[4+2] Cycloadditions of 3-tetrazolyl-1,2-diaza-1,3-butadienes: Synthesis of 3-tetrazolyl-1,4,5,6-tetrahydropyridazines

Article abstract of DOI:10.1002/ejoc.201101826

The synthesis of new 3-tetrazolyl-1,4,5,6-tetrahydropyridazines by Diels-Alder reactions of ethyl 3-(tetrazol-5-yl)-1,2-diaza-1,3-butadiene-1- carboxylates is reported. These 1,2-diaza-1,3-dienes reacted with electron-rich heterocycles, nucleophilic olefi

Full text of DOI:10.1002/ejoc.201101826

FULL PAPER
DOI: 10.1002/ejoc.201101826
[4+2] Cycloadditions of 3-Tetrazolyl-1,2-diaza-1,3-butadienes: Synthesis of
3-Tetrazolyl-1,4,5,6-tetrahydropyridazines
Susana M. M. Lopes,[a] Amadeu F. Brigas,[b] Francisco Palacios,[c] Américo Lemos,*[b] and
Teresa M. V. D. Pinho e Melo*[a]
Keywords: Tetrazoles / 1,2-Diaza-1,3-butadienes / Nitrogen heterocycles / Aza-Diels–Alder reactions / Density functional
calculations
The synthesis of new 3-tetrazolyl-1,4,5,6-tetrahydropyrid- cleophilic olefins and cumulenes, as well as with electron-
azines by Diels–Alder reactions of ethyl 3-(tetrazol-5-yl)-1,2-
diaza-1,3-butadiene-1-carboxylates is reported. These 1,2-
diaza-1,3-dienes reacted with electron-rich heterocycles, nu-
deficient dienophiles, to give the target compounds regiose-
lectively. Computational studies corroborated the rationaliza-
tion of the observed reactivity and selectivity.
diaza-1,3-diene, independently reported and using diverse
reaction conditions, was intercepted by both electron-rich[7j]
and -deficient[9] alkenes.
By using this synthetic strategy, functional groups such
as carboxyl, phosphonyl and/or phosphanyl, which are
found in molecules related to the regulation of important
biological functions, have been incorporated into 1,4,5,6-
tetrahydropyridazines.[10]
It is well established that 5-substituted 1H-tetrazoles are
effective bioisosteres of the carboxylic functionality because
they are more lipophilic and exhibit stronger metabolic sta-
bility, which can lead to enhance biological activity.[11]
Thus, the tetrazole ring has been successfully incorporated
into pharmacological drug formulations, namely, cardiovas-
cular or hypertension drugs.[12]
In this context, the availability of a synthetic route to
1,4,5,6-tetrahydropyridazines carrying a tetrazole moiety
could be of particular interest from the chemical and bio-
logical point of view.
Recently, we disclosed the first examples of Diels–Alder
reactions of 5-(1-nitrosovinyl)-1-substituted 1H-tetrazoles
2, generated in situ from the corresponding bromooximes
1, with electron-rich alkenes and heterocycles, allowing the
isolation of new tetrahydro-3-tetrazolyl-1,2-oxazines and
open-chain oximes. The subsequent reduction of two of
these adducts gave access to tryptophan analogues 5-(1-
aminoalkyl)-1-phenyl-, 5-(1-acetylamino)-1-benzyl- and 5-
(1-acetylamino)-1H-tetrazoles 4a–c (Scheme 1).[13]
Herein, as a continuation of our work on the hetero-
Diels–Alder reactions of heterodienes carrying a tetrazole
substituent, we report a study on the reactivity of 3-tetraz-
olyl-1,2-diaza-1,3-butadienes 5 towards dienophiles with
the aim of establishing a route to 3-tetrazolyl-1,4,5,6-tetra-
hydropyridazines 6 (Scheme 2).
Introduction
The structure of 1,4,5,6-tetrahydropyridazine is com-
monly encountered in a wide variety of biologically active
compounds. These have been reported to act at diverse mo-
lecular targets such as PDE-IV (PDE = phosphodiesterase)
inhibitors in asthma, allergies, anti-inflammatory dis-
eases,[1] non-steroidal progesterone receptor modulators, in
mammalian reproductive cycle regulation,[2] osteoporosis,[3]
cannabinoid CB1 receptor antagonists in obesity treat-
ments,[4] influenza neuraminidase inhibitors,[5] allosteric
modulators and agonists for the γ-aminobutyric acid
(GABAA) receptor in the central nervous system.[6]
Tetrahydropyridazines have been conveniently obtained
by hetero-Diels–Alder reactions of conjugated azoalkenes,
which are also named 1,2-diaza-1,3-butadienes. The great
majority of these involve inverse-electron-demand reactions
of electrophilic azoalkenes and electron-rich double bonds
or heterocycles.[7] However, reactions between 1,2-diaza-
1,3-dienes bearing substituents with neutral or electron-re-
leasing properties and electron-deficient dienophiles have
also been described, although to a minor extent.[8] A single
case has been found in the literature in which the same 1,2-
[a] Department of Chemistry, University of Coimbra,
3004-535 Coimbra, Portugal
E-mail: tmelo@ci.uc.pt
[b] CIQA, Department of Chemistry and Pharmacy, University of
Algarve,
Campus de Gambelas, 8005-139 Faro, Portugal
Fax: +351-289-819403
E-mail: alemos@ualg.pt
[c] Department of Organic Chemistry I, Faculty of Pharmacy,
University of the Basque Country,
Paseo de la Universidad n 7, 01006 Vitoria, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101826.
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[4+2] Cycloadditions of 3-Tetrazolyl-1,2-diaza-1,3-butadienes
was quantitatively converted into the corresponding hydraz-
one 9 and subsequent bromination gave hydrazone 10 as a
crystalline solid in 78% overall yield (Scheme 3).
In the next stage, the transient 1,2-diaza-1,3-diene 11 was
slowly generated from hydrazone 10 by the action of so-
dium carbonate in dichloromethane at room temperature in
the presence of a range of dienophiles to evaluate the scope
and limitations of its cycloaddition reactions.
Table 1. Cycloaddition reactions of 3-tetrazolyl-1,2-diaza-1,3-buta-
diene 11 with electron-rich dienophiles.
Scheme 1. Tryptophan analogues 4a–c from nitrosovinyltetrazoles
(Bn = benzyl).
Scheme 2. Proposed general route to 3-tetrazolyl-1,4,5,6-tetra-
hydropyridazines.
Results and Discussion
The most common and general method for the synthesis
or the in situ generation of conjugated 1,2-diaza-1,3-dienes
is the base-induced 1,4-dehydrohalogenation of α-halo-
hydrazones.[14] Therefore, α-bromohydrazone 10 was se-
lected as the 1,2-diaza-1,3-diene precursor and its synthesis
wascarriedout.Initiallyattemptsweremadetopreparehydraz-
one 10 by treating 5-bromoacetyl-1-phenyl-1H-tetrazole (8)
with ethyl hydrazinecarboxylate. To our surprise, and in
contrast to the rapid and easy formation of related hydraz-
ones by this approach,[15] the target compound could not
be isolated. However, 5-acetyl-1-phenyl-1H-tetrazole (7)
Scheme 3. Synthesis of hydrazones (NBS = N-bromosuccinimide).
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FULL PAPER
Initially, the reactivity of 3-tetrazolyl-1,2-diaza-1,3-buta-
Hetero-Diels–Alder reaction of 1,2-diaza-1,3-diene 11
diene (11) with electron-rich double bonds and heterocycles with 2,5-dimethylpyrrole and pyrrole led to the formation
was studied (Table 1). Reactions with ethyl vinyl ether and of bicyclic pyridazine 18 (39%) and open-chain hydrazone
dihydrofuran afforded cycloadducts 12 and 13, respectively, 19 (50%) as the end products (Table 1, entries 6 and 7). The
in very good yields and complete regioselectivity (Table 1, formation of these products can be rationalized by con-
entries 1 and 2). The observed selectivity was the one ex- sidering the re-aromatisation of the primarily formed cy-
pected for a [4+2] cycloaddition with inverse electron de- cloadduct 20 in the case of pyrrole and isomerisation of 20
mand. In the case of 3,4-dihydro-2H-pyran, the target tetra- to the thermodynamically more stable imine 18, in the case
hydropyridazine 14 was isolated in 72% alongside with the of 2,5-dimethylpyrrole because re-aromatisation is blocked
hydrazone 15 obtained in 15% yield (Table 1, entry 3). Al- (Scheme 4).
though a competitive 1,4-conjugate addition cannot be
The reaction of 1,2-diaza-1,3-diene 11 with indole was
ruled out, the formation of hydrazone 15 may be rational- more complicated than we anticipated. Carrying out the re-
ized by considering that the initial [4+2] cycloadduct un- action with various ratios of 1,2-diaza-1,3-diene/indole, we
dergoes pyridazine ring opening, induced in this case by the always isolated an inseparable mixture of products. These
required longer reaction time. It was also demonstrated that problems were not encountered when we used a protected
1,2-diaza-1,3-diene 11 reacted with electron-rich allenes, N-Boc-indole (Boc = tert-butyloxycarbonyl). In this case,
such as 1-phenoxypropan-1,2-diene, to give 5-methylene- the cycloadduct 21 was isolated as the only product, but in
tetrahydropyridazine derivative 16 in 52% yield (Table 1, a low yield (Scheme 5), clearly indicating the strong deacti-
entry 4).
vating effect of the Boc group. Similar problems have been
We then turned our attention to the reaction of 1,2-di- encountered before in reactions of other 1,3-disubstituted
aza-1,3-diene 11 with aromatic five-membered heterocycles. 1,2-diaza-1,3-dienes derivatives with indole.[15b] Serious
With furan, the expected bicyclic pyridazine 17 was ob-
tained in 68% yield (Table 1, entry 5). The structural assign-
ment of compound 17 was supported by two-dimensional
NOESY, HMQC and HMBC spectra (see the Supporting
Information). In the HMBC spectrum, the H-4 proton at δ
= 3.64 ppm showed a correlation with carbon atoms with
chemical shifts δ = 58.7 ppm (C-7a), 77.8 (C-4a), 139.0 (C-
8) and 150.6 ppm (C-3). From the HMQC spectrum, it was
established that the carbon with the chemical shift of δ =
26.3 ppm corresponded to a methylene group because it
was correlated with two protons with different chemical
shifts. The assignment of the C-6 and C-7 (δ = 149.6 and
102.5 ppm) carbon atoms was based on the correlation with
the vinylic protons at δ = 6.40 and 5.25–5.27 ppm, respec-
tively, observed in the HMQC spectrum. In the NOESY
spectrum, the protons with chemical shift δ = 5.25–
5.27 ppm showed a correlation with the protons H-4.
Scheme 5. Reaction of 1,2-diaza-1,3-diene 11 with N-Boc-indole.
Scheme 4. Reactions with pyrrole and 2,5-dimethylpyrrole.
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[4+2] Cycloadditions of 3-Tetrazolyl-1,2-diaza-1,3-butadienes
competition problems between formal [4+2] and [3+2] cy- quency analysis to confirm the nature of the stationary
cloadditions have also been reported in reactions of electro- points.
philic 1,3,4-trisubstituted 1,2-diaza-1,3-dienes with 1,3-di-
The results summarized in Figure 1 clearly indicate that
the cycloadditions of 1,2-diaza-1,3-diene 11 with acrylates
methylindole.[16]
The only work reporting hetero-Diels–Alder reactions of are LUMOazoalkene-controlled reactions, and consequently,
electron-deficient 1,2-diaza-1,3-butadienes with electro- they are inverse-electron-demand Diels–Alder reactions.
philic dienophiles[9] prompted us to investigate the behav- Furthermore, the values for the HOMO energies of acryl-
iour of conjugated 1,2-diaza-1,3-diene 11 with such com- ates may account for the different efficiency of their reac-
pounds. With methyl acrylate and methyl methacrylate the tions with 1,2-diaza-1,3-diene 11. FMO analysis for the cy-
corresponding tetrahydropyridazines 22 and 23 were iso- cloaddition reaction of this diene with ethyl vinyl ether also
lated as the only products (Scheme 6). No other regioiso- indicated that LUMOazoalkene–HOMOdienophiles was the
mers were found or isolated from the reaction media. The dominant interaction, clearly expressing its higher effi-
yields may be regarded as remarkable, considering the reac- ciency. Therefore, the FMO approach allows the rational-
tion conditions (24 h at room temperature) and the electro- ization of the observed reactivity as a concerted process in
philicity of the reagents. The regiochemistry of cycload- which azoalkene 11 participates in inverse-electron-demand
1
ducts was undoubtedly assigned by H NMR spectroscopy Diels–Alder reactions.
analysis, particularly illuminative was the H-6 proton in
tetrahydropyridazine 22, which appeared at δ = 5.05 ppm
1
as a multiplet. In the H NMR spectrum of compound 22
recorded at 25 °C several signals were broad. However, at
higher temperatures (60 and 100 °C; see the Supporting In-
formation) these signals became sharper, which indicated
that conformational isomerization at an ambient tempera-
ture was observed.
Figure 1. Relative energies [eV] for dienes and dienophiles (*: taken
from ref.[19]).
To be able to rationalize the regioselectivity observed in
the Diels–Alder reactions of 1,2-diaza-1,3-diene 11, quan-
tum chemical calculations were carried out at the DFT
level. The cycloaddition with 1,2-dihydrofuran was selected
as the model reaction and the endo transition structures
leading to the two regioisomers were calculated by using the
QST3 procedure available in Gaussian 09 (Figure 2). TS2 is
32.17 kJmol–1 more stable than TS1, which is consistent
with the observed exclusive formation of product 13.
Scheme 6. Reaction of 1,2-diaza-1,3-diene 11 with acrylates.
Because the reactivity pattern observed for 1,2-diaza-1,3-
diene 11, characterized by the reaction with both electron-
rich and -poor dienophiles, was unusual, frontier molecular
orbital (FMO) analysis of its hetero-Diels–Alder reactions
was carried out.[17] Although the observed regio- and
stereoselectivity are consistent with a concerted mechanism,
a stepwise process could also be possible. To shed some
light on this matter, theoretical calculations were performed
by using Gaussian 09.[18] All structures, including isoprene,
which was included for assessment purposes[19] (see the
Supporting Information), were fully optimized at the
structures for the reaction of 1,2-diaza-1,3-diene 11 with 1,2-dihy-
B3LYP/6-31G(d) and B3LYP/6-311G(d,p) levels with fre- drofuran (TS1 and TS2).
Figure 2. B3LYP/6-31G*-optimized geometries of transition-state
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A. Lemos, T. M. V. D. Pinho e Melo et al.
FULL PAPER
Finally, the reaction with cyclopentadiene was investi- carbazate in the presence of PTSA gave the corresponding
gated to try to establish the reactivity pattern as a 4π or hydrazone 26 in good yield. Attempts were made to obtain
2π reaction component. It was observed that 1,2-diaza-1,3- 27 by carrying out the reaction of compound 26 with NBS
diene 11 acted as a heterodiene and followed the common in CHCl3 at reflux; the reaction conditions used to convert
mode of reaction of 1,2-diaza-1,3-butadienes,[7g,7j,15b,20] al- hydrazone 9 to α-bromohydrazone 10 (see Scheme 3). How-
though some exceptions have been reported,[21] producing ever, mixtures of the target compound and starting material
the cycloadduct 24 isolated in good yield (Scheme 7). The were always obtained. A more efficient process was
structural assignment of compound 24 was supported by achieved when hydrazone 26 was treated with bromine in
two-dimensional NOESY, HMQC and HMBC spectra (see dioxane/ethyl ether to give hydrazone 27 in pure form.
the Supporting Information). In the HMBC spectrum, the
proton at δ = 3.10 ppm (proton attached to C-4) showed
connectivity with the carbon atoms at δ = 38.5 (C-5), 60.7
(C-7a), 135.4 (C-8) and 151.1 ppm (C-3). From the HMQC
spectrum, it was established that carbon atoms at δ = 25.9
and 38.5 ppm corresponded to methylene groups because
both showed correlations with two protons with different
chemical shifts (δ = 131.5 and 133.1 ppm) and the corre-
lation with the vinylic protons at δ = 5.88–5.90 ppm was
observed in the HMQC spectrum.
Scheme 8. Preparation of benzylhydrazone 27 (PTSA = p-tolu-
enesulfonic acid).
Hydrazone 27 was converted into the transient ethyl 3-
(1-benzyl-1H-tetrazol-5-yl)-1,2-diaza-1,3-butadiene-1-carb-
oxylate (28) by treatment with sodium carbonate in di-
chloromethane at room temperature and was trapped in situ
by dihydrofuran and methyl methacrylate, affording the
corresponding cycloadducts 29 and 30 in high yields. N-
Scheme 7. Reaction of 1,2-diaza-1,3-diene 11 with cyclopentadiene.
Deprotection of compounds 29 and 30 was carried out by
following a general procedure reported for the debenz-
It was important to establish that 1,4,5,6-tetra- ylation of N-benzylamines and 1-benzyl-1H-imidazoles
hydropyridazines with an unprotected tetrazolyl substituent using ammonium formate as the catalytic hydrogen transfer
could be obtained by our approach. The strategy was to agent.[13a,23] Thus, a suspension of compounds 29 or 30 and
prepare derivatives containing a 1-benzyltetrazolyl group, 10% Pd/C in methanol was treated with an excess of ammo-
which could be subsequently deprotected. Thus, α-bromo- nium formate and the mixture was heated at reflux for 1 h.
hydrazone 27 was selected as the target 1,2-diaza-1,3-buta- By using this methodology, 1,4,5,6-tetrahydropyridazines
diene precursor and prepared as outlined in Scheme 8. The 31 and 32 containing an N-unsubstituted tetrazole group
reaction of 5-acetyl-1-benzyl-1H-tetrazole (25)[22] with ethyl were obtained in very high yield (Scheme 9).
Scheme 9. Synthesis of benzyltetrazolyl tetrahydropyridizanes and their debenzylation.
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[4+2] Cycloadditions of 3-Tetrazolyl-1,2-diaza-1,3-butadienes
729 cm–1. MS (ESI): m/z (%) = 311(100) [M + Na+], 289 (86) [M
+ H+]. HRMS (ESI): calcd. for C13H17N6O2 [M + H+] 289.14077;
found 289.14075.
Conclusions
In this work, unprecedented Diels–Alder reactions of
ethyl 3-(tetrazol-5-yl)-1,2-diaza-1,3-butadiene-1-carboxyl-
ates were reported. These 1,2-diaza-1,3-dienes participated
in inverse-electron-demand aza-Diels–Alder reactions with
Ethyl 2-[2-Bromo-1-(1-phenyl-1H-tetrazol-5-yl)ethylidene]hydraz-
inecarboxylate (10):
A solution of 9 (0.73 mmol) and NBS
(0.73 mmol) in chloroform (15 mL) was heated at reflux. After 2 h
a large variety of dienophiles, including electron-rich and NBS (0.73 mmol) was added and the reaction mixture was kept at
reflux for an additional 14 h. The crude mixture was diluted with
dichloromethane and washed with water. The organic layer dried
with anhydrous Na2SO4 and the solvent was evaporated. Com-
pound 10 was purified by recrystallization in diethyl ether (0.201 g,
78%) as a white solid; m.p. 143–145 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.76 (br. s, 1 H), 7.57–7.47 (m, 5 H), 4.57 (s, 2 H),
4.17 (q, J = 7.2 Hz, 2 H), 1.21 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.9, 134.9, 132.1, 130.2, 130.1, 129.1,
-deficient 2π components, producing adducts and cycload-
ducts with a wide molecular diversity in good yields and
high regioselectivity. This unusual reactivity pattern allowed
the synthesis of a broad range of new 3-tetrazolyl-1,4,5,6-
tetrahydropyridazines and open-chain hydrazones. The new
1,4,5,6-tetrahydropyridazine derivatives carrying a tetrazole
moiety are molecules with relevance from chemical and bio-
logical points of view. FMO analysis of the cycloaddition
reactions allowed the rationalization of the observed reac-
126.2, 126.1, 63.1, 18.7, 14.3 ppm. IR (KBr): ν = 3165, 2986, 1717,
˜
1606, 1303, 1166, 1064, 761, 686 cm–1. MS (ESI): m/z (%) = 353
tivity. Additionally, rationalization of the observed regiose- (11) [M+], 305 (100), 291 (6), 275 (11). HRMS (ESI): calcd. for
C12H13BrN6O2 [M+] 353.03561; found 353.03426.
lectivity was supported by quantum chemical calculations.
Ethyl 2-[1-(1-Benzyl-1H-tetrazol-5-yl)-2-bromoethylidene]hydrazine-
carboxylate (27): Bromine (5.20 mmol) was added to a solution of
26 (3.47 mmol) in a mixture of diethyl ether/dioxane (70:30)
(35 mL). The reaction mixture was stirred at room temperature for
Experimental Section
General Considerations: DFT calculations were performed by using
24 h, poured onto a mixture of water/ice and extracted with diethyl
Gaussian 09.[18] Structures were initially built in GaussView 5.0 and
ether. The organic layer was dried with anhydrous Na2SO4 and the
occasionally pre-optimized at the PM6 level.[24] Calculations were
solvent was evaporated. Compound 27 was purified by recrystalli-
carried out with the B3LYP[25] functional and the 6-31G* and at
zation in diethyl ether (1.001 g, 79%) as a white solid; m.p. 145.8–
6-311G dp basis sets.[26] If more than one conformation was pos-
1
147.9 °C. H NMR (400 MHz, CDCl3): δ = 8.77 (br. s, 1 H), 7.44
sible, the most stable one was used. True minima were verified by
(br. s, 2 H), 7.31–7.30 (m, 3 H), 6.00 (s, 2 H), 4.41 (q, J = 7.2 Hz,
1
2 H), 1.39 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 148.9, 134.1, 133.8, 128.8, 128.7, 128.6, 63.4, 52.8, 18.2, 14.4
vibrational analysis. No solvent effects were calculated. H NMR
spectra were recorded on an instrument operating at 400 MHz and
13C NMR spectra at 100 MHz. Chemical shifts are expressed in
ppm relative to internal tetramethylsilane (TMS) and coupling con-
stants (J) are in Hz. IR spectra were recorded on a Nicolet 6700
FTIR spectrometer. Mass spectra were recorded under electrospray
ionization (ESI). HRMS spectra were recorded on a Finnigan
MAT95 S instrument. Melting points were recorded on a Reichert
hot stage. Flash column chromatography was performed with
Merck 9385 silica as the stationary phase.
ppm. IR (KBr): ν = 3225, 3170, 1716, 1596, 1428, 1319, 1057, 729
˜
cm–1. MS (ESI): m/z (%) = 389 (100) [M + Na+], 367 (82) [M +
H+], 341 (44), 319 (16), 287 (11). HRMS (ESI): calcd. for
C13H16BrN6O2 [M + H+] 367.05126; found 367.05170.
General Procedure for the Diels–Alder Reaction: Na2CO3
(2.8 mmol) was added to a solution of hydrazone 10 or 27
(0.57 mmol) and the appropriate dienophile (5.7 mmol) in CH2Cl2
(25 mL) and the reaction mixture was stirred at room temperature.
The mixture was then filtered through a Celite pad, which was
washed with dichloromethane. The solvent was evaporated and the
product was purified by flash chromatography.
General Procedure for the Synthesis of Hydrazones: A solution of 5-
acetyl-1-phenyl-1H-tetrazole (7) or 5-acetyl-1-benzyl-1H-tetrazole
(25) (5.3 mmol), ethyl carbazate (0.609 g, 5.8 mmol) and catalytic
PTSA (10 mg) in toluene (50 mL) was heated at reflux under N2
over a Dean–Stark trap until the theoretical amount of water was
removed (ca. 1 h). The solvent was removed and the solid was
recrystallized from diethyl ether to give the pure compound.
Ethyl
6-Ethoxy-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-
pyridazine-1-carboxylate (12): Eluent: ethyl acetate/hexane (1:3).
White solid (0.169 g, 87%); m.p. 98–100 °C (from ethyl acetate/hex-
1
ane). H NMR (400 MHz, CDCl3): δ = 7.51 (br. s, 5 H), 5.67 (br.
Ethyl 2-[1-(1-Phenyl-1H-tetrazol-5-yl)ethylidene]hydrazinecarboxyl-
ate (9): White solid (1.451 g, 99.8%); m.p. 145–148 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.35 (br. s, 1 H), 7.54–7.50 (m, 5 H), 4.14
(q, J = 7.2 Hz, 2 H), 2.43 (s, 3 H), 1.20 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 151.7, 135.5, 135.2, 130.0, 129.0,
s, 1 H), 4.13–4.07 (m, 2 H), 3.66–3.50 (m, 2 H), 3.07–3.00 (m, 1
H), 2.89–2.79 (m, 1 H), 2.27–2.22 (m, 1 H), 1.80–1.72 (m, 1 H),
1.14 (t, J = 7.2 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
151.1, 137.8, 135.4, 129.8, 128.9, 126.1, 63.9, 62.7, 22.7, 15.1, 14.4
ppm. IR (KBr): ν = 2966, 1714, 1620, 1497, 1399, 1319, 1169, 1136,
˜
992, 725, 688 cm–1. MS (ESI): m/z (%) = 367 (100) [M + Na+], 345
(97) [M + H+], 327 (7), 305 (7). HRMS (ESI): calcd. for
C16H21N6O3 [M + H+] 345.16696; found 345.16636.
126.4, 62.5, 14.4, 13.6 ppm. IR (KBr): ν = 3216, 3133, 1712, 1300,
˜
1166, 1054, 769, 689 cm–1. MS (ESI): m/z (%) = 297 (68) [M +
Na+], 276 (100) [M + H+] (22), 275. HRMS (ESI): calcd. for
C12H15N6O2 [M + H+] 275.12510; found 275.12598.
Ethyl
3-(1-Phenyl-1H-tetrazol-5-yl)-1,4,4a,5,6,7a-hexahydrofuro-
Ethyl 2-[1-(1-Benzyl-1H-tetrazol-5-yl)ethylidene]hydrazinecarboxyl-
ate (26): White solid (1.176 g, 77%); m.p. 116.3–118.0 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.31 (br. s, 1 H), 7.47 (br. s, 2 H), 7.31–
7.29 (m, 3 H), 6.04 (s, 2 H), 4.37 (q, J = 7.2 Hz, 2 H), 2.41 (s, 3
H), 1.38 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 150.6, 136.9, 134.4,128.9, 128.7, 128.5, 126.0, 62.8, 52.7, 14.5,
[2,3-c]pyridazine-1-carboxylate (13): Eluent: ethyl acetate/hexane
(2:1), white solid (0.175 g, 89%); m.p. 140–141 °C (from ethyl acet-
ate/hexane). 1H NMR (400 MHz, CDCl3): δ = 7.52 (br. s, 5 H),
5.64 (d, J = 3.2 Hz, 1 H), 4.17–4.09 (m, 2 H), 4.01–3.98 (m, 2 H),
3.21 (dd, J = 15.6, 4.0 Hz, 1 H), 2.42–2.29 (m, 3 H), 2.01–1.95 (m,
1 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 153.8, 150.8, 136.6, 135.3, 129.9, 129.0, 126.3, 80.8, 63.6, 63.0,
13.1 ppm. IR (KBr): ν = 3217, 3155, 1707, 1604, 1420, 1346, 1039,
˜
Eur. J. Org. Chem. 2012, 2152–2160
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2157

A. Lemos, T. M. V. D. Pinho e Melo et al.
FULL PAPER
30.6, 29.7, 24.3, 14.5 ppm. IR (KBr): ν = 2929, 2888, 1713, 1621,
7.2 Hz, 1 H), 2.01 (s, 3 H), 1.34 (s, 3 H), 1.17 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 173.9, 154.2, 150.9, 136.9,
135.3, 129.9, 129.0, 126.2, 67.9, 62.9, 60.2, 46.5, 33.8, 26.5, 20.3,
˜
1398, 1327, 1176, 1034, 965, 771, 692 cm–1. MS (ESI): m/z (%) =
365 (100) [M + Na+], 343 (53) [M + H+]. HRMS (ESI): calcd. for
m/z C16H19N6O3 [M + H+] 343.15131; found 343.15104.
14.5 ppm. IR (KBr): ν = 2979, 1713, 1611, 1402, 1326, 1170, 762,
˜
689 cm–1. MS (ESI): m/z (%) = 368 (100) [M + H+]. HRMS (ESI):
Ethyl
3-(1-Phenyl-1H-tetrazol-5-yl)-1,4,4a,5,6,8a-hexahydro-7H-
calcd. for C18H22N7O2 [M + H+] 368.18295; found 368.18192.
pyrano[2,3-c]pyridazine-1-carboxylate (14): Eluent: ethyl acetate/
hexane (1:1). White solid (0.146 g, 72%); m.p. 141–142 °C (from Ethyl 2-[1-(1-Phenyl-1H-tetrazol-5-yl)-2-(1H-pyrrol-2-yl)ethylidene]-
ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 7.50 (br. hydrazinecarboxylate (19): Eluent: ethyl acetate/hexane (1:1). White
s, 5 H), 5.40 (s, 1 H), 4.12–4.04 (m, 3 H), 3.69 (pseudo t, J =
solid (0.097 g, 50%); m.p. 179–181 °C (from ethyl acetate/hexane).
12.4 Hz, 1 H), 3.04–2.88 (m, 2 H), 2.10–1.82 (m, 4 H), 1.43 (br. d, 1H NMR (400 MHz, CDCl3): δ = 9.20 (br. s, 1 H), 8.73 (br. s, 1
J = 12.4 Hz, 1 H), 1.23 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR H), 7.53–7.51 (m, 5 H), 6.76 (s, 1 H), 6.11 (d, J = 2.0 Hz, 2 H),
(100 MHz, CDCl3): δ = 153.4, 150.9, 136.3, 135.4, 129.8, 128.9, 4.16 (s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 1.18 (t, J = 7.2 Hz, 3 H)
126.3, 78.4, 68.3, 62.9, 27.0, 26.2, 23.0, 19.8, 14.4 ppm. IR (KBr):
ppm. 13C NMR (100 MHz, CDCl3): δ = 152.0, 135.4, 135.0, 130.2,
ν = 2923, 2863, 1717, 1616, 1500, 1401, 1338, 1214, 941, 768, 693
129.0, 126.3, 122.2, 118.9, 108.6, 107.7, 62.6, 26.9, 14.4 ppm. IR
˜
cm–1. MS (ESI): m/z (%) = 379 (100) [M + Na+], 357 (51) [M +
(KBr): ν = 3389, 3310, 2976, 1757, 1613, 1485, 1293, 1161, 1116,
˜
H+]. HRMS (ESI): calcd. for C17H21N6O3 [M + H+] 357.16696; 1031, 765 cm–1. MS (ESI): m/z (%) = 340 (100) [M + H+], 276 (11),
found 357.16540.
247 (27), 203 (6). HRMS (ESI): calcd. for C16H18N7O2 [M + H+]
340.15165; found 340.15025.
Ethyl 2-[2-(3,4-Dihydro-2H-pyran-5-yl)-1-(1-phenyl-1H-tetrazol-5-
yl)ethylidene]hydrazine carboxylate (15): Eluent: ethyl acetate/hex-
ane (1:1). White solid (0.031 g, 15%); m.p. 99.6–101.4 °C (from di-
9-tert-Butyl 1-Ethyl-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,4a,9a-tetra-
hydro[3,4-b]indole-1,9-dicarboxylate (21): Compound 21 was ob-
ethyl ether). 1H NMR (400 MHz, CDCl3): δ = 8.53 (br. s, 1 H), tained as a white solid by following the general procedure using
7.54–7.50 (m, 5 H), 6.37 (s, 1 H), 4.15 (q, J = 7.2 Hz, 2 H), 3.91 2 equiv. of the dienophile, followed by purification by flash
(pseudo t, J = 5.2 Hz, 2 H), 3.57 (s, 2 H), 1.98–1.95 (m, 2 H), 1.89–
1.85 (m, 2 H), 1.21 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.8, 141.9, 136.2, 135.3, 130.1, 129.0, 126.3, 105.5,
chromatography [ethyl acetate/hexane (1:2); 0.042 g, 15%]; m.p.
157.7–159.5 °C (from ethyl acetate/hexane). 1H NMR (400 MHz,
CDCl3): δ = 7.27 (t, J = 6.0 Hz, 1 H), 7.50–7.45 (m, 4 H), 7.35 (d,
J = 7.6 Hz, 2 H), 7.16 (d, J = 7.2 Hz, 1 H), 6.97 (t, J = 7.2 Hz, 1
65.5, 62.5, 32.5, 23.2, 21.9, 14.4 ppm. IR (KBr): ν = 3245, 2980,
˜
1752, 1730, 1707, 1233, 1147, 764 cm–1. MS (ESI): m/z (%) = 357 H), 4.78 (br. d, J = 8.4 Hz, 1 H), 4.25–4.17 (m, 2 H), 3.39 (br. d, J
(100) [MH+]. HRMS (ESI): calcd. for C17H21N6O3 [M + H+]
357.16696; found 357.1674.
= 13.2 Hz, 1 H), 2.76 (dd, J = 17.6, 6.4 Hz, 1 H), 1.61 (s, 9 H),
1.20 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
154.9, 150.5, 137.9, 135.2, 129.8, 129.7, 129.0, 126.1, 125.0, 123.3,
Ethyl 5-Methylene-6-phenoxy-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,5,6-
tetrahydropyridazine-1-carboxylate (16): Compound 16 was ob-
tained as a white solid by following the general procedure using
3 equiv. of the dienophile followed by purification by flash
chromatography [ethyl acetate/hexane (1:2); 0.119 g, 52%]; m.p.
129.4–130.3 °C (from ethyl acetate/hexane). 1H NMR (400 MHz,
115.8, 82.4, 63.2, 54.8, 53.9, 28.4, 25.8, 14.5 ppm. IR (KBr): ν =
˜
2963, 1711, 1688, 1614, 1480, 1392, 1305, 1150, 754 cm–1. MS
(ESI): m/z (%) = 490 (100) [M + H+], 365 (3), 343 (25). HRMS
(ESI): calcd. for C25H28N7O4 [M
490.22016.
+
H+] 490.21973; found
CDCl3): δ = 7.47 (br. s, 5 H), 7.22–7.19 (m, 2 H), 7.00–6.91 (m, 3 1-Ethyl
6-Methyl
3-(1-Phenyl-1H-tetrazol-5-yl)-1,4,5,6-tetra-
H), 6.33 (s, 1 H), 5.24 (s, 1 H), 5.19 (s, 1 H), 3.99 (q, J = 6.8 Hz, hydropyridazine-1,6-dicarboxylate (22): Eluent: ethyl acetate/hexane
2 H), 3.78–3.66 (m, 2 H), 1.02 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (1:2) to (1:1). White solid (0.073 g, 36%); m.p. 145.8–147.6 °C
(100 MHz, CDCl3): δ = 155.4, 150.4, 1492, 135.3, 131.5, 130.0,
(from ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 7.53
129.0, 126.4, 123.6, 119.1, 116.4, 82.2, 63.2, 29.5, 14.4 ppm. IR
(s, 5 H), 5.05 (m, 1 H), 4.15–4.08 (m, 2 H), 3.76 (s, 3 H), 3.16
(KBr): ν = 2990, 1719, 1617, 1595, 1374, 1304, 1183, 918, 771, 696 (pseudo dd, J = 17.6, 3.6 Hz, 1 H), 2.55–2.45 (m, 2 H), 2.11–2.07
˜
cm–1. MS (ESI): m/z (%) = 427 (100) [M + Na+], 405 (71) [M +
H+], 311 (5). HRMS (ESI): calcd. for C21H21N6O3 [M + H+]
405.16696; found 405.16702.
(m, 1 H), 1.11 (br. s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.0, 150.7, 135.3, 129.8, 129.0, 126.0, 63.0, 52.9, 20.5, 19.3, 14.4
ppm. IR (KBr): ν = 2987, 1745, 1705, 1441, 1325, 1221, 1138, 765
˜
cm–1. MS (ESI): m/z (%) = 381 (100) [M + Na+], 331 (38). HRMS
(ESI): calcd. for C16H18N6NaO4 [M + H+] 381.12822; found
381.12817).
Ethyl
3-(1-Phenyl-1H-tetrazol-5-yl)-1,4,4a,7a-tetrahydrofuro[3,2-
c]pyridazine-1-carboxylate (17): Eluent: ethyl acetate/hexane (1:1).
White solid (0.131 g, 68%); m.p. 93.4–95.0 °C (from ethyl acetate/
hexane). H NMR (400 MHz, CDCl3): δ = 7.50 (br. s, 5 H), 6.40
(s, 1 H), 5.27–5.25 (m, 2 H), 5.14 (d, J = 9.2 Hz, 1 H), 4.11 (q, J
1
1-Ethyl 6-Methyl 6-Methyl-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,5,6-
tetrahydropyridazine-1,6-dicarboxylate (23): Eluent: ethyl acetate/
= 7.2 Hz, 2 H), 3.64 (dd, J = 16.8, 2.0 Hz, 1 H), 2.76 (dd, J = 16.8, hexane (1:1). White solid (0.101 g, 48%); m.p. 137.1–138.8 °C (from
1
4.4 Hz, 1 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, ethyl acetate/hexane). H NMR (400 MHz, CDCl3): δ = 7.54–7.52
CDCl3): δ = 154.1, 150.6, 149.6, 139.0, 135.2, 129.9, 128.9, 126.2,
(m, 5 H), 4.06–3.96 (m, 2 H), 3.74 (s, 3 H), 3.14–3.07 (m, 1 H),
2.77–2.68 (m, 1 H), 2.25–2.17 (m, 1 H), 2.11–2.04 (m, 1 H), 1.55
(s, 3 H), 1.09 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.5, 153.1, 150.8, 135.4, 134.1, 129.8, 126.2, 129.0,
102.5, 77.8, 62.7, 58.7, 26.3, 14.5 ppm. IR (KBr): ν = 3066, 2982,
˜
1711, 1614, 1497, 1377, 1326, 1169, 764, 690 cm–1. MS (ESI): m/z
(%) = 363 (100) [M + Na+], 341 (48) [M + H+]. HRMS (ESI):
calcd. for C16H17N6O3 [M + H+] 341.13566; found 341.13537.
62.8, 59.6, 52.8, 20.3, 20.1, 14.4 ppm. IR (KBr): ν = 2984, 2952,
˜
1747, 1720, 1621, 1322, 1084, 763, 687 cm–1. MS (ESI): m/z (%) =
395 (100) [M + Na+], 345 (31), 271 (8). HRMS (ESI): calcd. for
C17H20N6NaO4 [M + H+] 395.14382; found 395.14385.
Ethyl 4a,6-Dimethyl-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,4a,7a-tetra-
hydro-7H-pyrrolo[3,2-c]pyridazine-1-carboxylate (18): Eluent: ethyl
acetate/hexane (4:1). White solid (0.081 g, 39%); m.p. 145–146 °C
(from ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ =
7.50–7.53 (m, 5 H), 4.19 (t, J = 7.6 Hz, 1 H), 4.12 (q, J = 7.2 Hz,
2 H), 3.13 (m, 2 H), 2.63 (d, J = 17.2 Hz, 1 H), 2.44 (dd, J = 17.6,
Ethyl
3-(1-Phenyl-1H-tetrazol-5-yl)-1,4,4a,7a-tetrahydro-5H-cy-
clopenta[c]pyridazine-1-carboxylate (24): Eluent: ethyl acetate/hex-
ane (1:2). White solid (0.159 g, 83%); m.p. 99.5–100.9 °C (from
2158
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2152–2160

[4+2] Cycloadditions of 3-Tetrazolyl-1,2-diaza-1,3-butadienes
ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3): δ = 7.52 (br. 1 H), 2.08–2.04 (m, 2 H), 1.51 (s, 3 H), 1.27 (t, J = 6.8 Hz, 3 H)
s, 5 H), 5.88 (br. d, J = 6.0 Hz, 2 H), 5.01 (br. d, J = 5.6 Hz, 1 H),
4.11 (q, J = 7.2 Hz, 2 H), 3.10 (dd, J = 17.2, 6.0 Hz, 1 H), 2.75–
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 172.4, 152.7, 136.5,
59.4, 62.6, 52.4, 27.5, 19.8, 19.0, 14.2 ppm. IR (KBr): ν = 736,
˜
2.71 (m, 1 H), 2.59–2.54 (m, 1 H), 2.30–2.24 (m, 2 H), 1.16 (t, J = 1167, 1319, 1619, 1717, 1747, 2953 cm–1. MS (ESI): m/z (%) = 319
7.2 Hz, 3 H) ppm. 13C NMR: δ = 154.4, 151.1, 136.0, 135.4, 131.4,
(72) [M + Na+], 297 (100) [M + H+], 203 (12). HRMS (ESI): calcd.
133.1, 129.8, 128.9, 126.3, 62.6, 60.7, 38.5, 30.0, 25.9, 14.6 ppm. IR for C11H17N6O4 [M + H+] 297.13058; found 297.13060.
(KBr): ν = 2984, 1712, 1611, 1310, 1167, 761, 690 cm–1. MS (ESI)
˜
Supporting Information (see footnote on the first page of this arti-
m/z (%) = 361 (83) [M + Na+], 333 (30), 311 (100), 265 (49), 236
(9). HRMS (ESI): calcd. for C17H18N6NaO2 [M + H+] 361.13834;
found 361.13842.
1
cle): Copies of H and 13C NMR spectra for all new compounds,
HMQC and HMBC spectra for compound 24 and theoretical cal-
culation results.
Ethyl
3-(1-Benzyl-1H-tetrazol-5-yl)-1,4,4a,5,6,7a-hexahydrofuro-
[2,3-c]pyridazine-1-carboxylate (29): Eluent: ethyl acetate/hexane
Acknowledgments
(1:1). White solid (0.193 g, 95%); m.p. 100.3–102.1 °C (from ethyl
1
acetate/hexane). H NMR (400 MHz, CDCl3): δ = 7.44 (br. d, J =
Thanks are due to Fundação do Ministério de Ciência e Tecnologia
(FCT) (grant SFRH/BD/45128/2008; project PEst-C/QUI/UI0313/
2011), Fundo Europeu de Desenvolvimento Regional (FEDER),
Programa Operacional Factores de Competitividade (COMPETE)
and Quadro de Referência Estratégico Nacional (QREN) for finan-
cial support. We acknowledge the Nuclear Magnetic Resonance
Laboratory of the Coimbra Chemical Centre (www.nmrccc.uc.pt),
University of Coimbra, for obtaining the NMR spectroscopic data.
3.6 Hz, 2 H), 7.31–7.30 (m, 3 H), 6.07 (s, 2 H), 5.73 (d, J = 4.0 Hz,
1 H), 4.47–4.35 (m, 2 H), 4.00–3.95 (m, 2 H), 3.15 (dd, J = 17.6,
6.0 Hz 1 H), 2.44–2.29 (m, 3 H), 1.94–1.89 (m, 1 H), 1.34 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.9, 149.8,
138.3, 134.5, 128.8, 128.7, 128.6, 81.0, 63.9, 63.5, 52.5, 30.7, 29.9,
23.8, 14.5 ppm. IR (KBr): ν = 2944, 1726, 1619, 1409, 1318, 1034,
˜
726 cm–1. MS (ESI): m/z = 379 (100) [M + Na+], 357 (92) [M +
H+], 353 (8). HRMS (ESI): calcd. for C17H21N6O3 [M + H+]
357.16696; found 357.16703.
[1] H.-M. Eggenweiler, M. Wolf, N. Beier, J. Leibrock, M. Gassen,
T. Ehring, DE Patent 10064997, 2002 [Chem. Abstr. 2002, 137,
63348].
1-Ethyl 6-Methyl 3-(1-Benzyl-1H-tetrazol-5-yl)-6-methyl-1,4,5,6-
tetrahydropyridazine-1,6-dicarboxylate (30): Eluent: ethyl acetate/
hexane (1:1). Oil (0.172 g, 78%). 1H NMR (400 MHz, CDCl3): δ
= 7.41–7.40 (m, 2 H), 7.33–7.31 (m, 3 H), 6.07 (s, 2 H), 4.36–4.28
(m, 2 H), 3.79 (s, 3 H), 3.09–3.03 (m, 1 H), 2.68–2.59 (m, 1 H),
2.24–2.17 (m, 1 H), 2.10–2.04 (m, 1 H), 1.59 (s, 3 H), 1.29 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.5, 153.2,
149.7, 135.7, 134.6, 128.8, 128.6, 128.5, 63.4, 59.7, 52.9, 52.3, 28.3,
[2] a) S. S. Leonhardt, D. P. Edwards, Exp. Biol. Med. 2002, 227,
969–980; b) S. Palmer, C. A. Campen, G. F. Allan, P. Rybczyn-
ski, D. Haynes-Johnson, A. Hutchins, P. Kraft, M. Kiddoe, M.-
T. Lai, E. Lombardi, P. Pedersen, G. Hodgen, D. W. Combs, J.
Steroid Biochem. Mol. Biol. 2000, 75, 33–42; c) D. W. Combs,
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D. W. Combs, K. Reese, A. Phillips, J. Med. Chem. 1995, 38,
4880–4884.
20.4, 19.6, 14.4 ppm. IR (film): ν = 2986, 2952, 1746, 1718, 1623,
˜
1330, 1164, 727 cm–1. MS (ESI): m/z (%) = 409 (92) [M + Na+],
387 (100) [M + H+]. HRMS (ESI): calcd. for C18H23N6O4 [M +
H+] 387.17753; found 387.17757.
[3] D. W. Combs, WO 94/001412, 1994 [Chem. Abstr. 1994, 122,
31542].
[4] J. H. M. Lange, A. P. den Hartog, M. A. van der Neut, B. J.
van Vliet, C. G. Kruse, Bioorg. Med. Chem. Lett. 2009, 19,
5675–5678.
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Chen, K.-Y. Wang, B. J. Graves, G. Lawton, C. U. Kim, Bioorg.
Med. Chem. Lett. 1999, 9, 1751–1756.
General Procedure for N-Deprotection of Compounds 29 and 30: An-
hydrous ammonium formate (4.8 mmol) was added in a single por-
tion under nitrogen to a stirred suspension of compounds 29 or 30
(0.48 mmol) and an equal weight of 10% Pd/C in methanol
(17 mL). The resulting mixture was stirred under reflux for 1 h,
then cooled to room temperature and the catalyst was removed by
filtration through a Celite pad, which was then washed with meth-
anol. The combined filtrates were concentrated under reduced pres-
sure and the residue was dissolved in ethyl acetate and washed with
aqueous HCl (1 m). The organic layer was dried with anhydrous
Na2SO4 and the solvent was evaporated.
[6] P. J. Rybczynski, D. W. Combs, K. Jacobs, R. P. Shank, B. Du-
binsky, J. Med. Chem. 1999, 42, 2403–2408.
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De Crescentini, G. Favi, F. Felluga, C. Forzato, F. Mantellini,
P. Nitti, E. Valentin, E. Zangrando, Tetrahedron: Asymmetry
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centini, O. A. Attanasi, A. R. Ofial, H. Mayr, Chem. Eur. J.
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Sulfur Silicon Relat. Elem. 2008, 183, 2882–2890; f) E. Rossi,
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Xu, J.-C. Huang, Tetrahedron Lett. 2006, 47, 4129–4131; h) F.
Palácios, D. Aparicio, Y. López, J. M. de los Santos, C. Alonso,
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43, 4351–4353; k) O. A. Attanasi, L. De Crescentini, P. Filip-
pone, F. Fringuelli, F. Mantellini, M. Matteucci, O. Piermatti,
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165–169.
Ethyl 3-(1H-Tetrazol-5-yl)-1,4,4a,5,6,7a-hexahydrofuro[2,3-c]pyrid-
azine-1-carboxylate (31): Recrystallization in diethyl ether. White
1
solid (0.128 g, 99%); m.p. 172.4–174.0 °C (from diethyl ether). H
NMR (400 MHz, [D6]DMSO): δ = 5.66 (d, J = 4.4 Hz, 1 H), 4.28
(q, J = 7.2 Hz, 2 H), 3.90–3.86 (m, 1 H), 3.81–3.77 (m, 1 H), 2.97
(dd, J = 18.0, 6.8 Hz, 1 H), 2.34–2.21 (m, 2 H), 1.88–1.80 (m, 1 H),
1.30 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 153.3, 139.6, 81.1, 63.3, 62.5, 30.2, 29.5, 23.3, 14.4 ppm. IR
(KBr): ν = 3181, 2979, 1726, 1375, 1701, 1635, 1034, 770 cm–1. MS
˜
(ESI): m/z (%) = 267 (100) [M + H+], 202 (39). HRMS (ESI): calcd.
for C10H15N6O3 [M + H+] 267.12001; found 267.12007.
1-Ethyl
6-Methyl
6-Methyl-3-(1H-tetrazol-5-yl)-1,4,5,6-tetra-
hydropyridazine-1,6-dicarboxylate (32): Recrystallization in diethyl
ether. White solid (0.129 g, 91%); m.p. 181.0–183.2 °C (from di-
ethyl ether). 1H NMR (400 MHz, [D6]DMSO): δ = 4.22 (pseudo t,
J = 6.8 Hz, 2 H), 3.67 (s, 3 H), 2.92–2.88 (m, 1 H), 2.69–2.62 (m,
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Received: December 20, 2011
Published Online: February 27, 2012
2160
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Eur. J. Org. Chem. 2012, 2152–2160