Asymmetric Friedel-Crafts reactions of vinyl ethers with fluoral catalyzed by chiral binaphthol-derived titanium catalysts

Article abstract of DOI:10.1016/S0022-1139(99)00025-1

Asymmetric Friedel-Crafts reactions of vinyl ethers with fluoral catalyzed by chiral binaphthol-derived titanium catalysts gave reactive vinyl ether products. Sequential diastereoselective reactions of resultant vinyl ethers with m-CPBA provided highly functionalized organofluorine compounds in high enantiomeric purity.

Full text of DOI:10.1016/S0022-1139(99)00025-1

Journal of Fluorine Chemistry 97 (1999) 51±55
Short communication
Asymmetric Friedel±Crafts reactions of vinyl ethers with ¯uoral
catalyzed by chiral binaphthol-derived titanium catalysts
Akihiro Ishii1, Koichi Mikami*
Department of Chemical Technology, Tokyo Institute of Technology, Tokyo 152-8552, Japan
Received 27 November 1998; received in revised form 8 January 1999; accepted 8 January 1999
Dedicated to Professor Yoshiro Kobayashi on the occasion of his 75th birthday
Abstract
Asymmetric Friedel±Crafts reactions of vinyl ethers with ¯uoral catalyzed by chiral binaphthol-derived titanium catalysts gave reactive
vinyl ether products. Sequential diastereoselective reactions of resultant vinyl ethers with m-CPBA provided highly functionalized
organo¯uorine compounds in high enantiomeric purity. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Friedel±Crafts reaction; Asymmetric catalysis; Fluoral; Vinyl ether
1. Introduction
stereoselective oxidation reactions of the F±C products
(Scheme 1).
Asymmetric synthesis of organo¯uorine compounds is an
important issue in pharmaceutical chemistry [1,2] and
optoelectronic material science [3,4]. In particular, asym-
metric catalysis of carbon±carbon bond-forming reactions is
the most attractive method, because the carbon skeleton of
chiral organo¯uorine molecules can be constructed at the
time of asymmetric induction [5±7]. The Friedel±Crafts (F±
C) reaction is one of the most fundamental carbon±carbon
bond-forming reactions in organic synthesis [8±11]. How-
ever, its application to catalytic asymmetric synthesis has
been quite limited [12±20]. Recently, we reported the
asymmetric F±C reactions of aromatic compounds with
¯uoral catalyzed by chiral binaphthol-derived titanium
(BINOL-Ti) catalysts [21]. Herein, we disclose the catalytic
asymmetric F±C reaction of alkyl vinyl ethers instead of
aromatic compounds as a nucleophile and sequential dia-
2. Results and discussion
The catalyst (1a) prepared from 6,60-Br2-BINOL-Ti(O-
Pri)2/6,60-Br2-BINOL [22], which was the most effective
catalyst in the F±C reaction of aromatic compounds, was
®rst employed in this reaction (Table 1, run 1). However,
only the aldol product (4a) was obtained with high enantios-
electivity. We supposed that the F±C product would be
hydrolyzed by the acidic protons of the 6,60-Br2-BINOL-
Ti(OPri)2/6,60-Br2-BINOL complex. Accordingly, the cata-
lysts without proton sources were expected to be effective to
this F±C reaction. These catalysts were prepared in isolated
form by the previously reported procedure [23]. Thus, the
same reaction was examined using the isolated catalyst (1b)
Scheme 1.
prepared from (R)-6,60-Br2-BINOL and Cl2Ti(OPri)2 in the
presence of MS 4A without addition of Br2-BINOL (run 2).
The F±C product (3a) was obtained together with a small
amount of the aldol product (4a). The enantiomeric excess
*Corresponding author. Tel.: +81-3-5734-2142; fax: +81-3-5734-2776;
e-mail: kmikami@o.cc.titech.ac.jp
1On leave from Chemical Research Center, Central Glass Co. Ltd.,
Kawagoe, Saitama 350-1151, Japan.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 2 5 - 1

52
A. Ishii, K. Mikami / Journal of Fluorine Chemistry 97 (1999) 51±55
Table 1
Asymmetric Friedel±Crafts reactions of methyl vinyl ethers with fluoral catalyzed by BINOL-Ti catalysts
Run
Ether
Catalyst (1)
mol%
Yield (%)a
Enantiomeric
excess (%)b
(2)
3(E:Z)
4
1
2
3
4
a
(R)-6,60-Br2-BINOL-Ti(OPri)2/(R)-6,60-Br2-BINOL (a)
(R)-6,60-Br2-BINOL/Cl2Ti(OPri)2/MS 4A (b)
(R)-BINOL/Cl2Ti(OPri)2/MS 4A (c)
20
20
10
20
0
53
7
70 (R)c
58 (R)d
72 (R)e
85 (R)g
a
48 (1:2)
54 (1:2)
64 (5:1)
a
bf
±
(R)-BINOL/Cl2Ti(OPri)2/MS 4A (c)
±
a Isolated yield after silica gel column chromatography.
b The enantiomeric excess of 3a or 3b. Determined by chiral HPLC analysis of 4a or anti-4b obtained by acidic hydrolysis of 3a or 3b. In the hydrolysis of
(E)-3b, anti-isomer was obtained as the major diastereomer (anti/synˆca. 2) (The relative configuration of the major diastereomer was determined to be anti
on the basis of the chemical shifts of a-methyl carbon in 13C-NMR spectra (CDCl3) of 4b (syn: 11.9 ppm, anti: 16.3 ppm), see [26]). Chiral HPLC
conditions, 4a: Daicel, CHIRALPAK OD-H, n-hexane:i-PrOHˆ95:5, 0.8 ml/min, 254 nm, tRˆ10 min (3S), 12 min (3R). anti-4b: Daicel, CHIRALPAK AS,
n-hexane:i-PrOHˆ98:2, 0.8 ml/min, 254 nm, tRˆ11 min (2R, 3S), 38 min (2S, 3R).
c The enantiomeric excess of 4a.
d The enantiomeric excess of E,Z-mixture (2:3) of 3a.
e The enantiomeric excess of E,Z-mixture (1:2) of 3a.
f E:Zˆ1:1.
g The enantiomeric excess of (E)-3b.
of the F±C product was moderate. The product ratio of 3 vs.
4 was found to be critically in¯uenced by the preparative
procedure and the ligands of the catalysts. The isolated
catalyst (1c) derived from (R)-BINOL, which is less acidic
than the corresponding 6-Br-analogue, proved to be more
effective in terms of both chemical yield and enantioselec-
tivity (run 3). The aldol product was essentially not obtained
in this case. Thus, the BINOL-Ti catalyst was superior in
this reaction to the 6,60-Br2-BINOL-Ti catalyst in sharp
contrast to the F±C reaction of aromatic compounds. The
higher enantioselectivity was obtained in the reaction of
methyl vinyl ether (2b) possessing b-methyl substituent
irrespective of the geometry (run 4). This F±C reaction
with alkyl vinyl ethers was found to more easily proceed as
compared with that of aromatic compounds. Therefore, a
large excess of ¯uoral was not necessary because of the high
nucleophilicity of alkyl vinyl ethers.
The stereochemical assignments deserve special com-
ments. The geometries of products (3) were determined
on the basis of the chemical shifts in 1H-NMR spectra
(Fig. 1). In a similar manner to b-methylstyrene [24],
(Z)-3a shows the vinylic proton at higher ®eld (4.8 ppm).
Likewise, (E)-3b shows the vinylic methyl group at higher
®eld (1.7 ppm). The absolute con®guration of (E)-3b was
determined to be R by Mosher's method [25].2
Then we focused our attention to sequential diastereose-
lective oxidation reactions of the F±C products by m-CPBA
(Scheme 2). Regardless of the geometry of the F±C pro-
ducts, single diastereomer of a,b-dihydroxy ketone (7)
having a chiral quarternary carbon was obtained in high
chemical yield and high diastereoselectivity through the
acidic hydrolysis of intermediates (5 and 6). The other
diastereomer was not observed in the reaction mixture as
1
determined by H-NMR.
The relative stereochemistry was determined to be syn on
the bases of the chemical shifts of a-methyl carbons in
13C-NMR spectra of 7 [26].3 Therefore, the diastereoselec-
tivity can be explained as follows, the tri¯uoromethyl
substituent is located outside because of a 1,3-allylic strain
[27], and then m-CPBA should attack from the direction of
the hydroxy substituent perpendicular to the ole®n ꢀ-face
through hydrogen bonding (Fig. 2) [28,29].4 These products
are of synthetic importance because of similar skeletal
features to Merck L-784512 [30] with cyclooxygenase-2
selective inhibitory activity.
In summary, we have reported the asymmetric Friedel±
Crafts reactions of alkyl vinyl ethers with ¯uoral catalyzed
by chiral binaphthol-derived titanium catalysts and sequen-
tial diastereoselective oxidation reactions of the Friedel±
Crafts products.
2The chemical shift of vinylic methyl proton in 1H-NMR spectra
(CDCl3) of MTPA ester of (E)-3b: 1.60 ppm (S), 1.36 ppm (R);
ꢁS ꢁRˆpositive.
3syn: 23.4 ppm, anti: 25.1 ppm (CDCl3).
4Sharpless proposed the formation of hydrogen bond between hydroxy
groups and m-CPBA.

A. Ishii, K. Mikami / Journal of Fluorine Chemistry 97 (1999) 51±55
53
Fig. 1.
3. Experimental
ultra violet light (254 nm) and chiral column (Daicel
CHIRALCEL OD-H or AS). Peak area was calculated by
a Shimadzu model C-R6A as an automatic integrator.
Analytical thin layer chromatography (TLC) were per-
formed on glass plates pre-coated with silica gel (Merck
Kieselgel 60 F254, layer thickness 0.25 mm). Visuali-
zation was accomplished by UV light (254 nm) and
phosphomolybdic acid. Column chromatography was per-
formed on silica gel 60 (70±230 mesh) purchased from
Kanto. Molecular sieve (MS) 4A (activated powder) was
purchased from Aldrich. Dehydrated dichloromethane
and toluene were purchased from Kanto. Fluoral was gen-
erated by the addition of ¯uoral hydrate to conc. H2SO4 at
1008C.
1
General. H NMR and 13C NMR were measured on a
Varian Gemini 300 (300 MHz) spectrometers. Chemical
shifts of 1H NMR were expressed in parts per million
down®eld from tetramethylsilane as an internal standard
(0 ppm) in CDCl3. Signi®cant 1H NMR date were
tabulated in the following order: multiplicity (s: singlet;
d: doublet; t: triplet; q: quartet; quin: quintet; sex: sextet;
sep: septet, m: multiplet). Chemical shifts of 13C NMR
were expressed in parts per million in CDCl3 as an
internal standard (77.1 ppm). Liquid chromatographic
analyses were conducted on a JASCO PU-980 instru-
ment equipped with model UV-975 spectrometers as an
Scheme 2.

54
A. Ishii, K. Mikami / Journal of Fluorine Chemistry 97 (1999) 51±55
(Z)-3b pale yellow oil. 1H NMR (CDCl3) ꢁ 1.86 (s, 3H),
2.07 (d, Jˆ6.4 Hz, 1H), 2.39 (s, 3H), 3.30 (s, 3H), 4.44
(quin, Jˆ6.4 Hz, 1H), 7.12±7.24 (m, 4H).
3.3. Sequential diastereoselective oxidation reactions
To a solution of (E) or (Z)-3b (0.1 mmol) in methanol
(1 ml) was added m-CPBA (0.25 mmol) at room tempera-
ture. After stirring for 12 h, solvent was evaporated under
reduced pressure. The residue was diluted with dichloro-
methane and the organic layer was washed with sat.
NaHCO3, brine, and dried over MgSO4. Removal of solvent
under reduced pressure gave the mixture of 5 and 6. To a
solution of 5 and 6 in methanol±H2O (3:1, 3 ml) was added
p-TsOHÁH2O (0.5 mmol). After the mixture was stirred for
30 min under re¯ux condition, solvent was evaporated
under reduced pressure. The residue was diluted with
dichloromethane and the organic layer was washed with
sat. NaHCO3, brine, dried over MgSO4, and evaporated
under reduced pressure. Chromatographic separation by
silica gel (ethyl acetate:n-hexaneˆ1:4) gave 7 in 80% yield.
7 colorless needle. 1H NMR (CDCl3) ꢁ 1.74 (q,
Jˆ1.8 Hz, 3H), 2.44 (s, 3H), 3.21 (d, Jˆ10.5 Hz, 1H),
4.53 (s, 1H), 4.57 (dq, Jˆ10.5, 6.9 Hz, 1H), 7.30 (d,
Jˆ8.1 Hz, 2H), 7.95 (d, Jˆ8.1 Hz, 2H).
Fig. 2.
3.1. Preparation of catalysts
1a: To a solution of Ti(OPri)4 (0.05 mmol) in dehydrated
dichloromethane (0.75 ml) was added (R)-6,60-Br2-BINOL
(0.05 mmol) at room temperature under an argon atmo-
sphere. After stirring for 1 h, (R)-6,60-Br2-BINOL
(0.05 mmol) in dehydrated dichloromethane (0.75 ml)
was added to the mixture again. Catalyst solution was
prepared by stirring for additional 30 min.
1b, c: The mixture containing (R)-6,60-Br2-BINOL or
(R)-BINOL (1 mmol), Cl2Ti(OPri)2 (1 mmol), MS 4A (5 g)
and dehydrated dichloromethane (10 ml) was stirred at
room temperature under an argon atmosphere. After 1 h,
dehydrated toluene (20 ml) was added to the mixture. Clear
catalyst solution was recovered by centrifugal separator
followed by Celite ®ltration. Isolated catalyst was obtained
as a reddish brown solid by evaporating under reduced
pressure at room temperature.
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