Preparation of Alkyl Ethers with Diallyltriazinedione-Type Alkylating Agents (ATTACKs-R) Under Acid Catalysis

Article abstract of DOI:10.1002/ejoc.201900607

Diallyltriazinedione-type acid-catalyzed alkylating agents (ATTACKs-R) with 10 different alkyl groups (R), including benzyl, substituted benzyl, allyl, and methyl groups were synthesized. The palladium-catalyzed intramolecular O-to-N allylic rearrangement of 2,4-bis(allyloxy)-6-chloro-1,3,5-triazine was developed to introduce various alkoxy groups into the N,N′-dialkylated triazinedione skeleton. O-Alkylation of alcohols with ATTACKs-R was carried out in 1,4-dioxane in the presence of 2,6-di-tert-butylpyridinium trifluoromethanesulfonate or trifluoromethanesulfonic acid as a catalyst. Six selected ATTACKs-R bearing benzylic R groups were employed to prepare alkyl ethers from primary, secondary, and tertiary alcohols. The reactions of ATTACKs-R bearing an o-nitro-substituted benzyl group tended to afford low yields. Comparison of four different triazinedione-based benzylating reagents suggested that the N,N′-substituents affected the reactivity.

Full text of DOI:10.1002/ejoc.201900607

A Journal of
Accepted Article
Title: Preparation of Alkyl Ethers with Diallyltriazinedione-Type Acid-
Catalyzed Alkylating Agents (ATTACKs-R)
Authors: Hikaru Fujita, Rina Yamashita, Takanori Fujii, Kohei Yamada,
Masanori Kitamura, and Munetaka Kunishima
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900607
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900607
Supported by

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
Preparation of Alkyl Ethers with Diallyltriazinedione-Type Acid-
Catalyzed Alkylating Agents (ATTACKs-R)
Hikaru Fujita,[a] Rina Yamashita,[a] Takanori Fujii,[a] Kohei Yamada,[a] Masanori Kitamura,[a] and
Munetaka Kunishima*[a]
Abstract: Diallyltriazinedione-type acid-catalyzed alkylating agents
(ATTACKs-R) with 10 different alkyl groups (R), including benzyl,
substituted benzyl, allyl, and methyl groups were synthesized. The
palladium-catalyzed intramolecular O-to-N allylic rearrangement of
2,4-bis(allyloxy)-6-chloro-1,3,5-triazine was developed to introduce
various alkoxy groups into the N,N′-dialkylated triazinedione skeleton.
O-Alkylation of alcohols with ATTACKs-R was carried out in 1,4-
accessible through rearrangement of the benzyl groups in
TriBOT.[10]
dioxane
in
the
presence
of
2,6-di-tert-butylpyridinium
trifluoromethanesulfonate or trifluoromethanesulfonic acid as
a
catalyst. Six selected ATTACKs-R bearing benzylic R groups were
employed to prepare alkyl ethers from primary, secondary, and
tertiary alcohols. The reactions of ATTACKs-R bearing an o-nitro-
substituted benzyl group tended to afford low yields. Comparison of
four different triazinedione-based benzylating reagents suggested
that the N,N′-substituents affected the reactivity.
Scheme 1.
Previous synthetic routes toward N,N-dialkylated
benzyloxytriazinediones.
Introduction
2,4,6-Tris(benzyloxy)-1,3,5-triazine (TriBOT, Scheme 1) has
been previously reported as a triazine-based acid-catalyzed O-
benzylating reagent.[1,2] TriBOT was designed as an atom-
economic reagent and was readily prepared from cyanuric
chloride (1) and benzyl alcohol. This reagent was then employed
to convert alcohols and carboxylic acids into the corresponding
benzyl ethers and esters, respectively, under non-basic
conditions. A series of triazine-based acid-catalyzed reagents
were developed for p-methoxybenzylation,[3] tert-butylation,[4] and
allylation.[5] During the mechanistic studies on TriBOT, one of the
DMBOT exhibits superior reactivity to that of MonoBOT owing to
the fixed triazinedione skeleton comprising alkyl groups on the
nitrogen atoms. The O-benzylation reaction with DMBOT is
typically catalyzed by trifluoromethanesulfonic acid (TfOH) or 2,6-
di-tert-butylpyridinium trifluoromethanesulfonate (3). The latter is
suitable for the O-benzylation of acid-labile alcohols. Benzyl
cation species (possibly benzyl trifluoromethanesulfonate) are
formed during the reaction and react with alcohols. DMBOT is
practical to use due to its favorable physical properties (a non-
hygroscopic stable solid sufficiently soluble in organic solvents)
and easy removal of its coproduct. To date, notwithstanding the
practicability of DMBOT, the N,N′-dialkylated triazinedione
skeleton has been solely applied to O-benzylation.
intermediates,
6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(MonoBOT), was synthesized in two steps from 1.[6] Kinetic
studies indicated the high reactivity of MonoBOT compared to that
of TriBOT. Subsequently, further exploration of the core structure
led to N,N′-dimethylated benzyloxytriazinedione (DMBOT, R1 =
This paper describes the development of a series of triazinedione-
based reagents for acid-catalyzed O-alkylation. A new synthetic
approach toward the acid-catalyzed reagents extends the scope
of the alkyl groups transferred onto alcohols.
Me) as
a next-generation reagent for acid-catalyzed O-
benzylation.[7] N,N′-Dibenzylated analog 2 (R1 = Bn), which can
also be employed for acid-catalyzed O-benzylation,[8,9] is
Results and Discussion
[a]
Dr. Hikaru Fujita, Ms. Rina Yamashita, Mr. Takanori Fujii, Dr. Kohei
Yamada, Dr. Masanori Kitamura, and Prof. Dr. Munetaka 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.
The synthetic routes toward DMBOT and 2 from 1 require benzyl
alcohol, the alkyl source for the reagent, in the first step of the
synthesis. Thus, it is inconvenient to introduce various alkyl
groups into the reagent via these routes. Therefore, this paper
reports a new synthetic strategy—catalytic intramolecular O-to-N
allylic rearrangement[11,12] of a bis(allyloxy)triazine—to construct
an N,N′-diallylated triazinedione skeleton bearing a chloro group,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
which can be replaced in the last step of the synthesis. As
illustrated in Table 1, 2,4-bis(allyloxy)-6-chloro-1,3,5-triazine (4,
1.2 equiv) was heated in THF with PdCl2(PhCN)2 (0.5 mol-%) to
form 1,3-diallyl-6-chloro-1,3,5-triazine-2,4(1H,3H)-dione (5). This
was subsequently treated with an alcohol (ROH, 1 equiv), Et3N (2
equiv), and N-methylimidazole (20 mol-%) to afford the
corresponding diallyltriazinedione-type acid-catalyzed alkylating
agents (ATTACKs-R). ATTACKs-R with various benzylic alkyl
groups [benzyl (Bn), p-methoxybenzyl (PMB), p-methylbenzyl
(MBn), F13-fluorous benzyl (F13Bn), p-bromobenzyl (PBB), p-
nitrobenzyl (PNB), o-nitrobenzyl (ONB), and 4,5-dimethoxy-2-
nitrobenzyl (DMNB); entries 1–8; synthetically useful protecting
groups for alcohols[13]] as well as allyl and methyl groups (entries
9 and 10, respectively) were obtained in 85–100% yield. The
addition of a catalytic amount of N-methylimidazole facilitated the
substitution with alcohols to afford ATTACKs-R. Notably,
ATTACK-F13Bn was prepared from the expensive F13-fluorous
benzyl alcohol in high yield (95%, entry 4). These results are
comparable to the results of the previous synthesis of a
triazinedione-based acid-catalyzed reagent for the introduction of
the F13Bn group (48% yield based on the alcohol in two steps).[14]
This reagent lacked N,N′-dialkyl groups and thus resembled
MonoBOT. While ATTACK-PMB, ATTACK-allyl, and ATTACK-
Me were liquid at room temperature, all the other ATTACKs-R
were obtained as non-hygroscopic solids similar to DMBOT.
6
7
8
PNB
1.5
4
99
94
85
ONB
DMNB
3
9
allyl
Me
19
6
quant.
86
10
[a] Reaction time for the second step. [b] Isolated yield.
Following the procedure for DMBOT,[7] acid-catalyzed O-
alkylation with ATTACKs-R (1.2 equiv) was conducted in 1,4-
dioxane, at room temperature, in the presence of molecular
sieves 5 Å (Table 2). Initially, catalyst 3 and primary alcohol 6a
bearing a base-labile bromoalkyl group were employed for the
reaction. Several entries in this Table display yields determined
by 1H NMR spectroscopic analysis with an internal standard;
these are referred to as the NMR yields hereafter. The O-
benzylation with ATTACK-Bn and 3 (10 mol-%) afforded the
corresponding benzyl ether 7a-Bn in 3.5 h with 88% isolated yield
(entry 1). The reaction of ATTACK-PMB was completed in 20 min,
with a smaller amount of 3 (2 mol-%), to afford 7a-PMB in 80%
isolated yield (entry 2). The acid catalysts 3 (10 mol-%, entry 3)
and Sc(OTf)3 (10 mol-%, entry 4) were used for the O-p-
methylbenzylation with ATTACK-MBn, providing 7a-MBn in 87%
isolated yield and 92% NMR yield, respectively, within one hour.
The reactions with ATTACK-F13Bn (entry 5) and ATTACK-PBB
(entry 6) in the presence of 3 (10 mol-%) afforded 7a-F13Bn and
7a-PBB with 91% isolated yield and 93% NMR yield in 2 and 24
h, respectively. The syntheses of the nitrobenzyl ethers 7a-PNB
and 7a-ONB with the same catalyst were unfruitful (14 and 0%
NMR yield, 68 and 72 h, entries 7 and 8, respectively), while 7a-
DMNB was obtained with 26% NMR yield in seven hours (entry
9). As the O-allylation of 6a with ATTACK-allyl and 3 (10 mol-%)
was sluggish at room temperature (29% NMR yield in 29 h, entry
10), the reaction was carried out at 50 °C to improve the yield
(84% isolated yield in 6.5 h, entry 11). Next, the O-alkylation of 6a
was carried out with TfOH as the acid catalyst to strongly activate
the ATTACKs-R. Entries 12 and 13 reveal that the introduction of
the F13Bn and PBB groups with TfOH (10 mol-%) resulted in
shorter reaction times (30 min and five hours, respectively) than
those observed with 3 in entries 5 and 6 to afford the products in
99% NMR yield (entry 12) and 86% isolated yield (entry 13),
respectively. In contrast to the reaction of the low-yielding O-p-
nitrobenzylation with 3 (entry 7), the reaction with TfOH (20
mol-%) afforded 7a-PNB with 82% isolated yield in 23 h (entry 14).
The O-o-nitrobenzylation proceeded with TfOH (20 mol-%), albeit
a low isolated yield (16%, entry 15). The isolated yield of 7a-
DMNB in the reaction with 10 mol-% TfOH (20%, entry 16) was
comparable to the NMR yield with 3 (26%, entry 9). The low yields
Table 1. Synthesis of ATTACKs-R from various alcohols.
Entry
1
R
Structure
Time [h][a]
2.5
Yield
[%][b]
Bn
97
2
3
4
PMB
MBn
F13Bn
6
93
1.5
2.5
86
95
5
PBB
1.5
quant.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
observed in the syntheses of 7a-ONB (0–12 %) and 7a-DMNB
(26–29%) were attributed to the competing side reactions caused
by the o-nitro groups. o-Nitrosobenzaldehyde formation via
neighboring group participation was reported during the
hydrolysis of o-nitrobenzyl p-toluenesulfonate in aqueous
MeCN.[15] This suggested that similar side reactions affording
nitroso compounds could occur during the reactions of ATTACK-
ONB and ATTACK-DMNB. To the best of our knowledge, the
[a] Isolated yield. [b] Yields in parentheses were calculated from 1H NMR
spectroscopic analysis using an internal standard. [c] Not detected. [d] The
reaction was carried out at 50 °C. [e] The reaction was carried out at room
temperature to reflux temperature.
The reactivity of the ATTACKs-R (except for R = ONB, DMNB,
and Me) observed in Table 2 was in the order: ATTACKs with R
= PMB >MBn >F13Bn >Bn >PBB >allyl >PNB. This is consistent
with the order of carbocation stability (PMB cation >benzyl cation
>allyl cation)[19] as well as that of the electron-donating ability
reaction
of
O-o-nitrobenzylation
with
ONB
2,2,2-
trichloroacetimidate[16] has not been reported although 2,2,2-
trichloroacetimidates are widely used for acid-catalyzed O-
alkylation. DMNB 2,2,2-trichloroacetimidate was used to prepare
a DMNB ether using TfOH as an acid catalyst.[17,18] The low yields
(29–30%) together with the afforded results (entries 9 and 16)
suggest limitation of the DMNB ether synthesis under acid-
catalyzed conditions. O-Allylation with TfOH (10 mol-%) at room
temperature produced 7a-allyl with 35% NMR yield in 24 h (entry
17). O-Methylation of 6a was carried out with TfOH (10 mol-%) at
reflux temperature to afford 7a-Me with 56% isolated yield in
seven hours (entry 18).
+
based on p constants [OMe (–0.78) >Me (–0.31) >H (0) >Br
+
(0.15) >NO2 (0.79)], where a lower p value indicates stronger
conjugative stabilization toward a cationic reaction center by a p-
substituent.[20] Thus, development of a positive charge at the
reaction center is suggested during the O-alkylation with these
ATTACKs-R.
Table 3 summarizes the results of the acid-catalyzed O-alkylation
reactions with selected ATTACKs-R (R = Bn, PMB, MBn, F13Bn,
PBB, and PNB) for 10-acetoxydecanol (6b), chiral β-hydroxy
ester 6c, and 1-adamantanol (6d). The syntheses of 7b–d-Bn
with 3 (10 mol-%) resulted in high yields (89–97%, entry 1). The
O-p-methoxybenzylation reactions were conducted with 3 (2
mol-%) to afford 7b-PMB, 7c-PMB, and 7d-PMB in 89, 87, and
62% yield, respectively (entry 2). The use of 3 (10 mol-%) and the
corresponding ATTACKs-R produced 7b–d-MBn and 7b–d-
F13Bn in high yields (87–99%, entries 3 and 4, respectively). The
introduction of the PBB group into 6b and 6c with ATTACK-PBB
in the presence of 3 (10 mol-%) proceeded smoothly to afford 7b-
PBB and 7c-PBB in 89 and 85%, respectively (entry 5). Entry 6
illustrates that the use of TfOH (10 mol-%) improved the yields of
7b-PBB and 7c-PBB (90 and 95%, respectively). The use of the
same acid catalyst afforded 7d-PBB in 63% yield (entry 6). The
syntheses of 7b–d-PNB were carried out with TfOH (20 mol-%).
On the other hand, 7b-PNB was afforded in 84% yield at room
temperature, while heating at 50 °C was required to produce 7c-
PNB and 7d-PNB in high yields (95 and 92%, respectively, entry
7). HPLC analyses indicated that no racemization occurred during
the acid-catalyzed O-alkylation reactions of 6c.
Table 2. Acid-catalyzed O-alkylation of 6a with ATTACKs-R.
Entry
R
Acid catalyst [mol-%]
Time
Yield [%][a,b]
1
Bn
3 (10)
3.5 h
20 min
45 min
1 h
88 (96)
80 (89)
87 (93)
(92)
2
PMB
MBn
MBn
F13Bn
PBB
PNB
ONB
DMNB
allyl
3 (2)
3
3 (10)
4
Sc(OTf)3 (10)
3 (10)
5
2 h
91 (98)
(93)
6
3 (10)
24 h
68 h
72 h
2 h
7
3 (10)
(14)
Table 3. Acid-catalyzed O-alkylation of 6b-d with selected ATTACKs-R.
8
3 (10)
nd[c]
9
3 (10)
(26)
10
11[d]
12
13
14
15
16
17
18[e]
3 (10)
29 h
6.5 h
30 min
5 h
(29)
Entry
R
Acid
Reaction time, yield[a]
allyl
3 (10)
84 (89)
(99)
catalyst
[mol-%]
F13Bn
PBB
PNB
ONB
DMNB
allyl
TfOH (10)
TfOH (10)
TfOH (20)
TfOH (20)
TfOH (10)
TfOH (10)
TfOH (10)
7b-R
86 (94)
82 (91)
16
7d-R
7c-R
5 h, 93%[b]
23 h
69 h
2.5 h
24 h
7 h
1
2
3
4
Bn
3 (10)
3 (2)
4.5 h, 97%
10 min, 89%
1 h, 98%
9.5 h, 89%
10 min, 62%
2 h, 87%
PMB
MBn
F13Bn
10 min, 87%[b]
1 h, 96%[b]
20 (29)
(35)
3 (10)
3 (10)
2 h, 98%
4 h, 99%[b]
3 h, 92%
Me
56 (66)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
After the palladium-catalyzed O-N allylic rearrangement of 4 to a
[c]
5
PBB
3 (10)
24 h, 89%
5 h, 90%
24 h, 85%[b]
7 h, 93%[b]
–
common intermediate 5,
a variety of alkylating reagents
6
PBB
TfOH
(10)
6 h, 63%
ATTACKs-R can be efficiently prepared by nucleophilic
substitution with an alcohol. The use of the corresponding
ATTACKs-R with the acid catalyst (3 or TfOH) successfully
afforded Bn, PMB, MBn, F13Bn, PBB, PNB, allyl, and methyl
ethers. Since the syntheses of ONB and DMNB ethers under
7
PNB
TfOH
(20)
24 h, 84%
4 h, 95%[b,d]
5 h, 92%[d]
[a] Isolated yield. [b] No racemization was observed. [c] Not conducted. [d] The acid-catalyzed conditions are challenging, the reactions of
reaction was carried out at 50 °C.
ATTACKs-ONB and DMNB proceeded, but in low yields.
Comparison of DMBOT and ATTACK-Bn indicated that the
reactivity was improved by replacing the N,N′-dimethyl groups
with N,N′-diallyl groups.
Table 4 compares the acid-catalyzed O-benzylation of 3-
phenylpropanol (6e) with that of MonoBOT, DMBOT, ATTACK-
Bn, and 2 in the presence of TfOH (10 mol-%). Similar to DMBOT
(entry 2), ATTACK-Bn and 2 afforded the corresponding benzyl
Experimental Section
ether 7e-Bn in excellent yields (97–100% NMR yield, entries 3
and 4, respectively). The difference in the reaction times (5, 4, and
Nuclear magnetic resonance [1H NMR (400 or 600 MHz), 13C NMR (100
or 150 MHz)] spectra were determined on a JEOL JNM-ECS400
spectrometer. Chemical shifts for 1H NMR are reported as δ values relative
to tetramethylsilane as the internal standard and coupling constants are in
hertz (Hz). The following abbreviations are used for spin multiplicity: s =
singlet, d = doublet, t = triplet, m = multiplet, br = broad. Chemical shifts
for 13C NMR were reported in ppm relative to the center line of a triplet at
77.16 ppm for CDCl3. Mass spectra were measured on a Micromass
Zq2000 spectrometer (ESI-MS), JMS-SX102A (FAB). Chiral HPLC was
performed on a JASCO LC-2000 series using Daicel CHIRALPAK AS.
Analytical thin layer chromatography (TLC) was performed on Merck
precoated analytical plates, 0.25 mm thick, silica gel 60 F254. Flash
chromatography separations were performed on KANTO CHEMICAL
Silica Gel 6 N (spherical, neutral, 40–100 mesh) or diol-functionalized silica
gel (spherical, DIOL, 100 Å, 40–75 mesh). Reagents were commercial
grades and were used without any purification unless otherwise noted.
Dehydrated CH2Cl2, THF, and 1,4-dioxane were purchased from
commercial sources. All reactions sensitive to oxygen or moisture were
conducted under a N2 atmosphere. Known compounds (2[8,9], 3[21]) were
prepared as described in the literature.
1.5 h and 50 min for MonoBOT, DMBOT, ATTACK-Bn, and 2,
respectively) suggested that the reactivity of the triazinedione-
based reagents is affected by the N,N′-dialkyl groups. These
results indicated higher reactivity of ATTACK-Bn over that of
DMBOT.
Table 4. Comparison of acid-catalyzed O-benzylation with triazinedione-
based reagents.
2,4-Diallyloxy-6-chloro-1,3,5-triazine (4):[22] Allyl alcohol (4.10 mL, 60.3
mmol) and ethyldiisopropylamine (10.5 mL, 60.3 mmol) were added to a
solution of cyanuric chloride (3.69 g, 20.0 mmol) in CH2Cl2 (40 mL) at –
10 °C. The reaction mixture was allowed to warm to room temperature and
stirred for 24 h. The reaction mixture was poured into saturated aqueous
NaHCO3 (100 mL) and then extracted with CH2Cl2 (3 20 mL). The
combined organic layer was washed with brine (100 mL), dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 9:1)
afforded a colorless oil (4.33 g, 95%). 1H NMR (600 MHz, CDCl3): δ 6.09–
5.98 (m, 2H), 5.49–5.41 (m, 2H), 5.37–5.31 (m, 2H), 4.99–4.91 (m, 4H);
13C NMR (150 MHz, CDCl3): δ 172.9, 172.0, 131.0, 119.7, 69.7; IR
(CHCl3): 3047, 3032, 3005, 1556, 1537, 1329 cm–1; HRMS (DART-TOF)
Calcd for C9H11ClN3O2 ([M + H]+) 228.0540, found 228.0546; Anal. Calcd
for C9H10ClN3O2: C, 47.49; H, 4.43; N, 18.46. Found: C, 47.59; H, 4.46; N,
18.42.
Entry
Triazinedion
e
R1
Time
Yield [%][a]
1[b,c]
2[b]
3
MonoBOT
DMBOT
ATTACK-Bn
2
H
5 h
82
Me
allyl
Bn
4 h
97
1.5 h
50 min
quant.
97
4
[a] Calculated from 1H NMR spectroscopic analysis using an internal
standard. [b] Data from ref.[7] [c] The reaction concentration of 6e was 115
mM.
General procedure for preparation of ATTACK-R (GP-1).
Bis(benzonitrile)palladium(II) chloride (0.5 mol-%) was added to a solution
of 4 (1.2 equiv) in THF (0.24 M) at room temperature. The solution was
heated at reflux for 1–2 h and then cooled to 0 °C. An alcohol (ROH, 1
equiv), N-methylimidazole (20 mol-%), and Et3N (2 equiv) were added. The
reaction mixture was stirred at 0 °C to room temperature until TLC
monitoring indicated complete conversion. The reaction mixture was
poured into aqueous citric acid (10%) and then extracted with CH2Cl2. The
organic layer was washed with brine, dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to afford ATTACK-R.
Conclusions
The scope of the alkyl groups in the acid-catalyzed O-alkylating
reagents based on the N,N′-dialkyl triazinedione skeleton has
been extended to prepare ethers bearing Bn, PMB, MBn, F13Bn,
PBB, PNB, ONB, DMNB, allyl, and methyl groups. This was
achieved by a new synthetic strategy to construct the skeleton.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
1,3-Diallyl-6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-
h
and then cooled to
0
°C. 4-(3,3,4,4,5,5,6,6,7,7,8,8,8-
Bn): Following GP-1, bis(benzonitrile)palladium(II) chloride (9.6 mg, 25
µmol) was added to a solution of 4 (1.366 g, 6.00 mmol) in THF (25 mL) at
room temperature. The solution was heated at reflux for 1 h and then
cooled to 0 °C. Benzyl alcohol (519.9 µL, 5.00 mmol), N-methylimidazole
(79.0 µL, 1.00 mmol), and Et3N (1.39 mL, 10.0 mmol) were added. The
reaction mixture was stirred for 30 min at 0 °C and for 2 h at room
temperature. The reaction mixture was poured into aqueous citric acid
(10%, 30 mL) and then extracted with CH2Cl2 (2  30 mL). The combined
organic layer was washed with brine (30 mL), dried with Na2SO4, and
filtered. The filtrate was concentrated under reduced pressure. Silica gel
column chromatography (hexane/EtOAc = 7:3) afforded a white solid (1.46
g, 97%). Mp 67.0–67.7 °C; 1H NMR (400 MHz, CDCl3): δ 7.43–7.37 (m,
5H), 5.90 (ddt, J = 17.2, 10.3, 5.9 Hz, 1H), 5.81 (ddt, J = 16.4, 10.3, 5.9
Hz, 1H), 5.48 (s, 2H), 5.30 (dd, J = 17.2, 1.0 Hz, 1H), 5.24–5.16 (m, 3H),
4.51 (d, J = 5.9 Hz, 2H), 4.47 (d, J = 5.9 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 158.6, 154.0, 150.4, 133.9, 131.2, 130.6, 129.2, 128.9, 128.8,
119.3, 118.6, 71.9, 45.0, 44.7; HRMS (DART-TOF) Calcd for C16H18N3O3
([M + H]+) 300.1348, found 300.1355; Anal. Calcd for C16H17N3O3: C,
64.20; H, 5.72; N, 14.04. Found: C, 64.16; H, 5.87; N, 14.01.
Tridecafluorooctyl)benzyl alcohol (454.2 mg, 1.00 mmol) in THF (3.0 mL),
N-methylimidazole (15.8 µL, 0.20 mmol), and Et3N (278.8 µL, 2.00 mmol)
were added. The reaction mixture was stirred for 1 h at 0 °C and for 1.5 h
at room temperature. The reaction mixture was poured into saturated
aqueous NaHCO3 (20 mL) and then extracted with CH2Cl2 (5  10 mL).
The combined organic layer was washed with brine (20 mL), dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/acetone = 4:1)
1
afforded a white solid (614.1 mg, 95%). Mp 44.4–45.2 °C; H NMR (400
MHz, CDCl3): δ 7.37 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 5.90 (ddt,
J = 17.2, 10.3, 6.0 Hz, 1H), 5.81 (ddt, J = 16.9, 10.1, 6.0 Hz, 1H), 5.46 (s,
2H), 5.30 (dd, J = 17.2, 1.1 Hz, 1H), 5.24–5.15 (m, 3H), 4.51 (d, J = 6.0
Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 3.00–2.89 (m, 2H), 2.43–2.32 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 158.6, 154.0, 150.4, 140.4, 132.5, 131.3,
130.7, 129.4, 128.9, 128.5, 119.8, 119.3, 118.7–109.2 (m), 71.6, 45.1, 44.8,
33.0, 32.9, 32.8, 26.4, 26.3; HRMS (DART-TOF) Calcd for C24H21F13N3O3
([M + H]+) 646.1375, found 646.1383; Anal. Calcd for C24H20F13N3O3: C,
44.60; H, 3.12; N, 6.51. Found: C, 44.64; H, 3.16; N, 6.46.
1,3-Diallyl-6-(4-bromobenzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-PBB): Following GP-1, bis(benzonitrile)palladium(II) chloride
(9.6 mg, 25 µmol) in THF (5.0 mL) was added to a solution of 4 (1.366 g,
6.00 mmol) in THF (7.0 mL) at room temperature. The solution was heated
at reflux for 1.5 h and then cooled to 0 °C. 4-Bromobenzyl alcohol (935.2
mg, 5.00 mmol) in THF (8.0 mL), Et3N (1.4 mL, 10.0 mmol), and N-
methylimidazole (79.2 µL, 1.00 mmol) were added. The reaction mixture
was stirred for 10 min at 0 °C and for 1.5 h at room temperature. The
reaction mixture was poured into aqueous citric acid (10%, 30 mL) and
extracted with EtOAc (3  30 mL). The combined organic layer was
washed with saturated aqueous NaHCO3 (30 mL) and brine (50 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 7:3)
afforded a white solid (1.91 g, quant.). Mp 62.2–63.3 °C ; 1H NMR (400
MHz, CDCl3): δ 7.55–7.52 (m, 2H), 7.30–7.27 (m, 2H), 5.95–5.75 (m, 2H),
5.43 (s, 2H), 5.33–5.16 (m, 4H), 4.56 (ddd, J = 6.0, 1.5, 1.5 Hz, 2H), 4.47
(ddd, J = 5.5, 1.6, 1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 158.4, 153.8,
150.3, 132.9, 132.1, 131.1, 130.6, 130.5, 123.4, 119.3, 118.7, 71.0, 45.0,
44.8; IR (KBr): 3087, 1739, 1684, 1610, 1479, 1446, 1286 cm–1; HRMS
1,3-Diallyl-6-(4-methoxybenzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-PMB): Bis(benzonitrile)palladium(II) chloride (19.2 mg, 50.1
µmol) in THF (5.0 mL) was added to a solution of 4 (2.73 g, 12.0 mmol) in
THF (45 mL) at room temperature. The solution was heated at reflux for 1
h and then cooled to 0 °C. 4-Methoxybenzyl alcohol (1.24 mL, 9.96 mmol),
Et3N (2.79 mL, 20.0 mmol), and N-methylimidazole (158 µL, 2.00 mmol)
were added. The reaction mixture was stirred for 6 h at 0 °C and then
allowed to warm to room temperature. The reaction mixture was
concentrated under reduced pressure. Column chromatography (diol-
functionalized silica gel, hexane/CHCl3 = 7:3) afforded a clear colorless oil
(3.05 g, 93%): 1H NMR (400 MHz, CDCl3): δ 7.39–7.32 (m, 2H), 6.95–6.88
(m, 2H), 5.97–5.72 (m, 2H), 5.42 (s, 2H), 5.34–5.12 (m, 4H), 4.51 (d, J =
6.0 Hz, 2H), 4.44 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 160.3, 158.5, 154.0, 131.2, 130.8, 130.6, 125.9, 119.2, 118.5,
114.2, 55.4, 45.0, 44.7; IR (CHCl3): 2997, 1678, 1606, 1516, 1473, 1259,
1036 cm–1; HRMS (ESI-TOF) Calcd for C17H19N3NaO4 ([M + Na]+)
352.1273, found 352.1256.
(DART-TOF) Calcd for C16H17BrN3O3 ([M
+
H]+) 378.0453, found
1,3-Diallyl-6-[(4-methylbenzyl)oxy]-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-MBn): Following GP-1, bis(benzonitrile)palladium(II) chloride
(7.7 mg, 20.0 µmol) was added to a solution of 4 (1.093 g, 4.80 mmol) in
THF (5.0 mL) at room temperature. The solution was heated at reflux for
1.5 h and then cooled to 0 °C. 4-Methylbenzyl alcohol (488.6 mg, 4.00
mmol) in THF (3.0 mL), N-methylimidazole (63.3 µL, 0.80 mmol), and Et3N
(1.1 mL, 7.89 mmol) were added. The reaction mixture was stirred for 30
min at 0 °C and for 1 h at room temperature. The reaction mixture was
poured into saturated aqueous NaHCO3 (20 mL) and then extracted with
CH2Cl2 (5  10 mL). The combined organic layer was washed with brine
(20 mL), dried with Na2SO4, and filtered. The filtrate was concentrated
under reduced pressure. Silica gel column chromatography
(CH2Cl2/EtOAc = 19:1) afforded a white solid (1.084 g, 86%). Mp 56.7–
58.0 °C; 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 7.8 Hz, 2H), 7.21 (d, J
= 7.8 Hz, 2H), 5.90 (ddt, J = 17.2, 10.3, 5.8 Hz, 1H), 5.80 (ddt, J = 17.0,
10.4, 5.8 Hz, 1H), 5.44 (s, 2H), 5.30 (d, J = 17.2 Hz, 1H), 5.25–5.14 (m,
3H), 4.51 (d, J = 5.8 Hz, 2H), 4.45 (d, J = 5.8 Hz, 2H), 2.37 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 158.6, 154.0, 150.4, 139.2, 131.2, 130.9, 130.6,
129.5, 129.1, 129.0, 119.3, 118.6, 72.0, 45.0, 44.7, 21.4; HRMS (DART-
TOF) Calcd for C17H19N3O3 ([M + H]+): 314.1505, found 314.1500; Anal.
Calcd for C17H20N3O3; C, 65.16; H, 6.11; N, 13.41. Found: C, 65.11; H,
6.29; N, 13.39.
378.0443; Anal. Calcd for C16H16BrN3O3: C, 50.81; H, 4.26; N, 11.11: C,
64.20; H, 5.72; N, 14.04. Found: C, 50.77 ; H, 4.21; N, 11.51.
1,3-Diallyl-6-(4-nitrobenzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-PNB): Following GP-1, bis(benzonitrile)palladium(II) chloride
(9.6 mg, 25 µmol) in THF (5.0 mL) was added to a solution of 4 (1.366 g,
6.00 mmol) in THF (25 mL) at room temperature. The solution was heated
at reflux for 1 h and then cooled to 0 °C. 4-Nitrobenzyl alcohol (765.7 mg,
5.00 mmol) in THF (8.0 mL), Et3N (1.4 mL, 10.0 mmol), and N-
methylimidazole (79.2 µL, 1.00 mmol) were added. The reaction mixture
was stirred for 15 min at 0 °C and for 1.5 h at room temperature. The
reaction mixture was poured into aqueous citric acid (10%, 30 mL) and
extracted with EtOAc (3  30 mL). The combined organic layer was
washed with saturated aqueous NaHCO3 (30 mL) and brine (50 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 1:1 to 1:3)
1
afforded a white solid (1.70 g, 99%). Mp 122.6–123.4 °C; H NMR (400
MHz, CDCl3): δ 8.31–8.24 (m, 2H), 7.62–7.54 (m, 2H), 5.97–5.77 (m, 2H),
5.59 (s, 2H), 5.36–5.17 (m, 4H), 4.55–4.48 (m, 4H); 13C NMR (100 MHz,
CDCl3): δ 158.3, 153.6, 150.1, 148.2, 140.9, 131.0, 130.6, 129.0, 124.1,
119.2, 118.8, 69.9, 45.1, 44.8; IR (KBr): 1685, 1612, 1595, 1477, 1441,
1344, 1284 cm–1; HRMS (DART-TOF) Calcd for C16H17N4O5 ([M + H]+)
345.1199, found 345.1191; Anal. Calcd for C16H16N4O5: C, 55.81; H, 4.68;
N, 16.27. Found: C, 55.54 ;H, 4.68; N, 16.19.
1,3-Diallyl-6-[4-(3,3,4,4,5,5,6,6,7,7,8,8,8-
tridecafluorooctyl)benzyloxy]-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-F13Bn): Following GP-1, bis(benzonitrile)palladium(II) chloride
(2.3 mg, 6.0 µmol) was added to a solution of 4 (273.2 mg, 1.20 mmol) in
THF (2.0 mL) at room temperature. The solution was heated at reflux for 1
1,3-Diallyl-6-(2-nitrobenzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione
(ATTACK-ONB): Following GP-1, bis(benzonitrile)palladium(II) chloride
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
(9.6 mg, 25 µmol) was added to a solution of 4 (1.366 mg, 6.00 mmol) in
THF (12 mL) at room temperature. The solution was heated at reflux for 1
h and then cooled to 0 °C. 2-Nitrobenzyl alcohol (765.7 mg, 10.0 mmol) in
THF (13 mL), Et3N (1.4 mL, 10.0 mmol), and N-methylimidazole (79.2 µL,
1.00 mmol) were added. The reaction mixture was stirred for 30 min at
0 °C and for 3.5 h at room temperature. The reaction mixture was poured
into aqueous citric acid (10%, 30 mL) and extracted with EtOAc (3  30
mL). The combined organic layer was washed with saturated aqueous
NaHCO3 (30 mL) and brine (50 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
1,3-Diallyl-6-methoxy-1,3,5-triazine-2,4(1H,3H)-dione (ATTACK-Me):
Following GP-1, bis(benzonitrile)palladium(II) chloride (9.6 mg, 25 µmol)
in THF (5.0 mL) was added to a solution of 4 (1.366 g, 6.00 mmol) in THF
(20 mL) at room temperature. The solution was heated at reflux for 2 h and
then cooled to 0 °C. Methanol (197.8 µL, 5.00 mmol), Et3N (1.4 mL, 10.1
mmol), and N-methylimidazole (79.0 µL, 1.00 mmol) were added. The
reaction mixture was stirred for 10 min at 0 °C and for 6 h at room
temperature. The reaction mixture was poured into aqueous citric acid
(10%, 30 mL) and extracted with EtOAc (3  30 mL). The combined organic
layer was washed with saturated aqueous NaHCO3 (30 mL) and brine (60
mL), dried with Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure. Silica gel column chromatography (hexane/EtOAc =
3:2) afforded a clear yellow oil (963.3 mg, 86%). 1H NMR (CDCl3): δ 5.97–
5.77 (m, 2H), 5.33–5.18 (m, 4H), 4.51 (ddd, J = 6.0, 1.4, 1.4 Hz, 2H), 4.48
(ddd, J = 6.0, 1.4, 1.4 Hz, 2H), 4.07 (s, 3H); 13C NMR (CDCl3): δ 159.2,
153.9, 150.2, 131.2, 130.6, 119.0, 118.5, 57.0, 44.9, 44.6; IR (CHCl3):
3051, 2997, 1680, 1612, 1483, 1434 cm–1; HRMS (ESI-TOF) Calcd for
C10H13N3NaO3 ([M + Na]+) 246.0855, found 246.0861; Anal. Calcd for
C10H13N3O3: C, 53.81; H, 5.87; N, 18.82. Found: C, 53.69 ;H, 6.02; N,
18.69.
chromatography (twice, CH2Cl2/EtOAc
chromatography, and hexane/EtOAc
=
19:1 to 7:3 for the first
=
6:4 to 5:5 for the second
chromatography) afforded a white solid (1.611 g, 94%). Mp 131.1–
132.3 °C; 1H NMR (400 MHz, CDCl3): δ 8.18–8.12 (m, 1H), 7.73–7.65 (m,
1H), 7.62–7.54 (m, 2H), 5.97–5.75 (m, 4H), 5.35–5.16 (m, 4H), 4.53–4.45
(m, 4H); 13C NMR (150 MHz, CDCl3): δ 158.3, 153.7, 150.2, 148.0, 134.0,
131.1, 130.6, 130.5, 130.1, 129.6, 125.6, 119.2, 118.8, 68.4, 45.2, 44.8;
IR (KBr): 3076, 2952, 1739, 1682, 1606, 1469, 1342 cm–1; HRMS (DART-
TOF) Calcd for C16H17N4O5 ([M + H]+) 345.1199, Found 345.1214; Anal.
Calcd for C16H16N4O5: C, 55.81; H, 4.68; N, 16.27. Found: C, 55.58; H,
4.75; N, 16.17.
General procedure for acid-catalyzed O-alkylation with ATTACK-R
and 3 (GP-2). Pyridinium salt 3 (10 mol-%) was added to a mixture of an
alcohol (1 equiv), ATTACK-R (1.2 equiv), and molecular sieves 5A (25
mg/mL) in 1,4-dioxane (0.2 M) at room temperature. The reaction mixture
was stirred until TLC monitoring indicated complete conversion. The
reaction mixture was diluted with Et2O or EtOAc and filtered. The filtrate
was washed with saturated aqueous NaHCO3 and brine, dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
to afford the desired product.
1,3-Diallyl-6-(4,5-dimethoxy-2-nitrobenzyloxy)-1,3,5-triazine-
2,4(1H,3H)-dione
(ATTACK-DMNB):
Following
GP-1,
bis(benzonitrile)palladium(II) chloride (3.9 mg, 10 µmol) in THF (3.0 mL)
was added to a solution of 4 (546.4 mg, 2.40 mmol) in THF (2.0 mL) at
room temperature. The solution was heated at reflux for 1.5 h and then
cooled to 0 °C. 4,5-Dimethoxy-2-nitrobenzyl alcohol (426.4 mg, 2.00
mmol) in THF (5.0 mL), Et3N (554.5 µL, 4.00 mmol), and N-
methylimidazole (31.6 µL, 0.400 mmol) were added. The reaction mixture
was stirred for 10 min at 0 °C and for 3 h at room temperature. The reaction
mixture was poured into aqueous citric acid (10%, 10 mL) and extracted
with EtOAc (3  10 mL). The combined organic layer was washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried with Na2SO4,
and filtered. The filtrate was concentrated under reduced pressure. Silica
gel column chromatography (twice, hexane/EtOAc = 1:1 for the first
chromatography, and CHCl3/acetone =19:1 for the second
chromatography) afforded a yellow solid (687.4 mg, 85%). Mp 143.7–
144.9 °C ; 1H NMR (CDCl3): δ 7.75 (s, 1H), 7.06 (s, 1H), 5.95–5.76 (m, 2H),
5.84 (s, 2H), 5.34–5.16 (m, 4H), 4.50 (ddd, J = 5.9, 1.7, 1.7 Hz, 2H), 4.46
(ddd, J = 5.9, 1.6, 1.6 Hz, 2H), 3.99 (s, 3H), 3.98 (s, 3H); 13C NMR (CDCl3):
δ 158.4, 153.7, 153.3, 150.2, 149.3, 140.8, 131.1, 130.5, 123.8, 119.1,
118.7, 113.0, 108.6, 68.7, 56.8, 56.6, 45.1, 44.8; IR (KBr): 2972, 1734,
General procedure for acid-catalyzed O-alkylation with ATTACK-R
and trifluoromethanesulfonic acid (GP-3). Trifluoromethanesulfonic
acid (10 mol-%) was added to a mixture of an alcohol (1 equiv), ATTACK-
R (1.2 equiv), and molecular sieves 5A (25 mg/mL) in 1,4-dioxane (0.2 M)
at room temperature. The reaction mixture was stirred until TLC monitoring
indicated complete conversion. The reaction mixture was diluted with Et2O
or EtOAc and filtered. The filtrate was washed with saturated aqueous
NaHCO3 and brine, dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography to afford the desired product.
1678, 1601, 1437, 1294, 1217 cm–1
; HRMS (ESI-TOF) Calcd for
Benzyl 6-bromohexyl ether (7a-Bn):[23] Following GP-2, 3 (10.2 mg, 30
µmol) was added to a mixture of 6a (40.8 µL, 0.300 mmol), ATTACK-Bn
(107.8 mg, 0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane
(1.2 mL). After 3.5 h, the reaction mixture was diluted with EtOAc (50 mL)
and filtered. The filtrate was washed with saturated aqueous NaHCO3 (15
mL) and brine (15 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/acetone = 97:3) followed by recycling preparative HPLC afforded
C18H20N4NaO7 ([M + Na]+) 427.1230, found 427.1209.
1,3-Diallyl-6-allyloxy-1,3,5-triazine-2,4(1H,3H)-dione (ATTACK-allyl):
Following GP-1, bis(benzonitrile)palladium(II) chloride (9.6 mg, 25 µmol)
was added to a solution of 4 (1.366 g, 6.00 mmol) in THF (6 mL) at room
temperature. The solution was heated at reflux for 1 h and then cooled to
0 °C. Allyl alcohol (340 µL, 5.00 mmol), Et3N (1.4 mL, 10.0 mmol), and N-
methylimidazole (79.2 µL, 1.00 mmol) were added. The reaction mixture
was stirred for 15 min at 0 °C and for 1.5 h at room temperature. The
reaction mixture was poured into aqueous citric acid (10%, 30 mL) and
extracted with CH2Cl2 (4  10 mL). The combined organic layer was
washed with brine (50 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/EtOAc = 7:3) afforded a white solid (1.23 g, quant.). 1H NMR (600
MHz, CDCl3): δ 6.05–5.95 (m, 1H), 5.95–5.79 (m, 2H), 5.46–5.19 (m, 6H),
4.99–4.94 (m, 2H), 4.53–4.47 (m, 4H); 13C NMR (150 MHz, CDCl3): δ
158.4, 154.0, 150.4, 131.2, 130.6, 130.4, 120.5, 119.3, 118.6, 70.7, 45.0,
44.7; IR (KBr): 3076, 2952, 1739, 1682, 1606, 1469, 1342 cm–1; HRMS
(DART-TOF) Calcd for C12H16N3O3 ([M + H]+) 250.1192, Found 345.1214;
Anal. Calcd for C12H15N3O3: C, 55.81; H, 4.68; N, 16.27. Found: C, 55.58;
H, 4.75; N, 16.17. Anal. Calcd for C12H15N3O3: C, 57.82; H, 6.07; N, 16.86.
Found: C, 57.78; H, 6.12; N, 16.76.
1
a clear colorless oil (71.5 mg, 88%). H NMR (400 MHz, CDCl3): δ 7.40–
7.23 (m, 5H), 4.50 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H),
1.86 (quint, J = 7.0 Hz, 2H), 1.63 (quint, J = 7.1 Hz, 2H), 1.52–1.35 (m,
4H); 13C NMR (100 MHz, CDCl3): δ 138.7, 128.5, 127.8, 127.6, 73.0, 70.3,
34.0, 32.9, 29.7, 28.1, 25.5; HRMS (DART-TOF) Calcd for C13H20BrO ([M
+ H]+) 271.0698, found 271.0689.
6-Bromohexyl 4-methoxybenzyl ether (7a-PMB):[24] Following GP-2
with slight modification, 3 (2.0 mg, 5.9 µmol) in 1,4-dioxane (0.4 mL) was
added to a mixture of 6a (40.8 µL, 0.300 mmol), ATTACK-PMB (122.1 mg,
0.37 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.1 mL) at
room temperature. After 20 min, the reaction mixture was diluted with Et2O
(6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/CH2Cl2 = 1:1) afforded a clear colorless oil (72.4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
mg, 80%). 1H NMR (600 MHz, CDCl3): δ 7.29–7.23 (m, 2H), 6.91–6.85 (m,
2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.44 (t, J = 6.8 Hz, 2H), 3.40 (t, J = 6.8 Hz,
2H), 1.86 (tt, J = 6.8, 6.8 Hz, 2H), 1.61 (tt, J = 6.8, 6.8 Hz, 2H) 1.49–1.34
(m, 4H); 13C NMR (100 MHz, CDCl3): δ 159.2, 130.8, 129.3, 113.8, 72.7,
70.0, 55.4, 34.0, 32.8, 29.7, 28.1, 25.5; HRMS (DART-TOF) Calcd for
C14H25BrNO2 ([M + NH4]+) 318.1069, found 318.1069.
(hexane/CH2Cl2 = 1:1) afforded a pale yellow solid (77.6 mg, 82%). 1H
NMR (400 MHz, CDCl3): δ 8.25–8.17 (m, 2H), 7.54–7.46 (m, 2H), 4.60 (s,
2H), 3.52 (t, J = 6.4 Hz, 2H), 3.42 (t, J = 6.9 Hz, 2H), 1.88 (tt, J = 6.4, 6.4
Hz, 2H), 1.67 (tt, J = 6.9, 6.9 Hz, 2H), 1.55–1.37 (m, 4H); 13C NMR (100
MHz, CDCl3): δ 147.4, 146.5, 127.8, 123.8, 71.8, 71.0, 34.0, 32.8, 29.6,
28.1, 25.5; IR (KBr): 2943, 2868, 1510, 1342, 1128, 1105, 841, 739 cm–1
;
HRMS (DART-TOF) Calcd for C13H19BrNO3 ([M + H]+) 316.0548, found
316.0562; Anal. Calcd for C13H18BrNO3: C, 49.38; H, 5.74; N, 4.43. Found:
C, 49.44 ;H, 5.71; N, 4.39.
6-Bromohexyl 4-methylbenzyl ether (7a-MBn): Following GP-2, 3 (13.7
mg, 40 µmol) was added to a mixture of 6a (54.5 µL, 0.400 mmol),
ATTACK-MBn (150.4 mg, 0.480 mmol), and molecular sieves 5A (50.0
mg) in 1,4-dioxane (2.0 mL) at room temperature. After 45 min, the
reaction mixture was diluted with Et2O (50 mL) and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/CHCl3 = 6:4)
followed by recycling preparative HPLC afforded a clear colorless oil (99.6
mg, 87%). 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 7.8 Hz, 2H), 7.15 (d,
J = 7.8 Hz, 2H), 4.46 (s, 2H), 3.44 (t, J = 6.4 Hz, 2H), 3.40 (t, J = 6.9 Hz,
2H), 2.34 (s, 3H), 1.86 (quint, J = 7.2 Hz, 2H), 1.61 (quint, J = 7.0 Hz, 2H),
1.51–1.34 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 137.3, 135.6, 129.1,
127.9, 72.9, 70.1, 34.0, 32.9, 29.7, 28.1, 25.5, 21.3; HRMS (DART-TOF)
Calcd for C14H25BrNO ([M + NH4]+) 304.1099, found: 304.1112 Anal. Calcd
for C14H21BrO: C, 58.95; H, 7.42. Found: C, 59.05; H, 7.50.
6-Bromohexyl 2-nitrobenzyl ether (7a-ONB): Following GP-3 with slight
modification, trifluoromethanesulfonic acid (26.2 µL, 300 µmol) was added
to a mixture of 6a (204.2 µL, 1.50 mmol), ATTACK-ONB (619.8 mg, 1.80
mmol), and molecular sieves 5A (187.5 mg) in 1,4-dioxane (7.5 mL) at
room temperature. After 69 h, the reaction mixture was diluted with Et2O
(30 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (30 mL) and brine (30 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (twice, hexane/CH2Cl2
chromatography, and hexane/EtOAc
=
=
7:3 to 0:1 for the first
9:1 for the second
chromatography) afforded a white solid (76.4 mg, 16%). 1H NMR (600
MHz, CDCl3): δ 8.09–8.03 (m, 1H), 7.82–7.76 (m, 1H), 7.68–7.62 (m, 1H),
7.47–7.40 (m, 1H), 4.87 (s, 2H), 3.58 (t, J = 6.4 Hz, 2H), 3.43 (t, J = 6.7
Hz, 2H), 1.89 (tt, J = 7.1, 7.1 Hz, 2H), 1.68 (tt, J = 6.8, 6.8 Hz, 2H), 1.54–
1.41 (m, 4H); 13C NMR (150 MHz, CDCl3): δ 147.4, 135.5, 133.7, 128.7,
127.9, 124.7, 71.2, 69.5, 34.0, 32.8, 29.6, 28.1, 25.5; IR (CHCl3): 3039,
3014, 2941, 2864, 1531, 1344, 11110, 707 cm–1; HRMS (DART-TOF)
Calcd for C13H22BrN2O3 ([M + NH4]+) 333.0814, Found 333.0811; Anal.
Calcd for C13H18BrNO3: C, 49.38; H, 5.74; N, 4.43. Found: C, 49.44; H,
5.71; N, 4.39.
6-Bromohexyl
4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)benzyl
ether (7a-F13Bn): Following GP-2, 3 (4.8 mg, 14 µmol) was added to a
mixture of 6a (19.0 µL, 0.140 mmol), ATTACK-F13Bn (108.2 mg, 0.168
mmol), and molecular sieves 5A (25 mg) in 1,4-dioxane (1.0 mL) at room
temperature. After 2 h, the reaction mixture was diluted with Et2O (50 mL)
and filtered. The filtrate was washed with saturated aqueous NaHCO3 (10
mL) and brine (10 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/acetone = 97:3) followed by recycling preparative HPLC afforded
a clear colorless oil (78.8 mg, 91%). 1H NMR (400 MHz, CDCl3): δ 7.30 (d,
J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 4.48 (s, 2H), 3.47 (t, J = 6.7 Hz,
2H), 3.40 (t, J = 6.7 Hz, 2H), 2.96–2.86 (m, 2H), 2.46–2.25 (m, 2H), 1.86
6-Bromohexyl
4,5-dimethoxy-2-nitrobenzyl
ether
(7a-DMNB):
Following GP-3, trifluoromethanesulfonic acid (2.6 µL, 30 µmol) was added
to a mixture of 6a (40.8 µL, 0.300 mmol), ATTACK-DMNB (145.6 mg,
0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5 mL)
at room temperature. After 2.5 h, the reaction mixture was diluted with Et2O
(6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/AcOEt = 9:1) afforded a yellow solid (22.4 mg,
20%). 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.30 (s, 1H), 4.89 (s, 2H),
4.00 (s, 3H), 3.96 (s, 3H), 3.61 (t, J = 6.6 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H),
1.89 (tt, J = 6.6, 6.6 Hz, 2H), 1.71 (tt, J = 6.9, 6.9 Hz, 2H) 1.56–1.40 (m,
4H); 13C NMR (100 MHz, CDCl3): δ 153.9, 147.6, 139.3, 131.4, 109.5,
107.9, 71.2, 69.6, 56.5, 33.9, 32.8, 29.7, 28.1, 25.6; IR (KBr): 2937, 1518,
1462, 1319, 1273, 1223, 1115 cm–1; HRMS (DART-TOF) Calcd for Calcd
for C15H23BrNO5 ([M + H]+) 376.0760, found 376.0759; Anal. Calcd for
C15H22BrNO5: C, 47.88; H, 5.89; N, 3.72. Found: C, 47.74; H, 5.91; N, 3.68.
(quint, J = 7.3 Hz, 2H), 1.63 (quint, J = 7.1 Hz, 2H), 1.51–1.35 (m, 4H); 13
C
NMR (100 MHz, CDCl3): δ 138.6, 137.3, 128.5, 128.3, 118.4–111.2 (m),
72.7, 70.4, 34.0, 33.3, 33.1, 32.91, 32.87, 29.7, 28.1, 26.33, 26.2, 25.6;
HRMS (DART-TOF) Calcd for C21H26BrF13NO ([M + NH4]+) 634.0990,
found: 634.0960 Anal. Calcd for C21H22BrF13O: C, 40.86; H, 3.59. Found:
C, 40.96; H, 3.68.
4-Bromobenzyl 6-bromohexyl ether (7a-PBB):[25] Following GP-3,
trifluoromethanesulfonic acid (2.6 µL, 30 µmol) was added to a mixture of
6a (40.8 µL, 0.300 mmol), ATTACK-PBB (136.2 mg, 0.360 mmol), and
molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5 mL) at room
temperature. After 5 h, the reaction mixture was diluted with Et2O (6 mL)
and filtered. The filtrate was washed with saturated aqueous NaHCO3 (6
mL) and brine (6 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/CH2Cl2 = 7:3) afforded a clear colorless oil (89.8 mg, 86%). 1H
NMR (400 MHz, CDCl3): δ 7.50–7.43 (m, 2H), 7.24–7.17 (m, 2H), 4.44 (s,
2H), 3.45 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.4 Hz, 2H), 1.86 (tt, J = 6.6, 6.6
Hz, 2H), 1.62 (tt, J = 7.3, 6.4 Hz, 2H), 1.52–1.34 (m, 4H); 13C NMR (100
MHz, CDCl3): δ 137.8, 131.6, 129.4, 121.5, 72.3, 70.5, 34.0, 32.8, 29.7,
28.1, 25.5; HRMS (DART-TOF) Calcd for C13H19Br2O ([M + H]+) 348.9803,
found 348.9797.
Allyl 6-bromohexyl ether (7a-allyl):[5] Following GP-2 with slight
modification, 3 (13.7 mg, 40 µmol) was added to a mixture of 6a (54.5 µL,
0.400 mmol), ATTACK-allyl (118.5 mg, 0.48 mmol), and molecular sieves
5A (50 mg) in 1,4-dioxane (2.0 mL) at 50 °C. After 6.5 h, the reaction
mixture was diluted with Et2O (10 mL) and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/CH2Cl2 = 6:4)
afforded a clear colorless oil (74.1 mg, 84%).1H NMR (600 MHz, CDCl3):
δ 5.96–5.82 (m, 1H), 5.33–5.22 (m, 1H), 5.22–5.12 (m, 1H), 4.01–3.92 (m,
2H), 3.43 (t, J = 7.1 Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 1.87 (tt, J = 7.1, 7.1
Hz, 2H), 1.61 (tt, J = 7.1, 7.1 Hz, 2H), 1.50–1.35 (m, 4H); 13C NMR (150
MHz, CDCl3): δ 135.1, 116.9, 72.0, 71.3, 34.0, 32.9, 29.7, 28.1, 25.5; IR
(CHCl3): 3053, 2939, 2864, 1188, 928, 818, 700 cm–1; HRMS (DART-TOF)
Calcd for C9H21BrNO ([M + NH4]+) 238.0807, Found 238.0809.
6-Bromohexyl 4-nitrobenzyl ether (7a-PNB): Following GP-3 with slight
modification, trifluoromethanesulfonic acid (5.2 µL, 60 µmol) was added to
a mixture of 6a (40.8 µL, 0.300 mmol), ATTACK-PNB (124.0 mg, 0.360
mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5 mL) at room
temperature. After 23 h, the reaction mixture was diluted with Et2O (6 mL)
and filtered. The filtrate was washed with saturated aqueous NaHCO3 (6
mL) and brine (6 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
6-Bromohexyl methyl ether (7a-Me):[26] Following GP-3 with slight
modification, trifluoromethanesulfonic acid (2.7 µL, 31 µmol) was added to
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
a mixture of 6a (42.2 µL, 0.310 mmol), ATTACK-Me (83.3 mg, 0.373 mmol),
and molecular sieves 5A (37.5 mg) in 1,4-dioxane (0.2 M) at room
temperature. The reaction mixture was stirred for 1 h at room temperature,
for 30 min at 40 °C, for 30 min at 60 °C, for 30 min at 80 °C, for 4.5 h at
reflux, and then cooled to room temperature. The reaction mixture was
diluted with Et2O (6 mL) and filtered. The filtrate was washed with saturated
aqueous NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/AcOEt = 19:1) afforded a clear colorless oil (33.8
mg, 56%). 1H NMR (600 MHz, CDCl3): δ 3.41 (t, J = 7.0 Hz, 2H), 3.37 (t, J
= 6.2 Hz, 2H), 3.33 (s, 3H), 1.87 (tt, J = 7.0, 7.0 Hz, 2H), 1.63–1.55 (m,
2H), 1.51–1.42 (m, 2H), 1.42–1.33 (m, 2H); 13C NMR (150 MHz, CDCl3): δ
72.8, 58.7, 34.0, 32.9, 29.6, 28.1, 25.5; IR (CHCl3): 2937, 2862, 1720,
1111, 754, 700 cm–1; HRMS (DART-TOF) Calcd for C7H16BrO ([M + H]+)
195.0385, found 195.0390.
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/AcOEt = 9:1) afforded a clear colorless oil (89.6
mg, 89%). 1H NMR (400 MHz, CDCl3): δ 7.30–7.22 (m, 2H), 6.91–6.84 (m,
2H), 4.43 (s, 2H), 4.05 (t, J = 6.7 Hz, 2H), 3.80 (s, 3H), 3.43 (t, J = 6.7 Hz,
2H), 2.05 (s, 3H), 1.67–1.55 (m, 4H), 1.36–1.25 (m, 12H); 13C NMR (100
MHz, CDCl3): δ 171.4, 159.2, 130.9, 129.3, 113.8, 72.6, 70.3, 64.8, 55.3,
29.9, 29.6, 29.5, 29.3, 28.7, 26.3, 26.0, 21.1; HRMS (DART-TOF) Calcd
for C20H33O4 ([M + H]+) 337.2379, found 337.2363.
Methyl
(2R)-3-[(4-methoxybenzyl)oxy]-2-methylpropionate
(7c-
PMB):[28,29] Following GP-2 with slight modification, 3 (2.0 mg, 5.9 µmol)
in 1,4-dioxane (0.4 mL) was added to a mixture of 6c (33.1 µL, 0.300
mmol), ATTACK-PMB (122.1 mg, 0.37 mmol), and molecular sieves 5A
(37.5 mg) in 1,4-dioxane (1.1 mL) at room temperature. After 10 min, the
reaction mixture was diluted with Et2O (6 mL) and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (6 mL) and brine (6 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 9:1)
afforded a clear colorless oil (57.7 mg, 87%). 1H NMR (400 MHz, CDCl3):
δ 7.27–7.20 (m, 2H), 6.91–6.84 (m, 2H), 4.48–4.43 (m, 2H), 3.80 (s, 3H),
3.69 (s, 3H), 3.63 (dd, J = 9.2, 7.3 Hz, 1H), 3.46 (dd, J = 9.2, 6.0 Hz, 1H),
2.81–3.71 (m, 1H), 1.17 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ 175.3, 159.1, 130.2, 129.2, 113.7, 72.7, 71.6, 55.2, 51.7, 40.1, 14.0;
HRMS (DART-TOF) Calcd for C13H19O4 ([M + H]+) 239.1283, found
239.1285.
1-Acetoxydecyl 10-benzyl ether (7b-Bn):[7] Following GP-2, 3 (10.2 mg,
30 µmol) was added to a mixture of 6b (64.9 mg, 0.300 mmol), ATTACK-
Bn (107.8 mg, 0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-
dioxane (1.5 mL) at room temperature. After 4.5 h, the reaction mixture
was diluted with Et2O (50 mL) and filtered. The filtrate was washed with
saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried with Na2SO4,
and filtered. The filtrate was concentrated under reduced pressure. Silica
gel column chromatography (hexane/EtOAc = 9:1) afforded a clear
colorless oil (88.7 mg, 97%). 1H NMR (400 MHz, CDCl3): δ 7.53–7.20 (m,
5H), 4.50 (s, 2H), 4.05 (t, J = 6.9 Hz, 2H), 3.46 (t, J = 6.7 Hz, 2H), 2.04 (s,
3H), 1.74–1.48 (m, 4H), 1.50–1.15 (m, 12H); 13C NMR (100 MHz, CDCl3):
δ 171.4, 138.8, 128.5, 127.7, 127.6, 73.0, 70.6, 64.8, 29.9, 29.61, 29.56,
29.4, 28.7, 26.3, 26.0, 21.2; HRMS (DART-TOF) Calcd for C19H34NO3 ([M
+ NH4]+): 324.2539, found: 324.2529.
1-Adamantyl 4-methoxybenzyl ether (7d-PMB): Following GP-2 with
slight modification, 3 (2.0 mg, 5.9 µmol) in 1,4-dioxane (0.4 mL) was added
to a mixture of 6d (45.7 mg, 0.300 mmol), ATTACK-PMB (122.1 mg, 0.37
mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.1 mL) at room
temperature. After 10 min, the reaction mixture was diluted with Et2O (6
mL) and filtered. The filtrate was washed with saturated aqueous NaHCO3
(6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/Et2O = 19:1) afforded a clear colorless oil (50.6 mg, 62%). 1H
NMR (400 MHz, CDCl3): δ 7.30–7.24 (m, 2H), 6.90–6.82 (m, 2H), 4.44 (s,
2H), 3.79 (s, 3H), 2.17 (br s, 3H), 1.84 (d, J = 2.3 Hz, 6H), 1.70–1.59 (m,
6H); 13C NMR (150 MHz, CDCl3): δ 158.9, 132.3, 129.1, 113.8, 72.7, 62.1,
55.4, 41.9, 36.6, 30.7; IR (KBr): 2912, 2850, 1612, 1512, 1244, 1084, 1024,
822 cm–1; HRMS (DART-TOF) Calcd for C18H25O2 ([M + H]+) 273.1855,
found 273.1842.
Methyl (2R)-3-(benzyloxy)-2-methylpropionate (7c-Bn):[7] Following
GP-2, 3 (17.1 mg, 50 µmol) was added to a mixture of 6c (55.2 µL, 0.500
mmol), ATTACK-Bn (179.6 mg, 0.600 mmol), and molecular sieves 5A
(62.5 mg) in 1,4-dioxane (2.5 mL) at room temperature. After 5 h, the
reaction mixture was diluted with Et2O (50 mL) and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 9:1)
afforded a clear colorless oil (96.5 mg, 93%). 1H NMR (400 MHz, CDCl3):
δ 7.42–7.21 (m, 5H), 4.52 (s, 2H), 3.69 (s, 3H), 3.66 (dd, J = 9.2, 7.4 Hz,
1H), 3.49 (dd, J = 8.7, 6.0 Hz, 1H), 2.87–2.71 (m, 1H), 1.18 (d, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 175.4, 138.2, 128.4, 127.69, 127.66,
73.2, 72.0, 51.8, 40.3, 14.1; HRMS (DART-TOF): Calcd for C12H17O3 ([M
+ H]+) 209.11789, found: 209.1182.
10-Acetoxydecyl 4-methylbenzyl ether (7b-MBn): Following GP-2, 3
(13.7 mg, 40 µmol) was added to a mixture of 6b (86.5 mg, 0.400 mmol),
ATTACK-MBn (150.4 mg, 0.480 mmol), and molecular sieves 5A (50.0
mg) in 1,4-dioxane (2.0 mL) at room temperature. After 45 min, the
reaction mixture was diluted with Et2O (50 mL) and filtered. The filtrate
was washed with saturated aqueous NaHCO3 (15 mL) and (15 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 19:1)
afforded a clear colorless oil (125.5 mg, 98%). 1H NMR (400 MHz, CDCl3):
δ 7.24 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 4.46 (s, 2H), 4.05 (t, J
= 6.9 Hz, 2H), 3.44 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.04 (s, 2H), 1.67–1.54
(m, 4H), 1.40–1.18 (m, 12H); 13C NMR (100 MHz, CDCl3): δ 171.3, 137.2,
135.7, 129.1, 127.8, 72.8, 70.4, 64.7, 29.9, 29.6, 29.5, 29.3, 28.7, 26.3,
26.0, 21.3, 21.1; HRMS (DART-TOF) Calcd for C20H33O3 ([M + H]+)
321.2430, found 321.2441. Anal. Calcd for C20H32O3: C, 74.96; H, 10.07.
Found: C, 74.95; H, 10.22.
1-Adamantyl benzyl ether (7d-Bn):[7] Following GP-2, 3 (13.7 mg, 40
µmol) was added to a mixture of 6d (60.9 mg, 0.400 mmol), ATTACK-Bn
(143.7 mg, 0.480 mmol), and molecular sieves 5A (50.0 mg) in 1,4-dioxane
(2.0 mL) at room temperature. After 9.5 h, the reaction mixture was diluted
with Et2O (50 mL) and filtered. The filtrate was washed with saturated
aqueous NaHCO3 (15 mL) and brine (15 mL), dried with Na2SO4, and
filtered. The filtrate was concentrated under reduced pressure. Silica gel
column chromatography (hexane/acetone
= 97:3) afforded a clear
colorless oil (85.8 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 7.40–7.18 (m,
5H), 4.51 (s, 2H), 2.17 (br s, 3H), 1.94–1.79 (m, 6H), 1.72–1.55 (m, 6H);
13C NMR (100 MHz, CDCl3): δ 140.3, 128.4, 127.6, 127.1, 72.8, 62.4, 41.9,
36.6, 30.7; HRMS (DART-TOF) Calcd for C17H23O ([M + H]+) 243.1749,
found: 243.1760.
Methyl (2R)-3-[(4-methylbenzyl)oxy]-2-methylpropionate (7c-MBn):
Following GP-2, 3 (34.1 mg, 0.100 mmol) was added to a mixture of 6c
(110.4 µL, 1.00 mmol), ATTACK-MBn (376.0 mg, 1.20 mmol), and
molecular sieves 5A (125 mg) in 1,4-dioxane (5.0 mL) at room temperature.
After 1 h, the reaction mixture was diluted with Et2O (50 mL) and filtered.
The filtrate was washed with saturated aqueous NaHCO3 (15 mL) and
brine (15 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
10-Acetoxydecyl 4-methoxybenzyl ether (7b-PMB):[27] Following GP-2
with slight modification, 3 (2.0 mg, 5.9 µmol) in 1,4-dioxane (0.4 mL) was
added to a mixture of 6b (64.9 mg, 0.300 mmol), ATTACK-PMB (122.1 mg,
0.37 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.1 mL) at
room temperature. After 10 min, the reaction mixture was diluted with Et2O
(6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
(hexane/EtOAc = 19:1) followed by recycling preparative HPLC afforded a
clear colorless oil (206.6 mg, 93%). 1H NMR (400 MHz, CDCl3): δ 7.20 (d,
J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 4.50 (d, J = 13.4 Hz, 1H), 4.46 (d,
J = 13.4 Hz, 1H), 3.69 (s, 3H), 3.63 (dd, J = 8.7, 7.2 Hz, 1H), 3.47 (dd, J =
9.2, 6.0 Hz, 1H), 2.85–2.70 (m, 1H), 2.34 (s, 3H), 1.17 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 175.4, 137.4, 135.2, 129.1, 127.8, 73.1,
71.9, 51.8, 40.3, 21.3, 14.1; HRMS (DART-TOF): Calcd for C13H22NO3 ([M
+ NH4]+) 240.1600, found: 240.1588. Anal. Calcd for C13H18O3: C, 70.24;
H, 8.16. Found: C, 70.03; H, 8.37.
mixture of 6d (25.6 mg, 0.17 mmol), ATTACK-F13Bn (130.1 mg, 0.20
mmol), and molecular sieves 5A (25.0 mg) in 1,4-dioxane (1.0 mL) at room
temperature. After 3 h, the reaction mixture was diluted with Et2O (50 mL)
and filtered. The filtrate was washed with saturated aqueous NaHCO3 (15
mL) and brine (15 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/EtOAc = 97:3) afforded a clear colorless oil (90.5 mg, 92%). 1H
NMR (400 MHz,CDCl3): δ 7.31 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H),
4.48 (s, 2H), 2.95–2.82 (m, 2H), 2.47–2.22 (m, 2H), 2.18 (br s, 3H), 1.93–
1.79 (m, 6H), 1.75–1.56 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 138.8,
138.0, 128.3, 128.2, 118.8–108.4 (m), 72.9, 62.2, 46.0, 41.9, 36.9, 36.8,
36.6, 36.5, 33.4, 33.2, 33.0, 31.2, 30.9, 30.7, 26.32, 26.27, 26.2; HRMS
(DART-TOF): Calcd for C25H29F13NO ([M + NH4]+): 606.2042, found:
606.2014.
1-Adamantyl 4-methylbenzyl ether (7d-MBn): Following GP-2, 3 (17.1
mg, 50 µmol) was added to a mixture of 6d (76.1 mg, 0.400 mmol),
ATTACK-MBn (188.0 mg, 0.600 mmol), and molecular sieves 5A (62.5
mg) in 1,4-dioxane (2.0 mL) at room temperature. After 2 h, the reaction
mixture was diluted with Et2O (50 mL) and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/Et2O = 19:1)
followed by recycling preparative HPLC afforded a white solid (110.5 mg,
86%). Mp 47.9–48.9 °C; 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 7.8 Hz,
2H), 7.12 (d, J = 7.8 Hz, 2H), 4.46 (s, 2H), 2.32 (s, 3H), 2.17 (br s, 3H),
1.92–1.78 (m, 6H), 1.72–1.56 (m, 6H); 13C NMR (100 MHz, CDCl3): δ
137.2, 136.7, 129.0, 128.9, 127.6, 72.7, 62.3, 46.0, 41.9, 41.7, 36.7, 36.6,
36.5, 31.2, 30.8, 30.7, 21.3; HRMS (DART-TOF): Calcd for C18H25O ([M +
H]+): 257.1905, found: 257.1903. Anal. Calcd for C18H24O: C, 84.32; H,
9.44. Found: C, 84.14; H, 9.41.
10-Acetoxydecyl 4-bromobenzyl ether (7b-PBB): Synthesis following
GP-2. Pyridinium salt 3 (10.2 mg, 30 µmol) in 1,4-dioxane (0.6 mL) was
added to a mixture of 6b (64.9 mg, 0.300 mmol), ATTACK-PBB (136.2 mg,
0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (0.9 mL)
at room temperature. After 24 h, the reaction mixture was diluted with Et2O
(6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/EtOAc = 19:1) afforded a clear colorless oil
(103.0 mg, 89%).
Synthesis following GP-3. Trifluoromethanesulfonic acid (2.6 µL, 30 µmol)
was added to a mixture of 6b (64.9 mg, 0.300 mmol), ATTACK-PBB (136.2
mg, 0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (0.6
mL) at room temperature. After 5 h, the reaction mixture was diluted with
Et2O (6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/EtOAc = 9:1) afforded a clear colorless oil (104.1
mg, 90%).
10-Acetoxydecyl
4-(3,3,4,4,5,5,6,6,7,7,8,8,8-
tridecafluorooctyl)benzyloxy ether (7b-F13Bn): Following GP-2, 3 (5.0
mg, 15 µmol) was added to a mixture of 6b (31.6 mg, 0.15 mmol),
ATTACK-F13Bn (113.1 mg, 0.175 mmol), and molecular sieves 5A (25 mg)
in 1,4-dioxane (1 mL) at room temperature. After 2 h, the reaction mixture
was diluted with Et2O (50 mL) and filtered. The filtrate was washed with
saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried with Na2SO4,
and filtered. The filtrate was concentrated under reduced pressure. Silica
gel column chromatography (hexane/EtOAc = 19:1) afforded a clear
colorless oil (91.3 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.0
Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.48 (s, 2H), 4.05 (t, J = 6.9 Hz, 2H), 3.46
(t, J = 6.9 Hz, 2H), 3.00–2.83 (m, 2H), 2.44–2.24 (m, 2H), 2.04 (s, 3H),
1.70–1.57 (m, 4H), 1.42–1.20 (m, 12H); 13C NMR (100 MHz, CDCl3): δ
171.4, 138.5, 137.4, 128.4, 128.3, 119.8–108.9 (m), 72.7, 70.7, 64.8, 33.3,
33.1, 33.0, 29.9, 29.63, 29.59, 29.4, 28.7, 26.32, 26.27, 26.25, 26.0, 21.1;
HRMS (DART-TOF) Calcd for C27H34F13O3 ([M + H]+): 653.2300, Found:
653.2272 Anal. Calcd for C27H33F13O3: C, 49.70; H, 5.10, found: C, 49.78;
H, 5.28.
1H NMR (600 MHz, CDCl3):δ 7.49–7.43 (m, 2H), 7.24–7.18 (m, 2H), 4.44
(s, 2H), 4.05 (t, J = 6.9 Hz, 2H), 3.45 (t, J = 6.5 Hz, 2H), 2.05 (s, 3H), 1.66–
1.56 (m, 4H), 1.38–1.26 (m, 12H); 13C NMR (150 MHz, CDCl3): δ 171.4,
137.9, 131.6, 129.4, 121.4, 72.2, 70.8, 64.8, 29.9, 29.61, 29.57, 29.55,
29.4, 28.7, 26.3, 26.0, 21.2; IR (CHCl3): 3051, 2931, 2858, 2401, 1728,
1261 cm–1; HRMS (DART-TOF) Calcd for C19H30BrO3 ([M + H]+) 385.1378,
found 385.1366; Anal. Calcd for C19H29BrO3: C, 59.22; H, 7.59; N, 0.
Found: C, 58.84 ;H, 7.63; N, 0.10.
Methyl (2R)-3-[(4-bromobenzyl)oxy]-2-methylpropionate (7c-PBB):[30]
Synthesis following GP-2. Pyridinium salt 3 (10.2 mg, 30 µmol) in 1,4-
dioxane (0.6 mL) was added to a mixture of 6c (33.1 µL, 0.300 mmol),
ATTACK-PBB (136.2 mg, 0.360 mmol), and molecular sieves 5A (37.5 mg)
in 1,4-dioxane (0.9 mL) at room temperature. After 24 h, the reaction
mixture was diluted with Et2O (6 mL) and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (6 mL) and brine (6 mL), dried with
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 9:1)
afforded a clear colorless oil (73.5 mg, 85%).
Methyl
(2R)-3-[4-(3,3,4,4,5,5,6,6,7,7,8,8,8-
(7c-F13Bn):
tridecafluorooctyl)benzyloxy]-2-methylpropionate
Following GP-2, 3 (3.0 mg, 8.8 µmol) was added to a mixture of 6c (9.8 µL,
88.8 µmol), ATTACK-F13Bn (68.9 mg, 0.11 mmol), and molecular sieves
5A (12.5 mg) in 1,4-dioxane (0.6 mL) at room temperature. After 4 h, the
reaction mixture was diluted with Et2O (40 mL) and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 19:1)
afforded a clear colorless oil (48.9 mg, 99%). 1H NMR (400 MHz, CDCl3):
δ 7.27 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 4.50 (s, 2H), 3.70 (s,
3H), 3.66 (dd, J = 9.2, 7.3 Hz, 1H), 3.49 (dd, J = 9.2, 6.0 Hz, 1H), 2.97–
2.85 (m, 2H), 2.87–2.70 (m, 1H), 2.46–2.25 (m, 2H), 1.18 (d, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 175.4, 138.6, 136.8, 128.4, 128.2,
119.8–109.4 (m), 72.9, 72.1, 51.9, 40.3, 33.1 (t, J = 21.5 Hz), 26.27, 26.25,
14.1; HRMS (DART-TOF): Calcd for C20H23F13NO3 ([M + NH4]+): 572.1470,
found: 572.1461; Anal. Calcd for C20H19F13O3: C, 43.33; H, 3.45. Found:
C, 43.71; H, 3.65.
Synthesis following GP-3. Trifluoromethanesulfonic acid (2.6 µL, 30 µmol)
was added to a mixture of 6c (33.1 µL, 0.300 mmol), ATTACK-PBB (136.2
mg, 0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5
mL) at room temperature. After 7 h, the reaction mixture was diluted with
Et2O (6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/EtOAc = 9:1) afforded a clear colorless oil (79.7
mg, 93%), which was used for HPLC analysis.
1-Adamantyl
4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)benzyl
ether (7d-F13Bn):[14] Following GP-2, 3 (5.7 mg, 17 µmol) was added to a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
1H NMR (600 MHz, CDCl3): δ 7.49–7.43 (m, 2H), 7.21–7.15 (m, 2H), 4.47
(s, 2H), 3.70 (s, 3H), 3.64 (dd, J = 9.1, 7.3 Hz, 1H), 3.48 (dd, J = 9.1, 5.8
Hz, 1H), 2.83–2.73 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz,
CDCl3): δ 175.3, 137.3, 131.6, 129.3, 121.6, 72.5, 72.2, 51.9, 40.3, 14.1;
IR (CHCl3): 2956, 2868, 1734, 1489, 1092, 1012 cm–1; HRMS (DART-
TOF) Calcd for C12H16BrO3 ([M + H]+) 287.0283, found 287.0279.
(6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. Silica gel column chromatography
(hexane/EtOAc = 19:1) afforded a white solid (79.2 mg, 92%). 1H NMR
(400 MHz, CDCl3): δ 8.23–8.15 (m, 2H), 7.55–7.49 (m, 2H), 4.62 (s, 2H),
2.20 (s, 3H), 1.84 (m, 6), 1.72–1.59 (m, 6H); 13C NMR (150 MHz, CDCl3):
δ 148.2, 147.2, 127.7, 123.6, 73.5, 61.5, 41.8, 36.5, 30.7; IR (KBr): 2927,
2887, 2854, 1521, 1344, 1124, 1101 cm–1; HRMS (DART-TOF) Calcd for
C17H22NO3 ([M + H]+) 288.1600, found 288.1593; Anal. Calcd for
C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.69 ;H, 7.46; N, 4.79.
1-Adamantyl 4-bromobenzyl ether (7d-PBB):[30] Following GP-3 with
slight modification, trifluoromethanesulfonic acid (2.6 µL, 30 µmol) was
added to a mixture of 6d (45.7 mg, 0.300 mmol), ATTACK-PBB (136.2 mg,
0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5 mL)
at room temperature. After 6 h, the reaction mixture was diluted with Et2O
(6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/EtOAc = 49:1) followed by recycling preparative
HPLC afforded a white solid (60.6 mg, 63%). 1H NMR (400 MHz, CDCl3):δ
7.46–7.40 (m, 2H), 7.25–7.19 (m, 2H), 4.45 (s, 2H), 2.17 (br s, 3H), 1.86–
1.78 (m, 6H), 1.70–1.58 (m, 6H); 13C NMR (150 MHz, CDCl3): δ 139.4,
131.4, 129.2, 120.9, 73.1, 61.8, 41.8, 36.6, 30.7; IR (CHCl3): 2910, 1848,
1485, 1350, 1120, 1088 cm–1; HRMS (DART-TOF) Calcd for C17H25BrNO
([M + NH4]+) 338.1120, found 338.1106.
Acknowledgments
This work was partially supported by the JSPS Grants-in-Aid for
Scientific Research program (KAKENHI, grant number
17H03970).
Keywords: Nitrogen heterocycles • Alcohols • Ethers •
Protecting groups • Synthetic methods
[1]
[2]
K. Yamada, H. Fujita, M. Kunishima, Org. Lett. 2012, 14, 5026–5029.
K. Yamada, S. Yoshida, H. Fujita, M. Kitamura, M. Kunishima, Eur. J.
Org. Chem. 2015, 7997–8002.
10-Acetoxydecyl 4-nitrobenzyl ether (7b-PNB): Following GP-3 with
slight modification, trifluoromethanesulfonic acid (5.2 µL, 60 µmol) was
added to a mixture of 6b (64.9 mg, 0.300 mmol), ATTACK-PNB (124.0 mg,
0.360 mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5 mL)
at room temperature. After 24 h, the reaction mixture was diluted with Et2O
(6 mL) and filtered. The filtrate was washed with saturated aqueous
NaHCO3 (6 mL) and brine (6 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure. Silica gel column
chromatography (hexane/EtOAc = 9:1) afforded a yellow oil (88.5 mg,
84%). 1H NMR (400 MHz, CDCl3): δ 8.24–8.17 (m, 2H), 7.53–7.47 (m, 2H),
4.60 (s, 2H), 4.05 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 2.05 (s, 3H),
1.70–1.56 (m, 4H), 1.42–1.28 (m, 12H); 13C NMR (150 MHz, CDCl3): δ
171.4, 147.4, 146.6, 127.8, 123.7, 71.7, 71.3, 64.8, 29.8, 29.60, 29.57,
29.5, 29.3, 28.7, 26.3, 26.0, 21.2; IR (CHCl3): 3051, 2931, 1728, 1523,
1348, 1259, 1192 cm–1; HRMS (DART-TOF) Calcd for C19H30NO5 ([M +
H]+) 352.2124, found 352.2132; Anal. Calcd for C19H29NO5: C, 64.93; H,
8.32; N, 3.99. Found: C, 64.60;H, 8.48; N, 3.95.
[3]
[4]
[5]
[6]
[7]
K. Yamada, H. Fujita, M. Kitamura, M. Kunishima, Synthesis 2013, 45,
2989–2997.
K. Yamada, N. Hayakawa, H. Fujita, M. Kitamura, M. Kunishima, Eur. J.
Org. Chem. 2016, 4093–4098.
K. Yamada, N. Hayakawa, H. Fujita, M. Kitamura, M. Kunishima, Chem.
Pharm. Bull. 2017, 65, 112–115.
H. Fujita, N. Hayakawa, M. Kunishima, J. Org. Chem. 2015, 80, 11200–
11205.
H. Fujita, S. Kakuyama, M. Kunishima, Eur. J. Org. Chem. 2017, 833–
839.
[8]
[9]
M. Kunishima, H. Fujita, K. Yamada, 2013, WO2013073681.
M. Kunishima, H. Fujita, K. Yamada, 2014, US2014343281.
[10] P. A. Reynolds, G. F.; Nagel, C. J. M.; Larson, J. Chem. Res., Synop.
1982, 310–311.
[11] V. R. Likhterov, S. V. Klenovich, V. S. Étlis, L. A. Tsareva, É. G.
Pomerantseva, S. M. Shmuilovich, Chem. Heterocycl. Compd. 1988, 24,
308–311.
Methyl (2R)-3-[(4-nitrobenzyl)oxy]-2-methylpropionate (7c-PNB):
Following GP-3 with slight modification, trifluoromethanesulfonic acid (5.2
µL, 60 µmol) was added to a mixture of 6c (33.1 µL, 0.300 mmol),
ATTACK-PNB (124.0 mg, 0.360 mmol), and molecular sieves 5A (37.5
mg) in 1,4-dioxane (1.5 mL) at room temperature. The reaction mixture
was heated at 50 °C for 4 h and then cooled to room temperature. The
reaction mixture was diluted with Et2O (6 mL) and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (6 mL) and brine (6 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 9:1 to 17:3)
afforded a pale yellow solid (72.5 mg, 95%). Mp 37.0–37.6 °C; 1H NMR
(40 MHz, CDCl3): δ 8.24–8.17 (m, 2H), 7.47–7.44 (m, 2H), 4.62 (s, 2H),
3.71 (s, 3H), 3.71 (dd, J = 8.7, 7.8 Hz, 1H), 3.56 (dd, J = 8.7, 6.0 Hz, 1H),
2.89–2.76 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ 175.2, 147.5, 146.0, 127.7, 123.7, 72.7, 72.0, 52.0, 40.2, 14.1; IR (KBr):
2371, 1728, 1517, 1344, 1107, 1012 cm–1; HRMS (DART-TOF) Calcd for
C12H16NO5 ([M + H]+) 254.1029, found 254.1028; Anal. Calcd for
C12H15NO5: C, 56.91; H, 5.97; N, 5.53. Found: C, 56.84 ;H, 6.10; N, 5.51.
[12] P. Metz, C. Mues, A. Schoop, Tetrahedron 1992, 48, 1071–1080.
[13] P. G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th ed.,
John Wiley & Sons, Hoboken, 2014.
[14] M. Kunishima, R. Asao, K. Yamada, M. Kitamura, H. Fujita, J. Fluorine
Chem. 2016, 190, 68–74.
[15] L. J. Chen, L. T. Burka, Tetrahedron Lett. 1998, 39, 5351–5354.
[16] A. Adhikari, L. Radal, J. Chisholm, Synlett 2017, 28, 2335–2339.
[17] W. F. Veldhuyzen, Q. Nguyen, G. McMaster, D. S. Lawrence, J. Am.
Chem. Soc. 2003, 125, 13358–13359.
[18] S. Tang, Z. Wan, Y. Gao, J. S. Zheng, J. Wang, Y. Y. Si, X. Chen, H. Qi,
L. Liu, W. Liu, Chem. Sci. 2016, 7, 1891–1895.
[19] J. D. Kim, G. Han, L. S. Jeong, H. J. Park, O. P. Zee, Y. H. Jung,
Tetrahedron 2002, 58, 4395–4402.
[20] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165–195.
[21] G. A. Crispino, R. Breslow, J. Org. Chem. 1992, 57, 1849–1855.
[22] H. Koopman, J. Daams, Recl. des Trav. Chim. des Pays-Bas 2010, 79,
83–89.
[23] E. D. Nacsa, T. H. Lambert, Org. Lett. 2013, 15, 38–41.
[24] T.-S. Hu, Q. Yu, Y.-L. Wu, Y. Wu, J. Org. Chem. 2001, 66, 853–861.
[25] M. S. Bayerl, T. Braig, O. Nuyken, D. C. Müller, M. Groß, K. Meerholz,
Macromol. Rapid Commun. 1999, 20, 224–228.
1-Adamantyl 4-nitrobenzyl ether (7d-PNB): Following GP-3 with slight
modification, trifluoromethanesulfonic acid (5.2 µL, 60 µmol) was added to
a mixture of 6d (45.6 mg, 0.300 mmol), ATTACK-PNB (124.0 mg, 0.360
mmol), and molecular sieves 5A (37.5 mg) in 1,4-dioxane (1.5 mL) at room
temperature. The reaction mixture was heated at 50 °C for 5 h and then
cooled to room temperature. The reaction mixture was diluted with Et2O (6
mL) and filtered. The filtrate was washed with saturated aqueous NaHCO3
[26] D. Sahoo, S. Thiele, M. Schulte, N. Ramezanian, A. Godt, Beilstein J.
Org. Chem. 2010, 6, 20–24.
[27] K. Walsh, H. F. Sneddon, C. J. Moody, Tetrahedron 2014, 70, 7380–
7387.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
[28] R. D. Walkup, J. D. Kahl, R. R. Kane, J. Org. Chem. 1998, 63, 9113–
9116.
[29] A. Fürstner, E. Kattnig, O. Lepage, J. Am. Chem. Soc. 2006, 128, 9194–
9204.
[30] P. A. Albiniak, S. M. Amisial, G. B. Dudley, J. P. Hernandez, S. E. House,
M. E. Matthews, E. O. Nwoye, M. K. Reilly, S. F. Tlais, Synth. Commun.
2008, 38, 656–665.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900607
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents (about 350
characters)
Key Topic*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
NOTE: the final letter height should
not be less than 2 mm.))
*one or two words that highlight the emphasis of the paper or the field of the study
Layout 2:
FULL PAPER
O-Alkylating agents*
Hikaru Fujita, Rina Yamashita, Takanori
Fujii, Kohei Yamada, Masanori
Kitamura, and Munetaka Kunishima*
Page No. – Page No.
Diallyltriazinedione-type
acid-catalyzed
alkylating
agents
Title
(ATTACKs-R) have been developed in combination with various
alkyl groups (R). ATTACKs-R were prepared via the palladium-
catalyzed O-N allylic rearrangement of 2,4-bis(allyloxy)-6-chloro-
1,3,5-triazine followed by substitution of the chloro group with an
alcohol.
Preparation of Alkyl Ethers with
Diallyltriazinedione-Type Acid-
Catalyzed Alkylating Agents
(ATTACKs-R)
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.