1 - Acyl pyrazole

Statt Wasser konnen auch wasserfreie Carbonsauren eingcsetzt werden, als Nebenprodukt fallen dann 1-Acyl-pyrazole an157. 

A dififerent approach employs reaction of 1-acetyl pyrazoles (301) with 1,1-dielectrophiles (e.g., phosgene). Variation of the one-carbon electrophiles allows the introduction of other exocyclic groups to position 3 (Equation (42)). This procedure seems to be limited to 3,5-disubstituted 1-acyl pyrazoles <84JOC3672, 88JOC2889). 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

A solventless synthesis of pyrazoles, a green chemistry approach, has been described where an equimolar amount of the diketone and the hydrazine are mixed in a mortar with a drop of sulfuric acid and ground up. After an appropriate length of time ( 1 h) the product is purified to provide clean products. Even acyl pyrazoles 42 were obtained under the solvent-less reaction conditions in good yields. 

The templates used in these reactions have a significant impact on the reaction outcome and in determining product enantioselectivity. Sibi et al. also showed that changing the oxazolidinone template as in 119 to a 3,5-dimethylpyrazole in 131 resulted in a reversal of stereochemistry using the same chiral Lewis acid (Scheme 34) [91]. Additions in the presence of stoichiometric amounts of zinc triflate and ligand 19 gave good yields and moderate selectivities of 132. These acylated pyrazoles 131 form 5-membered... 

Azoles containing a free NH group react comparatively readily with acyl halides. yV-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (75) — (76) or type (79)—>(80) or (81). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. 

At least one mole of potassium carbonate was used to ensure that the o-acylated pyrazole intermediate of Step 7, (I), was converted into the product of Step 7, (II), by the Fries rearrangement as illustrated in Eq. 1 ... 

The ideas for delocalization of nitrogen lone pair electron density into an aromatic or heteroaromatic system were pursued through reduction of acylated pyrazoles and imidazoles to aldehydes in high yield. 3,5-Dimethyl-A -acylpyrazoles are easy to prepare and afford 77-96% yields of aldehydes with LiAlH4 in diethyl ether at 0 Further examples of this reaction have appeared.Although these later publications commented unfavorably on the ability of LiAlH4 to reduce acyl imidazoles to aldehydes (low yields), other workers have demonstrated that yields of 60-80% could be attained at temperatures of -20 to 4-20 °C in diethyl ether.It was considered that the earlier failure may have been caused by the presence of impurities in the acyl imidazoles. The latter are easy to prepare from the parent carboxylic acid and A jV -carbonyldiimidazole. 

Selective protection of 3-aminopyrazoles can lead to a variety of 3-acylaminopyrazole derivatives. 3-Aminopyrazole 317 could be selectively protected at N-2 giving BOC-protected pyrazole 318, which reacted with various acyl chlorides followed by BOG removal to provide 3-acylated pyrazoles 319 (Scheme 30) <2003TL4491>. Other protecting groups such as carbobenzyloxy (Cbz), benzyl (Bn), and SEM could be introduced at the N-2 position with biphasic conditions using potassium hydroxide as the base. A simple procedure for the BOG protection of H-1 of 3-aminopyrazoles has been described where 3-acylaminopyrazole derivatives could be prepared in good yields <2005TL933>. 

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

Fonnyl chromones react with arylhydrazines to produce 4-acyl-pyrazoles. ... 

Startg. m. warmed at 35° product. Y ca. 100%. - Ring closure to these N-acyl-pyrazole and -indazole derivs. as well as their ring opening with nucleophiles proceeds with great ease. F. e. s. T. Yamazaki and H. Shechter, Tetrah. Let. 1972, 4533. 

Hyunsoo Han of the University of Texas, San Antonio has described Tetrahedron Lett. 2007, 48,7094) an improved protocol for the enantioselective conversion of primary aUy-Uc carbonates 16 to secondary amines 17. Rene Peters of ETH Zurich has used (Angew. Chem. Int. Ed. 2007,46,7704) a related procedure for the construction of aminated cpiater-nary centers. Mukund P. Sibi of North Dakota State University has devised J. Am. Chem. Soc. 2007,129, 8064) a catalyst for the conjugate addition of the benzyloxyamine 20 to acyl pyrazoles, and Claudio Palomo of the Universidad de Pais Vasco has found (Angew. Chem. Int. Ed. 2007, 46, 8054) that a simple diphenyl prolinol catalyst will effect enantioselective a-amination of aldehydes. 

Substituted imidazoles can be acylated at the 2-position by acid chlorides in the presence of triethylamine. This reaction proceeds by proton loss on the (V-acylated intermediate (241). An analogous reaction with phenyl isocyanate gives (242), probably via a similar mechanism. Benzimidazoles react similarly, but pyrazoles do not (80AHC(27)24l) cf. Section 4.02.1.4.6). 

Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491 Z = NR, O, S) could isomerize to 3-azolinones (492). However, these compounds behave as true hydroxy derivatives and show phenolic properties. They give an intense violet color with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated by alkyl halides (to give 494 R = alkyl) and acylated by acid chlorides (to give 494 R = acyl). 

Acylindazoles are good acylating agents, particularly the 2-acetyl-7-nitro derivative (131). The acetylation of pyrazole by this compound proceeds quickly in chloroform and more slowly (about 15 min) in DMSO (66BSF3041). 

In addition to (461), Dorn has described the imine (463) isolated from 5-amino-l-methylpyrazole and arenesulfonyl chloride (80CHE1). Upon heating, or in the presence of triethylamine, it undergoes rearrangement to the more stable 5-bis(arylsul-fonamido)pyrazoles (464). 5-Iminopyrazolines (461) react with acyl chlorides at the exocyclic nitrogen atom to afford amidopyrazolium salts (B-76MI40402). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

The synthesis of pyrazolines and pyrazoles of the [CCNN + C] type with the creation of two bonds, N(2)-C(3) + C(3)-C(4) (or N(l)-C(5) + C(5)-C(4)), has been studied by several groups. Beam and coworkers have published a series of papers on the synthetic utility of lithiated hydrazones. Thus, the methylhydrazone of acetophenone (598) is converted by butyllithium into the dianion (599), which in turn reacts with methyl benzoate to afford the pyrazole (600) (76SC5). In earlier publications Beam et al. have used aldehydes and acyl chlorides to obtain pyrazolines and pyrazoles by the same method. 

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