 1% (w/w) aqueous K2CO3 (5 mL) and brine (5 mL), dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by preparative TLC (hexane/acetone = 40:1) to afford 2l (45.8 mg,
1
73%) as a clear colorless oil. H NMR (400 MHz, CDCl3):  = 7.37–7.23
(m, 5H), 4.49 (s, 2H), 3.58 (t, J = 8.1 Hz, 2H), 1.00 (t, J = 8.1 Hz, 2H), 0.02
(s, 9H); 13C NMR (100 MHz, CDCl3):  = 138.9, 128.5, 127.7, 127.5, 72.5,
67.8, 18.4, −1.2; LRMS (ESI): m/z 231 ([M+Na]+).
Benzyl 2-methylbut-3-yn-2-yl ether (2m):[3f] To a mixture of 1m (29.2 μL,
0.300 mmol), DMBOT (148.4 mg, 0.600 mmol), and MS5A (5.0 mg) in 1,4-
dioxane (1.00 mL, 0.3 M) was added 6 (10.2 mg, 0.030 mmol) at RT. The
reaction mixture was heated to 50 °C for 5.5 h. After cooled to RT, the
reaction mixture was quenched with NEt3 (6.3 µL), diluted with EtOAc (5
mL) and filtered to remove MS5A. The filtrate was washed with 1% (w/w)
aqueous K2CO3 (5 mL) and brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/acetone = 40:1) to afford 2m (36.3 mg, 70%) as
a clear colorless oil. 1H NMR (600 MHz, CDCl3):  = 7.39–7.30 (m, 4H),
7.29–7.23 (m, 1H), 4.64 (s, 2H), 2.47 (s, 1H), 1.56 (s, 6H); 13C NMR (150
MHz, CDCl3):  = 139.0, 128.4, 127.9, 127.5, 86.2, 72.4, 70.6, 66.7, 29.0;
LRMS (DART): m/z 175 ([M+H]+).
Benzyl 2-methyl-4-phenylbutan-2-yl ether (2i):[4k] To a mixture of 1i
(51.0 μL, 0.300 mmol), DMBOT (111.3 mg, 0.450 mmol), and MS5A (5.0
mg) in 1,4-dioxane (1.00 mL, 0.3 M) was added 6 (10.2 mg, 0.030 mmol)
at RT. The reaction mixture was heated to 50 °C for 3 h. After cooled to
RT, the reaction mixture was quenched with NEt3 (6.3 µL), diluted with
EtOAc (5 mL) and filtered to remove MS5A. The filtrate was washed with
1% (w/w) aqueous K2CO3 (5 mL) and brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/acetone
=
40:1) followed by recycling
1
Benzyl 2-phenylpropan-2-yl ether (2n):[3b] To a mixture of 1n (40.9 mg,
0.300 mmol), DMBOT (148.4 mg, 0.600 mmol), and MS5A (5.0 mg) in 1,4-
dioxane (1.00 mL, 0.3 M) was added 6 (10.2 mg, 0.030 mmol) at RT. The
reaction mixture was heated to 50 °C for 3 h. After cooled to RT, the
reaction mixture was quenched with NEt3 (6.3 µL), diluted with EtOAc (5
mL) and filtered to remove MS5A. The filtrate was washed with 1% (w/w)
aqueous K2CO3 (5 mL) and brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/acetone = 40:1) to afford 2n (43.8 mg, 65%) as
preparative HPLC to afford 2i (67.6 mg, 89%) as a clear colorless oil. H
NMR (400 MHz, CDCl3):  = 7.41–7.14 (m, 10H), 4.47 (s, 2H), 2.76–2.69
(m, 2H), 1.93–1.84 (m, 2H), 1.33 (s, 6H); 13C NMR (100 MHz, CDCl3):  =
143.0, 139.9, 128.50, 128.47, 128.45, 127.4, 127.3, 125.8, 75.1, 63.8, 42.6,
30.5, 25.9; LRMS (DART): m/z 255 ([M+H]+).
Ethyl (2S)-(benzyloxy)propanoate (2j):[4k] To a solution of 1j (34.1 μL,
0.300 mmol), DMBOT (89.0 mg, 0.360 mmol) and MS5A (15.0 mg) in 1,4-
dioxane (1.00 mL, 0.3 M) was added TfOH (2.6 µL, 0.030 mmol) at RT.
The reaction mixture was heated to 50 °C for 4 h. After cooled to RT, the
reaction mixture was diluted with EtOAc (20 mL), filtered to remove MS5A.
The filtrate was washed with sat. aqueous NaHCO3 (20 mL) and brine (20
mL), dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/EtOAc=
19:1) and preparative TLC (hexane/EtOAc = 19:1 × 2) to afford 2j (54.7
1
a clear colorless oil. H NMR (600 MHz, CDCl3):  = 7.52−7.48 (m, 2H),
7.40−7.20 (m, 8H), 4.24 (s, 2H), 1.64 (s, 6H); 13C NMR (150 MHz, CDCl3):
 = 146.3, 139.5, 128.43, 128.41, 127.6, 127.3, 127.1, 126.0, 77.3, 65.2,
28.7; LRMS (ESI): m/z 249 ([M+Na]+).
N,N'-Dimethylisocyanuric acid (7):[29] Crystalline solid; 1H NMR [400
MHz, (CD3)2SO]:  = 11.6 (br s, 1H), 3.10 (s, 6H); 13C NMR [100 MHz,
(CD3)2SO]:  = 150.5, 149.0, 28.1; LRMS (DART): m/z 158 ([M+H]+).
1
mg, 88%) as a clear colorless oil. H NMR (400 MHz, CDCl3):  = 7.40–
7.22 (m, 5H), 4.70 (d, J = 11.4 Hz, 1H), 4.45 (d, J = 11.4 Hz, 1H), 4.29–
4.15 (m, 2H), 4.05 (q, J = 6.9 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H), 1.30 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):  = 173.4, 137.7, 128.6, 128.1,
128.0, 74.2, 72.1, 61.0, 18.9, 14.4; LRMS (DART-MS): m/z 209 ([M+H]+).
1
2,2,2-Trichloroacetamide (8):[30] Crystalline solid; H NMR (600 MHz,
CDCl3):  = 6.58 (br s, 1H), 5.81 (br s, 1H); 13C NMR [100 MHz, (CD3)2SO]:
 = 163.0, 93.1; LRMS (DART): m/z 163 ([M+H]+).
2-Benzyloxy-1,2,3-propanetricarboxylic acid triethyl ester (2k):[2c] To
a solution of 1k (96.9 μL, 0.400 mmol), DMBOT (118.7 mg, 0.480 mmol)
and MS5A (33.3 mg) in 1,4-dioxane (1.33 mL, 0.3 M) was added TfOH (3.5
µL, 0.040 mmol) at RT. The reaction mixture was heated to 50 °C for 11 h.
After cooled to RT, the reaction mixture was diluted with EtOAc (10 mL),
filtered to remove MS5A. The filtrate was washed with 1%(w/w) aqueous
K2CO3 (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column
Acknowledgements
This work was supported by JSPS Research Fellowship for
Young Scientists (to H.F.), and partially supported by JSPS
KAKENHI Grant Numbers 26293003 and 26670001.
chromatography (hexane/EtOAc
= 4:1) and followed by recycling
preparative HPLC to afford 2k (80.1 mg, 55%) as a clear colorless oil. 1H
NMR (400 MHz, CDCl3):  = 7.42–7.15 (m, 5H), 4.58 (s, 2H), 4.24 (q, J =
7.2 Hz, 2H), 4.14 (q, J = 7.1 Hz, 4H), 3.25 (d, J = 15.6 Hz, 2H), 3.09 (d, J
= 15.6 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3):  = 170.7, 170.0, 137.8, 128.4, 127.8, 127.7, 78.9, 66.9,
61.8, 60.9, 39.5, 14.3; LRMS (DART): m/z 367 ([M+H]+).
Keywords: nitrogen heterocycles • alcohols • protecting groups
• alkylation • synthetic methods
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P. G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, John
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Commun. 1981, 1240-1241; b) H.-P. Wessel, T. Iversen, D. R. Bundle,
Benzyl 2-(trimethylsilyl)ethyl ether (2l):[6] To a mixture of 1l (36.7 μL,
0.300 mmol), DMBOT (148.4 mg, 0.600 mmol), and MS5A (5.0 mg) in 1,4-
dioxane (1.00 mL, 0.3 M) was added 6 (10.2 mg, 0.030 mmol) at RT. After
stirred for 12 h, the reaction mixture was quenched with NEt3 (6.3 µL),
J. Chem. Soc. Perkin Trans. 1 1985, 2247-2250; c)
U.
Widmer,
Synthesis 1987, 568-570; d) P. Eckenberg, U. Groth, T. Huhn, N. Richter,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601387
European Journal of Organic Chemistry
FULL PAPER
C. Schmeck, Tetrahedron 1993, 49, 1619-1624; e) H. S. Jensen, G.
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K. T. Howard, B. C. Duffy, M. R. Linaburg, J. D. Chisholm, Org. Biomol.
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For Dudley reagent, see: a) K. W. C. Poon, S. E. House, G. B. Dudley,
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[16] The benzyl groups introduced in the reaction are indicated in bold and
italic face in Tables 4 and 5.
[4]
For other reagents for O-benzylation under non-basic conditions, see: a)
R. U. Lemieux, T. Kondo, Carbohydr. Res. 1974, 35, C4-C6; b) J. M.
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[17] O-Benzylation of secondary and tertiary alcohols 2f-i with DMBOT
proceeded at a slower rate than that of primary alcohols 2a-e. The reason
for this is unclear at present.
[18] F. Sakai, N. Seki, Y. Tenda, H. Yamazaki, C. Miyamoto, M. Kuno, H.
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and a) Y. Ito, Y. Kobayashi, T. Kawabata, M. Takase, S. Terashima,
Tetrahedron 1989, 45, 5767-5790; b) R. Riclea, B. Aigle, P. Leblond, I.
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[21] It has been reported that methyl (R)-lactate, a chiral ester similar to 1j,
was O-benzylated with 79% yield when Dudley reagent (3 equiv,
prepared in situ) was used (ref. 3d).
[22] The 1H NMR spectra of the crude products contained a considerable
number of diarylmethylene peaks (3.9−4.1 ppm), suggesting that the O-
benzylation of 1k was in competition with Friedel-Crafts benzylation at
the benzyl group of 2k.
[5]
[6]
Encyclopedia of Reagents for Organic Synthesis, Vol.
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2 (Ed.: L.
We
recently
reported
4-(4,6-diphenoxy-1,3,5-triazin-2-yl)-4-
[23] The reaction of 1l with Dudley reagent was reported to proceed to
complete conversion with no evidence of decomposition. However, the
yield was not reported (ref. 3b)
benzylmorpholinium trifluoromethanesulfonate (DPT-BM) as a stable
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TriBOT was designed based on the concept that the formal trimerization
of the smallest unit of benzyl imidate leads to a triazine-based alkylating
reagent. See: a) K. Yamada, H. Fujita, M. Kunishima, Org. Lett. 2012, 14,
5026-5029; b) K. Yamada, S. Yoshida, H. Fujita, M. Kitamura, M.
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H. Fujita, M. Kitamura, M. Kunishima, Synthesis 2013, 45, 2989-2997; d)
K. Yamada, N. Hayakawa, H. Fujita, M. Kitamura, M. Kunishima, Eur. J.
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[8]
[9]
H. Fujita, N. Hayakawa, M. Kunishima, J. Org. Chem. 2015, 80, 11200-
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[10] Addition of powdered MS5A as a dehydrating agent decreased formation
of dibenzyl ether, which probably derives from residual moisture (ref. 7a).
Nevertheless, in some cases, repeated purification with recycling
preparative HPLC or preparative TLC was necessary to complete
removal of a trace amount of dibenzyl ether from a product.
[11] A. Zhdanko, M. E. Maier, ACS Catal. 2014, 4, 2770-2775.
[12] The coproduct 7 was isolated in 94% yield (based on DMBOT) under the
reaction conditions of entry 4 in Table 2.
[13] The pKa values of 8 were reported as 11.2 and 12. a) T. J. Donohoe, C.
J. R. Bataille, P. Innocenti, Org. React. 2012, 76, 1-48; b) B. C. Duffy, K.
T. Howard, J. D. Chisholm, Tetrahedron Lett. 2015, 56, 3301-3305. The
acidity of 7 would be similar to that of isocyanuric acid (pKa of 6.85 for
the first deprotonation). For the pKa value of isocyanuric acid, see: S.
Aoki, M. Shiro, T. Koike, E. Kimura, J. Am. Chem. Soc. 2000, 122, 576-
584.
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10.1002/ejoc.201601387
European Journal of Organic Chemistry
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Title
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Benzylating Reagent
H. Fujita, S. Kakuyama, M. Kunishima*
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N,N'-Dimethylated
Benzyloxytriazinedione: A Stable
Solid Reagent for Acid-Catalyzed O-
Benzylation
A triazinedione-based acid-catalyzed O-benzylating reagent, DMBOT, has been
developed. The fixation of the triazinedione skeleton of DMBOT with N,N'-dimethyl
groups as "an anchor" was essential to mild reaction conditions and high yields of
benzyl ethers. DMBOT has high practicability because (1) it is a stable solid in air at
room temperature, and (2) the coproduct can be easily removed by simple washing.
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