Atropisomerism in amidinoquinoxaline N-oxides: Effect of the ring size and substituents on the enantiomerization barriers

Article abstract of DOI:10.1021/jo502626f

The atropisomerism of novel 2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-oxides 1 bearing dissymmetric (ortho-substituted) 5-aryl residues and the homologous 1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxides 2 was investigated. The existence of a chiral axis was demonstrated for compound 1a by X-ray diffraction and by DFT calculations of the ground state geometry. The resolution of the atropisomeric enantiomers on chiral stationary phases is reported. The barriers to enantiomerization were determined by off-line racemization studies and/or by treatment of the plateau-shaped chromatograms during chromatography on chiral support. A clear ring size effect was evidenced. In all cases, six-membered amidine derivatives 1 showed higher barriers than the corresponding lower homologues 2, which also display lower sensitivity to the substituent size. Transition states for the interconversion of the atropisomers were located using DFT calculations, and involved the interaction of the ortho substituent with the formally sp² nitrogen in the amidine moiety. In contrast, in the most favored enantiomerization transition state of the 2-nitro derivative the ortho substituent is close to the N-oxide group. (Chemical Equation Presented).

Full text of DOI:10.1021/jo502626f

Article
pubs.acs.org/joc
Atropisomerism in Amidinoquinoxaline N-Oxides: Effect of the Ring
Size and Substituents on the Enantiomerization Barriers
Jimena E. Díaz,†,‡ Nicolas Vanthuyne,† Helene Rispaud,† Christian Roussel,*,† Daniel Vega,§
́
̀
and Liliana R. Orelli*,‡
†Aix Marseille Universite,
‡Departamento de Química Organ
(1113) Buenos Aires, Argentina
§Departamento Física de la Materia Condensada, Gerencia de Investigacion
́
Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
ica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET. Junín 956,
́
́
́ ́
y Aplicaciones, Comision Nacional de Energía Atomica y
ECyT, Universidad Nacional de General San Martín, Av. Gral. Paz 1499, (1650) San Martín, Buenos Aires, Argentina
S
* Supporting Information
ABSTRACT: The atropisomerism of novel 2,3-dihydro-1H-
pyrimido[1,2-a]quinoxaline 6-oxides 1 bearing dissymmetric
(ortho-substituted) 5-aryl residues and the homologous 1,2-
dihydroimidazo[1,2-a]quinoxaline 5-oxides 2 was investigated.
The existence of a chiral axis was demonstrated for compound
1a by X-ray diffraction and by DFT calculations of the ground
state geometry. The resolution of the atropisomeric
enantiomers on chiral stationary phases is reported. The
barriers to enantiomerization were determined by off-line
racemization studies and/or by treatment of the plateau-
shaped chromatograms during chromatography on chiral
support. A clear ring size effect was evidenced. In all cases,
six-membered amidine derivatives 1 showed higher barriers than the corresponding lower homologues 2, which also display
lower sensitivity to the substituent size. Transition states for the interconversion of the atropisomers were located using DFT
calculations, and involved the interaction of the ortho substituent with the formally sp2 nitrogen in the amidine moiety. In
contrast, in the most favored enantiomerization transition state of the 2-nitro derivative the ortho substituent is close to the N-
oxide group.
Attempts at studying the enantiomerization of atropisomeric
2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline N-oxides by means
of dynamic NMR were unsuccessful as the N-methylene signals
did not display the line broadening typical of an exchange
process, even when the sample was heated at +120 °C,
indicating that the enantiomerization barrier must be higher
than 80 kJ mol−1.14 As part of ongoing research on
atropisomerism15 and, in particular, on atropisomeric amidines
and related compounds,16 we investigate here the chiral
separation and enantiomerization barriers of a series of
atropisomeric 2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline N-
oxides 1 and the homologous 1,2-dihydroimidazo[1,2-a]-
quinoxaline 5-oxides 2. Analysis of both experimental and
theoretical data show some general trends regarding substituent
effects and amidine ring size sensitivity of the enantiomerization
barriers.
INTRODUCTION
■
2,3-Dihydro-1H-pyrimido[1,2-a]quinoxaline N-oxides repre-
sent a heterocyclic core of interest due to their pharmacological
properties. Some suitably substituted derivatives possess
antineoplastic activity,1 especially against hypoxic tumors.
Other pyrimidoquinoxaline 6-oxides have been employed as
antiamoebic2 and antianaerobic agents.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
spectroscopic,6 and pharmacological7 properties. We recently
demonstrated their ability to act as spin traps.8 In particular,
derivatives containing a dissymmetrical (ortho substituted) 5-
aryl substituent show diastereotopicity of the CH2 signals in
their 1H NMR spectra.6 Such behavior indicates the presence of
a chiral axis (C5-aryl), which entails the existence of two
atropisomers. Atropisomeric compounds have been described
as drugs9 and chiral selectors.10 The axial chirality in natural
compounds has been reviewed.11 Atropisomeric biaryls are
widely employed as chiral ligands, reagents, and catalysts in
stereoselective reactions.12 In particular, atropisomerism in
heterocyclic compounds has recently been reviewed.13
Received: November 17, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502626f
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Compounds 1,2 were submitted to HPLC on chiral support
using a screening unit equipped with 10 commercially available
chiral columns and chiroptical detection (CD at 254 nm). Our
objective was to find suitable conditions for the isolation of the
enantiomers in order to measure their enantiomerization
barriers. In most of the cases, several columns allowed the
baseline separation of the enantiomers using a classical mobile
phase composed of hexane and ethanol. Compounds 1b,g
underwent interconversion during the separation process,
displaying typical plateau shape chromatograms.19 Selected
examples are given in Table 1.
RESULTS AND DISCUSSION
■
The structure of amidinoquinoxaline N-oxides 1,2 under study
is shown in Scheme 1. We previously described the synthesis of
amidinoquinoxaline N-oxides 1a,d,e,f and 2a,e.6,8 The remain-
ing compounds were synthesized by our previously reported
method.4
Scheme 1. General Structure of Amidinoquinoxaline N-
Oxides
Regarding their stereostability, compounds 1,2 were sorted
into three groups. The first one (compounds 1c−f, 2d,e)
displayed well separated peaks corresponding to both
atropisomers, and thus their racemization could be monitored
by the off-column method. For the second group (compounds
1b,g, 2a), plateau-shaped chromatograms were obtained due to
on-column racemization, indicating a lower interconversion
barrier. This behavior is exemplified in Figure 3 for compound
1b.
Finally, the third group comprised compounds with
intermediate barriers (1a, 2c,f), which gave baseline separation
or plateau-shaped chromatograms according to the temper-
ature. All the barriers to enantiomerization were determined
using either classical off-line racemization kinetics20 or the
equation developed by Trapp and Schurig in the case of a
plateau,21 and are collected in Table 2. The enantiomerization
rates correspond to the racemization rates divided by a factor of
2.
DFT calculations (B3LYP/6-31+G(d,p) method) applied to
the o-tolyl derivative 1a indicate that the dihedral angle
comprising the chiral axis (C4−C5−C1′−C2′) has a value of
113.8°, thus entailing the existence of two enantiomeric forms
(Figure 1). A single-crystal X-ray diffraction of 1a confirms the
In order to assess the influence of steric effects on the
enantiomerization barriers of pyrimidoquinoxaline N-oxides 1,
their values were plotted vs the steric parameters developed for
substituted biaryls (B values),22 whenever available (Figure 4).
It can be observed that derivatives 1a,d−g show a very good
linear correlation, while the barrier of compound 1b is lower
than expected. Such behavior suggests, in principle, an
alternative enantiomerization path involving a stabilizing
interaction between the N(+) of the nitro group and the
oxygen of the N-oxide in the transition state.
A comparative analysis of the barriers reported in Table 2
shows that N-oxides 2 containing a five-membered amidine ring
show lower enantiomerization barriers than the corresponding
homologues 1. This could be due mainly to differences in the
external bond angles of the amidine moieties, which are decisive
in determining the resulting distances between interacting
groups. An interesting point is that this ring size effect also
involves a higher sensitivity of the barrier to the size and nature
of the ortho substituent in the six-membered than in the five-
membered rings. In Figure 5, a plot of the enantiomerization
barriers of both types of compounds is presented, showing that
the slopes are >1 when comparing the six-membered with the
five-membered rings. Furthermore, in the set of halogens the
slope is significantly higher than for the hydrocarbon
substituents (methyl and naphthyl). Such differences would
suggest that changes in the geometry between five- and six-
membered amidine rings would additionally determine subtle
variations in the hybridization of the formally sp2 nitrogen
which interacts with the ortho substituent in the transition
states. In fact, previous studies have shown that 1,2-diary-
limidazolines are considerably less basic than the homologous
tetrahydropyrimidines.23,24
Figure 1. B3LYP/6-31+G(d,p) computed structure of the M
atropisomer of 1a (left). Experimental structure as obtained by X-
ray diffraction (right).
theoretical results. The geometrical parameters determined in
the solid state are quite similar to those computed for the
isolated molecule; in particular, the dihedral angle mentioned
has a very similar value (112.4°). The experimental X-ray
structure of 1a (M enantiomer) is also displayed in Figure 1.
Interestingly, ortho substitution in the aryl group also brings
about a significant change in the EI mass spectra of
amidinoquinoxalines. In unsubstituted or para substituted
pyrimidoquinoxaline N-oxides 1h,i the base peak arises from
H· loss, according to the proposed mechanism depicted in
Figure 2 (left).17 In contrast, the base peak for atropisomeric
ortho substituted amidinoquinoxalines 1a,f and 2d,f results from
loss of the aryl substituent G· (Figure 2, right). In compounds
bearing a 2-naphthyl group (1,2c) this fragmentation is not
possible and the base peaks arise, respectively, from loss of OH·
(m/z = 310)18 or H· (m/z = 312).
In order to further investigate the path involved in the
enantiomerization process under study, the two possible
B
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Figure 2. Proposed fragmentation pathways leading to the base peaks in the mass spectra (EI) of amidinoquinoxalines 1a,f,h,i, and 2d,f.
Table 1. Selected Chiral HPLC Chromatographic Data for Atropisomers 1a−g, 2a−f
a
compd.
Ar
n
column
eluent
k1
k2
α
first eluted
1a
2-CH3C6H4
1
Chiralcel OJ-H (25 °C)
Chiralcel OD-H (25 °C)
Chiralcel OD-H
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
methanol
2.04
0.84
5.12
1.81
2.51
2.16
(−)
(+)
Plateau at 50 °C
Plateau at 5, 10, 15, and 20 °C
1.64
5.41
1b
1c
1d
1e
1f
2-NO2C6H4
1-C10H7
1
1
1
1
1
1
0
Chiralpak IB
Chiralpak AS-H
4.04
8.78
9.15
8.16
2.47
1.62
1.84
1.95
(−)
(−)
(−)
(−)
2-IC6H4
Chiralcel OJ-H (25 °C)
Chiralcel OJ-H (25 °C)
Chiralcel OJ-H (25 °C)
Chiralcel OD-H
2-BrC6H4
2-ClC6H4
2-FC6H4
4.99
4.18
1g
2a
Plateau at 7 °C
3.77
2-CH3C6H4
Chiralcel OJ-H (25 °C)
Chiralpak AD-H (25 °C)
Chiralpak AD-H
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
hexane:ethanol 50:50
4.44
2.20
1.18
1.27
(−)
(−)
1.77
Plateau at 35 °C
3.87
2c
1-C10H7
0
Chiralcel OJ-H (25 °C)
Chiralcel OJ-H
7.55
1.95
(+)
Plateau at 40 °C
2d
2e
2f
2-IC6H4
0
0
0
Chiralpak AS-3 (25 °C)
Chiralpak AD-H (25 °C)
Chiralpak AD-H (25 °C)
Chiralpak AD-H
0.96
2.25
2.30
1.22
1.27
1.94
1.57
(+)
(−)
(−)
2-BrC6H4
2-ClC6H4
4.37
3.61
Plateau at 50 °C
a
The sign of the first eluted enantiomer reported in Table 2 is the sign given by the circular dichroism detector at 254 nm in the mobile phase.
transition states for the interconversion of the atropisomers of
compound 1a were calculated using the DFT B3LYP/6-
31+G(d,p) method. Their geometries and relative energies are
displayed in Figure 6.
It can be seen that in the lower energy transition state (TS1),
the ortho substituent passes near the formally sp2 amidine
nitrogen. Similar results (TS1) were obtained for compounds
1c,e−g, 2a,c,e,f. The calculated enantiomerization barriers are
reported in Table 3.
Compound 1b represents an exception, since the transition
state in which the nitro group crosses over the N-oxide moiety
(TS2, Figure 7) is favored. This behavior may be explained
considering a stabilizing N+···O− interaction between the
electron deficient nitrogen atom within the nitro group and
the electron-rich oxygen of the N-oxide moiety in the transition
state. A related type of donor−acceptor interaction is known to
operate in other heterocyclic compounds bearing ortho-
nitrophenyl groups.25
CONCLUSIONS
■
A novel class of atropisomers derived from the amidinoqui-
noxaline N-oxide core was investigated. The chirality of the
compounds was demonstrated both by X-ray diffraction and
theoretical calculations. A screening of different chiral sta-
tionary phases and chromatographic conditions allowed for the
baseline separation of most of the compounds. Rotational
barriers were determined either by classical off-line racemiza-
tion kinetics or by deconvolution of the corresponding plateau-
shaped chromatograms, according to their magnitude. In three
examples, both methods gave similar results. The barriers were
also calculated using the DFT B3LYP/6-31+G(d,p) method
and a good correlation with the experimental values was in
general attained. With the exception of nitroderivative 1b, the
calculated transition state for the interconversion of the
atropisomers involves the interaction of the ortho substituent
with the formally sp2 nitrogen of the amidine ring. Six-
membered amidine derivatives showed in all cases higher
rotational barriers than the corresponding five-membered
homologues. Interestingly, the ring size effect also modifies
C
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Figure 4. Experimental barriers vs substituent B values for compounds
1a,b,d−g.
EXPERIMENTAL SECTION
■
Synthesis. Melting points were determined with a capillary
apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on a 500 MHz spectrometer, using deuteriochloroform as the
solvent. Chemical shifts are reported in parts per million (ppm)
relative to TMS as an internal standard. Coupling constants are
reported in Hz. D2O was employed to confirm exchangeable protons
(ex). Splitting multiplicities are reported as singlet (s), broad signal
(bs), doublet (d), double doublet (dd), doublet of double doublets
(ddd), triplet (t), triple doublet (td), pentet (p), and multiplet (m).
HRMS (ESI) were performed with a MicroTOF-Q spectrometer.
Reagents, solvents, and starting materials were purchased from
standard sources and purified according to literature procedures.
Synthesis of 5-aryl-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-
oxides 1 and 1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxides 2.
A mixture of the corresponding aminoamide 3 or 4 (1 mmol) and
ethyl polyphosphate (PPE, 1 mL/0.05 g) was refluxed for 5 h. After
reaching room temperature, the resulting solution was extracted with
water (5 × 6 mL). The aqueous phases were pooled, filtered, and
made alkaline with 10% aqueous NaOH. The mixture was extracted
with chloroform (3 × 15 mL). The organic phases were washed with
water, dried over sodium sulfate, and filtered. The chloroformic
solution was left at r.t. until no further conversion to compounds 1 was
evidenced by TLC (silica gel, chloroform:methanol 9:1). The solvent
was then removed in vacuo and the crude product was purified by
column chromatography (silica gel, chloroform:methanol 10:0−9:1).
Figure 3. Evolution of the chromatographic profile of 1b atropisomers
as a function of temperature: Chiralpak IB, hexane/ethanol (50:50), 1
mL/min, UV detection at 254 nm.
the sensitivity of the barriers to the substituent size, which is
comparatively higher for six-membered amidine derivatives.
The observed differences between both groups of compounds
were rather unexpected, as the structural variation occurs at a
considerable distance from the stereogenic axis. Finally, nitro
derivative 1b is the only compound in which in the rotation
transition state the ortho substituent crosses over the N-oxide
moiety.
Table 2. Barriers to Rotation for Compounds 1a−g, 2a−f
compd
Ar
n
rotational barrier (kJ/mol)
T (°C)
solvent
ethanol
t1/2 (min)
a
1a
2-CH3C6H4
1
99.2
30
50
25
40
78
50
50
7
114
11.5
1.7
300
62
b
99.8
hexane:ethanol 50:50
hexane:ethanol 50:50
ethanol
b
1b
1c
1d
1e
1f
2-NO2C6H4
1-C10H7
1
1
1
1
1
1
0
0
87.1
a
105.1
a
2-IC6H4
113.6
ethanol
a
2-BrC6H4
2-ClC6H4
2-FC6H4
2-CH3C6H4
1-C10H7
110.1
ethanol
527
70
a
104.6
ethanol
b
1g
2a
2c
81.5
methanol
1.5
13
b
95.3
35
30
40
50
40
30
50
hexane:ethanol 50:50
ethanol
a
100.3
175
48
b
100.3
hexane:ethanol 50:50
ethanol
a
2d
2e
2f
2-IC6H4
0
0
0
107.5
202
662
383
20
a
2-BrC6H4
2-ClC6H4
106.8
ethanol
a
102.3
ethanol
b
101.2
hexane:ethanol 50:50
a
b
Method: off-column racemization. Method: online plateau treatment.
D
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Figure 5. Rotational barriers of compounds containing 6- vs 5-membered amidine ring.
Compounds 1a,6d,8e,f6 and 2a,e6 were described in the literature.
Yields and analytical data of new compounds are as follows.
5-(2-Nitrophenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-
1
oxide 1b (0.155 g, 48%): mp 174−176 °C. H NMR (500 MHz,
CDCl3): δ 2.02−2.06 (2H, m), 3.47−3.57 (2H, m), 3.87−3.96 (2H,
m), 7.14 (1H, d, J = 8.5), 7.20−7.23 (1H, m), 7.55−7.58 (1H, m),
7.63−7.64 (2H, m), 7.78 (1H, t, J = 7.6), 8.24 (1H, d, J = 8.5), 8.36
(1H, d, J = 8.2). 13C NMR (500 MHz, CDCl3): δ 19.5, 43.6, 44.0,
111.2, 121.1, 122.0, 124.5, 126.0, 130.0, 130.2, 131.7, 132.0, 133.8,
135.1, 136.1, 144.5, 148.3. HRMS (ESI) m/z calcd for C17H14N4O3:
322.1066. Found: 322.1070.
5-(Naphthalen-1-yl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-
oxide 1c (0.101 g, 31%): mp 186−188 °C. H NMR (500 MHz,
Figure 6. Transition states for the enantiomerization of compound 1a
computed at the B3LYP/6-31+G(d,p) level.
1
CDCl3): δ 2.02−2.11 (2H, m), 3.47−3.59 (2H, m), 3.99 (2H, t, J =
6.1), 7.21−7.27 (2H, m), 7.44−7.50 (2H, m), 7.56−7.63 (4H, m),
7.91 (1H, d, J = 8.3), 7.96 (1H, d, J = 8.1), 8.41 (1H, dd, J = 8.1, 1.5).
13C NMR (500 MHz, CDCl3): δ 19.2, 43.1, 44.2, 112.2, 121.4, 123.2,
124.3, 125.7, 126.2, 126.5, 126.9, 128.5, 129.0, 130.4, 130.5, 130.9,
132.4, 133.8, 134.7, 138.8, 146.4. HRMS (ESI) m/z calcd for
C21H17N3O: 327.1372. Found: 327.1368.
Table 3. Calculated Rotational Barriers
calculated barrier
experimental barrier
compd
Ar
n
(kJ mol−1
88.3
)
(kJ mol−1
)
1a
2-CH3C6H4
1
99.2
99.8
5-(2-Fluorophenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-
1
1b
1c
1e
1f
2-NO2C6H4
1-C10H7
1
1
1
1
1
0
0
84.7
89.1
105.3
96.7
67.7
86.7
86.1
87.1
oxide 1g (0.139 g, 47%): mp 168−170 °C. H NMR (500 MHz,
105.1
110.1
104.6
81.5
CDCl3): δ 2.14 (2H, bs), 3.67 (2H, bs), 4.01 (2H, bs), 7.21−7.34 (4H,
m), 7.48−7.52 (2H, m), 7.61 (1H, t, J = 7.9), 8.41 (1H, d, J = 8.2). 13C
NMR (500 MHz, CDCl3): δ 19.5, 43.8, 44.0, 111.2, 116.0 (J = 21.5),
117.8 (J = 14.7), 121.3, 122.2, 124.15, 130.4, 131.6 (J = 2.9), 131.6 (J
= 9.8), 132.1, 135.1, 136.6, 145.0, 160.2 (J = 249.4). HRMS (ESI) m/z
calcd for C17H14FN3O: 295.1121. Found: 295.1124.
2-BrC6H4
2-ClC6H4
2-FC6H4
1g
2a
2c
2-CH3C6H4
1-C10H7
95.3
100.3
100.3
106.8
102.3
101.2
4-(Naphthalen-1-yl)-1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxide
2c (0.141 g, 45%): mp 100−102 °C. 1H NMR (500 MHz, CDCl3): δ
4.10−4.24 (4H, m), 6.90 (1H, dd, J = 8.1, 1.0), 7.15−7.18 (1H, m),
7.49−7.59 (4H, m), 7.62−7.65 (1H, m), 7.72 (1H, dd, J = 7.1, 1.1),
7.92−7.95 (1H, m), 8.01 (1H, d, J = 8.2), 8.32 (1H, dd, J = 8.3, 1.3).
13C NMR (500 MHz, CDCl3): δ 46.6, 54.2, 112.0, 121.2, 121.4, 124.8,
125.4, 126.1, 126.5, 126.8, 128.3, 128.9, 130.0, 130.7, 131.0, 132.4,
133.6, 133.7, 136.3, 153.5. HRMS (ESI) m/z calcd for C20H15N3O:
313.1215. Found: 313.1219.
2e
2f
2-BrC6H4
2-ClC6H4
0
0
105.5
96.0
4-(2-Iodophenyl)-1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxide 2d
1
(0.175 g, 45%): mp 139−141 °C. H NMR (500 MHz, CDCl3): δ
4.06−4.19 (2H, m), 4.19−4.23 (2H, m), 6.87 (1H, dd, J = 8.1, 1.1),
7.15 (1H, ddd, J = 8.3, 7.3, 1.1), 7.20 (1H, ddd, J = 8.0, 7.6, 1.6), 7.40
(1H, dd, J = 7.9, 1.6), 7.51−7.54 (1H, m), 7.54−7.56 (1H, m), 7.99
(1H, dd, J = 8.0, 0.9), 8.30 (1H, dd, J = 8.3, 1.1). 13C NMR (500 MHz,
CDCl3): δ 46.5, 53.9, 97.5, 112.2, 121.4, 121.4, 128.6, 130.7, 131.1,
131.1, 132.6, 133.5, 134.6, 138.0, 139.3, 152.4. HRMS (ESI) m/z calcd
for C16H12IN3O: 389.0025. Found: 389.0030.
Figure 7. Transition states for the enantiomerization of compound 1b
computed at the B3LYP/6-31+G(d,p) level.
4-(2-Chlorophenyl)-1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxide
1
2f (0.119 g, 40%): mp 170−172 °C. H NMR (500 MHz, CDCl3):
δ 4.08−4.26 (4H, m), 6.87 (1H, dd, J = 8.1, 1.1), 7.15 (1H, ddd, J =
E
DOI: 10.1021/jo502626f
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The Journal of Organic Chemistry
Article
8.3, 7.3, 1.1), 7.42−7.47 (2H, m), 7.49−7.57 (3H, m), 8.30 (1H, dd, J
= 8.3, 1.3). 13C NMR (500 MHz, CDCl3): δ 46.5, 54.3, 112.0, 121.1,
121.3, 127.1, 128.3, 129.9, 130.8, 130.8, 130.9, 131.1, 132.5, 133.6,
134.1, 152.6. HRMS (ESI) m/z calcd for C16H12ClN3O: 297.0669.
Found: 297.0665.
Synthesis of N-arylacetyl-N′-(2-nitroaryl)-1,3-propanediamines 3
and N-arylacetyl-N′-(2-nitroaryl)-1,2-ethanodiamines 4. Geneneral
Procedure: The acyl chloride (1 mmol) was added to a chloroformic
solution of the corresponding N-(o-nitrophenyl)-1,n-diamine (1
mmol), followed by aq 4% NaOH (1 mL). The mixture was shaken
for 15 min, after which the organic layer was separated, washed with
H2O, dried (Na2SO4), and filtered. The solvent was removed in vacuo.
The crude product was purified by flash chromatography on silica gel
using mixtures of chloroform:ethyl acetate as eluent.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for compounds 1b,c,g, 2c,d,f, 3b,c,g,
and 4c,d,f, chiral HPLC screening for compounds 1b−c and
2a,c,f, kinetic data for racemization for compounds 1a,c-f, 2c-f,
computational details, crystallographic data, and X-ray crystallo-
graphic file (CIF) for compound 1a. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: christian.roussel@univ-amu.fr.
*E-mail: lorelli@ffyb.uba.ar.
Notes
■
Compounds 3a,6d,8e,f6 and 4a,e6 were described in the literature.
Yields and analytical data of new compounds are as follows.
N-(2-Nitrophenyl)acetyl-N′-(2-nitrophenyl)-1,3-propanediamine
3b (0.283 g, 79%): mp 148−150 °C. 1H NMR (500 MHz, CDCl3): δ
1.93−1.99 (2H, m), 3.38 (2H, t, J = 6.8), 3.44−3.47 (2H, m), 3.88
(2H, s), 6.04 (1H, bs, ex), 6.66−6.69 (1H, m), 6.86 (1 H, d, J = 8.5),
7.39−7.53 (3H, m), 7.64 (1H, t, J = 7.6), 8.06 (1H, d, J = 8.2), 8.19
(1H, d, J = 8.7). 13C NMR (500 MHz, CDCl3): δ 29.1, 37.6, 40.5,
41.1, 113.7, 115.4, 125.2, 126.9, 128.5, 130.3, 130.6, 133.5, 133.7,
136.3, 145.3, 169.4. HRMS (ESI) m/z calcd for C17H18N4O5:
358.1277. Found: 358.1279.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the University of Buenos Aires
(20020100100935) and by CONICET (PIP 286).
■
REFERENCES
■
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(2H, s), 5.45 (1H, bs, ex), 6.56 (1H, dd, J = 8.7, 0.8), 6.62 (1H, dd, J =
8.5, 7.1), 7.32−7.56 (5H, m), 7.81−7.97 (3H, m), 8.13 (1H, dd, J =
8.5, 1.5). 13C NMR (500 MHz, CDCl3): δ 28.8, 37.2, 40.2, 41.8, 113.5,
115.3, 123.6, 125.4, 125.7, 126.2, 126.3, 126.8, 128.4, 128.6, 128.8,
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N-(2-Fluorophenyl)acetyl-N′-(2-nitrophenyl)-1,3-propanediamine
3g (0.271 g, 82%): mp 121−125 °C. 1H NMR (500 MHz, CDCl3): δ
1.87−1.92 (2H, m), 3.30−3.34 (2H, m), 3.37−3.41 (2H, m), 3.60
(2H, s), 6.02 (1H, bs, ex.), 6.64 (1H, ddd, J = 8.5, 7.0, 1.4), 6.80 (1H,
d, J = 8.0), 7.04−7.08 (1H, m), 7.11−7.14 (2H, m), 7.25−7.33 (2H,
m), 7.40−7.43 (1H, m), 8.06(1H, bs, ex), 8.14 (1H, dd, J = 8.7, 1.4).
13C NMR (500 MHz, CDCl3): δ 28.9, 36.8 (J = 2.7), 37.3, 40.3, 113.6,
115.3, 115.5 (J = 21.8), 121.5 (J = 15.4), 124.5 (J = 3.6), 126.8, 129.2
(J = 8.2), 131.6 (J = 3.6), 131.8, 136.2, 145.2, 160.8 (J = 245.2), 170.2.
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331.1335.
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1
0.283 g, 81%): H NMR (500 MHz, CDCl3): δ 3.30−3.45 (4H, m),
4.05 (2H, s), 5.60 (1H, bs, ex), 6.61−6.62 (1H, m), 6.87 (1H, d, J =
7.4), 6.91−7.46 (5H, m), 7.81−7.87 (3H, m), 8.16 (1H, dd, J = 8.6,
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̀
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1
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(0.395 g, 93%): mp 143−145 °C. H NMR (500 MHz, CDCl3): δ
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3.47−3.52 (4H, m), 3.71 (2H, s), 5.80 (1H, bs, ex), 6.64−6.69 (1H,
m), 6.94 (1 H, dd, J = 8.7, 1.0), 7.22−7.46 (5H, m), 8.05 (1H, bs, ex),
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