Short communication
Preparation of Spiropiperidines in Water
Ferenc Miklós1 and Ferenc Fülöp
1 Institute of Pharmaceutical Chemistry and2 Stereochemistry Research Group of the Hungarian Academy of Sciences,
University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
* Corresponding author: E-mail: fulop@pharm.u-szeged.hu
Received: 21-10-2008
Dedicated to Professor Branko Stanovnik on the occasion of his 70'h birthday
1,2,*
Abstract
An environmentally benign spirocyclization is described for the synthesis of 4-spiropiperidines from 2-aminocarbohy-drazides in water at room temperature without any catalyst. The condensation of carbocyclic 2-aminocarbohydrazides with ^-benzylpiperidinone (2) led to 3'-aminospiropiperidine-quinazolinones (3a-3d). Anthranilic hydrazide 4 gave 2-amino-W^-(1-benzylpiperidin-4-ylidene)benzohydrazide (7), while glycine hydrazide (8) reacted with 2 moles of 2 to afford 1-benzylpiperidin-4-ylidenamino-1,4,8-triazaspiro[4.5]decane (9). All products precipitated from the reaction mixture and were obtained in excellent yields. No further work-up or purification was necessary.
Keywords: Spirocyclization, spiropiperidines, spiroquinazolines, green synthesis, aqueous media, methylene-bridged quinazolines
1. Introduction
The piperidine ring is a common heterocyclic unit in many alkaloids, and is a key moiety in numerous drug candidates. A number of 4-spiropiperidines have been reported to possess biological and pharmaceutical activi-ties.1-3 Spirocyclic carbamate A (Figure 1) has been tested
as a novel, highly selective4 nitric oxide synthase inhibitor. Spiropiperidine-quinazoline B and its derivatives are used to treat inflammatory disease and pain.5 As a ligand of the nociceptin receptor, cis-spiropiperidine C exhibits a 20-fold higher affinity than that of its trans stereoisomer.6 4-Oxaimidazolidine heterocycle D has been used as an antagonist against addiction to narcotic analgesics,7 while

NH,
N H
O Et


N H

Me

,0

Figure 1.
some 1,4,8-triazaspiro[4.5]decan-2-ones display a high inhibitory index against the B-16 melanoma cell line.8 Moreover, compounds with a 3^-aminoquinazoline motif demonstrate interesting activities. Substituted amino-qui-nazolinethione E, for instance, exerts excellent insectici-dal activity against greenhouse whitefly,9 and quinazolin-4-one F exhibits inhibitory activity against haematopoietic prostaglandin D2 synthase.10 3^-Aminoquinazolino-nes are key intermediates for the synthesis of naphtho-fu-sed 1,4,5-oxadiazepinoquinazolinones,11 biologically active Schiff bases,12,13 triazocinoquinazolinones14 and 2-alkyl/aryl quinazolinones.15
Kouznetsov et al. reported16,17 that a four-step synthetic route from commercially available 1-benzyl-4-piperidinone and anilines provided an efficient preparation of spiro[piperidine-4,2'-(1'^)quinolines].16,17 Spiro-[1,2,4-benzotriazine-3(4H),4'-(1'-substituted)-piperidi-nes] were obtained through the air oxidation of 2-aminop-henylhydrazones of ^-benzylpiperidones.18 The effect of microwave irradiation on the formation of the spiroimida-zolidinone was investigated by Feliu et al.19 As compared with conventional heating, the microwave-assisted solidphase synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives from 1-benzyl-piperidin-4-one (2) and an a-amino acid amide was significantly improved. Spirocyclization of 1-acetyl-4-piperidone with 1,2-diamino-2-methylpro-pane in refluxing benzene gave 8-acetyl-2,2-dimethyl-1,4,8-triazaspiro[4.5]decane.20,21
2. Results and Discussion
We turned our attention to a greener and sustainab-le22,23 approach for the preparation of an N-benzylpiperi-dine derivative of 2',2"-disubstituted spiroquinazolinones. The use of water as a solvent for organic transformations offers numerous environmental benefits. In many reactions, a significant rate enhancement is observed in water relative to organic solvents. Water was found to be an ideal solvent for the multicomponent synthesis of heterocyc-les,24-28 for the preparation of 2-pyrrolecarbaldimines,29 octahydroquinazolinones,30 3,4-dihydropyrimidinones,31 pyrazoles and diazepines.32
We already developed a method by which diendo-and rfiexo-3-aminonorbornane(ene)-2-carbohydrazides (1a-1d) were applied to form heterocycles. Refluxing of the above hydrazides with y-oxoacid or y-ketoester in toluene yielded methylene-bridged phthalazino[1,2-&]quin-azolinones33 or cyclopenta[5,6]pyridazino[6,1-&]quinazo-linones.34
Our present aim was to expand the possibilities through the condensation of 1a-1d33 with 1-benzylpiperi-din-4-one (2). The target of this project was to prepare methylene-bridged spiropiperidines. Moreover, the chemical and stereochemical features of these saturated and partially saturated heterocycles, like those of their aromatic analogues, should be of importance from pharmacological aspects. To diendo-3-aminobicyclo[2.2.1]heptane-2-carbohydrazide 1a, or diendo-3-aminobicyclo[2.2.1] hept-5-ene-2-carbohydrazide 1b, or diexo-3-aminobicyc-lo[2.2.1]-heptane-2-carbohydrazide 1c, or diexo-3-amino-bicyclo[2.2.1]hept-5-ene-2-carbohydrazide 1d dissolved in water, N-benzylpiperidin-4-one was added dropwise. During stirring at room temperature, in about 10 min spi-ropiperidine derivatives 3a-3d started to precipitate (Scheme 1). After stirring for 12 h at ambient temperature, the precipitated diendo-methylene-bridged hexahydro-and tetrahydro-2',2"-disubstituted quinazolinones 3a and 3b, and their diexo analogues 3c and 3d were isolated by simple filtration. Under neutral conditions, the corresponding spiropiperidones were obtained in 92-97% yields.
Only a few reports describe the spirocyclization of anthranylhydrazide 4 with cycloalkanones. 3'-Amino-1', 2'-dihydrospiro[cyclohexane-1,2'-quinazolin] -4'(3' H)-one 6 was formed when 4 was refluxed with cyclohexano-ne 5 in acetic acid35 (Scheme 2) or in ethanol.36 It is important to note that a 3-cyclohexylidenamino derivative was obtained on the condensation of 4 and 2 or more equivalents of cyclohexanone.37-39
On analogy with the synthesis of 3a-3d, we attempted to prepare their aromatic derivatives. The condensation of anthranilic hydrazide 4 with 2 gave only the hydrazone 7 in high yield. This can be explained by the less nucleophilic character of the aromatic amine.
To investigate the limit of spirocyclization in water, we decided to explore the above-mentioned strategies in
Scheme 1.
O
15 min, A, AcOH {ref. 35)
Scheme 2.

the reaction of glycine hydrazide40 8 and 2; again, a crystalline product was precipitated in moderate yield (Scheme 3). The product was not an 1-amino-8-benzyl-2-oxo-1,4,8-triazaspiro[4.5]decane, but its benzylpiperidin-4-ylidenamino analogue 9, which was formed by the condensation of 8 with 2 moles of 2. When the reaction was repeated with 2 moles of 2 the yield of 9 increased to 87%.
bits a dd split, proved by the value of ~ 4 Hz47 for the 4'a-5' H-H coupling. The diexo annelation of the norborna-ne(ene) to the perhydropyrimidinone in 3c and 3d follows from the d split of 4'a-H, which is a doublet due to the coupling with 8'a-H (split by ~ 7.5 Hz). Each of the spiro compounds 3a-3d and 9 gave a 13C signal for a quaternary C-2' at 73-79 ppm. This chemical shift appears reasonable for an -NHCR2NH- system, where R is an alkyl
NH2
8
12 h, RT, H2O
Scheme 3.
It is presumed that the spirocylization of aminohy-drazides with benzylpiperidinone in aqueous media takes place without the formation of a Schiff base; the intermediate carbinolamines (hemiaminals) are transformed into the spiro compounds directly, by the elimination of wa-ter.41-44
During the cyclization, aminobicycloalkane(ene) carbohydrazide 1a-1d retained their configurations in all cases. The constitutions of the compounds were proved via their IR and NMR spectra. The IR spectra of 3b and 3d, with a norbornene skeleton, exhibit a characteristic absorption bands in the regions 3080-3050 cm-1 (v=CH) and 745-697 cm-1 (5=CH). The position of the latter band is governed by the stereochemical features of the spiroqui-nazolinones: in the IR spectra of the exo isomer, this band is in a lower interval (702 cm-1) than for the endo stereoisomer (734 cm-1).45 The presumed diendo and diexo configurations of the spirotricyclic compounds 3a, 3b and 3c, 3d were proved by 1H-NMR spectroscopy. For 3a and 3b, the diendo annelation of the norbornene moiety is revealed by the splittings.46 On diendo annelation, 4'a-H exhi-
group.48 The formation of 3'-amino-substituted compounds was confirmed by the appearances of NH2 signals in the 1H-NMR spectra (4.06-4.51 ppm) and the lack of two NH groups in IR.
3. Conclusion
In conclusion, a green approach has been demonstrated for the preparation of synthetically and pharma-ceutically relevant spiropiperidines. The condensations of 3-aminonorborane(ene)-2-hydrazides (1a-1d) with 1-benzylpiperidin-4-one (2) gave 3'-amino-substituted spi-ro[piperidine-4,2'-quinazolin]ones 3a-3d, while from less nucleophilic anthranilic hydrazide (4) a hydrazone 7 was formed. It was somewhat surprising that in the reaction of glycine hydrazide with 1-benzylpiperidin-4-one only a double condensed 1,4,8-triazaspiro[4.5]decane derivative 9 was obtained. At ambient temperature, all these reactions were complete in 12 h in water without the need for any catalyst. This method includes some important as-
pects, such as the use of water as a green solvent and mild reaction conditions.
4. Experimental
Melting points were determined on a Kofler apparatus and are uncorrected. 1H-NMR (400 Hz) and 13C-NMR (100 MHz) spectra were recorded on a Bruker Avance DRX 400 spectrometer, with TMS as internal reference and DMSO-d6 or CDClj as solvent. FT-IR spectra recordings were performed on a Perkin-Elmer 100 FT-IR spectrometer. Elemental analysis was carried out on a Perkin-Elmer 2400 elemental analyser.
Preparation of diendo- and diexo-3'-amino-1-benzyl-5',8'-methano-4'a,5',(6',7')8',8'a-(hexa)tetrahydrospi-ro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones (3a-
3d). To a stirred solution of hydrazides 1a-1d (5.0 mmol) in 10 mL of water, 0.95 g (5.0 mmol) of 1-benzyl-4-pipe-ridinone (2) was added in portions at room temperature. After vigorous stirring for 12 h, products 3a-3d precipitated. The precipitates of 3a-3d were filtered off, washed with water (15 mL), and dried upon a porous plate at 100 °C.
diendo-3'-Amino-1-benzyl-5',8'-methano-4'a,5', 6',7',8',8'a-hexahydrospiro[piperidine-4,2'(1'H)-qui-nazolin]-4'(3'H)-one (3a). Yield: 97%; colourless powder; m.p.: 202-204 °C (H2O); IR (KBr, cm-1): 3437 (NH), 3334, 3311 (NH2), 1623 (C=O), 1587 (C=O); 1H-NMR (CDCl3): 5 1.20-1.61 (8H, m, 2-6-H, 1'-NH, 6'-H, 7'-H 9'-H) 1.72 (1H, dd, J = 3.0, J = 13.5 Hz, 9'-H), 2.05 (1H, dd, J = 4.1 Hz, J = 8.8 Hz, 4'a-H), 2.24-2.46 (3H, m, 2-6-H), 2.50 (1H, s, 8'-H), 2.65-2.88 (4H, m, 2-6-H, 5'-H), 3.47 (1H, br s, 8'a-H), 3.54 (2H, s, benzyl CH2), 4.17 (2H, s, NH2), 7.18-7.37 (5H, m, Ar-H); 13C-NMR (CDCl3); 5 21.4, 23.4, 30.3, 35.0, 37.2, 40.0, 40.8, 45.2, 49.1, 49.5, 50.0, 62.3, 74.2, 126.6, 127.8 (2xC), 128.6 (2xC) 138.5, 170.5; Anal. calcd. for C2oH28N4O (%): C, 70.56; H, 8.29; N, 16.46. Found: C, 70.25; H, 8.48; N, 16.30; m/z [M+H]+\'e341.2.
diendo-3'-Amino-1-benzyl-5',8'-methano-4'a,5',8', 8'a-tetrahydrospiro[piperidine-4,2'(1'Ä)-quinazolin]-4'(3'H)-one (3b). Yield: 94%; colourless powder; m.p.: 186-188 °C (H2O); IR (KBr, cm-1): 3419 (NH), 3317, 3301 (NH2), 30^6 (v_CH), 1601 (C=O), 1572 (C=O), 733 (5=ch); 1H-NMR (CDa3): 5 0.63 (1H, br s, 1'-NH), 1.17 (1H, d, J = 13.0 Hz, 2-6-H) 1.48 (1H, d, J = 8.7 Hz, 9'-H), 1.64 (1H, d, J = 8.8 Hz, 9'-H), 1.78-2.49 (4H, m, 2-6-H), 2.64 (1H, dd, J = 4.0 Hz, J = 8.5 Hz, 4'a-H), 2.69-2.81 (3H, m, 2-6-H), 3.15 (1H, s, 8'-H), 3.47 (1H, s, 5'-H), 3.56 (2H, s, benzyl CH2), 3.80 (1H, br s, 8'a-H), 4.06 (2H, s, NH2), 6.18 (1H, dd, - = 2.9 Hz, J = 5.3 Hz, 7'-H), 6.44 (1H, d-d, J = 2.9 Hz, J = 5.0 Hz, 6'-H), 7.22-7.39 (5H, m,
Ar-H); 13C-NMR (DMSO-d6): 5 31.0, 34.3, 43.4, 46.1 (2xC), 47.0, 49.0, 49.3, 52.3, 61.8, 73.7, 126.7, 128.1 (2x-C), 128.6 (2xC) 133.9, 138.4, 138.5, 168.6; Anal. calcd. for C2oH2gN4O (%): C, 70.98; H, 7.74; N, 16.55. Found: C, 71.05; H, 7.48; N, 16.30; m/z [M+H]+\'e339.1.
diexo-3'-Amino-1-benzyl-5',8'-methano-4'a,5',6', 7',8',8'a-hexahydrospiro[piperidine-4,2'(1'H)-quina-zolin]-4'(3'Ä)-one (3c). Yield: 93%; colourless powder; m.p.: 183-185 °C (H2O); IR (KBr, cm-1): 3414 (NH), 3320, 3312 (NH2), 1623 (C_O), 1588 (C_O); 1H-NMR (DMSO-d6): 5 0.99 (1H, d, J _ 10.2 Hz, 9'-H) 1.12-2.01 (9H, m, 2-6-H, 1'-NH, 6'-H, 7'-H and 9'-H), 2.05 (1H, d, J _ 7.5 Hz, 4'a-H ), 2.09 (1H, s, 8'-H), 2.22-2.60 (5H, m, 2-6-H), 2.62 (1H, s, 5'-H) 3.04 (1H, t, J _ 8.4 Hz, 8'a-H) 3.45 (2H, s, benzyl CH2), 4.51 (2H, s, NH2), 7.19-7.36 (5H, m, Ar-H); 13C-NMR (DMSO-d6): 5 26.:;, 28.5, 29.9, 33.5, 33.8, 40.1, 42.0, 49.0, 49.1, 49.4, 54.7, 61.9, 72.4, 126.7, 128.1 (2xC), 128.7 (2xC) 138.9, 168.3; Anal. calcd. for C2oH28N4O (%): C, 70.56; H, 8.29; N, 16.46. Found: C, 70.3^; H, 8.35; N, 16.22; m/z [M+H]+\'e341.2.
diexo-3'-Amino-1-benzyl-5',8'-methano-4'a,5',8', 8' a-tetrahydrospiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-one (3d). Yield: 92%; colourless powder; m.p.: 162- 164 °C (H2O); IR (KBr, cm-1): 3426 (NH), 3319, 3311 (NH2), 3062 (V_CH), 1622 (C_O), 1586 (C_O), 702 (5_ch); 1H-NMR (DMSO-d6): 5 1.22 (1H, d, J = 9.6 Hz, 9'-CI),1.38-1.81 (4H, m, 9'-H, 2-6-H and 1'-NH), 1.86 (1H, d, J = 7.5 Hz, 4'a-H), 1.96-2.61 (6H, m, 2-6-H), 2.68 (1H, s, 8'-H), 2.92 (1H, t, J = 8.2 Hz, 8'a-H), 3.16 (1H, s, 5'-H), 3.43 (2H, s, benzyl-H) 4.51 (2H, s, NH2), 6.11 (1H, dd, J = 2.9 Hz, J = 5.7 Hz, 7'-H), 6.22 (1H, dd, J = 2.8 Hz, J = 5.6 Hz, 6'-H), 7.16-7.33 (5H, m, Ar-H); 13C-NMR (DMSO-d6): 5 30.0, 33.8, 43.4, 43.8, 45.4, 47.4, 49.0, 49.3, 50.8, 61.9, 73.1, 126.7, 128.1 (2xC), 128.6 (2xC) 135.5, 138.3, 138.8, 168.6; Anal. calcd. for C2oH2gN4O (%): C, 70.98; H, 7.74; N, 16.55. Found: C, 7(-.75; H, 7.96; N, 16.21; m/z [M+H]+\'e339.2.
Preparation of 2-amino-^'-(1-benzylpiperidin-4-ylide-ne)benzohydrazide (7). To a stirred solution of anthrani-lic hydrazide (4) (0.76 g, 5.0 mmol) in 15 mL of water, 0.95 g (5.0 mmol) of 1-benzyl-4-piperidinone (2) was added in portions at room temperature. After vigorous stirring for 12 h, product 7 precipitated. The precipitate of 7 was filtered off, washed with water (15 mL), and dried upon a porous plate at 100 °C.
Yield: 91%; colourless needles; m.p.: 165-167 °C (H2O); ir (KBr, cm-1): 3458, 3296 (NH2), 3229 (NHCO), 1622 (C_O), 1586 (C_O), 756 (Ar y_CH); 1H-NMR (DM-SO-d6): 5 2.35-2.49 (6H, m, cycloalkyl CH2), 2.52-2.58 (2H, m, cycloalkyl CH2), 3.54 (2H, s, benzyl CH2 ), 6.15 (2H, br s, NH2), 6.48-7.48 (9H, m, Ar-H), 10.41 (1H, s, NHCO); 13C-NNMR (DMSO-d6): 5 28.9, 35.3, 52.9, 54.0,
62.2, 115.5, 117.0, 127.8 (2xC), 129.1 (2xC), 129.6 (4x C), 139.2, 150.3, 162.1, 166.1; Anal. calcd. for C19H22N4O (%): C, 70.78; H, 6.88; N, 17.38. Found: C, 70.59; H, 6.91; N, 17.21.
1-(Benzylpiperidin-4-ylidenamino)-8-benzyl-2-oxo-1, 4,8-triazaspiro[4.5]decane (9). To a stirred solution of glycine hydrazide (8) (0.45 g, 5.0 mmol) in 10 mL of water, 0.95 g (5.0 mmol) or 1.89 g (10.0 mmol) of 1-benzyl-4-piperidinone (2) was added in portions at room temperature. After vigorous stirring for 12 h, product 9 precipitated. The precipitate 9 was filtered off, washed with water (10 mL), and dried upon a porous plate at 100 °C.
Yield: 45% or 87% (based on hydrazide 8); colourless powder; m.p.: 141-143 °C (H2O); IR (KBr, cm-1): 3285 (NH), 1685 (C=O), 1637 (C=Nf); 1H-NMR (DMSO-rf6): 5 1.43-2.76 (16H, m 2-6-H), 3.02 (1H, t, J = 9.3 Hz, 4-NH), 3.25 (2H, d, J = 9.2 Hz 3-H), 3.47 (2H, s, benzyl-H), 3.55 (2H, s, benzyl-H), 7.20-7.37 (10H, m, Ar-H); 13C-NMR (DMSO-d6): 5 31.4, 33.4 (2xC), 35.4, 47.5, 50.2 (2xC), 53.3, 54.1, 61.9, 62.8, 78.4, 127.7, 127.8, 129.0 (2xC), 129.1 (2xC), 129.5 (2xC), 129.6 (2xC) 139.2, 139.5, 167.9, 174.6; Anal. calcd. for C2gH33N5O (%): C, 72.36; H, 7.71; N, 16.23. Found: C, 72.55; H, 7.98; N, 16.01; m/z [M+H]+ 432.2.
5. Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA Nos. K75433 and T049407) for financial support.
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Povzetek
Opisana je okolju prijazna nekatalizirana spirociklizacija za pripravo 4-spiropiperidinov iz 2-aminokarbohidrazidov v vodi kot topilu. Kondenzacije karbociklicnih 2-aminokarbohidrazidov z ^-benzilpiperidinonom so vodile do 3'-ami-nospiropiperidine-kinazolinonov, antranilhidrazid je dal 2-amino-W-(1-benzilpiperidin-4-iliden)benzohidrazid, medtem ko je glicinhidrazid regiral z dvema ekvivalentoma N-benzilpiperidinona do ustreznega -benzilpiperidin-4-ilidena-mino-1,4,8-triazaspiro[4,5]dekana. Vsi produkti so bili enostavno izolirani s filtracijo z odličnimi izkoristki in čistočo.