Unusual reactions between aromatic carbon supernucleophiles and 1,2-diazabuta-1,3-dienes: Useful routes to new pyrazolone and cinnoline derivatives

Article abstract of DOI:10.1002/ejoc.200800445

Reactions between 1,3,5-tris(dialkylamino)benzenes and 1,2-diazabuta-1,3- dienes produce semicarbazone derivatives through attack of the supernucleophile aromatic carbon atom at the terminal carbon atom of the heterodiene reagent. The strong activation of the aromatic ring due to the presence of the three amino groups in a symmetrical relationship promotes electrophilic aromatic substitution by the neutral carbon atom of the electrophile. The resulting semicarbazones, in methanol in the presence of sodium methoxide, mainly afford pyrazolone derivatives, whereas in THF in the presence of sodium methoxide an unusual cyclization reaction produces cinnoline derivatives as the major products. Both cyclization reaction mechanisms are discussed. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800445

FULL PAPER
DOI: 10.1002/ejoc.200800445
Unusual Reactions Between Aromatic Carbon Supernucleophiles and
1,2-Diazabuta-1,3-dienes: Useful Routes to New Pyrazolone and Cinnoline
Derivatives
Luciano Forlani,*[a] Orazio A. Attanasi,[b] Carla Boga,[a] Lucia De Crescentini,[b]
Erminia Del Vecchio,[a] Gianfranco Favi,[b] Fabio Mantellini,[b] Silvia Tozzi,[a] and
Nicola Zanna[a]
Keywords: Aromatic substitution / Cyclization / Heterocycles / Michael additions
Reactions between 1,3,5-tris(dialkylamino)benzenes and 1,2-
diazabuta-1,3-dienes produce semicarbazone derivatives
through attack of the supernucleophile aromatic carbon atom
at the terminal carbon atom of the heterodiene reagent. The
strong activation of the aromatic ring due to the presence of
the three amino groups in a symmetrical relationship pro-
motes electrophilic aromatic substitution by the neutral car-
bon atom of the electrophile. The resulting semicarbazones,
in methanol in the presence of sodium methoxide, mainly af-
ford pyrazolone derivatives, whereas in THF in the presence
of sodium methoxide an unusual cyclization reaction pro-
duces cinnoline derivatives as the major products. Both cycli-
zation reaction mechanisms are discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
1,3,5-Tris(dialkylamino)benzene derivatives are strongly
activated neutral carbon nucleophiles able to display some
reactivity aspects toward electrophilic substrates featuring a
greater or lesser degree of activation. These very interesting
electron-rich benzenes were first synthesized in 1967[1a] and
were extensively studied[1] by Effenberger et al. Their super-
nucleophilic character permits reactions to be performed
under particularly mild conditions, and makes them suit-
able for mechanistic investigations. Recently, we isolated σ-
complexes (the so-called Wheland intermediates, W) from
electrophilic aromatic reactions between these nucleophiles
and diazonium salts.[2] Furthermore, reactions between
1,3,5-tris(dialkylamino)benzene derivatives and a more
electrophilic reagent – namely 1,4-dinitrobenzofuroxan
(DNBF) – permitted us to obtain the first evidence of a
carbon–carbon Wheland–Meisenheimer complex (WM,
Scheme 1), which was studied by NMR spectroscopy.[3a]
This observation is consistent with the strong electro-
philic power of DNBF, as quantitatively indicated by
Terrier[4] on the Mayr[5] electrophilicity scale. In the case of
Scheme 1. First examples of Wheland–Meisenheimer carbon–
carbon adducts.
reactions between DNBF and 2-aminothiazole derivatives
we also collected evidence of the presence of WM interme-
diates arising from the attack of the electrophilic reagent at
the 5-positions in the thiazole rings.[3b,3c]
The capability to form moderately stable Wheland inter-
mediates depends both on the activation of the reagents and
on experimental conditions that slow the proton elimi-
nation in the rearomatization process,[2b,2c] as shown in
Scheme 2.
[a] Department of Organic Chemistry “A. Mangini”, ALMA
MATER STUDIORUM – Università di Bologna, Facoltà di
Chimica Industriale,
Viale Risorgimento 4, 40136 Bologna, Italia
Fax: +39-051-2093654
E-mail: forlani@ms.fci.unibo.it
[b] Istituto di Chimica Organica, Università di Urbino “Carlo Bo”,
via I Maggetti 24, 61029 Urbino, Italia
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Scheme 2.
Eur. J. Org. Chem. 2008, 4357–4366
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L. Forlani et al.
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Especially when electron-withdrawing groups are present ysis may be necessary to activate the nucleophilic centres,
on the terminal carbon and/or nitrogen atoms, heterodiene as in the case of β-dicarbonyl derivatives. Often, the pres-
systems containing diaza groups are well-known electro- ence of a base makes it difficult to isolate Michael-type ad-
philes, able to undergo nucleophilic attack to yield Michael- ducts, because the subsequent cyclization to heterocyclic
like adducts. These 1,4-additions to 1,2-diazabuta-1,3- systems may take place rapidly. Our previous findings sug-
dienes (DBDs) with formation of new carbon–carbon or gested to us that 1,3,5-triaminobenzenes (TABs) might be
carbon–heteroatom bonds have been carried out with a reagents so strongly activated as to allow attack at the neu-
wide number of carbon (as activated methylene and me- tral electrophilic terminal carbon atom of the heterodiene
thyne compounds), oxygen, nitrogen, sulfur, selenium and moiety of a DBD, and this prompted us to explore that
phosphorus nucleophiles.[6,7] Previously, it had been re- possibility.
ported[8] that reactions between 1,2-diazabuta-1,3-dienes
Michael-like adducts 8–17 were obtained by addition, at
and amines take place by the classical nitrogen attack at the room temperature, of equimolar amounts of TABs (1 or 2)
terminal carbon atom of the heterodiene reagent to afford in chloroform to DBDs (3–7) in the same solvent, as shown
α-aminohydrazones, which represent interesting intermedi- in Scheme 3. The disappearance of the typical red colour of
ates from which to obtain many heterocyclic systems.
On the basis of these findings, and in view of the nucleo-
philic power at the aromatic carbon atoms exhibited by
1,3,5-tris(dialkylamino)benzene derivatives, we decided to
investigate the behaviour of these neutral carbon nucleo-
philes in Michael-type additions with DBDs under mild
neutral conditions.
the starting DBDs revealed the completion of the reactions.
Here we report that the addition reactions between the
1,3,5-tris(dialkylamino)benzenes 1 and 2 and several DBDs
take place easily, affording the addition products in high
yields. Under basic conditions these addition products un-
dergo cyclization, which can switch toward preferential for-
mation either of pyrazolone derivatives or of cinnoline de-
rivatives, depending on the solvent used.
Scheme 3. Michael-like addition reaction between TABs and DBDs.
Table 1 reports the yields of semicarbazones 8–17, the
physical properties and NMR spectroscopic data of which,
reported in the Experimental Section, agree with the struc-
tures shown in Scheme 3. It has to be noted that, in the
1
case of reactions of DBDs with 1, the H NMR spectra of
the crude reaction mixtures showed complete conversion af-
ter about 1 h, whereas the conversion of the morpholinyl
derivative 2 required longer reaction times (from 2 to 8 h)
and in some cases did not go to completion. The piperidinyl
derivative 1 is more reactive than the morpholinyl derivative
Results and Discussion
A) Reactions Between 1,3,5-Tris(dialkylamino)benzenes and
1,2-Diazabuta-1,3-dienes
Usually, DBDs react with nucleophilic reagents, and the 2, as would be expected on the basis of the electron-with-
reactions are promoted by the presence of bases. Base catal- drawing character of the morpholine oxygen atom as indi-
Table 1. Semicarbazones obtained from TABs 1 and 2 and DBDs 3–7.
R2N
Y
X
Z
Conversion (product ratio)[a]
Product[b] (yield%)
Piperidinyl
Piperidinyl
Piperidinyl
Piperidinyl
Piperidinyl
Morpholinyl
Morpholinyl
Morpholinyl
Morpholinyl
Morpholinyl
OEt
OMe
OMe
NMe2
NMe2
OEt
OMe
OMe
NMe2
NMe2
NH2
NH2
NH2
NH2
NHPh
NH2
NH2
NH2
NH2
NHPh
Me
Me
Et
Me
Me
Me
Me
Et
100% (80:20)
100% (80:20)
100% (75:25)
100% (100:0)
100% (100:0)
82% (83:17)
100% (85:15)
100% (80:20)
100% (100:0)
70% (100:0)
8 (77)[c]
9 (70)[c]
10 (74)[c]
11 (96)[c]
12 (95)[d]
13 (55)[d]
14 (83)[d]
15 (76)[d]
16 (93)[d]
17 (65)[d]
Me
Me
[a] Relative % ratio of products, calculated from the 1H NMR spectrum of the crude reaction mixture and referenced to the main
compound (8–17) with respect to a second product, as discussed in the text. [b] Product isolated by precipitation. [c] Yield of weighed
product precipitated from acetonitrile reaction mixture (second procedure, see Exp. Sect.). [d] Yield of weighed product obtained from
the first procedure (see Exp. Sect.).
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Useful Routes to New Pyrazolone and Cinnoline Derivatives
cated by, for instance, the pKa difference [pKa(morpholine) singlets at δ = 5.2–5.4 ppm are in the region relating to pro-
1
= 16.6, pKa(piperidine) = 18.9].[9] In some cases H NMR tons in benzylic positions and adjacent to electron-with-
spectra of the crude reaction mixtures showed the presence drawing groups, as would be expected for 7-H. N–H pro-
of signals for compounds 8–17 together with those of sim- tons exchanged quickly (H/D) on addition of D2O, while
ilar products (see later), in about 15–25% relative ratio. protons bonded to C-7 exchanged slowly (in about 12 h),
Compounds 8–17 were isolated in high purity (Ͼ98%) by as would be expected for protons bonded in positions α to
precipitation from acetonitrile (see Exp. Sect.).
COOR groups. In the cases of adducts 11, 12, 16 and 17,
When reactions between 1 or 2 and 1-(cyclohex-1-en-1- bearing amido groups instead of ester groups, 7-H did not
yl)-2-(4-nitrophenyl)diazene (18) were attempted, no reac- exchange.
tion products were detected, and after 72 h the decomposi-
tion of 18 became relevant. This was presumably the result
of the absence of electron-withdrawing groups on the
terminal carbon and/or nitrogen atoms of the heterodiene
system.
The lack of any reaction of 18 may be explained by bear-
Scheme 5. Isomeric forms for compound 8.
ing in mind that the electron-withdrawing electronic effects
of COOR or CONMe2 groups enhance the electrophilic
It is worthy of attention that 1H NMR spectra of adducts
power of the heterodiene terminal carbon atoms of DBDs
3–7. This supposition is also confirmed by the absence of
conversion in the reaction between 1 and 19.
The success achieved in obtaining stable Michael-type
adducts under neutral conditions prompted us to perform
the reaction in an NMR tube. Indeed, in view of our pre-
vious work,[2,3] evidence of Wheland intermediates (W,
Scheme 4) might be expected at low temperatures.
8–10 and 13–15 recorded immediately after their dissol-
ution in CDCl3 slowly change with time. Figure 1a and b
show 1H NMR spectra of compound 8 (chosen as an exam-
Scheme 4.
The reactions between compounds 1 or 2 and DBD 3
were carried out directly in NMR tubes in different solvents
(CDCl3, CD2Cl2, CD3CN) and at different temperatures
(from –70 to +25 °C), but no evidence of the presence of
possible
W complex-like intermediates in detectable
amounts was obtained. The only recorded signals were
those associated with the starting materials and with the
final semicarbazone derivatives, together (in cases of long
reaction times) with small amounts of isomeric forms and
of heterocyclic derivatives (see following sections).
Isomerism of Semicarbazones 8–17
1H NMR spectroscopic data, recorded in CDCl3, for all
semicarbazones 8–17 show very close chemical shift values
(see Exp. Sect.). Consequently, it is reasonable to suppose
that 8–17 have a common form. In particular, singlets at δ
= 6.6–6.7 ppm are clearly attributable to the two equivalent
Figure 1. 1H NMR spectra (selected window) of compound 8. Bot-
tom: spectrum recorded immediately after dissolution in CDCl3.
protons 3-H and 5-H of the aromatic rings (Scheme 5). The Top: spectrum recorded after 2 d.
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L. Forlani et al.
FULL PAPER
ple for discussion) recorded immediately after dissolution because in this latter case the ring-closure implies an intra-
in CDCl3, and after about 2 d, respectively. molecular nucleophilic substitution on the aromatic ring
New signals at δ = 5.1, 6.7 and 2.4 (CH3) ppm, similar with release of a morpholinyl (or piperidinyl) group.
to those of the starting compound, appeared. The gHSQC Clearly, the absolute and relative yields of pyrazolones and
spectrum showed that the signal at δ = 5.11 ppm belongs cinnolines are structure- and conditions-dependent.
to a proton bonded to C-7.
Prototropism of 8a can generate 8b and 8c (Scheme 5).
Among all the tautomeric forms, our data clearly indicate
8b and 8c as the most populated tautomers. The greater
extent of electronic conjugation in 8c with respect to 8b
favours 8c over 8b. In addition, the presence, in the 1H
NMR spectrum (see Exp. Sect.) of two distinct signals that
exchange with D2O in a 2:1 relative ratio also supports this
conclusion.
After 2 d in CDCl3, the relative amount of the new com-
pound has reached 15–25% with respect to the starting se-
micarbazone. Attempts to modify the relative ratio of sig-
nals associated with these isomeric forms by performing
several VT NMR experiments in CD3CN at temperatures
varying from –30 to +75 °C did not produce evidence of
modifications of the relative amounts of these isomers.
Scheme 6. Cyclization reactions of the adducts 8–10 and 13–15.
Other possible attributions of the new signals might also
relate to syn/anti isomerism. Although the lack of observa-
tion of any effect of variation of the temperature reduces
this possibility, the observation of a positive NOE effect
supports the possibility that the new signals may be associ-
1. Formation of Pyrazolones as Major Products
In methanol with 1 equiv. of sodium methoxide, semicar-
bazones 8–10 and 13–15 cyclized to give pyrazolones 20–
23 (see Table 2). Piperidinyl (8–10) and morpholinyl (15)
derivatives give pyrazolones 20, 21 and 23 as major prod-
ucts, whereaas morpholinyl derivative 22 was obtained in
equimolar amounts with respect to the cinnoline derivatives
27 and 28. (Obviously, the same pyrazolone 20 was ob-
tained from 8 and 9, whereas 22 was also obtained from
ated with a syn form of compound 8, as represented by 8d.
1
In all cases, the H NMR spectrum in [D6]DMSO shows
the presence of one product only.
Michael adducts 11, 12, 16 and 17 – bearing –CON-
(CH3)2 groups, with their feeble electron-withdrawing ef-
fects – did not show evidence of new isomeric forms.
both 13 and 14.)
B) Cyclization Reactions of Semicarbazones 8–17
The presence of the two different heterocycle systems can
In the presence of sodium methoxide, compounds 8–10 be clearly observed in the H NMR spectra of the crude
1
and 13–15 underwent cyclizations to produce pyrazolone reaction mixtures, each of which shows two signals, of rela-
derivatives 20–23 and cinnoline derivatives 24–29 in dif- tive intensity 1:1, in the spectral region for aromatic C–H
ferent relative ratios depending on the solvent used (δ = 7.3–7.6 ppm in CDCl3), attributable to the cinnoline
(Scheme 6). The pairs of reaction products were easily sepa- derivative, and one singlet at δ = 6.41–6.46 ppm, corre-
rable by column chromatography and fully characterizable, sponding to the hydrogen atoms of the aromatic ring of the
and their spectroscopic data agree with the structures pyrazolone derivative.
shown here. It is noteworthy that the formation of pyrazo-
The importance of the presence of the base in the cycliza-
lones under basic conditions had already been observed tion reactions affording pyrazolone derivatives may be ex-
with similar adducts,[6a–6c] whereas the formation of cinno- plained in terms of the formation of a powerfully charged
line derivatives is a new and completely unexpected result, nitrogen nucleophilic centre and subsequent ring closure
Table 2. Pyrazolones obtained from semicarbazones by cyclization in methanol in the presence of sodium methoxide.
Starting compd.
Y
Z
Conv.[a]
Pyrazolone vs. cinnoline (relative % ratio)[a]
Pyrazolone (yield %)[b]
8
OEt
OMe
OMe
OEt
OMe
OMe
Me
Me
Et
Me
Me
Et
100%
100%
100%
95%
50%
95%
20 (73) 24 (27)
20 (80) 25 (20)
21 (95) 26 (5)
22 (50) 27 (50)
22 (50) 28 (50)
23 (62) 29 (38)
20 (70)
20 (77)
9
10
13
14
15
21 (92)
22 (40)[c]
22 (25)[c]
23 (55)[c]
[a] Calculated from the 1H NMR spectrum of the crude reaction mixture. [b] Yield of pure product weighed after chromatographic
separation. [c] Low yield due to incomplete conversion caused by poor solubility of starting materials.
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Useful Routes to New Pyrazolone and Cinnoline Derivatives
Scheme 7.
through acylic nucleophilic substitution (Scheme 7, path a). mation of cinnoline derivatives (in the case of the starting
However, small amounts of pyrazolones are also formed compound 9, almost exclusively).
simply on chromatographic columns (silica gel, elution with
methanol) without base catalysis, and also in THF, in a very
slow and incomplete process. This occurrence can be easily
explained by considering that some basic centres, able to
favour proton departure and thus promoting the ring-clo-
sure reaction, are present in the semicarbazone derivatives.
Obviously, the addition of a strong base, such as sodium
methoxide, strongly favours this reaction.
Some reactions were also carried out under different ex-
perimental conditions. In THF, compound 8 showed similar
behaviour on addition of aq. NaOH (0.1 , 2 equiv.),
whereas a substitution of CH3ONa with DABCO gave rise
to low levels of conversion and only traces of cyclization
products. In THF in the absence of base, the cyclization of
15 was very slow (50% of conversion in 11 d) and produced
only the pyrazolone derivative. The reaction between com-
pound 10 and CH3ONa was carried out in CD3CN, and its
behaviour was monitored by 1H NMR spectroscopy, show-
ing the formation of the cyclization products 21 and 26 in
about 4:6 relative ratio. These findings clearly indicate that
the two ring-closure reactions giving pyrazolones or cinno-
lines are in competition and that the preferential formation
of a five- or a six-membered ring mainly depends on the
solvent used. In more strongly associating solvents, such as
THF and CH3CN, the formation of cinnolines predomi-
nates (Scheme 7, path b).
In Scheme 7, the ring-closure of the derivatives 8–10 and
13–15 to pyrazolone derivatives may be conceived as occur-
ring out of the plane of the benzene ring.
Compounds 11, 12, 16 and 17 (Y = NMe2) are not prone
to cyclization to yield pyrazolones, probably because the
carbonyl carbon atoms of their amido groups are less acti-
vated toward nucleophilic attack than ester carbonyl
groups. In addition, the protons α to the amido CO-
(NMe)2 groups of compounds 11, 12, 16 and 17 are less
acidic than those α to the ester groups in the adducts that
gave pyrazolone derivatives 20–23.
The unexpected formation of cinnoline derivatives is also
an interesting finding from the synthetic point of view, as
these heterocycles find application in the agrochemical, bio-
logical and pharmaceutical fields.[10] Some derivatives exhi-
2. Formation of Cinnolines as Major Products
In vigorously stirred THF with 2 equiv. of sodium meth- bit anti-inflammatory and antibiotic activity. Sometimes
oxide, pyrazolone and cinnoline derivatives are obtained they are synthesized from o-aminophenylethylene or o-ami-
from semicarbazones 8–10 and 13–15 in relative ratios dif- noacetophenones,[11] but the main routes are the cyclization
ferent from those obtained in methanol (see Table 3). The of ortho-substituted arylhydrazones or the diazotization of
change of the solvent from methanol to THF permits the o-substituted anilines.[12–14] The cyclization of hydrazones is
reaction pathway to be driven preferentially toward the for- achieved through Friedel–Crafts-type reactions.[14] In view
Table 3. Cinnolines obtained from semicarbazones by cyclization in THF in the presence of sodium methoxide.
Starting compd.
Y
Z
Conv.[a]
Cinnoline vs. pyrazolone (relative % ratio)[a]
Cinnoline (yield %)[b]
8
OEt
OMe
OMe
OEt
OMe
OMe
Me
Me
Et
Me
Me
Et
100%
95%
100%
67%
100%
85%
24 (75) 20 (25)
25 (93) 20 (7)
26 (55) 21 (45)
27 (85) 22 (15)
28 (58) 22 (42)
29 (69) 23 (31)
24 (72)
25 (90)
9
10
13
14
15
26 (46)
27 (55)[c]
28 (41)
29 (46)[c]
[a] Calculated from the 1H NMR spectrum of the crude reaction mixture. [b] Yield of pure product weighed after chromatographic
separation. [c] Low yield due to incomplete conversion caused by poor solubility of starting materials.
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of the importance of these compounds, we emphasize that stituents adjacent to the ring-fused carbon atoms of all the
the current reaction represents a new route to cinnoline de- cinnolines synthesized (and of many other compounds re-
rivatives under mild experimental conditions and in good ported here), which appear as broad signals, both in 1H and
to satisfactory yields. In addition, the presence of the ester in 13C NMR spectra (see the Supporting Information). This
functionalities in the 4-positions of the cinnoline derivatives observation prompted us to perform dynamic 1H NMR ex-
24–29 makes it possible to synthesize other derivatives.
periments at different temperatures on cinnoline derivative
Usually, the synthetic approach involving formation of 27, chosen as an example. Increasing of the temperature of
the cinnoline N-1–C-8a bond involves cyclization of o-halo- a [D6]DMSO solution of compound 27 from 25 to 115 °C
geno-α-hydrazonoacetophenones or related substrates[15] in caused, at first, the coalescence of the two methylene broad
which the formation of the six-membered ring proceeds in signals, and then their gradual sharpening to show a quartet
an SNAr fashion with displacement of the halide ion.[15] It centred at δ = 4.50 ppm, with a coupling constant of 7.0 Hz
is noteworthy that the reaction pathway for the formation with the adjacent methyl group. Through application of the
of cinnolines reported here involves a secondary amine (pi- Eyring equation,[17] these data permitted us to calculate an
peridine or morpholine) as a leaving group. The replace- energy barrier of ∆G# = (15.4Ϯ0.2) kcalmol–1 for the pro-
ment of amines in nucleophilic aromatic substitution reac- cess, typical for similar conformational restraints.[18] It is
tions has scarcely been investigated, though it has been re- reasonable to suppose that this phenomenon occurs in all
ported to occur[16] on aromatic substrates bearing electron- of the compounds 8–17 and 20–29, but it is especially evi-
withdrawing groups (e.g., nitro groups). In the reaction re- dent for compounds bearing ethoxycarbonyl groups.
ported here, strongly electron-donating groups are bonded
to the aromatic ring, so this reaction appears to be highly
Conclusions
unusual. However, the incipient charge separation, and the
closeness of both entering and leaving groups (as depicted
in I), facilitate six-membered ring-closure. Obviously, the
driving force for the new ring-formation is the final aroma-
tization step. In fact, the ring-closure and the departure of
the amino group is possible if the proton bonded to the
ureidic nitrogen atom α to the carbonyl amido group is
shifted onto the aromatic amino group as shown in the first
equilibrium of Scheme 7, path b, thus facilitating the subse-
quent loss of the neutral amine from intermediate I. After
the ring-closure, the sodium methoxide promotes the aro-
matization of the heterocyclic ring.
As with the cyclization to pyrazolones, the formation of
cinnoline derivatives does not occur with Michael-type ad-
ducts bearing CON(CH3)2 groups rather than COOR
groups. This may be explained by considering that the for-
mation of a negative charge on the ureidic nitrogen atom
capable of causing the aromatic nucleophilic substitution
on the aromatic ring can be achieved through different
pathways involving internal proton shifts. In this context,
the higher acidities of the 7-H protons of compounds 8–10
and 13–15 with respect to those of adducts 11, 12, 16 and
17 (see previous section on tautomerism) can play an im-
portant role.
The uncatalysed Michael-like addition reactions between
supernucleophiles and 1,2-diazabuta-1,3-dienes produce the
corresponding 1,4-adducts, which cyclize to pyrazolones
and cinnolines under basic conditions. These two heterocy-
clic derivatives are formed at the same time, and the relative
prevalence of each of the two cyclization reaction products
depends on the solvent used. The formation of pyrazolones
as major products occurs in methanol, whereas the unex-
pected formation of the cinnoline ring prevails in THF, a
more strongly associating solvent, through an intramolecu-
lar nucleophilic aromatic substitution involving the dis-
placement of a secondary amino group and represents a
new route to cinnoline derivatives.
Experimental Section
General Remarks: NMR spectra were recorded with Varian Gem-
ini 300 or Mercury 400 spectrometers operating at 300 or 400 MHz
1
(for H NMR) or at 75.36 or 100.56 MHz (for 13C NMR), respec-
tively. Signal multiplicities were established by DEPT experiments.
Chemical shifts for H NMR spectra in CDCl3 were referenced to
1
TMS; in other cases chemical shifts were referenced to the solvent
{δ = 77.0 ppm for 13C in CDCl3, δ = 3.31 and 49.0 ppm for 1H and
Finally, we would like to focus attention on a further
particularity of the compounds synthesized in this work. It
is predictable that the presence of bulky groups, such as
13C, respectively, in CD3OD, δ = 2.0 and 0.3 ppm for H and 13C,
1
respectively, in CD3CN, δ = 2.49 and 39.5 ppm for 1H and 13C,
respectively, in [D6]DMSO; coupling constants (J) in Hertz}. All
piperidinyl or morpholinyl substituents, in all the com- signals assigned to NH protons disappear after addition of D2O.
NOE and gHSQC experiments were carried out with a Varian In-
ova 600 spectrometer. ESI-MS spectra were obtained with a
WATERS 2Q 4000 instrument. Melting points were determined
with a Büchi 535 apparatus in open capillary tubes and are uncor-
rected. Silica gel plates supported on aluminium were employed for
analytical thin layer chromatography (TLC), and silica gel (230–
400 mesh) for flash chromatography (FC). IR spectra were re-
corded on a model 1600 FT-IR Perkin–Elmer spectrophotometer
in CHCl3 solution. IR spectra of compounds 8–10 and 13–15 con-
tain typical signals belonging both to ester (ca. 1830 cm–1) and
pounds synthesized here should make these molecules quite
rigid. This hypothesis is confirmed by the fact that 1H
NMR spectra of compounds 8, 13, 24 and 27 each present
two signals, one for each methylene hydrogen atom of the
ethoxycarbonyl group. This evidence clearly indicates non-
equivalence of the two methylene hydrogen atoms, probably
due to a rotational constraint of the ester group caused by
the proximity (peri position) of the piperidinyl (or morphol-
inyl) group. This non-equivalence is also evident for the
methylene signals of the piperidinyl (or morpholinyl) sub- amido groups (ca. 1692 and 1599 cm–1); NOE experiments showed
4362
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4357–4366

Useful Routes to New Pyrazolone and Cinnoline Derivatives
the (E) configuration for compound 8. Compounds 11, 12, 16, 17
and 20–23 showed typical signals belonging to amido groups. Cin-
nolines 24–29 showed typical signals (ca. 1729, 1609, 1540, 1435,
1380, 1255, 1150 cm–1). Sodium methoxide and solvents used are
commercially available materials, starting materials 1 and 2 were
synthesized as previously reported,[2a] and DBDs 3,[19] 4,[20] 5, 6,[21]
7, 18[22] and 19 were synthesized according to previously reported
procedures[23] as (E)/(Z) mixtures in variable relative ratios, de-
pending on the structures. Their characterization data, if not al-
ready reported, are described in the Supporting Information.
Methyl 3-[(Aminocarbonyl)hydrazono]-2-(2,4,6-tripiperidin-1-yl-
phenyl)pentanoate (10): Pale green solid; 0.057 g (74%); m.p. 152–
1
153 °C. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.09 (t, J
= 7.5 Hz, 3 H), 1.45–1.65 (m, 12 H), 1.65–1.80 (m, 6 H), 2.15–2.30
(dq, J = 7.5 Hz, 1 H), 2.37–2.51 (dq, J = 7.5 Hz, 1 H), 2.51–2.90
(m, 8 H), 3.08–3.18 (m, 4 H), 3.70 (s, 3 H), 4.45–4.80 (br. s, 1 H,
NH), 5.29 (s, 1 H), 5.45–5.80 (br. s, 1 H, NH), 6.65 (s, 2 H), 7.72
(br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C): δ
= 9.6 (CH3), 22.2 (CH2), 24.2 (CH2), 24.3 (CH2), 25.9 (CH2), 26.2
(CH2) 50.0 (CH3), 50.5 (CH2), 51.3 (CH), 54.8 (CH2), 107.7 (CH),
121.9, 152.5, 153.4, 154.3, 157.3, 172.8 ppm. MS (ES+): m/z = 513
[M + H]+. C28H44N6O3 (512.7): calcd. C 65.60, H 8.65, N 16.39;
found C 65.56, H 8.67, N 16.35.
Preparation of Semicarbazone Derivatives 8–17
First Procedure: 1,2-Diazabuta-1,3-diene derivative 3 (or 4–7,
0.150 mmol) was added to a solution of TAB 1 (or 2, 0.150 mmol in
2 mL of CHCl3) at room temperature with magnetic stirring until
disappearance of the red colour of the reaction mixture (from 1 to
8 h). The solution was then concentrated under reduced pressure.
The addition of CH3CN (2–3 mL) to the crude oil caused precipi-
tation of compounds 8–17 (Ͼ98% pure), which were collected by
filtration and analysed by MS and by 1H and 13C NMR spec-
troscopy. Further small amounts of compounds 8–17 remained in
the mother liquor, together, in some cases, with its isomeric product
(see later) or, sometimes, with unreacted starting materials. All
attempts to separate the reaction products by column chromatog-
raphy on silica gel (elution: Et2O/CH3OH from 0 to 100%, v/v)
decreased the yields of adducts, because variable amounts of cycli-
zation product (pyrazolones in 10–20% yields) were obtained after
elution with pure methanol under these conditions.
3-[(Aminocarbonyl)hydrazono]-N,N-dimethyl-2-(2,4,6-tripiperidin-1-
ylphenyl)butanamide (11): White solid; 0.074 g (96%); m.p. 197–
207 °C (dec.). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.35–
1.62 (m, 12 H), 1.63–1.79 (m, 6 H), 1.84 (s, 3 H) 2.35–2.70 (m, 8
H), 2.81 (s, 3 H), 2.96 (s, 3 H), 3.09–3.18 (m, 4 H), 4.40–4.80 (br.
s, 1 H, NH), 5.38 (s, 1 H), 5.62–6.02 (br. s, 1 H, NH), 6.64 (s, 2
H), 7.48 (br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz, CDCl3,
25 °C): δ = 15.7 (CH3), 24.2 (CH2), 24.3 (CH2), 25.9 (CH2), 26.3
(CH2), 35.6 (CH3), 37.2 (CH3), 50.5 (CH2), 51.6 (CH), 54.9 (CH2),
107.5 (CH), 122.1, 150.4, 152.4, 154.4, 157.2, 171.5 ppm. MS
(ES+): m/z = 512 [M + H]+. C28H45N7O2 (511.7): calcd. C 65.72,
H 8.86, N 19.16; found C 65.69, H 8.88, N 19.12.
3-[(Anilinocarbonyl)hydrazono]-N,N-dimethyl-2-(2,4,6-tripiperidin-
1-ylphenyl)butanamide (12): White solid; 0.084 g (95%); m.p. 149–
1
150 °C. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.46–1.65
Second Procedure: This procedure exploits the low solubility of
products 8–17 in CH3CN and permits the process to be simplified
and the recovery of the adducts to be increased. In this case, equi-
molar amounts of compound 1 and a DBD (3–7) were dissolved in
the minimum possible volume of CH3CN, and the reaction mixture
was stirred at room temperature for 1–2 h. Pure compounds 8–
12 precipitated from the reaction mixture and were recovered by
filtration in yields higher than those obtained in the first procedure
and in almost pure form. This method cannot be applied to mor-
pholinyl derivatives because of the very low solubility of compound
2 in acetonitrile.
(m, 12 H), 1.68–1.81 (m, 6 H), 1.95 (s, 3 H), 2.40–3.10 (m, 8 H),
2.77 (s, 3 H), 2.98 (s, 3 H), 3.14–3.21 (m, 4 H), 5.38 (s, 1 H), 6.70
(s, 2 H), 6.96–7.03 (m, 1 H), 7.20–7.32 (m, 4 H), 7.51 (br. s, 1 H,
NH), 7.88 (br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz, CDCl3,
25 °C): δ = 16.3 (CH3), 24.3 (CH2), 24.5 (CH2), 26.0 (CH2), 26.4
(CH2), 35.7 (CH3), 37.3 (CH3), 50.5 (CH2), 51.9 (CH), 54.9 (CH2),
107.7, 118.6, 122.5, 122.7, 128.8, 138.4, 150.6, 152.5, 153.3, 154.2,
171.3 ppm. MS (ES+): m/z = 588 [M + H]+. C34H49N7O2 (587.8):
calcd. C 69.47, H 8.40, N 16.68; found C 69.50, H 8.43, N 16.64.
Ethyl 3-[(Aminocarbonyl)hydrazono]-2-(2,4,6-trimorpholin-4-yl-
phenyl)butanoate (13): Pale yellow solid; 0.043 g (55%); m.p. 150–
165 °C (dec.). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.26
Ethyl 3-[(Aminocarbonyl)hydrazono]-2-(2,4,6-tripiperidin-1-ylphen-
yl)butanoate (8): Pale yellow solid; 0.059 g (77%); m.p. 121–122 °C.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.25 (t, J = 7.1 Hz,
3 H), 1.40–1.76 (m, 18 H), 1.86 (s, 3 H), 2.50–2.90 (m, 8 H), 3.00–
3.18 (m, 4 H), 4.16 (q, J = 7.1 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 1 H),
4.50–4.95 (br. s, 1 H, NH), 5.20 (s, 1 H), 5.45–6.00 (br. s, 1 H, NH),
6.64 (s, 2 H), 7.64 (br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz,
CDCl3, 25 °C): δ = 14.3 (CH3), 15.5 (CH3), 24.2 (CH2), 24.3 (CH2),
25.9 (CH2), 26.3 (CH2), 50.5 (CH2), 52.8 (CH), 54.9 (CH2), 60.2
(CH2), 107.4 (CH), 121.4, 149.4, 152.5, 154.5, 157.3, 172.1 ppm.
MS (ES+): m/z = 513 [M + H]+. C28H44N6O3 (512.7): calcd. C
65.60, H 8.65, N 16.39; found C 65.50, H 8.68, N 16.35.
1
(t, J = 7.2 Hz, 3 H), 1.93 (s, 3 H), 2.74–2.88 (m, 8 H), 3.12–3.20
(m, 4 H), 3.61–3.93 (m, 12 H), 4.15 (q, J = 7.2 Hz, 1 H), 4.21 (q,
J = 7.2 Hz, 1 H), 5.10–5.40 (br. s, 1 H, NH), 5.24 (s, 1 H), 5.40–
5.70 (br. s, 1 H, NH), 6.66 (s, 2 H), 8.52 (br. s, 1 H, NH) ppm. 13
C
NMR (100.56 MHz, CDCl3, 25 °C): δ = 14.3 (CH3), 16.2 (CH3),
48.9 (CH2), 49.9 (CH2), 53.5 (CH), 60.5 (CH2), 66.8 (CH2), 67.2
(CH2), 107.1 (CH), 122.4, 148.9, 151.9, 153.2, 157.1, 171.8 ppm.
MS (ES+): m/z = 519 [M + H]+. C25H38N6O6 (518.6): calcd. C
57.90, H 7.39, N 16.21; found C 57.83, H 7.42, N 16.15.
Methyl 3-[(Aminocarbonyl)hydrazono]-2-(2,4,6-trimorpholin-4-yl-
phenyl)butanoate (14): Pale yellow solid; 0.063 g (83%); m.p. 166–
167 °C. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.95 (s, 3
Methyl 3-[(Aminocarbonyl)hydrazono]-2-(2,4,6-tripiperidin-1-yl-
1
phenyl)butanoate (9): Pale yellow solid; 0.052 g (70%); m.p. 161–
H), 2.68–2.92 (m, 8 H), 3.11–3.22 (m, 4 H), 3.52–3.80 (m, 8 H),
3.71 (s, 3 H), 3.80–3.92 (m, 4 H), 4.45–4.85 (br. s, 1 H, NH), 5.26
(s, 1 H), 5.30–5.70 (br. s, 1 H, NH), 6.67 (s, 2 H), 7.73 (br. s, 1 H,
NH) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 16.2 (CH3),
48.9 (CH2), 51.6 (CH), 52.3 (CH3), 53.5 (CH2), 66.8 (CH2), 67.1
(CH2), 107.1 (CH), 122.5, 148.7, 151.9, 153.0, 156.9, 172.3 ppm.
MS (ES+): m/z = 505 [M + H]+. C24H36N6O6 (504.6): calcd. C
57.13, H 7.19, N 16.66; found C 57.07, H 7.21, N 16.68.
1
162 °C. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.45–1.65
(m, 12 H), 1.65–1.78 (m, 6 H), 1.90 (s, 3 H), 2.55–2.90 (m, 8 H),
3.10–3.20 (m, 4 H), 3.71 (s, 3 H), 4.20–4.95 (br. s, 1 H, NH), 5.21
(s, 1 H), 5.40–5.90 (br. s, 1 H, NH), 6.64 (s, 2 H), 7.44 (br. s, 1 H,
NH) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 15.5 (CH3),
24.2 (CH2), 24.3 (CH2), 25.9 (CH2), 26.3 (CH2), 50.5 (CH2), 51.4
(CH), 52.4 (CH3), 54.7 (CH2), 107.5 (CH), 121.5, 149.1, 152.6,
154.4, 157.0, 172.6 ppm. MS (ES+): m/z = 499 [M + H]+.
C27H42N6O3 (498.7): calcd. C 65.03, H 8.49, N 16.85; found C
64.97, H 8.51, N 16.87.
Methyl 3-[(Aminocarbonyl)hydrazono]-2-(2,4,6-trimorpholin-4-yl-
phenyl)pentanoate (15): White solid; 0.059 g (76 %); m.p. 248–
Eur. J. Org. Chem. 2008, 4357–4366
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4363

L. Forlani et al.
FULL PAPER
258 °C (dec.). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.15 153.0, 158.9 ppm. MS (ES+): m/z = 481 [M + H]+. C27H40N6O2
1
(t, J = 7.7 Hz, 3 H), 2.23–2.37 (m, 1 H), 2.37–2.52 (m, 1 H), 2.62–
2.92 (m, 8 H), 3.12–3.22 (m, 4 H), 3.60–3.78 (m, 8 H), 3.70 (s, 3
H), 3.83–3.92 (m, 4 H), 4.45–5.00 (br. s, 1 H, NH), 5.10–5.75 (br.
s, 1 H, NH), 5.35 (s, 1 H), 6.68 (s, 2 H), 7.94 (br. s, 1 H, NH) ppm.
13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 9.6 (CH3), 22.6 (CH2),
49.0 (CH2), 49.8 (CH2), 51.5 (CH), 53.6 (CH3), 66.8 (CH2), 67.1
(CH2), 107.3 (CH), 122.8, 151.8, 152.9, 153.0, 157.1, 172.5 ppm.
MS (ES+): m/z = 519 [M + H]+. C25H38N6O6 (518.6): calcd. C
57.90, H 7.39, N 16.21; found C 57.77, H 7.40, N 16.16.
(480.6): calcd. C 67.47, H 8.39, N 17.48; found C 67.35, H 8.41, N
17.44.
3-Methyl-5-oxo-4-(2,4,6-trimorpholin-4-ylphenyl)-2,5-dihydro-1H-
pyrazole-1-carboxamide (22): 0.019 g (40 % from 13). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.85 (s, 3 H), 2.40–3.05 (m, 8 H),
3.10–3.30 (m, 4 H), 3.55–3.80 (m, 8 H), 3.80–4.00 (m, 4 H), 4.65–
5.15 (br. s, 2 H, NH2), 6.42 (br. s, 1 H, NH), 6.43 (s, 2 H) ppm.
13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 13.2 (CH3), 49.2
(CH2), 52.3 (CH2), 66.85 (CH2), 66.92 (CH2), 101.0, 102.2 (CH),
102.9, 112.7, 138.8, 151.7, 152.2, 158.6 ppm. MS (ES+): m/z = 473
[M + H]+. C23H32N6O5 (472.5): calcd. C 58.46, H 6.83, N 17.78;
found C 58.24, H 6.86, N 17.72.
3-[(Aminocarbonyl)hydrazono]-N,N-dimethyl-2-(2,4,6-trimorpholin-
4-ylphenyl)butanamide (16): White solid; 0.072 g (93%); m.p. 210–
1
217 °C (dec.). H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.84
(s, 3 H), 2.65–2.92 (m, 8 H), 2.88 (s, 3 H), 2.96 (s, 3 H), 3.16–3.20
(m, 4 H), 3.50–3.80 (m, 8 H), 3.80–3.90 (m, 4 H), 4.45–4.80 (br. s,
1 H, NH), 5.42 (s, 1 H), 5.55–5.90 (br. s, 1 H, NH), 6.65 (s, 2 H),
7.56 (br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C):
δ = 16.1 (CH3), 35.7 (CH3), 37.4 (CH3), 49.0 (CH2), 51.8 (CH),
53.7 (CH2), 66.8 (CH2), 67.1 (CH2), 106.8 (CH), 122.5, 149.7,
151.7, 153.2, 157.1, 171.2 ppm. MS (ES+): m/z = 518 [M + H]+.
3-Ethyl-5-oxo-4-(2,4,6-trimorpholin-4-ylphenyl)-2,5-dihydro-1H-pyr-
azole-1-carboxamide (23): 0.027 g (55 %). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.11 (t, J = 7.5 Hz, 3 H), 2.37–3.46 (m, 14 H),
3.55–3.80 (m, 8 H), 3.82–4.00 (m, 4 H), 4.55–5.00 (br. s, 2 H, NH2),
6.43 (s, 2 H), 6.69 (br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz,
CDCl3, 25 °C): δ = 12.3 (CH3), 21.0 (CH2), 46.7(CH2), 49.2 (CH2),
52.2 (CH2), 66.8 (CH2), 66.9 (CH2), 67.4 (CH2), 99.9, 102.1 (CH),
103.1, 112.9, 143.8, 151.7, 152.1, 158.5 ppm. MS (ES+): m/z = 487
[M + H]+. C24H34N6O5 (486.6): calcd. C 59.24, H 7.04, N 17.27;
found C 59.30, H 7.06, N 17.21.
C
25H39N7O5 (517.6): calcd. C 58.01, H 7.59, N 18.94; found C
57.88, H 7.60, N 18.92.
3-[(Anilinocarbonyl)hydrazono]-N,N-dimethyl-2-(2,4,6-trimorpholin-
4-ylphenyl)butanamide (17): White solid; 0.058 g (65%); m.p. 177–
Cinnoline Derivatives 24–29: Sodium methoxide (0.2 mmol) was
added to a stirred solution of a semicarbazone (8–10 or 13–15,
0.1 mmol) in THF (2 mL). A red colour developed. The reaction
mixture was stirred until the disappearance of the red colour, and
the THF was then removed under reduced pressure. The crude ma-
terial was purified by FC on silica gel (eluents: light petroleum/
diethyl ether mixtures), and the pure cinnoline (24–29) was ob-
tained.
1
178 °C. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.95 (s, 3
H), 2.62–2.99 (m, 8 H), 2.89 (s, 3 H), 3.02 (s, 3 H), 3.16–3.22 (m,
4 H), 3.45–3.82 (m, 8 H), 3.82–3.98 (m, 4 H), 5.44 (s, 1 H), 6.72 (s,
2 H), 6.98–7.10 (m, 1 H), 7.20–7.28 (m, 4 H), 7.80 (br. s, 1 H, NH),
7.97 (br. s, 1 H, NH) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C):
δ = 16.5 (CH3), 35.7 (CH3), 37.5 (CH3), 49.0 (CH2), 52.0 (CH),
53.6 (CH2), 67.1 (CH2), 66.8 (CH2), 107.1 (CH), 118.6 (CH), 123.1
(CH), 128.9 (CH), 138.1, 150.0, 151.8, 153.1 (2ϫsig. overl.), 153.2,
171.0 ppm. MS (ES+): m/z:594 [M + H]+. C31H43N7O5 (593.7):
calcd. C 62.71, H 7.30, N 16.51; found C 62.69, H 7.32, N 16.47.
Ethyl 3-Methyl-5,7-dipiperidin-1-ylcinnoline-4-carboxylate (24):
Orange oil; 0.0275 g (72%). 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.40 (t, J = 7.2 Hz, 3 H), 1.44–1.88 (m, 12 H), 2.30–
3.05 (m, 2 H), 2.80 (s, 3 H), 2.93–3.02 (m, 2 H), 3.20–3.40 (m, 4 H),
4.21–4.34 (brm, 1 H), 4.55–4.77 (brm, 1 H), 7.36 (d, J = 2.5 Hz, 1
H), 7.49 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR (100.56 MHz, CDCl3,
25 °C): δ = 14.0 (CH3), 19.3 (CH3), 23.7 (CH2), 24.2 (CH2), 24.9
(br. s, CH2), 25.5 (CH2), 26.0 (br. s, CH2), 49.9 (CH2), 53.5 (br. s,
CH2), 57.5 (br. s, CH2), 61.5 (CH2), 106.5 (CH), 115.2, 118.5, 124.0,
147.5, 150.3, 152.2, 152.5, 168.2 ppm. MS (ES+): m/z = 383 [M +
H]+. C22H30N4O2 (382.5): calcd. C 69.08, H 7.91, N 14.65; found
C 69.11, H 7.93, N 14.62.
Pyrazolone Derivatives 20–23: An equimolar amount of sodium
methoxide was added at room temperature to a stirred solution of
semicarbazone derivative (8–10 and 13–15, 0.1 mmol) in MeOH
(2 mL). The solution became yellow. The mixture was stirred for
24–36 h, until disappearance of starting semicarbazone. The sol-
vent was removed under reduced pressure, and the crude material
was purified by column chromatography (elution with diethyl ether/
MeOH mixtures) to give pure pyrazolone derivatives 20–23.
3-Methyl-5-oxo-4-(2,4,6-tripiperidin-1-ylphenyl)-2,5-dihydro-1H-pyr-
azole-1-carboxamide (20): 0.036 g (77 % from 9). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.40–1.80 (m, 18 H), 2.27 (s, 3 H),
2.60–3.10 (m, 8 H), 3.10–3.20 (m, 4 H), 4.35–4.96 (br. s, 1 H, NH2),
5.10–5.55 (br. s, 1 H, NH2), 6.47 (s, 2 H), 6.52 (br. s, 1 H, NH) ppm.
1H NMR (400 MHz, CD3OD, 25 °C): δ = 1.65–1.97 (m, 18 H),
2.41 (s, 3 H), 2.90–3.01 (m, 8 H), 3.31–3.37 (m, 4 H), 6.72 (s, 2 H)
ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 13.4 (CH3), 24.2
(CH2), 24.3 (CH2), 26.0 (CH2), 26.1 (CH2), 50.7 (CH2), 53.5 (CH2),
101.4, 103.2 (CH), 103.8, 113.0, 139.2, 152.1, 153.1, 158.9 ppm. MS
(ES+): m/z = 467 [M + H]+. C26H38N6O2 (466.6): calcd. C 66.92,
H 8.21, N 18.01; found C 66.99, H 8.18, N 18.05.
Methyl 3-Methyl-5,7-dipiperidin-1-ylcinnoline-4-carboxylate (25):
Orange oil; 0.0331 g (90%). 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 1.40–2.10 (m, 12 H), 2.20–3.10 (m, 4 H), 2.78 (s, 3 H),
3.30–3.42 (m, 4 H), 4.01 (s, 3 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.50
(d, J = 2.4 Hz, 1 H) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C):
δ = 19.3 (CH3), 23.7 (CH2), 24.2 (CH2), 24.9 (br. s, CH2), 25.5
(CH2), 26.0 (br. s, CH2), 49.8 (CH2), 52.5 (CH3), 53.6 (br. s, CH2),
56.7 (br. s, CH2), 106.4 (CH), 115.2, 118.5 (CH), 123.9, 147.4,
150.2, 152.1, 152.5, 168.7 ppm. MS (ES+): m/z = 369 [M + H]+.
C21H28N4O2 (368.5): calcd. C 68.45, H 7.66, N 15.21; found C
68.49, H 7.64, N 15.18.
3-Ethyl-5-oxo-4-(2,4,6-tripiperidin-1-ylphenyl)-2,5-dihydro-1H-
pyrazole-1-carboxamide (21): 0.044 g (92%). 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 1.06 (t, J = 7.6 Hz, 3 H), 1.35–1.85 (m,
Methyl 3-Ethyl-5,7-dipiperidin-1-ylcinnoline-4-carboxylate (26):
Orange oil; 0.0176 g (46%). 1H NMR (400 MHz, CDCl3, 25 °C,
18 H), 2.60–3.10(m, 8 H), 2.80 (q, J = 7.6 Hz, 2 H), 3.10–3.20 (m, TMS): δ = 1.21 (t, J = 7.6 Hz, 3 H), 1.50–2.45 (m, 12 H), 2.70–
4 H), 4.45–5.00 (br. s, 2 H, NH2), 6.45 (s, 2 H), 6.48 (br. s, 1 H, 3.22 (m, 4 H), 3.05 (q, J = 7.6 Hz, 2 H), 3.32–3.42 (m, 4 H), 4.00
NH) ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 12.2 (CH3), (s, 3 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.51 (d, J = 2.4 Hz, 1 H) ppm.
21.1 (CH2), 24.2 (CH2), 24.3 (CH2), 26.0 (CH2), 26.2 (CH2), 50.7
(CH2), 53.4 (CH2), 100.4, 103.1 (CH), 103.8, 113.2, 144.2, 152.1,
13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 14.7 (CH3), 23.7
(CH2), 24.2 (CH2), 24.9 (br. s, CH2), 25.5 (CH2), 26.0 (br. s, CH2),
4364
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Eur. J. Org. Chem. 2008, 4357–4366

Useful Routes to New Pyrazolone and Cinnoline Derivatives
27.0 (CH2), 49.9 (CH2), 52.3 (CH3), 53.7 (br. s, CH2), 56.8 (br. s, form. After at least 2 d, the ratio between the two forms was about
CH2), 106.6 (CH), 115.2, 118.5 (CH), 123.2, 150.4, 152.1, 152.4,
80:20 and remained stable with time. A mixture containing com-
152.6, 168.6 ppm. MS (ES+): m/z = 383 [M + H]+. C22H30N4O2 pound 8 and its isomeric form was dissolved in CD3CN and moni-
(382.5): calcd. C 69.08, H 7.91, N 14.65; found C 69.05, H 7.92, N
14.67.
tored by VT 1H NMR experiments from –30 °C to +75 °C. Cooling
to –30 °C caused partial precipitation of starting materials, but the
spectrum showed an unmodified relative ratio of the two com-
pounds. Gradual heating caused redissolution of the solid, but the
relative product ratio remained unchanged. Because all attempts to
separate isomeric forms from the main compounds 8–10 and 13–15
by FC failed (in addition, during FC the formation of cyclization
products occurred), we report here only the 1H NMR signals of
minor isomers present in the spectra of the mixtures.
Ethyl 3-Methyl-5,7-dimorpholin-4-ylcinnoline-4-carboxylate (27):
Yellow solid; 0.0212 g (55%); m.p. 204–214 °C (dec.). 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 1.41 (t, J = 7.6 Hz, 3 H),
2.59–3.34 (m, 4 H), 2.83 (s, 3 H), 3.23–3.43 (m, 4 H), 3.55–3.90 (m,
4 H), 3.90–3.98 (m, 4 H), 4.38 (br. m, 1 H, CH2), 4.75 (br. m, 1 H,
1
CH2), 7.37 (d, J = 2.5 Hz, 1 H), 7.57 (d, J = 2.5 Hz, 1 H) ppm. H
NMR (400 MHz, [D6]DMSO, 115 °C): δ = 1.36 (t, J = 7.0 Hz, 3
H), 2.71 (s, 3 H), 2.77–2.99 (m, 4 H), 3.38–3.46 (m, 4 H), 3.62–3.80
(m, 4 H), 3.79–3.87 (m, 4 H), 4.50 (q, J = 7.0 Hz, 2 H), 7.45 (d, J
= 2.5 Hz, 1 H), 7.61 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR
(100.56 MHz, CDCl3, 25 °C): δ = 14.1 (CH3), 19.4 (CH3), 48.7
(CH2), 52.3 (br. s, CH2), 55.4 (br. s, CH2), 61.7 (CH2), 66.6 (CH2),
107.4 (CH), 115.2, 117.6 (CH), 123.8, 148.0, 149.0, 151.8 (2 signals
Isomer of Compound 8: 1H NMR (300 MHz, CDCl3, 25 °C, TMS):
δ = 1.28 (t, J = 7.1 Hz, 3 H), 1.40–1.76 (m, 18 H), 2.40 (s, 3 H),
2.50–2.90 (m, 8 H), 3.00–3.24 (m, 4 H), 4.33 (q, J = 7.1 Hz, 1 H),
4.41 (q, J = 7.1 Hz, 1 H), 5.15 (s, 1 H), 6.75 (s, 2 H), 8.35 (br. s, 1
H, exch.) 8.36 (br. s, 2 H, exch.) ppm.
Isomer of Compound 9: 1H NMR (300 MHz, CDCl3, 25 °C, TMS):
1.50–1.65 (m, 12 H), 1.65–1.80 (m, 6 H), 2.18 (s, 3 H), 2.55–2.90
(m, 8 H), 3.05–3.20 (m, 4 H), 3.72 (s, 3 H), 5.11 (s, 1 H), 6.67 (s, 2
H), 8.50 (br. s, 1 H, exch.) 8.71 (br. s, 2 H, exch.) ppm.
overlapped), 168.3 ppm. MS (ES+): m/z
= 387 [M +
H]+.
C20H26N4O4 (386.4): calcd. C 62.16, H 6.78, N 14.50; found C
62.21, H 6.80, N 14.53.
Methyl 3-Methyl-5,7-dimorpholin-4-ylcinnoline-4-carboxylate (28):
Yellow solid; 0.0153 g (41%); m.p. 201–209 °C (dec.). 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 2.60–3.30 (m, 4 H), 2.81 (s, 3
H), 3.30–3.45 (m, 4 H), 3.45–4.00 (m, 4 H), 3.90–3.96 (m, 4 H),
4.06 (s, 3 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.57 (d, J = 2.5 Hz, 1 H)
ppm. 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 19.5 (CH3), 48.7
(CH2), 52.5 (br. s, CH2), 52.6 (CH3), 55.3 (br. s, CH2), 66.6 (CH2),
107.3 (CH), 115.1, 117.6 (CH), 123.6, 148.0, 148.9, 151.76, 151.84,
168.8 ppm. MS (ES+): m/z = 373 [M + H]+. HRMS calcd. for
C19H24N4O4 372.17976; found 372.1799. C19H24N4O4 (372.4):
calcd. C 61.28, H 6.50, N 15.04; found C 61.25, H 6.51, N 15.00.
Isomer of Compound 10: 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 1.13 (t, J = 7.5 Hz, 3 H), 1.40–1.90 (m, 18 H), 2.15–
2.30 (dq, J = 7.5 Hz, 1 H), 2.37–2.51 (dq, J = 7.5 Hz, 1 H), 2.58–
3.08 (m, 8 H), 3.08–3.28 (m, 4 H), 3.70 (s, 3 H), 5.13 (s, 1 H), 6.67
(s, 2 H), 8.50 (br. s, 1 H, exch.), 8.95 (br. s, 2 H, exch.) ppm.
Isomer of Compound 13: 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 1.28 (t, J = 7.2 Hz, 3 H), 2.40 (s, 3 H), 2.45–3.20 (m, 8
H), 3.12–3.20 (m, 4 H), 3.61–3.93 (m, 12 H), 4.12 (q, J = 7.1 Hz,
1 H), 4.26 (q, J = 7.1 Hz, 1 H), 5.16 (s, 1 H), 6.70 (s, 2 H), 8.37
(br. s, 1 H, exch.) ppm.
Isomer of Compound 14: 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 2.17 (s, 3 H), 2.68–2.92 (m, 8 H), 3.11–3.22 (m, 4 H),
3.62–3.80 (m, 8 H), 3.73 (s, 3 H), 3.80–3.98 (m, 4 H), 5.15 (s, 1 H),
6.70 (s, 2 H), 8.55 (br. s, 1 H, exch.) ppm.
Methyl 3-Ethyl-5,7-dimorpholin-4-ylcinnoline-4-carboxylate (29):
Yellow solid; 0.0178 g (46%); m.p. 214–224 °C (dec.). 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 1.43 (t, J = 7.6 Hz, 3 H),
2.58–3.35 (m, 4 H), 3.06 (q, J = 7.6 Hz, 2 H), 3.32–3.41 (m, 4 H),
3.62–4.00 (m, 4 H), 3.90–3.96 (m, 4 H), 4.05 (s, 3 H), 7.37 (d, J =
2.5 Hz, 1 H), 7.58 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR
Isomer of Compound 15: 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 1.09 (t, J = 7.7 Hz, 3 H), 2.24–2.40 (m, 1 H), 2.41–2.61
(m, 1 H), 2.62–3.05 (m, 8 H), 3.12–3.22 (m, 4 H), 3.56–3.78 (m, 8
H), 3.72 (s, 3 H), 3.83–3.92 (m, 4 H), 5.21 (s, 1 H), 6.70 (s, 2 H),
8.77 (br. s, 1 H, exch.), 8.99 (br. s, 2 H, exch.) ppm.
(100.56 MHz, CDCl3, 25 °C):
δ = 14.7 (CH3), 27.1 (CH2),
48.7(CH2), 52.4 (br. s, CH2), 52.5 (CH3), 55.4 (br. s, CH2), 66.6
(CH2), 107.5 (CH), 115.1, 117.5 (CH), 123.0, 149.1, 151.7, 151.9,
152.9, 168.7 ppm. MS (ES+): m/z = 387 [M + H]+. C20H26N4O4
(386.4): calcd. C 62.16, H 6.78, N 14.50; found C 62.19, H 6.79, N
14.48.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for compounds 5–17 and 20–29 and
1
copies of H and 13C NMR spectra of new compounds 8–17, and
Study on the Formation of Semicarbazone Derivatives 8 and 13:
Compound 3 (0.030 mmol), dissolved in CD3CN (0.5 mL), was
added at –30 °C to an equimolar amount of 1 (or 2, in 0.5 mL of
20–29.
1
CD3CN) directly in an NMR tube. The H NMR spectrum of the
Acknowledgments
obtained solution showed the disappearance of the signals of the
starting materials and the appearance of new signals, attributable
to compound 8 (or 13). The reaction was monitored over 2 h. The
same reaction was also carried out in CD3CN at 25 °C, in CDCl3
at –30 °C and at 25 °C and in CD2Cl2 at –70 °C. In all cases no
evidence of formation of Wheland complexes was obtained, but
after about 1 h new stable signals, ascribed to an isomeric form of
8 (or 13), appeared (see following paragraph).
This work was supported by ALMA MATER STUDIORUM –
University of Bologna (ex-60% MIUR), funds for a fellowship to
the memory of Alessandro Zucchelli, University of Urbino, and
MIUR-PRIN.
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Eur. J. Org. Chem. 2008, 4357–4366
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Published Online: July 17, 2008
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