Fischer carbene/alkyne reactions

Of the nitrogen heterocycles that have been observed as the product of Fischer carbene/alkyne reactions, pyrroles are the most readily obtained, with at least two efficient. 

The insertion of alkynes into a chromium-carbon double bond is not restricted to Fischer alkenylcarbene complexes. Numerous transformations of this kind have been performed with simple alkylcarbene complexes, from which unstable a,/J-unsaturated carbene complexes were formed in situ, and in turn underwent further reactions in several different ways. For example, reaction of the 1-me-thoxyethylidene complex 6a with the conjugated enyne-ketimines and -ketones 131 afforded pyrrole [92] and furan 134 derivatives [93], respectively. The alkyne-inserted intermediate 132 apparently undergoes 671-electrocyclization and reductive elimination to afford enol ether 133, which yields the cycloaddition product 134 via a subsequent hydrolysis (Scheme 28). This transformation also demonstrates that Fischer carbene complexes are highly selective in their reactivity toward alkynes in the presence of other multiple bonds (Table 6). 

Non-heteroatom-stabilised Fischer carbene complexes also react with alkenes to give mixtures of olefin metathesis products and cyclopropane derivatives which are frequently the minor reaction products [19]. Furthermore, non-heteroatom-stabilised vinylcarbene complexes, generated in situ by reaction of an alkoxy- or aminocarbene complex with an alkyne, are able to react with different types of alkenes in an intramolecular or intermolecular process to produce bicyclic compounds containing a cyclopropane ring [20]. 

The electrophilic carbene carbon atom of Fischer carbene complexes is usually stabilised through 7i-donation of an alkoxy or amino substituent. This type of electronic stabilisation renders carbene complexes thermostable nevertheless, they have to be stored and handled under inert gas in order to avoid oxidative decomposition. In a typical benzannulation protocol, the carbene complex is reacted with a 10% excess of the alkyne at a temperature between 45 and 60 °C in an ethereal solvent. On the other hand, the non-stabilised and highly electrophilic diphenylcarbene pentacarbonylchromium complex needs to be stored and handled at temperatures below -20 °C, which allows one to carry out benzannulation reactions at room temperature [34]. Recently, the first syntheses of tricyclic carbene complexes derived from diazo precursors have been performed and applied to benzannulation [35a,b]. The reaction of the non-planar dibenzocycloheptenylidene complex 28 with 1-hexyne afforded the Cr(CO)3-coordinated tetracyclic benzannulation product 29 in a completely regio- and diastereoselective way [35c] (Scheme 18). 

Vinyl Fischer carbenes can be used as three-carbon components in Ni(0)-mediated and Rh(l)-catalyzed [3 + 2 + 21-reactions with alkynes (Schemes 48 and 49)142 and with allenes (Schemes 50 and 51).143 All three of the proposed mechanisms for the [3 + 2 + 2]-cycloadditions involve an initial carbene transfer from chromium to nickel or rhodium (Schemes 49, 52, and 53). As is seen from the products of the two [3 + 2 + 2]-reactions with 1,1-dimethylallene, although the nickel and rhodium carbenes 147G and 147K appear similar, the initial insertion of the allene occurs with opposite regioselectivity. 

Barluenga and co-workers reported a novel [2 + 2 + 2 + 1 (-reaction based on the use of two metals, the nickel-mediated [2 + 2 + 2 + l]-reaction of Fischer carbenes with alkynes (Scheme 73).142 While, at present, this process requires the stoichiometric use of both metals, it is highly regioselective, affords good yields, and is a novel route to seven-membered rings. 

Among the synthetically useful reactions of Fischer carbenes, the benzannulations are certainly the most prominent. In particular, the so-called Dotz reaction, first reported by Dotz in 1975 [3], is an efficient synthetic method that starting from aryl- or alkenyl-substituted alkoxycarbene complexes of chromium affords p-alkoxyphcnol derivatives by successive insertion of the alkyne and one CO ligand in an a,/Tunsaturated carbene, and subsequent electrocyclic ring closure (see Figure 1). 

The Dotz benzannulation reaction, based on the alkyne cycloaddition to chromium carbene complexes, is the most important application of Fischer carbene complexes. Among the various Fischer carbene complexes, alkoxy and aminocarbene complexes of chromium undergo a novel inter- and intramolecular tandem alkyne insertion/ carbene annotation sequence to give 9H-carbazoles and nf/-benzo[fl]carbazoles. 

Reaction of crowded chromium alkenyl Fischer carbene (50) with bulky ketene acetals provides an interesting entry to 3-substituted pent-l-ynoate (53)45 Formation of the alkyne can be rationalized by a 1,4-nucleophilic addition of the ketene on the unsaturated carbene complex (crowded complexes will not undergo potential 1,2-addition), following by oxonium (51) formation and fragmentation to a vinylidene carbene complex (52), which undergoes a 1,3-shift to the alkynylchromium complex leading the alkyne after reductive elimination. 

Vinylcyclopentenediones.1 The Fischer carbene 1 reacts with terminal alkynes (excess) in benzene (70°) to give as the major product a 2-vinylcyclopentene-l,3-dione (2) with incorporation of two molecules of carbon monoxide as well as the alkyne and formation of six C-C bonds. Reaction of an internal alkyne is possible, but the yield of cyclopentenediones is lower (27%, one example). 

The Fischer carbene complex 518 undergoes a benzannulation reaction with 1-hexyne to furnish the highly substituted chroman 519 (Equation 213) <1998TL2851>. Treatment of the same complex with various functionalized alkynes provides tricyclic chromans <1998SL61>. 

One of the main features of the benzannulation reaction of Fischer carbene complexes is the regiochemistry of the incorporation of alkynes into the assembled hydroquinone [53]. While terminal alkynes are incorporated with high regioselectivity (regardless of alkyl and aryl substituents), internal alkynes are prone to much poorer regioselectivity. Regioselectivity is virtually lost in the case of diarylacetylenes. 

Alkene- and alkyne-substituted Fischer carbenes participate as dienophiles in Diels-Alder reactions. The conditions are usually mild and the reaction proceeds smoothly at room temperature. Similar isomeric ratio and rate acceleration is observed to that of Lewis acid-promoted Diels-Alder reactions between methyl acrylates and dienes when compared to the uncatalyzed reactions. The reactions are endo-selective. Asymmetric Diels-Alder reactions are... 

Thermal reactions of Fischer carbenes with alkynes afford a variety of prodncts depending on the snbstrates. The reactions can be visnalized mechanistically as a [2 -F 2]cycloaddition... 

Thermal reaction of alkoxy-substituted Fischer carbenes of group 6 metals with alkynes has been applied to the... 

Many reactions afford, in addition to the naphthalene derivatives, mixtures of products. One of the major side reactions is the formation of indene derivatives directly from the metathesis intermediate without insertion of carbon monoxide. Other products frequently isolated as minor components are furans, cyclobutanones, and cyclopentenediones. The product distribution is dependent on numerous factors, including solvent, reaction temperature, concentration of the alkyne, and the nature of the aryl substituent. Molybdenum carbenes give, depending on the alkyne, either naphthols or indenes exclusively. The molybdenum Fischer carbenes can be tuned to give naphthoquinones by replacing one of the carbon monoxide ligands with a phosphine (Scheme 45). 

The benzannnlation reaction of aryl- and alkenyl-substituted Fischer carbenes with alkynes has been used... 

A variety of annulations leading to ring systems other than benzenes can be isolated from reactions of Fischer carbenes. Cyclopentenone derivatives are formed from a reaction of Z-6-amino-Q ,jS-unsaturated chromium carbenes with alkynes (Scheme 66). In contrast, -B-amino-Q, /3-unsaturated chromium carbenes reacts with alkynes to give cyclopentadienes (Scheme 67). 

Formation of polycyclic ring systems via intermolecular reactions of Fischer carbenes with alkynes can be achieved. In a metathesis-type reaction, reactions of 1,6-enynes afford... 

The reaction of alkenes with Fischer carbene complexes most typically leads to cyclopropane products however, the formation of a three-membered ring product from a reaction with an alkyne has been observed on only one occasion. The reaction of the cationic iron-carbene complex (199) with 2-butyne presumably leads to the formation of the cyclopropene (200), which was unstable with respect to hydride abstraction by the starting carbene complex and the ultimate product isolated from this reaction was the cyclopropenium salt (201) and the benzyl-iron complex (202). Cyclopropene products have never been observed from Group 6 carbene complexes despite the extensive investigations of these complexes with alkynes that have been carried out since the mid 1970s. 

In almost all situations the reactions of Fischer carbene complexes of chromium with alkynes lead to the formation of six-membered ring products, but on several occasions five-membered ring annulated products have been observed as minor products or as major products if the formation of six-membered rings is blocked. In an early report by Ddtz, the reaction of the 2,6-dimethylphenyl complex (209) was observed to react with diphenylacetylene to give the complexed and uncomplexed indenes (210) and... 

The reactions of Fischer carbene complexes with alkynes can under certain conditions lead to products that result from the incorporation of two alkynes, the carbene ligand and a carbon monoxide. In inter-molecular reactions, this is most commonly observed for acetylene itself or for sterically unhindered al-kynes. °2 As can be anticipated by the mechanism in Scheme 36, two-alkyne incorporated products of the type (258) are also favored for high alkyne concentration. Synthetically, the two-alkyne reactions are most useful in intramolecular reactions, two of which have been reported and are exemplified by the reactions in Scheme 43. The typical product from the reaction of a Fischer carbene complex with a diyne, such as (308), is a bicyclic phenol of the type (309). ° These products are apparently the result of the assembly of pieces indicated by (311). Under some conditions, dienones of the type (310) and (314) can be isolated, and it is thought they are the immediate precursors of the phenol products via an in situ reduction by a chromium(O) species. This reaction is completely regioselective with diyne (308) and the phenol (309) results from incorporation of the terminal alkyne of (308) before the disubstituted alkyne. Phenols of the type (309) have also been observed from the reaction of diynes with carbyne complexes. ... 

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