Versatile approach to densely substituted isoxazolines and pyrazolines: Focus on a quaternary carbon center as a constitutive feature

Article abstract of DOI:10.1016/j.tetlet.2020.151958

A new family of isoxazolines has been obtained via 1,3-dipolar cycloaddition in good to high yields under mild conditions. Our approach focused on construction of the heterocyclic ring and direct access to a quaternary carbon center at position 5. The met

Full text of DOI:10.1016/j.tetlet.2020.151958

Journal Pre-proofs
Versatile approach to densely substituted isoxazolines and pyrazolines: focus
on a quaternary carbon center as a constitutive feature
Abderrahmen Abdelli, Haythem Gharsa, Momtez Jmaï, Anne Gaucher,
Mohamed Lotfi Efrit, Hedi M'rabet, Damien Prim
PII:
S0040-4039(20)30401-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151958
TETL 151958
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 March 2020
7 April 2020
16 April 2020
Please cite this article as: Abdelli, A., Gharsa, H., Jmaï, M., Gaucher, A., Lotfi Efrit, M., M'rabet, H., Prim, D.,
Versatile approach to densely substituted isoxazolines and pyrazolines: focus on a quaternary carbon center as a
constitutive feature, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151958
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
©
2020 Published by Elsevier Ltd.

Tetrahedron Letters
journal homepage: www.elsevier.com
Versatile approach to densely substituted isoxazolines and pyrazolines: focus on a
quaternary carbon center as a constitutive feature
a,
b
a
c
a
Abderrahmen Abdelli *, Haythem Gharsa , Momtez Jmaï , Anne Gaucher , Mohamed Lotfi Efrit , Hedi
a
c,
M’rabet and Damien Prim 
a
Laboratoire de synthèse organique et hétérocyclique sélective-Evaluation d’activité biologique, LR17ES01, Université de Tunis El Manar, Faculté des Sciences
de Tunis, Campus universitaire, 2092 Tunis, Tunisie.
b
Laboratoire des Microorganismes et Biomolécules Actives, Faculté des Sciences de Tunis, Université de Tunis El Manar, 2092 Tunis, Tunisie.
Université Paris-Saclay, UVSQ, CNRS, Institut Lavoisier de Versailles, 78035, Versailles, France.
c
Abstract
A new family of isoxazolines has been obtained via 1,3-dipolar cycloaddition in good to high yields under mild conditions. Our approach focused on
construction of the heterocyclic ring and direct access to a quaternary carbon center at position 5. The methodology has also been extended to
pyrazoline analogues. The antibacterial activity of these compounds was evaluated, showing specific antibacterial activity against Staphylococcus
aureus. Six members of these heterocycles exhibited MIC values of 4 µg/mL.
Keywords:1,3-Dipolar cycloaddition, Isoxazolines, Pyrazolines, Staphylococcus aureus
—
——

Corresponding authors. Tel.: +331-3925-4454; e-mail: damien.prim@uvsq.fr
1
. Introduction
Isoxazolines are partially hydrogenated five-membered heterocycles containing neighbouring oxygen and nitrogen atoms. Members
of this family are key scaffolds of numerous naturally occurring and synthetic biologically active compounds.[1] The steady interest of
the scientific community for modulating biological properties has resulted in the development of effective and appealing synthetic
procedures towards densely substituted isoxazolines.[2-10] The incorporation of more diverse molecular functionalities to the
isoxazoline core as well as the construction of targets displaying a quaternary center in position 5 are among the current challenges in
this domain. Indeed, the C-5 site is crucial to tether isoxazoles to podophyllotoxin or coumarin derivatives in the elaboration of
molecular architectures which display potent insecticide, acaricide or anticancer properties.[11, 12] Moreover, the presence of a
quaternary carbon center at position 5 of the isoxazoline ring prevents aromatization of the heterocycle into the related isoxazoles.
Furthermore, the joint presence of a quaternary center and a functional group (CF )[5] were revealed to be crucial to the enhancement of
3
the biological properties of isoxazoline derivatives. Access to differently substituted isoxazoline cores is reported through two main
methodologies: cyclisation at the remote position or ring construction from oxime derivatives (Fig. 1).
Metal-mediated oxyhalogenation or oxidation of tertiary C-H bonds and photoredox processes are elegant procedures for promoting
cyclisation at remote positions and thus the formation of isoxazolines. Such methods are especially useful to produce quaternary carbon
centers substituted by aryl and alkyl groups as well as halides and di(tri)fluoromethyl groups.[6-10] Ring construction via conjugate
addition or cycloaddition from oxime derivatives and nitrile oxide intermediates is a convenient approach allowing the formation of
3
tertiary or quaternary C-5 centers mainly functionalized by alkyl, aryl or CF groups.[2-5] However, the installation of carboxylic ester,
sulfanyl or phosphonate groups at the C-5 position of the heterocycle remains less reported using both of the aforementioned
strategies.[13] In most of these examples such functional groups substitute tertiary C-5 centers, with carboxylic esters being rarely
found at a quaternary C-5 center.

2
Tetrahedron
Figure 1. Overview of literature methods and the construction of
remote position cyclisation
isoxazolines containing a quaternary C-5 center.
R
oxidation of tertiary
C-H bonds
R
R, R = CO2Me
R, R = Ph
N
N
N
R
O
5
R
HO
HO
R
In this paper we have focused on the installation of two
different functional groups, namely ethoxycarbonyl and
phosphonomethyl at the quaternary C-5 center of isoxazolines.
Our approach is based on the use of ethoxycarbonyl
allylphosphonate[14] and nitrile oxides as the starting materials
via a single step 1,3-dipolar cycloaddition under mild conditions.
Our general methodology was further extended to the preparation
of pyrazolines[15] from the same phosphonate precursor and
nitrile imines. In this family of heterocycles, access to quaternary
oxyhalogenation
X
X = Cl, Br, CF3, CF Cl
R = Ar , alkyl
2
N
di or trifluoromethylation
O 5 R
ring construction
R2 R3
R1
R1
H
conjugate addition
cycloaddition
R3
2
R , R3 = alkyl
+
N
N
O
R2
HO
5
O
R1
R1
2
3
R2
R3
R , R = alkyl, aryl,
C-5 centers bearing valuable functional groups such as CO
2
R and
Y
+
R3
O 5 R2
2
= Ar, R3 = CF3
3
N
N
R
CH PO(OR) remains a challenge. In addition, the preliminary
2
2
2
HO
R , R = alkyl, aryl
biological activities of both isoxazolines and pyrazolines against
R2 = Ar, R3 = CO2Me
Y = H, CO2H, Cl
this work
R2 = H, R3 = CH2PO(OEt)2
Staphylococcus aureus have been evaluated for the development
R2 = H, R3 = SO2Me, PO(OEt)2 of potential new antibacterial agents.
extension to pyrazolines
R1
2. Results and Discussion
PO(OR)2
single step
R1
R1
EtO2C
Cl
CO Et
1,3-Dipolar cycloaddition of alkenes to nitrile oxides, generated
in situ from N-hydroximoyl chlorides, has been widely used for
the synthesis of various heterocyclic structures.[16] We initially
chose allylphosphonate 7 and hydroximoyl chloride 9 as model
substrates to optimize the reaction conditions by testing several
CO2Et
2
N
N
N
N 5
PO(OR)2
O 5
PO(OR)2
Z
Ph
Z = OH
Z = NH-Ph
bases and solvents (Table 1). The reaction carried out in absence of a base led to the unchanged allylphosphonate 7 (Entry 1). We then
decided to prepare the corresponding nitrile oxide in situ by treatment of chlorooxime 9 in the presence of a base. In addition, we were
inspired by the reported methods for oxime cycloadditions, to use amine-type bases to access isooxazoline 12. Initially, we observed
that protic or aprotic solvents had no significant effect on the reaction time or yield (Entries 2 and 5). Increasing the temperature
reduced the reaction time, but unfortunately led to the formation of several by-products. Consequently, isoxazoline 12 was obtained
with a poor yield (Entry 4).
Bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine and Et
increase in the yields and in allylphosphonate conversion was observed, after 18-24 h, when Et
be noted that using more than 1.1 equivalent of Et N has no significant effect on the reaction yield. Although only small differences
were observed between the use of CH Cl and CHCl , the latter led to cleaner crude material avoiding the presence of unidentified side-
products. Thus, Et N/CHCl was determined as the most suitable base/solvent combination for the cycloaddition.
3
N were successively tested (Entries 6-9). A significant
3
N was used (Entries 2, 5, 8, 9). It should
3
2
2
3
3
3
Table 1. Preparation of 5-phosphonomethylisoxazoline 12.
Entry
Conditionsa
CH Cl , r.t
N, CH Cl , r.t
N, CH CN, r.t
N, CH Cl , reflux
Et N, C OH, r.t
DBU, CHCl , r.t
pyridine, CH CN, r.t
Et N, CHCl , r.t
Et N, CHCl , reflux
Time (h)b
Yield 12
(%)
Ph
CO2Et
PO(OEt)2
Conditions
Ph
N
2
CO Et
OH
+
N
PO(OEt)2
Cl
O
12
1
2
3
4
5
6
7
8
9
2
2
72
20
22
10
24
72
72
18
18
--
7
9
Et
Et
Et
3
2
2
72
68
35
68
50
52
75
70
3
3
3
2
2
3
2 5
H
3
3
3
3
3
3
a
Reaction was carried out using 7 (1 mmol), 9 (1.1 mmol) and base (1.1 mmol) in solvent (2 mL).
bReactions were monitored by TLC.

With the optimized reaction conditions in hand, we proceeded to synthesize a new family of 5-phosphonomethylisoxazolines 12-17
in 67-82% yield (Scheme 1).
Scheme 1. Cycloaddition of
allylphosphonates 7-8 towards
2-17.
hydroximoyl chlorides and
phosphonomethylisoxazolines
Ar
CO2Et
PO(OR)2
Ar
N
CO2Et
PO(OR)2
Et3N, CHCl3, r.t
OH
1
+
N
Cl
O
12-17
7
8
R = Et
R = Me
9
Ar =
As reported in the literature,
regioselective or lead to the
formation of mixture of
1,3-dipolar cycloaddition can be
1
0 Ar =
Me
CO2Et
PO(OR)2
Ar
a
1
1 Ar =
regioisomers.[17] In our case,
the cycloaddition was selective
as only one adduct could be
NCS
Pyridine
7, 8
CO2Et
Ar
OMe
N
Ph
Ar
N
Ph
N
H
N
MeO
N
PO(OR)2
H
N
Cl
Et3N, CH3CN
r.t, 12-16h
Ph
OMe
1
21-25
identified according to H and
18 Ar =
OMe
1
3
C NMR data. Similarly, proton
3
1
CO2Et
PO(OEt)2
CO2Et
CO2Et
PO(OEt)2
OMe
14 82%
decoupled
P
NMR
19 Ar =
N
N
PO(OMe)2
N
spectroscopy confirmed the
presence of a single adduct for
isoxazolines 12-17, displaying a
single signal in the range of 23-
O
O
O
MeO
1
2
75%
13 72%
2
0 Ar =
OMe
OMe
Me
Me
2
8 ppm. In our case, the steric
effect may explain the
regioselectivity of the reaction
as previously noted in several
CO2Et
PO(OMe)2
CO2Et
PO(OEt)2
CO2Et
PO(OMe)2
OMe
N
N
O
N
O
O
OMe
1
5
80%
16 70%
17 67%
1
,3-dipolar cycloadditions.[18]
CO2Et
CO2Et
PO(OMe)2
CO Et
2
Plausibly, the formation of
N
PO(OEt)2
N
N
N
PO(OEt)2
N
N
regioisomer (I) is favored in comparison with (II) (Fig. 2). Indeed,
the formation of regioisomer (II) appears less favorable due to the
steric hindrance between the aryl fragment of the nitrile oxide and
the phosphonate-ethoxycarbonyl groups of dipolarophiles 7-8. The
formation of regioisomer (I) was consistent with the 13C NMR data
which allowed discrimination between both potential adducts. The
Ph
Ph
Ph
21 90%
22 85%
23 82%
OMe
NO2
OMe
CO2Et
PO(OMe)2
CO Et
2
CO2Et
PO(OEt)2
1
3
N
C NMR spectra of isoxazolines 12-17 displayed a signal in the
N
N
PO(OEt)2
N
N
N
range 84-85 ppm, which precludes approach (II) and accounts for
the formation of a quaternary carbon alpha to the oxygen atom,
consistent with the spectroscopic data of regioisomer (I). In addition,
Ph
24 70%
Ph
Ph
25 78%
26 -
2
D HMBC NMR spectroscopy undoubtedly confirmed that only
a
b
regioisomer (I) was obtained. Indeed, protons H and H are
privileged spectators of the structure of the heterocycle and thus of the cycloaddition selectivity. As shown in the ESI, 2D HMBC NMR
spectroscopy exhibited characteristic correlations between H and H in complete agreement with the structure of regioisomer (I). At the
a
b
b
same time, no correlation between H and the (C=N) carbon of the heterocycle which potentially accounts for regioisomer (II) was
observed.
Figure 2. Proposed regioselectivity control for the 1,3-dipolar cycloaddition.
2D HMBC NMR
characteristic correlations
between H(a) and H(b)
X
We next examined the transformation of allylphosphonates 7-8 into 5-
phosphonomethylpyrazolines 21-25. Several studies have shown that 1,3-
dipolar cycloaddition between dipolarophiles and hydrazonyl chlorides,
which are used as a source of nitrile imines, is an efficient approach to
access 5- membered aza-heterocycles.[19, 20]
O
(a)
N
O
O
O
H
CO2Et
OR
X
P
OR
N
PO(OR)2
O
7-8
H
(b)
O
(I)
N
13C NMR
Scheme 2. Cycloaddition of hydrazonyl chlorides and allylphosphonates 7-8
towards 5-phosphonomethylpyrazolines 21-25.
X
84.41-85.64 ppm
In our case, we chose to examine the cycloaddition between
allylphosphonates 7-8 and hydrazonyl chlorides. The latter can be easily
generated in situ from hydrazones 18-20, using N-chlorosuccinimide
(NCS) in pyridine (Scheme 2). The resulting hydrazonyl chlorides
reacted smoothly with the allylphosphonates at room temperature to
afford the expected pyrazoline derivatives. The cycloaddition process led
to the formation of 5-phosphonomethylpyrazolines 21-25 in 70-90%
X
N
O
2
CO Et
O
O
O
O
N
PO(OR)2
OR
P
H
(b)
OR
7
-8
X
X
(II)
No correlation observed
on 2D HMBC NMR
N
O

4
Tetrahedron
yield (Scheme 2). Spectroscopic data were also consistent with the presence of a quaternary carbon center substituted by
phosphonomethyl, methylcarboxylate and nitrogen fragments. Surprisingly, the cycloaddition between allylphosphonates 7-8 and
hydrazones bearing an electron-withdrawing nitro group in both the meta and para positions did not allow the formation of the
corresponding pyrazolines, even with prolonged reaction times and at higher reaction temperatures. This might be attributed to either
the instability of the hydrazonyl chloride intermediate or the lack of reactivity of hydrazones bearing electron-withdrawing groups
precluding in situ formation of the hydrazonyl chloride at an early stage of the reaction.
Antibacterial activity
The biological activities of nine compounds were evaluated for their antibacterial properties against several bacterial species;
Staphylococcus aureus and Enterococcus faecalis classified as Gram-positive bacteria; Escherichia coli and Pseudomonas aeruginosa
classified as Gram-negative bacteria. The antibacterial activity of isoxazolines 12-17 and pyrazolines 21-25 was assessed using the disc-
diffusion and broth dilution methods.[21] Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and Enterococcus
faecalis Gram positive bacteria isolates showed no sensitivity to the tested compounds. Interestingly, growth inhibition was observed in
the Staphylococcus aureus strain that exhibited susceptibility to most of the evaluated compounds, especially 5-
phosphonomethylisoxazolines (12, 14 and 17) and 5-phoshonomethylpyrazolines (22, 23 and 24) which exhibited the lowest MIC
values of 4 µg/mL (Table 2). According to the antibacterial test results, the synthesized isoxazolines and pyrazolines showed specific
activity against Staphylococcus aureus Gram positive bacteria.
Table 2. Antimicrobial activity assays and minimal inhibitory concentrations (MIC) against Staphylococcus aureus.
Compounds
MIC (µg/mL)
1
1
1
1
2
2
2
4
5
7
1
2
4
4
32
4
16
4
2
2
2
3
4
5
4
4
32
4
Gentamicin
3
. Conclusion
In the present work, we have prepared novel 5-phosphonomethyl-isoxazoline derivatives incorporating a quaternary carbon center at
the C-5 position via 1,3-dipolar cycloaddition reactions from allylphosphonate precursors. This easy to implement and efficient strategy
allowed the synthesis of densely functionalized isoxazolines. The cycloaddition process was shown to be highly selective, leading to a
single adduct most plausibly due to steric factors. Our approach was also successfully extended to the preparation of 5-
phosphonomethyl-pyrazolines starting from allylphosphonates. Biological activities of the synthesized isoxazolines and pyrazolines
have been evaluated. Heterocycles bearing phosphonomethyl fragments exhibited specific activity against Staphylococcus aureus Gram
positive bacteria. Functionalization of the phosphonated isoxazolines and pyrazolines as well as the study of its effect on their biological
activities will be the subject of a forthcoming publication.
Acknowledgments
Authors are grateful to the Tunisian Ministry of Higher Education and Scientific Research, to the University of Tunis El Manar, to
the CNRS and the University of Versailles-Saint-Quentin-en-Yvelines for financial support.
References and notes
1
.
(a) Ajay Kumar, K.; Govindaraju, M.; Renuka, N.; Vasanth Kumar, G. J. Chem. Pharm. Res. 2015, 7, 250-257; (b) Lingaraju, G. S.; Balaji, K. S.;
Jayarama, S.; Anil, S. M.; Kiran, K. R.; Sadashiva, M. P. Bioorg. Med. Chem. Lett. 2018, 28, 3606–3612; (c) Znati, M.; Debbabi, M.; Romdhane, A.;

Jannet, H. B.; Bouajila, J. J. Pharm. Pharmacol. 2018, 70, 1700-1712; (d) Yang, R.; Zhang, Y.; Xu, H. Bioorg. Med. Chem. Lett. 2018, 28, 1410–
416; (e) Filali, I.; Bouajila, J.; Znati, M.; Bousejra-El Garah, F.; Jannet, H. B. J. Enzym. Inhib. Med. Chem. 2015, 30, 371–376.
(a) Pohjakallio, A.; Pihko, P. M.; Liu, J. J. Org. Chem. 2010, 75, 6712–6715; (b) Pohjakallio, A.; Pihko, P. M.; Laitinen, U. M. Chem. Eur. J. 2010,
6, 11325-11339.
(a) Han, L.; Zhang, B.; Zhu, M.; Yan, J. Tetrahedron Lett. 2014, 55, 2308–2311; (b) Li, Z.; Frings, M.; Yu, H.; Raabe, G.; Bolm, C. Org. Lett. 2018,
1
2
3
.
.
1
2
1
0, 7367-7370; (c) Zhao, S.; Jin, L.; Chen, Z-L.; Rui, X.; He, J-Y.; Xia, R.; Chen, K.; Chen, X-X.; Yin, Z-J.; Chen, X. RSC Adv. 2019, 9, 11585-
588; (d) Okusu, S.; Okazaki, H.; Tokunaga, E.; Soloshonok, V. A.; Shibata, N. Angew. Chem. Int. Ed. 2016, 55, 6744-6748.
4
5
.
.
Svejstrup, T. D.; Zawodny, W.; Douglas, J. J.; Bidgeli, D.; Sheikhc, N. S.; Leonori, D. Chem. Commun. 2016, 52, 12302 -12305.
Lahm, G. P; Cordova, D.; Barry, J. D.; Pahutski, T. F.; Smith, B. K.; Long, J. K.; Benner, E. A.; Holyoke, C. W.; Joraski, K.; Xu, M.; Schroeder, M.
E.; Wagerle, T.; Mahaffey, M. J.; Smith, R. M.; Tong, M.-H. Bioorg. Med. Chem. Lett. 2013, 23, 3001–3006.
Zhu, X. ; Wang, Y.-F. ; Ren, W. ; Zhang, F.-L. ; Chiba, S. Org. Lett. 2013, 15, 3214-3217.
Shi, D.; Qin, H.-T.; Zhu, C.; Liu, F. Eur. J. Org. Chem. 2015, 5084–5088.
Zhu, M.; Fun, W.; Guo, W.; Tian, Y.; Wang Z.; Xu, C.; Ji, B. Eur. J. Org. Chem. 2019, 1614–1619.
Dong, K.-Y.; Qin, H.-T.; Liu, F.; Zhu, C. Eur. J. Org. Chem. 2015, 1419–1422.
6
7
8
9
1
1
1
1
.
.
.
.
0. Li, X.; Ding, Y.; Qian, L.; Gao, Y.; Wang, X.; Yan, X.; Xu, X. J. Org. Chem. 2019, 84, 12656−12663.
1. Yang. R.; Zhang, Y.; Xu, H. Bioorg. Med. Chem. Lett. 2018, 28, 1410–1416.
2. Lingarajua, G. S.; Balajib, K. S.; Jayaramab, S.; Anila, S. M.; Kirana, K. R.; Sadashivaa, M. P. Bioorg. Med. Chem. Lett. 2018, 28, 3606–3612.
3. (a) Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O. R., J. Org. Chem. 2006, 71, 7337-7345; (b) Conti, P.; Pinto, A.; Tamborini, L.; Dunkel,
P.; Gambaro, V.; Visconti, G. L.; DeꢀMicheli, C. Synthesis 2009, 04, 591-596; (c) Chalyk, B. A.; Sosedko, A. S.; Volochnyuk, D. M.; Tolmachev, A.
A.; Gavrilenko, K. S.; Liashuk, O. S.; Grygorenko, O. O. Org. Biomol. Chem. 2018, 16, 9152-9164; (d) Perez, V.; Rabasso, N.; Fadel, A. Eur. J. Org.
Chem. 2016, 2016, 320–324.
1
1
4. For recent applications of ethoxycarbonyl allylphosphonate, see: (a) Abdelli, A.; Gaucher, A.; Efrit, M. L.; M’rabet, H.; Prim, D. Tetrahedron Lett.
2
015, 56, 1679-1681; (b) Abdelli, A.; Efrit, M. L.; Gaucher, A.; M’rabet, H.; Prim, D. Tetrahedron Lett. 2015, 56, 5397-5400; (c) Abdelli, A.;
Bourdreux, F.; Gaucher, A.; Efrit, M. L.; M’rabet, H.; Prim, D. Tetrahedron Lett. 2016, 57, 379-382; (d) Boufroura, H.; Abdelli, A.; Bourdreux, F.;
Gaucher, G.; Clavier, G.; Efrit, M. L.; M'rabet, H.; Prim, D. RSC Adv. 2017, 7, 18211-18216.
5. For recent evaluation of the bioblogical activities of pyrazoline dereivatives, see: (a) ElBordiny, H. S.; El-Miligu, M. M.; Kassab, S. E.; Dabees, H.;
Ali, W. A. M.; El-Hawash, S. A. M. Eur. J. Med. Chem. 2018, 145, 594-605; (b) Burmudžija, A.; Muškinja, J.; Ratković, Z.; Kosanić, M.; Ranković,
B.; Novaković, S. B.; Bogdanović, G. A. Inorg. Chim. Acta. 2018, 471, 570-576; (c) Kumar. G.; Tanwar, O.; Kumar, J.; Akther, M.; Sharma, S.;
Pillai, C.R.; Alam, M. M.; Zama, M.S. Eur. J. Med. Chem. 2018, 149, 139-147; (d) Chen, K.; Zhang, Y-L.; Fan, J.; Ma, X.; Qin, Y-J.; Zhu, H-L. Eur.
J. Med. Chem. 2018, 156, 722-737; (e) Yang, R.; Lv, M.; Xu, H. J. Agric. Food Chem. 2018, 66, 11254–11264.
6. Kotyatkina, A. I.; Zhabinsky, V. N.; Khripach, V. A. Russ. Chem. Rev. 2001, 70, 641-653.
1
1
1
7. Aurell, M. J.; Domingo, L. R.; Pérez, P. Tetrahedron 2004, 60, 11503–11509.
8. (a) Efremova, M. M.; Molchanov, A. P.; Stepakov, A. V.; Kostikov, R. R.; Shcherbakova, V. S.; Ivanov, A. V. Tetrahedron 2015, 71, 2071-2078. (b)
Sharipov, B. T.; Davidova, A. N.; Ryabova, A. S.; Galimzyanova, N. F.; Valeev, F. A. Chem. Heterocycl. Compd. 2016, 52, 31–40.
9. (a) Zou, H.; Zhu, H.; Shao, J.; Wu, J.; Chen, W.; Giulianotti, M. A.; Yu, Y. Tetrahedron 2011, 67,4887-4891; (b) Guo, C-X.; Zhang, W-Z.; Zhang,
N.; Lu, X-B. J. Org. Chem. 2017, 82, 7637−7642; (c) Kawai, H.; Yuan, Z.; Tokunaga, E. Org. Lett. 2012, 14, 5330-5333.
0. (a) Espildora, E.; Delgado, J. L.; Cruz, P.; Hoz, A.; López-Arza, V.; Langa, F. Tetrahedron 2002, 58, 5821-5826.; (b) Cruz, P.; Díaz-Ortiz, A.; García,
J.; Gómez-Escalonilla, M. J.; Hoz, A.; Langa, F. Tetrahedron Lett. 1999, 40, 1587-1590.
1
2
2
2
2
2
2
1. Balouiri, M.; Sadiki, M.; Ibn souda, S. K. J. Pharm. Anal. 2016, 6, 71-79.
2. Goering, B. K. Ph.D. Dissertation, Cornell University, 1995.
3. Haslam, E. Shikimic Acid Metabolism and Metabolites, John Wiley & Sons: New York, 1993.
4. Buchanan, J. G.; Sable, H. Z. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley-Interscience: New York, 1972; Vol. 2, pp 1–95.
5. Lyle, F. R. U.S. Patent 5 973 257, 1985; Chem. Abstr. 1985, 65, 2870.
Supplementary Material
The supplementary material contains experimental procedures and spectroscopic data for all new compounds.
Click here to remove instruction text...
Declaration of interests
☒
The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Highlights
☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
TETL-D-20-00354R1

6
Tetrahedron
Synthesis of isoxazolines and pyrazolines

from a common alllyhosphonate starting
material


Easy access to C5 quaternary carbon center
Selective 1,3-dipolar cycloaddition under
mild conditions

Specific antibacterial activity against
Staphylococcus aureus strain.
Graphical Abstract
R1
R1
CO Et
3 4
3 4
2
CO Et
CO2Et
PO(OR)2
2
PO(OR)2
2
N
2
N
PO(OR)2
O
1N 5
Ph
5
common
starting material
1
R= Me, Et
1
1 examples, 67-90% yield
1
R = Ar



Single step
Compounds with a quaternary C-5 center
Good activity against Staphylococcus aureus