Carbocations, Nicholas reaction

Complexation of an alkyne to dicobalthexacarbonyl is a well-known way to stabilize carbocationic charges generated in the carbon a to the alkyne. These carbocations react with different nucleophiles. This process, the Nicholas reaction [112], has been used to generate enynes that undergo, in a domino fashion, a PKR. 

Later on, Schreiber used consecutively these two reactions in the key step for the synthesis of diterpene (-i-)-epoxydictimene (73), starting from natural (R)-pulegone [116,117]. This approach was built on their preliminary studies on Lewis acid mediated intermolecular Nicholas reactions [118]. They prepared functionalized enyne 70 bearing a mixed acetal. This compound was transformed into its dicobalt-hexacarbonyl complex and, in the presence of a carefully selected Lewis acid, it formed a stabilized carbocation by release of the more accessible ethyl moiety. This cation reacted intramolecularly with the allylsilane giving the central eight membered ring of the natural product... 

Coupling of silyl enol ethers or boron enolates with Co2(CO)6-stabilized carbocations, generated via Lewis acid treatment of the appropriate propargyl ethers or aldehydes (aldol reaction), via the Nicholas reaction has been used to obtain large, highly strained, ring ketones. 

Several transition metal mediated processes rely on the participation of Lewis acids, among these, the Nicholas reaction figures prominently. After treatment with BF3-Et20, Co2(CO)6 complexed propargylic alcohols provide the carbocation, which can be trapped intramolecularly with various nucleophiles including epoxides (eq 55), or via hydride transfer from an appropriately poised benzyl moiety (eq 56) or aromatic rings. In the latter case, access to the relatively small [7] metacyclophane derivatives was possible. 

Inspired by the postulated biogenesis of polyether compounds, a valuable cascade cyclization approach was developed on the predictable carbocation formation of the Nicholas reaction using very mild acidic conditions (silica gel as promoter) with excellent yields via very often inefficient epoxide opening cascade (13AGE3659). 

The Nicholas and Pauson-Khand reactions, as well as the bond-angle effect, have been combined in a single synthetic scheme to make more efficient use of the cobalt. This has been done in a synthesis of epoxydictamine 7.90 (Scheme 7.24)." The Nicholas reaction was employed, in which a carbocation 7.87, generated from acetal 7.86, was trapped by an allylsilane nucleophile intramolecularly, to form the eight-membered ring... 

A similar Nicolas-Pauson-Khand combination was used in a synthesis of the ketone analogue of biotin 7.98, required for biochemical studies (Scheme 7.25). In this case, the Nicholas reaction was intermolecular, between allyl thiol as the nucleophile and carbocation 7.94 generated from alcohol 7.93. The Pauson-Khand reaction was then between the dicobalt complexed alkyne 7.95 and the double bond from the thiol moiety. The Pauson-Khand reaction proceeded with no stereoselectivity, and the diastereoisomers had to be chromatographically separated at a later stage. The synthesis was completed by reduction of the alkene of cyclopentenone 7.96, without using palladium-catalysed hydrogenation due to the sulfide moiety, and ester hydrolysis. 

The mechanism of the Nicholas reaction is best described as an SnI process. Protonation of the alcohol in 4 followed by loss of water from cation 8 yields cobalt-stabilized carbocation 5. Friedel-Crafts reaction of this electrophile with anisole provides resonance-stabilized carbocation 9 which, upon removal of a proton, furnishes the substitution product 6. In addition to electron rich aromatics like anisole, a variety of neutral carbo- and heterocyclic nucleophiles react successfully with the carbocation... 

Modifications to the standard Nicholas reaction generally fall into the following categories asymmetric reactions, use of heteroatom nucleophiles, use of metals other than cobalt, reactions of neutral electrophiles, reactions of carbocations not in the a-position, cycloadditions, and rearrangements. 

Kann recently investigated the intermolecular Nicholas reaction with substrates on the solid phase. In a detailed study with a variety of carbon and heteroatom nucleophiles, she demonstrated that the Nicholas reaction is a useful strategy for cleaving the substrate from the resin. Enyne 35 is available upon treatment of resin-bound cobalt-alkyne eomplex 34 with allyltrimethylsilane and boron trifluoride. Generation of the requisite carbocation results in eleavage from the polymer whieh is followed by a... 

Bertrand recently generated six- and seven-membered rings using a terminal alkene nucleophile in exocyclic intramolecular Nicholas reactions. Depending on the nature of the Lewis acid, the carbocation intermediate formed upon cyclization (e.g., 46) could be converted into a halide, amide, ester, or alkene. For example, alcohol 45 undergoes a 6-e [Pg.293]

Another important application of cobalt carbonyl complexes is the Nicholas reaction, i.e., creating stable carbocations from propargylic alcohols... 

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