Intramolecular, addition 3 + 2 -cycloaddition

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

Scheme 6.8 gives some examples of ketene-alkene cycloadditions. In Entry 1, dimethylketene was generated by pyrolysis of the dimer, 2,2,4,4-tetramethylcyclobutane-l,3-dione and passed into a solution of the alkene maintained at 70° C. Entries 2 and 3 involve generation of chloromethylketene by dehydrohalo-genation of a-chloropropanoyl chloride. Entry 4 involves formation of dichloroketene. Entry 5 is an intramolecular addition, with the ketene being generated from a 2-pyridyl ester. Entries 6, 7, and 8 are other examples of intramolecular ketene additions. 

An example of intramolecular addition of an azo group to an alkene has been described 233 irradiation of azoalkene 280 affords an almost quantitative yield of the diazetidine 281 with no competing elimination of nitrogen. An analogous cycloaddition is thought to be implicated in the photoreaction of azobenzene with diketene.234... 

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

The sequential intramolecular conjugate addition of the oxime followed by intramolecular dipolar cycloaddition of the intermediate nitrone affords a... 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

The most widely exploited photochemical cycloadditions involve irradiation of dienes in which the two double bonds are fairly close and result in formation of polycyclic cage compounds. Some examples are given in Scheme 6.7. Copper(I) triflate facilitates these intramolecular additions, as was the case for intermolecular reactions. 

Cycloaddition. In the presence of TiCl4-C6H5NHCH3 (1-2 1), 2-trimethylsilylmethyl allylic alcohols undergo intramolecular addition to 8,e-double bonds to provide bicyclo[3.3.0]octanes. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

Many intramolecular nitrone cycloadditions have been carried out on substrates containing a cyclic intervening bridge. Perhaps the simplest possibility here is an o-disubstituted aromatic substrate, as, for example, the nitrone derived from aldehyde (42), which cyclizes to the 5,6-fused isoxazolidine (43 Scheme 10).19 There are many additional possibilities the nitrones derived from biphenyl aldehyde... 

Several publications are devoted to the reactions of olefin cycloaddition to dihydroazines in the presence of Lewis acid and to an intramolecular addition in 1,4-dihydropyridines containing <9/+/z<9-alkenylaryl substituents at position 4 [374, 375, 376, 377, 378, 379]. 

Among the variety of terpenes which were synthesized with an intramolecular meta photocycloaddition as key step, triquinane derivatives were particularly well studied. Two isomers of these compounds are readily accessible via intramolecular meta cycloaddition in position 1,3 (Sch. 9). The following cyclopropanation reaction of intermediate O controls which of the angular or linear isomers is formed (Sch. 17) [67]. As this step is almost always unselective, both isomers are concomitantly formed. However, one of the isomers can be obtained predominantly via an additional photochemical equilibration step (compare Sch. 11). The triquinane frame is obtained by rupture of the distant C-C bond of the cyclopropane in connection to the 10-membered ring moiety. 

The double bonds of the thiophene skeleton can be exploited as a 2-component in 1,3-dipolar cycloaddition reactions. The first examples of an intramolecular addition of nitrile imines 73 to give products 74 and 75 are shown in Scheme 7 <1998J(P1)4103>. 

The intramolecular azide cycloaddition has also been used in approaches to the aspidosperma alkaloids <2004TL919, 20050BC213>. The cycloaddition of 123 proceeds directly to aziridine 124 in 80% yield (Equation 28) <2004TL919>. This is an interesting transformation in that none of the initially formed triazoline is observed and because of the high regioselectivity of the addition. A conceptually related approach to the synthesis of cephalotaxine has also been reported <1997TL4347>. 

Intramolecular vinylketene cycloadditions have also found use as an efficient method for the preparation of divinylcyclobutanols suitable for accelerated oxy-Cope rearrangement. A typical reaction sequence is outlined in Scheme 37. In this case the cyclobutanol salt produced by addition of vinyllithium to (270) at -78 C was observed to undergo 3,3-sigmatropic rearrangement simply upon wanning to room temperature the tricyclic enone (272) incorporating a tra/is-cyclooctene ring was thus formed in 62% overall yield from (270). 

Ortho addition to the arene ring also occurs in cage systems where geometrical constraints disallow other orientations of addition a common example is the intramolecular photochemical cycloaddition which can occur in... 

A competition between two kinds of cycloaddition is observable in some compounds. In a rather unusual case intramolecular addition predominates if the compound is left at room temperature in CH2C12 containing florisil, whereas the intermoleeular addition is promoted by heating the compound in boiling xylene.50... 

Intramolecular Additions - The predominant photochemical reaction of the allene derivatives (65) is (2 + 2)-cycloaddition yielding the housanes (66). The reaction occurs in a variety of solvents (e.g. hexane, acetonitrile or acetone) and the triplet excited state of (65) is implicated. In hexane and... 

The unsaturated 6-lactone (84) undergoes intramolecular photochemical (2 + 2)-cycloaddition to give (85)." The scope of the process has been evaluated and the 5-lactones (86-88) all behave similarly, affording the products shown in Scheme 2. The lactones (86) and (87) both cyclise in the two possible modes. Intramolecular cycloaddition reactions within polymethyldia-minebis(4-methyl-7-coumarinyl)oxyacetamides have been described. Zhu and Wu have reported that a biscoumarin system linked by a phenanthroline unit does not undergo photodimerisation. Instead, intramolecular addition of a coumarin unit to the phenanthroline occurs. 

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