Vinylphosphonium Salt-Mediated Reactions: A One-Pot Condensation Approach for the Highly cis-Selective Synthesis of N-Benzoylaziridines and the Green Synthesis of 1,4,2-Dioxazoles as Two Important Classes of Heterocyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.8b03388

An efficient, one-pot, and convenient approach for the reaction of the same precursors, trialkyl(aryl) phosphines, acetylene diesters, and benzhydroxamic acids has been developed to produce two important classes of heterocyclic compounds: N-benzoylaziridines and 1,4,2-dioxazoles. The strategy utilizes the intermediate solvation as a key step in product selectivity. The usefulness of the developed approach has been confirmed in the unprecedented highly cis-selective formation of the N-benzoylaziridines. In addition, the procedure provides a green alternative method for the synthesis of 1,4,2-dioxazoles employing a β-cyclodextrin nanoreactor in aqueous media.

Full text of DOI:10.1021/acs.orglett.8b03388

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Vinylphosphonium Salt-Mediated Reactions: A One-Pot
Condensation Approach for the Highly cis-Selective Synthesis of
N‑Benzoylaziridines and the Green Synthesis of 1,4,2-Dioxazoles as
Two Important Classes of Heterocyclic Compounds
Hamideh Ag‡hahosseini,† Ali Ramazani,*,† Nastaran Safarvand Jalayer,† Zahra Ranjdoost,†
§
§
́
Ali Souldozi, Katarzyna Slepokura, and Tadeusz Lis
†Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran
‡Department of Chemistry, Urmia Branch, Islamic Azad University, Urmia, Iran
§Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland
S
* Supporting Information
ABSTRACT: An efficient, one-pot, and convenient approach for the reaction
of the same precursors, trialkyl(aryl) phosphines, acetylene diesters, and
benzhydroxamic acids has been developed to produce two important classes
of heterocyclic compounds: N-benzoylaziridines and 1,4,2-dioxazoles. The
strategy utilizes the intermediate solvation as a key step in product selectivity.
The usefulness of the developed approach has been confirmed in the
unprecedented highly cis-selective formation of the N-benzoylaziridines. In
addition, the procedure provides a green alternative method for the synthesis
of 1,4,2-dioxazoles employing a β-cyclodextrin nanoreactor in aqueous media.
Scheme 1. Efficient One-Pot Synthesis of 1,4,2-Dioxazoles
(1) and N-Benzoylaziridines (2)
hosphine-mediated and phosphine-catalyzed reactions
1
Phave been widely reported for more than a century.
Phosphines can easily add onto a variety of electron-deficient
species, resulting in zwitterionic compounds as the important
synthetic intermediates.
The reaction of phosphines with carbonyl compounds has
been widely studied.2 In this regard, significant efforts have
been made to exploit reactions involving zwitterions derived
from activated acetylenediesters using trivalent phosphines in
Wittig reactions,3 annulations4 and cycloadditions.5 Mean-
while, the reaction between trivalent phosphorus compounds
and acetylenic esters in the presence of organic acids such as
CH acids, NH acids, OH acids, or SH acids to give a vinyl
trivalent phosphonium cation as the important intermediate
has been studied extensively.2
ziridines are an activated type of aziridines for the formation of
ketyls and radical intermediates under the nucleophilic ring
opening reactions.9 The development of synthetic methods for
the synthesis of aziridines in the stereoselective manner is of
relevance for the life-science industry.10,11 Aziridines are
known as key intermediates for many diverse products,12
such as bioactive aziridines and nonaziridine containing
bioactive compounds as well as natural products.13 Some
possible routes for the stereoselective synthesis of aziridines
featuring double bond aziridination,14 aziridination of
imines,10a,15 multicomponent reactions,11b organocatalytic
Herein, we describe a novel, one-pot, and convenient
reaction between trivalent phosphorus nucleophiles, acetylenic
esters and benzhydroxamic acids as the OH-organic acids in
the different solvent conditions to afford two classes of
heterocyclic compounds: 1,4,2-dioxazoles (1) and cis-2,3-
disubstituted N-benzoylaziridines (meso structure) (2)
(Scheme 1).
Aziridines with structural fascination,6 pharmaceutical
importance,7 and wide applications in synthetic chemistry8
have attracted particular attention from organic synthetic and
medicinal chemistry communities. In particular, N-benzoyla-
Received: October 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03388
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
asymmetric reactions,10b and so on. This study reports the
unprecedented catalyst-free cis-selective synthesis of N-
benzoylaziridines under operationally convenient conditions.
In addition to the pharmacological importance of 1,4,2-
dioxazoles, such as their antiamoebic activity16 and modest
central nervous system depressant activity,17 research also
explored their very important synthetic aspects as protecting
agents,18 nitrene precursors,19 nitrene transfer reagents,20 and
amidating reagents.21 Although the synthesis of 1,4,2-dioxazole
derivatives from the reaction of benzhydroxamic acids and
acetylene esters has been previously reported in methanol,17
the efficient synthesis of these compounds employing β-
cyclodextrin (β-CD) as a nanoreactor and trialkyl(aryl)
phosphine as an organocatalyst could realize the reaction in
water as a green process, which has not been reported so far.
Cyclodextrins have been widely used as nanoreactors in
organic syntheses. They act through reversible formation of
host−guest complexes with various organic compounds22 and
contribute greatly to the development of catalytic processes in
water.3,23
Initially, we optimized the reaction conditions for the
synthesis of 1,4,2-dioxazoles. Previously the use of methanol
was reported as a solvent for this reaction.17 We investigated
the use of water as a green, polar protic solvent with the
assistance of β-CD as a nanoreactor and trialkyl(aryl)
phosphine as an organocatalyst to afford 1,4,2-dioxazoles
with high yields and under green conditions (Table 1, entries
2−9). The hydrophobic cavity and the external hydrophilic
surface of β-CD nanoreactor enables it to process the insoluble
organic reactants reaction in aqueous media.
a
Table 1. Optimization of Reaction Conditions
Product
d
Yield (%)
β-
c
PPh3(molar CD temperature
b
entry
solvent
ratio)
(mg)
(°C)
1a
2a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
methanol
water
water
water
water
water
water
water
water
1,4-dioxane
DMSO
DMF
acetonitrile
acetonitrile
acetonitrile
acetonitrile
1
1
1
1
1
1
0.5
0.1
0
1
1
1
1
−
5
10
15
−
10
10
10
10
−
−
−
−
−
10
10
reflux
25
25
25
25
50
25
25
25
25
25
25
25
50
25
25
80
80
83
83
59
0
0
0
0
0
0
0
0
0
e
30
72
64
60
trace
trace
trace
trace
trace
trace
trace
78
85
84
85
70
85
0
1
1
f
0
a
Reaction conditions: triphenylphosphine (1 mmol), dimethyl
acetylenedicarboxylate (1 mmol), benzhydroxamic acid (1 mmol);
solvent (0.5 mL); adjusted reaction time (12 h for dioxazoles and 72
h for aziridines). Molar ratio of triphenylphosphine as an
organocatalyst to other reactants. In order to avoid side reactions,
the reaction began at −10 °C and the secondary temperature was
adjusted after 30 min. Isolated yields. Increased temperature led to
the conversion of dimethyl acetylenedicarboxylate to dimethyl
The required amount of trialkyl(aryl) phosphine as an
organocatalyst was investigated in the synthesis of 1,4,2-
dioxazoles (Table 1, entries 3, 7−9). It was observed that the
best yield was observed with equivalent molar ratios of
organocatalyst and reactants.24 It could be concluded that the
higher molar ratios of catalyst could prevent side reactions,25
such as polymerization of acetylenic esters26 at the initial
reaction steps.
b
c
d
e
f
fumarate. Reaction in the absence of trialkyl(aryl) phosphine.
Then, some of aprotic solvents were investigated as the
reaction media, and it was observed that the cis-N-
benzoylaziridines were obtained in excellent yields and only
a trace amount of 1,4,2-dioxazoles was observed as the
byproduct (Table 1, entries 10−16). Among the investigated
aprotic solvents, we selected acetonitrile as an optimized
solvent, because of its lower toxicity.
Furthermore, to avoid side reactions, both types of reactions
began at −10 °C and the secondary temperature was adjusted
after 30 min. In aqueous media, increasing the reaction
temperature leads to the conversion of dialkyl acetylenedi-
carboxylate to dialkyl fumarate and consequently decreases the
1,4,2-dioxazoles yields (Table 1, entry 6). Moreover, it was
observed that, in the selected aprotic solvent, acetonitrile,
increasing the reaction temperature above room temperature
resulted in lower N-benzoylaziridines yields (Table 1, entry
14). Indeed, the higher reaction temperature directed the
mechanism to an undesirable reaction between trialkyl(aryl)
phosphine and 2 equiv of dialkylacetylene diester to afford a
five-membered heterocyclic product.25
gave the corresponding products in excellent yields (Table 2).
Meanwhile, the scope of acetylene diesters was investigated
and the ethylacetylene dicarboxylate represented slightly better
yields compared with its dimethyl analogue. Moreover the
asymmetric substituted acetylene diesters were examined and
they did not afford any N-benzoylaziridines (Table 2, entries
16−18).
We proposed the following reaction mechanism for the
synthesis of heterocyclic compounds, 1,4,2-dioxazoles (1) and
N-benzoylaziridines (2) from the same reactants (Scheme 2).
Initially, the addition of trialkyl(aryl) phosphine to dialkyl
acetylenedicarboxylate afforded the expected reactive 1,3-
dipolar intermediate. Then, the hydrogen transfer from
benzhydroxamic acid to 1,3-dipolar intermediate gave the
benzhydroxamate as a nucleophile. In this step, the solvent
nature represents its influence on the reaction pathways. In
protic solvents, the solvation of the benzhydroxamate ion can
significantly decrease its nucleophilicity and direct reaction
pathway to the Michael addition. Subsequently, the 1,2-H shift
followed by the intramolecular cyclization afford the 1,4,2-
dioxazole derivatives. On the other hand, when an aprotic
solvent was employed, a hard acid/hard base reaction occurred
between phosphonium cation and benzhydroxamate anion.
The nucleophilic intramolecular cyclization leads to an
Encouraged by these results, we next investigated the
substrate scope of the reactions under the optimized reaction
conditions given in Table 1, entries 3 and 13. The scope of
benzhydroxamic acids was first investigated for the synthesis of
the 1,4,2-dioxazoles and N-benzoylaziridines and all of them
B
DOI: 10.1021/acs.orglett.8b03388
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope of Substrates and Product Selectivity
b
Product Yield
entry
solvent
R
R′
R′′
Ar
C6H5
C6H5
1 (%) 2 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH3
C2H5
CH3
C2H5
CH3
C2H5
C2H5
CH3
C2H5
C2H5
CH3
C2H5
CH3
C2H5
C2H5
CH3
C2H5
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
C2H5
CH3
C2H5
C2H5
CH3
C2H5
CH3
C2H5
C2H5
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C4H9
C6H5
C6H5
C6H5
a: 83
b: 85
c: 90
d: 95
e: 88
f: 93
g: 87
h: 97
i: 98
j: 94
trace
trace
trace
trace
trace
trace
trace
trace
a: 0
b: 0
c: 0
d: 0
e: 0
f: 0
g: 0
h: 0
i: 0
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-IC6H4
4-PhC6H4
4-PhC6H4
3-NO2C6H4
C6H5
H2O
H2O
j: 0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
a: 85
b: 87
c: 80
d: 83
b: 73
k: 0
l: 0
C6H5
4-BrC6H4
4-PhC6H4
C6H5
C6H5
C6H5
H
c
C6H5
C6H5
m: 0
a
Optimized reactions conditions: trialkyl(aryl) phosphine (1 mmol), acetylene diester (1 mmol), hydroxamic acid (1 mmol); solvent (0.5 mL);
reaction time (12 h for dioxazoles and 72 h for aziridines); reaction temperature (−10 °C for 30 min and then warmed to room temperature).
b
c
Isolated yields. Ethyl phenylacetylenecarboxylate.
Scheme 2. Possible Reaction Mechanism for the Synthesis of 1,4,2-Dioxazoles (1) and N-Benzoylaziridines (2)
C
DOI: 10.1021/acs.orglett.8b03388
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unstable five-membered ring, which produces N-benzoylazir-
idines after the elimination of trialkyl(aryl) phosphine oxide.
Our proposal for the cis-selectivity in forming the N-
benzoylaziridines is based on steric factors (Figure 1). The
AUTHOR INFORMATION
Corresponding Author
■
*E-mail addresses: aliramazani@gmail.com, aliramazani@znu.
ac.ir.
ORCID
Ali Ramazani: 0000-0003-3072-7924
Notes
The authors declare no competing financial interest.
DEDICATION
■
Figure 1. Preferred orientation in the transition state for the
cyclization.
Dedicated to Professor Dr. Issa Yavari on the occasion of his
70th birthday.
ester groups are likely to adopt a cis-orientation preferentially
to avoid unfavorable repulsive interactions with the benzoyl
group on the N atom and/or R′ of trialkyl(aryl) phosphine,
which results in the cis-aziridine configuration.
In summary, we have disclosed the unprecedented catalyst-
free cis-selective synthesis of N-benzoylaziridines and efficient
aqueous synthesis of 1,4,2-dioxazoles employing β-CD nano-
reactor under one-pot operationally convenient conditions.
The structures of both classes of compounds were confirmed
via single-crystal X-ray analysis (Figure 2).
REFERENCES
■
(1) Karanam, P.; Reddy, G. M.; Koppolu, S. R.; Lin, W. Tetrahedron
Lett. 2018, 59, 59.
(2) Ramazani, A.; Reza Kazemizadeh, A. Curr. Org. Chem. 2011, 15,
3986.
(3) Ramazani, A.; Ahmadi, Y.; Aghahosseini, H.; Joo, S. W.
Phosphorus, Sulfur Silicon Relat. Elem. 2016, 191, 354.
(4) Liu, C.-Z.; Han, Y.; Zhang, Y.-Y.; Sun, J.; Yan, C.-G. Synthesis
2018, 50, 3715.
(5) Alizadeh, A.; Mohammadi, R.; Bayat, F.; Zhu, L.-G. Tetrahedron
2017, 73, 4433.
(6) Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley−
VCH Verlag & Co: Weinheim, Germany, 2006.
(7) Gianolio, D. A.; Johnston, E. E.; Miller, R. J. U.S. Patent No.
7,387,836, 2008.
(8) (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A. ChemInform, 2004,
35, DOI: 10.1002/chin.200435254 (b) Stewart, I. C.; Lee, C. C.;
Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17616.
(c) Lu, P. Tetrahedron 2010, 66, 2549.
(9) (a) Stamm, H.; Assithianakis, P.; Weiss, R.; Bentz, G.; Buchholz,
B. J. Chem. Soc., Chem. Commun. 1984, 753. (b) Lin, P. Y.; Weiß, R.;
Werry, J.; Falkenstein, R.; Stamm, H. J. Prakt. Chem. 2000, 342, 153.
(10) (a) Bull, J. A.; Boultwood, T.; Taylor, T. A. Chem. Commun.
2012, 48, 12246. (b) Frankowski, S.; Bojanowski, J.; Saktura, M.;
Romaniszyn, M.; Drelich, P.; Albrecht, Ł. Org. Lett. 2017, 19, 5000.
(c) Moens, M.; De Kimpe, N.; D’hooghe, M. J. Org. Chem. 2014, 79,
5558. (d) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.-L.; Yousufuddin,
M.; Devarajan, D.; Ess, D. H.; Ku
61.
̈
rti, L.; Falck, J. R. Science 2014, 343,
Figure 2. X-ray structures of 1h and 2b. Arbitrary chosen enantiomers
are shown.
(11) (a) Zhang, S.; Li, L.; Xin, L.; Liu, W.; Xu, K. J. Org. Chem.
2017, 82, 2399. (b) Bew, S. P.; Liddle, J.; Hughes, D. L.; Pesce, P.;
Thurston, S. M. Angew. Chem., Int. Ed. 2017, 56, 5322. (c) Zhou, Y.;
Mukherjee, M.; Gupta, A. K.; Wulff, W. D. Org. Lett. 2017, 19, 2230.
(d) Wang, H.; Yang, J. C.; Buchwald, S. L. J. Am. Chem. Soc. 2017,
139, 8428. (e) Trost, B. M.; Saget, T.; Hung, C. I. Angew. Chem. 2017,
129, 2480. (f) Hajra, S.; Aziz, S. M.; Jana, B.; Mahish, P.; Das, D. Org.
Lett. 2016, 18, 532.
ASSOCIATED CONTENT
■
S
* Supporting Information
(12) Lu, P. Tetrahedron 2010, 66, 2549.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03388.
(13) Botuha, C.; Chemla, F.; Ferreira, F.; Perez-Luna, A. Heterocycles
in Natural Product Synthesis; Majumdar, K. C., Chattopadhyay, S. K.,
Eds.; Wiley: Hoboken, NJ, 2011; pp 3−39.
(14) Llaveria, J.; Beltran, A.; Sameera, W.; Locati, A.; Díaz-Requejo,
M. M.; Matheu, M. I.; Castillon, S.; Maseras, F.; Perez, P. J. J. Am.
Chem. Soc. 2014, 136, 5342.
Detailed experimental procedures, spectral data, and full
characterization (PDF)
(15) (a) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Org.
Lett. 2004, 6, 2377. (b) Boultwood, T.; Affron, D. P.; Trowbridge, A.
D.; Bull, J. A. J. Org. Chem. 2013, 78, 6632.
(16) Bhat, A. R.; Athar, F.; Azam, A. Eur. J. Med. Chem. 2009, 44,
926.
(17) Heindel, N. D.; Fives, W. P.; Carrano, R. A. J. Pharm. Sci. 1977,
66, 772.
Accession Codes
CCDC 1854997 and 1854998 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
(18) Couturier, M.; Tucker, J. L.; Proulx, C.; Boucher, G.; Dube, P.;
Andresen, B. M.; Ghosh, A. J. Org. Chem. 2002, 67, 4833.
D
DOI: 10.1021/acs.orglett.8b03388
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(19) Bizet, V.; Buglioni, L.; Bolm, C. Angew. Chem., Int. Ed. 2014, 53,
5639.
(20) Chen, M.; Sun, N.; Chen, H.; Liu, Y. Chem. Commun. 2016, 52,
6324.
(21) (a) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. J. Am. Chem. Soc.
2015, 137, 4534. (b) Park, J.; Chang, S. Angew. Chem., Int. Ed. 2015,
54, 14103. (c) Liang, Y.; Liang, Y. F.; Tang, C.; Yuan, Y.; Jiao, N.
Chem. - Eur. J. 2015, 21, 16395.
(22) (a) Hapiot, F.; Bricout, H.; Menuel, S.; Tilloy, S.; Monflier, E.
Catal. Sci. Technol. 2014, 4, 1899. (b) Hapiot, F. d. r.; Menuel, S. p.;
́
Ferreira, M.; Leger, B.; Bricout, H.; Tilloy, S. b.; Monflier, E. ACS
Sustainable Chem. Eng. 2017, 5, 3598. (c) Aghahosseini, H.;
Ramazani, A. Curr. Org. Chem. 2016, 20, 2817. (d) Aghahosseini,
H.; Ramazani, A.; Gouranlou, F.; Woo Joo, S. Curr. Org. Synth. 2017,
14, 810−864.
(23) Ramazani, A.; Ayoubi, S.; Ahmadi, Y.; Ahankar, H.;
Aghahosseini, H.; Woo Joo, S. Phosphorus, Sulfur Silicon Relat. Elem.
2015, 190, 2307.
(24) Yavari, I.; Nasiri, F.; Djahaniani, H. Phosphorus, Sulfur Silicon
Relat. Elem. 2003, 178, 2627.
(25) Johnson, A.; Tebby, J. J. Chem. Soc. 1961, 2126, 2126.
̈
(26) Trotus, I.-T.; Zimmermann, T.; Schuth, F. Chem. Rev. 2014,
114, 1761.
E
DOI: 10.1021/acs.orglett.8b03388
Org. Lett. XXXX, XXX, XXX−XXX