Methylene cycloaddition

The available literature data support the assertion that the outcome of the methylene cycloadditions depends to a large extent on the ability of the olefin to be coordinated to the palladium center. In that respect, the mechanism of palladium-catalyzed cyclopropanation appears to differ significantly from that of rho-dium(ll)-catalyzed cyclopropanations. One advantage of using palladium catalysts with diazomethane is associated with the possibility of synthesizing polycyclopropane adducts, a topic of current interest (vide infra) which has no general satisfactory solution with other diazo compound/catalyst combinations. This point is exemplified below for the cyclopropanation of the esters of trans-polyunsaturated acids. Moreover, the reactivity of the double bonds depends both on their position in the linear hydrocarbon chain and on their configuration (eq. (f)). 

The intramolecular [In + 2 rr] cycloaddition ofmethylenecyclopropane with the alkyne in 117 using isopropyl phosphite as a ligand affords the methylene-cyclopentene 118[55]. 

This reaction is called the Smmons-Smith reaction and is one of the few methods avail able for the synthesis of cyclopropanes Mechanistically the Simmons-Smith reaction seems to proceed by a single step cycloaddition of a methylene (CH2) unit from lodomethylzmc iodide to the alkene... 

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). 

In the alternative approach.the 1,3-dipolar system can be constructed in several ways. Treatment of a-chloroacylhydrazones of diaryl ketones and certain aralkyl and dialkyl ketones (382) with NaH in anhydrous THF gives l-(disubstituted methylene)-3-oxo-l,2-diazetidinium inner salts (383). Reaction of (383) with DMAD in methylene chloride gave (384), a 2 1 adduct with loss of CO. Double bond migration in (384) occurred on heating to give (385). The intermediate in the cycloaddition was found to be (386), which on heating lost CO to form a new ylide system which in turn underwent reaction with more DMAD <81JA7743). 

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

Furan, 2,3-dihydro-5-methyl-polymers, 1, 276 Furan, 2,3-dihydro-3-methylene- H NMR, 4, 577 Furan, 2,5-dihydro-2-methylene- H NMR, 4, 577 tautomerism aromaticity and, 4, 595 Furan, 2,5-dihydro-2-nitro-structure, 4, 550 Furan, 2,3-dihydroxy-tautomerism, 4, 37 Furan, 2,4-dihydroxy-tautomerism, 4, 37 Furan, 3,4-dihydroxy-tautomerism, 4, 37 Furan, 2,5-diiodo-nitration, 4, 602 synthesis, 4, 712 Furan, 3,4-diiodo-reactions, 4, 650 Furan, 2,3-dimethoxy-synthesis, 4, 625, 648 Furan, 2,5-dimethoxy-synthesis, 4, 648 Furan, 3,4-dimethoxy-cycloaddition reactions, 4, 64, 625 lithiation, 4, 651 reactions... 

In general, reaction of diazomethane with a, -unsaturated carbonyl compounds affords pyrazolines in which the nucleophilic methylene group is attached to the carbon atom of the carbonyl compound. According to Huisgen, the reactions belong to the general class of 1,3-dipolar cycloadditions. 

The aporphinoid alkaloid PO-3 (129) was also prepared by intermolecular benzyne cycloaddition between 1-methylene isoquinolines 148 and arynes derived from 147 (Scheme 53). The alkaloid was finally isolated by means of preparative thin layer chromatography (91JOC2984). 

The cycloaddition of methyleneketene 180 with 5-methylene-l,3-dioxane-4,6-dione 181 in principle allows all three double bonds of 180 to react with 181 (Scheme 120) [99JST187]. 

Thermal cycloadditions of butadiene to 3-bromo- 133 and 3-methoxy-5-methylene-2(5//)-furanones 220 were studied (95TL749). These systems contain substituents at C3 capable of stabilizing also a possible radical intermediate, influencing hereby the rate and/or the course of the reaction. Thus, the reaction of 133 and 220, respectively, with butadiene at 155°C afforded mixtures of the expected 1,4-cycloadducts 221 and 222, respectively, and of the cyclobutane derivatives... 

On the other hand, the corresponding tin precursor (63) undergoes smooth cycloaddition with a wide variety of aldehydes to produce the desired methylene-tetrahydrofnran in good yields [32, 33]. Thus prenylaldehyde reacts with (63) to give cleanly the cycloadduct (64), whereas the reaction with the silyl precursor (1) yields only decomposition products (Scheme 2.20) [31]. This smooth cycloaddition is attributed to the improved reactivity of the stannyl ether (65) towards the 7t-allyl ligand. Although the reactions of (63) with aldehydes are quite robust, the use of a tin reagent as precursor for TMM presents drawbacks such as cost, stability, toxicity, and difficult purification of products. 

This reaction can also be used for the synthesis of substituted 1-benzoxepins with one modification instead of the 4/T-benzopyran the 2/7-isomer must be used. 2-[Diazo(phosphoryl)meth-yl]-2//-benzopyrans decompose in the presence of ))3-allylpalladium chloride dimer with elimination of nitrogen to give 1-benzoxepins 2.192 In some cases, the reaction takes a different course and gives 2-methylene-2//-benzopyrans 3.192 In this respect, the bicyclic system behaves differently to the monocyclic diazo(pyranyl)methane. The 2-isomers of the latter structure could not be isolated and gave l//-l,2-diazepines.190 The 4//-benzopyrans do not form benzoxepins but undergo an intramolecular [2+1] cycloaddition to 3,4-dihydro-2,3,4-metheno-2//-ben-... 

The reaction of ethyl 2,2-diethoxyacrylate with alkynylalkoxycarbene complexes affords 6-ethoxy-2H-2-pyranylidene metal complexes [92] (Scheme 48). The mechanism that explains this process is initiated by a [2+2] cycloaddition reaction (see Sect. 2.3), followed by a cyclobutene ring opening to generate a tetracarbonylcarbene complex. This complex can be isolated and on standing for one day at room temperature renders the final 6-ethoxy-2Ff-pyranylidene pentacarbonyl complex. This last transformation requires the formal transfer of one carbonyl group and one proton from the diethoxy methylene moiety to the metal and to the C3 2H-pyranylidene ring, respectively, with concomitant cyclisation. Further studies on this unusual transformation have been extensively performed by Moreto et al. [93]. 

The reaction of methyl acrylate and acrylonitrile with pentacarbonyl[(iV,iV -di-methylamino)methylene] chromium generates trisubstituted cyclopentanes through a formal [2S+2S+1C] cycloaddition reaction, where two molecules of the olefin and one molecule of the carbene complex have been incorporated into the structure of the cyclopentane [17b] (Scheme 73). The mechanism of this reaction implies a double insertion of two molecules of the olefin into the carbene complex followed by a reductive elimination. 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

As mentioned in the introduction, the prototype o-QM is a highly reactive intermediates in organic reactions, including cycloaddition chemistry and DNA covalent modification, due to the high electrophilicity at the exocylic methylene carbon (see its dipolar representation in Scheme 2.11). 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

The electrostatic interactions in the complexes 19 were obviously sufficient to favor the zwitterionic structure in a manner that formation of the usual o-QM was suspended, so that all reactions typical of o-QMs in their quinoid form (such as [4 + 2]-cycloadditions) were suppressed or at least slowed down. Decomposition of the complex of a-tocopherol was immediate by fast heating to 40 °C or above. This caused disintegration of the complex 19, immediate rotation of the methylene group into the ring plane, and thus formation of the o-QM, which then showed the classical chemistry of such compounds. 

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