2.30 (12H, m, CBCHs), 2.75 (4H, S, -CH2-N-), 6.84 (4H,
m, ArH), 7.32 (4H, m, ArH). 13C NMR (CDCl3) δ 16.0, 31.1,
46.6, 60.2, 127.0, 127.8, 131.0, 147.3. (Found: C, 64.0; H,
6.3; N, 3.4%. Calcd for C22H26NCl3, C, 64.3; H, 6.4; N,
3.4%.) Mass m/z ) 373, 208, 179, and 125.
δ 14.9, 20.9 23.6, 31.1, 38.8, 39.2, 49.7, 51.4, 57.1, 127.7,
128.0, 131.8, 143.7, 161.2, 163.5. Mass (m/z) 279, 235, 224,
179.
1-[1-(4-Chlorphenyl)cyclobutyl)]-3-methyl Butylamine
(8). A mixture of formamide (7) (8.7 g, 0.03 mole), bis(2-
methoxy ethyl) ether (65 mL), concentrated hydrochloric acid
(22 mL), and water (22 mL) was stirred and heated under
reflux for 18 h. The reaction mixture was cooled and diluted
with water (80 mL). The resulting solution was washed with
ether (2 × 50 mL) andthen basified by addition of 5 M
aqueous sodium hydroxide (35 mL). The product was
extracted into ether (3 × 50 mL), and the extracts were
washed with brine (50 mL) and water (50 mL), dried over
Na2SO4, and evaporated. The residue was the crude title
compound (8), (7.5 g, 96%) as a brown oil: bp 120-128
°C /0.25-0.8 mmHg. IR (neat) 2970-2950, (br) (-NH,
CH3, CH2, and CH str), 1492, 1466 (CH3 bend and CH
scissor), 1367 (C-H bend), 1094 (p-substituted aromatic),
1-[1-(4-Chlorphenyl)cyclobutyl]-3-methyl butan-1-one
(6). A solution of 1-(4-chlorophenyl)cyclobutane carbonitrile
(3) (50 g, 0.26 mole) in dry toluene (180 mL) was added
dropwise under nitrogen to a stirred solution of isobutyl-
magnesium bromide [from isobutyl bromide (54.2 g, ∼43
mL, 0.395 mol) and magnesium turnings (9.6 g, 0.395 mol)]
in dry ether (180 mL). During the addition the ether was
removed by distillation at a rate approximately equal to the
addition of nitrile solution. When the addition was complete
and sufficient ether was removed for the internal temperature
to reach 90 °C, distillation was stopped, and the mixture was
stirred for 18 h at 90 °C. It was cooled to ambient
temperature, water (1 L) was added to the reaction mixture,
and the mixture was acidified by addition of 5 M hydro-
chloric acid. The reaction mixture was heated at 90-95 °C
for 2 h with stirring and allowed to cool. The product was
extracted into ether (3 × 200 mL). The extracts were washed
with water (2 × 100 mL), dried over (Na2SO4), and
evaporated. The residue was distilled to give title compound
(6), (52.9 g, 81%) as colorless oil, bp 100-120 °C/0.2 mm/
Hg: IR (neat) 2957 (C-H str), 1707 (CdO str), 1491, 1417
(CH3 bend and CH2 scissor), 1084 (p-substituted, aromatic),
1013 (aromatic C-H in plane bend). 1H NMR (CDCl3) 0.70
(6H, d, J ) 7.0 Hz -CHMe2), 1.85 (2H, m, -CBCHs), 1.90
(1H, m,-CH2CHMe2), 2.05 (2H, m, -CH2CHMe2), 2.35 (2H,
m, -CBCHs), 2.75 (2H, m, -CBCHs), 7.15 (2H, d, J )
7.0 Hz -ArH), 7.30 (2H, d, J ) 7.0 Hz -ArH). 13C NMR
(CDCl3) δ 15.69, 22.06, 23.87, 30.25, 45.24, 58.48, 127.57,
129.49, 128.73, 141.41. Mass (m/z), 250, 165, 137.
N-{1-[1-(4-Chlorophenyl/cyclobutyl]-3-methyl Buty}
Formamide (7). A mixture of ketone (6) (35.15 g, 0.14 mol)
and formic acid (9.5 mL) was added dropwise at 160 °C to
formamide (25 mL) in about 30 min. The reaction mixture
was heated at 180 °C for 24 h (the water formed in the
reaction was removed by distillation). The reaction mixture
was cooled to ambient temperature and diluted with water
(500 mL). The product was extracted with dichloromethane
(3 × 50 mL), and extracts were washed with water (2 × 50
mL), dried over (Na2SO4), and evaporated. The oily residue
was triturated with petroleum ether (60-80 °C), and the
resulting solid was filtered and dried in a vacuum to give
formamide (7), (11.9 g, 39%) as a colorless solid: mp 110-
112 °C. IR (KBr) 3340 (broad, -N-H str), 2955 (C-H str),
1650 (-CdO str), 1492, 1470 (CH3 bend and CH2 scissor),
1091 (p-substituted, aromatic), 1012 (aromatic C-H in plane
bend). 1H NMR (CDCl3) 0.60-0.77 (1H, m, -CH2CHMe2),
0.81-0.97 (6H, m, -CHMe2 [includes 0.82, d, (J ) 6.8 Hz)
and 0.95, d, (J ) 6.4 Hz)], 1.22 (1H, br, t, -CH2CHMe2),
1.49 (1H, m, -CHMe2), 1.86 (1H, m, -CBCH), 2.0-3.5
(5H, m, -CBCHs), 3.61 (0.28H, m, CHBuiNH), 4.62 (0.72H,
m, CHBuiNH), 7.15 (2H, d, J ) 7.0 Hz -ArH), 7.37 (2H,
d, J ) 7.0 Hz -ArH) 8.11 (0.28H, d, J ) 11.4 Hz, NHCHO),
8.29 (0.72H, d, J ) 11.4 Hz, NHCHO). 13C NMR (CDCl3)
1
1013, 824 (aromatic C-H). H NMR (CDCl3) 0.85 (3H, d,
J ) 6.6 Hz -CHMe), 0.90 (3H, d, J ) 6.6 Hz -CHMe),
0.50-1.00 (1H, m, -CH2CHMe2), 1.20 (1H, t, -CH2-
CHMe2), 1.66-1.75 (2H, m, -CBCHs), 1.90-1.98 (1H, m,
-CHMe2), 2.25-2.36 (2H, m, -CBCHs),), 2.45-2.55 (2H,
m, -CBCHs), 3.05 (1H, d, J ) 8.8 Hz, CHBuiNH2), 7.10
(2H, d, J ) 7.0 Hz -ArH), 7.25 (2H, d, J ) 7.0 Hz -ArH).
13C NMR (CDCl3) δ 15.1, 21.1, 23.9, 31.2, 41.0, 50.5, 56.0,
127.3, 128.6, 131.3, 144.1. Mass (m/z) 251, 235, 179, 153.
A solution of the oily free base (8) (3.3 g, 0.013 mol) in
ether (20 mL) was saturated with hydrogen chloride. The
precipitated solid was filtered, ground to a powder, and dried
in a vacuum to give the hydrochloride salt of (8), (1.73 g,
46%), as a white crystalline solid (mp 163-165 °C). IR
(KBr) 3000-2870 (br) (NH, CH3, CH2, CH, str), 1586 (NH
bend), 1484, 1467 (CH3, CH2, str), 1369 (CH3 bend), 1096
(p-substituted aromatic), 1010 (aromatic), 829 (aromatic). 1H
NMR (CDCl3) 0.85 (3H, d, J ) 6.6 Hz -CHMe), 0.90 (3H,
d, J ) 6.6 Hz -CHMe), 1.20 (1H, t, -CH2CHMe2),
1.90-1.98 (1H, m, -CHMe2), 1.8-2.2 (2H, m, -CBCHs),
2.3-2.7 (4H, m, -CBCHs), 3.55 (1H, br, CHBuiNH2),
7.25 (2H, d, J ) 7.0 Hz -ArH), 7.35 (2H, d, J ) 7.0 Hz
-ArH). 13C NMR (CDCl3) δ 15.1, 21.1, 23.9, 31.2, 41.0,
50.5, 56.0, 127.3, 128.6, 131.3, 144.1. Mass (m/z) 251, 235,
179, 153.
1-(4-Chlorophenyl)cyclobutyl Methylamine (13). A
mixture of carbonitrile (3), (90 g, 0.47 mol), 2-propanol (540
mL), and sodium borohydride (69 g, 1.88 mol) was stirred
and heated to reflux for 30 min. Methanol (125 mL) was
added to reflux temperature dropwise in about 3 h and
refluxed further for 18 h. The reaction mixture was brought
to ambient temperature, and the solvent was distilled off
under vacuum and diluted with water (500 mL). The product
was extracted with ethyl acetate (3 × 500 mL), and the
extracts were washed with water (2 × 250 mL), dried over
(Na2SO4), and evaporated. The residue was the crude title
compound (13), (64 g, 70%) as a brown oil, bp 200/0.1
mmHg. A solution of the oily free base (13) (50 g, 0.256
mole) in ether (500 mL) was saturated with hydrogen
chloride. The precipitated solid was filtered, ground to a
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