Visible-light-driven, radical-triggered tandem cyclization of o-hydroxyaryl enaminones: Facile access to 3-CF2/CF3-containing chromones

Article abstract of DOI:10.1021/acs.orglett.6b03441

A practical and straightforward synthetic route to construct a variety of 3-CF₂/CF₃-containing chromones via photoredox catalysis was developed. This novel protocol features a visible-light-induced radical-triggered tandem cyclizatio

Full text of DOI:10.1021/acs.orglett.6b03441

Letter
pubs.acs.org/OrgLett
Visible-Light-Driven, Radical-Triggered Tandem Cyclization of
o‑Hydroxyaryl Enaminones: Facile Access to 3‑CF /CF ‑Containing
2
3
Chromones
†
†
†
†
†
†
Haoyue Xiang, Qinglan Zhao, Zhenyu Tang, Junan Xiao, Pengju Xia, Chaoming Wang,
‡
,†
,†
Chunhao Yang, Xiaoqing Chen,* and Hua Yang*
†
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
‡
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R.
China
*
S Supporting Information
ABSTRACT: A practical and straightforward synthetic route to
construct a variety of 3-CF /CF -containing chromones via
2
3
photoredox catalysis was developed. This novel protocol features a
visible-light-induced radical-triggered tandem cyclization.
luorinated organic molecules, frequently found in a
Scheme 1. Synthetic Profiles Accessing 3-Fluorinated
F
number of biologically active natural products, pharma-
ceuticals, agrochemical reagents, and functional materials, have
attracted enormous interest. It is well-known that fluorinated
Chromones
1
analogues of pharmaceutically relevant compounds often
possess interesting properties conducive to drug development,
such as improved lipophilicity, electronegativity, bioavailability,
2
and metabolic stability. At present, approximately 30% of all
agrochemicals and 20% of all pharmaceuticals contain fluorine,
including best-selling drugs such as Lipitor, Lexapro, and
3
Prozac. Among various fluorinated moieties, difluoromethy-
lene (−CF −) and trifluoromethyl (CF −) groups are
2
3
specifically appealing. For instance, the CF group is usually
2
considered as a bioisostere for oxygen or carbonyl groups,
which leads to increased dipole moments, enhanced acidity of
4
its neighboring group, and conformational changes. Accord-
ingly, substantial efforts have been made toward the
incorporation of fluorinated functional groups into organic
molecules to modulate their biological activities.
scaffolds (Scheme 1, route A). In 2013, Yang’s group first
5
synthesized 3-CF -containing chromones via copper/palladi-
2
um-mediated cross-coupling of 3-iodochromones with ethyl
Chromones, widely found in many natural products and
pharmaceuticals with a variety of physiological and biological
activities, are versatile building blocks for constructing diversely
7
bromodifluoroacetate. However, the use of excessive copper
reagent and the necessity for preforming 3-iodochromones
imposed restrictions on its synthetic application. Afterward, a
copper-catalyzed, regioselective C−H α-trifluoromethylation of
α,β-unsaturated carbonyl compounds using Togni’s reagent was
developed by Bi et al., in which only one chromone substrate
was explored and the reaction was carried out at 80 °C under
6
featured heterocycles. Consequently, the preparation of
functionalized chromones, especially C3-functionalized ana-
logues, has received considerable synthetic attention. In general,
there are two major strategies for accessing 3-functionalized
chromones (Scheme 1). The first choice relies on the late-stage
functionalization of the C3-position of the preformed
chromone core structure, in which multiple synthetic steps
are requisite. Not surprisingly, this method was employed for
incorporating fluorinated functional groups into chromone
8
argon atmosphere. Alternatively, tandem cyclization reactions
Received: November 17, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
of o-hydroxyaryl enaminone afforded 3-functionalized chro-
mone in a more step-economic manner. This pathway was
Table 1. Investigation of Reaction Conditions
9
mostly initiated by the attack of electrophiles, such as halogens,
acyl, and −SMe. Recently, we developed a method to
synthesize SCF -containing chromones by using stoichiometric
3
amounts of AgSCF and trichloroisocyanuric acid (TCCA)
3
1
0
(Scheme 1, route B). Considering the importance and impact
b
entry
catalyst
eosin Y
solvent
base
yield (%)
of CF /CF groups in drug discovery, developing practical and
2
3
1
2
3
4
5
6
7
8
9
CH Cl2
Me N
−
−
2
3
step-economic approaches to synthesize the 3-CF /CF -
2
3
rhodamine B
CH Cl2
Me N
2
3
incorporated chromones is highly desirable, which would
enrich the library of fluorinated chromones and provide
valuable synthons for the synthesis of diverse fluorine-
containing heterocyclic scaffolds.
Ir(dtbbpy) (bpy) PF6
CH Cl2
Me N
26
2
2
3
Ir(ppy)3
CH Cl2
Me N
40
2
3
Ru(bpy) PF6
CH Cl2
Me N
trace
trace
23
3
2
3
Ir(ppy)3
Ir(ppy)3
MeCN
THF
Me N
3
In recent years, photoredox catalysis has experienced a
resurgence in interest as a powerful synthetic tool for easily
Me N
3
Ir(ppy)3
DCE
Me N
3
34
11
promoting radical reactions. In particular, it was found that, in
Ir(ppy)3
acetone
DMSO
MeCN
MeOH
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
Me N
45
3
the presence of photoredox catalysts, a variety of fluorinating
1
0
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Me N
20
3
reagents, including BrCF COR and Langlois/Togni/Umemoto
c
2
11
12
Me N
trace
c
3
reagents, could effectively generate CF and CF radicals,
2
3
Me N
−
3
12
respectively, under visible light. Driven by our continued
interest in fluorination of chromones, we herein report a
visible-light driven, radical-triggered cyclization of o-hydroxyar-
13
14
15
−
18
13
Et N
3
30
DBU
trace
53
ylenaminones to easily assemble 3-CF /CF -containing chro-
2
3
16
NaOAc
mones. Prominently, in contrast to all of the previous pathways,
this developed reaction proceeds under mild conditions upon
irradiation with household LEDs, avoiding heating and the
protection of inert atmosphere.
1
1
1
2
7
8
9
K CO3
2
trace
37
KH PO4
2
d
NaOAc
68
e
0
NaOAc
46
Initially, commercially available BrCF COOEt was chosen to
a
2
Reaction conditions: 1a (0.2 mmol), BrCF COOEt (2) (5 equiv),
2
generate active CF radical species via visible-light photoredox
2
base (2 equiv), catalyst (1 mol %), solvent (2 mL), irradiation with
white LEDs (18 W), rt, 24 h. Isolated yields. The major product was
4H-chromen-4-one. 2.5 equiv of BrCF COOEt was used. 1.2 equiv
of BrCF COOEt was used.
b c
catalysis. We commenced our exploration with the reaction of
E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one
d
e
(
(
(
2
1a) with BrCF COOEt (2) under irradiation of white LEDs
2
2
18 W) (Table 1). Catalyst screening demonstrated that
Ir(ppy) was the best choice, while eosin B and rhodamine B
were found to be ineffective in promoting this reaction (Table
Scheme 2. Substrate Scope for the Synthesis of 3-CF -
Containing Chromones
3
2
a
1
, entries 1−5). Subsequently, various solvents were screened
(
Table 1, entries 6−12), and acetone was the optimal choice
with a slightly improved yield (45%, entry 9). Interestingly,
only 4H-chromen-4-one was obtained in MeCN and MeOH
(entries 11 and 12). In addition, several bases were also
evaluated in the reaction, of which NaOAc provided the highest
yield (Table 1, entries 13−18). A decrease in the amount of
BrCF COOEt (2.5 equiv) further improved the corresponding
2
yield to 68% (Table 1, entry 19). However, further reduction of
the amount of BrCF COOEt (1.2 equiv) obviously sabotaged
2
the yield of 3a (Table 1, entry 20).
To evaluate the substrate scope of this approach, various (E)-
3
-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones 1
were prepared and subjected to the optimized reaction
conditions. Generally, regardles of the electron-donating or
electron-withdrawing substituent on the benzene moiety, the
title reaction proceeded smoothly and consistently provided the
corresponding products 3a−k in moderate to good yields. It
was found that the substrate with substituents at the para-
position of phenol groups in compounds 1 gave lower yields
than those substituted at the meta-position (Scheme 2, 3b vs 3g
and 3j vs 3c). Meanwhile, aryl substituents were also suitable
substrates, though the corresponding yields were relatively
lower (3h and 3i). Interestingly, the introduction of a fluorine
substituent at the meta-position of the phenol moiety in 1 gave
the desired product in better yield than a methoxy group
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), BrCF COOEt (2) (0.5
2
mmol, 2.5 equiv), NaOAc (0.4 mmol, 2 equiv), Ir(ppy) (1 mol %),
acetone (2 mL), irradiation with white LEDs (18 W), rt, 24 h, isolated
yields. Performed at 1 g scale.
3
b
(Scheme 2, 3j vs 3k). The practicality and scalability of this
protocol was successfully demonstrated by performing the
B
DOI: 10.1021/acs.orglett.6b03441
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Organic Letters
Letter
reaction for 3e on a gram scale under standard reaction
conditions to give a similar yield (46%).
Scheme 4. Control Experiments and Plausible Mechanism
Subsequently, we extended this newly developed radical-
triggered cyclization to install 3-CF -substituted chromones by
3
simply replacing BrCF COOEt with various CF3 radical
2
resources. In the model reaction using 1a, it was found that
Ph SCF OTf was the optimum CF source, giving the desired
2
3
3
3
-CF -substituted chromone 5a in a good yield (80%) under
3
standard conditions. As summarized in Scheme 3, the substrate
Scheme 3. Substrate Scope for the Synthesis of 3-CF -
3
a
Containing Chromones
attacked the CC of substrate 1 regioselectively to give radical
intermediate B. It was then quickly oxidized by [Ir(IV)
+
(
ppy) ] to form iminium intermediate C with the concurrent
3
regeneration of [Ir(ppy) ], which presumably contributed to
3
the excellent regioselectivity in the process of the insertion of
radical A. Subsequent cyclization of intermediate C gave di/
trifluoromethylated intermediates D. Ultimately, the N,N-
dimethyl group of intermediates D was eliminated to furnish
the desired products 3 or 5.
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), Ph SCF OTf (4) (0.4
2
3
In conclusion, we successfully developed a facile and general
synthetic route accessing a range of 3-CF /CF -containing
mmol, 2 equiv), NaOAc (0.4 mmol, 2 equiv), Ir(ppy) (1 mol %),
acetone (2 mL), irradiation with white LEDs (18 W), rt, 6 h, isolated
yields.
3
2
3
chromones via visible-light photoredox catalysis under mild
conditions. Preliminary mechanistic investigations indicated
that a radical-triggered tandem cyclization was involved in this
transformation. More importantly, this photoredox catalytic,
radical-triggered cyclization would offer a novel pathway to
access diverse fluorinated heterocycles.
scope of this reaction was quickly investigated. In general, the
yields for CF3 radical-triggered cyclization product 5 are
superior to those of CF -containing analogues 3. Notably, the
2
introduction of a halogen substituent at the para-position of the
phenol moiety in 1 led to a significant decrease in the
corresponding yields (Scheme 3, 5c−e). Otherwise, good yields
were generally achieved, and diverse functional groups were
well tolerated. Additionally, the structure of 5f was confirmed
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03441.
14
by X-ray crystallographic analysis.
To gain mechanistic insight into the reaction, several control
experiments were carried out. The desired products were not
obtainable in the absence of photocatalyst or light (Scheme 4,
conditions a/b), revealing that this transformation is a
photocatalytic process. When 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO), as a radical inhibitor, was added into the
reaction under standard conditions, no desired product was
detected (Scheme 4, conditions c). This result indicates that a
radical pathway may be involved in this transformation.
Moreover, when 4H-chromen-4-one was subjected to the
standard conditions, the desired products still could not be
achieved.
X-ray data for compound 5f (CIF)
1
13
General experimental information and H and C NMR
of new compounds (PDF)
AUTHOR INFORMATION
■
*
*
Corresponding Authors
E-mail: xqchen@csu.edu.cn.
E-mail: hyangchem@csu.edu.cn.
ORCID
On the basis of the obtained results, a plausible mechanism is
proposed in Scheme 4. Initially, the excited state [Ir(ppy) ]*
3
Hua Yang: 0000-0002-7404-4247
Notes
was generated under visible light irradiation and then oxidized
+
by BrCF COOEt or Ph SCF OTf to generate [Ir(IV) (ppy) ]
2
2
3
3
complex and R radical species A. Subsequently, the R radical
The authors declare no competing financial interest.
F
F
C
DOI: 10.1021/acs.orglett.6b03441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
12) For selected reviews and reported on fluoroalkylation reactions
ACKNOWLEDGMENTS
■
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Q.; Pan, C.; Cheng, Y.; Zhu, C. Chem. - Eur. J. 2013, 19, 14039.
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21576296 and
1676302) and Central South University.
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768. (e) Yu, C.; Iqbal, N.; Park, S.; Cho, E. J. Chem. Commun. 2014,
0, 12884. (f) Barata-Vallejo, S.; Bonesi, S. M.; Postigo, A. Org. Biomol.
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