Highly-substituted pyrazoles and pyridazines by MIRC reactions of hydrazone anions and nitrobutadienic fragments

Article abstract of DOI:10.1016/j.tetlet.2012.09.040

In prosecution of the synthetic exploitation of nitrobutadienes deriving from the initial ring-opening of nitrothiophenes, their multifaceted behavior finds a further clear-cut example in their Michael-type acceptor reactivity toward the anions of α-oxohy

Full text of DOI:10.1016/j.tetlet.2012.09.040

Tetrahedron Letters 53 (2012) 6394–6400
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly-substituted pyrazoles and pyridazines by MIRC reactions
of hydrazone anions and nitrobutadienic fragments
Lara Bianchi, Alessandro Carloni-Garaventa, Massimo Maccagno, Giovanni Petrillo, Carlo Scapolla,
⇑
Cinzia Tavani
Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2012
Revised 5 September 2012
Accepted 11 September 2012
Available online 18 September 2012
In prosecution of the synthetic exploitation of nitrobutadienes deriving from the initial ring-opening of
nitrothiophenes, their multifaceted behavior finds a further clear-cut example in their Michael-type
acceptor reactivity toward the anions of
a-oxohydrazones. Thus, depending on the starting diene, new
poly-functionalized pyrazoles are obtained. Furthermore, most interestingly, in one occasion a dichotomy
has been observed, depending on the nature of the Michael-type donor, leading with complete selectivity
to either 5-member or 6-member N-heterocycles. The outcome encompasses motifs for both mechanistic
and synthetic interest, for example, in the field of heterocycles endowed with possible pharmacological/
biological activity.
Keywords:
Nitrobutadienes
Nitrogen heterocycles
Pyrazoles
Ó 2012 Elsevier Ltd. All rights reserved.
Pyridazines
Michael-type additions
The ring-opening of 3,4-dinitrothiophene,1 2-nitrothiophene,2
and variously functionalized 3-nitrothiophenes3 has been for our
research group a valuable source of a pool of nitrobutadienic build-
ing-blocks which, differing by typology, number and/or position of
the substituents, exhibit a multi-faceted set of properties,4 not al-
ways predictable on the grounds of the well-known and much
more exploited behavior of the isolated nitrovinyl moiety.5
As an example, the concurrence of an arylnitroethenyl moiety
and a conjugated double bond has led to promising pharmacolog-
ical results regarding 2-nitro-1,3-dienes in the field of cancer
therapy.6
In particular, one rewarding application of such building-blocks
hinges upon the possibility to assemble heterocyclic structures in a
highly atom-economic way: thus, starting from a substituted
thiophene, the whole process can be envisaged as a ring-opening/
ring-closing protocol, sometimes involving a ring expansion, which
preserves all of the four original thiophenic carbons (Scheme 1).7
For such a goal, we became more recently interested in reac-
tions that allow the construction of the final heterocycle after an
initial intermolecular Michael-type addition on the nitrovinylic
moiety of our nitrobutadienes, a synthetic approach sometimes
indicated as a MIRC process.8
subject;9 this is because pyrazole derivatives exhibit a wide range
of biological properties, as represented, for instance, by anti-
hyperglycemic, anti-inflammatory, anti-obesity, or antitumor
activities.10
Among the plethora of more or less classic synthetic methods,11
the addition of hydrazones or hydrazone anions to nitrovinylic
systems has been recently described as an initial intermolecular
Michael-type process eventually providing a useful regioselective
access to 1,3,4- or 1,3,5-substituted pyrazoles.12 With the aim of
exploring and broadening the utility of this kind of approach, also
by decorating the heterocycle with functional groups which could
be of value in the perspective of further elaboration, we decided to
apply to different nitrobutadienic systems (1–4, Chart 1)13 the
NO2
heterocyclic target
X
Y
S
ring-opening
ring-closure
In the vast field of heterocycles, one surely appealing target is
the construction of the pyrazole nucleus, whose outstanding inter-
est is testified by the impressive number of publications on the
properly-functionalized
intermediate
building-block from
thiophene-ring opening
⇑
Corresponding author.
E-mail address: cinzia.tavani@unige.it (C. Tavani).
Scheme 1. Ring-opening/ring-closing protocol for heterocyclic synthesis from
nitrothiophenes.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.040

L. Bianchi et al. / Tetrahedron Letters 53 (2012) 6394–6400
6395
reaction with the
a
-COZ-substituted hydrazones 5a–d (Z = NMe2,16
(the oxidizing agent being most likely represented by the just elim-
inated nitrous acid) eventually lead to the expected12 pyrazoles
6a–d.
As reported in Scheme 3, the yield is satisfactory when Z = NMe2
and OBut, still acceptable in the case of Z = Ph, but unfortunately
drops to a disappointing value when Z = Me.
OBut,16 Ph,17 and Me,17 respectively), easily obtainable by a meth-
odology developed some years ago by some of us. The coupling,
whose expected outcome is depicted in Scheme 2, should allow
the synthesis of polysubstituted pyrazoles bearing, in particular,
a versatile 3-COZ functionality.18
The preliminary results herein (synthetically collected in the
Table at the end of the discussion for an easy, overall view) enlight-
en the general fulfillment of our expectations, guaranteeing for the
success of a synthetic approach which is furthermore accompanied
by some unexpected, likewise rewarding, outcomes: the latter
surely contribute in turn to further enlarge the range of heterocy-
cles accessible from our building-blocks.
The postulated pyrazolidinic intermediate 8 was actually iso-
lated in a few cases,20 confirming the occurrence of an apparently
unfavored 5-endo-trig reversible cyclization process, which is
effectively driven ahead by the strong acidic quencher (step iii).
For the anionic Michael adduct 7 it cannot be in principle ex-
cluded the concurrence of a charge-transfer equilibration between
the NO2-bound and the COZ-bound carbons (cf. the equilibration
between 13 and 130 or 1300 further in the text), that could assume
Typically,19 a THF solution of the nitrobutadiene was added to a
molar equivalent of the preformed (ButOK) hydrazone anion in THF
at ꢀ78 °C. After disappearance of the diene (TLC), trifluoroacetic
acid (TFA, 5 mol equiv) was added and the system left to react
for some time before allowing to reach room temperature for final
work-up.
The relevant results described below are strongly dependent on
the nitrobutadiene and, in some measure, on the hydrazone.
Nitrobutadiene 1, which was tested first, behaves, in the initial
step of the proposed mechanism (Scheme 3), as a plain nitrovinylic
Michael-type acceptor, and the conjugate addition of the hydra-
zone anion (step i) is followed by cyclization of the resulting nitr-
onate onto the electrophilic nitrogen of the diazo group (step ii).
After the acidic quenching (step iii),12a the elimination of nitrous
acid (step iv) followed by an oxidative aromatization (step v)
more importance depending on the acidity of the proton
a to
COZ. Actually, yield-reducing competitive pathways could well
play a role, contributing to explain the less satisfactory results
observed when Z is phenyl or methyl.
For nitrobutadiene 2, where a much more electron-withdrawing
sulfonyl group replaces the sulfanyl one, strongly increasing the
electrophilicity of the nitrovinyl moiety, a preliminary test with
hydrazone 5a disappointingly led to a rather complex mixture of
products, from which only the (E)-N,N-dimethyl-4-(4-methylsty-
ryl)-1-p-tolyl-1H-pyrazole-3-carboxamide (9a, Scheme 4) could
be isolated and identified, although in very modest yields (13%). A
search for more suitable experimental conditions is under way. It
seems anyway remarkable that 9a presents only three ring substit-
uents: as a matter of fact, two successive b-elimination processes
O2N
MeS
O2N
O2N
O2N
MeSO2
MeS
MeSO2
p-Tol
p-Tol
p-Tol
p-Tol
1
2
3
4
Chart 1. Nitrobutadienes employed in the reaction of Scheme 2.
O
O
O2N
X
1) ButOK, THF, -78°C
N
N
Z
+
p-Tol
N
N
H
p -Tol
Z
2) TFA
Y
Y
1: X = SMe; Y = -CH=CH-p-Tol (E)
5a
: Z = NMe2
X
5b: Z = OBut
2
: X = SO2Me; Y = -CH=CH-p-Tol (E)
3: X = -CH=CH-SMe (Z); Y = p-Tol
5c
5d
: Z = Ph
4: X = -CH=CH-SO2Me (Z); Y = p-Tol
: Z = Me
Scheme 2. Pyrazoles expected from the reactions between nitrobutadienes 1–4 and
a
-oxo-hydrazones 5a–d under basic conditions, followed by acidic quenching.12
O
6a
6b
N
: 70%
: 61%
Z
O
p-Tol
ButOK
N
TFA
6c: 54%
6d: 19%
1
5
N
p-Tol
N
Z
p-Tol
THF, -78 °C
6a-d
MeS
- H2
(v)
(i)
O
- HNO2
O
(iv)
O
Z
N
H
p-Tol
(iii)
p-Tol
p-Tol
MeS
N
N
(ii)
Z
Z
N
N
p-Tol
N
MeS
NO2
p-Tol
p-Tol
7
NO2
8
MeS
NO2
Scheme 3. Formation of pyrazoles 6a–d, according to the mechanistic rationalization advanced in ref. 12a.

6396
L. Bianchi et al. / Tetrahedron Letters 53 (2012) 6394–6400
O
O
1) ButOK, THF, -78 °C
p-Tol
N
(as the only product
N
N
Z
2) 2 (1 mol equiv.)
NMe2
p-Tol
separable from a
complex mixture of
unidentified
5a
p-Tol
N
3) TFA (excess)
p-Tol
compounds)
9a
: 13%
MeS
NO2
Scheme 4. Trisubstituted pyrazole 9a from the reaction of 5a-anion and nitrobut-
adiene 2.
Chart 2. Charge delocalization in the intermediate nitronate from the reaction
between 3 and 5.
most likely occur, the loss of methanesulfinic acid (MeSO2H) for-
mally ‘replacing’ the final oxidative step of Scheme 3.
ety of 4. First of all, such a carbanion appears more stabilized than
in all of the previous cases examined, as it effectively delocalizes its
charge not only on the nitrogroup, but also on the sulfonyl vinyl
moiety. Such an occurrence reasonably allows to the anion a life-
time long enough so that, as an alternative to the expected unfa-
vored 5-endo-trig cyclization to pyrazole, it could also equilibrate
with 130 or 1300 (Scheme 7) by transfer of the negative charge to
the position adjacent to the COZ moiety. The new anion (130 should
be the preferred structure, on the grounds of the alleged7b,d,e higher
stability of a nitrovinyl with respect to a sulfonylvinyl moiety,
although 1300 cannot be excluded) seems to have definitely more
chance to exist when the carbonyl involved is that of a ketone,
rather than that of an amide or of an ester, due to the higher ability
of the former to contribute to the stabilization of an adjacent neg-
ative charge.
The expected cyclization to pyrazoles is smoothly obtained, in-
stead, with nitrobutadiene 3, whereby two main products (10 and
100: Scheme 5) can be isolated from the final mixture, as a result of
a partial cis to trans isomerization at the remaining double bond of
the original nitrodiene array, the presumably more stable trans iso-
mer 100 generally overcoming the cis-isomer 10.
A possible rationale for such a configurational scrambling may
be searched in the involvement of the double bond undergoing
isomerization in the delocalization of the negative charge of the
intermediate nitronate (Chart 2), although its timing is presently
under closer investigation.
The isolation of much unreacted materials (ca. 44% of both
diene and hydrazone) from the reaction with
a-hydrazonoketone
5c under the usual conditions, prompted us to perform preliminary
attempts in search for optimization. While the increase of the reac-
tion time led to only minor variations in the overall outcome, it
was found that the rising of the temperature of steps 2 and 3
(Scheme 5) to -30 °C almost doubles the yield (50% for the cis/trans
mixture; 60% with respect to the reacted diene). Interestingly en-
ough, the diastereomeric ratio is, in this case, significantly in favor
of the cis isomer (ca. 70:30): a result which surely hinges on the
timing of the isomerization.
On the 130 (or 1300) anion, an electronically-inverted cyclization
process becomes possible, whereby a nucleophilic hydrazone an-
ion couples with an electrophilic nitrovinyl (or sulfonylvinyl) moi-
ety, easily providing a six-membered ring: thus, a 6-endo or,
possibly, a 6-exo intramolecular cyclization ways are in principle
recognizable, leading to the same final outcome.
A goal of undeniable significance from a preparative point of
view is represented by the almost quantitative formation of
12c,d when performing the whole process at 0 °C, under otherwise
identical experimental conditions (see Scheme 6): a result which
can be tentatively attributed to a more effective completion of
the overall process, with concurrent depletion of unidentified side
materials. It is worth mentioning that, as experimentally verified,
within the dichotomy of Scheme 6, a temperature increase does
not seem to either influence the dichotomy itself, or favor the for-
mation of for example, pyrazole 11b.
To our surprise, the sulfonyl-activated nitrobutadiene 4 exhibits
a much more interesting dichotomic behavior (Scheme 6), depend-
ing on the nature of Z in the COZ moiety of the hydrazone. As a
matter of fact, with the anions of
a-hydrazonoamide 5a and of
a-hydrazonoester 5b, pyrazoles (11a and 11b, respectively) are ob-
tained in good yields, herein characterized by a complete inversion
of the exocyclic C@C double-bond configuration; on the other
hand, quite unexpectedly, from the reactions with the anions of
A different attempt to drive the system toward the 6-member
heterocycle hinges upon the possibility to affect the competition
set up at the level of the intermediate anion in Scheme 7 by accel-
erating the proton transfer from 13 to 130 (or 1300), for example in a
protic solvent. As a matter of fact, the treatment of an equimolar
4 + 5 mixture with DBU (1 mol equiv) in refluxing ethanol21 effec-
tively leads to the 2,3-dihydropyridazino moiety 14, independently
on the nature of 5 (Scheme 8 and Table 1). The corresponding tetr-
ahydropyridazines 12 seem the most likely precursors, which
a
-hydrazonoketones 5c,d tetrahydropyridazines (12c and 12d,
respectively) are formed (Scheme 6), almost exclusively as single
diastereoisomers out of the three possible ones, whose configura-
tion has not been defined yet. Interestingly enough, the chemose-
lectivity is complete, no significant amounts of 12a,b or of 11c,d
having been detected under the conditions employed.
In order to understand the rationale of such a dichotomy, we
should consider the fate of the nitronate 13 (Scheme 7) deriving
from the attack of the hydrazone anion onto the nitrovinylic moi-
O
O
1) ButOK, THF, - 78 °C
N
N
Z
Z
2) 3 (1 mol equiv.)
5a-d
N
p-Tol
N
p-Tol
3) TFA (excess)
MeS
p-Tol
p-Tol
10'a-d
10a-d
MeS
10a + 10'a: 66% (25:75)
10b 10'b
+
: 52% (54:46)
10c 10'c
*
+
: 26% (32:68)
10d 10'd
+
: 74% (36:64)
*
5c
44% of unreacted diene, as well as of , also recovered
Scheme 5. Results obtained in the reactions of 5a–d anions with nitrobutadiene 3.

L. Bianchi et al. / Tetrahedron Letters 53 (2012) 6394–6400
6397
O
N
Z
p-Tol
N
11a
a
: 98%
: Z = NMe2
t
11b: 50%
b
: Z = OBu
p-Tol
1) ButOK, THF, -78 °C
2) 4 (1 mol equiv.)
MeO2S
5a-d
O
3) TFA (excess)
c
: Z = Ph
p-Tol
MeO2S
N
d: Z = Me
12c
: 59%*
Z
N
12d: 65%*
p-Tol
NO2
* A quite rewarding quantitative yield is obtained when salification (step1), coupling (step 2),
and quenching (step 3) are carried out at 0 °C, under otherwise identical experimental conditions.
Scheme 6. Dichotomy in the reaction between 4 and 5, sharply dependent on the structure of 5.
O
N
Z
+
H
p-Tol
N
11a b
,
p-Tol
MeO2S
NO2
Z = NMe2, OBut
5-endo-trig
O
O
O
p-Tol
p-Tol
N
N
p-Tol
N
Z
Z
N
N
N
Z
p-Tol
13'
p-Tol
13"
p-Tol
13
MeO2S
SO Me
SO Me
2
NO2
NO2
NO2
2
6-exo-trig
6-endo-trig
Z = Ph, Me
O
Z = Ph, Me
O
p -Tol
p -Tol
N
N
Z
Z
N
N
+ H
+ H
12c d
,
p-Tol
p-Tol
SO Me
2
SO Me
2
NO2
NO2
Scheme 7. A proposed rationale behind the observed dichotomic behavior of nitrobutadiene 4.
O
O
Z = Ph, Me
N
p-Tol
-Tol
p
N
N
H
Z
N
Z
experimental conditions: ref. 19
5a-d
MeO2S
+
NO2
-Tol
p
Piperidine, EtOH, reflux
DBU, EtOH, reflux
SO2Me
12c,d
NO2
p-Tol
O
4
experimental
conditions: ref. 21
-Tol
c: Z = Ph
d: Z = Me
p
N
N
Z
MeO2S
p-Tol
14a-d
Scheme 8. Dihydro- and tetrahydropyridazines from reactions of 5 and 4.
would undergo b-elimination of HNO2 in the basic medium to af-
ford the final conjugated azadiene. To confirm this very last point,
we have also successfully verified the feasibility of HNO2 elimina-
tion from 12c,d to obtain 14c,d with an alternative two-step route:
the use of piperidine in refluxing ethanol leading to an almost
quantitative smooth conversion in both cases (see Scheme 8).
In conclusion we feel that the preliminary results reported
herein represent further significant example of the very
interesting behavior, from the standpoint of both synthetic and
mechanistic aspects, of the nitrosubstituted conjugated butadienic
building-blocks of Chart 1. Once again,7 their synthetic versatility
is mirrored by the dependence of the final outcome on structural
a

6398
L. Bianchi et al. / Tetrahedron Letters 53 (2012) 6394–6400
Table 1
Overview of the main results obtained from the reactions of nitrobutadienes 1, 3, and 4 with hydrazones 5a–d under the conditions of ref.19, if not differently specified
O
O
O
O
Hydrazone
N
p-Tol
p-Tol
N
p-Tol
p-Tol
N
p-Tol
p-Tol
N
p-Tol
p-Tol
ButO
Ph
Me
Me2N
N
H
N
H
N
H
N
H
Michael
Acceptor
5b
5c
5d
5a
O
O
O
O
N
N
N
N
NO2
SMe
Me
Me2N
ButO
Ph
N
N
N
N
SMe
SMe
SMe
SMe
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
1
6a: 70%
6b: 61%
6c: 54%
6d: 19%
O
O
O
O
N
N
NO2
N
N
N
N
Ph
p-Tol
SMe
ButO
Me
Me2N
p-Tol
p-Tol
p-Tol
N
N
SMe
SMe
SMe
SMe
p-Tol
p-Tol
p-Tol
p-Tol
3
10c+10’c: 50%
10a+10’a: 66%
10b+10’b: 52%
10d+10’d: 74%
(60%)a
O
O
O
O
N
p-Tol
N
N
N
p-Tol
Me
Me2N
ButO
N
Ph
p-Tol
p-Tol
p-Tol
N
N
N
p-Tol
p-Tol
p-Tol
SO2Me
SO2Me
NO2
NO2
SO2Me
SO2Me
NO2
SO2Me
12d: 98%b
12c: 98%b
11a: 98%
11b: 50%
p-Tol
O
O
O
4
O
p-Tol
MeO2S
N
N
p-Tol
MeO2S
p-Tol
MeO2S
N
p-Tol
N
NMe2
p-Tol
OBut
Ph
p-Tol
Me
p-Tol
N
N
N
N
MeO2S
p-Tol
14a:71% c
14b: 80% c
14d: 81% c
14c: 72% c
aReaction carried out at ꢀ30 °C (see text); the yield in parentheses refers to the reacted substrate.
bReaction carried out at 0 °C (see Scheme 6).
cExperimental conditions: see ref. 21.
1990, 31, 4933–4936; (c) Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro,
P. Tetrahedron 1992, 48, 4407–4418.
2. Guanti, G.; Dell’Erba, C.; Leandri, G.; Thea, S. J. Chem. Soc., Perkin Trans. 1 1974,
2357–2360.
3. (a) Surange, S. S.; Kumaran, G.; Rajappa, S.; Rajalakshmi, K.; Pattabhi, V.
Tetrahedron 1997, 53, 8531–8540; (b) Dell’Erba, C.; Gabellini, A.; Novi, M.;
Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159–
8165.
4. (a) Bianchi, L.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Spinelli, D.; Tavani, C.
2,3-Dinitro-1,3-butadienes: versatile building blocks from the ring opening of
3,4-dinitrothiophene In Targets in Heterocyclic Systems: Chemistry and
Properties; Attanasi, O. A., Spinelli, D., Eds.; Società Chimica Italiana: Rome,
2007; Vol. 10 (2006), pp 1–23; (b) Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C.
Synthetic Exploitation of the Ring-Opening of 3,4-Dinitrothiophene In Topics in
heterocyclic systems: synthesis, reactions, and properties; Attanasi, O. A., Spinelli,
D., Eds.; Research Signpost Trivandrum: India, 1996; Vol 1, pp 1–12; (c)
Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.;
Spinelli, D.; Tavani, C.; Viale, M. Versatile building-blocks from the ring-
opening of 2- and 3-nitrothiophenes In Targets in Heterocyclic Systems:
Chemistry and Properties, Attanasi; Attanasi, O. A., Spinelli, D., Eds.; Società
Chimica Italiana: Rome, 2008; Vol. 11(2007), pp 1–20; (d) Bianchi, L.; Dell’Erba,
C.; Maccagno, M.; Morganti, S.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.;
Spinelli, D.; Tavani, C. ARKIVOC 2006, 7, 169–185.
and/or electronic factors. Herein, an additional variable is repre-
sented by the Michael-type donors, whose carbonyl (COZ) moiety
causes in turn, at least in one case (cf. Scheme 6), an appealing
dichotomic behavior, definitely enriching the pool of heterocycles
which can be assembled via the overall ring-opening/ring-closing
protocol of Scheme 1. Finally, the same COZ functionality charac-
terizes all of the heterocycles formed as a potentially powerful tool
for further manipulation.18
Acknowledgments
Financial support was provided by grants from Ministero
dell’Istruzione, dell’Università e della Ricerca (MIUR-Roma, PRIN
20085E2LXC).
References and notes
1. (a) Dell’Erba, C.; Spinelli, D.; Leandri, G. J. Chem. Soc., Chem. Commun. 1969, 549;
(b) Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron Lett.
5. (a) Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N. Eur. J. Org. Chem.
2009, 4091–4101; (b) Rai, V.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2006,

L. Bianchi et al. / Tetrahedron Letters 53 (2012) 6394–6400
6399
4693–4703; (c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877–1894.
(E)-N,N-Dimethyl-4-(4-methylstyryl)-5-(methylthio)-1-p-tolyl-1H-pyrazole-3-
carboxamide (6a). Yellow solid, mp 138–139 °C (light petroleum); 1H NMR
(CDCl3) d 2.13 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 3.04 (3H, s), 3.16 (3H, s), 7.13–
7.18 (4H, m), 7.29 (2H, d, J 8.1 Hz), 7.41 (2H, d, J 8.1 Hz), 7.48 (2H, d, J 8.4 Hz);
13C NMR (CDCl3) d 18.89, 21.22, 21.25, 35.16, 38.63, 116.58, 122.73, 125.45,
126.36, 129.33, 129.46, 130.46, 133.76, 134.88, 136.64, 137.54, 138.53, 144.77,
165.51. GC–MS: Rt 19.19, m/z 391(100)[M+ꢁ], 344(11), 331(23), 273(12),
154(15), 105(19), 91(12), 72(31), 65(11), 32(13).
6. (a) Viale, M.; Petrillo, G.; Maccagno, M.; Castagnola, P.; Aiello, C.; Cordazzo, C.;
Mariggiò, M. A.; Jadhav, S. A.; Bianchi, L.; Leto, G.; Rizzato, E.; Poggi, A.; Spinelli,
D. Eur. J. Pharmacol. 2008, 588, 47–51; (b) Petrillo, G.; Mariggiò, M. A.; Fenoglio,
C.; Aiello, C.; Cordazzo, C.; Morganti, S.; Rizzato, E.; Spinelli, D.; Maccagno, M.;
Bianchi, L.; Prevosto, C.; Tavani, C.; Viale, M. Bioorg. Med. Chem. Lett. 2008, 16,
240–247; (c) Viale, M.; Petrillo, G.; Aiello, C.; Fenoglio, C.; Cordazzo, C.;
Mariggiò, M. A.; Cassano, A.; Prevosto, C.; Ognio, E.; Maccagno, M.; Bianchi, L.;
Vaccarone, R.; Rizzato, E.; Spinelli, D. Pharmacol. Res. 2007, 56, 318–328.
7. (a) Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Scapolla, C.; Tavani, C.
Tetrahedron Lett. 2012, 53, 752–757; (b) Bianchi, L.; Maccagno, M.; Petrillo, G.;
Rizzato, E.; Sancassan, F.; Spinelli, D.; Tavani, C. Tetrahedron 2011, 67, 8160–8169;
(c) Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Severi, E.;
Spinelli, D.; Stenta, M.; Tavani, C. Chem. Eur. J. 2010, 16, 1312–1318; (d) Bianchi,
L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.;
Stenta, M.; Galatini, A.; Tavani, C. Tetrahedron 2009, 65, 336–343; (e) Bianchi, L.;
Dell’Erba, C.; Maccagno, M.; Morganti, S.; Novi, M.; Petrillo, G.; Rizzato, E.;
Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Tetrahedron 2004, 60, 4967–4973.
8. (a) Dumez, E.; Durand, A. C.; Guillaume, M.; Roger, P. Y.; Faure, R.; Pons, J. M.;
Herbette, G.; Dulcère, J. P.; Bonne, D.; Rodriguez, J. Chem. Eur. J. 2009, 15,
12470–12488; (b) Prempree, P.; Radviroongit, S.; Thebtaranonth, Y. J. Org.
Chem. 1983, 48, 3553–3556; (c) Little, R. D.; Dawson, J. R. Tetrahedron Lett.
1980, 21, 2609–2612.
(E)-tert-Butyl
4-(4-methylstyryl)-5-(methylthio)-1-p-tolyl-1H-pyrazole-3-
carboxylate (6b). Yellow solid, mp 130–131 °C (light petroleum); 1H NMR
(CDCl3) d 1.64 (9H, s), 2.11 (3H, s), 2.37 (3H, s), 2.43 (3H, s), 7.18 (2H, d, J
9.0 Hz), 7.29 (2H, d, J 9.0 Hz), 7.46 (4H, two overlapped d, J 9.0 Hz), 7.52 (2H, AB
system, J 18.6 Hz); 13C NMR (CDCl3) d 18.37, 21.29 (two isochronous carbons),
28.33, 82.06, 117.36, 125.01, 126.02, 126.36, 129.37 (two couples of
isochronous carbons), 131.99, 133.89, 135.02, 136.65, 137.55, 138.93, 142.46,
161.96. MS (ESI): m/z 421 [M+H]+, 443 [M+Na]+, 459 [M+K]+.
(E)-3-Benzoyl-(4-methylstyryl)-5-(methylthio)-1-p-tolyl-1H-pyrazole
(6c).
Yellow solid, mp 121–122 °C (light petroleum); 1H NMR (CDCl3) d 2.18 (3H,
s), 2.36 (3H, s), 2.44 (3H, s), 7.17 (2H, d, J 9.0 Hz), 7.32 (2H, d, J 9.0 Hz), 7.42–
7.59 (9H, m), 8.13–8.19 (2H, m); 13C NMR (CDCl3)
d 18.43, 21.29 (two
isochronous carbons), 117.07, 125.80, 126.10, 126.52, 128.14, 129.30, 129.53,
130.73, 132.34, 132.79, 134.29, 134.95, 136.66, 137.59, 137.71, 139.03, 147.35,
189.75. GC–MS: Rt 13.48, m/z 424(79) [M+ꢁ], 105(100), 77(55).
(E)-3-Acetyl-4-(4-methylstyryl)-5-(methylthio)-1-p-tolyl-1H-pyrazole
(6d).
9. Among the most recent articles, see e.g. (a) Santos, C. M. M.; Silva, A. M. S.; Jeko,
Yellow solid, mp 132–133 °C (EtOH); 1H NMR (CDCl3) d 2.13 (3H, s), 2.37
(3H, s), 2.46 (3H, s), 2.65 (3H, s), 7.18 (2H, d, J 7.8 Hz), 7.34 (2H, d, J 8.1 Hz),
7.45–7.51 (4H, two partly overlapped d, J 8.1 and 8.4 Hz), 7.67 (2H, AB system, J
17.1 Hz); 13C NMR (CDCl3) d 18.36, 21.30 (two isochronous carbons), 27.70,
117.27, 124.79, 125.82, 126.58, 129.31, 129.60, 132.66, 134.58, 135.04, 136.66,
137.60, 139.18, 147.48, 195.50. GC–MS: Rt 6.60, m/z 362(100) [M+ꢁ], 305(28),
272(19), 154(11), 91(16), 65(17), 43(44).
}
J.; Lévai, A. ARKIVOC 2012, 5, 265–281; (b) Wu, L.-L.; Ge, Y.-C.; He, T.; Zhang, L.;
Fu, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X. Synthesis 2012, 44, 1577–1583; (c)
Chandanshive, J. Z.; Gonzalez, P. B.; Tiznado, W.; Bonini, B. F.; Caballero, J.;
Femoni, C.; Comes Franchini, M. Tetrahedron 2012, 68, 3319–3328; (d)
Yamamoto, S.; Tomita, N.; Suzuki, Y.; Suzaki, T.; Kaku, T.; Hara, T.; Yamaoka,
M.; Kanzaki, N.; Hasuoka, A.; Baba, A.; Ito, M. Bioorg. Med. Chem. 2012, 20,
2338–2352; For recent review, see e.g. (e) Elguero, J.; Silva, A. M. S.; Tomé, A. C.
Five membered heterocycles: 1,2-azoles. part 1. pyrazoles In Modern
Heterocyclic Chemistry Chapter 8; Alvarez-Builla, J. A., Vaquero, J. J., Barluenga,
J., Eds.; Wiley-VCH: Weinheim, 2011; Vol. 2, pp 635–725; (f) Yet, L. ‘‘Pyrazoles’’
In: Joule, J. A. (Ed.), in Comprehensive Heterocyclic Chemistry III (series Eds.
Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.), Elsevier, Oxford,
2008, Chapter 4.01, Vol. 4, pp 1-141.
(E)-N,N-Dimethyl-4-(4-methylstyryl)-1-p-tolyl-1H-pyrazole-3-carboxamide (9a).
The compound was obtained in very small quantities and could not be fully
characterized;1H NMR (CDCl3) d 2.34 (3H, s), 2.40 (3H, s), 3.17 (3H, s), 3.22 (3H,
s), 6.88 (1H, d, J 16.5 Hz), 7.12-7.20 (3H, two partly overlapped d, J 8.1 and
16.5 Hz), 7.26 (2H, d, J 8.1 Hz), 7.37 (2H, d, J 8.1 Hz), 7.59 (2H, d, J 8.4 Hz), 8.08
(1H, s).
(Z)-N,N-Dimethyl-5-(2-(methylthio)vinyl)-1,4-di-p-tolyl-1H-pyrazole-3-carboxamide
(10a). White solid, mp 195.6–196.8 °C (EtOH); 1H NMR (CDCl3) d 2.10 (3H, s),
2.36 (3H, s), 2.40 (3H, s), 2.84 (3H, s), 3.03 (3H, s), 6.25 (1H, d, J 10.2 Hz), 6.31
(1H, d, J 9.6 Hz), 7.15 (2H, d, J 7.9 Hz), 7.23 (2H, d, J 8.1 Hz), 7.30 (2H, d, J
8.1 Hz), 7.42 (2H, d, J 8.1 Hz); 13C NMR (CDCl3) d 17.49, 21.17, 21.30, 34.87,
38.42, 113.58, 121.08, 124.63, 128.37, 129.10, 129.15, 129.36, 135.72, 136.47,
136.90, 137.33, 137.69, 145.73, 165.56. GC-MS: Rt 7.08, m/z 391(64) [M+ꢂ],
334(14), 319(18), 305(27), 299(100), 287(16), 273(32), 256(15), 190(20),
172(19), 164(10), 91(22), 72(29), 65(19).
(E)-N,N-Dimethyl-5-(2-(methylthio)vinyl)-1,4-di-p-tolyl-1H-pyrazole-3-carboxamide
(100a). The compound was obtained in very small quantities and could not be
fully characterized. 1H NMR (CDCl3) d 2.15 (3H, s), 2.37 (3H, s), 2.42 (3H, s),
2.88 (3H, s), 2.99 (3H, s), 6.02 (1H, d, J 15.6 Hz), 6.33 (1H, d, J 15.6 Hz), 7.13–
7.43 (8H, m).
(Z)- and (E)-tert-Butyl 5-(2-(methylthio)vinyl)-1,4-di-p-tolyl-1H-pyrazole-3-
carboxylate (10b and 100b, respectively). The 1H NMR analysis revealed that
the crude isolated by chromatography was a 54:46 mixture of Z/E isomers. All
the eluents tried for separation were unsuccessful. 1H NMR (CDCl3) d 1.34 (9H
E, s), 1.42 (9H Z, s), 2.07 (3H Z, s), 2.10 (3H E, s), 2.37 (3H Z, s), 2.40 (3H Z + 3H E,
s), 2.42 (3H E, s), 5.91 (1H E, d, J 15.6 Hz), 6.13 (1H Z, d, J 10.2 Hz), 6.16 (1H E, d,
J 15.6 Hz), 6.23 (1H Z, d, J 10.5 Hz), 7.13–7.30 (6H E + 6H Z, m), 7.38–7.47 (2H
E + 2H Z, m).
(Z)- and (E)-(5-(2-(Methylthio)vinyl)-1,4-di-p-tolyl-1H-pyrazol-3-yl)(phenyl)
methanone (10c and 10’c, respectively). The 1H NMR analysis revealed that
the crude isolated by chromatography was a 32:68 mixture of Z/E isomers. All
the eluents tried for separation were unsuccessful. 1H NMR (CDCl3) d 2.10 (3H
Z, s), 2.12 (3H E, s), 2.35 (3H Z, s), 2.38 (3H E, s), 2.41 (3H Z, s), 2.44 (3H E, s),
6.01 (1H E, d, J 15.6 Hz), 6.24 (1H Z, d, J 10.2 Hz), 6.28 (1H E, d, J 15.6 Hz), 6.31
(1H Z, d, J 10.2 Hz), 7.13–7.60 (11H E + 11H Z, m), 8.12–8.17 (2H E + 2H Z, m).
GC–MS: Rt 9.74, m/z 424(5) [M+ꢁ], 377(7), 299(6), 188(12), 105(100), 91(5),
77(44), 65(5), 51(9) and Rt 9.93, m/z 424(4) [M+ꢂ], 377(4), 299(9), 188(9),
105(100), 91(5), 77(44), 65(8), 51(4).
(Z)- and (E)-1-(5-(2-(Methylthio)vinyl)-1,4-di-p-tolyl-1H-pyrazol-3-yl)ethanone
(10d and 10’d, respectively). The 1H NMR analysis revealed that the
crude isolated by chromatography was a 36:64 mixture of Z/E isomers. All
the eluents tried for separation were unsuccessful. 1H NMR (CDCl3) d 2.07
(3H Z, s), 2.08 (3H E, s), 2.37 (3H Z, s), 2.39 (3H E, s), 2.42 (3H Z, s), 2.45
10. (a) Dadiboyena, S.; Nefzi, A. Eur. J. Med. Chem. 2011, 46, 5258–5275; (b)
Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Pyrazoles as drugs: facts and
fantasies In Targets in Heterocyclic Systems: Chemistry and Properties; Attanasi,
O. A., Spinelli, D., Eds.; Società Chimica Italiana: Rome, 2003; Vol. 6, pp 52–79.
11. Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. Chem. Rev. 2011,
111, 6984–7034.
12. (a) Deng, X.; Mani, N. S. Org. Lett. 2008, 10, 1307–1310; (b) Deng, X.; Mani, N. S.
Org. Lett. 2006, 8, 3505–3508; (c) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73,
2412–2415.
13. Methyl[(1Z,3E)-1-nitro-4-(p-tolyl)buta-1,3-dienyl]sulfide (1) derives from the
initial ring-opening of 2-nitrothiophene;2 (1E,3Z)-4-(methylsulfanyl)-2-nitro-
1-(p-tolyl)-1,3-butadiene (3) derives from the initial ring-opening of 3-
nitrothiophene;3
methyl[(1Z,3E)-1-nitro-4-(p-tolyl)buta-1,3-dienyl]sulfone
(2)14 and (1E,3Z)-4-(methylsulfonyl)-2-nitro-1-(p-tolyl)-1,3-butadiene (4)15
have been obtained by oxidation with MCPBA of 1 and 3, ‘respectively’.
14. Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Rocca, V.; Sancassan, F.;
Scapolla, C.; Severi, E.; Tavani, C. J. Org. Chem. 2007, 72, 9067–9073.
15. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.;
Severi, E.; Tavani, C. J. Org. Chem. 2005, 70, 8734–8738.
16. Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1996, 52, 5889–5898.
17. (a) Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 11239–
11248; (b) Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1993, 49,
235–242.
18. (a) Abdel-Wahab, B. F.; Abdel-Aziz, H. A.; Ahmed, E. M. Arch. Pharm. Chem. Life
Sci. 2008, 341, 734–739; (b) Farag, A. M.; Ali, K. A. K.; El-Debbs, T. M. A.;
Mayhoub, A. S.; Amr, A.-G. E.; Abdel-Hafez, N. A.; Abdulla, M. M. Eur. J. Med.
Chem. 2012, 45, 5887–5898; (c) Strocchi, E.; Fornari, F.; Minguzzi, M.;
Gramantieri, L.; Milazzo, M.; Rebuttini, V.; Breviglieri, S.; Camaggi, C. M.;
Locatelli, E.; Bolondi, L.; Comes Franchini, M. Eur. J. Med. Chem. 2012, 48, 391–
401; (d) Piscitelli, F.; Ligresti, A.; La Regina, G.; Gatti, V.; Brizzi, A.; Pasquini, S.;
Allarà, M.; Carai, M. A. M.; Novellino, E.; Colombo, G.; Di Marzo, V.; Corelli, F.;
Silvestri, R. Eur. J. Med. Chem. 2011, 46, 5641–5653; (e) Receveur, J.-M.; Murray,
A.; Linget, J.-M.; Norregaard, P. K.; Cooper, M.; Bjurling, E.; Nielsen, P. A.;
Högberg, T. Bioorg. Med. Chem. Lett. 2010, 20, 453–457; (f) Katoch-Rouse, R.;
Pavlova, O. A.; Caulder, T.; Hoffmann, A. F.; Mukhin, A. G.; Horti, A. G. J. Med.
Chem. 2003, 46, 642–645; (g) Bowles, D. M.; Boyles, D. C.; Choi, C.; Pfefferkorn,
J. A.; Schuyler, S.; Hessler, E. J. Org. Process Res. Dev. 2011, 15, 148–157.
(3H E, s), 2.54 (3H E, s), 2.60 (3H Z, s), 5.92 (1H E, d,
J 15.6 Hz), 6.16
19. Typical procedure for the reaction of the nitrobutadienes 1-4 with the anions of
a
-
(1H Z, d, J 10.5 Hz), 6.17 (1H E, d, J 15.9 Hz), 6.26 (1H Z, d, J 10.5 Hz), 7.13–7.47
(8H E + 8H Z, m).
oxohydrazones 5a-d in THF. In a flask, the appropriate hydrazone (5, 0.2 mmol)
was dissolved in THF (2.2 mL) under Argon at ꢀ78 °C, and ButOK (0.022 g,
0.2 mmol) was added as a solid. After 30 min under magnetic stirring, a
solution of the nitrobutadiene (0.2 mmol) in THF (2.2 mL) was added, and the
reaction mixture kept at ꢀ78 °C for 1–2 h. The reaction was then quenched
with TFA (0.114 g, 0.074 mL, 1 mmol), maintained at ꢀ78 °C for additional 2 h,
and finally allowed to reach room temperature. The mixture was then poured
into water, extracted with ethyl acetate, and dried over Na2SO4. After removal
of the solvent under reduced pressure, the residue was purified by column
chromatography using hexane/ethyl acetate mixtures.
(E)-N,N-Dimethyl-5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-
3-carboxamide (11a). Beige solid, mp 193–194 °C (EtOH); 1H NMR (CDCl3) d
2.39 (3H, s), 2.44 (3H, s), 2.80 (3H, s), 2.90 (3H, s), 2.99 (3H, s), 6.31 (1 H, d, J
15.6 Hz), 7.22–7.30 (4H, m), 7.34 (4H, app. s), 7.43 (1H, d, J 15.6 Hz); 13C NMR
(CDCl3) d 21.19, 21.28, 34.92, 38.44, 42.79, 124.75, 125.71, 127.35, 128.75,
129.23, 129.27, 129.80, 130.22, 132.36, 135.93, 138.34, 139.75, 146.59, 164.05.
GC-MS: Rt 9.24, m/z 423(34) [M+ꢁ], 366(21), 344(19), 299(99), 287(24),
273(100), 256(36), 242(16), 212(10), 164(10), 142(30), 128(21), 115(14),
106(12), 91(51), 77(16), 72(71), 65(52).

6400
(E)-tert-Butyl
L. Bianchi et al. / Tetrahedron Letters 53 (2012) 6394–6400
5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-3-carbo-
washed with water, and dried over Na2SO4. After removal of the solvent under
reduced pressure, the crude residue was purified by column chromatography
using hexane/ethyl acetate mixtures.
xylate (11b). Orange solid, mp 144–145 °C (EtOH); 1H NMR (CDCl3) d 1.34
(9H, s), 2.42 (3H, s), 2.44 (3H, s), 2.75 (3H, s), 6.12 (1H, d, J 15.9 Hz), 7.18 (2H, d,
J 8.4 Hz), 7.26 (2H, d, J 7.8 Hz), 7.29–7.39 (5H, m); 13C NMR (CDCl3) d 21.50,
21.60, 28.06, 43.02, 82.15, 126.11, 127.46, 128.83, 129.51, 129.61, 129.82,
130.45, 134.14, 136.02, 138.34, 140.24, 143.93, 161.13 (two carbons are
accidentally isochronous). MS (ESI): m/z 475 [M+Na]+, 491 [M+K]+.
N,N-dimethyl-6-(methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazine-3-
carboxamide (14a). Orange solid, mp 138–139 °C (dichloromethane/petroleum
ether);1H NMR (CDCl3) d 2.33 (3H, s), 2.34 (3H, s), 2.95 (3H, s), 2.97 (3H, s), 3.18
(3H, s), 3.23 (1H, dd, J 2.6 and 13.4 Hz), 3.66 (1H, dd, J 9.8 and 13.4 Hz), 5.72
(1H, ddd, J 2.7, 7.2 and 9.9 Hz), 6.24 (1H, d, J 6.9 Hz), 7.14 (4H, app. s), 7.18 (2H,
d, J 8.4 Hz), 7.32 (2H, d, J 8.7 Hz). 13C NMR (CDCl3) d 20.74, 21.38, 35.20, 38.83,
43.24, 47.30, 54.35, 115.63, 120.99, 127.06, 129.48, 130.28, 132.14, 132.71,
133.13, 138.45, 141.51, 141.97, 165.76. MS (ESI): m/z 426 [M+H]+.
3-Benzoyl-6-(methylsulfonylmethyl)-5-nitro-1,4-di-p-tolyl-1,4,5,6-tetrahydro-
pyridazine (12c). Yellow solid, mp 121–123 °C (EtOH); 1H NMR (CDCl3) d 2.26
(3H, s), 2.34 (3H, s), 2.73 (3H, s), 3.30–3.44 (2H, two partly overlapped dd, J 5.1,
5.7 and 15.0 Hz), 4.96 (1H, d, J 9.9 Hz), 5.35 (1H, dd, J 3.9 and 9.9 Hz), 5.45 (1H,
app. q), 7.10 (2H, d, J 8.1 Hz), 7.17 (2H, d, J 8.1 Hz), 7.21 (2H, d, J 8.7 Hz), 7.31
(2H, d, J 8.7 Hz), 7.37–7.47 (2H, m), 7.50–7.56 (1H, m), 7.93–7.97 (2H, m); 13C
NMR (CDCl3) d 20.72, 21.07, 40.16, 42.42, 49.81, 51.95, 86.06, 117.94, 127.81,
128.02, 130.20, 130.32, 130.38, 132.57, 132.75, 134.45, 136.25, 138.32, 141.16,
142.70, 188.91. MS (ESI): m/z 506 [M+H]+.
3-Acetyl-6-(methylsulfonylmethyl)-5-nitro-1,4-di-p-tolyl-1,4,5,6-tetrahydro-
pyridazine (12d). Yellow solid, mp 79–80 °C (EtOH); 1H NMR (CDCl3) d 2.30 (3H,
s), 2.38 (6H, s), 2.77 (3H, s), 3.28 (1H, dd, J 6.0 and 14.7 Hz), 3.39 (1H, dd, J 5.1
and 14.7 Hz), 4.73 (1H, d, J 7.7 Hz), 5.14 (1H, app. q), 5.28 (1H, dd, J 3.9 and
7.7 Hz), 7.02 (2H, d, J 8.1 Hz), 7.13 (2H, d, J 7.8 Hz), 7.26 (2H, d, J 8.1 Hz), 7.37
(2H, d, J 8.4 Hz); 13C NMR (CDCl3) d 20.86, 21.11, 24.90, 39.39, 42.44, 49.15,
51.66, 85.39, 119.85, 127.50, 130.15, 130.28, 133.69, 135.45, 138.15, 141.12,
141.99, 195.06. MS (ESI): m/z 444 [M+H]+.
tert-Butyl
6-(methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazine-3-
carboxylate (14b). Yellow solid, mp 86–88 °C (diethyl ether/petroleum
ether);1H NMR (CDCl3) d 1.30 (9H, s), 2.34 (3H, s), 2.37 (3H, s), 2.99 (3H, s),
3.21 (1H, dd, J 2.9 and 13.4 Hz), 3.56 (1H, dd, J 9.9 and 13.4 Hz), 5.77 (1H, ddd, J
2.9, 7.2 and 9.9 Hz), 6.02 (1H, d, J 7.2 Hz), 7.11 (2H, d, J 8.3 Hz), 7.15 (2H, d, J
8.2 Hz), 7.20 (2H, d, J 8.4 Hz), 7.43 (2H, d, J 8.6 Hz). 13C NMR (CDCl3) d 20.89,
21.42, 27.90, 43.30, 47.95, 54.40, 82.03, 116.36, 119.28, 127.63, 129.03, 130.35,
132.90, 133.70, 135.09, 137.90, 139.02, 141.23, 162.64. MS (ESI): m/z 477
[M+Na]+, 493 [M+K]+.
3-Benzoyl-6-(methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazine (14c).
Yellow solid, mp 189–190 °C (EtOH).; 1H NMR (CDCl3) d 2.32 (s, 3H), 2.33 (s,
3H), 2.99 (s, 3H), 3.20 (1H, dd, J 2.1 and 13.4 Hz), 3.61 (1H, dd, J 10.0 and
13.2 Hz), 5.85 (1H, ddd, J 2.1, 7.3 and 10.0 Hz), 6.25 (1H, d, J 7.2 Hz), 7.10 (4H,
app. s), 7.19 (2H, d, J 8.2 Hz), 7.32 (2H, d, J 8.7 Hz), 7.46–7.58 (2H, m), 7.60–7.65
(1H, m), 8.10–8.12 (2H, m). 13C NMR (CDCl3) d 20.66, 21.23, 43.17, 47.46, 54.70,
116.00, 120.35, 127.19, 128.17, 129.16, 130.30, 130.62, 132.70, 133.03, 133.67,
133.70, 136.83, 137.96, 140.81, 143.53, 189.27. MS (ESI): m/z 459 [M+H]+.
20. Preliminary analytical data for the pyrazolidine 8a, isolated as a secondary
product, after acidic quenching, from the reaction of hydrazone 5a and
nitrobutadiene 10 (Scheme 2 and 1: Y = CH@CH-p-anisyl):
(E)-4-(4-Methoxystyryl)-N,N-dimethyl-5-(methylthio)-5-nitro-1-(p-tolyl)pyrazoli-
dine-3-carboxamide (8a): 1H NMR (CDCl3): d 2.25 (3H, s), 2.39 (3H, s), 2.93 (3H,
s), 3.14 (3H, s), 3.80 (3H, s), 4.58 (1H, t, J 9.3 Hz), 5.71 (1H, d, J 9.6 Hz), 6.14 (1H,
dd, J 9.1, 15.8 Hz), 6.62 (1H, d, J 15.9 Hz), 6.84 (2H, d, J 8.7 Hz), 7.22 (2H, d, J
8.1 Hz), 7.31 (2H, d, J 8.7 Hz), 7.59 (2H, d, J 8.3 Hz). MS (ESI): m/z 457 [M+H]+.
3-Acetyl-6-(methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazine
(14d).
Yellow solid, mp 136–137 °C (EtOH);1H NMR (CDCl3) d 2.35 (3H, s), 2.38 (3H,
s), 2.55 (3H, s), 2.98 (3H, s), 3.19 (1H, dd, J 2.7 and 13.2 Hz), 3.52 (1H, dd, J 9.9
and 13.2 Hz), 5.78 (1H, ddd, J 2.7, 7.2 and 9.9 Hz), 6.05 (1H, d, J 7.2 Hz), 7.03
(2H, d, J 8.0 Hz), 7.13 (2H, d, J 8.0 Hz), 7.25 (2H, d, J 8.4 Hz), 7.45 (2H, d, J
8.4 Hz); 13C NMR (CDCl3) d 20.89, 21.42, 25.97, 43.41, 47.91, 54.58, 116.36,
120.08, 127.47, 128.99, 130.47, 132.69, 134.35, 134.61, 137.78, 140.82, 143.40,
194.88. MS (ESI): m/z 397 [M+H]+.
21. Typical procedure for the reaction of nitrobutadiene 4 with the anions of
oxohydrazones 5a–d in EtOH. In a flask, 4 (0.05 g) and the appropriate
a-
5
(1 mol equiv) were dissolved in EtOH (2.5 mL) and DBU (1 mol equiv) was
added. The solution was refluxed for 1 h under magnetic stirring, and the end
of reaction checked by TLC. The final mixture was diluted with ethyl acetate,