[3+2] Cycloaddition of oxaziridines with nitriles: Synthesis of 2,3-dihydro-1,2,4-oxadiazoles

Article abstract of DOI:10.1055/s-0029-1217186

A new and simpler preparation of 2,3-dihydro-1,2,4 oxadiazoles by synchronous [3+2] cycloaddition between oxaziridines and nitriles is presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217186

1806
LETTER
[3+2] Cycloaddition of Oxaziridines with Nitriles:
Synthesis of 2,3-Dihydro-1,2,4-Oxadiazoles
S
ynthesis of 2,3
u
-Dihydro-1,2
i
,4-Oxa
g
diazoles ino Troisi,* Ludovico Ronzini, Francesca Rosato, Valeria Videtta
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@unile.it
Received 20 February 2009
Recently, a [3+2]-cycloaddition reaction between oxaziri-
Abstract: A new and simpler preparation of 2,3-dihydro-1,2,4 ox-
dines and unactivated terminal alkynes was reported.17,18
The novelty of this reaction lies in the oxaziridine C–O
bond disconnection and the synchronous attack on the tri-
ple bond. In detail, the oxygen atom at the internal posi-
tion and the carbon atom at the terminal position interact.
As a consequence, the cycloaddition is regioselective for
adiazoles by synchronous [3+2] cycloaddition between oxaziridines
and nitriles is presented.
Key word: cycloaddition, oxaziridines, nitriles, 2,3-dihydro-1,2,4
oxadiazoles, heterocycles
the formation of isoxazolines (Scheme 2).
2,3-Dihydro-1,2,4-oxadiazoles (or D4-1,2,4-oxadiazo-
lines) are a lesser known class of heterocycles for which
toluene
reflux
R1
O
few syntheses and applications have been reported in the
literature.1 As such, the development of novel approaches
toward the synthesis of these compounds is of fundamen-
tal interest. Interestingly, the isomeric 4,5-dihydro-1,2,4-
oxadiazoles, which differ from the 2,3-dihydro-1,2,4-ox-
adiazoles only in the position of the ring double bond,
have been studied in significantly more detail; numerous
approaches for their synthesis2 and subsequent application
in various medical fields have been reported.3 To date, the
most common approaches for the synthesis of 2,3-dihy-
dro-1,2,4-oxadiazoles is based on the cycloaddition reac-
tion between nitrones and nitriles,4–9 which proceeds with
complete regiocontrol (Scheme 1).
R2
R1
O
N
R2
C CH
+
N
Ar
Ar
Ar = aryl; R1 = alkyl; R2 = alkyl or aryl
Scheme 2 [3+2]-Cycloaddition reaction between oxaziridines and
alkynes
The same reaction carried out with terminal alkenes pro-
vided direct access to isoxazolidines. Mechanistic analy-
sis of the reaction demonstrated that the cycloaddition
reaction proceeded through a synchronous attack.19
With these promising results as a starting point, we sought
to develop a corresponding [3+2] cycloaddition between
oxaziridines and nitriles to access 2,3-dihydro-1,2,4-oxa-
diazoles by employing the aforementioned reaction con-
ditions. The results of our investigation are summarized in
Table 1.
O
R2
R3
O–
N+
R1
R4
R1
N
R4
C N
+
N
R2
R3
Scheme 1 Synthesis of 2,3-dihydro-1,2,4-oxadiazoles by cycload-
Only 2,3-dihydro-1,2,4-oxadiazoles 1–6 and the starting
materials were isolated when the cycloaddition was car-
ried out in refluxing toluene20 for extended reaction times
(Table 1, entries 1, 3, 5–8). The reaction time could be
shortened and the yield increased when the nitrile was
used as the solvent itself,21 as the temperature could be
raised to 140 °C (Table 1, entries 2, 4, 9). Inspection of
our results indicated that there were no substantial elec-
tronic effects of either the oxaziridine or the nitrile, as was
reported with previous related systems.10–13 Electron-
withdrawing groups on the oxaziridine, such as benzo-
thiazole or pyridine, did not influence the rate or yield of
the reaction, nor did changes to the identity of the substit-
uent on the benzonitriles employed (H, 3-Cl, 3-NO2,
4-OMe, Table 1, entries 3, 5–7).
dition
The high degree of regioselectivity in this cycloaddition is
likely to be due to the fact that, during the course of the
reaction, the negatively charged oxygen atom of the nitro-
ne dipole is oriented toward the positively polarized car-
bon of the nitrile. It is further correlated with the
electronic nature of both components of the reaction as re-
gioselectivity improves with nitriles bearing electron-
withdrawing substituents and nitrones bearing electron-
donating substituents.10–13 It has also been reported that
the formation of nitrile complexes with platinum(IV) or
platinum(II)14–16 and with palladium(II)14 increases the
overall reactivity of the cycloaddition reaction with ni-
trones.
Next, the [3+2] cycloaddition was carried out under catal-
ysis conditions, by adding 10 mol% Pd(OAc)2 to a mix-
ture of oxaziridine (Ar1 = Ph) and benzonitrile. This
process afforded oxadiazoline 1 in the same yield and
SYNLETT 2009, No. 11, pp 1806–1808
Advanced online publication: 18.05.2009
DOI: 10.1055/s-0029-1217186; Art ID: D05909ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,3-Dihydro-1,2,4-Oxadiazoles
1807
reaction time as shown in Table 1, entry 1, contrary to that oxaziridines. In a preliminary attempt (1¢R,2S,3S)-3-phe-
reported.14,16
nyl-2-(1-phenylethyl)-oxaziridine24 reacted with benzoni-
trile giving oxadiazolines 8a and 8b in 38% of yield and
high diastereomeric ratio25 (Scheme 3). These efforts are
ongoing, and more results will be reported in the future.
Interestingly, no product was observed when aliphatic
nitriles were employed, even under the very forcing con-
ditions described above. This may be due to more pro-
nounced steric hindrance of the alkyl group as compared
to the phenyl group.
Ph
Ph
N
N
Ph
Ph
This and the preceding results are best rationalized by a
synchronous [3+2] cycloaddition as recently reported for
reaction with alkenes and alkynes17–19 rather than by a 1,3-
dipolar mechanism, such as for the reactions with
nitrones.10–16
N
N
N
+
Ph
Ph
O
O
O
Ph
Ph
N
8a 85%
[α]D –61.4
8b 15%
C
Ph
[α]D +62.8
(c 0.014, CHCl3)
(c 0.0115, CHCl3)
In summary, we have applied a [3+2] cycloaddition be-
tween oxaziridines and nitriles for the synthesis of the 2,3-
dihydro-1,2,4-oxadiazoles. The more ready access to
oxaziridines19 over nitrones22 could favor the use of the
described methodology for the synthesis of rare hetero-
cycles that have not been previously accessed due to syn-
thetic limitations. Furthermore, the formation of a new
stereogenic center at C-3 suggests that the reaction may be
rendered asymmetric by the incorporation of chiral
Scheme 3 Asymmetric synthesis of 2,3-dihydro-1,2,4-oxadiazoles
by cycloaddition
General Procedure
A solution of oxaziridine (1 equiv) and nitrile (3 equiv) in toluene
(15 mL) was heated to reflux for 120 h. The solvent was removed
under reduced pressure, and the resulting residue was purified di-
rectly by flash chromatography on silica gel deactivated with Et3N.
Table 1 [3+2]-Cycloaddition Reaction between Oxaziridines and Nitriles
O
Ar2
O
N
Ar2
C
N
+
N
Ar1
N
Ar1
Ar1 = aryl or heteroaryl
Ar2 = aryl
1–6
Entry
1
Ar1
Ar2
Solvent
toluene
Temp (°C)
110
Time (h)
120
Yield (%)a
23 (76)
1
2
3
4
benzonitrile
toluene
140
110
140
15
120
15
1 (86)
2 (77)
2 (88)
N
N
benzonitrile
5
6
toluene
toluene
110
110
120
120
3 (80)
4 (75)
N
Cl
N
N
O2N
7
8
9
toluene
110
110
140
120
120
15
5 (70)
6 (70)
6 (72)
MeO
S
toluene
N
S
benzonitrile
N
a Yield determined by GC analysis on the base of oxaziridines transformed.
Synlett 2009, No. 11, 1806–1808 © Thieme Stuttgart · New York

1808
L. Troisi et al.
LETTER
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Pombeiro, A. J. L. J. Phys. Chem. A. 2003, 107, 6108.
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Acknowledgment
Thanks are due to the University of Salento and C.I.N.M.P.I.S.
(Consorzio Interuniversitario Nazionale Metodologie e Processi
Innovativi di Sintesi) for financial support.
(15) Sarju, J.; Arbour, J.; Sayer, J.; Rohrmoser, B.; Scherer, W.;
Wagner, G. Dalton Trans. 2008, 5302.
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(19) Fabio, M.; Ronzini, L.; Troisi, L. Tetrahedron 2007, 63,
12896.
(20) Reaction conducted according to general procedure.
(21) Reaction conducted using benzonitrile as solvent (10 mL)
for 15 h according to the general procedure. Yields, after
chromatographic purification, were about 80%.
(22) (a) Osborn, H. M. I.; Gemmell, N.; Harwood, L. M. J. Chem.
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(23) Compound 1: Crude product was purified by flash
chromatography on silica gel deactivated with Et3N (PE–
Et2O, 8:2). 1H NMR (400 MHz, CDCl3): d = 1.23 (s, 9 H),
6.11 (s, 1 H), 7.25–7.54 (m, 8 H), 7.98 (d, J = 8.1 Hz, 2 H).
13C NMR (100.62 MHz, CDCl3): d = 25.0, 60.4, 85.8, 125.3,
126.6, 126.9, 128.0, 128.5, 131.9, 141.6, 161.4. GC-MS (70
eV): m/z = 280 (<1) [M+], 177 (50), 121 (35), 105 (20), 77
(25), 57 (100). FTIR (CHCl3): 3067, 2987, 2927, 2852,
1656, 1494, 1452, 1326 cm–1. Anal. Calcd for C18H20N2O: C,
77.11; H, 7.19; O, 5.71. Found: C, 77.09; H, 7.18; O, 5.69.
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(25) Diastereomeric ratio determined by 1H NMR on the crude
product.
Synlett 2009, No. 11, 1806–1808 © Thieme Stuttgart · New York