Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines

Article abstract of DOI:10.1021/acs.joc.7b02795

Nitroepoxides are easily transformed into benzodiazepines, tetrahydrobenzodiazepines, imidazopyridines, and N-alkyl tetrahydroquinoxalines by treatment with 2-aminobenzylamines, 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.

Full text of DOI:10.1021/acs.joc.7b02795

Subscriber access provided by Kent State University Libraries
Article
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 10, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 22
The Journal of Organic Chemistry
1
2
3
4
5
6
Regioselective Opening of Nitroepoxides with Unsymmetrical Diamines
7
8
9
Yazdanbakhsh L. Nosood,§ Azim Ziyaei Halimehjani,‡ and Florenci V. González*,§
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
§ Departament de Química Inorgànica i Orgànica, Universitat Jaume I. Castelló, Spain.
‡ Faculty of Chemistry, Kharazmi University. Tehran, Iran.
fgonzale@uji.es
Abstract Nitroepoxides are easily transformed into benzodiazepines, tetrahydrobenzodiazepines, imidazopyridines,
and N-alkyl tetrahydroquinoxalines by treatment with 2-aminobenzylamines, 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 beta position of the epoxide. These reactions represent an efficient way to prepare
privileged bioactive structures.
_____________________________________________________________________________________________________________________
Introduction
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 22
Nitrogenated heterocycles are important structural components of pharmaceuticals.1 Developing new synthetic
methods to access diverse nitrogenated heterocycles is important for medicinal chemistry.
1
2
3
4
5
6
7
8
9
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
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
3
4,5
medicinal chemistry, for example BMS-214662 which exhibits potent antitumor activity (Figure 1). 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
55 with aminoalcohols (Figure 2).23 Based upon proposed mechanism of the reaction between a nitroepoxide and a
56
57
58
59
60
2
ACS Paragon Plus Environment

Page 3 of 22
The Journal of Organic Chemistry
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).
1
2
3
4
5
6
7
Previous work
8
9
piperazines
tetrahydroquinoxalines
morpholines
benzoxazines
X
HN
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
R2
R1
[H–]
[O]
H2N
O
X
O
NO2
X
HN
R1
R1
– HNO2
R2
nitroepoxide
quinoxalines
R2
N
N
X = NH2, OH
R2
R1
This work
N
H
n
NH2
n = 0,1,2
Unsymmetrical
diamine
n
N
N
O
NH2
n
NO2
O
N
R1
– H2O
– HNO2
R2
[O]
R1
R2
nitroepoxide
R2
R1
[H–]
Regiocontrol
tetrahydrobenzodiazepines
tetrahydroquinoxalines
benzodiazepines
imidazopyridines
NO2
R1
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 1,2-
24
dicarbonyl compounds with 2-aminobenzylamine. 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,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 22
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).
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
Table 1. Synthesis of benzodiazepines a
Solvent
DCM
ratiob
2/1
yield
(%)c
31
Entry
R1, R2
epoxide
1a
products
2a/3a
1
Ph, Me
2
3
4
5
6
7
8
Ph, Me
Ph, Et
1a
1b
1c
1d
1e
1f
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
2a/3a
2b/3b
2c/3c
2d
3.2/1
2.4/1
3/1
65
73
61
79
82
76
32
pMe-Ph, Me
pNO2-Ph, Me
pCl-Ph, Me
mNO2-Ph, Me
n-Pr, Me
>9/1
>9/1
>9/1
>9/1
2e
2f
1g
2g
a Reactions were carried out using nitroepoxide (1.0 equiv) in ethanol (6 mL/mmol), 2-amino benzylamine
b
1
c
(1.2 equiv) at room temperature for 8 h. Ratio was calculated from H-NMR of crude mixture. Yield of isolated
products.
4
ACS Paragon Plus Environment

Page 5 of 22
The Journal of Organic Chemistry
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.
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
a
Table 2. Synthesis of tetrahydrobenzodiazepines
entry
R1, R2
Ph, Me
epoxide
1a
4/5b
3.3/1
2.5/1
2.9/1
>9/1
>9/1
>9/1
4
yield
(%)c
60
syn/antib
91/9
1
2
3
4
5
6
Ph, Et
1b
96/4
94/6
66
55
76
74
68
pMe-Ph, Me
pNO2-Ph, Me
pCl-Ph, Me
mNO2-Ph, Me
1c
1d
>99/1
>99/1
97/3
1e
1f
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 X-
ray diffraction analysis of compound 4f.
We next studied the reaction of nitroepoxides with 2-aminopyridines as an interesting diamino compound inspired by
27
previous work by Yu et al. 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
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 22
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
1
2
3
4
5
6
7
8
9
30
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
obtained resulting from the initial attack of the pyridine nitrogen to the beta position of the nitroepoxide (Figure 2).
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
6
ACS Paragon Plus Environment

Page 7 of 22
The Journal of Organic Chemistry
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-1,2-
benzenodiamines 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).
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
Resulting compounds 7a-e are the ones expected from the attack of secondary amine (more reactive) to the
32
nitroepoxide followed by reductive amination of the resulting amino ketone (Figure 2).
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
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 22
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.
1
2
3
4
5
6
7
Conclusions
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
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 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 (quadrupole-
hexapole-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
8
ACS Paragon Plus Environment

Page 9 of 22
The Journal of Organic Chemistry
chromatography (silicagel, n-hexane / ethyl acetate; 9:1). The product obtained as a yellow oil (yield 2.15g, 76%); 1H
1
2
3
4
5
6
7
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,
13
3H); 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
8
9
(E)-1-nitro-4-(2-nitroprop-1-en-1-yl)benzene: : A solution of nitroethane (44 mmol), n-butylamine (18 mmol), and
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
o
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 3.2g, 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 =
13
1.2 Hz, 3H); C NMR (75 MHz, Chloroform-d) δ 150.2, 148.1, 138.8, 130.7, 130.5, 124.0, 14.0; LRMS (EI): Mass
+
-1 22
calcd for C9H8N2O4 [M ]: 208.0; found 208.0; FT-IR δ 3075, 2992, 1516, 1313 cm .
(E)-1-chloro-4-(2-nitroprop-1-en-1-yl)benzene: Product was obtained as a pale yellow crystal (yield 2.9g, 91%),
o
1
mp 82-84 C; H 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
13
= 1.2 Hz, 3H); C 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
13
Hz, 3H); C 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
+
-1 28
(EI): Mass calcd for C9H8N2O4 [M ]: 208.0; found 208.0; FT-IR δ 3082, 2990, 1506, 1317 cm .
(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
51 purified by silica-gel chromatography (hexanes : ethyl acetate, 9:1 to 7:3) to give the pure product as an orange oil.
52
1
(yield 2.65g, 68%): H 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;
53
54
55
56
57
58
59
60
-1 35
HRMS (EI) calcd for C6H11NO2 (M) 129.0790, found 129.0791; IR (KBr) δ 3056, 2961, 1512, 1330 cm .
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 22
1
2
3
4
General procedure for the preparation of nitroepoxides22
5
6
7
8
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
9
o
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
at 0 C 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,
13
2H), 4.56 (s, 1H), 1.78 (s, 3H); C NMR (126 MHz, CDCl ) δ 131.0, 129.3, 128.7, 126.3, 88.8, 62.6, 12.2 ppm;
3
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
1
2-ethyl-2-nitro-3-phenyloxirane 1b: yellow oil, (yield 1.9g, 82%); 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
13
= 7.4 Hz, 3H); 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):
40 calcd for C10H11NO3 (M+) 193.0, found 193.0; calcd for C8H6O (M-CH2CH3-NO2) 118.0, found 118.0; FT-IR δ 2981,
41
-1
29
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2943, 1556, 1456, 1349, 937, 813 cm .
2-methyl-2-nitro-3-(p-tolyl)oxirane 1c.
1
yellow oil, (yield 744 mg, 75%): H NMR (500 MHz, CDCl3) δ 7.26−7.17 (m, 4H), 4.50 (s, 1H), 2.38 (s, 3H), 1.80
13
(s, 3H); C 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
10
ACS Paragon Plus Environment

Page 11 of 22
The Journal of Organic Chemistry
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); 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
2
3
4
5
6
7
8
9
1 22
10
11
12
13
14
15
16
.
o
3-(4-chlorophenyl)-2-methyl-2-nitrooxirane 1e: pale yellow crystal, (2.4g, yield 94%), mp 60-62 C (lit. 50-56
17 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
18
19
20
+
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 )
21
22
213.0, found 213.0; FT-IR δ 3004, 2898, 1558, 1400, 1351, 1084, 816 cm-1.34
23
24
25
o
1
26
27
28
29
30
31
32
33
34
35
36
37
38
39
2-methyl-2-nitro-3-(3-nitrophenyl)oxirane 1f: pale yellow crystal, (yield 2.4g, 89%), mp 80-83 C; H 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,
13
3H); 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)
+
-1
28
calcd for C9H8N2O5 (M ) 224.0, found 224.0; FT-IR δ 3082, 2954, 2904, 1529, 1417, 1350, 1088, 992 cm .
2-methyl-2-nitro-3-propyloxirane 1g.
40 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,
41
13
42
43
4H), 0.96 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl3) δ 87.9, 62.9, 29.7, 19.1, 13.6 ppm; HRMS (EI) calcd for
44
45
C6H11NO3 (M) 145.0739, found 145.0741; IR (KBr) δ 3028, 1555, 1029, 865 cm-1.35
46
47
48
49
50
51
52
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
53
54
mmol), and the mixture was stirred at room temperature for 10 h. Then the solvent was evaporated under reduced
55
56
57
58
59
60
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 22
pressure to yield a yellow oil which was purified by silicagel chromatography (n-hexane / ethyl acetate; 4:1), to give
1
2
3
4
the pure product.
5
6
o
1
2-methyl-3-phenyl-5H-benzo[e][1,4]diazepine 2a: yellow solid (mp 114-116 C), yield 58 mg 49%, H NMR (300
7
8
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
9
13
10
11
12
13
14
15
16
(d, J = 10.8 Hz, 1H), 2.36 (s, 3H); 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.
1
17 3-methyl-2-phenyl-5H-benzo[e][1,4]diazepine 3a: yellow oil, yield 19 mg 16%, H NMR (300 MHz, Chloroform-
18
19
20
21
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,
22
23
24
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 C H N 235.1235,
16 14
2
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
-1
found 235.1236; FT-IR δ 3059, 2919, 2835, 1630, 1557, 1446 cm .
2-ethyl-3-phenyl-5H-benzo[e][1,4]diazepine 2b: yellow solid, (mp 109- 112 C), yield 63 mg 51%, 1H NMR (300
o
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 =
13
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); C 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,
40 1445 cm-1
41
42
o
1
3-ethyl-2-phenyl-5H-benzo[e][1,4]diazepine 3b: yellow solid, (mp 116-118 C), yield 28 mg 22%, H NMR (300
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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
13
= 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); C 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
ACS Paragon Plus Environment

Page 13 of 22
The Journal of Organic Chemistry
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-
1
2
3
4
5
6
7
8
9
-1
10
11
12
13
14
15
16
IR δ 3056, 2955, 2847, 1586, 1474 cm .
o
1
3-methyl-2-(p-tolyl)-5H-benzo[e][1,4]diazepine 3c: yellow solid, (mp 123-125 C), yield 20 mg 16%, H 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,
17 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-
18
19
20
21
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.
22
23
24
25
26
27
1
2-methyl-3-(4-nitrophenyl)-5H-benzo[e][1,4]diazepine 2d: brown oil, yield 110 mg 79%, H NMR (300 MHz,
28
29
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
30
13
Hz, 1H), 3.84 (d, J = 10.8 Hz, 1H), 2.35 (s, 3H); C NMR (75 MHz, Chloroform-d) δ 164.5, 161.1, 148.7, 146.9,
31
32
33
34
35
36
37
38
39
+
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
-1
C16H13N3O2 280.1086, found 280.1081; FT-IR δ 3065, 2922, 2915, 1598, 1516 cm .
o
1
3-(4-chlorophenyl)-2-methyl-5H-benzo[e][1,4]diazepine 2e: yellow solid, (mp 99-102 C), yield 110 mg 82%, H
40 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,
41
42
43
13
1H), 3.79 (d, J = 10.8 Hz, 1H), 2.34 (s, 3H); C NMR (75 MHz, Chloroform-d) δ 165.6, 161.9, 147.0, 136.3, 135.0,
44
45
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
46
47
269.0846, found 269.0847; FT-IR δ 3062, 2917, 2837, 1588, 1474 cm-1.
48
49
50
51
52
2-methyl-3-(3-nitrophenyl)-5H-benzo[e][1,4]diazepine 2f: yellow crystal, (mp 146-147 oC), yield 106 mg 76%, 1H
53
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 =
54
55
56
57
58
59
60
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 22
13
10.8 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 2.37 (s, 3H); 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.
1
2
3
4
5
6
7
8
9
1
10
11
12
13
14
15
16
2-methyl-3-propyl-5H-benzo[e][1,4]diazepine 2g: yellow oil, yield 32 mg 32%); H 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),
13
1.83-1.50 (m, 4H), 0.98 (t, J = 7.4 Hz, 3H); C NMR (75 MHz, Chloroform-d) δ 146.8, 130.9, 128.3, 127.5, 126.6,
17 125.6, 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;
18
-1
19
20
FT-IR δ 3054, 2896, 2838, 1588, 1446 cm .
21
22
23
Experimental procedure for the preparation of 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepines:
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
To a solution of corresponding a-nitroepoxide (0.5 mmol), in ethanol (3 mL), 2-amino benzylamine was added (0.6
o
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 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
-1
for C16H18N2 239.1548, found 239.1549; FT-IR δ 3325, 3023, 2966, 2920, 2867, 1603, 748 cm .
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

Page 15 of 22
The Journal of Organic Chemistry
(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.
1
2
3
4
5
6
7
8
1
2-ethyl-3-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 4b: yellow oil, yield 63 mg 50%, H NMR (300
9
10
11
12
13
14
15
16
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
13
(m, 1H), 2.85-2.30 (bs, 2H), 1.15 – 0.96 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H); C NMR (75 MHz, Chloroform-d) δ
17 146.9, 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)
18
+
-
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
m/z: (M + H) Calcd for C17H20N2 253.1705, found 253.1705; FT-IR δ 3334, 3026, 2959, 2925, 2851, 1602, 748 cm
1
.
1
3-ethyl-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 5b: yellow oil, yield 20 mg 16%, H 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)
-1
Calcd for C17H20N2 253.1705, found 253.1704; FT-IR δ 3331, 2017, 2958, 2862, 1601, 752 cm .
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
40 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,
41
42
43
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,
44
45
13
1H), 2.95-2.35 (bs, 2H), 2.26 (s, 3H), 0.73 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, Chloroform-d) δ 147.1, 138.8,
46
47
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)+
48
49
50
-1
Calcd for C17H20N2 253.1705, found 253.1706; FT-IR δ 3314, 2961, 2919, 2857, 1604, 755 cm .
51
52
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
53
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,
54
55
56
57
58
59
60
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
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.
1
2
3
4
5
6
7
8
1
2-methyl-3-(4-nitrophenyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 4d: orange oil, yield 108 mg 76%, H
9
10
11
12
13
14
15
16
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
13
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); C NMR (75 MHz,
17 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
18
19
20
+
(ESI-TOF) m/z: (M + H) Calcd for C16H17N3O2 284.1399, found 284.1398; FT-IR δ 3343, 3054, 2960, 2922, 2852,
21
22
1603, 746 cm-1.
23
24
3-(4-chlorophenyl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine 4e: yellow oil, yield 101 mg 74%, 1H
25
26
27
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,
28
29
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 =
30
31
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,
32
+
33
34
35
36
37
38
39
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
-1
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%, H
40 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
41
42
43
44
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,
45
46
47
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,
48
49
50
+
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
51
52
284.1399, found 284.1397; FT-IR δ 3353, 3058, 2964, 2922, 2852, 1604, 731 cm-1.
53
54
55
56
57
58
59
60
General procedure for the preparation of imidazopyridines:
16
ACS Paragon Plus Environment

Page 17 of 22
The Journal of Organic Chemistry
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).
1
2
3
4
5
6
7
8
1
2-methyl-3-phenylimidazo[1,2-a]pyridine 6a: yellow oil, (yield 49 mg, 48%), H NMR (300 MHz, Chloroform-d)
9
10
11
12
13
14
15
16
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,
13
1H), 2.42 (s, 3H); C 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,
17 2922, 1664 cm-1.
18
19
1
2-ethyl-3-phenylimidazo[1,2-a]pyridine 6b: yellow oil, (yield 65 mg, 59%), H 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.
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
1
2,7-dimethyl-3-(p-tolyl)imidazo[1,2-a]pyridine 6c: yellow oil, (yield 49 mg, 44%), 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,
13
1.2 Hz, 1H), 2.43 (s, 3H), 2.39 (s, 3H); C 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
40 223.1231; FT-IR δ 3054, 2920, 2855, 1674 cm-1.
41
42
1
3-(4-chlorophenyl)-2-methylimidazo[1,2-a]pyridine 6d: pale yellow oil, (yield 83 mg, 69%), H 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.
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 22
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),
1
2
3
4
5
6
13
2.39 (s, 3H), 2.32 (s, 3H); C NMR (75 MHz, Chloroform-d) δ 144.7, 140.2, 135.3, 129.5, 129.4, 129.1, 127.9,
7
8
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
9
-1
10
11
12
13
14
15
16
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%), H 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,
13
17 1.7 Hz, 1H); 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,
18
+
19
20
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-
21
22
IR δ 3056, 2963, 2923, 1681 cm-1.
23
1
3-(4-chlorophenyl)-2,7-dimethylimidazo[1,2-a]pyridine 6g: pale yellow oil (yield 92 mg, 72%), H 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
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
-1
C15H13ClN2 257.0845, found 257.0845 ; FT-IR δ 2921, 2902, 1647 cm .
General procedure for the preparation of tetrahydroquinoxalines:
40 To a solution of nitroepoxide (0.5 mmol), in dichloromethane (3 mL), N-methyl phenylenediamine (1.5 equiv), was
41
42
43
44
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
45
46
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).
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1,3-dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline 7a: yellow oil (yield 81 mg, 68%), H 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
18
ACS Paragon Plus Environment

Page 19 of 22
The Journal of Organic Chemistry
13
Hz, 1H), 3.71 (bs, 1H), 2.71 (s, 3H), 0.83 (d, J = 6.6 Hz, 3H); 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.
1
2
3
4
5
6
7
8
9
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),
10
11
12
13
14
15
16
13
1.13 – 0.91 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); C 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
17 253.1705, found 253.1708; FT-IR δ 3373, 3057, 2962, 2875, 1598, 1509 cm-1.
18
19
1
1,3-dimethyl-2-(p-tolyl)-1,2,3,4-tetrahydroquinoxaline 7c: yellow oil, (yield 69 mg, 56%), H NMR (300 MHz,
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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-d ) δ 136.27, 136.22, 135.2, 133.8, 128.3, 127.9,
4
+
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.
1
2-(4-chlorophenyl)-1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline 7d: yellow oil, (yield 112 mg, 83%), H 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,
13
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); C 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;
40 HRMS (ESI-TOF) m/z: (M + H)+ Calcd for C16H17ClN2 273.1159, found 273.1159; FT-IR δ 3353, 3059, 2930, 2879,
41
42
43
-1
1597, 1488 cm .
44
45
1
1,3-dimethyl-2-(3-nitrophenyl)-1,2,3,4-tetrahydroquinoxaline 7e: orange-brown oil, (yield 108 mg, 76%), H
46
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,
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
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); C 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,
-1
1601, 1524 cm .
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 22
Acknowledgements
1
2
3
4
5
6
7
8
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.
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
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.
20
ACS Paragon Plus Environment

Page 21 of 22
The Journal of Organic Chemistry
(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.
1
2
3
4
5
6
7
8
(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.
9 (17) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7, 888.
10
11
12
13
(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.
14
(19) Pouw, B.; Nour, M.; Matsumoto, R. R. Eur. J. Pharmacol. 1999, 386, 181.
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
(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.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 22
(33) J2,3 coupling constant for compounds 7a-e is 3.4 Hz as for similar reported syn tetrahydroquinoxalines (see ref.
13).
1
2
3
4
5
6
(34) Vidal-Albalat, A.; Swiderek, K.; Izquierdo, J.; Rodríguez, S.; Moliner, V.; González, F. V. Chem. Commun.
2016, 52, 10060.
7
8
(35) Agut, J.; Vidal-Albalat, A.; Rodríguez, S.; González, F. V. J. Org. Chem. 2013, 78, 5717.
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
22
ACS Paragon Plus Environment