Condensed oxaziridine-mediated [3+2] cycloaddition: Synthesis of polyhetero-bicyclo compounds

Article abstract of DOI:10.1055/s-0030-1258819

Polyhetero-bicyclo compounds were synthesized by a regioselective [3+2]-cycloaddition reaction between stable condensed oxaziridines and alkenes, alkynes, and nitriles. These molecules showed considerable antimicrobial activity against several gram-positive bacteria.

Full text of DOI:10.1055/s-0030-1258819

LETTER
2781
Condensed Oxaziridine-Mediated [3+2] Cycloaddition: Synthesis of
Polyhetero-bicyclo Compounds
S
ynthesis of Polyh
a
etero-bicyc
l
lo Com
e
pounds and
r
Their
B
i
iologic
a
al Activities Videtta, Serena Perrone, Francesca Rosato, Pietro Alifano, Salvatore M. Tredici, Luigino Troisi*
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
Fax +39(0832)298732; E-mail: luigino.troisi@unisalento.it
Received 19 July 2010
camphor ring without further purification due to their in-
Abstract: Polyhetero-bicyclo compounds were synthesized by a
stability.5–12 In these cases the preparation of polycyclic
regioselective [3+2]-cycloaddition reaction between stable con-
tetrahydro-oxazolo[3,2-b]isoxazoles 1 was described.
Analogously, Coates et al. obtained cycloadducts 2 by re-
acting oxazoline N-oxides with electron-poor alkenes as
dipolarophiles.4a Likewise, they isolated the 2,3-dihydro-
oxazolo[3,2-b]isoxazoles 3 in the reactions with alkynes
activated by electron-withdrawing groups and the tetrahy-
dro-oxazolo[3,2-b][1,2,4]oxadiazol-2-ones 4 by the reac-
tion with phenyl isocyanate4a,b respectively (Figure 1).
densed oxaziridines and alkenes, alkynes, and nitriles. These mole-
cules showed considerable antimicrobial activity against several
gram-positive bacteria.
Key words: condensed oxaziridines, polyhetero-bicyclo, regio-
selectivity, [3+2] cycloaddition, bactericidal properties
Oxaziridines are very peculiar three-membered heterocy-
clic compounds containing three kinds of atoms having
different electronegativity in adjacent positions. They are
biologically active molecules, which have been shown to
possess bactericidal, viricidal, and cytoxic activities1a–1d
The well-known reactions of oxaziridines with amines
and sulfides may well explain their characteristic biologi-
cal properties as compared to those of analogous com-
pounds such as aziridines or oxiranes. The nucleophilic
reaction of amines and/or sulfides occurs exclusively at
the nitrogen atom of the oxaziridine ring and gives a car-
bonyl compound and an ylide.2 Due to their considerable
biological properties, the synthesis of more complex ox-
aziridines, the study of reactivity with unsaturated sys-
tems, and their action mechanism in biological systems
are of great interest. [3+2]-Cycloaddition reactions be-
tween oxaziridines condensed with heterocycles and un-
saturated systems have not previously been described in
the literature, probably because the synthesis and isolation
of oxaziridines as pure compounds is difficult. In fact,
condensed oxaziridines readily isomerize into the corre-
sponding more stable N-oxides, that have been used in cy-
cloaddition reactions with various dipolarophiles.
Oxazoline N-oxides may be synthesized following two
methods. Keana has shown that oxazolines, prepared by
the classical condensation between amino alcohols and
iminoether hydrochlorides, can be oxidized with the mag-
nesium salt of monoperphthalic acid followed by silica gel
induced isomerization giving the oxazoline N-oxides.3 Al-
ternatively, condensation of hydroxylamino alcohols as
their hydrochloride salts with triethyl orthoesters4a or
N,N-dimethylacetamide diethyl acetal4b affords oxazoline
N-oxides directly. In asymmetric cycloadditions with var-
ious electron-poor alkenes as dipolarophiles, Langlois et
al. used the chiral oxazoline N-oxides condensed with
R
O
R
O
O
O
EWG
EWG
O
N
N
N
O
R
1
2
3
R
R
O
O
O
Ph
EWG
Ph
N
N
N
O
O
4
5
Figure 1 Cycloadducts by oxazoline N-oxide
Moreover, 5,6-dihydro-3aH-oxazolo[3,2-b][1,2,4]oxa di-
azoles 5 have been obtained by 1,3-dipolar reactions be-
tween oxazoline N-oxides and nitriles coordinated with
Pt(II).13 Many of these reactions were not regioselective,
and various diastereomers were isolated. Furthermore, the
dipolarophiles generally required activatation by electron-
withdrawing groups or coordination to a transition metal.
Herein we report the synthesis of stable condensed oxazir-
idines and their regioselective attack on alkenes, alkynes,
and nitriles in [3+2]-cycloaddition reactions. Treatment of
2-methyl and 2-ethyl-4,5-dihydrooxazoles in diethyl ether
at 0 °C with MCPBA (1.1 mmol) and evaporation of the
solvent under reduced pressure at low temperature gave
the desired oxaziridines 6 and 7 (yield 97%) as pure com-
pounds which were immediately allowed to react with un-
saturated substrates (Scheme 1).
It was considerd that the strained oxaziridine ring of these
heterobicyclic compounds would be more reactive either
than the oxazoline N-oxides4–13 or than the simple uncon-
densed oxaziridines.14–17 Thus, oxaziridine 64a was react-
SYNLETT 2010, No. 18, pp 2781–2783
x
x
.x
x
.2
0
1
0
Advanced online publication: 08.10.2010
DOI: 10.1055/s-0030-1258819; Art ID: D19410ST
© Georg Thieme Verlag Stuttgart · New York

2782
V. Videtta et al.
LETTER
acetylene (3 equiv) in refluxing toluene. In both cases,
isoxazoles 12 and 13 (Scheme 3) were isolated as only the
products in 85% yield, after a reaction time of 10 minutes.
The elimination product 2,2-dimethyl-oxirane was not
isolated, presumably due to its volatility.
N
MCPBA
N
O
R
R
Et2O, 0 °C
O
O
6 R = Me
7 R = Et
Once again, the [3+2]-cycloaddition reactions were regio-
selective with the oxygen attacking the internal carbon
and the oxaziridine carbon attacking the external carbon
of the alkyne, affording the initial cycloadducts 10 and 11
that decompose to the more stable isoxazoles 1218 and
13.19 Repeating the reaction under the same conditions,
but at lower temperature (40 °C), only the rearranged
compounds 12 and 13 were observed. Analogous results
have been reported for the cycloaddition reactions be-
tween oxazoline N-oxides and methyl propargyl ester in
presence of dimethylamine hydrochloride.4b
Scheme 1 Condensed oxaziridines synthesis
ed with 2-vinylpyridine (3 equiv) in refluxing toluene, and
the reaction was followed by TLC and GC analysis. After
five hours, when the oxaziridine was completely reacted,
the reaction mixture was cooled to room temperature and
the solvent removed under reduced pressure. The crude
1
mixture was analyzed by H NMR spectroscopy, which
showed the formation of the two bicyclic products 8 with
a diastereomeric ratio of 2:1. Purification by column chro-
matography afforded the cis and trans isomers 8 in 88%
of total yield (Scheme 2). The mixture of diastereomeric
adducts was partially separated by further chromatogra-
phy, and the individual fractions were analyzed by H
NMR and NOESY spectroscopy showing that the cis iso-
mer was major component.
Oxaziridines 6 and 7 were also applied to [3+2]-cycload-
dition reaction with benzonitrile (3 equiv) in refluxing tol-
uene (Scheme 4). Reaction was complete after 30 minutes
and evaporation of the solvent and purification of the
crude mixture on silica gel gave the 1,2,4-oxadiazoles
1620 and 1721 in 88% of yield. In these cases, it was clear
that 16 and 17 resulted from decomposition of the initial
bicyclic cycloadducts, so the cycloadditions were con-
ducted under the same experimental conditions for a
shorter reaction time. After 10 minutes the 5,6-dihydro-
3aH-oxazolo[3,2-b][1,2,4]oxadiazoles 14 and 1513 were
isolated in 93% and 89% yield, respectively. Subsequent
heating 14 and 15 in refluxing toluene for 30 minutes re-
sulted in complete transformation into 16 and 17
(Scheme 4). Once again, cycloaddition had occurred with
excellent regioselectivity; the oxygen attacking the car-
bon and the carbon adding to the nitrogen of the nitrile
group.
1
O
N
N
O
N
O
R
N
toluene
reflux
+
O
R
8 R = Me 88%
9 R = Et 90%
6 R = Me
7 R = Et
Scheme 2 [3+2]-Cycloaddition reaction with 2-vinylpyridine
Thus, the condensed oxaziridine 6 showed excellent regi-
oselectivity in the [3+2]-cycloaddition reaction with the
2-vinylpyridine in which the oxygen attacks the internal
carbon of the dipolarophile and the oxaziridine carbon
binds the external carbon. In contrast, the analogous reac-
tions between oxazoline N-oxides and alkenes gives a
complex mixture of regioisomers.4a A similar result was
obtained also carrying out the reaction between the ox-
aziridine 7 and 2-vinylpyridine under the same experi-
mental conditions. Only the regioisomer 9 was formed in
90% yield and with a cis/trans ratio of 2:1 (Scheme 2).
No reaction between oxazoline N-oxides and nitrile moi-
eties has been previously observed, probably because of
the low reactivity of the nitrile groups and the instability
of the dipoles; although it has been demonstrated that co-
ordination of nitriles to Pt centers markedly enhances the
reactivity with the N-oxide compounds.13 The higher reac-
tivity of the condensed oxaziridines 6 and 7 described
herein, with respect to unstrained oxazoline N-oxides, was
evidenced by the fact that attempted reaction between
2,4,4-trimethyloxazoline N-oxide4a and phenylacetylene,
in toluene at reflux led to no new product after 24 hours.
With these promising initial results, we attempted [3+2]
cycloaddition between oxaziridines 6 and 7 and phenyl-
O
Ph
N
R
12 R = Me
13 R = Et
Ph
O
N
O
N
+
O
R
toluene
reflux
Ph
+
R
O
O
10 R = Me
11 R = Et
6 R = Me
7 R = Et
Scheme 3 [3+2]-Cycloaddition reaction with phenylacetylene
Synlett 2010, No. 18, 2781–2783 © Thieme Stuttgart · New York

LETTER
Synthesis of Polyhetero-bicyclo Compounds and Their Biological Activities
2783
Ph
detailed experimental procedures and characterization data for com-
O
toluene
110 °C
pounds 7–9.
N
O
N
10 min
R
Acknowledgment
14 R = Me
15 R = Et
N
O
Thanks are due to the University of Salento and C.I.N.M.P.I.S.
(Consorzio Interuniversitario Nazionale Metodologie e Processi In-
novativi di Sintesi) for financial support.
+
toluene
110 °C
30 min
N
Ph
O
R
toluene
110 °C
6 R = Me
7 R = Et
O
Ph
N
References and Notes
30 min
N
(1) (a) Chen, H.; Murray, J.; Kornberg, B.; Dethloff, L.; Rock,
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R
16 R = Me
17 R = Et
Scheme 4 [3+2]-Cycloaddition reaction with benzonitrile
Finally, we decided to react the condensed oxaziridines 6
and 7 with a C–N double bond, specifically with imine
1822 under the same cycloaddition conditions (Scheme 5).
However, either due to the imine basicity or steric hin-
drance, 6 and 7 acted as oxygenating agents23 giving the
nitrone 19 and the corresponding 4,5-dihydrooxazoles in
quantitative yield.
(5) Mauduit, M.; Kouklovsky, C.; Langlois, Y.; Riche, C. Org.
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N
O
R
+N
toluene
reflux
N
N
+
+
Ph
O–
Ph
R
O
O
19
18
6 R = Me
7 R = Et
2002, 3566.
Scheme 5 Reaction between condensed oxaziridines and imine
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The antimicrobial properties of these molecules were also
assayed on a battery of gram-positive (Staphylococcus au-
reus SA1; Staphylococcus epidermidis SE1; Micrococcus
luteus ML1) and gram-negative (Escherichia coli FB8;
Salmonella enterica sv. Typhimurium LT2; Vibrio har-
veyi AK1) bacterial strains using standard microbiologi-
cal procedures. They showed considerable/moderate
antimicrobial activity that will be discussed in another
manuscript.
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condensed oxaziridines and their reactivity with diverse
dipolarophiles (alkenes, alkynes, nitriles, and imines) is
described wherein condensed isoxazolidines, isoxazo-
lines, oxadiazoles, and nitrones were synthesized, respec-
tively. Due to the strained rings, the oxaziridines are very
reactive, undergoing [3+2]-cycloaddition reactions with
dipolarophiles without any activation with electron-with-
drawing groups and Pt(II). Moreover, the reactions pro-
ceeded with an excellent regioselectivity, with the oxygen
attacking the internal carbon of the unsaturated system.
(16) Troisi, L.; Fabio, M.; Rosato, F.; Videtta, V. ARKIVOC
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(17) Troisi, L.; Ronzini, L.; Rosato, F.; Videtta, V. Synlett 2009,
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(18) Commercially available compound.
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(20) Commercially available compound.
(21) Barrans, J. Compt. Rend. 1959, 249, 1096.
(22) Commercially available compound prepared according to
the Taguchi’s protocol: Westheimer, F. H.; Taguchi, K.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
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