Synthesis of Heteroannulated Indolopyrazines through Domino N-H Palladium-Catalyzed/Metal-Free Oxidative C-H Bond Activation.

A convenient approach to [1,2,5]oxadiazolo[3',4':5,6]pyrazino[2,3-b]indoles and their heteroannulated analogues bearing various aryl substituents in the backbone has been developed. This synthetic protocol is based on Pd-catalyzed Buchwald-Hartwig and subsequent annulation by intramolecular oxidative cyclodehydrogenation. The photophysical properties for new polycycles have been measured.

Introduction

Indolo[2,3-b]pyrazines are significant structural motifs possessing many important applications such as in medicinal chemistry and material sciences (Figure ). Namely, indolo[2,3-b]pyrazine derivatives display a wide range of promising biological activities, such as antibacterial,[1] anticancer,[2] and antiviral activities.[3] Many indolopyrazine derivatives have also been suggested as promising materials for organic electronics such as organic light-emitting diodes,[4] solar cells,[5] and organic transistor memory devices.[6]

Figure 1

Representative compound bearing the indolo[2,3-b]pyrazine core.

There are five main routes for construction of the indolopyrazine core that are described in the literature, and they should be discussed to identify their weaknesses (Scheme ). The most famous methods for the preparation of indolopyrazine consist in the condensation of isatin with o-phenylenediamine (route 1, Scheme )[1,2c,6,7] or condensation of in situ-generated 2,3-diaminoindole with α-dicarbonyl compounds (route 2, Scheme ).[8] Generally, the main limitations of these methods are obtaining regioisomeric mixtures of indolopyrazines, when unsymmetrical o-phenylenediamines or α-dicarbonyl compounds are used. Buchwald–Hartwig amination followed by C–H activation from secondary amines and 2,3-dibromoquinoxaline in one pot (route 3, Scheme )[9] and a two-step approach using Suzuki cross-coupling and subsequent annulation by Pd-catalyzed twofold C–N coupling reactions with primary amines (route 4, Scheme )[10] afford indolo[2,3-b]pyrazines in high yield but they similarly do not possess regioselectivity. Furthermore, routes 3 and 4 have not corresponded the concept of the pot, atom, and step economic (PASE)[11] synthetic procedure because it requires using 2,3-di(chloro)bromopyrazines that is necessary for an additional introduction of halogens in the pyrazine ring. Another regioselective method for the synthesis of the indolopyrazines based on a sequential rhodium-catalyzed formal [3+3] cycloaddition and aromatization reaction of various diazoindolinimines with azirines.[12] This protocol requires a highly expensive and non-eco-friendly rhodium catalyst and infrequent raw materials. All these features eventually lead to the necessity of developing new PASE processes to synthesize indolopyrazine and their heteroanalogues that will be based on the metal-free oxidative C–H bond functionalization (so-called SNH reaction).[13]

Scheme 1

Synthetic Routes to the Formation of the Indolo[2,3-b]pyrazine Scaffold

It should be mentioned that [1,2,5]oxadiazolo[3,4-b]pyrazine (so-called “ furazanopyrazine”) exhibits higher electron-withdrawing character than similar nonannulated pyrazine analogues and can be readily involved into the metal-free oxidative C–H bond functionalization.[14] Nowadays, there is only one example of the synthesis of unsubstituted 5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (I) and its 5-alkyl-substituted derivatives (II) as a new family of effective inhibitors for the β-catenin/T-cell factor protein–protein interaction (Scheme ).[15]

Scheme 2

Synthesis of 5H-[1,2,5]Oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (I) and its 5-Alkyl-Substituted Derivatives (II)

By the foregoing, furazanopyrizine derivatives have been selected as major precursors of novel aryl-substituted 5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indoles.

Results and Discussion

Synthesis

It has been found that the reaction of 5-(2-bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine 1 with aniline 2a afforded 5-phenyl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole 3a in good yield (Scheme ). The conditions of the domino reaction of 1 with aniline 2a were optimized (Table ). The ligand, palladium precursor, base, and solvent were varied. The results showed that tricyclohexylphosphine (PCy3) often gave better yields than other ligands. In fact, up to 45% yield of 3a was achieved by employment of PCy3 as a ligand in combination with Pd(OAc)2 as the Pd source (Table , entry 10).

Scheme 3

Domino Synthesis of 5-Phenyl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole 3a

Table 1

Optimization for the Synthesis of 3a

entry	Pd precursor (equiv)	ligand (20 mol %)	base (2.5 equiv)	solvent	yield 3a (%)
1	Pd(PPh3)4 (5 mol %)		K3PO4	1,4-dioxane	0
2	Pd(PPh3)4 (10 mol %)		K3PO4	1,4-dioxane	9
3	Pd(PPh3)2Cl2 (10 mol %)	PPh3	K3PO4	1,4-dioxane	15
4	Pd2(dba)3 (10 mol %)	PCy3	K3PO4	1,4-dioxane	28
5	Pd(OAc)2 (10 mol %)	XantPhos	K3PO4	1,4-dioxane	35
6	Pd(OAc)2 (10 mol %)	XPhos	K3PO4	1,4-dioxane	33
7	Pd(OAc)2 (10 mol %)	PCy3	DABCO	1,4-dioxane	0
8	Pd(OAc)2 (10 mol %)	PCy3	K2CO3	1,4-dioxane	35
9	Pd(OAc)2 (10 mol %)	PCy3	K3PO4	1,4-dioxane	40
10	Pd(OAc)2 (10 mol %)	PCy3	K3PO4	toluene	45

With the optimized conditions in hand, we examined the scope of the twofold C–N annulation reaction of 1 with various anilines 2b–i and benzylamine 2j. The results showed that the annulations gave the same yields for anilines bearing both electron-withdrawing and -donating substituents. However, the domino reactions with sterically crowded ortho-2b,f and meta-substituted 2c,g anilines have resulted in the expected 5-aryl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole 3 in lower yields than with unsubstituted 2a and para-substituted 2d,h anilines (Scheme ). In contrast, the reactions of 1 with alkylamines, using our optimized conditions (Table , entry 10), resulted in the formation of side products which were difficult to separate from the main product. The appropriate result was only achieved for the synthesis of product 3j derived from benzylamine in 59% yield. Structures of 5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indoles were verified by X-ray diffraction analysis performed for the single-crystal sample of 5-(m-tolyl)-substituted derivative 3i (Figure ), thus supporting the 1H and 13C NMR spectroscopic data.

Scheme 4

Synthesis and Structures of 5H-[1,2,5]Oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole Derivatives 3a–j

Figure 2

ORTEP of 3i with thermal ellipsoids at the 50% probability level.

A feasible reaction mechanism is depicted in Scheme . The reaction between the 1 and aniline 2a proceeds through the Buchwald–Hartwig amination, which gives intermediate A, followed by an intramolecular nucleophilic attack at C(6) position furazanopyrizine core B. The subsequent oxidation of dihydropyrazine intermediate B by air oxygen leads to the polycyclic system 3a.

To confirm this hypothesis, we carried out the reactions of furazanopyrazine 1 with aniline 2a without using any palladium catalyst only in the presence of various bases. It has been shown that transition-metal-free oxidative dehydrogenation cross-coupling reaction leads to 4a with the highest yield of 55% in the presence of sodium hydride as a base (Scheme ). Using these conditions allowed us to obtain a wide range of corresponding SNH products by the reaction of 1 with the same series of amines. It is supposed that these reactions’ C–H functionalization proceeds through nucleophilic substitution of hydrogen according to the two-step “Addition–Oxidation” mechanism.[13]

Scheme 5

Synthesis and Structures of N-Aryl-6-(2-bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amines 4a–i

To increase the yields of polycyclic compounds 3, we have carried out the annulation reaction of 4a in the earlier developed best conditions of Buchwald–Hartwig amination (Scheme ). Unfortunately, despite yields of intramolecular C–N coupling annulation being 72%, the two-step overall yield of 3a from compound 1 to 3a achieved only to 40%.

Scheme 6

Synthesis of 5-Phenyl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole 4a by Intramolecular Buchwald–Hartwig Amination

The suggested approach to the construction of the indolo[2,3-b]pyrazine core has also been applied successfully for the synthesis of different indolopyrazines with annulated benzene and/or thiophene rings (Scheme ). In this regard, it is noteworthy that the only reaction of 5-(3-bromothiophen-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine 5a with aniline 2a yielded desired 8-phenyl-8H-[1,2,5]oxadiazolo[3,4-b]thieno[2′,3′:4,5]pyrrolo[2,3-e]pyrazine 7a and compound 6a as a by-product. In other cases, the reactions of the bromine-substituted derivatives 5b–d with aniline 2a led to the classic Buchwald–Hartwig amination products 6b–d in 77–89% yields. Notably, using PCy3 as a ligand for the palladium catalyst in this case afforded products in yields only up to 40%, while the replacement of it by Xantphos significantly increased the yield of compounds 6b–d.

Scheme 7

Synthesis of Heteroannulated Indolopyrazine Derivatives 7a–d

Further treatment of amination products 6b–d by acids, followed by oxidation with air oxygen, also leads to similar cyclization products 7b–d. Following the literature, trifluoroacetic acid[16] was used for the cyclization of thiophenyl-substituted quinoxaline 6b, while a mixture of hydrochloric acid[17] in ethanol led to the transformation of amino derivatives 6a,c into indolopyrazines 7c,b in high yields (Scheme ).

Conclusions

In summary, we have described a convenient approach to construct derivatives of a key heterocyclic system, namely, [1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indoles, bearing various substituents in the pyrrole fragment, based on domino Pd-catalyzed Buchwald–Hartwig and subsequent annulation by intramolecular oxidative cyclodehydrogenation reactions. The two-step synthesis of other heteroannulated indolopyrazine analogues has been realized using this synthetic approach. The further design and synthesis of different indoloannulated derivatives using this reaction procedure, as well as the elucidation of photophysical and electronic properties of these polycyclic compounds, are currently in progress.

Experimental Section

General Information

All reagents and solvents were obtained from commercial sources and dried using standard procedures before use. 1H and 13C NMR spectra were obtained on Bruker DRX-400, AVANCE-500, and AVANCE-600 spectrometers with TMS as internal standards. Elemental analysis was carried out on a Eurovector EA 3000 automated analyzer. Melting points were determined on Boetius combined heating stages and were not corrected. All solvents used were dried and distilled as per standard procedures. IR spectra of samples (solid powders) were recorded on a Spectrum One Fourier transform IR spectrometer (PerkinElmer) equipped with a diffuse reflectance attachment (DRA). UV–vis spectra were recorded for ∼10–5 to 10–6 M CH2Cl2 solutions with a Shimadzu UV-2401PC spectrophotometer. X-ray diffraction analysis was performed on an automated X-ray diffractometer “Xcalibur E” based on the standard procedure. The deposition number CCDC 1989238 for 3i contains the Supporting Information crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

General Procedure for the Synthesis of 2-Bromophenyl and 3-(Bromothiophen-2-yl)-Substituted 1,4-Diazine Derivatives (1 and 5a–d)

Selenium dioxide (1.1 g, 10 mmol) was dissolved in 1,4-dioxane/H2O 15:1 (16 mL) and the mixture was heated at reflux for 5 min. 2′-Bromoacetophenone [or 2-acetyl-3-bromothiophene] (10 mmol) was added and heating continued for next 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the corresponding aryl glyoxal as light-yellow oil. The solution of 3,4-diaminofurazan [or 1,2-phenylenediamine] (10 mmol) and crude aryl glyoxal in a mixture of EtOH (5 mL) and CH3COOH (5 mL) was refluxed for 1 h. After that, the mixture was cooled down, and the precipitate was filtered off and washed with ethanol and then air-dried.

5-(2-Bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine (1)

2′-Bromoacetophenone and 3,4-diaminofurazan were used for the synthesis of product 1.

Yellow powder; yield 2.19 g (79%); mp 135 °C. 1H NMR (500 MHz, DMSO-d6): δ 9.44 (s, 1H), 7.91 (dd, J = 8.0, 1.1 Hz, 1H), 7.79 (dd, J = 7.6, 1.7 Hz, 1H), 7.68 (td, J = 7.6, 1.1 Hz, 1H), 7.63–7.59 (m, 1H). 13C NMR (126 MHz, DMSO-d6): δ 162.4, 157.1, 151.9, 151.1, 136.1, 133.4, 133.1, 132.4, 128.5, 121.0. Anal. Calcd for C10H5BrN4O (277.08): C, 43.35; H, 1.87; N, 20.22. Found: C, 43.41; H, 1.84; N, 20.10.

5-(3-Bromothiophen-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine (5a)

2-Acetyl-3-bromothiophene and 3,4-diaminofurazan were used for the synthesis of product 5a.

Pale yellow powder; yield 2.15 g (76%); mp 174–176 °C. 1H NMR (500 MHz, DMSO-d6): δ 9.79 (s, 1H), 8.19 (d, J = 5.3 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 154.5, 154.0, 151.9, 151.1, 135.3, 134.2, 134.1, 114.8. Anal. Calcd for C8H3BrN4OS (283.10): C, 33.94; H, 1.07; N, 19.79. Found: C, 33.92; H, 0.96; Br, 28.22; N, 19.69.

2-(3-Bromothiophen-2-yl)quinoxaline (5b)

2-Acetyl-3-bromothiophene and 1,2-phenylenediamine were used for the synthesis of product 5b.

Beige powder; yield 2.39 g (82%); mp 111–112 °C. 1H NMR (500 MHz, DMSO-d6): δ 9.72 (s, 1H), 8.15–8.09 (m, 2H), 7.98 (d, J = 5.3 Hz, 1H), 7.93–7.88 (m, 2H), 7.36 (d, J = 5.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 146.3, 142.7, 141.3, 140.7, 135.8, 132.8, 131.3, 131.1, 130.4, 128.9, 128.8, 109.8. Anal. Calcd for C12H7BrN2S (291.17): C, 49.50; H, 2.42; N, 9.62. Found: C, 49.54; H, 2.56; N, 9.38.

2-(2-Bromophenyl)pyrazine (5c)

Commercially available material 5c was used in our experiments.

2-(2-Bromophenyl)quinoxaline (5d)

2′-Bromoacetophenone and 1,2-phenylenediamine were used for the synthesis of product 5b.

Pale yellow powder; yield 2.28 g (77%); mp 112–113 °C (ref (18) 116–118 °C). 1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 8.21 (td, J = 6.1, 3.2 Hz, 2H), 7.85 (dt, J = 6.4, 3.4 Hz, 2H), 7.76 (dd, J = 8.0, 1.2 Hz, 1H), 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (td, J = 7.5, 1.2 Hz, 1H), 7.39 (td, J = 7.7, 1.7 Hz, 1H). Anal. Calcd for C14H9BrN2 (285.14): C, 58.97; H, 3.18; N, 9.82. Found: C, 58.88; H, 3.38; N, 9.69. Data similar to the literature.[18]

General Procedure for the Synthesis of 5-Aryl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indoles (3a–j)

A stirred mixture of 5-(2-bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine (1) (135 mg, 0.5 mmol), corresponding anilines (0.6 mmol), tricyclohexylphosphine (28 mg, 20 mol %), Pd(OAc)2 (11 mg, 10 mol %), and K3PO4 (265 mg, 1.25 mmol) in degassed 1,4-dioxane (15 mL) was heated at reflux under nitrogen for 15 h in a Schlenk tube. The reaction mixture was cooled, filtered, acidified with concentrated CH3COOH (1 mL), and dissolved with a mixture of EtOAc and water 1:1 (50 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried with MgSO4 and the solvents were evaporated. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography using hexane and ethyl acetate as an eluent.

5-Phenyl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3a)

Red powder; yield 65 mg (45%); mp 285–286 °C. R 0.45 (CHCl3/hexane = 1:1, v/v). 1H NMR (400 MHz, DMSO-d6): δ 8.41–8.38 (m, 1H), 7.83 (ddd, J = 8.4, 7.5, 1.3 Hz, 1H), 7.72–7.70 (m, 4H), 7.62 (ddt, J = 6.5, 4.9, 3.3 Hz, 1H), 7.50 (td, J = 7.6, 0.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 153.2, 151.7, 151.5, 148.8, 135.8, 133.5, 130.0, 129.0, 127.1, 124.8, 123.6, 118.3, 111.4. IR (DRA): 434, 446, 466, 496, 565, 592, 617, 627, 666, 691, 749, 775, 796, 807, 857, 880, 915, 946, 1008, 1019, 1030, 1057, 1081, 1110, 1168, 1180, 1128, 1259, 1307, 1330, 1379, 1445, 1486, 1502, 1551, 1586, 1598, 1621, 3079, 3099 cm–1. Anal. Calcd for C16H9N5O (287.28): C, 66.89; H, 3.16; N, 24.38. Found: C, 66.81; H, 3.18; N, 24.35.

5-(2-Methoxyphenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3b)

Red powder; yield 22 mg (14%); mp 248–250 °C. R 0.31 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.38 (dd, J = 7.7, 1.2 Hz, 1H), 7.80 (ddd, J = 8.4, 7.4, 1.3 Hz, 1H), 7.67–7.63 (m, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.48 (td, J = 7.5, 0.9 Hz, 1H), 7.41 (dd, J = 8.5, 1.2 Hz, 1H), 7.25 (td, J = 7.6, 1.2 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 3.77 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 155.7, 153.3, 152.2, 152.1, 149.5, 136.4, 131.8, 130.2, 125.1, 123.9, 121.7, 118.5, 113.7, 112.5, 56.3. Anal. Calcd for C17H11N5O2 (317.30): C, 64.35; H, 3.49; N, 22.07. Found: C, 64.42; H, 3.45; N, 21.93.

5-(3-Methoxyphenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3c)

Red powder; yield 76 mg (48%); mp 258–260 °C. R 0.25 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.42–8.37 (m, 1H), 7.83 (ddd, J = 8.4, 7.4, 1.3 Hz, 1H), 7.63 (t, J = 8.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.28 (dt, J = 3.6, 1.4 Hz, 2H), 7.21 (ddd, J = 8.4, 2.5, 1.0 Hz, 1H), 3.85 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 153.7, 152.2, 152.1, 152.0, 149.3, 136.4, 135.0, 131.3, 125.3, 124.1, 119.7, 118.8, 115.2, 113.4, 112.1, 56.0. Anal. Calcd for C17H11N5O2 (317.30): C, 64.35; H, 3.49; N, 22.07. Found: C, 64.30; H, 3.58; N, 22.09.

5-(4-Methoxyphenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3d)

Orange powder; yield 95 mg (60%); mp 271–273 °C. R 0.18 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 8.37 (ddd, J = 7.7, 1.3, 0.6 Hz, 1H), 7.81 (ddd, J = 8.5, 7.4, 1.3 Hz, 1H), 7.63–7.59 (m, 2H), 7.48 (td, J = 7.6, 0.8 Hz, 1H), 7.27–7.23 (m, 3H), 3.89 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 159.4, 153.2, 151.7, 151.5, 149.2, 135.8, 128.6, 125.9, 124.7, 123.4, 118.2, 115.2, 111.4, 55.5. IR (DRA): 453, 464, 484, 529, 567, 592, 623, 635, 644, 694, 725, 755, 771, 788, 797, 804, 815, 835, 842, 852, 875, 911, 936, 953, 969, 987, 1007, 1015, 1028, 1058, 1111, 1155, 1180, 1232, 1263, 1304, 1326, 1384, 1445, 1465, 1488, 1518, 1552, 1595, 1610, 1619, 3009, 3062 cm–1. Anal. Calcd for C17H11N5O2 (317.30): C, 64.35; H, 3.49; N, 22.07. Found: C, 64.51; H, 3.54; N, 22.26.

5-(3,4-Dimethoxyphenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3e)

Red powder; yield 111 mg (64%); mp 271–272 °C. R 0.28 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 8.37 (dt, J = 7.7, 0.9 Hz, 1H), 7.81 (ddd, J = 8.4, 7.4, 1.3 Hz, 1H), 7.48 (td, J = 7.5, 0.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.26 (dd, J = 5.4, 3.2 Hz, 2H), 7.22 (dd, J = 8.5, 2.2 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 153.2, 151.8, 151.5, 149.5, 149.4, 149.2, 135.8, 125.9, 124.6, 123.4, 119.8, 118.1, 112.3, 111.6, 110.9, 55.8. Anal. Calcd for C18H13N5O3 (347.33): C, 62.24; H, 3.77; N, 20.16. Found: C, 62.12; H, 3.61; N, 20.08.

5-(2-Nitrophenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3f)

Orange powder; yield 17 mg (10%); mp 274–275 °C. R 0.45 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.51–8.36 (m, 2H), 8.12 (td, J = 7.7, 1.5 Hz, 1H), 7.98 (ddd, J = 8.3, 6.5, 1.6 Hz, 2H), 7.89–7.83 (m, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 153.1, 152.1, 151.9, 151.8, 148.8, 146.4, 136.7, 136.4, 132.0, 131.6, 127.0, 126.9, 125.5, 124.7, 118.8, 112.1. Anal. Calcd for C16H8N6O3 (332.27): C, 57.84; H, 2.43; N, 25.29. Found: C, 57.89; H, 2.34; N, 25.17.

5-(3-Nitrophenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3g)

Orange powder; yield 56 mg (34%); mp 287–290 °C (decomp.). R 0.36 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.60 (t, J = 2.2 Hz, 1H), 8.48 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 8.43 (dd, J = 7.7, 1.2 Hz, 1H), 8.23 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 8.03 (t, J = 8.1 Hz, 1H), 7.86 (ddd, J = 8.5, 7.4, 1.3 Hz, 1H), 7.54 (td, J = 7.5, 0.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 153.7, 152.2, 152.1, 152.0, 149.1, 148.7, 136.4, 135.0, 134.3, 132.1, 125.4, 124.5, 124.3, 122.9, 119.0, 112.0. Anal. Calcd for C16H8N6O3 (332.27): C, 57.84; H, 2.43; N, 25.29. Found: C, 57.80; H, 2.25; N, 25.18.

5-(4-Nitrophenyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3h)

Orange powder; yield 91 mg (55%); mp 271–273 °C. R 0.35 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.60–8.56 (m, 2H), 8.44 (dd, J = 7.8, 1.2 Hz, 1H), 8.09–8.05 (m, 2H), 7.88 (ddd, J = 8.5, 7.4, 1.3 Hz, 1H), 7.57–7.52 (m, 2H). 13C NMR (151 MHz, DMSO-d6): δ 153.8, 152.2, 152.1, 152.0, 148.2, 147.2, 139.7, 136.4, 128.5, 125.8, 125.5, 124.7, 119.2, 112.2. IR (DRA): 463, 477, 492, 529, 598, 623, 689, 709, 747, 770, 793, 804, 827, 853, 865, 885, 913, 944, 1012, 1025, 1044, 1061, 1109, 1159, 1174, 1228, 1296, 1324, 1353, 1377, 1421, 1446, 1464, 1487, 1504, 1524, 1552, 1590, 1614, 3077, 3118 cm–1. Anal. Calcd for C16H8N6O3 (332.27): C, 57.84; H, 2.43; N, 25.29. Found: C, 57.54; H, 2.42; N, 25.15.

5-(m-Tolyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3i)

Red powder; yield 93 mg (62%); mp 262–264 °C. R 0.47 (CHCl3/hexane = 1:1, v/v). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 7.6 Hz, 1H), 7.87–7.77 (m, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.52–7.46 (m, 3H), 7.43 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 2.46 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ 153.2, 151.7, 151.5, 148.8, 139.6, 135.8, 133.4, 129.8, 129.7, 127.4, 124.7, 124.2, 123.5, 118.3, 111.5, 20.9. Anal. Calcd for C17H11N5O (301.30): C, 67.77; H, 3.68; N, 23.24. Found: C, 67.88; H, 3.65; N, 23.41.

5-Benzyl-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole (3j)

Red powder; yield 89 mg (59%); mp 210–212 °C. R 0.17 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.35–8.30 (m, 1H), 7.81 (td, J = 7.8, 7.4, 1.3 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.50–7.44 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 8.2, 6.6 Hz, 2H), 7.31–7.27 (m, 1H), 5.55 (s, 2H). 13C NMR (151 MHz, DMSO-d6): δ 153.6, 152.3, 152.3, 151.9, 148.5, 136.1, 136.0, 129.2, 128.2, 128.0, 125.2, 123.6, 118.8, 112.2, 44.9. Anal. Calcd for C17H11N5O (301.30): C, 67.77; H, 3.68; N, 23.24. Found: C, 67.56; H, 3.81; N, 23.24.

General Procedure for the Synthesis of N-Aryl-6-(2-bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amines (4a–i)

A stirred mixture of 5-(2-bromophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine (1) (135 mg, 0.5 mmol), corresponding anilines (0.6 mmol), and sodium hydride (24 mg, 1.0 mmol) in dry 1,4-dioxane (5 mL) was stirred at room temperature for 48 h. The reaction mixture was acidified with concentrated CH3COOH (1 mL). The solvent was distilled off in vacuo, and the crude product was purified by column chromatography using hexane and ethyl acetate as an eluent.

6-(2-Bromophenyl)-N-phenyl-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4a)

Yellow powder; yield 65 mg (55%); mp 174–175 °C. R 0.26 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 9.43 (s, 1H), 7.85 (dd, J = 8.1, 1.1 Hz, 1H), 7.76 (dd, J = 7.6, 1.7 Hz, 1H), 7.67 (td, J = 7.6, 1.2 Hz, 1H), 7.63–7.57 (m, 3H), 7.46–7.40 (m, 2H), 7.26 (tt, J = 7.3, 1.2 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 161.4, 152.4, 152.3, 150.2, 137.8, 133.5, 132.9, 132.0, 130.5, 129.0, 128.9, 127.6, 126.4, 124.8, 121.7. Anal. Calcd for C16H10BrN5O (368.19): C, 52.19; H, 2.74; N, 19.02. Found: C, 52.37; H, 2.63; N, 18.97.

6-(2-Bromophenyl)-N-(2-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4b)

Orange powder; yield 108 mg (54%); mp 207–208 °C. R 0.42 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.43 (s, 1H), 8.35–8.28 (m, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.82 (dd, J = 7.5, 1.7 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.68 (td, J = 7.8, 1.7 Hz, 1H), 7.27–7.20 (m, 1H), 7.14–7.06 (m, 2H), 3.68 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 161.2, 152.4, 151.2, 150.4, 150.1, 134.8, 133.7, 133.4, 131.6, 129.3, 126.8, 126.7, 122.0, 121.5, 121.3, 111.9, 56.7. Anal. Calcd for C17H12BrN5O2 (398.21): C, 51.27; H, 3.04; N, 17.59. Found: C, 51.50; H, 3.12; N, 17.81.

6-(2-Bromophenyl)-N-(3-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4c)

Yellow powder; yield 115 mg (58%); mp 171–172 °C. R 0.32 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 9.36 (s, 1H), 7.85 (dd, J = 8.1, 1.1 Hz, 1H), 7.75 (dd, J = 7.6, 1.7 Hz, 1H), 7.66 (td, J = 7.6, 1.2 Hz, 1H), 7.59 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.27–7.19 (m, 2H), 6.85 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.76 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 161.3, 159.7, 152.3, 152.2, 150.2, 139.0, 135.8, 133.5, 132.9, 132.1, 129.8, 128.9, 121.8, 117.0, 111.6, 110.6, 55.7. Anal. Calcd for C17H12BrN5O2 (398.21): C, 51.27; H, 3.04; N, 17.59. Found: C, 51.40; H, 2.97; N, 17.32.

6-(2-Bromophenyl)-N-(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4d)

Red powder; yield 125 mg (63%); mp 117–119 °C. R 0.35 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 9.34 (s, 1H), 7.84 (dd, J = 8.0, 1.1 Hz, 1H), 7.74 (dd, J = 7.6, 1.7 Hz, 1H), 7.65 (td, J = 7.5, 1.1 Hz, 1H), 7.58 (td, J = 7.8, 1.8 Hz, 1H), 7.53–7.45 (m, 2H), 7.02–6.97 (m, 2H), 3.77 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 161.5, 157.7, 152.5, 152.4, 150.2, 135.9, 133.5, 132.9, 131.9, 130.6, 128.9, 126.4, 121.7, 114.2, 55.8. Anal. Calcd for C17H12BrN5O2 (398.21): C, 51.27; H, 3.04; N, 17.59. Found: C, 51.50; H, 3.21; N, 17.58.

6-(2-Bromophenyl)-N-(3,4-dimethoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4e)

Dark red powder; yield 109 mg (51%); mp 166–167 °C. R 0.20 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 9.29 (s, 1H), 7.97–7.84 (m, 1H), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.66 (td, J = 7.6, 1.1 Hz, 1H), 7.59 (td, J = 7.8, 1.8 Hz, 1H), 7.29–7.22 (m, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H). 13C NMR (151 MHz, DMSO-d6): δ 161.4, 152.5, 152.3, 150.2, 148.7, 147.4, 135.8, 133.5, 132.9, 131.9, 130.8, 128.9, 121.7, 117.2, 111.9, 109.3, 56.13, 56.11. Anal. Calcd for C18H14BrN5O3 (428.24): C, 50.48; H, 3.30; N, 16.35. Found: C, 50.57; H, 3.28; N, 16.07.

6-(2-Bromophenyl)-N-(3-nitrophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4g)

Dark orange powder; yield 52 mg (25%); mp 163–165 °C. R 0.15 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.58 (t, J = 2.2 Hz, 1H), 8.23 (ddd, J = 8.2, 2.1, 0.9 Hz, 1H), 8.10 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 7.88 (dd, J = 8.1, 1.1 Hz, 1H), 7.78 (dd, J = 7.6, 1.7 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.69 (td, J = 7.5, 1.1 Hz, 1H), 7.63 (td, J = 7.8, 1.8 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 161.0, 152.2, 151.9, 150.3, 148.2, 139.2, 135.6, 133.6, 133.1, 132.2, 130.4, 130.4, 128.9, 121.8, 120.6, 118.7. Anal. Calcd for C16H9BrN6O3 (413.19): C, 46.51; H, 2.20; N, 20.34. Found: C, 46.36; H, 2.19; N, 20.07.

6-(2-Bromophenyl)-N-(4-nitrophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4h)

Orange powder; yield 79 mg (38%); mp 200–202 °C. R 0.23 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.36–8.29 (m, 2H), 8.06–8.01 (m, 2H), 7.87 (dd, J = 8.1, 1.1 Hz, 1H), 7.78 (dd, J = 7.6, 1.7 Hz, 1H), 7.69 (td, J = 7.5, 1.1 Hz, 1H), 7.62 (td, J = 7.8, 1.8 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 161.0, 151.9, 151.8, 150.3, 144.3, 144.2, 135.6, 133.6, 133.1, 132.4, 128.9, 124.8, 123.9, 121.8. Anal. Calcd for C16H9BrN6O3 (413.19): C, 46.51; H, 2.20; N, 20.34. Found: C, 46.71; H, 2.09; N, 20.36.

6-(2-Bromophenyl)-N-(m-tolyl)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-amine (4i)

Yellow powder; yield 102 mg (51%); mp 169–170 °C. R 0.50 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 9.35 (s, 1H), 7.85 (dd, J = 8.1, 1.1 Hz, 1H), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.66 (td, J = 7.5, 1.1 Hz, 1H), 7.58 (td, J = 7.8, 1.8 Hz, 1H), 7.50–7.44 (m, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.07 (ddt, J = 7.5, 1.8, 0.9 Hz, 1H), 2.32 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 160.9, 151.9, 151.8, 149.7, 137.8, 137.2, 135.3, 133.0, 132.4, 131.5, 128.4, 128.3, 126.6, 124.7, 121.4, 121.2, 21.0. Anal. Calcd for C17H12BrN5O2 (398.21): C, 51.27; H, 3.04; N, 17.59. Found: C, 51.37; H, 3.25; N, 17.54.

General Procedure for the Buchwald–Hartwig Cross-Coupling Reaction for the Synthesis of Compounds 6a and 7a

A stirred mixture of 5-(3-bromothiophen-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine (5a) (142 mg, 0.5 mmol), aniline (2a) (55 mg, 0.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (58 mg, 20 mol %), Pd(OAc)2 (11 mg, 10 mol %), and K3PO4 (265 mg, 1.25 mmol) in degassed 1,4-dioxane (15 mL) was heated at reflux under nitrogen for 15 h in a Schlenk tube. The reaction mixture was cooled, filtered, and dissolved with a mixture of AcOEt and water 1:1 (50 mL), and the organic layer was separated. The aqueous layer was extracted with AcOEt (2 × 25 mL). The combined organic extracts were dried with MgSO4 and the solvents were evaporated. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated. The crude products 6a and 7a were purified by column chromatography using hexane and ethyl acetate as an eluent.

2-([1,2,5]Oxadiazolo[3,4-b]pyrazin-5-yl)-N-phenylthiophen-3-amine (6a)

Violet powder; yield 15 mg (10%); mp 167–169 °C. R 0.12 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.19 (s, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.46–7.42 (m, 2H), 7.36–7.34 (m, 2H), 7.32 (d, J = 5.5 Hz, 1H), 7.18 (tt, J = 7.2, 1.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 157.2, 154.2, 152.1, 151.3, 150.7, 140.1, 137.4, 129.7, 124.1, 120.7, 118.7, 111.7. Anal. Calcd for C14H9N5OS (295.32): C, 56.94; H, 3.07; N, 23.71. Found: C, 56.72; H, 3.01; N, 23.48.

8-Phenyl-8H-[1,2,5]oxadiazolo[3,4-b]thieno[2′,3′:4,5]pyrrolo[2,3-e]pyrazine (7a)

Orange powder; yield 109 mg (74%); mp 274–275 °C. R 0.21 (CHCl3/hexane = 1:1, v/v). 1H NMR (600 MHz, DMSO-d6): δ 8.54 (d, J = 5.1 Hz, 1H), 7.80–7.77 (m, 2H), 7.70–7.67 (m, 2H), 7.55 (td, J = 7.3, 1.2 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H). 13C NMR (151 MHz, DMSO-d6): δ 159.4, 153.7, 151.6, 151.0, 148.0, 143.9, 135.1, 130.3, 128.7, 125.7, 114.6, 113.0. IR (DRA): 447, 485, 514, 556, 592, 606, 619, 649, 663, 675, 690, 704, 743, 759, 780, 793, 829, 859, 867, 882, 894, 915, 994, 1008, 1031, 1041, 1058, 1078, 1094, 1109, 1162, 1198, 1230, 1244, 1290, 1315, 1360, 1383, 1404, 1449, 1474, 1497, 1545, 1557, 1591, 3093, 3107 cm–1. Anal. Calcd for C14H7N5OS (293.30): C, 57.33; H, 2.41; N, 23.88. Found: C, 57.50; H, 2.47; N, 23.99.

General Procedure for the Buchwald–Hartwig Cross-Coupling Reaction for the Synthesis of Compounds 6b, 6c, and 6d

A stirred mixture of N-phenyl-2-(quinoxalin-2-yl)thiophen-3-amine (5b) [N-phenyl-2-(pyrazin-2-yl)aniline (5c) or N-phenyl-2-(quinoxalin-2-yl)aniline (5d) (0.5 mmol), aniline (2a) (55 mg, 0.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (58 mg, 20 mol %), Pd(OAc)2 (11 mg, 10 mol %), and K3PO4 (265 mg, 1.25 mmol) in degassed 1,4-dioxane (15 mL) was heated at reflux under nitrogen for 15 h in a Schlenk tube. The reaction mixture was cooled, filtered, and dissolved with a mixture of AcOEt and water 1:1 (50 mL), and the organic layer was separated. The aqueous layer was extracted with AcOEt (2 × 25 mL). The combined organic extracts were dried with MgSO4 and the solvents were evaporated. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated. The crude products 6b–d were purified by column chromatography using hexane and ethyl acetate as an eluent.

N-Phenyl-2-(quinoxalin-2-yl)thiophen-3-amine (6b)

Orange powder; yield 135 mg (89%); mp 148–150 °C. R 0.41 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.11 (s, 1H), 8.10 (dd, J = 8.3, 1.3 Hz, 1H), 8.01 (dd, J = 8.2, 1.4 Hz, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.82 (ddd, J = 8.3, 6.9, 1.5 Hz, 1H), 7.72 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.37–7.32 (m, 3H), 7.27–7.24 (m, 2H), 6.99 (tt, J = 7.3, 1.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 148.8, 145.5, 143.9, 142.4, 140.2, 139.3, 130.7, 130.1, 129.5, 128.7, 128.4, 127.8, 121.4, 120.8, 117.9, 113.5. Anal. Calcd for C18H13N3S (303.38): C, 71.26; H, 4.32; N, 13.85. Found: C, 71.07; H, 4.23; N, 13.84.

N-Phenyl-2-(pyrazin-2-yl)aniline (6c)

Yellow powder; yield 98 mg (79%); mp 82–84 °C. R 0.37 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 9.22 (s, 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.72 (t, J = 2.0 Hz, 1H), 8.57 (d, J = 2.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 4.0 Hz, 2H), 7.22 (t, J = 7.8 Hz, 2H), 7.10–7.02 (m, 3H), 6.86 (t, J = 7.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 153.1, 144.4, 142.9, 142.8, 142.1, 142.0, 130.5, 130.5, 129.2, 124.3, 120.8, 120.6, 118.5, 117.9. Anal. Calcd for C16H13N3 (247.29): C, 77.71; H, 5.30; N, 16.99. Found: C, 77.72; H, 5.29; N, 17.02.

N-Phenyl-2-(quinoxalin-2-yl)aniline (6d)

Yellow powder; yield 144 mg (77%); mp 122–123 °C. R 0.23 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.38 (s, 1H), 8.22 (dd, J = 8.2, 1.5 Hz, 1H), 8.09 (dd, J = 8.2, 1.5 Hz, 1H), 8.03 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 (dddd, J = 22.6, 8.4, 7.0, 1.5 Hz, 2H), 7.49–7.42 (m, 2H), 7.27 (dd, J = 8.5, 7.2 Hz, 2H), 7.20–7.15 (m, 2H), 7.10 (ddd, J = 8.1, 7.0, 1.4 Hz, 1H), 6.90 (tt, J = 7.2, 1.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 152.7, 145.8, 142.7, 142.5, 140.2, 139.9, 131.1, 130.9, 130.5, 129.7, 129.3, 128.7, 128.6, 123.6, 120.9, 120.5, 118.1, 117.9. Anal. Calcd for C20H15N3 (297.35): C, 80.78; H, 5.08; N, 14.13. Found: C, 80.70; H, 5.02; N, 14.20.

Synthesis of 4-Phenyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline (7b)

The suspension of N-phenyl-2-(quinoxalin-2-yl)thiophen-3-amine (6b) (152 mg, 0.5 mmol) in trifluoroacetic acid (5 mL) was stirred at 50 °C for 24 h. The solvent was removed under reduced pressure. The crude product 7b was purified by column chromatography using hexane and ethyl acetate as an eluent.

4-Phenyl-4H-thieno[2′,3′:4,5]pyrrolo[2,3-b]quinoxaline (7b)

Dark orange powder; yield 122 mg (81%); mp 200–201 °C. R 0.61 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 1H), 7.85 (dd, J = 40.7, 8.1 Hz, 2H), 7.52 (dt, J = 21.7, 7.3 Hz, 2H), 7.31–7.21 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.55 (dd, J = 62.2, 6.7 Hz, 2H), 5.96 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 150.1, 147.6, 147.2, 141.6, 141.4, 133.5, 131.2, 130.4, 129.7, 129.0, 128.4, 127.9, 126.7, 123.9, 121.7, 119.1. IR (DRA): 511, 538, 572, 607, 647, 698, 718, 737, 753, 789, 804, 841, 866, 894, 944, 974, 1017, 1048, 1062, 1100, 1128, 1139, 1164, 1190, 1209, 1234, 1272, 1313, 1348, 1380, 1402, 1430, 1446, 1482, 1516, 1529, 1577, 1596, 1618, 3057, 3099, 3181, 3279 cm–1. Anal. Calcd for C18H11N3S (301.37): C, 71.74; H, 3.68; N, 13.94. Found: C, 71.86; H, 3.35; N, 14.07.

General Procedure for the Synthesis of 5-Phenyl-5H-pyrazino[2,3-b]indole (7c) and 6-Phenyl-6H-indolo[2,3-b]quinoxaline (7d)

The suspension of N-phenyl-2-(pyrazin-2-yl)aniline (6c) [or N-phenyl-2-(quinoxalin-2-yl)aniline (6d)] (0.5 mmol) in EtOH/conc. HCl (10 mL, v/v 99:1) was refluxed for 1 h. The solvent was removed under reduced pressure. The crude products 7c and 7d were purified by column chromatography using hexane and ethyl acetate as an eluent.

5-Phenyl-5H-pyrazino[2,3-b]indole (7c)

Beige powder; yield 98 mg (80%); mp 158–160 °C. R 0.52 (EtOAc/hexane = 1:2, v/v). 1H NMR (500 MHz, CDCl3): δ 8.56 (d, J = 2.7 Hz, 1H), 8.43 (dt, J = 7.8, 1.0 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 7.65–7.60 (m, 4H), 7.59 (dd, J = 7.0, 1.3 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.50 (tt, J = 5.8, 2.6 Hz, 1H), 7.44 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 145.8, 141.4, 139.8, 137.6, 136.6, 135.3, 129.8, 129.3, 128.1, 127.1, 121.8, 121.7, 119.9, 110.7. IR (DRA): 449, 492, 533, 569, 594, 619, 638, 655, 695, 715, 740, 748, 762, 794, 804, 845, 866, 906, 936, 951, 973, 1012, 1024, 1077, 1104, 1149, 1157, 1171, 1211, 1230, 1270, 1281, 1304, 1327, 1344, 1407, 1456, 1477, 1503, 1545, 1579, 1596, 1621, 3055, 3072 cm–1. Anal. Calcd for C16H11N3 (245.28): C, 78.35; H, 4.52; N, 17.13. Found: C, 78.34; H, 4.76; N, 17.16.

6-Phenyl-6H-indolo[2,3-b]quinoxaline (7d)

Pale yellow powder; yield 109 mg (74%); mp 237–238 °C. R 0.32 (CHCl3/hexane = 1:1, v/v). 1H NMR (500 MHz, CDCl3): δ 8.57–8.51 (m, 1H), 8.32 (dd, J = 7.9, 1.9 Hz, 1H), 8.09 (dd, J = 7.9, 1.9 Hz, 1H), 7.77–7.62 (m, 7H), 7.54–7.49 (m, 2H), 7.44 (t, J = 7.5 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 145.8, 144.7, 140.5, 140.1, 139.8, 135.4, 131.0, 129.8, 129.2, 128.8, 128.2, 127.9, 127.1, 126.5, 122.6, 121.8, 119.8, 110.6. IR (DRA): 591, 619, 650, 695, 720, 749, 767, 781, 802, 830, 859, 909, 924, 955, 1007, 1016, 1027, 1043, 1074, 1101, 1134, 1148, 1175, 1207, 1228, 1254, 1305, 1320, 1337, 1355, 1392, 1405, 1460, 1471, 1484, 1504, 1583, 1598, 1609, 1629, 3057 cm–1. Anal. Calcd for C20H13N3 (295.34): C, 81.34; H, 4.44; N, 14.23. Found: C, 81.30; H, 4.51; N, 14.21.