Copyright © 2008 by Vincent M. Carroll 1 DIRECT INTRODUCTION

DIRECT INTRODUCTION OF THE TRIFLUOROMETHYL GROUP

Reported by Vincent M. Carroll December 4, 2008

Introduction The field of organofluorine chemistry has, in recent years, progressively developed a significant role in a wide range of applications (Figure 1).1 Among fluorinated compounds, trifluoromethyl- substituted molecules have generated considerable attention. The interesting medicinal properties that the trifluoromethyl group imparts have spurred synthetic efforts to selectively and directly introduce that group.2 Conventional strategies have relied on two approaches: one involves C-F bond formation via a functional group transformation by a fluorinating reagent (e.g. DAST and SF4), and the other includes C-C bond formation from a commercially available fluorine-substituted compound.3 More recent efforts have aimed to directly install the trifluoromethyl moiety at a late synthetic stage using inexpensive materials.4 To accomplish this, nucleophilic, electrophilic, free radical, and transition metal-catalyzed processes have been developed, with an emphasis on asymmetric induction. This lecture will focus on nucleophilic, electrophilic, free radical, and transition metal-catalyzed trifluoromethylation strategies.

Figure 1: Notable Drugs Containing a Trifluoromethyl Group

H CF3 N O F3C N Cl N O CF3 N O H NO S H 2 2 1 2 3 Efavirenz Celecoxib Fluoxetine (Sustiva) (Celebrex) (Prozac)

Nucleophilic Trifluoromethylation The initial challenges to realizing nucleophilic trifluoromethylation required controlling the inherent reactivity of the “naked” trifluoromethyl anion which readily decomposes into a fluoride anion and difluorocarbene.5 To circumvent this decomposition, strategies for stabilization have been achieved through bonding to transition metals (e.g. Cu) or main group elements (e.g. Si).5 6 Since its initial disclosure in 1984, the Ruppert-Prakash reagent, CF3SiMe3 (4), has become the reagent of choice for nucleophilic trifluoromethylation. For nucleophilic addition to occur, this reagent must be activated, which can be achieved with a fluoride source (Scheme 1). This process is believed to be a fluoride-initiated/alkoxide-catalyzed reaction proceeding through a proposed pentavalent silicon

Copyright © 2008 by Vincent M. Carroll 1 species (6).7 The application of this method has been well documented with a wide range of electrophiles being utilized, including imines, esters, imides, lactones, aldehydes, and ketones.8

Scheme 1: Mechanism of Nucleophilic Trifluoromethylation

O + - - + nBu4N F F3C O NBu4 Me3SiCF3 Me3SiF R1 R2 4 R1 R2

F3C OTMS 5 5 R1 R2

Me3SiCF3 CF3 Si + O F3C O nBu4N

R1 R2 R1 R2 6 Addition of 4 to chiral compounds in which the faces of a carbonyl group are diastereotopic leads to the diastereoselective introduction of the trifluoromethyl group. This process has been applied to amino acids (7), steroids (11), and sugars (12).9 More recently, trifluoromethylated chiral amines (15) were synthesized by addition to chiral sulfinylimines. Excellent diastereoselectivities and yields were obtained. Hydrolysis of the sulfinimine to the corresponding chiral amine salt proceeded readily without racemization (Scheme 2).10

Scheme 2: Applications in Nucleophilic Trifluoromethylation

CF F3C HO 3 O

CO Bn N CO2H N 2 OH Boc Boc O CF3 7 8 (81%) H H (overall yield: 57%) (dr > 97%) AcO N CO2Bn 10 Boc H H 1. TBAF AcO 9 11 (83%) 2. NH Cl/TBAF 4 (dr = 100:0)

CF3SiMe3 -O -+ 4 S 1. Ph3SnF2 NBu4 tBu N O - 2. TBAF O CF3 O O 14 Cl S O tBu N -+ O 1. Ph3SnF2 NBu4 H F3C O O OH 2. NH4Cl Cl 12 (88%) O O 13 15 (95%) (dr = 100:0) (dr > 99:1) Enantioselective trifluoromethylation is considerably less developed. Strategies for enantioselective additions have generally involved the use of cinchona alkaloids as chiral Lewis bases for aldehydes and ketones as first reported by Iseki et al. in 1994.11 First attempts yielded only moderate enantioselectivities and yields, but more recently, Shibata et al. developed a bis(cinchoninium)

Copyright © 2008 by Vincent M. Carroll 2 derivative (18) to achieve enantioselectivities in upwards of 95:5 er with aryl ketones (Scheme 3). Poor selectivity was observed when aryl aldehydes and aliphatic ketones were used.12

Scheme 3: Catalytic, Enantioselective Nucleophilic Trifluoromethylation of Ketones

1. Me3SiCF3 (2.0 equiv) 18 (10 mol%) HO CF O 3 N TMAF (10 mol%) HO Br- Ar R Ar R1 H N 1 toluene/CH2Cl2 (2/1) Br- H -60oC to -50oC, 2-30 h 16 17 N 2. TBAF/H2O, THF, rt, 1 h OH N 18

HO CF3 HO CF3 HO CF3 HO CF3

MeO 19 20 21 22 87% yield 84% yield 34% yield 85% yield 93:7 er 95:5 er 87:13 er 85:15 er To improve the selectivity for addition to aryl aldehydes, Feng et al. employed a combination of a chiral ammonium salt (25) with disodium (R)-binaptholate (26). This catalytic system achieved moderate to excellent yields (68-95%) and enantioselectivities (in upwards of 86:14) (Scheme 4). A proposed mechanism involves a hexavalent silicon species with activation of the carbonyl group of the aromatic aldehydes by the chiral ammonium catalysts.13

Scheme 4: Catalytic, Enantioselective Nucleophilic Trifluoromethylation of Aldehydes

1. Me3SiCF3 (2 equiv) O 25 (10 mol%), 26 (10 mol%) OH o Et2O, -15 C, MS 4A Ar H Ar CF CF3 2. TBAF/H2O, THF, rt, 1 h 3 23 24 N OH OH OH OH HO ONa - Br ONa CF3 CF3 CF3 CF3 MeO CF3 F N 27 28 29 30 25 26 72% yield 88% yield 86% yield 85% yield 78:22 er 79:21 er 79:21 er 86:14 er

Electrophilic Trifluoromethylation Although nucleophilic methods are well established, electrophilic trifluoromethylation is rather underdeveloped. Since the initial discovery of the first electrophilic trifluoromethylating species (31, 32) by Yagupol’skii et al. in 1984,14 two major classes of reagents have been developed. The first class, reported by Umemoto et al., is the trifluoromethylchalcogenium salts (33-36).15 These reagents react

Copyright © 2008 by Vincent M. Carroll 3 with an assortment of nucleophiles, including silyl enol ethers, enamines, thiolates, and electron rich aromatics yielding the trifluoromethylated products in useful yields.

Figure 2: Electrophilic Trifluoromethylating Reagents

Cl R1 R2 R1 R2

S R A R O2N S SbF - - - CF3 6 CF3 OTf CF3 OTf 31 R1=R2=Me 33 A=S, R=H 37 R1=R2=H 32 R1=OMe, R2=H 34 A=S, R=NO2 38 R1=F, R2=H 35 A=Se, R=H 36 A=Te, R=H

A major drawback of these reagents was their inability to successfully yield O- and N-CF3 compounds. This problem was circumvented by the same group after the development of O- (trifluoromethyl)-dibenzofuranium salts16 (39) as well as by Shreeve17 et al. with their non-heterocyclic fluoro- and nitro-substituted trifluoromethyldiarylsulfonium triflates (37, 38). Both sets of compounds successfully trifluoromethylated alcohols (40), phenols (41), amines, anilines (42), and pyridine (44) in moderate to excellent yields under mild conditions (Scheme 6).

Scheme 6: Electrophilic Trifluoromethylation of O- and N- Compounds

n-C10H21OCF3 40, 82%

OCF3 41, 75%

tBu

NHCF3 42, 93% O - CF3 SbF6 39

N(Me)2CF3 43, 49% - SbF6

N CF3 44, 70% - SbF6 Hypervalent iodine compounds based on the 1,2-benziodoxole core structure are a promising new set of electrophilic trifluoromethylating agents. Umemoto et al. previously established that this core structure is a viable source of perfluoroalkylating agents, but the trifluoromethyl derivative proved too unstable under their reaction conditions. Successfully synthesized in 200618 by Togni et al., 45 showed high functional group tolerance: amines, amides, carboxylic acids, alcohols, and alkynes were left untouched, while cyclic ß-keto esters (46), α-nitro esters (47), phosphines, and aromatic (48) and aliphatic thiols (49) were trifluoromethylated in moderate to high yields (Figure 3).19

F C I O O 3 O SCF3 CO Et O SCF3 2 O2N OH OEt CF3 Me O CF3 45 46 47 48 49 67% yield 99% yield 91% yield 53% yield Largely underdeveloped, the first example of asymmetric electrophilic trifluoromethylation was reported by Umemoto et al. utilizing chiral borepins in the alkylation of potassium enolates in moderate yields and diastereoselectivities.20 Stereochemical rationale coordinates the bulky Lewis acid on the less hindered α-face, with alkylation occurring on the ß-face.

Free Radical Trifluoromethylation

Carbonyl compounds bearing an α-CF3 represent synthetically useful moieties allowing for further transformation of the carbonyl group to a diversified array of trifluoromethylated products.

Because the electronegativity of the fluorines, CF3-X reagents do not readily undergo alkylation reactions; however, radical pathways represent an attractive solution for the synthesis of α-CF3 carbonyl compounds from these commercially available starting materials. Precedent for this type of transformation is extremely rare, especially for ketones because of the facile ß-elimination of the α-CF3 product.21

In 2005, Itoh et al. reported the successful generation of an α-CF3 ketone through radical trifluoromethylation. Respectable yields were obtained only in the presence of excess amounts of LDA and Ti(OiPr)4 (Scheme 7). Nonetheless, moderate yields of α-CF3 ketones were obtained, without any observable ß-elimination of fluoride. The linearity of the Ti-O bond is due to the back donation of a electron pair from oxygen into an empty d-orbital of titanium.22

Scheme 7: Radical Trifluoromethylation with Titanium Ate Enolates

CF3I (5 eq.) O O LDA (1.6 eq.) Ti(OiPr)4 (1.0 eq.) Et3B (1.0 eq.) CF o -78oC, 30 min o 3 R1 R2 THF, -78 C -78 C, 2 h R1 R2 30 min 54 55 O O O CF3 O CF3 CF3

CF3 56 57 58 59 81% yield 61% yield 64% yield 65% yield Investigation of the radical trifluoromethylations of the titanium-ate enolates also led to the discovery of lithium enolates as potential precursors. A variety of ketones were investigated using LDA

Copyright © 2008 by Vincent M. Carroll 5 to generate the lithium enolate. The reactions proceeded extremely rapidly and afforded moderate yields of the corresponding α-CF3 products (Scheme 8). The substrate scope, however, failed when esters and amides were present, along with poor yields for acyclic ketones.23

Scheme 8: Radical Trifluoromethylation with Lithium Enolates

Li O O O CF3I (5 eq.) LDA (1.0 eq.) Et3B (1.0 eq.) CF3 R1 R1 R1 THF, -78oC, 60 min -78oC R2 R2 R2 60 62 63 O O CF3 O

CF3 Ph CF3

tBu 81% 71% 43% ~1 s ~1 s ~1 s Although the addition to a trifluoromethyl radical has proven difficult to control, Iseki et al. reported moderate diastereoselectivities for reactions of lithium enolates, with the use of chiral oxazolidinones (Scheme 9). Removal of the chiral auxiliary with LiBH4 afforded synthetically useful α- trifluoromethyl alcohols without racemization.21

Scheme 9: Diastereoselective Trifluoromethylation of Chiral Imide Enolates

O O O O O O

R2 R2 R2 O N 1. LDA (1.3 eq.) 2. CF3I (5.0 eq.) O N O N o THF, -78 C, 60 min Et3B (1.0 eq.) CF3 CF3 o o H R1 -78 C to -20 C, 2 h H R1 H R1 64 65 66 O O O O O O

Me R2 R2 O N O N O N

CF3 CF3 CF3 H iPr H R1 H R1 70% yield 45% yield 70% yield 82:18 dr 84:16 dr 86:14 dr

Transition Metal-Catalyzed Trifluoromethylation The incorporation of the trifluoromethyl moiety by transition metal-mediated reactions (most notably by copper) is well established. Kobayashi et al. reported the trifluoromethylation of aryl, vinyl, alkyl, and heterocyclic halides by a trifluoromethyl copper species, generated from CF3I or CF3Br in the presence of copper powder.24 Decarboxylative trifluoromethylation of sodium trifluoroacetate and methyl fluorosulfonyldifluoroacetate (Scheme 10), as reported by Matsui and Chen respectively, generated the trifluoromethyl anion, which is subsequently trapped by copper to form the

Copyright © 2008 by Vincent M. Carroll 6 trifluoromethylcopper.25 Fuchikami reported a similar approach to the in situ generation and capture of trifluoromethyl copper species from CF3SiEt3. Aryl, vinyl iodides, allyl iodides and benzyl bromide were trifluoromethylated in low to excellent yields.26

Scheme 10: Trifluoromethylation using Methyl Fluorosulfonyldifluoroacetate

CuI, DMF FO2SCF2CO2Me R-X R-CF SO2 CO2 MeX 70oC, 2-6 h 3 X= Br, I CF 3 CF3 CF3 CF3

NO2 Cl 84% yield 61% yield 80% yield 68% yield These methods often require vigorous conditions for the reaction to proceed, which may not be compatible with sensitive functional groups. Kumadaki et al. in 2004 reported the α-trifluoromethylation of α,ß-unsaturated ketones in the presence of Et2Zn and RhCl(PPh3)3. Cyclic and acyclic systems were utilized, with moderate yields obtained.27

Conclusion and Outlook The interesting properties that the trifluoromethyl moiety imparts on organic compounds have stimulated a tremendous growth in synthetic methods for its incorporation in recent years. This has largely been accomplished through nucleophilic, electrophilic, free radical, and transition metal- catalyzed strategies. While nucleophilic trifluoromethylation has gained recent success, the other three methods are still in their infancy. This method has been applied to a wide variety of nucleophiles as well as diastereo- and enantioselective methods being reported. Further investigation of substrate scope, kinetic studies and computational modeling of enantioselective trifluoromethyl addition may result in further development of the field. Electrophilic trifluoromethylation has been developed by the chalcogenium and iodonium salts, but further mechanistic studies are needed to understand how these reagents are reacting and thus, limit its substrate scope. Free radical trifluoromethylation has been recognized only in recent years, but due to its lack of functional group compatibility (only cyclic and acyclic ketones have been employed), this method lacks synthetic feasibility. Transition metal-catalyzed trifluoromethylation by the use of copper and rhodium hold great promise for α-trifluoromethylated carbonyl compounds. Nonetheless, the utility for direct trifluoromethylation in late-stage functionalization is still an extremely attractive goal. Since the initial discoveries by Yagupol’skii and

Copyright © 2008 by Vincent M. Carroll 7 Ruppert, numerous reports have been reported that have ultimately advanced the field. However, robust, high yielding and stereoselective methods are still lacking.

References

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