C. Burkholder et al. / Tetrahedron Letters 42 (2001) 3459–3462
3461
NaBH4/EtOH
Ar1-CHOH-CF2S-Ar2
Ar1-COCF2S-Ar2
0°C to RT
NMe2
PhCHOHCF2SAr
N
Ar= C6H5; 45 min; 19 (65%)
Ar= 2-pyridyl; 2 h; 20 (61%)
N
CF2SAr
CHOHCF2SAr
HO
CHOHCF2SAr
Ar= C6H5; 1h; 21 (35%)
Ar= 2-pyridyl; 3 h; 22 (45%)
Ar= C6H5; 2 h; 16 (71%)
Ar= 2-pyridyl; 5 h; 17 (61%)
Ar= 2-pyrimidyl; 5 h; 18 (43%)
N
S
N
Ar= C6H5; 10 min; 23 (90%)
Scheme 4.
yield of substituted product 10 is only moderate. At
room temperature, these impurities are in less amount
but conversion is low.
2. Burkholder, C.; Dolbier, Jr., W. R.; Me´debielle, M. J.
Fluorine Chem. 2000, 102, 369–376.
3. (a) Save´ant, J.-M. Tetrahedron 1994, 50, 10117; (b) Rossi,
R. A.; Pierini, A. B.; Palacios, S. M. In Advances in Free
Radical Chemistry; Tanner, D. D., Ed. Nucleophilic Sub-
stitution by the SRN1 Mechanism on Alkyl Halides. JAI
Press: Greenwich, CT, 1990; pp. 193–252.
In order to get additional compounds for our screening
program, the Ar1-COCF2S-Ar2 derivatives were conve-
niently subjected to sodium borohydride reduction, in
ethanol, to give the corresponding Ar1-CHOH-CF2S-
Ar2 derivatives 16–23 in good yields (Scheme 4).
4. For a recent review: Pedersen, O. S.; Pedersen, E. B.
Synthesis 2000, 4, 479.
5. Brigaud, T.; Laurent, E. Tetrahedron Lett. 1990, 31,
2287–2290.
6. Furuta, S.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc.
Jpn. 1998, 71, 1939–1951.
In conclusion, to the best of our knowledge, this is the
first report of the substitution reactions of aromatic and
heterocyclic chlorodifluoromethylated ketones with sul-
fur nucleophiles11 and the application to the facile
synthesis of a-(heteroarylthio)-a,a-difluoroacetophe-
none derivatives. The products are good candidates for
further chemical elaboration and will be tested as
potential HIV-1 inhibitors. From the recent literature,7b
these derivatives could also find some application as
agrochemicals. Further experiments are currently under
way to confirm the SRN1 mechanism. The electrochemi-
cal induction of the SRN1 substitution will also be
performed to check if some of the yields could be
improved under less vigorous conditions, especially for
nucleophiles derived from pyridine, pyrimidine and
other nitrogen heterocycles.
7. (a) Takeda, S.; Kaneko, Y.; Eto, H.; Tokizawa, M.; Sato,
S.; Yoshida, K.; Namiki, S.; Ogawa, M. Chem. Pharm.
Bull. 2000, 48, 1097–1100; (b) Eto, H.; Kaneko, Y.;
Takeda, S.; Tokizawa, M.; Sato, S.; Yoshida, K.;
Namiki, S.; Ogawa, M.; Ishida, K.; Matsumoto, M.;
Asaoka, T. Chem. Pharm. Bull. 2001, 49, 173–182.
8. Yang, Z.-Y.; Burton, D. J. Heteroatom. Chem. 1992, 3,
261.
9. (a) Hapiot, P.; Me´debielle, M. J. Fluorine Chem. 2001,
107, 285–300; (b) Burkholder, C.; Dolbier, Jr., W. R.;
Me´debielle, M.; Ndedi, A. Tetrahedron Lett. 1998, 39,
8853–8856.
10. A typical representative procedure for the SRN1 reactions
is as follows: In a 25-ml, three-necked round-bottom flask
equipped with a magnetic stirrer, a reflux condenser and
a nitrogen inlet, anhydrous DMF (10 ml/mmol) by
syringe followed by 2 equivalents of NaH (95% dry) were
added under nitrogen. To the rapidly stirred gray suspen-
sion was added 2 equivalents of the nucleophile. Gas was
evolved and the NaH dissolved giving a clear solution
after 20 min of stirring. After stirring for 20 min, the
starting chlorodifluoromethylated ketone was added all at
once. The reaction was monitored by TLC and after total
consumption of the starting material, the solution was
hydrolyzed with an aqueous NaCl solution and the solu-
tion was extracted with dichloromethane (3×). The com-
bined organic extracts were washed with an aqueous
NaCl solution (5×) and dried over MgSO4. The solvent
was removed under reduced pressure and the crude
product was purified by silica gel chromatography.
Selected examples: 1-(4-Dimethylamino-naphthalen-1-yl)-
2,2-difluoro-2-(pyridin-2-ylsulfanyl)-ethanone 9: viscous
Acknowledgements
We thank Marie-Noelle Rager (ENSCP, Paris) for the
fluorine and proton NMR spectra and David Clain-
quart (Universite´ Denis Diderot-Paris 7) for the mass
spectra. Corinne Biou-Le Hec is sincerely thanked for
carrying out some preliminary experiments. M.M. and
S.A.-M. would like to thank the Universite´ Denis
Diderot-Paris 7 for a research grant (Appel d’offres
SIDA 1999).
References
1. Tozer, M. J.; Herpin, T. Tetrahedron 1996, 52, 8619–
8683.