Iridium-Catalyzed Aerobic Coupling of Salicylaldehydes with Alkynes: A Remarkable Switch of Oxacyclic Product

Article abstract of DOI:10.1002/chem.201801245

The iridium(III)/copper(II)-catalyzed dehydrogenative coupling of salicylaldehydes with internal alkynes proceeds efficiently under atmospheric oxygen through aldehyde C?H bond cleavage and decarbonylation. A variety of benzofuran derivatives can be synthesized by the environmentally benign procedure. DFT calculations suggest that this unique transformation involves the facile deinsertion of CO in the key metallacycle intermediate, which is in marked contrast to the corresponding rhodium(III) catalysis that leads to CO-retentive chromone derivatives.

Full text of DOI:10.1002/chem.201801245

A Journal of
Accepted Article
Title: Iridium-Catalyzed Aerobic Coupling of Salicylaldehydes with
Alkynes: A Remarkable Switch of Oxacyclic Product
Authors: Shintaro Yamane, Tomoaki Hinoue, Yoshinosuke Usuki,
Masumi Itazaki, Hiroshi Nakazawa, Yoshihiro Hayashi,
Susumu Kawauchi, Masahiro Miura, and Tetsuya Satoh
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To be cited as: Chem. Eur. J. 10.1002/chem.201801245
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COMMUNICATION
Iridium-Catalyzed Aerobic Coupling of Salicylaldehydes with
Alkynes: A Remarkable Switch of Oxacyclic Product
Shintaro Yamane,[a] Tomoaki Hinoue,[b] Yoshinosuke Usuki,[a] Masumi Itazaki,[a] Hiroshi Nakazawa,[a]
Yoshihiro Hayashi,[c] Susumu Kawauchi,[c] Masahiro Miura,*[b] and Tetsuya Satoh*[a]
Dedication ((optional))
Abstract: The iridium(III)/copper(II)-catalyzed dehydrogenative
coupling of salicylaldehydes with internal alkynes proceeds
efficiently under atmospheric oxygen through aldehyde C–H bond
cleavage and decarbonylation. A variety of benzofuran derivatives
can be synthesized by the environmentally-benign procedure. DFT
calculations suggest that this unique transformation involves the
facile deinsertion of CO in the key metallacycle intermediate, which
is in marked contrast to the corresponding rhodium(III) catalysis that
leads to CO-retentative chromone derivatives.
this reaction can be carried out using molecular oxygen as a
terminal oxidant without waste formation except for water and
CO. 2,3-Disubstituted benzofuran structures can be seen in
synthetic intermediates in producing various bioactive
compounds, natural products, and organic materials.[6] Therefore,
their synthetic methods via transition-metal-catalyzed direct
coupling of phenolic substrates with alkynes have been
developed.[7] Although these reactions can be step-economical
approaches, the addition of stoichiometric or even excess
amounts of metal salts is usually required as oxidants,
promoters, or Lewis acids. Liu, Lu, and co-workers reported the
Aldehydes are definitely highly versatile building blocks in
organic synthesis. Among functionalized aromatic aldehydes,
salicylaldehyde and its derivatives are readily available and
particularly useful for preparing various kinds of valuable fused
heterocyclic compounds as well as chelating agents such as
salens. Besides conventional condensation reactions involving
Claisen and Perkin reactions, latest techniques based on
transition-metal-catalysis have attracted attention for their
transformation. Thus, we[1] and other groups[2] have developed
the direct derivatization methods of salicylaldehydes through
aldehyde C–H bond arylation and alkenylation.[3] We also found
that salicylaldehydes undergo dehydrogenative annulation with
internal alkynes in the presence of a rhodium catalyst and a
copper salt oxidant to produce chromone derivatives (Scheme 1,
a: previous work).[4a] Later, similar reactions using cobalt[4b] and
ruthenium[4c] catalysts were reported for the construction of a
variety of flavonoid compounds. During our further studies of
transition-metal-catalyzed dehydrogenative coupling reactions,[5]
we succeeded in finding that treatment of the same combination
of substrates, salicylaldehydes and alkynes, using an iridium
catalyst together with a copper cocatalyst under atmospheric
oxygen in place of the rhodium system gives 2,3-disubstituted
benzofuran derivatives predominantly, accompanied by
dehydrogenation and decarbonylation (Scheme 1, b: this work).
Thus, the remarkable switch of product was realized by the
simple change of the catalytic system. It should be noted that
rhodium-
and
ruthenium-catalyzed
annulation
of
N-
phenoxybenzamides with alkynes utilizing internal oxidants to
address the drawback.[7a] However, an additional step is
required to introduce reducible directing groups onto the
phenolic substrates. The present reaction provides
a
straightforward pathway toward useful 2,3-disubstituted
benzofuran derivatives from readily available salicylaldehydes
through environmentally-benign aerobic dehydrogenative
annulation without the addition of a stoichiometric amount of
metal salts.
O
Rh, Co, or Ru-cat.
R
oxidant
O
Previous Work
O
R
R
R
H
+
R
OH
R
Ir-cat.
Cu-cat.
O2
O
This Work
Scheme 1. Dehydrogenative Annulation of Salicylaldehydes with Alkynes.
In an initial attempt, salicylaldehyde (1a) (0.5 mmol) was
treated with diphenylacetylene (2a) (0.5 mmol) in the presence
of catalytic amounts of [Cp*IrCl2]2 (0.01 mmol; 2 mol%) and
Cu(OAc)2•H2O (0.05 mmol; 10 mol%) in xylene (2.5 mL) at 160
oC for 24 h under O2. As a result, aerobic dehydrogenative
coupling proceeded accompanied by decarbonylation to
predominantly produce 2,3-diphenylbenzofuran (3aa) in 66%
yield, along with a minor amount (8%) of 2,3-diphenylchromone
(4aa)[4a] (entry 1 in Table 1). Decreasing the amount of
Cu(OAc)2•H2O to 5 mol% significantly reduced the yield of 3aa
(entry 2). Other cupper salts such as Cu(OCOCF3)2•H2O,
Cu(OTf)2•H2O, and CuO were less effective as co-catalysts than
Cu(OAc)2•H2O (entries 3-5). The addition of a catalytic amount
(10 mol%) of Na2CO3 as a base slightly accelerated the reaction
and increased the yield of 3aa (entry 6). NaHCO3 and KHCO3
were more effective to increase the yield to 77 and 75%,
[a]
S. Yamane, Prof. Dr. Y. Usuki, Dr. M. Itazaki, Prof. Dr. H.
Nakazawa, and Prof. Dr. T. Satoh
Department of Chemistry
Graduate School of Science, Osaka City University
3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
E-mail: satoh@sci.osaka-cu.ac.jp
[b]
[c]
Dr. T. Hinoue, Prof. Dr. M. Miura
Department of Applied Chemistry
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871, Japan
Dr. Y. Hayashi, Prof. Dr. S. Kawauchi
Department of Chemical Science and Engineering, School of
Materials and Chemical Technology, Tokyo Institute of Technology
2-12-1 (E4-6), Ookayama, Meguro-ku, Tokyo 152-8552, Japan
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201801245
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respectively (entries 7 and 8). In addition to these inorganic
bases, organic bases were also found to facilitate the reaction.
Thus, 3aa was obtained in 75 and 83% yields by using (i-Pr)2NEt
and DABCO, respectively (entries 9 and 10). Finally, DBU was
found to be the most effective base catalyst to improve the 3aa
yield to 93%, suppressing the formation of 4aa to 1% (entry 11).
Furthermore, 3aa was produced almost quantitatively under
conditions using a slightly excess amount (1.2 equiv.) of 1a
(entry 12). Since stoichiometric amounts of additives are not
required, the present reaction can be readily scaled up to a gram
scale. Thus, 3aa was obtained in 78% isolated yield (1.05 g)
from 1a (6 mmol) and 2a (5 mmol) (entry 13).
underwent the annulation with 1a to produce 3ah. The reaction
of an unsymmetrical alkyne, 1-phenyl-1-propyne (2i), with 1a
afforded 2-phenyl-3- methylbenzofuran (3ai) predominantly.
Only a trace amount (ca. 1%) of a regioisomer was detected by
GC-MS and 1H NMR. Compared to aromatic alkynes, an
aliphatic one, 4-octyne (2j), was less reactive under the standard
conditions to give 3aj in a lower yield. Commercially available,
variously substituted salicylaldehydes 1b-h also underwent the
annulative coupling with 2a to produce 3ba-3ha. It should be
noted that sterically hindered 4- and/or 7-substituted benzofuran
frameworks are readily constructed by the present procedure.
These frameworks seem to be difficult to prepare by the
previous coupling of phenolic substrates with alkynes.[7]
Table 1. Reaction of salicylaldehyde (1a) with diphenylacetylene (2a)[a]
R4
R4
O
R6
[Cp*IrCl2]2 (2 mol%)
Cu(OAc)2•H2O (10 mol%)
R3
R2
R6
R3
R2
O
O
Ph
H
[Cp*IrCl2]2 (2 mol%)
Cu-cat. (10 mol%)
R5
+
Ph
Ph
Ph
DBU (10 mol%)
xylene
O2 (1 atm), 160 oC
O
H
+
+
R5
OH
Ph
R1
base (10 mol%)
xylene
O2 (1 atm), 160 oC
R1
1
O
O
OH
Ph
3
2
1a
3aa
4aa
2a
R
OMe
MeO
entry
Cu-cat.
base
time
[h]
Yield [%][b]
4aa
OMe
OMe
3aa
66
14
28
0
R
1
2[c]
3
Cu(OAc)2•H2O
Cu(OAc)2•H2O
–
–
48
24
48
4
8
26
12
0
O
O
3ah, 49%
3ab: R = Me, 77%
3ac: R = t-Bu, 68%
3ad: R = OMe, 81%
3ae: R = CF3, 59%
3af: R = Cl, 54%
Me
n-Pr
Cu(OCOCF3)2•H2O
Cu(OTf)2•H2O
CuO
–
n-Pr
O
O
4
–
3ag: R = CO2Et, 37%
3ai, 58%[a]
3aj, 29%
5
–
4
5
10
11
8
Ph
Ph
Ph
O2N
6
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Na2CO3
NaHCO3
KHCO3
(i-Pr)2NEt
DABCO
DBU
DBU
DBU
30
48
24
24
8
68
77
75
75
83
93
Ph
Ph
O
Ph
O
O
OMe
R
7
3da, 68%
3ba: R = OMe, 52%
3ca: R = Cl, 56%
3ea, 38%
8
10
7
Me
OMe
Ph
Ph
9
Ph
Ph
O
Ph
10
11
12[d]
13[e]
16
1
Ph
O
O
MeO
Me
3ga, 59%
8
3fa, 36%
3ha, 34%
24
24
99 (84)
(78)
1
Scheme 2. Reaction scope of salicylaldehydes and alkynes. Reaction
conditions: (0.5-0.6 mmol), (0.5 mmol), [Cp*IrCl2]2 (0.01 mmol),
[f]
–
1
2
Cu(OAc)2•H2O (0.05 mmol), and DBU (0.05 mmol) in xylene (2.5 mL) under O2
(1 atm) at 160 oC for 4-48 h, unless otherwise noted. Yields after purification
were listed. [a] A trace amount (ca. 1%) of regioisomer was also detected by
GC-MS and 1H NMR.
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [Cp*IrCl2]2 (0.01
mmol), Cu-cat. (0.05 mmol), and base (0.05 mmol) in xylene (2.5 mL) under
O2 (1 atm) at 160 oC, unless otherwise noted. [b] GC yield based on the
amount of 2a used. Value in parentheses indicates yield after purification.
[c] With Cu(OAc)2•H2O (0.025 mmol). [d] With 1a (0.6 mmol). [e] With 1a (6
mmol), 2a (5 mmol), [Cp*IrCl2]2 (0.1 mmol), Cu(OAc)2•H2O (0.5 mmol), and
DBU (0.5 mmol) in xylene (10 mL). [f] Not determined.
The present annulation method was found to be applicable
to the synthesis of an analogue of naturally occurring, bioactive
eupomatenoid-1.[8] Thus, treatment of 1e (0.6 mmol) with alkyne
2k (0.5 mmol) using [Cp*IrCl2]2 (0.05 mmol) and Cu(OAc)2•H2O
(1 mmol) in the presence of DBU (0.05 mmol) in xylene (2.5 mL)
Under the optimized conditions (entry 12 in Table 1), 1a
coupled with 4,4’-substituted diphenylacetylenes 2b-g to give
the corresponding 2,3-diarylbenzofurans 3ab-3ag (Scheme 2).
o
at 160 C for 3 h under Ar gave 3ek in 41% yield (Scheme 3).[9]
As in the case using 2i (Scheme 2), only a trace amount (less
1
than 1%) of regioisomer was detected by GC-MS and H NMR,
Similarly,
3,3’,4,4’-tetramethoxydiphenylacetylene
(2h)
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O
indicating high regioselective nature of the present annulation
reaction.
Ph
–Cp*Rh
CuX2
Ph
Rh
O
H2O
E
Cp*
4aa
Me
O
Me
2a
M = Rh
[Cp*IrCl2]2 (0.05 mmol)
Cu(OAc)2•H2O (1 mmol)
O
O
H
CuX
Cp*MX2
O
1/2O2
+2HX
+
O
DBU (0.05 mmol)
xylene
Ar (1 atm), 160 oC, 3 h
O
1a
H
OH
O
M
Cp*
O
X
OMe
OMe
–HX
–HX
O
M
O
1/2O2
+2HX
Cp*
A
B
1e (0.6 mmol)
2k (0.5 mmol)
3ek, 41%
CuX
M = Ir
–CO
Scheme 3. Synthesis of 3ek.
H2O
CuX2
Ph
Cp*
Ph
2a
Ir
Cp*Ir
Ir
O
We previously performed the rhodium-catalyzed reaction of
with in the presence of [RhCl(cod)]2/C5H2Ph4 and
O
Cp*
1
2
C
D
3aa
Cu(OAc)2•H2O.[4a] To confirm the origin of the product switch, we
reinvestigated the reaction of 1a and 2a using [Cp*RhCl2]2 under
otherwise identical conditions to the present transformation
Scheme 5. Possible mechanism
(Scheme 4). As
a result, chromone 4aa was produced
exclusively, albeit with 30% yield, no benzofuran 3aa being
detected. It was of interest that a significantly enhanced yield of
4aa (80%) was obtained by eliminating DBU, along with a small
amount (2%) of 3aa. Thus, the product switch is definitively
attributable to the nature of the metals employed.
In a control experiment, 1a (0.04 mmol) was treated with
stoichiometric amounts of [Cp*IrCl2]2 (0.02 mmol) and DABCO
(0.04 mmol) in the absence of 2a in toluene-d8 at 100 oC for 4d,
resulting in the formation of a decarbonylation product, phenol
(5), in 34% yield (Scheme 6a). In this reaction, an iridacycle
similar to C appears to be formed and then be protonated to
release 5. When sodium 2-formylphenolate (1a’) was used in
place of 1a to suppress the protonation, a five-membered
iridacycle 6 that corresponds to CO-coordinated B (16%) could
be isolated (Scheme 6b). The structure was verified by X-ray
crystallography.[9] It was confirmed that 6 shows a catalytic
activity in the reaction of 1a with 2a (Scheme 6c). The slower
reaction rate could be attributed to the coordinated CO which
should be eliminated for the complex to enter the catalytic cycle.
[Cp*RhCl2]2 (2 mol%)
O
O
O
Ph
Cu(OAc)2•H2O
(10 mol%)
Ph
Ph
Ph
H
Ph
+
+
(DBU (10 mol%))
xylene
O2 (1 atm), 160 oC, 24 h
O
OH
Ph
1a
3aa
4aa
2a
w DBU
0%
2%
30%
80%
w/o DBU
Scheme 4. Cp*Rh-catalyzed reaction of 1a with 2a. GC yields are shown.
a)
O
[Cp*IrCl2]2 (0.02 mmol)
A plausible mechanism for the reaction of 1a with 2a is
illustrated in Scheme 5. In the case using a iridium catalyst,
coordination of the hydroxy function of 1a to Cp*IrX2 and
DABCO (0.04 mmol)
H
toluene-d8 (0.6 mL)
N2 (1 atm), 100 oC, 4 d
OH
OH
subsequent aldehyde C–H bond cleavage in
a resulting
1a (0.04 mmol)
5, 34%
intermediate A take place to form a five-memberd iridacycle
intermediate B.[10] Then, B undergoes decarbonylation, alkyne
insertion into the aryl–Ir bond of C, and reductive elimination
from the resulting six-membered iridacycle intermediate D to
produce 3aa. The Cp*Ir(I) species generated at the last step
may be reoxidized by a Cu(II) cocatalyst to regenerate the Ir(III)
active species along with Cu(I). The latter may be reoxidized
under O2 in the present reaction system. Meanwhile, under
rhodium catalysis, the intermediate B (M = Rh) may undergo
b)
O
O
[Cp*IrCl2]2 (0.075 mmol)
DABCO (0.15 mmol)
Cp*
CO
H
+
Ir
toluene-d8 (5 mL)
Ar (1 atm), 100 oC, 3 d
O
OH
ONa
1a' (0.15 mmol)
6, 16%
5, 15%
c)
O
Ph
6 (0.01 mmol)
alkyne insertion retaining the carbonyl forming
a
seven-
Ph
Cu(OAc)2•H2O (0.025 mmol)
H
+
Ph
membered rhodacycle E and final reductive elimination to give
4aa.
DBU (0.025 mmol)
xylene
O2 (1 atm), 160 oC, 24 h
O
OH
Ph
1a (0.3 mmol)
2a (0.25 mmol)
3aa, 25%
Scheme 6. Control experiments.
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DFT calculations were also performed to clarify the reaction
paths for the coupling reaction of 1a with 2a catalyzed under
iridium and rhodium catalyses (Figures S2 and S3), which gave
different products. As a result, it shows that the product
difference between the iridium- and rhodium-catalyzed reactions
is dominated by the equilibrium in the decarbonylation of the
five-membered metallacycle intermediate. The Gibbs free
energy diagram of the decarbonylations in the iridium- and
rhodium-catalyzed reactions is shown in Figure 1. Gibbs free
energy change of the iridium-catalyzed reaction was a negative
value (–3.7 kcal mol–1), while that of the rhodium-catalyzed
reaction was a positive value (3.5 kcal mol–1). This indicates that
the equilibrium of the iridium-catalyzed reaction is toward the
four-membered metallacycle intermediate, while that of the
rhodium-catalyzed reaction is toward the five-membered
metallacycle intermediate. Therefore, the alkyne insertion to the
four- and five-membered metallacycle intermediates leads to
distinct products in the iridium- and rhodium-catalyzed reactions,
respectively.
JPMJCR1522 to S.K.) and JSPS KAKENHI Grant Number
JP17K17720 (Grant-in-Aid for Young Scientists (B)) to Y.H. We
also thank Dr. H. Sato (Rigaku Corp.) for X-ray crystal-structure
analysis.
Keywords: C–H activation • iridium • annulation •
dehydrogenation • oxygen heterocycles
[1]
[2]
[3]
[4]
a) Y. Nishinaka, T. Satoh, M. Miura, H. Morisaka, M. Nomura, H. Matsui,
C. Yamaguchi, Bull. Chem. Soc. Jpn. 2001, 74, 1727; b) K. Kokubo, K.
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N. Kawahara, H. Suemune, J. Org. Chem. 2007, 72, 2543, and
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For reviews, see: a) M. Miura, T. Satoh, K. Hirano, Bull. Chem. Soc.
Jpn. 2014, 87, 751; b) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16,
11212; c) T. Satoh, M. Miura, Synthesis 2010, 3395;
Figure 1. Gibbs free energy diagram (in kcal mol–1) of the decarbonylation of
the five-membered metallacycle intermediates (M = Ir, Rh). The red and blue
lines indicate the diagram of the iridium- and rhodium-catalyzed reactions,
respectively.
For recent examples, see: a) J.-t. Liu, T. J. Do, C. J. Simmons, J. C.
Lynch, W. Gu, Z.-X. Ma, W. Xu, W. Tang, Org. Biomol. Chem. 2016, 14,
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Southall, X. Hu, W. Zheng, B. Neuenswander, C.-H. Cho, Y. Chen, S. A.
Worlikar, J. Aube, R. C. Larock, F. J. Schoenen, J. J. Marugan, T. J.
Liang, K. J. Frankowski, ACS Comb. Sci., 2015, 17, 641; d) R. Brkljaca,
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Chem. 2016, 12, 2065; i) H. Tsuji, C. Mitsui, Y. Sato, E. Nakamura, Adv.
Mater. 2009, 21, 3776.
In summary, we have demonstrated that various benzofuran
derivatives can be effectively prepared from readily available
salicylaldehydes and alkynes via iridium/copper catalyzed
aerobic dehydrogenative coupling. The procedure can be
applied to the synthesis of an analogue of naturally occurring,
bioactive eupomatenoid-1. We also succeeded in interpreting
the difference of products between the reactions under iridium
and rhodium catalyses by DFT calculations.
[7]
a) G. Liu, Y. Shen, Z. Zhou, X. Lu, Angew. Chem. 2013, 125, 6149;
Angew. Chem. Int. Ed. 2013, 52, 6033; b) Z. Zhou, G. Liu, Y. Shen, X.
Lu, Org. Chem. Front. 2014, 1, 1161; c) M. R. Kuram, M.
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2013, 4, 3706; e) W. Zeng, W. Wu, H. Jiang, L. Huang, Y. Sun, Z. Chen,
X. Li, Chem. Commun. 2013, 49, 6611.
Acknowledgements
This experimental work was supported by JSPS KAKENHI Grant
Number JP16H01037 (in Precisely Designed Catalysts with
Customized Scaffolding), JST (ACT-C), Nagase Science
Technology Foundation, and Yamada Science Foundation to
T.S. and JSPS KAKENHI JP 17H06092 (Grant-in-Aid for
Specially Promoted Research) to M.M. The numerical
calculations were carried out on the TSUBAME 3.0
supercomputer at the Tokyo Institute of Technology, Tokyo,
Japan, and on the supercomputer at the Research Center for
Computational Science, Okazaki, Japan. This computational
[8]
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work was supported by
a JST CREST (Grant Number
This article is protected by copyright. All rights reserved.

10.1002/chem.201801245
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
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COMMUNICATION
Shintaro Yamane, Tomoaki Hinoue,
Yoshinosuke Usuki, Masumi Itazaki,
Hiroshi Nakazawa, Yoshihiro Hayashi,
Susumu Kawauchi, Masahiro Miura,*
and Tetsuya Satoh*
R1
O
R1
R2
R3
R2
R3
R6
R6
R5
Ir / Cu-cat.
O2
H
+
R5
OH
O
R4
R4
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Construction of Benzofurans was achieved through a novel iridium(III)/copper(II)-
catalyzed dehydrogenative coupling of salicylaldehydes with internal alkynes
involving aldehyde C–H bond cleavage and decarbonylation. This reaction
proceeds efficiently under atmospheric oxygen. To clarify the mechanism of this
unique annulation, DFT calculations have been performed.
Iridium-Catalyzed Aerobic Coupling
of Salicylaldehydes with Alkynes: A
Remarkable Switch of Oxacyclic
Product
This article is protected by copyright. All rights reserved.