Synthesis of Novel 3D-Rich α-Amino Acid-Derived 3-Pyrazolidinones

Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative. The free amines were prepared by acidolytic deprotection. Title compound was also prepared by ‘ring switching’ transformation of N-Boc-pyrrolin-2(5H)one with hydrazine hydrate. Hydrogenolytic deprotection of 5-(N-alkyl-N-Cbz-aminomethyl)pyrazolidine-3-ones followed by cyclisation with 1,1’-carbonyldiimidazole (CDI) gave two novel representatives of perhydroimidazo[1,5-b] pyrazole, which is an almost unexplored heterocyclic system. Amidation of 3-oxopyrazolidine-5-carboxylic acid gave the corresponding carboxamides in moderate yields. Diastereomeric non-racemic carboxamides obtained from (S)-AlaOMe and (S)-ProOMe were separated by MPLC.

In the context of our ongoing work on the synthesis of chiral heterocycles with emphasis on pyrazole 33,34 and pyrazolidinone derivatives, 31,32 we reported the synthesis of tetrahydropyrazolo [1,5-c]pyrimidine-2,7-diones as the first representatives of a novel saturated heterocyclic system, 35,36 followed by preparation of closely related tetrahydropyrazolo [1,5-c]pyrimidine-3-carboxamides 37 and tetrahydro-1H-imidazo [1,5-b]pyrazole-2,6-diones. 38In ex-Glavač et al.: Synthesis of novel 3D-rich α-amino acid-derived ... tension, the first representatives of octahydro-2H-2a,2a 1 -diazacyclopenta[cd]inden-2-one as a novel tricyclic pyrazolidinone-based system were also prepared. 39Crucial for all of the above syntheses was the preparation of a pyrazolidinone key-intermediate with suitably functionalized substituent at position 5 allowing for cyclization to position 1.The 5-substituted pyrazolidinone was obtained by cyclization of the corresponding β-mesyloxy ester, which in turn was obtained in three steps from a suitably functionalized carboxylic acid. 31Pyrazolidinones with 2-hydroxyethyl 36 and 2-aminoethyl 35,37 functional groups at position 5 were used as key intermediates in the synthesis of novel saturated heterocyclic systems, while 5-[(S)-1-aminoalkyl] derivatives prepared from N-protected α-amino acids were used as scaffolds for potential organocatalysts 38 and as key-intermediates in the synthesis of 3-pyrrolinones. 40n addition to previously published 5-aminoethyl and 5-hydroxymethyl-3-pyrazolidinones, we also tried to prepare the 5-aminomethyl analogues, because they could be useful intermediates in the synthesis of novel saturated heterocycles in the imidazo [1,5-b]pyrazole and pyrazolo[1,5-a]pyrazine series.In this paper, we report the preparation and some follow-up transformations of 5-ami- nomethyl and 5-carboxy substituted 3-pyrazolidinones available from glycine derivatives and from dimethyl maleate, respectively.These novel pyrazolidinone derivatives are interesting intermediates in the synthesis of chiral saturated pyrazolidine-based heterocyclic systems.

2. General Procedure for the Synthesis of N-protected 5-aminomethyl-3pyrazolidinones 5a, 5b, and 5'b
Method A. Compounds 5a, 5b, and 5'b were prepared in a one-pot procedure following the combined slightly modified general literature procedures for the preparation of analogous compounds. 35,38,39

2. 1. Methyl 4-tert-butoxycarbonylamino-3oxobutanoate (2a) 42
Under argon, CDI (1.94 g, 12 mmol) was added to a solution of Boc-glycine (1a) (1.75 g, 10 mmol) in anh.THF (20 mL) and the mixture was stirred at room temperature for 2 h.Then a solid mixture of anh.MgCl 2 (0.893 g, 9.5 mmol) and potassium mono-methyl malonate (2.184 g, 14 mmol) was added under Ar in one portion via a powder funnel, which was rinsed with anh.THF (5 mL) and the mixture was stirred under Ar at r.t. for 20 h.Volatile components were evaporated in vacuo and the residue was triturated with EtOAc (80 mL).The resulting suspension was washed with 1 M aq.NaHSO 4 (2 × 20 mL) and brine (20 mL).The organic phase was dried over anh.Na 2 SO 4 , filtered, and the filtrate was evaporated in vacuo to give 2a, which was used in the next step without purification.Yield: 2.15 g (93%) of yellow oil.Spectral data were in agreement with the literature data. 42

2. 2. Methyl 4-tert-butoxycarbonylamino-3hydroxybutanoate (3a) 43
Finely powdered NaBH 4 (650 mg, 17.2 mmol) was slowly added to a cooled (0 °C) stirred solution of β-keto ester 2a (6.94 g, 30 mmol) in MeOH (100 mL) and the resulting mixture was stirred at 0 °C for 1 h and then quenched at 0 °C by the addition of H 2 O (150 mL) followed by the addition of 1 M aq.HCl (30 mL, 30 mmol).The product was extracted with dichloromethane (3 × 150 mL) and the combined organic phase was washed with brine (150 mL).The organic phase was dried over anh.Na 2 SO 4 , filtered, and the filtrate was evaporated in vacuo.The residue was dissolved in anh.toluene (30 mL) and the solution was evaporated in vacuo at 40 °C/2 mbar to give anhydrous crude 3a, which was used in the next step without further purification.Yield: 5.93 g (84%) of yellowish oil.Spectral data were consistent with the literature data. 43

General Procedure for Acidolytic
Deprotection of Compounds 5a, 5b, and 5'b.Synthesis of Free Amines 7-9 The precipitate was collected by filtration, washed with anh.Et 2 O (50 mL) and dried in vacuo to give 7-9.

6. 1. Preparation of the Free Diamines 12a,b
Boc 2 O (2.4 g, 11 mmol) was added to a stirred solution of 5c,d (9 mmol) in a mixture of dioxane (12 mL), water (25 mL), and Na 2 CO 3 (1.1 g, 10 mmol) and the mixture was stirred at r.t. for 24 h.Most of the dioxane was removed by evaporation in vacuo at 35 °C/50 mbar.EtOAc (50 mL) and brine (25 mL) were added to the aqueous residue, the biphasic system was transferred into a separatory funnel, shaken, and the phases were separated.The organic phase was washed with brine (2 × 20 mL), dried over anh.Na 2 SO 4 , filtered, and the filtrate was evaporated in vacuo.The residue was purified by CC (EtOAc/hexane, 1:1).Fractions containing the product were combined and evaporated in vacuo.Under argon, the residue was dissolved in anh.DMF (25 mL), K 2 CO 3 (691 mg, 5 mmol) and methyl iodide (934 µL, 15 mmol) were added and the mixture was stirred at r.t. for 72 h.Volatile components were evaporated in vacuo, EtOAc (100 mL) was added to the residue, and the mixture was washed with brine (3 × 30 mL).The organic phase was dried over anh.Na 2 SO 4 , filtered, and the filtrate was evaporated in vacuo.The residue was purified by CC (EtOAc/hexane, 1:1).Fractions containing the product were combined and evaporated in vacuo.The residue was dissolved in dichloromethane (20 mL), TFA (5 mL) was added and the mixture was stirred at r.t. for 24 h.Volatile components were evaporated in vacuo, EtOAc (150 mL) and brine (50 mL) were added, and the biphasic system was made alkaline by slow addition of solid K 2 CO 3 until pH 8-9 was reached.The mixture was stirred vigorously at r.t. for 5 min and then stirring was stopped and the phases were allowed to separate.The organic phase was washed with brine (2 × 10 mL), dried over anh.Na 2 SO 4 , filtered, and the filtrate was evaporated in vacuo.The residue was purified by CC (EtOAc/MeOH, 10:1).Fractions containing the product were combined and evaporated in vacuo to give 12a,b, which were used in the next step without further purification.

6. 2. Preparation of tetrahydro-1Himidazo[1,5-b]pyrazole-2,6-diones 14a,b
A mixture of crude 12c,d (1.5 mmol), methanol (20 mL), and 10% Pd-C (80 mg) was hydrogenated under 3 bar of H 2 at room temperature for 1.5 h.The catalyst was removed by filtration through a short pad of Celite®, washed with methanol (3 × 10 mL), and the combined filtrate was evaporated in vacuo.The residue was dissolved in toluene (20 mL) and the solution was evaporated in vacuo again to give anhydrous free diamine 13a,b.The crude diamine 13 (1.5 mmol) was dissolved in anh.DMF (5 mL), CDI (262 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 12 h.Volatile components were evaporated in vacuo and the residue was purified by CC (EtOAc-MeOH, 10:1).Fractions containing the product were combined an evaporated in vacuo.The residue (a mixture of 14 and imidazole) was dissolved in EtOAc Prepared from 12a (222 mg, 1.55 mmol) and CDI (265 mg, 1.55 mmol).Yield: 110 mg (42%) of yellow oil.

7. General Procedure for the Synthesis of 5-oxopyrazolidine-3-carboxamides 19a-d
Under argon, CDI (0.892 g, 5.5 mmol) was added to a stirred suspension of carboxylic acid 17 (1.031g, 5 mmol) in anh.acetonitrile (20 mL), the mixture was stirred at r.t. for 1.5 h, followed by addition of amine 18 (5 mmol).When amine 18 hydrochloride was used, one equivalent of N-methylmorpholine (NMM, 600 µL, 5 mmol) was added as well.The mixture was stirred at r.t. for 12 h and volatile components were evaporated in vacuo.The residue was taken up in dichloromethane (30 mL) and the solution was washed with 1 M aq.NaHSO 4 (2 × 20 mL), saturated aq.NaHCO 3 (2 × 20 mL), and brine (2 × 20 mL).The organic phase was dried over anh.Na 2 SO 4 , filtered, and the filtrate was evaporated in vacuo.Volatile components were evaporated in vacuo and the residue was purified by CC (EtOAc).Fractions containing the product were combined an evaporated in vacuo to give 19a-d.

Acknowledgement
The authors acknowledge the financial support from Slovenian Research Agency (research core funding No.