From N-sulfonyl,C-homoallyl-hydrazones to pyrazole and pyridazine (N 2)-heterocycles: The ultimate aromatization process

Article abstract of DOI:10.1016/j.tet.2014.05.005

Isomeric six- and five-membered (N₂)-aromatics, 6-methylpyridazines and 5-vinylpyrazoles, which energetic topological aromaticity is comparable to that of benzene, are shown to be efficiently produced by sequential isomerization-elimination processes from the corresponding 6-methylidene-1,4,5,6-tetrahydropyridazines and 5-vinylpyrazolines, respectively. The latter precursors are available from the same N-sulfonyl,C-homoallyl-hydrazone substrates by a suitable choice of previously reported conditions for Pd-catalyzed CH-oxidative C,N-ring closing processes. The generality of these cyclization, isomerization, and aromatization reactions, for which detailed mechanisms are proposed, provides a systematic access to wide ranges of 3,4,6-trisubstituted 6-methyl-1,4-dihydropyridazines and 6-methylpyridazines, and their 3,4,5-trisubstituted 5-vinylpyrazole isomers.

Full text of DOI:10.1016/j.tet.2014.05.005

Tetrahedron xxx (2014) 1e12
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Tetrahedron
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From N-sulfonyl,C-homoallyl-hydrazones to pyrazole and pyridazine
(N2)-heterocycles: the ultimate aromatization process
,
,
,
b
,
a,b,
*
Cleve Dionel Mboyi a b, Carine Duhayon a b, Yves Canac a , Remi Chauvin
*
a CNRS, LCC (Laboratoire de Chimie de Coordination), 205, route de Narbonne, F-31077 Toulouse, France
Universite de Toulouse, UPS, INP, LCC, F-31077 Toulouse, France
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Isomeric six- and five-membered (N2)-aromatics, 6-methylpyridazines and 5-vinylpyrazoles, which
energetic topological aromaticity is comparable to that of benzene, are shown to be efficiently produced
by sequential isomerizationeelimination processes from the corresponding 6-methylidene-1,4,5,6-
tetrahydropyridazines and 5-vinylpyrazolines, respectively. The latter precursors are available from the
same N-sulfonyl,C-homoallyl-hydrazone substrates by a suitable choice of previously reported conditions
for Pd-catalyzed CH-oxidative C,N-ring closing processes. The generality of these cyclization, isomeri-
zation, and aromatization reactions, for which detailed mechanisms are proposed, provides a systematic
access to wide ranges of 3,4,6-trisubstituted 6-methyl-1,4-dihydropyridazines and 6-methylpyridazines,
and their 3,4,5-trisubstituted 5-vinylpyrazole isomers.
Received 25 February 2014
Received in revised form 29 April 2014
Accepted 2 May 2014
Available online xxx
Keywords:
Aromatization
Dihydropyridazines
Hydrazones
Pyrazoles
Ó 2014 Elsevier Ltd. All rights reserved.
Pyrazolines
Pyridazines
1. Introduction
hydralazine,13 cilazapril14), their occurrence among natural prod-
ucts, like that of any N2 motif, is very limited. According to Kumar, in
Aromatic N-heterocycles are planar rigid units that are key to
biochemical recognition processes.1 Due to the H-bond acceptor
ability of the nitrogen atom, beside porphyrins (hemoglobin, cyto-
2013 only 18 natural products containing a pyrazole ring had been
identified.15 Even more strikingly, discarding a few natural hydro-
pyridazine derivatives (like monoamycin extracted from a Spec-
tromyces species),16 the aromatic pyridazine ring itself is extremely
rare in Nature, just found in pyridazomycin17 and amazerone, both
extracted from Streptomyces bacteria as well.18
From a more fundamental standpoint, basic properties such as
planarity, rigidity, stability and reactivity of p-conjugated N-hetero-
cycles can be compared on the basis of their relative aromatic char-
acters.19 Although N-heterocycles are more compact than parent
carbocycles (because of shorter endocyclic bonds), the first N-
chromes), vitamin B12, and a few a-aminoacids (tryptophan, histi-
dine), nucleobases are essential diaza-aromatics (under
representative tautomeric forms), which all contain a pyrimidine six-
membered ring. These nucleobases, either monocyclic (cytosine,
uracil, thymine), or bicyclic with an annelated imidazole five-
membered ring in purines (adenine, guanine), are thus based on
N/C/N amidine units. Adenine is also constitutive of redox co-
enzymes, which active motif in the oxidized form is an aromatic
heterocycle: the pyridine ring of nicotinamide in NAD, the pteridine
bicycle of riboflavine in FAD. Noteworthy, pteridine also contain
a pyrimidine ring, annelated with a pyrazine diaza-aromatic ring
based on the N/C/C/N diimine unit. In contrast to the N/Cx/N
units x¼1, 2, N/N hydrazine/diimide/azo units (x¼0) have been
considered for comparative purpose in five-membered pyrazoles (vs
imidazoles),2 and six-membered pyridazines (vs pyrimidines).3 Al-
though pyrazole4 and pyridazine5 rings are found in marketed arti-
ficial biologically active compounds (many pyrazoles6 and a few
pyridazines in herbicides such as credazine,7 pyridafol,8 pyridate,9
and drugs such as cefozopran,10 cadralazine,11 minaprine,12
monocycles (with a single N atom and without any
p-conjugating
substituent) are slightly less aromatic (by ca. 1e2%) than their parent
annulenic carbocycles: this is illustrated for pyridine versus benzene,
and for pyrrole and pyrrolide anion versus the cyclopentadienide
anion (Scheme 1), on the basis of the Aihara or Trinajstic’s topological
resonance energy,20 the scale of ‘exact’ energetic aromaticity, which
recently received a direct chemical interpretation.21 Likewise, an-
choring a p-conjugated substituent at a six-p-electron annulenic ring
results in a ca.10% decrease of the TRE (e.g., 0.249 for styrene vs 0.273
for benzene),20a and this trend also applies to heterocycles, e.g., to 2-
vinylpyrrole versus pyrrole (Scheme 1). Nevertheless further endo-
cyclic ‘a-azalogation’ (i.e., substitution of a methyne unit adjacent to
a first nitrogen atom by a second nitrogen atom, giving a N/N unit)
* Corresponding authors. Fax: þ335 61 55 30 03; e-mail address: chauvin@
lcc-toulouse.fr (R. Chauvin).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.005
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2
C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
C6 conj. extent:
C7 conj. extent:
C6 conj. extent: C5 conj. extent
(ref. monocycles):
H
CH2
R
H
H
C–H hyper-
conjugation
C7 N0
R = Me
H
0.2726
N
0.1554
0.2703
0.0200
0.3168
E
N
E
N
E
N
R
CH2
R = Me
N
C6 N1
E = :–, H+: 0.1262
E = :–, H+: 0.2745
E = :–, H+: 0.3130
E = H: 0.2462
0.2685
H
0.0438
E = H: 0.0607
E = H: 0.2188
vinyl-pyrazoles
E
N
pyridazine
E
N
N
R
N
N
CH2
E
R = Me
E
N
N
N
N
N
N
N
C5 N2
H
H
E = H: 0.2438
E = :–, H+: 0.2855
E = H: 0.2401
0.0825
0.2757
E = :–, H+: 0.1255
pyrazole
E = :–, H+: 0.3203
E = H: 0.2664
E = H: 0.0533
N
E
N
N
N
pyrimidine
E
N
N
N
R
E = :–, H+: 0.2818
E = H: 0.2397
N
CH2
0.2424
0.0855
R = Me
N
N
E
N
vinyl-imidazoles
E = :–, H+: 0.1006
E = H: 0.0460
N
N
0.2576
E
N
N
E
N
N
H
H
0.0866
E = H: 0.2156
E = H: 0.2185
pyrazine
E
N
N
E = :–, H+: 0.2855
N
R
E
N
CH2
imidazole
E = :–, H+: 0.3081
R = Me
N
N
N
N
0.2716
E = H: 0.2431
N
N
N
E = :–, H+: 0.1206
0.2215
E = :–, H+: 0.2775
0.1009
E = H: 0.0495
E = H: 0.2206
Scheme 1. Topological resonance energy of C5H6N2-isomeric diaza-cycles (including tautomeric forms), parent monoaza-cycles, and carbocyclic analogues calculated with the Van-
2
Catledge Huckel parameters for sp and sp3 N atoms.23 Values in resonance integral
b
units.24
€
restores aromaticity:22 pyridazine, pyrazole, and 5-vinylpyrazoles are
thus more aromatic than pyridine (þ3%), pyrrole (þ10%), and 5-
vinylpyrrole (þ8%), respectively (Scheme 1). The same pyridazine,
pyrazole, and vinylpyrazole are also more aromatic than diaza iso-
compounds. The comparison is hereafter addressed for C5H6N2-
isomeric 6-methylpyridazine and 5-vinylpyrazole derivatives.
Functional layout precursors of such isomers have indeed recently
been made available from a single substrate for Pd-catalyzed cy-
clization reactions. Among other transition metal-catalyzed
methods used for the preparation of N-heterocycles,25 Pd-
catalyzed CeH oxidative C,N-cyclization of N-sulfonyl,C-homo-
allyl-hydrazones was indeed shown to follow two distinct routes
depending on the electrophilicity of the Pd(II) catalytic center.26 If
the Pd(II) center is associated to non-coordinating anions such as
tosylates or triflates, 5-vinylpyrazolines of type A are produced
mers resulting from b-azalogation (giving a N/C/N unit), i.e., than
pyrimidine (þ7%), imidazole (þ10%), and vinylimidazole (ca. þ11%).
As a general trend (see details in Scheme 1), diimido compounds
(pyrazole and pyridazine derivatives) thus appear more aromatic
than simple imido counterparts (imidazole, pyrimidine, and pyrazine
derivatives).
Considering the above-mentioned intriguing biological and
structural properties of the diimido heterocycles, compelling
comparative studies first call for a systematic access to such
through a 5-exo-trig process from a
p-allyl complex intermediate
(Scheme 2a). In contrast, if the anionic ligands of the Pd(II) center
E
N
E
E
H
N
NH
N
[PdX2/L]/ox.
X = OTs, OTf
N
[PdX2/L]/ox.
X = OAc
N
N
N
a)
N
N
R
R
R
R
R'
R
R'
R'
R'
N
A
B
R'
N
H
N
N
N
N
b)
R = COR1
R1
R
R
Scheme 2. (a) Envisaged preparation of pyrazoles and pyridazines from pyrazolines A, and 1,4,5,6-tetrahydropyridazines B, respectively, obtained by Pd-cyclization of N-sulfonyl,C-
homoallyl-hydrazones.26 (b) Preparation of pyrazoles and pyridazines from vinyl-diazo precursors.30
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C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
3
are
tetrahydropyridazines of type B are formed, possibly through a 6-
endo-trig process from the assumed same -allyl complex (if, as
previously assumed, [recall Ref. 26a] no -allyl complex was in-
volved, a 6-exo-trig process in the strict sense should be invoked).
This fine control of the Baldwin rules27 for the formation of the
allowed products of types A and B thus opens a possible access to
isomeric 5-vinylpyrazole and 6-methylpyridazine, respectively. In
line with other systematic routes to pyrazoles28 and pyridazines,29
e.g., from a common vinyl-diazo precursor (Scheme 2b),30 suitable
procedures for the aromatization of isomeric precursors A and B are
hereafter described.
O,O-chelating
acetates,
6-methylidene-1,4,5,6-
2.2. Six-membered (N2)-heterocycles
complete set of N-arylsulfonyl-6-methylidene-1,4,5,6-
tetrahydropyridazine substrates prepared by Pd-catalyzed CeH
oxidative cyclization of N-sulfonyl,C-homoallyl-hydrazones26 1bek
was then considered (Table 1).
p
A
p
As shown in Table 1, the migration of the C]C double bond
observed from 1a was also found to take place from a wide range of
N-arylsulfonyl-6-methylidene-1,4,5,6-tetrahydropyridazines. In all
cases, the corresponding 1,4-dihydropyridazines 2aek were ob-
tained upon dissolution of the 1,4,5,6-tetrahydropyridazine pre-
cursors 1aek in ‘technical’ CHCl3 at room temperature. As
previously observed for 1a, pyridazines 1bek were shown to be
ꢁ
stable in CHCl3 stored over 4 A MS. 1,4-Dihydropyridazines 2aek
were fully characterized by spectroscopic methods in solution, and
the structures of 2a and 2e were confirmed by X-ray diffraction
analysis of single crystals (Fig. 1).33
2. Results and discussion
2.1. Context
In 1H and 13C NMR spectra, the main difference between the
pyridazine isomers 1 and 2 consists in the exclusive presence of
a methyl substituent ðdCH z2:20 ppm; dCH z20:0 ppmÞ in the 1,4-
The reactivity of the exocyclic double bond of the 6-
methylidene-1,4,5,6-tetrahydropyridazine 1a was recently evi-
denced by a quantitative conversion to the 1,4-dihydropyridazine
isomer 2a upon dissolution of 1a in chloroform at room tempera-
ture (Scheme 3).26 This observation suggests that the exo/endo
migration of the C]C bond is catalyzed by traces of acid in the
3
3
dihydropyridazine series 2. In the solid state, whereas the 1,4-
dihydropyridazines 2a and 2e adopt a boat-shaped conformation,
which prow is occupied by the sulfonyl-N atom and stern by the
methylene group (Fig. 1), the 1,4,5,6-tetrahydropyridazines 1 were
found to adopt rather a half-chair-type conformation.26 The steric
and electronic factors of the substituents exert a negligible or weak
effect on the acid-catalyzed isomerization of 1,4,5,6-
tetrahydropyridazines 1, and in all cases the most stable isomers
featuring an endocyclic C]C bond, namely the 1,4-
dihydropyridazines of type 2, were obtained. The isomerization
1/2 can be attributed not only to the exocyclic kinetic exposure of
the C]C bond in 1, but also to the trisubstitution thermodynamic
stabilization of the C]C bond in 2.
Whereas cyclohexadienes undergo oxidative aromatization to
benzene derivatives (e.g., by treatment with DDQ), the 1,4-
dihydropyridazines 2 are a priori prone to convert to the aro-
matic pyridazines by formal elimination of aryl sulfinic acid
(ArSO2H). The feasibility of the reaction was first investigated from
the reference 1,4-dihydropyridazine 2a using various bases, and
preliminary experiments in THF at 65 ꢀC evidenced the formation of
ꢁ
CHCl3 solvent used. In support of this, using CHCl3 stored over 4 A
molecular sieves (MS), no isomerization was observed and the
1,4,5,6-tetrahydropyridazine 1a was found stable under such con-
ditions. Related tautomerization processes have been evidenced in
general heterocyclic chemistry,31 in particular for the preparation
of pyrazole and pyrazoline derivatives.32
SO2Ph
N
SO2Ph
N
Me
r.t.
N
N
Ph
Ph
1a
2a
Scheme 3. The exocyclic/endocyclic migration of the C]C bond of the N-sulfonyl-6-
methylidene-1,4,5,6-tetrahydropyridazine 1a to the isomeric 1,4-dihydropyridazine 2a.
Table 1
Exocyclic/endocyclic isomerization of N-sulfonyl-6-methylidene-1,4,5,6-tetrahydropyridazines 1bek and of the reference substrate 1a (Scheme 3)a
Entry
Substrate
Productb
SO2Ph
Entry
Substrate
Productb
SO2Tol
N
Me
N
Me
N
N
1
1a
7
1g
2g
2a
SO2Tol
SO2Ph
N
Me
N
Me
N
N
2
3
1b
8
9
1h
Ph
2h
2b
SO2Tol
N
SO2Tol
Me
Me
N
N
1c
1i
N
2i
MeO
(continued on next page)
2c
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Me

4
C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
Table 1 (continued )
Entry
Substrate
Productb
SO2Tol
Me
Entry
10
Substrate
Productb
SO2Tol
N
N
Me
N
N
4
1d
1j
2d
2j
Et
SO2Tol
SO2Tol
N
N
Me
Me
N
N
5
1e
11
1k
2k
2e
F3C
SO2Tol
N
Me
N
6
1f
2f
Cl
a
Reaction conditions: CHCl3, rt, 2 h.
b
The 1,4-dihydropyridazines 2aek were obtained in quantitative yields and fully characterized without requirement of any purification techniques.
Fig. 1. Molecular views of the X-ray crystal structures of the 1,4-dihydropyridazines 2a (left), and 2e (right), with thermal ellipsoids drawn at the 30% probability level (for clarity, the
ꢀ
ꢁ
H atoms are omitted). For more details on 2a, 2e, see Experimental section. Selected bond distances [A] and angles [ ]. Compound 2a: C1eC2 1.5034(12), C1eN1 1.2837(11), N1eN2
1.4083(9), C1eC2eC3 108.73(8), C2eC1eN1123.94(8), N1eN2eC4 119.05(7). Compound 2e: C1eC2 1.504(2), C1eN11.285(2), N1eN2 1.3879(18), C1eC2eC3 109.63(13), C2eC1eN1
124.57(14), N1eN2eC4 120.44(12).
the pyridazine 3a (Scheme 4). The yield of the transformation was,
however, found to be highly dependent on the nature of the base:
high yields with either NaOAc or NaOH (90e92%), lower yield with
NaH (61%), and no conversion with Et3N.
(Table 2, entries 2e6 and 9; 40e96% yield). From the hindered
substrates 2g and 2h, the corresponding pyridazines were, how-
ever, produced in 54 and 46% yields only (Table 2, entries 7 and 8).
The alkyl representatives 2j and 2k were also found to undergo
aromatization in moderate yields (Table 2, entries 10 and 11).
The structure of the pyridazine products was determined by
spectroscopicmethodsinsolution, andconfirmedbyX-raydiffraction
analysis in the crystal state for the representatives 3a, 3b, 3c, 3g, 3h, 3i
(Fig. 2).31 In contrast to the 1,4-dihydropyridazines 2, and as expected,
the six-membered N2-heterocycle of 3 adopts a planar geometry in
the solid state. As a reference, geometrical data of the related pyr-
idazinium salt 3a0 in the solid state are also given (Table 3).33
Endocyclic bond lengths and angle values of the six-membered
ring of the pyridazine derivatives 2a, 3a, and 3a0 are in agreement
with the aromatic character of 3a and, to a lesser extent, to that of
3a0 (Table 3).
SO2Ph
N
Me
N
Me
Base (3 equiv.)
THF, 65°C, 3 h
N
N
Ph
Ph
2a
3a
Base
yield (%)
NaOAc
92
NaOH
90
Et3N
0
NaH
61
Scheme 4. Performances of bases in promoting aromatization of the 1,4-
dihydropyridazine reference substrate 2a.
The formation of pyridazines 3 from 2 corresponds to a base-
mediated elimination of aryl sulfinic acid (Scheme 5, route a).
This transformation involves a carbanionic intermediate from
which a sulfinate anion is expelled.34 Alternatively, 1,2-elimination
of aryl sulfinic acid might occur from a 1,6-dihydropyridazine
tautomer 20, which could however not be detected, possibly
The scope of the reaction was then investigated over the set of
substrates 2bek (Scheme 4, Table 2). The above conditions were
found to be efficient over a wide range of p-substituted 1,4-
dihydropyridazines, involving more or less electro-active groups
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C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
5
Table 2
Aromatization of N-sulfonyl-1,4-dihydropyridazine substrates 2bek, and the reference substrate 2a (Scheme 4)a
Entry
Substrate
Product
Yieldb (%)
Entry
Substrate
Product
Yieldb (%)
Me
N
N
N
N
Me
1
2a
92
7
2g
54
3a
3g
N
N
N
Me
Me
N
N
2
3
2b
2c
96
64
8
9
2h
2i
46
40
Ph
N
3h
3b
N
N
N
Me
Me
3c
3i
Me
Et
MeO
N
Me
N
Me
N
4
5
2d
2e
64
90
10
11
2j
71
43
3j
3d
N
N
Me
Me
N
N
2k
3k
3e
F3C
N
Me
N
6
2f
59
3f
Cl
a
Reaction conditions: NaOAc (3 equiv), THF, 65 ꢀC.
Yield of isolated product.
b
Fig. 2. Molecular views of the X-ray crystal structures of the pyridazines 3a (left), 3g (middle), and 3h (right), with thermal ellipsoids drawn at the 30% probability level (for clarity,
ꢀ
ꢁ
the H atoms are omitted). For more details on 3a, g, h and data for 3b, c, i, see Experimental section. Selected bond distances [A] and angles [ ]. Compound 3a: see Table 3.
Compound 3g: C1eC2 1.4136(15), C1eN1 1.3337(13), N1eN2 1.3518(12), C1eC2eC3 116.44(9), C2eC1eN1 122.74(10), N1eN2eC4 119.67(9). Compound 3h: C1eC2 1.4151(13),
C1eN1 1.3387(12), N1eN2 1.3404(11), C1eC2eC3 116.05(8), C2eC1eN1 121.75(8), N1eN2eC4 119.78(8).
because it undergoes aromatization to 3 by a concerted E2 elimi-
nation, thus more readily than 2 (which requires a two-step E1cb
mechanism). The present result provides definitive experimental
support for a previous claim about the transient formation of 1,4-
dihydopyridazines in the preparation of pyridazines from 1,4,5,6-
tetrahydropyridazine precursors.35
confirming the proposed eliminative-type mechanism (Scheme 5,
route a).
2.3. Five-membered (N2)-heterocycles
The preparation of aromatic five-membered isomers of meth-
ylpyridazines, namely vinylpyrazoles, was then envisaged from
vinylpyrazolines. Conditions similar to those used in the pyridazine
series were thus applied to the 5-vinylpyrazoline reference sub-
strate 4a (Scheme 6). In presence of 3 equiv of NaOH pellets in THF
at 65 ꢀC, the pyrazoline 4a was found to undergo deprotonation
over 3 h, affording the pyrazole 5a in 68% yield.
The scope of the reaction was then investigated over a set of N-
arylsulfonyl-5-vinylpyrazolines 4bei (Scheme 6).26 As indicated in
Table 4, the aromatization occurred from a wide range of substrates.
In the absence of a base, formation of the pyridazinium salt 3a0
was observed after 2a was kept in technical CH2Cl2 under air for
a few days (Scheme 5, route b). This result might indicate an oxi-
dative aromatization process after hydrolysis of the NeSO2Ar bond
of 2 to the 1,4-dihydropyridazine intermediate 200. The latter would
thus act as a hydride donor, just as the 1,4-dihydropyridine ring of
NADH, NADPH or Hantzsch esters does.
From 2a, the formation of phenyl sulfinic acid was evidenced by
IR and mass spectroscopic methods (ESIꢁ: m/z 141.0), thus
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6
C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
Table 3
ꢀ
0
ꢁ
Selected bond lengths (A) and angles ( ) from X-ray diffraction analyses of single crystals of the six-membered heterocycles 2a, 3a, and 3a
Lewis structures
2a
3aa
3a0
C1eC2
C2eC3
C3eC4
C1eN1
1.5034(12)
1.4917(13)
1.3300(13)
1.2837(11)
1.4396(10)
1.4083(9)
118.08(7)
108.73(8)
1.356(5)
1.348(6)
1.356(5)
1.356(5)
1.356(5)
1.348(6)
117.8(4)
117.8(4)
1.4182(16)
1.3680(19)
1.4084(17)
1.3302(15)
1.3259(15)
1.3345(16)
117.10(10)
119.36(11)
H
N
SO2Ph
PhSO3
Me
Me
N
N
Me
N
N
N
C4eN2
Ph
Ph
Ph
N1eN2
C1eN1eN2
C1eC2eC3
2a
3a'
3a
N2
N1
C1
C4
C3
C2
numbering scheme
a
The asymmetric unit contains half a molecule. Two positions have been assigned respectively, to C(3)/N(2) and C(2)/N(1) with half occupancy. A C2 symmetry axis
generates the full molecule. For molecular views, see Figs. 1 and 2.
SO2Ar
N
SO2Ar
O
S
N
Me
H
N
Me
N
base (B)
E2
N
N
+
B
+
+
+
BH
B
Me
Ar
OH
R
R
R
SO2Ar
Route a
3
sulfinic acid
H
2'
H
N
Me
E1cb
N
R
H
H
H
N
H
N
Route b
H2O
ArSO3
2
Me
O
S
Me
1/2 O2
- H2O
N
N
+
Ar
OH
Ar, R = C6H5
R
O
R
H
H
2''
sulfonic acid
3a'
Scheme 5. Proposed mechanisms for the formation of pyridazine derivatives 3 from 1,4-dihydropyridazines 2: (a) following a base-induced eliminative aromatization process; (b)
through an oxidative aromatization process.
ꢁ
quasi-similar endocyclic CeC [1.4030(16) and 1.4043(16) A] and
ꢁ
CeN [1.3438(15) and 1.3487(15) A] bond lengths.
SO2Ph
N
H
N
Noteworthy, no intermediate isomers resulting from a stepwise
migration of the terminal allylic C]C bond was detected upon
dissolution of 4 in ‘technical’ CHCl3. In spite of the a priori stabi-
lizing trisubstituted character of the C]C bond in the putative in-
termediate 40, the strained exocyclic environment of the former
destabilizes 40,36 thus preventing the formation of the N-sulfonyl-5-
ethylpyrazole 400 (Scheme 7). As previously suggested in the pyr-
idazine series, the formation of the pyrazoles 5 should proceed via
a base-induced eliminative aromatization process through either
E1cb (routes a and b) or E2 (route c) mechanisms. It is noteworthy
NaOH (3 equiv.)
THF, 65°C, 3 h
68%
N
N
Ph
Ph
5a
4a
Scheme 6. Aromatization of the N-sulfonyl-5-vinylpyrazoline reference 4a in presence
of NaOH.
Pyrazolines with electro-active substituents at the para-position of
the phenyl ring (Table 4, entries 2e6 and 9) and hindered pyrazo-
lines (Table 4, entries 7 and 8) can be indeed converted to the
corresponding pyrazoles in moderate to high yields (42e95%). The
pyrazole products 5aei were fully characterized by spectroscopic
methods, and also by X-ray diffraction analysis of a single crystal of
5h (Fig. 3).33
that re-protonation of the
p-allylic carbanionic intermediate of
route b would afford 40, and thus 400, which are not observed. The
routes a and c are therefore likely preferred: in both cases, after
elimination of the sulfinate anion, aromaticity-driven prototropy
leads to the observed pyrazoles 5 (Scheme 7).
The formation of 5-vinylpyrazoles was evidenced by 1H and 13
C
NMR spectroscopy through the disappearance of the CH2 group
signals of the pyrazoline precursors, and by the appearance of
alkene-type CH signals. As observed for pyridazines 3, the N2-
heterocycle of 5h adopts a planar geometry in the solid state. A
protic H atom shifts between the two adjacent N atoms of the
pyrazole ring (approximately 60% on N-2, 40% on N-1), resulting in
3. Conclusion
Aromatization of 6-methylidene-1,4,5,6-tetrahydropyridazines
and 5-vinylpyrazolines to 6-methylpyridazines and 5-
vinylpyrazoles generated from the same C-homoallyl-hydrazones,
respectively, has been shown to proceed under acidic and/or basic
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C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
7
Table 4
Aromatization from various types of N-sulfonyl-vinylpyrazolines 4bei, and the reference substrate 4a (Scheme 6)a
Entry
Substrate
Product
Yieldb (%)
Entry
Substrate
Product
Yieldb (%)
H
N
H
N
N
N
1
4a
68
7
4f
95
5f
5a
Cl
H
N
H
N
N
N
2
4b
42
8
4g
79
5b
5g
H
H
N
N
N
N
3
4c
62
9
4h
42
Ph
5c
5h
Me
H
N
H
N
N
N
4
4d
86
10
4i
94
5d
5e
5i
Et
MeO
H
N
N
5
4e
42
CF3
a
Reaction conditions: NaOH (3 equiv), THF, 65 ꢀC.
Yield of isolated product.
b
conditions, and no intermediate could be isolated in the base-
induced eliminative aromatization to the corresponding 5-
vinylpyrazoles, which are less aromatic than their six-membered
isomers (TREz0.24b vs 0.28b: see Scheme 1). Although no corre-
lation can be a priori claimed, it happens that the aromatization
sequence proceeds in higher yield in the pyridazine series than in
the vinylpyrazole series. The disclosed systematic approach pro-
vides alternative routes to methylpyridazine and vinylpyrazole
isomers, and unveils new horizons in the chemistry of the valuable
(N2)-heterocycles.
Fig. 3. Molecular view of the X-ray crystal structure of the pyrazole 5h, with thermal
ellipsoids drawn at the 30% probability level (for clarity, the H atoms are omitted).
4. Experimental section
ꢀ
ꢁ
Selected bond distances [A] and angles [ ]: C1eC2 1.4030(16), C2eC3 1.4043(16),
C1eN1 1.3487(15), C3eN2 1.3438(15), N1eN2 1.3494(15), C2eC1eN1 107.85(10),
C1eN1eN2 109.63(9), N1eN2eC3 108.59(9).
4.1. General remarks
eliminative conditions. Toward the strongly aromatic pyridazine
THF was dried and distilled over sodium/benzophenone. All
targets (TREz0.28b vs 0.27b for benzenic derivatives: see Scheme
other reagents were used as commercially available. Column
ꢁ
1), a stepwise mechanism is evidenced through 6-methyl-1,4-
dihydropyridazine intermediates generated under acidic treat-
ment (exocyclic/endocyclic migration of the C]C bond). In con-
trast, 5-vinylpyrazolines were found to be stable under acidic
chromatography was carried out on silica gel (60 A, CC 70e200
m
m).
The following analytical instruments were used. 1H and 13C NMR:
Bruker DPX 300, and Avance 400. NMR chemical shifts are given
in parts per million (ppm), with positive values to high frequency
d
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8
C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
(2 steps)
N
SO2Ar
N
BH
N
N
H
N
E1cb
H
H
R
R
R'
R'
N
SO2Ar
N
SO2Ar
N
SO2Ar
N
Route b
base
R
R'
5
taut.
E2
Route c
N
+
N
N
H
O
S
H
H
H
R
R'
R
R
R'
R'
4'
Route a
4''
4
Ar
OH
(1 or 2 steps)
N
SO2Ar
N
sulfinic acid
E1cb
N
N
H
H
R
R'
R
R'
Scheme 7. Proposed mechanisms for the formation of pyrazoles 5 from 5-vinylpyrazolines 4 through a base-induced eliminative aromatization process.
relative to the tetramethylsilane reference for 1H and 13C; coupling
constants J are given in hertz (Hz). Mass spectra were obtained on
a Perkin Elmer Sciex spectrometer (MS/MS API-365). 6-Methyl-
idene-1,4,5,6-tetrahydropyridazines and 5-vinylpyrazolines were
prepared according to the literature.26
(br s, 2H, CH2), 4.84 (br s,1H, CH), 7.20 (d, J¼8.4 Hz, 2H, CHar), 7.31 (d,
J¼8.4 Hz, 2H, CHar), 7.62 (d, J¼8.1 Hz, 2H, CHar), 7.94 (d, J¼8.1 Hz, 2H,
CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼19.85 (CH3), 21.38 (CH3), 21.61
(CH3), 23.97 (CH2), 102.28 (CH), 126.30 (CHar), 128.14 (CHar), 129.12
(CHar), 129.49 (CHar), 132.64 (Car), 134.51 (Car), 136.03 (Car), 140.24
(Car), 143.93 (CN), 148.94 (CN). MS (DCI-CH4): m/z: 341.13 [MHþ].
HRMS (ESþ): calcd for C19H21N2O2S 341.1324; found 341.1322.
4.2. Typical procedure for the preparation of the 1,4-
dihydropyridazines 2aek (example of 2a)
4.3.4. 3-(4-Ethylphenyl)-6-methyl-1-[(4-methylbenzene)sulfonyl]-
In a round flask (5 mL), 1,4,5,6-tetrahydropyridazine 1a was
dissolved in CHCl3. The mixture was then stirred at room temper-
ature for 2 h. The solvent was finally evaporated under reduced
pressure to give 2a as a white solid, which was fully characterized
without the need of any purification.
1,4-dihydropyridazine 2d. Yellow oil. 1H NMR (CDCl3, 300 MHz):
d
¼1.25 (t, J¼7.6 Hz, 3H, CH3), 2.24 (d, J¼1.2 Hz, 3H, CH3), 2.43 (s, 3H,
CH3), 2.68 (q, J¼7.6 Hz, 2H, CH2), 3.04 (br s, 2H, CH2), 4.84 (br s, 1H,
CH), 7.23 (d, J¼8.1 Hz, 2H, CHar), 7.32 (d, J¼8.1 Hz, 2H, CHar), 7.65 (d,
J¼8.4 Hz, 2H, CHar), 7.94 (d, J¼8.4 Hz, 2H, CHar). 13C NMR (CDCl3,
100.6 MHz):
d¼15.42 (CH3), 19.86 (CH3), 21.62 (CH3), 24.01 (CH2),
4.3. Characterization of the 1,4-dihydropyridazine products
2aek
28.74 (CH2), 102.27 (CH), 126.41 (CHar), 127.94 (CHar), 128.14 (CHar),
129.50 (CHar), 132.88 (Car), 134.51 (Car), 136.01 (Car), 143.94 (Car),
146.56 (CN), 148.96 (CN). MS (DCI-CH4): m/z: 355.15 [MHD]. HRMS
(ESþ): calcd for C20H23N2O2S 355.1480; found 355.1497.
4.3.1. 1-(Benzenesulfonyl)-6-methyl-3-phenyl-1,4-dihydropyridazine
2a. White solid. Mp 115e117 ꢀC. 1H NMR (CDCl3, 400 MHz):
d¼2.25
(s, 3H, CH3), 3.08 (br s, 2H, CH2), 4.87 (br s, 1H, CH), 7.39e7.43 (m,
3H, CHar), 7.55 (t, J¼7.6 Hz, 2H, CHar), 7.61 (t, J¼6.8 Hz, 1H, CHar),
7.72 (d, J¼8.0 Hz, 2H, CHar), 8.07 (d, J¼7.6 Hz, 2H, CHar). 13C NMR
4.3.5. 6-Methyl-1-[(4-methylbenzene)sulfonyl]-3-[4-(tri-
fluoromethyl)phenyl]-1,4-dihydropyridazine 2e. White solid. Mp
131e133 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
¼2.26 (d, J¼1.2 Hz, 3H,
(CDCl3, 100.6 MHz):
d
¼19.80 (CH3), 24.02 (CH2), 102.33 (CH), 126.36
CH3), 2.45 (s, 3H, CH3), 3.10 (br s, 2H, CH2), 4.85 (br s, 1H, CH), 7.34
(d, J¼8.0 Hz, 2H, CHar), 7.66 (d, J¼8.0 Hz, 2H, CHar), 7.82 (d, J¼8.4 Hz,
2H, CHar), 7.93 (d, J¼8.4 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
(CHar), 128.10 (CHar), 128.43 (CHar), 128.91 (CHar), 130.09 (CHar),
133.10 (CHar), 134.48 (Car), 135.34 (Car), 138.99 (CN),149.06 (CN). MS
(DCI-CH4): m/z: 313.10 [MHD]. HRMS (ESþ): calcd for C17H16N2O2S
312.0939; found 312.0937.
d
¼19.80 (CH3), 21.64 (CH3), 23.84 (CH2), 101.66 (CH), 125.42 (q,
J¼3.8 Hz, CHar),126.55 (CHar), 128.14 (CHar),129.62 (CHar), 131.45 (q,
J¼32.5 Hz, CCF3), 134.55 (Car), 135.83 (Car), 138.80 (Car), 144.28 (CN),
146.75 (CN). MS (DCI-CH4): m/z: 395.11 [MHþ]. HRMS (ESþ): calcd
for C19H18F3N2O2S 395.1041; found 395.1053.
4.3.2. 6-Methyl-1-[(4-methylbenzene)sulfonyl]-3-(naphthalen-2-yl)-
1,4-dihydropyridazine 2b. Yellow oil. 1H NMR (CDCl3, 400 MHz):
d
¼2.28 (br s, 3H, CH3), 2.43 (s, 3H, CH3), 3.21 (br s, 2H, CH2), 4.91 (br
s, 1H, CH), 7.34 (d, J¼8.0 Hz, 2H, CHar), 7.52e7.55 (m, 2H, CHar),
7.85e7.88 (m, 3H, CHar), 7.98 (d, J¼8.4 Hz, 3H, CHar), 8.05 (dd, J¼1.6
4.3.6. 3-(4-Chlorophenyl)-6-methyl-1-[(4-methylbenzene)sulfonyl]-
1,4-dihydropyridazine 2f. White solid. Mp 102e104 ꢀC. 1H NMR
and 7.8 Hz, 1H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d¼19.95 (CH3),
(CDCl3, 300 MHz):
d
¼2.24 (d, J¼1.2 Hz, 3H, CH3), 2.44 (s, 3H, CH3),
21.63 (CH3), 23.78 (CH2), 102.31 (CH), 123.61 (CHar), 126.29 (CHar),
126.48 (CHar), 127.08 (CHar), 127.72 (CHar), 128.16 (CHar), 128.18
(CHar), 128.60 (CHar), 129.56 (CHar), 132.87 (Car), 132.91 (Car), 134.08
(Car), 134.43 (Car), 135.99 (Car), 144.06 (CN), 148.39 (CN). MS (DCI-
CH4): m/z: 377.13 [MHD]. HRMS (ESþ): calcd for C22H21N2O2S
377.1324; found 377.1336.
3.05 (br s, 2H, CH2), 4.84 (br s, 1H, CH), 7.32e7.39 (m, 4H, CHar), 7.65
(d, J¼8.7 Hz, 2H, CHar), 7.91 (d, J¼8.1 Hz, 2H, CHar). 13C NMR (CDCl3,
100.6 MHz):
d
¼19.82 (CH3), 21.63 (CH3), 23.81 (CH2), 101.87 (CH),
127.58 (CHar), 128.11 (CHar), 128.64 (CHar), 129.57 (CHar), 133.91
(Car), 134.49 (Car), 135.89 (Car), 136.07 (Car), 144.15 (CN), 147.38 (CN).
MS (DCI-CH4): m/z: 361.08 [MHþ]. HRMS (ESþ): calcd for
C18H18N2O2SCl 361.0778; found 361.0786.
4.3.3. 6-Methyl-1-[(4-methylbenzene)sulfonyl]-3-(4-methylphenyl)-
1,4-dihydropyridazine 2c. Yellow oil. 1H NMR (CDCl3, 300 MHz):
4.3.7. 3-Methyl-2-[(4-methylbenzene)sulfonyl]-2H,4aH,5H,6H-benzo
d¼2.24 (d, J¼1.2 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.03
[h]cinnoline 2g. Brown solid. Mp 136e138 ꢀC. 1H NMR (CDCl3,
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C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
9
400 MHz):
d
¼1.63e1.74 (m, 1H, CH2), 2.12e2.17 (m, 1H, CH2), 2.23
cool down to room temperature, and water (3 mL) was added. The
aqueous layer was extracted with EtOAc (3ꢂ4 mL), and the com-
bined organic layers were washed with brine (3ꢂ4 mL) and dried
over MgSO4. After filtration, the solvent was evaporated under re-
duced pressure and the residue was purified by chromatography on
silica gel (pentane/EtOAc) to give 3a as a white solid (92%).
(br s, 3H, CH3), 2.44 (s, 3H, CH3), 2.74e2.83 (m, 2H, CH2), 2.89e2.98
(m, 1H, CH), 4.62 (t, J¼1.6 Hz, 1H, CH), 7.14 (d, J¼7.6 Hz, 1H, CHar),
7.25e7.34 (m, 4H, CHar), 7.98 (d, J¼8.0 Hz, 2H, CHar), 8.12 (dd,
J¼7.6 Hz and 1.2 Hz, 1H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼19.22 (CH3), 21.62 (CH3), 27.99 (CH2), 28.94 (CH2), 33.34 (CH),
107.47 (CH), 125.89 (CHar), 126.60 (CHar), 128.21 (CHar), 128.72
(CHar), 129.50 (CHar), 129.98 (CHar), 130.04 (Car), 135.26 (Car), 136.17
(Car), 139.99 (Car), 143.95 (CN), 149.06 (CN). MS (DCI-CH4): m/z:
352.13 [MHþ]. HRMS (ESþ): calcd for C20H20N2O2S 352.1245; found
352.1256.
4.5. Characterization of the pyridazine products 3aek
4.5.1. 3-Methyl-6-phenylpyridazine 3a. Yield 92%. White solid. Mp
106e108 ꢀC.37 1H NMR (CDCl3, 400 MHz):
d
¼2.76 (s, 3H, CH3), 7.38
(d, J¼8.8 Hz, 1H, CHar), 7.48e7.54 (m, 3H, CHar), 7.75 (d, J¼8.8 Hz,
4.3.8. 6-Methyl-1-[(4-methylbenzene)sulfonyl]-3,4-diphenyl-1,4-
1H, CHar), 8.07 (d, J¼7.6 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
dihydropyridazine 2h. Yellow oil. 1H NMR (CDCl3, 400 MHz):
d
¼22.08 (CH3), 123.86 (CHar), 126.89 (CHar), 127.23 (CHar), 128.95
d
¼2.29 (s, 3H, CH3), 4.62 (d, J¼6.0 Hz, 1H, CH), 5.09 (d, J¼6.0 Hz, 1H,
(CHar),129.73 (CHar), 136.50 (Car),157.21 (CN),158.53 (CN). MS (DCI-
CH4): m/z: 171.09 [MHþ]. HRMS (ESþ): calcd for C11H11N2 171.0922;
found 171.0920. IR (ATR): 3061, 2916, 1587, 1496, 1450, 1415, 1168,
CH), 7.05 (d, J¼6.8 Hz, 2H, CHar), 7.19e7.25 (m, 4H, CHar), 7.33 (t,
J¼7.2 Hz, 3H, CHar), 7.58 (t, J¼7.2 Hz, 2H, CHar), 7.72 (d, J¼6.8 Hz, 2H,
CHar), 8.11 (d, J¼7.2 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
1113, 1034, 1012, 850, 770, 739, 689 cmꢁ1
.
d
¼20.23 (CH3), 40.15 (CH), 107.46 (CH), 126.92 (CHar), 127.13 (CHar),
127.16 (CHar), 128.20 (CHar), 128.36 (CHar), 129.06 (CHar), 129.14
(CHar), 129.77 (CHar), 132.34 (Car), 133.31 (CHar), 135.11 (Car), 138.84
(Car), 141.70 (CN), 148.61 (CN). MS (DCI-CH4): m/z: 389.13 [MHþ].
HRMS (ESþ): calcd for C23H21N2O2S 389.1324; found 389.1335.
4.5.2. 3-Methyl-6-(naphthalen-2-yl)pyridazine
3b. Yield
96%.
Brown solid. Mp 179e182 ꢀC. 1H NMR (CDCl3, 400 MHz):
d¼2.76 (s,
3H, CH3), 7.35 (d, J¼8.8 Hz, 1H, CHar), 7.52e7.54 (m, 2H, CHar),
7.84e7.89 (m, 2H, CHar), 7.93e7.98 (m, 2H, CHar), 8.24 (d, J¼8.4 Hz,
1H, CHar), 8.50 (s, 1H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼22.09
4.3.9. 3-(4-Methoxyphenyl)-6-methyl-1-[(4-methylbenzene)sulfo-
(CH3), 124.03 (CHar), 124.20 (CHar), 126.52 (CHar), 126.53 (CHar),
126.96 (CHar), 127.29 (CHar), 127.75 (CHar), 128.76 (CHar), 133.38
(Car), 133.75 (Car), 133.96 (Car), 157.07 (CN), 158.54 (CN). MS (DCI-
CH4): m/z: 221.11 [MHþ]. HRMS (ESþ): calcd for C15H13N2 221.1079;
found 221.1083. IR (ATR): 3057, 2920, 2851, 1961, 1825, 1682, 1587,
1552, 1500, 1472, 1438, 1415, 1359, 1276, 1241, 1128, 1104, 1028, 959,
nyl]-1,4-dihydropyridazine 2i. Yellow oil. 1H NMR (CDCl3,
300 MHz):
d
¼2.23 (d, J¼1.6 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 3.02 (br
s, 2H, CH2), 3.85 (s, 3H, CH3), 4.84 (br s, 1H, CH), 6.91 (d, J¼9.0 Hz,
2H, CHar), 7.31 (d, J¼8.4 Hz, 2H, CHar), 7.68 (d, J¼9.0 Hz, 2H, CHar),
7.93 (d, J¼8.4 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
¼19.87
d
(CH3), 21.61 (CH3), 23.95 (CH2), 55.37 (CH3), 102.29 (CH), 113.73
(CHar), 127.88 (CHar), 128.11 (CHar), 129.48 (CHar), 134.51 (Car),
136.03 (Car), 143.91 (Car), 148.73 (CN), 157.49 (CN), 161.16 (Car). MS
(DCI-CH4): m/z: 357.13 [MHþ]. HRMS (ESþ): calcd for C19H21N2O3S
357.1273; found 357.1281.
943, 915, 859, 868, 844, 810, 824, 763, 746, 654 cmꢁ1
.
4.5.3. 3-Methyl-6-(4-methylphenyl)pyridazine 3c. Yield 64%. Brown
solid. Mp 118e121 ꢀC.38 1H NMR (CDCl3, 400 MHz):
d
¼2.44 (s, 3H,
CH3), 2.76 (s, 3H, CH3), 7.32e7.38 (m, 3H, CHar), 7.73 (d, J¼8.8 Hz,1H,
CHar), 7.98 (d, J¼8.0 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
4.3.10. 6-Methyl-1-[(4-methylbenzene)sulfonyl]-3-pentyl-1,4-
d
¼21.34 (CH3), 22.06 (CH3), 123.59 (CHar), 126.75 (CHar), 127.15
dihydropyridazine 2j. Brown solid. Mp 186e189 ꢀC. 1H NMR (CDCl3,
(CHar), 129.68 (CHar), 133.68 (Car), 139.87 (Car), 157.15 (CN), 158.24
400 MHz):
d
¼0.84e0.92 (m, 3H, CH3), 1.22e1.32 (m, 4H, CH2),
(CN). MS (DCI-CH4): m/z: 185.10 [MHþ]. HRMS (ESþ): calcd for
1.48e1.55 (m, 2H, CH2), 2.16 (s, 3H, CH3), 2.26 (t, J¼7.2 Hz, 2H, CH2),
2.43 (s, 3H, CH3), 2.51 (d, J¼0.8 Hz, 2H, CH2), 4.71 (s, 1H, CH), 7.29 (d,
J¼8.4 Hz, 2H, CHar), 7.86 (d, J¼8.0 Hz, 2H, CHar). 13C NMR (CDCl3,
C
12H13N2 185.1079; found 185.1087. IR (ATR): 2922, 2853, 1733,
1456, 812, 743 cmꢁ1
.
75.6 MHz):
d
¼13.90 (CH3), 20.66 (CH3), 21.64 (CH3), 22.34 (CH2),
4.5.4. 3-(4-Ethylphenyl)-6-methylpyridazine 3d. Yield 64%. Brown
solid. Mp 73e75 ꢀC. 1H NMR (CDCl3, 400 MHz):
25.25 (CH2), 27.90 (CH2), 31.24 (CH2), 34.66 (CH2),103.42 (CH),126.06
(CHar), 128.32 (CHar), 128.78 (CHar), 129.81 (CHar), 140.11 (Car), 144.79
(Car), 158.62 (CN), 162.74 (CN). MS (DCI-CH4): m/z: 320.15 [MHþ].
HRMS (ESþ): calcd for C17H24N2O2S 320.1559; found 320.1545.
d
¼1.30 (t, J¼8.0 Hz,
3H, CH3), 2.74 (q, J¼8.0 Hz, 2H, CH2), 2.77 (s, 3H, CH3), 7.35e7.38 (m,
3H, CHar), 7.74 (d, J¼8.4 Hz, 1H, CHar), 8.01 (d, J¼7.2 Hz, 2H, CHar).
13C NMR (CDCl3, 100.6 MHz):
d
¼15.48 (CH3), 22.08 (CH3), 28.73
(CH2), 123.63 (CHar), 126.86 (CHar), 127.15 (CHar), 128.51 (CHar),
133.92 (Car), 146.19 (Car), 157.19 (CN), 158.24 (CN). MS (DCI-CH4): m/
z: 199.12 [MHþ]. HRMS (ESþ): calcd for C13H15N2 199.1235; found
199.1237. IR (ATR): 3055, 2963, 2910, 1588, 1429, 1407, 1162, 1007,
4 . 3 . 11. 3 - M e t h y l - 2 - [ ( 4 - m e t h y l b e n z e n e ) s u l f o n y l ] -
2H,4aH,5H,6H,7H,8H,9H-cyclohepta[c]pyridazine 2k. Yellow oil. 1H
NMR (CDCl3, 400 MHz):
d¼1.32e1.43 (m, 4H, CH2), 1.60e1.70 (m,
6H, CH2), 2.14 (d, J¼1.6 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 2.55 (m, 1H,
CH), 4.61 (br s,1H, CH), 7.29 (d, J¼8.4 Hz, 2H, CHar), 7.88 (d, J¼8.4 Hz,
826, 754 cmꢁ1
.
2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d¼19.17 (CH3), 21.59 (CH3),
4.5.5. 3-Methyl-6-[4-(trifluoromethyl)phenyl]pyridazine 3e. Yield
90%. White solid. Mp 180e182 ꢀC.38 1H NMR (CDCl3, 400 MHz):
26.53 (CH2), 28.19 (CH2), 29.20 (CH2), 32.46 (CH2), 35.14 (CH2), 37.27
(CH), 108.68 (CH), 128.01 (CHar), 129.35 (CHar), 134.73 (Car), 136.27
(Car), 143.69 (CN), 160.72 (CN). MS (DCI-CH4): m/z: 319.15 [MHþ].
HRMS (ESþ): calcd for C17H23N2O2S 319.1480; found 319.1487.
d
¼2.80 (s, 3H, CH3), 7.44 (d, J¼8.8 Hz,1H, CHar), 7.80 (t, J¼8.0 Hz, 3H,
CHar), 8.20 (d, J¼8.4 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼22.12 (CH3), 123.99 (CHar), 124.04 (q, J¼272.2 Hz, CF3), 125.91 (q,
J¼3.8 Hz, CHar), 127.19 (CHar), 127.37 (CHar), 131.45 (q, J¼32.6 Hz,
CCF3), 139.84 (Car), 155.93 (CN), 159.33 (CN). MS (DCI-CH4): m/z:
238.07 [MHþ]. HRMS (ESþ): calcd for C12H9F3N2 238.0718; found
238.0719. IR (ATR): 3069, 2928, 1552, 1428, 1322, 1158, 1110, 1067,
4.4. Typical procedure for the preparation of pyridazines
3aek (example of 3a)
In an around flask (5 mL), were added successively 1,4-
dihydropyridazine 2a (0.064 mmol, 1 equiv), NaOAc (0.192 mmol,
3 equiv), a Teflon stirring bar, and THF (4 mL). The reaction mixture
was then stirred at 65 ꢀC for 3 h. The solution was then allowed to
1010, 830, 711 cmꢁ1
.
4.5.6. 3-(4-Chlorophenyl)-6-methylpyridazine 3f. Yield 59%. White
solid. Mp 146e149 ꢀC. 1H NMR (CDCl3, 400 MHz):
¼2.75 (s, 3H,
d
Please cite this article in press as: Mboyi, C. D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.005

10
C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
CH3), 7.38 (d, J¼8.8 Hz,1H, CHar), 7.47 (d, J¼8.0 Hz, 2H, CHar), 7.71 (d,
J¼8.8 Hz, 1H, CHar), 8.00 (d, J¼8.4 Hz, 2H, CHar). 13C NMR (CDCl3,
The solution was then allowed to cool down to room temperature,
and water (3 mL) was added. The aqueous layer was extracted with
EtOAc (3ꢂ4 mL), and the combined organic layers were washed
with brine (3ꢂ4 mL) and dried over MgSO4. After filtration, the
solvent was evaporated under reduced pressure and the residue
was purified by chromatography on silica gel (pentane/EtOAc) to
give 5a as a white solid (68%).
100.6 MHz):
d
¼22.08 (CH3), 123.57 (CHar), 127.29 (CHar), 128.11
(CHar), 129.17 (CHar), 134.90 (Car), 136.01 (Car), 156.10 (CN), 158.77
(CN). MS (DCI-CH4): m/z: 205.05 [MHþ]. HRMS (ESþ): calcd for
C
11H10ClN2 205.0533; found 205.0530. IR (ATR): 3057, 2922, 2853,
1595, 1489, 1422, 1399, 1333, 1092, 1008, 818, 759 cmꢁ1
.
4.5.7. 3-Methyl-5H,6H-benzo[h]cinnoline 3g. Yield 54%. Brown
solid. Mp 108e110 ꢀC. 1H NMR (CDCl3, 400 MHz):
4.7. Characterization of the pyrazole products 5aei
d¼2.71 (s, 3H,
CH3), 2.91e2.98 (m, 4H, CH2), 7.14 (s, 1H, CHar), 7.26 (t, J¼7.2 Hz, 1H,
4.7.1. 5-Ethenyl-3-phenyl-1H-pyrazole 5a. Yield 68%. White solid.
CHar), 7.36e7.44 (m, 2H, CHar), 8.57 (d, J¼7.6 Hz, 1H, CHar). 13C NMR
Mp 96e98 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
¼5.34 (d, J¼11.2 Hz, 1H,
(CDCl3, 100.6 MHz):
d
¼22.11 (CH3), 27.16 (CH2), 27.42 (CH2), 125.14
CH2), 5.76 (d, J¼17.6 Hz, 1H, CH2), 6.66 (s, 1H, CH), 6.68 (t, J¼11.2 Hz,
1H, CH), 7.34 (t, J¼7.2 Hz, 1H, CHar), 7.40 (t, J¼7.2 Hz, 2H, CHar), 7.70
(CHar), 125.44 (CHar), 127.53 (CHar), 128.01 (CHar), 129.96 (CHar),
131.79 (Car), 136.23 (Car), 137.79 (Car), 153.51 (CN), 158.43 (CN). MS
(DCI-CH4): m/z: 197.11 [MHþ]. HRMS (ESþ): calcd for C13H12N2
197.1079; found 197.1082. IR (ATR): 2955, 2920, 2847, 1606, 1487,
(d, J¼8.0 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
¼100.08 (CH),
d
116.05 (CH2), 125.69 (CHar), 126.25 (CHar), 128.20 (CHar), 128.82
(CHar), 131.43 (Car), 146.99 (CN), 148.86 (CN). MS (DCI-CH4): m/z:
171.09 [MHþ]. HRMS (ESþ): calcd for C11H11N2 171.0922; found
171.0920. IR (ATR): 2917, 2870, 1560, 1461, 1274, 1204, 1168, 1075,
1410, 1285, 1107, 1012, 890, 794, 753, 695 cmꢁ1
.
4.5.8. 6-Methyl-3,4-diphenylpyridazine 3h. Yield 46%. Brown solid.
Mp 117e119 ꢀC.39 1H NMR (CDCl3, 400 MHz):
¼2.81 (s, 3H, CH3),
1000, 964, 912, 806, 758, 687, 507 cmꢁ1
.
d
7.19 (d, J¼7.6 Hz, 2H, CHar), 7.28e7.34 (m, 7H, CHar), 7.43 (d,
4.7.2. 5-Ethenyl-3-(naphthalen-2-yl)-1H-pyrazole amine 5b. Yield
42%. Yellow solid. Mp 99e102 ꢀC. 1H NMR (CDCl3, 400 MHz):
J¼7.2 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
¼22.00 (CH3),
d
127.68 (CHar), 128.09 (CHar), 128.51 (CHar), 128.57 (CHar), 128.63
(CHar), 129.06 (CHar), 129.99 (CHar), 136.97 (Car), 137.01 (Car), 138.97
(Car), 157.78 (CN), 158.60 (CN). MS (DCI-CH4): m/z: 247.12 [MHþ].
HRMS (ESþ): calcd for C17H15N2 247.1235; found 247.1225. IR (ATR):
d
¼5.40 (d, J¼11.2 Hz, 1H, CH2), 5.80 (d, J¼17.6 Hz, 1H, CH2),
6.70e6.77 (m, 1H, CH), 6.81 (s, 1H, CH), 7.49 (br s, 2H, CHar), 7.85 (br
s, 2H, CHar), 7.87 (s, 2H, CHar), 8.18 (s, 1H, NH). 13C NMR (CDCl3,
100.6 MHz):
d
¼100.46 (CH), 116.14 (CH2), 123.79 (CHar), 124.34
3026, 2958, 1571, 1494, 1400, 1036, 1011, 889, 795, 752, 696 cmꢁ1
.
(CHar), 126.00 (CHar), 126.18 (CHar), 126.45 (CHar), 127.75 (CHar),
128.18 (CHar), 128.58 (CHar), 129.00 (Car), 133.15 (Car), 133.47 (Car),
146.80 (br s, CN), 149.50 (br s, CN). MS (DCI-CH4): m/z: 221.10
[MHþ]. HRMS (ESþ): calcd for C15H13N2, 221.1079; found 221.1075.
IR (ATR): 3121, 2918, 1559, 1428, 1270, 1164, 979, 895, 858, 802, 747,
4.5.9. 3-(4-Methoxyphenyl)-6-methylpyridazine
3i. Yield
40%.
¼2.76
White solid. Mp 136e138 ꢀC.38 1H NMR (CDCl3, 400 MHz):
d
(s, 3H, CH3), 3.89 (s, 3H, CH3), 7.04 (d, J¼8.4 Hz, 2H, CHar), 7.34 (d,
J¼8.8 Hz, 1H, CHar), 7.70 (d, J¼8.8 Hz, 1H, CHar), 8.05 (d, J¼8.4 Hz,
681, 627, 582, 527 cmꢁ1
.
2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼22.02 (CH3), 55.40 (CH3),
114.37 (CHar), 123.21 (CHar), 127.15 (CHar), 128.19 (CHar), 128.98
(Car), 156.76 (CN), 157.88 (CN), 161.07 (Car). MS (DCI-CH4): m/z:
201.10 [MHþ]. HRMS (ESþ): calcd for C12H13N2O 201.1028; found
201.1025. IR (ATR): 3046, 2957, 2925, 2839, 2046, 1912, 1605, 1508,
4.7.3. 5-Ethenyl-3-(4-methylphenyl)-1H-pyrazole amine 5c. Yield
62%. White solid. Mp 112e114 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
¼2.40
(s, 3H, CH3), 5.35 (dd, J¼1.0 Hz and 10.8 Hz, 1H, CH2), 5.76 (dd, J¼1.0 Hz
and 18.0 Hz,1H, CH2), 6.64 (s,1H, CH), 6.66e6.73 (m,1H, CH), 7.22 (d,
J¼8.0 Hz, 2H, CHar), 7.59 (d, J¼7.4 Hz, 2H, CHar). 13C NMR (CDCl3,
1427, 1283, 1249, 1172, 1114, 1034, 832, 814, 671 cmꢁ1
.
100.6 MHz):
d
¼21.29 (CH3), 99.75 (CH), 115.83 (CH2), 125.55 (CHar),
4.5.10. 3-Methyl-6-(4-pentylphenyl)pyridazine 3j. Yield 62%. Color-
less oil. 1H NMR (CDCl3, 400 MHz):
126.62 (CHar), 128.48 (Car), 129.53 (CHar), 138.12 (Car), 147.48 (CN),
d
¼0.90 (t, J¼6.4 Hz, 3H, CH3),
148.57 (CN). MS (DCI-CH4): m/z: 185.10 [MHþ]. HRMS (ESþ): calcd for
1.35 (m, 4H, CH2), 1.72e1.80 (m, 2H, CH2), 2.68 (s, 3H, CH3), 2.93 (t,
C
12H13N2 185.1079; found 185.1077. IR (ATR): 3069, 2919, 1509, 1453,
J¼8.0 Hz, 2H, CH2), 7.22 (br s, 2H, CHar). 13C NMR (CDCl3,
1376, 1166, 1047, 991, 965, 901, 820, 788, 689, 570, 523 cmꢁ1
.
100.6 MHz):
d
¼13.97 (CH3), 21.98 (CH3), 22.46 (CH2), 29.38 (CH2),
31.41 (CH2), 35.87 (CH2), 126.19 (CHar), 126.85 (CHar), 157.74 (CN),
4.7.4. 5-Ethenyl-3-(4-ethylphenyl)-1H-pyrazole amine 5d. Yield
86%. Brown solid. Mp 72e75 ꢀC. 1H NMR (CDCl3, 400 MHz):
161.49 (CN). MS (DCI-CH4): m/z: 165.1 [MHþ]. HRMS (ESþ): calcd for
d
¼1.28
C
10H17N2 165.1392; found 165.1395. IR (ATR): 2925, 2856, 1551,
(t, J¼7.2 Hz, 3H, CH3), 2.68 (q, J¼7.2 Hz, 2H, CH2), 5.36 (d, J¼11.2 Hz,
1H, CH2), 5.75 (d, J¼17.6 Hz,1H, CH2), 6.64 (s,1H, CH), 6.66e6.74 (m,
1436, 1165, 1080, 815, 680, 642, 525, 520 cmꢁ1
.
1H, CH), 7.25 (d, J¼7.6 Hz, 2H, CHar), 7.61 (d, J¼7.6 Hz, 2H, CHar). 13
C
4.5.11. 3-Methyl-6-{6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl}
NMR (CDCl3, 100.6 MHz):
d
¼15.51 (CH3), 28.67 (CH2), 99.82 (CH),
pyridazine 3k. Yield 43%. Brown oil. 1H NMR (CDCl3, 400 MHz):
115.86 (CH2), 125.62 (CHar), 126.61 (CHar), 128.36 (CHar), 128.67
(Car), 144.52 (Car), 147.42 (CN), 148.46 (CN). MS (DCI-CH4): m/z:
199.12 [MHþ]. HRMS (ESþ): calcd for C13H15N2 199.1235; found
199.1232. IR (ATR): 3133, 2920, 1716, 1508, 1431, 1258, 1258, 1161,
d
¼1.69e1.76 (m, 4H, CH2), 1.87e1.91 (m, 2H, CH2), 2.63 (s, 3H, CH3),
2.74 (br s, 2H, CH2), 3.21 (br s, 2H, CH2), 7.02 (s, 1H, CHar). 13C NMR
(CDCl3, 100.6 MHz):
d
¼26.59 (CH3), 27.51 (CH2), 29.71 (CH2), 32.19
(CH2), 34.84 (CH2), 36.41 (CH2), 126.59 (CHar), 142.60 (Car), 158.24
(CN), 163.14 (CN). MS (DCI-CH4): m/z: 162.12 [MHþ]. HRMS (ESþ):
calcd for C10H15N2 163.1235; found 163.1248. IR (ATR): 2926, 2853,
1113, 985, 909, 810, 723, 560, 521, 506 cmꢁ1
.
4.7.5. 5-Ethenyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole
5e. Yield 42%. Yellow solid. Mp 138e140 ꢀC. 1H NMR (CDCl3,
1607, 1509, 1430, 1285, 1252, 1174, 1035, 913, 813, 794, 672 cmꢁ1
.
400 MHz):
d
¼5.43 (d, J¼11.2 Hz, 1H, CH2), 5.76 (d, J¼17.6 Hz, 1H,
4.6. Typical procedure for the preparation of pyrazoles 5aei
(example of 5a)
CH2), 6.65e6.72 (m, 1H, CH), 6.73 (s, 1H, CH), 7.68 (d, J¼8.0 Hz, 2H,
CHar), 7.89 (d, J¼8.0 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼100.74 (CH), 116.67 (CH2), 124.01 (q, J¼271.8 Hz, CF3), 125.09
In a round flask (5 mL), were added successively pyrazoline 4a
(0.346 mmol,1 equiv), NaOH (1.038 mmol, 3 equiv), a Teflon stirring
bar, and THF (4 mL). The mixture was then stirred at 65 ꢀC for 3 h.
(CHar), 125.69 (q, JCF¼4.0 Hz, CHar), 125.74 (CHar), 130.00 (q,
J¼32.2 Hz, CCF3), 135.26 (Car), 145.83 (CN), 148.90 (CN). MS (DCI-
CH4): m/z: 239.08 [MHþ]. HRMS (ESþ): calcd for C12H10F3N2
Please cite this article in press as: Mboyi, C. D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.005

C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
11
3
ꢀ
ꢁ
239.0796; found 239.0802. IR (ATR): 3242, 2924, 1835, 1618, 1448,
1323, 1163, 1105, 1069, 1016, 986, 960, 915, 844, 804, 755, 708, 658,
594, 533, 501 cmꢁ1
b
¼91.243(2) , V¼1481.04(4) A , T¼100 K, space group: P21/n, Z¼4,
m
(Mo K
a
)¼0.227 mmꢁ1, 31,270 reflections measured, 3771 unique
(Rint¼0.020), 199 parameters, refinement on F, 3426 reflections
used in the calculations [I>3
s
(I)], R1¼0.0292, wR2¼0.0367.
4.7.6. 3-(4-Chlorophenyl)-5-ethenyl-1H-pyrazole 5f. Yield 95%.
White solid. Mp 108e111 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
¼5.38 (d,
4.8.2. Crystal data for 2e. C19H17F3N2O2S, M¼394.42 g molꢁ1
,
ꢁ
J¼11.2 Hz, 1H, CH2), 5.75 (d, J¼17.6 Hz, 1H, CH2), 6.62e6.69 (m, 2H,
CH), 7.38 (d, J¼7.2 Hz, 2H, CHar), 7.67 (d, J¼7.6 Hz, 2H, CHar), 10.57
monoclinic,
b
a¼14.1633(5), b¼8.3742(2),
c¼15.1505(5)
A,
3
ꢁ
¼105.975(3), V¼1727.56(10) A , T¼100 K, space group P21/n, Z¼4,
(br s, 1H, NH). 13C NMR (CDCl3, 100.6 MHz):
d
¼100.31 (CH), 116.36
m
(Cu K
a
)¼2.116 mmꢁ1, 20,565 reflections measured, 2613 unique
(CH2), 125.22 (CHar), 126.90 (CHar), 128.97 (CHar), 131.03 (Car),
133.94 (Car), 146.14 (CN) 149.48 (CN). MS (DCI-CH4): m/z: 205.05
[MHþ]. HRMS (ESþ): calcd for C11H10N2Cl 205.0533; found
205.0533. IR (ATR): 3088, 2917, 1491, 1443, 1283, 1163, 1093, 1003,
(Rint¼0.030), 244 parameters, refinement on F, 2449 reflections
used in the calculations [I>2
s
(I)], R1¼0.0322, wR2¼0.0439.
4.8.3. Crystal data for 3a. C11H10N2, M¼170.21 g molꢁ1, monoclinic,
964, 911, 830, 792, 697, 667, 539, 501 cmꢁ1
.
a¼5.7269(3), b¼22.9224(11), c¼7.1956(4) A,
b
¼112.312(6),
(Cu K
ꢁ
3
ꢁ
V¼873.87(8) A , T¼100 K, space group C2/c, Z¼4,
m
a
)¼
4.7.7. 3-Ethenyl-2H,4H,5H-benzo[g]indazole 5g. Yield 79%. Yellow
oil. 1H NMR (CDCl3, 400 MHz):
0.614 mmꢁ1, 2852 reflections measured, 658 unique (Rint¼0.012),
d
¼2.82 (t, J¼7.2 Hz, 2H, CH2), 2.97 (t,
66 parameters, refinement on F, 647 reflections used in the calcu-
J¼7.2 Hz, 2H, CH2), 5.33 (d, J¼11.6 Hz, 1H, CH2), 5.63 (d, J¼18.0 Hz,
1H, CH2), 6.61e6.68 (m, 1H, CH), 7.19e7.28 (m, 3H, CHar), 7.73 (t,
J¼4.0 Hz, 1H, CHar), 10.56 (br s, 1H, NH). 13C NMR (CDCl3,
lations [I>3
s
(I)], R1¼0.0991, wR2¼0.0926. The asymmetric unit
contains half a molecule. Two positions have been assigned, re-
spectively, to C(3)/N(2) and C(2)/N(1) with half occupancy. A two-
fold symmetry axis generates the full molecule.
100.6 MHz):
d
¼19.24 (CH2), 29.48 (CH2), 115.56 (CH2), 122.07 (CH),
124.92 (CHar), 126.81 (CHar), 127.60 (CHar), 128.29 (CHar), 133.21
(Car), 136.42 (Car), 139.34 (Car), 146.89 (CN), 155.78 (CN). MS (DCI-
CH4): m/z: 197.10 [MHþ]. HRMS (ESþ): calcd for C13H13N2 197.1079;
found 197.1077. IR (ATR): 3103, 2926, 1634, 1474, 1436, 1308, 1155,
4.8.4. Crystal data for 3a0. C17H16N2O3S, M¼328.39 g molꢁ1, or-
ꢁ
thorhombic, a¼18.1395(10), b¼7.2588(4), c¼11.8611(7) A,
3
ꢁ
V¼1561.76(15) A , T¼100 K, space group Pna21, Z¼4,
m(Mo K
a)¼
1081, 985, 906, 753, 734, 553, 514, 502 cmꢁ1
.
0.224 mmꢁ1
(Rint¼0.027), 209 parameters, refinement on F, 4559 reflections
used in the calculations [I>3
(I)], R1¼0.0294, wR2¼0.0333.
,
27,660 reflections measured, 5152 unique
4.7.8. 5-Ethenyl-3,4-Diphenyl-1H-pyrazole 5h. Yield 42%. White
solid. Mp 189e192 ꢀC. 1H NMR (CDCl3, 400 MHz):
s
d¼5.26 (d,
J¼11.2 Hz, 1H, CH2), 5.72 (d, J¼18.0 Hz, 1H, CH2), 6.52e6.60 (m, 1H,
4.8.5. Crystal data for 3b. C19H17F3N2O2S, M¼394.42 g molꢁ1
,
ꢁ
CH), 7.24e7.28 (m, 5H, CHar), 7.35e7.40 (m, 5H, CHar),11.44 (br s,1H,
monoclinic, a¼11.49986(18), b¼9.08278(12), c¼10.79807(17) A,
NH). 13C NMR (CDCl3, 100.6 MHz):
125.02 (CH), 126.98 (CHar), 127.84 (CHar), 128.40 (CHar), 128.48
(CHar), 130.48 (CHar), 131.71 (Car), 132.92 (Car), 142.96 (CN), 146.79
(CN). MS (DCI-CH4): m/z: 247.12 [MHþ]. HRMS (ESþ): calcd for
d
¼115.82 (CH2), 118.43 (Car),
b
¼100.3163(15), V¼1109.63(3) A , T¼100 K, space group P21/c, Z¼4,
3
ꢁ
m
(Mo K
a
)¼0.079 mmꢁ1, 23,837 reflections measured, 2842 unique
(Rint¼0.024), 154 parameters, refinement on F, 2336 reflections
used in the calculations [I>3
s
(I)], R1¼0.0379, wR2¼0.0464.
C
17H15N2 247.1235; found 247.1242. IR (ATR): 3139, 2921, 1602,
1443, 1263, 1179, 1113, 1071, 969, 914, 770, 752, 694, 613, 502 cmꢁ1
.
4.8.6. Crystal data for 3c. C12H12N2, M¼184.24 g molꢁ1, monoclinic,
ꢁ
a¼6.13072(10), b¼13.2919(2), c¼11.8273(2) A,
b
¼90.5889(15),
(Mo K
)¼
16,085 reflections measured, 2342 unique
(Rint¼0.019), 127 parameters, refinement on F, 1894 reflections used
in the calculations [I>3
(I)], R1¼0.0395, wR2¼0.0524.
3
ꢁ
4.7.9. 5-Ethenyl-3-(4-methoxyphenyl)-1H-pyrazole amine 5i. Yield
94%. White solid. Mp 114e116 ꢀC. 1H NMR (CDCl3, 400 MHz):
V¼963.74(3) A , T¼100 K, space group P21/c, Z¼4,
m
a
0.077 mmꢁ1
,
d
¼3.86 (s, 3H, CH3), 5.36 (d, J¼11.2 Hz, 1H, CH2), 5.76 (d, J¼18.0 Hz,
1H, CH2), 6.60 (s, 1H, CH), 6.66e6.73 (m, 1H, CH), 6.96 (d, J¼7.6 Hz,
s
2H, CHar), 7.63 (d, J¼7.6 Hz, 2H, CHar). 13C NMR (CDCl3, 100.6 MHz):
d
¼55.36 (CH3), 99.52 (CH), 114.28 (CHar), 115.89 (CH2), 124.07 (Car),
4.8.7. Crystal data for 3g. C13H12N2, M¼196.25 g molꢁ1, monoclinic,
ꢁ
126.48 (CHar), 126.94 (CHar), 147.25 (CN), 148.51 (CN), 159.73 (Car).
MS (DCI-CH4): m/z: 201.10 [MHþ]. HRMS (ESþ): calcd for C12H13N2O
201.1028; found 201.1017. IR (ATR): 3076, 2918, 1888, 1612, 1506,
a¼7.54824(18), b¼11.6750(4), c¼11.3748(4) A,
b
¼99.212(3),
3
ꢁ
V¼989.48(5) A , T¼100 K, space group P21/n, Z¼4,
m
(Cu K
a
)¼
0.615 mmꢁ1, 6153 reflections measured, 1513 unique (Rint¼0.017),
1431, 1252, 1180, 1030, 982, 913, 832, 794, 686, 598, 523, 508 cmꢁ1
.
136 parameters, refinement on F, 1411 reflections used in the cal-
culations [I>3
s
(I)], R1¼0.0303, wR2¼0.0371.
4.8. Crystal structure determination of compounds 2a, 2e, 3a,
3a0, 3b, 3c, 3g, 3h, 3i, and 5h
4.8.8. Crystal data for 3h. C17H14N2, M¼394.42 g molꢁ1, mono-
ꢁ
clinic,
a¼10.77108(12),
b¼9.80238(13),
c¼25.0180(3)
A,
3
ꢁ
X-ray diffraction data for the crystals were collected at 100 K on
b
¼92.1531(10), V¼2639.59(5) A , T¼100 K, space group P21/c, Z¼8,
an Oxford Diffraction Gemini diffractometer using Cu K
a
radiation
radiation
m
(Cu K
a
)¼0.571 mmꢁ1, 38,640 reflections measured, 3983 unique
ꢁ
source (2e, 3a, 3g, 3h, 3i, 5h,
l
¼1.54180 A) or Mo K
a
(Rint¼0.022), 344 parameters, refinement on F, 3730 reflections
source (2a, 3a0, 3b, 3c,
l¼0.71073 A). Multiscan absorption cor-
used in the calculations [I>3
s
(I)], R1¼0.0277, wR2¼0.0357.
ꢁ
rections were applied. The structures were solved by direct
methods using SIR9240 or SUPERFLIP,41 and refined by means of
least-square procedures using the PC version of CRYSTALS.42
Atomic scattering factors were taken from the International Ta-
bles for X-ray Crystallography.43 All non-hydrogen atoms were re-
fined anisotropically. Hydrogen atoms were refined with riding
constraints.
4.8.9. Crystal data for 3i. C12H12N2O, M¼200.24 g molꢁ1, mono-
ꢁ
clinic, a¼20.7510(14), b¼5.8173(3), c¼18.3779(12) A,
b¼115.374(8),
3
ꢁ
V¼2004.5(2) A , T¼100 K, space group C2/c, Z¼8,
m(Cu K
a)¼
0.693 mmꢁ1, 6465 reflections measured, 1875 unique (Rint¼0.018),
136 parameters, refinement on F, 1694 reflections used in the cal-
culations [I>3
s
(I)], R1¼0.0449, wR2¼0.0550.
4.8.1. Crystal data for 2a. C17H16N2O2S1, M¼312.39
g
molꢁ1
,
4.8.10. Crystal data for 5h. C17H14N2, M¼246.31 g molꢁ1, mono-
ꢁ
ꢁ
monoclinic, a¼9.90996(16), b¼9.6596(2), c¼15.4753(3) A,
clinic,
a¼10.59135(18),
b¼17.5216(3),
c¼27.9341(5)
A,
Please cite this article in press as: Mboyi, C. D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.005

12
C.D. Mboyi et al. / Tetrahedron xxx (2014) 1e12
24. The CeC resonance integral kept uniform for all the sp2-Cesp2-C bonds,
3
ꢁ
b
¼90.5984(15), V¼5183.67(16) A , T¼100 K, space group C2/c,
2
€
whatever the substituents. All the sp -C atoms are also given the same Huckel
Z¼16,
m
(Cu K
a
)¼0.581 mmꢁ1, 25,473 reflections measured, 4998
coulomb integral
reference monocycles (without any
a
¼0, whatever the substituents. TRE values for C6 and C5
unique (Rint¼0.018), 343 parameters, refinement on F, 4631 re-
p
-conjugated substituent) are also given.
TRE values were calculated as the enthalpies of the ‘twist-rocking’ equations
flections used in the calculations [I>3
s
(I)], R1¼0.0416,
~
~
€
½AÒA/A, where A is a given
p-cyclic molecular structure, A its Mobius-
wR2¼0.0556.
21
~
twistomer, and AÒA the twisted head-to-tail metathesis cyclo-dimer of A,
using the freeware HuLiS program: see references: (a) Goudard, N.; Carissan, Y.;
Hagebaum-Reignier, D.; Humbel, S. HuLiS 3.0, 2007, JDK 1.6.0_51. http://www.
hulis.free.fr/. (b) Carissan, Y.; Hagebaum-Reignier, D.; Goudard, N.; Humbel, S. J.
Phys. Chem. A 2008, 112, 13256.
Acknowledgements
The authors thank the Centre National de la Recherche Scien-
tifique for working facilities and financial support. The Gabonese
Agency of Scholarships is acknowledged for the doctoral fellowship
no 762241D of C.D.M.
ꢀ
ꢀ
25. (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402;
(b) Sadimenko, A. P. Adv. Heterocycl. Chem. 2010, 100, 175; (c) Gulevich, A. V.;
Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084.
26. (a) Mboyi, C. D.; Abdellah, I.; Duhayon, C.; Canac, Y.; Chauvin, R. ChemCatChem
2013, 5, 3014; (b) Dang, T. T.; Abdellah, I.; Canac, Y.; Chauvin, R. ChemCatChem
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Supplementary data
Acc. Chem. Res. 1993, 26, 476.
28. Selected examples on pyrazole syntheses: (a) Mallouk, S.; Bougrin, K.; Doua, H.;
Benhida, R.; Soufiaoui, M. Tetrahedron Lett. 2004, 45, 4143; (b) Waldo, J. P.;
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1H and 13C NMR spectra of all newly described compounds.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2014.05.005.
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Please cite this article in press as: Mboyi, C. D.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.005