Preparation of Unsaturated Aminonitriles from the Aza-Morita-Baylis-Hillman Reactions of Aldimines with Penta-2,4-dienenitrile

Abstract

N-(Phenylsulfonyl)aldimines undergo facile aza-Morita-Baylis-Hillman reactions with penta-2,4-dienenitrile in anhydrous DMF in the presence of catalytic 3-hydroxyquinuclidine and methanol to afford the corresponding unsaturated aminonitriles.

aza-Morita-Baylis-Hillman reaction - penta-2,4-dienenitrile - conjugated diene - N-(phenylsulfonyl)aldimines - unsaturated aminonitriles

References and Notes

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10

Preparation of Penta-2,4-dienenitrile (5)
Potassium tert-butoxide (11.76 g, 104.8 mmol) in anhydrous THF (150 mL) was added dropwise to diethyl cyano­-methylphosphonate (16.95 g, 95.76 mmol) in anhydrous THF (180 mL) at -78 °C. After 30 min, freshly distilled acrolein (6.00 g, 108 mmol) was added dropwise. The reaction mixture was stirred for 20 min and then warmed to r.t. and quenched with sat. aq NH₄Cl solution. The solution was extracted with Et₂O, washed with brine and H₂O, and dried (MgSO₄). The combined organic layers were concentrated on a rotary evaporator at r.t. and the residue was chromatographed on neutral alumina (hexanes-Et₂O, 3:1) to afford 5 (3.974 g, 53%) as a mixture of E/Z isomers (80:20, determined by NMR integration). ¹H NMR (300 MHz, CDCl₃): δ (E-isomer) = 7.00 (dd, J = 15.9, 10.8 Hz, 1 H), 6.42 (dt, J = 16.9, 10.8 Hz, 1 H), 5.61 (d, J = 16.9 Hz, 1 H), 5.55 (d, J = 10.2 Hz, 1 H); δ (Z-isomer) = 7.24 (d, J = 6.7 Hz, 1 H), 7.17 (d, J = 7.2 Hz, 1 H), 6.83 (dt, J = 10.3, 5.1 Hz, 1 H).

For the promotive effects of alcohols and related additives, see:

11a Aggarwal VK. Emme I. Fulford SY. J. Org. Chem.  2003,  68:  692 

11b Aggarwal VK. Dean DK. Mereu A. Williams R. J. Org. Chem.  2002,  67:  510 

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11k Drewes SE. Freese SD. Emslie ND. Roos GHP. Synth. Commun.  1988,  18:  1565 

12

Typical Procedure - Preparation of Phenyl Derivative 6a A solution of nitrile 5 (0.024 mL, 20.8 mg, 0.26 mmol), imine 1a (64 mg, 0.26 mmol), MeOH (60 µL, 1.5 mmol), and HQD (8.6 mg, 0.068 mmol) in 4 mL of anhydrous DMF was stirred for 8 h at r.t. The reaction mixture was diluted with Et₂O and washed with H₂O and brine. The organic layer was dried (MgSO₄), concentrated, and chromatographed (toluene-EtOAc,16:1). The product was recrystallized from CHCl₃-hexanes to afford 66 mg (79%) of the pure Z-isomer: white needles; mp 156-157 °C. IR (film): 3243, 2208, 1317, 1165 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 7.2 Hz, 2 H), 7.57 (m, 1 H), 7.47 (m, 2 H), 7.32-7.29 (m, 3 H), 7.18-7.15 (m, 2 H), 6.80 (d, J = 10.8 Hz, 1 H), 6.60 (dt, J = 16.4, 10.5 Hz, 1 H), 5.59 (d, J = 16.9 Hz, 1 H), 5.57 (d, J = 9.2 Hz, 1 H), 5.30 (d, J = 7.2 Hz, exchanged with D₂O, 1 H), 5.15 (d, J = 7.2 Hz, collapsed to s with D₂O, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 145.6, 140.1, 136.7, 133.2, 132.2, 129.4, 129.3, 129.2, 127,6, 127.5, 126.9, 115.4, 114.2, 59.9. MS: m/z (%) = 324 (2), 183 (51), 77 (100). HRMS: m/z calcd for C₁₈H₁₆N₂O₂S: 324.0933; found: 324.0939.
p-Chlorophenyl derivative 6b: white needles; mp 173-174 °C. IR (film): 3243, 2213, 1309, 1170 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 7.2 Hz, 2 H), 7.59-7.46 (m, 2 H), 7.31-7.25 (m, 3 H), 7.12 (d, J = 8.7 Hz, 2 H), 6.77 (d, J = 10.8 Hz, 1 H), 6.58 (dt, J = 16.4, 10.3 Hz, 1 H), 5.61 (d, J = 16.4 Hz, 1 H), 5.60 (d, J = 7.2 10.2 Hz, 1 H), 5.15 (d, J = 7.2 Hz, collapsed to s with D₂O, 1 H), 5.05 (d, J = 7.2 Hz, exchanged with D₂O, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.0, 139.9, 135.3, 135.1, 133.4, 132.0, 129.6, 129.3, 128.3, 128.1, 127.4, 115.2, 113.6, 59.4. MS: m/z (%) = 358 (4) [M⁺], 217 (78), 76 (100). HRMS: m/z calcd for C₁₈H₁₅ClN₂O₂S: 358.0543; found: 358.0520.
m-Chlorophenyl derivative 6c: off-white solid; mp 114-119 °C. IR (film): 3259, 2210, 1337, 1162 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.79 (d, J = 7.2 Hz, 2 H), 7.58-7.43 (m, 3 H), 7.27-7.17 (m, 2 H), 7.10-7.06 (m, 2 H), 6.77 (d, J = 10.8 Hz, 1 H), 6.57 (dt, J = 16.4, 10.8 Hz, 1 H), 5.69 (d, J = 7.7 Hz, exchanged with D₂O, 1 H), 5.59 (d, J = 16.4 Hz, 1 H), 5.58 (d, J = 10.8 Hz, 1 H), 5.14 (d, J = 7.7 Hz, collapsed to s with D₂O, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.1, 139.9, 138.6, 135.2, 133.3, 132.0, 130.6, 129.3, 129.2, 128.2, 127.35, 127.25, 125.1, 115.3, 113.5, 59.3. MS: m/z (%) = 358 (5) [M⁺], 217 (100), 141 (33), 77 (72). HRMS: m/z calcd for C₁₈H₁₅ClN₂O₂S: 358.0543; found: 358.0556.
o-Chlorophenyl derivative 6d: white solid; mp 137-141 °C. IR (film): 3266, 2217, 1337, 1175 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.80 (d, J = 7.2Hz, 2 H), 7.55-7.41 (m, 3 H), 7.33-7.21 (m, 4 H), 6.82 (d, J = 10.8 Hz, 1 H), 6.63 (dt, J = 16.4, 10.2 Hz, 1 H), 5.66-5.58 (m, 3 H), 5.36 (d, J = 7.7 Hz, exchanged with D₂O, 1 H). ¹³C NMR (75 Hz, CDCl₃): δ = 146.0, 139.8, 134.1, 133.1, 132.8, 132.2, 130.3, 130.2, 129.2, 128.7, 127.9, 127.7, 127.3, 115.3, 113.2, 56.6. MS: m/z (%) = 358 (3) [M⁺], 217 (100), 141 (22), 77 (47). HRMS: m/z calcd for C₁₈H₁₅ClN₂O₂S: 358.0543; found: 358.0554.
p-Cyanophenyl derivative 6e: white solid; mp 149-152 °C. IR (film): 3252, 2226, 1335, 1165 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.78 (d, J = 7.2 Hz, 2 H), 7.59-7.54 (m, 3 H), 7.47-7.42 (m, 2 H), 7.39-7.27 (m, 2 H), 6.73 (d, J = 11.3 Hz, 1 H), 6.55 (dt, J = 16.9, 10.3 Hz, 1 H), 5.97 (d, J = 8.2 Hz, exchanged with D₂O, 1 H), 5.62-5.57 (m, 2 H), 5.23 (d, J = 7.7 Hz, collapsed to s with D₂O, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.6, 141.7, 139.9, 133.4, 132.9, 131.9, 129.4, 128.8, 127.8, 127.3, 118.2, 115.1, 112.9, 112.8, 59.4. MS: m/z (%) = 349 (2) [M⁺], 208 (100), 141 (26), 77 (52). HRMS: m/z calcd for C₁₃H₁₀N₃ [M⁺ - C₆H₅SO₂]: 208.0875; found: 208.0859.
p-Methoxyphenyl derivative 6f: off-white solid; mp 139-142 °C. IR (film): 3252, 2210, 1316, 1163 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 7.2 Hz, 2 H), 7.60-7.56 (m, 1 H), 7.51-7.46 (m, 2 H), 7.07 (d, J = 8.7 Hz, 2 H), 6.83-6.79 (m, 3 H), 6.60 (dt, J = 16.4, 10.3 Hz, 1 H), 5.58 (d, J = 16.9 Hz, 1 H), 5.56 (d, J = 9.7 Hz, 1 H), 5.14-5.07 (m, 2 H, collapsed to s, 1 H, with D₂O), 3.78 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 160.1, 145.3, 140.1, 133.2, 132.2, 129.3, 128.7, 128.2, 127.5, 127.4, 115.6, 114.7, 114.5, 59.4, 55.5. MS: m/z (%) = 354 (4) [M⁺], 276 (12), 213 (44), 77 (100). HRMS: m/z calcd for C₁₉H₁₈N₂O₃S: 354.1038; found: 354.1020.
p-Carbomethoxy derivative 6g: white solid; mp 127-131 °C. IR (film): 3266, 2217, 1714, 1337, 1281, 1162 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.97 (d, J = 8.2 Hz, 2 H), 7.82 (d, J = 7.2 Hz, 1 H), 7.60-7.55 (m, 1 H), 7.50-7.45 (m, 2 H), 7.25-7.22 (m, 2 H), 6.78 (d, J = 11.3 Hz, 1 H), 6.58 (dt, J = 16.4, 10.8 Hz, 1 H), 5.61 (d, J = 16.4 Hz, 1 H), 5.60 (d, J = 10.3 Hz, 1 H), 5.37 (d, J = 7.7 Hz, exchanged with D₂O, 1 H), 5.22 (d, J = 7.7 Hz, collapsed to s with D₂O, 1 H), 3.92 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.4, 146.2, 141.3, 140.0, 133.4, 132.0, 130.9, 130.6, 129.3, 128.2, 127.4, 127.0, 115.2, 113.5, 59.6, 52.5. MS: m/z (%) = 382 (1) [M⁺], 157 (13), 141 (16), 76 (100). HRMS: m/z calcd for C₂₀H₁₈O₄N₂S: 382.0987; found: 382.0955.
o-Carbomethoxy derivative 6h: white solid; mp 127-132 °C. IR (film): 3283, 2217, 1713, 1270, 1165 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.86 (d, J = 6.7 Hz, 1 H), 7.72 (d, J = 7.7 Hz, 2 H), 7.46-7.27 (m, 6 H), 6.82 (d, J = 10.3 Hz, 1 H), 6.63 (dt, J = 16.9, 10.8 Hz, 1 H), 6.58 (d, J = 9.3 Hz, exchanged with D₂O, 1 H), 5.80 (d, J = 9.2 Hz, collapsed to s with D₂O, 1 H), 5.56 (d, J = 16.4 Hz, 1 H), 5.54 (d, J = 9.8 Hz, 1 H), 3.85 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.0, 145.3, 140.4, 138.1, 133.1, 132.8, 132.4, 131.8, 130.4, 129.0, 128.5, 128.3, 127.3, 127.1, 115.6, 113.9, 57.7, 52.9. MS: m/z (%) = 382 (0.1) [M⁺], 286 (52), 241 (16), 209 (39), 77 (100). HRMS: m/z calcd for C₁₄H₁₃N₂O₂ [M⁺ - PhSO₂]: 241.0977; found: 241.0974.
3-Pyridyl derivative 6i: white solid; mp 189-191 °C. IR (film): 2225, 1330, 1162 cm^-1. ¹H NMR (300 MHz, acetone-d ₆): δ = 8.54 (d, J = 2.0 Hz, 1 H), 8.49 (dd, J = 4.6, 1.6 Hz, 1 H), 8.41-8.06 (m, 5 H), 7.76-7.73 (m, 1 H), 7.34-7.29 (m, 1 H), 7.03 (d, J = 11.3 Hz, 1 H), 6.61 (dt, J = 16.9,10.3 Hz, 1 H), 5.74 (d, J = 16.4 Hz, 1 H), 5.65 (d, J = 9.7 Hz, 1 H), 5.54 (s, 1 H). ¹³C NMR (75 MHz, acetone-d ₆): δ = 151.0, 150.7, 149.6, 147.4, 146.8, 135.4, 133.6, 132.9, 129.4, 128.6, 125.1, 124.4, 115.9, 115.1, 58.3. MS: m/z (%) = 184 (100), 122 (24). HRMS: m/z calcd for C₁₁H₁₀N₃ [M⁺ - PhSO₂]: 184.0875; found: 184.0875.
2-Furanyl derivative 6j: off-white solid; mp 119-121 °C. IR (film): 3238, 2210, 1329, 1162 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.85-7.81 (m, 2 H), 7.60-7.46 (m, 3 H), 7.31 (dd, J = 1.8, 0.8 Hz, 1 H), 6.80 (d, J = 11.1 Hz, 1 H), 6.61 (dt, J = 16.6, 10.5 Hz, 1 H), 6.28 (dd, J = 3.3, 1.9 Hz, 1 H), 6.22 (d, J = 3.4 Hz, 1 H), 5.64 (d, J = 16.9 Hz, 1 H), 5.61 (d, J = 9.8 Hz, 1 H), 5.32 (d, J = 8.0 Hz, exchanged with D₂O, 1 H), 5.25 (d, J = 8.0 Hz, collapsed to s with D₂O, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 148.4, 145.9, 143.4, 139.9, 133.0, 131.9, 129.0, 127.8, 127.1, 114.9, 112.0, 110.7, 108.8, 53.9. MS: m/z (%) = 236 (10), 173 (100). HRMS: m/z calcd for C₁₀H₉N₂O [M⁺ - PhSO₂]: 173.0715; found: 173.0723.
1-Naphthyl derivative 6k: colorless crystals; mp 130-131 °C. IR (film): 3269, 2212, 1325, 1160 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.85-7.76 (m, 5 H), 7.56-7.31 (m, 7 H), 6.83 (d, J = 11.0 Hz, 1 H), 6.62 (dt, J = 16.5, 10.7 Hz, 1 H), 5.92 (d, J = 6.7 Hz, 1 H, collapsed to s with D₂O), 5.52 (d, J = 9.7 Hz, 1 H), 5.50, (d, J = 16.7 Hz, 1 H), 5.28 (d, J = 6.7 Hz, exchanged with D₂O, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 145.7, 139.9, 134.1, 133.0, 132.1, 130.0, 129.2, 129.0, 127.33, 127.26, 126.3, 125.5, 125.2, 122.3, 115.6, 114.1, 56.0. MS: m/z (%) = 375 (15), 374 (60), 233 (100), 217 (57), 154 (75), 77 (67). HRMS: m/z calcd for C₁₆H₁₃N₂ [M⁺ - PhSO₂]: 233.1079; found: 233.1099.