N-Trifluoromethyl Hydrazines,Indoles and Their Derivatives

Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N-CF₃ hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri- and tetra-substituted N-CF₃ hydrazines, hydrazones, sulfonyl hydrazines, and valuable N-CF₃ indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF₃)-NH₂ to function as a directing group in C−H functionalization is also showcased.     

Benzylamine as Hydrogen Transfer Agent: Cobalt‐Catalyzed Chemoselective C=C Bond Reduction of β‐Trifluoromethylated α,β‐Unsaturated Ketones via 1,5‐Hydrogen Transfer

An efficient cobalt‐catalyzed chemoselective reduction of β‐CF₃‐α,β‐unsaturated ketones using benzylamine as hydrogen transfer agent involving intramolecular 1,5‐hydrogen transfer is reported. The reaction proceeded smoothly with a relatively wide range of substrates including those bearing aromatic heterocycles such as a furyl ring system in high yields (74–92 %). This provides an efficient method for the synthesis of β‐CF₃ saturated ketones in one‐pot. This methodology was also applied to the selective C=C reduction of other enone substrates bearing no β‐CF₃‐substituent, of which β‐substituted or β,β‐disubstituted enones are tolerated, giving the desired products in good yields (72–75 %). Mechanistic studies indicate that the reaction involves 1,5‐hydrogen transfer.     

A variable temperature study of the 19-F N.M.R. spectrum of perfluorohexamethyltetrazan: Novel restricted rotation and hindered inversion at the nitrogen atoms [1]

At low temperatures, the ¹⁹F n.m.r. spectrum of the tetrazan (CF₃)₂NN(CF₃)N(CF₃)N(CF₃)₂ shows the presence of two isomers with a free energy difference in stability Δ$\text{G}$ of 2.2 kJ mol^-1. Both isomers show three types of CF₃ group which coalesce at -15°C to three systems of equal intensity (Δ$\text{G}$≠ 52 kJ mol^-1). At 40 °C the two signals assigned to the terminal CF₃ groups coalesce to a single band (Δ$\text{G}$≠ 65 kJ mol^-1).The behaviour is discussed in terms of restricted inversion at the nitrogen atoms, and hindered rotation about the N-N bonds.The hydrazines (CF₃)₂NN(CF₃)NO and (CF₃)₂NN(CF₃)NO₂ have temperature independent spectra.     

Difluoromethylation of Amines with Zn(CF3)Br · 2 CH3CN,Cd(CF3)2 · 2 CH3CN and the System Bi(CF3)3/AlCl3

The reactions of Zn(CF₃)Br · 2 CH₃CN, Cd(CF₃)₂ · 2 CH₃CN or Bi(CF₃)₃/AlCl₃ with tertiary amines lead to the formation of quaternary ammonium salts of the general formula [R₃NCF₂H]X. The reaction of 4‐N,N‐dimethylaminopyridine with Zn(CF₃)Br · 2 CH₃CN yields (N‐difluoromethyl)‐4‐N,N‐dimethylaminopyridinium bromide. Bi(CF₃)₃/AlCl₃ reacts with 1,4‐diazabicyclo[2.2.2]octane to form a mixture of mono‐ and bis(difluoromethylammonium) salts.     

Theoretical study on the reaction of (Z)‐CF3CHCHCF3 with OH radicals

The mechanism on the OH‐initiated atmospheric oxidation reaction of (Z)‐CF₃CH?CHCF₃ with and without O₂/NO has been investigated theoretically. The electronic structure information of the potential energy surface was obtained at the M06‐2X/aug‐cc‐pVDZ level, and the single‐point energies were refined by MCG3/3 method. The calculations show that the (Z)‐CF₃CH?CHCF₃ + OH reaction occurs via addition‐elimination mechanism, leading to products CF₃ and CF₃CH?CH(OH), rather than H‐abstraction mechanism at low temperature. Under atmospheric condition, the OH‐addition intermediate is likely to react rapidly with O₂/NO, and the likely products are CF₃C(O)H, CF₂(O), CF₃CH(OH)CH(O), FNO, and HO₂, as is proposed by experiment. © 2013 Wiley Periodicals, Inc.     

Fast Heavy‐Atom Tunneling in Trifluoroacetyl Nitrene

Chemical reactions involving quantum mechanical tunneling (QMT) increasingly attract the attention of scientists. In contrast to the hydrogen‐tunneling as frequently observed in chemistry and biology, tunneling solely by heavy atoms is rare. Herein, we report heavy‐atom tunneling in trifluoroacetyl nitrene, CF₃C(O)N. The carbonyl nitrene CF₃C(O)N in the triplet ground state was generated in cryogenic matrices by laser (193 or 266 nm) photolysis of CF₃C(O)N₃ and characterized by IR and EPR spectroscopy. In contrast to the theoretically predicted activation barriers (>10 kcal mol⁻¹), CF₃C(O)N undergoes rapid rearrangement into CF₃NCO with half‐life times of less than 10 min and unprecedentedly large ¹⁴N/¹⁵N kinetic isotope effects (1.18–1.33) in solid Ar, Ne, and N₂ matrices even at 2.8 K. The tunneling disappearance of CF₃C(O)N becomes much slower in the chemically active toluene and in 2‐methyltetrahydrofuran at 5 K.     

Copper‐Catalyzed Remote C(sp3)−H Trifluoromethylation of Carboxamides and Sulfonamides

Reported herein is an unprecedented protocol for trifluoromethylation of unactivated aliphatic C(sp³)?H bonds. With Cu(OTf)₂ as the catalyst, the reaction of N‐fluoro‐substituted carboxamides (or sulfonamides) with Zn(CF₃)₂ complexes provides the corresponding δ‐trifluoromethylated carboxamides (or sulfonamides) in satisfactory yields under mild reaction conditions. A radical mechanism involving 1,5‐hydrogen atom transfer of N‐radicals followed by CF₃‐transfer from Cu^II?CF₃ complexes to the thus formed alkyl radicals is proposed.     

New Trifluoromethylated Derivatives of Metal Nitride Clusterfullerenes: Sc3N@Ih‐C80(CF3)14 and Sc3N@D5h‐C80(CF3)16

Trifluoromethylated derivatives of Sc₃N@I_h‐C₈₀ and Sc₃N@D_5h‐C₈₀ were synthesized by the reaction with CF₃I at 440 °C. HPLC separation of the mixture of Sc₃N@D_5h‐C₈₀(CF₃)_n derivatives resulted in isolation and X‐ray structure determination of Sc₃N@D_5h‐C₈₀(CF₃)₁₆, which represents a precursor of the known Sc₃N@D_5h‐C₈₀(CF₃)₁₈. Among the CF₃ derivatives of Sc₃N@I_h‐C₈₀, two new isomers of Sc₃N@I_h‐C₈₀(CF₃)₁₄ ( Sc‐14‐VI and Sc‐14‐VII ) were isolated by HPLC, and their molecular structures were determined by X‐ray diffraction, thus enabling a comprehensive comparison of altogether seven isomers. Two types of addition patterns with different orientations of the Sc₃N cluster relative to the I_h‐C₈₀ fullerene cage were established. In particular, Sc‐14‐VII represents a direct precursor of the known Sc₃N@I_h‐C₈₀(CF₃)₁₆‐ II . All molecular structures exhibit an ordered position of a Sc₃N cluster inside the fullerene C₈₀ cage.     

N-sulfinyl-substituted arylhydrazines from N-sulfinyltrifluoromethansulfonamide

Arylhydrazines react with N-sulfinyltrifluoromethanesulfonamide CF₃SO₂NSO providing N-sulfinylarylhydrazines and trifluoromethanesulfonamide. The discovered reaction is a first example of a transfer of a sulfinyl group from N-sulfinylsulfonamides to hydrazines. The reasons of different hydrolytic stability of CF₃SO₂NSO and ArNHNSO are discussed.     

Synthesis and Properties of CF3(OCF3)CH‐Substituted Arenes and Alkenes†

A silver‐mediated oxidative trifluoromethylation of easily accessible α‐trifluoromethyl alcohols with TMSCF₃ was developed to access novel CF₃(OCF₃)CH‐containing compounds. Deprotonation of CF₃(OCF₃)CH‐substituted arenes afforded synthetically useful CF₃O‐substituted gem‐difluoroalkenes. Furthermore, evaluation of the lipophilicities (log P) indicated that CH(OCF₃)CF₃ is more lipophilic than the common fluorinated motifs such as CF₃, OCF₃, and SCF₃, thus rendering the CH(OCF₃)CF₃ motif appealing in drug discovery.     

Structural Design of Ionic Conduction Paths in Molecular Crystals for Selective and Enhanced Lithium Ion Conduction

The molecular crystals [Li{N(SO₂CF₃)₂}{C₆H₄(OCH₃)₂}₂] and [Li{N(SO₂CF₃)₂}{C₆F₂H₂(OCH₃)₂}₂] with solid‐state lithium ion conductivity have been synthesized by the addition of two equivalents of 1,2‐dimethoxybenzene or 1,2‐difluoro‐4,5‐dimethoxybenzene to Li{N(SO₂CF₃)₂}, respectively. Single‐crystal X‐ray diffraction analysis revealed the formation of ionic conduction paths with an ordered arrangement of lithium ions in these crystal structures, afforded by the self‐ assembled stacking of molecular‐based channels consisting of N(SO₂CF₃)₂ anion and 1,2‐dimethoxybenzene frameworks as a result of intermolecular aromatic and hydrogen interactions. These compounds show selective lithium ion conductivity as the anions behave as a component unit of the conduction paths. The relationship between the crystal structure and ionic conductivity of the molecular crystals provides a clue to the development of novel solid electrolytes based on molecular crystals showing fast and selective lithium ion conduction.     

Electrochemical and Chemical Syntheses of Trifluoromethylating Reagents and Trifluoromethyl Substituted Compounds

The electroreduction of the halofluoromethanes CF₃Br, CF₂Br₂ and CF₂BrCl has been studied in high‐pressure stainless steel autoclaves at different cathodes [Pt, steel (V2A, V4A), glassy carbon (GC)] and in various solvent‐supporting electrolyte systems (SSE), e.g. DMF/[Bu₄N]Br, NMP/[Bu₄N]BF₄ etc. The reduction potentials for CF₃Br increase from Pt (–1.6 V) < V2A (–1.8 V) < GC (–2.1 V) and are lower for CF₂Br₂ and CF₂BrCl suggesting a reductive cleavage of C‐X bonds as the first step. CF₂Br₂ and CF₂BrCl show a two‐step reduction in accord with the C–X bond energies (C–F > C–Cl > C–Br) and the “Perfluoro‐effect”. The electrolysis of CF₃Br in different SSE‐systems with sacrificial zinc or cadmium anodes has been reinvestigated with our experimental set‐up to elucidate the influence of the experimental conditions on the type and ratio of the products. The observed products CF₃MBr·42L and (CF₃)₂M·42L (M = Zn, Cd; L = DMF or AN) are the same as in the previous investigations, but are obtained in different ratios, as a rule caused by a parallel chemical corrosion of the respective anodes. By using aluminium as sacrificial anode no CF₃Al compounds are formed. The CF₃ species generated by electroreduction of CF₃Br react with the solvents via hydrogen abstraction and formation of CF₃H. The current yield with respect to the dissolution of the Al anode reaches 120 % indicating a considerable chemical corrosion in addition to the anodic oxidation. This result enabled a one‐pot trifluoromethylation reaction of NMP as organic carbonyl substrate and solvent with CF₃Br and aluminium powder (ratio 3 : 2) at higher temperatures (> 70 °C). The complete reaction of CF₃Br to give CF₃H and 1‐methyl‐2‐trifluoromethyl‐4,5‐dihydropyrrol allowed the isolation of the latter by vacuum condensation and distillation in 45 % yield, rel. to the CF₃Br used. Gallium and indium were also applied as sacrificial anodes in combination with CF₃Br as substrate. In both cases, anodic current yields of about 280 % indicated an extreme chemical corrosion together with cathodic metal depositions corresponding to the cathodic current yield. These deposits – in contrast to those of Zn and Cd – do not react with CF₃Br in Grignard‐type conversions to CF₃Ga and CF₃In compounds. So, the observed products (CF₃)_nMBr_3–n·L (M = Ga, In; n 1‐3; L = DMF, NMP) are obviously formed by chemical corrosion of the electro‐activated anodes. Finally, electrochemical and chemical trifluoromethylations were successfully carried out, using R₃SiCl (R = Me, Vi, Ph), Me₃M′Cl (M′ = Ge, Sn) and aluminium anodes or Al‐powder. The products were characterized either after isolation or in the product solutions by NMR‐spectroscopic investigations.     

Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench‐Stable Precursor (Me4N)SCF3

Reported herein is the one‐pot synthesis of trifluoromethylated amines at room temperature using the bench‐stable (Me₄N)SCF₃ reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF₃ with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N‐CF₃. The mildness and high functional group tolerance render the method highly attractive for the late‐stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.     

Silylhydrazine und dimere N,N′‐Dilithium‐N,N′‐bis(silyl)hydrazide – Synthesen,Reaktionen, Isomerisierungen

Silylhydrazines and Dimeric N,N′‐Dilithium‐N,N′‐bis(silyl)hydrazides – Syntheses, Reactions, Isomerisations Di‐tert.‐butylchlorosilane reacts with dilithiated hydrazine in a molar ratio to give the N,N′‐bis(silyl)hydrazine, [(Me₃C)₂SiHNH]₂, ( 5 ). Isomeric tris(silyl)hydrazines, N‐difluorophenylsilyl‐N′,N′‐bis(dimethylphenylsilyl)hydrazine ( 7 ) and N‐difluorophenylsilyl‐N,N′‐bis(dimethylphenylsilyl)hydrazine ( 8 ) are formed in the reaction of N‐lithium‐N′‐N′‐bis(dimethylphenylsilyl)hydrazide and F₃SiPh. Isomeric bis(silyl)hydrazines, (Me₃C)₂SiFNHNHSiMe₂Ph ( 9 ) and (Me₃C)₂‐ SiF(PhMe₂Si)N–NH₂ ( 10 ) are the result of the reaction of di‐tert.‐butylfluorosilylhydrazine and ClSiMe₂Ph in the presence of Et₃N. Quantum chemical calculations for model compounds demonstrate the dyotropic course of the rearrangement. The monolithium derivative of 5 forms a N‐lithium‐N′,N′‐bis(silyl)hydrazide ( 11 ). The dilithium salts of 5 ( 13 ) and of the bis(tert.‐butyldiphenylsilyl)hydrazine ( 12 ) crystallize as dimers with formation of a central Li₄N₄ unit. The formation of 12 from 11 occurs via a N′ → N‐silyl group migration. Results of crystal structure analyses are reported.     

Synthesis and structures of photoactive rhenium carbonyl complexes derived from 2‐(pyridin‐2‐yl)‐1,3‐benzothiazole, 2‐(quinolin‐2‐yl)‐1,3‐benzothiazole and 1,10‐phenanthroline

Carbon monoxide (CO) has recently been identified as a gaseous signaling molecule that exerts various salutary effects in mammalian pathophysiology. Photoactive metal carbonyl complexes (photoCORMs) are ideal exogenous candidates for more controllable and site‐specific CO delivery compared to gaseous CO. Along this line, our group has been engaged for the past few years in developing group‐7‐based photoCORMs towards the efficient eradication of various malignant cells. Moreover, several such complexes can be tracked within cancerous cells by virtue of their luminescence. The inherent luminecscent nature of some photoCORMs and the change in emission wavelength upon CO release also provide a covenient means to track the entry of the prodrug and, in some cases, both the entry and CO release from the prodrug. In continuation of the research circumscribing the development of trackable photoCORMs and also to graft such molecules covalently to conventional delivery vehicles, we report herein the synthesis and structures of three rhenium carbonyl complexes, namely, fac‐tricarbonyl[2‐(pyridin‐2‐yl)‐1,3‐benzothiazole‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₂H₈N₂S)(CO)₃](CF₃SO₃), ( 1 ), fac‐tricarbonyl[2‐(quinolin‐2‐yl)‐1,3‐benzothiazole‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₆H₁₀N₂S)(CO)₃](CF₃SO₃), ( 2 ), and fac‐tricarbonyl[1,10‐phenanthroline‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₂H₈N₂)(CO)₃](CF₃SO₃), ( 3 ). In all three complexes, the Re^I center resides in a distorted octahedral coordination environment. These complexes exhibit CO release upon exposure to low‐power UV light. The apparent CO release rates of the complexes have been measured to assess their comparative CO‐donating capacity. The three complexes are highly luminescent and this in turn provides a convenient way to track the entry of the prodrug molecules within biological targets.     

Water in Ionic Liquids: Correlation between Anion Hydrophilicity and Near‐Infrared Fingerprints

We show that fingerprints of the different states of water association can be clearly distinguished in the range of the first overtone of water′s symmetric O‐H stretching in the spectra of water‐saturated [EMIm]⁺‐based ionic liquids with anions of substantially different hydrophilicity, such as hydrophobic [(CF₃SO₂)₂N]^?, moderately hydrophilic [CF₃SO₃]^?, and highly hydrophilic [HSO₄]^?.     

Recyclizations of 2‐aminobenzylimines and thioaroylhydrazones of N‐substituted N‐hydroxy‐3‐oxobutanamides

A universal scheme is proposed for the molecular design of heterocyclic recyclizations by replacing the exocyclic hydroxyl groups in exo‐trig‐ ring‐chain tautomeric molecules with substituted amines or hydrazines. The practical applicability of this approach is demonstrated by the condensations of 5‐hydroxy‐5‐methyl‐3‐isoxazolidinones with thioaroyl‐hydrazines and 2‐aminomethylaniline. The condensation products were studied by modern ¹H, ¹³C and ¹⁵N NMR spectroscopic methods using three solvents: CDC1₃, DMSO[D₆] and CD₃CN. The solvent was found to have a strong effect to the relative amounts of the tautomers.     

Synthesen und NMR‐Untersuchungen von Salzen mit den neuen Anionen [PtXn(CF3)6‐n]2— (n = 0 ‐ 5, X = F,OH, Cl,CN) und die Kristallstrukturanalyse von K2[(CF3)2F2Pt(μ‐OH)2PtF2(CF3)2]·2H2O

Syntheses and NMR Spectroscopic Ivestigations of Salts containing the Novel Anions [PtX_n(CF₃)_6‐n]^2— (n = 0 ‐ 5, X = F, OH, Cl, CN) and Crystal Structure of K₂[(CF₃)₂F₂Pt(μ‐OH)₂PtF₂(CF₃)₂]·2H₂O The first syntheses of trifluoromethyl‐complexes of platinum through fluorination of cyanoplatinates are reported. The fluorination of tetracyanoplatinates(II), K₂[Pt(CN)₄], and hexacyanoplatinates(IV), K₂[Pt(CN)₆], with ClF in anhydrous HF leads after working up of the products to K₂[(CF₃)₂F₂Pt(μ‐OH)₂PtF₂(CF₃)₂]·2H₂O. The structure of the salt is determined by a X‐ray structure analysis, P2₁/c (Nr. 14), a = 11.391(2), b = 11.565(2), c = 13.391(3)Å, β = 90.32(3)°, Z = 4, R₁ = 0.0326 (I > 2σ(I)). The reaction of [Bu₄N]₂[Pt(CN)₄] with ClF in CH₂Cl₂ generates mainly cis‐[Bu₄N]₂[PtCl₂(CF₃)₄] and fac‐[Bu₄N]₂[PtCl₃(CF₃)₃], but in contrast that of [Bu₄N]₂[Pt(CN)₆] with ClF in CH₂Cl₂ results cis‐[Bu₄N]₂[PtX₂(CF₃)₄], [Bu₄N]₂[PtX(CF₃)₅] (X = F, Cl) and [Bu₄N]₂[Pt(CF₃)₆]. In the products [Bu₄N]₂[PtX_n(CF₃)_6‐n] (X = F, Cl, n = 0—3) it is possibel to exchange the fluoro‐ligands into chloro‐ and cyano‐ligands by treatment with (CH₃)₃SiCl und (CH₃)₃SiCN at 50 °C. With continuing warming the trifluoromethyl‐ligands are exchanged by chloro‐ and cyano‐ligands, while as intermediates CF₂Cl and CF₂CN ligands are formed. The identity of the new trifluoromethyl‐platinates is proved by ¹⁹⁵Pt‐ and ¹⁹F‐NMR‐spectroscopy.     

Gas‐Phase Generation and Decomposition of a Sulfinylnitrene into the Iminyl Radical OSN

The dipolar oxathiazyne‐like sulfinylnitrene RS(O)N, a highly reactive α‐oxo nitrene, has been rarely investigated. Upon flash vacuum pyrolysis of sulfinyl azide CF₃S(O)N₃ at 350 °C, an elusive sulfinylnitrene CF₃S(O)N was generated in the gas phase in its singlet ground state and was characterized by matrix‐isolation IR spectroscopy. Further fragmentation of CF₃S(O)N at 600 °C produced CF₃ and a novel iminyl radical OSN, an SO₂ analogue, which were unambiguously identified by IR spectroscopy. Consistent with the experimental observations, DFT calculations clearly support a stepwise decomposition mechanism of CF₃S(O)N₃.     

Base‐Catalyzed NN Bond Cleavage of Hydrazones: Synthesis of α‐Amino Ketones

An efficient Cs₂CO₃‐promoted synthesis of α‐amino ketones using hydrazines, aldehydes, and α‐haloketones as starting materials through a cascade condensation/nucleophilic substitution/N? N bond cleavage route is developed. The carbonyl group plays a key role in this novel N? N bond cleavage process.