2604
P. V. Ramachandran et al. / Tetrahedron Letters 45 (2004) 2603–2605
0
0
(
2e–i). However, the reduction of 2 ,6 -difluoroaceto-
were determined using several computational chemistry
methods. Full geometry optimizations were carried out
with density functional and ab initio methods. Fully
optimized structures were obtained with the Becke 3-
parameter functional where the nonlocal correlation is
provided by LYP expression (B3LYP) density func-
phenone (2j) provided the corresponding product alco-
hol (3j) in only 74% ee. On the basis of (S)-3a, we believe
that we have obtained the S-isomer in all of these cases.
This showed that the decrease in enantioselectivity
occurred only when both the ortho (2 , and 6 ) positions
were substituted with fluorine atoms.
0
0
8
tional method, and the second-order Moller Plesset
9
(MP2) perturbation method. The ab initio and density
Support for the assumption was provided by the prod-
uct alcohols 3k and 3l obtained from the reduction of
2 ,3 ,5 -trifluoroacetophenone (2k) and 2 ,3 ,4 ,5 -tetra-
fluoroacetophenone (2l) with 1 (Eq. 2). In both of these
functional methods used the 6-31G(d) basis set in all of
the calculations.
0
0
0
0
0
0
0
The dihedral angle in question is represented in Figure 1.
The Newman projections showing various dihedral
angles are also shown in Figure 1. When viewed along
the bond 2–3, the angle is positive if 4 has moved
clockwise from 1 and negative if it has moved anti-
clockwise.
cases the product alcohols were obtained in 95% and
9
6% ee, respectively.
F
F
O
F
F
OH
F
F
F
F
(
-)-1
O, -25 o
5%
Et
2
C
ð2Þ
We also compared the dihedral angles of the corre-
0
0
0
8
sponding 2 -substituted (2a, 2s, 2t, and 2u) and 2 ,5 -
disubstituted acetophenones (2g, 2p, 2q, and 2r). The
relation between the dihedral angles and the enantio-
meric excess of the corresponding alcohols are presented
in Table 1. The B3LYP, and MP2 results reveal those
ketones exhibiting planarity versus nonplanarity to the
plane of the aromatic ring. The calculations show better
quantitative agreement between B3LYP and MP2
results for the dihedral angle. When the dihedral angles
are compared with % ee, the general trend is that if the
ketone is in the plane or very near planarity there is high
3l
96% ee
2
l
In an unrelated project, we had observed poor ee and
0
0
very slow rates for the reduction of 2 ,6 -substituted
7
0
0
acetophenones. For example, 2 ,6 -dichloro-(2m) and
0
0
2 ,6 -dimethoxyacetophenone (2n) undergoes reduction
with 1 only at room temperature (rt) within 2 days and
provides the product alcohols in only 25% and 26% ee,
8
respectively (Eq. 3). Relatively, 74% ee obtained for the
0
0
reduction of 2 ,6 -difluoroacetophenone (2j) may be
attributed to the smaller size of the fluorine atoms as
compared to the chlorine atoms or methoxy groups.
4
X
O
1
2
X
O
X
OH
X
3
3
j: X = F, 74% ee
(
-)-1
X
3
m: X = Cl, 25% ee
4
ð3Þ
1
1
1
1
O, -25 o
3n: X = OMe, 26% ee
3o: X = Me, 45% ee
Et
2
C
X
X = F, Cl, Me, OMe
4
4
2
2
2
2
Further support for our hypothesis was obtained from
4
0
0
0o
+90o
+180
o
-90o
the reduction of 2 ,6 -dimethylacetophenone (2o) when
we obtained 45% ee for the product alcohol (3o). Such
low eeÕs are typical of unhindered aliphatic ketones. This
comparison led us to believe that the typical high eeÕs for
the product alcohols from aralkyl ketones might be
guaranteed only when the ketone is in the plane of the
aromatic ring. Losing the planarity between the ring and
the carbonyl might force ketones 2m, 2n, and 2o to
behave like aliphatic ketones resulting in poor ee for the
products. Experimental evidence for this hypothesis was
Figure 1. Newman projections showing dihedral angles of substituted
acetophenones.
Table 1. Relation between the dihedral angles ring-substituted ace-
tophenones and the enantiomeric excess achieved for reduction with
TM
DIP-Chloride
#
Acetophenone
substituent(s)
Dihedral angle
Alcohol
% ee
0
0
obtained by reducing the corresponding 2 ,5 -disubsti-
0
B3LYP
MP2
#
0
0
0
tuted acetophenones. Thus, 2 ,5 -dicholoro- (2p), 2 ,5 -
0
0
0
0
0
0
0
0
2b
2 -Fluoro
2 -Chloro
180
160.6
)179.9
0
)180
3b
3s
3t
95
96
92
96
95
95
94
96
74
25
26
45
dimethoxy- (2q) and 2 ,5 -dimethylacetophenone (2r)
were reduced with 1 when the corresponding alcohols
2
2
2
2
2
s
149.4
)179.8
0
t
2 -Methoxy
2 -Methyl
3
p, 3q, and 3r were obtained in 95%, 94%, and 96% ee,
u
g
p
3u
3g
3p
3q
3r
3l
0
0
respectively. The retarded rate of reduction of 2 ,6 -
disubstituted acetophenones could be attributed to the
sterics around the carbonyl moiety. Slow rate of
0
0
2 ,5 -Difluoro
2 ,5 -Dichloro
)180
149.9
)179.9
14.2
)179.9
161.4
)179.9
0 0
2q
2r
2 ,5 -Dimethoxy
2 ,5 -Dimethyl
2
0
0
0
0
0
0
0
0
reduction with 1 is characteristic of hindered ketones.
0.01
2
2
2
2
l
2 ,6 -Difluoro
2 ,6 -Dichloro
)26.8
89
60.8
)26.8
89.9
71.0
m
n
o
3m
3n
3o
For a more quantitative analysis, the dihedral angles
between the plane of the aromatic ring and the plane
containing the carbonyl groups in 2a, 2j, 2m, and 2n
2 ,6 -Dimethoxy
2 ,6 -Dimethyl
0
0
94.8
112.9