Benzyl carbenoids

Scheme 3.32. Mono- and bis-insertion of benzyl carbenoids into saturated zirconacycles.

Scheme 3.33. Insertion of benzyl carbenoids into unsaturated zircona-cycles.

Insertion of benzyl carbenoids into saturated bicychc zirconacycles gives initially a 1 1 mixture of the diastereoiso-meric zirconacyclohexanes (108) and (109). (109) undergoes a complete isomerization in a few minutes at 60 °C to the more stable diastereomer (108) (Scheme 40). 

Insertion of benzyl carbenoids into zirconacyclopentenes follows a different but mechanistically related process. 

Despite the unexpected challenges associated with benzylic carbenoid C-H insertion, the Davies group successfully employed this methodology toward the concise total syntheses of (+)-imperanene and (-)-a-conidendrin [84], Although the imperanene synthesis will be discussed in a later context (Sect. 4.2), the route to conidendrin 84 is outlined below (Scheme 17). The key carbenoid insertion took place between vinyldiazoester 82 and substituted toluene 81 in moderate yield, but provided the precursor (83) to the tricyclic structure in 92% ee. 

Compared with five-membered metallacycles, relatively fewer reports are known on the preparative methods and reaction chemistry of six-membered metallacycles. Whitby and coworkers have systematically investigated insertion of carbenoids into five-membered zirconacycles and developed a number of interesting six-membered zirconacycles [17, 26]. Isonitriles, 1-halo-l-lithioalkenes, allenyl carbenoids, allyl carbenoids, propargy carbenoids, benzyl carbenoids, and 1-nitrile-1-lithio epoxides can all insert into zirconacyclopentanes and zirconacyclopentenes to afford various six-membered zirconacycles (Eqs. 23,24). 

Interestingly, [Ee(F20-TPP)C(Ph)CO2Et] and [Fe(p2o-TPP)CPh2] can react with cyclohexene, THF, and cumene, leading to C-H insertion products (Table 3) [22]. The carbenoid insertion reactions were found to occur at allylic C-H bond of cyclohexene, benzylic C-H bond of cumene, and ot C-H bond of THF. This is the first example of isolated iron carbene complex to undergo intermolecular carbenoid insertion to saturated C-H bonds. 

Chloro(phenyl)carbene or carbenoid generated from benzal chloride reacts with potassium salts of benzylic, allylic, and other alkoxides to produce phenyl-substituted oxiranes 9 in high yields, as an approximately 1 1 mixture of cis... 

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... 

An electron-enriched 1,3-diene moiety as in the substrate 381 can act as a nucleophile toward an activated alkyne moiety (Scheme 94). Iwasawa340 has reported an elegant synthesis of a diquinane framework 382, which is catalyzed by various metals and the rhenium(i) complex appears to be the best catalyst among the metal complexes examined. Minor product 384 presumably is formed through an insertion of a carbenoid species into the neighboring activated benzylic C-H bond. The same carbenoid species can undergo a 1,2-H shift to give the major product 383. 

Enantiomerically pure a-lithiated ethers have been prepared from stannanes and turned out to react with electrophiles under retention. The configurational stability of the hthium carbenoid 19 has been deduced from equation 10 . Lithiated benzyl methyl ether, chelated by a chiral bis(oxazoline) ligand, proved itself to be configurationally stable as welP . ... 

C-H activation at a primary benzylic site was the key step in very short syntheses of lig-nans 206 and 207 (Scheme 14.27) [138]. Even though both the substrate 203 and the vinyl-diazoacetate 204 contain very electron-rich aromatic rings, C-H activation to form 205 (43% yield and 91% ee) is still possible because the aromatic rings are sterically protected from electrophilic aromatic substitution by the carbenoid. Reduction of the ester in (S)-205 followed by global deprotection of the silyl ethers completes a highly efficient three-step asymmetric total synthesis of (-i-)-imperanene 206. Treatment of (R)-205 in a more elaborate synthetic sequence of a cascade Prins reaction/electrophilic substitution/lacto-nization results in the total synthesis of a related lignan, (-)-a-conidendrin 207. 

We believe that the selectivity of methine (CH) insertion over methylene (CH2) insertion (Tab. 16.6) is a reflection of the polarizabihty of the rhodium carbenoid. As the carbenoid approaches the target C-H, the methine C-H is more electron-rich than the methylene C-H. A more easily polarized carbenoid would respond more fully to this and give proportionally more of the methine insertion product. Our design of the a-diazo ester 32 included the p-methoxy group on the benzene ring, so that the reactivity of the methylene benzylic C-H would approach that of the methine. Statistically, due to geometric constraints, only one of the two benzyhc methylene C-H groups is available for the insertion necessary for the cyclization to 36/37. 

This reaction apparently proceeds by way of the normal phosphonate condensation product, the diazoalkylidene, which then spontaneously loses nitrogen to form the transient alkylidene car-bene. Careful work showed that, after statistical corrections were applied, the reactivity of a C-H bond toward insertion was approximately 0.003 for primary C-H bonds (methyl), 1.0 for secondary C-H bonds (methylene), 7.5 for benzylic (methylene) C-H bonds and 18.6 for tertiary C-H bonds. These relative reactivities are very similar to those previously observed for intramolecular C-H insertion by an alkylidene carbenoid generated from a vinyl bromide27. It was shown subsequently that the alkylidene carbene insertion reaction proceeds with retention of absolute configuration28. Using this approach, (l )-3-dimethyl-3-phenyl-l-cyclopentene and (i )-4-methyl-4-phenyl-2-cyclohexcnonc were prepared in high enantiomeric purity. 

Hammerschmidt, F. Hanninger, A. Enantioselective deproto nation of benzyl phosphates by homochiral lithium amide bases. Configurational stability of benzyl carbanions with a dialkoxyphosphoryloxy substituent and their rearrangement to optically active a-hydroxy phosphonates. Chem. Ber. 1995, 328, 823-830. Avolio, S. Malan, C. Marek, I. Knochel, P. Preparation and reactions of functionalized magnesium carbenoids. Synlett 1999, 1820-1822. 

Treatment of 1-chloroalkyl phenyl sulfoxides with isopropylmagnesium chloride has been reported to yield magnesium carbenoids that also undergo 1,3-CH insertion to cyclopropanes (35) when a geminal methyl or benzyl group is present as in (34).36... 

Donor/acceptor-substituted carbenoids are usually much more chemoselective than the more established carbenoids functionalized solely with acceptor groups [lc]. The development of these donor/acceptor-substituted carbenoids has enabled enantioselective intermolecular C-H insertions to become a very practical process. These carbenoids have a strong preference for functionalizing C-H bonds where positive charge build-up at C in the transition state is favored but these electronic effects are counter-balanced by steric factors. Benzylic and allylic sites and C-H bonds adjacent to oxygen and nitrogen functionality are favored but these sites can also be sterically protected if desired. By appropriate consideration of the regiocontrolling elements, effective intermolecular C-H insertions at methyl, methylene, and methine sites have been achieved. 

Carbenoid generation of nitrogen ylides represents a useful alternative to the widely employed base-promoted methodology.49 The reaction of aliphatic diazo compounds with tertiary amines was first investigated by Bamford and Stevens in 1952.50 The formation of a-benzyl-a-dimethyl-aminofluorene (99) from the reaction of diazofluorene (97) with ben-zyldimethylamine is consistent with a mechanism involving the generation of ammonium ylide 98 which then undergoes a [l,2]-benzyl shift. 

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