Strong deshielding in aromatic isoxazolines

Article abstract of DOI:10.1002/mrc.4308

Very strong proton deshielding was found in di/tri-aromatic isoxazoline regioisomers prepared from acridin-4-yl dipolarophiles and stable benzonitrile oxides (BNO). Three alkenes, (acridin-4-yl)-CH=CH-R (R = COOCH₃, Ph, and CONH₂), r

Full text of DOI:10.1002/mrc.4308

Research article
Received: 23 March 2015
Revised: 1 July 2015
Accepted: 6 July 2015
Published online in Wiley Online Library: 14 September 2015
(wileyonlinelibrary.com) DOI 10.1002/mrc.4308
Strong deshielding in aromatic isoxazolines
Lucia Ungvarská Maľučká,a Mária Vilková,a Jozef Kožíšekb and Ján Imricha*
ABSTRACT: Very strong proton deshielding was found in di/tri-aromatic isoxazoline regioisomers prepared from acridin-4-yl
dipolarophiles and stable benzonitrile oxides (BNO). Three alkenes, (acridin-4-yl)-CH¼CH-R (R= COOCH3, Ph, and CONH2), reacted
with three BNO dipoles (2,4,6-trimethoxy, 2,4,6-trimethyl, 2,6-dichloro) to give pairs of target isoxazolines with acridine bound to
C-4 or C-5 carbon of the isoxazoline (denoted as 4-Acr or 5-Acr). Regioselectivity was dependent on both the dipolarophile and
dipole character. The ester and amide dipolarophile displayed variable regioselectivity in cycloadditions whereas the styrene
one afforded prevailing 4-Acr regioisomers. 2,4,6-Trimethoxy-BNO was most prone to form 5-Acr isoxazolines while mesitonitrile
oxide gave major 4-Acr isoxazolines. Basic hydrolysis of the amide cycloadduct led to an unexpected isoxazolone product. The
structure of the target compounds was studied by NMR, MS, and X-ray crystallography. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: NMR; 1H; 13C; 1,3-dipolar cycloadditions; regioselectivity; acridine; benzonitrile oxides; isoxazolines
DCs of 1,2-disubstituted alkenes with the nitrile oxides can in
principle afford two isoxazoline regioisomers resulting from two
Introduction
Though many acridine derivatives have been studied in the past as
mutually reversed orientations of the dipolarophilic CH¼CH bond
potent fluorophores and DNA ligands it is surprising that only
limited attention was devoted to 1,3-dipolar cycloadditions (DCs)
of acridine dipolarophiles so far.[1a–d] DCs with nitrile oxides (NOs),
for example, should afford isoxazolines transformable into
β-hydroxyketones and γ-aminoalcohols, versatile intermediates for
synthesis of natural products analogues.[2a–3] Isoxazolines them-
selves have also revealed a broad range of activities against influ-
enza viruses[4] and fungi,[5] an inhibition of group II phospholipase
A2,[6] glycoprotein IIb/IIIa receptor antagonism,[7] spermicidal and
anti-HIV activities,[8a–c] β-adrenergic receptor antagonist
properties,[9] and other valuable features.[10a–d] Thus, appropriate
derivatization of acridines by the isoxazoline scaffold could bring
new perspective pharmacophores.
Even though reactivity and regioselectivity of 1,3-dipolar cyclo-
additions of unsymmetrical alkenes with nitrile oxides have been
often studied,[11–13a–c] their mechanism is still poorly understood.
Selectivity prediction by a Frontier Molecular Orbital theory (FMO)
is not as fruitful as at classical cycloadditions because electronic
and steric effects can significantly alter the cycloaddition course.[14]
To rationalize it, explanations using a Houk model,[15a–c] secondary
orbital interactions, kinetic effects,[16a,b] etc., have been attempted;
nevertheless, further experimental data are still desired to elucidate
the matter. Polarity of the dipolarophilic double bond and steric
constraints may hinder or facilitate an approach of the bulky dipole
from a more or less sterically hindered face of the dipolarophile and
thus substantially alter the rate of formation and ratio of formed
regioisomeric products.[17]
and the dipole in the transition state. Consequently, two
regioisomeric products differ each from other by mutually ex-
changed substituents on isoxazoline C-4/C-5 carbons. To examine
the effects of dipolarophile substituents in a systematic manner,
we synthesized three starting (acridin-4-yl)alkenes with COOCH3
(4), phenyl (5), or CONH2 (6) substituent. As the dipoles, three stable
benzonitrile oxides, 2,4,6-trimethoxy-BNO (7a), mesitonitrile oxide
(MNO, 7b), and 2,6-dichloro-BNO (7c) were used in this work, while
unstable p- and m-substituted BNOs, which dimerized easily, were
set aside for a separate study. To compare the effects of the flanking
versus middle acridine ring on the reactivity and regioselectivity, we
shall present DCs of relative 9-substituted acridine dipolarophiles,
methyl 3-(acridin-9-yl)propenoate and 9-(2-styryl)acridine with the
BNOs 7a–c in the following paper.
Results and Discussion
Acridine dipolarophiles 4–6 were obtained from acridine-4-
carbaldehyde (3) that was synthesized by a simple Klanderman’s
method in high yield.[25] To prepare 3, starting 4-methylacridine
(1) was first transformed to 4-bromomethylacridine (2) with NBS
in tetrachloromethane under 2,2′-azobis(isobutyronitrile) (AIBN) ca-
talysis (Scheme 1).[26] Subsequent reaction of 2 with 2-nitropropane
and sodium in dry methanol afforded the aldehyde 3 in 89% yield.
The synthesis of 3 as given is an alternative of a Takahashi
method.[27]
Numerous papers have dealt with DCs of cinnamal-
dehydes,[15b,18a,b] cinnamates,[1a,16b] lactones,[19] cinnamamides,[20]
cinnamonitriles,[21] and stilbenes[22a–e] with the nitrile oxides up to
now, but only few works studied acridine dipolarophiles.[23,24] As
4-substituted acridines, especially carboxamides, are strong tumor
suppressors, we were interested in dipolarophiles with the alkene
moiety on acridine C-4 carbon. The acridine flanking ring together
with the alkenoic substituent on C-4 composes aromate-
alkenoate/aromate-alkene systems similar to cinnamates/stilbenes.
*
Correspondence to: Ján Imrich, P. J. Šafárik University, Faculty of Science, Institute
of Chemistry, NMR Laboratory, Moyzesova 11, 040 01 Košice, Slovakia.
E-mail: jan.imrich@upjs.sk
a P. J. Šafárik University, Faculty of Science, Institute of Chemistry, NMR Laboratory,
Moyzesova 11, 040 01 Košice, Slovakia
b Slovak Technical University, Faculty of Chemical and Food Technology,
Department of Physical Chemistry, Radlinského 9, 812 37 Bratislava, Slovakia
Magn. Reson. Chem. 2016, 17–27
Copyright © 2015 John Wiley & Sons, Ltd.

L. U. Maľučká et al.
Scheme 1. Synthesis of acridin-4-carbaldehyde (3). Reagents and
conditions: (i) NBS, AIBN, CCl4, 4 h, (ii) 2-nitropropane/Na/MeOH, DMSO, rt,
3 h.
The aldehyde 3 was further transformed to the ester 4, methyl
3-(acridin-4-yl)propenoate, using a Wittig reaction with methyl
(triphenylphosphoran ylidene) acetate by a mild Märkl and Merz
method in 42% yield (Scheme 2).[28] A styryl moiety was incorpo-
rated into 4-(2-styryl)acridine (5) by a Vedejs’s method.[29,30]
Benzyltriphenylphosphonium chloride was deprotonated by so-
dium hydride at low temperature to give an ylide as an orange sus-
pension. To this mixture, the aldehyde 3 was added to form the
dipolarophile 5 in 41% yield after 12 h. We used the same method
also for the synthesis of 3-(acridin-4-yl)propenamide (6), in which
amidomethyltriphenylphosphonium chloride was transformed to
a corresponding ylide by treatment with sodium hydride to give
Scheme 3. 1,3-Dipolar cycloaddition reactions of the dipolarophiles 4–6
with the nitrile oxides 7a–c. Reagents and conditions: (i) NOs 7a–c, CHCl3, rt.
Table 1. 1,3-Dipolar cycloadditions of 4–6 with 7a–d: Reaction time,
conversion, yields, and ratios of regioisomeric isoxazolines 8–13
Reactants Regio-isomers Time Conversion
Ratiosa
Isolated
4-Acr + 5-Acr (days)
(%)
4-Acr + 5-Acr (%) yieldsb
(%)
1
the amide 6 after 24 h in 55% yield. H and 13C NMR signals of
R = COOCH3 (4)
4 + 7a
4 + 7b
4 + 7c
8a + 9a + 9dc 13
100
100
81
12.4:87.6
59.8:40.2
28.8:71.2
0 + 23 + 11
44 + 32
the dipolarophiles 4–6 in CDCl3 were assigned using HMBC trans-
fers from both alkene protons to corresponding acridine carbons
and to phenyl C-1′′′ and C-2′′′,6′′′ carbons of styrene (in 5). Coupling
constants 16.0–16.4 Hz between these protons confirmed a trans (E)
configuration—none cis (Z) isomers were detected in the crude re-
action mixture.
8b + 9b
8c + 9c
29
50
17 + 16
R = Ph (5)
5 + 7a
5 + 7b
5 + 7c
d
10a + 11a
10b + 11b
10c + 11c
14
14
14
—
68.9:31.1
90.1:9.9
95.2:4.8
34 + 17
63 + 8
56 + 3
d
—
d
—
1,3-Dipolar cycloadditions of methyl 3-(acridin-4-yl)propenoate
(4) with 7a–c were performed at room temperature to ensure a
kinetic control presumed for DCs of alkenes with NOs,[31] until
the dipolarophile had been consumed (TLC and NMR monitor-
ing). To determine the conversion and regioselectivity precisely,
parallel reactions of the dipolarophile (0.04 mmol) and dipole
(0.12mmol) in CDCl3 (0.6mL) were carried out in a sealed NMR
tube at room temperature. Despite a triple molar excess of the
dipoles was used, it took days to achieve a complete or at least
prevailing conversion of the dipolarophile into mixtures of two
regioisomeric isoxazolines, methyl 4-(acridin-4-yl)-3-(substituted
phenyl)-4,5-dihydro-2-isoxazoline-5-carboxylates 8a–c denoted
as 4-Acrs and methyl 5-(acridin-4-yl)-3-(substituted phenyl)-4,5-
dihydro-2-isoxazoline-4-carboxylates 9a–c denoted as 5-Acrs
(Scheme 3, Table 1). The fastest reaction of 4 with 7a was fin-
ished in 13 days and that with 7b in 29days, both with 100%
conversion, while the slowest one was that of 7c with 81% con-
version in 50 days. The best regioselectivity for 8a/9a = 1:7.08
and moderate for 8b/9b= 1:0.67, 8c/9c=1:2.47 indicated that
selectivity was dependent on both, the character of the
dipolarophile and substituent effects within the dipole. Because
of the laborious separation of regioisomers with close Rf values,
from all reactions only small amounts of pure cycloadducts were
obtained. The reaction with 7a afforded 23% of 9a with a
R = CONH2 (6)
6 + 7a
6 + 7b
6 + 7c
12a + 13a
8
14
6
100
81
25.2:74.8
71.4:28.6
59.7:40.3
11 + 15
11 + 8
12b + 13b
12c + 13c
89
18 + 11
aDetermined from experiment in a sealed NMR tube by integration of
H-4 and H-5 methine doublets in 1H NMR spectra of the crude
reaction mixtures in CDCl3.
bIsolated yields after column chromatography and crystallization based
on the dipolarophiles 4, 5, 6.
cIsoxazoline 8a was not isolated after repeated chromatography. The
compound 9d was isolated in 11% yield.
dConversion could not be determined.
minimal amount of 8a (not isolated), together with 11% of a
monobrominated side product, methyl 5-(acridin-4-yl)-3-(3-
bromo-2,4,6-trimethoxyphenyl)-4,5-dihydro-2-isoxazoline-4-car-
boxylate (9d) coming from 2,4,6-trimethoxy-BNO (7a) contami-
nated by 3-bromo-2,4,6-trimethoxy-BNO (7d). Cycloaddition
with MNO (7b) led to the best summary yield of both
regioisomers 8b, 9b (76%), while only 33% yield was found for
the regioisomers 8c, 9c, together with some unreacted ester 4.
Cycloadditions of 4-(2-styryl)acridine (5) with 7a–c in the ratio 1:3
showed better regioselectivity (Scheme 3, Table 1). Improved puri-
fication of 7a after bromination led exclusively to two
trimethoxyphenyl isoxazolines 10a, 11a. Conversion of the styrene
5 could not be followed by NMR because of an overlap of olefinic
and aromatic signals. Nevertheless, the reaction time did not
exceed 14 days (TLC). All reactions afforded major 4-(acridin-4-yl)-
5-phenyl-3-(substituted phenyl)-4,5-dihydro-2-isoxazolines 10a–c
(4-Acrs) and the ratio 10/11 gradually increased from 1:0.45 (a),
through 1:0.11 (b), to 1:0.05 (c). A possible reason of this trend
may come from a growing steric repulsion in the transition state
Scheme 2. Synthesis of 4-substituted acridine dipolarophiles 4–6.
Reagents and conditions: i) Ph3P = CHCOOCH3, CH2Cl2, rt, 12 h or
Ph3P+CH2Ph Clꢀ, NaH, THF, ꢀ20 °C → rt, 12 h or Ph3P+CH2CONH2 Clꢀ, NaH,
CH2Cl2, ꢀ10 °C → rt, 24 h.
wileyonlinelibrary.com/journal/mrc
Copyright © 2015 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 17–27

Strong deshielding in aromatic isoxazolines
of a minor regioisomer formation caused by ortho-disubstituted
phenyl of the dipole. This idea was supported by our recent find-
ings on cycloadditions of 5 with para-substituted BNOs lacking
ortho-substituents in which only negligible regioselectivity has
been noted (results not given here). The acridin-4-yl skeleton of
the target isoxazolines in this study is believed to adopt a relaxed
position relative to both benzene rings of the dipole and the styryl
unit.
stereogenic centres in the products was not determined, relative
configuration of isoxazoline protons H-4, H-5 should be trans as
in the parent dipolarophile owing to a concerted cycloaddition
mechanism. 13C NMR signals of C-4 and C-5 carbons in the
isoxazolines were of prime importance for distinguishing the
regioisomers. Downfield-shifted signals between 82.7–90.3 ppm
unequivocally pertain to C-5 carbons next to O-1 oxygen,
whereas upfield-shifted signals between 54.2 and 66.7 ppm
belong to C-4 carbons. Two regioisomeric structures were then
resolved by analysis of the HSQC and HMBC spectra as exempli-
fied on a regioisomeric pair 8b–9b. The 13C NMR spectrum of
the 4-Acr derivative 8b displayed a C-5 signal at 84.7 ppm and
that of C-4 at 54.8ppm which provided HSQC cross-peaks with
a H-5 signal at 5.50 ppm and that of H-4 at 6.95 ppm, resp.
(3J45 = 5.2 Hz). Surprisingly, H-4 proton was more deshielded than
H-5 close to oxygen because of a magnetic anisotropy effect of
two nearby aromatic skeletons. To distinguish the regioisomers
4-Acr vs. 5-Acr, following HMBC correlations were crucial
(Table 4): in 8b, magnetization transfer from isoxazoline H-4
pointed at three-bond distant acridine signals C-3′ (128.5 ppm)
and C-4′a (146.0ppm), which on turn showed no cross-peaks
with the isoxazoline H-5 signal. Hence, acridine is attached to
isoxazoline C-4 carbon suggesting that 8b is a 4-(acridin-4-yl)-5-
carboxylate (4-Acr) regioisomer.
Cycloadditions of a new amide dipolarophile, 3-(acridin-4-yl)
propenamide (6), with NOs 7a–c in the ratio 1:1 in dry chloroform
at room temperature produced again two regioisomers,
4-(acridin-4-yl)-3-(substituted
phenyl)-4,5-dihydro-1,2-oxazol-5-
carboxamides 12a–c and 5-(acridin-4-yl)-3-(substituted phenyl)-
4,5-dihydro-1,2-oxazol-4-carboxamides 13a–c with close Rf factors,
moderate regioselectivity, and high conversion in reasonably short
time (Scheme 3, Table 1). Full conversion of 6 was observed only
with 7a in 8 days, 89% conversion in 6 days was found with 7c,
whereas 7b showed 81% conversion in 14 days. As the NMR spectra
of the mixtures b, c taken one week later still showed some starting
amide 6, the DCs were reversible with free energy differences of
about 4 kJ.molꢀ1. The product ratios with MNO and 2,6-dichloro-
BNO favored moderately 4-Acr regioisomers over 5-Acrs, 12b/
13b = 1:0.40 and 12c/13c = 1:0.68, resp., but not with trimethoxy-
BNO (12a/13a = 1:2.97).
The structure of cycloaddducts 8–13 was established by con-
certed application of NMR methods (1H and 13C NMR, DEPT, H,
H-COSY, gHSQC, gHMBC, NOESY, Tables 2 and 3) and X-ray crys-
tallography. Although absolute configuration of C-4 and C-5
In the compound 9b (Table 4), isoxazoline signals at 65.4ppm
(C-4) and 83.6ppm (C-5) correlated (HSQC) with doublets at
4.48 ppm (H-4) and 7.17ppm (H-5), resp. (3J45 = 7.4Hz). HMBC
transfers to acridine C-3′,4′a signals were observed from a very
Table 2. 1H NMR chemical shifts (ppm) and JHHa (Hz) in CDCl3
Comp.
Isoxazoline
Acridine
Dipole
Ph (styryl)
Me
Hα H-4 Hβ H-5 Jαβ J45 1′
2′
3′
5′
6′
7′
8′
9′ meta 3′′ para 4′′ o-Me p-Me ortho 2′′′ meta 3′′′ para 4′′′
4
7.07
7.49
7.20
—
9.05
8.70
8.76
—
16.2 8.02 7.55 8.02 8.33 7.81 7.55 8.02 8.76
16.0 7.91 7.53 8.08 8.33 7.77 7.56 8.00 8.72
16.0 8.22 7.68 8.18 8.31 7.93 7.68 8.22 9.17
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7.73
—
—
7.43
—
—
7.31
—
3.90
—
5
6
—
—
8a
—
—
—
—
—
—
—
—
—
—
—
—
—
—
8b
6.95
7.08
4.51
4.48
4.63
6.67
6.78
6.93
4.84
4.66
5.03
6.67
6.84
6.80
4.66
4.43
4.42
—
5.50
5.65
7.17
7.17
7.36
5.64
6.06
6.19
6.81
7.02
7.06
5.12
5.44
5.79
7.06
7.08
7.11
9.29
9.53
5.2 7.91 7.49 7.82 8.06 7.72 7.49 7.91 8.64 6.55
5.2 7.92 7.52 7.95 8.03 7.69 7.49 7.91 8.66 7.02
7.6 7.96 7.57 8.09 8.06 7.73 7.52 7.98 8.76 6.08
7.4 7.99 7.58 8.09 8.03 7.74 7.54 8.01 8.79 6.83
6.8 7.98 7.57 8.06 8.03 7.74 7.53 7.99 8.77 7.28
5.2 7.87 7.44 7.90 8.15 7.74 7.52 7.97 8.70 5.95
5.6 7.90 7.54 8.00 8.00 7.69 7.47 7.90 8.63 6.52
6.4 7.93 7.54 8.09 8.02 7.67 7.47 7.91 8.65 7.00
4.2 7.96 7.58 8.06 7.96 7.71 7.52 8.00 8.78 5.95
3.6 7.98 7.59 8.11 7.75 7.65 7.51 7.98 8.78 6.66
4.8 7.99 7.59 8.07 7.77 7.67 7.51 7.99 8.78 7.12
5.6 7.93 7.47 7.78 8.16 7.78 7.56 8.02 8.79 5.93
5.6 7.82 7.42 7.78 7.94 7.61 7.40 7.84 8.55 6.45
4.4 8.11 7.64 7.97 7.83 7.77 7.55 8.07 9.01 7.15
5.2 8.17 7.57 7. 98 8.14 7.78 7.57 8.19 8.83 6.10
4.8 8.08 7.61 8.08 8.02 7. 82 7.61 8.08 8.88 6.81
6.4 8.20 7.68 7.94 8.07 7.89 7.68 8.20 9.18 7.50
—
2.22 1.98
—
—
—
3.90
3.91
3.80
3.80
3.86
—
8c
6.88
—
—
—
—
—
—
9a
3.68 3.80
2.14 2.25
—
—
—
9b
—
—
—
—
9c
7.28
—
—
—
—
—
—
10a
10b
10c
11a
11b
11c
12a
12b
12cb
13a
13b
13cb
15c cis
15c trans
3.67 3.65
2.17 1.96
7.81
7.59
7.63
7.52
7.37
7.49
—
7.44
7.40
7.41
7.37
7.41
7.38
—
7.34
7.33
7.34
7.29
7.36
7.38
—
—
—
6.86
—
—
—
—
3.49 3.71
1.79 2.15
—
—
—
7.12
—
—
—
—
3.67 3.66
2.05 1.89
—
—
—
—
—
—
7.02
—
—
—
—
—
—
—
3.65 3.79
2.13 2.23
—
—
—
—
—
—
—
—
—
7.50
7.60
7.23
—
—
—
—
—
—
—
—
—
—
—
—
8.27 7.74 9.73 7.96 7.79 7.56 8.01 8.80 7.60
7.94 6.93 7.26 8.31 7.85 7.56 8.01 8.73 7.23
—
—
—
—
—
—
—
—
—
aJ1′2′ = 8.0–8.8 Hz, J2′3′ = 6.6–7.4 Hz, J1′3′ = 0.8–1.2 Hz, J5′6′ = 8.2–8.8 Hz, J6′7′ = 6.0–6.8 Hz, J7′8′ = 8.0–8.8 (9.2 Hz-15c cis) Hz, J5′7′ = 0.8–1.2 Hz, J6′8′ = 1.2–1.6 Hz;
J3′′4′′ = 8.4 (8c), 8.0 (10c), 7.2 (12c) Hz; J2′′′3′′′ = 7.2–8.0 Hz, J3′′′4′′′ = 7.2–7.6 Hz, J2′′′4′′′ = 1.2–1.6 Hz.
bMeasured in DMSO-D6.
Magn. Reson. Chem. 2016, 17–27
Copyright © 2015 John Wiley & Sons, Ltd.
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L. U. Maľučká et al.
Table 3. 13C NMR chemical shifts (ppm) in CDCl3 and DMSO-D6
Compound
Sa Isoxaz.
Cα
Cβ
Acridine
C = N
C-4
C-5
1’
2’
3’
4’
5’
6’
7’
8’
9’
8’a
9’a
4’a
10’a
4 - COOCH3
5 - Ph
C
C
C
-
120.3 141.8 129.4 126.2 130.6 132.9 130.1 130.5 126.6 127.9 136.2 126.6 125.2 146.9 148.8
130.5 125.2 127.6 125.6 125.8 135.9 130.0 130.1 125.6 127.9 136.0 126.8 126.5 147.0 148.4
124.3 135.7 130.0 125.5 128.3 132.5 128.5 130.9 126.0 129.2 136.8 126.1 126.2 146.1 147.9
-
6 - CONH2
-
4Ab-8a COOCH3
4A-8b COOCH3
4A-8c COOCH3
5Ab-9a COOCH3
5A-9b COOCH3
5A-9c COOCH3
4A-10a Ph
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
C
C
C
C
C
C
C
C
C
C
C
C
C
D
C
C
D
C
C
159.5
156.2
150.1
154.4
150.9
155.5
159.7
156.2
155.2
160.3
156.4
154.7
160.2
155.8
151.0
155.5
152.2
54.8
54.2
64.7
65.4
63.8
59.0
58.3
57.4
65.6
66.7
65.0
54.6
54.3
54.8
64.6
65.1
64.3
84.7 127.8 125.2 128.5 135.5 129.9 130.0 126.0 128.2 135.8 126.5 126.2 146.0 148.3
84.5 127.8 125.4 128.7 134.4 129.8 130.0 126.0 128.3 135.7 126.4 126.2 146.1 148.1
83.0 127.8 125.8 126.2 138.0 129.8 130.0 125.5 128.0 135.8 126.4 126.5 146.1 148.1
83.6 128.1 125.5 125.9 137.7 129.6 130.2 126.0 128.1 136.0 126.6 126.5 145.9 148.1
83.8 128.0 125.4 126.1 137.1 129.7 130.2 125.9 128.1 136.0 126.5 126.4 145.7 148.0
90.3 127.7 125.9 129.0 137.8 130.1 130.1 125.9 128.2 136.0 126.6 126.8 147.2 148.5
89.4 128.1 125.3 128.4 136.9 129.9 129.9 125.8 127.8 135.8 126.4 126.4 146.3 148.3
90.0 128.2 125.5 128.8 135.7 129.8 129.8 125.9 127.8 135.7 126.3 126.3 146.4 148.1
87.1 127.4 125.7 126.2 139.1 129.9 129.8 125.7 128.0 135.7 126.3 126.6 146.5 148.1
87.0 128.0 125.4 126.0 138.6 129.9 130.0 125.8 127.8 135.9 126.4 126.7 146.4 148.0
88.4 127.9 125.5 126.2 138.0 129.8 130.0 125.8 128.0 135.9 126.4 126.6 146.2 148.0
84.9 127.4 125.3 128.2 135.6 128.8 129.6 124.8 127.4 135.6 125.7 125.8 147.4 145.8
83.8 126.7 124.1 127.5 134.8 129.0 128.7 124.9 126.8 136.0 125.4 125.2 144.9 147.2
83.6 128.6 125.9 128.1 133.9 128.5 130.3 125.5 128.1 136.2 125.6 125.7 145.4 147.0
82.7 126.8 126.0 127.9 137.7 128.9 130.6 125.7 128.3 136.6 126.8 126.5 146.0 148.0
83.1 128.3 125.6 128.5 138.8 128.5 131.0 126.1 128.3 137.1 126.9 126.6 145.8 148.0
83.2 128.2 125.3 125.7 137.5 129.0 130.6 126.0 128.2 136.5 126.1 126.0 145.2 147.3
4A-10b Ph
4A-10c Ph
5A-11a Ph
5A-11b Ph
5A-11c Ph
4A-12a CONH2
4A-12b CONH2
4A-12c CONH2
5A-13a CONH2
5A-13b CONH2
5A-13c CONH2
15c cis
162.1 117.6 148.5 135.5 125.6 136.9 129.8 129.8 131.1 126.5 128.1 136.9 126.1 126.1 146.8 148.7
157.7 119.1 150.9 132.4 123.5 133.0 129.6 130.1 131.1 126.7 128.1 136.4 125.9 125.9 146.9 149.2
15c trans
aC = CDCl3, D = DMSO-D6; b 4A = 4-Acr, 5A = 5-Acr.
Table 4. Selected gHMBC correlations ( ) in 8b and 9b
Figure 1. Structure of the isoxazoline 8b and selected NOE enhancements
) confirming the structural elucidation.
(
C-5 carbon. Strong deshielding of H-5 at 7.17ppm is caused by
magnetic anisotropy of two nearby aromatic skeletons together
with deshielding by O-1 and 9b is thus a reversed 5-(acridin-4-
yl)-4-carboxylate (5-Acr) regioisomer.
8b, 4-Acr
9b, 5-Acr
From H-4
From H-5
From H-4
From H-5
6.95 ppm
5.50 ppm
4.48 ppm
7.17 ppm
Assignments of other acridine signals in 8–13 started from
acridine H-9′ singlet at ca. 8.7 ppm, which had NOESY correlation
with nearby H-1′/H-8′ protons. The NOEDIFF spectra of 8b (Fig. 1)
that showed mutual enhancements 3.90/1.21% between the
isoxazoline H-4 and acridine H-3′ signals and 11.60/10.47%
between the H-5 and H-3′ signals indicated that H-5 and acridine
H-3′ are disposed on the same face of the isoxazoline ring. NOE
enhancements between H-4 and H-5 (3.53/3.40%) and especially
large between H-4 and o-CH3 (9.25/16.80%) demonstrate a
compressed mutual arrangement of isoxazoline and phenyl ring.
C3′
128.5
C3′
C4′a
C4′
C4
125.9
145.9
137.7
65.4
C4′a
C4′
146.0
135.5
C4′
135.5
C4′
137.7
C4
54.8
C5
84.7
C5
83.6
C¼N
C¼O
159.5
171.2
C¼N
C¼O
159.5
171.2
C¼N
C¼O
154.4
169.5
C¼N
C¼O
154.4
169.5
Thus, 1,3-dipolar cycloadditions follow
a stereoconservative
deshielded isoxazoline methine H-5 signal at 7.17ppm which
had on turn a HSQC cross-peak with the C-5 signal at
83.6ppm. H-5 showed also other expected HMBC correlations
with C-4′, C-4, C¼N, and C¼O signals. Transfers from H-4 pointed
at C-4′, C-5, C¼N, and C¼O signals, and from acridine H-3′ back
to C-5. This evidenced that acridine was attached to isoxazoline
concerted mechanism with unknown degree of potential
unsynchronicity.
The structure of 9b was established unequivocally also by a sin-
gle crystal X-ray analysis (Fig. 2) that revealed one intramolecular
hydrogen bond O-1…H-3′–C-3′ (Table 5). Mesityl and isoxazoline
planes in 9b are mutually orthogonal. The acridin-4-yl skeleton is
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Magn. Reson. Chem. 2016, 17–27

Strong deshielding in aromatic isoxazolines
Table 3. (Continued)
Compound
Dipole phenyl
COOMe
CONH2
Ph (styryl)
o-2’’’
i-1’’
o-2’’
m-3’’
p-4’’
o-Me
p-Me
OCH3
i-1’’’
m-3’’’
p-4’’’
4 - COOCH3
5 - Ph
-
-
-
-
-
-
167.9
-
51.7
-
-
-
-
-
-
-
-
-
-
-
138.0
127.0
128.6
127.6
6 - CONH2
-
-
-
-
-
-
-
-
167.0
-
-
-
-
-
-
4Ab-8a COOCH3
4A-8b COOCH3
4A-8c COOCH3
5Ab-9a COOCH3
5A-9b COOCH3
5A-9c COOCH3
4A-10a Ph
-
-
-
-
-
-
-
-
-
124.3
127.4
99.1
124.4
127.5
100.9
125.1
128.2
100.3
125.0
127.7
98.6
123.1
127.3
100.2
125.0
127.1
126.7
126.9
137.3
135.5
159.8
137.1
135.5
160.0
137.2
135.6
159.7
137.1
135.5
158.9
138.8
134.2
159.8
137.4
134.7
131.1
131.1
128.3
127.8
90.7
128.6
128.0
91.1
128.3
127.8
90.9
128.6
128.3
90.1
127.1
127.6
91.2
128.8
128.3
128.5
128.0
138.2
130.4
162.6
138.9
131.1
162.3
137.9
130.1
162.1
138.3
130.6
161.6
137.3
131.2
162.4
137.3
131.9
132.3
131.6
20.2
-
20.8
-
171.2
170.8
169.8
169.5
168.2
-
52.7
-
-
-
-
52.9
-
-
-
-
55.9
19.7
-
55.3
21.1
-
52.3
-
-
-
-
52.6
-
-
-
-
52.9
-
-
-
-
56.1
20.3
-
55.4
20.8
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
142.1
126.8
128.3
127.7
4A-10b Ph
-
141.6
125.6
128.6
127.8
4A-10c Ph
-
140.9
126.1
128.5
128.1
5A-11a Ph
55.8
19.8
-
55.2
21.0
-
-
139.5
128.7
128.0
126.9
5A-11b Ph
-
138.8
128.5
128.2
127.5
5A-11c Ph
-
137.9
128.8
128.4
127.6
4A-12a CONH2
4A-12b CONH2
4A-12c CONH2
5A-13a CONH2
5A-13b CONH2
5A-13c CONH2
15c cis
55.3
18.9
-
55.2
19.7
-
172.7
173.1
172.2
171.6
170.7
168.1
168.2
169.5
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
56.1
20.0
-
55.3
21.1
-
-
-
15c trans
-
-
showed analogous structure-confirming magnetization transfer
from H-5 to C-3′ (Table 7).
The most striking conclusion of NMR analysis is that the acridinyl
substituent dramatically increases chemical shifts of vicinal
isoxazoline CH protons:
5-CH signals in 5-Acr regioisomers 9,11,13 are shifted downfield
by 0.87–1.94 ppm more than in 4-Acr regioisomers 8,10,12,
4-CH signals in 4-Acr regioisomers 8,10,12 are shifted downfield
even by 1.83–2.47 ppm more than in 5-Acr regioisomers 9,11,13.
To assess whether cycloadditions were controlled thermody-
namically or kinetically we measured temperature effects on the
reactivity and ratio of products in three reactions of the amide 6
with the dipoles 7a–c in the NMR tube at room and elevated
temperatures 40 °C and 60°C in CDCl3 until all dipolarophile had
been consumed (Table 8).
Figure 2. View of the compound 9b with displacement ellipsoids at the
At 60 °C, the cycloaddends reacted two to four-times faster
than at room temperature, thus reaction rate increased only
moderately. The temperature, growth had practically no effect
on the ratio of regioisomers. Were the cycloadditions kinetically
controlled, competitive reactions leading to two regioisomers
would probably be influenced to a different extent by tempera-
ture change, shifting thus the ratio of regioisomers in the mix-
ture. As this was not the case it may be assumed that either
(a) an activation energy of both cycloaddition routes is too high
relatively to a small temperature change used or (b) the thermo-
dynamic control of cycloadditions, which is enabled by very long
reaction times, determines resulting product ratios, despite only
laboratory temperature was used in almost all the synthetic
and NMR experiments.
25% probability level.
turned out of the orthogonality with the isoxazoline plane owing to
a less confined arrangement.
In the HMBC spectra of the products 10b and 11b from 4-(2-
styryl)acridine (5), new transfers from particular isoxazoline protons
to ortho carbons C-2′′′,6′′′ enabled again unequivocal resolution of
the both regioisomers (Table 6). In the first amidic regioisomer
12b, signals of C-5 (83.8ppm) and C-4 (54.3ppm) correlated with
those of H-5 (5.44 ppm) and H-4 (6.84ppm), resp.. Typical HMBC
transfers from H-4 to acridine C-3′ and C-4′a enabled unambiguous
assignment of
a 4-Acr regioisomer, 4-(acridin-4-yl)-3-(2,4,6-
trimetylphenyl)-4,5-dihydro-1,2-oxazol-5-carboxamide (12b). The
molecule of reversed 5-Acr regioisomer, 5-(acridin-4-yl)-3-(2,4,6-
To obtain a free carboxylic acid 14c as a precursor of new
intended isoxazoline derivatives, we studied basic hydrolysis of
trimethylphenyl)-4,5-dihydro-1,2-oxazol-4-carboxamide
(13b)
Magn. Reson. Chem. 2016, 17–27
Copyright © 2015 John Wiley & Sons, Ltd.
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L. U. Maľučká et al.
Table 5. Selected geometric parameters with estimated standard deviations for 9b
Distance [Å]
Angle [°]
Cell setting
Space group
a [Å]
Triclinic
O1–C5, 1.457 (3)
O1–N2, 1.414 (2)
C3–C4, 1.506 (3)
C3–C1′′, 1.479 (3)
C3–N2, 1.276 (3)
C4–C5, 1.531 (3)
C4–C41, 1.504 (3)
C5–C4′, 1.503 (3)
N2–C3–C1′′, 121.20 (2)
N2–C3–C4, 113.70 (2)
C1′′–C3–C4, 124.90 (19)
C41–C4–C3, 113.00 (18)
C41–C4–C5, 113.10 (2)
C3–C4–C5, 101.54 (17)
C4–C5–C4′, 113.53 (17)
O1–C5–C4, 104.80 (16)
O1–N2–C3, 110.11 (17)
N2–O1–C5, 109.82 (15)
–
P1
8.483 (4)
9.417 (2)
14.715 (6)
100.09 (3)
92.18 (3)
101.27 (3)
1131.8 (7)
2
b [Å]
c [Å]
α [°]
β [°]
γ [°]
V [Å3]
Z
Dihedral angles [°]
C4–C3–N2–O1
C3–N2–O1–C5
C3–C4–C5–O1
0.6 (3)
ꢀ0.1 (2)
0.7 (2)
C6′′–C1′′–C3–C4
C3–C4–C41–O42
C4–C5–C4′–C4′a
ꢀ95.3 (3)
83.5 (3)
72.2 (2)
Table 6. Selected gHMBC correlations ( ) in 10b and 11b
Table 7. Selected gHMBC correlations ( ) in 12b and 13b
12b, 4-Acr
13b, 5-Acr
10b, 4-Acr
11b, 5-Acr
From H-4
6.84 ppm
From H-5
From H-4
4.43 ppm
From H-5
From H-4
6.78 ppm
From H-5
From H-4
4.66 ppm
From H-5
5.44 ppm
7.08 ppm
6.06 ppm
7.02 ppm
C3′
127.5
144.9
134.8
C3′
C4′a
128.5
145.8
C3′
128.4
146.3
C3′
126.0
C4a′
C4′
C4′a
C4′
C¼N
134.8
160.2
C4′
138.8
83.1
C2′′′,6′′′ 125.6 C2′′′,6′′′ 128.5
C5
C4′
136.9
141.6
C4′
136.9
141.6
C4′
138.6
138.8
C4′
C1′′′
C4
138.6
138.8
66.7
C¼N
C¼O
160.2
173.1
C¼N
C¼O
155.5
170.7
C1′′′
C1′′′
C1′′′
C5
87.0
C¼N 159.7
C¼N
159.7
C¼N
160.3
C¼N 160.3
Table 8. Reaction times and ratios of the regioisomers from cycloaddi-
tions of the amide 6 with the nitrile oxides 7a–c after complete
conversion
the minor carboxamide regioisomer 13c with 10 equiv. of KOH
in ethanol over 4 h at elevated temperature to achieve its com-
plete conversion to only one product spot on the TLC plate. In
the 1H NMR spectrum, however, no isoxazoline signals of the
acid 14c were observed (Scheme 4). Instead, two diverse prod-
ucts with equal number of protons, similar chemical shifts and
signal shapes were obtained in the ratio 3.3:1. Our attempts to
separate them by chromatography using different mobile phases
were unsuccessful.
Regioisomers
25 °C
40 °C
60 °C
Ratioa
Time (h)
Time (h)
Time (h)
12a + 13a
12b + 13b
12c + 13c
192
336
144
96
48
1.0:2.0
1.9:1.0
1.2:1.0
240
120
192
96
aThe ratio was constant within the whole temperature range used.
NMR analysis suggested a mixture of isoxazolones 15c cis
(77%) and 15c trans (23%) (Scheme 5). Attempts to resolve
the spectra of two components in the mixture by selective
three-bond 1H,13C-HMBC transfers optimized for JCH = 12 or
5 Hz from exocyclic¼ CH protons to key isoxazolone C¼O and
C¼N carbons were not successful and did not allow to safely
assign the signals (Fig. 3).
Fortunately, repeated crystallization of the mixture of stereoiso-
mers afforded orange needles of the major stereoisomer whose
crystallographic analysis proved a cis configuration, 15c cis (Fig. 4,
Table 9). The dihedral angle between acridine and isoxazolone
planes, C3′–C4′–C41–C4, was small, ꢀ28.81°, and indicated a high
degree of coplanarity, while that between the isoxazolone and
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Strong deshielding in aromatic isoxazolines
Table 9. Selected geometric parameters with estimated standard devi-
ations for 15c cis
Distance [Å]
Cell setting
Orthorombic C4′–C41
1.420 (14)
0.929
Space group
P212121
6.9961 (19)
12.783 (4)
21.158 (6)
90
C41–H41
C41–C4
C4–C5
a [Å]
1.368 (14)
1.468 (14)
1.209 (12)
1.382 (12)
1.439 (12)
1.326 (13)
1.421 (14)
1.478 (14)
b [Å]
Scheme 4. Hydrolysis of the amide 13c. Reagents and conditions: (i) 10
equiv. KOH, EtOH, 40 → 60 °C; (ii) HCl (1:3).
c [Å]
C5–O51
C5–O1
O1–N2
N2–C3
C3–C4
α [°]
β [°]
90
γ [°]
90
V [Å3]
1892.1 (9)
4
Z
C3–C1′′
Dihedral angles [°]
C3′–C4′–C41–C4
ꢀ28.81 (2)
O51–C5–O1–N2
O1–N2–C3–C1′′
N2–C3–C1′′–C2′′
C3–C1′′–C6′′–C(H3)
178.72 (9)
ꢀ176.10 (9)
69.42 (1)
C4′a–C4′–C41–H41 ꢀ23.44 (1)
H41–C41–C4–C3
H41–C41–C4–C5
C41–C4–C5–O51
ꢀ0.91 (2)
174.88 (1)
5.13 (2)
Scheme 5. Reagents and conditions: (i) KOH, EtOH, 40 → 60 °C, 4 h; (ii) HCl
(1:3), 15c cis: 77%, 15c trans: 23%.
2.09 (2)
Table 10. Selected proton chemical shifts (ppm) of 15c cis and 15c
trans and their difference Δ
Isomer
¼CH
H-1′
H-2′
H-3′
H-5′
Figure 3. Selected gHMBC ( ) correlations in 15c. The experiment was
optimized for couplings of
the major isomer 15c cis, right—the minor isomer 15c trans.
,
,
,
. Left—
15c cis
9.29
9.53
0.24
8.27
7.94
0.33
7.74
6.93
0.81
9.73
7.26
2.47
7.96
8.31
0.35
15c trans
Δ, ppm
Table 11. Selected carbon chemical shifts (ppm) of 15c cis and 15c
trans
Isomer
C¼O
C¼N
¼CH ¼C-4
C-1′
C-2′
C-3′
Figure 4. Crystallographic structure of the isoxazolone 15c cis.
15c cis
168.2 162.1 148.5 117.6 135.5 125.6 136.9
2,6-dichlorophenyl moiety, N2–C3–C1′′–C2′′, was larger, 69.42°, sug-
gesting a closer-to-perpendicular arrangement of the particular
rings. The configuration cis seems to be energetically preferred with
these compounds, similarly to isoxazolones we have prepared from
unstable nitrile oxides.
The NMR spectra confirmed that near-to-coplanar mutual posi-
tion of acridin-4-yl and isoxazolone skeletons in the solid state
persisted also in the solution of cis and trans isomers. Whereas
acridine H-3′ signal in 15c trans was found at 7.26 ppm as ex-
pected, H-3′ signal in 15c cis was considerably, by 2.47 ppm,
deshielded (9.73 ppm, Table 10). So a large difference follows
15c trans 169.5 157.7 150.9 119.1 132.4 123.5 133.0
Δ, ppm 1.3 4.4 2.4 1.5 3.1 2.1 3.9
After all, we were interested in a mechanism of isoxazolone
formation, as only one similar transformation of isoxazolinyl es-
ters of our type to the isoxazolone structure has been described
so far.[32] On this route, ring-opening of the isoxazoline skeleton
under irradiation or acid/base addition has been described re-
peatedly in recent years.[33a–c] On this basis it was assumed that
basic hydrolysis can afford corresponding oximes which further
undergo the Beckmann rearrangement after acidification. In our
case, however, a concurrence of an ester hydrolysis and ring
opening may be expected. Taking into account the resulting
structure, the isoxazoline ring opening in basic conditions to po-
tassium oxime salt seems to run faster than hydrolysis of the
amide to the carboxylic acid. A subsequent nucleophilic addition
of an oxime oxygen anion onto the amide carbonyl (maybe al-
ready partially hydrolyzed) giving a tetrahedral intermediate
and following elimination of ammonium chloride after acidifica-
tion afforded finally the both stereoisomers.
from
a magnetic anisotropy effect of the spatially close
isoxazolone C¼O group in 15c cis (Figs. 3 and 4). Smaller differ-
ences of corresponding chemical shifts were registered also for
proton signals more distant from the C¼O group, H-2′
(0.81ppm) and H-1′ (0.33 ppm). In addition, a synergic action of
two electron-acceptor groups, C¼O and C¼N, elicited a strong
deshielding of exocyclic ¼ CH proton to 9.29 ppm in 15c cis
and 9.53 ppm in 15c trans as well as strong polarization of the
exocyclic double bond (¼C-4 ≈ 117–119 ppm, ¼C―H ≈ 148–
151 ppm, Table 11).
Magn. Reson. Chem. 2016, 17–27
Copyright © 2015 John Wiley & Sons, Ltd.
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L. U. Maľučká et al.
(ISD) and combined with
a
time-of-flight analyzer. 2,5-
Conclusions
Dihydroxybenzoic acid (DHB) was used as a matrix. The sample
(1mg) was dissolved in 1 mL of acetonitrile/water 1:1. For the spot
preparation, a mixture of 1μL of the matrix DHB with an analyte so-
lution (10 pmol/μL) was used. The sample spots were air-dried at
room temperature. Ion acceleration voltage was set to 5 kV. Sam-
ples were irradiated by a nitrogen laser at 337 nm. Typically, 100
shots were summed into a single mass spectrum.
Crystal data were obtained on a Bruker SMART 1000, Oxford Dif-
fraction Gemini R CCD diffractometer, and Oxford Diffraction
Xcalibur2 CCD. Data collection: CrysAlis CCD (Oxford Diffraction,
2006). Cell refinement: CrysAlis CCD. Data reduction: CrysAlis RED
(Oxford Diffraction, 2006). The program used to solve the structure:
SHELXS97 (Sheldrick, 1997). The program used to refine the struc-
ture: SHELXL97 (Sheldrick, 1997). Molecular graphics: DIAMOND
(Brandenburg, 1998).[34,35]
Dipolar cycloadditions of methyl 3-(acridin-4-yl)propenoate (4) and
3-(acridin-4-yl)propenamide (6) with activated o,p-substituted
benzonitrile oxides 7a–c (2,4,6-trimethoxy, 2,4,6-trimethyl, 2,6-
dichloro) contrasted with those of 4-(2-styryl)acridine (5). A
detailed NMR analysis of two series of isoxazoline regioisomers,
4-Acr and 5-Acr, allowed a closer insight on the regioselectivity of
these DCs. Correlation found between the regioselectivity and 13C
NMR chemical shifts of the dipolarophile may contribute to explana-
tion of the DC reaction mechanism. Whereas the ester 4 and amide 6
showed a stronger tendency to afford major 5-(acridin-4-yl)-
isoxazoline regioisomers, the phenyl group in the styrylacridine
5
significantly increased the regioselectivity in favor of
4-(acridin-4-yl)-isoxazoline ones. Regarding the dipoles,
2,4,6-trimethoxybenzonitrile oxide was most prone to give the
5-Acr isoxazolines while mesitonitrile oxide strongly preferred
the 4-Acr ones. Unusually high chemical shifts have been ob-
served for isoxazoline H-4, H-5 protons surrounded by aromatic
substituents. The isoxazoline 13c upon hydrolysis underwent an
unexpected transformation to isoxazolones 15c cis and 15c
trans. In the former, a very strong deshielding of acridine pro-
tons close to the C¼O group has been found.
Elemental analysis was performed on a Perkin-Elmer CHN 2400
elemental analyzer.
Synthesis of acridine-4-carbaldehyde (3)
To a stirred suspension of 4-bromomethylacridine (2, 1.00 g,
3.67 mmol) in dried dimethyl sulfoxide (2 mL), a solution that was
prepared by addition of 2-nitropropane (0.393 g, 0.040 mL,
4.41 mmol) to sodium (0.093 g, 4.04 mmol) in dry methanol (2mL)
was added dropwise over 1 h. The reaction mixture changed from
yellow to dark red and became homogenous. After 1 h stirring at
room temperature, the reaction mixture was poured into water
(100mL) and a yellow precipitate that formed was filtered off,
washed with cold water, and dried to give the aldehyde 3 (0.68 g,
89%, 118.0–119.0 °C (n-hexane)[27]).
The data obtained from this series and following one studying
acridin-9-yl dipolarophiles gave the basis for analysis of main fac-
tors influencing the regioselectivity, i.e. polarity of the dipolarophilic
CH¼CH double bond, electron-donor effects of substituents in the
BNO dipoles, and interactions between the aromatic rings in the
target isoxazolines.
Experimental
General information and materials
Synthesis of methyl 3-(acridin-4-yl)propenoate (4)
Reagents were commercial and used without further purification.
Solvents were distilled and dried using standard methods. Melting
points were measured on a Boetius apparatus and are uncorrected.
Thin-layer chromatography (TLC) was carried out on the aluminum
TLC plates coated with silica gel ALUGRAM* SIL G/UV254
(Macherey–Nagel, Germany) and visualized under UV light
(λ = 254 nm). Column chromatography (CC) was performed on
230–400-mesh silica gel (Merck). Preparative thin-layer chromatog-
raphy (PTLC) was made on the glass plates (25x10 cm) coated with
2 mm silica gel layer.
A mixture of a methyl (triphenylphosphoranylidene) acetate
ylide[36] (1.66g, 4.95mmol) and acridin-4-carbaldehyde (3, 1.0g,
4.83 mmol) in dry chloroform (5mL) was stirred overnight at room
temperature. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography (eluent
cyclohexane/acetone, 9:1v/v) and crystallized from ethyl acetate
to give the ester 4 as a pure E isomer.
Yield 530 mg, 42%. Bright yellow solid. Mp 120.0–122.0 °C.
[Found: C 77.40, H 4.86, N 5.19; C17H13NO2 (263.30); requires C
77.55, H 4.98, N 5.34].
1H, 13C, and 2D NMR (DEPT, H,H-COSY, gHSQC, gHMBC, NOESY)
spectra were recorded on a Varian Mercury Plus NMR spectrometer
(400.13 MHz for 1H) in deuteriochloroform or dimethyl sulfoxide-D6
(12c, 13c only) with tetramethylsilane as an internal standard
(0.00ppm) at room temperature. To determine the conversion
and regioselectivity of dipolar cycloadditions, parallel reactions of
the dipolarophile (0.04 mmol) and the dipole (0.12 mmol) in CDCl3
(0.6 mL) were carried out in a sealed NMR tube at room tempera-
ture. The percentage of conversion and the molar ratio of the
regioisomers formed was determined by comparing the integrals
of alkene protons signals and a sum of integrals of isoxazoline H-4
and H-5 signals. It was found, generally, that quantitative ratios of
both regioisomers were constant over the whole reaction course
with a less than 5% NMR integration error.
Synthesis of 4-(2-styryl)acridine (5)
Sodium hydride (60%, 145mg, 6.03 mmol) was added to a solution
of benzyltriphenylphosphonium chloride (1 g, 2.65 mmol) in anhy-
drous tetrahydrofuran (5mL). The solution was cooled below
ꢀ10 °C, stirred for 30 min, an equimolar amount of the aldehyde
3 (500 mg, 2.40 mmol) was added, stirring continued at ꢀ10 °C for
1 h, and at room temperature for next 12h. The solvent was evap-
orated under reduced pressure and the rest was purified by column
chromatography with an eluent cyclohexane/ethyl acetate (5:1v/v)
to obtain the dipolarophile 5. Styrylacridine 5 was obtained as a
pure E isomer.
Mass spectra (MS) were taken on a MALDI-TOF IV instrument
(Shimadzu, Kratos Analytical, England) with a positive matrix-
assisted laser desorption/ionization coupled with in-source decay
Yield 275 mg, 41%. Bright yellow solid. Mp 130.0–131.0 °C.
[Found: C 89.42, H 5.48, N 4.91; C21H15N (281.36) requires C 89.65,
H 5.37, N 4.98].
wileyonlinelibrary.com/journal/mrc
Copyright © 2015 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 17–27

Strong deshielding in aromatic isoxazolines
Synthesis of 3-(acridin-4-yl)propenamide (6)
CC: dichloromethane. Yield 28 mg, 16%. Yellow solid. Mp 209.0–
211.0 °C (acetone). [Found: C 63.69, H 3.70, N 6.06; C24H16Cl2N2O3
(451.31) requires C 63.87, H 3.57, N 6.21]; EI-MS (70 eV): m/z (%)
= 451 (32) [M]+., 438 (100), 313 (44), 285 (50).
4-(Acridin-4-yl)-5-phenyl-3-(2,4,6-trimethoxyphenyl)-4,5-dihydro-
2-isoxazoline (10a)
CC: petrolether/acetone, 10:1. Yield 60 mg, 34%. Yellow solid. Mp
50.0–53.0 °C (acetone/n-hexane). [Found: C 75.70, H 5.22, N 5.78;
C31H26N2O4 (490.56) requires C 75.90, H 5.34, N 5.71]; EI-MS
(70 eV): m/z (%) = 491 (90) [M]+., 476 (36), 387 (100), 179 (12).
5-(Acridin-4-yl)-4-phenyl-3-(2,4,6-trimethoxyphenyl)-4,5-dihydro-
2-isoxazoline (11a)
CC: petrolether/acetone, 10:1. Yield 30 mg, 17%. Yellow solid. Mp
60.0–63.0 °C (acetone/n-hexane). [Found: C 75.99, H 5.46, N 5.57;
C31H26N2O4 (490.56) requires C 75.90, H 5.34, N 5.71].
4-(Acridin-4-yl)-5-phenyl-3-(2,4,6-trimethylphenyl)-4,5-dihydro-2-
isoxazoline (10b)
CC: acetone/n-hexane, 4:1. Yield 100 mg, 63%. Yellow solid. Mp
74.0–76.0 °C (acetone/n-hexane). [Found: C 83.95, H 5.80, N 6.14;
C31H26N2O (442.56) requires C 84.13, H 5.92, N 6.33].
5-(Acridin-4-yl)-4-phenyl-3-(2,4,6-trimethylphenyl)-4,5-dihydro-2-
isoxazoline (11b)
CC: acetone/n-hexane, 4:1. Yield 12 mg, 8%. Yellow solid. Mp
84.0–86.0 °C (acetone/n-hexane). [Found: C 84.27, H 6.05, N 6.40;
C31H26N2O (442.56) requires C 84.13, H 5.92, N 6.33].
4-(Acridin-4-yl)-5-phenyl-3-(2,6-dichlorophenyl)-4,5-dihydro-2-
isoxazoline (10c)
Sodium hydride (60% purity, 0.115 g, 4.82mmol) was added to a so-
lution of amidomethyl triphenylphosphonium chloride (0.858 g,
2.41 mmol) in dry dichloromethane (5mL). The solution was cooled
below 0 °C and stirred for 30 min, then the aldehyde 3 (0.500g,
2.41 mmol) was added, stirring continued at ꢀ10 °C for 1 h and at
room temperature for next 24 h. The solvent was evaporated under
reduced pressure and the residue was purified by column chroma-
tography (cyclohexane/ethyl acetate, 1:4v/v) to give the amide 6 as
a pure E isomer.
Yield 654 mg, 55%. Yellow solid. Mp 250.0–252.0 °C (ethanol).
[Found: C 77.25, H 4.60, N 11.38; C16H12N2O (248.28) requires C
77.40, H 4.87, N 11.28].
General procedure for the synthesis of esters 8a–c, 9a–c, and
phenyl derivatives 10a–c, 11a–c
To a solution of the alkene 4, 5 (100mg, 1 equiv.) in dry chloroform
(4mL), the nitrile oxide 7a–c (3 equiv.) was added. The reaction
mixture was stirred at room temperature (1H NMR monitoring).
The solvent was evaporated under reduced pressure and a solid
was purified by column chromatography and/or preparative
thin-layer chromatography (see the eluent bottom) to give the
corresponding regioisomers.
Methyl 5-(acridin-4-yl)-3-(2,4,6-trimethoxyphenyl)-4,5-dihydro-2-
isoxazoline-4-carboxylate (9a)
CC: dichloromethane. Yield 41 mg, 23%. Yellow solid. Mp 163.0–
165.0 °C (acetone/n-heptane). [Found: C 68.40, H 5.28, N 5.75;
C27H24N2O6 (472.50) requires C 68.63, H 5.12, N 5.93].
Methyl 5-(acridin-4-yl)-3-(3-bromo-2,4,6-trimethoxyphenyl)-4,5-
dihydro-2-isoxazoline-4-carboxylate (9d)
CC: n-heptane/acetone, 4:1. Yield 93mg, 56%. Yellow solid. Mp
220.0–222.0°C (acetone). [Found: C 71.43, H 3.72, N 5.85;
C28H18Cl2N2O (469.37) requires C 71.65, H 3.87, N 5.97]; EI-MS
(70 eV): m/z (%) = 469 (100) [M]+., 438 (84), 433 (11), 363 (15), 313
(53), 298 (83), 285 (51), 110 (8).
Yield 20 mg, 11%. White solid. Mp 209.0–210.0 °C (acetone/
n-heptane). [Found: C 58.58, H 4.39, N 4.84; C27H23BrN2O6 (551.40)
requires C 58.81, H 4.20, N 5.08]; 1H NMR (400 MHz, CDCl3) δH =8.77
(1H, s, H-9′), 8.05 (1H, d, J 8.4 Hz, H-5′), 8.05 (1H, d, J 8.4 Hz, H-3′),
8.00–7.96 (2H, m, H-1′,8′), 7.74 (1H, ddd, J 8.4, 6.4, 1.2 Hz, H-6′),
7.58–7.51 (2H, m, H-2′,7′), 7.21 (1H, d, J 6.8 Hz, H-5), 6.27 (1H, s, H-5′
′), 4.53 (1H, d, J 6.8Hz, H-4), 3.90 (3H, s, OCH3-6′′), 3.81 (3H, s, OCH3),
3.73 (3H, s, OCH3-4′′), 3.72 (3H, s, OCH3-2′′).
5-(Acridin-4-yl)-4-phenyl-3-(2,6-dichlorophenyl)-4,5-dihydro-2-
isoxazoline (11c)
CC: n-heptane/acetone, 4:1. Yield 5 mg, 3%. Yellow solid. Mp
75.0–77.0 °C (acetone).
General procedure for the synthesis of carboxamides 12a–c,
13a–c
Methyl 4-(acridin-4-yl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-2-isoxazoline-
5-carboxylate (8b)
To a solution of 3-(acridin-4-yl)propenamide (6) (100mg, 1 equiv.)
in dry chloroform (4mL), the nitrile oxide 7a–c (3 equiv.) was added.
The reaction mixture was stirred at room temperature (1H NMR
monitoring). The solvent was evaporated under reduced pressure
and the purification was carried out by column chromatography
and/or preparative thin-layer chromatography (see the eluent bot-
tom) to give the corresponding solid regioisomers.
4-(Acridin-4-yl)-3-(2,4,6-trimethoxyphenyl)-4,5-dihydro-1,2-
oxazol-5-carboxamide (12a)
CC: toluene/acetone, 1:1. Yield 20 mg, 11%. Yellow solid. Mp
268.0–269.0°C (ethanol). [Found: C 68.40, H 5.22, N 9.30;
C26H23N3O5 (457.49) requires C 68.26, H 5.07, N 9.18]; ESI-MS: m/z
458 [M]+..
5-(Acridin-4-yl)-3-(2,4,6-trimethoxyphenyl)-4,5-dihydro-1,2-
oxazol-4-carboxamide (13a)
CC: toluene/acetone, 1:1. Yield 27 mg, 15%. Yellow solid. Mp
199.0–200.0°C (ethanol). [Found: C 68.43, H 4.90, N 8.99;
C26H23N3O5 (457.49) requires C 68.26, H 5.07, N 9.18]; ESI-MS: m/z
458 [M]+..
CC: n-heptane/acetone, 4:1. Yield 71 mg, 44%. Yellow crystals. Mp
59.0–60.0 °C (ethanol). [Found: C 76.31, H 5.48, N 6.45; C27H24N2O3
(424.50) requires C 76.40, H 5.70, N 6.60]; EI-MS (70 eV): m/z (%) = 463
(8) [M + K]+., 447 (36) [M + Na]+., 425 (100) [M]+., 409 (88), 367 (10),
340 (43), 305 (8), 282 (20), 265 (8), 200 (16), 179 (60), 156 (12), 139 (24).
Methyl 5-(acridin-4-yl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-2-isoxazoline-4-
carboxylate (9b)
CC: n-heptane/acetone, 4:1. Yield 51 mg, 32%. Yellow crystals. Mp
168.0–170.0 °C (ethanol). [Found: C 76.58, H 5.68, N 6.68; C27H24N2O3
(424.50) requires C 76.40, H 5.70, N 6.60]; EI-MS (70 eV): m/z (%) = 425
(100) [M]+., 407 (14), 348 (14), 295 (14), 210 (12).
Methyl 4-(acridin-4-yl)-3-(2,6-dichlorophenyl)-4,5-dihydro-2-isoxazoline-
5-carboxylate (8c)
CC: dichloromethane. Yield 29 mg, 17%. Yellow solids. Mp 190.0–
191.0 °C (acetone). [Found: C 63.64, H 3.30, N 6.04; C24H16Cl2N2O3
(451.31) requires C 63.87, H 3.57, N 6.21]; EI-MS (70eV): m/z (%)
= 451 (86) [M]+., 439 (66), 394 (74), 392 (86), 363 (33), 313 (47), 285
(43), 280 (100), 257 (6), 222 (56), 194 (6).
Methyl 5-(acridin-4-yl)-3-(2,6-dichlorophenyl)-4,5-dihydro-2-isoxazoline-
4-carboxylate (9c)
4-(Acridin-4-yl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-1,2-oxazol-
5-carboxamide (12b)
Magn. Reson. Chem. 2016, 17–27
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

L. U. Maľučká et al.
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5-(Acridin-4-yl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-1,2-oxazol-
4-carboxamide (13b)
CC: ethyl acetate/dichloromethane/hexsol, 10:5:4. Yield 13 mg,
8%. Yellow solid. Mp 285.0–286.0°C (ethanol). [Found: C 76.01, H
5.94, N 10.03; C26H23N3O2 (409.49) requires C 76.26, H 5.66, N 10.26].
4-(Acridin-4-yl)-3-(2,6-dichlorophenyl)-4,5-dihydro-1,2-oxazol-
5-carboxamide (12c)
CC: ethyl acetate/chloroform,1:8. Yield 32 mg, 18%. Yellow solid. Mp
245.0–246.0 °C (ethanol). [Found: C 63.49, H 3.20, N 9.33; C23H15Cl2N3O2
(436.30) requires C 63.32, H 3.47, N 9.63]; ESI-MS: m/z 437 [M]+..
5-(Acridin-4-yl)-3-(2,6-dichlorophenyl)-4,5-dihydro-1,2-oxazol-4-
carboxamide (13c)
CC: ethyl acetate/chloroform, 1:8. Yield 20 mg, 11%. Yellow solid. Mp
271.0–272.0 °C (ethanol). [Found: C 63.22, H 3.57, N 9.47; C23H15Cl2N3O2
(436.30) requires C 63.32, H 3.47, N 9.63]; ESI-MS: m/z 437 [M]+..
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To an ethanolic solution (5 mL) of the isoxazoline 13c (100 mg,
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for 4 h (TLC, cyclohexane/ethyl acetate, 1:1). The reaction mixture was
cooled, the solvent was evaporated and water (10 mL) was added to
the residue. The solution was acidified (HCl 3:1), a precipitate that
formed was extracted with diethyl ether (2 × 10 mL). Combined
organic layers were dried over MgSO4, filtered, and the solvent was
evaporated in vacuo. Crystallization from methanol gave a mixture
of orange crystals of the oxazolones 15c cis and 15c trans (85 mg,
88%). Mp 201.0–204.0 °C. [Found C 65.67, H 2.72, N 6.53;
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Crystallographic data
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Crystallographic data of 9b (CCDC 864812), and 15c cis (CCDC
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Financial support from the Slovak Grant Agency VEGA (grant no.
1/0672/11) and the Slovak State NMR Program (grant no.
2003SP200280203) is gratefully acknowledged. Authors also thank
to Assoc. Prof. Dr. Ivan Potočňák, UPJŠ Kosice, Faculty of Science, In-
stitute of Chemistry, Košice, Slovakia for the crystallographic analy-
sis of the isoxazolone 15c. Dr. Slávka Bekešová from the Institute of
Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia is
thanked for the measurement of the mass spectra.
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