Methyl Group as a Source of Structural DiVersity
THF (5 mL) and diisopropylamine (5 mmol, 0.7 mL) were added
and the mixture was cooled to -78 °C. n-BuLi (1.6 M in hexane,
5 mmol, 3.15 mL) was added dropwise and the mixture was stirred
for 15 min at the same temperature. 2-Picoline 1 (2 mmol, 200
µL) dissolved in THF (2 mL) was added dropwise and the resulting
orange solution was stirred for 15 min at -78 °C. MeSSMe (4
mmol, 355 µL) in THF (4 mL) was added dropwise and the mixture
was stirred for another 15 min, after which time TLC analysis
showed complete conversion. Water (2 mL) was added at -78 °C
and the temperature was raised to ambient temperature. The product
was extracted with ethyl acetate, washed with brine, and dried over
MgSO4. After filtration and solvent evaporation, the crude product
was purified by chromatography on silica gel (hexanes/ethyl acetate
135.9, 147.7, 159.9. MS (EI) m/z 225 (M+, 13%), 210 (32), 178
(47), 162 (42), 131 (100), 78 (52).
Spectroscopic data of compounds prepared analogously can be
found in Supporting Information.
General Procedure for Hydrolysis of Dithioacetals, Dithioket-
als, and Trithioortho Esters: Preparation of Pyridine-2-
carbothioic Acid S-Methyl Ester19 (44). Trithiortho ester 4
(1 mmol) was dissolved in acetonitrile (12 mL). Water (3 mL),
HgCl2 (2.2 mmol, 598 mg), and CaCO3 (2.2 mmol, 220 mg) were
added and the mixture was stirred at room temperature over-
night. The mixture was filtered over celite and dichloromethane
was added until no spot of product appeared on TLC. More water
was added and the organic phase was separated and dried over
MgSO4. After solvent evaporation the residue was purified by
chromatography on silica gel (hexanes/ethyl acetate 4/1) to give
145 mg of a white powder (94%), mp 58 °C. 1H NMR (200 MHz,
CDCl3) δ 2.45 (s, 3H), 7.53 (dt, J ) 4.8, 1.2 Hz, 1H), 7.86 (t, J )
7.6 Hz, 1H), 7.97 (d, J ) 7.6 Hz, 1H), 8.69 (d, J ) 4.2 Hz, 1H);
13C NMR (50 MHz, CDCl3) δ 11.4, 120.1, 127.6, 137.0, 149.0,
151.7, 193.9. MS (EI) m/z 153 (M+, 5%), 125 (10), 111 (19), 106
(30), 78 (100), 51 (37). Anal. Calcd for C7H7NOS (153.02): C,
54.88; H, 4.61; N, 9.14; S, 20.93. Found: C, 54.85; H, 4.71; N,
8.84; S, 20.37.
1
9/1) to furnish 315 mg (85% yield) of a pale yellow liquid. H
NMR (200 MHz, CDCl3) δ 2.13 (s, 6H), 4.95 (s, 1H), 7.17 (dd, J
) 6.2, 5.2 Hz, 1H), 7.46 (d, J ) 7.8 Hz, 1H), 7.68 (dd, J ) 7.8,
6.2 Hz, 1H), 8.52 (d, J ) 4.8 Hz, 1H); 13C NMR (50 MHz, CDCl3)
δ 13.8, 57.7, 121.3, 122.0, 136.4, 148.4, 158.8. MS (EI) m/z 186
([M + 1]+, 46%), 138 (100), 106 (32), 93 (35), 79 (40).
Spectroscopic data of compounds prepared analogously can be
found in Supporting Information.
Representative Procedure for the Synthesis of Trithioortho
Esters: Preparation of 2-Tris(methylthio)methyl Pyridine (4).
t-BuOK (10 mmol, 1.12 g) was dried for 2 h at 100 °C in vacuo.
THF (10 mL) and diisopropylamine (10 mmol, 1.4 mL) were added
and the mixture was cooled to -78 °C. n-BuLi (1.6 M in hexane,
10 mmol, 6.25 mL) was added dropwise and the mixture was stirred
for 15 min at the same temperature. 2-Picoline 1 (2 mmol, 200
µL) dissolved in THF (2 mL) was added dropwise and the resulting
orange solution was stirred for 15 min. MeSSMe (10 mmol, 890
µL) in THF (10 mL) was added dropwise and the mixture was
stirred at -78 °C for another 15 min, after which time TLC analysis
showed complete conversion. Water (2 mL) was added and the
temperature was raised to ambient temperature. The product was
extracted with ethyl acetate, washed with brine, and dried over
MgSO4. After filtration and solvent evaporation, the crude product
was purified by chromatography on silica gel (hexanes/ethyl acetate
Spectroscopic data of compounds prepared analogously can be
found in Supporting Information.
General Procedure for Formation of Ketals and Ortho
Esters: Preparation of 2-(1,1-Dimethoxy-ethyl)-pyridine (42).
The substrate (0.5 mmol, 99.5 mg) was dissolved in methanol
(5 mL). HgCl2 (1.65 mmol, 448 mg) and HgO (0.83 mmol, 180
mg) were added and the mixture was stirred at room temperature
overnight. The mixture was filtered over celite and dichloro-
methane was added until no spot of product appeared on TLC. After
solvent evaporation the residue was purified by chromatography
on silica gel (hexanes/ethyl acetate/triethylamine 6/3/1) to give 70
1
mg of a colorless syrup. H NMR (200 MHz, CDCl3) δ 1.64 (s,
3H), 3.23 (s, 6H), 7.22 (ddd, J ) 6.7, 4.8, 1.7 Hz, 1H), 7.60-7.80
(m, 2H), 8.67 (d, J ) 4 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ
23.9, 49.0, 101.5, 121.2, 136.1, 149.0, 160.4. MS (EI) m/z 152 ([M
- CH3]+, 14%), 136 (47), 122 (28), 104 (33), 89 (100), 78 (36),
51 (27).
1
95/5) to give 373 mg (81%) of a pale yellow solid, mp 45 °C. H
NMR (200 MHz, CDCl3) δ 1.98 (s, 9H), 7.20 (dd, J ) 6.2, 4.8
Hz, 1H), 7.77 (dd, J ) 8, 6.2 Hz, 1H), 8.07 (d, J ) 8.2 Hz, 1H),
8.50 (d, J ) 5 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 13.8, 76.1,
122.0, 122.4, 136.6, 146.8, 160.0. MS (EI) m/z 231 (M+, 88%),
184 (100), 136 (80), 122 (35), 78 (57). Anal. Calcd for C9H13NS3
(231.02): C, 46.71; H, 5.66; N, 6.05; S, 41.57. Found: C, 46.88;
H, 5.74; N, 6.37; S, 42.13.
Spectroscopic data of compounds prepared analogously can be
found in Supporting Information.
General Procedure for Ester Formation: Preparation of
5-Methyl-pyrazine-2-carboxylic Acid Methyl Ester (58). The
substrate (0.46 mmol, 113 mg) was dissolved in methanol (6 mL).
Water (1.5 mL), HgCl2 (1.52 mmol, 412 mg), and HgO (0.76 mmol,
164 mg) were added and the mixture was stirred at room
temperature overnight. The mixture was filtered over celite and
dichloromethane was added until no spot of product appeared on
TLC. More water was added and the organic phase was separated
and dried over MgSO4. After solvent evaporation the residue was
purified by chromatography on silica gel (hexanes/ethyl 4/1)to give
50 mg of a white solid, mp 92 °C. 1H NMR (200 MHz, CDCl3) δ
2.69 (s, 3H), 4.04 (s, 3H), 8.60 (s, 1H), 9.20 (s, 1H); 13C NMR (50
MHz, CDCl3) δ 21.6, 52.6, 140.1, 143.9, 145.0, 157.6, 164.3. MS
(EI) m/z 152 (M+, 8%), 122 (35), 94 (100), 66 (24), 53 (30). Anal.
Calcd for C7H8N2O2 (152.06): C, 55.26; H, 5.30; N, 18.41.
Found: C, 55.28; H, 5.20; N, 18.26.
Spectroscopic data of compounds prepared analogously can be
found in Supporting Information.
General Procedure for the Synthesis of Dithioketals: Prepa-
ration of 2-[1,1-Bis(methylthio)]but-3-enylpyridine (35). t-BuOK
(8 mmol, 896 mg) was dried for 2 h at 100 °C in vacuo. THF (8
mL) and diisopropylamine (8 mmol, 1.12 mL) were added and the
mixture was cooled to -78 °C. n-BuLi (1.6 M in hexane, 8 mmol,
5 mL) was added dropwise and the mixture was stirred for 15 min
at the same temperature. 2-Picoline 1 (2 mmol, 200 µL) dissolved
in THF (2 mL) was added dropwise and the resulting orange
solution was stirred for 15 min. MeSSMe (4 mmol, 355 µL) in
THF (4 mL) was added dropwise and the mixture was stirred at
-78 °C for 30 min. Allyl bromide (6 mmol, 520 µL) was added
dropwise and the mixture was stirred at -78 °C for 30 min. Water
(2 mL) was added and the temperature was raised to ambient
temperature. The product was extracted with ethyl acetate, washed
with brine, and dried over MgSO4. After filtration and solvent
evaporation, the crude product was purified by chromatography on
Spectroscopic data of compounds prepared analogously can be
found in Supporting Information.
General Procedure for Hydrolysis of Thio Compounds Using
PhI(OCOCF3)2. Solid [bis(trifluoroacetoxy)-iodo]benzene (0.5
mmol) was added to a room-temperature CH3CN/H2O solution
(1:1, 2.5 mL) of the thio compound (0.5 mmol) and TFA (5 mmol).
After 30 min, additional solid [bis(trifluoroacetoxy)-iodo]
benzene (1 mmol) was added, with the reaction being terminated
after 2.5 h. A saturated, aqueous solution of Na2CO3 was
added carrefully and the product was extracted with CH2Cl2. The
1
silica gel (hexanes/ethyl acetate mixtures). H NMR (200 MHz,
CDCl3) δ 1.95 (s, 6H), 2.98 (d, J ) 6.8 Hz, 2H), 4.95 (dd, J ) 5.8,
1 Hz, 1H), 5.02 (d, J ) 12.8 Hz, 1H), 5.66 (m, 1H), 7.15 (t, J )
5.2 Hz, 1H), 6.60-7.80 (m, 2H), 8.56 (d, J ) 4.8 Hz, 1H); 13C
NMR (50 MHz, CDCl3) δ 11.7, 42.1, 66.9, 117.1, 121.6, 132.4,
J. Org. Chem, Vol. 72, No. 19, 2007 7299