Indanylidenes, Part 1
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 3 407
dimethyl sulfoxide as solvent: NMR (DMSO-d6) δ 7.79 (br m,
1H, NH), 7.53 (s, 1H, Ar), 7.36 (s, 2H, Ar), 6.38 (t, 1H, dCH),
3.22-2.90 (m, 4H, CH2CH2), 2.65 (d, 3H, CH3). Anal. Calcd
for C12H12ClNO (MW ) 221.69): C, 65.02; H, 5.46; N, 6.32;
Cl, 15.99. Found: C, 64.93; H, 5.47; N, 6.27; Cl, 16.07.
hexanes (3:7) as eluent afforded 4.34 g (16%) of the component
that eluted first as a yellow solid. This was identified by NMR
to be 84. Concentration in vacuo of the fractions containing
the pure component that eluted second gave 17.3 g (65%) of a
yellow solid. The second component was identified by NMR to
be 85. Recrystallization of 1 g of the 85 from acetone/water
mixtures afforded the analytical sample: mp 72-73 °C (lit.13
mp 74 °C); NMR (CDCl3) δ 8.6 (s, 1H, Ar), 8.45 (d, 1H, Ar),
7.65 (d, 1H, Ar), 3.25 (m, 2H, CH2), 2.82 (m, 2H, CH2). Anal.
Calcd for C9H7NO3 (MW ) 177.17): C, 61.02; H, 3.98; N, 7.91.
Found: C, 60.90; H, 4.06; N, 7.93.
(b) P r ep a r a tion of 6-Am in o-1-in d a n on e (86). Platinum
oxide (0.4 g) was added to a solution of 85 (29.7 g, 0.17 mol) in
95% ethanol (250 mL), and the mixture was placed on a Parr
hydrogenation apparatus under 60 psi of hydrogen gas pres-
sure. This reduction is exothermic. After 40 min, the mixture
was removed from the hydrogenator and methanol was added
to dissolve the resulting solid. The catalyst was filtered, and
the filtrate was concentrated in vacuo. The residue was taken
up in 1.0 N hydrogen chloride (400 mL) and washed with
diethyl ether. The aqueous phase was chilled, and the pH was
adjusted to 7.0 with 1.0 N sodium hydroxide solution (400 mL).
After the mixture was stirred at room temperature for 18 h,
the resulting solid was filtered, washed with water, and air-
dried to give 19.6 g (78%) of 86 as a yellow solid: mp 171-
173 °C (lit.13 mp 171 °C); NMR (DMSO-d6) δ 7.21 (d, 1H, Ar),
6.92 (dd, 1H, Ar), 6.75 (d, 1H, Ar), 5.28 (br s, 2H, NH2), 2.90
(m, 2H, CH2), 2.53 (m, 2H, CH2). Anal. Calcd for C9H9NO (MW
) 147.17): C, 73.45; H, 6.16; N, 9.52. Found: C, 73.31; H, 6.21;
N, 9.45.
(c) P r ep a r a tion of 6-Cya n o-1-in d a n on e (87). The prepa-
ration of a solution of copper(I) cyanide in water (80 mL) was
as follows. A solution of sodium bisulfite (8.5 g, 0.08 mol) and
sodium hydroxide (4.1 g, 0.10 mol) in water (100 mL) was
added to a solution of copper(II) sulfate pentahydrate (41.2 g,
0.16 mol) and sodium chloride (10.9 g, 0.19 mol) in hot water
(200 mL). To this was added a solution of potassium cyanide
(28.3 g, 0.43 mol) in water (80 mL). The aqueous phase was
decanted, water (80 mL) was added to the resulting solid, and
the mixture was chilled to 0-5 °C.
The preparation of the diazonium salt of 86 was as follows.
A solution of sodium nitrite (8.6 g, 0.12 mol) in water (20 mL)
was added to a mixture of 86 (17.4 g, 0.12 mol) in concentrated
hydrogen chloride (30 mL) and water (45 mL). This mixture
was neutralized with sodium carbonate.
Met h od G. P r ep a r a t ion of (E)-N-Cyclop r op yl-2-(6-
ch lor o-1-in d a n ylid en e)a ceta m id e (30). (a ) P r ep a r a tion
of 2-Ch lor o-N-cyclop r op yla cet a m id e (81). Cyclopropyl-
amine (21.5 g, 0.376 mol, Aldrich) was added dropwise over 1
h to a solution of chloroacetyl chloride (21.3 g, 0.188 mol,
Aldrich) in diethyl ether (300 mL) at 0 °C. The reaction
mixture was diluted with chloroform (300 mL), and the
cyclopropylamine hydrochloride was removed by filtration. The
filtrate was evaporated in vacuo to give an off-white solid
residue. This residue was dissolved in dichloromethane (500
mL), washed with water (175 mL), filtered through glass wool,
and spin-evaporated in vacuo to give 24.4 g (97%) of 81: mp
74-78 °C; NMR (DMSO-d6) δ 8.27 (br s, 1H, NH), 3.95 (s, 2H,
CH2), 2.65-2.59 (m, 1H, CH), 0.67-0.37 (m, 4H, CH2CH2).
(b) P r ep a r a tion of [(N-Cyclop r op ylca r ba m oyl)m eth -
ylen e]tr ip h en ylp h osp h oiu m Ch lor id e (82). This compound
was prepared as described in part b of method F to give 82 as
an off-white solid: mp 245-249 °C; NMR (DMSO-d6) δ 8.8 (br
s, 1H, NH), 7.90-7.77 (m, 17H, Ar), 4.90 (d, 2H, J ) 14.83
Hz, PCH2), 2.51 (br s, 1H, CH), 0.56-0.19 (m, 4H, CH2CH2).
(c) P r ep a r a tion of (E)-N-Cyclop r op yl-2-(6-ch lor o-1-
in d a n ylid en e)a ceta m id e (30). This compound was prepared
in a manner analogous to part c of method F.
Met h od H. P r ep a r a t ion of (E)-N-Cyclop r op yl-2-(1-
in d a n ylid en e)a ceta m id e (29). (a ) P r ep a r a tion of Dieth yl
((Cyclop r op ylca r b a m oyl)m et h yl)p h osp h on a t e (83). 81
(20 g, 0.17 mol) was added in portions with stirring to triethyl
phosphite (28 g, 0.17 mol, Aldrich) at 110 °C. The solution was
then heated to 175 °C for 30 min and cooled to 125 °C, and
the volatiles were removed by distillation under aspirator
vacuum (17 mmHg) at this temperature. The residual oil was
stirred with pentane (200 mL) while cooling in an ice bath to
induce crystallization. Filtration gave 5.2 g (14%) of 83 as
white crystals: mp 51-56 °C. The liquor was concentrated and
cooled to give 25.3 g (71%) of a second crop: mp 50-56 °C.
Recrystallization from dichloromethane/hexanes mixtures gave
the analytical sample: mp 55-57 °C. Anal. Calcd for C9H18
-
NO4P: C, 45.96; H, 7.71; N, 5.95. Found: C, 45.85; H, 7.76;
N, 5.90.
(b) P r ep a r a t ion of (E)-N-Cyclop r op yl-2- (1-in d a n yli-
d en e)a ceta m id e (29). This compound was prepared in a
manner analogous to method E, with replacement of diethyl
carbamoylmethylphosphonate with 83. The reaction was
conducted initially at -50 °C, followed by stirring of the
mixture at -20 °C for 10 min. The solution was cooled to -45
°C prior to addition of the 1-indanone. After addition, the
mixture was stirred for 2 h instead of 18 h. The desired product
was isolated by chromatography on silica gel using ethyl
acetate/hexanes (1:2) as eluent to give a 32% yield of 29: mp
115-116 °C; NMR (DMSO-d6) δ 7.96 (br d, 1H, NH), 7.50 (d,
1H, J ) 7.4 Hz, Ar), 7.45-7.21 (m, 3H, Ar), 6.29 (br s, 1H,
dCH), 3.25-3.10 (m, 2H, CH2), 3.05-2.85 (m, 2H, CH2), 2.78-
2.60 (m, 1H, CH), 0.70-0.55 (m, 2H, CH2), 0.48-0.37 (m, 2H,
CH2); steady-state NOE, irradiation at δ 6.29, significant NOE
at δ 7.50 and δ 7.96. Anal. Calcd for C14H15NO (MW )
213.28): C, 78.84; H, 7.04; N, 6.57. Found: C, 78.74; H, 7.14;
N, 6.52.
To a mixture of the copper(I) cyanide solution and toluene
(100 mL) at 0-5 °C was added dropwise the diazonium salt
solution, keeping the temperature below 5 °C. After the
addition, the mixture was allowed to warm to room temper-
ature, and then the mixture was heated to 50-60 °C for 1 h
and allowed to come to room temperature over an 18 h period.
The resulting solid was filtered off and washed with diethyl
ether. The filtrate was extracted several times with diethyl
ether. The combined diethyl ether phase was washed with
saturated sodium chloride solution, dried (sodium sulfate), and
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel using dichloromethane as eluent to give
9.7 g (52%) of 87 as a pale-yellow solid: mp 105-107 °C (lit.26
mp 109 °C); NMR (CDCl3) δ 8.04 (d, 1H, Ar), 7.83 (dd, 1H,
Ar), 7.62 (dd, 1H, Ar), 3.24 (m, 2H, CH2), 2.75 (m, 2H, CH2).
Anal. Calcd for C10H7NO (MW ) 177.16): C, 76.42; H, 4.49;
N, 8.91. Found: C, 76.52; H, 4.53; N, 8.91.
The remainder of the synthesis was performed as described
in parts c-g of method A.
Met h od I. P r ep a r a t ion of (E)-2-(6-Cya n o-1-in d a n yli-
d en e)a ceta m id e (9). (a ) P r ep a r a tion of 4-Nitr o-1-in -
d a n on e (84) a n d 6-Nitr o-1-in d a n on e (85). 1-Indanone (20.0
g, 0.17 mol) was added in one portion to concentrated sulfuric
acid (170 mL) at 0 °C. A solution of potassium nitrate (16.9 g,
0.16 mol) in concentrated sulfuric acid (45 mL) was added in
small portions over a 1.3 h period. The mixture was stirred
for 1 h at -5 °C, then poured over 2 L of ice. The mixture was
left at room temperature for 18 h. The resulting solid was
filtered, washed with water, and air-dried to give 23.6 g (89%)
of an off-white solid. NMR and TLC indicated a mixture of
two isomers. Chromatography on silica gel using ethyl acetate/
Meth od J . P r ep a r a tion of (Z)-2-(6-F lu or o-1-in d a n yli-
d en e)a ceta m id e (65). A solution of 7 (20 g, 104.6 mmol) in
dichloromethane/methanol/3:1 (1000 mL) was irradiated by an
Ace-Hanovia high-pressure quartz mercury vapor lamp for 0.5
h. The volatiles were removed by spin evaporation in vacuo to
give a beige residue. This residue was chromatographed on
silica gel 60 using a step gradient going from ethyl acetate/
hexanes, 1:1, to ethyl acetate/ethanol, 1:1. Fractions containing
(Z)-2-(6-fluoro-1-indanylidene)acetamide were combined and
concentrated by spin evaporation in vacuo. The resulting solid