2178 J . Org. Chem., Vol. 61, No. 6, 1996
Stevens and De Kimpe
Hz, CH2Cl). 13C-NMR 15.70 (Me); 29.27 (CH); 38.18 (CH2);
41.51 (CH2); 46.47 (CH2); 48.82 (CH2); 166.45 (CdN). IR
(NaCl): 1715 cm-1 (C)N). MS m/z: 145 (M+, 2); 96 (2); 69
(84); 68 (5); 55 (3); 54 (3); 53 (4); 42 (7); 41 (100).
N -[3-(Ch lor om e t h yl)-1-cyclob u t ylid e n e ]-sec-b u t yl-
a m in e (4d ). Yield: 77%. 1H-NMR: 0.82 (3H, t, J ) 7.2 Hz,
Me); 1.09 (3H, d, J ) 6.3 Hz, Me); 1.45-1.55 (2H, m, NCHCH2);
2.6-2.8 (3H, m, 2 × CH + CHCH2Cl); 2.9-3.2 (3H, m, 2 ×
CH + CHN); 3.65 (2H, t, J ) 6.3 Hz, CH2Cl). 13C-NMR: 11.03
(Me); 21.54 (Me); 29.49 (CHCH2Cl); 30.69 (CH2); 38.47 (CH2);
41.44 (CH2); 48.86 (CH2Cl); 58.24 (NCH); 164.45 (C)N). IR
(NaCl): 1710 cm-1 (CdN). MS m/z: 173 (M+, 3); 97 (40); 91
(4); 82 (13); 81 (4); 68 (7); 57 (56); 56 (5); 55 (19); 54 (3); 44 (9);
43 (4).
(100); 83 (23); 82 (48); 81 (16); 80 (16); 68 (44); 67 (27); 56 (21);
55 (62); 54 (20); 42 (32); 41 (53). Anal. Calcd for C11H19N: C,
79.94; H, 11.59; N, 8.47. Found: C, 80.10; H, 11.44; N, 8.32.
Syn th esis of 2-Eth yl-2-a za bicyclo[2.1.1]h exa n e (14c).
To 0.14 g (3.7 mmol) of lithium aluminum hydride in 20 mL
of dry ether was added dropwise 0.37 g (2.5 mmol) of N-
ethylimine 4c at room temperature, and the mixture was
refluxed for 16 h. After cooling, 0.3 g of water and 30 mL of
ether were added carefully to the mixture, and the aluminum
salts were filtered off afterwards. After drying (MgSO4), the
solvent was distilled off to give 0.23 g of crude 2-ethyl-2-
azabicyclo[2.1.1]hexane (14c) as an oil (yield 57%; purity 70%).
Further purification of this compound could be done by flash
chromatography. Elution of the impurities was performed on
silica gel using ethyl acetate/dichloromethane (9:1), followed
by desorption of the product using dichloromethane/methanol
(1:1) as eluent. Evaporation of the solvent yielded 0.05 g (18%)
of pure 2-ethyl-2-azabicyclo[2.1.1]hexane (14c). 1H-NMR: 1.54
(3H, t, J ) 7.3 Hz, Me); 2.13 (4H, ∼d, J ) 6.6 Hz, 2 × CH2);
2.73 (1H, brs, NCH); 2.94-2.99 (1H, m, CHbridgehead); 3.22 (2H,
∼q, J ) 6.9 Hz, NCH2Me); 3.8-3.9 (1H, brs, NCH); 4.15 (1H,
d, J ) 6.3 Hz,, NCH). 13C-NMR: 10.76 (CH3); 36.0 very broad
signal for 2 × CH2 bridge; 38.65 (CHbridgehead); 48.10 (NCH2Me);
55.11 (CH2N); 65.35 (CHbridgehead). IR (NaCl) νmax: 1470, 1450,
N -[3-(Ch lor om e t h yl)-1-cyclob u t ylid e n e ]-t er t -b u t yl-
a m in e (4e). Yield: 76%. 1H-NMR: 1.23 (9H, s, t-Bu); 2.6-
2.8 (2H, m, 2 × CH); 2.8-2.9 (1H, m, CH); 3.0-3.1 (1H, m,
CH); 3.15-3.30 (1H, m, CH); 3.65 (2H, dd, J 1 ) 7.3 Hz, J 2
)
6.6 Hz, CH2Cl). 13C-NMR: 29.67 (CH); 29.97 (t-Bu); 42.42
(CH2); 43.32 (CH2); 48.93 (CH2Cl); 56.49 (Cquat.); 163.27 (s,
CdN). IR (NaCl): 1710 cm-1 (CdN). MS m/z: 173 (M+, 1);
158 (1); 122 (2); 97 (8); 82 (5); 57 (100); 41 (44).
Syn t h esis of 2-Isop r op yl-2-a za b icyclo[2.1.1]h exa n e
(14a ). To 0.17 g (4.5 mmol) of lithium aluminum hydride in
10 mL of dry THF was added dropwise 0.72 g (4.5 mmol) of
imine 4a , dissolved in 2 mL of dry THF. The reaction mixture
was refluxed for 18 h, and after cooling, 20 mL of ether was
added followed by 2 mL of sodium hydroxide (2 N). The
organic layer was dried (MgSO4) and filtered. The solvent was
removed by distillation using a Vigreux column. 2-Isopropyl-
2-azabicyclo[2.1.1]hexane (14a ) was obtained as an oil (0.48
g) in 86% yield. An analytical sample was obtained by
preparative gas chromatography (3 m column, GE SE-30 (7%),
internal diameter 0.4 cm). The crude mixture could also be
purified by conversion of 14a to the hydrochloride 15 upon
treatment with dry hydrogen chloride in ether. The melting
point of the hydrochloride could not be measured due to
decomposition of the product. 1H-NMR (500 MHz): 1.09 (6H,
d, J ) 6.1 Hz, CHMe2); 1.41 (2H, dd, J 1 ) 4.5 Hz, J 2 ) 1.9 Hz,
2 × CH); 1.61 (2H, m, 2 × CH); 2.47 (1H, sept, J ) 6.1 Hz,
CHMe2); 2.68 (2H, brs, CH2N); 2.70 (1H, m, CHbridgehead); 3.63
(1H, dt, J 1 ) 6.4 Hz, J 2 ) 1.9 Hz, CHbridgehead). 13C-NMR: 22.03
(Me); 36.73 (CH2); 39.82 (CH); 52.76 (CHMe2); 54.93 (CH2N);
1395, 910 cm-1
.
MS m/z: 111 (M+, 5); 110 (28); 96 (57); 84
(26); 82 (29); 70 (12); 69 (37); 68 (41); 67 (22); 56 (54); 55 (43);
54 (26); 42 (100).
Syn th esis of 2-sec-Bu tyl-2-azabicyclo[2.1.1]h exan e (14d).
To a suspension of 0.182 g (4.7 mmol) of lithium aluminum
hydride in 20 mL of dry THF was added dropwise 0.83 g (4.7
mmol) of N-sec-butylimine 4d at room temperature. The
reaction mixture was refluxed during 16 h followed by addition
of 0.36 g of water in 5 mL of diethyl ether. The mixture was
then extracted three times with ether, dried (MgSO4), and
filtered. After careful evaporation of the solvent 0.7 g of the
crude mixture (containing (30% of THF) was obtained (yield
of 14d : 72%). The mixture was further purified by flash
chromatography using CH2Cl2: MeOH (1:1) as eluent (Rf )
0.04). Due to the lability of the product, the purity was not
better than 90% after chromatography. Attempts to purify
14d by treatment with gaseous hydrogen chloride in dry
diethyl ether failed. 1H-NMR: 0.90 (3H, t, J ) 7.3 Hz, Me);
1.08 (3H, d, J ) 6.3 Hz,Me); 1.2-1.4 (2H, m, CH2); 1.39-1.41
(2H, m, 2 × CH); 1.45-1.68 (2H, m, 2 × CH); 2.2-2.3 (1H, m,
CHN); 2.63-2.76 (3H, m, CH2N + CHbridge); 3.65 (1H, d × t,
J 1 ) 6.6 Hz, J 2 ) 1.65 Hz, CHbridge). 13C-NMR: 10.33 (Me);
17.99 (Me); 28.03 (CH2); 36.06 (CH2); 37.12 (CH2); 39.66
(CHbridge); 55.24 (CH2); 59.26 (CHN); 60.81 (CHbridge). IR (NaCl)
61.17 (CHN). IR (NaCl) νmax: 1585, 1385, 1315, 1182 cm-1
.
MS m/z: 125 (M+, 55); 110 (100); 84 (25); 83 (33); 82 (60); 70
(21); 69 (16); 68 (66); 67 (35); 56 (85); 55 (93); 44 (47); 43 (54);
42 (63); 41 (87). Anal. Calcd for C8H15N: C, 76.74; H, 12.07;
N, 11.19. Found C, 76.69; H, 12.13; N, 11.06.
ν
max: 2940, 1460, 1375, 1050 cm-1 MS m/z: 139 (M+, 39);
.
Syn t h esis of 2-Cycloh exyl-2-a za bicyclo[2.1.1]h exa n e
(14b). To 0.12 g (2.7 mmol) of lithium aluminum hydride in
20 mL of diethyl ether was added dropwise 0.55 g (2.7 mmol)
of N-[(3-chloromethyl)-1-cyclobutylidene]cyclohexylamine (4b)
in 3 mL of dry ether, and the mixture was refluxed for 16 h.
After cooling, the reaction mixture was poured into 5 mL of
sodium hydroxide (2 N) and extracted with ether (3 × 20 mL).
After drying (MgSO4), filtration, and evaporation of the
solvent, 0.4 g of crude product was obtained (1H-NMR; GC;
purity: 85%). Further purification could be done by flash
chromatography but led to a considerable loss of product. The
impurities were therefore first eluted from the silica gel using
ethyl acetate/methanol (9:1) followed by desorption of the
bicyclo[2.1.1]hexane derivative using dichloromethane/metha-
nol (1:1). After evaporation of the solvent, pure 2-cyclohexyl-
2-azabicyclo[2.1.1]hexane (14b ) was obtained (yield: 26%).
1H-NMR: 1.0-1.3 (4H, m, 4 × HCH); 1.3-1.45 (2H, m, 2 ×
HCH); 1.61 (4H, brs, CH2, CH2); 1.73-1.77 (2H, brs, 2 × HCH);
1.91-1.95 (2H, m, 2 × HCH); 2.0-2.14 (1H, m, CHN); 2.69
(3H, s, CH2N, CHbridgehead; complete overlap of signals); 3.69
(1H, dt, J 1 ) 6.9 Hz, J 2 ) 2.0 Hz, CHbridgehead). 1H-NMR
(C6D6): 1.0-1.45 (10 H, m); 1.65-1.77 (2H, m, 2 × CH); 1.80-
1.85 (2H, m, 2 × CH); 2.04-2.13 (1H, m, CHN); 2.45-2.50
124 (61); 111 (33); 110 (100); 84 (65); 82 (60); 70 (35); 69 (41);
68 (58); 67 (53); 57 (42); 56 (88); 55 (81); 54 (37); 44 (76).
Syn th esis of N-(3-Meth ylcyclobu tyl)-ter t-bu tyla m in e
(16). To a solution of 88 mg (2.3 mmol) of lithium aluminum
hydride in 10 mL of dry THF was added dropwise 0.4 g (2.3
mmol) of γ-chloroimine 4e, and the mixture was refluxed for
8 h. After cooling, 0.8 g of water was added and the mixture
was filtered. The filtrate was dried (MgSO4) and filtered, and
after evaporation of the solvent, 0.32 g (81%) of crude N-(3-
methylcyclobutyl)-tert-butylamine (16) was obtained (GC;
purity 95%). An analytical sample was obtained by prepara-
tive gas chromatography. 1H-NMR: 1.02 (3H, d, J ) 6.6 Hz,
Me); 1.07 (9H, s, tert-Bu); 1.24 (2H, m, 2 × CH); 1.93 (1H, m,
CHMe); 2.40 (2H, m, 2 × CH); 3.15 (1H, m, CHN). 13C-NMR:
21.94 (Me); 23.95 (CH); 29.99 (tert-Bu); 42.53 (2 × CH2); 45.12
(CH); 50.82 (Cquat.). IR (NaCl) νmax: 2960, 2870, 1455, 1360,
1265 cm-1. MS m/z: 141 (M+, 2); 126 (3); 99 (38); 84 (80); 57
(32); 44 (37); 43 (100). Anal. Calcd for C9H19N: C, 76.53; H,
13.56; N, 9.91. Found: C, 76.40; H, 13.59; N, 9.87.
Ack n ow led gm en t. The authors are indebted to the
Belgian National Fund of Scientific Research for finan-
cial support. They also like to thank Lic. D. Van Haver
(Fac. Sciences, University of Gent) for the help with the
database searches.
(1H, m, CHbridgehead); 2.58 (2H, s, CH2N); 3.58 (1H, d × t, J 1
)
6.59 Hz, J 2 ) 1.65 Hz, CHbridgehead). 13C-NMR: 25.17 (2 × CH2);
26.18 (CH2); 32.09 (2 × CH2); 36.66 (2 × CH2); 39.48
(CHbridgehead); 54.48 (CH2N); 60.04 (CHbridgeheadN); 61.53 (CHN).
IR (NaCl) νmax: 2940, 2860, 1455, 1218 cm-1. MS m/z: 165
(M+, 27); 150 (23); 124 (15); 123 (16); 122 (55); 108 (15); 84
J O951865B