3- pyrazoles, acid-catalysed

An improved route to 3-(p-D-ribofuranosyl)pyrazole has been described, starting from 2,3-O-isopropylidene-D-ribofuranose and involving acetylenic intermediates. A stereocontrolled route to 4(5)-(P-D-ribofuranosyl)imidazole (115) has also been developed the epimeric mixture 114 was obtained via addition of a lithiated imidazole to 2,3,5-tri-O-benzyl-D-ribofuranose, and cyclization of this under modified Mitsunobu conditions gave selectively the P-product. A mechanistic rationale was presented, and the 2 -deoxycompound was similarly made. Various other 2 -deoxy-C-nucleosides of type 116 have been prepared in a non-stereoselective way by reaction of lithiated heterocycles with 3,5-(9-Tips-2-deoxyribose, followed by acid-catalysed cyclization compoimds made included the 2-furyl, 2-indolyl, 2-pyridyl and benzothiophen-2-yl analogues. ... 

The pyrazofurin analogue 98 has been prepared by a sequence involving cycloaddidon of an alkyne to (2,3,5-tri-0-benzyl-p-D-ribofuranosyl)diazomethane,i ii whilst 99 was made by oxidation of a protected ribosyl p-nitrophenylhydrazone and cycloaddidon of the resultant nitrilimine widi methyl propiolate.1 Skmie 3- and 4-D l rxofiitaiiosyl pyrazoles have been prq red acid-catalysed cyclizad[Pg.258]

Electrophilic Reactions. Further studies aimed at the correlation of the reactivity of five-membered heteroaromatic rings towards electrophiles have been reported. Acid-catalysed hydrogen exchange rates were measured (n.m.r.) for isoxazole, isothiazole, and their 3- and 5-methyl derivatives. Extrapolated values for the rate constants at 100 °C and pH 0 were obtained and compared with those for other ring systems. Quantitative effects of the methyl groups reflect the relative degree of bond fixation, and indicate that the aromaticity increases in the series isoxazole, pyrazole, and isothiazole. ... 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

Intramolecular (4+2 cycloaddition reactions of pyridazino(4,S-with acetylenic side-chain dienophiles were found to provide convenient access to /-annelated phthalazine derivatives 94JHC(31)3571. Base-catalysed cycli-sation of pyrazoles (11) followed by oxidation was shown to yield cinnoline-4-carboxylic acid l-A/-oxides (13) (93CC1756). 

Chalchones were recently also used as substrates for addition of indolines catalysed by quinine-derived squaramides and for addition of pyrazole catalysed by 9-epi-QA in combination with l-hydro)y-2-naphthoic acid additive. 

In 2009, Lin et al. reported an enantioselective synthesis of an important Janus kinase inhibitor, INCBO18424, the key step of which was an asymmetric aza-Michael addition of pyrazoles to an a,p-unsaturated aldehyde catalysed by a chiral diarylprolinol silyl ether. The use of benzoic acid or 4-nitrobenzoic acid as an additive was shown to increase the reaction rate. The highest enantioselectivities of up to 93% ee were observed for the reactions using the more sterically hindered organocatalysts (Scheme 1.68). 

Variously substituted allylic alcohols react with pyrazol-5-ones forming 4-substituted pyrazol-5-ones in yields ranging from 60 to 99% with 66 to 97% ee. The reactions are catalysed by a palladium complex with a chiral phosphoramidite ligand and a chiral phosphoric acid in THF (tetrahydrofuran) at 10 °C. 

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