Abstract
A visible-light photocatalytic radical addition reaction of dihydroquinoxalin-2-ones to trifluoromethyl ketones has been established using Ru(bpy)3Cl2 as photocatalyst, acetonitrile as solvent, and HP Single Blue LED as the source of light. The reaction provides a straightforward approach to the synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl-substituted tertiary alcohol moiety in moderate to good yields under mild conditions.
Introduction
The synthesis of fluorinated molecules is a fundamental task for synthetic organic chemistry, due to the presence of fluorine atoms in a vast number of pharmaceuticals, agrochemicals, and materials.1 In this context, the trifluoromethyl group (CF3) has received a significant amount of attention and is often used in medicinal chemistry to replace the methyl group to prevent its metabolic oxidation, to adjust the steric and electronic properties or to increase the lipophilicity of biological active compounds.2 Therefore, the organic synthesis of building blocks bearing a trifluoromethyl moiety is very attractive. One of the most efficient and direct ways to incorporate a trifluoromethyl group into organic molecules is the use of trifluoromethyl ketones as reagents.3 So, a wide range of synthetic methodologies have been described using nucleophilic addition reactions with trifluoromethyl ketones as electrophiles. However, the radical–radical coupling or radical addition reactions using trifluoromethyl ketones are less studied, and relatively few examples are known. The radical–radical coupling and radical addition reactions are powerful C–C bond formation processes that have been recently established using visible-light photocatalysis, and several synthesis of secondary and tertiary alcohols have been reported.4 In this context, very few examples have been described using radical reactions for the synthesis of trifluoromethyl carbinols (Scheme 1). Meggers, in 2016, described an elegant photocatalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from tertiary amines and trifluoromethyl ketones using a chiral iridium photocatalyst. These authors described 15 examples with good yields with excellent stereoselectivity.5 In 2018, Wang and co-workers presented a coupling reaction of tertiary N-arylamines and aldehydes, ketones, and imines using visible-light photocatalysis, showing one example with trifluoroacetophenone.6 Later in 2019, Liu and co-workers reported one example (27% yield) of a radical–radical coupling of trifluoroacetophenone and cyclohexene using fac-Ir(ppy)3 as photocatalyst.7 Finally in 2021, Ohmiya and Nagao described one example of the photocatalytic synthesis of a tertiary trifluoromethyl alcohol from the reaction of 2-phenylisobutyric acid and trifluoroacetophenone.8 Herein, we present the reaction of trifluoromethyl ketones9 and dihydroquinoxalin-2-ones using visible-light photoredox catalysis leading to the synthesis of trifluoromethyl alcohols bearing a dihydroquinoxalin-2-one moiety. Dihydroquinoxalin-2-ones are privileged nitrogen heterocycles that are present in a broad assortment of biologically active compounds such as antiviral, antibiotic, anticancer, or anti-inflammatory drugs.10 Consequently, the functionalization of this class of nitrogen heterocycles is significant for medicinal and pharmaceutical chemistry. Many methodologies have been established, with the visible-light photocatalytic functionalization being one of the most straightforward and sustainable approaches.11 Continuing with our interest in the photocatalytic functionalization of dihydroquinoxalin-2-ones,12 we hypothesized that this class of heterocycles could be an appropriate precursor of α-amino radicals13 to perform the radical addition reaction to trifluoromethyl ketones under visible-light photocatalysis.
Scheme 1. Examples of Photocatalytic Radical Reactions Using Trifluoromethyl Ketones.
Results and Discussion
We started our studies with the reaction of 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) with 2,2,2-trifluoroacetophenone (2a) in the presence of different visible-light photocatalysts in acetonitrile as a solvent at room temperature and under HP (High Power) Single Blue LED irradiation (Table 1). 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one is a challenging molecule because of the possible formation of two α-amino radicals at the α-position to the amide or at the benzylic position. The initial raction using 1 mol % Ru(bpy)3Cl2 under irradiation of HP Single Blue LED (455 nm) afforded the corresponding trifluoromethyl alcohol 3aa (diastereoisomers mixture) in 73% yield after 2.5 h reaction time (entry 1), although without diastereoselectivity. Other photocatalysts such Eosin Y or 4-CzIPN (2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile) were unsuccessful, and the formation of alcohol 3aa was not observed. Unexpectedly, when Ru(bpy)3(PF6)2 was used as photocatalyst, product 3aa was obtained with only 23% yield after 24 h (entry 4). A solvent screening (entries 5–7) with Ru(bpy)3Cl2 photocatalyst did not improve the results obtained with acetonitrile. Increasing the amount of trifluoroacetophenone was detrimental for the conversion to product 3aa (entries 8–10), and it was isolated with lower yield (56–66%). As we described before for a photocatalytic Giese addition of 1a,12c in order to improve the conversion, we decided to use (PhO)2PO2H as a Brønsted acid additive. Unfortunately, the obtained yield for 3aa was lower (26%). We could perform the reaction at the 0.2 mmol scale obtaining the same yield (entry 12). Finally, several control experiments were carried out showing that the model reaction did not occur without the presence of the Ru(bpy)3Cl2 photocatalyst (entry 13) or without visible-light irradiation (entry 14).
Table 1. Optimization of the Reaction Conditionsa.
| Entry | Photocatalyst | Solvent | Additive | t (h) | drb | Yield (%)c |
|---|---|---|---|---|---|---|
| 1 | Ru(bpy)3Cl2·H2O (1%) | CH3CN | - | 2.5 | 1:1 | 73 |
| 2 | Eosin Y (5%) | CH3CN | - | 24 | - | - |
| 3 | 4-CzIPN (2%) | CH3CN | - | 24 | - | - |
| 4 | Ru(bpy)3(PF6)2 (1%) | CH3CN | - | 23 | 1:1 | 23 |
| 5 | Ru(bpy)3Cl2·H2O (1%) | DMF | - | 5 | 1:1 | 63 |
| 6 | Ru(bpy)3Cl2·H2O (1%) | CH2Cl2 | - | 24 | 1:1 | >5b |
| 7 | Ru(bpy)3Cl2·H2O (1%) | THF | - | 24 | 1:1 | >5b |
| 8d | Ru(bpy)3Cl2·H2O (1%) | CH3CN | - | 2.5 | 1:1 | 66 |
| 9e | Ru(bpy)3Cl2·H2O (1%) | CH3CN | - | 2.5 | 1:1 | 56 |
| 10f | Ru(bpy)3Cl2·H2O (1%) | CH3CN | - | 2.5 | 1:1 | 58 |
| 11 | Ru(bpy)3Cl2·H2O (1%) | CH3CN | (PhO)2PO2H (10%) | 24 | 1:1 | 26 |
| 12g | Ru(bpy)3Cl2·H2O (1%) | CH3CN | - | 2.5 | 1:1 | 72 |
| 13 | - | CH3CN | - | 24 | - | - |
| 14h | Ru(bpy)3Cl2·H2O (1%) | CH3CN | - | 24 | - | - |
Reaction conditions: 0.13 mmol of 1a, 0.1 mmol 2a, x mol % of photocatalyst in 1 mL of solvent at rt under an Ar atmosphere and HP Blue LED (450 nm) irradiation.
Determined by 1H NMR.
Isolated yield of 3aa.
Reaction was performed with 0.1 mmol of 1a and 0.3 mmol 2a.
Reaction was performed with 0.1 mmol of 1a and 0.2 mmol 2a.
Reaction was performed with 0.1 mmol of 1a and 0.13 mmol 2a.
Reaction performed with 0.26 mmol of 1a, 0.2 mmol of 2a in 2 mL of CH3CN at rt under HP Blue LED (455 nm) irradiation.
Reaction performed under darkness.
Under the above optimized reaction conditions (entry 1, Table 1), the reaction scope of 1,4-dihydroquinoxalin-2-one derivatives with trifluoroacetophenone 2a was first studied (Scheme 2). A range of dihydroquinoxalin-2-ones were suitable for this reaction obtaining good yields, although without diastereoselectivity (almost 1:1 dr for all the examples). Initially, we evaluated the effect of the protecting group at the nitrogen of the amine of dihydroquinoxalin-2-one 1. The reaction tolerates different benzylic substituents, affording the corresponding trifluoromethyl carbinols 3ba and 3ca with good yields. Moreover, dihydroquinoxalin-2-one 1d bearing a heteroaromatic benzyl moiety furnished product 3da in good yield. Additionally, the group CH2CO2Me is allowed giving the corresponding quinoxalin-2-one 3ea, although with lower yield (55%). Moreover, 1,4-disubstituted-3,4-dihydroquinoxalin-2-ones could be used under the optimized reaction conditions giving the corresponding products 3fa and 3ga with good yields (60% for both examples). The substitution in the parent aromatic ring of 3,4-dihydroquinoxalin-2-one was also examined under the optimal reaction conditions. To our delight, 3,4-dihydroquinoxalin-2-one bearing an electron-donating (Me) or electron-withdrawing (Br) group at the 7-position on the aromatic ring furnished the corresponding tertiary alcohols 3ha and 3ia in good yields (59% and 68%, respectively). Nevertheless, 3,4-dihydroquinoxalin-2-ones with a methyl substituent at either the 5 or the 8 position were not suitable substrates for our methodology. Interestingly, the less electron-rich substrate 1l bearing a secondary amine was found to be competent under the reaction conditions furnishing the product 3la in moderate yield.
Scheme 2. Scope of the Radical Addition Reaction Regarding the Dihydroquinoxalin-2-one Derivatives 1.
Reaction conditions: 1 (0.26 mmol), 2a (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation of a HP single LED (450 nm). Isolated yields after column chromatography. Diastereomeric ratio determined by 1H NMR.
Subsequently, the scope and limitation of various trifluoromethyl aryl ketones 2 were explored (Scheme 3). The incorporation of either electron-donating groups (Me, Et, or MeO) or electron-withdrawing groups (Cl or Br) on the benzene ring of trifluoromethyl ketones 2 had no obvious impact on the reaction, and the corresponding products (3aa–3al) were obtained in 40–70% yields. The presence of a MeO group in the ortho position to the carbonyl group of 2 had a slight influence on obtaining the trifluoromethyl alcohol 3ak with lower yield (37%), but somewhat higher diastereoselectivity (59:41 dr). Furthermore, trifluoromethyl ketones with two substituents at the aromatic ring or bearing a heteroaromatic ring were tested in the radical addition reaction, affording the products 3al and 3am with moderate yields. Besides, non-aromatic trifluoromethyl ketone 2n was found to be able to react under the optimized conditions but provide the expected product (3an) in low yield.
Scheme 3. Scope of the Radical Addition Reaction Regarding the Trifluoromethyl Aryl Ketones 2.
Reaction conditions: 1 (0.26 mmol), 2 (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere with irradiation of a HP single LED (455 nm). Isolated yields after column chromatography. Diastereomeric ratio determined by 1H NMR.
Finally, the utility of our protocol was further applied to trifluoroacetophenone 2o resulting in the incorporation of the indometacin core, a nonsteroidal anti-inflammatory drug (Scheme 4). Hence, indometacin was coupled with p-hydroxytrifluoroacetophenone in the presence of DCC, obtaining the corresponding ester 2o in 97% yield. This derivative was subjected to our photoredox radical addition protocol furnishing the desired dihydroquinoxalin-2-one derivative bearing the indometacin scaffold (3ao) in 64% yield.
Scheme 4. Synthesis of Indometacin-Derived Trifluoroacetophenone 2o and Its Subsequent Radical Addition Reaction with Dihydroquinoxalin-2-one 1a.
Reaction conditions: 1a (0.26 mmol), 2o (0.2 mmol), and Ru(bpy)3Cl2·H2O (1%) in 2 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation of a HP Single LED (455 nm). Isolated yield after column chromatography. Diastereomeric ratio determined by 1H NMR.
To further expand the substrate scope of this reaction, other trifluoromethyl ketones were used as sources of trifluoromethyl ketyl radicals. As disclosed in Scheme 5, ethyl 3,3,3-trifluoropyruvate 4 proved to be a suitable substrate for this transformation, even though the corresponding alcohol product 5 was isolated in low yield.
Scheme 5. Scope of the Radical Addition Reaction Regarding the 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one 1a with Ethyl 3,3,3-trifluoropyruvate 4.
Reaction conditions: 1a (0.13 mmol), 4 (0.1 mmol), and Ru(bpy)3Cl2·H2O (1%) in 1 mL of CH3CN and stirred at rt under an Ar atmosphere and irradiation of a HP single LED (450 nm). b0.1 mmol of 1a and 0.13 mmol of 4 were used. Isolated yields after column chromatography. Diastereomeric ratio determined by 1H NMR.
To demonstrate the utility of our photocatalytic protocol for the synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl alcohol, we also performed the reaction of 1a and trifluoroacetophenone 2a at 1 mmol scale under HP Single Blue LED or sunlight irradiation (Scheme 6A). Interestingly, when the reaction was performed under sunlight irradiation, we obtained the product 3aa with higher yield (80%). Finally, we carried out the reduction of the amide group present in the dihydroquinoxalin-2-one derivative 3 with LiAlH4 in THF at 70 °C, obtaining the corresponding dihydroquinoxaline 6 with 70% yield (Scheme 6B). Moreover, we attempted dehydration of the product 3aa using SOCl2/pyridine;14 however, we obtained the quinoxalin-2-one derivative 7 in 81% yield from the nucleophilic substitution of the OH group by Cl.
Scheme 6. (A) 1 Mmol Scale Reactions Using HP Single Blue LED or Sunlight Irradiation an Ar Atmosphere. (B) Synthetic Transformations. Isolated Yields after Column Chromatography.
To gain insight into the mechanism of the reaction, we first examined the reduction potential values of each component in the reaction mixture. Ru(bpy)3Cl2 potentials in MeCN are well stablished, and this complex can act either as an oxidant with *E1/2 = +0.77 V vs SCE or as a reductant with *E1/2= −0.81 V vs SCE.15 Reduction potentials of several substituted 2,2,2-trifluoroacetophenones were reported in 1990 by Liu.16 This authors examined the effect of several substituents at the aromatic ring and found that the parent 2,2,2-trifluoroacetophenone (2a) has a reduction potential of −1.40 V vs SCE. Besides, we have previously reported the reduction potential of 4-benzylquinoxalin-2-one 1a in an earlier work (+0.80 V vs SCE).12c Based on the thermodynamics of canonical photoredox reactivity, we can exclude a Single Electron Transfer (SET) event between the excited state of the ruthenium catalyst and either the trifluoroacetophenone 2a (via an oxidative quenching pathway) or 4-benzylquinoxalin-2-one 1a (via a reductive quenching pathyway). This assumption is further confirmed by luminescence quenching studies in which both trifluoroacetophenone 2a and 4-benzylquinoxalin-2-one 1a were unable to independently deactivate the excited state of Ru(bpy)3Cl2 (Figure 1A).
Figure 1.
Emission spectrum of Ru(bpy)3Cl2·6H2O (0.02 mM) for (A) solutions of increasing concentration of trifluoroacetophenone 2a (A0 = 0 mM; A1 = 9.6 mM; A2 = 19.2 mM); (B) solutions of constant concentration of quinoxalin-2-one 1a (9.6 mM) and increasing concentration of trifluoroacetophenone 2a (B0 = 0 mM; B1 = 9.6 mM; B2 = 19.2 mM); and (C) solutions of constant concentration of trifluoroacetophenone 2a (9.6 mM) and increasing concentration of quinoxalin-2-one 1a (C0 = 0 mM; C1 = 9.6 mM; C2 = 19.2 mM). (D) Stern–Volmer plot for the emission spectrum (at 600 nm) depicted in (C).17
These findings led us to explore other pathways dictating this reactivity. First, we performed a Stern–Volmer quenching study maintaining the amount of both the 4-benzylquinoxalin-2-one 1a and Ru(bpy)3Cl2 in each solution and varying the amount of trifluoroacetophenone 2a. After recording the emission spectrum of each sample, only a modest change was observed, which can be attributed to experimental errors (Figure 1B). Then, we repeated the same experiment but now maintain constant the amount of trifluoroacetophenone 2a and Ru(bpy)3Cl2 and vary the concentration of 4-benzylquinoxalin-2-one 1a. This time we obtained a set of emission spectra consistent with a Stern–Volmer relationship (Figure 1C), and therefore we can establish a Stern–Volmer constant (KSV) of 25.9 M–1 (Figure 1D).17 This study revealed that the excited state of Ru(bpy)3Cl2 can be quenched (presumably via a SET) by 4-benzylquinoxalin-2-one 1a only if trifluoroacetophenone 2a is present. These finding can be explained by admitting an interaction between 1a and 2a that makes 1a more prone to oxidation.
At this point, we wanted to explore the interaction between 1a and 2a. We envisioned that a solution of 4-benzylquinoxalin-2-one 1a in MeCN-d3 could be titrated with trifluoroacetophenone 2a while monitoring the process by NMR.17 Unfortunately, we did not observe any NMR change that could be attributed to an interaction between 1a and 2a (Figure S1),17 especially regarding the amidic N–H bond of 1a and a possible Proton Coupled Electron Transfer process like those reported by Knowles.18
Furthermore, to confirm the participation of a closed photoredox cycle and to exclude a radical chain process, we determined the quantum yield of the process. First, we determined the photon flux of our photochemical setup using standard ferrioxalate actinometry (Figure S3),17 and then, we found out that the quantum yield of our methodology is as low as Φ = 0.21 ± 0.02, showing that the participation of a chain mechanism is unlikely (Figure S4).17 We have also performed a light/off experiment (Figure 2) for the reaction between 1a and 2a, showing as well that the mechanism should be a closed photoredox cycle.
Figure 2.
On/off experiment for the radical addition reaction between dihydroquinoxalin-2-one 1a and trifluoroacetophenone 2a.
With all this information, we were able to postulate a plausible reaction mechanism for our photochemical protocol (Scheme 7). The absorption of a 455 nm photon promotes Ru(bpy)3Cl2 to its excited state. Then, a sort of aggregate between 1a and 2a facilitated the SET from the excited photocatalyst to 1a, yielding the corresponding radical cation A as well as the RuI form of the catalyst.19 The radical cation A can experience Proton Transfer (PT) to form the α-amino radical B, which has a nucleophilic character and can react with trifluoroacetophenone 2a to generate O-centered radical C. This radical B can react with itself through an unproductive pathway to form the dimeric compound 8.12c The RuI species, which has a strong reductive behavior (EII/I1/2 = −1.33 V vs SCE), is able to reduce radical C to its corresponding alkoxide anion D. Finally, another PT event over alkoxide D furnishes the desired product 3aa.
Scheme 7. Mechanistic Hypothesis for the Generation of 3aa from 1a and 2a under Photoredox Conditions.
Conclusion
In summary, we have described the synthesis of trifluoromethyl tertiary alcohols bearing a dihydroquinoxalin-2-one framework (25 examples) through a photocatalytic radical addition of dihydroquinoxalin-2-ones to trifluoromethyl ketones enabled by a reductive quenching cycle of Ru(bpy)3Cl2. Our protocol provides rapid and efficient access to synthetic useful dihydroquinoxalin-2-ones bearing trifluoromethyl and hydroxyl groups under mild reaction conditions and simple operational protocol using HP Single LED of 455 nm. It is also important to note that our protocol is operative in the late-stage functionalization of a value-added indometacin-derived trifluoroacetophenone substrate. In addition, the reaction can be scaled up to 1 mmol using HP Single LED (455 nm) as well as sunlight irradiation. Moreover, several synthetic transformations have been performed, and a plausible reaction mechanism has been postulated.
Experimental Section
General Methods
Reactions were carried out in Schlenk tubes oven-dried overnight at 120 °C. Commercial reagents were used as purchased. Reactions were monitored by TLC analysis using Merck Silica Gel 60 F-254 thin layer plates. Flash column chromatography was performed on Merck silica gel 60, 0.040–0.063 mm and visualized using both a UV lamp (254 nm) and then a CAM solution (an aqueous solution of ceric ammonium molybdate). Melting points were determined in capillary tubes. NMR spectra were run at 300 MHz for 1H and 75 MHz for 13C using residual nondeuterated solvent as internal standard (CHCl3: δ 7.26 and 77.00 ppm, respectively). Chemical shifts are given in ppm. The carbon type was determined by DEPT experiments. High resolution mass spectra (ESI) were recorded on a AB SCIEX Triple TOF spectrometer equipped with an electrospray source with a capillary voltage of 4.5 kV (ESI). MeCN was degassed by three freeze–pump–thaw cycles and stored over 3 Å MS for 48 h at least. Prior to use, MeCN was bubbled with Ar for 10 min. Commercially available High Power Single LEDs manufactured by Intelligent LED Solutions (purchased from Farnell, internal reference 3583117) with an emission band centered at 455 nm were used as a light source. These LEDs lay on an aluminum block to ensure proper heat dissipation. Photochemical reactions were conducted in conventional borosilicate glass Schlenk flasks situated at 2 cm to the HP Single LED. Ru(bpy)4Cl2·6H2O and Eosin Y were purchased by Merck-Aldrich. 4-CzIPN20 and dihydroquinoxalinones12c1 were known compounds and were synthesized according to literature-reported procedures.
Specific Procedure for the Synthesis of Indometacin-Derived Trifluoroacetophenone 2o
To a stirred solution of commercially available indometacin (196.8 mg, 0.55 mmol, 1.1 equiv) in DCM (5 mL) were added p-hydroxytrifluoroacetophenone (95.1 mg, 0.5 mmol, 1 equiv) and DCC (155 mg, 0.75 mmol, 1.5 equiv), and the resulting mixture was stirred at room temperature for 16 h. Then, the crude reaction mixture was filtered through a pad of Celite eluting with Et2O. This yellow solution was concentrated under reduced pressure, and the residue was purified by column chromatography using hexane:EtOAc as eluent to afford the desired product (257 mg, 0.485 mmol, 97% yield) as a white solid.
1H NMR (300 MHz, CDCl3) δ 8.29–7.93 (m, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 6.71 (dd, J = 9.0, 2.5 Hz, 1H), 3.95 (s, 2H), 3.84 (s, 3H), 2.47 (s, 3H); 19F{1H} NMR (282 MHz, CDCl3) δ −71.87; 13C{1H} NMR (75 MHz, CDCl3) δ 179.2 (q, JC–F = 35.4 Hz, C), 168.3 (C), 168.2 (C), 156.1 (C), 139.4 (C), 136.4 (C), 133.6 (C), 131.9 (q, JC–F = 2.0 Hz, CH), 131.2 (CH), 130.8 (C), 130.3 (C), 129.2 (C+CH), 127.4 (C), 122.3 (CH), 116.5 (q, JC–F = 290.8 Hz, C), 115.0 (CH), 111.7 (CH), 111.2 (C), 101.2 (CH), 55.7 (CH3), 30.5 (CH2), 13.4 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C27H20ClF3NO5+ Calcd for 530.0977; Found 530.0984.
General Procedure for the Photocatalytic Radical Addition of Quinoxalin-2-ones to Trifluoroacetophenone (GP-1)
In an oven-dried Schlenk tube, the corresponding quinoxalin-2-one 1 (0.26 mmol, 0.13 equiv) and Ru(bpy)3Cl2·6H2O (1.5 mg, 1 mol %) were placed and the flask was evacuated and backfilled with Ar (×3). Then, anhydrous and degassed CH3CN (2 mL), as well as the corresponding trifluoroacetophenone 2 (0.2 mmol, 0.1 equiv), was added via syringe. The reaction mixture was stirred under the irradiation of a High-Power Blue LED (455 nm) while being cooled with a fan to keep the temperature at 20 °C. Once the reaction was finished (TLC), the mixture was purified by column chromatography using hexane:EtOAc or hexane:Et2O mixtures to afford compound 3.
Specific Procedure for the Photocatalytic Radical Addition of 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) to Ethyl 3,3,3-trifluoropyruvate (4) (SP-1)
In an oven-dried Schlenk tube, the corresponding 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 47.6 mg, 0.2 mmol, 0.1 equiv) and Ru(bpy)3Cl2 (1.5 mg, 1 mol %) were placed, and the flask was evacuated and backfilled with Ar (×3). Then, anhydrous and degassed CH3CN (2 mL), as well as 3,3,3-trifluoropyruvate (4, 34 μL, 0.26 mmol, 1.3 equiv), was added via syringe. The reaction mixture was stirred under the irradiation of a High-Power Blue LED (455 nm) while being cooled with a fan to keep the temperature at 20 °C. Once the reaction was finished (TLC), the mixture was purified by column chromatography using hexane:EtOAc mixtures to afford compound 5.
Specific Procedure for the Photocatalytic Radical Addition of 4-Benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) to 2,2,2-Trifluoroacetophenone (2a) 1 mmol Scale Reaction (SP-2)
In an oven-dried Schlenk tube, 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 312 mg, 1.3 mmol, 1.3 equiv) and Ru(bpy)3Cl2·6H2O (5.0 mg, 1 mol %) were placed, and the flask was evacuated and backfilled with Ar (×3). Then, anhydrous and degassed CH3CN (7 mL), as well as 2,2,2-trifluoroacetophenone (2a, 212 μL, 1.0 mmol 1 equiv) was added via syringe. The reaction mixture was stirred under the irradiation of several High-Power Blue LEDs (455 nm) while being cooled with a fan to keep the temperature at 20 °C. Once the reaction was finished (TLC), the mixture was purified by column chromatography using hexane:EtOAc mixtures to afford compound 3aa (240 mg, 0.58 mmol, 58% yield) as a mixture of diastereoisomers (3aa′ and 3aa″, 59:41 dr).
Specific Procedure for the photocatalytic radical addition of 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a) to 2,2,2-trifluoroacetophenone (2a) under sunlight irradiation (SP-3)
In an oven-dried Schlenk tube, 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 465 mg, 1.95 mmol, 1.3 equiv) and Ru(bpy)3Cl2·6H2O (7.5 mg, 1 mol %) were placed and the flask was evacuated and backfilled with Ar (×3). Then, anhydrous and degassed CH3CN (10 mL), as well as 2,2,2-trifluoroacetophenone (2a, 316 μL, 1.5 mmol 1 equiv) was added via syringe. The reaction mixture placed at the upper part of the building in sunny hours and was stirred for 2.5 h. Once the reaction was finished (TLC), the mixture was purified by column chromatography using hexane:EtOAc mixtures to afford compound 3aa (495 mg, 1.2 mmol, 80% yield) as a mixture of diastereoisomers (3aa′ and 3aa″, 53:47 dr).
Specific Procedure for the reduction of 3a (SP-4)
In a 50 mL round bottomed flask equipped with a condenser, compound 3aa (78.4 mg, 0.19 mmol, 1 equiv) was placed. The flask was purged with N2 and then dry THF (5 mL) was added. The solution was cooled to 0 °C and LiAlH4 (125 μL, 0.76 mmol, 4 equiv., 4 M in THF) was added dropwise. The reaction mixture was progressively warmed up and heated (in an oil bath) at reflux temperature for 2 h. After this period, the reaction mixture was cooled again to 0 °C and the excess LiAlH4 was quenched with sat. aq. NH4Cl (5 mL) and the organics were extracted with DCM (×3). The combined organic layers were washed with brine (×1) and dried over anhydrous MgSO4. After evaporating the solvent, the residue was purified by column chromatography using hexane:EtOAc mixtures, obtaining quinoxaline derivative 6.
Specific Procedure for the Chlorination of 3aa (SP-5)
In a 10 mL round bottomed flask equipped with a condenser, compound 3aa (26.9 mg, 0.07 mmol, 1 equiv) was placed. The flask was purged with N2 and then DCM (2 mL) was added. SOCl2 (10 μL, 0.13 mmol, 2 equiv) and pyridine (11 μL, 0.13 mmol, 2 equiv) were successively added and the reaction mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was directly purified by column chromatography using hexane:Et2O mixture to afford compound 7.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3aa)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3aa was obtained as a mixture of diastereoisomers (50:50 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3aa′ (29.7 mg, 0.07 mmol, 36% yield, brown oil) and 3aa″ (30.1 mg, 0.07 mmol, 36% yield, brown oil).
Characterization of 3aa′
1H NMR (300 MHz, CDCl3) δ 9.64 (s, 1H), 7.64 (dd, J = 6.6, 2.9 Hz, 2H), 7.46–7.36 (m, 3H), 7.22 (tdd, J = 4.5, 3.6, 1.5 Hz, 3H), 7.01 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H), 6.97–6.90 (m, 3H), 6.82 (td, J = 7.5, 1.4 Hz, 1H), 6.63 (dd, J = 7.8, 1.3 Hz, 1H), 4.82 (s, 1H), 4.59 (d, J = 15.8 Hz, 1H), 4.38 (s, 1H), 3.48 (d, J = 15.8 Hz, 1H); 19F{1H} NMR (282 MHz, CDCl3) δ −73.17; 13C{1H} NMR (75 MHz, CDCl3) δ 165.7 (C), 136.3 (C), 134.7 (C), 133.1 (C), 128.9 (CH), 128.8 (CH), 128.3 (CH), 127.8 (CH), 127.4 (CH), 126.6 (C), 126.5 (q, J = 1.8 Hz, CH), 125.19 (q, J = 287.2 Hz, CF3), 124.7 (CH), 120.8 (CH), 116.9 (CH), 116.0 (CH), 79.4 (q, J = 28.2 Hz, C), 67.2 (CH), 57.4 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H20F3N2O2+ Calcd for 413.1471; Found 413.1465.
Characterization of 3aa″
1H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.24–7.14 (m, 4H), 7.13–7.02 (m, 4H), 6.92 (ddd, J = 8.2, 7.4, 1.4 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.63 (td, J = 7.7, 1.2 Hz, 1H), 6.38 (dd, J = 7.8, 1.3 Hz, 1H), 4.81 (d, J = 16.0 Hz, 1H), 4.73 (s, 1H), 4.66 (s, 1H), 4.21 (d, J = 16.0 Hz, 1H). 19F{1H} NMR (282 MHz, CDCl3) δ −74.24. 13C{1H} NMR (75 MHz, CDCl3) δ 164.8 (C), 136.6 (C), 134.2 (C), 133.6 (C), 128.82 (CH), 128.79 (CH), 127.8 (CH), 127.7 (CH), 127.3 (CH), 126.9 (q, J = 1.8 Hz, CH), 125.7 (C), 124.72 (CH), 124.68 (q, J = 265.9 Hz, CF3), 120.0 (CH), 116.4 (CH), 115.5 (CH), 78.6 (q, J = 27.1 Hz, C), 66.4 (CH), 56.5 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H20F3N2O2+ Calcd for 413.1471; Found 413.1462.
4-(4-Methoxybenzyl)-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ba)
Using 4-(4-methoxybenzyl)-3,4-dihydroquinoxalin-2(1H)-one (1b, 69.8 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ba was obtained as a mixture of diastereoisomers (52:48 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 8:2): 3ba′ + 3ba″ (74.5 mg, 0.16 mmol, 90% yield, brown oil).
1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 9.03 (s, 1H), 7.61 (dd, J = 6.6, 2.9 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.41–7.32 (m, 3H), 7.22–7.14 (m, 1H), 7.13–7.04 (m, 2H), 7.04–6.90 (m, 5H), 6.88–6.71 (m, 9H), 6.68–6.57 (m, 1H), 6.33 (dd, J = 7.8, 1.4 Hz, 1H), 4.90–4.69 (m, 3H), 4.65 (s, 1H), 4.51 (d, J = 15.3 Hz, 1H), 4.34 (s, 1H), 4.14 (d, J = 15.6 Hz, 1H), 3.75–3.67 (m, 6H), 3.42 (d, J = 15.3 Hz, 1H). 19F{1H} NMR (282 MHz, CDCl3) δ −73.26, −74.23. 13C{1H} NMR (75 MHz, CDCl3) δ 165.8 (C), 165.0 (C), 159.3 (C), 159.2 (C), 134.8 (C), 134.3 (C), 133.78 (C), 133.3 (C), 128.9 (CH), 128.8 (CH), 128.7 (CH), 128.6 (C), 128.3 (CH), 128.2 (C), 127.7 (CH), 127.0 (q, J = 1.7 Hz, CH), 126.8 (C), 126.6 (q, J = 1.7 Hz, CH), 125.9 (C), 124.8 (CH), 124.7 (CH), 120.9 (CH), 120.0 (CH), 117.3 (CH), 116.8 (CH), 115.9 (CH), 115.6 (CH), 114.22 (CH), 114.19 (CH), 79.3 (q, J = 28.2 Hz, C), 78.5 (q, J = 27.1 Hz, C), 66.6 (CH), 66.0 (CH), 57.2 (CH2), 56.4 (CH2), 55.4 (CH3), 55.2 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O3+ Calcd for 443.1577; Found 443.1583.
3-(2,2,2-Trifluoro-1-hydroxy-1-phenylethyl)-4-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinoxalin-2(1H)-one (3ca)
Using 4-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinoxalin-2(1H)-one (1c, 79.6 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ca was obtained as a mixture of diastereoisomers (52:48 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3ca′ + 3ca″ (73.0 mg, 0.152 mmol, 76% yield, brown oil).
1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 9.19 (s, 1H), 7.63 (dd, J = 6.6, 2.8 Hz, 2H), 7.52–7.37 (m, 9H), 7.24–7.06 (m, 5H), 7.08–6.95 (m, 3H), 6.91 (td, J = 8.2, 1.4 Hz, 1H), 6.87–6.78 (m, 2H), 6.76–6.69 (m, 2H), 6.65 (td, J = 7.7, 1.1 Hz, 1H), 6.38 (dd, J = 7.8, 1.3 Hz, 1H), 4.82 (d, J = 16.4 Hz, 1H), 4.72–4.55 (m, 4H), 4.36 (s, 1H), 4.24 (d, J = 16.5 Hz, 1H), 3.53 (d, J = 16.4 Hz, 1H). 19F{1H} NMR (282 MHz, CDCl3) δ −62.58, −62.61, −73.09, −74.16. 13C{1H} NMR (75 MHz, CDCl3) δ 165.5 (C), 164.7 (C), 140.8 (q, J = 1.1 Hz, C), 140.6 (q, J = 1.1 Hz, C), 134.6 (C), 134.0 (C), 132.9 (C), 132.5 (C), 130.00 (q, J = 32.5 Hz, C), 129.98 (q, J = 32.4 Hz, C), 129.1 (CH), 129.0 (CH), 128.4 (CH), 127.8 (CH), 127.44 (CH), 127.41 (CH), 126.8 (q, J = 1.6 Hz, CH), 126.5 (q, J = 1.7 Hz, CH), 126.4 (C), 125.8 (q, J = 2.6 Hz, CH), 125.7 (q, J = 2.6 Hz, CH), 125.0 (CH), 124.8 (CH), 120.9 (CH), 120.3 (CH), 116.2 (CH), 116.1 (CH), 116.0 (CH), 115.7 (CH), 79.7 (q, J = 27.6 Hz, C), 78.8 (q, J = 27.6 Hz, C), 67.9 (CH), 66.9 (CH), 56.3 (CH2), 55.7 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H19F6N2O2+ Calcd for 481.1345; Found 481.1341.
4-(Thiophen-2-ylmethyl)-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3da)
Using 4-(thiophen-2-ylmethyl)-3,4-dihydroquinoxalin-2(1H)-one (1d, 63.5 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3da was obtained as a mixture of diastereoisomers (58:42 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 8:2): 3da′ + 3da″ (51.0 mg, 0.12 mmol, 61% yield, brown oil).
1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.31 (s, 1H), 7.69–7.60 (m, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.44–7.36 (m, 3H), 7.20–6.80 (m, 13H), 6.73–6.62 (m, 3H), 6.30 (dd, J = 7.8, 1.2 Hz, 1H), 5.02–4.92 (m, 2H), 4.88 (s, 1H), 4.69–4.59 (m, 2H), 4.40 (d, J = 16.2 Hz, 1H), 4.35–4.29 (m, 1H), 3.49 (d, J = 16.1 Hz, 1H); 19F{1H} NMR (282 MHz, CDCl3) δ −73.61, −74.77; 13C NMR (75 MHz, CDCl3) δ 165.4 (C), 164.8 (C), 139.3 (C), 138.8 (C), 134.7 (C), 134.0 (C), 132.8 (C), 132.3 (C), 129.0 (CH), 128.8 (CH), 128.3 (CH), 127.6 (CH), 127.0 (C), 127.0 (C), 127.0 (CH), 126.8 (CH), 126.7 (CH), 126.6 (CH), 126.6 (CH), 126.6 (CH), 125.7 (CH), 125.6 (CH), 124.8 (CH), 124.8 (CH), 121.5 (CH), 120.8 (CH), 117.8 (CH), 117.5 (CH), 115.9 (CH), 115.5 (CH), 79.1 (q, JC–F = 26.2 Hz, C), 78.1 (q, JC–F = 25.9 Hz, C), 66.6 (CH), 65.7 (CH), 53.1 (CH2), 52.6 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C21H18F3N2O2S+ Calcd for 419.1036; Found 419.1037.
Methyl 2-(3-Oxo-2-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-1(2H)yl) acetate (3ea)
Using methyl 2-(3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetate (1e, 57.3 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ea was obtained as a mixture of diastereoisomers (51:49 dr) that cannot be separated by column chromatography using hexane:Et2O mixtures (from 5:5 to 2:8): 3ea′ + 3ea″ (43.2 mg, 0.11 mmol, 55% yield, brown oil).
1H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 9.16 (s, 1H), 7.63 (dd, J = 6.8, 2.9 Hz, 2H), 7.56–7.47 (m, 2H), 7.38–7.30 (m, 3H), 7.19–7.04 (m, 3H), 7.02–6.80 (m, 4H), 6.80–6.73 (m, 1H), 6.73–6.64 (m, 2H), 6.39 (dd, J = 7.8, 1.4 Hz, 1H), 5.56 (s, 1H), 5.27 (s, 1H), 4.53 (s, 1H), 4.38 (d, J = 18.5 Hz, 1H), 4.23 (s, 1H), 4.07 (d, J = 18.5 Hz, 1H), 3.93 (d, J = 18.5 Hz, 1H), 3.64 (s, 3H), 3.63 (s, 3H), 3.09 (d, J = 18.5 Hz, 1H). 19F{1H} NMR (282 MHz, CDCl3) δ −73.38, −74.14. 13C{1H} NMR (75 MHz, CDCl3) δ 171.2 (C), 170.9 (C), 165.2 (C), 164.5 (C), 134.4 (C), 133.8 (C), 132.7 (C), 132.3 (C), 128.9 (CH), 128.8 (CH), 128.1 (CH), 127.6 (CH), 127.1 (C), 127.0 (q, J = 1.8 Hz, CH), 126.6 (C), 126.60 (q, J = 1.8 Hz, CH), 125.1 (q, J = 281.9 Hz, CF3), 124.9 (q, J = 286.9 Hz, CF3), 124.6 (CH), 124.5 (CH), 121.9 (CH), 121.3 (CH), 117.3 (CH), 116.1 (CH), 115.9 (CH), 79.0 (q, J = 27.6 Hz, C), 77.9 (q, J = 26.5 Hz, C), 69.0 (CH), 67.9 (CH), 56.9 (CH2), 56.3 (CH2), 52.4 (CH3), 52.3 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C19H18F3N2O4+ Calcd for 395.1213; Found 395.1217.
1,4-Dibenzyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3fa)
Using 1,4-dibenzyl-3,4-dihydroquinoxalin-2(1H)-one (1f, 85.4 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3fa was obtained as a mixture of diastereoisomers (53:47 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3fa′ + 3fa″ (60.8 mg, 0.12 mmol, 60% yield, brown oil).
1H NMR (400 MHz, CDCl3) δ 7.64–7.58 (m, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.42–7.34 (m, 3H), 7.32–7.17 (m, 13H), 7.17–7.03 (m, 5H), 7.02–6.86 (m, 5H), 6.85–6.74 (m, 4H), 6.59 (t, J = 6.9 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 5.24 (d, J = 16.0 Hz, 1H), 5.11–4.76 (m, 6H), 4.71–4.58 (m, 2H), 4.56 (s, 1H), 4.32 (d, J = 15.9 Hz, 1H), 3.60 (d, J = 15.6 Hz, 1H); 19F{1H} NMR (282 MHz, CDCl3) δ −73.67, −74.55. 13C{1H} NMR (75 MHz, CDCl3) δ 164.4 (C), 163.9 (C), 136.7 (C), 136.3 (C), 135.9 (C), 135.5 (C), 134.9 (C), 134.7 (C), 134.4 (C), 134.3 (C), 129.6 (C), 128.86 (CH), 128.79 (CH), 128.75 (CH), 128.70 (CH), 128.64 (CH), 128.59 (CH), 128.1 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.4 (CH), 127.3 (CH), 127.2 (CH), 126.9 (CH), 126.5 (q, J = 1.8 Hz, CH), 126.2 (CH), 124.8 (q, J = 286.4 Hz, CF3), 124.5 (CH), 124.4 (CH), 121.1 (CH), 120.1 (CH), 117.9 (CH), 117.2 (CH), 115.9 (CH), 115.7 (CH), 78.33 (q, J = 27.1 Hz, C), 78.33 (q, J = 27.1 Hz, C), 67.4 (CH), 66.8 (CH), 57.9 (CH2), 56.9 (CH2), 46.2 (CH2), 45.7 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C30H26F3N2O2+ Calcd for 503.1941; Found 503.1937.
4-Benzyl-1-methyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ga)
Using 4-benzyl-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (1g, 65.6 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ga was obtained as a mixture of diastereoisomers (53:47 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3ga′ + 3ga″ (50.4 mg, 0.12 mmol, 60% yield, colorless oil). Representative NMR signals for either the major and the minor diastereoisomer are labeled with one or two asterisks, respectively.
1H NMR (300 MHz, CDCl3) δ 7.56–7.49 (m, 2H*), 7.40–7.30 (m, 6H), 7.26–7.17 (m, 5H), 7.12–6.99 (m, 5H), 6.98–6.85 (m, 6H), 6.77 (ddd, J = 12.9, 8.1, 1.4 Hz, 2H), 6.65 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H**), 6.42 (dd, J = 8.1, 1.4 Hz, 1H**), 5.07 (s, 1H*), 4.96 (s, 1H**), 4.87 (d, J = 16.0 Hz, 1H**), 4.72 (s, 1H**), 4.48 (d, J = 15.4 Hz, 1H*), 4.37–4.32 (m, 2H), 3.52 (d, J = 15.4 Hz, 1H*), 3.26 (s, 3H*), 3.13 (s, 3H**). 19F{1H} NMR (282 MHz, CDCl3) δ −73.88*, −74.11**. 13C{1H} NMR (75 MHz, CDCl3) δ 164.3 (C*), 163.9 (C**), 136.5 (C), 136.0 (C), 134.9 (C), 134.3 (C), 134.2 (C), 133.9 (C), 130.4 (C), 128.73 (CH), 128.71 (CH), 128.7 (CH), 128.6 (CH), 128.0 (CH), 127.9 (CH), 127.72 (CH), 127.70 (CH), 127.65 (CH), 127.3 (CH), 126.8 (q, J = 1.7 Hz, CH), 126.5 (q, J = 2.2 Hz, CH), 125.1 (q, J = 286.9 Hz, CF3), 124.9 (q, J = 293.0 Hz, CF3), 124.3 (CH), 124.2 (CH), 121.3 (CH), 119.7 (CH), 117.8 (CH), 116.2 (CH), 114.7 (CH*), 114.4 (CH**), 78.4 (q, J = 28.2 Hz, C), 77.9 (q, J = 27.1 Hz, C), 67.0 (CH), 66.8 (CH), 58.1 (CH2), 56.23 (q, J = 1.6 Hz, CH2), 29.0 (CH3), 28.9 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1629.
4-Benzyl-7-methyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ha)
Using 4-benzyl-7-methyl-3,4-dihydroquinoxalin-2(1H)-one (1h, 65.6 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ha was obtained as a mixture of diastereoisomers (51:49 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3ha′ (25.7 mg, 0.06 mmol, 30% yield, colorless oil) and 3ha″ (24.7 mg, 0.06 mmol, 29% yield, colorless oil).
Characterization of 3ha′
1H NMR (300 MHz, CDCl3) δ 9.25 (s, 1H), 7.61 (dd, J = 6.8, 3.0 Hz, 2H), 7.41–7.34 (m, 3H), 7.24–7.18 (m, 3H), 7.00–6.91 (m, 2H), 6.87–6.79 (m, 2H), 6.42 (d, J = 1.6 Hz, 1H), 4.81 (s, 1H), 4.53 (d, J = 15.6 Hz, 1H), 4.33 (d, J = 0.9 Hz, 1H), 3.48 (d, J = 15.6 Hz, 1H), 2.24 (s, 3H); 19F{1H} NMR (282 MHz, CDCl3) δ −73.34; 13C{1H} NMR (75 MHz, CDCl3) δ 165.6 (C), 136.4 (C), 134.8 (C), 130.9 (C), 130.5 (C), 128.8 (CH), 128.7 (CH), 128.2 (CH), 127.8 (CH), 127.5 (CH), 126.7 (C), 126.5 (d, J = 1.7 Hz, CH), 125.4 (CH), 117.4 (CH), 116.5 (CH), 79.2 (q, J = 27.8 Hz, C), 67.1 (CH), 57.9 (CH2), 20.6 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1633.
Characterization of 3ha″
1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.20–7.07 (m, 4H), 7.07–7.02 (m, 2H), 7.02–6.93 (m, 2H), 6.67–6.56 (m, 2H), 6.12 (s, 1H), 4.72–4.60 (m, 2H), 4.53 (s, 1H), 4.08 (d, J = 15.9 Hz, 1H), 2.06 (s, 3H); 19F{1H} NMR (282 MHz, CDCl3) δ −74.21; 13C{1H} NMR (75 MHz, CDCl3) δ 165.0 (C), 136.8 (C), 135.5 (C), 134.4 (C), 131.1 (C), 128.7 (CH), 128.7 (CH), 127.7 (CH), 127.7 (CH), 127.4 (CH), 126.9 (q, J = 2.3 Hz, CH), 125.8 (C), 125.3 (CH), 116.7 (CH), 116.1 (CH), 78.6 (q, J = 27 Hz, C), 66.5 (CH), 57.0 (CH2), 20.4 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1619.
4-Benzyl-7-bromo-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ia)
Using 4-benzyl-7-bromo-3,4-dihydroquinoxalin-2(1H)-one (1i, 82.5 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ia was obtained as a mixture of diastereoisomers (50:50 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3ia′ + 3ai″ (66.8 mg, 0.136 mmol, 68% yield, colorless oil). Representative NMR signals for either the major and the minor diastereoisomer are labeled with one or two asterisks, respectively.
1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H**), 9.23 (s, 1H*), 7.57–7.45 (m, 2H**), 7.37 (d, J = 7.5 Hz, 2H*), 7.33–7.24 (m, 1H*+2H**), 7.16–7.05 (m, 8H), 7.00 (dd, J = 8.6, 2.1 Hz, 1H**), 6.97–6.83 (m, 6H), 6.72–6.61 (m, 2H**), 6.50 (d, J = 8.6 Hz, 1H*), 6.38 (d, J = 2.2 Hz, 1H*), 4.63–4.53 (m, 2H*), 4.48 (d, J = 15.8 Hz, 1H**) 4.32–4.35 (m, 1H*+1H**), 4.25 (s, 1H**), 4.03 (d, J = 15.9 Hz, 1H*), 3.53 (d, J = 15.8 Hz, 1H**); 19F{1H} NMR (282 MHz, CDCl3) δ −73.17**, −74.01*; 13C{1H} NMR (75 MHz, CDCl3) δ 165.1 (C), 164.4 (C), 136.1 (C), 135.9 (C), 134.4 (C), 134.0 (C), 132.7 (C), 132.3 (C), 129.2 (CH), 129.0 (CH), 128.9 (CH), 128.4 (CH), 128.0 (CH), 128.0 (CH), 127.9 (CH), 127.8 (C), 127.3 (CH), 127.2 (CH), 127.1 (C), 126.7 (q, J = 1.8 Hz, CH), 126.3 (q, J = 1.7 Hz, CH), 118.6 (CH), 118.2 (CH), 117.7 (CH), 117.5 (CH), 112.3 (C), 111.5 (C), 79.8 (q, J = 27.9 Hz, C), 78.9 (q, J = 27.4 Hz, C), 67.2 (CH), 66.5 (CH), 57.0 (CH2), 56.6 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19BrF3N2O2+ Calcd for 491.0577; Found 491.0582.
3-(2,2,2-Trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3la)
Using 3,4-dihydroquinoxalin-2(1H)-one (1l, 38.5 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoroacetophenone (2a, 28.1 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3la was obtained as a mixture of diastereoisomers (50:50 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 9:1 to 7:3): 3la′ + 3la″ (26.4 mg, 0.082 mmol, 41% yield, colorless oil).
1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.31 (s, 1H), 7.60–7.50 (m, 2H), 7.49–7.41 (m, 2H), 7.35–7.26 (m, 3H), 7.25–7.16 (m, 3H), 6.82 (s, 1H), 6.74–6.66 (m, 1H), 6.66–6.60 (m, 3H), 6.56 (d, J = 7.1 Hz, 1H), 6.51 (dd, J = 7.8, 1.4 Hz, 1H), 6.49–6.35 (m, 3H), 6.16 (d, J = 2.6 Hz, 1H), 5.87 (d, J = 3.3 Hz, 1H), 4.56 (d, J = 3.3 Hz, 1H), 4.46 (d, J = 2.5 Hz, 1H); 19F{1H} NMR (282 MHz, DMSO-d6) δ −72.18, −72.44; 13C NMR (75 MHz, DMSO-d6) δ 162.7 (C), 162.1 (C), 136.1 (C), 135.7 (C), 133.0 (C), 132.6 (C), 128.3 (CH), 128.0 (CH), 127.8 (CH), 127.4 (CH), 126.7 (CH), 126.4 (CH), 125.4 (C), 124.8 (C), 122.8 (CH), 122.4 (CH), 117.1 (CH), 117.0 (CH), 114.3 (CH), 114.0 (CH), 112.9 (CH), 112.9 (CH), 79.4 (q, JC–F = 26.0 Hz, C), 79.3 (q, JC–F = 25.7 Hz, C), 60.9 (CH), 60.3 (CH); HRMS (ESI/Q-TOF) m/z [M + H]+ C16H14F3N2O2+ Calcd for 323.1002; Found 323.1004.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-(p-tolyl)ethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ab)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(p-tolyl)ethan-1-one (2b, 31 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ab was obtained as a mixture of diastereoisomers (60:40 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ab′ (28.0 mg, 0.06 mmol, 30% yield, brown oil) and 3ab″ (18.7 mg, 0.04 mmol, 20% yield, brown oil).
Characterization of 3ab′
1H NMR (300 MHz, CDCl3) δ 9.21 (s, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.24–7.15 (m, 5H), 7.06–6.86 (m, 4H), 6.81 (td, J = 7.6, 1.4 Hz, 1H), 6.62 (dd, J = 7.8, 1.3 Hz, 1H), 4.65 (s, 1H), 4.59 (d, J = 15.8 Hz, 1H), 4.35 (s, 1H), 3.50 (d, J = 15.8 Hz, 1H), 2.38 (s, 3H). 19F{1H} NMR (282 MHz, CDCl3) δ −73.34. 13C{1H} NMR (75 MHz, CDCl3) δ 165.5 (C), 138.8 (C), 136.4 (C), 133.2 (C), 131.7 (C), 129.0 (CH), 128.7 (CH), 127.8 (CH), 127.4 (CH), 126.5 (C), 126.4 (q, J = 1.8 Hz, CH), 125.2 (d, J = 286.9 Hz, CF3), 124.7 (CH), 120.7 (CH), 116.7 (CH), 115.8 (CH), 79.4 (q, J = 27.9 Hz, C), 67.3 (CH), 57.3 (CH2), 21.1 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1621.
Characterization of 3ab″
1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.24–7.16 (m, 3H), 7.06 (dd, J = 7.2, 2.2 Hz, 2H), 6.97–6.85 (m, 3H), 6.78 (d, J = 7.8 Hz, 1H), 6.65 (td, J = 7.6, 1.2 Hz, 1H), 6.39 (dd, J = 7.7, 1.3 Hz, 1H), 4.79 (d, J = 16.0 Hz, 1H), 4.63 (s, 1H), 4.59 (s, 1H), 4.19 (d, J = 16.0 Hz, 1H), 2.22 (s, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.38. 13C{1H} NMR (75 MHz, CDCl3) δ 164.8 (C), 138.6 (C), 136.7 (C), 133.6 (C), 131.2 (C), 128.8 (CH), 128.4 (CH), 127.7 (CH), 127.3 (CH), 126.8 (d, J = 1.8 Hz, CH), 125.8 (C), 124.6 (CH), 119.8 (CH), 116.4 (CH), 115.5 (CH), 78.6 (q, J = 27.1, 26.5 Hz, C), 66.4 (CH), 56.5 (CH2), 20.9 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1624.
4-Benzyl-3-(1-(4-ethylphenyl)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ac)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 1-(4-ethylphenyl)-2,2,2-trifluoroethan-1-one (2c, 33 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ac was obtained as a mixture of diastereoisomers (53:47 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ac′ (13.6 mg, 0.03 mmol, 15% yield, yellow oil) and 3ac″ (12.1 mg, 0.03 mmol, 14% yield, yellow oil).
Characterization of 3ac′
1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.24–7.17 (m, 5H), 6.99 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H), 6.95–6.86 (m, 3H), 6.80 (td, J = 7.5, 1.4 Hz, 1H), 6.62 (dd, J = 7.8, 1.4 Hz, 1H), 4.69 (s, 1H), 4.56 (d, J = 15.7 Hz, 1H), 4.33 (s, 1H), 3.45 (d, J = 15.8 Hz, 1H), 2.68 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −73.29. 13C{1H} NMR (101 MHz, CDCl3) δ 165.4 (C), 145.1 (C), 136.4 (C), 133.2 (C), 132.0 (C), 128.8 (CH), 127.81 (CH), 127.77(CH), 127.4 (CH), 126.5 (CH), 124.7 (CH), 120.6 (CH), 116.9 (CH), 115.7 (CH), 79.4 (d, J = 26.3 Hz, C), 67.3 (CH), 57.3 (CH2), 28.5 (CH2), 15.4 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C25H24F3N2O2+ Calcd for 441.1784; Found 441.1791.
Characterization of 3ac″
1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.24–7.21 (m, 3H), 7.06 (dd, J = 7.4, 2.1 Hz, 2H), 6.93–6.86 (m, 3H), 6.76 (d, J = 8.1 Hz, 1H), 6.61 (td, J = 7.6, 1.3 Hz, 1H), 6.34 (dd, J = 7.8, 1.9 Hz, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.62 (s, 1H), 4.58 (s, 1H), 4.21 (d, J = 15.9 Hz, 1H), 2.51 (q, J = 7.6 Hz, 2H), 1.13 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.38. 13C{1H} NMR (101 MHz, CDCl3) δ 164.7 (C), 144.9 (C), 136.7 (C), 133.6 (C), 131.2 (C), 128.8 (CH), 127.7 (CH), 127.3 (CH), 127.2 (CH), 126.9 (q, J = 2.5 Hz, CH), 125.8 (C), 124.6 (CH), 119.8 (CH), 116.4 (CH), 115.4 (CH), 78.5 (q, J = 27.1 Hz, C), 66.5 (CH), 56.5 (CH2), 28.3 (CH2), 15.4 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C25H24F3N2O2+ Calcd for 441.1784; Found 441.1793.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-(4-methoxyphenyl)ethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ad)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(4-methoxyphenyl)ethan-1-one (2d, 31 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ad was obtained as a mixture of diastereoisomers (54:46 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ad′ (22.7 mg, 0.05 mmol, 27% yield, yellow oil) and 3ad″ (20.2 mg, 0.05 mmol, 23% yield, yellow oil).
Characterization of 3ad′
1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.23–7.18 (m, 3H), 7.04–6.89 (m, 6H), 6.81 (td, J = 7.5, 1.4 Hz, 1H), 6.63 (dd, J = 7.8, 1.4 Hz, 1H), 4.68 (s, 1H), 4.59 (d, J = 15.8 Hz, 1H), 4.32 (s, 1H), 3.81 (s, 3H), 3.52 (d, J = 15.8 Hz, 1H). 13C{1H} NMR (282 MHz, CDCl3) δ −73.56. 13C{1H} NMR (75 MHz, CDCl3) δ 165.4 (C), 160.0 (C), 136.4 (C), 133.1 (C), 128.8 (CH), 127.9 (CH), 127.8 (CH), 127.4 (CH), 126.7 (C), 126.5 (C), 125.2 (d, J = 287.5 Hz, CF3), 124.7 (CH), 120.7 (CH), 116.9 (CH), 115.8 (CH), 113.6 (CH), 79.19 (d, J = 27.6 Hz, C), 67.3 (CH), 57.4 (CH2), 55.2 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O3+ Calcd for 443.1577; Found 443.1574.
Characterization of 3ad″
1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.24–7.19 (m, 3H), 7.07 (dd, J = 7.3, 2.2 Hz, 2H), 6.92 (ddd, J = 8.1, 7.3, 1.4 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.70–6.57 (m, 3H), 6.38 (dd, J = 7.8, 1.4 Hz, 1H), 4.83 (d, J = 16.0 Hz, 1H), 4.66 (s, 1H), 4.62 (s, 1H), 4.24 (d, J = 16.0 Hz, 1H), 3.70 (s, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.63. 13C{1H} NMR (75 MHz, CDCl3) δ 164.9 (C), 159.8 (C), 136.7 (C), 133.6 (C), 130.9 (d, J = 283.6 Hz, CF3), 128.8 (CH), 128.3 (d, J = 2.2 Hz, CH), 127.8 (CH), 127.3 (CH), 125.9 (C), 125.7 (C), 124.7 (CH), 119.9 (CH), 116.4 (CH), 115.4 (CH), 113.0 (CH), 78.2 (d, J = 27.6 Hz, C), 66.5 (CH), 56.5 (CH2), 55.2 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O3+ Calcd for 443.1577; Found 443.1582.
4-Benzyl-3-(1-(4-chlorophenyl)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ae)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(4-chlorophenyl)ethan-1-one (2e, 30 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ae was obtained as a mixture of diastereoisomers (50:50 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ae′ (24.1 mg, 0.05 mmol, 27% yield, yellow oil) and 3ae″ (24.4 mg, 0.05 mmol, 27% yield, yellow oil).
Characterization of 3ae′
1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H)., 7.24–7.21 (M, 3H), 7.04–6.91 (m, 4H), 6.84 (ddd, J = 7.8, 7.1, 1.6 Hz, 1H), 6.57 (dd, J = 7.8, 1.4 Hz, 1H), 4.65 (s, 1H), 4.60 (d, J = 15.5 Hz, 1H), 4.32 (s, 1H), 3.60 (d, J = 15.6 Hz, 1H). 13C{1H} NMR (282 MHz, CDCl3) δ −73.70. 13C{1H} NMR (75 MHz, CDCl3) δ 165.0 (C), 136.0 (C), 135.1 (C), 133.2 (C), 132.8 (C), 128.9 (CH), 128.4 (CH), 128.0 (CH), 127.5 (CH), 126.8 (C), 124.9 (CH), 124.6 (q, J = 283.3 Hz, CF3), 121.4 (CH), 117.6 (CH), 115.9 (CH), 79.0 (d, J = 28.2 Hz, C), 66.9 (CH), 58.1 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19ClF3N2O2+ Calcd for 447.1082; Found 447.1088.
Characterization of 3ae″
1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.25 7.20 (m, 3H), 7.10–7.07 (m, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.94 (ddd, J = 8.1, 7.4, 1.4 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 6.68 (td, J = 7.7, 1.3 Hz, 1H), 6.35 (dd, J = 7.8, 1.4 Hz, 1H), 4.96–4.81 (m, 1H), 4.63 (s, 1H), 4.31 (d, J = 15.8 Hz, 1H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.60. 13C{1H} NMR (75 MHz, CDCl3) δ 164.7 (C), 136.4 (C), 135.0 (C), 133.3 (C), 132.6 (C), 128.9 (CH), 128.6 (d, J = 2.2 Hz, CH), 127.9 (CH), 127.7 (CH), 127.4 (CH), 125.5 (C), 125.0 (CH), 124.7 (q, J = 286.4 Hz, CF3), 120.3 (CH), 116.9 (CH), 115.5 (CH), 77.8 (d, J = 27.6 Hz, C), 66.3 (CH), 56.9 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19ClF3N2O2+ Calcd for 447.1082; Found 447.1085.
4-Benzyl-3-(1-(4-bromophenyl)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (3af)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one (2f, 30 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3af was obtained as a mixture of diastereoisomers (58:42 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3af′ (36.3 mg, 0.08 mmol, 37% yield, yellow oil) and 3af″ (26.4 mg, 0.05 mmol, 27% yield, yellow oil).
Characterization of 3af′
1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.63–7.38 (m, 4H), 7.24–7.21 (m, 3H), 7.07–6.92 (m, 4H), 6.87 (td, J = 7.5, 1.6 Hz, 1H), 6.58 (dd, J = 7.8, 1.4 Hz, 1H), 4.66 (s, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.34 (s, 1H), 3.63 (d, J = 15.5 Hz, 1H). 13C{1H} NMR (282 MHz, CDCl3) δ −73.68. 13C{1H} NMR (75 MHz, CDCl3) δ 165.0 (C), 136.0 (C), 133.7 (C), 132.8 (C), 131.3 (CH), 128.9 (CH), 128.3 (q, J = 1.8 Hz, CH), 128.0 (CH), 127.5 (CH), 126.9 (C), 124.9 (d, J = 286.9 Hz, CF3), 124.86 (CH), 123.4 (C), 121.5 (CH), 117.6 (CH), 115.9 (CH), 79.1 (q, J = 28.2 Hz, C), 66.8 (CH), 58.1 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19BrF3N2O2+ Calcd for 491.0577; Found 491.0570.
Characterization of 3af″
1H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.27–7.21 (m, 3H), 7.17 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.94 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 4.90 (d, J = 16.0 Hz, 1H), 4.85 (s, 1H), 4.63 (s, 1H), 4.34 (d, J = 15.9 Hz, 1H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.60. 13C{1H} NMR (75 MHz, CDCl3) δ 164.6 (C), 136.4 (C), 133.3 (C), 133.1 (C), 130.7 (CH), 128.9 (CH), 127.9 (CH), 127.4 (CH), 125.5 (C), 125.0 (CH), 123.4 (C), 120.4 (CH), 117.0 (CH), 115.5 (CH), 77.8 (d, J = 27.1 Hz), 66.3 (CH), 57.0 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19BrF3N2O2+ Calcd for 491.0577; Found 491.0572.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-(m-tolyl)ethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ag)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(m-tolyl)ethan-1-one (2g, 31 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ag was obtained as a mixture of diastereoisomers (58:42 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ag′ (24.8 mg, 0.06 mmol, 31% yield, yellow oil) and 3ag″ (19.6 mg, 0.05 mmol, 24% yield, yellow oil).
Characterization of 3ag′
1H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 7.40 (d, J = 10.2 Hz, 2H), 7.32–7.25 (m, 1H), 7.26–7.15 (m, 4H), 7.00 (td, J = 7.8, 7.4, 1.5 Hz, 1H), 6.96–6.87 (m, 3H), 6.81 (td, J = 7.6, 1.3 Hz, 1H), 6.62 (dd, J = 7.8, 1.1 Hz, 1H), 4.73 (s, 1H), 4.56 (d, J = 15.7 Hz, 1H), 4.34 (s, 1H), 3.45 (d, J = 15.8 Hz, 1H), 2.36 (s, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −73.13. 13C{1H} NMR (75 MHz, CDCl3) δ 165.5 (C), 138.0 (C), 136.3 (C), 134.7 (C), 133.2 (C), 129.7 (CH), 128.8 (CH), 128.1 (CH), 127.8 (CH), 127.4 (CH), 127.2 (q, J = 1.8 Hz, CH), 126.5 (C), 124.7 (CH), 123.6 (q, J = 2.8 Hz, CH), 120.7 (CH), 116.8 (CH), 115.8 (CH), 79.4 (q, J = 27.9 Hz, C), 67.3 (CH), 57.3 (CH2), 21.6 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1633.
Characterization of 3ag″
1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 7.41–7.17 (m, 5H), 7.14–7.04 (m, 2H), 7.03–6.89 (m, 3H), 6.83 (d, J = 7.8 Hz, 1H), 6.64 (td, J = 7.6, 1.3 Hz, 1H), 6.37 (dd, J = 7.8, 1.4 Hz, 1H), 4.85 (d, J = 16.0 Hz, 1H), 4.72 (s, 1H), 4.65 (s, 1H), 4.25 (d, J = 16.0 Hz, 1H), 2.08 (s, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.36. 13C{1H} NMR (75 MHz, CDCl3) δ 164.8 (C), 137.5 (C), 136.6 (C), 134.0 (C), 133.7 (C), 129.5 (CH), 128.8 (CH), 127.8 (CH), 127.6 (CH), 127.3 (CH), 126.1 (q, J = 281.4 Hz, CF3), 125.6 (C), 124.7 (CH), 123.9 (q, J = 1.8 Hz, CH), 119.9 (CH), 116.3 (CH), 115.3 (CH), 78.5 (q, J = 27.6 Hz, C), 66.5 (CH), 56.4 (q, J = 1.7 Hz, CH2), 21.3 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O2+ Calcd for 427.1628; Found 427.1621.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-(3-methoxyphenyl)ethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ah)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(3-methoxyphenyl)ethan-1-one (2h, 32 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ah was obtained as a mixture of diastereoisomers (53:47 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ah′ (23.1 mg, 0.05 mmol, 26% yield, yellow oil) and 3ah″ (20.6 mg, 0.05 mmol, 24% yield, yellow oil).
Characterization of 3ah′
1H NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.23–7.17 (m, 5H), 7.10–6.87 (m, 5H), 6.81 (td, J = 7.5, 1.4 Hz, 1H), 6.64 (dd, J = 7.8, 1.4 Hz, 1H), 4.83 (s, 1H), 4.59 (d, J = 15.7 Hz, 1H), 4.35 (s, 1H), 3.78 (s, 3H), 3.49 (d, J = 15.7 Hz, 1H). 13C{1H} NMR (282 MHz, CDCl3) δ −73.15. 13C{1H}NMR (75 MHz, CDCl3) δ 165.6 (C), 159.6 (C), 136.3 (C), 133.1 (C), 129.3 (CH), 128.8 (CH), 127.9 (CH), 127.4 (CH), 126.5 (C), 125.1 (q, J = 287.5 Hz, CF3), 124.8 (CH), 120.8 (CH), 118.9 (q, J = 2.2 Hz, CH), 116.9 (CH), 115.9 (CH), 114.6 (CH), 112.2 (q, J = 2.0 Hz, CH), 79.3 (q, J = 27.6 Hz, C), 67.2 (CH), 57.4 (CH2), 55.2 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O3+ Calcd for 443.1577; Found 443.1579.
Characterization of 3ah″
1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 7.25–7.15 (m, 3H), 7.09–7.00 (m, 5H), 6.92 (ddd, J = 8.7, 7.3, 1.5 Hz, 1H), 6.80 (dd, J = 8.1, 1.3 Hz, 1H), 6.74 (ddd, J = 7.7, 2.5, 1.4 Hz, 1H), 6.65 (td, J = 7.6, 1.3 Hz, 1H), 6.44 (dd, J = 7.8, 1.4 Hz, 1H), 4.81 (d, J = 16.0 Hz, 1H), 4.74 (s, 1H), 4.66 (s, 1H), 4.19 (d, J = 16.0 Hz, 1H), 3.60 (s, 3H). 13C{1H} NMR (282 MHz, CDCl3) δ −74.18. 13C{1H} NMR (75 MHz, CDCl3) δ 164.7 (C), 159.1 (C), 136.6 (C), 135.9 (C), 133.7 (C), 128.8 (CH), 128.8 (CH), 127.8 (CH), 127.3 (CH), 125.8 (C), 124.7 (CH), 119.9 (CH), 119.3 (q, J = 1.7 Hz, CH), 116.2 (CH), 115.5 (CH), 114.8 (CH), 112.5 (q, J = 1.7 Hz, CH), 78.7 (q, J = 27.6 Hz, C), 66.4 (CH), 56.4 (CH2), 55.0 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O3+ Calcd for 443.1577; Found 443.1583.
4-Benzyl-3-(1-(3-chlorophenyl)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ai)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one (2i, 29 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ai was obtained as a mixture of diastereoisomers (55:45 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ai′ (30.0 mg, 0.07 mmol, 33% yield, yellow oil) and 3ai″ (24.6 mg, 0.05 mmol, 28% yield, yellow oil).
Characterization of 3ai′
1H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.48 (t, J = 2.0 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.26–7.20 (m, 3H), 7.17–7.05 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.98–6.91 (m, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.66 (td, J = 7.7, 1.4 Hz, 1H), 6.37 (dd, J = 7.8, 1.3 Hz, 1H), 4.94 (s, 1H), 4.90 (d, J = 16.0 Hz, 1H), 4.64 (s, 1H), 4.31 (d, J = 16.0 Hz, 1H); 19F{1H} NMR (282 MHz, CDCl3) δ −74.58; 13C{1H} NMR (75 MHz, CDCl3) δ 164.6 (C), 136.4 (C), 136.1 (C), 135.5 (C), 134.0 (C), 133.3 (C), 129.0 (CH), 128.9 (CH), 128.8 (CH), 127.9 (CH), 127.7 (d, J = 2.2 Hz, CH), 127.4 (CH), 125.4 (C), 125.3 (q, J = 1.6 Hz, CH), 125.1 (CH), 124.6 (d, J = 285.8 Hz, CF3), 120.5 (CH), 117.0 (CH), 115.5 (CH), 77.8 (d, J = 27.6 Hz, C), 66.2 (CH), 57.0 (q, J = 1.7 Hz, CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19ClF3N2O2+ Calcd for 447.1082; Found 447.1085.
Characterization of 3ai″
1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 7.60 (t, J = 1.7 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.37 (dt, J = 8.0, 1.5 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.26–7.19 (m, 3H), 7.03 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.99–6.91 (m, 3H), 6.88–6.80 (m, 1H), 6.63 (dd, J = 7.8, 1.3 Hz, 1H), 4.78 (s, 1H), 4.61 (d, J = 15.5 Hz, 1H), 4.33 (s, 1H), 3.56 (d, J = 15.5 Hz, 1H);19F{1H} NMR (282 MHz, CDCl3) δ −73.52; 13C{1H} NMR (75 MHz, CDCl3) δ 165.1 (C), 136.7 (C), 135.9 (C), 134.5 (C), 132.8 (C), 129.4 (CH), 129.1 (CH), 128.9 (CH), 128.0 (CH), 127.5 (CH), 127.1 (d, J = 2.2 Hz, CH), 127.02 (d, J = 295.8 Hz, CF3), 126.7 (C), 124.9 (CH), 124.7 (d, J = 2.2 Hz, CH), 121.4 (CH), 117.6 (CH), 115.9 (CH), 78.9 (d, J = 28.2 Hz, C), 66.9 (CH), 58.1 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19ClF3N2O2+ Calcd for 447.1082; Found 447.1090.
4-Benzyl-3-(1-(3-bromophenyl)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (3aj)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 1-(3-bromophenyl)-2,2,2-trifluoroethan-1-one (2j, 30 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3aj was obtained as a mixture of diastereoisomers (54:46 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3aj′ (33.9 mg, 0.07 mmol, 35% yield, yellow oil) and 3aj″ (28.8 mg, 0.06 mmol, 29% yield, yellow oil).
Characterization of 3aj′
1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.53 (tdd, J = 7.9, 1.9, 1.0 Hz, 2H), 7.30–7.17 (m, 4H), 7.03 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 6.99–6.92 (m, 3H), 6.85 (td, J = 7.5, 1.5 Hz, 1H), 6.62 (dd, J = 7.8, 1.4 Hz, 1H), 4.80 (s, 1H), 4.61 (d, J = 15.5 Hz, 1H), 4.32 (d, J = 1.0 Hz, 1H), 3.55 (d, J = 15.6 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −73.48; 13C{1H} NMR (75 MHz, CDCl3) δ 165.1 (C), 136.9 (C), 135.9 (C), 132.8 (C), 132.1 (CH), 130.0 (q, J = 2.2 Hz, CH), 129.7 (CH), 128.9 (CH), 128.0 (CH), 127.6 (CH), 126.8 (C), 125.2 (q, J = 2.2 Hz, CH), 125.0 (CH), 122.6 (C), 121.4 (CH), 117.6 (CH), 115.9 (CH), 78.8 (q, J = 28.2 Hz, C), 66.9 (CH), 58.2 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19BrF3N2O2+ Calcd for 491.0577; Found 491.0580.
Characterization of 3aj″
1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.30 (dd, J = 1.9, 1.0 Hz, 1H), 7.25–7.20 (m, 4H), 7.08 (dd, J = 7.2, 2.3 Hz, 1H), 6.98–6.92 (m, 2H), 6.87 (dd, J = 7.9, 1.3 Hz, 1H), 6.67 (td, J = 7.5, 1.4 Hz, 1H), 6.38 (dd, J = 7.8, 1.4 Hz, 1H), 4.97 (s, 1H), 4.90 (d, J = 15.8 Hz, 1H), 4.64 (s, 1H), 4.30 (d, J = 15.9 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −74.53; 13C NMR (75 MHz, CDCl3) δ 164. (C), 136.39 (C), 136.36 (C), 133.3 (C), 131.9 (CH), 130.5 (q, J = 2.2 Hz, CH), 129.0 (CH), 128.9 (CH), 127.9 (CH), 127.4 (CH), 125.7 (q, J = 1.8 Hz, CH), 125.5 (C), 125.2 (CH), 124.6 (q, J = 286.4 Hz, CF3), 122.1 (C), 120.5 (CH), 116.9 (CH), 115.6 (CH), 77.7 (q, J = 27.6 Hz, C), 66.1 (CH), 57.0 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19BrF3N2O2+ Calcd for 491.0577; Found 491.05781.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-(2-methoxyphenyl)ethyl)-3,4-dihydroquinoxalin-2(1H)-one (3ak)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(2-methoxyphenyl)ethan-1-one (2k, 32 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3ak was obtained as a mixture of diastereoisomers (59:41 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3ak′ + 3ak″ (32.7 mg, 0.07 mmol, 37% yield, yellow oil). Representative NMR signals for either the major and the minor diastereoisomer are labeled with one or two asterisks, respectively.
1H NMR (300 MHz, CDCl3) δ 9.36 (s, 1H*), 9.17 (s, 1H**), 7.49–7.46 (m, 2H), 7.37 (ddd, J = 8.8, 7.4, 1.6 Hz, 1H), 7.33–7.10 (m, 10H), 7.05–6.79 (m, 10H), 6.76–6.68 (m, 2H), 6.63 (dd, J = 7.7, 1.5 Hz, 1H*), 6.61–6.51 (m, 2H), 6.02 (s, 1H**), 4.96 (d, J = 15.8 Hz, 1H**), 4.75 (s, 1H*), 4.46 (d, J = 16.0 Hz, 1H*), 4.40 (d, J = 15.5 Hz, 1H**), 3.84 (d, J = 15.5 Hz, 1H*), 3.72 (s, 3H*), 3.63 (s, 3H**); 13C{1H} NMR (282 MHz, CDCl3) δ −72.60 *, −74.25**; 13C{1H} NMR (75 MHz, CDCl3) δ 163.8 (C**), 163.2 (C*), 158.0 (C*), 157.7 (C*), 137.0 (C**), 136.8 (C*), 135.8 (C*), 134.9 (C**), 134.1 (C**), 133.9 (C*), 130.3 (CH), 130.2 (CH), 128.7 (CH), 128.6 (CH), 128.54 (CH), 128.51 (CH), 128.46 (CH), 127.53 (CH), 127.48 (CH), 127.4 (CH), 123.9 (CH), 123.5 (CH), 122.9 (C), 121.5 (CH), 121.0 (CH), 120.7 (C), 119.40 (CH), 119.38 (CH), 115.3 (CH), 115.2 (CH), 112.4 (CH), 112.2 (CH), 83.7 (d, J = 27.1 Hz, C*), 83.3 (d, J = 26.5 Hz, C**), 66.51 (CH*), 66.48 (CH**), 55.96 (CH2), 55.94 (CH3**), 55.86 (CH3*); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H22F3N2O3+ Calcd for 443.1577; Found 443.1589.
4-Benzyl-3-(1-(3,4-dichlorophenyl)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (3al)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 1-(3,4-dichlorophenyl)-2,2,2-trifluoroethan-1-one (2l, 32 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3al (41.2 mg, 0.09 mmol, 43% yield, yellow oil) was obtained as a mixture of diastereoisomers (57:43 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3al′ (23.4 mg, 0.05 mmol, 25% yield, yellow oil) and 3al″ (17.8 mg, 0.04 mmol, 18% yield, yellow oil).
Characterization of 3al′
1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 7.68 (t, J = 1.2 Hz, 1H), 7.42 (t, J = 1.1 Hz, 2H), 7.25–7.23 (m, 3H), 7.09–6.95 (m, 4H), 6.88 (ddd, J = 7.8, 7.0, 1.8 Hz, 1H), 6.60 (dd, J = 7.8, 1.4 Hz, 1H), 4.69 (s, 1H), 4.64 (d, J = 15.4 Hz, 1H), 4.33 (s, 1H), 3.71 (d, J = 15.4 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −73.87; 13C{1H} NMR (75 MHz, CDCl3) δ 164.7 (C), 135.7 (C), 134.8 (C), 133.3 (C), 132.6 (C), 132.6 (C), 130.0 (CH), 129.0 (q, J = 1.9 Hz, CH), 128.9 (CH), 128.2 (CH), 127.6 (CH), 127.0 (C), 125.94 (q, J = 1.8 Hz, CH), 125.91 (q, J = 274.5 Hz, CF3), 125.0 (CH), 121.9 (CH), 118.1 (CH), 115.9 (CH), 78.5 (q, J = 28.2 Hz, C), 66.7 (CH), 58.7 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H18Cl2F3N2O2+ Calcd for 481.0692; Found 481.0699.
Characterization of 3al″
1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.26–7.21 (m, 3H), 7.14–7.06 (m, 3H), 6.97 (ddd, J = 8.6, 7.2, 1.4 Hz, 1H), 6.91–6.86 (m, 1H), 6.70 (td, J = 7.6, 1.4 Hz, 1H), 6.36 (dd, J = 7.8, 1.4 Hz, 1H), 5.02 (s, 1H), 4.93 (d, J = 15.9 Hz, 1H), 4.63 (s, 1H), 4.37 (d, J = 15.8 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −74.83; 13C{1H} NMR (75 MHz, CDCl3) δ 164.4 (C), 136.3 (C), 134.2 (C), 133.2 (C), 133.2 (C), 132.1 (C), 129.7 (q, J = 2.2 Hz, CH), 129.4 (CH), 128.9 (CH), 128.0 (CH), 127.4 (CH), 126.6 (q, J = 2.2 Hz, CH), 125.31 (CH), 125.28 (C), 120.7 (CH), 117.3 (CH), 115.4 (CH), 77.2 (q, J = 32.1 Hz, C), 66.1 (CH), 57.3 (d, J = 1.7 Hz, CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H18Cl2F3N2O2+ Calcd for 481.0692; Found 481.0697.
4-Benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-(thiophen-2-yl)ethyl)-3,4-dihydroquinoxalin-2(1H)-one (3am)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 2,2,2-trifluoro-1-(thiophen-2-yl)ethan-1-one (2m, 26 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3am was obtained as a mixture of diastereoisomers (58:42 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3am′ (25.1 mg, 0.06 mmol, 30% yield, yellow oil) and 3am″ (18.4 mg, 0.04 mmol, 22% yield, yellow oil).
Characterization of 3am′
1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.38 (dd, J = 5.1, 1.2 Hz, 1H), 7.24–7.17 (m, 4H), 7.06 (dd, J = 5.1, 3.7 Hz, 1H), 7.03–6.92 (m, 4H), 6.84 (ddd, J = 7.8, 6.8, 1.9 Hz, 1H), 6.67 (dd, J = 7.7, 1.3 Hz, 1H), 5.37 (s, 1H), 4.64 (d, J = 15.7 Hz, 1H), 4.34 (s, 1H), 3.47 (d, J = 15.7 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −75.61; 13C{1H} NMR (101 MHz, CDCl3) δ 166.0 (C), 138.8 (C), 136.2 (C), 133.0 (C), 128.80 (CH), 127.96 (CH), 127.5 (CH), 126.7 (CH), 126.53 (q, J = 2.2 Hz, CH), 126.4 (C), 124.9 (CH), 124.5 (q, J = 286.9 Hz, CF3), 121.2 (CH), 117.9 (CH), 115.8 (CH), 78.5 (q, J = 29.3 Hz, C), 67.4 (CH), 58.2 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C21H18F3N2O2S+ Calcd for 419.1036; Found 419.1039.
Characterization of 3am″
1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 7.29–7.18 (m, 4H), 7.16–7.05 (m, 3H), 7.02–6.87 (m, 1H), 6.82 (dt, J = 3.6, 1.1 Hz, 1H), 6.73–6.61 (m, 2H), 6.39 (dd, J = 7.8, 1.3 Hz, 1H), 5.41 (s, 1H), 4.98 (d, J = 16.1 Hz, 1H), 4.66 (s, 1H), 4.39 (d, J = 16.0 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −76.67; 13C{1H} NMR (101 MHz, CDCl3) δ 165.1 (C), 138.0 (C), 137.9 (C), 136.6 (C), 133.5 (C), 129.1 (CH), 128.9 (CH), 127.9 (CH), 127.3 (CH), 127.1 (CH), 126.7 (CH), 125.0 (CH), 120.1 (CH), 116.9 (CH), 115.4 (CH), 78.5 (q, J = 29.6 Hz, C), 66.2 (CH), 56.7 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C21H18F3N2O2S+ Calcd for 419.1036; Found 419.1037.
3-(1-(4-Chlorophenyl)-2,2,2-trifluoro-1-hydroxyethyl)-4-(4-methoxybenzyl)-3,4-dihydroquinoxalin-2(1H)-one (3cd)
Using 4-(4-methoxybenzyl)-3,4-dihydroquinoxalin-2(1H)-one (1c, 69.8 mg, 0.26 mmol, 1.3 equiv) and 1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-one (2d, 30 μL, 0.2 mmol, 1 equiv), according to GP-1, compound 3cd was obtained as a mixture of diastereoisomers (60:40 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 3cd′ (35.3 mg, 0.07 mmol, 37% yield, yellow oil) and 3cd″ (23.7 mg, 0.05 mmol, 25% yield, yellow oil).
Characterization of 3cd′
1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.9 Hz, 1H), 7.07–6.95 (m, 2H), 6.92–6.84 (m, 3H), 6.75 (d, J = 8.7 Hz, 1H), 6.56 (dd, J = 7.7, 1.3 Hz, 1H), 4.71 (s, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.31 (s, 1H), 3.73 (s, 3H), 3.58 (d, J = 15.2 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −73.81; 13C{1H} NMR (75 MHz, CDCl3) δ 165.1 (C), 159.3 (C), 135.0 (C), 133.2 (C), 132.9 (C), 129.0 (CH), 128.3 (CH), 127.8 (C), 127.1 (C), 124.9 (q, J = 272.0 Hz, CF3), 124.8 (CH), 121.5 (CH), 118.0 (CH), 115.8 (CH), 114.2 (CH), 78.8 (q, J = 28.2 Hz, C), 66.3 (CH), 58.0 (CH2), 55.2 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H21ClF3N2O3+ Calcd for 477.1187; Found 477.1192.
Characterization of 3cd″
1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 6.5 Hz, 2H), 6.99 (d, J = 6.0 Hz, 2H), 6.97–6.81 (m, 2H), 6.77 (d, J = 8.7 Hz, 2H), 6.69 (td, J = 7.6, 1.3 Hz, 1H), 6.32 (dd, J = 7.8, 1.4 Hz, 1H), 4.88 (s, 1H), 4.80 (d, J = 15.5 Hz, 1H), 4.60 (s, 1H), 4.23 (d, J = 15.6 Hz, 1H), 3.74 (s, 3H); 19F{1H} NMR (282 MHz, CDCl3) δ −72.34; 13C{1H} NMR (75 MHz, CDCl3) δ 164.7 (C), 159.3 (C), 135.0 (C), 133.5 (C), 132.6 (C), 128.8 (CH), 128.6 (q, J = 2.2 Hz, CH), 128.3 (C), 127.7 (CH), 125.7 (C), 124.9 (CH), 120.4 (CH), 117.3 (CH), 115.4 (CH), 114.2 (CH), 77.72 (q, J = 27.6 Hz, C), 65.9 (CH), 56.8 (CH2), 55.2 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C24H21ClF3N2O3+ Calcd for 477.1187; Found 477.1189.
Ethyl 3-(1-benzyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-4,4,4-trifluoro-3-hydroxybutanoate (3an)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and ethyl 4,4,4-trifluoro-3-oxobutanoate (2n, 29 uL, 0.2 mmol, 1 equiv), according to GP-1, compound 3an was obtained as a mixture of diastereoisomers (55:45 dr) that cannot be separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:22): 3an′ + 3an″ (16.9 mg, 0.04 mmol, 20% yield, yellow oil).
1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 8.25 (s, 1H), 7.32–7.19 (m, 6H), 7.17–7.12 (m, 4H), 7.00–6.95 (m, 2H), 6.93–6.86 (m, 2H), 6.85–6.79 (m, 2H), 6.74–6.69 (m, 2H), 5.80 (s, 1H), 5.46 (s, 1H), 4.91–4.84 (m, 2H), 4.58–4.43 (m, 3H), 4.34 (s, 1H), 4.26–4.02 (m, 4H), 3.07 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.4 Hz, 1H), 2.76 (d, J = 16.3 Hz, 1H), 2.66 (d, J = 16.4 Hz, 1H), 1.29–1.21 (m, 6H); 19F{1H} NMR (282 MHz, CDCl3) δ −77.50, −77.68; 13C{1H} NMR (75 MHz, CDCl3) δ 171.7 (C), 171.5 (C), 163.8 (C), 163.2 (C), 136.7 (C), 136.5 (C), 133.8 (C), 133.0 (C), 128.7 (CH), 128.7 (CH), 127.8 (CH), 127.7 (CH), 127.7 (CH), 127.5 (CH), 127.1 (C), 127.0 (C), 124.4 (CH), 124.4 (CH), 120.6 (CH), 120.2 (CH), 117.2 (CH), 116.6 (CH), 115.3 (CH), 115.1 (CH), 65.1 (CH), 64.8 (CH), 61.7 (CH2), 61.7 (CH2), 57.9 (CH2), 56.9 (CH2), 35.2 (q, J = 1.7 Hz, CH2), 33.9 (CH2), 13.91 (CH3), 13.85 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C21H22F3N2O4+ Calcd for 423.1526; Found 423.1527.
4-(1-(1-Benzyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)phenyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (3ao)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 62 mg, 0.26 mmol, 1.3 equiv) and 4-(2,2,2-trifluoroacetyl)phenyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (2o, 106 mg, 0.2 mmol, 1 equiv), according to GP-1, compound 3ao was obtained as a mixture of diastereoisomers (55:45 dr) that were separated by column chromatography using DCM:EtOAc mixtures (from 99:1 to 95:5): 3ao′ (54.1 mg, 0.07 mmol, 35% yield, yellow oil) and 3ao″ (44.2 mg, 0.06 mmol, 29% yield, yellow oil).
Characterization of 3ao′
1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.23–7.16 (m, 3H), 7.09 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 2.5 Hz, 1H), 7.03–6.95 (m, 1H), 6.94–6.86 (m, 4H), 6.80 (td, J = 7.5, 1.5 Hz, 1H), 6.71 (dd, J = 9.0, 2.5 Hz, 1H), 6.61 (dd, J = 7.8, 1.3 Hz, 1H), 4.82 (s, 1H), 4.56 (d, J = 15.6 Hz, 1H), 4.29 (s, 1H), 3.92 (s, 2H), 3.84 (s, 3H), 3.48 (d, J = 15.6 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (282 MHz, CDCl3) δ −73.95; 13C{1H} NMR (75 MHz, CDCl3) δ 169.0 (C), 168.3 (C), 165.0 (C), 156.1 (C), 151.1 (C), 139.4 (C), 136.3 (C), 136.0 (C), 133.8 (C), 133.0 (C), 132.4 (C), 131.2 (CH), 130.9 (C), 130.5 (C), 129.2 (CH), 128.8 (CH), 127.9 (CH), 127.9 (q, JC–F = 1.5 Hz, CH), 127.5 (CH), 126.6 (C), 124.8 (CH), 121.2 (CH), 121.2 (CH), 117.4 (CH), 115.8 (CH), 115.0 (CH), 111.8 (C), 111.7 (CH), 101.3 (CH), 78.9 (q, JC–F = 28.2 Hz, C), 67.0 (CH), 57.9 (CH2), 55.8 (CH3), 30.6 (CH2), 13.4 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C42H34ClF3N3O6+ Calcd for 768.2083; Found 768.2099.
Characterization of 3ao″
1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.53–7.36 (m, 4H), 7.25–7.14 (m, 3H), 7.10–7.03 (m, 2H), 7.00 (d, J = 2.5 Hz, 1H), 6.94–6.83 (m, 2H), 6.82–6.74 (m, 3H), 6.69 (dd, J = 9.0, 2.5 Hz, 1H), 6.60 (td, J = 7.6, 1.3 Hz, 1H), 6.35 (dd, J = 7.8, 1.3 Hz, 1H), 4.89–4.77 (m, 2H), 4.61 (s, 1H), 4.25 (d, J = 15.9 Hz, 1H), 3.85 (s, 2H), 3.83 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (282 MHz, CDCl3) δ −74.88; 13C{1H} NMR (75 MHz, CDCl3) δ 168.8 (C), 168.3 (C), 164.6 (C), 156.1 (C), 151.0 (C), 139.4 (C), 136.5 (C), 136.2 (C), 133.8 (C), 133.3 (C), 131.8 (C), 131.2 (CH), 130.8 (C), 130.4 (C), 129.2 (CH), 128.8 (CH), 128.3 (d, JC–F = 1.4 Hz, CH), 127.8 (CH), 127.3 (CH), 125.6 (C), 124.8 (CH), 120.5 (CH), 120.2 (CH), 116.5 (CH), 115.6 (CH), 115.0 (CH), 111.8 (C), 111.6 (CH), 101.3 (CH), 78.1 (d, JC–F = 27.4 Hz, C), 66.5 (CH), 56.6 (CH2), 55.7 (CH3), 30.5 (CH2), 13.4 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C42H34ClF3N3O6+ Calcd for 768.2083; Found 768.2102.
Ethyl 2-(1-Benzyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate (5)
Using 4-benzyl-3,4-dihydroquinoxalin-2(1H)-one (1a, 23.8 mg, 0.1 mmol, 1 equiv) and ethyl 3,3,3-trifluoropyruvate (4, 17 μL, 0.13 mmol, 1.3 equiv), according to SP-1, compound 5 was obtained as a mixture of diastereoisomers (54:46 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 5′ (5.5 mg, 0.014 mmol, 14% yield, yellow oil) and 5″ (4.7 mg, 0.011 mmol, 11% yield, yellow oil).
Characterization of 5′
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.26–7.22 (m, 3H), 7.07 (dd, J = 7.2, 2.4 Hz, 2H), 7.01–6.83 (m, 3H), 6.72 (dd, J = 7.9, 1.6 Hz, 1H), 4.63 (d, J = 15.1 Hz, 1H), 4.57 (s, 1H), 4.53–4.36 (m, 1H), δ 4.29–4.16 (m, 1H), 4.19 (d, J = 15.0 Hz, 1H), 3.78 (s, 1H), 1.35 (t, J = 7.2 Hz, 3H);19F{1H} NMR (282 MHz, CDCl3) δ −73.97; 13C{1H} NMR (75 MHz, CDCl3) δ 167.95 (q, J = 1.1 Hz, C), 161.8 (C), 136.1 (C), 133.2 (C), 129.2 (C), 128.7 (CH), 128.0 (CH), 127.8 (CH), 125.6 (d, J = 266.5 Hz, CF3), 124.0 (CH), 121.9 (CH), 119.1 (CH), 115.6 (CH), 81.3 (q, J = 29.3 Hz, C), 64.3 (CH2), 63.6 (CH), 59.3 (CH2), 13.9 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C20H20F3N2O4+ Calcd for 409.1370; Found 409.1373.
Characterization of 5″
1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 7.25–7.21 (m, 2H), 7.15 (dd, J = 7.9, 1.7 Hz, 2H), 6.99-6.84 (m, 3H), 6.79 (td, J = 7.5, 1.4 Hz, 1H), 6.70 (dd, J = 7.8, 1.5 Hz, 1H), 4.94 (d, J = 15.9 Hz, 1H), 4.77 (s, 1H), 4.50–4.18 (m, 4H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (282 MHz, CDCl3) δ −73.71; 13C{1H} NMR (75 MHz, CDCl3) δ 167.7 (C), 163.8 (C), 136.7 (C), 133.2 (C), 128.7 (CH), 127.6 (CH), 127.3 (CH), 127.1 (C), 124.3 (CH), 120.1 (CH), 116.3 (CH), 115.0 (CH), 79.8 (q, J = 28.7 Hz, C), 65.4 (CH), 64.6 (CH2), 56.0 (q, J = 1.7 Hz, CH2), 13.7 (CH3); HRMS (ESI/Q-TOF) m/z [M + H]+ C20H20F3N2O4+ Calcd for 409.1370; Found 409.1378.
1-(1-Benzyl-1,2,3,4-tetrahydroquinoxalin-2-yl)-2,2,2-trifluoro-1-phenylethan-1-ol (6)
Using 4-benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3aa, 78.4 mg, 0.19 mmol, 1 equiv), according to SP-4, compound 6 was obtained as a mixture of diastereoisomers (52:48 dr) that were separated by column chromatography using hexane:EtOAc mixtures (from 95:5 to 75:25): 6′ (27.8 mg, 0.068 mmol, 36% yield, yellow oil) and 6″ (25.7 mg, 0.062 mmol, 34% yield, yellow oil).
Characterization of 6′
1H NMR (300 MHz, CDCl3) δ 7.62 (dd, J = 6.4, 2.8 Hz, 2H), 7.52–7.33 (m, 4H), 7.22–7.08 (m, 3H), 6.90 (dd, J = 7.4, 2.2 Hz, 2H), 6.79–6.67 (m, 2H), 6.60 (td, J = 7.5, 1.2 Hz, 1H), 6.49 (dd, J = 8.3, 1.0 Hz, 1H), 4.11 (d, J = 17.1 Hz, 1H), 4.07–3.97 (m, 2H), 3.32–3.21 (m, 1H), 3.01 (d, J = 17.1 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −71.82; 13C{1H} NMR (75 MHz, CDCl3) δ 137.8 (C), 137.5 (C), 135.3 (C), 130.4 (C), 128.4 (CH), 128.3 (CH), 128.2 (CH), 126.90 (CH), 126.88 (CH), 126.3 (CH), 126.2 (q, J = 289.7 Hz, CF3), 122.2 (CH), 116.7 (CH), 116.0 (CH), 112.9 (CH), 82.5 (d, J = 25.4 Hz, C), 60.1 (CH), 54.0 (CH2), 42.6 (q, J = 2.2 Hz, CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H22F3N2O+ Calcd for 399.1679; Found 399.1677.
Characterization of 6″
1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.53–7.37 (m, 4H), 7.34–7.20 (m, 5H), 6.88–6.78 (m, 2H), 6.74–6.56 (m, 2H), 5.12 (d, J = 17.1 Hz, 1H), 4.57 (d, J = 17.1 Hz, 1H), 4.19 (dd, J = 3.5, 1.7 Hz, 1H), 3.02 (dd, J = 11.2, 1.7 Hz, 1H), 2.91 (dd, J = 11.2, 3.4 Hz, 1H);19F{1H} NMR (282 MHz, CDCl3) δ −72.58; 13C{1H} NMR (75 MHz, CDCl3) δ 138.4 (C), 137.6 (C), 134.5 (C), 129.8 (C), 128.7 (CH), 128.62 (CH), 128.56 (CH), 127.3 (CH), 127.2 (CH), 126.2 (q, J = 1.4 Hz, CH), 122.4 (CH), 117.2 (CH), 116.3 (CH), 113.8 (CH), 81.5 (q, J = 27.1 Hz, C), 59.2 (CH), 54.6 (q, J = 3.3 Hz, CH2), 41.0 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H22F3N2O+ Calcd for 399.1679; Found 399.1675.
4-Benzyl-3-(1-chloro-2,2,2-trifluoro-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (7)
Using 4-benzyl-3-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)-3,4-dihydroquinoxalin-2(1H)-one (3aa, 26.9 mg, 0.05 mmol, 1 equiv), according to SP-5, compound 7 was obtained as a mixture of diastereoisomers (50:50 dr) that were separated by column chromatography using hexane:Et2O mixtures (from 5:5 to 2:8): 7′ (11.3 mg, 0.025 mmol, 40% yield, yellow oil) and 7″ (11.5 mg, 0.025 mmol, 40% yield, yellow oil).
Characterization of 7′
1H NMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 7.67 (d, J = 6.5 Hz, 2H), 7.46–7.35 (m, 3H), 7.22–7.12 (m, 3H), 6.98–6.84 (m, 3H), 6.77 (td, J = 7.6, 1.2 Hz, 1H), 6.71–6.62 (m, 2H), 4.86 (s, 1H), 4.32 (d, J = 15.8 Hz, 1H), 3.42 (d, J = 15.9 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −67.14; 13C{1H} NMR (75 MHz, CDCl3) δ 161.0 (C), 136.3 (C), 133.4 (C), 133.3 (C), 129.5 (CH), 128.7 (CH), 128.4 (CH), 127.9 (q, J = 2.2 Hz, CH), 127.7 (CH), 127.3 (C), 127.2 (CH), 124.1 (CH), 124.0 (q, J = 284.7 Hz, CF3), 120.1 (CH), 116.1 (CH), 115.4 (CH), 77.1 (q, J = 27.7 Hz, C), 67.9 (CH), 56.4 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19ClF3N2O+ Calcd for 431.1133; Found 431.1136.
Characterization of 7″
1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.45–7.20 (m, 6H), 7.14 (dd, J = 7.6, 1.7 Hz, 2H), 6.97 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.82–6.71 (m, 1H), 6.46 (dd, J = 7.7, 1.2 Hz, 1H), 5.01 (d, J = 15.7 Hz, 1H), 5.00 (s, 1H), 4.48 (d, J = 15.7 Hz, 1H); 13C{1H} NMR (282 MHz, CDCl3) δ −69.14; 13C{1H} NMR (101 MHz, CDCl3) δ 161.1 (C), 136.5 (C), 133.3 (C), 132.5 (C), 129.2 (CH), 128.9 (CH), 128.1 (CH), 127.9 (CH), 127.7 (q, J = 2.0 Hz, CH), 127.5 (CH), 127.2 (C), 124.2 (CH), 120.3 (CH), 116.4 (CH), 115.0 (CH), 68.2 (CH), 56.9 (CH2); HRMS (ESI/Q-TOF) m/z [M + H]+ C23H19ClF3N2O+ Calcd for 431.1133; Found 431.1132.
1,1′-Dibenzyl-1,1′,4,4′-tetrahydro-[2,2′-biquinoxaline]-3,3′(2H,2′H)-dione (8)
In low-yielding reactions, a large amount of dimeric dihydroquinoxalin-2-one (8) was obtained. It was isolated as a single diasteromer by removing the mother liquor and washing the solid with DCM. The presence of this dimeric specie is consistent with the generation of the α-aminoradical under our photoredox conditions.
1H NMR (300 MHz, DMSO-d6) δ 10.68 (bs, 2H), 7.25–7.11 (m, 6H), 7.07–6.96 (m, 4H), 6.88 (dd, J = 7.3, 1.9 Hz, 2H), 6.79–6.63 (m, 4H), 6.41 (dd, J = 7.5, 1.7 Hz, 2H), 4.65 (d, J = 15.7 Hz, 2H), 4.02 (d, J = 15.8 Hz, 2H), 3.94 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 164.4 (C), 137.5 (C), 132.4 (C), 128.4 (CH), 127.2 (CH), 127.1 (CH), 127.0 (C), 123.0 (CH), 118.7 (CH), 115.0 (CH), 114.1 (CH), 63.2 (CH), 53.2 (CH2); HRMS (ESI-QTOF) m/z [M + H]+ C30H27N4O2 Calcd for 475.2129; Found 475.2133.
Acknowledgments
Financial support from grant PID2020-116944GB funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” and AICO/2020/68 funded by Conselleria d′Innovació, Universitat, Ciència i Societat Digital are acknowledged. J.R.-B. thanks the Ministerio de Ciencia, Innovación y Universidades for a FPU predoctoral contract (FPU17/00688). C. V. thanks the RyC contract (RYC-2016-20187) funded by MCIN/AEI/10.13039/501100011033 and by “European Union NextGenerationEU/PRTR”. Access to NMR, MS, and X-ray facilities from the Servei Central de Suport a la Investigació Experimental (SCSIE)-UV is also acknowledged.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c01139.
1H, 19F, and 13C NMR spectra for all compounds. FAIR Data is available as Supporting Information for Publication and includes the primary NMR FID files for Compounds 3, 5, 6, 7, and 8 (PDF)
FAIR data, including the primary NMR FID files, for compounds 2o, 3aa, 3ab, 3ac, 3ad, 3ae, 3af, 3ag, 3ah, 3ai, 3aj, 3ak, 3al, 3am, 3an, 3ao, 3ba, 3ca, 3cd, 3da, 3ea, 3fa(1), 3ga, 3ha, 3ia, 3la, 5, 6, 7 (ZIP)
The authors declare no competing financial interest.
Supplementary Material
References
- a Purser S.; Moore P. R.; Swallow S.; Gouverneur V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320–330. 10.1039/B610213C. [DOI] [PubMed] [Google Scholar]; b Hagmann W. K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359–4369. 10.1021/jm800219f. [DOI] [PubMed] [Google Scholar]; c Prakash G. K. S.; Wang F. Fluorine: The New Kingpin of Drug Discovery. Chim. Oggi 2012, 30, 30–36. [Google Scholar]; d Wang J.; Sánchez-Roselló M.; Aceña J. L.; del Pozo C.; Sorochinsky A. E.; Fustero S.; Soloshonok V. A.; Liu H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011). Chem. Rev. 2014, 114, 2432–2506. 10.1021/cr4002879. [DOI] [PubMed] [Google Scholar]; e Inoue M.; Sumii Y.; Shibata N. Contribution of Organofluorine Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633–10640. 10.1021/acsomega.0c00830. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Wang Q.; Song H.; Wang Q. Fluorine-containing agrochemicals in the last decade and approaches for fluorine incorporation. Chin. Chem. Lett. 2022, 33, 626–642. 10.1016/j.cclet.2021.07.064. [DOI] [Google Scholar]
- a Hiyama T.Organofluorine Compounds. Chemistry and Applications; Springer: New York, 2000. [Google Scholar]
- Kelly C. B.; Mercadante M. A.; Leadbeater N. E. Trifluoromethyl ketones: properties, preparation, and application. Chem. Commun. 2013, 49, 11133–11148. 10.1039/c3cc46266h. [DOI] [PubMed] [Google Scholar]
- a Xie J.; Jin H.; Hashmi A. S. K. The recent achievements of redox-neutral radical C–C cross-coupling enabled by visible-light. Chem. Soc. Rev. 2017, 46, 5193–5203. 10.1039/C7CS00339K. [DOI] [PubMed] [Google Scholar]; b Xia Q.; Dong J.; Song H.; Wang Q. Visible-Light Photocatalysis of the Ketyl Radical Coupling Reaction. Chem.—Eur. J. 2018, 25, 2949–2961. 10.1002/chem.201804873. [DOI] [PubMed] [Google Scholar]
- Wang C.; Qin J.; Shen X.; Riedel R.; Harms K.; Meggers E. Asymmetric Radical-Radical Cross-Coupling through Visible-Light-Activated Iridium Catalysis. Angew. Chem., Int. Ed. 2016, 55, 685–688. 10.1002/anie.201509524. [DOI] [PubMed] [Google Scholar]
- Xia Q.; Tian H.; Dong J.; Qu Y.; Li L.; Song H.; Liu Y.; Wang Q. N-Arylamines Coupled with Aldehydes, Ketones, and Imines by Means of Photocatalytic Proton-Coupled Electron Transfer. Chem.—Eur. J. 2018, 24, 9269–9273. 10.1002/chem.201801886. [DOI] [PubMed] [Google Scholar]
- Vu M. D.; Das M.; Guo A.; Ang Z.-E.; Dokić M.; Soo H. S.; Liu X.-W. Visible-Light Photoredox Enables Ketone Carbonyl Alkylation for Easy Access to Tertiary Alcohols. ACS Catal. 2019, 9, 9009–9014. 10.1021/acscatal.9b02401. [DOI] [Google Scholar]
- Ota K.; Nagao K.; Ohmiya H. Synthesis of Sterically Hindered α-Hydroxycarbonyls through Radical-Radical Coupling. Org. Lett. 2021, 23, 4420–4425. 10.1021/acs.orglett.1c01358. [DOI] [PubMed] [Google Scholar]
- a For other reactions using trifluoromethyl ketones under visible-light irradiation, see:Castro L. C. M.; Bezier D.; Sortais J.-B.; Darcel C. Iron Dihydride Complex as the Pre-catalyst for Efficient Hydrosilylation of Aldehydes and Ketones Under Visible Light Activation. Adv. Synth. Catal. 2011, 353, 1279–1284. 10.1002/adsc.201000676. [DOI] [Google Scholar]; b Bézier D.; Jiang F.; Roisnel T.; Sortais J.-B.; Darcel C. Cyclopentadienyl-NHC Iron Complexes for Solvent-Free Catalytic Hydrosilylation of Aldehydes and Ketones. Eur. J. Inorg. Chem. 2012, 2012, 1333–1337. 10.1002/ejic.201100762. [DOI] [Google Scholar]; c Xu X.; Min Q.-Q.; Li N.; Liu F. Visible light-promoted umpolung coupling of aryl tri-/difluoroethanones with 2-alkenylpyridines. Chem. Commun. 2018, 54, 11017–11020. 10.1039/C8CC06748A. [DOI] [PubMed] [Google Scholar]; d Mavroskoufis A.; Rajes K.; Golz P.; Agrawal A.; Ruß V.; Götze J. P. N.; Hopkinson M. N. N-Heterocyclic Carbene Catalyzed Photoenolization/Diels-Alder Reaction of Acid Fluorides. Angew. Chem., Int. Ed. 2020, 59, 3190–3194. 10.1002/anie.201914456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Rösner M.; Billhardt-Troughton U.-M.; Kirsh R.; Kleim J.- P.; Meichsner C.; Riess G.; Winkler I. U.S. Patent 5,723,461, 1998.; b Ren J.; Nichols C. E.; Chamberlain P. P.; Weaver K. L.; Short S. A.; Chan J. H.; Kleim J.-P.; Stammers D. K. Relationship of Potency and Resilience to Drug Resistant Mutations for GW420867X Revealed by Crystal Structures of Inhibitor Complexes for Wild-Type, Leu100Ile, Lys101Glu, and Tyr188Cys Mutant HIV-1 Reverse Transcriptases. J. Med. Chem. 2007, 50, 2301–2309. 10.1021/jm061117m. [DOI] [PubMed] [Google Scholar]; c Cass L. M.; Moore K. H. P.; Dallow N. S.; Jones A. E.; Sisson J. R.; Prince W. T. The Bioavailability of the Novel Nonnucleoside Reverse Transcriptase Inhibitor GW420867X Is Unaffected by Food in Healthy Male Volunteers. J. Clin. Pharmacol. 2001, 41, 528–535. 10.1177/00912700122010401. [DOI] [PubMed] [Google Scholar]; d Tanimori S.; Nishimura T.; Kirihata M. Synthesis of novel quinoxaline derivatives and its cytotoxic activities. Bioorg. Med. Chem. Lett. 2009, 19, 4119–4121. 10.1016/j.bmcl.2009.06.007. [DOI] [PubMed] [Google Scholar]; e Eary C. T.; Jones Z. S.; Groneberg R. D.; Burgess L. E.; Mareska D. A.; Drew M. D.; Blake J. F.; Laird E. R.; Balachari D.; O′Sullivan M.; Allen A.; Marsh V. Tetrazole and ester substituted tetrahydoquinoxalines as potent cholesteryl ester transfer protein inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 2608–2613. 10.1016/j.bmcl.2007.01.112. [DOI] [PubMed] [Google Scholar]; f Chen J. J.; Qian W.; Biswas K.; Viswanadhan V. N.; Askew B. C.; Hitchcock S.; Hungate R. W.; Arik L.; Johnson E. Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists. Bioorg. Med. Chem. Lett. 2008, 18, 4477–4481. 10.1016/j.bmcl.2008.07.055. [DOI] [PubMed] [Google Scholar]
- a Shi L.; Zhou H.; Wu J.; Li X. Advances in the Chemistry of Quinoxalinone Derivatives. Mini-Rev. Org. Chem. 2014, 12, 96–112. 10.2174/1570193X11666141029004418. [DOI] [Google Scholar]; b Ke Q.; Yan G.; Wu X. Recent advances in the direct functionalization of quinoxalin-2(1H)-ones. Org. Biomol. Chem. 2019, 17, 5863–5881. 10.1039/C9OB00782B. [DOI] [PubMed] [Google Scholar]; c Rostoll-Berenguer J.; Blay G.; Pedro J. R.; Vila C. Recent Advances in Photocatalytic Functionalization of Quinoxalin-2-ones. Eur. J. Org. Chem. 2020, 2020, 6148–6172. 10.1002/ejoc.202000746. [DOI] [Google Scholar]
- a Rostoll-Berenguer J.; Blay G.; Muñoz M. C.; Pedro J. R.; Vila C. A Combination of Visible-Light Organophotoredox Catalysis and Asymmetric Organocatalysis for the Enantioselective Mannich Reaction of Dihydroquinoxalinones with Ketones. Org. Lett. 2019, 21, 6011–6015. 10.1021/acs.orglett.9b02157. [DOI] [PubMed] [Google Scholar]; b Rostoll-Berenguer J.; Blay G.; Pedro J. R.; Vila C. Copper-Catalyzed Aerobic Oxidative Alkynylation of 3,4-Dihydroquinoxalin-2-ones. Synthesis 2020, 52, 544–552. 10.1055/s-0039-1690244. [DOI] [Google Scholar]; c Rostoll-Berenguer J.; Blay G.; Pedro J. R.; Vila C. Photocatalytic Giese Addition of 1,4-Dihydroquinoxalin-2-ones to Electron-Poor Alkenes Using Visible Light. Org. Lett. 2020, 22, 8012–8017. 10.1021/acs.orglett.0c02953. [DOI] [PubMed] [Google Scholar]; d Rostoll-Berenguer J.; Capella-Argente M.; Blay G.; Pedro J. R.; Vila C. Visible-light-accelerated amination of quinoxalin-2-ones and benzo[1,4]oxazin-2-ones with dialkyl azodicarboxylates under metal and photocatalyst-free conditions. Org. Biomol. Chem. 2021, 19, 6250–6255. 10.1039/D1OB01157J. [DOI] [PubMed] [Google Scholar]
- Ding W.; Lu L.-Q.; Liu J.; Liu D.; Song H.-T.; Xiao W.-J. Visible Light Photocatalytic Radical-Radical Cross-Coupling Reactions of Amines and Carbonyls: A Route to 1,2-Amino Alcohols. J. Org. Chem. 2016, 81, 7237–7243. 10.1021/acs.joc.6b01217. [DOI] [PubMed] [Google Scholar]
- Hornyák G.; Fetter J.; Lempert K.; Párkányi L.; Németh G.; Poszávácz L.; Simig G. Dissimilar reactivities of diastereomeric 1,1,1-trifluoro-3-(4-methoxyphenyl)-2,3-diphenylpropan-2-ols in an attempted elimination reaction. J. Fluor. Chem. 2001, 108, 239–244. 10.1016/S0022-1139(01)00364-5. [DOI] [Google Scholar]
- Prier C. K.; Rankic D. A.; MacMillan D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322–5363. 10.1021/cr300503r. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang J.-S.; Liu K.-T.; Su Y. O. Electrochemical reduction of substituted α,α,α-trifluoroacetophenones. Linear relationship between cyclic voltammetric peak potentials and Hammett substituent constants. J. Phys. Org. Chem. 1990, 3, 723–731. 10.1002/poc.610031105. [DOI] [Google Scholar]
- See Supporting Information for further details.
- Gentry E. C.; Knowles R. R. Synthetic Applications of Proton-Coupled Electron Transfer. Acc. Chem. Res. 2016, 49 (8), 1546–1556. 10.1021/acs.accounts.6b00272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- The Ru(I) is not reductant enough (E = −1.33 V vs SCE) to directly reduce trifluoroacetophenone (E = −1.4 V vs SCE) so a radical–radical coupling mechanism is excluded.
- Luo J.; Zhang J. Donor-Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)-C(sp2) Cross-Coupling. ACS Catal. 2016, 6, 873–877. 10.1021/acscatal.5b02204. [DOI] [Google Scholar]
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