Scope and Mechanism of Intramolecular Aziridination
A R T I C L E S
phoryl azide (3.9 mL, 5.0 g, 18.1 mmol) was added. The solution
was heated at reflux for 100 min, p-methoxybenzyl alcohol (3.7
mL, 4.1 g, 30.0 mmol) was added Via syringe, and heating was
resumed for 12 h. The solution was concentrated under reduced
pressure, and the resulting yellow, oily residue was purified by flash
chromatography using a gradient of 5-10% EtOAc/hexane to give
4.5 g (83%) of urethane (+)-24 as a colorless oil, which crystallized
procedures10,12,14 except that CH2Cl2 was used as solvent instead
of benzene. TLC analyses (CHCl3/MeOH ) 10:1) showed complete
reaction after 13 h. Satd aq K2CO3 (20 mL) was added, and the
product was extracted with ether (2 × 15 mL). The organic layers
were combined, dried with MgSO4, and treated with TFA (90 mg,
0.79 mmol). Evaporation of the solvent provided the pure TFA
salt of 1-azatricyclo [2.2.1.02,6]-heptane (26) as a yellow oil: yield,
47
1
at -15 °C. Data for crystalline (+)-24: TLC Rf 0.75 (10% EtOAc-
83.0 mg (0.406 mmol, 67%); H NMR (CDCl3, 400 MHz)
δ
1
hexane); mp 43-44 °C; [R]25 +5.67° (c 1.1, CHCl3); H NMR
10.30-11.30 (m, 1H), 3.70 (s, 2H), 2.92 (s, 2H), 2.72 (s, 1H), 1.89
(app d, 2H, Japp ) 12.4 Hz), 1.74 (app dd, 2H, Japp ) 13.2, 1.6
Hz); 13C NMR (CDCl3, 100 MHz) δ 161.0 (q, J ) 38.4 Hz), 115.8
(q, J ) 286.6 Hz), 51.0, 38.1, 31.0, 29.1. Free aziridine: 1H NMR
(CDCl3, 400 MHz)47 δ 2.22 (s, 2H), 2.18 (s, 2H), 2.08 (s, 1H),
1.34 (app d, 2H, Japp ) 11.2 Hz), 1.21 (app dd, 2H, Japp ) 11.2,
1.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 55.8, 31.8, 31.5, 28.5; IR
(NaCl): 3027, 2924, 1446, 1393; HRMS (ESI-HRMS) m/z calcd
for (M + H+) 96.0813, found 96.0717.
D
(CDCl3, 500 MHz) as a 5:2 mixture of two rotamers: δ 7.30 (d,
2H, J ) 8.5 Hz), 6.88 (d, 2H, J ) 8.5 Hz), 5.20 (s, 1H), 5.03 (s,
2H), 4.68 (br s, 1H), 3.80 (s, 3H,), 3.36 (m, 1H), 3.15 (m, 1H),
2.30 (m, 1H), 1.94 (m, 2H), 1.58 (s, 3H), 1.03 (s, 3H,), 0.83 (s,
3H,); 13C NMR (CDCl3, 125 MHz) δ 159.7(s), 156.7(s), 148.5 (s),
130.2 (d, 2C), 128.9 (s), 121.4 (d), 114.1 (d, 2C), 66.6 (t), 55.4
(q), 49.7 (d), 46.6 (s), 42.4 (t), 34.3 (t), 26.5 (q), 19.9 (q), 12.5 (q);
HRMS (ESI) m/z calcd for C18H26NO3 (M + H)+ 304.1913, found:
304.1910.
The following preparative aziridinations were conducted as
described above for the unsubstituted 1-azatricyclo [2.2.1.02,6]hep-
tane (26).
(-)-(1R)-4-Methoxybenzyl (2,2,3-Trimethylcyclopent-3-enyl)-
methylcarbamate ((-)-24). Crystalline urethane ent-22 (6.2 g, 84%)
was prepared as described above for (+)-22 starting from (-)-R-
campholenic acid (-)-ent-22 (4.1 g, 24.4 mmol): mp 42-44 °C;
[R]25D -5.23° (c 2.9, CHCl3); the 1H and 13C NMR spectra of (-)-
24 were identical to those previously recorded for carbamate (+)-
24; HRMS (ESI) m/z calcd for C18H26NO3 (M + H)+ 304.1913,
found: 304.1912.
2-Methyl-1-azatricyclo [2.2.1.02,6]heptane (27). Amine 10 as the
TFA salt (105 mg, 0.47 mmol), K2CO3 (350 mg, 2.5 mmol), CH2Cl2
(20 mL), Pb(OAc)4 (440 mg, 1.00 mmol), time (2 h), TFA (70
mg, 0.61 mmol), yield of aziridine 27 TFA salt (81 mg, 78%): 1H
NMR (CDCl3, 400 MHz)47 δ 10.50-11.00 (m, 1H), 3.63 (s, 1H),
3.05 and 2.91 (ABdd, JAB ) 9.2 Hz, 2H), 2.67 (s, 1H), 1.90 (app
ABd1, Japp ) 12.4 Hz, 1H), 1.85 (app ABXdd1, Japp ) 12.4, 1.2
Hz, 1H), 1.78 (app ABd2, Japp ) 12.4 Hz, 1H), 1.71 (app ABXdd2,
Japp ) 12.4, 1.2 Hz, 1H), 1.71 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 159.5-162.0 (m), 112.0-123.0 (m), 112.0-123.0 (m), 51.6, 49.8,
(()-4-Methoxybenzyl (2,2,3-Trimethylcyclopent-3-enyl)methyl-
carbamate ((()-24). Urethane (()-24 (oil, 2.7 g, 83%) was prepared
as described above for (+)-24 starting from (()-R-campholenic
1
acid (()-22 (1.8 g, 10.7 mmol). The H and 13C NMR spectra of
1
43.9, 36.4, 32.4, 31.1, 11.8. Free aziridine: H NMR (CDCl3, 500
compound (()-24 were identical to those previously recorded for
carbamate (+)-24; HRMS (ESI) m/z calcd for C18H26NO3 (M +
H)+ 304.1913, found: 304.1910.
MHz)47 δ 2.39 and 2.25 (app ABdd, Japp ) 9.9 Hz, 2H), 2.00-2.11
(br m, 1H), 2.08 (s, 1H), 1.32-1.40 (m, 2H), 1.35 (s, 3H),
1.16-1.24 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 56.7, 39.1,
38.5, 37.0, 33.1, 31.6, 16.0; IR (NaCl): 3289, 2960, 1557, 1455,
1377; HRMS (ESI-HRMS) m/z calcd for (M + H+) 110.0970,
found: 110.0968.
(+)-(1S)-(2,2,3-Trimethylcyclopent-3-enyl)methylamine ((+)-25).
Hydrolysis of the (S)-carbamate (+)-24 was accomplished following
a literature procedure.48 A solution of (+)-24 (4.0 g, 13.20 mmol)
and KOH (10.0 g, 178.6 mmol) in 30 mL of 95% EtOH (4% H2O)
was heated at reflux for 2.5 h, cooled to 0 °C, and acidified with
concd HCl. The solution was partially concentrated under reduced
pressure, diluted with water (150 mL), and extracted with CH2Cl2
(2 × 25 mL). The aq phase was cooled again to 0 °C, basified
with KOH pellets, and extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were dried (K2CO3) and evaporated at
atmospheric pressure to yield 1.7 g (93%) of amine (+)-25 as a
clear oil: TLC Rf 0.24 (alumina, 1% MeOH-CHCl3); [R]25D +9.11°
2,6-Dimethyl-1-Azatricyclo [2.2.1.02,6]heptane (28). Amine 13
TFA salt (100 mg, 0.42 mmol), K2CO3 (310 mg, 2.24 mmol),
CH2Cl2 (20 mL), Pb(OAc)4 (380 mg, 0.84 mmol), time 1 h, TFA
(60 mg, 0.53 mmol), yield of aziridine 28 TFA salt (80 mg, 81%):
1H NMR (CDCl3, 500 MHz)47 δ 10.30-10.70 (m, 1H), 3.01 (s,
2H), 2.60 (s, 1H), 1.83 (app dd, Japp ) 13.0, 1.0 Hz, 2H), 1.79
(app dd, Japp ) 12.5, 1.5 Hz, 2H), 1.65 (s, 6H); 13C NMR (CDCl3,
125 MHz) δ 160.9 (q, J ) 38.1 Hz), 116.0 (q, J ) 287.9 Hz),
1
53.2, 52.2, 37.8, 31.4, 9.6. Free aziridine: H NMR (CDCl3, 500
1
(c 1.1, CHCl3); H NMR (CDCl3, 500 MHz) δ 5.21 (br s, 1H),
MHz) δ 2.53 (s, 2H), 2.16 (s, 1H), 1.35-1.44 (m, 4H), 1.38(s,
6H); 13C NMR (CDCl3, 125 MHz): δ 56.3, 45.1, 38.4, 32.3, 12.5;
IR (NaCl): 3252, 2949, 1557, 1455, 1386; HRMS (ESI-HRMS)
m/z calcd for (M + H+) 124.1126, found: 124.1121.
2.84 (dd, 1H, J ) 12, 4.5 Hz), 2.62 (dd, 1H, J ) 12, 10 Hz), 2.37
(m, 1H), 1.93-1.79 (m, 2H), 1.58 (br s, 3H), 1.49 (br s, 2H), 1.02
(s, 3H), 0.77 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ 148.7, 121.5,
53.6, 46.6, 43.3, 34.5, 26.6, 19.9, 12.5.
7,7-Dimethyl-1-azatricyclo[2.2.1.02,6]heptane (30) and its Meth-
iodide Salt (31). Nagata’s procedure for the synthesis of bridged
aziridines was followed.14 To a stirred suspension of primary amine
20 (894 mg, 7.3 mmol) and anhyd K2CO3 (4.02 g, 29 mmol) in
150 mL of CH2Cl2 was added Pb(OAc)4 (6.45 g, 14.5 mmol) in
2-g portions. After 20 h, the solids were filtered, and the resulting
filtrate was passed through a small column of basic alumina
(Aldrich, 50.0 g, 150 mesh, 58 Å) under vacuum. The column was
washed using a gradient of 1-2% MeOH/CH2Cl2 as eluent.
Fractions containing the aziridine (TLC alumina, 1% MeOH/CH2Cl2
single spot at Rf 0.7 when visualized with I2 vapors) were combined
and washed with 10% aq HCl. The aq layer was cooled to 0 °C,
basified with NaOH pellets, extracted with Et2O (total volume 250
mL), and dried over anhyd K2CO3. For characterization purposes,
a small portion of this solution was evaporated (0 °C) using a stream
of nitrogen to give aziridine 30 as a colorless and highly volatile
liquid: 1H NMR (CDCl3, 500 MHz) δ 2.19 (s, 2H), 1.79 (d, 2H, J
) 11 Hz), 1.59 (s, 1H), 1.13 (d, 2H, J ) 11 Hz), 1.02 (s, 6H).
Methyl iodide (905 µL, 14.5 mmol) was added to the above dry
(-)-(1R)-[2,2,3-Trimethylcyclopent-3-enyl)]methylamine ((-)-
25). Hydrolysis of urethane (-)-24 (4.2 g, 13.86 mmol) following
the procedure described above for (+)-25, gave the enantiomeric
amine ent-25 (1.8 g, 93%). Data for (-)-25: [R]25D -9.16° (c 3.8,
1
CHCl3). The H and 13C NMR spectra of (-)-25 were identical to
those previously recorded for (+)-25.
(()-[2,2,3-Trimethylcyclopent-3-enyl)]methylamine ((()-25). Hy-
drolysis of urethane (()-24 (2.2 g, 7.26 mmol) following the
procedure described above for (+)-25, gave the racemic amine (()-
1
25 (0.91 g, 89%). The H and 13C NMR spectra of (()-25 were
identical to those previously recorded for (+)-25.
Aziridination Reactions. 1-Azatricyclo [2.2.1.02,6]heptane (26).
A suspension of anhyd K2CO3 (460 mg, 3.33 mmol) in a solution
of amine 6 as its trifluoracetic acid (TFA) salt (129 mg, 0.611 mmol)
in 40 mL of dry CH2Cl2 was stirred magnetically as 580 mg (1.27
mmol) of solid Pb(OAc)4 was added according to literature
(48) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515–518.
9
J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009 12005