Pd(OAc)2-catalyzed orthogonal synthesis of 2-hydroxybenzoates and substituted cyclohexanones from acyclic unsaturated 1,3-carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2019.05.041

A Pd-catalyzed orthogonal synthesis of substituted 2-hydroxybenzoates and substituted cyclohexanones was developed for the first time. The substituted 2-hydroxybenzoates were obtained from acyclic unsaturated 1,3-carbonyl compounds using a combination of catalytic Pd(OAc)₂ and Cu(OAc)₂. On the other hand, the substituted cyclohexanones were produced from similar substrates via catalytic Pd(OAc)₂ and hydrogen chloride. Each transformation was clean, easy to work up, provided the desired compounds in good purities, and did not require column chromatography purification.

Full text of DOI:10.1016/j.tetlet.2019.05.041

Accepted Manuscript
Pd(OAc)2-Catalyzed Orthogonal Synthesis of 2-Hydroxybenzoates and Substi-
tuted Cyclohexanones from Acyclic Unsaturated 1,3-Carbonyl Compounds
Toshinori Miyagi, Sho Okada, Naoya Tada, Masahiro Sugihara, Natsuko
Kagawa, Tetsuhiko Takabatake, Masahiro Toyota
PII:
S0040-4039(19)30484-8
https://doi.org/10.1016/j.tetlet.2019.05.041
TETL 50813
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 February 2019
14 May 2019
20 May 2019
Please cite this article as: Miyagi, T., Okada, S., Tada, N., Sugihara, M., Kagawa, N., Takabatake, T., Toyota, M.,
Pd(OAc)2-Catalyzed Orthogonal Synthesis of 2-Hydroxybenzoates and Substituted Cyclohexanones from Acyclic
Unsaturated 1,3-Carbonyl Compounds, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.05.041
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1
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.
Pd(OAc)2-Catalyzed Orthogonal Synthesis of 2-
Hydroxybenzoates and Substituted
Cyclohexanones from Acyclic Unsaturated 1,3-
Carbonyl Compounds
Leave this area blank for abstract info.
Toshinori Miyagi, Sho Okada, Naoya Tada, Masahiro Sugihara, Natsuko Kagawa, Tetsuhiko Takabatake, and
Masahiro Toyota*
Pd(OAc)2
(cat.)
Pd(OAc)2
(cat.)
O
O
OH
O
O
O
R2
R2
R2
R1
R1
R1
Cu(OAc)2 (cat.)
DMSO
HCl (cat.)
R3
R3
R3
1,4-dioxane

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Pd(OAc)2-Catalyzed Orthogonal Synthesis of 2-Hydroxybenzoates and
Substituted Cyclohexanones from Acyclic Unsaturated 1,3-Carbonyl
Compounds
Toshinori Miyagi,a Sho Okada,a Naoya Tada,a Masahiro Sugihara,a Natsuko Kagawa,b Tetsuhiko Takabatake,c and
Masahiro Toyota a,*
a Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, 599-8531, Japan
b Center for Environment, Health and Field Science, Chiba University, 6-2-1 Kashiwa-no-ha, Kashiwa, Chiba 277-0882, Japan
c Advanced Materials Development Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka, 3-chome, Konohana-ku, Osaka, 554-8558, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Pd-catalyzed orthogonal synthesis of substituted 2-hydroxybenzoates and substituted
cyclohexanones was developed for the first time. The substituted 2-hydroxybenzoates were
obtained from acyclic unsaturated 1,3-carbonyl compounds using a combination of catalytic
Pd(OAc)2 and Cu(OAc)2. On the other hand, the substituted cyclohexanones were produced
from similar substrates via catalytic Pd(OAc)2 and hydrogen chloride. Each transformation was
clean, easy to work up, provided the desired compounds in good purities, and did not require
column chromatography purification.
Available online
Keywords:
Palladium acetate
Orthogonal synthesis
2-Hydroxybenzoate
Substituted cyclohexanone
2009 Elsevier Ltd. All rights reserved.
Introduction
labeled cyclization products,9 useful for pharmacokinetics, could
be obtained using this protocol. (iii) Under the reaction
Among the well-evaluated transition metal catalysts,1
palladium catalysts are most frequently used for numerous
practical transformations in both academia and in the chemical
industries.2 There are many reasons for this; for instance,
Pd(OAc)2 is stable,3 inexpensive, non-toxic,4 and versatile
enough to be used for various organic synthetic reactions.5 Our
research group has steadily developed a range of new catalytic
reactions utilizing Pd(OAc)2.6 To preferentially synthesize six-
membered ring compounds using a palladium catalyst, it is often
necessary to set up a conformational restriction for substrates or a
restriction for a reactive position of substrates. We became
interested in designing a novel catalytic reaction to construct six-
membered ring compounds without exceptions using rather
simple substrates. Additionally, controlling the selectivity of Pd
catalysts in different cyclizations to assemble valuable building
blocks, which are useful in synthetic organic chemistry, remains
challenging, and success has been rewarding. In this paper, we
report the recent discovery and development of an orthogonal
synthesis7 that produces 2-hydroxybenzoates and substituted
cyclohexanones from acyclic unsaturated 1,3-carbonyl
compounds using a catalytic amount of Pd(OAc)2 (Scheme 1).8
This orthogonal synthesis displayed the following characteristics:
(i) Two different types of 6-membered ring compounds at
different oxidation stages could be catalytically obtained from
acyclic unsaturated 1,3-carbonyl compounds. (ii) Most starting
materials could be synthesized from acetoacetates; therefore, 13C-
conditions described, a 6-endo-trig cyclization10 proceeded
without exception. (iv) The present orthogonal reaction
proceeded smoothly without the need for ligands.
Pd(OAc)2
(cat.)
Pd(OAc)2
(cat.)
O
O
OH
O
O
O
R2
R2
R2
R1
R1
R1
condition A
condition B
R3
R3
R3
1
2
3
Scheme 1. Pd(OAc)2-Catalyzed Orthogonal Synthesis.
Our investigation was initially focused on the 2-
hydroxybenzoate synthesis. Two different procedures have been
reported thus far for the construction of 2-hydroxybenzoates from
acyclic compounds. Snider demonstrated an oxidative radical
cyclization using excess amounts of Mn(OAc)3 in the presence of
Cu(OAc)2 (Scheme 2, A).11 Recently, Orellana reported an
alternative protocol for the synthesis of 2-hydroxybenzoates by
means of
a combination of Pd-catalyzed intramolecular
hydroalkylation and oxidation reactions. In this case, two
equivalents of chloranil were required for the oxidation of the
initially cyclized intermediates (Scheme 2, B).12 It appeared to us
that analogous chemistry might be effected in one synthetic step
by employing only catalytic amounts of Pd(OAc)2 via
cycloalkenylation, followed by oxidation and tautomerization,
under one atmosphere of oxygen (Scheme 2, C).

2
11% yield, together with 61% 1a (Table 1, entry 4). Compared to
the use of ethereal solvent (Table 1, entries 5 and 6), this reaction
was cleaner, and only 1a and 2a were obtained with good
recovery. We next searched for a reoxidant to obtain 2a
effectively. Although CuCl2 and 1,4-benzoquinone (BQ) were
ineffective (Table 1, entries 9 and 10), Cu(OAc)2 (20 mol %)
proved to be an effective reoxidant, and 2a was produced in 77%
yield (Table 1, entry 7). When this reaction was conducted with
10 mol % Cu(OAc)2, the isolated yield of 2a decreased to 58%.
Additionally, using four equivalents of Cu(OAc)2 under a
nitrogen atmosphere gave 2a (32%) together with 1a (19%).
Ethereal solvents, such as DME (Table 1, entry 8), THF, and 1,4-
dioxane, were unsuitable for this catalytic system. Under a
nitrogen atmosphere, this reaction did not proceed at all, and 1a
was recovered. A combination of Cu(OAc)2 and oxygen was
found to be essential for this catalytic process. Several other
palladium catalysts, including PdCl2 (Table 1, entry 11),
Pd(TFA)2 (Table 1, entry 12), Pd(acac)2 (2%), and
PdCl2(MeCN)2 (1%), were also examined in this process, but
none proved to be better than Pd(OAc)2.
Snider and Peterson et al., 1987
O
O
OH
Mn(OAc)3 H2O (2 equiv)
Cu(OAc)2 (1 equiv)
CO2Me
(A)
OMe
1a
2a
Orellana et al., 2016
(1) PdCl2(MeCN)2 (10 mol %)
(2) chloranil (2 equiv)
1a
2a
(B)
This Work
Pd(OAc)2 (cat.)
1a
2a
(C)
condition A
Scheme 2. 2-Hydroxylbenzoate Synthesis.
Results and Discussion
Our investigation began with an effort to optimize the reaction
conditions (Scheme 1, condition A) for the one-pot synthesis of
2-hydroxybenzoates using Pd(OAc)2. Methyl 3-oxohept-6-enoate
(1a) was selected as a model substrate for the optimization
process. A number of different reaction parameters, such as the
catalyst, solvent, and reoxidant, were evaluated to optimize this
transformation.
10 mol % Pd(OAc)2
20 mol % Cu(OAc)2
O
OH
R3
R1
R2
R3
R1
R2
DMSO, 45 °C
O
2 (1 atm), 23 h
1a-j
2a-j
Substrate
Substrate
O
Product and Yieldc
Product and Yieldc
Table 1. Evaluation of the Reaction Conditions for
Cycloaromatization (condition A).
OH
O
OH
CO2Me
CO2Me
Me
CO2Me
Me
CO2Me
O
O
OH
Pd(OAc)2
CO2Me
OMe
60 °C, 17 h
1a
2a
1f
2f
(77%)
(68%)
O
2 (1 atm)
O
OH
O
1a
2a
OH
CO2Et
Me
Me
CO2Et
Me
Me
CO2Et
CO2Et
entry
catalyst
(mol %)
200
100
50
10
10
10
10
reoxidant
solvent
isolated
yield (%)
35
34
1b
2g
(66%)
2b
1g
(71%)
1a
2
3
4
5
none
none
none
none
none
none
DMSO
DMSO
DMSO
DMSO
DME
O
OH
OH
O
CO2Et
Me
CO2Me
Me
CO2Me
Me
CO2Me
Me
19
11 [61]e
11 [53]e
1h
2c
(66%)
2h
(67%)
1c
6
1,4-dioxane 10 [57]e
OH
O
OH
O
c
7b
8b
9b
10b
11
12
Cu(OAc)2 DMSO
Cu(OAc)2 DME
77
Bn
CO2Me
Me
Bn
CO2Et
Me
CO2Et
Me
CO2Et
Me
c
10
10
13 [17]e
27
c
1d
2i (74%)b
CuCl2
DMSO
DMSO
DMSO
DMSO
2d (55%)
1i
O
10
BQd
7 [58]e
0 [82]e
7 [47]e
OH
O
O
O
CO2Me
10f
none
none
Me
a
2c
(93%)
10g
b
aThis reaction was run for 3.5 h under a nitrogen atmosphere.
1e
1j
2j
(71%)
c
d
Reactions were carried out at 45 °C. 20 mol %. 200 mol % 1,4-
benzoquinone. eYields in parentheses are the recovered starting
material. fPdCl2. gPd(TFA)2.
a50 mol % Pd(OAc)2 was used. This reaction was carried out at
60 °C for 23 h. cIsolated yield.
b
Scheme 3. Catalytic Formation of 2-Hydroxybenzoates from Acyclic
Unsaturated 1,3-Carbonyl Compounds.
Since 2.0 equiv of Pd(OAc)2 were theoretically required for
cycloaromatization of 1a, we first allowed 1a to react with a
stoichiometric amount of Pd(OAc)2 in DMSO at 60 °C for 3.5 h
under a nitrogen atmosphere. The desired annulation product 2a
was obtained in 35% yield with small amounts of impurities
(Table 1, entry 1). Surprisingly, no other compounds were
produced under the described reaction conditions. Although 1a
was completely consumed, the conversion efficiency was low,
probably because organic molecules were partially taken into the
palladium complex. A similar phenomenon was observed under
the reaction conditions described in entries 2 and 3. This reaction
was rendered catalytic by gradually decreasing the catalyst
loading. Performing the reaction at 60 °C using 10 mol %
Pd(OAc)2 under one atmosphere of oxygen provided 2a in an
The scope and limitations of this cycloaromatization were next
examined using various 1,3-carbonyl compounds. The results are
summarized in Scheme 3. The ethyl ester 1b also afforded the
cyclized product 2b with a chemical yield similar to 1a.
Interestingly, methyl (E)-3-oxooct-6-enoate (1c) gave rise to the
2,6-disubstituted benzoate 2c in 66% yield. The ethyl ester 1d
resulted in a further reduction in the chemical yield. The
compound 2c was also prepared from 1e, an olefin isomer of 1c,
in 93% yield using 50 mol % Pd(OAc)2. Methyl 2-hydroxy-3-
methylbenzoate (2f),
a topographical isomer of 2c, was
synthesized in 68% yield, and the ethyl ester 1g afforded 2g in
66% yield. When the reaction was conducted using methyl (E)-4-
methyl-3-oxooct-6-enoate (1h), the 2,3,6-trisubstituted benzoate

3
2h was obtained in a reasonable yield. The more complex 2,3,6-
trisubstituted benzoate 2i was produced in good yield from 1i,
and this result demonstrated the utility of this catalytic reaction.
The unsaturated 1,3-diketone 1j was also suitable for this
cycloaromatization process, and the corresponding 1-(2-
hydroxyphenyl)ethan-1-one (2j) was produced in 71% yield. It is
worth mentioning that this transformation was clean, easy to
work up, produced the desired compounds in good purities, and
did not require column chromatography purification. The
regioselective functionalization of benzenes is quite difficult and
requires several steps;13 however, prefuctionalized acyclic
substrates can potentially provide the desired product in a single
step using the present protocol.
various types of cyclized products were obtained in good yields
across the board. One of the important features of this reaction is
the formation of the intermediate II via the complex I. (Scheme
6). Once the intermediate II is formed, the complex III was
formed, from which a continuous addition–β-elimination process
provided the palladium enolate intermediate IV. Finally,
protonolysis15 of IV gave rise to 3a. We envisioned that we could
prepare a similar intermediate II in situ by adding HCl to a
mixture of 1a, along with catalytic amounts of Pd(OAc)2.
Pd(OAc)2 + 2HCl
O
CO2Me
3a
PdCl2 + 2AcOH
HCl
According to these results, we proposed the reaction
mechanism shown in Scheme 4. After activation of an isolated
olefin of 1a by Pd(OAc)2, an enolate moiety in A attacks the
terminal carbon to form the alkyl palladium intermediate B. β-
Elimination of acetoxypalladium(II) hydride (D) gives 1,4-diene
C, which will be oxidized by Pd(OAc)2 to afford 2a. The
palladium species D will produce Pd(0), which would be
oxidized by Cu(OAc)2 or directly by oxygen to generate
O
CO2Me
O
ClPd
CO2Me
CO2Me
1a
IV
OH
CO2Me
O
1
PdCl2
Pd(OAc)2. The H NMR spectrum of the reaction intermediate
I
O
shows the possibility that intermediate C may exist. (See the SI.)
HPdCl
III
CO2Me
OH
HCl
CO2Me
O
PdCl
II
CO2Me
O
OH
Pd(OAc)2
CO2Me
CO2Me
A
Pd
Scheme 6. Plausible Reaction Mechanism of Hydroalkylation.
AcO
AcOH
B
1a
C
A variety of reaction conditions were examined to effect the
conversion of methyl 3-oxohept-6-enoate (1a) to methyl 2-
oxocyclohexane-1-carboxylate (3a).
Pd(OAc)2
CO2Me
Pd(OAc)2
AcO Pd OOH
AcOH
H2O2
OH
O
O
Table 2. Evaluation of the Reaction Conditions for Hydroalkylation
(condition B).
Pd
Cu(I)
H
Pd
OAc
D
O2
Pd(0)
2a
3 mol % Pd(OAc)2
O
O
O
Cu(II)
O2
CO2Me
10 mol % HCl
OMe
1,4-dioxane, 60 °C
Scheme 4. Possible Reaction Mechanism.
1a
3a
O
2 (1 atm), 25 h
The 6-membered cyclic compounds were exclusively obtained
because the conformations that provided the 6-membered cyclic
compounds were more stable than the conformations that
provided the 5-membered cyclic compounds (see the SI).
Additionally, although this process should be an equilibrium
reaction, this equilibrium reaction was terminated as long as the
aromatic compound could be formed, so that only the
thermodynamically stable benzoate was obtained.
entry
Pd(OAc)2
(mol %)
HCl
solvent
Isolated
yield (%)
4 [64]b
67
81
48
48
76
9 [77]
26 [52]
64
(mol %)a
1
2
3
4
5
6
7
8
9
10
10
10
10
3
3
3
3
20
20
10
10c
10
10
3
6
10
10
DMSO
DME
DME
DME
DME
1,4-dioxane
1,4-dioxane
1,4-dioxane
CHCl3
Widenhoefer et al., 2001
PdCl2(MeCN)2
O
O
O
O
(10 mol %)
3
3d
(D)
OMe
OMe
10
1,4-dioxane
60
1a
3a
b
a4 M HCl in 1,4-dioxane. Yields in parentheses are the recovered
starting material. cTMSCl was used instead of HCl. dPdCl2 was used
instead of Pd(OAc)2.
This Work
1a
Pd(OAc)2 (cat.)
3a
(E)
No desired product 3a was obtained in the absence of
hydrogen chloride. The results are summarized in Table 2.
DMSO (Table 2, entry 1), toluene, MeCN, and THF proved
totally ineffective; however, DME gave 3a in moderate yield
(Table 2, entry 2). Interestingly, reducing the amount of
hydrogen chloride to 10 mol % improved the chemical yield to
81% (Table 2, entry 3). The reasons for this improvement are
unknown; however, oxygen molecules were necessary in this
reaction. Although TMSCl can be used instead of HCl, it was
condition B
Scheme 5. Catalytic Substituted Cyclohexanone Synthesis.
We next focused on the catalytic intramolecular
hydroalkylation process depicted in equation E (Scheme 5). In
2001,
Widenhoefer
demonstrated
an
intramolecular
hydroalkylation of 1a to form 2-oxocyclohexane-1-carboxylate
(3a) using catalytic amounts of PdCl2(MeCN)2 (Scheme 5, D).14
The reaction proceeded smoothly under mild conditions, and

4
found to decrease the yield (Table 2, entry 4).16 Encouraged by
these observations, we next lowered the amount of Pd(OAc)2 to 3
mol %. Although the chemical yield of 3a decreased to 48%
(Table 2, entry 5), better results were obtained when DME was
replaced by 1,4-dioxane (Table 2, entry 6). It turned out that 10
mol % hydrogen chloride was required in this reaction (Table 2,
entries 7 and 8). Halogenated solvents, such as DCM and
chloroform, were also useful for this transformation (Table 2,
entry 9). When this reaction was performed using PdCl2 in 1,4-
dioxane, the isolation yield of 3a was inferior to that of entry 6
(Table 2, entry 10). Although there is no experimental support,
the generation of PdCl(OAc) could not be ruled out.
1 equiv HCl in 1,4-dioxane at 70 °C for 48 h, 92% of 3m was
obtained with the recovery of 1n (6%). Even ketones 1n–1m
gave the corresponding cyclization products in good yields,
probably because the ketones were easily enolized under
hydrochloric acid conditions.
OH
13C
OH
13C
CO2Et
CO2Et
Me
5
7
(29% for 2 steps)
CO2Et
(7% for 2 steps)
O
13C
CO2Et
O
13C
O
13C
4
CO2Et
With these optimized conditions, we tested the scope of this
protocol using several structurally varied acyclic unsaturated 1,3-
dicarbonyl compounds, and the results are incorporated into
Scheme 7.
Me
6
8
(65% for 2 steps)
(87% for 2 steps)
3 mol% Pd(OAc)2
O
O
Scheme 8. Application to the Synthesis of 13C-Labeld Compounds
5–8.
R3
R1
R2
R3
R1
R2
10 mol% HCl
1,4-dioxane, 60 °C
The antitumor activity of aspirin has prompted numerous
attempts toward elucidating this unexpected mode of action.17
The development of a concise synthetic method for producing
13C-labled aspirin derivatives should facilitate metabolite
identification and qualification during metabolic pathway
monitoring.18 We demonstrated the two-step synthesis of ethyl 2-
hydroxybenzoate-2-13C (5) from the commercially available ethyl
3-oxobutanoate-3-13C (4). Additionally, ethyl (1S*,2R*)-2-
O
2 (1 atm), 25 h
3a-m
1a-n
Product and Yielda
Substrate
Substrate
O
Product and Yielda
O
O
O
O
O
CO2Me
CO2Me
Me
Me
Me
3j
(68%)
O
1a
3a
(76%)
1j
O
O
O
methyl-6-oxocyclo-hexane-1-carboxylate-6-13C
(6)
was
O
O
CO2Et
CO2Et
Me
stereoselectively prepared using the present methodology
(Scheme 8). Similarly, 13C-labled compounds 7 and 8 were
synthesized. These application examples clearly demonstrate the
utility of this catalytic reaction method.
Me
Me
1b
1k
3b
3k
(68%)
(66%)
O
O
O
O
In summary, we successfully explored the novel reactivity of
Pd(OAc)2 through this orthogonal synthesis. This orthogonal
synthesis displayed the following characteristics. (1) Substituted
phenols and substituted cyclohexanones could be synthesized
selectively using common acyclic unsaturated 1,3-carbonyl
compounds in the presence of catalytic Pd(OAc)2. (2) The
starting material was completely consumed and only the desired
cyclization product was formed. (3) Purification was not
required. (4) This orthogonal reaction was ligand-free.
CO2Me
CO2Me
Me
Me
1c
1l
3l
(72%)
3c
(97%)
O
O
O
O
CO2Et
CO2Et
Me
Me
1m
1d
3m
3m
(72%)
(92%)
3d
3c
(91%)
O
O
CO2Me
Acknowledgments
(43%)
We would like to thank Professor Barry M. Trost (Stanford
University) for the fruitful discussions. We would also like to
acknowledge Kawaken Fine Chemicals for contributing the
palladium acetate.
1e
1n
a Isolated yield.
Scheme 7. Catalytic Formation of Substituted Cyclohexanones from
Appendix A. Supplementary data
Supplementary data to this article can be found online.
References and notes
Acyclic Carbonyl Compounds.
The ethyl ester 1b was found to afford the corresponding
cyclized form 3b in moderate yield. Surprisingly, the
thermodynamically stable 2,3-trans-cyclohexanones 3c and 3d
were obtained in a single stereoisomer from the corresponding
(E)-3-oxooct-6-enoates 1c and 1d, respectively, in excellent
yields. In contrast with 1c and 1d, 3c was obtained in a relatively
low yield (43%) using methyl 3-oxooct-7-enoate (1e). This
reaction was next applied to the 1,3-diketones. As a result, 3j was
produced from 1j in moderate yield, and trans-2-acetyl-3-
methylcyclohexan-1-one (3k) was afforded from 1k as a single
stereoisomer in 66% yield. The utility of this reaction was
expanded by subjecting the unsaturated ketone 1l to this protocol,
and 2-phenylcyclohexanone (3l) was obtained in good yield.
Surprisingly, 1m was smoothly cyclized to give 3m in 72% yield.
When this reaction was conducted using 10 mol % Pd(OAc)2 and
1. For some recent leading reviews, see: (a) Bellina, F.; Rossi, R. Chem.
Rev. 2010, 110, 1082-1146. (b) Jana, R.; Pathak, T. P.; Sigman, M. S.
Chem. Rev. 2011, 111, 1417-1492. (c) Magano, J.; Dunetz, J. R.
Chem. Rev. 2011, 111, 2177-2250. (d) Yamamoto, Y. Chem. Rev.
2012, 112, 4736-4769. (e) Johansson Seechurn, C. C. C.; Kitching, M.
O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51,
5062-5085. (f) Huang, L.; Arndt, M.; Gooβen, K.; Heydt, H.; Gooβen,
L. J. Chem. Rev. 2015, 115, 2596-2697. (g) Yang, L.; Huang, H.
Chem. Rev. 2015, 115, 3468-3517. (h) Cherney, A. H.; Kadunce, N.
T.; Reisman, S. E. Chem. Rev. 2015, 115, 9587-9652. (i) Petrone, D.
A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116, 8003-8104. (j) Henry,
M. C.; Mostafa, M. A. B.; Sutherland, A. Synthesis, 2017, 49, 4586-
4598. (k) Labinger, J. A. Chem. Rev. 2017, 117, 8483-8496. (l) Yang,
Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787-8863. (m) Wei, Y.;

5
Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117, 8864-8907. (n)
Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247-9301. (o)
Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Chem. Rev. 2017, 117,
9163-9227. (p) Dong, Z.; Ren, Z.; Thompson, S.J.; Xu, Y.; Dong, G.
Chem. Rev., 2017, 117, 9333-9403. (q) Fumagalli, G.; Stanton, S.;
Bower, J. F. Chem. Rev. 2017, 117, 9404-9432. (r) Kumar, A.; Bhatti,
T. M.; Goldman, A. S. Chem. Rev. 2017, 117, 12357-12384. (s)
Kalck, P.; Urrutigoïty, M. Chem. Rev. 2018, 118, 3833-3861.
17. Alonso, L.; Ai, G.; Spitale, R. C.; Bhat, G. J. Br. J. Cancer, 2014,
111, 61-67.
18. Fendt, S-M. et al., Curr. Opin. Biotechnol., 2015, 34, 189-201.
2. For some recent leading reviews, see: (a) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147-1169. (b) McDonald, R. I.; Liu, G.;
Sthal, Chem. Rev. 2011, 111, 2981-3019. (c) Majumdar, K. C.;
Samanta, S.; Sinha, B. Synthesis, 2012, 44, 817-847. (d) Wu, W.;
Jiang, H. Acc. Chem. Res. 2012, 45, 1736-1748. (e) Wu, X.-F.;
Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1-35. (f) Yin, G.;
Mu, X.; Liu, G. Acc. Chem. Res. 2016, 49, 2413-2423. (g) Ruiz-
Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564-12649. (h)
Baudoin, O. Acc. Chem. Res. 2017, 50, 1114-1123. (i) He, J.; Wasa,
M.; Chan, K. S. L., Shao, Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754-
8786. (j) Biffis, A.; Centomo, P.; Del Zotto, A.; Zecca, M. Chem. Rev.
2018, 118, 2249-2295. (k) Wang, D.; Weinstein, A. B.; White, P. B.;
Stahl, S. S. Chem. Rev. 2018, 118, 2636-2679.
3. Carole, W. A.; Colacot, T. J. Chem. Eur. J. 2016, 22, 7686-7695.
4. Egorova, K. S.; Ananikov, V. P. Angew. Chem., Int. Ed. 2016, 55,
12150-12162.
5. Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic
Synthesis. John Wiley and Sons, New York, NY. 1995.
6. For our contribution to the palladium-catalyzed cyclizations: (I)
Development of palladium-catalyzed cycloalkenylation, see: Toyota,
M.; Wada, T.; K. Fukumoto.; Ihara, M. J. Am. Chem. Soc. 1998, 120,
4916-4925. Applications to Natural Product Synthesis, see: (a)
Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc.
2000, 122, 9036-9037. (b) Toyota, M.; Sasaki, M.; Ihara, M. Org.
Lett. 2003, 5, 1193-1195. (c) Toyota, M.; Asano, T.; Ihara, M. Org.
Lett. 2005, 7, 3929-3932. Scope and limitations, see: (a) Toyota, M.;
Rudyanto, M.; Ihara, M. J. Org. Chem. 2002, 67, 3374-3386. (b)
Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa, M.;
Ihara, M. Org. Lett. 2002, 4, 4293-4296. (II) Development of 2nd
generation palladium-catalyzed cycloalkenylation, see: Hibi, A.;
Toyota, M. Tetrahedron Lett. 2009, 50, 4888-4891. Applications to
Natural Product Synthesis, see: (a) Saeki, M.; Toyota, M. Tetrahedron
Lett. 2010, 51, 4620-4622. (b) Takeda, K.; Toyota, M. Tetrahedron
Lett., 2011, 52, 5872-5875. Scope and limitations, see: Takeda, K.;
Toyota, M. Tetrahedron, 2011, 67, 9909-9921.
7. For
a definition of orthogonal synthesis, see: Wong, C.-H.;
Zimmerman, S. C. Chem. Commun. 2013, 49, 1679-1695. Selected
examples, see: (a) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2008, 130, 1558-1559. (b) Hui, B. W.-Q.; Chiba, S. Org.
Lett. 2009, 11, 729-732.
8. We originally set out to find a new catalytic reaction to produce six-
membered ring compounds just after a publication related to our
development
of
the
2nd
generation
palladium-catalyzed
cycloalkenylation (Tetrahedron Lett., 2009, 50. 4888). Additionally,
we presented our discovery of the Pd(OAc)2-catalyzed
cycloaromatization at the 60th Annual Meeting of the Pharmaceutical
Society of Japan Kinki-branch in 2010 (See: Abstract, page 58).
9. 13C-labeled aspirin could be useful for pharmacokinetics, see: J. Burm
et al. Lancet. 2011, 378, 2018-2087.; Other examples, see: (a)
Setchell, K. DR et al. Am. J. Clin. Nutr. 2003, 77, 411-419. (b)
Brindle, K. M, J. Am. Chem. Soc. 2015, 117, 6418-6427.
10. J. E. Baldwin. J. C. S. Chem. Comm. 1976, 734-736.
11. Mohan, R.; Kates, S. A.; Dombroski, M. A.; Snider, B. B.
Tetrahedron Lett. 1987, 28, 845-848; Peterson, J. R.; Egler, R. S.;
Horsley, D. S. Winter, T. J. ibid. 1987, 28, 6109-6112; Snider, B. B.;
Patricia, J. J. J. Org. Chem. 1989, 54, 38-46.
12. Samadi, S.; Orellana, A. ChemCatChem. 2016, 8. 2472-2475.
13. Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901-2916.
14. (a) Pei, T.; Wiedenhoefer, R. A. J. Am. Chem. Soc., 2001, 123,
11290-11291. (b) Idem. Chem. Commun. 2002, 650-651. (c) Qian, H.;
Widenhoefer, R. A. J. Am. Chem. Soc., 2003, 125, 2056-2057.
15. Qian, H.; Pei, T.; Widenhoefer, R. A. Organometallics, 2005, 24,
287-301.
16. Han, X.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem. Eur. J., 2004,
10, 6333-6342.

6
•
•
•
•
•
Pd(OAc)2-catalyzed orthogonal synthesis of benzoates
and cyclohexanones
Pd(OAc)2-catalyzed one-pot synthesis of 2-
hydroxybenzoates
Pd(OAc)2-HCl-catalyzed one-pot synthesis of
substituted cyclohexanones
Pd(OAc)2-catalyzed one-pot synthesis of 13C-labeled
2-hydroxybenzoates
Pd(OAc)2-HCl-catalyzed one-pot synthesis of 13C-
labeled cyclohexanones