Synthesis and structure of (1S)-{2-[(1S)-hydroxyethyl]phenyl}-1-phenyl-2,2, 2-trifluoroethanol

Full text of DOI:10.1134/S0012500810120025

ISSN 0012ꢀ5008, Doklady Chemistry, 2010, Vol. 435, Part 2, pp. 314–318. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © I.N. Shishkina, E.Yu. Sokolovskaya, Yu.V. Nelyubina, K.A. Lysenko, V.M. Dem’yanovich, N.S. Zefirov, 2010, published in Doklady Akademii Nauk,
2010, Vol. 435, No. 4, pp. 482–486.
CHEMISTRY
Synthesis and Structure of (1S)ꢀ{2ꢀ[(1S)ꢀHydroxyethyl]phenyl}ꢀ
1ꢀphenylꢀ2,2,2ꢀtrifluoroethanol
I. N. Shishkinaa, E. Yu. Sokolovskayaa, Yu. V. Nelyubinab, K. A. Lysenkob,
V. M. Dem’yanovicha, and Academician N. S. Zefirova
Received May 13, 2010
DOI: 10.1134/S0012500810120025
In recent years, there has been growing interest in
In this paper, we describe the synthesis of (1
)ꢀhydroxyethyl]phenyl}ꢀ1ꢀphenylꢀ2,2,2ꢀtrifluoꢀ
roethanol (1a) based on ( )ꢀ1ꢀphenylethanol (
(Scheme 1). We have shown previously [2] that the
condensation of orthoꢀlithiated alcohol ( ) with benꢀ
zophenones allows preparation of chiral 1,4ꢀdiols useꢀ
ful as chiral catalysts similarly to BINOLs [3] and
TADDOLs [4].
S)ꢀ{2ꢀ
[(1S
organofluorine compounds due to their anomalous
physical properties and high biological activity. This is
exemplified by recently developed antiallergic pharꢀ
maceutical Fluticasone [1]. Optically active fluorineꢀ
containing alcohols and ketones are important buildꢀ
ing blocks in organic synthesis.
S
2)
3
H3C
H3C
H3C
H3C
H
H
H
H
(S)
(S)
(S)
(S)
OH
OH
OH
OLi 1. PhCOCF3
OH
OH
BuLi*
Et2O
+
2. H2O
(S)
(R)
Li
CF3
Ph
1a
Ph
1b
CF3
2
3
*1.1 equiv. of
nꢀBuLi, then 1.1 equiv. of secꢀBuLi.
Scheme 1.
Initially, lithiation procedures were tested using densations with other ketones containing no fluorine,
racemic alcohol . The lithiation of by reacting with this fact seems to be caused by the much higher reacꢀ
2 equivalents of ꢀBuLi followed by condensation with
PhCOCF3 leads to desired diol in a yield not higher
4
n
4
tivity of PhCOCF3.
7
The low yields of the diol and considerable
amounts of byproducts are likely to result from the
insufficient basicity of nꢀBuLi to provide orthoꢀlithiaꢀ
29% (Scheme 2). The NMR spectrum of the reaction
mixture indicates the presence of byproducts, mainly
compounds
explained by the reduction of trifluoroacetophenone
with lithium alcoholate followed by reaction of enol
(resulting from the oxidation of compound ) with
8 and 10. Their formation can be
tion. The replacement of the second equivalent of
BuLi by secꢀBuLi led to a considerable increase in the
yield of (65%).
nꢀ
5
7
9
5
PhCOCF3. Such a reduction with lithium alcoholates
was observed in the work [5] for perfluoroalkyl phenyl
ketones. It should be noted that we did not observe the
The reaction proceeds nonselectively to form two
diastereomeric diols (7a and 7b) in 1.3 : 1 ratio. The
major diastereomer 7a was isolated from reaction mixꢀ
ture by crystallization from a petroleum ether–diethyl
ether mixture. We failed to obtain second diastereomer
7b in a pure state.
formation of compounds of type 8 and 10 in the conꢀ
a Moscow State University, Moscow, 119991 Russia
b Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, ul. Vavilova 28, Moscow,
119991 Russia
The synthesis of chiral diastereomeric diols 1a and
1b from compound
2 was carried out by procedure
developed for the racemic alcohol (Scheme 1).
314

SYNTHESIS AND STRUCTURE
315
C(14)
C(15)
c
0
b
C(13)
(a)
(b)
C(12)
F(2)
C(6)
C(3)
C(5)
C(4)
C(7)
C(11)
C(9)
C(10)
C(16)
C(2)
C(1)
C(8)
F(3)
F(1)
O(1)
O(2)
7a
a
Fig. 1. (a) Structure of diol 7a (some hydrogen atoms are omitted for clarity); (b) a fragment of crystal packing along the
tallographic axis.
c
crysꢀ
We isolated chiral diol 1a in pure state but failed to the nascent chiral center is the same as that of the iniꢀ
grow a crystal suitable for Xꢀray diffraction study. tial alcohol (Fig. 1a). Thus, we may attribute (S,S
Therefore, we performed Xꢀray diffraction analysis for configuration to the major diastereomer 1a prepared
)
racemic diol 7a and found that the configuration of from compound 2.
H3C
H
H3C
H
OH
OH
OLi PhCOCF3
nꢀBuLi
H3C
H3C
H
H
Li
Ph CF3
OH
nꢀBuLi
OLi
6
7
F3C
H
4
5
PhCOCF3
OLi
OH
+
O
OH
F3C
8
9
Ph
10
PhCOCF3
Scheme 2.
According to Xꢀray diffraction study, the geometriꢀ chair and halfꢀboat conformations and has the followꢀ
ing puckering parameters: the total puckering ampliꢀ
tude = 0.410, the polar angle = 16.0 , and the
phase angle ψ2 = 0 [6].
cal parameters of diol 7a is within the range typical for
this class of compounds. It is interesting to note that 7a
molecules in crystal unite to form hexamers produced
due to hydrogen bonds of average strength (O···O
S
θ
°
°
To describe quantitatively hydrogen bonding, we
performed a topological analysis of total electron denꢀ
sity distribution function obtained through precise
Xꢀray diffraction study of crystal of compound 7a in
the context of the Bader theory [7]. Interaction energy
was estimated on the basis of the Espinosa–Lecomte
2.7386(7)–2.8212(12) Å
and composed of alternating molecules of different
chirality, ( ) and ( ), around the crystalloꢀ
,
∠
OHO 153(1)–172(1) )
°
S,
S
R,
R
c
graphic axis (Figs. 1 and 2). The sixꢀmembered
pseudoꢀring composed of oxygen atoms involved into
hydrogen bonding has a shape intermediate between semiquantitative correlation [8, 9] developed and sucꢀ
DOKLADY CHEMISTRY Vol. 435
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2010

316
SHISHKINA et al.
Fig. 2. Hydrogenꢀbonded hexamer formed by six molecules of diol 7a in crystal. (a) A structure of hexamer; (b) distribution of
deformation electron density in the region of sixꢀmembered ring formed by O(2)–H(2O)···O(2) hydrogen bonds (the ring has
–3
chair conformation, two of six oxygen atoms are displaced from figure plane). Contour lines are plotted with step of 0.1 eÅ ,
nonpositive contours are shown by dashed lines.
cessfully used to describe hydrogen bonding [10, 11]. strong positive one at 230 nm caused by electronic
The resulting energies of the O(1)–H(1O)···O(2) and transitions in the aromatic chromophores. The shortꢀ
O(2)–H(2O)···O(2) hydrogen bonds in the crystal of wavelength positive Cotton effect of compound 1a is
7a were found to be 5.2 and 7.4 kcal/mol, respectively. similar to that observed for (
S,S)ꢀ1,4ꢀaminoalcohols
For comparison, the corresponding value for a hexꢀ obtained from )ꢀ ꢀdimethylꢀ1ꢀphenylethyꢀ
(S N,N
amer built of water molecules in a crystal of piperiꢀ lamine. Thus, CD spectra can be used to determine
dineꢀ2ꢀcarboxylic acid tetrahydrate [11] is within the configuration of the carbinol center formed in the
5.2⎯8.9 kcal/mol with a stabilization energy of reaction of derivatives of diarylꢀ and triarylcarbinols
7.2 kcal/mol (per water molecule).
with aminoethyl or hydroxyethyl substituents in one of
benzene rings.
The stabilization energy of the hexamer in the crysꢀ
tal of 7a (on account of the presence of additional C–
H··· contacts with an energy of about 1 kcal/mol) is
π
EXPERIMENTAL
higher than 13 kcal/mol; i.e., this associate is rather
stable. The resulting cavity in it (about 35 Å3 in volꢀ
ume) can accommodate, for example, a water moleꢀ
cule and hold it due to a system of hydrogen bonds.
Similarly, diol 7а can behave as a host when it forms
clathrates with small molecules of close size. The
noted hydrogenꢀbonded clusters unite with each other
1H NMR spectra were recorded on a Varian XRꢀ
400 spectrometer (operating at 400 MHz) in CDCl3
solutions using TMS as an internal reference. IR specꢀ
tra in CCl4 were obtained with an URꢀ20 spectrophoꢀ
20
tometer; [α]D was measured with an EPOꢀ1 polarimꢀ
eter (VNIEKIPRODMASh, Moscow) in ethanol in
0.25ꢀ and 0.1ꢀdm cuvettes. CD spectra were measured
on a JASCO Jꢀ600 dichrograph (Japan).
via weaker interactions of C–H···F and C–H··· types
π
(minimal C···F and C···C distances are 3.4421(7) and
3.5813(7) Å, respectively) to form a 3D scaffold.
1ꢀ[2ꢀ(1ꢀHydroxyethyl)phenyl]ꢀ1ꢀphenylꢀ2,2,2ꢀ
The measurement of CD spectra of diol 1а with trifluoroethanol (a mixture of diastereomeric diols 7a
) configuration in the range 300–200 nm (Fig. 3) and 7b). A hexane solution of ꢀBuLi (5.5 mL of 2.0 M
showed the presence of two Cotton effects (CE): a solution, 0.011 mol) and a hexane solution of sec
weak positive effect in the range of 270–250 nm and a BuLi (7.8 mL of 1.4 M solution, 0.011 mol) were
(
S,S
n
ꢀ
DOKLADY CHEMISTRY Vol. 435
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2010

SYNTHESIS AND STRUCTURE
317
added sequentially to a solution of 1.22 g (0.01 mol) of
1ꢀphenylethanol ( ) in anhydrous ether in an argon
−
3
[
Θ
] × 10
4
atmosphere, the mixture was kept for 3.5 h, and then
1.7 g (0.095 mol) of trifluoroacetophenone was added.
After 24 h, the mixture was treated with water, and the
organic layer was separated and dried over MgSO4.
The solvent was removed, and unreacted phenylethaꢀ
nol was distilled off in a vacuum to give a mixture of
diastereomeric diols in 1.3 : 1 ratio in 65% yield (deterꢀ
mined from 1H NMR spectra of reaction mixtures).
2
80
75
1ꢀ[2ꢀ(1ꢀHydroxyethyl)phenyl]ꢀ1ꢀphenylꢀ2,2,2ꢀ
trifluoroethanol (7a) was isolated by crystallization of a
20
10
0
mixture of the diastereomeric diols
ether (bp 40–70 C)–diethyl ether mixture. Mp
170
7 from petroleum
1
°
°
C.
1H NMR (
, ppm): 0.93 (d, 3H, CH3–CH),
δ
2.38(s, 1H, OH), 4.91 (q, 1H, CH3–CH), 5.14 (s, 1H,
OH), 7.29–7.46 (m, 6H, arom.), 7.43 (t, 1H, arom.),
7.54 (d, 1H, arom.), 7.72 (d, 1H, arom.).
IR (KBr pellet,
, cm–1): 3490–3200 (wide, νOH);
ν
200
230
260
290
, nm
(CCl4 solution): 3590 (narrow, νOH), 3520–3150
λ
(wide).
For C16H15F3O2 anal. calcd. (%): C, 64.86; H, 5.10.
Found (%): C, 65.04; H, 5.04.
Fig. 3. CD spectra (in ethanol):
ethyl]phenyl}ꢀ1ꢀphenylꢀ2,2,2ꢀtrifluoroethanol,
{2ꢀ[(1 )ꢀ(dimethylamino)ethyl]phenyl}ꢀ1ꢀphenylꢀ2,2,2ꢀ
1
, (1
S
)ꢀ{2ꢀ[(1
S
)ꢀhydroxyꢀ
2
, (1 )ꢀ1ꢀ
S
S
trifluoroethanol.
1ꢀ(1
2,2,2ꢀtrifluoroethanol (a mixture of diastereomeric
diols 1a and 1b) was obtained from ( )ꢀ1ꢀphenylethaꢀ
. Yield 67%, diastereꢀ
S)ꢀ[2ꢀ(1ꢀHydroxyethyl)phenyl]ꢀ1ꢀphenylꢀ
S
monochromator, the
11 498 unique reflections (
ω
scan mode,
2
θmax = 90 ) and
°
nol similarly to racemic diols
omer ratio is 1.3 : 1.
7
R(
int = 0.0825) were used
)
in further calculations. The structure was solved by
direct methods and refined by fullꢀmatrix leastꢀ
squares techniques in the anisotropic–isotropic
approximation on F2. Hydrogen atoms were located
from a difference Fourier syntheses and refined isotroꢀ
pically. The final residuals were: wR2 = 0.1350, GOF =
1.005 for all reflections (R1 = 0.0434 calculated for
(1S)ꢀ{2ꢀ[(1S)ꢀHydroxyethyl]phenyl}ꢀ1ꢀphenylꢀ
2,2,2ꢀtrifluoroethanol (1a). The compound was isoꢀ
lated by crystallization of a mixture of diastereomeric
diols
1
from petroleum ether (bp 40–70
°
C)–diethyl
ether mixture. Mp 117
anol).
°
C, [α]2D0 —100.0
(c
°
1, ethꢀ
8064 reflections with
PLUS software complex.
I
> 2 (I)) using the SHELXTL
σ
1H NMR (
(s, 1H, OH), 4.91 (q, 1H, CH3–CH), 5.14 (s, 1H,
), 7.29–7.46 (m, 6H, arom.), 7.43 (t, 1H, arom.),
7.54 (d, 1H, arom.), 7.72 (d, 1H, arom.).
IR (KBr pellet,
, cm–1): 3490–3200 (wide, νOH);
δ
, ppm): 0.93 (d, 3H, CH3–CH), 2.38
OH
Multipole refinement of 7a was carried out in the
framework of the Hansen–Koppens formalism [12]
using XD software package [13] with core and valence
electron densities obtained from wave functions based
on the relativistic solution of the Dirac–Fock equaꢀ
tion. Prior to refinement, C–H and O–H bond disꢀ
tances were normalized to the standard values of 1.08
and 0.98 Å, respectively. Multipole expansion was
confined by the octapole level for fluorine, oxygen,
and carbon atoms and by the dipole level for hydrogen
atoms. The refinement was performed for Fhkl. All
covalently bonded atom pairs fulfill the Hirshfeld criꢀ
terion for bond rigidity [14]. The residual electron
ν
(CCl4 solution): 3590 (narrow, νOH), 3520–3150
(wide).
For C16H15F3O2 anal. calcd. (%): C, 64.86; H, 5.10.
Found (%): C, 65.01; H, 5.01.
Xꢀray diffraction study of compound 7a. Crystals are
rhombohedral at 100 K:
a
= 22.437(1),
c = 14.429(1) Å,
V
= 6290.7(6) Å3
,
dcalcd. = 1.408 g cm–1, space group
R
3 , Z
= 18. The intensities of 66 694 reflections were
e
Å–3 (in proximity to
measured on a Smart APREX2 CCD automated difꢀ
fractometer at 100 K (Mo radiation, graphite
density was not higher than 0.22
the C(6) nucleus). The search for bonding interactions
K
α
DOKLADY CHEMISTRY Vol. 435
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318
SHISHKINA et al.
4. Seebach, D., Beck, A.K., and Heckel, A., Angew.
Chem., 2001, vol. 40, pp. 92–138.
5. Sokeirik, Y.S., Sato, K., Omote, M., et al., Tetrahedron
Lett., 2006, vol. 47, pp. 2821–2824.
and calculation of topological characteristics of the
electron density distribution function for them was
carried out using the WINXPRO program [15]. The
final residuals were:
R
= 0.0330, Rw = 0.0364, GOF =
> 3
6. Zefirov, N.S., Palyulin, V.A., and Dashevskaya, E.E.,
0.8061 for 8056 reflections with
I
σ
(I).
J. Phys. Org. Chem., 1990, vol. 3, pp. 147–158.
The full set of Xꢀray diffraction data was deposited
with the Cambridge Crystallographic Data Centre
(no. 772906) for compound 7a, 12 Union Road, Camꢀ
bridge CB2 1EZ, UK; fax: +44ꢀ1223/336ꢀ033; eꢀmail:
deposit@ccdc.cam.ac.uk; http://www.ccdc.cam/ ac/uk).
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,
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ACKNOWLEDGMENTS
11. Lyssenko, K.A., Nelyubina, Yu.V., Kostyanovsky, R.G.,
and Antipin, M.Yu., Chem. Phys. Chem., 2006, vol. 7,
pp. 2453–2455.
12. Hansen, N.K. and Koppens, P., Acta Crystallogr., Sect.
A, 1978, vol. 34, pp. 909–921.
This work was supported by the Council for Grants
of the President of the Russian Federation for Support
of Young Doctors of Science (grant no. MD–
237.2010.3).
13. Koritsansky, T.S., Howard, S.T., Richter, T., et al., XDꢀA
Computer Program Package for Multipole Refinement
and Topological Analysis of Charge Densities from Difꢀ
fraction Data, 2003.
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DOKLADY CHEMISTRY Vol. 435
Part 2
2010