Synthesis of poly-functionalized pyrazoles and pyridazines from nitrobutadienes: an interesting dichotomy of practical relevance

Article abstract of DOI:10.1016/j.tet.2015.08.014

The initial ring-opening of 3-nitrothiophene and further structural modifications lead to nitrobutadienic building-blocks whose synthetic usefulness in the field of heterocycles has been widely demonstrated. As a further example, the Michael addition of a

Full text of DOI:10.1016/j.tet.2015.08.014

Accepted Manuscript
Synthesis of Poly-functionalized Pyrazoles and Pyridazines from Nitrobutadienes: an
Interesting Dichotomy of Practical Relevance
Lara Bianchi, Alessandro Carloni-Garaventa, Massimo Maccagno, Marcella Pani,
Giovanni Petrillo, Carlo Scapolla, Cinzia Tavani
PII:
S0040-4020(15)01191-6
10.1016/j.tet.2015.08.014
TET 27036
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 June 2015
Revised Date: 24 July 2015
Accepted Date: 3 August 2015
Please cite this article as: Bianchi L, Carloni-Garaventa A, Maccagno M, Pani M, Petrillo G, Scapolla
C, Tavani C, Synthesis of Poly-functionalized Pyrazoles and Pyridazines from Nitrobutadienes: an
Interesting Dichotomy of Practical Relevance, Tetrahedron (2015), doi: 10.1016/j.tet.2015.08.014.
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1
ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of Poly-functionalized Pyrazoles and Pyridazines from Nitrobutadienes:
an Interesting Dichotomy of Practical Relevance
Lara Bianchi, Alessandro Carloni-Garaventa, Massimo Maccagno, Marcella Pani, Giovanni Petrillo,* Carlo
Scapolla, and Cinzia Tavani

2
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Synthesis of Poly-functionalized
Pyrazoles and Pyridazines from Nitrobutadienes:
an Interesting Dichotomy of Practical Relevance
Lara Bianchi, Alessandro Carloni-Garaventa, Massimo Maccagno, Marcella Pani,
Giovanni Petrillo,* Carlo Scapolla and Cinzia Tavani
Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
giovanni.petrillo@unige.it
Abstract. The initial ring-opening of 3-nitrothiophene and further structural modifications lead to
nitrobutadienic building-blocks whose synthetic usefulness in the field of heterocycles has been
widely demonstrated. As a further example, the Michael addition of a hydrazone anion to the
nitrovinyl moiety of nitrobutadienes generates 1,2-diazaheterocycles as the final result of an overall
MIRC process. Depending on the nature of the substituents on the Michael-type acceptor and on the
hydrazono nucleophile, an interesting dichotomy is observed, that leads to either 5-member or 6-
member N-heterocycles with complete selectivity. The results obtained appear to be both of
mechanistic and synthetic interest e.g. in the field of heterocycles endowed with potential
pharmacological/biological activity.
Keywords: Nitrogen heterocycles / Michael additions / nitrobutadienes / pyrazoles / pyridazines.
1
. Introduction
The synthesis of N-heterocycles is a goal of utmost importance in organic, bioorganic and
1
pharmaceutical chemistry, and the intermediacy of conjugated nitrodienes has been recently
2
reviewed. In this field, over the last two decades our research group has provided a valuable
contribution thanks to the versatility of building-blocks such as 4-11 (Scheme 1). Such poly-
functionalized units, most conveniently obtainable from the initial ring-opening of suitably-
3
-5
substituted nitrothiophenes with secondary amines, followed by modifications of the original
functionalities so as to meet specific requirements, both structural and electronic (Scheme 1),
6
exhibit a multi-faceted behaviour: this obviously encompasses the well-known reactivity of e.g.
7
nitrovinyl, nitroenaminic, sulfonylvinyl systems. Accordingly, the nitrobutadienes reported in
Scheme 1 have provided sulfur, oxygen and/or nitrogen atoms for the construction of a number of
different heterocycles in an overall ring-opening/ring-closing protocol characterized by a high atom
8
economy.

3
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NO2
NO2
O N
2
NO2
NRR'
Ar
R'RN
Ar
S
1
O N
2
O N
2
4
5
X
Y
NO2
NO2
NO2
NO2
SMe
SMe
SO Me
2
R'RN
Ar
Ar
S
X
Y
X
Y
X
Y
2
6
7
8
X = H, SPh, SO Ph; Y = H.
2
X = H; Y = H, SR(Ar), SO R(Ar), COMe, COOR, CN. X-Y = CH=CH-CH=CH
2
NO2
SMe
NO2
SMe
NO2
SO Me
2
S
3
NO
2
R'RN
Ar
Ar
9
10
11
Scheme 1. Nitrobutadienic building-blocks from the initial ring-opening of nitrothiophenes 1-3.
More recently, the construction of poly-functionalized heterocycles has been successfully
performed by means of an initial Michael-type addition onto the nitrovinylic moiety of
8
a,d-h
nitrobutadienes,
a synthetic approach sometimes indicated as a Michael addition Induced Ring
9
Closure (MIRC) process.
1
0
In this line, preliminary results on the reaction between the model nitrobutadienes 12a and
3a (Scheme 1, Ar = p-Tol, X = Y = H in 7 and 8, respectively), purposely chosen in order to
1
provide two significantly different electronic distribution patterns on the diene moiety, and the
anions of hydrazones 14a-d, have enlightened the possibility to apply the initial Michael-type
addition strategy also to the preparation of heterocycles containing two adjacent nitrogen atoms (cf.
6
b
Scheme 2). Actually, with the exception of some pyrazolines, similar structures were still lacking
in our expanding “pool” although pyrazoles, in particular, surely represent appealing targets: the
wide range of biological and pharmacological activities displayed by such molecules (among
1
1
which: anti-hyperglycemic, anti-inflammatory, anti-obesity, or antitumoral ) accounts for the
impressive amount of literature which continuously deals with relevant synthetic or applicative
1
2
aspects.
On the grounds of the preliminary results, it seemed therefore worthwhile to fully investigate
the behaviour of nitrobutadienes 13 in order to better define the scope of the access to highly-
functionalized pyrazoles or pyridazines such as 16 or 17, respectively, and also to gain more
information on the origin of the dichotomic behaviour that generates different N-heterocyclic
structures. Relevant results are reported hereinafter.

4
ACCEPTED MANUSCRIPT
Scheme 2. Pyrazoles 15 and 16, and tetrahydropyridazines 17 from the reaction between 12a and
1
3a-g with the anions of α-oxohydrazones 14a-d. Data for 12a and 13a are from a preliminary
1
0
communication.
2
. Results and discussion
Dichotomic behaviour of nitrosulfonylbutadienes 13
As shown in Scheme 2, the behavior of nitrobutadienes 12a and 13a towards the anions
t
(
generated with Bu OK) of hydrazones 14a-d in THF at -78 °C turns out to be markedly different.
On one side, sulfide 12a effectively builds-up a pyrazole nucleus independently of the nature of Z
in the employed hydrazone, with a partial inversion of the exocyclic C=C double-bond
1
0
configuration.
Much more interestingly, depending on the nature of Z, sulfone 13a produces two different
heterocycles. The latter reaction was therefore considered to deserve a deeper insight and was first
of all extended to other substrates with different Ar moieties. The results obtained by treatment of
nitrobutadienes 13b-f with the α-oxohydrazones 14a-d (Scheme 2, Tables 1 and 2) cleanly line-up
with the preliminary ones for the model p-tolyl derivative 13a: whichever the nature of Ar,
t
hydrazones 14a,b (Z = NMe and OBu , respectively) exclusively furnish the tetra-substituted
2
pyrazoles 16 (Table 1), while 14c,d (Z = Ph and Me, respectively) exclusively lead to the likewise

5
ACCEPTED MANUSCRIPT
fully-substituted tetrahydropyridazines 17 (Table 2). Interestingly enough, not even traces of
1
0
pyridazine derivatives have ever been observed for similar reactions on sulfide 12a.
a
Table 1. Tetra-substituted pyrazoles 16 from the reaction of Scheme 2.
b
Entry Substrate
Ar in 13
Hydrazone Z in 14
Pyrazole 16 (Yields %)
c
1
2
3
4
5
6
7
13a
“
p-Tolyl
14a
14b
14a
14b
14a
14b
14a
NMe2
16aa (98%)
t
c
“
p-Anisyl
“
OBu
16ab (50%)
13b
“
NMe2
16ba (54%)
16bb (63%)
16ca (50%)
16cb (71%)
t
OBu
13c
p-Cl-Phenyl
“
NMe2
t
“
OBu
d
e
13d
o-Tolyl
NMe2
NMe2
NMe2
16da (74%; 88:12)
d
8
9
13e
13f
2-Thienyl
14a
14a
16ea (93%)
2-Naphthyl
f
a
t
Reaction conditions (if not otherwise stated): i) 14 (1 equiv with respect to 13), Bu OK (1 equiv) in THF/Ar, -78 °C,
b
3
0'; ii) 13 (0.1 M in THF), 1-2 h; iii) TFA (5 equiv), -78 °C (2h) to rt, overnight. Yields of chromatographically pure
c
d
e
1
f
products. Data from ref. 10. Quenching with 20 equiv of TFA. Z:E ratio, as judged by H NMR analysis. Complex
final mixture.
a
Table 2. Tetra-substituted tetrahydropyridazines 17 from the reaction of Scheme 2.
b
Entry Substrate
Ar in 13
Hydrazone Z in 14 Pyridazine 17 (Yields %)
c
1
13a
p-Tolyl
14c
Ph
17ac (98%)
c
2
3
4
5
6
7
8
9
“
13b
“
“
14d
14c
14d
14c
14d
14c
14d
14c
14d
Me
Ph
17ad (98%)
p-Anisyl
17bc (75%)
17bd (90%)
17cc (75%)
17cd (75%)
17dc (68%)
17dd (69%)
d
“
Me
Ph
13c
“
p-Cl-Phenyl
“
Me
Ph
13d
“
o-Tolyl
“
Me
Ph
13f
“
2-Naphthyl
“
1
0
Me
17fd (98%)
a
t
Reaction conditions: i) 14 (1 equiv with respect to 13), Bu OK (1 equiv) in THF/Ar, 0 °C, 30'; ii) 13 (0.1 M in
b
c
THF), 0.5-1 h; iii) TFA (5 equiv), 0 °C to rt, 1 h. Yields of chromatographically pure products. Data from ref.
1
d
0. Complex final mixture.

6
ACCEPTED MANUSCRIPT
As far as tetrahydropyridazines 17 are concerned, we noticed that a considerable yield
improvement could be obtained by performing both deprotonation of 14 and addition of 13 at 0 °C,
concomitantly reducing the time for quenching to 1 h. Yields reported in Table 2 are those obtained
in such optimized conditions.
1
0
As outlined in the preliminary communication, a reasonable mechanistic pathway to the
pyrazole nucleus can be envisaged as depicted in Scheme 3, whereby a Michael-type addition of the
hydrazone anion to the nitrovinyl moiety of 12 or 13 (step a) is followed by the intramolecular
1
3
attack of the resulting nitronate A onto the diazo group (step b), which exploits the driving force
represented by intramolecularity.
Scheme 3. Proposed mechanism for the formation of pyrazoles 15 and 16.
From pyrazolidine C, aromatization could in principle be achieved via base-catalyzed β-
elimination of nitrous acid (step d’), followed by oxidation: the latter presumably accomplishable,
in the absence of external added oxidants, by the cleaved nitrite anion itself, as already verified in
8
a
previous different instances. Nonetheless, in such conditions, the process proves to be quite
sluggish, leading to partial decomposition and to a meagre overall balance.
On the other hand, acidic quenching (excess TFA) after disappearance of substrate,
1
3a
effectively drives the reaction to completion favouring the elimination of nitrous acid (step d) by
protonation of the nitro group; deprotonation and oxidation (by nitrous acid: see above) of the
resulting iminium cation (D) (steps e and f) lead to the final pyrazole derivative. The quantitative

7
ACCEPTED MANUSCRIPT
protonation of the pyrazolidine anion (B, or possibly B’) should also lead to a more efficient result,
minimizing alternative, decomposition pathways.
The observed configurational scrambling at the exocyclic double bond, only partial in the case
1
0
of 15a, but complete in the case of 16 (with the exception of 16da: Table 1, entry 7), may be
rationalized considering that the intermediate open-chain nitronate A may delocalize the negative
charge onto the adjacent double bond: a delocalization which is expected to be more important for
sulfones 13 than for sulfides 12. It should also be considered that the closure of the pyrazolidine
nucleus is probably a slow step, due to the low electrophilic character of the diazo group: thus the
anion could be allowed to equilibrate according to the relevant stability of the two stereoisomers,
and much more so for the sulfones which, thanks to effective charge delocalization, should
experience a longer lifetime in the reaction conditions. The preference for the E configuration
shown by 16 is predictably due to steric reasons, and steric factors most likely play a role in
determining the only partial isomerization in the case of the hindered o-methylphenyl derivative
(
16da).
The most intriguing aspect of the system under study is surely the dichotomic behaviour
Scheme 2) displayed by sulfones 13, as mirrored by the complete chemoselectivity observed in
(
dependence of the nature of Z in the COZ moiety of the hydrazone employed: the anions of the α-
hydrazonoamide 14a and of the α-hydrazonoester 14b giving pyrazoles 16 in good yields, while the
anions of α-hydrazonoketones 14c and 14d leading to tetrahydropyridazines 17 (Scheme 2), almost
exclusively as single diastereoisomers out of the three possible ones (for configurational attribution
see further in the text).
In order to explain such a dichotomy, we considered (Scheme 4) that the nitronate 18 (i. e.
nitronate A of Scheme 3, with n = 2), should be particularly stabilized by charge-delocalization on
both the nitro group, and the sulfonylvinyl moiety (see also above in the text). Such an occurrence
reasonably allows the anion a longer lifetime, so that, as an alternative to the expected unfavoured
5-endo-trig cyclization to pyrazole, it could also equilibrate with 18’ or 18’’ (Scheme 4) by transfer
of the negative charge to the position adjacent to the COZ moiety. The new anion (18’’ being most
likely the preferred structure, on the grounds of the alleged higher stability of a nitrovinyl with
8
d,e,g,h
respect to a sulfonylvinyl moiety
) 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 negative charge.

8
ACCEPTED MANUSCRIPT
Scheme 4. The proposed rationale behind the dichotomic behavior of nitrobutadienes 13a-e.
On the tautomerized 18’’ (or 18’) anion, an electronically-inverted cyclization process
becomes possible, whereby a nucleophilic hydrazone anion couples with an electrophilic nitrovinyl
(or sulfonylvinyl) moiety, easily providing a six-membered ring: thus, 6-endo-trig or, possibly,
6-exo-trig cyclization routes are in principle recognizable, leading to the same final outcome 17.
1
4
To confirm our hypothesis, we carried out quantum-mechanical calculations on the
carbanionic intermediates 18, 18’ and 18’’ for the model amide (aa) and methyl ketone (ad)
derivatives. As shown in Chart 1, for the ketone derivatives there is no substantial difference among
the relative stabilities of the three tautomeric anions, and therefore in the acidities of the
corresponding conjugated acids. However, in the case of the amide 18aa is significantly more stable
than the other ones: this brings the acidity of the hydrogen in α to the nitro group to be considerably
15
higher (more than 4 units of pK ) than that of the hydrogen in α to the amido group.
a

9
ACCEPTED MANUSCRIPT

1
0
ACCEPTED MANUSCRIPT
In line with the proposed rationale, it is reasonable that the competition between the two
pathways may be affected by the choice of the reaction medium and, as the formation of a
tetrahydropyridazine needs an efficient proton transfer, a protic solvent would conceivably direct
the reaction towards 17, accelerating the proton transfer from 18 to 18’ or 18’’. Interestingly, the
treatment of an equimolar 13 + 14 mixture with DBU (1 equiv) in refluxing ethanol effectively
leads to the dihydropyridazino ring of 19, independent of the nature of COZ (Scheme 5 and Table
3).
Scheme 5. Dihydro- and tetrahydro-pyridazines 19 and 17 from reactions of 13 and 14.
a
Table 3. Dihydropyridazines 19 from the reaction of 13 and 14 with DBU in EtOH (Scheme 5).
b
Entry Substrate
Ar in 13
Hydrazone Z in 14
Dihydropyridazines (Yields %)
1
2
3
4
5
6
7
8
9
13a
“
p-Tolyl
14a
14b
14c
14d
14a
14b
14c
14d
14a
14b
14c
14d
14a
14c
14d
NMe2
19aa (71%)
t
OBu
19ab (80%)
19ac (72%)
“
“
“
Ph
Me
“
“
19ad (81%)
19ba (52%)
19bb (87%)
19bc (99%)
13b
“
p-Anisyl
NMe2
t
OBu
“
“
“
Ph
Me
“
“
19bd (84%)
19ca (70%)
13c
“
p-Cl-Phenyl
NMe2
t
1
0
1
2
3
4
5
“
OBu
19cb (88%)
1
1
1
1
1
“
“
Ph
Me
19cc (78%)
“
“
19cd (95%)
13f
“
2-Naphthyl
NMe2
Ph
19fa (63%)
“
“
19fc (68%)
“
Me
19fd (68%)

1
1
ACCEPTED MANUSCRIPT
a
b
Reaction conditions: 13 (50 mg), 14 (1 equiv), DBU (1 equiv) in EtOH (3 mL), reflux, 1h; aqueous quenching.
Yields of isolated products.
The most likely precursor of 19 is represented by the tetrahydropyridazine 17, which would
undergo β-elimination of HNO in the basic medium to afford the final conjugated azadiene. To
2
confirm this very last point, we have successfully verified the feasibility of HNO elimination from
2
1
7ac and 17ad to obtain 19ac and 19ad by means of an alternative two-step route: the use of
piperidine in refluxing ethanol leading to an almost quantitative smooth conversion in both cases
see Scheme 5).
For the formation of dihydropyridazines 19, the sequence of Scheme 6 can be envisaged, in
(
which the base guarantees, whatever the nature of Z, the proton exchange that eventually leads to
the 6-endo-trig cyclization and HNO elimination; note that, overall, only one equivalent of base is
2
required to drive the reaction to completion.
Scheme 6. DBU-assisted proton-transfers in ethanol at reflux.
This methodology also gives the 6-membered pyridazine system when the COZ is an amide
or an ester function, so bypassing the obstacle represented by the dichotomic behavior described in
Scheme 2.
On the other hand, it should be noted that the other drawback, i.e. the failure to obtain
pyrazoles when COZ in 14 is a ketonic moiety (Z = alkyl, aryl), is in turn very easily bypassed,
insofar as pyrazoles 16 can be obtained (although as diastereomeric mixtures) by oxidation of the
methylthio substituent in 15, typically employing MCPBA in dichloromethane (Scheme 7).
Successful oxidation tests have been carried out on the diastereomeric mixtures isolated from
10
the reaction of Scheme 2: almost quantitative yields are coupled with a complete stereospecificity,
the Z / E ratio of sulfides being recovered unaltered in the corresponding sulfones.

1
2
ACCEPTED MANUSCRIPT
Scheme 7. Sulfonylvinylpyrazoles 16 obtained by oxidation of the corresponding sulfides 15.
Relative Configuration attribution for tetrahydropyridazines 17
As already stated above, tetrahydropyridazines 17 are obtained as a single racemic
diastereoisomer out of the possible four. The relative configurations can be assigned based on the
1
H NMR coupling constants (J(4H-5H) and J(5H-6H)). The available data (collected in Table 4) show
that, when changing COZ from benzoyl to acetyl, chemical shifts and/or coupling constants
inherent to protons 4-H, 5-H, 6-H in the heterocyclic ring undergo some significant variations.
1
a
Table 4. H NMR spectroscopic data for the tetrahydropyridazine ring protons of the racemic 17.
b
c
d
1
7
COZ
Ar
δ
(4-H)
δ
(5-H)
δ
(6-H)
J(4H-5H)
J(5H-6H)
1
7ac Benzoyl
p-Tolyl
p-Anisyl
p-Cl-Phenyl
o-Tolyl
4.97
4.95
4.97
5.19
4.73
4.72
4.73
4.93
4.93
5.35
5.35
5.33
5.45
5.44
5.47
9.9
9.6
9.9
9.0
7.7
7.5
8.1
6.8
8.1
4.0
4.2
1
7bc
“
“
“
17cc
7dc
3.9
1
5.43 (2H, m)
no det.
3.9
1
1
7ad Acetyl
p-Tolyl
5.28
5.13
5.13
5.18
5.10
5.26
7bd
7cd
7dd
7fd
“
“
“
“
p-Anisyl
p-Cl-Phenyl
o-Tolyl
5.28
5.25
5.35
5.42
3.9
1
3.9
1
3.9
1
2-Naphthyl
3.9
a
Chemical shifts
δ in ppm from internal TMS, coupling constants J in Hz, solvent CDCl . No long-range coupling was
3
b c d
detected at 300 MHz. Doublet. Doublet of doublets. Doublet of partially overlapped triplets (apparent quadruplet).
In particular, as far as the coupling constants are concerned, while the J(4H-5H) values seem
definitely to correspond to a trans axial-axial coupling for COPh derivatives (J(4H-5H) = 9.0-9.9),

1
3
ACCEPTED MANUSCRIPT
some doubts arise for COMe ones; on the other hand, J(5H-6H) definitely seem in agreement with a
cis relationship for both series of compounds. The doubt about the relative stereochemistry at C-4
and C-5 in the acetyl derivatives was definitely solved by the X-ray structural analysis of 17bd
(Figure 1) as a representative model system for the series.
Figure 1. Ortep of 17bd.
Conclusions
The biological/pharmacological interest in N-heterocyclic structures fosters a continuous
approach to new synthetic pathways overcoming limitations and/or drawbacks of known protocols.
The results herein insert a further tile into the overgrowing patchwork of N-heterocycle synthesis by
means of the exploitation of powerful building-blocks such as poly-functionalized conjugated
nitrobutadienes.
The most remarkable feature is surely represented by the dichotomic behaviour of Scheme 2,
whereby the nature of the final heterocycle is tuned by the Z substituent and by the resulting
acidifying power of the acetyl (COZ) moiety onto the α-hydrogen atom of intermediate 18: this is
rationalized in Scheme 4 and substantiated by the quanto-mechanical results reported in Chart 1.
On the other hand, the two “drawbacks” envisaged from the dichotomy of Scheme 2 can be
both overcome as far as a) by modifying the reaction conditions, the diazine nucleus can be
effectively attained independently on the nature of Z (Scheme 5), while b) pyrazoles “prohibited”
by the use of 13 as substrates can be in turn easily prepared when starting from the corresponding
sulfides 12 and performing a final, almost quantitative MeS to MeSO stereospecific oxidation
2
(Scheme 7).

1
4
ACCEPTED MANUSCRIPT
Overall, we feel that the results herein represent a significant upgrade in the field of the
synthesis of diversely functionalized N-heterocycles of possible biological/pharmacological
interest.
Experimental Section
1
13
Materials and methods: H NMR and C NMR spectra were recorded with a Varian Mercury 300
Plus spectrometer, at 300 and 75 MHz, respectively; chemical shifts (TMS as internal reference) are
reported as
HP 5890/5971 (EI 70 eV) system equipped with a HP-1 MS capillary column (12 m x 0.2 mm i.d x
.33 ꢀm). High-resolution mass spectra (HRMS) were obtained with an Agilent MSD TOF mass
δ values (ppm). Gas chromatography - mass spectrometry (GC-MS) was performed on
0
spectrometer, and recorded in positive ion mode with an electrospray (ESI) source. Melting points
were determined with a Büchi 535 apparatus and are uncorrected. IR spectra were recorded on a
-1
Perkin Elmer Spectrum 65 FT-IR and wave numbers are reported in cm . Petroleum ether and light
petroleum refer to the fractions with bp 40-60 °C and 80-100 °C, respectively. Silica gel 230-400
mesh was used for column chromatography, all solvents being distilled before use. Tetrahydrofuran
(THF) was purified by standard methods and distilled over potassium benzophenone ketyl before
use. All other commercially available reagents were used as received.
1
6
17
10
Compounds 13a-f, 14a-d and 15aa-ad have been already described.
Reactions of sulfones 13a-f with the anions of hydrazones 14a,b at -78 °C
In a flask, the appropriate hydrazone 14 (0.2 mmol, 1 equiv vs. the nitrobutadiene 13) was dissolved
in THF (2.2 mL) under Ar and magnetic stirring; the temperature was brought to -78 °C and a 1M
t
solution of Bu OK (1 equiv) was added. After 30 min, a THF solution of the appropriate
nitrobutadiene (0.2 mmol in 2.2 mL) was added, and the reaction mixture kept at - 78 °C for 1-2 h.
TFA (5 equiv) was then added, and the mixture maintained at – 78 °C under magnetic stirring for 2
h, and finally allowed to reach room temperature overnight. The mixture was then poured into water
and extracted with ethyl acetate. The organic phases were dried over Na SO , filtered and the
2
4
solvent removed under reduced pressure. The obtained crude was purified by chromatography on a
silica gel column, using petroleum ether/ethyl acetate mixtures as eluent.
Reactions of sulfones 13a-f with the anions of hydrazones 14c,d at 0 °C
A modification of the methodology described above was employed wherein the temperature was
maintained at 0 °C throughout, and allowed to reach 25 °C within 1 h after quenching with TFA.
(
E)-N,N-Dimethyl-5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-3-carboxamide
1
0
-1
(16aa). Beige solid, mp 193-194 °C (ethanol). IR (ATR): ṽ (cm ) 1639 (s), 1512 (m), 1386 (m),
1
1
311 (m), 1306 (m), 1292 (s), 1137 (s), 1126 (s), 1107 (m). H NMR (CDCl , 300 MHz):
δ
(ppm)
3
2
.39 (3H, s), 2.44 (3H, s), 2.80 (3H, s), 2.90 (3H, s), 2.99 (3H, s), 6.31 (1H, d, J 15.6 Hz), 7.23-7.30
1
3
(4H, m), 7.34 (4H, app. s), 7.43 (1H, d, J 15.6 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 21.4, 21.5,
3
35.1, 38.6, 43.0, 125.0, 125.9, 127.6, 128.9, 129.5, 130.0, 130.4, 132.6, 136.1, 138.5, 139.9, 146.8,

1
5
ACCEPTED MANUSCRIPT
+
1
64.2. GC-MS: m/z 423(34) [M ], 366(21), 344(19), 299(99), 287(24), 273(100), 256(36), 242(16),
2
12(10), 164(10), 142(30), 128(21), 115(14), 106(12), 91(51), 77(16), 72(71), 65(52). HRMS (ESI)
+
m/z calcd [M + H] C H N O S 424.1689, found 424.1684.
23
26
3
3
1
0
tert-Butyl (E)-5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-3-carboxilate (16ab).
1
Orange solid, mp 144-145 °C (ethanol). H NMR (CDCl , 300 MHz):
δ (ppm) 1.34 (9H, s), 2.42
3
(
3H, s), 2.44 (3H, s), 2.75 (3H, s), 6.12 (1H, d, J 15.7 Hz), 7.18 (2H, d, J 8.4 Hz), 7.26 (2H, d, J 7.8
1
3
Hz), 7.29-7.37 (5H, m). C NMR (CDCl , 75 MHz):
δ
(ppm) 21.4, 21.5, 28.0, 42.9, 82.1, 126.0,
3
1
27.4, 128.7, 129.4, 129.5, 129.7, 130.4, 134.1, 135.9, 138.3, 140.2, 143.8, 161.0 (two isochronous
+
carbons). HRMS (ESI) m/z calcd [M + H] C H N O S 453.1843, found 453.1847.
2
5
29
2
4
(
E)-4-(4-Methoxyphenyl)-N,N-dimethyl-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
1
carboxamide (16ba). Colourless solid, mp 168-169 °C (ethanol). H NMR (CDCl , 300 MHz):
δ
δ
3
(
ppm) 2.45 (3H, s), 2.80 (3H, s), 2.91 (3H, s), 3.00 (3H, s), 3.85 (3H, s), 6.32 (1H, d, J 15.6 Hz),
1
3
6
.98 (2H, d, J 8.7 Hz), 7.30-7.35 (6H, m), 7.43 (1H, d, J 15.6 Hz). C NMR (CDCl , 75 MHz):
3
(
1
4
ppm) 21.4, 35.1, 38.7, 43.0, 55.4, 114.7, 122.7, 124.7, 125.9, 126.0, 128.8, 129.5, 130.4, 130.9,
32.6, 132.6, 136.2, 140.0, 159.9. HRMS (ESI) m/z calcd [M + H] C H N O S 440.1639, found
23 26 3 4
40.1634.
+
tert-Butyl
carboxylate (16bb). Colourless solid, mp 197-198 °C (ethanol). IR (ATR): ṽ (cm ) 1715 (s), 1611
w), 1517 (w), 1500 (m), 1461 (w), 1367 (w), 1321 (w), 1310 (w), 1298 (s), 1246 (m), 1213 (m),
(E)-4-(4-methoxyphenyl)-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
-1
(
1
1
δ
8
4
1
175 (w), 1155 (s), 1138 (s), 1126 (s), 1047 (w), 1026 (w), 1016 (m). H NMR (CDCl , 300 MHz):
3
(ppm) 1.36 (9H, s), 2.45 (3H, s), 2.77 (3H, s), 3.87 (3H, s), 6.14 (1H, d, J 15.6 Hz), 7.00 (2H, d, J
1
3
.4 Hz), 7.23 (2H, d, J 8.4 Hz), 7.31-7.36 (5H, m). C NMR (CDCl , 75 MHz):
2.9, 55.5, 82.1, 114.3, 123.8, 126.0, 127.0, 128.7, 129.4, 130.4, 131.1, 134.1, 135.9, 140.2, 143.9,
59.7, 161.1. HRMS (ESI) m/z calcd [M + H] C H N O S 469.1792, found 469.1798.
δ (ppm) 21.4, 28.0,
3
+
2
5
29
2
5
(
E)-4-(4-Chlorophenyl)-N,N-dimethyl-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
-
carboxamide (16ca). Red solid, mp 107-110 °C (taken-up with petroleum ether). IR (ATR): ṽ (cm
1
1
)
1633 (m), 1511 (m), 1385 (w), 1305 (m), 1130 (s), 1090 (m), 1004 (m). H NMR (CDCl , 300
3
MHz):
δ (ppm) 2.45 (3H, s), 2.81 (3H, s), 2.97 (3H, s), 3.01 (3H, s), 6.27 (1H, dd, J 15.9 Hz), 7.32-
1
3
7.46 (9H, m). C NMR (CDCl , 75 MHz):
δ
(ppm) 21.4, 35.3, 38.7, 42.9, 123.9, 125.9, 129.2,
3
1
29.1, 129.5, 129.5, 130.5, 131.1, 132.8, 134.8, 136.0, 140.2, 146.6, 163.8. HRMS (ESI) m/z calcd
+
[
M + H] C H ClN O S 444.1143, found 444.1140.
22 23 3 3
tert-Butyl
(E)-4-(4-chlorophenyl)-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
-1
carboxylate (16cb). Yellow solid, mp 151-152 °C (ethanol). IR (ATR): ṽ (cm ) 1726 (m), 1489
(
w), 1370 (m), 1320 (w), 1314 (w), 1295 (m), 1217 (m), 1158 (m), 1139 (s), 1130 (s), 1104 (m),
1
1
2
7
1
092 (m), 1020 (w), 1004 (w). H NMR (CDCl , 300 MHz):
.78 (3H, s), 6.10 (1H, d, J 15.6 Hz), 7.25 – 7.37 (7H, m), 7.46 (2H, d, J 8.4 Hz). C NMR (CDCl ,
δ
(ppm) 1.35 (9H, s), 2.45 (3H, s),
3
1
3
3
5 MHz):
δ (ppm) 21.4, 28.0, 42.9, 82.4, 125.9, 126.0, 129.1, 129.1, 129.2, 130.4, 131.4, 134.1,
+
34.7, 135.8, 140.4, 143.7, 160.7 (two isochronous carbons). HRMS (ESI) m/z calcd [M + H]
C H ClN O S 473.1296, found 473.1292.
24
26
2
4

1
6
ACCEPTED MANUSCRIPT
(
Z)-N,N-Dimethyl-5-[2-(methylsulfonyl)vinyl]-4-o-tolyl-1-p-tolyl-1H-pyrazole-3-carboxamide
1
(16da). Yellow solid. H NMR (CDCl , 300 MHz):
δ
(ppm) 1.92 (3H, s), 2.25 (3H, s), 2.41 (3H, s),
3
3
.01 (3H, s), 3.12 (3H, s), 6.34 (1H, d, J 11.6 Hz), 6.90 (1H, d, J 11.6 Hz), 7.13- 7.31 (6H, m), 7.42
1
3
(2H, d, J 8.4 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.2, 21.3, 35.3, 39.0, 40.9, 123.7, 125.0,
3
1
25.9, 128.3, 130.0, 130.6, 130.7, 131.2, 131.2, 132.9, 133.4, 136.9, 137.9, 138.7, 146.3, 164.5.
+
HRMS (ESI) m/z calcd [M + H] C H N O S 424.1689, found 424.1683.
2
3
26
3
3
(
E)-N,N-Dimethyl-5-(2-(methylsulfonyl)vinyl)-4-(2-thienyl)-1-p-tolyl-1H-pyrazole-3-
-1
carboxamide (16ea). Pale green solid, mp 167-168 °C (ethanol). IR (ATR): ṽ (cm ) 1633 (s), 1513
1
(
m), 1384 (w), 1315 (w), 1292 (s), 1260 (w), 1138 (s), 1114 (m), 1043 (w), 1017 (w). H NMR
CDCl , 300 MHz): (ppm) 2.45 (3H, s), 2.83 (3H, s), 2.99 (3H, s), 3.04 (3H, s), 6.39 (1H, d, J
5.6 Hz), 7.12 (1H, dd, J 5.1 and 3.5 Hz), 7.16 (1H, dd, J 3.5 and 1.3 Hz), 7.33 (4H, s), 7.43 (1H,
(
1
δ
3
1
3
dd, J 5.1 and 1.3 Hz), 7.49 (1H, d, J 15.6 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 21.4, 35.2,
3
3
1
8.8, 42.9, 117.7, 125.8, 127.7, 128.1, 128.9, 128.9, 130.0, 130.5, 130.5, 133.6, 136.0, 140.2, 147.2,
+
63.7. HRMS (ESI) m/z calcd [M + H] C H N O S 416.1097, found 416.1095.
20
22
3
3 2
[
6-(Methylsulfonylmethyl)-5-nitro-1,4-di-p-tolyl-1,4,5,6-tetrahydropyridazin-3-yl](phenyl)
1
0
1
methanone (17ac). Yellow solid, mp 121-123 °C (ethanol). H NMR (CDCl , 300 MHz):
2
9
δ
(ppm)
.26 (3H, s), 2.34 (3H, s), 2.73 (3H, s), 3.31-3.44 (2H, m), 4.96 (1H, d, J 9.8 Hz), 5.35 (1H, dd, J
.7 and 4.0 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
3
13
Hz), 7.31 (2H, d, J 8.7 Hz), 7.38-7.47 (2H, m), 7.50-7.57 (1H, m), 7.93-7.97 (2H, m). C NMR
CDCl , 75 MHz): (ppm) 20.9, 21.2, 40.3, 42.6, 49.9, 52.1, 86.2, 118.1, 128.0, 128.2, 130.3,
30.5, 130.5, 132.7, 132.9, 134.6, 136.4, 138.5, 141.3, 142.8, 189.1. HRMS (ESI) m/z calcd [M +
(
1
δ
3
+
H] C H N O S 506.1744, found 506.1749.
2
7
28
3
5
1
-[6-(Methylsulfonylmethyl)-5-nitro-1,4-di-p-tolyl-1,4,5,6-tetrahydropyridazin-3-yl]ethanone
1
0
-1
(17ad). Yellow solid, mp 79-80 °C (ethanol). IR (ATR): ṽ (cm ) 1675 (m), 1556 (s), 1511 (s),
1
1
2
5
360 (m), 1303 (s), 1260 (m), 1163 (m), 1135 (s), 1089 (w). H NMR (CDCl , 300 MHz):
.30 (3H, s), 2.38 (6H, s), 2.77 (3H, s), 3.28 (1H, dd, J 14.8 and 5.7 Hz), 3.39 (1H, dd, J 14.8 and
.0 Hz), 4.73 (1H, d, J 7.6 Hz), 5.14 (1H, app. q), 5.28 (1H, dd, J 7.6 and 3.9 Hz), 7.02 (2H, d, J 8.1
δ
(ppm)
3
1
3
Hz), 7.13 (2H, d, J 7.8 Hz), 7.26 (2H, d, J 8.1 Hz), 7.36 (2H, d, J 8.4 Hz). C NMR (CDCl , 75
3
MHz):
δ (ppm) 21.0, 21.3, 25.0, 39.5, 42.6, 49.3, 51.8, 85.5, 120.0, 127.6, 130.3, 130.4, 133.8,
+
135.6, 138.3, 141.3, 142.1, 195.2. HRMS (ESI) m/z calcd [M + H] C H N O S 444.1588, found
22 26 3 5
444.1585.
[
4-(4-Methoxyphenyl)-6-(methylsulfonylmethyl)-5-nitro-1-p-tolyl-1,4,5,6-tetrahydropyridazin-
-1
3
-yl](phenyl)methanone (17bc). Yellow solid, mp 160-161 °C (ethanol). IR (ATR): ṽ (cm ) 1641
(
m), 1560 (s), 1511 (s), 1302 (s), 1270 (m), 1251 (m), 1185 (m), 1175 (m), 1149 (s), 1137 (m), 1120
1
(s), 1025 (m). H NMR (CDCl , 300 MHz):
δ (ppm) 2.34 (3H, s), 2.73 (3H, s), 3.28-3.48 (2H, m),
3
3.73 (3H, s), 4.95 (1H, d, J 9.6 Hz), 5.35 (1H, dd, J 9.6 and 4.2 Hz), 5.44 (1H, dd, J 9.6 and 5.4
Hz), 6.82 (2H, d, J 8.7 Hz), 7.18-7.23 (4H, m), 7.30 (2H, d, J 8.7 Hz), 7.40-7.46 (2H, m), 7.52-7.57
1
3
(
1H, m), 7.95 (2H, app. d). C NMR (CDCl , 75 MHz): δ (ppm) 20.9, 39.9, 42.5, 50.0, 52.1, 55.4,
3

1
7
ACCEPTED MANUSCRIPT
8
1
6.2, 115.1, 118.1, 127.6, 128.2, 129.2, 130.4, 130.5, 132.7, 134.6, 136.4, 141.3, 142.9, 159.6,
+
89.1. HRMS (ESI) m/z calcd [M + H] C H N O S 522.1693, found 522.1692.
27
28
3
6
1
-[4-(4-Methoxyphenyl)-6-(methylsulfonylmethyl)-5-nitro-1-p-tolyl-1,4,5,6-
1
tetrahydropyridazin-3-yl]ethanone (17bd). Yellow solid, mp 165-166 °C (ethanol). H NMR
CDCl , 300 MHz): (ppm) 2.38 (6H, s), 2.78 (3H, s), 3.27 (1H, dd, J 15.0 and 6.3 Hz), 3.40 (1H,
(
δ
3
dd, J 15.0 and 5.1 Hz), 3.77 (3H, s), 4.72 (1H, d, J 7.5 Hz), 5.14 (1H, app. q), 5.28 (1H, dd, J 7.5
and 3.9 Hz), 6.85 (2H, d, J 9.0 Hz), 7.06 (2H, d, J 8.7 Hz), 7.27 (2H, d, J 8.4 Hz), 7.37 (2H, d, J 8.7
1
3
Hz). C NMR (CDCl , 75 MHz):
1
δ (ppm) 21.0, 25.0, 39.1, 42.6, 49.7, 51.8, 55.4, 85.5, 115.0,
3
+
20.0, 128.7, 128.9, 130.4, 135.6, 141.3, 142.1, 159.6, 195.2. HRMS (ESI) m/z calcd [M + H]
C H N O S 460.1537, found 460.1532.
22
26
3
6
[
4-(4-Chlorophenyl)-6-(methylsulfonylmethyl)-5-nitro-1-p-tolyl-1,4,5,6-tetrahydropyridazin-3-
-1
yl](phenyl)methanone (17cc). Brown solid, mp 104-106 °C (ethanol). IR (ATR): ṽ (cm ) 1646
(
m), 1158 (s), 1511 (s), 1491 (m), 1340 (m), 1304 (s), 1262 (m), 1197 (m), 1168 (m), 1132 (s), 1117
1
(s), 1092 (s), 1054 (m), 1015 (m). H NMR (CDCl , 300 MHz):
δ 2.34 (3H, s), 2.73 (3H, s), 3.27-
3
3
.44 (2H, m), 4.97 (1H, d, J 9.9 Hz), 5.33 (1H, dd, J 9.9 and 3.9 Hz), 5.47 (1H, app. q), 7.14-7.36
1
3
(8H, m), 7.38-7.50 (2H, m), 7.51-7.61 (1H, m), 7.94 (2H, app. d). C NMR (CDCl , 75 MHz): δ
3
(
1
5
ppm) 20.9, 40.1, 42.6, 49.9, 52.1, 85.9, 118.1, 128.3, 129.5, 129.9, 130.5, 130.5, 132.9, 134.6,
34.7, 134.9, 136.2, 141.1, 141.9, 188.8. HRMS (ESI) m/z calcd [M + H] C H ClN O S
26 25 3 5
26.1198, found 526.1192.
+
1
3
-[4-(4-Chlorophenyl)-6-(methylsulfonylmethyl)-5-nitro-1-p-tolyl-1,4,5,6-tetrahydropyridazin-
-1
-yl]ethanone (17cd). Orange solid, mp 101-102 °C (ethanol). IR (ATR): ṽ (cm ) 1672 (m), 1558
(
m), 1511 (m), 1492 (m), 1361 (m), 1303 (s), 1161 (m), 1135 (s), 1091 (s), 1063 (m), 1044 (m),
1
1
5
014 (m). H NMR (CDCl , 300 MHz):
δ
(ppm) 2.39 (6H, s), 2.78 (3H, s), 3.27 (1H, dd, J 14.8 and
3
.9 Hz), 3.37 (1H, dd, J 14.8 and 5.1), 4.73 (1H, d, J 8.1 Hz), 5.18 (1H, app. q), 5.25 (1H, dd, J 8.1
and 3.9 Hz), 7.10 (2H, d, J 8.4 Hz), 7.27 (2H, d, J 8.4 Hz), 7.31 (2H, d, J 8.4 Hz), 7.37 (2H, d, J 8.6
1
3
Hz). C NMR (CDCl , 75 MHz):
1
δ (ppm) 21.0, 25.0, 39.3, 42.6, 49.4, 51.8, 85.3, 119.8, 129.2,
3
+
29.8, 130.5, 134.5, 135.5, 135. 8, 141.1, 141.4, 195.0. HRMS (ESI) m/z calcd [M + H]
C H ClN O S 464.1041, found 464.1046.
21
23
3
5
[
6-(Methylsulfonylmethyl)-5-nitro-4-o-tolyl-1-p-tolyl-1,4,5,6-tetrahydropyridazin-3-yl]
1
(phenyl)methanone (17dc). Yellow solid, mp 155-156 °C (ethanol). H NMR (CDCl , 300 MHz):
3
δ
1
(ppm) 2.35 (3H, s), 2.68 (3H, s), 2.73 (3H, s), 3.36 (1H, dd, J 15.0 and 5.1 Hz), 3.45 (1H, dd, J
5.0 and 5.1 Hz), 5.19 (1H, d, J 9.0 Hz), 5.36-5.50 (2H, m), 6.98 (1H, d, J 7.1 Hz), 7.04-7.17 (2H,
m), 7.17-7.27 (3H, m), 7.31 (2H, d, J 8.6 Hz), 7.36-7.46 (2H, m), 7.48-7.58 (1H, m), 7.91 (2H, app.
1
3
d). C NMR (CDCl , 75 MHz):
δ
(ppm) 19.6, 20.9, 37.0, 42.5, 49.9, 52.1, 85.6, 118.5, 126.4,
3
1
27.0, 128.1, 128.5, 130.5, 132.0, 132.6, 134.4, 134.8, 136.4, 138.0, 141.3, 143.2, 189.1 (two
+
isochronous carbons). HRMS (ESI) m/z calcd [M + H] C H N O S 506.1744, found 506.1740.
27
28
3
5
1
-[6-(Methylsulfonylmethyl)-5-nitro-4-o-tolyl-1-p-tolyl-1,4,5,6-tetrahydropyridazin-3-yl]
-1
ethanone (17dd). Pale pink solid, mp 211- 212 °C (ethanol). IR (ATR): ṽ (cm ) 1668 (m), 1560
s), 1507 (m), 1359 (m), 1321 (m), 1300 (s), 1266 (m), 1242 (m), 1187 (m), 1169 (s), 1145 (m),
(

1
8
ACCEPTED MANUSCRIPT
1
1
(
125 (s), 1096 (m), 1039 (m). H NMR (CDCl , 300 MHz):
δ
(ppm) 2.35 (3H, s), 2.39 (3H, s), 2.58
3H, s), 2.77 (3H, s), 3.29 (1H, dd, J 14.4 and 6.6 Hz), 3.44 (1H, dd, J 14.7 and 4.8 Hz), 4.93 (1H,
d, J 6.6 Hz), 5.10 (1H, br q), 5.35 (1H, dd, J 6.9 and 3.9 Hz), 6.77 (1H, d, J 7.5 Hz), 7.08-7.24 (3H,
3
13
m), 7.28 (2H, d, J 8.7 Hz), 7.37 (2H, d, J 8.7 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 19.6, 21.0,
3
2
1
4.9, 36.6, 42.6, 49.1, 51.9, 84.3, 120.6, 126.5, 126.9, 128.5, 130.4, 131.9, 135.2, 135.8, 137.3,
+
41.3, 142.2, 195.2. HRMS (ESI) m/z calcd [M + H] C H N O S 444.1588, found 444.1591.
2
2
26
3
5
1
-[6-(Methylsulfonylmethyl)-4-(2-naphthyl)-5-nitro-1-p-tolyl-1,4,5,6-tetrahydropyridazin-3-yl]
-1
ethanone (17fd). Yellow solid, mp 118-120 °C (ethanol). IR (ATR): ṽ (cm ) 1675 (m), 1555 (s),
1
1
δ
1
7
509 (s), 1359 (m), 1303 (s), 1257 (m), 1164 (m), 1129 (s), 1088 (m). H NMR (CDCl , 300 MHz):
3
(ppm) 2.40 (3H, s), 2.41 (3H, s), 2.77 (3H, s), 3.32 (1H, dd, J 14.7 and 6.0 Hz), 3.42 (1H, dd, J
4.7 and 5.1 Hz), 4.93 (1H, d, J 8.1 Hz), 5.25 (1H, app. q), 5.42 (1H, dd, J 8.1 and 4.2 Hz), 7.27-
.31 (3H, m), 7.41 (2H, d, J 8.4 Hz), 7.45-7.51 (2H, m), 7.58 (1H, s), 7.75-7.85 (3H, m). C NMR
(ppm) 21.0, 25.1, 40.0, 42.6, 49.5, 51.8, 85.5, 119.7, 125.1, 126.7, 126.8,
27.2, 127.9, 128.0, 129.7, 130.5, 133.1, 133.5, 134.2, 135.6, 141.2, 142.0, 195.1. HRMS (ESI) m/z
1
3
(CDCl , 75 MHz): δ
3
1
+
calcd [M + H] C H N O S 480.1588, found 480.1585.
25
26
3
5
Reactions of nitrobutadienes 13a-c,f with hydrazones 14a-d and DBU in ethanol
In a flask, the appropriate nitrobutadiene 13 (50.0 mg) and hydrazone 14 (1 equiv) were dissolved
in EtOH (3 mL) and DBU was added (1 equiv) under magnetic stirring. The mixture was then
warmed to reflux for 1 h, and when completed (as verified by TLC), diluted with ethyl acetate and
washed with water. The organic phase was dried over Na SO , filtered and the solvent removed
2
4
under reduced pressure. The obtained crude was purified by chromatography on a silica gel column,
using petroleum ether/ethyl acetate mixtures as eluent.
N,N-Dimethyl-6-(methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazine-3-carboxamide
1
0
-1
(
1
3
19aa). Orange solid, mp 138-139 °C (dichloromethane/petroleum ether). IR (ATR): ṽ (cm )
1
621 (s), 1508 (s), 1287 (s), 1166 (m), 1126 (s), 1082 (s), 1060 (m), 1036 (m). H NMR (CDCl ,
3
00 MHz):
δ (ppm) 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
1
3
(
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). C NMR
CDCl , 75 MHz): (ppm) 20.7, 21.4, 35.2, 38.8, 43.2, 47.3, 54.4, 115.6, 121.0, 127.1, 129.5,
(
1
δ
3
+
30.3, 132.1, 132.7, 133.1, 138.5, 141.5, 142.0, 165.8. HRMS (ESI) m/z calcd [M + H]
C H N O S 426.1846, found 426.1850.
23
28
3
3
tert-Butyl
6-(methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazine-3-carboxylate
1
0
-1
(19ab). Yellow solid, mp 86-88 °C (diethyl ether/petroleum ether). IR (ATR): ṽ (cm ) 1710 (m),
1
1
3
2
509 (m), 1367 (w), 1297 (m), 1272 (m), 1255 (m), 1168 (s), 1110 (s), 1036 (w). H NMR (CDCl ,
3
00 MHz):
δ (ppm) 1.30 (9H, s), 2.34 (3H, s), 2.36 (3H, s), 2.99 (3H, s), 3.21 (1H, dd, J 13.4 and
.9 Hz), 3.56 (1H, dd, J 13.4 and 9.9 Hz), 5.77 (1H, ddd, J 9.9, 7.2 and 2.9 Hz), 6.02 (1H, d, J 7.2
1
3
Hz), 7.08-7.17 (4H, m), 7.20 (2H, d, J 8.4 Hz), 7.43 (2H, d, J 8.6 Hz). C NMR (CDCl , 75 MHz):
3
δ
1
4
(ppm) 20.8, 21.3, 27.8, 43.2 47.8, 54.3, 81.9, 116.2, 119.2, 127.5, 128.9, 130.2, 132.8, 133.6,
+
35.0, 138.0, 138.9, 141.1, 162.5. HRMS (ESI) m/z calcd [M + H] C H N O S 455.1999, found
25
31
2
4
55.1993.

1
9
ACCEPTED MANUSCRIPT
[
(
(
6-(Methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazin-3-yl](phenyl)methanone
1
0
-1
19ac). Yellow solid, mp 189-190 °C (ethanol). IR (ATR): ṽ (cm ) 1647 (m), 1527 (w), 1507
m), 1319 (w), 1309 (w), 1296 (m), 1285 (m), 1270 (w), 1248 (w), 1201 (m), 1186 (m), 1177 (m),
1
1
2
1
149 (m), 1137 (s), 1055 (w), 1031 (w), 1015 (w), 1011 (w). H NMR (CDCl , 300 MHz):
δ
(ppm)
3
.31 (3H, s), 2.33 (3H, s), 2.98 (3H, s), 3.19 (1H, dd, J 13.3 and 2.5 Hz), 3.61 (1H, dd, J 13.2 and
0.0 Hz), 5.84 (1H, ddd, J 9.5, 7.3 and 2.1 Hz), 6.25 (1H, d, J 7.1 Hz), 7.10 (4H, app. s), 7.19 (2H,
1
3
d, J 8.4 Hz), 7.32 (2H, d, J 8.6 Hz), 7.52 (2H, app. t), 7.62 (1H, app. t), 8.11 (2H, app. d). C NMR
CDCl , 75 MHz): (ppm) 20.8, 21.4, 43.3, 47.6, 54.8, 116.1, 120.5, 127.3, 128.3, 129.3, 130.4,
30.8, 132.8, 133.2, 133.8, 133.8, 137.0, 138.1, 141.0, 143. 7, 189.4. HRMS (ESI) m/z calcd [M +
(
1
δ
3
+
H] C H N O S 459.1737, found 459.1733.
2
7
27
2
3
1
0
1
-[6-(Methylsulfonylmethyl)-1,4-di-p-tolyl-1,6-dihydropyridazin-3-yl]ethanone
(19ad).
-1
Yellow solid, mp 136-137 °C (ethanol). IR (ATR): ṽ (cm ) 1668 (s), 1511 (m), 1487 (m), 1370
(
m), 1310 (m), 1293 (s), 1285 (m), 1250 (m), 1196 (s), 1191 (s), 1180 (s), 1139 (s), 1112 (m), 1096
1
(m), 1036 (w), 1021 (w). H NMR (CDCl , 300 MHz):
δ (ppm) 2.35 (3H, s), 2.37 (3H, s), 2.54 (3H,
3
s), 2.98 (3H, s), 3.19 (1H, dd, J 13.2 and 2.7 Hz), 3.51 (1H, dd, J 13.2 and 9.9 Hz), 5.78 (1H, ddd, J
.9, 7.2 and 2.7 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,
9
13
d, J 8.4 Hz), 7.45 (2H, d, J 8.4 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.9, 21.4, 26.0, 43.4,
3
4
7.9, 54.6, 116.4, 120.1, 127.5, 129.0, 130.5, 132.7, 134.4, 134.6, 137.8, 140.8, 143.4, 194.9.
+
HRMS (ESI) m/z calcd [M + H] C H N O S 397.1580, found 397.1576.
2
2
25
2
3
4
-(4-Methoxyphenyl)-N,N-dimethyl-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazine
-
-
3-carboxamide (19ba). Yellow solid, mp 103-104 °C (toluene/petroleum ether). IR (ATR): ṽ (cm
1
1
)
1631 (m), 1609 (m), 1509 (s), 1291 (s), 1245 (s), 1170 (s), 1126 (s), 1083 (m), 1024 (m). H
NMR (CDCl , 300 MHz): (ppm) 2.33 (3H, s), 2.94 (3H, s), 2.97 (3H, s), 3.15 (3H, s), 3.24 (1H,
dd, J 13.5 and 2.7 Hz), 3.63 (1H, dd, J 13.5 and 9.6 Hz), 3.81 (3H, s), 5.72 (1H, ddd, J 9.6, 7.2 and
δ
3
2
.7 Hz), 6.21 (1H, d, J 7.2 Hz), 6.86 (2H, d, J 8.7 Hz), 7.13-7.24 (4H, m), 7.32 (2H, d, J 8.7 Hz).
1
3
C NMR (CDCl , 75 MHz):
δ (ppm) 20.8, 35.2, 38.8, 43.3, 47.3, 54.4, 55.4, 114.2, 115.6, 120.5,
3
+
128.4, 128.5, 130.3, 131.7, 132.7, 141.5, 142.0, 159.9, 165.8. HRMS (ESI) m/z calcd [M + H]
C H N O S 442.1795, found 442.1799.
23
28
3
4
tert-Butyl 4-(4-methoxyphenyl)-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazine-3-
1
carboxylate (19bb). Yellow solid, mp 78-80 °C (toluene/petroleum ether). H NMR (CDCl , 300
3
MHz):
δ (ppm) 1.31 (9H, s), 2.34 (3H, s), 2.98 (3H, s), 3.21 (1H, dd, J 13.2 and 2.4 Hz), 3.55 (1H,
dd, J 13.2 and 9.6 Hz), 3.82 (3H, s), 5.76 (1H, ddd, J 9.6, 7.5 and 2.6 Hz), 6.00 (1H, d, J 7.2 Hz),
13
6
.87 (2H, d, J 8.4 Hz), 7.15 (2H, d, J 8.6 Hz), 7.20 (2H, d, J 8.4 Hz), 7.43 (2H, d, J 8.5 Hz). C
NMR (CDCl , 75 MHz): (ppm) 20.8, 27.9, 43.3, 47.8, 54.3, 55.5, 82.0, 113.7, 116.2, 118.8, 128.9,
δ
3
+
1
30.3, 130.3, 132.4, 133.6, 139.0, 141.1, 159.6, 162.6. HRMS (ESI) m/z calcd [M + H]
C H N O S 471.1948, found 471.1943.
25
31
2
5
[
4-(4-Methoxyphenyl)-6-(methylsulfonylmethyl)-1-(p-tolyl)-1,6-dihydropyridazin-3-yl]
-1
(phenyl)methanone (19bc). Yellow solid, mp 105-106 °C (ethanol). IR (ATR): ṽ (cm ) 1607 (m),
1
1
597 (m), 1508 (s), 1291 (s), 1247 (s), 1174 (s), 1155 (s), 1131 (s), 1073 (w), 1026 (m). H NMR

2
0
ACCEPTED MANUSCRIPT
(
CDCl , 300 MHz):
δ
(ppm) 2.33 (3H, s), 2.98 (3H, s), 3.19 (1H, dd, J 13.2 and 2.5 Hz), 3.60 (1H,
dd, J 13.2 and 10.0 Hz), 3.77 (3H, s), 5.83 (1H, ddd, J 9.8, 7.2 and 2.5 Hz), 6.22 (1H, d, J 7.2 Hz),
.82 (2H, d, J 8.7 Hz), 7.11-7.21 (4H, m), 7.32 (2H, d, J 8.7 Hz), 7.48-7.57 (2H, m), 7.58-7.66 (1H,
3
6
1
3
m), 8.07-8.13 (2H, m). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.8, 43.4, 47.7, 54.9, 55.4, 114.1,
3
1
1
16.2, 120.0, 128.4, 128.7, 129.1, 130.5, 130.8, 132.8, 132.9, 133.8, 137.0, 141.0, 143.7, 159.7,
+
89.5. HRMS (ESI) m/z calcd [M + H] C H N O S 475.1686, found 475.1680.
27
27
2
4
1
-[4-(4-Methoxyphenyl)-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazin-3-yl]
-1
ethanone (19bd). Yellow solid, mp 194-195 °C (ethanol). IR (ATR): ṽ (cm ) 1663 (s), 1609 (w),
1
1
2
513 (s), 1489 (m), 1368 (m), 1338 (w), 1294 (s), 1241 (s), 1173 (s), 1144 (s), 1131 (s), 1085 (m),
1
066 (m), 1031 (m), 1023 (m). H NMR (CDCl , 300 MHz):
δ (ppm) 2.37 (3H, s), 2.54 (3H, s),
3
.97 (3H, s), 3.19 (1H, d, J 13.2 and 2.4 Hz), 3.50 (1H, dd, J 13.2 and 9.9 Hz), 3.81 (3H, s), 5.77
(
1H, ddd, J 9.9, 7.5 and 2.7 Hz), 6.02 (1H, d, J 6.9 Hz), 6.86 (2H, d, J 8.7 Hz), 7.07 (2H, d, J 8.7
1
3
Hz), 7.25 (2H, d, J 8.7 Hz), 7.45 (2H, d, J 8.7 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.9, 26.0,
3
4
1
3.4, 48.0, 54.6, 55.4, 113.7, 116.4, 119.7, 128.8, 129.9, 130.5, 132.3, 134.4, 140.9, 143.3, 159.5,
+
94.9. HRMS (ESI) m/z calcd [M + H] C H N O S 413.1530, found 413.1526.
22
25
2
4
4
3
1
-(4-Chlorophenyl)-N,N-dimethyl-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazine-
-1
-carboxamide (19ca). Yellow solid, mp 85-86 °C (toluene/petroleum ether). IR (ATR): ṽ (cm )
638 (m), 1506 (m), 1403 (m), 1295 (m), 1203 (m), 1172 (m), 1128 (m), 1090 (s), 1040 (m), 1013
1
(m). H NMR (CDCl , 300 MHz):
δ
(ppm) 2.34 (3H, s), 2.96 (3H, s), 2.98 (3H, s), 3.13 – 3.29 (4H,
3
m), 3.66 (1H, dd, J 13.2 and 9.9 Hz), 5.75 (1H, app. t), 6.26 (1H, d, J 7.2 Hz), 7.13-7.23 (4H, m),
1
3
7
.28-7.36 (4H, m). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.8, 35.3, 38.9, 43.2, 47.2, 54.3, 115.7,
3
1
22.0, 128.6, 129.0, 130.4, 131.3, 133.0, 134.7, 141.2, 141.4, 165.4 (two isochronous carbons).
+
HRMS (ESI) m/z calcd [M + H] C H ClN O S 446.1300, found 446.1305.
2
2
25
3
3
tert-Butyl
4-(4-chlorophenyl)-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazine-3-
-1
carboxylate (19cb). Yellow solid, mp 100-101 °C (ethanol). IR (ATR): ṽ (cm ) 1700 (m), 1493
(
m), 1319 (m), 1297 (m), 1281 (m), 1268 (m), 1257 (m), 1170 (m), 1133 (s), 1121 (s), 1092 (m),
1
1
2
9
073 (m), 1042 (m), 1015 (m). H NMR (CDCl , 300 MHz):
δ
(ppm) 1.31 (9H, s), 2.34 (3H, s),
3
.98 (3H, s), 3.21 (1H, dd, J 13.2 and 2.7 Hz), 3.56 (1H, dd, J 13.2 and 9.9 Hz), 5.80 (1H, ddd, J
.9, 7.2 and 2.7 Hz), 6.03 (1H, d, J 7.2 Hz), 7.16 (2H, d, J 8.4 Hz), 7.21 (2H, d, J 8.4 Hz), 7.32 (2H,
13
d, J 8.4 Hz), 7.43 (2H, d, J 8.7 Hz). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.8, 27.9, 43.2, 47.7,
3
5
4.2, 82.2, 116.3, 120.0, 128.5, 129.1, 130.3, 131.9, 134.0, 134.0, 136.6, 138.0, 141.0, 162.2.
+
HRMS (ESI) m/z calcd [M + H] C H ClN O S 475.1453, found 475.1454.
2
4
28
2
4
[
4-(4-Chlorophenyl)-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazin-3-yl](phenyl)
-1
methanone (19cc). Yellow solid, mp 202-203 °C (ethanol). IR (ATR): ṽ (cm ) 1660 (m), 1649
(
m), 1505 (m), 1447 (w), 1286 (s), 1263 (w), 1252 (m), 1234 (w), 1174 (s), 1156 (m), 1144 (s),
1
1
131 (s), 1091 (m), 1066 (m), 1012 (w). H NMR (CDCl , 300 MHz):
δ
(ppm) 2.33 (3H, s), 2.96
3
(3H, s), 3.19 (1H, dd, J 13.0 and 2.5 Hz), 3.61 (1H, dd, J 13.0 and 10.1 Hz), 5.86 (1H, ddd, J 9.9,
7
8
.2 and 2.5 Hz), 6.25 (1H, d, J 7.1 Hz), 7.15 (2H, d, J 8.5 Hz), 7.19 (2H, d, J 8.8 Hz), 7.26 (2H, d, J
1
3
.5 Hz), 7.32 (2H, d, J 8.7 Hz), 7.47-7.52 (2H, m), 7.56-7.72 (1H, m), 8.08 (2H, app. d). C NMR
(ppm) 20.8, 43.2, 47.5, 54.7, 116.2, 121.5, 128.4, 128.7, 128.7, 128.8, 130.5,
(CDCl , 75 MHz):
δ
3

2
1
ACCEPTED MANUSCRIPT
+
130.7, 132.2, 132.9, 134.1, 135.4, 136.9, 140.8, 142.9, 189.2. HRMS (ESI) m/z calcd [M + H]
C H ClN O S 479.1191, found 479.1187.
26
24
2
3
1
-[4-(4-Chlorophenyl)-6-(methylsulfonylmethyl)-1-p-tolyl-1,6-dihydropyridazin-3-yl]ethanone
-1
(19cd). Yellow solid, mp 201-202 °C (ethanol). IR (ATR): ṽ (cm ) 1666 (s), 1511 (m), 1485 (s),
1
1
402 (m), 1370 (m), 1335 (m), 1304 (m), 1291 (s), 1280 (s), 1253 (m), 1242 (m), 1188 (s), 1178 (s),
1
138 (s), 1094 (s), 1017 (m). H NMR (CDCl , 300 MHz):
δ (ppm) 2.38 (3H, s), 2.53 (3H, s), 2.97
3
(3H, s), 3.20 (1H, dd, J 12.9 and 2.4 Hz), 3.51 (1H, dd, J 12.9 and 9.9 Hz), 5.81 (1H, ddd, J 9.9, 7.2
and 2.6 Hz), 6.06 (1H, d, J 7.1 Hz), 7.08 (2H, d, J 8.4 Hz), 7.22-7.33 (4H, m), 7.45 (2H, d, J 8.7
1
3
Hz). C NMR (CDCl , 75 MHz):
1
δ (ppm) 20.9, 25.8, 43.3, 47.9, 54.5, 116.4, 121.1, 128.4, 129.0,
3
+
30.5, 131.7, 133.9, 134.6, 136.2, 140.7, 142.6, 194.7. HRMS (ESI) m/z calcd [M + H]
C H ClN O S 417.1034, found 417.1030.
21
22
2
3
N,N-Dimethyl-6-(methylsulfonylmethyl)-4-(2-naphthyl)-1-p-tolyl-1,6-dihydropyridazine-3-
-1
carboxamide (19fa). Yellow solid, mp 185-186 °C (ethanol). IR (ATR): ṽ (cm ) 1644 (m), 1623
(
s), 1611 (m), 1503 (s), 1412 (m), 1404 (m), 1304 (s), 1296 (s), 1269 (m), 1246 (m), 1199 (), 1174
1
(m), 1140 (s), 1126 (s), 1080 (s), 1061 (m), 1046 (m), 1032 (s), 1013 (m). H NMR (CDCl , 300
3
MHz):
δ (ppm) 2.34 (3H, s), 2.94 (3H, s), 2.98 (3H, s), 3.20 (3H, s), 3.28 (1H, dd, J 13.2 and 2.4
Hz), 3.71 (1H, dd, J 13.2 and 9.6 Hz), 5.79 (1H, ddd, J 9.6, 7.2 and 2.4 Hz), 6.38 (1H, d, J 6.9 Hz),
1
3
7
7
1
.20 (2H, d, J 8.4 Hz), 7.36 (3H, app. d), 7.44-7.52 (2H, m), 7.73-7.87 (4H, m). C NMR (CDCl ,
3
5 MHz):
δ (ppm) 20.8, 35.2, 38.8, 43.2, 47.4, 54.5, 115.7, 121.9, 125.0, 126.5, 127.8, 128.4, 128.4,
30.3, 132.3, 132.8, 133.2, 133.4, 133.5, 141.5, 142.0, 165.7 (two couples of isochronous carbons).
+
HRMS (ESI) m/z calcd [M + H] C H N O S 462.1846, found 462.1841.
2
6
28
3
3
[
6-(Methylsulfonylmethyl)-4-(2-naphthyl)-1-p-tolyl-1,6-dihydropyridazin-3-yl](phenyl)
-1
methanone (19fc). Yellow solid, mp 196-197 °C (ethanol). IR (ATR): ṽ (cm ) 1644 (s), 1597 (m),
506 (s), 1320 (m), 1294 (s), 1280 (m), 1267 (m), 1259 (m), 1194 (m), 1174 (m), 1154 (m), 1142
1
1
(m), 1132 (s), 1126 (s), 1055 (m), 1040 (m). H NMR (CDCl , 300 MHz): δ (ppm) 2.34 (3H, s),
3
2
9
.98 (3H, s), 3.22 (1H, dd, J 13.1 and 2.5 Hz), 3.66 (1H, dd, J 13.2 and 10.0 Hz), 5.90 (1H, ddd, J
.9, 7.2 and 2.5 Hz), 6.38 (1H, d, J 7.1 Hz), 7.21 (2H, d, J 8.4 Hz), 7.23-7.28 (1H, m), 7.37 (2H, d,
J 8.7 Hz), 7.40-7.46 (2H, m), 7.47-7.58 (2H, m), 7.61-7.69 (1H, m), 7.72 (1H, d, J 8.5 Hz), 7.75-
1
3
7
1
1
4
.81 (3H, m), 8.13 (2H, app. d). C NMR (CDCl , 75 MHz): δ (ppm) 20.8, 43.2, 47.6, 54.9, 116.2,
3
21.5, 125.5, 126.3, 126.4, 126.5, 127.8, 128.1, 128.3, 128.3, 130.5, 130.7, 132.8, 133.0, 133.2,
33.3, 133.9, 134.4, 137.0, 140.9, 143.5, 189.3. HRMS (ESI) m/z calcd [M + H] C H N O S
+
30
27
2
3
94.1664, found 494.1661.
1
-[6-(Methylsulfonylmethyl)-4-(2-naphthyl)-1-p-tolyl-1,6-dihydropyridazin-3-yl]ethanone
-1
(
(
(
19fd). Yellow solid, mp 219-220 °C (toluene/petroleum ether). IR (ATR): ṽ (cm ) 1672 (s), 1507
s), 1367 (m), 1321 (w), 1304 (s), 1295 (s), 1202 (s), 1180 (s), 1141 (s), 1128 (s), 1083 (m), 1031
1
m). H NMR (CDCl , 300 MHz):
δ (ppm) 2.39 (3H, s), 2.57 (3H, s), 3.00 (3H, s), 3.23 (1H, dd, J
3
13.2 and 2.6 Hz), 3.58 (1H, dd, J 13.2 and 9.9 Hz), 5.84 (1H, ddd, J 9.9, 7.5 and 2.6 Hz), 6.18 (1H,
d, J 7.1 H), 7.16 (1H, dd, J 8.4 and 1.8 Hz), 7.27 (2H, d, J 8.4 Hz), 7.41-7.52 (4H, m), 7.69 (1H, s),
1
3
7
.76 (1H, d, J 8.5 Hz), 7.79-7.86 (2H, m). C NMR (CDCl , 75 MHz):
δ
(ppm) 20.9, 25.9, 43.4,
3
48.0, 54.7, 116.5, 121.0, 126.0, 126.2, 126.3, 127.5, 127.8, 128.2, 130.5, 130.5, 132.8, 133.0, 133.3,

2
2
ACCEPTED MANUSCRIPT
+
1
35.0, 135.4, 140.8, 143.2, 194.8. HRMS (ESI) m/z calcd [M + H] C H N O S 433.1580, found
25 25 2 3
433.1583.
Reactions of tetrahydropyridazines 17ac and 17ad to dihydropyridazines 19ac and 19ad
In a flask, the appropriate diazine 17 (0.60 mmol) dissolved in EtOH (2 mL) was added with
piperidine (2 drops) and warmed to reflux for 1 h under magnetic stirring. After verifying the end of
reaction by TLC, the mixture was then diluted with ethyl acetate, washed with water and dried over
Na SO . Filtration and removal of the solvent under reduced pressure allowed to obtain the crude
2
4
1
product 19, almost pure at the H-NMR analysis (quantitative yields).
Oxidation reactions of sulfides 15aa and 15ac to sulfones 16aa and 16ac
In a flask, the appropriate sulfide 15 (50.0 mg, prepared as described in ref. 8) dissolved in CH Cl2
2
(5 mL) was added with MCPBA (77%, 2.2 equiv) under magnetic stirring. The end of the reaction
was verified by TLC. The final mixture was diluted with CH Cl , washed with NaHSO 5% in
2
2
3
water, then with Na CO saturated solution and finally with water. The organic phase was dried
2
3
over Na SO , filtered and concentrated under reduced pressure. The obtained crude was almost pure
2
4
1
(
as a diastereomeric Z:E mixture) at the H-NMR analysis (quantitative yields).
(
E)
and
(Z)-N,N-Dimethyl-5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-3-
1
carboxamide (16aa). Yellow solid. H NMR (CDCl , 300 MHz):
δ (ppm) 2.02 (3H Z, s), 2.36 (3H
3
Z, s), 2.40 (3H E + 3H Z, s), 2.45 (3H E, s), 2.81 (3H E, s), 2.91 (3H E, s), 2.96 (3H Z, s), 3.00 (3H
E, s), 3.05 (3H Z, s), 6.32 (1H E, d, J 15.6 Hz), 6.47 (1H Z, d, J 11.7 Hz), 7.06 (1H Z, d, J 11.4 Hz),
7.15-7.38 (8H E + 8H Z, d, J 8.1 Hz), 7.44 (1H E, d, J 15.6 Hz).
(
E) and (Z)-1-{5-[2-(Methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazol-3-yl}ethanone (16ad).
1
Beige solid. H NMR (CDCl , 300 MHz):
δ (ppm) 1.98 (3H Z, s), 2.37 (3H Z, s), 2.42 (3H Z + 3H
3
E, s), 2.47 (3H E, s), 2.57 (3H E, s), 2.62 (3H Z, s), 2.76 (3H E, s), 6.15 (1H E, d, J 15.6 Hz), 6.39
(1H Z, d, J 11.4 Hz), 6.95 (1H Z, d, J 11.4 Hz), 7.16 – 7.37 (5H E + 6H Z, m), 7.37 (4H, E, s), 7.44
(
2H Z, d, J 8.4 Hz).
1
A few milligrams of the E compound could be isolated. Beige solid. H NMR (CDCl , 300 MHz):
δ
3
(
ppm) 2.42 (3H, s), 2.47 (3H, s), 2.56 (3H, s), 2.76 (3H, s), 6.15 (1H, d, J 15.6 Hz), 7.21 (2H, d, J
1
3
8
.3 Hz), 7.27 (2H, d, J 8.0 Hz), 7.33 (1H, d, J 15.7 Hz) 7.37 ( 4H, s). C NMR (CDCl , 75 MHz):
δ
3
(
1
ppm) 21.3, 21.4, 27.9, 42.8, 125.7, 126.5, 127.9, 129.1, 129.5, 129.6, 130.4, 134.4, 135.8, 138.4,
40.2, 148.1, 193.6 (two isochronous carbons). HRMS (ESI) m/z calcd [M + H] C H N O S
22 23 2 3
+
395.1424, found 395.1427.
Crystal data for compound 17bd
C H N O S, M = 459.5, light yellow-coloured crystal with truncated pyramid shape, and
22
25
3
6
maximum dimensions 0.40 × 0.40 × 0.2 mm. Monoclinic, space group P2 /c, a = 8.927(1) Å, b =
1
3
2
2.430(4) Å, c = 11.713(2) Å, β = 101.72(1) Å, V = 2296.4(6) Å , Z = 4, F(000) = 968, d = 1.329
calc
3
-1
g/cm , µ (MoKα) = 0.18 mm . Crystals were grown from ethanol.
Intensity data were collected at 295 K on a Bruker-Nonius MACH3 diffractometer (graphite
-1
monochromated Mo Kα radiation):
ω
-θ scans, scan width 1.05°, minimum speed 0.97° min , θ
=
max

2
3
ACCEPTED MANUSCRIPT
2
8°; 6009 total measured reflections, 5518 independent reflections of which 2954 with F > 4 σ(F );
o o
18
the structure was solved with the SIR2014 program, by applying Direct Methods procedures. The
initial Fourier map showed 26 peaks which were attributed to the proper atomic species (non-
hydrogen atoms), in agreement with the expected chemical formula. This partial model was then
refined by means of full-matrix least squares cycles using the SHELXL program, and completed
with the additional peaks taken from the difference Fourier map. After some cycles of anisotropic
refinement of the heavier atoms, all hydrogen atoms were also obtained in subsequent difference
1
9
Fourier maps. Their coordinates and isotropic displacement parameters (U ) could be freely
iso
refined, except for two methyl groups (C13 and C15), which showed large anisotropic displacement
parameters. In this case, the H atoms were restrained in idealized positions (AFIX 137 instruction)
with the corresponding U value constrained to 1.2 times the U of the bonded C atom.
iso
eq
The final agreement indices are: R1= 0.057, over 2954 reflections with F > 4σ F , and wR2 =
o
o
0
0
.133, for 367 refined parameters and 5518 reflections, mean shift/e.s.d = 0.003, Goodness of fit S =
-3
-3
.973, ∆ρmin = -0.23 eÅ , ∆ρ = +0.20 eÅ .
max
Figure 1 shows the ortep diagram of the molecule with atom numbering. Bond distances and bond
angles are in the normal range if compared with tabulated values for similar compounds and no
notably short intermolecular contact is found. In accordance with the general classification of
2
0
puckering in six-membered rings, the central ring formed by N1, N2, C3, C4, C5, C6 exhibits an
envelope (or half-boat) conformation, being the C6 atom out of the mean plane defined by the other
five atoms (distance C6-plane ≅ 0.7 Å). The substituents to the asymmetric carbon atoms of the
central ring (C4, C5, C6) are arranged in the crystal in trans-cis conformation.
As no H atoms are directly bound to the more electronegative elements N, O, S, only hydrogen
bonds of C-H…O type can be established between the molecules. Although these interactions are
quite numerous in this structure (11 different contacts), they are rather weak, as attested by the
donor…acceptor distances (C….O), whose values are well greater than (only in two cases, slightly
lower than) the sum of the van der Waals radii.
Crystallographic data (CIF file, FCF file) for the structure in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplementary publication numbers CCDC-
1403698. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 IEZ, UK [fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
Financial support was provided by grants from Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR-Roma, PRIN 2010FPTBSH) and Genoa University (PRA 2013). Dr. Cinzia
Bottinelli is gratefully acknowledged for performing IR analyses.
Supplementary Data
1
13
Spectroscopic data; copies of the H and C NMR spectra for all compounds; details of the
computational studies; crystallographic materials for compound 17bd.

2
4
ACCEPTED MANUSCRIPT
References and Notes
1.
(a) Vo, C.-V. T.; Bode, J. W. J. Org. Chem. 2014, 79, 2809-2815. (b) Lednicer, D. Strategies
for Organic Drug Synthesis and Design, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2nd
edn, 2009.
2
.
.
Ballini, R.; Araújo, N.; Gil, M. V.; Román, E.; Serrano, J. A. Chem. Rev. 2013, 113, 3493-
3
515.
3
(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. 1990, 31,
4
933-4936. (c) Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron
992, 48, 4407-4418.
1
4
.
.
Guanti, G.; Dell’Erba, C.; Leandri, G.; Thea, S. J. Chem. Soc., Perkin Trans. 1 1974, 2357-
360.
(a) Surange, S. S.; Kumaran, G.; Rajappa, S.; Rajalakshmi, K.; Pattabhi, V. Tetrahedron
997, 53, 8531-8540. (b) Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.;
2
5
1
Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159-8165.
6.
(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-Di-
nitrothiophene. 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)
Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.;
Tavani, C.; Viale, M. Versatile Nitrobutadienic Building-Blocks from the Ring-Opening of 2-
and 3-Nitrothiophenes. In Targets in Heterocyclic Systems: Chemistry and Properties;
Attanasi, O. A., Spinelli, D., Eds.; Società Chimica Italiana: Rome, 2008; Vol. 11 (2007), pp
1
-20. (c) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Petrillo, G.; Rizzato, E.;
Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Arkivoc 2006, vii, 169-185.
7
.
.
(a) Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N. Eur J. Org. Chem. 2009, 4091-
4
101. (b) Rai, V.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2006, 4693-4703. (c) Berner, O.
M.; Tedeschi, L.; Enders, D. Eur J. Org. Chem. 2002, 1877-1894.
8
(a) Bianchi, L.; Maccagno, M.; Pani, M.; Petrillo, G.; Scapolla, C.; Tavani, C. “A straight
access to functionalized carbazoles by tandem reaction between indole and nitrobutadienes”
Tetrahedron DOI: 10.1016/j.tet.2015.05.046. (b) Bianchi, L.; Maccagno, M.; Petrillo, G.;
Scapolla, C.; Tavani, C.; Tirocco, A. Eur. J. Org. Chem. 2014, 39-43. (c) Bianchi, L.;
Ghelfi, F.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Spinelli, D.; Stenta, M.; Tavani, C. Eur. J.
Org. Chem. 2013, 6298-6309. (d) Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.;

2
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Scapolla, C.; Tavani, C. Tetrahedron Lett. 2012, 53, 752-757. (e) Bianchi, L.; Maccagno, M.;
Petrillo, G.; Rizzato, E.; Sancassan, F.; Spinelli, D.; Tavani, C. Tetrahedron 2011, 67, 8160-
8
169. (f) 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. (g) 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. (h) 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.
9.
(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.
1
0. Bianchi, L.; Carloni-Garaventa, A.; Maccagno, M.; Petrillo, G.; Scapolla, C.; Tavani, C.
Tetrahedron Lett. 2012, 53, 6394-6400.
1
1. (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 (2002), pp 52-79.
1
2. For recent reviews see: (a) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem. Rev. 2011, 111, 6984-7034. (b) Elguero, J.; Silva, A. M. S.; Tomé, A. C. “Five
Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles” in Modern Heterocyclic Chemistry
(Eds. Alvarez-Builla, J. A.; Vaquero, J. J.; Barluenga, J.), Wiley-VCH, Weinheim, 2011,
Chapter 8, Vol. 2, pp 635-725. (c) Yet, L. “Pyrazoles” (Ed. Joule, J. A.) 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. Among the most
recent articles concerning synthetic methods, see e.g.: (d) Mykhailiuk, P. K. Org. Biomol.
Chem. 2015, 13, 3438-3445. (e) Liang, D.; Zhu, Q. Asian J. Org. Chem. 2015, 4, 42-45. (f)
Vanjari, R.; Guntreddi, T.; Kumar, S.; Singh, K. N. Chem. Commun. 2015, 51, 366-369.
Among recent articles concerning applicative aspects, see e.g.: (g) Altomonte, S.; Baillie, G.
L.; Ross, R. A.; Zanda, M. RSC Adv. 2015, 5, 13692-13701. (h) Basha, S. S.; Reddy, P. R.;
Padmaya, A.; Padmavathi, V.; Mouli, K. C.; Vijaya, T. Med. Chem. Res. 2015, 24, 954-964.
(i) Pinna, G.; Curzu, M. M.; Dore, A.; Lazzari, P.; Ruiu, S.; Pau, A.; Murineddu, G.; Pinna, G.
A. Eur. J. Med. Chem. 2014, 85, 747-757.
13. Deng, X.; Mani, N. S. Org. Lett. 2008, 10, 1307-1310.

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6
ACCEPTED MANUSCRIPT
1
1
1
1
4. DFT/B3LYP/6-311++G**/SM8(THF) calculation have been performed; for more details, see
the Supporting Info.
5. pK = ꢁE / 2.303 RT; at -78 °C (the temperature at which the reaction was performed): 2.303
a
-1
-1
RT = 2.303 * 8.314 J K mol * 195 K = 3.7 kJ/mol.
6. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.;
Tavani, C. J. Org. Chem. 2005, 70, 8734-8738.
7. Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1996, 52, 5889-5898; Dell’Erba,
C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 11239-11248; Dell’Erba, C.;
Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1993, 49, 235-242.
1
8. SIR2014. http://wwwba.ic.cnr.it/content/sir2011-v10; Burla, M. C.; Caliandro, R.; Carrozzini,
B.; Cascarano, G. L.; Giacovazzo, C.; Mallamo, M.; Mazzone, A.; Polidori, G. 2014 In
preparation.
1
2
9. Sheldrick, G. M. Acta Crystallogr. A64, 2008, 112-122.
0. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354-1358.

1
ACCEPTED MANUSCRIPT
Synthesis of Poly-Functionalized
Pyrazoles and Pyridazines from Nitrobutadienes:
an Interesting Dichotomy of Practical Relevance
Lara Bianchi, Alessandro Carloni-Garaventa, Massimo Maccagno, Marcella Pani
Giovanni Petrillo,* Carlo Scapolla and Cinzia Tavani
Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
giovanni.petrillo@unige.it
Supplementary Data
Table of Contents
1.
2.
3.
4.
5.
Experimental Section………………………………………………………………. S 2
1
13
H and C NMR Spectra…………………………………………………………... S 10
Calculations on 18, 18ʹ and 18ʹʹ…………………………………………………… S 44
X-ray Crystallographic Study on 17bd……………………………………………. S 46
References………………………………………………………………………….. S 48

2
ACCEPTED MANUSCRIPT
Experimental Section
1
13
Materials and methods: H NMR and C NMR spectra were recorded with a Varian Mercury 300
Plus spectrometer, at 300 and 75 MHz, respectively; chemical shifts (TMS as internal reference) are
reported as
δ values (ppm). High-resolution mass spectra (HRMS) were obtained with an Agilent
MSD TOF mass spectrometer, and recorded in positive ion mode with an electrospray (ESI) source.
Melting points were determined with a Büchi 535 apparatus and are uncorrected. IR spectra were
-1
recorded on a Perkin Elmer Spectrum 65 FT-IR and wave numbers are reported in cm . Petroleum
ether and light petroleum refer to the fractions with bp 40-60 °C and 80-100 °C, respectively. Silica
gel 230-400 mesh was used for column chromatography, all solvents being distilled before use.
Tetrahydrofuran (THF) was purified by standard methods and distilled over potassium
benzophenone ketyl before use. All other commercially available reagents were used as received.
1
2
3
Compounds 13a-g, 14a-d, and 15aa-ad have been already described.
Reactions of sulfones 13a-f with the anions of hydrazones 14a,b at -78 °C
In a flask, the appropriate hydrazone 14 (0.2 mmol, 1 equiv vs. the nitrobutadiene 13) was dissolved
in THF (2.2 mL) under Ar and magnetic stirring; the temperature was brought to -78 °C and a 1M
t
solution of Bu OK (1 equiv) was added. After 30 min, a THF solution of the appropriate
nitrobutadiene (0.2 mmol in 2.2 mL) was added, and the reaction mixture kept at - 78 °C for 1-2 h.
TFA (5 equiv) was then added, and the mixture maintained at -78 °C under magnetic stirring for 2
h, and finally allowed to reach room temperature overnight. The mixture was then poured into water
and extracted with ethyl acetate. The organic phases were dried over Na SO , filtered and the
2
4
solvent removed under reduced pressure. The obtained crude was purified by chromatography on a
silica gel column, using petroleum ether/ethyl acetate mixtures as eluent.
Reactions of sulfones 13a-f with the anions of hydrazones 14c,d at 0 °C
A modification of the methodology described above was employed wherein the temperature was
maintained at 0 °C throughout, and allowed to reach 25 °C within 1 h after quenching with TFA.
(
E)-N,N-Dimethyl-5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-3-carboxamide
3
-1
(16aa). Beige solid, mp 193-194 °C (ethanol). IR (ATR): ṽ (cm ) 1639 (s), 1512 (m), 1386 (m),
1
1
311 (m), 1306 (m), 1292 (s), 1137 (s), 1126 (s), 1107 (m). H NMR (CDCl , 300 MHz):
δ
(ppm)
3
2
.39 (3H, s), 2.44 (3H, s), 2.80 (3H, s), 2.90 (3H, s), 2.99 (3H, s), 6.31 (1H, d, J 15.6 Hz), 7.23-7.30
13
(4H, m), 7.34 (4H, app. s), 7.43 (1H, d, J 15.6 Hz). C NMR (CDCl , 300 MHz):
δ
(ppm) 21.4,
3
2
1
1.5, 35.1, 38.6, 43.0, 125.0, 125.9, 127.6, 128.9, 129.5, 130.0, 130.4, 132.6, 136.1, 138.5, 139.9,
+
46.8, 164.2. HRMS (ESI) m/z calcd [M + H] C H N O S 424.1689, found 424.1684.
2
3
26
3
3
3
tert-Butyl (E)-5-[2-(methylsulfonyl)vinyl]-1,4-di-p-tolyl-1H-pyrazole-3-carboxilate (16ab).
1
Orange solid, mp 144-145 °C (ethanol). H NMR (CDCl , 300 MHz):
δ (ppm) 1.34 (9H, s), 2.42
3
(
3H, s), 2.44 (3H, s), 2.75 (3H, s), 6.12 (1H, d, J 15.7 Hz), 7.18 (2H, d, J 8.4 Hz), 7.26 (2H, d, J 7.8
1
3
Hz), 7.29-7.37 (5H, m). C NMR (CDCl , 300 MHz):
δ (ppm) 21.4, 21.5, 28.0, 42.9, 82.1, 126.0,
3

3
ACCEPTED MANUSCRIPT
1
27.4, 128.7, 129.4, 129.5, 129.7, 130.4, 134.1, 135.9, 138.3, 140.2, 143.8, 161.0 (two carbons are
+
accidentally isochronous). HRMS (ESI) m/z calcd [M + H] C H N O S 453.1843, found
25
29
2
4
453.1847.
(
E)-4-(4-Methoxyphenyl)-N,N-dimethyl-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
1
carboxamide (16ba). Colourless solid, mp 168-169 °C (ethanol). H NMR (CDCl , 300 MHz):
δ
δ
3
(
ppm) 2.45 (3H, s), 2.80 (3H, s), 2.91 (3H, s), 3.00 (3H, s), 3.85 (3H, s), 6.32 (1H, d, J 15.6 Hz),
1
3
6
.98 (2H, d, J 8.7 Hz), 7.30-7.35 (6H, m), 7.43 (1H, d, J 15.6 Hz). C NMR (CDCl , 75 MHz):
3
(
1
4
ppm) 21.4, 35.1, 38.7, 43.0, 55.4, 114.7, 122.7, 124.7, 125.9, 126.0, 128.8, 129.5, 130.4, 130.9,
32.6, 132.6, 136.2, 140.0, 159.9. HRMS (ESI) m/z calcd [M + H] C H N O S 440.1639, found
23 26 3 4
40.1634.
+
tert-Butyl
carboxylate (16bb). Colourless solid, mp 197-198 °C (ethanol). IR (ATR): ṽ (cm ) 1715 (s), 1611
w), 1517 (w), 1500 (m), 1461 (w), 1367 (w), 1321 (w), 1310 (w), 1298 (s), 1246 (m), 1213 (m),
(E)-4-(4-methoxyphenyl)-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
-1
(
1
1
δ
8
2
1
175 (w), 1155 (s), 1138 (s), 1126 (s), 1047 (w), 1026 (w), 1016 (m). H NMR (CDCl , 300 MHz):
3
(ppm) 1.36 (9H, s), 2.45 (3H, s), 2.77 (3H, s), 3.87 (3H, s), 6.14 (1H, d, J 15.6 Hz), 7.00 (2H, d, J
13
.4 Hz), 7.23 (2H, d, J 8.4 Hz), 7.31- 7.36 (5H, m). C NMR (CDCl , 75 MHz):
8.0, 42.9, 55.5, 82.1, 114.3, 123.8, 126.0, 127.0, 128.7, 129.4, 130.4, 131.1, 134.1, 135.9, 140.2,
43.9, 159.7, 161.1. HRMS (ESI) m/z calcd [M + H] C H N O S 469.1792, found 469.1798.
δ (ppm) 21.4,
3
+
2
5
29
2
5
(
E)-4-(4-Chlorophenyl)-N,N-dimethyl-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
-
carboxamide (16ca). Red solid, mp 107-110 °C (taken-up with petroleum ether). IR (ATR): ṽ (cm
1
1
)
1633 (m), 1511 (m), 1385 (w), 1305 (m), 1130 (s), 1090 (m), 1004 (m). H NMR (CDCl , 300
3
MHz):
δ (ppm) 2.45 (3H, s), 2.81 (3H, s), 2.97 (3H, s), 3.01 (3H, s), 6.27 (1H, dd, J 15.9 Hz), 7.32-
1
3
7
1
.46 (9H, m). C NMR (CDCl , 75 MHz): δ (ppm) 21.4, 35.3, 38.7, 42.9, 123.9, 125.9, 129.2,
29.1, 129.5, 129.5, 130.5, 131.1, 132.8, 134.8, 136.0, 140.2, 146.6, 163.8. HRMS (ESI) m/z calcd
3
+
[
M + H] C H ClN O S 444.1143, found 444.1140.
22
23
3
3
tert-Butyl
(E)-4-(4-chlorophenyl)-5-[2-(methylsulfonyl)vinyl]-1-p-tolyl-1H-pyrazole-3-
-1
carboxylate (16cb). Yellow solid, mp 151-152 °C (ethanol). IR (ATR): ṽ (cm ) 1726 (m), 1489
(
w), 1370 (m), 1320 (w), 1314 (w), 1295 (m), 1217 (m), 1158 (m), 1139 (s), 1130 (s), 1104 (m),
1
1
2
7
1
092 (m), 1020 (w), 1004 (w)
.78 (3H, s), 6.10 (1H, d, J 15.6 Hz), 7.25- 7.37 (7H, m), 7.46 (2H, d, J 8.4 Hz). C NMR (CDCl ,
.
H NMR (CDCl , 300 MHz):
δ
(ppm) 1.35 (9H, s), 2.45 (3H, s),
3
1
3
3
5 MHz):
δ (ppm) 21.4, 28.0, 42.9, 82.4, 125.9, 126.0, 129.1, 129.1, 129.2, 130.4, 131.4, 134.1,
+
34.7, 135.8, 140.4, 143.7, 160.7 (two isochronous carbons). HRMS (ESI) m/z calcd [M + H]
C H ClN O S 473.1296, found 473.1292.
24
26
2
4
(
Z)-N,N-Dimethyl-5-[2-(methylsulfonyl)vinyl]-4-o-tolyl-1-p-tolyl-1H-pyrazole-3-carboxamide
1
(16da). Yellow solid. H NMR (CDCl , 300 MHz):
δ
(ppm) 1.92 (3H, s), 2.25 (3H, s), 2.41 (3H, s),
3
3
7
1
1
.01 (3H, s), 3.12 (3H, s), 6.34 (1H, d, J 11.6 Hz), 6.90 (1H, d, J 11.6 Hz), 7.13 – 7.31 (6H, m),
1
3
.42 (2H, d, J 8.4 Hz). C-NMR (CDCl , 75 MHz):
δ (ppm) 20.2, 21.3, 35.3, 39.0, 40.9, 123.7,
3
25.0, 125.9, 128.3, 130.0, 130.6, 130.7, 131.2, 131.2, 132.9, 133.4, 136.9, 137.9, 138.7, 146.3,
+
64.5. HRMS (ESI) m/z calcd [M + H] C H N O S 424.1689, found 424.1683.
23
26
3
3