Tandem reactions of 1,2,4-oxadiazoles with allylamines

Article abstract of DOI:10.1021/ol201676g

A reaction of 3-chloro-1,2,4-oxadiazoles with allylamine and diallylamine has been investigated. 3,3a,4,5-Tetrahydroisoxazolo[3,4-d]pyrimidines are produced through a tandem ANRORC/[3 + 2]cycloaddition pathway consisting of the addition of allylamine to t

Full text of DOI:10.1021/ol201676g

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4749–4751
Tandem Reactions of 1,2,4-Oxadiazoles
with Allylamines
Antonio Palumbo Piccionello,* Andrea Pace, and Silvestre Buscemi
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO), Sez.
ꢀ
Chimica Organica, Universita degli Studi di Palermo, Viale delle Scienze, Parco
d’Orleans II, Ed. 17, I-90128 Palermo, Italy
apalumbo@unipa.it
Received July 14, 2011
ABSTRACT
A reaction of 3-chloro-1,2,4-oxadiazoles with allylamine and diallylamine has been investigated. 3,3a,4,5-Tetrahydroisoxazolo[3,4-d]pyrimidines
are produced through a tandem ANRORC/[3 þ 2]cycloaddition pathway consisting of the addition of allylamine to the 1,2,4-oxadiazole, followed by
ring opening, nitrone formation, and finally cycloaddition. 3-N-Allylamino-1,2,4-oxadiazoles were also obtained as minor products through a
classical SNAr. Conversely, a reaction with diallylamine produces 3-N,N-diallylamino-1,2,4-oxadiazole and imidazoline through tandem SNAr/
aziridination and nucleophilic ring opening.
ANRORC (Addition of a Nucleophile, Ring Opening,
and Ring Closure) reactions represent a useful strategy for
ring transformation of heterocyclic systems.1 ANRORC
rearrangements of six-membered heterocycles have been
extensively studied by Van der Plas and co-workers,1 while
ANRORC reactions of five-membered systems concern
electron-poor heterocycles such as 1,3,4-oxadiazoles,2 1,3,
4-thiadiazoles,3 nitroimidazoles,2,4 bis(1,3,4-thiadia-
zol-2-yl)-1,3,5-triazinium halides,5 isothiazole,6 and
isoxazoles.7
preparation of several fluorinated heterocycles (i.e., 1,2,
4-triazoles,9 1,2,4-oxadiazoles,10 1,2,4-triazines,9b,11
1,2,4-oxadiazinones,12 indazoles13) via ANRORC
reactions.
In this context, the presence of a strongly electron-with-
drawing fluorinated group, linked at the C(5) of 1,2,4-
oxadiazoles, has been so far considered as “conditio sine
qua non” for the ANRORC reactivity. Only recently, we
have demonstrated the ANRORC reactivity of 3-chloro-
1,2,4-oxadiazoles also in the absence of C(5)-linked elec-
tron-withdrawing groups.14 In the latter case, it was sug-
gested that the presence of a chlorine linked at C(3) of the
Taking advantage of 1,2,4-oxadiazole reactivity and
their high tendency to rearrange,8 we have reported the
(1) Van der Plas, H. C. Adv. Heterocycl. Chem. 1999, 74, 1–253.
(9) (a) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Spinelli, D. J. Org.
Chem. 2003, 68, 605–608. (b) Buscemi, S.; Pace, A.; Palumbo Piccionello,
A.; Pibiri, I.; Vivona, N.; Giorgi, G.; Mazzanti, A.; Spinelli, D. J. Org.
Chem. 2006, 71, 8106–8113. (c) Palumbo Piccionello, A.; Pace, A.;
Buscemi, S.; Vivona, N. ARKIVOC 2009, vi, 235–244.
(10) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Lanza, C. Z.;
Spinelli, D. Eur. J. Org. Chem. 2004, 974–980.
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r
10.1021/ol201676g
2011 American Chemical Society
Published on Web 08/09/2011

oxadiazole ring leads to the formation of a chloro-oxime
intermediate after the ring opening induced by the attack
of the nucleophile. Considering that such an intermediate
could represent a nitrile oxide precursor, we envisaged the
possibility of a tandem ANRORC/[3 þ 2]cycloaddition
reaction with nucleophiles containing an olefinic moiety
(Figure 1).
Table 1. Products Distribution for Reaction of Compounds 1
with Allylamine
2 yield
(%)a
3 yield
(%)a
entry
Reactant
R
1
2
1a
Ph
56
21
16
85
68
77
57
61
63
40
35
14
10
14
18
19
14
18
33
19
1b (60)b
1c (58)b
1d
4-MeOPh
4-MePh
3
4
4-ClPh
Figure 1. Schematic representation for the tandem ANRORC/
[3 þ 2]cycloaddition reaction.
5
1e
4-NO2Ph
4-CF3Ph
2-furanyl
2-thiophenyl
4-pyridyl
benzyl
6
1f
7
1g
1h (19)b
1ic
Such an approach represents a new entry for the obtain-
ment of heteroannelated isoxazolines15 by using 3-chloro-
1,2,4-oxadiazoles as a masked nitrile oxide. Here we report
the study of the reaction of 3-chloro-1,2,4-oxadiazoles 1,
with allylamine as an olefin-tethered nucleophile. Selected
3-chloro derivatives 1aꢀj, variously substituted at C(5),
were obtained from the corresponding 3-amino-1,2,4-
oxadiazoles.14,16 Compounds 1 were reacted in refluxing
methanol in the presence of a 15-fold excess of allylamine
giving tetrahydro-isoxazolo[3,4-d]pyrimidines 2, as major
products, together with 3-N-allylamino-1,2,4-oxadiazoles
3 (Table 1). All reactions were performed for 9 h, except
that for compound 1i (Table 1, entry 9) which reached
100% conversion in 3 h. Complete conversion of the
starting material, after 9 h of heating, was not achieved
for those derivatives bearing an electron-donating group
linkedatC(5) of the oxadiazolering(Table1, entries2, 3, 8,
10), while prolonged reflux (>9 h) caused formation of
degradation products.
8
9
10
1j (36)b
a Isolated yield. b Recovered substrate. c Reaction time: 3 h.
Scheme 1. Proposed Mechanism for the Reactions of 1 with
Allylamine
From a mechanistic point of view, the formation of the
observed products 2 and 3 could be ascribed to the
presence of two competing reaction pathways both involv-
ing an initial attack of allylamine on the oxadiazole ring
(Scheme 1).
In route a (Scheme 1), and in analogy to ANRORC
reactions reported for 1,2,4-oxadiazoles,9ꢀ14 the initial
nucleophilic attack on the C(5) of the oxadiazole ring
causes ring opening into chloro-oxime intermediate 4.
Subsequent elimination of HCl leads to the in situ
formation of the nitrile oxide intermediate 5 which,
through a [3 þ 2] heterocyclization, yields tetrahydro-
isoxazolo[3,4-d]pyrimidines 2. Conversely, initial at-
tack of the allylamine nitrogen on C(3) (Scheme 1,
route b) leads to N-allylamino-oxadiazoles 3, through
a classic SNAr.16a This mechanistic rationale is sup-
ported by product distribution data, where com-
pounds bearing electron-withdrawing groups linked
at C(5) of the oxadiazole ring gave a higher conversion
of starting materials 1 and higher yields of isoxazolo-
pyrimidines 2. In order to consider the effect of the
amine structure on the reaction outcome, we have
considered the reactivity of representative compound
1a with N,N-diallylamine under the previously re-
ported conditions (9 h, refluxing MeOH) (Scheme 2).
(15) (a) Chiacchio, U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.;
Grassi, G.; Piperno, A.; Privitera, T.; Romeo, G. Tetrahedron 2001, 57,
ꢀ
3425–3433. (b) Alcaide, B.; Almendros, P.; Saez, E. Arkivoc 2004, iv,
137–152. (c) Sengupta, J.; Mukhopadhyay, R.; Bhattacharjya, A.;
Bhadbhade, M. M.; Bhosekar, G. V. J. Org. Chem. 2005, 70, 8579–
8582. (d) Ghorai, S.; Mukhopadhyay, R.; Kundu, A. P.; Bhattacharjya,
A. Tetrahedron 2005, 61, 2999–3012. (e) Chatterjee, N.; Pandit, P.;
Halder, S.; Patra, A.; Mait, D. K. J. Org. Chem. 2008, 73, 7775–7778.
(16) (a) Eloy, F.; Deryckere, A.; Van Overstraeten, A. Bull. Soc.
Chim. Bel. 1969, 78, 47–53. (b) Fontana, G.; Palumbo Piccionello, A.
Tetrahedron Lett. 2011, 52, 884–886.
4750
Org. Lett., Vol. 13, No. 17, 2011

Scheme 2. Reaction of Compound 1a with Diallylamine
Scheme 4. Proposed Mechanism for the Formation of Imida-
zoline 7
In this case only the SNAr product 6 was obtained in low
yield (12%), thus suggesting that with a hindered nucleo-
phile the ANRORC pathway is suppressed. When the
reaction was conducted under more forcing conditions,
in refluxing DMF, the yield of compound 6 was doubled
and the unexpected imidazoline 7 was obtained as a major
product (Scheme 3). From a mechanistic point of view,
formation of imidazoline 7 could be explained on the basis
of the initial formation of amino-substituted oxadiazole 6
followed by a thermally induced breaking of the OꢀN
bond of the 1,2,4-oxadiazole ring, leading to the nitrene
Scheme 3. Thermal Rearrangement of 1a in the Presence of
Diallylamine
Scheme 5. Thermal Rearrangements of 6
intermediate 8 (Scheme 4). Intramolecular aziridination
leads to the formation of a bicyclic intermediate 9
(Scheme 4). Interemediate 9 leads to final imidazoline 7
through regioselective aziridnine ring opening by action of
chloride on the less hindered carbon (Scheme 4, route a),
while pyrimidine derivative 10, obtainable from the com-
petitive attack of chloride, was not observed (Scheme 4,
route b) according to previously reported results for
aziridine ring opening by a halide ion.17 Formation of
imidazoline 7 was also observed from thermal rearrange-
ment of oxadiazole 6 in refluxing DMF in the presence of
an excess of chloride, while thermal treatment of com-
pound 6 in the absence of a chloride ion did not allow
isolation of bicyclic intermediate 9, probably due to de-
composition during workup (Scheme 5).
entry of thermally induced aziridination of the 1,2,4-
oxadiazole ring acting as a nitrene equivalent.
In conclusion, the reactivity of 3-chloro-1,2,4-oxadia-
zoles with allylamines was investigated, showing two
novel thermal rearrangements. Reaction with allyla-
mine yielded tetrahydro-isoxazolo[3,4-d]pyrimidines 2,
which, to the best of our knowledge, has not been
previously reported in the literature. With respect to
previously reported ANRORC rearrangements where
the ring-closure step consists of an intramolacular cy-
clocondensation reaction, a novel tandem ring open-
ing/[3 þ 2] dipolar cycloaddition is reported. Moreover,
reaction with diallylamine allowed the obtainment of
highly substituted imidazoline through an unprecedent
thermally induced intramolecular aziridination.
It is interesting to note that the aziridination of N(2) of
the 1,2,4-oxadiazole ring was previously observed just as
photochemical intermolecular18 or intramolecular19 reac-
tivity. Thus, the reported reactivity represents the first
Acknowledgment. Financial support through the Uni-
versity of Palermo is gratefully acknowledged.
(17) As a recent example, see: Proust, N.; Gallucci, J. C.; Paquette,
L. A. J. Org. Chem. 2008, 73, 6279–6282.
(18) Palumbo Piccionello, A.; Pibiri, I.; Pace, A.; Raccuglia, R. A.;
Buscemi, S.; Vivona, N.; Giorgi, G. Heterocycles 2007, 71, 1529–1537.
(19) Palumbo Piccionello, A.; Pace, A.; Pibiri, I.; Buscemi, S. ARKI-
VOC 2009, vii, 156–167.
Supporting Information Available. Synthetic details,
13
characterization data, and 1Hꢀ C NMR spectra of
compounds 2, 3, 6, and 7. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
4751