Journal of Medicinal Chemistry
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(CH2Cl2:MeOH, 50:1) to yield (2S)-(2,3-dihydrobenzo[1,4]dioxin-2-
yl)methanol. This alcohol was processed according to method A to
give crude (2S)-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methylamine as a
light-yellow oil. The oil was purified by flash-column chromatography
(CH2Cl2:MeOH, 10:1) to yield a purified oil. A portion of this oil
(4.82 g, 29 mmol) in 2-propanol (250 mL) was treated with 1 N HCl
(30 mL), heated on steam bath until homogeneous, and let cool to
room temperature. After 3 h, the mixture was ice cooled for 2 h to give
a flaky solid, which was recrystallized from 2-propanol to yield a white
solid HCl salt, [α]D −69.6 (c 1.06, EtOH). This white solid was
partitioned between CH2Cl2 and dilute NaOH; the organic solution
was dried (NaSO4) and concentrated in vacuo to yield oily (2S)-(2,3-
dihydrobenzo[1,4]dioxin-2-yl)methylamine, [α]D −57.8 (c 1.40,
CHCl3). The oil (2.1 g, 12.7 mmol) and sulfamide (2.44 g, 25.4
mmol) were refluxed in 1,4-dioxane (75 mL) for 2 h, and the crude
product was purified by flash-column chromatography
(CH2Cl2:MeOH, 10:1) to yield a white solid, which was recrystallized
from CH2Cl2 to yield the title compound as a white crystalline solid,
mp 102−103 °C; [α]D −45.1 (c 1.05, MeOH). 1H NMR (DMSO-d6)
δ 3.10 (dd, J = 6.9, 13.7 Hz, 1H), 3.20 (dd, J = 5.5, 13.7 Hz, 1H), 3.97
(dd, J = 6.9, 11.4 Hz, 1H), 4.3 (m, 2H), 6.81 (bd s, 3H, NH), 6.86 (m,
4H). Anal. Calcd (C9H12N2O4S): C, 44.25; H, 4.95; N, 11.47; S, 13.13.
Found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.
DMF (10 mL). 1-Ethyl-3-dimethylaminopropylcarbodiimide (EDC;
4.84 g, 25 mmol) was added at room temperature, and the mixture was
stirred for 30 min; ammonium hydroxide (28%, 2.26 mL, 33.4 mmol)
was added, and the mixture was stirred for 16 h. The reaction mixture
was diluted with CH2Cl2 (50 mL) and water (50 mL), and the pH was
adjusted to ∼3 (pH paper) by addition of 1 N HCl. The organic phase
was separated, and the aqueous phase was extracted twice with
CH2Cl2. The combined organic solution was dried (Na2SO4) and
evaporated in vacuo to yield an oil, which was purified with flash-
column chromatography (ethyl acetate) to yield the carboxamide as a
white solid (4.35 g, 97%). 1H NMR (CDCl3) δ 2.10 (m, 1H), 2.40 (m,
1H), 2.75−2.95 (m, 2H), 4.54 (dd, J = 3.0, 9.4 Hz, 1H), 5.50 (bd s,
1H), 6.55 (bd s, 1H), 6.85−6.95 (m, 2H), 7.10−7.20 (m, 2H). The
amide (5.35 g, 30 mmol; from several preparations) in THF (90 mL)
was treated with 1 M LiAlH4 in THF (36 mL, 36 mmol) with stirring,
and the mixture was stirred at room temperature for 20 h. The
reaction was cooled in an ice bath, quenched (1.4 mL of water, 1.4 mL
of 3 N NaOH, 2.8 mL of water), and stirred for 2 h at room
temperature. The solids were filtered; the filtrate was dried (K2CO3)
and evaporated in vacuo to an oil, which was purified via flash-column
chromatography (ethyl acetate/MeOH/ammonium hydroxide,
90:9:1) to yield chroman-2-ylmethylamine (3.50 g, 71%) as an oil,
MS (ES) m/z 164 (MH+). A mixture of this amine (1.63 g, 10 mmol)
and sulfamide (1.92 g, 20 mmol) in 1,4-dioxane (50 mL) was refluxed
for 2 h, cooled, and evaporated in vacuo to an oil, which was purified
via flash-column chromatography (CH2Cl2/MeOH, 10:1) to give a
white solid. Recrystallization from ethyl acetate/hexane furnished 8 as
a white solid (1.52 g, 63%), mp 100−101 °C. MS (ES) m/z 241 (M −
N-((2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl)-N-methylsulfa-
mide (6). Racemic (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine
(825 mg, 5 mmol) in ethyl formate (15 mL) was refluxed for 30
min and evaporated in vacuo to yield N-((2,3-dihydrobenzo[1,4]-
dioxin-2-yl)methyl)formamide as an oil. This oil in diethyl ether (25
mL) was treated with 1 M LiAlH4 in THF (9.0 mL, 9.0 mmol) at 0 °C
and stirred for 5 h at room temperature. The reaction was cooled in an
ice bath and quenched with water (0.50 mL), followed by 3 N NaOH
(0.50 mL) and water (0.50 mL). The mixture was stirred at room
temperature for 1 h, and the solid was filtered off. The filtrate was
evaporated in vacuo to yield a residue, which was partitioned between
1 N HCl and diethyl ether. The aqueous phase was basified with 1 N
NaOH and extracted with diethyl ether. The organic phase was dried
(MgSO4) and evaporated in vacuo to yield N-((2,3-dihydro-benzo-
[1,4]dioxin-2-yl)methyl)-N-methylamine as an oil (0.40 g). MS (ES)
1
H). H NMR (CDCl3) δ 1.85 (m, 1H), 2.05 (m, 1H), 2.85 (m, 2H),
3.35 (m, 1H), 3.50 (m, 1H), 4.22 (m, 1H), 4.59 (s, 2H), 4.91 (s, 1H),
6.79 (d, J = 8.1 Hz, 1H), 6.87 (dd, J = 7.3, 7.5 Hz, 1H), 7.10 (m, 2H).
Anal. Calcd (C10H14N2O3S): C, 49.57; H, 5.82; N, 11.56; S, 13.23.
Found: C, 49.57; H, 5.80; N, 11.75; S, 13.33.
N-(2-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)ethyl)sulfamide (9). Po-
tassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-
(2,3-dihydrobenzo[1,4]dioxole) (6.87 g, 30 mmol) in DMSO (90
mL), and the mixture was stirred at room temperature for 20 h. The
reaction mixture was diluted with water (250 mL) and extracted twice
with diethyl ether. The organic solution was washed with water,
washed twice with brine, dried (Na2SO4), and evaporated in vacuo to
yield 2-cyanomethyl-(2,3-dihydrobenzo[1,4]dioxole) as a white solid
(4.90 g, 93%). 1H NMR (CDCl3) δ 2.78 (d, J = 6.1 Hz, 2H), 4.08 (dd,
J = 6.2, 11.6 Hz, 1H), 4.31 (dd, J = 2.3, 11.5 Hz, 1H), 4.50 (m, 1H),
6.89 (m, 4H). This material was dissolved in THF (50 mL), treated
with 1 M BH3-THF (80 mL, 80 mmol), and the mixture refluxed for 5
h, then stirred at room temperature for 16 h. With ice-bath cooling, 2
N HCl was added until pH 1 was achieved. The reaction mixture was
stirred for 1 h at room temperature and evaporated in vacuo to yield
an oil. The oil was partitioned between 3 N NaOH and diethyl ether,
and the diethyl ether solution was washed with brine, dried (Na2SO4),
and evaporated in vacuo to yield crude 2-(2,3-dihydrobenzo[1,4]-
dioxin-2-yl)ethylamine (2.80 g, 58%), MS (ES) m/z (MH+) 180. This
amine (2.80 g, 15.6 mmol) in 1,4-dioxane (100 mL) was combined
with sulfamide (3.0 g, 31 mmol) and heated to reflux for 2 h. The
solution was cooled and evaporated in vacuo to give an orange solid,
which was purified by flash-column chromatography (CH2Cl2/MeOH,
10:1) to yield a white solid. The solid was recrystallized from CH2Cl2
to yield 9 as a white solid (2.12 g), mp 101−103 °C. MS (ES) m/z (M
− H) 257. 1H NMR (CDCl3) δ 1.94 (dd, J = 6.5, 12.9, 2H), 3.43 (dd,
J = 6.4, 12.9 Hz, 2H), 3.94 (dd, J = 7.4, 11.3 Hz, 1H), 4.30 (m, 2H),
4.52 (s, 2H), 4.70 (m, 1H), 6.86 (m, 4H). Anal. Calcd
(C10H14N2O4S): C, 46.50; H, 5.46; N, 10.85; S, 12.41. Found: C,
46.48; H, 5.60; N, 10.81; S, 12.41.
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m/z 180 (MH+). H NMR (CDCl3) δ 2.50 (s, 3H), 2.85 (m, 2H),
4.02 (dd, J = 7.9, 11.6 Hz, 1H), 4.30 (m, 2H), 6.85 (m, 4H). A
solution of this amine (380 mg, 2.1 mmol) and sulfamide (820 mg, 8.5
mmol) in 1,4-dioxane (15 mL) was refluxed for 1.5 h and evaporated
in vacuo to yield a crude residue. The residue was purified via flash-
column chromatography (ethyl acetate/heptane, 1:1), and the
resultant solid was recrystallized from ethyl acetate/hexane to yield
6 as a white solid (330 mg), mp 97−98 °C. MS (ES) m/z 257 (M −
H). 1H NMR (CDCl3) δ 2.99 (s, 3H), 3.40 (dd, J = 5.9, 14.9 Hz, 1H),
3.51 (dd, J = 6.7, 14.9 Hz, 1H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 4.29
(dd, J = 2.3, 11.5 Hz, 1H), 4.46 (m, 1H), 4.52 (bd s, 2H), 6.86 (m,
4H). Anal. Calcd (C10H14N2O4S): C, 46.50; H, 5.46; N, 10.85; S,
12.41. Found: C, 46.48; H, 5.65; N, 10.90; S, 12.07.
N-((2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl)-N′,N′-dimethylsul-
famide (7). Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine
(8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were
combined in DMF (10 mL) and cooled in an ice bath as
dimethylsulfamoyl chloride (1.44 g, 10 mmol) was added. The
reaction mixture was stirred for 3 h with continued cooling, after which
the reaction mixture was partitioned between ethyl acetate and water,
and the organic solution was washed with brine, dried (MgSO4), and
evaporated in vacuo to yield an oil. The oil was purified using flash-
column chromatography (EtOAc:heptane, 1:1) to yield a white solid,
which was recrystallized (EtOAc/hexanes) to yield title compound 7
1
as a white floccular solid, mp 76−78 °C. MS (ES) 273 (MH+). H
NMR (CDCl3) δ 2.82 (s, 6H), 3.36 (m, 2H), 4.04 (dd, J = 7.0, 11.4,
1H), 4.27 (dd, J = 2.3, 11.4 Hz, 1H), 4.35 (m, 1H), 4.59 (bd m, 1H,
NH), 6.87 (m, 4H). Anal. Calcd (C11H16N2O4S): C, 48.52; H, 5.92;
N, 10.29; S, 11.78. Found: C, 48.63; H, 5.62; N, 10.20; S, 11.90.
N-(Chroman-2-ylmethyl)sulfamide (8). Example of method B.
Chroman-2-carboxylic acid (4.5 g, 25 mmol) and 1-hydroxybenzo-
triazole (3.86 g, 25 mmol) were combined in CH2Cl2 (40 mL) and
(2S)-(−)-N-((6-Fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl)-
sulfamide (10e). A DMF (200 mL) solution of 4-fluoro-2-
hydroxyacetophenone (8.94 g, 58 mmol) and potassium carbonate
(8.84 g, 64 mmol) was treated with (R)-glycidyl m-nitrophenylsulfo-
nate (15.0 g, 58 mmol) and the reaction stirred at 40−45 °C for 7 h.
The reaction was cooled to room temperature and poured into water
(500 mL) and extracted with t-butyl methyl ether (3 × 350 mL). The
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dx.doi.org/10.1021/jm400894u | J. Med. Chem. 2013, 56, 9019−9030