A new palladium(II)-catalyzed [3,3] aza-Claisen rearrangement of 3-allyloxy-5-aryl-1,2,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2010.12.058

A new efficient palladium(II)-catalyzed [3,3] aza-Claisen, formal sigmatropic rearrangement of 3-allyloxy-5-aryl-1,2,4-oxadiazoles was developed. The mechanism was studied by analyzing the regiochemical and stereochemical course of the reaction. The resul

Full text of DOI:10.1016/j.tetlet.2010.12.058

Tetrahedron Letters 52 (2011) 884–886
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A new palladium(II)-catalyzed [3,3] aza-Claisen rearrangement
of 3-allyloxy-5-aryl-1,2,4-oxadiazoles
⇑
Gianfranco Fontana, Antonio Palumbo Piccionello
Dipartimento di Chimica Organica ‘E. Paternò’, Università degli Studi di Palermo, V.le delle Scienze, Ed. 17, I-90128 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A new efficient palladium(II)-catalyzed [3,3] aza-Claisen, formal sigmatropic rearrangement of 3-allyl-
oxy-5-aryl-1,2,4-oxadiazoles was developed. The mechanism was studied by analyzing the regiochemical
and stereochemical course of the reaction. The results obtained indicated the intervention of a cationic
pallada-cycle similar to the one postulated for the Cope rearrangement of 1,5-dienes.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 October 2010
Revised 7 December 2010
Accepted 13 December 2010
Available online 21 December 2010
Keywords:
Aza-Claisen
1,2,4-Oxadiazoles
1,2,4-Oxadiazolones
Palladium
The [3,3] aza-Claisen rearrangement is a sigmatropic process
In a preliminary set of experiments 3-allyloxy-5-phenyl-1,2,4-
oxadiazole 1a was reacted with palladium acetate (Pd(OAc)2) and
CuCl2 at different molar ratio and temperatures, following a 23 fac-
torial experimental design (Table 1), in order to deduce the best
reaction conditions for the obtainment of the rearranged com-
pound 2a.
that involves an allylic transfer in N-allyl, N-vinyl amines, or related
systems that leaves to the formation of c
,d-unsaturated imines.1 It
was efficiently employed in a number of useful transformations
such as the stereospecific synthesis of 20,30-dideoxynucleoside
precursors.2
Pd(II) salts are known to catalyze many synthetically useful for-
mal [3,3]-sigmatropic rearrangements in 1,5-dienes,3 allyl vinyl
ethers, and also in aza-Claisen-type processes involving allylic imi-
dates and some allyl-substituted heterocyclic frameworks, that in-
clude 2-allyloxypyridines,4 5-allylthio-1,2,4-triazin-3(2H)-ones,5
4-allylthiopyrimidin-2(1H)-ones,5 and 2-(allylthio)pyrimidin-
4(3H)-ones.6 Recently, a chiral Pd(II) catalyst, (S)-COP-Cl has been
used in an interesting enantioselective [3,3] rearrangement of
allyloxypyridines and other related heterocycles.7
On the other hand, 1,2,4-oxadiazoles present many applications
in medicinal chemistry,8 such as peptidomimetics and enzyme
inhibitors,9 apoptosis inducers,10 or as unnatural bases in the
extension of DNA strands.11 Among these, N(2)-substituted 1,2,4-
oxadiazolones represent an emerging class of bioactive mole-
cules,12 mainly represented by the quisqualic acid, the sole natural
1,2,4-oxadiazole, responsible for the QUIS effect, that is, the agonist
effect toward a number of amino acid receptors in the SNC.13
In light of this, in this Letter we describe a new Pd(II)-catalyzed
[3,3] aza-Claisen rearrangement involving 3-allyloxy-1,2,4-oxadi-
azoles to give the related N(2)-substituted 1,2,4-oxadiazol-3-ones.
The reaction shows an high sensitivity toward the presence of
Cu(II), as it can be seen comparing entries 1–4 with 5–8. Further,
from the data reported in Table 1 it can be deduced that the effect
of temperature is dramatic when Cu(II) is present (entries 5,7 and
6,8) while it is substantially negligible when Cu(II) is absent
Table 1
Optimization of the reaction conditionsa for the rearrangement of compound 1a to 2a
O
N
O
N
Pd(OAc)2/CuCl2
THF
N
N
Ph
O
Ph
O
1a
2a
Exp. No.
Pd(OAc)2 (mol %)
T (°C)
CuCl2 (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
5
10
5
10
5
10
5
10
25
25
50
50
25
25
50
50
—
—
—
—
5
5
5
5
17
38
25
30
52
70
95
97
a
All the reactions were performed by mixing 1a 0.07 M in dry THF (3 mL) with
⇑
Corresponding author. Tel.: +39 091 596903; fax: +39 091 596825.
E-mail address: apalumbo@unipa.it (A. Palumbo Piccionello).
Pd(OAc)2 and CuCl2 and stirring the solution for 12 h.
b
Isolated yields.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.058

G. Fontana, A. Palumbo Piccionello / Tetrahedron Letters 52 (2011) 884–886
885
(entries 1,3 and 2,4). Finally, the effect of an increase in the Pd(II)
concentration from 5% to 10% mol/mol is negligible at 50 °C in
the presence of Cu(II) (entries 7 and 8). The un-catalyzed reaction
was quite ineffective as no detectable amount of transposed
product 2a was found after refluxing a solution of 1a and CuCl2
in THF for 24 h. Hence, all of the subsequent experiments were car-
ried out at the experimental conditions corresponding to entry 7 of
Table 1.14
(5 mol % Pd(II), 5 equiv Cu(II), at 50 °C, Table 2), to give the trans-
posed products 2.14 The results are summarized in Table 2.
The reaction yields range from 45% to 95%. In the case of the
more sterical demanding cyclohexyl-substituted compound 1e,
the yield dramatically dropped to 33%.
The transposition process occurs with quite complete regiose-
lectivity, as it can be seen from the formation of the N(2)-20-(E)-
butenyl-substituted product 2b and the N(2)-10-alkyl-substituted
products 2c,d.
Moreover, a very high degree of stereoselectivity was observed
in the case of the substrate 1b that exclusively gave rise to the for-
mation of the compound 2b with a 100% E stereochemistry of the
side chain double bond.
In order to get further information concerning the mechanism
of the reaction, we prepared a set of 3-(20-alkenyloxy)-5-aryl-
1,2,4-oxadiazoles 1b–g, by a known procedure starting from the
3-amino-5-aryl-1,2,4-oxadiazoles
3
(Scheme 1).15 These com-
pounds were converted to the corresponding 3-chloro-5-aryl-
1,2,4-oxadiazoles 4 by in situ diazotization/chlorination with
NaNO2/HCl.16 Then the desired 3-(20-alkenyloxy) derivatives were
obtained by reacting the chloro-derivatives with the necessary
alkoxide.
Two alternative possible reaction pathways (Scheme 2) were
postulated by analogy with the well known palladium-catalyzed
Cope transposition reaction.17
In the path a, a nucleophilic attack by the N(2) on the Pd(II)-g2
-
The compounds 1b–g were subjected to the reaction conditions
previously optimized for the transposition of compound 1a
coordinated double bond, in the intermediate 5, brings to the for-
mation of a six members cationic pallada-cycle 6 that accounts
for the observed regioselectivity. This intermediate, in turn, is
opened by an anti-b-Pd,O-elimination step to give the final prod-
uct. The pseudoequatorial disposition of the methyl-substituent
in the cyclic intermediate accounts for the observed stereoselectiv-
ity in the formation of compound 2b.
HO
R2
R1
Cl
N
NH2
N
R1
O
N
N
N
NaNO2/HCl
N
R2
Ar
O
Ar
O
The alternative path b, that would involve an initial oxidative
Ar
tBuOK, THF, rt
O
addition step to give an unusual
g
3-allyl-Pd(IV) intermediate 7,
3
4
1
can be ruled out as it should bring to the formation of the same
regioisomer (or mixture of) starting from both the compounds
1b,c. This kind of Pd(IV) intermediates were postulated in the Cope
rearrangement of some 1,5-dienes in oxidative conditions, in the
presence of the Pd(II)/Cu(II) catalytic system,17a that may occur
Scheme 1. Synthesis of the 3-(20-alkenyloxy)-5-aryl-1,2,4-oxadiazoles 1.
Table 2
Results of the transposition reaction of compounds 1a–g
via a mechanism involving a bis(g
3-allyl)Pd(IV) intermediate, as
it was deduced by the authors on the ground of both reasonable
theoretical considerations and strong experimental evidences.
Further, the beneficial effect of the presence of Cu(II) in the
reaction media could be ascribed to an oxidative stabilization of
the pallada-alkyl cation toward the possible b-hydride reductive
elimination, with acetate anion acting as a base. This hypothesis
is enforced by the appearance of the ‘black-palladium’ within the
reaction vessel, indicative of the occurrence of a Pd(II)/Pd(0) reduc-
tion process, that accompanies the decrease of the yield in the
transformation of 1a performed without Cu(II) (Table 1). This
observation is in agreement with an evidence reported by Lei
et al.18 that showed how Cu(II) is effective in promoting the oxida-
tive cleavage of the carbon–palladium bond (see the conversion of
the intermediate 6 to the product 2, Scheme 2) preventing the pos-
sible b-hydride elimination-Pd(II)/Pd(0) reduction to occur and
prompted us to choose a Cu(II) salt as a co-oxidant.
R1
O
N
O
N
R1
N
Pd(OAc)2/CuCl2
THF, 50 °C
R2
N
O
O
R2
R3
R3
1
2
Entry
Compound
R1
R2
R3
Yielda (%)
1
2
3
4
1a
1b
1c
1d
H
Me
H
H
H
Me
Ph
H
H
H
H
95
79
86
64
H
O
N
5
1e
33
N
O
6
7
1f
1g
H
H
H
H
MeO
NO2
62
45
In summary, the whole of the data collected seems to indicate
the operation of the reaction mechanism depicted in path a
a
Isolated yields, reaction conditions as in note 14.
R1
O
N
Pd
N
R1
R2
Ar
Ar
O
R2
R1
2+
R1
O
O
N
- Pd(II)
O
N
+ Pd(II)
path a
N
N
Pd
R2
Ar
O
N
N
N
R1
Pd
Ar
Ar
O
O
O
R2
N
2
O
1
R2
5
+ Pd(II)
R1
6
path b
O Pd(IV)
N
R2
N
Ar
O
7
Scheme 2. Mechanism of the transposition reaction.

886
G. Fontana, A. Palumbo Piccionello / Tetrahedron Letters 52 (2011) 884–886
References and notes
N
Ar
O
Pd
N
O
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(Scheme 2). As a consequence, the loss of efficacy observed in the
formation of the cyclohexyl-substituted compound 2e can be ex-
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bicyclic intermediate 6e (Fig. 1).
Moreover, a comparison between the reactivity of compounds
1a, 1f, and 1g shows as the reaction efficiency is not related to
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the reaction yield occurs with both the electron-withdrawing –
NO2 group and with the electron-releasing –OMe group. In the
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In conclusion, a new efficient palladium(II)-catalyzed [3,3] aza-
Claisen sigmatropic rearrangement of 3-allyloxy-1,2,4-oxadiazoles
was developed and an insight on the reaction mechanism was
gained by analyzing the regio- and stereoselectivity of the reaction.
From a synthetic point of view, the proposed rearrangement repre-
sents a new entry for the obtainment of N-substituted 1,2,4-oxa-
diazolones, structurally related to quisqualic acid, as valuable
synthons of pharmaceutical interest.
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14. Typical experimental procedure for the rearrangement reaction: 5.6 mg
(0.025 mmol) of Pd(OAc)2 and 336 mg (2.5 mmol) of CuCl2 and 0.5 mmol of
the allylic substrate were solubilized in dry THF (15 mL) under Ar and stirred
for 12 h at 50 °C. The resulting dark green solution was reduced to a little
volume by rotavapor. Then 10 mL of water were added and the aqueous phase
was extracted with EtOAc. The organic phase was washed with water and brine
and dried onto Na2SO4. The product was purified by flash chromatography (Si
gel LichroprepÒ 15–25, 25–40 1:1; elution with light petroleum ether/EtOAc
from 50:1 to 5:1).
Compounds 1a–c are reported in Ref. 15. Characterization data of new
compounds (1d–g, 2a–g) are available in the Supplementary data.
15. Palumbo Piccionello, A.; Pace, A.; Pibiri, I.; Buscemi, S. ARKIVOC 2009, VII, 156–
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Acknowledgments
We acknowledge the financial support of this work, by Univer-
sità di Palermo and ‘Ministero dell’Istruzione, Università e Ricerca
(MIUR)’, grant ‘PRIN 2008’ No. 20085E2LXC_004.
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47–53.
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Supplementary data
18. Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett. 2004, 45, 1785–1788.
19. Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron
2008, 64, 4004–4010.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.058.