Development of triazine-based benzylating reagents possessing T-butyl group on the triazine core: Thermally controllable reagents for the initiation of reaction

Article abstract of DOI:10.1248/cpb.c17-00897

Benzylating reagents, 4-(4,6-di-t-butyl-1,3,5-triazin-2-yl)-4-benzylmorpholinium triflate, and related derivatives have been developed. The reagents release benzyl triflate as a benzyl cation equivalent upon heating the solution to 40°C under neutral conditions. The O-benzylation of alcohols using a stoichiometric amount of these reagents afforded corresponding benzyl ethers in good to high yields. This was due to the presence of a bulky t-butyl group on the triazine ring of these reagents that prevents the consumption of benzyl triflate via a side reaction with a morpholinotriazine derivative.

Full text of DOI:10.1248/cpb.c17-00897

Vol. 66, No. 3
Chem. Pharm. Bull. 66, 303–308 (2018)
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Regular Article
Highlighted Paper selected by Editor-in-Chief
Development of Triazine-Based Benzylating Reagents Possessing t-Butyl
Group on the Triazine Core: Thermally Controllable Reagents for the
Initiation of Reaction
Yukiko Karuo, Kohei Yamada, and Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa
University; Kakuma-machi, Kanazawa, Ishikawa 920–1192, Japan.
Received November 7, 2017; accepted December 8, 2017
Benzylating reagents, 4-(4,6-di-t-butyl-1,3,5-triazin-2-yl)-4-benzylmorpholinium triflate, and related de-
rivatives have been developed. The reagents release benzyl triflate as a benzyl cation equivalent upon heating
the solution to 40°C under neutral conditions. The O-benzylation of alcohols using a stoichiometric amount
of these reagents afforded corresponding benzyl ethers in good to high yields. This was due to the presence
of a bulky t-butyl group on the triazine ring of these reagents that prevents the consumption of benzyl tri-
flate via a side reaction with a morpholinotriazine derivative.
Key words benzylating reagent; triazine; thermally controllable
The benzyl group is a protecting group for alcohols that is ing nucleophilic property of morpholinotriazine (Y-a), a co-
stable under strong acidic and basic conditions, and its de- product arising from DPT-BM (X-a), because it consumes
protection is easily achieved via hydrogenolysis under mild BnOTf to form a regioisomeric N-benzyl triazinium salt (Z-a)
conditions. Therefore, the benzyl group has been used for as a byproduct, which no longer acts as a benzylating reagent
several organic synthetic reactions and various benzylation under the reaction conditions. Although Y-a is less nucleo-
methods have been developed.1,2) Recently, we have devel- philic, the side reaction proceeds at the most nucleophilic site
oped several alkylating reagents based on the characteris- of the triazine nitrogen owing to the high electrophilicity of
tics of 1,3,5-triazine. 2,4,6-Tris(benzyloxy)-1,3,5-triazine BnOTf. Thus, an excess of DPT-BM (X-a) (>2.0 equiv.) is
(TriBOT),3,4)
2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine required to obtain benzyl ethers in good yields. Despite its salt
(TriBOT-PM),5) 6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione structure, the solubility of the DPT-BM (X-a) in dimethoxy-
(MonoBOT),6,7) 2,4,6-tris(t-butoxy)-1,3,5-triazine (TriAT- ethane (DME) is higher than that of the non-charged Y-a (the
tBu),8) 2,4,6-tris(allyloxy)-1,3,5-triazine (TriAT-allyl),9) and saturation solubility in DME: 0.12mol/L). By exploiting this
N,N′-dimethylated
6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)- property, the production of byproduct Z-a can be reduced by
dione (DMBOT)10) achieve the alkylation of various alcohols performing the reaction in a high concentration of alcohols.
in good to excellent yields in the presence of a catalytic Since a significant amount of Y-a is precipitated, the relative
amount of an acid. 4-(4,6-Diphenoxy-1,3,5-triazin-2-yl)-4-ben- concentration of Y-a is decreased compared with that of the
zylmorpholinium triflate (DPT-BM (X-a))11,12) converts acid- alcohols. This results in relatively increasing the benzylation
or alkali-labile alcohols into corresponding benzyl ethers rate of the alcohols compared to that of Y-a. However, such
because of the nearly neutral conditions (Fig. 1).
conditions are not suitable for alcohols exhibiting a low re-
DPT-BM (X-a) has several advantages compared with other activity or a low solubility in DME. When the O-benzylation
representative benzylating reagents, such as benzyl triflate of a sterically hindered alcohol (1a) with DPT-BM (X-a) (1.2
(BnOTf)13) and 2-benzyloxy-1-methylpyridinium triflate (Dud- equiv.) in the presence of MS5A, which was used as a dehy-
ley reagent),14–18) available under neutral conditions. DPT-BM drating reagent to remove residual moisture, was performed at
(X-a) is a non-hygroscopic and stable solid, allowing its treat- concentrations of 1.0 and 0.2mol/L, the yields of 2a were in-
ment under atmospheric conditions. This reagent has a good sufficient (86 and 76%), although a better result was obtained
reactivity and can release BnOTf as a benzyl cation species when a higher concentration of 1a was used (Table 1, entries
at room temperature, when dissolved in solvents. However, 1, 2).
one major drawback of DPT-BM (X-a) is a slightly remain-
We envisioned that increasing steric hindrances around the
Fig. 1. The Benzylation with DPT-BM (X-a) Proceeds under Nearly Neutral Conditions
*To whom correspondence should be addressed. e-mail: kunisima@p.kanazawa-u.ac.jp
© 2018 The Pharmaceutical Society of Japan

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Table 1. O-Benzylation of Sterically Hindered Alcohol 1a with Benzylating Reagent X
Entry
X
Conc. of 1a [mol/L]
Time [h]
Temp. [°C]
Yield of 2a [%]a)
Yield of Z [%]a)
1
2
3
4
5
6
X-a
X-a
X-b
X-b
X-c
X-d
1.0
0.2
0.2
0.2
0.2
0.2
2
2
rt
rt
86
76
93
93
92
93
22 (Z-a)
29 (Z-a)
0 (Z-b)
0 (Z-b)
1 (Z-c)
0 (Z-d)
56
4
rt
40
40
40
4
4
a) Yields were calculated by 1H-NMR analysis using an internal standard.
Chart 1. The Synthetic Scheme of the New Benzylating Reagent (X-b)
nitrogen atoms on the triazine ring might prevent the forma- liberation of the benzyl cation species, BnOTf, from X-b was
tion of N-benzyltriazinium compounds that correspond to Z-a. slower than that from DPT-BM (X-a) due to the replacement
In this paper, we report the development of a new benzylating of electron-withdrawing phenoxy groups with the electron-
reagent (X-b) that was designed by replacing the two phenoxy donating t-butyl groups, which would decrease the leaving
groups of DPT-BM (X-a) with a sterically bulky t-butyl group. ability of Y-b. Heating at 40°C shortened the reaction time to
The benzylating reagent, X-b, was prepared according to 4h and improved the yield to 93% (entry 4).
the procedure shown in Chart 1. The copper-catalyzed cross-
To accelerate the O-benzylating reaction with X-b, we in-
coupling of t-butyl magnesium chloride with cyanuric chloride vestigated the optimal conditions using primary alcohol, 1b,
afforded 2,4-di-t-butyl-6-chloro-1,3,5-triazine (3),19) which was as a model alcohol (Table 2). Under the same condition as in
converted into 2,4-di-t-butyl-6-trifluoromethanesulfonyloxy- Table 1, entry 3, the reaction was slow and required 56h for
1,3,5-triazine (5) via 4,6-di-t-butyl-1,3,5-triazin-2(1H)-one its completion (entry 1). Despite the addition of a catalytic
(4) using our original method.6,7,10,20) The treatment of 5 with amount of triflic acid to activate X-b, the reaction time could
N-benzylmorpholine in Et2O afforded 4-(4,6-di-t-butyl-1,3,5- not be reduced (entry 2). When the reaction was conducted at
triazin-2-yl)-4-benzylmorpholinium triflate (X-b) as a precipi- 40°C, 1b completely disappeared within 5h, and product 2b
tate in 89% yield.
was afforded in 95% yield (entry 3). Moreover, the reaction
To compare the benzylating ability of X-b with that of at 60°C completed within 1h (entry 4). Compared with entry
DPT-BM (X-a), the benzylation of 1a was performed under 3, when the reaction was performed at a higher concentra-
the same condition shown in Table 1, entry 2. As a result, the tion, the yield of 2b decreased and a longer reaction time
reaction proceeded to afford 2a in 93% yield, and the gen- was required (entry 5).21) The yield of 2b decreased to 80%
eration of the corresponding N-benzyltriazinium Z-b was not in CH2Cl2 (entry 6), whereas high yields were maintained in
detected probably because the introduction of bulky t-butyl ethereal solvents such as 1,4-dioxane and diglyme (entries 7,
groups to the triazine ring prevented the Z-b formation (Table 8).
1, entry 3). However, the completion of benzylation required a
We examined the scope and limitations of various alcohols
longer time than Table 1, entry 2. This would be because the for the benzylation using X-b at optimal conditions mentioned

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Table 2. The Screening of the Benzylation of Primary Alcohol 1b Using X-b
Entry
Solvent
Additive
Temp. [°C]
Time [h]
Yield [%]a)
1
DME
DME
MgO (1.2 equiv.)
TfOH (1mol%)
rt
56
54
5
91
81
95
97
89
80
95
96
2
rt
3
DME
MgO (1.2 equiv.)
MgO (1.2 equiv.)
MgO (1.2 equiv.)
MgO (1.2 equiv.)
MgO (1.2 equiv.)
MgO (1.2 equiv.)
40
60
40
40
40
40
4
5b)
DME
1
DME
28
24
10
9.5
6
CH2Cl2
1,4-Dioxane
Diglyme
7
8
a) Yields were calculated by 1H-NMR analysis using an internal standard. b) The reaction was performed in 1.0mol/L DME solution of 1b.
in the entries 3, 4 in Table 2. The results are summarized in respectively (Chart 2[A]). A similar reaction was conducted
Table 3. For comparison, the yields using DPT-BM (X-a) or in the absence of Y-a because the relative nucleophilicities of
Dudley reagent that were reported in the literature are also Y-b, Y-c, and Y-d were ambiguous owing to the low yields of
listed. The benzylation of simple primary alcohols, 1b and 1c, Z-b, Z-c, and Z-d, which result from the high nucleophilicity
proceeded in high yields (entries 1, 2). Bulky secondary and of Y-a. As a result, Z-b, Z-c, and Z-d were formed in a ratio
tertiary alcohols, 1a and 1d–f, were converted into their cor- of 0:77:23, respectively (Chart 2[B]). To conduct the reaction
responding benzyl ethers in >80% yields which are compa- in the presence of one equivalent of Y-b, other benzylating
rable to those using DPT-BM (X-a) (entries 3, 5, 7, 9). When reagents were used instead of X-b. The reaction employing
the reaction temperature was increased to 60°C, the reactions DPT-BM (X-a) in the presence of Y-b, Y-c, and Y-d also
completed within 1h without a decrease of the yields (entries produced a similar ratio of products as in reaction [A] (Chart
4, 6, 8, 10). Base-labile alcohols, such as 1g and 1h, possess- 2[C]). When X-d was employed as the benzylating reagent
ing a chloroalkyl or acetoxy group, provided benzyl ethers, 2g in the presence of Y-b and Y-c, only a slight increase in Z-c
and 2h, in high yields (entries 11, 12). β-Hydroxyester 1i and was observed, and Z-b was not produced (Chart 2[D]). These
2-(trimethylsilyl)ethanol 1j, which are prone to decompose experimental results clearly indicate that Y-b that possesses
under acidic or basic conditions, were converted into products two t-butyl groups on the triazine ring does not react with a
2i and 2j, respectively, in good yields (entries 13, 14). No benzyl cation species at all.
racemization was observed during the benzylation of 1i. The
As we previously reported,11) these results again indicate
O-benzylation of cholesterol 1k also afforded the correspond- that the formation of Z proceeds intermolecularly between
ing ether 2k in good yields (entries 15, 16). Although tertiary BnOTf and Y, and not via an intramolecular rearrangement.
alcohols, such as 1l and 1m, and their ethers (2l and 2m) are As expected, the introduction of a bulky t-butyl group into the
known to decompose under acidic or heating conditions, 2l triazine core caused a decrease in the rate of the N-benzylation
and 2m were obtained without decomposition using approxi- of Y; therefore, the O-benzylation of alcohols produced high
mately stoichiometric amount of X-b (entries 17–20). In par- yields by using only 1.2 equiv. of X-b, X-c, or X-d.
ticular, better yields were observed at 40°C, which is milder
than the temperature used for Dudley reagent.
We reported that DPT-BM (X-a) dissolved in CDCl3 disap-
peared according to first-order kinetics, and the release of the
The formation of N-benzyltriazinium Z-b from X-b was benzyl cation species from DPT-BM (X-a) may occur via a
not observed in all the reactions listed in Table 3. Therefore, nucleophilic attack to the N-benzyl group by the triflate coun-
we synthesized the benzylating reagents possessing a t-butyl ter anion11) (SN2 reaction, Fig. 2). Thus, we conducted a kinetic
and an alkoxy group on the triazine ring (X-c and X-d) to study of the degradation of X-b, X-c, and X-d because the re-
study the effect of t-butyl group on the formation of the corre- lease rate of BnOTf from X should be affected by substituents
sponding N-benzyltriazinium (Z-c and Z-d). The benzylation on the triazine ring. As a result, all the reagents degraded ac-
of 1a using X-c or X-d resulted in the formation of 2a in cording to first-order kinetics. The order of the first-order re-
higher yields compared with that obtained using DPT-BM action rate constants, k of X, were determined to be DPT-BM
(X-a), and it did not produce N-benzyltriazinium Z-c or Z-d (X-a)>X-d>X-c>X-b (Table 4). This result can be accounted
(Table 1, entries 5, 6).
for by the electronic effect of the substituents on the triazine
23)
,
the
To compare the relative nucleophilicities of the morpho- ring. Based on the Hammett’s substituent constant, σm
linotriazines Y,22)
which are co-products produced from X electron-withdrawing ability of the phenoxy group is larger
and could undergo N-benzylation to form N-benzyltriazinium than that of the methoxy group. In contrast, the t-butyl group
Z, crossover experiments were performed. A mixture of the has an electron-donating ability. The observed first-order rate
equimolar amount of morpholinotriazines, Y-a, Y-c, and Y-d, constants of X are assumed to correlate with the leaving abil-
was treated with the same amount of X-b, which is a source ity of Y altered by the substituents on the triazine. It has been
of benzyl cation species. As a result, N-benzyltriazinium, Z-a, reported that the Hammett equation is applicable to triazine
Z-b, Z-c, and Z-d, were produced in a ratio of 94:0:4:2, derivatives using the sum of σm of two substituents on the tri-

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Table 3. Benzylation of Several Alcohols Using X-b, and the Comparison of Benzylating Ability with
Other Benzylating Reagents
a: Isolated yields. b: X-a (2.0 equiv.), MgO (2.0 equiv.), DME (1.0mol/L), r.t., 2h.11) c: The yield was determined
by 1H-NMR analysis because a small amount of Y-b could not be separated from 2c. d: The yield was determined
by 1H-NMR analysis because a small amount of Bn2O could not be separated from 2. e: X-a (2.0 equiv.), MgO (2.0
equiv.), DME (1.0mol/L), r.t., 4h.11) f: X-a (3.0 equiv.), MgO (3.0 equiv.), DME (1.0mol/L), r.t., 19h.11) g: X-a (3.0
equiv.), MgO (3.0 equiv.), DME (1.0mol/L), r.t., 7h.11) h: X-a (3.0 equiv.), MgO (3.0 equiv.), DME (1.0mol/L), r.t.,
2h.11) i: Dudley reagent (2.0 equiv.), MgO (2.0 equiv.), PhCF3 (0.1–0.5mol/L), 83°C, 24h.14) j: The authors described
that the yield was not determined because a small amount of Bn2O could not be separated from 2k.15) k: Dudley re-
agent (2.0 equiv.), PhCF3, 120°C (MW), 20min.17)
azine ring.24–26) In the case of these benzylating reagents, the X can be modulated by the inclusion of electron-donating or
Hammett plot for the degradation rate also provides a good electron-withdrawing substituents on the triazine ring using
linear relation (Fig. 3). The positive ρ value (3.471) shows that the σm as an indicator.
electron-withdrawing groups stabilize the transition state by
The low reactivity of X-b is an advantage from an experi-
delocalization of the electron density increasing on the mor- mental point of view. The benzylation using DPT-BM (X-a)
pholine nitrogen. These results indicate that the reactivity of must be initiated by adding the reagent in the solid state to

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307
a: These crossover experiments were performed in the presence of an equimolar amount of morpholinotriazines and a benzylating reagent. b: The product ratio was
determined by 1H-NMR analysis.
Chart 2. The Crossover Experiments of Y in the Presence of Benzyl Cation Species
the alcohol solution under anhydrous conditions because DPT- using a pre-prepared solution of X-b, which can be added to
BM (X-a) rapidly decomposes when dissolved in a solvent. In a solution of reactants because X-b has a sufficient stability
contrast, the benzylating reaction with X-b can be conducted to allow it to be dissolved in a solvent at room temperature.

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Vol. 66, No. 3 (2018)
Acknowledgment This work was partially supported by
Japan Society for the Promotion of Science (JSPS) KAKENHI
Grant No.17H03970, 16K08160.
Conflict of Interest The authors declare no conflict of
interest.
Fig. 2. The Generation of Benzyl Cation Species from DPT-BM (X-a)
Supplementary Material The online version of this ar-
ticle contains supplementary materials (detailed experimental
procedure, physical data, and NMR spectra of isolated prod-
ucts).
Table 4. First-Order Reaction Rate Constant k of the Benzylating Re-
agents X
References and Notes
1) Wuts P. G. M., “Greene’s Protective Groups in Organic Synthesis,”
5th ed., John Wiley & Sons, Inc., New Jersey, 2014.
2) Kocieński P. J., “Protecting Groups,” 3rd ed., Thieme, Stuttgart,
2005.
3) Yamada K., Fujita H., Kunishima M., Org. Lett., 14, 5026–5029
(2012).
X
k×10−3 (/min)
X-a
X-b
X-c
X-d
35.5
0.1
2.5
5.0
4) Yamada K., Yoshida S., Fujita H., Kitamura M., Kunishima M.,
Eur. J. Org. Chem., 2015, 7997–8002 (2015).
5) Yamada K., Fujita H., Kitamura M., Kunishima M., Synthesis, 45,
2989–2997 (2013).
6) Fujita H., Hayakawa N., Kunishima M., J. Org. Chem., 80, 11200–
11205 (2015).
7) Kunishima M., Asao R., Yamada K., Kitamura M., Fujita H., J.
Fluor. Chem., 190, 68–74 (2016).
8) Yamada K., Hayakawa N., Fujita H., Kitamura M., Kunishima M.,
Eur. J. Org. Chem., 2016, 4093–4098 (2016).
9) Yamada K., Hayakawa N., Fujita H., Kitamura M., Kunishima M.,
Chem. Pharm. Bull., 65, 112–115 (2017).
10) Fujita H., Kakuyama S., Kunishima M., Eur. J. Org. Chem., 2017,
833–839 (2017).
11) Yamada K., Tsukada Y., Karuo Y., Kitamura M., Kunishima M.,
Chem. Eur. J., 20, 12274–12278 (2014).
12) Yamada K., Karuo Y., Tsukada Y., Kunishima M., Chem. Eur. J.,
22, 14042–14047 (2016).
13) Lemieux R. U., Kondo T., Carbohydr. Res., 35, C4–C6 (1974).
14) Poon K. W. C., House S. E., Dudley G. B., Synlett, 2005, 3142–3144
(2005).
Fig. 3. Hammett Plot for Degradation of the Benzylating Reagents Xa)
a) The log(k×10−3), which is based on k in Table 4, vs. the sum of σm are shown
in this plot. See the supporting information for details.
15) Poon K. W. C., Dudley G. B., J. Org. Chem., 71, 3923–3927 (2006).
16) Poon K. W. C., Albiniak P. A., Dudley G. B., Org. Synth., 84,
295–305 (2007).
17) Albiniak P. A., Dudley G. B., Synlett, 2010, 841–851 (2010).
18) Wang T.-W., Intaranukulkit T., Rosana M. R., Slegeris R., Simon J.,
Dudley G. B., Org. Biomol. Chem., 10, 248–250 (2012).
19) Hintermann L., Xiao L., Labonne A., Angew. Chem. Int. Ed., 47,
8246–8250 (2008).
Therefore, the initiation and rate of benzylating reaction can
be controlled by heating the reactant solution prepared at
room temperature to an appropriate temperature.
In conclusion, we successfully developed a new benzylating
reagent, X-b, by replacing the phenoxy groups on DPT-BM
(X-a) with bulky t-butyl groups. The incorporation of two t-
butyl groups into the triazine ring of the benzylating reagent
inhibited the side reaction to form N-benzyltriazinium Z-b
because the morpholinotriazine Y-b cannot undergo reac-
tion with BnOTf owing to the steric hindrance of the t-butyl
groups. Hence, the O-benzylation of alcohols with a stoichio-
metric amount of X-b (1.2 equiv.) afforded benzyl ethers in
good to high yields. A solution of X-b is stable, allowing its
treatment at room temperature; however, the benzylation pro-
ceeds at 40°C. As a result of the kinetic study, the electronic
effect of the substituents installed on the triazine ring affects
the reactivity of the benzylating reagents. This result indicates
that the leaving abilities of the morpholinotriazines correlate
with the reactivity of the corresponding benzylating reagent
and can be controlled by the substituents on the triazine core.
20) Hioki K., Ohshima K., Sota Y., Tanaka M., Kunishima M., Synthe-
sis, 2009, 542–544 (2009).
21) The reason for the decrease in the reaction rate at a high con-
centration is unclear. As we previously reported in ref. 11, as the
concentration of DPT-BM (X-a) increases, the degradation rate of
DPT-BM (X-a) becomes slow. We assume that the benzylation with
X-b at a high concentration exhibits a similar effect.
22) See supplementary materials for the synthesis of these morpholi-
notriazines.
23) Hansch C., Leo A., Taft R. W., Chem. Rev., 91, 165–195 (1991).
24) Fukushima Y., Nohara N., Hashida Y., Sekiguchi S., Matsui K.,
Bull. Chem. Soc. Jpn., 44, 794–798 (1971).
25) Fukushima Y., Hashida Y., Matsui K., Nippon Kagaku Kaishi, 3,
629–634 (1972).
26) Sasaki A., Kimura Y., Nippon Kagaku Kaishi, 10, 939–944 (1994).