Asymmetric Nitro-Mannich Reaction Applicable to Imines
were added to a vial containing a stirrer bar in an inert
atmosphere box. A septum was fitted and the vial was removed
from the box and placed under N2. Dry THF (1.0 mL) was
added and the mixture was stirred for 1 h at room temperature
then cooled to -30 °C. During this time, a vivid, sea-green
solution was obtained (any blue coloration indicates formation
of the hydrated catalyst complex). To a second vial, also in an
inert atmosphere box, was added imine (0.20 mmol, 1.00
equiv). A septum was fitted and the vial was removed from
the box and placed under N2. Dry THF (1.0 mL) was added
and the solution was added via cannula transfer to the catalyst
solution at -30 °C. The catalyst/imine solution was stirred for
5 min at -30 °C before addition of trimethylsilyl nitropropan-
ate 1 (80 µL, 1.50 equiv). The mixture was stirred for 40 h25
at -30 °C, then warmed to room temperature. The mixture
was partitioned between petroleum ether and saturated aque-
ous EDTA, the aqueous layer was discarded, and the organic
phase was further washed with EDTA. The organic phase was
dried with MgSO4 and evaporated to yield crude â-nitroamine
3. Purification was achieved by flash column chromatography
with a short (∼5 cm) column of silica.
SCHEME 4
be crystalline and X-ray analysis revealed the absolute
stereochemistry to be 4R,5S as depicted in Scheme 4. On
the basis of this finding, we tentatively assigned the
absolute stereochemistry of the other â-nitroamine prod-
ucts 3b-k as (1S,2R).22 Although ongoing, our experi-
ments to determine the origins of enantioselectivity
remain inconclusive due to no firm evidence as to the
geometry of the imine and silyl nitronate in the reactive
complex.23
We believe this protocol to be the most general and
efficient version of the nitro-Mannich reaction reported
to date. Although this protocol requires prederivatization
of the nitro species, it uses the lowest reported loading
of commercially available metal catalyst and chiral
ligand, and gives the highest yields and selectivities for
such a broad substrate range including nonaromatic
aldimines. These results go some way to characterizing
the nitro-Mannich process as a general route to enan-
tiomerically pure â-nitroamines and compliments exist-
ing asymmetric methodology for the aldol, Henry, and
nitroaldol reactions (Scheme 1). The â-nitroamine prod-
ucts are readily reduced to enantiomerically pure 1,2-
diamines, which is a prominent structural feature of
many biologically important molecules, and will therefore
be of great use as building blocks in asymmetric synthe-
sis.
3b. Prepared using general procedure above from 2b,
chromatography (6:1, hexanes:EtOAc) gave a pure major
diastereoisomer as a yellow oil (52 mg, 84%): 1H NMR for
(1S,2R)-3b (C6D6) δ 0.46 (3H, t, J ) 7.3 Hz), 1.40-1.60 (1H,
m), 1.71 (1H, dqd, J ) 14.5, 10.9, 7.3 Hz), 3.11 (3H, s), 3.90
(1H, br d), 4.29 (1H, ddd, J ) 10.9, 6.7, 3.1 Hz), 4.49 (1H, br
t, J ) 6.8 Hz), 6.23 (2H, d, J ) 8.9 Hz), 6.44 (2H, d, J ) 8.9
Hz), 6.75-7.00 (5H, m); 1H NMR data correspond to literature
values;3 HPLC (Chiralpak AS 150 mm column with guard, 95:5
hexane:IPA, 0.15 mL/min), 15.6 min (minor), 17.3 min (major)
shows 94% ee.
General Procedure for Reduction of the Nitro Group
and Subsequent Formation of Imidazolidinone. Sa-
marium metal (40 mesh, 0.21 g, 1.40 mmol) and 1,2-diiodoet-
hane (0.37 g, 1.30 mmol) were added to a rigorously flame-
dried Schlenk tube. A triple evacuation/N2 fill was carried out,
then THF (2 mL) was added and the mixture was stirred for
1 h under N2. A further 10 mL of THF was added and the
mixture was stirred for 2 h until an intense, deep blue solution
was obtained. To this was added crude â-nitroamine (0.20
mmol) in MeOH (1 mL) and THF (3 mL) via cannula transfer.
The mixture was left to stir for 16 h. After addition of oxalic
acid (0.25 g, 2.80 mmol) in water (10 mL) the mixture was
filtered (Celite) and THF was removed in vacuo. The resulting
aqueous phase was basified to pH >12 (NaOH) and EtOAc
(10 mL) was added. The aqueous phase was washed with
EtOAc (3 × 10 mL). The combined organics were washed with
saturated sodium thiosulfate (10 mL) and saturated brine (10
mL) before drying (MgSO4) and evaporation to yield crude,
monoprotected 1,2-diamine. The crude product was dissolved
in DCM (6 mL) and MeOH (3 mL), then saturated NaHCO3
(1 mL) and water (1 mL) were added. The mixture was stirred
under N2 at room temperature for 5 min then CSCl2 (23 µL,
0.30 mmol) was added and the mixture was left to stir for 16
h. The mixture was partitioned between water (10 mL) and
DCM (10 mL) and the water phase was further washed with
DCM (2 × 10 mL). The combined organics were dried with
MgSO4 and concentrated in vacuo to give crude product as a
brown semisolid. Column chromatography (4:1 hexane:EtOAc)
followed by recrystallization (hexane/EtOAc) afforded the pure
thioimidazolidinone.
Experimental Section
General Procedure for the Synthesis of Imines. Basic
Al2O3 (1.0 g per mmol) was added to a solution of p-anisidine
(purified by dissolution in Et2O, followed by treatment with
activated charcoal, filtration, and evaporation; stored in a
darkened container <0 °C) in DCM (5 mL per mmol) under
N2 at room temperature and after a period of 5 min carbonyl
compound (1 equiv) was added. The mixture was left to stir
for 14 h at room temperature before filtration through Celite
and removal of solvents in vacuo, to yield the crude imine.
Recrystallization from hexane/EtOAc afforded analytically
pure imines.
2b. Prepared using the general procedure above, p-anisidine
(1.23 g, 10.0 mmol) and benzaldehyde (1.06 g, 10.0 mmol) gave
crude 2b as a pale-brown solid. Recrystallization afforded off-
white platelets (1.86 g, 88%): mp 68-70 °C (lit.24 mp 65 °C);
1H NMR (CDCl3) δ 3.85 (3H, s), 6.95 (2H, d, J ) 8.9 Hz), 7.25
(2H, d, J ) 8.9 Hz), 7.40-7.55 (3H, m), 7.80-7.95 (2H, m),
8.50 (1H, s). H NMR data correspond to literature values .3
1
General Procedure for Asymmetric Nitro-Mannich
Coupling. Rigorously dried Cu(OTf)2 (7.3 mg, 20 µmol, 0.10
equiv) and (S)-tBu-BOX ligand (6.5 mg, 22 µmol, 0.11 equiv)
8b. Prepared using the general procedure above from 3b,
recrystallization (hexane/EtOAc) of crude material afforded
diastereomerically pure 8b as small, clear needles (38 mg,
61%): mp 148-150 °C; IR (solid) 3188, 1500, 1249, 1031 cm-1
;
(22) 3h has 1R,2R stereochemistry, but the sense of stereoinduction
is as drawn.
1H NMR (CDCl3) δ 0.83 (3H, t, J ) 7.6) Hz, 1.18 (2H, m), 3.73
(3H, s), 4.22 (1H, q, J ) 6.0 Hz), 5.26 (1H, d, J ) 9.2 Hz), 6.40
(1H, br s), 6.78 (2H, d, J ) 8.4 Hz), 7.20-7.30 (7H, m); 13C
NMR (CDCl3) δ 10.9, 23.9, 55.4, 60.7, 71.3, 114.0, 128.2, 128.3,
(23) One could forward a plausible mechanism along the lines of
that offered by Evans for enantioselective Henry reactions catalyzed
by a copper acetate-bis(oxazoline) catalyst, but we feel this system is
more complicated and awaits further investigation. See: Evans, D.
A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2004, 125, 12692.
(24) Aly, M. F.; Grigg, R. Tetrahedron 1988, 44, 7271.
(25) All substrates screened needed 35-40 h to give good conversion.
J. Org. Chem, Vol. 70, No. 14, 2005 5669