Photo-oxidative Cross-Dehydrogenative Coupling-Type Reaction of Thiophenes with α-Position of Carbonyls Using a Catalytic Amount of Molecular Iodine

Article abstract of DOI:10.1021/acs.orglett.7b00428

A metal-free photo-oxidative intermolecular C-H/C-H coupling reaction of thiophenes is demonstrated with carbonyls using a catalytic amount of molecular iodine. In this system, molecular oxygen in the air acted as a terminal oxidant to regenerate molecular iodine. A mechanistic study was also performed.

Full text of DOI:10.1021/acs.orglett.7b00428

Letter
pubs.acs.org/OrgLett
Photo-oxidative Cross-Dehydrogenative Coupling-Type Reaction of
Thiophenes with α‑Position of Carbonyls Using a Catalytic Amount
of Molecular Iodine
Yusuke Sudo, Eiji Yamaguchi,* and Akichika Itoh*
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
*
S Supporting Information
ABSTRACT: A metal-free photo-oxidative intermolecular C−
H/C−H coupling reaction of thiophenes is demonstrated with
carbonyls using a catalytic amount of molecular iodine. In this
system, molecular oxygen in the air acted as a terminal oxidant
to regenerate molecular iodine. A mechanistic study was also
performed.
he introduction of heteroarenes at the α-position of
Scheme 1. Summary of C−C Bond-Forming Reaction at the
α-Position of Carbonyls with Heteroarenes
T
carbonyls is one of the fundamental research topics in
organic synthesis, as the molecules that contain such fragments
are ubiquitously found in naturally occurring molecules and
pharmaceuticals and exhibit diverse biological and pharmaco-
1
logical activities. Owing to diverse pharmaceutical applications,
methodologies for construction of a C−C bond at the α-
position of carbonyls have been extensively investigated
2
(
Scheme 1). While the reaction with a C-centered radical,
which leads to the corresponding carbon−carbon bond-forming
product, is one of the most well-established reactions, the
generation of radical species from α-halo carbonyls is mediated
by a radical initiator or a mediator such as AIBN, tin, or
3
trialkylborane. However, many radical initiation systems
require harsh reaction conditions and functional group
tolerance and also produce byproducts. Therefore, more
atom-economical reactions that use photoredox catalysis to
chemoselectively reduce a suitable carbon−halogen bond under
4
mild conditions have been studied. Although numerous
photocatalysts based on Ru or Ir have been investigated during
the past decades, these complexes are expensive and potentially
5
toxic. The coupling reaction of halogenated heteroarenes with
6
carbonyls is a suitable method for forming a C−C bond. This
methodology shows good functional group tolerance and
generally a better yield compared with the above reaction.
However, the method requires a precious transition-metal
complex. Recently, a stoichiometric heavy- or transition-metal-
catalyzed intermolecular C−H/C−H coupling reaction be7-
tween carbonyls and heteroarenes has been reported.
Furthermore, a Mn-catalyzed cross-dehydrogenative coupling
reaction of heteroarenes with carbonyls using cheap NaIO as
4
8
co-oxidant was reported by Yamaguchi and co-workers.
dehydrogenative C−C bond-forming reaction from two C−H
However, a catalytic and aerobic oxidation methodology has
not been achieved for the CDC coupling of heteroarenes with
carbonyls.
10
bonds of indole with malonate. This system proceeded at
room temperature under visible light irradiation from CFL with
We have studied aerobic photo-oxidative reactions mediated
9
by a halogen source. During the course of this study, we have
Received: February 12, 2017
observed a rare-metal-free catalytic photoaerobic intramolecular
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00428
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
aerobic oxygen as a terminal oxidant. On the basis of this
pioneering result, a metal-free intermolecular catalytic cycliza-
tion reaction should be achievable using heteroarenes with
carbonyls. Herein, we describe the development of a practical
method for an aerobic photo-oxidative intermolecular C−H/
C−H coupling of carbonyls and thiophenes using a catalytic
amount of molecular iodine (Scheme 1).
With the optimal conditions in hand, we investigated the
scope of C−H/C−H coupling of tris(ethoxycarbonyl)methane
(2a) with thiophenes (1) (Scheme 2). When 2-phenyl-
Scheme 2. Substrate Scope Exploration Using Thiophene
a,b
and Thiazole Derivatives 1 with Triester 2a
We first investigated the C−H/C−H coupling reaction of 1a
with 2a in the presence of a catalytic amount of molecular
iodine with visible light irradiation at room temperature to
achieve a dehydrogenative-type coupling reaction leading to 3a
(Table 1 and Table S1). First, the solvent was considered while
Table 1. Optimization Study of C−H/C−H Coupling of 2-
a
Methylthiophene 1a with Triester 2a
b,c
entry
base
solvent (mL)
yield (%)
d
1
Ca(OH)2
Ca(OH)2
Ca(OH)2
Ca(OH)2
Ca(OH)2
Ca(OH)2
Ca(OH)2
CaCO3
CHCl (1)
trace
trace
trace
20
3
d
2
DMAc (1)
d
3
DMSO (1)
MeOH (1)
EtOAc (1)
MeCN (1)
d
4
d
a
5
38
Conditions: The mixture of 1 (0.3 mmol), 2a (4.0 equiv), I (0.2
2
d
6
52
equiv), and K PO (1.25 equiv) in MeCN (4 mL) and water (0.4 mL)
3 4
was stirred for 20 h in an aerobic atmosphere at an ambient
7
8
MeCN/H O (2/0.2)
67
2
temperature and irradiated with four 22 W compact fluorescent lamps.
MeCN/H O (2/0.2)
58
2
b
e
Isolated yield.
9
MeCN/H O (2/0.2)
58
2
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
Mg(OH)2
CsOH
MeCN/H O (2/0.2)
63
2
thiophene (1b) was used, the coupling proceeded well to
give the corresponding product 3b in 72% yield. Substituents at
the aryl group on the thiophene ring did not affect the reactivity
of this C−C bond-forming reaction. A 2,3-diarylated thiophene
also reacted smoothly to give the corresponding product 3h in
moderate yield. To our delight, benzoyl-protected 2-thiophe-
nemethanol (1i) also reacted without undesired oxidation
reactions at the benzylic position. In contrast to these results,
electron-poor thiophenes, such as 2-chloro (1j), 2-methox-
ycarbonyl (1k), and 2-formyl (1l), did not react under the
present conditions. Moreover, 2-phenyl (1m), 5-phenyl (1n),
and 2,5-diphenylthiazole (1o) were also compatible under the
optimal conditions and gave the monocoupling product in
moderate to good yields.
MeCN/H O (2/0.2)
72
2
Cs CO
MeCN/H O (2/0.2)
72
2
3
2
K HPO
2
MeCN/H O (2/0.2)
60
4
2
K PO
MeCN/H O (2/0.2)
72
3
4
4
4
2
K PO
3
MeCN/H O (3/0.3)
72
2
K PO
3
MeCN/H O (4/0.4)
80 (77)
(83)
2
f
K PO4
3
MeCN/H O (4/0.4)
2
a
Conditions: The mixture of 2-methylthiophene 1a (0.3 mmol), 2a
4.0 equiv), I (0.2 equiv), and base (1.0 equiv) in solvent and water
was stirred for 20 h in an aerobic atmosphere at ambient temperature
and irradiated with four 22 W compact fluorescent lamps. Yields were
determined by H NMR analysis of the crude reaction mixture.
Numbers in parentheses refer to isolated yield. 2.0 equiv of 2a was
employed. 0.2 equiv of CaI was employed instead of I . 1.25 equiv of
K PO was employed.
(
2
b
1
c
d
e
f
2
2
3
4
After the functional group tolerance of heteroarenes was
demonstrated, the diversity of carbonyls was further inves-
tigated under optimal conditions (Scheme 3).
maintaining a concentration of 0.3 M (entries 1−6). The use of
acetonitrile as a solvent led to C−C bond formation, resulting
in 3a as the main product although with incomplete conversion
of thiophene 1a (entry 6). Conducting the reaction in a mixed
solvent of acetonitrile and water provided the desired product
Overall, moderate to good yields of 3 were obtained, and
various substituents on the carbonyls, e.g., amide, ketone, and
sulfonyl, showed little effect on the efficiency of the reaction.
1
The H NMR analysis of the crude reaction mixture of 3p
2
a in higher yield (entry 7). We then investigated base
showed a large amount of the corresponding hydroxylated
trimethylcarboxylate. This indicated that the ethyl ester moiety
could suppress the oxidation at the α-position of carbonyl.
Unfortunately, diethyl methylmalonate and diethyl malonate
did not react with thiophene to give the corresponding
screening with various salts (entries 8−14). Ultimately, a
combination of catalytic molecular iodine and K PO (1.0
equiv) delivered the product 3a in 72% NMR yield (entry 14).
The yield of product was increased to 80% (77% isolated)
when the reaction was conducted at a lower concentration
3
4
11
products 3t and 3u.
(
entry 16). Finally, efforts to increase the yield revealed that a
We conducted detailed control experiments to elucidate the
role of molecular iodine in this CDC-type reaction (Scheme 4,
eq a). Under the optimized reaction conditions in the absence
of molecular iodine, 1a is not converted into the desired
product. The reaction in the dark did not give a product, even
small excess of K PO over the stoichiometric level was
3
4
essential to yield the product (83% isolated yield, entry 17). All
reactions gave the corresponding hydroxylated malonate 2a-
OH in moderate yield.
B
DOI: 10.1021/acs.orglett.7b00428
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope Exploration Using 1a with
Carbonyls 2
Figure 1. Plausible reaction mechanism.
radical species I. Addition of I to thiophenes and iodination of
the generated radical gave intermediate II. Finally, aromatiza-
tion of II furnished product 3.
Scheme 4. Mechanistic Studies
In conclusion, a novel and concise route to gain α-
heteroarylated carbonyls via an aerobic photo-oxidative C−
H/C−H coupling reaction of heteroarenes with carbonyls,
mediated by molecular iodine has been developed. This
reaction proceeds through activation of cheap and abundant
molecular iodine and the formation of C−C bonds. In contrast
to traditional methods leading to similar products, the
advantages of this methodology are mild reaction conditions,
operational simplicity, and an inexpensive and abundant
molecular iodine catalyst.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00428.
Experimental and characterization data; 1H and 13
spectra (PDF)
C
when heated. This coupling reaction under an argon
atmosphere gave 12% of product, and the results demonstrated
that only a trace amount of 1a was coupled with 2a in the
absence of molecular oxygen. Moreover, radical-trapping
reagents (galvinoxyl, BHT, and TEMPO) completely sup-
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: yamaguchi@gifu-pu.ac.jp.
E-mail: itoha@gifu-pu.ac.jp.
ORCID
pressed the reaction. These experiments revealed that I , visible
2
light, and molecular oxygen are indispensable in this trans-
formation, and the reaction could proceed through the radical
intermediate. To gain an insight into the role of iodine, several
experiments were carried out (eq b). The yield of 3a was
decreased to 34% when the reaction was performed without
K PO in air. And the reaction using hydroiodic acid as catalyst
Eiji Yamaguchi: 0000-0002-1167-8832
Akichika Itoh: 0000-0003-3769-7406
Notes
3
4
The authors declare no competing financial interest.
also gave the product in 33% yield. However, the reaction using
HI in the dark did not furnish the product. Based on these
results, we assumed that molecular iodine could be (re)-
generated from iodide in the presence of oxygen and act as a
catalyst. Finally, to clarify the intermediate of this reaction,
iodinated ester 2a-I was used as a coupling partner (eq c). As a
result, the reaction gave the desired product in 40% yield and
ACKNOWLEDGMENTS
This research was supported by the Asahi Glass Foundation.
■
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■
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DOI: 10.1021/acs.orglett.7b00428
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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DOI: 10.1021/acs.orglett.7b00428
Org. Lett. XXXX, XXX, XXX−XXX