1,2,4-oxadiazole rearrangements involving an NNC side-chain sequence

Article abstract of DOI:10.1021/ol901687n

The thermal rearrangement of N-1,2,4-oxadlazol-3-yl-hydrazones into 1,2,4-triazoie derivatives is reported. This represents the first example of a three-atom side-chain rearrangement involving an NNC sequence linked at the C(3) of the oxadiazole. The reac

Full text of DOI:10.1021/ol901687n

ORGANIC
LETTERS
2009
Vol. 11, No. 17
4018-4020
1,2,4-Oxadiazole Rearrangements
Involving an NNC Side-Chain Sequence
Antonio Palumbo Piccionello,* Andrea Pace, Silvestre Buscemi, and
Nicolo` Vivona
Dipartimento di Chimica Organica “E. Paterno`”, UniVersita` degli Studi di Palermo,
Viale delle Scienze - Parco d’Orleans II, I-90128 Palermo, Italy
apalumbo@unipa.it
Received July 23, 2009
ABSTRACT
The thermal rearrangement of N-1,2,4-oxadiazol-3-yl-hydrazones into 1,2,4-triazole derivatives is reported. This represents the first example of
a three-atom side-chain rearrangement involving an NNC sequence linked at the C(3) of the oxadiazole. The reactions carried out under
solvent-free conditions produced good to high yields of the final products.
Heterocyclic ring rearrangements are reactions that have been
well documented in the literature.1 Among the most inves-
tigated ring-transformation reactions, the Boulton-Katritzky
rearrangement (BKR) consists of an interconversion between
two five-membered heterocycles where a three-atom side
chain and a pivotal annular nitrogen are involved (1f2).2
The reaction has been the subject of numerous synthetic
applications1c,2,3 and has intriguing mechanistic aspects.4
This rearrangement, also classified as an internal nucleo-
philic substitution,3a,b,4a-f,5 typically occurs on 1-oxa-2-
azoles (D ) O) that are O-N bond-containing heterocycles:
isoxazoles,3a,b 1,2,4-oxadiazoles,3 1,2,5-oxadiazoles,3a,b and
1,2,5-oxadiazole-2-oxides.3b,6
When the nucleophilic Z atom in the side chain attacks
the electrophilic N(2) ring nitrogen, the O(1) ring oxygen
(4) For recent mechanistic studies on azole-to-azole interconversion
reactions of the Boulton-Katritzky type, see: (a) Cosimelli, B.; Guernelli,
S.; Spinelli, D.; Buscemi, S.; Frenna, V.; Macaluso, G. J. Org. Chem. 2001,
66, 6124–6129. (b) Cosimelli, B.; Frenna, V.; Guernelli, S.; Lanza, C. Z.;
Macaluso, G.; Petrillo, G.; Spinelli, D. J. Org. Chem. 2002, 67, 8010–
8018. (c) D’Anna, F.; Frenna, V.; Macaluso, G.; Morganti, S.; Nitti, P.;
Pace, V.; Spinelli, D.; Spisani, R. J. Org. Chem. 2004, 69, 8718–8722. (d)
D’Anna, F.; Ferroni, F.; Frenna, V.; Guernelli, S.; Lanza, C. Z.; Macaluso,
G.; Pace, V.; Petrillo, G.; Spinelli, D.; Spisani, R. Tetrahedron 2005, 61,
167–178. (e) D’Anna, F.; Frenna, V.; Macaluso, G.; Marullo, S.; Morganti,
S.; Pace, V.; Spinelli, D.; Spisani, R.; Tavani, C. J. Org. Chem. 2006, 71,
5616–5624. For DFT studies on monocyclic BKR, see: (f) Bottoni, A.;
Frenna, V.; Lanza, C. Z.; Macaluso, G.; Spinelli, D. J. Phys. Chem. A 2004,
108, 1731–1740. (g) Pace, A.; Pibiri, I.; Palumbo Piccionello, A.; Buscemi,
S.; Vivona, N.; Barone, G. J. Org. Chem. 2007, 72, 7656–7666. (h) Pace,
A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009,
(1) See for example: (a) Van der Plas, H. C. Ring Transformation of
Heterocycles; Academic Press: New York, 1973; Vol. 1. (b) Van der Plas,
H. C. Ring Transformation of Heterocycles; Academic Press: New York,
1973; Vol. 2. (c) L’abbe´, G. J. Heterocycl. Chem. 1984, 21, 627–638. (d)
Van der Plas, H. C. AdV. Heterocycl. Chem. 1999, 74, 1–253. See also
specific classes of ring transformations reviewed in (e) ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: Oxford, 1984; Vols. 1-8. (f) ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier:
Amsterdam, 1996; Vols. 1-9.
(2) (a) Boulton, A. J.; Katritzky, A. R.; Hamid, A. M. J. Chem. Soc.
(C) 1967, 2005–2007. (b) Afridi, A. S.; Katritzky, A. R.; Ramsden, C. A.
J. Chem. Soc., Perkin Trans. 1 1976, 315–320.
(3) (a) Ruccia, M.; Vivona, N.; Spinelli, D. AdV. Heterocycl. Chem. 1981,
29, 141–169. (b) Vivona, N.; Buscemi, S.; Frenna, V.; Cusmano, G. AdV.
Heterocycl. Chem. 1993, 56, 49–154. (c) Korbonits, D.; Kanzel-Szvoboda,
I.; Horvath, K. J. Chem. Soc., Perkin Trans. 1 1982, 759–766. (d) Horvath,
K.; Korbonits, D.; Naray-Szabo, G.; Simon, K. J. Mol. Struct. (THEOCHEM)
74, 351–358
(5) Vivona, N.; Cusmano, G.; Ruccia, M.; Spinelli, D. J. Heterocy-
cl.Chem. 1975, 12, 985–988
(6) Makhova, N. N.; Ovchinnikov, I. V.; Kulikov, A. S.; Molotov, S. I.;
Baryshnikova, E. L. Pure Appl. Chem. 2004, 76, 1691–1703
.
.
1986, 136, 215–227
.
.
10.1021/ol901687n CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

acts as an internal leaving group, and the O-N bond is
cleaved. With Z atoms different from oxygen (for instance,
Z ) N, S, C), the process is irreversible; the driving force is
the formation of a more stable N-N, S-N, or C-N bond
replacing the less stable O-N bond.
The only example involving a nucleophilic carbon (Z )
C) in an NCC side chain concerned the rearrangement, under
basic conditions, of some N-(1,2,4-oxadiazol-3-yl)-ꢀ-enami-
noketones into imidazole.7,8 Moreover, although the effect
of the type of side chain (X ) Y-ZH) on the obtention of
different heterocycles has been extensively investigated,3b
so far, no study has investigated the involvement of an NNC
side chain. Therefore, in the context of our research on
heterocyclic rearrangements, we wanted to investigate the
occurrence of a BKR in a 1,2,4-oxadiazole series containing
a side-chain of the type NNC and possessing a potentially
nucleophilic carbon (Z ) C).
oxadiazole 59 through SNAr with methylhydrazine (Scheme
1). The classic X ) Y-ZH sequence in the general BK
Scheme 1. Preparation of Hydrazine 6
scheme points out the key role of the potentially acidic Z-H
proton whose abstraction, under base catalysis conditions,
generates the attacking nucleophilic site in the side chain.
Our selected substrates lack this structural feature, therefore
no catalytic effect should be expected on the reaction of
compounds 3 in the presence of a base.
As a matter of fact, an attempt to conduct the rearrange-
ment under basic conditions (t-BuOK/DMF) on representa-
tive compound 3a yielded 3-methylamino-5-phenyl-1,2,4-
oxadiazole 810 together with benzonitrile and only trace
amounts of triazole 4a (<2%) (Scheme 2).
In this work, we report the rearrangement of N-methyl-
N-(5-phenyl-1,2,4-oxadiazol-3-yl)hydrazones 3 into trisub-
stituted-1,2,4-triazoles 4 (Figure 1).
Scheme 2. Base-Induced Reaction of Compound 3a
Figure 1. NNC side-chain rearrangement of 1,2,4-oxadiazole.
Selected substrates 3a-i were obtained in good yield from
the condensation of aromatic aldehydes 7a-i with N-methyl-
N-(5-phenyl-1,2,4-oxadiazol-3-yl)hydrazine 6 (Table 1; for
experimental details, see Supporting Informations). In turn,
compound 6 was obtained from 3-chloro-5-phenyl-1,2,4-
Table 1. Condensation of Hydrazine 6 with Aromatic
Aldehydes 7a-i
Formation of oxadiazole 8, in the presence of t-BuOK,
could be ascribed to the base-induced cleavage of the
hydrazone N-N bond (Scheme 2). On the other hand,
heating compounds 3 at reflux in most common organic
solvents (toluene, benzene, MeOH, DMF, acetonitrile) gener-
ally left the starting material unchanged. Nevertheless,
heating compounds 3 for 30 min at temperatures 30 °C higher
entry
product
3a R ) Ph
3b R ) 4-MePh
3c R ) 4-MeOPh
3d R ) 4-NO2Ph
3e R ) 4-ClPh
3 yield%a
(7) (a) Ruccia, M.; Vivona, N.; Cusmano, G. Tetrahedron Lett. 1972,
13, 4959–4960. (b) Ruccia, M.; Vivona, N.; Cusmano, G. Tetrahedron 1974,
30, 3859–3864.
1
2
3
4
5
6
7
8
9
83
97
70
94
93
89
85
76
68
(8) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N.; Pani,
M. Tetrahedron 2008, 64, 4004–4010.
(9) Eloy, F.; Deryckere, A.; Van Overstraeten, A. Bull. Soc. Chim. Bel.
1969, 78, 47–53.
(10) Buscemi, S.; Cicero, M. G.; Vivona, N.; Caronna, T. J. Chem. Soc.,
Perkin Trans. 1 1988, 1313–1315.
3f R ) 4-BrPh
3g R ) 4-CF3Ph
3h R ) 2-thiophenyl
3i R ) 2-furanyl
(11) (a) Bird, C. W. Tetrahedron 1985, 41, 1409–1414. (b) Katritzky,
A. R.; Barczynski, P.; Musumarra, G.; Pisano, D.; Szafran, M. J. Am. Chem.
Soc. 1989, 111, 7–15. (c) Bird, C. W. Tetrahedron 1992, 48, 335–340. (d)
Bean, G. P. J. Org. Chem. 1998, 63, 2497–2506. (e) Katritzky, A. R.; Jug,
K.; Oniciu, D. C. Chem. ReV. 2001, 101, 1421–1449. (f) Balaban, A. T.;
Oniciu, D. C.; Katritzky, A. R. Chem. ReV. 2004, 104, 2777–2812.
a Isolated yield.
Org. Lett., Vol. 11, No. 17, 2009
4019

than the corresponding melting point, under solvent-free
conditions, yielded 3-(het)arylsubstituted-N-1-methyl-5-(N-
benzoylamino)-1H-1,2,4-triazoles 4 (Table 2; for experi-
Scheme 3
.
Proposed Mechanism for Rearrangement of
Compounds 3
Table 2. Thermal Rearrangement of Hydrazones 3 into
Triazoles 4
entry
product
4a R ) Ph
4b R ) 4-MePh
4c R ) 4-MeOPh
4d R ) 4-NO2Ph
4e R ) 4-ClPh
4, yield %a
3 (%)b
1
2
3
4
5
6
7
8
9
63
61
71
51
80
53
99
81
71
15
18
12
28
10
21
-
In conclusion, despite a plethora of studies on the
Boulton-Katritzky reaction, the reported results introduce
the first example of an NNC side chain in this type of
rearrangement. Besides opening the way to further mecha-
nistic studies, the precursor accessibility, the solvent-free
conditions, the easy workup, and the good product yields
allow consideration of this methodology for the designed
synthesis of highly functionalized triazolamines which are
known for their biological activity.12
4f R ) 4-BrPh
4g R ) 4-CF3Ph
4h R ) 2-thiophenyl
4i R ) 2-furanyl
16
-
a Isolated yield. b Recovered starting material.
mental details, see Supporting Informations). Despite the fact
that total conversion of the starting materials was not
achieved for all compounds, prolonged heating was avoided
to prevent side-product formation.
From a mechanistic point of view, formation of triazoles
4 can be explained if one invokes the species 9 as a key
intermediate (Scheme 3). Such an intermediate could arise
either directly from 3, through a BKR involving the side-
chain carbon atom as a nucleophilic site, or from a bicyclic
precursor formed from an initial 6π-assisted heteroelectro-
cyclic reaction.3b In both cases, the driving force of the
reaction could be identified as the higher aromaticity of 1,2,4-
triazole ring with respect to 1,2,4-oxadiazole.11
Acknowledgment. Financial support through the Univer-
sity of Palermo is gratefully acknowledged.
Supporting Information Available: Synthetic details,
1
characterization data, and H-13C NMR spectra of com-
pounds 3, 4, and 6. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL901687N
(12) For recent examples, see: (a) Chen, C.; Dagnino, R., Jr.; Huang,
C. Q.; McCarthy, J. R.; Grigoriadis, D. E. Bioorg. Med. Chem. Lett. 2001,
11, 3165–3168. (b) Lowe, R. F.; Nelson, J.; Dang, T. N.; Crowe, P. D.;
Pahuja, A.; McCarthy, J. R.; Grigoriadis, D. E.; Conlon, P.; Saunders, J.;
Chen, C.; Szabo, T.; Kung Chen, T.; Bozigian, H. J. Med. Chem. 2005, 48,
1540–1549. (c) Akbarzadeh, T.; Tabatabai, S. A.; Khoshnoud, M. J.;
Shafaghic, B.; Shafieea, A. Bioorg. Med. Chem. 2003, 11, 769–773. (d)
Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.; Nishimura, H.;
Sigiura, M.; Fukaya, C.; Kagitani, Y. J. Med. Chem. 1996, 39, 3019–3029.
The possibility of other thermal rearrangements already
studied for similar substrates (such as a MANC)4g was
excluded on the basis of the obtained product.
4020
Org. Lett., Vol. 11, No. 17, 2009