Methylenecyclopropanes, cycloaddition with

Finally, both difluoromethylenecyclopropane (456) (Table 41, entry 5) and its isomer 2,2-difluoro-methylenecyclopropane (5) (Scheme 73) gave a [2 + 2] cycloaddition with l,l-dichloro-2,2-difluoroethylene (520), but the latter required more drastic conditions. Compound 5 reacted with dienes similarly to perfluoromethylenecyclopropane, affording exclusively [4 + 2] cycloadducts (see Sect. 2.1.1) [9],... 

The alkylidenecarbenes generated via base-induced a-elimination can also be trapped by cycloaddition with external alkenes. For example, the treatment of alkenyliodonium salt 55 with a strong base in the presence of excess styrene gives methylenecyclopropane 56 in good yield (Scheme 26) [47]. 

A variety of alkenes can participate in the cycloaddition. Simple alkenes such as ethylene and allene will react to form methylenecyclopentane adducts. Facile cycloadditions with strained alkenes are also observed. For example, norbomene reacts smoothly with (79) to give only the exo adduct (80) in good yield (equation 64). Electron-deficient alkenes, having an ester, ketone or sulfone activating group, are also substrates. However, the methylenecyclopropane cycloaddition does not appear to be very chemoselective. This is demonstrated by the Pd-catalyzed reaction of (79) with 2,3-dimethoxycar-bonylnorbomadiene, where both double bonds of the norbomadiene react to an almost equal extent (equation 65). ... 

The use of alkynes in transition metal catalyzed reactions is often complicated by their tendency to undergo cyclo-tiimerization and -tetramerization. Thus, it is useful to note that a phosphite-modified catalyst, Ni(COD)2Aris(o-phenylphenyl) phosphite (TOPP), promotes codimerization of alkynes with methylenecyclopropane and its a ylidene analogs. Both electron-rich and electron-poor alkynes participate in cycloaddition with moderate regioselectivity. Opposite regiochemistiy is sometimes observed widi disubstituted alkylidene systems (equations 97-99). 

The Pd -catalyzed [3 + 2] cycloaddition reactions of (97) exhibit very different selectivities from those of the corresponding methylenecyclopropane codimerizations. One major distinction is the chemoselec-tivity only electron-deficient alkenes will react to form methylenecyclopentane. The nucleophilic nature of this TMM synthon is indicated in the exclusive annulation of the electron-poor double bond of 2,3-di-methoxycarbonylnorbomadiene (equation 109). - No such differentiation of alkenes is evident in the methylenecyclopropane codimerization with the same diene (equation 65). 

Indeed, both kinds of cycloaddition products (Type A and Type B) can be obtained in the presence of Ni(0) catalysts while Pd(0) catalysts exclusively lead to Type A codimers. The real course of these reactions however is somewhat more complicated. While distal ring-opening via Route a really leads to cycloaddition products of Type A, proximal ring-opening via Route b results only in an isomerization of methylenecyclopropane. Cycloaddition products of Type B are obtained indirectly via oxidative coupling of two alkene units with low-valent nickel followed by a cyclo-propylmethyl/3-butenyl rearrangement22,148b). Reductive elimination terminates the catalytic cycle (Eq. 78). 

In contrast to ketenes, keteneimines readily undergo metal-catalyzed [3+21-cycloadditions with methylenecyclopropanes. Depending on the substituents in both educts, pyrroles, a-methylene-A3-pyrrolines or iminocyclopentenes can be synthesized selectively in good to excellent yields. The substituent of the imino group determines... 

Methylenecyclopropane undergoes [2-1-2] cycloadditions with a variety of alkenes including itself. The latter reaction, the dimerization of methylenecyclopropane, will be discussed in Section 5.2.3.1.3.1. 

A suitable approach to the synthesis of spiro[2.3]hexanes is the [2-1-2] cycloaddition of alkenes to the double bond of methylenecyclopropanes. This reaction is often described as a codimerization and usually requires catalysis by a nickel(O) complex such as bis(cycloocta-l,5-diene)nickel. l,l-Dimethyl-2-methylenecyclopropane reacts with alkyl acrylates to give a mixture of alkyl cis- and tranj-l,l-dimethylspiro[2.3]hexane-5-carboxylates 1 (19-40%) and alkyl 3,3-dimethyl-4-methylenecyclopentanecarboxylate 2 (60-81 %). The proportion of spiro [2.3]hexane derivative was highest when rer/-butyl acrylate was used as the activated alkene. 

Methylenecyclopropane undergoes photosensitized [2 + 2] cycloaddition with various substituted alkenes. Irradiation of acetone solutions of maleic anhydride or substituted derivatives and methylenecyclopropane in the presence of benzophenone as a sensitizer gave spiro[2.3]hexa-nes 24 in good yields. 

Substituted 1,2,4-triazines and 1,2,4,5-tetrazines are known to undergo [2-1-4] cycloaddition with inverse electron demand when reacted with alkenes. The primary bicyclic product loses nitrogen to give dihydropyridines and dihydropyridazines, respectively. The reaction of methylenecyclopropane with dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate at room temperature gave the spiro-dihydropyridazine 2 in 80% yield. ... 

At least one methylenecyclopropane derivative with two electron-withdrawing substituents on the double bond has been isolated and unequivocally characterized by spectroscopic methods. Methyl 2-cyclopropylidene-3-(phenylsulfinyl)acetate (30) is prepared by oxidation of the phenylsulfanyl derivative 29 with dimethyldioxirane under strictly anhydrous conditions. Compound 30 is a marginally stable crystalline material at room temperature in the absence of nucleophiles, but it rapidly adds water on standing in air or upon attempted chromatography on silica gel. " It also undergoes rapid cycloadditions (see Section 5.2.3.2.1.2.). 

Cyclopropylidene-l,3-dioxanes or -1,3-dioxolanes are ketene acetals and examples of bis-donor-substituted methylenecyclopropanes which undergo facile cycloaddition with electron-deficient alkenes 12. Thus, spiro[2.3]pentanone acetals 13 were obtained after reaction in an aromatic solvent either at room temperature or 40 C. Upon subsequent aqueous workup, hydrolytic cleavage of a C-C bond of the cyclobutane ring took place rather than the expected acetal hydrolysis (Table 7). This cycloaddition was found to proceed in a stepwise fashion as reaction of the dimethyl ( )-but-2-enedioate gave a cisj tram mixture of cycloadducts on further heating, this ratio changed. 

A further noteworthy side reaction of palladium-catalyzed methylenecyclopropane cycloadditions is the isomerization of 2-(n-alkyl) methylenecyclopropanes to isoprene-type dienes, and subsequent reaction of the latter with electron-deficient alkenes to form cyclohexenes in a Diels — Alder reaction, rather than providing [3 + 2]-addition products. 

In addition to strained and unstrained hydrocarbons, as well as unsaturated esters, a variety of cyclic substrate types undergo [3-1-2] cycloaddition with methylenecyclopropanes. Some representative examples of such cyclopentaannulation reactions are discussed in this section. 

Methylenecyclopropanes 9 with geminally disubstituted alkene moieties undergo palladium-catalyzed [3-1-2] cycloaddition reactions with carbon dioxide under pressure. Besides cycloadduct 10 arising from formal distal cleavage of the MCP, furan-2(5//)-one 11, resulting from double-bond isomerization, is formed in variable amounts, depending on the substrate as well as the specific catalyst used. ... 

Cycloadditions. Methylenecyclopropane reacts with electron-deficient alkenes photochemically and in the presence of BU2S2. This free radical reaction leads to methylenecyclopentane products, in which the electron-withdrawing substituent is at an allylic position. 

Cycloaddition. W-(Diphenylmethylene)-4-methylben-zenesulfonamide (2) has been used as a dienophile in a hetero [3 + 2] cycloaddition. Dipolar trimethylenemethane (TMM, 21), generated by means of thermolysis of methylenecyclopropane (22), undergoes [3 + 2] cycloaddition with the reagent to regio-selectively afford the acetal of the a-methylene-y-lactam product 23. This product is quite acid-sensitive and may he isolated as the corresponding a-alkyhdene-y-amino ester. The cycloadduct serves as a synthetic precursor to y-amino acid derivatives (eq 13). 

Methylenecyclopropane is also a convenient TMM precursor for the cycloaddition reaction. Both nickel(O) and palladium(O) complexes can catalyze the [3 + 2] cycloaddition of aUcylidenecyclopropanes with aUcenes and alkynes (Scheme 12). ° Unlike the Ni-catalyzed reaction, the regioselectivity in the Pd-catalyzed reaction with alkene is independent of the structure of the starting aUcylidenecyclopropanes, which indicates that this reaction also proceeds via TMM-Pd as mentioned above. The TMM-Pd generated from aUcylidenecyclopropanes can undergo a stereoselective intramolecular cycloaddition with alkynes,and the regiochemistry is different from the Ni-catalyzed reaction... 

Alkenylboronates activated with either an ester or a sulfone group have been engaged in [3+2] cycloadditions with methylenecyclopropanes to afford methylenecyclopen-tanes in good yields. The cycloaddition reactions were highly stereoselective and yielded exclusively the corresponding trans-disubstituted products. The carbon-boron bond of the cycloadducts can be further transformed by oxidation to give the corresponding cyclopentanols (Scheme 9.47) [lOOj. 

Abstract Transition metal-catalyzed cycloadditions of cyclopropanes have been well developed over the past several decades, leading to numerous new types of cycloadditions which are complementary to the traditional cycloadditions for the synthesis of carbocycles. Cycloadditions of vinylcyclopropanes (VCPs) and methylenecyclopropanes (MCPs) constitute two main aspects of this field. VCPs can act either as five-carbon synthons or three-carbon synthons, depending on whether the vinyl substituent is acting as an additional two-carbon synthon or not. As five-carbon synthons, VCPs are involved in [5-1-1], [5-1-2], [5-I-2-1-1], and [5+1+2-I-1] cycloadditions. As three-carbon synthons, VCPs are mainly involved in [3-1-2] and [3-1-2-t-l] cycloadditions. MCPs mostly act as three-carbon synthons and can have [3-1-2] cycloadditions with different jt systems. Other types of cycloadditions involving MCPs are also reviewed, such as [3-rl], [3+2+2], and [4+3+2] cycloadditions. CycloadditirMis of some other unusual cyclopropane derivatives are also introduced briefly. The cycloadditions of VCPs and MCPs have found applications in total synthesis and some representative molecules are tabulated as selected examples. 

The Wittig olehnaticni of cyclopropanone hemiacetal to generate the intermediate methylenecyclopropanes 30 and the subsequent cycloaddition with tetra-substituted thiophene 1-oxides can be carried out in a one-pot operation with overall good yields. X-Ray diffraction analysis of 31 and 32, two of the cycloadducts, confirmed that their relative configurations were endo, syn (Scheme 22) [14]. 

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