Acetylides reactions with carbonyl compounds

All acetylenes with a terminal triple bond are instantaneously converted into the alkali acetylides by alkali amides in liquid ammonia. For many alkylations with primary alkyl halides liquid ammonia is the solvent of choice and the functionalization with oxirane can also be carried out in it with good results. Reactions of ROOM with sulfenyladng agents (R SSR1, R SON, R SSC R ) or elemental sulfur, selenium or tellurium are mostly very successful in ammonia, the same holds for the preparation of ROC1 from RC=CM and iodine. The results of couplings with carbonyl compounds are very variable. 

Similarly, l-bromo-l,l-difluoro-2-alkynes, which were prepared by the reaction of lithium acetylides with CF2ClBr [284] or CF2Br2 [285], also reacted with carbonyl compounds in the presence of zinc to afford the corresponding a,a-difluoropropargyl alcohol [285]. This reaction has been utilized for the preparation of 3-fluoro-2,5-disubstituted furans [286] and other fluorinated biologically active compounds [285,287] (Scheme 99). 

An acetylide ion is another example of a carbon nucleophile that reacts with carbonyl compounds. When the reaction is over, a weak acid (one that will not react with the triple bond, such as pyridinium ion), is added to the reaction mixture to protonate the alkoxide ion. 

This reaction was initially reported by Favorskii in 1905 and subsequently extended by Babayan in 1939. It is a base-promoted or -catalyzed ethynylation of aldehydes and ketones to produce secondary or tertiary acetylenic alcohols or glycols using anhydrous KOH or NaOH. Therefore, it is generally known as the Favorskii-Babayan reaction or Favorskii reaction. Although it has been proposed that this reaction might involve a reaction between acetylene and the adduct from the ketone and KOH or a coupling of potassium acetylide with the carbonyl compounds, the most recent experimental results indicate that potassium hydroxide and acetylene first form a complex, rather than potassium acetylide in liquid ammonia, which then reacts with carbonyl compounds to form the acetylenic alcohols, where ammonia functions as a co-catalyst. The experimental evidence includes... 

THE REACTIONS OF CARBONYL COMPOUNDS WITH ACETYLIDE IONS... 

Reaction of carbonyl compounds with acetylide ions (Section 17.5). The mechanism is shown on page 801. 

Sodium acetylide (prepared from sodium amide) is useful for the condensations with primary alkyl halides. However, secondary, tertiary, and primary halides branched at the second carbon atom are dehydrohalogenated to olefins by the reagent. Iodides react at a faster rate than bromides and the latter faster than chlorides. Chlorides are rarely used. The bromides are more common for preparative reactions. Sodium acetylide can also react with carbonyl compounds to yield acetylenic carbinols. 

The reaction of monodeprotonated [ C2]acetylene with carbonyl compounds has been exploited as a means of extension of the carbon chain of various terpenes and steroids by two [ " C]carbon atoms. In the simplest case, reaction of potassium [ C2]acetylide with steroid ketone 1 and subsequent acid catalyzed cleavage of the enol ether protecting group gave 17a-[ C2]ethynyltestosterone (2). The sequential addition of deprotonated [ C2]acetylene to carbonyl compounds opens access to symmetrical or unsymmetrical [2,3- C2]alkyn-l,4-diols is exemplified in the synthesis of all-tran -/3-[15,15 - C2]-carotene ([ C2]provitamin A). Thus, treatment of lithium [ C2]acetylide with terpene aldehyde 2 followed by double deprotonation of the resultant alkynol 4 and reaction with a second equivalent of 3 provided alkyne-l,4-diol 5 the requisite key intermediate. Subsequent acid-catalyzed dehydration of 5 followed by Lindlar s catalyst-mediated partial hydrogenation and photoisomerization afforded the final product". ... 

Reactions in liquid ammonia (cf. Chapter 3, Section III) require a certain amount of care, since the solvent is low boiling (—33 ) and its fumes are noxious. Nevertheless, with reasonable caution, the preparation of an ammonia solution of sodium acetylide can be carried out as described. The reagent so prepared can then be directly used for displacements on alkyl halides or for additions to suitable carbonyl compounds. Examples of both reactions are given. 

Methylsulfinyl carbanion (dimsyl ion) is prepared from 0.10 mole of sodium hydride in 50 ml of dimethyl sulfoxide under a nitrogen atmosphere as described in Chapter 10, Section III. The solution is diluted by the addition of 50 ml of dry THF and a small amount (1-10 mg) of triphenylmethane is added to act as an indicator. (The red color produced by triphenylmethyl carbanion is discharged when the dimsylsodium is consumed.) Acetylene (purified as described in Chapter 14, Section I) is introduced into the system with stirring through a gas inlet tube until the formation of sodium acetylide is complete, as indicated by disappearance of the red color. The gas inlet tube is replaced by a dropping funnel and a solution of 0.10 mole of the substrate in 20 ml of dry THF is added with stirring at room temperature over a period of about 1 hour. In the case of ethynylation of carbonyl compounds (given below), the solution is then cautiously treated with 6 g (0.11 mole) of ammonium chloride. The reaction mixture is then diluted with 500 ml of water, and the aqueous solution is extracted three times with 150-ml portions of ether. The ether solution is dried (sodium sulfate), the ether is removed (rotary evaporator), and the residue is fractionally distilled under reduced pressure to yield the ethynyl alcohol. 

In the Favorski reaction [8], etbyne is coupled with a carbonyl compound in the presence of powdered alkali hydroxide suspended in an organic solvent, in which the acetylene has good solubility. Some acetylenic carbinols, derived from ketones, can be obtained in high yields by introducing acetylene at atmospheric pressure. The active intermediate possibly is a metal acetylide formed in low concentration. 

Several preparative methods exist for the synthesis of 3(2//)-dihydrofuranones. 2,5-Disubstituted or 2,2,5,5-tetrasubstituted 3(2i/)-dihydrofuranones are usually prepared by reaction of sodium or lithium acetylide with a ketone to yield an alkynic alcohol which is then treated with a carbonyl compound in the presence of base to afford alkynic diols. Mercury catalyzed hydration of the resultant diols in the presence of acid affords the furanones in good yields (76JMC709). 

Two different approaches are commonly used for the synthesis of alkynes. In the first, an appropriate electrophile undergoes nucleophilic attack by an acetylide ion. The electrophile may be an unhindered primary alkyl halide (undergoes Sn2), or it may be a carbonyl compound (undergoes addition to give an alcohol). Either reaction joins two fragments and gives a product with a lengthened carbon skeleton. This approach is used in many laboratory syntheses of alkynes. 

These reactions work because, although each starting material contains two carbonyl groups, one is more electrophilic and therefore more reactive towards nucleophiles (OH in the first case lithium acetylide in the second) than the other. We can order carbonyl compounds into a sequence in which it will usually be possible to react those on the left with nucleophiles in the presence of those on the right. 

Ethynyl carbinols (propargylic alcohols) such as 134 (Scheme 2.58) represent another important group of oxidation level 3 compounds. Their preparation involves nucleophilic addition of acetylides to the carbonyl group, a reaction that is nearly universal in its scope. Elimination of water from 134 followed by hydration of the triple bond is used as a convenient protocol for the preparation of various conjugated enones 135. Easily prepared O-acylated derivatives are extremely useful electrophiles in reactions with organocuprates, which proceed with propargyl-allenyl rearrangements to furnish allene derivatives 136. 

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