Alkynylation of ketones

Alkynylations of ketones with bis(hydroxycamphorsulfonamides) ligand bearing xylenediamine as linker. 

In addition, the most efficient mem-ligand depicted above was successfully applied, in 2006, to the alkynylation of ketones. Thus, Liu et al. showed that this ligand was able to catalyse the enantioselective addition of phenylacetylene to various ketones, using Cu(OTf)2 as the starting base in toluene. The results were excellent and homogeneous not only for substituted aryl alkyl ketones, but also for aliphatic methyl ketones (Scheme 4.6). 

Scheme 4.28 Alkynylations of ketones with C2-symmetric bis(sulfonamides) ligand.

Chiral Zn(salen) catalyzed enantioselective alkynylation of ketones has been examined by Cozzi82 and by Saito and Katsuki83. Camphorsulfonamide/Cu(OTf)284, Ti(0-i-Pr)4/BINOL85 and Et3Al/cinchona alkaloid86 systems have also been reported. Chiral / -amino alcohols work as chiral catalysts without an additional Lewis acid component87. 

A direct and satisfactory procedure for tertiary alkyl-alkynyl coupling has been developed by Negishi and Baba, who used trialkynylaluminums readily obtainable from the corresponding alkynyllithiums and anhydrous AICI3 [92]. For instance, tris(l-hexynyl)aluminum underwent a remarkably clean reaction with 1-adamantyl bromide to produce cross-coupled product 96 in 96 % yield. It is noteworthy that the reaction enables novel geminal alkyl-alkynylation of ketones this reaction should find a considerable application in natural product synthesis (Sch. 60). 

The enantioselective alkynylation of ketones catalyzed by Zn(salen) complexes has been reported [24]. Polymeric salen ligand 30 was prepared with a polycondensation reaction and subsequently used as a polymeric chiral ligand of Zn. The polymeric Zn(salen) complex (prepared by 30) was then used as a catalyst of asymmetric addihon of phenylacetylene to aldehyde in the presence of 2 equivalents of Et/Zri. Subsequent asymmetric alkynylahon of 31 gave 33 in 96% yield and 72% ee (Scheme 3.9) [25]. 

The first example of the catalytic enantioselective addition of lithium acetylide to carbonyl compounds without the aid of other metal sources has been reported. Chiral lithium binaphtholate effectively catalysed such enantio-selective alkynylation of ketones with up to 93% ee. 

Alkynylation of Ketones. By combining catalytic amounts of copper(II) trifiate and camphorsulfonamides an effective chiral catalyst system is produced, which is effective in the production of tertiary propargyUc alcohols, with good to excellent enantioselectivities. These reactions represent a highly enan-tioselective catalytic addition of afkynyl zinc reagents to simple ketones (eq 43). 

Scheme 13.2 Chiral modifiers 8a-d used in the enantioselective alkynylation of ketone 5...

Example 5.5 Propose the retrosynthesis of TM 5.5 and then its synthesis using a couple of reactions, alkynylation of ketone-hydration of the triple bond in the intermediary carbinol. 

Katsuki and Saito reported the Zn(salen)-catalyzed asymmetric alkynylation of ketones (Scheme 4.43) [38]. They used 8mol% of an in situ generated Zn(II) complex with chiral salen ligand (124) with axially chiral binaphthyl units. For a wide range of ketones and terminal acetylenes, the alkynylated products (123) were obtained in moderate to good yields with high enantioselectivities. 

A direct procedure for tert-alkyl-alkynyl coupling using tert-alkyl chloride or bromide was reported by Negishi and Baba. The reaction provides successive geminal alkyl-alkynylation of ketones (Scheme 6.6) [6]. 

Finally (d + aV dditions of 1-alkenyl and 1-alkynyl anions to carbonyl groups should be mentioned. Examples are the addition of vinylmagnesium bromide to ketones e.g. in the first step of Torgov s steroid synthesis (I.N. Nazarov, 1957), and the famous alkynylation of... 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

Despite the great success of the transmetalation process in the enantiose-lective arylation of ketones, its extension to allylation or alkynylation reactions failed, providing the corresponding tertiary alcohols with enantiomeric excesses never higher than 50% ee. On the other hand, more success has been found in the alkenylation of ketones. The process started with the hydrozirconation of terminal alkynes to give the corresponding alkenylzirconium intermediates, which were transmetalated by reaction, in this case, with various ketones in the presence of the HOCSAC ligand. This protocol tolerated the presence of other carbon-carbon multiple bonds on the alkyne, as well as different functionalities and achieved excellent results for alkyl ketones, a,(3-unsaturated ketones and even dialkylketones, as shown in Scheme 4.22. 

Another example of Au-catalyzed was reported using alkynyl cyclopropyl ketones as a starting material. Trisubstituted furans were given in high yields under mild condition via a domino reaction process and an example is given below <06AG(I)6704>. 

The study of alkynylation of methyl ketones using a terminal alkyne, ZnMe2, and a salen derivative 196 as a chirality inductor provided a new method for the preparation of ct-hydroxyacetylenes (197, Scheme 112).292... 

Alternatively, the reaction of cyclopropylethynylmagnesium bromide with cyclo-propanone hemiacetal gives l-(cyclopropylethynyl)cyclopropanol (equation 152)232. The reaction of cyclopropanone acetal with other alkynyl Grignard reagents serves as a general route to alkynylcyclopropanols. Similarly, alkynyllithium derivatives of vitamin D were coupled with cyclopropane carbonyl isoxazolidine to give the corresponding alkynyl-cyclopropyl ketones (equation 153). 

Isotellurazoles 4 were obtained in low yields (3-11%) by the one-pot reaction of alkynyl ketones with hydroxylamino-O-sulfonic acid and K2Te in aqueous solution containing sodium acetate (83S824 87H1587). A plausible mechanism of the reaction includes formation of the oxime derivative and subsequent nucleophilic addition of telluride anion to the triple bond followed by cyclization to 4. The reaction is accompanied by the formation of telluro bis(alkenyl ketones) 5 in yields approximately equal to those of 4. When alkynyl aldehydes are used instead of ketones, the single reaction products are the tellurobis(alkenyl nitriles) 6 (83S824). 

An easy and simple synthesis of different chiral fran -l-arenesulfonylamino-2-isoborneolsulfonylaminocyclohexane derivatives (41) has been reported.108 These ligands have proved to be excellent promoters for the catalytic enantioselective alkylation and arylation of ketones (up to 99% ee), very good for the alkenylation process, and modest for the allylation and alkynylation reactions. 

Indium trichloride promotes catalytically the addition of alkynylstannanes to aldehydes (Table 25).42 Metallic indium also mediates the same Barbier-type coupling between alkynyl halides and aldehydes or ketones to give secondary or tertiary propargyl alcohols (Table 26). Secondary alcohols can be oxidized in situ according an Oppenauer process.395 Thus, alkynyl ketones have been prepared from aldehydes via an indium-mediated alkynylation reaction followed by an indium-mediated Oppenauer oxidation. They are also obtained via an indium-mediated alkynylation of the relevant acyl chlorides (Table 27).396... 

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