5-Ethynylpyrazole

The same type of reaction occurs in the work of Hauptman (76T1293), who, studying the chemistry of diethynylcarbenes, found that the pyrolysis of the lithium salts of diethynylketone tosylhydrazones 5 (140-150°C) in the presence of olefins leads to cyclopropanes. This process results in the formation of the corresponding 3-ethynylpyrazoles. The formation of l-p-tolylsulfonyl-3-alkynylpyrazoles from hydrazone runs in milder conditions (50°C, 14 h) (Scheme 24). 

For example, 3-ethynylpyrazole shows bands at 2120 cm and 3275 cm . 5-Ethynyl-l-methylpyrazole shows bands at 3290 cm and 2120 cm (68LA113). 

The acidity of 4-acetylenenylpyrazoles increases by 0.3-0.7 log units on introducing CH2NH2 group into position 5 of the ring. Chlorine atoms have the greatest acidifying effect. Chlorine atom in position 5 increases the acidity of l-methyl-3-ethynylpyrazole. 

The first representative of the acetylenic derivatives, 3(5)-ethynylpyrazole, was obtained by condensation of diacetylene with diazomethane by Kuhn and Henkel (41LA279) and later by other authors (69IZV2546), and by reaction of acetylene with diazopropyne (62AG252 68LA113) (Scheme 2). 

The composition of the mixture of products of different structures depends on the diacetylene diazomethane ratio (68LA124). With a 1 1 ratio of butadiyne and diazomethane, 3(5)-ethynylpyrazole dominates (55%). The yields of isomeric 3- and 5-ethynyl-l-methylpyrazoles are 8 and 11%, respectively. The double excess of diazomethane leads mainly to a mixture of N-methylated isomers (81%), 10% of 3(5)-ethynylpyrazole, and a small amount (3%) of bipyrazole (68LA124) (Scheme 3). 

Using chloro- or bromoenines, one can immediately obtain 4-ethynylpyrazoles (omitting the stage of pyrazolenine isolation) which is accompanied by methylation and the formation of the mixture of 3- and 5-sulfonyl-l-methyl-4-acetylenylpyra-zoles in about 1 2 ratio (total yield 37%) (Scheme 14). 

After having determined the nature of the side reaction it became clear that in order to obtain the desired ethynylpyrazole 11 the reaction between the ketone and PCI5 would have to be performed at low temperature. Indeed, the reaction was carried out in CH2CI2 at room temperature and a mixture of chlorides 7 and 8 was obtained. Dehydrochlorination of this mixture gave 66% of 3,5-dimethyl-4-ethynylpyrazole (11). Thus, by varying the conditions it is possible to carry out the reaction of the ketone with phosphorus pentachloride selectively in any of the above-mentioned directions. 

Thus, depending on the conditions, the reaction of methylpyrazolylketones with phosphorus pentachloride leads to products from substitution of the carbonyl oxygen by chlorine, o, /3-dichlorovinylpyrazoles, that can be dehydrohalo-genated with sodium amide to ethynylpyrazoles or to Q ,/3-dichloroethylenes. The... 

Similarly, the cross-coupling of N-protected 4-ethynylpyrazole with 1-(1-ethoxyethyl)-4-iodo- l//-pyrazole leads only to disubstituted butadiyne (2001 UP 1) (Scheme 50). 

The pyrolysis of 1-propynoylpyrazoles gives alkynylpyrazoles (85TL6373 94AJC991). The peeuliarity of these eompounds is that the ethynyl group is bound to nitrogen atoms. Flash vaeuum pyrolysis (EVP) of 1-propynoylpyrazole at 700-900°C/0.1 torr gives 1-ethynylpyrazole in low yield (Seheme 58). 

Ring-methylated 1-ethynylpyrazoles were similarly obtained as minor produets in the pyrolysis of 3,5-dimethyl- and a mixture of 3- and 5-methyl- 1-propynoylpyrazoles. Pyrolysis of the 3-methyl derivative gave only pyrazolo[l,5-a]pyridin-5-ol... 

The high aeidity of ethynylpyrazoles 24.0-30.4 92IZV507) determines the high reaetivity of the terminal aeetylenes and offers the possibility of obtaining a great number of the funetionally substituted pyrazolylaeetylenes. 

Pyrazolylaeetylides are rare in a free form. The only example is ethynylpyrazole eopper salt obtained by means of interaetion between terminal aeetylene and CuCl (2001UP1) (Seheme 77). 

Thus, the hydrogenation of isomeric l-ethynyl-3-methyl- and l-ethynyl-5-methylpyrazoles by hydrogen with 10% Pd/C in l-ethyl-3-methyl- and 1-ethyl-5-methylpyrazoles was used to prove the structure of iV-ethynylpyrazoles formed from pyrolysis of the corresponding iV-propynoylazoles (94AJC991) (Scheme 79). 

The hydration of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethynylpyrazole was performed with p-toluenesulfonic acid monohydrate in acetonitrile (2 h, room temperature) to give the corresponding 4-acetyl derivative. An alkyl substituent at the triple bond decreases the rate of hydration the conversion of 5-amino-3-cyano-l-(2,6-dichloro-4-trifiuoromethylphenyl)-4-(prop-l-yn-l-yl) pyrazole to the 4-propanoylpyrazole was completed after 18 h (98INP9804530 99EUP933363). 

The series of l,3-dimethyl-5-ethynylpyrazoles, including the functionally substituted ones, was obtained at lower temperature (100-105° C, 10 wt % of powdered KOH, 1.5-2 mm Hg) (86TH1). 

In (73S47) the cleavage of the trimethylsilyl protector is used to prepare the nitrogen-unsubstituted 3-aryl-5-ethynylpyrazoles (Scheme 96). 

Ethynylpyrazole was obtained under similar conditions in 46% yield (88M253). There are other examples of the trimethylsilyl cleavage with aqueous solution of potassium hydroxide for l-(hetaryl)-4-(trimethylsilylethynyl)pyrazole derivatives (96EUP703234). 

Ethynyl derivative 50 was prepared by interaction of potassium carbonate with5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilyl-ethynylpyrazole in methanol for 10 min (97INP9707102 98INP9804530 98INP9824767 99EUP933363) (Scheme 98). 

Attempts were made to perform heterocyclization with 4-phenylethynyl- and 4-ethynyl-5-aminomethyl-l,3-dimethylpyrazole where, on the one side, a strained six-membered ring can be formed, and, on the other side, the aliphatic amino group is more nucleophilic than the aromatic (Scheme 112). However, all attempts to cyclize the ethynylpyrazole and its phenyl analog failed (86TH1). 

Indeed, in the speetrum of ethynylpyrazole 94, the triple bond appears at 2112 em and then in the speetrum of earbinol 95, as in other disubstituted aeetylenes, their frequeney inereases by about 100 em . Note that the high intensity of the 2112 em band of eompound 94 is likely to result from the elevated eleetron density at position 4 of the pyrazole ring and the resulting inerease in the dipole moment of the triple bond eonjugate to it. 

For 1-ethynylpyrazole, l-ethynyl-3,5-dimethylpyrazole, l-ethynyl-3-methylpy-razole, and l-ethynyl-5-methylpyrazole, the ehemieal shifts of the methyne protons appear in CDCI3 at 3.14, 3.22, 3.05, and 3.21 ppm, respeetively (94AJC991). 

A comparison between the values of the acidity of ethynylpyrazoles and the energies of heterocyclic cleavage of the C—H bond calculated by the CNDO-2 method (75KGS821) has revealed a correlation between these values (Fig. 2). 

The effect of substituents in the ring on the mobility of a methyne proton can be followed from the series of 5-substituted l-methyl-4-ethynylpyrazoles and 1,3-dimethyl-4-ethynylpyrazoles. In both structural series, the acidity of compounds increases with a change in the character of substituents in the following order CH3 < H < CH2NH2 < Cl. 

The increasing CH acidity in the ethynylpyrazole series points to the advantageous inductive nature of this influence. Although the data are rather scarce, some correlation is observed between the ethynyl group values and (T constants of substituents in heterocycles (Fig. 3). 

Diacetylene reacts with diazomethane in an ether solution at 0°C to form 5-ethynylpyrazole (80) (65ZOR610). The second diazomethane molecule adds to the remaining triple bond much more slowly. The bis adduct, 5,5 -dipyrazole (81), was isolated in 35% at a 1 2 diacetylene diazomethane molar ratio. 

Dipolar addition of 2-diazopropane to diacetylene in EtaO at -25°C to give 3,3-dimethyl-5-ethynylpyrazole (83) (42% yield) and at 0°C to give dipyrazole 84 (60% yield) has been described (83TL1775). 

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