Utilisation of chiral enaminones and azomethine imines in the synthesis of functionalised pyrazoles

Chiral enaminones, derived from commercially available enantipure starting materials, such as (+)-camphor and α -amino acids, were employed in cycloconcensation reactions with hydrazine derivatives to afford the corresponding pyrazoles, functionalised with terpene, alanine, 2-phenylethylamine, and β -amino alcohol moiety. On the other hand, recent study on stereocontrol in cycloadditions of racemic (1 Z ,4 R *,5 R *)-1-arylmethylidene-4-benzoylamino-5- phenylpyrazolidin-3-one-1-azomethine imines, available in three steps from hippuric acid, showed, that stereodirecting phenyl group, as well as ortho -substituents at the aromatic ring, control the selectivity of these cycloadditions. In extension, these results are now applied in a study, which is oriented towards combinatorial synthesis of pyrazolo[1,2– a ]pyrazolone type of peptidomimetics with variable, yet predictable configuration.


Introduction
Pyrazoles belong among the most reparesentative five-membered heterocyclic systems. 1 Despite the fact, that pyrazole ring is rarely a constituent of natural products, numerous synthetic pyrazole derivatives found use in various pharmaceutical, agrochemical, photographic, and other applications.Such examples of important pyrazole derivatives are natural products (S)pyrazolylalanine, 2 pyrazomycin, 3 and withasomine 4 and synthetic compounds sildenafil (Viagra®), 5 lonazolac, 6 difenamizole, 7 mepirizole, 8 phenidone, 9 and bicyclic pyrazolidinone LY 186826. 10n the other hand, synthesis and transformations of heterocyclic compounds represent the major topics of our research interest, which is primarily focused on development of synthetic methodologies for the preparation of various heterocyclic systems.In extention, these methodologies are then used for preparation of various types of heterocyclic compunds, which are functionalised with an amino acid, hydroxy acid, amino alcohol, polyol, nucleoside, terpene, dipeptide, and realted structural motifs. 11Within this context, a part of our studies was also focused on the synthesis of functionalised pyrazoles.For this purpose, we used two 3+2 heterocyclisation approaches, which are, also in general, the most frequently employed methods for the formation of the pyrazole ring: a) cyclocondensation between a hydrazine derivative and a suitably functionalised chiral enaminone as enamino masked 1,3-dicarbonyl compound analogue and b) 1,3-dipolar cycloaddition of chiral 3-pyrazolidinone-1-azomethine imine to a suitable dipolarophile.
The present review represents a summary of our most recent results in the synthesis of functionalised pyrazoles.

Syntheses of functionalised pyrazoles from chiral enaminones
In the last two decades, a series of 2-substituted alkyl 3-(dimethylamino)propenoates 1 and related enaminones was synthesized and used for the preparation of various heterocyclic systems, functionalised heterocycles, and natural product analogues. 12,13Recently, 3-(dimethylamino)propenoates 1 and analogs also found use in combinatorial synthesis. 14The most usual synthesis of alkyl 3-(dimethylamino)propenoates 1 consists of a treatment of an active methylene compound 2 with a formamide acetal.Propenoates 1 exhibit similar reactivity as their parent 1,3-dicarbonyl compounds: a) they react with electrophiles at position 2 and b) two electrofilic sites at positons 3 and 1 enable cyclisations with various 1,2-and 1,3-dinucleophiles leading to five-and six-membered heterocyclic systems.Reactions of 1 with nucleophiles are acid-catalysed and proceed by initial substitution of the dimethylamino group, followed condensation to the carbonyl group. 12

ARKAT
For example, in the reactions of 1 with hydrazine derivatives 3, substitution of the dimethylamino group takes place first to give the enehydrazines 4 (or tautomeric hydrazones 4'), followed by cyclisation to the carbonyl group to give the intermediate 5.In the case of enamino ketones (X = alkyl, aryl, etc.), elimination of water affords the 4,5-disubstituted pyrazole 6, while in the case of enamino esters and enamino amides, 4-substituted 5-hydroxypyrazoles 7 and/or their tautomers 7' are usually formed. 12In some cases, the intermediates 4/4' 15,16 and 5 17 were isolated under mild reaction conditions and their structures were confirmed by X-Ray diffraction (Scheme 1).

Synthesis of pyrazolyl and pyrazolo[1,5-a]pyrimidinyl substituted 2-phenylethylamines and β-amino alcohols 2.3.1 Synthesis of L-3-phenylalanine and L-threonine derived enamino ketones
According to the literaturely known methodology, 29 the N-protected L-3-phenylalanines 28a,b were transformed into the Weinreb amides 29a,b, which were then treated with excess ethynylmagnesium bromide.Upon quenching excess Grignard reagent with aqueous NaHSO 4 , the corresponding ethynyl ketones 30a,b were obtained in 90 and 61% yield, respectively.Addition of diethylamine to the triple C≡C bond then afforded enamino ketones 31a,b in 92% and 86% yield, respectively.On the other hand, upon treatment of 29a with excess ethynylmagnesium bromide followed by quenching with aqueous NH 4 Cl, the N-methyl-Nmethoxy substituted enaminone 32 was obtained in 50% yield.Formation of 32 could be explained by initial formation of the ethynyl ketone 30a followed by addition of N,Odimethylhydroxylamine to the triple C≡C bond.Similarly, the enaminone 37 was prepared in four steps from N-benzyloxycarbonyl-L-threonine (33) (Scheme 5).In the reaction of 37 with 5-amino-1H-pyrazole-4-carbonitrile (38c), simultaneous removal of the ketal protecting group also took place (Scheme 6). 30 COOBn
On the other hand, our previous study on reactions of 1-arylmethylidene-5,5dimethylpyrazolidin-3-on-1-azomethine imines with methyl propiolate showed, that the regioselectivity was strongly dependent on the ortho-substituents at the aromatic ring. 49This results prompted us to investigate also the influence of ortho-substituents in chiral azomethine imines 47 on stereoselectivity and regioselectivity of cycloadditions.
Possible explanation for different selectivity might be examplified at best by cycloadditions of 47a-f to dimethyl maleate.Dipoles 47a-d with free ortho-positions in the aromatic ring can adopt the planar conformation 47'a-d allowing transition state for the concerted 1,3-dipolar cycloaddition.Formation of the compounds 49a-d could be explained by preferential endo-approach of dipolarophile from the less hindered face of the (1Z,4R*,5R*)dipole.On the other hand, such planar conformation is not possible in the case of dipoles 47e,f with two ortho-substituents.Alternatively, stereoselective formation of 49e,f might be explained by a two-step 1,4-addition-cyclization mechanism. 52In the mezomeric structures 47'e,f, rotation around the N(1)-C(1') single bond gives the rotamers 47''e,f with the bulky aryl group twisted away from the phenyl ring at position 3. Conformers 47''e,f can undego Michael-type antiaddition to the dipolarophile to form the intermediate zwitterions (or a biradicals), 52 which cyclise into the final products 49e,f (Scheme 11). 51

Scheme 11
Stereoselective formation of compounds 49e,f could also be in agreement with the exoapproach of the dipolarophile from the less hindered face of the (1E,4R*,5R*)-dipoles 47e,f.ARKAT However, this explanation does not seem suitable, since both, (Z)-and (E)-planar conformation of dipoles 47'e,f would be sterically unfavourable due to two ortho-substituents and because Z/Eisomerization of dipoles 47e,f at 150 °C would consequently lead to a mixture of isomeric cycloadducts.In order to determine the possible Z/E-isomerisation, 1 H NMR and NOESY spectra of azomethine imine 47f were recorded at 29, 62, 100, and 150 °C.Only one set of signals, observed in 1 H NMR spectra even at 150 °C, was in agreement with retention of the (Z)configuration.On the other hand, decreasing NOE between 1'-H and 5-H did not exclude the possibility of Z/E-isomerisation (Scheme 12). 51In continuation, we focused our attention also on combinatorial studies.Since the reaction and isolation conditions for azomethine imines 47 are allways the same (the dipoles precipitate from the reaction mixture), a series of azomethine imines 47 has recently been prepared by the parallel solution-phase approach and isolated simply by filtration, washing, and drying.In extention, the solution-phase approach was applied for the combinatorial synthesis of 15 tetrahydro-5Hpyrazolo [1,2-a]pyrrolo [3,4-c]pyrazole-1,3,5(2H,3aH)-triones 54a-o by reacting five azomethine imines 47a,b,d,e,f with three maleimides 53a-c.Maleimides were chosen, since they are also, like dimethyl maleate, the cisoid-dipolarophiles and cycloadditions were exspected to proceed stereoselectively regardles to the ortho-substituents at the aromatic ring (c.f.Scheme 9).Upon heating in anisole followed by cooling, evaporation, trituration with ether, filtration, washing, and thorough drying, all products 54a-i and 54j-o were isolated in analytically pure form in 18-89% yields. 53According to exspectations, two stereochemical types of cycloadducts, 54a-i and 54j-o, were formed, depending on ortho-substituents at the aromatic ring.Surprisingly, recent NMR and X-ray structural determinations showed, that the configurations at positions 6, 7 and 9 were in agreement with the previously established stereocontrol, while the configurations at positions 3a and 9a were not. 51This might be due to possible isomerisation at positions 3a and 9a in cycloadduct 54 or/and due to different steric demand of the dipolarophile 53 in comparison to dimethyl maleate (Scheme 13). 53