Valentin Duvauchelle
email: valentin.duvauchelle@unimes.fr

David Bénimélis
email: david.benimelis@unimes.fr

Patrick Meffre
email: patrick.meffre@unimes.fr

Zohra Benfodda
email: zohra.benfodda@unimes.fr

Catalyst-Free Site Selective Hydroxyalkylation of 5-Phenylthiophen-2-amine with α-Trifluoromethyl Ketones through Electrophilic Aromatic Substitution

Keywords: hydroxyalkylation, trifluoromethyl hydroxyalkylation, trifluoromethyl ketone, catalyst-free, site selective, chemoselective, 2-aminothiophene, 5-phenylthiophen-2-amine

come

Introduction

2-aminothiophene (2-AT) moiety is widespread in FDA-approved drugs and is a privileged scaffold in medicinal chemistry that is known to confer many biological activities [START_REF] Bozorov | 2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry[END_REF][START_REF] Thanna | Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis[END_REF][START_REF] Scheich | Novel small molecule inhibitors of MDR mycobacterium tuberculosis by NMR fragment screening of antigen 85C[END_REF][4][START_REF] Desantis | Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity[END_REF]. As examples, substituted-2-AT moiety such as compound 1 (Figure 1a) demonstrated activity against Mycobacterium tuberculosis by targeting the Ag85 enzymes [START_REF] Scheich | Novel small molecule inhibitors of MDR mycobacterium tuberculosis by NMR fragment screening of antigen 85C[END_REF]. PD 81723 [START_REF] Thanna | Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis[END_REF]Figure 1a) has been shown to be the first allosteric specific and selective adenosine A 1 receptor ligands [START_REF] Narlawar | Hybrid ortho/allosteric ligands for the adenosine A1 receptor[END_REF]. Compound 3 has been described as a hepatitis B virus replication inhibitor [START_REF] Tang | 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors[END_REF] and compound 4 showed antimicrobial activity against A. fumigatus, G. candidum, C. albicans and S. racemosum [START_REF] Aly | Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents[END_REF]. 2-AT derivatives are mostly synthesized using Gewald reaction [START_REF] Campaigne | The synthesis of 2,5-diarylthiophenes[END_REF][START_REF] Gewald | Heterocyclen aus CH-aciden Nitrilen, VIII. 2-Amino-thiophene aus methylenaktiven Nitrilen; Carbonylverbindungen und Schwefel[END_REF]. Technically, it involves condensation of a carbonyl derivative, a α-cyanoester in the presence of sulfur source. To this day, used methodologies often undergo to the generation of trisubstituted thiophene ring with an electron withdrawing group-particularly negative mesomeric effect-on C 3 atom (Figure 1a) [START_REF] Minetto | Microwave-assisted Paal-Knorr reaction-Three-step regiocontrolled synthesis of polysubstituted furans, pyrroles and thiophenes[END_REF][START_REF] Revelant | Microwave-assisted synthesis of 5-substituted 2-aminothiophenes starting from arylacetaldehydes[END_REF][13][START_REF] Ibrahim | Uses of ethyl benzoyl acetate for the synthesis of thiophene, pyran, and pyridine derivatives with antitumor activities[END_REF][START_REF] Hwang | Multicomponent petasis reaction for the synthesis of functionalized 2-aminothiophenes and thienodiazepines[END_REF].

Over recent decades, interest for hydroxyalkylation on aryl derivatives as C-C bond forming reaction has grown [START_REF] Touré | Natural product synthesis using multicomponent reaction strategies[END_REF][START_REF] Bauer | Iron catalysis in organic synthesis[END_REF][START_REF] Poulsen | Catalytic asymmetric Friedel-Crafts alkylation reactions-Copper showed the way[END_REF][START_REF] Nie | Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates[END_REF]. Ullyot first reported hydroxyalkylation of aryl compounds with a carbonyl derivative under acidic conditions as new way to synthesize benzoins [START_REF] Fuson | A new synthesis of benzoins. 2 ,4 ,6 -trimethylbenzoin[END_REF]. Thereafter, synthesis methodologies have been refined to fit with chemical diversity: heteroaryls were used as substrates; carbonyl derivatives were more complex, likewise the Lewis acids. The methodologies described, respectively, by Schnakenburg [START_REF] Pillaiyar | Reaction of indoles with aromatic fluoromethyl ketones: An efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water[END_REF], Ramanathan [START_REF] Harikrishnan | Friedel-Crafts hydroxyalkylation through activation of a carbonyl group using AlBr3: An easy access to pyridyl aryl/heteroaryl carbinols[END_REF] and Chatti [START_REF] Medimagh | A facile preparation of trisubstituted amino-furan and -thiophene derivatives[END_REF] are relevant examples of hydroxyalkylation on heteroaryls scaffolds (Figure 1b,c).

Hence, trifluoromethyl group introduction onto 2-AT via hydroxyalkylation methodology provides a dual benefit: it introduces a chemical diversity that was lacking in 2-ATs and it inserts the trifluoromethyl group, which is very interesting from a medicinal point of view because it is known to confer biological properties of high value [START_REF] Purser | Fluorine in medicinal chemistry[END_REF][START_REF] Umemoto | Electrophilic perfluoroalkylating agents[END_REF][START_REF] Prakash | Perfluoroalkylation with organosilicon reagents[END_REF][START_REF] Kirij | Trifluoromethylation of heterocumulenes with trimethyl(trifluoromethyl)silane in the presence of fluoride ions: Synthesis of trifluoroacetamides and trifluorothioacetamides from isocyanates and isothiocyanates[END_REF]. Chemists are currently faced with the difficult task of increasing the efficacy of this kind of reactions while also seeking greener processes [START_REF] Horváth | Innovations and green chemistry[END_REF]. As we know, a more responsible use of metals as catalysts as well as the use of atom economical reactions participate in the development of a greener chemistry [START_REF] Trost | On inventing reactions for atom economy[END_REF][START_REF] Trost | Atom economy-A challenge for organic synthesis: Homogeneous catalysis leads the way[END_REF][START_REF] Anastas | Green chemistry: Principles and practice[END_REF]. To our knowledge, the site-selective, metal-and catalyst-free trifluoromethyl hydroxyalkylation of unprotected 5-phenylthiophen-2-amine has never been described in the literature. Herein, we report the trifluoromethyl hydroxyalkylation methodology we developed in presence of various α-trifluoromethyl ketones (Figure 1d). Hence, trifluoromethyl group introduction onto 2-AT via hydroxyalkylat methodology provides a dual benefit: it introduces a chemical diversity that was lack in 2-ATs and it inserts the trifluoromethyl group, which is very interesting from medicinal point of view because it is known to confer biological properties of high va [START_REF] Purser | Fluorine in medicinal chemistry[END_REF][START_REF] Umemoto | Electrophilic perfluoroalkylating agents[END_REF][START_REF] Prakash | Perfluoroalkylation with organosilicon reagents[END_REF][START_REF] Kirij | Trifluoromethylation of heterocumulenes with trimethyl(trifluoromethyl)silane in the presence of fluoride ions: Synthesis of trifluoroacetamides and trifluorothioacetamides from isocyanates and isothiocyanates[END_REF]. Chemists are currently faced with the difficult task of increasing the efficacy this kind of reactions while also seeking greener processes [START_REF] Horváth | Innovations and green chemistry[END_REF]. As we know, a m

Results

To begin, the synthesis of compound 8 has been investigated as described in Scheme 1. 2-bromo-5-nitrothiophene 5 and phenylboronic acid 6, which under Suzuki-Miyaura coupling conditions, developed in our laboratory by Boibessot et al., form intermediate 7 in 86% yield after purification [32]. Then, we realized the reduction in the nitro function, following Zhang and co-workers methodology, in the presence of hydrazine hydrate in absolute ethanol at 50 • C for 15 min, followed by the careful addition of Raney nickel to smoothly yield to 8 [START_REF] Nguyen | Synthesis and pharmacological evaluation of 1-phenyl-3-thiophenylurea derivatives as cannabinoid type-1 receptor allosteric modulators[END_REF]. (90% yield after purification).

phenylthiophen-2-amine has never been described in the literature. Herein, we re trifluoromethyl hydroxyalkylation methodology we developed in presence of va trifluoromethyl ketones (Figure 1d).

Results

To begin, the synthesis of compound 8 has been investigated as descr Scheme 1. 2-bromo-5-nitrothiophene 5 and phenylboronic acid 6, which Suzuki-Miyaura coupling conditions, developed in our laboratory by Boib al., form intermediate 7 in 86% yield after purification [32]. Then, we reali reduction in the nitro function, following Zhang and co-workers methodo the presence of hydrazine hydrate in absolute ethanol at 50 °C for 15 min, fo by the careful addition of Raney nickel to smoothly yield to 8 [START_REF] Nguyen | Synthesis and pharmacological evaluation of 1-phenyl-3-thiophenylurea derivatives as cannabinoid type-1 receptor allosteric modulators[END_REF]. (90% yie purification).

Scheme 1. Synthesis of precursor 8.

On running 1 H NMR analysis of compound 8 in D2O deuteriation on C3 a been observed (Scheme 2). On the 1 H spectra, H3 signal disappears and H4 signal as a singlet at 7.28 ppm. On 13 C spectra, C3 atom couples with the deuterium it c give a triplet at 123.40 ppm (See Supplementary Materials for More Details, Fig and S2). The deuteriation on C3 atom seems to be due to the positive mesomeric (+M of the amino group responsible for the reactivity shown thereafter. 17 A p mechanism of this deuteriation is proposed in Scheme 3, such as suggested by and his team [START_REF] Garnett | Catalytic deuterium exchange reactions with organics. XIV. Distinction between associative and dissociative π-complex substitution mechanisms[END_REF]. A delocalization of the lone pair of nitrogen atoms would re deuteriation on C3 atom to generate the intermediate 10 before the rearomatizatio structure to afford 9. Scheme 3. Proposed mechanism for the deuteriation of 9.

The reactivity of 8 was then studied in the presence of other electro When 8 is reacted with p-anisaldehyde or acetophenone in toluene under re Scheme 1. Synthesis of precursor 8.

On running 1 H NMR analysis of compound 8 in D 2 O deuteriation on C 3 atom has been observed (Scheme 2). On the 1 H spectra, H 3 signal disappears and H 4 signal appears as a singlet at 7.28 ppm. On 13 C spectra, C 3 atom couples with the deuterium it carries to give a triplet at 123.40 ppm (See Supplementary Materials for More Details, Figures S1 andS2).

Suzuki-Miyaura coupling conditions, developed in our laborato al., form intermediate 7 in 86% yield after purification [32]. The reduction in the nitro function, following Zhang and co-worker the presence of hydrazine hydrate in absolute ethanol at 50 °C fo by the careful addition of Raney nickel to smoothly yield to 8 [33 purification).

Scheme 1. Synthesis of precursor 8.

On running 1 H NMR analysis of compound 8 in D2O deuteriat been observed (Scheme 2). On the 1 H spectra, H3 signal disappears an as a singlet at 7.28 ppm. On 13 C spectra, C3 atom couples with the deu give a triplet at 123.40 ppm (See Supplementary Materials for More and S2). The deuteriation on C3 atom seems to be due to the positive me of the amino group responsible for the reactivity shown therea mechanism of this deuteriation is proposed in Scheme 3, such as su and his team [START_REF] Garnett | Catalytic deuterium exchange reactions with organics. XIV. Distinction between associative and dissociative π-complex substitution mechanisms[END_REF]. A delocalization of the lone pair of nitrogen atom deuteriation on C3 atom to generate the intermediate 10 before the rea structure to afford 9. Scheme 3. Proposed mechanism for the deuteriation of 9.

The reactivity of 8 was then studied in the presence of o When 8 is reacted with p-anisaldehyde or acetophenone in toluen The deuteriation on C 3 atom seems to be due to the positive mesomeric (+M) effect of the amino group responsible for the reactivity shown thereafter. 17 A plausible mechanism of this deuteriation is proposed in Scheme 3, such as suggested by Garnett and his team [START_REF] Garnett | Catalytic deuterium exchange reactions with organics. XIV. Distinction between associative and dissociative π-complex substitution mechanisms[END_REF]. A delocalization of the lone pair of nitrogen atoms would result in a deuteriation on C 3 atom to generate the intermediate 10 before the rearomatization of the structure to afford 9.

To begin, the synthesis of compound 8 has been investigated as descr Scheme 1. 2-bromo-5-nitrothiophene 5 and phenylboronic acid 6, which Suzuki-Miyaura coupling conditions, developed in our laboratory by Boib al., form intermediate 7 in 86% yield after purification [32]. Then, we reali reduction in the nitro function, following Zhang and co-workers methodo the presence of hydrazine hydrate in absolute ethanol at 50 °C for 15 min, fo by the careful addition of Raney nickel to smoothly yield to 8 [START_REF] Nguyen | Synthesis and pharmacological evaluation of 1-phenyl-3-thiophenylurea derivatives as cannabinoid type-1 receptor allosteric modulators[END_REF]. (90% yie purification).

Scheme 1. Synthesis of precursor 8.

On running 1 H NMR analysis of compound 8 in D2O deuteriation on C3 a been observed (Scheme 2). On the 1 H spectra, H3 signal disappears and H4 signal as a singlet at 7.28 ppm. On 13 C spectra, C3 atom couples with the deuterium it c give a triplet at 123.40 ppm (See Supplementary Materials for More Details, Fig and S2). The deuteriation on C3 atom seems to be due to the positive mesomeric (+M of the amino group responsible for the reactivity shown thereafter. 17 A p mechanism of this deuteriation is proposed in Scheme 3, such as suggested by and his team [START_REF] Garnett | Catalytic deuterium exchange reactions with organics. XIV. Distinction between associative and dissociative π-complex substitution mechanisms[END_REF]. A delocalization of the lone pair of nitrogen atoms would re deuteriation on C3 atom to generate the intermediate 10 before the rearomatizatio structure to afford 9. Scheme 3. Proposed mechanism for the deuteriation of 9.

The reactivity of 8 was then studied in the presence of other electro When 8 is reacted with p-anisaldehyde or acetophenone in toluene under re The reactivity of 8 was then studied in the presence of other electrophiles. When 8 is reacted with p-anisaldehyde or acetophenone in toluene under reflux, no reaction occurs and only starting materials are recovered (See Supplementary Materials, Table S1). Facing this lack of reactivity, we decided to use stronger electrophilic compounds to exploit the natural reactivity of 2-AT. α-trifluorinated ketones have been chosen, as suggested in the literature [START_REF] Khodakovskiy | Noncatalytic electrophilic oxyalkylation of some five-membered heterocycles with 2-(trifluoroacetyl)-1,3-azoles[END_REF]. In that case, when 8 is in the presence of α-trifluorinated ketone 11e in toluene under reflux, substitution product 12e is obtained in good yields. It suggests that α-trifluomethyl ketone are harder electrophiles than methyl ketones, following the hard and soft acids and bases theory [START_REF] Nenajdenko | Preparation of α,β-unsaturated ketones bearing a trifluoromethyl group and their application in organic synthesis[END_REF][START_REF] Ho | The hard soft acids bases (HSAB) principle and organic chemistry[END_REF]. Temperature has been investigated. Best yield of 83% has been obtained when temperature was set to 120 • C. At 100 • C, the reaction was incomplete and decomposition products have been observed at 140 • C (Table 1, entries 1-3). When an excess of α-trifluorinated ketone 11e (1.5 and 2.0 equiv.) was reacted with 8, yields stayed similar (Table 1, entries 4-5).

Table 1. Optimization studies for the synthesis of 12e.

entries 1-3). When an excess of α-trifluorinated ketone 11e (1.5 and 2.0 equi reacted with 8, yields stayed similar (Table 1, entries 4-5).

The reaction occurs under metal and catalyst free conditions, in toluene unde for 2 to 5 h. As predicted, the reaction is site selective. This reactivity may be dire the +M effect of the amino group, which confers an enhanced nucleophilic react the C3 atom and allows reaction with α-trifluoromethyl ketones as electrophiles acidic catalytic conditions are used (AlCl3 or Sc(OTf)3) no product is observed, s that the donor effect of the amino group is sufficient to observe the formation desired derivative (See Supplementary Materialsfor more details, Table S2). Additionally, when the amino group is replaced by the electron withdrawin group on 7, no substitution product is formed in presence of ketone 11e. Whethe presence or absence of acidic catalysis (AlCl3 and Sc(OTf)3 10 mol%, see Supplem Materials for More Details, Table S3), only the starting material has been re showing that the amine function is important. The presence of +M effect of the function is crucial in the reactivity (Scheme 4). To investigate the scope of the proposed methodology, various α-trifluoro ketones 11a-o were allowed to react with 5-phenylthiophen-2-amine 8 in stoechi amounts in toluene under reflux for 2 to 4.5 h (Scheme 5). The aliphatic nature of th grafted on ketone did not prevent the reactivity and substitution molecules are fo The reaction occurs under metal and catalyst free conditions, in toluene under reflux for 2 to 5 h. As predicted, the reaction is site selective. This reactivity may be directed by the +M effect of the amino group, which confers an enhanced nucleophilic reactivity of the C 3 atom and allows reaction with α-trifluoromethyl ketones as electrophiles. When acidic catalytic conditions are used (AlCl 3 or Sc(OTf) 3 ) no product is observed, showing that the donor effect of the amino group is sufficient to observe the formation of the desired derivative (See Supplementary Materialsfor more details, Table S2).

Additionally, when the amino group is replaced by the electron withdrawing nitro group on 7, no substitution product is formed in presence of ketone 11e. Whether in the presence or absence of acidic catalysis (AlCl 3 and Sc(OTf) [START_REF] Scheich | Novel small molecule inhibitors of MDR mycobacterium tuberculosis by NMR fragment screening of antigen 85C[END_REF] 10 mol%, see Supplementary Materials for More Details, Table S3), only the starting material has been recovered showing that the amine function is important. The presence of +M effect of the amino function is crucial in the reactivity (Scheme 4).

for 2 to 5 h. As predicted, the reaction is site selective. This reactivity the +M effect of the amino group, which confers an enhanced nucle the C3 atom and allows reaction with α-trifluoromethyl ketones as acidic catalytic conditions are used (AlCl3 or Sc(OTf)3) no product is that the donor effect of the amino group is sufficient to observe th desired derivative (See Supplementary Materialsfor more details, Tab Additionally, when the amino group is replaced by the electron group on 7, no substitution product is formed in presence of ketone presence or absence of acidic catalysis (AlCl3 and Sc(OTf)3 10 mol%, Materials for More Details, Table S3), only the starting material h showing that the amine function is important. The presence of +M function is crucial in the reactivity (Scheme 4). To investigate the scope of the proposed methodology, variou ketones 11a-o were allowed to react with 5-phenylthiophen-2-amine amounts in toluene under reflux for 2 to 4.5 h (Scheme 5). The aliphatic grafted on ketone did not prevent the reactivity and substitution mole To investigate the scope of the proposed methodology, various α-trifluoromethyl ketones 11a-o were allowed to react with 5-phenylthiophen-2-amine 8 in stoechiometric amounts in toluene under reflux for 2 to 4.5 h (Scheme 5). The aliphatic nature of the group grafted on ketone did not prevent the reactivity and substitution molecules are formed in good yields (12a: 87%, 12b: 81%). Aryls and heteroaryls groups were also investigated and good to excellent yields were obtained with 6-membered rings (12e-j: 75-93%), giving slightly better yields than 5-membered rings (12c: 76%, 12d: 69%). Steric hindrance did not seem to be a determining factor because aromatic bicycles reacted smoothly to afford desired compounds in very good yields too (12k: 80%, 12l: 72%). In most cases, the hydroxyalkylation was observed in good to excellent yields after purification with flash chromatography (69-93%). Reaction did not occur in the presence of ketones 11m, 11n and 11o. Anyway, this reaction seems to be substrate-dependent, in light of the absence of reactivity for α-trifluoromethyl ketones 11m-o. The presence of pyrrole and indole, known to be two rich electron heterocycles, may be responsible for the deactivation of the hard nucleophilic center that is the trifluoromethyl ketones 11n and 11o [START_REF] Davies | Intermolecular reactions of electron-rich heterocycles with copper and rhodium carbenoids[END_REF]. Considering the perfluoro-2-hexanone 11m, no example of such reactivity has been reported in the literature for the last 20 years (see Supplementary Materials for More Details, Table S4).

good yields (12a: 87%, 12b: 81%). Aryls and heteroaryls groups were also investigated and good to excellent yields were obtained with 6-membered rings (12e-j: 75-93%), giving slightly better yields than 5-membered rings (12c: 76%, 12d: 69%). Steric hindrance did not seem to be a determining factor because aromatic bicycles reacted smoothly to afford desired compounds in very good yields too (12k: 80%, 12l: 72%). In most cases, the hydroxyalkylation was observed in good to excellent yields after purification with flash chromatography (69-93%). Reaction did not occur in the presence of ketones 11m, 11n and 11o. Anyway, this reaction seems to be substrate-dependent, in light of the absence of reactivity for α-trifluoromethyl ketones 11m-o. The presence of pyrrole and indole, known to be two rich electron heterocycles, may be responsible for the deactivation of the hard nucleophilic center that is the trifluoromethyl ketones 11n and 11o [START_REF] Davies | Intermolecular reactions of electron-rich heterocycles with copper and rhodium carbenoids[END_REF]. Considering the perfluoro-2-hexanone 11m, no example of such reactivity has been reported in the literature for the last 20 years (see Supplementary Materials for More Details, Table S4). An X-ray crystal structure was carried out to establish the authe structure. We can observe that the structure has a planar part composed of th Scheme 6. Mechanistic proposal for the coupling reaction with 5-phenyl-2-aminothiophene 8 and α-trifluoromethyl ketone.

An X-ray crystal structure was carried out to establish the authenticity of 12j structure. We can observe that the structure has a planar part composed of the phenyl and thiophenyl moiety. Then, alkylation observed and assessed on C 2 atom is composed of a pyridyl group almost perpendicular to both other aromatic cycles. A very strong intramolecular H-bond is observed between the new hydroxyl generated group and the amine group of the thiophenyl moiety [N 1 -H 1c • • • O 1 2.187 Å and 129 • ] (Figure 2a,b). This bond, stabilizing the whole structure, could drive the reaction. Another one is observed between nitrogen atom of pyridyl group and hydroxyl function [O 1 -H 1c S3 andS4, Tables S5-S9). The expansion of the packing diagram also showed the alternance of R and S enantiomers in the crystal mesh. (Figure 2b). Since no catalysts or chiral auxiliaries were used, we did not expect the reaction to be enantioselective. An X-ray crystal structure was carried out to establish the authenticity of 12j structure. We can observe that the structure has a planar part composed of the phenyl and thiophenyl moiety. Then, alkylation observed and assessed on C2 atom is composed of a pyridyl group almost perpendicular to both other aromatic cycles. A very strong intramolecular H-bond is observed between the new hydroxyl generated group and the amine group of the thiophenyl moiety [N1-H1c ⋯ O1 2.187 Å and 129°] (Figure 2a,b). This bond, stabilizing the whole structure, could drive the reaction. Another one is observed between nitrogen atom of pyridyl group and hydroxyl function [O1-H1c ⋯ N2 2.237 Å and 137°]. (See Supplementary Materials, Figures S3 andS4, Tables S5-S9). The expansion of the packing diagram also showed the alternance of R and S enantiomers in the crystal mesh. (Figure 2b). Since no catalysts or chiral auxiliaries were used, we did not expect the reaction to be enantioselective.

Conclusions

In summary, we have developed an atom-economical approach to synthesize sitespecific substituted 5-phenylthiophen-2-amine from simple and commercially available starting materials, namely, α-trifluoromethyl ketones and 5-phenylthiophen-2-amine, by exploiting a trifluoromethyl hydroxyalkylation reaction. The chosen scope shows the variety we can introduce on 5-phenylthiophen-2-amine scaffold. The reaction showed good to excellent yields after purification (69-93%) and with a total chemoselectivity given that only carbon-carbon bond is formed. The site selective introduction of trifluoromethyl hydroxyalkyl groups contrasts with traditionally inserted substituents with -M effect on thiophene scaffold. Moreover, the chemo-and regioselectivity described allows flexibility in substitutions possibilities in drug discovery.

Materials and Methods

General Experimental Methods

All reagents were purchased from commercial suppliers (Acros Geel-Belgium, Sigma Aldrich L'lsle-d'Abeau Chesnes-France, Alfa Aesar Kandel-Germany and TCI Zwijndrecht-Belgium) and were used without further purification. NMR spectra were recorded with a Bruker Avance 300 spectrometer (300 MHz and 75 MHz for 1 H and 13 C NMR, respectively) and Bruker Avance 400 spectrometer (376.5 MHz for 19 F). Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively, using residual solvent signals as reference for the 1 H and 13 C. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, br s = broad signal, dd = doublet of doublets, dt = double of triplets, m = multiplet. High-resolution mass spectra (HRMS) were obtained by electrospray using a TOF analyzer Platform. IR spectra were obtained using a Jasco FT-IR 410 instrument as a thin film on NaCl disc as stated; only structurally important peaks (

Conclusions

In summary, we hav specific substituted 5-phe starting materials, namely exploiting a trifluoromet variety we can introduce good to excellent yields af that only carbon-carbon b hydroxyalkyl groups con thiophene scaffold. Moreo in substitutions possibilit

Materials and Method

General Experimental M

All reagents were p Sigma Aldrich L'lsle-d'A Zwijndrecht-Belgium) a recorded with a Bruker A NMR, respectively) and B shifts (δ) and coupling con solvent signals as referen singlet, d = doublet, t = tri = double of triplets, m = m by electrospray using a TO IR 410 instrument as a thi (ῡ) are presented in cm -1 . R aluminum silica gel plate Stuart scientific SMP10 performed on a Grace Rev were obtained on the W Hypersil C18 column (3 µ flow rate, photodiodearra of water and acetonitrile ( obtained on the Waters A BEH C18 column (1.7 µm photodiodearray detectio and acetonitrile (each con

Preparation of 5-Pheny

Starting from 2-brom (3.6 mmol; 440 mg) and P mL, 2.3:1, v/v) was added reaction mixture was reflu (50 mL) and filtered throu The aqueous solution wa were combined, dried ove give the crude compoun (silica gel, AcOEt/Petrole compound. 2-nitro-5-phe ) are presented in cm -1 . Reactions were monitored with Merck Kieselgel 60F 254 precoated aluminum silica gel plates (0.25 mm thickness). Melting points were determined on a Stuart scientific SMP10 apparatus and are uncorrected. Flash chromatography was performed on a Grace Reveleris X2 using a 40 µm packed silica cartridge. HPLC analyses were obtained on the Waters Alliance 2795 using the following conditions: Thermo Hypersil C18 column (3 µm, 50 mm × 2.1 mm), 20 • C column temperature, 0.2 mL/min flow rate, photodiodearray detection (210-400 nm), mobile phase consistent of a gradient of water and acetonitrile (each containing 0.1% trifluoroacetic acid). UPLC analyses were obtained on the Waters Acquity H-Class using the following conditions: Waters Acquity BEH C18 column (1.7 µm, 50 × 2.1 mm), 25 • C column temperature, 0.5 mL/min flow rate, photodiodearray detection (TUV-214 nm), mobile phase consistent of a gradient of water and acetonitrile (each containing 0.1% of formic acid).

Preparation of 5-Phenylthiophen-2-amine (8)

Starting from 2-bromo-5-nitrothiophene 5 (2.4 mmol; 500 mg), phenylboronic acid 6 (3.6 mmol; 440 mg) and Pd(PPh 3 ) 4 (0.12 mmol; 140 mg) in a mixture of toluene/ethanol (16 mL, 2.3:1, v/v) was added a [2 M] of aqueous solution of Na 2 CO 3 (4.8 mmol; 4.5 mL). The reaction mixture was refluxed over 15 h. The cold solution was diluted with ethyl acetate (50 mL) and filtered through a Celite pad, and the filtrate was diluted with water (60 mL). The aqueous solution was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude compound. The residue was purified by flash column chromatography (silica gel, AcOEt/Petroleum ether (PE), 0/100 ramping to 100/0, v/v) to give the desired compound. 2-nitro-5-phenylthiophene (7): Yield: 86% (756 mg); yellow powder: mp 124-126 • C (lit. [32] 123-124 • C); R f : 0.51 (PE/AcOEt: 8/2). ν max /cm -1 1512 (N-O). 1 H NMR (300 MHz, DMSO-d6) δ 7.47-7.55 (m, 3H, 3H Ar ), 7.66-7.55 (m, 1H, H Ar ), 7.80-7.87 (m, 2H, 2H Ar ), 8.17 (d, 1H, J = 4.5 Hz, H Ar ). 13 The synthesis of 5-phenylthiophen-2-amine (8) was prepared according to a procedure described by Zhang et al. or with minor modifications thereof [START_REF] Nguyen | Synthesis and pharmacological evaluation of 1-phenyl-3-thiophenylurea derivatives as cannabinoid type-1 receptor allosteric modulators[END_REF]. To a solution of 2-nitro-5-phenylthiophene [START_REF] Tang | 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors[END_REF] (1.71 mmol; 300 mg) and Pd/C (0.28 mmol; 30 mg) in absolute ethanol (5 mL, C = 0.1 M) was added hydrazine hydrate (15 eq). The reaction was stirred at 50 • C for 20 min and an excess of Raney nickel slurry in water (1.2 eq) was slowly added. The reaction was monitored by TLC (PE/AcOEt 70/30). After 1.5 h, when the bubbling ceased, the mixture was cooled to room temperature and filtered through celite. The filtrate was condensed under reduced pressured and the crude was purified on flash silica gel chromatography (PE/AcOEt 100/0 ramping 0/100 v/v) to afford the desired product. 5-phenylthiophen-2-amine (8): Yield: 90% (232 mg); white powder: mp 127-129 • C. R f : 0.64 (PE/EtOAc: 70/30). ν max /cm -1 3110 (NH). 1 In a round bottom flask, 5-phenylthiophen-2-amine (8) (1eq, 0.57 mmol; 100 mg), and the corresponding trifluorinated compound (12a-o) (1eq, 0.57 mmol) are added in 2mL of dry toluene under reflux and inert atmosphere until complete substrate consumption followed by TLC (PE/AcOEt 7/3) and HPLC (H 2 O/ACN). The cold solution is then diluted with AcOEt (50 mL) and water (50 mL). The aqueous layer is extracted with ethyl acetate (3 × 50 mL) and the combined organic layers are washed with water (50 mL), brine (50 mL), dried over MgSO 4 and concentrated under reduced pressure to give the crude compound (brown oil). The residue is further purified by flash column chromatography (silica gel, AcOEt/PE, 0/100 ramping to 100/0, v/v) to give the desired compound as a brown powder or brown crystals.

2-(2-amino-5-phenylthiophen-3-yl)-1,1,1-trifluoropropan-2-ol (12a): Yield: 87% (142 mg); brown powder: mp 135-137 • C. R f : 0.44 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3615 (NH), 3362 (OH), 1609 (N-H) and 1144 (C-OH). 1 H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 3H, CH 3 ), 5.87 (br s, 2H, NH 2 ), 6.72 (s, 1H, H Ar ), 7.03 (s, 1H, OH), 7.12 (t, J = 7.3 Hz, 1H, H Ar ), 7.29 (t, J = 7.5 Hz, 2H, 2H Ar ), 7.40 (d, J = 8.1 Hz, 2H, 2H Ar ). 13 C NMR (75 MHz, DMSO-d6) δ 23.11 (CH 3 ), 73.87 (q, 2 J CF = 28. [START_REF] Narlawar | Hybrid ortho/allosteric ligands for the adenosine A1 receptor[END_REF]

Molecules 2022 ,Figure 1 .

 20221 Figure 1. Background and overview. (a) Bioactives 2-AT derivatives. (b) Method to access trifluoromethyl hydroxyalkylated indole. (c) Methods to access to hydroxyalkylated thiophenes. First hypothesis based on previous studies.

Figure 1 .

 1 Figure 1. Background and overview. (a) Bioactives 2-AT derivatives. (b) Method to access to trifluoromethyl hydroxyalkylated indole. (c) Methods to access to hydroxyalkylated thiophenes. (d) First hypothesis based on previous studies.

Scheme 2 .

 2 Scheme 2. Deuteriation of 8 on C3 atom in presence of deuterium oxide.

Scheme 2 .

 2 Scheme 2. Deuteriation of 8 on C3 atom in presence of deuterium oxide.

Scheme 2 .

 2 Scheme 2. Deuteriation of 8 on C 3 atom in presence of deuterium oxide.

Scheme 2 .

 2 Scheme 2. Deuteriation of 8 on C3 atom in presence of deuterium oxide.

Scheme 3 .

 3 Scheme 3. Proposed mechanism for the deuteriation of 9.

Scheme 4 .

 4 Scheme 4. Attempts of hydroxyalkylation of 7.

Scheme 4 .

 4 Scheme 4. Attempts of hydroxyalkylation of 7.

Scheme 4 .

 4 Scheme 4. Attempts of hydroxyalkylation of 7.

Scheme 5 .Scheme 5 .Scheme 6 .

 556 Scheme 5. Scope of substituted aminothiophenes. Reactions conditions: 5-phenylthiophen-2-amine 8 (1.0 equiv.), α-trifluoromethyl ketones 11a-o (1.0 equiv.), toluene (3.5 mL/mmol), under argon for 2-4.5 h, 120 °C. Yields obtained after purification on flash chromatography. Not isolated, only starting materials have been recovered. A mechanistic proposal is given in Scheme 6 for the conversion of 8 into 15 through a similar mechanism of an electrophilic aromatic substitution [39-41]. First step is the attack of C3 atom on electrophilic center of trifluoromethyl ketone to afford intermediate 14. Then, aromatization drives the formation of structure 15. Scheme 5. Scope of substituted aminothiophenes. Reactions conditions: 5-phenylthiophen-2-amine 8 (1.0 equiv.), α-trifluoromethyl ketones 11a-o (1.0 equiv.), toluene (3.5 mL/mmol), under argon for 2-4.5 h, 120 • C. Yields obtained after purification on flash chromatography. Not isolated, only starting materials have been recovered. A mechanistic proposal is given in Scheme 6 for the conversion of 8 into 15 through a similar mechanism of an electrophilic aromatic substitution [39-41]. First step is the attack of C 3 atom on electrophilic center of trifluoromethyl ketone to afford intermediate 14. Then, aromatization drives the formation of structure 15. olecules 2022, 27, x FOR PEER REVIEW

Scheme 6 .

 6 Scheme 6. Mechanistic proposal for the coupling reaction with 5-phenyl-2-aminothiophene 8 and α-trifluoromethyl ketone.

Figure 2 .

 2 Figure 2. (a) XP diagram of compound 12j with atomic numbering scheme; (b) Expansion of the packing diagram of compound 12j within the crystal mesh trough intra-and intermolecular hydrogen bonds.

4. 3 .

 3 Procedure for the Preparation of Trifluorohydroxyalkyl-5-Phenylthiophen-2-amine (12a-12l)

  0829. 1-(2-amino-5-phenylthiophen-3-yl)-2,2,2-trifluoro-1-(p-tolyl)ethan-1-ol (12f): Yield: 75% (155 mg); brown powder: mp 113-115 • C. R f : 0.56 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3628 (NH), 3336 (OH), 1610 (N-H) and 1157 (C-OH).1 H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H, CH 3 ), 5.48 (br s, 2H, NH 2 ), 6.95 (s, H, H Ar ), 7.10-7.21 (m, 3H, 3H Ar ), 7.29-7.42 (m, 7H, 6H Ar , OH). 13 C NMR (75 MHz, DMSO-d6) δ 20.65 (CH 3 ), 76.78 (q, 2 J CF = 28.3 Hz, C-CF 3 ), 114.47 (C Ar ), 122.00 (C Ar ), 122.87 (C Ar ), 123.57 (2CH Ar ), 125.70 (CH Ar ), 126.96 (q, 1 J CF = 279.0 Hz, CF 3 ), 127.07 (2CH Ar ), 128.54 (2CH Ar ), 129.00 (2CH Ar ), 134.30 (C Ar ), 135.83 (C Ar ), 137.57 (C Ar ), 152.46 (C Ar ). 19 F NMR (376 MHz, DMSO-d6) δ -76.22 (CF 3 ). HPLC: t R : 34.05 min. HRMS: [M + H] + calcd for C 19 H 17 F 3 NOS: 346.0986; found: 364.0977. 1-(2-amino-5-phenylthiophen-3-yl)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-ol (12g): Yield: 79% (165 mg); brown powder: mp 115-116 • C. R f : 0.46 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3612 (NH), 3376 (OH), 1609 (N-H) and 1144 (C-OH). 1 H NMR (300 MHz, DMSO-d6) δ 5.52 (br s, 2H, NH 2 ), 6.95-7.00 (m, 1H, H Ar ), 7.11-7.18 (m, 1H, H Ar ), 7.21 (t, J = 8.9 Hz, 2H, 2H Ar ), 7.32 (t, J = 7.7 Hz, 2H, 2H Ar ), 7.37-7.42 (m, 2H, 2H Ar ), 7.44 (s, 1H, OH), 7.48-7.54 (m, 2, 2H Ar ).13 C NMR (75 MHz, DMSO-d6) δ 76.51 (q, 2 J CF = 28.[START_REF] Tang | 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors[END_REF] Hz, C-CF 3 ), 114.05 (CH Ar ), 114.78 (d, 2 J CF = 22.5 Hz, 2CH Ar ), 121.75 (CH Ar ), 123.07 (C Ar ), 123.63 (2CH Ar ), 125.77 (CH Ar ), 126.22 (q, 1 J CF = 286.5 Hz, CF 3 ), 129.00 (2CH Ar ), 129.45 (d, 3 J CF = 8.3 Hz, 2CH Ar ), 134.25 (C Ar ), 134.88 (C Ar ), 152.63 (C Ar ), 161.96 (d, 1 J CF = 243.0 Hz, C Ar -F). 19 F NMR (376 MHz, DMSO-d6) δ -75.15 (CF 3 ), -114.21 (C Ar -F). HPLC: t R : 30.28min. HRMS: [M + H] + calcd for C 18 H 14 F 4 NOS: 368.0727; found: 368.0725. 1-(2-amino-5-phenylthiophen-3-yl)-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-ol (12h): Yield: 81% (177 mg); brown powder: mp 120-122 • C. R f : 0.46 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3601 (NH), 3349 (OH), 1596 (N-H) and 1136 (C-OH).

Table 1 .

 1 Optimization studies for the synthesis of 12e.

	Entry	11e Equivalent (eq.)	T (°C)	Yield (%
	1 a	1	100	70%
	2 a	1	120	83%
	3 a	1	140	47%
	4 a	1.5	120	82%
	5 a	2	120	81%

a Experiment conducted in toluene. b Yields obtained after purification on flash chromatogr

Table 1 .

 1 Optimization studies for the synthesis of 12e.

	Entry	11e Equivalent (eq.)	T (°C)
	1 a	1	100
	2 a	1	120
	3 a	1	140
	4 a	1.5	120
	5 a	2	120

a Experiment conducted in toluene. b Yields obtained after purification on flas

  • • • N 2 2.237 Å and 137 • ]. (See Supplementary Materials, Figures

  C NMR (DMSO-d 6 , 75 MHz) δ 124.07 (CH Ar ), 126.29 (2CH Ar ), 129.54 (2CH Ar ), 130.35 (CH Ar ), 131.37 (CH Ar ), 131.48 (C Ar ), 149.32 (C Ar ), 151.52 (C-NO 2 ). UPLC: t R : 3.15 min; purity: 97%; HRMS: [M + H] + calculated for C 10 H 8 NO 2 S: 206.0276; found: 206.0276.

  H NMR (300 MHz, DMSO-d6) δ 5.77 (br s, 2H, NH 2 ), 5.86 (d, J = 3.8 Hz, 1H, H Ar ), 7.01 (d, J = 3.8 Hz, 1H, H Ar ), 7.05-7.12 (m, 1H, H Ar ), 7.24-7.31 (m, 1H, H Ar ), 7.35-7.41 (m, 1H, H Ar ). 1 H NMR (300 MHz, D 2 O) δ 7.30 (s, 1H, H Ar ), 7.38-7.50 (m, 3H, 3H Ar ), 7.64-7.69 (m, 2H, 2H Ar ). 13 C NMR (75 MHz, DMSO-d 6 ,) δ 104.72 (CH Ar ), 123.05 (CH Ar ), 123.39 (2CH Ar ), 125.01 (C Ar ), 125.08 (CH Ar ), 128.80 (2CH Ar ), 135.04 (C Ar ), 154.51 (C-NH 2 ). 13 C NMR (75 MHz, D 2 O) δ 122.06 (CH Ar ), 123.40 (t, J = 15.7 Hz, CD Ar ), 125.53 (2CH Ar ), 128.48 (CH Ar ), 129.07 (C Ar ), 129.22 (2CH Ar ), 132.67 (CH Ar ), 142.24 (C-NH 2 ). UPLC: t R : 3.15 min; purity: 97%; HRMS: [M + H] + calcd for C 10 H 10 NS: 176.0528; found: 176.0527.

  Hz, C-CF 3 ), 113.42 (C Ar ), 122.89 (C Ar ), 123.17 (CH Ar ), 123.48 (2CH Ar ), 125.49 (CH Ar ), 126.60 (q, 1 J CF = 285.[START_REF] Aly | Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents[END_REF] Hz, CF 3 ), 128.84 (2CH Ar ), 134.43 (C Ar ), 152.47 (C Ar ).19 F NMR (376 MHz, DMSO-d6) δ -80.50 (CF 3 ). HPLC: t R : 30.[START_REF] Horváth | Innovations and green chemistry[END_REF] min. HRMS: [M + H] + calcd for C 13 H 13 NOSF 3 : 288.0670; found: 288.0685. ; brown powder: mp 118-119 • C. R f : 0.37 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3615 (NH), 3375 (OH), 1596 (N-H) and 1145 (C-OH). 1 H NMR (300 MHz, DMSO-d6) δ 3.16 (d, J = 14.2 Hz, 1H, CH 2a ), 3.51 (d, J = 14.2 Hz, 1H, CH 2b ), 5.71 (br s, 2H, NH 2 ), 6.92 (s, 1H, H Ar ), 7.08-7.21 (m, 5H, 5H Ar ), 7.26-7.35 (m, 4H, 3H Ar , OH), 7.37-7.42 (m, 2H, 2H Ar ).The signal corresponding to CH 2 appears under the solvent signal on 13 C spectrum. Yet, the signal appears on DEPT-135 spectrum. 13 C NMR (75 MHz, DMSO-d6) δ 38.82 (CH 2 ), 78.04 (q, 2 J CF = 27.2 Hz, C-CF 3 ), 110.57 (C Ar ), 120.78 (C Ar ), 122.90 (C Ar, CH Ar ), 123.49 (2CH Ar ), 125.49 (2CH Ar ), 126.26 (CH Ar ), 126.43 (q, 1 J CF = 287.2 Hz, CF 3 ), 127.48 (2CH Ar ), 128.85 (2CH Ar ), 130.83 (2CH Ar ), 134.46 (C Ar ), 135.34 (C Ar ), 152.85 (C Ar ). 19 F NMR (376 MHz, DMSO-d6) δ -76.34 (CF 3 ). HPLC: t R : 32.13 min. HRMS: [M + H] + calcd for C 19 H 17 F 3 NS: 364.0977; found: 364.0982. 76% (147 mg); brown powder: mp 126-128 • C. R f : 0.46 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3615 (NH), 3362 (OH), 1596 (N-H) and 1159 (C-OH). 1 H NMR (300 MHz, DMSO-d6) δ 5.80 (br s, 2H, NH 2 ), 6.57-6.52 (m, 2H, H Ar ), 6.65 (s, 1H, H Ar ), 7.18-7.08 (m, 1H, H Ar ), 7.29 (d, J = 1.4 Hz, 2H, H Ar ), 7.30 (s, 2H, H Ar ), 7.61 (s, 1H, OH),[START_REF] Tang | 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors[END_REF].76 (dd, J = 1.7, 0.9, 1H, H Ar ).13 C NMR (75 MHz, DMSO-d6) δ 74.82 (q, 2 J CF = 30.4 Hz, C-CF 3 ), 109.21 (CH Ar ), 110.42 (CH Ar ), 110.54 (C Ar ), 122.60 (CH Ar ), 122.78 (C Ar ), 123.50 (2CH Ar ), 125.11 (q, 1 J CF = 286.1 Hz, CF 3 ), 125.73 (CH Ar ), 128.96 (2CH Ar ), 134.11 (C Ar ), 143.60 (CH Ar ), 150.91 (C Ar ), 153.01 (C Ar ). 19 F NMR (376 MHz, DMSO-d6) δ -74.25 (CF 3 ). HPLC: t R : 30.28 min. HRMS: [M + H] + calcd for C 16 H 12 F 3 NO 2 S: 339.0535; found: 339.0532. Ar ), 7.26-7.37 (m, 5H, 4H Ar , OH), 7.58 (d, J = 4.9 Hz, 1H, H Ar ). 13 C NMR (75 MHz, DMSO-d6) δ 76.19 (q, 2 J CF = 27.7 Hz, C-CF3), 113.09 (CH Ar ), 122.08 (CH Ar ), 122.89 (CH Ar ), 123.57 (2CH Ar ), 125.79 (CH Ar ), 126.05 (q, 1 J CF = 280.9 Hz, CF 3 ), 126.41 (CH Ar ), 126.75 (CH Ar ), 126.99 (CH Ar ), 128.99 (2CH Ar ), 134.13 (C Ar ), 143.25 (C Ar ), 152.88 (C Ar ). 19 F NMR (376 MHz, DMSO-d6) δ -76.06 (CF 3 ). HPLC: t R : 32.27 min. HRMS: [M + H] + calcd for C 16 H 13 F 3 NOS 2 : 356.0391 ; found: 356.0397. ; brown powder: mp 116-118 • C. R f : 0.60 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3376 (NH, OH), 1608 (N-H) and 1147 (C-OH). 1 H NMR (300 MHz, DMSO-d6) δ 5.50 (br s, 2H, NH 2 ), 6.95 (s, 1H, H Ar ), 7.15 (t, J = 7.1 Hz, 1H, H Ar ), 7.28-7.44 (m, 8H, 7H Ar , OH), 7.49 (d, J = 7.2 Hz, 2H, 2H Ar ). 13 C NMR (75 MHz, DMSO-d6) δ 76.90 (q, 2 J CF = 27.9 Hz, C-CF 3 ), 114.35 (C Ar ), 122.00 (CH Ar ), 123.00 (C Ar ), 123.63 (2CH Ar ), 125.67 (q, 1 J CF = 281.2 Hz, CF 3 ), 125.79 (CH Ar ), 127.16 (2CH Ar ), 128.02 (2CH Ar ), 128.35 (CH Ar ), 129.06 (2CH Ar ), 134.30 (C Ar ), 138.80 (C Ar ), 152.53 (C Ar ). 19 F NMR (376 MHz, DMSO-d6) δ -75.54 (CF 3 ). HPLC: t R : 32.93 min. HRMS: [M + H] + calcd for C 18 H 15 NOSF 3 , 350.0826; found 350.

	2-(2-amino-5-phenylthiophen-3-yl)-1,1,1-trifluoro-3-phenylpropan-2-ol (12b): Yield: Yield: 69% (140 mg); brown powder: mp 120-121 • C. R f : 0.46 (PE/AcOEt: 70/30 v/v). ν max /cm -1 3619 (NH), 3244 (OH), 1606 (N-H) and 1157 (C-OH). 1 H NMR (300 MHz, DMSO-d6) δ 5.52 (br s, 2H, NH 2 ), 6.83 (s, 1H, H Ar ), 7.04 (t, 1H, J = 4.2 Hz, H Ar ), 7.10-7.16 (m, 2H, H 1-(2-amino-5-phenylthiophen-3-yl)-2,2,2-trifluoro-1-phenylethan-1-ol (12e): Yield: 82% 81% (168 mg)1-(2-amino-5-phenylthiophen-3-yl)-2,2,2-trifluoro-1-(thiophen-2-yl)ethan-1-ol (12d): (163 mg)

1-(2-amino-5-phenylthiophen-3-yl)-2,2,2-trifluoro-1-(furan-2-yl)ethan-1-ol (12c): Yield:

  1 H NMR (300 MHz, DMSO-d6) δ 5.53 (br s, 2H, NH 2 ), 6.98 (s, 1H, H Ar ), 7.15 (t, J = 7.2 Hz, 1H, H Ar ), 7.32 (t, J = 7.7 Hz, 2H, 2H Ar ), 7.38-7.42 (m, 2H, 2H Ar ), 7.45-7.51 (m, 5H, 4H Ar , OH). 13 C NMR (75 MHz, DMSO-d6) δ 76.44 (d, 2 J CF = 28.8 Hz, C-CF 3 ), 113.80 (C Ar ), 121.67 (CH Ar ), 123.11 (C Ar ), 123.63 (2CH Ar ), 123.92 (q, 1 J CF = 272.3 Hz, CF 3 ), 125.79 (CH Ar ), 127.99 (2CH Ar ), 129.00 (2CH Ar ), 129.17 (2CH Ar ), 133.12 (C Ar ), 134.21 (C Ar ), 137.70 (C Ar ), 152.68 (C Ar ). 19 F NMR (376 MHz, DMSO-d6) δ -75.10 (CF 3 ). HPLC: t R : 30.28 min. HRMS: [M + H] + calcd for C 18 H 14 ClF 3 NOS: 384.0431; found: 384.0428

Supplementary Materials:The following are available online, FigureS1: 1 H spectra of 9 in D 2 O (singlet at 7.28 ppm; 300 MHz); FigureS2:13 C spectra of 9 in D 2 O (triplet at 123.40 ppm; 75 MHz); Figure S3: Crystal structure of compounds 12j; Figure S4: (A) XP diagram of compound 12j with atomic numbering scheme; (B) Expandation of the packing diagram of compound 12j within the crystal mesh trough intra and intermolecular hydrogen bonds; TableS1: Optimization attempts for the synthesis of 16-17; TableS2: Optimization studies for the synthesis of 12e; TableS3: Optimization

Acknowledgments:

We gratefully thank the French Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (MESRI). The authors also thank the University of Nîmes and the Occitanie Region for the financial support.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest:

The authors declare no conflict of interest.

Sample Availability: Samples of the compounds are available from the authors.