Direct Nucleophilic Substitution of Alcohols Using an Immobilized Oxovanadium Catalyst

Article abstract of DOI:10.1002/ejoc.202100569

Direct nucleophilic substitution of alcohols with thiols or carbon nucleophiles was achieved using a mesoporous silica-supported oxovanadium catalyst (VMPS4). Benzyl and allyl alcohols were compatible in this reaction under mild conditions, affording the products in high yields. The VMPS4 catalyst showed excellent chemoselectivity toward alcohols in the presence of acid-labile functional groups, which is in contrast to that observed for the commonly used Lewis acid catalysts, which exhibit poor selectivity. The VMPS4 catalyst could be recycled by simple centrifugation, and the catalytic activity was maintained over seven cycles.

Full text of DOI:10.1002/ejoc.202100569

Full Papers
doi.org/10.1002/ejoc.202100569
Direct Nucleophilic Substitution of Alcohols Using an
Immobilized Oxovanadium Catalyst
[a]
[a]
[a]
[a, b]
[a]
Tomoya Nishio, Shin Yoshioka, Kai Hasegawa, Kenzo Yahata,
Kyohei Kanomata, and
[a]
Shuji Akai*
Direct nucleophilic substitution of alcohols with thiols or carbon
nucleophiles was achieved using a mesoporous silica-supported
oxovanadium catalyst (VMPS4). Benzyl and allyl alcohols were
compatible in this reaction under mild conditions, affording the
products in high yields. The VMPS4 catalyst showed excellent
chemoselectivity toward alcohols in the presence of acid-labile
functional groups, which is in contrast to that observed for the
commonly used Lewis acid catalysts, which exhibit poor
selectivity. The VMPS4 catalyst could be recycled by simple
centrifugation, and the catalytic activity was maintained over
seven cycles.
Introduction
Direct substitution of alcohols is considered as one of the most
important challenges for the development of green engineering
[1]
in pharmaceutical and chemical industries and has been
mainly studied using Brønsted acids, Lewis acids, and transition
[2–4]
metal catalysts.
However, the strong Lewis acidity of these
catalysts often results in poor functional group tolerance. While
direct catalytic substitution of π-activated alcohols such as allyl
alcohols has been widely accomplished via transition metal π-
allyl intermediates, the use of benzylic alcohols in these
transformations is relatively rare and requires harsh reaction
[5–9]
conditions.
Additionally, despite the remarkable advantages
of heterogenous catalysts with regard to their handling and
reuse, only a few direct substitution reactions of alcohols have
[10–12]
been reported using such catalysts.
Recently, oxovanadium species have been employed as
racemization catalysts for alcohols. For example, oxovanadium
[
13–15]
[16]
compounds such as VOSO ·nH O
and VO(OSiPh3)3 and a
4
2
[17]
polymer-bound vanadyl phosphate were found to be active
in the racemization of allyl and benzyl alcohols. Racemization of
alcohols has often been combined with lipase-catalyzed kinetic
resolution for realizing chemoenzymatic dynamic kinetic reso-
Figure 1. Mesoporous silica-supported oxovanadium (VMPS4) and its appli-
cation in direct CÀ O bond activation of alcohols. (a) The structure of VMPS4;
(
b) Dynamic kinetic resolution of allyl alcohols by VMPS4-catalyzed
[18,19]
lution (DKR).
We recently reported a mesoporous silica-
racemization and following lipase-catalyzed enantioselective acylation; (c)
VMPS4-catalyzed direct nucleophilic substitution of alcohols.
supported oxovanadium catalyst (VMPS4) in which oxovana-
dium was covalently bound on the surface of the mesoporous
[20]
silica pore of 4-nm inner diameter (Figure 1a). VMPS4 was
highly compatible with lipase and also exhibited excellent
activity in the DKR of allyl, propargyl, and benzyl alcohols
[21–28]
(Figure 1b).
We speculated that the racemization by VMPS4
[
a] T. Nishio, S. Yoshioka, K. Hasegawa, Dr. K. Yahata, Dr. K. Kanomata,
Prof. Dr. S. Akai
Graduate School of Pharmaceutical Sciences,
Osaka University
in these reactions proceeded via a cationic intermediate
generated due to CÀ O bond cleavage in the substrate
[21]
alcohols. Considering this, we envisioned that VMPS4 could
also catalyze the direct substitution of alcohols in the presence
of an appropriate nucleophile in the reaction medium.
1-6, Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: akai@phs.osaka-u.ac.jp
https://handai-seizo.jp/?lang=en
b] Dr. K. Yahata
[
Herein, we report the VMPS4-catalyzed substitution reac-
tions of benzyl alcohols (Figure 1c). Sulfur nucleophiles were
mainly used in this study, because resultant benzylic sulfides
are widely found in bioactive compounds and pharmaceutical
Current address: Max-Planck-Institut für Kohlenforschung,
45470 Mülheim/Ruhr, Germany
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100569
Eur. J. Org. Chem. 2021, 1–7
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Papers
doi.org/10.1002/ejoc.202100569
[
29,30]
agents.
Some carbon nucleophiles were also successfully
and 5a as well as products 3aa and 4a in the resultant mixture
by H NMR spectroscopy (Table 2). VMPS4 exhibited highly
1
employed to demonstrate the versatility of the present method-
ology.
chemoselective activation of alcohol 1a against acetate 5a;
almost complete conversion of 1a to thioether 3aa was
achieved, while 5a remained intact (Entry 1). When commer-
[13–15]
Results and Discussion
cially available VOSO ·nH O
was used, the conversion was
4
2
reasonably low even after 24 h, and a significant amount of 4a
was produced despite the high chemoselectivity for 1a over 5a
(Entry 2). VO(OSiPh ) was not effective as a catalyst, although it
Initially, the reaction conditions were screened using benzyl
alcohol 1a, bearing a 4-methoxy group, as the substrate and
dodecane-1-thiol 2a as the nucleophile (Table 1) in the
presence of VMPS4. When the reaction was conducted using 1a
0.2 M), 2a (3.0 equiv.), and VMPS4 (4 mol%) in toluene at room
temperature (RT), the desired thioether 3aa was obtained in
6% NMR yield, along with a significant amount of self-
condensation side-product 4a (28%, Entry 1, Figure S1a). A
higher yield and an improved chemoselectivity were obtained
in MeCN (Entry 2). The yield, chemoselectivity, and reaction rate
improved drastically in CH Cl (Entry 3). Although the reaction
was conducted in other halogenated solvents such as CHCl3,
ClCH CH Cl, and PhCF (Entries 4–6), the highest yield was
3
3
was successfully employed in the direct amination of allyl
[31]
alcohols (Entry 3). It is noteworthy that the immobilization of
oxovanadium species onto a mesoporous silica (MPS) surface
drastically improved the catalytic activity (Entry 1 vs 2–3).
Although the precise role of MPS is still elusive, the polar
environment in the MPS pore might be considered responsible
(
2
[22]
for accelerating the reaction. Some other commonly used
[9]
[32]
[33,34]
Lewis acid catalysts, namely B(C F ) , InCl3, Na[AuCl4],
6
5 3
[7]
and BiBr3, consumed both alcohol 1a and acetate 5a,
resulting in poor chemoselectivity (Entries 4–7). This clearly
demonstrates the high activity and superior chemoselectivity of
VMPS4 in the direct CÀ O bond cleavage of alcohols. The specific
selectivity of VMPS4 for alcohol over acetate could be
rationalized by the favorable covalent VÀ O bond formation
between alcohol substrates and oxovanadium species of VMPS
2
2
2
2
3
obtained in CH Cl , which also gave the best results in
previously reported other type of VMPS4-catalyzed reactions,
such as racemization of allyl and propargyl alcohols.
Reducing the amount of 2a to 1.2 equiv. did not reduce the
2
2
[23,28]
[20,35–37]
product yield (Entry 7). Interestingly, the formation of undesired
involved in the catalytic cycle.
4
a was almost suppressed by reducing the concentration of 1a
Chemoselectivity of the VMPS4-catalyzed substitution was
further investigated using benzyl alcohol 1b or thiol 6
(Scheme 1) as a substrate. Although the reaction required a
higher temperature such as 80°C to proceed, it afforded
to 0.1 M, and 3aa was obtained in a quantitative yield (Entry 8,
Figure S1b).
Under the optimal conditions for achieving high yield and
selectivity, the chemoselectivity of VMPS4 was compared to
those of the previously reported Lewis acid catalysts. Thus, a
thioether 3ba in a moderate yield, along with a considerable
amount of styrene and a trace amount of self-condensation
product 4b (eq. 1). The same reaction at room temperature did
not afford any products. In contrast, the reaction of 6 afforded
only a trace amount of 3ba, and most of 6 was recovered
unreacted (eq. 2). Thus, VMPS4 selectively activated alcohols in
the presence of thiols.
1
:1 mixture of benzyl alcohol 1a and its acetate 5a was treated
with various catalysts in the presence of 2a (1.2 equiv. to the
sum of the equivalents of 1a and 5a), and the chemoselectivity
was evaluated by determining the molar ratios of residual 1a
Table 1. Optimization of reaction conditions of VMPS4-catalyzed thioe-
therification of benzyl alcohol 1a.
[a]
[a]
Table 2. Chemoselectivity of VMPS4 and other Lewis acid catalysts.
[
b]
Entry Solvent
Equiv.
2a)
Time
[h]
Yield [%] of
3aa
Yield [%] of
4a
Entry
Catalyst
VMPS4
Time
Molar ratio (1a:5a:3aa:4a)
[b]
[b,c]
(
1
2
15 min
24 h
3 h
15 min
1 h
18 h
5 min
3:48:48:trace
28:50:8:13
47:42:nd:nd
19:28:43:5
3:27:56:trace
18:25:51:nd
nd:3:96:trace
1
2
3
4
5
6
7
8
Toluene
MeCN
3.0
3.0
3.0
4
4
1
4
4
4
1
1
26
42
91
69
50
27
91
99
28
6
7
13
24
27
7
VOSO
VO(OSiPh
B(C
InCl
Na[AuCl
BiBr
4
·nH
2
O
[
[
[
c]
3
4
5
6
7
3
)
3
CH
2
Cl
2
6
F
5
)
3
d]
d]
CHCl
ClCH
3
3.0
3
2
CH
2
Cl 3.0
3.0
4
]
PhCF
3
3
CH
CH
2
Cl
Cl
2
2
1.2
1.2
[
d]
[a] Unless otherwise noted, the reaction was conducted with 1a
0.14 mmol), 5a (0.14 mmol), 2a (1.2 equiv. to the sum of the equivalents
of 1a and 5a, 0.34 mmol), and the indicated catalyst (4 mol%,
0.011 mmol) in CH Cl (0.05 M each, 2.8 mL) at room temperature. [b]
NMR of the crude reaction mixture with 1,1,2-
trichloroethene as an internal standard. Yield of 4a is represented based
on the monomeric alcohol unit. nd: not detected. [c] Molecular sieve 3 A
2
trace
(
[
(
a] Unless otherwise noted, the reaction was conducted with 1a
0.10 mmol), 2a, and VMPS4 (4 mol%) in the indicated solvent (0.2 M) at
2
2
1
1
room temperature (RT). [b] Yield was determined by H NMR of the crude
reaction mixture with 1,1,2-trichloroethene as an internal standard. [c]
Yield of 4a is represented based on the monomeric alcohol unit. [d]
Reaction was conducted with 0.1 M of 1a.
Determined by
H
[
31]
(0.20 g) was added. [d] Catalyst loading was 1 mol%.
Eur. J. Org. Chem. 2021, 1–7
www.eurjoc.org
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Papers
doi.org/10.1002/ejoc.202100569
alcohols were first examined. Introduction of halogen at the
para-position of benzyl alcohol improved the yield relative to
that obtained with unsubstituted benzyl alcohol 1b (Entries 1–3
vs Scheme 1). The highest yield was obtained with fluorine as
the substituent, probably because of the resonance effect of
the halogen atom. On the other hand, nitro-substituted benzyl
alcohol 1f did not afford any product (Entry 4). Benzyl alcohol
1
g bearing a cyclopropyl group at the α-position reacted
smoothly to give the corresponding thioether 3ga (Entry 5).
This is in sharp contrast to the reactions using a π-coordinating
Lewis acid catalyst, which promotes ring expansion to furnish
[38]
pyrrolidines. Tertiary alcohol 1h also reacted to afford 3ha in
a moderate yield (Entry 6). In the case of tertiary cyclic alcohol
1
i, a more thermodynamically stable conjugated thioether 3ia
was obtained, probably via an allyl cation intermediate
[23]
generated from 1i (Entry 7). Allyl alcohols 1j and 1k were
also compatible in the present reaction, affording products 3ja
and 3ka (Entries 8 and 9). On the other hand, simple aliphatic
alcohols such as 1l and 1m did not afford any products at 80°C
Scheme 1. Reactivity comparison between alcohol and thiol. Reaction was
conducted with 1b/6 (0.20 mmol), 2a (0.24 mmol), and VMPS4 (8 mol%) in
1
1
,2-dichloroethane (0.1 M) at 80°C. Yields were determined by H NMR of
the crude reaction mixture with 1,1,2-trichloroethene as an internal standard.
Yields of 4a and 7 are represented based on the monomeric alcohol and
thiol units, respectively. nd: not detected.
for 12 h (Entries 10 and 11).
Next, the reaction scope of the nucleophiles was examined
(Scheme 2). The reaction with arylthiol 2b afforded product
3
ab in 88% yield [Eq. (1)]. 3-Mercaptopropanoic acid 2c was
The scope and limitation of the present VMPS4-catalyzed
reaction were investigated next (Table 3). A series of benzyl
also used for this reaction to understand the competition
between thiol and carboxylic acid as a nucleophile. Indeed,
[
a]
Table 3. Scope and limitation of VMPS4-catalyzed thioetherification.
b
Entry
1
Conditions
3
Yield [%]
[
[
[
[
c]
c]
c]
c]
1
2
3
4
1c: X=F
ClCH
ClCH
ClCH
2
2
2
CH
CH
CH
2
2
2
Cl, 80°C, 12 h
Cl, 80°C, 24 h
Cl, 80°C, 24 h
3ca
3da
3ea
3fa
78 (4c: nd)
62 (4d: 9)
60 (4e: 20)
nr (4f: –)
1d: X=Cl
1e: X=Br
1f: X=NO
, 130°C, 24 h
2
Cl
2
CHCHCl
2
5
6
1g
1h
CH
CH
2
2
Cl
Cl
2
2
, RT, 24 h
, RT, 24 h
3ga
3ha
79
65
7
1i
CH
2
Cl
2
, RT, 24 h
3ia
75
8
9
CH
CH
2
2
Cl
Cl
2
2
, RT, 3 h
, RT, 1 h
85
69
[
[
c]
c]
1
0
1l
ClCH
ClCH
2
2
CH
CH
2
2
Cl, 80°C, 12 h
Cl, 80°C, 12 h
3la
nr
nr
1
1
1m
3ma
[
a] Unless otherwise noted, the reaction was conducted with 1a (0.20 mmol), 2a (0.24 mmol), and VMPS4 (4 mol%) in the indicated solvent (0.2 M). [b]
Isolated yield. Yields of 4 are indicated in the parentheses. nr: no reaction. [c] Reaction was conducted using 8 mol% of VMPS4.
Eur. J. Org. Chem. 2021, 1–7
www.eurjoc.org
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Papers
doi.org/10.1002/ejoc.202100569
Figure 2. Recycling test of VMPS4 catalyst. Every reaction was conducted
with 1a (0.33 mmol), 2a (0.40 mmol), and VMPS4 (4 mol%) in CH Cl (0.1 M).
2
2
Although the color of VMPS4 changed from ash white to dark
red during the first reaction, a high catalytic activity was
maintained even after seven recycles.
Scheme 2. Further reaction scope with various nucleophiles. Unless other-
wise noted, the reaction was conducted with 1a (0.20 mmol), the indicated
nucleophile (0.24 mmol), and VMPS4 (4 mol%) in CH
determined after isolation. Ar=C -4-OMe.
2 2
Cl (0.1 M). Yields were
6
H
4
Conclusion
In conclusion, we developed the direct nucleophilic substitution
of benzyl alcohols using a mesoporous silica-supported oxova-
nadium (VMPS4) catalyst. The catalyst exhibited high chemo-
selectivity for alcohols over acetates, which is in contrast to that
observed with other commonly used Lewis acid catalysts, which
exhibit poor chemoselectivity. VMPS4 could also selectively
activate alcohols over thiols. This reaction has a broad substrate
scope, and some carbon nucleophiles were also compatible in
this reaction. Importantly, the high catalytic activity of VMPS4
was maintained for more than seven recycles. Further inves-
tigations to develop new applications of VMPS4 in catalytic
transformations are currently in progress in our laboratory.
thioether 3ac was predominantly formed, along with a trace
amount of ester 3ac’ [Eq. (2)]. Furthermore, carbon nucleophiles
such as N-Me indole 8 and 1,3,5-trimethoxybenzene 10 were
employed, and the corresponding products 9 and 11 were
obtained in high yields [Eqs. (3) and (4)].
Although a precise reaction mechanism has not yet been
elucidated, we assume that the reaction proceeds through a
benzyl cation intermediate, which is generated by the reaction
[21,22]
of 1 with VMPS4.
The formation of a cationic intermediate
was suggested by the reaction of optically active alcohol (S)-1a
with VMPS4, which afforded the product 3aa in a racemic form
(Scheme S2 and Scheme S3a). In addition, the prominent
substituent effects on the Ph group (Table 3, Entries 1–4) and
high reactivity of tertiary alcohol 1h (Table 3, Entry 6) also Experimental Section
indicate the generation of benzyl cations in the reaction
pathway. However, we currently do not exclude the possibility
General procedure: [Table 1, Entry 8] Under argon atmosphere,
VMPS4 (40 mg, 8.6 μmol of vanadium) was added to a CH Cl2
2
of an S 2-type mechanism and racemization preequilibrium of
solution (2.0 mL, 0.1 M) of alcohol 1a (31 mg, 0.20 mmol) and thiol
2a (58 μL, 0.24 mmol) at room temperature. The reaction mixture
was stirred at room temperature for 1 h. After that, the reaction
mixture was filtered through a pad of Celite, and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane to hexane/EtOAc=97:3) giving 3aa
as a colorless oil (64 mg, 95%).
N
the alcohol, because 1a smoothly racemized during the
reaction (Scheme S3b).
Finally, the recyclability of the VMPS4 catalyst was inves-
tigated (Figure 2). After complete conversion of the substrate
1
a, the reaction mixture was centrifuged, and the supernatant
containing the product was collected by decantation and
concentrated in vacuo. The residue was purified by chromatog-
raphy to give 3aa. The precipitated VMPS4 was washed with
EtOAc, centrifuged, and dried in vacuo. The recovered VMPS4
was used for the next reaction under identical conditions.
Dodecyl(1-(4-methoxyphenyl)ethyl)sulfane (3aa): IR (NaCl): 2924,
À 1
1
2
8
854, 1248, 1036 cm ; H NMR (400 MHz, CDCl ) δ=7.26 (d, J=
.0 Hz, 2H), 6.85 (d, J=8.0 Hz, 2H), 3.92 (q, J=7.0 Hz, 1H), 3.80 (s,
3
3H), 2.32–2.23 (m, 2H), 1.58–1.40 (m, 2H), 1.54 (d, J=7.0 Hz, 3H),
1
3
1.30–1.23 (m, 18H), 0.88 (t, J=7.0 Hz, 3H); C NMR (100 MHz, CDCl )
3
Eur. J. Org. Chem. 2021, 1–7
www.eurjoc.org
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Papers
doi.org/10.1002/ejoc.202100569
À 1
1
δ=158.6, 136.4, 128.4, 113.9, 55.4, 43.5, 32.1, 31.4, 29.8 , 29.7 ,
75% yield (57 mg); a colorless oil; IR (NaCl): 2924, 2854 cm ; H
0
8
2
9.7 , 29.6, 29.5 , 29.5 , 29.4, 29.1, 22.9, 22.8, 14.3; HRMS(EI) m/z
NMR (500 MHz, CDCl ) δ=7.40–7.38 (m, 2H), 7.33–7.29 (m, 2H),
7.26–7.22 (m, 1H), 6.12–6.11 (m, 1H), 3.58–3.54 (m, 1H), 2.64–2.55
6
3
1
3
+
*
calcd. for C H OS [M ]: 336.2487, found: 336.2482.
21
36
(
m, 2H), 2.44–2.41 (m, 2H), 2.05–1.98 (m, 2H), 1.85–1.73 (m, 2H),
Dodecyl(1-phenylethyl)sulfane (3ba): Purified by column chroma-
to-graphy using hexane to hexane/toluene=19:1 as an eluant;
1
7
1
2
.64–1.58 (m, 2H), 1.41–1.36 (m, 2H), 1.28–1.26 (m, 16H), 0.88 (t, J=
13
.0 Hz, 3H); C NMR (100 MHz, CDCl ) δ=141.9, 139.0, 128.4, 127.3,
À 1
1
3
5
8% yield (25 mg); a colorless oil; IR (NaCl): 2924, 2854 cm ; H
25.4, 125.3, 41.7, 32.1, 31.3, 30.2, 29.8 , 29.7 , 29.7 , 29.6 , 29.5,
2
9
6
9
NMR (400 MHz, CDCl ) δ=7.35–7.21 (m, 5H), 3.94 (q, J=7.0 Hz, 1H),
3
9.4, 29.2 , 29.2 , 27.5, 22.9, 20.5, 14.3; HRMS(EI) m/z calcd. for
9
5
2
.33–2.27 (m, 2H), 2.17 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 1.52–1.43 (m,
+
*
C H S [M ]: 358.2694, found: 358.2689.
13
24 38
2H), 1.33–1.19 (m, 18H), 0.88 (t, J=7.0 Hz, 3H); C NMR (100 MHz,
CDCl ) δ=144.4, 128.6, 127.4, 127.1, 44.2, 32.1, 31.4, 29.8, 29.7, 29.6,
(E)-Dodecyl(4-phenylbut-3-en-2-yl)sulfane (3ja): Purified by col-
umn chromatography using hexane/toluene=19:1 as an eluant;
85% yield (57 mg); a colorless oil; IR (NaCl): 2924, 2854, 1448,
3
2
9.5, 29.3, 29.1, 22.8 , 22.7 , 14.3; HRMS(EI) m/z calcd. for C H S
4 6 20 34
+
*
[M ]: 306.2381, found: 306.2380.
À 1
1
9
62 cm ; H NMR (400 MHz, CDCl ) δ=7.39–7.37 (m, 2H), 7.33–7.30
3
Dodecyl(1-(4-fluorophenyl)ethyl)sulfane (3ca): Purified by column
chromatography using hexane to hexane/EtOAc=49:1 as an
(m, 2H), 7.25–7.21 (m, 1H), 6.35 (d, J=15.5 Hz, 1H), 6.06 (dd, J=
5.5, 9.0 Hz, 1H), 3.50 (dq, J=9.0, 7.0 Hz, 1H), 2.53–2.38 (m, 2H),
À 1
eluant; 78% yield (90 mg); a colorless oil; IR (NaCl): 2963, 1248 cm ;
1
H NMR (400 MHz, CDCl ) δ=7.32-7.28 (m, 2H), 7.02–6.97 (m, 2H),
13
3
3
3
.93 (q, J=7.0 Hz, 1H), 2.33–2.22 (m, 2H), 1.57–1.43 (m, 2H), 1.54 (d,
1
2
3
28.7, 127.6, 126.4, 42.7, 32.1, 31.0, 29.8 , 29.7 , 29.7 , 29.6 , 29.5,
4 9 5 7
+
*
13
J=7.0 Hz, 3H), 1.24–1.22 (m, 18H), 0.88 (t, J=7.0 Hz, 3H); C NMR
9.4, 29.2, 22.8, 20.8, 14.3; HRMS(EI) m/z calcd. for C H S [M ]:
2
2
36
(
8
100 MHz, CDCl ) δ=161.8 (d, J =244.5 Hz), 140.1, 128.8 (d, J =
3
C
F
C
F
32.2538, found: 332.2538.
.0 Hz), 115.3 (d, J =22.0 Hz), 43.5, 32.1, 31.4, 29.8, 29.7, 29.6, 29.5,
CF
19
2
9.4, 29.3, 29.1, 22.9, 22.8, 14.3; F NMR (470 MHz, CDCl ) δ=-115.7;
(E)-Dodecyl(4-(4-methoxyphenyl)but-3-en-2-yl)sulfane (3ka): Puri-
fied by column chromatography using hexane/EtOAc=50:1 as an
eluant; 69% yield (71 mg); a colorless oil; IR (NaCl): 2955, 2854,
3
+
*
HRMS(EI) m/z calcd. for C H FS [M ]: 324.2287, found: 324.2286.
20
33
(
1-(4-Chlorophenyl)ethyl)(dodecyl)sulfane (3da): Purified by col-
À 1
1
1
608, 1250, 1038 cm ; H NMR (500 MHz, CDCl ) δ=7.31 (d, J=
3
umn chromatography using hexane to hexane/toluene=19:1 as an
9
.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 6.29 (d, J=15.5 Hz 1H), 5.91 (dd,
eluant; 62% yield (51 mg); a colorless oil; IR (NaCl): 2924, 2854,
J=15.5, 9.0 Hz, 1H), 3.81 (s, 3H), 3.48 (dq, J=9.0, 7.0 Hz, 1H), 2.51–
À 1
1
1
7
2
093 cm ; H NMR (400 MHz, CDCl ) δ=7.27 (s, 4H), 3.91 (q, J=
3
2
1
1
2
.38 (m, 2H), 1.62–1.49 (m, 2H), 1.39 (d, J=7.0 Hz, 3H), 1.37–1.23 (m,
.0 Hz, 1H), 2.31–2.24 (m, 2H), 1.53 (d, J=7.0 Hz, 3H), 1.49–1.43 (m,
H), 1.30–1.22 (m, 18H), 0.88 (t, J=7.5 Hz, 3H); C NMR (100 MHz,
13
8H), 0.88 (t, J=7.0 Hz, 3H); C NMR (100 MHz, CDCl ) δ=159.2,
13
3
30.6, 129.6, 128.8, 127.5, 114.1, 55.4, 42.8, 32.0, 30.9, 29.8, 29.74,
9.7 , 29.6, 29.4 , 29.3 , 29.1, 22.8, 20.9, 14.2; HRMS(EI) m/z calcd. for
CDCl ) δ=143.0, 132.6, 128.7 , 128.6 , 43.5, 32.1, 31.4, 29.8, 29.7,
3
3
9
0
4
7
2
9.6, 29.5, 29.4, 29.3, 29.0, 22.8 , 22.8 , 14.3; HRMS(EI) m/z calcd. for
+
*
4
6
C H OS [M ]: 362.2643, found: 362.2646.
35
+
*
23 38
C H ClS [M ]: 340.1992, found: 340.1991.
2
0
33
(
4-(tert-Butyl)phenyl)(1-(4-methoxyphenyl)ethyl)sulfane
(3ab):
(
1-(4-Bromophenyl)ethyl)(dodecyl)sulfane (3ea): Purified by col-
Purified by column chromatography using hexane/EtOAc=49:1 as
an eluant; 88% yield (87 mg); a colorless oil; IR (NaCl): 2963, 1248,
umn chromatography using hexane to hexane/toluene=19:1 as an
eluant; 60% yield (60 mg); a colorless oil; IR (NaCl): 2924, 2853,
À 1 1
1
034 cm ; H NMR (500 MHz, CDCl ) δ=7.29–7.24 (m, 6H), 6.84 (d,
À 1
1
3
1
7
1
011 cm ; H NMR (400 MHz, CDCl ) δ=7.42 (d, J=9.0 Hz, 2H),
3
J=9.0 Hz, 2H), 4.30 (q, J=7.0 Hz 1H), 3.80 (s, 3H), 1.61 (d, J=7.0 Hz,
.22 (d, J=9.0 Hz, 2H), 3.88 (q, J=7.0 Hz, 1H), 2.33–2.20 (m, 2H),
.52 (d, J=7.0 Hz, 3H), 1.48–1.42 (m, 2H), 1.30–1.21 (m, 18H), 0.87 (t,
13
3
H), 1.31 (s, 9H); C NMR (100 MHz, CDCl ) δ=158.7, 150.5, 135.5,
3
1
32.6, 131.9, 128.5, 125.9, 113.8, 55.4, 47.6, 34.6, 31.4, 22.6; HRMS(EI)
13
J=7.0 Hz, 3H); C NMR (100 MHz, CDCl ) δ=143.5, 131.6, 129.1,
+
*
3
m/z: calcd. for C H OS [M ]: 300.1548, found: 300.1544.
1
9
24
1
2
20.7, 43.6, 32.1, 31.4, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.0, 22.8,
79 +
*
2.7, 14.3; HRMS(EI) m/z calcd. for C H BrS [M ]: 384.1486,
3-((1-(4-Methoxyphenyl)ethyl)thio)propanoic acid (3ac): Purified
by column chromatography using hexane/EtOAc/AcOH=80:19:1
as an eluant; 88% yield (50 mg); a colorless oil; IR (NaCl): 1710,
20
33
found: 384.1479.
(
Cyclopropyl(phenyl)methyl)(dodecyl)sulfane (3ga): Purified by
À 1 1
1
248, 1033 cm ; H NMR (500 MHz, CDCl ) δ=11.27 (bs, 1H), 7.26
3
column chromatography using hexane/toluene=19:1 as an eluant;
7
NMR (500 MHz, CDCl ) δ=7.37–7.31 (m, 4H), 7.26–7.23 (m, 1H), 3.13
(d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 3.96 (q, J=7.5 Hz, 1H),
À 1
1
9% yield (53 mg); a colorless oil; IR (NaCl): 2924, 2854 cm ; H
13
3
.80 (s, 3H), 2.57–2.48 (m, 4H), 1.54 (d, J=7.5 Hz, 3H); C NMR
3
(100 MHz, CDCl ) δ=178.2, 158.8, 135.6, 128.4, 114.0, 55.4, 43.8,
3
(
d, J=10.0 Hz, 1H), 2.36–2.27 (m, 2H), 1.49–1.43 (m, 2H), 1.31–1.22
+
*
3
4.5, 25.9, 22.7; HRMS(EI) m/z calcd. for C H O S [M ]: 240.0820,
12 16 3
(m, 18H), 0.88 (t, J=7.0 Hz, 3H), 0.75–0.73 (m, 1H), 0.52–0.47 (m,
found: 240.0817.
13
1
H), 0.45–0.40 (m, 1H), 0.25–0.20 (m, 1H); C NMR (100 MHz, CDCl3)
δ=142.9, 128.5, 128.0, 127.1, 55.0, 32.1, 31.2, 29.8, 29.7, 29.6 , 29.5 ,
3-(1-(4-Methoxyphenyl)ethyl)-1-methyl-1H-indole (9): Purified by
column chromatography using hexane/EtOAc=19:1 as an eluant;
94% yield (49 mg); colorless oil; IR (NaCl): 1510 cm ; H NMR
2
5
2
9.5 , 29.3, 29.1, 22.8, 17.4, 14.3, 6.5, 4.9; HRMS(EI) m/z calcd. for
0
+
*
À 1
1
C H S [M ]: 332.2538, found: 332.2544.
2
2
36
(
400 MHz, (CD ) CO) δ=7.30 (t, J=7.0 Hz, 2H), 7.21 (d, J=9.0 Hz,
H), 7.11-7.07 (m, 2H), 6.89 (t, J=7.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H),
3 2
(
1,1-Diphenylethyl)(dodecyl)sulfane (3ha): Purified by column
2
4
3
1
2
1
chromatography using hexane/toluene=19:1 as an eluant; 65%
.30 (q, J=7.5 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 1.63 (d, J=7.5 Hz,
À 1
1
yield (50 mg); a colorless oil; IR (NaCl): 2925, 2854 cm ; H NMR
500 MHz, CDCl ) δ=7.42 (d, J=7.5 Hz, 4H), 7.30 (t, J=7.5 Hz, 4H),
13
H); C NMR (100 MHz, (CD ) CO) δ=158.8, 140.2, 138.4, 129.0,
3
2
(
3
28.2, 126.7, 122.0, 120.7, 120.3, 119.1, 114.3, 110.0, 55.4, 36.8, 32.7,
7
.22 (t, J=7.5 Hz, 2H), 2.26 (t, J=7.5 Hz, 2H), 2.07 (s, 3H), 1.42 (quint,
+
*
3.1; HRMS(EI) m/z calcd. for C H NO [M ]: 265.1467, found: 265.
1
3
18 19
J=7.5 Hz, 2H), 1.31–1.19 (m, 18H), 0.88 (t, J=7.0 Hz, 3H); C NMR
100 MHz, CDCl ) δ=146.6, 128.1, 128.0, 126.6, 56.1, 32.1, 30.7, 30.3,
465.
(
3
2
9.8, 29.7, 29.6, 29.5, 29.3, 29.2, 29.0, 22.8, 14.3; HRMS(EI) m/z calcd.
1,3,5-Trimethoxy-2-(1-(4-methoxyphenyl)ethyl)benzene (11): Puri-
fied by column chromatography using hexane/EtOAc=19:1 as an
eluant; 89% yield (53 mg); a colorless oil; IR (NaCl): 1605 cm ; H
+
*
for C H S [M ]: 382.2694, found: 382.2693.
26
38
À 1
1
Dodecyl(3-phenylcyclohex-2-enyl)sulfane (3ia): Purified by col-
umn chromatography using hexane/toluene=19:1 as an eluant;
NMR (400 MHz, CDCl ) δ=7.20 (d, J=8.5 Hz, 2H), 6.77 (d, J=8.5 Hz,
3
2H), 6.12 (s, 2H), 4.69 (q, J=7.5 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.70
Eur. J. Org. Chem. 2021, 1–7
www.eurjoc.org
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Papers
doi.org/10.1002/ejoc.202100569
1
3
(
s, 6H), 1.62 (d, J=7.5 Hz, 3H); C NMR (100 MHz, CDCl ) δ=159.4,
[13] S. Wuyts, J. Wahlen, P. A. Jacobs, D. E. De Vos, Green Chem. 2007, 9,
104–1108.
[14] A. S. De Miranda, M. V. M. De Silva, F. C. Dias, S. P. De Souza, R. A. C.
3
1
1
1
3
59.1, 157.1, 138.9, 128.3, 116.1, 113.0, 91.5, 55.9, 55.4, 55.3, 32.4,
8.2; HRMS(EI) m/z calcd. for C H O [M ]: 302.1518, found:
+
*
18
22
4
Leão, R. O. M. A. De Souza, React. Chem. Eng. 2017, 2, 375–381.
15] L. A. De Almeida, T. H. Marcondes, C. D. F. Milagre, H. M. S. Milagre,
ChemCatChem 2020, 12, 2849–2858.
16] S. Akai, K. Tanimoto, Y. Kanao, M. Egi, T. Yamamoto, Y. Kita, Angew.
Chem. Int. Ed. 2006, 118, 2654–2657.
02.1512.
[
[
Acknowledgements
[17] S. Akai, R. Hanada, N. Fujiwara, Y. Kita, M. Egi, Org. Lett. 2010, 12, 4900–
903.
4
[
18] Z. S. Seddigi, M. S. Malik, S. A. Ahmed, A. O. Babalghith, A. Kamal, Coord.
This work was financially supported by the JSPS KAKENHI
18H02556and 20 K22542) and Platform Project for Supporting
Chem. Rev. 2017, 348, 54–70.
(
[19] S. Akai, G. A. I. Moustafa, in Kinetic Control in Synthesis and Self-Assembly
Eds.: M. Numata, S. Yagai, T. Hamura), Academic Press, 2019, pp. 21–43.
[
[
(
Drug Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research (BINDS))
from AMED under Grant Number 21am0101084. We thank Taiyo
Kagaku Co. Ltd., for kindly providing mesoporous silica. High-
resolution mass spectrometry analysis was supported by the
Analytical Instrumentation Facility, Graduate School of Engineer-
ing, Osaka University.
20] S. Akai, Chem. Lett. 2014, 43, 746–754.
21] M. Egi, K. Sugiyama, M. Saneto, R. Hanada, K. Kato, S. Akai, Angew.
Chem. Int. Ed. 2013, 52, 3654–3658; Angew. Chem. 2013, 125, 3742–
3746.
[
22] K. Sugiyama, Y. Oki, S. Kawanishi, K. Kato, T. Ikawa, M. Egi, S. Akai, Catal.
Sci. Technol. 2016, 6, 5023–5030.
[23] S. Kawanishi, K. Sugiyama, Y. Oki, T. Ikawa, S. Akai, Green Chem. 2017,
9, 411–417.
1
[
24] K. Sugiyama, S. Kawanishi, Y. Oki, M. Kamiya, R. Hanada, M. Egi, S. Akai,
Bioorg. Med. Chem. 2018, 26, 1378–1386.
[
[
25] S. Kawanishi, S. Oki, D. Kundu, S. Akai, Org. Lett. 2019, 21, 2978–2982.
26] F. Kühn, S. Katsuragi, Y. Oki, C. Scholz, S. Akai, H. Gröger, Chem.
Commun. 2020, 56, 2885–2888.
Conflict of Interest
[
[
[
27] K. Higashio, S. Katsuragi, D. Kundu, N. Adebar, C. Plass, F. Kühn, H.
Gröger, S. Akai, Eur. J. Org. Chem. 2020, 1961–1967.
28] I. Tsuchimochi, S. Hori, Y. Takeuchi, M. Egi, T. Satoh, K. Kanomata, T.
Ikawa, S. Akai, Synlett 2021, 32, 822–828.
The authors declare no conflict of interest.
29] M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr. Top. Med. Chem. 2016, 16,
Keywords: Heterogeneous catalysis
Nucleophilic substitution · Oxovanadium · Thioethers
· Mesoporous silica ·
1200–1216.
[
30] W. Jiang, N. Li, L. Zhou, Q. Zeng, ACS Catal. 2018, 8, 9899–9906.
[
31] T. Sakuramoto, T. Hirao, M. Tobisu, T. Moriuchi, ChemCatChem 2019, 11,
1175–1178.
[
[
[
32] M. Yasuda, T. Somyo, A. Baba, Angew. Chem. Int. Ed. 2006, 45, 793–796;
Angew. Chem. 2006, 118, 807–810.
33] M. Georgy, V. Boucard, J. M. Campagne, J. Am. Chem. Soc. 2005, 127,
[
1] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L. Leazer,
R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks,
T. Y. Zhang, Green Chem. 2007, 9, 411–42.
2] E. Emer, R. Sinisi, M. G. Capdevila, D. Petruzziello, F. De Vincentiis, P. G.
Cozzi, Eur. J. Org. Chem. 2011, 647–666.
14180–14181.
[
34] T. Ohshima, Y. Nakahara, J. Ipposhi, Y. Miyamoto, K. Mashima, Chem.
Commun. 2011, 47, 8322–8324.
[
[
[
[
[
[
[
3] A. Baeza, C. Nájera, Synthesis 2014, 46, 25–34.
[35] B. M. Trost, J. S. Tracy, Acc. Chem. Res. 2020, 53, 1568–1579.
[36] M. Sako, S. Takizawa, H. Sasai, Tetrahedron 2020, 76, 131645.
[37] H. Kang, M. R. Herling, K. A. Niederer, Y. E. Lee, P. Vasu Govardhana R-
eddy, S. Dey, S. E. Allen, P. Sung, K. Hewitt, C. Torruellas, G. J. Kim, M. C.
Kozlowski, J. Org. Chem. 2018, 83, 14362–14384.
4] M. Dryzhakov, E. Richmond, J. Moran, Synthesis 2016, 48, 935–959.
5] K. J. Miller, M. M. Abu-Omar, Eur. J. Org. Chem. 2003, 1294–1299.
6] S. Podder, J. Choudhury, S. Roy, J. Org. Chem. 2007, 72, 3129–3132.
7] S. Biswas, J. S. M. Samec, Chem. Asian J. 2013, 8, 974–981.
8] K. Kuciński, G. Hreczycho, Eur. J. Org. Chem. 2017, 5572–5581.
9] S. S. Meng, Q. Wang, G. Bin Huang, L. R. Lin, J. L. Zhao, A. S. C. Chan, RSC
Adv. 2018, 8, 30946–30949.
[
38] W. Rao, P. W. H. Chan, Chem. Eur. J. 2008, 14, 10486–10495.
[
10] J. S. Yadav, B. V. Subba Reddy, T. Pandurangam, K. V. Raghavendra Rao,
K. Praneeth, G. G. K. S. Narayana Kumar, C. Madavi, A. C. Kunwar,
Tetrahedron Lett. 2008, 49, 4296–4301.
Manuscript received: May 11, 2021
Revised manuscript received: June 23, 2021
Accepted manuscript online: June 25, 2021
[
[
11] J. Wang, Y. Masui, M. Onaka, Synlett 2010, 2010, 2493–2497.
12] M. A. Tandiary, Y. Masui, M. Onaka, RSC Adv. 2015, 5, 15736–15739.
Eur. J. Org. Chem. 2021, 1–7
www.eurjoc.org
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPERS
A mesoporous silica-supported oxo-
vanadium catalyst enabled the direct
substitution of benzyl and allyl
alcohols with sulfur and carbon nu-
cleophiles. The catalyst showed high
chemoselectivity for alcohols in the
presence of acid-labile functional
groups and could be recycled more
than seven times.
T. Nishio, S. Yoshioka, K. Hasegawa,
Dr. K. Yahata, Dr. K. Kanomata,
Prof. Dr. S. Akai*
1
– 7
Direct Nucleophilic Substitution of
Alcohols Using an Immobilized Oxo-
vanadium Catalyst