Regioselective Opening of Nitroepoxides with Unsymmetrical

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Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines Yazdanbakhsh Lotfi Nosood, Azim Ziyaei Halimehjani, and Florenci V. González J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02795 • Publication Date (Web): 09 Jan 2018 Downloaded from http://pubs.acs.org on January 16, 2018

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The Journal of Organic Chemistry

1 2 3 4 5 6 7 8 9 Yazdanbakhsh L. Nosood,§ Azim Ziyaei Halimehjani,‡ and Florenci V. González*,§ 10 § 11 Departament de Química Inorgànica i Orgànica, Universitat Jaume I. Castelló, Spain. 12 ‡ 13 Faculty of Chemistry, Kharazmi University. Tehran, Iran. 14 15 [email protected] 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Abstract Nitroepoxides are easily transformed into benzodiazepines, tetrahydrobenzodiazepines, imidazopyridines, 42 and N-alkyl tetrahydroquinoxalines by treatment with 2-aminobenzylamines, 2-aminopyridines and N-alkyl 1,243 44 diaminobenzenes respectively. Regioselectivity is controlled through attack of the most nucleophilic nitrogen of the 45 unsymmetrical diamine to the beta position of the epoxide. These reactions represent an efficient way to prepare 46 47 privileged bioactive structures. 48 49 50 51 _____________________________________________________________________________________________________________________ 52 53 54 55 Introduction 56 57 58 59 ACS Paragon Plus Environment 60

Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Nitrogenated heterocycles are important structural components of pharmaceuticals.1 Developing new synthetic methods to access diverse nitrogenated heterocycles is important for medicinal chemistry. Benzodiazepines moiety has been classified as a “privileged scaffold” in medicinal chemistry and many bioactive compounds bear this core.2 Compounds containing tetrahydrobenzodiazepine moiety find numerous applications in medicinal chemistry,3 for example BMS-214662 which exhibits potent antitumor activity (Figure 1).4,5 Also tetrahydrobenzodiazepines have been used as intermediates in organic synthesis.6-9 Compounds that possess 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 anticonvulsants,19 potassium channel openers20 and anti-HIV agents.21 Nitroepoxides, easily prepared through the straigthforward epoxidation of nitroalkenes, represent unique building blocks for the preparation of 1,2-difunctionalized compounds, particularly heterocycles.

Figure 1. Examples of biologically active heterocycles.

We previously reported the transformation of nitroepoxides into quinoxalines, pyrazines, piperazines and tetrahydroquinoxalines by reaction with symmetrical diamines,22 and morpholines and benzoxazines when treated with aminoalcohols (Figure 2).23 Based upon proposed mechanism of the reaction between a nitroepoxide and a

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diamine (Figure 2), we envisaged that an unsymmetrical diamine would afford corresponding regioisomeric heterocycle by attack of the most nucleophilic nitrogen to the beta position of the nitroepoxide (Figure 2).

Previous work piperazines X tetrahydroquinoxalines

HN

O R1

[H–]

H 2N NO2

R2 nitroepoxide

X

R2

N

N

R1

R2

X O

HN

– HNO2

R1

[O]

X = NH2, OH

morpholines benzoxazines

R2

R1

quinoxalines

This work N n H n = 0,1,2 NH2 O R1

Unsymmetrical NO2 diamine

R2 nitroepoxide

– HNO2

Regiocontrol

NO2

R1

N R1

n

NH2 O R2

N – H2O

R1

[H–]

n

N R2 [O]

tetrahydrobenzodiazepines benzodiazepines tetrahydroquinoxalines imidazopyridines

R2

Figure 2. Reaction design for heterocycles.

Results and discussion 5H-Benzo[e][1,4]diazepines are interesting heterocycles which are commonly prepared by condensation of 1,2dicarbonyl compounds with 2-aminobenzylamine.24 Nitroepoxides represent a valid alternative to an otherwise less synthetically accessible 1,2-dicarbonyl compounds.22,23,25,26,27,28,29 We began our studies of the preparation of benzodiazepines by combining nitroepoxide 1a with 2-aminobenzylamine (1.2 equivalents) 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. Best result was obtained by using ethanol as a solvent (Table 1, ACS Paragon Plus Environment

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entry 2). Under these conditions, a 3/1 mixture of regioisomeric benzodiazepines 2a and 3a were 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 regioisomer (2d-f) (Table 1, entries 3-4) in good yield. Nitroepoxide 1g with two alkyl substituents afforded benzodiazepine 2g in low yield (Table 1, entry 8). The structure of resulting compounds was confirmed by X-ray diffraction analyses of compounds 2b and 2f (see Supporting Information). Table 1. Synthesis of benzodiazepines a

Solvent

ratiob

Entry

R1 , R2

epoxide

1

Ph, Me

1a

DCM

2a/3a

2/1

yield (%)c 31

2

Ph, Me

1a

Ethanol

2a/3a

3.2/1

65

3

Ph, Et

1b

Ethanol

2b/3b

2.4/1

73

4

pMe-Ph, Me

1c

Ethanol

2c/3c

3/1

61

5

pNO2-Ph, Me

1d

Ethanol

2d

>9/1

79

6

pCl-Ph, Me

1e

Ethanol

2e

>9/1

82

7

mNO2-Ph, Me

1f

Ethanol

2f

>9/1

76

8

n-Pr, Me

1g

Ethanol

2g

>9/1

32

products

a

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


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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. Table 2. Synthesis of tetrahydrobenzodiazepines a

entry

R1 , R2

epoxide

4/5b

1

Ph, Me

1a

3.3/1

2

Ph, Et

1b

3

pMe-Ph, Me

4

yield (%)c 60

2.5/1

4 syn/antib 91/9 syn/antic 96/4

1c

2.9/1

94/6

55

pNO2-Ph, Me

1d

>9/1

>99/1

76

5

pCl-Ph, Me

1e

>9/1

>99/1

74

6

mNO2-Ph, Me

1f

>9/1

97/3

68

66

a

Reactions were carried out using nitroepoxide (1.0 equiv) in ethanol (6 mL/mmol), 2-amino benzylamine (1.2 equiv) at room temperature for 8 h then sodium borohydride (2.0 equiv.). b Ratio was calculated from 1H-NMR of crude mixture. c Yield of isolated products. The relative stereochemistry of tetrahydrobenzodiazepines was assigned based on NMR studies and confirmed by Xray diffraction analysis of compound 4f. We next studied the reaction of nitroepoxides with 2-aminopyridines as an interesting diamino compound inspired by previous work by Yu et al.27 Nitroepoxide 1a was treated with 2-amino pyridine (1.5 equivalents) in tetrahydrofuran as a solvent, the resulting imidazopyridine 6a was obtained in low yield. Solvent screening was then performed in ACS Paragon Plus Environment

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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 procedure, imidazopyridines 6a-g were prepared by reaction of nitroepoxides 1a-e with 2-amino pyridine or 2-amino-4-methyl pyridine (Scheme 1). In all cases a single regioisomeric compound was obtained resulting from the initial attack of the pyridine nitrogen to the beta position of the nitroepoxide (Figure 2).30 The structure of compounds 6a-g was asigned by NMR: NOE experiments (Scheme 2) and by comparison with reported data.31

Scheme 1. Synthesis of imidazopyridines 6a-g One-pot procedure for the preparation of N-substituted tetrahydroquinoxalines from nitroepoxides was next studied. The reaction of nitroepoxides 1a-e with N-methyl-1,2-diaminobenzene and sodium triacetoxyborohydride as a reductive agent afforded syn tetrahydroquinoxalines 7a-e as reaction products in good yield. Dichloromethane gave


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higher chemical yields than ethanol. In case of previously reported preparation of non-substituted 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. Reversely if N-methyl-1,2benzenodiamines is 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). 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 was asigned by NMR: NOE experiments (Scheme 2) and coupling constants.33

Scheme 2. Synthesis of tetrahydroquinoxalines 7a-e


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Nitroepoxides having two alkyl groups did not afford desired heterocycles when submitted to the above mentioned reactions for the preparation of tetrahydrobenzodiazepines, imidazopyridines nor 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 1,2diaminobenzene, 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 aforementioned privileged bioactive structures. Further investigations of the utility of nitroepoxides in synthesis are ongoing and will be reported in the future.

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 (quadrupolehexapole-TOF) mass spectrometer with an orthogonal Z-spray-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 oC 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 ACS Paragon Plus Environment

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chromatography (silicagel, n-hexane / ethyl acetate; 9:1). The product obtained as a yellow oil (yield 2.15g, 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);

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C 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-1.29 (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 oC for 2 h. The crude product that separated on cooling was filtered and recrystallized from ethanol. Product was obtained as a yellow crystal (yield 3.2g, 95%), mp 106-108 oC; 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); 13C 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 2.9g, 91%), mp 82-84 oC; 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 2.9g, 86%), mp 54-55 oC; 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-1.28 (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 16h. Excess solvent was evaporated in vacuo and the crude nitroaldol was dissolved in CH2Cl2 (12 mL), cooled with an ice-bath and then methanesulfonylchloride (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 2M HCl (10 mL), 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 2.65g, 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), 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


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General procedure for the preparation of nitroepoxides22 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 NaOH 2M (3.9 mL, 6.1 mmol) and stirred at 0 oC for 10 minutes. Then, ice water was added (10 mg), extracted with diethyl ether (3 x 30 mL), the combined organic phases 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 1.8g, 84%): 1H NMR (500 MHz, CDCl3) δ 7.41 (m, 3H), 7.30 (m, 2H), 4.56 (s, 1H), 1.78 (s, 3H);

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C 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 1.9g, 82%); 1H 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);

13

C 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-1.29

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-1.29


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2-methyl-2-nitro-3-(4-nitrophenyl)oxirane 1d: yellow crystal, (yield 2.6g, 96%), mp 90-93 oC;1H NMR (300 MHz, Chloroform-d) δ 8.37 – 8.26 (m, 2H), 7.60 – 7.49 (m, 2H), 4.69 (s, 1H), 1.82 (s, 3H);

13

C 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 cm1 22

.

3-(4-chlorophenyl)-2-methyl-2-nitrooxirane 1e: pale yellow crystal, (2.4g, yield 94%), mp 60-62 oC (lit. 50-56 ºC);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 2.4g, 89%), mp 80-83 oC; 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);

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C 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-1.28

2-methyl-2-nitro-3-propyloxirane 1g. Yellowish oil (yield 1.2g, 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


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pressure to yield a yellow oil which was purified by silicagel 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 oC), 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);

13

C 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, Chloroformd) 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 (ESI-TOF) 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 oC), 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 oC), 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.


12

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2-methyl-3-(p-tolyl)-5H-benzo[e][1,4]diazepine 2c: orange oil, yield 56 mg 45%, 1H NMR (300 MHz, Chloroformd) 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; FTIR 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 oC), 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, Chloroformd) 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 (ESITOF) 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);

13

C 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 oC), 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 (ESI-TOF) 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 oC), 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 =


13


10.8 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 2.37 (s, 3H);

13

Page 14 of 22

C NMR (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, Chloroformd) 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 2,3,4,5-tetrahydro-1H-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 NaBH4 (1 mmol, powder), was added at 0 oC and the resulting mixture was stirred for 6h 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 silicagel 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 14 ACS Paragon Plus Environment

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(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);

13

C 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 cm1

.

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,


15


Page 16 of 22

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);

13

C 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:


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To a solution of nitroepoxide (0.5 mmol) in ethanol (3 mL) was added 2-amino pyridine (1.5 equivalents) 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 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%),

1

H 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);

13

C 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.


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Page 18 of 22

2,7-dimethyl-3-phenylimidazo[1,2-a]pyridine 6e: yellow oil, (yield 61 mg, 55%), 1H NMR (300 MHz, Chloroformd) 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);

13

C 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);

13

C 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; FTIR 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 resulting mixture was stirred for 24 h. Then a solution of 50% aqueous NaOH solution (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 silicagel 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


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Hz, 1H), 3.71 (bs, 1H), 2.71 (s, 3H), 0.83 (d, J = 6.6 Hz, 3H);

13

C 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; FT-IR δ 3375, 3062, 2971, 2870, 1601, 1524 cm-1.


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Acknowledgements 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 Científica from Universitat Jaume I for technical support.

Supporting Information Available: Graphical NMR spectra of all compounds and X-ray crystallography data. This material is available free of charge via the Internet at http://pubs.acs.org. References and Footnotes (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. (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.; Tsarkova, 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.; Sagar, M. V. P.; Pushpavalli, S. N. C. V. L; Ray, P.; Pal-Bhadra, M. Med. Chem. Commun. 2010, 1, 355. (12) Veron, J. B.; Allouchi, H.; Enguehard Gueiffier, C.; Snoeck, R.; De Clercq, G. A. E.; Gueiffier, A. 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. ACS Paragon Plus Environment

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(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 cites herein. (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.; Matssuhisa, A.; Yoden, T.; Yamagiwa, Y.; Yanagisawa, I.; Shibanuma, T.; Nohira, H. Bioorg. Med. Chem. 2000, 8, 393. (21) Patel, M.; McHugh Jr., R. J.; Cordova, B. C.; Klabe, R. M.; Erickson-Vitanen, S.; Trainor, G. L.; Rogers, 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. (29) Meninno, S.; Napolitano, L.; Lattanzi, A. Catal. Sci. Technol. 2015 5, 124. (28) Halimehjani, A. Z.; Nosood, Y. L. 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 and 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 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.; Engehard-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. ACS Paragon Plus Environment

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(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-Albalat, A.; Rodríguez, S.; González, F. V. J. Org. Chem. 2013, 78, 5717.


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Regioselective Opening of Nitroepoxides with Unsymmetrical

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