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DOI: 10.1055/s-2006-958412
BF3·OEt2-Mediated C-C Bond-Forming Reaction of α-Hydroxyketene-(S,S)-acetals with Active Methylene Compounds and Its Application in the Synthesis of Substituted 3,4-Dihydro-2-pyridones
Publication History
Publication Date:
20 December 2006 (online)
Abstract
The C-C bond-forming reaction between α-hydroxyketene-(S,S)-acetals 2 and active methylene compounds is described. Mediated by boron trifluoride etherate (BF3·OEt2), a series of C-C bond coupling products, 2-(2-acetyl-1-methyl-3-oxobutyl)-N-aryl-3,3-bis(ethylthio)acrylamides 3 was obtained in high to excellent yields by the reaction of 2a-e (R1 = Ar) with acetylacetone. Various N-aryl-substituted 3,4-dihydropyridones 5 were prepared in high yields from 3 via a two-step procedure. Upon the reaction of 2f (R1 = H) with active methylene compounds, 3,4-dihydropyridones 6 and/or 7, were obtained in a one-pot reaction with moderate to good yields.
Keywords
C-C bond-forming reaction - α-hydroxyketene-(S,S)-acetals - active methylene compounds - substituted 3,4-dihydro-2-pyridones - one-pot synthesis
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References and Notes
Preparation of 3 (3a as an example); Typical Procedure: To a well-stirred suspension of 2a (1.0 mmol, 0.31 g) in anhyd acetylacetone (15 mmol, 1.55 mL) was added BF3·OEt2 (1.2 mmol, 0.15 mL). The mixture was stirred for 40 min at 0 °C until the reaction was complete (as indicated by TLC) and neutralized with aq NaHCO3 (10%). After workup, the crude product was purified by column chromatography (eluent: PE-EtOAc, 5:1) to give 3a in 87% yield.
Selected data for compounds 3:
2-(2-Acetyl-1-methyl-3-oxobutyl)-
N
-phenyl-3,3-bis(ethylthio)acrylamide (
3a): white solid; mp 88-91 °C. 1H NMR (500 MHz, CDCl3): δ = 1.15 (d, J = 6.5 Hz, 3 H), 1.17-1.21 (m, 3 H), 1.25-1.66 (m, 3 H), 2.23 (s, 3 H), 2.24 (s, 3 H), 2.61-2.92 (m, 4 H), 4.06 (d, J = 11.5 Hz, 1 H), 4.21 (m, 1 H), 7.12-7.15 (m, 1 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.58 (t, J = 7.5 Hz, 2 H), 7.75 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 204.0, 202.6, 164.7, 146.6, 136.7, 132.8, 128.1 (2 × C), 123.6, 118.8 (2 × C), 71.8, 37.4, 30.1, 28.5, 26.8, 26.5, 17.0, 14.3, 13.8. IR (KBr): 3340, 2968, 2360, 1732, 1698, 1653, 1529, 760 cm-1. MS: m/z = 394.1 [M + H]+. Anal. Calcd for C20H27NO3S2: C, 61.04; H, 6.91; N, 3.56. Found: C, 60.90; H, 6.75; N, 3.44.
2-(2-Acetyl-1-methyl-3-oxobutyl)-
N
-
o
-tolyl-3,3-bis(ethylthio)acrylamide (
3c): white solid; mp 97-99 °C. 1H NMR (500 MHz, CDCl3): δ = 1.17 (d, J = 7.0 Hz, 3 H), 1.18-1.21 (m, 3 H), 1.29-1.31 (m, 3 H), 2.25 (s, 3 H), 2.26 (s, 3 H), 2.35 (s, 3 H), 2.63-2.92 (m, 4 H), 4.10 (d, J = 11.0 Hz, 1 H), 4.24-4.27 (m, 1 H), 7.08 (t, J = 7.5 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 2 H), 7.62 (s, 1 H), 7.98 (d, J = 7.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 203.6, 202.7, 164.9, 146.8, 134.6, 132.6, 129.6, 128.0, 125.8, 124.2, 121.6, 71.7, 37.3, 30.0, 28.6, 26.9, 26.5, 17.2, 17.0, 14.1, 13.7. IR (KBr): 3364, 2975, 2924, 2360, 2170, 1694, 1668, 1517, 1456, 769 cm-1. MS: m/z [M + H]+ calcd for C21H29NO3S2: 407.2; found: 408.6. Anal. Calcd for C21H29NO3S2: C, 61.88; H, 7.17; N, 3.44. Found: C, 61.57; H, 6.81; N, 3.23.
Preparation of 5 (5a as an example); Typical Procedure: To a well-stirred suspension of 3a (1.0 mmol, 0.43 g) in EtOH (10 mL) was added NaOH (1.2 mmol, 0.05 g). The mixture was stirred at 60 °C for 1.0 h, and then poured into H2O (80 mL) under stirring. The precipitated solid was collected by filtration, washed with H2O (3 × 30 mL) and then dried in vacuo to afford the product 4a (0.31 g, 87%) as a white solid. To a well-stirred suspension of 4a (1.0 mmol, 0.35 g) in anhyd CH2Cl2 (10 mL) were added TiCl4 (1.2 mmol, 0.14 mL) and Et3N (1.4 mmol, 0.20 mL). The mixture was stirred for about 2 h until the reaction was complete (as indicated by TLC) and neutralized with aq NaHCO3 (10%). After workup, the crude product was purified by column chromatography (eluent: PE-EtOAc = 15:1) to give 5a in 85% yield.
Selected data for compounds 5:
3-[Bis(ethylthio)methylene]-4,6-dimethyl-1-phenyl-3,4-dihydropyridin-2(1
H
)-one (
5a): yellow solid; mp 87-89 °C. 1H NMR (500 MHz, CDCl3): δ = 1.16 (d, J = 6.5 Hz, 3 H), 1.25-1.30 (m, 6 H), 1.55 (s, 3 H), 2.82-2.94 (m, 4 H), 4.00-4.02 (q, J = 6.5 Hz, 1 H), 5.21 (d, J = 6.5 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 162.4, 141.4, 137.6, 137.3, 133.4, 128.4, 128.0 (2 × C), 126.6, 109.0 (2 × C), 33.5, 28.1, 27.8, 19.3, 19.1, 14.2, 13.4. IR (KBr): 3063, 2962, 2921, 2867, 2360, 2170, 1648, 1595, 1539, 1489, 699 cm-1. MS: m/z = 334.3 [M + H]+. Anal. Calcd for C18H23NOS2: C, 64.82; H, 6.95; N, 4.20. Found: C, 64.64; H, 6.79; N, 4.04.
3-[Bis(ethylthio)methylene]-1-(4-chlorophenyl)-4,6-dimethyl-3,4-dihydropyridin-2(1
H
)-one (
5b): yellow solid; mp 136-137 °C. 1H NMR (500 MHz, CDCl3): δ = 1.14 (d, J = 6.5 Hz, 3 H), 1.23-1.32 (m, 6 H), 1.55 (s, 3 H), 2.81-2.95 (m, 4 H), 3.99-4.02 (q, J = 6.5 Hz, 1 H), 5.22 (d, J = 7.5 Hz, 1 H), 7.10 (t, J = 8.5 Hz, 2 H), 7.37 (d, J = 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 162.4, 142.2, 136.7, 136.2, 132.9, 132.4, 129.4, 128.2 (2 × C), 109.5 (2 × C), 33.4, 28.2, 27.7, 19.3, 19.0, 14.2, 13.4. IR (KBr): 3070, 2964, 2927, 2865, 1644, 1487, 1454, 1085, 775 cm-1. MS: m/z = 368.1 [M + H]+. Anal. Calcd for C18H22ClNOS2: C, 58.75; H, 6.03; N, 3.81. Found: C, 58.58; H, 5.96; N, 3.70.
X-ray diffraction data for 7b has been deposited at the Cambridge Crystallographic Data Centre with supplementary publication number CCDC 611469.
20
Preparation of 6 and 7 (6a as an example); Typical Procedure: To a well-stirred suspension of 2f (1.0 mmol, 0.235g) in acetylacetone (15 mmol, 1.55 mL) was added BF3·OEt2 (1.2 mmol, 0.2 mL). The mixture was stirred at 0 °C for 2 h until the reaction was complete (as indicated by TLC) and neutralized with aq NaHCO3 (10%). After workup, the crude product was purified by column chromatography (eluent: PE-EtOAc = 5:1) to give 6a in 89% yield.
Selected data for compounds 6 and 7:
5-Acetyl-3-[bis(ethylthio)methylene]-4,6-dimethyl-3,4-dihydropyridin-2(1
H
)-one (
6a): yellow solid; mp 66-68 °C. 1H NMR (500 MHz, CDCl3): δ = 1.15 (d, J = 7.0 Hz, 3 H), 1.17-1.34 (m, 6 H), 2.28 (s, 3 H), 2.34 (s, 3 H), 2.81-3.03 (m, 4 H), 4.60 (q, J = 7.0 Hz, 1 H), 7.98 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 195.9, 162.7, 146.7, 142.6, 132.8, 117.1, 35.8, 29.0, 28.7, 28.1, 18.7, 18.5, 14.3, 13.6. IR (KBr): 3246, 3093, 2963, 2924, 2865, 2360, 2342, 1673, 1617, 1577, 1230, 786 cm-1. MS: m/z = 300.0 [M + H]+. Anal. Calcd for C14H21NO2S2: C, 56.15; H, 7.07; N, 4.68. Found: C, 56.08; H, 6.95; N, 4.43.
3-[Bis(ethylthio)methylene]-4,6-dimethyl-5-methyloxycarbonyl-3,4-dihydropyridin-2(1
H
)-one (
6c): yellow solid; mp 115-116 °C. 1H NMR (500 MHz, CDCl3): δ = 1.12 (d, J = 7.5 Hz, 3 H), 1.24-1.31 (m, 6 H), 2.30 (s, 3 H), 2.83-3.01 (m, 4 H), 3.77 (s, 3 H), 4.59-4.60 (q, J = 7.5 Hz, 1 H), 7.46 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 167.1, 163.3, 148.0, 143.8, 133.6, 109.1, 51.4, 36.2, 30.1, 29.2, 19.8, 18.8, 15.1, 14.5. IR (KBr): 3187, 3090, 2943, 2927, 1709, 1673, 1629, 1525, 1486, 1345, 1217, 1182, 772 cm-1. MS: m/z = 316.1 [M + H]+. Anal. Calcd for C14H21NO3S2: C, 53.30; H, 6.71; N, 4.44. Found: C, 53.13; H, 6.63; N, 4.29.
3-[(Difluoroboryloxy)(ethylthio)methylene]-4,6-dimethyl-5-methyloxycarbonyl-3,4-dihydropyridin-2(1
H
)-one (
7c): yellow solid; mp 98-100 °C. 1H NMR (500 MHz, CDCl3): δ = 1.16 (d, J = 6.5 Hz, 3 H), 1.37 (t, J = 7.5 Hz, 3 H), 2.32 (s, 3 H), 3.12-3.17 (q, J = 7.5 Hz, 2 H), 3.78 (s, 3 H), 3.79-3.81 (q, J = 6.5 Hz, 1 H), 6.84 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ =185.6, 166.5, 160.8, 141.2, 110.6, 95.4, 51.8, 28.9, 24.4, 21.7, 19.0, 14.7. IR (KBr): 2927, 2284, 1786, 1758, 1731, 1592, 1491, 1383, 1028 cm-1. MS: m/z = 320.1 [M + H]+. Anal. Calcd for C12H16BF2NO4S: C, 45.16; H, 5.05; N, 4.39. Found: C, 45.05; H, 4.99; N, 4.15.