Conjugate addition of 2-(bromomethyl)- and 2-(2-bromoethyl)- piperidine to alkyl acrylates: application towards the synthesis of 2-(methoxycarbonyl)indolizidine

Conjugate addition of 2-(bromomethyl)- and 2-(2-bromoethyl)piperidine hydrobromide to methyl and ethyl acrylate in the presence of triethylamine afforded the corresponding 3-[2-(bromomethyl)piperidin-1-yl]propanoates and 3-[2-(2-bromoethyl)piperidin-1-yl]propanoates for the first time. Furthermore, methyl 3-[2-(bromomethyl)piperidin-1-yl]propanoate was converted into the novel 2-(methoxycarbonyl)indolizidine upon treatment with lithium diisopropylamide in THF. The latter ester was easily reduced by means of lithium aluminium hydride in diethyl ether, affording 2-(hydroxymethyl)indolizidine in high yield.

Introduction 1 The conjugate addition of amines onto ,-unsaturated carbonyl compounds, often referred to as the 'aza-Michael reaction', comprises an important methodology in organic synthesis towards the preparation of β-aminocarbonyl derivatives. 1 Furthermore, compounds containing the βaminocarbonyl motif in their molecular framework are of importance as biologically relevant targets and as intermediates in the synthesis of β-amino ketones, β-amino acids, and β-lactam antibiotics, 2 hence the interest in their preparation.Whereas the 1,4-addition of a variety of piperidine derivatives onto alkyl acrylates is known in the literature, 3 the aza-Michael reaction of 2-(-haloalkyl)piperidines has not been reported so far.
In the present paper, the conjugate addition of 2-(bromomethyl)-and 2-(2bromoethyl)piperidines across methyl and ethyl acrylate is described.The applicability of the addition products is demonstrated by the synthesis of 2-(methoxycarbonyl)indolizidine for the first time, which was further reduced to 2-(hydroxymethyl)indolizidine.
In the past decades, a whole range of lipophilic skin alkaloids has been isolated from frogs from the Dendrobatidae, Mantellinae, Myobatrachidae and Bufonidae families. 4Among others, pyrrolizidines, indolizidines and quinolizidines have been characterized.Besides from amphibian skin, interesting alkaloids were also isolated from plants 5 and from micro-organisms. 6Many of these compounds have caught the attention of the medical world due to their potential biological activities, 7 which explains the interest in new methodologies towards these azaheterocyles.

Results and Discussion
2-(Bromomethyl)-and 2-(2-bromoethyl)piperidine hydrobromide salts 2a,b were prepared from the corresponding alcohols 1a,b by treatment with hydrogen bromide in water (48%) upon reflux for 24 hours (Scheme 1), in accordance with a literature protocol. 8Despite their inherent reactivity and synthetic potential, -bromoamines 2a and 2b have only been studied to a limited extend up to now. 9 Subsequently, the conjugate addition of piperidines 2a,b onto alkyl acrylates was investigated.At first, 2-(bromomethyl)piperidine hydrobromide (2a) was treated with 1.05 equiv of an acrylate (methyl, ethyl and tert-butyl acrylate) in dichloromethane in the presence of 1.05 equiv of triethylamine at room temperature for 16 hours, 3a albeit without any success.In all cases, no reaction was observed and the starting compound was recovered.If, however, piperidine hydrobromides 2a,b were suspended in methyl or ethyl acrylate, followed by the addition of 1.05 equiv of triethylamine at 0 °C, a stirring period of 16 hours at room temperature and then a second addition of 1.05 equiv of triethylamine, the corresponding novel 1-(2alkoxycarbonylethyl)piperidines 3a-d were isolated in good yields (Scheme 1).It should be noted that the latter addition products 3 are rather unstable in pure form, and thus should be stored in solution (e.g. in diethyl ether) or used immediately for further elaboration.Furthermore, the presence of water has to be avoided during the aza-Michael addition, as nucleophilic displacement of bromide by water takes place smoothly and results in the formation of 2-(hydroxymethyl)-and 2-(2-hydroxyethyl)piperidines 4. The latter piperidine alcohols were also obtained as the major components upon attempted purification of 3-(piperidin-1yl)propanoates 3 by means of column chromatography on silica gel.Indeed, if water is added deliberately for the reaction of piperidines 2a,b with methyl acrylate (H2O/methyl acrylate 1/1) following the same procedure as described above (i.e.2.1 equiv Et3N, 0 °C to r.t., 16 hours), were obtained as the sole reaction products in good yields (Scheme 2).

Scheme 2
Based on detailed GC-analysis of the reaction mixtures obtained after treatment of piperidine hydrobromide 2a with acrylates in the presence of triethylamine, the presence of a minor constituent was observed in very small quantities (< 5%).This side-product could be isolated in pure form by means of preparative gas chromatography, and was identified as 4a,8adiazaperhydroanthracene (6). 10 The formation of the latter tricyclic compound can be rationalized considering the dimerization of 2-(bromomethyl)piperidine (2a) through double nucleophilic substitution via intermediate 5 (Scheme 3).In the final part, the application of 3-(piperidin-1-yl)propanoates 3 for the construction of a bicyclic framework was investigated.For this purpose, the reaction of methyl 3-[2-(bromomethyl)piperidin-1-yl]propanoate (3a) with lithium diisopropylamide (LDA) was evaluated with the intention to induce ring closure of the intermediate enolate 7, formed by deprotonation by LDA, through nucleophilic displacement of bromide (Scheme 4).Thus, treatment of piperidine 3a with 1.1 equiv of LDA in THF at 0 °C afforded 2-(methoxycarbonyl)indolizidine (8) for the first time after 16 hours at room temperature (Scheme 4).Based on GC-analysis, two diastereomers cis-8 and trans-8 were present in the reaction mixture in a ratio of 45/55 (cis/trans or vice versa).These isomers appeared to be inseparable by means of column chromatography (SiO2) and preparative gas chromatography.Further derivatization of indolizidine ester 8 was performed using 2 equivalents of lithium aluminium hydride in diethyl ether, affording the corresponding 2-(hydroxymethyl)indolizidine (9) 11

Experimental Section
General Procedures. 1 H NMR spectra were recorded at 270 MHz (JEOL JNM-EX 270) with CDCl3 as solvent and tetramethylsilane as internal standard. 13C NMR spectra were recorded at 68 MHz (JEOL JNM-EX 270) with CDCl3 as solvent.Mass spectra were obtained with a mass spectrometer (VARIAN MAT 112, 70 eV) using a GC-MS coupling (RSL 200, 20 m glass capillary column, i.d.0.53 mm, He carrier gas).IR spectra were measured with a Perkin Elmer 1310 spectrophotometer or a Spectrum One FT-IR.Elemental analyses were performed with a PerkinElmer Series II CHNS/O Analyzer 2400.Dichloromethane was dried over calcium hydride, while diethyl ether and THF were dried by distillation over sodium benzophenone ketyl.Other solvents were used as received from the supplier.

Synthesis of 3-[2-(bromomethyl)piperidin-1-yl]propanoates 3a,b and 3-[2-(2bromoethyl)piperidin-1-yl]propanoates 3c,d. General procedure
To an ice-cooled suspension of dry piperidine hydrobromide 2 (5 mmol) in alkyl acrylate (5 mL) was added slowly triethylamine (5.25 mmol).The resulting mixture was stirred for 16 hours at room temperature, after which an additional amount of triethylamine (5.25 mmol) was added.After 10 minutes, the excess of alkyl acrylate and triethylamine was removed in vacuo, and the obtained paste was suspended in diethyl ether (10 mL).After a stirring period of 10 minutes at room temperature, the resulting mixture was filtered under nitrogen atmosphere and the solvent was removed in vacuo, affording alkyl 3-(piperidin-1-yl)propanoate 3. Due to its lability, the crude alkyl 3-(piperidin-1-yl)propanoate 3 was used immediately as such for further elaboration or dissolved in dry diethyl ether for conservation at -18 °C.Because of the instability of propanoates 3, no elemental analyses were performed.

Synthesis of 3-[2-(hydroxymethyl)piperidin-1-yl]propanoate (4a) and 3-[2-(2hydroxyethyl)piperidin-1-yl]propanoate (4b). General procedure
To an ice-cooled suspension of piperidine hydrobromide 2 (5 mmol) in methyl acrylate (5 mL) and water (5 mL) was added slowly triethylamine (5.25 mmol).The resulting mixture was stirred for 16 hours at room temperature, after which an additional amount of triethylamine (5.25 mmol) was added.After 10 minutes, the excess of methyl acrylate and triethylamine was removed in vacuo, and the obtained paste was suspended in diethyl ether (10 mL).After a stirring period of 10 minutes at room temperature, the resulting mixture was filtered under nitrogen atmosphere and the solvent was removed in vacuo, affording methyl 3 Scheme 3