Eco-friendly organocatalyst- And reagent-controlled selective construction of diverse and multifunctionalized 2-hydroxybenzophenone frameworks for potent UV-A/B filters by cascade benzannulation

Article abstract of DOI:10.1039/d0gc01011a

The organocatalyst- and reagent-controlled highly selective synthesis of diversely functionalized novel 2-hydroxybenzophenone frameworks, such as 2-hydroxy-3′-formylbenzophenones, 7-(2′-hydroxybenzoyl)-2-naphthaldehydes, and 2-hydroxybenzophenones, under green conditions, for the development of potent UV-A/B filters is described. The organocatalyzed benzannulation reactions proceed individually via [3 + 3] cycloaddition for the synthesis of 2-hydroxy-3′-formylbenzophenones and [4 + 2] cycloaddition for 2-hydroxybenzophenones. With this methodology, an unprecedented double benzannulation allows one-pot construction of diverse 7-(2′-hydroxybenzoyl)-2-naphthaldehydes via [3 + 3 + 4] cycloaddition. This protocol features a broad substrate scope, high functional-group tolerance, and operational simplicity in an environmentally benign green solvent. The synthesized compounds are successfully utilized for further transformations and well characterized as potent UV-A/B filters.

Full text of DOI:10.1039/d0gc01011a

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DOI: 10.1039/D0GC01011A
ARTICLE
Eco-friendly organocatalyst- and reagent-controlled selective
construction of diverse and multifunctionalized 2-
hydroxybenzophenone frameworks for potent UV-A/B filters by
cascade benzannulation
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Muhammad Saeed Akhtar,a Raju S. Thombal,a Ramuel John Inductivo Tamargo,a Won-Guen Yang,b
Sung Hong Kim,b and Yong Rok Leea*
The organocatalyst- and reagent-controlled highly selective synthesis of diversely functionalized novel 2-
hydroxybenzophenone
frameworks,
such
as
2-hydroxy-3'-formylbenzophenones,
7-(2’-hydroxybenzoyl)-2-
naphthaldehydes, and 2-hydroxybenzophenones, under green conditions, for the development of potent UV-A/B filters is
described. The organocatalyzed benzannulation reactions proceed individually via [3+3] cycloaddition for the synthesis of
2-hydroxy-3'-formylbenzophenones and [4+2] cycloaddition for 2-hydroxybenzophenones. With this methodology, an
unprecedented double benzannulation allows one-pot construction of diverse 7-(2’-hydroxybenzoyl)-2-naphthaldehydes
via [3+3+4] cycloaddition. This protocol features a broad substrate scope, high functional-group tolerance, and operational
simplicity in an environmentally benign green solvent. The synthesized compounds are successfully utilized for further
transformations and well characterized as potent UV-A/B filters.
hydroxylation of benzophenones (Scheme 1C)16 and oxime
ethers (Scheme 1D)17 have been used for the preparation of 2-
hydroxybenzophenones. Despite the significant achievements
of these methods, there are still drawbacks in the requisite
preparation of pre-functionalized starting materials, undesired
dihydroxylation, two-step reaction conditions, and high
loading of noble metals and strong oxidants. In this context,
eco-friendly and atom-economic synthetic methods are still
highly desirable.
Recently, organocatalysts have been gradually introduced in
organic syntheses owing to their valuable advantages of being
less toxic, less polluting, more eco-friendly, and more
economically viable than stoichiometric organic reagents and
organometallic catalysts.18 In addition, transformations in
green solvents have been widely adopted by synthetic
chemists because of the increasing demand and motivation to
develop sustainable and environmentally benign protocols
with regard to safety, health, pharmaceutical, industrial, and
environmental concerns.19
Introduction
The 2-hydroxybenzophenone framework is ubiquitous in a
wide range of natural products and biologically active
molecules.1 This moiety has been used as a valuable building
block in the synthesis of various pharmaceuticals and natural
products.2 Molecules bearing 2-hydroxybenzophenone
skeletons display a wide range of biological activities, such as
antimicrobial,3 anti-inflammatory,4 antioxidant,5 anticancer,6
anticoccidial,7 anti-HIV,8 and antitubulin activities.9 In
particular, they have widely been used as valuable chemical
auxiliaries,10 sun-protection materials11 and as important
precursors for the synthesis of chiral ligands12 and
fluorophores.13 Owing to their importance and usefulness,
several synthetic methods for the synthesis of 2-
hydroxybenzophenones have been developed. Typical
methods include Fries rearrangement of phenyl esters
(Scheme 1A)14 and Friedel–Crafts acylation of phenols (Scheme
1B).15 These two reactions provided undesired para-isomers,
which were generally difficult to separate and purify. Apart
from these reactions, transition-metal-catalyzed direct C–H
aSchool of Chemical Engineering, Yeungnam University, Gyeongsan 38541,
Republic of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631; Tel: +82-53-
810-2529.
bAnalysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu
41566, Republic of Korea.
Electronic Supplementary Information (ESI) available: [Experimental procedures,
characterization data, X-ray crystallographic structure and data for 5 (CCDC
1991823) and 34 (CCDC 1991825). See DOI: 10.1039/x0xx00000x]
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Journal Name
Classical reactions
product 4 was obtained in 68, 76, and 55% yields,VrieewspAreticclteiOvenllinye,
and compound 3 was not isolated (entries 5–7). To optimize
O
DOI: 10.1039/D0GC01011A
OH
O
(A)
the formation of products 3 or 4, various solvents such as
DMSO, CH3CN, H2O, and EtOH were screened in the presence
of Cat. II (entries 8–14) or Cat. VI (entries 15–20) under various
temperature and catalyst loading conditions. The best result
(91%) for 3 was achieved by using 10 mol% of Cat. II in EtOH at
60 °C for 22 h (entry 13) and that (85%) for 4 was obtained
with Cat. VI (20 mol%) in EtOH at 80 °C for 15 h. The structures
of 3 and 4 were identified by an analysis of their spectral data.
(B)
R
R
OH
O
Fries
rearrangement
Friedel-Crafts
regioselectivity problem
R
regioselectivity problem
[Pd]
PPh3
[Pd]
O
OMe
oxone
oxidants
N
(D)
R
(C)
R
1
di-hydroxylation problem
2-steps
The H NMR spectrum of 3 showed a singlet methyl peak at
δ=2.51 ppm, a singlet peak of the formyl group at δ=10.04
ppm, three aromatic singlet peaks at δ=7.93, 7.89, and 7.73
ppm, and a phenolic OH peak at δ=11.86 ppm. In the case of 4,
Transition-metal-catalyzed C-H hydroxylations
Scheme 1. Reported strategies for 2-hydroxybenzophenone synthesis.
O
O
1
the H NMR spectrum showed a methyl peak at δ=2.42 ppm,
R1
R
R1
OH
O
H
R3
R2
H
OH O
an aromatic singlet peak at δ 7.47 ppm, and another singlet
phenolic proton peak at δ=12.03 ppm. The structure of 3 was
further confirmed by X-ray analysis of the structurally related
compound 5.
O
O
O
R3
R3
R
R1
R2
R2
R2
R
H
Cat. II
EtOH
Cat. VI
EtOH
path a
path c
R3
O
H
O
2-Hydroxy-3'-formylbenzophenones
2-Hydroxybenzophenones
Cat. II
H
Table 1. Optimization of the reaction conditions for synthesis of 3 and 4a
EtOH
OH
O
H
OH O
OH
O
O
O
O
O
OH
O
path b
7-(2'-Hydroxybenzoyl)-2-naphthaldehydes
N
H
N
H
Cat. II
Catalyst
Solvent
R
H
H
+
+
Cat. VI
4
3
1a
2a
Catalyst (mol%)
O
H
Scheme 2. Organocatalyst-controlled direct construction of divergent and novel
Yield (%)b
2-hydroxybenzophenone frameworks.
Entry
Solvent
Condition
3
4
34
5
80 oC, 15 h
80 oC, 15 h
80 oC, 20 h
23
78
35
1
2
Cat. I (20)
Cat. II (20)
Cat. III (20)
Toluene
Toluene
Toluene
We previously reported In(III)-catalyzed reactions of 3-
formylchromones with β-enamino esters for the synthesis of
simple 2-hydroxybenzophenones bearing dicarboalkoxy
groups.20 In a continuation of our studies on the development
of new green methodologies for potent UV-A/B filters, this
paper reports the atom-economical organocatalyst-controlled
selective construction of diversely functionalized novel 2-
hydroxybenzophenone frameworks, such as 2-hydroxy-3'-
formylbenzophenones (path a), 7-(2’-hydroxybenzoyl)2-2-
naphthaldehydes (path b), and 2-hydroxybenzophenones
(path c), by cascade benzannulations via [3+3], [3+3+4], and
[4+2] cycloadditions in a green solvent (Scheme 2).
3
14
4
80 oC, 20 h
65
0
Cat. IV (10)
Cat. V (20)
Cat. VI (20)
Toluene
Toluene
9
68
80 oC, 20 h
5
80 oC, 20 h
80 oC, 20 h
80 oC, 30 h
80 oC, 20 h
80 oC, 20 h
80 oC, 12 h
80 oC, 12 h
60 oC, 22 h
40 oC, 36 h
100 oC, 15 h
80 oC, 20 h
100 oC, 36 h
80 oC, 15 h
80 oC, 30 h
80 oC, 15 h
0
0
6
Toluene
Toluene
DMSO
76
55
12
9
Cat. VII (20)
Cat. II (20)
Cat. II (20)
Cat. II (20)
Cat. II (20)
Cat. II (10)
Cat. II (10)
Cat. II (10)
Cat. VI (20)
Cat. VI (20)
Cat. VI (20)
Cat. VI (20)
Cat. VI (10)
Cat. VI (30)
7
8
25
65
51
82
9
CH3CN
10
11
12
13
14
15
16
17
18
19
20
H2O
14
6
EtOH
EtOH
EtOH
trace
0
85
91
48
0
0
EtOH
DMSO
65
CH3CN
H2O
72
54
85
65
83
0
0
0
0
0
EtOH
EtOH
EtOH
Results and discussion
We first examined the reaction of 3-formylchromone (1a)
with trans-2-pentenal (2a) by using different organocatalysts
and solvents (Table 1). After the initial attempt in the presence
of 20 mol% of L-proline (Cat. I), products 3 and 4 were isolated
in 23 and 34% yields, respectively (entry 1). With 20 mol% of
(S)-diphenyl(pyrrolidin-2-yl)methanol (Cat. II), which bears
bulky groups, the yield of 3 was increased to 78%, whereas 4
was isolated in 5% yield (entry 2). If (S)-2-
(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (Cat. III) or (S)-
2-(bis(3,5-bis(trifluoromethyl)phenyl)((trimethylsilyl)
CF3
O
N
CF3
CF3
OH
N
H
N
H
H
Cat. I
O
Si
Cat. V
Cat. VI
O
Si
N
OH
N
H
H
N
H
Cat. II
N
H
Cat. III
Cat. IV
Cat. VII
CF3
aReaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), catalyst, and solvent (5.0
mL).
bYield of isolated product after column chromatography.
oxy)methyl)pyrrolidine (Cat. IV), bearing even more bulky
groups, were employed, the yield of product 3 was not
improved (entries 3 and 4). However, with pyrrolidine (Cat. V),
piperidine (Cat. VI), and diethylamine (Cat. VII) as the catalyst,
With the optimized conditions in hand, we explored the
substrate scope for the formation of 2-hydroxy-3-
2 | J. Name., 2012, 00, 1-3
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ARTICLE
formylbenzophenones by employing substituted 3-
formylchromones 1a–1n and ,β-unsaturated aldehydes 2a–
2g, and 2j (Table 2) in the presence of Cat. II. Reactions of 1b–
1e, bearing electron-donating groups (Me, i-Pr, and OMe) at
the 6- or 7-position on the chromone moiety, with 2a
proceeded smoothly, and the corresponding products 5–8
were obtained with 78–88% yields. Similarly, treatment of 1f–
1h, bearing electron-withdrawing halogen substituents (Cl, Br,
and F) at the 6-position of the chromone moiety, with 2a
successfully generated products 9–11 with 76–82% yields.
Moreover, the strong electron-withdrawing NO2 group was
well tolerated on the 3-formylchromone molecule;
corresponding product 12 was obtained with 85% yield.
Interestingly, disubstituted 3-formylchromones 1j and 1k,
bearing two electron-withdrawing groups (6,8-dichloro or 6,8-
dibromo), or 1l, with both an electron-donating and an
electron-withdrawing substituent (6-Cl and 7-Me) were also
well tolerated, and corresponding products 13–15 were
produced with 76–83% yields. In addition, treatment of 1a
with trans-2-hexenal (2b) or trans-2-heptenal (2c) proceeded
smoothly to produce the desired products 16 and 17 with 75
and 84% yields. Reactions of 1a with trans-2-octenal (2d),
trans-2-nonenal (2e), or trans-2-decenal (2f), with long chains,
afforded corresponding products 18–20 with 81–86% yields.
Similarly, the reactions of substituted 3-formylchromone 1e
and 1f, bearing substituents on the benzene ring, with 2b or 2c
were performed, and corresponding products 21–24 were
obtained with 68–79% yields. Moreover, the reaction of 3-
formylchromone (1a) with (E)-4-phenylbut-2-enal (2j) bearing
aromatic substituent afforded the desired product 25 in 72%
yield. However, with 3-methyl-2-butenal (2g), desired product
26 was not obtained; instead, the starting materials were
recovered. In addition, 4-oxo-4H-benzo[h]chromene-3-
carbaldehyde (1m) and 1-oxo-1H-benzo[f]chromene-2-
carbaldehyde (1n), bearing polyaromatic
Table 2. Formation of diverse 2-hydroxy-3'-formylbenzophenones 5–32from
DOI: 10.1039/D0GC01011A
substituted 3-formylchromones 1a–1n and ,β-unsaturated aldehydes 2a–2g, and 2j
View Article Online
a
OH
O
O
O
O
Cat. II
EtOH
R2
H
H
R
60 o
C
R1
O
R2
22 h
R1
R
1a-1n
2a 2g, 2j
-
5-32
H
O
A) 2-Hydroxyformylbenzophenone frameworks bearing electron-donating groups on the
phenol moiety
OH
O
OH
O
MeO
R
O
H
O
H
5
6
7
R= Me (81%)
R= i-Pr (78%)
R= OMe (88%)
CCDC 1991823
8
(85%)
5
X-ray structure of
B) 2-Hydroxyformylbenzophenone frameworks bearing electron-withdrawing groups or both
donating and withdrawing groups on the phenol moiety
OH
O
OH
O
OH
R
O
X
9
R= Cl (79%)
10
11
12
R= Br (82%)
R= F (76%)
Cl
X
O
H
O
H
R= NO2 (85%)
O
H
13
14
X= Cl (76%)
X= Br (83%)
15
(77%)
C) 2-Hydroxyformylbenzophenone frameworks bearing various alkyls/aryl on the
formylbenzene ring
OH
O
OH
O
R2
R2
OH
O
R2
MeO
2 = Et (72%)
21
22
R
Cl
2 = Pr (79%)
O
O
H
R
O
H
2 = Et (75%)
2 = Pr (68%)
23
R
R
O
H
OH
OH
O
24
2
16
17
18
19
20
R = Et (75%)
R = n-Pr (84%)
R = n-Bu (81%)
R = n-pentyl (86%)
2
2
2
2
R = n-hexyl (81%)
26
(0%)
25
(72%)
O
H
O
H
D) 2-Hydroxyformylbenzophenone frameworks bearing polyaromatic ring on the phenol
moiety and alkyls on the formyl benzene ring
OH
O
OH
O
R2
R2
2 = Me (78%)
R
R
R
2 = Me (65%)
2 = Et (69%)
2 = Pr (75%)
30
31
32
R
R
R
27
28
29
2 = Et (72%)
2 = Pr (83%)
O
H
O
H
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), Cat. II (10 mol%) and EtOH (5.0
mL).
rings, were successfully combined with 2a, 2b, or 2c to
produce the corresponding angular compounds 27–29 (65–
75%) and linear compounds 30–32 (72–83%).
To explore the substrate scope of this protocol, further
reactions with trans-crotonaldehyde (2h) as a substrate were
then performed (Table 3). Surprisingly, treatment of 1a with
1.2 equivalents of 2h and Cat. II in ethanol at 60 °C for 22 h did
not provide desired product 33’; instead, compound 33 was
unexpectedly produced in 48% yield. Importantly, with 2.4
equivalents of 2h, the yield of 33 increased to 75%. A number
of reactions were carried out with 3-formylchromones 1a–1c,
1e–1g, and 1n and 2h (2.4 equiv.) under the standard
conditions, which resulted in the formation of synthetically
useful 2-hydroxynaphthophenones 33–39, bearing a formyl
group, with 68–81% yields. The structures of the synthesized
compounds were confirmed by analysis of their spectral data
and X-ray analysis of 34.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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A) Performed cross-reaction using 2a and 2h
OH
Table 3. Formation of diverse 7-(2’-hydroxybenzoyl)-2-naphthaldehydes 33–39 from
substituted 3-formylchromones 1a–1c, 1e–1g, or 1n and trans-crotonaldehyde (2h)a
View Article Online
DOI: 10.1039/D0GC01011A
O
H
O
OH
O
H
33
(0%)
O
OH
O
H
O
O
R
H
2h
O
O
O
O
H
O
O
(1.0 equiv.)
33 39
-
2h
OH
O
40
(0%)
+ O
H
H
Cat. II
R
OH
O
H
O
Cat. II
EtOH
EtOH
H
O
1a
60 oC, 22 h
1a 1c 1e 1g 1n
-
,
-
,
2a
(1.0 equiv.)
60 oC, 22 h
33'
OH
O
O
H
41
(0%)
A) 7-(2-Hydroxybenzoyl)naphthaldehyde frameworks bearing electron-donating
groups on the phenol moiety
OH
O
H
3
(78%)
OH
O
H
O
H
O
B) Performed in situ reaction of 1f with 2h and 2a or 2b
O
b
c
33
33
H
(48%)
(75%)
O
34
(68%)
OH
Cl
O
H
O
H
OH
O
O
O
O
O
H
O
Cl
H
2a 2b
-
R1
60 oC, 15 h
2b
2h
R1
Cat. II
EtOH
rt, 10 h
35
(73%)
, R1 = Me (68%)
, R1 = Et (73%)
42
, R1 = Et 43
OH
O
H
1f
, R1 = Me
2a
CCDC 1991825
O
34
X-ray structure of
Scheme 3. (a) Cross reaction of 1a with 2a and 2h. (b) One pot construction of 7-(2’-
hydroxybenzoyl)-2-naphthaldehydes 42 and 43.
MeO
36
(72%)
B) 7-(2-Hydroxybenzoyl)naphthaldehyde frameworks bearing electron-withdrawing
groups and polyaromatic ring on the phenol moiety
The scope of the reaction was further extended for the
OH
X
O
H
OH
O
H
formation
of
diverse
and
functionalized
2-
O
O
hydroxybenzophenones 44–73 without any formyl groups by
employing the series of 3-formylchromones 1a–1j and 1l–1n
with ,β-unsaturated aldehydes 2a–2i in the presence of Cat.
VI (Table 4). Treatment of 1a with crotonaldehyde (2h) gave
readily available 2-hydroxybenzophenone (44) with 74% yield.
Combination of 1a with 2b–2f afforded the desired products
45–49 with 82–89% yields. Importantly, with 3-methyl-2-
butenal (2g) and (E)-2-phenyl-2-butenal (2i), the desired
products 50 and 51 were produced with 91 and 82% yields,
respectively. The combination of 1b–1e, bearing electron-
donating groups, with 2a, 2h, or 2i proceeded smoothly, and
the corresponding products 52–57 were obtained with 70–
89% yields. Treatment of 1f–1i, bearing electron-withdrawing
groups, with 2a, 2g, or 2i was also successful, and products 58–
64 were isolated with 69–90% yields. Reactions of 1j or 1l,
bearing two substituents on the benzene ring, with 2a or 2g
provided the corresponding products 65–67 with 73–88%
yields. Furthermore, 1m or 1n, bearing polyaromatic rings,
were successfully combined with 2b, 2g, or 2i to afford
products 68–73 (75–93%).
37
38
X= Cl (69%)
X= Br (80%)
39
(81%)
aReaction conditions: 1 (1.0 mmol), 2 (2.4 mmol), Cat. II (10 mol%) and EtOH (5.0
mL). bReaction with 1.2 equiv. of 2h. cReaction with 2.4 equiv. of 2h.
To
provide
7-(2’-hydroxybenzoyl)-2-naphthaldehyde
derivatives bearing alkyl substituents on the benzene ring,
further experiments between 3-formylchromones 1a or 1f and
,β-unsaturated aldehydes 2a, 2b, or 2h were performed
(Scheme 3). Treatment of 1a (1.0 mmol) with 2a (1.0 mmol)
and 2h (1.0 mmol) under the standard reaction conditions
provided only product 3 (78%), without the formation of the
other possible products 33, 40, and 41. This result showed the
significant difference in chemoselectivity between the two
different ,β-unsaturated aldehydes. Other reactions were
attempted to form diverse products by sequential in situ
reactions through the combination of two different ,β-
unsaturated aldehydes. Treatment of 1f (1.0 mmol) with 2h
(1.0 mmol) at room temperature for 10 h, followed by addition
of 2a (1.0 mmol) or 2b (1.0 mmol) at 60 °C for 15 h provided
products 42 or 43 with 68 and 73% yields, respectively.
To explore the applicability of benzannulation reactions, we
carried out the gram-scale reactions under standard reaction
conditions (Scheme 4) and successfully isolated the desired
products 3 and 4 in 76 and 81% yields, respectively (for details,
see ESI).
To investigate the application of this protocol, the
conversion of the synthesized compound 55 into biologically
interesting molecules via C−H activation was next attempted
(Scheme 5). Rh(III)-catalyzed direct C−H alkenylation of 55 with
several acrylates, such as methyl, ethyl, phenyl, or benzyl
acrylates (3a–3d) at 60 °C for 12 h produced the Heck type
products 74–77 with 71–85% yields, respectively, and that
4 | J. Name., 2012, 00, 1-3
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with styrene (3e) provided 78 with 92% yield. In addition, with results showed that compounds II and 80 are the
View Article Online
N-phenyl maleimide (3f), addition product 79 was produced intermediates for the formation of 9 DoOfI: t1h0.e10329-/hDy0dGrCo0x1y0-131'A-
with 58% yield.
formylbenzophenone series. Furthermore, reaction of 2a with
Cat. VI in refluxing benzene for 3 h afforded intermediate VII,
which was confirmed by 1H NMR and HRMS of the crude
mixture (see ESI). The reaction of intermediate VII with 1a in
Table 4. Formation of diverse 2-hydroxybenzophenones 44–73 from substituted 3-
formylchromones 1a–1j or 1l–1n and ,β-unsaturated aldehydes 2a–2ia
o
ethanol at 80 C for 2 h provided compound 4 in 80% yield
O
O
OH
O
O
(Scheme 6d). The possibility of the formation of products via
[4+2] cycloaddition starting from 2a was also investigated by
employing 1,4-naphthoquinone (81). Treatment of 81 with 2a
in the presence of Cat. VI in ethanol at 80 °C for 10 h provided
82 with 76% yield through a formal [4+2] cycloaddition and air
oxidation (Scheme 6e). In the case of [3+3+4] cycloaddition,
the reaction of 33’ with 2h in the presence of Cat. II did not
provide the desired product 33, which showed that compound
33’ was not an intermediate for the formation of 33 (Scheme
6f).
R1
R2
R1
H
Cat. VI
R
H
EtOH
R3
O
80 o
C
R
R2
R3
15 h
1a-1j, 1l-1n
2a-2i
44 73
-
A) 2-Hydroxybenzophone and its frameworks bearing various alkyl and phenyl
moieties on the benzene ring
OH
O
OH
O
OH
O
50
(91%)
3
45
46
47
48
49
R = Et (83%)
OH
O
R3
3
44
R3= n-Pr (86%)
(74%)
R3= n-Bu (82%)
R3= n-pentyl (86%)
R = n-hexyl (89%)
51
(82%)
B) 2-Hydroxybenzophone frameworks bearing electron-donating groups on the
phenol moiety
OH
O
O
OH
O
OH
O
O
O
OH
O
H
Cat. II
10 mol%
H
(a)
+
MeO
O
MeO
EtOH, 60 o
C
2a
1a
R3
(89%)
57
52
53
54
R= Me (72%)
R= i-Pr (70%)
R= OMe (81%)
(12 mmol, 1.0g)
O
O
(10 mmol, 1.74g)
3
R
O
H
55
56
R = H (82%)
3
3
4
(1.82g, 76%)
R = Me (88%)
O
OH
O
C) 2-Hydroxybenzophone frameworks bearing various electron-withdrawing groups
or both electron-donating and withdrawing groups on the phenol moiety
Cat. VI
H
H
+
(b)
20 mol%
OH
O
OH
O
OH
O
EtOH, 80 o
C
O
2a
1a
(12 mmol, 1.0g)
(1.72g, 81%)
(10 mmol, 1.74g)
58
Scheme 4. Gram scale synthesis of 3 and 4.
(69%)
63
64
OH
R= Cl (73%)
R= NO2 (75%)
O
Cl
59 R= Cl (85%)
R
R
OH
O
60
61
62
R= Br (76%)
R= F (90%)
R= NO2 (83%)
Cl
O
O
OR
OR
3a 3d
R2
3e
-
2
3
Cl
R3
65
66
OH O
R = H, R = Me (73%)
R = Me, R = H (88%)
[Cp*RhCl2]2
AgSbF6
[Cp*RhCl2]2
AgSbF6
2
3
67
(82%)
Cl
OH
O
55
D) 2-Hydroxybenzophenone frameworks bearing polyaromatic ring on the phenol
moiety and alkyls or phenyl moeities on benzene ring
AgOAc
AgOAc
DCE, 60 o
C
DCE, 60 o
12 h
C
MeO
74
O
12 h
OH
O
OH
O
R = Me (82%)
R = Et (71%)
R = Ph (79%)
R = Bn (85%)
OH
O
MeO
[Cp*RhCl2]2
75
76
77
78
(92%)
N
Ph
AgSbF6, AgOAc
AcOH
R2
R2
R = H, R = Et (91%)
DCE, 60 o
12 h
C
3f
O
N
2
3
R3
71
72
R = H, R = Et (93%)
R = Me, R = H (85%)
R3
3
2
3
O
Ph
2
68
69
OH
O
70
(87%)
2
3
R = Me, R = H (75%)
O
OH
O
73
(84%)
79
(58%)
MeO
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), Cat. VI (20 mol%) and EtOH (5.0
mL).
Scheme 5. Conversion of 55 to functionalized molecules 74-79.
To elucidate the reaction mechanism via intermediates,
control experiments for the formation of products 4, 9, 33, and
intermediate 80 were next attempted (Scheme 6). First,
reaction of 2a with Cat. II in DMSO-d6 provided intermediate II,
which could not be isolated by column chromatography.
However, this crude intermediate II was confirmed by 1H NMR
and HRMS of the crude mixture (See ESI). The reaction of
intermediate II with 1f provided corresponding intermediate
80 in 54% yield (Scheme 6a). When 1f was also treated with 2a
in the presence of Cat. II in ethanol at room temperature for
10 h, intermediate 80 was isolated with 91% yield, without any
formation of an aromatic ring (Scheme 6b). Intermediate 80
was successfully converted into aromatic compound 9 with
82% yield under the standard conditions (Scheme 6c). These
To confirm the mechanism of the products, we conducted
further reactions with deuterated compound d-1a under
standard reaction conditions (Schemes 6g and 6h). Treatment
of d-1a with 2a in the presence of Cat. II, provided the product
d-3 in 90% yield, retaining the two deuteriums derived from a
formyl group and 2-position on d-1a (Scheme 6g). However, in
the case of Cat. VI, mono-deuterated product d-4 was
obtained in 86% yield, retaining only one deuterium from 2-
position (Scheme 6h). These control experiments indicated
that Cat. II and Cat. VI chemoselectively produced the
products d-3 and d-4 through [3+3] and [4+2] cycloadditions,
respectively.
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Journal Name
another intermediate X with regeneration of VtiehweArtcicaletOanlylinset
through deprotonation. Intermediate X finally gives 4 through
elimination of formic acid and ring opening. Importantly, after
the reaction, the presence of formic acid was confirmed by GC-
MS analysis of the crude reaction mixture, providing evidence
of this reaction pathway (see ESI, Fig. S3, S4).
O
O
DOI: 10.1039/D0GC01011A
O
1f
Cat. II
(0.3 mmol)
N
OH
Cl
(0.3 mmol)
O
H
(a)
DMSO-d6
rt,1 h
EtOH
(1:1)
rt, 10 h
2a
80
(54%)
II
(0.3 mmol)
Confirmed intermediate II by 1H NMR & HRMS
O
O
O
O
Cl
Cl
A) Reaction pathway for the formation of 3
H
H
O
Cat. II
(b)
(c)
EtOH
rt, 10 h
O
O
O
80
(91%)
2a
1f
O
OH
Cl
R
R
R
R
N
N
O
Cat. II
1a
N
N
Cl
2a
H
Cat. II
O
-H2O
-H2O
O
O
III
EtOH
O
I
II
9
(82%)
60 oC, 15 h
R= C(Ph)2OH
80
O
H
O
O
OH
O
O
1a
H2O
Cat. VI
(0.3 mmol)
3
(0.3 mmol)
N
H
IV
-Cat. II
(d)
O
EtOH
benzene
reflux, 3 h
H
N
V
80 oC, 2 h
2a
4
(80%)
(0.3 mmol)
VII
R
Confirmed intermediate VII by 1H NMR & HRMS
B) Reaction pathway for the formation of 4
O
O
O
O
Cat. VI
H
N
N
N
(e)
(f)
EtOH
H
Cat. VI
80 o
C
10 h
H
O
-H2O
2a
81
82
O
(76%)
2a
VI
VII
O
VIII
H2O
H
OH
O
H
OH
O
H
O
2h
N
O
O
O
O
N
O
O
O
X
H
Cat. II
X
EtOH
33'
60 oC, 25 h
33
(0%)
4
O
Cat. VI
-
X
-HCOOH
1a
IX
VIII
OH
O
D
O
O
D
O
X = CHO
C) Reaction pathway for the formation of 33
Cat. II
10 mol%
D
H
(g)
(h)
D
(90%)
O
O
EtOH, 60 o
C
R= C(Ph)2OH
2a
d-1a
d-3
O
R
R
R
N
N
O
H
O
Cat. II
O
1a
-H2O
XIII
OH
O
N
2h
H
Cat. VI
20 mol%
-H2O
D
H
O
N
R
XI
XII
EtOH, 80 o
C
O
d-1a
D
XII
D
2a
R
d-4
(86%)
O
R
O
N
H
Scheme 6. Control experiments.
N
O
N
Michael-type
addition
XIV
Based on the control experiments and the observed
products, plausible mechanisms for 3, 4, and 33 are depicted
in Scheme 7. For the formation of 3, in the presence of Cat. II,
2a first gives enamine intermediate II, via iminium ion I
formation followed by deprotonation (Scheme 7A).
Nucleophilic addition of intermediate II to 1a gives another
iminium ion intermediate III by removal of water. In the
formation of enamine intermediate II, [4+2] cycloaddition did
not proceed owing to steric hindrance by the bulky group on
Cat. II. Instead, intermediate III gives intermediate IV through
resonance structure formation; IV is cyclized to afford V by
O
N
R
Intramolecular
cyclization
R
XV
H
R
R
OH
O
N
OH
O
N
33
Elimination
& Ring opening
Aromatization
& Hydrolysis
XVI
Electrocyclization
XVII
Scheme 7. Plausible mechanistic pathways for the formation of 3, 4, and 33.
The formation of product 33 can be explained as shown in
Scheme 7C. The control experiment depicted in Scheme 6f
showed that compound 33’ is not an intermediate for the
formation of 33. Thus, in the presence of Cat. II, 2h gives
enamine intermediate XII via XI, which reacts with 1a to give
intermediate XIII. Intermediate XIII undergoes further
nucleophilic addition to furnish intermediate XIV.
Intramolecular cyclization of XIV gives another intermediate
XV, which undergoes subsequent regeneration of the catalyst
and ring opening to give intermediate XVI. 6π-
Electrocyclization of XVI will generate intermediate XVII, which
intramolecular
cyclization.
Ring
opening
through
deprotonation and the subsequent hydrolysis finally give 3
with regeneration of Cat II. In this case, double cyclization
products were not produced through further nucleophilic
addition of intermediate II to intermediates III or IV because of
steric hindrance of the methyl group on intermediates III and
IV. In the formation of 4, enamine intermediate VIII formed via
VI and VII undergoes formal [4+2] cycloaddition with 1a to give
Diels–Alder adduct IX (Scheme 7B). Intermediate IX gives
6 | J. Name., 2012, 00, 1-3
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ARTICLE
undergoes aromatization and hydrolysis to produce the final ratio comes closer to 1. In addition, the in vitro critical
View Article Online
DOI: 10.1039/D0GC01011A
wavelength values in excess of 370 nm satisfy the classification
product 33.
The chemoselectivity of compounds 3 and 4 is probably due requirements for extensive UVA/UVB protection.23 We
to the intermedeates II and VII produced by the reaction of 2a exclusively employed in vitro testing of sunscreens by using
with Cat. II or Cat. VI. To justify chemoselectivity of two the known method based on spectrophotometric analysis of
products 3 and 4, we used a simple energy-minimization dilute solutions (see the ESI). With this information in hand, we
calculation of intermediates II and VII using MM2 of have also calculated the in vitro sun protection factor (SPF) to
ChemBio3D. The energy minimized structures of II and VII further gauge the potential of our synthesized products
were shown in supplementary information (See ESI, Fig. S5). relative to OBZ (Table 5).
Based on energy minimized structures, it is assumed that the
access of a butadiene moiety to the enone of dienophile 1a to
Table 5 Summary of optical properties of the representative synthesized compounds
give the Diels-Alder product is difficult due to steric hindrance
and blocking by the phenyl rings (See ESI, Fig. S6a). For this
reason, the product derived from Diels-Alder reaction did not
λmax
ε(mol -1
λc
Broad
UVA/UV
B Ratio
Entry
SPF
(nm)
cm-1 L)
(nm)
spectrum
305
350
290
321
304
395
3212
4762
3
8
376
358
Y
1.09
0.41
6.33 ± 0.05
proceed, instead compound
3
was isolated through
condensation of II and 1a followed by intramolecular
cyclization and ring opening. In the case of VII, there is no
steric hindrance to give compound 4 via Diels-Alder reaction
(See ESI, Fig. S6b).
11912
8000
18.25 ±
0.20
N
10599
4762
18.33 ±
0.19
12
14
36
37
44
386
382
357
367
362
Y
Y
0.50
0.85
0.43
0.59
0.92
355
4871
6.12 ± 0.04
UV absorption studies
290
333
20263
12068
25.18 ±
0.22
Benzophenones are highly utilized and valued scaffolds as
active ingredients in sunscreen, as a result of their optical and
chemical properties.21 However, one of the most popular
materials used widely as a sunscreen ingredient, oxybenzone,
is known to cause allergic reactions and skin cancer;21b this has
prompted the development and design of novel derivatives as
new UVA/UVB filters that potentially provide better
protection. To determine the feasibility and efficiency of the
synthesized molecules as UV filters, the UV absorption
properties of the synthetic compounds (3, 8, 12, 14, 36, 37, 44,
45, 51, 54, 62, 63 and 64) were evaluated in comparison with
the structurally related oxybenzone (OBZ; Fig. 1).
N
N
N
352
340
5170
8000
8.95 ± 0.07
11.61 ±
0.13
15.10 ±
0.14
45
335
10395
361
N
0.81
13.15 ±
0.15
51
54
62
63
64
330
370
8000
5116
363
389
389
371
391
N
Y
Y
Y
Y
0.67
1.55
0.60
0.92
0.79
4.50 ± 0.03
340
400
9959
8762
25.08 ±
0.21
345
5224
6.44 ± 0.08
302
400
285
325
9693
9034
14336
9197
15.20 ±
0.17
16.31 ±
0.15
OBZ
353
N
0.40
Based on our results, compounds 12, 36, 62, and 64 exhibit
superior photoprotective properties in terms of molar
absorptivity, broad spectrum absorption, UVA/UVB ratio, and
SPF. The presence of additional π-bonds and functional groups
in the benzophenone scaffold increases the UVA protection
based on the λc value and UVA/UVB ratio. The UV absorption
properties of the synthetic compounds are comparable to the
standard sunscreen ingredient OBZ and are better in terms of
the λc, broad-spectrum classification, and SPF values. Product
8, structurally identical to OBZ, exhibits the same UV filtering
capacity, as expected.
The mathematical method used to calculate SPF from the
UV/Vis absorption is only treated as an initial screening
procedure to determine which synthesized compounds exhibit
good potential as UV protection agents. Further tests with
more sophisticated equipment and methods are beyond the
Fig. 1 Normalized absorbance of representative synthesized compounds from
280–500 nm with OBZ.
The UV protection properties were first evaluated by
determining several important parameters of the UVA/UVB
ratio and molar extinction coefficient based on λmax, as shown
in Table 5. The critical wavelength (λc) calculation and the
UVA/UVB ratio are based on Diffey method.22 The effective
UVA and UVB attenuation values become more similar as the
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4
5
6
(a) S. A. Khanum, S. Shashikanth and A. V. Deepak, Bioorg.
scope of this work and are intended for future specialized
works. In addition, these UV absorption parameters can be
improved through combinations of ingredients in the
sunscreen formulation, which generate possible synergies to
improve performance, particularly when evaluated in vivo.
Chem., 2004, 32, 211; (b) S. A. Khanum, V.VieGwirAirstihcl,e SO.nlinSe.
DOI: 10.1039/D0GC01011A
Suparshwa and N. F. Khanum, Bioorg. Med. Chem. Lett.,
2009, 19, 1887; (c) M. C. Cuquerella, V. Lhiaubet-Vallet, J.
Cadet and M. A. Miranda, Acc. Chem. Res., 2012, 45, 1558.
(a) T. Tzanova, M. Gerova, O. Petrov, M. Karaivanova and D.
Bagrel, Eur. J. Med. Chem., 2009, 44, 2724; (b) B. P.
Bandgar, S. A. Patil, J. V. Totre, B. L. Korbad, R. N. Gacche, B.
S. Hote, S. S. Jalde and H. V. Chavan, Bioorg. Med. Chem.
Lett., 2010, 20, 2292.
(a) A. Krick, S. Kehraus, C. Gerhauser, K. Klimo, M. Nieger, A.
Maier, H.-H. Fiebig, I. Atodiresei, G. Raabe, J. Fleischhauer
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Granell, R. Qadir, J. Quirante, C. Calvis, R. Messeguer, J.
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Conclusions
In conclusion, we have developed an eco-friendly
organocatalyst-controlled methodology for the highly selective
synthesis of polyfunctionalized 2-hydroxybenzophenone
frameworks, such as 2-hydroxy-3'-formylbenzophenones, 7-
(2’-hydroxybenzoyl)-2-naphthaldehydes,
and
2-
hydroxybenzophenones, via cascade benzannulation through
individual [3+3] cycloadditions, [3+3+4] cycloadditions, and
[4+2] cycloadditions, with readily available 3-formylchromones
and ,β-unsaturated aldehydes as the starting materials. The
novel protocol uses eco-benign, operationally simple, atom-
economic, inexpensive, non-toxic, and readily available
organocatalysts. The synthesized compounds were successfully
employed for C−H alkenylation and alkylation reactions for the
development of new and biologically interesting materials. The
synthesized compounds showed superior photoprotective
properties relative to the readily available sunscreen
ingredient oxybenzone.
7
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIT)
(2018R1A2B2004432). This research was supported by the
Nano Material Technology Development Program of the
Korean National Research Foundation (NRF) funded by the
Korean Ministry of Education, Science, and Technology
(2012M3A7B4049675).
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Graphical Abstract
Eco-friendly organocatalyst- and reagent-controlled selective construction of
diverse and multifunctionalized 2-hydroxybenzophenone frameworks for potent
UV-A/B filters by cascade benzannulation
Muhammad Saeed Akhtar, Raju S. Thombal, Ramuel John Inductivo Tamargo, Won-Guen Yang, Sung Hong Kim, and Yong Rok Lee*
Divergent Construction of Novel 2-Hydroxybenzophenone Frameworks
O
O
R1
R1
OH
O
H
OH O
H
R3
R2
O
O
O
R3
R1
R2
R3
R2
R2
R
H
R
R
Cat. II
EtOH
Cat. VI
EtOH
R3
O
O
H
Cat. II
EtOH
catalyst and reagent controlled
benzannulation
H
potent UV-A/B filters
OH
OH
O
H
metal or base free
N
N
H
Cat. II
H
O
atom economic protocol in
green conditions
Cat. VI
R
The organocatalyst- and reagent-controlled highly selective synthesis of diversely functionalized novel 2-hydroxybenzophenone
frameworks for potent UV-A/B filters is developed
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J. Name., 2013, 00, 1-3 | 9
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