Structures and reactivities of 1-oxo-cycloalkan-2-ylideneacetic acids. A 1H NMR, modelling and photochemical study

Article abstract of DOI:10.1016/S0040-4020(00)00662-1

Four 1-oxo-cycloalkan-2-ylideneacetic acids, differing in the size of the aliphatic ring and in the nature of the condensed unsaturated cycle, exhibit different reactivities towards hydrazine, leading in only one case to the desired tryciclic pyridazinone. The observed differences in behaviour cannot be ascribed to different configurations at the exocyclic double bond of the four acids: ¹H NMR experiments, combined with UV photolysis, have shown that all compounds have been prepared in the E form and are stable in the absence of light and catalysts. The photochemically obtained Z isomers show an increasing tendency to form tricyclic lactones with increasing size of the aliphatic ring. A theoretical structural analysis of the E and Z isomers, the tricyclic lactones and some of the hypothetical intermediates of the reaction with hydrazine suggests the size of the aliphatic ring and the associated flexibility to be crucial in modulating the ability of these compounds to form tricyclic products. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00662-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7561–7571
Structures and Reactivities of 1-Oxo-cycloalkan-2-ylideneacetic
Acids. A 1H NMR, Modelling and Photochemical Study
c
d
a
Stefano Ghelli,a M. Paola Costi,b, Lucio Toma, Daniela Barlocco and Glauco Ponterini
*
aDipartimento di Chimica, via Campi 183, 41100 Modena, Italy
bDipartimento di Scienze Farmaceutiche, via Campi 183, 41100 Modena, Italy
cDipartimento di Chimica Organica, via Taramelli 10, 27100 Pavia, Italy
dIstituto di Chimica Farmaceutica e Tossicologica, v.le Abruzzi 42, 20131 Milano, Italy
Received 25 February 2000; revised 7 July 2000; accepted 20 July 2000
Abstract—Four 1-oxo-cycloalkan-2-ylideneacetic acids, differing in the size of the aliphatic ring and in the nature of the condensed
unsaturated cycle, exhibit different reactivities towards hydrazine, leading in only one case to the desired tryciclic pyridazinone. The
1
observed differences in behaviour cannot be ascribed to different configurations at the exocyclic double bond of the four acids: H NMR
experiments, combined with UV photolysis, have shown that all compounds have been prepared in the E form and are stable in the absence of
light and catalysts. The photochemically obtained Z isomers show an increasing tendency to form tricyclic lactones with increasing size of
the aliphatic ring. A theoretical structural analysis of the E and Z isomers, the tricyclic lactones and some of the hypothetical intermediates of
the reaction with hydrazine suggests the size of the aliphatic ring and the associated flexibility to be crucial in modulating the ability of these
compounds to form tricyclic products. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
literature,1 the tricyclic pyridazinones of general structure
1 (see Scheme 1) have been widely employed in different
fields of medicinal chemistry. In particular, cardiovascular,
Since the appearance of the first benzocinnolinone in the
Scheme 1.
Keywords: tryciclic pyridazinone; arylidenecarboxyilic acids; UV photolysis; conformational studies.
* Corresponding author. Fax: ϩ39-59-378560; e-mail: costimp@unimo.it
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00662-1

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S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
antisecretory, antiulcer, analgesic and antiinflammatory
effects have been associated with these compounds.2
Although more than one approach has been proposed for
their synthesis,3–6 the most common method is depicted in
Scheme 1. Accordingly, the bicyclic ketone 2 is condensed
with glyoxylic acid to give the unsaturated acid 3, which is
easily reduced to the corresponding 4, which is then cyclised
with hydrazine hydrate to the dihydroderivate 5, and finally
oxidised to 1. However, while unsubstituted 5, as well as its
analogues carrying electron attracting groups on the phenyl
moiety, could easily be dehydrogenated by bromine in
acetic acid, analogues of compound 5 having electron
donating groups on the phenyl ring underwent parallel
bromination, leading to poor yields and complex reaction
mixtures.7 To overcome this side reaction, different oxidis-
ing systems were employed, e.g. sodium m-nitro-benzen-
sulfonate in alkaline medium.8,9 However, while this agent
gave the desired 1b and c from the corresponding 5b and c
in almost quantitative yields, in the case of 5a no evidence
of 1a was detected in the reaction mixture.10 Therefore,
direct condensation of unsaturated 3 with hydrazine to
give the corresponding 1 would be desirable. We therefore
decided to explore the possibility of cyclising the indanyl-
ideneacetic acid 3a, its higher homologues 3b and c and the
thiophene analogue 3d with hydrazine hydrate. Indeed,
compound 1a was obtained by this route. On the other
hand, reaction of compounds 3b–d with hydrazine hydrate
proved inefficient in giving compounds 1b–d (Scheme 2).
configuration at the double bond, from geometrical
constraints dictated by the different sizes of the aliphatic
rings, or from electronic reasons. As an example of the
latter, Lutz and co-workers found that while cis-b-aroyl-
b-methylacrylic acids, which are structurally related to
compounds 3, easily cyclised to the corresponding lactones,
the b-hydrogenated acids showed no tendency to cyclise
under the same conditions.11–12 To determine which of the
possible causes was truly responsible for the different
chemical behaviours of compounds 3, we first carried out
a structural investigation aimed at determining the con-
figuration of the exocyclic double bond. This includes 1D
and 2D 1H NMR extensive study, corroborated by
modelling of the isolated molecules performed by the
PM3 semiempirical approach. Subsequent photochemical
experiments, monitored by UV–visible and 1H NMR
spectra, have provided conclusive evidence about the struc-
tures of the starting isomers and have revealed different
tendencies of compounds 3 to form cyclic products, also
confirmed by PM3 modelling. An attempt at rationalising
the observed reactivities of compounds 3a and b towards
hydrazine was finally made on the basis of calculated
relative stabilities of the intermediates of two competitive
reaction paths.
Results and Discussion
NMR structural investigation
These somewhat unexpected findings prompted us to
investigate the reasons for different reactivities in the series
3a–d. This could, in principle, result from a different
Non-photolysed solutions. The 1H NMR spectra of freshly
prepared non-irradiated solutions of compounds 3 in
Scheme 2.

S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
7563
Figure 1. 1H NMR spectra of compounds 3a–d. trace (a) isomer E-3a; trace (b) mixture of E-3a (peaks not labelled) and Z-3a (peaks labelled with ء) in molar
ratio 100:35; trace (c) isomer E-3b; trace (d) mixture of isomers E-3b (no label), Z-3b (peaks labelled with ء) and 6b (peaks labelled with #) in molar ratio of
30:100:10; trace (e) isomer E-3c; trace (f) mixture of isomers E-3c (peaks no labelled) and 6c (peaks labelled with #) in molar ratio of 100:100; trace (g) isomer
E-3d; trace (h) mixture of isomers E-3d (peaks no labelled), Z-3d (peaks labelled with ء) and 6c (peaks labelled with #) in molar ratio of 40:20:100.

7564
S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
˚
˚
DMSO-d6 (Fig. 1, traces a, c, e and g) show that only one
species is present in each solution and the multiplicity of the
aliphatic hydrogen signals points to the magnetic equiva-
lence of the methylenic protons bound to the same carbon
atom, that is H23, H24 and H25 (see Table 1, data sets E-3a–
d). Moreover, NOEs between protons H10 and H3 appear in
the spectra of compounds 3a and b, but not in those of
compounds 3c and d. While this indicates a preferential E
configuration at the double bond in the latter two
compounds, doubts still exist as to the configuration at the
same double bond in compounds 3a and b: in fact, the
calculated distances between H10 and the two H3 atoms,
in both E and Z isomers of these molecules, are short enough
as to give rise to a non-negligible dipole–dipole interaction,
and thus to a detectable NOE (values between 3.71 and
4.07 A, for the E isomers, and between 2.30 and 3.39 A,
for the Z isomers, were calculated). To resolve this
uncertainty, photoisomerisation of compounds 3 around
the C2–C10 double bond was attempted by UV photolysis,
following the early reports of this kind of photoreactivity of
structurally related b-aroylacrylic acids.11–13
1
Photolysed solutions. Following UV irradiation, the H
NMR spectrum of compound 3a showed a new set of signals
(Fig. 1 - trace b, peaks labelled with ) in addition to that
previously described (Fig. 1, trace a) in a molar ratio of
30:100. The two sets exhibited the same pattern of spin
multiplicity and very small differences in the chemical
shifts. Both showed NOE between protons H10 and H3;
however, this was much stronger for the new phototropic
ء
Table 1. 1H NMR chemical shift (d, ppm), spin multiplicities, coupling constants (J, Hz) and main correlations of signal of compounds 3 and 6 (sˆsinglet,
bsˆbroad singlet; dˆdoublet, tˆtriplet, qˆquintet, overˆoverlapped)
Peak
E-3a
Z-3a
Peak
E-3b
Z-3b
6b
d
J
d
J
d
J
d
J
d
J
H10
H23
6.65 t
4.17 d
2.2
2.2
6.71 t
3.92 bs
1.8
–
H10
H2-3
H2-4
H5
H6
H7
6.77 t
3.41 td
3.10 t
7.53 m
7.72 td
7.51 td
8.05 dd
1.7
6.6, 1.7
6.6
6.43 t
2.99 td
3.15 t
7.53 m
7.70 td
7.59 td
8.01 dd
13.00bs
1.5
6.6; 1.5
6.6
6.10 d
3.05 m
3.30 m
7.32 dd
7.45 m
7.45 m
7.62 dd
–
1.5
Over
Over
7.4; 1.2
Over
Over
7.4;1.7
H4
H5
H6
H7
7.77 d
7.85 t
7.58 t
7.89 d
7.8
7.8
7.8
7.8
–
7.72 d
7.830 t
7.58 t
7.87 d
13.16bs
7.8
7.8
7.8
7.8
Over
Over
7.9, 1.2
7.9, 1.2
7.9; 1.2
–
6.1; 1.2
7.9; 1.2
7.9; 1.2
–
H8
COOH 13.10bs
COOH 13.00bs
OH
7.845 s
–
Correlations: (E-3a) NOESY: H10 –H23; H23–H4; H4–H5; H5–H6; H6–H7; (Z-3a) NOESY: H10 –H23; H23–H4; (E-3b) NOESY: H10 –H23; H23–H24; H24–
H5; H5–H6; H6–H7; H7–H8; (Z-3b) NOESY: H10 –H23; H23–H24; H2–H5; H5–H6; H6–H7; H7–H8
Peak
E-3c
6c
Peak
E-3d
Z-3d
6d
d
J
d
J
d
J
d
J
d
J
H10
H23
6.66 s
2.78 t
6.03 d
(a) 3.08 dt
(e) 2.86
2.0
14.3; 3.2
Over
6.40 s
2.88 t
6.03 t
2.60
Over
Over
6.06 d
1.6
6.5
6.8
(a) 3.08 m Over
(e) 2.84tm Over
(a) 1.75 qt
(e) 2.20 m
(a) 3.0 ddd
H24
H25
2.09 q
2.87 t
(a) 1.49 qd 13.1;3.3
2.12 q
3.10 t
6.8
6.8
2.02 q
3.08
(e) 2.21 m
(a) 3.34 t
(e) 2.86
7.29 dd
7.67 t
Over
13.3
Over
Over
7.2; 1.5
Over
Over
Over
(e) 3.08 m Over
H6
H7
H8
H9
7.42 dd
7.67 td
7.51 td
7.78 dd
7.6; 0.7
7.6; 1.3
7.6; 1.2
7.6; 1.3
7.49 d
7.43 d
5.3
5.3
7.46 d
7.41 d
4.9
4.9
7.31 d
7.17 d
5.3
5.3
7.35 m
7.35 m
COOH 12.12 bs
OH
12.95 s
12.80 bs
8.26 s
8.12 s
Correlations: (E-3c) COSY: H9–H8; H8–H7; H7–H6; H25–H24; H24–H23; H23–H10 — NOESY: H9–H8; H8–H7; H7–H6; H6–H25; H25–H24; H24–H23;
6c) COSY: H9–H8; H8–H7; H7–H6; H5a–H5e; H5a/e–H4a/e; H4a–H4e; H4a/e–H3a/e; H3a–H3e; H6–H5e; H3a–H10; NOESY: H6–H5a; H5a–H5e;
H5a–H4e; H5e–H4e; H4a–H4e; H4a/e–H3e; H4e–H3a; H3a–H3e; H3e–H10; (E-3d) NOESY: H25–H24; H25–H23; H24–H23; (Z-3d) NOESY: H25–H24;
H25–H23; H24–H23; 6d) NOESY: same as compound 6c

S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
7565
Figure 2. NOESY spectrum of the mixture of E-3a (peaks no labelled) and Z-3a (peaks labelled with ء) in molar ratio 100:35, in the region of H10 –H3 NOEs.
Figure 3. 3D plots and heats of formation (kJ molϪ1) of the minimum-energy conformations of the E and Z isomers of compounds 3 and of the cyclic
compounds 6 obtained by PM3 calculations.

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S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
the same carbon. This feature is accounted for by the hemi-
acetalic structure 6b (see Fig. 3 and Table 1), as it contains a
new chiral centre (C1) which makes the methylenic hydro-
gen bound to the same carbon atoms diastereotopic. Also, a
new singlet, appearing at 7.84 ppm, can be assigned to the
hydroxylic hydrogen atom. NOE was not detected with 6b
because the concentration of this species is too low.
For the sake of completeness, compounds 3c and 3d were
also studied after UV irradiation. The 1H NMR spectrum of
compound 3c showed a new set of signals (labelled with # in
trace f of Fig. 1) in addition to the one previously described
and assigned to the E isomer. The relative intensities of the
two sets of signals were 90:100. In the new set, the signals of
protons H23 and H24 appeared as complex multiplets,
suggesting a loss of magnetic equivalence of these hydro-
gens, and a singlet appeared at 8.26 ppm. Similarly to the
case of 6b, these features can be assigned to the hemi-
acetalic product 6c. Moreover, the NOEs, the coupling
pattern and the values of the coupling constants (Table 1)
all support this assignment (Fig. 4).
Figure 4. Minimum-energy conformations of the cyclic compounds 6c,
obtained by PM3 calculations, with NOEs observed in NOESY spectrum.
species than for the initial one, even though the latter was
present in higher concentration (Fig. 2). This suggests a
decreased distance between the two hydrogen atoms in the
photoproduct and the identification of the starting and
photochemically produced species as, respectively, the E
and Z isomers (E-3a and Z-3a in Table 1 and in Fig. 3).
The 1H NMR spectrum of compound 3b shows, after
irradiation, three sets of signals having relative intensities
30:100:10 (shown with no label, asterisk and # in trace d of
Fig. 1, respectively). The first two have patterns and NOEs
(not shown) similar to those found for compound 3a and can
thus be assigned to the E and Z isomers (E-3b and Z-3b in
Fig. 3), the latter being a photoproduct. The third set of
signals differs from the other two in that the H23 and H24
signals appear as complex multiplets, suggesting loss of
magnetic equivalence of the methylenic protons bound to
Finally, the 1H NMR spectrum of the photolysed solution of
compound 3d shows three sets of signals with relative inten-
sities 40:20:100 with (respectively no label, asterisk and # in
trace h of Fig. 1). An analysis similar to that described for
compounds 3b and c leads to their assignment, respectively,
as the E and Z isomers (E-3d and Z-3d), and the hemi-
acetalic structure 6d, the latter two being the photoproducts.
It is relevant to the mechanism of formation of the hemi-
acetalic forms to observe that, whenever checked during
photolysis the ratio of Z to 6 forms were independent of
time and of the irradiation dose. This suggests that, in all
cases, the two forms equilibrate with each other in times of
the order of few minutes or shorter.
Evolution of the UV–visible absorption spectra upon
photolysis
Indications in full agreement with the previously described
conclusions about the structures of the starting species and
the photoproducts come from the analysis of the changes in
the UV–visible absorption spectra of compounds 3 brought
about by UV photolysis (experimental details are provided
in the corresponding section). Irradiation of 3a in aceto-
nitrile (the reason for the choice of this solvent is given in
the Experimental section) caused the spectral changes
shown in Fig. 5a. The absorption band evolved to a nearly
photostationary spectrum quite similar to the starting one;
both maxima were at ca. 262 nm, but the shoulder at about
275 nm increased upon photolysis so that the band centre
moved slightly to the red. An isosbetic point at 266 nm was
fairly well preserved throughout irradiation, suggesting that
the main process taking place was a photoreversible trans-
formation involving one reagent and either one product or a
mixture of rapidly equilibrating products. The same held for
compound 3b, whose spectrum in acetonitrile evolved, upon
photolysis, to an almost photostationary spectrum keeping
two fairly good isosbestic points at 231 and 288 nm
(Fig. 5b). The maximum of the photostationary spectrum
was essentially unshifted relative to that of the starting
one. The only relevant difference between the UV spectral
behaviour of compounds 3a and b is that irradiation of the
Figure 5. Changes in the UV–visible absorption spectra of compounds
3a–d in acetonitrile caused by photolysis with the 313 and 365 nm
mercury-lamp lines. The directions of spectral evolution with irradiation
time are indicated by arrows. The sample concentrations (mol lϪ1), maxi-
mum absorbances in 2 mm cuvettes and total irradiation times (minutes)
were as follows: (a) 4.5×10Ϫ4, 1.45, 64; (b) 5.7×10Ϫ4, 1.50, 70; (c)
8.5×10Ϫ4, 1.65, 175; (d) 6.1×10Ϫ4, 1.50, 132.

S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
7567
latter resulted in a pronounced hypochromism, whereas for
the former, a very small increase in the absorption band area
(if anything) was caused by photolysis. Both observed
spectral evolutions are consistent with the H NMR-based
identification of the photoproducts of 3a and b as, respec-
tively, Z-3a and a mixture of rapidly equilibrating Z-3b and
6b.
mum, initially at 235 nm, lowered and moved to 232 nm.
Two isosbestic points, at 208 and 223 nm, were preserved
throughout irradiation. The final spectrum is reminiscent of
the spectra of substituted thiophenes: e.g. 2,3-dimethyl
thiophene in isooctane has a maximum at 233 nm.16 The
observed bleaching of the intense E-species band with maxi-
mum at 248 nm for 3c and 235 nm for 3d, assumed to be a
‘conjugation’ band, i.e. to arise from an electronic excitation
delocalised over a large molecular fragment, is consistent
with the change in the hybridisation of the C1 atom from sp2
to sp3, associated with the reduction of the main chromo-
phore to an ortho-disubstituted benzene or thiophene. This,
in turn, agrees with the conclusion reached from the NMR
experiments that the main photoproducts for 3c and d are
the hemiacetalic 6c and d species. A pronounced hypo-
chromism, similar to the one associated with the formation
of the cyclic 6c and d forms, was observed in the photo-
chemical formation of the cyclic lactone of cis-b-benzoyl-
b-methylacrylic acid from the trans form of the acid,
closely related with compounds E-3a–c.12
1
The UV spectral evolutions of compounds 3c and d upon
irradiation were qualitatively different from those of the first
two molecules, but they were similar to each other. In fact,
rather than approaching a photostationary state, these two
molecules exhibited a progressive bleaching of the main
absorption bands. This was particularly evident for 3c
(Fig. 5c) whose band, having a maximum at 248 nm,
eventually disappeared leaving a shoulder around 230 nm
and two additional features: (i) a structured absorption with
peaks at about 265 and 272 nm and a shoulder around
258 nm, typical of alkyl substituted benzene (e.g. o-xylene
in heptane features two peaks at 263 and 271 nm and a
shoulder at 257 nm;14 o-methylbenzyl alcohol in isooctane
shows peaks at 264 and 273 nm15); (ii) a wavy shoulder
between 280 and 330 nm assignable to an impurity since
it was left unchanged by photolysis and it was not observed
in the spectrum of compound 3d (a fluorescence analysis
confirmed this assignment). Similarly, photolysis of
compound 3d caused a dramatic decrease in the intensity
of the initial band (Fig. 5d). The shoulders around 260
and 300 nm disappeared almost completely, while the maxi-
To sum up, compounds 3, all in the E configuration, under-
went efficient photoreactions yielding different products:
while the Z-3a isomer was obtained with the compound
featuring the five-membered aliphatic ring, the hemiacetalic
tricyclic forms 6c and d were the dominant photoproducts
with the seven-membered aliphatic-ring compounds.
Compound 3b is intermediate, though closer to 3a, in as
much as its main photoproduct was Z-3b, but a small
Scheme 3.

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S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
amount of the cyclic 6b was also obtained. It is therefore
likely that light-induced twisting about the C2–C10 double
bond is operative in all cases but, while the Z isomer of 3a is
very stable, those of 3c and d undergo very fast, unobserv-
able cyclisation to the identified stable products 6c and d. A
sounder mechanistic analysis of these photoreactions is
outside the scope of the present article, and is left for future
work. The photoreactivity of 3a–d is summarised in
Scheme 3.
the tricyclic form on going from 3a to 3b to 3c and d is
qualitatively reflected by the relative order of stability of
these forms, in comparison with the Z forms, indicated by
the calculated heats of formation.
Reactivities towards hydrazine hydrate
Compounds 3c and d, when reacted with hydrazine in
water–acetic acid, yielded a complex mixture of several
products each present in small amount, 3a and 3b, however,
followed clear though distinct reaction pathways: 3a
cyclised to 1a while 3b gave a different tryciclic derivative
7b (Scheme 4). It is reasonable to think that both derive
from the same hydrazone intermediate I which can cyclise
with its NH2 group either on the carboxyl group to give II,
precursor of 1a, or on the double bond to give the 2-pyrazo-
line III which, on acetylation of NH gives 7b. An
intermediate similar to III has been proposed in the
Wolff–Kishner reduction of 2-arylmethylene-1-tetra-
lone.17,18 To investigate the reasons for the preference of
different reaction paths, we performed quantum mechanical
calculations (PM3) on I, II and III. Their heats of formation
are reported in Scheme 4. Intermediate IIa has a lower heat
of formation than IIIa, whereas the opposite occurs with
intermediates IIb and IIIb. As already indicated by the
calculated heat of formation of the hemiacetalic form 6a
(Fig. 3), formation of a tricyclic species with two penta-
tomic rings, such as IIIa, is strongly unfavoured due to
severe strain. So, simple thermodynamic considerations
might account for the different reaction paths followed by
the two compounds. On the other hand, we cannot rule out
the possibility that equilibration between reactants I and
products II and III be not achieved. Should this be the
case, kinetic control would be effective.
Theoretical analysis of the structures
To explore the relative stabilities of the E, Z and hemi-
acetalic forms of compounds 3, the preferred conformations
and the heats of formation of these compounds were
theoretically determined using a full geometry optimisation
(see the Experimental section for the computational details).
Fig. 3 shows the three-dimensional structural plots of the
minimum-energy conformations of each compound
together with the corresponding heats of formation. Quite
interestingly, while compounds E-3a and b are planar or
quasi-planar, the two compounds with the seven-membered
aliphatic ring are strongly distorted in both E and Z con-
figurations, with the ‘acrylic-acid’ moiety almost normal to
the phenyl or thiophene plane. This qualitative structural
difference is reflected in the absorption spectra of the
E-3a–c species: the spectra of the first two compounds are
bathochromically shifted with respect to the spectrum of the
third one (see the initial spectra in Fig. 5), in keeping with
them having more extended, approximately coplanar
chromophores. The E orientation is the preferred one for
3a, whereas 3b–d exhibit almost the same heats of forma-
tion for the two geometrical isomers. The latter is in contrast
with the results of the NMR measurements, which indicate
the E isomer as the only one present in fresh solutions of all
compounds. The contradiction, however, is only apparent
because, due to the very high potential-energy barrier for
twisting about the exocyclic C–C double bond, the ground-
state E–Z interconversion is extremely slow in the absence
of catalysts, as also indicated by the observed stability of the
composition of the photolysed samples over several hours or
days. Therefore, the dominant presence of E species in fresh
solutions of all compounds probably results from a stereo-
selectivity of the route followed to synthesise them, and has
little to do with the equilibrium populations of the two
isomers. On the contrary, the calculated heats of formation
of the 6 forms can be analysed with reference to the ratios of
the equilibrium populations of the Z and hemiacetalic forms
found in the NMR experiments following photolysis
because, as previously pointed out, such an equilibration
occurs rapidly with respect to the time needed for the
measurements. As clearly shown in Fig. 3 the heats of
formation of the hemiacetalic forms are systematically
lower, in absolute value, than those of the Z species.
While this result is in keeping with the experimental observ-
ations about 3a, for which no tricyclic form was observed in
equilibrium with the Z isomer, it cannot account for the low
but significant amount of 6b and the very large amounts of
6c and d observed. The discrepancy might arise from a
systematic stabilisation of the hemiacetalic forms relative
to the Z isomers arising from stronger solvation of the
former, an effect not accounted for by the calculations. On
the other hand, the observed increasing propensity to give
Conclusions
The difference in the observed reactivities of the four 1-oxo-
cycloalkan-2-ylideneacetic acids 3a–d with hydrazine
hydrate cannot be traced back to different conformations
at the exocyclic C–C double bond. In fact, in freshly
prepared non-irradiated solutions, all these compounds are
present as E isomers. Following photoisomerization to the Z
forms, differences among the reactivities of the four
compounds are observed, with an increasing propensity to
give the tricyclic forms 6 with increasing size of the ali-
phatic ring, likely associated with reduced strain. In
particular, compounds 3a and b having smaller aliphatic
cycles, can give cyclic products only in the presence of
suitable reagents. Reaction with hydrazine hydrate, being
probably controlled by the relative stabilities of the inter-
mediates of competitive paths (IIa and b and IIIa and b in
Scheme 4), cleanly leads to products 1a and 7b, respec-
tively. The severe strain in the hypothetical tricyclic deriva-
tives 6a and IIIa, featuring two pentatomic rings, can
explain the observed differencies in the results of both
photochemistry and reaction with hydrazine of compound
3a with respect to 3b. On the other hand, the fast and
thermodynamically favoured cyclization of the Z forms of
compounds 6c and d, featuring a seven-membered aliphatic
ring, suggests a general propensity of these compounds to
give cyclic products, even without hydrazine hydrate, as

S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
7569
Scheme 4.
soon as the Z forms are produced in the presence of light,
catalysts or under drastic experimental conditions. In this
context, replacement of thiophene for benzene does not
qualitatively change the observed behaviour. The change
along the 3a–d series of the intrinsic propensity for cyclisa-
tion is probably responsible for the complex pattern of
reactivity towards hydrazine hydrate exhibited by these
compounds.
Experimental
Reaction with hydrazine
Compounds 3 (1 mmol) were refluxed with hydrazine
hydrate (2 mmol) in acetic acid (10 ml) for three hours.
After cooling, in the case of 3a19 and 3b20 a precipitate
formed, which was filtered by suction, thoroughly washed
with diethyl ether, and then identified from analytical and
spectral data as 1a and 7b, respectively. On the other hand,
with 3c20 and 3d21 complex reaction mixtures were
obtained, in which only traces of the benzo- and, respec-
tively, thiophene-heptapyridazinone were present. 1a:
In conclusion, we have shown that such compounds as 3a–
c, which differ only in the size of the aliphatic ring, while
showing similar photochemical behaviours, exhibit different
profiles of chemical reactivity. Rings of different sizes can
deeply alter the energetic ranking of the reaction products as
well as intermediates. Since constrained analogues of bio-
active compounds are often obtained through insertion of a
–(CH2)n– chain between the correct positions of the parent
molecule, care must be paid in the choice of the chain length
so as to affect the geometry, but not the stability and the type
of reactivity of the obtained compound.
1
white-grey powder, mp 298–302ЊC; H NMR (DMSO-d6)
4.06 (d, 1.5 Hz, 2H), 7.05 (t, 1.5 Hz, 1H), 7.55 (m, 2H), 7.66
(m, 1H), 7.87 (m, 1H), 12.98 (bs, 1H, exch. with D2O). Anal.
calcd C 71.73, H 4.38, N 15.21; found C 71.68, H 4.45, N
15.37. 7b: white-grey powder, mpϾ230ЊC; 1H NMR
(DMSO-d6) 1.60 (m, 0.68H), 2.00 (m, 0.32H), 2.15 (m,
1H), 2.15 (s, 3H), 3.00 (m, 2H), 3.60 (m, 0.32H), 3.80 (m,

7570
S. Ghelli et al. / Tetrahedron 56 (2000) 7561–7571
0.68H), 4.40 (d, 10 Hz, 0.32H), 4.95 (d, Jˆ10 Hz, 0.68H),
7.36 (m, 3H), 7.88 (m, 1H), 13.00 (s, 1H, exch. with D2O).
Anal. calcd C 65.11, H 5.46, N 10.85; found C 64.83, H
5.71, N 11.16.
experiments performed in deuterated dimethylsulfoxide and
monitored by 1H NMR spectroscopy.
Computational details
1H NMR measurements
Calculations were performed with the PM3 method,22
implemented in the HyperChem package,23 and were
carried out at the RHF level. The geometry of each
compound was fully optimised and energy minimised.
Whenever several different starting conformations were
possible for a given compound, an optimisation procedure
was carried out from each starting geometry, leading to a
single absolute minimum in all cases.
All NMR measurements were performed at proton
frequency on an AMX-400 WB Bruker spectrometer
operating at 9.39 T and equipped with a 1H/X 5 mm reverse
probehead. All spectra were recorded at 30ЊC and scaled
using the residual signal of the DMSO-d6 peak resonating
at 2.6 ppm as the internal reference. Experimental
parameters for 1D spectra were as follows: basic spectral
frequencyˆ400.130 MHz,
spectral
widthˆ6400 Hz
(14 ppm), time-domain data points: 32 K, pulse widthˆ
3.5 s (45Њ flip angle), recycle delayˆ8 s, number of
scansˆ32. FIDs were zero filled to 64 K frequency-domain
data points and Fourier transformed without filtering.
NOESY spectra were recorded using 2048 time-domain
points (F2 dimension) and 512 increments (F1 dimension),
32 scans per increment, TPPI Phase Cycle, a 2400 Hz
(6 ppm) spectral width in both dimensions and a mixing
time of 400 ms. FIDs were processed doubling the number
of point in the F1 dimension and applying a sine square
window function (shifted by p/2 rad) in both dimensions
before Fourier transformation.
Acknowledgements
`
This work was supported by the Ministero dell’Universita e
della Ricerca Scientifica e Tecnologica (MURST, Rome).
Technical assistance by M. Bandiera (Modena) is gratefully
acknowledged.
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