Observations on the α-fluorination of α-phenylsulfanyl esters using difluoroiodotoluene

Article abstract of DOI:10.1016/S0040-4039(00)00616-X

α-Phenylsulfanyl esters are fluorinated in the α-position when treated with the hypervalent iodine reagent difluoroiodotoluene. Excess reagent can lead to α-fluoro sulfoxides, which can then undergo thermal syn elimination to produce vinyl fluorides. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00616-X

Tetrahedron Letters 41 (2000) 4463±4466
Observations on the a-¯uorination of a-phenylsulfanyl esters
using di¯uoroiodotoluene
Michael F. Greaney and William B. Motherwell*
Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK
Received 24 March 2000; accepted 10 April 2000
Abstract
a-Phenylsulfanyl esters are ¯uorinated in the a-position when treated with the hypervalent iodine reagent
di¯uoroiodotoluene. Excess reagent can lead to a-¯uoro sulfoxides, which can then undergo thermal syn
elimination to produce vinyl ¯uorides. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: halogenation; hypervalent elements; ¯uorine and compounds.
The a-¯uorination of sulfoxides or sul®des through the ¯uoro-Pummerer reaction is known as
1
an e€ective strategy for the synthesis of a-¯uoro sul®des and a number of reagents have been
shown to e€ect this transformation; notably DAST, xenon di¯uoride, the combination of tetra-
2
3
4
5
butylammonium dihydrogentri¯uoride and 1,3-dibromo-5,5-dimethylhydantoin, N±F reagents
6
and electrochemical oxidation in the presence of triethylamine±HF complexes. The a-¯uoro
7
19
sul®des synthesised in this manner have attracted much attention as enzyme inhibitors, as
8
F
9
NMR structural probes in proteins and as synthons for vinyl ¯uorides.
We have previously demonstrated that hypervalent di¯uoroiodoarenes have a particular anity
1
0
for sulfur-containing functional groups and exploited this in the ¯uorination of cephalosporins,
dithioketals,11 arylthioglycosides and xanthate esters. As part of our ongoing interest in the
use of di¯uoroiodoarenes as mild and selective ¯uorinating agents, we therefore elected to investigate
the behaviour of a series of a-phenylsulfanyl esters in the ¯uoro-Pummerer reaction.
12
13
From a mechanistic standpoint, we envisaged, as outlined in Scheme 1, that the reaction
pathway would involve an initial nucleophilic attack by the sulfur atom at the electrophilic iodine
centre to form an iodosulfonium salt 1. The enhanced acidity of the protons adjacent to the ester
carbonyl group would then encourage the liberated ¯uoride anion to function as a base with
resultant formation of the classical Pummerer intermediate 2. Subsequent trapping of cation 2
with nucleophilic ¯uoride anion would then yield the product a-¯uoro sul®de 3.
To the best of our knowledge there has been only one isolated report concerning the ¯uoro-
Pummerer reaction of hypervalent di¯uoroiodoarenes with sul®des. Fuchigami found that ethyl
14
*
Corresponding author. Tel: 0171 380 7533; fax: 0171380 7524; e-mail: w.b.motherwell@ucl.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00616-X

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464
Scheme 1.
(arylsulfanyl)acetates could be ¯uorinated using a solution of electrogenerated p-methoxy-
iodobenzene di¯uoride in the presence of an excess of Et N 3HF. However, reactions were
.
3
incomplete, necessitating two equivalents of ¯uorinating agent and the product ¯uorides were
isolated in moderate yields (<50%). Our results using di¯uoroiodotoluene (DFIT) in the
15
16
¯uoro-Pummerer reaction of some a-phenylsulfanylacetates are shown in Table 1.
Table 1
Synthesis of a-¯uoro sul®des
a

4
465
Examination of the results (entries 1±4) shows that the expected a-¯uoro sul®des were formed
cleanly and in good overall yields upon treatment with only one single equivalent of DFIT in
DCM. It was also of interest to note (entries 2 and 3) that capture of the Pummerer intermediate
by ¯uoride anion was faster than cyclisation to give a g-lactone by p-participation. Most
signi®cantly, a second ¯uorination was also possible with the a,a-di¯uorosul®de 6 (entry 5) being
formed on treatment of the ethyl derivative 4e with two equivalents of DFIT. Two sequential
¯
¯
uoro-Pummerer reactions have been found to be problematic with the widely-employed
uorinating agent DAST. The ®nding that addition of a third equivalent (entry 6) led to the
2b
a,a-di¯uorosulfoxide 7 was also worthy of note and suggested possible applications to the synthesis
of vinyl ¯uorides. Accordingly, we found that treatment of the syn-lactone 8 with two equivalents
of DFIT gave a 41% yield of the a-¯uoro sulfoxide. The ¯uorine atom was introduced exclusively
syn to the 5-phenyl substituent17 and the sulfoxide was formed as a 5:2 mixture of diastereo-
isomers (Scheme 2). Subsequent thermal elimination of benzenesulfenic acid then furnished the
2
-¯uoro-2-buten-4-olide 10. It was later found that isolation of the intermediate a-¯uoro sulfoxide
was unnecessary. Thus, treatment of 11 with DFIT followed by aqueous work-up and thermolysis
of the crude product in re¯uxing toluene gave the 2-¯uoro-2-buten-4-olide 12 directly in 43%
yield.
Scheme 2.
Previous syntheses of these ¯uorinated synthons have required an E-selective Wittig±Horner
18
reaction of an aldehyde with a ¯uorophosphonate followed by hydrolytic ring-closure. Sulfanylation
of an appropriate lactone followed by DFIT treatment, hydrolysis and syn elimination thus
represents a versatile alternative.
In summary, the readily prepared, crystalline and organic-soluble ¯uorinating agent, di¯uoro-
iodotoluene, o€ers an exceptionally mild method for the a-¯uorination of sul®des, without the
necessity for any further additions of external ¯uoride sources or catalysts. Furthermore, the
novel sequential ¯uorination/oxidation character of the reagent o€ers a potentially general
approach to vinyl ¯uorides.
Acknowledgements
We thank the EPSRC for the award of a studentship to M.F.G.

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466
References
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5. Prepared by the trans-halogenation of dichloroiodotoluene with aq. hydro¯uoric acid and mercuric oxide in
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449 and references cited therein.
1
1
1
1
1
1
1
6. Typical procedure: A solution of prenyl (phenylsulfanyl)acetate 4c (1.1 mmol) in DCM (6 mL) was treated with
ꢀ
DFIT (1.2mmol) under nitrogen at 0 C in a polypropylene ¯ask. The reaction mixture was stirred for 2 h then
quenched with water. The mixture was extracted with DCM, the combined extracts dried over MgSO
4
and
concentrated in vacuo. Flash chromatography (SiO
2
) eluting with petroleum ether/diethyl ether 90/10 gave prenyl
^
max
ꢁ
1
1
(
NMR (300 MHz, CDCl
Hz), 7.33±7.57 (5H, m); F NMR (470 MHz, CDCl
C H FO S: 255.0855. Found: 255.0861.
2-¯uoro-2-phenylsulfanyl)acetate 5c (178mg, 64%) as a colourless oil. IR (thin ®lm/cm ): ꢀ
1752s (CˆO); H
2
3
): ꢁ 1.68 (3H, s), 1.75 (3H, s) 4.58 (2H, d J 8 Hz), 5.21±5.25 (1H, m), 6.07 (1H, d JHF 52
1
9
2
3
): ꢁ ^158.6 (d, JFH 52 Hz); HRMS (FAB) calcd. for
1
3
15
2
1
1
7. Fluorination of lactone 8 with 1 equiv. of DFIT gave 3-syn-¯uoro-4,5-dihydro-3-phenylsulfanyl-5-phenyl-2(3H)-
furanone in 62% yield. The stereochemistry was established by X-ray crystallography and will be discussed in the
full paper.
8. (a) Patrick, T. B.; Lanahan, M. V.; Yang, C.; Walker, J. K.; Hutchinson, C. L.; Neal, B. E. J. Org. Chem. 1994,
9, 1210. (b) Kvõcala, J.; Plocar, J.; Vlasakova, R.; Paleta, O.; Pelter, A. Synlett 1997, 986.
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