Acetylenic ketones, oxidation

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

These conclusions were supported by the results obtained in a study of the reactions of various types of acetylenes with TTN (94). Hydration of the C=C bond was found to occur to a very minor extent, if at all, with almost all of the compounds studied, and the nature of the products formed was dependent on the structure of the acetylene and the solvent employed. Oxidation of diarylacetylenes with two equivalents of TTN in either aqueous acidic glyme or methanol as solvent resulted in smooth high yield conversion into the corresponding benzils (Scheme 23). The mechanism of this oxidation in aqueous medium most probably involves oxythallation of the acetylene, ketonization of the initially formed adduct (XXXV) to give the monoalkylthallium(III) derivative (XXXVI), and conversion of this intermediate into a benzoin (XXXVII) by a Type 1 process. Oxidation of (XXXVII) to the benzil (XXXVIII) by the second equivalent of reagent would then proceed in exactly the same manner as described for the oxidation of chalcones, deoxybenzoins, and benzoins to benzils by TTN. The mechanism of oxidation in methanol solution is somewhat more complex and has not yet been fully elucidated. 

The heterogeneous catalytic system iron phthalocyanine (7) immobilized on silica and tert-butyl hydroperoxide, TBHP, has been proposed for allylic oxidation reactions (10). This catalytic system has shown good activity in the oxidation of 2,3,6-trimethylphenol for the production of 1,4-trimethylbenzoquinone (yield > 80%), a vitamin E precursor (11), and in the oxidation of alkynes and propargylic alcohols to a,p-acetylenic ketones (yields > 60%) (12). A 43% yield of 2-cyclohexen-l-one was obtained (10) over the p-oxo dimeric form of iron tetrasulfophthalocyanine (7a) immobilized on silica using TBHP as oxidant and CH3CN as solvent however, the catalyst deactivated under reaction conditions. 

The secondary ethynylcarbinols were oxidized to the corresponding acetylenic ketones ... 

Pattenden and Teague have prepared tricyclic diol 684 which is epimeric to the naturally occurring A < -capnellene-8p,10a-diol (68S) Their strategy, which is summarized in Scheme LXXI, encompasses two critical cyclization steps. The first is the Lewis acid-catalyzed ring closure of enol acetate 686 and the second involves reductive closure of acetylenic ketone 687. It is of interest that the oxidation of 688 proved to be stereospecific. 

Novel practical methods using various reagents, such as [Co(OAc)Br],1355 sulfur trioxide,1356 or ds-dioxoruthenium complexes,1357 were developed to transform alkynes to 1,2-diketones. Radical-catalyzed aerobic oxidation using A-hydro-xyphthalimide combined with a transition metal (Co, Cu, or Mn) affords a,P-acetylenic ketones in good yields.1358 Oxidation by the HOF. acetonitrile complex yields diketones, ketoepoxides, or cleavage products.1359 Ozonolysis of acetylenes combined with trapping techniques affords to isolate various derivatives.1360,1361 New information for the ozonolysis of acetylene was acquired by quantum-chemical investigatons.1362... 

Bowden, K., I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon (1946) Researches on acetylenic compounds. Part I. The preparation of acetylenic ketones by oxidation of acetylenic carbinols and glycols. Journal of the Chemical Society (London), 39-45. 

Let us now consider the synthesis of isoxazole 4.28, a drug for the treatment of bronchial asthma. The most direct preparation of isoxazolyl ketone 4.24 is the cycloaddition of unstable bromonitrile oxide 4.22 (prepared in situ by dehydrobromination of 4.21) with acetylenic ketone 4.23. Observe the regioselectivity of this reaction. Both electron-donating and electron-withdrawing groups on the acetylenic components in such cycloadditions tend to occur at the C5 position in the final isoxazole and not at C4. Bromination of ketone 4.24 affords bromoketone 4.25 which is 4.23 n... 

The a,p-acetylenic ketones can be synthesized in good yields by the selective mono-hydroboration-oxidation process of conjugated diynes. The monohydroboration of conjugated diynes with disiamylborane places boron preferentially at the internal triple position of the diyne system. The resultant organoboranes on treatment with sodium hydroxide and 30% H202 afforded the a,P-acetylenic ketones (Eq. 33) 79). 

Cabarrocas G, Ventura M, Maestro M, Mahia J, Villalgordo JM (2001) Synthesis of novel optically pure quinolyl-P-amino alcohol derivatives from 2-amino thiophenol and chiral a-acetylenic ketones and their IBX-mediated oxidative cleavage to IV-Boc quinolyl carboxamides. Tetrahedron Asymmetry 12 1851-1863... 

Secondary acetylenic alcohols, prepared in good yields from acetylenic Gtignard reagents and aldehydes, are oxidized to acetylenic ketones... 

Conjugated acetylenic ketones can be prepared in about 40% yield by oxidation of alkynes with chromium trioxide-pyridine complex ... 

Hydroboration followed by oxidation provides an indirect route for hydration of diynes and constitutes an efficient route to acetylenic ketones as demonstrated by the synthesis of 206 in 75% yield from diyne 205... 

In the presence of hydrogen chloride, a-acetylenic ketones react with thioacetic acid to give a monothio-)S-diketone which is converted to a 1,2-dithiolium ion by phosphorus pentasulfide or hydrogen sulfide. These reactions, which involve some sort of oxidation, are discussed in the next paragraph. 

Oxidations with manganese dioxide are well suited for the preparation of unsaturated and acetylenic ketones [524]. The yields depend on the method of preparation, dryness and particle size of the oxidant, and, to a smaller extent, on reaction temperatures and times [SOS] (equation 254). 

Acetylenic ketones, synthons for 1,3-keto-aldehydes, also take part regioselectively in condensations, as do chalcones (a chalcone has the form ArCH=CHC(0)Ar), though of course an oxidant must be incorporated in this latter case. Hexafluorophosphoric acid is recommended for the condensation of phloroglu-cinols and alkynyl-ketones ... 

Other studies have dealt with hydrogen abstraction from the solvent by the photosensitizing drug nalidixic acid [98a], hydrogen transfer in an-thraquinone/xanthene systems [98b], photoreductions of quinones by alcohols [98c] and of acetylenic ketones by various hydrogen donors [98d], the oxidation of NADH analogues [98e-98g], and the reaction of 4-methyl-2-quinolinecarbonitrile with optically active phenylpropionic acid [98h],... 

Last year the exciting development from Hirao s group of alkylvanadium reagents which add oxidativity to aldehydes to give good yields of ketones was reported. They have now reported an extension of the method to include alkynylvanadium dichlorides permitting the preparation of a,0-acetylenic ketones [equation (3)].27 28 29... 

Scheme 28), and vanadium acetylides, formed from acetylenic Grignard or lithium compounds and VCl, react with aldehydes to give a, S-acetylenic ketones via oxidative nucleophilic addition (Scheme... 

Esters 106 (R = Me, Et or Pr = Et, Pr, r-Bu or PhCHi) of aliphatic carboxylic acids react with lithium acetylides 107 (R = H, C5 Hi i or Ph) in the presence of boron trifluoride etherate in THE to give acetylenic ketones 108 (equation 18). Palladium-[tetrakis(triphenylphosphine)]-copper(I) iodide catalyses the oxidative addition-decarboxylation of propargyl methyl carbonates, e.g. 109, with terminal alkynes to yield 1,2-dien-4-ynes (allenylacetylenes) 110. The regiochemistry of the palladium-catalyzed addition of phenylacetylene to the allenic ester 111 depends on the nature of the catalyst used palladium(III) acetate-triphenylphosphine yields a 81 19 mixture of adducts 112 and 113, while in the presence of tetrakis(carbomethoxy)palladacyclopentadiene-tris(2,4,6-trimethoxyphenyl)phosphine the ratio is reversed to 9 91 k... 

Brinkmeyer and Kapoor have now found that acetylenic ketones, RC= CCOR, are reduced by LiAlH4 and 1 at — 78° with the highest enantiomeric selectivity observed to date. Thus CH3Ce CCOCH2CH(CH3)2 is reduced to the corresponding (R)-alcohol with an enantiomeric excess of 827 . Similar asymmetric reductions were observed with seven other ketones of this type. Propargylic ketones are readily available by reaction of lithium acetylides with aldehydes followed by Jones oxidation of the propargylic alcohols. 

Horner-Emmons reaction of the acetylenic ketone 34 with the phosphonate 35 provided a mixture of the (E)- and (Z)-esters 36 and 37 in 90% yield. After separation, the (Z)-ester 37 was converted into the allene 38 by treatment with DIBAH (yield 92%) and oxidation of 38 with Mn02 provided the unstable a,P-unsaturated aldehyde 39 with retention of the (Z)-configuration. 

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