STEREOSELECTIVE SYNTHESIS AND CONFIGURATION
281
Crystallographic data and X-ray experiment details for 4
and 5
5.35 (q, 1H, ëF3CHOH, J = 8.5); 7.33–7.57 (m, 6H,
ë6ç5 and OH). [α]D –9.9° (c 1, ethanol).
The reaction of 1‡ with ethyl heptafluorobutyrate
afforded only one diastereomeric alcohol 5 (yield
50%), which crystallized from the reaction mixture as
dark crystals, mp 76°ë (from ethanol). IR (film), ν, cm−1:
Compound
Parameter
4
5
Molecular formula
Molecular weight
System
C13H19F3NO+I– C14H16F7NO
389.19 347.28
Orthorhombic
P212121
10.3367(3)
1
3000–2300 (broad band), 3070. H NMR (400 MHz,
CDCl3, TMS, δ, ppm, J, Hz): 1.41 (d, 3H, CH3CH,
J = 6.8); 2.21 (s, 6H, (CH3)2N); 4.53 (q, 1H, ëç3ëç,
J = 6.8); 5.20 and 5.26 (dd, 1H, ëF2CHOH, J = 8.5);
7.31–7.40 (m, 5H, C6H5); 11.25 (br. s, 1H, OH). [α]D
Space group
a, Å
10.2998(6)
11.1931(8)
13.5220(9)
1558.9(2)
−40.3° (c 1, ethanol); iodomethylate of 2b, mp 150°ë b, Å
10.7516(3)
13.8522(4)
1539.48(8)
(decomp.), [α]D –42.4° (c 1, ethanol).
c, Å
V, Å3
Z
This reaction can be considered as an example of a
“domino reaction” in which the ketone formed in the
first condensation stage is then reduced with participa-
tion of the ethoxide anion, which gives off a hydride ion
[6]. In the ketones formed, the carbonyl carbon atom
may undergo donor–acceptor interaction with the nitro-
gen lone pair, similarly to the transannular interaction
in some cyclic amino ketones [7]. This is indicated by
the pronounced shift of the carbonyl band in the IR
spectrum of ketone 3 (νë=é 1670 cm–1) with respect to
4
Data collection range
2.40–29.00
7671
2.36–29.00
10732
4140
over θ, deg
Number of measured re-
flections
Number of independent
reflections
3952
Degree of data collec-
tion, %
99.6
100.0
that for phenyl trifluoromethyl ketone (νë=é 1720 cm–1).
In addition, it follows from earlier X-ray diffraction
data for 2-[1-(S)-N,N-dimethylaminoethyl]benzophe-
none [4] that the carbonyl carbon atom and the dimeth-
ylamino-group nitrogen atom are proximate in space.
This results in a relatively rigid five-membered ring
structure, which is expected to be attacked from the less
hindered side, i.e., from the hydrogen (rather than
methyl group) side at the chiral amine center, giving
rise to an (R) carbinol center (Fig. 1).
An alternative explanation is also possible: first a
hemiaminal is formed and then it is attacked stereospe-
cifically by a hydride ion, which leads to nucleophilic
SN2 substitution. Figure 2 shows the route of reduction
of hemiaminal 6 derived from the ketone formed in the
condensation of 1a with C3F7COOEt. It can be taken
Refinement method
Full-matrix least-squares on F2
Number of reflec-
tions/constraints/param-
eters
3952/0/211
4140/10/243
S on F2
1.054
1.032
R1 0.0504
wR2 0.1136
R1 0.0707
wR2 0.1248
–
R [I > 2σ(I)]
R1 0.0181
wR2 0.0397
R1 0.0195
wR2 0.0402
0.00 (0.02)
R (all data)
Absolute structure pa-
rameter
amine 1 (Figs. 3a, 3b). This confirms our assumption
that, in both cases, hydride ion transfer involves a six- concerning the reaction stereochemistry. The absolute
membered transition state to give an (R)-configured
carbinol center. The process stereoselectivity depends
on the bulk of the fluoroalkyl group, as can be easily
seen in Fig. 2. Apparently, the hemiaminal is formed
stereoselectively, which determines the outcome of the
reaction: in the case of trifluoroacetate, the amino alco-
hol diastereomers 2a and 2b are formed in a 2 : 1 ratio,
configuration of compound 4 was also determined
objectively based on the Flack parameter [8].
The single-crystal X-ray diffraction study of 4 and 5
was carried out at 100 K on a Bruker SMART APEX II
CCD automated three-circle diffractometer with a two-
dimensional detector (MoKα radiation, graphite mono-
while the reaction with heptafluorobutyrate gives only chromator, ϕ and ω scan modes). The crystallographic
one diastereomer 5.
data and some X-ray experiment details for 4 and 5 are
summarized in the table. Both structures were solved
by direct methods using theSHELXTL Plus software.
The OH hydrogen atoms were revealed objectively
from the difference electron density synthesis. The
positions of other hydrogen atoms were calculated and
refined in the riding model. The structures were refined
by the least-squares method in the full-matrix anisotro-
To determine the configuration of the newly formed
chiral carbinol center, the iodomethylate of the major
diastereomer of the trifluoromethyl amino alcohol 2‡
(4) and the single crystal of 5 were studied by X-ray dif-
fraction. The X-ray diffraction data attest unambigu-
ously to the (R) configuration of the carbinol centers
in 4 (and, hence, in 2a) and 5 on the basis of the known
(S) configuration of the chiral center of the starting pic (for OH hydrogen atoms, isotropic) approximation.
DOKLADY CHEMISTRY Vol. 423 Part 1 2008