Efficient one pot and chemoselective synthesis of functionalized 3-bromo-4,5-dihydroisoxazole derivatives via 1,3-dipolar cycloaddition reactions of nitrile oxides

Article abstract of DOI:10.1016/j.tet.2017.10.003

A novel, metal-free and chemoselective approach for the synthesis of 4,5-dihydroisoxazole derivatives has been developed by the reaction of readily accessible starting materials including 4-oxo-4H-chromene-3-carbaldehyde, 1-phenyl-2-(1,1,1-triphenyl-λ

Full text of DOI:10.1016/j.tet.2017.10.003

Accepted Manuscript
Efficient one pot and chemoselective synthesis of functionalized 3-bromo-4,5-
dihydroisoxazole derivatives via 1,3-dipolar cycloaddition reactions of nitrile oxides
Abdolali Alizadeh, Atefeh Roosta, Reza Rezaiyehrad, Mohammadreza Halvagar
PII:
S0040-4020(17)31011-6
10.1016/j.tet.2017.10.003
TET 29006
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 May 2017
Revised Date: 18 September 2017
Accepted Date: 2 October 2017
Please cite this article as: Alizadeh A, Roosta A, Rezaiyehrad R, Halvagar M, Efficient one pot and
chemoselective synthesis of functionalized 3-bromo-4,5-dihydroisoxazole derivatives via 1,3-dipolar
cycloaddition reactions of nitrile oxides, Tetrahedron (2017), doi: 10.1016/j.tet.2017.10.003.
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Leave this area blank for abstract info.
Efficient One Pot and Chemoselective
Synthesis of Functionalized 3-Bromo-4,5-dihydro
isoxazole Derivatives via 1,3-Dipolar Cycloaddition
Reactions of Nitrile Oxides
Abdolali Alizadeh,* Atefeh Roosta, Reza Rezaiyehrad, Mohammadreza Halvagar
aDepartment of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
bChemistry & Chemical Engineering Research Center of Iran (CCERCI), Pajohesh Blvd,17th Km of Tehran-
Karaj Highway, Tehran, Iran. post code: 1496813151
1

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Efficient One Pot and Chemoselective Synthesis of Functionalized 3-
Bromo-4,5-dihydroisoxazole Derivatives via 1,3-Dipolar Cycloaddition
Reactions of Nitrile Oxides
Abdolali Alizadeh,a* Atefeh Roosta,a Reza Rezaiyehrad,a Mohammadreza Halvagarb
aDepartment of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
bChemistry & Chemical Engineering Research Center of Iran (CCERCI), Pajohesh Blvd,17th Km of
Tehran-Karaj Highway, Tehran, Iran. post code: 1496813151
Abstract— A novel, metal-free and chemoselective approach for the synthesis of 4,5-
dihydroisoxazole derivatives has been developed by the reaction of readily accessible starting
materials including 4-oxo-4H-chromene-3-carbaldehyde, 1-phenyl-2-(1,1,1-triphenyl-λ5
-
phosphanylidene)ethan-1-one and dibromoformaldoxime under mild conditions in the presence
of KHCO3.
Keywords: 4-Oxo-4H-chromene-3-carbaldehyde, 1-Phenyl-2-(1,1,1-triphenyl-λ5-phosphanylidene)ethan-1-one,
Dibromoformaldoxime, 4,5-Dihydroisoxazole, Chemoselective, One pot, Multicomponent Reactions
*Corresponding author, Tel.: +98 21 8800663; fax: +98 21 88006544; e-mail: aalizadeh@modares.ac.ir
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1. Introduction
Heterocyclic compounds play a substantial role in pharmaceutical sciences and synthetic organic
chemistry. They occur in many biologically active compounds and synthetic drugs, and they are
also useful as key intermediates for synthesizing natural products.1 They widely exist in additives
and modifiers used in chemical industries such as cosmetics, plastics, reprographic and
information storage.1c Among the most widely used nitrogen- and oxygen-containing five
membered heterocycles are the 4,5-dihydroisoxazoles which are widespread in nature.
The 4,5-dihydroisoxazole (2-isoxazoline) moieties are important building blocks of numerous
compounds with broad biological activities,2 and are versatile intermediates for the synthesis of a
variety of natural products. Also, they can be exposed to chemical transformations and converted
into diverse useful compounds such as β-hydroxy carbonyls,3 α,β-unsaturated oximes,4 γ-amino
alcohols,5 and β-hydroxy nitriles.6 Moreover, 2-isoxazoline units are important pharmacophores
and exhibit significant biological activities such as antifungal,7,8 anti-inflammatory,9
antibacterial,10 analgesic,11 antiviral and anti-HIV.12
Isoxazoline derivatives also present an acceptable influence on animal models of thrombosis.13
Some heterocyclic systems containing 2-isoxazoline such as isocarboxazid, oxacillin,
valdecoxib, micafungin, and leflunomide are used as drugs.14
On the other hand, the quinoline scaffolds possess a wide spectrum of biological activities
including anticancer, antiviral, anti-inflammatory,15a anticonvulsant,15b antimalarial15c,15d and
non-opioid analgesics.15e Various approaches have been reported in the literature for the
synthesis of functionalized 2-isoxazolines. One of the reliable strategies for the preparation of
4,5-dihydroisoxazoles is the 1,3-dipolar cycloaddition16 of an alkene with nitrile oxide. In fact, in
these reactions, the nitrile oxide has been achieved through in situ formation and then the [3+2]
cycloaddition reaction has occured. In this context, we used bromonitrile oxide as the dipole
body to form 3-bromo-4,5-dihydroisoxazole derivatives.
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2. Results and Discussion
Recently, we have reported an efficient method for the synthesis of pyrazoles from 4-oxo-4H-
chromene-3-carbaldehyde, hydroxylamine hydrochloride and hydrazonoyl chlorides by
exploring a three-component 1,3-dipolar cycloaddition reaction in one-pot protocol.17 As part of
our continued interest in the synthesis of diverse heterocyclic compounds of biological
significance,18 we report herein the synthesis of some novel 3-bromo-4,5-dihydroisoxazole
derivatives from simple dibromoformaldoxime, different aldehydes (4-oxo-4H-chromene-3-
carbaldehyde, 2-chloroquinolone-3-carbaldehyde and tetrazolo[1,5-a]quinoline-4-carbaldehyde)
and 1-phenyl-2-(1,1,1-triphenyl-λ5-phosphanylidene)ethan-1-one and potassium hydrogen
carbonate as base via a 1,3-dipolar cycloaddition three component reaction using
dichloromethane as solvent at room temperature (Scheme 1).
Scheme 1. Synthesis of substituted 3-bromo-4,5-dihydroisoxazoles 3 and 3'
Quinolines and their derivatives are valuable component of pharmaceutically active compounds.
The quinolone moiety can also be easily identified in the structure of various naturally occurring
alkaloids. They have been accompanied by a wide spectrum of biological activities.19,20 The
fusion of quinoline scaffold to the tetrazole unit is noticed to grow the biological activity. The
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tetrazole group is regarded as analogues to carboxylic group as a pharmacore and possesses wide
range of pronounced activities such as anti-inflammatory,21 anti-AIDS,22 CNS dispersant,23
anticonvulsant,24 antimycobacterial,25 etc.. In particular, tetrazolo[1,5-a]quinoline-4-
carbaldehyde performs as a pivotal synthetic intermediate for the synthesis of new
pharmaceutically valuable compounds26. Chromone and its derivatives exhibit a wide spectrum
of medicinal properties including antimicrobial27, antitumour,28 and antiviral29 activities.
Therefore, given the biological properties of these three combinations and their availability, we
decided to use these compounds to synthesize 4,5-dihydro isoxazole derivatives.
The synthesis of the title compounds involves the reaction of the aldehyde moiety with a Wittig
reagent to form the α,β-unsaturated compound, which on 1,3-dipolar cyclization reaction with
bromoformaldoxime in the presence of KHCO3 base furnishes 3-bromo-4,5-dihydroisoxazoles in
excellent yields. The progress of the reaction was monitored by TLC. After completion of the
reaction, products 3 and 3' as two diastereomers were obtained in 80-90 % yield. Additional
functionalizations were investigated, as shown in Table 1 and Table 2. Various functional groups
were introduced at the 4- and 5-position of 2-isoxazoline in excellent yields (80-90%).
As anticipated from our initial results, these reactions proceeded very cleanly at room
temperature and no undesirable side reactions were observed.
Table 1 Synthesis of 3-(4-benzoyl-3-bromo-4,5-dihydroisoxazol-5-yl)-4H-chromen-4-one
derivatives
N
O
O
Br
R
R
O
O
O
O
O
R'
R'
R
CHO
+
Ph3P
OH
Br
3
CH2Cl2
N
Br
+
N
KHCO3, rt, 3-5 h
O
R'
Br
O
1
2
O
O
3'
5

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Entry
R
H
H
H
H
Cl
R’
H
Products
3a, 3'a
3b, 3'b
3c, 3'c
3d, 3'd
3e, 3'e
aRatio of 3 : 3'
Yield (%)
1
2
3
4
5
86 : 14
94 : 6
90
85
85
87
82
Br
Cl
Me
H
> 98 : 2
96 : 4
> 98 : 2
aMeasured by 1H NMR spectroscopy
Table
yl](phenyl)methanone
yl)(phenyl)methanone derivatives
2
Synthesis
of
[3-bromo-5-(2-chloroquinolin-3-yl)-4,5-dihydroisoxazol-4-
and
(3-bromo-5-tetrazolo[1,5-a]quinolin-4-yl-4,5-dihydroisoxazol-4-
Entry
Aldehyde
R’
H
Products
3f, 3'f
aRatio of 3 : 3' Yield (%)
1
2
3
4
2-chloroquinolone-3-carbaldehyde
2-chloroquinolone-3-carbaldehyde
tetrazolo[1,5-a]quinoline-4-carbaldehyde
32 : 68
72 : 28
85
82
80
82
3g, 3'g
3h, 3'h
3i, 3'i
Br
H
76 : 24
tetrazolo[1,5-a]quinoline-4-carbaldehyde Me
> 98 : 2a
aMeasured by 1H NMR spectroscopy
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The structure of all the products were confirmed upon careful analysis of the data obtained from
IR, mass, 1H NMR, and 13C NMR spectra. The mass spectrum of 3a displayed the molecular ion
peak at the appropriate m/z value. In the IR spectrum of 3a, two absorption bands at 1680 and
1632 cm-1, two absorption bands at 1590 and 1464 cm-1, and an absorption band at 1220 cm-1,
which are related to C=O, Ar and C-O stretching frequencies, clearly indicated the most
1
significant functional groups of the product. The H NMR spectrum of 3a exhibited two signals
at 5.42 and 6.04 ppm, readily recognized as two CH hydrogen atoms of the isoxazoline ring. A
signal at 8.12 ppm belonged to the olefinic hydrogen. Seven other signals in the range of 7.43-
8.17 ppm belong to the nine aromatic hydrogens gave rise to characteristic signals in the
1
aromatic region of the spectrum. Observation of 17 distinct signals in the H-decoupled 13C
NMR spectrum of 3a is in agreement with the proposed structure. Finally the structure of the
major regioisomer (3'f) of 3f was confiremed by X-ray crystal structure analysis (Fig. 1).
Fig. 1 ORTEP diagram of 3'f.
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A plausible mechanism for the formation of 3-(4-benzoyl-3-bromo-4,5-dihydroisoxazol-5-yl)-
4H-chromen-4-one 3a is depicted in Scheme 2. Initially, the Wittig reagent and the aldehyde
moiety form the α,β-unsaturated compound 4a and X-ray analysis showes that the
stereochemistry of olefine intermediate 4a is trans. Then, the in situ generated bromonitrile oxide
undergoes [3+2] dipolar cycloaddition with the mentioned alkene 4a to afford the corresponding
3-bromo-4,5-dihydroisoxazole 3a and 3’a.
Scheme 2. Mechanistic rationale for the synthesis of 3a and 3’a.
3. Conclusion
In summary, we have reported a rapid, simple, and efficient protocol for the synthesis of 3-
bromo-4,5-dihydroisoxazole derivatives from easily available starting materials via 1,3-dipolar
cycloaddition reactions involving bromonitrile oxide as 1,3-dipole, in a chemoselective manner.
The simplicity of experimental procedure, mild, catalyst free conditions, and ready availability of
starting materials, render this strategy as an attractive method for the synthesis of 3-bromo-4,5-
dihydroisoxazole derivatives.
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4. Experimental
All starting materials were synthesized according to the literature. Elemental analyses for C, H
and N were performed using a Heraeus CHN–O–Rapid analyzer. Mass spectra were recorded on
an Aglient Technologies 5975C VL MSD mass spectrometer operating at an ionization potential
of 70 eV. 1H NMR (500.13 MHz) and 13C NMR (125 MHz) spectra were obtained using Bruker
DRX-500 AVANCE spectrometers. IR spectra were recorded as KBr pellets on a NICOLET FT-
IR 100 spectrometer; absorbances are reported in cm-1. M. p. points were measured on an
Electrothermal 9100.
4.1. General synthesis procedure (for example, 3a).
The aldehyde compound (1 mmol), 1-phenyl-2-(1,1,1-triphenyl-λ5-phosphanylidene)ethan-1-one
(1 mmol), dibromoformaldoxime (1 mmol) and KHCO3 (1mmol) were combined in a vessel in
DCM as solvent and the reaction mixture was stirred at room temperature for 3-5 hours. The
product was obtained after purification by column chromatography on silica gel.
4.1.1. 3-(4-Benzoyl-3-bromo-4,5-dihydroisoxazol-5-yl)-4H-chromen-4-one (3a). Cream
powder, m.p = 172-174 °C, 0.36 g, yield: 90%. IR (KBr) (νmax, cm-1): 1680 and 1632 (C=O),
1590 and 1464 (Ar), 1220 (C-O). Anal. Calcd. for C19H12BrNO4 (398.21): C, 57.31; H, 3.04; N,
3.52%. Found C, 57.39; H, 3.01; N, 3.56%. MS (EI, 70 eV): m/z (%): 398 (3), 318 (9), 249 (6),
1
213 (3), 173 (13), 148 (4), 105 (100), 77.1 (40), 51.1 (9). H NMR (500.13 MHz, CDCl3) of
3
3
major diastereoisomer (86 : 14): δH 5.42 (1H, d, JHH = 7.5 Hz, CH4), 6.04 (1H, dd, JHH = 7.5
4
3
3
Hz, JHH = 1.1 Hz, CH5), 7.43 (1H, t, JHH = 7.1 Hz, CH6’), 7.52 (1H, d, JHH = 7.9 Hz, CH8’),
7.54 (2H, t, 3JHH = 8.0 Hz, 2CHmeta of Ph), 7.66 (1H, t, 3JHH = 7.3 Hz, CHpara of Ph), 7.72 (1H, t,
3JHH = 7.8 Hz, 4JHH = 1.6 Hz, CH7’), 8.08 (2H, dd, 3JHH = 7.2 Hz, 4JHH = 0.9 Hz, 2CHortho of Ph),
3
8.12 (1H, d, 4JHH = 1.1 Hz, CH2’), 8.17 (1H, dd, JHH = 8.0 Hz, 4JHH = 1.6 Hz, CH5’). 13C NMR
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of major and minor diastereoisomer (75.46 MHz, CDCl3): δC 64.2 (CH4), 82.17 (CH5), 118.5
(CH8’), 121.1 (C-Br), 123.8 (C3’), 125.8 (CH6’), 125.8 (CH5’), 129.1 (2CHmeta of Ph), 129.5
(2CHortho of Ph), 134.5 (CHpara of Ph), 134.5 (C4’a), 135.5 (Cipso-C=O), 135.8 (CH7’), 153.8
1
(CH2’), 156.6 (C8’a), 176.5 (C4’=O), 192.9 (C=O). H NMR (500.13 MHz, CDCl3) of minor
diastereoisomer (86 : 14):
δ
H 5.12 (1H, d, 3JHH = 8.7 Hz, CH4), 5.92 (1H, d, 3JHH = 8.7 Hz, CH5),
3
3
7.43 (1H, t, JHH = 7.1 Hz, CH6’), 7.52 (1H, d, 3JHH = 7.9 Hz, CH8’), 7.54 (2H, t, JHH = 8.0 Hz,
3
4
2CHmeta of Ph), 7.65 (1H, t, 3JHH = 7.4 Hz, CHpara of Ph), 7.72 (1H, t, JHH = 7.8 Hz, JHH = 1.6
Hz, CH7’), 8.09 (2H, dd, 3JHH = 8.5 Hz, 2CHortho of Ph), 8.03 (1H, s, CH2’), 8.23 (1H, dd, 3JHH
8.4 Hz, 4JHH = 1.9 Hz, CH5’).
=
4.1.2. 3-(3-Bromo-4-(4-bromobenzoyl)-4,5-dihydroisoxazol-5-yl)-4H-chromen-4-one (3b).
White powder, m.p = 184-186 °C, 0.39 g, yield 83%. IR (KBr) (νmax, cm-1): 1682 and 1642
(C=O), 1580 and 1465 (Ar), 1214 (C-O). Anal. Calcd. for C19H11Br2NO4 (477.11): C, 47.83; H,
2.32; N, 2.94%. Found C, 47.89; H, 2.30; N, 2.91%. MS (EI, 70 eV): m/z (%): 475 (1), 396 (3),
292 (2), 239 (2), 213 (3), 186 (1), 185.9 (11), 184.9 (96), 183 (100), 173 (21), 156.9 (25), 155
(31), 121 (14), 120 (9), 104 (13), 92 (15), 77 (9), 76 (32), 75 (25), 74 (10), 64 (9), 63 (17), 53
(12), 51 (8), 50 (22). 1H NMR (500.13 MHz, CDCl3): H 5.32 (1H, d, 3JHH = 7.5 Hz, CH4), 6.01
δ
4
3
4
(1H, dd, 3JHH = 7.5 Hz, JHH = 1.2 Hz, CH5), 7.43 (1H, dt, JHH = 7.6 Hz, JHH = 0.9 Hz, CH6’),
3
3
3
7.51 (1H, d, JHH = 8.4 Hz, CH8’), 7.67 (2H, t, JHH = 8.6 Hz, 2CH of Ar), 7.72 (1H, dt, JHH
=
7.8 Hz, 4JHH = 1.6 Hz, CH7’), 7.95 (2H, d, 3JHH = 8.6 Hz, 2CH of Ar), 8.11 (1H, d, 4JHH = 1.2 Hz,
3
4
13
CH2’), 8.14 (1H, dd, JHH = 8.0 Hz, JHH = 1.5 Hz, CH5’). C NMR (125.75 MHz, CDCl3): δC
64.2 (CH4), 81.9 (CH5), 118.4 (CH8’), 121.0 (C-Br), 123.6 (C3’), 125.6 (CH6’), 125.8 (CH5’),
129.9 (Cipso-Br), 130.8 (2CH of Ar), 132.3 (2CH of Ar), 134.4 (CH7’), 134.5 (C4’a), 135.2 (Cipso
CO), 153.6 (CH2’), 156.5 (C8’a), 176.4 (C4’=O), 191.9 (C=O).
-
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4.1.3. 3-(3-Bromo-4-(4-chlorobenzoyl)-4,5-dihydroisoxazol-5-yl)-4H-chromen-4-one (3c).
White powder, m.p = 193-195 °C, 0.38 g, yield 87%. IR (KBr) (νmax, cm-1): 1681 and 1629
(C=O), 1465 (Ar), 1215 (C-O). Anal. Calcd. for C19H11BrClNO4 (432.66): C, 52.75; H, 2.56; N,
3.24%. Found C, 52.71; H, 2.59; N, 3.28%. MS (EI, 70 eV): m/z (%): 432 (3), 431 (11), 352
(43), 350 (35), 306 (3), 260 (12), 212 (11), 175 (1), 139 (100), 140 (10), 141 (32), 111 (40), 113
(14), 120 (8), 75 (17). 1H NMR (500.13 MHz, CDCl3):
δ
H 5.33 (1H, d, 3JHH = 7.4 Hz, CH4), 6.01
(1H, d, 3JHH = 7.4 Hz, CH5), 7.43 (1H, t, 3JHH = 7.4 Hz, CH6’), 7.50 (2H, t, 3JHH = 8.5 Hz, 2CH of
3
3
4
Ar), 7.51 (1H, d, JHH = 7.7 Hz, CH8’), 7.72 (1H, dt, JHH = 7.1 Hz, JHH = 1.3 Hz, CH7’), 8.03
3
3
13
(1H, d, JHH = 8.5 Hz, 2CH of Ar), 8.11 (1H, s, CH2’), 8.14 (1H, d, JHH = 7.9 Hz, CH5’). C
NMR (125.75 MHz, CDCl3):
δ
C 64.2 (CH4), 82.0 (CH5), 118.4 (CH8’), 121.0 (C-Br), 123.6 (C3’),
125.6 (CH6’), 125.7 (CH5’), 129.3 (2CH of Ar), 130.7 (2CH of Ar), 134.1 (C4’a), 134.4 (CH7’),
135.2 (Cipso-C=O), 141.1 (Cipso-Cl), 153.6 (CH2’), 156.5 (C8’a), 176.4 (C4’=O), 191.7 (C=O).
4.1.4. 3-[3-Bromo-4-(4-methylbenzoyl)-4,5-dihydroisoxazol-5-yl]-4H-chromen-4-one (3d).
White powder, m.p = 179-180 °C, 0.33 g, yield 80%. IR (KBr) (νmax, cm-1): 1646 and 1607
(C=O), 1463 and 1590 (Ar), 1251 (C-O). Anal. Calcd. for C20H14BrNO4 (412.24): C, 58.27; H,
3.42; N, 3.40%. Found C, 58.20; H, 3.49; N, 3.45%. MS (EI, 70 eV): m/z (%): 332 (2), 213 (3),
183 (6), 173 (19), 171 (4), 155 (4), 146 (7), 127 (4), 121 (10), 120 (25), 119 (100), 104 (5), 93
(2), 92 (11), 91 (47), 90 (5), 89 (9), 77 (3), 65 (15), 64 (4), 63 (8), 53 (3). 1H NMR (500.13 MHz,
CDCl3): δ
H 2.41 (3H, s, Me), 541 (1H, d, 3JHH = 7.5 Hz, CH4), 6.01 (1H, dd, 3JHH = 7.5 Hz, 4JHH
= 1.0 Hz, CH5), 7.32 (2H, d, 3JHH = 8.1 Hz, 2CH of Ar), 7.42 (1H, dt, 3JHH = 7.6 Hz, 4JHH = 0.9
Hz, CH6’), 7.50 (1H, d, 3JHH = 8.4 Hz, CH8’), 7.71 (1H, dt, 3JHH = 7.8 Hz, 4JHH = 1.6 Hz, CH7’),
4
7.96 (2H, d, 3JHH = 8.2 Hz, 2CH of Ar), 8.09 (1H, d, JHH = 1.0 Hz, CH2’), 8.16 (1H, dd, 3JHH
=
4
13
8.0 Hz, JHH = 1.5 Hz, CH5’). C NMR (125.75 MHz, CDCl3): δC 21.8 (Me), 63.9 (CH4), 82.1
(CH5), 118.3 (CH8’), 121.0 (C-Br), 123.8 (C3’), 125.7 (CH6’ and CH5’), 129.5 (2CH of Ar), 129.7
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(2CH of Ar), 133.2 (C4’a), 134.3 (CH7’), 135.6 (Cipso-C=O), 145.6 (C-Me), 153.8 (CH2’), 156.4
(C8’a), 176.3 (C4’=O), 192.2 (C=O).
4.1.5. 3-(4-Benzoyl-3-bromo-4,5-dihydroisoxazol-5-yl)-6-chloro-4H-chromen-4-one (3e).
White powder, m.p = 153-154 °C, 0.38 g, yield 87%. IR (KBr) (νmax, cm-1): 1682 and 1639
(C=O), 1456 (Ar), 1212 (C-O). Anal. Calcd. for C19H11BrClNO4 (432.66): C, 52.75; H, 2.56; N,
3.24%. Found C, 52.71; H, 2.50; N, 3.29%. MS (EI, 70 eV): m/z (%): 432 (1), 351 (3), 247 (2),
217 (2), 209 (3), 207 (9), 180 (3), 155 (4), 154 (4), 126 (7), 105 (100), 106 (14), 89 (3), 78 (4),
75 (3), 63 (7), 53 (5), 51 (13), 50 (4). 1H NMR (500.13 MHz, CDCl3): H 5.37 (1H, d, 3JHH = 7.5
δ
Hz, CH4), 6.04 (1H, d, 3JHH = 7.5 Hz, CH5), 7.48 (1H, d, 3JHH = 8.9 Hz, CH8’), 7.54 (2H, t, 3JHH
3
=7.6 Hz, 2CHmeta of Ph), 7.64-7.69 (2H, m, CHpara of Ph and CH7’), 8.06 (2H, d, JHH = 8.0 Hz,
4
13
2CHortho of Ph), 8.11 (1H, d, JHH = 2.5 Hz, CH2’), 8.12 (1H, s, CH5’). C NMR (125.75 MHz,
CDCl3):
δ
C 64.1 (CH4), 81.8 (CH5), 120.1 (CH8’), 121.3 (C-Br), 124.6 (C3’), 125.1 (CH5’), 129.0
(2CHmeta of Ph), 129.3 (2CHortho of Ph), 131.8 (C6’), 134.4 (CH7’), 134.6 (CHpara of Ph), 135.5
(C4’a), 135.7 (Cipso-CO), 153.8 (CH2’), 154.8 (C8’a), 175.2 (C4’=O), 192.6 (C=O).
4.1.6. [3-bromo-4-(2-chloroquinolin-3-yl)-4,5-dihydroisoxazol-5-yl](phenyl)methanone (3'f).
White powder, m.p = 138-140 °C, 0.35 g, yield 85%, IR (KBr) (νmax, cm-1): 1685 (C=O), 1587
and 1449 (Ar), 1234 (C-O). Anal. Calcd. for C19H12BrClN2O2 (415.67): C, 54.90; H, 2.91; N,
6.74%. Found C, 54.95; H, 2.96; N, 6.70%. MS (EI, 70 eV): m/z (%):415 (2), 311 (2), 202 (2),
201 (2), 192 (4), 191 (2), 190 (11), 166 (4), 165 (3), 164 (2), 162 (2), 140 (4), 139 (4), 127 (3),
1
113 (2), 106 (18), 105 (100), 101 (2), 78 (3), 77 (41), 75 (3), 63 (2), 51 (11), 50 (3). H NMR
(500.13 MHz, CDCl3) of major isomer (32 : 68):
δ
H 5.21 (1H, d, 3JHH = 7.0 Hz, CH4’), 5.85 (1H,
3
3
3
d, JHH = 7.0 Hz, CH5’), 7.50 (2H, t, JHH = 7.8 Hz, 2CHmeta of Ph), 7.68 (1H, t, JHH = 7.3 Hz,
3
3
CHpara of Ph), 7.77 (1H, d, JHH = 8.5 Hz, CH5), 7.80 (1H, d, JHH = 8.2 Hz, CH8), 7.87 (2H, t,
3JHH = 7.8 Hz, CH6 and CH7), 8.06 (2H, d, 3JHH = 7.6 Hz, 2CHortho of Ph), 8.12 (1H, s, CH4). 13C
12

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NMR of major isomer (125.75 MHz, CDCl3): δC 66.1 (CH4’), 84.2 (CH5’), 127.1 (C4a), 127.7
(CH6), 127.9 (CH8), 128.4 (CH5), 128.9 (2CHmeta of Ph), 129.7 (2CHortho of Ph), 130.5 (C3),
131.5 (CH7), 133.8 (C-Br), 134.5 (CHpara of Ph), 136.2 (CH4), 139.8 (Cipso of Ph), 147.5 (C8a),
149.4 (C-Cl), 190.8 (C=O). Crystal data for 3'f C19H12BrClN2O2 (CCDC 1574900): MW
415.56, orthorhombic, P b c a, a = 10.485(2) Å, b = 14.400(3) Å, c = 23.012(5) Å, α = 90.00,
90.00,
dimension 0.35 × 0.263 × 0.2 mm, radiation, Mo Kα (λ = 0.71073 Å), 1.77≤2
data were collected at 293(2) K with a Bruker APEX area-detector diffractometer, and
employing /2 scanning technique, in the range of -12 ≤ h ≤11, -17 ≤ k ≤ 17, -27 ≤ l ≤ 27; the
=
β
=
γ
= 90.00, V = 3474.4(12) Å3, Z = 8, Dc = 1.589 mg/m3, F (000) = 1664, crystal
≤ 26.85, intensity
θ
ω
θ
structure was solved by a direct method, all non-hydrogen atoms were positioned and anisotropic
thermal parameters refined from 3066 observed reflections with R (into) = 0.1067 by a full-
1
matrix least-squares technique converged to R = 0.0386 and Raw = 0.0606 [I>2sigma(I)]. H
NMR of minor isomer (500.13 MHz, CDCl3): δ
H 5.84 (1H, d, 3JHH = 5.9 Hz, CH4’), 6.45 (1H, d,
3JHH = 5.9 Hz, CH5’), 7.53 (2H, t, 3JHH = 7.6 Hz, 2CHmeta of ph), 7.60-7.64 (3H, m, CHpara of Ph
and CH6 and CH7), 8.00 (1H, d, 3JHH = 8.4 Hz, CH5), 8.03 (1H, d, 3JHH = 8.4 Hz, CH8), 8.04 (2H,
3
13
d, JHH = 7.6 Hz, 2CHortho of Ph), 8.39 (1H, s, CH4). C NMR of minor isomer (125.75 MHz,
CDCl3):
δ
C 56.7 (CH4’), 87.7 (CH5’), 126.9 (C4a), 127.8 (CH6), 128.1 (CH8), 128.3 (CH5), 129.1
(2CHmeta of Ph), 129.3 (2CHortho of Ph), 131.2 (CH7), 133.5 (C3), 134.8 (CHpara of Ph), 135.2 (C-
Br), 136.2 (CH4), 139.0 (Cipso of Ph), 147.1 (C-Cl), 147.5 (C8a), 192.1 (C=O).
4.1.7.
[3-Bromo-5-(2-chloroquinolin-3-yl)-4,5-dihydroisoxazol-4-yl](4-
bromophenyl)methanone (3g). White powder, m.p = 155-157 °C, 0.37 g, yield 87%, IR (KBr)
(νmax, cm-1): 1682 (C=O), 1580 and 1487 (Ar), 1256 (C-O). Anal. Calcd. for C19H11Br2ClN2O2
(494.57): C, 46.14; H, 2.24; N, 5.66%. Found C, 46.10; H, 2.29; N, 5.61%. MS (EI, 70 eV): 494
(1), 457 (4), 415 (1), 378 (6), 376 (6), 311 (3), 275 (1), 241 (1), 202 (4), 201 (3), 200 (4), 192
13

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(10), 191 (5), 190 (31), 186 (9), 185 (97), 184 (9), 183 (100), 167 (4), 166 (7), 165 (7), 164 (7),
162 (10), 157 (25), 155 (27), 149 (5), 143 (3), 140 (6), 139 (5), 138 (3), 128 (3), 127 (10), 126
1
(4), 114 (3), 113 (3), 104 (4), 101 (7), 76 (14), 75 (12), 74 (4), 50 (6). H NMR (500.13 MHz,
3
CDCl3) of major diastereoisomer (72 : 28): δH 5.14 (1H, d, JHH = 6.0 Hz, CH4’), 6.44 (1H, d,
3
3
3JHH = 6.0 Hz, CH5’), 7.64 (1H, t, JHH = 7.8 Hz, CH7), 7.66 (1H, d, JHH = 8.5 Hz, CH5), 7.69
(2H, d, 3JHH = 8.5 Hz, 2CH of Ar), 7.79 (1H, t, 3JHH = 8.3 Hz, CH6), 7.91 (2H, d, 3JHH = 8.5 Hz,
3
2CH of Ar), 8.02 (1H, d, JHH = 8.4 Hz, CH8), 8.40 (1H, s, CH4). 13C NMR of major
diastereoisomer (125.75 MHz, CDCl3): δC 66.1 (CH4’), 84.2 (CH5’), 126.9 (C3’-Br), 127.9
(CH6), 128.1 (CH8), 128.3 (CH5), 128.3 (Cipso-Br), 130.5 (C3), 131.3 (CH7), 132.1 (C4a), 132.5
(2CH of Ar), 133.9 (Cipso-C=O), 136.2 (CH4), 146.9 (C8a), 147.5 (C-Cl), 191.2 (C=O). 1H NMR
3
(500.13 MHz, CDCl3) of minor diastereoisomer(72 : 28): δH 5.79 (1H, d, JHH = 5.2 Hz, CH4’),
3
5.83 (1H, d, 3JHH = 5.5 Hz, CH5’), 7.53 (1H, d, 3JHH = 8.5 Hz, CH5), 7.64 (1H, t, JHH = 7.8 Hz,
CH7), 7.69 (2H, d, 3JHH = 8.5 Hz, 2CH of Ar), 7.79 (1H, t, 3JHH = 8.3 Hz, CH6), 7.90 (2H, d, 3JHH
3
13
= 8.7 Hz, 2CH of Ar), 8.05 (1H, d, JH-H = 8.6 Hz, CH8), 8.10 (1H, s, CH4). C NMR of minor
diastereoisomer (125.75 MHz, CDCl3): δC 56.6 (CH4’), 87.6 (CH5’), 127.1 (C3’), 127.6 (CH5),
128.0 (CH6), 128.4 (CH8), 128.7 (Cipso-Br), 130.0 (C3), 131.2 (2CH of Ar), 131.5 (CH7), 132.3
(2CHortho of Ar), 132.2 (C4a), 132.9 (Cipso-C=O), 133.1 (CH4), 147.5 (C8a), 149.3 (C2), 190.0
(C=O).
4.1.8.
(3-Bromo-5-[1,2,3,4]tetrazolo[1,5-a]quinolin-4-yl-4,5-dihydroisoxazol-4-
yl)(phenyl)methanone (3h). White powder, m.p = 190 °C, 0.33 g, yield 80%, IR (KBr) (νmax
,
cm-1): 1683 (C=O), 1614 (C=N), 1532 and 1448 (Ar), 1220 (C-O). Anal. Calcd. for
C19H12BrN5O2 (422.24): C, 54.05; H, 2.86; N, 16.59%. Found C, 54.09; H, 2.81; N, 16.51%. MS
(EI, 70 eV): m/z (%): 422 (0.1), 343 (3), 342 (13), 314 (3), 297 (3), 296 (2), 283 (3), 256 (2), 255
(2), 218 (1), 197 (2), 179 (4), 170 (6), 154 (5), 153 (3), 152 (6), 151 (2), 143 (8), 142 (8), 141
14

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(11), 140 (3), 129 (2), 128 (4), 127 (6), 126 (2), 125 (3), 116 (5), 115 (21), 114 (14), 113 (3), 106
(25), 105 (100), 101 (4), 100 (2), 90 (3), 89 (8), 88 (7), 87 (4), 78 (9), 77 (87), 76 (7), 75 (6), 74
(4), 64 (3), 63 (8), 62 (4), 52 (3), 51 (22), 50 (7). 1H NMR (500.13 MHz, CDCl3):
δH 5.81 (1H, d,
3
3JHH = 6.9 Hz, CH4’), 6.60 (1H, dd, JHH = 6.9 Hz, 4JHH = 2.7 Hz, CH5’), 7.54 (2H, t, 3JHH = 6.8
3
3
Hz, 2CHmeta of Ph), 7.68 (1H, t, JHH = 6.7 Hz, CHpara of Ph), 7.77 (1H, t, JHH = 7.3 Hz, CH6),
3
3
3
7.93 (1H, t, JHH = 7.3 Hz, CH7), 8.04 (1H, d, JHH = 7.7 Hz, CH5), 8.11 (2H, d, JHH = 7.6 Hz,
3
4
2CHortho of Ph), 8.17 (1H, s, CH4), 8.70 (1H, dd, JHH = 8.3 Hz, JHH = 2.7 Hz, CH8). 13C NMR
(125.75 MHz, CDCl3): δC 63.8 (CH4’), 82.8 (CH5’), 116.4 (CH8), 122.2 (C-Br), 128.1 (CH6),
128.2 (C4a), 128.6 (2CHmeta of Ph), 129.1 (2CHortho of Ph and CH5), 130.1 (C3), 130.6 (CH7),
131.4 (CH4), 134.3 (CHpara of Ph), 134.3 (C8a), 134.7 (Cipso of Ph), 146.0 (C2), 191.6 (C=O).
4.1.9.
(3-Bromo-5-[1,2,3,4]tetrazolo[1,5-a]quinolin-4-yl-4,5-dihydroisoxazol-4-yl)(4-
methylphenyl)methanone (3i). White powder, m.p = 178-179 °C, 0.37 g, yield 85%, IR (KBr)
(νmax, cm-1): 1674 (C=O), 1607 (C=N), 1534 and 1460 (Ar), 1260 (C-O). Anal. Calcd. for
C20H14BrN5O2 (436.27): C, 55.06; H, 3.23; N, 16.05%. Found C, 55.01; H, 3.29; N, 16.01%. MS
(EI, 70 eV): m/z (%): 436 (0.1), 356 (5), 354 (4), 326 (5), 325 (4), 298 (2), 297 (2), 259 (3), 231
(4), 179 (3), 170 (3), 157 (4), 154 (3), 152 (4), 142 (5), 141 (8), 140 (4), 130 (3), 127 (5), 120
(21), 119 (100), 116 (3), 115 (12), 114 (10), 101 (3), 92 (6), 91 (62), 89 (10), 65 (21), 63 (9), 51
1
3
3
(5). H NMR (500.13 MHz, CDCl3): δH 5.79 (1H, d, JHH = 7.0 Hz, CH4’), 6.57 (1H, d, JHH
=
3
3
7.0 Hz, CH5’), 7.32 (2H, d, JHH = 8.0 Hz, 2CH of Ar), 7.76 (1H, t, JHH = 7.5 Hz, CH6), 7.92
(1H, t, 3JHH = 7.6 Hz, CH7), 7.99 (2H, d, 3JHH = 8.2 Hz, 2CH of Ar), 8.03 (1H, d, 3JHH = 7.9 Hz,
3
CH5), 8.15 (1H, s, CH4), 8.68 (1H, d, JHH = 8.3 Hz, CH8). 13C NMR (125.75 MHz, CDCl3): δC
21.8 (Me), 64.04 (CH4’), 83.3 (CH5’), 116.8 (CH8), 122.7 (C-Br), 128.5 (CH6), 128.7 (C4a), 129.5
(CH5), 129.7 (2CHmeta of Ar), 129.7 (2CHortho of Ar), 130.3 (C3), 131.1 (CH7), 131.8 (CH4),
134.1 (C8a), 135.3 (Cipso-C=O), 145.4 (Cipso-Me), 146.0 (C2), 191.4 (C=O).
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