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

An original and effective approach for achieving trifluoromethyl hydroxyalkylation of 5-phenylthiophen-2-amine using α-trifluoromethyl ketones is described. In the last few years, reaction of Friedel-Crafts had been widely used to realize hydroxyalkylation on heterocycles such as indoles or thiophenes by means of Lewis acid as catalyst. Additionally, amine functions are rarely free when carbonyl reagents are used because of their tendency to form imines. This is the first time that a site-selective electrophilic aromatic substitution on C3 atom of an unprotected 5-phenylthiophen-2-amine moiety is reported. The liberty to allow reaction in neutral conditions between free amine is valuable in a synthesis pathway. The reaction proceeds smoothly using an atom-economical metal-and catalyst-free methodology in good to excellent yields. A mechanism similar to an electrophilic aromatic substitution has been proposed.

Over recent decades, interest for hydroxyalkylation on aryl derivatives as C-C bond forming reaction has grown [16][17][18][19]. Ullyot first reported hydroxyalkylation of aryl compounds with a carbonyl derivative under acidic conditions as new way to synthesize benzoins [20]. 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 [21], Ramanathan [22] and Chatti [23] 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 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 [24][25][26][27]. Chemists are currently faced with the difficult task of increasing the efficacy this kind of reactions while also seeking greener processes [28]. 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 [33]. (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 [33]. (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.  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 [34]. 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 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 and S2).
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  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 [34]. 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 [34]. 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 [33]. (90% yie purification).  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 [34]. 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 3. Proposed mechanism for the deuteriation of 9.
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 [35]. 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 [36,37]. 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) 3 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).

Scheme 4. Attempts of hydroxyalkylation of 7.
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 [38]. 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 [38]. 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). 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][40][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. 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][40][41]. First step is the attack of C 3 atom on electrophilic center of trifluoromethyl ketone to afford intermediate 14. 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  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 · · · N 2 2.237 Å and 137 • ]. (See Supplementary Materials, Figures S3 and S4, 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. 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 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 and S4, 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.

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

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