Preparation of Polyfunctional Tertiary Amines via the Electrophilic ­Amination of Arylmagnesium Compounds Using N-Chloroamines

Pradipta Sinha; Paul Knochel

doi:10.1055/s-2006-951560

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Synlett 2006(19): 3304-3308
DOI: 10.1055/s-2006-951560

LETTER

Preparation of Polyfunctional Tertiary Amines via the Electrophilic Amination of Arylmagnesium Compounds Using N-Chloroamines

Pradipta Sinha, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany
Fax: +49(89)218077680; e-Mail: Paul.Knochel@cup.uni-muenchen.de;

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Publication History

Received 31 August 2006
Publication Date:
23 November 2006 (online)

Abstract
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Abstract

Functionalized arylmagnesium compounds prepared via a halogen-magnesium exchange reaction using aryl iodides or bromides and i-PrMgCl·LiCl, react rapidly with benzyl-N-chloroamines at -45 °C providing polyfunctional tertiary amines in good yields. The methodology is also successfully applied to the preparation of chiral N-chloroamines with retention of chirality.

Key words

electrophilic amination - polyfunctional tertiary amines - arylmagnesium compounds - halogen-magnesium exchange - N-chloroamines

References and Notes

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7

Preparation of 4-{ N -Methyl- N -[(1 R )-1-phenyl-ethyl]amino}benzonitrile ( 3d); Typical Procedure:
A flame-dried argon-flushed 25-mL two-necked round-bottomed flask equipped with a magnetic stirrer and septum was charged with 4-bromobenzonitrile (186 mg, 1.02 mmol) dissolved in THF (1 mL) and cooled to -20 °C. Isopropylmagnesium chloride lithium chloride (0.71 mL, 1.1 mmol, 1.55 M in THF) was added dropwise to the above solution and I-Mg exchange was monitored by GC analysis until completion. The organomagnesium reagent thus formed was further cooled to -45 °C and a solution of N-chloro-N-[(1R)-1-phenylethyl]methylamine (1b; 170 mg, 1.0 mmol) in THF (2 mL) was added to it dropwise. The reaction mixture was stirred at -45 °C for 15 min and was quenched with a sat. solution of NH₄Cl and the residue was extracted with Et₂O (2 × 10 mL), washed with brine (2 × 10 mL), and dried over Na₂SO₄. Solvent removal under reduced pressure followed by flash chromatography over silica gel (eluent: pentane-Et₂O, 90:10) afforded 3d (165 mg, 70%) as a viscous yellow liquid. ¹H NMR (300 MHz, CDCl₃): δ = 7.35 (d, J = 9.1 Hz, 2 H), 7.14-7.29 (m, 5 H), 6.67 (d, J = 9.1 Hz, 2 H), 5.09 (q, 1 H), 2.67 (s, 3 H), 1.50 (d, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.3, 141.2, 133.5, 128.6, 127.3, 126.5, 120.5, 111.8, 97.6, 55.9, 31.9, 16.9. MS (EI, 70 eV): m/z (%) = 236 (48), 221 (53), 205 (9), 132 (23), 105(100), 103 (7). HRMS: m/z calcd for C₁₆H₁₆N₂: 236.1313; found: 236.1326. IR (film): 3029, 2977, 2213, 1605, 1519, 1449, 1385, 1180, 817, 701 cm^-1.
2-{ N -Methyl- N -[(1 R )-1-phenylethyl]amino}benzoic Acid Ethyl Ester ( 3e): ¹H NMR (300 MHz, CDCl₃): δ = 7.49 (m, 1 H), 7.09-7.23 (m, 6 H), 6.81-6.89 (m, 2 H), 4.51 (q, 1 H), 4.16-4.32 (m, 2 H), 2.47 (s, 3 H), 1.36 (d, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.9, 151.4, 142.2, 131.4, 130.4, 128.1, 127.1, 126.8, 125.3, 120.5, 120.3, 61.8, 60.8, 36.0, 17.7, 14.2. MS (EI, 70 eV): m/z (%) = 283 (10), 268 (100), 254 (36), 222 (16), 178 (25), 132 (29), 105(87), 77 (21). HRMS: m/z calcd for C₁₈H₂₁NO₂: 283.1572; found: 283.1554. IR (film): 3028, 2979, 1716, 1596, 1448, 1366, 1121, 701 cm^-1.
3-[ N -(4-Bromobenzyl)- N -methylamino]benzonitrile ( 3f): ¹H NMR (300 MHz, CDCl₃): δ = 7.36 (d, J = 8.8 Hz, 2 H), 7.18 (m, 1 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.88 (m, 1 H), 6.82 (m, 2 H), 4.42 (s, 2 H), 2.98 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 149.3, 136.6, 131.9, 129.9, 128.1, 121.0, 120.0, 119.6, 116.3, 114.8, 113.0, 55.8, 38.7. MS (EI, 70 eV): m/z (%) = 302 (34), 300(35), 171 (98), 169 (100), 145 (10), 102 (9), 90 (18). HRMS: m/z calcd for C₁₅H₁₃BrN₂: 300.0262; found (C₁₅H₁₃ ⁷⁹BrN₂): 300.0238. HRMS: m/z calcd for C₁₅H₁₃BrN₂: 300.0262; found (C₁₅H₁₃ ⁸¹BrN₂): 302.0220. IR (film): 3042, 2922, 2225, 1599, 1486, 1382, 1071, 1010, 774 cm^-1.
4-[ N -(4-Bromobenzyl)- N -methylamino]benzoic Acid Methyl Ester ( 3g): ¹H NMR (300 MHz, CDCl₃): δ = 7.85 (d, J = 9.1 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 8.4 Hz, 2 H), 6.63 (d, J = 9.1 Hz, 2 H), 4.53 (s, 2 H), 3.83 (s, 3 H), 3.07 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.2, 152.5, 136.8, 131.8, 131.4, 128.2, 120.9, 117.8, 110.9, 55.5, 51.5, 38.6. MS (EI, 70 eV): m/z (%) = 335 (36), 333 (38), 304 (6), 302 (8), 178 (31), 171 (99), 169 (100), 132 (17), 90 (30), 89 (24), 77 (10). HRMS: m/z calcd for C₁₆H₁₆BrNO₂: 333.0364; found (C₁₆H₁₆ ⁷⁹BrNO₂): 333.0353. HRMS: m/z calcd for C₁₆H₁₆BrNO₂: 333.0364; found (C₁₆H₁₆ ⁸¹BrNO₂): 335.0321. IR (film): 2952, 1698, 1607, 1434, 1386, 1287, 1191, 770 cm^-1.
N -Benzyl- N -ethyl-4-iodoaniline ( 3h): ¹H NMR (300 MHz, CDCl₃): δ = 7.31 (d, J = 9.1 Hz, 2 H), 7.11-7.26 (m, 5 H), 6.37 (d, J = 9.1 Hz, 2 H), 4.41 (s, 2 H), 3.36 (q, 2 H), 1.12 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 147.9, 138.5, 137.7, 128.6, 126.9, 126.4, 114.4, 76.6, 53.8, 45.3, 11.9. MS (EI, 70 eV): m/z (%) = 337 (100), 322 (42), 260 (9), 230 (5), 195 (7), 91 (56), 77 (2). HRMS: m/z calcd for C₁₅H₁₆IN: 337.0327; found: 337.0308. IR (film): 2966, 2922, 1589, 1454, 1359, 1268, 1076, 733 cm^-1.
2-( N -Benzyl- N -ethylamino)benzoic Acid Ethyl Ester ( 3i): ¹H NMR (300 MHz, CDCl₃): δ = 7.51 (m, 1 H), 7.09-7.27 (m, 6 H), 6.95 (m, 1 H), 6.85 (m, 1 H), 4.25 (q, 2 H), 4.21 (s, 2 H), 3.01 (q, 2 H), 1.28 (t, J = 7.1 Hz, 3 H), 0.93 (t, J = 6.9 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.9, 150.4, 138.8, 131.4, 130.6, 128.2, 128.1, 126.8, 126.3, 121.3, 120.8, 60.8, 56.6, 47.3, 14.2, 11.8. MS (EI, 70 eV): m/z = 283 (2), 255 (13), 254 (76), 208 (100), 192 (16), 146 (39), 91 (49), 77 (9). HRMS: m/z calcd for C₁₈H₂₁NO₂: 283.1572; found: 283.1548. IR (film): 3063, 2977, 2931, 2872, 1720, 1597, 1446, 1366, 1249, 761, 732 cm^-1.
N -Benzyl- N -ethylpyridin-3-amine ( 3j): ¹H NMR (300 MHz, CDCl₃): δ = 8.06 (m, 1 H), 7.85 (m, 1 H), 7.14-7.27 (m, 5 H), 6.97 (m, 1 H), 6.85 (m, 1 H), 4.45 (s, 2 H), 3.42 (q, 2 H), 1.15 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.2, 138.2, 137.5, 134.9, 128.7, 127.0, 126.4, 123.5, 118.4, 53.7, 45.1, 11.9. MS (EI, 70 eV): m/z (%) = 212 (21), 197 (20), 135 (6), 91 (100), 65 (8). HRMS: m/z calcd for C₁₄H₁₆N₂: 212.1313; found: 212.1292. IR (film): 2971, 2926, 1730, 1582, 1494, 1432, 791, 731 cm^-1.
3-{ N -Methyl- N -[1-(naphthalen-2-yl)ethyl]amino}benzo-nitrile ( 3k): ¹H NMR (300 MHz, CDCl₃): δ = 7.83 (m, 3 H), 7.71 (m, 1 H), 7.49 (m, 2 H), 7.25-7.38 (m, 2 H), 6.98-7.07 (m, 3 H), 5.23 (q, 1 H), 2.73 (s, 3 H), 1.66 (d, J = 6.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 150.0, 139.2, 133.3, 132.6, 129.9, 128.4, 127.9, 127.6, 126.3, 125.9, 125.4, 124.9, 119.8, 119.7, 116.8, 115.4, 113.0, 56.5, 31.9, 16.3. MS (EI, 70 eV): m/z (%) = 286 (9), 271 (6), 255 (2), 155 (100), 135 (5), 115 (3). HRMS: m/z calcd for C₂₀H₁₈N₂: 286.1470; found: 286.1476. IR (film): 3057, 2973, 2882, 2226, 1593, 1496, 1376, 1112, 821, 761 cm^-1.
4-{ N -Hexyl- N -[(1 S )-1-phenylethyl]amino}benzoic Acid Methyl Ester ( 3l): ¹H NMR (300 MHz, CDCl₃): δ =7.91 (d, J = 9.1 Hz, 2 H), 7.26-7.38 (m, 5 H), 6.73 (d, J = 9.1 Hz, 2 H), 5.21 (q, 1 H), 3.88 (s, 3 H), 3.14-3.26 (m, 2 H), 1.66 (d, J = 6.6 Hz, 3 H), 1.53 (m, 2 H), 1.27 (m, 6 H), 0.90 (t, J = 6.9 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.3, 151.9, 141.8, 131.3, 128.5, 127.1, 126.9, 116.9, 111.5, 56.2, 51.4, 46.3, 31.3, 28.2, 26.7, 22.5, 17.6, 13.9. MS (EI, 70 eV): m/z (%) = 339 (14), 324 (17), 268 (13), 164 (41), 105 (100), 77 (5). HRMS: m/z calcd for C₂₂H₂₉NO₂: 339.2198; found: 339.2188. IR (film): 2929, 2855, 1709, 1606, 1519, 1278, 1186, 769 cm^-1.