Discovery of orthogonal synthesis using artificial intelligence: Pd(OAc)2-catalyzed one-pot synthesis of benzofuran and bicyclo[3.3.1]nonane scaffolds

Article abstract of DOI:10.1016/j.tetlet.2020.152275

A synthetic route for the common intermediate, methyl 2-formylbenzofuran-7-carboxylate (7a), to efficiently assemble three bioactive benzofurans 4–6 was explored using the artificial intelligence system SYNSUP. Among the routes proposed by SYNSUP, we investigated a three-step synthesis of 7a using methyl 4-ally-3-oxohept-6-enoate (10). A new catalytic reaction was found in which 7a was directly obtained from 10 in a single step with a yield of 24percent. It was found that this chemical yield could be increased to 74percent when methyl 3-allyl-2-hydroxybenzoate (9a), an intermediate of the above one-pot transformation, was subjected to the catalytic process. In addition, in this catalytic process, 8a (76percent) and 11 (77percent) were each selectively synthesized from 10 by changing only the solvent. Therefore, we created a novel orthogonal synthesis of methyl 2-methylbenzofuran-7-carboxylate (8a) and methyl 9-oxobicyclo[3.3.1]nona-3,6-diene-1-carboxylate (11). Finally, the total syntheses of bioactive benzofurans 4–6 were completed smoothly using 7a and 8a.

Full text of DOI:10.1016/j.tetlet.2020.152275

Journal Pre-proofs
Discovery of orthogonal synthesis using artificial intelligence: Pd(OAc)2-cata‐
lyzed one-pot synthesis of benzofuran and bicyclo[3.3.1]nonane scaffolds
Tetsuhiko Takabatake, Keisuke Fujiwara, Sho Okamoto, Ryo Kishimoto,
Natsuko Kagawa, Masahiro Toyota
PII:
S0040-4039(20)30742-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152275
TETL 152275
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 June 2020
14 July 2020
19 July 2020
Please cite this article as: Takabatake, T., Fujiwara, K., Okamoto, S., Kishimoto, R., Kagawa, N., Toyota, M.,
Discovery of orthogonal synthesis using artificial intelligence: Pd(OAc)2-catalyzed one-pot synthesis of
benzofuran and bicyclo[3.3.1]nonane scaffolds, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152275
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Discovery of orthogonal synthesis using
artificial intelligence: Pd(OAc)2-catalyzed
one-pot synthesis of benzofuran and
bicyclo[3.3.1]nonane scaffolds
Leave this area blank for abstract info.
Tetsuhiko Takabatake, Keisuke Fujiwara, Sho Okamoto, Ryo Kishimoto, Natsuko Kagawa, and Masahiro
Toyota

Tetrahedron Letters
Discovery of orthogonal synthesis using artificial intelligence: Pd(OAc)2-
catalyzed one-pot synthesis of benzofuran and bicyclo[3.3.1]nonane scaffolds
Tetsuhiko Takabatake,a Keisuke Fujiwara,b Sho Okamoto,b Ryo Kishimoto,b Natsuko Kagawa,c and Masahiro
Toyotab,*
a Advanced Materials Development Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka, 3-chome, Konohana-ku, Osaka, 554-8558
bDepartment of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
cCenter for Environment, Health and Field Sciences, Chiba University, 6-2-1 Kashiwa-no-ha, Kashiwa, Chiba 277-0882, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A synthetic route for the common intermediate, methyl 2-formylbenzofuran-7-carboxylate (7a), to
efficiently assemble three bioactive benzofurans 4-6 was explored using the artificial intelligence system
SYNSUP. Among the routes proposed by SYNSUP, we investigated a three-step synthesis of 7a using
methyl 4-ally-3-oxohept-6-enoate (10). A new catalytic reaction was found in which 7a was directly
obtained from 10 in a single step with a yield of 24%. It was found that this chemical yield could be
increased to 74% when methyl 3-allyl-2-hydroxybenzoate (9a), an intermediate of the above one-pot
transformation, was subjected to the catalytic process. In addition, in this catalytic process, 8a (76%)
and 11 (77%) were each selectively synthesized from 10 by changing only the solvent. Therefore, we
created a novel orthogonal synthesis of methyl 2-methylbenzofuran-7-carboxylate (8a) and methyl 9-
oxobicyclo[3.3.1]nona-3,6-diene-1-carboxylate (11). Finally, the total syntheses of bioactive
benzofurans 4-6 were completed smoothly using 7a and 8a.
Available online
Keywords:
Artificial intelligence
Pd(OAc)2 catalyst
benzofuran
bicyclo[3.3.1]nonane
2009 Elsevier Ltd. All rights reserved.
Introduction
Artificial intelligence (AI) is defined as the ability of machines
to interpret data, make decisions, and carry out tasks in a way
similar to humans.1 AI is already widely used in many commercial
and scientific fields. Algorithms predict what we like, anticipate
our behavior, and diagnose medical conditions with impressive
speed. AI is also being used to identify diseases, and can even
outperform human experts when it comes to diagnosing disease.2
We are entering a world where conversation with machines is
going to be both enlightening and more efficient in many areas.
How is AI going to change our world? There are no certain
answers to that question at the present time. In contrast, the first
introduction of AI into the field of synthetic organic chemistry was
more than 50 years ago, however, the evolution of AI in this field
has been extremely slow.3 One of the reasons is that it takes a
significant amount of time to experimentally evaluate proposed
synthetic routes using AI. Our laboratory has been engaged in the
evolution of SYNSUP (an AI program)4 since 2007. Recently, we
have succeeded in the stereoselective synthesis of SCH 47949 (3),
which inhibits the absorption of cholesterol from the small
intestine, using SYNSUP (Scheme 1).5 After tuning a part of the
reaction substrate structure proposed by SYNSUP, basic treatment
of 1 in the presence of two silylation reagents provided trans β-
lactam 2 in a stereoselective manner. Finally, the five-step
transformation of 2 proceeded smoothly and the desired SCH
47949 (3) was obtained in a reasonable chemical yield (Scheme
1). It is worth noting that the present functional group
manipulation for the synthesis of 3 was identical to the synthetic
routes proposed by SYNSUP.
Scheme 1. AI (SYNSUP)-designed total synthesis of SCH 47949 (3).
As part of our drug synthesis program using SYNSUP, we
embarked on the creation of a potential intermediate to concisely
synthesize bioactive benzofuran analogs. Not surprisingly, some
rather simple benzofuran derivatives showed a wide variety of
significant bioactivities. Among them, we especially became
interested in unnatural bioactive products 4-6 (Figure 1).6
Figure 1. Structures of known bioactive benzofuran analogs 4-6.

Unknown compound 7a was selected as a potential intermediate
for the assembly of target molecules 4-6, and efficient synthetic
routes were searched using SYNSUP. As a result, 36 synthetic
routes were proposed in a short time (see Supporting Information-
1). We attempted to determine a method of synthesis of 7a from
methyl 4-allyl-3-oxohept-6-enoate (10), since this proposed route,
shown below, involved a catalytic reaction reported by our
laboratory(Scheme 2).7
reaction was carried out without either Cu(OAc)2 or oxygen
individually or together, no cyclization product was obtained.
When substance 10 was treated with 10 mol % Pd(OAc)2 in
dimethyl sulfoxide (DMSO) in the presence of 20 mol %
Cu(OAc)2 at room temperature under one atmosphere of oxygen
for 21 hours, methyl 9-oxobicyclo[3.3.1]nona-3,6-diene-1-
carboxylate (11)11 was obtained in a 43% yield, together with a
14% yield of methyl 3-allyl-2-hydroxybenzoate (9a) and an 8%
yield of methyl 3-allyl-2-hydroxycyclohexa-1,4-diene-1-
carboxylate (13) (Table 1, entry 1). This result suggested that both
9a and 11 were produced from the common intermediate 13.
Samples were continuously taken from the reaction and monitored
by TLC analysis. As a result, the first catalytic cyclization
consumed approximately 7 hours and only the intermediate 13 was
obtained in a 62% yield (Table 1, entry 2). To obtain methyl 2-
methylbenzofuran-7-carboxylate (8a) as a major product, the
Scheme 2. Retrosynthetic route for 7a proposed by SYNSUP.
Results and Discussion
First, we investigated the transformation of 10 into 9a using
Orellana’s protocol.8 A PdCl2(MeCN)2-catalyzed cyclization of 10
followed by oxidation with two equivalent chloranil provided 9a
in an 18% yield, which was subjected to PdCl2-catalyzed
cyclization9 to afford 8a (62%). Finally, an allylic oxidation of 8a
was performed with IBX10 to give the desired intermediate 7a in a
9% yield. Accordingly, the total yield of the preparation of 7a from
10 was only 1%. The extremely low chemical yield of the IBX
oxidation at the allylic position in 8a was the biggest problem with
this process, and the transformation of 10 to 9a was the first
stumbling block. Incidentally, an allylic oxidation of 8a using
SeO2 was completely unsuccessful (Scheme 3).
13
amount of Cu(OAc)2 was increased to 3 equivalents.12,
Unfortunately, only 2-hydroxybenzoate 9a was isolated in a 78%
yield (Table 1, entry 3). At this point, we expected that heating
must be required for the cyclization of phenol 9a. On heating 9a
with 10 mol % Pd(OAc)2 and 3 equivalents of Cu(OAc)2 at 60 °C,
it was found that the target molecule, methyl 2-formylbenzofuran-
7-carboxylate (7a), was directly produced, although at a low yield
(24%), along with a 13% yield of methyl 2-methylbenzofuran-7-
carboxylate (8a) and a 21% yield of bicyclic compound 11 (Table
1, entry 4). The structure of 7a was determined by NMR
techniques (COSY, HMBC, HMQC). To efficiently obtain 7a, the
catalytic amount of Pd(OAc)2 was increased to 20 mol %.
Interestingly, not only were the chemical yields of 7a, 8a, and 11
decreased, but methyl 2H-chromene-8-carboxylate (12) was also
produced via a 6-endo-trig cyclization mode in a 10% yield (Table
1, entry 5).14 When the reaction solvent was changed to MeCN,
only benzofuran 8a was obtained, in a 44% yield (Table 1, entry
6). The reaction was conducted using 10 mol % Pd(OAc)2 and 1
equivalent Cu(OAc)2 in MeCN at 50 ˚C in the presence of 2
equivalent DMSO13 to furnish benzofuran 8a in a 76% yield (Table
1, entry 7). To our surprise, changing MeCN to THF gave rise to
bicyclo[3.3.1]nonane 11 in a 77% yield as a single isomer (Table
1, entry 7). It is worth mentioning that only Snider’s group has
reported the one-step preparation of 11 from 10 using radical
reaction conditions; however, the chemical yield was 11% as a 2:1
mixture of the olefin isomers.11 Because bicyclic compound 11 is
highly functionalized, 11 could be used as a synthon for the
Scheme 3. Linear synthesis of 7a from 10.
Next, we applied Pd(OAc)2-catalyzed cycloaromatization7 to
methyl 4-allyl-3-oxohept-6-enoate (10). Perhaps because the
reactivity of substrate 10 to Pd (II) was extremely high, subtle
differences in the reaction solvent, additive, reaction temperature,
reaction time, and work-up method greatly affected the isolation
yields of each product and the reproducibility of this process.
Therefore, we tested the reaction conditions using 10 mol %
Pd(OAc)2 with a purity of 99.98% for the following investigations.
Among various studies on the reaction conditions, some
characteristic results are summarized in Table 1. When this
Table 1. Cyclization of methyl 4-allyl-3-oxohept-6-enoate (10).
yield (%)
Cu(OAc)2
(mol %)
Additive
(equiv)
temp
time
(h)
entry
solevent
(˚C)
7a
0
8a
0
9a
14
0
11
43
0
12
0
13
8
1
2
20
20
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
MeCN
THF
none
none
Rt
Rt
Rt
60
60
60
50
50
50
60
60
21
7
0
0
0
62
0
3
300
300
300
300
100
20
none
37
23
24
22
26
20
24
24
24
0
0
78
0
0
0
4
5a
none
24
10
0
13
10
44
76
0
21
5
0
0
none
0
10
0
0
6
none
0
0
0
7
DMSO (2)
DMSO (2)
none
0
0
0
0
0
8
0
11
16
0
77
19
0
0
0
9
20
THF
0
0
0
0
10b
11c
None
none
DMSO
DMSO
none
0
0
0
53
65
none
0
0
0
0
0
(a) 20 mol % Pd(OAc)2 was used. (b) 10 mol %
Pd(TFA)2 was used. (c) 10 mol % PdCl2 was used.

synthesis of terpenes, such as upial15 and trifarienols.16 It is
obvious that 2 equivalent DMSO is necessary for oxidizing Pd(0)
to Pd(II) (Table 1, entry 9). Both Pd(TFA)2 and PdCl2 provided
methyl 3-allyl-2-hydroxycyclohexa-1,4-diene-1-carboxylate (13),
respectively, in a moderate yield (Table 1, entries 10 and 11). The
cyclization reaction using other solvents such as DMF, CH2Cl2,
and 1,4-dioxane was also investigated, but the chemical yield of
each product was drastically reduced.
compound 14a, but neither compound produced 2-
formylbenzofuran 7a (Scheme 6).
Since the direct conversion of 10 into 7a was difficult, a detour
route via the easily obtainable 9a was examined. Scheme 4
summarizes the results of a Pd(OAc)2-catalyzed one-pot synthesis
of 2-formylbenzofuran 7a using 2-allylphenol 9a and the substrate
scope. The electron-withdrawing group next to the hydroxyl group
in 9a resulted in an improvement in yield. For example, when 9a
was heated with 10 mol % Pd(OAc)2 and 20 mol % Cu(OAc)2 at
100 ˚C in DMSO under one atmosphere of oxygen for 23 hours,
7a was isolated in a 73% yield, together with 8a (11%) and acetate
14a (2%). Substrate 9b with an electron-withdrawing chloride at
the para position of the benzene ring afforded the desired aldehyde
7b, in a 68% yield, as well as 8b (13%) and 14b (3%).
Unsubstituted 2-allylphenol 9c furnished 7c in a moderate yield,
and also produced 8c (10%) and 14c (3%). On the other hand,
substrate 9d with an electron-donating group at the ortho position
of the benzene ring produced 7d in a 52% yield with 8d (14%) and
14d (5%). The methylenedioxy group in 9e survived under the
reaction conditions to give rise to 7e (51%), 8e (17%), and 14e
(6%). In this reaction, the electron-donating group tends to reduce
the yield. All of the above products were easily isolated by flash
column chromatography. It is worth emphasizing that there are no
reports of a one-step conversion of 2-allylphenols 9 to 2-
formylphenols 7.
Scheme 5. Orthogonal cyclizations of 1,4-cyclohexadiene 13.
Scheme 6. Transformational examination of 8a and 14a.
According to the experimental results, we proposed the reaction
mechanism shown in Scheme 7. 2-Allylphenol 9a and bicyclic
compound 11 were produced via the monocyclization intermediate
13.17 By properly selecting the reaction temperature and the
reaction solvent, 9a and 11 can be produced separately. When the
catalytic reaction of 10 was conducted in MeCN at 50 ˚C in the
presence of 2 equivalents of DMSO, 8a was obtained via 9a as the
sole product. The initial target molecule 7a was directly obtained
from acyclic compound 10, although at a low yield of 24%. Based
on the experimental results of Schemes 4-6, we considered how 7a
was generated. After a regioselective acetoxypalladation on the
olefinic moiety in 9a, intramolecular oxypalladation of 15
proceeded to lead to 16 as a mixture of stereoisomers.18 Reductive
elimination of 16 gave diacetate 18, which was hydrolyzed to 7a.19
On the other hand, generation of the palladium-hydride species 17
followed by reductive elimination gave 18, which isomerized to
thermodynamically stable 14a.19, 18b. The Pd(0) species produced
in this process were reoxidized to Pd(OAc)2 by Cu(OAc)2 in the
presence of oxygen. Additionally, since there might be oxidizing
agents generated in the system, we cannot rule out that Pd(IV) is
involved in the reaction mechanism.
Scheme 4. Pd(OAc)2-catalyzed one-pot synthesis of 2-formylbenzo-
furans 9a-e.
Additional experiments were conducted as shown below to
estimate the reaction mechanism of the cyclization reaction of
compound 10. By changing the reaction conditions, compounds 8a
and 11 can clearly be produced separately from the reaction
intermediate 13 (Scheme 5). Additionally, the reaction conditions
shown in entry 4 of Table 1 were applied to compound 8a and
Scheme 7. Plausible reaction mechanism.
With the desired compounds 7a and 8a in hand, we attempted
to complete the total syntheses of bioactive benzofurans 4-6. Ester

aldehyde 7a, obtained from 10 by a two-step process in 57%
overall yield, was subjected to LAH reduction followed by MnO2
oxidation to afford dialdehyde 20 (86% for two steps). Subsequent
dimethylation and MnO2 oxidation gave rise to diacetate 4 in an
88% yield through two steps. 2-Methylbenzofuran 8a was
transformed into the corresponding tropine ester 5 in an 85%
overall yield utilizing hydrolysis followed by a Schottem‒
Baumann reaction. On the other hand, another tropine ester, 6, was
synthesized via 21. Acidic reduction of the furan component in 8a
was conducted at 0 ˚C using TFA and Et3SiH to furnish 21 in an
81% yield. Hydrolysis of 21 and a Schottem‒Baumann reaction
provided tropine ester 6 as a mixture of two diastereoisomers in an
80% overall yield. The spectroscopic properties of synthetic
benzofurans 4-6 were identical with those reported for 4-6,
respectively (Scheme 8).6
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Acknowledgements
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We would like to thank Sumitomo Chemical for allowing us to
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Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Discovery of orthogonal synthesis using
artificial intelligence: Pd(OAc)2-catalyzed
one-pot synthesis of benzofuran and
bicyclo[3.3.1]nonane scaffolds
Leave this area blank for abstract info.
Tetsuhiko Takabatake, Keisuke Fujiwara, Sho Okamoto, Ryo Kishimoto, Natsuko Kagawa, and Masahiro
Toyota