Acetylenic aldehydes, preparation

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

FRAGMENTATION OF a,(J-EPOXYKETONES TO ACETYLENIC ALDEHYDES AND KETONES PREPARATION OF 2,3-EPOXYCYCLOHEXANONE AND ITS FRAGMENTATION TO 5-HEXYNAL... 

The N-aminoaziridine version7 of the a,/3-epoxyketone->alkynone fragmentation is a possible alternative in situations where the simple tosylhydrazone version6-9 fails. The tosylhydrazone method often gives good yields at low reaction temperatures, but it tends to be unsuccessful with the epoxides of enones that are not cyclic or are not fully substituted at the /5-carbon atom. For example, it has been reported9 that 2,3-epoxycyclohexanone docs not produce 5-hexynal by the tosylhydrazone route. The A-aminoaziridine method can also be recommended for the preparation of acetylenic aldehydes as well as ketones. 

Cyclic a,p-unsaturated ketones can be cleaved by treatment with base of their epoxy tosylhydrazone derivatives to give acetylenic ketones. The reaction can be applied to the formation of acetylenic aldehydes (R=H) by using the corresponding, 2,4-dinitrotosylhydrazone derivatives.Hydrazones (e.g., 47) prepared from... 

Isothiazoles.1 These heterocycles can be prepared by reaction of a-acetylenic aldehydes or ketones with hydroxylamine-O-sulfonic acid and then with sodium hydrosulfide in a buffered aqueous solution. 

Arenetellurolates, ethenetellurolates, and alkanetellurolates prepared by reduction of diorgano ditellurium compounds with sodium borohydride in ethanol, THF/ethanol, or DMSO add to acetylenes in regioselective and iran.y-stereoselcctive reactions to produce aryl ethenyl tellurium products either predominantly or exclusively as (Z)-isomers. The yields are almost always higher than 70%. In reactions with acetylenic aldehydes, ketones, carboxylic acids, and esters the arenetellurolate becomes bonded to the carbon atom in a [i-position to the carbonyl group. 

Other difunctional compounds have been made. A few examples are noteworthy. Olefinic carbinols of the types RCH =CHCH,OH and RCHOHCH = CH, on treatment with dry hydrogen bromide or chloride undergo allylic rearrangements to yield equilibrium mixtures of isomeric unsaturated halides. Acetylenic carbinols prepared from sodium acetylide and aldehydes or ketones can be converted to their chlorides by means of anhydrous hydrogen chloride at —5°C. However, it should be noted that, in the reaction of dimethylethynylcarbinol,... 

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

Eelix, D., Wintner, C., Eschenmoser, A. Eragmentation of a,P-epoxyketones to acetylenic aldehydes and ketones preparation of 2,3-epoxycyclohexanone and its fragmentation to 5-hexynal. Org. Synth. 1976, 55, 52-56. 

A route to a, 8-acetylenic aldehydes is based on the fact that triethyl orthoformate in the presence of zinc iodide as catalyst reacts with a terminal acetylene with elimination of ethanol and formation of an acetal, as illustrated for the preparation of phenylpropargyl aldehyde. The reactants are heated neat with the catalyst to about 135°, and ethanol is removed by distillation (about 1 hr.). 

Cyclic enediynes. The realization that a number of antitumor antibiotics contain an enediyne core which is essential for their activity has led to extensive methods for synthesis of this ring system. One approach involves an aldol reaction with an acetylenic aldehyde protected as the Co2(CO)6 adduct. Thus the keto aldehyde 1, prepared in five conventional steps from cyclopcntenc-l,3-dione, on treatment with dibutylboron triflate and N(C2H5)y cydizes to 2 in 69% yield. Attempted dccomplexation with N-methyl-... 

Chlorination of sulfur compounds. Conversion of sulfides to carbonyl compounds by way of a-chlorination with S02C12 is quite useful. Thus acetylenic aldehydes can be prepared by a two-step process. In the presence of AgN03 or KNO. sulfuryl chloride transforms sulfides directly into a-chloro sulfoxides. ... 

A variety of propargylamines can be prepared by three-component Mannich condensation of acetylenes, aldehydes, and secondary amines (Scheme 7.19) [66, 67). These reactions were performed using CuCl to activate the acetylene component. Reaction times varied from 3-36 h. Silver iodide has recently been used to catalyze the reaction [68]. 

A general procedure has been published for the synthesis of retinoids, including vitamin A, by direct condensation of the side-chain, as ethyl 3,7-dimethylnona-2,4,6-trien-8-ynoate (80) to the appropriate cyclic ketone, e.g. 2,2,6-trimethyl-cyclohexanone (81). The acetylenic intermediate (82) is readily converted into vitamin A and derivatives. The side-chain reagent (80) is prepared in high yield by Emmons reaction between the acetylenic aldehyde (83) and the phospho-senecioate (84). In another synthesis of trans- tamm A, jS-ionylideneacetal-... 

This reaction has been used in the preparation of acetylenic aldehydes and ketones in addition, it has been used to synthesize middle-size cyclic ketones. 

Several improvements in acylation techniques were announced. Butyllithium wwas determined to be superior to sodium amide in preparation of amide ions for ammonolysis reactions with esters. Phosgene is more reactive than ethyl chloroformate toward eneamines. The intermediate acyl chlorides may then be converted to a variety of products. a-Acetylenic aldehydes are easily prepared by the action of acetylenic Grignard reagents upon ethyl formate. ... 

Reddy s group reported a silver-catalyzed annulation of enynyl azides to pyridine derivatives in 2015 [8], 3,6-Disubstituted pyridines were prepared in good yields through Ag-mediated aza-annulation of 2-en-4-ynyl azides which were derived from MBH-acetates of acetylenic aldehydes. 5-Iodo-3,6-Disubstituted pyridines can be prepared from enynyl azides having an electron-rich substituent on the alkyne functionality with I2 as the promoter (Scheme 2.5). 

In order to improve diastereoselectivity with the acetylenic aldehydes, the allenylborane 3 with a greater difference of the steric demands of the two groups at the Y carbon (/-butyldimethylsilyl vs. hydrogen) than that of 2a (trimethylsilyl vs. methyl) was prepared for condensation with 30 (Scheme 8). Essentially only 33 was produced, leading to the enediynes 34 and 35 with high isomeric purity. 

Eschenmoser has published an extensive account of the fragmentation of ttjff-epoxy-ketones to alkynones numerous examples illustrate the course of thermolysis of hydrazones derived from ajS-epoxy-ketones and substituted aminoaziridines (Scheme 111). This preparatively useful method is also applicable to the preparation of acetylenic aldehydes. 

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