Insertion reactions alkylidenecarbenes

Alkylidenecarbenes undergo a carbon-hydrogen-insertion reaction that leads to a mixture of two isomeric products, 2-substituted furo[3,2- ]pyridines, 109, and 2-substituted furo[2,3-. 

The initial conceptualization of the agelastatin A problem took on the form shown below (Scheme 5).17 The key transform in this sequence features intramolecular addition of an amide-derived anion to a tethered alkynyliodonium salt within 33. The alkylidenecarbene generated from this nucleophilic addition, 32, then has a choice of two diastereotopic C-H bonds (Ha or Hb) for 1,5 insertion. Reaction with Ha would provide an advanced intermediate 31 en route to the target 28. Successful execution of this plan would extend alkynyliodonium salt chemistry in three new directions (1) use of an amine derivative as a nucleophile, (2) intramolecularity in the nucleophile addition step, and (3) diastereoselectivity upon alkylidenecarbene C-H insertion. At the initiation of this project, a lack of precedent on any of these topics suggested that focused scouting experiments to assess feasibility would be prudent before beginning work towards the natural product itself. 

The mechanisms for the insertion reactions of alkylidenecarbenes with methanol were investigated at the B3LYP/6-311G(d,p) level of the theory.57 The products are predicted to be vinyl ethers with a mixture of cis- and trans -isomers. The reactivity of the carbenes decreases in the order HFC=C > HC1C=C > HBrC=C > H(Me)C=... 

M. Akiyama, T. Awamura, K. Kimura, Y. Hosomi, A. Kobayashi, K. Tsuji, A. Kuboki, and S. Ohira, Stereocontrolled synthesis of the aminocyclitol moiety of (+)-trehazolin via C-H insertion reaction of alkylidenecarbene, Tetrahedron Lett., 45 (2004) 7133-7136. 

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>. 

Gilbert and Blackburn showed that the generation of an alkylidenecar-bene intermediate is a viable route to 3-pyrrolin-2-ones (Scheme 41 1986JOC3656). Treatment of the 2-oxopropanamide 184 with dimethyl diazomethyl(phosphonate) (185) and TBuOK gives the 3-pyrroHn-2-one 187. The 3-pyrrolin-2-one ring is formed by an intramolecular C—H insertion reaction involving alkylidenecarbene intermediate 186. 

Alkylidenecarbenes 40 generated by the reaction of alkynyl p-phenylene)bis-iodonium ditriflates 39 with phenoxide anion undergo selective intramolecular aromatic C—H insertion, thereby providing 2-substituted benzofurans 41 (93TL4055) (Scheme 15). 

Reaction of alkynylbisiodonium ditriflates (48) with sodium phenoxide gave rise to good yields of benzoflirans by 1,5-CH insertion of the intermediate alkylidenecarbene (49) 61 Tjle selectivity of 1,5-CH insertion of carbene (50) was observed to be highly dependent on the method of carbene generation.62... 

The pareitropone project began quite by accident after an unexpected observation expanded our thinking about potentially accessible targets for alkynyliodonium salt/alkylidenecarbene chemistry (Scheme 18). Treatment of the tosylamide iodonium salt 125 with base under standard conditions was designed to provide no more than routine confirmation of the aryl C-H insertion capabilities, which were first exposed in indoleforming reactions using tosylanilide anion nucleophiles and propynyl(phenyl)iodonium triflate,5b of the intermediate carbene 126. However, this substrate did not perform as expected, since only trace amounts of the 1,5 C-H insertion product 127 was detected. One major product was formed, and analysis of its spectral data provided yet another surprising lesson in alkynyliodonium salt chemistry for us. The data was only consistent with the unusual cycloheptatriene structure 129. 

Reactions of alkynyliodonium salts 119 with nucleophiles proceed via an addition-elimination mechanism involving alkylidenecarbenes 120 as key intermediates. Depending on the structure of the alkynyliodonium salt, specific reaction conditions, and the nucleophile employed, this process can lead to a substituted alkyne 121 due to the carbene rearrangement, or to a cyclic product 122 via intramolecular 1,5-carbene insertion (Scheme 50). Both of these reaction pathways have been widely utilized as a synthetic tool for the formation of new C-C bonds. In addition, the transition metal mediated cross-coupling reactions of alkynyliodonium salts are increasingly used in organic synthesis. 

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]. 

In such reactions, insertion of the intermediate alkylidenecarbenes into the ortho-CH bonds of the aromatic ring is preferred over insertion into the y-CH bonds of the aliphatic side chain. 

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 ... 

Alkylidenecarbenes 126 give pyrrol-2-ones via intramolecular C—H insertion. As a synthetic method, the reaction is best suited for substrates in which the nitrogen of amides 127 is symmetrically substituted (86JOC3656). 

The first step in this scheme is a Michael addition of the nucleophile to the j5-carbon of the alkynyliodonium salt to give the ylide 102. Loss of iodobenzene from 102 gives alkylidenecarbene 103, which rearranges to alkyne 104 in the absence of external traps. This mechanism is experimentally supported by the isolation of cyclic by-products 108 besides the major products, the alkynyl esters 107 in the reaction of alkynyliodonium salt 105 with nucleophiles (equation 67). These cyclic enol ethers are the result of the insertion of the intermediate carbene 106 into the tertiary-8-carbon-hydrogen bond. 

In another example, Postel and co-workers used functionalized carbohydrates to produce P-substituted polyoxygenated furans. Treatment of functionalized benzylidene precursors with TMS-N3 in the presence of dibutyltin oxide gave the corresponding furan in 10% yield. The authors used a computational approach to rationalize furan formation via a series of cascade fragmentation reactions obtained during 1,5-C-H insertion from alkylidenecarbenes. 

Cyclopent-2-enone ring. A mixture of startg. iodonium salt and K-/cr/-butoxide allowed to react in tetrahydrofuran at — 78° until reaction complete product. Y 61 %. The formation of the bicyclic compd. can be explained by regioselective 1,5-carbon-hydrogen insertion of the alkylidenecarbene intermediate. F.e.s. M. Ochiai et al., J Am. Chem. Soc. 110, 6565-6 (1988). 

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