FLUORINATION
Figure 4 – Best reaction conditions for the deoxofluorination from acyl fluoride
‣ high yield ( 99 %); the reaction did not proceed without nHF-Py . In the second example , using DAST as the deoxofluorinating reagent , the reaction occurred but at a very low yield of 25 %. When we used Deoxo-Fluor , XtalFluor E or tetrabutylammonium triphenyldifluorosilicate ( TBAT ), the reaction did not proceed at all . Deoxyfluorination can be applied to aromatic , heterocyclic and aliphatic groups . Fluolead gave the desiring fluorinated product in high yield . However , some have observed that removal of the side product , aryl-sulfinyl fluoride ( Ar-SOF ), is difficult when using Fluolead .
New work-up method
For this reason , we have developed several methods to remove Ar-SOF effectively , as shown in Figure 5 . A recently developed work-up method based on amino alcohol is the most effective . Since the difficulty in removing Ar-SOF comes from its properties , we would like to firstly introduce these and then the details of new method . Ar-SOF is to some extent more stable than the corresponding halide , chloride and bromide . It reacts with strong alkaline solutions , such as potassium hydroxide , but completing the hydrolysis takes some time , usually overnight . This reaction eventually gives S-diaryl-sulfonothioate ( Ar-S ( O 2
) -
S-Ar ), which is totally different from the expected product , aryl-sulfinic acid ( Ar-SO 2 H ).
Ar-SO 2
H undergoes disproportionation reactions during hydrolysis and ’ by this means , is transferred to the sulfonothioate . It is also difficult to remove this sulfonothioate from
the desired fluorinated product by recrystallisation , due to its low polarity . In this case , column chromatography is recommended . Various methods have been developed to overcome the difficulty of removing the side product . Our newly developed amino alcohol method is the best in terms of the quality of product and the ease of operation . In method , we normally use the tertiary amino alcohol , such as 2- ( dimethylamino ) ethanol , to avoid any reaction between Ar-SOF and the amino group of the amino alcohol . The charging amount of amino alcohol to the reaction mixture is estimated to be 1.5 molar equivalent vs . its Fluolead amount . The reaction with Ar-SOF proceeds quantitatively , even at ice bath temperatures , and affords the corresponding Ar-sulfinate ester shown in Figure 5 . This reaction is highly exothermic , because the amino alcohol is neutralised with the free HF in the mixture as well as reacts with Ar-SOF . After the formation of the sulfonate ester , the mixture is neutralised with a weak base , such as potassium carbonate , to remove the excess HF . Acetic acid is added , which converts the Ar-sulfinate into a water-soluble acetic acid salt . This salt can be removed to the water layer with the wash of the organic layer . Using hydrochloric acid instead of acetic acid gives water-insoluble salt , which can be removed by filtration . Which acid to use should be chosen depending on the properties of the products and solvents used in the reaction . •
* We would like to acknowledge the help of Dr Teruo Umemoto , president of IM & T Research , and Professor Norio Shibata of Nagoya Institute of Technology
* FLUOLEAD is a registered trademark of UBE Industries
Southida Nachampassak
BUSINESS DEVELOPMENT MANAGER , EMEA & AMERICAS ,
UBE INDUSTRIES ( PHARMACEUTICAL DIVISION )
Figure 5 – New work-up method with amino-alcohol to remove Ar-SOF
J j s . nachampassak @ ube . com www . ube . com
60 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981