Triazine-Based Cationic Leaving Group: Synergistic Driving Forces for Rapid Formation of Carbocation Species

Article abstract of DOI:10.1021/acs.joc.8b00331

A new triazine-based cationic leaving group has been developed for the acid-catalyzed alkylation of O- and C-nucleophiles. There are two synergistic driving forces, namely, stable C=O bond formation and charge-charge repulsive effects, involved in the rapid generation of the carbocation species in the presence of trifluoromethanesulfonic acid (～200 mol %). Considerable rate acceleration of benzylation, allylation, and p-nitrobenzylation was observed as compared to the reactions with less than 100 mol % of the acid catalyst. The triazine-based leaving group showed superior p-nitrobenzylation yield and stability in comparison to common leaving groups, trichloroacetimidate and bromide. A plausible reaction mechanism (the cationic leaving group pathway) was proposed on the basis of mechanistic and kinetic studies, NMR experiments, and calculations.

Full text of DOI:10.1021/acs.joc.8b00331

Subscriber access provided by ECU Libraries
Triazine-Based Cationic Leaving Group: Synergistic
Driving Forces for Rapid Formation of Carbocation Species
Hikaru Fujita, Satoshi Kakuyama, Shuichi Fukuyoshi,
Naoko Hayakawa, Akifumi Oda, and Munetaka Kunishima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00331 • Publication Date (Web): 04 Apr 2018
Downloaded from http://pubs.acs.org on April 4, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 28
The Journal of Organic Chemistry
1
2
3
4
5
Triazine-Based Cationic Leaving Group: Synergistic Driving Forces for Rapid Formation of Carbocation
Species
6
7
8
9
Hikaru Fujita,† Satoshi Kakuyama,† Shuichi Fukuyoshi,† Naoko Hayakawa,† Akifumi Oda,‡ Munetaka
Kunishima*,†
†Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
University, Kakumaꢀmachi, Kanazawa 920ꢀ1192, Japan
‡Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempakuꢀku, Nagoya, Aichi 468ꢀ8503, Јapan
Table of Content
ABSTRACT
A new triazineꢀbased cationic leaving group has been developed for the acidꢀcatalyzed alkylation of Oꢀ and
Cꢀnucleophiles. There are two synergistic driving forces, namely, stable C=O bond formation and chargeꢀcharge
repulsive effects, involved in the rapid generation of the carbocation species in the presence of
trifluoromethanesulfonic acid (~200 mol%). Considerable rate acceleration of benzylation, allylation, and
pꢀnitrobenzylation was observed as compared to the reactions with less than 100 mol% of the acid catalyst. The
triazineꢀbased leaving group showed superior pꢀnitrobenzylation yield and stability in comparison to common
leaving groups, trichloroacetimidate and bromide. A plausible reaction mechanism (the cationic leaving group
pathway) was proposed on the basis of mechanistic and kinetic studies, NMR experiments, and calculations.
INTRODUCTION
To date, a large number of leaving groups (LGs) have been developed because of the fundamental importance of
substitution reactions in organic chemistry.1 Most of the reported LGs are either anionic or neutral. Cationic LGs2–4
have also been reported in studies relating to the decomposition reactions of dicationic compounds.5 However, their
application to organic synthesis is limited because the dicationic precursors are generally unstable and difficult to
prepare in advance. Instead, the in situ activation of LGs by diprotonation is a rational and useful method to form
cationic LGs from easyꢀtoꢀhandle, neutral precursors (Scheme 1). The strong driving force of bond cleavage to
separate dications into monocations is known as the chargeꢀcharge repulsive effect of diprotonated intermediates
called superelectrophiles.6 Successful applications of such LG activation were reported for halogenation7,8 and
FriedelꢀCrafts type reactions,9,10 whose proposed or possible reaction mechanisms involved the formation of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 28
1
2
3
4
5
cationic LGs (Figure 1).11 However, these reactions were carried out using a large excess (typically the solvent) of a
strong acid or a superacid. Furthermore, such cationic LGs only cleaved weak nitrogenꢀhalogen (Cl, Br, or I) bonds
+
or provided carbocations stabilized by heteroatoms such as acylium ions and isocyanate cations (O=C=NR2 ). Also,
6
7
8
9
the nucleophiles in such reactions were limited to aromatic compounds and alkenes. In order to overcome these
issues, we propose herein a new concept of cationic LGs, which exhibit an additional driving force to facilitate the
formation of the carbocation species.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. In situ activation of a LG by diprotonation followed by substitution with a nucleophile to form a
cationic LG
NuH
NuR + H+
2H+
2+
+
R
LG
R
LG—H2
LG—H2
in situ
dicationic
cationic LG
intermediate
(Ref. 7)
(Ref. 8)
X
X
N
N
HO
OH
HO
OH
N
N
X
X
X = Cl, Br, I
O
X = Cl, Br, I
(Ref. 10)
(Ref. 9)
H
O
NO2H
Y
O
OMe
Z
N
H
R2N
O
H
H
O
OMe
Y = O, Z = R
Y = O or S, Z = NR2
Figure 1. Previously reported dicationic intermediates activated in situ. Proposed cationic LGs are indicated in
dashed squares.
We have developed a series of triazineꢀbased alkylating reagents, which generate a variety of carbocation species
under acidic conditions.12 Stable C=O bond formation (10–11 kcal/mol stabilization)13 in the LGs is considered to
be a key driving force of these reactions. For example, 1-Bn-H+, formed by the monoprotonation of
2ꢀbenzyloxyꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine (1-Bn), afforded neutral triazineꢀbased LG 2 and a benzyl cation species,
probably benzyl trifluoromethanesulfonate, with a halfꢀlife of 42 min at 25 °C (Scheme 2a).12d Similar stable bond
formation has also been utilized as a driving force for wellꢀdesigned LGs.14 Thus, we conceived that the
2+
diprotonated alkoxytriazines 1-R-H2 would exhibit a synergistic combination of driving forces, namely, stable
C=O bond formation and chargeꢀcharge repulsive effects (Scheme 2b). We found that this double acceleration leads
to a rapid generation of highly reactive carbocation species without the need for heteroatom stabilization from
stable precursors (2ꢀalkoxyꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine, 1-R) in the presence of only less than two equivalents of
a superacid catalyst. Alcohols, carboxylic acids, and an aromatic compound were chosen as nucleophiles for
ACS Paragon Plus Environment

Page 3 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
alkylation with this carbocation species. Mechanistic and kinetic studies, NMR experiments, and calculations
rationalized the design concept of the triazineꢀbased cationic LGs, and provided us insights into the reaction
mechanism.
7
8
9
Scheme 2. Synergistic Driving Forces of a Triazine-Based Cationic LG
(a)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TfO
Bn
O
O
C=O bond
formation
Bn OTf
Bn OTf
H
H
N
N
N
N
+
MeO
(b)
N
OMe
MeO
N
OMe
1-Bn-H+
2
C=O bond
formation
Charge-charge
repulsive effects
R
O
O
Synergistic
driving forces
NuH
H
H
H
H
R+
N
N
N
N
+
NuR
+
MeO
N
OMe
2+
MeO
N
2-H+
OMe
1-R-H2
H+
RESULTS AND DISCUSSION
Acid-Catalyzed Alkylation Using Triazine-Based Reagents. We first carried out Oꢀbenzylation of alcohol 3a in
1,4ꢀdioxane using 1-Bn in the presence of trifluoromethanesulfonic acid (TfOH) at 25 °C. Powdered molecular
sieves 5A were added as a dehydrating agent to remove residual moisture.12a Interestingly, when 200 mol% of
TfOH (182 mol% based on 1-Bn) was used, the Oꢀbenzylation was complete within a minute and afforded the
corresponding benzyl ether 4a in 84% yield (Table 1, entry 1).15 In contrast, almost no reaction took place with 100
mol% (91 mol% based on 1-Bn) of TfOH in 1 min (entry 2). These results suggested that the reaction mechanism
was dependent on the amount of TfOH.
Table 1. Acid-Catalyzed Benzylation of 3a Using 1-Bn
OBn
TfOH
+
N
N
Ph
OH
Ph
OBn
1,4ꢀdioxane
OMe
MS5A
3a
(1 equiv)
4a
(1 equiv)
MeO
N
25 °C
1-Bn
(1.1 equiv)
1 min
entry TfOH (mol%) 4a (%)a recovered 3a (%)a
1
200
84
1
2
100
1
99
a Calculated from 1H NMR analysis using an internal standard.
We applied the reaction conditions with 1-Bn and TfOH (200 mol%) to various nucleophiles (Table 2). Chloroalkyl,
bromoalkyl, and fluorous alcohols (3b, 3c, and 3e, respectively) were Oꢀbenzylated in high yields (89–90%, entries
1–3). The Oꢀbenzylation of aliphatic and conjugated carboxylic acids (3f and 3g, respectively) afforded the
corresponding benzyl esters 4f and 4g in 86% yield (entries 4 and 5). Furthermore, the Cꢀbenzylation of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 28
1
2
3
4
5
6
7
8
9
pentamethylbenzene (3h) also proceeded smoothly (94% yield, entry 6). Similar Oꢀ and Cꢀallylation reactions were
conducted using 2ꢀallyloxyꢀ4,6ꢀdimethoxytriazine (1-allyl) in the presence of TfOH (200 mol%). As a result, allyl
haloalkyl ethers (5b, 5d, and 5e; entries 1–3), allyl esters (5f and 5g, entries 4 and 5), and allylpentamethylbenzene
(5h, entry 6) were obtained in good to high yields (71–95%) within 10–20 min. Longꢀchain bromoalkyl alcohol 3d
was used for the Oꢀallylation instead of 3c to increase the boiling point of the product. The lower isolated yields of
5b and 5e in comparison to their NMR yields (84% vs 90% of 5b; 71% vs 88% of 5e) were attributed to their
volatility. Furthermore, it was possible to introduce the pꢀnitrobenzyl (PNB) group in the nucleophiles by using
2ꢀ(pꢀnitrobenzyl)oxyꢀ4,6ꢀdimethoxytriazine (1-PNB) and TfOH (200 mol%). Similarly, PNB ethers (6b, 6c, and
6e; entries 1–3), PNB esters (6f and 6g, entries 4 and 5), and pentamethyl(pꢀnitrobenzyl)benzene (6h, entry 6) were
obtained in good to high yields (76–97%), although 10 h were required for the completion of the reactions. As
shown in entry 1, when 100 mol% of TfOH was used for the Oꢀallylation (or Oꢀpꢀnitrobenzylation) of 3b with
1-allyl (or 1-PNB), only 1% of the corresponding allyl (or PNB) ether 5b (or 6b) was obtained in 10 min (or 10 h).
Again, these results imply a change in the reaction mechanism depending on the amount of TfOH. The successful
alkylation of arene 3h (entry 6) suggested that benzyl, allyl, and PNB cations were the intermediates of the
reactions with 1-Bn, 1-allyl, and 1-PNB, respectively. The increasing order of the reaction times, i.e., 1 min for
benzylation < 10–20 min for allylation < 10 h for pꢀnitrobenzylation, reflected the order of stability of the
corresponding carbocations.16,17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Introduction of Benzyl, Allyl, and p-Nitrobenzyl (PNB) Groups to Various Nucleophiles Using 1-Bn,
1-allyl, and 1-PNB in the Presence of TfOH (200 mol%)
OR
TfOH (200 mol%)
N
N
+
Nu
H
Nu
R
1,4ꢀdioxane, MS5A, rt
MeO
N
OMe
3
4 R
( = Bn)
5 (R = allyl)
1-Bn
1 min (for
)
(1 equiv)
(1.1 equiv)
1-Bn (R = Bn)
1-allyl (R = allyl)
10 min (for 1-allyl)
1-PNB
6
(R = PNB)
10 h (for
)
1-PNB
(R = PNB)
entry nucleophile
product
yield of
(%)a
4b
4
yield of
(%)a
5
yield of
(%)a
6
O
O
1
2
3
5b
6b
Cl
OH
Cl
OR
90
84b (90)c
1c,d
95
1c,d
3b
4c (n = 1)
5d (n = 11)
87e
6c (n = 1)
97
Br
OR
n
89
3c (n = 1), 3d (n = 11)
4e
5e
6e
90
71b (88)c
91
3e
ACS Paragon Plus Environment

Page 5 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
4
4f
86f
5f
76f,g
6f
O
Ph
84
R
O
O
7
8
3f
5
6
O
4g
86h
5g
74g,h
6g
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
O
Ph
76
3g
Me
Me
Me
4h
5h
6h
Me
Me
Me
Me
R
92
95
94
Me
Me
Me
3h
a
b
c
e
Isolated yields. Isolated yields were lower than the NMR yields because of the volatility of the products.
1
d
Calculated from H NMR spectroscopic analysis using an internal standard. TfOH (100 mol%) was used.
Reaction time was 20 min. f 1.3 equivalents of 1-Bn or 1-allyl were used. g Molecular sieves (3Å) were used. h 1.2
equivalents of 1-Bn or 1-allyl were used.
Next,
we
conducted
the
acidꢀcatalyzed
Oꢀ1ꢀadamantylation
of
3a
using
2ꢀ(1ꢀadamantyl)oxyꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine (1-Ad) (Table 3). The corresponding 1ꢀadamantyl ether 7a was
obtained in high yield in the presence of both 100 and 200 mol% of TfOH (90%, entry 1; 92%, entry 2). In contrast
to the alkylation reactions shown in Table 2, the increased amount of TfOH had little influence on the reaction time
(7.5 h, entry 1; 3 h, entry 2). Entry 3 shows the incomplete formation of 7a at 25 min with TfOH (200 mol%).
However, careful monitoring of the reaction revealed the rapid disappearance of 1-Ad in the presence of TfOH
(200 mol%), and the slow formation of 7a from 3a and a moderately stable intermediate, probably 1ꢀadamantyl
trifluoromethanesulfonate18 (Figure 2, details in Figures S1 and S2). A gradual decrease in the amount of 1-Ad was
observed when 100 mol% of TfOH was used. In contrast, it disappeared almost completely within 30 s in the
presence of 200 mol% of TfOH. Therefore, a change in the reaction mechanism was also evident in the case of the
reaction with 1-Ad. The substitution at 1ꢀadamantyl group is considered to be a suitable model to study typical SN1
behavior since βꢀelimination or rearꢀside nucleophilic attack is not allowed.19 Thus, these results suggest that the
carbocation species forms from 1-R via an SN1 mechanism in the presence of an excess amount of TfOH.
Table 3. Acid-Catalyzed O-1-Adamantylation Using 1-Ad
entry
TfOH (mol%)
time
yield of
7a (%)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 28
1
2
3
4
5
1
2
3
100
200
200
7.5 h
3 h
90a
92b
78a
6
25 min
7
8
a Calculated from 1H NMR spectroscopic analysis using an internal standard. b Isolated yield.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Time course of 1-Ad and 7a in acidꢀcatalyzed Oꢀ1ꢀadamantylation of 3a with 100 or 200 mol% of TfOH.
Reaction conditions: 3a (50 mM, 1 equiv), 1-Ad (1 equiv), TfOH (100 or 200 mol%), 1ꢀchlorooctane (internal
standard, 1 equiv), 1,4ꢀdioxane, rt. Aliquots were withdrawn from the reaction mixture at indicated time and treated
with an excess amount of EtOH containing iPr2EtN.
Comparison of the Triazine-Based LG with Other LGs. To demonstrate the synthetic utility of alkylation with
the triazineꢀbased reagents described above, we compared their reactivity and stability with those of other common
alkylating reagents, namely, alkyl 2,2,2ꢀtrichloroacetimidate (RꢀTCAI) and alkyl bromide (RꢀBr).
OꢀpꢀNitrobenzylation. Interestingly, the Oꢀpꢀnitrobenzylation of an alcohol with PNBꢀTCAI has been seldom
reported despite the usefulness of PNB as a protecting group.20 In fact, only one report referred to this reaction
briefly, but the experimental details were not described.21 We attempted the TfOHꢀcatalyzed Oꢀpꢀnitrobenzylation
of 3b with PNBꢀTCAI (Table 4). It was found that the yields of 6b under these conditions were moderate (40% in
CH2Cl2, entry 1; 72% in 1,4ꢀdioxane, entry 2) even though the reactions were performed in the presence of TfOH
(20 mol%). When the amount of TfOH was increased to 200 mol%, the yield did not improve (64%, entry 3). In
these cases, various amounts of Oꢀtrichloroacetimidoyl and trichloroacetyl products of 3b (respectively, 12–23% in
total, details are given in Table S1) were observed as byꢀproducts. Owing to these competing side reactions, it was
difficult to achieve high yields in Oꢀpꢀnitrobenzylation with PNBꢀTCAI. An alternative method to introduce the
PNB group is the combination of PNBꢀBr and a silver salt such as Ag2O. These conditions are chosen because
Williamson ether synthesis cannot to be applied as a result of the decomposition of PNBꢀBr under strongly basic
conditions.20 Chloroalkyl alcohol 3b was converted to 6b with PNBꢀBr/Ag2O in 87% yield (entry 4). However, the
ACS Paragon Plus Environment

Page 7 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
reaction of bromoalkyl alcohol 3c led to poor yield of the product (13%, entry 5). Therefore, it is worth noting that
the reaction of 1-PNB with TfOH allowed the introduction of the PNB group to baseꢀ and silverꢀsensitive alcohols
3b and 3c, and excellent yields (95 and 97%, entries 1 and 2 in Table 2, respectively) were attainable.
7
8
9
Table 4. O-p-Nitrobenzylation Using p-Nitrobenzyl 2,2,2-Trichloroacetimidate (PNB-TCAI) and
p-Nitrobenzyl Bromide (PNB-Br)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry reagent, additive
solvent
time
(h)
yield
(%)a
40
1
PNBꢀTCAI (1.1 equiv) CH2Cl2
TfOH (20 mol%)
32
2
PNBꢀTCAI (1.1 equiv) 1,4ꢀdiox 6.5
TfOH (20 mol%)
aneb
PNBꢀTCAI (1.1 equiv) 1,4ꢀdiox 0.5
73 (72)c
64
3
TfOH (200 mol%)
PNBꢀBr (1.2 equiv)
Ag2O (1.2 equiv)
PNBꢀBr (1.2 equiv)
Ag2O (1.2 equiv)
aneb
4
CH2Cl2
24
24
87
5d
CH2Cl2
13
a Calculated from 1H NMR spectroscopic analysis using an internal standard. b Molecular sieves (5Å) were added. c
Isolated yield. d Alcohol 3c was used instead of 3b to obtain PNB ether 6c.
Stability. As shown in Tables 2 and 3, the triazineꢀbased LGs showed remarkable reactivity in the presence of an
excess amount of TfOH. On the other hand, they were found to be highly stable under other more common
conditions. Table 5 summarizes the results of the experiments demonstration the inertness of the triazineꢀbased LGs.
The benzyl derivatives, namely, 1-Bn, BnꢀTCAI, and BnꢀBr, were exposed to (A) acidic (TsOHꢀH2O (0.5 equiv),
CH2Cl2/MeOH, rt, 5 min), (B) nucleophilic [Et2NH (2.5 equiv), CH2Cl2, rt, 1 h], and (C) reductive [Zn (5 equiv),
NH4Cl (5 equiv), EtOH, reflux, 5 min] conditions, respectively.22 In these experiments, 1-Bn was recovered almost
quantitatively in all cases (96–98% recovery, entry 1). In contrast, considerable decomposition was observed for
BnꢀTCAI and BnꢀBr. While BnꢀTCAI was resistant to condition (B) (96% recovery), it decomposed to benzyl
alcohol almost completely under conditions (A) and (C) (entry 2). On the other hand, BnꢀBr was partially stable
under condition (A) (63% recovery), although it did not survive under conditions (B) and (C) (entry 3). Thus, it was
evident that the triazineꢀbased LGs had superior stability in comparison to TCAI and bromide, providing
practicability for handling and possibility of acting as protecting groups of carbocation species for selective
transformations.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 28
1
2
3
4
5
Table 5. Stability of LGs under the Acidic, Nucleophilic, and Reductive conditions.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry starting
material
conditions recovery (%)a
1
Ab
Bc
Cd
Ab
Bc
Cd
Ab
Bc
Cd
98
1-Bn
96
96
tracee
2
3
BnꢀTCAI
BnꢀBr
96
n.d.f,g
63
traceh
n.d.g
a
Calculated from 1H NMR spectroscopic analysis using an internal standard. b Acidic conditions: TsOHꢀH2O (0.5
equiv), CH2Cl2/MeOH (1:1, 0.2 M), rt, 5 min. c Nucleophilic conditions: Et2NH (2.5 equiv), CH2Cl2 (0.2 M), rt, 1 h.
d Reductive conditions: Zn (5 equiv), NH4Cl (5 equiv), EtOH (0.5 M), reflux, 5 min. e Benzyl alcohol was obtained
f
g
h
in 83% yield. Benzyl alcohol was obtained in 96% yield. Not detected. Benzyldiethylamine was obtained in
86% yield.
Mechanistic Studies. NMR analysis. To observe the protonation behavior of the triazineꢀbased LGs by TfOH, we
performed 13C NMR analysis (NoDꢀNMR) in 1,4ꢀdioxane using 2,4,6ꢀtrimethoxyꢀ1,3,5ꢀtriazine (1-Me) as a model
compound. Figure 3 plots the chemical shifts of the methyl group in 1-Me (1 equiv) versus the amount of TfOH (0–
500 mol%). A linear downfield shift from 55.0 to 58.6 ppm was observed when the concentration of TfOH was less
than 100 mol%. This downfield shift was linear and gradual (58.6136 to 58.7572 ppm) in the range of 105–500
mol% TfOH. This gradual shift (0.1436 ppm) is significant because only a small change (± 0.0062 ppm at the
maximum) was detected in the carbon chemical shifts of dodecane, which was used as a control during the addition
of TfOH (0–500 mol%) under the same conditions (details are given in Table S3). The downfield shifts of 1-Me
can be explained by the quantitative formation of 1-Me-H+ by monoprotonation with TfOH (< 100 mol%) and the
subsequent equilibration to the diprotonated form 1-Me-H22+ with an excess of TfOH (> 100 mol%).23
ACS Paragon Plus Environment

Page 9 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
OMe
N
OMe
N
OMe
H+
H+
H
H
H
N
N
N
N
7
8
MeO
N
OMe
MeO
N
OMe
MeO
N
OMe
2+
1-Me
1-Me-H+
1-Me-H2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. NMR spectroscopic analysis of the protonation of 1-Me with TfOH.
Kinetic Study. We studied the kinetics of the Oꢀbenzylation of 3a (100 mM) using benzyloxytriazine 8 (100 mM) in
the presence of various amounts of TfOH (95–200 mM (or mol% based on 8)) to gain insights into the mechanism
of the reaction (Table 6). This kinetic study was performed at −10 °C to decrease the reaction rate to a measurable
degree. 1,2ꢀDimethoxyethane (DME) (m.p. −58 °C) was used as a solvent instead of 1,4ꢀdioxane (m.p. 12 °C)
because DME has similar properties to those of 1,4ꢀdioxane; it dissolves TfOH well and shows favorable solvent
effects in the acidꢀcatalyzed Oꢀbenzylation.12a Compound 8 possesses lipophilic cyclohexylmethyl groups instead
of methyl groups, which increase its solubility in DME. Firstꢀorder kinetics were observed for the decrease in the
[8-H+] concentration with any [TfOH].24,25 The observed firstꢀorder kinetic constants (kobs) are summarized in Table
6 (entries 1–5). It was concluded that the trifluoromethanesulfonate anion (TfO−) did not affect the rateꢀdetermining
step because the addition of TfONnBu4 had no effect on the reaction rate (entry 3 vs 6). This result also indicated
that the influence of ionic strength could be ignored. Figure 4 clearly shows that kobs increased sharply when
[TfOH] > 100 mM (i.e., concentration of TfOH was greater than 100 mol%), which supported the formation of a
dicationic intermediate. The reaction rate in the case of [TfOH] = 200 mM was more than 800 times faster than that
the reaction with [TfOH] = 95 mM. Interestingly, a careful analysis revealed that the increase in the value of kobs
could be correlated with the square of [TfOHex]. Here, [TfOHex] is defined by [TfOH] − 100 mM and represents the
concentration of an excess amount of TfOH over 8 (listed in Table 6). The likely linear relationship between
[TfOHex]2 and kobs (r2 = 0.975) is shown in Figure 5.26 This correlation may suggest that two molecules of TfOHex
are involved in the transition state.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 28
1
2
3
Table 6. Observed First-Order Rate Constants of TfOH-Catalyzed O-Benzylation with 8
4
5
6
7
8
Ph 3OH
Ph 3OBn
TfOH
(95–200 mM)
3a
4a
(100 mM)
+
+
DME, MS5A
–10 °C
TfO
O
OBn
9
N
N
HN
NH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
O
O
N
O
8 (100 mM, 1 equiv)
entry TfOH
TfOHex
k
obs (10−3 relativ
or min−1)a
e rate
(mM or (mM
mol%)
mol%)
ꢀ
1
2
3
4
5
95
0.0831 ± 1.00
0.0343
110
140
170
200
140
10
40
70
100
40
1.42
0.54
13.6
1.2
±
±
±
±
17.1
164
413
801
165
34.3
4.5
66.6
6.1
6b
a
13.7
Rate constants (kobs) were determined by HPLC analysis using pꢀnitrotoluene as an internal standard.
Measurement of kobs was repeated three times each except for entry 6. b TfONnBu4 (100 mM) was added.
Figure 4. Dependence of kobs on [TfOH] for the TfOHꢀcatalyzed Oꢀbenzylation with 8.
ACS Paragon Plus Environment

Page 11 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Linear relationship between [TfOHex]2 and kobs
.
Calculations. Since results depicted in Figure 3 suggested the formation of a dicationic species of 1-Me, we
calculated the energy differences between Nꢀ or Oꢀprotonated mono/dication of 1-Me in 1,4ꢀdioxane using
protonated 1,4ꢀdioxane as a proton donor (Figures 6 and 7, B3LYP/6ꢀ31+G(d,p)). As shown in Figure 6, it was
evident that the Nꢀprotonation of the triazine nitrogen provided significant stabilization (−20.5 kcal/mol). This is in
agreement with the quantitative formation of 1-Me-H+ by TfOH shown in Figure 3. In contrast, the Oꢀprotonation
of 1-Me was a disfavored process (1-Me-H+ (O), +12.1 kcal/mol). Calculations for the dications of 1-Me are
2+
shown in Figure 7. The most stable dication was the N,N'ꢀdiprotonated 1-Me-H2 (+15.1 kcal/mol). This result
indicated that the further protonation of 1-Me-H+ to form 1-Me-H2 was disfavored (+35.6 kcal/mol). The other
2+
2+
2+
2+
possible dications (1-Me-H2 (OO), 1-Me-H2 (o-NO), and 1-Me-H2 (p-NO)) had higher energies than that of
1-Me-H22+ (37.7–66.9 kcal/mol).
E (kcal/mol)
ꢀ
H
O
Me
O
O
N
N
+12.1
+
MeO
N
OMe
OMe
N
H
1-Me-H + (O)
O
N
+
MeO
N
OMe
O
OMe
1-Me
H
O
O
N
N
0 kcal/mol
+
–20.5
MeO
N
OMe
1-Me-H+
Figure 6. Calculated energy differences (kcal/mol) of the Nꢀ or Oꢀprotonated monocation of 1-Me
(B3LYP/6ꢀ31+G(d,p), in 1,4ꢀdioxane).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7. Calculated energy differences (kcal/mol) of the Nꢀ or Oꢀprotonated dications of 1-Me
(B3LYP/6ꢀ31+G(d,p), in 1,4ꢀdioxane).
The tautomerization energy from 1-H-H+ to 2-H+ was calculated to be −8.49 kcal/mol in 1,4ꢀdioxane, which
reflected the stability of the C=O bond in 2-H+ (Scheme 3a). Furthermore, the model reaction between 1-Me-H+
and methanol to give 2-H+ and dimethyl ether was calculated to be a favored process in 1,4ꢀdioxane (−12.8
kcal/mol, Scheme 3b). Therefore, the C=O bond formation in cationic LG 2-H+ can be an effective driving force
for the generation of carbocation species from 1-R-H+, similar to that in a triazineꢀbased neutral LG.13
Scheme 3. Calculated Energy differences of (a) the tautomerization of 1-H-H+ to 2-H+ and (b) the model
reaction between 1-Me-H+ and methanol to give 2-H+ and dimethyl ether (B3LYP/6-31+G(d,p), in
1,4-dioxane)
H
O
O
ꢀE = –8.49 kcal/mol
H
H
H
(a)
N
N
N
N
MeO
N
OMe
MeO
N
OMe
1-H-H+
2-H+
Me
O
O
H
H
H
N
N
N
N
ꢀE = –12.8 kcal/mol
(b)
MeO
N
OMe
MeO
N
OMe
1-Me-H+
2-H+
+
+
MeO
H
MeO Me
ACS Paragon Plus Environment

Page 13 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Further calculations were performed to compare the driving forces in isodesmic reactions of triazine compounds,
where a methyl cation was hypothetically exchanged (Scheme 4). The favored reaction in Scheme 4a (–14.3
kcal/mol) predicted the formation of the neutral LG 2 from 1-Me-H+ rather than that of 9, which is an tautomer of 2.
2+
Similarly, the formation of the cationic LG 2-H+ from 1-Me-H2 was calculated to be more favored than that of
9-H+ (–14.1 kcal/mol, Scheme 4b). A large energy difference (–64.0 kcal/mol) was found in the methyl cation
2+
exchange between 1-Me-H2 and 2 to give 2-H+ and 1-Me-H+ (Scheme 4c). This stabilization (–64.0 kcal/mol)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
overwhelms the energy difference of the second protonation process calculated in Figures 6 and 7 (1-Me-H+ to
2+
1-Me-H22+, +35.6 kcal/mol). Therefore, the reaction affording the triazineꢀbased cationic LG (1-Me-H2 to
2-H+) would be favored over the formation of the neutral LG (1-Me-H+ to 2). Chargeꢀcharge repulsive effects can
explain the large driving force of the formation of 2-H+.
Scheme 4. Calculated Isodesmic Reactions for the Hypothetical Methyl Cation Exchange Between (a)
1-Me-H+ and 9, (b) 1-Me-H22+ and 9-H+, and (c) 1-Me-H22+ and 2 (B3LYP/6-31+G(d,p), in 1,4-dioxane)
Me
O
OMe
O
OMe
H
H
H
H
ꢀE = –14.3 kcal/mol
N
N
N
N
N
N
N
N
(a)
+
+
MeO
N
OMe
O
N
OMe
MeO
N
OMe
MeO
N
OMe
1-Me-H+
9
2
1-Me-H+
Me
O
OMe
N
O
OMe
H
H
H
O
H
H
H
H
H
ꢀE = –14.1 kcal/mol
N
N
N
N
N
N
N
(b)
+
+
MeO
N
OMe
N
9-H+
OMe
MeO
N
2-H+
OMe
MeO
N
OMe
2+
2+
1-Me-H2
1-Me-H2
Me
O
Me
O
O
O
H
H
H
H
H
H
ꢀE = –64.0 kcal/mol
N
N
N
N
N
N
N
N
(c)
+
+
MeO
N
OMe
2+
MeO
N
OMe
MeO
N
2-H+
OMe
MeO
N
OMe
2
1-Me-H+
1-Me-H2
Reaction Mechanisms. On the basis of the above considerations, we proposed a plausible reaction mechanism of
TfOHꢀcatalyzed alkylation with 1-R (Figure 8). As a large K1 was indicated by the model experiments and
calculations (Figures 3 and 6), protonation of 1-R by TfOH was considered to proceed quantitatively to give the
monocation/TfO− salt 9. This salt generated the neutral LG 2 along with the corresponding carbocation species,
probably alkyl triflate (ROTf), which may form carbocation (R+−OTf) depending on the ionizing ability of the R
group (neutral LG pathway). If an excess amount of TfOH was used, the equilibrium (K2) would lead to the second
protonation of 1-R. Although the reason for the likely secondꢀorder kinetic dependence of kobs on [TfOHex] (Figure
5) is unclear, a possible explanation is the dimerization of TfOHex to the (TfOHex)2 species (K3).27 This
interpretation has been previously proposed to explain the similar secondꢀorder kinetic behavior of TfOHꢀmediated
dealkylative lactonization.28 If the second protonation by (TfOHex)2 to afford the dication salt 10 is necessary for
the formation of ROTf along with cationic LG 2-H+ and the regenerated TfOHex (cationic LG pathway), the rate
law for the decrease in concentration of 9 is given by Eq. 1. This is because 9 is consumed via both neutral and
cationic LG pathways.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 28
1
2
3
4
5
6
ꢀ ꢂ
d ꢁ
ꢀ
ꢂ
d ROTf
−
=
dꢃ
dꢃ
ꢀ ꢂ ꢂ
ꢀ
= ꢄꢅ ꢁ + ꢄꢆ ꢇꢈ
ꢄn + ꢄcꢊ2ꢊ3ꢀTfOH ꢂ2
ꢀ ꢂ ꢌ ꢍ
= ꢉ ꢋ ꢁ # 1
ex
7
8
Since there are three basic nitrogen atoms in the 1,3,5ꢀtriazine ring, the monocation and dication of 1-R should
have regioisomers, including the less active forms as shown in Figure 9 (see discussion of model compounds in
Scheme 4). Nevertheless, similar to the previous analysis of acidꢀcatalyzed Oꢀbenzylation with
benzyloxytriazines,12d we treated them as a mixture of the regioisomers because this protonation equilibrium is
inevitable. Only the active regioisomers of 9 and 10 are shown in Figure 8. In the case of R = Bn, [TfOHex] should
be constant throughout the reaction because TfOHex is regenerated rapidly by the fast reaction between BnOTf and
a nucleophile. Therefore, the decrease in [9] follows firstꢀorder kinetics, where kobs is equal to kn + kcK2K3[TfOHex]2.
The kinetic parameters of the Oꢀbenzylation studied in Table 6 are given by the slope and the yꢀintercept in Figure 5,
respectively: kn = 1.99 × 10−3 min−1 (–10 °C) and kcK2K3 = 6.50 × 10−6 min−1mM−2 (–10 °C). Similar to the
benzylation reaction, nucleophile alkylation with ROTf would be faster than its formation when R = allyl or PNB.
In contrast, alkylation is slower when R = 1ꢀadamantyl, as discussed for Figure 2.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 8. Plausible reaction mechanisms.
ACS Paragon Plus Environment

Page 15 of 28
The Journal of Organic Chemistry
1
2
3
4
monocation
OR
OR
H
5
N
N
N
N
6
MeO
N
OMe
MeO
N
OMe
7
8
H
active
less active
9
dication
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OR
OR
H
H
H
N
N
N
N
MeO
N
OMe
MeO
N
OMe
H
active
less active
Figure 9. The regioisomers of the monocation and dication of 1-R.
The neutral LG pathway is operative in the presence of less than 100 mol% of TfOH, while the cationic LG
pathway predominates when only a small amount of TfOH (~ 200 mol%) is added. This "switching" of the reaction
mechanism is an interesting property of the triazineꢀbased LGs.29
CONCLUSION
We have developed a new, triazineꢀbased cationic LG 2-H+ for acidꢀcatalyzed alkylation in the presence of TfOH
(~200 mol%). Alkyl groups such as benzyl, allyl, PNB, and 1ꢀadamantyl were introduced to the Oꢀ and
Cꢀnucleophiles in good to high yields. The reaction times were dramatically shorter than the alkylation reactions
with < 100 mol% of TfOH, except for the case of Oꢀ1ꢀadamantylation. Advantages of the triazineꢀbased cationic
LGs over TCAI and Br were demonstrated by comparing the ease of Oꢀpꢀnitrobenzylation and stability. The
formation of the dicationic intermediate 1-R-H22+ was supported by NMR experiments and theoretical calculations.
Kinetic studies using a model compound clarified the remarkable acceleration of the formation of the benzyl cation
species in the presence of an excess amount of TfOH. A new reaction mechanism, i.e., the cationic LG pathway,
was suggested on the basis of mechanistic studies. We have proposed that the origin of the rapid formation of
carbocation species from 1-R-H22+ can be rationalized by the synergistic combination of two driving forces in 2-H+,
namely, stable C=O bond formation and chargeꢀcharge repulsive effects. These driving forces were evaluated by
calculations of the model compounds. The concept of the cationic LG described here expands the utility of
1,3,5ꢀtriazines and allows us to apply this new strategy for substitution reactions in organic synthesis.
EXPERIMENTAL SECTION
General Information. NMR spectra were recorded on a JEOL JNMꢀECS400 spectrometer [1H NMR (400 MHz),
13C NMR (100 MHz), 19F NMR (376 MHz)] or a JEOL JNMꢀECA600 [1H NMR (600 MHz), 13C NMR (150
MHz)]. Chemical shifts for 1H NMR are reported in parts per million (δ) relative to tetramethylsilane as the internal
standard. Coupling constant (J) are reported in hertz (Hz). The following abbreviations are used for spin
multiplicity: s = singlet, d = doublet, t = triplet, m = multiplet. Chemical shifts for 13C NMR are reported in parts
per million (δ) relative to the solvent [CDCl3, δ 77.16]. Chemical shifts for 19F NMR are reported in parts per
million (δ) relative to α,α,αꢀtrifluorotoluene [CDCl3, δ −62.82]. IR spectra were recorded on a Horiba FTꢀ720
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 28
1
2
3
4
5
6
7
8
9
FREEXACTꢀII spectrophotometer and were reported in wavenumbers (cm−1). Mass spectra were measured on
JMSꢀT100TD (DARTꢀMS) and JMSꢀ700(2) (EIꢀMS). Analytical thin layer chromatography (TLC) was performed
using glass plates precoated with 0.25 mm silica gel impregnated with a fluorescent indicator (254 nm). Preparative
TLC separations were performed using glass plates precoated with 0.25 mm silica gel impregnated with a
fluorescent indicator (254 nm). Flash chromatography was performed using silica gel (spherical, neutral, 40–100
mesh). Recycling preparative HPLC was performed with Japan Analytical Industry LCꢀ928 equipped with GPC
columns Jaigelꢀ1H and 2H. All reactions sensitive to oxygen or moisture were conducted under a nitrogen
atmosphere. Reagents were commercial grades and were used without any purification unless otherwise noted.
TfOH (>98.0% purity), dehydrated 1,4ꢀdioxane, CH2Cl2, THF, and MeOH were purchased from commercial
sources and used without further purification. DME and ethyldiisopropylamine were purchased from commercial
sources and distilled before use. Cyanuric chloride and 2ꢀchloroꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine were recrystallized
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
from
hexane/chloroform
before
use.
Known
compounds
[1-Bn,
1-Me,
and
2ꢀchloroꢀ4,6ꢀbis(cyclohexylmethoxy)ꢀ1,3,5ꢀtriazine] were prepared as described in the literature.12d
Benzyl 2ꢀ(2ꢀchloroethoxy)ethyl ether (4b).12a TfOH (52.7 ꢁL, 0.60 mmol) was to a mixture of 3b (31.7 ꢁL, 0.30
mmol), 1-Bn (81.6 mg, 0.33 mmol), and MS5A (5 mg) in 1,4ꢀdioxane (1.00 mL) at room temperature. After 1 min,
the reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (10 mL), and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 9:1) to
afford a clear colorless oil (57.7 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 7.38–7.25 (m, 5H), 4.58 (s, 2H), 3.77 (t,
J = 6.0 Hz, 2H), 3.72–3.67 (m, 2H), 3.66–3.61 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 138.3, 128.5, 127.9, 127.8,
73.5, 71.5, 70.9, 69.5, 42.9. LRMS (DARTꢀTOF): m/z 215 ([M + H]+).
Benzyl 2ꢀbromoethyl ether (4c).12a TfOH (52.7 ꢁL, 0.60 mmol) was added to a mixture of 3c (21.4 ꢁL, 0.30 mmol),
1-Bn (81.6 mg, 0.33 mmol), and MS5A (10 mg) in 1,4ꢀdioxane (1.00 mL) at room temperature. After 1 min, the
reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (10 mL), and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 19:1) to afford a
clear colorless oil (57.1 mg, 89%). 1H NMR (CDCl3, 600 MHz): δ 7.40–7.25 (m, 5H), 4.59 (s, 2H), 3.79 (t, J = 6.2
Hz, 2H), 3.49 (t, J = 6.2 Hz, 2H). 13C NMR (CDCl3, 150 MHz): δ 137.9, 128.6, 128.0, 127.9, 73.3, 70.1, 30.6.
LRMS (DARTꢀTOF): m/z 215 ([M + H]+).
Benzyl 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluorodecyl ether (4e). TfOH (52.7 ꢁL, 0.60 mmol) was added
to a mixture of 3e (139.2 mg, 0.30 mmol), 1-Bn (81.6 mg, 0.33 mmol), and MS5A (5 mg) in 1,4ꢀdioxane (0.50 mL)
at room temperature. After 1 min, the reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (10
mL), and filtered. The filtrate was washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL),
dried with Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column
1
chromatography (hexane/EtOAc = 19:1) to afford a clear colorless oil (150.4 mg, 90%). H NMR (CDCl3, 600
MHz): δ 7.49–7.25 (m, 5H), 4.55 (s, 2H), 3.77 (t, J = 6.5 Hz, 2H), 2.50–2.39 (m, 2H). 13C NMR (CDCl3, 100
MHz): δ 137.7, 128.7, 128.0, 127.8, 120.5–105.6 (perfluorocarbons), 73.5, 62.2 (t), 31.7 (t). 19F NMR (CDCl3, 376
MHz): δ −80.8, −113.4, −121.8, −122.0, −122.8, −123.7, −126.2. Anal. Calcd for C17H11F17O: C, 36.84; H, 2.00.
ACS Paragon Plus Environment

Page 17 of 28
The Journal of Organic Chemistry
1
2
3
4
5
Found: C, 37.10; H, 2.20. HRMS (doubleꢀfocusing, EI) m/z: [M]+ Calcd for C17H11F17O 554.0538. Found:
554.0526. IR (CHCl3): 1603, 1259, 1240, 1195, 1178, 1151 cm−1.
Benzyl 3ꢀbenzoylpropionate (4f).12c TfOH (52.7 ꢁL, 0.60 mmol) was added to a mixture of 3f (53.5 mg, 0.30 mmol),
1-Bn (96.4 mg, 0.39 mmol), and MS5A (5 mg) in 1,4ꢀdioxane (0.50 mL) at room temperature. After 1 min, the
reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 4:1) to afford a
pale yellow oil (69.6 mg, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.00–7.95 (m, 2H), 7.59–7.54 (m, 1H), 7.49–7.44
(m, 2H), 7.39–7.25 (m, 5H), 5.15 (s, 2H), 3.34 (t, J = 6.6 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H). 13C NMR (CDCl3, 100
MHz): δ 198.2, 172.9, 136.7, 136.0, 133.4, 128.8, 128.7, 128.37, 128.35, 128.2, 66.7, 33.5, 28.4. LRMS
(DARTꢀTOF): m/z 269 ([M + H]+).
Benzyl (E)ꢀcinnamate (4g)12c TfOH (105.3 ꢁL, 1.2 mmol) was added to a mixture of 3g (88.9 mg, 0.60 mmol),
1-Bn (178.0 mg, 0.72 mmol), and MS5A (10 mg) in 1,4ꢀdioxane (1.00 mL) at room temperature. After 1 min, the
reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 19:1) and
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
preparative TLC (hexane/EtOAc = 19:1) to afford a clear pale yellow oil (122.5 mg, 86%). H NMR (CDCl3, 400
MHz): δ 7.73 (d, J = 16.0 Hz, 1H), 7.59–7.48 (m, 2H), 7.46–7.30 (m, 8H), 6.49 (d, J = 16.0 Hz, 1H), 5.26 (s, 2H).
13C NMR (CDCl3, 100 MHz): δ 167.0, 145.3, 136.2, 134.5, 130.5, 129.0, 128.8, 128.43, 128.40, 128.3, 118.0, 66.5.
LRMS (DARTꢀTOF): m/z 239 ([M + H]+).
Benzylpentamethylbenzene (4h).12a TfOH (52.7 ꢁL, 0.60 mmol) was added to a mixture of 3h (44.5 mg, 0.30
mmol), 1-Bn (81.6 mg, 0.33 mmol), and MS5A (10 mg) in 1,4ꢀdioxane (1.00 mL) at room temperature. After 1 min,
the reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (hexane/CH2Cl2 = 9:1) to
afford a white solid (66 mg, 92%). Mp 111–112 °C; 1H NMR (CDCl3, 400 MHz): δ 7.26–7.11 (m, 3H), 7.03 (d, J =
7.4 Hz, 2H), 4.11 (s, 2H), 2.27 (s, 3H), 2.24 (s, 6H), 2.17 (s, 6H). 13C NMR (CDCl3, 100 MHz): δ 140.8, 133.9,
133.3, 132.9, 132.6, 128.5, 128.1, 125.7, 36.3, 17.1, 17.01, 17.00. LRMS (DARTꢀTOF): m/z 239 ([M + H]+).
2ꢀAllyloxyꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine (1-Allyl).30 NꢀMethylmorpholine (1.10 mL, 10 mmol) was added to a
suspension of 2ꢀchloroꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine (1.756 g, 10.0 mmol) and ethyldiisopropylamine (2.09 mL,
12.0 mmol) in allyl alcohol (10.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h and room
temperature for 0.5 h. The reaction mixture was quenched with AcOH (0.57 mL) and concentrated under reduced
pressure. The residue was dissolved in hexane/EtOAc (1:1, 10 mL). The solution was washed with 10% aqueous
citric acid (10 mL) followed by brine (10 mL), dried with Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography (hexane/EtOAc = 4:1) followed by recrystallization
1
from hexane to afford a white solid (1.79 g, 91%). Mp 36 °C; H NMR (CDCl3, 400 MHz): δ 6.06 (m, J = 17.4,
10.6, 5.5 Hz, 1H), 5.42 (d, J = 17.4, 1H), 5.30 (d, J = 10.6 Hz, 1H), 4.92 (d, J = 5.5 Hz, 2H), 4.03 (s, 6H). 13C NMR
(CDCl3, 150 MHz): δ 173.6, 172.9, 131.7, 119.1, 69.0, 55.5. LRMS (DARTꢀTOF): m/z 198 ([M + H]+).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 28
1
2
3
4
5
6
7
8
9
Allyl (2ꢀ(2ꢀchloroethoxy)ethyl ether (5b).31 TfOH (52.7 ꢁL, 0.60 mmol) was added to a mixture of 3b (31.7 ꢁL,
0.30 mmol), 1-allyl (65.1 mg, 0.33 mmol), and MS5A (5 mg) in 1,4ꢀdioxane (0.50 mL) was added at room
temperature. After 10 min, the reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (10 mL), and
filtered. The filtrate was washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with
Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography
(hexane/EtOAc = 9:1) to afford a clear colorless oil (41.5 mg, 84%). 1H NMR (CDCl3, 600 MHz): δ 5.92 (ddt, J =
18.0, 10.0, 4.8 Hz, 1H), 5.28 (ddt, J = 18.0, 1.6, 1.6 Hz, 1H), 5.19 (ddt, J = 10.7, 1.6, 1.6 Hz, 1H), 4.04 (ddd, J =
4.8, 1.6, 1.6 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H), 3.71–3.67 (m, 2H), 3.66–3.60 (m, 4H). 13C NMR (CDCl3, 150
MHz): δ 134.8, 117.4, 72.4, 71.6, 70.9, 69.5, 42.8. LRMS (DARTꢀTOF): m/z 165 ([M + H]+).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Allyl 12-bromododecyl ether (5d). TfOH (35.1 ꢁL, 0.40 mmol) was added to a mixture of 3d (53.0 mg, 0.20
mmol), 1-allyl (43.4 mg, 0.22 mmol), and MS5A (3.3 mg) in 1,4ꢀdioxane (0.33 mL) at room temperature. After 20
min, the reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (10 mL), and filtered. The filtrate
was washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography
(hexane/EtOAc = 49:1) to afford a clear colorless oil (53.3 mg, 87%). 1H NMR (CDCl3, 600 MHz): δ 5.92 (ddt, J =
17.2 , 10.7, 5.5 Hz, 1H), 5.27 (dd, J = 17.2, 1.4 Hz, 1H), 5.25 (dd, J = 10.7, 1.4 Hz, 1H), 3.96 (d, J = 5.5 Hz, 2H),
3.42 (t, J = 6.9 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 1.90–1.80 (m, 2H), 1.62–1.54 (m, 2H), 1.46–1.38 (m, 2H), 1.37–
1.10 (m, 14H). 13C NMR (CDCl3, 150 MHz): δ 135.3, 116.8, 72.0, 70.7, 34.2, 33.0, 29.9, 29.71, 29.68, 29.66, 29.64,
29.57, 28.9, 28.3, 26.3. Anal. Calcd for C15H29BrO: C, 59.01; H, 9.57. Found: C, 58.97; H, 9.84. HRMS
(DARTꢀTOF) m/z: [M + H]+ Calcd for C15H30BrO 305.1480. Found: 305.1508. IR (CHCl3): 2929, 2856, 1464,
1095 cm−1.
Allyl 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8ꢀheptadecafluorodecyl ether (5e).32 TfOH (52.7 ꢁL, 0.60 mmol) was added to a
mixture of 3e (139.2 mg, 0.30 mmol), 1-allyl (65.1 mg, 0.33 mmol), and MS5A (5 mg) in 1,4ꢀdioxane (0.50 mL) at
room temperature. After 10 min, the reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (10 mL),
and filtered. The filtrate was washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried
with Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column
1
chromatography (hexane/EtOAc = 19:1) to afford a clear colorless oil (107.2 mg, 71%). H NMR (CDCl3, 600
MHz): δ 5.90 (ddt, J = 18.0, 9.9, 4.8 Hz, 1H), 5.30 (ddt, J = 18.0, 1.5, 1.5 Hz, 1H), 5.22 (ddt, J = 9.9, 1.5, 1.5 Hz,
1H), 4.01 (ddd, J = 4.8, 1.5, 1.5 Hz, 2H) , 3.73 (t, J = 6.8 Hz, 2H), 2.42 (tt, J = 18.8, 6.8 Hz, 2H). 13C NMR (CDCl3,
100 MHz): δ 134.3, 121.6–106.8 (perfluorocarbons), 117.6, 72.3, 62.1 (t), 31.7 (t). 19F NMR (CDCl3, 376 MHz): δ
−80.8, −113.5, −121.8, −122.0, −122.8, −123.7, −126.2. LRMS (DARTꢀTOF): m/z 505 ([M + H]+).
Allyl 3ꢀbenzoylpropionate (5f).33 TfOH (52.7 ꢁL, 0.60 mmol) was added to a mixture of 3f (53.5 mg, 0.30 mmol),
1-allyl (76.9 mg, 0.39 mmol), and MS3A (5 mg) in 1,4ꢀdioxane (0.50 mL) at room temperature. After 10 min, the
reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 4:1) to afford a
pale yellow oil (49.6 mg, 76%). 1H NMR (CDCl3, 600 MHz): δ 7.98 (d, J = 7.9 Hz, 2H), 7.57 (t, J = 7.9 Hz, 1H),
7.47 (t, J = 7.9 Hz, 2H), 5.93 (ddt, J = 17.3, 10.6, 5.8 Hz, 1H), 5.33 (dd, J = 17.3, 1.7 Hz, 1H), 5.24 (dd, J = 10.6,
ACS Paragon Plus Environment

Page 19 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.7 Hz, 1H), 4.62 (d, J = 5.8 Hz), 3.33 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H). 13C NMR (CDCl3, 150 MHz): δ
198.1, 172.7, 136.7, 133.4, 132.3, 128.8, 128.2, 118.4, 65.5, 33.5, 28.3. LRMS (DARTꢀTOF): m/z 219 ([M + H]+).
Allyl (E)ꢀcinnamate (5g).34 TfOH (52.7 ꢁL, 0.6 mmol) was added to a mixture of 3g (44.4 mg, 0.30 mmol), 1-allyl
(71.0 mg, 0.36 mmol), and MS3A (25 mg) in 1,4ꢀdioxane (0.50 mL) at room temperature. After 10 min, the
reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 19:1) to afford a
clear colorless oil (41.8 mg, 74%). 1H NMR (CDCl3, 600 MHz): δ 7.72 (d, J = 15.8 Hz, 1H), 7.56–7.50 (m, 2H),
7.42–7.36 (m, 3H), 6.47 (d, J = 15.8 Hz, 1H), 6.00 (ddt, J = 17.0, 11.4, 5.8 Hz, 1H), 5.38 (dt, J = 17.0, 1.4 Hz), 5.28
(dt, J = 11.4, 1.4 Hz, 1H), 4.72 (ddd, J = 5.8, 1.4, 1.4 Hz, 2H). 13C NMR (CDCl3, 150 MHz): δ 166.8, 145.2, 134.5,
132.4, 130.5, 129.0, 128.2, 118.4, 118.0, 65.4; LRMS (DARTꢀTOF): m/z 189 ([M + H]+).
Allylpentamethylbenzene (5h).35 TfOH (52.7 ꢁL, 0.60 mmol) was added to a mixture of 3h (44.5 mg, 0.30 mmol),
1-allyl (65.1 mg, 0.33 mmol), and MS5A (5 mg) in 1,4ꢀdioxane (0.50 mL) at room temperature. After 10 min, the
reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was washed
with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane) to afford a white solid
(53.5 mg, 95%). 1H NMR (CDCl3, 600 MHz): δ 5.93 (ddt, J = 17.4, 9.8, 4.8 Hz, 1H), 5.00 (ddt, J = 9.8, 1.8, 1.8 Hz,
1H), 4.88 (ddt, J = 17.4, 1.8, 1.8 Hz), 3.45 (ddd, J = 4.8, 1.8, 1.8 Hz, 2H), 2.24 (s, 3H), 2.23 (s, 6H), 2.22 (s, 6H).
13C NMR (CDCl3, 150 MHz): δ 136.4, 133.4, 133.0, 132.5, 132.4, 115.0, 34.8, 17.0, 16.9, 16.6. LRMS
(DARTꢀTOF): m/z 189 ([M + H]+).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4-Dimethoxy-6-(p-nitrobenzyloxy)-1,3,5-triazine (1-PNB). Ag2O (139.0 mg, 0.60 mmol) was added to a
solution of pꢀnitrobenzyl alcohol (76.6 mg, 0.500 mmol) and 2ꢀchloroꢀ4,6ꢀdimethoxyꢀ1,3,5ꢀtriazine (105.3 mg,
0.600 mmol) in CH2Cl2 (10.0 mL) at room temperature. After stirred at 35 °C for 66 h, the reaction mixture was
directly purified by column chromatography (CH2Cl2/EtOAc = 19:1) to afford colorless crystals (141.7 mg, 97%).
1
Mp 174.8−176.0 °C; H NMR (400 MHz, CDCl3): δ 8.27−8.21 (m, 2H), 7.66−7.60 (m, 2H), 5.55 (s, 2H), 4.04 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 173.8, 172.9, 147.9, 142.8, 128.5, 124.0, 68.3, 55.7. Anal. Calcd for
C12H12N4O5: C, 49.32; H, 4.14; N, 19.17. Found: C, 48.92; H, 4.14; N, 19.01. HRMS (DARTꢀTOF): [M + H]+
Calcd for C12H13N4O5 293.0886. Found: 293.0888. IR (KBr): 1562, 1363, 1335, 1134, 1111 cm−1.
(2-(2-Chloroethoxy)ethyl p-nitrobenzyl ether (6b). TfOH (87.8 ꢁL, 1.0 mmol) was added to a mixture of 3b
(52.8 ꢁL, 0.50 mmol), 1-PNB (160.7 mg, 0.55 mmol), and MS5A (8.3 mg) in 1,4ꢀdioxane (0.83 mL) at room
temperature. After 10 h, the reaction mixture was diluted with EtOAc (10 mL), and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (5 mL) followed by brine (5 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (hexane/CH2Cl2 = 1:1) to
afford a clear pale brown oil (123.4 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 8.24−8.17 (m, 2H), 7.56−7.50 (m,
2H), 4.69 (s, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.77−3.69 (m, 4H), 3.66 (t, J = 5.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 147.5, 146.1, 127.8, 123.7, 72.1, 71.5, 70.8, 70.3, 42.9. Anal. Calcd for C11H14ClNO4: C, 50.88; H, 5.43;
N, 5.39. Found: C, 50.73; H, 5.39; N, 5.42. HRMS (DARTꢀTOF): [M + H]+ Calcd for C11H15ClNO4 260.0690.
Found: 260.0712. IR (CHCl3): 2866, 1608, 1531, 1346, 1105, 860 cm−1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 28
1
2
3
4
5
6
7
8
9
2ꢀBromoethyl pꢀnitrobenzyl ether (6c).36 TfOH (87.8 ꢁL, 1.0 mmol) was added to a mixture of 3c (35.6 ꢁL, 0.50
mmol), 1-PNB (160.7 mg, 0.55 mmol), and MS5A (8.3 mg) in 1,4ꢀdioxane (0.83 mL) at room temperature. After
10 h, the reaction mixture was quenched with 2,6ꢀlutidine, diluted with EtOAc (5 mL), and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (5 mL) followed by brine (5 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 19:1) to
afford a clear pale yellow oil (126.1 mg, 97%). 1H NMR (CDCl3, 600 MHz): δ 8.21 (d, J = 8.6 Hz, 2H), 7.54 (d, J =
8.6 Hz, 2H), 4.70 (s, 2H), 3.87 (t, J = 5.8 Hz, 2H), 3.54 (s, J = 5.8 Hz, 2H). 13C NMR (CDCl3, 150 MHz): δ 147.6,
145.5, 127.8, 123.8, 71.9, 70.7, 30.3. LRMS (DARTꢀTOF): m/z 260 ([M + H]+).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-Heptadecafluorodecyl p-nitrobenzyl ether (6e). TfOH (26.3 ꢁL, 0.30 mmol) was
added to a mixture of 3e (69.6 mg, 0.15 mmol), 1-PNB (48.2 mg, 0.165 mmol), and MS5A (2.5 mg) in 1,4ꢀdioxane
(0.25 mL) at room temperature. After 10 h, the reaction mixture was quenched with 2,6ꢀlutidine, diluted with
EtOAc (10 mL), and filtered. The filtrate was washed with saturated aqueous NaHCO3 (10 mL) followed by brine
(10 mL), dried with Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/acetone = 4:1) to afford a crystalline solid (81.5 mg, 91%). 1H NMR (CDCl3, 400
MHz): δ 8.23 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.65 (s, 2H), 3.84 (t, J = 6.4 Hz, 2H), 2.49 (tt, J = 18.4,
6.4 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 147.6, 145.3, 127.8, 123.9, 120.4–107.5 (perfluorocarbons), 72.1,
63.0, 31.7. 19F NMR (CDCl3, 376 MHz): δ −80.8, −113.4, −121.7, −122.0, −122.8, −123.7, −126.2. Anal. Calcd for
C17H10F17NO3: C, 34.07; H, 1.68; N, 2.34. Found: C, 33.73; H, 1.79; N, 2.64. HRMS (doubleꢀfocusing, EI) m/z:
[M]+ Calcd for C17H10F17NO3 599.0389. Found: 599.0392. IR (KBr): 2360, 1606, 1522, 1373, 1356, 1250, 1203,
1151, 1108 cm−1.
pꢀNitrobenzyl 3ꢀbenzoylpropionate (6f).37 TfOH (87.8 ꢁL, 1.00 mmol) was added to a mixture of 3f (89.1 mg, 0.50
mmol), 1-PNB (160.7 mg, 0.55 mmol), and MS5A (8.3 mg) in 1,4ꢀdioxane (0.83 mL) at room temperature. After
10 h, the reaction mixture was quenched with NEt3, diluted with EtOAc (3 mL), and filtered. The filtrate was
washed with aqueous 1 M HCl (3 mL) followed by brine (3 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/CHCl3 = 1:1) to afford a
white solid (132.1 mg, 84%). Mp 73–74 °C; 1H NMR (CDCl3, 600 MHz): δ 8.22 (d, J = 8.6 Hz, 2H), 7.98 (d, J =
7.6 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 8.6, 2H), 7.48 (t, J = 7.6 Hz, 2H), 5.25 (s, 2H), 3.36 (t, J = 6.5 Hz,
2H), 2.86 (t, J = 6.5 Hz, 2H). 13C NMR (CDCl3, 150 MHz): δ 198.0, 172.6, 147.8, 143.4, 136.5, 133.5, 128.8, 128.4,
128.2, 123.9, 65.1, 33.4, 28.3. LRMS (DARTꢀTOF): m/z 314 ([M + H]+).
pꢀNitrobenzyl (E)ꢀcinnamate (6g).38,39 TfOH (26.3 ꢁL, 0.30 mmol) was added to a mixture of 3g (22.2 mg, 0.15
mmol), 1-PNB (48.2 mg, 0.165 mmol), and MS5A (2.5 mg) in 1,4ꢀdioxane (0.25 mL) at room temperature. After
10 h, the reaction mixture was quenched with pyridine, diluted with EtOAc (10 mL), and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 9:1) to
afford a white solid (33.3 mg, 78%). Mp 117 °C; 1H NMR (CDCl3, 600 MHz): δ 8.24 (d, J = 8.6 Hz, 2H), 7.77 (d, J
= 16.1 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.56–7.52 (m, 2H), 7.45–7.35 (m, 3H), 6.51 (d, J = 16.1 Hz, 1H), 5.35 (s,
2H). 13C NMR (CDCl3, 100 MHz): δ 166.6, 147.8, 146.2, 143.5, 134.2, 130.8, 129.1, 128.5, 128.3, 124.0, 117.2,
64.9; LRMS (DARTꢀTOF): m/z 284 ([M + H]+).
ACS Paragon Plus Environment

Page 21 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Pentamethyl(pꢀnitrobenzyl)benzene (6h).40 TfOH (87.8 ꢁL, 1.00 mmol) was added to a mixture of 3h (74.1 mg,
0.50 mmol), 1-PNB (160.7 mg, 0.55 mmol), and MS5A (8.3 mg) in 1,4ꢀdioxane (0.83 mL) at room temperature.
After 10 h, the reaction mixture was quenched with NEt3, diluted with EtOAc (3 mL), and filtered. The filtrate was
washed with aqueous 1 M HCl (3 mL) followed by brine (3 mL), dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane/CHCl3 = 1:1) to afford a
white solid (133.1 mg, 94%). Mp 131–132 °C; 1H NMR (CDCl3, 600 MHz): δ 8.09 (d, J = 8.9 Hz, 2H), 7.18 (d, J =
8.9 Hz, 2H), 4.20 (s, 2H), 2.28 (s, 3H), 2.25 (s, 6H), 2.14 (s, 6H). 13C NMR (CDCl3, 150 MHz): δ 149.0, 146.4,
134.1, 133.0, 132.7, 132.3, 128.8, 123.8, 36.4, 17.2, 17.05, 17.02. LRMS (DARTꢀTOF): m/z 284 ([M + H]+).
2-(1-Adamantyloxy)-4,6-dimethoxy-1,3,5-triazine (1-Ad). Cyanuric chloride (1.84 g, 10 mmol) was added to a
suspension of 1ꢀadamantanol (1.52 g, 10 mmol) and nꢀBuLi (2.6 M in hexane, 3.85 mL, 10 mmol) in THF (50 mL)
was added at −10 °C. The reaction mixture was stirred at room temperature for 2 h and at reflux temperature for 45
min, and then cooled to 0 °C. Ethyldiisopropylamine (5.18 mL, 30 mmol), MeOH (50 mL), and
Nꢀmethylpyrrolidine (317 µL, 3.0 mmol) was added. After stirred for 23 h at room temperature, the reaction
mixture was concentrated to half volume under reduced pressure. After addition of aqueous 10% citric acid (50 ml),
the mixture was extracted with EtOAc (300 mL). The organic layer was washed with brine (100 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 17:3) followed by recrystallization from CHCl3/MeOH to afford the a colorless
crystalline solid (2.28 g, 78%). Mp 180–181 °C; 1H NMR (CDCl3, 400 MHz): δ 4.00 (s, 6H), 2.33 (m, 6H), 2.23 (m,
3H), 1.70 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 173.3, 172.4, 83.9, 55.3, 41.4, 36.3, 31.2. Anal. Calcd for
C15H21N3O3: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.59; H, 7.24; N, 14.35. HRMS (DARTꢀTOF) m/z: [M + H]+
Calcd for C15H22N3O3 292.16612. Found: 292.16424. IR (CHCl3): 2916, 2856, 1570, 1558, 1466, 1431, 1381, 1360,
1298, 1221, 1140, 1111 cm−1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Adamantyl 3-phenylpropyl ether (7a). TfOH (87.8 ꢁL, 1.00 mmol) was added to a mixture of 3a (68.1 µL,
0.50 mmol), 1-Ad (160.2 mg, 0.55 mmol), and MS5A (50 mg) in 1,4ꢀdioxane (10.0 mL) at room temperature. After
3 h, the reaction mixture was quenched with pyridine, diluted with EtOAc (50 mL), and filtered. The filtrate was
washed with saturated aqueous NaHCO3 (50 mL) followed by brine (40 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (hexane/CH2Cl2 = 2:1) to
afford a clear colorless oil (124.0 mg, 92%). 1H NMR (CDCl3, 400 MHz): δ 7.33–7.12 (m, 5H), 3.42 (t, J = 6.4 Hz,
2H), 2.68 (t, J = 7.8 Hz, 2H), 2.19–2.08 (m, 3H), 1.85 (tt, J = 7.8, 6.4 Hz, 2H), 1.74 (m, 6H), 1.62 (m, 6H). 13C
NMR (CDCl3, 100 MHz): δ 142.5, 128.6, 128.4, 125.8, 72.0, 59.0, 41.8, 36.7, 32.6, 32.3, 30.7; Anal. Calcd for
C19H26O: C, 84.39; H, 9.69. Found: C, 84.19; H, 9.85. HRMS (DARTꢀTOF) m/z: Calcd for C19H27O ([M+H]+):
271.20619, Found: 271.20374; IR (CHCl3): 3045, 2912, 2854, 1454, 1249, 1115, 1088 cm−1.
General Procedure for TfOH-Catalyzed O-1-Adamantylation Using 1-Ad. TfOH (100 or 200 mol%, 50 or 100
mM) was added to a mixture of 3a (1 equiv, 50 mM), 1-Ad (1 equiv, 50 mM), and 1ꢀchlorooctane (internal
standard, 1 equiv, 50 mM) in 1,4ꢀdioxane at room temperature. Aliquots were withdrawn from the reaction mixture
at indicated time and treated with an excess amount of EtOH containing ethyldiisopropylamine to convert
1
1ꢀadamantyl trifluoromethanesulfonate to 1ꢀadamantyl ethyl ether. The yields were determined by H NMR
spectroscopic analysis using the internal standard.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 28
1
2
3
4
5
6
7
8
9
pꢀNitrobenzyl 2,2,2ꢀtrichloroacetimidate (PNBꢀTCAI).41 1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀene (7.5 ꢁL, 0.050 mmol)
was added to a solution of pꢀnitrobenzyl alcohol (382.9 mg, 2.50 mmol) and trichloroacetonitrile (1.25 mL, 12.5
mmol) in CH2Cl2 (2.50 mL) at room temperature. After 6 h, 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (11.2 ꢁL, 0.075
mmol) was added. After additional 1 h, the reaction mixture was concentrated under reduced pressure. The residue
was purified by column chromatography (hexane/EtOAc, 6:1) followed by recrystallization from hexane/CHCl3 to
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
afford colorless crystals (735.2 mg, 99%). H NMR (400 MHz, CDCl3): δ 8.49 (br s, 1H), 8.28−8.23 (m, 2H),
7.63−7.59 (m, 2H), 5.45 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 162.2, 147.9, 142.9, 128.0, 124.0, 91.0, 69.2.
HRMS (DARTꢀTOF): [M + H]+ Calcd for C9H8N2O3Cl3 296.9601. Found: 296.9581. IR (KBr): 3319, 2945, 1664,
1514, 1344, 1296, 1101, 1013, 800 cm−1.
2-(2-Chloroethoxy)ethyl 2,2,2-trichloroacetimidate. 1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀene (11.2 ꢁL, 0.075 mmol)
was added to a solution of 3b (158 ꢁL, 1.50 mmol) and trichloroacetonitrile (0.75 mL, 7.5 mmol) in CH2Cl2 (1.50
mL) at 0 °C. After 30 min, 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (22.4 ꢁL, 0.15 mmol) was added. After additional
20 min, the reaction mixture was quenched with AcOH (14 ꢁL), and then concentrated under reduced pressure. The
residue was purified by column chromatography (hexane/CH2Cl2, 1:1) to afford a clear colorless oil (326.1 mg,
81%). 1H NMR (400 MHz, CDCl3): δ 8.34 (br s, 1H), 4.49−4.44 (m, 2H), 3.90−3.85 (m, 2H), 3.82 (t, J = 5.8 Hz,
2H), 3.64 (t, J = 5.8 Hz, 2H). 13C NMR (150 MHz, CDCl3): δ 162.9, 91.4, 71.6, 68.83, 68.81, 42.9. Anal. Calcd for
C6H9Cl4NO2: C, 26.80; H, 3.37; N, 5.21. Found: C, 26.70; H, 3.34; N, 5.11. HRMS (DARTꢀTOF): [M + H]+ Calcd
for C6H10Cl4NO2 267.9466. Found: 267.9487. IR (CHCl3): 3342, 2962, 1666, 1309, 1090, 650 cm−1.
2-(2-Chloroethoxy)ethyl 2,2,2-trichloroacetate. Pyridine (266 ꢁL, 3.30 mmol) was added to a solution of 3b (317
ꢁL, 3.00 mmol) and trichloroacetic anhydride (603 ꢁL, 3.30 mmol) in THF (6.0 mL) at 0 °C. The reaction mixture
was stirred at 0 °C for 30 min and at room temperature for 20 min. The reaction mixture was diluted with hexane (6
mL), filtered through a Celite pad, and concentrated under reduced pressure. The residue was purified by column
chromatography (hexane/EtOAc, 2:1) to afford a clear colorless oil (658.7 mg, 81%). 1H NMR (600 MHz, CDCl3):
δ 4.55−4.51 (m, 2H), 3.87−3.83 (m, 2H), 3.80 (t, J = 5.7 Hz, 2H), 3.63 (t, J = 5.7 Hz, 2H). 13C NMR (150 MHz,
CDCl3): δ 162.1, 89.8, 71.6, 68.5, 68.2, 42.8. Anal. Calcd for C6H8Cl4O3: C, 26.70; H, 2.99. Found: C, 26.50; H,
3.03. HRMS (DARTꢀTOF): [M + H]+ Calcd for C6H9Cl4O3 268.9306. Found: 268.9313. IR (CHCl3): 2870, 1766,
1261, 1138, 1028, 827 cm−1
General Procedure for the Stability Comparison of LGs under the Acidic Conditions. pꢀToluenesulfonic acid
monohydrate (0.5 equiv) was added to a solution of the benzyl derivative [1-Bn, BnꢀTCAI, or BnꢀBr (0.1–0.2
mmol, 1 equiv)] in CH2Cl2/MeOH (1:1, 0.5 M) at room temperature. After stirred for 5 min, the reaction mixture
was quenched with triethylamine (1 equiv), passed through silica gel (EtOAc as an eluent), and concentrated under
1
reduced pressure. The residue was analyzed by H NMR spectroscopic analysis using 6ꢀmethylcoumarin as an
internal standard.
General Procedure for the Stability Comparison of LGs under the Nucleophilic Conditions. Diethylamine (2.5
equiv) was added to a solution of the benzyl derivative [1-Bn, BnꢀTCAI, or BnꢀBr (0.1–0.2 mmol, 1 equiv)] in
CH2Cl2 (0.2 M) at room temperature. After stirred for 1 h, the reaction mixture passed through silica gel (EtOAc as
an eluent) and concentrated under reduced pressure. The residue was analyzed by 1H NMR spectroscopic analysis
using 6ꢀmethylcoumarin as an internal standard.
ACS Paragon Plus Environment

Page 23 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General Procedure for the Stability Comparison of LGs under the Reductive Conditions. A mixture of the
benzyl derivative [1-Bn, BnꢀTCAI, or BnꢀBr (0.25 mmol, 1 equiv)], zinc (81.7 mg, 1.25 mmol, 5 equiv), and
ammonium chloride (66.9 mg, 1.25 mmol, 5 equiv) in EtOH (0.50 mL, 0.5 M) was heated at reflux for 5 min. After
cooled to room temperature, the mixture was passed through silica gel (EtOAc as an eluent) and concentrated under
1
reduced pressure. The residue was analyzed by H NMR spectroscopic analysis using 6ꢀmethylcoumarin as an
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
internal standard.
General Procedure for NMR Spectroscopic Analysis of the Protonation of 1-Me with TfOH. TfOH (0, 50, 95,
105, 150, 200, or 500 mol%) and 1-Me (1 equiv, 40 mM) were dissolved in 1,4ꢀdioxane (600 ꢁL). The solution was
used for 13C NMR spectroscopic analysis (NoDꢀNMR, 600 MHz, 20 °C).
2-(Benzyloxy)-4,6-bis(cyclohexylmethoxy)-1,3,5-triazine (8). NꢀMethylimidazole (40 ꢁL, 0.50 mmol) was added
to a solution of 2ꢀchloroꢀ4,6ꢀbis(cyclohexylmethoxy)ꢀ1,3,5ꢀtriazine (1.70 g, 5.00 mmol),12d benzyl alcohol (2.57
mL, 25.0 mmol), and ethyldiisopropylamine (958 ꢁL, 5.50 mmol) in THF (10.0 mL) at room temperature. The
reaction mixture was heated at reflux for 35 h and then cooled to room temperature. The mixture was diluted with
Et2O (20 mL), and washed with H2O (100 mL), 1 M aqueous HCl (10 mL), and brine (10 mL). The organic layer
was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column
chromatography (hexane/EtOAc, 20:1) followed by recrystallization from hexane to afford colorless crystals (1.85
g, 88%). Mp 113.5−116.0 °C; 1H NMR (600 MHz, CDCl3): δ 7.47−7.42 (m, 2H), 7.39−7.30 (m, 3H), 5.44 (s, 2H),
4.18 (d, J = 6.2 Hz, 2H), 1.87−1.64 (m, 12H), 1.32−1.13 (m, 6H), 1.07−0.97 (m, 4H). 13C NMR (150 MHz,
CDCl3): δ 173.4, 173.0, 135.6, 128.6, 128.5, 73.8, 69.9, 37.2, 29.8, 26.5, 25.8. Anal. Calcd for C24H33N3O3: C,
70.04; H, 8.08; N, 10.21. Found: C, 70.31; H, 8.07; N, 10.25. HRMS (DARTꢀTOF): [M + H]+ Calcd for
C24H34N3O3 412.2600. Found: 412.2617. IR (KBr): 2925, 2852, 1568, 1448, 1340, 1140 cm−1.
General Procedure for the Kinetic Study of O-Benzylation Using 8. TfOH (33.4, 38.6, 49.1, 59.7, or 70.2 ꢁL;
95, 110, 140, 170, or 200 mol%; 0.381−0.800 mmol) was added to a solution of 8 (164.6 mg, 0.400 mmol, 1 equiv),
3a (54.5 ꢁL, 0.400 mmol, 1 equiv), pꢀnitrotoluene (16.5 mg, 0.120 mmol, 0.3 equiv) and MS5A (20.0 mg) in DME
(4.00 mL) at −10 ± 0.5 °C. Aliquots (40 ꢁL) were withdrawn from the reaction mixture at intervals, diluted with
pyridine solution (8 mM, 2.0 mL) in H2O−MeCN (1:3), and filtered. HPLC analysis was performed using a
gradient solvent system of H2O/MeCN (4:1 to 1:4) and pꢀnitrotoluene as an internal standard. In the case of entry 6
in Table 6, the reaction was carried out in the presence of TfONnBu4 (1 equiv).
Calculations. All calculations were performed using Gaussian09.42 Energy minimum was obtained without any
constraints by density functional theory (DFT) calculation with the B3LYP functional and the 6ꢀ31+G(d,p) basis set
in 1,4ꢀdioxane using the conductorꢀlike polarizable continuum model (CPCM). Vibrational frequency calculations
confirmed that there is no imaginary frequency for the energyꢀminimum geometries. In addition, the relative
energies were corrected for the zeroꢀpoint energy.
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge on the ACS Publications website. Kinetics and
computional details, 1H and 13C NMR spectra (PDF).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 28
1
2
3
4
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
*kunisima@p.kanazawaꢀu.ac.jp
Notes
The authors declare no competing financial interest.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACKNOWLEDGMENT
This work was supported by the Japan Society for the Promotion of Science (JSPS) in form of a Research
Fellowship for Young Scientists (to H. F.), and partially supported by the JSPS GrantsꢀinꢀAid for Scientific
Research program (KAKENHI, grant numbers 17H03970, 26293003, and 26670001). The computations were
performed using Research Center for Computational Science, Okazaki, Japan.
REFERENCES
(1) (a) Hanessian, S.; Lou, B. Stereocontrolled Glycosyl Transfer Reactions with Unprotected Glycosyl Donors.
Chem. Rev. 2000, 100, 4443–4464. (b) Lepore, S. D.; Mondal, D. Recent Advances in Heterolytic Nucleofugal
Leaving Groups. Tetrahedron 2007, 63, 5103–5122. (c) Naredla, R. R.; Klumpp, D. A. Contemporary Carbocation
Chemistry: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 6905–6948.
(2) Weiss, R.; Engel, S. Electrostatic Activation of Nucleofuges: Cationic Leaving Groups. Angew. Chem. Int. Ed.
1992, 31, 216–217.
(3) (a) Kollonitsch, J.; Marburg, S.; Perkins, L. M. Fluorodesulfurization. A New Reaction for the Formation of
CarbonꢀFluorine Bonds. J. Org. Chem. 1976, 41, 3107–3111. (b) Fascione, M. A.; Adshead, S. J.; Mandal, P. K.;
Kilner, C. A.; Leach, A. G.; Turnbull, W. B. Mechanistic Studies on a Sulfoxide Transfer Reaction Mediated by
Diphenyl Sulfoxide/Triflic Anhydride. Chem. Eur. J. 2012, 18, 2987–2997.
(4) (a) Corr, M. J.; Gibson, K. F.; Kennedy, A. R.; Murphy, J. A. Amidine Dications as Superelectrophiles. J. Am.
Chem. Soc. 2009, 131, 9174–9175. (b) Corr, M. J.; Roydhouse, M. D.; Gibson, K. F.; Zhou, S.; Kennedy, A. R.;
Murphy, J. A. Amidine Dications: Isolation and [Fe]ꢀHydrogenaseꢀRelated Hydrogenation. J. Am. Chem. Soc. 2009,
131, 17980–17985. (c) Kovacevic, L. S.; Idziak, C.; Markevicius, A.; Scullion, C.; Corr, M. J.; Kennedy, A. R.;
Tuttle, T.; Murphy, J. A. Superelectrophilic Amidine Dications: Dealkylation by Triflate Anion. Angew. Chem. Int.
Ed. 2012, 51, 8516–8519.
(5) Nenajdenko, V. G.; Shevchenko, N. E.; Balenkova, E. S.; Alabugin, I. V. 1,2ꢀDications in Organic Main Group
Systems. Chem. Rev. 2003, 103, 229–282.
(6) Klumpp, D. A. Superelectrophiles: Chargeꢀcharge repulsive effects. Chem. Eur. J. 2008, 14, 2004–2015.
(7) (a) Prakash, G. K. S.; Mathew, T.; Hoole, D.; Esteves, P. M.; Wang, Q.; Rasul, G.; Olah, G. A.
NꢀHalosuccinimide/BF3–H2O, Efficient Electrophilic Halogenating Systems for Aromatics. J. Am. Chem. Soc. 2004,
126, 15770–15776. (b) Le Darz, A.; Castelli, U.; Mokhtari, N.; MartinꢀMingot, A.; Marrot, J.; Bouazza, F.; Karam,
O.; Thibaudeau, S. Tandem Superelectrophilic Activation for the Regioselective Chlorofluorination of Recalcitrant
Allylic Amines. Tetrahedron 2016, 72, 674–689.
(8) (a) Mendonça, G. F.; Magalhães, R. R.; de Mattos, M. C. S.; Esteves, P. M. Trichloroisocyanuric acid in H2SO4:
ACS Paragon Plus Environment

Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
An Efficient Superelectrophilic Reagent for Chlorination of Isatin and Benzene Derivatives. J. Braz. Chem. Soc.
2005, 16, 695–698. (b) de Almeida, L. S.; Esteves, P. M.; de Mattos, M. C. S. Superelectrophilic Bromination of
Deactivated Aromatic Rings with Tribromoisocyanuric Acid—An Experimental and DFT Study. Tetrahedron Lett.
2009, 50, 3001–3004. (c) Mendonça, G. F.; Senra, M. R.; Esteves, P. M.; de Mattos, M. C. S. Trichloroisocyanuric
Acid in 98% Sulfuric Acid: A Superelectrophilic Medium for Chlorination of Deactivated Arenes. Appl. Catal. A
Gen. 2011, 401, 176–181. (d) da Ribeiro, R.; Esteves, P.; de Mattos, M. Superelectrophilic Iodination of
Deactivated Arenes with Triiodoisocyanuric Acid. Synthesis 2011, 739–744.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Raja, E. K.; DeSchepper, D. J.; Nilsson Lill, S. O.; Klumpp, D. A. Friedel–Crafts Acylation with Amides. J.
Org. Chem. 2012, 77, 5788–5793. (b) Raja, E. K.; Nilsson Lill, S. O.; Klumpp, D. A. Friedel–CraftsꢀType
Reactions with Ureas and Thioureas. Chem. Commun. 2012, 48, 8141–8143.
(10) (a) Sumita, A.; Kurouchi, H.; Otani, Y.; Ohwada, T. AcidꢀPromoted Chemoselective Introduction of Amide
Functionality onto Aromatic Compounds Mediated by an Isocyanate Cation Generated from Carbamate. Chem.
Asian J. 2014, 9, 2995–3004. (b) Sumita, A.; Otani, Y.; Ohwada, T. Tandem Buildup of Complexity of Aromatic
Molecules Through Multiple Successive Electrophile Generation in One Pot, Controlled by Varying the Reaction
Temperature. Org. Biomol. Chem. 2016, 14, 1680–1693.
(11) Some intramolecular rearrangement reactions of superelectrophiles can be considered as special cases of
substitution with cationic leaving groups. Klumpp, D. A. Molecular Rearrangements of Superelectrophiles.
Beilstein J. Org. Chem. 2011, 7, 346–363.
(12) (a) Yamada, K.; Fujita, H.; Kunishima, M. A Novel AcidꢀCatalyzed OꢀBenzylating Reagent with the Smallest
Unit of Imidate Structure. Org. Lett. 2012, 14, 5026–5029. (b) Yamada, K.; Fujita, H.; Kitamura, M.; Kunishima, M.
A
Practical
Method
for
pꢀMethoxybenzylation
of
Hydroxy
Groups
Using
2,4,6ꢀTris(pꢀmethoxybenzyloxy)ꢀ1,3,5ꢀTriazine (TriBOTꢀPM).Synth. 2013, 45, 2989–2997. (c) Yamada, K.;
Yoshida, S.; Fujita, H.; Kitamura, M.; Kunishima, M. OꢀBenzylation of Carboxylic Acids Using
2,4,6ꢀTris(benzyloxy)ꢀ1,3,5ꢀtriazine (TriBOT) under Acidic or Thermal Conditions. Eur. J. Org. Chem. 2015,
7997–8002. (d) Fujita, H.; Hayakawa, N.; Kunishima, M. Study of the Reactivities of AcidꢀCatalyzed
OꢀBenzylating Reagents Based on Structural Isomers of 1,3,5ꢀTriazine. J. Org. Chem. 2015, 80, 11200–11205. (e)
Yamada, K.; Hayakawa, N.; Fujita, H.; Kitamura, M.; Kunishima, M. Development of a TriazineꢀBased
tertꢀButylating Reagent, TriATꢀtBu. Eur. J. Org. Chem. 2016, 4093–4098. (f) Kunishima, M.; Asao, R.; Yamada,
K.; Kitamura, M.; Fujita, H. Development of AcidꢀCatalyzed Fluorous Benzylating Reagents Based on a
Triazinedione Core. J. Fluor. Chem. 2016, 190, 68–74. (g) Yamada, K.; Hayakawa, N.; Fujita, H.; Kitamura, M.;
Kunishima, M. Study of OꢀAllylation Using TriazineꢀBased Reagents. Chem. Pharm. Bull. 2017, 65, 112–115. (h)
Fujita, H.; Kakuyama, S.; Kunishima, M. N,N′ꢀDimethylated Benzyloxytriazinedione: A Stable Solid Reagent for
AcidꢀCatalyzed OꢀBenzylation. Eur. J. Org. Chem. 2017, 833–839. (i) Kunishima, M.; Yamada, K.; Fujita, H.;
Kitamura, M. Novel Alkylating Reagents Designed by the Characteristics of 1,3,5ꢀTriazines. J. Synth. Org. Chem.
Japan 2017, 75, 1023–1034.
(13) Enolꢀtoꢀketo tautomerization of 2,4ꢀbis(benzyloxy)ꢀ6ꢀhydroxyꢀ1,3,5ꢀtriazine was calculated to provide 9.69–
11.2 kcal/mol stabilization in HF/6ꢀ31G level of theory. This energy difference corresponds to the driving force of
the reaction in Scheme 2a. Srinivas, K.; Sitha, S.; Sridhar, B.; Jayathirtha Rao, V.; Bhanuprakash, K.; Ravikumar, K.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
Tautomerism of Bis(2,4ꢀbenzyloxy)ꢀ6ꢀ(5H)ꢀoneꢀ1,3,5ꢀtriazine:
QuantumꢀChemical Investigation. Struct. Chem. 2006, 17, 561–568.
A
Combined Crystallographic and
(14) (a) Schmidt, R. R.; Kinzy, W. AnomericꢀOxygen Activation for Glycoside Synthesis: The Trichloroacetimidate
Method. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123. (b) Montalbetti, C. A. G. N.; Falque, V. Amide Bond
Formation and Peptide Coupling. Tetrahedron 2005, 61, 10827–10852.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) OꢀMethylated product was not detected. This indicated that the methyl groups of 1-Bn were less reactive than
the benzyl group.
(16) An allyl cation has less stability than a benzyl cation. 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.
(17) The σ+ value of the nitro group (0.79) indicates that the benzyl cation is strongly destabilized by the
substitution of pꢀnitro group. Hansch, C.; Leo, A.; Taft, R. W. A Survey of Hammett Substituent Constants and
Resonance and Field Parameters. Chem. Rev. 1991, 91, 165–195.
(18) 1ꢀAdamantyl trifluoromethanesulfonate can be isolated due to its moderate stability. Takeuchi, K.; Moriyama,
T.; Kinoshita, T.; Tachino, H.; Okamoto, K. Synthesis and Some Reactions of 1ꢀadamantyl
Trifluoromethanesulfonate. Chem. Lett. 1980, 9, 1395–1398.
(19) Bentley, T. W.; Carter, G. E. The SN2ꢀSN1 Spectrum. 4. The SN2 (Intermediate) Mechanism for Solvolyses of
tertꢀButyl Chloride: A Revised Y Scale of Solvent Ionizing Power Based on Solvolyses of 1ꢀAdamantyl Chloride. J.
Am. Chem. Soc. 1982, 104, 5741–5747.
(20) Fukase, K.; Tanaka, H.; Toriib, S.; Kusumoto, S. 4ꢀNitrobenzyl Group for Protection of Hydroxyl Functions.
Tetrahedron Lett. 1990, 31, 389–392.
(21) Stefan, E.; Taylor, R. E. 1,5ꢀHydride Transfer Protocol for the Synthesis of βꢀBranched Polyketide Structural
units. Tetrahedron Lett. 2015, 56, 3416–3419.
(22) Yu, B.; Yu, H.; Hui, Y.; Han, X. Trichloroacetimidate as an Efficient Protective Group for Alcohols. Synlett.
1999, 753–755.
(23) The N,N'ꢀdiprotonation of 2,4,6ꢀtrialkylꢀ1,3,5ꢀtriazine with TfOH was reported. (a) Amer, M. I.; Booth, B. L.;
Noori, G. F. M.; Proença, M. F. J. R. P. The Chemistry of Nitrilium Salts. Part 3. The Importance of Triazinium
Salts in Houben–Hoesch Reactions Catalyzed by Trifluoromethanesulphonic Acid. J. Chem. Soc., Perkin Trans. 1
1983, 1075–1082. (b) Li, W.; Shi, M. Brønsted Acid TfOHꢀMediated [3 + 2] Cycloaddition Reactions of
Diarylvinylidenecyclopropanes with Nitriles. J. Org. Chem. 2008, 73, 4151–4154. (c) Salnikov, G. E.; Genaev, A.
M.; Vasiliev, V. G.; Shubin, V. G. Interaction of Acetonitrile with Trifluoromethanesulfonic Acid: Unexpected
Formation of a Wide Variety of Structures. Org. Biomol. Chem. 2012, 10, 2282–2288.
(24) Throughout this paper, [TfOH] represents a stoichiometric concentration because the acid will exist in various
forms in the reaction system because of its high ionization ability.
(25) Similar to the previous kinetic study (Ref. 12d), [8-H+] was estimated as [8]obs − 5 mM when [TfOH] is 95
mM, where [8]obs is the concentration of 8 observed in HPLC analysis, and represents the sum of [8] and [8-H+] in
the reaction mixture. As the reaction proceeded very slowly in the case of [TfOH] = 95 mM, only the early stage of
the reaction (~20% conversion) was analyzed. Nevertheless, the reaction was considered as a firstꢀorder reaction
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
1
2
3
4
5
because we have previously reported the firstꢀorder kinetics of 1-Bn-H+ in the presence of 95 mol% of TfOH. In
the case of 110–200 mM of [TfOH], [8-H+] was estimated as [8]obs because 8 would be completely protonated by
TfOH.
6
(26) The coefficient of determination (r2) between kobs ([TfOH] > 100 mM) and [TfOHex], [TfOHex]3, or [TfOHex]4
was lower than that of [TfOHex]2 (0.902–0.944 vs 0.975, details are given in Figures S9–11). In addition, their
yꢀintercepts (–10.7, 7.35, and 10.4 in the case of [TfOHex], [TfOHex]3, and [TfOHex]4, respectively) were not close
to 0.0831, which is kobs in the case of [TfOH] = 95 mol%. Therefore, a linear relationship between kobs and
[TfOHex], [TfOHex]3, or [TfOHex]4 is unlikely.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(27) Stoyanov, E. S.; Kim, K.ꢀC.; Reed, C. A. A Strong Acid that Does Not Protonate Water. J. Phys. Chem. A 2004,
108, 9310–9315.
(28) Muñoz, M. P.; LloydꢀJones, G. C. Triflic Acid Mediated Dealkylative Lactonisation via NMRꢀObservable
Alkyloxonium Intermediates. Eur. J. Org. Chem. 2009, 516–524.
(29) Switching and competition of the reaction mechanisms involving monocation and dication intermediates have
been reported for some acidꢀcatalyzed reactions. (a) Zoltewicz, J. A.; Clark, D. F.; Sharpless, T. W.; Grahe, G.
Kinetics and Mechanism of the AcidꢀCatalyzed Hydrolysis of Some Purine Nucleosides. J. Am. Chem. Soc. 1970,
92, 1741–1750. (b) Ghigo, G.; Maranzana, A.; Tonachini, G. A Change from Stepwise to Concerted Mechanism in
the AcidꢀCatalysed Benzidine Rearrangement: A Theoretical Study. Tetrahedron 2012, 68, 2161–2165.
(30) Likhterov, V. R.; Lobova, S. I. Method for the Preparation of 2,4ꢀDimethoxyꢀ6ꢀallyloxyꢀsymꢀtriazine. Chem.
Heterocycl. Compd. 1983, 19, 685–685.
(31) Sun, X.ꢀG.; Hou, J.; Kerr, J. B. CombꢀShaped Single Ion Conductors Based on Polyacrylate Ethers and
Lithium Alkyl Sulfonate. Electrochim. Acta 2005, 50, 1139–1147.
(32) Sugiyama, M.; Okada, J.; Yoshino, K.; Yamamuro, A.; Nakamura, K. Preparation of Allyl Perfluoroalkyl
Ethers without Using Solvents or Catalysts. Jpn. Kokai Tokkyo Koho, JP 1997208513.
(33) Doyle, M. P.; Van Leusen, D. Rearrangements of Oxocyclopropanecarboxylate Esters to Vinyl Ethers.
Disparate Behavior of TransitionꢀMetal Catalysts. J. Org. Chem. 1982, 47, 5326–5339.
(34) Nakamura, A.; Hamasaki, A.; Goto, S.; Utsunomiya, M.; Tokunaga, M. Irreversible Catalytic Ester Hydrolysis
of Allyl Esters to Give Acids and Aldehydes by Homogeneous Ruthenium and Ruthenium/Palladium Dual Catalyst
Systems. Adv. Synth. Catal. 2011, 353, 973–984.
(35) Tsukada, N.; Yagura, Y.; Sato, T.; Inoue, Y. Rhodiumꢀ and IridiumꢀCatalyzed Allylation of ElectronꢀRich
Arenes with Allyl Tosylate. Synlett 2003, 1431–1434.
(36) Cross, P. E.; Arrowsmith, J. E.; Thomas, G. N.; Gwilt, M.; Burges, R. A; Higgins, A. J. Selective Class III
Antiarrhythmic Agents. 1. Bis(arylalkyl)amines. J. Med. Chem. 1990, 33, 1151–1155.
(37) Fisher, J. W.; Trinkle, K. L. Iodide Dealkylation of Benzyl, PMB, PNB, and tꢀButyl NꢀAcyl Amino Acid
Esters via Lithium Ion Coordination. Tetrahedron Lett. 1994, 35, 2505–2508.
(38) Crosignani, S.; White, P. D.; Linclau, B. PolymerꢀSupported OꢀAlkylisoureas: Useful Reagents for the
OꢀAlkylation of Carboxylic Acids. J. Org. Chem. 2004, 69, 5897–5905.
(39) Gedye, R. N.; Smith, F. E.; Westaway, K. C. The Rapid Synthesis of Organic Compounds in Microwave Ovens.
Can. J. Chem. 1988, 66, 17–26.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
(40) Pozdnyakovich, Y. V.; Kondratova, G. B.; Shein, S. M. ipsoꢀBenzylation of Hexamethylbenzene and
2,3,4,5,6ꢀPentamethyldiphenylmethane. Zh. Org. Khim. 1982, 18, 2621.
(41) Clegg, W.; Pogue, H. J.; Lowe, M. P.; Butterfield, I. M.; Jackson, R. F. W. pꢀNitrobenzyl Trichloroacetimidate.
Acta Crystallogr. Sect. C Cryst. Struct. Commun. 1995, 51, 741−743.
6
7
8
(42) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A.; Bloino, J.; Janesko, B. G.;
Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; WilliamsꢀYoung, D.;
Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V.
G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida,
M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, Jr., J. A.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.;
Klene, M.; Adamo, C.; Cammi, R.; J. Ochterski, W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox,
D. J. Gaussian 09, Revision E.01 (Gaussian, Inc., Wallingford CT, 2013).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment