Methylenecyclopropanes cycloadditions

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). ... 

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). 

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. 

An interesting synthetic method for the [3.3.3]propellane 74 by intramolecular cycloaddition of a disubstituted methylenecyclopropane with an iinsa-... 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

Similarly, partially fluorinated and perfluorinated methylenecyclopropanes [57, 52], cyclopropenes [55, 84, 55], cyclobutenes [75, 56], and bicychc alkenes [57, 55, 59, 90] apparently denve dienophilic reactivity from relief of their ground-state strain during reaction Thus 2,2-difluoromethylenecyclopropane and perfluoromethylenecyclopropane undergo exclusive [244] cycloadditions [57, 52] (equations 72 and 73), whereas (difluoromethylene)cyclopropane undergoes only [24-2] cycloadditions [57]... 

An interesting strategy for the synthesis of pyrrolizidines and indolizidines has been developed by Brandi and co-workers. Cycloaddition between nitrones or nitrile oxides with methylenecyclopropanes generates strained tricyclic spiro compounds, which are prone toward further transformations, such as rearrangement, ring opening, and new ring closure (Scheme 10.17).116... 

Whereas the parent MCP (1) is not reported to give [4 + 2] cycloadditions, bicyclopropylidene (3) has been shown to give Diels-Alder adducts. Bicyclo-propylidene (3) is a unique olefin, combining the structural features of a tetra-substituted ethylene and two methylenecyclopropane units. The central... 

The cycloadditions of nitrones to methylenecyclopropanes 285-287 (Table 23), 299 (Table 24, entry 3), and 311 (Table 25, entry 7) substituted on the ring occur with very high diastereofacial selectivity. Nitrone 256 gives with 1-methyl-ene-2-phenylcyclopropane (285) a mixture of four isomers in a 2 2 1 1 ratio... 

Fig. 3. Preferred TS trajectory for the cycloaddition of 5-substituted pyrroline N-oxides to ring-substituted methylenecyclopropanes...

A positive feature of the reaction is that nitrile oxides are more regioselective, in cycloadditions to methylenecyclopropanes, compared to nitrones. Only traces (up to 5%) of the 4-spirocyclopropane regioisomers are generally observed with methylenecyclopropanes unsubstituted on the exocyclic double bond. The yields are only moderate, but higher with more stable nitrile oxides (Table 27, entries 5, 6, 10-12). 

Due to their tendency to dimerize in different thermal conditions, the formal [2 + 2] cycloaddition reaction of methylenecyclopropane derivatives and their... 

The first [2 + 2] cycloaddition of methylenecyclopropane which has been reported involves the use of tetrafluoroethylene (482) (Table 38, entry 1) [131], an olefin having a high tendency to give cycloadditions in a [2 + 2] fashion, which are considered to occur in a two-step process involving diradical intermediates. In the same article, the author reports unsuccessful attempts to react methylenecyclopropane with maleic anhydride or acrylonitrile [131]. 

Two other [2 + 2] cycloadditions on methylenecyclopropane have been carried out with particular alkenes. The first one is the reaction with the capto-datively substituted olefin 496a, which affords the spirohexane cycloadduct 497a in modest yields (Table 39, entry 1) [126]. The low yield is partially... 

The last [2 + 2] cycloaddition performed onto methylenecyclopropane itself consists of the use of ketene derivatives, particularly of dimethylketene 508 (Table 40, entry 1) [133]. The result is an almost equimolar mixture of the two possible regioisomers 511, albeit no yield has been reported. Anyway, the particular reactivity of methylenecyclopropane was confirmed, since it was found to be around 15 times more reactive than isobutene [133]. The scarce regioselectivity of this cycloaddition was confirmed by the reactions of the same ketene 508 with 2,2-disubstituted methylenecyclopropanes (entries 2 and 3) [134], BCP has also been shown to be reactive towards chloro-substituted ketenes 509 and 510, affording the expected cycloadducts 514 and 515 in mild conditions (entries 4 and 5) [13b],... 

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],... 

Table 46. Metal-catalysed cycloadditions of methylenecyclopropanes 1,250 and 345 to alkyl acrylates 56a and 576...

An alternative approach to [3 + 2 + 2]-cycloadditions has been reported by Saito and co-workers and involves cleavage of a methylenecyclopropane to produce, after capture with two alkynes, the cycloheptadiene products shown in Scheme 54.144 In a mechanistically distinct [3 + 2 + 2]-reaction, Murakami and Miura report a route to a cycloheptadienone involving the capture of two alkynes initiated by a Suzuki coupling to 2-cyanophenylboronic acid (Equation (32)).145... 

The reaction of methylenecyclopropane with azides is the earliest 1,3-dipolar cycloaddition reported so far on this system [53,54]. 

Table 23. Cycloadditions of nitrones to ring-substituted methylenecyclopropanes... 

Cycloadditions onto Methylene- and Alkylidenecyclopropane Derivatives Table 27. Cycloadditions of nitrile oxides 337-343 to methylenecyclopropanes... 

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