Studies on the oxidation and fluorination of α-phenylsulfanylacetamides using difluoroiodotoluene

Article abstract of DOI:10.1016/S0040-4039(00)00617-1

α-Phenylsulfanylacetamides are fluorinated in the α-position when treated with difluoroiodotoluene (DFIT) in a fluoro-Pummerer reaction. For N- phenyl amides an intramolecular Friedel-Crafts reaction may compete and produce heterocycles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00617-1

Tetrahedron Letters 41 (2000) 4467±4470
Studies on the oxidation and ¯uorination of
a-phenylsulfanylacetamides using di¯uoroiodotoluene
Michael F. Greaney and William B. Motherwell*
Department of Chemistry, University College London, 20 Gordon Street, London WCIH OAJ, UK
Received 24 March 2000; accepted 10 April 2000
Abstract
a-Phenylsulfanylacetamides are ¯uorinated in the a-position when treated with di¯uoroiodotoluene
(DFIT) in a ¯uoro-Pummerer reaction. For N-phenyl amides an intramolecular Friedel±Crafts reaction
may compete and produce heterocycles. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: halogenation; oxidation; ¯uorine and compounds; hypervalent elements.
In the preceding communication,1 we have shown that di¯uoroiodotoluene (DFIT, 1) is a mild
and e€ective reagent for the a-¯uorination of a-phenylsulfanyl acetates and that two sequential
¯uoro-Pummerer reactions to give a,a-di¯uorosul®des can be achieved when two equivalents of
DFIT are used. We were also intrigued by the ®nding that, for those substrates such as 2 in which
formation of a second Pummerer cation is blocked, DFIT can then function as an oxidant to give
sulfoxides 4, presumably via hydrolysis of an iodosulfonium salt species such as 3 (Scheme 1).
The fact that an a,a-di¯uoroester 5 was not formed by subsequent nucleophilic displacement of
sulfur by ¯uoride anion in 3 suggested to us that the ester carbonyl group could well be responsible
for the relative longevity of iodosulfonium salts such as 3, especially when the conversion of
thioketals to geminal di¯uorides2 by DFIT is considered, since this transformation necessarily
requires, at some stage, replacement of sulfur by ¯uorine in an a-¯uoro sul®de intermediate. In
continuation of this study on the ¯uoro-Pummerer chemistry of DFIT it was therefore of interest
to examine a-phenylsulfanylacetamides as substrates. A range of amides were accordingly prepared,
some of which contained suitably placed double bond functionality which could feasibly intercept
the Pummerer cation in an intramolecular cyclisation, thus potentially forming ¯uorinated
heterocycles in addition to ¯uoro-Pummerer products. The results of treating these amides with
DFIT are shown below in Table 1 which reveals that the outcome of the reaction is critically
dependant on the substituents attached to the nitrogen atom of the amide.3
* Corresponding author. Tel: 0171 380 7533; fax: 0171 380 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)00617-1

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Scheme 1.
Table 1
Treatment of a-phenylsulfanylacetamides with DFIT

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As in the case of esters, a-¯uorination of the amides in entries 1±5 takes place in good overall
yield, and the use of a second equivalent of DFIT (entry 2) leads to a simple one-pot method for
a,a-di¯uorination. Substrate 1a was also selected to demonstrate the stability of DFIT under
storage, a six month old batch of the reagent producing ¯uoride 2a in 61% yield as compared
with the 71% yield with freshly prepared reagent. Although no competing cyclisation reactions
were observed at 0ꢀC, presumably as a consequence of the preferred transoid conformation of the
amide linkage, it was of interest to note that reactions performed at higher temperature (entries 6,
7 and 8) did lead to competitive formation of heterocyclic products which can formally be derived
by p-participation from the aromatic ring, as illustrated in Scheme 2 for the exclusive formation
of the oxindole derivative 4c from 1f. The absence of any acyclic ¯uorinated product in this
reaction, relative to the mixtures obtained in the cases of the benzylamine derivatives 1d and 1e
(entries 5 and 6) can be attributed to the faster rate of 5-exo-trig ring closure.4
Scheme 2.
To some extent, these reactions mirror the results of Tamura and Ishibashi,5 who have repor-
ted that tertiary a-phenylsul®nyl acetamides are much better substrates for Pummerer induced
cyclisations than their secondary amide congeners. The isolated yields of heterocycles are mod-
erate and poorer than those yields recorded by Tamura6 for similar cyclisaitons of a-phe-
nylsulfanyl acetamides mediated by iodobenzene(bistri¯uoroacetate). However, potential exists
for the incorporation of a further carbon±¯uorine bond forming step in the lactam products using
the di¯uoride and work is in progress in this area. Finally, to our surprise, the last three entries
9±11 demonstrate once again that DFIT can function as a convenient reagent for the oxidation of
the phenylsulfanyl group to the sulfoxide. At this stage, it is apparent that in all of the substrates
1a±1h studied, formation of the initial iodosulfonium salt can occur at 0ꢀC. However, the evolution
or otherwise of this intermediate, either to give a-¯uoro sul®des, sulfoxides or cyclised products is
strongly in¯uenced by the substituents around the nitrogen atom of the amide group. This stands

4470
in stark contrast to the reactions of the a-phenylsulfanyl esters described in the preceding paper
where a-¯uorination was always observed to precede oxidation of sul®de to sulfoxide. Clearly, a
simple extrapolation from ester to amide cannot be made. Furthermore, although it is tempting
at ®rst sight to speculate that neighbouring group participation from the amide carbonyl group
could lead to displacement of a second ¯uoride anion from the initially formed iodosulfonium
salt and that such a process would be more facile for amides than for esters, the diversity in
product evolution for various amides cannot be simply explained.
In summary, the foregoing results have indicated that DFIT is a mild and readily controlled
reagent for the ¯uoro-Pummerer reaction of a-phenylsulfanyl esters and acetamides. The reagent
is easily prepared through the trans-halogenation of dichloroiodotoluene with aqueous hydro-
¯uoric acid and mercuric oxide in DCM, and isolated as an o€-white crystalline solid.7 The chief
by-product of reaction, iodotoluene, is readily separated from all but the most non-polar products,
and can be easily recycled.
Acknowledgements
We thank the EPSRC for the award of a studentship to M.F.G.
References
1. Greaney, M. F.; Motherwell, W. B. Tetrahedron Lett. 2000, 41, 4463.
2. Motherwell, W. B.; Wilkinson, J. A. Synlett 1991, 191.
3. Typical procedure: A solution of N-benzyl-(phenylsulfanyl)acetamide 1e (1 equiv.) in DCM was treated with
DFIT (1.1 equiv.) under nitrogen and re¯uxed for 1 h. The reaction mixture was quenched with water and
extracted with DCM. Drying of the combined extracts over MgSO4 and concentration in vacuo gave an oil that
was chromatographed (SiO2) eluting with petroleum ether/diethyl ether 80/20 to a€ord 3-oxo-4-phenylsulfanyl-
1,2,3,4-tetrahydroisoquinoline 4b (45mg, 11%) as a colourless oil. IR (thin ®lm/cm^1): ꢀmax 3248m (NH), 1644s
ꢁ
(CˆO); 1H NMR (400 MHz, CDCl3): ꢁ 4.33 (2H, d J 6 Hz), 4.94 (1H, s), 6.72 (1H, br), 6.83±7.61 (9H, m); HRMS
(FAB) calcd. for C15H13NOS (MH+): 256.0800. Found: 256.0796; and N±benzyl-(2-¯uoro-2-phenylsulfanyl)-
ꢁ
acetamide 2e (152 mg, 35%) as colourless crystals; m.p. 65ꢀC (DCM/PE 30±40); IR (thin ®lm/cm^1): ꢀmax 3391s
(NH), 1669s (CˆO), 1516m (amide II), 1H NMR (300 MHz, CDCl3): ꢁ 4.18±4.32 (2H, m), 6.02 (1H, d 2JHF 52Hz),
6.35 (1H, br), 6.90±7.55 (10H, m); 19F NMR (282 MHz, CDCl3): ꢁ ^156.8 (dd J 53, 3 Hz). Anal. calcd for
C15H14FNOS: C, 65.43; H, 5.12; N, 5.09; S, 11.65%. Found: C, 65.35; H, 5.00; N, 4.98; S, 11.89%.
4. Baldwin, J. E. Chem. Commun. 1976, 734.
5. Tamura, Y.; Uenishi, J.-I.; Maeda, H.; Choi, H.-D.; Ishibashi, H. Synthesis 1981, 534.
6. Tamura, Y.; Yakura, T.; Shirouchi, Y.; Haruta, J.-I. Chem. Pharm. Bull. 1986, 34, 1061.
7. Carpenter, W. J. Org. Chem. 1966, 31, 2688.