Insertion alkylidene carbenes

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). 

C-H insertion of an alkylidene carbene intermediate, which was generated via the Michael addition of a sulfinate anion to the acetylenic p-carbon. In MeOH,... 

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. 

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. 

Scheme 1.3.18 Asymmetric synthesis of monocyclic 2,3-dihydrofurans via O—Si bond insertion of alkylidene carbenes.

Both the lack of regioselectivity observed for the intramolecular insertion of alkylidene carbenes derived from (E)- and (Z)-A -iodanes 108 and the high degree of stereo convergence of the olefin geometry of vinylsulfonium salts indicate the intermediacy of the free alkylidene carbene [Eq. (99)] [53,172]. 

As shown above, insertion of alkylidene carbenes is highly regioselective. However, when the normal 1,5-C-H insertion pathway is blocked, 1,4- or 1,6-C-H insertion takes place [Eq. (109)]. Thus, the cyclobutene 121 [192] and the six-membered enol ether 123 [193] were obtained in modest yields. Intramolecular insertion into carbon-carbon double bond provides a method for synthesis of cyclopenten-annulated dihydropyrrole 124, which results from homolytic scission of a methylenecyclopropane intermediate [194]. 

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]. 

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]. 

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. 

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). 

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>. 

The conversion of the carbonyl group of an 7V,7V-disubstituted 2-aminoketone to an alkylidene carbene leads to insertion of the carbene into one of the nitrogen substituents and the formation of a five-membered ring at the oxidation level of a dihydropyrrole. Manganese dioxide readily converts such species (or indeed pyrrolidines ) into the aromatic pyrroles. ... 

A new two-step preparation of pyrroles from (3-amino ketones and trimethylsilyldiazo-methane was developed by Aoyama and Shioiri <97SL1063>. Treatment of the N-substituted (5-amino ketones 15 with lithium trimethylsilyldiazomethane affords the alkylidene carbene intermediates 16 which undergo intramolecular insertion to yield the 2-pyrrolines 17. In this instance, dehydrogenation to the corresponding pyrroles was accomplished using Mn02-... 

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. 

Alkylidene carbenes 14 undergo a 1,6-C-H insertion at the /ren-position of naphthols 13 to yield dibenzo[bc]pyrans (Scheme 13) <01TL6031>. 

The unique [3,3,3]propellane sesquiterpenoid modhephene (322) has also been synthesized (Scheme 40). The crucial construction of the propellane system was achieved by a thermally induced intramolecular carbene insertion of the intermediate alkylidene carbene derived from (332). 

A general method for the cyclization of an unactivated 1,1-disubs-tituted alkene to the corresponding cyclopentene has been described. Bromination followed by the addition of KHMDS in the same pot gave the vinyl bromide intermediate, which reacted further in situ to give the alkylidene carbene. This is then inserted in a 1,5-fashion into a C-H bond to yield the corresponding cyclopentene (eq 44). KHMDS proved to be superior in this process as compared to LiHMDS and NaHMDS. 

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). ... 

The intramolecular variant of the alkylidene carbene cyclization is achieved by treating functionalized alkynyliodonium salts with a suitable nucleophile. These cyclizations are exemplified by the following works the preparation of various functionalized 2,5-dihydrofurans by treatment of 3-alkoxy-l-alkynyl-(phenyl)iodonium triflates with sodium benzenesulfinate [1002], employment of the alkylidene carbene cyclization in the total syntheses of natural products agelastatin A and agelastatin B [1003] and preparation of the tricyclic core of ( )-halichlorine through the use of an alkynyliodonium salt/alkylidenecarbene/1,5 C—H insertion sequence [1004]. In particular, Wardrop and Fritz have employed the sodium benzenesulfinate-induced cyclization of alkynyliodonium triflate 751 for the preparation of dihydrofuran 752 (Scheme 3.295), which is a key intermediate product in the total synthesis of ( )-magnofargesin [1002]. 

Scheme 5.51 Generation and intramolecular insertion of alkylidene carbene.

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