Pyrazole aldehydes, synthesis

A further example of electrophilic substitution is the synthesis of pyrazole aldehydes by formylation with dimethylformamide.620,628... 

Pyrazoles. A synthesis of polysubstituted pyrazoles is completed in one step by the Emmons-Wadsworth reaction of these reagents with aldehydes. 

The acidic character of the hydrogen atoms of C-methyl groups linked to the pyrazolium ring (Figure 22 Section 4.04.2.1.1(11)) facilitates a number of reactions difficult to carry out with neutral pyrazoles. Since efficient methods of dealkylation have been described (Section 4.04.2.3.lO(ii)), the synthesis via the pyrazolium salt is a useful alternative. The same behaviour is observed for indazolium salts, for example, nucleophilic addition to aromatic aldehydes (78JOC1233). 

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. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

In some cases a choice of multicomponent or linear protocol for the treatment of pyruvic acids, aminoazole, and aldehydes allows obtaining different heterocycles. For instance, MCR involving 5-aminopyrazoles or sequence pathway via preliminary synthesis of arylidenpyruvic acids led to positional isomers 36 and 37, respectively (Scheme 15) [4, 61, 68]. It is interesting to note that the same strategy applied to 3-amino-l,2,4-triazole or to amino-W-aryl-lH-pyrazole-4-carboxamide reactions gave no effect and the final compound for both the protocols were the same [52, 61, 62]. 

A rapid and high yielding synthesis of pyrazolo[3,4- pyrimidinones by reaction of aromatic aldehydes with 4-amino-l-methyl-3-propyl-177-pyrazole-5-carboxamide intermediates in the presence of copper chloride has recently been reported for the synthesis of Viagra analogues <2005H(65)1821>. 

Acetals of /9-keto aldehydes are hydrolyzed in acid media and hence under these conditions they give pyrazoles just as the ketoaldehydes themselves.297-300 Recently the bis-acetal of malondialdehyde has been used extensively for the synthesis of pyrazoles unsubstituted on the ring carbon atoms the reaction yields single products since the bis-acetal is symmetrical.217,271,273,301-307 Cyclization takes place in... 

Diazo compounds have also been used as precursors in the preparation of pyrazoles and indazoles. The copper-promoted cycloaddition reaction of lithium acetylides 18 with diazocarbonyl compounds 19 provided a direct and efficient approach to the synthesis of pyrazoles 20 <07AG(I)3242>. A facile, efficient, and general method for the synthesis of 1-arylated indazoles 22 and A-unsubstituted indazoles 23 by the 1,3-dipolar cycloaddition of benzynes, generated from 21, with diazomethane derivatives has been reported <07AG(I)3323>. Reaction of diazo(trimethylsilyl)methylmagnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were applied to the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate <07S3371>. 

Shu-Jiang and co-workers [76] have developed a green approach for the synthesis of biologically important indeno[2,l-c]pyrazolo[5,4-/7]pyridines 36 via a MCR of a suitable aldehyde, 3-methyl-l-phenyl-l//-pyrazol-5-amine and 1,3-indane-dione in water under microwave irradiation without the aid of any catalyst. This protocol has the prominent advantages of being environmentally benign and having... 

A green approach for the synthesis of polyfimctionalized pyrazolo[4, 3 5,6]pyrido [2,3-rfl-pyrimidines 60 was elaborated by Tu and co workers [104] via a MCR of an aromatic aldehyde, a 3-methyl-1-phenyl-l//-pyrazol-5-amine and 1-methylbarbituric acid in water under microwave irradiation without catalyst. The yield of this reaction was affected by the volume of water. This protocol could be applied to aromatic aldehydes with either electron-withdrawing or electron-donating groups and also to heterocychc aldehydes giving excellent yields (Scheme 44). 

Organ and co-workers [120] described a unique approach to MCRs using a microwave-assisted, continuous flow process for the synthesis of new series of tetrahydro-pyrazolo[3,4-6]quinolin-5(6//)-ones 79. An aldehyde, dimedone, and 5-amino-3-methyl-l//-pyrazole were reacted, yielding the desired compound 79 in moderate to excellent yields. It was proved that the electronic properties of the substituted benzaldehydes have an important impact on the conversions as with electron-donating groups rather low yields were obtained (Scheme 60). 

A one-pot efficient method for the synthesis of derivatives 67 and 68 by condensation reaction of barbituric acids, lH-pyrazol-5-amines and aldehydes under solvent-free conditions has been reported (Scheme 16) [39]. These products were evaluated in vitro for their antibacterial activities against E. coli (ATCC 25922), P. aeruginosa (ATCC 85327), Enterococcus faecalis (ATCC 29737), Bacillus subtilis (ATCC 465), Bacillus pumilus (PTCC 1114), Micrococcus luteus... 

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3-phenyl- or 3-pyridylpyrazoles 27 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-(pyridyl)acetylene with diazo compounds 26 generated in situ from aldehydes 25 has been reported <03JOC5381>. Cyclization of ortho-(arylethynyl)benzene diazonium salts 28 having substituents at the para-position of the aryl ring furnished indazoles 29 <03TL5453>. 

The pyrazole ring is resistant to most reducing agents and survives intact when other heterocycles are cleaved. An illustration is provided by the reaction of the pyrazoloimidazolidinone (1) with LAH. Here the imidazolidine unit is sensitized to nucleophilic attack by the presence of a lactam carbonyl group, and the product formed is the monocyclic pyrazole (2). The stability of pyrazoles to reduction has been exploited in a synthesis of aldehydes from acyl halides. Thus N-acylpyrazoles (3) on reduction with LAH produce complexes of the type (4) these when hydrolyzed yield aldehydes and the parent pyrazoles (5). ... 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

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