Content area
Piperazine is one of the most frequently found scaffolds in small-molecule FDA-approved drugs. In this study, a general approach to the synthesis of piperazines bearing substituents at carbon and nitrogen atoms utilizing primary amines and nitrosoalkenes as synthons was developed. The method relies on sequential double Michael addition of nitrosoalkenes to amines to give bis(oximinoalkyl)amines, followed by stereoselective catalytic reductive cyclization of the oxime groups. The method that we developed allows a straightforward structural modification of bioactive molecules (e.g., α-amino acids) by the conversion of a primary amino group into a piperazine ring.
Full text
1. Introduction
Among saturated N-heterocycles, piperazine is the second most frequently found scaffold in small-molecule FDA-approved drugs [1]. The piperazine moiety is found in various pharmaceuticals, such as antipsychotic, anticancer, antidepressant, antihistamine, antianginal, anti-inflammatory, antiviral, and imaging agents [2,3]. Moreover, the piperazine ring is the key structural motif in several blockbuster drugs, including Gleevec (Imatinib) and Viagra (Sildenafil). Apart from medical use, piperazines are commonly applied as pesticides [4], ligands in catalysts [5], CO2-capturing materials [6], as building blocks in crystal design [7,8], and in polymer production [9,10].
Given the importance of piperazines, numerous synthetic approaches have been developed to access the broad chemical space of these heterocycles [11,12]. A common strategy relies on the functionalization of the parent molecule, which is easily accomplished by the addition of electrophiles at N-atoms and cross-coupling reactions [13,14,15,16]. Direct functionalization at C-atoms in piperazine is challenging (although some progress has been achieved in recent years [17,18]), and the synthesis of carbon-substituted piperazines is often accomplished via cyclization of the corresponding linear diamine precursors [11,12]. Alternative strategies employing the hydrogenation of pyrazines [19], [3+3]-type dimerization of aziridines [20], ring-opening reactions in DABCO derivatives [21], and ring expansion reactions in imidazolines [22] are limited by the specific structure of the starting materials. Overall, the synthesis of polysubstituted piperazines still remains a challenging problem.
For drug design purposes, the construction of piperazine ring 1 from a primary amino group is a useful synthetic strategy (Scheme 1). Since a plethora of pharmaceuticals and natural products contain a primary amino group, this synthetic tool would generate their potentially potent piperazine modifications [23]. Several attempts were undertaken to develop this methodology using 1,5-dihaloamines, diethanolamines, and their derivatives as cyclizing agents (Scheme 1). For example, Watanabe et al. [24] reported a hydrogen borrowing strategy to assemble piperazines from simple amines and N-substituted diethanolamines, yet the yields of the products were low in many cases. Huang and Li et al. [25] developed a one-pot protocol for the conversion of primary amines into piperazines by cyclization with tosylbis(2-(tosyloxy)ethyl)amine. However, these methods were applied only to the synthesis of C-unsubstituted piperazine derivatives, most likely due to a limited availability of the corresponding substituted diethanolamine derivatives and their reduced reactivity in these reactions. Also, harsh reaction conditions are required, under which complex substrates may not be tolerated. To develop a more general method, we suggested a conceptually different strategy (Scheme 1), which involves the conversion of a primary amine into bis(oximinoalkyl)amine 2 through double Michael addition to nitrosoalkenes (NSA), followed by catalytic reductive cyclization of the dioxime unit to give a piperazine ring. In our recent work, we have shown that a related cyclization of dioximes of 1,5-diones provides an expedient route to piperidines [26].
2. Results and Discussion
The first step of the suggested sequence requires the double oximinoalkylation of a primary amine through a Michael reaction with nitrosoalkenes NSA. Due to the instability of NSA, suitable precursors are used to generate these species in situ [27,28,29]. In the previous studies by our group [26,30] and other researchers [31], it has been shown that silylated ene-nitrosoacetals 3 are convenient precursors of NSA providing high chemoselectivity when coupling with various types of nucleophiles, including amines [32,33,34]. Using this methodology, a series of symmetrically substituted dialdo- and diketooximes 2a–o was prepared by the treatment of simple primary amines with 2.1 equiv. of the corresponding ene-nitrosoacetals 3a–c (R1 = H, Me, Ph, respectively, Scheme 2), followed by methanolysis of the resulting O-silyl ethers. In most cases, dioximes 2 were formed in high yields, except for sterically hindered amines (tert-butylamine and α-phenylethylamine leading to products 2b,k) and α-amino acid esters (products 2g,h). In the latter case, the lower efficiency is likely due to the self-dimerization of α-amino acid esters to diketopiperazines as a side process. Also, in the reaction with L-leucine ethyl ester, a noticeable amount of a mono-addition product was obtained.
Typically, dioximes 2 were obtained and characterized as mixtures of E/Z-isomers (the isomeric ratio slightly changed with time and depended on the solvent). For dialdooximes 2a–h, E,E- and E,Z-isomers were formed in comparable quantities, while for diketooximes, the 2i–n E,E-isomer was often predominant. The stereochemical assignment of oxime groups was performed on the basis of known relationships between the configuration of the C=N bond and chemical shifts of neighboring atoms in 1H and 13C NMR spectra (see Supplementary Materials for details on stereochemistry elucidation) [33,34]. The assigned configuration was additionally confirmed by 2D 1H−1H NOESY correlations and 1JCH coupling constants in the C(N)H unit [35] for dioxime 2a.
Dioximes 2a–o were then subjected to catalytic hydrogenation conditions (Scheme 2). Two heterogeneous catalysts, namely palladium on charcoal (5%-Pd/C) and Raney® nickel (Ra-Ni), were chosen for this study since these cheap and readily available catalysts often show the best performance in the hydrogenation of oximes [26,36]. It was found that hydrogenation of a model dialdooxime 2a gave the desired piperazine 1a in 44% yield with 5%-Pd/C catalyst at 40 bar H2/50 °C (method A1), while in the reaction with Ra-Ni (method B1), a complex mixture of products formed. The protection of piperazine 1a with a Boc group during the hydrogenation was advantageous in terms of the product yield and isolation simplicity (cf. yields of products 1a and Boc-1a). Optimized conditions (method A2) were successfully applied to a series of dialdooximes 2a–h that gave the corresponding Boc-piperazines Boc-1 in moderate to good yields. Expectedly, the alkene moiety in dioxime 2d and the benzylic C−N bond in dioximes 2e,f was not tolerated under hydrogenation conditions with Pd/C, leading to piperazines Boc-1d’ and Boc-1e’. The reductive debenzylation process was suppressed by using the Ra-Ni catalyst, as demonstrated by a synthesis of chiral piperazine Boc-1f from dioxime 2f derived from α-phenylethylamine by method B2.
Importantly, the developed approach allowed the building up of a piperazine ring in amino acid derivatives, as shown for glycine and L-leucine esters (products Boc-1g and Boc-1h) as examples. We believe that piperazine-modified peptides can be prepared in a similar manner.
In contrast to dialdooximes 2a−h, diketooximes 2i−o underwent the desired reductive cyclization with Ra-Ni catalyst (Scheme 2), while poor conversion was observed with 5%-Pd/C (studies with model substrate 2i). Moreover, protection with Boc2O (method B2) was inefficient in this case due to the small reaction rate attributed to a sterically encumbered environment around the nitrogen atom in 2,6-disubstituted piperazines. Thus, protection with more reactive propionic anhydride (method B3) or no protection (method B1) was performed in the hydrogenation of diketooximes 2i−o. Using these procedures, a series of 2,6-disubstituted piperazines 1 or their N-propionyl derivatives EtCO-1 was successfully prepared (Scheme 2). Note that the benzylic C−N bonds remained intact in products EtCO-1k,m, and 1o.
In the reductive cyclization of diketooximes 2i−o, cis-isomers of the corresponding piperazines 1 formed predominantly. In some cases, the process was stereospecific, and only 2,6-cis-isomers were obtained. Note that 2,6-diaryl-substituted piperazines of type 1o have scarcely been described in the literature, and those which have been reported have the 2,6-trans-configuration [18]. So far, the reductive cyclization of dioximes 2 appears to be the only available synthetic route to cis-2,6-diaryl-piperazines [37]. The comparison of NMR spectra of the obtained piperazines with those previously reported for cis-1n [38] and trans-1o [18] confirmed the stereochemical assignment (see Supplementary Materials for details on stereochemistry elucidation).
In the next stage, we aimed to adapt the developed strategy to access unsymmetrical 2-substituted piperazines (Scheme 3a). To accomplish this, a sequential assembly of unsymmetrically substituted dioximes 2 from two different NSA precursors was required. However, the reaction of n-butylamine with an equimolar amount of NSA precursor 3a gave a complex mixture containing products of mono- and bis-addition (4a and 2a, respectively). Selective Michael addition of one equivalent of nitrosoethylene was accomplished only when a significant excess of n-butylamine (12 equiv.) was employed. The monooxime 4a obtained was then used in a reaction with a second NSA precursor 3b,d,e that afforded unsymmetrically substituted dioximes 2p−r. Note that changing the sequence of the addition of NSA residues (i.e., initial addition of 3b to nBuNH2 followed by addition of 3a) was found to produce dioxime 2p at a lower overall yield. The reductive cyclization of these dioximes was successfully accomplished by hydrogenation with a 5%-Pd/C catalyst according to method A2 to give the corresponding racemic 2-substituted N-Boc-protected piperazines Boc-1p−r in good yields.
To showcase the utility of the developed strategy, the synthesis of a fused piperazine derivative, namely 1,4-diazabicyclo [4.3.0]nonane 5, was accomplished (Scheme 3b). The titled compound represents a building block in the synthesis of numerous pharmaceutically relevant molecules, in particular, hNK1 antagonist Orvepitant [39,40,41,42]. Dioxime 2s was prepared by the sequential addition of NSA precursors 3a and 3f to excess benzylamine (the major fraction of benzylamine that did not react in the first stage could be regenerated). In the hydrogenation of dioxime 2s over 5%-Pd/C (method A1), reductive cyclization of the dioxime motif and catalytic debenzylation occurred. Subsequent lactamization of the transient γ-aminoester upon heating in toluene produced the desired bicyclic product 5.
The proposed mechanism for the reductive cyclization of dioximes 2 into piperazines 1 is depicted in Scheme 4 [26]. The key stages involved catalytic hydrogenolysis of both N−O bonds to give diimine intermediate I-1, followed by its cyclization to give dihydropyrazine I-2. Subsequent hydrogenation of the C=N bond in I-2, elimination of ammonia, and reduction of dihydropyrazine I-3 afforded the final piperazine product 1. The observed predominant formation of 2,6-cis-isomers of piperazines 1 can be explained by the addition of dihydrogen from the less hindered side of the C=N bond in I-3, opposite to substituent R2.
3. Materials and Methods
Full compound characterization, detailed synthetic procedures, and copies of NMR spectra are provided in Supplementary Materials.
3.1. General Information
All the reactions were carried out in oven-dried (150 °C) glassware. NMR spectra were recorded at room temperature with peaks of residual solvents as internal standards. Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). For 13C spectra of Boc-1c, EtCO-1j, 2e, and 4d apodization with exponential multiplication (3 Hz) was used. 1H-15N HMBC spectra were recorded using CH3NO2 as a relative compound. HRMS was measured on an electrospray ionization (ESI) instrument with a time-of-flight (TOF) detector. Column chromatography was performed using silica gel 40–60 μm 60A with petroleum ether−ethyl acetate mixtures as eluents. Analytical thin-layer chromatography was performed on silica gel plates with QF-254. Visualization was accomplished with UV light and/or a solution of ninhydrin/CH3CO2H in ethanol.
CH2Cl2 and Et3N were distilled from CaH2; Et2O was distilled from LiAlH4; DMF was distilled from CaH2 under reduced pressure. Petroleum ether (PE), methanol, ethanol, CHCl3, and ethyl acetate were distilled without drying agents. Raney® nickel (Ra-Ni, ca. 50% slurry in water), 5%-Pd/C, n-butylamine, benzylamine, tert-butylamine, cyclopentylamine, allylamine, (S)-α-phenylethylamine, propionic anhydride, dmap, glycine ethyl ester hydrochloride, and L-leucine ethyl ester hydrochloride were commercial grade and were used as received. Ene-nitrosoacetals 3a (R1 = H), 3b (R1 = Me), 3c (R1 = Ph), 3d (R1 = Et), 3e (R1 = CH2Ph), 3f (R1 = CH2CH2CO2Me) were prepared in one step by the silylation of the corresponding aliphatic nitro compounds, in accordance with literature procedures (see ref. [26] and Supplementary Material for details).
3.2. General Procedures
General procedure for the synthesis of symmetrically substituted dioximes 2a−m,o. A solution of ene-nitrosoacetal 5 (2.1 mL, 1M in CH2Cl2) was added dropwise to a solution of an amine (1 mmol) in CH2Cl2 (1 mL), and the mixture was vigorously stirred at room temperature for 24 h. Then, MeOH (2 mL) was added to the reaction mixture and vigorously stirred for 8 h. Then, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel.
General procedure for the synthesis of monooximes 4. Amine (10–14 equiv.) was added to a solution of ene-nitrosoacetal 5 in dichloromethane (1 equiv, 1 M in CH2Cl2), and the mixture was stirred at room temperature for 24 h. Then, MeOH (5 mL) was added to the mixture and stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (PE:EtOAc = 5:1 → 3:1 → 1:1).
Synthesis of unsymmetrically substituted dioximes 2p−2s. Ene-nitrosoacetal 5 (0.6 mL, 1M in CH2Cl2) was added dropwise to a solution of monooxime 4 (0.5 mmol) in CH2Cl2 (1 mL), and the mixture was vigorously stirred at room temperature for 24 h. Then, MeOH (2 mL) was added to the reaction mixture and vigorously stirred for 8 h. Then, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel.
General procedure for the synthesis of free piperazines 1 with 5%-Pd/C catalyst (method A1). A 5%-Pd/C catalyst (50 mg per 0.5 mmol of 2) was added to a solution of dioxime 2 (1 equiv.) in methanol (0.1 M). The vial was placed in a steel autoclave which was flushed and filled with hydrogen to a pressure of ca. 40 bar. Hydrogenation was conducted at this pressure and 50 °C for 6 h with vigorous stirring. Then, the autoclave was cooled to rt and slowly depressurized, the catalyst was filtered off, and the solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent EtOAc:MeOH = 3:1).
General procedure for the synthesis of Boc-protected piperazines Boc-1 with 5%-Pd/C catalyst (method A2). A 5%-Pd/C catalyst (50 mg per 0.5 mmol of 2) was added to a solution of dioxime 2 (1 equiv.) and Boc2O (3 equiv.) in methanol (0.1 M of 2). The vial was placed in a steel autoclave which was flushed and filled with hydrogen to a pressure of ca. 40 bar. Hydrogenation was conducted at this pressure and 50 °C for 6 h with vigorous stirring. Then, the autoclave was cooled to rt and slowly depressurized, the catalyst was filtered off, and the solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent PE:EtOAc = 5:1).
General procedure for the synthesis of free piperazines 1 with Raney nickel catalyst (method B1). A suspension of Ra-Ni (ca. 50 mg per 0.5 mmol of 2) in methanol (1 mL) was added to a vial containing a solution of dioxime 2 (1 equiv.) in methanol (0.1 M). The vial was placed in a steel autoclave which was flushed and filled with hydrogen to a pressure of ca. 40 bar. Hydrogenation was conducted at this pressure and 50 °C for 6 h with vigorous stirring. Then, the autoclave was cooled to rt and slowly depressurized, the catalyst was filtered off, and the solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent PE:EtOAc = 5:1 → 3:1 → 1:1 → EtOAc).
General procedure for the synthesis of Boc-protected piperazines Boc-1 with Raney nickel catalyst (method B2). A suspension of Ra-Ni (ca. 50 mg per 0.5 mmol of 2) in methanol (1 mL) was added to a solution of dioxime 2 (1 equiv.) and Boc2O (3 equiv.) in methanol (0.1 M of 2). The vial was placed in a steel autoclave which was flushed and filled with hydrogen to a pressure of ca. 40 bar. Hydrogenation was conducted at this pressure and 50 °C for 6 h with vigorous stirring. Then, the autoclave was cooled to rt and slowly depressurized, the catalyst was filtered off, and the solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent PE:EtOAc = 5:1).
General procedure for the synthesis of propionyl-protected piperazines EtCO-1 with Raney nickel catalyst (method B3). A suspension of Ra-Ni (ca. 50 mg per 0.5 mmol of 2) in methanol (1 mL) was placed into a vial containing a solution of dioxime 2 (1 equiv.) in methanol (0.1 M). The vial was placed in a steel autoclave which was flushed and filled with hydrogen to a pressure of ca. 40 bar. Hydrogenation was conducted at this pressure and 50 °C for 6 h with vigorous stirring. Then, the autoclave was cooled to rt and slowly depressurized, the catalyst was filtered off, and the solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL per 0.5 mmol of 2) and propionic anhydride (3 equiv.), then triethylamine (3 equiv.) and dmap (1 equiv.) were added to the solution. The mixture was placed in a refrigerator (about 0 °C) for 12 h. Then the solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (eluent PE:EtOAc = 5:1 → 3:1 → 1:1).
3.3. Characterization of Final Products
1-Butylpiperazine (1a). The compound was prepared according to the general procedure from dioxime 2a (90 mg, 0.481 mmol). Yield: 30 mg (44%, method A1). Yield: 0 mg (0%, method B1). Yield: 0 mg (0%, method B2). Rf = 0.3 (EtOAc-MeOH, 3:1). Colorless oil. 1H NMR (300 MHz, COSY, CDCl3) δ 6.76 (br. s, 1H, NH), 3.22–3.12 (m, 2H, CH2), 2.92–2.82 (m, 2H, CH2), 2.82–2.73 (m, 2H, CH2), 2.32 (t, J = 8.0 Hz, 2H, CH2CH2CH2CH3), 2.26–2.12 (m, 2H, CH2), 1.52–1.37 (m, 2H, CH2CH2CH2CH3), 1.37–1.23 (m, 2H, CH2CH2CH2CH3), 0.89 (t, J = 7.3 Hz, 3H, CH2CH2CH2CH3). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 57.9 (CH2CH2CH2CH3), 57.5 (CH2NBu), 51.9 (CH2NH), 29.2 (CH2CH2CH2CH3), 20.8 (CH2CH2CH2CH3), 14.1 (CH2CH2CH2CH3). 1H NMR (300 MHz, DMSO-d6) δ 7.96 (br s, 1H, NH), 3.04–2.88 (m, 2H, CH2), 2.85–2.66 (m, 2H, CH2), 2.49–2.41 (m, 2H, CH2), 2.26 (t, J = 7.0 Hz, 2H, CH2CH2CH2CH3), 2.15–1.99 (m, 2H, CH2), 1.45–1.33 (m, 2H, CH2CH2CH2CH3), 1.33–1.19 (m, 2H, CH2CH2CH2CH3), 0.87 (t, J = 7.2 Hz, 3H, CH2CH2CH2CH3). HRMS (ESI): m/z calcd. for [C8H19N2]+ 143.1543, found 143.1544 [M + H]+.
Tert-butyl 4-butylpiperazine-1-carboxylate (Boc-1a). The compound was prepared according to the general procedure (method A2) from dioxime 2a (90 mg, 0.481 mmol). Yield: 86 mg (74%). Rf = 0.8 (PE–EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.53–3.41 (m, 4H, CH2), 2.45–2.39 (m, 4H, CH2), 2.35 (t, J = 8.0 Hz, 2H, CH2CH2CH2CH3), 1.56–1.47 (m, 2H, CH2CH2CH2CH3), 1.45 (s, 9H, CH3-C), 1.39–1.25 (m, 2H, CH2CH2CH2CH3), 0.91 (t, J = 7.3 Hz, 3H, CH2CH2CH2CH3). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 154.8 (C=O), 79.8 (C), 58.6 (CH2CH2CH2CH3), 53.1 (CH2NBu), 42.9 (CH2NBoc), 28.8 (CH2CH2CH2CH3), 28.6 (CH3−C), 20.8 (CH2CH2CH2CH3), 14.1 (CH2CH2CH2CH3). HRMS (ESI): m/z calcd. for [C13H27N2O2]+ 243.2067, found 243.2066 [M + H]+.
Tert-butyl 4-(tert-butyl)piperazine-1-carboxylate (Boc-1b). The compound was prepared according to the general procedure (method A2) from dioxime 2b (80 mg, 0.428 mmol). Yield: 44 mg (42%). Rf = 0.5 (PE-EtOAc, 1:1). White solid. 1H NMR (300 MHz, CDCl3) δ 3.65–3.18 (m, 4H, CH2NBoc), 2.68–2.18 (m, 4H, CH2NC), 1.43 (s, 9H, CH3CO), 1.04 (s, 9H, CH3CN). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 154.8 (C=O), 79.5 (C–O), 54.1 (C–CH3), 45.8 (CH2NC), 44.2 (CH2NBoc), 28.6 (CH3CO), 26.0 (CH3CN). Mp = 50–53 °C. 1H NMR spectrum is in agreement with previously published data [18].
Tert-butyl 4-cyclopentylpiperazine-1-carboxylate (Boc-1c). The compound was prepared according to the general procedure (method A2) from dioxime 2c (90 mg, 0.452 mmol). Yield: 49 mg (43%). Rf = 0.6 (PE-EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.44 (m, 4H, CH2), 2.48 (m, 1H, CH), 2.43 (m, 4H, CH2), 1.84 (m, 2H, CH2CH), 1.76−1.61 (m, 2H, CH2CH), 1.61−1.48 (m, 2H, CH2CH2CH), 1.45 (s, 9H, CH3), 1.40–1.33 (m, 2H, CH2CH2CH). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 13C NMR (75 MHz, CDCl3) δ 154.9 (C=O), 79.7 (C), 67.6 (CH), 52.2 (CH2N−Cyp), 43.6 (CH2NBoc), 30.5 (CH2CH2CH), 28.6 (CH3−C), 24.2 (CH2CH2CH). 15N NMR (300 MHz, HMBC, CDCl3) δ −295.8 (N-CH), −321.8 (N-Boc) (relative to nitromethane). HRMS (ESI): m/z calcd. for [C14H27N2O2]+ 255.2067, found 255.2061 [M + H]+.
Tert-butyl 4-propylpiperazine-1-carboxylate (Boc-1d’). The compound was prepared according to the general procedure (method A2) from dioxime 2d (50 mg, 0.292 mmol). Yield: 45 mg (68%). Rf = 0.75 (PE-EtOAc, 1:1). Colorless oil. 1H NMR spectrum is in agreement with previously published data [43].
Di-tert-butyl piperazine-1,4-dicarboxylate (Boc-1e’). The compound was prepared according to the general procedure (method A2) from dioxime 2e (100 mg, 0.453 mmol). Yield: 75 mg (63%). Rf = 0.85 (PE-EtOAc, 1:1). White solid. 1H NMR (300 MHz, CDCl3) δ 3.35 (s, 8H, CH2), 1.43 (s, 18H, CH3). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 154.8 (2 C=O), 80.1 (2 C), 43.6 (4 CH2), 28.5 (6 CH3). HRMS (ESI): m/z calcd. for [C14H27N2O4]+ 287.1965, found 287.1958 [M + H]+.
Tert-butyl (S)-4-(1-phenylethyl)piperazine-1-carboxylate (Boc-1f). The compound was prepared according to the general procedure (method B2) from dioxime 2f (90 mg, 0.383 mmol). Yield: 53 mg (48%). Colorless oil. Rf = 0.8 (PE–EtOAc, 1:1). [α]D = −30.3 (c = 0.25, MeOH, 26 °C). 1H NMR spectrum is in agreement with previously published data [18].
Tert-butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (Boc-1g). The compound was prepared according to the general procedure (method A2) from dioxime 2g (55 mg, 0.253 mmol). Yield: 45 mg (65%). Rf = 0.8 (PE–EtOAc, 1:1). Colorless oil. 1H NMR spectrum is in agreement with previously published data [44].
Tert-butyl (S)-4-(1-ethoxy-4-methyl-1-oxopentan-2-yl)piperazine-1-carboxylate (Boc-1h). The compound was prepared according to the general procedure (method A2) from dioxime 2h (100 mg, 0.366 mmol). Yield: 55 mg (46%). Rf = 0.7 (PE–EtOAc, 1:1). [α]D = −18.6 (c = 1, MeOH, 26 °C). Colorless oil. 1H NMR (300 MHz, HSQC, CDCl3) δ 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 3.43 (m, 4H, CH2NBoc), 3.31 (m, 1H, CHN), 2.63 (m, 4H, CH2NCH), 1.62 (m, 3H, CHCH2CH and CHCH3), 1.45 (s, 9H, CH3–C), 1.28 (t, J = 7.1 Hz, 3H, CH2CH3), 0.92 (d, J = 6.2 Hz, 3H, CH3CH), 0.90 (d, J = 6.2 Hz, 3H, CH3CH). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 171.9 (O–C=O), 154.7 (N–C=O), 79.6 (C), 65.6 (CHN), 60.3 (CH2CH3), 49.1 (CH2NCH), 44.1 (CH2NBoc), 37.9 (CHCH2CH), 28.4 (CH3–C), 25.0 (CH3CH), 22.5 (CH3CH), 14.4 (CH2CH3). HRMS (ESI): m/z calcd. for [C17H33N2O4]+ 329.2435, found 329.2428 [M + H]+.
1-(4-Butyl-2,6-dimethylpiperazin-1-yl)propan-1-one (EtCO-1i). The compound was prepared according to the general procedure (method B3) from dioxime 2i (90 mg, 0.420 mmol). A mixture of stereoisomers that were separated by column chromatography. Cis:trans = 6.1:1. Yield: 50 mg (53%). Rf = 0.5 (PE–EtOAc, 1:1). Colorless oil. Cis-isomer: 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 4.76–3.72 (m, 2H, CHCH3), 2.67 (d, J = 11.3 Hz, 2H, CH2CH), 2.33 (q, J = 7.4 Hz, 2H, COCH2CH3), 2.29 (t, J = 6.9 Hz, 2H, CH2CH2CH2CH3), 2.04 (dd, J = 11.3, 4.4 Hz, 2H, CH2CH), 1.52–1.38 (m, 4H, CH2CH2CH2CH3 and CH2CH2CH2CH3), 1.33 (d, J = 6.8 Hz, 6H, CH3CH), 1.15 (t, J = 7.4 Hz, 3H, COCH2CH3), 0.92 (t, J = 7.1 Hz, 3H, CH2CH2CH2CH3). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 172.7 (C=O), 58.2 (CH2CH), 57.9 (CH2CH2CH2CH3), 49.1 (CHCH3), 45.4 (CHCH3), 29.1 (CH2CH2CH2CH3), 26.4 (COCH2CH3), 21.4 (CH3CH), 21.1 (CH3CH), 20.5 (CH2CH2CH2CH3), 14.1 (CH2CH2CH2CH3), 9.8 (CH3CH2CO). HRMS (ESI): m/z calcd. for [C13H27N2O]+ 227.2118, found 227.2109 [M + H]+. Trans-isomer: 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 3.91 (m, 2H, CHCH3), 2.67 (d, J = 11.0 Hz, 2H, CH2CH), 2.50–2.20 (m, 6H, CH2CH, COCH2CH3 and CH2CH2CH2CH3), 1.52–1.39 (m, 2H, CH2CH2CH2CH3), 1.36 (d, J = 6.5 Hz, 6H, CH3CH), 1.32–1.21 (m, 2H, CH2CH2CH2CH3), 1.13 (t, J = 7.4 Hz, 3H, COCH2CH3), 0.91 (t, J = 7.2 Hz, 3H, CH2CH2CH2CH3). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 175.7 (C=O), 58.5 (CH2CH2CH2CH3), 58.0 (CH2CH), 49.1 (CHCH3), 29.4 (CH2CH2CH2CH3), 27.9 (COCH2CH3), 20.6 (CH2CH2CH2CH3), 20.1 (CH3CH), 14.2 (CH2CH2CH2CH3), 9.9 (CH3CH2CO). HRMS (ESI): m/z calcd. for [C13H27N2O]+ 227.2118, found 227.2113 [M + H]+.
1-(4-Cyclopentyl-2,6-dimethylpiperazin-1-yl)propan-1-one (EtCO-1j). The compound was prepared according to a general procedure (method B3) from dioxime 2j (90 mg, 0.442 mmol). A mixture of stereoisomers that were separated by column chromatography. Cis:trans = 2.8:1. Yield: 72 mg (69%). Rf = 0.6 (PE–EtOAc, 1:1). Cis-isomer: Colorless oil. 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 4.69–3.85 (m, 2H, CHCH3), 2.77 (d, J = 11.2 Hz, 2H, NCH2CHN), 2.47 (ddd, J = 15.4, 8.4, 7.0 Hz, 1H, CH2CHCH2), 2.34 (q, J = 7.3 Hz, 2H, CH2CH3), 2.07 (dd, J = 11.2, 4.3 Hz, 2H, NCH2CHN), 1.88–1.75 (m, 2H, CH2CHCH2), 1.68 (m, 2H, CH2CH2CH), 1.56 (m, 2H, CH2CH2CH), 1.48–1.37 (m, 2H, CH2CHCH2), 1.33 (d, J = 6.8 Hz, 6H, CH3CH), 1.16 (t, J = 7.3 Hz, 3H, CH2CH3). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 172.7 (C=O), 66.5 (CHN), 57.1 (NCH2CHN), 48.8 (CHCH3), 46.1 (CHCH3), 30.8 (CH2CH2CH), 26.3 (COCH2CH3), 24.3 (CH2CH2CH), 21.2 (CH3CH), 9.8 (CH3CH2). HRMS (ESI): m/z calcd. for [C14H27N2O]+ 239.2118, found 239.2117 [M + H]+. Trans-isomer: Colorless oil. 1H NMR (300 MHz, HSQC, CDCl3) δ 3.88 (m, 2H, CHCH3), 2.70 (d, J = 11.3 Hz, 2H, NCH2CHN), 2.58 (ddd, J = 15.7, 8.6, 6.9 Hz, 1H, CH2CHCH2), 2.49–2.23 (m, 4H, NCH2CHN and CH2CH3), 1.88–1.44 (m, 8H, CH2CH2CH and CH2CH2CH), 1.34 (d, J = 6.5 Hz, 6H, CHCH3), 1.11 (t, J = 7.4 Hz, 3H, CH2CH3). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 175.7 (C=O), 67.2 (CH2CHCH2), 56.8 (NCH2CHN), 49.1 (CHCH3), 30.7 (CH2CH2CH), 30.6 (CH2CH2CH), 27.8 (COCH2CH3), 24.1 (CH2CH2CH), 20.2 (CH3CH), 9.8 (CH3CH2CO). HRMS (ESI): m/z calcd. for [C14H27N2O]+ 239.2118, found 239.2115 [M + H]+.
1-(2,6-Dimethyl-4-((S)-1-phenylethyl)piperazin-1-yl)propan-1-one (EtCO-1k). The compound was prepared according to the general procedure (method B3) from dioxime 2k (80 mg, 0.302 mmol). An inseparable mixture of stereoisomers. Cis:trans = 3:1. Yield: 51 mg (62%). Rf = 0.7 (PE–EtOAc, 1:1). [α]D = –12.9 (c = 0.07, MeOH, 25 °C). Cis-isomer (characterized in mixture with trans-isomer): Colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.45–7.17 (m, 5H, Ph), 4.62–3.78 (m, 2H, CHCH3), 3.38 (q, J = 6.7 Hz, 1H, CHPh), 2.89 (m, 1H, CH2CH), 2.59 (m, 1H, CH2CH), 2.41–2.22 (q, J = 7.5 Hz, 2H, CH3CH2CO), 2.16 (dd, J = 11.1, 4.4 Hz, 1H, CH2CH), 2.05 (dd, J = 11.4, 4.3 Hz, 1H, CH2CH), 1.43–1.29 (m, 6H, 2CHCH3), 1.29 (d, J = 6.8 Hz, 3H, CH3CHPh), 1.15 (t, J = 7.5 Hz, 3H, CH3CH2CO). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 172.5 (C=O), 144.4 (i-Ph), 128.3 (m-Ph), 127.5 (o-Ph), 127.1 (p-Ph), 64.1 (CHPh), 56.1 (CH2CH), 54.6 (CH2CH), 49.2 (CH2CHCH3), 46.8 (CH2CHCH3), 26.3 (COCH2CH3), 21.3 (CH3CHCH2), 21.0 (CH3CHCH2), 19.8 (CH3CHPh), 9.7 (COCH2CH3). Trans-isomer (characterized in mixture with cis-isomer): Colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.45–7.17 (m, 5H, Ph), 3.88 (m, 2H, CHCH3), 3.55 (q, J = 6.7 Hz, 1H, CHPh), 2.72 (m, 2H, CH2CH), 2.41–2.22 (q, J = 7.5 Hz, 2H, CH3CH2CO), 2.31 (m, 2H, CH2CH), 1.43–1.29 (m, 9H, 2 CH3CH and CH3CHPh), 1.15 (t, J = 7.5 Hz, 3H, CH3CH2CO). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 175.9 (C=O), 144.3 (i-Ph), 128.4 (m-Ph), 127.5 (o-Ph), 127.0 (p-Ph), 64.3 (CHPh), 55.7 (CH2CH), 54.6 (CH2CH), 49.3 (CH2CHCH3), 27.9 (COCH2CH3), 20.2 (CH3CHCH2), 19.9 (CH3CHCH2), 19.5 (CH3CHPh), 9.7 (COCH2CH3). HRMS (ESI): m/z calcd. for [C17H27N2O]+ 275.2118, found 275.2113 [M + H]+.
Ethyl 2-(3,5-dimethyl-4-propionylpiperazin-1-yl)acetate (EtCO-1l). The compound was prepared according to the general procedure (method B3) from dioxime 2l (70 mg, 0.285 mmol). An inseparable mixture of stereoisomers. Cis:trans = 5.1:1. Yield: 50 mg (69%). Rf = 0.7 (PE–EtOAc, 1:1). Colorless oil. Cis-isomer (characterized in mixture with trans-isomer): 1H NMR (300 MHz, HSQC, CDCl3) δ 4.42–4.10 (m, 2H, CHCH3), 4.18 (q, J = 7.1 Hz, 2H, COOCH2CH3), 3.22 (s, 2H, CH2CO2Et), 2.73 (d, J = 11.1 Hz, 2H, CHCH2), 2.40–2.25 (m, 4H, CHCH2+COCH2CH3), 1.38 (d, J = 6.7 Hz, 6H, CHCH3), 1.28 (t, J = 7.1 Hz, 3H, COOCH2CH3), 1.16 (t, J = 7.4 Hz, 3H, COCH2CH3). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 172.6 (C=O), 170.2 (COOCH2CH3), 60.4 (COOCH2CH3), 59.4 (CH2COOEt), 57.6 (CH2CH), 49.0 (CHCH3), 46.4 (CHCH3), 26.2 (COCH2CH3), 20.9 (CH3CH), 19.9 (CH3CH), 14.2 (COOCH2CH3), 9.6 (COCH2CH3). Trans-isomer (characterized in mixture with trans-isomer): 1H NMR (300 MHz, HSQC, CDCl3) δ 4.18 (q, J = 7.1 Hz, 2H, COOCH2CH3), 3.96 (dtd, J = 11.6, 6.5, 3.9 Hz, 2H, CHCH3), 3.29 (d, J = 7.6 Hz, 2H, CH2CO2Et), 2.92 (dd, J = 11.5, 3.8 Hz, 2H, CHCH2), 2.57 (dd, J = 11.5, 5.0 Hz, 2H, CHCH2), 2.40–2.25 (m, 2H, COCH2CH3) 1.38 (d, J = 6.7 Hz, 6H, CHCH3), 1.28 (t, J = 7.1 Hz, 3H, COOCH2CH3), 1.16 (t, J = 7.4 Hz, 3H, COCH2CH3). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 172.6 (C=O), 170.4 (COOCH2CH3), 60.4 (COOCH2CH3), 59.3 (CH2COOEt), 56.9 (CH2CH), 49.0 (CHCH3), 27.6 (COCH2CH3), 20.9 (CH3CH), 14.2 (COOCH2CH3), 9.6 (COCH2CH3). HRMS (ESI): m/z calcd. for [C13H25N2O3]+ 257.1860, found 257.1852 [M + H]+.
1-(4-Benzyl-2,6-dimethylpiperazin-1-yl)propan-1-one (EtCO-1m). The compound was prepared according to the general procedure (method B3) from dioxime 2m (100 mg, 0.4 mmol). Obtained as a sole cis-isomer. Yield: 74 mg (71%). Rf = 0.6 (PE–EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.44–7.16 (m, 5H, Ph), 4.56 (m, 1H, CHCH3), 3.91 (qd, J = 6.4, 4.2 Hz, 1H, CHCH3), 3.50 (s, 2H, CH2Ph), 2.68 (d, J = 11.3 Hz, 2H, CH2CH), 2.35 (m, 2H, CH2CH3), 2.14 (dd, J = 11.3, 4.2 Hz, 2H, CH2CH), 1.39 (d, J = 6.4 Hz, 6H, CHCH3), 1.16 (t, J = 7.5 Hz, 3H, CH2CH3). 13C{1H} NMR (75 MHz, DEPT135, CDCl3) δ 172.6 (C=O), 138.5 (i-Ph), 128.6 (m-Ph), 128.3 (o-Ph), 127.1 (p-Ph), 62.7 (CH2Ph), 57.9 (CH2CH), 48.2 (CH3CH), 44.9 (CH3CH), 26.3 (COCH2CH3), 21.3 (CH3CH), 19.8 (CH3CH), 9.7 (CH2CH3). HRMS (ESI): m/z calcd. for [C16H25N2O]+ 261.1961, found 261.1958 [M + H]+.
Tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (1n). The compound was prepared according to the general procedure (method B1) from dioxime 2n (110 mg, 0.423 mmol). Obtained as a sole cis-isomer. Yield: 37 mg (46%). Rf = 0.4 (PE–EtOAc, 1:1). Colorless oil. 1H NMR spectrum is in agreement with previously published data [38].
(3S,5R)-1-Butyl-3,5-diphenylpiperazine (1o). The compound was prepared according to the general procedure (method B1) from dioxime 2o (90 mg, 0.296 mmol). Obtained as a sole cis-isomer. Yield: 53 mg (61%). Rf = 0.3 (PE–EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, HSQC, CDCl3) δ 7.62–7.24 (m, 10H, Ph), 4.31–4.19 (m, 2H, CH), 3.08 (dd, J = 11.3, 2.6 Hz, 2H, CHCH2), 2.59–2.45 (m, 2H, CH2CH2CH2CH3), 2.16 (t, J = 10.8 Hz, 2H, CHCH2), 1.58 (m, 2H, CH2CH2CH2CH3), 1.35 (m, 2H, CH2CH2CH2CH3), 0.93 (t, J = 7.3 Hz, 3H, CH2CH2CH2CH3) (N–H was not observed). 13C{1H} NMR (75 MHz, HSQC, DEPT135, CDCl3) δ 142.3 (p-Ph), 128.4 (m-Ph), 127.7 (i-Ph), 127.2 (o-Ph), 60.7 (CHCH2), 59.9 (CH), 58.4 (CH2CH2CH2CH3), 28.4 (CH2CH2CH2CH3), 20.7 (CH2CH2CH2CH3), 14.0 (CH2CH2CH2CH3). HRMS (ESI): m/z calcd. for [C20H27N2]+ 295.2169, found 295.2161 [M + H]+.
Tert-butyl 4-butyl-2-methylpiperazine-1-carboxylate (Boc-1p). The compound was prepared according to the general procedure (method A2) from dioxime 2p (48 mg, 0.239 mmol). Yield: 32 mg (53%). Rf = 0.75 (PE–EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 4.19 (s, 1H, CH), 3.79 (m, 1H, CH2NBoc), 3.11 (m, 1H, CH2NBoc), 2.79 (m, 1H, CH2NBu), 2.67 (m, 1H, CH2CH), 2.44-2.16 (m, 2H, CH2CH2CH2CH3), 2.09 (m, 1H, CH2CH), 1.95 (m, 1H, CH2NBu), 1.45 (s, 9H, CH3C), 1.43 (m, 2H, CH2CH2CH2CH3), 1.28–1.18 (m, 2H, CH2CH2CH2CH3), 1.14 (d, J = 6.7 Hz, 3H, CH3CH), 0.81 (t, J = 7.2 Hz, 3H, CH2CH2CH2CH3). 13C{1H} NMR (75 MHz, COSY, HSQC, DEPT135, CDCl3) δ 150.8 (C=O), 79.4 (C), 58.3 (CH2CH2CH2CH3), 57.5 (CH2CH), 53.6 (CH2NBu), 47.0 (CH), 39.0 (CH2NBoc), 28.9 (CH2CH2CH2CH3), 28.5 (CH3−C), 20.6 (CH2CH2CH2CH3), 16.1 (CH3CH), 14.0 (CH2CH2CH2CH3). HRMS (ESI): m/z calcd. for [C14H29N2O2]+ 257.2224, found 257.2218 [M + H]+.
Tert-butyl 4-butyl-2-ethylpiperazine-1-carboxylate (Boc-1q). The compound was prepared according to the general procedure (method A2) from dioxime 2q (50 mg, 0.233 mmol). Yield: 45 mg (71%). Rf = 0.75 (PE–EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 3.99 (m, 1H, CHCH2CH3), 3.91 (m, 1H, CH2NBoc), 3.11 (m, 1H, CH2NBoc), 2.83 (m, 1H, CH2NBu), 2.49–2.25 (m, 2H, CH2CH), 2.06 (m, 1H, CH2NBu), 1.94–1.78 (m, 3H, CH2CH2CH2CH3 + CHCH2CH3), 1.78–1.62 (m, 3H, CH2CH2CH2CH3 and CHCH2CH3), 1.46 (s, 9H, CH3−C), 1.35 (m, 2H, CH2CH2CH2CH3), 0.94 (t, J = 7.3 Hz, 3H, CH2CH2CH2CH3), 0.88 (t, J = 7.3 Hz, 3H, CHCH2CH3). 13C{1H} NMR (75 MHz, COSY, HSQC, DEPT135, CDCl3) δ 155.4 (C=O), 79.5 (C), 58.3 (CH2CH2CH2CH3), 55.0 (CH2CH), 53.6 (CH2NBu), 52.6 (CHCH2CH3), 39.0 (CH2NBoc), 28.4 (CH3−C), 23.0 (CH2CH2CH2CH3), 22.1 (CHCH2CH3), 20.5 (CH2CH2CH2CH3), 14.0 (CH2CH2CH2CH3), 10.8 (CHCH2CH3). HRMS (ESI): m/z calcd. for [C15H31N2O2]+ 271.2380, found 271.2372 [M + H]+.
Tert-butyl 2-benzyl-4-butylpiperazine-1-carboxylate (Boc-1r). The compound was prepared according to the general procedure (method A2) from dioxime 2r (60 mg, 0.217 mmol). Yield: 54 mg (75%). Rf = 0.8 (PE–EtOAc, 1:1). Colorless oil. 1H NMR (300 MHz, COSY, HSQC, CDCl3) δ 7.45–7.16 (m, 5H, Ph), 4.21 (m, 1H, CH), 4.02–3.89 (m, 1H, CH2NBoc), 3.22 (td, J = 12.9, 3.4 Hz, 1H, CH2NBoc), 3.10 (dd, J = 13.0, 9.1 Hz, 1H, CH2Ph), 2.88 (dd, J = 13.0, 6.9 Hz, 1H, CH2Ph), 2.85 (m, 1H, CH2NBu), 2.71 (d, J = 11.5 Hz, 1H, CH2CH), 2.37 (m, 1H, CH2CH2CH2CH3), 2.22 (m, 1H, CH2CH2CH2CH3), 2.02 (dt, J = 12.5, 6.2 Hz, 1H, CH2NBu), 1.95–1.90 (m, 1H, CH2CH), 1.51–1.43 (m, 4H, CH2CH2CH2CH3 + CH2CH2CH2CH3), 1.41 (s, 9H, CH3−C), 0.95 (t, J = 7.1 Hz, 3H, CH2CH2CH2CH3). 13C{1H} NMR (75 MHz, COSY, HSQC, DEPT135, CDCl3) δ 154.7 (C=O), 139.5 (i-Ph), 129.5 (m-Ph), 128.4 (o-Ph), 126.1 (p-Ph), 79.5 (C), 58.3 (CH2CH2CH2CH3), 54.0 (CH2CH), 53.6 (CH2NBu), 53.5 (CH), 39.3 (CH2NBoc), 36.2 (CH2Ph), 28.9 (CH2CH2CH2CH3), 28.4 (CH3−C), 20.6 (CH2CH2CH2CH3), 14.0 (CH2CH2CH2CH3). HRMS (ESI): m/z calcd. for [C20H33N2O2]+ 333.2537, found 333.2528 [M + H]+.
Hexahydropyrrolo [1,2-a]pyrazin-6(2H)-one (5). A 5%-Pd/C catalyst (50 mg) was added to a solution of dioxime 2s (50 mg, 0.163 mmol) in methanol (2 mL). The vial was placed in a steel autoclave which was flushed and filled with hydrogen to a pressure of ca. 40 bar. Hydrogenation was conducted at this pressure and 50 °C for 5 h with vigorous stirring. Then, the autoclave was cooled to rt and slowly depressurized, the catalyst was filtered off, and the solution was concentrated under reduced pressure. The residue was dissolved in toluene (2.5 mL). Et3N (0.25 mL, 1.8 mmol) was added to the solution and left at 90 °C for 2.5 h with vigorous stirring. The residue was subjected to column chromatography on silica gel (eluent EtOAc:MeOH = 5:1 → 3:1 → 2:1 → 1:1) to give 11 mg (48%) of product 5 as a colorless oil. Rf = 0.3 (EtOAc–MeOH, 3:1). 1H NMR spectrum is in agreement with previously published data [41].
4. Conclusions
In conclusion, a general approach to the synthesis of piperazines bearing substituents at carbon and nitrogen atoms was developed utilizing primary amines and nitrosoalkenes as synthons. The method relies on the sequential double Michael addition of nitrosoalkenes to amines to give bis(oximinoalkyl)amines followed by catalytic reductive cyclization of oxime groups. The reductive cyclization of diketooximes is stereoselective and results in cis-isomers of 2,6-disubstituted piperazines. Importantly, the method developed in this work allows straightforward structural modification of bioactive molecules (e.g., α-amino acids) by the conversion of a primary amino group into the piperazine ring. Also, the method is appropriate in the preparation of complex pharmaceutically relevant piperazine-based scaffolds, such as 1,4-diazabicyclo[4.3.0]nonanes.
E.V.P. performed all the experiments and prepared the supporting information; A.Y.S. designed the work and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
The data presented in this study are available in
The authors declare no conflict of interest.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
![View Image - Scheme 1. Background of this study and the current work [24,25].](https://media.proquest.com/media/hms/THUM/2/4n2YT?_a=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%2BgIBWYIDA1dlYooDHENJRDoyMDI2MDEyMDIzMjcyNDg3MTo0MDU3NTE%3D&_s=jtRUumoXPYv9Iw404zE4a29eqeM%3D "View Image - Scheme 1. Background of this study and the current work [24,25].")
Scheme 2. Assembly of C-unsubstituted and 2,6-disubstituted piperazines 1 from primary amines via double oximinoalkylation followed by reductive cyclization of dioximes 2. For 2,6-disubstituted piperazines (1i−o series), the structure of the major diastereomer is shown. The yields and diastereomeric ratios (d.r.) refer to the isolated products. Ene-nitrosoacetals 3: 3a (R1 = H), 3b (R1 = Me), 3c (R1 = Ph).
Scheme 3. Assembly of 2-substituted piperazines 1 (a) and fused piperazine derivative 5 (b) from primary amines via sequential double oximinoalkylation and reductive cyclization. Ene-nitrosoacetals 3: 3a (R1 = H), 3b (R1 = Me), 3d (R1 = Et), 3e (R1 = CH2Ph), 3f (R1 = CH2CH2CO2Me).
Supplementary Materials
The supporting information can be downloaded at:
References
1. Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem.; 2014; 57, pp. 10257-10274. [DOI: https://dx.doi.org/10.1021/jm501100b]
2. Rathi, A.K.; Syed, R.; Shin, H.-S.; Patel, R.V. Piperazine derivatives for therapeutic use: A patent review (2010-present). Expert Opin. Ther. Pat.; 2016; 26, pp. 777-797. [DOI: https://dx.doi.org/10.1080/13543776.2016.1189902] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27177234]
3. Shaquiquzzaman, M.; Verma, G.; Marella, A.; Akhter, M.; Akhtar, W.; Khan, M.F.; Tasneem, S.; Alam, M.M. Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents. Eur. J. Med. Chem.; 2015; 102, pp. 487-529. [DOI: https://dx.doi.org/10.1016/j.ejmech.2015.07.026] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26310894]
4. Zhang, W.; Guo, S.; Yu, L.; Wang, Y.; Chi, Y.R.; Wu, J. Piperazine: Its role in the discovery of pesticides. Chin. Chem. Lett.; 2023; 34, 108123. [DOI: https://dx.doi.org/10.1016/j.cclet.2022.108123]
5. Kant, R.; Maji, S. Recent advances in the synthesis of piperazine based ligands and metal complexes and their applications. Dalton Trans.; 2021; 50, pp. 785-800. [DOI: https://dx.doi.org/10.1039/D0DT03569F]
6. Park, D.J.; Choi, J.H.; Kim, Y.E.; Nam, S.C.; Lee, K.B.; Yoon, Y.I. Chemical Absorption of Carbon Dioxide Using Aqueous Piperidine Derivatives. Chem. Eng. Technol.; 2017; 40, pp. 2266-2273. [DOI: https://dx.doi.org/10.1002/ceat.201700375]
7. Guo, W.; Fu, X.; Chen, J. Supramolecular adducts of mesocyclic diamines with various carboxylic acids: Charge-assisted hydrogen-bonding in molecular recognition. J. Saudi Chem. Soc.; 2020; 24, pp. 885-895. [DOI: https://dx.doi.org/10.1016/j.jscs.2020.09.005]
8. Lesnikov, V.K.; Nelyubina, Y.V.; Sukhorukov, A.Y. Piperazine-1,4-diol (PipzDiol): Synthesis, stereodynamics and assembly of supramolecular hydrogen-bonded 2D networks. New J. Chem.; 2022; 46, pp. 20386-20394. [DOI: https://dx.doi.org/10.1039/D2NJ03012H]
9. Zhang, M.; Wang, Y.; Zeng, G.; Yang, S.; Liao, X.; Sun, D. Antibacterial activity and mechanism of piperazine polymer. J. Appl. Polym. Sci.; 2021; 138, 50451. [DOI: https://dx.doi.org/10.1002/app.50451]
10. Jalageri, M.D.; Nagaraja, A.; Puttaiahgowda, Y.M. Piperazine based antimicrobial polymers: A review. RSC Adv.; 2021; 11, pp. 15213-15230. [DOI: https://dx.doi.org/10.1039/D1RA00341K]
11. Gettys, K.E.; Ye, Z.; Dai, M. Recent Advances in Piperazine Synthesis. Synthesis; 2017; 49, pp. 2589-2604. [DOI: https://dx.doi.org/10.1055/s-0036-1589491]
12. Magriotis, P.A. Recent progress toward the asymmetric synthesis of carbon-substituted piperazine pharmacophores and oxidative related heterocycles. RSC Med. Chem.; 2020; 11, pp. 745-759. [DOI: https://dx.doi.org/10.1039/D0MD00053A]
13. Nishiyama, M.; Yamamoto, T.; Koie, Y. Synthesis of N-arylpiperazines from aryl halides and piperazine under a palladium tri-tert-butylphosphine catalyst. Tetrahedron Lett.; 1998; 39, pp. 617-620. [DOI: https://dx.doi.org/10.1016/S0040-4039(97)10659-1]
14. Thamban Chandrika, N.; Shrestha, S.K.; Ngo, H.X.; Tsodikov, O.V.; Howard, K.C.; Garneau-Tsodikova, S. Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents. J. Med. Chem.; 2018; 61, pp. 158-173. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.7b01138] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29256601]
15. Liu, J.; Fitzgerald, A.E.; Mani, N.S. Reductive Amination by Continuous-Flow Hydrogenation: Direct and Scalable Synthesis of a Benzylpiperazine. Synthesis; 2012; 44, pp. 2469-2473. [DOI: https://dx.doi.org/10.1055/s-0032-1316550]
16. Srinivas, V.; Mohan, C.D.; Baburajeev, C.P.; Rangappa, S.; Jagadish, S.; Fuchs, J.E.; Sukhorukov, A.Y.; Chandra,; Mason, D.J.; Sharath Kumar, K.S. et al. Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2. Bioorg. Med. Chem. Lett.; 2015; 25, pp. 2931-2936. [DOI: https://dx.doi.org/10.1016/j.bmcl.2015.05.047]
17. Durand, C.; Szostak, M. Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization. Organics; 2021; 2, pp. 337-347. [DOI: https://dx.doi.org/10.3390/org2040018]
18. Firth, J.D.; O’Brien, P.; Ferris, L. Synthesis of Enantiopure Piperazines via Asymmetric Lithiation–Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent. J. Am. Chem. Soc.; 2016; 138, pp. 651-659. [DOI: https://dx.doi.org/10.1021/jacs.5b11288] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26683825]
19. Huang, W.-X.; Liu, L.-J.; Wu, B.; Feng, G.-S.; Wang, B.; Zhou, Y.-G. Synthesis of Chiral Piperazines via Hydrogenation of Pyrazines Activated by Alkyl Halides. Org. Lett.; 2016; 18, pp. 3082-3085. [DOI: https://dx.doi.org/10.1021/acs.orglett.6b01190] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27295391]
20. Trinchera, P.; Musio, B.; Degennaro, L.; Moliterni, A.; Falcicchio, A.; Luisi, R. One-pot preparation of piperazines by regioselective ring-opening of non-activated arylaziridines. Org. Biomol. Chem.; 2012; 10, pp. 1962-1965. [DOI: https://dx.doi.org/10.1039/c2ob07099e]
21. Halimehjani, A.Z.; Badali, E. DABCO bond cleavage for the synthesis of piperazine derivatives. RSC Adv.; 2019; 9, pp. 36386-36409. [DOI: https://dx.doi.org/10.1039/C9RA07870C] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35540608]
22. Ruider, S.A.; Müller, S.; Carreira, E.M. Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles. Angew. Chem. Int. Ed.; 2013; 52, pp. 11908-11911. [DOI: https://dx.doi.org/10.1002/anie.201306563] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24115402]
23. Zhang, R.-H.; Guo, H.-Y.; Deng, H.; Li, J.; Quan, Z.-S. Piperazine skeleton in the structural modification of natural products: A review. J. Enzym. Inhib. Med. Chem.; 2021; 36, pp. 1165-1197. [DOI: https://dx.doi.org/10.1080/14756366.2021.1931861] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34080510]
24. Tsuji, Y.; Huh, K.T.; Ohsugi, Y.; Watanabe, Y. Ruthenium complex catalyzed N-heterocyclization. Syntheses of N-substituted piperidines, morpholines, and piperazines from amines and 1,5-diols. J. Org. Chem.; 1985; 50, pp. 1365-1370. [DOI: https://dx.doi.org/10.1021/jo00209a004]
25. Huang, J.; Xu, W.; Xie, H.; Li, S. One-Step Cyclization: Synthesis of N-Heteroalkyl-N′-tosylpiperazines. J. Org. Chem.; 2012; 77, pp. 7506-7511. [DOI: https://dx.doi.org/10.1021/jo3012896]
26. Pospelov, E.V.; Boyko, Y.D.; Ioffe, S.L.; Sukhorukov, A.Y. Synthesis of Bis(β-Oximinoalkyl)malonates and Their Catalytic Reductive Cyclization to Piperidines. Adv. Synth. Catal.; 2022; 364, pp. 2557-2564. [DOI: https://dx.doi.org/10.1002/adsc.202200424]
27. Boyko, Y.D.; Dorokhov, V.S.; Sukhorukov, A.Y.; Ioffe, S.L. Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: A review and perspective. Beilstein J. Org. Chem.; 2017; 13, pp. 2214-2234. [DOI: https://dx.doi.org/10.3762/bjoc.13.220]
28. Lopes, S.M.M.; Cardoso, A.L.; Lemos, A.; Pinho e Melo, T.M.V.D. Recent Advances in the Chemistry of Conjugated Nitrosoalkenes and Azoalkenes. Chem. Rev.; 2018; 118, pp. 11324-11352. [DOI: https://dx.doi.org/10.1021/acs.chemrev.8b00375]
29. Gilchrist, T. Nitroso-alkenes and Nitroso-alkynes. Chem. Soc. Rev.; 1983; 12, pp. 53-73. [DOI: https://dx.doi.org/10.1039/cs9831200053]
30. Naumovich, Y.A.; Ioffe, S.L.; Sukhorukov, A.Y. Michael Addition of P-Nucleophiles to Conjugated Nitrosoalkenes. J. Org. Chem.; 2019; 84, pp. 7244-7254. [DOI: https://dx.doi.org/10.1021/acs.joc.9b00924]
31. Feger, H.; Simchen, G. Reaktionen der Trialkylsilyl-trifluormethansulfonate, V. Synthese und Reaktionen von N,N-Bis(trialkylsiloxy)-1-alken-1-aminen. Liebigs Ann. Chem.; 1986; 1986, pp. 1456-1465. [DOI: https://dx.doi.org/10.1002/jlac.198619860817]
32. Semakin, A.N.; Sukhorukov, A.Y.; Lesiv, A.V.; Khomutova, Y.A.; Ioffe, S.L.; Lyssenko, K.A. A Convenient Method for the Synthesis of Poly(β-hydroxyiminoalkyl)amines from Aliphatic Nitro Compounds. Synthesis; 2007; 2007, pp. 2862-2866. [DOI: https://dx.doi.org/10.1002/chin.200808058]
33. Semakin, A.N.; Sukhorukov, A.Y.; Ioffe, S.L.; Tartakovsky, V.A. A General Procedure for the Synthesis of Unsymmetrically Substituted Tris(β-oximinoalkyl)amines. Synthesis; 2011; 2011, pp. 1403-1412.
34. Makarenkova, L.M.; Bliznets, I.V.; Ioffe, S.L.; Strelenko, Y.A.; Tartakovsky, V.A. The chemistry of N,N-bis (trialkylsilyloxy) enamines. 2. Alkylation of primary amines with N,N-bis(trimethylsilyloxy) enamines. Russ. Chem. Bull.; 2000; 49, pp. 1261-1269. [DOI: https://dx.doi.org/10.1007/BF02495772]
35. Fraser, R.R.; Bresse, M. The effect of stereochemistry on 1JC—H at the sp2 carbons of oxime, hydrazone, and imine derivatives of aldehydes. Can. J. Chem.; 1983; 61, pp. 576-578. [DOI: https://dx.doi.org/10.1139/v83-102]
36. Redina, E.A.; Ivanova, I.I.; Arkhipova, N.Y.; Kustov, L.M. Heterogeneous Catalysis as an Efficient Tool for Selective Hydrogenation of Oximes to Amines and Hydroxylamines. Catalysts; 2022; 12, 1614. [DOI: https://dx.doi.org/10.3390/catal12121614]
37. Nagaraj, M.; Boominathan, M.; Muthusubramanian, S.; Bhuvanesh, N. Synthesis of novel N-hydroxy heterocycles via intramolecular reductive cyclization of diketoximes by NaBH3CN. Org. Biomol. Chem.; 2011; 9, pp. 4642-4652. [DOI: https://dx.doi.org/10.1039/c1ob05232b]
38. Johnson, J.K.; Skoda, E.M.; Zhou, J.; Parrinello, E.; Wang, D.; O’Malley, K.; Eyer, B.R.; Kazancioglu, M.; Eisermann, K.; Johnston, P.A. et al. Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer. ACS Med. Chem. Lett.; 2016; 7, pp. 785-790. [DOI: https://dx.doi.org/10.1021/acsmedchemlett.6b00186]
39. Di Fabio, R.; Alvaro, G.; Braggio, S.; Carletti, R.; Gerrard, P.A.; Griffante, C.; Marchioro, C.; Pozzan, A.; Melotto, S.; Poffe, A. et al. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg. Med. Chem.; 2013; 21, pp. 6264-6273. [DOI: https://dx.doi.org/10.1016/j.bmc.2013.09.001]
40. Atkinson, B.N.; Steadman, D.; Mahy, W.; Zhao, Y.; Sipthorp, J.; Bayle, E.D.; Svensson, F.; Papageorgiou, G.; Jeganathan, F.; Frew, S. et al. Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors. Bioorg. Med. Chem. Lett.; 2020; 30, 126751. [DOI: https://dx.doi.org/10.1016/j.bmcl.2019.126751]
41. Manetti, D.; Ghelardini, C.; Bartolini, A.; Bellucci, C.; Dei, S.; Galeotti, N.; Gualtieri, F.; Romanelli, M.N.; Scapecchi, S.; Teodori, E. Design, Synthesis, and Preliminary Pharmacological Evaluation of 1,4-Diazabicyclo[4.3.0]nonan-9-ones as a New Class of Highly Potent Nootropic Agents. J. Med. Chem.; 2000; 43, pp. 1969-1974. [DOI: https://dx.doi.org/10.1021/jm991170t] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10821709]
42. Scapecchi, S.; Martini, E.; Manetti, D.; Ghelardini, C.; Martelli, C.; Dei, S.; Galeotti, N.; Guandalini, L.; Novella Romanelli, M.; Teodori, E. Structure–activity relationship studies on unifiram (DM232) and sunifiram (DM235), two novel and potent cognition enhancing drugs. Bioorg. Med. Chem.; 2004; 12, pp. 71-85. [DOI: https://dx.doi.org/10.1016/j.bmc.2003.10.025]
43. Chandrika, N.T.; Shrestha, S.K.; Ngo, H.X.; Garneau-Tsodikova, S. Synthesis and investigation of novel benzimidazole derivatives as antifungal agents. Bioorg. Med. Chem.; 2016; 24, pp. 3680-3686. [DOI: https://dx.doi.org/10.1016/j.bmc.2016.06.010]
44. Arutla, V.; Leal, J.; Liu, X.; Sokalingam, S.; Raleigh, M.; Adaralegbe, A.; Liu, L.; Pentel, P.R.; Hecht, S.M.; Chang, Y. Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo. ACS Comb. Sci.; 2017; 19, pp. 286-298. [DOI: https://dx.doi.org/10.1021/acscombsci.6b00179]
45. Dilman, A.D.; Tishkov, A.A.; Lyapkalo, I.M.; Ioffe, S.L.; Strelenko, Y.A.; Tartakovsky, V.A. Novel Convenient Method for the Synthesis of N,N-Bis(trimethylsilyloxy)enamines. Synthesis; 1998; 1998, pp. 181-185. [DOI: https://dx.doi.org/10.1055/s-1998-2019]
46. Dilman, A.D.; Ioffe, S.L.; Mayr, H. Determination of the Nucleophilicities of N,N-Bis(silyloxy)enamines. J. Org. Chem.; 2001; 66, pp. 3196-3200. [DOI: https://dx.doi.org/10.1021/jo0015927] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11325288]
47. Sukhorokov, A.Y.; Bliznets, I.V.; Lesiv, A.V.; Khomutova, Y.A.; Strelenko, Y.A.; Ioffe, S.L. The Chemistry of N,N-Bis(siloxy)enamines. Part 8. A General Method for the Preparation of α-Azido Oximes from Aliphatic Nitro Compounds. Synthesis; 2005; 2005, pp. 1077-1082. [DOI: https://dx.doi.org/10.1002/chin.200541057]
48. Dilman, A.D.; Tishkov, A.A.; Lyapkalo, I.M.; Ioffe, S.L.; Kachala, V.V.; Strelenko, Y.A.; Tartakovsky, V.A. Synthesis of N,N-bis(silyloxy)enamines with a functionalized double bond. J. Chem. Soc. Perkin Trans. 1; 2000; pp. 2926-2929. [DOI: https://dx.doi.org/10.1039/b004268o]
49. Walton, M.C.; Yang, Y.-F.; Hong, X.; Houk, K.N.; Overman, L.E. Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile. Org. Lett.; 2015; 17, pp. 6166-6169. [DOI: https://dx.doi.org/10.1021/acs.orglett.5b03171] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26605985]
50. Biancalana, L.; Bortoluzzi, M.; Ferretti, E.; Hayatifar, M.; Marchetti, F.; Pampaloni, G.; Zacchini, S. The reactions of α-amino acids and α-amino acid esters with high valent transition metal halides: Synthesis of coordination complexes, activation processes and stabilization of α-ammonium acylchloride cations. RSC Adv.; 2017; 7, pp. 10158-10174. [DOI: https://dx.doi.org/10.1039/C7RA00073A]
51. Toma, L.; Cignarella, G.; Barlocco, D.; Ronchetti, F. Molecular mechanics and 1H NMR conformational study of 3,8-diazabicyclo[3,2,1] octanes and related cis-2,6-dimethylpiperazines active on opioid receptors. Tetrahedron; 1992; 48, pp. 159-166. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)80588-3]
52. Crosignani, S.; Gonzalez, J.; Swinnen, D. Polymer-Supported Mukaiyama Reagent: A Useful Coupling Reagent for the Synthesis of Esters and Amides. Org. Lett.; 2004; 6, pp. 4579-4582. [DOI: https://dx.doi.org/10.1021/ol0480372] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15548080]
53. Wang, T.; Kadow, J.F.; Zhang, Z.; Yin, Z.; Gao, Q.; Wu, D.; Parker, D.D.; Yang, Z.; Zadjura, L.; Robinson, B.A. et al. Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives. Bioorg. Med. Chem. Lett.; 2009; 19, pp. 5140-5145. [DOI: https://dx.doi.org/10.1016/j.bmcl.2009.07.076] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19664921]
54. Wodtke, R.; Steinberg, J.; Köckerling, M.; Löser, R.; Mamat, C. NMR-based investigations of acyl-functionalized piperazines concerning their conformational behavior in solution. RSC Adv.; 2018; 8, pp. 40921-40933. [DOI: https://dx.doi.org/10.1039/C8RA09152H] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35557922]
55. Maurer, A.; Hoevelmann, S.; Martin, E.; Hentsch, B.; Gassen, M.; Kraus, J.; Krauss, R.; Vincek, A.-S. Novel compounds as histone deacetylase inhibitors. U.S. Patent; 10/624,571, 11 August 2005; (4SC AG and G2M Cancer Drugs AG)
56. Hesse, M.; Meier, H.; Zeeh, B. Spektroskopische Methoden in der Organischen Chemie; Georg Thieme Verlag: Stuttgart, Germany, New York, NY, USA, 2005; 200.
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.