Carbene cyclization

Padwa and co-workers (36-38) developed a process concerning a tandem carbene cyclization-cycloaddition sequence that led to the formation of products of greater complexity in a single step (Scheme 4.25). 

Carbene cyclization 36 Carvone (starting material) 33 Citlalitrione synthesis 24 C-H Activation 122 C-H to alcohol 157... 

A number of appropriate diazo precursors have been subjected to tandem carbene cyclization-iso-munchnone intramolecular cycloaddition.129 Thus, (232a) was cyclized with rhodium acetate to provide a tricyclic tetrahydrofuran (232b) cyclized similarly and produced just one stereoisomer. 

Cyclopentenes are commonly formed in the reaction of the appropriate alkynyliodonium salts with enolate anions. Various alkynyliodonium tetrafluo-roborates interact with / -dicarbonyl enolates to give products of cyclopentene annulation in 50-90% yield [121]. Several examples of such annulations are shown in Scheme 59. The carbene cyclization can also occur when the long alkyl... 

Three principal carbene-based approaches to the construction of heterocycles can be recognized. These include (1) the carbene cyclization reaction, (2) ring contraction or expansion with carbene intermediacy, and (3) cyclization or cycloaddition of unstable primary products of carbene reactions. 

Intermediate heterocyclic ylides may be stabilized by [1,2]- or [2,3]- rearrangements (Scheme 5). The [l,2]-shift may result in expelling an ylide heteroatom from the initially formed ylide (Scheme 6). The 1,3-dipolar cycloaddition of ylides generated by carbene cyclization onto the heteroatom of the C=Z double-bond allows an additional ring to be formed and provides a route to bridged and bridged-fused systems (Scheme 7). 

Carbene cyclization onto an oxygen atom followed by a rearrangement... 

Carbene cyclization reactions offer a convenient and efficient method for the synthesis of five-membered sulfur-containing rings. These may involve both carbene insertion into a C—H bond and ylide formation. 

Two short syntheses of racemic ipalbidine ( )-(842) are shown in Scheme 109. The synthesis by Jefford et al. commenced with conjugate addition between pyrrole and Ae atropate ester 849 followed by homologation of the acid 850 with diazomethane and rhodium-induced intramolecular carbene cyclization of the resulting diazoketone 851 (574). The bicyclic product 852 was converted into ( )-842 in a further four steps. The approach taken by Danishefsky and Vogel centered on acid-catalyzed cyclocondensation between the silyl ketene acetal 853 and A -pyrroline (854) to give indolizidinone 855 (575). Reduction of the lactam and cleavage of the aryl ether completed the synthesis of ( )-842. 

The formation of large rings from smaller cyclic olefins (53, 54, 117, 120) can be interpreted (36) to involve terminal carbenes cyclizing upon... 

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]. 

The rearrangement of 308b to 311 involves initial nucleophilic attack of the thioxo sulfur to the acetic a carbon atom (species 313). Analogies with the first formal intermediate of the carbene cyclization reaction (species 314) are striking. 

Scheme 14.53 Chiu s synthesis of (-)-indicol (340) by a rhodium-catalyzed domino carbene cyclization/cycloaddition reaction.

Carbene centers adjacent to double bonds (vinyl carbenes) cyclize to cyclopro-penes. ... 

The (l-ethynyl)-2-propenyl acetate derivative 111 undergoes an interesting PdCl2(PhCN)2-catalyzed cyclization to form the 2-cyclopentenone 112[47], A Pd-carbene complex is assumed to be an intermediate of the formation of 112. 

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

Due to the commercial availability of EMME in good purity, there has not been a need to develop new methods to prepare 3-anilino-acrylates therefore, only a few alternatives have been reported. One approach described thermal carbene generation from 37, and rearrangement to form 38. Cyclization in refluxing 1,2-dichlorobenzene (1,2-DCB) provided the 2, 3, 4-trisubstituted quinolines. An electron-withdrawing group (EWG) on the carbene carbon was required for this reaction, and therefore led to the EWG substitution in the 2-position of the quinoline. 

Cyclization takes place when tert-butylisocyanide, benzaldehyde, anilinium chloride, and carbonyl(dicyano)cyclopentadienyl ferrate are reacted, the carbene complex 42 being the result (95JOM(491)135). /50-butyraldehyde, tert-butyl isocyanide, ammonium hexafluorophosphate, and [(T -Cp)Fe(CO)(CN)2] give the cationic bis-carbene 43. 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

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). 

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