Synthesis of dibenzocycloketones by acyl radical cyclization from aromatic carboxylic acids using methylene blue as a photocatalyst

Article abstract of DOI:10.1039/c9gc02380a

An efficient intramolecular radical cyclization reaction via photoredox catalysis was developed for the synthesis of dibenzocycloketone derivatives using methylene blue as a photosensitizer. This strategy could be widely used to synthesize large heterocycles due to the unique reactivity of phosphoranyl radicals formed by a polar/SET crossover between an aromatic carboxylic acid and a phosphine radical cation. Attractive features of this process include generation of an acyl radical by an inexpensive and metal-free photocatalyst, which effectively undergoes a cyclization process.

Full text of DOI:10.1039/c9gc02380a

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DOI: 10.1039/C9GC02380A
R2
O
O
O
O
via -scission and intramolecular

R1
R1
acyl radical cyclization
OH
R2
O
Methylene blue, PPh , h

3
O
33 examples
49%-83%
Metal-free
Methylene blue as photocatalyst
Carboxylic acids as substrate



Mild conditions


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DOI: 10.1039/C9GC02380A
ARTICLE
Synthesis of Dibenzocycloketones by Acyl Radical Cyclization from
Aromatic Carboxylic Acids via Methylene Blue as Photocatalyst
Hongshuo Jiang,a,b Guijie Mao,a Hongfeng Wu,a,b Qi An,a,b Minghui Zuo,a,b Weihao Guo,a,b Chunzhao
Received 00th January 20xx,
Accepted 00th January 20xx
Xu,a,b Zhizhong Sun, *a,b and Wenyi Chu*a,b
DOI: 10.1039/x0xx00000x
An efficient intramolecular radical cyclization reaction via photoredox catalysis was developed for synthesis of
dibenzocycloketone derivatives by using methylene blue as photosensitizer proceeds. This strategy could be widely used to
synthesize large heterocycles by the unique reactivity of phosphoranyl radicals formed by the polar/SET crossover between
aromatic carboxylic acid and phosphine radical cation. Attractive features of this process include generation of acyl radical
by inexpensive and metal-free photocatalyst, which effectively undergoes cyclization process.
wastewater in the process of post-treatment.6 In this
circumstance, cross-couplings involving C−H bond activation
catalyzed by transition-metal has been emerged as a good
Introduction
Dibenzocycloketone derivatives are ubiquitous structural
motifs found in natural products, biologically active molecules,
as well as functional materials (Scheme 1).1 More specifically,
with the feature of anti-HIV-1,2 anti-cancer3 and anti-
inflammatory,4 the study of dibenzocycloketone derivatives has
become a promising field of organic chemistry.
method for the construction of a carbon–carbon skeleton.7
Nevertheless, transition metal catalysis requires the substrate
with a suitable structure for connecting the metal center and
reaction site, which limits the selection range of the substrate.8
Moreover, there are reports of other methods of building this
skeleton structure such as intramolecular Minisci acylation,9
intramolecular dehydrogenative cyclization,10 trifluorotoluene
hydrodefluorination reaction,11 and intramolecular homolytic
acylation by corresponding selenoesters.12 Despite of the
advances in the synthesis of dibenzocycloketone derivatives,
these methods still suffered from the need for harsh reaction
conditions, the limited structural diversity and the functional
group tolerability.
OH HO
O
OH
O
O
OH
OH
HO
O
Cl
O
O
O
O
O
Cl
OH
HO
Garbogiol
Arugosin F
Pestalachloride B
OH
OH
N
Carboxylic acids is attractive and widely by using synthon to
make acyl radical, because carboxylic acids as starting materials
O
HO
HO
O
HO
HO
O
O
O
are not only abundant and inexpensive but also readily available
O
13
Doxepin
Protosappanin A
Caesalpin P
in great structural diversity.
In recent years, the novel
Scheme 1. Dibenzocyclocketones natural products and drugs.
application of visible-light photoredox catalysis to organic
synthesis has emerged as an efficient tool, and novel strategies
targeting carboxylic acids as building blocks have been
developed.14 In particular, it has attracted attention as an ideal
way to generate radicals from decarboxylation of carboxylic
acids by photoredox catalysis.15 At present, many valuable
transformations of this carboxylic acid mode were reported. In
2015, Bergonzini and co-workers reported carboxylic acids were
used to generate acyl radicals via single-electron transfer (SET)
by means of visible-light photoredox catalysis (Scheme 2A, a).16
In 2017, Zhu and co-workers reported the first photocatalytic
intramolecular acyl radical coupling for constructing
carbon−carbon bond using a readily available carboxylic acids as
the acyl source via photoredox catalysis, which expanded new
applications of carboxylic acids in organic synthesis(Scheme 2A,
b).17 These methods can afford the acyl radical by a single
electron reduction of a mixed acid anhydride formed in situ
Therefore, there are a few synthetic strategies available for
the preparation of dibenzocycloketone. In general, this kind of
compounds is synthesized through Friedel-Crafts acylation via
electrophilic aromatic substitution catalyzed by Lewis-acid or
Brønsted-acid.5 However, excess stoichiometric acid catalyst
was required in this reaction because of forming complexation
between the ketone product and the acid catalyst, which
resulted in the waste of the catalyst and the production of acidic
a. School of Chemistry and Materials Science, Heilongjiang University, Harbin
150080, P. R. China. E-mail address:wenyichu@hlju.edu.cn. TEL/FAX: +86-451-
86609135.
b. Key Laboratory of Chemical Engineering Process & Technology for High-efficiency
Conversion, College of Heilongjiang Province, Harbin 150080, P. R. China.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
from an aromatic acid by
Journal Name
highly reducing iridium prepare dibenzocycloketone derivatives (Scheme 2C). In this
a
View Article Online
photocatalyst. In 2018, Doyle and colleagues reported the process phosphoranyl radicals coulDdOI:b1e0.103a9c/cCe9sGsCed0238v0iAa
Intramolecular acyl radical cyclizations of carboxylic acids by nucleophilic addition of an acid to a phosphine radical cation
using β-scission of phosphoranyl radicals to produce acyl generated by photoinduced single-electron transfer.24 The
radicals via expensive iridium photocatalyst (Scheme 2A, c).18 phosphoranyl radical could undergo β-scission to form a strong
This method was independent of higher substrate redox P−O double bond and acyl radical and then undergo
potentials. It is a promising advancement in photocatalytic intramolecular acyl radical cyclization.25 In addition, we
strategies. Therefore, the development of effective and anticipated that this strategy would complete the direct
inexpensive
strategies
for
direct
preparation
of conversion to the corresponding acyl radical, independent of
dibenzocycloketone from carboxylic acid will be a valuable goal. substrate-dependent redox potential and functional group
Methylene blue (MB) has seen as an organic photosensitizer properties. Ultimately, this method could be applied to
in diverse biological and medical applications.19 Since MB is a construct large heterocyclic compounds by intramolecular
acylation reaction.
A. previous work
a)
Me
O
N
O
O
O
Ir Catalyst
DMDC
N
Ph
Ph
OH
blue LEDs
Me
Ph
Table 1. Optimization of reaction conditionsa
Ph
b)
c)
O
O
O
O
O
photocatalyst
OH
OH
Ir Catalyst
DMDC
base,PPh3
OH
blue LEDs
O
solvent,O2,white LEDs,24h
O
O
2a
1a
O
O
O
Ir Catalyst
Ph2POEt, TRIP-SH
entr
y
1
catalyst
Methylene blue
Eosin Y
base
solvent
yield (%)b
blue LEDs
O
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
DMA
DMA
DMA
DMA
DMA
64
0
B. Photoinduced Redox Cycling of Methylene Blue
h
2
3
4
5
MB
O2
LMB
MB
*
N
S
Electron
transfer
O2
Fluorescein
Rhodmine B
0
N
N
+H+
Electron transfer
MB
Methylene blue
0
C. this work: Photoredox-Catalyzed Inttamolecular Radical Acylation
[Ir(dFCF3ppy)2dt
bbpy]PF6
50
R2
O
O
P
O
O
Ph
Ph
Ph
Ar
O
-scission
cyclization
6
7
Methylene blue
Methylene blue
Methylene blue
Methylene blue
K2HPO4
Cs2CO3
DABCO
TMEDA
DMA
DMA
DMA
DMA
DMA
DMF
38
26
39
42
R1
Ar
OH
P
Ar
O
Ph
Ph
Ph
O

metal-free photocatalyst
 Mild conditions
Independent of higher redox potentials
8
Scheme 2. Different approaches for acylation cyclization.
9
member of the thiazine dye family having a triplet state, the
triplet sensitizer MB and the substrate interact to form a radical,
or in the case of oxygen, produce singlet oxygen. Flash
photolysis studies have indicated that the photoreduction
occurs by electron transfer (ET) steps, producing a semireduced
MB radical (MB•) as an intermediate (Scheme 2B).20 With this
10
11
12
13
Methylene blue 2,4,6-collidine
76,70c,0(d,e)
Methylene blue
Methylene blue
Methylene blue
2,4,6-collidine
2,4,6-collidine
2,4,6-collidine
67
61
42
DMSO
CH3CN/
H2O
ox
knowledge, our aim is to use methylene blue (E1/2 = +1.13 V
14
15
Methylene blue
--
2,4,6-collidine
2,4,6-collidine
DCM/
H2O
45
0
versus SCE (Saturated Calomel Electrode))21 as photocatalyst to
develop an effective acyl intramolecular cyclization ， which
would undergo single-electron transfer (SET) process with
triphenylphosphine (Eox = +0.98 versus SCE)22 to afford a
phosphine radical cation under visible light.
DMA
a Reaction conditions: 1a (0.2 mmol), photocatalyst (2.0 mol%), PPh3 (1.5
eq.) and base (1.0 eq.) in solvent 2 ml, irradiation with white light LEDs
at 25 °C for 24 h, the reaction completed (monitored by TLC). b isolated
To our knowledge ，intramolecular acyl radical reactions is
widely used in the synthesis of five- and six-membered
dibenzocycloketones, while the synthesis of seven- and eight-
membered dibenzocycloketones is rare, especially the eight-
membered ring.23 We wondered if carboxylic acid substrates
would produce acyl radical, followed formation of
dibenzocycloketones with more complex and diverse structural
backbones by intramolecular radical cyclization. Herein, we
report a practical and simple process of acyl radical cyclization
using MB as a photocatalyst, carboxylic acid derivatives as an
acyl radical source by tetravalent phosphinecentered radicals to
c
yield by flash column chromatography. Control experiment Ph2POEt
d
e
instead of PPh3. Control experiment without white LEDs. Control
experiment without PPh .
Results and discussion
According to previous studies on the photoredox catalysis,
the conditions for the reaction were investigated by used 2-(2-
phenoxyacetyl)benzoic acid (1a) as model substrate, and the
experimental results were summarized in Table 1. As a
preliminary experiment, 1a as the substrate was irradiated
2 | J. Name., 2012, 00, 1-3
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ARTICLE
under visible light from a white LEDs in DMA at room
temperature in presence of 2,6-lutidine and PPh3 with
methylene blue as photocatalyst. The reaction gave desired
product 2a in a 64% yield in 24 h (Table 1, entry 1), showing that
this intramolecular radical cyclization is feasible. This
experimental result encouraged us to study the reaction
conditions by optimizing photocatalysts, bases and solvents.
Firstly, the photocatalyst as a crucial factor was investigated.
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Table 2. Substrates scope of the inDtrOaIm: 1o0.l1e0c3u9l/aCr9GrCa0d2ic3a8l0A
cyclization reactiona
R2
O
O
R1
R1
Methylene blue
2,4,6-collidine,PPh3
OH
R2
DMA,O2,white LEDs,24h
O
O
O
O
2
1
Me
Cl
F
Ph
O
O
O
O
O
O
ox
Dye photocatalyst was used including Eosin Y (E1/2 = +0.76 V
O
O
O
O
O
ox
versus SCE), Fluorescein (E1/2 = +0.87 V versus SCE) and
O
O
O
O
O
O
O
O
Rhodmine B (E1/2ox = +0.91 V versus SCE), no product was found
(76%)
COOMe
(83%)b
2c,
2e,
2b,
(72%)
CONMe2
2d,
(73%)
NO2
2a,
(67%)
CN
COOEt
ox
(Table 1, entries 2-4). While [Ir(dFCF3ppy)2dtbbpy]PF6 (E1/2
=
O
+0.97 V versus SCE) was used as photocatalyst, the reaction only
gave a 50% yield (Table 1, entry 5). Next, bases including
organic bases and inorganic bases were also been screened. The
use of inorganic bases K2HPO4 and Cs2CO3 gave relatively low
yields (38% and 26%) of 2a (Table 1, entries 6-7). The use of
organic bases such as triethylenediamine (DABCO) and
tetramethylethylenediamine (TMEDA) gave relatively low yields
(39% and 42%) of 2a (Table 1, entries 8-9). Use of 2,4,6-collidine
as the base in place of 2,6-lutidine gave a good yield of 76%
(Table 1, entry 10). Some aprotic solvents were also screened
as reaction solvents. Polar aprotic solvents such as DMF and
DMSO gave good yields in 67% and 61%, respectively (Table 1,
entries 11-12). The use of CH3CN/H2O (v/v=4:1) gave a low yield
in 42% (Table 1, entry 13). The use of DCM/H2O (v/v=4:1) gave
also a low yield in 45% (Table 1, entry 14). When Ph2POEt was
used instead of PPh3, the product yield was slightly reduced
(Table 1, entry 10c). There was not desired product was
detected in the control experiment without PPh3 or the light
source or the photocatalyst (Table 1, entries 10d,e and 15),
which indicated PPh3, the light source and the photocatalyst
were essential in the reaction.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2j,
2h,
2i,
(59%)
(65%)
(62%)
2g,
(69%)
2f,
(66%)
O
Me
Cl
Br
Me
OMe
O
O
O
O
O
O
2k,
O
O
2n,
O
O
(75%)
2m,
2o,
(62%)
(60%)
2l,
(63%)
Cl
(66%)
Me
F
O
O
O
O
O
Cl
Cl
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
2q,
2p,
(53%)
2t,
(61%)
Cl
(58%)
2r,
2s,
(58%)
(52%)
O
O
Cl
Cl
Me
Cl
O
O
O
O
O
Cl
O
2v,
O
O
2w,
O
O
2y,
(57%)
2u,
(73%)
(65%)
(61%)
2x,
(64%)
a
Reaction conditions: Compound 1 (0.2 mmol), methylene blue (2.0
mol%), PPh3 (1.5 eq.) and 2,4,6-collidine (1.0 eq.) in DMA 2 ml, irradiation
with white light LEDs at 25 °C for 24 h, the reaction completed
(monitored by TLC). Isolated yield after purification by column
chromatography. b The reaction was carried out on a 4 mmol gram-scale
with under standard condition (63% yield, 0.64g).
Based on the above results, optimized conditions of the
intramolecular radical cyclization were 2.0 mol% MB as the
photocatalyst, 1.5 equiv. of PPh3 as additive, 1.0 equiv. of 2,4,6-
collidine as base in DMA under irradiation visible light from
white LEDs at room temperature.
Having conditions optimized, we investigated a variety of
different carboxylic acids to expand the scope of the reaction.
Representative examples were shown in Table 2.
First, the compound 1a without substituent group gave
desired product 2a with 76% yield. Next, based on the
characteristics of the intramolecular acylation reaction, we
focus on the expansion of acylated aromatic ring (phenol part).
The substituents on para-position of the phenolic hydroxyl
group afforded the desired products 2b-2j in medium to good
yields (59–83%). By contrast, the electron-donating substituent
(-Me, 2b, 83%) was more favorable to the reaction compared
with electron-drawing substituent (-NO2, 2j, 59%). The
substituents (-Me, -Cl and -Br) on meta-position of the phenolic
hydroxyl group also gave the desired products 2k, 2l and 2m in
medium to good yields (63–75%). However, no regioisomer
formation was observed in the reaction. This may be due to the
fact that the aromatic radical cyclization process rarely exhibits
regioselectivity. While the substituents were at the ortho
position, the products (2n, 2o and 2p) were only obtained in
moderate yields (53–62%). Compared with the above
experimental results such as 2n and 2b, this reduction of yields
may be caused by the steric-hindrance effect. The carboxylic
acids with two substituents (2q, 2r and 2s) also participated in
the reaction providing similarly moderate yields (52–58%).
Furthermore, the substrate containing naphthalene (2t) also
produced the desired products in 61% of yields. Substituents on
the aromatic moiety of carboxylic acids were also tolerated.
Compared to the yields of 2u, 2w and 2x, the substituent
position showed little influence on the reaction efficiency (61%,
65% and 64%, respectively). Compared with the electron-rich
group –Me (2v), electron-deficient group –Cl (2w) on the meta
position of the carboxyl showed an obviously low reaction
activity and yield (73% and 65%, respectively). Finally, the
substituents on different aromatic rings also gave the target
product 2y in 51% of yields.
Next, we investigated the scope of heteroaromatic substrates.
3-Position of pyridine (2z) was tested and resulted in promising
yield (49%). It was noteworthy that 2- and 4- positions of the
pyridine ring gave no products. This phenomenon may be due
to the electron-deficient effect of the 2- and 4-positions relative
to the 3-position (2z).9a Moreover, heterocyclic carboxylic acid
with the indole moiety also participated in the process with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
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Table 3. Substrates scope of heteroaromatic substrates
and other linkersa
DOI: 10.1039/C9GC02380A
(a)
N
O
O
O
O
O
TEMPO
Methylene blue
2,4,6-collidine,PPh3
OH
P(O)Ph3
O
O
O
O
DMA,O2,white LEDs,24h
O
Methylene blue
O
OH
2,4,6-collidine,PPh3
O
Ar
1a
acyl radical III, 18%
2a, not fromed
DMA,O2,white LEDs,24h
X
Ar
X
(b)
O
O
1
2
Methylene blue
2,4,6-collidine,PPh3
under O2 atmosphere 2a, 75%
under N2 atmosphere 2a, 34%
OH
X = -COCH2O-, -CH2CH2-, -CH2O-,
-CH2-, -O-, -NH-, -S-
O
DMA,O2,white LEDs,24h
O
O
O
2a
O
O
1a
O
O
N
NH
O
Scheme 4. Mechanism research.
O
O
O
(Scheme 4a). The above experiment implied the involvement of
a radical species in this process. When the reaction was carried
out under O2 atmosphere, the reaction effect was hardly
affected. However, when the reaction is in an N2 atmosphere,
the reaction is inhibited (Scheme 4b). This showed that an
appropriate amount of oxygen is necessary in the reaction
system.
O
2ac,
2aa,
2ab,
(77%)
(62%)
2z,
(53%)
(81%)
(74%)
(49%)
O
O
O
O
O
N
H
S
2ad,
2ae,
2ag,
(86%)
(75%)
2af,
a Reaction conditions: Compound 1 (0.2 mmol), methylene blue (2.0
mol%), PPh3 (1.5 eq.) and 2,4,6-collidine (1.0 eq.) in DMA 2 ml,
irradiation with white light LEDs at 25 °C for 24 h, the reaction
completed (monitored by TLC). Isolated yield after purification by
column chromatography.
Based on the above experiments, a plausible mechanism for
O
H
O
H+
O2
cyclization
-
H2O2
HO2
O
O
O
TEMPO
O
O
medium yield of product 2aa (53%). Finally, we directed our
attention to delineating the scope of other linkers than alfa-
keto ethers. Pleasantly, we found that this strategy could be
applied to other linker substrates to readily build
dibenzocycloketone skeletons (2ab-2ag) in medium to good
yields (62–86%). The carbon atom linkers (2ab, 81%; 2ad, 86%)
had higher yields compared to the heteroatom linkers (2ac, 77%;
2ae, 75%; 2af, 74%; 2ag, 62%). We compared the 1H NMR data
of known compounds with previous studies, proving the correct
assignment of the proposed dibenocycloketone structure.26
A further demonstration of the value of this plan was tested
IV
acyl radical III
O2
O2
N
O
O
O
O
MB
-scission
P(O)Ph3
O
photoredox
cycle
Ph
P
2a
MB
h
O
Ph
Ph
O
O
V
MB
O
-H+
P
Ph
I
P
O
Ph
Ph
Ph
Ph
Ph
O
OH
II
O
O
1a
Scheme 5. A Plausible Mechanism.
the intramolecular radical cyclization is proposed in Scheme 5.
According to the literature reported, the intramolecular radical
cyclization tends to the ortho-position of aryl C−H component
compared to ipso position of alkyl phenol.29 The photocatalyst
MB is excited to generate MB* under irradiation of white light.
Next, a SET process of the triphenylphosphine (PPh3) is caused
by MB* to give MB• and phosphine radical cation I. Polar
nucleophilic addition to the cation with carboxylic acid would
generate phosphoranyl radical II, which upon β-scission would
generate the corresponding acyl radical III and
triphenylphosphine oxide. If excess TEMPO is add in the
reaction, the acyl radical III can be trapped to obtain the
compound V. Acyl radical III undergoes intramolecular addition
to deliver the intermediate IV. The reduced MB• was then
oxidized by the residue oxygen from the air in the reaction tube
to regenerate the ground state MB to complete the catalytic
(a)
N
HCl
1) Cl
O
Mg
N
O
Methylene blue
2,4,6-collidine,PPh3
DMA,O2,white LEDs,24h
OH
O
THF,toluene,65°C,2h
2) HCI-gas,65°C,1.5h
O
O
1ac
2ac
Doxepin Hydrochloride
(b)
O
O
Methylene blue
2,4,6-collidine,PPh3
OH
1) MeI, NaOH,rt,2h
DMA,O2,white LEDs,24h
N
H
2) PhMgBr, HClO4
CH2Cl2,rt,3h
N+
N
H
-
ClO4
2af
1af
Acr+-Mes ClO4-
Scheme 3. Preparation of Doxepin Hydrochloride and 9-
Mesityl-10-methylacridinium Perchlorate (Acr+-Mes
by the preparation of tricyclic antidepressants Doxepin
Hydrochloride, which was widely used in the treatment of
chronicpain and depression (Scheme 3
9-Mesityl-10-methylacridinium Perchlorate (Acr+-Mes ClO4 ) in
a similar way, which was a dual sensitizer with the capacity of
efficient singlet oxygen formation and electron-transfer
reaction (Scheme 3b).28
a
).27 We also synthesized
•−
cycle. At the same time, the generated O2 abstracted a
hydrogen atom from IV to provide 2a and HO2 . Finally, HO2
anion was protonated to form H2O2.
-
−
−
Two control experiments (shown in Scheme 4) were
conducted to insight into the acylation cyclization process.
When 2.0 equiv. of TEMPO was added as a radical quencher, the
reaction under standard conditions did not give desired product.
However, the formation of Acyl-TEMPO adduct and the by-
product triphenylphosphine oxide were observed in low yield
Conclusions
In conclusion, a convenient acyl radical cyclization reaction is
developed to synthesize dibenzocycloketone derivatives via
photoredox catalysis under irradiation of white light. Our
research shows that sensitizers using organic dyes as
4 | J. Name., 2012, 00, 1-3
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Green Chemistry
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photocatalysts can use low-cost materials that are
environmentally friendly in line with the concept of green
chemistry. Moreover, this method could be extended to the
gram-scale due to good functional-group compatibility and no
harsh condition. Finally, based on some experimental results
and literatures, a plausible mechanism for the intramolecular
cyclization of acyl radical is proposed. The further reactivity and
applicability of acyl radicals for the synthesis of other
heterocyclic structures by photoredox catalyzed transformation
is currently underway in our laboratory.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for financial support from the Research Project
of the Natural Science Foundation of Heilongjiang Province of
China (No. B2018012).
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Green Chemistry
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View Article Online
DOI: 10.1039/C9GC02380A
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