Transition‐Metal‐Catalyzed Propargylic Substitution

Abstract

alkynes · asymmetric catalysis · nucleophilic substitution · propargylic substitution · transition metalsThe nucleophilic substitution of allylic substrates under the catalysis of transition metals has been investigated extensively; [1] however, somewhat surprisingly, the corresponding catalytic propargylic substitution was not studied in much detail until recently. The Nicholas reaction, which involves the nucleophilic substitution of cobalt-complexed propargylic alcohols, enables the incorporation of a wide range of functionalities through the use of various nucleophiles, but has the drawback that a stoichiometric amount of the metal complex is used.[2] There is thus a need for a catalytic propargylation process. Several issues need to be considered in the development of such a reaction: 1) the type of nucleophiles that can be used; 2) restrictions in terms of the propargylic substrate (terminal/internal, aliphatic/aromatic); 3) whether or not the hydroxy functionality requires prior activation; 4) the risk of competing allene formation; 5) possibilities for development of an asymmetric version. We discuss herein the recent developments in this area, with a special focus on asymmetric processes. Organocatalytic methods are not covered, but have been reviewed recently by Kabalka and Yao. [3] One of the earliest transition-metal-catalyzed propargylic substitution reactions described was the copper-catalyzed propargylation reaction reported in 1994 by Murahashi and co-workers, [4] who examined several copper catalysts in the reaction between propargylic phosphates and amine nucleophiles (Scheme 1). Copper(I) chloride was found to give the best results. With this catalyst, propargylic amines were formed in high yields. The reaction is limited to terminal alkynes, but allows the use of both aliphatic and aromatic amines.Nishibayashi and co-workers studied the corresponding asymmetric copper-catalyzed propargylation reaction by using copper(I) triflate together with chiral diphosphine ligands.[5] A variety of aniline derivatives were screened as nucleophiles. The product was formed with up to 89 % ee with chloro-substituted N-methylaniline (Scheme 2). Aliphatic amine nucleophiles could also be used, although the enantioselectivity was lower in this case. The reaction is limited to terminal propargylic acetates with aromatic substituents; the attempted use of an aliphatic propargylic acetate was not successful.Simultaneously with this account, van Maarseveen and co-workers reported the use of chiral bisoxazoline (pybox) ligands and copper catalysis in propargylic amination reactions.[6] Four different copper complexes as well as eight pybox ligands were screened in the propargylic substitution of terminal propargylic acetates with aniline derivatives. Copper(I) iodide in conjunction with ligand 2 gave the best results: The substitution product was formed with up to 88 % ee (Scheme 3). The nature of the base was found to be important not only for the reaction rate, but also for the stereoselectivity. Diisopropylamine ...

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

“…If the reaction is performed in water, propargylic alcohols are formed. 40,41 This pathway is not a major one for primary propargyl substrates (Fig. 2, entry 1), but becomes dominant if the propargyl cation is stabilized further by methyl groups.…”

Efficient synthesis of di- and trisubstituted 2-aryloxazoles via ytterbium(III) triflate catalyzed cyclization of tertiary propargylic alcohols with aryl amides

“…Cyclizations of 2a with starting alcohols where the identity of R 3 was either an alkyl or heterocycle functional group or a terminal alkyne moiety were also found to proceed well and afford 3le3n in 51e88% yield ( Table 2, entries 11e13). In contrast, reactions of 2a with propargylic alcohols where either or both R 1 and R 2 was a methyl functional group, as in 1o and 1p, gave either a mixture of side products that could not be identified by 1 H NMR analysis or near quantitative recovery of the substrates (Table 2, entries 14,15). Similarly, reaction of 2a with the secondary alcohol 1q led to the preferential formation of the corresponding N-propargylation adduct 4 in 31% yield in addition to recovery of the substrate in 31% yield (entry 16).…”

Applications of the Nicholas Reaction in the Synthesis of Natural Products

“…The time limit also means that the application of the Nicholas reaction in the synthesis of enediyne anticancer antibiotics will not be discussed here [10][11][12]. Worth mentioning is also the fact that catalytic systems have been developed in recent years [13][14][15], which will probably in some cases come to replace this stoichiometric substitution reaction, but these have not yet attained the wide scope of the Nicholas reaction, and also do not provide the 'bending' of the alkyne via cobalt carbonyl complexation that makes it such an attractive method to use in natural product synthesis which in many cases involves ringformation.…”