An Expedient Three-Component Approach to the Synthesis of α,α-Disubstituted Amines under Barbier-like Conditions

Abstract

A series of α,α-disubstituted amines such as diarylmethylamines, 1,2-diarylethylamines, and amino esters have been prepared in acetonitrile using a simple and expedient three-component Mannich-type procedure involving organic halides, aldehyde derivatives, and amines. Reactions are conducted under Barbier-like conditions using simple organic halides and zinc dust for the in situ generation of organozinc reagents.

amines - halides - multicomponent reactions - organometallic reagents - zinc

References and Notes

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10

During the course of a previous work dealing with the synthesis of benzylzinc bromide (nonpublished results), we could observe that the reaction is more rapid in MeCN than in THF (>2 times faster). Additionally, it was observed by Gosmini et al. that the solvent is of crucial importance in the cobalt-catalyzed synthesis of arylzinc halides, which cannot be conducted in THF (see ref. 13 for details).

11

This is consistent with previous works demonstrating that organozinc reagents have to be used in sufficient excess (>2 equiv) to react efficiently with aldehydes and amines (see ref. 9 for details).

12

Coupling products were characterized using ¹H NMR (400 MHz, CDCl₃), ¹³C NMR (100 MHz, CDCl₃), mass spectrometry, and when useful ¹⁹F NMR (376 MHz, CDCl₃), and IR spectroscopy.
Data for Selected Compounds N -(1-Phenyloctan-2-yl)-aniline (1) Colorless oil; yield 2.21 g (79%). ATR-FTIR (neat): 3405, 3025, 2926, 2855, 1600, 1504, 792, 691 cm^-1. ¹H NMR: δ = 7.41-7.29 (m, 7 H), 6.79 (t, J = 7.3 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 2 H), 3.75-3.73 (m, 1 H), 3.58 (br s, 1 H), 2.97 (dd, J = 13.6,4.6 Hz, 1 H), 2.91 (dd, J = 13.6, 6.4 Hz, 1 H), 1.69-1.40 (m, 10 H), 0.97 (t, J = 7.0 Hz, 3 H). ¹³C NMR: δ = 147.7, 138.7, 129.7, 129.5, 128.4, 126.3, 117.0, 113.2, 53.7, 40.2, 34.2, 31.9 29.4, 26.2, 22.7, 14.2. MS: m/z (%) = 191 (13), 190 (100), 118 (9), 106 (39), 91 (6), 55 (6). Anal. Calcd for C₂₀H₂₇N: C, 85.35; H, 9.67; N, 4.98. Found: C, 85.68; H, 9.99; N, 4.57.
Allyl-[2-(4-bromo-phenyl)-1-phenyl-ethyl]-amine (5)
Yellow oil; yield 2.05 g (65%). ATR-FTIR (neat): 3324, 3062, 3025, 2919, 2833, 1642, 1487, 1453, 1071, 1011, 915, 803, 756, 699 cm^-1. ¹H NMR: δ = 7.40-7.26 (m, 7 H), 6.99 (d, J = 7.9 Hz, 2 H), 5.76-5.88 (m, 1 H), 5.09-5.05 (m, 2 H), 3.90 (t, J = 7.0 Hz, 1 H), 3.14 (dd, J = 14.2, 4.7 Hz, 1 H), 3.01 (dd, J = 14.2, 6.5 Hz, 1 H), 2.92 (d, J = 6.8 Hz, 2 H), 1.50 (br s, 1 H). ¹³C NMR: δ = 143.1, 137.7, 136.7, 131.4, 131.1, 128.4, 127.3, 127.2, 120.2, 115.8, 63.7, 50.0, 44.5. MS: m/z (%) = 179 (5), 178 (6), 165 (5), 147 (11), 146 (100), 129 (8), 104 (7), 91 (35), 90 (8), 89 (5). Anal. Calcd for C₁₇H₁₈BrN: C, 64.57; H, 5.74; N, 4.43. Found: C, 64.30; H, 5.75; N, 4.30.
Ethyl ( N -Phenylamino)-3-phenylpropionate (7)
Pale yellow solid; yield 1.48 g (55%); mp 71-73 °C. ATR-FTIR (neat, cm^-1): 3384, 3025, 2980, 2925, 1712, 1602, 1218, 760, 689. ¹H NMR: δ = 7.42 (d, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.3 Hz, 2 H), 7.28 (t, J = 7.0 Hz, 1 H), 7.14 (t, J = 7.6 Hz, 2 H), 6.71 (t, J = 7.3 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 2 H), 4.87 (t, J = 6.6 Hz, 1 H), 4.64 (br s, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 2.84 (d, J = 6.2 Hz, 2 H), 1.23 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 171.2, 146.8, 142.2, 129.2, 128.8, 127.5, 126.3, 117.8, 113.7, 60.8, 55.0, 42.9, 14.2. MS: m/z (%) = 269 (20), 183 (14), 182 (100), 180 (9), 104 (17), 77 (6). Anal. Calcd for C₁₇H₁₉NO₂: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.65; H, 7.05; N, 5.07.

13 The efficient chemical synthesis of arylzinc reagents has been described in acetonitrile starting from aryl bromides and using a cobalt-catalyzed process, see: Fillon H. Gosmini C. Périchon J. J. Am. Chem. Soc.  2003,  125:  3867 

14 α-Bromo esters proved to react with preformed imines in the presence of zinc dust under ultrasound activation to furnish mixtures of β-amino esters and β-lactams, depending on the reaction temperature, see: Ross NA. MacGregor RR. Bartsch RA. Tetrahedron  2004,  60:  2035. 

15

This constitutes nonoptimized reaction conditions, which may likely be improved during the course of a separate study.

16a Buriez O. Cannes C. Nédélec J.-Y. Périchon J. J. Electroanal. Chem.  2000,  495:  57 

16b Buriez O. Nédélec J.-Y. Périchon J. J. Electroanal. Chem.  2001,  506:  162 

16c Buriez O. Kazmierski I. Périchon J. J. Electroanal. Chem.  2002,  537:  119