Experimental and DFT studies on competitive heterocyclic rearrangements. Part 2: A one-atom side-chain versus the classic three-atom side-chain (Boulton-Katritzky) ring rearrangement of 3-acylamino-1,2,4-oxadiazoles

Article abstract of DOI:10.1021/jo701306t

(Chemical Equation Presented) The experimental investigation of the base-catalyzed rearrangements of 3-acylamino-1,2,4-oxadiazoles evidenced a new reaction pathway which competes with the well-known ring-degenerate Boulton-Katritzky rearrangement (BKR). T

Full text of DOI:10.1021/jo701306t

Experimental and DFT Studies on Competitive Heterocyclic
Rearrangements. Part 2:1 A One-Atom Side-Chain versus the
Classic Three-Atom Side-Chain (Boulton-Katritzky) Ring
Rearrangement of 3-Acylamino-1,2,4-oxadiazoles‡
Andrea Pace,*,† Ivana Pibiri,† Antonio Palumbo Piccionello,† Silvestre Buscemi,†
Nicolo` Vivona,† and Giampaolo Barone*,§
Dipartimento di Chimica Organica “E. Paterno`” and Dipartimento di Chimica Inorganica e Analitica “S.
Cannizzaro”, UniVersita` degli Studi di Palermo, Viale delle Scienze, Parco d’Orleans II, Edificio 17,
I-90128 Palermo, Italy
pace@unipa.it; gbarone@unipa.it
ReceiVed June 19, 2007
The experimental investigation of the base-catalyzed rearrangements of 3-acylamino-1,2,4-oxadiazoles
evidenced a new reaction pathway which competes with the well-known ring-degenerate Boulton-
Katritzky rearrangement (BKR). The new reaction consists of a one-atom side-chain rearrangement that
is base-activated, occurs at a higher temperature than the BKR, and irreversibly leads to the corresponding
2-acylamino-1,3,4-oxadiazoles. An extensive DFT study is reported to elucidate the proposed reaction
mechanism and to compare the three possible inherent routes: (i) the reversible three-atom side-chain
ring-degenerate BKR, (ii) the ring contraction-ring expansion route (RCRE), and (iii) the one-atom
side-chain rearrangement. The results of the computational investigation point out that the latter route is
kinetically preferred over the RCRE and can be considered as the ground-state analogue of a previously
proposed C(3)-N(2) migration-nucleophilic attack-cyclization (MNAC) photochemically activated
pathway. The MNAC consists of the formation of a diazirine intermediate, involving the exocyclic nitrogen,
that eventually evolves into a carbodiimide intermediate (migration); the latter undergoes a single
intramolecular nucleophilic attack-cyclization step leading to the final 2-acylamino-1,3,4-oxadiazole.
Introduction
widely used as biologically active molecules, pharmaceuticals,
and new materials in thermally and/or (photo)electronically
stressed devices.3
Among the most investigated ring-transformation reactions,
the monocyclic Boulton-Katritzky rearrangement (BKR) con-
Heterocyclic ring rearrangements represent a class of reactions
which is largely documented in the literature.2 In the hands of
the synthetic heterocyclist, these rearrangements are a useful
tool in order to obtain different heterocyclic systems. Moreover,
these reactions are very important to assess both the thermal
and photochemical stability of heterocyclic systems that are
(2) 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.
‡ Dedicated to Professor Domenico Spinelli in the occasion of his 75th
birthday.
† Dipartimento di Chimica Organica “E. Paterno`”. Fax: +39091596825.
§ Dipartimento di Chimica Inorganica e Analitica “S. Cannizzaro”. Fax:
+39091427584.
(1) For Part 1, see: Pace, A.; Buscemi, S.; Vivona, N.; Silvestri, A.;
Barone, G. J. Org. Chem. 2006, 71, 2740-2749.
10.1021/jo701306t CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/07/2007
7656
J. Org. Chem. 2007, 72, 7656-7666

Temperature-Controlled Heterocyclic Rearrangement
SCHEME 1. General Scheme of the Boulton-Katritzky
Rearrangement (BKR)
SCHEME 2
sists of an interconversion between two five-membered hetero-
cycles where a three-atom side chain and a pivotal annular
nitrogen are involved (Scheme 1).4 This reaction is widely
documented in the literature because of its application in the
synthesis of several target molecules2c,4,5 as well as for the
intriguing mechanistic aspects.6 This reaction, also classified
as an internal nucleophilic substitution,5a,b,6a-f,7 typically occurs
on 1-oxa-2-azoles (1; D ) O) that are O-N bond-containing
five-membered heterocycles [isoxazoles,5a,b 1,2,4-oxadiazoles,5
1,2,5-oxadiazoles (furazans),5a,b and 1,2,5-oxadiazole-2-oxides
(furoxans)5a,b,8].
(the intrinsic ring stability, the nature and position of the
substituents, etc.) become important in determining the direction
of the equilibrium and, in some cases, the irreversibility of the
reaction. Some typical rearrangements of this kind, referred to
the 1,2,4-oxadiazole ring as a substrate, are (Scheme 2) (i) the
stereospecific spontaneous irreversible transformation of Z-
oximes of 3-acyl-1,2,4-oxadiazoles 3 into the corresponding
3-acylamino-1,2,5-oxadiazoles (furazans) 4;10,11 (ii) the base-
catalyzed interconversion between 3-(o-hydroxyphenyl)-1,2,4-
oxadiazoles 5 and 3-acylamino-benzisoxazoles 6, where the
equilibrium composition depends on factors such as the type
of base used (strong bases favoring the oxadiazole) and the
nature of the R substituent;12 and (iii) the irreversible base-
catalyzed rearrangement of the enolate form of 3-acetonyl-1,2,4-
oxadiazoles 7 into the corresponding 3-acylaminoisoxazoles 8.13
In turn, the rearrangement of isoxazole (8; R ) Ar) into oxazole
9 has been reported by heating in DMF in the presence of
t-BuOK and was suggested to occur through a ring contraction-
ring expansion (RCRE) mechanism involving a deprotonated
form of the starting acylaminoisoxazole 8.14
When the nucleophilic Z atom in the side chain attacks the
electrophilic N(2) ring nitrogen, the O(1) ring oxygen in (1; D
) O) acts as an internal leaving group and the O-N bond is
cleaved. When the Z atom is different from oxygen (for instance,
Z ) N, S, C), the process is irreversible, the driving force being
the formation of a more stable N-N, S-N, or C-N bond
replacing the less stable O-N bond. In this case, the reactivity
toward the BKR will be determined by the structure of the
starting heterocycle, the nucleophilic character of the Z atom,
the nature of the solvent, and the possible presence of a base.9
On the other hand, when Z is also an oxygen atom (1; D ) Z
) O), the reaction is potentially reversible since an O-N bond
is broken and a new one is formed. In such a case, other factors
(3) (a) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Hetero-
cycles in Life and Society; Wiley: Chichester, UK, 1997. (b) ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds; Pergamon
Press: Oxford, 1984; Vol. 1.
(4) (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.
(5) (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.; Horva´th, K. J. Chem. Soc., Perkin Trans. 1 1982, 759-766. (d) Horva´th,
K.; Korbonits, D.; Nara´y-Szabo`, G.; Simon, K. J. Mol. Struct. (THEOCHEM)
1986, 136, 215-227.
(9) The base catalysis increases the nucleophilic character of the ZH
side-chain moiety. Nevertheless, the occurrence of an acid-catalyzed pathway
has been recently observed for the BKR of Z-arylhydrazones of 3-benzoyl-
5-amino-1,2,4-oxadiazole into 1,2,3-triazoles.6b,c,e Moreover, copper(II)
acetate catalysis has been reported for the BKR of some arylhydrazones of
3-benzoyl-1-oxa-2-azoles. Buscemi, S.; Frenna, V.; Vivona, N.; Spinelli,
D. J. Chem. Soc., Perkin Trans. 1 1993, 2491-2493.
(10) (a) Vivona, N.; Frenna, V.; Buscemi, S.; Ruccia, M. J. Heterocycl.
Chem. 1985, 22, 97-99. (b) Vivona, N.; Buscemi, S.; Frenna, V.; Ruccia,
M.; Condo`, M. J. Chem. Res. (M) 1985, 2184-2197; (S) 1985, 190. (c)
Andrianov, V. G.; Eremeev, A. V. Chem. Heterocycl. Compd. (Engl. Transl.)
1990, 26, 1199-1213.
(6) 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. Moreover, for DFT studies on bicyclic BKR, see for
example: (g) Eckert, F.; Rauhut, G. J. Am. Chem. Soc. 1998, 120, 13478-
13484. (h) Rauhut, G. J. Org. Chem. 2001, 66, 5444-5448. (i) Pen˜a-
Gallego, A.; Rodr´ıguez-Otero, J.; Cabaleiro-Lago, E. M. J. Org. Chem.
2004, 69, 7013-7017.
(11) Interestingly, the transformation of 1,2,5-oxadiazole-2-oxides into
1,2,4-oxadiazoles has been claimed as a first step along two cascade BKRs
of 3-arylazo-4-acylaminofuroxans into 4-amino-5-nitro-2H-1,2,3-triazoles.8c
See also: (a) Baryshnikova, E. L.; Kulikov, A. S.; Ovchinnikov, I. V.;
Solomentsev, V. S.; Makhova, N. N. MendeleeV Commun. 2001, 230-
232. (b) Molotov, S. I.; Kulikov, A. S.; Strelenko, Yu. A.; Makhova, N.
N.; Lyssenko, K. A. Russ. Chem. Bull. (Engl. Transl.) 2003, 52, 1829-
1834.
(12) Harsani, K. J. Heterocycl. Chem. 1973, 10, 957-961.
(13) Ku¨bel, B. Monatsh. Chem. 1983, 114, 373-376. For a similar
rearrangement leading to a 5-trifluoromethylisoxazole, see: Sumimoto, S.;
Ishizuka, I.; Ueda, S; Takase, A.; Okuno, K. Jpn. Patent 01009978, 1989;
Chem. Abstr. 1989, 111, 57722.
(14) Buscemi, S.; Frenna, V.; Vivona, N. Heterocycles 1991, 32, 1765-
1772.
(15) (a) Vivona, N.; Ruccia, M.; Cusmano, G.; Marino, M. L.; Spinelli,
D. J. Heterocycl. Chem. 1975, 12, 1327-1328. (b) La Manna, G.; Buscemi,
S.; Frenna, V.; Vivona, N.; Spinelli, D. Heterocycles 1991, 32, 1547-1557.
(c) Andrianov, V. G.; Makushenkov, S. V.; Eremeev, A. V. MendeleeV
Commun. 1992, 129-130. (d) Buscemi, S.; Frenna, V.; Vivona, N.; Petrillo,
G.; Spinelli, D. Tetrahedron 1995, 51, 5133-5142. (e) La Manna, G.;
Buscemi, S.; Vivona, N. J. Mol. Struct. (THEOCHEM) 1998, 452, 67-74.
(f) Buscemi, S.; Frenna, V.; Pace, A.; Vivona, N.; Cosimelli, B.; Spinelli,
D. Eur. J. Org. Chem. 2002, 1417-1423. (g) Buscemi, S.; Pace, A.; Frenna,
V.; Vivona, N. Heterocycles 2002, 57, 811-823.
(7) Vivona, N.; Cusmano, G.; Ruccia, M.; Spinelli, D. J. Heterocycl.
Chem. 1975, 12, 985-988.
(8) See for example: (a) Boulton, A. J.; Frank, F.; Huckstep, M. R. Gazz.
Chim. Ital. 1982, 112, 181-183. (b) Sheremetev, A. B.; Makhova, N. N.;
Friedrichsen, W. AdV. Heterocycl. Chem., 2001, 78, 66-188. (c) Makhova,
N. N.; Ovchinnikov, I. V.; Kulikov, A. S.; Molotov, S. I.; Baryshnikova,
E. L. Pure Appl. Chem. 2004, 76, 1691-1703.
J. Org. Chem, Vol. 72, No. 20, 2007 7657

Pace et al.
SCHEME 3. General Scheme and Examples of
Ring-Degenerate BKR of 1,2,4-Oxadiazoles
roalkyl group determines an irreversible transformation of
3-acetylamino-5-perfluoroheptyl-1,2,4-oxadiazole 15 into the
corresponding 3-perfluorooctanoylamino-1,2,4-oxadiazole 16.15g
Besides the several examples of BKR, there are many other
ring rearrangements in which the 1,2,4-oxadiazole system is
involved. Among azoles, in fact, the 1,2,4-oxadiazole is one of
the least aromatic17 and easily undergoes photochemical1,18 or
ANRORC-like19 rearrangements into more stable heterocycles.
In a recent paper, we investigated the competition between
three different photoinduced rearrangements of 3-amino (or
3-alkylamino)-1,2,4-oxadiazoles (17; R ) H, alkyl) and pointed
out the importance of anionic forms and tautomeric equilibria
in determining the experimentally observed reactivity.1 The role
of the photoirradiation was determinant to weaken the O-N
bond and promote the formation of strained three-membered
heterocyclic intermediates. One of the three rearrangements
involved a C(3)-N(2) migration-nucleophilic attack-cycliza-
tion (MNAC) route, which was evidenced in the thermally
driven reactivity of one of the proposed photolytic intermediates
(Scheme 4a). For instance, in the case of 17 (R ) alkyl), this
reaction route implies the formation of a diazirine intermediate
(19; R ) alkyl) which can be interpreted as a one-atom side-
chain rearrangement involving the exocyclic nitrogen.1,20 The
diazirine (19; R ) alkyl) completes the C(3)-N(2) migration
step by developing into the more stable carbodiimide (20; R )
alkyl). The latter is attacked by an external nucleophile and
finally cyclizes into the triazole (22; R ) alkyl) (Scheme 4a).
Only a few examples of thermally induced MNAC reactivity
are reported, all requiring the first atom of the side chain to be
a strong nucleophilic site. One case regards the base-promoted
rearrangement of 3-N-arylamino-5-methoxy-1,2,4-oxadiazoles
into 1,2,4-triazolin-5-ones.20a In the case of enaminoketone 23
(Scheme 4b), the availability of an internal nucleophile in the
carbodiimide 26 (arising from diazirine 25) allows one to
complete the nucleophilic attack and the cyclization in a single
step producing the pyrazole 27.20b Interestingly, a competing
rearrangement into the imidazole 28, through the carbanion 24,
is also observed20b following the classic three-atom (N-C-C)
side-chain BKR.21
An interesting case is represented by 3-acylamino-1,2,4-
oxadiazoles 10, where the identity of the three-atom chains (A-
B-D ) X-Y-Z ) N-C-O) allows a ring-degenerate BKR
to occur (Scheme 3).7,15,16
A fully degenerate BKR has been evidenced15a in the case
of the anion of the 3-acetylamino-5-methyl-1,2,4-oxadiazole (10;
R1 ) R2 ) CH3) for which the involvement of a planar
symmetrical transition state 12 has been debated in several
computational studies.15b,c,e For 3-aroylamino derivatives 13, the
substituents on the aryl moiety will differently affect the neutral
(13 / 14) and anionic forms (13- / 14-) equilibria.15d,f When
neutral forms are involved, the equilibrium is generally shifted
toward the 5-aryl-substituted component 14 as a result of a
diaryloid stabilization;7,15d,f by contrast, when anionic forms are
considered, stabilization of the negative charge on the aroy-
lamino chain plays an important role in the equilibrium.15d,f
Interestingly, the electron-withdrawing ability of the perfluo-
On the basis of these results, it is our opinion that, while
photoinduced MNAC rearrangements follow a downhill path
starting from neutral or anionic excited states, similar reactions
in the ground state require (i) a strong base catalysis to create
an anionic nucleophilic center at the first atom of the side chain,
and (ii) heating to overcome the activation barrier for the
formation of strained three-membered ring intermediates.
Because of the potential acidity of the N-H proton, 3-acy-
lamino-1,2,4-oxadiazoles are suitable substrates to assess the
(16) Ring-degenerate rearrangements of O-N bond-containing azoles
are also known in the 1,2,5-oxadiazole series.10c See also: (a) Andrianov,
V. G.; Semenikhina, V. G.; Eremeev, A. V.; Gaukhman, A. P. Chem.
Heterocycl. Compd. (Engl. Transl.) 1988, 24, 1410. (b) Andrianov, V. G.;
Semenikhina, V. G.; Eremeev, A. V. Chem. Heterocycl. Compd. (Engl.
Transl.) 1991, 27, 102-104.
(17) In the class of five-membered heterocyclic systems, 1,2,4-oxadia-
zoles are among the least aromatic with an index of aromaticity I5 ) 39 or
IA ) 48. (a) Bird, C. V. Tetrahedron 1985, 41, 1409-1414. (b) Bird, C. V.
Tetrahedron 1992, 48, 335-340.
(18) For photoinduced rearrangements involving the 1,2,4-oxadiazole
heterocycle, see: (a) Vivona, N.; Buscemi, S. Heterocycles 1995, 41, 2095-
2116 and references cited therein. (b) Buscemi, S.; Vivona, N.; Caronna,
T. J. Org. Chem. 1995, 60, 4096-4101. (c) Buscemi, S.; Vivona, N.;
Caronna, T. J. Org. Chem. 1996, 61, 8397-8401. (d) Vivona, N.; Buscemi,
S.; Asta, S.; Caronna, T. Tetrahedron 1997, 53, 12629-12636. (e) Buscemi,
S.; Pace, A.; Vivona, N.; Caronna, T.; Galia, A. J. Org. Chem. 1999, 64,
7028-7033. (f) Buscemi, S.; Pace, A.; Vivona, N.; Caronna, T. J.
Heterocycl. Chem. 2001, 38, 777-780. (g) Buscemi, S.; Pace, A.; Pibiri,
I.; Vivona, N. J. Org. Chem. 2002, 67, 6253-6255. (h) Buscemi, S.;
D’Auria, M.; Pace, A.; Pibiri, I.; Vivona, N. Tetrahedron 2004, 60, 3243-
3249. (i) Pace, A.; Pibiri, I.; Buscemi, S.; Vivona, N. J. Org. Chem. 2004,
69, 4108-4115. (j) Buscemi, S.; Pace, A.; Palumbo Piccionello, A.; Pibiri,
I.; Vivona, N. Heterocycles 2004, 63, 1619-1628. (k) Pace, A.; Pibiri, I.;
Buscemi, S.; Vivona, N. Heterocycles 2004, 63, 2627-2648. (l) Buscemi,
S.; Pace, A.; Palumbo Piccionello, A.; Pibiri, I.; Vivona, N. Heterocycles
2005, 65, 387-394. (m) Pace, A.; Buscemi, S.; Vivona, N. J. Org. Chem.
2005, 70, 2322-2324.
(19) For recent examples of ANRORC2d (Addition of a Nucleophile Ring-
Opening Ring-Closure) rearrangements of 1,2,4-oxadiazoles see: (a)
Buscemi, S.; Pace, A.; Palumbo Piccionello, A.; Macaluso, G.; Vivona,
N.; Spinelli, D.; Giorgi, G. J. Org. Chem. 2005, 70, 3288-3291. (b)
Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Spinelli, D. J. Org. Chem.
2003, 68, 605-608. (c) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Lanza,
C. Z.; Spinelli, D. Eur. J. Org. Chem. 2004, 974-980. (d) Buscemi, S.;
Pace, A.; Palumbo Piccionello, A.; Pibiri, I.; Vivona, N.; Giorgi, G.;
Mazzanti, A.; Spinelli, D. J. Org. Chem. 2006, 71, 8106-8113. (e) Palumbo
Piccionello, A.; Pace, A.; Pibiri, I.; Buscemi, S.; Vivona, N. Tetrahedron
2006, 62, 8792-8797.
(20) (a) Jones, S. S.; Staiger, D. B.; Chodosh, D. F. J. Org. Chem. 1982,
47, 1969-1971. (b) Braun, M.; Buchi, G.; Bushey, D. F. J. Am. Chem.
Soc. 1978, 100, 4208-4213.
(21) (a) Ruccia, M.; Vivona, N.; Cusmano, G. Tetrahedron Lett. 1972,
4959-4960. (b) Ruccia, M.; Vivona, N.; Cusmano, G. Tetrahedron 1974,
30, 3859-3864.
7658 J. Org. Chem., Vol. 72, No. 20, 2007

Temperature-Controlled Heterocyclic Rearrangement
SCHEME 4. Photochemically (a) and Thermally (b) Induced Examples of the C(3)-N(2) Migration-Nucleophilic
Attack-Cyclization (MNAC) Rearrangements in 1,2,4-Oxadiazoles
SCHEME 5. Base-Catalyzed Thermally Induced
Rearrangements of 3-Acylamino-1,2,4-oxadiazoles
conditions, the starting material remained essentially unchanged.
For a comparison with previous investigations,23 an analytical
scale reaction of 3-acetylamino-5-methyl-1,2,4-oxadiazole 29a
was also performed in DMF-d7 containing t-BuOK and followed
1
by H NMR as a function of temperature and reaction time
(Figure 1). The NMR spectra showed coalescence of the two
methyl signals of 29a- at about 115 °C, in agreement with
previously reported observations in DMSO-d6.15a Moreover, by
standing at temperatures higher than 110 °C, the formation of
1,3,4-oxadiazole 30a is significantly observed, as a competitive
reaction, together with the fast Boulton-Katritzky rearrange-
ment (Figure 1). However, while the BKR is a reversible
process, the transformation into 1,3,4-oxadiazole 30a is irrevers-
ible. Finally, if cooled before completion of the reaction, the
spectrum of the reaction mixture shows the presence of both
1,2,4-oxadiazole 29a- and 1,3,4-oxadiazole 30a-.
The rearrangement into 1,3,4-oxadiazoles could be explained
by two alternative, but experimentally indistinguishable, routes
both involving a diazirine (31 or 31′) and a carbodiimide
intermediate 32 (Scheme 6). In the MNAC route, the exocyclic
nitrogen of the starting oxadiazole is involved in the formation
of the diazirine intermediate 31, causing the cleavage of the
O-N ring bond. In the RCRE route, instead, the O-N bond is
broken and the original N(4) of the oxadiazole ring is involved
with the N(2) in the formation of the diazirine 31′, chemically
but not topologically identical to 31. To determine the energetic
relationship between the BKR, RCRE, and MNAC routes, we
performed a computational study at the hybrid DFT B3LYP
possibility of a thermally induced one-atom side-chain rear-
rangement to occur. As mentioned above (see Scheme 3),
equilibria of these substrates have been studied considering
different substituents. However, the anionic forms’ equilibria
have never been thoroughly investigated at a temperature higher
than 40 °C,22 and this might have precluded the observation of
energetically higher reaction pathways.
In this article, we report on (i) a newly discovered thermally
induced base-catalyzed rearrangement of 3-acylamino-1,2,4-
oxadiazoles into 2-acylamino-1,3,4-oxadiazoles and (ii) a
theoretical study, performed by DFT calculations, to rationalize
the experimental findings and to determine the structures and
the energies of intermediates and transition states involved in
the proposed reaction pathways.
Results and Discussion
At first, we investigated the reactivity of 3-acylamino-1,2,4-
oxadiazoles 29a-d, whose fully degenerate BKR would be
nonproductive, to assess the occurrence of a one-atom side-
chain rearrangement. Oxadiazoles 29a-d, heated in DMF at
150 °C and in the presence of t-BuOK, produced the corre-
sponding 2-acylamino-1,3,4-oxadiazoles 30a-d in 60-77%
yields (Scheme 5).
(23) A previously reported,15a dynamic NMR experiment, performed in
DMSO-d6 on 3-acetylamino-5-methyl-1,2,4-oxadiazole 29a in the presence
of t-BuOK, showed coalescence of the two methyl signals at 112 °C, and
an activation barrier of ∆Gq ) 82 ( 1.7 kJ/mol was evaluated for the BKR
equilibrium of chemically, but not topologically, identical 29a- and 29a′-
anions (see Figure 2). However, in that occasion, due to the short time
spent at 112 °C, the low resolution of NMR spectra, and the extended
exchange of the methyl protons with DMSO deuteria, no further rearrange-
ment was detected.
The observed rearrangement must involve deprotonated
intermediates since, in the absence of base and under the same
(22) Higher temperatures were used for a short experimental time during
a dynamic NMR study on the BKR of the anion of 3-acetylamino-5-methyl-
1,2,4-oxadiazole 29a.15a
J. Org. Chem, Vol. 72, No. 20, 2007 7659

Pace et al.
conjugation. In this step, the cleavage of the O-N ring bond is
anchimerically assisted by the attack of the Nexocyclic moiety on
the N(2). In the absence of such assistance, the cleavage of the
O-N ring bond in the first step, 29a- f 31′, of the RCRE
route requires overcoming an even higher activation barrier
(∆Gq
) 192.5 kJ/mol) and is therefore the less favored
RCRE
route.
Continuing along the reaction coordinate, the diazirine
intermediate 31 can follow two alternative routes: (i) the
equilibration, through a one-atom side-chain fully degenerate
rearrangement, with the equivalent diazirine 31′; this rearrange-
ment involves a TS with C2 symmetry and has an activation
barrier of 88.9 kJ/mol,25 which is of the same order of magnitude
as those calculated for 29a- f 31 and 29a- / 29a′- processes;
(ii) the development into the more stable carbodiimide 32 which
will eventually cyclize into the anionic 1,3,4-oxadiazole 30a-.
This latter route implies an initial conformational change of
diazirine 31 (or 31′) into 31′′, less stable by 5.2 kJ/mol; from
this conformer, the transformation into the carbodiimide 32 has
an activation barrier of only 18.9 kJ/mol; therefore, this second
route will be favored. The final step consists of a fast cyclization
of intermediate 32 into the 1,3,4-oxadiazole product 30-. In
summary, while the base-catalyzed BKR is a fast reversible
equilibrium, the MNAC route is a slow irreversible reaction
which requires higher temperatures to be initiated and to produce
the more stable 1,3,4-oxadiazoles; finally, the RCRE is the less
favored pathway in the competition.
FIGURE 1. 1H NMR spectra of compound 29a in DMF-d7 in the
presence of t-BuOK as a function of temperature and reaction time.
level (see Computational Details in the Experimental Section),
using 3-acetylamino-5-methyl-1,2,4-oxadiazole 29a as a model
compound, and the results obtained, both in vacuo and in the
mimicked DMSO solvent,24 are summarized in Table 1 and
illustrated in Figure 2.
This mechanistic picture has been further verified by studying
the reactivity of differently substituted 3-acylamino-1,2,4-
oxadiazoles 33 and 36 (Scheme 7). Each one of these isomers,
heated in DMF/t-BuOK in two separate preparative scale
experiments, yielded a mixture of 1,3,4-oxadiazoles isomers 34
and 35 in approximately the same ratio (34:35 ) 70:30).
The energies calculated along the reaction coordinate of
neutral and deprotonated 29a and 29a-, and the geometries of
the transition states and intermediates, allowed us to rationalize
several aspects of this newly discovered reactivity of 3-acy-
lamino-1,2,4-oxadiazoles. As expected, in agreement with the
experimental results, the 1,3,4-oxadiazole product, in either its
neutral 30a or anionic 30a- forms, is by far more stable than
1,2,4-oxadiazole 29a or 29a-, respectively. Along the anionic
reaction coordinate, the three routes available for the evolution
of starting 1,2,4-oxadiazole 29a- are energetically well dif-
ferentiated. The fully degenerate Boulton-Katritzky rearrange-
ment equilibrium, 29a- / 29a′-, involves a fully planar
transition state with C2V symmetry and has the lowest activation
energy (∆GqBKR ) 79.1 kJ/mol) among the competing reactions.
The calculated value is in excellent agreement with the activation
barrier, ∆Gq ) 82 ( 1.7 kJ/mol, experimentally measured in a
previous study,15a and made us confident about the quality of
the chosen computational approach. Both the MNAC and the
RCRE routes, instead, require an initial highly endoergonic step
leading to a strained diazirine intermediate (31 or 31′). The high
activation energy of the first step, 29a- f 31, of the MNAC
First of all, it is worth remarking that starting 1,2,4-
oxadiazoles 33 and 36 correlate with each other through a BKR
equilibrium involving either neutral or anionic species.7,15d In
this case, the equilibrium composition for the neutral BKR 33
/ 36 did not significantly vary upon solvent change from
MeOH (33:36 ) 91:9 at 40 °C)15d to DMSO or DMF (see
Experimental Section). An anionic equilibrium composition of
33-:36- ) 63:37 was determined at 40 °C using a t-BuOK/
(25) In a previous paper,1 we pointed out the possibility of a thermal
equilibrium to occur between the diazirine B (formed through a migration
step from oxadiazole A) and the diazirine C (originated through a ring-
contraction step from oxadiazole A).
route (∆Gq
) 131.0 kJ/mol) can be justified considering
MNAC
the remarkable bending of the Nexocyclic-C(3)-N(2) bond angle
which is required along this step. Moreover, a rotation of the
C(3)-Nexocyclic bond is required to allow the overlap between
the Nexociclic (nucleophilic site) and N(2) (electrophilic site)
orbitals; this rotation drives the carbonyl group on a plane
orthogonal to the rest of the molecule with consequent loss of
In that occasion, the occurrence of a B f C transformation, for R ) H,
was claimed to justify the experimental findings. As a comparison, the
activation barriers for this diazirine interconversion in MeOH were calculated
to be ∆Gq ) 105.0 kJ/mol (for B f C; R ) H), ∆Gq ) 96.2 kJ/mol (for
C f B; R ) H), ∆Gq ) 129.4 kJ/mol (for B f C; R ) CH3), and ∆Gq )
74.3 kJ/mol (for C f B; R ) CH3).
(24) An analytical reaction performed on representative 29a in DMSO/
t-BuOK gave comparable results to those obtained in DMF. Therefore,
although preparative scale reactions described in this article have been
performed in DMF, we chose to use the available DMSO model solvent to
mimic the polar aprotic solvent media in our computational study.
7660 J. Org. Chem., Vol. 72, No. 20, 2007

Temperature-Controlled Heterocyclic Rearrangement
SCHEME 6. Alternative Reaction Routes for the Ring Rearrangement of 1,2,4-Oxadiazole 29a into 1,3,4-Oxadiazole 30a
TABLE 1. Standard Free Energy Values (∆G°, kJ/mol) Relative to 29a,a for Neutral, and to 29a-,a for Anionic Species or Transition States,
and Activation Barriers (∆Gq, kJ/mol), Relative to the Given Starting Compound, along the Anionic Reaction Coordinate, Calculated In Vacuo
and in DMSO at 298.15 K
Neutral Species
∆G° in vacuo
0.0
∆G° in DMSO
0.0
Anionic Species
∆G° in vacuo
0.0
∆G° in DMSO
0.0
29a
30a
29a-
30a-
31
-20.7
-19.0
-48.3
73.1
-41.1
104.2
31′′
32
70.6
-11.2
109.4
29.2
Transition States
[29a- f 29a′-]q
[29a-f31]q
∆G° in vacuo
∆G° in DMSO
∆Gq in vacuo
∆Gq in DMSO
79.1
64.2
102.0
160.1
152.7
96.9
79.1
131.0
192.5
193.1
128.3
36.3
64.2
102.0
160.1
79.6
26.3
19.4
131.0
192.5
88.9
18.9
7.1
[29a- f 31′]q
[31 f 31′]q
[31′′ f 32]q
[32 f 30a-]q
8.2
a The standard free energy values calculated at the B3LYP/6-31++G(d,p) level for compounds 29a and for 29a- are -509.37138 and -508.82729 au,
respectively; the solvation free energy values for 29a and for 29a- are -7.60 and -55.83 kcal/mol, respectively (see Computational Details in the Experimental
Section).
oxadiazole ) 0.5 ratio in DMSO-d6.26 This result is in agreement
with the previously reported ratio 33-:36- ) 62:38 in CD3OD
at 40 °C, determined by using a base/substrate ratio of 1.5,15d
and shows the little dependence from the solvent also for the
anionic BKR equilibrium.
Besides undergoing the Boulton-Katritzky rearrangement,
each anion (33- or 36-) of the starting 1,2,4-oxadiazoles is able
to produce any of the 1,3,4-oxadiazoles isomers 34 and 35
through different competing pathways (Scheme 8). DFT cal-
culations, performed on neutral and anionic species along the
reaction coordinate of both 1,2,4-oxadiazoles 33 and 36, clarified
some aspects of the observed reactivity, and the results are
summarized in Table 2 and illustrated in Figure 3.
Also in this case, analogously to what observed for 29a and
30a, 1,3,4-oxadiazoles 34 and 35 and their anions 34- and 35-
were more stable than the starting 1,2,4-oxadiazoles 33 and 36
and their anions 33- and 36-, respectively. Interestingly, the
thermodynamic of structural change from 1,2,4-oxadiazole to
1,3,4-oxadiazole is not significantly affected by the change of
the substituents (from methyl to phenyl) on either the amide
chain or the oxadiazole ring. In fact, the free energy values of
the1,2,4-oxadiazolef1,3,4-oxadiazoletransformation∆G°1,3,4-1,2,4
are about -20 kJ/mol (for the neutral forms) and about -40
kJ/mol (for anionic forms) for compounds 29a/30a, 33/35, and
36/34 (see Tables 1 and 2).
By comparing values of Table 2, it is interesting to outline
the considerable influence of the DMSO solvent in determining
the relative stability especially of the anionic species involved
in the process. In fact, for example, the stability order of anions
34- and 35- in DMSO is different than in vacuo. Another
remarkable case is the energy difference between the anionic
species 33- and 36-. While in vacuo 33- is about 7 kJ/mol
less stable than 36-, in DMSO the difference decreases to 1.4
kJ/mol, and the two species can be considered as essentially
isoenergetic, within the numerical accuracy of the selected
computational method. This means that DMSO has a more
pronounced stabilizing effect for 33- than for 36-, in agreement
with the experimentally established equilibrium composition in
DMSO, 33-:36- ) 63:37 (see above).27 On the other hand, the
stability order of neutral species is not affected by the solvent;
(27) Calculations on anions 33- and 36- in MeOH showed anion 33-
being 0.5 kJ/mol more stable than 36-, in good agreement with the
experimentally determined equilibrium composition in CD3OD.15d On the
other hand, due to the experimental difficulties encountered,26 a rigorous
comparison between the experimental and computational data is not possible
in the case of BKR equilibrium 33- / 36- in DMSO for which the little
discordance about the stability order is within the numerical accuracy of
the computational method. In our opinion, only the explicit consideration
of coordinating solvent molecules in our DFT calculation, in addition to
the PCM approach, could in this isolated case reproduce the stability order,
experimentally determined.
(26) An accurate determination of the anionic BKR equilibrium 33-
/
36- composition would require a higher base/substrate ratio to guarantee
for complete deprotonation of the starting oxadiazole.15d However, the use
of t-BuOK/oxadiazole ratios higher than 0.5 in DMSO-d6 was not achievable
because of low solubility of the formed salts. Moreover, an even lower
solubility of these salts was observed when DMF-d7 was used.
J. Org. Chem, Vol. 72, No. 20, 2007 7661

Pace et al.
FIGURE 2. Standard free energy profiles along the reaction coordinate of 1,2,4-oxadiazole 29a in solution, at 298.15 K.
SCHEME 7. Base-Catalyzed Thermal Rearrangements of
3-Acetylamino-5-phenyl- (33) and 3-Benzoylamino-5-methyl-
(36) 1,2,4-oxadiazoles
79.0 kJ/mol) is practically identical to the one calculated for
the BKR of 29a-. Therefore, under the used reaction conditions
(excess of t-BuOK and 150 °C), either oxadiazole 33 or 36
should undergo a fast BKR equilibrium yielding the anionic
mixture 33-/36-. From this equilibrium mixture, each of the
oxadiazole anions, 33- or 36-, can then follow either the RCRE
or the MNAC route. The activation barriers for the RCRE route
(33- f 39 or 36- f 37), respectively, 196 and 214 kJ/mol, are
different along the two reaction coordinates of 33- and 36-,
resulting about 19 kJ/mol more favored in the case of 33-. On
the other hand, the MNAC route (33- f 37 or 36- f 39) has
a much lower activation energy, about 130 kJ/mol, which is
almost identical for 33- and 36-, and should be by far a more
favored pathway than the RCRE.
for instance, neutral oxadiazoles 33 is 7.9 kJ/mol more stable
than 36 both in vacuo and in DMSO. These data are in
agreement with the experimentally observed neutral BKR
equilibrium significantly shifted in favor of 33 (33:36 ) 91.6:
8.4 at 25 °C).
In analogy with the study performed on the rearrangement
of oxadiazole 29a, we also considered the possible equilibration
between the two diazirine intermediates 37 and 39. Although
involving a noteworthy activation barrier (80.5 kJ/mol), this
equilibrium cannot be excluded on the basis of computational
The calculated activation barrier for the Boulton-Katritzky
rearrangement between anions 33- and 36- in DMSO (∆Gq )
7662 J. Org. Chem., Vol. 72, No. 20, 2007

Temperature-Controlled Heterocyclic Rearrangement
SCHEME 8. Competition between BKR, MNAC, and RCRE Routes in the Rearrangements of Oxadiazoles 33 and 36
TABLE 2. Standard Free Energy Values (∆G°, kJ/mol) Relative to 36,a for Neutral, and to 36-,a for Anionic Species or Transition States, and
Activation Barriers (∆Gq, kJ/mol), Relative to the Given Starting Compound, along the Anionic Reaction Coordinate, Calculated In Vacuo and
in DMSO at 298.15 K
Neutral Species
∆G° in vacuo
-7.9
∆G° in DMSO
-7.9
Anionic Species
∆G° in vacuo
6.7
∆G° in DMSO
1.4
33
34
35
36
33-
34-
35-
36-
37
-20.7
-30.7
0.0
-18.2
-44.9
-50.1
0.0
81.7
77.9
-1.5
87.4
90.0
-6.4
-38.8
-37.1
0.0
107.9
111.5
34.2
114.8
124.8
29.8
-26.5
0.0
37′
38
39
39′
40
Transition States
[33- f 36-]q
[33- f 37]q
[33- f 39]q
[36- f 37]q
[36- f 39]q
[37 f 39]q
∆G° in vacuo
∆G° in DMSO
∆Gq in vacuo
∆Gq in DMSO
79.0
69.6
110.3
170.1
185.6
111.7
162.2
106.9
107.0
17.2
80.4
133.5
197.0
214.3
133.5
195.3
129.7
135.0
39.0
62.9
103.6
163.4
185.6
111.7
80.5
29.0
17.0
18.7
19.4
132.1
195.6
214.3
133.5
87.4
18.2
10.2
4.8
8.2
[37′ f 38]q
[39′ f 40]q
[38 f 34-]q
[40 f 35-]q
13.0
38.0
a The standard free energy values calculated at the B3LYP/6-31++G(d,p) level for compounds 36 and 36- are -701.06922 and -700.53489 au, respectively;
the solvation free energy values for 36 and for 36- are -8.39 and -53.23 kcal/mol, respectively (see Computational Details in the Experimental Section).
kinetic data. In fact, such a barrier is of the same order of
magnitude of the BKR barrier and is even lower than those
calculated for the migration steps 33- f 37 and 36- f 39;
hence the 37 / 39 equilibrium should be accessible at the
experimental temperatures and conditions. However, once a
diazirine is formed, its evolution into the corresponding carbo-
diimide (37 f 37′ f 38 or 39 f 39′ f 40) has a much lower
activation energy (10-20 kJ/mol) than its equilibration with
the other diazirine.
Overall, the energy profiles along the reaction coordinate of
the two oxadiazoles 33- and 36- are very similar; therefore,
following the two irreversible MNAC routes, the transformation
of 33- and 36- should occur at the same rate without provoking
any significant shift of the fast (under the reaction conditions)
reversible BKR equilibrium. This hypothesis is supported by
the analytical NMR determinations, where the same product
distribution of 34-:35- ) 72:28 was obtained after heating, in
two separate experiments, either oxadiazole 33 or 36 with 2
equiv of t-BuOK for 3 h at 150 °C in DMF-d7 (see Experimental
Section). Indeed, this product distribution resembles the BKR
equilibrium composition 33-:36- ) 63:37 observed at 40 °C
in DMSO-d6 (see above). Unfortunately, a rigorous comparison,
under the same conditions, between the 1,3,4-oxadiazole final
product distribution and the 1,2,4-oxadiazoles BKR equilibrium
composition could not be achieved because of experimental
difficulties.26
Finally, one may consider that, in the experimental conditions
of the present study, the final 1,3,4-oxadiazoles’ distribution is
a function of their anion stability and is essentially thermody-
namically, and not kinetically, controlled; in fact, in DMSO,
34- is 1.7 kJ/mol more stable than 35-, which implies a
theoretical 34-:35- ) 62:38 ratio at 150 °C, in agreement with
the experimentally observed product ratio.
Conclusions
The competition between two thermally induced rearrange-
ments of 3-acylamino-1,2,4-oxadiazoles in the presence of
t-BuOK has been rationalized in terms of process reversibility
and reaction rates. The reversible ring-degenerate Boulton-
Katritzky rearrangement is in competition with a slower, but
irreversible, one-atom side-chain rearrangement leading to the
more stable 1,3,4-oxadiazoles. This competition originates from
the presence of two alternative nucleophilic sites in the side
J. Org. Chem, Vol. 72, No. 20, 2007 7663

Pace et al.
FIGURE 3. Standard free energy profiles along the reaction coordinate of 1,2,4-oxadiazoles 33 and 36 in solution, at 298.15 K.
chain of the deprotonated 3-acylamino-1,2,4-oxadiazole reagent.
At a first glance, the anionic reagent can follow three possible
routes each characterized by well differentiated transition states
and activation energies. In the BKR, the nucleophilic attack of
the side-chain oxygen atom on the electrophilic N(2) ring atom
is geometrically favored and occurs through a planar [3.3.0]
bicyclic transition state. In the migration step of the MNAC
route, instead, the side-chain nitrogen atom is involved as a
nucleophile in the formation of a planar [3.1.0] bicyclic
transition state. This step requires higher temperatures to
overcome the activation barrier mostly due to geometrical
restrains. On the other hand, the planar [2.1.0] bicyclic transition
state, involved in the ring-contraction step of the RCRE route,
is too high in energy to be reached at the used reaction
temperatures.
In a second time, the migration step of the MNAC route is
then completed by the development of the diazirine into the
more stable carbodiimide intermediate. This process is faster
than the equilibration between the diazirine intermediates which,
in turn, has an energy barrier comparable to that of the BKR
and requires a planar [1.1.0] bicyclic transition state. Finally,
since the carbodiimide intermediate possesses a nucleophilic
site, an intramolecular nucleophilic attack occurs on the central
carbodiimide carbon completing the nucleophilic attack-
cyclization of the MNAC route in one step and yielding the
final 1,3,4-oxadiazole product.
Overall, the driving force of the reaction is the higher stability
of the 1,3,4-oxadiazole system with respect to the 1,2,4-
oxadiazole heterocycle. The well different activation energies
involved in the competing routes allow one to selectively control
7664 J. Org. Chem., Vol. 72, No. 20, 2007

Temperature-Controlled Heterocyclic Rearrangement
TABLE 3. Equilibrium Composition of the BKR of Compounds
33 or 36 in Neutral Conditions
which reaction will be observed, among the BKR and the
MNAC route, by choosing the appropriate reaction temperature.
DMSO-d6
DMF-d7
Experimental Section
temp (°C)
33 (%)
36 (%)
33 (%)
36 (%)
Starting Materials. Compounds 29a,15a 29c,28 33,7 and 36 were
synthesized as previously reported. Compounds 29b and 29d were
similarly prepared by acylation of the corresponding 3-amino
compounds,15g with the appropriate acyl chloride in pyridine at room
temperature. 3-Butanoylamino-5-propyl-1,2,4-oxadiazole 29b (83%)
had mp 85-87 °C (from benzene/light petroleum). IR (nujol) 3250,
25
40
120
91.6
90.8
85.7
8.4
9.2
14.3
91.5
90.2
84.1
8.5
9.8
15.9
with authentic synthetic samples of 34 and 35. 2-Benzoylamino-
5-methyl-1,3,4-oxadiazole 34 had mp 184-186 °C (from EtOH).
1
3229, 3107, 1699 cm-1. H NMR (300 MHz, DMSO-d6): δ 0.94
IR (nujol) 3122, 1714 cm-1. H NMR (300 MHz, DMSO-d6): δ
1
(t, 3H, J ) 7.4 Hz), 1.0 (t, 3H, J ) 7.4 Hz), 1.64 (m, 2H), 1.79 (m,
2H), 2.40 (t, 2H, J ) 7.2 Hz), 2.89 (t, 2H, J ) 7.3 Hz), 11.02 (s,
1H). HRMS calcd for C9H15N3O2 197.1164; found 197.1164. 3-(2-
Thiophenecarbonyl)amino-5-(thien-2-yl)-1,2,4-oxadiazole 29d (80%)
had mp 188-190 °C (from benzene). IR (nujol) 3200, 3100, 1673
cm-1. 1H NMR (300 MHz, DMSO-d6): 7.31 (dd, 1H, J ) 4.6 Hz,
J ) 3.6 Hz), 7.43 (dd, 1H, J ) 3.6 Hz, J ) 4.2 Hz), 8.03 (d, 1H,
J ) 4.6 Hz), 8.08 (d, 1H, J ) 3.6 Hz), 8.17 (d, 1H, J ) 4.2 Hz),
8.26 (d, 1H, J ) 3.6 Hz), 11.80 (s, 1H). HRMS calcd for
C11H7N3O2S2 276.9980; found 276.9977.
General Procedure for Preparative Scale Base-Catalyzed
Rearrangements of 3-Acylamino-1,2,4-oxadiazoles 29a-d, 33,
and 36. 3-Acylamino-1,2,4-oxadiazoles 29a-d, 33, or 36 (300 mg)
were dissolved in 5 mL of dry DMF together with 2.1 equiv of
t-BuOK, and the mixture was allowed to stir at 150 °C for 6-8 h,
until complete conversion of the starting substrate was reached.
The reaction was quenched by addition of water and neutralized
with concentrated HCl. The aqueous phase was then extracted with
EtOAc (3 × 20 mL), and the combined organic layers were washed
with H2O, dried on Na2SO4, and filtered. After solvent removal,
the residue was chromatographed using silica gel (0.040-0.063
mm) and mixtures of EtOAc and light petroleum (fraction boiling
in the range 40-60 °C) in various ratios.
2.56 (s, 3H), 7.65 (m, 3H), 8,00 (m, 2H), 12.04 (s, 1H). HRMS
calcd for C10H9N3O2 203.0695; found 203.0691. 2-Acetylamino-
5-phenyl-1,3,4-oxadiazole 35 had mp 220-222 °C (from EtOH)
(lit.30 mp 223 °C). IR (nujol) 3136, 1729 cm-1. 1H NMR (300 MHz,
DMSO-d6): δ 2.23 (s, 3H), 7.66 (m, 3H), 7.97 (m, 2H), 11.77 (s,
1H).
Rearrangement of 36. Chromatography of the residue yielded
0.27 g (90%) of a mixture of 1,3,4-oxadiazoles isomers 34 and 35
in a 34:35 ) 68:32 ratio (determined by NMR as described above).
Dynamic NMR Experiment for the Rearrangement of 29a-
in DMF. 1,2,4-Oxadiazole 29a (6.0 mg; 0.04 mmol) was dissolved
in DMF-d7 (0.35 mL) and added to a solution of t-BuOK (7.0 mg;
0.06 mmol) in DMF-d7 (0.4 mL) in an NMR tube. 1H NMR spectra
were registered on the same sample at different temperatures over
a period of 60 min. Compound 29a: 1H NMR (300 MHz, DMF-
d7) δ 2.18 (s, 3H), 2.55 (s, 3H), 10.89 (s, 1H). Anion 29a-: 1H
NMR (300 MHz, DMF-d7) δ 1.84 (s, 3H), 2.29 (s, 3H). Compound
30a: 1H NMR (300 MHz, DMF-d7) δ 2.20 (s, 3H), 2.46 (s, 3H),
11.51 (s, 1H). Anion 30a-: 1H NMR (300 MHz, DMF-d7) δ 1.86
(s, 3H), 2.22 (s, 3H). Representative spectra are illustrated in Figure
1 in the chemical shift range of the methyl signals.
Equilibration between 33 and 36 in DMSO-d6 and DMF-d7.
In four separate NMR tubes, either 3-acetylamino-5-phenyl-1,2,4-
oxadiazole 33 (10.0 mg; 0.05 mmol) or 3-benzoylamino-5-methyl-
1,2,4-oxadiazole 36 (10.0 mg; 0.05 mmol) was dissolved in DMSO-
d6 (0.75 mL) or DMF-d7 (0.75 mL). The four tubes were kept under
identical temperature conditions in a thermostated bath.
Rearrangement of 29a. Chromatography of the residue yielded
2-acetylamino-5-methyl-1,3,4-oxadiazole 30a (0.18 g; 60%), mp
180-182 °C (from EtOH) (lit.29 mp 180-181 °C). IR (nujol) 3148,
1736, 1725 cm-1. 1H NMR (300 MHz, DMSO-d6): δ 2.17 (s, 3H),
2.49 (s, 3H), 11.44 (s, 1H).
The composition of the 33/36 mixture (see Table 3) was
determined by 1H NMR, by comparison of the integrals of methyl
signals of 33 (2.19 ppm in DMSO-d6; 2.25 ppm in DMF-d7) and
36 (2.64 ppm in DMSO-d6; 2.61 ppm in DMF-d7). The equilibrium
was considered reached when the composition of the 33/36
mixtures, from either 33 or 36, resulted the same.
Rearrangement of 29b. Chromatography of the residue yielded
2-butanoylamino-5-propyl-1,3,4-oxadiazole 30b (0.23 g; 77%), mp
89-92 °C (from benzene/light petroleum). IR (nujol) 3150, 1708
1
cm-1. H NMR (300 MHz, DMSO-d6): δ 0.95 (t, 3H, J ) 7.3
Hz), 1.0 (t, 3H, J ) 7.4 Hz) 1.63 (m, 2H), 1.74 (m, 2H), 2.42 (t,
2H, J ) 7.3 Hz), 2.81 (t, 2H, J ) 7.3 Hz), 11.48 (s, 1H). HRMS
calcd for C9H15N3O2 197.1164; found 197.1162.
Rearrangement of 29c. Chromatography of the residue yielded
2-benzoylamino-5-phenyl-1,3,4-oxadiazole 30c (0.23 g; 77%), mp
205-206 °C (from MeOH) (lit.29 mp 201-202 °C). IR (nujol) 3150,
1716 cm-1. 1H NMR (250 MHz, DMSO-d6): δ 7.58-7.74 (m, 6H),
7.98-8.11 (m, 4H), 12.30 (s, 1H).
Rearrangement of 29d. Chromatography of the residue yielded
2-(2-thiophenecarbonyl)amino-5-(thien-2-yl)-1,3,4-oxadiazole 30d
(0.19 g; 63%), mp 210-212 °C (from EtOH). IR (nujol) 3107,
1700 cm-1. 1H NMR (300 MHz, DMSO-d6): δ 7.30 (dd, 1H, J )
3.5 Hz, J ) 4.7 Hz), 7.35 (dd, 1H, J ) 4.7 Hz, J ) 3.8 Hz), 7.81
(d, 1H, J ) 3.8 Hz), 7.98 (d, 1H, J ) 4.7 Hz), 8.01 (d, 1H, J ) 4.7
Hz), 8.13 (d, 1H, J ) 3.5 Hz), 12.44 (s, 1H). HRMS calcd for
C11H7N3O2S2 276.9980; found 276.9976.
Rearrangement of 33. Chromatography of the residue yielded
0.26 g (87%) of a mixture of 1,3,4-oxadiazoles isomers 34 and 35
in a 34:35 ) 70:30 ratio, determined by comparing integrals of the
methyl 1H NMR signals (in DMSO-d6) of 34 (at δ ) 2.56) and 35
(at δ ) 2.23). Analytical samples of oxadiazoles 34 and 35
(obtained from enriched chromatographic fractions) were compared
Equilibration between 33 and 36 in DMSO-d6 in the Presence
of t-BuOK. In two separate NMR tubes, either 33 (6.0 mg; 0.03
mmol) or 36 (6.0 mg; 0.03 mmol) was dissolved in DMSO-d6 (0.35
mL). A solution of t-BuOK (1.7 mg; 0.015 mmol) in DMSO-d6
(0.4 mL) was added to each tube. The obtained solution, opaque at
rt, became clear at 40 °C. Both tubes were kept in a thermostated
bath at 40 °C for 2.5 h. The composition of the 33-/36- mixture
1
was determined by H NMR, by comparison of the integrals of
methyl signals at 2.17 ppm (for 33-) and 2.43 ppm (for 36-). The
obtained ratios were 33-:36- ) 63.6:36.4 from 33, and 33-:36-
) 62.5:37.5 from 36, indicating that the equilibrium was complete,
within experimental error.
Analytical Determination of Product Distribution from Rear-
rangements of 33 and 36 in DMF-d7 in the Presence of t-BuOK.
In two separate NMR tubes, either 33 (4.0 mg; 0.02 mmol) or 36
(4.0 mg; 0.02 mmol) was dissolved in DMF-d7 (0.35 mL). A
solution of t-BuOK (4.5 mg; 0.04 mmol) in DMF-d7 (0.4 mL) was
added to each tube, and a precipitate of the potassium salts of 33-
and 36- was formed. The two tubes were then kept in a
thermostated bath for 3 h at 150 °C (temperature at which the
suspension became a clear solution). After cooling at rt (no
(28) Buscemi, S.; Vivona, N. Heterocycles 1994, 38, 2423-2432.
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J. Org. Chem, Vol. 72, No. 20, 2007 7665

Pace et al.
precipitate was observed from the two pale-yellow solutions), the
composition of the 34-/35- mixture was determined by 1H NMR,
by comparison of the integrals of methyl signals at 2.28 ppm (for
34-) and 1.91 ppm (for 35-). The obtained ratios, considered equal
within experimental error, were 34-:35- ) 71.7:28.3 from 33, and
34-:35- ) 72.2:27.8 from 36.
Computational Details. The molecular and anionic species
considered, shown in Figures 2 and 3, were the lowest energy
tautomers and/or conformers found for each isomer in the DMSO
solvent (see below). Their geometry was fully optimized by using
the hybrid DFT B3LYP method31 and the 6-31++G(d,p) basis set.32
Their Cartesian coordinates are available in the Supporting Informa-
tion.
in vacuo.34 The solvation free energy in DMSO was calculated by
the conductor-like polarized continuum model,35 without further
optimization of the geometry (i.e., single point calculations) within
the solvent medium. Some test cases have in fact demonstrated
that the subsequent geometry optimization in DMSO, although
computationally expensive, did not produce significant differences
with the structures and the solvation free energies evaluated for
the geometries already optimized in vacuo.
All calculations were performed by the Gaussian98 program
package.36
Acknowledgment. Financial support from the University of
Palermo is gratefully acknowledged.
Supporting Information Available: Cartesian coordinates,
B3LYP energy (in au), and standard thermochemical data (in au)
at 298.15 K of all compounds and transition states reported in Tables
1 and 2 as well as illustrated in Figures 2 and 3. H NMR spectra
of compounds 29b,d, 30a-d, 34, and 35 in DMSO-d6. This material
is available free of charge via the Internet at http://pubs.acs.org.
Transition-state structures were found by the synchronous transit
guided quasi-Newton method.33 Vibration frequency calculations,
within the harmonic approximation, were performed to confirm
whether each obtained geometry represented a transition state or a
minimum in the potential energy surface. All of the minimum
energy structures presented only real vibrational frequencies,
whereas all of the transition state structures found were first-order
saddle points.
1
JO701306T
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To take into account the relative stabilization of intermediates,
the standard free energies, at 298.15 K, of the considered species
have been evaluated by vibrational frequency calculations of the
in vacuo species. Their free energy in DMSO solution was evaluated
by adding the solvation free energy to the free energy of the species
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