Convenient Synthesis of N-Heterocycle-Fused Tetrahydro-1,4-diazepinones

A general approach towards the synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1H-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation—yielding target pyrazolo[1,5-a][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1H-indole- and ethyl 1H-benzo[d]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by 1H, 13C, and 15N-NMR spectroscopy and HRMS investigation.

In this work, the formation of the desired 1-(oxiran-2-ylmethyl)-3-aryl-1H-pyrazole-5-carboxylates by alkylation of easily accessible NH-pyrazoles [48] with 2-(chloromethyl)oxirane was optimized using 1a as a model compound. As shown in Table 1, reaction outcome is highly dependent on the choice of the base and the solvent. First, application of different bases in solvent-free conditions was investigated. When ethyl 3-phenyl-1Hpyrazole-5-carboxylate 1a was treated with 2-(chloromethyl)oxirane in the presence of K2CO3 at 70 °C (Entry 1) [49], a full conversion of 1a was only achieved after 16 h affording regioisomer 2a in 24% yield. Reaction using Cs2CO3 as a base at lower temperature (Entry 2) [50] proceeded giving isomers 2a and 3a in 3:2 ratio. Interestingly, when reaction was conducted using NaH (Entry 3), it proved to proceed in high regioselectivity. However, as the major product the undesired 5-phenyl-1H-pyrazole-3-carboxylate 3a was obtained. Reaction with KOH in the presence of a catalytic amount of TBAB [51] also did not provide an increase in the yield of desired regioisomer 2a (Entry 4). Subsequently, alkylation reaction conditions were investigated in the presence of solvent. To our satisfaction, both Cs 2 CO 3 (Entry 5) [52] and NaH (Entry 6) in DMF [53] provided desired isomer 2a as the major product in high regioselectivity. An attempt to perform reaction in refluxing ACN using Cs 2 CO 3 as a base [54] gave similar results (Entry 7). Interestingly, we noticed that alkylation using NaH proved to be highly regiospecific as the ratio of obtained products was drastically shifted by changing the reaction media. The use of DMF as a solvent in the presence of NaH was selected as the most suitable approach to synthesize ethyl 1-(oxiran-2-ylmethyl)-3-phenyl-1H-pyrazole-5-carboxylates 2a-h as it required overall reduced reaction time and temperature for full conversion of pyrazoles 1a-h (Scheme 1). Although the reactions exhibit high regioselectivity, obtained yields did not exceed 53-61% due to instability of products 2a-e during the purification process. in methanol (Scheme 1). Reaction monitoring indicated that ring closure proceeds rapidly to form a 1,4-diazepinone ring fused to pyrazole as no intermediate or side products have been observed, as opposed to the study reported by Shen et al. [28]. Reactions with primary amines, such as 2-methoxyethyl-, allyl-and benzylamines, afforded pyrazole-diazepinones 4i-x in good to excellent yields (70-98%), while reactions with ammonia gave derivatives 4a-e in substantially lower yields of 3456%. Interestingly, tetrahydro-4H-pyrazolo[1,5-a] [1,4]diazepin-4-ones 4g,h bearing a methyl substituent in either 2-or 3-position as well as 2,3-unsubstituted pyrazole 4f were obtained in higher yields (70-91%) compared to their phenyl-substituted counterparts 4a-e. Scheme 1. Synthesis of tetrahydro-4H-pyrazolo[1,5-a] [1,4]diazepin-4-ones 4a-x via N-alkylation and subsequent cyclisation reactions.
To substantiate the structures of novel compounds, an unambiguous assignment of chemical shifts was carried out by investigating combined NMR spectroscopic data, i.e., 1 H, 13 C-HSQC, 1 H, 13 C-HMBC, 1 H, 15 N-HMBC and 1 H, 1 H-NOESY. In principle, cyclisation of ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2a with ammonia could form two different isomers 4a and 4a′ ( Figure 3). The 1 H, 13 C-HMBC experiment revealed a threebond correlation between NH proton at δ 8.248.31 ppm and C-3a carbon at δ 139.4 ppm. Moreover, the same NH proton exhibited strong three-bond connectivity with tertiary C-7 carbon at 69.4 ppm. Interactions between C-4 carbon and 3-H at δ 7.16 ppm as well as 6-HaHb protons were observed. Strong three-bond connectivity was observed in the 1 H, 15 N-HMBC spectrum between 7-H proton and pyrrole-like nitrogen atom N-9 at δ 175.4 ppm. In case of putative isomer 4a′, the heteronuclear multiple bond correlations between NH proton and secondary aliphatic carbons should be observed. Furthermore, C-4 carbon would not exhibit three-bond correlation with aliphatic protons connected to a secondary carbon atom. Subsequently, alkylation reaction conditions were investigated in the presence of solvent. To our satisfaction, both Cs2CO3 (Entry 5) [52] and NaH (Entry 6) in DMF [53] provided desired isomer 2a as the major product in high regioselectivity. An attempt to perform reaction in refluxing ACN using Cs2CO3 as a base [54] gave similar results (Entry 7). Interestingly, we noticed that alkylation using NaH proved to be highly regiospecific as the ratio of obtained products was drastically shifted by changing the reaction media. The use of DMF as a solvent in the presence of NaH was selected as the most suitable approach to synthesize ethyl 1-(oxiran-2-ylmethyl)-3-phenyl-1H-pyrazole-5-carboxylates 2a-h as it required overall reduced reaction time and temperature for full conversion of pyrazoles 1a-h (Scheme 1). Although the reactions exhibit high regioselectivity, obtained yields did not exceed 5361% due to instability of products 2a-e during the purification process.
Differentiation between major 2a and minor 3a isomers was implemented based on 1 H, 13   The structure of minor regioisomer 3a was elucidated in a similar manner. The 1 H, 13 C-HMBC spectrum indicated that NCH2 protons correlate with pyrazole C-5 carbon at 146.2 ppm. Unambiguous distinction amongst both regioisomers can be determined using the 1 H, 1 H-NOESY experiment. Close-in-space proton interaction was observed between phenyl ring 2′(6′)-H protons and pyrazole 4-H proton at δ 6.84 ppm, whereas regioisomer 3a additionally exhibited NOEs between aromatic phenyl ring 2′(6′)-protons and The structure of minor regioisomer 3a was elucidated in a similar manner. The 1 H, 13 C-HMBC spectrum indicated that NCH 2 protons correlate with pyrazole C-5 carbon at −146.2 ppm. Unambiguous distinction amongst both regioisomers can be determined using the 1 H, 1 H-NOESY experiment. Close-in-space proton interaction was observed between phenyl ring 2 (6 )-H protons and pyrazole 4-H proton at δ 6.84 ppm, whereas regioisomer 3a additionally exhibited NOEs between aromatic phenyl ring 2 (6 )-protons and NCH 2 protons at δ 4.26-4.47 ppm.
According to the synthetic strategy, ethyl 1-(oxiran-2-ylmethyl)-3-aryl-1H-pyrazole-5carboxylates 2a-h were further used to obtain novel fused pyrazole-diazepinone systems via oxirane ring-opening. Due to high ring-strain, epoxides are prone to undergoing ringopening reactions upon treatment with various nucleophiles [55] alone, or under the use of transition metal or organocatalysts [56][57][58]. On the other side, small heterocycles are also able to react with diverse electrophiles, affording a variety of functionalized molecules. Unlike the nucleophilic ring-opening reactions, the electrophilic ring-opening of small heterocycles cannot proceed by itself [59]. Methods reported in the literature for the epoxide ring-opening with amines are mainly focused on reactions mediated by a range of catalysts, activators, and promoters, in either solvent or solvent-free media [55,[60][61][62][63]. In our study, intermediates 2a-h were treated with various primary amines or ammonia in methanol (Scheme 1). Reaction monitoring indicated that ring closure proceeds rapidly to form a 1,4-diazepinone ring fused to pyrazole as no intermediate or side products have been observed, as opposed to the study reported by Shen et al. [28]. Reactions with primary amines, such as 2-methoxyethyl-, allyl-and benzylamines, afforded pyrazole-diazepinones 4i-x in good to excellent yields (70-98%), while reactions with ammonia gave derivatives 4a-e in substantially lower yields of 34-56%. Interestingly, tetrahydro-4H-pyrazolo[1,5a] [1,4]diazepin-4-ones 4g,h bearing a methyl substituent in either 2-or 3-position as well as 2,3-unsubstituted pyrazole 4f were obtained in higher yields (70-91%) compared to their phenyl-substituted counterparts 4a-e.
To substantiate the structures of novel compounds, an unambiguous assignment of chemical shifts was carried out by investigating combined NMR spectroscopic data, i.e., 1 H, 13 C-HSQC, 1 H, 13 C-HMBC, 1 H, 15 N-HMBC and 1 H, 1 H-NOESY. In principle, cyclisation of ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylate 2a with ammonia could form two different isomers 4a and 4a ( Figure 3). The 1 H, 13 C-HMBC experiment revealed a threebond correlation between NH proton at δ 8.24-8.31 ppm and C-3a carbon at δ 139.4 ppm. Moreover, the same NH proton exhibited strong three-bond connectivity with tertiary C-7 carbon at 69.4 ppm. Interactions between C-4 carbon and 3-H at δ 7.16 ppm as well as 6-H a H b protons were observed. Strong three-bond connectivity was observed in the 1 H, 15 N-HMBC spectrum between 7-H proton and pyrrole-like nitrogen atom N-9 at δ −175.4 ppm. In case of putative isomer 4a , the heteronuclear multiple bond correlations between NH proton and secondary aliphatic carbons should be observed. Furthermore, C-4 carbon would not exhibit three-bond correlation with aliphatic protons connected to a secondary carbon atom.
A brief experiment was performed with minor regioisomer 3a in order to investigate if cyclisation reaction is possible when carboxylate and oxirane fragments are distanced via an additional nitrogen atom. Ethyl 1H-pyrazole-3-carboxylate 3a was treated with either ammonia or benzyl amine; however, analysis of LC/MS and NMR data indicated that both reactions resulted in the oxirane ring opening without subsequent cyclisation. Molecules 2022, 27, x FOR PEER REVIEW 6 of 29 A brief experiment was performed with minor regioisomer 3a in order to investigate if cyclisation reaction is possible when carboxylate and oxirane fragments are distanced via an additional nitrogen atom. Ethyl 1H-pyrazole-3-carboxylate 3a was treated with either ammonia or benzyl amine; however, analysis of LC/MS and NMR data indicated that both reactions resulted in the oxirane ring opening without subsequent cyclisation.

General
The reagents and solvents were purchased from commercial suppliers and used without further purification unless otherwise indicated. Reaction progress was monitored

General
The reagents and solvents were purchased from commercial suppliers and used without further purification unless otherwise indicated. Reaction progress was monitored by thin-layer chromatography (TLC) on pre-coated ALUGRAM ® Xtra SIL G/UV 254 plates (Macherey-Nagel™, Düren, Germany). The purification of the reaction mixtures was performed using flash chromatography on a glass column, stationary phase-silica gel (high-purity grade 9385, pore size 60 Å, particle size 230-400 mesh, Merck KGaA, Darmstadt, Germany). The 1 H, 13   To a 0.5 M solution of sodium ethoxide (1.1 eq) in ethanol, appropriate acetophenone (1 eq) and diethyl oxalate (1 eq) were added, and the resulting mixture was stirred at room temperature for 16 h in an inert atmosphere. Upon completion, the reaction mixture was quenched with 1 M HCl solution until neutral pH and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate 15/1, v/v). Obtained ketoester (1 eq) was dissolved in a mixture of ethanol and acetic acid (7/3, v/v, 0.2 M), 55% aqueous hydrazine hydrate solution (1.1 eq) was added, and the reaction mixture was stirred at room temperature for 16 h. Subsequently, solvents were evaporated, and residue was dissolved in ethyl acetate and washed with 10% aqueous NaHCO 3 solution. Organic layer was washed again with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate/methanol gradient from 8/1/0.1 to 1/1/0.1, v/v/v) to give corresponding pyrazoles 1a-h in good yields (75-87%).
Procedure b. Benzimidazole-2-carboxylate 5f (1 eq) was dissolved in dry dimethyl formamide (0.3 M) and NaH (1.5 eq; 60% dispersion in mineral oil) was added followed by 2-(chloromethyl)oxirane (1.5 eq). The reaction mixture was stirred at 60 • C for 4 h. Upon completion, the reaction mixture was cooled to 0 • C, quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography.