Development of a Storable Triazinone-Based Reagent for O- p-Methoxybenzylation under Mild Heating Conditions

Article abstract of DOI:10.1021/acs.orglett.9b00732

A new triazinone-based reagent for O-p-methoxybenzylation has been developed. In spite of its stability in solid form, this reagent converts a free alcohol into the corresponding p-methoxybenzyl ether with mild heating (50-60 °C) in a solution. High funct

Full text of DOI:10.1021/acs.orglett.9b00732

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Development of a Storable Triazinone-Based Reagent for
O‑p‑Methoxybenzylation under Mild Heating Conditions
Hikaru Fujita,† Hiromitsu Terasaki,† Satoshi Kakuyama,† Kazuhito Hioki,‡
and Munetaka Kunishima*,†
†Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
‡Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan
S
* Supporting Information
ABSTRACT: A new triazinone-based reagent for O-p-methox-
ybenzylation has been developed. In spite of its stability in solid
form, this reagent converts a free alcohol into the corresponding p-
methoxybenzyl ether with mild heating (50−60 °C) in a solution.
High functional group tolerance can be achieved because the
reaction does not require the addition of an acidic or basic
activator.
he p-methoxybenzyl (PMB) group is one of the most
useful protecting groups for alcohols owing to the high
term storage. In 2013, we reported 2,4,6-tris(p-methoxybenzy-
loxy)-1,3,5-triazine (TriBOT-PM, Figure 1) as a stable and
easy-to-handle reagent for PMB ether synthesis.4 However,
these reagents require an activator such as a Brønsted/Lewis
acid3−15 or an electrophile16−18 for the reaction. Because of
this, the limitation of functional group compatibility is still
inevitable. Although thermal O-p-methoxybenzylation with
PMB-TCAI was found to proceed in the absence of an
activator, the harsh reaction conditions (>100 °C, ∼24 h)
would be problematic if the alcohol has sensitive function-
alities.
T
stability of PMB ethers under a wide range of reaction
conditions.1 Unlike benzyl protection, the PMB group can be
cleaved under mild oxidative or acidic conditions, and it thus
enables selective transformation in multistep syntheses. PMB
ethers are commonly prepared by Williamson ether synthesis
by using PMB chloride (Figure 1) with a strong base such as
We report herein a new, storable reagent for O-p-
methoxybenzylation under mild heating conditions without
the use of an activator. The synthesis of the new p-
methoxybenzylating reagent 1 is shown in Scheme 1. The
core structure 1,3,5-triazin-2(1H)-one, which was previously
evaluated in our study on acid-catalyzed benzylating
reagents,19 achieved the compatibility between the reactivity
and stability of 1. On the basis of our previous findings, the
substituents of 1 (the tert-butyl and N-propargyl groups) were
rationally designed to suppress an N-alkylating side reaction
that was occasionally observed in the reaction of triazine-based
alkylating reagents.4,20−24 The sterically bulky tert-butyl group
on the triazine ring effectively reduced the N-benzylating side
reaction caused by benzyl cation species.25 In addition, the
fixation of the heterocyclic core structure through the
introduction of the N-substituent inhibited the side reaction
that occurred via core structure isomerization during acid-
Figure 1. Reagents to convert alcohols into PMB ethers under basic
or acidic conditions.
sodium hydride. However, this method is difficult to apply to
alcohols with base-labile functionalities. Furthermore, the use
of PMB chloride on a large scale is undesirable because it is not
only a lachrymator but also a potentially hazardous chemical.2
In fact, addition of a stabilizer (potassium or calcium
carbonate) is required to prevent autocatalytic production of
HCl gas, which may cause overpressurization and rupture of
containers. To overcome the problems of PMB chloride, a
number of O-p-methoxybenzylating reagents have been
developed in the past few decades.3−18 For example, PMB
2,2,2-trichloroacetimidate (PMB-TCAI, Figure 1) is widely
used to introduce the PMB group under nonbasic conditions,3
although the stability of this reagent is not satisfactory for long-
Received: February 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00732
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
room temperature (25−30 °C) under open air for 20 days
(Figure S1).
Scheme 1. Synthesis of the New p-Methoxybenzylating
Reagent 1
Next, we carried out O-p-methoxybenzylation of 3-phenyl-
propanol (5a) by using 1.5 equiv of 1 (Table 1). The
corresponding PMB ether 6a was obtained upon heating them
together at 50 °C for 4 h in MeNO2 (entry 1). However, the
yield was moderate (63%) because N-p-methoxybenzylated
triazinedione 7 was formed competitively in 45% yield.
MeNO2 gave the best 6a/7 ratio among the solvents screened
(Table S1). Because an iodide salt is often used in Williamson
ether synthesis to facilitate the nucleophilic substitution,1 we
added tetra-n-butylammonium iodide (nBu4NI, 20 mol %) to
the reaction mixture (entry 2). As a result, the yields of 6a and
7 were changed (33% and 65%, respectively), indicating that
the addition of a salt can affect the reaction selectivity. The
bromide salt (nBu4NBr) gave a result similar to that with
nBu4NI (entries 2 versus 3), whereas the salts composed of
trifluoromethanesulfonate and p-toluenesulfonate (nBu4NOTf,
n
entry 4; Bu4NOTs, entry 5) afforded improved yields of 6a
(80% and 84%, respectively). An increased reaction concen-
tration (from 0.4 to 0.6 M) further improved the yield (90%,
entry 6). However, an increase in the salt amount (from 20 to
100 mol %) had no effect (entries 7 versus 6). The use of 1-
ethyl-3-methylimidazolium methanesulfonate (emimOMs)
also gave 6a in 90% yield (entry 8). When the reaction was
carried out by using 1 (2 equiv) with nBu4NOTs (entry 9), we
found 6a (90%) along with small amounts of symmetric acetal
8 and bis(p-methoxyphenyl)methane (9) in the crude mixture.
These byproducts suggested a side reaction between 6a and a
PMB cation species via a Friedel−Crafts type reaction
pathway.4,28 To suppress this side reaction, we conducted
the reaction in the presence of ethereal solvents because the
Friedel−Crafts-type side reactions were considerably inhibited
by these solvents in our previous study of acid-catalyzed O-
catalyzed O-benzylation.26 The propargyl group was selected
to be the N-substituent for 1.27
As shown in Scheme 1, we synthesized 1 via intermediates
2−4 in 54% overall yield through selective and successive
substitution of the three chlorides in 2,4,6-trichloro-1,3,5-
triazine. The phenoxy group was used as a temporal
substituent. Compound 1 was isolated as a stable solid and
stored in a refrigerator (∼5 °C) for up to 22 months. No
detectable decomposition was observed after 1 was stored at
Table 1. Conditions Screening for O-p-Methoxybenzylation of 5a with 1
a
a
entry
solvent
1 (equiv)
salt additive (mol %)
concn (M)
time (h)
6a (%)
7
(%)
45
1
2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
none
nBu4NI (20)
0.4
0.4
0.4
0.4
0.4
0.6
0.6
0.6
0.6
0.6
0.6
1.0
1.0
4
10
10
5
63
33
35
80
84
90
90
90
90
88
65
65
26
25
23
22
29
41
29
43
37
45
3
nBu4NBr (20)
nBu4NOTf (20)
nBu4NOTs (20)
nBu4NOTs (20)
nBu4NOTs (100)
emimOMs (20)
nBu4NOTs (20)
nBu4NOTs (20)
nBu4NOTs (20)
nBu4NOTs (20)
nBu4NOTs (20)
4
5
5
6
5
7
5
8
9
5
7
10
MeNO2/1,2-dimethoxyethane (4:1)
MeNO2/1,4-dioxane (4:1)
chlorobenzene
7
b
c
11
7
93 (90)
d
12
d
2
86
89
13
MeCN
1.5
a
b
1
Calculated from H NMR spectroscopic analysis by using an internal standard, unless otherwise noted. The reaction was carried out on a 0.3
c
d
mmol scale. Isolated yield. The reaction was carried out at 80 °C.
B
DOI: 10.1021/acs.orglett.9b00732
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Letter
benzylation.20 Whereas with MeNO2/1,2-dimethoxyethane
(4:1) as the solvent, the reaction afforded 6a in 88% yield
(entry 10), the use of MeNO2/1,4-dioxane (4:1) provided an
Scheme 2. O-p-Methoxybenzylation of 5g and 5b in One
Flask with 1 in the Presence of a Trace Amount of Pyridine
1
improved result (93% yield based on H NMR analysis, 90%
isolated yield, entry 11). Under the reaction conditions of
entry 11, coproducts 7 and 10 were isolated in 35% and 65%
yield based on 1, respectively. Additionally, the p-methox-
ybenzylation of 5a in chlorobenzene and acetonitrile under
modified conditions (1.0 M, 80 °C) gave satisfactory yields
(entries 12 and 13, 86 and 89% yield, respectively).
As shown in Figure 2, we conducted the O-p-methox-
ybenzylation of alcohols 5b−g under the reaction conditions of
mol %). As a result, 6g and 6b were obtained in 74% and 89%
yield, respectively. This result is remarkable because all of the
functionalities sensitive to acid, base, and silver salts in 5g and
5b were compatible under the reaction conditions.
As shown in Scheme 3, we carried out the synthesis of 6a on
a 3 mmol scale, which is 10 times larger than the reaction scale
Scheme 3. Synthesis of 6a with 1 on a 3 mmol Scale
of entry 11 in Table 1. As a result, 6a was obtained in 86%
yield, indicating the scalability of the O-p-methoxybenzylation
with 1.
The thermal behavior of 1 was studied by differential
scanning calorimetry (DSC). Figure 3 shows the DSC curve
Figure 2. O-p-Methoxybenzylation of alcohols with sensitive
functionalities by using 1. (a) Isolated yields. (b) The reaction (7
h) was carried out with 1 (3 equiv).
entry 11 in Table 1. Since our purpose was to investigate the
functional group tolerance, these known alcohols were selected
although their O-p-methoxybenzylation reactions under
appropriate conditions were reported individually. The
reaction of 2-bromoethanol (5b), which is sensitive to bases
and silver salts,29 provided 6b in 87% yield.30 The tert-
butyldimethylsilyl (TBS) group of the primary hydroxy group
in 5c survived during the O-p-methoxybenzylation to give 6c in
88% yield.7 The PMB ether of 2-(trimethylsilyl)ethanol (5d)
was obtained in 84% yield despite the fact that 5d can be
decomposed via Peterson olefination under acidic or basic
conditions.4 Secondary alcohol 5e provided the corresponding
PMB ether 6e in 89% yield, while tertiary alcohol 5f afforded
6f in 75% yield. The use of 1 (3 equiv) gave a slightly
improved yield of 6f (78%). The introduction of the PMB
group into a highly acid-labile alcohol 5g under acid-catalyzed
conditions is known to be challenging.30 It was reported that
PMB ether 6g was not obtained from 5g under the standard
conditions for O-p-methoxybenzylation with PMB-TCAI
developed by Rai et al. [5 mol % La(OTf)3, toluene, room
temperature] because of the rapid decomposition of 5g,
whereas the use of boron trifluoride as a catalyst at low
temperature provided 6g only in 8% yield.31 Product 6g was
obtained in 61% yield when the reaction was carried out with
La(OTf)3 at −78 °C in the presence of thioanisole. In contrast,
our procedure with 1 afforded 6g in 67% yield, which indicates
the mildness of the reaction conditions. Furthermore, we
found that the addition of a trace amount of pyridine was
effective for this reaction (Table S2). As shown in Scheme 2,
we carried out the O-p-methoxybenzylation of 5g and 5b
together in one flask by using 1 in the presence of pyridine (2
Figure 3. DSC curve for 1 at a heating rate of 10 °C/min.
for 1 at a heating rate of 10 °C/min. It was observed that the
melting process (initiating at 96.8 °C, Tmin = 111.9 °C) was
immediately followed by an exothermal decomposition
(initiating at 115.4 °C, Tmax = 118.5 °C). Similar
decompositions associated with melting were observed in
some cases.32,33 The melting enthalpy (21.8 kJ/mol) and the
heat release of the decomposition reaction (55.3 kJ/mol) were
determined for 1 by neglecting the superposition of the peaks.
To confirm the thermal decomposition of 1, we heated 1 to
120 °C for 30 min without a solvent under a nitrogen
atmosphere. No mass loss was observed after the heating,
whereas we found that 1 was completely consumed and
converted into 7 in 89% yield (determined by 1H NMR
analysis by using an internal standard), along with trace
amounts of impurities including 10.34 Obviously, this O-to-N
C
DOI: 10.1021/acs.orglett.9b00732
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rearrangement reaction to form 7 produces no gas, and thus, 1
will have low risk for overpressurization of containers during
storage, in contrast to PMB chloride.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00732.
■
S
As the PMB cation is more stable than the benzyl cation,35
the reaction of 1 is likely to proceed via PMB cation species.
This is supported by the formation of the Friedel−Crafts-type
byproducts 8 and 9. The plausible reaction mechanism is
shown in Figure 4. Heating in a solution facilitates the
Tables S1 and S2, experimental details, and spectro-
scopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kunisima@p.kanazawa-u.ac.jp.
ORCID
Hikaru Fujita: 0000-0002-0430-9705
Munetaka Kunishima: 0000-0002-3296-490X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the JSPS Grants-in-Aid
for Scientific Research program (KAKENHI, Grant No.
17H03970).
REFERENCES
■
(1) Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis,
5th ed.; John Wiley & Sons, 2014.
(2) Brewer, S. E.; Vickery, T. P.; Bachert, D. C.; Brands, K. M. J.;
Emerson, K. M.; Goodyear, A.; Kumke, K. J.; Lam, T.; Scott, J. P.
Thermal Hazard Evaluation of 4-Methoxybenzyl Chloride (PMB-Cl).
Org. Process Res. Dev. 2005, 9, 1009−1012.
(3) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. MPM (4-
Methoxybenzyl) Protection of Hydroxy Functions under Mild Acidic
Conditions. Tetrahedron Lett. 1988, 29, 4139−4142.
(4) Yamada, K.; Fujita, H.; Kitamura, M.; Kunishima, M. A Practical
Method for p-Methoxybenzylation of Hydroxy Groups Using 2,4,6-
Tris(p-methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM). Synthesis
2013, 45, 2989−2997.
Figure 4. Plausible reaction mechanism for O-p-methoxybenzylation
with 1.
(5) Kamaike, K.; Tsuchiya, H.; Imai, K.; Takaku, H. Synthesis of 2′-
or 3′-O-(4-Methoxybenzyl)nucleosides and Its Application in the 3′-
Terminal Nonanucleotide Sequence of Rous Sarcoma Virus 35S RNA
Synthesis. Tetrahedron 1986, 42, 4701−4711.
(6) Nakajima, N.; Saito, M.; Ubukata, M. Preparation and Reaction
of 4-Methoxybenzyl (MPM) and 3,4-Dimethoxybenzyl (DMPM)
Perfluoroimidates. Tetrahedron Lett. 1998, 39, 5565−5568.
(7) Sharma, G. V. M.; Mahalingam, A. K. A Facile Conversion of
Alcohols into p-Methoxybenzyl Ethers (PMB-Ethers) Using p-
Methoxybenzyl Alcohol-Yb(OTf)3. J. Org. Chem. 1999, 64, 8943−
8944.
(8) Hanessian, S.; Hoan Khai, H. Solution and Solid Phase p-
Alkoxybenzylation of Alcohols under Neutral Conditions. Tetrahedron
Lett. 1999, 40, 671−674.
(9) Nakano, M.; Kikuchi, W.; Matsuo, J.; Mukaiyama, T. An
Efficient Method for the p-Methoxybenzylation of Hydroxy Groups
with 2-(4-Methoxybenzyloxy)-3-nitropyridine. Chem. Lett. 2001, 30,
424−425.
(10) Krishna, P.; Lavanya, B.; Mahalingam, A.; Reddy, V. V.;
Sharma, G. FeCl3 and FeCl3-SiO2 Catalysed Selective p-Methox-
ybenzylation of Alcohols with p-Methoxybenzyl Alcohol (PMB-OH).
Lett. Org. Chem. 2005, 2, 360−363.
(11) Stewart, C. A.; Peng, X.; Paquette, L. A. An Efficient Means for
Generating p-Methoxybenzyl (PMB) Ethers under Mildly Acidic
Conditions. Synthesis 2008, 2008, 433−437.
(12) Kotturi, S. R.; Tan, J. S.; Lear, M. J. A Mild Method for the
Protection of Alcohols Using a para-Methoxybenzylthio Tetrazole
ionization of 1 into intimate ion pair 11, which can form N-
PMB-rearranged product 7 despite the steric hindrance of the
tert-butyl group. An alcohol reacts with 11 to afford the
corresponding PMB ether and coproduct 10. When nBu4NOTs
is present in the reaction mixture, 11 would be separated by
conversion into PMB p-toluenesulfonate36 and Bu4N salt 12.
n
O-p-Methoxybenzylation of an alcohol with PMB p-toluene-
sulfonate provides the PMB ether, along with p-toluenesulfonic
acid, which is captured by 12 to give 10 and regenerate
nBu4NOTs.
In conclusion, we have developed the O-p-methoxybenzy-
lation of alcohols by using triazinone-based reagent 1, which is
stable to storage and can be handled in solid form. The O-p-
methoxybenzylation with 1 proceeded without problems on a
3 mmol scale. DSC analysis with thermal decomposition study
revealed that 1 decomposes to a rearranged product at around
115 °C. On the other hand, 1 is sufficiently reactive in solution
under mild heating conditions (50−60 °C) to convert a free
alcohol into the PMB ether. Therefore, 1 can be considered as
a ready-to-use, synthetic PMB cation equivalent. The reaction
of 1 was carried out with a neutral salt (nBu4NOTs) but
without an acidic, basic, or electrophilic activator, so it was
compatible with sensitive functional groups.
D
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(PMB-ST) under Dual Acid−Base Activation. Tetrahedron Lett. 2009,
50, 5267−5269.
of Reverse Transcriptase: Synthesis and Rationalization of the
Biological Data on Both Wild-Type Enzyme and Relevant Clinical
Mutants. J. Med. Chem. 2007, 50, 6580−6595. For the synthesis of 6g,
(13) Chavan, S. P.; Harale, K. R. A Very Practical and Selective
Method for PMB Protection of Alcohols. Tetrahedron Lett. 2012, 53,
4683−4686.
́
see: Islas-Gonzalez, G.; Benet-Buchholz, J.; Maestro, M. A.; Riera, A.;
̀
Pericas, M. A. Boron Trifluoride-Induced, New Stereospecific
́
Rearrangements of Chiral Epoxy Ethers. Ready Access to Enantiopure
4-(Diarylmethyl)-1,3-dioxolanes and 4,5-Disubstituted
Tetrahydrobenzo[c]oxepin-4-ols. J. Org. Chem. 2006, 71, 1537−1544.
(31) Rai, A. N.; Basu, A. An Efficient Method for para-
Methoxybenzyl Ether Formation with Lanthanum Triflate. Tetrahe-
dron Lett. 2003, 44, 2267−2269.
(14) Barroca-Aubry, N.; Benchekroun, M.; Gomes, F.; Bonnaffe, D.
p-Methoxybenzyl-N-phenyl-2,2,2-trifluoroacetimidate: A Versatile
Reagent for Mild Acid Catalyzed Etherification. Tetrahedron Lett.
2013, 54, 5118−5121.
(15) Zhang, L.; Gonzalez-de-Castro, A.; Chen, C.; Li, F.; Xi, S.; Xu,
L.; Xiao, J. Iron-Catalyzed Cross Etherification of Alcohols to Form
Unsymmetrical Benzyl Ethers. Mol. Catal. 2017, 433, 62−67.
(16) Okada, M.; Kitagawa, O.; Fujita, M.; Taguchi, T. A Mild
Method for Generation of p-Methoxybenzyl Cation through NIS-
Mediated Activation of p-Methoxybenzyl 4-Pentenyl Ether. Tetrahe-
dron 1996, 52, 8135−8142.
(32) Musuc, A. M.; Razus, D.; Oancea, D. Investigation of Thermal
Stability of Some Nitroaromatic Derivatives by DSC. An. Univ.
Bucuresti. Chimie 2002, 11, 147−152.
(33) Musuc, A. M.; Razus, D.; Oancea, D. A DSC Study of the
Thermal Decomposition of 2-Methoxyamino-3,5-dinitro-pyridine. An.
Univ. Bucuresti. Chimie 2007, 16, 25−30.
(34) 4,6-Dimethoxy-1-methyl-1,3,5-triazin-2(1H)-one underwent O-
to-N methyl rearrangement upon heating: Handelsman-Benory, E.;
Botoshansky, M.; Greenberg, M.; Shteiman, V.; Kaftory, M. Methyl
Rearrangement of Methoxy-Triazines in the Solid- and Liquid-State.
Tetrahedron 2000, 56, 6887−6897.
(35) Kim, J. D.; Han, G.; Jeong, L. S.; Park, H. J.; Zee, O. P.; Jung, Y.
H. Study of the Stability of Carbocations by Chlorosulfonyl
Isocyanate Reaction with Ethers. Tetrahedron 2002, 58, 4395−4402.
(36) PMB p-toluenesulfonate is known to be highly reactive because
it begins polymerization even at −70 °C. Kochi, J. K.; Hammond, G.
S. Benzyl Tosylates. I. Preparation and Properties. J. Am. Chem. Soc.
1953, 75, 3443−3444.
(17) Nwoye, E. O.; Dudley, G. B. Synthesis of para-Methoxybenzyl
(PMB) Ethers under Neutral Conditions. Chem. Commun. 2007,
1436−1437.
(18) Kasprzycka, A.; Ptaszek-Budniok, A.; Szeja, W. Simple and
Efficient Method for the Protection of Hydroxyl Groups as 4-
Methoxybenzyl Ethers. Synth. Commun. 2014, 44, 2276−2284.
(19) Fujita, H.; Hayakawa, N.; Kunishima, M. Study of the
Reactivities of Acid-Catalyzed O-Benzylating Reagents Based on
Structural Isomers of 1,3,5-Triazine. J. Org. Chem. 2015, 80, 11200−
11205.
(20) Yamada, K.; Fujita, H.; Kunishima, M. A Novel Acid-Catalyzed
O-Benzylating Reagent with the Smallest Unit of Imidate Structure.
Org. Lett. 2012, 14, 5026−5029.
(21) Yamada, K.; Tsukada, Y.; Karuo, Y.; Kitamura, M.; Kunishima,
M. Development of a New Benzylating Reagent Spontaneously
Releasing Benzyl Cation Equivalents at Room Temperature. Chem. -
Eur. J. 2014, 20, 12274−12278.
(22) Yamada, K.; Yoshida, S.; Fujita, H.; Kitamura, M.; Kunishima,
M. O-Benzylation of Carboxylic Acids Using 2,4,6-Tris(benzyloxy)-
1,3,5-triazine (TriBOT) under Acidic or Thermal Conditions. Eur. J.
Org. Chem. 2015, 2015, 7997−8002.
(23) Kunishima, M.; Asao, R.; Yamada, K.; Kitamura, M.; Fujita, H.
Development of Acid-Catalyzed Fluorous Benzylating Reagents Based
on a Triazinedione Core. J. Fluorine Chem. 2016, 190, 68−74.
(24) Yamada, K.; Hayakawa, N.; Fujita, H.; Kitamura, M.;
Kunishima, M. Development of a Triazine-Based tert-Butylating
Reagent, TriAT-tBu. Eur. J. Org. Chem. 2016, 2016, 4093−4098.
(25) Karuo, Y.; Yamada, K.; Kunishima, M. Development of
Triazine-Based Benzylating Reagents Possessing t-Butyl Group on the
Triazine Core: Thermally Controllable Reagents for the Initiation of
Reaction. Chem. Pharm. Bull. 2018, 66, 303−308.
(26) Fujita, H.; Kakuyama, S.; Kunishima, M. N,N′-Dimethylated
Benzyloxytriazinedione: A Stable Solid Reagent for Acid-Catalyzed O-
Benzylation. Eur. J. Org. Chem. 2017, 2017, 833−839.
(27) In initial studies, we attempted to prepare N-methyl and N-allyl
analogues of 1. However, isolation of these compounds were
unsuccessful because of decomposition during purification. In
contrast, N-propargyltriazinone 1 was successfully isolated as a stable
solid by recrystallization.
(28) Kern, N.; Dombray, T.; Blanc, A.; Weibel, J.-M.; Pale, P.
Silver(I)-Catalyzed Deprotection of p-Methoxybenzyl Ethers: A Mild
and Chemoselective Method. J. Org. Chem. 2012, 77, 9227−9235.
(29) Fujita, H.; Kakuyama, S.; Fukuyoshi, S.; Hayakawa, N.; Oda, A.;
Kunishima, M. Triazine-Based Cationic Leaving Group: Synergistic
Driving Forces for Rapid Formation of Carbocation Species. J. Org.
Chem. 2018, 83, 4568−4580.
(30) PMB ethers 6b and 6g were prepared from 5b and 5g in 54%
and 85% yield with PMB chloride under basic conditions,
respectively. For the synthesis of 6b, see: Mugnaini, C.; Alongi, M.;
Togninelli, A.; Gevariya, H.; Brizzi, A.; Manetti, F.; Bernardini, C.;
Angeli, L.; Tafi, A.; Bellucci, L.; Corelli, F.; Massa, S.; Maga, G.;
́
́
Samuele, A.; Facchini, M.; Clotet-Codina, I.; Armand-Ugon, M.; Este,
J. A.; Botta, M. Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors
E
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