On the reactivity of nitrosoimidazoles with acids (the Cusmano-Ruccia reaction): A continuous source of new ring-into-ring interconversion

Article abstract of DOI:10.1016/j.tetlet.2014.01.060

An extension of the 'Cusmano-Ruccia' reaction is reported. 6-(4-chlorophenyl)-3-methyl-5-nitrosoimidazo[2,1-b]oxazole by the action of hydrochloric acid gives 3-(4-chlorobenzoyl)-5-methyl-1,2,4-oxadiazole (13); presumably via ammonium ion, CO₂ and methanol elimination. The relevance of the nature of the atom of the B-ring linked to C-2 of the imidazole for the occurrence of the ring-into-ring interconversion has been once more confirmed.

Full text of DOI:10.1016/j.tetlet.2014.01.060

Tetrahedron Letters 55 (2014) 1488–1490
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
On the reactivity of nitrosoimidazoles with acids
(the Cusmano–Ruccia reaction): a continuous source of new
ring-into-ring interconversion
b
c
a
d
Barbara Cosimelli a, , Vincenzo Frenna , Mirella Rambaldi , Elda Severi , Domenico Spinelli
⇑
a Dipartimento di Farmacia, Università di Napoli ‘Federico II’, Via D. Montesano 49, 80131 Napoli, Italy
b Dipartimento Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università di Palermo, Viale delle Scienze, ed. 16, 90128 Palermo, Italy
c Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy
d Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, Via F. Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An extension of the ‘Cusmano–Ruccia’ reaction is reported. 6-(4-chlorophenyl)-3-methyl-5-nitrosoimi-
dazo[2,1-b]oxazole by the action of hydrochloric acid gives 3-(4-chlorobenzoyl)-5-methyl-1,2,4-oxadiaz-
ole (13); presumably via ammonium ion, CO2 and methanol elimination. The relevance of the nature of
the atom of the B-ring linked to C-2 of the imidazole for the occurrence of the ring-into-ring interconver-
sion has been once more confirmed.
Received 11 December 2013
Revised 9 January 2014
Accepted 14 January 2014
Available online 20 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Condensed nitrosoimidazoles
Ring-into-ring interconversion
Multi-step processes
3-Acyl-1,2,4-oxadiazoles
Studies on heterocyclic compounds cover more than half of the
organic chemistry papers. Special interest is devoted to aromatic
five- and six-membered ring derivatives containing nitrogen also
because they carry out fundamental functions in a variety of life
processes.1 Moreover several and several drugs or promising hits
contain their structures.2 For all of these reasons we have been
strongly involved in the study of ring-into-ring interconversion of
heterocycles from different points of view (synthetic,3,4 mechani-
cistic,3d,f,5 computational6 and pharmacological7).
In the last two decades our research groups have been involved
in attempts to extend the ‘old’ Cusmano–Ruccia reaction8 (the
conversion of some 4(or5)-aryl-5(or4)-nitrosoimidazoles 1 into
3-aroyl-1,2,4-oxadiazoles 2 by the action of acids; Scheme 1, route
a) to several nitrosoimidazoles condensed with different five-(3;
thiazole, Scheme 1, route b, formation of 4)7a,9 and six-membered
heterocycles (5, 7 and 9; pyridine, pyrimidine and pyridazine;
Scheme 1, routes c–e, formation of 6, 8 and 10)10 observing in every
instance an unlikely behaviour.
B-ring can stay unchanged, see route c, or can be only slightly mod-
ified, see route e), the stability of intermediates and/or final prod-
ucts. Indeed we have observed that the B-ring is strongly modified
and involved in the interconversion only when X is a heteroatom
(for example: X = S, route b; X = N, route d). Of peculiar interest
is the reaction of 6-aryl-5-nitrosoimidazo[2,1-b]thiazoles 3 with
acids: we obtained the 8-aryl-8-hydroxy-8H-[1,2,4]oxadiazol-
o[3,4-c][1,4]thiazinones 4. Compound 4, their acetals and some
other derivatives obtained by ring opening of the thiazine ring
show important pharmacological activities as LTCC (L-type calcium
channel) blockers7a–d,11 and as inhibitor of MDR1 (multidrug resis-
tance of type 1) activity.7e,f
Following the above research line (Scheme 1) we have now
enlarged our interest to the study of the reactivity with acid of
6-(4-chlorophenyl)-3-methyl-5-nitrosoimidazo[2,1-b]oxazole 12,
C12H8ClN3O2, mp 140–142 °C dec., green: it represents the first
example of this kind of nitroso compounds reported in the literature
and strictly resembles 3 (the oxazole ring replacing the thiazole one,
that is an oxygen atom substitutes a sulfur one in the condensed B
ring). Compound 12 was obtained by nitrosation from the relevant
6-(4-chlorophenyl)-3-methylimidazo[2,1-b]oxazole (11).12
By heating (2–3 h) an ethanolic solution of 12 with hydrochloric
acid (2 M) or by direct treatment of a solution of the non-isolated
12 in acetic acid/water with ethanol and hydrochloric acid we ob-
tained from the reaction mixture by chromatographic separation
on a silica gel column (eluant/petroleum ether/ethyl acetate from
Interestingly, several factors seem to affect the course of the
occurring reactions, among them are the aromaticity of the B-ring
condensed to imidazole, the nature of the C–X bond (see the gen-
eral formula of the condensed imidazoles BA: X is the atom of the
B-ring linked to C-2 of the imidazole ring; when X is a C-atom, the
⇑
Corresponding author. Tel.: +39 081 678614; fax: +39 081 678107.
E-mail address: barbara.cosimelli@unina.it (B. Cosimelli).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.060

B. Cosimelli et al. / Tetrahedron Letters 55 (2014) 1488–1490
1489
NO
Ar
COAr
+
H2O
HCl
+
N
HN
+ NH4Cl
Cusmano-Ruccia Reaction:
N
Ar
O
(EtOH)
route a
Ar
N
1
2
Cusmano-Ruccia type Reactions:
OH
OH
N
S
N
NO
Ar
9 YCHnX = N=CCl-CH=CH
3 YCHnX = CH=CH-S
Y
nB
X
Cl
N
Ar
N
N
(CH)
A
Ar
+
+ H3O+, - NH4
+ H3O+
(EtOH)
N
O
O
N
O
route e
route b
O
10
BA
4
7 YCHnX = CH=CH-CH=N
5 YCHnX = CH=CH-CH=CH
+ H3O+
+ H3O+
- NO+
+
- NH4
route d
route c
+NO+
O
Ar
N
N
Ar
N
N
H2N
O
8
6
Scheme 1. Routes a, b, d and e are multi-step processes.
4:1 to 1:1) a colourless compound (mp 109–110 °C) with moderate
yield (global yield of the process 11 ? 12 ? 13: 20%). HRMS gave
for it an experimental MW 222.01964 versus the calculated value
222.01961 for C10H7ClN2O2. An accurate analysis of 1H (two cou-
ples of aromatic protons, d = 8.16 and d = 7.71, and a singlet for
three aliphatic protons, d = 2.73, accordingly with the presence of
a 4-chlorophenyl ring and of a methyl group respectively), 13C
NMR (a signal coherent with a carbonyl group, d = 181.85 and
two signals indicating the presence of two sp2 carbons bound to
electronegative atoms d = 178.2 and d = 165.1, that is the two
C@N bonds of the oxadiazole ring) and the electron impact-mass
spectra has allowed to assign it the structure of the already known
3-(4-chlorobenzoyl)-5-methyl-1,2,4-oxadiazole (13).13
A comparison between the formulas of 12 and 13 indicates that
the reaction occurs, as expected (see Scheme 1, routes a, b, d and e)
with the loss of a nitrogen atom of the starting imidazole ring (as
ammonium ion),8–10 but unexpectedly with the loss of two further
carbon atoms, thus giving a derivative of 1,2,4-oxadiazole.
This behaviour in some way recalls the one observed while
studying the reactivity of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,
2-a]pyrimidine 7, which, by the action of hydrochloric acid, gives
5-amino-3(4-chlorobenzoyl)-1,2,4-oxadiazole. In this last instance
the presumably first-formed product derived from an ammonium
ion elimination collapses to an 1,2,4-oxadiazole derivative, which
in turn by the loss of a three-carbon fragment furnishes the final
product 8.10
To understand the course of the reaction now examined one
must take into account what it is already known about the reactiv-
ity of derivatives of nitrosoimidazoles. It is well known that com-
pounds 1, 3, 7 and 9 by the action of hydrochloric acid gave a
hydrolytic opening reaction of the imidazole ring with ammonium
ion elimination.
Taking into account this information and considering the ability
of linear polyfunctionalysed intermediates to give ring-closing
reactions (particularly easy to take place, because of thermody-
namic reasons, if five- or six-membered rings can be obtained)
we can hypothesise that the reaction occurs according to the ten-
tative pathway reported in Scheme 2: thus entering in the general
scheme of an ANRORC process.14
In the instance of 12 the above ring-opening would provide in
the first stage by losing an ammonium ion the oxazolone 14, which
in the experimental hydrolytic (acidic) conditions would furnish
the intermediate 15 by carbon dioxide elimination. Compound 15
in turn by a ring-closing reaction could give the 1,2,4-oxadiazoline
16: this non-aromatic intermediate by losing a molecule of metha-
nol and aromatisation finally could supply the 1,2,4-oxadiazole 13.
Interestingly, 13 and several other 3-aroyl-5-alkyl-1,2,4-oxadi-
azoles are intermediates (via a Boulton–Katritzky reaction)3a,b,g
for the syntheses of many 3-amino-4-aryl-1,2,5-oxadiazoles
known for their pharmacological properties as central suppres-
sants, anticonvulsants and muscle relaxants.15
Me
Me
CH3COOH
NO
N
N
Cl
Cl
Cl
NaNO2
O
N
O
N
11
12
+H3O+
+
-NH4
In summary, we can say that the Cusmano–Ruccia reaction
extended to variously condensed nitrosoimidazoles can be an
important source of new ring-into-ring interconversion was able
to furnish new compounds that can show interesting pharmaco-
logical activities or can be intermediates for active compounds.
Moreover the reaction now observed once more confirms that
only when in the C–X bond (see BA) X is a heteroatom, in the
present instance oxygen, the B-ring is strongly involved in the evo-
lution of the reaction.
Cl
NOH
O
NOH
Me
Me
O
+H2O
-CO2
N
N
H
O
OH
O
O
15
ring closing
14
O
Cl
Cl
HN
N
Acknowledgments
Me
HOH2C
N
N
-CH3OH
Me
O
O
This work has been supported by a grant from the University of
Bologna, Italy (RFO), and by a grant from the University of Palermo
(ex 60%).
13
16
Scheme 2. Proposed mechanism for the 11 ? 12 ? 13 process.

1490
B. Cosimelli et al. / Tetrahedron Letters 55 (2014) 1488–1490
Palumbo Piccionello, A.; Guarcello, A.; Pace, A.; Buscemi, S. Eur. J. Org. Chem.
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A solution of sodium nitrite (0.6 g; 8.7 mmol) in water (10 mL) was added,
under cooling and stirring, to
a
solution of 6-(4-chlorophenyl)-3-
methylimidazo[2,1-b]oxazole (11, 1 g; 4 mmol) in acetic acid (20 mL). After
10 min at room temperature the green precipitate was collected and
crystallized from ethanol (yield 35%). Mp 140–142 °C dec. 1H NMR
(400 MHz, DMSO-d6) d: 8.48 (AA0 part of AA0XX0 system, H-20 and H-60); 7.97
(1H, H-2); 7.68 (XX0 part of AA0XX0 system, H-30 and H-50); 2.44 (3H, CH3). 13C
NMR (100 MHz, DMSO-d6) d: 159.1; 156.7; 154.8; 137.9; 136.6; 131.4 (2C);
130.6; 129.2 (2C); 10.8. EI-MS (m/z,%): 261 (M+, 100); 226 (45); 165 (88); 137
(27); 111 (25); 102 (34); 75 (30); 50 (12). HMRS calcd for C12H8ClN3O2:
261.03050. Found: 261.03039.
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