Visible-Light-Induced External Radical-Triggered Annulation to Access CF2-Containing Benzoxepine Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b00131

A facile and diversified synthesis of functionalized CF₂-containing benzoxepine derivatives via photoredox catalysis was achieved in this work. This novel protocol features broad substrate scope, mild reaction conditions, operational simplicity, easy scale-up, and versatile derivatization, which would facilitate its practical and broad applications in the construction of valuable and synthetically challenging heterocycles.

Full text of DOI:10.1021/acs.orglett.8b00131

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced External Radical-Triggered Annulation To
Access CF2‑Containing Benzoxepine Derivatives
Haoyue Xiang,† Qing-Lan Zhao,† Peng-Ju Xia,† Jun-An Xiao,‡ Zhi-Peng Ye,† Xiong Xie,† Huan Sheng,†
Xiao-Qing Chen,*,† and Hua Yang*,†
†College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
‡College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning 530000, China
S
* Supporting Information
ABSTRACT: A facile and diversified synthesis of function-
alized CF2-containing benzoxepine derivatives via photoredox
catalysis was achieved in this work. This novel protocol
features broad substrate scope, mild reaction conditions,
operational simplicity, easy scale-up, and versatile derivatiza-
tion, which would facilitate its practical and broad applications
in the construction of valuable and synthetically challenging
heterocycles.
enzoxepines and their derivatives, as representative seven-
membered cyclic ethers, are widely encountered structural
emerged to rapidly install functionalized benzoxepines,4 which
primarily relied on the metal-mediated cyclizations, such as
palladium,4a rhodium,4d osmium,4e gold,4f and silver.4g Despite
these impressive advances, in view of step-economy and green
and sustainable chemistry, pursuing new annulation pathways
accessing such valuable ring systems with higher bond-forming
efficiency under mild conditions is of continued interest.
B
motifs in many natural products and pharmaceuticals1 (Figure 1)
Radical-triggered cascade reactions serve as ideal strategies in
the synthesis of heterocyclic scaffolds, owing to multiple bonds
which can be formed under a single set of reaction conditions. In
recent years, photoredox catalysis has experienced a resurgence
in interest as a powerful synthetic tool for effectively promoting
radical-involved transformations.5 Particularly, the visible-light-
induced radical addition cascade annulation has demonstrated its
synthetic utility in the construction of various ring systems6 but
has rarely been extended to the assembly of a seven-membered
cyclic system, especially benzoxepine. In a recent report
describing photoredox catalytic cyclization of enaminones
promoted by fluorinated radicals to synthesize fluorinated
chromones,7 we demonstrated that the CC double bond in
the enaminone motif showed an advantageous reactivity in the
radical addition. Concurrently, the amino group acted as an
excellent reductive quencher to regenerate the corresponding
photocatalyst and drive the progress of the photocatalytic
reaction while avoiding the need of adding stoichiometric
reductants. We envisioned that merging an enaminone moiety
with other functionality by rational design would provide a
versatile photocatalytic platform in the assembly of challenging
ring systems. Following this rationale, we intentionally
preinstalled an enaminone moiety and olefin unit in the substrate
Figure 1. Representative examples of important molecules containing a
benzoxepine core skeleton.
with a variety of physiological and biological activities. Thus,
development of efficient strategies to easily assemble this
significant scaffold has received considerable attention.
Unlike five- and six-membered cyclic ethers, the construction
of seven-membered ethers may be more problematic due to
unfavorable entropic penalties and transannular interactions
associated with their formation.2 While challenging, the synthesis
of benzoxepines has attracted intensive efforts to answer the
needs of synthetic and medicinal chemistry. Generally, two major
strategies accessing benzoxepines, intermolecular and intra-
molecular modes, predominately contributed to the progress of
the methodology. A variety of transition-metal-catalyzed
intermolecular [m + n]-cyclizations have been developed to
construct this important heterocycle.3 Very recently, the groups
of Jiang,3g Ren,3h and Meng3i reported base-mediated [4 + 3]-
annulation. Alternatively, various intramolecular annulations
Received: January 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
and thus designed novel precursors (E)-1-(2-(allyloxy)phenyl)-
3-(substituted amino)prop-2-en-1-ones 1 that can be readily
synthesized from o-hydroxyacetophenones (Scheme 1).
Table 1. Investigation of Reaction Conditions
Scheme 1. Strategy Accessing Seven-Membered Cyclic Ethers
b
entry
catalyst
eosin Y
solvent
base
yield (%)
1
2
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
MeCN
THF
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
trace
trace
30
rhodamine B
3
Ir(dtbbpy)(bpy)2PF6
Ir(ppy)3
4
18
5
Ru(bpy)3PF6
12
6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
15
It was commonly accepted that the chemical and physical
properties of heterocycles could be readily altered upon
introduction of fluorinated functional groups, which is beneficial
for modulating their biological activities.8 Given the recent
success on the difunctionalization of alkenes9 and the
significance of difluorinated analogues in medicinal chemistry,
2-bromo-2,2-difluoroacetic acid ethyl ester (BrCF2COOEt)10
could be considered an ideal fluorinated radical source. As part of
our continued interest in the photoredox catalysis,7,11 we
reasoned that simultaneous assembly of benzoxepines and
installment of the CF2 unit can be easily realized under
photocatalytic conditions (Scheme 1). We, herein, report a
visible-light-driven external radical-triggered intramolecular
annulation to efficiently assemble CF2-bearing benzoxepines,
which would surely enrich the library of diverse fluorine-
containing seven-membered heterocycles.
7
Me3N
18
8
DBU
trace
trace
<10
22
9
K2CO3
KH2PO4
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
14
DCE
34
CH2Cl2
DMF
42
trace
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40c
d
57
e
52
d,f
Ir(dtbbpy)(bpy)2PF6
Ir(dtbbpy)(bpy)2PF6
d,g
d,h
a
We commenced our exploration with the reaction of (E)-1-(2-
(allyloxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (1a) with
BrCF2COOEt (2) under irradiation of white LEDs (30 W)
(Table 1). Catalyst screening demonstrated that Ir(dtbbpy)-
(bpy)2PF6 was the premium choice, whereas eosin Y and
rhodamine B were ineffective in this reaction (Table 1, entries 1−
5). Noticeably, it was found that the enamine group was
unexpectedly hydrolyzed, giving benzoxepine 3a bearing a 1,3-
dicarbonyl functional group as the corresponding enol.
Conceivably, the resulting 1,3-dicarbonyl moiety offers broader
synthetic opportunities for further derivatization of the resulting
benzoxepines. Subsequently, several bases were also evaluated in
the reaction, of which NaOAc provided the highest yield (Table
1, entries 6−10). In addition, various solvents were also screened
(Table 1, entries 11−16), and CH2Cl2 was the optimal choice
with a slightly improved yield (42%, Table 1, entry 14). Further
increasing the amount of the catalyst did not improve the
chemical yield (Table 1, entry 17). Because water is necessary for
this transformation, 0.4 mL of H2O (CH2Cl2/H2O = 10:1) was
added to this system, and desired product 3a was obtained in
57% yield. However, adding more water led to a slightly
decreased yield. To gain mechanistic insight into the reaction,
several control experiments were carried out. The desired
product could not be obtained in the absence of photocatalyst or
light (Table 1, entries 20 and 21), revealing that this
transformation is a photocatalytic process. When TEMPO, as a
radical inhibitor, was added into the reaction, no desired product
was detected (Table 1, entry 22). This result indicates that a
radical pathway may be involved in this transformation.
Reaction conditions: 1a (0.4 mmol), BrCF2COOEt (2) (2.5 equiv),
base (2 equiv), catalyst (1 mol %), solvent (4 mL), irradiation with
b
c
white LEDs (30 W), rt, 48 h. Isolated yields. 5 mol % of catalyst was
d
e
used. 0.4 mL of water was added. 1 mL of water was added.
f
g
h
Without catalyst. Without light. 3 equiv of TEMPO was added.
Scheme 2. Substrate Scope for the Synthesis of CF2-Bearing
a
Benzoxepines
a
Reaction conditions: 1 (0.4 mmol, 1 equiv), 2 (1.0 mmol, 2.5 equiv),
NaOAc (0.8 mmol, 2 equiv), Ir(dtbbpy)(bpy)2PF6 (1 mol %),
CH2Cl2/H2O (4 mL/0.4 mL), irradiation with white LEDs (30 W), rt,
48 h, isolated yields.
evaluated, which were generally tolerated well in this protocol.
Specifically, for the substituent at the para-position of the phenol
group in the substrate, the presence of a methoxy group evidently
undermined the yield while other substituents consistently
provided moderate to good yields (Scheme 2, 3b−3f). The
electronic feature of substituents at the meta-position of the
To evaluate the substrate scope of this approach, various (E)-
1-(2-(allyloxy)phenyl)-3-(dimethylamino)prop-2-en-1-ones 1
were prepared and subjected to the optimized reaction
conditions. As summarized in Scheme 2, the substitution
patterns on the phenyl moiety were first modulated and
B
DOI: 10.1021/acs.orglett.8b00131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
phenol moiety slightly affected the efficacy of this reaction, and
thus comparable chemical yields were secured (Scheme 2, 3g−
3j). Disubstituted products 3k and 3i were also successfully
prepared in moderate yields. It is noteworthy that the
preparation of the corresponding products bearing Cl or Br
would facilitate the expansion to a wider variety of functionalized
benzoxepines through subsequent cross-coupling reactions. In
contrast to the unsubstituted olefin substrate, the Me-substituted
counterpart 1m was unable to proceed in the cyclization.
Encouraged by the above results, we next turned our attention
to the effects of N-substituents (as illustrated in Scheme 3).
Scheme 4. Scale-Up and Synthetic Utility of This Reaction
Scheme 3. Variation of Enaminone for the Synthesis of CF2-
Bearing Benzoxepines
a
a
Reaction conditions (all of the reactions were not optimized): (a)
Et3N, 2-chlorobenzoyl chloride, CH2Cl2, rt; (b) NaOAc, EtOH, reflux;
(c) 4-chlorophenylhydrazine hydrochloride, EtOH, reflux for 30 min
then NaOAc; (d) ethyl 2-amidinoacetate hydrochloride, NaOAc,
EtOH, rt.
ester 6 in 75% yield. Interestingly, deformylation was observed
when treating 3a with NaOAc in EtOH under reflux, leading to
the deformylated derivative 7. Fused tricyclic analogues 8 and 9
could be effectively assembled by treating 3a with 4-chloro-
phenylhydrazine hydrochloride and ethyl 2-amidinoacetate
hydrochloride, respectively.12 Notably, such fused tricyclic
benzoxepine analogues exhibited attractive anticancer activity
in the previous studies.1e,f Thus, the operational ease and
diversity for the derivatization of the as-prepared products could
greatly broaden the versatility for this protocol in drug discovery.
On the basis of the obtained results in Table 1, a plausible
mechanism is proposed in Scheme 5. Initially, the excited state
a
Reaction conditions: 4 (0.4 mmol, 1 equiv), BrCF2COOEt (2) (1.0
mmol, 2.5 equiv), NaOAc (0.8 mmol, 2 equiv), Ir(dtbbpy)(bpy)2PF6
(1 mol %), CH2Cl2/H2O (4 mL/0.4 mL), irradiation with white LEDs
(30 W), rt, 48 h, isolated yields.
Scheme 5. Plausible Mechanism
Differently, under the standard conditions, N-monosubstituted
substrates 4 gave the corresponding benzoxepines 5 with the
amino groups remaining, even in the presence of water.
Presumably, the final deamination step was significantly hindered
by the inherently inert leaving capability of primary amino groups
in substrate 4. Given the fact that amino groups widely
encountered structural fragments in many pharmaceuticals,
modification of the amino group further diversifies the structural
features of benzoxepines. As water seemed unnecessary in this
transformation, we attempted to remove water from the reaction
system, but a decreased yield was obtained. Both acyclic and
cyclic substituents on amines were well tolerated in the reaction.
Similar yields were achieved for the acyclic substrates (Scheme 3,
5a and 5b). For those bearing cyclic substituents, the five-
membered analogue gave a relatively higher yield (Scheme 3,
5c−5f). Meanwhile, diversely substituted benzylamines were
also tolerated (Scheme 3, 5g−5o). Finally, the structure of 5g
was confirmed by X-ray crystallographic analysis.
Noticing the mildness of the reaction conditions, we exploited
the practicality and scalability of this protocol. Thus, the title
reaction for enaminones 1a was performed at gram scale under
the standard reaction conditions, which proceeded smoothly to
give the corresponding product 3a in 62% yield without any loss
of efficiency. As expected, benzoxepine 3 can be readily
transformed into other interesting derivatives owing to the
presence of 1,3-dicarbonyl functional groups (Scheme 4). First,
esterification of 3a by acyl chloride was achieved easily to furnish
[Ir(dtbbpy)(bpy)2PF6]* was generated under visible-light
irradiation, which was further oxidized by BrCF2COOEt to
generate [Ir(IV) (dtbbpy)(bpy)2PF6]+ complex and RF radical
species A. Subsequently, the RF radical attacked the propenyl
group of substrate 1 or 4 chemoselectively to generate a
sequential radical addition cascade process, giving radical
intermediate B. It was then quickly oxidized by [Ir(IV)
(dtbbpy)(bpy)2PF6]+ to form iminium intermediate C with the
concurrent regeneration of [Ir(dtbbpy)(bpy)2PF6]. The result-
ing iminium ion C was quickly hydrolyzed by water to furnish the
final product 3 (path a). In the case of the monosubstituted
iminium ion, the deprotonation followed by tautomerization
would ultimately provide the corresponding enamine 5 (path b).
In conclusion, we successfully developed a facile and
diversified protocol accessing a range of CF2-containing
benzoxepines via visible-light photoredox catalysis under mild
conditions. Moreover, the scalability of the reaction and
versatility of the transformations for the obtained benzoxepines
would greatly broaden the practical applications of the developed
protocol in drug discovery. The design and application of
C
DOI: 10.1021/acs.orglett.8b00131
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00131.
1
General experimental information and copies of H and
13C NMR of new compounds (PDF)
Accession Codes
CCDC 1815308 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xqchen@csu.edu.cn.
*E-mail: hyangchem@csu.edu.cn.
ORCID
Haoyue Xiang: 0000-0002-7404-4247
Hua Yang: 0000-0002-5518-5255
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (Nos. 21776318,
21676302, and 81703365), China Postdoctoral Science
Foundation (2017M610504), and Central South University.
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DOI: 10.1021/acs.orglett.8b00131
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