Regioselective construction of diverse and multifunctionalized 2-hydroxybenzophenones for sun protection by indium(III)-catalyzed benzannulation

Article abstract of DOI:10.1039/c6cc02381a

Diverse and functionalized 2-hydroxybenzophenone derivatives were synthesized efficiently in good to excellent yield via the highly regioselective indium(iii)-catalyzed [2+2+2] benzannulation of 3-formylchromones with β-enamino esters or β-enamino ketones

Full text of DOI:10.1039/c6cc02381a

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Regioselective construction of diverse and
multifunctionalized 2-hydroxybenzophenones for sun
Cite this:DOI: 10.1039/c6cc02381a
protection by indium(III)-catalyzed benzannulation†
Received 18th March 2016,
Accepted 22nd April 2016
Hongyun Cai, Likai Xia and Yong Rok Lee*
DOI: 10.1039/c6cc02381a
www.rsc.org/chemcomm
Diverse and functionalized 2-hydroxybenzophenone derivatives
were synthesized efficiently in good to excellent yield via the highly
regioselective indium(III)-catalyzed [2+2+2] benzannulation of
3-formylchromones with b-enamino esters or b-enamino ketones.
This benzannulation reaction proceeds via a domino Michael/retro-
Michael/6p-electrocyclization/deformylation reaction. In addition,
2-hydroxybenzophenones were also prepared by the indium(III)-
catalyzed [4+2] benzannulation reaction between 3-substituted
chromen-4-ones and b-enamino esters or b-enamino ketones. Further-
more, the effects of substituents and p conjugation on the character-
istics of the UV-Vis spectrum of synthesized 2-hydroxybenzophenones
were examined. Compound 10s exhibited higher sun protection activity
than oxybenzone which is used in most popular sunscreens.
Fig. 1 Representative examples of benzophenone-containing drugs and
sun-protecting materials.
products (e.g. sunscreens) that prevent ultraviolet light from
passing through the skin.15
Owing to their important bioactivities and pharmaceutical
applications, a number of synthetic approaches for the prepara-
tion of benzophenones and their derivatives have been developed.
The classical strategies involve mainly Friedel–Crafts acylations16
or reactions of aryllithium or magnesium reagents with aldehydes
followed by oxidation.17 Other representative examples include
palladium-catalyzed cross coupling reaction of arylboronic acids
with carboxylic acids,18 rhodium-catalyzed reaction of potassium
trifluoro(organo)borates with arylaldehydes,19 iron-catalyzed
carbonylative Suzuki reactions,20 and nickel-catalyzed addition
of arylboronic acids to nitriles21 (Scheme 1).
Benzophenone is an important structural motif, which is
present in many biologically active natural products as well as
pharmaceuticals.1 These benzophenone-based molecules have
a wide range of pharmacological properties, such as anti-
oxidant,2 antityrosinase,3 antibacterial,4 antifungal,5 antiviral,6
cytotoxicity,7 anti-HIV,8 anticancer,9 anti-hepatitis B,7 and
Mycobacterium tuberculosis (Mtb) pantothenate synthetase inhi-
bitory activities.10 Fig. 1 shows some commercially available
drugs and sun-protection materials that contain a benzo-
phenone moiety. For example, ketoprofen (1) is a nonsteroidal
anti-inflammatory drug (NSAID) with analgesic and antipyretic
effects.11 Tolcapone (2, brand name Tasmar) is used to treat
Parkinson’s disease.12 Fenofibrate (3), which is marketed as
Tricor, is used mainly to reduce the cholesterol levels in patients
at risk of cardiovascular disease.13 In addition, benzophenones
are also used widely as photosensitizers and represent one of the
most important substance classes in photochemistry.14 In parti-
cular, UV-A/B filters, such as 2-hydroxybenzophenones (4–7) are
the most commonly used active ingredients in sun protection
Although many methods have been developed for the synthesis
of benzophenones through typical procedures and transition-metal
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749,
Republic of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631;
Tel: +82-53-810-2529
Scheme 1 Transition-metal-catalyzed coupling reactions for the construc-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6cc02381a
tion of benzophenones.
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Table 1 Optimization of reaction conditions for the synthesis of 10a
catalyzed reactions, there are no examples for the direct construc-
tion of 2-hydroxybenzophenones utilizing indium(III)-catalyzed
benzannulation. For 2-hydroxybenzophenones, Me3SiOTf-catalyzed
domino reaction of 1-aryl-1,3-bis(silyloxy)buta-1,3-dines and
3-formylchromones via formal [3+3] cycloaddition has been
reported.22 On the other hand, environmentally benign and
efficient approaches for the direct construction of highly function-
alized and diverse 2-hydroxybenzophenones from commercially
available starting materials are still desirable. In this regard,
benzannulation is one of the most important and valuable
strategies for the construction of desirable aromatic rings, which
prompt us to develop new approaches for the synthesis of
2-hydroxybenzophenones. Over the previous few years, a range
of benzannulation reactions have been developed for forming
highly substituted benzenes.23 Recently, the transition-metal-free
multicomponent benzannulation reactions of sodium sulfonate
with 4-bromocrotonate and a,b-unsaturated aldehydes24 or 1,3-
dicarbonyls with nitroalkenes and dialkyl acetylenedicarboxylates
have been described for the preparation of diverse benzene
rings.25 To the best of our knowledge, there is no report on
multicomponent benzannulation between 4-oxo-4H-chromene-
3-carbaldehydes and b-enamino esters or b-enamino ketones. We
became interested in the benzannulation reactions as a powerful
means of synthesizing a variety of aromatics and hetero-
aromatics, such as biaryls,26 anthraquinones and tetracene-
diones,27 carbazoles,28 and pyridines.29 As part of an ongoing
Entry
Catalyst (mol%)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
1,4-Dioxane
Toluene
THF
24
24
24
24
15
12
8
0
0
0
Hf(OTf)4 (5)
Y(OTf)3 (5)
Yb(OTf)3 (5)
Cu(OTf)2 (10)
AgOTf (10)
ln(OTf)3 (5)
ln(OTf)3 (2)
ln(OTf)3 (10)
ln2O3 (30)
ln(acac)3 (30)
lnCl3 (10)
0
25
75
85
72
83
Trace
50
20
25
15
10
20
14
75
65
0
8
8
9
10
11
12
13
14
15
16
17
18
19
20
24
15
15
15
15
15
15
15
10
12
24
lnBr3 (10)
ln(OTf)3 (5)
ln(OTf)3 (5)
In(OTf)3 (5)
ln(OTf)3 (5)
ln(OTf)3 (5)
ln(OTf)3 (5)
ln(OTf)3 (5)
EtOH
DMSO
H2O
a
Reaction conditions: 8a (0.5 mmol), 9a (1.1 mmol), solvent (5.0 mL),
b
room temperature. Isolated yield.
study in this area, this paper reports the direct one-pot construction lowered the yield of 10a (entries 8 and 9). With other indium
of diverse 2-hydroxybenzophenones by the indium(III)-catalyzed catalysts, the yield of 10a did not improve (entries 10–13). In other
benzannulation of readily available 4-oxo-4H-chromene-3-carbalde- non-/low-polar solvents, 10a was produced in 10–20% yield
hydes with b-enamino esters or b-enamino ketones (Scheme 2, (entries 14–17), whereas 10a was produced in polar solvents such
eqn (1)). As an application of this protocol, this paper also describes as ethanol and dimethylsulfoxide in 75 and 65% yield, respectively
novel benzannulation between 3-substituted chromenones and (entries 18 and 19). On the other hand, 10a was not obtained in
b-enamino esters or b-enamino ketones for producing a range water (entry 20). Among the tested Lewis acids, In(OTf)3 exhibited
of 2-hydroxybenzophenones (Scheme 2, eqn (2)).
superior catalytic efficiency to other Lewis acids, which would be
To produce 2-hydroxybenzophenones, we first examined the attributed to their charge density.30 Furthermore, the recently
reaction of 3-formylchromone (8a) with 9a in the presence of reported density functional theory (DFT) calculations showed that
several catalysts. The results are depicted in Table 1. No products low LUMO levels of In(OTf)3 would be responsible for the for-
were produced in the absence of a catalyst (entry 1). The initial mation of stable coordination intermediate with carbonyl com-
attempts with rare-earth metal triflates, such as Hf(OTf)4, Y(OTf)3, pounds,31a and the strong affinities with carbonyl groups were
or Yb(OTf)3, in acetonitrile at room temperature for 24 h, did not also observed in other In(OTf)3-catalyzed reactions.31b
provide any of the desired products, but the reaction materials
Under the optimized conditions, this study further explored the
decomposed (entries 2–4). Other metal triflates were also generality of this benzannulation reaction employing different
screened, and the best yield (85%) was achieved with 5 mol% of 3-formylchromones 8a–8l (Fig. S1, ESI†) with various b-enamino
In(OTf)3 in acetonitrile at room temperature for 8 h (entries 5–7). esters 9a–9d (Table 2). The reactions of 8a with b-enamino esters
Decreasing In(OTf)3 to 2 mol% or increasing In(OTf)3 to 10 mol% 9b–9d bearing ethyl, prenyl, or benzyl group on the ester moiety
provided the corresponding products 10b–10d in 92, 81, and 78%
yield, respectively. Next, the reactions of 8b bearing an electron-
donating group on the benzene ring with 9a, 9c, or 9d in MeCN at
room temperature for 6–18 h afforded 2-hydroxybenzophenones
10e–10g in 82, 72, and 75% yield, respectively. Similarly, reactions
of 8c–8e bearing other electron-donating groups with b-enamino
esters 9a–9d provided the corresponding 2-hydroxybenzophenones
10h–10l in 68–78% yield. Further reactions of 3-formylchromones
bearing electron-withdrawing groups on the benzene ring were
also successful. A combination of 8f–8i with b-enamino esters
9a–9d gave the desired products 10m–10s in 80–91% yield. With 8j
Scheme 2 Our strategy for the construction of diverse and various
2-hydroxybenzophenones by [2+2+2] and [4+2] benzannulation.
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Table 2 Formation of diverse 2-hydroxybenzophenones 10b–10x by
reactions of 3-formyl chromones 8a–8l with various b-enamino esters 9a,b
Table 4 Formation of 2-hydroxybenzophenones 14a–14r by reaction of
3-functionalized chromen-4-ones 13a–13m with b-enamino esters 9 or
b-enamino ketones 11
a
Reaction conditions: chromene-3-carbaldehyde (0.5 mmol), b-enamino
b
ester (1.1 mmol), ln(OTf)3 (5 mol%), acetonitrile (5.0 mL). Isolated
yields. Reaction was carried out at 60 1C.
c
or 8k bearing two substituents on the benzene ring, products
10t–10v were produced in 81, 75, and 78% yield, respectively.
Interestingly, with 8l, the desired products 10w and 10x were
formed in 75 and 78% yield, respectively.
The scope of the reaction was extended further by employing
3-formylchromones 8a, 8d, 8f, or 8m and other b-enamino ketones
11a–11c as shown in Table 3. When 8a, 8d, 8f, or 8m were treated
with 11a under optimized reaction conditions, products 12a–12d
were formed in 75, 70, 83, and 75% yield, respectively. Further-
more, the treatment of 8d or 8m with 11b or 11c containing
substituted acetophenone groups also provided the desired pro-
ducts 12e and 12f in 85 and 82% yield, respectively.
This benzannulation reaction was further applied to various
3-functionalized chromen-4-ones for the construction of diverse
2-hydroxybenzophenones (Table 4). The reaction of 13a with 9b
at room temperature for 3 h provided 14a in 91% yield, whereas
the treatment of 13b with 9c or 9d afforded the desired products
14b and 14c in 90 and 88% yield, respectively. With chromenyl
acrylates 13c–13e bearing electron-donating groups on the
chromen-4-one ring, products 14d–14f were produced in 92,
86, and 81% yield, respectively. Similarly, reactions of other
chromenyl acrylates 13f–13h with bearing electron-withdrawing
groups on the chromen-4-one ring provided the desired products
14g, 14h, and 14i in 87, 86, and 83% yield, respectively. Combi-
nation of chromenylacrylates 13i or 13j bearing two substituents
on the benzene ring with b-enamino esters afforded the products
14j and 14k in 82 and 78% yields. Further reaction of 13a with
b-enamino ketone 11a gave product 14l in 92% yield. In the cases
of chromenones 13k and 13l bearing 3-oxobutenyl or chalcone
group at the 3-position, the desired products 14m–14p were
formed in 82–92% yield. Importantly, reactions of 13m bearing
an acrylonitrile group at the 3-position instead of carbonyl
groups with the corresponding b-enamino esters provided products
14q and 14r in 81 and 75% yield, respectively.
Table 3 Formation of 2-hydroxybenzophenones 12a–12f by reaction
3-formyl chromones 8a, 8d, 8f and 8m with b-enamino ketones 11a–11ca,b
Based on the observed products and control experiments
(Scheme S1, ESI†), the mechanism for the formation of 10a can
be explained as shown in Scheme 3. The 3-formylchromone 8a
first gives complex A in the presence of In(OTf)3 catalyst to
enhance the reactivity of Michael-type addition,32 which is followed
by nucleophilic attack by 9a to afford intermediate B. A subsequent
a
Reaction conditions: chromene-3-carbaldehyde (0.5 mmol), b-enamino
ketone (1.1 mmol), catalyst ln(OTf)3 (5 mol%), acetonitrile (5.0 mL).
b
c
Isolated yields. Reaction was carried out at 60 1C.
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This study was supported by the National Research Founda-
tion of Korea (NRF) grant funded by the Korea government
(MSIP) (NRF-2014R1A2A1A11052391) and the Nano Material
Technology Development Program (2012M3A7B4049675).
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