Exploiting the CNC side chain in heterocyclic rearrangements: Synthesis of 4(5)-acylamino-imidazoles

Article abstract of DOI:10.1021/ol1013087

(Equation Presented). A new variation on the Boulton-Katritzky reaction is reported, namely, involving use of a CNC side chain. A novel Montmorillonite-K10 catalyzed nonreductive transamination of a 3-benzoyl-1,2,4-oxadiazole afforded a 3-(α-aminobenzyl)-1,2,4-oxadiazole, which was condensed with benzaldehydes to afford the corresponding imines. In the presence of strong base, these imines underwent Boulton-Katritzky-type rearrangement to afford novel 4(5)-acylaminoimidazoles.

Full text of DOI:10.1021/ol1013087

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3491-3493
Exploiting the CNC Side Chain in
Heterocyclic Rearrangements: Synthesis
of 4(5)-Acylamino-imidazoles
Antonio Palumbo Piccionello,* Silvestre Buscemi, Nicolo` Vivona, and
Andrea Pace
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 June 7, 2010
ABSTRACT
A new variation on the Boulton-Katritzky reaction is reported, namely, involving use of a CNC side chain. A novel Montmorillonite-K10
catalyzed nonreductive transamination of a 3-benzoyl-1,2,4-oxadiazole afforded a 3-(r-aminobenzyl)-1,2,4-oxadiazole, which was condensed
with benzaldehydes to afford the corresponding imines. In the presence of strong base, these imines underwent Boulton-Katritzky-type
rearrangement to afford novel 4(5)-acylaminoimidazoles.
The Boulton-Katritzky (BK) rearrangement represents one
of the most investigated ring-transformation reactions1 as a
result of its synthetic applications2,3 and intriguing mecha-
nistic aspects.4,5
It consists of an interconversion between two five-
membered heterocycles where a three-atom side chain and
a pivotal annular nitrogen are involved (1 f 2).1 This
rearrangement typically occurs on O-N bond-containing
heterocycles (D ) O)3,6 with the O(1) ring oxygen acting
as an internal leaving group. The O-N bond is cleaved by
the nucleophilic attack of the side-chain Z atom at the
electrophilic N(2) ring nitrogen. This reaction is affected by
the aromaticity and relative stability of the five-membered
heterocycles 1and 2. Moreover, with Z atoms different from
oxygen, the reaction is irreversibly shifted toward the
formation of a more stable N-N, S-N, or C-N bond.
(1) (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.
Although the effect of the type of side chain (X ) Y-ZH)
on the obtainment of different heterocycles has been
extensively investigated,3b few studies have regarded the
involvement of a nucleophilic carbon (Z ) C) at the side
chain. The only examples of this kind have involved a NCC
side chain in the base-induced rearrangement of N-(1,2,4-
oxadiazol-3-yl)-ꢀ-enaminoketones into imidazoles7,8 and
involved a NNC side chain recently reported for the thermal
rearrangement of N-(1,2,4-oxadiazol-3-yl)hydrazones into
1,2,4-triazoles.9 Therefore, in the context of our research on
heterocyclic rearrangements, we wanted to investigate the
(2) (a) L’abbe´, G. J. Heterocycl. Chem. 1984, 21, 627–638. (b)
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds;
Pergamon Press: Oxford, 1984; Vols. 1-8. (c) ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds; Elsevier:
Amsterdam, 1996; Vols. 1-9
.
(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)
1986, 136, 215–227. (e) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7,
4337–4348. (f) Van Arnum, S. D.; Niemczyk, H. J. J. Heterocycl. Chem.
2009, 46, 909–913
.
10.1021/ol1013087  2010 American Chemical Society
Published on Web 07/08/2010

occurrence of a BK rearrangement of tautomeric imines 3
and 4, which contain a CNC side chain linked to the C(3)
of a 1,2,4-oxadiazole ring, into imidazole derivatives 5
(Scheme 1).
Scheme 2. Preparation of Amine 7
Scheme 1. CNC Side-Chain Rearrangement of 1,2,4-Oxadiazole
In fact, the nonreductive transamination of ketones usually
occurs with base-catalyzed 1,3-proton shift of imines and
subsequent hydrolysis,12 although acidic13 or thermally
induced14 tautomerization of fluorinated imine-derivatives
have been recently proposed.
The amine 7 was then used for the synthesis of imines
4a-i through condensation with aromatic aldehydes 8a-i
(see Table 1).
Any attempt to obtain imines 3 directly from oxadiazole
610 through classic methods failed because of product
hydrolysis during the workup of the reaction mixture. On
the other hand, isolation of amine 7 in almost quantitative
yield was achieved by reaction of 6 with benzylamine in
toluene at 60 °C for 24 h and in the presence of Montmo-
rillonite K10 (Mont-K10) (Scheme 2). Formation of amine
7 is explained on the basis of a nonreductive transamination
of ketone 6 with benzylamine acting as nitrogen donor.
According to Montmorillonite-promoted imine formation,8,11
this pathway consists of an initial Mont-K10-catalyzed
condensation of benzylamine with ketone 6.
Table 1. Condensation of Amine 7 with Aldehydes 8a-i
Nevertheless, the acid catalyst will also promote tautomer-
ization of 3a into imine 4a and the final hydrolysis into amine
7 (Scheme 2). This reaction represents the first example of
a biomimetic nonreductive transamination involving the
employment of an acidic heterogeneous catalyst and exploit-
ing a one-pot methodology.
entry
product
4 yield (%)a
1
2
3
4
5
6
7
8
9
a: Ar ) Ph
97
89
95
91
82
85
88
80
83
b: Ar ) 4-MePh
c: Ar ) 4-MeOPh
d: Ar ) 4-NO2Ph
e: Ar ) 4-CF3Ph
f: Ar ) 4-FPh
g: Ar ) 4-ClPh
h: Ar ) 4-BrPh
i: Ar ) 4-Me2NPh
(4) For recent mechanistic studies on azole-to-azole interconversion
reactions of the Boulton-Katritzky type, see: (a) Cosimelli, B.; Frenna,
V.; Guernelli, S.; Lanza, C. Z.; Macaluso, G.; Petrillo, G.; Spinelli, D. J.
Org. Chem. 2002, 67, 8010–8018. (b) D’Anna, F.; Frenna, V.; Macaluso,
G.; Morganti, S.; Nitti, P.; Pace, V.; Spinelli, D.; Spisani, R. J. Org. Chem.
2004, 69, 8718–8722. (c) 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. (d) 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: (e) Pace, A.; Pibiri, I.; Palumbo Piccionello, A.; Buscemi, S.;
Vivona, N.; Barone, G. J. Org. Chem. 2007, 72, 7656–7666. (f) Pace, A.;
Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74,
351–358.
a Isolated yields.
The reactions were conducted at room temperature by
using acetic acid as solvent, and the final products were
obtained in pure form by crystallization of the reaction
residue (see Supporting Information). The latter approach
(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.
(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.
(12) (a) Cram, D. J.; Guthrie, R. D. J. Am. Chem. Soc. 1966, 88, 5760–
5765. (b) Guthrie, R. D.; Meister, W.; Cram, D. J. J. Am. Chem. Soc. 1967,
89, 5288–5290. For recent examples, see: (c) Cainelli, G.; Giacomini, D.;
Trere`, A.; Pilo Boyl, P. J. Org. Chem. 1996, 61, 5134–5139. (d) Soloshonok,
V. A.; Yasumoto, M J. Fluorine Chem. 2006, 127, 889–893.
(13) Berbasov, D. O.; Ojemaye, I. D.; Soloshonok, V. A. J. Fluorine
Chem. 2004, 125, 603–607.
(8) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N.; Pani,
M. Tetrahedron 2008, 64, 4004–4010.
(9) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N. Org.
Lett. 2009, 11, 4018–4020.
(10) Vivona, N.; Frenna, V.; Buscemi, S.; Ruccia, M. J. Heterocycl.
Chem. 1985, 22, 97–99.
(11) Braibante, M. E. F.; Braibante, H. S.; Missio, L.; Andricopulo, A.
(14) Yasumoto, M.; Ueki, H.; Soloshonok, V. A. J. Fluorine Chem.
2007, 128, 736–739.
Synthesis 1994, 898–900
.
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Org. Lett., Vol. 12, No. 15, 2010

represented a significant improvement in terms of workup
procedures by avoiding chromatographic purification and
consequent hydrolysis of the imino moiety and allowing high
yields of the final product to be isolated. The classic X )
Y-ZH sequence in the general BK rearrangement scheme
(see above) points out the key role of the potentially acidic
Z-H proton.
N(2) atom of the oxadiazole ring. Rearomatization of
intermediates 10 and final protonation produces target
imidazoles 5 (Scheme 3). In conclusion, we report the first
exampleofaCNCsidechaininvolvedintheBoulton-Katritzky
reaction, which enhances the breadth of this well-studied and
widely applied reaction. Starting substrates were obtained
Scheme 3
.
Proposed Mechanism for BK Rearrangement of
Table 2. Rearrangement of Imines 4 into Imidazoles 5
Compounds 4
entry
product
5 yield (%)a
1
2
3
4
5
6
7
8
9
a: Ar ) Ph
89
86
63
80
80
76
71
71
52
b: Ar ) 4-MePh
c: Ar ) 4-MeOPh
d: Ar ) 4-NO2Ph
e: Ar ) 4-CF3Ph
f: Ar ) 4-FPh
g: Ar ) 4-ClPh
h: Ar ) 4-BrPh
i: Ar ) 4-Me2NPh
through an unprecedented Mont-K10-catalyzed nonreductive
ketone transamination, whose general applicability is cur-
rently under investigation.
a Isolated yields.
Considering the biological activity of 4(5)-acylamino-
imidazoles16 and the renewed interest in the synthesis of 4(5)-
aminoimidazoles,17 the reported rearrangement represents a
valid approach toward target imidazoles. The precursor
accessibility, the easy workup, and the good product yields,
encourage further use of this synthetic methodology.
Deprotonation under basic conditions generates the X )
Y-Z- anionic side chain where Z- is the nucleophilic site
attacking the N(2). In substrates 4a-i, such deprotonated
side chain can be achieved considering the potential acidic
character of methine C-H directly linked to C(3) of the
oxadiazole ring. In fact, thermal rearrangement reactions of
4a-i under basic conditions (t-BuOK) in refluxing DMF
yielded imidazoles 5a-i in good to high yields (Table 2).
On the other hand, attempts to perform this rearrangement
in the absence of a base by refluxing compounds 4 in most
common organic solvents (toluene, benzene, DMF, aceto-
nitrile) or by heating under solvent-free conditions, led to
decomposition of starting material. Moreover, the use of
protic solvents (MeOH, EtOH) led to hydrolysis of the imines
4a-i into amine 7 and the corresponding aldehyde 8a-i.
These findings confirmed the requirement of a base for the
reaction to occur. From a mechanistic point of view, the
driving force of the reaction could be ascribed to the higher
aromatic stabilization of the imidazole ring with respect to
the 1,2,4-oxadiazole, according to Bird’s index.15 According
to the general scheme of the BK rearrangement, the involve-
ment of the base in the formation of imidazoles 5 is explained
through the initial formation of allyl anions 9, which
undergoes an internal nucleophilic substitution at the pivotal
Acknowledgment. Financial support through the Univer-
sity of Palermo is gratefully acknowledged.
Supporting Information Available: Synthetic details,
characterization data, and 1H and 13C NMR spectra of
compounds 4, 5, and 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1013087
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