Sequential Continuous-Flow Synthesis of 3-Aryl Benzofuranones

Article abstract of DOI:10.1002/asia.202100461

A sequential continuous-flow system to produce 3-aryl benzofuranones was developed. Starting from 2,4-di-tert-butylphenol and glyoxylic acid monohydrate, both the initial cyclocondensation and the subsequent Friedel?Crafts alkylation were catalyzed by the same heterogeneous catalyst, Amberlyst-15H. The catalyst has a promising life-time for these two steps, and it was able to be recovered and reused for several runs without deactivation. By using the established flow system, 5,7-di-tert-butyl-3-(3,4-dimethylphenyl)-3H-benzofuran-2-one (Irganox HP-136), which is a commercial antioxidant, was prepared in 88% two-step yield. Reactions with various aromatic compounds proceeded well under flow conditions to afford 3-aryl benzo-furanone derivatives in high yields with good functional group compatibility.

Full text of DOI:10.1002/asia.202100461

doi.org/10.1002/asia.202100461
Communication
Sequential Continuous-Flow Synthesis of 3-Aryl Benzofuranones
Hai-Long Xin,[a] Xiaofeng Rao,[a] Haruro Ishitani,*[b] and Shū Kobayashi*[a, b]
reports[7] also described possible synthetic methods. However,
the processes summarized above all employ expensive cata-
lysts, or toxic and explosive reagents, or proceed under harsh
reaction conditions, which are not suitable for sustainable
industrial productions. A more efficient, environmentally com-
patible, and easily operated process is highly desired.
Abstract: A sequential continuous-flow system to produce
3-aryl benzofuranones was developed. Starting from 2,4-di-
tert-butylphenol and glyoxylic acid monohydrate, both the
initial cyclocondensation and the subsequent FriedelÀ Crafts
alkylation were catalyzed by the same heterogeneous
catalyst, Amberlyst-15H. The catalyst has a promising life-
time for these two steps, and it was able to be recovered
and reused for several runs without deactivation. By using
the established flow system, 5,7-di-tert-butyl-3-(3,4-dimeth-
ylphenyl)-3H-benzofuran-2-one (Irganox HP-136), which is a
commercial antioxidant, was prepared in 88% two-step
yield. Reactions with various aromatic compounds pro-
ceeded well under flow conditions to afford 3-aryl benzo-
furanone derivatives in high yields with good functional
group compatibility.
The development of a sequential continuous-flow method
offers an ideal strategy. In general, flow reactions present
numerous advantages over conventional batch reactions with
respect to environmental compatibility, reaction efficiency, and
operational safety.[8] In particular, heterogeneous reactions
using packed column reactors are attractive as the work-up is
much simplified as there is no requirement for filtration of
catalysts which in batch, can result in catalyst residues or
quenching agents which may contaminate the product.[9] This
particular characteristic is particularly important for planning
sequential multistep flow synthesis. Here, we describe our
approach to the synthesis of 3-aryl benzofuranones in two
sequential-flow steps, with each step catalyzed by the same
heterogeneous acid catalyst, Amberlyst-15H (Scheme 1).
In recent decades, aryl benzofuranones and related derivatives
have attracted wide attention because of their various bio-
logical activities, pharmacological applications, and industrial
relevance.[1] A typical example is their application as a carbon-
centered radical antioxidant in the polymer industry.[2] Indeed,
5,7-di-tert-butyl-3-(3,4-dimethylphenyl)-3H-benzofuran-2-one (Ir-
ganox HP-136) has an excellent ability to donate a benzylic
hydrogen atom with concomitant formation of a highly stable
benzofuranonyl free radical, which has led to this compound
being used as a commercial antioxidant to stabilize hydro-
carbon polymers in melt processing at a high temperature.[3]
Several synthetic routes to α-aryl benzofuranones have
been developed. A seminal report utilized p-TsOH-catalyzed
cyclocondensation of glyoxylic acid with phenol starting
materials, followed by a FriedelÀ Crafts alkylation.[4] An alter-
native approach involves formation of mandelic acids first,
followed by Ni(OTf)2-catalyzed tandem FriedelÀ Crafts/lactoniza-
2,4-Di-tert-butylphenol
(1)
and
glyoxylic
acid
monohydrate[10] were selected as starting materials for the
optimization of reaction conditions. Initially, the reactions were
performed in dichloroethane (DCE) under reflux conditions, and
several heterogeneous acid catalysts were screened, as shown
in Table 1. All the selected catalysts, including both Lewis and
Brønsted acids, gave moderate to good yields (entries 1–6). In
entries 4 and 6, decomposition of the starting material was
observed to give low yields. In other cases, the reactions were
incomplete and most of the starting materials remained.
Among them, Amberlyst-15H showed the best performance;
this material is a sulfonic acid bearing cation-exchange resin
that is widely used in organic synthesis because of its environ-
mental benefits and excellent reusability.[10] Amberlyst-15H can
be used to promote the formation of benzofuran effectively,
avoiding the use of metals with all the associated drawbacks
such as toxicity, higher cost, and the eventual necessity of
complex ligands and threshold values in pharmaceutical
products. When considering the feasibility of a flow operation,
the solubility of the starting materials in the reaction system is
crucial. Given the poor solubility of glyoxylic acid in dichloro-
ethane (DCE) and PhCl (entries 1 and 7), further screening was
required to find an appropriate solvent. Reactions in DMF,
MeCN, and THF did not proceed, and only phenol 1 remained.
Alcohol solvents dissolve glyoxylic acid very well, and, promis-
ingly, the reaction in trifluoroethanol gave the product in 93%
°
tion reaction with phenol derivatives at 160 C to give the target
molecules.[5] A TfOH-catalyzed cascade ortho CÀ H activation/
lactonization of phenols with α-aryl-α-diazoacetates was also
reported that enabled the synthesis of Irganox HP-136.[6] Other
[a] Dr. H.-L. Xin, Dr. X. Rao, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo, Hongo
113-0033 Bunkyo-ku, Tokyo (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[b] Prof. Dr. H. Ishitani, Prof. Dr. S. Kobayashi
Green & Sustainable Chemistry Social Cooperation Laboratory, Graduate
School of Science
°
yield in the presence of Amberlyst-15H at 80 C after stirring for
3 h(entry 13).
The University of Tokyo, Hongo
113-0033 Bunkyo-ku, Tokyo (Japan)
E-mail: hishitani@chem.s.u-tokyo.ac.jp
With the selected catalyst and solvent in hand, a flow
system for the cyclocondensation step was set up. After the
initial tuning of reaction parameters such as temperature, flow
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100461
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Scheme 1. Reported synthetic routes to Irganox HP-136 and this work.
Table 1. Screening of heterogeneous acid catalysts and solvents for the cyclocondensation step.
Entry
Catalyst
Solvent
Yield [%][a]
1
2
Amberlyst 15H
Zr-Zeolite
DCE
DCE
90
44
3
4
5
MC-Sc(OTf)3
DCE
DCE
DCE
81
65
10
Nafion
Dowex H+
6
7
8
Si-Tosic acid
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
DCE
PhCl
DMF
MeCN
40
95
trace
trace
trace
40
9[b]
10[b]
11[b]
12[b]
13[b,c]
THF
EtOH
CF3CH2OH
CF3CH2OH
93
93
1
°
[a] Determined by H NMR analysis using 1,1,2,2-tetrachloroethane as internal standard. [b] Reaction temperature was 80 C. [c] Reaction time was 3 h.
rate, catalyst loading, and flow direction, the basic flow setup
was established as shown in Figure S1 (see Supporting
Information (SI)). A stock solution of 0.1 M 2,4-di-tert-butylphe-
nol (1) and glyoxylic acid monohydrate (1.2 equiv) in trifluor-
oethanol was flowed using a pump at a flow rate of 0.18 mL/
min through an SUS column (4.8 mm×200 mm) packed with
2.0 g of Amberlyst-15H (total acid amount; 8.8 meq, the ratio of
1 fed per an hour to sulfonic acid sites, 1/-SO3H was calculated
to be 0.12 hÀ 1.). A column heater was employed to heat the
by evaluating the process mass intensity (PMI),[11] which
confirmed the advantages of using heterogeneous catalysts;
the trifluoroethanol solvent could also be reused in the flow
system (Table 2). Indeed, recycling experiments, carried out
using recovered trifluoroethanol and reusing the catalyst-
packed reactor with the same contents, confirmed that
consistently high yields were achieved for four runs.
We then focused on developing the second FriedelÀ Crafts
alkylation under flow conditions. Preliminary investigations
were conducted under batch conditions using purified 3-
hydroxy-benzofuranone 2 (Table 3). Interestingly, Amberlyst-
15H was also the best catalyst for this step (entry 1), although
the reaction required a higher temperature (entry 6). Various
°
flow column reactor at 80 C, the column reactor was set
vertically, and the flow direction was fixed as top-to-bottom,
which gave an improved and more stable reaction performance.
We estimated the void volume of the 4.8×200 mm SUS column
(3.6 mL) was 2.8 mL, thus an ideal residence time of the reaction
at 0.18 mL/min substrates flow was calculated to be 15.6 min.
The outlet of the flow reactor was connected to a reservoir and
the product sample solution was collected for 2 h during 120 h
operation. Under the standard flow conditions shown in
Table 2, the desired product 2 was constantly obtained in 91–
94% yields. No deactivation was observed after continuous
reaction for 120 h. The overall reaction economy was assessed
°
solvents gave good yields (>95%) at 120 C. Notably, the
reaction in trifluoroethanol resulted in a high yield, suggesting
the possibility of using this solvent in a sequential flow system.
In addition, the use of o-xylene (3a) itself as solvent allowed the
°
reaction temperature to be reduced to 105 C, and the desired
4a was obtained in 95% yield.
We next designed three flow setups for the FriedelÀ Crafts
alkylation under continuous-flow conditions (Table 4). In en-
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Table 2. Continuous-flow cyclocondensation reaction.
Time [h]
2–4
91
4–6
94
6–8
93
22–24
91
118–120
92
Yield [%][a]
Run[b]
1st
94
2nd
92
3rd
93
4th
92
Yield [%][a,c]
[a] Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as internal standard. [b] CF3CH2OH was recovered by distillation and reused for the 2nd,
3rd, and 4th runs; The same column-packed Amberlyst 15H was used for each run. [c] Yield after 16–18 h was determined.
Table 3. Screening of heterogeneous acid catalysts and solvents for the FriedelÀ Crafts alkylation.
Entry
Catalyst
Solvent
Temp.
Yield[a]
[%]
°
[ C]
1
2
3
4
5
6
7
8
9
Amberlyst 15H
Zr-zeolite
MC-Sc(OTf)3
Nafion
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
Amberlyst 15H
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
o-xylene
CF3CH2OH
dichlorobenzene
100
100
100
100
110
120
105
120
120
62
trace
10
40
75
95
95
97
96
1
[a] Determined by H NMR analysis using 1,1,2,2-tetrachloroethane as internal standard.
Table 4. Continuous-flow FriedelÀ Crafts alkylation.
°
Entry
Solvent
Temp[ C]
Yield[a] [%]
4–6 h
92
41
6–8 h
94
37
98–100 h
92
1
o-xylene
CF3CH2OH
dichlorobenzene
105
120
120
2[b]
3[b]
92
93
93
1
[a] Determined by H NMR analysis using 1,1,2,2-tetrachloroethane as internal standard. [b] 5.0 equiv. of 3a were used.
try 1, a stock solution of 2 (0.1 M, isolated) in o-xylene 3a was
prepared. The prepared solution was flowed at a flow rate of
0.15 mL/min through an SUS column (4.8 mm×300 mm diame-
ter) packed with 3.0 g of Amberlyst-15H (total acid amount;
13.2 meq). In this case, over 92% yield of 4a was obtained and
the yield was kept for over 100 h. Although the batch reaction
gave a good yield when it was performed in trifluoroethanol
using a sealed tube to allow the reaction to reach the indicated
temperature, in the flow system the reaction using trifluoroe-
thanol led to refluxing in the flow column and gave a
disappointing yield.[12] It turned out that the use of a higher
boiling point solvent would be a better choice for this flow
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benzofuranones. The substrate scope for the FriedelÀ Crafts
alkylation is summarized in Scheme 2. The final 10 mL resulting
solution for each substrate was concentrated and purified by
column chromatography to afford isolated 4 (see SI). For liquid
aromatic substrates, such as p-xylene (3b) and anisole (3d), the
reactions were conducted under neat conditions with a solvent
amount of those aromatics to produce the corresponding
products 4b and 4d in 96% and 85% yields, respectively. For
the synthesis of 4c, the Ar-H was a commonly used reagent,
but the indicated reaction temperature was higher than the
boiling point, so a mixed solution of Ar-H/dichlorobenzene
(1:9) was used. For substrates 3e–m, which are mainly solid
aromatics at ambient temperature, 2.0 equiv. of these Ar-H
were used as dichlorobenzene solutions, which was sufficient to
promote the reaction in moderate to good yields. Phenol,
halogen, ether, and thioether moieties were well tolerated. The
regioselectivity was directed by both electronic density and
steric effects.
Based on the present systematic optimization, a two-step
continuous-flow synthesis of Irganox HP-136 was demonstrated
(Scheme 3). The cyclocondensation step was conducted under
the established flow conditions to yield a solution with high
yield of 2. After a simple solvent switch from trifluoroethanol to
o-xylene to make a 0.1 M solution, the FriedelÀ Crafts alkylation
was conducted in another flow reactor under the indicated
reaction conditions for 6 h. At this stage we conducted solvent
exchange as an off-line manner. Finally, a total yield of 88%
over the two steps was confirmed by an isolation from 54 mL of
the product solution. We also tested a mixed solvent without
solvent switching and found that the system could provide a
similar two-step yield (see SI). Considering the recycling of the
solvent and total TON of this reaction, we envision the above
method as the optimal.
Scheme 2. Substrate scope for the FriedelÀ Crafts alkylation in flow. [a] Ar-H
°
as solvent. [b] Temperature was 105 C. [c] Solvent was a mixture of ArH/
dichlorobenzene=1:9.
In conclusion, we have developed a sequential continuous-
flow system to produce 3-aryl benzofuranones through a
cyclocondensation and subsequent FriedelÀ Crafts alkylation.
Notably, both the steps were catalyzed by the same heteroge-
neous catalyst, Amberlyst-15H, under the indicated reaction
conditions. 5,7-Di-tert-butyl-3-(3,4-dimethylphenyl)-3H-benzo-
furan-2-one (Irganox HP-136), which is a commercial antioxidant
used to stabilize hydrocarbon polymers in melt processing at a
high temperature, was prepared by using the current flow
method in 88% two-step yield. In addition, various aromatics
reacted with intermediate 2 to afford 3-aryl benzofuranone
derivatives under the flow conditions in high yields with good
functional group compatibility.
Scheme 3. Sequential continuous-flow synthesis of 4a (Irganox HP-136).
Acknowledgements
reaction. The results shown in entry 3 demonstrated the use of
alternative conditions for the flow reaction, with a stock
solution of 2 (isolated, 0.1 M) and 5.0 equiv. of o-xylene (3a) in
dichlorobenzene. Similar to the results summarized in entry 1,
excellent yields of the product 4a were obtained.
This work was supported in part by a Grant-in-Aid for Scientific
Research from the New Energy and Industrial Technology Develop-
ment Organization (NEDO) project, Japan.
With the above information in hand, we managed the
solvent in this flow system to expand the substrate scope for a
series of aromatic substrates to afford the target 3-aryl
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Continuous-flow
Amberlyst-15H · 3-Aryl Benzofuranones · Irganox HP-136
·
Heterogeneous catalyst
·
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Manuscript received: April 29, 2021
Revised manuscript received: May 27, 2021
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Chem Asian J. 2021, 16, 1–6
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Communication
COMMUNICATION
Dr. H.-L. Xin, Dr. X. Rao, Prof. Dr. H.
Ishitani*, Prof. Dr. S. Kobayashi*
1 – 6
A sequential continuous-flow system
to produce 3-aryl benzofuranones
via an initial cyclocondensation and
subsequent Friedel-Crafts alkylation
catalyzed by the same reusable heter-
ogeneous catalyst, Amberlyst-15H,
was developed. Various 3-aryl benzo-
furanone derivatives under flow con-
ditions were synthesized in high
yields with good functional group
compatibility. A commercial antioxi-
dant Irganox HP-136 was prepared in
88% two-step yield.
Sequential Continuous-Flow
Synthesis of 3-Aryl Benzofura-
nones