molecules Article Evaluation of Efficient and Practical Methods for the Preparation of Functionalized Aliphatic Trifluoromethyl Ethers Taras M. Sokolenko 1, Maya I. Dronkina 1,†, Emmanuel Magnier 2, Lev M. Yagupolskii 1,‡ and Yurii L. Yagupolskii 1,3,* 1 Institute of Organic Chemistry, NAS of Ukraine, Murmans’ka St. 5, Kiev 02660, Ukraine; [email protected] 2 Bâtiment Lavoisier, Université de Versailles-Saint-Quentin, 45 Avenue des Etats-Unis, Versailles 78035, France; [email protected] 3 Enamine Ltd, A. Matrosova str. 23, Kiev 01103, Ukraine * Correspondence: [email protected]; Tel.: +380-44-559-03-49 † Retired. ‡ Passed away. Academic Editor: Thierry Billard Received: 28 April 2017; Accepted: 11 May 2017; Published: 14 May 2017 Abstract: The “chlorination/fluorination” technique for aliphatic trifluoromethyl ether synthesis was investigated and a range of products with various functional groups was prepared. The results were compared with oxidative desulfurization-fluorination of xanthates with the same structure. Keywords: fluorination; chlorination; oxidative desulfurization-fluorination; antimony trifluoride; hydrogen fluoride; trifluoromethyl ethers 1. Introduction Fluorine is one of the most favorite heteroatoms for incorporation into small molecules in life science-oriented research. In particular, commercial pharmaceuticals and agrochemicals frequently contain single fluorine atoms or trifluoromethyl groups [1–4]. Nevertheless, growing interest in emergent fluorinated substituents, like α-fluorinated ethers, has been observed within recent years [5–8]. While aromatic trifluoromethyl ethers, since their first publication [9] in 1955, have been extensively studied and widely used as pharmaceuticals and crop protection agents, as well as critical components for liquid crystals design [3–6,10], aliphatic trifluoromethyl ethers are less studied. Only a few practical methods for the synthesis of such compounds have been developed. Fluorination of fluoroformates with SF4 leads to aliphatic trifluoromethyl ethers. For instance, methyl(trifluoromethoxy) acetate was obtained by this method [11]. Nucleophilic substitution of benzylic halogen or α-halogen atoms in acetophenones with perfluoroalcoholate anions is a suitable method for aliphatic ether preparation [12]. Oxidative desulfurization-fluorination of xanthates is now the most attractive method for primary alkyl trifluoromethyl ether synthesis. At least 42 publications concerning this reaction are cited in Reaxys. N-Bromo- [13] or N-iodosuccinimide [14], dibromodimethylhidantoine [15,16], and IF5 [17] are suitable oxidants in this reaction. Complexes pyridine-HF or NEt3-HF are commonly used as fluorine atom sources. Bromine trifluoride [18] or p-nitrophenylsulfur chlorotetrafluoride [19] were used as oxidants and fluorinating agents. A number of new methods for trifluoromethyl ether synthesis were developed over the past ten years. The progress in this field was well summarized in the [6]. It is also worth noting the recent publication concern to asymmetric bromotrifluoromethoxylation of alkenes [8]. Molecules 2017, 22, 804; doi:10.3390/molecules22050804 www.mdpi.com/journal/molecules MoleculesMolecules 20172017,, 2222,, 804804 22 ofof 1010 MoleculesAA2017 numbernumber, 22, 804 ofof newnew methodsmethods forfor trifluoromethyltrifluoromethyl etherether synthessynthesiiss werewere developeddeveloped overover thethe ppastast 2tenten of 10 years.years. TheThe progressprogress inin thisthis fieldfield waswas wellwell summarizedsummarized inin thethe [6][6].. ItIt isis alsoalso worthworth notingnoting thethe recentrecent publicationpublication concernconcern toto asymmetricasymmetric bromotrifluoromethoxylationbromotrifluoromethoxylation ofof alkenesalkenes [8][8].. Surprisingly, and to the best of our knowledge, common for aromatic and revisited for Surprisingly,Surprisingly, andand toto thethe bestbest ofof ourour knowledge,knowledge, commoncommon forfor aromaticaromatic andand revisitedrevisited forfor heterocycles [20] trifluoromethyl ether synthesis “chlorination/fluorination” technique was not heterocyclesheterocycles [20][20] trifluoromethyltrifluoromethyl etherether synthessynthesiiss ““chlorination/fluorination”chlorination/fluorination” techniquetechnique waswas notnot investigatedinvestigatedinvestigated enough enoughenough for forfor aliphatic aliphaticaliphatic substrates substratessubstrates in order inin orderorder to compare toto comparecompare existing existingexisting methods methodsmethods due to duedue the necessitytoto thethe tonecessitynecessity choose the toto mostchoosechoose effective thethe mostmost ones effectiveeffective leading onesones to theleadingleading best t yieldstoo thethe bestbest and yields theyields lowest andand the percentagethe lowestlowest percentagepercentage of byproducts. ofof Itbyproducts. wasbyproducts. reported ItIt that waswas only reportedreported 1,1,1-trifluoro-2-(trichloromethoxy)propane thatthat onlyonly 1,1,11,1,1--trifluorotrifluoro--22--(trichloromethoxy)propane(trichloromethoxy)propane fluorination with fluorinationfluorination anhydrous withwith HF yieldedanhydrousanhydrous the corresponding HFHF yieldyieldeded thethe trifluoromethyl correspondingcorresponding ether trifluoromethyltrifluoromethyl [21]. The aim etherether of this [21][21] work.. TheThe was aimaimto ofof answer thisthis workwork the was questionwas toto “isansweranswer a “chlorination/fluorination” thethe quequestionstion ““isis aa “chlorination/fluorination”“chlorination/fluorination” technique suitable for the techniquetechnique aliphatic trifluoromethoxy-containingsuitablesuitable forfor thethe aliphaticaliphatic compoundtrifluoromethoxytrifluoromethoxy preparation--containingcontaining as it is forcompoundcompound aromatic preparationpreparation ones” and to asas compare itit isis forfor results aromaticaromatic of this onesones method”” andand with toto comparecompare oxidative desulfurization-fluorinationresultsresults ofof thisthis methodmethod withwith oxidative atoxidative the same desulfurizationdesulfurization substrates. --fluorinationfluorination atat thethe samesame substratsubstrates.es. 2.2.2. Results ResultsResults and andand Discussion DiscussionDiscussion WeWeWe based basedbased our ourour research researchresearch on onon hydroxyacetic hydroxyacetichydroxyacetic and andand ββ--hydroxypropionic-hydroxypropionichydroxypropionic acidacid acid derivatives,derivatives, derivatives, andand and alcoholsalcohols alcohols containingcontainingcontaining two twotwo and andand three threethree carbon carboncarbon atoms, atomsatoms including,, includingincluding branched branchedbranched structures structuresstructures with withwith phtalimido phtalimidophtalimido end endend groups groupsgroups as modelasas modelmodel objects. objects.objects. XanthatesXanthatesXanthates1a 1a1a–g––ggwere werewere prepared preparedprepared ininin aaa one-potoneone--potpot procedureprocedure startingstarting fromfrom from sodiumsodium sodium alcoholatesalcoholates alcoholates ofof of !-hydroxysubstitutedωω--hhydroxysubstitutedydroxysubstituted aliphatic aliphaticaliphatic esters, esters,esters, nitriles,nitriles, and and NN N-protected--protectedprotected alkanolaminesalkanolamines alkanolamines byby by thethe the actionaction action ofof of carboncarbon carbon disulfidedisulfidedisulfide and andand methyliodide. methyliodide.methyliodide. TargetTarget productsproducts werewere were obtainedobtained obtained withwith with highhigh high yieldsyields yields inin inallall all casescases cases (Scheme(Scheme (Scheme 1).1). 1). NaH,NaH, CSCS22 thenthen MeIMeI SSMMee OO RR OOHH RR SS 1a-g1a-g OO OO MMee OO OO NN SS OO Me O O Me O O S S 1c1c S 1a1a S 1b1b SS SS SS OO OO OO OO MMee SS NN NN NN NN SS OO SS MMee OO OO S OO SS OO OO OO S OOMMee 1f 1g1g 1d1d SS 1e1e SS 1f SS SchemeSchemeScheme 1. 1.1. Synthesis SynthesisSynthesis andand structures structures ofof methylxanthates.methylxanthates. Chlorination of xanthates 1a–g readily occurred with elemental chlorine to produce ChlorinationChlorination ofof xanthatesxanthates 1a1a––gg readilyreadily occurredoccurred with elemental elemental chlorine chlorine to to produce produce trichloromethyletherstrichloromethylethers 2a2a––gg,, whichwhich werewere isolatedisolated withwith almostalmost quantitativequantitative yieldsyields (Scheme(Scheme 2).2). trichloromethylethers 2a–g, which were isolated with almost quantitative yields (Scheme2). ChloroderivativesChloroderivatives 2a2a––gg cancan bebe storedstored inin aa fridgefridge andand theythey areare extremelyextremely sensitivesensitive toto moisture.moisture. Chloroderivatives 2a–g can be stored in a fridge and they are extremely sensitive to moisture. MethodMethod A:A: SbFSbF33 withwith SbClSbCl55 (cat.)(cat.) CCll SSMMee 22 MethodMethod B:B: HFHF withwith SbClSbCl55 (cat.)(cat.) OOCCFF OO OOCCCCll3 33 RR RR 3 RR SS 1a-g1a-g 2a-g2a-g 3a-g3a-g MethodMethod C:C: PyPy // HFHF7070 %%,, DBHDBH SchemeSchemeScheme 2. 2.2. Syntheses SynthesesSyntheses ofof trifluoromethoxiderivatives. trifluoromethoxiderivatives.trifluoromethoxiderivatives. AntimonyAntimonyAntimony trifluoridetrifluoridetrifluoride (method(method (method A)A) A) andand and hydrogenhydrogen hydrogen fluoridefluoride fluoride (method(method (method B)B) werewere B)usedused were forfor chlorinechlorine used for-- chlorine-fluorinefluorinefluorine exchangeexchange exchange becausebecause because theythey areare they thethe are cheapestcheapest the cheapest forfor thisthis for reaction.reaction. this reaction. AntimoniumAntimonium