Methyl carbenoid

Allene and its derivatives react with the chloro(methyl)carbenoid, generated with butyllithium, and gives both mono- as well as diadducts. A significant amount of the adduct of chloro(methyl)carbenoid to hex-2-ene was formed hex-2-ene results from the reaction of butyl-lithium with 1,1-dichloroethane. For example, formation of 3-7 and 8-10. 

The stereoselectivity of chloro(methyl)carbenoid addition to ketene alkyl silyl acetals has been investigated.75... 

Kreiter and Formacek have obtained C NMR data for several Cr and W carbene complexes (123) (Tables XXXVI and XXXVII). They found that increased shielding of the carbene carbon occurred when R = phenyl was substituted for R = methyl. They attributed this to n donation from the aromatic ring to the vacant p orbital on the carbene carbon. Also the carbene carbons in cis 7V-methyl carbenoid ligands appeared at higher fields than in the corresponding trans fV-methyl derivatives. Finally, the shifts of ail carbons of the R and R" ligands were downfield from their typical positions due to the electron withdrawing power of the electron deficient carbene. 

In 1963, Dauben and Berezin published the first systematic study of this syn directing effect (Scheme 3.15) [37]. They found that the cyclopropanation of 2-cyclohexen-l-ol 32 proceed in 63% yield to give the syn isomer 33 as the sole product. They observed the same high syn diastereoselectivity in a variety of cyclic allylic alcohols and methyl ethers. On the basis of these results, they reasonably conclude that there must be some type of coordinative interaction between the zinc carbenoid and the substrate. 

The synthesis of vinylaziridines through reactions between allylic carbenoid reagents and imines (i.e., Darzen-type reactions) was first reported by Mauze in 1980 [13]. Treatment of aldimines or ketimines 16 with gem-chloro(methyl)allyllithium (17) afforded N-substituted vinylaziridines 18 (Scheme 2.6). Similarly, 2,3-trans-N-diphenylphosphinyl-2-vinylaziridines 21 were prepared with good stereoselectivities (trans cis= 10 1 Scheme 2.7) by treatment of a-bromoallyllithium (20) with N-diphenylphosphinyl aldimines 19 in the presence of zinc chloride [14]. 

Diazomethane is also decomposed by N O)40 -43 and Pd(0) complexes43 . Electron-poor alkenes such as methyl acrylate are cyclopropanated efficiently with Ni(0) catalysts, whereas with Pd(0) yields were much lower (Scheme 1)43). Cyclopropanes derived from styrene, cyclohexene or 1-hexene were formed only in trace yields. In the uncatalyzed reaction between diazomethane and methyl acrylate, methyl 2-pyrazoline-3-carboxylate and methyl crotonate are formed competitively, but the yield of the latter can be largely reduced by adding an appropriate amount of catalyst. It has been verified that cyclopropane formation does not result from metal-catalyzed ring contraction of the 2-pyrazoline, Instead, a nickel(0)-carbene complex is assumed to be involved in the direct cyclopropanation of the olefin. The preference of such an intermediate for an electron-poor alkene is in agreement with the view that nickel carbenoids are nucleophilic 44). 

Diverging results have been reported for the carbenoid reaction between alkyl diazoacetates and silyl enol ethers 49a-c. Whereas Reissig and coworkers 60) observed successful cyclopropanation with methyl diazoacetate/Cu(acac)2, Le Goaller and Pierre, in a note without experimental details u8), reported the isolation of 4-oxo-carboxylic esters for the copper-catalyzed decomposition of ethyl diazoacetate. According to this communication, both cyclopropane and ring-opened y-keto ester are obtained from 49 c but the cyclopropane suffers ring-opening under the reaction conditions. 

This sequence illustrates a very general method for the synthesis of methyl y-oxoalkanoates which are valuable intermediates in organic synthesis.3 6 The scope of the cyclopropanation reaction is very broad only functional groups interacting with the carbenoid generated from melhyl diazoacetate are not compatible. Use of Rh2(OAc)4 instead of Cu(acac)2 as catalyst did not afford better yields.3 The cyclopropanation reaction has been performed with similar efficiency on scales from 4 mmol up to 500 mmol. 

The earlier examples of [2 + 1] cycloaddition of a carbene (or carbenoid) on the double bond of alkylidenecyelopropanes to yield spiropentane derivatives were observed as undesired side reactions in the synthesis of alkylidenecyelopropanes through the addition of a carbene to a substituted allene [161]. In some cases the spiropentane derivative was obtained as the major product [161a, c] especially when a large excess of the carbene reagent was used. For example, when methyl 3,4-pentadienoate (610) was treated with a ten-fold excess of methylene iodide and zinc-copper couple the two products 611 and 612 were isolated in 1 4.5 ratio (Scheme 86) [161a]. 

Various alkyl- and aryl-substituted [3]radialenes could be prepared from 1,1-dihaloal-kenes using organometallic pathways. Hexamethyl-[3]radialene (25), the first [3]radialene to be synthesized, was obtained in a very low yield by treatment of l,l-dibromo-2-methyl-1-propene (22) with butyllithium8,9. The lithium carbenoid 23 and the butatriene 24 are likely intermediates of this transformation (Scheme 2), the former being the source of an unsaturated carbene moiety which is transferred onto the latter. However, the outer double bonds of 24 are more readily cyclopropanated than the central one. 

At 62% yield, the main product of the reaction of 42b with MeLi (molar ratio 1 5.5) was l,2-dichloro-2-methylbicyclo[2.1.1]hexane (66). Again, the most probable mechanism leading to 66 is addition of MeLi to carbene 54 (X=H, X=C1), followed by lithium chlorine exchange of the intermediate tertiary alkyllithium base 67 with the trichloride 42b. An alternative mechanism, addition of LiCl to carbene 54 and methylation of the intermediate carbenoid by MeLi, formed during the reaction from MeLi and 42b, is less probable.24... 

Although alkylidenecarbenes (R)2C=C and carbenoids 22-24 have an ip-hybridized carbene center similar to that of vinylidenecarbenes, the reactivity will be subject to the steric influence of substituents R3 and R4 because its location is closer to the carbene center than vinylidenecarbenes (Scheme 11). The steric effect was exerted in the reactions of 2-methylpropenylidene 22 generated from 2-methyl-1-chloropropene and butyllithium (BuLi) (Scheme ll).22 23 The results are summarized in Table 5. A more detailed discussion on the stereoselectivity of this reaction will be revisited in Section HI. A. 

So far, the reports on copper and silver scorpionate catalysis are limited to ethyl diazoacetate as the carbenoid precursor, and it is questionable whether these catalysts can be used with other classes of diazo compounds. The reaction of the more stable methyl diazomalonate resulted in the formation of a remarkable O-bound diazo complex, which was thermally stable (Equation (9)).76... 

The benzylic C-H activation has been effectively applied to the enantioselective synthesis of (+)-imperanene (Equation (16)).80 The key step was the Rh2(i -DOSP)4-catalyzed functionalization of the benzylic methyl C-H bond in arene 2. An impressive feature of this transformation was that both the carbenoid and substrate contained very electron-rich aromatic rings, which were compatible with the highly electrophilic carbenoids because they were still sterically protected. 

The C-H insertion a to nitrogen can be extended to acyclic systems. The reaction with jY-benzyl-iV-methylamine is an excellent example of the interplay between steric and electronic effects. The benzylic position would be electronically the most activated, but due to the steric crowding, the C-H insertion occurred exclusively at the iV-methyl site (Equation (27)).86 This is a general method for generating a-aryl-/5-amino acid derivatives. The N,N-dimethylamino group undergoes a very favorable C-H insertion by the donor/acceptor-substituted carbenoids. Indeed, the reaction is so favorable that double C-H insertion was readily achieved to form the elaborated -symmetric amine 10 (Equation (28)).87... 

Ligand 55c is also efficient in the cyclopropanation of other alkenes. 1,1 -Disub-stituted alkenes afford cyclopropanes in high enantioselectivity with ethyl diazoacetate as carbenoid source, Eq. 25 (34). Internal dissymetric trans alkenes are also excellent substrates. trans-P-Methyl styrene afforded a 95 5 diastereomeric mixture with cyclopropane 56a predominating in 96% ee, when the butylated hydroxy toluene (BHT) diazoester was used, Eq. 26 (35). 

The utilization of the dibromides 315 permitted the generation of 311 by MeLi. Since MeLi is less reactive as a nucleophile than wBuLi, the ring opening of 311 by addition of the methyl anion analogous to the formation of 314 (Scheme 6.67) was of no importance. However, in the case of 315 (R = CH2Ph), the intramolecular insertion of the transient carbenoid or carbene, leading to 312, was the main reaction and hence the cause of low yields of the respective cycloadducts 316, 317, 319 and 320. Whether such an insertion has to be blamed for the very modest yields of 316 and 317 with R= Me could not be proved [154]. 

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