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The VCD spectra of several chiral compounds containing the CF3 group are reviewed and analyzed. The list of compounds contains pharmaceutically relevant molecules as well as simple model molecules, having the value of case studies. In particular we point out the importance of the sign of the VCD band relative to some stretching normal mode of CF3 in the region 1110–1150 cm−1, as diagnostic of the configuration of stereogenic carbons C* to which the CF3 group is bound: the correspondence (−) ↔ (R) and (+) ↔ (S) holds for 100% of 1-aryl-2,2,2-trifluoroethanols. DFT calculations confirm these conclusions, but for the rule established here they serve just as a check. This rule is tested on two new compounds, namely N-tert-butanesulfinyl-1-(quinoline-4-yl)-2,2,2-trifluoroethylamine, 8, and 4-[2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, 10, both containing two stereogenic elements, one of them being an asymmetric carbon C* of unknown configuration binding a CF3 group. Discussion of the general validity of the rule is provided and some further tests are run on compounds in well-established drugs.

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

A novel approach to regioselectively substituted and stereoselectively α-trifluoromethylated tryptamines is reported based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)- or (S)-tert-butanesulfinyltrifluoroacetaldimine. Boc- and sulfinylamido-protected α-trifluoromethyltryptamines are obtained in 60-70% yield and 85/15 dr by just heating equimolar amounts of the two reaction partners at 80-90 °C for 2-3 h without a solvent. The absolute configuration of the amino α-carbon has been assigned based on the vibrational circular dichroism (VCD) spectral analysis. The two protecting group can be chemoselectively removed allowing further regio- and stereoselective elaboration of the ene products to various biologically interesting compounds.

Diethyl 2-alkyl-2-hydroxymalonates react with DAST almost exclusively at the ester carbonyl giving a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxyalkanoates, 1,1-bis(ethoxydifluoromethyl)alkan-1-ols when administered at room temperature in dichloromethane. The reaction was exploited in the synthesis of nucleus- and side-chain polyfluorinated indoles. The fluorination of substituted diethyl 2-[(1- tert -butoxycarbonylindol-3-yl)methyl]-2-hydroxymalonates with DAST gave a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxy-3-(1- tert -butoxycarbonylindol-3-yl)propionate, diastereomeric 1′- tert -butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) and only traces of 1,1-bis(ethoxydifluoromethyl)-2-(1- tert -butoxycarbonylindol-3-yl)ethanol. The composition of these mixtures changes depending on the reaction conditions. Regioselectively substituted ethyl 2-hydroxy-2-[(1- tert -butoxycarbonylindol-3-yl)methyl]-3,3,3-trifluoropropionate reacts with DAST at 0 °C in dichloromethane giving satisfactory yields of the corresponding 1-ethoxy-2-[(1- tert -butoxycarbonylindol-3-yl)methyl]-1,1,3,3,3-pentafluoropropan-2-ols as the exclusive reaction products. In the same reaction conditions, ethyl 3-(1- tert -butoxycarbonylindol-3-yl)-2-hydroxypropionate mainly provides 1′- tert -butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) together with the “normal” fluorination product ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-fluoropropionate. A plausible mechanism of this process is proposed in the following.

Novel, optically pure 2-{4-methyl[2]paracyclo[2](5,8)quinolinophan-2-yl}-4-aryl/alkyloxazolines (QUIPHANOX) exhibiting both planar and central chirality have been prepared by reacting (Rp)- and (Sp)-2-cyano-4-methyl[2]paracyclo[2](5,8)quinolinophane with 2-aryl/alkyl-2-aminoethanols. The reaction of each of the above N,N-ligands with [Ru(η(6)-p-cymene)Cl2]2 in methanol, in the presence of either NH4PF6 or NaBPh4, gave the corresponding half-sandwich [(η(6)-p-cymene)Ru(QUIPHANOX)Cl](+)Y(-), (Y(-) = PF6(-), BPh4(-)) as stable complex salts exhibiting planar and carbon- and metal-centered chirality. The unknown absolute configuration (AC) at the metal was determined by (1)H NMR and by theoretical calculations of electronic circular dichroism (ECD) spectra and subsequently confirmed by crystallographic X-ray analysis. (Rp) and (Sp)-ligands afforded (RRu)- and (SRu)-configured complexes, respectively, independent of the AC at the chiral carbon of the oxazoline moiety.

A survey of some recent synthetic approaches to regioselectively fluorinated six member condensed homo- and heteropolycyclic aromatic compounds by complementary cyclization methods is reported.

Accepted Manuscript version. The Published Journal Article is available on the Journal of Chromatography A, Volume 1232, pages 128–133 (DOI: https://doi.org/10.1016/j.chroma.2011.10.090). Supplementary Material available free of charge on the article webpage. © 2011. This Manuscript version is made available under the CC-BY-NC-ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/ ABSTRACT Enantioselective high performance liquid chromatography (HPLC) coupled with a detection system based on the simultaneous measurement of UV absorption and electronic circular dichroism (ECD) allows a complete stereochemical characterization of chiral compounds, once the relationship between sign of the chiroptical properties and absolute configuration is determined. In the present communication, the development of enantioselective HPLC methods for the resolution of a series of fluorinated 2-phenanthrenylpropionic acids (1-6) is reported. Different chiral stationary phases (CSPs) were tested: Chiralcel® OJ, Chiralcel® OD, Chiralpak® AD, (S,S)-Whelk-O® 1, Chirobiotic™ T and α1-acid glycoprotein (AGP). The results allow the application of the methods to a reliable determination of the enantiomeric excess for all the examined compounds; the highest enantioselectivity values were obtained with the Hibar® [(S,S)-Whelk-O® 1] column for some of the examined compounds. In the case of rac-2-(6-fluorophenanthren-1-yl)propionic acid (1), the relationship between circular dichroism and absolute configuration of the enantiomeric fractions was determined by ECD analysis and time-dependent density functional theory (TD-DFT) calculations. The experimental ECD spectrum of the second-eluted fraction of 1 on the Hibar® [(S,S)-Whelk-O® 1] column was found to be in excellent agreement with the theoretical ECD spectrum of (S)-1; therefore, the absolute configuration of the first- and second-eluted enantiomers on the (S,S)-Whelk-O® 1 CSP was assessed as (R) and (S), respectively, and the elution orders of the enantiomeric forms of 1 were determined on all the different CSPs.

The free energies of activation for the aryl-aryl rotation of 17 biphenyl derivatives, bearing a heavy heteroatom (S, Se, Te, P, Si, Sn) as ortho substituent, have been measured by variable temperature NMR. These numbers, so called B values, represent a meaningful measure of the steric hindrance exerted by the selected substituents. DFT computations match quite satisfactorily the experimental barriers and the ground state geometries as well (determined, in two cases, by X-ray diffraction). The present values extend the available list of B values and thus provide an enlarged basis for the compilation of the space requirements of standard substituents, based solely on experimental determinations.

The size of a series of typical substituents has been probed by dynamic NMR measurements of the barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful because only mono-ortho substituted compounds were investigated and thus the results are not compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of conjugation forces at the planar transition state. Alpha-Hydroxyhexafluoroisopropyl is slightly more bulky than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl and methoxy, respectively. Trifluoromethyl is somewhat smaller than isopropyl.

Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step procedure involving metalation/bromination of fluorinated Boc-protected anilines, N -propargylation of the resulting o -bromoarylcarbamate and reductive radical cyclization of the product with tributyltin hydride/AIBN. 3-Methyleneindolines, as valuable, versatile intermediates, can be transformed into highly functionalized 3-substituted indoles by ene-type reactions using different enophiles. Thus, fluoro-, trifluoromethyl- and trifluoromethoxy-substituted diethyl 2-hydroxy-2-[(1 H -indol-3-yl)methyl]malonates, ethyl 2-hydroxy-3-(1 H -indol-3-yl)propionates and ethyl 2-hydroxy-3-(1 H -indol-3-yl)-2-trifluormethylpropionates were obtained in 77–86% yield by simply heating the corresponding tert -butyl 3-methyleneindoline-1-carboxylate with an equimolar amount of diethyl ketomalonate, ethyl glyoxalate and ethyl 3,3,3-trifluoropyruvate, respectively, at 100 °C, without solvent, for 0.5–4 h.

( S )-2-Pyridyl-imino-[2.2]paracyclophane ligands 1 and 2 were synthesized by a condensation reaction of 2-COR-C 5 H 4 N ( 1 : R = H; 2 : R = Me) with enantiopure (−)- S -amino-[2.2]-paracyclophane. The reactions of 1 and 2 with [Ru(η 6 -cymene)Cl(μ-Cl)] 2 afforded complexes [Ru(η 6 -cymene)Cl(N,N)]X ( 3 : N,N = 1 ; 4 : N,N = 2 ; X - = BPh 4 - , PF 6 - , BF 4 - ) that were completely characterized in solution. For 4 PF 6 the solid state structure was determined by X-ray single-crystal diffractometric studies. Two diastereoisomers [( S Ru , S L ) and ( R Ru , S L )] were obtained in solution due to the presence of the planar chirality of paracyclophane (L) and the central chirality on ruthenium. 1 H-NOESY NMR experiments were used to determine the chirality of the metal center and, consequently, to identify ( S Ru , S L ) and ( R Ru , S L ) diastereoisomers. The cymene orientation, obtained by intramolecular 1 H-NOESY NMR investigations, and the relative anion–cation position, determined by interionic 1 H-NOESY or 19 F, 1 H-HOESY NMR studies, depended on the nature of the diastereoisomer.

Regioselectively nucleus and/or side-chain fluorinated 2-(phenanthr-1-yl)- and 2-(phenanthr-2-yl)propionic acids 1-5 were prepared using phenanthren-1(2H)-ones 6a-c as key intermediates. Thus, ethyl 2-(fluorophenanthryl)propionates 11 were obtained in good yields by Reformatsky reaction of 6a-c with ethyl 2-bromopropionate followed by dehydratation and DDQ-promoted aromatization of the resulting beta-hydroxyesters. Side-chain alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 14 were obtained by bromine/lithium permutation of dihydrophenanthryl bromides 12a-c with butyllithium followed by quenching of the lithiated intermediates with methyl pyruvate or ethyl 3,3,3-trifluoropyruvate and subsequent DDQ-promoted aromatization. The alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 25 were prepared by reacting 8-bromo-1,3-difluorophenanthrene 24 with butyllithium for 10 seconds at -110 degrees C and subsequent addition of the suitable pyruvate to the lithiated intermediates. Alkyl 2-hydroxy-2-(phenanthr-2-yl)propionates 26 and 29 were suitably obtained by site-selective metalation of 1,3-difluorophenanthrene 28 and the bromophenanthrene 24, respectively, with LDA followed by quenching of the metalated intermediates with the suitable alkyl pyruvate. Fluorination of the above alpha-hydroxypropionates with DAST, followed by the alkaline hydrolysis, allowed the expected 2-(phenanthryl)propionic acids 1-5 to be obtained in satisfactory overall yields.

Rates of E2 elimination of D,L-1,2dichloro-1,2-diphenylethane (1) and the analogous dibromide (2) were measured in aqueous cetyltrimethylammonium chloride and hydroxide (CTACI and CTAOH), cetyltripropylammonium hydroxide (CTPAOH), didodecyldimethylammonium chloride and hydroxide (DDDACI and DDDAOH), and N,N-dimethyl-N-(2-hydroxyethyl)-n-hexadecylammonium hydroxide (DOH,OH). Micelles or other association colloids of these surfactants increase rates in solutions that contain OH-, and DOH,-OH is much more effective than the nonfunctional surfactants. Variations of first-order rate constants, k obs , with [surfactant] or [OH-] are fitted by a pseudophase model with water and micelles as distinct reaction media, to give second-order rate constants in the latter. These rate constants are in the sequence DOH,OH > CTPAOH DDDACl > DDDAOH CTAOH > CTACl. Micelles favor reactions of 2 over 1, relative to reactivities in water, due to differences in amphiphilic interactions with the leaving halide ions.

Organic sulfides are selectively oxidized to the corresponding sulfoxides in high yields and under very mild conditions using 35% hydrogen peroxide in CHCl3 in the presence of catalytic amounts of 1, 1, 1-trifluoroacetone.

The use of dielec. measurements to assign mol. configurations was examd. with model compds. of the chloroalkane, chloroalkene and chlorocumulene type. A dielec. microcell is described which allowed measurements of 0.35 mL samples under exclusion of air. Both benzene and cyclohexane were used as solvents. Different theories of dielec. const. are compared to evaluate dipole moments. Dipole moments are analyzed in terms of bond moments. The results can be summarized as follows: (i) dielec. measurements are feasible up to 1 M solns. without substantial deviation from linearity; (ii) in general, the dipole moments found in both solvents are similar; the arom. solvent, however, causes a substantial decrease of the values obtained for chloroalkenes with two bulky substituents at the double bonds; (iii) the (E) isomers of chloroalkenes exhibit significantly higher dipole moments than the corresponding (Z) isomers; (iv) isomers of nonchlorinated alkenes of cumulenes with dipole moments below 0.6 D cannot be discriminated dielec.; (v) on the other hand, if the dipole moments of the compds. exceed 1 D, configurations can be assigned unambiguously on the basis of dielec. data even in cases where other approaches fail. [on SciFinder (R)]

CAN promoted oxidative cyclization of dimethyl 4-pentenylmalonate has been investigated in MeOH and in AcOH. The product distribution and the regioselectivity of the reaction (5-exo/6-endo ratio) appear to be very sensitive to the reaction conditions as well as the presence and the nature of copper salts, which can also be exploited from the synthetic point of view.

Unsymmetrical 1,4-diketones are prepared in good yields (60–80%) by cerium (IV) ammonium nitrate oxidative cross-coupling between 1,2-disubstituted and 1-substituted trimethylsilyl enol ethers.

Diaryl, dialkyl and alkyl aryl sulfides are oxidized by cerium (IV) ammonium nitrate in H2 O/CH 2 Cl 2, in the presence of tetra-n-butylammonium bromide, at room temperature, to give sulfoxides in yields ranging between 90 and 100%.

Addition d'acetone, butanone-2, methyl-3 butanone-2, acetylacetate d'ethyle au butadiene-1,3. Obtention de composes d'addition 1,2 et 1,4

Aromatic compounds undergo homolytic malonylation by reaction with cerium(IV) ammonium nitrate and dimethyl malonate in methanol at room temperature.

1,4-diketones and 4-ketoaldehydes dimethylacetals can be prepared in good yields (65%–82%) by the cerium(IV) ammonium nitrate promoted reaction of ketones with isopropenyl acetate and vinyl acetate, respectively.

"Isoretinolq I was prepd. in 55% yield by methylation of II, obtained by reaction of III with the (chlorodihydrofuryl)copper IV. Oxidn. of I with Me2SO contg. N,N'-dicyclohexylcarbodiimide gave a stereoisomeric mixt. of retinal. Similarly, Me2C:CHCH2CH2CMe:CHCH:C:CMeCH2CH2OH was prepd. from geranyl bromide and IV and oxidized to give 4,5-dehydrofarnesal, Me2C:CHCH2CH2CMe:CHCH:CHCMe:CHCHO, which was reduced to give 4,5-dehydrofarnesol, Me2C:CHCH2CH2CMe:CHCH:CHCMe:CHCH2OH. [on SciFinder (R)]