Coumarins 2+2 -photocycloadditions

Addition to six-membered oxygen heterocycles is also common. The photocycloaddition of 5,7-dimethoxycoumarin to tetramethylethylene has been described,269 and 4-hydroxycoumarin (326) undergoes facile addition to cyclohexene on direct irradiation to give the cyclobutane (327)270 analogous additions to a variety of other alkenes have been reported, and the cycloaddition of 4-methoxycoumarin to 2-methylpropene has been employed in a synthesis of l,2-dihydrocyclobuta[c]coumarin.271 Photoaddition of the 1,2-bisenol lactone (328) to tran.s-stilbene yields propellane (329),272 and [ 2 + 2] cycloaddition is observed along with other competing photoreactions on irradiation of chromone in the presence of alkenes.273... 

Photocycloaddition of C-P4-C. The photochemistry of coumarin and its derivatives has been the subject of numerous investigations, mainly as a consequence of its importance in biological systems [119-127], Irradiation of 7,7 -polymethylene-di(oxycoumarin)s at low concentrations yields only syn head-to-head and head-to-tail intramolecular cyclomers. Steric factors introduced in the corresponding molecule by methyl groups at the 4-positions of the coumarins led predominantly the syn head-to-tail cyclomer (Fig. 12). At higher concentrations, the amounts of intermolecular photoproducts increase as expected. 

Thiocoumarin photodimerizes more efficiently than does coumarin in solution and yields the head-to-head product. The photocycloaddition with 2,3-dimethylbut-2-ene affords a 4 1 mixture of the as- and trans-fused adducts, but terminal alkenes give only the m-fused cyclobutane in which the unsubstituted C atom has added to C-3 of the thiocoumarin (Equation 68) <1991JPH(57)231 >. Thiocoumarin reacts ca. 5 times faster under irradiation with tetrachloroethene than does isothiocoumarin (Scheme 70). Both thiocoumarins afford the appropriate m-fused adduct (Equation 69) <1997HCA1865>. 

The direct irradiation of the parent coumarin in the presence of alkenes results only in an inefficient photodimerization and [2 + 2]-photocycloaddition. Lewis acid coordination appears to increase the singlet state lifetime, and leads to improved yields in the stereospecific [2 + 2]-photocycloaddition [95]. Alternatively, triplet sensitization can be employed to facilitate a [2 + 2]-photocycloaddition. Yields of intramolecular [2 + 2]-photocycloadditions remain, however, even with electron-rich alkenes in the medium range at best. The preference for HT addition and for formation of the exo-product is in line with mechanistic considerations discussed earlier for other triplet [2 + 2]-photocycloadditions [96, 97]. Substituted coumarins were found to react more efficiently than the parent compound, even under conditions of direct irradiation. 3-Substituted coumarins, for example, 3-methoxy-carbonylcoumarin [98], are most useful and have been exploited extensively. The reaction of 3-ethoxycarbonylcoumarin (100) with 3-methyl-l-butene yielded cleanly the cyclobutane 101 (Scheme 6.36) with a pronounced preference for the exo-product (d.r. = 91/9). Product 101 underwent a ring-opening/ring-closure sequence upon treatment with dimethylsulfoxonium methylide to generate a tetrahydrodibenzofur-an, which was further converted into the natural product ( )-linderol A (102) [99]. 

Thiocoumarin (127) underwent [2 + 2]-photocycloaddition reactions in better yields than 126. In contrast to coumarin, cis- and trans-fused products are being found, however, for example, in the reaction with 2,3-dimethyl-2-butene, possibly because the thiopyran ring is more flexible than the pyran ring due to the longer C—S bonds. HTproduct is favored with electron donor-substituted olefins [121]. Electron acceptor substitution in 3-position, as in 3-cyano-l-thiocoumarin (128), leads to an improved performance in [2 + 2]-photocycloaddition reactions [122]. 

Other examples of favored formation of cyclobutanes include photocycloadditions of tri-fluoromethyl-substituted coumarins with dienes,and of 5-(trifluoromethyl)-l,3-dioxin-4-ones, e.g. 3, with alkenes, " - - " as well as intramolecular photocycloadditions, such as those of bicyclo[2.2.2]octadiene and tricyclononadiene derivatives. 

The photochemical behavior of coumarin and its derivatives has been the subject of numerous investigations. Triplet-sensitized cycloaddition efficiently gives the photodimers and cross-cycloadducts with simple alkenes. A kinetic study on the photocycloaddition of coumarin 106a has been reported (89JA8653). 

Photodimerisation of 7-fluoro-4-methylcoumarin (159) yields the topo-chemically expected anti-Kl photodimer (160) whereas 6-fluoro-4-methylcou-marin (161) produces the related syn-HH photodimer (162), but in higher yield. This apparent anomaly has been rationalised in terms of formation of the 5yn-HH photodimer by reaction at defect sites. Moreover, the failure of the parent coumarin to undergo the [2 + 2] photocycloaddition which is observed for the fluorine derivative illustrates the importance of substitution of H by F. 

The photobiological activity of the psoralens is related, at least in part, to the ability of these coumarins to undergo [ 2 + 2] photocycloaddition to pyrimidine bases in DNA. The two cis-syn adducts (101) and (102) have now been obtained by irradiation of 2 -deoxycytidine in the presence of 3-carbethoxypsoralen, whereas reversible [ 2 + 2] dimerisation of the coumarin nucleus is preferred on solid state irradiation of the 8-alkoxypsoralen derivative (103). ° [ 2 +, 2] Photoadditions of 7-aminocoumarins... 

The photocycloadditions of 2,3-dimethyl-l,3-diene with 4-(alk-l-ynyl)-substituted coumarins (5) produced a mixture of 4 + 2- and 4 + 4-cycloadducts (6) and (7), respectively. However, the corresponding thiocoumarins (8) yielded a single 4 + 2-cycloadduct (9) (Scheme 2)." The intramolecular photocycloadditions (>290nm) of 1,3-enynes with 2-pyridone yielded 2 + 2- and 4 + 4-cycloadducts. The Rh(I)-catalysed formal 5+l-/2 + 2 + 2-cycloaddition of 1-yne-vinylcyclopropanes (10) with two carbon monoxide units produced multifunctional angular tricyclic 5/5/6 compounds (11) in a one-step mechanism (Scheme 3). ... 

Photocycloaddition of coumarin derivatives functionalized by Si02 nanoparticles or based on self-assembled monolayer afforded [2 + 2] photocycloadducts (273). " Self-assembled phenylethynylene bisurea macrocycles and cucurbit[8]uril (CB[8j) catalyzed the photodimerization of coumarin derivatives " It is noticeable that four dimers of coumarin and 6-alkylcoumarin were easily cleaved to the corresponding monomers. 1,1-Dimethylnaphthalenone photodimerized to give head-to-head cyclobutane, which was photocleavable linkers. ... 

Pyrrolo[2,l-a]isoquinoline derivatives (27) were synthesized using Cgo-Bodipy dyads (28) as excellent photosensitizers (Scheme 13)/ Direct irradiation of glycine methyl ester to Ceo afforded [3 - - 2] cycloadduct/ Akasaka and his coworkers found the photocycloaddition of 2-ada-mantane-2,3-[3ff]diazirine and disilyliranes to Cso-metallofullerenes/ Intra- and inter-molecular photocycloaddition of alkenes to coumarin, quinolone, and isoquinolone derivatives have been reported by several groups. Griesbeck et al. found that the intramolecular photocycloaddition of cyclohexene moiety to coumarin (29) was catalysed by molecular ojygen. [2 + 2] Photocross dimer (33) of coumarin derivative (31) and 5-fluorouracil derivative (32) was obtained by laser irradiation/ Bach reported enantioselective intramolecular photocycloaddition of coumarins (34) to alkenes catalysed by a chiral Lewis acid (36) (Scheme 14)/ ... 

The [2-1-2]-cycloaddition reactions in inclusion crystals, or host-guest crystals, have been thoroughly reviewed. Coumarin 61a, thiocoumarin 61b, and cyclohex-2-enone 62 efficiently undergo single-crystal-to-single-crystal enantioselective photodimerization in inclusion complexes with chiral host compounds (R,R)-(-)-fra s 63a, (R,R)- -)-trans 63b, and (-)-64, respectively. The products are (-)-anri-HH 65a (100% EE), +)-anti-HH 65b (100% EE), and -)-syn-trans 66 (48% EE) dimers. An example for enantioselective intramolecular [2+2]-photocycloadditions in inclusion crystals is the reaction of guest 67 in chiral host 68. Irradiation of the powdered inclusion crystals in water suspension affords the optically active photocyclization product 69 with 100% EE in 90% yield. 

Intermolecular photocycloaddition reactions of 2-pyrones with alkenes have been much less extensively studied than those of coumarins. A typical reaction of coumarin 11 with an alkene is the formation of 12 (Scheme 4). The photocycloaddition reaction of dehydroacetic acid 13 with cyclohexene was first reported by Takeshita et al. in 1973 (Scheme 5). Irradiation of a mixture of 13 and cyclohexene leads to the formation of a diastereomeric mixture of [2+2]-cycloadducts 14, together with the usual dimer of the 2-pyrone. 

I- 2] Photocycloadditions are the most common psoralen photoaddition reactions. Ciamician and Silber first proposed a cyclobutane structure for a photodimer of coumarin. Von Wessely and Dinjaski and von Wessely and Plaichinger found that the same reaction occurs with UV-irradiated psoralens. They obtained dimers in which the pyrone rings of both monomers are joined through a cyclobutane ring (pyrone-pyrone dimer). 

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