2-Azabicyclo[2.1.1]hexane Ring System
128.4, 128.9 (CH), 140.6 (C). Anal. Found: C, 83.04; H, 9.17;
N, 7.36. C13H17N requires C, 83.37; H, 9.15; N, 7.48.
CDCl3): δ 1.68 (dd, J ) 4.6, 1.6 Hz, 2H), 1.79 (m, 2H), 2.70
(bs, 5H), 3.64 (s, 2H), 7.22-7.47 (m, 5H). 13C NMR (62.9 MHz,
CDCl3): δ 21.0 (CH2), 36.5 (CH), 39.4 (CH2), 55.9 (CH2), 57.9
(CH2), 68.4 (C), 117.4 (CN), 127.0, 128.3, 128.5 (CH), 139.2
(C). m/z: 213.13917; C14H17N2 [MH+] requires 213.13918.
1-Meth yl-2-a za bicyclo[2.1.1]h exa n e Hyd r och lor id e, 6‚
HCl, a n d P icr a te Sa lt of 6. A solution of 5 (0.48 g, 2.57 mmol)
in ethanol (15 mL) was hydrogenated over 10% Pd/C (0.14 g)
for 24 h. The reaction mixture was filtered through Celite, and
dry HCl gas was passed through the cooled filtrate. Removal
of solvent left a dark oil, which was dissolved in the minimum
of CH2Cl2 and treated with ether to precipitate the hydrochlo-
ride salt. This was filtered and dried under vacuum to afford
1-Cya n om et h yl-2-a za b icyclo[2.1.1]h exa n e-2-ca r b ox-
ylic Acid Ben zyl Ester , 12b. The mesylate 11b (350 mg, 1.08
mmol) in dry acetonitrile (5 mL) was reacted with KCN (280
mg, 4.30 mmol) and 18-crown-6 (4.4 mg, 0.165 mmol). After
48 h of heating at 60 °C and workup as described for 12a , the
solid product was chromatographed (7:3 petrol/ether saturated
with NH3, Rf 0.23) to give 12b (215 mg, 78%); a small sample
was recrystallized from ether for CHN analysis and X-ray
determinations, mp 86.5-88.0 °C. 1H NMR (250 MHz,
CDCl3): δ 1.51 (dd, J ) 4.7, 1.95 Hz, 2H), 1.92 (m, 2H), 2.72-
2.75 (m, 1H), 3.24 (s, 2H), 3.42 (s, 2H), 5.04 (s, 2H), 7.12-7.29
(m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 21.6 (CH2), 34.1 (CH),
42.9, 52.3, 66.5 (CH2), 68.2 (C), 117.2 (CN), 127.6, 127.9, 128.4
(CH), 136.3 (C), 155.8 (C). m/z: 257.12900; C15H17N2O2 [MH+]
requires 257.12905. Anal. Calcd for C15H16N2O2: C, 70.29; H,
6.29; N, 10.93. Found: C, 70.39; H, 6.54; N, 11.13. X-ray
crystallographic data for 12b are recorded in Supporting
Information.
1
6‚HCl, which was used without further purification. H NMR
(90 MHz, CDCl3): δ 1.70 (s, 3H), 1.83 (brs, 4H), 2.78 (brs (1H),
3.30-3.48 (m, 2H), 9.88 (brs, exch. 2 × NH). Solutions of the
free amine 6 were prepared as required by dissolution of the
salt in water and basification with 2 M aqueous NaOH. The
free amine was then extracted into ether (or an alternative
solvent such as a low-boiling chlorofluorocarbon) and dried by
passage through a short column of MgSO4. 1H NMR (90 MHz,
CDCl3): δ 1.70 (s, 3H), 1.83 (brs, 4H), 2.78 (brs, 1H), 3.30-
3.48 (m, 2H), 9.88 (brs, NH). The hydrochloride 6‚HCl was
hygroscopic, and a solution of 6 in ether was used to prepare
an analytical sample of 6 as the picrate salt. A solution of the
free amine was concentrated carefully under reduced pressure
and treated with a dry, saturated solution of picric acid in ether
until no further precipitate appeared. The supernatant was
removed from the precipitate, which was washed with a small
aliquot of cold, dry ether. The precipitate was recrystallized
from 80% ethanol/water, filtered, and dried under vacuum to
afford the picrate salt of 6 as a yellow crystalline solid, mp
(2-Aza bicyclo[2.1.1]h ex-1-yl)-a ceton itr ile, 12c. The car-
bamate 17 (20 mg, 0.144 mmol) was reacted with KCN (37
mg, 0.57 mmol) and 18-crown-6 (6 mg, 0.023 mmol) in dry
acetonitrile (3 mL) and heated at 80 °C for 168 h. After workup
as described for 12a , chromatography (9:1 ether/methanol
saturated with NH3, Rf 0.14) yielded 12c as a yellow oil (12
1
1
166-172 °C (dec). H NMR (250 MHz, CDCl3): δ 1.22 (bd, J
mg, 70%). H NMR (300 MHz, CDCl3): δ 1.40 (dd, J ) 4.38,
) 4 Hz, 2H), 1.38 (s, 3H), 1.55 (bd, 2H), 2.03 (brs, NH), 2.64
(m, 1H), 2.97 (brs, 2H). Anal. Found: C, 44.09; H, 4.32; N,
17.02. C12H14N4O7 requires C, 44.18; H, 4.33; N, 17.17.
1.77 Hz, 2H), 1.79 (m, 2H), 2.10 (bs, NH), 2.79 (m, 2H), 2.81
(m, 1H), 3.07 (s, 2H). 13C NMR (75.8 MHz, CDCl3): δ 22.0
(CH2), 37.2 (CH), 41.8, 49.3 (CH2), 64.9, 116.9 (C). m/z: 123
(MH+).
1-Meth a n esu lfon ic Acid (2-Ben zyl-2-a za bicyclo[2.1.1]-
h ex-1-ylm eth yl) Ester , 11a . Methanesulfonyl chloride (0.726
mL, 9.39 mmol) was added dropwise to a solution of the alcohol
3a (1.74 g, 8.53 mmol) in dry CH2Cl2 (15 mL) followed by dry
triethylamine (2.38 mL, 17.06 mmol). The reaction was heated
at 30 °C for 20 h, filtered to remove triethylamine hydrochlo-
ride, and washed with distilled water (2 × 25 mL) and finally
with saturated NaHCO3 (30 mL). The organic layer was dried
with anhydrous MgSO4, filtered, and evaporated under re-
duced pressure to yield 11a (2.10 g, 88%) as a brown oil, which
was used without further purification. (Rf 0.29 in ether
(2-Ben zyl-2-a za bicyclo[2.1.1]h ex-1-yl) Acetic Acid Eth -
yl Ester , 13a . The nitrile 12a (0.691 g, 3.25 mmol) was heated
in 8 N HCl (5 mL) at 90 °C for 96 h. After cooling and
evaporation to dryness under reduced pressure, thionyl chlo-
ride (4 mL, 54.37 mmol) was added. The mixture was heated
to 40 °C for 5 h and evaporated to dryness, and absolute
ethanol (5 mL) was added. The mixture was stirred at room
temperature for 15 min and evaporated to dryness, and the
solid remaining was dissolved in 1 N HCl (5 mL). After
washing with ethyl acetate (2 × 5 mL), the aqueous layer was
basified with ammonium hydroxide and extracted with CH2-
Cl2 (5 × 10 mL). The combined organic layers were dried with
anhydrous MgSO4 and filtered, and the solvent was removed
under reduced pressure. Chromatography (7:3 petrol/ether
saturated with NH3, Rf 0.43) gave 13a (0.296 g, 35%) as a
colorless oil. 1H NMR (250 MHz, CDCl3): δ 1.25 (t, J ) 7.0
Hz, 3H), 1.66 (dd, J ) 4.6, 1.6 Hz, 2H), 1.70 (m, 2H), 2.68 (s,
2H), 3.66 (s, 2H), 3.73 (m, 1H), 4.14 (q, J ) 7.0 Hz, 2H), 7.18-
7.45 (m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 14.2 (CH3), 36.4
(CH), 37.2 (CH2), 39.6 (CH2), 57.4 (CH2), 60.3 (CH2), 69.7 (C),
128.1, 128.2, 128.6 (CH), 140.0 (C), 171.1 (CdO). νmax
(CDCl3): 1732 cm-1. m/z: 260.16500; C16H22NO2 [MH+] re-
quires 260.16505.
1
saturated with NH3). H NMR (250 MHz, CDCl3): δ 1.61 (dd,
J ) 4.6, 1.4 Hz, 2H), 1.71 (m, 2H), 2.65 (s, 3H), 2.92 (s, 3H),
3.65 (s, 2H), 4.38 (s, 2H), 7.1-7.4 (m, 5H). 13C NMR (62.9 MHz,
CDCl3): δ 36.7 (CH), 37.4 (CH3), 38.1 (CH2), 56.4 (CH2), 57.6
(CH2), 68.4 (CH2), 70.8 (C), 126.9, 128.2, 128.5 (CH), 139.3 (C).
νmax (CDCl3): 3430, 1638, 1628 cm-1. m/z: 282.11639 (MH+);
C
14H20NO3S [MH+] requires 282.11644.
1-Met h a n esu lfon yloxym et h yl-2-a za b icyclo[2.1.1]h ex-
a n e-2-ca r boxylic Acid Ben zyl Ester , 11b. Compound 3b
(606 mg, 2.45 mmol) in CH2Cl2 (10 mL) was treated with
methanesulfonyl chloride (0.209 mL, 2.695 mmol) and dry
triethylamine (0.683 mL, 4.9 mmol) using the procedure for
11a and gave 11b (0.670 g, 81%) as a pale yellow oil (Rf 0.76
1
in 4:1 petrol/ether saturated with NH3). H NMR (250 MHz,
2-Ben zyl-1-(3-m et h ylisoxa zolyl-5-ylm et h yl)-2-a za b i-
cyclo[2.1.1]h exa n e, 14a . Butyllithium (1.57 M solution; 800
µL) was added to acetone oxime (13.2 mg, 0.18 mmol) in THF
(580 µL). The solution was heated at 60 °C for 5 min in a sealed
reacti-vial. A solution of the ester 13a (40 mg, 0.15 mmol) in
THF (240 mL) was injected, and the mixture was stirred at
60 °C for 45 min. Concentrated HCl (800 mL) was added, and
the solution was heated in the sealed reacti-vial at 100 °C for
3 h. After neutralization with aqueous NaHCO3 and extraction
with ethyl acetate (3 × 8 mL), the organic layers were
combined, dried over anhydrous MgSO4, and filtered, and the
solvent removed under reduced pressure to yield a brown oil,
which was chromatographed (7:3 ether/petrol, Rf 0.35) to give
CDCl3): δ 1.47 (dd, J ) 4.0, 1.7 Hz, 2H), 1.94 (m, 2H), 2.74
(m, 1H), 2.92 (s, 3H), 3.42 (s, 2H), 4.76 (s, 2H), 5.02 (s, 2H),
7.2-7.4 (m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 34.7 (CH),
37.3 (CH3), 41.5, 52.2, 66.6, 68.6 (CH2), 69.7 (C), 127.9, 128.0,
128.5 (CH), 136.3 (C), 155.6 (C). νmax (CDCl3): 1750, 1685, 1636
cm-1. m/z: 326.10622; C15H20NO5S [MH+] requires 326.10620.
(2-Ben zyl-2-a za bicyclo[2.1.1]h ex-1-yl)-a ceton itr ile, 12a .
Potassium cyanide (1.47 g, 22.51 mmol) and 18-crown-6 (0.238
g, 0.90 mmol) were added to a solution of mesylate 11a (1.58
g, 5.63 mmol) in dry acetonitrile (8 mL). The mixture was
heated at 60 °C for 72 h, cooled, triturated with ether, and
filtered, and the solvent was removed under reduced pressure.
Chromatography (4:1 petrol/ether saturated with NH3, Rf 0.77)
gave 12a (0.778 g, 65%) as a colorless oil. 1H NMR (250 MHz,
1
an impure sample of 14a (10 mg) as a colorless oil. H NMR
(250 MHz, CDCl3): δ 1.44-1.63 (m, 4H), 2.26 (s, 3H), 2.58-
J . Org. Chem, Vol. 68, No. 24, 2003 9353