Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via [1,3]dipolar cycloaddition reactions

Article abstract of DOI:10.1016/j.tetlet.2015.02.006

A group of novel 4-bromo-7,9-dimethyl-1-aryl-2-oxa-3,7,9-triaza-spiro[4.5]dec-3-ene-6,8,10-trione derivatives is prepared through 1,3-dipolar cycloadditions between benzylidenes and bromonitrile oxide. This reaction is shown to have high atom economy.

Full text of DOI:10.1016/j.tetlet.2015.02.006

Accepted Manuscript
Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via [1,3]dipolar cycloaddi-
tion reactions
Ebrahim Soleimani, Hossein Yazdani
PII:
S0040-4039(15)00249-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.006
TETL 45869
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 November 2014
15 January 2015
1 February 2015
Please cite this article as: Soleimani, E., Yazdani, H., Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via
[1,3]dipolar cycloaddition reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.006
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Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via [1,3]dipolar cycloaddition
reactions
Ebrahim Soleimani a,b,∗, Hossein Yazdani a
aDepartment of Chemistry, Razi University, Kermanshah 67149-67346, Iran.
bDepartment of Chemistry, College of Sciences, Kermanshah branch, Islamic Azad
University, Kermanshah, Iran.
Abstract:
A
group of novel 4-bromo-7,9-dimethyl-1-aryl-2-oxa-3,7,9-triaza-
spiro[4.5]dec-3-ene-6,8,10-trione derivatives is prepared through 1,3-dipolar
cycloadditions between benzylidenes and bromonitrile oxide. This reaction is shown to
have high atom economy.
Keywords:
1,3-dipolar
cycloaddition,
bromonitrile,
4,5-dihydroisoxazoles,
dibromoformaldoxime.
The synthetic utility of the 1,3-dipolar cycloaddition reaction is evident from the number
and scope of targets that can be prepared by this chemistry.1-4 As one of the most
thoroughly investigated 1,3-dipoles, nitrile oxides are arguably the most useful due to
their ability to generate nitrogen- and oxygen-based functionalities from the
cycloadducts, as well as the potential to install multiple stereogenic centers through high
degrees of regio- and stereoselectively.5-9
Several simple and convenient methods for the preparation of nitrile oxides have been
developed over the years. One of the important procedures for the easy access and
preparative use of nitrile oxides is the in situ technique with hydroximoyl halides.10-12
∗Corresponding author. Fax: +98 831 4274559; e-mail addresses: E_soleimanirazi@yahoo.com, E-
soleimani@razi.ac.ir (E. Soleimani).
1

The 3-isoxazolidone nucleus constitutes the basic skeleton of natural compounds such as
the antibiotic, D-cycloserine,13 the L-canavanine catabolite,14 and a series of compounds
that have been designed in medicinal chemistry as ligands for different receptors of the
central nervous system.15 The construction of isoxazoline and isoxazole rings by the 1,3-
dipolar cycloaddition (13DC) of a nitrile oxide to an alkene or alkyne has proven to be
extremely useful.5-9, 16
In continuation of our interest in the synthesis of heterocyclic compounds based
on multicomponent reactions (MCRs),17 we describe the synthesis of spiro 3-bromo-4,5-
dihydroisoxazoles 7 in high yields via the two-component condensation reaction of 5-
benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-triones
3
and
dibromoformaldoxime (6) in THF using KHCO3 at room temperature (Scheme 1). It
should be noted that 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-triones 3
were synthesized by the condensation between barbituric acids 1 and benzaldehydes 2 in
ethanol over 1 hour at room temperature.18 Dibromoformaldoxime (6) was synthesized by
the reaction of glyoxylic acid (4) with hydroxylamine hydrochloride (5) followed by
bromination according to the literature.19
2

O
O
X
X
N
N
EtOH
+
1 h, r.t.
R
H
O
O
O
X
X
1
2
N
R
N
O
O
O
X
X
3
N
N
THF/KHCO3
r.t
+
O
R
O
HO
Br
Br
N
O
N
7
Br
O
6
1. H2O, r.t
2. Br2, r.t
OH
NH -OH.HCl
2
+
H
O
4
5
Scheme 1.
We chose the reaction of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(1a, X = Me) with dibromoformaldoxime (6) as a model system for an optimization
study. We first investigated the reaction rate in different solvents by measuring the
isolated yield of the product, using identical amounts of reactants in the presence of 1.5
equivalents of KHCO3 for a fixed reaction time of 24 hours at room temperature. The
desired product was obtained in solvents such as THF, ethyl acetate, and toluene, but
THF gave the product in the highest yield. Next, different basic catalysts including
Na2CO3, K2CO3, Et3N, NaOH, KHCO3 and NaHCO3 were examined in the reaction. The
results indicated that although K2CO3 and Na2CO3 were found to be effective, the best
result was obtained when KHCO3 (1.5 equiv) was utilized as the base.
With optimized conditions established, we next extended the process to two different
barbituric acids, barbituric acid and 1,3-dimethylbarbituric acid, and various aldehydes
including benzaldehyde, 4-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-
3

fluorobenzaldehyde, 4-methoxybenzaldehyde and 3-methylbenzaldehyde. The results in
Figure 1 show that all the reactions proceeded smoothly to afford the expected 3-bromo-
4,5-dihydroisoxazole derivatives in good to excellent yields. The structures of the
1
products were deduced from their IR, mass, H NMR and 13C NMR spectra (see the
Supporting Data).
Figure 1. Structures of the prepared spiro 3-bromo-4,5-dihydroisoxazole derivatives.a,b
aReaction conditions: benzylidene 3 (1 mmol), dibromoformaldoxime (6) (1 mmol),
KHCO3 (1.5 mmol), THF (4 mL), r.t., 24 h. Isolated yields.
b
To explore the scope and limitations of this process, we further examined the reactions of
various aliphatic aldehydes with 1,3-dimethylbarbituric acid in ethanol at room
temperature. However, in all these cases, the desired products 3 were not formed.
Mechanistically, it is conceivable that the reaction involves the initial formation of the
bromonitrile oxide 8 via the reaction of dibromoformaldoxime (6) with KHCO3. Next,
this bromonitrile oxide undergoes a 1,3-dipolar cycloaddition with benzylidenes 3 to
afford the 3-bromo-4,5-dihydroisoxazole derivatives 7 (Scheme 2).
4

O
O
X
X
N
N
Br
C
Me
Me
HO
Br
N
N
N
KHCO3
O
O
N
O
R
O
3
Br
Br
R
O
O
N
6
8
7
Scheme 2. Proposed mechanism for the reaction
It is important to note that two isomers (A and B) are expected for the product (Figure 2).
1
However the H NMR and 13C NMR spectra of the crude reaction mixtures were
consistent with one isomer. Therefore, the reaction proceeded with high regioselectively.
This might be due to the fact that there would be repulsion between the R and Br groups
in the isomer B. Therefore we expected compound A as the major product.
O
O
Me
Me
O
Me
Me
N
N
O
N
N
O
R
O
R
O
Br
N
O
N
Br
A
B
Figure 2. Structures of the two regioisomers.
In conclusion, the efficient synthesis of spiro 3-bromo-4,5-dihydroisoxazole derivatives
in THF, in the presence of KHCO3 as the base has been described. A two-component
reaction involving 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-triones 3 and
dibromoformaldoxime (6) afforded the desired spiro products in good to excellent yields.
A range of aromatic aldehydes was used, including examples bearing electron-donating
or electron-withdrawing substituents. We hope that this approach may be of value to
5

others seeking novel synthetic fragments with unique properties for medicinal chemistry
programs.
Synthesis of benzylidene derivatives 3
A solution of a benzaldehyde 2 (1 mmol) and a barbituric acid 1 (1 mmol) in EtOH (5
mL) was stirred for 1 h at room temperature. After completion of the reaction, as
indicated by TLC, the solid residue was removed by filtration and washed with H2O (3×5
mL) to afford the pure products as colorless crystals.
Synthesis of dibromoformaldoxime (6)
To a stirred solution of glyoxylic acid (4) (10 mmol) in H2O (50 ml) was added
hydroxylamine hydrochloride (5) (10 mmol) and the solution was stirred for 24 h at room
temperature. Next, NaHCO3 (20 mmol) was added carefully followed by CH2Cl2 (60
ml). To the two-phase, well-stirred mixture at 6 ˚C was added Br2 (1 ml) dropwise over
20 min. Upon completion of the addition of Br2, the solution was stirred for 3 h. The
organic layer was separated and the aqueous layer was extracted with CH2Cl2 (50 ml).
The combined organic extract was dried (MgSO4), filtered and evaporated. The residue
was crystallized from n-hexane (50 mL). Yield 1.60 g (81%), m.p. 65-66 °C (Lit.19 m.p.
63-65 °C), white crystals.
General procedure for the synthesis of spiro 3-bromo-4,5-dihydroisoxazoles 7a-g
To a solution of benzylidene 3 (1 mmol) and dibromoformaldoxime (6) (1 mmol) in THF
(5 mL) was added KHCO3 (1.5 mmol) and the mixture stirred for 24 h at room
temperature. After completion of the reaction, as indicated by TLC, the solvent was
removed under vacuum and the solid residue was washed with H2O (5 mL). The solid
6

residue was crystallized from CH2Cl2/n-hexane (1:2) to afford the products as colorless
crystals.
4-Bromo-1-(4-fluorophenyl)-7,9-dimethyl-2-oxa-3,7,9-triaza-spiro[4.5]dec-3-ene-
6,8,10- trione (7a)
White powder (yield 80%); mp 187-200 °C. IR (KBr) (νmax/cm-1): 3362, 2958, 2920,
1725, 1685, 1600, 1506. MS, m/z (%): 384 (M++2), 382 (M+), 304, 287, 274, 258, 154,
85, 57. 1H NMR (400 MHz, CDCl3): δH (ppm) 2.75 (3H, s, CH3), 3.35 (3H, s, CH3), 4.95
(1H, s, CH), 7.00-7.20 (4H, m, H-Ar). 13C NMR (100 MHz, CDCl3): δC (ppm) 24.7
(CH3), 25.7 (CH3), 64.7 (CC=O), 84.0 (CH), 112.5, 121.0, 127.0, 133.0, 145.3, 159.1,
160.0, 161.2, 162.0 (C-Ar, 3C=O, C=N). Anal. Calcd for C14H11BrFN3O4: C, 43.77; H,
2.89; N, 10.94. Found: C, 43.73; H, 2.92; N, 10.91.
4-Bromo-1-phenyl-2-oxa-3,7,9-triaza-spiro[4.5]dec-3-ene-6,8,10-trione (7f)
White powder (yield 90%); mp 201-203 °C. IR (KBr) (νmax/cm-1): 3350, 3330, 2980,
2925, 1730, 1675, 1600, 1510. MS, m/z (%): 338 (M++2), 336 (M+), 278, 259, 258, 216,
128, 120, 121, 58, 43. 1H NMR (400 MHz, CDCl3): δH (ppm) 4.90 (1H, s, CH), 7.00-7.35
13
(5H, m, H-Ar), 8.35-8.70 (2H, br s, 2NH). C NMR (100 MHz, CDCl3): δC (ppm) 66.3
(CC=O), 84.5 (CH), 117.0, 121.2, 124.3, 131.6 (C-Ar), 144.5, 145.5, 157.6, 160.5
(3C=O, C=N). Anal. Calcd for C12H8BrN3O4: C, 42.63; H, 2.38; N, 12.43. Found: C,
42.60; H, 2.36; N, 12.44.
Acknowledgements
We gratefully acknowledge financial support from the Iran National Science Foundation
(INSF) and the Research Council of Razi University.
7

Supplementary data
Experimental procedures and spectral data for all new compounds are available.
Supplementary data related to this article can be found at http://
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Graphical abstract
Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via [1,3]dipolar cycloaddition
reactions
Ebrahim Soleimani*, Hossein Yazdani
O
O
X
X
N
N
EtOH
+
1 h, r.t.
R
H
O
O
O
X
X
N
R
N
O
O
O
X
X
N
N
THF/KHCO3
r.t
+
O
R
O
HO
Br
Br
N
O
N
Br
O
1. H2O, r.t
2. Br2, r.t
OH
NH -OH.HCl
2
+
H
O
11

O
O
X
X
N
N
EtOH
+
1 h, r.t.
R
H
O
O
O
X
X
1
2
N
R
N
O
O
O
X
X
3
N
N
THF/KHCO3
r.t
+
O
R
O
HO
Br
Br
N
O
N
7
Br
O
6
1. H2O, r.t
2. Br2, r.t
OH
NH -OH.HCl
2
+
H
O
4
5
Scheme 1. Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles
12