8420 J . Org. Chem., Vol. 65, No. 25, 2000
Davies et al.
stirring. The pH is adjusted to 8.0 with 50% sodium hydroxide,
and the mixture is aged with stirring for 30 min. The layers
are separated, and the aqueous layer is extracted with
isopropyl acetate. The organic layers are concentrated succes-
sively with the concomitant addition of IPAC to give a ∼30 wt
% solution aldehdye 5 with KF < 200 µg/mL. IPAC (160 mL)
and aniline (12.8 g, 0.137 mol) were added, and the mixture
was heated to 60 °C. Diphenyl phosphite (60 g, 86 wt %
technical grade, 0.212 mol) was added over 1 h. The mixture
was seeded with N,P-acetal 6, and heptane (180 mL) was
added over 1 h. The mixture was cooled to 15 °C, and the
product isolated by filtration. The cake was slurry washed with
water followed by IPAC/heptane (1:1) and dried to give N,P-
acetal as a colorless solid (46.5 g) in 76% yield: mp 135-137
°C; 1H NMR (400 MHz CDCl3) δ 8.69 (t, 1H, J ) 2.3 Hz), 7.26
(m, 4H), 7.15 (m, 7H), 6.98 (m, 2H), 6.77 (t, 1H, J ) 7.4 Hz),
6.64 (dd, 2H, J 1)8.6 Hz, J 2)0.9 Hz), 5.17 (d, 1H, J ) 24.7
Hz), 4.89-5.09 (br, 1H), 2.55 (d, 3H, J ) 2.0 Hz); 13C NMR
(100 MHz CDCl3) L 158.4, 158.3, 150.2, 150.1, 150.0, 149.9,
148.7, 148.7, 145.4, 145.2, 136.0, 135.9, 129.7, 129.7, 129.4,
129.3, 128.0, 125.50 125.3, 123.5, 123.5, 120.5, 120.5, 120.2,
120.1, 119.2, 115.5, 114.0, 54.2, 52.7, 23.9. Anal. Calcd for
C25H23N2O3P: C, 69.8; H, 5.4; N, 6.5. Found: C, 69.8; H, 5.2;
N, 6.3.
1-(6-Meth yl-3-p yr id in yl)-2-[4-(m eth ylsu lfon yl)p h en yl]-
eth a n on e 2. P r oced u r e A: To a suspension of N,P-acetal 6
(44.38 g, 0.100 mol) and sulfonylbenzaldehyde (22.14 g, 0.113
mol) in tetrahydrofuran (150 mL) and isopropyl alcohol (300
mL) at 25 °C was added dropwise potassium tert-butoxide (71
mL, 1.6 M in THF, 0.113 mol) over 2 h. The resulting solution
was aged 30 min and was treated with 2 N HCl (200 mL).
The homogeneous reaction mixture was aged 1 h and was
heated to 45 °C. Sodium hydroxide (5 N) was added dropwise
to the reaction mixture (71 mL) to pH 5.0-5.3. The reaction
mixture was aged 1 h at 45 °C and cooled to -15 °C over 3 h.
The product was filtered, and the cake was washed with cold
IPA/water (1:1) and water and dried by a nitrogen sweep to
give ketosulfone 2 (24.91 g) as an off-white solid in 86%
isolated yield.
Hz, J 2)2.3 Hz), 7.2 (m, 5H), 4.21 (s, 2H), 2.60 (s, 3H), 2.44 (s,
3H); 13C NMR (100 MHz CDCl3) δ 196.0, 163.3, 149.6, 137.2,
136.1, 130.5, 129.8, 129.2, 127.0, 123.3, 45.1, 24.7, 15.8. Anal.
Calcd for C15H15NOS: C, 70.01; H, 5.87; N, 5.44. Found: C,
69.96; H, 5.82; N, 5.37.
1-(6-Meth yl-1-oxid o-3-p yr id in yl)-2-[4-(m eth ylsu lfon yl)-
p h en yl]eth a n on e 17: mp 180-183 °C; 1H NMR (400 MHz
CDCl3) δ 8.85 (s, 1H), 7.92 (d, 2H, J ) 8.3 Hz), 7.73 (d, 1H, J
) 8.0 Hz), 7.42 (m, 3H), 4.33 (s, 2H), 3.05 (s, 3H), 2.58 (s, 3H);
13C NMR (100 MHz CDCl3) δ 192.5, 153.7, 139.7, 139.5, 139.0,
132.7, 130.6, 127.8, 126.5, 124.3, 45.1, 44.4, 18.03. Anal. Calcd
for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59. Found: C, 59.11;
H, 4.98; N, 4.52.
1-(6-m eth yl-3-p yr id in yl)-2-[4-(m eth ylsu lfin yl)p h en yl]-
eth a n on e 18: mp 133-134 °C;1H NMR (400 MHz CDCl3) δ
9.12 (s, 1H), 8.16 (dd, 1H, J 1)8.1 Hz, J 2)2.0 Hz), 7.62 (d, 2H,
J ) 8.1 Hz), 7.43 (d, 2H, J ) 8.1), 7.28 (d, 1H, 8.3 Hz), 4.34 (s,
2H), 2.71 (s, 3H), 2.63 (s, 3H); 13C NMR (100 MHz CDCl3) δ
195.3, 163.7, 149.4, 144.53, 137.0, 136.1, 130.5, 123.9, 123.4,
45.1, 43.8, 24.7. HRMS Found: 273.10, Calcd for C15H15
NO2S: 273.08.
-
5-Ch lor o-3-(4-m eth a n esu lfon ylp h en yl)-6′-m eth yl[2,3′]-
bip yr id in yl 1. To a suspension of ketosulfone 2 (7.24 g,
0.025mol) in dry THF (50 mL) at 0 °C was added dropwise a
20 wt % solution of t-BuOK in THF (0.0263 mol). The yellow
slurry was stirred at room temperature for 45 min, and the
hexafluorophosphate salt 29 (8.05 g, 0.0263 mol) was added
in one portion. The resulting mixture was stirred at room
temperature for 45 min and transferred dropwise with a
cannula under nitrogen pressure to a solution of acetic acid
(0.175 mol) and TFA (0.02 mol) in THF (25 mL) at 25-30 °C.
The mixture was stirred for 45 min, and ammonium hydroxide
(15 mL, 0.25) was added in one portion. The resulting dark
solution was heated at reflux for 3 h and cooled to ambient.
The phases are cut, and the organic layer was concentrated
under reduced pressure. Column chromatography on silica gel
eluting with ethyl acetate/hexane gave the bipyridine as a
colorless solid (8.42 g) in 94% yield. Rf 0.5 IPA/hexane/
triethylamine (69:30:1); DSC onset 136.7 °C, peak 138.1 °C;
1H NMR (400 MHz CDCl3) δ 8.69 (d, 1H, J ) 2.3 Hz), 8.36 (3,
1H, J ) 2.2 Hz), 7.88 (d, 2H, J ) 8.4 Hz), 7.72 (d, 1H, J ) 2.3
Hz), 7.54 (dd, 1H, J 1)8.0 Hz, J 2)2.3 Hz), 7.38 (d, 2H, J ) 8.5
Hz), 7.07 (d, 1H, J ) 8.0 Hz), 3.06 (s, 3H), 2.51 (s, 3H); 13C
NMR (100 MHz CDCl3) δ 158.4, 152.2, 149.7, 148.3, 143.7,
140.1, 137.9, 137.2, 135.18. 131.1, 130.0, 130.3, 127.8, 122.7,
44.4, 24.1. Anal. Calcd for C18H15ClN2O2S. C, 60.25; H, 4.21;
N, 7.81. Found: C, 60.30; H, 4.25; N, 7.85.
P r oced u r e B: To a solution of sulfide 15 (270 g, 1.05 mol)
and sulfuric acid (2 N, 20 mL) in methanol (2700 mL) at 55
°C was added a solution of sodium tungstate (6.0 g, 0.02 mol)
in water (200 mL). Hydrogen peroxide (380 mL, 30% aq) was
added over 2 h. Water (3000 mL) was added over 0.5 h, and
the mixture was cooled to ambient. The product was isolated
by filtration, washed with water, and dried to give ketosulfone
2 as a colorless solid (269 g) in 89% isolated yield. DSC peak
1
185.6 °C; H NMR (400 MHz CDCl3) δ 9.10 (s, 1H), 8.15 (dd,
1H, J 1)8.1 Hz, J 2)2.3 Hz), 7.89 (d, 2H, J ) 8.4 Hz), 7.45 (d,
2H, J ) 8.3 Hz), 7.28 (d, 1H, J ) 8.1 Hz), 4.37 (s, 2H), 3.03 (s,
3H), 2.63 (s, 3H); 13C NMR (100 MHz CDCl3) L 194.8, 163.9,
149.4, 140.1, 139.3, 136.0, 130.6, 129.0, 127.6, 123.4, 45.1, 44.4,
24.7. Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84.
Found: C, 62.27; H, 5.17; N, 4.74.
1-(6-Meth yl-3-p yr id in yl)-3-(4-m eth a n esu lfon ylp h en yl)-
fu r a n 23: mp 203 °C; 1H NMR (400 MHz DMSO-d6) δ 8.53 (d,
1H, J ) 2.4 Hz), 7.90 (m, 2H0, 7.73 (dd, 1H, J 1)8.3 Hz, J 2)2.4
Hz), 7.69 (d, 1H, J ) 2.0), 7.62 (m, 2H), 7.23 (d, 1H, J ) 8.3
Hz), 6.75 (d, 1H, J ) 2.0), 3.08 (s, 3H), 2.52 (s, 3H); (100 MHz
CDCl3) δ 158.9, 148.0, 147.1, 144.5, 140.8, 140.1, 135.7, 130.1,
128.7, 125.2, 124.3, 122.8, 114.4, 44.5, 24.0. HRMS Calcd for
1-(4-(Met h ylsu lfon yl)p h en yl) 2-[4-(m et h ylsu lfon yl)-
1
p h en yl]eth a n on e 12: mp 151-153 °C; H NMR (300 MHz,
C
17H16NO3S: [M + H]+ ) 314.085. Found: 314.087.
d6-DMSO) L 8.29 (d, J ) 8 Hz, 2H), 8.10 (d, J ) 8 Hz, 2H),
7.89 (d, J ) 8 Hz, 2H), 7.55 (d, J ) 8 Hz, 2H), 4.67 (s, 2H),
3.30 (s, 3H), 3.22 (s, 3H). Anal. Calcd for C16H16O5S2: C, 54.53;
H, 4.58. Found: C, 54.95; H, 4.58.
2-Ch lor oa m in oa cr olein 26. A solution of chloromalonal-
dehyde (110.5 g, 1.0 mol) in 2-propanol (150 mL) was concen-
trated to a dark brown oil which was added to a solution of
ammonium hydroxide (46 mL) in 2-propanol (200 mL which
resulted in an exotherm to 40 °C. The mixture was stirred for
12 h at ambient temperature, and the product was isolated
by filtration. The cake was washed with 2-propanol and dried
to give the aminoacrolein 26 (84 g) as an off white solid in
80% isolated yield: mp 150-152 °C; 1H NMR (300 MHz CDCl3)
L 9.13 (s, 1H), 7.55 (s, 1H); Anal. Calcd C3H4ClNO: C, 34.15;
H, 3.82; N, 13.27. Found: C, 34.22; H, 3.73; N, 13.11.
2-Ch lor oa m in oa cr olein d im er 28: mp 108-109 °C; 1H
NMR (200 MHz CD3CN) δ 9.27 (s, 2H), 7.92 (s, 2H), 2.14 (s,
1H); 13C NMR (100 MHz DMSO-d6) δ 222.0, 184.4, 156.4. Anal.
Calcd for C6H5Cl2NO2: C, 37.14; H, 2.60; N, 7.22. Found: C,
37.15; H, 2.50; N, 7.07.
1-(6-Meth yl-3-p yr id in yl)-2-[4-(m eth yl su lfid e)p h en yl]-
eth a n on e 15. To a slurry of magnesium turnings (191 g, 7.86
mol) in toluene (4 L) was added a solution of 4-thiomethyl-
benzyl chloride (566 g, 3.28 mol) in THF (0.545 L, 6.73 mol),
maintaining the temperature below 36 °C. The Grignard
solution is transferred to a solution of Weinreb amide (300 g,
1.66 mol) in toluene (1.7 L), maintaining the temperature
below - 10 °C. The mixture was aged for 1 h and then
quenched by the addition of aqueous acetic acid (50 wt %, 0.5
L). Toluene and water were added and the layers separated.
The aqueous layer was extracted with toluene (×2) and
concentrated to a yellow solid. Recrystallization from isopropyl
acetate/heptane (9 L) gave the ketosulfide as a colorless solid
1
(342 g) in 80% isolated yield: mp 111-113 °C; H NMR (400
MHz CDCl3) δ 9.09 (d, 1H, J ) 1.6 Hz), 8.12 (dd, 1H, J 1)8.1
J O000870Z