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Contribution

Chemistry of Trifluoroacetimidoyl Halides as Versatile Fluorine-containing Building Blocks

Kenji Uneyama

Professor of Emeritus, Department of Applied Chemistry, Okayama University Okayama 700-8530, Okayama, Japan

1. Outline of trifluoroacetimidoyl halides develop more sophisticated building blocks. They should be synthesized in high yields from easily available starting The trifluoromethyl group involved in organic compounds materials and should contain highly potential functional plays important roles as a key functional group in groups usable for further molecular modification. On this medicine, agricultural chemicals and electronic materials basis, trifluoroacetimidoyl halides are one of the unique and like liquid crystals. Common methods for introducing the valuable CF3-containing synthetic building blocks due to trifluoromethyl group (CF3 group) into organic compounds the following promising profiles; a) easy one-step are categorized into three; 1) the use of building blocks synthesis from a very available trifluoroacetic acid in containing CF3 group, 2) trifluoromethylation by the use of excellent yields, b) relatively stable to be stored, and c) trifluoromethylating agents such as CF3-TMS, FSO2CO2Me, containing highly potential functional groups such as CF3, CF3I, etc., and 3) the transformation of a functional group imino C=N double bond and halogen (Scheme 1). such as CCl3 and CO2H groups to CF3 group by the use of fluorinating agents such as F2 and HF. The method 3 is (Synthesis) conventionally used for the industrial mass production of Imidoyl halides 1 (X: Cl, Br) are synthesized from CF3-containing molecules, which are mostly structurally trifluoroacetic acid in excellent yields (85-95%) as shown 2) simple and stable molecules. On the other hand, methods in Scheme 2. It is also possible to use PPh3Cl2 instead of 1 and 2 have been used for the structurally complex and carbon tetrachloride (CCl4) due to the prohibition of its use. 1) valuable CF3-molecules in small laboratory bases. In industrial manufacturing, the corresponding Not many CF3-containing synthetic blocks are trifluoroacetamide can be converted to imidoyl chloride by commercially available, therefore it is very important to the use of phosphorus oxychloride.2c)

oxidative addition to defluorinative low-valent metals functionalization or X lithium-halogen exchange

CF3 NR

alkylation or hydrogenation

+

CF3 NR 4 X ¥

CF3 NR CF3 NR 5 1 : X = Cl, Br, I ¥¥ 2 : X = I, SePh, N=N-C(Ph)3 3 : X = Pd, Rh, Si, Zn, Mg, Li CF3 NR 6

Scheme 1.

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NAr NAr CCl4 + PPh3 + Et3N NaI / acetone CF3CO2H + ArNH2 reflux 85-95% F3CCl quant. F3CI

Scheme 2.

Imidoyl iodide 1 (X: I) is synthesized quantitatively from the corresponding chloride by the exchange of chlorine for 2. Reactions of trifluoroacetimidoyl halides with iodine with NaI in acetone. Imidoyl chloride 1 is relatively nucleophilic reagents stable, therefore it is sometimes possible to recover the unreacted 1 by silica gel column chromatography. 2.1. The reactions with oxygen nucleophiles Trifluoroacetimidoyl halides 1 are hydrolyzed slowly under acidic or neutral conditions, but rapidly under basic Since the imino carbon of imidoyl chloride 1 has high conditions. In contrast, nonfluorinated imidoyl halides electrophilicity, the reaction with alcohols easily occurs with rapidly react with water to form amides in general. The a base catalyst under mild conditions and produces the acid stability arises from the restrained protonation of the corresponding imidates 7 and 10 in good yields (Scheme imino group by an electron-withdrawing effect of the CF3- 3 and 4). group. Each of imidates 7 3) and 10 4) can be used for the synthesis of fluorinated amino acid derivatives through (Reactions) rearrangement. The driving force of these rearrangements Imidoyl halides 1 have very wide use in various organic arises from higher thermodynamic stability of the reactions; via carbocation 4, radical 5 and carbanion corresponding amides than the starting imidates. Imidoyl species 6 (Scheme 1). For example, the chloride 1 (X=Cl) chloride 1 reacts with diazoalcohol 12 to produce the amide can be used for nucleophilic substitution reactions with 13 (Scheme 5).5) The carbene intermediate generated from nucleophiles or acid-catalyzed Friedel-Crafts reactions to 13 is attacked by amido carbonyl oxygen intramolecularly, convert chlorine to other functional groups. Iodo, seleno followed by the rearrangement to form 14. The rearrange- and azo-imidoyl compounds 2 produce radical species 5 ment is highly substituent dependent. For example, the by photochemical and thermal reactions, which form new trichloroacetamide 15 is converted to 16 by the 1,2-shift of carbon-carbon bonds with alkenes, alkynes and aromatic the aryl group. In the overall transformation (Scheme 5), compounds. Imidoyl halide 1 can be converted to the the hydroxyl group at C-3 of 12 shifts to C-2 of 14 via the corresponding imidoyl metals 3 by the oxidative addition to imidate-amide rearrangement. low valent transition metals or the halogen-metal exchange reaction, which can also form new carbon-carbon bonds by the electrophilic reactions with electrophiles or the transition metal-catalyzed cross-coupling reactions (Scheme 1).

PMP PMP PMP PMP N 2) N HN N 3) 1) CO R CO R Rf 2 Rf 2 Rf Cl 71-92% Rf OCO2R 81-89% OH OH 7 8 9

1) HOCH2CO2R, Et3N / benzene, 50 ¡C, 5 h; 2) LiTMP / DME-THF, -105 -70 ¡C; 3) NaBH4, ZnCl2 / i-PrOH-THF Rf = CF3, CClF2, C3F7

Scheme 3.

OTHP OTHP OMe R R PMP 2) PMP NHPMP N 1) N N

82-98% 70-98% CO2H F3C Cl F3C O F3C O R 10 11 1) n-BuLi / allylic alcohols / THF, -78 ¡C; 2) benzene, rt

Scheme 4.

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CF3 Ar 2 Ar CO2R OH N O 1 N 1) R 2 2 2) + CO2R CO2R O CF3 R1 R1 F3C Cl 31-96% 79-99% 1 N2 N2 ArN 12 13 14

1) DBU / CH2Cl2, 0 ¡C to rt; 2) Rh2(OAc)4 / CH2Cl2, 0 ¡C to rt;

CCl3 CCl3

HN O HN O CF3 Rh2(OAc)4 2 Ph CO2R Ar Ar N O CH2Cl2, 0 ¡C NPh OBz OBz 1) BzO N2 CO R2 O 75-98% 2 + 15 16 F3C Cl OHC OBz 94% OBz BzO OBz OH Scheme 5. OBz 17 1) K CO / acetone, 12h, rt 2 3 18

Me O Me O Me Me Me Me OBz Me O Me O O 1) BzO OCF3 BzO + OBz 92% OBz NPh HO 20 O 21 19 BzO O BzO 1) TMSOTf, MS 4A / CH Cl , rt OBz 2 2 Scheme 6.

Since Yu et al reported that trifluoroacetimidate 19 is a 2.2. Reaction with nitrogen nucleophiles novel glycosyl donor due to its high reactivity with alcohols and the good leaving ability of the trifluoroacetimidoyl group Chlorine of the imidoyl chloride 1 can be replaced under Lewis acid-catalyzed conditions,6b) the trifluoro- smoothly with nitrogen nucleophiles to give various acetimidate 19 has been often used for the glycosylation iminoamides, which are transformed into useful trifluoro- reaction.6) The reaction of trifluoroacetimidates (glycosyl methyl nitrogen heterocycles. Some synthetic applications donor) with alcohols (glycosyl acceptor) occurs smoothly such as oxidative cyclization of 22 with t-BuOCl to CF3- under mild conditions in high yields as shown in Scheme benzotriazine 23,7) reaction with phenylhydrazine followed 6. by condensation-cyclization to the CF3-triazole 24, and 8) cyclization via imidoyl azide to the CF3-tetrazole 25 are shown in Scheme 7. The difluoromethyl quinazoline 28 is synthesized by the successive cyclization-defluorination sequence via aziridine intermediate 27 starting from imidamide 26 (Scheme 8).9)

OMe OMe OMe Scheme 7. 1) 2) N HN N

F C Cl 81% N 76% N 3 F3C N F3C N 22 23

t 1) (Me2C=N)2-NH2NH2 / DMF-H2O; 2) BuOCl / CH2Cl2, -70 ¡C rt

Ph N NAr 1), 2) NAr 3) N N N N O F C Cl F C Cl N 3 84%N 3 87% F3C Ar F3C Ar or 24 25 1) PhNHNH2 / benzene; 2) ClCO2Et-Py / benzene; 3) NaN3 / acetone-H2O

Scheme 8. X X - X N 1) N N

t F C CO tBu t F3C NCO2Bu 54-91% 3 N 2 F2HC NCO2Bu

Bn Bn Bn 26 27 28 1) LiTMP / THF, -60 ¡C

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2.3. Reaction with carbon nucleophiles metathesis reaction with Grubbs’ catalyst derived β,β- difluoro cyclic amino acid 36 (Scheme 11).12) The related Imidoyl chloride 1 can also react with carbon 5- and 6-membered β,β-difluoro cyclic amino acids have nucleophiles, therefore it is often used for the part of CF3- been synthesized from the corresponding fluorinated containing compounds. Examples of the syntheses of imidoyl chlorides.13) The same methods can be applied to 10) 2-CF3-substituted quinolone carboxylic acid 29 and both the synthesis of trifluoro, difluoro and chlorodifluoro diastereoisomers of 2-thio-3-aminobutanoic ester 3011) are alanines 37 (Scheme 12).14) shown in Schemes 9 and 10, respectively. Diastereoselective reduction of the enamine 38, which Fustero et al have synthesized an optically pure cyclic is synthesized from chiral oxazoline 39 and imidoyl amino acid 36 via the reaction of difluoroimidoyl chloride chlorides, provides β-amino acid derivatives 40. This 31 with optical active sulfoxide 32, followed by the method gave optically pure β-amino acids 42 (Scheme diastereoselective reduction of imino group using the 13).15) sulfinyl group as a chiral auxiliary. A ring-closing

Me Me Me NAr O CbzN O 1) 1) S N HN 2) N Cl + S Me Ph Ph CO2Me F F F F F3CCl 70% F3C 67% F3C OH 31 32 33 MeO2C MeO2C 1) NaH, CH (CO Me) / THF; 2) heating in xylene 29 CbzHN O 2 2 2 2) 2) S Ph 61% from 26 Scheme 9. F F 75-40% 98% de 34

O O n NH n LDA/THF PMP n N 3) N PMP N O O N -78 → 0 ¡C CO2H + t 75-87% t t CO2 Bu Bu-S CO2 Bu F C F F F3CCl 80% 3 F F F t F S Bu 35 36

NaBH (6.0 eq.) / ZnBr / PMP 1) (i) LDA / THF, -78 ¡C, (ii) Bu NBH THF-MeOH, -70 ¡C, 4 2 NH 4 4 (iii) CAN / MeCN-H2O, (iv) ClCO2Bn, K2CO3; CH2Cl2, rt, 1 h, t CO2 Bu 2) (i) TFA, (ii) K2CO3, (iii) NaBH4, (iv) BzOH, DCC, DMAP, PMP 70% (syn/anti = >99/1>) F3C N (v) CH2=CH(CH2)nBr, NaH, DMF; 3) Grubbs' RCM. StBu CO tBu F C 2 3 NaBH (6.0 eq. )/ THF, Scheme 11. t 4 PMP S Bu DGDE, 0 ¡C → rt, 3 h, NH t CO2 Bu 81% (syn/anti =11/89) F3C StBu Ar Ar Ar O N O O HN 1)N 2) S + Ar Me S S Rf Cl Ar Ar Rf PMP NH NH3 Cl Rf 33-98% NH 2 t t CO2 Bu CO2H CO2 Bu F3C F3C F3C 68% 99% StBu StBu O NHCbz NHCbz StBu 3) 4) NHCbz 5) 1) CAN, H NNH ; 2) aq HCl / MeOH 30 S HO 65-70% 2 2 Ar Rf 70-90% Rf Rf CO2H 37 Rf= CF3, CClF2, CHF2 Scheme 10. 1) LDA (2.0 eq.), THF, -78 ¡C; 2) Bu4NBH4 / MeOH, -70 ¡C; 3) (i) CAN, MeCN / H2O, rt, (ii) ClCO2Bn / dioxane, 50% aq. K2CO3; 4) (i) TFAA / MeCN, s-collidine, 0 ¡C, (ii) 10% K2CO3, (iii) NaBH4, H2O; 5) RuO2¥xH2O / NaIO4, acetone / H2O, rt.

Scheme 12.

R1 *R N NHR1 *R N N 1) 2) + O Rf O Rf Cl 60-92% 60-90% 2 2 R 39 R 10-56% de 38 Rf = CF3, CF2Cl *R N NHR1 N NHAr ArHN 3) O O Rf O Rf Rf OR R2 41 42 40

1) LDA / THF, -78 ¡C, 2-8 h; 2) NaBH4, ZnI2 / CH2Cl2, rt or H2, Pd/C, MeOH, rt; 3) (i)1N HCl, heat, (ii) ROH / HCl. Scheme 13.

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X X X

N 1) N 2) R1 N 56-92% 45-82% F3C Cl R1 F C Cl 3 Br F3C R1 43 44

1) NBS, BPO / CCl4, reflux; 2) Mg / THF

Scheme 14.

Ar Ar N N O 1) Grubbs cat. OR* + Cl Cl OR* FF F F 76% (E/Z=12:1) O 45 46 47

CO R* Ar Ar 2 HN 3) HN 2) Ar F 4) N CO R* F 2 CO2R* 78% F 52% F Cl (60% de) FF 49 50 48 R* : (1R, 2S, 5R)-8-phenylmenthyl ; Ar = p-MeO-phenyl

1) [(IMesH2)(PCy3)Cl2Ru=CHPh] (5 mol %); 2) H2/Pd/C; 3) LDA / THF; 4) HCO2NH4 Pd / C (10%)/EtOH, microwave, 100 ¡C / 45 min.

Scheme 15.

2.4. Intramolecular reactions with carbon 3. Radical reaction of trifluoroacetimidoyl halides nucleophiles and the related compounds

The intramolecular reaction of the imidoyl moiety with When the functional group X of the trifluoroacetimidoyl carbon nucleophiles has been used for the synthesis of derivatives 2 is iodine, selenium or azo functional groups, nitrogen heterocycles. Bromine at the benzyl position of the corresponding radical 5 is produced by photo- imidoyl chlorides 43 reacts chemoselectively with irradiation or heating, which triggers the radical reaction magnesium even in the presence of aromatic C-Cl bond, with alkenes and alkynes. Scheme 16 shows both intra- then intramolecular substitution follows to produce 2-CF3- molecular and intermolecular reactions. Photoreaction of indole derivative 44 (Scheme 14).16) Hydrogenation of 47 51 with phenylacetylene produces a mixture of isomers 52 followed by intramolecular alkylation produces β-amino-α,β- and 53. Attack of the vinyl radical intermediate at the ipso unsaturated cyclic ester 49. The compound 47 is position and the breaking of C-N bond of the spiro ring synthesized from difluoroimidoyl chloride 45 and chiral followed by the 1,2-migration lead to compound 52. On acrylate 46. Diastereoselective hydrogenation of 49 the other hand, the breaking of C-C bond followed by the produces 5-membered cyclic amino acid 50 in a moderate 1,2-migration lead to another compound 53.18b) de (Scheme 15).17) 3-Ketoindole 55 is produced by the photolysis of 54. The intramolecular carbo-iodination to a triple bond via the imidoyl radical intermediate and the subsequent hydrolytic transformation of iodoalkylidene moiety to an acyl group results in 3-ketoindole 55 as a final product.18a)

N CF Ph NAr 1) MeO 3 +PhC CH MeO F3C I 37-55% +

51 1) MeCN, hν Ph N CF3 52 53 R R O R I hν . CF 2) 53-69% 3 N CF3 NCF3 N H 54 55 2) hν / acetone-H2O R = alkyl, Ph

Scheme 16.

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and it immediately reacts with nucleophiles to produce 60. 4. Reactions with trifluoroacetimidoyl metals At above −60 °C, unstable lithium species 59 dimerizes via carbene intermediate 61 (Scheme 18).21) The Trifluoroacetimidoyl metals 57 are potentially applicable corresponding zinc species generated with Zn-Al in DMF for a variety of syntheses of trifluoromethyl nitrogen at room temperature is more stable than lithium species compounds via the metal-based C-C bond formations. and smoothly reacts with electrophiles (Scheme 19).22) Three active species 56, 57, and 58 are available with Imidoyl magnesium is generated by the reaction of various X shown in Scheme 17. Many reports have been imidoyl chloride 1 with magnesium in the presence of already published especially about isopropenyl metals 56.19) TMS-Cl in THF. The magnesium species is relatively stable On the other hand, trifluoroacetyl metals 58 are very to be handled at 0 °C. Selective silylation of 1 on the imino unstable and only trifluoroacetyl palladium species has carbon at −70 °C gives imidoyl silane 62 in about 70% yield been employed for organic synthesis.20) The chemistry of (Scheme 20).23) Interestingly, the reaction at 0 °C gives trifluoroacetimidoyl metals 57 has been extensively the double silylation product 63 in good yields. The explored in our group. In this account, the chemistries of successive magnesium-promoted C-Cl and C-F bond the trifluoroacetimidoyl metals 57, their preparation, activations proceed leading to the formation of 63.24) This properties, reactions, and synthetic applications are bis-silylated enamine 63 has three reaction sites; nitrogen, described. C-1 and C-2. The stepwise activation of nitrogen and then The stability of the imidoyl metals 57 is primarily C-1 with KF provides 64. Meanwhile, the activation of dependent on the degree of the covalency of the carbon- nitrogen with Lewis acid and then C-1 with KF gives 65. metal bond. The smaller difference of electronegativities The Lewis acid-catalyzed alkylation of 63 on C-2 with between carbon and metal gives higher stability (Figure benzaldehyde produces 66a. Then, the benzoate 66b is 1). For example, Pd species are stable even at 130 °C for transformed to a precursor 68b of 4-hydroxy-3,3-difluoro- a long time. Meanwhile, lithium species have to be kept at 2-aminobutanoic acid (Scheme 20, 21).24) Fluoride ion- a temperature lower than at least −60 °C, although the catalyzed desilylative allylation on amino nitrogen and lithium species are most reactive as carbanions. aza-Claisen rearrangement of 69 gives difluoro compounds Imidoyl lithium 59 is formed in situ by the exchange 70, 71, and 72 (Scheme 21).25) reaction of iodine with lithium on treating 1 with butyl lithium,

X 56 : X = CH2 Li 57 : X = NAr 58 : X = O F3C metal BuLi / ether metal = Li, Mg, Zn, Si, B, Sn, Rh, Pd NAr NAr NAr -78 ¡C electrophiles F3C I F3C Li F3C E 26-89% 51 59 60 Scheme 17. electrophiles; PhCHO, DMF, PhCOCl, PhCOMe, ClCO2Et

NAr LiNAr .. F3C Li F3C 59 61

Scheme 18. NAr NAr .. + F3C Metal F3C Metal

Ionic Covalent Zn

Zn-Al / HMPA-DMF NAr Mg NAr Li Zn Si Rh Pd C rt / 0.5 h Ph + PhCHO F3C F C 3 I 21-94% OH 1.0 1.3 1.7 1.92.0 2.2 2.3 2.6 Electronegativity Scheme 19.

Figure 1. Ionic Charactoer of Carbon-Metal Bond in Trifluoroacetimidoyl Metal

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Mg

Mg/TMSCl NAr NAr THF / -75 ¡C F CCl F3C TMS TMS = SiMe3 3 73% 162 1 NAr Mg/TMSCl NAr(TMS) E NAr E1 NAr THF / 0 ¡C F F E2 TMS E2 F3CCl F F 80-85% F 1 63F 64 65

TMS PMP PMP PMP PMP N OR N OBz N OBz N 1) F 2) 3) TMS I Ph TMS Ph Ph CO2R 88% 96% F 63 F F F F F F 66a R = H 67 68a R = Et (98%) 66b R = Bz 68b R = Bn (97%)

1) PhCHO, BF3-Et2O / CH2Cl2, 0 ¡C, 1.5 h; 2) KF, I2 / CH2Cl2, rt, 6.5 h; 3) Pd2(dba)3 CHCl3 / K2CO3, CO (1 atm) / ROH / toluene, rt, 20 h

Scheme 20.

Ar N

SiMe3 FF 70 R3 2) R1 Br R3 41% Me Si Ar 3 N Ar R2 R1 N 2) F Ar F N SiMe 2 3 R F SiMe 59% F SiMe 79-92% 3 3 F 63 F 3) 71 69 88% PMP 1) KF-CuI-DMF, 40 ¡C, 2-4 h N 2) xylene, 140 ¡C, 36 h SiMe3 3) xylene, 180 ¡C, 14 h F F 72 Scheme 21.

The fluoride ion-catalyzed desilylation of 62 can Palladium species 75 can be generated from any imidoyl generate the penta-valent silicate intermediate 73, an halides (X = I, Br, Cl). However, oxidative addition of the imidoyl carbanion equivalent which is much more stable halide to low valent palladium is rate-determining so that than the lithium species and can be handled and alkylated iodo imidoyl is the most useful for the reaction where the even at 50 °C to give 74 (Scheme 22).26) Therefore, the oxidative addition and nucleophilic substitution of the imidoyl imidoyl silane 62 is useful for the reaction with the less halide with nucleophiles in the reaction solution are reactive electrophiles. competitive, and in particular the nucleophilic reaction is faster than the oxidative addition. Imidoyl palladium species 75 is used for various C-C bond formations and synthetic applications as shown in Schemes 23 and 24. Both the Heck-Mizorogi reaction with 1-alkenes and the Si Sonogashira reaction with alkynes are very successful for the preparations of ene-imines and yne-imines, NAr - NAr TBAF NAr respectively.27) Pd-catalyzed carboalkoxylation of 1 (X=I) F3C SiMe F C SiMe 3 40-88% F C E 3 3 F 3 with primary alcohols such as benzyl and ethyl alcohols 62 73 74 provides 3,3,3-trifluoro-2-iminopropanoates in excellent yields, which are good precursors for trifluoroalanine.28) electrophiles: ArCHO, PhCOR, ClCO Et 2 It is noteworthy that even tert-butyl ester 78 (R=t-Bu) can 29) Scheme 22. be prepared in 60-70% yields in DMF or DMI as solvents. In the absence of nucleophiles which trap the palladium species, α-diimines 79 are formed via dimerization of 75 (Scheme 23).30)

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Pd

NAr NAr Pd(0) F3C Pd-X F3CX 1 75 X = I, Br, Cl (reactivity; I > Br > Cl)

NAr NAr F C F3C R 3 RR R 76 77 1) NAr 3)

F3C Pd-X CO ROH 75 NAr ArN NAr 2) 4) F CCOR 3 2 F3CCF3 78 79

1) Pd2(dba)3¥CHCl3 / K2CO3 / toluene, 60-65 ¡C, 48-95%

2) PdCl2, PPh3, CuI / CH3CN-toluene, rt-65 ¡C, 47-92%

3) Pd2(dba)3¥CHCl3 / CO, ROH / K2CO3 / toluene, rt, 27-98%

4) Pd2(dba)3¥CHCl3 / CO / K2CO3 / DMF, 70 ¡C, 34-82%

Pd2(dba)3¥CHCl3 / CO tBuOH / K CO / DMF NAr 2 3 NAr rt t FCI F3CCO2Bu 3 62% 51 80 Scheme 23.

Optically pure β,β-difluoroproline 86 is synthesized from A halogen atom of imidoyl halides 1 is not incorporated bromodifluoroacetimidoyl iodide 81 (Scheme 24).31) Ester into products obtained in so far as these examined 82 is prepared from imidoyl iodide 81 under Pd catalyzed reactions (Scheme 23). However, incorporation of both an carboalkoxylation conditions and its imino group is imidoyl moiety and a halogen atom into a product would subjected to asymmetric hydrogenation under increase its additional synthetic value. Scheme 25 shows 32) Pd(OCOCF3)2 catalyst in trifluoroethanol to produce 83 an example in which both a halogen atom and an imidoyl with 88% ee.32) The radical allylation of 83 and enantio- moiety can be utilized effectively for the synthesis.33) A meric enrichment of 84 by recrystallization followed by chlorine atom at the 4-position of the quinoline ring is ozonolysis, dehydration and then hydrogenation of 85 lead useful for the construction of quinolone carboxylic acid 89. to the synthesis of enantiomerically pure proline 86.31)

PMP PMP PMP Scheme 24. N 1) N 2) HN X X X I CO2R' 75-98% CO2R' FF F F (30-88% ee) FF 81 82 83 X = H, F, Cl, Br, C2F5 R' = Et, Bn, tBu

PMP HO Boc Boc HN 3) 4), 5) N 6) N CO Bn 87% 2 CO2Bn 83% CO2Bn FF F F >99% ee F F 84 85 86

' 1) Pd2(dba)3¥CHCl3 (Pd: 0.10 eq.), CO (1 atm), R OH, K2CO3, toluene or DMF, DMI, rt; 2) Pd(OCOCF3)2, (R)-BINAP, H2 (100 atm), CF3CH2OH, rt, 24h; 3) AllylSnBu3, AIBN / toluene; 4) (i) CAN / MeCN-H2O, (ii) CbzCl / NaHCO3 (84%); 5) O3 / CH2Cl2 (90%); 6) (i) PPh3Cl2 / DMF, (ii) RhCl(PPh3)-H2

O Cl CO H Scheme 25. 2 Cl 1) X X X N Rf N Rf 74-88% NRf H 87 88 89

Rf = CF3, CHF2, C3F7; X = H, F, CO2Et

1) Pd2(dba)3 / BINAP/ AcONa / toluene, 30 ¡C, 5 h,

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Rhodium catalyst also activates imidoyl chloride 90. Introduction of alkyne at the ortho position of an N-aryl ring 5. Conclusion and imidoyl carbon via imidoyl rhodium species gives the quinoline ring 91. Reactions with various alkynes construct Nowadays, about ten percent of the drugs currently substituted quinoline skeletons effectively (Scheme 26).34) commercialized involve the fluorine atom or a fluorinated functionality which markedly enhances their biological activity. Fluorinated compounds thus have been receiving Rh great attention. However, one of the biggest problems in the synthetic organic fluorine chemistry is a lesser X X availability of the starting fluorinated compounds usable for the target molecules. On this basis, synthetic organic R N 1) N + chemists are responsible for developing versatile F3C Cl 42-82% F3CR fluoroorganic synthetic blocks which can be supplied by 90 91 the conventional reactions of highly available starting substrates such as trifluoroacetic acid, for example. 1) [RhCl(cod)] / DPPE, toluene / 110 ¡C 2 Trifluoroacetimidoyl halides are such useful and reliable compounds which justify the requirement for the synthetic R Yield(%) regioa organic fluorine chemistry. They are prepared by one step C6H13 68 94:6 reaction of trifluoroacetic acid in an excellent yield under SiMe3 82 95:5 very conventional conditions. The imidoyl halides 1 C H SiMe tBu 46 99:1 2 4 2 provide us versatile reactivity as the imidoyl carbocation, CH2SiMe2Ph 52 95:5 Ph 42 99:1 radical and carbanion species, in particular imidoyl metals, CH(OMe)2 70 99:1 all of which are reliable for the organic synthesis and will CO2Et 70 29:71 be used more in future. a regioisomer ratio

Scheme 26.

References 6) a) Peng, W.; Han, X.; Yu, B. Synthesis 2004, 1641- 1) a) Japan Society for Promotion of Science, 155 1647.; b) Yu, B.; Tao, H. J. Org. Chem. 2002, 67, 9099- Fluorine Chemistry Committee Ed. “Introduction to 9102; c) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, Fluorine Chemistry”, 2004, Sankyo Publishing Co. Ltd, 2405-2407; d) Al-Mahari, N.; Botting, N. P. Japan; b) Uneyama, K. “Organofluorine Chemistry”, Tetrahedron Lett. 2006, 47, 8703-8706; e) Bedini, E.; 2006, Blackwell Publishing, Oxford, UK Carabellese, A.; Barone, G.; Parrilli, M. J. Org. Chem. 2) a) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, 2005, 70, 8064-8070; f) Hanashima, S.; Castagner, B.; H.; Uneyama, K. J. Org. Chem. 1993, 58, 32-35; Esposito, D.; Nokami, T.; Seeberger, P. H. Org. Lett. b) Synthesis of imidoyl chloride 1 by the radical 2007, 9, 1777-1780; g) Thomas, M.; Gesson, J.-P.; reaction of isonitriles with CF3I: Huang, W. S.; Yuan, Papot, S. J. Org. Chem. 2007, 72, 4262-4264. C. Y.; Wang, Z. Q. J. Fluorine Chem. 1995, 74, 279- 7) Uneyama, K.; Sugimoto, K. J. Org. Chem. 1992, 57, 282; c) Industrial scale production of 1, Hagiya, K.; 6015-6019. Sato, Y.; Koguro, K.; Mitsui S. PCT Int. Appl. WO2005- 8) Uneyama, K.; Yamashita, F.; Sugimoto, K.; Morimoto, 035484. O. Tetrahedron Lett. 1990, 31, 2717-2718. 3) Uneyama, K.; Hao J.; Amii, H. Tetrahedron Lett. 1998, 9) Hao, J.; Ohkura, H.; Amii, H.; Uneyama, K. Chem. 39, 4079-4082. Commun. 2000, 1883-1884. 4) Berkowitz, D. B.; Wu, B.; Li, H. Org. Lett. 2006, 8, 971- 10) Uneyama, K.; Morimoto, O.; Yamashita, F. Tetrahedron 974. Lett. 1989, 30, 4821-4824. 5) Xu, F.; Zhang, S.; Wu, X.-G.; Liu, Y.; Shi, W.; Wang, J. 11) Ohkura, H.; Handa, M.; Katagiri, T.; Uneyama, K. Org. Lett. 2006, 8, 3207-3210. J. Org. Chem. 2000, 67, 2692-2695.

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12) Fustero, S.; Sanz-Cervera, J. F., del Pozo, C.; Acena, 21) a) Watanabe, H.; Yamashita, F.; Uneyama, K. J. L. ACS Symposium Series 949 (Current Tetrahedron Lett. 1993, 34, 1941-1944; b) Watanabe, Fluoroorganic Chemistry), 2006, 54-68. H.; Yan, F.-Y.; Sakai, T.; Uneyama, K. J. Org. Chem. 13) six membered compounds: Fustero, S.; Sanchez- 1994, 59, 758-761. Rosello, M.; Rodrigo, V.; del Pozo, C.; Zanz-Cerver, J. 22) Tamura, K.; Yan, F.-Y.; Takashi, T.; Uneyama, K. F.; Simon, A. Org. Lett. 2006, 8, 4129-4132: Bull. Chem. Soc. Jpn. 1994, 67, 300-303. five membered compounds: Fustero, S.; Sanchez- 23) Akamatsu, C.; Yamauchi, Y.; Kobayashi, T.; Ozeki, Y.; Rosello, M.; Sanz-Cervera, J. F.; Acena, J. L.; sel Pozo, Takagi, J.; Amii, H.; Uneyama, K. Synthesis 2006, 1836- C.; Fernandez, B.; Bartolome, A.; Asensio, A. Org. Lett. 1840. 2006, 8, 4633-4636. 24) Kobayashi, T.; Nakagawa, T.; Amii, H.; Uneyama, K. 14) Fustero, S.; Navorro, A.; Pina, B.; Soler, J. G.; Org. Lett. 2003, 5, 4297-4300. Bartolomé, A.; Asensio, A.; Simón, A.; Bravo, P.; Fronza, 25) Amii, H.; Ichihara, Y.; Nakagawa, T.; Kobayashi, T.; G.; Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621- Uneyama, K. Chem. Commun. 2003, 2902-2903. 2624. 26) Uneyama, K.; Noritake, C.; Sadamune, S. J. Org. 15) Fustero, S.; Salavert, E., Pina, B.; de Arellano, C. R.; Chem. 1996, 61, 6055-6057. Asensio, A. Tetrahedron 2001, 57, 6475-6486. 27) Uneyama K.; Watanabe, H. Tetrahedron Lett. 1991, 16) Wang, Z.; Ge, F.; Wan, W. H.; Jiang, J. Hao, 32, 1459-1462. J. Fluorine Chem. 2007, 128, 1143-1152. 28) Watanabe, H.; Hashizume, Y.; Uneyama, K. 17) Fustero, S.; Sanchez-Rosello, M.; Sanz-Cervera, J. F.; Tetrahedron Lett. 1992, 33, 4333-4336. Acena, J. L.; sel Pozo, C.; Fernandez, B.; Bartolome, 29) Amii, H.; Kishikawa, Y.; Kageyama, K.; Uneyama, K. A.; Asensio, A. Org. Lett. 2006, 8, 4633-4636. J. Org. Chem. 2000, 65, 3404-3408. 18) a) Ueda, Y.; Watanabe, H.; Uemura, J.; Uneyama, K. 30) Amii, H.; Kohda, M.; Seo M.; Uneyama, K. Tetrahedron Lett. 1993, 34, 7933-7934; b) Dan-oh, Y.; Chem. Commun. 2003, 1752-1753. Matta, H.; Uemura, J.; Watanabe, H.; Uneyama, K. 31) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org. Bull. Chem. Soc. Jpn. 1995, 68, 1497-1507. Chem. 2004, 69, 5132-5134. 19) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res., 32) Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313- submitted for publication. 315. 20) a) Kakino, R.; Shimizu, I.; Yamamoto, A. Bull. Chem. 33) Isobe, M.; Takagi, J.; Katagiri, T.; Uneyama, K. Soc. Jpn. 2001, 74, 371-376; b) Kakino, R.; Yasumi, submitted for publication. S.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 34) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 2002, 75, 137-148. 3, 1109-1112.

(Received Mar. 2008)

Introduction of authors

Kenji Uneyama Professor of Emeritus, Okayama University.

Kenji Uneyama was born in Osaka, Japan in 1941. He studied chemistry at the Department of Applied Chemistry, Osaka City University, where he received Bs. Eng., in 1964, Ms. Eng. in 1966, and Dr. Engineering in 1969. His professional academic career started as a lecturer at the Department of Applied Chemistry, Okayama University in 1969, where he was promoted to an associate professor in 1970, and to a professor in 1984. He has been a visiting professor at the Univ. of Paris (Chatenay-Malabry) and the Univ. of Valencia. He served as the vice chair for the editorial board of Chem. Lett. and Bull. Chem. Soc. Jpn. and has been the member of the editorial board of J. Fluorine Chem. Since 1985, he has been involved in study on organofluorine chemistry, which focuses on the synthetic methodology of organic fluorine compounds and covers particularly the chemistry of trifluoroacetimidoyl halides and the C-F bond activation for synthetic chemistry. He has received Award of the Society of Synthetic Organic Chemistry, Japan 1997 and ACS Award for Creative Work in Fluorine Chemistry 2007.

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