1,3-dipolar cycloaddition reaction of nitrile oxides revisited - Unusual side products characterized by 2d NMR

Article abstract of DOI:10.1002/jhet.1792

Cycloaddition of (4-trifluoromethyl)phenylnitrile oxide to N-(4-methoxyphenyl)acrylamide afforded bicyclic tetrahydro-oxazolo-(3,2-b)[1,3] oxazine-2-carboxamide derivative in result of N-acylation of the initially formed cycloadduct by the dipolarophile.

Full text of DOI:10.1002/jhet.1792

572
1,3-Dipolar Cycloaddition Reaction of Nitrile Oxides Revisited—Unusual
Vol 51
Side Products Characterized by 2D NMR
*
M. Gucma and W. M. Gołębiewski
Institute of Industrial Organic Chemistry, Annopol 03-236 Warsaw, Poland
*
E-mail: golebiewski@ipo.waw.pl
Received June 18, 2012
DOI 10.1002/jhet.1792
Published online 25 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
CF3
O
O
O
O
N
O
O
N
NH
8
2
3
6
5
NH
+
Catalyst
O
CH3
NH
2''
3''
R
N
O
N
2'
3'
OCH3
OCH3
O
CF3
CF3
OCH3
R = H
R = CH3
CF3
Cycloaddition of (4-trifluoromethyl)phenylnitrile oxide to N-(4-methoxyphenyl)acrylamide afforded
bicyclic tetrahydro-oxazolo-(3,2-b)[1,3]oxazine-2-carboxamide derivative in result of N-acylation of the
initially formed cycloadduct by the dipolarophile. 2:1 Cycloaddition of the same dipole to N-(4-methoxyphenyl)
crotonamide yielded dihydro[1,2]-oxazolo[2,3-d][1,2,4]oxadiazole-7-carboxamide because of the second
addition of the dipole to the C═N bond of the first formed 2-isoxazoline compound. Structures of the
products have been elucidated by an extensive application of 1D and 2D NMR spectroscopy.
J. Heterocyclic Chem., 51, 572 (2014).
INTRODUCTION
yield and purity of the desired substances. There is a
relative shortage of data concerning side products in the
1,3-dipolar cycloaddition reaction of nitrile oxides. The
only reported side products concern dimerization and
other transformations of the dipoles.
Most nitrile oxides are unstable, some of them are
explosive. In the absence of dipolarophiles, nitrile oxides
A easily dimerize at ambient and lower temperatures to
give furoxans (1,2,5-oxadiazole 2-oxides) B, which are
products of the kinetical control [7]. The furoxans are
not dead-end side products with regard to cycloaddition
but can afford back nitrile oxides by thermolytic cyclore-
version [8].
DFT calculations (B3LYP/6.31G*) for acetonitrile
oxide and p-chlorobenzonitrile oxide have demonstrated
that dimerizations were two-step processes involving
dinitroso alkene intermediates, and the limiting stage was
C–C bond formation [7].
Dimerization routes are shown in Scheme 1 [9]. Under
basic (trimethylamine, triethylamine, or pyridine) [10–12]
or acidic conditions (excess of BF3) [13,14], dimerizations
can give also 1,2,4-oxadiazole 4-oxides C more thermody-
namically stable than furoxans or 1,4,2,5-dioxadiazines D[7],
which are usually regarded as minor products [9]. Isocya-
nates E can be formed only at elevated temperatures; this is
the main reaction of sterically stabilized nitrile oxides.
2-Isoxazolines are versatile intermediates in the synthesis
of many complex biologically active compounds that can
be easily transformed by reductive N–O bond cleavage to
several important compounds such as b-hydroxy ketones,
b-hydroxy esters, a,b-unsaturated carbonyl compounds, or
iminoketones [1]. The most useful method of 2-isoxazoline
preparation is the 1,3-dipolar cycloaddition reaction of
nitrile oxides to alkenes [2]. The nitrile oxides can be formed
either by Huisgen method from aldoximes by chlorination
and base-induced dehydrochlorination [2] or by Mukayama
method from primary nitro compounds and phenyl
isocyanates [3]. Diastereoselective and enantioselective
cycloadditions have been studied extensively with applica-
tion of optically active substrates and chiral catalysts [4].
Several obstacles such as propensity of nitrile oxides to
dimerize and form unreactive complexes with metal catalysts
as well as interaction of tertiary amines used to generate
nitrile oxides with Lewis acids had to be overcome [5].
Coordination of amine bases to Lewis acid could be
circumvented by, for example, application of Amberlyst
21, a strongly basic ion exchange resin, as a base to generate
nitrile oxides from hydroximinoyl chlorides [6].
In synthesizing biologically active compounds, it is
important to identify the observed side products and
competitive reactions pathways negatively influencing
© 2013 HeteroCorporation

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Unusual Side Products in 1,3-Dipolar Cycloaddition Reaction
573
Scheme 1. Dimerization and isomerization of nitrile oxides.
Figure 1. Minor side products shown with selected HMBC correlations.
structure C, then at least three multiplets would be expected.
The same NMR behavior was observed for the other two
products—unsubstituted benzonitrile oxide dimer 5a and
(4-isopropyl)phenylnitrile oxide dimer 5c.
We carried out many cycloaddition reactions of 21
nitrile oxides to two unsaturated alcohols, 14 esters, and
12 amides mediated by complexes of lanthanides and other
Lewis acids with chiral ligands obtaining products with
variable regioselectivities and enantioselectivities up to
99%, including several biologically active carboxamides
[15–18]. Herein, we wish to present the results of a
thorough analysis of the reaction mixtures that showed
the presence of several side products, some of which were
quite unexpected and interesting from the synthetic point
of view. It led to the discovery of novel 2-isoxazoline
N-acylation by N-alkenylamide.
The first new side products observed by us were
5-chloromethyl-3-aryl-4,5-dihydro-isoxazoles 6a,b (Fig. 1)
formed in the 1,3-dipolar cycloaddition reaction of the
corresponding benzonitrile oxides with different dipolaro-
philes run in anhydrous methylene chloride with Amberlyst
(Rohm and Haas, Germany) 21 as a base to generate dipoles
from hydroximinochlorides. Structures of both products
were established by spectral methods. High-resolution
(HR) EIMS of 6a, isolated in cycloaddition of 1a dipole,
35
showed the composition C10H10ClNO. The 1H NMR
spectrum exhibited five aromatic protons, one proton mul-
tiplet at d 4.99, two one-proton geminally coupled doublets
at d 3.72 and 3.58 correlated in HMBC spectrum with
dC79.8 and 38.6 signals, and two one proton geminally cou-
pled doublets at d 3.50 and 3.35. This data indicated a 3,5-di-
substituted 2-isoxazoline system with a C5-CH2Cl side
group and were confirmed by HSQC and COSY spectra.
The higher molecular weight analogue 6b, isolated in
cycloadditions of 1b dipole, showed the composition
RESULTS AND DISCUSSION
We have recently examined the cycloaddition reaction
of benzonitrile oxides 1a–c with a,b-unsaturated amides
2a,b and have obtained products 3–4 (Scheme 2).
All the reaction mixtures contained, similarly as in our
previous studies, small amounts of nitrile oxide dimers
(2–3%) that were isolated and analyzed by spectral methods.
Our results showed, on the contrary to the literature data,
that they are not furoxans, but rather 1,4.2.5-dioxadiazines
35
1
C H9F3ClNO in HRMS. The H and 13C NMR spectra
11
differed only in the aromatic region, and structure of the
product was established similarly as previously described.
Both compounds could be formed by the cycloaddition
of nitrile oxide to allylic chloride (an unknown artifact).
Isoxazoline 6a was obtained before as the main product
in this type of reaction [19].
1
5a–c (Fig. 1). H NMR spectrum of (4-trifluoromethyl)
phenyl nitrile oxide dimer shows only two multiplets
corresponding to the symmetrical 2,4-di(4-trifluoromethyl)
phenyl)-1,4,2,5-dioxadiazine (5b). If this nitrile oxide dimer
had a furoxan structure B or 1,2,4-oxadiazole 4-oxide
Scheme 2. Cycloaddition of nitrile oxides to unsaturated amides, the main products.
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The second side product, isolated in cycloaddition
isoxazoline H5 and H4 signals. Field desorption mass
spectroscopy (FD-MS) showed the molecular ion at m/z
565, corresponding to an increase of molecular weight
by 187 mu compared with the carboxamide 4b. This
result indicated an addition of the second dipole unit to
the isoxazoline 4b C═N bond and rationalized an upfield
shift of H2 and H3 peaks of the side product 8 (Scheme 3).
19F NMR spectroscopy demonstrated the presence of two
fluorine signals at ꢀ63.1 and ꢀ63.6 ppm, and HR electro-
spray mass spectroscopy exhibited the quasi-molecular
formula as C27H21N3O4F6Na. HMBC-15N spectroscopy
proved disappearance of N signal at ꢀ2.7 ppm having
cross peak with H4 of isoxazoline 4b and appearance of
a new N signal of isoxazolidine 8 at ꢀ66.2 ppm correlated
with CH3 protons. The COSY, HSQC, and HMBC correla-
tions confirmed the structure of 8 and enabled the complete
of 1a dipole, was 5-methyl-3-(4-trifluoromethyl)phenyl-
4,5-dihydroisoxazole (7) (Fig. 1). HRMS showed the
composition C11H10F3NO. The 1H NMR spectrum exhib-
ited a typical pattern of 3,5-disubstituted 2-isoxazoline
system, differing from spectra of compounds 6a,b in a
larger separation of H4 signals (0.51 ppm compared with
0.15 ppm in 6a,b), and the presence of C5 methyl group
was proved by the HSQC correlation of a three H triplet
at d 1.39 with C6 triplet at d 21.2 in DEPT spectrum.
Compound 7 could be formed in the 1,3-dipolar cyclo-
addition reaction of (4-trifluoromethyl)phenyl nitrile oxide
1b with 1-propene. Careful GC–MS analysis of the
dichloromethane eluate from Amberlyst 21-filled column
showed the presence of this alkene. This result indicated
a drawback of the method used to generate nitrile oxides.
The third interesting new side product 8 was isolated in
the cycloaddition reaction of (4-trifluoromethyl)phenylnitrile
oxide (1b) with N-(4-methoxyphenyl)crotonamide (2b)
mediated by the complex of ytterbium triflate with
1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (Scheme 3).
There was neither chiral induction nor regioselectivity in this
reaction, on the contrary to the other catalytic systems with
different ligands elaborated by us [18], but the overall yield
of two regioisomers 3b, 4b formed in 1:1 ratio was high
(90%). The 1H NMR spectrum of the side product 8 showed
a resemblance to the spectrum of N-(4-methoxyphenyl)-3-(4-
trifluoromethylphenyl)-4,5-dihydroisoxazole-4-carboxamide
(4b). The difference was the presence of two additional
low-field two-proton doublets and an upfield shift of the
1
assignment of H and 13C NMR spectra (see Experimental
part). Strong NOE between H7 and H20 protons indicated
their cis relationship; b-orientation of the C7a aromatic
ring was assumed on the basis of molecular modeling
(the PM3 method).
The recently reported cycloaddition reaction of phosphonyl
nitrile oxides and acrylonitrile gave a similar 2:1 cycloaddition
product with the trans relationship of C7/C7a substituents
[20]. Similar cycloaddition of 4-alkoxyphenylnitrile oxide
to vinylacetic acid afforded exclusively a bicyclic 2:1
adduct because of the low dipolarophilic reactivity of
the vinylacetic acid in comparison with the initially
formed 3,5-disubstituted isoxazoline. Configuration of
the product was not established [21].
Scheme 3. Formation of the side product 8. Selected NOEs, COSYs and HMBC correlations observed in 8.
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The next interesting new side product was a bicyclic
amide (10) formed in the reaction of (4-trifluoromethyl)
phenylnitrile oxide (1b) with N-(4-methoxyphenyl)acrylamide
(2a) (Scheme 4). 1H NMR spectrum contained all the signals
of the expected cycloaddition product, N-(4-methoxyphenyl)-
3-(4-trifluoromethyl)phenyl-4,5-dihydroisoxazole-5-carbox-
amide (3a), and additionally a two-proton triplet at 2.73 ppm,
and a two-proton multiplet at 4.50 ppm. The latter signal
collapsed to a triplet with the same coupling (6.1 Hz) as
shown by the 2.73 ppm triplet, when the spectrum was
recorded in CD2Cl2. The 2D NMR COSY spectrum con-
firmed coupling of these signals as well as the presence of
the isoxazolidine system (coupling of H2 with H3 protons).
dihedral angle of 32ꢁ only using modified Karplus equation
[23]. Large H2/H3A J of 11.8 Hz indicated an antirelation-
ship of these protons. The molecular modeling indicated
the boat conformation of six-membered heterocyclic ring
after energy optimization using PM3 semi-empirical
method. It could be favored because of the diminished
bond eclipsing in result of nitrogen atom presence and lack
of “flagpole” position atoms at either end of the molecule,
occupied by the carbonyl and oxygen atom. Unfortunately,
we were unable to determine structure of compound 10 by
X-ray crystallography, because of lack of an appropriate
crystal form. However, chemical equivalence of H5 and
H6 protons and small value of vicinal H5/H6 coupling could
indicate rather a rapid equilibrium of several different
conformations including a boat, twist-boat, and half-chair,
1
One bond H–13C correlation (HSQC) demonstrated cross
peaks of H 4.50 multiplet and H 2.73 triplet with carbon
61.5 and 35.6 ppm signals, respectively. The position of the
first carbon peak indicated a proximity of an ether function.
The HMBC spectrum showed the presence of the second
carbonyl group at d 167.4 exhibiting the cross peaks with
H 2.73 and 4.50 ppm signals. IR spectrum confirmed the
presence of two carbonyl functions. The first group absorbed
at 1668 cmꢀ1, a typical value for secondary acyclic amides.
The second peak at 1749 cmꢀ1 could be ascribed to ring-
fused g-lactams or a,b-unsaturated d-lactones [22]. These
data suggested the presence of isoxazoline C═N bond
annelated six-membered heterocyclic ring and rather a
d-lactam structure. The EI-MS spectrum showed a molecular
ion of 436 mu and HR ESI-MS exhibited the quasi-molecular
formula as C21H19F3N2O5Na (Scheme 4).
1
at the NMR time scale. Low-temperature H NMR spectra
should shed some light on this topic. In the quest to find
1
different “frozen” conformations, we have run H NMR
spectra in deuterioacetone at ꢀ60 to 90ꢁC. Unexpectedly,
the only change was a lowered H5/H6 coupling constant
from 6.1 Hz at RT to 5.0 Hz at ꢀ90ꢁC and a low-field shift
of protons in the vicinity of carbonyl groups. This d shift
was particularly pronounced for NH (0.64ppm). Minor
low-field d shifts were observed for H2 (0.12) and H3A
(0.09). This result could be explained by an association of
the diamide 10 with the solvent acetone. Such intermolecu-
lar interactions of carbonyl compounds are well known [24].
Aggregation of acetone and its derivatives studied by the
static dielectric method has recently shown a parallel dipole
alignment [25]. In our molecule, the carbonyl dipoles are
perpendicular to the long molecular axis, and this would
favor a head-to-tail association leading to an increased
polarization of both carbonyl groups and a downfield shift
of the proximate protons. This aggregation is important
already at RT as witnessed by the low-field position of the
NH signal at 9.1 ppm in acetone compared with position
in CD2Cl2 at 7.24 ppm. The observed large negative temper-
ature effect on the aggregation has been recorded in the
literature [26,27]. The temperature effect on coupling
constant could indicate a conformational bias toward a
flexible boat at lower temperatures [28].
Stereochemistry of this adduct was examined with help
1
of H NMR spectroscopy. The striking feature was the
chemical equivalence at room temperature spectra of H5
and H6 peaks and a small value of vicinal H5/H6 coupling
constant of 6.1 Hz only, not compatible with a rigid chair
conformation, where large diaxial coupling constant would
be expected for one proton pair. This value of J is low even
after accounting for the effect of electronegative atoms
lowering the coupling constant and corresponds to a
Scheme 4. Presumed formation of the side product 10.
Further information concerning the spatial structure of
the product was provided by the 1H NOESY spectrum that
unexpectedly showed strong NOE of NH proton with H-6
signal. Another diagnostic NOE was observed for upfield
H3A and aromatic H20/H60 signals. The correlations
indicate spatial proximity of these protons and are shown
in Figure 2, displaying one of possible conformations of
10 with cis ring fusion and an envelope conformation of
the isoxazolidine ring.
Compound 10 could be envisaged as arising from
transformations of a 1:2 adduct. When an experiment was
carried out in which a threefold excess of the dipolarophile
2a was applied, the main product was, as expected, the
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Figure 3. Biologically active isoxazolidino[3,2-b]benzooxazin-9-ones.
were modified. It originated from the coupling of two
N-(4-methoxyphenyl)acrylamide units with (4-trifluoromethyl)
benzonitrile oxide (1b). Its formation constitutes the
first example of 2-isoxazoline derivative N-acylation by
N-alkenylamide. Preparation of 10 may be considered as an
alternative approach to the synthesis of the known valuable
anti-inflammatory compounds such as 11. The other
unusual novel product –arylo-dihydro[1,2]oxazolo[2,3-d]
[1,2,4]oxadiazole-7-carboxamide 8 derivative was formed
by successive cycloaddition of two (1b) dipole moieties with
one dipolarophile unit. Further research is in progress to find
the scope of the reactions and to analyze the biological
activity of the new products.
Figure 2. Selected NOEs, COSYs, and HMBC correlations observed in
the favored conformation of 10.
bicyclic derivative 10 isolated in 65% yield. The
suggested reaction pathway could involve isoxazoline 3a
N-acylation with the amide 2a followed by an attack
of the nucleophilic water molecule on the intermediate
ion pair 9a and regioselective Michael-type addition of
hydroxy group of 9b to carbon–carbon double bond.
Several literature examples are available of amides as
acylation agents. N-acylpyrroles are active acylation
agents in reactions with different nucleophiles [29]. N-
acylbenzotriazoles are used to efficiently convert Wang
resin-linked amines into primary, secondary, and tertiary
amides [30]. A twisted amide, 3-pivaloyl-1,3-thiazolidine-2-
thione, was a selective acylating agent for diols under
neutral conditions [31]. To the best of our knowledge, it
is the first example of 2-isoxazoline adduct acylation by
the dipolarophile of an N-alkenyl amide type.
A literature search of the isoxazolo-oxazinone systems
has turned our attention to the related structure of 3,3a-
dihydro-2H,9H-isoxazolo[3,2-b]benzooxazin-9-ones (11)
(Fig. 3) that exhibited good anti-inflammatory activity,
low toxicity, and virtually no gastric irritation [32]. Our
method of synthesis could provide an alternative excess
to the analogues of this valuable heterocyclic system.
EXPERIMENTAL
Reagent grade chemicals were used without further purification
unless otherwise noted. Elemental analyses were performed on Ele-
mentar Vario (Warsaw, Poland) EL III apparatus. Spectra were
obtained as follows: IR spectra on JASCO (Warsaw, Poland)
FTIR-420 spectrometer; 1H NMR spectra on Varian (Warsaw,
Poland) 200 UNITY plus-200, Varian 500 UNITY plus-500, and
Varian VNMRS 600 spectrometers in deuterated chloroform or
acetone using TMS as internal standard; EI mass spectra on AMD
M-40, ESI mass spectra on LCT (Micromass, Warsaw, Poland);
and FD mass spectra on GCT Premier. Flash chromatography was
carried out using silica gel S 230-400 mesh (Merck, Darmstadt,
Germany). Hydroximinoyl acid chlorides were prepared from the
corresponding aryl aldehyde oximes and NCS in DMF [33].
Typical procedure for the cycloaddition of nitrile oxides to
unsaturated amides.
A mixture of (+)-(4,6-benzylidene)
methyl-a-D-glucopyranoside (1.0 mmol) and Yb(OTf)3 (1.0 mmol)
in dry dichloromethane was stirred at RT for 30 min. Dipolarophile
N-(4-methoxyphenyl)acrylamide) (2a) (1 mmol) was added
dropwise followed by a solution of the dipole in the same
solvent generated by passing a hydroximinoyl chloride solution
(1.3 mmol) through a column of Amberlyst 21 over 20–30 min.
The solution was stirred at RT for about 19 h, water was added
to quench the reaction, the reaction mixture was extracted with
a brine and dried (Na2SO4), and the crude product obtained
after evaporation of the solvent in vacuo was purified by
flash column chromatography on silica gel using gradient of
hexanes–ethyl acetate mixtures as an eluent.
CONCLUSION
A careful analysis of reaction mixtures obtained in
the 1,3-dipolar cycloaddition reaction of nitrile oxides to
unsaturated amides revealed the presence of several side
products. The most interesting derivative N-(4-methoxyphe-
nyl)-7-oxo-3a-[4-(trifluoromethyl)phenyl]tetrahydro-2H,5H-
[1,2]oxazolo[3,2-b][1,3]oxazine-2-carboxamide (10) could
be obtained as the main product when reaction conditions
N-(4-Methoxyphenyl)-3-(4-trifluoromethylphenyl)-4,5-
dihydroisoxazole-5-carboxamide (3a).
It was obtained in
60% yield [18] as a wax.
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N-(4-Methoxyphenyl)-4-methyl-3-(4-trifluoromethylphenyl)-
4,5-dihydroisoxazole-5-carboxamide (3b) [18]. It was obtained
in 45% yield as a wax. 1H NMR (acetone, 200 MHz) d: 9.13
(bs, 1H, NH), 8.03 (d, J = 8.4 Hz, 2H, H60, H20), 7.82 (d,
J = 8.4 Hz, 2H, H50, H30) 7.68 (d, J = 9.1Hz, 2H, H00, H600), 6,87
(d, J = 9.1 Hz, 2H, H300, H500), 4.94 (d, J = 4.2 Hz, 1H, H5), 4.28
(qd, J = 7.2: 4.2 Hz, 1H, H4), 3.76 (s, 3H, CH3O), 1.43 (d,
J = 7.2 Hz, 3H, CH3); 15N NMR (acetone, 600 MHz from
HMBC) d: ꢀ11.2 (s, N2), ꢀ257.2 (d, J = ꢀ100 Hz, HNC═O);
HR ESI-MS Calcd for C19H17N2O3F3Na 401.1089, found
(dd, J = 11.5; 7.5 Hz, 1H, H6b), 3.52 (dd, J = 17.0; 10.5 Hz,
1H, H4a), 3.37 (dd, J = 17.0; 6.8 Hz, 1H, H4b); 13C NMR
(50.3 MHz, CDCl3) d: 155.4 (C3), 132.7 (C10), 127.8 (q,
J = 18.5 Hz, C40), 127.2 (C60, C20, 2C), 126.0 (q, J = 4.0 Hz,
2C, C30, C50), 80.5 (C5), 44.9 (C4), 38.3 (C6); 19F NMR
(471 MHz, CDCl3) d: ꢀ63.3; EIMS m/z 263 (M+, 40), 244
(M+ ꢀ F, 10), 214 (M+ ꢀ CH2Cl, 86), 186 (M+ ꢀ CH2Cl–
C2H4, 100); HRMS Calcd for C11H9NOClF3 263.0325,
found 263.0316.
5-Methyl-3-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole
(7). It was obtained as an oil in 2–10% yield. IR (KBr) n: 2925,
2854, 1619, 1598, 1562, 1490, 1457, 1432, 1411, 1380, 1330,
1169, 1129, 1073, 1034, 970, 918, 909, 848, 838, 810, 770,
401.1077.
N-(4-Methoxyphenyl)-3-(4-isopropylphenyl)-4-methyl-4,5-
dihydroisoxazole-5-carboxamide (3c). It was obtained as a
white-brownish semisolid in 8% yield [18].
740, 601 cmꢀ1 1H NMR (acetone-d6, 600 MHz) d: 7.91 (d,
;
J = 8.2 Hz, 2H, H50, H30), 7.78 (d, J = 8.2 Hz, 2H, H60, H20),
4.91 (m, 1H, H5), 3.58 (dd, J = 16.7; 10.3 Hz, 1H, H4a), 3.07
(dd, J = 16.7; 8.3 Hz, 1H, H4b), 1.39 (d, J = 6.3 Hz, 3H, H3C);
13C NMR (151 MHz, acetone-d6, from HMBC) d: 156.3 (C3)
(H20, H60, H4a, H4b), 135.2 (C40) (H50, H30), 131.4 (C10) (H20,
H60), 127.9 (C60, C20) (H30, H50, H20, H60), 126.4 (C30, C50)
(H60, H20, H50, H30), 124.2 (CF3) (H30, H60), 79.0 (C5) (H4a,
H4b, H3C), 41.4 (C4) (H3C), 21.1 (CH3) (H4a, H4b); 19F NMR
(471 MHz, CDCl3) d: ꢀ63.25; 15N NMR (600MHz, acetone-d6,
HMBC) d: ꢀ6.7 (N2) (H4a, H4b); ESI-MS m/z 252 (M+ + Na),
230 (M+ + H); HRMS: Calcd for C11H11NOF3 230.0793, found
230.0802.
N-(4-Methoxyphenyl)-5-methyl-3-(4-trifluoromethylphenyl)-
4,5-dihydroisoxazole-4-carboxamide (4b). It was obtained
in 45% yield as a wax. 1H NMR (acetone, 600 MHz) d: 9.68
(s, 1H, NH), 7.94 (d, J = 8.2 Hz, 2H, H50, H30), 7.75 (d,
J = 8,2 Hz, 2H, H20, H60), 7.52 (d, J = 9.0 Hz, 2H, H200, H600),
6.86 (d, J = 9.0 Hz, 2H, H500, H300), 5.08 (qd, J = 7.0; 6.6 Hz,
1H, H5), 4.46 (d, J = 7.0 Hz, 1H, H4), 3,75 (s, 3H, CH3O),
1.51 (d, J = 6.6 Hz, 3H, CH3); 15N NMR (acetone, 600 MHz
from HMBC) d: ꢀ2,7 (s, N2) (H4), ꢀ249.2 (d, J = ꢀ100 Hz,
HNC═O) (HN, H200, H600).
N-(4-Methoxyphenyl)-3-(4-isopropylphenyl)-5-methyl-4,5-
dihydroisoxazole-4-carboxamide (4c). It was obtained as a
yellowish semisolid in 32% yield [18].
3,6-Diphenyl-1,4,2,5-dioxadiazine (5a). It was obtained as
a brownish wax. IR (KBr) 3075, 1595, 1575, 1502, 1421, 774,
693, 655; 1H NMR (CDCl3, 200 MHz) d: 7.50 (m, 4H), 7.45
(m, 6H).
3-[(4-(Trifluoromethyl)phenyl]-N-(4-methoxyphenyl)-6-methyl-
7a-[4-(trifluoromethyl)phenyl]-7,7a-dihydro-6H-[1,2]oxazolo
[2,3-d][1,2,4]oxadiazole-7-carboxamide (8). It was obtained in
7% yield as a wax. IR (KBr) n: 2940, 2927, 2840, 1666, 1620,
1601, 1513, 1460, 1413, 1325, 1300, 1245, 1170, 1131, 1068,
1020, 910, 860, 840, 801, 780, 700, 678, 605cmꢀ1 1H NMR
.
3,6-Bis[4-(trifluoromethyl)phenyl]-1,4,2,5-dioxadiazine
(acetone-d6, 600 MHz) d: 8.98 (s, 1H, NH), 8.16 (d, J = 8.1 Hz,
2H, H200, H600), 7.97 (d, J = 8.3 Hz, 2H, H30, H50), 7.90 (d,
J = 8.1Hz, 2H, H300, H500), 7.86 (d, J = 8.3 Hz, 2H, H20, H60),
7.49 (dd, J = 9.1; 2.8Hz, 2H, H2000, H6000), 6.89 (dd, J = 9.1;
2.8 Hz, 2H, H3000, H5000), 4.62 (dq, J = 10.4; 5.9 Hz, 1H, H6), 3.77
(s, 3H, H3CO), 3.60 (d, J = 10.4 Hz, 1H, H7), 1.38 (d, J = 5.9 Hz,
3H, H3C); 13C NMR (acetone-d6, 125 MHz, from HMBC) d:
161.9 (C═O), 157.4 (C3), 156.5 (C4000), 143.1 (C10), 132.8 (C100),
(5b).It was obtained as a brownish wax. IR (KBr) 1595, 1407,
1327, 1133, 845; 1H NMR (CDCl3, 500 MHz) d: 7.76 (d,
J = 8.3 Hz, 2H, H20, H60), 7.65 (d, J = 8.9 Hz, 2H, H50, H30).
3,6-Bis[4-(propan-2-yl)phenyl]-1,4,2,5-dioxadiazine (5c).
It was obtained as a brownish wax. 1H NMR (CDCl3,
200 MHz) d: 7.48 (dd, J = 8.5; 2.0 Hz, 2H, H20, H60), 7.30
(d, J = 8.5 Hz, 2H, H50, H30), 2,9 (m, 1H, HC(CH3)2),1.28
(d, J = 6.8 Hz, H3CCH), 1.27 (d, J = 7.2 Hz, H3CCH);
EIMS m/z 322 (M+, 6), 161 (i-Pr-C6H4C═NO, 34), 120
(i-PrC6H4 + H, 100).
00
132.1 (C1000), 131.5 (C40), 128.7 (CF3 ), 128.2 (C200, C600), 127.3
0
(CF3 ), 126.7 (C20, C60), 126.2 (C300, C500), 125.7 (C30, C50),
125.0 (C400), 121.5 (C2000, C6000), 113.7 (C3000, C5000), 107.8 (C7a),
78.7 (C6), 69.0 (C7), 54.0 (CH3O), 14.7 (CH3); 19F NMR
(acetone-d6, 470MHz) d: ꢀ63.6, ꢀ63.1; 15N NMR (600 MHz,
acetone-d6, from HMBC) d: ꢀ247.5 (HNC═O, J15N–1H = 100 Hz)
(HN, H2000, H6000), ꢀ66.2; FD-MS m/z 565 (M+, 27), 531 (34),
358 (74), 207(60), 173 (58); HRMS: Calcd for C27H21N3O4F6Na
588.1334, found 588.1346.
5-(Chloromethyl)-3-phenyl-4,5-dihydro-1,2-oxazole (6a). It
was obtained as a brownish wax. IR (KBr) n: 2940, 2924, 2854,
1597, 1560, 1490, 1445, 1375, 1355, 1266, 1073, 1000, 911,
892, 812, 762, 739, 692, 546 cmꢀ1
;
1H NMR (CDCl3,
600 MHz) d: 7.68 (m, 2H, H20, H60), 7.42 (m, 3H, H50, H40,
H30), 4.99 (m, 1H, H5), 3.72 (dd, J = 11.3; 4.3 Hz, 1H, H6a),
3.58 (dd, J = 11.3; 7.5 Hz, 1H, H6b), 3.50 (dd, J = 16.9; 10.5 Hz,
1H, H4a), 3.35 (dd, J = 16.9; 6.4 Hz, 1H, H4b); 13C NMR
(126 MHz, CDCl3) d: 156.1 (C3), 130.3 (C10), 129.0 (C40),
128.7 (C60, C20), 126.7 (C30, C50), 79.7 (C5), 44.8 (C4), 38.5
(C6); 15N NMR (600 MHz, CDCl3, from HMBC) d: ꢀ15.5
(N-2) (H4a, H4b); EIMS m/z 195 (M+), 197 (M+). HRMS
Calcd for C10H10ClNO = 195.0451, found 195.0424.
N-(4-Methoxyphenyl)-7-oxo-3a-[4-(trifluoromethyl)phenyl]
tetrahydro-2H,5H-[1,2]oxazolo[3,2-b][1,3]oxazine-2-carboxamide
(10).
It was obtained as a white down, mp 186–187ꢁC
(dichloromethane-hexanes), 25%. The yield was increased to
65%, when a threefold excess of the dipolarophile was applied.
IR (KBr) n: 3377, 3150, 3120, 3020, 2990, 2930, 2840, 1749
(d-lactam), 1668 (O═CNH, amide), 1630, 1600, 1530, 1514,
1453, 1412, 1324, 1300, 1260, 1240, 1200, 1170, 1128, 1105,
5-(Chloromethyl)-3-[4-(trifluoromethyl)phenyl]-4,5-dihy-
droisoxazole (6b). It was obtained as a white solid, mp 82–
83ꢁC. IR (KBr) n: 2920, 2850, 1616, 1598, 1562, 1440, 1412,
1328, 1242, 1169, 1111, 1070, 1035, 1014, 970, 916, 890, 873,
1070, 1035, 901, 831, 805, 770, 760, 650 cmꢀ1 1H NMR
;
(acetone-d6, 600 MHz) d: 9.09 (s, 1H, NH), 7.86 (d, J = 8.2 Hz,
2H, H20, H60), 7.75 (d, J = 8.2 Hz, 2H, H30, H50), 7.52 (dt, J = 7.6;
2.1 Hz, 2H, H200, H600), 6.83 (dt, J = 7.6; 2.1 Hz, 2H, H300, H500),
5.29 (dd, J = 11.8; 6.7 Hz, 1H, H2), 4.50 (m, 2H, H5), 3.81
845, 820, 760, 727, 600 cmꢀ1 1H NMR (CDCl3, 500 MHz) d:
;
7.88 (d, J = 8.5 Hz, 2H, H50, H30), 7.67 (d, J = 8.5 Hz, 2H, H60,
H20), 5.06 (m, 1H, H5), 3.75 (dd, J = 11.5; 4.0 Hz, 1H, H6a), 3.62
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

578
M. Gucma and W. M. Gołębiewski
Vol 51
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(dd, J = 17.2; 11.8 Hz, 1H, H3x), 3.73 (s, 3H, H3CO), 3.71
(dd, J = 17.2; 6.7 Hz, 1H, H3y), 2.73 (t, J = 6.2 Hz, 2H, H6);
1H NMR (CD2Cl2, 600 MHz) d: 7.74 (d, J = 8.2 Hz, 2H, H20,
H60), 7.65 (d0,0 J = 8.2 Hz, 2H, H30, H50), 7.38 (dt, J = 9.0 Hz,
2H, H200, H6 ), 7.24 (bs, 1H, NH), 6.83 (dt, J = 9.0; 1.9 Hz,
2H, H300, H500), 5.23 (dd, J = 10.3; 8.1 Hz, 1H, H2), 4.55
(t, J = 6.1 Hz, 2H, H5), 3.78 (s, 3H, OCH3), 3.65 (d, J = 8.1 Hz,
1H, H3A), 3.64 (d, J = 10.3Hz, 1H, H3B), 2.71 (t, J = 6.1 Hz,
2H, H6) ppm; 19F NMR (470 MHz, acetone-d6) d = ꢀ63.4;
EIMS m/z (% intensity) 436 (M+, 19), 265 (10), 177 (27,
H2C═CHCONHC6H4OCH3), 172 (25), 145 (15, F3CC6H4),
125 (100, H═NC6H4OCH3); ESI-MS m/z 459 (M+ + Na);
HR ESI-MS: Calcd for C21H19F3N2O5Na = 459.1144, found
459.1149. Anal. Calcd for C21H19F3N2O5: C, 57.80; H, 4.39;
N, 6.42. Found: C, 57.78; H 4.41; N, 6.35.
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Acknowledgments. This work was supported in part by the Polish
Ministry of Science and Higher Education Research (grant N N209
003 638) which is gratefully acknowledged.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet