Recent advances in the synthesis of polysubstituted 3-pyrazolidinones

An account of recent developments in the field of 3-pyrazolidinone chemistry is given with special focus on the synthesis and transformations of 5-substituted 4-benzyloxycarbonylamino-3-pyrazolidinones, pyrazolo[1,2-a ]pyrazole-based peptide analogues, and tetrahydropyrazolo-[1,5-c ]pyrimidine-2,7-diones. In terms of practical application, polyfunctionalized 3-pyrazoli-dinones as 'aza-deoxa' analogues of cycloserine, peptide mimetics based on 3-amino-2-oxo-1,5-diazabicyclo[3.3.0]octane-7-carboxylic acid, and 1,6-disubstituted tetrahydropyrazolo[1,5-c ]- pyrimidine-2,7-diones as the first representatives of a novel saturated heterocyclic system were prepared by these newly developed synthetic methods.


Introduction
3-Pyrazolidinone (Figure 1) and its derivatives are cyclic (internal) hydrazides of 3hydrazinopropanoic acid, which are commonly available by treatment of α,β-unsaturated carboxylic acid derivatives with hydrazine hydrate.In spite of their structural simplicity and ease of preparation, there were almost no reports on 3-pyrazolidinones in the early times of organic chemistry until the second half of the 20 th century.2][3][4][5][6] Since that time, the importance of 3-pyrazolidinones has risen significantly, due to their applicability in industrial processes and biological activity.So far, progress on 3-pyrazolidinone chemistry has been reviewed by Dorn in 1981, 7 Claramunt and Elguero in 1991, 8 and in part by Svete in 2008. 9Pyrazolidinone derivatives have been employed as dyes in food and other industries. 7,10,11Their bioactivities range from analgesic and antipyretic (phenazone), [12][13][14] antiinflammatory (phenylbutazone), [12][13][14] and anorectic (BW357U), 15 to inhibitory activities of cyclooxygenase and lipoxygenase in BW755C and phenidone, respectively. 16,170][21][22][23] Some important 3-pyrazolidinones are presented in (Figure 1).Due to their applicability and biological activity, pyrazolidin-3-one derivatives, both monoand bi-cyclic, remain attractive synthetic targets.Particular challenge is associated with their enantio-and/or diastereoselective synthesis.Most of the early studies were performed on achiral and on lightly substituted chiral pyrazolidinones. 7,85][26] Camphor derived pyrazolidin-3-one has been successfully employed as chiral auxiliary 27 while pyrazolidinone templates have been used in enantioselective Diels-Alder cycloadditions. 287][38] Most of our work in this field was based on chiral racemic (4R*,5R*)-4-benzoylamino-5-phenylpyrazolidin-3-one as the model compound, which is easily available from 4-benzylidene-2-phenyl-5(4H)-oxazolone by heating with excess hydrazine hydrate. 3,24This model compound was successfully employed in the synthesis of βpyrazolylalanine-and β-amino-β-phenylalanine derivatives and pyrazolo [1,2-a]pyrazole-based peptide mimetics. 9In extension, we became interested in the preparation of saturated 6-aminoperhydropyrazolo[1,2-a]pyrazole-1(or 2)-carboxylates that could serve as building blocks for incorporation into oligopeptides.Another important issue was the preparation of non-racemic peptide analogues, available either by resolution or by asymmetric synthesis.Finally, literature search revealed that saturated bicyclic pyrazolidinone-based heterocyclic systems are pretty much unknown.In this account, our recent developments in the synthesis of 3-pyrazolidinones and their fused analogs are presented.

From α,β-unsaturated esters
8][9] In the case of functionalized acrylates, however, the use of excess hydrazine hydrate represents a limitation, since nucleophile-sensitive functional groups may also react.This limitation cannot be avoided by the use of nucleophileresistant protecting groups, since they are usually difficult to remove.Consequently, deprotection and further derivatisations are hardly feasible.For example, the amino function in the products derived from (4R*,5R*)-4-benzoylamino-5-phenylpyrazolidin-3-one (1) could not be deprotected without destroying the heterocyclic system as well.For this reason, we decided to perform the synthesis of N-benzyloxycarbonyl protected compounds to allow N-deprotection and further transformations of the products.First, 3-substituted methyl 2-(benzyloxycarbonylamino)acrylates 3a-i were prepared by Wittig-Horner condensation of methyl 2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (2) with aldehydes and ketones following a slightly modified procedure by Schmidt and co-workers. 39][42]  Scheme 1. Synthesis of 3-pyrazolidinones 4a-i.
Recently, non-racemic 3-pyrazolidinones have been prepared from L-phenylalanine.N-Cbz-(S)-3-phenylalanine (9) was converted into the corresponding β-keto ester 10 45 in 43% yield via the addition of Li-enolate of methyl acetate to the reactive imidazolide of 9. Subsequent reduction of 10 with NaBH 4 , followed by chromatographic separation and re-crystallization gave isomerically pure (3R,4S)-β-hydroxy ester 11. 46 Mesylation of 11 in pyridine gave 12, which was further treated with excess hydrazine hydrate in CH 2 Cl 2 to yield the desired pyrazolidin-3-one in full conversion as an inseparable mixture of epimers 13 and 13′ in a ratio of 62:38 and in 57% yield.Following the same reaction conditions, cyclization of 12 with methylhydrazine yielded two regioizomeric pyrazolidinones each as a mixture of epimers in 100% conversion.The products 14, 14′, 15, and 15′ were formed in a ratio of 35:26:26:13.Chromatographic separation yielded pure isomers 14, 14′, and 15 in 25%, 18%, and 10% yield, respectively.Performing the reaction under identical conditions in DMF did not significantly change the product ratio.The formation of two regioisomers in the reaction of 12 with methylhydrazine was not unexpected.The poor diastereoselectivity of the formation of 13/13′-15/15′ implies that substitution of the mesylate group with hydrazine proceeds, either via a mixed S N 1/S N 2 mechanism, or alternatively, via initial elimination of mesylate group, followed by 1,4-addition of hydrazine to the so formed α,β-unsaturated ester intermediate (Scheme 4).Finally, 5-(2-aminoethyl) substituted 3-pyrazolidinones have also been synthesized in six steps from methyl acrylate (16).Following literature examples, 48 solvent-free DBU-catalysed Michael addition of benzylamine, 1-butylamine, and 1-propylamine to 16 gave methyl alaninates 17a-c, which were Cbz-protected and the so formed N-alkyl-N-Cbz-β-alanine esters 18a-c were hydrolyzed to afford N-alkyl-N-Cbz-β-alanines 19a-c 46 in 34-51% yields over three steps.Masamune-Claisen condensation of 19a-c with monomethyl magnesium malonate was carried out according to the literature procedure for homologation of closely related amino acid derivatives 48,[50][51][52]

Transformations on the ring
It is within this context that functionalization at the ring nitrogen atoms is usually performed.On account of the cyclic hydrazide structure of 3-pyrazolidinones, the reactivities of the two nitrogen atoms differ significantly.The more basic and more nucleophilic N( 1) is also more reactive.It preferably reacts with sp 2 electrophiles, such as carbonyls, electron-deficient alkenes and alkynes, and carbocations (S N 1 substrates), whereas reactions with sp 3 type of electrophiles (S N 2 substrates, such as primary alkyl halides) are usually difficult.A better way to obtain the corresponding 1-(primary alkyl)-3-pyrazolidinones is reduction of easily available azomethine imines with complex hydrides, e.g. with NaBH 4 or NaBH 3 CN.54  A recent example of sequential derivatization of 5-substituted (4R*,5R*)-4benzyloxycarbonylamino-3-pyrazolidinones is a simple five-step synthesis of fully substituted (4R*,5R*)-4-aminopyrazolidin-3-ones as analogues of D-cycloserine.It comprises a two-step preparation of 5-substituted (4R*,5R*)-4-benzyloxycarbonylamino-3-pyrazolidinones 4 (cf.Scheme 1), reductive alkylation at N(1), alkylation of the amidic N(2) with alkyl halides, and simultaneous hydrogenolytic deprotection/reductive alkylation of the primary amino group.The major advantage of the synthesis is that it enables an easy stepwise functionalization of the 3pyrazolidinone core with only two types of common reagents, aldehydes (or ketones) and alkyl halides (Figure 3).2) was performed with primary alkyl halides in DMF in the presence of K 2 CO 3 at r.t. to furnish the fully substituted 4-amino-3-pyrazolidinones 26a-h in 45-97% yields (Scheme 6). 42 Another, somewhat surprising, transformation was observed in the attempted preparation of (1Z,4R*,5R*)-2-amino-5-phenyl-3-pyrazolidinone (36) by catalytic hydrogenation of the Cbzprotected compound 4e.Instead of the desired product 36, the N-aminohydantoin 39 was obtained in 69% yield.Also here, the reaction pathway is explainable by sequential hydrogenolytic cleavage of the benzylic C-O and C-N bonds in 4e to give the α-amino hydrazide 37.Under slightly elevated pressure (3 bar), the amine 37 and CO 2 are in equilibrium with the carbamic acid 38, which cyclizes to N-amino hydantoin 39. 40 The proposed mechanism is supported by known, closely related examples of cyclizations of N-benzyloxycarbonyl-αamino acid hydrazides [55][56][57] and α-semicarbazidoacetates 58-60 into 3-aminoimidazolidine-2,4diones.Besides, the above transformation is also related to Bucherer's synthesis of hydantoins, which proceeds in a closed vessel under slightly elevated pressure utilizing CO 2 (or carbonate) as a C 1 -synthon (Scheme 9).

N N
Though very useful for the determination of reactivity and selectivity of the above [3+2] cycloadditions, 9,38 the obtained cycloadducts were not suitable for incorporation into peptides, since carboxy and amino functions (CO 2 Me and NHCOPh, respectively) could not be selectively deprotected without cleaving the pyrazolo[1,2-a]pyrazolone system as well.Thus, selective deprotection of a heterocyclic dipeptide was mandatory for a viable method for the synthesis of peptide mimetics.To do this, we decided to try out a classical peptide chemistry approach utilizing a combination of Boc and Cbz protecting groups.Cycloadditions of 1-arylmethylidene-4-benzyloxycarbonyl-amino-3-oxopyrazolidin-1-azomethine imines to tert-butyl 2-alkenoate would give selectively deprotectable dipeptides enabling derivatization of the carboxy and the amino function.Furthermore, coupling of the racemic dipeptide with an enantiomerically pure reagent (e.g. with α-amino acid derivative), followed by separation of the so formed diastereomers would give non-racemic tripeptides. 41he starting 3-pyrazolidinones 4 and azomethine imines 24 were prepared as described previously (cf.1][42] First, cycloadditions of 5-phenyl substituted dipoles 24a,b to tert-butyl acrylate were carried out under standard conditions, i.e. in refluxing anisole. 9omewhat expectedly, 40   In contrast, cycloadditions of 24c,d to tert-butyl methacrylate were regio-and stereoselective.Cycloaddition to dipole 24c followed by chromatographic separation furnished diastereomeric cycloadducts 48c and 49c in 35% and 9% yield, respectively, while cycloaddition to the ortho-disubstituted dipole 24d gave compound 49d as the only product in 66% yield (Scheme 14). 41heme 14. Cycloaddition of azomethine imines 24c,d to t-butyl methacrylate.
However, the weakest link in the above synthesis of peptide analogues was the [3+2] cycloaddition step, which had to be performed in refluxing anisole to assure a complete conversion of the starting dipole (cf.Schemes 10 and 12-14).Since epimerization of an α-amino acid (and their derivatives) is usually fast above 100 °C, the use of enantiopure azomethine imines for the synthesis of the non-racemic cycloadducts would not make sense.This serious drawback could by overcome by catalysis, which should significantly lower the required reaction temperature.This has been previously shown by regio-and stereo-selective copper(I) iodidecatalyzed cycloadditions of ethyl propiolate in refluxing dichloromethane. 76In contrast, the noncatalyzed cycloadditions required harsh thermal activation (~150 °C) and led to mixtures of isomeric cycloadducts. 77In extension, an optimized Cu-catalyzed method that allowed the preparation of separable non-racemic products under mild conditions was developed.Cycloaddition of azomethine imine 41a with methyl propiolate was chosen as the model reaction in search for suitable reaction conditions.Since the cycloadduct 66a is highly fluorescent (bright yellow fluorescence at 375 nm), simple and effective monitoring of the reaction progress was feasible by TLC.Optimization process revealed, that a full conversion of reactants at room temperature was performed at best in acetonitrile in the presence of CuI and Hünig base.Under these optimized conditions, the conversion of 41a was complete after 12 hours and the cycloadduct 66a was isolated in 98% yield upon chromatographic workup.Cycloadditions of racemic azomethine imines 41a-c,f,g to tert-butyl (S)-(3-oxopent-4-yn-2-yl)carbamate [78][79][80] under the above conditions afforded mixtures of diastereomeric cycloadducts 68a-c,f/68′a-c,f and 69g/69′g in 68-95% yields.Subsequently, diastereomers 68a-c,f/68′a-c,f and 69g/69′g were separated by medium-performance liquid chromatography (MPLC) to furnish diastereomerically pure non-racemic compounds 68a-c,f, 68′a-c,f, 69g, and 69′g in 3-45% yields. 81Also here, the regioselectivity and stereoselectivity of the cycloadditions and relative configurations of cycloadducts were in agreement with previous results obtained by closely related cycloadditions (Scheme 18). 9,38,41,76cheme 18. Formation of non-racemic products 66, 68, and 69.

Pyrazolo[1,5-c]pyrimidines
Recently, a series of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 73a-h, the first representatives of a so far unexplored saturated heterocyclic system, has been synthesized in twelve steps from methyl acrylate (16).The first part of the synthesis comprises a seven-step preparation of 5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 23a-c (cf.Scheme 5).Unfortunately, attempts to prepare N(2)-substituted pyrazolidinones by cyclizations of the mesylates 22 with cyclohexyl-, tert-butyl-, and phenylhydrazine failed.Consequently, a different, somewhat longer approach was applied.First, the pyrazolidinone 23a was treated with ClCOOBn to afford the Cbz-protected derivative 70a (R = Cbz) in 70% yield.However, subsequent N-methylation with MeI did not proceed to completion and the N-methylated intermediate 71a was obtained in only 18% yield.Subsequent removal of both Cbz groups by catalytic hydrogenation, cyclisation of the intermediate 1,4-diamine with 1,1′-carbonyldiimidazole (CDI), and chromatographic workup furnished the first final product 73a in 30% yield over two steps (Path A, Scheme 19).On the other hand, 1-Boc analogues of 70, prepared by treatment of 23a-c with Boc 2 O in 73-97% yields, readily underwent alkylation of the amidic nitrogen N(2) to give the fully substituted intermediates 71b-h in 49-73% yields.Acidolytic removal of the Boc group gave the 1-unsubstituted pyrazolidinones 72b-g in 77-99% yields.Subsequent hydrogenolysis of the Cbz group followed by cyclisation of the so-formed free 1,4diamine with CDI, and chromatographic workup furnished title compounds 73b-h in 28-65% yields over the last two steps.This somewhat tedious twelve-step synthesis was simplified by performing it, as far as possible, in a one-pot manner (Path B, Scheme 19). 53

Structural Features of 3-Pyrazolidinones
72][73][74][75][76][77] The 1 H-NMR spectroscopic data of the pyrazolidinones 4 and 25-33 and azomethine imines 24 revealed some interesting structural features of these compounds.In solution, these pyrazolidinone derivatives can equilibrate between two envelope conformers A and C via the planar conformer B (Scheme 21).The conformations in solution were established on the basis of the magnitude of the vicinal coupling constant.[42]
The anticipated U-shaped structure of the pyrazolo[1,2-a]pyrazole-based peptides 43-65 and 58′-65′ was confirmed by X-ray diffraction and by NMR.The X-ray structures of dipeptides 46b and its free amino derivative, 46d, and tripeptides 60′, 61′, and 63′ exhibit the U-shaped structure of the peptide chain.The U-shape of 60′ is additionally stabilized by intramolecular N-H•O=C hydrogen bond donated by N13 from the alanyl residue and accepted by O9 of the C=O group.In CDCl 3 solution, formation of (7′)C=O•H-N-C(2) intramolecular hydrogen bond in tripeptides 58/58′-62/62′ with the C-terminal (S)-alanyl residue was supported by 1 H NMR spectroscopy.Typically, the signals for the non-hydrogen bonded amidic NH protons appeared at a chemical shift of δ = 5-7 ppm, while the signals for the hydrogen bonded 2-NH protons exhibited higher chemical shift, δ = 7.5-9.3ppm.For example, in the 1 H NMR spectrum of tripeptide 60′ with the C-terminal (S)-alanine residue, a doublet for the H-N-C(2) proton at 8.39 ppm indicates non-covalent interactions of this NH group, explainable by (7′)C=O•H-N-C(2) intramolecular hydrogen bond.In contrast, a broad singlet for 2-NH proton at 4.94 ppm in the 1 H NMR spectrum of tripeptide 64′ with the N-terminal (S)-alanine residue does not support hydrogen bonding of this NH group (Figure 5).The absolute configurations of the non-racemic tripeptides 60′, 61′, and 63′ were unambiguously established by X-ray diffraction.Consequently, the configurations of their diastereomers 60, 61, and 63 were determined unambiguously as well. 41Unfortunately, we have so far been unable to prepare single crystals for unambiguous determination of the absolute configuration of the other representative diastereomers.In the absence of a firm proof, tentative configurations were proposed for the other diastereomers on the basis of correlation between specific rotation and absolute configuration. 41,81n addition to X-ray structures of the representative tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 73, 44,53 a more detailed 3D structure of title compounds 73a-r was also established on the basis of characteristic vicinal coupling constants, 3 J H-H .Large coupling constants, 3 J 3Ha-3aH = 3 J 4Ha-5Hb = 12.5 Hz and 3 J 4Ha-3aH = 10.5 Hz are in agreement with antiperiplanar trans-orientation of these nuclei.Accordingly, the pyrimidine and the pyrazole part of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-dione system must both adopt a halfchair conformation in which C(3) and C(4) point out of the plane of the system and 3-Ha, 3a-H, 4-Ha, and 5-Hb are axial (Figure 6). 44,53igure 6.Characteristic NMR data for compounds 73a-r.

References
cycloadducts.In 1996, he became an Assistant Professor, an Associate Professor in 2001, and a Full Professor in 2006.His research interest involve fundamental and applied organic synthesis with emphasis on development of novel reagents and synthetic methods, heterocyclic synthesis, combinatorial synthesis, stereoselective synthesis, 1,3-dipolar cycloaddition reactions, and chemisty of enaminones and 3-pyrazolidinones.He is particularly interested in the synthesis of novel chemical entities based on functionalized heterocycles, such as heterocyclic analogues of peptides.