Enantioselective electrophilic fluorinations: A study of the fluorine-transfer from achiral N-F reagents to cinchona alkaloids

Article abstract of DOI:10.1016/S0022-1139(03)00085-X

A transfer fluorination on cinchona alkaloids with the aid of achiral N-F fluorine-transfer reagents is described. Ten commercially available reagents were evaluated. Selectfluors 9 and 10, Accufluor 11,N-fluorobenzenesulfonimide (NFSi) 13, and N-fluoro-2,6-dichloropyridinium tetrafluoroborate 17 are effective fluorine-transfer reagents. The N-fluoroammonium salts of cinchona alkaloids thus prepared were employed in the construction of stereogenic fluorinated carbon centers with enantioselectivity as high as 85%. We also demonstrated that ionic liquids are effective green solvents for the development of this methodology.

Full text of DOI:10.1016/S0022-1139(03)00085-X

Journal of Fluorine Chemistry 122 (2003) 189–193
Enantioselective electrophilic fluorination: a study of the
fluorine-transfer from achiral N–F reagents to cinchona alkaloids
Christine Baudequin, Jean-Franc¸ois Loubassou, Jean-Christophe Plaquevent,
Dominique Cahard*
UMR 6014 de l’IRCOF (Institut de Recherche en Chimie Organique Fine), Universite de Rouen, Rue Tesniere, F-76821
´
`
Mont Saint Aignan Cedex, France
Received 23 January 2003; received in revised form 11 March 2003; accepted 11 March 2003
Abstract
A transfer fluorination on cinchona alkaloids with the aid of achiral N–F fluorine-transfer reagents is described. Ten commercially available
reagents were evaluated. SelectfluorsTM 9 and 10, AccufluorTM 11, N-fluorobenzenesulfonimide (NFSi) 13, and N-fluoro-2,6-dichloropyr-
idinium tetrafluoroborate 17 are effective fluorine-transfer reagents. The N-fluoroammonium salts of cinchona alkaloids thus prepared were
employed in the construction of stereogenic fluorinated carbon centers with enantioselectivity as high as 85%. We also demonstrated that ionic
liquids are effective ‘‘green’’ solvents for the development of this methodology.
# 2003 Published by Elsevier Science B.V.
Keywords: N-Fluoro compounds; Transfer fluorination; Enantioselective electrophilic fluorination; Ionic liquids
1. Introduction
Chiral [N–F]þ fluorinating agents have thus been high-
lighted as a class of reagents possessing distinctive stability,
reactivity and enantioselectivity, characteristics which com-
pare favourably with the previous class of neutral N–F
reagents 1–7.
Commercially available achiral electrophilic fluorinating
agents of the N–F class have allowed the development of
new methodology for the synthesis of fluorinated molecules
[1]. Achiral N–F reagents were used in enantioselective
fluorination of b-ketoesters mediated by chiral phase-trans-
fer catalysts [2] or metal catalysts [3,4]. Chiral N–F
reagents, described by us and others, have emerged for
the asymmetric construction of fluorinated carbon centers
[5]. The synthesis of reagents 1–7 requires several steps, the
ultimate step being the N–F bond formation, by means of
either elemental fluorine F2 or FClO3 (Fig. 1) [6–11]. In
order to overcome the disadvantages of using elemental
fluorine, we proceeded by transfer fluorination. Naturally
occurring cinchona alkaloids were selected as the source of
chirality to prepare in a single step the new class of [N–F]þ
reagents 8 (Fig. 1). In this way we demonstrated that N-
fluoroammonium salts of cinchona alkaloids 8, prepared by
transfer fluorination with SelectfluorTM are efficient enan-
tioselective electrophilic fluorinating agents [12–15].
In the achiral series, the pioneering work on transfer
fluorination not requiring the use of elemental fluorine
was reported by Banks and co-workers in the preparation
of N-fluoroquinuclidinium salts [16]. Taylor and Meier
produced N-fluoro sulfonamides by transfer fluorination
with N-fluorobenzenesulfonimide (NFSi) from the corres-
ponding potassium salt of sulfonamides while fluorine-
transfer starting from the neutral sulfonamides failed [17].
Singh and Shreeve also reported an application of Select-
fluorTM in electrophilic fluorination of primary and second-
ary amines [18]. In this paper we describe a study of 10
fluorine-transfer reagents for the preparation of chiral
N-fluoroammonium salts of cinchona alkaloids and their
application in enantioselective electrophilic fluorination.
2. Results and discussion
In this investigation, we explored the commercially avail-
able fluorine-transfer reagents. Three of these electrophilic
fluorinating agents are based on triethylenediamine salts
* Corresponding author. Tel.: þ33-2-35-52-24-66/63;
fax: þ33-2-35-52-29-71.
E-mail address: dominique.cahard@univ-rouen.fr (D. Cahard).
0022-1139/$ – see front matter # 2003 Published by Elsevier Science B.V.
doi:10.1016/S0022-1139(03)00085-X

190
C. Baudequin et al. / Journal of Fluorine Chemistry 122 (2003) 189–193
Fig. 1. Chiral electrophilic fluorinating agents.
(F-TEDA 9–11), 12 is derived from quinuclidine, 13 is a
sulfonimide, 14 is a sulfonamide and compounds 15–18 are
a series of agents consisting of a pyridinium ring and its
counter anions (Fig. 2).
less powerful fluorine-transfer reagent [16] did not lead to
F-pClBzQN-BF4. A comparison between N-fluorobenzene-
sulfonimide 13 and sulfonamide 14 revealed that only
NFSi was capable of transfer fluorination, demonstrating
the necessity of two strong electron withdrawing groups in
the sulfonimide. Moreover, NFSi is a cheaper alternative to
SelectfluorTM. Within the series of N-fluoropyridinium salts,
the fluorinating ability is determined by substituents on the
pyridine ring. Methyl groups decrease the ability while
chlorine atoms have the opposite effect thus making the
agents 17 suitable for transfer fluorination. The relationship
between variable fluorinating power and 19F NMR chemical
shifts of N-fluoropyridinium salts was discussed by Ume-
moto et al. [19].
The reaction was performed either in acetonitrile or in an
ionic liquid such as 1-hexyl-3-methylimidazolium hexa-
fluorophosphate [hmim][PF6]. The transfer fluorination
from reagents 9–18 to the tertiary nitrogen site in p-chloro-
benzoylquinine (pClBzQN) was studied and followed by 19
F
and 1H NMR analysis (Scheme 1). The reaction was found
to be complete within 30 min with fluorine-transfer reagents
9–11, 13 and 17 (Table 1). Other reagents tried lacked
sufficient fluorinating power to make possible an efficient
fluorine-transfer.
In our original study, only SelectfluorTM tetrafluoroborate
9 was explored [12], we now validate the series of F-TEDA
salts 10 and 11 as efficient fluorine-transfer reagents. The N-
fluoroquinuclidinium salt 12 which was described as a
Particularly interesting among the five effective fluorine-
transfer reagents is the N-fluoro-2,6-dichloropyridinium
tetrafluoroborate 17 which possesses a higher fluorine con-
tent (3.94 mmol/g) than other competitive fluorine-transfer
Fig. 2. Achiral electrophilic fluorinating agents.

C. Baudequin et al. / Journal of Fluorine Chemistry 122 (2003) 189–193
191
Scheme 1.
Table 1
Study of the transfer fluorination on p-chlorobenzoylquinine (pClBzQN)
Achiral N–F reagent
19F NMR (d in ppm)
Chiral [N–F]þ reagent
19F NMR (d in ppm)
9
10
11
12
13
14
15
16
17
18
46.2; À149.5; À149.6
46.1; À78.1
F-pClBzQN-BF4
F-pClBzQN-OTf
F-pClBzQN-BF4
No reaction
43.6; À149.9; À150.0
43.7; À78.1
42.2; À149.8; À149.9
57.8; À150.1
43.6; À149.9; À150.0
À38.6
F-pClBzQN-N(SO2Ph)2
No reaction
No reaction
43.7
À37.6
47.4; À78.1
17.2; À149.7; À150.4
31.4; À149.2; À150.2
43.7; 35.2; À148.8; À149.0; À150.1
No reaction
F-pClBzQN-BF4/2,6-dichloropyridine
No reaction
43.6; À149.9; À150.0
reagents (2.82 mmol/g for 9, 2.09 mmol/g for 10, 3.11
mmol/g for 11, and 3.17 mmol/g for 13) and is therefore
more cost effective.
19a and 19b (Scheme 2). This step was performed in
acetonitrile, however the choice of solvent was broadened
to ionic liquids [20]. Results are reported in Table 2.
With fluorine-transfer reagents which are not effective,
we attempted the transfer fluorination on a mixture cinchona
alkaloid, silyl enol ether and N–F reagent, but the fluorinated
product was not obtained.
As summarised in Table 2, the substrates were fluorinated
in excellent yields with good enantioselectivities. Ee’s are
similar whatever the chiral [N–F]þ salt and whatever their
synthetic route since the tetrafluoroborate salt prepared from
Some fluorine-transfer reagents used in the preparation
of F-pClBzQN salts lead to by-products. For instance,
SelectfluorsTM 9, 10 and AccufluorTM 11 produce TEDA
monoquaternary ammonium salts. N-Fluoro-2,6-dichloro-
pyridinium tetrafluoroborate 17 produces an equimolecular
amount of 2,6-dichloropyridine while NFSi 13 leads to
nothing else other than the expected salt F-pClBzQN-
N(SO2Ph)2.
Having prepared these F-pClBzQN salts bearing either a
BF4À, a OTfÀ or a (PhSO2)2NÀ counter anion, we examined
their behaviour in enantioselective electrophilic fluorination
on trimethylsilyl enol ether of methyl and benzyl indanone
Table 2
Enantioselective electrophilic fluorination of silyl enol ethers
Fluorine- Chiral [N–F]þ
Substratea Product Yield Ee
transfer
reagent
agent
(%)
(%)b
9
13
17
F-pClBzQN-BF4 19a
F-pClBzQN-N(SO2Ph)2 19a
20a
20a
20a
90
91
97
64
62
67
F-pClBzQN-BF4
19a
9
10
11
13
17
F-pClBzQN-BF4
F-pClBzQN-OTf
F-pClBzQN-BF4
19b
19b
19b
20b
20b
20b
20b
20b
98
88
92
94
97
84
81
82
85
81
F-pClBzQN-N(SO2Ph)2 19b
F-pClBzQN-BF4 19b
a The enantioselective fluorination was run at À40 8C in acetonitrile.
Scheme 2.
b Determined by HPLC analysis.

192
C. Baudequin et al. / Journal of Fluorine Chemistry 122 (2003) 189–193
SelectfluorTM 9, AccufluorTM 11 or N-fluoro-2,6-dichloro-
pyridinium tetrafluoroborate 17 gave ee’s ranging from 81 to
84%.
Reactions performed in 1-hexyl-3-methylimidazolium
hexafluorophosphate [hmim][PF6] were stirred for 2 h at
20 8C and the mixture product and solvent directly used in
the enantioselective fluorination of silyl enol ethers 19a and
19b.
3. Conclusion
4.2. Enantioselective fluorination: preparation of (R)-2-
benzyl-2-fluoro-indan-1-one
The fluorine-transfer long associated with hazardous ele-
mental fluorine can now be achieved with a range of safer N–
F reagents. We have demonstrated that transfer fluorination
can be performed not only with SelectfluorsTM 9 and 10 but
also by means of various N–F fluorine-transfer reagents
(AccufluorTM 11, NFSi 13 and N-fluoro-2,6-dichloropyridi-
nium tetrafluoroborate 17). Other reagents possessing lower
fluorinating power (12, 14–16 and 18) failed to transfer the
fluorine atom to the cinchona alkaloids. The chiral N-fluor-
oammonium salts of cinchona alkaloids, thus prepared, are
efficient enantioselective electrophilic fluorinating agents.
N-Fluorobenzenesulfonimide (0.2 mmol, 63.1 mg) and p-
chlorobenzoylquinine (0.2 mmol, 92.6 mg) were placed in a
10 ml round-bottomed flask containing dry acetonitrile
(2 ml) and the mixture was stirred for 1 h at room tempera-
ture under nitrogen atmosphere. The reaction mixture was
then cooled to À40 8C and (2-benzyl-3H-inden-1-yloxy)-
trimethyl-silane (0.185 mmol, 54.5 mg) in dry acetonitrile
(3 ml) was added dropwise. The reaction was stirred for a
further 12 h at À40 8C, which was followed by quenching
with water (5 ml). The fluorinated product was extracted
with ethylacetate (3ꢀ 10 ml). The organic layers were
combined and washed with 5% aqueous HCl (20 ml), satu-
rated aqueous NaHCO3 (2ꢀ 20 ml), and brine (2ꢀ 20 ml).
The organic phase was dried over MgSO4, and filtered.
Concentration in vacuo and purification by chromatography
(silica gel, heptane/diethyl ether 20%) afforded (R)-2-ben-
zyl-2-fluoro-indan-1-one (94% yield, 85% ee determined by
HPLC analysis using a Chiralcel OB-column (10% iPrOH-
heptane, 1 ml/min, l ¼ 254 nm, retention time: R (major)
9.5 min, S (minor) 13.4 min). Spectral data are in agreement
with literature values [20].
4. Experimental
All commercially available reagents were used without
1
further purification. H, 13C and 19F NMR spectra were
recorded on a Bruker Avance 300 spectrometer. Chemical
shifts are reported in ppm using CFCl3 as internal standard in
CD3CN solvent.
4.1. Transfer fluorination: preparation of N-fluoro-p-
chlorobenzoylquininium benzenesulfonimidate
F-pClBzQN-N(SO2Ph)2
N-Fluorobenzenesulfonimide (1.58 g, 5 mmol) in aceto-
nitrile (10 ml) was added slowly to an equimolar amount of
p-chlorobenzoylquinine (2.31 g, 5 mmol) in acetonitrile
(10 ml). The reaction was completed within 30 min. Acet-
onitrile was removed under reduced pressure and the
resulting white solid was dried in vacuo to afford F-
Acknowledgements
This investigation has been performed with the support of
Rhodia Organique. We are grateful to Mr. J. Hine (Ugarit
Chimie) for a generous gift of N-fluoro-2,6-dichloropyridi-
nium tetrafluoroborate 17.
1
pClBzQN-N(SO2Ph)2 (100% yield). H NMR (300 MHz)
d 9.09 (d, J ¼ 5:6 Hz, 1H), 8.40–8.00 (m, 8H), 7.84 (dd,
J ¼ 9:1, 2.3 Hz, 1H), 7.70–7.30 (m, 10H), 5.90 (m, 1H),
5.25 (m, 1H), 5.22 (d, J ¼ 16:9 Hz, 1H), 5.10 (d,
J ¼ 10:5 Hz, 1H), 4.87 (m, 2H), 4.62 (m, 1H), 4.49
(m, 1H), 4.10 (s, 3H), 3.58 (m, 1H), 3.31 (m, 1H), 2.87
(m, 1H), 2.67 (m, 2H), 2.44 (m, 1H); 13C NMR (75 MHz) d
164.9, 162.1, 149.6, 144.1, 141.6, 138.4, 137.2, 136.9,
133.8, 133.2, 130.6, 129.1, 128.7, 128.4, 128.3, 126.4,
126.1, 121.1, 119.3, 102.8, 73.5 (d, J ¼ 8:7 Hz), 69.4 (d,
J ¼ 8:7 Hz), 68.1 (d, J ¼ 5:1 Hz), 59.7 (d, J ¼ 8:7 Hz),
57.2, 44.2, 28.4, 28.3, 26.0; 19F NMR (282 MHz) d 43.7
(1F) ppm; MS (FABþ): 481 (cation).
The procedure was similar when SelectfluorTM 9, Accu-
fluorTM 11 or N-fluoro-2,6-dichloropyridinium tetrafluoro-
borate 17 were used for the transfer fluorination leading to
F-pClBzQN-BF4, and when SelectfluorTM 10 was used to
prepare F-pClBzQN-OTf.
References
[1] G. Sankar Lal, G.P. Pez, R.G. Syvret, Chem. Rev. 96 (1996)
1737.
[2] D.Y. Kim, E.J. Park, Org. Lett. 4 (2002) 545.
[3] L. Hintermann, A. Togni, Angew. Chem. Int. Ed. 39 (2000) 4359.
[4] Y. Hamashima, K. Yagi, H. Takano, L. Tamas, M. Sodeoka, J. Am.
Chem. Soc. 124 (2002) 14530.
[5] K. Muniz, Angew. Chem. Int. Ed. 40 (2001) 1653.
[6] E. Differding, R.W. Lang, Tetrahedron Lett. 29 (1988) 6087.
[7] F.A. Davis, P. Zhou, C.K. Murphy, Tetrahedron Lett. 34 (1993)
3971.
[8] F.A. Davis, P. Zhou, C.K. Murphy, G. Sundarababu, H. Qi, R.M.
Przeslawski, B.-C. Chen, P.J. Carroll, J. Org. Chem. 63 (1998)
2273.
[9] Y. Takeuchi, T. Koizumi, T. Suzuki, A. Satoh, K. Konno, Japanese
patent JP 09,249,653, Chem. Abstr. 127 (1997) 262674j.
[10] Y. Takeuchi, T. Suzuki, A. Satoh, T. Shiragami, N. Shibata, J. Org.
Chem. 64 (1999) 5708.

C. Baudequin et al. / Journal of Fluorine Chemistry 122 (2003) 189–193
193
[11] Y. Takeuchi, A. Satoh, T. Suzuki, A. Kameda, M. Dohrin, T. Satoh,
T. Koizumi, K.L. Kirk, Chem. Pharm. Bull. 45 (1997) 1085.
[12] D. Cahard, C. Audouard, J.C. Plaquevent, N. Roques, Org. Lett. 23
(2000) 3699.
[15] N. Shibata, E. Suzuki, Y. Takeuchi, J. Am. Chem. Soc. 122 (2000)
10728.
[16] M. Abdul-Ghani, R.E. Banks, M.K. Besheesh, I. Sharif, R.G. Syvret,
J. Fluorine Chem. 73 (1995) 255.
[13] D. Cahard, C. Audouard, J.C. Plaquevent, L. Toupet, N. Roques,
Tetrahedron Lett. 42 (2001) 1867.
[17] D.M. Taylor, G.P. Meier, Tetrahedron Lett. 41 (2000) 3291.
[18] R.P. Singh, J.M. Shreeve, Chem. Commun. (2001) 1196.
[19] T. Umemoto, K. Harasawa, G. Tomizawa, J. Fluorine Chem. 53
(1991) 369.
[14] B. Mohar, J. Baudoux, J.C. Plaquevent, D. Cahard, Angew. Chem.
Int. Ed. 40 (2001) 4214;
B. Mohar, J. Baudoux, J.C. Plaquevent, D. Cahard, Angew. Chem.
113 (2001) 4339.
[20] C. Baudequin, J.C. Plaquevent, C. Audouard, D. Cahard, Green
Chem. 4 (2002) 584.