Intermolecular photocycloadditions

As was mentioned in Section 13.2, the [27t + 27i] photocycloaddition of alkenes is an allowed reaction according to orbital symmetry considerations. Among the most useful reactions in this categoty, from a synthetic point of view, are intramolecular [27t + 2ti] cycloadditions of dienes and intermolecular [2ti + 2ti] cycloadditions of alkenes with cyclic a, -unsaturated carbonyl compounds. These reactions will be discussed in more detail in Section 6.4 of Part B. 

Stereoselective intermolecular [2- -2]-photocycloaddition reactions of unsaturated heterocycles with formation of fused systems 98S683. 

Intermolecular photocycloadditions of alkenes can be carried out by photosensitization with mercury or directly with short-wavelength light.179 Relatively little preparative use has been made of this reaction for simple alkenes. Dienes can be photosensitized using benzophenone, butane-2,3-dione, and acetophenone.180 The photodimerization of derivatives of cinnamic acid was among the earliest photochemical reactions to be studied.181 Good yields of dimers are obtained when irradiation is carried out in the crystalline state. In solution, cis-trans isomerization is the dominant reaction. 

The presence of Cu(I) salts promotes intermolecular photocycloaddition of simple alkenes. Copper(I) triflate is especially effective.182 It is believed that the photoreactive species is a 2 1 alkene Cu(I) complex in which the two alkene molecules are brought together prior to photoexcitation.183... 

Numerous examples of intermolecular and intramolecular photocycloaddition to heterocyclic systems (including the dimerization of individual heterocycles) have now been reported. Two types of cycloaddition can readily be effected photochemically, namely, [n2 + 2] and [ 4 + 4] additions. Although concerted suprafacial additions of this type are allowed photochemical processes, in reality many cycloadditions occur via diradicals, zwitterions or exciplexes. 

This chapter deals with [2 + 2]cycloadditions of various chromophors to an olefinic double bond with formation of a four-membered ring, with reactions proceeding as well in an intermolecular as in an intramolecular pattern. Due to the variety of the starting materials available (ketones, enones, olefins, imines, thioketones, etc.. . .), due to the diversity of products obtained, and last but not least, due to the fact that cyclobutanes and oxetanes are not accessible by such a simple one-step transformation in a non-photo-chemical reaction, the [2+2]photocycloaddition has become equivalent to the (thermal) Diels-Alder reaction in importance as for ring construction in organic synthesis. 

The synthetic applications 440) and mechanistic aspects 4411 of intermolecular photocycloaddition reactions of arenes to olefins have been reviewed recently. Intramolecular cycloadditions442a,b) have been studied in the context of the photochemical behaviour of bichromophoric molecules, as to investigate interchromophoric interactions in polyfunctional molecules. Three types of addition products can be formed in the photocycloaddition of benzene to an alkene (4.37)441. ... 

The first total synthesis of kelsoene was achieved by Mehta and Srinivas [7, 8]. The tricyclic scaffold was established by an intermolecular [2+2]-photocycloaddition of diquinane enone rac-6 and 1,2-dichloroethylene (7) as the key step (Scheme 2). As a consequence of the steric hindrance implemented... 

The fact that all approaches employing the intermolecular photocycloaddition key step used the same precursor for the construction of the four-membered ring renders enone 6 the key intermediate of the different synthetic strategies. It is therefore sensible to compare first the different strategies to synthesize precursor 6. Afterwards, the different ways to complete the syntheses of kelsoene will be discussed. 

In conclusion, the three groups which applied the intermolecular photocycloaddition as the key step in their approach to kelsoene (1) reported different strategies to synthesize the irradiation precursor 6 in racemic or enantiomerically pure form. After the photocycloaddition step the syntheses of kelsoene were completed in different ways. The next section describes the different strategies employed in the second half of the way to kelsoene. 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

An intermolecular [2+2] photocycloaddition of 2,2-dimethyl-l,3-dioxin-4-one and A -methyldihydropyrrole was the key step in the synthesis of kainic acid analogs. The cyclobutane intermediate was hydrolyzed with sodium methoxide to give ketoester 181 in good yield (Scheme 40) <2002SL167, 2003T3307>. 

As mentioned at the beginning of this section, intermolecular [2 + 2] photocycloadditions quite often afford product mixtures, depending on the alkene used as a ground state partner. A complete overview of such reactions described in the last twenty years would be far beyond the scope of this section and therefore attention will be directed to examples where the symmetric substitution pattern of the alkene allows for the formation of a specific cyclobutane derivative. 

Intermolecular [2 + 2] photocycloadditions of either 2-pyrones126 or cyclohexa-2,5-dienones127 proceed in low yields due to either competing [4 + 2] cycloadditions or due to monomolecular rearrangements. 

The N=N double bon d does take part in a few photocycloaddition reactions to give cyclic compounds with two adjacent nitrogen atoms in the ring. Intermolecular (2 + 2 cycloadditions are not known, but some intramolecular examples of this reaction are reported for quite complex compounds 15.27 in which the reacting groups are held fairly rigidly in an orientation suitable for reaction. A (4 + 2) cycloaddition takes place when naphthalene is irradiated with an electron-deficient cvdrc azo-compound (5.28). 

Schuster s and Weedon s results support Bauslaugh s proposed mechanism that emphasizes the effect of the ratio between cyclization and the alternative fragmentation pathway of the diradical intermediate, on the regioselectivity in the intermolecular photocycloadditions, and propose not to consider the oriented 7r-complex (exciplex) as an intermediate in the mechanistic pathway of the [2 + 2] photocycloaddition of enones to alkenes. 

Prediction of the regioselectivity in the intermolecular photocycloaddition of enones to alkenes following this method provides similar results to those rationalized by the oriented -complex. However, it is in contrast with Weedon s previously discussed trapping results which indicate no selectivity in the first bond formation at the a- or /J-carbon positions in cyclic enones. 

The intermolecular photocycloaddition of alkenes to cyclic enones was found to afford cis- and trans-fused bicyclic systems. This stereoselectivity and the diastereofacial selectivity of chiral alkenes and/or enones is discussed below. 

Cis,anti,cis products are favored in the intermolecular photocycloaddition of cyclopentenones with cyclic alkenes87 (Scheme 34). However, intermolecular photoaddition of some cyclohexenones provided preferred /raw. -fused product as the major product with cyclic alkenes60. From the large number of examples presented in Schemes 37, 42, 43, 45, 46, 48 and other examples, it could be concluded that cis -fused products are usually preferred. 

Further studies, on the same principle, were carried out by Lange and coworkers on the intermolecular photocycloadditions of cyclohexenones 167 to alkene 168, possessing different chiral auxiliaries at the enone91 or alkene92. Diastereomeric mixtures of cis,anti,cis 169 and cis,syn,cis isomers were obtained in low to moderate diastereomeric excess (Scheme 37). 

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