New atropisomers derived from amidinoquinoxaline N-oxides: Synthesis and NMR characterization

Article abstract of DOI:10.1016/j.molstruc.2010.07.050

The complete ¹H and ¹³C NMR characterization of some representative examples of five and six-membered amidinoquinoxaline N-oxides 1 with dissymmetric aryl substituents and their methiodides 2 is reported. Compounds 1 were synthesized

Full text of DOI:10.1016/j.molstruc.2010.07.050

Journal of Molecular Structure 982 (2010) 50–56
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
New atropisomers derived from amidinoquinoxaline N-oxides: Synthesis
and NMR characterization
*
Jimena E. Díaz, Ma. Beatriz García, Liliana R. Orelli
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Junin 956, (1113) Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
The complete 1H and 13C NMR characterization of some representative examples of five and six-mem-
bered amidinoquinoxaline N-oxides 1 with dissymmetric aryl substituents and their methiodides 2 is
reported. Compounds 1 were synthesized by ring closure of N-arylacetyl-N0-(2-nitrophenyl)alkylenedi-
amines 3, followed by spontaneous heterocyclization. Methiodides 2 were prepared by quaternization
of the parent heterocycles with methyl iodide. Complete assignment of the 1H and 13C NMR resonances
of compounds 1,2 was made on the basis of the correlations observed in their HSQC, HMBC and NOESY
spectra. The 1H NMR spectra of compounds 1,2 display diasterotopicity of methylenic hydrogens, indic-
ative of molecular chirality due to the presence of a chiral axis (ONC-Ar bond). Further support for the
existence of the atropisomers for compounds 1a,b is presented, on the basis of spectral and theoretical
data.
Article history:
Received 5 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Keywords:
Atropisomerism
NMR
Hindered rotation
Amidinoquinoxaline N-oxides
Nitrogen heterocycles
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
atropisomerism [12]. As part of our research on nitrogen heterocy-
cles with hindered rotation [13–17], we present here the synthesis
2,3-Dihydro-1H-pyrimido[1,2-a]quinoxaline N-oxides repre-
sent a heterocyclic core of wide interest due to the pharmacologi-
cal properties of some members, acting as antibacterials [1],
antiamoebics [2] and antineoplastics [3]. As part of our research
on nitrogen heterocycles, we reported a novel methodology for
their synthesis [4], and investigated some of their chemical [5]
and pharmacological [6] properties. The reported examples include
5-alkyl and 5-aryl derivatives, the latter with unsubstituted or
symmetrically (para) substituted aryl groups. Amidinoquinoxaline
N-oxides 1 with dissymmetrical aryl substituents are expected to
have the plane of the ortho substituted aryl ring significantly
twisted with respect to the heterocyclic ring system, entailing in
principle the existence of conformational enantiomers (atropisom-
ers). Atropisomerism is a property of some molecules that exist as
enantiomeric forms due to restricted rotation around certain single
bonds, which behave as chiral axes. Atropisomeric compounds
have been described acting as drugs [7] and chiral selectors [8].
The effect of axial chirality in natural compounds has been re-
viewed [9]. Atropisomeric biaryls are widely employed as chiral li-
gands, reagents and catalysts in stereoselective reactions [10]. In
the last years, there is a growing interest for the development of
stable non-biaryl atropisomers, due to their potential employment
in stereo and enantioselective synthesis [11]. In particular, litera-
ture shows several examples of heterocylic compounds displaying
and NMR study of novel non-biaryl atropisomers derived from the
amidinoquinoxaline N-oxide heterocyclic core.
2. Experimental
2.1. Synthesis
N-arylacetyl-N0-(2-nitrophenyl)alkylenediamines 3 were syn-
thesized by acylation of N-(2-nitrophenyl)trimethylene or ethylen-
ediamines. Yields and analytical data of compounds 3a–e are as
follows.
N-(2-Methylphenyl)acetyl-N0-(2-nitrophenyl)-1,3-propanedi-
amine (3a) was obtained as an oil (78%). 1H NMR: d = 8.16 (1H, dd,
J = 8.6 and 1.5 Hz), 8.03 (1H, bs, ex), 7.39–7.45 (1H, m), 7.16–7.23
(4H, m), 6.76 (1H, d, J = 8.1 Hz), 6.65 (1H, ddd, J = 8.6, 6.9 and
1.2 Hz), 5.46 (1H, bs, ex), 3.61 (2H, s), 3.25–3.38 (4H, m), 2.28
(3H, s), 1.85 (2H, p, J = 6.9 Hz). MS (EI), m/z 343 (M+.). Anal. Calcd.
for C19H25N3O3: C, 66.45; H, 7.34; N, 12.24, found: C, 66.34; H,
7.41; N, 12.20.
N-(2-Chlorophenyl)acetyl-N0-(2-nitrophenyl)-1,3-propanedi-
amine (3b) was obtained as a yellow solid (84%), Mp 107–109 °C
(ethanol/water). 1H NMR: d = 8.18 (1H, dd, J = 8.5 and 1.5 Hz),
8.06 (1H, bs, ex), 7.25–7.46 (5H, m), 6.81 (1H, d, J = 8.7 Hz), 6.67
(1H, ddd, J = 8.5, 7.1 and 1.3 Hz), 5.66 (1H, bs, ex), 3.74 (2H, s),
3.41 (2H, q, J = 6.6 Hz), 3.32–3.36 (2H, m), 1.91 (2H, p, J = 6.8 Hz).
MS (EI), m/z 363 (M+.). Anal. Calcd. for C18H22ClN3O3: C, 59.42; H,
6.09; N, 11.55, found: C, 59.30; H, 6.12; N, 11.51.
* Corresponding author. Tel./fax: +54 1149648250.
E-mail address: lorelli@ffyb.uba.ar (L.R. Orelli).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.07.050

J.E. Díaz et al. / Journal of Molecular Structure 982 (2010) 50–56
51
N-(2-Bromophenyl)acetyl-N0-(2-nitrophenyl)-1,3-propanedi-
amine (3c) was obtained as a yellow solid (80%), Mp 125–127 °C
(ethanol/water). 1H NMR: d = 8.14 (1H, dd, J = 8.5 and 1.5 Hz),
8.03 (1H, bs, ex), 7.57 (1H, dd, J = 7.8 and 0.9 Hz), 7.12–7.43 (4H,
m), 6.78 (1H, d, J = 8.0 Hz), 6.63 (1H, ddd, J = 8.5, 7.1 and 1.3 Hz),
5.59 (1H, bs, ex), 3.72 (2H, s), 3.37 (2H, q, J = 6.4 Hz), 3.28–3.34
(2H, m), 1.86–1.90 (2H, m). MS (EI), m/z 391 (M+.). Anal. Calcd.
for C17H18BrN3O3: C, 52.06; H, 4.63; N, 10.71, found: C, 51.98; H,
4.68; N, 10.67.
C16H12BrN3O: C, 56.16; H, 3.53; N, 12.28, found: C, 56.06; H,
3.57; N, 12.26.
Synthesis of dihydroamidinoquinoxaline N-oxide methiodides
2. General procedure.
A mixture of the corresponding compound 1 (1 mmol) and
methyl iodide (3 mmol) in anhydrous methylene chloride
(10 mL) were refluxed protected from moisture. The reaction was
monitored by TLC (silica gel, chloroform–methanol 9:1) until no
further conversion to compounds 2 was evidenced. The solution
was evaporated in vacuo and the crude products were purified by
crystallization.
Yields and analytical data of compounds 2a,b are as follows.
5-(2-Methylphenyl)-4-methyl-2,3-dihydro-1H-pyrimido[1,2-a]-
quinoxalinium iodide 6-oxide 2a was obtained as a yellow solid
(52%), Mp 251–253 °C (isopropanol). MS (EI), m/z 291 (M+.-ICH3)
[18,19]. Anal. Calcd. for C19H20IN3O: C, 52.67; H, 4.65; N, 9.70,
found: C, 52.56; H, 4.69; N, 9.66.
N-(2-Methylphenyl)acetyl-N0-(2-nitrophenyl)ethylenediamine
(3d) was obtained as a yellow solid (100%), Mp 110–112 °C (etha-
nol/water). 1H NMR: d = 8.16 (1H, dd, J = 8.7 and 1.7 Hz), 8.04 (1H,
bs, ex), 7.41–7.47 (1H, m), 7.10–7.24 (4H, m), 6.94 (1H, d,
J = 8.7 Hz), 6.67 (1H, ddd, J = 8.7, 6.9 and 1.3 Hz), 5.60 (1H, bs,
ex), 3.60 (2H, s), 3.46–3.48 (4H, m), 2.24 (3H, s). MS (EI), m/z 329
(M+.). Anal. Calcd. for C18H23N3O3: C, 65.63; H, 7.04; N, 12.76,
found: C, 65.52; H, 7.07; N, 12.73.
N-(2-Bromophenyl)acetyl-N0-(2-nitrophenyl)ethylenediamine
(3e) was obtained as a yellow solid (86%), Mp 134–136 °C (ethanol/
water). 1H NMR: d = 8.18 (1H, dd, J = 8.5 and 1.5 Hz), 8.09 (1H, bs,
ex), 7,59 (1H, dd, J = 8.0 and 1.0), 7.44–7.47 (1H, m), 7.30–7.35
(2H, m), 7.18 (1H, ddd, J = 8.0, 6.9 and 2.4), 6.97 (1H, dd, J = 8.7
and 1.2), 6.69 (1H, ddd, J = 8.5, 7.1 and 1.2), 5.83 (1H, bs, ex),
3.75 (2H, s), 3.51–3.55 (4H, m). MS (EI), m/z 377 (M+.). Anal. Calcd.
for C16H16BrN3O3: C, 50.81; H, 4.26; N, 11.11, found: C, 50.73; H,
4.29; N, 11.09.
4-(2-Methylphenyl)-3-methyl-1,2-dihydroimidazo[1,2-a]quin-
oxalinium iodide 5-oxide 2b was obtained as a yellow solid (64%),
Mp > 270 °C (isopropanol). MS (EI), m/z 277 (M+.-ICH3). Anal. Calcd.
for C18H18IN3O: C, 51.57; H, 4.33; N, 10.02, found: C, 51.49; H, 4.36;
N, 9.99.
2.2. Spectra
1H and 13C NMR spectra were recorded on a Bruker Avance II
500 spectrometer operating at 500.13 and 125.77 MHz, respec-
tively. Spectra were acquired from samples as solutions at room
temperature in 5 mm tubes. Unless otherwise indicated, deutero-
chloroform was used as the solvent. The standard concentration
of the samples was 10 and 40 mg/mL for 1H and 13C NMR spectra,
respectively. Chemical shifts (d) are reported in ppm, referenced to
TMS as an internal standard. Coupling constants (J) are reported in
Hz. Multiplicities are quoted as singlet (s), doublet (d), double dou-
blet (dd), doublet of doublet of doublets (ddd), triplet (t), double
triplet (dt), quartet (q) and multiplet (m). Phase-sensitive NOESY,
HSQC and HMBC spectra were recorded on a Bruker Avance II
500 spectrometer.
Synthesis of dihydroamidinoquinoxaline N-oxides 1. General
procedure.
A mixture of the aminoamide 3 (0.5 g) and PPE (10 mL) was re-
acted for 0.5–2 min in a microwave oven (Sanyo EM-D2031)
adapted for reflux heating, alternating 10 s of irradiation at
280 Watt and 10 s without irradiation. After reaching ambient
temperature, the resulting solution was extracted with water
(5 ꢀ 10 mL). The aqueous phases were pooled, filtered and made
alkaline with 10% aqueous NaOH. The mixture was extracted with
chloroform (3 ꢀ 20 mL). The organic phases were washed with
water, dried over sodium sulphate and filtered. The chloroformic
solution was left at r.t. until no further conversion to compounds
1 was evidenced by TLC (silica gel, CHCl3–methanol 9:1). The sol-
vent was then removed in vacuo and the crude product was puri-
fied by column chromatography (silica gel, CHCl3–methanol
10:0 ? 9:1). Yields and analytical data of compounds 1a–d are as
follows.
2.3. Theoretical calculations
Input geometries for compounds 1a,b were preoptimized with
the semiempirical method AM1. The structure/s thus obtained
were then optimized with the HF/6-31Gꢁꢁ method [20]. The result-
ing minima were subjected to frequency calculations with non-
imaginary frequencies obtained.
5-(2-Methylphenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxa-
line 6-oxide 1a was obtained as a yellow solid (53%), Mp 198–
200 °C (hexane/ethyl acetate). MS (EI), m/z 291 (M+.). Anal. Calcd.
for C18H17N3O: C, 74.20; H, 5.88; N, 14.42, found: C, 74.05; H,
5.93; N, 14.39.
3. Results and discussion
5-(2-Chlorophenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxa-
line 6-oxide 1b was obtained as a yellow solid (51%), Mp 170–
172 °C (hexane/ethyl acetate). MS (EI), m/z 311 (M+.). Anal. Calcd.
for C17H14ClN3O: C, 65.49; H, 4.53; N, 13.48, found: C, 65.38; H,
4.55; N, 13.46.
The compounds described in this work are shown in Fig. 1. The
synthetic procedure for compounds 1, 2 is depicted in Scheme 1.
The precursor N-(2-nitrophenyl)-N0-arylacetyl di (or tri) methylen-
5-(2-Bromophenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxa-
line 6-oxide 1c was obtained as a yellow solid (53%), Mp 158–
160 °C (hexane/ethyl acetate). MS (EI), m/z 355 (M+.). Anal. Calcd.
for C17H14BrN3O: C, 57.32; H, 3.96; N, 11.80, found: C, 57.23; H,
3.98; N, 11.78.
4-(2-Methylphenyl)-1,2-dihydroimidazo[1,2-a]quinoxaline 5-
oxide 1d was obtained as a yellow solid (52%), Mp 165–167 °C
(hexane/ethyl acetate). MS (EI), m/z 277 (M+.). Anal. Calcd. for
C
17H15N3O: C, 73.63; H, 5.45 N, 15.15, found: C, 73.49; H, 5.50; N,
15.15.
4-(2-Bromophenyl)-1,2-dihydroimidazo[1,2-a]quinoxaline 5-
oxide 1e was obtained as a yellow solid (51%), Mp 179–180 °C
(hexane/ethyl acetate). MS (EI), m/z 341 (M+.). Anal. Calcd. for
Fig. 1. Amidinoquinoxalines 1a–d and methiodides 2a,b.

52
J.E. Díaz et al. / Journal of Molecular Structure 982 (2010) 50–56
G
Cl
G
NH
NH2
( )n
O
NH
NH
( )n
NO2
O
NO2
3
PPE MW
I
( )n
N
( )n
N
( )n
N
CH3
G
N
N
N
N
ICH3
G
G
CH2Cl2
-H2O
N
NO2
O-
O-
2
1
Scheme 1. Synthesis of amidinoquinoxaline N-oxides 1 and their quaternary salts 2.
Table 1
1H NMR signals of compounds 1a–e, 2a,b.
b
b
( )n
( )n
a
c
c
a
I
j
j
N
N
N
N
N CH3
i
i
G
G
h
h
N
3´
4´
3´
4´
g
g
O-
O- 6´
6´
5´
5´
1
2
1a 2a
,
1b 1c
(n=1, G=Cl); (n=1, G=Br)
(n=1, G=CH3);
1d 2b
1e
,
(n=0, G=CH3); (n=0, G=Cl)
Compounds
a
c
b
g–j
30–60
G
N–CH3
1aA
2.83 (t, 6.1)
3.22–3.33 (m)
3.53–3.65 (m)
3.52–3.66 (m)
4.06–4.12 (m)
4.06–4.12 (m)
3.58–3.66 (m)
4.14–4.27 (m)
1.29–1.34 (m)
g: 8.76 (dd, 8.2, 1.4)
30–50: 7.26–7.34 (m)
60: 7.57 (d, 7.1)
2.47 (s)
–
h: 6.88 (ddd, 8.2, 7.1, 1.0)
i: 7.11 (ddd, 8.5, 7.1, 1.4)
j: 6.36 (dd, 8.5, 1.0)
1bB
1cB
1dB
1eB
2aC
2bC
3.86–3.95 (m)
3.85–3.94 (m)
4.13–4.21 (m)
4.13–4.22 (m)
2.04–2.10 (m)
g: 8.39 (dd, 8.3, 1.4)
h: 7.20 (ddd, 8.3, 7.3, 1.0)
i: 7.51–7.56 (m)
7.39–7.44 (m),
7.51–7.56 (m)
–
–
j:7.11 (dd, 8.2, 1.0)
2.02–2.09 (m)
g: 8.39 (dd, 8.2, 1.5)
30: 7.7 (dd, 8.1, 1.1)
–
–
h: 7.19 (ddd, 8.2, 7.3, 0.9)
i: 7.52 (ddd, 8.4, 7.3, 1.5)
j: 7.11 (dd, 8.4, 0.9)
40: 7.32 (ddd, 8.1, 7.5, 1.6)
50: 7.47 (dt, 7.5, 1.1)
60: 7.37 (dd, 7.5, 1.6)
–
g: 8.29 (dd, 8.2, 1.2)
h: 7.11–7.15 (m)
i: 7.49–7.53 (m)
30–50: 7.31–7.42 (m)
2.32 (s)
–
j: 6.85 (dd, 8.0, 0.7)
–
g: 8.27 (dd, 8.3, 1.4)
30: 7.72 (dd, 8.0, 0.7)
40: 7.35 (ddd, 8.0, 7.1, 2.1)
50,60: 7.44–7.50 (m)
–
–
h: 7.12 (ddd, 8.3, 7.3, 1.1)
i: 7.52 (ddd, 8.1, 7.3, 1.4)
j: 6.85 (dd, 8.1, 1.1)
4.19–4.24 (m) and
4.68–4.71 (m)
2.34–2.44 (m)
g: 8.43 (dd, 8.3, 1.3)
h: 7.73–7.75 (m)
i: 8.03–8.06 (m)
j: 8.13 (d, 8.5)
30, 60: 7.43–7.48 (m)
40: 7.51 (dt, 7.6, 1.4)
50: 7.38 (t, 7.6)
2.33 (s)
2.26 (s)
2.51 (s)
2.47 (s)
4.66–4.73 (m)
–
g: 8.34 (d, 8.3)
h: 7.69–7.72 (m)
i: 8.04–8.07 (m)
j: 7.84 (d, 8.3)
30, 60: 7.47–7.50 (m)
40: 7.56 (t, 7.5)
50: 7.43 (t, 7.5)
A
B
C
Spectrum run in C6D6.
Spectrum run in CDCl3.
Spectrum run in DMSO-d6.

J.E. Díaz et al. / Journal of Molecular Structure 982 (2010) 50–56
53
Table 2
13C NMR signals of compounds 1a–e, 2a,b.
b
b
( )n
( )n
a
c
c
a
I
j
j
k
f
N
N
N
k
N
N
N CH3
i
i
d
d
G
G
2´
1´
1´
2´
h
h
e
e
3´
4´
3´
4´
f
g
g
O-
O- 6´
6´
5´
5´
1
2
1a 2a
,
1b 1c
(n=1, G=Cl); (n=1, G=Br)
(n=1, G=CH3);
1d 2b
1e
(n=0, G=CH3); (n=0, G=Cl)
,
Compounds
1aA
1bB
1cB
1dB
1eB
2aC
2bC
13C signals
a
b
c
42.80
43.66
19.70
44.56
43.55
19.57
44.50
54.31
–
46.52
54.43
46.51
19.44
51.03
46.09
–
53.04
19.52*
44.05
–
46.52
d
e
f
g
h
i
j
144.49
141.33
130.89
121.38
120.96
130.71
110.62
135.47
131.50
138.00
125.27,
128.68,
129.80
130.24
19.44*
–
144.71
139.58
130.08*
121.31
121.73
131.95
110.99
135.48
130.24*
133.64*
127.00,
129.74,
130.44,
131.02
–
144.48
140.61
129.94
121.18
121.58
131.85
110.91
135.39
132.32
122.98
132.74
130.41
127.55
130.96
–
153.12
137.45
130.93
121.35
121.09
132.22
111.98
133.58
128.50*
137.93*
125.98,
129.16,
130.04,
130.45
19.63
152.59
136.15
130.82
121.41
121.15
132.56
112.12
133.73
130.65
123.51
133.08
131.25
127.83
131.12
–
151.93
135.89
132.32
120.68
127.29
134.66
116.86
133.26
130.33
140.29
130.84*
131.00*
126.63
129.92
19.99
150.84
132.58
132.92
120.71
127.02
135.22
116.82
131.52
126.76
139.79
130.84
131.73
126.84
130.44
19.38
k
10
20
30
40
50
60
G
N+–CH3
–
–
–
–
43.56
35.39
A
B
C
Spectrum run in C6D6.
Spectrum run in CDCl3.
Spectrum run in DMSO-d6.
*
Exchangeable assignment.
Table 3
Unambiguous assignment of compound 1c.
b
e
c
a
j
N
N
N
k
i
Br
d
2´
1´
h
f
3´
g
O-
6´
4´
5´
Position
d
1H
d
13C (HSQC)
d
13C (HMBC)
d
1H (NOESY)
a
b
c
3.85–3.94
2.02–2.09
3.48–3.58, 3.60–3.65
43.55
19.57
44.50
19.57, 44.50, 144.48, 135.39
43.55, 44.50
19.57, 43.55, 140.61, 144.48
2.02–2.09, 7.11
3.85–3.94; 3.48–3.58, 3.60–3.65
2.02–2.09
d
e
f
g
h
i
–
–
–
8.39
7.19
7.52
7.11
–
–
–
7.70
7.32
7.47
7.37
144.48
140.61
129.94
121.18
121.58
131.85
110.91
135.39
132.32
122.98
132.74
130.41
127.55
130.96
–
–
–
–
–
–
7.19
8.39, 7.52
7.19
3.85–3.94
–
–
–
135.39, 110.91
110.91, 129.94
135.39, 110.91
129.94
–
–
j
k
10
20
30
40
50
60
–
127.55, 132.32
122.98, 130.96
132.32, 132.74
122.98, 130.41, 140.61
7.32
7.70, 7.47
7.37, 7.32
7.47

54
J.E. Díaz et al. / Journal of Molecular Structure 982 (2010) 50–56
Complete assignment of a representative compound (1c) is shown
in detail in Table 3. The aromatic region in the 1H NMR spectrum of
1c shows eight signals, each corresponding to one hydrogen,
belonging to two different spin systems. In the NOESY spectrum,
the N-methylene signal centered at ca. 3.91 ppm correlates with
the double doublet at 7.11. Such signals were assigned respectively
as CH2(a) and H(j), and the multiplet centered at ca. 2.05 ppm as
CH2(c). The remaining methyne signals belonging to the benzo
fused ring were tentatively attributed on the basis of their multi-
plicity and J values, and the assignment confirmed by the correla-
tions observed in the NOESY spectrum. The corresponding 13C
resonances were attributed considering the correlations in the
HSQC spectrum. In the HMBC spectrum, both N-methylenes corre-
late with a quaternary carbon (d = 144.48 ppm), which was as-
signed as C(d). One of them, centered at 3.91 ppm correlates in
the HMBC spectrum with another quaternary carbon at
135.39 ppm. Such signal also correlates with H(i) and H(g) and
was therefore assigned as C(k). Hydrogens H(h) and H(j) correlate
with another quaternary carbon at 129.94 ppm, assigned as C(f).
Hydrogens H(c) show a long range correlation with a quaternary
carbon at 140.61 ppm assigned as C(e), which in turn correlates
with a methyne in the aryl moiety, H(60) (d = 7.37 ppm). The
remaining methyne signals within the aryl ring H(30–50) were
attributed on the basis of their multiplicity and J values, and the
assignment confirmed by NOESY. The corresponding 13C reso-
nances were attributed considering the correlations in the HSQC
spectrum. In the HMBC spectrum H(30) and H(50) correlate with a
quaternary carbon at 132.32 ppm, assigned as C(10), while H(40)
and H(60) correlate with the remaining quaternary carbon at
122.28 ppm, assigned as C(20).
Fig. 2. N-methylene signals of the 1H NMR spectrum of compound 1a (C6D6): (a)
normal and (b) with simultaneous decoupling of CH2(b).
ediamines 3 were prepared by selective N-monoacylation of N-(2-
nitrophenyl)ethylene (or trimethylene)diamines. Microwave-as-
sisted cyclodehydration of compounds 3 with ethyl polyphosphate
(PPE) [21] led to the corresponding 1-(2-nitrophenyl)-2-arylacetyl
dihydroimidazoles or 1,4,5,6-tetrahydropyrimidines. Such com-
pounds undergo spontaneous in situ cyclization to dihydroamidi-
noquinoxaline N-oxides 1.
1H NMR spectra of dihydropyrimidoquinoxaline N-oxides previ-
ously reported by us, bearing a phenyl or symmetrical (para substi-
tuted) 5-aryl residue, show equivalence of the geminal protons
within the trimethylene portion [4], which appear as two triplets
(each one corresponding to an N–CH2) and a multiplet (for the
C–CH2–C). This pattern indicates a time averaged planar conforma-
tion for the amidine ring at room temperature. At variance with
this, the trimethylenic portion of the ortho substituted derivative
1a (Fig. 2a) shows nonequivalence of both hydrogens within one
of the N-methylenes (d = 3.22–3.33 ppm). When the spectrum of
1a was recorded with simultaneous decoupling of the C–CH2–C fre-
1H NMR chemical shifts and multiplicities of compounds 1 are
given in Table 1. 13C NMR chemical shifts of compounds 1 are given
in Table 2. Assignment of the resonances was made on the basis of
the correlations observed in their HSQC, HMBC and NOESY spectra.
Fig. 3. Conformational minima for compounds 1a and 1d at the HF/6-31Gꢁꢁ level.

J.E. Díaz et al. / Journal of Molecular Structure 982 (2010) 50–56
55
Fig. 5. N-methylene signals of the 1H NMR spectrum of compound 1b (CDCl3): (a)
normal and (b) with simultaneous decoupling of CH2(b).
spectrum in the presence of a suitable enantiopure chiral agent,
provided that the interconversion barrier between both enantio-
meric forms is high enough. In fact, it was observed that the single
line corresponding to the CH3 substituent on the 5-aryl group of 1a
(Fig. 4a) splits into two singlets when the spectrum is recorded in
the presence of a suitable amount of enantiopure Pirkle’s alcohol
(Fig. 4b) [23].
We examined next the methylenic portion in the 1H NMR spec-
trum of compound 1b (Fig. 5a). In this case, hydrogens within both
N-methylene groups (d = 3.86–3.95 and 3.52–3.66 ppm) appear
diastereotopic. Simplification of the spectrum by decoupling the
C–CH2–C signal (Fig. 5b) yielded two AB-type systems with
Jgem = 16.5 and 12.5 Hz, respectively.
To gain further insight into the magnitude of the interconver-
sion barriers of the atropisomers under study, the 1H NMR spec-
trum of 1b was acquired at progressively higher temperatures
with simultaneous decoupling of the C–CH2–C signal. The N-meth-
ylene signals did not display the line broadening typical of an ex-
change process, even when the sample was heated at +120 °C,
indicating that the enantiomerization barrier must be higher than
20 kcal molꢂ1 [24].
Fig. 4. The 1H methyl signal of compound 1a (spectrum run in CDCl3): (a) normal
and (b) in chiral environment.
quency (d = 1.29–1.34 ppm), the N-methylene signal was simpli-
fied, yielding a typical AB-type system (Fig. 2b). This geminal cou-
pling (Jgem = 16.3 Hz) arises from chemical nonequivalence of both
protons (d = 3.30 and 3.24 ppm).
Although the spectra of two enantiomers in an achiral environ-
ment are indistinguishable, the presence of diastereotopic nuclei
constitutes an indirect evidence of molecular chirality [22]. In
our case, molecular asymmetry would result from the preference
for a twisted conformation of the sterically hindering ortho-tolyl
substituent with respect to the dynamic plane of the heterocyclic
ring. In such conformation the ONC-aryl bond becomes a chiral
axis, resulting in a pair of atropisomeric forms for compound 1a.
To check this hypothesis, we explored the conformational ground
state geometries of this compound by ab initio theoretical calcula-
tions. Two initial energy minima were identified at the AM1 level,
which were then optimized employing the HF/6-31Gꢁꢁ method.
The resulting structures, corresponding to one of the atropisomers,
are shown in Fig. 3, together with their relative energies. The struc-
tures were labelled as anti and syn, according to the relative orien-
tations of the methyl and CH2(b) moieties. The calculated energy
The ground state geometry of five-membered amidinoquinoxa-
line 1c was also investigated with the HF/6-31Gꢁꢁ method. Two
minima were initially located at the AM1 level, due to pyramidal-
ization of the formally sp3 nitrogen atom within the amidine ring.
Both structures were further optimized with the ab initio method,
0
0
yielding a single structure in which the C2 —C1 —C4—C3a dihedral
difference between them is very low (less than 0.05 kcal molꢂ1
)
and therefore their interconversion should be a fast process at
room temperature, taking into account previous data on analogous
tetrahydropyrimidine systems [14,15]. In the more stable anti con-
0
0
formation of compound 1a, the dihedral angle C2 —C1 —C5—C4a has
a value of 108.0°, thus entailing the existence of two conforma-
tional enantiomers.
As mentioned before, the spectra of two enantiomers in an achi-
ral environment do not differ. Nevertheless, direct evidence of their
existence in solution can be obtained by recording the 1H NMR
Fig. 6. N-methylene signals of the 1H NMR spectrum of compound 2a (DMSO-d6).

56
J.E. Díaz et al. / Journal of Molecular Structure 982 (2010) 50–56
angle had a value of 113.3° (Fig. 3). This indicates for such com-
pound the existence of two enantiomeric forms. In fact, the 1H
NMR spectrum of dihydroimidazoquinoxaline N-oxides 1d,e also
show unusual splitting of the N-methylene signals, attributable
to nonequivalence of the geminal hydrogens. For such compounds,
decoupling experiments aimed at simplifying the signals were
unsuccessful due to close proximity of the multiplets.
Two representative examples of amidinoquinoxalinium N-oxi-
des (compounds 2a,b) were also studied. Such compounds were
synthesized by quaternization of the parent amidines with methyl
iodide (Scheme 1). Assignment of the 1H and 13C resonances of
salts 2a,b, performed by analysis of their HSQC and HMBC spectra,
are shown in Tables 1 and 2, respectively. As expected, methiod-
ides 2a,b also show 1H NMR features indicative of molecular asym-
metry, entailing the existence of atropisomeric forms. The
diastereotopic N-methylene signals of compound 2a are shown
in Fig. 6. The magnitude of the nonequivalence between geminal
hydrogens in such compound is high enough to observe two well
separated signals in the case of CH2(a), both of which correlate
with one 13C signal at 46.51 ppm in the HSQC spectrum.
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We have identified a new group of heterocyclic conformational
enantiomers (atropisomers) derived from five and six-membered
amidinoquinoxaline N-oxides. The computational chemical study
of two representative members (compounds 1a,d) predicts for
such compounds ground state geometries in which the ortho
substituted aryl residue is nearly perpendicular to the plane of
the heterocycles. This creates a source of molecular asymmetry,
resulting in two enantiomeric forms. Indirect evidence of the chi-
rality of such compounds is observed in their 1H NMR spectra, in
which geminal hydrogens belonging to one or both N-methylene
groups appear diastereotopic. Direct observation of the atropisom-
ers of compound 1a in solution was achieved employing an enan-
tiopure chiral solvating agent. Quaternary salts 2a,b derived from
the parent amidines also show spectral features indicative of axial
chirality.
The complete assignment of the 1H and 13C signals of amidino-
quinoxalines 1a–e and methiodides 2a,b was performed by analy-
sis of the correlations observed in their HSQC, HMBC and NOESY
spectra.
Acknowledgements
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[23] W.H. Pirkle, J. Am. Chem. Soc. 106 (1984) 477.
[24] J. Sandström, Dynamic NMR Spectroscopy, Academic Press, London, 1982
(Chapter 6).
This work was supported by the University of Buenos Aires (B-
096 Grant) and by CONICET (PIP 11420090100286). We are also
grateful to Martín Rodríguez Saá and to Dr. Gernot Eskuche for
technical collaboration. We thank Prof. L. Lunazzi (University of
Bologna) for the high temperature NMR measurements.