number 137 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. 2 number 137 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. 3 number 137 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 4 number 137 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.