Stituted in the 1-Position by an Electron Withdrawing Group

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Current Organic Synthesis, 2014, 11, 00-00 1 A Simplified Protocol for Routine Chemoselective Syntheses of Piperazines Sub- stituted in the 1-Position by an Electron Withdrawing Group

Dana Nmeková-Herová and Pavel Pazdera*

1Centre for syntheses at sustainable conditions and their management, Chemistry Department, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic

Abstract: We report a simplified protocol for the routine direct chemoselective preparation of various piperazines substituted in the 1- position by an electron withdrawing group. These syntheses are based on the reaction of piperazine-1-ium cation with different electrophilic reagents such as acyl chlorides, anhydrides, sulfonyl chlorides, carbamoyl chlorides, and nitrourea as well. Piperazine-1-ium cation was chosen because the reactions of piperazine with electrophilic reagents in different solvents at usual temperatures are not chemoselective and provide mixtures comprising 1-substituted, 1,4-disubstituted and unsubstituted piperazine as well. Simultaneously, the mono- protonation of piperazine is the simplest synthetic method for its protection/deprotection in comparison with the currently used mono- benzylation, mono-Boc-protection, etc. Computer modeling of acid-base equilibria for piperazine and model 1-acetylpiperazine was used as the basis for the prediction of reaction conditions suitable for the synthesis. It was found that for in situ generating of starting piperazine-1-ium cation from piperazine the application of acetic acid as reaction medium or the chemisorption of piperazine on weakly acidic cation-exchanger resin were highly acceptable in terms of both reaction times and yields. The using of resin supported piperazine- 1-ium cation in reaction with carboxylic anhydrides or nitrourea is an example of the solid phase synthesis with ionically bonded substrate. Furthermore, syntheses in acetic acid medium were effectively catalyzed by Cu+, Cu2+ or Al3+ ions supported on weakly acidic cation-exchanger resin as well. Finally, it was observed that application of the solid support metal catalysis afforded target products in shortened reaction times and in 82-95% yields.

Keywords: 1-monosubstituted piperazine, ionically-bound substrate, metal catalysis, piperazine, piperazine-1-ium cation, resin supported metal ion, solid phase synthesis.

INTRODUCTION Piperazine structural motive appears in chemical structure of a Piperazine and piperazine structural motives are connected with lot of pharmaceuticals or in chemical structure of potential pharma- many of medicinal drugs. Piperazine is a potent anthelmintic used ceuticals from group of substituted disulfonamides. These pharma- in the therapy of ascariasis (roundworm) and oxyuriasis (thread- ceuticals are widely used for pain moderation or for suppressing of worm) infestations. The piperazines were originally named because pain, which is evoked from bradykinin receptors 1 [4]. Structural of their chemical similarity with piperidine, a constituent of piper- motive of piperazine also appears in chemical structure of CXC- chemokine receptor ligands and in chemical structure of 3,4- ine in the black pepper plant. Piperazine owes its anthelmintic activity to its ability to induce flaccid paralysis of the muscles of the disubstituted cyclobuten-1,2-diones [5]. These pharmaceuticals are parasite [1]. Piperazines were reported in gene transfer reactions as used for treatment of prophylaxis or for treatment of various dis- well [2] and quaternary piperazinium salts showed spasmolytic, eases evoked by abnormal TNF- production and diseases treatable anthelmintic and germicidal activity. Some piperazine derivatives by IL-10 such as acute and chronic inflammatory diseases, allergic possess high biological activity for multidrug resistance in cancer and autoimmune diseases [6]. Other type of drugs containing struc- and malaria treatment [3]. tural motive of piperazine are 2,3-dihydro-3-[4-(substituted)piperazinyl]-1H-isoindol-1-ones which are used for treatment of hyper- Piperazines are a broad class of chemicals which are included in tension [7], further CCR5 antagonists, which are used for treatment several stimulants (1-benzylpiperazine - BZP, 3-trifluoromethyl- of HIV-1 [8] and hybrid and isosteric analogues of 1-acetyl-4- phenylpiperazine monohydrochloride - TFMPP, etc.) as well as in dimethylpiperazinium iodide (ADMP) and 1-fenyl-4-dimethyl- anti-vertigo agents (1-diphenylmethyl-4-methylpiperazine - Cycliz- piperazinium iodide (DMPP). These pharmaceuticals are effective ine, 1-(m-chloro-alpha-phenylbenzyl)-4-(m-methylbenzyl)-pipera- for central nicotinic acetylcholine receptors (nAChRs), which play zine dihydrochloride monohydrate - Meclizine). Commonly known main role in neurodegenerative diseases, for example Parkinson and Sildenafil citrate, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3- Alzheimer disease [9]. propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)phenylsulfonyl]-4-methylpiperazine sold as Viagra, Revatio and under various other trade Structural motive of 1-(pyrid-4-yl)piperazine also appears in μ- opioid receptors (MOR) antagonists [10], in indole compositions for names, is the first drug used to treat erectile dysfunction and pul- monary arterial hypertension (PAH). Analogous to Sildenafil, the treatment of nephritis [11], in piperazine structural compositions which are used for dissolving of blood clots during heart or brain drug Vardenafil, 4-[2-ethoxy-5-(4-ethylpiperazine-1-yl)sulfonyl- phenyl]-9-methyl-7-propyl-3,5,6,8-tetraza-bicyclo[4.3.0]nona-3,7,9- strokes [12] and in 4-arylpiperazines with positive allosteric modu- lation of metabotropic glutamate receptors 5 (mGluR5) which are trien-2-one, is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxin. used for treatment of schizophrenic patients [13]. An introduction of a piperazine structural motive into the drug molecule is usually realized via the 1-monosubstituted piperazine. *Address correspondence to this author at the Centre for syntheses at sustainable conditions and their management, Chemistry Department, Masaryk University, Preparation of these 1-monosubstituted piperazine derivatives is Kamenice 5, Brno, 625 00, Czech Republic; Tel: +420 608 209 346; in general very complicated by formation of symmetrical 1,4-disub- E-mails: [email protected], and [email protected]

O E H H O N N N N O + E H2O + + O N+ N N pH = 3 HN Cl HH HH H Scheme 1. Direct introduction of methoxycarbonyl functional group on Scheme 2. General preparation of various 1-monosubstituted piperazines by piperazine in acidified water. direct method based on the reaction of piperazine-1-ium cation with electrophilic agents. stituted piperazines while a part of piperazine remains unreacted in tion into fundamental as well as practical pharmaceutical research the reaction mixture. For this reason, synthetic process, where one and development. The new simplified protocol for the routine direct nitrogen atom is protected [14] (mainly by Boc, alkoxycarbonyl, chemoselective preparation of these and similar piperazine deriva- acyl or benzyl groups), are used for the preparation of 1-mono- tives could help detect this problem. substituted piperazine derivatives. Desired substituent is bound on the other nitrogen atom and deprotection of an intermediary product RESULTS AND DISCUSSION follows. The introduction of protecting groups usually does not give satisfactory yields. Those 1-monosubstituted piperazines are very We decided to prepare various 1-EWG-monosubstituted precious building blocks because they are not included in the port- piperazines by direct method based on the reaction of piperazine-1- folio of all chemical suppliers. For example 4-(methoxycarbonyl) ium cation, because protonation of amines is the simplest method of piperazine-1-ium chloride sells for 208 USD/g (Santa Cruz Bio- their protection and subsequent deprotection as well. Electrophilic technology, Inc., USA) or 4-(N,N-diethylkarbamoyl)piperazine-1- agents for 1-monosubstitution reaction on piperazine-1-ium were ium chloride sells for 114 USD/250 mg (Enamine Ltd., Ukraine). chosen either from the family of acyl and similar reagents such as From the literature some direct 1-monosubstitution reaction of acyl chlorides, anhydrides, sulfonyl chlorides, carbamoyl chlorides or nitrourea was used (Scheme 2). piperazine are known, for example direct introduction of methoxycarbonyl functional group on piperazine in water at pH = 3 (Scheme Furthermore, the clue of our solution was based on the premiss 1) in very poor yield about 30 % [15]. Main problems of these syn- that nucleophilicity of piperazine is greater than the nucleophilicity theses are their low yields generally and very frequent use of envi- of the monosubstituted piperazine if the correlation between the ronmentally inappropriate chlorinated solvents (e.g. 1-Boc- basicity and nucleophilicity [16] for unsubstituted and monosubsti- piperazine prepared in dichloromethane, price 100 USD/5 g (VWR tuted piperazine is applied. Comparison of acid-base constants,

International, LLC)). expressed as pKA/pKB values [17], for piperazine, 1-acetylpipera- Finally, piperazines substituted in the 1-position by a broad zine, and 1-(4-toluensulfonyl)piperazine is demonstrated in (Table 1). spectrum of electron withdrawing groups (EWGs) could be very (Fig. 1) shows a distribution of piperazine-1,4-diium, interesting building blocks for development of novel drugs. How- piperazine-1-ium cations and piperazine, respectively, in the de- ever, their poor accessibility and high price prevents their introduc- pendence on pH values in water solution. Distribution diagram

Table 1. Comparison of acid-base constants of piperazine, 1-acetylpiperazine, and 1-(4-toluensulfonyl)piperazine.

pKA1 pKA2 pKB1 pKB2

Piperazine 5.68 9.82 4.18 8.32

1-Acetyl 7.94 - 6.06 -

1-(4-Toluensulfonyl) 7.39 - 6.61 -

Fig. (1). Distribution of piperazine-1,4-diium, piperazine-1-ium cations and piperazine in the dependence on pH value in water solution.

Direct Preparation of 1-EWG-Substituted Piperazines Current Organic Synthesis, 2014, Vol. 11, No. 6 3

Fig. (2). Distribution of 1-acetylpiperazine and 1-acetylpiperazine-1-ium cation in the dependence on pH value in water solution.

Table 2. Reaction of piperazine-1-ium cation with electrophilic reagents.

Compound R Catalyst Precipitating Solvent Temperature [°C] Reaction Time [h] Yield

1 CH3O- - Ethyl acetate room 8 71

Cu2+ Ethyl acetate room 2 95

2 CH3- - Ethyl acetate room 7 70

Cu2+ Ethyl acetate room 2 82

3 C6H5- - Acetone room 9 73

Cu2+ Acetone room 2 83

4 (CH3CH2)2N- - Acetone room 24 33

Cu2+ Acetone room 2.5 85

3+ 5 CH3(CH2)10- Al Ethyl acetate 30 3 89 show that piperazines co-exist mostly in monoprotonated form in By methods mentioned above we prepared a set of 1- relatively broad interval of pH values in a weak acidic area. This is monosubstituted piperazine derivatives under mild conditions an area of pH values that is characteristic for dissociation equilib- and in very good yields, see (Scheme 3, Table 2) and (Scheme 4, rium of lower carboxylic acids. Therefore, we decided to use acetic Table 3). acid as the ideal reaction medium. CH3COO~ The presence of an acyl group as an electron withdrawing group H H in 1-acylpiperazine molecule causes a decrease in the basicity of the N+ O second nitrogen atom N4 (see Table 1 and Fig. 2), and thus de- RCOCl H N+ N crease its nucleophilicity. Although the decrease in ba- H Cl- R sicity/nucleophilicity by action of present acyl, sulfonyl and similar N electron withdrawing group is not as significant as the effect of H piperazine mono-protonation, is sufficient for protection N4 in 1- Scheme 3. General reaction of piperazine-1-ium cation with electrophilic acylpiperazine molecule against entry of further electrophilic rea- reagents in acetic acid possibly catalyzed by supported metal. gent. Thus, it was found that protonation as an act of the protection of 1-substituted piperazines of this type against subsequent reaction R1 with electrophilic agents is not necessary. CH3COO~ O SO On the other hand, we assumed that nucleophilicity of pipera- H H zine-1-ium cation in comparison with non-protonated piperazine + N N 1 will be lower as well because of lower basicity (Table 1). R SO2Cl

Due to this reason we improved activation of used electrophilic N+ agents by metal ion catalysis, i. e. metal ions supported on indus- N Cl- H trial weakly acidic cation-exchange resins, concretely. Supported HH 2+ + 3+ Cu , Cu and Al were applied for this reason as the most effec- Scheme 4. General reaction of piperazine-1-ium cation with sulfonyl chlo- tive catalyst [18]. rides in acetic acid catalyzed by supported Cu+.

4 Current Organic Synthesis, 2014, Vol. 11, No. 6 Nmeková-Herová and Pazdera

Table 3. Reaction of piperazine-1-ium cation with electrophilic reagents.

Compound R1 Catalyst Precipitating Solvent Temperature [°C] Reaction Time [h] Yield

+ 6 CH3- Cu Acetone room 2 93

+ 7 C6H5- Cu Acetone room 2 95

Furthermore, we investigate the possibility to prepare lin (Franklin, MA, USA). 2,5-Dihydroxybenzoic acid (DHB) matri- piperazine-1-ium cation as ionically supported on a suitable acidic ces were tried for MALDI TOF measurement. Red phosphorus was cation-exchanger resin and to realize a 1-piperazine monosubstitu- used for external calibration [19]. The fraction diagrams of all three tion as a solid phase synthesis with ionically-bound substrate. The forms of piperazine and both forms of 1-acetylpiperazine in de- use of strongly acidic cation exchange resin (sulfonated styrene- pendence on pH were calculated using Hydra/Medusa Chemical divinyl benzene) was found to be unsuitable because of its high Equilibrium Database and Plotting Software [20]. acidity. In this case, piperazine was supported as a piperazine-1,4- diium cation. On the other hand, weakly acidic cation exchange SYNTHESES resin of polyacrylic acid type, which can be approximated as - General Protocol Utilizing In situ Formed Piperazine-1-ium methylglutaric acid with values pK = 4.25 and pK = 6.22 [17], A1 A2 Acetate (Compounds 1-7) generates just with piperazine the piperazine-1-ium cations. Piperazine (8.61 g, 100 mmol) was dissolved in 80 ml of glacial This route protected and supported piperazine-1-ium was pre- acetic acid at 40 °C and then cooled to room temperature. Into this pared by chemisorption of its chloride solution (formed by mixing solution methyl chloroformate (10.0 g, 106 mmol), acetyl chloride of piperazine with piperazine-1,4-diium dichloride in methanol solution) on a weakly acidic resin ionized in Na+-cycle. Suitable (8.3 g, 106 mmol), benzoyl chloride (15.5 g, 106 mmol), N,N- electrophiles for subsequent reactions proved carboxylic acid anhy- diethylcarbamoyl chloride (15.0 g, 101 mmol), dodecanoyl chloride drides such as acetic, benzoic, acetic formic anhydride, succinic, (22.2 g, 101 mmol), methanesulfonyl chloride (12.0 g, 104 mmol) maleic and phthalic anhydride or nitrourea as well, which upon or benzenesulfonyl chloride (18.0 g, 102 mmol) were added drop- reaction not formed strong acidic side products in contrast to alkyl wise. An appropriate solid supported catalyst was added and reac- or acyl halides. tion mixture was stirred under the conditions specified in (Table 2, 3). The reaction was monitored by TLC (eluent MeOH). After the The actual reactions were then carried out in a solution of ace- end of reaction, the catalyst was separated by suction and the fil- tone at 40 °C, the molar ratio of supported piperazine-1-ium: car- trate was purified by charcoal, acid was evaporated and the product boxylic anhydride was 1:0.75, the reaction time varied between 4-6 was precipitated by addition of suitable solvent. The pure product hrs. The reaction with nitrourea was implemented in boil ethanol. was obtained by recrystallization. Synthetic details are demon- As the resulting 1-EWG-substituted piperazines are orders of mag- strated in (Table 2, 3) above. nitude weaker bases than piperazine, upon reaction occurred on their release into the solution in the form of fine crystals light read- Product Characterization ily separable from the resin bead by decantation their suspension or remained dissolved in the reaction solution. In this case, products 4–(Methoxycarbonyl)piperazine-1-ium Chloride (1) were isolated by evaporating the solvent and the oily substances converted into salts by treatment with ethanolic hydrogen chloride. State: white crystalline solid M.p.: 171.1-172.1 °C [ethanol : acetone : diethyl ether (3:1:2)] 1H NMR (300 MHz, D O) /ppm: 3.70-3.97 (4H, m, CH ); 3.65 EXPERIMENTAL 2 2 (3H, s, OCH3); 3.27-3.56 (4H, m, CH2). 13 Materials and Methods C NMR (75 MHz, D2O) /ppm: 156.6 (C=O); 53.5 (OCH3); 41.3 + All reagents were purchased from commercial suppliers and (2*CH2N); 35.1 (2*CH2N ). used without further purification. All of the solvents were purified Purity (acid-base potentiometric titration) min. 99.1 %. according to the standard methods before use. Purolite C 104Plus Calcd for C6H13N2O2: 145.180; Found: 145.175. ® (Purolite Worldwide), i. e. weakly acidic polyacrylic cation- 4-Acetylpiperazine-1-ium Chloride (2) exchanger resin of macroporous type, ionic form H+, total volume capacity 4.5 mmol/ml, specific gravity 1.19 g/ml, was used as solid State: white crystalline solid support for both metal and piperazine-1-ium cations. Supported M.p.: 189.5-190.8 °C (isopropylalcohol-water), lit.: 161-163 °C Cu+, Cu2+ and Al3+ catalysts were obtained from TauChem Ltd., [21] 1 http://www.tau-chem.sk. The reactions were monitored by TLC, H NMR (300 MHz, D2O) /ppm: 3.45-4.51 (2H, m, which was conducted on aluminum plates TLC Silica gel 60 F254 by CH2NCOCH3); 4.06-4.11 (2H, m, CH2NCOCH3); 3.28-3.41 (4H, Merck. Spots were detected using an UV lamp CAMAG (wave- m, CH2NHCH2); 2.04 (3H, s, COCH3). 13 + length 254 nm or 366 nm), iodine vapor or ninhydrin reagent. Melt- C NMR (75 MHz, D2O) /ppm: 169.4 (C = O); 50.6 (CH2N ); ing points were measured on a Boetius apparatus PHMK 05 (VEB 44.3 (CH2N); 38.8 (CH2N); 21.4 (CH3). Kombinat Nagema) and are uncorrected. NMR spectra were ob- Purity (acid-base potentiometric titration) min. 99.2 % tained on a Bruker Avance NMR III ™ 300 MHz for hydrogen Calcd for C6H13N2O: 129.180; Found: 129.174. spectrum and Bruker Avance III ™ 500 MHz for carbon spectrum, 4-Benzoylpiperazine-1-ium Chloride (3) using wideband probe BBFO. Infrared spectra were obtained from spectrometer Bruker Tensor 27. Samples were measured in the State: white crystalline solid form of KBr tablets. The resulting spectra were processed and ana- M.p.: 278.9-280.0 °C (isopropylalcohol-water), lit.: 274-275 °C lyzed using OPUS 5.6 program. MALDI TOF mass spectra were [22] 1 measured on an AXIMA CFR mass spectrometer from Kratos Ana- H NMR (300 MHz, D2O) /ppm: 7.42-7.79 (5H, m, Ar-H), 3.75- lytical Ltd. (Manchester, United Kingdom) equipped with a nitro- 4.59 (2H, m, CH2NCOCH3), 4.26-4.34 (2H, m, CH2NCOCH3), gen laser wavelength of 337 nm from Laser Science Inc. of Frank- 3.28-3.79 (4H, m, CH2NHCH2).

Direct Preparation of 1-EWG-Substituted Piperazines Current Organic Synthesis, 2014, Vol. 11, No. 6 5

13 C NMR (75 MHz, D2O) /ppm: 165.0 (C=O); 135.2 (CAr); 129.2 filtrate was acidified with 20 ml of methanolic hydrogen chloride + (CHAr); 128.5 (CHAr); 126.9 (CHAr); 49.7 (CH2N ); 43.3 (CH2N); (conc. 4 mmol/ml) and then evaporated in vacuo to dryness. 10.17 g 38.1 (CH2N). (64 mmol) piperazine-1,4-diium dichloride was obtained. Purity (acid-base potentiometric titration) min. 99.6 % The resin beads were washed 3 times by 200 ml of methanol Calcd for C H N O: 191.250; Found: 191.245. 11 15 2 and 2 times with 150 ml of acetone and dried on air to constant 4-(N,N-Diethylcarbamoyl)piperazine-1-ium Chloride (4) weight (62.8 g). State: white crystalline solid Prepared resin containing piperazine-1-ium (8 g of resin, 17.3 M.p.: 184.1-185.2 °C [methanol : acetone (3:2)], lit.: 150-152 °C mmol of piperazine) was suspended in 50 ml of acetone solution [23] containing 13 mmol of corresponding carboxylic anhydride and the 1 H NMR (300 MHz, D2O) /ppm: 3.70-3.92 (4H, m, CH2); 3.29- mixture was stirred for 4-6 hrs. at 40 °C until consumption of the 3.54 (4H, m, CH2); 3.18 (4H, q, NCH2, J = 7.1 Hz); 1.14 (6H, t, starting anhydride (TLC in methanol, detecting spots by UV light CH3, J = 7.1 Hz). and/or iodine vapors). Reaction with nitrourea was carried out as 13 C NMR (75 MHz, D2O) /ppm: 163.5 (C=O); 47.1 (CH2); 41.0 + described above in ethanol under reflux for 6 hrs. (2*CH2N); 35.6 (CH2); 35.0 (2*CH2N ); 14.1 (2*CH3). Purity (acid-base potentiometric titration) min. 98.9 % After the reaction was completed, the acetone solution or suspension containing the microcrystalline product was decanted and Calcd for C9H20N3O: 186.275; Found: 186.262 the resin was washed twice with acetone (40 mL). The acetone 4-(Dodecanoyl)-piperazine-1-ium Chloride (5) parts were combined and the acetone was evaporated. The solid State: white crystalline solid residue was recrystallized, in the case of acetyl derivative and urea M.p.: 172.0-173.7 °C (isopropylalcohol) product the oily residue was mixed with 10 ml of ethanolic hydro- 1 H NMR (300 MHz, D2O) /ppm: 3.72-3.90 (4H, m, CH2); 3.31- gen chloride (2 mmol/ml) and concentrated to crystallization by 3.49 (4H, m, CH2); 2.25 (2H, t, CH2, J = 7.2 Hz); 1.13-1.61 (18H, evaporation in vacuo. Synthetic details are demonstrated in (Table m, CH2); 0.87 (3H, s, CH3). 4, 5) below and (Scheme 5) shows general reaction of ionically- 13 C NMR (75 MHz, D2O) /ppm: 174.6 (C=O); 44.1 (2*CH2N); bound solid supported piperazine-1-ium with carboxylic anhy- + 35.9 (2*CH2N ); 35.6 (CH2); 33.4 (CH2); 32.0 (CH2); 28.6-31.0 drides. (7*CH2); 24.0 (CH2); 23.1 (CH2); 14.7 (CH3). Purity (acid-base potentiometric titration) min. 98.9 % R2 Calcd for C17H35N2O: 283.423; Found: 283.414. H H CO N+ Anhydride 4-(Methylsulfonyl)piperazine-1-ium Chloride (6) or nítrourea N State: white crystalline solid M.p.: 192.4-193.7 °C [methanol : acetone (3:2)]; lit.: 216-219 °C N N [24], 185-187 °C [25] H H 1 H NMR (300 MHz, D2O) /ppm: 3.79-3.91 (4H, m, CH2); 3.30- Scheme 5. General reaction of ionically-bound solid supported piperazine- 3.50 (4H, m, CH2); 2.86 (3H, s, CH3). 13 1-ium with carboxylic anhydrides or nitrourea. C NMR (75 MHz, D2O) /ppm: 44.2 (2*CH2N); 36.3 (CH3); 35.8 + (2*CH2N ). Purity (acid-base potentiometric titration) min. 98.8 % Product Characterization Calcd for C H N O S: 165.235; Found: 165.229. 5 13 2 2 4-Acetylpiperazine-1-ium Chloride (2) 4-(Benzenesulfonyl)piperazine-1-ium Chloride (7) State: white crystalline solid State: white crystalline solid Yield: 1.65 g (77 % based on acetic anhydride). M.p.: 176.4-177.7 °C [methanol : acetone (3:2)] M.p.: 190.9-191.5 °C (water-isopropylalcohol), lit.: 161-163 °C 1H NMR (300 MHz, D O) /ppm: 7.59-7.70 (5H, m, Ar-H); 3.74- [21] 2 1 3.92 (4H, m, CH2); 3.33-3.50 (4H, m, CH2). H NMR (300 MHz, D2O) /ppm: 3.45-4.51 (2H, m, 13 C NMR (75 MHz, D2O) /ppm: 140.6 (CAr); 133.0 (CHAr); 128.6- CH2NCOCH3); 4.06-4.11 (2H, m, CH2NCOCH3); 3.28-3.41 (4H, + 129.2 (4*CH ); 44.1 (2*CH N); 33.8 (2*CH N ). m, CH2NHCH2); 2.04 (3H, s, COCH3). Ar 2 2 13 + Purity (acid-base potentiometric titration) min. 98.1 % C NMR (75 MHz, D2O) /ppm: 169.4 (C = O); 50.6 (CH2N ); Calcd for C10H15N2O2S: 227.304; Found: 227.295. 44.3 (CH2N); 38.8 (CH2N); 21.4 (CH3). Purity (acid-base potentiometric titration) min. 99.5 % General Protocol Utilizing Ionically-Bound Solid Supported Calcd for C6H13N2O: 129.180; Found: 129.175. Piperazine-1-ium (Compounds 2, 8-13) 4-Formylpiperazine-1-ium Chloride (8) Purolite C 104 Plus (50 g) was suspended in 200 ml of water State: white crystalline solid. and saturated aqueous potassium carbonate solution was added Yield 1.60 g (76 % based on acetic formic anhydride). under the stirring until pH value of the solution remained between 8 M.p.: 267.5-269.1 °C (water-ethanol). and 9 after 10 minutes after the last addition. Aqueous solution was 1H NMR (300 MHz, D O) /ppm: 8.48 (s, 1H, HC=O); 3.42-4.55 then decanted; the resin beads were washed 3 times by 200 ml of 2 (2H, m, CH2); 4.04-4.10 (2H, m, CH2); 3.26-3.40 (4H, m, 2*CH2). water and 2 times with 150 ml of methanol. 13 + C NMR (75 MHz, D2O) /ppm: 162.4 (C=O); 50.8 (CH2N ); 44.5 Piperazine (8.61 g, 100 mmol) was dissolved in 100 ml of (CH2N); 40.8 (CH2N). methanol, and the piperazine-1,4-diium dichloride monohydrate Purity (acid-base potentiometric titration) min. 99.4 % (17.7 g, 100 mmol) was added and the solution was stirred at 50 °C. Calcd for C5H11N2O: 115.154; Found: 115.149. Then, resin modified according to the above described procedure 1-Benzoylpiperazine (9) was suspended in the prepared solution of piperazine-1-ium chloride and mixture was stirred for three hour. The methanolic solution State: white crystalline solid containing potassium chloride in the form of microsuspension was Yield: 1.94 g (78 % based on benzoic anhydride). decanted, the potassium chloride was removed by suction and the M.p.: 74.7-75.1 °C (water); lit.: 73.0-75.0 °C [26]

6 Current Organic Synthesis, 2014, Vol. 11, No. 6 Nmeková-Herová and Pazdera

Table 4. Reaction of ionically-bound solid supported piperazine-1-ium with carboxylic anhydrides.

Compound Anhydride R2 Temperature [°C] Reaction Time [h] Yield

2 Acetic anhydride CH3- 40 4-6 77

8 Acetic formic anhydride H- 40 4-6 76

9 Benzoic anhydride C6H5- 40 4-6 78

10 Succinic anhydride -(CH2)2COOH 40 4-6 74

11 Maleic anhydride -CH=CHCOOH 40 4-6 74

12 Phthalic anhydride -C6H4COOH 40 4-6 78

Table 5. Reaction of ionically-bound solid supported piperazine-1-ium with nitrourea.

Compound Reactant R2 Temperature [°C] Reaction Time [h] Yield

13 Nitrourea NH2- reflux 6 83

1 H NMR (300 MHz, CDCl3) /ppm: 7.36-7.39 (m, 5H, ArH); 3.50- 4-(Aminocarbonyl)piperazine-1-ium Chloride (13) 3.58 (m, 4H, 2*CH2); 2.84-2.86 (m, 4H, 2xCH2); 1.92 (bs, 1 H, State: white crystalline solid NH). 13 Yield: 1.79 g (83 % based on nitrourea). C NMR (75 MHz, CDCl3) /ppm: 171.12 (C=O); 135.91 (CAr); M.p.: 208.0-209.2 °C (decomp., methanol : aceton); lit.: 207.0- 130.00 (CHAr); 128.15 (2*CHAr); 127.14 (2*CHAr); 44.90 208.0 °C [29] (2*CH2N); 44.10 (2*CH2N). 1 H NMR (300 MHz, DMSO-d6) /ppm: 9.18 (br s, 2H, CONH2), Purity (acid-base potentiometric titration) min. 99.6 % + + 5.91 (br s, 2H, N H2), 3.97-3.02 (8H, m, 4*CH2). Calcd for C11H14N2O+H : 191.250. Found: 191.246. 13 C NMR (75 MHz, DMSO-d6) /ppm: 159.0 (C=O); 49.6 + 4-Oxo-4-piperazine-1-ylbutanoic Acid (10) (CH2N ); 42.7 (CH2N); 36.1 (CH2N). Purity (acid-base potentiometric titration) min. 99.5 % State: white crystalline solid Calcd for C H N O: 130.168; Found: 130.160. Yield: 1.78 g (74 % based on succinic anhydride). 5 12 3 M.p.: 141.5-142.7 °C (water); lit.: 142.0-143.0 °C [27] 1 H NMR (300 MHz, CDCl3) /ppm: 8.19 (bs, 2H, NH+COOH); CONCLUSION 3.42-3.55 (m, 4H, 2*CH ); 2.87-3.02 (m, 4H, 2*CH ); 2.55-2.62 2 2 New synthetic protocol for the routine direct chemoselective (m, 4H, 2*CH ). 2 preparation of various piperazines substituted in the 1-position by 13C NMR (75 MHz, CDCl ) /ppm: 180.05 (COOH); 175.20 3 an electron withdrawing group was evaluated. This is based on the (C=O); 44.11 (2*CH N); 43.90 (2*CH N); 32.50 (CH ); 28.65 2 2 2 reaction of piperazine-1-ium cation with different electrophilic (CH2). + reagents such as acyl chlorides, anhydrides, sulfonyl chlorides, Calcd for C H N O +H : 187.216; Found: 187.207. 8 14 2 3 carbamoyl chlorides, and nitrourea as well. A new method of prepa- (2E)-4-Oxo-4-piperazine-1-ylbut-2-enoic Acid (11) ration of 1-monosubstituted piperazine derivatives is very benefi- State: white crystalline solid cial, because until now no one has come up with the idea to use one Yield: 1.78 g (74 % based on maleic anhydride). nitrogen atom of the piperazine for its simple protonation. Com- M.p.: 137.5-138.9 °C (water); lit.: 139.0 °C [27] puter modeling of behavior of piperazine depending on the pH were 1 carried out and according to the results, we concluded that the pro- H NMR (300 MHz, CDCl3) /ppm: 7.89 (bs, 2H, NH+COOH); 6.52 (d, J=10.2, 1H, =CH); 5.95 (d, J=10.2, 1H, =CH); 3.56-3.64 tonation of the nitrogen atom is the simplest, most effective and most elegant method of preventing unwanted formation of 1,4- (m, 4H, 2*CH2); 2.80-2.92 (m, 4H, 2*CH2). 13 disubstituted product. Assumption was fully confirmed by number C NMR (75 MHz, CDCl3) /ppm: 168.71 (COOH); 164.32 of syntheses. Further, we prepared a piperazine-1-ium cation ioni- (C=O); 134.90 (CH=); 133.50 (CH=); 44.90 (2*CH2N); 42.85 (2*CH2N). cally bound to a suitable acidic cation exchange resin and it was + Calcd for C8H12N2O3+H : 185.201; Found: 185.197. used for monosubstitution as a solid phase synthesis with ionically- bound substrate. The main advantages of our protocol is high sim- 2-(Piperazine-1-ylcarbonyl)benzoic Acid (12) plicity, one-pot performance, use non-toxic solvents only, mild State: white crystalline solid reaction conditions, no generation of waste, short time of reactions Yield: 2.39 g (78 % based on phthalic anhydride). and high yields. M.p.: 299.8-300.2 °C (decomp., water: acetone); lit.: 300 °C [28] 1 Finally, a new various piperazines substituted in the 1-position H NMR (300 MHz, CDCl3) /ppm: 7.96 (bs, 2H, NH+COOH); by an electron withdrawing group and other their analogues could 7.91-7.93 (m, 1H, ArH); 7.48-7.54 (m, 1H, ArH), 7.34-7.39 (m, 1H, be very interesting building blocks for development of novel drugs ArH); 7.03-7.07 (m, 1H, ArH); 3.50-3.58 (m, 4H, 2*CH2); 2.84- in practical pharmaceutical research and development. 2.86 (m, 4H, 2*CH2); 1.92 (bs, 1 H, NH). 13 C NMR (75 MHz, CDCl3) /ppm: 178.00 (COOH); 169.23 CONFLICT OF INTEREST (C=O); 135.15 (CAr); 134.90 (CHAr); 131.12 (CHAr); 129.00 (CAr); 128.60 (CHAr); 127.13 (CHAr); 44.90 (2*CH2N); 44.11 (2*CH2N). + The authors confirm that this article content has no conflict of Calcd for C12H14N2O3+H : 235.259; Found: 235.251. interest.

Direct Preparation of 1-EWG-Substituted Piperazines Current Organic Synthesis, 2014, Vol. 11, No. 6 7

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Received: July 04, 2014 Revised: September 25, 2014 Accepted: September 30, 2014