Intramolecular 1,3-cydoaddition

Smart, R.P. and Wagner, P.J. (1995) Regioselectivity in intramolecular cydoaddition of double bonds to triplet acylbenzenes II. Effects of substituents meta to the tether. Tetrahedron Letters, 36, 5131-5134. 

Linear, as well as angular, benzannulated perhydroazulenes 88 and 89, which are related to some important classes of diterpenes, have been synthesized (Scheme 8.26) [34] by the intramolecular cydoaddition of the carbonyl ylide generated by the irradiation of a, 3-epoxyketone 86 and 87, respectively. 

Intramolecular cydoadditions also give useful results [74] (Figure 9.34). The cycloadditions of imides derived from Z-crotonic, methacrylic and 0,0-dimethylaciylic acids are less selective. Similarly, the use of lower amounts of Et2AlCl or other Lewis acids decreases the selectivity. These results have been interpreted by the intervention of cationic chelated complex 9.68, which is held in the s-cis conformation, and there is now NMR evidence for this intermediate... 

The authors reason that direct irradiation of (54) must induce bond fission to yield the radical pair (57) as well as yielding the cycloadduct. Rebonding within the radical pair (57) can yield (53) which would then undergo the photocycloaddition to yield the cycloadduct (55). Intramolecular cydoaddition is observed on irradiation of the enones (58). The reaction is both wavelength and temperature dependent. Irradiation through Pyrex brings about the formation of a cisitrans mixture of the alkene moiety as the main reaction. Low yields of the two adducts (59a) and (59b) are also formed under these conditions. When a quartz vessel is used the cycloaddition assumes major importance. From the results obtained it is clear that there is a preference for the formation of isomer (59a). Both the isomeric products arise from the biradical intermediate (60) which is formed by addition at the P carbon of the enone moiety and affords the more stable biradical. 

Intramolecular cydoaddition of furan has been performed successfully on a solid support in the presence of solvent under open-vessel or sealed-vessel microwave irradiation conditions. Whereas intramolecular reaction of furan 23 does not occur with classical heating [61], the reaction was performed sussessfully in 64% yield by using microwave activation (Scheme 11.6). 

Bashiardes et al. [94] described an intramolecular cydoaddition reaction of unprotected carbohydrates 126, involving a nitrone ylide dipole 127 derived from the 1-aldehydic position, and an co-olefinic moiety constructed from the 6-hydroxyl function (Scheme 11.32). In this enantiomeric synthesis of novel bicyclic oxazoli-dines bearing a quaternary bridgehead, 128, a comparative study was performed of classical heating conditions and microwave-assisted cydoaddition, both in the same reaction medium, aqueous ethanol. All the examples provided products in yields which were improved from approximately 60% to 90%, basically because of the cleaner reactions. The reaction times were reduced from 48 h to just 1 h. 

They are even more strict in intramolecular cydoadditions that they not only nicely solve regioselectivity problems but are also highly recommended for the introduction of quaternary carbon atoms [63, 64]. 

Another very elegant and subtle manipulation of the transition state was elaborated for a directed intramolecular cydoaddition aiming at terpenes of the kaurane type 329 [122]. 

As was the case with reactions of vinylindoles, the most elaborate synthetic targets approached by the indole-2,3-quinodimethane route have been alka-loids[18]. The route has been applied to aspidospenna[l9 ] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by W-acylation of an Ai-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 -P 4 cydoaddition then occurs. 

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

Intramolecular 1,3-dipolar cydoadditions to acceptor-substituted allenes are rare [357]. The synthesis of triazole 386 from the precursor 384 is one of the few examples [120]. 

Thermal intramolecular [2 + 2]-cydoadditions of phenylsulfonyl-substituted allenes 33 gave 34 stereoselectively. An initial carbon-carbon bond formation occurred at the central allenic carbon and the proximal olefmic carbon. The resulting non-allylic radical 35 is unstable and cyclizes rapidly which may account for the high stereoselectivity [30]. 

An intramolecular [3 + 2]-cydoaddition reaction occurred at either the terminal or internal C=C bond in the following examples [77, 78] ... 

The intramolecular allene-furan cydoaddition led to the formation of a mixture of two exo-adducts, 139 and 140 (5 4) [121]. Heating the mixture at reflux in mesity-lene gave an equilibrium mixture of 139 and 140 in a ratio of 2 1. 

Bispropargyl ether 222 isomerized on treatment with tBuOK into the naphthalene 223 via the intramolecular [4+2]-cydoaddition of the phenylallene with the acetylene moiety. Similar reactions of enynyl propargyl ether 224 took place at room temperature to give two isomeric isobenzofurans, 225 and 226. The major product 226 presumably arises from the intramolecular [4 + 2]-cycloaddition of the bisallenyl ether, whereas the minor product 225 is formed by the [4 + 2]-cycloaddition of the monoallenyl ether [180]. 

On the basis of these findings, a pathway for this cydoaddition is proposed in Scheme 7.24. The first step is the nucleophilic attack of the carbon atom in the 2-position of 1,3-cyclohexanedione on the Cy atom of the allenylidene complex to give a vinylidene complex, which is transformed into an alkenyl complex by intramolecular nucleophilic attack of the oxygen atom of a hydroxy group of an enol on the C, atom of the vinylidene complex. By the use of Ic with its bulkier alkanethio moiety as a catalyst and at lower temperature, a subsequent intramolecular cyclization may be slow enough to make isolation of the alkylated product possible. 

The direct photolysis of a-(alkenyloxy)silyl-substituted diazoacetate 76a leads to a carbene, which undergoes an intramolecular [2 +1] cydoaddition with the terminal alkene to afford 77a in 55% yield (Scheme 4.35) [55]. An oc-alkenysilyl-substituted diazoacetate 76b also leads to 77b in 68% yield (Scheme 4.35) upon direct irradiation [56]. 

The photochemical intramolecular [3 + 2] cydoaddition of arenes with a tethered alkene leads to polycydic compounds. This reaction is better suited to the synthesis of natural products than to intermolecular [3 + 2] cydoaddition. A carbonyl group in the tether fails to produce any good results, because this chromophore can quench the... 

Mizuno et al. recently have reported a novel intramolecular [3 + 2] cydoaddition of l-cyano-2-(4-pentenyl)naphthalene derivatives 119 [90]. The direct photolysis of 119 in acetonitrile gave the [3 + 2] cycloadducts 120 in good yields (Scheme 4.60). 

Kaneko, C., Suzuki, T., Sato, M., and Naito, T. (1987) Cydoadditions in syntheses. XXXII. intramolecular photocycloaddition of 4-(w-alkenyloxy) quinolin-2(lH)-one synthesis of 2-substituted cydobuta[c]quinolin-3 (4H)-ones. Chemical el Pharmaceutical Bulletin, 35, 112-123. 

The expected intramolecular 1,3-dipolar cydoaddition product 171 was only a minor product (3%). The formation of major product 169 was explained through an intramolecular Michael reaction of the enolate ion. 

Coldham, I. and Hufton, R. (2005) Intramolecular dipolar cydoaddition reactions of azomethine ylides. Chemical Reviews, 105, 2765-2810. 

Dittami, J.P., Nie, X.-Y., Buntel, C.J., and Rigatti, S. (1990) Photoinitiated intramolecular ylide-alkene cydoaddition reaction. Tetrahedron Letters, 31, 3821-3824. 

The most characteristic photochemical reaction of aromatic compounds is their cydoaddition with alkenes. The intramolecular reaction is suitable for the synthesis of complex structures, such as those depicted in Scheme 9.49, where [3+2]-photocycloaddition leads to structures which resemble natural products (aphidico-line and stemoclinone). An interaction of the arene singlet excited state with the alkene ground state gives rise to the meta adduct [83, 84]. 

Scheme 21 Access to tricyclic isoxazolidines by an inter-intramolecular cross-coupling-cydoaddition cascade [81]...

Enantioenriched (-)-rosmarinedne, which belongs to the group of pyrrolizidine alkaloids [413], has been synthesized by Goti, Brandi and coworkers applying an intramolecular 1,3-dipolar cydoaddition as the key step [414], The required nitrone was obtained in situ from L-malic acid. Moreover, 1,3-dienes as precursors for a cy-... 

The combination of two successive [4+2] cydoadditions has already been described by Diels and Alder [la] for the reaction of dimethyl acetylenedicarboxylate with an excess of furan. A beautiful, more modem, example is the synthesis of pagodane (4-5) by Prinzbach [2], in which an intermolecular Diels-Alder reaction of 4-1 and 4-2 to give 4-3 is followed by an intramolecular cycloaddition. The obtained 4-4 is then transfonned into 4-5 (Scheme 4.1). 

The key step in the synthesis of4-354 is the retro-1,3-dipolar cydoaddition of the isoxazolidine 4-351 to give the nitronate 4-352, which underwent an intramolecular 1,3-dipolar cydoaddition. The obtained cydoadduct 4-353 can be transformed in a few steps into the desired target 4-354 (Scheme 4.78). 

Goti, Brandi and coworkers developed an effective synthesis of (-)-rosmarinecine (4-357) via a domino cydoreversion-intramolecular nitrone cydoaddition of 4-355, which led to 4-356 (Scheme 4.79) [125]. 

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cydization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cydoadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

---