A facile and convenient synthesis of 1,2,3,6-tetrahydropyridazines using azodicarboxylates under lanthanum triflate catalysis

Article abstract of DOI:10.3987/COM-01-9272

The hetero-Diels-Alder reaction catalyzed by lanthanum triflate hydrate using diethyl azodicarboxylate as dienophile, yielding differently substituted 1,2,3,6-tetrahydropyridazines, is described.

Full text of DOI:10.3987/COM-01-9272

HETEROCYCLES, Vol. 55, No. 8, pp. 1599 - 1604, Received, 18th June, 2001
A
FACILE
AND
CONVENIENT
SYNTHESIS
OF
1,2,3,6-
TETRAHYDROPYRIDAZINES USING AZODICARBOXYLATES UNDER
LANTHANUM TRIFLATE CATALYSIS
Massimo Curini,* Francesco Epifano, Maria Carla Marcotullio, and Ornelio
Rosati
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica
Organica, Facoltà di Farmacia, Università degli Studi, Via del Liceo, 06123
Perugia, Italy; E-mail: cecchere@unipg.it
Abstract - The hetero-Diels-Alder reaction catalyzed by lanthanum triflate hydrate
using diethyl azodicarboxylate as dienophile, yielding differently substituted
1,2,3,6-tetrahydropyridazines, is described.
The Diels-Alders reaction is one of the most useful method in synthetic organic chemistry. The use of azo
compounds in this process has been known for over seventy years and different types of cyclic and
acyclic azodienophiles have been widely employed.1 In particular, azodicarboxylates are very reactive
and have been used in combination with many kinds of dienes to synthetize pyridazine heterocycles. The
reaction of diethyl azodicarboxylate (DEAD) with cyclopentadiene, described by Diels and coworkers in
1925, is of historical importance as it is one of the first examples of a [4+2] cycloaddition process.2
Generally the hetero-Diels-Alder reactions between dienes and azodicarboxylate dienophiles are
thermally or photochemically promoted;1-3 during the last decades it has also been reported that
microwave irradiation accelerates reaction rates and yields.4
In the last fifteen years lanthanide triflates have been found as unique Lewis acids, able to effectively
promote several carbon-carbon and carbon-heteroatom bond formation reactions in aqueous media.5
Sc(OTf)3 has been employed in the Diels-Alder reaction,6 while other Ln(OTf)3 has been successfully
employed for aza-Diels-Alder reactions, using different dienes and imines, generated in situ from
aldehydes and benzylamine hydrochloride or phenylalanine methyl ester, as dienophiles.7 More recently
lanthanide complexes other than triflates, including chiral ones, have been also employed for the same
purpose.8

As a part of our ongoing efforts to investigate the use of Ln(OTf)3 as catalysts in solvent-free conditions,
we recently reported the high yielding synthesis of 1,5-benzodiazepine derivatives catalyzed by
Yb(OTf)3.9 Herein we wish to report the application of La(OTf)3 hydrate catalysis to the hetero-Diels-
Alder reaction using DEAD as dienophile to synthetize differently substituted 1,2,3,6-
tetrahydropyridazines, whose structure is incorporated in a lot of natural and biologically active
compounds (Scheme 1).10
CO2Et
CO2Et
CO2Et
N
N
N
N
La(OTf)3
rt
+
R
Et2OC
R
Scheme 1
The reaction was carried out in solvent-free conditions for 30 min using diene (1.0 mmol) and DEAD (1.0
mmol) in the presence of La(OTf)3 hydrate (0.02 mmol) at room temperature. The results are summarized
in the Table 1. The importance of adding the catalyst becomes evident when considering that, carrying
out
a trial experiment mixing DEAD and 2,3-dimethyl-1,3-butadiene alone under the same
conditions, after 30 min the Diels-Alder adduct was obtained in less than 15 %
reaction
yield.
It’s noteworthy that we obtained nearly quantitative yields in all cases and in particular in using alkoxy-
and acetoxybutadienes: the corresponding Diels-Alder adducts (6) and (7) are in fact important
intermediates for the synthesis of cyclitols, carbohydrates and related natural products.11 Another synthon
of
natural
and
natural-derived
biologically
active
compounds is
the
1,2,3,6-
tetrahydropyridazincarboxylate (8); compounds of such a structure have been employed as precursors of
2,3,4,5-tetrahydropyridazine-3-carboxylic acids, constituents of antrimycins, aurantimycins, luzopeptins,
quinoxapeptins and their semi-synthetic analogues, peptides and despeptides with antibiotic, antiviral and
antitumour activities.10a
Using 1,3-cyclohexadiene as diene we obtained an equimolar mixture of the Diels-Alder adduct (5a) and
(5b), derived from an ene reaction. This kind of reactivity of cyclohexadienes towards azodicarboxylates
is however well documented in the literature.3a,12
Best results were obtained using just 0.02 equivalents of La(OTf)3 hydrate: upper loading had no
significant improvements. The catalyst, recovered by filtration from the reaction media could be reused
several times without any loss of activity; the reaction to yield compound (1) has been repeated three

more times, through the catalyst washed with CH2Cl2 and dried at 70 °C for 2 h, with the following
yields: 98%, 99%, 97%.
Table 1. La(OTf)3 hydrate catalyzed hetero-Diels-Alder reaction
Diene
Product
Yield %a
99
CO2Et
N
N
CO2Et
1
CO2Et
CO2Et
N
N
99
99
2
CO2Et
CO2Et
N
N
3
CO2Et
CO2Et
N
N
98
99
4
Et2OC
NHCO2Et
CO2Et
CO2Et
N
N
N
+
5a
5b
1:1
MeO
MeO
MeO
CO2Et
CO2Et
N
N
98
98
MeO
6
OAc
OAc
CO2Et
CO2Et
N
N
7
CO2Et
CO2Et
OEt
CO2Et
N
N
89
CO2Et
OEt
8
aYields of pure isolated products, characterized by IR, GC-MS, 1H NMR and 13C NMR.

In summary an easy work-up procedure, mild conditions, short reaction times, the low loading and the complete
recyclability of the catalyst and nearly quantitative yields make our methodology a valid and alternative
contribution to the existing processes in the field of azo dienophiles based hetero-Diels-Alder reactions.
ACKNOWLEDGEMENT
Financial support from MURST, Italy and Università degli Studi di Perugia is gratefully acknowledged.
EXPERIMENTAL
General procedure: A mixture of diene (1.0 mmol) and diethyl azodicarboxylate (1.1 mmol) was well
stirred with La(OTf)3 hydrate (0.02 mmol) at rt for 30 min; CH2Cl2 was added to get La(OTf)3
crystallized; the catalyst was filtered under reduced pressure and the residue purified by silica gel column
chromatography using CH2Cl2 as eluent, yielding pure tetrahydropyridazine.
1
Diethyl 4-methyl-1,2,3,6-tetrahydro-1,2-pyridazincarboxylate (1): colorless oil; IR (cm-1) 1710; H
NMR (200 MHz, CDCl3) δ 1.29 (t, 6H, J = 7.1 Hz), 1.73 (s, 3H), 3.59-3.88 (m, 2H), 4.11-4.25 (m, 2H),
4.32 (q, 4H, J = 7.1 Hz), 5.44-5.56 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 155.8, 155.7, 130.94, 117.61,
62.6, 62.4, 47.3, 47.0, 19.9, 14.5, 14.4; GC/MS: M+ = 242. Anal. Calcd. for C11H18N2O4: C, 54.53; H,
7.49; N, 11.56. Found: C, 54.56; H, 7.48; N, 11.58.
1
Diethyl 4,5-dimethyl-1,2,3,6,-tetrahydro-1,2-pyridazincarboxylate (2): colourless oil; IR; H NMR;13
13C NMR.14 Anal. Calcd. for C12H20N2O4: C, 56.24; H, 7.87; N, 10.93. Found: C, 56.25; H, 7.85; N,
10.91.
1
Diethyl 3-methyl-1,2,3,6-tetrahydro-1,2-pyridazincarboxylate (3): colorless oil; IR (cm-1) 1709; H
NMR (200 MHz, CDCl3) δ 1.17-1.35 (m, 9H), 3.66-3.79 (m, 2H), 4.07-4.25 (m, 4H), 4.35-4.41 (m, 1H),
13
5.61-5.83 (m, 2H); C NMR (50 MHz, CDCl3) δ 156.8, 155.7, 129.12, 122.32, 62.0, 61,8, 50.1, 42.3,
18.2, 14.5, 14.4; GC/MS: M+ = 242. Anal. Calcd. for C11H18N2O4: C, 54.53; H, 7.49; N, 11.56. Found: C,
54.54; H, 7.46; N, 11.59.
Diethyl cis-3,6-dimethyl-1,2,3,6-tetrahydro-1,2-pyridazincarboxylate (4): colourless oil; IR (cm-1)
1
1710; H NMR (200 MHz, CDCl3) δ 1.19-1.38 (t, 6H, J = 7.0 Hz), 1.51-1.65 (d, 6H, J = 6.7 Hz), 4.03-
13
4.28 (q, 4H, J = 7.0 Hz), 4.69-4.82 (m, 2H), 5-43-5.56 (m, 1H), 5.75-5.89 (m, 1H); C NMR;14 M+ =
256. Anal. Calcd. for C12H20N2O4: C, 56.24; H, 7.87; N, 10.93. Found: C, 56.27; H, 7.84; N, 10.90.
1
Diethyl 2,3-diazabicyclo[2.2.2]oct-5-ene-2,3-dicarboxylate (5a): colorless oil; IR; H NMR;12 13C
NMR.15 Anal. Calcd. for C12H20N2O6: C, 49.99; H, 6.99; N, 9.72. Found: C, 49.96; H, 7.01; N, 9.72.

1
Diethyl N-2,5-cyclohexadienylhydrazino-N,N-dicarboxylate (5b): white solid, mp 52-53 °C; IR; H
NMR;12 13C NMR (50 MHz, CDCl3) δ 156.9, 156.8, 132.2, 131.9, 129.0, 128.8, 62.2, 62.0, 50.1, 20.4,
14.4, 14.3; GC/MS: M+ = 256. Anal. Calcd. for C12H18N2O4: C, 56.68; H, 7.13; N, 11.02. Found: C,
56.69; H, 7.12; N, 11.01.
Diethyl 4,5-dimethoxy-1,2,3,6-tetrahydro-1,2-pyridazincarboxylate (6): colorless oil; IR (cm-1) 1711;
1H NMR (200 MHz, CDCl3) δ 1.23-1.36 (t, 6H, J = 7.0 Hz), 3.71 (s, 6H), 4.15-4.32 (q, 4H, J = 7.0 Hz),
4.33-4.51 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 154.1, 134.3, 62.8, 58.6, 47.9, 14.5; GC/MS: M+ = 288.
Anal. Calcd. for C12H20N2O6: C, 49.99; H, 6.99; N, 9.72. Found: C, 49.96; H, 7.01; N, 9.72.
Diethyl 3-methylcarbonyloxy-1,2,3,6-tetrahydro-1,2-pyridazincarboxylate (7): colorless oil; IR (cm-
1) 1740, 1710; 1H NMR (200 MHz, CDCl3) δ 1.18-1.26 (t, 6H, J = 7.0 Hz), 2.12 (s, 3H), 4.15-4.25 (q, 4H,
13
J = 7.0 Hz), 4.35-4.48 (m, 2H), 5.60-5.74 (m, 1H), 5.76-5.83 (m, 1H), 6.18-6.27 (m, 1H); C NMR (50
MHz, CDCl3) δ 168.3, 155.1, 155.0, 134.5, 125.7, 69.3, 62.4, 62.2, 20.7, 14.4, 14.3; GC/MS: M+ = 286.
Anal. Calcd. for C12H18N2O6: C, 50.35; H, 6.34; N, 9.79. Found: C, 50.33; H, 6.32; N, 9.82.
Triethyl cis-6-ethoxy-5-methyl-1,2,3,6-tetrahydro-1,2,3-pyridazinetricarboxylate (8): colorless oil;
IR (cm-1) 1745, 1716; 1H NMR (200 MHz, CDCl3) δ 1.23-1.35 (m, 9H), 1.66 (t, 3H, J = 7.0 Hz), 1.76 (s,
13
3H), 3.43-3.62 (m, 2H), 4.05-4.25 (m, 8H), 5.52-5.64 (m, 1H); C NMR (50 MHz, CDCl3) δ 168.6,
154.6, 154.4, 135.7, 120.6, 79.5, 67.2, 62.6, 61.4, 60.6, 20.6, 15.3, 14.5, 14.3, 14.2; GC/MS: M+ = 358.
Anal. Calcd. for C16H26N2O7: C, 53.62; H, 7.31; N, 7.82. Found: C, 53.60; H, 7.31; N, 7.84.
REFERENCES AND NOTES
1.
S. M. Weinreb and R. R. Staib, Tetrahedron, 1982, 38, 3087; b) T. Kametani and S. Hibino,
Adv. Heterocycl. Chem., 1987, 42, 245.
2.
3.
O. Diels, J. H. Blom, and W. Koll, Ann. Chem., 1925, 443, 242.
For selected examples of hetero-Diels-Alder reactions using azodicarboxylates see: a) A. Shah and
M. V. George, Tetrahedron, 1971, 27, 1291; b) G. Kresze, M. Morper, and A. Bijev, Tetrahedron
Lett., 1977, 2259; c) H. Hiranuma and S. I. Miller, J. Org. Chem., 1983, 48, 3096; d) A.Toepfer
and R. R. Schmidt, Carbohydr. Res., 1993, 247, 159; e) S. Moriyama, T. Mochizuki, Y. Ohshima,
and T. Saito, Bull. Chem. Soc. Jpn., 1994, 67, 2876.
4.
5.
M. Avalos, R. Babiano, P. Cintas, F. R. Clemente, J. L. Jimenez, J. C. Palacios, and J. B. Sanchez,
J. Org. Chem., 1999, 64, 6297 and references cited herein.
C. Qian and L. Wang, Tetrahedron, 2000, 56, 7193.

6.
7.
8.
9.
S. Kobayashi, I. Hachiya, M. Araki, and H. Ishitani, Tetrahedron Lett., 1993, 34, 3755.
L. B. Yu, D. P. Chen, and P. G.Wang, Tetrahedron Lett., 1996, 37, 2169.
C. Qian and L. Wang, Tetrahedron Lett., 2000, 41, 2203.
M. Curini, F.Epifano, M. C. Marcotullio, and O. Rosati, Tetrahedron Lett., 2001, 42, 3159.
10 I. H. Aspinall, P. M. Cowley, G. Mitchell, C. M. Raynor, and R. J. Stoodley, J. Chem. Soc.,
Perkin Trans. 1, 1999, 2591 and references cited herein; b) L. Zhang, M. A. Williams, D. B.
Mendel, P. A. Escarpe, X. Chen, K. Y. Wang, B. J. Graves, G. Lawton, and C. U. Kim, Bioorg.
Med. Chem. Lett., 1999, 9, 1751.
11.
A. K Forrest and R. R. Schmidt, Tetrahedron Lett., 1984, 25, 1769.
12 G. Jenner and R. Ben Salem, J. Chem. Soc., Perkin Trans. 2, 1990, 1961 and references cited
herein.
13.
14.
G. De Simoni, G. Faita, P. P. Righetti, and L. Toma, Tetrahedron, 1990, 46, 7951.
T. H. Fisher, J. C. Crook, and S. Chang, Tetrahedron, 1987, 43, 2443.
15. Y. Nomura, N. Masai, and Y. Takeuchi, J. Chem. Soc., Chem. Comm., 1975, 307.