Organic Letters
Letter
Table 1. Screening of Conditions for Coupling between 1a
and 2a
With the optimal conditions in hand, we investigated the
scope of both aldehydes 1 and imines 2 in this enantioselective
reductive cross-coupling. Scheme 1, left summarizes the
reaction with aromatic aldehydes 1. Various substituent
patterns of alkyl moieties on the aromatic ring did not affect
the enantioselectivity and product yield (3bf−3ef). Function-
alities such as methoxy, fluoro and chloro, methylthio and
trifluoromethoxy groups were tolerated at the meta and para
positions of the benzene ring of the aromatic aldehydes (3ff−
a
3
jf). The chiral β-amino alcohol containing a heteroaromatic
ring could be prepared with a useful level of enantioselectivity
3kf). Aliphatic aldehydes resulted in no cross-coupling and
(
gave the corresponding α-silyl-substituted alcohol without the
production of β-amino alcohol (data not shown). Thus, the
Brook rearrangement in aliphatic aldehydes was slower than
that in aryl aldehydes.
,
bc
change from standard
conditions
yield
(%)
ee (%
ee)
c
entry
1
X
The scope of imine 2 as a coupling partner was also
examined (Scheme 1, right). The enantiocontrol of the α-
stereogenic center in the obtained chiral β-amino alcohol was
secured regardless of the steric or electronic natures of the
imines. For example, alkyl substituents at the para-position or
ortho-position of the aromatic ring of 2 were tolerated (3cg−
H (2a)
none
none
none
none
none
99 (96) 24,
2
2
1
6
8
2
2
3
4
5
6
7
8
9
2-OMe (2b)
4-OMe (2c)
2-tBu (2d)
96 (93) 58,
5
96 (89) 26,
2
3
ci). A halogen substituent remained untouched (3cj).
59 (58) 12,
1
Aldimines having aromatic systems such as naphthalene and
thiophene served as suitable substrates (3ck and 3cl). The
aliphatic imines resulted in no cross-coupling (data not
shown). This protocol was also applicable to ketimine 2m,
allowing the construction of chiral β-amino alcohols 3am−3
cm and 3gm bearing a highly congested carbon scaffold. These
β-amino alcohols are difficult to prepare with the reductive
2-O(CH
2
)
)
2
OEt (2e)
O(CH
82 (82) 71,
7
2-O(CH
2
2
2
)
2
OMe none
99
99
99
79,
76
82,
(2f)
2f
c-octane instead of tol
THF instead of tol
DME instead of tol
78
2f
24,
2
4
3
cross-coupling system reported by Lin and Sato.
2f
2f
99
99
4, 4
Next, the deprotection of the aromatic substituent on the
nitrogen atom in the β-amino alcohol obtained by the
enantioselective copper catalysis was examined (Scheme 2).
The chiral β-amino alcohol 3af was derivatized to N-aryl
oxazolidinone 4af utilizing carbodiimidazole under basic
conditions. On the other hand, several representative
deprotection conditions using oxidants and acids were not
effective due to the occurrence of carbon−carbon bond
cleavage (retro-pinacol type reaction) producing the aldehyde
10
11
12
c-octane, NaOSiMe
instead of tol,
NaOtBu
3
83,
81
2f
2f
c-octane, NaOSiMe3,
99 (81) 89,
89
4
0 °C instead of tol,
NaOtBu, 80 °C
entry 11 with 15-crown 85
7, 5
5
-ether
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), NaOtBu (0.22
mmol), PhMe SiBpin (0.3 mmol), CuCl (10 mol %), (S, S)-L1·HBF
10 mol %), toluene (1 mL), 80 °C, 3 h. H NMR yield based on 2.
Yield of the isolated product is in parentheses. Diastereomeric ratio
1:1−1:2).
2
4
5
b
1
(
and imine. The N-aryl group was smoothly removed by
c
6,7
trichloroisocyanuric acid to provide the oxazolidinone 5af.
(
The diastereomers of 5af could be easily separated by silica gel
column chromatography.
On the basis of our previous study on copper catalysis using
4
hindered tBu substituent at the ortho position caused a
aldehydes as α-alkoxyalkyl anions, a possible reaction pathway
decrease in both the product yield and enantioselectivity (entry
for this reductive cross-coupling is outlined in Figure 2. The
transmetalation of chiral NHC-ligated copper(I) alkoxide
complex (A) with a silylboronate produced the silylcopper(I)
4
). Thus, the positive effect of the o-methoxy group in entry 2
is caused by its coordination ability not its steric bulk. To
increase this effect, longer ethylene glycol groups were
introduced (entries 5 and 6). The improvement of
enantioselectivity was found to be in good correlation with
the ethylene glycol length. The reaction with imine 2f resulted
in 79% enantioselectivity of 3af.
species (B) and Me SiOBpin. The enantioselective addition of
3
8
B across the carbonyl moiety of aromatic aldehyde (1)
followed by [1,2]-Brook rearrangement with inversion of
configuration generates the chiral α-silyloxybenzylcopper(I)
9
intermediate (D). After the conversion of D to the cuprate
Changing the solvent to the less polar cyclooctane slightly
improved the enantioselectivity (Table 1, entry 7). Ether
solvents such as THF and DME greatly inhibited the
asymmetric induction (entries 8 and 9). By changing the
intermediate (E) with an additional alkoxide base, E reacts
with the imine (2) in a stereospecific manner to give the
corresponding sodium amide F and regenerates the copper
catalyst A. The intramolecular coordination between the ortho
ethylene glycol group and a sodium center in F might suppress
the dissociation of the chiral NHC ligand caused by the
coordination of F to a copper center.
alkoxide base from NaOtBu to NaOSiMe and lowering the
3
reaction temperature, the β-amino alcohol was obtained in
9
9% yield and high enantioselectivity (entries 10 and 11).
Addition of 15-crown 5-ether resulted in low enantioselectivity
entry 12).
In conclusion, we have presented a copper-catalyzed
enantioselective reductive cross-coupling using aromatic
(
B
Org. Lett. XXXX, XXX, XXX−XXX
Mitsui, Atsuhisa
