Ring-ring interconversions of nitrosoimidazoles. The effect of some condensed six-membered rings on the reactivity

Article abstract of DOI:10.1016/S0040-4020(00)00600-1

The study of the effect of a condensed ring on the reactivity of nitrosoimidazoles with hydrochloric acid has been extended to some six-membered rings: thus, the reactivity of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (6), 6-chloro-2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-b]pyridazine (7), 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-a]pyrimidine (8a) and 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-a]pyrazine (9) has been examined. The striking differences observed in the reactivity of compounds 6-9 (denitrosation, ring-opening with ammonia elimination, ring-ring interconversion with the unexpected loss of a C₃ fragment and decomposition, respectively) have been discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00600-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6527±6532
Ring±Ring Interconversions of Nitrosoimidazoles. The Effect of
some Condensed Six-Membered Rings on the Reactivity
a
b
b
Roberta Billi,a Barbara Cosimelli,a, Domenico Spinelli, Aldo Andreani and Alberto Leoni
*
aDipartimento di Chimica Organica `A. Mangini', Via S. Donato 15, I-40127 Bologna, Italy
bDipartimento di Scienze Farmaceutiche, Via Belmeloro 6, I-40126 Bologna, Italy
Received 19 April 2000; revised 6 June 2000; accepted 22 June 2000
AbstractÐThe study of the effect of a condensed ring on the reactivity of nitrosoimidazoles with hydrochloric acid has been extended to
some six-membered rings: thus, the reactivity of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (6), 6-chloro-2-(4-chlorophenyl)-3-
nitrosoimidazo[1,2-b]pyridazine (7), 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-a]pyrimidine (8a) and 2-(4-chlorophenyl)-3-nitrosoimi-
dazo[1,2-a]pyrazine (9) has been examined. The striking differences observed in the reactivity of compounds 6±9 (denitrosation, ring-
opening with ammonia elimination, ring±ring interconversion with the unexpected loss of a C3 fragment and decomposition, respectively)
have been discussed. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
It is noteworthy that with both nitrosoimidazoles 1 and the
nitrosoimidazothiazole the rearrangement leads to
products (2 and 4, respectively) which contain the same
3
The action of hydrochloric acid at room temperature on
4(5)-nitroso-5(4)-phenylimidazoles 1 affords 3-benzoyl-
1,2,4-oxadiazoles 2 through a ring-opening/ring-closing
process which involves elimination of ammonia
(Scheme 1).1
number of carbon atoms as the starting materials.
In the framework of our interest in nitrogen compounds with
mutagenic activity,3,5 in ring±ring interconversions1a±c,6 and
the study of the factors that can affect the course of ring
transformations in derivatives of nitrosoimidazoles, we
herein report on the results obtained when changing the
ring condensed with the imidazole from the ®ve-membered
thiazole to some six-membered ones. Thus we have tested
the reactivity of compounds 6±9, and found signi®cant
differences between the selected systems, these being: in 6
the only heteroatom of the condensed ring is the common
nitrogen atom, whereas compounds 7±9 possess a second
nitrogen atom ortho, meta or para with respect to the
bridge-head nitrogen; furthermore, it should be remarked
that only 8 shows a situation similar to that of 3 as far as
it concerns the presence of a heteroatom (a nitrogen atom vs.
a sulphur atom in 3) linked to the C-2 of the imidazole ring.
For these reasons the systems 6±9 appear to be good probes
We have also shown2 that the course of this reaction can
be affected by the presence of a ring condensed with the
imidazole (at N-1 and C-2). Thus, by re¯uxing 6-(4-chloro-
phenyl)-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazole 3 (a
compound with mutagenic activity)3 in the presence of
hydrochloric acid, a novel ring transformation is observed,
with formation of 8-(4-chlorophenyl)-8-hydroxy-5-methyl-
8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-one 4: also in
this case the ring±ring interconversion is accompanied
only by ammonia elimination (Scheme 2). Because 4
inhibited the cell growth of some tumour-derived cell
lines (colon cancer, melanoma and breast cancer)4a and
showed some interesting cardiovascular properties4b we
have recently extended this ring±ring interconversion to
several nitrosoimidazothiazoles substituted both in the
6-aryl4a and in the thiazole moiety4c with the aim of
obtaining new suitable thiazinooxadiazolones for studies
of structure/activity relationships. Moreover, by carrying
out the reaction at room temperature we have been able to
isolate the reaction intermediate 5, so providing useful
information on the reaction mechanism.4a
Keywords: ring±ring interconversions; heterocyclic rearrangements;
condensed nitrosoimidazoles.
* Corresponding author. Tel.: 139-051243218; fax: 139-051244064;
e-mail: cosimel@ms.fci.unibo.it
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00600-1

6528
R. Billi et al. / Tetrahedron 56 (2000) 6527±6532
Scheme 2.
Figure 1.
Scheme 3.
for the study of the in¯uence of the structure of a condensed
ring on the reactivity of nitrosoimidazoles (Fig. 1).
required herein instead of the heteroatom (sulphur)±carbon
bond breaking undergone by 3 (Scheme 3).2,4a
The behaviour of 6 well ®ts in with known properties of
imidazo[1,2-a]pyridines such as those reported hereinafter.
First of all, X-ray structural investigations on the latter
compounds have pointed out10 the overall aromatic charac-
ter of the condensed system, as indicated by the coplanarity
of the two heterocyclic rings and by the carbon±carbon
Results
Reactivity of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
a]-pyridine (6) with hydrochloric acid
Ê
bond lengths, that never exceed 1.42 A (observed range:
Ê
1.35±1.42 A). Moreover the Dimroth rearrangement occurs
In experimental conditions similar to those used for the 3!4
rearrangement (i.e. 3 h re¯ux in ethanol with excess hydro-
chloric acid) 6 (coloured product) remained practically
unchanged (recovered: ca. 90%). By prolonged re¯ux
(7 days) 6 gave high yields (ca. 85%) of a colourless product
identi®ed as 2-(4-chlorophenyl)-imidazo[1,2-a]pyridine 10
on the basis of its 1H and 13C NMR, and MS spectra and by
comparison with an authentic sample:7 a behaviour which
well matches both the high reactivity of the imidazole ring
only when the imidazo[1,2-a]pyridine system is activated
by a nitro group at the 6- or 8-position,11 which deeply
increases the electrophilic character of the pyridine ring
enabling it to react with the strongly nucleophilic hydroxide
ion.
Reactivity of 6-chloro-2-(4-chlorophenyl)-3-nitroso-
imidazo[1,2-b]pyridazine (7) with hydrochloric acid
²
towards electrophiles and the essential characteristics of
nitrosation±denitrosation reactions. On the other hand,
³
By 3 h re¯ux in ethanol with excess hydrochloric acid,
compound 7 (green) gave a colourless product (yield:
54%), identi®ed as 1-[3-chloro-6-oxo-1(6H)-pyridazinyl]-
2-(4-chlorophenyl)-1,2-ethanedione 1-oxime 11 on the
the stability of the imidazopyridine ring system with respect
to ring±ring interconversions can be related both to the low
electrophilic character of the carbon atom (i.e. C-8a) which
should be attacked by the water nucleophile and to the fact
that a carbon±carbon bond breaking would be eventually
1
basis of its H and 13C NMR and mass spectra. The oxime
proved stable also after prolonged re¯ux (18 h) (Scheme 4).
²
E.g. the imidazole can easily be brominated (formation of 2,4,5-tribro-
moimidazole)8a or nitrated (formation of 4-nitroimidazole).8b
The reversibility of aromatic nitrosation, due to the low electrophilic
Reactivity of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
a]pyrimidine (8a) with hydrochloric acid
³
character of the nitrosonium ion, is clearly evidenced by sizeable kinetic
isotope effects (kH/kD 1.3±4.5) mirroring a slow deprotonation of the inter-
mediate s-complex.9
In experimental conditions similar to those used for the 3!4
rearrangement 8a (green, C12H7ClN4O) reacted giving a

R. Billi et al. / Tetrahedron 56 (2000) 6527±6532
6529
Scheme 4.
Scheme 5.
colourless product (yield: 40%), whose high-resolution
mass spectrum and elemental analysis are in agreement
with the molecular formula C9H6ClN3O2. The formation
of such a compound thus implies the expected elimination
of ammonia together with the unexpected loss of a three-
carbon fragment with respect to the starting material. On the
grounds of its spectral properties and by comparison with
literature data the product has been identi®ed as the known
mentioned 1-alkyl-1,2-dihydro-2-iminopyrimidines, which
is condensed with the nitrosoimidazole system; in principle,
it is thus possible to hypothesise that the three-carbons loss
precedes the opening of the nitrosoimidazole ring to 13.
Nonetheless, our experimental conditions (acidic solution)
appear completely different from those used by Perrin and
Pitman15 (strongly alkaline solution) to decompose the
above-mentioned ring-opened intermediates. Furthermore,
in an independent experiment we have ascertained that an
ethanolic solution of 2-(4-chlorophenyl)-imidazo[1,2-a]-
pyrimidine remains essentially unaltered when treated
with hydrochloric acid (8 h, 808C): this observation suggests
that, at least in acidic solution, opening of the imidazole
ring, triggered by the 3-nitrosogroup, is a prerequisite for
the three-carbon fragment loss.
5-amino-3-(4-chlorobenzoyl)-1,2,4-oxadiazole
(Scheme 5).
12a12±14
In order to understand the course of the 8a!12a conversion,
it is ®rst of all necessary to ascertain whether the loss of the
three-carbon fragment precedes or follows the nitroso-
imidazole ring-opening.
As a matter of fact it is well known that 1-alkyl-1,2-dihydro-
2-iminopyrimidines can undergo addition of water,
followed by a reversible ring ®ssion which eventually
leads to isomerisation products (Dimroth rearrangement).15
It has also been reported that ring-opened intermediates can
decompose giving malonodialdehyde (i.e. a three-carbon
fragment) and substituted guanidines.15 Actually, 8a
contains an atomic skeleton similar to that of the above-
Moreover by carrying out the reaction at room temperature
in dioxane we have been able to isolate an intermediate
which afforded 12a by further re¯ux in ethanol. The
structure of the intermediate obtained has been studied
spectroscopically: its mass spectrum shows Mz1 at 277
according with C12H8ClN3O3 and its 1H and 13C NMR
spectra ®t well with the structure of both (Z)-3-{[3-(4-
chlorobenzoyl)-1,2,4-oxadiazol-5-yl]amino}-2-propenal 15a
Scheme 6.

6530
R. Billi et al. / Tetrahedron 56 (2000) 6527±6532
and (Z)-3-[3-(4-chlorobenzoyl)-5-imino-1,2,4-oxadiazol-
4(5H)-yl]-2-propenal 16a.
ring opening occurs in 6, which only undergoes proto-
denitrosation (see Scheme 3).
The latter observation allows us to de®nitively conclude that
the loss of the three-carbon fragment follows the ring-
opening of the nitrosoimidazole and, on the other hand,
provides a signi®cant insight into the reaction mechanism.
Thus (Scheme 6), the ®rst step of the overall transformation
could well be a hydrolytic ring-opening of 8a to 13a
analogous to the 3 to 5 process, accompanied by ammonia
elimination: a hypothesis which is strongly supported by the
observed formation of 11 from 7. Conceivably, the reaction
scheme is completed by (a) ring-closure of 13a to the
non-aromatic 3-(4-chlorobenzoyl)-8a-hydroxy-8aH-1,2,4-
oxadiazolo[4,5-a]pyrimidine 14a, (b) acidic hydrolysis of
a carbon±nitrogen bond to the isolated 15a or 16a, and (c)
further hydrolysis with loss of a three-carbon fragment and
formation of the ®nal compound 12a. Unfortunately no
choice could be made between structures 15a and 16a,
Thus, in compounds 1, 3, 7 and 8 the nucleophilic attack of
water causes the hydrolytic opening of the imidazole ring
with elimination of ammonia. In the case of 3 and 8 the
intermediates 5 and 13 eventually furnish by further heating
4 and 12, respectively. In contrast, in the case of 7 the
product of hydrolytic opening of the imidazole ring (i.e.
11, structurally similar to 5) is the ®nal reaction product.
Why does the reaction stop at this stage? Probably because
the further evolution of the reaction would require, in 11, the
thermodynamically unfavourable carbon±carbon bond
breaking between the primitive C-2 and C-3 ring positions.
The results herein should thus be of valuable help in focuss-
ing the factors that affect the ring±ring interconversion
mechanism in condensed nitrosoimidazoles. One such
factor can undoubtedly be identi®ed in the presence of a
low-energy heteroatom±carbon bond in the heterocycle
originally condensed with the imidazole ring: as a matter
of fact the feeble ±CO±S± bond of 5, the intermediate from
ring-opening of 3, most likely represents the driving force
1
both of which are compatible with the experimental H
and 13C NMR spectra. With the aim to resolve the structure
we have also performed a particular 2D NMR sequence
(g-HNMQC)16 to evidentiate any H±N coupling, but no
correlation for the proton resonance at 12.27 ppm could
be detected which would allow a de®nitive assignment.
for an SN process triggered by the oxime oxygen and
ac
eventually leading to the ®nal product via opening of the
thiazole ring. Likewise, 13, structurally similar to 5, can
evolve (possibly via the formation of 14) by hydrolysis of
the N-1/C-6 or of the N3/C4 bond of the pyrimidine ring: the
ensuing 15 or 16, respectively, would then furnish the ®nal
product 12.
Interestingly the reaction with 2-phenyl-3-nitroso-
imidazo[1,2-a]pyrimidine 8b similarly led to 3-benzoyl-5-
amino-1,2,4-oxadiazole 12b (yield: 54%) fostering the hope
for a more general applicability of the process.
Reactivity of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
a]pyrazine (9) with hydrochloric acid
Experimental
1H and 13CNMR spectra were recorded on a Varian Gemini
300 Instrument in the Fourier transform mode at 21^0.58C
in DMSO-d6. Chemical shifts (d) in ppm from tetramethyl-
silane and coupling constants in Hz, respectively, are
reported. The g-HNMQC experiment16 was performed
using a Varian Unity PFG 400 instrument operating at a
In experimental conditions similar to those used for the 3!4
rearrangement, 9 gave only decomposition products; similar
results were obtained at room temperature both in ethanol
and in dioxane.
1
frequency of 399.94 MHz for H observation. Pulses for
1H and 15N were calibrated at 9.2 and 36 ms, respectively.
The long range delay in the sequence was optimised for
3.5 Hz. Mass spectra were recorded on a VG70 70E
apparatus. All melting points were obtained with an Electro-
thermal apparatus. All new compounds gave satisfactory
elementary analyses (C, H, N and halogens). Solvents
were removed under reduced pressure. Silica gel plates
(Merck F254) and silica gel 60 (Merck 230±400 mesh)
were used for analytical TLC and for column-chromato-
graphy, respectively. Compounds 8a and 8b were obtained
according to literature methods.18
Discussion
In the attempt to rationalise the striking differences in the
reactivity of compounds 1, 3, 6±9 outlined above we can
con®dently assume that the ®rst stage of the ring opening of
nitrosoarylimidazoles in the presence of acids (i.e. in con-
ditions where both arylimidazoles and condensed aryl-
imidazoles should by themselves be stable) is represented
by the protonation of the nitrosogroup.§ This enhances the
electrophilicity of the imidazole ring making it amenable to
the attack of even such a weak nucleophile as water to C-2:
the following ring opening easily occurs in the case of 1 (in
a few minutes at room temperature),1,17 while it requires
re¯uxing (3 h or more) in the case of 3,2,4a 7 and 8 indicating
that the presence of a condensed ring signi®cantly lowers
the reactivity (for steric reasons and/or by increasing the
stability of the heterocyclic systems). As expected, the
presence of an electronegative heteroatom (sulphur or
nitrogen) in the condensed ring (cf. compounds 3, 7±9)
does favour the nucleophilic attack insofar as no imidazole
2-(4-Chlorophenyl)-3-nitrosoimidazo[1,2-a]pyridine (6).
A solution of sodium nitrite (0.60 g, 8.7 mmol) in water
(10 ml) was added, under cooling and stirring, to a solution
of 2-(4-chlorophenyl)-imidazo[1,2-a]pyridine7 (0.91 g,
4 mmol) in acetic acid (20 ml). After 2 h at room tempera-
ture, the mixture was neutralised with NaOH 2 M and the
green precipitate was collected and crystallised from
ethanol (mp 227±2288C, 0.62 g, 60%); [Found: C, 60,5;
H, 3.2; N, 16.2. C13H8ClN3O requires C, 60.6; H, 3.1; N,
16.3%]. dH 9.82 (1H, ddd, J5,6ˆ6.6 Hz, J5,7ˆ1.2 Hz,
§
The same result would be obtained, of course, by ring protonation.

R. Billi et al. / Tetrahedron 56 (2000) 6527±6532
6531
J5,8ˆ1.2 Hz, H-5), 8.59 (2H, AA0 part of AA0XX0 system,
H-20 and 60), 8.08 (2H, m, H-7 and H-8), 7.70 (2H, XX0 part
of AA0XX0 system, H-30 and 50), 7.53 (1H, ddd,
J5,6ˆ6.6 Hz, J6,7ˆ6.4 Hz, J6,8ˆ2.2 Hz, H-6). dC 157.13
(C-2), 153.07 (C-3), 145.26 (C-8a), 137.71 (C-7), 136.65
(C-40), 131.72 (C-20/60), 130.24 (C-10), 129.05 (C-3050),
126.24 (C-5), 120.94 (C-6), 117.35 (C-8). MS m/z 257
(M1, 100%), 194 (60), 192 (68), 123 (17), 78 (61). HRMS
257.03588, C13H8ClN3O requires 257.03559 (Cl-35
isotope).
J6,7ˆ6.7 Hz, J6,8ˆ1.1 Hz, H6). dC 144.85 (C-8a), 143.10
(C-2), 132.82 (C-10), 132.09 (C-40), 128.74 (C-30/50),
127.22 (C-20/60), 126.97 (C-5), 125.22 (C-7), 116.65
(C-8), 112.45 (C-6), 109.49 (C-3). HRMS 228.04619,
C13H9ClN2 requires 228.04543 (Cl-35 isotope).
Reaction of 6-chloro-2-(4-chlorophenyl)-3-nitrosoimi-
dazo[1,2-b]pyridazine (7) with hydrochloric acid. Hydro-
chloric acid (2 M; 4 ml) was added to a stirred solution of
6-chloro-2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-b]pyrid-
azine 7 (1.17 g, 4 mmol) in 80 ml of ethanol and re¯uxed for
9 h. Removal of the solvent left a solid, which was washed
with water and identi®ed as 1-[3-chloro-6-oxo-1(6H)pyri-
dazinyl]-2-(4-chlorophenyl)-1,2-ethanedione 1-oxime 11
(0.66 g, 53%), that did not change by further re¯uxing
(18 h). Mp 168±1708C [Found: C, 46.4; H, 2.3; N, 13.3.
C12H7Cl2N3O3 requires C, 46.2; H, 2.3; N, 13.5%]. dH
13.81 (1H, s, exch., OH), 8.00 (2H, AA0 part of AA0XX0
system, H-20 and 60), 7.73 (1H, d, J4,5ˆ9.9 Hz, H-4), 7.66
(2H, XX0 part of AA0XX0 system, H-30 and 50), 7.25 (1H, d,
J4,5ˆ9.9 Hz, H-5). dC 183.74 (C-2), 156.92 (C-6), 143.93
(C-3), 138.74 (C-1), 138.52 (C-40), 135.70 (C-5/4), 133.70
(C-10), 132.53 (C-4/5), 131.85 (C-20 and C-60), 128.58 (C-30
and C-50). HRMS 310.98583, C12H7Cl2N3O3 requires
310.98645 (Cl-35 isotope).
6-Chloro-2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
b]pyridazine (7). A mixture of 3-amino-6-chloropyridazine
(1.04 g, 8 mmol) and 2-(4-chlorophenyl)-N-hydroxy-2-
oxoethanimidoyl chloride19 (0.87 g, 4 mmol) in ethanol
(100 ml) was stirred at room temperature for 30 min and
then left for 3 h. The green precipitate was collected and
crystallised from ethanol (mp 219±2208C, 0.64 g, 55%);
[Found: C, 49.3; H, 2.2; N, 19.2. C12H6Cl2N4O requires C,
49.2; H, 2.1; N, 19.1%]. dH 8.61 (1H, d, J7,8ˆ9.5 Hz, H-7),
8.52 (2H, AA0 part of AA0XX0 system, H-20 and 60), 8.05
(1H, d, J7,8ˆ9.5 Hz, H-8), 7.72 (2H, XX0 part of AA0XX0
system, H-30 and 50). MS m/z 292 (M1, 99%), 278 (37), 275
(47), 263 (17), 241 (35), 229 (100), 227 (50), 149 (21), 114
(84), 75 (25), 73 (74), 63 (19). HRMS 291.99228,
C12H6Cl2N4O requires 291.99187 (Cl-35 isotope).
Reaction of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
a]pyrimidine (8a) with hydrochloric acid. (A) 5-Amino-
3-(4-chlorobenzoyl)-1,2,4-oxadiazole 12a. Hydrochloric
acid (2 M; 4 ml) was added to a stirred solution of 2-(4-
chlorophenyl)-3-nitrosoimidazo[1,2-a]pyrimidine 8a (1.03 g,
4 mmol) in 60 ml of ethanol. The reaction mixture was
re¯uxed until complete disappearance of the green colour
(ca. 1.5 h). Removal of the solvent left a solid which gave
5-amino-3-(4-chlorobenzoyl)-1,2,4-oxadiazole 12a (0.36 g,
40%) after puri®cation by ¯ash-chromatography (ethyl
acetate/petroleum ether 40±608C, 1:1, v/v). Mp 234±
2358C (lit1d,12 236±2378C). dH 8.28 (2H, br s, exch.,
NH2), 8.15 (2H, AA0 part of AA0XX0 system, H20 and 60),
7.67 (2H, XX0 part of AA0XX0 system, H-30 and 50). dC
183.19 (CO), 172.45 (C-5), 165.77 (C-3), 139.68 (C-40),
133.91 (C-10), 132.11 (C-20 and C-60), 129.08 (C-30 and
C-50). MS m/z 223 (M1, 46%), 152 (16), 139 (100), 111
(57), 75 (35). IR (KBr) 1665 cm21. HRMS 223.01468,
C9H6ClN3O2 requires 223.01485 (Cl-35 isotope). The 13C
NMR and mass spectra well compare with the reported
ones13,14 (e.g. the medium and the largest 13C chemical
shift differences being 0.12 and 0.26 ppm, respectively).
2-(4-Chlorophenyl)-3-nitrosoimidazo[1,2-a]pyrazine (9).
A mixture of 2-aminopyrazine (0.76 g, 8 mmol) and 2-
(4-chlorophenyl)-N-hydroxy-2-oxoethanimidoyl chloride19
(0.87 g, 4 mmol) in ethanol (100 ml) was stirred at room
temperature for 30 min and then left for 3 h. The green
precipitate was collected and crystallised from ethanol
(mp 203±2048C, 0.41 g, 40%) [Found: C, 55.6; H, 2.6; N,
21.5. C12H7ClN4O requires C, 55.7; H, 2.7; N, 21.7%]. dH
9.62 (1 H, d, J8,6ˆ1.5 Hz, H-8), 9.48 (1H, dd, J6,5ˆ4.3 Hz,
J6,8ˆ1.5 Hz, H-6), 8.64 (2H, AA0 part of AA0XX0 system,
H-20 and 60), 8.59 (1H, d, J5,6ˆ4.3 Hz, H-5), 7.75 (2H, XX0
part of AA0XX0 system, H30 and 50). dC 156.48 (C-2),
153.14 (C-3), 144.01 (C-8), 139.49 (C-6) 137.01 (C-8a),
136.78 (C-40), 131.79 (C-20/60), 129.98 (C-10), 129.36
(C-30/50), 117.26 (C-5). MS m/z 258 (M1, 98%), 241 (15),
223 (18), 203 (18), 195 (100), 193 (41), 123 (19), 114 (18),
103 (20), 98 (26), 79 (34), 52 (27). HRMS 258.03066,
C12H7ClN4O requires 258.03084 (Cl-35 isotope).
Reaction of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
a]pyridine (6) with hydrochloric acid. Hydrochloric acid
(2 M; 4 ml) was added to a stirred solution of 2-(4-chloro-
phenyl)-3-nitrosoimidazo[1,2-a]pyridine 6 (1.03 g, 4 mmol)
in 60 ml of ethanol and re¯uxed for 3 h without valuable
transformation of 6. After re¯uxing until complete dis-
appearance of the green colour (ca. 7 days), the removal
of the solvent left a solid which after puri®cation by ¯ash-
chromatography (ethyl acetate/benzene, 1:5, v/v) was
identi®ed as 2-(4-chlorophenyl)-imidazo[1,2-a]pyridine 10
(0.78 g, 85%). Mp 208±2098C (lit.7 2088C). dH 8.53 (1H,
ddd, J5,6ˆ6.7 Hz, J5,7ˆ1.1 Hz, J5,8ˆ1.1 Hz, 5-H), 8.44 (1H,
d, J3,8ˆ1.1 Hz, H-3), 7.99 (2H, AA0 part of AA0XX0 system,
H-20 and 60), 7.58 (1H, dddd, J7,8ˆ9.1 Hz, J6,8ˆ1.1 Hz,
J5,8ˆ1.1 Hz, J3,8ˆ1.1 Hz, H-8), 7.50 (2H, XX0 part of
AA0XX0 system, H-30 and 50), 7.26 (1H, ddd, J7,8ˆ9.1 Hz,
J6,7ˆ6.7 Hz, J5,7ˆ1.1 Hz, H-7), 6.91 (1H, ddd, J5,6ˆ6.7 Hz,
(B) (Z)-3-{[3-(4-chlorobenzoyl)-1,2,4-oxadiazol-5-yl]amino}-
2-propenal 15a or (Z)-3-[3-(4-chlorobenzoyl)-5-imino-1,2,4-
oxadiazol-4(5H)-yl]-2-propenal 16a. Hydrochloric acid (2 M;
4 ml) was added to a stirred solution of 2-(4-chlorophenyl)-3-
nitrosoimidazo[1,2-a]pyrimidine 8a (1.03 g, 4 mmol) in
60 ml of dioxane; after 5 h at room temperature the removal
of the solvent left a solid containing unchanged 8a, the
intermediate 15a or 16a and the ®nal product 12a. The
mixture was separated by column-chromatography. In the
presence of hydrochloric acid by re¯uxing in ethanol (1 h)
the intermediate gave 12a. Spectral data for intermediate
15a or 16a: dH 12.27 (1H, br s, exch., NH), 9.49 (1H, d,
J1,2ˆ8.2 Hz, H-1), 8.18 (2H, AA0 part of AA0XX0 system,
H-20 and 60), 7.93 (1H, d, J2,3ˆ13.7 Hz, H-3), 7.70 (2H, XX0

6532
R. Billi et al. / Tetrahedron 56 (2000) 6527±6532
part of AA0XX0 system, H-30 and 50); 5.91 (1H, dd,
J2,3ˆ13.7 Hz, J1,2ˆ8.2 Hz, H-2). dC 191.93 (C-1), 181.90
(CO), 168.18 (C-500), 165.13 (C-300), 148.14 (C-3), 139.75
(C-40), 133.37 (C-10), 131.99 (C-20 and C-60), 128.95 (C-30
and C-50), 113.73 (C-2). MS m/z 277 (M1, 1%), 223 (18),
207 (9), 139 (100), 111 (55), 75 (33).
Forti, G. Arch. Pharm. Chem., Sci. Ed. 1987, 15, 41±49 (and
references cited therein).
4. (a) Billi, R.; Cosimelli, B.; Spinelli, D.; Rambaldi, M.
Tetrahedron 1999, 55, 5433±5440. (b) Cosimelli, B.; Budriesi, B.;
Chiarini, A.; Rossi, M.; Spinelli, D. In preparation. (c) Billi, R.;
Cosimelli, B.; Leoni, A.; Spinelli, D. J. Heterocycl. Chem. in press.
5. Hrelia, P.; Vigagni, F.; Maffei, F.; Fimognari, C.; Lamartina, L.;
Spinelli, D.; Juric, P.; Guerra, M. C.; Cantelli Forti, G.
Mutagenesis 1995, 10, 171±177; Hrelia, P.; Vigagni, F.; Morotti,
M.; Cantelli Forti, G.; Barbieri, C. L.; Spinelli, D.; Lamartina, L.
Chem.-Biol. Interact. 1993, 86, 229±254; Hrelia, P; Fimognari, C.;
Reaction of 2-phenyl-3-nitrosoimidazo[1,2-a]pyrimidine
(8b) with hydrochloric acid!5-amino-3-benzoyl-1,2,4-
oxadiazole 12b. Operating as reported under A, 8b
(0.90 g, 4 mmol) gave 12b (0.41 g, 54%) after puri®cation
by ¯ash-chromatography (ethyl acetate/petroleum ether
40±608C, 1:1, v/v). Mp 193±1948C (lit1d 1938C).
Á
Maffei, F.; Spinelli, D.; Lamartina, L.; Sarva, M. C.; Cantelli Forti,
G. Chem.-Biol. Interact. 1999, 118, 99±111.
6. (a) Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocycl. Chem.
1981, 29, 141±169. (b) Frenna, V.; Macaluso, G.; Consiglio, G.;
Cosimelli, B.; Spinelli, D. Tetrahedron 1999, 55, 12885±12896
and references therein. See also, Vivona, N.; Buscemi, S.; Frenna,
V.; Cusmano, G. Adv. Heterocycl. Chem. 1993, 56, 49±154.
Reaction of 2-(4-chlorophenyl)-3-nitrosoimidazo[1,2-
a]pyrazine (9) with hydrochloric acid. Hydrochloric
acid (2 M; 4 ml) was added to a stirred solution of 2-(4-
chlorophenyl)-3-nitrosoimidazo[1,2-a]pyrazine 9 (1.03 g,
4 mmol) in 60 ml of ethanol and re¯uxed for 3 h. Removal
of the solvent left an untreatable tar. Similar results were
obtained also by working either at room temperature or in
dioxane.
7. Buu-Hoi, Ng. Ph.; Hoan, Ng. Recl. Trav. Chim. Pays-Bas 1949,
È
68, 441±472.
8. (a) Balaban, I. E.; Pyman, F. L. J. Chem. Soc. 1922, 121, 947±
958. (b) Fargher, R. G.; Pyman, F. L. J. Chem. Soc. 1919, 115,
217±260.
9. Challis, B. C.; Higgins, J.; Lawson, A. J. J. Chem. Soc., Chem.
Commun. 1970, 1223±1224; Dix, L. R.; Moodie, R. B. J. Chem.
Soc., Perkin Trans. 2 1986, 1097±1101.
Acknowledgements
We thank CNR and MURST for the ®nancial support.
Investigation supported by University of Bologna (funds
for selected research topics). We thank the NMR Laboratory
of Spectroscopy, Glaxo Wellcome Medicines Research
Center (Verona, Italy) for the g-HNMQC spectrum.
10. Tafeenko, V. A.; Paseshnichenko, K. A.; Schenk, H. Z.
Kristallogr. 1996, 211, 457±463.
11. (a) Guerret, P.; Jacquier, R.; Maury, G. J. Heterocycl. Chem.
1971, 8, 643±650. (b) Jacquier, R.; Lopez, H.; Maury, G.
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