A New and Practical Procedure for the Bruylants Reaction. Zinc-Mediated Synthesis of Tertiary Homoallylamines and β-Aminoesters

Abstract

N,N-Disubstituted α-aminonitriles undergo Bruylants reaction under Barbier and Reformatsky conditions with activated halides, in the presence of zinc and 10 mol% HOAc. The high yields and the simple operational conditions make this reaction an appealing approach to N,N-disubstituted homoallylamines and β-aminoesters.

α-aminonitriles - Bruylants reaction - tertiary amines - zinc - metathesis

References

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Zinc-Mediated Bruylants Reaction - General procedure: To a stirred solution of the α-aminonitrile 1 (0.5 mmol) in dry THF (1 mL) were sequentially added allyl bromide or ethyl bromoacetate (1 mmol), zinc dust (1 mmol), and HOAc (0.05 mmol in 0.05 mL of dry THF). A slightly exothermic reaction occurred. The mixture was stirred at r.t. for 2 h, quenched with sat. Na₂CO₃ and then extracted three times with Et₂O. The organic extracts were dried (MgSO₄), filtered, evaporated and the crude product purified by chromatography on silica gel or neutral Al₂O₃ (hexane/EtOAc mixtures). Selected data for representative examples: 1-(1-Phenyl-3-butenyl)-pyrrolidine ( 2a). Colourless oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.22-7.05 (m, 5 H), 5.53-5.39 (m, 1 H), 4.90-4.72 (m, 2 H), 3.06 (dd. J = 4.2, 9.3 Hz, 1 H), 2.65-2.55 (m, 1 H), 2.52-2.40 (m, 3 H), 2.38-2.20 (m, 2 H), 1.79-1.60 (m, 4 H). ¹³C NMR (70 MHz, CDCl₃): δ = 142.5, 135.4, 128.2, 128.0, 126.9, 116.4, 70.9, 52.7, 40.5, 23.2. HRMS: exact mass calcd for C₁₄H₁₉N [M + Na]⁺ 224.1415. Found: 224.1399. N -Allyl- N -benzyl-1-cyclohexyl-3-buten-1-amine ( 2h). Colourless oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.30-7.08 (m, 5 H), 5.96-5.60 (m, 2 H), 5.17-4.80 (m, 4 H), 3.79 (d, J = 14.4 Hz, 1 H), 3.54 (d, J = 14.1 Hz, 1 H), 3.22 (ddt, J _t = 1.7 Hz, J _d = 4.9 Hz, J _d = 14.2 Hz, 1 H), 3.08 (dd, J = 7.5 Hz, J = 14.4 Hz, 1 H), 2.42-2.22 (m, 2 H), 2.18-2.03 (m, 1 H), 2.00-1.90 (m, 1 H), 1.70-1.50 (m, 4 H), 1.45-1.30 (m, 3 H), 1.22-0.71 (m, 3 H). ¹³C NMR (70 MHz, CDCl₃): δ = 141.0, 139.0, 138.0, 128.7, 128.0, 126.5, 116.1, 115.1, 62.9, 54.4, 53.6, 40.7, 32.1, 31.1, 31.0, 26.7, 26.6. HRMS: exact mass calcd for C₂₀H₂₉N [M + H]⁺ 284.2378. Found: 284.2388. Ethyl 3-Phenyl-(1-pyrrolidinyl)propanoate ( 3h). Colourless oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.34-7.05 (m, 5 H), 3.88 (q, J = 7.2 Hz, 2 H), 3.63 (dd. J = 5.7, 9.0 Hz, 1 H), 2.90 (dd. J = 5.7, 14.7 Hz, 1 H), 2.63 (dd. J = 9.0, 14.7 Hz, 1 H), 0.99 (t, J = 7.2 Hz, 3 H). ¹³C NMR (70 MHz, CDCl₃): δ = 171.5, 141.5, 128.1, 128.0, 127.4, 66.4, 60.2, 52.1, 41.6, 23.2, 13.9. IR (thin layer): ν = 1728 cm^-1. HRMS: exact mass calcd for C₁₅H₂₁NO₂ [M + H]⁺ 248.1651. Found: 248.1667. Ethyl 3-[Allyl(benzyl)amino]-3-cyclohexylpropanoate ( 3h). Colourless oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.40-7.18 (m, 5 H), 5.89-5.86 (m, 1 H), 5.21-5.02 (m, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.75 (d, J = 14.1 Hz, 1 H), 3.43 (d, J = 14.1 Hz, 1 H), 3.18 (m, 1 H), 3.01-2.86 (m, 2 H), 2.58 (dd, J = 5.1 Hz, J = 15.0 Hz, 1 H), 2.26 (dd, J = 7.2 Hz, J = 15.0 Hz, 1 H), 2.18-2.14 (m, 1 H), 1.80-1.58 (m, 4 H), 1.40-1.05 (m, 3 H), 1.25 (t, J = 7.2 Hz, 3 H), 0.98-0.80 (m, 2 H). ¹³C NMR (70 MHz, CDCl₃): δ = 173.8, 140.3, 137.3, 128.8, 128.0, 126.6, 116.6, 61.0, 60.3, 54.1, 53.1, 41.1, 33.3, 31.0, 30.3, 26.5, 26.4, 26.3, 14.2. IR (thin layer): ν = 1734 cm^-1. HRMS: exact mass calcd for C₂₁H₃₁NO₂ [M + Na]⁺ 352.2252. Found: 352.2237.

<A NAME="RG14603ST-11">11</A> The addition of allylzinc species to preformed iminium ions has been previously reported: Courtois G. Harama M. Mi giniac P. J. Organomet. Chem.  1981,  218:  275 ; see also ref. 6d

<A NAME="RG14603ST-12">12</A> It has already been shown that HOAc is able to accelerate zinc-mediated allylation of aldehydes under Barbier conditions: Oda Y. Matsuo S. Saito K. Tetrahedron Lett.  1992,  33:  97 

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<A NAME="RG14603ST-14">14</A> A Bruylants reaction on N-benzyl-2-cyano-piperidine, involving a preformed organozinc species generated from ethyl bromoacetate has been once reported: Dartiguelongue C. Payan S. Duval O. Gomes LM. Waigh RD. Bull. Soc. Chim. Fr.  1997,  134:  769 

<A NAME="RG14603ST-15">15</A> For a review of the application of RCM to the synthesis of nitrogen-containing compounds see: Phillips AJ. Abell AD. Aldrichimica Acta  1999,  32:  75 

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To a solution of homoallylamine 2 (0.11 mmol) in dry, degassed toluene (3.5 mL) was added ruthenium alkylidene 5 (4 mol%). The solution was stirred at 85 °C for 4 h 30 min, then pentane was added, followed by celite and charcoal. The mixture was stirred at r.t. overnight, then filtered and concentrated. Chromatography on silica gel (hexane/EtOAc) afforded tetrahydropyridines 6.

<A NAME="RG14603ST-17">17</A> Smith AB. Leahy JW. Noda I. Remiszewski SW. Liverton NJ. Zibuck R. J. Am. Chem. Soc.  1992,  114:  2995 

<A NAME="RG14603ST-18">18</A> Michael JP. In The Alkaloids   Vol. 55:  Cordell GA. Academic Press; San Diego: 2001. 

<A NAME="RG14603ST-19">19</A> N-Benzyl-2-cyano-piperidine was prepared in 62% yield by a modified Polonovski-Potier reaction, treating N-benzyl-piperidine N-oxide with TFAA and KCN (caution!), as described in the literature for similar compounds: Compernolle F. Ashty Saleh M. Van den Branden S. Toppet S. Hoornaert G. J. Org. Chem.  1991,  56:  2386