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A. E. Rosamilia et al.
1
3022m, 2928s, 2870s, 2207s, 1512m, 1067s cm–1. H NMR δ 2.30, s,
3H, Me; 3.28, ddd, J 14.4, 3.9, 2.0 Hz, 1H and 3.49, ddd, J 14.4, 9.4, 2.5
Hz, 1H, H4; 3.85, ddd, J 12.1, 9.4, 2.0 Hz, 1H and 4.15, ddd, J 12.1, 3.9,
2.5 Hz, 1H, H3; 4.17, d, J 13.8 Hz, 1H and 5.04, d, J 13.8 Hz, 1H, H6;
5.77, s, 1H, H1; 7.10–7.15, m, 5H, ArH; 7.29–7.35, m, 3H, ArH. 13C
NMR δ 21.26, Me; 51.73, C4; 54.14, C6; 68.43, C3; 85.28, C1; 118.14,
CN; 127.49, C2´,6´; 128.67, 129.31, ArCH; 129.46, C3´,5´; 130.02,
133.36, ArCH; 133.25, C5a; 137.97, 138.87, 139.58, C9a,1´,4´. Mass
Spectrum (EI): m/z 278 (M+, 4%), 277 (10), 263 (6), 247 (63), 233 (35),
209 (75), 195 (26), 194 (26), 193 (36), 192 (41), 179 (100), 178 (88),
165 (26), 95 (26), 89 (37), 82 (19).
added to the solution of the aluminium reagent and the mixture was
heated under nitrogen at 80°C for 17 h. The mixture was cooled to
ambient temperature and poured over a slurry of silica gel (3 g) in
dichloromethane which was stirred (30 min) then filtered. The
filtercake was washed with methanol (70 mL) and the filtrate
concentrated to give a green solid (0.23 g), which was washed with
chloroform to leave the insoluble carboxamidine (4a). The solid was
collected by filtration and dried to give (4a) as a white solid (80 mg,
38%), m.p. 225–227°C (Found: m/z 282.1596. C17H20N3O [M + H]+
1
requires m/z 282.1596). H NMR (CD3OD) δ 3.47–3.64, m, 2H, H4;
3.87, apparent dt, J 12.7, 4.2, Hz, 1H and 4.18, ddd, J 12.7, 8.7, 5.0 Hz,
1H, H3; 4.72, d, J 13.1 Hz, 1H and 5.11, d, J 13.1 Hz, 1H, H6; 5.84, s,
1H, H1; 7.13–7.16, m, 1H, ArH; 7.22–7.42, m, 8H, ArH. 13C NMR
(CD3OD) δ 47.01, C4; 54.26, C6; 69.25, C3; 85.74, C1; 128.47, C2´,6´;
128.92, ArCH; 129.54, C3´,5´; 129.67, 130.38, 130.70, ArCH; 132.85,
ArC; 134.00, ArCH; 143.02, 143.82 ArC; 158.24, C=NH. Mass
Spectrum (ESI): m/z 282.3 [M + H]+.
1-Phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine (Nor-nefopam)
(3a)
i) Preparation Using Lithium Aluminium Hydride
Nor-nefopam (3a) was prepared following a modification of a
procedure used in the literature.[8] A solution of the carbonitrile (2a)
(0.81 g, 3.1 mmol) in dry tetrahydrofuran (5 mL) was added dropwize
over 10 min to a stirred suspension of lithium aluminium hydride
(0.35 g, 9.2 mmol) in dry tetrahydrofuran (60 mL) in an ice bath. After
the addition was complete, the mixture was refluxed for 2 h. The vessel
was cooled in an ice bath and the reaction quenched by the addition of
sodium sulfate decahydrate. The mixture was filtered and the solid
washed with tetrahydrofuran. The filtrate was evaporated to yield nor-
nefopam (3a) as a pure brown oil (0.72 g, 99%) (Found: m/z 240.1383.
Calc. for C16H18NO [M + H]+: 240.1388). 1H NMR δ 2.83, ddd, J 14.6,
5.3, 2.5 Hz, 1H and 2.91, ddd, J 14.6, 7.4, 2.7 Hz, 1H, H4; 3.68, ddd, J
12.0, 7.4, 2.5 Hz, 1H, H3; 3.81, d, J 13.2 Hz, 1H, H6; 3.89, ddd, J 12.0,
5.3, 2.7 Hz, 1H, H3; 4.57, d, J 13.3 Hz, 1H, H6; 5.82, s, 1H, H1; 6.92,
d, J 7.3 Hz, 1H, ArH; 7.03–7.23, m, 8H, ArH. 13C NMR δ 47.75, C4;
51.49, C6; 71.60, C3; 83.69, C1; 127.38, C2´,6´; 127.42, 127.43,
128.21, ArCH; 128.40, C3´,5´; 129.21, 131.74, ArCH; 139.32, 139.85,
142.73, ArC. The NMR data were consistent with literature data.[27]
ii) From Nor-nefopam (3a) Using Pyrazole-1H-carboxamidine
hydrochloride[12]
Nor-nefopam (3a) (0.23 g, 0.96 mmol), pyrazole-1H-carboxamidine
hydrochloride (0.14 g, 0.96 mmol) and diisopropylethylamine (0.13 g,
1 mmol) were dissolved in acetonitrile (1 mL) and the mixture stirred
for 16 h at ambient temperature. Addition of diethyl ether (5 mL) gave
a precipitate, which was collected by filtration and washed with ether
and dichloromethane. The crude product was purified by flash
chromatography using
a mixture of dichloromethane/methanol/
ammonia (aq, 25%) (40 : 10 : 1 v/v). The appropriate fractions were
collected and further purified by trituration with hexane and
chloroform. The residual solid was collected by filtration to give the
hydrochloride salt of the guanidine (4a) as a white solid (153 mg, 50%),
m.p. 168–171°C (Found: C, 63.8; H, 6.6; N, 13.0%. C17H20ClN3O
requires C, 64.3; H, 6.3; N, 13.2%). 1H NMR (CD3OD) δ 3.55–3.71, m,
2H, H4; 3.95, apparent dt, J 12.7, 4.2, Hz, 1H and 4.26, ddd, J 12.7, 8.7,
5.2 Hz, 1H, H3; 4.78, d, J 13.0 Hz, 1H and 5.19, d, J 13.0 Hz, 1H, H6;
5.91, s, 1H, H1; 7.21–7.25, m, 1H, ArH; 7.30–7.49, m, 8H, ArH. 13C
NMR (CD3OD) δ 46.92, C4; 54.24, C6; 69.20, C3; 85.79, C1; 128.44,
C2´,6´; 128.93, ArCH; 129.53, C3´,5´; 129.68, 130.40, 130.70, ArCH;
132.78, ArC; 133.98, ArCH; 142.96, 143.78, ArC; 158.21, C=NH.
A similar reaction in N,N-dimethylformamide gave the guanidine
(4a) in 23% yield.
ii) Preparation Using Sodium Hydroxide[28]
A solution of the carbonitrile (2a) (0.30 g, 1.1 mmol) and sodium
hydroxide (0.09 g, 2.27 mmol) in ethylene glycol (10 mL) was stirred
and heated at 130°C for 15 min. The mixture was cooled and the free
base (3a) extracted using 40 mL of an ether/water mixture (1 : 1).
Purification by acid/base extraction gave (3a) as an oil (0.11 g, 40%).
The spectroscopic data was identical to that described above.
1-(4-Tolyl)-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine-5-
carboxamidine (4b)
1-(4-Tolyl)-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine (4´-Methyl-nor-
nefopam) (3b)
The carboxamidine (4b) was prepared from the carbonitrile (2b) using
the aluminium reagent described above. A solution of the carbonitrile
(2b) (200 mg, 0.719 mmol) in dry benzene (5 mL) was added to a
solution of the aluminium reagent [prepared from trimethylaluminium
in toluene (2.0 M, 0.6 mL, 1.20 mmol) and ammonium chloride (0.061
g, 1.14 mmol) in dry benzene (5 mL)] and the mixture was heated under
nitrogen at 80°C for 21 h. Workup as described above using a slurry of
silica gel (3 g) in dichloromethane and washing of the filtercake with
methanol (80 mL) gave a green solid (0.21 g). The solid was washed
with dichloromethane to leave the insoluble carboxamidine, which was
collected by filtration and dried to give (4b), as a white solid (60 mg,
29%), m.p. 248–257°C (Found: m/z 296.1756. C18H22N3O [M + H]+
requires m/z 296.1763). νmax (Nujol) 3305m, 3144m, 1648s, 1606m,
1461s, 1095m, 790m, 752s cm–1. 1H NMR (CD3OD) δ 2.30, s, 3H, Me;
3.42–3.62, m, 2H, H4; 3.80, apparent dt, J 12.6, 4.2, Hz, 1H and 4.16,
ddd, J 12.6, 8.8, 5.1 Hz, 1H, H3; 4.70, d, J 13.0 Hz, 1H and 5.11, d, J
13.0 Hz, 1H, H6; 5.79, s, 1H, H1; 7.1–7.2, m, 5H, ArH; 7.32–7.40, m,
3H, ArH. 13C NMR (CD3OD) δ 21.24, Me; 46.92, C4; 54.28, C6; 69.19,
C3; 85.83, C1; 128.46, C2´,6´; 129.61, ArCH; 130.13, C3´,5´; 130.37,
130.69, ArCH; 132.76, ArC; 134.37, ArCH; 138.81, 140.09, 144.01,
ArC; 158.25, C=NH. Mass Spectrum (ESI): m/z 296.2 [M + H]+.
The hydrochloride salt of the guanidine (4b) was prepared from the
nor-nefopam homologue (3b) (0.18 g, 0.71 mmol), pyrazole-1H-
carboxamidine hydrochloride (0.10 g, 0.71 mmol) and
diisopropylethylamine (0.09 g, 0.71 mmol) in acetonitrile (0.36 mL).
The 4´-methyl nor-nefopam analogue (3b) was prepared using lithium
aluminium hydride as described above. Reaction of the carbonitrile (20)
(0.60 g, 2.16 mmol) with lithium aluminium hydride (0.25 g, 6.48 mmol)
gave the title compound (3b) as a brown oil (0.54 g, 100%) (Found: m/
z 254.1539. C17H20NO [M + H]+ requires m/z 254.1545). νmax (neat)
2922s, 2863m, 1620m, 1512m, 1448m, 1378w, 1177m, 1108s, 1086s,
1019m, 909m, 781m, 740s, 732s, 634m cm–1. 1H NMR δ 2.29, s, 3H,
Me; 2.93, ddd, J 14.5, 5.3, 2.5 Hz, 1H and 3.01, ddd, J 14.5, 7.4, 2.7 Hz,
1H, H4; 3.78, ddd, J 12.0, 7.4, 2.5 Hz, 1H, H3; 3.91, d, J 13.3 Hz, 1H,
H6; 4.00, ddd, J 12.0, 5.3, 2.7 Hz, 1H, H3; 4.70, d, J 13.3 Hz, 1H, H6;
5.78, s, 1H, H1; 7.01, d, J 7.3 Hz, 1H, ArH; 7.09, d, J 8.2 Hz, 2H, H2´,6´;
7.13–7.25, m, 3H, ArH; 7.18, d, J 8.2 Hz, 2H, H3´,5´. 13C NMR δ 21.18,
Me; 47.81, C4; 51.62, C6; 71.70, C3; 83.87, C1; 127.42, C2´,6´; 127.48,
128.19, ArCH; 129.18, C3´,5´; 129.26, 131.84, ArCH; 137.19, 139.33,
139.92, 140.15, ArC. Mass Spectrum (ESI): m/z 254.1 [M + H]+.
1-Phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine-5-carboxamidine
(4a)
i) From the Carbonitrile (2a) Using an Aluminium Reagent[11]
A solution of trimethylaluminium in toluene (2.0 M, 0.6 mL,
1.20 mmol) was added under nitrogen to a suspension of ammonium
chloride (0.0655 g, 1.23 mmol) in dry benzene (5 mL) in an ice/salt
bath. The mixture was stirred at ambient temperature for 1 h. A solution
of the carbonitrile (2a) (0.20 g, 0.76 mmol) in dry benzene (5 mL) was