Intramolecular cycloadditions, alkenes

Considerably better yields are obtained when the alkene is significantly strained, as in the synthesis of [3]peristylane (5). Note in this case that flash-vacuum pyrolysis is the method of choice for the final step. The intramolecular addition step in the synthesis of ( —)-cyclo-copacamphene (8) and in a very similar synthesis of (+ )-cyclosativene presumably also gain assistance from ring strain. It should be noted that in these last two syntheses, the diazoalkane-alkene intramolecular cycloaddition succeeded where attempted carbene-alkene cycloadditions had failed. 

Generation of 1-Azadienes. 0-Silyloximes have also been used to generate 1-azadienes for [4 + 2] cycloadditions. Thus an 0-silyloxime of an a, -unsaturated aldehyde can be treated with an acid chloride or chloroformate in the presence of chlorotri-methylsilane and aluminum chloride to give an a-cyanohydrox-amic acid derivative, which upon mild thermolysis forms an aza-diene (eq 2). These azadienes undergo efficient intermolecular [4 + 2] cycloadditions or, with a tethered alkene, intramolecular cycloadditions. 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

Intramolecular cycloadditions between cyclobutadiene and an oxygen-tethered unactivated alkene (alkyne) offers an attractive route to benzo[c]furans (Scheme 26, <96JA9196>). 

Using the same sequence, tricyclic quinolinoisoxazoline 108 was formed on intramolecular cycloaddition starting with aminocyclohexene derivative 105 viabromo alkene 106 and nitro alkene 107 (Scheme 13) [17]. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

Reductions of y-nitroketones yield cyclic nitrones, which undergo inter- and intramolecular cycloaddition to various alkenes. The result of addition to acrylonitrile is shown in Eq. 8.42, in which a mixture of regio- and stereoisomers is formed.65... 

Reaction of the aldehyde-tethered furanone 244 with pipecolinic acid results in the formation of the oxazolopyr-idine derivative 245, which undergoes spontaneous decarboxylation to give the ylide 246. This in turn undergoes an intramolecular cycloaddition with the tethered exomethylene group to give 247, or with the endocyclic alkene to give the furoindolizine 248 <1997T10633> (Scheme 66). 

Interaction of a carbonyl group with an electrophilic metal carbene would be expected to lead to a carbonyl ylide. In fact, such compounds have been isolated in recent years 14) the strategy comprises intramolecular generation of a carbonyl ylide whose substituent pattern guarantees efficient stabilization of the dipolar electronic structure. The highly reactive 1,3-dipolar species are usually characterized by [3 + 2] cycloaddition to alkynes and activated alkenes. Furthermore, cycloaddition to ketones and aldehydes has been reported for l-methoxy-2-benzopyrylium-4-olate 286, which was generated by Cu(acac)2-catalyzed decomposition of o-methoxycarbonyl-m-diazoacetophenone 285 2681... 

Intramolecular cycloadditions of a,p-unsaturated lactones to alkenes have been used as key step in the synthesis of a precursor of the terpene reserpine 480) (4.68) and of fused cyclooctanes (4.69) 481 ... 

Tethered alkenes feature in the synthesis of benzofuran-fused chromans 48 <00JCS(P1)1387> through intramolecular cycloadditions. 

The reaction course is shown in Scheme 4. Enyne 12 reacts with 2 to give vinyl carbene complex 17, which is in a state of equilibrium with vinyl ketene complex 21. [2+2] Cycloaddition of the ketene moiety and alkene part in 21 gives cyclob-utanone 22. On the other hand, the vinyl carbene complex 17 reacts with the alkene intramolecularly to produce metalacyclobutane 18. From metalacyclob-utane 18, reductive elimination occurs to give cyclopropane derivative 23. Ret-... 

Whenever you see a five-membered heterocycle, think 1,3-dipolar cycloaddition. The heterocyclic rings shown can be made from an intramolecular cycloaddition of a nitrone and the alkene. The nitrone must be made from the hydroxylamine and formaldehyde. 

The presence of an oxygen atom in the chain linking the two alkene moieties does not appear to affect the efficiency of the cyclizations encountered. Thus, the (2 + 2)-intramolecular cycloaddition of the divinyl ether 101a in ether solution with CuOTf... 

Intramolecular 1,3-dipolar cycloadditions have proven to be especially use fid in synthesis. The addition of nitrones to alkenes serves both to form a carbon-carbon bond and to introduce oxygen and nitrogen functionality.86 Entry 7 in Scheme 6.5 is an example. The nitrone B is generated by condensation of the aldehyde group with 7V-methylhydrox-ylamine and then goes on to product by intramolecular cycloaddition. 

The addition to alkenes normally leads to unstable adducts that lose carbon dioxide under the reaction conditions. The intramolecular cycloaddition of the sydnone (30) takes place at room temperature, however (Equation (5)) and the cycloadduct (31) has been characterized <86HCA927>. The unstable species formed by the loss of carbon dioxide are also azomethine ylides. It is therefore possible for a second 1,3-dipolar addition to take place, as illustrated in Scheme 6 for the reaction of 3-phenylsydnone with Al-phenylmaleimide <86TL317,92JA8414>. This 2 1 addition has been used as the basis of a synthesis of polyimides. Imides of the type (32) were used as the dipolarophiles and their reaction with 3-phenylsydnone gave linear polymers <87MM726>. 

CEJ1358> and the ruthenium mediated isomerization of double bonds (cf. Scheme 89, Section 8.11.7) <2007TL137> are recent examples of transition metal catalyzed manipulations at the side chain carbon atoms of 1,3-heterocycles. A novel side-chain addition reaction of aldehydes to 6-alkylidene-l,3-dioxin-4-ones was used for the construction of intermediates of lophotoxin <2006CJC1226>. An acid-catalyzed intramolecular cycloaddition of a hydroxy group to an alkene has been effected by the presence of an adjacent 1,3-dithiane moiety <2006TL4549>. 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

The in situ formation of nitrones from oximes by 1,3-APT or 1,2-prototropy is clearly a powerful synthetic strategy but conventional nitrone generation, in particular hydroxylamine-carbonyl condensation, has been applied to numerous syntheses, in intra- and intermolecular mode (258). Accordingly, the ring systems similar to those synthesized using 1,3-APT/intramolecular nitrone-alkene cycloaddition (INAC) methodology by Heaney (313-315) (see Section 1.11.2) or Padwa and Norman (340) have been made using conventionally prepared nitrones (Scheme 1.67). As with the previous examples, once formed, the nitrones are suitably placed for a spontaneous intramolecular cycloaddition reaction with the... 

The intramolecular cycloaddition of a silyl nitronate bearing a dipolarophilic appendage provides easy access to fused, bicyclic isoxazolidines (22). This process, in general, is very facile, and has allowed the use of unfunctionalized alkenes as dipolarophiles (Table 2.39) (106,124). Thus, a silyl nitronate bearing an allyl group will undergo the [3 + 2] cycloaddition at room temperature over 15 h to provide the corresponding isoxazoline upon acidic workup in moderate yield. 

Epoxide 96 was prepared such that photolytic conversion to the carbonyl ylide could be followed by an intramolecular cycloaddition with the tethered pendant olefin. However, photolysis of epoxide 96 led only to the formation of the regio-isomer 97 and the aldehyde 98 with no evidence of the corresponding cycloadduct. It was presumed that 97 arose from the ylide by thermal recyclization to the epoxide while 98 could form through the loss of a carbene from the ylide. The failure of the tethered alkene to undergo cycloaddition may have resulted from a poor trajectory for the cycloaddition. An extended analogue (99) allowed greater flexibility for the dipolarophile to adopt any number of conformations. Photolysis of epoxide 99 did lead to formation of the macrocyclic adduct 100, albeit in modest yields. 

Intramolecular ylide formation with the lactone carbonyl oxygen (53) in 145 provided a carbonyl ylide 146 that was trapped with Al-phenyl maleimide to give cycloadduct 147. Likewise (54), carbonyl yhde 149, derived from ester 148, suffers intramolecular cycloaddition with the tethered alkene to deliver acetal 150 in 87% yield. An enantioselective version of this process has also been described (Scheme 4.33). 

Cozzi and co-workers (243,263) studied the influence of the double-bond configuration on the stereochemical course of the intramolecular cycloaddition of chiral alkenes, where the stereocenter is located outside the isoxazoline ring (Table 6.15). On the basis of experimental results as well as theoretical calculations, two models were proposed for the reaction with (Z)- and ( )-aIkenes, in accord with the model proposed for a-X-substituted alkenes (see Section 6.2.3.1). 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

Intramolecular cycloaddition of nitrile ylides to olefinic dipolarophiles linked to the dipole by a three-atom chain leads to pyrazoles fused to five-membered rings. Work on stereoselectivity in such reactions has been carried out using the reactant 266 in which the alkene moiety is linked to the C-terminus via a tether that incorporates an enantiomerically pure (R) stereogenic group (165). Both diastereo-isomers 267 and 268 were isolated and it was found that the reaction showed moderate stereoselectivity favoring 267. 

Conformational constraints induced by various ortho-substitutents in 1-aUyloxy-2-azidomethylbenzenes (97) were used to accelerate intramolecular cycloadditions of the azide group to alkenes (21) (Scheme 9.21). For the unsubstituted azide 96, high temperature was required for the cycloaddition and the yield of the cycloadduct 100 was low. The monosubstituted azide 97 underwent cycloaddition in refluxing benzene in 10 h to give the cycloadduct 101 in good yield. Disubstituted azides 98 and 99 underwent 1,3-dipolar cycloaddition in 5-7 h to give the triazolines 102 and 103. 

Buchanan et al. (48) reported a new route to the synthesis of the chiral hydroxy-pyrrolidines 234 and 238 from D-erythrose (230) via an intramolecular cycloaddition of an azide with an alkene (Scheme 9.48). Wittig reaction of the acetonide 230 with (carbethoxyethylene)triphenylphosphorane gave the ( ) and (Z) alkenes 231 and 232. On conversion into the triflate followed by its reaction with KN3, the ( ) isomer 231 allowed the isolation of the triazoline 234 in 68% overall yield, which on treatment with sodium ethoxide afforded the diazo ester 235 in 86% yield. 

Pearson and Schkeryantz (56) developed a novel approach for synthesis of (i)-lycorane (280) using an intramolecular cycloaddition of an azide with an co-chloro alkene (Scheme 9.56). The bromide 276 was smoothly converted into the required chloro azide 277 in several steps. 1,3-Dipolar cycloaddition of the azide 277 in benzene at 140 °C followed by extrusion of nitrogen gave the unstable... 

Pearson and Walavalkar (57) reported a facile approach to the synthesis of ( )-tyloporine (288) based on an intramolecular cycloaddition of an azide with an co-chloroalkene (Scheme 9.57). The required (Z) alkene 285 was prepared from homoveratric acid (284). Treatment of the chloro alkene 285 with sodium azide... 

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