A New One-Pot, Three-Component Synthesis of 2,3,5-Substituted or Annulated-6-(Methylthio)pyridines

Abstract

A new one-pot, three-component synthesis of 2,3,5-substituted (or 2,3-annulated)-6-(methylthio)pyridines by reacting acyclic or cyclic active methylene ketones, ammonium acetate, and bis(methylthio)acrolein (1) or its 2-phenyl analogue 8 (as 3-carbon-1,3-biselectrophilic components) in the presence of either AcOH-TFA (4:1) or ZnBr₂ (or ZnI₂) catalysts has been reported.

Key words

pyridines - cycloannulation - one-pot - three-component synthesis - bis(methylthio)acrolein - ammonium acetate

References and Notes

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25

The structures of all newly synthesized compounds were confirmed with the help of spectral and analytical data.

26

General Procedure for One-Pot, Three-Component Synthesis of 2,3,5-Substituted or 2,3-Annulated-6-(methylthio)pyridines 4, 7, 9, and 10cProcedure A A solution of appropriate ketone (1.0 mmol), bis(methyl-thio)acrolein (1, 3.0 mmol) or 2-phenyl-3-bis(methyl-thio)acrolein (8, 1.1 mmol), and NH₄OAc (20 mol) in AcOH-TFA (5 mL, 4:1) was heated with stirring at 110 ˚C for 8-10 h (monitored by TLC). The mixture was then neutralized with sat. NaHCO₃ solution (25 mL) and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extracts were washed with H₂O (2 × 50 mL), brine (50 mL), dried (Na₂SO₄), and evaporated under reduced pressure to afford crude product which was purified by column chromatography over SiO₂ using EtOAc-hexane (1:9) as eluent.
Procedure B
A mixture of appropriate ketone (1.0 mmol), bis(methyl-thio)acrolein (1, 3.0 mmol) or 2-phenyl-3-bis(methyl-thio)acrolein (8, 1.1 mmol), NH₄OAc (20 mol), and ZnBr₂ or ZnI₂ (15 mol%) was heated in a sealed tube at 110 ˚C for
5-8 h (monitored by TLC). The residue was partitioned between sat. NaHCO₃ solution (30 mL) and CHCl₃ (30 mL), and was extracted with CH₂Cl₂ (3 × 15 mL). The organic layer was washed with H₂O (2 × 50 mL), brine (50 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give crude product which was purified by column chromatography on SiO₂ using EtOAc-hexane (1:9) as eluent.
2-(4-Methoxyphenyl)-6-methylthiopyridine (4a)
Yield 63% (0.15 g); white solid; mp. 81-82 ˚C; R _f = 0.52 (hexane-EtOAc, 9:1). IR (KBr): 2919, 1602, 1555, 1448 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 9.0 Hz, 2 H, ArH), 7.49 (t, J = 7.8 Hz, 1 H, ArH), 7.35 (d, J = 7.6 Hz, 1 H, ArH), 7.05 (d, J = 7.8 Hz, 1 H, ArH), 6.92 (d, J = 8.8 Hz, 2 H, ArH), 3.85 (s, 3 H, OMe), 2.64 (s, 3 H, SMe). ^¹³C NMR (100 MHz, CDCl₃): δ = 160.5, 159.1, 156.2, 136.6, 131.3, 128.1, 119.2, 114.8, 114.0, 55.3, 13.2. ESI-HRMS: m/z calcd for C₁₃H₁₄NOS [M + H]⁺: 232.0796; found: 232.0794. 2,3-Bis(4-methoxyphenyl)-6-methylthiopyridine (4c)
Yield 63% (0.21 g); white solid; mp 161-162 ˚C; R _f = 0.50 (hexane-EtOAc, 19.1). IR (KBr): 2950, 1684, 1509 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.49 (d, J = 8.1 Hz, 1 H, ArH), 7.35 (dd, J = 6.7, 2.1 Hz, 2 H, ArH), 7.14 (d, J = 8.3 Hz, 1 H, ArH), 7.07 (dd, J = 6.6, 2.2 Hz, 2 H, ArH), 6.74-6.81 (m, 4 H, ArH), 3.78 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 2.62 (s, 3 H, SMe). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 158.8, 157.5, 155.1, 139.7, 131.5, 131.4, 131.2, 130.5, 130.4, 119.3, 113.9, 113.3, 55.2, 55.1, 13.7. MS: m/z (%) = 337(100) [M⁺]. Anal. Calcd (%) for C₂₀H₁₉NO₂S (337.43): C, 71.19; H, 5.68; N, 4.15. Found: C, 71.23; H, 5.70; N, 4.18.
2-Methylthioindeno[1,2- b ]pyridin-5-one (7a)
Yield 78% (0.18 g); pale yellow solid; mp 145-146 ˚C; R _f = 0.54 (hexane-EtOAc, 9:1); IR (KBr): 2920, 1720, 1575, 1401 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.57 (d, J = 7.3 Hz, 1 H, ArH), 7.49 (d, J = 7.3 Hz, 1 H, ArH), 7.46 (d, J = 8.0 Hz, 1 H, ArH), 7.37 (t, J = 7.4 Hz, 1 H, ArH), 7.24 (t, J = 7.4 Hz, 1 H, ArH), 6.84 (d, J = 8.1 Hz, 1 H, ArH), 2.51 (s, 3 H, SMe). ^¹³C NMR (100 MHz, CDCl₃): δ = 191.1, 167.1, 165.1, 142.7, 135.0, 134.4, 130.7, 130.3, 123.5, 123.4, 120.5, 119.8, 13.3. MS: m/z (%) = 227(100) [M⁺]. Anal. Calcd (%) for C₁₃H₉NOS (227.28): C, 68.70; H, 3.99; N, 6.16. Found: C, 68.76; H, 4.00; N, 6.18.
6-Methylthio-3,5-diphenyl-[2,3′]bipyridinyl (9d)
Yield 64% (0.23 g); light yellow solid; mp 160-161 ˚C; R _f = 0.45 (hexane-EtOAc, 5:1). IR (KBr): 2916, 1575, 1445, 1377 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.77 (br s, 1 H, ArH), 8.50 (dd, J = 4.9, 1.4 Hz, 1 H, ArH), 7.71 (dt, J = 8.0, 1.9 Hz, 1 H, ArH), 7.55-7.52 (m, 2 H, ArH), 7.51 (s, 1 H, ArH), 7.50-7.40 (m, 3 H, ArH), 7.33-7.27 (m, 3 H, ArH), 7.23-7.20 (m, 2 H, ArH), 7.17-7.15 (m, 1 H, ArH), 2.60 (s, 3 H, SMe). ^¹³C NMR (100 MHz, CDCl₃): δ = 156.6, 151.4, 150.9, 148.7, 139.1, 138.9, 137.4, 137.1, 135.3, 135.0, 131.7, 129.5, 129.1, 128.7, 128.5, 128.4, 127.5, 122.6, 13.8. MS: m/z (%) = 355(100) [M + 1], 354(60) [M⁺]. Anal. Calcd (%) for C₂₃H₁₈N₂S (354.46): C, 77.93; H, 5.12; N, 7.90. Found: 77.97; H, 5.13; N, 7.93.
6-Methylthio-5-phenyl-[2,2′]bipyridinyl (9i)
Yield 68% (0.19 g); colorless solid; mp 100-101 ˚C; R _f = 0.47 (hexane-EtOAc, 19:1). IR (KBr): 2916, 1546, 1428, 1354 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.71 (dd, J = 4.9, 0.74 Hz, 1 H, ArH), 8.54 (d, J = 8.1 Hz, 1 H, ArH), 8.27 (d, J = 7.8 Hz, 1 H, ArH), 7.88 (td, J = 7.7, 1.7 Hz, 1 H, ArH), 7.56 (d, J = 7.8 Hz, 1 H, ArH), 7.49-7.40 (m, 5 H, ArH), 7.37-7.34 (m, 1 H, ArH), 2.62 (s, 3 H, SMe). ^¹³C NMR (100 MHz, CDCl₃): δ = 157.3, 155.2, 152.9, 148.3, 137.8, 137.3, 136.5, 129.1, 128.4, 128.3, 123.9, 121.4, 116.5, 13.8. MS: m/z (%): 279(100) [M + 1], 278(30). Anal. Calcd (%) for C₁₇H₁₄N₂S (278.37): C, 73.35; H, 5.07; N, 10.06. Found: C, 73.32; H, 5.09; N, 10.09.

28

Comparable yields of pyridines 9 were obtained by using either ZnBr₂ or ZnI₂ catalyst.

29

Lower yields of pyridines 4a-g with ZnBr₂ (conditions B) catalyst at 110 ˚C are presumably due to the decomposition of bis(methylthio)acrolein(1) at higher temperature.

30

The ^¹H NMR of all desulfurized compounds 11c,d, 12h,i displayed a low field signal between δ = 8.63-8.96 ppm due to the pyridine H-6 proton which further confirmed the regiochemistry of the products.
2,3-Bis(4-methoxyphenyl)pyridine (11c)
Yield 93% (0.27 g); white solid; mp 82-83 ˚C; R _f = 0.5 (hexane-EtOAc, 19:1). IR (KBr): 2935, 2838, 1607, 1511, 1429 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.63 (dd, J = 4.6, 1.7 Hz, 1 H, ArH), 7.67 (dd, J = 7.6, 1.7 Hz, 1 H, ArH), 7.31 (dd, J = 6.7, 2.1 Hz, 2 H, ArH), 7.29-7.26 (m, 1 H, ArH), 7.11 (dd, J = 6.7, 2.1 Hz, 2 H, ArH), 6.83 (dd, J = 6.8, 1.9 Hz, 2 H, ArH), 6.78 (dd, J = 6.8, 1.9 Hz, 2 H, ArH), 3.81 (s, 3 H, OMe), 3.79 (s, 3 H, OMe). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.2, 158.8, 156.7, 147.9, 138.4, 135.3, 132.8, 132.5, 131.1, 130.6, 121.6, 113.8, 113.3, 55.22, 55.18. MS: m/z (%) = 292(100) [M + 1], 291(40) [M⁺]. Anal. Calcd (%) for C₁₉H₁₇NO₂ (291.34): C, 8.33; H, 5.88; N, 4.81. Found: C, 78.39; H, 5.90; N, 4.84.