Carbene addition cyclization

CHEMICAL MODIFICATION The following chemical modifications of cis-1,4-polyisoprene are employed as a convenient way of altering physical and mechanical properties hydrohalogenation, halogenation, oxidation, ozonolysis, hydrogenation, carbene addition, cyclization. ... 

The key cyclization in Step B-2 was followed by a sequence of steps that effected a ring expansion via a carbene addition and cyclopropyl halide solvolysis. The products of Steps E and F are interesting in that the tricyclic structures are largely converted to tetracyclic derivatives by intramolecular aldol reactions. The extraneous bond was broken in Step G. First a diol was formed by NaBH4 reduction and this was converted via the lithium alkoxide to a monomesylate. The resulting (3-hydroxy mesylate is capable of a concerted fragmentation, which occurred on treatment with potassium f-butoxide. 

Reaction of recently synthesized 1 -al kvnyl />-( trifluoromethyl )phenyl]( tetrafluoro-borato)-X3-bromanes with 2-mercapto- benzimidazole or benzothiazole in dichloro-methane at 0°C under argon resulted in a domino Michael addition-carbene rearrangement-cyclization reaction to produce directly tricyclic heterocycles in high yields (Scheme 67).103... 

The first approach is realizable via a variety of typical carbene reactions. Cyclizations not involving a heteroatom include formation of a new C—C bond as a result of an intramolecular C—H insertion of a carbene (Scheme 1) or its addition onto multiple carbon-carbon bonds [intramolec-... 

The third carbene-based approach to heterocycles consists in cycliza-tion or cycloaddition of unstable intermediates of carbene reactions. Inter-molecular carbene addition to the heteroatom of C=Z bond produces an ylide capable of being stabilized via 1,3- or 1,5-cyclization or via [3 + 2]-cycloaddition (Scheme 15). 

Carbene reactions provide a versatile approach to the synthesis of five-membered nitrogen-containing rings. Of particular importance here are intramolecular insertion of a carbene into C — H and N — H bonds, addition onto multiple carbon-carbon bonds, intermediate formation of ylides as a result of carbene addition onto the heteroatom followed by rearrangement, cycloaddition, and cyclization. 

Epoxidations, carbene additions, etc. of 2,3-epoxycitral have been studied.209 A very detailed investigation of the dye-sensitized photoxidation of a-nerol (92) showed the formation of the diols (93) and (94) with no cyclized products.210 Allo-ocimene and myrcene on autoxidation in DMF or DMSO give an odd variety... 

Most common are carbene additions, [2 -1- 2]-cycloadditions, [2 -1- 3] heterodipolar cycoladditions [238], and [2 -1- 4]-cycloadditions that comprise Diels-Alder and hetero-Diels-Alder (HDA) reactions [239]. Apart from these, there are also a number of tandem cyclization or condensation reactions that are formal cycloadditions. 

The addition of sulfur nucleophiles to alkynes is a less developed transformation. However, Yamamoto described the attack of the sulfur atom of aryl thioethers to afford benzothiophenes (equation 31). More recently, it has been showed that propargylic thioethers or thioacetals undergo migration to give carbenes that cyclize in hydroarylation processes and thiocarbamates that evolve by propargylic rearrangement. Thiosilanes can perform as both sulfur nucleophiles and silicon electrophiles in intramolecular reactions to afford benzothiophenes (equation 32). ... 

Various flve-membered heterocycles can be prepared by inter- or intramolecular addition/cyclizations of appropriate nucleophiles with alkynyliodonium salts via alkylidene carbene intermediates [856, 978, 979]. The intermolecular variant of this cyclization has been employed in the synthesis of 3-substituted-5,6-dihydroimidazo[2,l-( ]thiazoles [997], 2-substituted imidazo[l,2-a]pyrimidines [998] and 2-substituted-imidazo[l,2-fl]pyridines [999]. In a representative example, 2-substituted imidazo[l,2-fl]pyridines 744 were synthesized in good yield by cyclocondensation of 2-aminopyridine (742) with alkynyl(phenyl)iodonium tosylates 743 under mild conditions (Scheme 3.293) [999]. The mechanism of this cyclization involves... 

A stepwise 1,7-vinyl shift was proposed to account for the reaction after carbene addition to make the cyclopropene. Deuterium labeling studies were consistent with this pathway. Interestingly, upon heating to 145°C the phenyl-substituted 5.2.0 tetraene isomerized to 2-phenylindene in what appears to be a cyclization of the cycloheptatriene moiety followed by opening of the bicyclo[2.1.0]pentene and a 1,5-hydrogen shift (Scheme 10.9). 

The cyclopentene derivatives 9 undergo both 1,5- and 1,7-dipolar electrocyclizations to yield mixtures of pyrazoles 10 and benzodiazepines 11. In addition, loss of nitrogen results in the carbenes 12, which cyclize to the tetrahydrocyclopent[fl]indenes 13.117... 

Those reactions that have found general use for the preparation of aziridines can be grouped into two broad classes addition and cyclization processes, and each of these categories can be further divided. Addition processes can be classified as being C2+N1 reactions (addition of nitrenes, or nitrene equivalents [ nitrenoids ], to alkenes Scheme 4.1) or (J N1+C1 reactions (addition of carbenes or carbenoids to imines Scheme 4.2). 

Scheme 4 Access to various a,/ -unsaturated carbene complexes from alkynylcarbene complexes 23. A 1,3-Dipolar cycloaddition. B Diels-Alder reaction. C Ene reaction. D [2+2] Cycloaddition. E Michael-type addition followed by cyclization. F Michael-type additions...

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

Addition of acyl anions generated from acylsilanes to a,(3-unsaturated ketones using N-heterocyclic carbenes (NHCs) derived from thiazolium salts as catalyst produced 1,4-diketones, which cyclized to form the corresponding furans in good yields under an acidic condition <06JOC5715>. 

Asymmetric induction has also been achieved in the cyclization of aliphatic alcohol substrates where the catalyst derived from a spirocyclic ligand differentiates enantiotopic alcohols and alkenes (Equation (114)).416 The catalyst system derived from Pd(TFA)2 and (—)-sparteine has recently been reported for a similar cyclization process (Equation (115)).417 In contrast to the previous cases, molecular oxygen was used as the stoichiometric oxidant, thereby eliminating the reliance on other co-oxidants such as GuCl or/>-benzoquinone. Additional aerobic Wacker-type cyclizations have also been reported employing a Pd(n) system supported by A-heterocyclic carbene (NHC) ligands.401,418... 

In order to destabilize the likely unproductive 6-membered chelate structure of type K (Scheme 17) that might be formed if the catalyst reacts with the 4-pen-tenoate entity, the cyclization was run in the presence of a Lewis acid which competes with the evolving carbene for the Lewis basic ester group. Such an additive has to be compatible with the RCM catalyst, should provoke a minimum of acid-catalyzed side reactions, and must undergo a kinetically labile coordination with the relay substituent. Ti(OiPr)4 was found to meet these stringent requirements... 

In addition to reactions characteristic of carbonyl compounds, Fischer-type carbene complexes undergo a series of transformations which are unique to this class of compounds. These include olefin metathesis [206,265-267] (for the use as metathesis catalysts, see Section 3.2.5.3), alkyne insertion, benzannulation and other types of cyclization reaction. Generally, in most of these reactions electron-rich substrates (e.g. ynamines, enol ethers) react more readily than electron-poor compounds. Because many preparations with this type of complex take place under mild conditions, Fischer-type carbene complexes are being increasingly used for the synthesis [268-272] and modification [103,140,148,273] of sensitive natural products. 

Balme G, Bouyssi D, Monteiro N (2006) The Virtue of Michael-Type Addition Processes in the Design of Transition Metal-Promoted Cyclizative Cascade Reactions. 19 115-148 Barluenga J, Rodriguez F, Fanands FJ, Fldrez J (2004) Cycloaddition Reaction of Group 6 Fischer Carbene Complexes. 23 59-121 Basset J-M, see Candy J-P (2005) 16 151-210... 

Sames et al. have reported the intramolecular cyclization of alkene-amide substrates catalyzed by [Ir(COE)2Cl]2 and the A-heterocyclic carbene ligand, N, A -bis-(2,6-diisopropylphenyl)-imidazolyl, via olefin insertion following oxidative addition of an sp C-H bond (Scheme 11) [117]. 

An exo-type cyclization, proceeding through a cycloalkylidene carbene (49 n = 1, 3, 4), was proposed to explain the formation of enynes (50) and (52) from alkynyl lithium species (48). The proposed carbene (49) could be trapped by addition to cyclohexene and the cycloalkyne intermediate (51) was trapped by Diels-Alder reaction with 1,3-diphenylisobenzofiiran. 

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