Pyrazoles alkynes

Pyrazoles are formed when the diazo compounds react with alkynes or with functionalized alkenes, viz. the enols of /3-diketones. Pyrazolenines (353 Section 4.04.2.2.1) are isolated from disubstituted diazomethanes. Many pyrazoles, difficult to obtain by other methods, have been prepared by this procedure, for example 3-cyanopyrazole (616) is obtained from cyanoacetylene and diazomethane (7iJCS(C)2i47), 3,4,5-tris(trifiuoromethyl)pyrazole (617) from trifluorodiazoethane and hexafluoro-2-butyne (8lAHC(28)l), and 4-phenyl-3-triflylpyrazole (618 R =H) from phenyltriflylacetylene and diazomethane (82MI40402). An excess of diazomethane causes iV-methylation of the pyrazole (618 R = H) and the two isomers (618 R = Me) and (619) are formed in a ratio of 1 1. 

Burger s criss-cross cycloaddition reaction of hexafluoracetone-azine (76S349) is also a synthetic method of the [CNN + CC] class. In turn, the azomethines thus produced, (625) and (626) (79LA133), can react with alkenes and alkynes to yield azapentalene derivatives (627) and (628), or isomerize to A -pyrazolines (629) which subsequently lose HCF3 to afford pyrazoles (630 Scheme 56) (82MI40401). 

Hydrazoyl halides are useful reagents for the synthesis of pyrazolines and pyrazoles (80JHC833). The elimination of HX, usually with triethylamine, is now the preferred method for the generation of the nitrilimine (621) in situ. Although in some cases it is not clear if the mechanism involves a nitrilimine (621) (as for example in the Fusco method in which sodium salts of /3-diketones are used), in other reactions it is the most reasonable possibility. For example, the synthesis of pyrazolobenzoxazine (633) from the hydrazoyl halide (631) probably occurs via the nitrilimine (632). Trifluoromethylpyrazoles (634) have been prepared by the reaction of a hydrazoyl halide and an alkynic compound in the presence of triethylamine (82H(19)179). 

Monosubstituted hydrazones react with alkenes and alkynic compounds to yield pyrazolidines and pyrazolines, respectively (71LA(743)50, 79JOC218). Oxidation often occurs during the reaction and pyrazoles are isolated as the end product. 

TABLE XXVn. l-Methyl-l,6-dihydropyrazolo[3,4-c]pyridin-7-ones Prepared by Cyclization of Vicinal 4-(Alkyn- l-yl)pyrazole-5-carboxylic Acid Amides [90IZV2089]. 

Isosydnones (146) react with alkynes to give pyrazoles (150). For example, 4,5-diphenylisosydnone (146, R = R = Ph) and ethyl phenyl propiolate gives 4-ethoxycarbonyl-l,3,5-triphenylpyrazole (150, R = R = R = Ph, R = CO Et) identical with the product from 4,5-diphenylsydnone (1, R = R = Ph). The rate of 1,3-cycloaddition for isosydnones (146) is relatively slow in comparison with sydnones (1).2o, 04 number of other cycloaddition reactions of isosydnones with alkenes, alkynes, and carbonyl compounds have been reported. ... 

The 1,3-dipolar cycloaddition of diazo compounds with alkynes represents a standard method for the preparation of pyrazoles. The initially formed... 

Trifluoromethyl-substituted pyrazoles are easily obtained using trifluoromethyl-alkynes as dipolarophiles (Table 8.2, entry 9). Thus, treatment of 4,4,4-trifluorobut-2-ynoic acid with excess diazomethane gave methyl 4-(trifluoromethyl)pyrazole-4-carboxylate (45%) accompanied by its N - (32%) and -methylated (6.5%) derivatives (267). Another convenient route to CF3-substituted pyrazoles involves dipolar cycloaddition of appropriately CF3-substituted alkenes followed by eliminative aromatization (76,77,268). For example, the reaction of alkenes such as (CF3)2C=C(H)COAr with ethyl diazoacetate gave 4-aroyl-5-trifluoromethylpyra-zole-3-carboxylates (268). 

Acetylenedicarboxylic acid esters and related activated alkynes are routinely used as dipolarophiles for diazo dipoles. Recent examples include the use of diazo compounds 20 (49), 23 (51), and 24 (52) (Scheme 8.7), 25 (56) (Scheme 8.8), diazoacetaldehyde dimethylacetal (41) (which after cycloaddition and deprotection gave the corresponding pyrazole-3-carbaldehyde), ethyl 3-diazopyruvate (270), p-tolyl-trifluoromethyldiazomethane (271), bis(trifluoromethyl)diazomethane (272), and diazomethylenephosphoranes (60). 

The most important method for the synthesis of 3i/-pyrazoles is by 1,3-dipoIar cycloaddition between a diazo compound and an alkyne, although alkenes bearing suitable leaving groups have also been used. Other methods include the cyclization of vinyldiazo compounds, and the oxidation of pyrazolines. 

The reaction between alkynes and diazomethane, or monosubstituted diazomethanes, has been known for almost a century to yield l//-pyrazoles7 and is an important method for preparing these compounds.2,5,6 It proceeds via a 1,3-dipolar cycloaddition (Scheme 1) giving initially a 3//-pyrazole (4),... 

Reactions are normally carried out in anhydrous ether at room temperature or below and take from minutes to days to go to completion. Some have been conducted in more polar solvents such as MeCN or DMF, and sometimes an excess of the alkyne has been used as the solvent. Exceptionally, higher temperatures have been employed, but this usually results in isolation of the l//-pyrazole from rearrangement. 

Section II,A,1 3//-Pyrazoles have been prepared from 1,3,3,3-tetra-fluoropropyne and DPD169 and from l-thioalkyl-2-trimethlsiIylethynes with DAP.170 One of the latter alkynes was formed via valence isomerism of a thioketene.170... 

TABLE 8.2. PYRAZOLES 200-203 FROM ALKYNES R C=CR2 AND DIAZOCOMPOUNDS R3R4CN2... 

Alkynes add nitrile oxides and diazoalkanes to give isoxazoles (60) and pyrazoles (61), respectively, in 1,3-dipolar cycloadditions. If an alkene is used instead of an alkyne the non-aromatic analogues (62 Z = NH, O) result (94AHC(60)26l) yields are best when the alkene contains an electron-withdrawing substituent. 

NiCl(H)(PCy3)2] complex the chloride may be replaced by alkenes, alkynes, pyridine, pyrazole and imidazole giving complexes of the type [Ni(H)L(PCy3)2]Y (Y = BPI14, BF4).1216,1212... 

Ollis, and Ramsden520 treated 99, 100 and 101 with neat EPP and obtained the pyrazole 103 and the phenylpropiolic ester dimer 104, but no 105. A comparative study was carried out with phenylacetylene. When 100 was heated with DM AD in dioxane, 25% of the pyrazole 106 was obtained. These authors have concluded that the cycloaddition of alkynes to isosydnones is analogous to that of sydnones but the reactions are slower and the cycloadducts are obtained in lower yields. 

Nitrile imine cycloadditions provide access to pyrazolines and pyrazoles. Intramolecular cyclizations to alkynes were first reported in 1974.88 Perhaps the most useful method for generation of nitrile imines involves 1,3-elimination of hydrogen chloride from an a-chlorohydrazone. Tetrazoles and sydnones are also precursors to nitrile imines. 

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