Evaluation of Efficient and Practical Methods for the Preparation Of

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, and and to to the the best best of of our our knowledge, knowledge, common common for for aromatic aromatic and and revisitedrevisited for for heterocycles [20] trifluoromethyl ether synthesis “chlorination/fluorination” technique was not heterocyclesheterocycles [20][20] trifluoromethyltrifluoromethyl ether ether synthes synthesiiss ““chlorination/fluorination”chlorination/fluorination” technique technique was was not not investigatedinvestigatedinvestigated enough enoughenough for forfor aliphatic aliphatic aliphatic substrates substratessubstrates in order inin order order to compare to to compare compare existing existing existing methods methods methods due to due due the necessity to to the the 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” the the que questionstion ““isis a a “chlorination/fluorination” “chlorination/fluorination” technique suitable for the technique technique aliphatic trifluoromethoxy-containing suitable suitable for for the the aliphatic aliphatic compoundtrifluoromethoxytrifluoromethoxy preparation--containingcontaining as it is for compound compound aromatic preparation preparationones” and to as as compare it it is is for for results aromatic aromatic of this ones ones method”” andand with to to compare compare 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 prepared prepared in in in aaa one-potoneone--potpot procedure procedure starting starting from from from sodium sodium sodium alcoholates alcoholates alcoholates of of of ω-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 1d 1f1f SS 1g1g 1d SS 1e1e 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 of of xanthates xanthates 1a1a––gg readilyreadily occurred occurred with elemental elemental chlorine chlorine to to produce produce trichloromethyletherstrichloromethylethers 2a2a––gg,, whichwhich werewere isolated isolated with with almost almost quantitative quantitative 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 Antimonium pentachloridepentachloride pentachloride waswas was used as catalyst in both cases. Pyridine-HF70% and dibromodimethylhidantoine (DBH) (method

C) were used for oxidative desulfurization-ﬂuorination. It must be added that xanthates 1a–g were converted to triﬂuoromethyl ethers by the last method in the one-pot synthesis (Scheme2). MoleculesMolecules 2017 2017, 22, 22, 804, 804 3 of3 of10 10

MoleculesMolecules 2017 2017, 22, 22, 804, 804 3 of3 of 10 10 usedused as as catalyst catalyst in in both both cases. cases. Pyridine Pyridine-HF-HF70%70% and and dibromodimethylhidant dibromodimethylhidantoineoine (DBH) (DBH) (method (method C) C) MoleculesMolecules 2017 2017, 22, 22, 804, 804 3 of3 of10 10 MoleculeswereMoleculeswere used used2017 2017 , for22, 22 for, 804, oxidative804 oxidative desulfurization desulfurization-fluorination.-fluorination. It It must must be be added added that that xanthates xanthates 1a 1a–g– g3were3 of wereof 10 10 usedused as as catalyst catalyst in in both both cases. cases. Pyridine Pyridine-HF-HF70%70% and and dibromodimethylhidant dibromodimethylhidantoineoine (DBH) (DBH) (method (method C) C) Molecules 2017, 22, 804 3 of 10 convertedconvertedMolecules 2017 to to trifluoromethyl, 22trifluoromethyl, 804 ethers ethers by by the the last last method method in in the the one one-pot-pot synthesis synthesis (Scheme (Scheme 2). 2). 3 of 10 MoleculesusedwereMoleculeswereused as used as used2017 2017catalyst catalyst , for22, 22 for, 804, oxidative804 in oxidative in both both cases. desulfurization cases. desulfurization Pyridine Pyridine-HF--fluorination.HF-fluorination.70%70% and and dibromodimethylhidant dibromodimethylhidant It It must must be be added added that thatoineoine xanthates xanthates(DBH) (DBH) (method 1a(method 1a–g– g3were 3 of wereof C)10 10C) usedused as as catalyst catalyst in in both both cases. cases. Pyridine Pyridine-HF-HF70%70% and and dibromodimethylhidant dibromodimethylhidantoineoine (DBH) (DBH) (method (method C) C) convertedInIn the the to case trifluoromethyl case of of trichloromethoxyacetate trichloromethoxyacetate ethers by the last 2a 2amethod fluo fluorinationrination in the byone by bothpot both synthesis methods methods (Scheme A A and and B 2). B failed. failed. The The wereusedconvertedwere as used used catalyst forto for trifluoromethyl oxidative oxidativein both cases. desulfurization desulfurization ethers Pyridine by -theHF-fluorination.-fluorination. last70% and method dibromodimethylhidant It in It must the must one be be - addedpot added synthesis that thatoine xanthates xanthates(Scheme(DBH) (method 1a2). 1a– g– gwere were C) weredesiredweredesiredused used used ascompound compound catalyst for for oxidative oxidative in3a 3aboth was was desulfurization desulfurizationpreparedcases. prepared Pyridine with with- fluorination.low--fluorination. HFlow yield70% yield and only onlydibromodimethylhidant It It by must by must oxidative oxidative be be added added desulfurization desulfurization that that oine xanthates xanthates (DBH)-fluorination-fluorination 1a 1a(method––gg werewere of ofC) usedconvertedwereusedconverted Inas usedasIn thecatalyst catalyst the to caseforto trifluoromethyl case trifluoromethyl oxidative in ofin of both trichloromethoxyacetateboth trichloromethoxyacetate cases. cases. desulfurization ethers ethersPyridine Pyridine by by the- HFthe--HFfluorination. last70% last70%2a 2amethodand andfluomethod fluo dibromodimethylhidant rinationdibromodimethylhidantrination in It in the must the byone byone be bothpot both - addedpot synthesis methods synthesis methods thatoineoine xanthates(Scheme A (DBH) (SchemeA (DBH) and and B (method 2).B (method failed. 1a2).failed. – g were The C) TheC) convertedxanthateconvertedxanthateMoleculeswere used 1a2017 to 1ato ( trifluoromethylTable , fortrifluoromethyl(22Table, 804 oxidative 1 ,1 Entry, Entry desulfurization1 ethers). 1ethers ).On On the by bythe thecontrary, the contrary, last -lastfluorination. method method fluorination fluorination in in the It the must oneof one of trichloromethoxypropanecarboxylicpot-trichloromethoxypropanecarboxylic bepot addedsynthesis synthesis that (Scheme (Scheme xanthates 2). 2). 1a–g 3were of 10 weredesiredconvertedweredesired In usedIn used thecompound thecompound to for case for trifluoromethyl case oxidative oxidative of of 3a trichloromethoxyacetate 3a trichloromethoxyacetate was was desulfurization desulfurizationprepared prepared ethers bywith with thefluorination.-low fluorination. lastlow 2a yield 2amethod yieldfluo fluo onlyrination onlyrination Itin It by must theby must oxidative byoxidativeone by be be bothpot both added added desulfurizationsynthesis methods desulfurization methods that that xanthates A(Schemexanthates A and and-fluorination - Bfluorination B2). failed.1a 1a failed. ––gg were were The Theof of acidsacidsconvertedIn Inderivati derivati the the case casetoves vestrifluoromethyl of2b of 2b trichloromethoxyacetate– trichloromethoxyacetatec– andc and xanthates xanthates ethers 1b by 1b– cthe– wasc was last2a 2a successfully fluo successfullymethodfluorinationrination in performedthe byperformed by one both both-pot methods methodsb synthesis yb yall all three three A A (Scheme andmethods and methods B B failed. failed.2). (Table (Table The The 1 , 1 , converteddesiredxanthateconvertedxanthatedesiredIn compound the 1acompound to 1a to case(trifluoromethylTable trifluoromethyl(Table of 13a trichloromethoxyacetate, 1 3a Entry,was Entry was prepared 1 prepared ethers). 1ethers ).On On theby bythewith withthecontrary, the contrary, low last lastlow 2a yieldmethod method yield fluofluorination fluorination onlyrination only in in by the theby oxidative one oxidativeofbyone of trichloromethoxypropanecarboxylic- bothpot-trichloromethoxypropanecarboxylicpot synthesis desulfurization synthesis methods desulfurization (Scheme A(Scheme and-fluorination - Bfluorination 2). 2). failed. The of of desirededesiredntryentry 2,3In compound 2,3compound ). the ). In case In the the of3a 3a case trichloromethoxyacetatewas casewas ofprepared prepared of nitrile nitrile with with2c 2c reaction low lowreaction yield yield2a fluo withonly only withrination by SbFby SbF oxidative oxidative3 3(method by(method both desulfurization desulfurization methods A) A) lead lead A to andto- fluorination- lowfluorination low B failed. yield yield of of Theof of xanthateacidsdesiredacidsxanthateIn Inderivati Inderivati the compound the the1a 1a case ( case caseTable ves(Tableves of of2b of 2b 1 trichloromethoxyacetate3a– trichloromethoxyacetate,1 c–Entry ,wascand Entry and xanthatesprepared 1xanthates ).1 ).On On the thewith1b 1bcontrary,– contrary,c– lowcwas 2a was2a 2a yield fluorinationsuccessfully fluo successfullyfluorinationfluo fluorination onlyrinationrination by by performed oxidative by performedof bothby of trichloromethoxypropanecarboxylic both bothtrichloromethoxypropanecarboxylic methods methodsdesulfurization methodsb yb yall all A three andthree A A andBmethods and failed.methodsfluorination B B failed. failed. The (Table (Table desired The The of1 , 1 , xanthatetrifluoromethyletherxanthatetrifluoromethyletherdesired 1a 1acompound ( Table(Table 1 1, ,Entry3c3a Entry3c was(Table (Table 1 1prepared).). On 1On , 1 Entry,the the Entry contrary,with contrary, 4 ). 4 ).low Thus, Thus, yieldfluorination fluorination the the only presence presence by of oxidativeof trichloromethoxypropanecarboxylic oftrichloromethoxypropanecarboxylic of electron electron desulfurization-withdr-withdrawingawing-fluorination carboxylic carboxylic of desiredacidsexanthatedesiredntryeacidscompoundntry derivati 2,3 derivaticompound 2,3compound 1a). ). In(3aTableves In veswas the 2b the 2b3a 1–3a prepared, casec –wasEntry caseandcwas and prepared of xanthatesprepared of1 xanthates). withnitrile On nitrile lowthe with 1bwith 2c 1b2ccontrary, yield– c reaction–low lowwascreaction was only yield yieldsuccessfully successfullyfluorination by withonly only with oxidative by SbFby SbF oxidativeperformed oxidative 3 performed of3 desulfurization-fluorination (method trichloromethoxypropanecarboxylic(method desulfurization desulfurizationb yb A) yall A) all three lead three lead methods to methods to- fluorination- fluorinationlow low of yield(Table yield( xanthateTable of of1of ,of 1 , acidsgroupacidsgroupxanthate derivati derivaticlose close 1a to ves to ves(theTable the 2b 2breaction –reaction– c1c and, andEntry xanthatescent xanthates cent 1er). er Onprevented prevented 1bthe 1b– –ccontrary,c was was successful successfulsuccessfully successfully fluorination fluorination fluorination performed performed of trichloromethoxypropanecarboxylic processes. processes. b byy all all three three methods methods ( Table(Table 1 1, , xanthateetrifluoromethyletheracidsxanthatentrytrifluoromethylether1aentry(Table derivati 2,3 2,31a ).1a 1 ).(, InTable(Table Entryves In the 2b the 1 1,– 1). case,cEntry3c Entrycaseand3c On( Table( ofTable xanthates1 the of 1).). nitrile On 1nitrileOn contrary,,1 Entry,the the Entry 1b2c contrary, 2ccontrary, – 4creaction ). fluorination 4wasreaction ). Thus, Thus, successfully fluorination fluorination the with the with presence of presence SbF trichloromethoxypropanecarboxylic SbF performed 3of of3(method trichloromethoxypropanecarboxylic of(methodtrichloromethoxypropanecarboxylic of electron electron b y A) all A)- withdr -three leadwithdr lead methodsawing toawing to low low carboxylic carboxylic yield(Table yield acids of1 of, eentryntryacidsIn In 2,3 general, 2,3derivati general,).). In In ves thefluorination the fluorination 2b case case–c and of of of xanthates nitrileof nitriletrichloromethylethers trichloromethylethers 2c2c 1b reaction–reactionc was successfully with with 2d 2d – SbFg– SbF gand and3 3performed (methodxanthates(method xanthates A)b1d A)y 1d –all leadg– lead gwiththree with to toprotected methods protected low low yield yield (aminoTable amino of of 1 , acidstrifluoromethylethergroupeacidsntrygrouptrifluoromethyletherderivatives derivati derivaticlose 2,3 close). to In ves2btoves the –the 2bc 2breactionand –reaction– c case3cc and xanthates3cand ( Table ( xanthates ofTable centxanthates cent nitrile er 1 er,1b 1 prevented Entry, prevented– Entry 1bc 1b2cwas– –c 4c reaction).was 4was successfully ). Thus,successful Thus, successfulsuccessfully successfully thewith the presencefluorination performed presencefluorination SbF performed performed3 (method of of by electronprocesses. electronprocesses. allb by y three A)all all- withdrthree- leadthreewithdr methods methods awingmethods toawing low (Table carboxylic ( carboxylic yieldTable(Table1, entry 1 of1, , trifluoromethylethergrouptrifluoromethylethergroupentrys s(Table 2,3(Table). In1 ,1 Entry, theEntry 3c 3c case4 ( –4Table(7Table–) 7 results) of results 1 nitrile1, , Entry Entryin in higher 2chigher 4 4). ). reaction Thus, Thus,yields yields the the of with of presence fluorinated presence fluorinated SbF3 of of(method products electron electronproducts - A)withdr -3dwithdr 3d– leadg– gasawing awingas compared to compared low carboxylic carboxylic yield with with of egrouptrifluoromethyletherentrygroupntry2,3).In In 2,3close general, 2,3 close general, the).). Into case Into the thefluorinationthe the offluorination reaction nitrilereaction case case3c (Table of2c cent of ofcentreaction nitrileof nitriletrichloromethylethers er 1trichloromethyletherser, prevented Entry prevented 2c with2c reaction 4reaction). SbF Thus,successful successful(method with the with 2d presence2d fluorination– A)SbFfluorinationg– SbF gand leadand3 3 (methodxanthates(method toofxanthates low electronprocesses. processes. yield A)1d A) 1d -– withdr ofleadg– lead gwith trifluoromethylether with toawing toprotected protected low low carboxylic yield yield amino amino of of3c groupthegroupthetrifluoromethylether same same close close reaction reaction to to the the ofreaction reactionof carboxylic carboxylic 3c (cent Tablecent eracidser acidsprevented 1prevented, Entryderivatives. derivatives. 4 ).successful successful Thus,3 Trifluoromethylethers Trifluoromethylethers the fluorination fluorination presence of processes. processes. electron with with linear- withdr linear chain awingchains 3ds carboxylic3d,e, ewere were trifluoromethylethergroupgrouptrifluoromethylethergroup(TableIns In close general,s1( Table,general,( EntryTable to 1the ,fluorination 4).1 Entry,fluorination Entryreaction Thus, 3c 3c 4( –4Table( the7Table– )7cent results)of presence resultsof trichloromethylethers 1er 1,trichloromethylethers , Entryprevented Entryin in higher of higher 4 electron-withdrawing4).). Thus, Thus,successfulyields yields the the of 2d of presence fluorinated2d presencefluorination –fluorinatedg– gand and xanthates carboxylicof xanthates of electronproducts electronprocesses.products 1d group-1dwithdr -–3dwithdrg –3d gwith– gwith– closegasawing awingasprotected compared protected compared to thecarboxylic carboxylic reactionamino aminowith with preparedpreparedgroupInIn general, general, close with with to highfluorination fluorinationhighthe yieldsreaction yields by of byofcent alltrichloromethylethers trichloromethylethersall erthree three prevented methods. methods. successful Oxidative Oxidative 2d 2d––g fluorinationg and anddesulfurization desulfurization xanthates xanthates processes. 1d 1d-–fluorin–g-gfluorin with with ationprotected protectedation of of xanthate xanthateamino amino groupgroupthegroupthegroupcenter same Insame sclose closegeneral,s( preventedTable (reactionTable reaction to to the1 the ,fluorination1 Entry ,of reaction Entry reactionsuccessfulof carboxylic carboxylic 4 –47 –cent) 7 cent results)of fluorinationresults ertrichloromethylethersacidser acidsprevented prevented in derivatives.in higherderivatives. higher processes. successful successfulyields yields Trifluoromethylethers Trifluoromethylethers of 2dof fluorinatedfluorination fluorination–fluorinatedg and xanthates products processes. productsprocesses. with 1dwith –3d glinear 3d linearwith–g– gas chainasprotected comparedchain compareds 3ds 3d, eamino, ewerewith werewith group1fgroup1f gave gavess In ( aTable( Tablegeneral,abetter better 1 1 ,result ,Entry resultEntryfluorination than 4 than4––77) )fluorinationresults resultsfluorination of trichloromethylethers in in higher higher of of chloroderivative chloroderivative yields yields of of fluorinated 2dfluorinated–g 2f and2f with with xanthates products productsSbF SbF3 or3 or HF1d 3d HF3d– –g(–Tableg (gwith Tableas as compared compared1protected ,1 e, ntryentry 6 ).with 6aminowith ).An An thepreparedgrouppreparedthe sameIn sameIns Ingeneral, general,(Table general,reactionwith reactionwith 1 highfluorination ,fluorination highEntry fluorinationof of yieldscarboxylic yieldscarboxylic 4–7 )by ofresults byof ofalltrichloromethylethers acidstrichloromethylethersall trichloromethylethersacidsthree three in derivatives. higherderivatives. methods. methods. yields TrifluoromethylethersOxidative TrifluoromethylethersOxidative of2d 2d 2dfluorinated––g–g andg anddesulfurizationand desulfurization xanthates xanthates xanthates products with 1d with1d1d–- fluorin–g3d -linearg–fluorin with g linear–withgwith as ationprotectedchain protectedation comparedchain protected ofs of3ds xanthate 3d ,xanthateaminoe amino, ewere aminowith were theethessentialegroupssential same sames differencereaction ( reactionTabledifference 1 of, of Entrywas carboxylic wascarboxylic observed 4observed–7) results acids acids in in fluorination derivatives. derivatives.influorination higher yields ofTrifluoromethylethers Trifluoromethylethersof trichloromethylether trichloromethylether of fluorinated products with 2gwith 2g and andlinear linear3d xanthate –xanthateg chain aschain compared s1gs 3d1g 3d(Table ,e(,Tablee were were with 1 , 1 , groupprepared1fthegroup1fpreparedgroups gave samegaves s ( aTable( Tablea (Tablereactionbetterwith betterwith 1 high1 ,1 result,Entry,high resultEntry Entryof yieldscarboxylic yields than4 than4– 4–7)–77) by)fluorinationresults resultsbyfluorination results all acidsall three inthree in in derivatives.higher higher highermethods. of methods.of chloroderivative chloroderivative yields yields yields OxidativeTrifluoromethylethers Oxidative of of of fluorinated fluorinated fluorinated 2fdesulfurization 2fdesulfurization with with products productsSbF products SbF3 withor3 or HF -3dfluorin HF 3d-linearfluorin3d –(–gTable (–g Tableasg asation as chaincomparedation compared1 compared ,1 e,of sntrye of3dntry xanthate xanthate, e6 ).with were6with ).An with An preparedepreparedntryethentry same7 ).7 ).Fluorination with Fluorinationwith reaction high high ofyields yields of carboxylic of compo compo by by all allund und threeacids three 2g 2g byderivatives.methods. methods.by methods methods Oxidative Oxidative ATrifluoromethylethers A and and B Bdesulfurizationled desulfurization led to to low low yields yields with-fluorin- fluorinof of lineartrifluoromethylether trifluoromethyletherationation chain of of sxanthate xanthate3d,e were the1fepreparedthessentiale1fthe ssentialgave same gavesame same a differencereaction abetter reactionwithdifference reactionbetter high result ofresult of was of carboxylic yieldswascarboxylic carboxylicthan thanobserved observed byfluorination fluorination allacids acids acidsinthree in fluorinationderivatives. derivatives.fluorination derivatives. methods.of of chloroderivative chloroderivative ofTrifluoromethylethers OxidativeTrifluoromethylethersof trichloromethylether Trifluoromethylethers trichloromethylether 2fdesulfurization 2f with with SbF SbF 3 with 2gorwith3 2g withor andHF- fluorinandlinearHF linear linear(xanthateTable (xanthateTable chaination chain chains1 ,1 e s,1gof ntrys e3d1g ntry 3d(xanthate3d,eTable ,e( ,Table6e were). 6were ).wereAn 1An , 1 , 1f1f gave gave a a better better result result than than fluorination fluorination of of chloroderivative chloroderivative 2f 2f with with SbF SbF3 3or or HF HF ( Table(Table 1 1, ,e entryntry 6 6).). An An 3gentry3gprepared. Nevertheless,. Nevertheless, 7). Fluorination with oxidativehigh oxidative ofyields compo desulfurization desulfurization byund all three2g by methods.-methodsfluorination-fluorination AOxidative and of of xanthate B xanthate led desulfurization to 1glow 1g allowed yieldsallowed ofobtaining-fluorin obtaining trifluoromethyletheration ether ether of 3g xanthate 3g with with preparede1fpreparedssentialeprepared ntryssentialgave 7 a ). difference with better Fluorinationwithdifference with high highresult high wasyields yieldswas yieldsthan ofobserved observedcompo by fluorinationby by all all all und three inthree threein fluorination 2gfluorination methods. methods.ofby methods. chloroderivative methods ofOxidative Oxidativeof Oxidativetrichloromethylether Atrichloromethylether and Bdesulfurization 2fdesulfurization led desulfurization-fluorination with to lowSbF 3yields 2gor 2g -andHFfluorin- fluorinand of (xanthateTable trifluoromethyletherxanthateationation 1, eof 1gofntry 1g of xanthate (xanthateTable xanthate( Table6). An 1 , 1 , equantitativeessentialquantitativessential1f gave difference differencea better yield. yield. resultIt was Itwasshould should observed thanobserved be befluorination noted noted in in fluorinationthat fluorination that both ofboth chloroderivative substrates substrates of of trichloromethylether trichloromethylether (1g (1g and and 2f 2g with 2g) are) are SbF secondar 2g secondar2g3 orand and HF xanthatey xanthate y(alcoholTable alcohol 1 1gderivatives. ,1g ederivatives. ntry( Table(Table 6). 1 1An, , 1fe3ge1fntryssential3g1fe gave. ntry gaveNevertheless,.gave Nevertheless, 7 ).7a a). Fluorinationdifferencebetter abetterFluorination better result result oxidative resultoxidative was ofthan than of observedcompo than compo desulfurizationfluorination fluorinationdesulfurization fluorinationundund in 2gfluorination 2g by of byof -methodschloroderivativefluorination chloroderivative of-methodsfluorination chloroderivative of Atrichloromethylether A and ofand of xanthate B xanthate 2fB led2f ledwith with to2f to low1gwith SbF 1glowSbF allowed yieldsallowed3 SbF3yieldsor2g or HF andHF oforobtaining (ofobtaining Tabletrifluoromethylether(xanthate HFTable trifluoromethylether (Table 1 1, ether,e eetherntry1gntry1 ,( Table3g entry6 3g6). with). An withAn 1 6). , eentryntryessential 7 7).). Fluorination Fluorination difference wasof of compo compo observedundund 2gin 2g fluorinationby by methods methods ofA A andtrichloromethylether and B B led led to to low low yields yields 2g3 of andof trifluoromethylether trifluoromethylether xanthate 1g (Table 1 , e3gquantitativeeessentialntryquantitative3gAnssential. Nevertheless,. Nevertheless, essential 7). difference Fluorinationdifference yield. yield. difference oxidative TableIt oxidativewas TableItwasshould shouldof observed1. wasobservedcompo 1.Structures desulfurization beStructures observeddesulfurizationbe noted undnoted in in andfluorination2g that fluorination andthat in by yields fluorinationboth yields -bothmethodsfluorination-fluorination substratesof substratesof chlorinatedof ofchlorinated trichloromethylether Atrichloromethylether of and trichloromethyletherof ( of1g xanthate( 1gB andxanthate and ledand and fluorinated 2g tofluorinated 2g )1glow are )1g areallowed secondarallowedyields 2gsecondar 2gproducts. andproducts. 2gand ofobtainingand obtaining xanthatey trifluoromethyletherxanthate yalcohol xanthatealcohol ether 1g derivatives.ether1g derivatives. 1g( Table (3gTable (Table3g with with 1 1, 1 , , 3g3g.e .Nevertheless,ntry Nevertheless, 7). Fluorination oxidative oxidative of compodesulfurization desulfurizationund 2g by-fluorination-fluorination methods A of ofand xanthate xanthate B led to1g 1g low allowed allowed yields obtaining obtaining of trifluoromethylether ether ether 3g 3g with with equantitative3gentryquantitativentryentry. Nevertheless, 7 7). 7).). Fluorination Fluorination Fluorination yield. yield. oxidative It Itshould ofshould of ofcompo compo compound desulfurizationbe be notedund notedund 2g that2g 2gthat by by bothby methods -bothmethodsfluorination methods substrates substrates A A Aand and of and(1g (xanthateB 1gB andled Bled and led to2g to 2g tolow ) 1g loware) low areallowed yields secondaryields secondar yields of ofobtaining oftrifluoromethylethery trifluoromethylether yalcohol trifluoromethylether alcohol ether derivatives. derivatives. 3g with quantitativequantitative3g. Nevertheless, yield. yield. ItTable Itoxidative Tableshould should 1. 1. Structures be Structuresbe desulfurization noted noted andthat that and yieldsboth bothyields-fluorination substrates ofsubstrates of chlorinated chlorinated ( 1g (of1g andxanthate andand fluorinated 2g 2gfluorinated) )are are1g secondar allowedsecondar products. products. yYieldobtainingy alcoholYield alcohol % % derivatives. derivatives.ether 3g with 3gquantitative3g3g. .Nevertheless, Nevertheless,. Nevertheless, yield. oxidative oxidative It oxidative should desulfurization desulfurizationbe desulfurization-fluorination noted YieldthatYield both-fluorination-fluorination substrates of of ( of1gxanthate xanthate xanthateand 2g 1g) 1g are1g allowed allowed allowedsecondar obtaining obtaining obtainingy alcohol ether ether derivatives. ether 3g 3g3g with withwith Table 1. Structures and yields of chlorinated and fluorinatedMethod products.Method Method quantitativequantitativequantitativeEntryEntry yield. yield. Chlorinatedyield.Chlorinated TableItTable TableIt shouldIt should should 1.1. P1. roductStructuresStructures P Structuresberoduct be benoted noted noted andand thatand that that yields yieldsbothyields both both substrates of ofsubstratesFluorinatedof substrates chlorinatedFluorinatedchlorinated chlorinated ( 1gP(1g roduct(P and 1gand roductand and and fluorinated fluorinated2gfluorinated 2g )2g )are are) are Methsecondar secondar secondar products.products. products.od yYieldy alcoholYieldMethod y alcohol alcohol % % derivatives. derivatives. derivatives.Method quantitative yield. It should be notedYield%Yield that % both substrates (1g and 2g) are secondary alcohol derivatives. Table 1. Structures and yields of chlorinated and fluorinatedMethMethA Aod products.od YieldMethodMethodYieldB B % % MethodMethodC C EntryEntry ChlorinatedChlorinatedTable P roduct1.Product Structures and yieldsFluorinated ofFluorinated chlorinated P roductProduct and fluorinated products.YieldYield % % TableTable 1. 1. Structures Structures and andYield%Yield% yields yields of of chlorinated chlorinated and and fluorinated fluorinated products. products. EntryEntry MChlorinatedMeChlorinatede TableOO P 1.roductProductStructures YieldYield and yieldsFluorinatedM ofFluorinatedeMe chlorinatedOO Product Product and fluorinated MethMethA Aod od products. MethodYieldMethodB B % MethodMethodC C Entry Chlorinated Product Fluorinated Product MethMethodod MethodMethodYield % MethodMethod Entry ChlorinatedOO Product Yield% % FluorinatedOO Product tracestraces YieldYieldtracestraces % % 3636 1 1 %87%Yield 87 O MethA Aod MethodB B MethodC C Entry MChlorinatedMe e OOO POroductCClCl YieldYield MFluorinatedMe e OO ProductOCFCF AA BB CC Entry Chlorinated Product3 3 % Fluorinated Product3 3 MethMethtracesMethtracesodod od MethodYieldMethodtracesMethodtraces % MethodMethodMethod3636 EntryEntry ChlorinatedChlorinatedChlorinatedOO2a2a P Productroduct % FluorinatedFluorinatedOFluorinatedO3a3a P Productroduct A B C Entry1 1 MMe e OO Yield%%87% 87 MeMe OO MMee ProductOO OOCClC3 l MMee ProductOO OOCFC3F A B C O 3 O 3 MethodtracesAtracesA A MethodtracesBtracesB B MethodC36C 36 C 1 1 O 2aO2a 8787 O 3aO3a tracestraces tracestraces 3636 1 MeOO 87 MeOOO 1 MOeO OOOCClC3 l3 87 Me OOOCFC3F3 traces traces 36 MMeeO OO OO CCCCl3l3 MMeeO OO OO CCFF3 3 1 O2a2a 87 OOO3a3a tracestraces53traces53 tracestraces69traces69 366336 63 36 1 OO 2a2a O CCl3 87 MMe eOOO3a3a OOCOCF3FC F 12 1 2 OO O CC l 878987 89 O C F3 3 traces traces 36 MeMeOO2a OOOCOCCClCllC3 l3 3a OO CCFF 3 3 3 3 OO 3 3 53 69 63 2a Me OO 3b3b3a CF 53 69 63 2 2 OO2a2b2a2b 8989 MeOO3a3a OO C3F 3 MMe eOOOO OOCClC l 3 3 O 5353 6969 6363 O Me O3b3b CF 53 69 63 2 2 2b2b 8989 Me OOOO OOCF3 3 53 69 63 22 MeMeOOO OOCCClCl 8989 MMee OO OO CCFF33 MMee OO OOOCCCClCl 3l 3 53 69 63 O CC33l33 Me O 3b 3b OOOCFCC3FF3 22 Me O 2b2b O CCl 8989 3b3b 3 53532253 22 53 6966 69 66 69 636663 63 66 63 3 32 NN 2b2b 3 9292 89 NMNe O O CF3 2 2 Me O O CCl 8989 MMee OO 3b OO CCFF3 3 MMee OO OOOOCCCCCll3ll 3 OOCFCF 2b2c2c 3 33 3c 3c3b 3 3 2222 6666 6666 3 3 NN 2b 9292 NN 3b3b 2b2b OOCClCl OOCFCF OO CCCCl 3l 3 3 3 2c 33 3c3cOO CCFF3 3 2222 6666 6666 N O O2c NN O O 2222 6666 6666 3 3 NN O CCl 9292 NN O CF 33 N O CC3 l 9292 3 2222 66 66 66 2c2cOO CCCCl l 3 3c3c O CF3 3 N ONON 3 3 92 N O3cN3cONOO CCFF3 3 22 66 66 2c2c N 229022 90 669366 93 669666 96 4 43 N O CC l 9696 92 NN 3 3 NN 2c O C3Cl3 9292 3c O OCFC3F3 ONO ONO3c OO2cO2cON2c2d2d OO3cO3cON3d3d 9090 9393 9696 4 4 OOCCClCl 9696 O C F O 3 3 O O C3F3 ON N N N 9090 9393 9696 4 NNOO2d 2d 96 OONO NOO 3d3d 909090 93 93 9696 96 4 4 OO O OCCClCl 9696 O OCFCF 44 N OOCCCCl 3l 3 9696 N OO CCFF3 3 OOOO 3 3 O OO 3 3 90 93 96 4 OO N2d 2d 96 O N 3d3d 90 93 96 NN 2d2d O CCl3 ONON 3d3d O CF3 9090 9393 9696 4 O CCl 96 O CF 4 4 O OOCCCl l 3 9696 O 3 ONO N 2d 3 3 ONO N 3d OO CCFF3 3 O 2d O 8888 9090 9595 5 5 OO 2d2d 9595 OO 3d3d3d ONON O OCFCF ONON O OCFCF OO 3 3 OO 3 3 8888 9090 9595 5 2e2e 95 3e 3e 88 90 95 5 5 O 9595 O ON N O OCFCF ONON O OCFCF NNOO 3 3 NNO 3 3 8888 9090 9595 OO 2e 2e OO 3e 3e 8888 9090 9595 5 5 N 9595 N 55 O O O OCFCF 9595 O O O OCFCF 88 90 95 O N OOCCFF3 3 OO ON OOCCFF3 3 5 OONNO 2e 2e 3 3 95 NN 3e 3e 3 3 88 90 95 2e2e 3e3e 8888 9090 9595 5 O MeMeO CF3 95 O MeMOe CF3 5 5 O O CF 9595 O O CF OONO N2e OOCCFF 3 OON ON3e OOCCFF 3 2e 3 3 3e 3 3 6060 6262 8585 6 2e2eMeMOeOCFCF 82 3e3eMeMOe CF 60 62 85 6 6 MeMe 3 3 8282 M eMe O C3F3 MoleculesMolecules 2017 2017, 22, 22, 804, 804 ONO ONO 4 of4 of 10 10 OOOON OOOON 6060 6262 8585 MeMe CF MeMe 6 6 OMeM2fMeMe2feOO C3F3 8282 OMeM3fMeMe3feOOCFC3F N N N N 3 ONNOO Me ONNOO Me 6060 6262 8585 OOO OOO 6060 6262 8585 6 6 MeM2fe2fMOeOCFC3F3 8282 MeM 3fe3fMOeOCFC3F3 66 MNMeeMMeeOO CCFF3 8282 MNMeeMMeeOO CCFF O O 3 O O 3 3 60 62 85 OO N O CF O N O CF 6 NNM Ne 2f2f 3 82 ONN MN e 3f 3 60 62 85 M2f2fe O CF M3fe O CF 602360 23 623462 34 859985 99 7 6 OMMee OOCCFlF 3 85 82 OMMee3f3f OOOCCFCFF 3 23 34 99 67 6 7 O C3C33l3 828582 85 O C33F3 OO O 2f O 3f OO M eMe 2f OO OM eMe 2f2f2g2g 3f3f3g3f3g

Note: Method A: SbF3 with SbCl5 (cat.), method B: HF with SbCl5 (cat.), method C: Py / HF70 %, DBH. Note:Note: Method Method A: A: SbF3 SbF3 with with SbCl5 SbCl5 (cat.) (cat.), m, methodethod B: B: HF HF with with SbCl5 SbCl5 (cat.) (cat.), m, methodethod C: C: Py Py / HF70/ HF70 %, %, DBH DBH. .

It It must must be be added added that that fluorination fluorination with with pyridine pyridine-HF-HF complex complex (method (method C) C) requires requires special special polyethylenepolyethylene or or polytetrafluoroethylene polytetrafluoroethylene plastic plastic equipment, equipment, fluorination fluorination with with anhydrous anhydrous HF HF (method (method B) B) requirerequire stainless stainless steel steel autoclave autoclave but but fluorination fluorination with with antimony antimony trifluoride trifluoride (method (method A) A) was was performedperformed in in common common glass glass equipment. equipment. All All investigated investigated methods methods of of fluorination fluorination (A, (A, B ,B and, and C) C) can can bebe applied applied for for the the large large-scale-scale experiment. experiment. Thus, Thus, methyl methyl 3 - 3(trifluoromethoxy)propanoate-(trifluoromethoxy)propanoate 3b 3b was was preparedprepared in in quantity quantity above above 25 25 g gat at once once and and protected protected amine amine 3d 3d was was obtained obtained in in ca. ca. 50 50 g gat at once once by by allall three three methods. methods. The The protective protective phthalimide phthalimide group group can can be be removed removed by by common common methods methods and and was was documenteddocumented in in [16] [16]. .

3.3. Materials Materials and and Methods Methods

1H1H-NMR-NMR spectra spectra were were recorded recorded at at 300 300 MHz MHz with with a aVarian Varian VXR VXR-3-00300 spectrometer spectrometer (Varian (Varian Inc, Inc, PaloPalo Alto, Alto, CA, CA, USA USA), )at, at 500 500 MHz MHz with with a aBruker Bruker AVANCE AVANCE DRX DRX 500 500 instrument instrument (Bruker, (Bruker, Billerica, Billerica, MA, MA, USA)USA), or, or at at 400 400 MHz MHz with with Varian Varian UNITY UNITY-Plus-Plus 400 400 spectrometer spectrometer (Varian (Varian Inc, Inc, Palo Palo Alto, Alto, CA, CA, US USAA). ). 13C13C-NMR-NMR-spectra-spectra (proton (proton decoupled) decoupled) were were recorded recorded on on a aBruker Bruker AVANCE AVANCE DRX DRX 500 500 instrument instrument at at 125125 MHz MHz, or, or at at 100 100 MHz MHz w withith Varian Varian UNITY UNITY-Plus-Plus 400 400 spectrometer. spectrometer. 19 F19-FNMR-NMR spectra spectra were were recorded recorded atat 188 188 MHz MHz with with a aVarian Varian Geminy Geminy-200-200 instrument instrument (Varian (Varian Inc, Inc, Palo Palo Alto, Alto, CA, CA, USA USA), )or, or at at 376 376 MHz MHz withwith Varian Varian UNITY UNITY-Plus-Plus 400 400 spectrometer. spectrometer. Chemical Chemical shifts shifts are are given given in in ppm ppm relative relative to to Me Me4Si4Si and and 1 13 19 CClCCl3F,3F, respectively, respectively, as as internal internal or or external external standards. standards. H1H-, -, C13C-, -, and and F19-FNMR-NMR spectra spectra of of the the compoundscompounds can can be be found found in in Supplementary Supplementary materials. materials. LC LC-MS-MS spectra spectra were were registered registered on on an an “Agilent “Agilent 11001100 Ser Series”ies” instrument instrument with with diode diode-matrix-matrix and and mass mass-selective-selective detector detector “Agilent “Agilent 1100 1100 LS/MSD LS/MSD SL” SL” (ionization(ionization method method: :chemical chemical ionization ionization at at atmospheric atmospheric pressure; pressure; ionization ionization chamber chamber operation operation conditionsconditions: simultaneous: simultaneous scanning scanning of of positive positive and and negative negative ions ions in in the the rang range e80 80–1000–1000 m m/z/,z Agilent, Agilent Technologies,Technologies, Santa Santa Clara, Clara, CA, CA, US USAA). ).GC GC-MS-MS spectra spectra were were registered registered on on a aHewlett Hewlett-Packard-Packard HP HP GC/MSGC/MS 5890/5972 5890/5972 instrument instrument (EI (EI 70 70 eV) eV) (Philips (Philips, Bothell,, Bothell, WA, WA, US USAA). )Melting. Melting points points were were determined determined inin open open capillaries capillaries using using an an SMP3 SMP3 instrument instrument (Stuart (Stuart Scientific Scientific Bibby Bibby Sterlin Sterlin Ltd, Ltd, Stone, Stone, Staffordshire, Staffordshire, UKUK). ). Elemental Elemental analysis analysis was was performed performed in in the the An Analyticalalytical Laboratory Laboratory of of the the Institute Institute of of Organic Organic Chemistry,Chemistry, NAS NAS of of Ukraine, Ukraine, K Kieiv.ev. UnlessUnless otherwise otherwise stated, stated, commercially commercially-available-available reagents reagents were were purchased purchased from from Enamine Enamine Ltd Ltd. . andand were were used used without without purification. purification. Antimony Antimony trifluoride trifluoride was was sublimated sublimated immediately immediately prior prior to to use. use. AnhydrousAnhydrous hydrogen hydrogen fluoride fluoride was was distilled distilled in in the the presences presences of of SOCl SOCl2. 2HF. HF70%70%/p/yridinepyridine was was prepared prepared accordingaccording to to the the Olah Olah method method [22] [22]. Solvents. Solvents were were dried dried befor before euse use by by standard standard methods. methods. All All reactions reactions werewere performed performed in in an an a rgonargon atmosphere. atmosphere. For For column column chromatography chromatography, Merck, Merck Kieselgel Kieselgel 60 60 silica silica gel gel (Merck,(Merck, Darmstadt, Darmstadt, Germany Germany) )was was used. used. Thin Thin-layer-layer chromatography chromatography ( TLC) (TLC) was was carried carried out out on on aluminumaluminum-backed-backed plates plates coated coated with with silica silica gel gel (Merck (Merck Kieselgel Kieselgel 60 60 F254 F254, ,Merck, Merck, D Darmstadt,armstadt, GermanyGermany). ).

3.1.3.1. Synthesis Synthesis of of X Xanthatesanthates 1a 1a–c–:c General: General P rocedureProcedure CarbonCarbon disulfide disulfide (18.1 (18.1 mL, mL, 0.3 0.3 mol) mol) was was added added dropwise dropwise at at − 30−30 °C °C to to the the suspension suspension of of sodium sodium hydridehydride (60% (60% in in mineral mineral oil) oil) (4.4 (4.4 g, g, 0.11 0.11 mol) mol) in in anhydrous anhydrous dimethyl dimethylformamideformamide (DMF (DMF) (200) (200 mL). mL). To To thisthis mixture mixture the the solution solution of of corresponding corresponding hydroxyderivatives hydroxyderivatives (0.1 (0.1 mol) mol) in in anhydrous anhydrous DMF DMF (15 (15 mL) mL) waswas added added dropwise dropwise for for 3 3h hwith with mechanistic mechanistic stirring stirring at at − 30−30 °C. °C. After After addition addition was was completed completed, the, the mixturemixture was was warmed warmed to to room room temperature temperature and and stir stirredred for for 3 3h. h. The The color color of of the the mixture mixture gradually gradually changedchanged to to dark dark red. red. The The reaction reaction mixture mixture was was cooled cooled to to − 10−10 °C °C and and methyl methyl iodide iodide (7.8 (7.8 mL, mL, 0.12 0.12 mol) mol) waswas added added dropwise. dropwise. The The mixture mixture was was warmed warmed to to room room temperature, temperature, stirred stirred for for 3 3h huntil until the the color color

Molecules 2017, 22, 804 4 of 10

It must be added that fluorination with pyridine-HF complex (method C) requires special polyethylene or polytetrafluoroethylene plastic equipment, fluorination with anhydrous HF (method B) require stainless steel autoclave but fluorination with antimony trifluoride (method A) was performed in common glass equipment. All investigated methods of fluorination (A, B, and C) can be applied for the large-scale experiment. Thus, methyl 3-(trifluoromethoxy)propanoate 3b was prepared in quantity above 25 g at once and protected amine 3d was obtained in ca. 50 g at once by all three methods. The protective phthalimide group can be removed by common methods and was documented in [16].

3. Materials and Methods 1H-NMR spectra were recorded at 300 MHz with a Varian VXR-300 spectrometer (Varian Inc., Palo Alto, CA, USA), at 500 MHz with a Bruker AVANCE DRX 500 instrument (Bruker, Billerica, MA, USA), or at 400 MHz with Varian UNITY-Plus 400 spectrometer (Varian Inc, Palo Alto, CA, USA). 13C-NMR-spectra (proton decoupled) were recorded on a Bruker AVANCE DRX 500 instrument at 125 MHz, or at 100 MHz with Varian UNITY-Plus 400 spectrometer. 19F-NMR spectra were recorded at 188 MHz with a Varian Geminy-200 instrument (Varian Inc, Palo Alto, CA, USA), or at 376 MHz with Varian UNITY-Plus 400 spectrometer. Chemical shifts are given in ppm relative to Me4Si and CCl3F, respectively, as internal or external standards. 1H-, 13C-, and 19F-NMR spectra of the compounds can be found in Supplementary materials. LC-MS spectra were registered on an “Agilent 1100 Series” instrument with diode-matrix and mass-selective detector “Agilent 1100 LS/MSD SL” (ionization method: chemical ionization at atmospheric pressure; ionization chamber operation conditions: simultaneous scanning of positive and negative ions in the range 80–1000 m/z, Agilent Technologies, Santa Clara, CA, USA). GC-MS spectra were registered on a Hewlett-Packard HP GC/MS 5890/5972 instrument (EI 70 eV) (Philips, Bothell, WA, USA). Melting points were determined in open capillaries using an SMP3 instrument (Stuart Scientific Bibby Sterlin Ltd, Stone, Staffordshire, UK). Elemental analysis was performed in the Analytical Laboratory of the Institute of Organic Chemistry, NAS of Ukraine, Kiev. Unless otherwise stated, commercially-available reagents were purchased from Enamine Ltd. and were used without purification. Antimony trifluoride was sublimated immediately prior to use. Anhydrous hydrogen fluoride was distilled in the presences of SOCl2. HF70%/pyridine was prepared according to the Olah method [22]. Solvents were dried before use by standard methods. All reactions were performed in an argon atmosphere. For column chromatography, Merck Kieselgel 60 silica gel (Merck, Darmstadt, Germany) was used. Thin-layer chromatography (TLC) was carried out on aluminum-backed plates coated with silica gel (Merck Kieselgel 60 F254, Merck, Darmstadt, Germany).

3.1. Synthesis of Xanthates 1a–c: General Procedure Carbon disulﬁde (18.1 mL, 0.3 mol) was added dropwise at −30 ◦C to the suspension of sodium hydride (60% in mineral oil) (4.4 g, 0.11 mol) in anhydrous dimethylformamide (DMF) (200 mL). To this mixture the solution of corresponding hydroxyderivatives (0.1 mol) in anhydrous DMF (15 mL) was added dropwise for 3 h with mechanistic stirring at −30 ◦C. After addition was completed, the mixture was warmed to room temperature and stirred for 3 h. The color of the mixture gradually changed to dark red. The reaction mixture was cooled to −10 ◦C and methyl iodide (7.8 mL, 0.12 mol) was added dropwise. The mixture was warmed to room temperature, stirred for 3 h until the color changed from dark red to yellow and poured into ice (600 g), and extracted with tert-buthylmethyl ether (MTBE) (5 × 50 mL). The extract was washed with brine (5 × 50 mL) and dried with MgSO4. The solvent was removed at atmospheric pressure and the residue distilled in vacuum.

3.1.1. Methyl ([(methylsulfanyl)carbonothioyl]oxy)acetate 1a

◦ 1 Yield 15.5 g (86%). Yellow oil: bp 129–130 C (20 Torr). H-NMR (400 MHz, CDCl3): δ 2.60 (s, 3H, 13 SCH3), 3.77 (s, 3H, OCH3), 5.15 (s, 2H, CH2). C-NMR (100 MHz, CDCl3): δ 19.5 (s, SCH3), 52.4 Molecules 2017, 22, 804 5 of 10

+ (s, OCH3), 67.6 (s, CH2), 167.1 (s, C=O), 215.8 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 180 (69) [M] . Anal. calcd for C5H8O3S2: C, 33.32; H, 4.47; S, 35.58; found: C, 33.14; H, 4.51; S, 35.51.

3.1.2. Methyl 3-([(methylsulfanyl)carbonothioyl]oxy)propanoate 1b

◦ 1 Yield 17.8 g (92%). Yellow oil: bp 94–95 C (0.5 Torr). H-NMR (400 MHz, CDCl3): δ 2.52 (s, 3H, SCH3), 3 3 13 2.80 (t, J = 6.4 Hz, 2H, CH2), 3.70 (s, 3H, OCH3), 5.15 (t, J = 6.4 Hz, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 18.7 (s, SCH3), 32.9 (s, CH2), 51.6 (s, OCH3), 68.2 (s, CH2), 170.2 (s, C=O), 215.2 (s, C=S). + GC-MS, 70 eV, m/z (rel. int.): 194 (62) [M] . Anal. calcd for C6H10O3S2: C, 37.09; H, 5.19; S, 33.01; found: C, 37.17; H, 5.29; S, 32.94.

3.1.3. O-(2-Cyanoethyl)-S-methyl-dithiocarbonate 1c

◦ 1 Yield 14.3 g (89%). Yellow oil: bp 94–95 C (0.3 Torr). H-NMR (300 MHz, CDCl3): δ 2.53 (s, 3H, SCH3), 3 3 13 2.82 (t, J = 6.3 Hz, 2H, CH2), 4.73 (t, J = 6.3 Hz, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 17.3 (s, CH2), 18.9 (s, SCH3), 66.2 (s, CH2), 116.1 (s, C≡N), 214.9 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 161 (67) + [M] . Anal. calcd for C5H7NOS2: C, 37.24; H, 4.38; S, 39.77; found: C, 37.30; H, 5.44; S, 39.70.

3.2. Synthesis of Xanthates 1d–g: General Procedure To the stirred solution of hydroxyderivatives (0.1 mol) in anhydrous DMF (50 mL) sodium hydride (60% in mineral oil) (4.4 g, 0.11 mol) was added with mechanistic stirring between −5 and 0 ◦C. After addition, stirring was continued for 2 h at room temperature. Carbon disulﬁde (9 mL, 0.15 mol) was added dropwise at 0 ◦C. The reaction mixture was warmed to room temperature and stirred for 5 h. The color of the one was gradually changed to dark red. The reaction mixture was cooled to 0 ◦C and methyl iodide (7.8 mL, 0.12 mol) was added dropwise. The mixture was warmed to room temperature, stirred for 3 h until the color changed from dark red to yellow and poured into ice (100 g), extracted with CH2Cl2 (3 × 50 mL). The extract was washed with water (3 × 50 mL) and dried with MgSO4. After removal of the solvent the product was washed with hexane and dried in vacuum.

3.2.1. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl] S-Methyl Dithiocarbonate 1d

◦ 1 Yield 27.8 g (99%). Yellow powder: mp 105–106 C. H-NMR (400 MHz, CDCl3): δ 2.49 (s, 3H, SCH3), 3 3 4.10 (t, J = 5.6 Hz, 2H, CH2), 4.82 (t, J = 5.6 Hz, 2H, CH2), 7.71–7.73 (m, 2H, arom H), 7.83–7.86 (m, 2H, 13 arom H). C-NMR (125 MHz, DMSO-d6): δ 18.4 (s, SCH3), 36.3 (s, CH2), 70.6 (s, CH2), 123.2 (s, arom. C), 131.6 (s, arom. C), 134.6 (s, arom. C), 167.7 (s, C=O), 215.2 (s, C=S). LC-MS, m/z: 282 [M + H]+. Anal. calcd for C12H11NO3S2: C, 51.23; H, 3.94; N, 4.98; S, 22.79; found: C, 51.30; H, 4.00; N, 4.98; S, 22.70.

3.2.2. O-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl] S-Methyl Dithiocarbonate 1e

◦ 1 Yield 29.5 g (100%). Yellow powder: mp 101–102 C. H-NMR (300 MHz, DMSO-d6): δ 2.08–2.12 3 3 (m, 2H, CH2), 3.34 (s, 3H, SCH3), 3.71 (t, J = 6.3 Hz, 2H, CH2), 4.58 (t, J = 6.0 Hz, 2H, CH2), 7.83–7.85 13 (m, 4H, arom H). C-NMR (100 MHz, DMSO-d6): δ 18.8 (s, SCH3), 27.3 (s, CH2), 35.0 (s, CH2), 72.4 (s, CH2), 123.4 (s, arom. C), 132.1 (s, arom. C), 134.7 (s, arom. C), 168.3 (s, C=O), 215.6 (s, C=S). LC-MS, + m/z: 296 [M + H] . Anal. calcd for C13H13NO3S2: C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.92; H, 4.52; N, 4.68; S, 21.70.

3.2.3. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpropyl] S-Methyl Dithiocarbonate 1f

◦ 1 Yield 27.5 g (89%). Yellow powder: mp 85–86 C. H-NMR (300 MHz, CDCl3): δ 1.77 (s, 6H, 2CH2), 13 2.47 (s, 3H, SCH3), 4.98 (s, 2H, CH2), 7.70–7.73 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H). C-NMR (125 MHz, CDCl3): δ 18.5 (s, SCH3), 26.2 (s, 2CH3), 58.7 (s, C), 77.1 (s, CH2), 122.5 (s, arom. C), 131.4 (s, arom. C), 133.6 (s, arom. C), 168.8 (s, C=O), 214.7 (s, C=S). LC-MS, m/z: 310 [M + H]+. Anal. calcd for C14H15NO3S2: C, 54.35; H, 4.89; N, 4.53; S, 20.73; found: C, 54.42; H, 4.96; N, 4.50; S, 20.75. Molecules 2017, 22, 804 6 of 10

3.2.4. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-methylethyl] S-Methyl Dithiocarbonate 1g

◦ 1 3 Yield 28.9 g (98%). Yellow powder: mp 85–86 C. H-NMR (300 MHz, CDCl3): δ 1.43 (d, J = 6.4 Hz, 2 3 2 3H, CH3), 2.48 (s, 3H, SCH3), 3.89 (dd, J = 14.4 Hz, J = 3.2 Hz, 1H, CH2), 4.04 (dd, J = 14.4 Hz, 3 J = 7.6 Hz, 1H, CH2), 6.00–7.10 (m, 1H, CH), 7.70–7.72 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H). 13 C-NMR (125 MHz, CDCl3): δ 17.5 (s, CH3), 18.9 (s, SCH3), 43.7 (s, CH2), 77.6 (s, C), 123.5 (s, arom. C), 132.0 (s, arom. C), 134.2 (s, arom. C), 168.1 (s, C=O), 215.3 (s, C=S). LC-MS, m/z: 296 [M + H]+. Anal. calcd for C13H13NO3S2: C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.88; H, 4.86; N, 4.69; S, 21.76.

3.3. Synthesis of Trichloroderivatives 2a–g: General Procedure Chlorine was bubbled through the solution of xanthate 1a–g (50 mmol) in carbon tetrachloride (50 mL) at 0 ◦C for 1 h. The reaction mixture was warmed to 20 ◦C and chlorine was bubbled for further 1 h. Methylene chloride (10 mL) was added to the reaction mixture and chlorine was bubbled for further 1 h. Excess of chlorine was removed with stream of nitrogen. After removal of the solvent, product was distilled in vacuum or washed with hexane and dried in vacuum.

3.3.1. Methyl (trichloromethoxy)acetate 2a

◦ 1 Yield 9.0 g (87%). Colorless liquid: bp 87–88 C (10 Torr). H-NMR (400 MHz, CDCl3): δ 3.83 (s, 3H, 13 OCH3), 4.64 (s, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 52.7 (s, OCH3), 66.7 (s, CH2), 112.6 (s, CCl3), 166.2 (s, C=O). Anal. calcd for C4H5Cl3O3: C, 23.16; H, 2.43; Cl, 51.27; found: C, 33.12; H, 2.40; Cl, 52.35.

3.3.2. Methyl 3-(trichloromethoxy)propanoate 2b

◦ 1 Yield 9.8 g (89%). Colorless liquid: bp 64–65 C (0.5 Torr). H-NMR (300 MHz, CDCl3): δ 2.76 3 3 13 (t, J = 6.4 Hz, 2H, CH2), 3.71 (s, 3H, OCH3), 5.35 (t, J = 6.4 Hz, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 32.9 (s, CH2), 51.7 (s, OCH3), 66.4 (s, CH2), 111.9 (s, CCl3), 169.7 (s, C=O). Anal. calcd for C5H7Cl3O3: C, 27.12; H, 3.19; Cl, 48.02; found: C, 27.07; H, 3.12; Cl, 48.09.

3.3.3. 3-(Trichloromethoxy)propanenitrile 2c

◦ 1 Yield 8.7 g (92%). Colorless liquid: bp 77–78 C (0.3 Torr). H-NMR (300 MHz, CDCl3): δ 2.83 3 3 13 (t, J = 6.6 Hz, 2H, CH2), 4.29 (t, J = 6.6 Hz, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 17.6 (s, CH2), 64.8 (s, CH2), 111.9 (s, CCl3), 115.5 (s, C≡N). Anal. calcd for C4H4Cl3NO: C, 25.50; H, 2.14; Cl, 56.44; N, 7.43; found: C, 25.55; H, 2.14; Cl, 56.50; N, 7.40.

3.3.4. 2-[2-(Trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2d

◦ 1 3 Yield 14.8 g (96%). Colorless powder: mp 93–94 C. H-NMR (300 MHz, CDCl3): δ 4.06 (t, J = 5.3 Hz, 3 13 2H, CH2), 4.34 (t, J = 5.3 Hz, 2H, CH2), 7.74–7.76 (m, 2H, arom H), 7.83–7.86 (m, 2H, arom H). C-NMR (100 MHz, CDCl3): δ 36.4 (s, CH2), 68.1 (s, CH2), 112.5 (s, CCl3), 123.5 (s, arom. C), 131.8 (s, arom. C), 134.2 (s, arom. C), 167.8 (s, C=O). Anal. calcd for C11H8Cl3NO3: C, 42.82; H, 2.61; Cl, 34.47; N, 4.54; found: C, 42.90; H, 2.52; Cl, 34.50; N, 4.44.

3.3.5. 2-[3-(Trichloromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 2e

◦ 1 Yield 15.3 g (95%). Colorless powder: mp 102–103 C. H-NMR (400 MHz, CDCl3): δ 2.12–2.19 (m, 3 3 2H, CH2), 3.83 (t, J = 6.8 Hz, 2H, CH2), 4.16 (t, J = 6.0 Hz, 2H, CH2), 7.60–7.70 (m, 2H, arom H), 13 7.80–7.90 (m, 2H, arom H). C-NMR (125 MHz, CDCl3): δ 27.3 (s, CH2), 35.1 (s, CH2), 69.6 (s, CH2), 112.4 (s, CCl3), 123.3 (s, arom. C), 132.0 (s, arom. C), 134.0 (s, arom. C), 168.2 (s, C=O). Anal. calcd for C12H10Cl3NO3: C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75; H, 3.10; Cl, 33.00; N, 4.40.

3.3.6. 2-[1,1-Dimethyl-2-(trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2f

◦ 1 Yield 13.8 g (82%). Colorless powder: mp 93–94 C. H-NMR (500 MHz, CDCl3): δ 1.79 (s, 6H, 2CH3), 13 4.53 (s, 2H, CH2), 7.68–7.71 (m, 2H, arom H), 7.75–7.80 (m, 2H, arom H). C-NMR (125 MHz, CDCl3): Molecules 2017, 22, 804 7 of 10

δ 24.7 (s, 2CH3), 58.8 (s, C), 75.6 (s, CH2), 112.6 (s, CCl3), 123.1 (s, arom. C), 131.9 (s, arom. C), 134.1 (s, arom. C), 169.4 (s, C=O). Anal. calcd for C13H12Cl3NO3: C, 46.39; H, 3.59; Cl, 31.60; N, 4.16; found: C, 46.45; H, 3.50; Cl, 31.68; N, 4.05.

3.3.7. 2-[2-(Trichloromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 2g

◦ 1 3 Yield 13.7 g (85%). Colorless powder: mp 96–97 C. H-NMR (300 MHz, CDCl3): δ 1.55 (d, J = 6.3 Hz, 2 3 2 3 3H, CH3), 3.79 (dd, J = 14.1 Hz, J = 3.6 Hz, 1H, CH2), 4.06 (dd, J = 14.1 Hz, J = 8.1 Hz, 1H, CH2), 4.80–4.95 (m, 1H, CH), 7.70–7.80 (m, 2H, arom H), 7.85–7.95 (m, 2H, arom H). 13C-NMR (125 MHz, CDCl3): δ 18.4 (s, CH3), 42.1 (s, CH2), 78.2 (s, C), 123.5 (s, arom. C), 132.5 (s, arom. C), 134.2 (s, arom. C), 167.9 (s, C=O). Anal. calcd for C12H10Cl3NO3: C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75; H, 3.20; Cl, 33.00; N, 4.35.

3.4. Fluorination of Trichloromethoxy Derivatives 2a–g with Antimony Triﬂuoride (Method A)

3.4.1. Fluorination of Esters 2a–b and Nitrile 2c: General Procedure The mixture of pounded antimony triﬂuoride (17.9 g, 100 mmol) and antimonium pentachloride (1.5 g, 5 mmol) was carefully heated to 30−35 ◦C with mechanistic stirring to a homogenous pasty mass formation. The mixture was cooled to 0 ◦C and trichloromethoxy derivative 2a–c (50 mmol) was added at once. The reaction mixture was heated at 90 ◦C for 10 min. Then the mixture was heated to 120−135 ◦C with simultaneous vacuum (150 Torr) distillation of the product in the trap cooled with crushed ice. The pure product was obtained after redistillation.

3.4.2. Fluorination of Protected Amines 2d–g: General Procedure The mixture of pounded antimony trifluoride (17.9 g, 100 mmol) and antimonium pentacloride (1.5 g, 5 mmol) was carefully heated to 30−35 ◦C with mechanistic stirring to a homogenous pasty mass formation. The mixture was cooled to 0 ◦C and trichloromethoxy derivative 2d–g (50 mmol) was added at once. The reaction mixture was gradually heated firstly at 25 ◦C for 30 min, then at 45 ◦C for 30 min, and finally at 95 ◦C for 20 min. After cooling to room temperature the reaction mixture was washed with CH2Cl2 (5 × 50 mL), combined organic extracts were washed with 10% aqueous HCl solution (10 × 20 mL) then with water (5 × 20 mL) and dried with MgSO4. The solution was filtered through SiO2 and evaporated to dryness. The pure product was obtained after crystallization from hexane.

3.5. Fluorination of Trichloromethoxy Derivatives 2a–g with Hydrogenfluoride (Method B): General Procedure Trichloromethoxy derivative 2a–g (50 mmol) was placed into stainless steel autoclave (100 mL ◦ volume) and cooled to −40 C. Anhydrous HF (50 mL) and SbCl5 (0.75 g, 2.5 mmol) were added at the same temperature. Autoclave was sealed and the reaction mixture was heated at 45 ◦C for 0.5 h, then at 95 ◦C for 2.5 h, and cooled to room temperature. Excess of hydrogen fluoride and hydrogen chloride formed in the reaction were distilled in a polyethylene trap cooled to −15 ◦C. The residue was dissolved in CH2Cl2 (100 mL) washed with saturated aqueous K2CO3 solution (4 × 20 mL), then with water (3 × 20 mL), dried with MgSO4, and filtered through SiO2. After removal of the solvent, the product was distilled in vacuum or crystallized from hexane and dried in vacuum.

3.6. Fluorination of Xanthate 1a–g with Pyridine-Hydrogenﬂuoride and 1,3-Dibromo-5,5-Dimethylhydantoin (DBH) (Method C): General Procedure Reactions were performed in a polyethylene ﬂask (500 mL) equipped with an additional polyethylene funnel, magnetic stirrer, and BOLA PTFE coated temperature probe. ◦ Complex HF70%-pyridine was added dropwise at −78 C to a suspension of DBH (42.9 g, 0.15 mol) in CH2Cl2 (130 mL). The mixture was stirred for 10 min and the solution of corresponding xanthate 1a–g (0.05 mol) in CH2Cl2 (70 mL) was added at the same temperature. The reaction mixture was Molecules 2017, 22, 804 8 of 10 stirred at −78 ◦C for 1 h, warmed to room temperature, stirred for 5 h and poured into ice (100 g). As saturated aqueous solution of Na2SO3 was added to the mixture until the red color of the mixture changed to light yellow. Then the mixture was neutralized with aqueous K2CO3 solution. The organic layer was separated and the aqueous solution was extracted with CH2Cl2 (3 × 50 mL). Combined organic extracts were washed with water (3 × 500 mL) and dried with MgSO4. After removal of the solvent, the product was distilled or crystallized from hexane and dried in vacuum.

3.6.1. Methyl (triﬂuoromethoxy)acetate 3a Yield 2.84 g (36% method C). Colorless liquid: bp 102–104 ◦C (lit. 110 ◦C[11]). 1H-NMR (400 MHz, 13 CDCl3): δ 3.81 (s, 3H, OCH3), 4.48 (s, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 52.5 (s, OCH3), 62.9 3 19 (q, JCF = 2.5 Hz, CH2), 121.4 (q, JCF = 256.4 Hz, CF3), 166.5 (s, C=O). F-NMR (376.5 MHz, CDCl3): δ + −62.12 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 158 (46) [M] . Anal. calcd for C4H5F3O3: C, 30.39; H, 3.19; found: C, 30.12; H, 3.04.

3.6.2. Methyl 3-(triﬂuoromethoxy)propanoate 3b Yield 4.55 g (53% method A). Yield 5.9 g (69% method B). Yield 5.4 g (63% method B). Colorless liquid: ◦ 1 3 bp 124–125 C. H-NMR (300 MHz, CDCl3): δ 2.64 (t, J = 5.4 Hz, 2H, CH2), 3.66 (s, 3H, OCH3), 3 13 4.17 (t, J = 5.4 Hz, 2H, CH2). C-NMR (125 MHz, CDCl3): δ 33.2 (s, CH2), 51.3 (s, OCH3), 62.2 (q, 3 19 JCF = 3.3 Hz, CH2), 121.0 (q, JCF = 253.3 Hz, CF3), 169.8 (s, C=O). F-NMR (188 MHz, CDCl3): δ + −61.88 (s, CF3). GC-MS, 70 eV, m/z (rel. int.): 172 (52) [M] . Anal. calcd for C5H7F3O3: C, 34.89; H, 4.10; found: C, 34.55; H, 4.02.

3.6.3. 3-(Triﬂuoromethoxy)propanenitrile 3c Yield 1.5 g (22% method A). Yield 4.6 g (66% method B). Yield 4.6 g (66% method B). Colorless liquid: bp ◦ 1 3 3 100–102 C (120 Torr). H-NMR (300 MHz, CDCl3): δ 2.70 (t, J = 6.3 Hz, 2H, CH2), 4.11 (t, J = 6.3 Hz, 13 3 2H, CH2). C-NMR (125 MHz, CDCl3): δ 18.0 (s, CH2), 61.2 (q, JCF = 3.4 Hz, CH2), 115.3 (s, C≡N), 19 120.8 (q, JCF = 255.1 Hz, CF3). F-NMR (188 MHz, CDCl3): δ −62.10 (s, CF3). GC-MS, 70 eV, m/z (rel. + int.): 139 (66) [M] . Anal. calcd for C4H4F3NO: C, 34.54; H, 2.90; N, 10.07; found: C, 34.40; H, 2.84; N, 9.90.

3.6.4. 2-[2-(Triﬂuoromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 3d Yield 11.65 g (90% method A). Yield 12.0 g (93% method B). Yield 12.4 g (96% method B). Colorless ◦ ◦ ◦ 1 powder: mp 73–74 C (lit. 77 C[16]), bp 100–102 C (0.2 Torr). H-NMR (300 MHz, CDCl3): δ 3.93 (t, 3 3 J = 5.3 Hz, 2H, CH2), 4.20 (t, J = 5.3 Hz, 2H, CH2), 7.70–7.77 (m, 2H, arom H), 7.80–7.90 (m, 2H, arom 13 H). C-NMR (125 MHz, CDCl3): δ 36.7 (s, CH2), 63.9 (s, CH2), 121.7 (q, JCF = 255.2 Hz, CF3), 123.5 (s, 19 arom. C), 131.8 (s, arom. C), 134.2 (s, arom. C), 167.8 (s, C=O). F-NMR (188 MHz, CDCl3): δ −61.55 + (s, CF3). LC-MS, m/z: 260 [M + H] . Anal. calcd for C11H8F3NO3: C, 50.98; H, 3.11; N, 5.40; found: C, 50.90; H, 3.23; N, 5.44.

3.6.5. 2-[3-(Triﬂuoromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 3e Yield 12.0 g (88% method A). Yield 12.3 g (90% method B). Yield 13.0 g (96% method B). Colorless ◦ 1 powder: mp 77–78 C. H-NMR (400 MHz, CDCl3): δ 2.04–2.12 (m, 2H, CH2), 3.70–3.82 (m, 2H, CH2), 13 4.00–4.12 (m, 2H, CH2), 7.68–7.72 (m, 2H, arom H), 7.80–7.88 (m, 2H, arom H). C-NMR (125 MHz, CDCl3): δ 28.0 (s, CH2), 34.8 (s, CH2), 65.1 (s, CH2), 121.6 (q, JCF = 254.0 Hz, CF3), 123.4 (s, arom. C), 19 132.1 (s, arom. C), 134.2 (s, arom. C), 168.3 (s, C=O). F-NMR (376.5 MHz, CDCl3): δ −61.49 (s, CF3). + LC-MS, m/z: 274 [M + H] . Anal. calcd for C12H10F3NO3: C, 52.75; H, 3.69; N, 5.13; found: C, 52.77; H, 3.70; N, 5.22. Molecules 2017, 22, 804 9 of 10

3.6.6. 2-[1,1-Dimethyl-2-(triﬂuoromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 3f Yield 8.6 g (60% method A). Yield 8.9 g (62% method B). Yield 12.2 g (85% method B). Colorless powder: ◦ 1 mp 73–74 C. H-NMR (300 MHz, CDCl3): δ 1.69 (s, 6H, 2CH3), 4.35 (s, 2H, CH2), 7.60–7.67 (m, 2H, 13 arom H), 7.70–7.77 (m, 2H, arom H). C-NMR (125 MHz, CDCl3): δ 24.8 (s, 2CH3), 58.3 (s, C), 70.7 (s, CH2), 120.2 (q, JCF = 253.3 Hz, CF3), 122.5 (s, arom. C), 131.3 (s, arom. C), 133.6 (s, arom. C), 168.9 (s, 19 + C=O). F-NMR (376.5 MHz, CDCl3): δ −61.11 (s, CF3). LC-MS, m/z: 288 [M + H] . Anal. calcd for C13H12F3NO3: C, 54.36; H, 4.21; N, 4.88; found: C, 54.47; H, 4.47; N, 4.85.

3.6.7. 2-[2-(Triﬂuoromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 3g Yield 3.1 g (23% method A). Yield 4.6 g (34% method B). Yield 13.5 g (99% method B). Colorless powder: ◦ 1 2 3 mp 71–72 C. H-NMR (500 MHz, CDCl3): δ 1.40–1.43 (m, 3H, CH3), 3.79 (dd, J = 14.0 Hz, J = 2.0 Hz, 1H, CH2), 3.94–4.00 (m, 1H, CH2), 4.80–4.95 (m, 1H, CH), 7.74 (s, 2H, arom H), 7.87 (s, 2H, arom H). 13 C-NMR (125 MHz, CDCl3): δ 18.6 (s, CH3), 42.3 (s, CH2), 72.9 (s, C), 121.5 (q, JCF = 255.1 Hz, CF3), 19 123.5 (s, arom. C), 131.7 (s, arom. C), 134.2 (s, arom. C), 168.0 (s, C=O). F-NMR (376.5 MHz, CDCl3): + δ −59.19 (s, CF3). LC-MS, m/z: 274 [M + H] . Anal. calcd for C12H10F3NO3: C, 52.75; H, 3.69; N, 5.13; found: C, 52.70; H, 3.44; N, 4.12.

4. Conclusions The “chlorination/fluorination” technique for aromatic trifluoromethyl ether syntheses, since 1955, has been a powerful driver of research in organofluorine chemistry. More than 30,000 substances [4] with such a group were prepared in the last half century. It was shown that this method, as well as oxidative desulfurization-fluorination, can be successfully applied for a wide range of aliphatic substrates with various functional groups. It requires cheap reagents and it is promising in industrial applications.

Supplementary Materials: 1H-, 13C-, and 19F-NMR spectra of products associated with this article are available online. Author Contributions: L.M.Y. conceived idea of the article; T.M.S., M.I.D., E.M., and Y.L.Y. conceived and performed the experiments; and T.M.S. and Y.L.Y. wrote the paper. All authors except L.M.Y. read and approved the final manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.

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