Carbene-tethered alkynes

The formation of substituted cyclopropane rings by the reaction of alkenes with Fischer carbenes has been known for some time [58]. More recently, cyclopropyl groups have been produced as parts of bicyclic and tricyclic ring systems by, formally, the reaction of Fischer carbenes with one equivalent of alkene and one equivalent of alkyne. Indeed, this reaction type proceeds through alkene trapping of a metal carbene generated in situ. The various methodologies that have been developed may be divided into three classes the intermolecular reaction of a,co-enynes with Fischer carbenes, the partially intramolecular reaction of Fischer carbene-tethered alkynes with alkenes, and the fully intramolecular reactions of Fischer carbene-tethered enynes. No fiilly intramolecular version of this reaction has been reported. 

An unexpected varying regiochemistry in intramolecular benzannulation has also been observed in the synthesis of cyclophanes. As mentioned above, there are only two possible regiochemical outcomes in the benzannulation reaction, which differ in the direction of alkyne incorporation. / -Tethered vinyl-carbene chromium complexes undergo an intramolecular benzannulation reaction with incorporation of the tethered alkyne with normal regioselectivity to give meta-cyclophanes [28]. 

The single best piece of evidence for the intermediacy of vinylketene complexes is however the isolation and characterization by Wulff22 of amine-stabilized T74-vinylketenechromium(0) complexes (42) from the thermolysis of the chromium carbene complexes 43, containing a tethered alkyne functionality. This was the first time that a d6-rf-vinylketene complex of any group 6 metal had been isolated. 

Padwa and co-workers (89TL2633 93JA2637) have elaborated an elegant modification of the cyclization/cycloaddition approach that involves the displacement of a carbene center and provides access to O-bridged compounds with an indenone moiety. An illustrative example is the synthesis of compound 718 through the Rh(II)-catalyzed decomposition of a-diazo ketones bearing tethered alkyne units in the presence of a dipolarophile (91JOC2523). 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Vinyl cyclopropanes tethered to an aUcyne chain 127 were also subjected to the cycloisomerisation reaction in presence of the NHC-Ni catalyst system (Scheme 5.34) [39], The product formation depends on the substrate used and the NHC hgand. When SIPr carbene is used, three different products were obtained depending on the size of the R group attached to the alkyne moiety. If R is small (like a methyl) product 128 is obtained exclusively. If R is Et or Pr a mixture of 128 and 129 is obtained in 3 2 to 1 2 ratio, respectively. However, when R is large groups such as Bu or TMS only product 130 is obtained. When IfBu carbene 131 is used as the ligand, cycloisomerisation of 127 afforded product 128 exclusively, regardless of substituent size (Scheme 5.34) [39]. 

Mori has reported that in the reaction of chromium carbene 25 with an alkyne containing a tethered 4-amidobutyne unit (26), a postulated vinylketene complex (27) is intercepted by nucleophilic amide attack, yielding a mixture of lactams (28 and 29).15 The expected naphthol 30 was also isolated in low yield. 

The methoxyketene 297, coordinated to Cr carbonyl, is formed from methoxy-carbene easily by insertion of CO under irradiation [90]. An ester is formed by the reaction of ketene with alcohol. The aminocarbene complex 298 was prepared from benzamide and converted to phenylalanine ester 300 under irradiation of sunlight in alcohol via ketene 299 [91]. The eight-membered lactone 304 was prepared in high yield by the reaction of the alkyne 301 having the OH group in a tether with Cr carbene without irradiation. The vinylcarbene 302 is formed at first and converted to the vinylketene intermediate 303 as expected. The keto lactone 304 is formed from 303 by intramolecular reaction with the OH group and hydrolysis [92],... 

The opposite sequence is described with alkynyl silyloxy-tethered enynes. A cascade CM-RCM reaction proceeds in the presence of a second generation ruthenium carbene to give cyclic siloxanes. The initial CM is directed to occur on the alkyne by employing sterically hindered substituted alkenes tethered to the alkyne via a silyl ether group [24] (Scheme 11). 

Steroid-type molecules, e.g., 48, were generated from (l-alkynyl)carbene complex 11 by [4+2] cycloaddition of a TBSO butadiene to the C2-C3 triple bond of lk and subsequent two-alkyne annulation to the M = C bond (Scheme 17).75 Other polycyclic compounds have been obtained similarly by insertion of several alkyne units tethered by a carbon chain.76,77 It should be noted that an annulation of an aromatic ring instead of a 1,4-cycIohexa-diene is achieved if the diene component contains a potential leaving group, as shown in Schemes 16 and 17. 

In a variation of the reactions in Scheme 44, Rudler has reported that the alkene which intercq)ts the vinyl carbene complex leading to cyclopropane products can be tethered onto the starting carbene complex.This was extensively studied for the reaction of the carbene complex (334) with a number of alkynes leading to bicycloheptanones of the type (336). ° This reaction is quite general (14 examples, 44-95%) and is regioselective with terminal alkynes, i.e. it occurs in the same sense that has been observed for the benzannuladon reaction (R = H in 336). Acetylene fails and cyclooctyne gives a reduced... 

The intramolecular DOtz reaction, in which the alkyne is tethered to the carbene, improves synthetic efficiency and regiocontrol, although internal alkynes work better than terminal alkynes [30], Such cycloadditions provided the kqr to a synthesis of the antibiotic deoxy-frenolicin [Eq. (12)] [31] and played a role in work aimed toward the synthesis of the ben-zofuran angelicin, in which a 3-furylcarbene complex aimulates toward C2 of the furan, avoiding forming an isobenzofuran structure [Eq. (13)] [32]. 

Gold-catalysed intramolecular oxidation of terminal alkynes with an arenesulfinyl group as the tethered oxidant has been reported to involve a gold carbene generation via alkyne oxidation. DFT studies suggest that the cyclized product is formed via an intramolecular [3,3]-sigmatropic rearrangement instead of the previously proposed Friedel-Crafts-type cyclization (Scheme 12) ... 

Addition of dicarboethoxycarbene to cycloocta-1,3-diene yields a mixture of cis-and fran -cyclopropane adducts, probably by addition of the singlet carbene on the partially isomerized diene (due to the irradiation). Diastereoselective cyclopropan-ation of a ,/3-unsaturated acetals has been described using a camphor-derived chiral auxiliary. Intramolecular cyclopropenation of a diazo ester, tethered through a naphthalene, to an alkyne was catalysed by rhodium acetate and reported as a efficient method unfortunately, the use of chiral rhodium catalysts gave a less efficient reaction and did not provide high asymmetric induction. ... 

The Wulff-Ddtz reaction is another approach to the synthesis of the cyclophane system by formal [2 + 2 + 2] cycloaddition. The intramolecular benzannulation of the Fischer carbene complex, which has an alkyne tethered to the a-position of the alkenyl substituent, gave a para-cyclophane in moderate yield under highly diluted conditions (Scheme 8.6) [6]. 

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