Flow Friedel–Crafts alkylation of 1-adamantanol with arenes using HO-SAS as an immobilized acid catalyst

Article abstract of DOI:10.1002/jccs.202000518

In this communication flow Friedel–Crafts alkylation was studied using hydroxy-substituted sulfonic acid-functionalized silica as a catalyst and 1-adamantanol as a model substrate. The reaction of 1-adamantanol (1a) with toluene (2a) proceeded well with 5 min of residence time at 120°C to give good yield of 1-tolyladamantane (3a) as a 1:9 mixture of meta and para isomers. When the flow synthesis was carried out over 2.5 hr of running time, the collected five fractions contain the product 3a in 97–92% yields, suggesting the durability of the catalyst.

Full text of DOI:10.1002/jccs.202000518

Received: 15 November 2020
DOI: 10.1002/jccs.202000518
Revised: 22 November 2020
Accepted: 24 November 2020
S P E C I A L I S S U E P A P E R
Flow Friedel–Crafts alkylation of 1-adamantanol with
arenes using HO-SAS as an immobilized acid catalyst
Takayoshi Kasakado1 | Mamoru Hyodo1 | Akihiro Furuta2
|
Aina Kamardine2 | Ilhyong Ryu1,3
| Takahide Fukuyama2
1Organization for Research Promotion,
Abstract
Osaka Prefecture University, Sakai, Japan
2Department of Chemistry, Graduate
School of Science, Osaka Prefecture
University, Sakai, Japan
3Department of Applied Chemistry,
National Chiao Tung University, Hsinchu,
Taiwan
Flow Friedel–Crafts alkylation was studied using hydroxy-substituted sulfonic
acid-functionalized silica as a catalyst and 1-adamantanol as a model substrate.
The reaction of 1-adamantanol (1a) with toluene (2a) proceeded well with
5 min of residence time at 120ꢀC to give good yield of 1-tolyladamantane (3a)
as a 1:9 mixture of meta and para isomers. When the flow synthesis was car-
ried out over 2.5 hr of running time, the collected five fractions contain the
product 3a in 97–92% yields, suggesting the durability of the catalyst.
Correspondence
Ilhyong Ryu, Department of Applied
Chemistry, National Chiao Tung
University, 1001 University Road,
Hsinchu 30010, Taiwan.
K E Y W O R D S
1-aryladamantanes, flow Friedel–Crafts alkylation, hydroxy-substituted sulfonic acid-
functionalized silica
Email: ryu@nctu.edu.tw
Funding information
JSPS for Grant-in Aid for Scientific
Research (B), Grant/Award Number:
19H02722; MOST, Taiwan, Grant/Award
Number: 108-2636-M-009-007
1 | INTRODUCTION
of a flow reactor, and (c) no need for separation of prod-
ucts from the catalyst.[3,4]
Organic synthesis routinely uses Brønsted acids, such as
hydrochloric acid, sulfuric acid, and p-toluene sulfonic
acid, as catalyst. However, some of acid catalysts are cor-
rosive and require neutralization prior to being disposed
of as wastes. In this regard, the use of heterogeneous
solid acid catalysts has distinct advantages over that of
homogeneous acid catalysts in terms of safe handling, no
need for neutralization after the reaction, and easy sepa-
ration from products allowing for reuses of the catalyst.[1]
In recent years, flow reaction technology has been
adopted in a wide range of organic synthesis.[2] The com-
bination of a heterogeneous solid acid catalyst and con-
tinuous flow system has several important features: (a) a
reaction space capable of keeping catalysts in large excess
to substrates, (b) a rapid heat exchange through the wall
During the course of our study on flow organic
synthesis,[5] we came across the silica-gel based heteroge-
neous acid catalyst, hydroxy-substituted sulfonic acid-
functionalized silica (HO-SAS),[6] sulfonic acid-modified
silica gel bearing β-hydroxy functionality. This catalyst is
particularly useful in terms of thermal stability (up to
130ꢀC) and enhanced acidity due to the β-hydroxy substi-
tution. Indeed, in our previous works using a flow-setup
based on a packed bed reactor containing HO-SAS
(Figure 1), we were able to conduct flow Fischer esterifi-
cation reaction (Scheme 1, Equation 1)[7] and flow dehy-
dration reaction of allylic alcohols (Scheme 1,
Equation 2)[8,9] with a short period of residence time.
Friedel–Crafts alkylation reaction starting with alcohols
is a highly green process,[10,11] since water is the only
byproduct as in the cases of Fischer esterification and
dehydration of alcohols. In this communication, we
Dedicated to the memory of Prof. Jun-ichi Yoshida.
J Chin Chem Soc. 2020;1–5.
http://www.jccs.wiley-vch.de
© 2020 The Chemical Society Located in Taipei & Wiley-VCH GmbH
1

2
KASAKADO ET AL.
report the HO-SAS-catalyzed Friedel–Crafts alkylation
reaction of 1-adamantanol in flow (Scheme 1,
Equation 3). Previous work on Friedel–Crafts alkylation
reaction of 1-adamantanol employed an equimolar
amount of triflic acid and ionic liquid, such as BMIM
(OTf),[12] which required biphasic workup. Conse-
quently, we were pleased to find that the flow Friedel–
Crafts alkylation reaction of 1-adamantanol by HO-SAS
catalyst proceeded smoothly to give good yields of
1-aryladamantanes.
First, as a model study, the HO-SAS-catalyzed
Friedel–Crafts alkylation of 1-adamantanol (1a) and tolu-
ene (2a) was investigated using both batch and flow reac-
tors (Table 1). Using a glass-made reactor, the reaction of
1a (0.08 M) and 2a HO-SAS (377 mg, 100ꢀC, 2 hr)
proceeded to give 1-p-tolyladamantane (3a) in a yield of
70% with a ratio of o/m/p = 0/10/90 (Entry 1). Then we
examined the reaction using a flow setup shown in
Figure 1: a stainless-steel column (4.0 mm id × 50 mm
length) filled with HO-SAS (377 mg, 0.155 mmol as
-SO3H moiety), for which a back pressure regulator was
connected to the end of the column reactor. Thus, a tolu-
ene solution of 1-adamantanol ([1a] = 0.08 M) was intro-
duced to the above catalyst-packed column, which was
immersed in an oil bath heated to 100ꢀC. At this temper-
ature, product 3a was obtained in a yield of 59% with a
residence time of 30 min (Entry 2). When the oil bath
temperature was raised to 120ꢀC, 3a was obtained with a
yield of 83% with the same ratio of o/m/p = 0/10/90
(Entry 3). Then the flow reaction was carried out with a
shorter residence time and, to our delight, it was found
that the product yield could be maintained even with a
residence time of 5 min (Entry 4).[13] On the other hand,
further shortening the reaction time caused a decrease of
the yield (Entry 5, Entry 6). The high efficiency of the
present flow catalysis owes to a large catalyst/substrate
ratio of 3.7 as well as immediate washing out of water
from the catalyst area.
FIGURE 1 Flow set-up for acid catalysis using HO-SAS and a
stain-less-steel packed-bed reactor
Using the same flow-setup and optimized conditions
(Entry 4 in Table 1),[14] we then studied the reaction of
1-adamantanol (1a) and toluene (2a) over a prolonged
SCHEME 1 Concept: flow acid catalysis using HO-SAS as an
immobilized catalyst
TABLE 1 Batch and flow Friedel–Crafts alkylation of 2a and 1a using HO-SAS
Entry
Reaction mode
Batch
Temp. (ꢀC)
100
Reaction time
2 hr
Yield (%)a,b
1
2
3
4
5
6
70
59
83
82
58
52
Flow
100
30 min
30 min
5 min
Flow
120
Flow
120
Flow
120
2 min
Flow
120
1 min
aToluene solution of 1a (0.08 M) was used. Isolated yields by silica gel chromatography are given.
b3a contains 10% of meta isomer.

KASAKADO ET AL.
3
methyl groups. On the other hand, the observation of a sig-
nificant amount of ortho isomer for 3b, is due to a strong
electron-donating effect of a methoxy group, which has been
well precedented in Friedel–Crafts alkylation reactions.[15]
In summary, using HO-SAS as an immobilized acid cat-
alyst in a packed-bed reactor, we have shown that flow
Friedel–Crafts alkylation reaction of 1-adamantanol (1a)
with typical arenes proceeded well at 120ꢀC to give good
yields of the corresponding 1-aryladamantanes. Extremely
shortened reaction (residence) time in flow is compared
favorably to that of a batch reaction (5 min vs. 2 hr). These
results could be rationalized by a high catalyst/substrate
ratio available for flow packed bed reactor system. The time
course experiment for the flow synthesis of 3a over the
period of 2.5 hr proved the durability of the catalytic activ-
ity, which is presumably based on the fact that water is
washed out consistently from the packed bed reactor. The
protocol is operationally simple, thus bypassing tedious
workup procedures required for a batch process. We are
now extending the utility of flow acid catalysis based on
HO-SAS to some other cationic reaction processes.
SCHEME 2 Time course for the flow reaction of 2a and 1a
using HO-SAS
ACKNOWLEDGMENTS
We thank JSPS for Grant-in Aid for Scientific Research
(B) (No. 19H02722). Ilhyong Ryu thanks the Ministry of
Science and Technology, Taiwan (MOST108-2636-M-
009-007) and the Center for Emergent Functional Matter
Science at NCTU for additional support.
SCHEME 3 Flow Friedel–Crafts alkylation using HO-SAS
ORCID
operation time (2.5 hr) (Scheme 2). After discarding the
first flow fraction that had eluted over the first 10 min,
each fraction was collected every 30 min. It was revealed
that the product 3a was obtained in a similarly high yield
of 97–92% in each of these fractions, suggesting the dura-
bility of the acid catalyst.
Ilhyong Ryu https://orcid.org/0000-0001-7715-4727
Takahide Fukuyama https://orcid.org/0000-0002-3098-
2987
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[13] Typical procedure: 1-adamantanol (1a, 65 mg, 0.43 mmol) was
dissolved in toluene (2a, 5.0 ml, 47.2 mmol) and placed in a
syringe equipped with a syringe pump. This solution was fed
into a stainless steel-made column (4.0 mm × 50 mm) filled
with HO-SAS (A, 377 mg, 0.155 mmol as -SO3H moiety), the
flow rate was 0.097 ml/min. This column was immersed in an
oil bath (120ꢀC). The reaction mixture firstly eluted for 10 min
was discarded, and the latter eluted reaction mixture was col-
lected for 10 min, evaporated to give the crude product which
was purified with column chromatography on SiO2 to give the
product 3a (16 mg, 0.068 mmol, 82% yield). 1H NMR
(500 MHz, CDCl3): 1.79 (m, 6H), 1.94 (m, 6H), 2.12 (m, 3H),
2.35 (s, 3H), 7.18 (d, 2H, J = 7.8 Hz), 7.30 (d, 2H, J = 7.8 Hz).
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[14] Time course experiment: 1-adamantanol (1a) (383 mg,
2.51 mmol) was dissolved in toluene (30 ml), and trans-
ferred (flow rate = 0.096 ml/min) by a HPLC pump. The
methanol solution was fed into a stainless steel column
(4.0 mm × 50 mm) filled with HO-SAS (A, 362 mg). A back-
pressure regulator (40 psi) was connected to the end of the
tube. Then, the column was immersed into an oil bath (120ꢀC).
The reaction mixture firstly eluted for 10 min was discarded.
The following portions were collected every 30 min (total fifth
time) in glass flasks and analyzed by GC. The combined reac-
tion mixture was evaporated and the crude product was purified

KASAKADO ET AL.
5
with column chromatography on SiO2 to give the product 2a
(254 mg, 92%, 1.12 mmol).
[15] G. A. Olah, J. A. Olah, T. Ohyama, J. Am. Chem. Soc. 1984,
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How to cite this article: Kasakado T, Hyodo M,
Furuta A, Kamardine A, Ryu I, Fukuyama T. Flow
Friedel–Crafts alkylation of 1-adamantanol with
arenes using HO-SAS as an immobilized acid
catalyst. J Chin Chem Soc. 2020;1–5. https://doi.
org/10.1002/jccs.202000518
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.