Alkylidene carbenes insertion reactions

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. 

In subsequent work, Gilbert showed that the alkylidene carbene insertion reaction proceeds with retention of absolute configuration. Using this approach, cyclopentene (45) and cyclohexene (46) were prepared in high enantiomeric purity (equation 18). 

Various 2-substituted benzofurans 165 are obtained by the interaction of iodo-nium salts 164 with sodium phenoxide in methanol (Scheme 63) [126, 127]. This reaction proceeds via the intramolecular alkylidene carbene insertion into the ortho-CH bond of the phenoxy ring. Furopyridine derivatives 167 can be prepared similarly by the intramolecular aromatic C-H insertion of the alkylidenecarbenes generated by the reaction of alkynyliodonium tosylates 166 with potassium salts of 4- or 3-hydroxypyridines [128]. 

Insertions into tertiary C—H bonds can be carried out with moderate yields. Among other less common reactions improved by the use of PTC-generated CCI2 are the carbylamine synthesis (RNH2 — R NC) (33). Alkylidene carbene (R2C=C ) and alkenyUdene carbene (R2C=C=C ) adducts have also been prepared (34,35). 

Feldman reported a route to dihydropyrroles, pyrroles, and indoles via the reaction of sulfonamide anions with alkynyliodonium triflates <96JOC5440>. Thus, upon nucleophilic addition of the anion of 91 to the p-carbon of the alkynyliodonium salt, the alkylidene carbene 92 is generated which can the undergo C-H insertion to the desired product 93. 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Alkylidenes (alkylidene carbenes) are valence isomers of alkynes. They have been prepared by alkyne pyrolysis, by homologation of ketones, and by generation of alkenyl anions bearing oc-leaving groups. Generated by any of these means, an alkylidene will insert intramolecularly into a remote C- H bond to form a new C—C bond and thus a cyclopentene. A concerted two-electron process, this reaction proceeds with retention of absolute configuration at the C - H site. 

Intramolecular carbene insertion has been utilized as a route to thiepins and benzothiepins but is seriously complicated by C—H insertion side reactions leading to alkylidene thiopyrans (Scheme 17) (78TL3567, 78CL723), while the generation of the 9-carbene from thioxanthene (via the diazo species) results in dimerization to the bisthioxanthylene compound. 

The cyclopentene annulations can also occur in the reactions of alkynyliodo-nium salts with nitrogen- and sulfur nucleophiles (Scheme 61). Specifically, azi-docyclopentene 155 is formed upon treatment of octynyliodonium tosylate 154 with sodium azide in dichloromethane [123]. The reaction of alkynyliodonium salt 156 with sodium toluenesulfinate results in the formation of substituted indene 157 via alkylidene carbene aromatic C-H bond insertion [124]. 

Most reactions of this category involve the base-induced generation of alkylidene-carbenes (R2C = C ) which undergo an intramolecular 1,5-carbon-hydrogen insertion providing a useful route for the construction of substituted cyclopentenes a competing intramolecular pathway is rearrangement to alkynes. 

These highly reactive yet stable species are strong electrophiles of tetraphilic character, since nucleophiles may attack three different carbon atoms (a,/ ,a ) and iodine. In most reactions the first step is a Michael addition at fi-C with formation of an alkenyl zwitterionic intermediate (ylide) which normally eliminates iodoben-zene, generating an alkylidene carbene then, a 1,2-shift of the nucleophile ensues. The final result is its combination with the alkynyl moiety which behaves formally as an alkynyl cation. The initial adduct may react with an electrophile, notably a proton, in which case alkenyl iodonium salts are obtained also, cyclopentenes may be formed by intramolecular C-H 1,5-insertion from the alkylidenecarbenes ... 

Alkynyltriphenylbismuthonium salts react with sodium />-toluenesulfinate in dual reaction modes depending on the solvents employed (Equation (133)).217 When the reaction is conducted in DMF, 1-tosylcyclopentene is formed through 1,5-C-H insertion of an alkylidene carbene intermediate, generated via Michael addition of the sulfinate anion to the /3-carbon. When the reaction is carried out in MeOH, l,2-bis(sulfonyl)alkenes are produced via sequential Michael addition and nucleophilic substitution of the sulfinate anion. 

Alkylidenecarbenes are valuable intermediates for intermolecular C-H insertion reactions. They allow for a stereo-controlled synthesis of 2,5-diyhdrofurans, since C-H insertion proceeds with retention of configuration at an existing stereocenter. Upon using the Seyferth method for alkylidene carbene formation with the ketoaldehyde 32, the alkylidene intermediate of the aldehyde underwent 1,2-hydride shift, whereas the alkylidene formed from the keto function underwent 1,5-C-H insertion to give the dihydrofuran product (Equation 52) <2005TL7483>. 

The first preparative use of intramolecular C—insertion in organic synthesis was developed by Dreiding, who reported in 1979 that, on flash vacuum pyrolysis, a conjugated alkynyl ketone such as (36) is smoothly converted to a mixture of the cyclized enones (37) and (38) (equation 15). This elegant reaction apparently proceeds via isomerization of the alkyne to the corresponding alkylidene carbene. 

The insertion reactions described above probably proceed via the free alkylidene carbenes. The analogous alkylidene carbenoids also insert efficiently into remote C—H bonds. Ochiai has demonstrated that such alkylidene carbenoids are conveniently generated from the corresponding iodinium tosylates. Depending on the substitution pattern employed, either [5 -1- 0] cyclization to give (49 equation 19), or [2 + 3] cyclization to give (52 equation 20), can be obtained. 

When acyclic and cyclicl-alkenyl aminosulfoxonium salts were allowed to react with a base, p-silyloxy alkylidene carbenes were generated, which underwent a l,5-0,Si-bond insertion and 1,2-silyl migration to form 2,3-dihydrofurans <04JA485ft>. As can be seen in the scheme below, 2,3-dihydrofurans could also be formed from various 2,2-dimethyl-5-methoxy-carbonyloxy-3-pentyn-l-ols in the presence of p-methoxyphenol via a palladium-catalyzed cyclization reaction <04TL1861>. 

Insertion reactions of alkylidene carbenes offer a useful entry to cyclopentene ring systems (4.81). Insertion is most effective with dialkyl-substituted alkylidene carbenes (R = alkyl), since rearrangement of the alkylidene carbene to the alkyne occurs readily when R = H or aryl. A number of methods have been used to access alkylidene carbenes. One of the most convenient uses a ketone and the anion of trimethylsilyl diazomethane. Addition of the anion to the ketone and eUmination gives an intermediate diazoalkene, which loses nitrogen to give the alkylidene carbene. For example, a synthesis of the antibiotic (-)-malyngolide started from the ketone 102 (4.82). The insertion reaction takes place with retention of configuration at the C—H bond. 

Lithium trimethylsilyldiazomethane has proved particularly useful in the conversion of ketones into alkylidene carbenes, vide supra, that readily undergo 1,5 C-H insertion reactions to afford cyclopentenes (eq 56). Yields are generally good and the chemoselectivity of C-H insertion is predictable. The C-H insertion of the singlet carbene into heteroatom-bearing stereocenters proceeds with retention of stereochemistry (eqs 57 and 58). Reaction with acetals affords spiroketals (eq 59) or 2-cyclopentenones after acetal hydrolysis (eq 60). ... 

Elimination reactions are just the opposite of migratory insertions. The most common reactions are summarized in Figure 6. If one electron counts the carbene in Figure 6 as an alkylidene, then the reaction would be called a G-H oxidative addition to the metal center. 

Reaction of the cyanohydrin mesylate 38 with azide (NaN3-CH2Cl2) led not to the product of simple displacement, but to the vinyl azide 40 in 30% yield, through the alkylidene carbene 39 (Scheme 7), which could be trapped by insertion into cyclohexene or triethylsilane. ... 

Reactions with Carbonyl Compounds Followed by Insertion Reactions. IV-Substituted -aminoketones react with TMSC(Li)N2 to give 2-pyrroUne derivatives via the alkylidene carbene intermediates by intramolecular N-H insertion, analogously to the reaction of -acyl-A(-tosylanilines with TMSC(Li)N2 (eq 21). Dehydrogenation of the 2-pyrrolines with active Mn02 (CMD, chemical manganese dioxide, produced for battery manufacture) affords the corresponding pyrroles (eq 24). ... 

A cyclopropenation involving selective insertion of alkylidene carbenes into the Ca-Si bond of a-silyl ketones has been achieved by the reaction of TMSC(Li)N2 with a-silyl ketones that are prepared by the indium chloride-catalyzed reaction between TMSCHN2 and aldehydes (eq 28). In the case of a-silyl-a -alkoxy ketones, the Cy-H insertion competitively occurs and a mixture of cyclopropenes (Ca-Si insertion products) and dihydrofurans (Cy-H insertion products) are formed in preference of the former (eq 29). 

In the area of carbocyclic nucleoside antibiotics, hydrolysis of the racemic esters 40 (R= n-Bu or ii-CeHis) by the lipase from Candida rugosa proceeds with very high enantiomeric selectivity, and from the resolved materials both enantiomers of aristeromydn were made by an established route. The authors report that a previous similar method (Vol.21, p. 182) is not as enantioselective. In a new synthesis of neplanocin A (43), the alcohol 41, derived from D-ribose, was converted to the cyclopentene 42 using an intramolecular insertion reaction of an alkylidene carbene. The new stereocentre in 42 was mostly of the wrong P-configuration, but could be corrected by a process of desilylation, oxidation and borohydride reduction. The biosynthesis of neplanocin A (43) and aristero-mycin has been reinvestigated, and the cyclopentenone 44 has been proposed as an intermediate, which is converted to aristeromycin via neplanocin A without any bifurcation. The 3-deaza-analogue 45 of 5 - or-aristeromydn has been prepared, and the antiviral activity of it and of the 7-deaza-compound (Vol.27, p. 235) are reported. ... 

These carbene (or alkylidene) complexes are used for various transformations. Known reactions of these complexes are (a) alkene metathesis, (b) alkene cyclopropanation, (c) carbonyl alkenation, (d) insertion into C-H, N-H and O-H bonds, (e) ylide formation and (f) dimerization. The reactivity of these complexes can be tuned by varying the metal, oxidation state or ligands. Nowadays carbene complexes with cumulated double bonds have also been synthesized and investigated [45-49] as well as carbene cluster compounds, which will not be discussed here [50]. 

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