Alkyl carbenoids insertion reactions

Clayden and Julia reported the 1,3-C,H insertion reaction of lithium carbenoid (69) derived from a primary alkyl chloride (68) by H-Li exchange reaction (eqnation 19). Treatment of 68 with a mixture of n-BuLi and tert-BnOK gave three prodncts. These... 

Metal hydride species can undergo an insertion reaction with an olefinic double bond, resulting in the formation of a metal alkyl species which then generates the requisite carbenoids by a-hydride abstraction [110-112] ... 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

While this methodology could be extended to more-substituted cyclooctene oxides (Scheme 56, Equation 12), examination of cycloheptene oxide (Scheme 56, Equation 13) revealed the need for considerably longer reaction times, leading to reduced yields due to competing carbenoid-insertion pathways (cycloheptanone formation and reductive alkylation) <2002AGE2376, 2003OBC4293>. 

Carbenes and carbenoids undergo various reactions, that is, they can add to double and triple bonds, insert into C-H bonds, and undergo skeletal rearrangements. A carbon atom with only six electrons will do almost anything to get another two. Carbenes are too reactive to be isolated and stored they are trapped in frozen argon for spectroscopic study at very low temperatures. Alkyl carbenes insert much more selectively than methylene, which does not differentiate between primary, secondary, and tertiary C-H bonds. 

Scheme 1.8 Asymmetric C—H bond insertion reactions of dirhodium carbenoids derived from a-alkyl-a-diazo ester reported by Hashimoto.

The most recent example of pyrrolidine synthesis by C-H functionalization was illustrated in 2014, when Che and coworkers demonstrated the synthesis of pseu-doheliotridane, a simple pyrrolidine alkaloid, by employing a ruthenium-catalyzed C-H insertion reaction (Scheme 16.44) [89]. Although diazocarbonyl compounds are generally required as the precursor of the metal carbenoid intermediate, they utilized an alkyl diazomethane as the carbene source. To this end, tosylhydrazone 192 was reacted with [Ru(TTP)(CO)] (TTP tetra(p-tolyl)porphyrin) (1 mol%) and KjCOj, which generated ruthenium carbene 193 in situ, followed by C-H insertion to produce pseudohehotridane in 95% yield with high diastereoselectivity. 

Cyclic a-diazocarbonyl compounds (59) and enynones (61) have been used as Rh-and Zn-carbenoid precursors, respectively. Cyclic derivatives (59) have been found to favour intermolecular Rh-catalysed cyclopropanation reactions, relative to the formation of conjugated alkene (60) by intramolecular -hydride elimination as is usually observed in the case of a-alkyl-a-diazocarbonyl compounds this high level of chemoselectivity is reported for the first time. Rh-carbenoids derived from (59) have also promoted cyclo-propenation reactions as well as diverse X-H insertion reactions (i.e., X = C, N, O, S). In parallel, highly functionalized cyclopropylfiirans (62) have been successfiilly prepared from an alkene and an enynone (61) by a cyclization/cyclopropanation sequence conducted in the presence of catalytic amounts of ZnCl2, which is cheap and of low toxicity computations support the probable participation of intermediate Fisher-type Zn(II) carbene complexes (63). 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

In addition to insertion into p-C—H bonds, cyclopropylidenes can undergo other reactions such as alkylation (c/. Section 4.7.3.2), dimerization, insertion into C—H bonds of the ether solvent (equation 60)183 or reaction with alkenes to afford spirocyclopropanes (equation 61).184 Addition of stoichiometric amounts of Bu OK has been shown to promote the reactions of lithium carbenoids, even at -83 C, with THF to give the insertion product (equation 62).185 Addition to alkenes is also promoted under these conditions. Intramolecular addition of the carbenoid to double bonds has been exploited in the synthesis of spirotricyclic compounds (equation 63).186... 

The overall mechanistic picture of these reactions is poorly understood, and it is conceivable that more than one pathway may be involved. It is generally considered that cycloheptatrienes are generated from an initially formed norcaradiene, as shown in Scheme 30. Equilibration between the cycloheptatriene and norcaradiene is quite facile and under acidic conditions the cycloheptatriene may readily rearrange to give a substitution product, presumably via a norcaradiene intermediate (Schemes 32 and 34). When alkylated products are directly formed from the intermolecular reaction of carbenoids with benzenes (Scheme 33 and equation 36) a norcaradiene considered as an intermediate alternatively, a mechanism may be related to an electrophilic substitution may be involved leading to a zwitterionic intermediate. A similar intermediate has been proposed143 in the intramolecular reactions of carbenoids with benzenes, which result in substitution products (equations 37-40). It has been reported,144 however, that a considerable kinetic deuterium isotope effect was observed in some of these systems. Unless the electrophilic attack is reversible, this would indicate that a C—H insertion mechanism is involved in the rate-determining step. 

A vast array of chiral catalysts have been developed for the enantioselective reactions of diazo compounds but the majority has been applied to asymmetric cyclopropanations of alkyl diazoacetates [2]. Prominent catalysts for asymmetric intermolecular C-H insertions are the dirhodium tetraprolinate catalysts, Rh2(S-TBSP)4 (la) and Rh2(S-DOSP)4 (lb), and the bridged analogue Rh2(S-biDOSP)2 (2) [7] (Fig. 1). A related prolinate catalyst is the amide 3 [8]. Another catalyst that has been occasionally used in intermolecular C-H activations is Rh2(S-MEPY)4 (4) [9], The most notable catalysts that have been used in enantioselective ylide transformations are the valine derivative, Rh2(S-BPTV)4 (5) [10], and the binaphthylphosphate catalysts, Rh2(R-BNP)4 (6a) and Rh2(R-DDNP)4 (6b) [11]. All of the catalysts tend to be very active in the decomposition of diazo compounds and generally, carbenoid reactions are conducted with 1 mol % or less of catalyst loading [1-3]. 

A widely exploited procedure for bringing about carbenoid reactions of organic mono- and fifem-dihalides is by use of lithium alkyls. Examples are given in equations (11) and (12). Dimeric olefin formation, stereospecific cyclopropane formation from olefins, and insertion into carbon-hydrogen bonds have all been observed in suitable cases, together with further reactions of these products with excess of the lithium alkyl. 

Some examples of catalytic cyclopropanation reactions with diazoacetamides are given in Table 14. In reactions with a-diazo-A,7V-dimethylacetamide catalyzed by tetraacetatodi-rhodium, cyclopropane yields decrease with decreasing alkene reactivity (ethoxyethene, 82% styrene, 47% cyclohexene, 21%). - Furthermore, with A-alkyl substituents larger than methyl, intramolecular carbenoid C-H insertion is in competition with alkene addition, e.g. formation of 4.i -259... 

In view of the remarkable stability of metal homoenolates of esters, the existence of homoenolate species containing a 3-halo substituent, i.e. zinc carbenoid moiety connected to an ester group, appeared to be possible. Indeed, when a silyl ketene acetal is treated with a carbenoid generated from CHBrj and Et2Zn, two types of highly intriguing reactions ensue [58]. With a purely aliphatic substrate, Eq. (61), an alkyl cyclopropylcarboxylate due to intramolecular p-CH-insertion of the intermediate zinc carbenoid formed. When the substrate contained an olefmic double bond in the vicinity of the carbenoid function, Eq. (62), in particular an intermediate derived from an a,P-unsaturated ester, internal cyclo-propanation occurred to give bicyclic or tricyclic product (Table 15). 

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