A reaction of 1,2-diamines and aldehydes with silyl cyanide as cyanide pronucleophile to access 2-aminopyrazines and 2-aminoquinoxalines

Abstract

A new condensation reaction of ethylene-1,2-diamines or o-phenylenediamines and aromatic aldehydes with TMSCN as a cyanide-pronucleophile is documented. The reaction proceeds through a tandem sequence of desilylation, Strecker reaction, amidine-forming cyclization and dehydrogenative aromatization, and provides a straightforward synthetic route to access synthetically and biologically important motifs, 3-aryl substituted 2-aminopyrazines and 2-aminoquinoxalines. DBU with its unique function and rate-accelerating effect has made it possible to realize a reaction that involves several C–C/N/Si bond forming/breaking events. Interestingly, the protocol has enabled the desired tandem pathway, switching exclusively from usual transformations.

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Introduction

Trialkylsilyl cyanide in Si-hypercoordination by a Lewis base generates a silicate intermediate that the bears potential to release active cyanide nucleophiles. This chemical property of especially trimethylsilyl cyanide (TMSCN) as an effective cyanide pronucleophile has been utilized extensively, since the first reports by Evans¹ and Lidy² in 1973, in the cyanosilylation reaction of carbonyl compounds. The exploitation of such a property of TMSCN is also known in the addition to imines (Strecker³ and Reissert reactions⁴), aziridines⁵ (average dissociation energy of N–Si is 420 kJ mol⁻¹), oxiranes,⁶ and nitrones.⁷

The multicomponent reaction (MCR)⁸ is a powerful tool for exploring the synthesis of a wide range of molecular skeletons, including heterocyclic scaffolds.⁹ In the direction of use of bifunctional substrates in the MCR, although keto-acids have received significant attention, 1,2-diamines are relatively underexplored.¹⁰ The reactions provide 1,4-diazaheterocycles possessing amidine with substitutions derived from isocyanides. However, the full potential of reactivity of amidine functionality that is used in versatile reactions can be realized only after possibility of removal of the substitutions (e.g., by dealkylation) of 2-secondary amine in this class of compounds, which would allow structural diversification. Herein, we report a new tandem multicomponent reaction of ethylenediamine or o-phenylenediamine (OPDA) and aldehyde with trialkylsilyl cyanide as cyanide-pronucleophile and its nitrile functionality as an effective electrophile, which affords an efficient and direct route to access 2-amine and 3-aryl substituted pyrazine and quinoxaline scaffolds.

The compounds containing pyrazine or quinoxaline, including their 2-amino derivatives are known to display a wide range of therapeutic activities. Furthermore, 2-aminopyrazines and 2-aminoquinoxalines are excellent synthones for construction of versatile N-heterocycles especially via reactions of amidine functionality and pyrazine is a valuable nucleus for arene C–H functionalization. These heterocyclic azines are also used as ligands in metal-complex catalysts. Despite their enormous importance, surprisingly, the synthesis of 2-aminopyrazine is limited to classical methods (Scheme 1a). It was first accomplished by a classical imine-formation based condensation reaction of glyoxal with 2-aminoacetamidine.¹¹ The intramolecular amidine-forming reaction via nucleophilic addition of amine with nitrile functionality of a Schiff base obtained from diaminomaleonitrile (DAMN) and benzoyl cyanide towards construction of 2-aminopyrazine was reported.¹² Later, the reaction was modified by oxidative conditions for Schiff base derived from ethylenediamine and benzoyl cyanide.¹³

Scheme 1 (a) Literature methods for the synthesis of 2-aminopyrazine; (b) literature methods for the synthesis of 2-aminoquinoxaline.

Other methods include Chichibabin amination of pyrazine using sodamide,¹⁴ amination of 2-halopyrazine using ammonia¹⁵ or sodium azide,¹⁶ Curtius rearrangement¹⁷ of pyrazine-2-carbamate derived from corresponding carboxylic acid and subsequent trapping of isocyanate with alcohol. These methods are obviously feeble for preparation of versatile functionalized/substituted 2-aminopyrazines that are required in current drug discovery research and as synthones in the organic synthesis.

2-Aminoquinoxaline (Scheme 1b) has been prepared by Chichibabin amination¹⁴ of quinoxaline, a three-steps process involving condensation of OPDA, aldehyde and tetramethylbutyl isocyanide, oxidation by DDQ and de-iso-octylation,¹⁸ and a recent process of condensation of OPDA, aldehyde and sodium cyanide/potassium cyanide.¹⁹ The preparation of 2-aminoquinoxalines via a reaction of 2-nitrosoanilines with 2-nitrobenzylcyanides has narrow substrate scope.²⁰ Therefore, literature-precedence is well-indicating the importance of development of a strategy that can enable in a straightforward and efficient process to access 2-aminopyrazines and is also applicable to preparation of 2-aminoquinoxalines.

Results and discussion

At the outset, we envisaged that chemistry aspects associated with the present reaction of 1,2-diamine, aldehyde and TMSCN could cause potential problems for its development (Scheme 2). An acid as a reactant/catalyst in a MCR provides required electrophilic activation; on the other hand, acid in the MCR reaction using TMSCN causes the undesired Strecker reaction,²¹ and in the reaction of phenylenediamine with aldehyde produces benzimidazole (almost exclusively) and N-benzylimidazole.²² Secondly, in the present reaction, the dehydrogenative aromatization is only the irreversible transformation, an important requirement of MCR to proceed, and requires the oxidative conditions. In addition, the aromatic aldehyde in the presence of cyanide anion is known to undergo benzoin condensation.²³ To minimize/circumvent these impediments, we judiciously considered the conditions. Importance were given to nucleophilic desilylation of TMSCN by a non-protic base,²⁴ generation of silyl-based byproduct that can act as Lewis acid for required chemoselective electrophilic activation of functionalities, and presence of oxidant effective for promoting in situ dehydrogenative aromatization.

Scheme 2 Possible transformations of the reaction.

A model reaction of o-phenylenediamine and 4-chlorobenzaldehyde with TMSCN for construction of 2-aminoquinoxaline was chosen. In preliminary screening of various conditions, formation of benzimidazole as a major or exclusive product was observed, indicating high preference of imine's electrophilic attack by intramolecular amine nucleophile over the desire attack by in situ generated cyanide anion (Strecker reaction). We were glad to see that the usual reaction course forming benzimidazole was switched to desired direction of Strecker–Ugi pathway by DABCO-mediated nucleophilic activation of TMSCN in the reaction under oxygen (balloon pressure) as oxidant. No benzimidazole product formed, although the desired 2-aminoquinoxaline was obtained in low (30%) yield (Table 1, entry 1). Furthermore, the product derived from benzoin condensation did not form. Changing oxidizing agent to DDQ or copper(II) acetate resulted in more side reactions. We realized the importance of the nucleophilic activation of TMSCN in promoting the present reaction and thus considered screening of various amine bases (Table 1, entries 2–7). The reaction with DBU was found to be dramatically faster (completed at 1 h) compared to all other bases in which the conversions were substantially incomplete after 24 h.²⁵ For DBU-mediated reaction, great chemoselectivity as well as good yield (70%) were obtained by lowering the reaction temperature to an optimum (RT) and using an optimal quantity (1.2 equiv.) of TMSCN and DBU. For reaction with L-proline or 2-hydroxypyridine, which act as dual nucleo/electrophilic activators, substrates remained nearly intact and a mixture of products formed in traces. Use of anhydrous form of reaction solvent (THF) provided similar yield, although little of product formed in aqueous solvent, ruling out the possibility of HCN as active cyanating species. The screening of solvents (used as received commercially without prior distillation) indicated that 1,4-dioxane was best. Increasing the dilution from 1 (M) solution to an optimal 0.33 (M) enhanced further the yield (92%). Pre-formation of imine was found to be non-mandatory although it was required for a faster reaction. It is interesting to note the distinctive features of bases, which were found important for promoting the present reaction involving TMSCN as cyanide-pronucleophile as well as Strecker–Ugi-type pathway. The obtained results were not in correlation with common parameters of bases, Brønsted basicity (pK_HB⁺), carbon basicity,²⁶ H-bonding basicity (pK_HB)²⁷ and carbon-nucleophilicity (see Table S1 in ESI†). Non-involvement of HCN as cyanating species in the reaction rules out also the influence of pK_HB. The silicon-philicity of amine “N” of bases to react with TMSCN is certainly a significant influencing factor. The results along with high rate-acceleration clearly exemplify the unique function of DBU²⁸ as extremely efficient promoter and superior to other bases, which suggests that the sterically hindered nucleophilic tertiary amidine–amine motif of DBU is important to facilitate the reaction, although the exact reason is currently unclear. This represents an important finding in addition to the previous disclosures of DBU as an effective catalyst/promoter, in contrast to its usual hindered basic property, explored in (hetero)aromatic O/N–H methylation,^25a carboxylic acid esterification,^25b and the Baylis–Hillman reaction involving stabilization of the intermediate β-ammonium enolate.^25c

Table 1 Optimization of reaction conditions for the synthesis of 2-aminoquinoxaline

#	Base (equiv.)	Temp. (°C)	TMSCN (equiv.)	Solvent (mL)	Time (h)	Yield^b (%)
a Substrates, reagents and conditions: 1,2-phenylenediamine (1 mmol), ArCHO (1 equiv.), TMSCN (1.2 equiv.), base, solvent (3 mL), O2, Temp. (°C), 36–48 h.b Yield for maximum conversion in optimum time.c RT (25–27 °C).
1	DABCO (1)	70	1	THF (1)	24	30
2	DBU (1)	70	1	THF (1)	1	34
3	TMEDA (1)	70	1	THF (1)	24	16
4	DIPEA (1)	70	1	THF (1)	24	25
5	Triethylamine (1)	70	1	THF (1)	24	18
6	Piperazine (1)	70	1	THF (1)	24	8
7	Piperidine (1)	70	1	THF (1)	24	12
8	L-Proline (1)	70	1	THF (1)	24	NR
9	2-Hydroxypyridine (1)	70	1	THF (1)	24	NR
10	DBU (1)	RT^c	1	THF (1)	24	62
11	DBU (1.2)	RT	1.2	THF (1)	24	70
12	DBU (1.2)	RT	1.2	Anhyd. THF (1)	24	72
13	DBU (1.2)	RT	1.2	DMF (1)	24	42
14	DBU (1.2)	RT	1.2	1,4-Dioxane (1)	24	81
15	DBU (1.2)	RT	1.2	2-Methyl–THF (1)	24	60
16	DBU (1.2)	RT	1.2	PEG-400 (1)	24	43
17	DBU (1.2)	RT	1.2	t-Butyl methyl ether (1)	24	38
18	DBU (1.2)	RT	1.2	n-Butanol (1)	24	70
19	DBU (1.2)	RT	1.2	t-Butanol (1)	24	62
20	DBU (1.2)	RT	1.2	1,4-Dioxane (2)	24	87
21	DBU (1.2)	RT	1.2	1,4-Dioxane (3)	36	92
22	DBU (1.2)	RT	1.2	1,4-Dioxane (5)	48	77

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Next, we were curious to immediate check the applicability of the approach to the synthesis of 2-aminopyrazines, which is relatively underexplored. Accordingly, a reaction of ethylene-1,2-diamine and 4-chlorobenzaldehyde with TMSCN was performed. Surprisingly, the desired 2-aminopyrazine was obtained in 35% yield only and the conversion remained substantially incomplete. The use of oxidizing agents, DDQ, CAN, CuCl₂, AgNO₃ or MnO₂ was ineffective to improve the yield. Gratifyingly, MnO₂ in alkaline methanolic solution²⁹ provided 2-aminopyrazine in 75% yield. With this optimized protocol, we investigated its generality for varied starting materials (Table 2). We were pleased to find that aromatic aldehydes containing both electron-withdrawing as well as electron-donating functionalities and heteroaromatic aldehydes underwent the reaction smoothly. Unfortunately, aliphatic aldehydes (isobutyraldehyde, octanal, phenylpropionaldehyde) produced multiple products along with desired 2-aminopyrazines, according to mass spectrometry, which could not be isolated. The variation of ethylenediamine component is also viable in the method. In case of unsymmetric diamines, the regioselective formation of one product (Table 2, 6g–6i) was observed. The structures of these regioisomeric-products were confirmed by 2D NMRs (HMBC, HMQC, see ESI†). Diaminomaleonitrile also was found to be a feasible substrate in the reaction. It is noteworthy that the present approach offers a convenient one-step synthesis of 3-aryl-2-aminopyrazines from readily available and simpler starting materials, while these compounds have been previously prepared either by arylation of 2-aminopyrazines with aryl lithium³⁰ or by pre-functionalization of 2-aminopyrazines followed by Suzuki-coupling using arylboronic acid.³¹

Table 2 Synthesis of 3-aryl-2-aminopyrazines^a,b

3-Aryl-2-aminopyrazines

a Substrates, reagents and conditions: 1,2-diamine (1 mmol), ArCHO (1 equiv.), TMSCN (1.2 equiv.), DBU (1.2 equiv.), 1,4-dioxane (3 mL), O₂, RT (25–27 °C), 3 h, then MnO₂ in 0.4 M KOH in MeOH (10 mL), 16–18 h.b Isolated yield for maximum conversion in optimum time.c Reaction was performed at 70 °C.d Diaminomaleonitrile was used as diamine.e MnO₂ in 0.4 M KOH in MeOH was not added.

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Next, we set out to explore the scope of the developed methodology for preparation of 2-aminoquinoxalines (Table 3). Various aldehydes and 1,2-phenylenediamines were investigated. Pleasingly, the method was found to be flexible in accommodating a wide range of aldehydes, including aromatic aldehydes possessing electron-withdrawing as well as electron-donating groups, heteroaromatic, alkyl, arylalkenyl, and metallocene-derived aldehydes and the products were obtained in good-to-excellent yields. Indole-3-carboxaldehyde without NH-protection underwent also the reaction smoothly. Remarkably, the methodology afforded also a high-yielding access to pyridine-fused pyrazine-2-amine, another biologically important heterocycle. Interestingly, the present approach eliminated the formation of benzimidazoles³² and N-benzylated benzimidazoles,³³ which are easily produced in the reported reactions of 1,2-phenylenediamines with aldehydes, and benzoins^19b derived from condensation of aromatic aldehydes.

Table 3 Synthesis of 3-aryl-2-aminoquinoxalines^a,b

3-Aryl-2-aminoquinoxalines

a Substrates, reagents and conditions: 1,2-phenylenediamine (1 mmol), ArCHO (1 equiv.), TMSCN (1.2 equiv.), DBU (1.2 equiv.), 1,4-dioxane (3 mL), O₂, RT (25–27 °C), 36–48 h.b Isolated yield.

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Conclusions

In conclusion, we have developed a new reaction of 1,2-diamines and aldehydes with TMSCN, which affords an efficient and diversity-feasible entry to 3-aryl substituted 2-aminopyrazines and 2-aminoquinoxalines. In the established protocol, a complete switch from usual transformations of these substrates producing benzimidazole, N-benzylbenzimidazole, and benzoin to desired tandem pathway of a sequence of desilylation, Strecker reaction, amidine-forming cyclization and dehydrogenative aromatization has been accomplished. The function of DBU as most efficient and rate-accelerating reagent has been found to be crucial. This reaction opens a new path to straightforward preparation of 2-aminopyrazines, which have been previously obtained by multi-steps and non-convenient synthetic approaches, and is also applicable to efficient preparation of 2-aminoquinoxalines. The practical features of the protocol are the use of readily available substrates, applicability to versatile substrates and moderate-to-excellent yields. Given the fact that 2-aminopyrazines and 2-aminoquinoxalines are present in biologically active compounds and used as valuable synthetic precursors, the present work is resourceful in broad applications.

Experimental section

General information

Infrared (IR) spectra were recorded on a FTIR with ATR & IR Microscope spectrometer. ¹H NMR spectra were measured on a 400 MHz spectrometer. Data were reported as follows: chemical shifts in ppm from tetramethylsilane as an internal standard in CDCl₃/CD₃OD/DMSO-d₆ integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, ddd = doublet of doublet of doublet, br = broad), and coupling constants (Hz). ¹³C NMR spectra were measured on a 100 MHz spectrometer with complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent/TMS as an internal standard. High-resolution mass spectra (HRMS) were performed on a high resolution LCMS/MS instrument with “Q-TOF” mass analyser. For thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used. The products were purified by column chromatography on neutral alumina.

The starting materials and solvents were used as received from commercial suppliers without further purification.

Representative experimental procedure for the synthesis of 3-(4-chlorophenyl)quinoxalin-2-amine (4a)

A mixture of 1,2-phenylenediamine (108 mg, 1 mmol) and p-chlorobenzaldehyde (141 mg, 1 mmol, 1 equiv.) in 1,4-dioxane (0.2 mL) taken in a round-bottomed flask was heated at 70 °C for 30 min in a pre-heated silicon oil bath. The solution was then cooled to room temperature. 1,4-Dioxane (3 mL), DBU (0.18 mL, 1.2 mmol, 1.2 equiv.) and TMSCN (0.15 mL, 1.2 mmol, 1.2 equiv.) were added and the resultant mixture was stirred for 5 minutes. The reaction mixture was then allowed to stir at RT under oxygen atmosphere (using O₂ balloon) until completion of reaction (36 h) as indicated by TLC. The volatiles were evaporated under rotary evaporator and the crude mixture was purified by column chromatography on neutral alumina (60–325 mesh) eluting with 20% ethyl acetate–hexane. It provided 3-(4-chlorophenyl)quinoxalin-2-amine (235 mg, 92%).

Other compounds (4b–p) were synthesized following this procedure and purified on neutral alumina using 20–30% ethyl acetate–hexane as eluent.

Representative experimental procedure for synthesis of 3-(4-chlorophenyl)pyrazin-2-amine (6a)

A mixture of ethylenediamine (0.08 mL, 1 mmol) and p-chlorobenzaldehyde (141 mg, 1 mmol, 1 equiv.) in 1,4-dioxane (0.2 mL) taken in a round-bottomed flask was heated at 70 °C for 15 min in a pre-heated silicon oil bath. The solution was cooled to room temperature. 1,4-Dioxane (0.5 mL), DBU (0.18 mL, 1.2 mmol, 1.2 equiv.) and TMSCN (0.15 mL, 1.2 mmol, 1.2 equiv.) were added. The resultant mixture was then stirred at RT for 3 h under oxygen atmosphere (using O₂ balloon) and 10 mL solution of MnO₂ (174 mg, 2 mmol, 2 equiv.) in 0.4 M KOH in methanol was added to it. The mixture was stirred at RT until completion of reaction as indicated by TLC (18 h). It was filtered through celite bed and purified by column chromatography on neutral alumina (60–325 mesh) eluting with 25% ethyl acetate–hexane. It gave 3-(4-chlorophenyl)pyrazin-2-amine (167 mg, 81% yield).

Other compounds (6b–l) were synthesized following this procedure and purified on neutral alumina using 25–40% ethyl acetate–hexane as eluent.

3-(4-Chlorophenyl)pyrazin-2-amine¹³ (6a)

White crystalline solid, 154 mg, 75%, m.p. 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.95 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 6.21 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 153.6, 141.8, 138.4, 136.8, 133.5, 133.0, 130.4, 129.1 ppm; IR: ν_max 3305, 3163, 1638, 1527, 1430, 819 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₀H₉ClN₃ [M(³⁵Cl) + H]⁺ 206.0485, found: 206.0484.

3-(4-Fluorophenyl)pyrazin-2-amine (6b)

Light yellow solid, 134 mg, 71%, m.p. 125–127 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.73 (dd, J = 8.9 Hz, J = 5.6 Hz, 2H), 7.30 (dd, J = 8.9 Hz, J = 8.9 Hz, 2H), 6.16 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 162.5 (d, J_C–F = 243 Hz), 153.6, 141.5, 138.8, 134.4 (d, J_{C–C–C–C–F} = 3 Hz), 132.9, 130.7 (d, J_{C–C–C–F} = 8 Hz), 115.9 (d, J_C–C–F = 21 Hz) ppm; IR: ν_max 3364, 3165, 1633, 1507, 1429, 1219 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₀H₉FN₃ [M + H]⁺ 190.0780, found: 190.0778.

3-Phenylpyrazin-2-amine¹³ (6c)

White crystalline solid, 120 mg, 69%, m.p. 158–160 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 7.24 Hz 2H), 7.51–7.41 (m, 3H), 6.12 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 153.6, 141.4, 139.7, 138.0, 132.9, 129.1, 128.9, 128.5 ppm; IR: ν_max 3306, 3187, 1637, 1527, 1427 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₀H₁₀N₃ [M + H]⁺ 172.0875, found: 172.0867.

3-(p-Tolyl)pyrazin-2-amine¹³ (6d)

White crystalline solid, 128 mg, 69%, m.p. 80–82 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.90 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 6.02 (s, 2H), 2.53 (s, 3H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 153.5, 141.1, 139.9, 138.4, 135.1, 132.9, 129.7, 128.3, 21.3 ppm; IR: ν_max 3305, 3168, 1640, 1529, 1432, cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₁H₁₂N₃ [M + H]⁺ 186.1031, found: 186.1027.

3-(4-Methoxyphenyl)pyrazin-2-amine (6e)

Light yellow solid, 139 mg, 69%, m.p. 113–115 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.88 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz 2H), 6.05 (s, 2H), 3.81 (s, 3H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 159.9, 153.5, 140.8, 139.7, 132.9, 130.3, 129.8, 114.5, 55.7 ppm; IR: ν_max 3436, 1613, 1512, 1432, 1250, 1175 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₁H₁₂N₃O [M + H]⁺ 202.0980, found: 202.0979.

3-(Furan-2-yl)pyrazin-2-amine

White crystalline solid, 120 mg, 74%, m.p. 115–117 °C; ¹H NMR (400 MHz, DMSO): δ 7.95 (d, J = 2.5 Hz, 1H), 7.86 (s, 1H), 7.85 (s, 1H), 7.09 (d, J = 3.1 Hz, 1H), 6.69 (dd, J = 3.4 Hz, J = 1.8 Hz, 1H), 6.53 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO): δ 152.0, 151.5, 143.9, 141.5, 132.6, 129.6, 112.4, 110.5 ppm; IR: ν_max 3487, 1633, 1524, 1489, 1220, 1155 cm⁻¹; HRMS (ESI) m/z: calcd. for C₈H₈N₃O [M + H]⁺ 162.0667, found: 162.0674.

3-(4-Chlorophenyl)-6-methylpyrazin-2-amine (6g)

Off-white solid, 101 mg, 46%, m.p. 190–192 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.90 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 4.71 (s, 2H), 2.41 (s, 3H) ppm; ¹³C{¹H}NMR (100 MHz, CDCl₃): δ 151.2, 150.6, 136.3, 135.8, 134.7, 134.1, 129.5, 129.2, 20.9 ppm; IR: ν_max 3364, 3167, 1644, 1526, 1424, 825 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₁H₁₁ClN₃ [M(³⁵Cl) + H]⁺ 220.0642, found: 220.0634.

3-(4-Fluorophenyl)-6-methylpyrazin-2-amine (6h)

Off-white solid, 111 mg, 55%, m.p. 142–144 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.75 (s, 1H), 7.69 (dd, J = 8.8 Hz, J = 5.6 Hz, 2H), 7.27 (dd, J = 8.9 Hz, J = 8.9 Hz, 2H), 6.02 (s, 2H), 2.28 (s, 1H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 162.3 (d, J_C–F = 244 Hz), 152.5, 150.2, 135.8, 134.5 (d, J_{C–C–C–C–F} = 3 Hz), 132.1, 130.6 (d, J_{C–C–C–F} = 9 Hz), 115.9 (d, J_C–C–F = 21 Hz), 20.9 ppm; IR: ν_max 3418, 3055, 1619, 1510, 1400, 1200 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₁H₁₁FN₃ [M + H]⁺ 204.0937, found: 204.0941.

3-(4-Methoxyphenyl)-6-methylpyrazin-2-amine (6i)

Off-white solid, 58 mg, 27%, m.p. 125–127 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.88 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.74 (s, 2H), 3.85 (s, 3H), 2.39 (s, 3H) ppm; ¹³C{¹H}NMR (100 MHz, CDCl₃): δ 159.9, 151.3, 149.5, 137.6, 133.8, 129.8, 129.4, 114.4, 55.4, 20.9 ppm; IR: ν_max 3308, 3184, 1609, 1511, 1429, 1247, 1175 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₂H₁₄N₃O [M + H]⁺ 216.1137, found: 216.1132.

3-(4-Chlorophenyl)-5,6,7,8-tetrahydroquinoxalin-2-amine (6j)

White crystalline solid, 142 mg, 55% yield, m.p. 160–162 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 5.83 (s, 2H), 2.69–2.67 (m, 4H), 1.80–1.78 (m, 4H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 151.1, 148.7, 139.8, 137.0, 135.3, 133.0, 130.4, 128.9, 31.2, 30.6, 23.2, 22.8 ppm; IR: ν_max 3305, 3172, 2937, 1639, 1419, 832 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₅N₃Cl [M + H]⁺ 260.0955, found: 260.0946.

3-(Furan-2-yl)-5,6,7,8-tetrahydroquinoxalin-2-amine (6k)

A white crystalline solid, 127 mg, 59% yield, m.p. 161–163 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, J = 0.9 Hz, 1H), 6.97 (d, J = 3.3 Hz, 1H), 6.64 (dd, J = 3.3 Hz, J = 1.8 Hz, 1H), 6.18 (s, 2H), 2.69–2.67 (m, 4H), 1.80–1.78 (m, 4H), ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 152.3, 149.2, 148.7, 143.4, 139.4, 126.7, 112.3, 109.5, 31.4, 30.7, 23.2, 22.8 ppm; IR: ν_max 3494, 1622, 1410, 1216, 1156 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₂H₁₄N₃O [M + H]⁺ 216.1137, found: 216.1132.

3-(4-Chlorophenyl)-6-cyanopyrazin-2-amine (6l)

Yellow solid, 85 mg, 37%, m.p. >200 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.42 (s, 2H), ppm; ¹³C{¹H}NMR (100 MHz, CDCl₃): δ 154.9, 147.8, 140.2, 134.9, 134.5, 130.6, 129.3, 118.2, 115.4 ppm; IR: ν_max 3455, 3144, 2924, 2226, 1627, 1526, 1469, 750 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₁H₇ClN₄ [M(³⁵Cl) + Na]⁺ 253.0257, found: 253.0252.

3-(4-Chlorophenyl)quinoxalin-2-amine^19b (4a)

Light yellow solid, 235 mg, 92% yield, m.p. 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.82–7.76 (m, 3H), 7.60–7.55 (m, 4H), 7.39–7.35 (m, 1H), 6.63 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 151.9, 145.1, 141.9, 137.2, 136.3, 134.5, 130.8, 130.3, 129.2, 128.9, 125.5, 124.6 ppm; IR: ν_max 3377, 3131, 1646, 1421, 751 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₁N₃Cl [M(³⁵Cl) + H]⁺ 256.0642, found: 256.0636.

3-(2-Chlorophenyl)quinoxalin-2-amine^19b (4b)

Light yellow solid, 205 mg, 80% yield, m.p. 190–192 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, J = 8.1 Hz, 1H), 7.63–7.57 (m, 3H), 7.56–7.50 (m, 3H), 7.40–7.36 (m, 1H), 6.49 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 152.0, 145.3, 142.4, 136.5, 136.1, 132.6, 131.5, 131.2, 130.4, 130.2, 128.9, 128.1, 125.6, 124.3 ppm; IR: ν_max 3464, 3105, 1637, 1434, 752 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₁N₃Cl [M(³⁵Cl) + H]⁺ 256.0642, found: 256.0634.

3-(4-Fluorophenyl)quinoxalin-2-amine (4c)

A light brown solid, 203 mg, 85%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.82–7.79 (m, 3H), 7.58–7.57 (m, 2H), 7.39–7.34 (m, 3H), 6.59 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 163.1 (d, J_C–F = 244 Hz), 152.9, 145.4, 141.8, 137.2, 133.9 (d, J_{C–C–C–C–F} = 3 Hz), 131.3 (d, J_{C–C–C–F} = 9 Hz), 130.1, 128.9, 125.5, 124.5, 116.1 (d, J_C–C–F = 21 Hz) ppm; IR: ν_max 3429, 1639, 1427, 1233 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₁N₃F [M + H]⁺ 240.0937, found: 240.0930.

3-(4-Bromophenyl)quinoxalin-2-amine³⁴ (4d)

Light yellow solid, 242 mg, 81%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, J = 8.1 Hz, 1H), 7.75–7.70 (m, 4H), 7.58–7.57 (m, 2H), 7.39–7.35 (m, 1H), 6.64 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 151.8, 145.1, 141.9, 137.2, 136.7, 132.1, 131.1, 130.3, 128.9, 125.5, 124.6, 123.2 ppm; IR: ν_max 3432, 1637, 1429, 751 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₁N₃Br [M(⁷⁹Cl) + H]⁺ 300.0136, found: 300.0132.

3-(4-Nitrophenyl)quinoxalin-2-amine³⁴ (4e)

Brown solid, 236 mg, 89%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.64–7.59 (m, 2H), 7.42–7.38 (m, 1H), 6.76 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 151.8, 148.2, 144.2, 144.0, 142.2, 137.1, 130.8, 130.6, 129.1, 125.6, 124.8, 124.3 ppm; IR: ν_max 3432, 1640, 1434, 1343 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₁N₄O₂ [M + H]⁺ 267.0882, found: 267.0874.

3-Phenylquinoxalin-2-amine^19b (4f)

Yellow solid, 190 mg, 86%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, J = 8.0 Hz, 1H), 7.78–7.75 (m, 2H), 7.58–7.53 (m, 5H), 7.39–7.36 (m, 1H), 6.56 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 151.9, 146.2, 141.8, 137.5, 137.3, 130.1, 129.8, 129.2, 128.9, 128.8, 125.5, 124.5 ppm; IR: ν_max 3371, 3148, 1646, 1428 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₁₂N₃ [M + H]⁺ 222.1031, found: 222.1028.

3-(p-Tolyl)quinoxalin-2-amine^19b (4g)

Yellow solid, 190 mg, 81%, m.p. 174–176 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.80 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.57–7.55 (m, 2H), 7.38–7.35 (m, 3H), 6.53 (s, 2H), 2.40 (s, 3H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 151.9, 146.2, 141.7, 139.3, 137.3, 134.6, 129.9, 129.8, 128.84, 128.77, 125.5, 124.5, 21.4 ppm; IR: ν_max 3433, 1645, 1428 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₅H₁₄N₃ [M + H]⁺ 236.1188, found: 236.1180.

3-(4-Methoxyphenyl)quinoxalin-2-amine^19b (4h)

Light brown solid, 209 mg, 83%, m.p. 154–156 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.56–7.54 (m, 2H), 7.38–7.35 (m, 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.54 (s, 2H), 3.84 (s, 3H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 160.8, 150.7, 145.6, 140.9, 138.2, 129.9, 129.7, 129.3, 128.9, 125.6, 125.2, 118.8, 116.2, 114.6, 55.5 ppm; IR: ν_max 3425, 3148, 1607, 1429, 1252, 1176 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₅H₁₄N₃O [M + H]⁺ 252.1137, found: 252.1130.

3-(Naphthalen-2-yl)quinoxalin-2-amine^19b (4i)

Light green solid, 236 mg, 87%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (s, 1H), 8.10–8.00 (m, 3H), 7.89–7.84 (m, 2H), 7.63–7.57 (m, 4H), 7.41–7.37 (m, 1H), 6.71 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 152.1, 146.1, 141.8, 137.4, 134.9, 133.7, 133.2, 130.1, 129.1, 128.9, 128.8, 128.3, 128.1, 127.4, 126.9, 126.6, 125.5, 124.5 ppm; IR: ν_max 3390, 3049, 1598, 1424 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₈H₁₄N₃ [M + H]⁺ 272.1188, found: 272.1184.

3-(Furan-2-yl)quinoxalin-2-amine^19b (4j)

Light brown solid, 190 mg, 90%, m.p. 148–150 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (dd, J = 1.7 Hz, J = 0.7 Hz, 1H), 7.80 (ddd, J = 8.1 Hz, J = 7.2 Hz, J = 0.7 Hz, 1H), 7.56–7.55 (m, 2H), 7.41–7.36 (m, 2H), 6.93 (s, 2H), 6.76 (dd, J = 3.5 Hz, J = 1.7 Hz, 1H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO): δ 151.3, 150.2, 145.4, 141.2, 136.6, 134.7, 130.2, 128.6, 125.5, 125.0, 113.4, 112.8 ppm; IR: ν_max 3483, 1637, 1494, 1422, 1275, 1037 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₂H₁₀N₃O [M + H]⁺ 212.0824, found: 212.0816.

3-(Thiophen-2-yl)quinoxalin-2-amine^19b (4k)

Light green solid, 166 mg, 73%, m.p. 135–137 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (dd, J = 3.8, J = 0.9 Hz, 1H), 7.81–7.78 (m, 2H), 7.59–7.54 (m, 2H), 7.42–7.37 (m, 1H), 7.25 (dd, J = 5.1 Hz, J = 3.8 Hz, 1H), 6.84 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 150.8, 141.6, 141.2, 139.3, 136.8, 130.3, 130.0, 128.9, 128.42, 128.40, 125.5, 125.0 ppm; IR: ν_max 3369, 3153, 1642, 1557, 1438, 1415 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₂H₁₀N₃S [M + H]⁺ 228.0595, found: 228.0593.

3-(Pyridin-2-yl)quinoxalin-2-amine^19b (4l)

Light brown solid, 175 mg, 79%, m.p. 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.76 (dd, J = 4.8 Hz, J = 0.9 Hz, 1H), 8.66 (d, J = 8.1 Hz, 1H), 8.09 (ddd, J = 9.5 Hz, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.90 (dd, J = 8.2 Hz, J = 0.9 Hz, 1H), 7.65–7.58 (m, 3H), 7.42 (ddd, J = 8.2 Hz, J = 6.6 Hz, J = 1.6 Hz, 1H), ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 156.0, 152.9, 148.1, 142.7, 138.4, 138.2, 136.4, 131.1, 129.4, 125.4, 124.9, 124.6, 123.8 ppm; IR: ν_max 3319, 3130, 1629, 1605, 1423, 1022 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₃H₁₀N₄ [M + H]⁺ 223.0984, found: 223.0979.

3-(1H-Indol-3-yl)quinoxalin-2-amine (4m)

Light green solid, 185 mg, 71%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 11.71 (s, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H), 7.82 (dd, J = 7.8 Hz, J = 0.9 Hz, 1H), 7.56–7.47 (m, 3H), 7.36 (ddd, J = 8.2 Hz, J = 6.9 Hz, J = 1.5 Hz, 1H), 7.25–7.15 (m, 2H), 6.65 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 152.0, 142.8, 140.0, 137.5, 136.9, 128.6, 128.2, 128.1, 126.9, 125.3, 124.4, 122.8, 122.3, 120.7, 112.2, 111.7 ppm; IR: ν_max 3433, 1646, 1531, 1438 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₆H₁₃N₄ [M + H]⁺ 261.1140, found: 261.1136.

3-(Ferrocenyl)quinoxalin-2-amine³⁴ (4n)

Light brown solid, 263 mg, 80%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 12.37 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.15–7.11 (m, 2H), 5.04 (s, 2H), 4.47 (s, 2H), 4.10 (s, 5H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 153.4, 144.4, 135.2, 121.9, 121.5, 118.4, 111.0, 74.8, 70.2, 69.8, 67.8 ppm; IR: ν_max 3431, 2923, 2857, 1622, 1420 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₈H₁₅FeN₃ [M + Na]⁺ 352.0524, found: 352.0535.

6,7-Dichloro-3-(4-chlorophenyl)quinoxalin-2-amine (4o)

Light brown solid, 265 mg, 82%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (s, 1H), 7.78–7.76 (m, 3H), 7.60 (d, J = 8.5 Hz, 2H), 7.01 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 152.6, 146.9, 141.4, 136.1, 135.6, 134.9, 132.5, 130.9, 129.6, 129.3, 126.2, 126.1 ppm; IR: ν_max 3472, 3362, 3137, 1641, 1443, 764, 750 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₄H₉Cl₃N₃ [M(³⁵Cl) + H]⁺ 323.9862, found: 323.9862.

3-(4-Chlorophenyl)pyrido[3,4-b]pyrazin-2-amine (4p)

Yellow solid, 195 mg, 76%, m.p. >200 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.47 (d, J = 5.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 5.7 Hz, 1H), 7.28 (s, 2H) ppm; ¹³C{¹H}NMR (100 MHz, DMSO-d₆): δ 154.4, 152.1, 147.8, 147.5, 145.9, 135.5, 134.9, 133.4, 130.9, 129.3, 118.8 ppm; IR: ν_max 3296, 3107, 1643, 1544, 1426 cm⁻¹; HRMS (ESI) m/z: calcd. for C₁₃H₁₀ClN₄ [M(³⁵Cl) + H]⁺ 257.0594, found: 257.0595.

Acknowledgements

We gratefully acknowledge financial support from DST, New Delhi for this investigation. GP and NG is thankful for the fellowship provided by NIPER, Mohali.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Scanned ¹H and ¹³C spectra for products 4a–p, 6a–l and 2D spectra (HMQC and HMBC) of 6h and 6i. See DOI: 10.1039/c6ra12028h

‡ The authors have contributed equally.

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