2- ethynyl-, hydration

Since 17a-ethynyl-17 -hydroxy steroids are so readily prepared, they represent attractive starting materials for conversion to 20-ketopregnanes. Standard methods for the hydration of aliphatic acetylenes (e.g, mercuric salts alone, with aniline, or with BF3) give variable results, and sometimes no product at all, due to D-homo rearrangement. 233,235,265-7 mercury... 

In an equivalent pattern, 3-phenyl-5-ethynyl-pyrazole 349) is synthesized by transforming l,4-bis(TMS)-butadiyne 38) via benzoylchloride 242) into the corresponding l-benzoyl-4-TMS-l,3-butadiyne (J47)48. Subsequent acid-catalyzed ring closure with hydrazine hydrate and then hydrolysis under basic conditions yields 3-phenyl-5-ethynyl-pyrazole (349)208 (Scheme 49). 

The work of Nazarov on vinyl ethynyl carbinols involves condensation of vinylacetylene with ketones in the presence of caustic potash and also their conversions, many of which are catalytic in nature. A review of his work involving polymerization, isomerization, hydrogenation, and other conversions was published by him (252). Hydration of divinylacetylenes in methanol solution in the presence of mercuric sulfate and sulfuric acid gave vinyl alkyl ketones. These can be reacted with hydrogen sulfide, amines, etc., to yield heterocyclic compounds. Substituted vinyl alkyl ketones underwent spontaneous cyclization to cyclopentenones. Nazarov summarized a decade of this research in this field in 1951 (253). His general review of organic syntheses based on acetylene is also of interest in this connection (254). 

The so-called trimerization of propynal in the presence of piperidine acetate provides a synthesis of 4-ethynyl-4//-pyran-3,5-dicarbaldehyde (149) (50LA(568)34> it should be noted that the structure proposed for the product in the original work has been corrected (64CB1959). In the absence of moisture, the reaction fails and it seems likely that the synthesis involves hydration of the alkyne to the divinyl ether. Finally, condensation with the third molecule of the aldehyde results in cyclization to the product (Scheme 20). 

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. 

Like the double bond, the carbon-carbon triple bond is susceptible to many of the common addition reactions. In some cases, such as reduction, hydroboration and acid-catalyzed hydration, it is even more reactive. A very efficient method for the protection of the triple bond is found in the alkynedicobalt hexacarbonyl complexes (.e.g. 117 and 118), readily formed by the reaction of the respective alkyne with dicobalt octacarbonyl. In eneynes this complexation is specific for the triple bond. The remaining alkenes can be reduced with diimide or borane as is illustrated for the ethynylation product (116) of 5-dehydro androsterone in Scheme 107. Alkynic alkenes and alcohols complexed in this way show an increased structural stability. This has been used for the construction of a variety of substituted alkynic compounds uncontaminated by allenic isomers (Scheme 107) and in syntheses of insect pheromones. From the protecting cobalt clusters, the parent alkynes can easily be regenerated by treatment with iron(III) nitrate, ammonium cerium nitrate or trimethylamine A -oxide. ° ... 

In steroid series, the presence of ethynyl groups in position 17a provides orally active compounds then metabolized, by hydration of the triple bond, to 17a-methylketones (Figure 20.24). 

Figure 27, Two sections of the complex hydrogen bond pattern in a hydrated dialkyne (drawn using published atomic coordinates [76]). The molecules carry two ethynyl and two hydroxyl groups. Since there are two dialkyne molecules and an additional water molecules in the asymmetric crystal unit, there are four independent ethynyl and six O-H donors in the crystal lattice.

Like the classical conversion of acetylene into acetaldehyde, the treatment of a (2-substituted-ethynyl)phosphonic diester with sulphuric acid in the presence of mercury(II) sulphate, with subsequent drenching, affords the 2-oxo compound through hydration and a prototropic shift. Sturtz et were thus able to convert a series of diethyl (alk-1-ynyl)phosphonates into diethyl (2-oxoalkyl)phosphonates. The conversion of a cycloalka-none into the 2,5-dioxoalkyl species 619 following the neat generation of the side-chain in 618 and the conversions of 620 into 621 and of 622 into 623 are further examples of the same process . Sulphuric acid itself is able to convert the series 624 into the corresponding 625 (Z = OH, OMe or OEt) ... 

In the sedative-hypnotic series, most of the acetylenic alcohols are used as carbamic esters meparfynol, ethinamate, etc. The bromoethynyl moiety confers an acidity comparable to that induced by a trichloromethyl group (compare for example chlorobutanol with 3-methyl-pentyne-3-ol). Bromoethynylcyclohexanol is sufficiently acidic to form salts its bismuth salt was used for a while as an antisyphilitic drug under the name of biarsamide. In the steroid series the metabolism of the ethynyl group can lead (by hydration of the triple bond) to 17 a-methylketones. 

A similar reaction has been observed for the hydration of a-ethynyl alcohols. Under normal Rupe rearrangement conditions (acidic media) the reaction proceeds as follows ... 

Using the fluorinated a-ethynyl alcohol (48), the reaction under Rupe conditions was hydration of the triple bond to 49 on prolonged reaction this gave rise to an acyloin condensation to yield 50. 

It has been found that (S)-4-[[[l-(4-fluorophenyl)-3-(l-methyl-ethyl)-lH-indol-2-yl]-ethynyl]-hydroxyphosphinyl]-3]-hydroxybutanoic acid, disodium salt, is capable of existing in three crystalline hydrate and one liquid crystalline phase depending on the relative humidity to which the compound is exposed [58]. Among other things, these have been found to exhibit varying fluorescence properties in their respective solid states [59]. As shown in Fig. 4, the particle morphology of these... 

Mercury. A short account of the discovery of metal-catalyzed hydration of alkynes by Kucherov (1881) appeared on the occasion of its 125th anniversary [116]. Mercury-catalyzed hydration of alkynes has been used as mechanistic principle for devising fluorogenic probes for mercuric ions by two research teams. In one system, a 3-butyn-l-yl group at the phenolic oxygen of a fluorescein dye was cleaved via catalytic oxymercuration and elimination to releases a fluorescent dye (Scheme 20) [117]. In another system the mercury-catalyzed hydration of an ethynyl to an acetyl group provoked the quenching of fluorescence in a coumarine-based dye [118]. 

Complex reactions with consecutive or parallel steps are commonly encountered in catalytic slurry reactors, e.g. in hydration of propylene oxide, ethynylation of formaldehyde to bu-tinediol or hydrogenation of unsatturated oils [35, 36, 37, 38, 39]. If one can assume in a simplified analysis of these reactions that the concentrations of the liquid reactants are in excess, compared to the gaseous one (Aj ) the rate of reaction of the gaseous reactant (in the absence of intraparticle diffusion) can be expressed as... 

Reaction of the mixed cuprate (165) with cyclohexenone gave a high yield of (166), from which the )3-ethynyl ketone (167) was obtained by treatment with lead tetraacetate in acetonitrile. Analogously, (168) led to (169) after hydration of the acetylene. 

The competitive experiments were carried out with a series of terminal al-kynes characterized by similar electronic properties but differing in portions of the molecule remote from the reaction site. For aliphatic alkyne, the three substrates ethynyl cyclohexane, 1-octyne (which represents an acyclic isomer of the former substrate), and 1-dodecyne were tested, with the free catalyst compared to the encapsulated catalyst. In the former case, after a short induction time, the initial reaction rate for the three substrates showed similar behavior for 1-dodecyne and 1-octyne, while the cyclic isomer, being slightly more electron rich, reacted 1.5 times faster (Fig. 7.8a). Encapsulation of the catalyst led to a magnification of the favorable hydration of the cyclic substrate that reacted more than twice as rapidly as the longer substrate. It is likely that extended linear substrates, that in their extended conformation are approximately 1.4 and 2.1 times longer than ethynyl cyclohexane, have to fold to better complement the residual space left available within Ihe cavity occupied by the catalyst. 

FIGURE 7.8 Comparison of substrate selectivity displayed by the NHC-Au(I) catalyst in the hydration reaction of alkynes free in solution and encapsulated in the hexamer (a) preferential hydration of cyclic ethynyl cyclohexane rather than acyclic aUphatic terminal alkynes and of (b) shorter rather than longer aromatic rigid alkynes. 

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