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ACS Omega
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10.1021/acsomega.4c03979
Article
Metal-Free Synthesis of Polysubstituted Triazoloquinoxalines Using Alkynols as the Key Building Blocks
Masaryk Berenika
https://orcid.org/0000-0001-7288-8617
Soural Miroslav *
Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 779 00 Olomouc, Czech Republic
* Email: miroslav.soural@upol.cz.
05 09 2024
17 09 2024
9 37 3856938582
25 04 2024
27 08 2024
15 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

o-Phenylenediamines, o-nitroanilines, and Boc-o-phenylenediamines were converted to N-Ts/Ns-o-phenylenediamines, followed by Mitsunobu alkylation with prop-2-yn-1-ols. After one-pot azidation, the resulting intermediates underwent Huisgen cycloaddition, which yielded Ts/Ns-dihydrotriazoloquinoxalines. Cleavage of the arylsulfonyl moiety provided (dihydro)triazoloquinoxalines with the possibility of modifying the N5 position. The application of but-3-yn-1-ols and pent-4-yn-1-ols allowed the preparation of benzotriazolodiazepines and benzotriazolodiazocines. The developed protocols enable the preparation of diversely substituted products from readily available starting materials under mild and metal-free conditions.

GrantovÃ¡ Agentura CeskÃ© Republiky 10.13039/501100001824 21-06553S Univerzita PalackÃ©ho v Olomouci 10.13039/501100007059 IGA_PrF_2024_028 Univerzita PalackÃ©ho v Olomouci 10.13039/501100007059 IGA_LF_2024_038 Univerzita PalackÃ©ho v Olomouci 10.13039/501100007059 IGA_LF_2024_007 document-id-old-9ao4c03979
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pmcIntroduction

In recent decades, the 1,2,3-triazole scaffold has been extensively used by medicinal chemists to modify the structures of biologically active compounds. In addition to being directly included in pharmacophores and/or their peripheral substitution to fine-tune the properties of drugs,1,2 conjugation via triazoles by bioorthogonal reactions between alkynes and azides has been widely utilized to study intracellular processes.3,4 An individual group of bioactive triazoles consists of derivatives bearing additional fused heterocyclic scaffolds. In this regard, [1,2,3]triazolo[1,5-a]quinoxalines (TQs) were reported as ligands of benzodiazepine and adenosine receptors5,6 and agonists of the G-protein-coupled niacin receptor.7 Consequently, various synthetic pathways leading to TQs have been investigated. Different approaches starting from aryl iodides have been developed, with Cu catalysis8−12 or Ru catalysis13 required to accomplish azidation and/or the cycloaddition step. Eventually, the combination of both Cu and Pd catalysis within the reaction sequence was reported.14 A general method based on Ugi multicomponent reaction and noncatalyzed Huisgen cyclization was recently introduced for 4-oxo derivatives, however, with a high temperature needed for the cycloaddition step.15 Preparation of one TQ derivative using a metal-free and azide-free protocol was also described.16,17

In our ongoing research, we focused on synthetic pathways leading to fused triazoles using alkynols for the installation of alkyne moieties. Recently, we developed Huisgen cycloadditions for triazolodiazepines18 and triazolodiazepinones19 starting from Ns-(homo)azidoalanine. In this article, the application of a noncatalyzed Huisgen cycloaddition to yield TQs from Ns/Ts-phenylenediamines is reported.

Results and Discussion

Although primarily targeting a metal-free pathway, we initially tested a previously reported approach9 in which copper catalysis was used for the conversion of N-acyl-2-iodoanilines to TQs. To mimic this strategy for N-sulfonyl analogs, 2-iodoaniline was reacted with 4-nitrobenzenesulfonyl chloride (4-NsCl), and the resulting Ns-2-iodoaniline 2 was alkylated with 3-phenylprop-2-yn-1-ol using the Mitsunobu procedure (Scheme 1). Intermediate 3a was subjected to Cu-catalyzed cycloaddition with sodium azide under previously reported conditions;9 however, the formation of TQs (or the corresponding triazoles) was not observed, and only decomposition to a mixture of unknown compounds occurred. Intermediates 3b and 3c bearing electron-withdrawing groups provided the same results.

Scheme 1 Attempts to Prepare TQs from Alkynol and Iodoaniline Using Cu Catalysis

Reagents and conditions: (i) 4-nitrobenzenesulfonyl chloride, dichloromethane (DCM), pyridine, rt, 2 h; (ii) alkynol, triphenylphosphine (TPP), diisopropylazadicarboxylate (DIAD), anh. THF, rt, 2 h; and (iii) various conditions adopted from the literature.9

Consequently, we switched from 2-iodoaniline to o-phenylenediamines as the starting materials. Notably, o-azidoaniline was not considered a suitable alternative due to its problematic availability and due to interference of the azido group with triphenylphosphine during Mitsunobu alkylation. Direct sulfonylation (Method A, Scheme 2) of o-phenylenediamine 4a with 4-NsCl resulted in limited regioselectivity and led to the formation of disulfonylated byproducts that were difficult to separate (yields < 40%). Alternatively, diamines substituted with suitable directing functional groups (3-Cl: 4b, 4-COOMe: 4c, 4-NO2: 4d) furnished the desired sulfonamides in acceptable crude purities and isolated yields. Method A was also successfully applied to symmetrical diamine 4e. For unsubstituted o-phenylenediamine and its derivatives lacking sufficient regioselectivity, we developed two alternative approaches. Method B was based on monoprotection of 4a with di-t-butyl dicarbonate, followed by sulfonylation. Although this alternative requires two additional steps compared to Method A, its simplicity and almost quantitative yield make it the method of choice. Method C consisted of the use of nitroanilines as precursors of o-phenylenediamines. Although the reactivity was compromised and the sulfonylation of 7a and 7b was difficult to complete, the subsequent catalytic hydrogenation furnished desired sulfonamides 9b, 9g, and 9h in high yields.

Scheme 2 Alternative Starting Materials and Their Conversion to Sulfonamides

Reagents and conditions: (i) 4-NsCl or TsCl, pyridine (DCM), rt; for individual reaction times, see the Experimental Section; (ii) Boc2O, DCM, 0 °C; (iii) 25% TFA/DCM, rt; and (iv) H2, Pd/C, EtOH, 2 or 16 h (for 8c).

The obtained sulfonamides 9a–h were reacted with different primary or secondary alkynols: propargyl alcohol, 3-phenylprop-2-yn-1-ol, 3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-ol, but-2-yn-1-ol, 4-phenylbut-3-yn-2-ol, hex-3-yn-2-ol and 4-phenylbut-3-yn-1-ol (Scheme 3). The last two building blocks mentioned were included to test the possible preparation of larger cycles: benzotriazolodiazepines and benzotriazolodiazocines. Mitsunobu alkylation smoothly afforded the corresponding intermediate 10. In some cases, the separation of diisopropylhydrazine-1,2-dicarboxylate (DIHD) was problematic, but traces of DIHD were easily and quantitatively removed after the next reaction step. The formation of azides was performed in one pot via the corresponding diazonium salts. Under developed and optimized conditions using 10% HCl/acetonitrile 2:3 (v/v) as the solvent, products 11 spontaneously precipitated from the reaction mixture and were isolated by simple filtration in excellent crude purity and high yields. Only in the cases of 11i–k, the oily products were extracted.

Scheme 3 Synthesis of DihydroTQs and Homological Scaffolds

Reagents and conditions: (i) alkynol, triphenylphosphine (TPP), diisopropylazadicarboxylate (DIAD), anh. THF, rt, 2 h; (ii) (a) HCl/ACN/H2O, NaNO2, 0 °C, 30 min; (b) NaN3, H2O, rt, 30 min; (iii) DMSO, 45 °C, 3–5 h; and (iv) DMSO, 90 °C, 3 h (15a) or 48 h (15b).

An interesting result was obtained after azidation of intermediate 10d (R1 = Cl): analysis of the isolated product revealed the formation of cyclic product 12e bearing hydroxy instead of chloro substitution. This result indicated spontaneous quantitative cycloaddition and nucleophilic substitution via the formation of Meiseinheimer complex B in the diazonium salt stage (Scheme 4). This hypothesis was supported by the detection of hydroxydiazonium intermediate C with LC–MS analysis prior to reaction with sodium azide.

Scheme 4 Spontaneous Formation of the Hydroxyl Derivative 12e from 10dvia Meisenheimer Complex A

Not only intermediate 11e but also all azides 11 were highly prone to cycloaddition: when standing in DMSO-d6 solution prior to NMR analysis, the corresponding Ts/Ns-TQs 12 were detected in the 1H spectra. For this reason, only selected intermediates were fully characterized. The completion to TQs at room temperature was observed after 48–72 h; however, the reaction time could be shortened to 3–5 h by heating of intermediates 11 in DMSO to 45 °C. The products were quantitatively formed without any impurities, precipitated by water, and isolated as single compounds. The formation of larger cycles was substantially more demanding and required heating to 90 °C for 3 h (benzotriazolodiazepine 15a) or 48 h (benzotriazolodiazocine 15b); however, no side products were detected.

Next, we proceeded with the cleavage of the Ns/Ts group, leading to full aromatization of the scaffold by using 1,8-diazabicyclo[5.4.0]undec-7-ene (Scheme 5).

Scheme 5 Desulfonylation and Oxidation of Ns/Ts-TQs to Fully Aromatic Analogs

Reagents and conditions: (i) DBU, DMSO, rt or 90 °C, 3–15 h; (ii) mercaptoethanol, DBU, DMSO, rt, 30 min; and (iii) MnO2, toluene, 110 °C, 24 h (17d from 18) or 80 °C, 24 h (17a,b from 16a,b).

Notably, the isolation of Ts/Ns-TQs prior to this step was not necessary because the direct cleavage of sulfonamides to produce 17 was feasible by the addition of DBU to the reaction mixture after Huisgen cycloaddition. This alternative shortened the reaction pathway and had a positive effect on the overall yield. The reaction conditions for desulfonylation strongly depended on the C–H acidity at the C4 position: unsubstituted derivatives were smoothly converted using DBU at room temperature (compounds with R3 = aryl) or at elevated temperature (compounds with R3 = alkyl), whereas derivatives 12m,n (R4 = Me) and intermediates 15a,b were resistant to this protocol. In such cases, the cleavage of Ns with thiolate was performed, followed by the aromatization of 16a,b with MnO2. This alternative furnished products 17a,b, whereas N-unsubstituted benzotriazolodiazocine 19 was completely resistant to oxidation. A surprising result was obtained from the oxidation of benzotriazolodiazepine 18, which was converted to triazoloquinoxaline 17d. Scheme 6 shows a plausible mechanism for this conversion. After oxidation to conjugated enamine A, this intermediate can undergo further oxidative attack, leading to the formation of N-formyl derivatives and aldehydes as previously reported for MnO2 oxidative cleavage of substituted anilines.20 Intermediate B can cyclize to C followed by further oxidation, decarboxylation, and dehydration (or vice versa) resulting in aromatic scaffold 17d. The reason for unreactivity of compound 19 toward the analogical conversion may be its impossibility to form the fully conjugated enamine of type A. We also tested the reactivity of compound 15a under identical conditions as for the oxidation of 18 (MnO2, toluene, 110 °C, 24 h) but compound 17d was not obtained, and only a mixture of unknown products was detected. On the other hand, LCMS analysis of the reaction after 6 h indicated the partial conversion of 15a to the oxidized analog (ESI+ 446, corresponds to Ns-derivative type A, see Supporting Information). Further heating led to decomposition; however, this observation partially supports the suggested mechanism.

Scheme 6 Hypothetical Mechanism for Oxidative Ring Contraction of 18

In contrast to direct DBU cleavage, the removal of sulfonamides with thiolate resulted in the liberation of the secondary amine, which was used as a strategy for N5 modification of the TQ scaffold with various electrophiles. This possibility was demonstrated by the acetylation and methylation of compound 16c, which was synthesized using conditions identical to those used for 16a and 16b (Scheme 7). Furthermore, C4-methyl derivatives 17a and 17b were smoothly converted to the corresponding aldehydes, which opens the door to a wide range of transformations with different nucleophiles.21 As an illustrative example, Schiff base 24 was synthesized by using aniline.

Scheme 7 Further Modification of TQs at C4 and N5 Positions

Reagents and conditions: (i) MeI, DBU, DMSO, 50 °C, 16 h; (ii) Ac2O, DBU, DMSO, 50 °C, 3 h; (iii) SeO2, THF, reflux, 3 h; and (iv) aniline, EtOH, 70 °C, 3 h.

Conclusions

We developed a simple synthetic strategy for accessing [1,2,3]triazolo[1,5-a]quinoxalines starting from various alkynols and o-phenylenediamines or 2-nitroanilines. In contrast to previous approaches, triazole formation is based on a noncatalyzed Huisgen cycloaddition, which can be accomplished at room temperature. In the case of higher alkynols, the preparation of benzotriazolodiazepines and benzotriazolodiazocines is possible, although under harsh conditions. Importantly, the synthesis starts from inexpensive and readily available building blocks, and the developed protocols can be used to variously modify the target scaffold at positions C2, C4, and N5 and the benzene ring. Consequently, the method can be utilized to synthesize diverse TQs in the search for compounds for different applications.

Experimental Section

Solvents and chemicals were purchased from Sigma-Aldrich (Milwaukee, WI, www.sigmaaldrich.com), Acros Organic (Geel, Belgium, www.acros.com), and Fluorochem (Hadfield, United Kingdom, www.fluorochem.co.uk). Anhydrous solvents were dried over 4 Å molecular sieves or stored as received from commercial suppliers. Reactions were performed in round-bottom flasks fitted with rubber septa under positive pressure of nitrogen or in pressure ampules, unless stated otherwise.

Reactions were monitored by LCMS analysis or thin-layer chromatography (TLC) using aluminum plates precoated with silica gel (silica gel 60 F254, Merck, The United States) impregnated with a fluorescent indicator. TLC plates were visualized by exposure to ultraviolet light (λ = 254 nm) and/or by submersion in aqueous ceric ammonium molybdate (CAM) solution and/or potassium permanganate (KMnO4) and/or vanillin solution, followed by brief heating. The LCMS analyses were carried out on a UHPLC-MS system consisting of UHPLC chromatograph Acuity with a photodiode array detector and single quadrupole mass spectrometer (Waters), using X-Select C18 silica gel with the mobile phase consisting of 10 mM ammonium acetate (AmAc) in H2O and CH3CN. The ESI source operated at a discharge current of 5 μA, vaporizer temperature of 350 °C, and capillary temperature of 200 °C. For the LCMS analysis, samples were extracted into CH3CN/H2O (20% or 50%; 1 mL).

All 1D NMR experiments were performed using a Jeol ECA400II (400 MHz) and/or ECX500 spectrometer (JEOL RESONANCE, Tokyo, Japan) at magnetic field strengths of 9.39 and 11.75 T, corresponding to resonance frequencies of 400 MHz (for 1 H), 100.6 MHz (for 13C), 500.16 MHz (for 1H), and 125.77 MHz (for 13C) at 26–27 °C. Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) are reported in Hertz (Hz). The signals of CDCl3, DMSO-d6, and TFA-d signals were set at 7.26, 2.50, and 11.50 ppm in 1H NMR spectra and to 77.16, 39.52, and 164.2 ppm in 13C NMR spectra, respectively. Abbreviations in NMR spectra: brs, broad singlet; s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doublets; dt, doublet of triplets; t, triplet; td, triplet of doublets; m, multiplet; p, pentet; q, quartet; qd, quartet of doublets; qt, quartet of triplets.

HRMS analysis was performed using LCMS (Dionex Ultimate 3000, Thermo Fischer Scientific, MA, USA) with an Exactive Plus Orbitrap high-resolution mass spectrometer (Thermo Exactive Plus, Thermo Fischer Scientific, MA, USA) operating at a positive or negative full scan mode (120 000 FWMH) in the range of 100–1000 m/z with electrospray ionization working at 150 °C and a source voltage of 3.6 kV. Chromatographic separation was performed on C18 silica gel (Phenomenex Gemini, 50 × 2 mm, 3 μm particle) with isocratic elution and mobile phase (MP) containing CH3CN/10 mM AmAc (80/20; v/v). The samples were dissolved in CH3CN or CH3CN/H2O (1/1; v/v).

Synthetic Procedures

Synthesis of N-(2-Iodophenyl)-4-nitrobenzenesulfonamide 2

2-Iodoaniline 1 (2.5 g, 11.4 mmol, 1 equiv), pyridine (1 mL, 12.5 mmol, 1.1 equiv), and 4-NsCl (2.78 g, 12.5 mmol, 1.1 equiv) were dissolved in DCM (20 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then washed with 2 × 50 mL of 10% AcOH and the combined aqueous layers were washed with 2 × 150 mL of DCM. The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo. Crystallization of the crude product from DCM/EtOAc (20:1, v/v) afforded the pure product 2 (2.1 g, 46% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.44–8.38 (m, 2H), 7.98–7.91 (m, 2H), 7.85 (dd, J = 7.9, 1.4 Hz, 1H), 7.34 (ddd, J = 8.0, 7.4, 1.5 Hz, 1H), 7.07–7.00 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 149.8, 146.3, 139.8, 137.5, 129.1, 129.1, 128.4, 128.4, 124.7, 99.2.

Synthesis of tert-Butyl(2-aminophenyl)carbamate 5a

o-Phenylenediamine 4a (1.08 g, 10 mmol, 1 equiv) was dissolved in 25 mL of DCM and the reaction flask was placed in an ice bath. Boc2O (2.08 g, 10 mmol, 1 equiv) was added in portion to the stirring solution over an interval of 2 h. After the last portion was added, the reaction mixture was removed from the ice bath and left at room temperature on a magnetic stirrer for an additional 16 h. The reaction mixture was evaporated to dryness in vacuo. The crude product was purified by silica gel chromatography using Hex:EtOAc (3:7, v/v) to give pure product 5a (4.55 g, 73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31–7.24 (m, 1H), 7.03–6.95 (m, 1H), 6.84–6.73 (m, 2H), 6.24 (bs, 1H), 3.62 (brs, 2H), 1.51 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 154.0, 140.0, 126.3, 125.0, 119.8, 117.8, 91.0, 80.7, 28.5.

Synthesis of tert-Butyl(2-((4-nitrophenyl)sulfonamido)phenyl)carbamate 6a

Compound 5a (1.68 mg, 8.08 mmol, 1 equiv), 4-NsCl (1.883 g, 8.484 mmol, 1.05 equiv), and pyridine (682.5 μL, 8.484 mmol, 1.05 equiv) were dissolved in DCM (15 mL) and stirred at room temperature for 2 h. Later, the reaction mixture was evaporated to dryness in vacuo. The colorless oil was poured into 50 mL of water and vigorously shaken. The resulting white precipitate was filtered off under reduced pressure and washed several times with water. After being dried, pure product 6a (3.12 g, 98% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.40–8.09 (m, 2H), 7.99–7.65 (m, 3H), 7.26–7.07 (m, 4H), 6.48 (s, 1H), 1.51 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 154.0, 150.3, 145.5, 133.5, 128.7, 128.6, 126.9, 125.8, 124.2, 123.3, 82.2, 28.4. HRMS (ESI neg.) m/z: [M + H]+ calcd for C17H19N3O6S, 393.0911; found, 393.0919

Synthesis of 4-Methyl-N-(2-nitrophenyl)benzenesulfonamide 8a

Nitroaniline 7a (200 mg, 1.45 mmol) was dissolved in 0.5 mL of pyridine, and the reaction mixture was stirred for 30 min at 100 °C. Subsequently, pTsCl (606 mg, 3.2 mmol) was added portionwise over 3 h. The reaction was then stirred at 100 °C for another 24 h. Later, the reaction mixture was poured onto crushed ice, yielding a deep orange solid precipitate, which was recrystallized in MeOH (10 mL) to give pure product 8a (205 mg, 48% yield) as a deep yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 8.10 (dd, J = 8.4, 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 1.3 Hz, 1H), 7.77–7.68 (m, 2H), 7.57 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.28–7.23 (m, 2H), 7.14 (ddd, J = 8.6, 7.3, 1.3 Hz, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 145.0, 137.2, 136.0, 135.9, 134.1, 130.2, 127.4, 126.3, 123.9, 121.2, 21.7.

Synthesis of N-(4-Chloro-2-nitrophenyl)-4-methylbenzenesulfonamide 8b

4-Chloronitroaniline 7b (688 mg, 4 mmol) and pTsCl (1.52 g, 8 mmol) were dissolved in dry DCM (10 mL) and dry pyridine (12 mmol, 1 mL) was added. The mixture was stirred at room temperature for 24 h, after which another portion of pTsCl (380 mg, 2 mmol) was added. The reaction was stirred at room temperature for another 48 h. Later, the reaction mixture was shaken with 100 mL of water, and the aqueous phase was extracted with 3 × 100 mL of EtOAc. The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo yielding an orange oil, which was participated from EtOH/H2O (4:1, v/v) to give product 8b (467 mg, 36% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.75–7.65 (m, 2H), 7.53 (dd, J = 9.0, 2.5 Hz, 1H), 7.30–7.25 (m, 2H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 145.2, 137.3, 136.0, 135.6, 132.7, 130.3, 129.4, 127.4, 125.9, 122.5, 21.7.

Synthesis of N-(4-Methoxy-2-nitrophenyl)-4-methylbenzenesulfonamide 8c

4-Methoxynitroaniline 7c (336 mg, 2 mmol) and pTsCl (380 mg, 2 mmol) were dissolved in 1 mL of pyridine and stirred at room temperature for 6 h. Subsequently, the reaction mixture was poured into 150 mL of saturated NH4Cl solution and extracted into EtOAC (3 × 100 mL). The combined organic layers were evaporated to dryness in vacuo. The yellow-orange oil was dissolved in 4 mL of EtOH followed by the addition of 4 mL of water to form turbidity, which was removed after brief heating. The mixture was allowed to stand overnight to form yellow crystals of product 8c (514 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.67–7.56 (m, 2H), 7.48 (d, J = 3.0 Hz, 1H), 7.25–7.14 (m, 3H), 3.81 (s, 3H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.3, 144.7, 139.2, 135.7, 130.1, 127.3, 126.7, 124.9, 123.2, 109.2, 56.1, 21.7.

Synthesis of N-(2-Aminophenyl)-4-nitrobenzenesulfonamide 9a

Compound 6a (3.12 g, 8.08 mmol) was dissolved in 25 mL of a 25% TFA solution in DCM and the mixture stirred at room temperature for 2 h. TFA/DCM was removed under N2, and the orange oil was poured into 100 mL of saturated NaHCO3 solution and shaken vigorously until the reaction mixture stopped foaming. The resulting precipitate was filtered off under reduced pressure and dried to give the pure product 9a (2.22 g, 95% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 8.49–8.22 (m, 2H), 8.01–7.82 (m, 2H), 6.91 (ddd, J = 8.0, 7.2, 1.5 Hz, 1H), 6.72 (dd, J = 7.8, 1.5 Hz, 1H), 6.62 (dd, J = 8.1, 1.5 Hz, 1H), 6.42 (ddd, J = 7.9, 7.2, 1.5 Hz, 1H), 4.91 (brs, 2H). 13C NMR (101 MHz, DMSO-d6) δ 149.7, 145.9, 144.4, 128.4, 127.9, 127.4, 124.3, 119.7, 116.2, 115.7

Synthesis of N-(2-Aminophenyl)-4-methylbenzenesulfonamide 9b

5a (1.1 g, 5.3 mmol, 1 equiv) and pTsCl (1.1 g, 5.83 mmol, 1.1 equiv) was dissolved in 10 mL of DCM and pyridine (504 μL, 5.83 mmol, 1.1 equiv) was added to the stirring solution at room temperature. The reaction was monitored by LCMS. After 3 h, the reaction mixture was evaporated to dryness in vacuo. The clear oily product was shaken in 20 mL of water to precipitate a white crystalline substance, which was filtered off under reduced pressure. The crystalline product of 6b was then transferred to a flask and dissolved in 20 mL of a 25% TFA solution in DCM. After the reaction was complete, the TFA/DCM solution was blown under N2. The purple oily substance was poured into 50 mL of a saturated NaHCO3 solution and vigorously shaken. The resulting precipitate was filtered off under reduced pressure and washed with water. After being dried, pure product 9b (1.23 g, 89% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.70–7.58 (m, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.04 (ddd, J = 8.1, 7.0, 1.8 Hz, 1H), 6.74 (dd, J = 8.1, 1.3 Hz, 1H), 6.59–6.47 (m, 2H), 3.35 (brs, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.5, 144.1, 136.1, 129.8, 129.1, 128.7, 127.7, 121.3, 118.8, 117.3, 21.7.

General Procedure for Direct Sulfonylation (Products 9c–f)

The corresponding diamine 4b–e (2 mmol) was dissolved in 15 mL of THF (4b, 4c) or in 10 mL of DCM (4d, 4e), and pyridine (160 μL, 2 mmol) was added to the solution. The reaction mixture was placed in an ice bath and cooled to 0 °C. Then, 4-NsCl (400 mg, 1.8 mmol, for synthesis of 9c and 9d) or pTsCl (380 mg, 2 mmol, for synthesis of 9e and 9f) was added in portion. The reaction was monitored by TLC. After 2 h, the reaction was quenched with 100 mL of water and extracted with 3 × 100 mL of DCM or 3 × 100 mL of EtOAc (9e). The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo. The crude products were purified by silica gel chromatography or crystallized from an appropriate solvent.

N-(2-Amino-3-chlorophenyl)-4-nitrobenzenesulfonamide 9c

The crude product was purified by crystallization from EtOH to give pure product 9c (430 mg, 66% yield) as a yellow-brown fine crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.44–8.28 (m, 2H), 8.01–7.82 (m, 2H), 7.12 (dd, J = 8.0, 1.5 Hz, 1H), 6.69 (dd, J = 7.9, 1.5 Hz, 1H), 6.46 (t, J = 8.0 Hz, 1H), 5.07 (brs, 2H). 13C NMR (101 MHz, DMSO-d6) δ 149.8, 145.5, 141.1, 128.4, 128.1, 126.2, 124.5, 121.3, 118.2, 116.2. HRMS (ESI pos.) m/z: [M + H]+ calcd for C12H10ClN3O4S, 328.0154; found, 328.0155

Methyl 4-Amino-3-((4-nitrophenyl)sulfonamido)benzoate 9d

The crude product was purified by being suspended in EtOH and washed with EtOH/H2O (1:1, v/v) on a frit to give pure product 9d (338 mg, 57% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (brs, 1H), 8.46–8.28 (m, 2H), 7.98–7.84 (m, 2H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 5.75 (s, 2H), 3.69 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.7, 149.8, 149.1, 145.5, 129.5, 129.3, 128.5, 124.4, 118.7, 116.3, 114.6, 51.4. HRMS (ESI pos.) m/z: [M + H] + calculated for C14H13N3O6S, 352.0598; found, 352.0599

N-(2-Amino-5-nitrophenyl)-4-methylbenzenesulfonamide 9e

The crude product was purified by crystallization in DCM to give 9e (470 mg, 77%) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.81 (dd, J = 9.1, 2.7 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.60–7.58 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.67 (d, J = 9.1 Hz, 1H), 6.46 (s, 2H), 2.36 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 150.9, 143.5, 136.5, 135.3, 129.6, 126.9, 124.1, 122.8, 119.3, 113.8, 21.0.

N-(2-Amino-4,5-dimethylphenyl)-4-methylbenzenesulfonamide 9f

The crude product was purified by silica gel chromatography using Hex/EtOAc with 1% AcOH (1:3, v/v) to give 9f (355 mg, 59% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.67–7.60 (m, 2H), 7.26–7.23 (m, 2H), 6.53 (s, 1H), 6.31 (s, 1H), 2.42 (s, 3H), 2.11 (s, 3H), 1.95 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.6, 141.8, 137.2, 136.7, 129.5, 129.5, 127.6, 126.9, 119.2, 118.6, 21.6, 19.5, 18.6.

10 General Procedures for Catalytic Hydrogenation (Products 9b, 9g, and 9h)

Compounds 8a–c were dissolved in EtOH (1 mL per 0.1 mmol) and 10 mol% 10% Pd/C or 5 mol% PtO2 (for 9g) was added to the mixture. Subsequently, the flask with the reaction mixture was sealed with a septum and bubbled with N2 and then with H2 for 15 min. The reaction mixture was stirred for an additional 2 h (H, Cl) or 16 h (OMe) at room temperature under a H2 atmosphere. The end of the reaction was indicated by LCMS. The reaction mixture was filtered through a microfilter, and the EtOH was evaporated in vacuo. The substance was either used without further purification or was purified by silica gel chromatography or crystallization.

N-(2-Aminophenyl)-4-methylbenzenesulfonamide 9b

The product 9b was obtained without further purification as a white solid (131 mg, 98%).

N-(2-Amino-4-methoxyphenyl)-4-methylbenzenesulfonamide 9g

The crude product was purified by crystallization in EtOH/H2O (2:1, v/v) to give product 9g (350 mg, 88% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 7.65–7.58 (m, 2H), 7.26–7.24 (m, 2H), 6.31 (d, J = 8.7 Hz, 1H), 6.24 (d, J = 2.7 Hz, 1H), 6.05 (dd, J = 8.7, 2.8 Hz, 1H), 5.94 (s, 1H), 3.71 (s, 3H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.3, 146.5, 143.7, 136.2, 130.3, 129.7, 127.8, 127.1, 114.0, 104.4, 101.7, 55.4, 21.7.

N-(2-Amino-4-chlorophenyl)-4-methylbenzenesulfonamide 9h

The crude product was purified by silica gel chromatography using Hex/EtOAc (7:3, v/v) to give pure product 9h (330 mg, 81% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.66–7.59 (m, 2H), 7.30–7.26 (m, 2H), 6.72 (d, J = 2.3 Hz, 1H), 6.47 (dd, J = 8.4, 2.3 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.92 (s, 1H), 4.18 (s, 2H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 146.0, 144.3, 135.7, 134.6, 129.9, 129.9, 127.7, 119.5, 118.4, 116.6, 21.7.

General Procedure for N-Alkylation (Products 3a–c, 10a–n, and 13a,b)

TPP (1.5–3 equiv) and DIAD (2–3 equiv) were dissolved in anhydrous THF (3 mL per 1 mmol TPP) and stirred for 30 min at 0 °C. The appropriate alkynol (1.5–2 equiv) and sulfonamide 2 (for 3a–c) or 9a–h (for 10a–n) were added to the solution. The reaction was stirred at room temperature and monitored by LCMS or TLC. After 2 h, THF was evaporated in vacuo, and the reaction mixture was quenched with water (50 mL per 1 mmol of starting sulfonamide) and extracted with DCM (3x the same volume as the volume of water used). The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo. The crude product was purified by silica gel chromatography or recrystallized to remove the reaction byproduct, diisopropylhydrazine-1,2-dicarboxylate (DIHD).

N-(2-Iodophenyl)-4-nitro-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 3a

The crude product was purified by silica gel chromatography using DCM/Hex (5:1, v/v) to give pure product 3a (641 mg, 64% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-d6) δ 8.49–8.36 (m, 2H), 8.14–8.06 (m, 2H), 8.03 (dd, J = 7.9, 1.4 Hz, 1H), 7.43 (ddd, J = 8.0, 7.4, 1.5 Hz, 1H), 7.39–7.28 (m, 3H), 7.24–7.17 (m, 3H), 7.07 (dd, J = 7.9, 1.5 Hz, 1H), 4.92 (d, J = 18.3 Hz, 1H), 4.54 (d, J = 18.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 150.1, 144.4, 140.4, 140.1, 131.1, 131.1, 130.0, 129.5, 129.3, 128.9, 128.6, 124.6, 121.3, 103.7, 85.5, 83.1, 41.8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C21H15IN2O4S, 518.9870; found, 518.9878.

N-(2-Iodophenyl)-4-nitro-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)benzenesulfonamide 3b

The crude product was purified by silica gel chromatography using DCM/hexane (5:2, v/v) to give the pure product 3b (462 mg, 74% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.45–8.38 (m, 2H), 8.13–8.07 (m, 2H), 8.03 (dd, J = 7.9, 1.5 Hz, 1H), 7.71–7.66 (m, 2H), 7.47–7.40 (m, 3H), 7.21 (td, J = 7.6, 1.6 Hz, 1H), 7.08 (dd, J = 7.9, 1.5 Hz, 1H), 4.94 (d, J = 18.4 Hz, 1H), 4.61 (d, J = 18.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 150.1, 144.3, 140.4, 140.1, 131.9, 131.1, 130.1, 129.5, 129.3, 128.9 (q, J = 32 Hz), 125.6, 125.5 (q, J = 3.7 Hz), 124.7, 123.8 (q, J = 273.5 Hz) 103.6, 86.1, 84.1, 41.8. (ESI pos.) m/z: [M + H]+ calcd for C22H14F3IN2O4S, 586.9744; found, 586.9745.

N-(2-Iodophenyl)-4-nitro-N-(3-(4-nitrophenyl)prop-2-yn-1-yl)benzenesulfonamide 3c

The crude product was purified by silica gel chromatography using DCM to give product 3c (135 mg, 48% yield) as an orange-yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.39–8.30 (m, 2H), 8.21–8.09 (m, 2H), 8.09–7.97 (m, 2H), 7.94 (dd, J = 8.0, 1.4 Hz, 1H), 7.44–7.32 (m, 3H), 7.28 (dd, J = 7.9, 1.7 Hz, 1H), 7.14 (ddd, J = 7.9, 7.3, 1.7 Hz, 1H), 5.04 (d, J = 18.3 Hz, 1H), 4.46 (d, J = 18.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 150.2, 147.0, 144.2, 140.3, 140.2, 132.4, 131.1, 130.1, 129.5, 129.4, 128.0, 124.7, 123.8, 103.6, 88.5, 83.8, 41.8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C21H14IN3O6S, 563.9721; found, 563.9736.

N-(2-Aminophenyl)-4-methyl-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)benzenesulfonamide 10a

The crude product was purified by silica gel chromatography using Hex/EtOAc (3:1, v/v), followed by recrystallization from EtOH/H2O (1:1, v/v) to give pure product 10a (725 mg, 64% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 7.75–7.67 (m, 2H), 7.56–7.49 (m, 2H), 7.32–7.28 (m, 2H), 7.25 (dd, J = 8.6, 0.7 Hz, 2H), 7.13 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 6.80 (dd, J = 8.1, 1.4 Hz, 1H), 6.67 (dd, J = 7.9, 1.5 Hz, 1H), 6.55 (ddd, J = 8.0, 7.3, 1.4 Hz, 1H), 4.82 (d, J = 17.8 Hz, 1H), 4.42 (d, J = 17.8 Hz, 1H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 146.5, 144.1, 136.0, 131.8, 130.3 (q, J = 34.5 Hz), 130.1, 129.5, 129.3, 128.5, 126.3, 125.3 (q, J = 3.8 Hz), 124.7, 123.9 (q, J = 271.2 Hz), 118.0, 116.8, 86.4, 84.1, 41.7, 21.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H19F3N2O2S, 445.1192; found, 445.1189.

N-(2-Aminophenyl)-4-nitro-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)benzenesulfonamide 10b

The crude product was purified by silica gel chromatography using Hex/EtOAc (3:1, v/v), followed by recrystallization from EtOH/H2O (2:1, v/v) to give pure product 10b (793 mg, 69% yield) as a yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 8.37–8.20 (m, 2H), 8.11–7.96 (m, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.23–7.12 (m, 1H), 6.83 (dd, J = 8.1, 1.3 Hz, 1H), 6.71–6.48 (m, 2H), 4.94 (d, J = 17.9 Hz, 1H), 4.44 (d, J = 18.0 Hz, 1H), 4.23 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 150.4, 146.3, 144.6, 131.8, 130.8 (q, J = 32.9 Hz), 130.7, 129.8, 129.1, 125.7, 125.5 (q, J = 38 Hz), 124.0, 123.8 (q, J = 272.3 Hz), 123.8, 118.3, 117.2, 85.5, 84.7, 42.1. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H16F3N3O4S, 476.0886; found, 476.0890.

N-(2-Aminophenyl)-4-nitro-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 10c

The crude product was purified by silica gel chromatography using Hex:EtOAc (4:1, v/v) followed by recrystallization from EtOH/H2O (1:1, v/v) to give 11c (574 mg, 68% yield) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.31–8.17 (m, 2H), 8.10–7.96 (m, 2H), 7.37–7.25 (m, 3H), 7.20–7.13 (m, 3H), 6.84 (dd, J = 8.1, 1.4 Hz, 1H), 6.70 (dd, J = 8.0, 1.5 Hz, 1H), 6.63–6.52 (m, 1H), 5.00 (d, J = 18.0 Hz, 1H), 4.34 (d, J = 18.0 Hz, 1H), 3.82 (bs, 2H). 13C NMR (101 MHz, CDCl3) δ 150.3, 146.1, 144.8, 131.5, 130.6, 130.0, 129.2, 129.1, 128.6, 124.6, 123.9, 121.9, 118.4, 117.2, 86.3, 8 3.1, 42.4. HRMS (ESI pos.) m/z: [M + H]+ calcd for C21H17N3O4S, 408.1013; found, 408.1012.

N-(2-Amino-6-chlorophenyl)-4-nitro-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 10d

The crude product was purified by silica gel chromatography using Hex/EtOAc (3:1, v/v) to give 10d (335 mg, 74% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.36–8.17 (m, 2H), 8.10–7.97 (m, 2H), 7.37–7.26 (m, 5H), 7.20–7.14 (m, 2H), 6.63 (dd, J = 8.0, 1.5 Hz, 1H), 6.51 (t, J = 8.0 Hz, 1H), 5.00 (d, J = 18.0 Hz, 1H), 4.66 (s, 2H), 4.34 (d, J = 18.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 150.4, 144.5, 143.6, 131.5, 130.7, 130.0, 129.2, 128.6, 127.7, 124.8, 124.0, 121.7, 120.8, 117.3, 86.6, 8 2.7, 42.3 HRMS (ESI pos.) m/z: [M + H]+ calcd for C21H16ClN3O4S, 442.0623; found, 442.0617.

Methyl 4-Amino-3-((4-nitro-N-(3-phenylprop-2-yn-1yl)phenyl)sulfonamido)benzoate 10f

The crude product was purified by silica gel chromatography using Hex:EtOAc (7:3, v/v) followed by recrystallization from Hex/EtOAc (2:1, v/v) to give pure product 10f (300 mg, 53% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39–8.29 (m, 2H), 8.09–8.01 (m, 2H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.41–7.27 (m, 4H), 7.20 (dt, J = 6.7, 1.7 Hz, 2H), 6.77 (d, J = 8.7 Hz, 1H), 6.24 (s, 2H), 4.94 (d, J = 18.6 Hz, 1H), 4.34 (d, J = 18.6 Hz, 1H), 3.63 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.4, 151.7, 149.9, 144.1, 131.9, 131.2, 131.0, 129.9, 128.9, 128.5, 124.2, 121.4, 120.7, 115.4, 114.7, 85.6, 83.9, 51.2, 41.2. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H19N3O6S, 466.1067; found, 466.1075.

N-(2-Amino-5-nitrophenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 10g

The crude product was purified by silica gel chromatography using Hex/EtOAc (7:3, v/v), followed by recrystallization from EtOH to give product 10g (147 mg, 71% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 9.0, 2.5 Hz, 1H), 7.74–7.65 (m, 3H), 7.34–7.26 (m, 3H), 7.25–7.19 (m, 4H), 6.78 (d, J = 9.0 Hz, 1H), 5.05 (s, 2H), 4.79 (d, J = 17.8 Hz, 1H), 4.37 (d, J = 17.7 Hz, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 152.7, 145.1, 138.0, 134.2, 131.6, 129.8, 128.9, 128.7, 128.4, 126.4, 123.7, 121.9, 114.8, 86.8, 82.3, 42. 2, 21.7. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H19N3O4S, 422.1169; found, 422.1162.

N-(2-Amino-4,5-dimethylphenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 10h

The crude product was purified by silica gel chromatography, followed by recrystallization from EtOH to give product 11g (119 mg; 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.77–7.70 (m, 2H), 7.33–7.26 (m, 3H), 7.25–7.17 (m, 4H), 6.61 (s, 1H), 6.49 (s, 1H), 4.81 (d, J = 17.9 Hz, 1H), 4.34 (d, J = 17.9 Hz, 1H), 4.00 (s, 2H), 2.39 (s, 3H), 2.15 (s, 3H), 1.96 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.9, 143.8, 138.6, 136.4, 131.5, 130.2, 129.3, 128.6, 128.5, 128.3, 126.1, 122.7, 122.7, 118.1, 85.4, 8 4.1, 42.0, 21.7, 19.8, 18.8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C24H24N2O2S, 405.1631; found, 405.1627.

N-(2-Amino-4-methoxyphenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 10i

The crude product was purified by silica gel chromatography using Hex/EtOAc (7:3, v/v) followed by recrystallization from EtOH/water (2:1, v/v) to give product 10i (270 mg, 71%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 7.80–7.64 (m, 2H), 7.31–7.13 (m, 7H), 6.59 (d, J = 8.8 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 6.09 (dd, J = 8.8, 2.8 Hz, 1H), 4.83 (d, J = 17.8 Hz, 1H), 4.32 (d, J = 17.8 Hz, 1H), 3.73 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.8, 147.6, 143.8, 136.1, 131.6, 130.4, 129.4, 128.6, 128.5, 128.3, 122.6, 118.1, 104.1, 101.2, 85.4, 83.9, 55.3, 42.1, 21.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H22N2O3S, 407.1424; found, 407.1422.

N-(2-Amino-4-chlorophenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 10j

The crude product was purified by silica gel chromatography using Hex/EtOAc (7:3, v/v) followed by recrystallization from EtOH to give pure product 10j (300 mg, 42% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.24–8.14 (m, 2H), 8.05–7.93 (m, 2H), 7.39–7.23 (m, 4H), 7.18 (ddd, J = 7.7, 7.2, 1.5 Hz, 1H), 7.12–7.10 (m, 1H), 6.84 (dd, J = 8.1, 1.4 Hz, 1H), 6.78 (dd, J = 8.0, 1.5 Hz, 1H), 6.56 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 5.54 (q, J = 7.0 Hz, 1H), 4.23 (s, 2H), 1.39 (dd, J = 7.1, 0.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.2, 148.1, 144.2, 131.2, 130.6, 130.3, 129.8, 129.1, 128.6, 123.6, 121.9, 120.9, 118.0, 117.1, 87.7, 8 5.9, 48.9, 20.3. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H19ClN2O2S, 411.0929; found, 411.0934.

N-(2-Aminophenyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide 10k

The crude product was purified by silica gel chromatography using Hex:EtOAc (7:3, v/v) followed by recrystallization from Et2O to give pure product 10k (295 mg, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04–7.85 (m, 2H), 7.57–7.53 (m, 2H), 7.38 (ddd, J = 8.2, 7.2, 1.6 Hz, 1H), 7.07 (dd, J = 8.1, 1.4 Hz, 1H), 6.87 (dd, J = 7.9, 1.6 Hz, 1H), 6.45 (ddd, J = 7.9, 7.2, 1.4 Hz, 1H), 4.81 (d, J = 17.6 Hz, 1H), 4.51 (d, J = 17.5 Hz, 1H), 3.03 (bs, 2H), 2.71 (s, 3H), 2.42 (t, J = 2.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 146.4, 144.1, 135.7, 130.0, 129.5, 129.4, 128.5, 124.7, 118.1, 116.8, 78.2, 73.7, 40.9, 21.7. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H16N2O2S, 301.1005; found, 301.1003.

N-(2-Aminophenyl)-N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide 10l

The crude product was purified by silica gel chromatography using Hex:EtOAc (7:3, v/v) to give 10l (185 mg, 42% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.69–7.60 (m, 2H), 7.31–7.22 (m, 2H), 7.09 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 6.77 (dd, J = 8.0, 1.4 Hz, 1H), 6.61 (dd, J = 7.9, 1.6 Hz, 1H), 6.53 (ddd, J = 8.0, 7.6, 1.4 Hz, 1H), 4.52 (d, J = 17.4 Hz, 1H), 4.11 (d, J = 17.6 Hz, 1H), 3.77 (bs, 2H), 2.44 (s, 3H), 1.66 (t, J = 2.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 146.4, 143.8, 136.1, 129.8, 129.4, 129.2, 128.6, 125.2, 118.0, 116.7, 81.5, 73.5, 41.7, 22.1, 21.8, 21.7, 3.6. HRMS (ESI poz.) m/z: [M + H]+ calcd for C17H18N2O2S, 315.1162; found, 315.1159.

N-(2-Aminophenyl)-N-(hex-3-yn-2-yl)-4-nitrobenzenesulfonamide 10m

The crude product was purified by silica gel chromatography using Hex:EtOAc (2:1, v/v) followed by recrystallization from EtOH to give pure product 10m (690 mg, 63% yield) as a yellow solid. 1H NMR (400 MHz, CDCl 3) δ 8.32–8.27 (m, 2H), 8.00–7.96 (m, 2H), 7.15 (ddd, J = 8.1, 7.2, 1.5 Hz, 1H), 6.81 (dd, J = 8.1, 1.4 Hz, 1H), 6.69 (dd, J = 8.1, 1.5 Hz, 1H), 6.52 (ddd, J = 8.0, 7.3, 1.5 Hz, 1H), 5.30 (qt, J = 7.0, 2.1 Hz, 1H), 1.99 (qdd, J = 7.3, 2.1, 1.0 Hz, 2H), 1.28 (d, J = 7.1 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.3, 148.0, 144.4, 130.5, 130.4, 130.0, 123.4, 120.9, 117.8, 117.0, 87.7, 78.1, 48.7, 20.8, 13.5, 12.3. HRMS (ESI pos.) m/z: [M + H]+ calcd for C18H19N3O4S, 374.1169; found, 374.1161.

N-(2-Aminophenyl)-4-nitro-N-(4-phenylbut-3-yn-2-yl)benzenesulfonamide 10n

The crude product was purified by silica gel chromatography using Hex/EtOAc (7:3, v/v) and subsequent precipitation from Et2O to give pure product 10n (180 mg, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.76–7.66 (m, 2H), 7.34–7.23 (m, 5H), 7.22–7.15 (m, 2H), 6.79 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 8.5, 2.4 Hz, 1H), 4.81 (d, J = 17.7 Hz, 1H), 4.35 (d, J = 17.8 Hz, 1H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.6, 144.2, 135.7, 135.6, 131.6, 130.5, 129.6, 128.7, 128.6, 128.4, 123.4, 122.4, 118.0, 116.3, 85.7, 83.4, 41.9, 21.7. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H19N3O4S, 422.1169; found, 422.1165.

N-(2-Aminophenyl)-4-nitro-N-(4-phenylbut-3-yn-1-yl)benzenesulfonamide 13a

The crude product was purified by recrystallization in DCM to give pure product 13a (280 mg, 67% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40–8.30 (m, 2H), 8.06–7.93 (m, 2H), 7.34 (s, 5H), 7.05 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 6.76 (dd, J = 8.1, 1.4 Hz, 1H), 6.55 (dd, J = 7.9, 1.6 Hz, 1H), 6.44 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 5.16 (s, 2H), 3.96 (dt, J = 13.2, 7.2 Hz, 1H), 3.69–3.50 (m, 1H), 2.62 (dt, J = 17.1, 7.2 Hz, 1H), 2.55–2.51 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 149.8, 147.7, 144.2, 131.6, 129.6, 129.1, 128.5, 128.2, 124.5, 122.7, 121.5, 116.1, 115.9, 87.4, 82.0, 50.0, 19.0. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H19N3O4S, 422.1169; found, 422.1174.

N-(2-Aminophenyl)-4-nitro-N-(5-phenylpent-4-yn-1-yl)benzenesulfonamide 13b

The crude product was purified by silica gel chromatography using Hex:EtOAc (3:1, v/v) to give product 13b (305 mg, 71% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.36–8.27 (m, 2H), 7.92–7.82 (m, 2H), 7.37–7.32 (m, 2H), 7.32–7.21 (m, 3H), 7.12 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 6.81 (dd, J = 8.1, 1.4 Hz, 1H), 6.55 (ddd, J = 7.9, 7.3, 1.4 Hz, 1H), 6.26 (dd, J = 7.9, 1.5 Hz, 1H), 4.25 (s, 2H), 4.14–4.01 (m, 1H), 3.35 (ddd, J = 13.0, 8.0, 5.2 Hz, 1H), 2.53–2.44 (m, 2H), 2.03–1.61 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 150.4, 147.0, 143.7, 131.7, 130.1, 129.4, 128.4, 127.9, 127.9, 124.2, 124.0, 123.7, 118.6, 117.5, 88.4, 81.8, 51.5, 27.6, 17.0. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H21N3O4S, 436.1326; found, 436.1323.

12 General Procedure for Azidation (Products 11a–n and 14a,b)

50 mg of 10a–n or 14a,b was dissolved in 2 mL of 50% AcOH/ACN (1:1, v/v) (10a,b) or in 2 mL of 90% AcOH/dioxane (1:1, v/v) (10c, 10h, 10k, 10l, 13a, 13b) or in 2–10 mL (depending on solubility) of 10% HCl/ACN (2:3, v/v) (10f, 10g, 10i, 10j, 10m, 10n). The solution was cooled in an ice bath to 0 °C and a cooled solution of NaNO2 (1.2 equiv in 1 mL of water) was added dropwise into the stirring mixture. The reaction was then stirred at 0 °C for 30 min, and then the solution of NaN3 (2 equiv in 1 mL of water) was added dropwise. If the reaction mixture was not clear, it was filtered through a microfilter before adding NaN3. The reaction was stirred for another 30 min and then the resulting precipitate was filtered off under reduced pressure. The oily products 11i, 11j, 11k, and 14b were isolated by addition of water (50 mL) followed by extraction into DCM (3 × 50 mL). The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo.

N-(2-Azidophenyl)-4-methyl-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)benzenesulfonamide 11a

Pale yellow solid (201 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.48–8.19 (m, 2H), 8.05–7.95 (m, 2H), 7.56–7.50 (m, 2H), 7.45 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 7.34–7.26 (m, 3H), 7.24–7.12 (m, 2H), 4.71 (s, 2H).

N-(2-Azidophenyl)-4-nitro-N-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)benzenesulfonamide 11b

Orange solid (540 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 7.75–7.65 (m, 4H), 7.48–7.39 (m, 5H), 7.30 (dd, J = 8.1, 1.4 Hz, 1H), 7.18 (td, J = 7.6, 1.5 Hz, 1H), 7.07 (dd, J = 7.9, 1.5 Hz, 1H), 4.72 (s, 2H), 2.39 (s, 3H).

N-(2-Azidophenyl)-4-nitro-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 11c

Beige solid (115 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 8.35–8.28 (m, 2H), 8.06–7.97 (m, 2H), 7.44 (td, J = 7.7, 1.6 Hz, 1H), 7.29 (ddd, J = 7.0, 5.5, 2.2 Hz, 2H), 7.25–7.10 (m, 6H), 4.69 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 145.9, 132.4, 131.6, 130.9, 129.3, 129.0, 129.0, 128.5, 125.4, 124.1, 122.0, 120.0, 86.5, 82.6, 42.1.

Methyl 4-Azido-3-((4-nitro-N-(3-phenylprop-2-yn-1-yl)phenyl)sulfonamido)benzoate 11f

White solid (66 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 8.33–8.25 (m, 2H), 8.10 (dd, J = 8.4, 1.9 Hz, 1H), 8.06–7.99 (m, 2H), 7.87 (d, J = 1.9 Hz, 1H), 7.33–7.27 (m, 2H), 7.26–7.23 (m, 2H), 7.21–7.13 (m, 2H), 4.67 (s, 2H), 3.86 (s, 3H).

N-(2-Azido-5-nitrophenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 11g

Yellow solid (90 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 9.0, 2.7 Hz, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.76–7.67 (m, 2H), 7.55 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.40–7.31 (m, 3H), 7.23–7.14 (m, 2H), 4.75 (s, 2H), 2.38 (s, 3H).

N-(2-Azido-4,5-dimethylphenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 11h

Orange solid (67 mg, 78%). Not characterized due to partial spontaneous cyclization prior to NMR analysis.

N-(2-Azido-4-methoxyphenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 11i

Colorless oil. Used for the next step without isolation.

N-(2-Azido-4-chlorophenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide 11j

Colorless oil. Used for the next step without isolation.

N-(2-Azidophenyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide 11k

Orange oily substance. Used for the next step without isolation.

N-(2-Azidophenyl)-N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide 11l

Orange solid (110 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.70–7.60 (m, 2H), 7.38–7.32 (m, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.19–7.03 (m, 3H), 4.35 (s, 2H), 2.43 (s, 3H), 1.66 (t, J = 2.4 Hz, 3H). 13C NMR 101 MHz, CDCl3 δ 143.8, 139.3, 136.9, 132.5, 130.1, 130.0, 129.4, 128.2, 125.0, 119.9, 81.8, 73.2, 41.3, 21.7, 3.6.

N-(2-Azidophenyl)-N-(hex-3-yn-2-yl)-4-nitrobenzenesulfonamide 11m

Brown-yellow solid (155 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 8.35–8.30 (m, 2H), 8.01–7.95 (m, 2H), 7.44 (ddd, J = 8.1, 5.5, 3.5 Hz, 1H), 7.25 (dd, J = 8.5, 1.0 Hz, 1H), 7.09–6.99 (m, 2H), 5.21 (qt, J = 7.0, 2.1 Hz, 1H), 1.96 (qd, J = 7.5, 2.2 Hz, 2H), 1.28 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 145.5, 142.0, 131.7, 130.9, 129.9, 126.7, 124.7, 123.7, 120.1, 87.8, 77.8, 48.3, 21.3, 13.5, 12.2.

N-(2-Azidophenyl)-4-methyl-N-(4-phenylbut-3-yn-2-yl)benzenesulfonamide 11n

White solid (66 mg, 62%). Not characterized due to partial spontaneous cyclization prior to NMR analysis.

N-(2-Azidophenyl)-4-nitro-N-(4-phenylbut-3-yn-1-yl)benzenesulfonamide 14a

Yellow solid (126 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 8.31–8.23 (m, 2H), 7.96–7.88 (m, 2H), 7.45–7.40 (m, 1H), 7.34 (dd, J = 7.9, 1.6 Hz, 1H), 7.31–7.25 (m, 5H), 7.20–7.13 (m, 2H), 3.87 (bs, 2H), 2.63 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) 145.8, 139.0, 133.5, 131.7, 130.8, 129.0, 128.4, 128.4, 128.2, 125.6, 124.1, 123.2, 119.8, 86.0, 82.9, 50.1, 20.5.

N-(2-Azidophenyl)-4-nitro-N-(5-phenylpent-4-yn-1-yl)benzenesulfonamide 14b

Brown oil (240 mg, 75% yield). Not characterized; used crude for the next step.

13 General Procedure for Cyclization (12a–n and 15a,b)

Azide intermediate was dissolved in DMSO (1 mL to 50 mg) and subsequently, the mixture was stirred at 45 °C for 5 h (11a–n) or at 90 °C for 3 h (15a) or at 90 °C for 48 h (15b). Products 12a–n and 15a were obtained by precipitation from DMSO after the addition of water (1–2 mL). The oily product 15b was poured into 50 mL of water and subsequently extracted into EtOAc (3 × 50 mL). The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo.

5-Tosyl-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12a

Beige solid (75 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 8.02–7.97 (m, 1H), 7.97–7.89 (m, 1H), 7.80 (s, 4H), 7.56–7.49 (m, 2H), 6.97–6.89 (m, 2H), 6.87–6.75 (m, 2H), 5.23 (s, 2H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 145.0, 141.4, 133.4, 130.7 (q, J = 33.6 Hz), 129.5, 129.4, 129.1, 129.0, 128.7, 127.3, 126.7, 126.5, 126.4 (q, J = 3.5 Hz), 124.1 (q, J = 272 Hz), 125.2, 117.5, 42.6, 21.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H17F3N4O2S, 471.1097; found, 471.1101.

5-((4-Nitrophenyl)sulfonyl)-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12b

Beige solid (550 mg, 87%). 1H NMR (400 MHz, TFA-d) δ 8.15–8.06 (m, 3H), 8.00–7.90 (m, 3H), 7.82–7.67 (m, 4H), 7.55–7.47 (m, 2H), 5.47 (d, J = 1.6 Hz, 2H). 13C NMR (101 MHz, TFA-d) δ 153.3, 144.3, 141.5, 137.4 (q, J = 33.8 Hz), 135.0, 132.8, 131.5, 130.6, 130.5, 130.3, 129.7, 129.6 (q, J = 3.7 Hz), 129.5, 127.6, 126.9, 125.5 (q, J = 271.5 Hz) 120.9, 43.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H14F3N5O4S, 502.0791; found, 502.0793.

5-((4-Nitrophenyl)sulfonyl)-3-phenyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12c

Beige solid (132 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.06–7.98 (m, 1H), 7.95–7.90 (m, 1H), 7.89–7.83 (m, 2H), 7.67–7.45 (m, 7H), 7.23–7.16 (m, 2H), 5.25 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 150.3, 143.2, 141.8, 129.8, 129.6, 129.5, 129.3, 129.2, 128.8, 128.8, 127.9, 126.6, 126.5, 124.0, 123.9, 117.8, 42.9. HRMS (ESI pos.) m/z: [M + H]+ calcd for C21H15N5O4S, 434.0918; found, 434.0908.

Methyl 5-((4-Nitrophenyl)sulfonyl)-3-phenyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline-7-carboxylate 12f

White solid (20 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 1.7 Hz, 1H), 8.24 (dd, J = 8.4, 1.8 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.90–7.85 (m, 2H), 7.64–7.55 (m, 4H), 7.53–7.47 (m, 1H), 7.24–7.19 (m, 2H), 5.27 (s, 2H), 4.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.2, 150.4, 143.5, 141.7, 132.2, 130.9, 130.7, 130.1, 129.7, 129.4, 129.0, 127.9, 126.7, 126.4, 124.1, 124.0, 117.8, 53.0, 42.8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H17N5O6S, 492.0972; found, 492.0965.

7-Nitro-3-phenyl-5-tosyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12g

Yellow solid (20 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 8.9, 2.4 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.65–7.62 (m, 2H), 7.58–7.53 (m, 2H), 7.51–7.44 (m, 1H), 7.01–6.97 (m, 2H), 6.89–6.84 (m, 2H), 5.27 (s, 2H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 146.9, 145.5, 143.4, 133.3, 129.8, 129.5, 129.2, 129.2, 128.7, 128.0, 126.7, 126.6, 126.4, 124.6, 124.4, 123.9, 118.0, 42.4, 21.7. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H17N5O4S, 448.1074; found, 448.1076.

7,8-Dimethyl-3-phenyl-5-tosyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12h

Beige solid (16 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.69–7.57 (m, 3H), 7.57–7.47 (m, 2H), 7.49–7.38 (m, 1H), 6.98–6.90 (m, 2H), 6.85–6.76 (m, 2H), 5.15 (s, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.6, 142.7, 138.2, 137.6, 133.6, 130.1, 129.4, 129.3, 128.6, 127.3, 126.7, 126.6, 124.8, 124.1, 118.0, 42.8, 21.6, 20.0, 19.9. HRMS (ESI pos.) m/z: [M + H]+ calcd for C24H22N4O2S, 431.1536; found, 431.1532.

8-Methoxy-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 12i

White solid (150 mg, 71% after two steps). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 9.0 Hz, 1H), 7.68–7.58 (m, 2H), 7.58–7.49 (m, 2H), 7.49–7.39 (m, 2H), 7.00 (dd, J = 9.0, 2.9 Hz, 1H), 6.97–6.86 (m, 2H), 6.87–6.77 (m, 2H), 5.16 (s, 2H), 3.91 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 144.7, 142.9, 133.3, 130.3, 130.1, 129.9, 129.4, 129.3, 128.7, 126.7, 126.6, 124.3, 119.8, 114.9, 101.9, 56.1, 42.7, 21.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H20N4O3S, 433.1329; found, 433.1328.

8-Chloro-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 12j

White solid (154 mg, 85% after two steps). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.65–7.59 (m, 2H), 7.56–7.50 (m, 2H), 7.48–7.41 (m, 2H), 7.01–6.88 (m, 2H), 6.88–6.77 (m, 2H), 5.18 (s, 2H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 145.1, 143.0, 134.7, 133.3, 130.1, 130.0, 129.6, 129.6, 129.4, 128.9, 128.5, 126.6, 126.5, 125.7, 124.2, 117.6, 42.6, 21.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H17ClN4O2S, 437.0834; found, 437.0831.

5-Tosyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12k

White solid (30 mg, 32% after two steps). 1H NMR (400 MHz, CDCl3) δ 8.00–7.88 (m, 2H), 7.53–7.43 (m, 2H), 7.40 (d, J = 0.9 Hz, 1H), 7.09–7.03 (m, 2H), 6.96–6.89 (m, 2H), 5.07 (d, J = 0.8 Hz, 2H), 2.25 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.9, 133.5, 129.5, 129.3, 128.8, 128.7, 128.4, 128.3, 127.1, 126.7, 117.3, 42.1, 21.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H14N4O2S, 327.0910; found, 327.0900.

3-Methyl-5-tosyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12l

White solid (28 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.02–7.82 (m, 2H), 7.54–7.38 (m, 2H), 7.12–7.00 (m, 2H), 6.94 (d, J = 8.1 Hz, 2H), 4.94 (s, 2H), 2.26 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.9, 138.3, 133.8, 129.6, 129.4, 128.8, 128.2, 127.0, 126.5, 124.9, 117.2, 41.8, 21.6, 9.9. HRMS (ESI pos.) m/z: [M + H]+ calcd for C17H16N4O2S, 341.1067; found, 341.1064.

3-Ethyl-4-methyl-5-((4-nitrophenyl)sulfonyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 12m

Yellow solid (20 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 8.00–7.87 (m, 4H), 7.57–7.46 (m, 2H), 7.33–7.27 (m, 2H), 5.74 (q, J = 7.1 Hz, 1H), 2.68 (dd, J = 7.6, 2.5 Hz, 2H), 1.37 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.3, 143.5, 142.0, 129.6, 129.5, 129.0, 128.6, 128.5, 127.8, 123.9, 123.8, 117.4, 49.0, 20.7, 18.3, 13. 8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C18H17N5O4S, 400.1074; found, 400.1075.

4-Methyl-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 12n

White solid (27 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 8.09–7.98 (m, 1H), 7.97–7.90 (m, 2H), 7.89–7.83 (m, 1H), 7.73–7.65 (m, 4H), 7.63–7.56 (m, 2H), 7.54–7.46 (m, 1H), 7.28–7.19 (m, 2H), 5.87 (q, J = 7.0 Hz, 1H), 1.46 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 149.8, 141.1, 140.9, 129.9, 129.4, 129.3, 129.1, 129.0, 128.7, 128.2, 128.1, 127.7, 126.1, 124.2, 123.7, 117.3, 48.8, 19.4. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H17N5O4S, 448.1074; found, 448.1074.

6-((4-Nitrophenyl)sulfonyl)-3-phenyl-5,6-dihydro-4H-benzo[b][1,2,3]triazolo[1,5-d][1,4]diazepine 15a

Orange solid (150 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.06–7.95 (m, 2H), 7.85–7.68 (m, 4H), 7.61–7.52 (m, 4H), 7.52–7.45 (m, 2H), 7.45–7.38 (m, 1H), 4.36 b(s, 2H), 3.05 (brs, 2H). 13C NMR (101 MHz, DMSO-d6) δ 149.2, 143.9, 143.0, 134.5, 133.7, 131.1, 130.2, 130.1, 130.0, 128.9, 128.6, 128.1, 127.3, 126.6, 124.4, 51.9, 20.8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C22H17N5O4S, 448.1074; found, 448.1076.

7-((4-Nitrophenyl)sulfonyl)-3-phenyl-4,5,6,7-tetrahydrobenzo[b][1,2,3]triazolo[1,5-d][1,4]diazocine 15b

Isolated as brown oil (216 mg, 68% yield after two steps). Recrystallization from EtOH gave a brown crystalline solid. 1H NMR (400 MHz, CDCl3) δ 8.16–8.01 (m, 2H), 7.75–7.68 (m, 1H), 7.68–7.60 (m, 2H), 7.60–7.50 (m, 5H), 7.49–7.42 (m, 2H), 7.42–7.36 (m, 1H), 4.72 (brs, 1H), 3.23 (brs, 2H), 2.61 (brs, 1H), 2.08–1.97 (p, 2H). 1H NMR (400 MHz, DMSO-d6) δ 8.30–8.19 (m, 2H), 7.81–7.60 (m, 7H), 7.50 (dd, J = 8.4, 6.8 Hz, 2H), 7.44–7.38 (m, 1H), 7.33 (dd, J = 7.8, 1.5 Hz, 1H), 4.43 (brs, 1H), 3.16 (brs, 1H), 2.38 (brs, 1H), 2.00 (brs, 2H). 13C NMR (101 MHz, CDCl3) δ 150.1, 145.2, 144.6, 136.0, 135.0, 133.9, 132.1, 131.6, 131.1, 130.7, 129.1, 128.4, 128.1, 127.8, 126.9, 124.5, 53.1, 27.8, 21.8. HRMS (ESI pos.) m/z: [M + H]+ calcd for C23H19N5O4S, 462.1231; found, 462.1226.

Synthesis of 5-((4-Nitrophenyl)sulfonyl)-3-phenyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxalin-9-ol 12e

Compound 10d (250 mg, 0.535 mmol, 1 equiv) was dissolved in a mixture of 10 mL of ACN and 3 mL of 75% AcOH. The solution was cooled to 0 °C and vigorously stirred on a magnetic stirrer. Subsequently, a solution of 3 mL of NaNO2 (74 mg, 1.07 mmol, 2 equiv) was added. The reaction was stirred in an ice bath for 30 min, and then 4 mL of aqueous NaN3 solution (139 mg, 2.14 mmol, 4 equiv) was added. The reaction was stirred for an additional 15 min and then quenched with 50 mL of water and extracted into DCM (3 × 50 mL). The combined organic layers were dried using MgSO4, filtered, and evaporated to dryness in vacuo. The crude product was purified by precipitation in 50% AcOH/ACN (5:2, v/v), followed by filtration under reduced pressure to give a pale pink solid (50 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.04–7.90 (m, 2H), 7.71–7.56 (m, 4H), 7.54–7.47 (m, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.26 (dd, J = 8.0, 1.2 Hz, 1H), 7.23–7.11 (m, 3H), 5.25 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 149.8, 148.8, 141.2, 140.6, 129.3, 129.2, 128.7, 128.6, 128.6, 127.7, 126.5, 125.9, 124.2, 118.4, 117.9, 117.7, 42.3. HRMS (ESI pos.) m/z: [M + H]+ calcd for C21H15N5O5S, 450.1097; found, 450.0866.

General Procedures for Desulfonylation (Products 17c–l)

DBU (2 equiv) was added to a solution of 12a–l (50–100 mg per mL) and the solution was stirred for 3–5 h at room temperature for (12a–j) or at 90 °C (12k–l) for 24 h. Subsequently, water was added (three to five times the volume compared to the DMSO used), resulting in precipitation of the products, which were obtained by filtration under reduced pressure.

3-(4-(Trifluoromethyl)phenyl)-[1,2,3]triazolo[1,5-a]quinoxaline 17c

White solid (17 mg, 85%).1H NMR (400 MHz, TFA-d) δ 9.99 (s, 1H), 8.97 (dd, J = 8.5, 1.3 Hz, 1H), 8.39 (dd, J = 8.4, 1.3 Hz, 1H), 8.24–8.17 (m, 1H), 8.12–8.04 (m, 3H), 7.94–7.86 (m, 2H). 13C NMR (101 MHz, TFA-d) δ 153.2, 145.5, 137.7, 137.6 (q, J = 33.7 Hz), 135.4, 131.3, 131.2, 129.6, 129.6 (q, J = 3,7 Hz), 128.8, 126.0 (q, J = 271.5 Hz), 125.9, 125.4, 119.7. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H9F3N4, 315.0.0852; found, 315.0.0838.

3-Phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 17d

Brown solid (17 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.33–8.08 (m, 3H), 8.03–7.78 (m, 2H), 7.68–7.43 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 144.1, 141.3, 136.0, 130.4, 129.4, 128.9, 126.9, 125.3, 123.2, 115.1, 114.9. HRMS (ESI pos.) m/z: [M + H]+ calcd for C15H10N4, 247.0978; found, 247.0977.

3-Phenyl-[1,2,3]triazolo[1,5-a]quinoxalin-9-ol 17e

Pale brown solid (15 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.09–8.01 (m, 2H), 7.74 (dd, J = 8.2, 1.2 Hz, 1H), 7.69–7.58 (m, 3H), 7.56–7.51 (m, 1H), 7.41 (dd, J = 8.1, 1.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 148.4, 141.8, 138.2, 129.8, 129.6, 129.5, 127.6, 123.3, 120.6, 117.5, 114.9. HRMS (ESI pos.) m/z: [M + H]+ calcd for C15H10N4O, 263.0927; found, 263.0923.

Methyl 3-Phenyl-[1,2,3]triazolo[1,5-a]quinoxaline-7-carboxylate 17f

White solid (18 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.87 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 8.5 Hz, 1H), 8.45 (dd, J = 8.6, 1.8 Hz, 1H), 8.13–7.97 (m, 2H), 7.63–7.56 (m, 2H), 7.56–7.49 (m, 1H), 4.04 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.8, 144.7, 143.2, 136.4, 132.3, 131.2, 130.8, 129.8, 129.7, 129.6, 129.1, 127.6, 123.8, 116.2, 52.9. HRMS (ESI pos.) m/z: [M + H]+ calcd for C17H12N4O2, 305.1033; found, 305.1031.

7-Nitro-3-phenyl-5-tosyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 17g

Yellow solid (21 mg, 88%). 1H NMR (400 MHz, TFA-d) δ 9.94 (s, 1H), 9.32–9.20 (m, 1H), 9.13–8.95 (m, 1H), 8.92–8.74 (m, 1H), 7.97–7.88 (m, 2H), 7.68–7.56 (m, 3H). 13C NMR (101 MHz, TFA-d) δ 152.6, 151.3, 149.1, 135.2, 133.0, 132.6, 132.4, 130.7, 130.0, 127.1, 126.5, 124.1, 121.0. HRMS (ESI pos.) m/z: [M + H]+ calcd for C15H9N5O2, 292.0829; found, 292.0826.

7,8-Dimethyl-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 17h

Beige solid (18 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.51 (s, 1H), 8.17–8.01 (m, 2H), 7.94 (s, 1H), 7.61–7.55 (m, 2H), 7.52–7.46 (m, 1H), 2.57 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 142.5, 142.4, 141.1, 138.7, 135.2, 130.4, 130.0, 129.4, 129.2, 127.5, 124.4, 123.6, 115.9, 20.6, 20.1. HRMS (ESI pos.) m/z: [M + H]+ calcd for C17H14N4, 275.1291; found, 275.1289.

8-Methoxy-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 17i

Pink solid (34 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.15–8.01 (m, 4H), 7.62–7.55 (m, 2H), 7.52–7.46 (m, 1H), 7.33 (dd, J = 9.1, 2.8 Hz, 1H), 4.06 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.4, 142.2, 140.5, 131.5, 131.3, 130.2, 129.4, 129.2, 127.4, 127.3, 123.7, 118.9, 97.3, 56.4. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H12N4O, 277.1084; found, 277.1076.

8-Chloro-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 17j

White solid (35 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.08–8.01 (m, 2H), 7.71 (dd, J = 8.8, 2.3 Hz, 1H), 7.66–7.55 (m, 2H), 7.55–7.45 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 143.8, 143.7, 137.2, 134.5, 130.9, 130.1, 129.9, 129.6, 129.4, 127.7, 126.9, 123.6, 116.1. HRMS (ESI pos.) m/z: [M + H]+ calcd for C15H9ClN4, 281.0589; found, 281.0586.

[1,2,3]Triazolo[1,5-a]quinoxaline 17k

White solid (100 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.83–8.62 (m, 1H), 8.40 (s, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 1H), 7.97–7.64 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 143.3, 136.6, 130.7, 130.4, 129.5, 129.0, 127.1, 126.3, 116.0. HRMS (ESI pos.) m/z: [M + H]+ calcd for C9H6N4, 171.0665; found, 171.0664.

3-Methyl-[1,2,3]triazolo[1,5-a]quinoxaline 17l

Beige solid (45 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.64–8.56 (m, 1H), 8.20–8.09 (m, 1H), 7.91–7.85 (m, 1H), 7.84–7.79 (m, 1H), 2.71 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 144.4, 139.2, 135.9, 130.2, 129.8, 128.8, 125.5, 124.6, 115.0, 10.0. HRMS (ESI pos.) m/z: [M + H]+ calcd for C10H8N4, 185.0822; found, 185.0819.

General Synthesis Procedure for Denosylation with Thiolate (Products 16a–16c, 18, and 19)

Compounds 12b, 12m, 12n, 15a, and 15b (1 equiv) were dissolved in DMSO. The reaction vessel was closed with a lid with a rubber stopper and the solution was subsequently bubbled with N2 for at least 2 min. An equimolar solution of DBU and mercaptoethanol in DMSO (2 equiv) was then added to the solution via a needle. After the addition, the mixture was stirred for 30 min. The end of the reaction was indicated by LCMS. The reaction mixture was quenched with water to precipitate products 16a–c, which were obtained by filtering under reduced pressure and washing the filter several times with water. To obtain substances 18 and 19, the reaction was quenched with 50 mL of water and extracted with 3 × 50 mL of DCM. The combined organic layers were dried with MgSO4, filtered, and evaporated to dryness in vacuo. The crude product was subsequently purified by silica gel chromatography using Hex/EtOAc (3:1–1:1, v/v).

3-Ethyl-4-methyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 16a

White solid (190 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.0, 1.4 Hz, 1H), 7.12 (ddd, J = 8.1, 7.5, 1.5 Hz, 1H), 6.88 (ddd, J = 8.0, 7.5, 1.2 Hz, 1H), 6.76 (dd, J = 8.0, 1.2 Hz, 1H), 4.90 (q, J = 6.6 Hz, 1H), 3.99 (s, 1H), 2.75 (q, J = 7.6 Hz, 2H), 1.50 (d, J = 6.6 Hz, 3H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.5, 134.6, 128.8, 128.3, 122.3, 119.4, 116.7, 115.3, 45.7, 22.5, 18.7, 14.1. HRMS (ESI pos.) m/z: [M + H]+ calcd for C12H14N4, 215.1291; found, 215.1290.

4-Methyl-3-phenyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 16b

White solid (115 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.0, 1.4 Hz, 1H), 7.84–7.71 (m, 2H), 7.53–7.43 (m, 2H), 7.42–7.34 (m, 1H), 7.17 (td, J = 7.7, 1.4 Hz, 1H), 6.93 (td, J = 7.8, 1.2 Hz, 1H), 6.82 (dd, J = 8.1, 1.2 Hz, 1H), 5.22 (qd, J = 6.6, 2.1 Hz, 1H), 4.10 (s, 1H), 1.48 (d, J = 6.6 Hz, 3H). HRMS (ESI pos.) m/z: [M + H]+ calculated for C16H14N4, 263.1291; found, 263.1289.

3-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 16c

White solid (82 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 8.04–7.91 (m, 2H), 7.85 (dt, J = 8.2, 1.8 Hz, 3H), 7.16 (ddd, J = 8.2, 7.3, 1.5 Hz, 1H), 6.91 (dd, J = 8.2, 1.2 Hz, 1H), 6.86–6.74 (m, 1H), 6.61 (d, J = 1.9 Hz, 1H), 4.91 (d, J = 1.7 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 139.8, 137.2, 134.3, 128.8, 128.0 (q, J = 31.9 Hz), 126.8, 126.7, 126.9 (q, J = 3,7 Hz), 124.2 (q, J = 272 Hz), 120.9, 117.6, 115.8, 115.0, 38.5. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H11F3N4, 317.1009; found, 317.1001.

3-Phenyl-5,6-dihydro-4H-benzo[b ][1,2,3]triazolo[1,5-d][1,4]diazepine 18

Orange solid (90 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.2, 1.5 Hz, 1H), 7.78–7.67 (m, 2H), 7.52–7.43 (m, 2H), 7.43–7.34 (m, 1H), 7.23 (ddd, J = 8.0, 7.2, 1.5 Hz, 1H), 7.01 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.85 (dd, J = 8.1, 1.4 Hz, 1H), 4.07 (s, 1H), 3.70 (dd, J = 6.2, 5.1 Hz, 2H), 3.25 (dd, J = 6.3, 5.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 144.3, 138.4, 132.9, 131.4, 129.4, 128.9, 128.0, 127.7, 126.0, 124.6, 120.8, 120.7, 48.1, 24.1. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H14N4, 263.1291; found, 263.1288.

3-Phenyl-4,5,6,7-tetrahydrobenzo[b][1,2,3]triazolo[1,5-d][1,4]diazocine 19

Beige solid (50 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.87–7.74 (m, 2H), 7.51–7.42 (m, 2H), 7.42–7.32 (m, 2H), 7.19 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 6.78 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 6.68 (dd, J = 8.3, 1.3 Hz, 1H), 4.11 (t, J = 6.7 Hz, 1H), 3.18 (t, J = 6.6 Hz, 2H), 3.08 (m, J = 5.8 Hz, 2H), 1.84 (brs, 2H). 13C NMR (101 MHz, CDCl3) 143.4, 142.5, 133.7, 131.6, 130.2, 129.9, 128.9, 127.9, 126.8, 120.5, 118.6, 118.0, 41.1, 28.3, 20.1. HRMS (ESI pos.) m/z: [M + H]+ calcd for C17 H16N4, 277.1448; found, 277.1446.

General Procedure for Ring Oxidation (Products 17a and 17b)

16a or 16b (1 equiv) was dissolved in toluene and 5 equiv of MnO2 was added. The mixture was heated to 80 °C for 16 h. The end of the reaction was indicated by TLC with visualization by a KMnO4 solution. The mixture was filtered and evaporated to dryness in vacuo.

3-Ethyl-4-methyl-[1,2,3]triazolo[1,5-a]quinoxaline 17a

White solid (92%). 1H NMR (500 MHz, CDCl3) δ 8.70–8.52 (m, 1H), 8.14–7.89 (m, 1H), 7.75–7.56 (m, 2H), 3.24 (q, J = 7.6 Hz, 2H), 2.93 (s, 3H), 1.50 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 152.6, 145.0, 136.3, 129.0, 129.0, 128.5, 125.6, 124.3, 115.4, 23.5, 20.3, 14.6. HRMS (ESI pos.) m/z: [M + H]+ calcd for C12H12N4, 213.1135; found, 213.1133.

4-Methyl-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxaline 17b

White solid (98%). 1H NMR (500 MHz, CDCl3) δ 8.78–8.64 (m, 1H), 8.11–8.03 (m, 1H), 7.77–7.69 (m, 2H), 7.69–7.65 (m, 2H), 7.57–7.52 (m, 3H), 2.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.0, 143.9, 136.5, 130.8, 130.6, 129.4, 129.3, 129.2, 128.9, 128.6, 125.6, 124.3, 115.7, 24.3. HRMS (ESI pos.) m/z: [M + H] + calculated for C16H12N4, 261.1135; found, 261.1132.

Synthesis of 5-Methyl-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinoxaline 20

Compound 16c (31 mg, 0.1 mmol) was dissolved in 1 mL of DMSO, and DBU (40 μL, 0.27 mmol, 2.7 equiv) and MeI (60 μL, 0.96 mmol, 9.6 equiv) were added. The reaction was heated to 50 °C overnight. The next day, 3 mL of water was added to precipitate a brown powder. The crude product was purified by silica gel chromatography using Hex:EtOAc (7:3, v/v) to obtain compound 20 as a white solid (26 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 7.9, 1.5 Hz, 1H), 7.86–7.77 (m, 2H), 7.75–7.67 (m, 2H), 7.27 (ddd, J = 8.2, 7.5, 1.5 Hz, 1H), 6.98–6.90 (m, 1H), 6.80 (dd, J = 8.3, 1.2 Hz, 1H), 4.67 (s, 2H), 3.00 (s, 3H). HRMS (ESI pos.) m/z: [M + H]+ calcd for C17H13F3N4, 331.1165; found, 331.1164.

Synthesis of 1-(3-(4-(Trifluoromethyl)phenyl)-[1,2,3]triazolo[1,5-a]quinoxalin-5(4H)-yl)ethan-1-one 21

Compound 16c (20 mg, 0.064 mmol) was dissolved in 0.5 mL of DMSO, and DBU (40 μL, 0.26 mmol, 4 equiv) and Ac2O (40 μL, 0.42 mmol, 6.5 equiv) were added to the solution. The reaction mixture was heated to 50 °C for 3 h. Subsequently, 1 mL of water was added to precipitate the product. Compound 21 was obtained by filtration under reduced pressure and washing with 10 mL of water as a beige solid (22 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 8.33–8.14 (m, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.62–7.31 (m, 3H), 5.38 (s, 2H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.71, 141.65, 133.63, 130.5 (q, J = 32.6 Hz), 129.00, 128.17, 128.13, 128.04, 127.63, 127.07, 126.21 (q, J = 3.8 Hz), 125.11, 124.2 (q, J = 272 Hz), 118.29, 38.28, 22.31. HRMS (ESI pos.) m/z: [M + H]+ calcd for C18H13F3N4O, 359.1114; found, 359.1109.

General Procedure for Methyl Oxidation (Products 22 and 23)

Compound 17a or 17b was dissolved in THF, and then 1.5 equiv of SeO2 was added. The mixture was refluxed for 3 h and monitored by LCMS. Later, the reaction mixture was evaporated to dryness in vacuo and subsequently poured with 50 mL of water and extracted with 3 × 50 mL of EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness in vacuo. The crude product was purified by silica gel chromatography using Hex:EtOAc (7:3, v/v).

3-Ethyl-[1,2,3]triazolo[1,5-a]quinoxaline-4-carbaldehyde 22

Orange solid (52 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ 10.12 (s, 1H), 8.74 (ddd, J = 8.3, 1.4, 0.5 Hz, 1H), 8.27 (ddd, J = 8.2, 1.4, 0.5 Hz, 1H), 7.91 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.80 (ddd, J = 8.2, 7.3, 1.4 Hz, 1H), 3.48 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 191.1, 148.3, 146.9, 135.6, 133.2, 131.1, 129.2, 126.9, 121.6, 116.1, 21.4, 15.0. HRMS (ESI pos.) m/z: [M + H]+ calcd for C12H10N4O, 227.0927; found, 227.0924.

3-Phenyl-[1,2,3]triazolo[1,5-a]quinoxaline-4-carbaldehyde 23

Yellow solid (21 mg, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.78 (dd, J = 8.3, 1.3 Hz, 1H), 8.39 (dd, J = 8.2, 1.3 Hz, 1H), 8.09 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.97 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.77–7.64 (m, 2H), 7.60–7.43 (m, 3H). 13C NMR spectra were not recorded due to poor solubility. HRMS (ESI pos.) m/z: [M + H]+ calcd for C16H10N4O, 275.0927; found, 275.0926.

Synthesis of 1-(3-Ethyl-[1,2,3]triazolo[1,5-a]quinoxalin-4-yl)-N-phenylmethanimine 24

Compound 20 (5 mg, 0.027 mmol) was dissolved in 0.5 mL of dry EtOH, and aniline (5 μL, 0.053 mmol, 2 equiv) was added. The reaction mixture was heated to 70 °C for 2 h. Later, 200 μL of water was added and the solution was allowed to crystallize. The product was obtained as a yellow crystalline solid (3.5 mg, 43% yield). 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.77–8.69 (m, 1H), 8.16 (dd, J = 8.1, 1.3 Hz, 1H), 7.89–7.67 (m, 2H), 7.55–7.44 (m, 2H), 7.43–7.31 (m, 3H), 3.58 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.5 Hz, 3H). HRMS (ESI pos.) m/z: [M + H]+ calcd for C18H15N5, 302.1400; found, 302.1400.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c03979.1H and 13C spectra of the synthesized compounds (PDF)

Supplementary Material

ao4c03979_si_001.pdf

The authors declare no competing financial interest.

Acknowledgments

This work was supported by a grant from the Czech Science Foundation (Project 21-06553S) and internal grants from Palacky University (IGA_PrF_2024_028, IGA_LF_2024_038, and IGA_LF_2024_007).
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