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

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.

C-C bond-forming reaction - α-hydroxyketene-(S,S)-acetals - active methylene compounds - substituted 3,4-dihydro-2-pyridones - one-pot synthesis

References and Notes

1a March J. Advanced Organic Chemistry   4th ed.:  Wiley; New York: 1992. 

1b Current Trends in Organic Synthesis   Scolastico C. Nicotra F. Plenum; New York: 1999. 

2a Trost BM. Science  1991,  254:  1471 

2b Kabalka GW. Yao M.-L. Borella S. Wu Z.-Z. Org. Lett.  2005,  7:  2865 ; and references therein

3 Yasuda M. Somyo T. Baba A. Angew. Chem. Int. Ed.  2006,  45:  793 

4 Motokura K. Fujita N. Mori K. Mizugaki T. Ebitani K. Kaneda K. Angew. Chem. Int. Ed.  2006,  45:  2605 

For reviews on the synthesis and application of α-oxoketene-(S,S)-acetals, see:

5a Dieter RK. Tetrahedron  1986,  42:  3029 

5b Tominaga Y. J. Heterocycl. Chem.  1989,  26:  1167 

5c Junjappa H. Ila H. Asokan CV. Tetrahedron  1990,  46:  5423 

5d Kolb M. Synthesis  1990,  171 

5e Junjappa H. Ila H. Phosphorus, Sulfur Silicon  1994,  35:  95 

5f Junjappa H. Ila H. Mohanta PK. In Progress in Heterocyclic Chemistry   Vol. 13:  Gribble GH. Gilchrist LT. Pergamon Press; Oxford: 2001.  Chap. 1. p.1-24  

6a Bi X. Dong D. Liu Q. Pan W. Zhao L. Li B. J. Am. Chem. Soc.  2005,  127:  4578 

6b Dong D. Bi X. Liu Q. Cong F. Chem. Commun.  2005,  28:  3580 

6c Zhao L. Liang F. Bi X. Sun S. Liu Q. J. Org. Chem.  2006,  71:  1094 

6d Bi X. Dong D. Li Y. Liu Q. J. Org. Chem.  2005,  70:  10886 

7a Liu Q. Che G. Yu H. Liu Y. Zhang J. Zhang Q. Dong D. J. Org. Chem.  2003,  68:  9148 

7b Yu H. Liu Q. Yin Y. Fang Q. Zhang J. Dong D. Synlett  2004,  999 

7c Bi X. Liu Q. Sun S. Liu J. Pan W. Zhao L. Dong D. Synlett  2005,  49 

7d Zhao Y. Liu Q. Zhang J. Liu Z. J. Org. Chem.  2005,  70:  6913 

8a Yin Y. Wang M. Liu Q. Hu J. Sun S. Kang J. Tetrahedron Lett.  2005,  46:  4399 

8b Pan W. Dong D. Sun S. Liu Q. Synlett  2006,  1090 

9 Thomas AD. Asokan CV. Tetrahedron Lett.  2002,  43:  2273 

10 Nair SK. Jose AM. Asokan CV. Synthesis  2005,  1281 

Selected examples:

11a Kuethe JT. Comins DL. J. Org. Chem.  2004,  69:  5219 

11b Huang S. Comins DL. Chem. Commun.  2000,  569 

11c Kuethe JT. Comins DL. Org. Lett.  2000,  2:  855 

11d Avenoza A. Busto JH. Cativiela C. Corzana F. Peregrina JM. Zurbano MM. J. Org. Chem.  2002,  67:  598 

Reviews on the synthesis of pyridones:

12a McKillop A. Boulton A. In Comprehensive Heterocyclic Chemistry   Vol. 2, Part 2A:  Katritzky AR. Rees CW. Pergamon Press; New York: 1984.  p.67ff 

12b Jones G. In Comprehensive Heterocyclic Chemistry   Vol. 5:  Katritzky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  p.167-243  

12c Torres M. Gil S. Parra M. Curr. Org. Chem.  2005,  9:  1757 

13 Review on synthetic methods for 2-pyridones: Torres M. Gil S. Parra M. Curr. Org. Chem.  2005,  9:  1757 ; and references cited therein

Selected examples:

14a Wagman AS. Wang L. Nuss JM. J. Org. Chem.  2000,  65:  9103 

14b Carles L. Narkunan K. Penlou S. Rousset L. Bouchu D. Ciufolini MA. J. Org. Chem.  2002,  67:  4304 

14c Itami K. Yamazaki D. Yoshida J. Org. Lett.  2003,  5:  2161 

14d Ferraccioli R. Carenzi D. Motti E. Catellani M. J. Am. Chem. Soc.  2006,  128:  722 

15a Ouyang Y. Dong D. Yu H. Liang Y. Liu Q. Adv. Synth. Catal.  2006,  348:  206 

15b Pak CS. Choi EB. Synthesis  1992,  1291 

16

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.

17

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.

18

X-ray diffraction data for 7b has been deposited at the Cambridge Crystallographic Data Centre with supplementary publication number CCDC 611469.

19 Bordwell FG. Acc. Chem. Res.  1988,  21:  456 

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.

21 Bisaro F. Prestat G. Vitale M. Poli G. Synlett  2002,  1823 

22a Bernasconi CF. Tetrahedron  1989,  45:  4017 

22b Bernasconi CF. Brown SD. Ali M. Rappoport Z. Yamataka H. Salim H. J. Org. Chem.  2006,  71:  4795 

23a Jones RCF. Begley MJ. Peterson GE. Sumaria S. J. Chem. Soc., Perkin Trans. 1  1990,  1959 

23b Balasubramanian S. Ward DL. Nair MG. J. Chem. Soc., Perkin Trans. 1  2000,  567