Chromones and bischromones: an account of photoinduced reactions

This account provides a survey of phototransformations of chromones occurring through the cycloadditions, oxidations, isomerizations and reorganizations. Photochemistry of the variety of bischromones occurring through intramolecular photo-H-abstractions and thus leading to angular tetracyclic photoproducts has also been reviewed. In the bischromones, the photoproduct formations and their distributions were found to be dependent upon the length and structure of the intermediate spacer units


Introduction
Chromones 1 have been the subject of the considerable chemical interest in the past decades.They occur widely in nature and exhibit important biological as well as pharmacological activities. 2 They are photochemically very active and lead to the generation of some exotic heterocyclic compounds. 3Flavonoids 4 are the chromones that are also most abundantly distributed in nature.Peucenin, 5 eugenitol 6 and isoeugenitol 7 are some commonly occurring chromones.The chromones are also well known for their antioxidant, 8 biocidal, 9 wound healing, 10 anti-inflammatory, 11 antiulcer, 12 and immune-stimulatory 13 activities.Recently, some chromones are also reported as anti-HIV agents. 14Khellin 15 1 and 2,4-thiazolidenedione 16 2 are the chromones that are used as antispasmodic agent, in the treatment of anginapectoris and antidiabetic agent that improve peripheral insulin resistance in type-II diabetic patients respectively.These pharmacological activities have been the major incentives behind the synthesis of the chromones and their derivatives.

Chromones
As chromones are present in all parts of the plant kingdom, they are exposed to sun light for longer durations of time that make them liable to undergo some photo-structural transformations.
As chromones are bichromophoric substrates that contain double bond as well as C=O group as the chromophoric units which can undergo photo-excitation either in isolation or in conjugation.

Photocycloaddition reactions
Photocycloaddition reactions of chromones with different olefins and related compounds are known to provide the products both through [3+2] and [2+2]π cycloaddition reactions.[2+2]π photocycloaddition reactions are extensively studied by Hanifin and Cohen. 17These photoaddition reactions involve an electrophilic attack by C-3 of chromone involving n→π* triplet excitation with the fact that only phosphorescence is observed and no fluorescence is observed.It is consistent with the idea that intersystem crossing from n→π* singlet to triplet should be rapid when singlet to triplet energy gap is small. 18Singlet-triplet energy gap for chromone in 2M THF is only about 5-kcal/mol.
Irradiation of a solution of chromone 4 with 1,1-dimethoxyethylene 5 gave photoproducts 6 and 7.But further studies have shown that 7 was a secondary photolysis product arising from 6.

Scheme 3
Large-coupling constant for these photocycloaddition products by [2+2]π addition revealed the cis orientation. 19The mechanism of cyclobutane formation is probably best described as an unsensetized 19c and electrophilic attack by C α of the n→π* chromone triplet on the most nucleophilic carbon atom of the olefin to give a

Photodimerization
Mukerjee 20 and coworkers have reported the phototransformation of 3-methoxychromone 10 where H-abstraction coupled with dimerization has led to the formation of dimeric oxetanol 12.

Scheme 5
Under photolytic conditions, the chromones undergo fast enolisation.Upon the irradiation of 13a for 1-2 min., the orange photoenol 14a was formed which displayed a λ max at 460 mµ.But orange color faded very quickly which led to the reformation of 13a.

Scheme 10
The formation of 28 from 26 could be analysed through the intermediacy of 2,3-epoxy-2hydroxy-1-indanone 27 which can be formed by a formal [σ 2 +π 2 ] cycloaddition.Recently, some work has been done in our lab upon the photolysis of 3-hydroxy-2thienylchromone in cyclohexane 28 that also resulted similar type of ring contracted photoproduct 30.

Photoxidation and reduction reactions
Chromones are also liable to undergo photo-oxidation 29 and photoreduction 30 that lead to a wide variety of products.Photo-oxidation of 3-hydroxyflavone 31 has been found to yield 32 and 33 as product through the reorganization and degradation.

Scheme 15
But, at room temperature, the triplets of 37 and 39 were poorly quenched by 1methylnaphthalene (E T =59.6 Kcal/mol), diene (E T =59 kcal/mol) and ferrocene (E T =40kcal/mol).In contrast, triplet of 38, which has a lower E T than 37 and 39, was very efficiently quenched by these molecules.
Spectroscopic triplet energies (E T ) of 37, 38 and 39 were estimated as 69, 62 and 67 Kcal/mol, respectively.The triplets of these 37 and 39 may probably undergo structural relaxation to geometric forms from which energy transfer to benzophenone would be of highly endothermic process.
There were difference in the behavior of triplets of two chromones 38 and 39.As it was evident from the quenching behaviors, the triplets of 38 that undergo very little or no relaxation while that in the case of 39 was pronounced.This difference was attributable to the fact that, while in the ground state the minimization of the nonbonding interaction involving the adjacent phenyl groups, occured through the partial twisting of the phenyl groups from the plane of chromone moiety, in the triplet excited state it was effected by twisting about the ene.

ARKAT 2.8 Photoinduced H-abstraction
H-abstractions by the excited carbonyl chromophores have been the most investigated photochemical reactions.These H-abstractions can be manipulated for the generation of some exotic heterocyclic compounds. 32

3-Alkoxychromones
The phototransformations of the 3-alkoxychromones 29 41 did not provide any ring contracted product 42 corresponding to 28 and 30, but resulted tetracyclic compound 40 which could be ascribed from the intramolecular H-abstraction by photoexcited C=O group.

Scheme 16
A product similar to 40 has also been known to be formed from 3-methoxyflavones by irradiation either under nitrogen 33 or oxygen. 34It is also reported that the 5-hydroxyl group Hbonded to the 4-carbonyl that causes photoresistance in flavonoids.

Scheme 18
Here, product distributions depend upon the substituents on the thiophene ring.This study explained that (i) How a thiophene moiety (stabilization energy (SE) 32 Kcalmol -1 affect the product formation/distribution compared with a furan (SE = 16-18 Kcalmol -1 ) or phenyl moiety (SE = 36 Kcalmol -1 ) at C-2 and (ii) whether phototranspositions could become available in these photoreactions: a route common in the photolysis of 2-aryl/alkyl thiophenes. 37

Scheme 19
Even the solvent polarity (C 6 H 6 , MeOH) did not have any significant influence on the product distributions.This suggests that the formation of 47 is intramolecular and probably occurs through a 1,5-sigmatropic migration, in enol 46a, formed initially by the abstraction of hydrogen from 3-alkoxy group by the excited C=O group of the pyrone moiety.
Regarding the effect of the substitution at C-2 of the pyrone ring on product formation/distribution, an examination showed that in case of furyl, methylfuryl or methylthiophene chromones, only the photocyclised products similar to 47 were obtained.In others carrying phenyl or thiophene rings, both photocyclised, as 47 and photocyclodehydrogenated, as 48 are formed.For such results, the only assignable reason could be the difference in the electron density in the ring moiety at C-2.
In phototransformations of 3-alkoxy-2-(2'-furyl)chromones 38 in dry benzene, no dehydrogenated product was obtained as discussed above.The primary product was a dihydrofuryl derivative 49 that further underwent photoringcontraction 39,40 to a cyclopropyl carbonyl compound 50.When photoirradiation was carried out in MeOH, then photoproduct 51 was also realized along with the 49 and 50.
Here, again the formation of photoproducts 57 and 58 from 56 and 60 & 61 from 59, as shown in scheme 22, could be analyzed only through the involvement of 1,4-biradicals.

Scheme 22
Mechanistically, the formation of photoproduct 61 may be ascribed again from the ring contraction 38 of the dihydroproduct 60, it could not be directly obtained from the photolysis of 59.That was conformed from the observations that further photoirradiation of 60 provided 61 as the photoproduct.Photolysis of 2-thienyl-3-allyloxy-chromones 62 under similar conditions also furnished tetracyclic photoproducts 63 and 64.

Scheme 25
Similar aromatic photoproducts were formed when phenyl or substituted phenyl group was present at 2-position of thiochromone (69a & 69b) and similar chromones having R' = H, CH 3 and phenyl at C-2 position did not show any photoreactivity.The above photoreactions can be envisaged as being initiated through H-abstraction from 3-alkoxy group by excited C=S, for the H-abstraction, the energy of the excited C=S group and the strength of 3-O-C-H bond need to be ARKAT compatible.The energy of the excited thiones 48 is known to be between 160-200 KJmol -1 .In aromatic and unstrained cyclic thiones these states lie well below the threshold for intramolecular chemical transformations, the quantum yield of net photochemical consumption of 4H-1-benzopyrone-4-thione 49 is 5×10 -4 .Thus activation of C-H bond is necessary for reaction to occur.Though in chromones containing carbonyl group the H to be abstracted from 3-alkoxy group is activated by O-atom, does not seem to be adequate.A further activation is necessary and a phenyl group provides that.

Styrylchromones
Phototransformations of some styrylchromones have also been studied in detail. 50

Scheme 27
Similarly, photoirradiation of other styrylchromone 78 provided following three photoproducts 79, 80 and 81.Out of which two are linear and one is angular.

Scheme 28
But when the styrylchromones containing electron rich heterocycles (thiophene, furan) in place of phenyl at C-2 were photoirradiated, then only compound that could be isolated were angular tricyclic pyranoalcohols 82. 51,52

Spiropyrans: photochemical synthesis
Spirocyclic systems find extensive uses in various fields 54 developed earlier by various methods. 55A photochemical approach, as shown in scheme 30, towards the synthesis of complex spiropyrans 56 has been developed.

Scheme 31a
The better yields of the photoproducts in the above cases could be explained on the basis of the higher stabilities of 1,4-biradicals 99, provided by the naphthalene moiety, involved in these photoreactions.But, when the naphthalene moiety was replaced by an electron captive group (-COOEt) 93, then photoirradiation 57 resulted in the very low yields of the tetracyclic photoproducts 94 (10%) and 95 (5%) and always about 80% of starting material was recovered unreacted.Inspite of our best efforts, we were unable to isolate any cyclopropyl carbonyl derivative similar to 50, from the photolysis of 2-furylchromones 87 and 93.

Scheme 31b
Similar results (97 and 98) were observed when 2-phenylchromones 96 were photoirradiated in benzene, as shown in scheme 32.These observations may be ascribed to the lesser stability of the intermediate 1,4-biradical 100 than 99.Here, it appears that radical stabilizing effect of the ester group is offset by its inductive effect.

Bischromones
Bischromones are the bichromophoric compounds that are formed by joining the two chromone nuclei together through the carbon chains of varying length and structure.Some of the bischromones have been found to exhibit some important pharmacological 59 properties.1][62] But, in our lab, a very general and simple approach has been developed for the synthesis of bischromones. 63These synthesis were carried out in the presence of Bu 4 N + I -as PTC which not only decreased the reaction time drastically but also improved the yield of the bischromones.Bischromones are also photochemically active specially their 3-alkoxy derivatives.

3-Alkoxybischromones: Effect of length of intermediate spacer
Recently we have reported solution phase photolysis of 3-alkoxy-2-phenyl/thienyl 63 /furyl 42 bischromones, as shown in scheme 33 and 34.Our interest in these photoreactions were many folds: (i) 2,3-double bond of pyrone ring may undergo intramolecular [2+2] photocycloaddition reaction (ii) Photoreactions may be initiated through the γ-H-abstraction by the photo excited carbonyl (C=O) chromophore from -OCH 2 -group.The behavior of these bischromones towards photolysis seems dependent upon the length of the alkyl chain joining the two chromone nuclei.That is, there is no reaction when n=0, reaction occurs only on one side when n=1 and 2, and involves both sides of the molecules when n=3 and 8. 43 This may be rationalized on the basis of intramolecular complex formation between the two chromone moieties in these molecules.Herein, the governing factor could be the lifetime of the excited states involved and the free energy change accompanying the reactions.The possibility of the formation of the intramolecular complex is limited by the probability of overlapping of the two nuclei bearing the chromophores in the lifetime of the excited states involved.An intramolecular complex ARKAT formation can lead to the deactivation.An increase in the length of intervening alkyl chain shall increase the number of rotamers.Consequently, this decreases the tendency of intramolecular complex formation and deactivation of the excited state in turn.This is corroborated by the observation that the recovery of the starting bischromones was more than the 95% when n=0, ~60% when n=1 or 2, ~20% when n=3 and only 5% when n=8. 43 Although the possibility of the formation of the photoproducts similar to 104 and 105 from bischromones 101 (n=1 and 2) can not altogether be excluded, we were unable to isolate such products.However, investigations upon the photolytic behavior of the biscoumarins [64][65][66] and bispyrones, 67 the intramolecular cycloadditions involving the double bond of the pyrone ring have been reported; however in this study, no such intramolecular [2+2] photocycloaddition was observed and reaction occurred only through the H-abstractions.The intermolecular [2+2] photocycloadditions on 4-oxo-4H-pyrones is well documented. 17,19,68

p-Xylylbischromones
Further to study the behaviour of the intermediate 1,4-biradicals and affect of their stabilities upon the photoproduct formations and their distributions, these phototransformations were extended upon the bischromones built around p-xylyl moiety. 69n these bischromones also the photoproduct could be realized only through the intramolecular photo-H-abstraction.But, it is important to mention here that the photolysis of

Scheme 37
The chemical efficiency of these photoreactions was poor as the recovery of the bischromones 121 has been around 80% and this was inspite of the fact that photoreactions here were initiated through the involvement of benzylic hydrogens.This might be explained on the basis of the ease of intramolecular complex formation between the two units of the substrate that may come in close proximity to each other in one of the conformation leading to the deactivation of the excited molecule.This proximity factor also found support from earlier reports where the bischromone with ethylene (n = 0 in 101 and 109) as spacer failed to undergo any photoreaction whereas in the p-xylene based bischromone, the recovery of substrate was around 40%.In the later, the chromones were too far apart to be involved in complex formation.

Summary
Chromones and bischromones especially their 3-alkoxy derivatives provide themselves interesting substrates to study their photochemical reactions as these compounds undergo very easy intramolecular H-abstractions to yield numerous important tetracyclic products that are otherwise not possible to prepare under the normal thermal routes.The mild conditions under which these reactions are performed without the use of any precious and toxic reagents means that these synthesis are clearly of immense utilities in the area of synthetic organic chemistry for the development of exotic compounds.Thus, these chemical routes present an opportunity for the development of clean and green methods of the product formations.
The photolysis of 3-allyloxy-chromones bearing an electron captive substituent(-COOEt) and 3-cycloalkoxy-chromones offer simple and unique strategies for the synthesis of vinyl ethers and complex spiropyrans respectively.One area in which we see huge synthetic potential is in the bichromones and chromones based cyclophanes.Studies of these cyclophanes will provide an important contribution in the area of host guest relationship and supramolecular photochemistry.
In our present researches, we are focusing to investigate these photo H-abstractions in the bischromones built around trans-2-butenes, 2-butyne, cycloalkenes and heterocyclic rings like pyrrole, thiophene, furan and pyridine.This work will guide us to comment upon the various factors controlling the stabilities of the intermediate 1,4-biradicals and thus the product formations and their distributions in these photoreactions.As such, future of photochemistry of 3-alkoxychromones and bischromones look particularly bright and fruitful.

58
Scheme 32a Scheme 33 Scheme 35 1,4-diradical intermediate such as 8a followed by formation of cyclobutane ring.Competition reaction might be depending upon the olefin used for initial H-abstraction.
Upon longer irradiation of 14a, the photoenolisation coupled with cyclisation led to tetracyclic product 21b 15.

Scheme 14 2.7 Laser flash photolysis
30ara et al.30have made a detailed investigation on the photochemical reduction of chromones.Here, products 35 and 36 were obtained from the photoreduction of 2,3-double bond and >C=O group respectively. ARKATK.
filtered UV light led to cyclised 47 and cyclodehydrogenated 48 angular products involving both thiophene and alkoxy groups similar to 44 and 45.
Many methods are available45,46to obtain vinyl ethers, but this is the simplest method among them.