Introduction

4-Pentynylamine derivatives have been employed not only as a useful synthetic intermediate for preparation of various biologically important compounds such as pyrrolidine and piperidine derivatives [1,2,3,4,5,6,7,8], but also as a connecting unit of biologically active compounds through click chemistry [9,10,11,12]. Most of these compounds were synthesized by the conventional substitution reaction of 4-pentynyl halides with nitrogen nucleophiles [13, 14] or the reduction of the 4-pentynoyl amides [8], but these protocols sometimes require harsh conditions and functional group compatibility is also limited.

We previously reported the ReI(CO)5-catalyzed generation of α,β-unsaturated carbene complex intermediates from propargyl ethers and applied it to the reaction with siloxydienes to give cycloheptadiene derivatives [15]. This reaction was further extended to the ReI(CO)5-catalyzed hydropropargylation reaction of silyl enol ethers with propargyl ethers to give 4-pentynol derivatives [16]. In this paper, we report further expansion of this methodology to the reaction of enamides instead of silyl enol ethers to give synthetically useful 4-pentynylamine derivatives, which proceeds under neutral conditions using just a catalytic amount of a transition metal complex.

The choice of the substituent on the nitrogen atom was examined first using propargyl diphenylmethyl ether 1 as a precursor of α,β-unsaturated carbene complex intermediate according to the similar procedure for the reaction with silyl enol ethers (Table 1, A) [16]. While the reaction of pyrrolidine enamine of cyclohexanone 2b or β,β-dimethyl-substituted enimide derived from phthalimide 2c did not give the product at all, the reaction of β,β-dimethyl-substituted enamide derived from pyrrolidone 2a [17] gave the desired hydropropargylation product 3a in good yield. The enamide 2a is thought to retain sufficient nucleophilicity compared to enimide 2c without suppressing the catalytic activity of the Re catalyst due to the lower basicity compared to enamine 2b. Thus, by heating a mixture of enamide 2a and two equivalents of propargyl diphenylmethyl ether 1 in the presence of 6 mol% amount of ReI(CO)5 at 100 °C in dioxane for 10 h, the desired hydropropargylation product 3a was obtained in 71% yield. Use of other ReX(CO)5 (X = Cl, Br) catalysts or other solvents lowered the yield considerably.

Table 1 Generality of Substratea
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The generality of the reaction was examined concerning the substituent on the nitrogen atom (Table 1, A), and enamides of cyclic amides, such as piperidone and oxazolidone, were found to give the corresponding products 3e and 3 f in moderate to good yields while enamide of acylic amide 2d turned out to be unapplicable. Next the substituent on the alkene moiety was examined using enamides derived from pyrrolidone (Table 1, B). It was found that cyclohexylidene enamide also gave the corresponding substituted 4-pentynylamine derivatives 3 g in a reasonable yield. α,β-Disubstituted enamides also gave the products 3i~k with high diastereo-selectivity. In these reactions, the enamides of (E)-geometries (E: Z ≥ 90: 10) were employed [17], but as the diastereoselectivity is determined at the stage of the 1,5-hydrogen transfer step, the high diastereoselectivity is thought to be realized due to the restricted transition state of the intramolecular hydrogen transfer (See Fig. 1). The structure of 3i was determined by single crystal X-ray analysis of its dimerized product obtained by the coupling reaction of the terminal alkyne. Interestingly, β-methoxy-substituted enamide gave the product 3l in which the propargyl substituent was introduced to the carbon substituted with the amido group. This implies that β-methoxy enamide actually worked as an enol ether nucleophile instead of enamide. Again the product was obtained with high diastereoselectivity starting from (Z)-enamide. The structure of 3 l was determined by the single crystal X-ray analysis.

Fig. 1
figure 1

Deuterium experiment and proposed reaction mechanism

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When a secondary enamide 2 m was employed, a contiguous hydropropargylation-cyclization-hydropropargylation reaction was found to proceed in a reasonable yield (Table 1, C). Treatment of a secondary enamide 2 m with two equivalents of 1 gave pyrrolidine derivative 3 m in 45% yield. The reaction first gave the hydropropargylation intermediate A, which underwent 5-exo cyclization of the amide nitrogen onto the terminal alkyne to give another enamide B through electrophilic activation of the alkyne moiety by the Re catalyst. This further underwent another hydropropargylation reaction to give the final product 3 m. Thus, a synthetically useful pyrrolidine derivative with an unsaturated sidearm was prepared in a simple single operation. Pyrrolidine derivative 3 m could be a useful precursor for the preparation of pyrrolizidine alkaloids, which are widely found in nature as a biologically active compounds [18, 19], by further intramolecular addition reaction of the nitrogen towards the alkyne moiety.

The reaction was thought to proceed in a similar manner to the previous reaction with silyl enol ethers [16, 20]. First, α,β-unsaturated carbene complex intermediate is generated from the propargyl ether and then enamides add to this complex in a 1,4-addition manner to give alkenylrhenium intermediate C. The 1,5-hydrogen transfer of the hydrogen atom of the alkenylrhenium moiety to the iminium carbon generates vinylidene complex D, which liberates the product with regeneration of the rhenium catalyst. This mechanism was supported by the deuterium labelling experiments as shown in Fig. 1. Starting from the propargyl ether 1-D deuterated at the diphenyl-substituted carbon, 4-pentynylamine derivatives 3a-D deuterated at the α-position of nitrogen atom was obtained with complete deuteration.

In conclusion, a concise method for preparation of 4-pentynylamine derivatives, which are useful intermediates for the synthesis of nitrogen containing compounds, is developed starting from enamides and a propargyl ether. By using a secondary enamide, consecutive reactions proceeded to afford a pyrrolidine derivative in a single operation. Further application of this methodology to the preparation of biologically active compounds is now in progress.

Experimental

General procedure of hydropropargylation of enamide

A mixture of ReI(CO)5 (5.4 mg, 0.012 mmol, 6 mol%), enamide 2 [17] (0.2 mmol, 1.0 equiv.) and propargyl ether 1 (88.9 mg, 0.4 mmol, 2.0 equiv.) in 1,4-dioxane (1.0 ml) was stirred for 10 h at 100 °C under a N2 atmosphere. The reaction mixture was quenched by addition of TMEDA (0.2 ml) and was concentrated under reduced pressure in vacuo. The crude material was purified by silica-gel column chromatography (ethyl acetate/hexane = 1/3) to give the corresponding product.

Crystallographic data of compounds 3i-dimer and 3 l have been deposited in the Cambridge Crystallographic Data Centre as CCDC 1883232 for 3i-dimer and CCDC 1883244 for 3j. The data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.