Exploiting the Chiral Ligands of Bis(imidazolinyl)- and Bis(oxazolinyl)thiophenes—Synthesis and Application in Cu-Catalyzed Friedel–Crafts Asymmetric Alkylation

Five new C2-symmetric chiral ligands of 2,5-bis(imidazolinyl)thiophene (L1–L3) and 2,5-bis(oxazolinyl)thiophene (L4 and L5) were synthesized from thiophene-2,5-dicarboxylic acid (1) with enantiopure amino alcohols (4a–c) in excellent optical purity and chemical yield. The utility of these new chiral ligands for Friedel–Crafts asymmetric alkylation was explored. Subsequently, the optimized tridentate ligand L5 and Cu(OTf)2 catalyst (15 mol%) in toluene for 48 h promoted Friedel–Crafts asymmetric alkylation in moderate to good yields (up to 76%) and with good enantioselectivity (up to 81% ee). The bis(oxazolinyl)thiophene ligands were more potent than bis(imidazolinyl)thiophene analogues for the asymmetric induction of the Friedel–Crafts asymmetric alkylation.

In recent years, the application of nitroolefins as electrophiles has also been gaining notable interest among pharmacists due to the activation functionality of the nitro groups, which facilitate easy conversion to other useful functional groups to achieve numerous eyecatching chemical entities [48,49]. Furthermore, optically active Friedel-Crafts-alkylated product of indole with nitroolefins can also serve as an antecedent for the preparation of various drug molecules such as physostigmine [50,51], which acts as a clinically active anticholinergic drug [52], Recently, some examples of nitroalkenes have also been reported as Michael acceptors in metal-catalyzed asymmetric reaction due to the presence of strong electron-withdrawing nitro-groups [48,53,54] e.g., rhodium-catalyzed additions of boronic acids to nitroalkenes [55], copper-catalyzed dialkylzinc additions to nitroalkenes [56,57], conjugated reductions of nitroalkenes [58] and the organo-catalyzed additions of 1,3dicarbonyl compounds to nitroalkenes [59,60].
Moreover, to date, most of the research work has been done with the main family of chiral ligands predominantly belonging to di-phosphine, diamine, di-ol, etc., i.e., phosphorous-, nitrogen-and oxygen-containing substrate. Very little research has been done in the recent past on developing chiral ligands based on sulfur-containing compounds. Therefore, researchers are highly interested in developing new chiral ligands based on a sulfur-containing moiety due to their high coordination ability to the most of the transition metals [61]. The sulfur atom is also considered as a soft atom that can bind strongly to soft metals, in particular copper metal Cu(II). In addition, sulfur-containing ligands are poor π-acceptors and poor σ-donors as compared to phosphine ligands, resulting in strong metal-sulfur bond strength. However, sulfur-containing ligand precursors are easily available, having extra advantages such as easy storage due to their higher tolerance to air as compared to phosphine-containing ligands, which makes them highly stable [61].
Recently, chiral ligand-Lewis acid-catalyzed asymmetric induction of indole with prochiral β-nitroolefin has become one of the most significant and successful pathways for accessing highly functionalized optically pure building blocks. Our research group has reported a new catalytic system based on the Cu(II) metal/chiral thiophene-2,5-bis(βamino alcohol) ligands for an asymmetric Henry reaction of nitromethane with aromatic aldehyde with excellent ee (up to 94.6%) and chemical yield (up to 99%) [62]. In continuation of our research program, therefore, the design and synthesis of novel chiral 2,5-bis(imidazolinyl)thiophene and 2,5-bis(oxazolinyl)thiophene box-type ligands and their applications in various asymmetric catalyses remains a remarkable and interesting research topic to organic chemists. However, chiral ligands based on 2,5-bis(imidazolinyl)thiophene and 2,5-bis(oxazolinyl)thiophene framework could also be advantageous for several asymmetric transformations other than Friedel-Crafts alkylation reactions, such as asymmetric Henry reactions [63,64], Diels-Alder reactions [65,66], enantioselective additions of diethylzinc to acyclic enones [67][68][69], asymmetric allylic substitutions [70,71] and asymmetric cyclopropanation [72,73] reactions, etc. Keeping in mind the wide range of chiral applications of 2,5-bis(imidazolinyl)thiophene and 2,5-bis(oxazolinyl)thiophene box-type ligands and the diverse functionality of nitroolefins, we have decided to focus on this particular research field.
Under inert condition, ligands (L4 and L5), were prepared from thiophene-2,5-dicarb oxamide alcohol (4b and 4c) by ring closure reaction upon being treated with tosylchoride (1.25 eq.) and triethylamine (4.0 eq.) in the presence of a catalytic amount of DMAP (cat. 0.1eq.) in dichloromethane (CH 2 Cl 2 ) after 48 h of stirring at room temperature. The ligands were then purified by column chromatography, using 95% CH 2 Cl 2 /CH 3 OH as an eluent to afford pure ligands L4 and L5 (Scheme 1) with 60% and 55% isolated yield, respectively. The formations of the compound thiophene-2,5-dicarboxamide alcohol (3a) and all the ligands (L1-L5) were confirmed and characterized by NMR and mass spectroscopy analysis. Scheme 1. 2,5-bis(imidazolinyl)thiophene (L1-L3) and 2,5-bis(oxazolinyl) thiophene (L4 and L5). Reaction conditions: (I) SOCl 2 (8 mL/g), cat. DMF, 24 h, reflux; (II) i. CH 2 Cl 2 , TEA (5 eq.), −10 • C; ii. Amino alcohol (3a-c) (2.1 eq.); (III) 4a, SOCl 2 (8.8 mL/g), refluxed, 24 h; (IV) i. 5a, Et 2 O, TEA (12.0 eq.), 0 • C; ii. 2.5 eq. R 1 NH 2 (6a-c), 0 • C, then r.t., 12 h; (V) NaOH (15% aq. soln., 15 mL/g), r.t, 24 h; (VI) 4b-4c, Tosylchloride (1.25 eq.), DMAP (cat. 0.1 eq.), TEA (4.0 eq.), CH 2 Cl 2 , r.t, 48 h, N 2 .  As soon as we had in our hand optically pure ligands L1-L5, we decided to carry out the catalytic activity in an asymmetric Friedel-Crafts alkylation reaction between indoles 8a-d and nitrostyrene derivatives 9a-h. Indole (8a) and p-fluoronitrostyrene (9a) have been chosen as a model substrate for the reaction parameters optimization. In order to identify the best ligands for the asymmetric catalysis, initially, the Friedel-Crafts alkylation reaction of indole (8a) and p-fluoronitrostyrene (9a) was performed with the screened chiral bis(imidazoline) and bis(oxazoline) ligands L1-L5 (15 mol%) and Cu(OTf) 2 (15 mol%) as metal sources in toluene at room temperature for 48 h, and the subsequent findings are documented in Table 1. It is evident from the results summarized in Table 1, entries 1-5, that the thiophene-2,5-bis(oxazoline) ligand L5 performed very well under the above-mentioned reaction conditions and afforded Friedel-Crafts alkylation adduct 10a at 66% chemical yield with 75% enantiomeric excess (ee) (  [1][2][3]. In order to improve the chemical yield, the reaction was repeated with ligand L5, and reaction time was extended up to 72 h, but no significant changes were observed (Table 1; entry 6). Aiming to improve the chemical yield as well as enantioselectivity output of the reaction, a set of trials was conducted by variation of the loading of catalyst L5:Cu(OTf) 2 at 5, 10 and 20 mol%. The results showed that regardless of the % catalyst loading, the chemical yield was lower (20%, 46% and 65%, respectively) and did not result in any significant changes for the enantioselectivity (65%, 71% and 74% ee) ( Table 1, entries 7-9). The influences of the solvent effects were also studied; Friedel-Crafts alkylation reactions of indole (8a) and p-fluoronitrostyrene (9a) were also performed using a ligand-metal ratio of 15 mol% of L5:Cu(OTf) 2 at room temperature in several solvents, such as tetrahydrofuran, methanol, acetonitrile, dichloromethane, n-hexane and ethylacetate, within various time frames (84- 2 ] in toluene at room temperature in 48 h was the optimum set of reaction conditions to afford the final C-C bond formation adduct. Interestingly, it is clear from the preliminary results that oxazolinyl-based ligands are more potent than imidazolinyl-based ones; more interestingly, the substitution at the oxazolinyl moiety showed to also be critical for the asymmetric induction. Further investigation for better understanding is highly recommended. Interestingly, it is clear from the preliminary results that oxazolinyl-based ligands are more potent than imidazolinyl-based ones; more interestingly, the substitution at the oxazolinyl moiety showed to also be critical for the asymmetric induction. Further investigation for better understanding is highly recommended. Next, another two factors were also investigated, namely metal salts and temperature effects. Therefore, a Friedel-Crafts alkylation of indole (8a) with p-fluoronitrostyrene (9a) was carried out using 15 mol% of ligand L5 with the combination of several metal triflates, such as Zn(OTf)2, Mg(OTf)2, Er(OTf)2 and Yb(OTf)2, and metal chlorides such as FeCl3 and Next, another two factors were also investigated, namely metal salts and temperature effects. Therefore, a Friedel-Crafts alkylation of indole (8a) with p-fluoronitrostyrene (9a) was carried out using 15 mol% of ligand L5 with the combination of several metal triflates, such as Zn(OTf) 2 , Mg(OTf) 2, Er(OTf) 2 and Yb(OTf) 2 , and metal chlorides such as FeCl 3 and PdCl 2 , in toluene at 25 • C, and the results are summarized in Table 2. It was observed from the metal screening that Zn(OTf) 2 , FeCl 3 and PdCl 2 yielded product 10a with excellent to good chemical yields (97%, 80% and 70%, respectively), while the enantioselectivity remains negligible (Table 2, entries 1, 5 and 6). Two attempts were carried out at low (0 • C) and high (70 • C) temperature for 92 h and 24 h, respectively, and henceforth, 42% and 70% chemical yields with 76% and 65% enantioselectivity were observed (Table 2, entries 7 and 8). The results showed no significant changes for either the chemical yield or the enantioselectivity ( Table 2, entry 8). From the overall findings, a catalyst generated in situ from ligand L5 and Lewis acid Cu(OTf) 2 in toluene was found to be the optimum reaction condition for the asymmetric Friedel-Crafts alkylation of indole (8a) and p-fluoronitrostyrene (9a).
Interestingly, when the asymmetric Friedel-Crafts alkylation of indole 8a with nitrostyrene 9a was performed at a large scale (10-fold), both the yield (76%) and enantioselectivity (77% ee) were improved (Table 3, entry 1).  [82] [a] All the reactions were conducted on a 0.2 mmol scale; [b] isolated yields after column purification; [c] the ee values were determined by chiral HPLC using a Daicel OD-H column (25 cm × 4.6 mm × 5 µm) [74]; [d] the absolute configuration was determined as (S) or (R) comparing their retention time and sign of optical rotation reported in the literature; [e] the absolute configuration was assigned as (S) or (R) assuming uniform reaction mechanism and comparing with retention time and sign of optical rotation; [LS] large-scale reaction yield and enantiomeric excess (ee).
Finally, to examine another nitrostyrene system for the Friedel-Crafts arylation, two nitrostyrene (9i and 9j)-based indole scaffold were synthesized and characterized. The synthesized indole-based nitrostyrenes 9i and 9j were used as substrates for the asymmetric Friedel-Crafts arylation using our optimized method, but they unfortunately did not succeed in affording the final desired chiral FC products 10u and 10v, as shown in Scheme 2. The requisite final compounds either did not occur or decomposed.
In Figure 3, the proposed cycle of the catalytic mechanism has been shown, where in the intermediates (II) and (III), it has been clearly shown that the addition of an incoming nucleophilic group from the Si face is more favorable than the Re face since the latter is a more sterically hindered face as compared to former.  In case of Friedel-Craft product with indole, the retention time of the S enantiomer was found to be lesser than the R enantiomer in the chiral HPLC analysis using Daicel OD-H chiral column and n-hexane/iso-propanol system in the reported literature, while for FC products with 5-bromoindole it was found to be vice versa. Therefore, the absolute configuration of the synthesized chiral FC products 10a-d, 10g, 10i-l, 10o, 10q, 10s and 10t was assigned as S, while 10e, 10f, 10h, 10m, 10n, 10p and 10r were assigned as R by comparing their retention time and optical rotation values found in reported literature, assuming that the reaction took place via uniform mechanistic pathway (Table 3) [41,74].

General
Reagents obtained from commercial suppliers were used without further purification. Preparation of bis(imidazoline) and bis(oxazoline) ligands was performed in dried glassware flasks under a static pressure of nitrogen. Solvents were dried prior to use following standard procedures. Reactions were monitored by thin layer chromatography using Merck silica gel 60 Kieselgel F254 TLC (Merck, Kenilworth, NJ, USA), and column chromatography was performed on silica gel 100-200 (40-63 µm, ASTM) from Merck using the indicated solvents. 1 H and 13 C-NMR spectra were recorded in CDCl 3 and DMSO-d 6 on a Jeol Spectrometer (Jeol, Tokyo, Japan) (400 MHz and 500 MHz). The chemical shifts are reported in ppm. All the racemic products were freshly prepared as per the method reported in the literature [83]. Infrared spectra were recorded on a Thermo Scientific Nicolet iS10 FT-IR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA). Enantiomeric ratios were determined by analytical chiral HPLC analysis on a Shimadzu LC-20A (Shimadzu, Kyoto, Japan) Prominence instrument with a chiral stationary phase using Daicel OD-H columns (Chiral Technologies Europe, Illkirch-Graffenstaden, France) and 70-75% n-hexane/iso-propanol as eluents (Supplementary Materials). Optical rotations were obtained with a PerkinElmer 343 Polarimeter (PerkinElmer, Waltham, MA, USA). Melting points (m.p.) were recorded on a Thomas-Hoover capillary melting point apparatus (Thomas-Hoover, Texas City, USA) and were not corrected. Mass spectrometric analysis was done using ESI mode on an Agilent Technologies 6410-triple quad LC/MS instrument (Agilent, Santa Clara, CA, USA). Elemental analyses were performed on Perkin-Elmer PE 2400 CHN Elemental Analyzer with autosampler, CHN mode. X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer and processed with CrysAlisPro software v. 1.171.41.93a (Rigaku Oxford Diffraction, Yarnton, UK, 2020) using Cu K_ radiation".

GP1:
A 100-mL round bottom flask was charged with thiophene-2,5-dicarboxlyic acid (1) (0.5 mg, 2.9 mmol) and SOCl 2 (7 mL). A catalytic amount of DMF (3 drops) was added, and the reaction was reflux for 24 h under inert atmosphere. The reaction was then cooled, and excess SOCl 2 was removed under reduced pressure to give the corresponding crude acid chloride (2). The crude acid chloride 2 (2.9 mmol) solution in CH 2 Cl 2 (10 mL) was then slowly added to a pre-stirred solution of amino alcohol 3a-c (6.9 mmol, 2.1 eq.) and triethylamine (2 mL, 5 eq.) in CH 2 Cl 2 (35 mL) at −10 • C. The reaction was then stirred at ambient temperature for 24 h. After reaction completion, the solvents were removed and the residue was poured into water (55 mL). Upon standing at room temperature for 4 h, solid product was precipitated out, which was then collected by filtration and purified by column chromatography using 100-200 mesh silica gel and CH 2 Cl 2 /MeOH (95:5) as an eluent to afford pure products 4a-c. GP2: Thiophene-2,5-dicarboxamide alcohol (4a) (1.0 g, 2.92 mmol) in SOC1 2 (8.76 mL) was refluxed for 24 h. After removal of SOCl 2 , ice-water was added to the residue and the product was extracted with CH 2 Cl 2 (3 × 25 mL). The combined extracts were washed with brine and dried over anhydrous Na 2 SO 4 . The organics were evaporated to give the crude thiophene-2,5-dicarboxamid dichloride (5a). The crude dichloride (5a) was then dissolved in dry diethyl ether (20 mL) and the insoluble impurities were filtered out. To this solution, dry triethylamine (4.9 mL, 35.0 mmol, 12.0 eq.) was added, followed by arylamine (6a-c) (2.5 eq.). After stirring for 12 h at room temperature, 15% NaOH (15 mL) was added and stirred for another 24 h. The aqueous portion was extracted with dichloromethane (3 × 20 mL) and then washed with brine. The combined organics were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude thiophene-2,5bis(imidazolinyl)thiophene ligands (L1-L3). The pure ligands (L1-L3) were isolated by column chromatography, using the combination of ethylacetate/petroleumether/Et 3 N (v:v:v = 75:24:1) as an eluent.

Synthesis of the β-nitrostyrene (9a-j)
All the β-nitrostyrenes (9a-j) were synthesized by using well-known methods reported in the literature [84]. An oven-dried round bottom flask (100 mL) was charged with aldehydes (10.0 mmol), nitromethane (3.70 g, 60.0 mmol), piperidine (85 mg, 1.0 mmol) and toluene as solvent (10 mL). Anhydrous FeCl 3 (16.2 mg, 1.0 mmol) was then added to it. The reaction mixture was reflux gently for 4 h under dry condition, using guard tube. The completion of the reaction was confirmed by TLC, and the reaction mixture was cooled to room temperature. The excess solvent was removed under reduced pressure, and the residue was purified by silica gel (100-200 mesh) column chromatography to afford pure β-nitrostyrenes 9a-j as yellow solid product (yield 75-90%).

Conclusions
In summary, we have synthesized new C 2 -symmetric 2,5-bis(oxazolinyl)thiophene and 2,5-bis(imidazolinyl)thiophene ligands based on thiophene systems and successfully tested them in asymmetric Friedel-Crafts alkylation reactions of indole with trans β-nitroolefins. Our newly developed catalytic system (15 mol% of L5:Cu(OTf) 2 in toluene at 25 • C) was found to be applicable in inducing chirality into nitroalkylated indoles with low to good yields (35-76%) and low to good enantioselectivity (21-81%) at room temperature. On the basis of the screening performed, this methodology could be an alternative tool for asymmetric Friedel-Crafts reactions using this catalytic system. The advantage of this catalytic system is that it is easy to prepare the chiral ligands from the widely accessible thiophene precursor, and the reaction can also be performed at room temperature as compared to other catalytic system carried out at lower temperatures. There is an ongoing research project to explore more utilities for these new chiral thiophene ligands and their applications in asymmetric transformation, and its outcome will be communicated soon in future.