Facile synthesis of new spirothiadiazolopyridazines by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1080/00397910500182697

New derivatives of the spiro type of pyridazines have been synthesized by 1,3-dipolar cycloaddition of N-aryl-C-ethoxycarbonylnitrile imines with pyridazin-3(2H)-thiones. When the nitrile oxide was used, the corresponding pyridazin-3(2H)-one was obtained

Full text of DOI:10.1080/00397910500182697

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Facile Synthesis of New
Spirothiadiazolopyridazines by
1,3‐Dipolar Cycloaddition
S. Abouricha a b , E. M. Rakib a , N. Benchat b , M.
Alaoui a , H. Allouchi c & B. El Bali d
a Laboratoire de Chimie Organique et Analytique,
Faculté des Sciences et Techniques, Béni‐Mellal,
Morocco
b Département de Chimie, Faculté des Sciences,
Oujda, Morocco
c Laboratoire de Chimie Physique, Faculté de
Pharmacie, SPOT E.A., Tours, France
d Laboratoire d'Analyses, d'Essais et d'Environnement
(L.A.E.E.), Département de Chimie, Faculté des
Sciences “Dhar Mehraz”, Fès, Morocco
Published online: 18 Aug 2006.
To cite this article: S. Abouricha , E. M. Rakib , N. Benchat , M. Alaoui , H. Allouchi
& B. El Bali (2005) Facile Synthesis of New Spirothiadiazolopyridazines by 1,3‐Dipolar
Cycloaddition, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:16, 2213-2221
To link to this article: http://dx.doi.org/10.1080/00397910500182697
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Synthetic Communicationsw, 35: 2213–2221, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500182697
Facile Synthesis of New
Spirothiadiazolopyridazines by
1,3-Dipolar Cycloaddition
S. Abouricha
Laboratoire de Chimie Organique et Analytique, Faculte des Sciences et
´ ´
Techniques, Beni-Mellal, Morocco and Departement de Chimie,
´
´
Faculte des Sciences, Oujda, Morocco
E. M. Rakib
Laboratoire de Chimie Organique et Analytique, Faculte des Sciences et
´
Techniques, Beni-Mellal, Morocco
´
N. Benchat
´ ´
Departement de Chimie, Faculte des Sciences, Oujda, Morocco
M. Alaoui
Laboratoire de Chimie Organique et Analytique, Faculte des Sciences et
´
Techniques, Beni-Mellal, Morocco
´
H. Allouchi
´
Laboratoire de Chimie Physique, Faculte de Pharmacie, SPOT E.A.,
Tours, France
B. El Bali
Laboratoire d’Analyses, d’Essais et d’Environnement (L.A.E.E.),
´ ´
Departement de Chimie, Faculte des Sciences “Dhar Mehraz”,
`
Fes, Morocco
Abstract: New derivatives of the spiro type of pyridazines have been synthesized by
1,3-dipolar cycloaddition of N-aryl-C-ethoxycarbonylnitrile imines with pyridazin-
Received in Poland April 4, 2005
Address correspondence to E. M. Rakib, Laboratoire de Chimie Organique et
´ ´
Analytique, Faculte des Sciences et Techniques, BP 523, 23000 Beni-Mellal,
Morocco. E-mail: rakib1@caramail.com
2213

2214
S. Abouricha et al.
3(2H)-thiones. When the nitrile oxide was used, the corresponding pyridazin-3(2H)-one
was obtained from the intermediate spirooxathiazole by elimination of isothiocyanate
group. The peri- and regioselectivity of the reaction were ascertained by X-ray analysis
and 13C NMR spectroscopy of the cycloadducts 3–9.
Keywords: Cycloadditions, pyridazin-3(2H)-thione, regioselectivity, spiro
compounds, X-ray analysis
INTRODUCTION
Pyridazin-3(2H)-ones and their fused-ring derivatives have recently received
much more attention because of their various biological activities. Several
pyrrolopyridazinones are known for their antiproliferative, antiviral,[1,2]
antimicrobial, and antifungal activity[3] and are inhibitors of phospholipase
A2[4] or exhibit profound inhibition of lipid peroxidation in vitro.[5] Some
imidazo[1,2-b]pyridazine derivatives are reported to be interesting biological
substances such as cyclin-dependent kinase (CDK) inhibitors[6] and anti-
histaminics.[7] Also, some thieno[3,4-d]pyridazines were used as modules of
protein tyrosine phosphatases (PTPases).[8] In most cases, the pyridazino-
fused-ring systems have been prepared generally by cyclization reactions of
pyridazines with different intermediate reagents and by palladium-catalyzed
coupling reactions of pyridazinone derivatives.[9,10] In this article we have
developed a synthesis of new spirothiadiazolopyridazines by 1,3-dipolar
cycloaddition. The presence of two potential dipolarophilic functionalities
C55N and C55S, is making pyridazinethiones very interesting from the
vantage point of dipolar cycloaddition. The reaction of pyridazin-3(2H)-
thiones 1(a, b) with N-aryl-C-ethoxycarbonylnitrile imines, generated in situ
from ethylhydrazono-a-bromoglyoxylates 2(a–d)[11] and triethylamine, was
performed in tetrahydrofuran (THF) at room temperature. In all the cases,
only one type of spirothiadiazolopyridazines 3–9 was obtained in good
yields (Scheme 1). No adduct resulting from a condensation on the double
bond C55N was detected under the identical conditions. The reaction was
exclusively periselective.
The structural assignments of the spirothiadiazolopyridazines 3–9 are
1
based on a full characterization by 300-MHz H NMR and 75-MHz 13C
NMR spectra. The formulae were confirmed by single crystal X-ray
analysis of compound 4.
The 13C NMR spectra of cycloadducts 3–9 showed in particular a signal
at 98.2–98.7 ppm because of the carbon C-3; this confirms the addition of the
dipole to the double bond C55S. Furthermore, the direction of the cyclo-
addition is unique (heteroatom of the dipole is linked to the carbon of the
C55S dipolarophile site). The reaction is thus regioselective.
Thus, we have elucidated these peri- and regioselctivity problems using
the X-ray crystallographic analysis, which reveals unambiguously that the

New Spirothiadiazolopyridazines
2215
Scheme 1.
condensation of the dipoles happened exclusively on the C55S dipolarophile
site of the pyridazin-3(2H)-thione 1(a, b) (Fig. 1).
In contrast to N-aryl-C-ethoxycarbonylnitrile imines, the action of 2,4,6-
trimethylbenzonitrile oxide 10[12] on the pyridazin-3(2H)-thione 1a led to a
mixture of two products: pyridazin-3(2H)-one 11 and 2,4,6-trimethylphenyl-
isothiocyanate 12 (Scheme 2). The monoadduct spiro type was not identified.
Figure 1. X-ray structure of cycloadduct 4.

2216
S. Abouricha et al.
Scheme 2.
The physical and spectral characteristics of compound 11 are the same as to
those described in the literature.[13] The structure of 12 was checked on the basis
of 1H and 13C NMR spectroscopies. To explain the production of compounds 11
and 12, we propose the following mechanism: the initial phase of the reaction
leads to a spiro-type cycloadduct resulting from the addition of a dipole on
the double bond thioxo C55S; the spirooxathiazole thus formed is not stable.
The heterocyclic ring is easily opened and the aryl group migrates toward the
nitrogen (similar to Beckmann rearrangement), which finally leads to the oxo
compound 11 by elimination of isothiocyanate 12.
In summary, we have prepared new spirothiadiazolopyridazines by 1,3-
dipolar cycloaddition of N-aryl-C-ethoxycarbonylnitrile imines to the corre-
sponding pyridazin-3(2H)-thiones. These cycloadditions were found to be
highly peri- and regioselective, giving the cycloadducts in good yields.
EXPERIMENTAL
General Instrumentation
Melting points were determined using a Bu¨chi-Tottoli apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 577 spectrometer
1
using KBr disks; only noteworthy IR absorptions are listed (cm21). H and
13C NMR spectra were recorded in CDCl3 and solution (unless otherwise
specified) with TMS as an internal reference using a Bruker AC 300-MHz
(1H) or 75-MHz (13C) instruments; chemical shifts are given in d ppm
downfield from TMS. Multiplicities of 13C NMR resources were assigned
by distortionless enhancement by polarization transfer (DEPT) experiments.

New Spirothiadiazolopyridazines
2217
Elemental-analysis data were taken on a Perkin-Elmer 240C elemental-
analytical instrument. Column chromatography was carried out on SiO2
(silica gel 60, Merck, 0.063–0.200 mm). TLC was carried out on SiO2
(silica gel 60, F 254 Merck, 0.063–0.200 mm) and the spots located with
UV light. All solvents were dried or purified by standard methods.[14]
Commercial reagents were used without further purification unless stated.
Compounds 1(a, b) were prepared by reaction of pyridazin-3(2H)-ones[13]
with P2S5 in refluxing pyridine.
6-Methyl-4,5-dihydropyridazine-3(2H)-thione 1a: Yield 80%, yellow
1
solid; mp 127–1298C; H NMR (CDCl3) d 2.10 (s, 3H, CH3), 2.36 (m, 2H,
CH2), 2.90 (m, 2H, CH2), 10.75 (s, 1H, NH); 13C NMR (CDCl3) d 23.8
(CH3), 24.3 (CH2), 33.5 (CH2), 158.7 (C-6), 193.4 (C55S). Anal. calcd. for
C5H8N2S: C, 46.85; H, 6.29; N, 21.85. Found: C, 46.90; H, 6.25; N, 21.89.
6-Phenyl-4,5-dihydropyridazine-3(2H)-thione 1b: Yield 60%, yellow
solid; mp 156–1588C; 1H NMR (CDCl3) d 2.85 (m, 2H, CH2), 3.06 (m, 2H,
CH2), 7.51 (m, 3H), 7.78 (m, 2H), 10.72 (s, 1H, NH); 13C NMR (CDCl3) d
20.9 (CH2), 33.8 (CH2), 126.1 (2CH), 128.8 (2CH), 130.7 (CH), 142.0 (C),
155.5 (C-6), 194.0 (C55S). Anal. calcd. for C10H10N2S: C, 63.13; H, 5.30;
N, 14.72. Found: C, 63.19; H, 5.26; N, 14.68.
Preparation of Spiro[10-H-4,2,1-Thiadiazolo-(3,50)-4,5-dihydro-2H-
pyridazine] 3–9, General Procedure
Triethylamine (2 mL, 9 mmol) dissolved in THF (5 mL) was added dropwise
to a solution of pyridazin-3(2H)-thione 1(a, b) (5 mmol) and ethylhydrazono-
a-bromoglyoxylate 2(a–d) (5 mmol) in THF (50 mL). The mixture was
stirred 18 h at room temperature. After evaporation of the solvent, the
residue was purified by column chromatography on silica gel using hexane
and ethyl acetate as eluents.
30-Ethoxycarbonyl-6-methyl-10-(p-chlorophenyl)spiro[10H-4,2,1-thiadiazolo-
(3,50)-4,5-dihydro-2H-pyridazine] 3: Yield 65%, orange solid; mp 84–868C.
1
IR: 1720 (CO), 3020 (NH); H NMR (CDCl3): d 1.36 (t, J ¼ 7.2 Hz, 3H,
CH3), 1.94 (s, 3H, CH3), 2.24 (m, 2H, CH2), 2.47 (m, 2H, CH2), 4.36
(t, J ¼ 7.2 Hz, 2H, CH2O), 6.15 (s, 1H, NH), 7.25 (d, J ¼ 7.8 Hz, 2H), 7.48
(d, J ¼ 7.8 Hz, 2H); 13C NMR (CDCl3): d 14.5 (CH3), 23.2 (CH3), 27.6
(CH2), 30.7 (CH2), 62.7 (CH2O), 98.6 (C-3), 122.9 (2CH), 129.2 (2CH), 130.7
(C), 134.4 (C), 139.8 (C-30), 148.5 (C-6), 160.5 (CO). Anal. calcd. for
C15H17ClN4O2S: C, 51.06; H, 4.86; N, 15.88. Found: C, 51.12; H, 4.82; N, 15.92.
30-Ethoxycarbonyl-6-methyl-10-(p-nitrophenyl)spiro[10H-4,2,1-thiadiazolo-
(3,50)-4,5-dihydro-2H-pyridazine] 4: Yield 60%, orange solid; mp

2218
S. Abouricha et al.
143–1458C. IR: 1730 (CO), 3080 (NH); 1H NMR (CDCl3): d 1.36
(t, J ¼ 7.2 Hz, 3H, CH3), 1.95 (s, 3H, CH3), 2.28 (m, 2H, CH2), 2.52
(m, 2H, CH2), 4.36 (t, J ¼ 7.2 Hz, 2H, CH2O), 6.32 (s, 1H, NH), 7.67
(d, J ¼ 9.3 Hz, 2H), 8.06 (d, J ¼ 9.3 Hz, 2H); 13C NMR (CDCl3): d 14.3
(CH3), 23.0 (CH3), 27.1 (CH2), 30.1 (CH2), 62.8 (CH2O), 98.4 (C-3), 118.7
(2CH), 124.9 (2CH), 137.1 (C), 143.2 (C-30), 146.8 (C), 148.7 (C-6), 159.8
(CO). Anal. calcd. for C15H17N5O4S: C, 49.58; H, 4.72; N, 19.27. Found:
C, 49.54; H, 4.70; N, 19.24.
30-Ethoxycarbonyl-6-methyl-10-(p-methylphenyl)spiro[10H-4,2,1-thiadi-
azolo-(3,50)-4,5-dihydro-2H-pyridazine] 5: Yield 75%, white solid; mp
101–1038C. IR: 1720 (CO), 3040 (NH); 1H NMR (CDCl3): d 1.37
(t, J ¼ 7.2 Hz, 3H, CH3), 1.92 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.35 (m, 2H,
CH2), 2.43 (m, 2H, CH2), 4.36 (t, J ¼ 7.2 Hz, 2H, CH2O), 6.09 (s, 1H, NH),
7.10 (d, J ¼ 8.1 Hz, 2H), 7.41 (d, J ¼ 8.1 Hz, 2H); 13C NMR (CDCl3): d
14.5 (CH3), 21.1 (CH3), 23.2 (CH3), 27.8 (CH2), 31.0 (CH2), 62.4 (CH2O),
98.7 (C-3), 122.7 (2CH), 129.6 (2CH), 133.2 (C), 135.6 (C), 138.6 (C-30),
148.2 (C-6), 160.7 (CO). Anal. calcd. for C16H20N4O2S: C, 57.81; H, 6.06;
N, 16.85. Found: C, 57.78; H, 6.05; N, 16.82.
30-Ethoxycarbonyl-6-methyl-10-(p-methoxyphenyl)spiro[10H-4,2,1-thiadi-
azolo-(3,50)-4,5-dihydro-2H-pyridazine] 6: Yield 70%, yellow solid; mp
79–818C. IR: 1710 (CO), 3000 (NH); 1H NMR (CDCl3): d 1.36
(t, J ¼ 7.2 Hz, 3H, CH3), 1.91 (s, 3H, CH3), 2.41 (m, 2H, CH2), 2.43
(m, 2H, CH2), 3.79 (s, 3H, OCH3), 4.36 (t, J ¼ 7.2 Hz, 2H, CH2O), 6.07
(s, 1H, NH), 6.83 (d, J ¼ 9.0 Hz, 2H), 7.41 (d, J ¼ 9.0 Hz, 2H); 13C NMR
(CDCl3): d 14.6 (CH3), 23.2 (CH3), 27.8 (CH2), 31.2 (CH2), 55.8 (OCH3),
62.4 (CH2O), 98.7 (C-3), 114.3 (2CH), 125.3 (2CH), 132.9 (C), 134.0
(C-30), 148.2 (C-6), 158.2 (C), 160.8 (CO). Anal. calcd. for C16H20N4O3S:
C, 55.16; H, 5.79; N, 16.08. Found: C, 55.14; H, 5.81; N, 16.11.
30-Ethoxycarbonyl-6-phenyl-10-(p-chlorophenyl)spiro[10H-4,2,1-thiadiazolo-
(3,50)-4,5-dihydro-2H-pyridazine] 7: Yield 80%, yellow solid; mp 167–
1
1698C. IR: 1715 (CO), 3120 (NH); H NMR (CDCl3): d 1.37 (t, J ¼ 7.2 Hz,
3H, CH3), 2.58 (m, 2H, CH2), 2.94 (m, 2H, CH2), 4.36 (t, J ¼ 7.2 Hz, 2H,
CH2O), 6.83 (s, 1H, NH), 7.24 (d, J ¼ 8.1 Hz, 2H), 7.37 (m, 3H), 7.51
(d, J ¼ 8.1 Hz, 2H), 7.71 (m, 2H); 13C NMR (CDCl3): d 14.5 (CH3), 23.9
(CH2), 30.5 (CH2), 62.6 (CH2O), 98.2 (C-3), 122.8 (2CH), 125.1 (2CH),
128.6 (2CH), 129.2 (2CH), 129.4 (CH), 130.6 (C), 134.3 (C), 136.8 (C),
139.6 (C-30), 145.2 (C-6), 160.3 (CO). Anal. calcd. for C20H19ClN4O2S: C,
57.90; H, 4.62; N, 13.50. Found: C, 57.88; H, 4.62; N, 13.51.
30-Ethoxycarbonyl-6-phenyl-10-(p-methylphenyl)spiro[10H-4,2,1-thiadiazolo-
(3,50)-4,5-dihydro-2H-pyridazine] 8: Yield 76%, yellow solid; mp 141–1438C.
IR: 1710 (CO), 3110 (NH); 1H NMR (CDCl3): d 1.38 (t, J ¼ 7.2 Hz, 3H, CH3),

New Spirothiadiazolopyridazines
2219
2.35 (s, 3H, CH3), 2.52 (m, 2H, CH2), 2.92 (m, 2H, CH2), 4.37 (t, J ¼ 7.2 Hz,
2H, CH2O), 6.67 (s, 1H, NH), 7.13 (d, J ¼ 8.4 Hz, 2H), 7.38 (m, 3H), 7.45
(d, J ¼ 8.4 Hz, 2H), 7.70 (m, 2H); 13C NMR (CDCl3): d 14.5 (CH3), 21.1
(CH3), 24.1 (CH2), 30.9 (CH2), 62.4 (CH2O), 98.4 (C-3), 122.7 (2CH), 125.1
(2CH), 128.6 (2CH), 129.1 (CH), 129.7 (2CH), 133.1 (C), 135.7 (C), 137.1
(C), 138.5 (C-30), 145.0 (C-6), 160.6 (CO). Anal. calcd. for C21H22N4O2S: C,
63.94; H, 5.62; N, 14.20. Found: C, 63.90; H, 5.64; N, 14.17.
30-Ethoxycarbonyl-6-phenyl-10-(p-methoxyphenyl)spiro[10H-4,2,1-thiadi-
azolo-(3,50)-4,5-dihydro-2H-pyridazine] 9: Yield 75%, red solid; mp 105–
1
1078C. IR: 1725 (CO), 3100 (NH); H NMR (CDCl3): d 1.37 (t, J ¼ 7.2 Hz,
3H, CH3), 2.47 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.80 (s, 3H, OCH3), 4.36
(t, J ¼ 7.2 Hz, 2H, CH2O), 6.62 (s, 1H, NH), 6.86 (d, J ¼ 8.4 Hz, 2H), 7.36
(m, 3H), 7.46 (d, J ¼ 8.4 Hz, 2H), 7.68 (m, 2H); 13C NMR (CDCl3): d 14.5
(CH3), 24.2 (CH2), 31.2 (CH2), 55.8 (OCH3), 62.4 (CH2O), 98.3 (C-3), 114.4
(2CH), 125.1 (2CH), 125.3 (2CH), 128.6 (2CH), 129.1 (CH), 132.8 (C),
133.9 (C), 137.1 (C-30), 145.1 (C-6), 158.3 (C), 160.7 (CO). Anal. calcd. for
C21H22N4O3S: C, 61.45; H, 5.40; N, 13.65. Found: C, 61.40; H, 5.41; N, 13.64.
Reaction of 2,4,6-Trimethylbenzonitrile Oxide 10 with Pyridazin-
3(2H)-Thione 1a
A solution of pyridazin-3(2H)-thione 1a (0.5 g, 4 mmol) and 2,4,6-trimethyl-
benzonitrile oxide 10 (0.65 g, 4 mmol) in THF was stirred at room temperature
for 20 h. The reaction mixture was concentrated in vacuo and the residue was
purified by column chromatography on silica gel using hexane and ethyl
acetate as eluents.
6-Methyl-4,5-dihydropyridazin-3(2H)-one 11: Yield 65%, white solid, mp
1
75–778C; H NMR (CDCl3) d 2.05 (m, 2H, CH2), 2.12 (s, 3H, CH3), 2.48
(m, 2H, CH2), 8.71 (s, 1H, NH); 13C NMR (CDCl3) d 22.9 (CH3), 25.9
(CH2), 26.1 (CH2), 152.9 (C-6), 167.2 (CO). Anal. calcd. for C5H8N2O: C,
53.56; H, 7.19; N, 24.98. Found: C, 53.48; H, 7.22; N, 24.94.
2,4,6-Trimethylphenyl isothiocyanate 12: Yield 54%, yellow solid; mp
1
62–638C; H NMR (CDCl3) d 2.25 (s, 6H, CH3), 2.36 (s, 3H, CH3), 7.20
(s, 2H, H-Ph); 13C NMR (CDCl3) d 18.8 (2CH3), 21.3 (CH3), 129.0 (2CH),
135.1 (2C), 137.3 (C). Anal. calcd. for C10H11NS: C, 67.77; H, 6.21; N,
7.91. Found: C, 67.78; H, 6.19; N, 7.89.
Crystal Structure Determination
Crystal data for 4: C15H17N5O4S; monoclinic; space group C2/c;
˚
a ¼ 21.053(4), a ¼ 90.00; b ¼ 7.891(2), b ¼ 113.16(3); c ¼ 21.788(4) A,

2220
S. Abouricha et al.
˚
Table 1. Selected geometrical parameters (A, 8) of
the cycloadduct 4
Bond lengths
Angles
S1 C13
1.736(4)
1.873(4)
1.402(5)
1.369(4)
1.406(5)
1.193(5)
1.467(5)
1.291(5)
C13 S1 C15
89.9(2)
117.5(4)
123.5(4)
123.4(4)
118.3(4)
120.0(4)
109.0(4)
108.6(3)
S1 C15
N3 N10
N5 N9
N9 N5 C16
C16 N5 C15
O6 N8 O4
N5 C16
O7 C23
N8 C14
N9 C13
O6 N8 C14
N9 C13 C23
N3 C15 N5
C17 C15 S1
3
g ¼ 90.008, V ¼ 3327.9(12) A , Z ¼ 8; Dc ¼ 1.451 g cm23, T ¼ 293 K,
˚
l(MoKa) ¼ 0.71073 A, m ¼ 0.227 mm21, F(000) ¼ 1520; 4835 reflections
˚
measured; 1046 reflections observed [I ꢀ 2s(I)]; final R ¼ 0.3847 for 1046
reflections observed [I ꢀ 2s(I)]. All measurements of the crystals with
dimensions of 0.075 ꢁ 0.125 ꢁ 0.225 mm were performed on a CAD-4
Enraf-Nonius diffractometer equipped with a graphite monochromator for
umax ¼ 308 [h: 229 : 29, k: 0 : 11, l: 230 : 30]. The structure was refined
using the SHELXL program.[15] The refinement was based on F2. All the non-
hydrogen atoms were anisotropically refined. Hydrogen atoms were located in
an electron-difference map and refined using a riding model. Refinement was
finished at R1 ¼ 03847, wR2 ¼ 0.0582.
Supplementary data on this structure have been deposited [CCDC
255529], which can be obtained free of charge using the link www.ccdc.
cam.ac.uk or from the CCDC, 12 Union Road Cambridge CB2 1EZ, UK;
fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk]. Selected geometri-
cal parameters, bond lengths and angles are listed in Table 1 according to the
numbering scheme adopted in Figure 1.
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