P. Bałczewski et al. / Tetrahedron 65 (2009) 8727–8732
8731
as in other processes or final products having any contact with
human being.
(0.544 g, 10.25 mmol) was added dropwise with stirring during 2 hr
at rt. Then, stirring was continued for additional 48 h and methanol
was evaporated. The crude product was preliminarily kept under
vacuum (1 hr, 25 ꢀC, 1 mmHg) to give quantitatively 1.58 g of the
crude product 10. After the vacuum treatment, the amount of acry-
lonitrile still remained below 150–180 ppm. For the effective re-
moval of acrylonitrile below 100 ppm, the crude product was further
dissolved in methylene chloride and washed with water three times.
Another procedure involving azeotropic removal of acrylonitrile
with EtOH was effective up to the level of 150 ppm. It involved
dissolution of 10 in EtOH, evaporation of the azeotrope (twice,
1ꢁ200 mL, then 1ꢁ300 mL) and keeping the final product under
vacuum for 10 h at 60–68 ꢀC/0.01 Torr.
This reaction was scaled up (see the main text). The combined
crude products from three runs (>500 g of 10) after evaporation of
methanol were dissolved in methylene chloride (2 L) and this so-
lution was divided into two parts. Each volume was washed with
water (3ꢁ500 mL) then dried over MgSO4, filtered and evaporated
to give 10 containing only 75 ppm of acrylonitrile.
4. Experimental
4.1. General
1H NMR (200 and 500 MHz) and 13C NMR (50 and 125 MHz)
spectra were recorded using a Bruker AC-200 and a Bruker DRX-500
spectrometers, respectively. Mass spectra were obtained using
a Finnigan Mat 95 spectrometer. Column chromatography was done
using Merck silica gel (F254 60, 70–230 and 270–400 mesh). The
Merck TLC plates were developed in methanol containing 1% aq
ammonia for analysis of 12–17. Starting amines and acrylonitrile
were commercial products. Organic solvents were purified by
standard procedures.
4.2. 3-{4-[2-(2-Cyanoethylamino)ethyl]-piperazin-
1-yl}propionitrile (5)
White solid: mp¼49–52 ꢀC; [found: C, 72.12; H, 10.19; N, 17.62.
C19H32N4 requires C, 72.11; H, 10.18; N, 17.71]; nmax(KBr) 3461(br),
3312, 2921, 2847, 2246, 1650, 1448, 1130; dH (200 MHz, CDCl3) 0.75–
1.60 (m, 17H), 1.65–1.95 (5H, m), 2.32–2.44 (1H, m), 2.45–2.57 (4H,
m), 2.66–2.78 (1H, m), 2.83–3.00 (4H, m); dC (50 MHz, CDCl3)
118.64, 55.35, 52.92, 44.25, 42.28, 42.07, 34.10, 33.29, 32.40, 31.89,
29.31, 27.60, 19.02; m/z (CI, isobutane) 317(100 MHþ); m/z (FAB,
þVE) 317(100 MHþ).
To a stirred solution of the amine 1 (0.80 g, 6.2 mmol) in
methanol (3 mL), acrylonitrile (0.66 g, 12.4 mmol) was added
dropwise during 2 h at 0 ꢀC. Stirring was continued for an addi-
tional 2 h at this temperature and for 20 h at room temperature.
The solvent was evaporated and the crude product was purified by
column chromatography using methanol–25% ammonium hy-
droxide in water (100:1) as an eluent. Yield 1.28 g (88%). Oil:
nmax(film) 3309, 2943, 2816, 2247, 1461, 1352, 1161, 1012; dH
(200 MHz, CDCl3) 1.65 (1H, br s), 2.58–2.39 (14H, m), 2.75–2.61 (4H,
m), 2.94 (2H, t, J¼6.6 Hz); dC (50 MHz, CDCl3) 118.6, 118.5, 57.1, 53.0,
52.6, 52.28, 45.3, 44.8, 18.4, 15.5; HRMS (EI): Mþ, found 236.1882.
C12H22N5 requires 236.1875.
4.6. 3-(3-{(2-Cyanoethyl)-[3-(2-cyanoethylamino)
propyl]amino}propylamino)propionitrile (12)
To a stirred solution of the amine 3 (46.0 g, 0.351 mol) in MeOH
(175 mL), acrylonitrile (372 g, 7.02 mol, 462 mL) was added at 0 ꢀC.
The solution was stirred for 30 min at this temperature and an
excess of acrylonitrile and MeOH was evaporated. To the remaining
viscous liquid (103.7 g), EtOH (2ꢁ25 mL) was added, mixed and
then evaporated to remove the azeotrope using water pump and
then oil pump. The product contained not more than 5% of a tet-
rakisaddition compound (MS analysis), 2% of the starting amine 3
and 85 ppm of acrylonitrile. Oil: [found: C, 61.98; H, 8.83; N, 28.95.
C15H26N6 requires C, 62.04; H, 9.02; N, 28.94]; Rf [MeOHþ1% (25%
NH3 in water]¼0.45; dH (200 MHz, CDCl3) 2.86–2.93 (4H, m), 2.65–
2.74 (6H, m), 2.44–2.54 (10H, m), 1.55–1.68 (4H, m); dC (50 MHz,
CDCl3) 118.4, 118.2, 50.2, 48.1, 47.8, 45.7, 43.8, 26.0, 17.2, 15,8; dN15
(50 MHz, MeNO2, INVGATE) 36.8 (2N), 38.2 (1N), 246.3 (1N), 246.4
(2N), m/z (FAB, þVE) 291(100 MHþ).
4.3. 3-[4-(2-Aminoethyl)piperazin-1-yl]propionitrile (7)
To a stirred solution of 1 (1.80 g, 13.9 mmol) in methanol (6 mL),
acrylonitrile (0.74 g, 13.9 mmol) was added dropwise during 2 h at
0 ꢀC. Stirring was continued for additional 2 h at this temperature and
for 20 h at the room temperature. The solvent was evaporated, and
the crude product was purified by column chromatography using
methanol–25% ammonium hydroxide in water (100:1). Yield 1.88 g
(74%).Oil: nmax(film) 3367, 2942, 2812, 2247, 1593, 1461, 1352, 1161,
1011; dH (200 MHz, CDCl3) 1.28 (2H, br s), 2.58–2.31 (12H, m), 2.80–
2.62 (4H, m); dC (50 MHz, CDCl3) 117.9, 60.1, 53.7, 52.3, 51.6, 37.8,14.7;
HRMS (EI): Mþ, found 183.1612. C9H19N4: requires 183.1610.
4.4. 3-(4-{2-[Bis-(2-cyanoethyl)-amino]-ethyl}-piperazin-
1-yl)-propionitrile (8)
4.7. 3-[{3-[{3-[Bis-(2-cyanoethyl)amino]propyl}-
(2-cyanoethyl)amino]propyl}-(2-cyanoethyl)-
amino]propionitrile (13)
To a stirred solution of the amine 1 (0.50 g, 3.87 mmol) in
methanol (1.5 mL), acrylonitrile (2.16 g, 40.6 mmol) was added
slowly at room temperature. Stirring was continued for 48 h, the
solvent was evaporated, and the crude product was purified by
column chromatography using methanol–25% ammonium hydroxide
in water (100:1) as an eluent. Yield 0.85 g (94%). Oil: nmax(film)
3355, 3188, 2948, 2816, 2247, 1463, 1357, 1161, 1133, 1011; dH
(200 MHz, CDCl3) 2.58–2.35 (16H, m), 2.75–2.65 (4H, m),, 2.92 (4H,
t, J¼6.8 Hz); dC (50 MHz, CDCl3) 118.6 (CN), 118.5 (2 CN), 56.4, 53.1
(2C), 53.0, 52.4 (2C), 50.7, 50.0 (2C), 16.9 (2CH2CN), 15.6 (CH2CN);
HRMS (EI): Mþ, found 288.2063. C15H24N6 requires 288.2062.
A solution of the amine 3 (46.0 g, 0.351 mol) in acrylonitrile
(372 g, 7.02 mol, 462 mL) was stirred for 5 days at room tempera-
ture and an excess of acrylonitrile was evaporated under reduced
pressure to give quantitatively pure 13 as an oil insoluble in water:
[found: C, 63.61; H, 7.92; N, 28.50. C21H32N68 requires C, 63.61; H,
8.13; N, 28.26]; dH (200 MHz, CDCl3) 1.53–1.69 (6H, m), 2.45–2.58
(14H, m), 2.61–2.76 (6H, m), 2.81–2.94 (6H, m); dC (50 MHz, CDCl3,
INVGATE) 15.8 (1C), 16.0 (4C), 24.3 (2C), 48.6 (5C), 50.3 (2C), 50.4
(2C), 118.6 (4C), 119.1 (1C); m/z (FAB, þVE) 397 (100 MHþ).
4.5. 3-{4-[-(2-Cyanoethylamino)cyclohexyl-methyl]-
cyclohexylamino}propionitrile (10)
4.8. Determination of a level of acrylonitrile. HPLC details
Concentrations of acrylonitrile in the synthesized products were
determined by a high performance liquid chromatography. Mea-
surements were carried out under specified conditions:
4,40-Methylenobis(cyclohexylamine) 2 (1.05 g, 5 mmol) was dis-
solved in methanol (2 mL) and to the resulting solution acrylonitrile