One-Pot Synthesis of Benzo[4_,5]imidazo[2_,1-a]isoquinolines and Isoquinolino[3_,4-b]quinoxalines via Tandem Cyclization Strategies

Abstract

Two operationally simple one-pot protocols have been developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1–a]isoquinolines and isoquinolino[3,4–b]quinoxalines. Optimization data and substrate scope for these atom-economical transformations, which engage commercially available o-phenylenediamines and o-cyanobenzalde-hydes, are discussed.

Graphical Abstract

The extensive chemical literature reflects both the intriguing structural features and the far-reaching pharmaceutical applications of heterocyclic compounds.¹ Indeed, the development of effective methodology to construct complex heterocyclic structures plays an important role in the drug discovery process,² and these methods often enable the rapid generation of diverse small molecule libraries for high-throughput screening.³ In that context, one-pot tandem/domino reactions are powerful tools for the assembly of novel fused-ring systems from simple building blocks. These strategies employ atom- and step-economical transformations to introduce structural complexity by allowing multiple bond-forming events to occur in one transformative operation.⁴ Recently, we and others have reported tandem reactions as novel routes to attractive heterocyclic scaffolds.⁵ The targets of studies reported here are amino-functionalized benzo[4,5]imidazo[2,1–a]isoquinoline and isoquinolino[3,4–b]-quinoxaline cores as they appear in many bioactive compounds possessing antitumor, anticancer, antibacterial, antituberculosis, and antimalarial activities.⁶

One representative example is of a ring system embedding an isoquinolino[3,4–b]quinoxaline core, which was synthesized by relatively harsh conditions.⁷ The synthesis of benzo[4,5]-imidazo[2,1–a]isoquinolines has previously been accomplished by transition-metal-catalyzed cross-coupling reactions.⁸ These methods are interesting but generally require prefunctionalization of precursors and often confront purification challenges in meeting rigorous limits for heavy metal impurities in drug research.⁹ These limitations prompted our investigation into a more effective transition-metal-free method to construct the aforementioned heterocyclic motifs.

Recently, Cheon et al.^10a and earlier Jiao et al.^10b demonstrated convenient protocols for the synthesis of benzimidazoles (e.g., 2) from o-phenylenediamines and aldehydes via a condensation/aerobic oxidation sequence. For example, in the Cheon work, initial condensation of an aniline with benzaldehyde produced imine intermediate 1, which subsequently underwent 5-exo-tet cyclization promoted by a nucleophilic catalyst (KI) to furnish benzimidazole 2 after aerobic oxidation (Scheme 1). Building on a 1987 report from Smith et al., who employed cyanide and N-o-nitrobenzylidene to give cinnoline 1-oxide analogues,^11a Cheon et al.^10a employed o-phenylenediamines, aldehydes, and cyanide anion to produce 2-aminoquinoxalines (6, X = H).¹¹

Scheme 1.

Synthetic Strategies toward Benzo[4,5]imidazo[2,1–a]isoquinolines and Isoquinolino[3,4–b]quinoxalines

Building on these strategies, we envisioned that appropriate methods could be developed for the synthesis of our target scaffolds (Scheme 1) when X = CN. Specifically, N-alkylation of 2a with an RCH₂X electrophile (R = EWG) followed by base-mediated cyclization was envisioned to transform 2a into tetracycle 4. Conversely, addition of the 2-amino moiety of 5 to the electrophilic aryl nitrile (X = CN) would, after air oxidation, result in formation of the fused isoquinoline substructure 7. Herein, we report one-pot routes to amino-functionalized benzo[4,5]imidazo[2,1–a]isoquinolines and isoquinolino[3,4–b]quinoxalines via the tandem annulation of o-cyanobenzaldehydes with o-phenylenediamines derivatives.

We began our studies by examining the feasibility of the N-alkylation reaction between benzimidazole 2a and an RCH₂X-type electrophile, such as ethyl 2-bromoacetate. This alkylation would install an enolizable moiety on one of the benzimidazole nitrogens and deprotonation with added base would generate the corresponding enolate anion. Subsequent intramolecular attack of this enolate onto the nitrile of the benzonitrile would form an isoquinoline ring affording tetracyclic product 4.

Indeed, treating o-phenylenediamine and o-cyanobenzaldehyde with a stoichiometric amount of KI in DMF at 80 °C cleanly delivered 2a in excellent yield (Scheme 1).^10,11 Having this benzimidazole substrate in hand, the stage was set for a detailed study of the tandem N-alkylation/base-mediated cyclization of 2a to 4a. As summarized in Table 1, various reaction conditions were evaluated for the 2a → 4a conversion. Surprisingly, the use of a strong base, NaH in acetone or THF at 0 °C, did not promote the transformation, rather resulting in the recovery of starting material (entries 1 and 2). However, a low yield of 4a was observed with a weaker base: K₂CO₃ in acetone at 80 °C (entry 3). Switching to the more polar solvent DMF and heating at the same temperature (entry 4) significantly improved the reaction, delivering the desired product in 54% yield. Interestingly, the uncyclized intermediate 3a could not be isolated under any of these conditions, suggesting its conversion to 4a is rapid. The structure of tetracyclic product 4a was unambiguously established by X-ray crystallographic analysis (see the Supporting Information).¹²

Table 1.

Optimization Studies: Tandem Process of 2a→4a

entry	solvent	base	temp (°C)	yielda (%)
1	acetone	NaH	0	NRb
2	THF	NaH	0	NRb
3	acetone	K2CO3	80	<10
4	DMF	K2CO3	80	54

^aYield reported is the overall yield of 4a from 2a.

^bNR denotes no reaction occurred

The solvent compatibility of these two steps (e.g., DMF for both formation of 2a and its subsequent conversion to 4a) encouraged us to combine the efficient benzimidazole formation step with the subsequent tandem N-alkylation/base-mediated cyclization to give a one-pot synthesis of 4. Once optimized conditions were in hand for this one-pot method, we set out to explore the generality and limitation of this method. As depicted in Table 2, the one-pot protocol effectively transformed a variety of o-phenylenediamines, electrophiles, and o-cyanobenzaldehyde into the corresponding tetracycles (4a–e) in moderate overall yields. The scope was, however, restricted to symmetrical o-phenylenediamines since the N-alkylation of unsymmetrical o-phenylenediamines results in an intractable mixture of products.

Table 2.

Substrate Scope: One-Pot Route to Benzo[4,5]imidazo[2,1–a]isoquinolin-5-amines^a

^aIsolated yields. Products characterized by ¹H, ¹³C NMR, IR, and HRMS.

As outlined in Scheme 1, formation of 2 proceeds via the cyclization of imine intermediate 1. We thus envisioned that cyanide addition to imine 1a followed by subsequent heterocyclization could lead to isoquinolino[3,4–b]quinoxalines 7 via the 3,4-dihydroquinoxalin-2-amine intermediate 5. Our speculation leading into this study was that 2-aminoquinoxaline 5 (X = CN) would not be isolable because 5 would cascade on to 7 faster than it would undergo oxidation to 6 even though, when X ≠ CN, oxidation of 5 does lead to 6.¹¹ Proceeding with that idea, initial investigations centered on defining conditions to best provide imine intermediate 1a, since the o-phenylenediamine plus o-cyanobenzaldehyde going to imine reaction (see Scheme 1) is plagued by the imine undergoing cyclization to unwanted benzimidazole 2a. As outlined in Table 3, we set out to address this question with optimization studies and we were pleased to find that the reaction run in THF under nitrogen led to an excellent conversion to imine 1a (entry 3). Other solvent systems/conditions also produced 1a, but together with variable amounts of benzimidazole 2a.

Table 3.

Iminoaniline Optimization Studies

entry	solvent	conditions	yield (%)
1	MeOH	rt	63
2	DCM	rt	51
3	THF	rt/N2	98
4	DMF	rt	90
5	MeCN	rt	15
6	THF	rt/open air	58

Interestingly, DMF gave 1a in high yield (Table 3, entry 4) and it was also the only solvent to promote subsequent annulation in the presence of added M⁺CN⁻ to afford 7a in a one-pot protocol (see Table 4); other polar aprotic solvents, such as MeCN, HMPA, and DMSO, resulted in no detectable formation of 7a. In addition, THF (the most efficient solvent for the formation of 1a) with added M⁺CN⁻ gave only a trace amount of 7a. In all cases, the only identified side product, together with unreacted starting materials, was benzimidazole 2a.

Table 4.

One-Pot Isoquinolino[3,4–b]quinoxaline (7a) Optimization Studies

entry	M+CN−	solvent	conditionsa	yieldb (%)
1	KCN	DMF	under N2/NaCl	15
2	KCN	DMF	under N2/18-crown-6	28
3	KCN	DMF	under N2/none	31
4	KCN	MeCN	under N2/none	0
5	NaCN	DMF	under N2/none	37
6	NaCN	DMF	open air/none	36
7	NaCN	MeCN	under N2/none	0
8	NaCN	HMPA	under N2/none	0
9	NaCN	DMSO	under N2/none	0
10	NaCN	THF	under N2/Bu4NCl	tracec

^aConditions: under N₂ or open to the air/additive.

^bOverall yield.

^cTrace; determined by LCMS of the crude reaction.

In light of these one-pot two-step results, we also examined a two-pot method (Scheme 2). Here, performing step one (imineformation) in THF, concentration under vacuum, and subsequent addition of NaCN in DMF delivered the targeted 7a but the overall yield (28%) was comparable to the one-pot method (see Table 4, entry 6). The inescapable conclusion of these one- and two-pot o-phenylenediamines plus o-cyanobenzaldehyde going to isoquinolino[3,4–b]quinoxalines studies is that (i) imine 1 is reluctant to react with cyanide (leading to recovered starting materials upon workup; the major issue when reactions are run at room temperature) and (ii) there is unwanted benzimidazole formation (1 → 2; this becomes a significant issue when reactions are heated to 80 °C). Together, these two issues deter the effectiveness of 1 → 5 (Scheme 1), thekey transformation required for isoquinolino[3,4–b]quinoxaline formation.

Scheme 2.

Two-Pot Synthetic Route to Isoquinolino[3,4–b]quinoxaline 7a and 7b

Finally, it is noteworthy that 7a and 7b are highly fluorescent, suggesting potential fluorophore applications. Despite their slight electronic differences, both 7a and 7b have λ_max^excitation bands of 292, 392, and 414 nm that do not vary in the solvents examined (chloroform, acetonitrile, acetone, and ethanol; i.e., polar aprotic to polar protic solvents). Likewise, both isoquinolino[3,4–b]quinoxalines display similar emission profiles ranging from 430 to 460 nm, but these small changes do not result in a visual fluorescence change in the examined solvents. The UV-Vis and fluorescence spectra of 7a and 7b can be found in the accompanying Supporting Information.

In summary, we have developed one-pot two-step routes to novel amino-functionalized benzo[4,5]imidazo[2,1–a]-isoquinolines as well as novel amino-functionalized isoquinolino-[3,4–b]quinoxalines starting from the same substrates: o-phenylenediamines and o-cyanobenzaldehyde. The former proceeds via benzimidazole formation followed by N-alkylation/cyclization, whereas the latter involves nucleophilic addition of cyanide to the imine intermediate and subsequent annulation.

EXPERIMENTAL SECTION

General Methods.

All solvents and reagents were purchased from commercial suppliers and used without further purification. Analytical thin-layer chromatography was carried out on silica precoated glass plates (silica gel 60 F254, 0.25 mm thickness) and visualized with UV light at 254 nm. Flash chromatography was performed with 60 Å, 35–70 μm particle-size silica gel. Concentration refers to rotary evaporation under reduced pressure. ¹H NMR spectra were recorded on an NMR spectrometer operating at 600 MHz at ambient temperature with CDCl₃ or DMSO-d₆ as solvent. ¹³C NMR spectra were recorded on an NMR spectrometer operating at 150 MHz at ambient temperature with CDCl₃ or DMSO-d₆ as solvent. Data for ¹H NMR are recorded as follows: δ chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet; br, broad), coupling constant (Hz), integration. Chemical shifts are reported in parts per million relative to CDCl₃ (¹H NMR: δ 7.26; ¹³C NMR: δ 77.16), DMSO-d₆ (¹H NMR, δ 2.50; ¹³C NMR, δ 39.52), or TMS (¹H NMR, δ 0.00). Infrared spectra were recorded on an FT-IR spectrometer (with a Platinum ATR attachment) with the major peaks listed. Melting points were recorded on an automated melting point system. Liquid chromatography/mass spectrometry (LC/MS) data were obtained to verify molecular mass and analyze purity of products. The specifications of the LC/MS instrument are as follows: electrospray (+) ionization, mass range of 100–1500 Da, 5 V cone voltage, C18 column (2.1 mm × 50 mm × 3.5 μm), gradient mobile phase consisting of acetonitrile, water, and 0.1% formic acid (FA) buffer, and a flow rate of 0.2 mL/min. High-resolution mass spectra were obtained on an orbitrap (ion trap) mass spectrometer equipped with an electrospray ionization source, operating in the positive or negative ion mode. Samples were introduced into the source via loop injection at a flow rate of 150 μL/min, in a solvent system of 1:1 acetonitrile:water with 0.1% formic acid. The spectra were externally calibrated using the standard calibration mixture, and then further calibrated internally to <2 ppm with the lock mass tool.

CCDC 1432428 (for 1a; see Table 3) and CCDC 1432427 (for 4a; see Table 1) contain the supplementary 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.

(E)-2-(((2-Aminophenyl)imino)methyl)benzonitrile (1a).

o-Phenylenediamine (1 mmol, 108 mg) and o-cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 μL) at room temperature under N₂. After 30 min, an orange precipitate was formed, and stirring was continued until reaction was judged complete by thin-layer chromatography (TLC). The resulting solid was collected by filtration and washed with minimal amounts of cold THF to afford 1a (216 mg, 98%) as a yellow solid. Mp: 108–109 °C.IR(neat): v_max = 3451,3348,2223,1602, 1491, 1322, 1261, 1152, 963, 766, 742 cm⁻¹. ¹NMR (600 MHz, DMSO-d₆): δ = 8.85 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H),7.95 (d, J = 7.6Hz, 1H), 7.81 (t, J = 7.6 Hz, 1h), 7.63 (t, J = 7.6 Hz, 1h), 7.31 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1h), 6.79 (d, J = 7.6 Hz, 1h), 6.59 (t, J = 7.6 Hz, 1H), 5.50 (s, 2H). ¹³C NMR (151 MHz, DMSO-d₆): S = 151.3,145.4, 138.2,134.7,133.3,133.1,130.8,130.7,129.1,118.9,116.7,116.0,115.1, 109.1. HRMS calcd for [C₁₄H₁₁N₃ + H]⁺: 222.1031, found 222.1014.

2-(1H-Benzo[d]imidazol-2-yl)benzonitrile (2a).

o-Phenylenediamine (1 mmol, 108 mg), o-cyanobenzaldehyde (1 mmol, 131 mg), and KI (1 mmol, 166 mg) were dissolved in DMF (10 mL) and the mixture stirred at 80 °C in an open flask for 22–24 h. Upon completion and cooling to room temperature, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 × 100 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (gradient 25–50% EtOAc/hexane) to afford 2a as a white solid (190 mg, 87% yield). Mp: 255–256 °C. IR (neat): v_max = 3062, 2677, 2226, 1621, 1455, 1433, 1401, 1371, 1316, 1284, 1229, 1137, 1080,1007,972,765,745 cm⁻¹.¹H NMR (600 MHz, DMSO-d₆): δ = 10.35 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1h), 7.56 (m, 2H), 7.34 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆): δ = 151.3, 145.4,138.2, 134.7, 133.3, 133.1, 130.8, 130.7, 129.1, 118.9, 116.7, 116.0, 115.1, 109.1. HRMS calcd for [C₁₄H₉N₃ + H]⁺: 220.0875, found 220.0858.

Ethyl 5-Aminobenzo[4,5]imidazo[2,1 -a]isoquinoline-6-carboxy-late (4a).

Benzo[d]imidazole 2a (1 mmol, 219 mg) was dissolved in DMF (10 mL) containing potassium carbonate (2 mmol, 276 mg) and ethyl 2-bromoacetate (1.2 mmol, 200 mg); the resulting mixture was stirred at 80 °C for 24 h. Upon completion, water (30 mL) was added to the cooled mixture, which was subsequently extracted with ethyl acetate (3 × 100 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting crude material was purified by column chromatography and subsequent recrystallization from ethanol afforded 4a (200 mg, 66%) as a yellow solid. Mp: 182–183 °C (recrystallized in EtOH). IR(neat): v_max = 3420, 3288, 2985, 1682, 1634, 1617, 1542, 1512, 1451, 1361, 1250, 1189, 1094, 1024, 753 cm⁻¹.¹H NMR (600 MHz, CDQ3): δ = 8.81 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.79 (d, J =8.0Hz,1H), 7.71 (t, J = 7.5 Hz, 1H), 7.61 (t, J= 7.5 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.39 (t, J= 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1h), 6.07 (s, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H). ¹³C NMR (151 MHz, CDQ3): δ = 163.8, 144.9, 143.7, 139.6, 132.4, 131.0, 130.0, 126.1, 126.0, 125.7,123.5, 122.1, 121.2, 119.8, 114.6, 105.0, 61.5, 14.4. HRMS calcd for [C₁₈H₁₅N₃O₂ + H]⁺: 306.1243, found 306.1231.

Benzo[4,5]imidazo[2,1-a]isoquinolines (4a-e). General Procedure A.

The appropriate o-phenylenediamine (1 mmol), o-cyanobenzaldehyde (1 mmol, 131 mg), and KI (1 mmol, 166 mg) were dissolved in DMF (10 mL) and stirred at 80 °C in an open flask for 22–24 h. Potassium carbonate (2 mmol, 276 mg) and the appropriate alkylating agent (R²CH₂Br; 1.2 mmol) were added to the reaction vessel, the contents were sealed, and the mixture was heated at 80 °C for 24 h. Upon completion and cooling, water (30 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 × 100 mL). The combined organics were then washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting crude material was purified by column chromatography and the resulting product was recrystallized from ethanol to afford 4a-e.

Ethyl 5-Aminobenzo[4,5]imidazo[2,1-a]isoquinoline-6-carboxy-late (4a).

Prepared according to general procedure A. The crude material was purified by flash chromatography (2.5% MeOH/DCM) to afford 4a as a yellow solid (200 mg, 66% yield): see spectral data listed above.

(5-Aminobenzo[4,5]imidazo[2,1-a]isoquinolin-6-yl)-phenylmethanone (4b).

Prepared according to general procedure A. The crude material was purified by flash chromatography (2.5% MeOH/DCM) to afford 4b as an orange solid (236 mg, 70% yield). Mp: 263–264 °C (recrystallized in EtOH). IR (neat): v_max = 3284, 3156, 1625, 1607, 1563, 1535, 1455, 1344, 1299, 1251, 1070, 923, 906, 846, 771,733,684 cm⁻¹.¹H NMR (600 MHz, DMSO-d₆): S = 8.94 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.86 (m, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.55 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (m, 3H), 7.04 (d, J = 7.5 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.12 (s, 2H). ¹³C NMR (151 MHz, DMSO-d₆): δ = 187.3, 143.5, 143.1, 139.3, 138.3, 132.6, 131.2, 131.0, 130.3, 128.8,128.5,125.8,125.3,125.2,124.3,122.8,121.1,119.3,113.0, 109.5. HRMS calcd for [C₂₂H₁₅N₃O + H]⁺: 338.1293, found 338.1285.

Ethyl 5-Amino-9,10-dimethylbenzo[4,5]imidazo[2,1–a]-isoquinoline-6-carboxylate (4c).

Prepared according to general procedure A. The crude material was purified by flash chromatography (2.5% MeOH/DCM) to afford 4c as a yellow solid (183 mg, 55% yield). Mp: 217–218 °C (recrystallized in EtOH). IR (neat): v_max = 3408, 3286, 3167, 2981, 2914, 1682, 1622, 1582, 1543, 1511, 1–4-55, 1363, 1292, 1246, 1185, 1156, 1082, 1024, 895, 844, 757, 684 cm⁻¹.¹H NMR (600 MHz, CDCl₃): δ = 8.78 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.74–7.64 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.30 (s, 1H), 6.02 (s, 2h), 4.51 (q, J = 7.2 Hz, 2H), 2.43 (s, 6H), 1.37 (t, J =7.2 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ = 164.0, 144.4, 142.4, 139.3, 132.6, 131.0, 130.9, 130.3, 129.6, 126.4, 125.8, 125.4, 122.0, 119.7, 114.7, 105.3, 61.4, 21.0, 20.6, 14.4. HRMS calcd for [C₂₀H₁₉N₃O₂ + H]⁺: 334.1556, found 334.1543.

(5-Amino-9,10-dimethylbenzo[4,5]imidazo[2,1-a]isoquinolin-6-yl)phenylmethanone (4d).

Prepared according to general procedure A. The crude material was purified by flash chromatography (gradient 3050% EtOAc/hexane) to afford product 4d as a red solid (180 mg, 46% yield). Mp: 220–221 °C (recrystallized in EtOH). IR (neat): v_max = 3283,3155,1627,1565, 1537,1448, 1343,1290, 1248,1176,1090,983, 913, 892, 829, 768, 714, 691 cm⁻¹. ¹H NMR (600 MHz, CDCl₃): δ = 8.87 (d, J =8.0 Hz, 1H),7.91 (d, J =8.0 Hz, 1H),7.78 (t, J =8.0 Hz, 1H), 7.68 (ddd, J =8.0,7.5,1.4 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.5 Hz, 2h), 7.35 (td, J = 7.5, 1.4 Hz, 1H), 7.20 (t, J = 7.5 Hz, 2H), 6.76 (s, 1H), 6.10 (s, 2H), 2.27 (s, 3H), 2.06 (s, 3H). ¹³C NMR (151 MHz, CDCl₃): δ = 188.6.143.7.142.2.138.4.137.9.132.8.132.6.131.1.131.0.130.1.129.9, 128.9, 128.8, 126.3, 125.9, 125.6, 122.4, 119.5, 113.8, 113.7, 20.5, 20.4. HRMS calcd for [C_MH₁₉N3O + H]⁺: 366.1606, found 366.1593.

Ethyl 5-Aminonaphtho[2′,3′:4,5]imidazo[2,1-a]isoquinoline-6-carboxylate (4e).

Prepared according to general procedure A. The crude material was purified by flash chromatography (10% MeOH/DCM) to afford product 4e as a yellowish tan solid (114 mg, 30% yield). Mp: 217.1–218.6 °C. IR (neat): v_max =3282, 3166, 3132, 2200, 2138, 2066,1666 cm⁻¹.¹H NMR (600 MHz, CDCl₃): δ = 8.93 (d, J = 9.87 Hz, 1H), 8.40 (s, 1H), 8.05 (d, J = 8.63 Hz, 1H), 7.96 (m, 2H), 7.88 (d, J = 8.88 Hz, 1H), 7.82 (t, J = 15.05, 7.65 Hz, 1H), 7.77 (t, J = 15.29,7.65 Hz, 1H), 7.44 (m, 2H), 6.05 (bs, 2H), 4.58 (q, J= 21.84, 7.85, 7.59 Hz, 2H),1.35 (t, J = 14.17, 7.33 Hz, 3h). ¹³C NMR (150 MHz, CDCl₃): δ = 163.7.148.3.143.5.139.1.132.9.131.1.130.9.130.7.129.1.128.1.127.9, 126.7, 126.6, 126.0, 124.0, 123.9, 122.0, 116.0, 110.9, 105.4, 61.5, 14.3. HRMS calcd for [C₂₂H₁₇N₃O₂ + H]⁺: 356.1394, found 356.1399.

Isoquinolino[3,4-b]quinoxalin-5-amine (7a). One-Pot Protocol.

o-Phenylenediamine (1 mmol, 108 mg) and o-cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 μL) at room temperature. After 30 min, a precipitate was formed, and stirring was continued until the reaction was judged complete by TLC. To this reaction mixture was added sodium cyanide (1.1 mmol, 54 mg) in DMF (10 mL), and the resulting mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction flask to afford a yellow precipitate, which was collected by filtration and washed with cold chloroform to afford 7a (91 mg, 37%) as a yellow solid: mp Mp: >400 °C. IR(neat): v_max =3348, 3127, 2742, 1666, 1607, 1589, 1513, 1477, 1451, 1431, 1399, 1360, 1234, 1150, 1017,913, 753 cm⁻¹. ¹H NMR (600 MHz, DMSO-d₆): S = 9.10 (dd, J =8.0, 1.3 Hz, 1H), 8.47 (d, J =8.0 Hz, 1H), 8.17 (dd, J= 8.0, 1.3 Hz, 1H), 8.09 (s, 2H), 8.03–7.97 (m, 2H), 7.93 (td, J = 7.7, 1.3 Hz, 1H), 7.80 (ddd, J = 8.0, 6.6, 1.4 Hz, 1H), 7.72 (ddd, J = 8.0, 6.6, 1.4 Hz, 1h). ¹³C NMR (151 MHz, DMSO-d₆): δ = 159.2, 149.7, 143.1, 138.5, 136.1.133.1.131.5.130.5.129.7.128.5.127.7.127.0.124.4.124.2.122.2, HRMS calcd for [C₁₅H₁₀N₄ + H]⁺: 247.0984, found 247.0965.

9,10-Dimethylisoquinolino[3,4-b]quinoxalin-5-amine (7b). One-Pot Protocol.

4,5-Dimethylbenzene-1,2-diamine (1 mmol, 136 mg) and o-cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 μL) at room temperature. After 30 min, a precipitate was formed, and stirring was continued until the reaction was judged to be complete by TLC. To this reaction mixture was added sodium cyanide (1.1 mmol, 54 mg) in DMF (10 mL) and the resulting mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction flask to afford a yellow precipitate, which was collected by filtration and washed with cold chloroform to afford 7b (82 mg, 30%) as a yellow solid: mp 333–334 °C. IR (neat): v_max =3506, 3403, 3314, 3174, 1640, 1617, 1585, 1517, 1446, 1408, 1358, 1214, 1004, 869, 767, 729, 674 cm⁻¹. ¹H NMR (600 MHz, DMSO-d₆): S = 9.03 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.09–7.93 (m, 3H), 7.91–7.85 (m, 2H), 7.75 (s, 1H), 2.46 (s, 6H). ¹³C NMR (151 MHz, DMSO-d₆): δ = 158.9, 149.1, 142.2, 140.6.138.0.137.6.135.2.133.6.131.8.130.4.127.6.126.7.124.7.124.2, 122.0, 20.1, 19.8. HRMS calcd for [C₁₇H₁₄N₄ + H]⁺: 275.1297; found 275.1281.

Isoquinolino[3,4-b]quinoxalin-5-amine (7a). Two-Step Protocol.

o-Phenylenediamine (1 mmol, 108 mg) and o-cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 μL) at room temperature. After 30 min, a precipitate was formed, and stirring was continued until the reaction was judged complete by TLC. THF was removed in vacuo resulting in an orange oil. To this oil was added sodium cyanide (1.1 mmol, 54 mg) in DMF (10 mL), and the resulting mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction flask to afford a yellow precipitate, which was collected by filtration and washed with cold chloroform to obtain 7a (69 mg, 28%): see the spectral data above.

9,10-Dimethylisoquinolino[3,4-b]quinoxalin-5-amine (7b). Two-Step Protocol.

4,5-Dimethylbenzene-1,2-diamine (1 mmol, 136 mg) and o-cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 μL) at room temperature. After 30 min, a precipitate formed, and stirring was continued until the reaction was judged complete by TLC. THF was removed in vacuo resulting in an orange oil. To this oil was added sodium cyanide (1.1 mmol, 54 mg) in DMF (10 mL), and the resulting mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction flask to afford an off-yellow/orange precipitate, which was collected by filtration and washed with cold chloroform to afford 7b (82 mg, 30%) as a yellow-brown solid: see the spectral data above.