SCHEME 3a
quenched by slow addition of the resultant suspension to a
heavily stirred biphasic solution of Et2O (50 mL), saturated
aqueous sodium-potassium tartrate (50 mL), and 2.0 M aqueous
NaOH (1.5 mL). After 3 h of vigorous stirring, two clear phases
were obtained and separated. The aqueous phase was extracted
with CH2Cl2 (4 × 25 mL), and the organic phases were combined,
dried over potassium carbonate, filtered, and concentrated under
reduced pressure, which afforded 282 mg of a yellow-orange oil.
The oily residue and di-tert-butyl dicarbonate (484 mg, 2.22
mmol) were charged in a 25-mL, round-bottomed flask then
dissolved in THF (2.5 mL) and 2.0 M aqueous NaOH (2.5 mL),
and the resultant mixture was stirred for 60 min. The reaction
mixture was extracted with CH2Cl2 (4 × 10 mL), and the organic
phases were combined, dried over sodium sulfate, filtered, and
concentrated under reduced pressure, which afforded 530 mg
of an orange oil. Flash chromatography of the oily residue was
performed using EtOAc/hexane (gradient 0:100-10:90), which
afforded 173 mg of 11a (89%) as a colorless oil: Rf 0.24 (EtOAc/
a Reagents and conditions: (a) nitrosobenzene, benzene, rt; (b)
H2 (1 bar), 10% Pd/C, 0.3 M HCl/MeOH, rt (61%, 2 steps).
studies (COSY, NOESY, HMBC, HMQC), it became clear
that this compound was (1R,7aS)-1,3-diphenyl-5,6,7,7a-
tetrahydro-1H-pyrrolo[1,2-c]imidazole (12; Scheme 3). No
other diastereoisomer was observed, and the enantio-
meric purity of 12 was 82% ee, thus it was clear that
racemization occurred to some extent during this process.
A mechanism consistent with the formation of this
product is shown in Scheme 4. Many of the steps are
interchangeable, but the end product is the same. The
partial racemization observed could occur by epimeriza-
tion of the phenyl-substituted carbon adjacent to the
imine produced after the cleavage of the bicycloadduct.
However, if a different mechanism operates, one could
propose a competition of a SN1 and SN2 process under
the strongly acidic conditions. This reaction establishes
a new approach for the preparation of enantioenriched
2-substituted pyrrolidines bearing an R-chiral secondary
amine. The generality, the scope, and mechanistic aspects
of this reaction are under investigation in our laborato-
ries.
hexane, 15:85); [R]20 16.7 (c 2.22, C6H6); 1H NMR (C6D6, 400
D
MHz) δ 7.31 (br s, 2H), 7.20-7.12 (m, 3H), 7.12-7.02 (m, 2H),
6.71 (t, J ) 7.3 Hz, 1H), 6.43 (d, J ) 7.8 Hz, 2H), 5.76 (br s, 1H),
5.71 (br s, 1H), 5.38 (dq, J ) 10.0, 2.0 Hz, 1H), 4.57 (br m, 1H),
4.26 (br s, 1H), 3.62 (br s, 1H), 3.22 (d, J ) 19.0 Hz, 1H), 1.29
1
(s, 9H); H NMR (C6D6, 400 MHz, 70 °C) δ 7.33 (d, 2H), 7.20-
7.12 (m, 3H), 7.12-7.03 (m, 2H), 6.69 (tt, J ) 7.3, 0.9 Hz, 1H),
6.57 (dd, J ) 8.6, 0.9 Hz, 2H), 5.77 (br m, 2H), 5.47 (dqd, J )
10.2, 1.8, 0.7 Hz, 1H), 4.50 (br d, J ) 8.6 Hz, 1H), 4.27 (br s,
1H), 3.61 (br s, 1H), 3.27 (dq, J ) 19.2, 2.3 Hz, 1H), 1.32 (s, 9H);
13C NMR (C6D6, 75 MHz) δ 155.5, 147.2 (2C), 139.8, 129.7, 128.8
(2C), 128.1, 127.8 (2C) 127.6, 124.6, 118.3, 114.0 (2C), 79.7, 54.8,
49.5, 40.1, 28.3 (3C); FTIR (neat) 3369, 2975, 2930, 1691, 1658,
1602, 1500, 1413, 1364, 1308, 1254, 1168, 1119, 749, 695 cm-1
;
LRMS (APCI) calcd for C22H27N2O2 (M + H)+ 351.2, found 351.1.
The enantiomeric purity of 11a was determined as 98% ee by
HPLC analysis (Chiralpak AD-H, 95:5 n-hexane:i-PrOH, 1.0 mL/
min: (-)-11a, tr ) 7.7 min; (+)-11a, tr ) 10.9 min).
From the same reaction mixture was isolated 76 mg of tert-
butyl benzyl[(1S)-1-(methoxymethyl)-2-methylpropyl]car-
bamate (or N-benzyl-N-Boc-O-methylvalinol) (45%) as a
colorless oil: Rf 0.40 (EtOAc/hexane, 15:85); [R]20D -12.4 (c 1.23,
Experimental Section
1
C6H6); H NMR (C6D6, 400 MHz, 70 °C) δ 7.34 (d, J ) 7.4 Hz,
N-[(1E)-[(1S,4R,6R)-2,6-Diphenyl-3-oxa-2,5-diazabicyclo-
[2.2.2]oct-7-en-5-yl](phenyl)methylene]-N-[(1S)-1-(meth-
oxymethyl)-2-methylpropyl]amine (9a). Nitrosobenzene (24
mg, 0.22 mmol) and dihydropyridine derivative 8a (40 mg, 0.11
mmol) were dissolved in C6D6 (1 mL) and charged in an oven-
dried NMR tube and the resultant golden-brown solution was
left to stand for 2 h at room temperature: 1H NMR (C6D6, 400
MHz) δ 7.33 (br s, 4H), 7.21 (br m, 3H), 7.11 (br m, 5H), 6.93
(m, 2H), 6.84 (t, J ) 7.2 Hz, 1H), 5.97 (s, 1H), 5.90 (br m, 1H),
5.42 (br s, 1H), 5.40 (t, J ) 6.6 Hz, 1H), 4.44 (s, 1H), 3.09 (m,
2H), 2.81 (s, 3H), 2.74 (br s, 1H), 1.77 (m, 1H), 1.01 (d, J ) 6.8
Hz, 3H), 0.88 (d, J ) 6.8 Hz, 3H); 13C NMR (C6D6, 75 MHz) δ
158.4, 152.0, 141.2, 135.0, 130.9, 129.3, 129.3, 129.1 (2C), 129.0
(2C), 128.7, 128.3 (2C), 127.8 (2C), 127.3 (2C), 123.0, 122.8, 118.1
(2C), 76.2, 64.3, 63.6, 59.2, 58.8, 31.2, 20.7, 18.6; FTIR (neat)
3062, 3029, 2958, 2927, 2873, 1634, 1597, 1489, 1452, 1377,
1344, 1301, 1113, 1019, 846, 757, 700 cm-1; LRMS (APCI) calcd
for C30H34N3O2 (M + H)+ 468.3, found 468.2.
tert-Butyl (2R,3S)-3-Anilino-2-phenyl-3,6-dihydropyri-
dine-1(2H)-carboxylate (11a). Nitrosobenzene (71 mg, 0.663
mmol) and dihydropyridine derivative 8a (200 mg, 0.555 mmol)
were charged in an oven-dried, 10-mL round-bottomed flask then
dissolved in benzene (4 mL), and the resultant golden-brown
solution was stirred for 2 h at room temperature. In a separate
flame-dried 50-mL round-bottomed flask, lithium aluminum
hydride (253 mg, 6.66 mmol) was suspended in Et2O (8 mL),
the solution was cooled to 0-5 °C by means of an ice-water
bath, followed by slow addition of aluminum chloride (6 mL of
a 0.37 M solution in Et2O, 2.22 mmol), and the light gray
suspension was stirred for 15 min. The previously prepared
solution of cycloadduct (9a) was diluted with Et2O (6 mL) and
slowly added to the freshly prepared alane suspension via a
syringe. The resultant light-yellow suspension was then warmed
to room temperature and stirred for 16 h. The reaction was
2H), 7.18-7.11 (m, 2H) 7.06 (t, J ) 7.4 Hz, 1H), 4.51 (br m, 1H),
4.32 (d, J ) 15.6, 1H), 3.82 (br s, 1H), 3.43 (br m, 1H), 3.34 (dd,
J ) 10.2, 3.7 Hz, 1 H), 2.90 (s, 3H), 1.94 (br m, 1H), 1.38 (s, 9H),
0.84 (m, 6H); 13C NMR (C6D6, 100 MHz, 70 °C) δ 156.7, 141.4,
128.6 (3C), 127.1 (2C), 79.6, 74.0, 63.8, 58.5, 50.4, 29.3, 28.9 (3C),
20.8 (2C); FTIR (neat) 3435, 2974, 2930, 1690, 1454, 1409, 1389,
1249, 1166, 1113, 772, 734, 700 cm-1; LRMS (APCI) calcd for
C
18H30NO3 (M + H)+ 308.2, found 308.2. Anal. calcd for C18H29
-
NO3: C, 70.32; H, 9.51; N, 4.56. Found: C, 70.45; H, 9.58; N,
4.62.
From the same reaction mixture was isolated 52 mg of tert-
butyl benzyl[(1S)-1-(hydroxymethyl)-2-methylpropyl]car-
bamate (or N-benzyl-N-Boc-valinol)13 (32%) as a colorless
oil: Rf 0.15 (EtOAc/hexane, 15:85); [R]20 -20.1 (c 2.66, C6H6);
D
1H NMR (C6D6, 400 MHz, 70 °C) δ 7.29 (d, J ) 7.4 Hz, 2H),
7.18-7.11 (m, 2H), 7.06 (t, J ) 7.4 Hz, 1H), 4.32 (d, J ) 15.4,
1H), 4.21 (br m, 1H), 3.66 (br m, 2H), 3.27 (br m, 1H), 2.19 (br
s, 1H), 1.37 (s, 9H), 1.67 (d, J ) 1.6 Hz, 3H), 0.83 (d, J ) 1.8 Hz,
3H); 13C NMR (C6D6, 100 MHz, 70 °C) δ 157.5, 140.5, 129.0 (3C),
127.7 (2C), 80.3, 68.2, 63.9, 52.3, 28.8 (3C), 28.2, 20.8, 20.7; FTIR
(neat) 3436, 2972, 2875, 1668, 1605, 1455, 1411, 1367, 1250,
1166, 1110, 1076, 865, 737, 701 cm-1; LRMS (APCI) calcd for
C17H28NO3 (M + H)+ 294.2, found 294.1. Anal. calcd for C17H27
-
NO3: C, 69.59; H, 9.28; N, 4.77. Found: C, 69.43; H, 9.28; N,
4.78.
(1R,7aS)-1,3-Diphenyl-5,6,7,7a-tetrahydro-1H-pyrrolo-
[1,2-c]imidazole (12). Nitrosobenzene (71 mg, 0.663 mmol) and
dihydropyridine derivative 8a (200 mg, 0.555 mmol) were
charged in a 10-mL, round-bottomed flask and dissolved in
benzene (4 mL), and the resulting golden-brown solution was
(13) Ma´rquez, F.; Montoro, R.; Llebaria, A.; Lago, E.; Molins, E.;
Delgado, A. J. Org. Chem. 2002, 67, 308-311.
2370 J. Org. Chem., Vol. 70, No. 6, 2005