A synthesis of (S)-α-(fluorodiphenylmethyl)alkylamines by HF-pyridine treatment of 4-alkyl-5,5-diphenyl-oxazolidinones

Article abstract of DOI:10.1016/S0957-4166(00)00142-7

Treatment of enantiomerically pure (S)-4-alkyl-5,5-diphenyl-oxazolidinones, themselves derived from appropriate amino acids, with HF-pyridine (Olah's reagent) generated a range of (S)-α-(fluorodiphenylmethyl)alkylamines. These compounds represent a novel range of fluorinated chiral amines. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00142-7

Tetrahedron: Asymmetry 11 (2000) 2033±2036
A synthesis of (S)-a-(¯uorodiphenylmethyl)alkylamines by
HF±pyridine treatment of 4-alkyl-5,5-diphenyl-oxazolidinones
David O'Hagan,* Frederique Royer and Mustafa Tavasliy
Department of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, UK
Received 28 March 2000; accepted 6 April 2000
Abstract
Treatment of enantiomerically pure (S)-4-alkyl-5,5-diphenyl-oxazolidinones, themselves derived from
appropriate amino acids, with HF±pyridine (Olah's reagent) generated a range of (S)-a-(¯uoro-
diphenylmethyl)alkylamines. These compounds represent a novel range of ¯uorinated chiral amines.
# 2000 Elsevier Science Ltd. All rights reserved.
We recently described the synthesis of a range of novel (S)-a-(diphenylmethyl)alkylamines 1a±e
from a variety of (S)-amino acids1,2 as shown in Scheme 1. The key step in the route is the ®nal
one where the oxazolidinones 2a±e, when treated under standard hydrogenation conditions,
delivered amines 1a±e, as a consequence of O-benzyl cleavage and subsequent decarboxylation.
Scheme 1. Reagents: (i) PhMgBr (5 equiv.), Et2O, 40±50%; (ii) triphosgene, Et3N, 80±90%; (iii) H2, Pd/C, (3 atm),
MeOH/AcOH, 70%
We now report that treatment of the oxazolidinones 2a±d3 and 44 with HF±pyridine (Olah's
reagent)5,6 results in a decarboxylative hydro¯uorination reaction to generate the corresponding
¯uorinated amines 3a±d and 5 (Table 1). The general route to the ¯uorinated amines is outlined in
Scheme 2.
* Corresponding author. E-mail: david.O'hagan@durham.ac.uk
y
Presently at: Afyon Kocatepe University, Usak Faculty of Education, Chemistry Teaching, Usak, Turkey.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00142-7

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D. O'Hagan et al. / Tetrahedron: Asymmetry 11 (2000) 2033±2036
Table 1
Physical properties and spectroscopic data for the (S)-¯uorinated amines 3a±d and 5
Scheme 2. (i) HF±pyridine

D. O'Hagan et al. / Tetrahedron: Asymmetry 11 (2000) 2033±2036
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These reactions were typically carried out over 30 h. Shorter periods of time resulted in
unreacted oxazolidinones. If the reactions are left to stir for extended periods the products
become susceptible to elimination. For example, in the case of oxazolidinone 2b extended treat-
ment generated ketone 77 which was isolated after 4 days stirring at ambient temperature. This
presumably arose after HF elimination from 3b to generate the intermediate enamine 6. Hydro-
lysis on work-up would then a€ord ketone 7 as illustrated in Scheme 3.
Scheme 3. (i) HF±pyridine, 4 days, aq. work-up
It was important to determine if the ¯uorinated amines 3a±d and 5 were enantiomerically pure
and that no racemisation had occurred during the HF±pyridine reaction. To this end ¯uorinated
amine 3a was prepared as a racemate and was then treated with (S)-a-methoxyphenylacetic acid 8
as a chiral solvating agent to generate the corresponding salt in solution. Fig. 1 illustrates a
comparison of the selected regions of the 1H NMR spectra of the diastereoisomeric salts generated
from (S)-a-methoxyphenylacetic acid 8 and either (RS)-3a or (S)-3d. It is clear that a single dia-
stereoisomeric salt is generated in the latter case and within the level of detection there is no
1
indication of any racemisation. The H NMR spectrum of the analogous salt of amine 3d was
also judged to be enantiomerically pure. Thus, we are con®dent that the ¯uorination reactions
outlined in Scheme 2 are not susceptible to racemisation.
Figure 1. Selected regions of the 1H NMR spectra of the salts (S)-a-methoxyphenylacetic acid 8 and (RS)-3a or (S)-3a
These compounds can be made in both enantiomeric series starting from the appropriate
amino acids and they o€er a range of new ¯uorinated chiral amines for applications in asymmetric
synthesis and as components for combinatorial libraries.

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D. O'Hagan et al. / Tetrahedron: Asymmetry 11 (2000) 2033±2036
Experimental. Preparation of 3a±d and 5: A suspension of the oxazolidinones (3±5 mM) 2a±d
and 41,2 in 70% HF±pyridine (10±15 ml) was stirred for 31 h at ambient temperature in a te¯on
vessel (bottle) and then the reaction mixture was cooled to 0ꢀC and quenched with aqueous KOH
(7 M) until the solution was basic (pH 13±14). The organics were then extracted into Et2O (four
times), dried over MgSO4 and concentrated under reduced pressure. Conc. HCl solution (1 ml)
was added and the resultant suspension was dissolved in water and the aqueous layer washed
with Et2O (20 mlÂ3). The residual aqueous solution was then made basic (pH 13±14) by addition
of NaOH pellets, and the amines 3a±d and 5 were extracted into Et2O (20 mlÂ3). The compounds
could be further puri®ed by chromatography over silica gel.
Acknowledgements
We thank the Afyon Kocatepe University, Turkey for a YOK Studentship (M.T.) and also the
EPSRC Mass Spectroscopy Service at the University of Wales, Swansea, for high resolution mass
spectroscopy.
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