A Synthesis of Functionalized Dihydro-1H-pyrroles from Nef-Isocyanide 
Adducts and Enamines

Issa Yavari; Reza Hosseinpour; Ramin Pashazadeh

doi:10.1055/s-0031-1290369

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Synlett 2012; 23(11): 1662-1666
DOI: 10.1055/s-0031-1290369

letter

A Synthesis of Functionalized Dihydro-1H-pyrroles from Nef-Isocyanide Adducts and Enamines

Issa Yavari*

Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran, Fax: +98(21)82883455 eMail: yavarisa@modares.ac.ir

,

Reza Hosseinpour

Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran, Fax: +98(21)82883455 eMail: yavarisa@modares.ac.ir

,

Ramin Pashazadeh

Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran, Fax: +98(21)82883455 eMail: yavarisa@modares.ac.ir

› Institutsangaben

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Publikationsverlauf

Received: 14. März 2012

Accepted after revision: 23. April 2012

Publikationsdatum:
14. Juni 2012 (online)

Abstract
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Abstract

α-Ketoimidoyl chlorides, obtained from α-addition of acyl chlorides onto alkyl isocyanides, are treated with enamines to afford 5-(alkylimino)-4-hydroxy-4,5-dihydro-1H-pyrrole-2,3,4-tricarboxylates and 2-(alkylimino)-3-hydroxy-2,3-dihydro-1H-pyrrole-3,4-dicarboxylates in good to excellent yields.

Key words

Nef-isocyanide adduct - enaminone - imidoyl chloride - pyrrole - chemoselective reaction

References and Notes
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19 Synthesis of 7 and 13; General Procedure: To a magnetically stirred solution of alkylamine 3 (1 mmol) in anhydrous MeCN (2 mL), was added either dialkyl acetylenedicarboxylate 4 (1 mmol) or 1,3-dicarbonyl compound 11 (1 mmol). This solution was added to α-ketoimidoyl chloride 5 [obtained from the alkyl chloroglyoxalate 1 (1 mmol) and alkyl isocyanide 2 (1 mmol) at room temperature]. After completion of the reaction [ca. 6 h; reaction monitored by TLC (EtOAc–hexane, 1:5)], the cream precipitate was separated, washed with hexane–Et₂O, and neutralized with Et₃N in a mixture of H₂O–MeOH to the give product. Trimethyl 1-Benzyl-5-(cyclohexylimino)-4,5-dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7a): Yield: 0.31 g (70%); cream powder; mp 124–126 °C. IR (KBr): 3431 (OH), 1749 (C=O), 1675 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = δ = 1.22–1.93 (m, 10 H, 5 CH₂), 3.05–3.10 (m, 1 H, CH), 3.60 (s, 3 H, MeO), 3.65 (s, 3 H, MeO), 3.75 (s, 3 H, MeO), 4.16 (br s, 1 H, OH), 4.63 (d, ² J = 15.6 Hz, 1 H, CH₂N), 4.80 (d, ² J = 15.6 Hz, 1 H, CH₂N), 7.17 (t, ³ J = 7.0 Hz, 2 H, 2 CH), 7.20 (t, ³ J = 7.0 Hz, 1 H, CH), 7.24 (d, ³ J = 7.0 Hz, 2 H, 2 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 23.9 (CH₂), 24.0 (CH₂), 25.5 (CH₂), 34.0 (CH₂), 34.5 (CH₂), 45.2 (CH), 51.2 (MeO), 52.8 (MeO), 53.3 (MeO), 57.5 (CH₂N), 77.3 (C-OH), 104.3 (C), 127.3 (2 CH), 128.1 (2 CH), 128.7 (CH), 136.4 (C), 150.6 (C), 152.8 (C=N), 161.6 (C=O), 161.9 (C=O), 170.7 (C=O). MS (EI): m/z (%) = 444 (2) [M]⁺, 385 (48), 353 (65), 293 (15), 271 (30), 211 (35), 151 (5), 91 (100), 55 (15). Anal. Calcd. for C₂₃H₂₈N₂O₇ (444.19): C, 62.15; H, 6.35; N, 6.30. Found: C, 62.11; H, 6.27; N, 6.34. Trimethyl 5-(Cyclohexylimino)-4,5-dihydro-4-hydroxy-1-(4-methylbenzyl)-1H-pyrrole-2,3,4-tricarboxylate (7b): Yield: 0.33 g (72%); cream powder; mp 114–116 °C. IR (KBr): 3430 (OH), 1751 (C=O), 1663 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.21–1.72 (m, 10 H, 5 CH₂), 2.29 (s, 3 H, Me), 2.78 (br s, 1 H, OH), 3.63 (s, 3 H, MeO), 3.71 (s, 3 H, MeO), 3.77 (s, 3 H, MeO), 4.10–4.25 (m, 1 H, CH), 4.62 (d, ² J = 15.5 Hz, 1 H, CH₂N), 4.78 (d, ² J = 15.5 Hz, 1 H, CH₂N), 6.90–7.20 (m, 5 H, 5 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 20.9 (Me), 24.0 (2 CH₂), 25.5 (CH₂), 34.0 (CH₂), 34.5 (CH₂), 45.0 (CH), 51.2 (MeO), 52.8 (MeO), 53.3 (MeO), 57.5 (CH₂N), 77.2 (C-OH), 104.2 (C), 127.3 (2 CH), 128.9 (2 CH), 133.4 (C), 137.0 (C), 150.6 (C), 152.8 (C=N), 161.6 (C=O), 162.0 (C=O), 170.8 (C=O). MS (EI): m/z (%) = 458 (2) [M]⁺, 399 (48), 367 (40), 293 (12), 239 (10), 211 (28), 151 (10), 105 (100), 79 (12), 55 (12). Anal. Calcd. for C₂₄H₃₀N₂O₇ (458.21): C, 62.87; H, 6.59; N, 6.11. Found: C, 62.81; H, 6.62; N, 6.19. Trimethyl 5-(Cyclohexylimino)-4,5-dihydro-4-hydroxy-1-(4-methyloxybenzyl)-1H-pyrrole-2,3,4-tricarboxylate (7c): Yield: 0.33 g (70%); cream powder; mp 96–98 °C. IR (KBr): 3429 (OH), 1747 (C=O), 1664 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.24–1.74 (m, 10 H, 5 CH₂), 2.28 (s, 3 H, Me), 3.63 (s, 3 H, MeO), 3.73 (s, 3 H, MeO), 3.77 (s, 3 H, MeO), 3.78 (s, 3 H, MeO), 3.64–3.68 (m, 1 H, CH), 4.62 (d, ² J = 15.4 Hz, 1 H, CH₂N), 4.64 (br s, 1 H, OH), 4.75 (d, ² J = 15.4 Hz, 1 H, CH₂N), 6.80 (d, ³ J = 8.6 Hz, 2 H, 2 CH), 7.13 (d, ³ J = 8.6 Hz, 2 H, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 24.1 (CH₂), 24.2 (CH₂), 25.7 (CH₂), 34.2 (CH₂), 34.7 (CH₂), 44.9 (CH), 51.4 (MeO), 53.0 (MeO), 53.5 (MeO), 55.2 (MeO), 57.7 (CH₂N), 76.6 (C-OH), 104.3 (C), 113.7 (2 CH), 128.7 (C), 128.8 (2 CH), 150.8 (C), 153.0 (C), 159.9 (C=N), 161.8 (C=O), 162.1 (C=O), 170.9 (C=O). MS (EI): m/z (%) = 474 (10) [M]⁺, 415 (18), 383 (9), 293 (6), 211 (12), 136 (7), 151 (10), 121 (100), 83 (9), 55 (15). Anal. Calcd. for C₂₄H₃₀N₂O₈ (474.2): C, 60.57; H, 6.37; N, 5.90. Found: C, 60.68; H, 6.25; N, 5.83. 4-Ethyl 2,3-Dimethyl 1-benzyl-5-(cyclohexylimino)-4,5-dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7d): Yield: 0.35 g (76%); cream powder; mp 105–107 °C. IR (KBr): 3431 (OH), 1750 (C=O), 1667 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.18–1.75 (m, 10 H, 5 CH₂), 1.24 (t, ³ J = 7.0 Hz, 3 H, Me), 3.62 (s, 3 H, MeO), 3.69 (s, 3 H, MeO), 3.86–3.88 (m, 1 H, CH), 4.21 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.57 (d, ² J = 15.8 Hz, 1 H, CH of CH₂N), 4.88 (br s, 1 H, OH), 5.91 (d, ² J = 15.8 Hz, 1 H, CH of CH₂N), 7.23–7.29 (m, 5 H, 5 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 12.6 (Me), 23.5 (CH₂), 23.5 (CH₂), 25.0 (CH₂), 33.5 (CH₂), 34.0 (CH₂), 44.3 (CH), 49.9 (MeO), 51.7 (MeO), 56.8 (OCH₂), 61.6 (CH₂N), 76.6 (C-OH), 105.2 (C), 126.6 (2 CH), 126.7 (CH), 127.5 (2 CH), 136.3 (C), 150.4 (C), 154.8 (C=N), 161.4 (C=O), 161.8 (C=O), 169.1 (C=O). MS (EI): m/z (%) = 458 (2) [M]⁺, 385 (60), 353 (80), 307 (10), 271 (37), 225 (17), 181 (10), 126 (12), 91 (100), 55 (18). Anal. Calcd. for C₂₄H₃₀N₂O₇ (458.21): C, 62.87; H, 6.59; N, 6.11. Found: C, 62.74; H, 6.27; N, 6.02. 4-Ethyl 2,3-Dimethyl 5-(cyclohexylimino)-4,5-dihydro-4-hydroxy-1-(4-methylbenzyl)-1H-pyrrole-2,3,4-tricarboxylate (7e): Yield: 0.31 g (65%); cream powder; mp 96–98 °C. IR (KBr): 3426 (OH), 1753 (C=O), 1665 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.03 (t, ³ J = 7.1 Hz, 3 H, Me), 1.21–1.73 (m, 10 H, 5 CH₂), 2.27 (s, 3 H, Me), 3.60–3.70 (m, 1 H, CH), 3.61 (s, 3 H, MeO), 3.68 (s, 3 H, MeO), 4.21 (br s, 1 H, OH), 4.26 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.52 (d, ² J = 15.6 Hz, 1 H, CH₂N), 4.86 (d, ² J = 15.6 Hz, 1 H, CH₂N), 7.03 (d, ³ J = 7.9 Hz, 2 H, 2 CH), 7.07 (d, ³ J = 7.9 Hz, 2 H, 2 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.9 (Me), 21.0 (Me), 24.1 (CH₂), 24.2 (CH₂), 25.7 (CH₂), 34.2 (CH₂), 34.7 (CH₂), 45.0 (CH), 51.2 (MeO), 52.8 (MeO), 57.6 (OCH₂), 62.8 (CH₂N), 76.9 (C-OH), 104.6 (C), 127.4 (2 CH), 128.9 (2 CH), 133.6 (C), 137.0 (C), 150.7 (C), 153.1 (C=N), 161.8 (C=O), 162.0 (C=O), 170.3 (C=O). MS (EI): m/z (%) = 472 (2) [M]⁺, 399 (34), 367 (34), 307 (10), 285 (14), 225 (15), 181 (5), 143 (4), 105 (100), 55 (12). Anal. Calcd. for C₂₅H₃₂N₂O₇ (472.22): C, 63.54; H, 6.83; N, 5.93. Found: C, 63.65; H, 6.73; N, 5.85. 4-Ethyl 2,3-Dimethyl 1-allyl-5-(cyclohexylimino)-4,5-dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7f): Yield: 0.26 g (65%); cream powder; mp 82–84 °C. IR (KBr): 3430 (OH), 1753 (C=O), 1666 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.20 (t, ³ J = 7.1 Hz, 3 H, Me), 1.23–1.68 (m, 10 H, 5 CH₂), 3.54–3.58 (m, 1 H, CH), 3.60 (s, 3 H, MeO), 3.84 (s, 3 H, MeO), 4.00–4.04 (m, 1 H, CH₂N), 4.06–4.08 (br s, 1 H, OH), 4.13–4.17 (m, 1 H, CH₂N), 4.22 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 5.05 (d, ³ J = 10.3 Hz, 1 H, H₂C=), 5.08 (d, ² J = 17.1 Hz, 1 H, H₂C=), 5.65–5.72 (m, 1 H, =CH-). ¹³C NMR (125 MHz, CDCl₃): δ = 13.8 (Me), 23.9 (CH₂), 24.0 (CH₂), 25.5 (CH₂), 34.0 (CH₂), 34.5 (CH₂), 44.0 (CH), 51.1 (MeO), 52.8 (MeO), 57.5 (OCH₂), 62.7 (CH₂N), 77.2 (C-OH), 104.2 (C), 116.8 (H₂C=), 131.7 (=CH-), 150.7 (C), 152.4 (C=N), 161.6 (C=O), 161.9 (C=O), 170.2 (C=O). MS (EI): m/z (%) = 408 (2) [M]⁺, 355 (20), 303 (100), 253 (80), 221 (95), 166 (28), 126 (24), 105 (8), 55 (25). Anal. Calcd. for C₂₀H₂₈N₂O₇ (408.19): C, 58.81; H, 6.91; N, 6.86. Found: C, 58.71; H, 6.82; N, 6.83. 4-Ethyl 2,3-Dimethyl 1-butyl-5-(cyclohexylimino)-4,5-dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7g): Yield: 0.30 g (70%); cream powder; mp 94–96 °C. IR (KBr): 3414 (OH), 1753 (C=O), 1660 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.84 (t, ³ J = 7.3 Hz, 3 H, Me), 1.15–1.70 (m, 14 H, 7 CH₂), 1.21 (t, ³ J = 7.1 Hz, 3 H, CH₃), 3.32–3.37 (m, 1 H, CH), 3.86–3.55 (d, ³ J = 7.1 Hz, 2 H, CH₂N), 3.62 (s, 3 H, MeO), 3.91 (s, 3 H, MeO), 4.10 (br s, 1 H, OH), 4.20 (q, ³ J = 7.1 Hz, 2 H, OCH₂). ¹³C NMR (125 MHz, CDCl₃): δ = 13.6 (Me), 13.9 (Me), 19.5 (CH₂), 24.0 (CH₂), 24.1 (CH₂), 25.7 (CH₂), 30.3 (CH₂), 34.2 (CH₂), 34.7 (CH₂), 42.2 (CH), 51.1 (MeO), 53.1 (MeO), 57.7 (OCH₂), 62.7 (CH₂N), 77.3 (C-OH), 103.5 (C), 151.6 (C), 153.0 (C=N), 162.0 (C=O), 162.1 (C=O), 170.4 (C=O). MS (EI): m/z (%) = 424 (2) [M]⁺, 351 (33), 319 (100), 287 (10), 263 (10), 237 (10), 182 (14), 142 (8), 126 (5), 57 (15). Anal. Calcd. for C₂₁H₃₂N₂O₇ (424.22): C, 59.42; H, 7.60; N, 6.60. Found: C, 59.46; H, 7.68; N, 6.72. Triethyl 1-Benzyl-5-(cyclohexylimino)-4,5-dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7h): Yield: 0.25 g (50%); cream powder; mp 80–82 °C. IR (KBr): 3430 (OH), 1733 (C=O), 1672 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.10 (t, ³ J = 7.1 Hz, 3 H, Me), 1.19 (t, ³ J = 7.1 Hz, 3 H, Me), 1.26 (t, ³ J = 7.1 Hz, 3 H, Me), 1.25–1.89 (m, 10 H, 5 CH₂), 3.60–3.66 (m, 1 H, CH), 4.11 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.15 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.23 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.57 (br s, 1 H, OH), 4.63 (d, ² J = 15.8 Hz, 1 H, CH₂N), 4.90 (d, ² J = 15.8 Hz, 1 H, CH₂N), 7.22–7.26 (m, 5 H, 5 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 15.0 (Me), 15.4 (Me), 15.6 (Me), 25.5 (CH₂), 25.6 (CH₂), 27.1 (CH₂), 35.6 (CH₂), 36.2 (CH₂), 46.6 (CH), 59.1 (OCH₂), 61.4 (OCH₂), 63.9 (OCH₂), 64.3 (CH₂N), 78.1 (C-OH), 105.9 (C), 128.7 (2 CH), 128.8 (2 CH), 129.7 (CH), 138.2 (C), 152.1 (C), 154.5 (C=N), 162.8 (C=O), 163.1 (C=O), 171.9 (C=O). MS (EI): m/z (%) = 486 (2) [M]⁺, 413 (2), 367 (4), 299 (15), 207 (18), 178 (8), 105 (10), 91 (100), 77 (5), 52 (4). Anal. Calcd. for C₂₆H₃₄N₂O₇ (486.24): C, 64.18; H, 7.04; N, 5.76. Found: C, 64.12; H, 6.98; N, 5.73. Diethyl 1-Benzyl-2-(cyclohexylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3,4-dicarboxylate (13a): Yield: 0.33 g (78%); colorless solid; mp 85–87 °C. IR (KBr): 3357 (OH), 1729 (C=O), 1641 (C=O), 1604 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.20 –1.80 (m, 10 H, 5 CH₂), 1.24 (t, ³ J = 7.1 Hz, 3 H, Me), 1.30 (t, ³ J = 7.1 Hz, 3 H, Me), 2.31 (s, 3 H, Me), 2.29 (s, 3 H, Me), 3.63–3.72 (m, 1 H, CH), 4.13 (br s, 1 H, OH), 4.21 (m, 2 H, OCH₂), 4.27 (m, 2 H, OCH₂), 4.64 (d, ² J = 16.1 Hz, 1 H, CH₂N), 5.05 (d, ² J = 16.1 Hz, 1 H, CH₂N), 7.15–7.30 (m, 5 H, 5 CH of aryl). ¹³C NMR (125 MHz, CDCl₃): δ = 12.8 (Me), 14.1 (Me), 14.3 (Me), 24.3 (2 CH₂), 25.7 (CH₂), 34.3 (CH₂), 34.7 (CH₂), 43.8 (CH), 57.4 (OCH₂), 59.3 (OCH₂), 62.4 (CH₂N), 82.0 (C-OH), 103.6 (C), 126.4 (CH), 127.1 (CH), 128.5 (CH), 137.5 (CH), 154.2 (C), 160.6 (C=N), 163.8 (C=O), 171.5 (C=O). MS (EI): m/z (%) = 428 (2) [M]⁺, 355 (72), 309 (100), 283 (12), 227 (60), 200 (10), 132 (19), 91 (94), 69 (54), 55 (51). Anal. Calcd. for C₂₄H₃₂N₂O₅ (428.23): C, 67.27; H, 7.53; N, 6.54. Found: C, 67.22; H, 7.46; N, 6.48. Diethyl 1-Benzyl-2-(tert-butylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3,4-dicarboxylate (13b): Yield: 0.26 g (65%); colorless crystals; mp 80–82 °C. IR (KBr): 3373 (OH), 1749 (C=O), 1656 (C=O), 1612 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.21 (t, ³ J = 7.1 Hz, 3 H, Me), 1.23 (t, ³ J = 7.1 Hz, 3 H, Me), 1.24 (s, 9 H, CMe₃), 2.35 (s, 3 H, Me), 4.10–4.28 (m, 4 H, 2 OCH₂), 4.43 (br s, 1 H, OH), 4.58 (d, ² J = 15.8 Hz, 1 H, CH₂N), 5.10–5.19 (d, ² J = 15.8 Hz, 1 H, CH₂N), 7.20–7.35 (m, 5 H, 5 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.2 (Me), 14.0 (Me), 14.4 (Me), 31.0 (CMe₃), 51.9 (CMe₃), 59.5 (OCH₂), 62.2 (OCH₂), 62.5 (CH₂N), 77.9 (C-OH), 102.1 (C), 126.6 (CH), 127.1 (CH), 128.5 (CH), 138.5 (CH), 160.1 (C), 161.2 (C=N), 164.5 (C=O), 172.0 (C=O). MS (EI): m/z (%) = 402 (10) [M]⁺, 329 (74), 283 (79), 227 (100), 181 (22), 131 (28), 91 (83), 57 (55). Anal. Calcd. for C₂₂H₃₀N₂O₅ (402.22): C, 65.65; H, 7.51; N, 6.96. Found: C, 65.71; H, 7.62; N, 7.03. Diethyl 1-Benzyl-2,3-dihydro-3-hydroxy-5-methyl-2-(1,1,3,3-tetramethylbutylimino)-1H-pyrrole-3,4-dicarboxylate (13c): Yield: 0.24 g (52%); yellow oil. IR (KBr): 3393 (OH), 1743 (C=O), 1676 (C=O), 1608 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.83 (s, 3 H, CMe₂), 1.27 (t, ³ J = 7.1 Hz, 3 H, Me), 0.98 (s, 3 H, CMe₂), 1.23 (m, 3 H, Me), 1.25 (s, 9 H, CMe₃), 1.26 (m, 3 H, Me), 1.40 (d, ² J = 12.1 Hz, 1 H, CH₂), 1.43 (d, ² J = 12.1 Hz, 1 H, CH₂), 1.90 (s, 3 H, Me), 4.08 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.12 (br s, 1 H, OH), 4.20 (q, ³ J = 7.1 Hz, 2 H, OCH₂), 4.58 (d, ³ J = 16.4 Hz, 1 H, CH ₂N), 5.22 (d, ³ J = 16.4 Hz, 1 H, CH ₂N), 7.15–7.35 (m, 5 H, 5 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.2 (Me), 14.1 (Me), 14.6 (Me), 29.7 (CMe₃), 31.4 (CMe₂), 31.6 (CMe₂), 31.9 (CH₂), 51.8 (CMe₃), 55.8 (CMe₂), 58.6 (OCH₂), 59.2 (OCH₂), 62.0 (CH₂N), 79.0 (C-OH), 103.1 (C), 126.2 (CH), 126.7 (CH), 127.3 (CH), 138.1 (CH), 160.0 (C), 161.7 (C=N), 164.2 (C=O), 171.3 (C=O). MS (EI): m/z (%) = 458 (5) [M]⁺, 385 (11), 341 (14), 273 (24), 227 (31), 196 (27), 172 (26), 147 (37), 131 (22), 91 (100). Anal. Calcd. for C₂₆H₃₈N₂O₅ (458.28): C, 68.10; H, 8.35; N, 6.11. Found: C, 68.05; H, 8.29; N, 6.17. Ethyl 4-Acetyl-1-benzyl-2-(cyclohexylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13d): Yield: 0.29 g (75%); cream powder; mp 110–112 °C. IR (KBr): 3243 (OH), 1749 (C=O), 1686 (C=O), 1615 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.15–1.75 (m, 10 H, 5 CH₂), 1.28 (t, ³ J = 7.2 Hz, 3 H, Me), 2.19 (s, 3 H, Me), 2.29 (s, 3 H, Me), 3.74–3.75 (m, 1 H, CH), 4.16–4.29 (m, 2 H, OCH₂), 4.40 (br s, 1 H, OH), 4.63 (d, ² J = 16.2 Hz, 1 H, CH₂N), 5.13 (d, ² J = 16.5 Hz, 1 H, CH₂N), 7.20 (d, ³ J = 7.2 Hz, 2 H, 2 CH), 7.24 (t, ³ J = 7.2 Hz, 1 H, CH), 7.28 (d, ³ J = 7.2 Hz, 2 H, 2 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 14.8 (Me), 14.9 (Me), 25.0 (CH₂), 25.1 (CH₂), 26.6 (CH₂), 30.1 (Me), 35.1 (CH₂), 35.6 (CH₂), 44.8 (CH), 58.1 (OCH₂), 63.4 (CH₂N), 78.9 (C-OH), 116.6 (C), 127.3 (CH), 128.1 (CH), 129.5 (CH), 138.1 (CH), 155 (C), 160.1 (C=N), 172.5 (C=O), 191.9 (C=O). MS (EI): m/z (%) = 398 (2) [M]⁺, 325 (100), 283 (4), 243 (45), 229 (10), 201 (12), 106 (15), 91 (96), 79 (14), 58 (45). Anal. Calcd. for C₂₃H₃₀N₂O₄ (398.22): C, 69.62; H, 8.06; N, 7.11. Found: C, 69.74; H, 8.14; N, 7.18. Ethyl 4-Acetyl-1-benzyl-2-(tert-butylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13e): Yield: 0.26 g (70%,); cream powder; mp 115–117 °C. IR (KBr): 3395 (OH), 1738 (C=O), 1687 (C=O), 1572 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.23 (t, ³ J =7.1 Hz, 3 H, Me), 1.28 (s, 9 H, CMe₃), 2.21 (s, 3 H, Me), 2.29 (s, 3 H, Me), 3.70 (br s, 1 H, OH), 4.12–4.30 (m, 2 H, OCH₂), 4.58 (d, ² J = 16.1 Hz, 1 H, CH₂N), 5.23 (d, ² J = 16.1 Hz, 1 H, CH₂N), 7.22 (d, ³ J = 7.7 Hz, 2 H, 2 CH), 7.23 (d, ³ J = 7.7 Hz, 2 H, 2 CH), 7.28 (d, ³ J = 7.7 Hz, 2 H, 2 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.9 (Me), 14.3 (Me), 29.4 (Me), 30.9 (CMe₃), 41.2 (CMe₃), 55.0 (OCH₂), 61.8 (CH₂N), 78.4 (C-OH), 114.2 (C), 126.4 (CH), 126.7 (CH), 126.9 (CH), 128.5 (CH), 137.6 (C), 149.8 (C), 158.9 (C=N), 171.1 (C=O), 190.9 (C=O). MS (EI): m/z (%) = 372 (22) [M]⁺, 299 (25), 243 (100), 195 (40), 149 (23), 117 (38), 106 (98), 106 (70), 90 (98), 79 (18), 57 (35). Anal. Calcd. for C₂₁H₂₈N₂O₄ (372.2): C, 67.72; H, 7.58; N, 7.52. Found: C, 67.81; H, 7.64; N, 7.58. Ethyl 4-Acetyl-1-(2-chlorobenzyl)-2-(cyclohexylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13f): Yield: 0.32 g (74%); cream powder; mp 109–111 °C. IR (KBr): 3272 (OH), 1750 (C=O), 1651 (C=O), 1543 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.11–1.97 (m, 10 H, 5 CH₂), 1.27 (d, ³ J =7.1 Hz, 3 H, Me), 2.18 (s, 3 H, Me), 2.24 (s, 3 H, Me), 3.74 (br s, 1 H, OH), 3.90–4.18 (m, 1 H, CH), 4.16–4.30 (m, 2 H, OCH₂), 4.74 (d, ² J = 17.1 Hz, 1 H, CH₂N), 5.08 (d, ² J = 17.1 Hz, 1 H, CH₂N), 7.09–7.36 (m, 4 H, 4CH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.7 (Me), 14.0 (Me), 23.7 (Me), 23.8 (CH₂), 25.2 (CH₂), 28.8 (Me), 33.7 (CH₂), 34.2 (CH₂), 41.2 (CH), 56.7 (OCH₂), 62.1 ((CH₂N), 77.5 (C-OH), 115.5 (C), 126.6 (CH), 126.7 (CH), 127.9 (CH), 129.0 (CH), 131.6 (C), 133.9 (C), 153.6 (C), 158.6 (C=N), 171.1 (C=O), 190.8 (C=O). MS (EI): m/z (%) = 432 (2) [M]⁺, 359 (100), 301 (14), 277 (70), 228 (20), 148 (55), 127 (98), 106 (78), 89 (65), 77 (35), 55 (24). Anal. Calcd. for C₂₃H₂₉ClN₂O₄ (432.18): C, 63.81; H, 6.75; N, 6.47. Found: C, 63.89; H, 6.83; N, 6.5. Ethyl 4-Acetyl-1-buyl-2-(cyclohexylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13g): Yield: 0.28 g (78%); cream powder; mp 124–126 °C. IR (KBr): 3240 (OH), 1749 (C=O), 1661 (C=O), 1600 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.99 (t, ³ J = 7.2 Hz, 3 H, Me), 1.26 (t, ³ J = 7.2 Hz, 3 H, Me), 1.20–1.86 (m, 14 H, 7 CH₂), 2.33 (s, 3 H, Me), 2.58 (s, 3 H, Me), 3.54–3.70 (m, 1 H, CH), 3.93 (d, ² J = 16.0 Hz, 1 H, CH₂N), 4.20 (br s, 1 H, OH), 4.28 (d, ² J = 16.0 Hz, 1 H, CH₂N), 4.30–4.35 (m, 2 H, OCH₂). ¹³C NMR (125 MHz, CDCl₃): δ = 14.8 (Me), 14.9 (Me), 25.0 CH₂), 25.1 (CH₂), 26.6 (CH₂), 30.1 (Me), 35.1 (CH₂), 35.6 (CH₂), 44.8 (CH), 58.1 (OCH₂), 63.4 (CH₂N), 78.9 (C-OH), 116.6 (C), 127.3 (CH), 128.1 (CH), 129.5 (CH), 138.1 (CH), 155 (C), 160.1 (C=N), 172.5 (C=O), 191.9 (C=O). MS (EI): m/z (%) = 364 (2) [M]⁺, 291 (100), 236 (10), 210 (96), 183 (10), 154 (15), 127 (10), 98 (20), 84 (18), 67 (25), 57 (59). Anal. Calcd. for C₂₀H₃₂N₂O₄ (364.24): C, 65.91; H, 8.85; N, 7.69. Found: C, 65.93; H, 8.89; N, 7.64. Methyl 4-Acetyl-1-benzyl-2-(cyclohexylimino)-2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13h): Yield: 0.31 g (80%); cream powder; mp 98–100 °C. IR (KBr): 3279 (OH), 1737 (C=O), 1673 (C=O), 1566 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.10–2.15 (m, 10 H, 5 CH₂), 1.96 (s, 3 H, Me), 2.26 (s, 3 H, Me), 3.74 (br s, 1 H, OH), 3.85 (s, 3 H, OMe), 3.92–4.08 (m, 1 H, CH), 5.08 (d, ² J = 16.5 Hz, 1 H, CH₂N), 5.12 (d, ² J = 16.5 Hz, 1 H, CH₂N), 7. 20–7.26 (m, 5 H, 5 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 14.7 (Me), 26.0 (CH₂), 26.1 (CH₂), 26.7 (CH₂), 31.2 (Me), 33.3 (CH₂), 33.4 (CH₂), 49.0 (CH), 56.1 (OCH₂), 59.1 (CH₂N), 83.0 (C-OH), 123.4 (C), 128.0 (CH), 126.7 (CH), 129.6 (CH), 129.0 (CH), 130.4 (C), 134.8 (C), 157.2 (C), 167.5 (C=N), 168.5 (C=O), 194.1 (C=O). MS (EI): m/z (%) = 384 (2) [M]⁺, 291 (100), 229 (34), 209 (14), 164 (12), 127 (20), 99 (35), 83 (50), 70 (25), 55 (96). Anal. Calcd. for C₂₃H₃₀N₂O₄ (398.22): C, 69.32; H, 7.59; N, 7.03. Found: C, 69.33; H, 7.62; N, 6.64. Ethyl 4-acetyl-2-(cyclohexylimino)-2,3-dihydro-3-hydroxy-5-methyl-1-(4-methylbenzyl)-1H-pyrrole-3-carboxylate (13i): Yield: 0.34 g (82%); cream powder; mp 124–126 °C. IR (KBr): 3250 (OH), 1748 (C=O), 1662 (C=O), 1610 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.15–2.07 (m, 10 H, 5 CH₂), 1.20 (t, ³ J =7.1 Hz, 3 H, Me), 2.22 (s, 3 H, Me), 2.26 (s, 3 H, Me), 2.33 (s, 3 H, Me), 3.64 (br s, 1 H, OH), 3.90–3.93 (m, 1 H, CH), 4.10–4.32 (m, 2 H, OCH₂), 4.89 (d, ² J = 16.3 Hz, 1 H, CH₂N), 5.91 (d, ² J = 16.3 Hz, 1 H, CH₂N), 7.03 (d, ³ J = 7.8 Hz, 2 H, 2 CH), 7.07 (d, ³ J = 7.8 Hz, 2 H, 2 CH). ¹³C NMR (125 MHz, CDCl₃): δ = 14.7 (Me), 15.3 (Me), 22.4 (Me), 25.7 (CH₂), 25.8 (CH₂), 31.1 (Me), 31.2 (CH₂), 32.2 (CH₂), 48.2 (CH), 59.0 (OCH₂), 65.1 (CH₂N), 82.9 (C-OH), 123.3 (C), 127.9 (CH), 130.8 (CH), 130.9 (C), 139.3 (C), 157.2 (C), 167.4 (C=N), 168.1 (C=O), 194.0 (C=O). MS (EI): m/z (%) = 412 (22) [M]⁺, 339 (100), 297 (24), 257 (22), 204 (23), 120 (60), 105 (97), 84 (60), 67 (30), 56 (47). Anal. Calcd. for C₂₄H₃₂N₂O₄ (412.24): C, 69.88; H, 7.82; N, 6.79. Found: C, 69.82; H, 7.87; N, 6.72

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A Synthesis of Functionalized Dihydro-1H-pyrroles from Nef-Isocyanide Adducts and Enamines

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