Synthesis of 2,4-Methanoproline Analogues
3-(Ch lor om et h yl)-1-[(1-m et h ylet h yl)a m in o]cyclob u -
ta n eca r bon itr ile (14). Hydrogen cyanide gas was generated
by adding a concentrated hydrochloric acid solution to potas-
Gen er a l P r oced u r e for th e Syn th esis of (2-Alk yl-2-
a za bicyclo[2.1.1]h ex-1-yl)m eth yla m in e (20). A solution of
0.2 g (1.4 mmol) 2-alkyl-2-azabicyclo[2.1.1]hexane-1-carboni-
trile 19 in 10 mL of dry ether was slowly added to a solution
of 1.5 equiv of LiAlH4 in 1 mL of dry ether at 0 °C. The reaction
is stirred overnight at room temperature, followed by careful
addition of water to neutralize the excess of lithium aluminum
hydride. The mixture is filtered over Celite and washed with
ether. The filtrate was dried overnight on magnesium sulfate,
filtered, and evaporated to give the pure (2-alkyl-2-azabicyclo-
[2.1.1]hex-1-yl)methylamine 20 (purity >97%). Spectral data
are available in Supporting Information.
sium cyanide (2.4 g, 5 equiv) in
a well-ventilated hood
(ca u tion !). The gas was passed through a tube containing
CaCl2 and an empty wash bottle and was then bubbled into a
solution of 1.18 g of imine 12a (7.4 mmol) dissolved in 50 mL
of dry ether. The reaction mixture was stirred at 0 °C for 5 h
while a nitrogen flow was used as HCN gas carrier through
the setup. The exhaust of gas was passed again through an
empty wash bottle and twice through a 6 N solution of sodium
hydroxide (wash bottle) to trap the excess of hydrogen cyanide
gas. After 5 h, the ether was evaporated, and 1.35 g of pure
3-(chloromethyl)-1-[(1-methylethyl)amino]cyclobutanecarbo-
nitrile 14 was obtained as a mixture of cis/trans isomers (3/1;
98% yield): 1H NMR (270 MHz, CDCl3) δ 1.08 (6H, d, J ) 6.3
Hz, major), 1.11 (6H, d, J ) 6.3 Hz, minor), 2.01-2.09 (2H,
m, major), 2.29-2.42 (4H, m, minor), 2.67-2.91 (3H, m, major
and minor), 3.13 (1H, sept, J ) 6.3 Hz, major and minor), 3.59
(2H, d, J ) 6.3 Hz, major), 3.65 (2H, d, J ) 6.3 Hz, minor);
13C NMR (68 MHz, CDCl3) δ major 23.40, 30.53, 39.33, 46.85,
48.21, 49.70, 122.17; minor 23.68, 31.68, 37.90, 47.01, 48.37,
50.73, 121.92; IR (NaCl) 2219 cm-1; MS (cis, the trans
derivative forms 19a during GC-analysis) no M+, 173/171 (14),
95 (51), 83 (78), 43 (55), 41 (100). Anal. Calcd for C9H15 Cl N2:
C, 57.90; H, 8.10. Found: C, 58.13; H, 8.28.
3-(Br om om eth yl)-1-[(1-m eth yleth yl)am in o]cyclobu tan e-
ca r boxylic Acid Hyd r obr om id e (16). A solution of 0.52 g
(12.8 mmol) of 3-(chloromethyl)-1-[(1-methylethyl)amino]cy-
clobutanecarbonitrile 14 in 13 mL of concentrated hydrobromic
acid (48% solution in water) was refluxed overnight. After
cooling of the reaction mixture, 10 mL of distilled water was
added, and the mixture was filtered over a paper filter and
washed with water. Evaporation of the solvent and recrystal-
lization from a water/methanol mixture (1/1) gave 0.7 g (2.1
mmol, 76%) of the amino acid 16: 1H NMR (270 MHz, D2O) δ
1.23 (6H, d, J ) 6.6 Hz), 2.25-2.34 (2H, m), 2.67-2.77 (2H,
m), 2.85 (1H, sept, J ) 7.6 Hz), 3.49 (2H, d, 6.6 Hz), 3.54 (1H,
sept, J ) 6.2 Hz); 13C NMR (68 MHz, D2O) δ 20.34, 31.37,
36.44, 38.32, 51.24, 58.54, 173.65; IR (KBr) 1737 cm-1; MS
(methyl ester, after treatment with diazomethane) 263/265
(M+, 2), 248/250 (2), 204/206 (26), 143 (44), 128 (100), 82 (22).
Anal. Calcd for C9H17 Br2 N O2: C, 32.65; H, 5.18. Found: C,
32.76; H, 5.11.
Gen er a l P r oced u r e for th e Syn th esis of 2-Alk yl-2-
a za bicyclo[2.1.1]h exa n e-1-ca r boxylic Acid Hyd r och lo-
r id es (21). An amount of 0.2 g of 2-alkyl-2-azabicyclo[2.1.1]-
hexane-1-carbonitrile 19 was dissolved in 3 mL of a 6 N
hydrochloric acid solution. The reaction mixture was refluxed
overnight and evaporated under reduced pressure. Distilled
water was added and evaporated again. The amino acids were
crystallized from water and methanol (1/1). To obtain mass
spectra, the amino acids were derivatized to the corresponding
methyl esters using diazomethane under standard conditions.
2-(1-Meth yleth yl)-2-a za bicyclo[2.1.1]h exa n e-1-ca r box-
ylic Acid Hyd r och lor id e (21a ). There were two ways to
synthesize compound 21a : (a) The first started from compound
19a and is described above. (b) To a solution of 0.11 g of sodium
hydroxide in 5 mL of distilled water was 0.3 g (0.91 mmol) of
amino acid 16, and the mixture was heated until reflux. After
1.5 h the reaction mixture was evaporated and 5 mL of 6 N
hydrogen chloride solution was added. After evaporation of the
solution under vacuum, the crystals obtained were extracted
with acetone and subsequently recrystallized from acetone
giving 88 mg (0.44 mmol) of 2-(1-methylethyl)-2-azabicyclo-
[2.1.1]hexane-1-carboxylic acid hydrochloride 21a (yield
48%): 1H NMR (270 MHz, D2O) δ 1.30 (6H, d, J ) 6.6 Hz),
1.92-2.04 (2H, m), 2.34-2.40 (2H, m), 2.88 (1H, br s), 3.44
(1H, d, J ) 9.9 Hz), 3.71 (1H, d, J ) 9.9 Hz), 3.84 (1H, sept, J
) 6.6 Hz); 13C NMR (68 MHz, D2O) δ 18.41, 19.33, 35.61, 36.28,
45.42, 56.94, 57.14, 75.99, 169.84; IR (KBr): 1728 cm-1; MS
(methyl ester, from the reaction with diazomethane) 183 (M+,
34), 168 (81), 124 (22), 108 (26), 82 (100). Anal. Calcd for C9H16
-
ClNO2: C, 52.56; H, 7.84. Found: C, 52.99; H, 7.63. The other
spectral data are available in Supporting Information.
2,4-Meth a n op r olin e Hyd r och lor id e 22. A suspention of
0.05 g (0.197 mmol) of 21e and 0.02 g of Pd/C (0.1 equiv; 10%
Pd/C)in 1 mL of dry methanol was stirred at room temperature
in a H2-bottle (5 bar H2). After stirring overnight, the suspen-
tion was filtered over Celite, and 0.03 g of 22 was obtained
(99%). Removal of the hydrochloride using Dowex 50 (H+ form)
gave the natural 2,4-methanoproline. For spectral data see ref
1.
Gen er a l P r oced u r e for th e Syn th esis of 2-Alk yl-2-
a za bicyclo[2.1.1]h exa n e-1-ca r bon itr iles (19). To a solution
of 16.6 mmol N-[3-(chloromethyl)-1-cyclobutylidene]amines 12
in 30 mL of dry methanol was added 3 equiv. of acetone
cyanohydrine, and the reaction mixture was refluxed under a
nitrogen atmosphere for 5 days. Purification could be per-
formed by two means. The first way was by flash chromatog-
raphy. After removal of the solvent (MeOH) under vacuum,
30 mL of dichloromethane was added together with 3-4 g of
silica, and the solvent was again evaporated. The product was
then purified by flash chromatography, which has the disad-
vantages of being time-consuming and leading to a lower yield.
The second way was more convenient and consisted of an acid
base extraction. After removal of the solvent under vacuum,
20 mL of a 2 N HCl solution was added. The solution was
extracted with diethyl ether to remove the access of acetone
cyanohydrine (3 × 40 mL). A concentrated K2CO3 solution was
added to the water layer until basic, followed by an extraction
of the water layer with dichloromethane (3 × 50 mL). After
drying the organic layer with MgSO4, filtration and evapora-
tion of the solvent lead to the end products with a significant
higher yield. Spectral data are available in Supporting Infor-
mation.
Ack n ow led gm en t. This work was supported by the
Belgian IWT (Instituut ter bevordering van het Weten-
schappelijk en Technologisch Onderzoek in Vlaanderen;
Institute for the promotion of Innovation by Science and
Technology in Flanders) and the FWO-Vlaanderen
(Fonds voor Wetenschappelijk Onderzoek-Vlaanderen,
Fund for Scientific Research Flanders (Belgium)).
Su p p or tin g In for m a tion Ava ila ble: Spectral and char-
acterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O025897S
J . Org. Chem, Vol. 67, No. 18, 2002 6513