Alkynyl ketones, preparation

The alkynyl ketones 840 can be prepared by the reaction of acyi chlorides with terminal alkynes, Cul in the presence of Et3N is the cocatalyst[719]. (1-Alkynyl)tributylstannanes are also used for the alkynyl ketone synthesis[720]. The a,. 3-alkynic dithio and thiono esters 842 can be prepared by the reaction of the corresponding acid chloride 841 with terminal alkynes[721,722]. 

Pyridines 158 have been also prepared by cyclocondensation of alkynyl ketones 157 and amino acrylates in DMSO as the solvent at 170 °C for 20 min (Scheme 56 and Sect. 5.2 for more details) [102,103]. 

The first preparative use of intramolecular C—H insertion in organic synthesis was based on the observation that on flash vacuum pyrolysis, a conjugated alkynyl ketone such as 1-(1-methyl-cyclopentyl)-2-propynonc is smoothly converted to a mixture of the cyclizcd enones 1 and 223. This elegant reaction apparently proceeds via isomerization of the alkyne to the corresponding alkylidene carbcne, followed by subsequent intramolecular C-H insertion. It should be noted that despite a 3 2 statistical predominance of primary C-H bonds over secondary C—H bonds, a marked preference for insertion into the latter (methylene) is observed. 

Aldehydes and ketones have also been prepared by nucleophilic cleavage of resin-bound O-alkyl hydroxamic acids (Weinreb amides [744]) with lithium aluminum hydride [745] or Grignard reagents (Entries 1 and 2, Table 3.41). Similarly, support-bound thiol esters can be cleaved with Grignard reagents to yield ketones [272], or with reducing agents to yield aldehydes (Entry 3, Table 3.41). Polystyrene-bound sele-nol esters (RCO-Se-Pol) react with alkynyl cuprates to yield alkynyl ketones [746]. 

The carbonylation of aryl iodide in the presence of terminal alkynes affords acyl alkynes. Bidentate ligands such as DPPF give good results [241]. When PI13P is used, phenylacetylene is mainly converted to diphenylacetylene. The alkynyl ketones 488 are prepared by the reaction of the alkenyl triflate 487 with phenylacetylene and CO [242],... 

Alkynylsilanes can be converted into alkynylcoppers by treatment with Cu salts in an aprotic polar solvent such as l,3-dimethyl-2-imidazolidinone (DMI).62 The Cu-promoted coupling reactions via the Si-Cu transmetallation of alkynylsilanes are valuable for the syntheses of alkynyl ketones, 1,3-diynes, 1,3-enynes, and 1-aryl-l-alkynes from acid chlorides,62 alkynyl chlorides,63 alkenyl iodides,64 and aryl iodides,64 respectively (Equation (12)). In addition, symmetric 1,3-diynes can be prepared by the CuCl-mediated homocoupling of alkynylsilanes.65 653... 

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... 

Midland and others reported that B-isopinocampheyl-9-borabicyclo[3.3.l]no-nane [Alpine-Borane (7 )-79] is an effective reagent for the highly asymmetric reduction of alkynyl ketones to afford the propargylic alcohol 8030 (Scheme 4.3z). The reagent (R)-19 is prepared from (+)-a-pinene and 9-borabicyclo[3.3.1]no-nane (9-BBN) and often represented as 19banana. The levels of asymmetric... 

Alkynyl ketones can be prepared using the former useful methodology. Starting from propargyl aldehyde diethyl acetals and benzotriazole under toluene reflux, l-(benzotriazol-1-yl) propargyl ethyl ethers were prepared in 83-84% yield. The deprotonation is very... 

Reductive cyclization. Potassium in liquid ammonia is an effective reagent for reductive cyclization of 5-alkynyl ketones. This reaction provides an efficient route to the D ring of gibberellic acid (1 —> 2). Sodium naphthalenide has been employed in a similar fashion for the preparation of 2-methylenecyclopentanols and 2-giethyl-enecyclohexanols (3 — 4). ... 

An asymmetric reducing agent (49), prepared from LAH, (-)-)V-methylephedrine (14) and 3,5-di-methylphenol in a 1 1 2 ratio, reduces acetophenone with 83.8% A series of aromatic and alkynyl ketones are reduced by (49) to the corresponding (f )-alcohols (Scheme 1)P Some of the products are useful intermediates for the synthesis of 7-lactone insect pheromones. " ... 

We have found that alkynylsilanes are smoothly converted into alkynylcopper compounds by treatment with CuCl in l,3-dimethyl-2-imidazohdinone (DMI) the copper reagents can be isolated in good yields [563]. This study was the first example of preparation and isolation of organocopper compounds by use of organosilicon reagents. The Si-Cu transmetalation is applicable to the synthesis of alkynyl ketones by Cu-catalyzed alkynylation of acid chlorides (Scheme 10.217). We have also shown that a Cu-mediated system is effective in the cross-coupling reaction between arylsilanes or heteroarylsilanes and aryl hahdes [564]. 

Though not proved, alkynyl-ketones could also be involved as reactive intermediates in the regioselective preparation of 3,5-diarylisoxazoles 19 through four-component coupling of terminal alkynes 17, hydroxylamine, carbon monoxide, and aryl iodides 18, in the presence of a palladium catalyst. The reaction proceeds at room temperature and an ambient pressure of CO in an aqueous solvent system <05OL4487>. 

Benzodiazepines and naphthodiazepines (16) have also been prepared by addition and condensation of o-phcnylenediamine, JV-methyl-and A7-phenyl-o-phenylcnediamines, and 2,3-diaminonaphthalene with a-alkynyl ketones.34 ... 

A well-established preparative method of alkynyl ketones 110 is the Sonogashira-type carbonylation of aryl halides in the presence of terminal alkynes. (Trimethylsi-lyOpyridylethyne (111), deprotected in situ, reacted with 3-iodotoluene and CO to give the alkynyl m-tolyl ketone 112 using DPPF as a hgand. Pd-catalyzed reductive cyclization of 112 using HCO2H afforded the 1,8-naphthyridine 113 [48]. 

Aromatic compounds with nitro groups ortho to the alkyne have been converted into indoles (eq 9). Alkynyl ketones have been prepared from either the corresponding acyl halides or by carbonylative ethynylation of vinyl halides and triflates with TMSA. 

The synthesis of 112 was then modified to provide a single enantiomer. This called for an asymmetric synthesis of cyclization substrate 111. This was accomplished by Midland reduction of ketone 113 to provide 114 with excellent enantioselectivity (Steroids-21). Alkylation of 114 with the appropriate bromide (prepared from 2-methylfuran according to the procedures described on Steroids-18), followed by a few well-precedented reactions, gave 115, and thence 111 and 112. Application of the Midland reduction is notable. This is a relatively early application of a reagent-controlled asymmetric synthesis. It is also notable that the Midland method works extremely well on alkyl alkynyl ketones (because they look like aldehydes to the reagent) and thus, is well-suited to this application. ... 

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