F8BINOL, an electronically perturbed version of BINOL with remarkable configurational stability

Article abstract of DOI:10.1021/ol991244v

(formula presented) Substitution of hydrogens by fluorines at the 5, 5′, 6, 6′, 7, 7′, 8, and 8′ positions of BINOL strongly affects distribution of electron density within the biaryl skeleton but has a very small influence on the torsion angle. The most

Full text of DOI:10.1021/ol991244v

ORGANIC
LETTERS
2000
Vol. 2, No. 1
41-44
F8BINOL, an Electronically Perturbed
Version of BINOL with Remarkable
Configurational Stability
Andrei K. Yudin,* L. James P. Martyn, Subramanian Pandiaraju, Juan Zheng, and
Alan Lough
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto,
Ontario M5S 3H6, Canada
ayudin@chem.utoronto.ca
Received November 11, 1999
ABSTRACT
Substitution of hydrogens by fluorines at the 5, 5′, 6, 6′, 7, 7′, 8, and 8′ positions of BINOL strongly affects distribution of electron density
within the biaryl skeleton but has a very small influence on the torsion angle. The most important consequence of this structural alteration
is the dramatic increase in configurational stability of homochiral F BINOL.
8
Modern asymmetric synthesis demands new and improved
catalytic transformations. While many important discoveries
in this area are due to serendipity, understanding the balance
of steric and electronic factors is required in order to fine
tune a catalyst to achieve optimal rate and selectivity in a
particular reaction. A lot of research in recent years has been
devoted to the development of chiral ligands. Among these,
BINOL (1) and related molecules with axial chirality have
found wide utility in asymmetric catalysis.1 Over the years,
several modifications of the BINOL skeleton aimed at
changing its steric as well as electronic properties have been
reported.2 Thus, partially hydrogenated BINOL was used in
enantioselective alkylation of aldehydes,2a conjugate addition
of diethylzinc to cyclic enones,2b and ring opening of
epoxides.2c Incorporation of bromine atoms at the 6 and 6′
positions of 1, rather remote from the catalytic site, was
shown to increase the enantioselectivity of the corresponding
titanium catalysts in glyoxolate-ene reactions.2d Bulky
triarylsilyl groups at the 3 and 3′ positions of 1 led to
increased levels of enantiofacial discrimination of prochiral
aldehydes in asymmetric Diels-Alder reactions.2e 3,3′-
Dinitrooctahydrobinaphthol was applied in titanium-catalyzed
asymmetric oxidation of methyl p-tolyl sulfide.2f
In this Letter we report our efforts in designing a new
class of chiral polyfluoroaryl ligands based on 1. We
reasoned that substitution of hydrogens by fluorines at the
5, 5′, 6, 6′, 7, 7′, 8, and 8′ positions of 1 should induce
considerable electronic perturbation of the aromatic system
in the resulting 5,5′,6,6′,7,7′,8,8′-octafluoro-2,2′-dihydroxy-
1,1′-binaphthyl (F8BINOL, 2). Figure 1 features a comparison
of electrostatic potential surfaces (AM1) of 1 and 2 and
reveals a noticeable difference in the distribution of electron
density. The electron-deficient nature of the aromatic rings
should raise the oxidative stability of 2 compared to 1 as
(1) Noyori, R Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994.
(2) (a) Chan, A. S. C.; Zhang, F. Y.; Yip, C. W. J. Am. Chem. Soc.
1997, 119, 4080. (b) Zhang, F. Y.; Chan, A. S. C. Tetrahedron: Asymmetry
1998, 9, 1179. (c) Iida, T.; Yamamoto, N.; Matsunaga, S.; Woo, H. G.;
Shibasaki, M. Angew. Chem., Int. Ed. 1998, 37, 2223. (d) Terada, M.;
Motoyama, Y.; Mikami, K. Tetrahedron Lett. 1994, 35, 6693. (e) Maruoka,
K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110,
310. (f) Reetz, M. T.; Merk, C.; Naberfeld, G.; Rudolph, J.; Griebenow,
N.; Goddard, R. Tetrahedron Lett. 1997, 38, 5273.
10.1021/ol991244v CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/18/1999

We have found that such a combination of steric and
electronic alterations in fact leads to a dramatic increase in
configurational stability of homochiral 2 with electronic
effects playing a decisive role.
The racemic form of 2 was prepared according to Scheme
1. Tetrafluorobenzyne, generated by treating a hexane
solution of chloropentafluorobenzene with n-butyllithium at
-15 °C, was reacted with 3-methoxythiophene5 in a Diels-
Alder reaction. Upon in situ extrusion of sulfur, 2-methoxy-
5,6,7,8-tetrafluoronaphthalene (3) was obtained in 52%
yield.6 5,6,7,8-Tetrafluoro-2-naphthol (4), prepared from 3
by demethylation with BBr3 in dichloromethane, did not
undergo the FeCl3-catalyzed oxidative coupling (Scheme 1,
path a) commonly used for the preparation of 1 from
2-naphthol.7 The relatively high oxidation potential of 4 (1.84
V vs Ag/AgCl) is a likely reason for the observed lack of
reactivity. Therefore, we chose a reductive route (Scheme
1, path b) through the intermediacy of the 1-brominated
derivative 5, prepared in 88% yield by treating 3 with
N-bromosuccinimide in acetonitrile. The Ullmann coupling
of 5, facilitated by the presence of aromatic fluorines, gave
the desired bis(methoxy) product 6 in 85% yield. Demethyl-
ation of 6 with BBr3 furnished 2 in 90% yield. Following
recrystallization from methanol/water, pure 2 was obtained
as white solid (mp 235 °C), soluble in common organic
solvents. After several unsuccessful attempts to resolve 2,
we were able to fractionally crystallize the diastereomeric
bis[(-)-menthoxycarbonyl] derivatives 7 and 8, obtained by
reacting racemic 2 with excess (-)-menthyl chloroformate
in quantitative yield.8 Saponification of each diastereomer
with LiOH in THF followed by extraction with diethyl ether
afforded (-)-F8BINOL ([R]25D -40°, c ) 1, THF) and (+)-
Figure 1. Electrostatic potential surfaces (AM1) of BINOL (1)
and F8BINOL (2) obtained with Spartan Pro. The color code spans
from -20 (red) to +20 kcal/mol (blue).
well as increase the acidity of the ring-bound hydroxyl
groups. This could translate into modulated binding to metals
as well as reactants in the F8BINOL-mediated processes.
Furthermore, since the fluorine atom is only 0.27 Å larger
than the hydrogen atom,3 one could anticipate a small
increase in the barrier to axial torsion upon octafluorination.4
F8BINOL ([R]21 +39°, c ) 1, THF), respectively. The
D
enantiomeric excess, determined by chiral HPLC (Chiralpak
AD column, hexane/2-propanol 9:1, 1 mL/min), was found
Scheme 1a
a Key: (a) n-BuLi, hexanes, -15 °C; (b) 3-methoxythiophene, -15 °C to rt, 12 h; (c) BBr3, CH2Cl2, rt, 10 h; (d) FeCl3, H2O, reflux; (e)
NBS, CH3CN, rt, 1 h; (f) Cu°, 175 °C, 24 h; (g) (-)-menthyl chloroformate, pyridine, CH2Cl2, rt, 2 h; (h) fractional crystallization (MeOH);
(i) LiOH, THF/H2O, rt, 2 h.
42
Org. Lett., Vol. 2, No. 1, 2000

to be >99% in each case. The (S)-absolute configuration of
the (-) enantiomer was determined by the X-ray analysis
of its bis[(-)-menthoxycarbonyl] derivative. Notably, the
same relationship exists between the absolute configuration
and the sign of optical rotation of 1.8
To elucidate the effect of fluorine substitution on atropi-
somerism and configurational stability of 2, we investigated
racemization of its S-enantiomer. The racemization of
homochiral 1 in both acidic and basic media is well known.9
The acid-promoted process is believed to proceed through
protonation of the C(1) carbon atom of the binaphthyl ring
followed by rotation of the naphthyl moiety around the
resulting C(sp2)-C(sp3) bond. Besides the steric influence
on the rotation barrier,4 fluorine substitution was found to
minimize the acid-promoted racemization, presumably due
to destabilization of the cationic intermediate 9 (Scheme 2).
In the case of base-induced racemization, the enantiomeric
excess of (-)-1 decreased from 99% to 0% after 12 h in
boiling 5% aqueous NaOH. It was proposed earlier that this
path proceeds through deprotonation of the hydroxyl groups
leading to an anionic intermediate that undergoes rotation
around the C(1)-C(1′) bond.9 We have found that the pKa′
of the hydroxyl group in 1 decreases by 1 unit upon fluorine
substitution of the aromatic scaffold (1, pKa′ 10.28; 2, pKa′
9.29). Thus, we expected (-)-2 to racemize at least as readily
as (-)-1 under basic conditions. However, (-)-2 dissolved
in aqueous NaOH solution and remained configurationally
stable at room temperature. When the temperature was raised
to 100 °C, no racemization was observed after 24 h, once
again indicating configurational stability.10
The molecular structure of homochiral 2, determined by
X-ray analysis, is shown in Figure 2.11 The torsion angle
Scheme 2
Figure 2. ORTEP diagram of R-(+)-2.
We have observed a dramatic increase in configurational
stability of (-)-2 under acidic conditions: when subjected
to reflux in a 1:1 mixture of THF and 13% aqueous HCl, no
racemization was detected by chiral HPLC after 24 h. In
comparison, (-)-1 was racemized under these conditions
(from 99% to 13% ee, determined using Chiralpak AS
column, hexane/2-propanol 9:1, 1 mL/min).
between the tetrafluoronaphthol planes in R-(-)-2 (79.7°)
is only 1.4° larger than in the parent protio derivative R-(-)-1
(78.3°).12 Thus, fluorination appears to have a fairly insig-
nificant steric influence on the torsion angle and the observed
effect on the structural integrity of 2 must be primarily
electronic in nature. The desired conformational flexibility,
(3) Smart, B. E. In Organofluorine compounds: Principles and Com-
mercial Applications; Banks, R. E., Ed.; Plenum Press: New York, 1994;
Chapter 3.
(4) (a) Schlosser, M.; Michel, D. Tetrahedron 1996, 52, 99 and references
therein. (b) Soloshonok, V. A. Enantiocontrolled Synthesis of Fluoroorganic
Compounds; Wiley: New York, 1999. (c) Garc´ıa Mart´ınez, A.; Os´ıo
Barcina, J.; de Fresno Cerezo, A.; Rivas, R. G. J. Am. Chem. Soc. 1998,
120, 673. (d) Tang, T.-H.; Nowakowska, M.; Guillet, J. E.; Csizmadia, I.
G. J. Mol. Struct. 1991, 232, 133.
(10) Partial decomposition due to nucleophilic aromatic substitution of
fluorines by hydroxyl groups was observed under these conditions: Yudin,
A. K.; Martyn, L. J. P. Unpublished data.
(11) Crystal data: 2 C20H6F8O2, Mr ) 430.25, orthorhombic, C2221, a
) 7.9676(2), b ) 13.3257(4), and c ) 29.0028(7) Å, V ) 3079.34(14) Å3,
Z ) 8, Dx ) 1.856 g cm-3, λ(Mo KR) ) 0.71073 Å, µ(Mo KR) ) 0.185
mm-1, F(000) ) 1712, T ) 100.0(1) K, 11618 reflections collected, R(F)
) 0.0564, R(wF2) ) 0.0749 for all 3508 independent reflections, [R(F) )
0.0353, R(wF2) ) 0.0707 for 2644 data with F > 4σ(Fo)]. Data were
collected on a Nonius Kappa-CCD. Data were integrated and scaled using
the Denzo-SMN package (Otwinowski, Z.; Minor, W. Methods Enzymol.
1997, 276, 307). The structure was solved and refined using SHELXTL
V5.0. (Sheldrick, G. M. SHELXTL/PC V5.1 Users Manual (1997), Bruker
Analytical X-ray Systems, Madison, WI) All non-hydrogen atoms were
refined with anisotropic parameters. Hydrogen atoms were included in
geometric positions and treated as riding atoms.
(5) Gronowitz, S. Ark. Kemi 1958, 12, 239.
(6) The side reaction between tetrafluorobenzyne (2 equiv) and sulfur
to give octafluorodibenzothiophene accounts for the moderate yield.
(7) Pummerer, R.; Prell, E.; Rieche, A. Ber. 1926, 59B, 2159.
(8) For resolution of BINOL through separation of the bis[(-)-men-
thoxycarbonyl] derivatives, see: Fabbri, D.; Delogu, G.; De Lucchi, O. J.
Org. Chem. 1995, 60, 6599.
(9) Kyba, E. P.; Gokel, G. W.; de Jong, F.; Koga, K.; Sousa, L. R.;
Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J. J. Org. Chem.
1977, 42, 4173.
(12) Toda, F.; Tanaka, K.; Miyamoto, H.; Koshima, H.; Miyahara, I.;
Hirotsu, K. J. Chem. Soc., Perkin Trans. 2 1997, 1877.
Org. Lett., Vol. 2, No. 1, 2000
43

one of the most important characteristics of BINOL allowing
it to coordinate a wide variety of metals,1 should be preserved
in 2.
derived asymmetric catalysts as well as other applications
of the octafluorobinaphthyl scaffold.
Acknowledgment. We thank the National Science and
Engineering Research Council (NSERC), Canada Foundation
for Innovation (CFI), the Connaught Fund, the Research
Corporation, and the University of Toronto for financial
support. We also thank Mr. Tung Siu for determining the
redox potentials and Ms. Alicja Koprianiuk and Ms. Ag-
niezhka Zaucha for the pKa′ measurements.
In summary, fluorine substitution confers remarkable
configurational stability on homochiral 5,5′,6,6′,7,7′,8,8′-
octafluoro-2,2′-dihydroxy-1,1′-binaphthyl. At the same time,
a 10-fold increase in acidity of the ring-bound hydroxyl
groups takes place. Similar trends should operate for other
substituents at the 2 and 2′ positions, eventually providing
robust catalysts with modulated reactivities. Reactions that
involve highly acidic and/or oxidative conditions13 under
which 1 is configurationally or structurally unstable seem
to be particularly attractive. Most importantly, both enanti-
omers of 2 can be readily prepared from commercially
available starting materials. The documented minimal steric
influence of fluorine substitution coupled with its significant
electronic effect on axial chirality may become a general
paradigm for the design of new and improved ligands.14,15
We are currently exploring the scope of the F8BINOL-
Supporting Information Available: Experimental pro-
cedures and full characterization of compounds 2-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL991244V
(14) For studies related to electronic effects of substituents on chiral
ligands in asymmetric catalysis, see: (a) Palucki, M.; Finney, N. S.; Pospisil,
P. J.; Gu¨ler, M. L.; Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 948. (b) RajanBabu, T. V.; Casalnuovo, A. L. J. Am. Chem. Soc. 1996,
118, 6325. (c) Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 931.
(13) The oxidation potential of F8BINOL (2.07V vs Ag/AgCl) is 0.6 V
more positive than that of BINOL (1.47 V vs Ag/AgCl).
(15) Jendralla, H.; Li, C. H.; Paulus, E. Tetrahedron: Asymmetry 1994,
5, 1297.
44
Org. Lett., Vol. 2, No. 1, 2000