N-Hydroxypyrazoles

N-Hydroxypyrazoles are of interest as acylation and phosphorylation catalysts. Pyrazoles with strongly electron withdrawing groups (pKa < 9) 32 can be oxidized under buffered KHSO5 conditions to provide hydroxypyrazoles 33 in fair to good yields <96MC139>. 

Few new methods for direct functionalization of pyrazoles were reported. Notable is the N-hydroxylation of pyrazoles (c/., 17) with benzoyl peroxide [95LA1563]. These N-hydroxypyrazoles, after O-protection, undergo a-metallation and electrophile trapping processes to afford functionalized N-hydroxypyrazoles (19) [95JOC4998], The O-stannylpyrazole (20), on metallation, undergoes an 0 >C stannyl migration to stannylpyrazole (21). Direct sulfinylation of the 5-amino-3-cyanopyrazole (26) occured at C-4 [EUP668269]. 

The N- hydroxypyrazoles (523 R = H) and the pyrazole N- oxides (268 Section 4.04.2.1.3 (xiii)) have been reduced to pyrazoles by means of zinc in acetic acid and catalytic hydrogenation, respectively (75MI40402). 

Diazo coupling is expected to occur only with highly reactive systems, and experiment bears this out. Diazonium ions couple with the anions of N-unsubstituted imidazoles at the 2-position (e.g. 125 yields 126) and with indazoles (127) in the 3-position. In general, other azoles react only when they contain an amino, hydroxyl, or potential hydroxyl group, e.g. the 4-hydroxypyrazole (128), the triazolinone (129) and the thiazolidinedione (130) (all these reactions occur on the corresponding anions). 

Sometimes compounds which exist predominantly in the hydroxyl form give products of N-methylation with diazomethane, for example 3-hydroxy-5-phenylisothiazole (63AHCi2)245) of course, the ambident anion (493) is an intermediate. 3-Hydroxypyrazoles, under rather severe conditions, can be converted into 3-chloropyrazoles with POCI3 <66AHQ6)347). 

Af-Hydroxypyrazoles 38 and their N -oxides 39 are converted by f-BuOCI to the 4-chloro-47/-pyrazoles 40 and 41, respectively25,26,56 (Scheme 14). Unlike Scheme 6, the reaction proceeds even when R1 and R are alkyl. When... 

Substituted pyrazole 1-oxides 74 can be prepared by N-oxidation of 1-substituted pyrazoles 89, by A/-alkylation of 1 -hydroxypyrazoles 90, or by cyclization of 1,3-oximimines, conjugated oximenamines, or conjugated 1,3-nitrosoimines. 

N-Alkylation of 1-hydroxypyrazoles 90 produces 2-substituted pyrazole 1-oxides 91 (Scheme 26). Competing O-alkylation of the... 

Hydroxypyrazole 1-oxides are chlorinated at C4 using N-chlorosuc-cinimide (NCS) (1980JOC76) to give 4-chloro derivatives 215 (Hal1 = Cl), which can be further chlorinated at C4 using a second equivalent of NCS or f-BuOCl (1980JOC76). 

Hydroxypyrazole 1-oxides devoid of 4-substituents 214 were nitrated at the 4-position by HONO or n-butyl nitrite giving rise to the... 

The 1-hydroxypyrazoles exist as the neutral structure (ISla) and not in the N-oxide form (151b), although in water there is a small percentage of the latter present. For tautomerism of 2-hydroxyindazole see (82JOC4323). 

Hydroxypyrazole 180 was selectively N-alkylated to the corresponding 2-alkyl-pyrazole-l-oxides 181, which could be subsequently deoxygenated and C-halogenated forming 1-alkyl-5-halopyrazoles 182 (Scheme 7) <2001S1053>. 

N -Hydroxy groups can be acetylated (AC2O) and O-alkylated in basic media by methyl iodide. 1-Hydroxypyrazole 2-oxides are quite strong acids. 

From the results quoted in Section 4.04.2.1.3(x) the stability of acetyl derivatives of indazolone decreases in the order iV(l)-acetyl>N (2)-acetyl>0(3)-acetyI. The reactivity of 3-hydroxypyrazoles is covered by Dorn s comprehensive review (80CHE1). Amongst the results reported there are the Claisen rearrangement of allyloxypyrazoles (47Sa) - (47Sb) and a method for transforming 3-hydroxy- into 3-chloro-pyrazoles via the pyrazolone (476) and the chloropyrazolium chloride (477). Methylation of 3-hydroxypyrazole (478 X = OH) affords the pyrazolone (476), which in turn is transformed into the salt (477) by reaction with phosphorus oxychloride. The final step is the thermolysis of (477) that yields the 3-chloropyrazole (478 X = Cl)... 

Chattaway and co-workers287-290,294 have synthesized a number of l-aryl-2-pyrazolin-4-ones which, as a rule, have been considered to have the 4-hydroxypyrazole structures. However, some of these must have the 2-pyrazolin-4-one structure due to disubstitution at C-5. Emerson and Beegle425 have synthesized some 2-pyrazolin-4-ones unsubstituted at N-l permitting more possibilities for isomerism. These will be discussed later. 

Hydroxypyrazol-3-one 333 formed the O- and N-acylated pyrazol-3-ones 335a-e... 

A Haloform-type reaction occurs between trichloromethyl-substituted 1,3-diketones and hydrazine or. N-methylhydroxylamine to afford hydroxypyrazoles (e.g., 26) and 2-methyl-3-isoxazolones, respectively.6... 

Isolation of a I-hydroxypyrazole 2-oxide by chelation. Nitrosation of ben-zalacetone oxime with n-butyl nitrite in aqueous ethanol containing pyridine and C0CI2 (0.5 eq.) leads to the chelate (1), a violet solid, which on treatment with acid gives the oxide (2). The oxide had not been isolated previously because under nitrosating conditions it is converted into (3) and (4). 

Standard methods involving glycosyl halide or ester derivatives in reaction with protected heterocycles have been applied to the synthesis of various glycosyl derivatives of 5-fluoro-uracil and -cytosine, a number of nitro-imidazoles and -pyrazoles, thiadiazines and oxadiazolo-thiadiazines, and 5-methylthio derivatives of -uracil, -4-thiouracil, and -cytosine,/3-D-ribofuranosyl derivatives of 2-thio-6-azauracil, diethyl 4-hydroxypyrazole-3,5-dicarboxylate, 5-acetyl-uraeil, 2,4- and 2,5-thiazolidinediones, 4-thiomethyl-2-azapurine, 2-hydroxypurine, 3-deaza-adenine-8- C, l-deaza-8-azaguanine, imidazo-(l,2- )l,3,5-triazenes, e.g., (5), //n-benzo-guanosine, -inosine, and -xanthosine (6), and a derivative of lV-2-(i3-D-ribopyranosyl)benzotriazoie. Likewise 2-0-... 

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