CF3-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

Abstract

"The extraordinary instability of such an "ion" accounts for many of the peculiarities of organic reactions" - Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations - carbocations substituted with electron-withdrawing groups - are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF₃-substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations.

Keywords: carbocation; organic synthesis; superelectrophile; trifluoromethyl.

Figure 1

Stabilizing interaction in the CF₃CH₂⁺ carbenium ion (top) and structure of the first observable fluoronium ion 1 (bottom) (δ in ppm).

Scheme 1

Isodesmic equations accounting for the destabilizing effect of the CF₃ group. ΔE in kcal⋅mol⁻¹, calculated at the 4-31G level.

Scheme 2

Stabilizing effect of fluorine atoms by resonance electron donation in carbenium ions (δ in ppm).

Scheme 3

Direct in situ NMR observation of α-(trifluoromethyl)carbenium ion or protonated alcohols. Δδ = δ_19F,product − δ_{19F,precursor} (δ in ppm).

Scheme 4

Reported ¹³C NMR chemical shifts for the α-(trifluoromethyl)carbenium ion 10c (δ in ppm).

Scheme 5

Direct NMR observation of α-(trifluoromethyl)carbenium ions in situ (δ in ppm).

Scheme 6

Illustration of the ion pair solvolysis mechanism for sulfonate 13f. YOH = solvent.

Figure 2

Solvolysis rate for 13a–i and 17.

Figure 3

Structures of allyl triflates 18 and 19 and allyl brosylate 20. Bs = p-BrC₆H₄SO₂.

Figure 4

Structure of tosylate derivatives 21.

Figure 5

a) Structure of triflate derivatives 22. b) Stereochemistry outcomes of the reaction starting from (R)-(−)-22f. c) Rate-limiting step in poorly ionizing solvents.

Scheme 7

Solvolysis reaction of naphthalene and anthracenyl derivatives 26 and 29.

Figure 6

Structure of bisarylated derivatives 34.

Figure 7

Structure of bisarylated derivatives 36.

Scheme 8

Reactivity of 9c in the presence of a Brønsted acid.

Scheme 9

Cationic electrocyclization of 38a–c under strongly acidic conditions.

Scheme 10

Brønsted acid-catalyzed synthesis of indenes 42 and indanes 43.

Scheme 11

Reactivity of sulfurane 44 in triflic acid.

Scheme 12

Solvolysis of triflate 45f in alcoholic solvents.

Scheme 13

Synthesis of labeled ¹⁸O-52.

Scheme 14

Reactivity of sulfurane 53 in triflic acid.

Figure 8

Structure of tosylates 56 and 21f.

Scheme 15

Resonance forms in benzylic carbenium ions.

Figure 9

Structure of pyrrole derivatives 58 and 59.

Scheme 16

Resonance structure 60↔60’.

Scheme 17

Ga(OTf)₃-catalyzed synthesis of 3,3’- and 3,6’-bis(indolyl)methane from trifluoromethylated 3-indolylmethanols.

Scheme 18

Proposed reaction mechanism.

Scheme 19

Metal-free 1,2-phosphorylation of 3-indolylmethanols.

Scheme 20

Superacid-mediated arylation of thiophene derivatives.

Scheme 21

In situ mechanistic NMR investigations.

Scheme 22

Proposed mechanisms for the prenyltransferase-catalyzed condensation.

Scheme 23

Influence of a CF₃ group on the allylic S_N1- and S_N2-mechanism-based reactions.

Scheme 24

Influence of the CF₃ group on the condensation reaction.

Scheme 25

Solvolysis of 90 in TFE.

Scheme 26

Solvolysis of allyl triflates 94 and 97 and isomerization attempt of 96.

Scheme 27

Proposed mechanism for the formation of 95.

Scheme 28

Formation of α-(trifluoromethyl)allylcarbenium ion 100 in a superacid.

Scheme 29

Lewis acid activation of CF₃-substituted allylic alcohols.

Scheme 30

Bimetallic-cluster-stabilized α-(trifluoromethyl)carbenium ions.

Scheme 31

Reactivity of cluster-stabilized α-(trifluoromethyl)carbenium ions.

Scheme 32

α-(Trifluoromethyl)propargylium ion 122↔122’ generated from silyl ether 120 in a superacid.

Scheme 33

Formation of α-(trifluoromethyl)propargylium ions from CF₃-substituted propargyl alcohols.

Scheme 34

Direct NMR observation of the protonation of some trifluoromethyl ketones in situ and the corresponding ¹⁹F NMR chemical shifts. Δδ = δ_19F,product − δ_{19F,precursor} (δ in ppm).

Scheme 35

Selected resonance forms in protonated fluoroketone derivatives.

Scheme 36

Acid-catalyzed Friedel–Crafts reactions of trifluoromethyl ketones 143a,b and 147a–c.

Scheme 37

Enantioselective hydroarylation of CF₃-substituted ketones.

Scheme 38

Acid-catalyzed arylation of ketones 152a–c.

Scheme 39

Reactivity of 156 in a superacid.

Scheme 40

Reactivity of α-CF₃-substituted heteroaromatic ketones and alcohols as well as 1,3-diketones.

Scheme 41

Reactivity of 168 with benzene in the presence of a Lewis or Brønsted acid.

Scheme 42

Acid-catalyzed three-component asymmetric reaction.

Scheme 43

Anodic oxidation of amines 178a–c and proposed mechanism.

Scheme 44

Reactivity of 179b in the presence of a strong Lewis acid.

Scheme 45

Trifluoromethylated derivatives as precursors of trifluoromethylated iminium ions.

Scheme 46

Mannich reaction with trifluoromethylated hemiaminal 189.

Scheme 47

Suitable nucleophiles reacting with 192 after Lewis acid activation.

Scheme 48

Strecker reaction involving the trifluoromethylated iminium ion 187.

Scheme 49

Reactivity of 199 toward nucleophiles.

Scheme 50

Reactivity of 204a with benzene in the presence of a Lewis acid.

Scheme 51

Reactivity of α-(trifluoromethyl)-α-chloro sulfides in the presence of strong Lewis acids.

Scheme 52

Anodic oxidation of sulfides 213a–h and Pummerer rearrangement.

Scheme 53

Mechanism for the electrochemical oxidation of the sulfide 213a.

Scheme 54

Reactivity of (trifluoromethyl)diazomethane (217a) in HSO₃F.

Figure 10

a) Structure of diazoalkanes 217a–c and b) rate-limiting steps of their decomposition.

Scheme 55

Deamination reaction of racemic 221 and enantioenriched (S)-221.

Scheme 56

Deamination reaction of labeled 221-d₂. Elimination products were formed in this reaction, the yield of which was not determined.

Scheme 57

Deamination reaction of 225-d₂. Elimination products were also formed in this reaction in undetermined yield.

Scheme 58

Formation of 229 from 228 via 1,2-H-shift.

Scheme 59

Deamination reaction of 230. Elimination products were formed in this reaction, the yield of which was not determined.

Scheme 60

Deamination of several diazonium ions. Elimination products were formed in these reactions, the yield of which was not determined.

Scheme 61

Solvolysis reaction mechanism of alkyl tosylates.

Scheme 62

Solvolysis outcome for the tosylates 248 and 249 in HSO₃FSbF₅.

Figure 11

Solvolysis rate of 248, 249, 252, and 253 in 91% H₂SO₄.

Scheme 63

Illustration of the reaction pathways. TsCl, pyridine, −5 °C (A); 98% H₂SO₄, 30 °C (B); 98% H₂SO₄, 30 °C (C); NaOH (aq), evaporation, extraction with MeOH (D); and moist Et₂O–H⁺, reflux (E).

Scheme 64

Proposed solvolysis mechanism for the aliphatic tosylate 248.

Scheme 65

Solvolysis of the derivatives 259 and 260.

Scheme 66

Solvolysis of triflate 261. SOH = solvent.

Scheme 67

Intramolecular Friedel–Crafts alkylations upon the solvolysis of triflates 264 and 267.

Scheme 68

α-CF₃-enhanced γ-silyl elimination of cyclobutyltosylates 270a,b.

Scheme 69

γ-Silyl elimination in the synthesis of a large variety of CF₃-substituted cyclopropanes. Pf = pentafluorophenylsulfonate. For 277c and 276g, no pyridine was used. For 276g, the yield refers to the protonated pyridinium tosylate. *NMR yield.

Scheme 70

Synthetic pathways to 281. ^aNMR yields.

Scheme 71

The cyclopropyl-substituted homoallylcyclobutylcarbenium ion manifold.

Scheme 72

Reactivity of CF₃-substituted cyclopropylcarbinyl derivatives 287a–c. LG = leaving group.

Scheme 73

Reactivity of CF₃-substituted cyclopropylcarbinyl derivatives 291a–c.

Scheme 74

Superacid-promoted dimerization or TFP.

Scheme 75

Reactivity of TFP in a superacid.

Scheme 76

gem-Difluorination of α-fluoroalkyl styrenes via the formation of a “hidden” α-R_F-substituted carbenium ion 306↔306’.

Scheme 77

Solvolysis of CF₃-substituted pentyne 307.

Scheme 78

Photochemical rearrangement of 313.

Figure 12

Structure of 2-norbornylcarbenium ion 318 and argued model for the stabilization of this cation.

Figure 13

Structures and solvolysis rate (TFE, 25 °C) of the sulfonates 319–321. Mos = p-MeOC₆H₄SO₂.

Scheme 79

Mechanism for the solvolysis of 323. SOH = solvent.

Scheme 80

Products formed by the hydrolysis of 328.

Scheme 81

Proposed carbenium ion intermediates in an equilibrium during the solvolysis of tosylates 328, 333, or 334.