3-Methoxalylchromones - Versatile reagents for the regioselective synthesis of functionalized 2,4′-dihydroxybenzophenones, potential UV-filters

Article abstract of DOI:10.1039/c1ob05931a

The reaction of 1,3-bis-silyl enol ethers with 3-methoxalylchromones affords a great variety of functionalised 2,4′-dihydroxybenzophenones. These products are formed by a domino Michael/retro-Michael/Mukaiyama-aldol reaction. The synthesized compounds are

Full text of DOI:10.1039/c1ob05931a

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PAPER
3-Methoxalylchromones – versatile reagents for the regioselective synthesis of
functionalized 2,4¢-dihydroxybenzophenones, potential UV-filters†
Viktor O. Iaroshenko,*a,b Alina Bunescu,a,c Anke Spannenberg,c Linda Supe,a Maria Milyutinaa and
Peter Langer*a,c
Received 9th June 2011, Accepted 16th August 2011
DOI: 10.1039/c1ob05931a
The reaction of 1,3-bis-silyl enol ethers with 3-methoxalylchromones affords a great variety of
functionalised 2,4¢-dihydroxybenzophenones. These products are formed by a domino
Michael/retro-Michael/Mukaiyama-aldol reaction. The synthesized compounds are promising
candidates for the synthesis of the novel UV-A/B and UV-B filters.
A filters. Alternatively, UV-A/B filters, which combine a UV-A
Introduction
and UV-B filter in one molecule, are also frequently employed.
Organisms rely on nucleic acids (RNA and DNA) for storage of
Functionalised benzophenones, such as benzophenone-3 (oxyben-
zone), are widely used in UV-A/B filters.3 However, due to allergic
reactions caused by the photosensitizing effects of oxybenzone, the
development of new UV-A/B filters is of considerable interest.3
On the other hand, molecular composites containing benzophe-
nones are widely used as photosensitizers. Due to the photo-
chemical properties of the benzophenone scaffold, they represent
one of the most important substance classes in photochemistry.4
Functionalised 2-hydroxybenzophenones are widely used as sun-
creams.3 At the same time, functionalised benzophenones have
found various medicinal and technical applications. They occur in
a variety of natural products and represent important core struc-
tures for the development of pharmaceuticals.5 For example, the
benzophenone phenstatin has been reported to be an antitubulin
agent.6
We have previously reported that 2,4¢-dihydroxybenzophenones
can be prepared by domino reaction of 3-acetyl- and 3-formyl-
chromones 1a, b with functionalised 1,3-bis-silyl enol ethers.7 Re-
cently, we have reported the synthesis of 3-methoxalylchromone,8a
containing an additional ester group, and its reactions with
electron-rich nitrogen heterocycles. Herein, we report what
are, to the best of our knowledge, the first reactions of 3-
methoxalylchromone and related derivatives with 1,3-bis-silyl enol
ethers. These reactions result in the diastereoselective formation of
highly functionalized 9-oxo-4,4a,9,9a-tetrahydro-1H-xanthenes
instead of the expected benzophenones. However, the correspond-
ing tetrahydro-1H-xanthenes could be transformed into func-
tionalized benzophenones by treatment with para-toluenesulfonic
acid. The products reported herein are not readily available by
other methods.
their genetic information encoded in the sequences of the four
nucleobases adenine, cytosine, guanine and thymine (uracil in
RNA). The damage of the DNA and RNA matrix causes mistakes
during the replication and transcription, which leads to mutations
of the genome and disorders in cell functions. Ultraviolet radiation
can cause damages of nucleic acids.1,2 The most dangerous sunlight
radiation lies in the range of < 280 nm, the so-called UV-C band,
however, this UV light is absorbed by ozone in upper parts of the
atmosphere.2 The UV-B (320–290 nm) and UV-A (400–320 nm)
bands remain in the sunlight and also contribute significantly to
the negative effects of sun radiation.1,2
Overexposure to sunlight causes dimerization of two pyrimidine
molecules (e.g., [2 + 2] cycloaddition of thymine), which is the most
important photoreaction caused by UV-B and UV-C radiation of
DNA in cells. This results in photoallergic and cytotoxic reactions
and skin cancer; the latter is induced by photochemical reactions
of the DNA.
An important way to protect the skin against UV radiation relies
on the application of sun-creams. Optimal sun-creams should
have a broad and strong absorption of UV-A (400–320 nm)
and UV-B radiation (320–280 nm).3 Other important parameters
of sun-creams include photostability, thermostability, chemical
stability (particularly against water) and a moderate lipophilicity.
Sun-creams often contain a mixture of UV-A and UV-B filters.3
Salicylates (e.g. ethylhexyl salicylate) and dibenzoylmethanes
(e.g. 4-butyl-4-methoxydibenzoylmethane) are widely used as UV-
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str., 3a, 18059,
Rostock, Germany. E-mail: viktor.iaroshenko@uni-rostock.de; Fax: +49
381 49864112; Tel: +49 381 4986410
bNational Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33,
01033, Ukraine. E-mail: iva108@googlemail.com
cLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str., 29a, 18059, Rostock, Germany
Results and discussion
The synthesis of 3-methoxalylchromones 3a–c and 3-
(dichloroacetyl)chromone 4, containing a CHCl2 group as a
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05931a
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Table 1 Optimization of the synthesis of 6f
Table 2 Synthesis of compounds 6 and 7
a
Activation
Time
Reaction
Temperature
6
5
R1
R2
R3
R4
%
3 : 5:TMSOTf
%a 6f
a
b
c
d
e
f
a
b
c
f
g
i
a
f
a
d
i
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CCl2H
H
H
H
H
H
H
Br
Br
Me
Me
H
Me
Et
Bn
H
H
H
H
H
Me
H
H
H
52
1 : 2 : 1
1 : 2 : 2
1 : 2 : 3
1 : 4 : 2
1 : 2 : 2
1 : 2 : 2
1 h
1 h
1 h
1 h
15 min
1 h
0 ◦
0 ◦
0 ◦
0 ◦
0 ◦
C
C
C
C
C
16
42
38
22
0b
47b
41b
43b
52b
42
i-Bu
i-Pent
Me
Me
i-Bu
Me
i-Pr
Me
-78 ◦
C
0b
g
h
i
51
80
71
45
a Yields of isolated products. b No conversion (by TLC).
j
H
Me
7c
54
masked formyl group, and their reactions with amino-substituted
heterocycles have recently been reported.8 Based on our previously
reported studies related to the reaction of 1,3-bis-silyl enol ethers
(Table 1, ESI†) with 3-acetyl- and 3-formylchromones,7 we ex-
pected that the reaction of 3a–c and 4 with 1,3-bis-silyl enol ethers
would result in the formation of 2,4¢-dihydroxybenzophenones
containing an additional ester group. As a test reaction, the
reaction of 5i with 3a was carried out which surprisingly yielded
9-oxo-4,4a,9,9a-tetrahydro-1H-xanthene 6f as the major product
(Scheme 1). By optimization of the reaction conditions, we have
found that the best yield was obtained using TMSOTf as the
catalyst (Table 1). In contrast, the use of TiCl4, AlCl3, AlBr3,
TiBr4, and SnCl4 resulted in a failure (formation of mixtures of
unidentified products). The stoichiometry and reaction time also
played an important role.
a Yields of isolated products. b These compounds were not transformed to
8. c Compound 7 exist in a keto form (Fig. 3).
Scheme 1 Formation of 3-methoxalylchromones 3 and 3-(dichloro-
acetyl)chromone 4.
Scheme 3 Proposed mechanism. Reagents and conditions: (i): 3 or 4 with
TMSOTf, 20 ◦C, 1 h; (ii): 5, CH2Cl2, 0–20 ◦C; (iii): 10% HCl.
With the optimized reaction conditions in hand we have directed
our efforts toward the study of the scope and limitation of the
reaction. 1,3-Bis-silyl enol ethers 5, readily reacted with 3a–c to
give the coresponding polycyclic products 6a–j in 41–80% yields
and with excellent diastereoselectivity (Schemes 2 + 3, Table 2).
The variation of the substituents at the terminal position of 5 has
a influence on the yields. In addition, we have observed the highest
yields for R3 = i-Bu and R2 = Br.
Having studied the reaction of chromones 3 with 1,3-bis-
silyl enol ethers 5 we have switched on the chromone 4. 3-
Dichloroacetylchromone 4 was synthesised following the same
strategy used for 3 (Scheme 1). The chemical behaviour of 4 in the
reaction with 5 is not similar to 3. It should be mentioned that
starting with 1,3-bis-silyl enol ether 5i, the product 7 was formed
with a higher yield than 6f. Product 7 was formed as a mixture
of diastereomers, that makes the NMR methods not sufficient to
corroborate the obtained structure. Following the same procedure
with other 1,3-bis-silyl enol ethers 5 the reaction of 4 delivered a
mixture of diastereomers, which could not be separated.
Recently, Sosnovskikh et al.9 developed the synthesis of diverse
3-(polyfluoroacyl)chromones 1c. We and others10 studied the
Scheme 2 Reagents and conditions: (i): 3a with TMSOTf, 20 ◦C, 1 h; (ii):
5a–j, CH2Cl2, 0–20 ◦C; (iii): 10% HCl.
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application of these chromones for the preparation of many
heterocycles and carbocycles. In this context we considered com-
pounds 1c as the suitable building blocks for the benzophenones
synthesis (Fig. 1). Unfortunately, all reactions of 1c with 1,3-bis-
silyl enol ethers experienced a failure. The reason can be that
chromones 1c are existing in a form of the corresponding hydrate
at the CF3CO group.9
Fig. 3 Molecular structure of compound 7.
two possible paths for the subsequent cyclohexene ring formation,
namely Re and Si attack on the pro-chiral carbonyl group, each of
it will deliver different diastereomers. Felkin–Anh model reveals
that conformation B2 with lower energy should be predominant.
On the other hand another driving force that stabilizes the
conformation B2 is formation of the chelated moiety B3, where
the carbonyl group is coordinated on the silica atom. Due to the
facts mentioned above the Re attack is realizing for this cyclization
delivering the only one diastereomer isolated.
The compounds from scaffold 6 exist in enol-form which is
supported by the intramolecular hydrogen bond (Fig. 2). In
contrary, in the case of compound 7, where such bonding is not
possible, the keto-form predominates (Fig. 3).
Fig. 1 Relevant benzophenone derivatives.
The mechanism of this interesting domino reaction is outlined
in Scheme 3 and relies on three main steps. The initial formation
of the O-TMS-pyrylium salt A is followed by attack of the
(most nucleophilic) carbon atom C-4 of diene 5 on position 2
of the pyrylium salt to give adduct B. The subsequent TMSOTf-
catalyzed intramolecular aldol condensation delivers intermediate
C. The isolation of the products 6 and 7 was achieved after the
addition of hydrochloric acid (10%), which resulted in cleavage of
the TMS-groups (Fig. 2).
To perform the ring-opening reaction of 6, acidic media were
taken as reaction conditions. The substrate 6a, which was taken
as a model compound for the optimization of the reaction
condition, underwent the desired ring-open cascade chemistry by
the prolonged reflux in TFA to yield 2,4¢-dihydroxybenzophenone
8a as a single regioisomer, albeit in a disappointing yield of 22%.
A poor yield (20%) was obtained when the reaction was carried
out in glacial acetic acid (reflux). During the optimization of
the reaction conditions it was found that the best yield (63%)
was obtained when p-toluenesulfonic acid (PTSA) in ethanol was
employed. Moreover, it was applied a two-step one pot procedure
starting from 3 and 5 to reach 8; the yields in this case were
significantly higher (Table 3).
The synthesis of 8j took place in only one step, without
PTSA/ethanol reflux, and the product precipitated with no need
of further purification. This could also be observed in the case
of 8k. Unfortunately the aromatization in one step took place
with only 32% yield so that the second step was needed to get
56% yield. The implicated reaction proceeds most probably via
the formation of intermediates type D, E, depicted on the Scheme
4, that describes the presumable mechanism of the reaction.
The ring-opening reaction, followed by aromatization did not
take place for the derivative 7 containing CCl2H-function. Both
acidic media (PTSA/ethanol) and basic media (KOH/methanol)
have been tried without success. A mixture of unidentified products
was formed.
The constitution of scaffold 8 was established by crystallo-
graphic analysis of the obtained single crystals of compounds 8i
(Fig. 4), and 8j, 8p (Figures 5 and 6 in the ESI†).11 The crystal
structure of compound 8i contains two intramolecular hydrogen
bonds between O(1) and O(2), O(5) and O(7). The plane of
the ortho-salicylic substituent is rotated about 57◦ regarding the
central benzoic ring, the corresponding dihedral angle C(6)C(7)–
C(8)C(13) is 70.3(2)◦. In addition, the methoxycarbonyl group is
Fig. 2 Molecular structure of compound 6b.
The structures of products 6 and 7 were established by spectro-
scopic methods. The structures of 6b, 6c, and 7 were independently
confirmed by X-ray crystal structure analyses (Figs 2, 3 and 4 in
ESI†).11 The relative configuration of the products was assigned
based on the crystallographic analysis. A trans relationship was
observed for the bridgehead hydrogen atoms which is in good
agreement with the coupling constant (3JH,H ~ 13 Hz between these
1
protons in the H NMR spectrum). In the case of 7, we have
succeed to grow a single crystal, during the crystallization only
one isomer precipitated, its structure was solved and is depicted
on the Fig. 3.
This interesting phenomenon can be explained by the Felkin-
Anh model throughout the mechanistic reaction presentation
(Scheme 3). After the formation of the intermediate B, there are
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Table 3 Synthesis of benzophenones 8
Table 4 Synthesis of benzophenones 10
a
a
8
5e
R2
R3
R4
%
10
Ar
%
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
a
e
h
i
j
k
l
H
H
H
H
H
H
H
H
Me
n-Bu
n-Oct
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Bu
Me
Me
Me
Me
Me
i-Pr
Me
Me
Me
H
H
H
Me
63b (50c)
84b
10a
10b
10c
10d
(4-OCH3)C6H4
(4-C2H5)C6H4
(4-Cl)C6H4
60
60
70
39
80b
67b (45c)
66b
(3-CF3)C6H4
Et
a Yields of isolated products.
n-Non
n-Tetradec
n-Hexadec
(CH2)2Ph
(CH2)3Cl
(CH2)4Cl
H
H
Me
n-Non
n-Hexadec
(CH2)4Cl
H
70b
74b
m
n
o
p
a
f
72b
37b
In order to modify the scaffolds 8 the Pd-mediated C–C cou-
plings by the transformation of 8 into bistriflate derivatives with
the subsequent application of Suzuki protocol was undertaken.
As a model compound we have taken 8a, which was successfully
transformed into bistriflate derivative 9a (Scheme 5). The Suzuki
reaction of 9a with arylboronic acids afforded the novel benzophe-
nones derivatives 10a–d in good yields (Scheme 5, Table 4). The
reactions were carried out using Pd(PPh3)4 (6 mol%) as a catalyst.
The employment of other bases, such as Cs2CO3, resulted in a
decreased overall yield. Potassium phosphate (K3PO4) was used as
the base and 1,4-dioxane (110 ◦C, 4 h) as the solvent. All products
were isolated in pure form by chromatographic purification. In
most cases, a small amount of the corresponding biphenyls could
H
H
H
53d
56b (32d)
49b (45c)
72b (63c)
75b
Br
Br
Br
Br
Br
Br
Me
Me
Me
Me
Me
i
k
m
p
a
d
i
77b
54b
82b
60b (58c)
63b
s
t
v
w
H
Me
n-Non
n-Hexadec
74b
k
m
63b
72b
a Yields of isolated products. b Two step one pot procedure. c he reaction
was conducted sequentially via the isolation of 6. d Product isolated after
the first step. e For list of 5 see Table 1 in the ESI.†
1
be detected in the crude product before chromatography (by H
NMR and GC-MS).
Scheme 5 Reagents and conditions: (i): CH2Cl2, pyridine (4.0 equiv) -78–0
◦C, under argon atmosphere, 4 h; (ii): 1,4-dioxane Ar-B(OH)2 (2.5 equiv),
K3PO4 (3.0 equiv), 6 mol% Pd(PPh3)4, 90 ◦C, under argon atmosphere,
4 h; (iii): 1,4-dioxane, Ph-B(OH)2 (4.0 equiv), KF (4.5 equiv), 7 mol%
Pd(PPh3)4, 90 ◦C, under argon atmosphere, 4 h.
Scheme 4 Reagents and conditions: (i): EtOH, p-TsOH (3 mol%), reflux,
5–10 h.
Similarly, compound 8l (R2 = Br) was successfully transformed
into the bistriflate derivative 9b and subsequently coupled with
phenyl boronic acid. In this case, our optimal condition used
for the synthesis of 10 experienced a failure, by delivering an
inseparable mixture of bis-substituted products. By using KF
instead of K3PO4 the synthesis of 11 was succeed with a yield
of 50%.
UV-Study
To develop a new UV-A/B filter, the UV absorptions of the
polycyclic system 6 and of the benzophenones 8 and 10 were
studied (Tables 2–4 and Figs 1–3 in the ESI†).
Electron transfers (p→p* resp. n→p*) in the benzophenones
8 resulted in three lmax at 230 nm (UVC), 240–280 nm (UVC)
and 315–380 nm (UVA/UVB). As expected, the best absorptions
Fig. 4 Molecular structure of compound 8i.
also not in the plane with the ring, the corresponding C(8)C(9)–
C(14)O(3) angle is 57.4(2)◦.
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were observed for high conjugated systems like benzophenones
10a–d and 11, with absorption coefficients e = 25000–37000
cm-1mol-1l, which are very high compered with other known
UVA/UVB filters.3 These compounds exhibit strong absorptions
in the range of lmax = 230 nm (UVC) and 300 nm (UVB). Weaker
absorptions coefficients were observed for the polycyclic system 6
at wavelengths similar to the ones of benzopenones 8. This makes
them to a less promising UVA/UVB filter.
3 (a) H. Langhals and K. Fuchs, Chem. Unserer Zeit, 2004, 38, 98–112
and references cited therein; (b) N. A. Shaath, Photochem. Photobiol.
Sci., 2010, 9, 464–469.
4 X. Cai, M. Sakamoto, M. Fujitsuka and T. Majima, Chem.–Eur. J.,
2005, 11, 6471 and references cited therein.
5 For salicylic esters and salicylic glycosides (e.g. salicortin), see for
example: Ro¨mpp Lexikon Naturstoffe (ed.: W. Steglich, B. Fugmann, S.
Lang-Fugmann), Thieme, Stuttgart: 1997.
6 G. R. Pettit, B. Toki, D. L. Herald, P. Verdier-Pinard, M. R. Boyd, E.
Hamel and R. K. Pettit, J. Med. Chem., 1998, 41, 1688–1695.
7 P. Langer, Synlett, 2007, 1016–1025.
8 (a) S. Mkrtchyan, V. O. Iaroshenko, S. Dudkin, A. Gevorgyan, M.
Vilches-Herrera, G. Ghazaryan, D. Volochnyuk, D. Ostrovskyi, Z.
Ahmed, A. Villinger, V. Ya. Sosnovskikh and P. Langer, Org. Biomol.
Chem., 2010, 8, 5280–5284; (b) D. Ostrovskyi, V. O. Iaroshenko, I. Ali,
S. Mkrtchyan, A. Villinger, A. Tolmachev and P. Langer, Synthesis,
2011, 133–141; (c) V. O. Iaroshenko, S. Mkrtchyan, G. Ghazaryan,
A. Hakobyan, A. Maalik, L. Supe, A. Villinger, A. Tolmachev, D.
Ostrovskyi, V. Ya. Sosnovskikh and P. Langer, Synthesis, 2010, 469–
480.
9 (a) V. Ya. Sosnovskikh and R. A. Irgashev, Synlett, 2005, 1164–1166;
(b) V. Ya. Sosnovskikh, R. A. Irgashev and M. A. Barabanov, Synthesis,
2006, 2707–2718; (c) V. Ya. Sosnovskikh and R. A. Irgashev, Heteroat.
Chem., 2006, 17, 99–103.
For the absorption maxima of compounds 8 and 10, electron-
donor groups led to a slight blue shift, while electron-acceptor
groups (Br, Cl, CF3) led to a slight red shift.
Conclusion
In summary, a new two-step synthetic strategy for the assembling
of new benzophenones derivatives by the domino-cascade reaction
of 3-acylated benzo-g-pyrones and 1,3-bis-silyl enol ethers was de-
veloped. This method gives a green light to a set of functionalized
benzophenones which are of considerable interest as novel UV
filters with good UV absorbing properties. Functionalization of
the scaffolds was explored by Suzuki coupling reaction.
10 (a) A. Kotljarov, V. O. Iaroshenko, D. M. Volochnyuk, R. A. Irgashev
and V. Ya. Sosnovskikh, Synthesis, 2009, 3869–3879; (b) A. Kotljarov,
R. A. Irgashev, V. O. Iaroshenko, D. Sevenard and V. Ya Sosnovskikh,
Synthesis, 2009, 3233–3242.
11 Crystallographic data (excluding structure factors) for the structure
6b, 6c, 7, 8i, 8j, and 8p reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. 832478–832483 can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk, or via
www.ccdc.cam.ac.uk/data_request/cif.
Notes and references
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the Nucleic Acids, vol. 1, Wiley, New York, 1990.
2 M. G. Friedel, M. K. Cichon, T. Carell, CRC Handbook of Organic
Photochemistry and Photobiology, CRC Press, Boca Raton, 2nd edn,
2004.
7558 | Org. Biomol. Chem., 2011, 9, 7554–7558
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