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

Jun Liu; Fushun Liang; Qun Liu; Bing Li

doi:10.1055/s-2006-958412

LETTER

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

Jun Liu, Fushun Liang*, Qun Liu*, Bing Li
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax: +86(431)5099759; e-Mail: liangfs112@nenu.edu.cn;

Abstract

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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

References and Notes

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Selected examples:

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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.

<A NAME="RW15306ST-19">19</A> Bordwell FG. Acc. Chem. Res. 1988, 21: 456

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.

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