Polystyrene-bound cinchona alkaloids: Application to enantioselective electrophilic fluorination of silyl enol ethers

Article abstract of DOI:10.1055/s-2004-817781

A panoply of new polystyrene-bound cinchona alkaloids (PS-CA) has been prepared, and exploited for the design of unprecedented enantioselective electrophilic fluorinating agents. Compared to nonsupported [N-F]⁺ reagents, the polystyrene-bound N

Full text of DOI:10.1055/s-2004-817781

856
LETTER
Polystyrene-bound Cinchona Alkaloids: Application to Enantioselective
Electrophilic Fluorination of Silyl Enol Ethers
P
olystyrene-boun
a
d
C
inchona
p
A
lkaloids tiste Thierry, Christophe Audouard, Jean-Christophe Plaquevent, Dominique Cahard*
UMR 6014 CNRS de l’IRCOF (Institut de Recherche en Chimie Organique Fine), Université de Rouen, 1 Rue Tesnière,
76821 Mont Saint Aignan Cedex, France
E-mail: dominique.cahard@univ-rouen.fr
Received 23 December 2003
Few polymeric analogues of achiral electrophilic fluori-
Abstract: A panoply of new polystyrene-bound cinchona alkaloids
(PS-CA) has been prepared, and exploited for the design of un-
precedented enantioselective electrophilic fluorinating agents.
Compared to nonsupported [N-F]+ reagents, the polystyrene-bound
nating reagents of the N-F class have been described,5
moreover chiral polymeric derivatives are unknown.
Cinchona alkaloids present at least three points of attach-
N-fluoro ammonium salts of cinchona alkaloids show comparable ment to a solid-phase. Very often the vinyl group serves
efficiency and ready purification of the fluorinated reaction
to graft the molecule, with or without a spacer; quite often
products. One PS-CA was recycled 3 times without loss of stereo-
chemical performance.
the polymer is attached at the C9-hydroxy group, whereas
there are very few reports concerning the attachment of
cinchona alkaloids onto the methoxy function of quinine
Key words: polymer, cinchona alkaloids, enantioselective synthe-
sis, electrophilic fluorination
or quinidine (Figure 1).
spacer
Enantioselective electrophilic fluorination is a very chal-
common
lenging asymmetric process, and the discovery of efficient
most common
asymmetric fluorination methods is one of the most fasci-
nating aspects of modern organofluorine chemistry.1 We
have developed a fundamentally new class of enantio-
selective electrophilic fluorinating reagents: the [N-F]+
reagents derived from cinchona alkaloids which have
demonstrated high performances in the fluorination of
various substrates; ees up to 94% were recorded.2,3 The
development of recoverable and recyclable reagents sup-
ported on a range of polymeric matrixes is a valuable
approach which offers several advantages: the ease of
physical separation of the polymer, a facilitated product
purification, and the potential recycling. However, the
efficiency of the supported reagents is often lower than
that of the corresponding nonsupported reagents. During
the last three years, our contribution in the field of poly-
mer-bound organocatalysts consisted of the anchorage of
the ammonium salts of cinchona alkaloids on a polymeric
support to produce highly efficient phase-transfer cata-
lysts.4 We decided to examine some of the polymer-bound
cinchona alkaloids as precursors for the preparation of
unprecedented fluorinating agents. The nitrogen atom of
the quinuclidine moiety of the cinchona alkaloid, unlike
the phase-transfer catalysts, must be left free to carry the
fluorine atom. We report in this communication the syn-
thesis of a series of polystyrene-bound cinchona alkaloid
derivatives, and their application to the enantioselective
electrophilic fluorination.
spacer
N
O
C9
C6'
O
N
rare
Figure
1
Cinchona alkaloids: QN = quinine, QD = quinidine,
CN = cinchonine, CD = cinchonidine
The anchorage of cinchona alkaloids at those three sites
was explored; the structures are depicted in Figure 2. Both
soluble and insoluble polymeric supports were evaluated.
Insoluble polystyrene-bound cinchona alkaloids (PS-CA)
of type I were obtained by heterogenization of cinchona
alkaloids by means of the commercially available cross-
linked carboxypolystyrene resin [1% divinylbenzene
(DVB)]. The carboxylic acid function reacted in thionyl
chloride at reflux to give the acyl chloride, then, after
removal of the excess of thionyl chloride under vacuum, a
solution of cinchona alkaloid in dichloromethane was
added to the polymer, and the mixture was stirred for three
days at room temperature (Scheme 1). The loading values
were determined by nitrogen analysis (0.12 mmolg–1 for
PS-QN and 0.15 mmolg–1 for PS-QD).
Soluble polymers have not received as much attention as
their insoluble counterparts. We have prepared soluble
polymeric cinchona alkaloids of type I easily by poly-
merization of the dihydro cinchona alkaloid O9-(4-vinyl-
benzoate) in the presence of a catalytic amount of AIBN
in refluxing dry benzene (Scheme 1).6,7 Interestingly, this
approach allows us to reach high loadings of reagents,
thus circumverting the low atom economy associated with
the use of Merrifield resins. These polymers are soluble in
SYNLETT 2004, No. 5, pp 0856–0860
0
2.
0
4.
2
0
0
4
Advanced online publication: 17.02.2004
DOI: 10.1055/s-2004-817781; Art ID: D30403ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polystyrene-bound Cinchona Alkaloids
857
I soluble
n
I insoluble
H
H
N
H
N
H
O
O
O
O
R
R
N
N
II
n
H
N
HO
H
O
O
N
O
H
HO
V
N
H
N
H
R
HO
H
N
n
N
R = H, OMe
N
H
O
O
N
IV
H
N
HO
III
H
O
N
Figure 2 Polystyrene-bound cinchona alkaloids
Type I insoluble PS-CA
1. SOCl2, reflux, 8 h
2. QN (or QD), CH2Cl2, 20 °C, 3 d
H
O
N
O
O
H
CO2H
N
O
Type I soluble PS-CA
n
H
N
H
N
H
N
N
HO
O
O
R
H
O
H
H
R
R
4-vinylbenzoyl chloride
NEt3, CH2Cl2, 20 °C
2 mol% AIBN, benzene
reflux, 48 h
N
N
DHCA
O9-(4-VB) DHCA
poly (O9-(4-VB) DHCA)
Scheme 1
a wide range of organic solvents such as toluene, dichloro- are very few reports of demethoxylated quinine or quini-
methane, chloroform, tetrahydrofuran, or acetonitrile, and dine derivatives grafted on polymeric supports.8
can be easily recovered by precipitation in diethyl ether.
Demethoxylation of dihydroquini(di)ne was carried out
following Heidelberger’s method in refluxing concentrat-
ed HBr to give the dihydrocuprei(di)ne analogues.9 The
Types II, III, and IV PS-CA have the point of attachment
onto the methoxy function of quinine or quinidine. There
Synlett 2004, No. 5, 856–860 © Thieme Stuttgart · New York

858
B. Thierry et al.
LETTER
Type II soluble polymeric CA
n
H
HO
H
HO
N
N
1. 4-Vinylbenzoyl chloride,
NEt3, CH2Cl2, 20 °C
H
H
O
HO
2. 2 mol% AIBN, benzene,
reflux, 48 h
O
N
N
Type III soluble polymeric CA
n
O
N
O
N
1. 4-Vinylbenzoyl chloride,
NEt3, CH2Cl2, 20 °C
H
H
HO
O
2. 2 mol% AIBN, benzene,
reflux, 48 h
O
N
N
Scheme 2
cyclic ether derivative of quinidine used in type III PS-CA group of cinchonidine was transformed to a terminal
synthesis was obtained according to Hoffmann et al.10 alkyne,11 which was further deprotonated to react with the
Soluble polymeric cinchona alkaloids of type II and III Merrifield resin affording the type V of PS-CA.
were prepared by polymerization of the corresponding
cinchona alkaloid C6¢-(4-vinylbenzoate) in the presence of
a catalytic amount of AIBN in refluxing dry benzene
(Scheme 2).
We next examined the transfer fluorination on PS-CA
with the aid of achiral N-F fluorine-transfer reagents
such as SelectfluorTM or N-fluorobenzenesulfonimide
(NFSI).12 We proceeded either by using an in situ combi-
Type IV PS-CA was obtained by grafting the cinchona al- nation to generate the fluorinating agent, or by means of a
kaloid at the C6¢ on a Merrifield resin. Finally, the vinyl preformed PS-[CA-F]+ reagent. In the first instance, the
Table 1 Enantioselective Fluorination of Silyl Enol Ethers with PS-[CA-F]+ Agentsa
OSiMe3
O
combination
R
PS-CA / Selectfluor
R
n
F
n
1a : n = 1; R = Me
1b : n = 1; R = Bn
2a,b
Entry
PS-CA Type
CA
CD
CN
QD
QN
QN
QN
QN
QD
QN
QNd
QNe
Substrate
1a
T (°C)
–40
–40
–40
–40
–78
–40
–78
–40
–40
–40
–40
Product
2a
Yield (%)b
Ee (%)c
15 (R)
13 (S)
41 (S)
48 (R)
59 (R)
80 (R)
86 (R)
43 (S)
54 (R)
80 (R)
85 (R)
1
2
I soluble
I soluble
I soluble
I soluble
I soluble
I soluble
I soluble
I insoluble
I insoluble
I soluble
I soluble
71
80
95
95
68
98
72
41
52
96
98
1a
2a
3
1a
2a
4
1a
2a
5
1a
2a
6
1b
2b
7
1b
2b
8
1b
2b
9
1b
2b
10
11
1b
2b
1b
2b
a The fluorinations were run in THF–MeCN for 18 h.
b Yields refer to purified products.
c Determined by HPLC analysis, using a chiral column [Chiralcel OB, 2-propanol–hexane (1:9), 1.0 mL/min, lmax = 254 nm].
d NFSI, instead of Selectfluor, was used in combination with the PS-QN.
e The PS-[QN-F]+ reagent was isolated prior to the fluorination reaction.
Synlett 2004, No. 5, 856–860 © Thieme Stuttgart · New York

LETTER
Polystyrene-bound Cinchona Alkaloids
859
1. heterogenization
PS-
fluorinating
reagent
+
1. fluorination
by Et2O addition
fluorinated
product
PS-CA
+
fluorinated
product
2. neutral quench
2.centrifugation
substrate
1. homogenization
2. transfluorination
PS-CA
Recycling
Figure 3 Recovery, separation, and reuse of soluble poly [O9-(4-VB)-DHQN]
Table 2 Recycling of the Poly [O9-(4-VB)-DHQN] in the Enantio-
selective Fluorination of 1ba
‘one-pot’ two step reaction (transfer fluorination and
enantioselective electrophilic fluorination) was preferred
to examine the feasibility of the fluorination of silyl enol
ethers. To determine suitable reaction conditions for the
enantioselective fluorination, trimethylsilyl enol ethers of
2-methyl- and 2-benzyl-1-indanone were selected as
model compound for screening of the different PS-[CA-
F]+ reagents. In the first series of experiments, the polysty-
rene-bound cinchona alkaloids of type I, both soluble and
insoluble polymers, served in the fluorination reactions
(Table 1). We noticed that PS-[QN-F]+ reagent induced a
higher degree of enantioselection (Table 1, entries 1–4).
Soluble polymeric reagents provided higher yields and
greater enantiomeric excesses than their insoluble cross-
linked analogues, demonstrating the superiority of the sol-
uble polymers in this application (Table 1, entries 6–9).
Substrate 1b achieved the highest enantiomeric excesses;
up to 86%. The use of NFSI in the transfer fluorination re-
action gave identical results (Table 1, entry 10). The use
of the preformed PS-[QN-F]+ provided an excellent 85%
ee with a quantitative yield (Table 1, entry 11). We clearly
demonstrated that PS-[QN-F]+ shows comparable perfor-
mance, somewhat higher than the use of nonsupported
fluorinating agents; F-pClBzQN-BF4 gave 82% ee on the
same substrate.12 To improve the enantioselectivity, we
screened others PS-CA types (II–V). However, the results
were very disappointing since all the enantiomeric ex-
cesses recorded were in the range 1–29%.
Run
1
Reaction time (h)
Yield (%)b
Ee (%)c
80
18
18
18
18
98
96
95
95
2
82
3
81
4
81
a All reactions were run in THF/MeCN at –40 °C; NFSI was used as
the transfer fluorinating agent.
b Yields refer to purified products.
c Determined by HPLC analysis, using a Chiralcel OB column.
Upon completion of the fluorination of 1b, water was add-
ed to the reaction mixture and the amount of solvent was
reduced by evaporation. Then, diethyl ether was added to
cause the precipitation of the polymer which was isolated
by centrifugation (Figure 3). The recovered poly [O9-(4-
VB)-DHQN] gave identical stereochemical performance
over at least three cycles (Table 2).
In summary, we have designed the first polymer-bound
enantioselective electrophilic fluorinating reagents. We
have demonstrated that the soluble polymers retain the
virtues of the solution-phase approach. The facile recov-
ery of the polystyrene-bound cinchona alkaloid by solid/
liquid separation allowed performing an efficient re-
cycling without any loss of enantioselectivity. Although
unsuccessful in the fluorination reaction, the polymeric
cinchona alkaloid carriers of types II–V might be potential
organocatalysts in other reactions which are currently
under investigation.
Since it is highly desirable to recover and to reuse the
chiral carrier of fluorine, we next examine the possibility
of recycling our most successful polystyrene-bound
cinchona alkaloid; results of the recycling are summarized
in Table 2.13
Acknowledgment
The authors thank Rhodia Organique Fine, and the Ministère de la
Recherche et de la Technologie for financial support.
Synlett 2004, No. 5, 856–860 © Thieme Stuttgart · New York

860
B. Thierry et al.
LETTER
J = 7 Hz), 6.53 (m, 1 H), 5.67 (d, 1 H, J = 18 Hz), 5.18 (d, 1
H, J = 11 Hz), 3.81 (s, 3 H), 3.27 (m, 1 H), 2.77 (m, 1 H),
2.62 (m, 3 H), 1.85 (m, 1 H), 1.77 (s, 1 H), 1.48–1.18 (m, 5
H), 1.07 (m, 1 H), 0.73 (t, 3 H, J = 7 Hz). 13C NMR: d =
165.7, 158.3, 147.8, 145.1, 144.4, 142.8, 136.1, 132.1,
130.3, 129.1, 127.4, 126.6, 122.3, 119.0, 117.3, 101.8, 74.5,
59.8, 55.9, 51.1, 50.3, 37.7, 27.5, 26.5, 25.8, 23.8, 12.3. A
solution of O9-(4-vinylbenzoyl dihydroquinine (2.19 mmol)
and 2,2¢-azobisisobutyronitrile (7.0 mg, 0.04 mmol, 0.02
equiv) in dry benzene (20 mL) was refluxed under nitrogen
atmosphere. After 48 h, the solution was cooled to r.t.,
concentrated to about 5 mL and poured onto Et2O. The
precipitate was filtered, washed with EtOH and dried to
afford the Poly [O9-(4-Vinylbenzoyl) dihydroquinine]:
Yield = 60%. 1H NMR: d = 8.57 (m, 1 H), 7.77 (m, 3 H),
7.31 (m, 1 H), 7.13 (m, 2 H), 6.59 (m, 2 H), 3.76 (s, 3 H),
3.17–2.88 (m, 4 H), 2.48 (m, 1 H), 2.16 (m, 1 H), 1.52–1.01
(m, 11 H), 0.58 (m, 3 H). 13C NMR: d = 167.0, 158.3, 147.8,
146.9, 143.2, 132.2, 128.3, 128.5, 128.2, 127.1, 122.6,
122.5, 118.7, 101.7, 74.9, 59.5, 59.4, 58.6, 58.2, 43.2, 37.6,
29.1, 28.1, 28.0, 25.7, 22.7, 12.4. [a]D23 +197.2 (c 1.21,
CHCl3). Anal. Calcd for C29H32N2O3: C, 76.03; H, 7.06; N,
6.14; O, 10.51. Found: C, 76.33; H, 7.33; N, 5.87; O, 10.47.
(8) (a) Hermann, K.; Wynberg, H. Helv. Chim. Acta 1977, 60,
2208. (b) Aglietto, M.; Chiellini, E.; D’Antone, S.; Ruggeri,
G.; Solaro, R. Pure Appl. Chem. 1988, 60, 415.
References
(1) (a) Muñiz, K. Angew. Chem. Int. Ed. 2001, 40, 1653.
(b) Muñiz, K. Organic Synthesis Highlights, Vol. 5;
Schmalz, H.-G.; Wirth, T., Eds.; Wiley-VCH: Weinheim,
2003, 201–209.
(2) (a) Cahard, D.; Audouard, C.; Plaquevent, J. C.; Roques, N.
Org. Lett. 2000, 2, 3699. (b) Cahard, D.; Audouard, C.;
Plaquevent, J. C.; Toupet, L.; Roques, N. Tetrahedron Lett.
2001, 42, 1867. (c) Mohar, B.; Baudoux, J.; Plaquevent, J.
C.; Cahard, D. Angew. Chem. Int. Ed. 2001, 40, 4214.
(d) Baudequin, C.; Plaquevent, J. C.; Audouard, C.; Cahard,
D. Green Chem. 2002, 4, 584. (e) Zoute, L.; Audouard, C.;
Plaquevent, J. C.; Cahard, D. Org. Biomol. Chem. 2003, 1,
1833.
(3) For a similar approach by means of [N-F]+ reagents, see:
(a) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc.
2000, 122, 10728. (b) Shibata, N.; Suzuki, E.; Asahi, T.;
Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001. (c) Shibata,
N.; Ishimaru, T.; Suzuki, E.; Kirk, K. L. J. Org. Chem. 2003,
68, 2494. (d) By means of transition metal catalysts:
Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 2000, 39,
4359. (e) See also: Hamashima, Y.; Yagi, K.; Takano, H.;
Tamas, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
14530. (f) See further: Hamashima, Y.; Takano, H.; Hotta,
D.; Sodeoka, M. Org. Lett. 2003, 5, 3225. (g) By phase-
transfer catalysis: Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4,
545. (h) By fluorodesilylation: Greedy, B.; Paris, J. M.;
Vidal, T.; Gouverneur, V. Angew. Chem. Int. Ed. 2003, 42,
3291.
(c) Dannelli, T.; Annunziata, R.; Benaglia, M.; Cinquini, M.;
Cozzi, F.; Tocco, G. Tetrahedron: Asymmetry 2003, 14, 461.
(9) Heidelberger, M.; Jacobs, W. A. J. Am. Chem. Soc. 1919, 41,
817.
(4) (a) Thierry, B.; Plaquevent, J. C.; Cahard, D. Tetrahedron:
Asymmetry 2001, 12, 983. (b) Thierry, B.; Perrard, T.;
Audouard, C.; Plaquevent, J. C.; Cahard, D. Synthesis 2001,
11, 1742. (c) Thierry, B.; Plaquevent, J. C.; Cahard, D.
Tetrahedron: Asymmetry 2003, 14, 1671.
(5) (a) Banks, R. E.; Tsiliopoulos, E. J. Fluorine Chem. 1986,
34, 281. (b) Umemoto, T.; Nagayoshi, M.; Adachi, K.;
Tomizawa, G. J. Org. Chem. 1998, 63, 3379.
(10) Braje, W.; Frackenpohl, J.; Langer, P.; Hoffmann, H. M. R.
Tetrahedron 1998, 54, 3495.
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(13) Typical Experimental Procedure: To the poly [O9-(4-VB)-
DHQN] (0.25 mmol, 114.15 mg) in MeCN (1 mL) was
added under nitrogen atmosphere N-
(6) Song, C. E.; Roh, E. J.; Lee, S.-g.; Kim, I. O. Tetrahedron:
Asymmetry 1995, 6, 2687.
(7) Experimental Procedure for the Preparation of Poly [O9-
(4-Vinylbenzoyl) Dihydroquinine] (PS-CA Type I
Soluble): A solution of 4-vinylbenzoic acid (500 mg, 3.38
mmol, 1 equiv) in thionyl chloride (4.92 mL, 67.6 mmol, 20
equiv) was refluxed for 1 h. After cooling the mixture to r.t.,
the excess of thionyl chloride was removed by concentration
under reduced pressure to afford 4-vinylbenzoyl chloride
(562.5 mg, 3.38 mmol, brown solid). To this solid was
added, under nitrogen at r.t., 20 mL of freshly distilled
CH2Cl2, the dihydroquinine (3.38 mmol, 1.10 g, 1 equiv) and
Et3N (470 mL, 3.38 mmol, 1 equiv). The mixture was then
stirred for 15 h at r.t. Then, the reaction was quenched with
H2O, and the organic layer was washed with 1 M Na2CO3
solution, brine, dried and concentrated under reduced
pressure. The solid was then purified by flash
fluorobenzenesulfonimide (74.4 mg, 0.224 mmol, 1 equiv),
and the mixture was stirred for 1 h at r.t. Then, the solution
containing the N-fluoro-bound reagent was added to a
solution of trimethylsilyl enol ether 1b (0.25 mmol, 73.7 mg,
1 equiv) in THF (1 mL) at –40 °C within 2 h. The solution
was stirred for 16 h, then H2O was added (9 mM, 2 equiv).
The solution was concentrated under reduced pressure to a
saturated solution and Et2O was added (10 mL) to cause the
heterogenization. The polymer was recovered by
centrifugation and extraction of the supernatant liquid. A
second similar purification procedure was conducted after
dissolution of the polymer in the minimun amount of
CH2Cl2. The filtrates were then concentrated under reduced
pressure and purified by flash chromatography
(cyclohexane–Et2O, 9:1), leading to the fluorinated ketone
2b (see ref. 2d for spectroscopic data). The enantiomeric
excess was then determined by HPLC using Chiracel OB
column.
chromatography (acetone–EtOAc, 4:1) to afford a white
solid. O9-(4-Vinylbenzoyl) Dihydroquinine: Yield = 59%.
1H NMR: d = 8.59 (d, 1 H, J = 4.5 Hz), 7.90 (m, 3 H), 7.40
(s, 1 H), 7.23 (m, 2 H), 7.20 (d, 2 H, J = 2 Hz), 6.65 (d, 1 H,
Synlett 2004, No. 5, 856–860 © Thieme Stuttgart · New York