Cyclization reactions methylenecyclopropanes

In a similar manner, cyclopropane-containing benzvalene can be used as the alkene component in intermolecular Pauson-Khand reactions.Several examples of intermolecular Pauson-Khand cyclizations of methylenecyclopropanes and alkynes are reported to give bicyclic car-bocycles. Ethynylcyclopropyl-substituted chromium carbonyl complexes have also been used in palladium-catalyzed coupling reactions. 

The kinetics of these reactions in comparison with those for methylenecyclo-propane analogs of compounds 160 have been studied by following the progress at pressures up to 3 kbar by on-line FT-IR spectroscopy [129]. The rate-enhancing influence of the additional strain in 160 overcompensates the expected retarding effect of the increased steric shielding by the second cyclopropane unit in 1 compared to methylenecyclopropane, and the cyclization rates for compounds 160 were faster by a factor of 6.8 to 8.1 in comparison with the corresponding methylenecyclopropane derivatives. 

Additional spectroscopic information on the chemistry of the TMM triplet state now has been provided by the experiments of Maier et al., who have prepared TMM in substantial quantities by the irradiation of methylenecyclopropane in a xenon matrix at 10 K in the presence of codeposited halogen atoms. This experiment has permitted them to record the infrared (IR) spectmm of TMM, all the observable bands of which are in agreement with those calculated by ab initio methods. They also were able to supply direct evidence for a photochemical ring-closure reaction, TMM —> methylenecyclopropane, by irradiation of the biradical at 254 nm. The disappearance of the TMM IR absorptions is accompanied by growth of the methylenecyclopropane bands. Of course, this observation cannot be taken as a demonstration that the reaction reported by Dowd and Chow, namely, thermal cyclization of TMM, actually occurs. 

The highly strained double bond in methylenecyclopropane displays enhanced reactivity in cycloaddition reactions. In addition to normal [4+2] cycloaddition to 1,3-dienes (e.g. equation 13)32, methylenecyclopropane and its derivatives have a pronounced tendency to undergo thermal [2+2] cycloaddition reactions. For example, thermal dimerization of methylenecyclopropane in the gas phase results in formation of isomeric dispirooctanes 16 and 17 (equation 14)33. This unusual cyclization is considered to proceed via a stepwise radical mechanism involving the intermediacy of biradical 18 (equation 15)34. Equation 15 demonstrates that methylenecyclopropanes possessing substituents capable of stabilizing intermediate radicals undergo efficient [2+2] dimerization even... 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

The intermolecular addition of carbamates to 1,3-dienes (equation 147) under mild conditions has been described as well. The hydrothiolation of 1,3-dienes has also been reported. " Other related conjugate additions can be performed over methylenecyclopropanes (equation 148) with sulfonamides and the resulting product cyclizes by a second hydroamination of an olefin, finally yielding cyclic sulfonamides. This behavior is reproduced in a similar reaction for the ring opening of vinylcyclopropanes with sulfonamides. One more example in this group of reactions is the synthesis of dUiydrobenzofurans from aryl-allyl ethers. ... 

A related version of this cyclization is the reaction illustrated in Eqs (170) and (171) [428], in which methylenecyclopropane was cleaved with TiCU to give the similar allyl cationic intermediate which adds to the double bond of allylsilane to give the cyclopentane framework. 

Surprisingly, additions of electrophiles, radicals, and nucleophiles to methylene cyclopropane have rarely been executed under synthetic conditions. A sequence leading to the complement inhibitor K-76 published recently" very smartly takes advantage of a methylenecyclopropane participation in the polyene cyclization shown in equation 197. Hydroxylation of the vinylcyclopropane double bond and hydrogenolysis of the three membered ring are subsequent essential reactions. 

In the base-induced cyclization of a number of y-chloro-y-nitro carboxylic esters and derivatives, it was found that use of excess base led to elimination of nitrous acid resulting in methylenecyclopropanes. Thus, reaction of ethyl 4-chloro-4-nitropentanoate (1) with one equivalent of sodium hydride in dimethylformamide gave, in addition to a 53% yield of ethyl 2-methyl-2-nitrocyclopropanecarboxylate(2), 12% of ethyl 2-methylenecyclopropanecarboxylate (3). The latter could be prepared in 70% yield from the former, or in 55% yield from the starting ester by the use of two equivalents of sodium hydride. 

Kim developed a new entry into A -heterocycles by radical cyclizations onto alkyl azides. Iodides, bromides and thionocarbonates (Scheme 28, Eq. 28.1) are suitable radical precursors. 5-Exo cyclizations afford 3,3-triazenyl radicals that lose N2 to furnish an aminyl radical [79]. Following this work, Kilburn has applied this strategy to the formation of spiro-heterocycles from methylenecyclopropanes [80]. Finally, this reaction was applied as a key step in a very elegant cascade synthesis of aspi-dospermidine developed by Murphy (Scheme 28, Eq. 28.2) [81]. 

The concept of ring opening of cyclopropylcarbinyl radicals has been extended to substituted methylenecyclopropanes. As shown in Scheme 4, the crucial step in the reaction sequence is the regioselective addition of a substituted thiyl radical. After opening of the cyclopropane ring, the resulting radical adds to the olefin. Subsequent cyclization and reductive regeneration of the thiyl radical with concomitant liberation of the methylenecyclopentane product complete this transformation [6]. 

Olah et al. reported the triflic acid-catalyzed isobutene-iso-butylene alkylation, modified with trifluoroacetic acid (TFA) or water. They found that the best alkylation conditions were at an acid strength of about//q = —10.7, giving a calculated research octane number (RON) of 89.1 (TfOH/TFA) and91.3 (TfOH/HaO). Triflic acid-modified zeohtes can be used for the gas phase synthesis of methyl tert-butyl ether (MTBE), and the mechanism of activity enhancement by triflic acid modification appears to be related to the formation of extra-lattice Al rather than the direct presence of triflic acid. A thermally stable solid catalyst prepared from amorphous silica gel and triflic acid has also been reported. The obtained material was found to be an active catalyst in the alkylation of isobutylene with n-butenes to yield high-octane gasoline components. A similar study has been carried out with triflic acid-functionalized mesoporous Zr-TMS catalysts. Triflic acid-catalyzed carbonylation, direct coupling reactions, and formylation of toluene have also been reported. Tritlic acid also promotes transalkylation and adaman-tylation of arenes in ionic liquids. Triflic acid-mediated reactions of methylenecyclopropanes with nitriles have also been investigated to provide [3 + 2] cycloaddition products as well as Ritter products. Tritlic acid also catalyzes cyclization of unsaturated alcohols to cyclic ethers. ... 

Reaction with Methylenecyclopropanes. Methylenecyclo-propanes can serve as alkene substrates in Mn(OAc)3 processes. The reaction proceeds first by regioselective addition of the mal-onic ester radical on the alkene, followed by rapid ring opening of the cyclopropyl radical intermediate. The latter leads to free radical cyclization on the aromatic ring, followed by rearomatiza-tion to furnish the 3,4-dihydronaphthalene product in acceptable yield (eq 27). The method accepts different radical precursors, such as -ketoesters and /3-cyanoesters. When -diketones and more sterically hindered methylenecyclopropanes are used, it is possible to block the tandem reaction, and classical cyclization occurs (eq 28). ... 

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