Intramolecular 2+2 -cycloadditions, thermal

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

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. 

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-... 

Scheme 6.186) [347]. The condensation of O-allylic and O-propargylic salicylalde-hydes with a-amino esters was carried out either in the absence of a solvent or - if both components were solids - in a minimal volume of xylene. All reactions performed under microwave conditions rapidly proceeded to completion within a few minutes and typically provided higher yields compared to the corresponding thermal protocols. In the case of intramolecular alkene cycloadditions, mixtures of hexa-hydrochromeno[4,3-b]pyrrole diastereoisomers were obtained, whereas transformations involving alkyne tethers provided chromeno[4,3-b]pyrroles directly after in situ oxidation with elemental sulfur (Scheme 6.186). Independent work by Pospisil and Potacek involved very similar transformations under strictly solvent-free conditions [348]. 

Intramolecular thermal [4+2] cycloaddition occurs smoothly, though at a high temperature, upon heating of the appropriately substituted electron-poor oxadiazole containing electron-rich alkene fragment (Equation 1) <2002JOC7361>. 

Although an intramolecular thermal [2 + 2] allene-ketene cycloaddition reaction was reported, the regioselectivity was moderate [55]. 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

Polysubstituted pyridines 312 can be prepared by a sequence involving an intramolecular thermal or high-pressure Diels-Alder cycloaddition of oximino dienophile 310,... 

Similarly, Takano et al. (79) reported the intramolecular, asymmetric cycloaddition of ylides derived from thermal decomposition of aziridines 255 with the stereoselectivity rationalized by the formation of a postulated nine-membered transition state 256 in which the benzyloxymethyl group was forced into an equatorial disposition. The resultant pyrrolidine 257 contained three new stereo-genic centers, each imposed with high control (Scheme 3.87). 

In a novel total synthesis of the tricyclic sesquiterpene (—)-longifolene, an intramolecular diazoalkane cycloaddition to a cyclohexadienone ring followed by thermal ring contraction of the resulting pyrazoline gave the tricychc vinylcyclo-propane 261 and this constitutes the key steps in this synthesis (314) (Scheme 8.63). The interesting features of this sequence are the separation of dipole and dipolarophile by five atoms and the formation of a seven-membered ring in the cycloaddition step. 

The initial photochemical reaction is intramolecular ortho cycloaddition leading to bicyclo[4.2.0]octa-2,4-diene derivatives. These normally are not detected because they undergo rapid thermal disrotatory ring opening to all-cis cyclooctatrienes which have large extinction coefficients and absorb a second photon to undergo electrocyclic ring closure to the photostable bicyclo[4.2.0] octa-2,7-dienes. 

The intramolecular thermal [5+2] cycloaddition of 3-alkoxy-4-pyrones with sulfur- (e.g., 416) or silicon- (e.g., 419) tethered alkenes has been shown to occur with complete regio- and stereochemical control to give adducts 417 and 421, respectively. The adducts can be converted by reduction and oxidation, respectively, to the bicyclic products 418 and 421 (Scheme 69) <1993JOC5585>. It should be noted that this thermal [5+2] cycloaddition has not been realized in a bimolecular mode <1977JOC3976>. This methodology serves as an alternative to the reaction of electron-deficient alkenes with pyrone-derived 4-methoxy-3-oxidopyrylium ylides <1992TL2115>. 

Thermal (2 + 2)-cycloaddition reactions have never been reviewed so far, although occasionally a few reactions have been discussed in other review articles.20,21 The literature on this subject is summarized here in four subsections. First the mechanistic aspects of thermal (2 + 2)-cyclo-addition reactions are dealt with and subsequently a review is given of (2 + 2)-cycloadditions of heterocycles with olefins and compounds having other double bonds, with acetylenes, and with heterocumulenes. The reactions with acetylenes are discussed under two separate headings, covering (1) reactions with nonaromatic heterocycles and (2) reactions with heteroaromatics. The reactions included are exclusively inter-molecular (2 + 2)-cycloadditions. No examples are known of intramolecular thermal (2 + 2)-cycloadditions of two isolated -electron systems or of thermal electrocyclizations of conjugated 4/r-electron systems of heterocyclic compounds (Appendix). 

An intramolecular photochemical cycloaddition suggested for inclusion in the undergraduate laboratory curriculum couples a ground-state Diels-Alder reaction with the sunlight-induced cage formation of (13a) from the crystals of the thermal adduct (14a),7 as depicted in Scheme 1. Marchand and Allen8 have reported an improved synthesis of the pentacycloundecane (15) using the photochemical intramolecular cycloaddition of the dienedione (14b), which was achieved in 86% yield by acetone-sensitized irradiation. 

The Diels-Alder reaction is a thermal cycloaddition involving 1,3-dienes and alkenes, and [3+21-cyclo-addition reactions involve a Ji bond and a 1,3-dipole. The Cope, oxy-Cope, and Claisen rearrangements are thermal, intramolecular reactions of 1,5-dienes. [2+2]-Cycloadditions usually involve reaction between two alkenes, or certainly two Ji bonds. A reaction that is different from any seen so far occurs with certain alkenes and allylic systems. In its fundamental form, it is "the indirect substituting of a compound with a double bond... 

Thermal cycloaddition of 81 proceeded with involvement of the olefinic bond a to the carbonyl group to give 82. A similar result was obtained with the benzylidene analog of 81. It was therefore necessary to remove the C-6 blocking group prior to cycloaddition. Deblocked adduct 83 on refluxing in <7-dichloro-benzene underwent intramolecular cycloaddition smoothly via the indicated ster-ically favorable exo transition state to produce ( )-D-homoestrone methyl ether 83a in 95% yield. Compound 83a had been previously converted to ( )-estrone by Johnson et al. (see Volume 2, pp. 681-682). 

These heterocycles are conveniently prepared via intramolecular dipolar cycloaddition (Equation 66) or by thermal rearrangement of thiazolidine-iV-oxides (Equation 74). The first method is generally more successful and general. 

Condensation of the aldehyde 9 and A-methyl-glycine gives an intermediate imininum ion which is trapped intramolecularly to give an oxazolidinone. Thermal elimination of CO2 generates an azomethine ylide that undergoes ready intramolecular dipolar cycloaddition onto the alkene. The di-flised product will have the lower activation energy. See C. J. Lovely and H. Mahmud, Tetrahedron Lett., 40 (1999), 2079. 

Intramolecular thermal and catalytic [4 + 2] cycloaddition in 2-alkenyl-furans 05UK707. 

H (II), I (III), and J(IV) has been achieved through a flexible and expedient strategy that features a cascade sequence involving two concurrent [3,3] sigmat-opic rearrangements and an unusual intramolecular formal [2 + 2] thermal cycloaddition reaction between an electron-rich stilbene and a prenyl group [109]. 

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