Recent advances in organofluorine chemistry ~ ~~~ JONATHAN M. PERCY School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT Reviewing the literature published between January 1992 and April 1995 1 2 2.1 2.2 2.3 2.4 2.5 3 3.1 3.2 3.3 3.4 3.5 3.6 4 4.1 4.2 5 6 Introduction Fluorinated carbon nucleophiles Perfluoroalkyl organometallic reagents Fluoroalkenyl organometallic reagents Met allat ed fluoroenol derivatives Fluoroenolates and enol silyl ethers Phosphonyl- and sulfonyl-stabilized carbanions Fluorinated carbon electrophiles Fluoroalkyl ketones a-Fluoro-a$-unsaturated carbonyl compounds P-Fluoro-a,p-unsaturated carbonyl compounds y-Fluoro-a,P-unsaturated carbonyl compounds Fluoroalkyl epoxides Fluoroallylic electrophiles Pericyclic reactions Diels-Alder and dipolar cycloadditions Sigmatropic rearrangements and ene reactions Free radical reactions References 1 Introduction This Review deals with advances in the chemistry of fluorinated building blocks which are small, readily- available, and manipulable molecules that already contain one or more fluorine atoms.The article concentrates on aliphatic chemistry wherein lies the main intellectual challenge. No effort will be made to cover the burgeoning literature describing functional group transformations with reagents such as DAST, elemental fluorine, or xenon difluoride.lP2 Recent more specialized reviews have discussed routes to fluorinated amino acids3 and aspects of the electrochemistry of organofluorine compound^.^ The material is organized under fairly broad headings reflecting the relative youth of much of the chemistry.2 Fluorinated carbon nucleophiles 2.1 Perfluoroalkyl organometallic reagents A multitude of methods exist for the trifluoromethylation of organic substrates, forming the subject of a recent specialized re vie^.^ One particularly accessible method uses commercially- available (trifluoromethyl) trimethylsilane (Ruppert’s reagent) 1 which adds efficiently to carbonyl electrophiles in the presence of fluorine ion sources. The reactive species is presumably the silicon-ate complex 3 and recent applications have included syntheses of deoxysugars in both hexose6 and pentose7 series. Scheme 1 shows a typical sequence from protected ribonolactone 2 through to D-lyxose ketal 4; yields of adducts are high but the reagent usually shows low diastereoselectivity in the addition step.Other peduoroalkylation reactions (i) 2. THF (ii) EtNF (cat.) (iii) TBAF 4 1 Me3SiCF3 Scheme 1 4 (69%) have been described by Uno and co-workers.8 Readily-available perfluoroalkyl iodides undergo halogen-metal exchange at low temperature. The first formed perfluoroalkyllithium reagent reacted with the iodide precursor to afford iodinate complex 5 (Scheme 2). The ate-complex was believed to act as a reservoir for the reactive perhoroalkyllithium reagents. When the complexes were generated in the presence of electrophiles, good yields of adducts could be obtained via the removal of the reactive but thermally-unstable perfluoroalkyllithium reagent 6 from the equilibrium. Scheme 2 In the presence of boron trifluoride etherate, good yields of adducts with imines were obtained.’ Scheme 3 depicts the addition of perffuorohexyl iodide to imine 7 affording 8 in moderate chemical yield but with high diastereoselectivity.Percy: Recent advances in organofluorine chemistry 251Scheme 3 2.2 Fluoroalkenyl organometallic reagents The pioneering work of Normant, Burton, and others has formed the subject of a recent review." Readily available 2-bromo-l,l,l-trifluoropropene can be used in a range of organometallic reactions. Scheme 4 shows a Barbier reaction with aldehydes mediated by a zinc-copper couple to afford allylic alcohols 9.'' RCHO F3CA& ZWCU co~pIe, OM; F3C HO 50 OC, 4-8 hours 9 R = Pr, Pr', Ph (7045%) Scheme 4 Interestingly, the vinylzinc reagent 10, prepared by stoichiometric chemistry in THF or DMF, failed to react with aldehydes.The reactive species in the Barbier reaction was believed to be an unsolvated vinylorganometallic reagent. Hu and co-workers have described coupling reactions of 10 with (bromoviny1)-dialkylboranes (Scheme 5), leading to triene 11.12 The bromide reacted directly with alkynes under palladium catalysis in the presence of copper( I) iodide to afford trifluoromethyl enynes in good yield. PdC12(PPh& NaOEt, PhH 60 %, 3 hours 1 F3C h n - h x 11 (68%) Scheme 5 An analogue 12 of the fungal metabolite siccayne has been prepared in this way (Scheme 6).13 Enynyl silane 13 has been added to aldehydes in the presence of a fluoride source to afford allylic alcohols 14. Aromatic aldehydes give high (70-80%) yields of adducts but additions to aliphatic aldehydes were less efficient (Scheme 7).Treatment of 2-bromo-l,l,l-trifluoropropene with LDA (2 equivalents) afforded lithio trifluoropropyne 15 OMOM PdCl2(PPh& CUI, EtaN, THF c r.t., 10 hours OMOM OMOM 12 (85%) Scheme 6 13 CSF, 1- THF, -20 OC RCHo I F3c\R OH 14 R = 4MeO-Ph. Ps, Et !jO-8!j% Scheme 7 which was trapped in situ, with 3-(benzyloxy)propanal at the start of a synthesis of 2,6-dideoxy-6,6,6-trifluorosugars. l4 Lipase-catalysed resolution of 16 allowed the isolation of the enantiomer 17 in high ( > 99%) e.e. (Scheme 8). The protected L-oliose analogue 18 was obtained following standard manipulations. 18 Scheme 8 17 (40%; >99% e.e.) Difluorovinylboranes (see Section 2.3 for their synthesis) are versatile carbon nucleophiles; Scheme 9 shows some of the products available from borane 19. Transmetallation with copper(1) salts in HMPA affords a reactive difluorovinylcopper reagent.Phosphine oxide 20 was obtained in good yield following transmetallation of 19, reaction with the phosphorus electrophile, and oxidation with excess hydrogen per~xide.'~ Vinyl halides16 and aryl iodides17 coupled efficiently with 19 under palladium catalysis to afford styrenes 21 (with retention of alkene configuration) and dienes 22 252 Contemporary Organic Synthesisrespectively. The vinylcopper reagent was sufficiently reactive to afford good yields of enones 23 upon treatment wth acid chlorides." R' P' ( i ) Cul, HMPA * F+RI 20 (88%) (ii) Arl. PddbasPPh3 I F 21 Ar = 4-02NPh, 4-MeOPh 90-94% F 19 R = Bu".Bus P' CuI, HMPA Pd2dbao.PP h3 I (i)Cul,HMPA ~ FhR2 (ii) R~COCI F O 23 Scheme 9 Because of the low reactivity of fluorovinylcopper reagents, conjugate addition of fluoroalkenyl units to enones had not been reported until the publication of a solution by Yamamoto and co- w o r k e r ~ . ~ ~ When complexed with a tris( ary1oxy)aluminium complex (ATPH 24), enones underwent 1,4-addition with an excess of fluoroalkenyllithium reagents at low temperature, affording adducts 25 and 26 in good yield (Schemes 10 and 11). The procedure therefore avoided transmetallation (and consequent loss of reactivity) of the fluoroalkenyl nucleophile. Ph 24 (ATPH) (9 ATPH, CHzCh, hexane c (i9 C2F5LI c2F5 25 (51%) Scheme 10 -bF (9 ATPH, CH&, hexarm (I9 F,C=CFLI, -78 "C F 26 (75%) 6 Chromium carbene chemistry has been found to accommodate fluoroalkenyl components. A highly substituted fluorophenol27 has been formed in a low yielding carbene annulation sequence (Scheme 12).20 Less reactive fluoroalkenyllithium reagents, or alkynes bearing sterically demanding substituents, failed to yield phenolic products.(i) PhGCPh, Bu'OMe, 55 "c (i9 FOCI, DMF 1 OH Ph I OMe 27 (35%) Scheme 12 McCarthy and co-workers have described chemistry that affords synthetic equivalents to a-fluoroalkenyl anions.21 A squalene epoxidase inhibitor (28) has been prepared using a modified Suzuki coupling from an a-fluoroalkenyl iodide (Scheme 13).22 Interestingly, the iodide was prepared from a vinylstannane precursor which presumably failed to undergo Stille coupling.This result suggests that such species are relatively poor coupling partners in palladium-catalysed procedures. Nevertheless, a Stille coupling was used successfully during the synthesis of thymidylate synthetase inhibitor 31 (Scheme 14), though DMF was required as the solvent and the reaction occurred slowly.23 Coupling was also achieved with acid chlorides and aryl iodides. Mild protodesilylation of 30 completed the synthesis of 31. The synthesis of the a-fluoroalkenyl anion equivalent 29 is discussed in Section 2.5. Vinylphosphonates have also been prepared from the corresponding iodides by a coupling reaction.24 0 -0.1 R NaOH, Pd(PPh& F F 28 (82%) R=T*- Scheme 11 Scheme 13 Percy: Recent advances in organofluorine chemistry 25329 Pd(PPhd4 _I_c DMF 30 R = SiM% (28%) F M e 3 s i d s n B " 3 25 O C 29 Scheme 14 2.3 Metallated fluoroenol derivatives A dehydrofluorination/metallation sequence from commercial 2,2,2-trifluoroethyl tosylate (32) provides the entry point to Ichikawa's versatile borane 19 via 1,Zrnetal-ate rearrangement (Scheme 15) of complex 33.18 More recently, two groups have ,"" Bu"Li F3C THF,-78OC - 32 F F u F When 35 adds to aldehydes or ketones, the first- formed alkoxide undergoes a rapid transacylation reaction,26(a) releasing basic enolate 37 which can be trapped with non-enolizable aldehydes, to afford aldol products 38 in high yield though with low stereoselectivity (Scheme 17).26(b) OLi -78 to 0 oc F oCONEt2 37 (€)-H&CH=CHCHO 1 OH 0 38 (62% 1:l syn:anfi) Scheme 17 2.4 Fluoroenolates and enol silyl ethers The Reformatsky reaction of ethyl bromodifluoroacetate (39) with aldehydes (Scheme 18) is a ubiquitous process for the synthesis of compounds containing a difluoromethylene group.The zinc-promoted reaction appears to be BRI -78 OC [ '9;R2] 33 1 Ooc R F+BR2 t 19 R = Bu", BU8, (CHd3Ph Scheme 18 Scheme 15 developed chemistry of the metallated enol carbamate 35, derived from 34, in independent s t u d i e ~ . ~ ~ , ~ ~ ( ~ ) The intermediate is a versatile carbon nucleophile; the reaction with (trimethylsily1)methyl triflate affords an ally1 silane 36 that adds to aldehydes in the presence of a fluoride ion source (Scheme 16).25 OCON Et2 OCONEt2 34 i. 35 R+ JCHo F+SiMer TBAF F F THF,O°C F 36 R = Pr', Ph 3844% ?H BrF2CCO2Et - Zn, THF 39 Aor ))) 0 fl: 40 39 Zn, THF A I '1 41 II Scheme 16 Scheme 19 254 Contemporary Oqanic Synthesisparticularly amenable to scale-up; indeed the Eli Lilly plant scale route to the anti-tumour nucleoside gemcitabine is based upon the rea~tion.'~ The addition reaction displays low diastereoselectivity.On a large-scale, the unwanted diastereoisomer was removed by recrystallization of a benzoate derivative. On smaller-scales, chromatographic separation or recrystallization may be possible. An inhibitor of interleukin-lfl converting enzyme has been prepared28 from 39 and lactam aldehyde 40. The highly electron-withdrawing nature of the CF2 group was evinced by the coexistence of 41 with hemiacylal42 (Scheme 19). Doherty and co-workers have explored the ultrasound promoted Reformatsky reaction to prepare renin inhibitors." On a small-scale, sonication conditions minimized racemization of the sensitive aldehyde 43, though attempts to use the procedure on a large-scale were unsuccessful.Instead, (R)-diastereoisomer 44 was obtained in high purity (>95% d.e. after crystallization) via the thermal reaction, though an excess of 39 was required to obtain reproducible yields (Scheme 20). 44 II 45 HCJ&O&i DCC,DMSO I I CH&, 0 O C to r.t. 46 (7&Q5%) Scheme 20 Percy: Recent advances in organofluorine chemistry An interesting, modified Pfitzer-Moffat oxidation procedure has been developed which allows conversion of the secondary alcohol 45 into ketone 46 in good yield (75-90%) with minimal epimerization a- to the ketonic carbonyl group.Scheme 21 shows the synthesis of a 4,4-difluoro-~- arginine analogue 49.30 Reformatsky reaction with Garner's aldehyde (47) was followed by treatment with thiocarbonyldiimidazole and free radical deoxygenation to afford 48 in good yield. h i d e reduction proceeded smoothly with Red-Al, followed by protection of the primary amino group and manipulation to 49. 47 O (i) 39 Zn. THF ))) o O C to r.t. (ii) I@=S ' d y C F & O & t OCSlm 48 ( i ) NH3. Et20,-78 OC (ii) Red-AI, PhMe, r.t (iii) Cbz-CI. NaHQ. EtOAc Scheme 21 An extended ester enolate has been generated and trapped in high yield when chlorodifluorocrotonate (50) was treated with aldehydes in the presence of a zinc-copper couple (Scheme 22).31 The crotonate was prepared by Wadsworth-Horner-Emmons reaction upon chlorodifluoroacetaldehyde and the extended (i) LIAIH., Et&, -78 OC c'F2cco2Et (ii) ( E t 0 ) ~ P O C H ~ O g ~ c ' F 2 c ~ C 0 2 E t Et3N, LiEr.THF 50 (&I%) Zn(Cu) couple PhCHO I THF, 0 % 51 (61%; 1:l syn:anti) Scheme 22 255Reformatsky reaction gave good yields of y,y-difluoro homoallyl alcohols 51 with a range of aldehydes. Yields with ketone electrophiles were relatively poor. An aldol reaction between ketone 52 and paraformaldehyde was used recently in the synthesis of a potential myristoyl transferase inhibitor 54 (Scheme 23).32 The reaction was catalytic in titanium tetrachloride and, though direct, occurred in modest yield. Aldol53 was elaborated by activation to the triflate and displacement by a thiolate nucleophile.Scheme 23 More efficient Mukaiyama aldol reactions have been performed with difluoroenoxysilanes. Newer methods for their synthesis have exploited the Brook rearrangement. Treatment of acylsilane 55 with a Grignard reagent affords an adduct 56 that collapses to silic-ate species, 57 (Scheme 24). The carbon-silicon bond is then sufficiently reactive to cause cleavage of an antiperiplanar carbon-fluorine bond, forming the enoxysilane 58.33 Using isopropylmagnesium bromide as the nucleophile allowed 59 to be isolated in excellent yield. 55 56 57 Scheme 24 OSiPh3 OSiPh3 F+H F$h F F 59 58 (8&100%) A similar approach was followed by P ~ r t e l l a ~ ~ who introduced a trifluoromethyl nucleophile using Rupperts reagent 1 and the non-hygroscopic fluoride source, 60, described by Gingras (Scheme 25).35 The difluoroenoxysilanes undergo Mukaiyama aldol reactions when treated with titanium tetrachloride in the presence of aldehydes.A brassinosteroid analogue has been synthesized via this approach.33 Lithium difluoroenolates have also been deployed in the aldol reaction though only low diastereoselectivities have been reported to date.26(b) [Ph3SnF2]NBu4 60 OH 0 0 OSiMe2R2 F+Rl TCI4- phvR PhCHO RiKSiMe2R2 - TclF . . .. R’ = odyl, Ph -78 to -30 Dc F CH2CI2 F7 ‘F R2 = Me, But R = Ph, 71% 4d79yo -78 O C to r.t. Scheme 25 2.5 Phosphonyl- and sulfonyl-stabilized carbanions McCarthy36 has described a range of useful reactions based upon fluoromethylphenylsulfone (61). Though the preparation of the compound is non-trivial, it can be used to prepare a-fluorovinylsulfones with interesting properties.Treatment of 61 with an amide base in the presence of diethylphosphochloridate affords a highly stabilized carbanion that is still sufficiently reactive to undergo a Wadsworth-Horner-Emmons reaction with aldehydes and ketones (Scheme 26). Mixtures of (E)- and (Z)-vinylsulfones are obtained, which have been separated in some cases.37 Treatment with tributyltin hydride/AIBN results in stannylative desulfonylat ion2’ with retention of configuration to afford 62. The stannyl group can then be used to introduce an iodine, fluorine, or hydrogen atom (Scheme 27). Protodestannylation22 occurred on treatment with sodium methoxide, ammonia in methanol, or TBAF, while reaction with SelectfluorTM 63 in acetonitrile resulted in a high yielding tidfluorine exchange,38 The chemistry has been used in the syntheses of an antitumour nucleoside 64,39 and analogues of eugenol methyl ether 65, a sex attractant of the Oriental Fruit Fly.40 Scheme 26 62 MeCN.80 % F q R F Scheme 27 63 256 Contemporary Organic SynthesisH O T c Me0 MeorF HO i 64 65 An interesting application of sulfone 61 involves trapping the lithium anion with (chloromethy1)dimethylphenylsilane to afford 66 as a stable crystalline solid in good yield.4' Retreatment with butyllithium, followed by the addition of an aldehyde triggered a Peterson-type elimination in which carbon-sulfur bond cleavage occurred from the silic-ate to afford an allylic silylether 67 (Scheme 28).Silane 66 is therefore an extremely useful alternative synthetic equivalent for the a-fluoroethenyl anion. 66 i OSiMe2Ph 67 Scheme 28 Fluorinated phosphonate carbanions have been used to prepare mimics of biologically important phosphate esters. O'Hagan and Nie~chalk~~ have described a synthesis of 70 (Scheme 29) involving the alkylation of the fluorophosphonate carbanion 68 with the primary alkyl triflate 69. Free radical deoxygenation provides an attractive alternative to alkylation chemistry. Bu"Li, Me3SiCI Me3SY PO(OEt)2 BrF2CPO(OEt)2 THF, -78 OC ti 68 (0 69 (ii) LiOEt. EtOH (iii) NH4Ci 83% OTf (iv) Me3SiBr (v) C6HllNH2 I Martin and c o - ~ o r k e r s ~ ~ have described the basic methodology which was used in a recent syntheses of the phosphoserine analogue* 71 (Scheme 30) and nucleotide 5'-deoxy- 5'-difl~oromethylphosphonates~~ 72.The OCSOPh 86% PhMe 68% (iii) HCI. EtOH (iv) RuCI~, NaIO4 (XI4. MeCN 1 phosphate buffer H02CeCF2PO(OEt)2 NHBOC 71 (32%) Scheme 30 attachment of the difluoromethylenephosphonato group to secondary carbon centres remains a problem, though two potentially general solutions have emerged. Addition of a lithiodifluorophosphonate to methyl vinyl ketone, followed by rearrangement of the allylic alcohol product afforded 73 in good yield as a single stereoisomer (Scheme 31).46 Scheme 32 shows a conjugate addition solution to the pr~blem.~' In the presence of cerium(m) chloride, the lithiodifluorophosphonate added to nitroalkenes in acceptable yield to produce 74. $ 8 H d \OH 72 (B= U, C, A) Scheme 29 73 (82%) Scheme 31 Percy: Recent advances in organofluorine chernistty 257I addition of iododifluoromethyl ketone 78 to N,AJ- dimethylacrylamide afforded the ketoamide in good yield.Treatment with aqueous ammonia converted the reactive difluoromethylene ketone into the corresponding imine. Cyclization followed by dehydrofluorination completed the synthesis of pyrrole 79. (I) LDA. Cec!, THF, -78 OC RqNo2 'F~cpo(oEt)2 (ii) (E)-RHC=CHNG - (iii) HOAc CFpPO(OEt);! 74 R = Et, Pi, But, t% 25-62% Scheme 32 3 Fluorinated carbon electrophiles 3.1 Fluoroalkyl ketones Fluoroalkyl ketones and related carbonyl compounds are reactive carbon electrophiles with diverse synthetic and medicinal chemistry. Fluoroalkyl ketones form the subject of a recent review.48 Fluoromethyl ketones were prepared by a sequence involving a sulfoxide elimination (Scheme 33).The conjugate base of 75 added to aldehydes in excellent yield. Flash vacuum pyrolysis of the adducts has afforded ketones 76 in moderate yield.49 Simple compounds of this type should be available from the reaction between silyl enol ethers and the Selectfluorm reagent?' Alternatively, the N,N- diisopropylcarbamate of difluoroethanol functions as an acyl anion equivalent (77) upon treatment with strong base (Scheme 34)' Difluoromethyl ketones have been prepared from trifluoroethanol by a similar but higher yielding route.26(a) 0 0 I I II LDA. -78 OC F 1O:l THF:HMPA Ph0'? - F 7s 1 PhCH2CH0 76 (45%) 9lYo Scheme 33 OR 40% Scheme 34 Difluoromethylene ketones are usually prepared by the Reformatsky chemistry described in Section 2.4.An alternative approach was recently described by Burton and Qiu?' and deployed in syntheses of B-fluoropyrroles (Scheme 35).53 Palladium-catalysed 79 (9o-Yo.f Scheme 35 Trifluoromethyl ketones have been prepared in good yield using a new method described by Zard and co-w~rkers.~~ The reaction proceeds via an acyl ketene intermediate but requires the formation of an acid chloride (Scheme 36), which limits the range of functionality that can be present. Kitazume and (F3CCO)20 T F3c9 H217 c1p(CH2)7 0 759/0 0 Scheme 36 co-workers have prepared furanyl trifluoromethyl ketones en route to a range of 6-deoxy- 6,6,6-trifluoro~ugars.~~ Trifluoroacetylation of lithio- 2-trimethylsilylfuran afforded ketone 80; reduction of the ketone afforded alcohol 81 as a racemic modification in excellent overall yield from furan (Scheme 37).Lipase resolution followed by furan oxidation afforded optically pure butenolide 82 which was converted into a range of optically-pure 6-deoxy-6,6,6-trifluorosugars, including 83 (Scheme The direct perfluoroacylation of alkynes has been achieved using an interesting procedure (Scheme 38).56 Presumably, the sequence involves the initial formation of a vinyl cation which is intercepted by the sulfur nucleophilic to afford vinyl sulfonium salt 84. Demethylation affords 85 in which some isomerization has occurred. Peracetic acid oxidation led to the formation of 86 in excellent chemical yield as the single (Z)-stereoisomer. Analogues of vitamin E have been prepared using Wittig 37).2 5 8 Contemporary Otganic SynthesisF3C* TMS HO 81 (82%; 5 steps) .I TBSO F3cYr HO' 83 Scheme 37 C0CF.q CH2C12. -40 OC 84 [95% ( E ) : ( Z ) = 2:3] H202 COCFS Ph 9 HOAc P h F C O C F , reflux S0,Me SMe 86 (88%) 85 (95% ( E ) : ( Z ) = 1 :3] Scheme 38 reactions of trifluoromethylketones, which show high reactivity towards phosphorus ylidsS7 Scheme 39 shows the preparation of an intermediate 87 from ethyl trifluoroacetoacetate which displays the usual (Z)-selectivity in the reaction of trifluoromethyl ketones with unstablized ylids. A useful aldehyde equivalent has been prepared from ethyl trifluoroacetate. Dibal-H reduction gave 88 in situ. Further treatment with an allylstannane and zinc bromide afforded good yields of homoallylic alcohols (Scheme 40).58 h- 87 [(E ):(Z) = 23:7n Scheme 39 Scheme 40 3.2 a-Fluoro-a, fl-unsaturated carbonyl compounds The standard method for the preparation of a-fluoro-enals and -enones involves the fragmentation of chlorofluorocyclopropanes, obtained by halocarbene additions to enol ethers.59 A full discussion of this methodology lies outside the range of this review and few applications in target synthesis have been reported in the open literature.However, the extensive use made of this methodology by Johnson and co-workers is discussed later in this review. The synthesis of a-fluoroenoate esters by Wadsworth-Horner- Emmons methodology has been described by Burton and Thennapan.60 A recent application Piva (Scheme 41) displayed the usual selective formation of the (E)-alkene diastereoisomer.61 Photoisomerization of adduct 89 afforded P,y-unsaturated ester 90 as a mixture of diastereoisomers in moderate yield.A bY complementary procedure has been described by F i c o 2 E t PO( OEt), (i) Bunti, THF, -78 OC - (ii) TBSO(CH2)2CH0 89 F [80%; ( E ) : ( Z ) = 98:2] h, Et3N CH&. 0 O C I Scheme 41 Clemenceau and Cousseau.62 Sodium salt 91 reacted with aldehydes to afford (Z)-fluoroenoates in moderate chemical yield. High diastereoselectivities resulted when bulky aldehydes were used in the reaction. Scheme 42 shows the most selective example. (Z)-Fluorothioenoates were prepared using the a-fluoroacrylate-P-cation equivalent 92 prepared from fluoroacetonitrile by a simple procedure (Scheme 43). Grignard reagents added at the carbonyl group and treatment with acid initiated dehydration with double bond migration and formation of an allylic thioacetal; thioacetal hydrolysis affords 93.63 Percy: Recent advances in olganojluorine chemistry 2590 Scheme 42 F /CN- MeS,&,, THF.HMPA hne6 83YO -78 OC Dibal-H CH& 0 OC (ili) Pr'MgCI.Et$, r.t. I (hr) HgCIz. MeCN (a%) M e S A CHO reflux mcosMe ' F 93 (67%) Me& 92 (70%) Scheme 43 A palladium-catalysed route to a-fluoroenones (Scheme 44) was published recently,64 based upon chemistry developed by Tsuji. In acetonitrile, ketoester 94 underwent decarboxylative elimination to afford enone 95 in good chemical yield. More highly substituted derivatives have been prepared from (2H)tetrafluoropropanol. Conversion into the tosylate and brief exposure to n-butyllithium yielded enol tosylate 96 as a mixture of diastereoisomers.Treatment with a secondary amine in the presence of a fluoride ion source led to the formation of /?-aminoenal97 in excellent yield (Scheme 45).65 94 Scheme 44 95 (74%) HF~CCF~CH~OTS B""Li_ THF HF&$OTs+ ph/(,,,H2 -78% 10% TBAF EtSN. THF 97 (94%) 3 3 fl-Fluoro-a, /?-unsaturated carbonyl compounds Fluorine atoms located on the /&carbon of an a,fl-unsaturated carbonyl compound are replaced readily in additiodelimination reactions with nucleophiles. Ichikawa has used difluoroenones to prepare highly substituted enones shows a recent example. There is a significant difference in reactivity between the di- and mono- fluoroenones 98 and 99, allowing the incremental replacement of the two fluorine atoms with different carbon nucleophiles.Carbon nucleophiles were delivered via cuprate and zincate reagents. A similar sequential displacement with heteroatom nucleophiles has also been described.67 Scheme 46 98 99 [79%; ( E ) : ( Z ) = 89:11] PhfiuMgI O V P h +B" Bu 100 [85%; (E):(Z) = 1:1] Scheme 46 3.4 y-Fluoro-a, fl-unsaturated carbonyl compounds Seebach and co-workers have described a range of useful reactions based upon chiral dioxinone 101 derived from trifluoroacetoacetate.68 Scheme 47 shows a diastereoselective conjugate addition of a Gilman reagent. Conjugate additions of alkyllithium reagents to y,y,y-trifluoroenones in the presence of the ATPH complex were described by Yamamoto and c o - ~ o r k e r s .~ ~ Taguchi and co-workers have described the preparation and reactions of the interesting bromodifluorocrotonate ester 102, which underwent Michael additions with lithium enolates to furnish adducts 103 (Scheme 4Q7' However, when the intermediate enolate was treated with triethylborane and oxygen, trans-cyclopropane 104 was formed in good yield. The reaction is interesting because it presumably involves alkylation of a boron enolate, rather than a free radical reaction. The product cyclopropanes were produced in high e.e. when chiral enolates were used in the Michael addition." 101 85% 3(5):3(R) >98:2 Scheme 45 260 Contemporary Organic Synthesis Scheme 47CO2TMP F F PO(OEt)2 NaHMDS BrF2CCH0 + CF,Br 1 02 R = Bu' B u b , C T 2 T M P (THF,DMI CF2Br 103 (70%) OLi THF.DMI 104 (73%) (TMP = 2,4,6-trimethylphenyl) Scheme 48 An efficient preparation of y,y,y-trifluoro- crotonates has been reported by Shen and G ~ o . ~ ~ Treatment of 105 with Grignard reagents followed by acidic work-up led to the formation of esters 106 in good yield with high (E)-selectivity (Scheme 49). (0 PhCkCMgBr Et@. 25 "c F 3 c r o 2 f 3 ~ t Ph3P<c0cF3 c C02But (ii) HOAc, r.t. 105 Scheme 49 Ph 106 [88%; (Z):(€) = 1288 3.5 Fluoroalkyl epoxides Epoxides are useful building blocks for the synthesis of fluorinated compounds; fluoroalkyl epoxides are more resistant to cleavage under acidic conditions than their non-fluorinated congeners but undergo nucleophilic ring opening. The fluoroalkyl epoxide 108 was formed when the corresponding ketone 107 was treated with diazomethane in ether.Bravo and co-workers have used this approach to prepare a range of optically-enriched building blocks,73 achieving asymmetric induction with a chiral sulfoxide auxiliary. Scheme 50 shows elaboration via Pummerer rearrangement and hemithioacetal hydrolysis which afforded reactive epoxyaldehyde 109. A range of related epoxides containing different fluoroalkyl groups have been prepared.74 Nucleophiles open the product epoxides in the usual way, via attack at the less-hindered carbon atom. Trifluoromethyl epoxides have been prepared from trifluoromethyl ketones and from trifluoromethyl enol ethers. 107 109 Scheme 50 BCguC and co-workers have reported that trifluoromethylenol ethers underwent oxidation with mCPBA in high yield to afford isolable epoxides 110 (Scheme 51).75 When treated with magnesium bromide etherate, bromotrifluoromethylketones were obtained in good yield.Nucleophilic ring- opening with azide was used in the preparation of human leukocyte elastase inhibitor^.^^ 110 (90%) Scheme 51 Ring-opening of chlorodifluoromethyl epoxides 111, obtained via epoxidation of the corresponding, easily-prepared enol ethers, was achieved upon treatment with t-butyllithium in THF at low temperature, affording difluoroallylic alcohols, including 112, in good yield (Scheme 52).77 Seebach R = CH&H(OEt)2 1 1 1 (60 '10) Scheme 52 and co-workers have developed a route to the optically-pure epoxyester 114 from 4,4,4-trifluoro- 3-oxobutanoate 113 (Scheme 53).78 Phenylcuprate nucleophiles attacked the epoxyester at C-(2), phenylmagnesium bromide attacked competitively at C-(2) and C-( 1) while organolithium reagents and alkyl Grignard reagents attacked at the carbonyl carbon leaving the epoxide intact.(i) LDA 0 F ~ c * * ~ c o ~ E ~ &C02Et - OH (ii) I2 (iii) H@ (N) DBU F3C 113 114 Scheme 53 Percy: Recent advances in organofluorine chemistry 26 13.6 Fluoroallylic electrophiles Though unusual, electrophiles of this type feature in some interesting processes. Difluoroallylic acetates react with Grignard reagents with copper(1) catalysis to afford sN2’ alkylation products in good yield though with variable stereoselectivity. Tellier and Sauvetre have studied the reaction extensively and a recent publication provides some experimental detail^.'^ The rates of competing processes may be very similar.Scheme 54 shows a situation in which nucleophilic attack occurs competitively at fluorinated and non-fluorinated allylic termini. The identical proportions of 115 and 116 illustrate the similar reactivities of the two allylic systems. Diene 117 arises from nucleophilic attack on 115 with loss of fluoride. Exposure of difluoroallylic alcohols to DAST provides a useful synthesis of trifluoromethylalkenes. Yields were not reported but a range of alkenes were prepared. Scheme 55 depicts a typical procedure.80 116 (25%) + 117 (30%) Scheme 54 HO Et&, M F Boc Qtj BOC Scheme 55 The fluoride ion can also function as a leaving group in sN2’ displacements. Lithium amides have been added to cx-trifluoromethylstyrene to afford useful yields of difluoroallylic amines.8’ The lithium cation may provide some assistance to the C-F bond cleavage; an attractive six-centre transition state has been written for the reaction (Scheme 56).Difluoroallylic amines were of some interest as MA0 inhibitors and have been prepared by a less efficient route. F*F Scheme 56 4. Pericyclic reactions 4.1 Diels-Alder and dipolar cycloadditions Dienophiles bearing fluorine atoms attached directly to the carbon-carbon double bond are rare; the propensity for thermal [2 + 21 cycloaddition displayed by fluoroalkenes is well known. 5-Fluorodioxinone 118 has been employed as a component in a Diels-Alder reaction; 118 reacted with Danishefsky’s diene to afford the expected cycloadduct in moderate yield under high pressure conditions (Scheme 57).Dioxinones with an additional substituent at the 6-position failed to react under these conditions. A more efficient reaction was reported with the more electron- deficient trifluoromethyl congener.82 0 36 H Scheme 57 A reactive dienophile, prepared from 119, has been prepared in situ from bromotrifluoropropene via an efficient sequence. High yields of cycloadducts were obtained with electron rich dienes, including furan under mild conditions (Scheme 58).83 119 Scheme 58 Tipping and co-worke~s~~ have reported the smooth cycloaddition reactions of trifluoromethyl propiolate derivative 120 with furan. Pyrolysis of the cycloadduct 121 led to the elimination of ethene, setting the stage for a second cycloaddition reaction between furan 122 and hexafluorobutyne (Scheme 59).262 Contemporary Organic SynthesisCOpEt !! 6 F3 120 Scheme 59 a-Trifluoromethyl styrene added to Danishefsky's diene under high pressure conditions, leading to cyclohexenone derivative 123 after hydrolysis (Scheme 60).85 The reaction was used to prepare the steroidal A-c ring system with an angular trifluoromethyl group. Fluoroalkyl imines have been explored as building blocks for the synthesis of nitrogen heterocycles with fluoroalkyl substituents. In the presence of boron trifluoride etherate, 124 added efficiently to Danishefsky's diene to afford a separable mixture of dihydropyridinones (Scheme 61).86 The chemical yield and diastereoisomeric purity of each adduct were high. OMe I Ph + phTcF3 15kBa - n c F 3 50 OC hydroquinol TMSO 123 (80%) Scheme 60 0 OMe I I F3B .O Et2 g :""?I - N Ph CH2C12 HF~C** TMSO Y -78% I fi Ph 1 124 82% (81 : 1 9 anfisyn ) Scheme 61 Homo- and hetero-dienes displaying useful reactivity have been described.Azadiene 125 was prepared from readily-available 2-fluoroacrolein by Schlosser and Ghosh (Scheme 62)87 and added smoothly to DMAD to afford fluoropyridine 126 after hydrolysis. Reissig has described a wide range of cycloaddition reactions of nitrosoalkene 127.*' The heterodiene is reactive and easy to prepare; Scheme 63 depicts a high yielding reaction with l-methoxyallene to afford cyclo adduct 128 in excellent yield. F rw (1) 80 %* Fqco2w C O * k $ + (ii) H30+ I c02Me NMe2 125 126 (70%) Scheme 62 Me0 127 128 (92%) Scheme 63 The LUMO-lowering effects exerted by the trifluoromethyl and carboxylic ester groups are similar.89 Pyrrolidines have been prepared via the reaction of an azomethine ylid with a range of trifluoromethylalkenes.a-Trifluoromethylstyrene reacted smoothly to afford cycloadduct 129 in good yield (Scheme 64). a-Methylstyrene failed to react under the same conditions. The formal [2 + 21 cycloaddition between fluoroketene and the optically-pure imine 130 was exploited in an efficient asymmetric synthesis of a fluorinated P-lactam (Scheme 65).90 Fluoroketene was generated in situ from fluoroacetyl chloride and triethylamine. Lactam 131 was obtained in moderate chemical yield though in high e.e. (299%). Lactam 132 was converted into a configurationally fixed alkylmalonamide component of an HIV protease inhibitor." CH&I2 r.t.+ phwcF3 Bn 129 (80%) Scheme 64 HzFCCOCl NPMP 130 131 R = H 132 R = Bn Scheme 65 4.2 Sigmatropic rearrangements and ene reactions A recent review describes the many applications of [3,3]-rearrangements in organofluorine chemistry.92 Perhaps the most developed methodology uses the Ireland silyl ketene acetal rearrangement. This has Percy: Recent advances in organojluorine chemistry 263proved to be a powerful tool in the hands of Welch and co-~orkers.~~ Allylic fluoroacetate 133 was prepared from highly toxic fluoroacetyl chloride; the (Z)-silyl ketene acetal was formed upon treatment with bulky triisopropyl silyl triflate. Scheme 66 shows a diastereoselective rearrangement. The rearrangement products have been utilized in syntheses of 2,3-dideoxy-2-fluoro-3-C-methyl pentose nucle~sides.~~ In a tetrasubstituted series, alcohol 140 was converted into acetate 141 and tributylstannyl methyl ether 142 (Scheme 69).Ireland rearrangement of 141 afforded a 4 : 1 mixture of acids 143 and 145, whereas Still-Wittig rearrangement of 142 led to the formation of homoallyl alcohols 144 and 146 in a 3 : 7 ratio.97 133 >95% (151 symanri ) Scheme 66 143 R2 = C02H 144 R ~ = O H OPr' pN (i) PrbH.HCI F (ii) - PrbH &;' + Ph F 134 (27%) B u ' C ~ ~ H 1 T L ~ 145'C FYco2pi Ph -eA4 Scheme 67 135 1 36 1 37 in sitv 1 139 Scheme 68 + X R'0 - Orthoester 134 was prepared from fluoroacetonitrile and used in the Johnson-Claisen rearrangement (Scheme 67). A range of a-fluoroesters was prepared in this way though the yields were low.The formation of the product ester as a 1 : 1 mixture of diastereoisomers implied that ketene acetal formation did not occur in a stereoselective manner.95 Johnson and c o - ~ o r k e r s ~ ~ have explored a range of rearrangements for the stereoselective construction of highly substituted fluoroalkenes. Fragmentation of cyclcopropane 136 in the presence of alcohol 135 led to the formation of 137 which rearranged to 138 in situ. Reduction with Dibal followed by orthoester Claisen rearrangement afforded 139 as a single alkene diastereoisomer (Scheme 68).96 Scheme 69 138 (71%) $111 140 R' = H 141 R' =Ac 142 R' = CH2SnBu3 F R* 145 R2=C02H 146 R2=OH A number of less common rearrangements have produced interesting results. A Brown Algae pheromone has been prepared by a Cope rearrangement in which strain relief and the weakness of the distal bond within a difluorocyclopropane contributed to an unusually facile conversion9' of divinylcyclopropane 147 into cycloheptadiene 148 (Scheme 70).Difluoroallylic 6 Bun 147 148 (78%) Scheme 70 alcohols have been transposed via the [2,3]-Wittig rearrangement shown in Scheme 71. Trifluoroethanol has been converted into a highly functionalized species containing a CF2 group in this way.w Mikami and co-workersl" have described a catalytic asymmetric ene reaction using trifluoroacetaldehyde (Scheme 72). The ene reaction proceeded in high e.e., though the efficiency was lower when 2-methyl-2-butene was used in the reaction. 264 Contemporaly Organic SynthesisOH OMEM LDA, THF -78 to -30 OC F F 0- Scheme 71 982 syn:anfi MY0 8.8.Scheme 72 5. Free radical reactions The high strength of the C-F bond renders it virtually inert under the conditions used to trap and generate free radicals. Fluorine atoms may exert a significant effect on the course of free radical reactions though the magnitude and direction of the effects remain far from clear. Recent physical organic studies have demonstrated the highly electrophilic a-nature of perfluoroalkyl radicals. The SOMO energy is relatively low because of delocalization of the unpaired spin into the ,8 C-F o* orbitals, and the inductive electron withdrawal exerted by the perfluoroalkyl group. Set against this effect is the SOMO raising interaction with the non- bonding electron pairs on the fluorine atoms borne on the radical centre.The trifluoromethyl radical therefore has ~r-character.'~'-~~~ Buttle and Motherwell have demonstrated that difluoromethyl radicals display some nucleophilic character. '04 Higher yields of cyclization products were obtained when an electrophilic alkene was present to trap the difluoromethyl radical. Scheme 73 shows a successful cyclizat ion. C02Me C02Me F5 BrF2C Bu3SnH Me02C L AIBN, PhMe Me02c Me02C reflux J 65% Me02C Scheme 73 The precursor was constructed by bromodifluoromethylation of a malonate carbanion in moderate yield. According to Bravo and co- workers, difluoromethyl radicals are electrophilic and highly reactive though their studies do not provide evidence either in support of or against this view.lo5 Cyclization of 149 afforded 150 as a single stereoisomer in moderate yield.The preference for the halomethyl group to assume an equatorial orientation is presumably reinforced by the necessity to avoid a 1,3-diaxial repulsion with the axial hydroxyl group (Scheme 74). A range of enantiomerically pure difluorocyclohexanes were prepared from 150. Similar routes to monofluorocyclohexaneslo6 and difluorocyclopentanes107 have been described by these authors. Bu3SnH reflux OH -O OH 150 (500/,) 149 Scheme 74 Takeuchi has described a general free radical route to tertiary alkyl fluorides from esters of dibromofluoroacetic acid.''* The allylstannane fragmentation method was used to prepare adduct 151 which underwent free radical addition to acrylonitrile (Scheme 75), or Reformatsky reaction with aldehydes.A high yielding bromodecarboxylation was achieved using Barton methodology; iodidebromide exchange set the stage for a second radical allylation affording 152. D H&=CHCH,SnBu3 Br2FCC02Et AlBN 151 H&=CHCN Bu3SnH, AIBN vCN F C02Et CN H2C=CMeCH2SnBu3 \ 4 TCN F I AlBN 152 Scheme 75 Radicals generated at the position fl to C-F bonds are expected to be more electrophilic than analogous alkyl radicals. Shimizu and co-w~rkers'~~ have described a useful bromofluorinationhadical cyclization sequence (Scheme 76). Bromofluoride 153 and the cyclized product 154 were obtained as single stereoisomers. The catalytic conditions described by Stork proved effective in the cyclizat ion. Percy: Recent advances in organofluorine chemistry 265153 (61%) 154 Scheme 76 Taguchi has explored the scope of cyclizations involving primary and secondary Q,Q-difluoroalkyl radicals.' lo Difluorotetrahydropyrans and cyclohexanes were prepared; Scheme 77 shows an efficient cyclization.Precursor 155 was prepared via a lengthy sequence involving the elaboration of a Reformatsky adduct of 39. The cyclic product 156 was obtained as a 1.2: 1 mixture of cis and trans isomers. The presence of the fluorine atoms had no effect on the efficiency of the cyclization reaction. A subsequent study extended the range of cyclizations to include trifluoromethyl alkyl and alkenyl radicals (Scheme 78)."' 155 Scheme 77 OMOM Bu3SnH AIBN, PhH ____c reflux 86% Scheme 78 6 References 1 J.A. Wilkinson, Chem. Rev., 1992, 92, 505.2 O.A. 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