5132 J . Org. Chem., Vol. 61, No. 15, 1996
Stanetty and Krumpak
2,2-Dim eth yl-N-(3-flu or oph en yl)pr opan eth ioam ide (3).
A solution of 1 (10.00 g, 51.21 mmol) and Lawesson reagent
(11.39 g, 28.17 mmol) in 100 mL of dry toluene was refluxed
for 24 h, the solvent evaporated, and the residue purified by
flash chromatography (petroleum ethersethyl acetate, 5:1) to
give 3 (7.00 g, 65%) as pale yellow crystals after recrystalli-
zation from diisopropyl ether: mp 92-93 °C; 1H-NMR (CDCl3)
δ 1.48 (s, 9H), 6.89-7.06 (m, 1H), 7.21-7.39 (m, 2H), 7.56-
7.68 (m, 1H), 8.75 (bs, 1H); 13C-NMR (CDCl3) δ 30.1, 45.6,
111.9, 113.7, 119.9, 129.9, 140.2, 157.5, 213.7. Anal. Calcd
for C11H14FNS: C, 62.53; H, 6.68; N, 6.63. Found: C, 62.48;
H, 6.77; N, 6.52.
2,2-Dim eth yl-N-(3-ch lor oph en yl)pr opan eth ioam ide (4).
A solution of 2 (50.00 g, 236.2 mmol) and Lawesson reagent
(57.00 g, 141.0 mmol) in 500 mL of dry toluene was refluxed
for 30 h and worked up as described for 3 to yield 4 (30.70 g,
57%) as pale yellow crystals from diisopropyl ether: mp 101-
102 °C; 1H-NMR (CDCl3) δ 1.43 (s, 9H), 7.23 (dd, 1H), 7.33 (t,
1H), 7.48 (dd, 1H), 7.69 (ds, 1H); 13C-NMR (CDCl3) δ 30.1, 45.5,
123.1, 124.9, 126.9, 129.7, 134.0, 139.9, 213.9. Anal. Calcd
for C11H14ClNS: C, 58.01; H, 6.20; N, 6.15. Found: C, 58.16;
H, 6.02; N, 6.07.
Syn th esis of Ben zoth ia zoles via Lith ia tion of 3 a n d
4. Gen er a l P r oced u r e. A 5% solution of the thioamide 3 or
412 (1 equiv) in dry THF was treated with n-BuLi (2.8 equiv
2.5 M solution in n-hexane) at -75 ( 5 °C. The mixture was
allowed to warm to rt within 2 h, then cooled again to -65 (
5 °C, and the electrophile (1.5 equiv) was added. At -20 °C
the reaction mixture was treated with 2 M HCl or H2O and
extracted with ethyl acetate or ether, and the combined organic
layers were dried over Na2SO4 and evaporated. The crude
product was purified as described.
2-(1,1-Dim eth yleth yl)-7-m eth yl-1,3-ben zoth ia zole (5):
from 3; electrophile, MeI; purification, flash chromatography
(petroleum ether-ethyl acetate, 5:1); 62%; pale yellow liquid;
bp 170-175 °C/0.4 mbar (kugelrohr distillation for analysis);
1H-NMR (CDCl3) δ 1.52 (s, 9H), 2.53 (s, 3H), 7.10 (d, 1H), 7.34
(t, 1H), 7.83 (d, 1H); 13C-NMR (CDCl3) δ 21.3, 30.6, 38.2, 119.9,
124.5, 125.8, 131.4, 135.2, 153.0, 181.0. Anal. Calcd for
C12H15NS: C, 70.20; H, 7.36; N, 6.82. Found: C, 70.45; H,
7.52; N, 6.59.
2-(1,1-Dim et h ylet h yl)-7-(m et h ylt h io)-1,3-b en zot h ia -
zole (6): from 3; electrophile, Me2S2; purification, kugelrohr
distillation; 80% yellow oil; bp 155-160 °C/0.53 mbar; 1H-NMR
(CDCl3) δ 1.52 (s, 9H), 2.58 (s, 3H), 7.22 (d, 1H), 7.40 (t, 1H),
7.82 (dd, 1H); 13C-NMR (CDCl3) δ 16.5, 30.6, 38.3, 120.0, 122.7,
126.2, 131.0, 135.3, 152.7, 181.9. Anal. Calcd for C12H15NS2:
C, 60.72; H, 6.37; N, 5.90. Found: C, 61.18; H, 6.53; N; 5.85.
2-(1,1-Dim eth yleth yl)-1,3-ben zoth iazol-7-am in e (7): from
4; electrophile, (PhO)2PON3 (DPPA). The reaction mixture
was kept at -65 ( 5 °C for 1.5 h and allowed to warm up to
-20 °C during an additional 1.5 h. Red-Al (Aldrich) (10.80 g,
52.68 mmol, 3.4 M solution in toluene) was added at -80 °C.
The mixture was stirred at -80 °C for 2 h and then quenched
with ice water. The precipitate was filtered and washed with
toluene and ether, the aqueous layer of the filtrate was
extracted with ether, and the combined organic layers were
dried over Na2SO4 and evaporated to dryness. The residue
was kugelrohr distilled and recrystallized from petroleum
ether to give 7: yield 33% colorless crystals; mp 105-107 °C;
1H-NMR (CDCl3) δ 1.51 (s, 9H), 3.85 (bs, 2H), 6.64 (d, 1H),
7.25 (t, 1H), 7.48 (d, 1H); 13C-NMR (CDCl3) δ 30.7, 38.3, 109.7,
113.5, 121.7, 126.8, 140.6, 154.5, 180.7. Anal. Calcd for
C11H14N2S: C, 64.04; H, 6.84; N, 13.58. Found: C, 64.33; H,
6.66; N, 13.40.
C16H22N2OS: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.05; H,
7.95; N, 9.59.
2-(1,1-Dim et h ylet h yl)-1,3-b en zot h ia zole-7-ca r b oxylic
a cid (9): from 3; electrophile, CO2 gas; purification, recrys-
tallization from diisopropyl ether-CHCl3 (2:1); 77% yield as
colorless crystals; mp 193-194 °C; 1H-NMR (DMSO-d6) δ 1.49
(s, 9H), 7.61 (t, 1H), 8.05 (d, 1H), 8.22 (d, 1H); 13C-NMR
(DMSO-d6) δ 30.3, 37.8, 124.8, 126.0, 126.5, 126.9, 134.7, 153.7,
166.6, 184.0. Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57;
N, 5.95. Found: C, 61.01; H, 5.57; N, 5.88.
7-Ben zoyl-(1,1-d im eth yleth yl)-1,3-ben zoth ia zole (10):
from 3; electrophile, PhCN; purification, flash chromatography
(petroleum ether-ethyl acetate, 5:1) and subsequent recrys-
tallization from petroleum ether; 66% yield as colorless
crystals; mp 80-82 °C; 1H-NMR (CDCl3) δ 1.58 (s, 9H), 7.45-
7.64 (m, 4H), 7.77-7.84 (m, 3H), 8.25 (d, 1H); 13C-NMR (CDCl3)
δ 30.6, 38.2, 124.9, 127.3, 128.2, 129.2, 129.5, 130.1, 132.0,
135.1, 137.6, 154.6, 185.9, 195.1. Anal. Calcd for C18H17
-
NOS: C, 73.19; H, 5.80; N, 4.75. Found: C, 72.92; H, 5.90;
N, 5.00.
2-(1,1-Dim eth yleth yl)-1,3-ben zoth ia zole-7-ca r boxa ld e-
h yd e (11): From 3; electrophile, DMF; purification, flash
chromatography (petroleum ether-ethyl acetate, 5:1) and for
analysis recrystallization from petroleum ether; 84% yield as
1
colorless crystals; mp 75-76 °C; H-NMR (CDCl3) δ 1.53 (s,
9H,), 7.62 (t, 1H), 7.88 (d, 1H), 8.25 (d, 1H), 10.19 (s, 1H); 13C-
NMR (CDCl3) δ 30.6, 38.2, 125.7, 128.5, 130.6, 130.5, 132.2,
154.6, 186.0, 190.5. Anal. Calcd for C12H13NOS: C, 65.72;
H, 5.97; N, 6.39. Found: C, 65.63; H, 6.01; N, 6.29.
1-[2-(1,1-Dim et h ylet h yl)-7-(1,3-ben zot h ia zolyl)]cyclo-
h exa n ol (12): from 3; electrophile, cyclohexanone; purification,
flash chromatography (petroleum ether- ethyl acetate, 5:1)
and subsequent recrystallization from MeO-tert-Bu; 44% yield
as colorless crystals; mp 119-119.5 °C; 1H-NMR (CDCl3) δ 1.50
(s, 9H), 1.61-2.05 (m, 11H), 7.30 (dd, 1H), 7.41 (t, 1H), 7.89
(dd, 1H); 13C-NMR (CDCl3) δ 21.8, 25.4, 30.6, 37.1, 37.8, 73.9,
119.9, 121.4, 125.5, 130.7, 143.4, 154.5, 183.0. Anal. Calcd
for C17H24NOS: C, 70.30; H, 8.33; N, 4.82. Found: C, 70.41;
H, 8.13; N, 5.04.
2-(1,1-Dim eth yleth yl)-1,3-ben zoth ia zol-7-ol (13): from 4;
B(OMe)3 (0.5 mL) was added at -80 °C, the reaction mixture
was stirred at 0 °C for 1 h. Glacial AcOH (1.19 mL) and H2O2
(2.98 mL, 30%) were added, and the solution was stirred
overnight, quenched with H2O, and acidified with 2 M HCl,
followed by the usual workup: purification, flash chromatog-
raphy (petroleum ether-ethyl acetate, 5:1); 66% yields as
1
orange crystals; mp 154-156 °C; H-NMR (CDCl3) δ 1.53 (s,
9H), 6.79 (d, 1H), 7.24 (t, 1H), 7.54 (d, 1H), 8.83 (bs, 1H); 13C-
NMR (CDCl3) δ 30.7, 38.7, 109.6, 113.8, 122.8, 127.2, 151.6,
154.4, 183.7. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22;
N, 6.69. Found: C, 63.50; H, 7.52; N, 6.47.
2-(1,1-Dim eth yleth yl)-1,3-ben zoth iazole-7-m eth an ol (14):
from 4; electrophile, paraformaldehyde; purification, flash
chromatography (petroleum ether-ethyl acetate, 5:1) and
subsequent kugelrohr distillation (150 °C/0.01 mbar) for
analysis; 41% yield as colorless crystals; mp 139-140 °C; 1H-
NMR (CDCl3) δ 1.56 (s, 9H), 2.30 (bs, 1H), 4.91 (s, 2H), 7.30
(d, 1H), 7.41 (t, 1H), 7.92 (d, 1H); 13C-NMR (CDCl3) δ 30.3,
37.8, 62.6, 120.5, 121.7, 125.5, 131.6, 136.3, 152.9, 181.5. Anal.
Calcd for C12H15NOS: C, 65.12; H, 6.83; N, 6.33. Found: C,
65.26; H, 6.76; N, 6.56.
Syn th esis of Th ioca r ba m a tes 15-17. Gen er a l P r oce-
d u r e. A solution of the corresponding isothiocyanate and
methanol (10 equiv) or 2-propanol (10 equiv) respectivelysin
the case of 2-propanol, 1 equiv of triethylamine was addedswas
refluxed for 12 h under N2. The reaction mixture was
concentrated, and the residual crude product was filtered and
recrystallized.
N-(3-F lu or op h en yl)th ioca r ba m ic a cid O-m eth yl ester
(15): 79% yield as colorless crystals; mp 60-61 °C (petroleum
ether); 1H-NMR (CDCl3) δ 4.15 (s, 3H), 6.73-6.94 (m, 1H), 7.07
(bs, 1H), 7.15-7.35 (m, 2H), 8.90 (bs, 1H); 13C-NMR (CDCl3)
δ 59.7, 109.1, 112.1, 116.8, 130.1, 138.4, 162.7, 189.1. Anal.
Calcd for C8H8FNOS: C, 51.88; H, 4.35; N, 7.56. Found: C,
51.85; H, 4.16; N, 7.49.
2-(1,1-Dim eth yleth yl)-N-(1′,1′-d im eth yleth yl)-1,3-ben -
zoth ia zole-7-ca r boxa m id e (8): from 3; electrophile, t-BuN-
CO; purification, recrystallization from diisopropyl ether; 76%
colorless crystals; mp 177-178 °C; 1H-NMR (CDCl3) δ 1.51 (s,
9H), 1.53 (s, 9H), 6.25 (bs, 1H), 7.48 (t, 1H), 7.51 (dd, 1H), 8.10
(dd, 1H); 13C-NMR (CDCl3) δ 28.8, 30.5, 38.0, 51.9, 121.0, 125.1,
125.4, 128.4, 134.1, 154.5, 165.1, 185.9. Anal. Calcd for
(12) If the reaction was run with both educts yields are shown in
Scheme 2.