Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines

Jan 9, 2018 - Cu(II)/Proline Catalyzed Reductive-coupling of Sulfuryl Chloride and P(O)-H for P-S-C Bond Formation. The Journal of Organic Chemistry...
1 downloads 0 Views 1MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 1252−1258

pubs.acs.org/joc

Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines Yazdanbakhsh L. Nosood,§ Azim Ziyaei Halimehjani,‡ and Florenci V. González*,§ §

Departament de Química Inorgànica i Orgànica, Universitat Jaume I, Castelló 12071, Spain Faculty of Chemistry, Kharazmi University, Tehran 15719-14911, Iran

‡

S Supporting Information *

ABSTRACT: Nitroepoxides are easily transformed into benzodiazepines, tetrahydrobenzodiazepines, imidazopyridines, and N-alkyl tetrahydroquinoxalines by treatment with 2aminobenzylamines, 2-aminopyridines, and N-alkyl 1,2-diaminobenzenes, respectively. Regioselectivity is controlled through attack of the most nucleophilic nitrogen of the unsymmetrical diamine to the β position of the epoxide. These reactions represent an efficient way to prepare privileged bioactive structures.

■

anticonvulsants,19 potassium channel openers,20 and anti-HIV agents.21 Nitroepoxides, easily prepared through the straightforward epoxidation of nitroalkenes, represent unique building blocks for the preparation of 1,2-difunctionalized compounds, particularly heterocycles. We previously reported the transformation of nitroepoxides into quinoxalines, pyrazines, piperazines, and tetrahydroquinoxalines by reaction with symmetrical diamines22 and morpholines and benzoxazines when treated with amino alcohols (Figure 2).23 Based upon proposed mechanism of the reaction between a nitroepoxide and a diamine (Figure 2), we envisaged that an unsymmetrical diamine would afford the corresponding regioisomeric heterocycle by attack of the most nucleophilic nitrogen to the β position of the nitroepoxide (Figure 2).

INTRODUCTION Nitrogenated heterocycles are important structural components for pharmaceuticals.1 Developing new synthetic methods to access diverse nitrogenated heterocycles is important for medicinal chemistry. The benzodiazepine moiety has been classified as a “privileged scaffold” in medicinal chemistry, and many bioactive compounds bear this core.2 Compounds containing the tetrahydrobenzodiazepine moiety find numerous applications in medicinal chemistry,3 for example, BMS-214662, which exhibits potent antitumor activity (Figure 1).4,5 Also tetrahy-

■

RESULTS AND DISCUSSION 5H-Benzo[e][1,4]diazepines are interesting heterocycles that are commonly prepared by condensation of 1,2-dicarbonyl compounds with 2-aminobenzylamine.24 Nitroepoxides represent a valid alternative to otherwise less synthetically accessible 1,2-dicarbonyl compounds.22,23,25−27,29,28 We began our studies of the preparation of benzodiazepines by combining nitroepoxide 1a with 2-aminobenzylamine (1.2 equiv) in dichloromethane. The reaction afforded a mixture of benzodiazepines 2a and 3a (Table 1, entry 1) in low chemical yield. In order to improve the yield and selectivity of the reaction, other conditions were evaluated. The use of a base (triethyl amine and potassium tert-butoxide) did not improve it. The best result

Figure 1. Examples of biologically active heterocycles.

drobenzodiazepines have been used as intermediates in organic synthesis.6−9 Compounds that possess the imidazopyridine moiety display antitumor, antifungal, antibacterial, antiviral, and antiprotozoal activities,10−15 and some are currently marketed drugs such as zolpidem used for the treatment of sleep disorder (Figure 1), anxyolitic drug alpidem16 and antiulcer drug zolimidine.17 Tetrahydroquinoxalines have been studied as potent cholesteryl ester transfer protein inhibitors (Figure 1),18 © 2018 American Chemical Society

Received: November 4, 2017 Published: January 9, 2018 1252

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258

Article

The Journal of Organic Chemistry Table 2. Synthesis of Tetrahydrobenzodiazepinesa

entry

R1, R2

epoxide

4/5b

4 syn/antib

yield (%)c

1 2 3 4 5 6

Ph, Me Ph, Et p-Me-Ph, Me p-NO2-Ph, Me p-Cl-Ph, Me m-NO2-Ph, Me

1a 1b 1c 1d 1e 1f

3.3/1 2.5/1 2.9/1 >9/1 >9/1 >9/1

91/9 96/4 94/6 >99/1 >99/1 97/3

60 66 55 76 74 68

a

Reactions were carried out using nitroepoxide (1.0 equiv) in ethanol (6 mL/mmol) and 2-amino benzylamine (1.2 equiv) at room temperature for 8 h then sodium borohydride (2.0 equiv). bRatio was calculated from 1H NMR of crude mixture. cYield of isolated products.

Figure 2. Reaction design for heterocycles.

Table 1. Synthesis of Benzodiazepinesa

entry

R1, R2

epoxide

solvent

products

ratiob

yieldc (%)

1 2 3 4 5 6 7 8

Ph, Me Ph, Me Ph, Et p-Me-Ph, Me p-NO2-Ph, Me p-Cl-Ph, Me m-NO2-Ph, Me n-Pr, Me

1a 1a 1b 1c 1d 1e 1f 1g

DCM ethanol ethanol ethanol ethanol ethanol ethanol ethanol

2a/3a 2a/3a 2b/3b 2c/3c 2d 2e 2f 2g

2/1 3.2/1 2.4/1 3/1 >9/1 >9/1 >9/1 >9/1

31 65 73 61 79 82 76 32

The relative stereochemistry of tetrahydrobenzodiazepines was assigned based on NMR studies and confirmed by X-ray diffraction analysis of compound 4f. We next studied the reaction of nitroepoxides with 2aminopyridines as an interesting diamino compound inspired by previous work by Yu et al.27 Nitroepoxide 1a was treated with 2-amino pyridine (1.5 equiv) in tetrahydrofuran as a solvent; the resulting imidazopyridine 6a was obtained in low yield. Solvent screening was then performed in order to increase the yield. Methanol and dichloromethane gave reaction product, but chemical yield was very low (less than 30%); ethanol was again the best option affording compound 6a in satisfactory yield (Scheme 1). Following this experimental Scheme 1. Synthesis of Imidazopyridines 6a−g

a

Reactions were carried out using nitroepoxide (1.0 equiv) in ethanol (6 mL/mmol) and 2-amino benzylamine (1.2 equiv) at room temperature for 8 h. bRatio was calculated from 1H NMR of crude mixture. cYield of isolated products.

was obtained by using ethanol as a solvent (Table 1, entry 2). Under these conditions, a 3/1 mixture of regioisomeric benzodiazepines 2a and 3a was obtained, which could be separated by chromatography. Various nitroepoxides were subjected to reaction conditions to explore the scope of the process (Table 1). Nitroepoxides 1d, 1e, and 1f afforded single regioisomers (2d−f) (Table 1, entries 5−7) in good yield. Nitroepoxide 1g with two alkyl substituents afforded benzodiazepine 2g in low yield (Table 1, entry 8). The structure of the resulting compounds was confirmed by X-ray diffraction analyses of compounds 2b and 2f (see Supporting Information). We then evaluated a one-pot procedure for the preparation of tetrahydrobenzodiazepines starting from nitroepoxides. Compounds 4a−f were obtained when treating nitroepoxides 1a−f with 2-aminobenzylamine in ethanol followed by addition of sodium borohydride (Table 2). The reactions afforded tetrahydrobenzodiazepines as syn isomers in all cases. Regioisomeric compounds 5a−c were obtained as minor compounds in these reactions.

procedure, imidazopyridines 6a−g were prepared by reaction of nitroepoxides 1a−e with 2-amino pyridine or 2-amino-4methylpyridine (Scheme 1). In all cases, a single regioisomeric compound was obtained resulting from the initial attack of the pyridine nitrogen to the β position of the nitroepoxide (Figure 2).30 1253

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258

Article

The Journal of Organic Chemistry

privileged bioactive structures. Further investigations of the utility of nitroepoxides in synthesis are ongoing and will be reported in the future.

The structure of compounds 6a−g was assigned by NMR NOE experiments (Scheme 2) and by comparison with reported data.31

■

Scheme 2. Synthesis of Tetrahydroquinoxalines 7a−e

EXPERIMENTAL SECTION

General Information. Unless otherwise specified, all reactions were carried out under nitrogen atmosphere with magnetic stirring. All solvents and reagents were obtained from commercial sources and were purified according to standard procedures before use. 1H NMR spectra and 13C NMR spectra were measured in CDCl3 (1H, 7.24 ppm; 13C 77.0 ppm) solution at 30 °C on a 300 MHz or a 500 MHz NMR spectrometer. Mass spectra were measured in a QTOF I (quadrupole-hexapole-TOF) mass spectrometer with an orthogonal Zspray-electrospray interface. EM Science Silica Gel 60 was used for column chromatography, while TLC was performed with precoated plates (Kieselgel 60, F254, 0.25 mm). Preparation of Nitroalkenes. (E)-(2-Nitrobut-1-en-1-yl)benzene. A solution of nitroethane (44 mmol), n-butylamine (18 mmol), and the aldehyde (16 mmol) in acetic acid (8 mL) was heated at 80 °C for 2 h. The crude product was extracted with dichloromethane, washed with brine, and dried over Na2SO4. Then the solvent was evaporated and the residue was purified by column chromatography (silica gel; n-hexane/ethyl acetate, 9:1). The product was obtained as a yellow oil (yield 2.15 g, 76%); 1H NMR (300 MHz, chloroform-d) δ 7.90 (s, 1H), 7.43−7.23 (m, 5H), 2.76 (q, J = 7.4 Hz, 2H), 1.17 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 153.3, 133.1, 132.3, 130.0, 129.6, 129.0, 20.7, 12.5; LRMS (EI) mass calcd for C10H11ClNO2 [M+] 177.0; found 177.0; FT-IR δ 2974, 2938, 1518, 1330 cm−1.28 (E)-1-Nitro-4-(2-nitroprop-1-en-1-yl)benzene. A solution of nitroethane (44 mmol), n-butylamine (18 mmol), and the aldehyde (16 mmol) in acetic acid (8 mL) was heated at 80 °C for 2 h. The crude product that separated on cooling was filtered and recrystallized from ethanol. Product was obtained as a yellow crystal (yield 3.2 g, 95%), mp 106−108 °C; 1H NMR (300 MHz, chloroform-d) δ 8.39−8.28 (m, 2H), 8.10 (s, 1H), 7.68−7.56 (m, 2H), 2.48 (d, J = 1.2 Hz, 3H); 13 C NMR (75 MHz, chloroform-d) δ 150.2, 148.1, 138.8, 130.7, 130.5, 124.0, 14.0; LRMS (EI) mass calcd for C9H8N2O4 [M+] 208.0; found 208.0; FT-IR δ 3075, 2992, 1516, 1313 cm−1.22 (E)-1-Chloro-4-(2-nitroprop-1-en-1-yl)benzene. Product was obtained as a pale yellow crystal (yield 2.9 g, 91%), mp 82−84 °C; 1H NMR (300 MHz, chloroform-d) δ 8.05 (s, 1H), 7.51−7.40 (m, 2H), 7.44−7.33 (m, 2H), 2.46 (d, J = 1.2 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 148.0, 136.0, 132.2, 131.1, 130.8, 129.2, 14.0; LRMS (EI) mass calcd for C9H8ClNO2 [M+] 197.0; found 197.0; FT-IR δ 3091, 2988, 1508, 1304 cm−1.34 (E)-1-Nitro-3-(2-nitroprop-1-en-1-yl)benzene. Product was obtained as a pale yellow crystal (yield 2.9 g, 86%), mp 54−55 °C; 1H NMR (300 MHz, chloroform-d) δ 8.33−8.27 (m, 2H), 8.11 (s, 1H), 7.84−7.60 (m, 2H), 2.49 (d, J = 1.1 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 149.8, 148.4, 135.4, 134.1, 130.6, 130.1, 124.3, 124.2, 13.9; LRMS (EI) mass calcd for C9H8N2O4 [M+] 208.0; found 208.0; FT-IR δ 3082, 2990, 1506, 1317 cm−1.29 (E)-2-Nitrohex-2-ene. To a stirred solution of butyraldehyde (2.7 mL, 30 mmol) in nitroethane (11 mL, 150 mmol) at room temperature was added dropwise triethylamine (420 μL, 3 mmol). The resulting mixture was stirred under N2 for 16 h. Excess solvent was evaporated in vacuo, and the crude nitroaldol was dissolved in CH 2 Cl 2 (12 mL) and cooled with an ice-bath, and then methanesulfonyl chloride (2.9 mL, 36 mmol) and ethyldiisopropylamine (11.1 mL, 63 mmol) were added. The solution was allowed to warm up to room temperature and stirred until TLC analysis indicated consumption of nitroaldol (19 h). Water and CH2Cl2 (10 mL each) were added, and the organic phase was separated, washed with 2 M HCl (10 mL) and brine, dried (MgSO4), and concentrated to yield an orange oil, which was purified by silica-gel chromatography (hexanes/ ethyl acetate, 9:1 to 7:3) to give the pure product as an orange oil (yield 2.65 g, 68%): 1H NMR (300 MHz, CDCl3) δ 7.02 (t, J = 7.9 Hz, 1H), 2.14 (q, J = 7.4 Hz, 2H), 2.07 (s, 3H), 1.64−1.25 (m, 2H),

A one-pot procedure for the preparation of N-substituted tetrahydroquinoxalines from nitroepoxides was next studied. The reaction of nitroepoxides 1a−e with N-methyl-1,2diaminobenzene and sodium triacetoxyborohydride as a reductive agent afforded syn tetrahydroquinoxalines 7a−e as reaction products in good yield. Dichloromethane gave higher chemical yields than ethanol. In the case of a previously reported preparation of nonsubstituted tetrahydroquinoxalines upon reaction of nitroepoxides with 1,2-benzenodiamines22 borane was used as a reductive agent to convert in situ formed aromatic quinoxalines into tetrahydroquinoxalines. Conversely, if N-methyl-1,2-benzenodiamines are used then aromatic quinoxalines are not formed; hence sodium triacetoxyborohydride is adequate for the reductive conversion of N-methyl dihydroquinoxaline intemediate into desired N-methyl tetrahydroquinoxaline (see Figure 2). The resulting compounds 7a−e are the ones expected from the attack of secondary amine (more reactive) to the nitroepoxide followed by reductive amination of the resulting amino ketone (Figure 2).32 The regio- and stereochemistry of compounds 7a−e were assigned by NMR NOE experiments (Scheme 2) and coupling constants.33 Nitroepoxides having two alkyl groups did not afford desired heterocycles when submitted to the above-mentioned reactions for the preparation of tetrahydrobenzodiazepines, imidazopyridines, or tetrahydroquinoxalines.

■

CONCLUSIONS In summary, we reported herein that benzodiazepines, imidazopyridines, and N-methyl tetrahydroquinoxalines can be easily prepared by treating nitroepoxides with 2-aminobenzylamines, 2-aminopyridines, and N-alkyl 1,2-diaminobenzene, respectively. Also tetrahydrobenzodiazepines can be easily obtained by using 2-aminobenzylamine and sodium borohydride as a reductive agent. These reactions are regioselective and represent an efficient way to prepare the aforementioned 1254

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258

Article

The Journal of Organic Chemistry 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 147.6, 136.0, 30.0, 21.5, 13.5, 12.2 ppm; HRMS (EI) calcd for C6H11NO2 (M) 129.0790, found 129.0791; IR (KBr) δ 3056, 2961, 1512, 1330 cm−1.35 General Procedure for the Preparation of Nitroepoxides.22 To a stirred ice-bath cold suspension of nitroalkene (12.1 mmol) in methanol (37.6 mL) containing hydrogen peroxide 50% aqueous solution (2.4 mL, 42.8 mmol) was added aqueous 2 M NaOH (3.9 mL, 6.1 mmol), and the mixture was stirred at 0 °C for 10 min. Then, ice water was added (10 mg), the mixture was extracted with diethyl ether (3 × 30 mL), and the combined organic phases were washed with brine (45 mL), dried with Na2SO4, and concentrated under vacuum to afford a yellowish oil, which was purified by silica gel chromatography (n-hexane/ethyl acetate, 9:1). 2-Methyl-2-nitro-3-phenyloxirane, 1a. The obtained product was a pale yellow oil (yield 1.8 g, 84%): 1H NMR (500 MHz, CDCl3) δ 7.41 (m, 3H), 7.30 (m, 2H), 4.56 (s, 1H), 1.78 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 131.0, 129.3, 128.7, 126.3, 88.8, 62.6, 12.2 ppm; HRMS (EI) calcd for C9H9NO3 (M) 179.0582, found 179.0587; IR (KBr) δ 3062, 3028, 2948, 1555, 1495, 1354, 1158, 899 cm−1.34 2-Ethyl-2-nitro-3-phenyloxirane, 1b. Yellow oil, yield 1.9 g, 82%: 1 H NMR (300 MHz, chloroform-d) δ 7.49−7.40 (m, 3H), 7.37−7.30 (m, 2H), 4.54 (s, 1H), 2.50 (dq, J = 14.9, 7.4 Hz, 1H), 1.73 (dq, J = 14.9, 7.4 Hz, 1H), 1.10 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 131.1, 129.3, 128.7, 126.3, 92.5, 63.2, 19.5, 7.6; LRMS (EI): calcd for C10H11NO3 (M+) 193.0, found 193.0; calcd for C8H6O (M-CH2CH3−NO2) 118.0, found 118.0; FT-IR δ 2981, 2943, 1556, 1456, 1349, 937, 813 cm−1.28 2-Methyl-2-nitro-3-(p-tolyl)oxirane, 1c. Yellow oil, yield 744 mg, 75%: 1H NMR (500 MHz, CDCl3) δ 7.26−7.17 (m, 4H), 4.50 (s, 1H), 2.38 (s, 3H), 1.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.6, 129.5, 128.0, 126.4, 89.1, 62.8, 21.1, 12.4 ppm; HRMS (EI) calcd for C10H11NO3 (M) 193.0739, found 193.0745; IR (KBr) δ 3062, 3025, 2948, 1552, 1346, 1158, 899 cm−1.28 2-Methyl-2-nitro-3-(4-nitrophenyl)oxirane, 1d. Yellow crystal, yield 2.6 g, 96%, mp 90−93 °C: 1H NMR (300 MHz, chloroformd) δ 8.37−8.26 (m, 2H), 7.60−7.49 (m, 2H), 4.69 (s, 1H), 1.82 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 148.6, 137.9, 127.5, 124.0, 88.3, 61.4, 12.4; LRMS (EI) calcd for C9H8N2O5 (M+) 224.0, found 224.0; calcd for C8H5NO3 (M-CH3−NO2) 163.0, found 163.0; FT-IR δ 3081, 3025, 2943, 1514, 1343, 1102, 861 cm−1.22 3-(4-Chlorophenyl)-2-methyl-2-nitrooxirane, 1e. Pale yellow crystal, 2.4 g, yield 94%, mp 60−62 °C (lit. 50−56 °C):22 1H NMR (300 MHz, chloroform-d) δ 7.48−7.35 (m, 2H), 7.33−7.19 (m, 2H), 4.54 (s, 1H), 1.80 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 135.5, 129.5, 129.1, 127.8, 88.6, 62.0, 12.3; LRMS (EI) calcd for C9H8ClNO3 (M+) 213.0, found 213.0; FT-IR δ 3004, 2898, 1558, 1400, 1351, 1084, 816 cm−1.34 2-Methyl-2-nitro-3-(3-nitrophenyl)oxirane, 1f. Pale yellow crystal, yield 2.4 g, 89%, mp 80−83 °C: 1H NMR (300 MHz, chloroform-d) δ 8.22 (dt, J = 7.4, 2.2 Hz, 1H), 8.16−8.12 (m, 1H), 7.66−7.55 (m, 2H), 4.61 (s, 1H), 1.74 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 148.5, 133.2, 132.3, 130.1, 124.4, 121.5, 88.3, 61.3, 12.4; LRMS (EI) calcd for C9H8N2O5 (M+) 224.0, found 224.0; FT-IR δ 3082, 2954, 2904, 1529, 1417, 1350, 1088, 992 cm−1.29 2-Methyl-2-nitro-3-propyloxirane, 1g. Yellowish oil, yield 1.2 g, 68%: 1H NMR (300 MHz, CDCl3) δ 3.39 (t, J = 5.7 Hz, 1H), 1.89 (s, 3H), 1.66−1.43 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 87.9, 62.9, 29.7, 19.1, 13.6 ppm; HRMS (EI) calcd for C6H11NO3 (M) 145.0739, found 145.0741; IR (KBr) δ 3028, 1555, 1029, 865 cm−1.35 Experimental Procedure for the Preparation of 5H-Benzo[e][1,4]diazepines. To a solution of corresponding a-nitroepoxide (0.5 mmol) in ethanol (3 mL), 2-amino benzylamine was added (0.6 mmol), and the mixture was stirred at room temperature for 10 h. Then the solvent was evaporated under reduced pressure to yield a yellow oil, which was purified by silica gel chromatography (n-hexane/ ethyl acetate; 4:1), to give the pure product. 2-Methyl-3-phenyl-5H-benzo[e][1,4]diazepine, 2a. Yellow solid (mp 114−116 °C), yield 58 mg, 49%: 1H NMR (300 MHz, chloroform-d) δ 7.48−7.39 (m, 2H), 7.36−7.23 (m, 6H), 7.17−7.08

(m, 1H), 4.68 (d, J = 10.8 Hz, 1H), 3.81 (d, J = 10.8 Hz, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 166.2, 163.1, 147.1, 136.5, 131.1, 130.1, 128.6, 128.5, 128.0, 127.8, 126.5, 125.1, 54.1, 26.8; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H14N2 235.1235, found 235.1239; FT-IR δ 3050, 2917, 2848, 1590, 1445 cm−1. 3-Methyl-2-phenyl-5H-benzo[e][1,4]diazepine, 3a. Yellow oil, yield 19 mg, 16%: 1H NMR (300 MHz, chloroform-d) δ 7.80−7.70 (m, 2H), 7.49−7.39 (m, 4H), 7.39−7.24 (m, 2H), 7.25−7.13 (m, 1H), 4.59 (d, J = 11.0 Hz, 1H), 3.75 (d, J = 11.0 Hz, 1H), 1.98 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 166.3, 161.0, 146.9, 137.3, 130.7, 128.9, 128.7, 128.4, 128.2, 127.7, 127.0, 126.0, 54.5, 24.4; HRMS (ESITOF) m/z (M + H)+ Calcd for C16H14N2 235.1235, found 235.1236; FT-IR δ 3059, 2919, 2835, 1630, 1557, 1446 cm−1. 2-Ethyl-3-phenyl-5H-benzo[e][1,4]diazepine, 2b. Yellow solid (mp 109−112 °C), yield 63 mg. 51%: 1H NMR (300 MHz, chloroform-d) δ 7.44−7.39 (m, 2H), 7.38−7.24 (m, 6H), 7.11 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 3.77 (d, J = 10.8 Hz, 1H), 2.65 (qd, J = 7.5, 1.7 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 171.3, 163.0, 147.1, 136.8, 131.2, 130.0, 128.5, 128.4, 127.9, 127.8, 126.3, 125.2, 54.2, 32.6, 11.2; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H16N2 249.1392, found 249.1390; FT-IR δ 3054, 2964, 2842, 1591, 1445 cm−1. 3-Ethyl-2-phenyl-5H-benzo[e][1,4]diazepine, 3b. Yellow solid (mp 116−118 °C), yield 28 mg, 22%: 1H NMR (300 MHz, chloroform-d) δ 7.77−7.71 (m, 2H), 7.45−7.40 (m, 4H), 7.36−7.27 (m, 2H), 7.22− 7.14 (m, 1H), 4.61 (d, J = 10.9 Hz, 1H), 3.73 (d, J = 10.9 Hz, 1H), 2.69−1.92 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 166.5, 165.4, 147.0, 137.4, 131.0, 130.7, 128.7, 128.3, 128.1, 127.8, 126.8, 125.9, 54.4, 30.3, 10.3; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H16N2 249.1392, found 249.1389; FT-IR δ 3062, 2967, 2846, 1633, 1558, 1449 cm−1. 2-Methyl-3-(p-tolyl)-5H-benzo[e][1,4]diazepine, 2c. Orange oil, yield 56 mg, 45%: 1H NMR (300 MHz, chloroform-d) δ 7.40−7.21 (m, 5H), 7.15−7.01 (m, 3H), 4.65 (d, J = 10.8 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.35 (s, 3H), 2.27 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 166.5, 163.0, 147.2, 140.3, 133.7, 131.3, 129.2, 128.4, 128.0, 127.8, 126.4, 125.1, 54.1, 26.9, 21.37; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H16N2 249.1392, found 249.1394; FT-IR δ 3056, 2955, 2847, 1586, 1474 cm−1. 3-Methyl-2-(p-tolyl)-5H-benzo[e][1,4]diazepine, 3c. Yellow solid (mp 123−125 °C), yield 20 mg, 16%: 1H NMR (300 MHz, chloroform-d) δ 7.75−7.56 (m, 2H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.37−7.22 (m, 4H), 7.20−7.14 (m, 1H), 4.59 (d, J = 11.0 Hz, 1H), 3.74 (d, J = 11.0 Hz, 1H), 2.37 (s, 3H), 2.00 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 166.0, 161.3, 146.9, 141.2, 134.5, 130.6, 129.4, 128.4, 128.1, 127.7, 126.9, 126.0, 54.3, 24.4, 21.5; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H16N2 249.1392, found 249.1390; FT-IR δ 2918, 2844, 1553, 1431 cm−1. 2-Methyl-3-(4-nitrophenyl)-5H-benzo[e][1,4]diazepine, 2d. Brown oil, yield 110 mg, 79%: 1H NMR (300 MHz, chloroform-d) δ 8.21−8.10 (m, 2H), 7.66−7.56 (m, 2H), 7.43−7.26 (m, 3H), 7.21− 7.12 (m, 1H), 4.76 (d, J = 10.8 Hz, 1H), 3.84 (d, J = 10.8 Hz, 1H), 2.35 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 164.5, 161.1, 148.7, 146.9, 142.3, 130.4, 129.1, 128.8, 127.9, 127.1, 125.4, 123.8, 54.5, 26.5; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H13N3O2 280.1086, found 280.1081; FT-IR δ 3065, 2922, 2915, 1598, 1516 cm−1. 3-(4-Chlorophenyl)-2-methyl-5H-benzo[e][1,4]diazepine, 2e. Yellow solid (mp 99−102 °C), yield 110 mg, 82%: 1H NMR (300 MHz, chloroform-d) δ 7.51−7.19 (m, 7H), 7.13 (ddd, J = 7.8, 6.9, 1.6 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 3.79 (d, J = 10.8 Hz, 1H), 2.34 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 165.6, 161.9, 147.0, 136.3, 135.0, 130.9, 129.4, 128.8, 127.8, 126.7, 125.2, 54.2, 26.7; HRMS (ESITOF) m/z (M + H)+ Calcd for C16H13N2Cl 269.0846, found 269.0847; FT-IR δ 3062, 2917, 2837, 1588, 1474 cm−1. 2-Methyl-3-(3-nitrophenyl)-5H-benzo[e][1,4]diazepine, 2f. Yellow crystal (mp 146−147 °C), yield 106 mg, 76%: 1H NMR (300 MHz, chloroform-d) δ 8.32 (ddd, J = 2.3, 1.7, 0.5 Hz, 1H), 8.18 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.76 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H), 7.50 (ddd, J = 8.2, 7.7, 0.5 Hz, 1H), 7.42−7.26 (m, 3H), 7.19−7.12 (m, 1H), 4.74 (d, J = 10.8 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 2.37 (s, 3H); 13C NMR 1255

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258

Article

The Journal of Organic Chemistry (75 MHz, chloroform-d) δ 164.4, 160.7, 148.4, 146.9, 138.2, 133.9, 130.5, 129.6, 128.7, 127.9, 127.0, 125.5, 124.7, 123.1, 54.4, 26.5; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H13N3O2 280.1086, found 280.1086; FT-IR δ cm−1 3079, 2968, 2851, 1617, 1527 cm−1. 2-Methyl-3-propyl-5H-benzo[e][1,4]diazepine, 2g. Yellow oil, yield 32 mg, 32%: 1H NMR (300 MHz, chloroform-d) δ 7.32−7.25 (m, 2H), 7.25−7.20 (m, 1H), 7.17−7.10 (m, 1H), 4.60−4.30 (bs, 1H), 3.75−3.45 (bs, 1H), 2.03 (s, 3H), 1.83−1.50 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 146.8, 130.9, 128.3, 127.5, 126.6, 125.6, 53.7, 40.5, 23.2, 20.1, 14.06; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C13H16N2 201.1392, found 201.1390; FT-IR δ 3054, 2896, 2838, 1588, 1446 cm−1. Experimental Procedure for the Preparation of 2,3,4,5Tetrahydro-1H-benzo[e][1,4]diazepines. To a solution of the corresponding a-nitroepoxide (0.5 mmol) in ethanol (3 mL), 2-amino benzylamine was added (0.6 mmol), and the mixture was stirred at room temperature for 10 h. Then NaBH4 (1 mmol, powder) was added at 0 °C, and the resulting mixture was stirred for 6 h at room temperature. Then water (4 mL) was added, and the mixture was extracted with dichloromethane (3 × 5 mL). The organic layers were combined, washed with brine, and dried over Na2SO4. Then the solvent was evaporated under reduced pressure, and residue was purified by silica gel chromatography (n-hexane/ethyl acetate; 2:1) to give the pure product. 2-Methyl-3-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 4a. Yellow oil, yield 56 mg, 47%: 1H NMR (300 MHz, chloroform-d) δ 7.38−7.31 (m, 2H), 7.28−7.19 (m, 3H), 7.05−6.95 (m, 2H), 6.75 (td, J = 7.4, 1.2 Hz, 1H), 6.62 (dd, J = 8.1, 1.3 Hz, 1H), 4.12 (d, J = 3.2 Hz, 1H), 4.11 (d, J = 15.1 Hz, 1H), 3.97 (d, J = 15.1 Hz, 1H), 3.76 (qd, J = 6.8, 3.4 Hz, 1H), 3.05−2.50 (bs, 3H), 0.72 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 147.0, 141.9, 130.1, 129.3, 128.2, 127.5, 127.4, 127.1, 120.2, 119.1, 68.8, 55.8, 52.9, 15.2; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H18N2 239.1548, found 239.1549; FT-IR δ 3325, 3023, 2966, 2920, 2867, 1603, 748 cm−1. 3-Methyl-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 5a. Yellow oil, yield 15 mg, 13%: 1H NMR (300 MHz, chloroform-d) δ 7.32−7.13 (m, 5H), 7.06−6.93 (m, 2H), 6.75 (td, J = 7.4, 1.2 Hz, 1H), 6.60 (dd, J = 7.7, 1.2 Hz, 1H), 4.44 (d, J = 3.3 Hz, 1H), 4.05 (AB q, J = 15 Hz, 2H), 3.27 (qd, J = 6.6, 3.3 Hz, 1H), 2.20−1.85 (bs, 2H), 0.95 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 148.6, 141.2, 130.0, 129.5, 128.4, 127.6, 127.2, 126.9, 120.4, 118.9, 66.3, 57.9, 49.3, 14.4; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H18N2 239.1548, found 239.1546; FT-IR δ 3332, 3024, 2961, 2920, 2865, 1601, 753 cm−1. 2-Ethyl-3-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 4b. Yellow oil, yield 63 mg, 50%,: 1H NMR (300 MHz, chloroform-d) δ 7.43−7.34 (m, 2H), 7.30−7.20 (m, 3H), 7.02 (t, J = 7.3 Hz, 2H), 6.75 (td, J = 7.4, 1.2 Hz, 1H), 6.69−6.61 (m, 1H), 4.16 (d, J = 2.9 Hz, 1H), 4.13 (d, J = 15.2 hz, 1H), 4.01 (d, J = 15.2 Hz, 1H), 3.51−3.40 (m, 1H), 2.85−2.30 (bs, 2H), 1.15−0.96 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 146.9, 141.6, 129.7, 129.4, 128.2, 127.6, 127.5, 127.2, 120.0, 119.1, 68.3, 62.8, 52.8, 21.1, 11.0; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H20N2 253.1705, found 253.1705; FT-IR δ 3334, 3026, 2959, 2925, 2851, 1602, 748 cm−1. 3-Ethyl-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 5b. Yellow oil, yield 20 mg, 16%: 1H NMR (300 MHz, chloroform-d) δ 7.34−7.20 (m, 3H), 7.19−7.14 (m, 2H), 7.08−6.94 (m, 2H), 6.77 (td, J = 7.4, 1.2 Hz, 1H), 6.57 (dd, J = 7.8, 1.2 Hz, 1H), 4.41 (d, J = 3.2 Hz, 1H), 4.03 (AB q, J = 15 Hz, 2H), 3.04 (qd, J = 7.4, 3.2 Hz, 1H), 2.32−1.87 (bs, 2H), 1.66−1.44 (m, 2H), 0.81 (t, J = 7.4 Hz, 2H); 13C NMR (75 MHz, chloroform-d) δ 148.5, 141.0, 129.7, 129.1, 128.4, 128.0, 127.3, 127.2, 120.8, 119.4, 65.6, 63.9, 48.8, 29.7, 11.0; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H20N2 253.1705, found 253.1704; FT-IR δ 3331, 2017, 2958, 2862, 1601, 752 cm−1. 2-Methyl-3-(p-tolyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 4c. Yellow oil, yield 52 mg, 41%: 1H NMR (300 MHz, chloroform-d) δ 7.24 (d, J = 8.1 Hz, 2H), 7.10−6.95 (m, 4H), 6.75 (td, J = 7.4, 1.2 Hz, 1H), 6.62 (dd, J = 8.1, 1.2 Hz, 1H), 4.13 (d, J = 15.1 Hz, 1H), 4.09 (d, J = 3 Hz, 1H), 3.96 (d, J = 15.1 Hz, 1H), 3.75

(qd, J = 6.8, 3.2 Hz, 1H), 2.95−2.35 (bs, 2H), 2.26 (s, 3H), 0.73 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 147.1, 138.8, 136.7, 130.0, 129.3, 128.9, 127.5, 127.3, 120.1, 119.0, 68.5, 55.8, 52.8, 21.0, 15.3; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H20N2 253.1705, found 253.1706; FT-IR δ 3314, 2961, 2919, 2857, 1604, 755 cm−1. 3-Methyl-2-(p-tolyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 5c. Yellow oil, yield 18 mg, 14%: 1H NMR (300 MHz, chloroform-d) δ 7.08 (s, 4H), 7.04−6.93 (m, 2H), 6.76 (td, J = 7.4, 1.2 Hz, 1H), 6.61 (dd, J = 7.8, 1.2 Hz, 1H), 4.43 (d, J = 3.2 Hz, 1H), 4.07 (bs, 2H), 3.31 (qd, J = 6.7, 3.2 Hz, 1H), 2.28 (s, 3H), 2.15−1.85 (brs, 2H), 1.01 (d, J = 6.7 Hz, 2H); 13C NMR (75 MHz, chloroform-d) δ 148.8, 138.0, 137.1, 129.7, 129.2, 127.9, 126.8, 120.5, 119.0, 116.2, 65.6, 57.7, 48.6, 29.7, 21.0; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H20N2 253.1705, found 253.1707; FT-IR δ 3307, 2957, 2922, 2854, 1652, 754 cm−1. 2-Methyl-3-(4-nitrophenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 4d. Orange oil, yield 108 mg, 76%: 1H NMR (300 MHz, chloroform-d) δ 8.19−8.06 (m, 2H), 7.63−7.52 (m, 2H), 7.03 (t, J = 7.7 Hz, 2H), 6.78 (td, J = 7.4, 1.2 Hz, 1H), 6.65 (dd, J = 7.8, 1.2 Hz, 1H), 4.24 (d, J = 3.3 Hz, 1H), 4.17 (d, J = 15.3 Hz, 1H), 3.99 (d, J = 15.3 Hz, 1H), 3.85 (qd, J = 6.8, 3.3 Hz, 1H), 2.71−1.92 (bs, 2H), 0.73 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 148.9, 147.2, 146.7, 129.4, 129.3, 128.6, 127.8, 123.4, 120.5, 119.1, 68.0, 55.1, 52.1, 15.5; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H17N3O2 284.1399, found 284.1398; FT-IR δ 3343, 3054, 2960, 2922, 2852, 1603, 746 cm−1. 3-(4-Chlorophenyl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 4e. Yellow oil, yield 101 mg, 74%: 1H NMR (300 MHz, chloroform-d) δ 7.35−7.28 (m, 2H), 7.25−7.19 (m, 2H), 7.05− 6.96 (m, 2H), 6.79−6.71 (m, 1H), 6.65−6.59 (m, 1H), 4.13 (d, J = 15.2 Hz, 1H), 4.09 (d, J = 3.3 Hz, 1H), 3.96 (d, J = 15.1 Hz, 1H), 3.77 (qd, J = 6.8, 3.3 Hz, 1H), 3.15−2.45 (bs, 2H), 0.72 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 147.0, 140.1, 132.9, 129.6, 129.3, 129.0, 128.3, 127.6, 120.2, 118.9, 67.9, 55.5, 52.4, 15.5; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H17N2Cl 273.1159, found 273.1156; FT-IR δ 3315, 3062, 2965, 2927, 2820, 1603, 751 cm−1. 2-Methyl-3-(3-nitrophenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, 4f. Orange oil, yield 96 mg, 68%: 1H NMR (300 MHz, chloroform-d) δ 8.30 (t, J = 2.0 Hz, 1H), 8.07 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.77 (dt, J = 7.9, 1.5 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.5 Hz, 2H), 6.78 (td, J = 7.4, 1.2 Hz, 1H), 6.69−6.61 (m, 1H), 4.24 (d, J = 3.3 Hz, 1H), 4.17 (d, J = 15.3 Hz, 1H), 4.00 (d, J = 15.3 Hz, 1H), 3.87 (qd, J = 6.8, 3.3 Hz, 1H), 2.21−1.82 (bs, 2H), 0.75 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 148.2, 146.9, 143.5, 134.1, 129.4, 129.3, 129.1, 127.8, 122.7, 122.4, 120.5, 119.1, 67.6, 55.1, 52.0, 15.6; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H17N3O2 284.1399, found 284.1397; FT-IR δ 3353, 3058, 2964, 2922, 2852, 1604, 731 cm−1. General Procedure for the Preparation of Imidazopyridines. To a solution of nitroepoxide (0.5 mmol) in ethanol (3 mL) was added 2-amino pyridine (1.5 equiv), and the mixture was stirred at room temperature for 8 h. Then the solvent was evaporated under reduced pressure, and resulting crude oil was purified by silica gel chromatography (n-hexane/ethyl acetate, 1:2). 2-Methyl-3-phenylimidazo[1,2-a]pyridine, 6a. Yellow oil, yield 49 mg, 48%: 1H NMR (300 MHz, chloroform-d) δ 8.03 (dt, J = 6.9, 1.2 Hz, 1H), 7.58−7.31 (m, 6H), 7.09 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.66 (td, J = 6.8, 1.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 144.3, 140.7, 129.4, 129.3, 129.1, 128.1, 124.2, 123.0, 121.4, 116.8, 112.0, 13.8; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C14H12N2 209.1079, found 209.1073; FT-IR δ 3065, 2922, 1664 cm−1. 2-Ethyl-3-phenylimidazo[1,2-a]pyridine, 6b. Yellow oil, yield 65 mg, 59%: 1H NMR (300 MHz, chloroform-d) δ 7.98 (dt, J = 6.9, 1.2 Hz, 1H), 7.54 (dt, J = 9.1, 1.1 Hz, 1H), 7.52−7.30 (m, 5H), 7.08 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.64 (td, J = 6.8, 1.2 Hz, 1H), 2.74 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 146.3, 144.5, 129.7, 129.4, 129.1, 128.2, 124.1, 123.1, 120.9, 117.0, 111.9, 21.0, 14.4; HRMS (ESI-TOF) m/z (M + H)+ Calcd for 1256

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258

Article

The Journal of Organic Chemistry C15H14N2 223.1235, found 223.1230; FT-IR δ 3058, 2967, 2927, 1671 cm−1. 2,7-Dimethyl-3-(p-tolyl)imidazo[1,2-a]pyridine, 6c. Yellow oil, yield 49 mg, 44%: 1H NMR (300 MHz, chloroform-d) δ 8.03 (dt, J = 6.9, 1.2 Hz, 1H), 7.65−7.59 (m, 1H), 7.29 (s, 4H), 7.18−7.13 (m, 1H), 6.73 (td, J = 6.8, 1.2 Hz, 1H), 2.43 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 143.3, 138.6, 130.0, 129.4, 125.5, 125.2, 123.2, 121.7, 120.5, 116.3, 112.6, 21.3, 13.2; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C15H14N2 223.1235, found 223.1231; FT-IR δ 3054, 2920, 2855, 1674 cm−1. 3-(4-Chlorophenyl)-2-methylimidazo[1,2-a]pyridine, 6d. Pale yellow oil, yield 83 mg, 69%: 1H NMR (300 MHz, chloroform-d) δ 8.00 (dt, J = 6.9, 1.2 Hz, 1H), 7.67 (dt, J = 9.1, 1.2 Hz, 1H), 7.53−7.42 (m, 2H), 7.39−7.29 (m, 2H), 7.23 (ddd, J = 9.2, 6.9, 1.3 Hz, 1H), 6.79 (td, J = 6.8, 1.2 Hz, 1H), 2.43 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 143.3, 139.2, 134.7, 130.8, 129.7, 126.8, 126.0, 123.1, 120.5, 116.4, 113.2, 13.1; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C14H11ClN2 243.0689, found 243.0687 ; FT-IR δ 2920, 2852, 1670 cm−1. 2,7-Dimethyl-3-phenylimidazo[1,2-a]pyridine, 6e. Yellow oil, yield 61 mg, 55%: 1H NMR (300 MHz, chloroform-d) δ 7.91 (dd, J = 7.0, 0.9 Hz, 1H), 7.52−7.32 (m, 5H), 7.27 (dt, J = 1.9, 1.1 Hz, 1H), 6.49 (dd, J = 7.1, 1.7 Hz, 1H), 2.39 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz, chloroform-d) δ 144.7, 140.2, 135.3, 129.5, 129.4, 129.1, 127.9, 122.3, 120.8, 115.2, 114.6, 21.2, 13.7; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C15H14N2 223.1235, found 223.1235; FT-IR δ 3059, 2921, 2856, 1675 cm−1. 2-Ethyl-7-methyl-3-phenylimidazo[1,2-a]pyridine, 6f. Yellow oil, yield 69 mg, 58%: 1H NMR (300 MHz, chloroform-d) δ 7.87 (dd, J = 7.0, 0.9 Hz, 1H), 7.48−7.31 (m, 5H), 7.28 (dt, J = 2.0, 1.0 Hz, 1H), 6.47 (dd, J = 7.0, 1.7 Hz, 1H); 13C NMR (75 MHz, chloroform-d) δ 145.9, 144.9, 135.0, 129.6, 129.6, 129.1, 128.0, 122.3, 120.2, 115.5, 114.4, 21.2, 21.0, 14.4; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H16N2 237.1392, found 237.1391; FT-IR δ 3056, 2963, 2923, 1681 cm−1. 3-(4-Chlorophenyl)-2,7-dimethylimidazo[1,2-a]pyridine, 6g. Pale yellow oil, yield 92 mg, 72%: 1H NMR (300 MHz, chloroform-d) δ 7.86 (dd, J = 6.9, 0.9 Hz, 1H), 7.47−7.38 (m, 2H), 7.34−7.28 (m, 2H), 7.27 (dd, J = 1.8, 1.0 Hz, 1H), 6.52 (dd, J = 7.0, 1.7 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 4H); 13C NMR (75 MHz, chloroform-d) δ 144.9, 140.5, 135.6, 133.8, 130.6, 129.4, 128.0, 122.1, 119.7, 115.4, 114.8, 21.2, 13.7; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C15H13ClN2 257.0845, found 257.0845; FT-IR δ 2921, 2902, 1647 cm−1. General Procedure for the Preparation of Tetrahydroquinoxalines. To a solution of nitroepoxide (0.5 mmol) in dichloromethane (3 mL), N-methyl phenylenediamine (1.5 equiv) was added dropwise, and the mixture was stirred for 48 h at room temperature. Then sodium triacetoxyborohydride (1.5 mmol, 3 equiv) was added, and the resulting mixture was stirred for 24 h. Then a solution of 50% aqueous NaOH (150 μL) was added, and the mixture was stirred for 2 h. Then magnesium sulfate (50 mg) was added, and the mixture was stirred for additional 1.5 h. Then the mixture was filtered and concentrated to yield a yellow crude oil, which was purified through silica gel chromatography (n-hexane/ethyl acetate; 4:1). 1,3-Dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 7a. Yellow oil, yield 81 mg, 68%: 1H NMR (300 MHz, chloroform-d) δ 7.24− 7.12 (m, 3H), 7.05−6.99 (m, 2H), 6.79−6.63 (m, 1H), 6.58−6.44 (m, 3H), 4.12 (d, J = 3.4 Hz, 1H), 3.71 (bs, 1H), 2.71 (s, 3H), 0.83 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 139.2, 135.5, 133.0, 128.4, 127.9, 127.2, 119.9, 116.6, 113.7, 109.9, 67.6, 48.2, 37.2, 18.8; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H18N2 239.1549, found 239.1545; FT-IR δ 3374, 3055, 2925, 2867, 1599, 1508 cm−1. 3-Ethyl-1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline, 7b. Orange oil, yield 90 mg, 71%: 1H NMR (300 MHz, methanol-d4) δ 7.37−6.85 (m, 5H), 6.72−6.19 (m, 4H), 4.22−4.02 (bs, 1H), 3.55− 3.25 (bs, 1H), 2.70−2.45 (bs, 3H), 1.13−0.91 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, methanol-d4) δ 139.3, 135.0, 133.8, 128.4, 127.4, 126.6, 118.7, 116.7, 113.0, 109.9, 65.4, 54.7, 36.2, 25.2, 9.2; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H20N2 253.1705, found 253.1708; FT-IR δ 3373, 3057, 2962, 2875, 1598, 1509 cm−1.

1,3-Dimethyl-2-(p-tolyl)-1,2,3,4-tetrahydroquinoxaline, 7c. Yellow oil, yield 69 mg, 56%: 1H NMR (300 MHz, methanol-d4) δ 7.08−6.96 (m, 4H), 6.71−6.47 (m, 4H), 4.15 (d, J = 3.4 Hz, 1H), 3.82−3.65 (bs, 1H), 2.72 (s, 3H), 2.29 (s, 3H), 0.88 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, methanol-d4) δ 136.27, 136.22, 135.2, 133.8, 128.3, 127.9, 118.8, 116.5, 113.1, 109.6, 66.8, 48.1, 36.1, 19.7, 17.4; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C17H20N2 253.1705, found 253.1707; FT-IR δ 3366, 3066, 2926, 2868, 1598, 1509 cm−1. 2-(4-Chlorophenyl)-1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline, 7d. Yellow oil, yield 112 mg, 83%: 1H NMR (400 MHz, chloroform-d) δ 7.17−7.13 (m, 2H), 7.00−6.93 (m, 2H), 6.71 (td, J = 7.7, 1.9 Hz, 1H), 6.59−6.44 (m, 3H), 4.10 (d, J = 3.4 Hz, 1H), 3.70 (qd, J = 6.5, 3.4 Hz, 1H), 2.69 (s, 3H), 0.82 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, chloroform-d) δ 137.7, 135.1, 133.0, 132.9, 129.8, 128.1, 120.0, 116.8, 113.6, 110.0, 67.0, 48.0, 37.1, 18.6; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H17ClN2 273.1159, found 273.1159; FT-IR δ 3353, 3059, 2930, 2879, 1597, 1488 cm−1. 1,3-Dimethyl-2-(3-nitrophenyl)-1,2,3,4-tetrahydroquinoxaline, 7e. Orange-brown oil, yield 108 mg, 76%: 1H NMR (400 MHz, chloroform-d) δ 8.06−7.98 (m, 1H), 7.94 (t, J = 1.9 Hz, 1H), 7.41− 7.30 (m, 2H), 6.61−6.46 (m, 4H), 4.23 (d, J = 3.4 Hz, 1H), 3.74 (qd, J = 6.6, 3.4 Hz, 1H), 2.72 (s, 3H), 0.83 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, chloroform-d) δ 147.9, 141.6, 134.5, 129.1, 123.3, 122.3, 120.2, 117.3, 113.7, 110.2, 67.3, 47.8, 37.2, 18.6; HRMS (ESI-TOF) m/z (M + H)+ Calcd for C16H17N3O2 284.1399, found 284.1399; FTIR δ 3375, 3062, 2971, 2870, 1601, 1524 cm−1.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02795. Graphical NMR spectra of all compounds and X-ray crystallography data (PDF) Crystallography information for compounds 2b, 2f, and 4f (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Azim Ziyaei Halimehjani: 0000-0002-0348-8959 Florenci V. González: 0000-0001-5709-734X Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financed by Generalitat Valenciana (AICO/ 2016/32). We thank A. Vidal-Albalat for helpful discussions. ́ We also thank Serveis Centrals d’Instrumentació Cientifica from Universitat Jaume I for technical support.

■

REFERENCES

(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257. (2) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65. (3) Beghyn, T.; Deprez-Poulain, R.; Willand, N.; Folleas, B.; Deprez, B. Chem. Biol. Drug Des. 2008, 72, 3. (4) Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.; Cho, Y.; Chong, S.; Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S. H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.; Mitt, T.; Patel, M.; Penhallow, B. A.; Ricca, C.; Rose, W. C.; Schmidt, R.; Slusarchyk, W. A.; Vite, G.; Manne, V. J. Med. Chem. 2000, 43, 3587. (5) Johnston, S. R. D. IDrugs 2003, 6, 72. (6) Dragan, V.; McWilliams, J. C.; Miller, R.; Sutherland, K.; Dillon, J. L.; O’Brien, M. K. Org. Lett. 2013, 15, 2942. 1257

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258

Article

The Journal of Organic Chemistry (7) Li, Y.; Fang, X.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2013, 52, 9568. (8) Voskressensky, L. G.; Borisova, T. N.; Babakhanova, M. I.; Akbulatov, S. V.; Tsar'kova, A. S.; Titov, A. A.; Khrustalev, V. N.; Varlamov, A. V. Russ. Chem. Bull. 2012, 61, 1220. (9) Chen, B. C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Zhao, R. Tetrahedron Lett. 2001, 42, 1245. (10) Kim, O.; Jeong, Y.; Lee, H.; Hong, S.-S.; Hong, S. J. Med. Chem. 2011, 54, 2455. (11) Kamal, A.; Reddy, J.S.; Ramaiah, M. J.; Dastagiri, D.; Bharathi, E. V.; Prem Sagar, M. V.; Pushpavalli, S. N. C. V. L; Ray, P.; Pal-Bhadra, M. MedChemComm 2010, 1, 355. (12) Veron, J. B.; Allouchi, H.; Enguehard Gueiffier, C.; Snoeck, R.; De Clercq, G. A. E.; Gueiffier, A.; Andrei, G. Bioorg. Med. Chem. 2008, 16, 9536. (13) Scribner, A.; Dennis, R.; Hong, J.; Lee, S.; McIntyre, D.; Perrey, D.; Feng, D.; Fisher, M.; Wyvratt, M.; Leavitt, P.; Liberator, P.; Gurnett, A.; Brown, C.; Mathew, J.; Thompson, D.; Schmatz, D.; Biftu, T. Eur. J. Med. Chem. 2007, 42, 1334. (14) Bode, M. L.; Gravestock, D.; Moleele, S. S.; van der Westhuyzen, C. W.; Pelly, S. C.; Steenkamp, P. A.; Hoppe, H. C.; Khan, T.; Nkabinde, L. A. Bioorg. Med. Chem. 2011, 19, 4227. (15) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun. 2015, 51, 1555 and references therein. (16) Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. J. Med. Chem. 2008, 51, 7243. (17) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7, 888. (18) Eary, C. T.; Jones, Z. S.; Groneberg, R. D.; Burgess, L. E.; Mareska, D. A.; Drew, M. D.; Blake, J. F.; Laird, E. R.; Balachari, D.; O’Sullivan, M.; Allen, A.; Marsh, V. Bioorg. Med. Chem. Lett. 2007, 17, 2608. (19) Pouw, B.; Nour, M.; Matsumoto, R. R. Eur. J. Pharmacol. 1999, 386, 181. (20) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Yoden, T.; Yamagiwa, Y.; Yanagisawa, I.; Shibanuma, T.; Nohira, H. Bioorg. Med. Chem. 2000, 8, 393. (21) Patel, M.; McHugh, R. J., Jr.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Trainor, G. L.; Rodgers, J. D. Bioorg. Med. Chem. Lett. 2000, 10, 1729. (22) Vidal-Albalat, A.; Rodríguez, S.; González, F. V. Org. Lett. 2014, 16, 1752. (23) Capel, E.; Vidal-Albalat, A.; Rodríguez, S.; González, F. V. Synthesis 2016, 48, 2572. (24) Ayaz, M.; Martínez-Ariza, G.; Hulme, C. Synlett 2014, 25, 1680. (25) Zhao, D.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Tetrahedron 2016, 72, 5285. (26) Weiss, K. M.; Wei, S.; Tsogoeva, S. B. Org. Biomol. Chem. 2011, 9, 3457. (27) Guo, X.; Shao, J.; Liu, H.; Chen, B.; Chen, W.; Yu, Y. RSC Adv. 2015, 5, 51559. (28) Meninno, S.; Napolitano, L.; Lattanzi, A. Catal. Sci. Technol. 2015, 5, 124. (29) Ziyaei Halimehjani, A.; Lotfi Nosood, Y. Org. Lett. 2017, 19, 6748. (30) For previous publications reporting regioselective opening of epoxides with 2-amino pyridine, see: Gray, A. P.; Heitmeier, D. E.; Spinner, E. E. J. Am. Chem. Soc. 1959, 81, 4351. Gogoll, A.; Oscarsson, S. Tetrahedron 1990, 46, 2539. (31) A previous publication reported the reaction between nitroepoxide 1a and 2-amino pyridine under basic conditions affording the regioisomer of 6a (ref 27). However, synthetic and NMR studies performed in our lab concluded that the reaction product that the authors reported is the same one we obtained (6a). For spectroscopic data of regioisomers of 6a and 6b, see: (a) Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W. J. Org. Chem. 2013, 78, 12494. (b) Delaye, P.O.; Pénichon, M.; Allouchi, H.; Enguehard-Gueiffier, C.; Gueiffier, A. Org. Biomol. Chem. 2017, 15, 4199.

(32) For some cases also the dihydroquinoxaline resulting from the attack of the primary amine to the nitroepoxide followed by dehydration was detected as traces. (33) J2,3 coupling constant for compounds 7a−e is 3.4 Hz as for similar reported syn tetrahydroquinoxalines (see ref 13). (34) Vidal-Albalat, A.; Swiderek, K.; Izquierdo, J.; Rodríguez, S.; Moliner, V.; González, F. V. Chem. Commun. 2016, 52, 10060. (35) Agut, J.; Vidal, A.; Rodríguez, S.; González, F. V. J. Org. Chem. 2013, 78, 5717.

1258

DOI: 10.1021/acs.joc.7b02795 J. Org. Chem. 2018, 83, 1252−1258