Reactions of 3-acylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone: One-pot synthesis of functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins

Article abstract of DOI:10.1039/c2ob07020k

Reactions of 3-methoxalyl-, 3-polyfluoroacyl- and 3-aroylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone in the presence of DBU proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent formal [3 + 3] cyclocondensation to functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins, depending on the substituent at the 3-position. An NMR study and X-ray crystallographic analysis are reported. The compounds synthesized can be considered as promising scaffolds for the design of the novel UV-A/B and UV-B filters.

Full text of DOI:10.1039/c2ob07020k

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 9344
www.rsc.org/obc
PAPER
Reactions of 3-acylchromones with dimethyl 1,3-acetonedicarboxylate and
1,3-diphenylacetone: one-pot synthesis of functionalized 2-hydroxybenzo-
phenones, 6H-benzo[c]chromenes and benzo[c]coumarins†
Viktor O. Iaroshenko,*a,b Iryna Savych,a Alexander Villinger,a Vyacheslav Ya. Sosnovskikhc and
Peter Langera,d
Received 1st December 2011, Accepted 16th October 2012
DOI: 10.1039/c2ob07020k
Reactions of 3-methoxalyl-, 3-polyfluoroacyl- and 3-aroylchromones with dimethyl 1,3-
acetonedicarboxylate and 1,3-diphenylacetone in the presence of DBU proceed at the C-2 atom of the
chromone system with pyrone ring-opening and subsequent formal [3 + 3] cyclocondensation to
functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins, depending on
the substituent at the 3-position. An NMR study and X-ray crystallographic analysis are reported. The
compounds synthesized can be considered as promising scaffolds for the design of the novel UV-A/B and
UV-B filters.
Chromones (4H-1-benzopyran-4-ones, 4H-chromen-4-ones) are
very attractive targets for combinatorial library synthesis due to
their wide range of valuable biological activities.1 Many natural
and synthetic chromones have occupied an important place in
drug research, as one of the so-called privileged drug scaffolds.2
In addition, they are used as valuable synthetic intermediates in
the preparation of new carbo- and heterocyclic systems.3 The
biological and industrial importance of chromones has led to a
considerable amount of synthetic work in the field of 3-substi-
tuted chromones, especially 3-formylchromone and its deriva-
tives.4 These compounds have attracted attention long ago as
highly reactive compounds, which can serve as the starting sub-
stances in the syntheses of a whole series of heterocycles with
useful properties due to three strong electrophilic centers (C-2
and C-4 atoms of the chromone system and the carbonyl carbon
of the 3-CHO group). In the chromone ring, the oxygen atom at
the 1-position diminishes electron density on the adjacent C-2
atom and two carbonyl groups withdraw electrons through a
double bond, hence the 2-position of 3-acylchromones is highly
reactive toward the nucleophiles. That is why the reactions of
these compounds with nucleophiles start predominantly from the
attack of the unsubstituted C-2 atom (1,4-addition) and are
accompanied by pyrone ring-opening to form the β-dicarbonyl
intermediate capable of regioselective intramolecular cycliza-
tions.4,5 However, because such chromones possess three electro-
philic centers, their interaction with dinucleophiles is sometimes
difficult to predict.
We envisaged that introduction of powerful electron-with-
drawing groups such as methoxalyl, polyfluoroacyl and aroyl
into the 3-position of a chromone would increase its reactivity
toward nucleophilic reagents and open up a broad synthetic
scope of this important oxygen-containing heterocyclic system.
Unlike 3-formylchromones,4,5 3-methoxalylchromones 1,6
3-polyfluoroacylchromones 27 and 3-aroylchromones 38 (Fig. 1)
have not received much attention despite their potential interest
as building blocks in organic synthesis for the construction of
2-hydroxybenzophenones and benzo[c]coumarins via the reac-
tions with 1,3-C,C-dinucleophiles.
The substituted 2-hydroxybenzophenone framework is ubiqui-
tous in a wide variety of naturally occurring and synthetic com-
pounds that exhibit important biological activities.9 Recently, we
have developed a domino Michael/retro-Michael/aldol process
that takes place between 3-formylchromones and 1,3-bis(silyl
enol ethers) in the presence of catalytic trimethylsilyl triflate to
generate functionalized 2-hydroxybenzophenones.10 3-Formyl-
chromones are also known to undergo Michael addition and
cyclization reactions with dimethyl 1,3-acetonedicarboxylate
under basic conditions to produce similarly functionalized
2-hydroxybenzophenones I.11 Recently reported syntheses of
benzo[c]coumarin skeleton II, which is present in a number of
pharmacologically relevant natural products, such as autumn-
ariol,12 autumnariniol,13 alternariol,14 and altenuisol,15 rely on
aInstitut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059
Rostock, Germany. E-mail: viktor.iaroshenko@uni-rostock.de,
iva108@googlemail.com; Fax: +49 381 49864112;
Tel: +49 381 4986410
bNational Taras Shevchenko University, 62 Volodymyrska Str.,
01033 Kyiv, Ukraine
cDepartment of Chemistry, Ural Federal University, 51 Lenina Ave.,
620083 Ekaterinburg, Russia
dLeibniz-Institut für Katalyse an der Universität Rostock e.V., Albert
Einstein Str. 29a, 18059 Rostock, Germany
†Electronic supplementary information (ESI) available. CCDC
855690–855695, 905448–905453. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob07020k
9344 | Org. Biomol. Chem., 2012, 10, 9344–9348
This journal is © The Royal Society of Chemistry 2012

View Article Online
The diversity of properties of 3-acylchromones is due to the
fact that, being actually highly reactive geminally activated
push–pull alkenes with a good leaving group at the β-carbon
atom, whose role is played by the phenolate anion, they acquire
the ability to undergo additional transformations related to
opening and recyclization of the γ-pyrone ring. Strangely
enough, but these compounds have long remained out of sight of
chemists engaged in organic synthesis, and their systematic
study has started only in recent years. Nevertheless, it is already
clear that chromones 1 and 2 are valuable substrates for the syn-
thesis of diverse heterocycles with a potential biological
activity.6,20 3-Aroylchromones 3 are less reactive than chro-
mones 1 and 2 due to steric and electronic factors, however, their
reactivity can be enhanced by introducing electron-withdrawing
substituents, such as a nitro group and a fluorine atom, into the
aroyl moiety. In the initial study we have prepared a series of
substituted chromones 1–3 starting from easily accessible
3-dimethylamino-1-(2-hydroxyaryl)prop-2-en-1-ones by a one-
pot acylation procedure.6–8 Note that 3-polyfluoroacylchromones
2 were prone to the facile and reversible covalent hydrate for-
Fig. 1 3-Acylchromones 1–3 used for the reactions with 1,3-C,C-
dinucleophiles.
1
mation as observed from their H and 19F NMR spectra, which
contained two sets of signals (Fig. 1).7
Continuing our research program dedicated to the design and
synthesis of novel heterocyclic compounds and in view of the
unique biological properties displayed by many chromones and
coumarin derivatives1,24 Iaroshenko’s laboratory started investi-
gation in this area by the study of the reactions of chromones
1–3 with dimethyl 1,3-acetonedicarboxylate. It was found that
the treatment of chromones 1 (X = CO2Me) with dimethyl aceto-
nedicarboxylate (1.1 equiv.) in dioxane at room temperature in
the presence of DBU (1.3 equiv.)11 resulted in the formation of
functionalized 2-hydroxybenzophenones 4a–g with an excellent
regioselectivity and in good yields (46–87%). In most cases, the
reaction was complete after 10–12 h and the products could be
isolated by simple filtration of the precipitate formed or by
column chromatography over silica gel. The progress of the reac-
tion was monitored by TLC, and the results are summarized in
Scheme 2.
While dimethyl acetonedicarboxylate reacts with chromones 1
at the methoxalyl group (route a) to produce compounds 4a–g,
its reactions with chromones 2 (X = RF) under the same con-
ditions took an entirely different course and gave a series of 6H-
benzo[c]chromenes 5a–n in 56–78% yields. This heterocyclic
system certainly is the product of the primary 1,4-addition fol-
lowed by the pyrone ring-opening, attack of the second CH2
group on the carbonyl bound to the aromatic cycle, and ring-
closure involving the phenolic hydroxyl and RFCO group (route
b). It is necessary to underline that in this case the attack of the
CH2 group is mainly directed to the carbonyl at the aromatic
ring, due to which the RFCO group remains free and can partici-
pate in the formation of cyclic semiketal form 5. This result
clearly shows that the present methodology could be applicable
to various types of 3-polyfluoroacylchromones 2, providing a
rapid route to the synthesis of a wide range of the RF-containing
6H-benzo[c]chromene derivatives 5 (Scheme 2).
Scheme 1 Reactions of 3-substituted chromones with dialkyl 1,3-
acetonedicarboxylates.
sequential [3 + 3]-cycloaddition–Suzuki cross-coupling reac-
tions,16 Me3SiOTf-mediated condensation of 1,3-bis(silyl enol
ethers) with chromones followed by a domino retro-Michael–
aldol–lactonization process,17 and reactions of chromone and
3-nitrochromone with dialkyl acetonedicarboxylates.11,18 It is inter-
esting that the condensation of 3-bromochromones with dimethyl
acetonedicarboxylate gave a highly unexpected product contain-
ing a cyclopropyl ring III,11 whereas from 3-cyanochromones
5H-chromeno[2,3-b]pyridine IV was obtained (Scheme 1).19
It should be noted that all these reactions with 3-substituted
chromones, leading to various types of products I–IV, proceed
via nucleophilic 1,4-addition at the 2-position followed by
opening of the γ-pyrone ring. Although 3-substituted chromones
(3-formyl-,4,5 3-trifluoroacetyl-,7,20 3-dichloroacetyl-,21 3-meth-
oxalyl-,6 3-cyano-,22 and 3-nitrochromones23) are widely used as
valuable synthetic intermediates in the preparation of new
heterocycles, examples of the participation of chromones 1–3 in
any reactions with 1,3-C,C-dinucleophiles are lacking, a fact
prompting us to investigate their reactions with dimethyl 1,3-
acetonedicarboxylate and 1,3-diphenylacetone. We are reporting
the straightforward synthesis of functionalized 2-hydroxy-
benzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins
from chromones 1–3 as 1,3-dielectrophiles and two mentioned
active methylene compounds.
Thus, the most important step in determining the structure of a
product is intramolecular cyclization of intermediate A (route a
or b). From this point of view, it clearly appears that the more
reactive methoxalyl group has a proclivity to the formation of
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9344–9348 | 9345

View Article Online
The regiochemistry of compounds 4b,c,k,m, 5h and 6a,d was
unambiguously confirmed by X-ray single crystal analyses
(Fig. S1–S7, see the ESI†).25 In addition, the HMBC spectrum
of 6d displayed cross-peaks between the resonances of the
ortho-H-2′, H-6′ (δ 7.85 ppm, 2H) and H-9 (δ 8.08 ppm) and the
benzoyl carbonyl (δ 196.4 ppm); for 4i the most informative
were the cross-peaks between the salicyloyl carbonyl (δ
196.1 ppm) and the hydrogen atoms H-3′, H-5′ (δ
6.79–6.83 ppm), H-4′, H-6′ (δ 7.31–7.41 ppm) and H-5 (δ
7.99 ppm).
The reaction of chromones 1 and 3 with 1,3-diphenylacetone
as a 1,3-C,C-dinucleophile was also investigated. It was expected
that the nucleophilic C atom of 1,3-diphenylacetone would
cleave the pyrone ring to give via intermediate A the required
substituted benzenes. In fact, we found that this condensation,
under the same reaction conditions at reflux, affords target pro-
ducts 7a–g and 8a–e, molecules of which consist of four or five
aromatic ring fragments (Scheme 3). In this case, intramolecular
attack of the methylene group on the more reactive methoxalyl
or nitrobenzoyl carbonyls (except for 2-nitrobenzoyl) leads to
the 2-hydroxybenzophenone derivatives 7a–e in 42–74% yields
(route a), whereas the reaction of 3-(2-nitrobenzoyl)chromones 3
proceeds at the salicyloyl carbonyl group to give compounds
8a–c in 59–73% yields (route b). As expected, both carbonyl
groups of 3-benzoyl- and 3-(2-thenoyl)chromones 3 reacted with
1,3-diphenylacetone to give mixtures 7f + 8d and 7g + 8e
(routes a and b), from which compounds 7f,g and 8d,e were iso-
lated by column chromatography in a pure state.
Scheme 2 Synthesis of compounds 4–6.
2-hydroxybenzophenone derivatives 4, while a partially hydrated
polyfluoroacyl group of chromones 2 would be responsible for
their observed different reactivity.
It is important that similar reactions of 3-(2-nitrobenzoyl)chro-
mone 3 (X = 2-NO2C6H4) afforded benzo[c]coumarins 6a–c
(route b), due to the fact that in this case intramolecular cycliza-
tion took place with the participation of the OH and CO2Me
groups. On the other hand, polyfunctionalized 2-hydroxybenzo-
phenones 4h–j were obtained in 47–83% yields from 3-aroyl-
chromones 3 (X = 3-NO2C6H4, 4-NO2C6H4, 3,5-(NO2)2C6H3)
and dimethyl acetonedicarboxylate (route a, Scheme 2). When
3-benzoyl-, 3-(2-thenoyl)- and 3-(2-fluorobenzoyl)chromones 3
(X = Ph, 2-C4H3S, 2-FC6H4) were used, the reaction also pro-
ceeded smoothly to give, however, mixtures 4k + 6d, 4l + 6e
and 4m + 6f, from which 2-hydroxybenzophenones 4k–m and
benzo[c]coumarins 6d–f were isolated by column chromato-
graphy in a pure form. The reaction includes the nucleophilic
1,4-addition of the first CH2 group with concomitant opening of
the pyrone ring and subsequent intramolecular cyclization with
the participation of the second CH2 group and the ArCO moiety
to give compounds 4h–m; for intramolecular attack of the
salicyloyl radical the reaction would result in the benzo[c]cou-
marins 6a–f.
In the NMR spectra of 7a–g in DMSO-d6, the phenolic OH
groups appeared as two singlets at δ 8.6–9.3 and 10.5–11.6 ppm
(intramolecular O–H⋯OvC hydrogen bond); in contrast, in
compounds 8a–e they were observed at
δ 8.4–8.7 and
8.9–9.2 ppm. Moreover, the HMBC spectrum of 7e displayed
cross-peaks between the salicyloyl carbonyl (δ 197.9 ppm) and
the hydrogen atoms H-3′, H-5′ (δ 6.74–6.81 ppm) and H-4′, H-6′
(δ 7.36–7.41 ppm). The exact structure of 7d,f,g and 8c,e was
established by X-ray single crystal analysis (Fig. S8–S12, see the
ESI†).25
It is necessary to mention that not all 3-substituted chromones
reacted with 1,3-diphenylacetone and dimethyl acetonedicarbox-
ylate with the formation of the corresponding benzenes; in the
case of 3-(2-phenylethynyl)chromone, prepared for this study,
the reaction led to the mixture of inseparable regioisomers, low
soluble in common organic solvents. We also hoped to spread
Thus, higher reactivity of the carbonyl group connected to the
3-NO2C6H4, 4-NO2C6H4 and 3,5-(NO2)2C6H3 than 2-HOC6H4
of intermediate A toward the CH2 group was shown. Clearly the
electron-withdrawing NO2 group enhances the electrophilicity of
the ArCO and encourages nucleophilic addition at this carbonyl
group. Unexpectedly lower reactivity of 2-O2NC6H4CO
appeared to be a result of the steric effect of the ortho-substituted
nitro group. These results show the interplay of electronic and
steric factors on the course of the reaction with dimethyl acetone-
dicarboxylate and make it very useful for a combinatorial
approach to the synthesis of novel benzene derivatives with
potential biological activity and useful physical properties.
Scheme 3 Synthesis of compounds 7 and 8.
9346 | Org. Biomol. Chem., 2012, 10, 9344–9348
This journal is © The Royal Society of Chemistry 2012

View Article Online
has been shown for compounds 5, where due to the rigidity of
the structure the maximal overlapping between the orbitals of
two benzene rings is realized; in this case, the absorption coeffi-
cients were ε = 29 000–84 000 cm−1 mol−1 L. For compound 5f
we have observed the highest absorption coefficient of ε =
84 000 cm−1 mol−1 L in this series. In general, absorptions
observed in the current study for the scaffolds 4, 5 and 7 are sig-
nificantly higher compared with other known UVA/UVB filters29
and with the UV-filters we have prepared in our recent study.28
One of the strong requirements for suncream-additives is an
increased water solubility which ensures the good miscibility of
the components in the emulsion. This was achieved by the
above-mentioned hydrolysis of the ester derivatives to the corre-
sponding salts and subsequent transformation into the acids 9.
The water solubility of these compounds is prominent even at
room temperature and lies in a range of 10–20 g L−1. Moreover,
the potassium salts, which were isolated in many cases as inter-
mediates of the hydrolysis process, have increased solubility of
about 20–40 g L−1
.
Scheme 4 Hydrolysis of compounds 4 and 5.
In conclusion, we have developed a simple and convenient
method for the synthesis of functionalized 2-hydroxybenzophe-
nones, 6H-benzo[c]chromenes and benzo[c]coumarins by formal
[3 + 3] cyclocondensations of 3-acylchromones with dimethyl-
1,3-acetonedicarboxylate and 1,3-diphenylacetone. The products
constitute an important structural subunit of a variety of biologi-
cally active compounds, which are not readily available by other
methods. The biological evaluation of the synthesized com-
pounds is currently being studied in our laboratories. Neverthe-
less, due to the strong UV-absorption properties of many of the
representatives the libraries synthesized here can also find a use
in the preparation of the sun-protective materials and creams.
the scope on the unsymmetrical 1,3,5-tricarbonyls, however,
these attempts experienced a failure.
Further experiments were conducted to study the base-
mediated hydrolysis of the products obtained. We found that
compounds 4a,b,e,g, when treated with potassium hydroxide in
refluxing methanol, underwent conversion into tricarboxylic
acids 9a,b,e,g (80–92% yields, Scheme 4). The parent 3-methoxy-
benzene-1,2,4-tricarboxylic acid was first obtained as the minor
product of the oxidation of gladiolic acid.26
Next, taking into account the above results and that the benzo-
[c]coumarin ring is an important structural fragment of many
natural and biologically active substances,12–15 it was of interest
to evaluate the behavior of 6H-benzo[c]chromenes 5c,n in their
reactions with potassium hydroxide with the purpose of the prep-
aration of novel benzo[c]coumarin derivatives. We found that
these compounds react with potassium hydroxide to produce
10c,n in 70 and 92% yields, respectively (Scheme 4). The for-
mation of 10 can be rationalized by assuming that the initially
formed salt 5′ undergoes a haloform reaction followed by sub-
sequent protonation and cyclization. Interestingly, although the
chemistry of the benzo[c]coumarin system has been well
documented,11,16–18,27 compounds 10 are hitherto unreported.
Experimental
General procedure for the synthesis of compounds 4–8
To a stirred reaction mixture of the corresponding chromone
(1.0 mmol) and 1,3-C,C-dinucleophile (1.1 mmol) in dioxane
(6–7 mL), DBU (0.20 mL, 1.3 mmol) was added slowly via a
syringe at room temperature. Stirring at room temperature (for
dimethyl acetonedicarboxylate) or at reflux (for 1,3-diphenylace-
tone) was continued until chromone was consumed completely
(followed by TLC, approximately 10–12 h). The reaction
mixture was quenched with an aqueous solution of 10% NH4Cl
and extracted with chloroform, dried (Na2SO4), the solvent was
distilled off under reduced pressure, and the resulting residue
was subjected to column chromatography on silica gel using
heptane–ethylacetate (5 : 1) as an eluent, slowly increasing the
polarity up to 3 : 1 to give the isolated products.
UV-study
Very recently we have communicated the synthesis of a series of
benzophenones as novel UV-filters with the intensive absorption
in the A and B UV-range.28 Inspired by our recent study and
taking into account the structural similarities of the compounds
synthesized here with presently known UV-filters used indust-
rially for the production of sunlight protective materials, we have
undertaken the study of the UV-activity of the library of com-
pounds synthesized. As is shown in the ESI,† benzophenones 4
and 7 have shown the intensive absorption resulting in three
λmax at 230 nm (UVC), 240–290 nm (UVC) and 315–380 nm
General procedures for the synthesis of compounds 9 and 10
To a stirred reaction mixture of the corresponding compound 4
or 5 (1.0 mmol) in methanol (6–7 mL) potassium hydroxide
(8.0 mmol) was added. The reaction mixture was heated under
reflux. Stirring and heating were continued until the reagent was
consumed completely (followed by TLC, approximately 2 days).
The solvent was distilled off in a vacuum and the resulting
residue was quenched with water, then neutralized with an
(UVA/UVB) with the absorption coefficients
ε
=
45 000–89 000 cm−1 mol−1 L. As expected, the high absorption
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9344–9348 | 9347

View Article Online
H. Reinke and P. Langer, Eur. J. Org. Chem., 2006, 3638–3644;
(e) M. Lubbe, B. Appel, A. Flemming, C. Fischer and P. Langer, Tetra-
hedron, 2006, 62, 11755–11759.
aqueous solution of HCl (30%). The resulting residue was
filtered and dried.
11 M. A. Terzidis, C. A. Tsoleridis, J. Stephanidou-Stephanatou, A. Terzis,
C. P. Raptopoulou and V. Psycharis, Tetrahedron, 2008, 64, 11611–
11617.
Acknowledgements
12 W. T. L. Sidwell, H. Fritz and C. Tamm, Helv. Chim. Acta, 1971, 54,
207–215.
13 C. Tamm, Arzneim.-Forsch., 1972, 22, 1776–1784.
14 H. Raistrick, C. E. Stickings and R. Thomas, Biochem. J., 1953, 55,
421–433.
Financial support by the Landesgraduirte (scholarships for I. S.)
is acknowledged.
15 R. W. Pero, D. Harvan and M. C. Blois, Tetrahedron Lett., 1973, 14,
945–948.
Notes and references
16 (a) I. Hussain, V. T. H. Nguyen, M. A. Yawer, T. T. Dang, C. Fischer,
H. Reinke and P. Langer, J. Org. Chem., 2007, 72, 6255–6258;
(b) V. T. H. Nguyen and P. Langer, Tetrahedron Lett., 2005, 46, 1013–
1015.
1 (a) G. P. Ellis, Chromenes, Chromanones and Chromones, in The Chem-
istry of Heterocyclic Compounds, Wiley, New York, 1977, vol. 31;
(b) S. T. Saengchantara and T. W. Wallace, Nat. Prod. Rep., 1986, 465–
475.
17 (a) B. Appel, N. N. R. Saleh and P. Langer, Chem.–Eur. J., 2006, 12,
1221–1236; (b) E. Ullah, B. Appel, C. Fischer and P. Langer, Tetra-
hedron, 2006, 62, 9694–9700; (c) M. Lubbe, B. Appel, A. Flemming,
C. Fischer and P. Langer, Tetrahedron, 2006, 62, 11755–11759;
(d) P. Langer and B. Appel, Tetrahedron Lett., 2003, 44, 5133–5135.
18 G. Haas, J. L. Stanton and T. Winkler, J. Heterocycl. Chem., 1981, 18,
619–622.
19 (a) C. K. Ghosh, Synth. Commun., 1978, 8, 487–490; (b) C. K. Ghosh,
D. K. SinhaRoy and K. K. Mukhopadhyay, J. Chem. Soc., Perkin Trans.
1, 1979, 1964–1968.
20 (a) V. Y. Sosnovskikh, R. A. Irgashev and M. I. Kodess, Tetrahedron,
2008, 64, 2997–3004; (b) V. Y. Sosnovskikh, I. A. Khalymbadzha,
R. A. Irgashev and P. A. Slepukhin, Tetrahedron, 2008, 64, 10172–
10180; (c) A. Kotljarov, R. A. Irgashev, V. O. Iaroshenko, D. V. Sevenard
and V. Y. Sosnovskikh, Synthesis, 2009, 3233–3242; (d) A. Kotljarov,
V. O. Iaroshenko, D. M. Volochnyuk, R. A. Irgashev and
V. Y. Sosnovskikh, Synthesis, 2009, 3869–3879.
21 V. O. Iaroshenko, S. Mkrtchyan, G. Ghazaryan, A. Hakobyan, A. Maalik,
L. Supe, A. Villinger, A. Tolmachev, D. Ostrovskyi, V. Y. Sosnovskikh,
T. V. Ghochikyan and P. Langer, Synthesis, 2011, 469–479.
22 (a) V. Y. Sosnovskikh, V. S. Moshkin and M. I. Kodess, Tetrahedron
Lett., 2009, 50, 6515–6518; (b) V. Y. Sosnovskikh, V. S. Moshkin and
M. I. Kodess, J. Heterocycl. Chem., 2010, 47, 629–633;
(c) V. Y. Sosnovskikh, V. S. Moshkin and M. I. Kodess, Izv. Akad. Nauk
Ser. Khim., 2010, 602–611 (Russ. Chem. Bull., Int. Ed., 2010, 59,
615–625).
23 (a) D. Ostrovskyi, V. O. Iaroshenko, A. Petrosyan, S. Dudkin, I. Ali,
A. Villinger, A. Tolmachev and P. Langer, Synlett, 2010, 2299–2303;
(b) V. O. Iaroshenko, S. Mkrtchyan, A. Gevorgyan, M. Vilches-Herrera,
D. V. Sevenard, A. Villinger, T. V. Ghochikyan, A. Saghiyan,
V. Y. Sosnovskikh and P. Langer, Tetrahedron, 2012, 68, 2532–2543.
24 M. E. Riveiro, N. De Kimpe, A. Moglioni, R. Vázquez, F. Monczor,
C. Shayo and C. Davio, Curr. Med. Chem., 2010, 17, 1325–1338, and
references cited therein.
25 X-Ray crystallographic data (excluding structure factors) for the structures
4b,c,k,m, 5h, 6a,d, 7d,f,g and 8c,e reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC 855690–855695, 905448–905453 and
can be accessed with the ESI.†
26 D. Gardner, J. F. Grove and D. Ismay, J. Chem. Soc., 1954, 1817–1819.
27 (a) O. Fatunsin, V. O. Iaroshenko, S. Dudkin, S. Mkrtchyan, A. Villinger
and P. Langer, Tetrahedron Lett., 2010, 51, 4693–4695;
(b) V. O. Iaroshenko, M. S. A. Abbasi, A. Villinger and P. Langer, Tetra-
hedron Lett., 2011, 52, 5910–5912.
28 V. O. Iaroshenko, A. Bunescu, A. Spannenberg, L. Supe, M. Milyutina
and P. Langer, Org. Biomol. Chem., 2011, 9, 7554–7558.
29 (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.
2 D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103,
893–930.
3 (a) C. Morin and R. Beugelmans, Tetrahedron, 1977, 33, 3183–3192;
(b) M. A. Ibrahim, T. E. Ali, Y. A. Alnamer and Y. A. Gabr, ARKIVOC,
2010, i, 98–135; (c) C. K. Chosh, J. Heterocycl. Chem., 2006, 43, 813–
820; (d) C. K. Ghosh and S. K. Karak, J. Heterocycl. Chem., 2005, 42,
1035–1042; (e) V. Y. Sosnovskikh, Usp. Khim., 2003, 72, 550–578
(Russ. Chem. Rev., 2003, 72, 489–516).
4 (a) C. K. Ghosh, J. Heterocycl. Chem., 1983, 20, 1437–1445;
(b) G. Sabitha, Aldrichimica Acta, 1996, 29, 15–25; (c) W. D. Jones and
W. L. Albrecht, J. Org. Chem., 1976, 41, 706–707; (d) H. Chen, F. Xie,
J. Gong and Y. Hu, J. Org. Chem., 2011, 76, 8495–8500; (e) L. Zhao,
F. Xie, G. Cheng and Y. Hu, Angew. Chem., Int. Ed., 2009, 48, 6520–
6523.
5 (a) C. K. Ghosh and A. Patra, J. Heterocycl. Chem., 2008, 45, 1529–
1547; (b) C. K. Ghosh, Heterocycles, 2004, 63, 2875–2898;
(c) R. Gašparová and M. Lácová, Molecules, 2005, 10, 937–960.
6 (a) J. H. Park, S. U. Lee, S. H. Kim, S. Y. Shin, J. Y. Lee, C.-G. Shin,
K. H. Yoo and Y. S. Lee, Arch. Pharmacal Res., 2008, 31, 1–5;
(b) S. Mkrtchyan, V. O. Iaroshenko, S. Dudkin, A. Gevorgyan,
M. Vilches-Herrera, G. Ghazaryan, D. Volochnyuk, D. Ostrovskyi,
Z. Ahmed, A. Villinger, V. Y. Sosnovskikh and P. Langer, Org. Biomol.
Chem., 2010, 8, 5280–5284; (c) D. Ostrovskyi, V. O. Iaroshenko, I. Ali,
S. Mkrtchyan, A. Villinger, A. Tolmachev and P. Langer, Synthesis, 2011,
133–141.
7 (a) I. Yokoe, K. Maruyama, Y. Sugita, T. Harashida and Y. Shirataki,
Chem. Pharm. Bull., 1994, 42, 1697–1699; (b) V. Y. Sosnovskikh and
R. A. Irgashev, Synlett, 2005, 1164–1166; (c) V. Y. Sosnovskikh,
R. A. Irgashev and M. A. Barabanov, Synthesis, 2006, 2707–2718;
(d) V. Y. Sosnovskikh and R. A. Irgashev, Heteroat. Chem., 2006, 17,
99–103.
8 (a) F. Eiden and H. Haverland, Arch. Pharm., 1967, 300, 806–810;
(b) F. Eiden and H. Haverland, Arch. Pharm., 1968, 301, 819–826.
9 (a) Y.-L. Huang, C.-C. Chen, Y.-J. Chen, R.-L. Huang and B.-J. Shieh,
J.Nat. Prod., 2001, 64, 903–906; (b) R. W. Fuller, C. K. Westergaard,
J. W. Collins, J. H. Cardellina and M. R. Boyd, J. Nat. Prod., 1998, 62,
67–69; (c) T. Tzanova, M. Gerova, O. Petrov, M. Karaivanova and
D. Bagrel, Eur. J. Med. Chem., 2009, 44, 2724–2730; (d) G. R. Reddy,
C.-C. Kuo, U.-K. Tan, M. S. Coumar, C.-Y. Chang, Y.-K. Chiang,
M.-J. Lai, J.-Y. Yeh, S.-Y. Wu, J.-Y. Chang, J.-P. Liou and H.-P. Hsieh,
J. Med. Chem., 2008, 51, 8163–8167; (e) G. Tang, Z. Nikolovska-
Coleska, S. Qiu, C.-Y. Yang, J. Guo and S. Wang, J. Med. Chem., 2008,
51, 717–720; (f) S. Rancon, A. Chaboud, N. Darbour, G. Comte,
C. Bayet, P.-N. Simon, J. Raynaud, A. Di Pietro, P. Cabalion and
D. Barron, Phytochemistry, 2001, 57, 553–557.
10 (a) M. A. Yawer, I. Hussain, C. Fischer, H. Görls and P. Langer, Tetra-
hedron, 2008, 64, 894–900; (b) P. Langer and B. Appel, Tetrahedron
Lett., 2003, 44, 7921–7923; (c) V. T. H. Nguyen, B. Appel and P. Langer,
Tetrahedron, 2006, 62, 7674–7686; (d) B. Appel, S. Rotzoll, R. Kranich,
9348 | Org. Biomol. Chem., 2012, 10, 9344–9348
This journal is © The Royal Society of Chemistry 2012