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DOI: 10.1055/s-0028-1083529
A New One-Pot, Three-Component Synthesis of 2,3,5-Substituted or Annulated-6-(Methylthio)pyridines
Publication History
Publication Date:
01 October 2008 (online)
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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
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References and Notes
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.
Comparable yields of pyridines 9 were obtained by using either ZnBr2 or ZnI2 catalyst.
29Lower 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.
30The 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.