Hetero-Diels–Alder and Ring-Opening Reactions of Furans Applied to the Synthesis of Functionalized Heterocycles

Article abstract of DOI:10.1002/ejoc.201700453

Furans have been explored as a scaffold for the synthesis of a range of heterocyclic compounds, exploring their dienophilic behaviour towards nitroso- and azoalkenes as the first step. Acid-catalysed rearrangements of these cycloadducts, 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines and 1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazines, were studied. Using 1 equiv. of TFA, the bicyclic heterocycles derived from furan and 2-methylfuran were converted into furans bearing side-chains incorporating oxime and hydrazone groups by ring-opening of the six-membered ring with the concomitant aromatization of the furan ring. The use of TFA as solvent led to rearrangement via spirocyclic intermediates, followed by furan ring-opening to afford functionalized isoxazoles or pyrazoles. Furthermore, furo-oxazines derived from 2,5-dimethylfuran, in which furan aromatization is precluded, were converted efficiently into 6H-1,2-oxazines through a furan ring-opening reaction upon thermolysis in the presence of a catalytic amount of p-toluenesulfonic acid. The tetrahydrofuro[3,2-c]pyridazines derived from furan and dimethylfuran underwent acid-catalysed addition reactions, leading to 6-substituted hexahydrofuro[3,2-c]pyridazines, when in the presence of alcohols or water.

Full text of DOI:10.1002/ejoc.201700453

A Journal of
Accepted Article
Title: Hetero-Diels-Alder and Ring-opening Reactions of Furans
Applied to the Synthesis of Functionalized Heterocycles
Authors: Américo J.S. Alves, Susana M. M. Lopes, Marta S.C.
Henriques, José A. Paixão, and Teresa M. V. D. Pinho e Melo
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
Hetero-Diels-Alder and Ring-opening Reactions of Furans Applied to
the Synthesis of Functionalized Heterocycles
Américo J. S. Alves,1 Susana M. M. Lopes,1 Marta S. C. Henriques,2 José A. Paixão2
and Teresa M. V. D. Pinho e Melo1*
1 CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
2 CfisUC and Physics Department, University of Coimbra, 3004-516 Coimbra, Portugal
E-mail: tmelo@ci.uc.pt
O
O
XH
X
X
X
R3 = Me
R3
N
N
TFA
N
R3
N
N
R3
O
O
R1
R1
PTSA, D
O
R1
R1
R1
HO
X = O
X = O or NR'
TFA (1 equiv.)
R2 = H
R2 = R3 = Me
R'
O
R2
R3
X
X
N
N
N
N
OR
R3
R3
Acid, ROH
R2/R3 = H or Me
R1
O
R1
O
R1
R2
X = NR'
R2
X = O or X = NR'
ABSTRACT: Furans were explored as scaffold for the synthesis of a range of heterocyclic compounds,
exploring the dienophilic behaviour towards nitroso- and azoalkenes as the first step. Acid-catalysed
rearrangements of these cycloadducts, 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines and 1,4,4a,7a-
tetrahydrofuro[3,2-c]pyridazines, were studied. Using 1 equivalent of TFA, the bicyclic heterocycles
derived from furan and 2-methylfuran, are converted into furans bearing side-chains incorporating oxime
and hydrazone groups by ring-opening of the six-membered ring with the concomitant aromatization of
the furan ring. The use of TFA as solvent can lead to rearrangements via the generation of spirocyclic
intermediates followed by furan ring-opening to afford functionalized isoxazoles or pyrazoles.
Furthermore, furo-oxazines derived from 2,5-dimethylfuran, where furan aromatization is precluded, are
converted efficiently into 6H-1,2-oxazines via a furan ring-opening reaction upon thermolysis in presence
of a catalytic amount of p-toluenesulfonic acid. Tetrahydrofuro[3,2-c]pyridazines derived from furan and
dimethylfuran undergo acid-catalyzed addition reaction, leading to 6-substitued-hexahydrofuro[3,2-
c]pyridazines, when in presence of alcohols or water.
Keywords: Furans / Nitrosoalkenes / Azoalkenes / Rearrangements / Nitrogen-containing Heterocycles
1
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
INTRODUCTION
Biomass is already a considerable source of chemical building blocks. One of the
biomass-derived platform molecules is furan, which is easily produced by
decarbonylation of furfural.[1] The rich chemistry of furan makes it a particularly
interesting scaffold in organic synthesis since it can be easily converted into a wide
range of heterocyclic, alicyclic and acyclic structures, some of which finding
application in natural product synthesis and medicinal chemistry. Thus, there is an
increasing interest in exploring furan chemistry, particularly transformations of furan
derivatives into nitrogen-containing heterocycles, which are highly privileged scaffolds
in vast areas of chemistry.[2]
Hetero-Diels-Alder reaction of conjugated nitrosoalkenes and azoalkenes with furans
has been used as a route to 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines and 1,4,4a,7a-
tetrahydrofuro[3,2-c]pyridazines, respectively.[3-8] The reactivity of these bicyclic
systems can be further explored to give functionalized heterocyclic compounds.
Recently, we described the reactivity of 2,2-(difuran-2-yl)propane (3) towards nitroso-
and azoalkenes generated by base-mediated dehydrohalogenation of α-halooximes (e.g.
1) and α-halohydrazones (e.g. 6), respectively (Scheme 1).[8] The expected hetero-Diels-
Alder adducts, 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines 4 and tetrahydrodrofuro[3,2-
c]pyridazines 8, were obtained in good yield. The furo-oxazines were easily converted
into the corresponding bis(furan-2-yl)methanes 5 bearing an open-chain oxime.
However, attempts to convert tetrahydrofuro[3,2-c]pyridazines into the corresponding
open chain hydrazones were unsuccessful. Interestingly, in the presence of HCl, they
underwent a rearrangement giving 6-(2-oxobutyl)-1,6-dihydropyridazine derivatives, in
a process having as its key step a furan ring-opening reaction. The synthesis of
tetrahydrofuro[3,2-c]pyridazines, derived from 2-methylfuran, and the subsequent acid-
catalysed rearrangement to the corresponding 6-(2-oxopropyl)-1,6-dihydropyridazines
was also reported.
2
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
CO2tBu
NHCO2tBu
O
NOH
CH2Cl2
r.t., 16-48 h
Na2CO3
N
CH2Cl2
r.t., 16-46 h
Na2CO3
N
N
Br
N
R
R
Br
R
R
O
2
1a R = CO2Et
1b R = p-BrC6H4
7
6a R = CO2Et
6b R = p-BrC6H4
O
O
O
3
3
O
CO2tBu
N
N
N
O
R
O
O
4 52-64%
R
8 63-66%
O
CH2Cl2 r.t., 23 h
CHCl3, HCl 2 M in Et2O, r.t.
OH
N
CO2tBu
N
N
O
O
R
O
O
5 91-96%
R
9 62-73%
Scheme 1. Reactivity of 2,2-(difuran-2-yl)propane (3) towards nitroso- and azoalkenes.[8]
Herein, further developments on the use of furans for the construction of novel
heterocyclic compounds are described, exploring the dienophilic behaviour of furans
towards conjugated nitrosoalkenes and azoalkenes as the first step.
RESULTS AND DISCUSSION
Hetero-Diels-Alder reaction of furans with azoalkenes
In situ treatment of α-bromoarylhydrazones 10 with sodium carbonate led to the
generation of the transient azoalkenes 11, which were trapped by furan, 2-methylfuran
and 2,5-dimethylfuran (Table 1). The expected cycloadducts 12 were obtained in good
yields, ranging from 59% to 94%. In same cases, cycloadducts 12a and 12e were
obtained together with the formation of the corresponding open-chain hydrazones 13
(Entries 1, 2, 9), resulting from tetrahydrofuro[3,2-c]pyridazine ring-opening with the
concomitant aromatization of the furan ring. Due to its high reactivity, azoalkene 11b
can lead to formation of the self-condensation product 14 as side product. This was
observed in the reaction of azoalkene 11b with furan (Entries 4-5). It's noteworthy that
the efficient synthesis of 12a and 12j can also be achieved under solventless conditions
(Entries 2, 3, 11 and 19). In the case of compounds 12b, 12g and 12h, stirring for 24 h
under solventless conditions led to mixtures of the target compound and unreacted
starting hydrazone, due to the low solubility of the latter. However, adding DCM (1 mL)
3
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
as cosolvent and further stirring for 19 h allowed the synthesis of the expected cycloadducts in
yields ranging from 59% to 63% (Entries 6, 13 and 15).
Table 1. Synthesis of 1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazines 12 via Hetero-Diels-Alder reaction of
furans with azoalkenes.
O
R3
R2
Ar
N
Ar
Ar
N
Na2CO3
DCM, r.t.
10 - 100 equiv.
7 - 48 h
NH
N
R3
N
N
R1
O
Br
R1
R1
R2
12
10a R1 = CO2Et
10b R1 = Ph
11
10c R1 = p-NO2C6H4
10d R1 = p-FC6H4
Furan Reaction
(equiv) Time
Entry
R1
Ar
R2
R3
Product
1
2
CO2Et
CO2Et
CO2Et
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
100
40
18 h
23 h
19 h
24 h
24 h
43 h
7.5 h
48 h
24 h
32 h
31 h
7 h
12a 72%a
12a 70%a,b
12a 87%b
12b 34%c
12b 76%c
12b 59%d
12c 73%
12d 81%
12e 54%a
12f 63%
3
H
80
4
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
Ph
H
10
5
Ph
H
100
40
6
Ph
H
7
p-NO2C6H4
p-FC6H4
CO2Et
Ph
H
100
100
17
8
H
9
Me
Me
Me
Me
Me
Me
Me
10
11
12
13
14
15
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
o,p-(NO2)2C6H3
17
Ph
40
12f 93%b
12g 91%
12g 63%d
12h 61%
12h 60%d
p-NO2C6H4
p-NO2C6H4
p-FC6H4
p-FC6H4
17
40
43 h
22 h
43 h
17
40
4
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
16
17
18
19
20
21
CO2Et
CO2Et
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
15
15
15
40
15
15
8 h
12i 50%
12i 84%
12j 94%
12j 78%b
12k 59%
12l 94%
24 h
23 h
23 h
24 h
23 h
o,p-(NO2)2C6H3 Me
o,p-(NO2)2C6H3 Me
o,p-(NO2)2C6H3 Me
o,p-(NO2)2C6H3 Me
Ph
p-NO2C6H4
p-FC6H4
a open-chain hydrazone was also isolated
b solventless
c self-condensation product was also isolated
d solventless for 24 h, followed by the addition of 1 mL of DCM further stirring for 19 h.
Ph
Ar
N
Ph
N
NH
N
N
R
NAr
O
EtO2C
Ph
13a R = H
13b R = Me
14 Ar = o,p-(NO2)2C6H3
Reactivity of tetrahydrofuro[3,2-c]pyridazines
The acid-catalyzed rearrangement of tetrahydrofuro[3,2-c]pyridazines was explored
(Scheme 2). Treatment of cycloadduct 12a with TFA (1 equiv.) at room temperature for
5 h, using dichloromethane as solvent, afforded product 15 in 20% yield. Structural
assignment of compound 15 was supported by two-dimensional spectra (COSY,
NOESY, HSQC and HMBC, see Supporting Information). As Mackay et al. described
for another tetrahydrofuro[3,2-c]pyridazine derivative,[3] we also observed that by
changing the solvent to methanol, ketals 16 were obtained in a 1:1 ratio of isomers 16a
and 16b, in 26% overall yield. The stereochemistry of compounds 16a and 16b was
established based on NOESY spectra. In the NOESY spectrum of compound 16a, cross
peaks were observed between proton H-7a (4.52 ppm) and proton H-4a (4.65-4.69 ppm)
and the latter showed correlation with protons of the methoxy group (3.36 ppm). On the
other hand, in the NOESY spectrum of compound 16b a correlation was observed
between protons H-4a/H-7a, which present overlapping signals at 4.30-4.37 ppm, with
5
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
proton H-6 (5.03 ppm). Compounds 15 and 16 were formed by protonation of the 2,3-
dihydrofuran ring followed by nucleophilic attack by water and methanol, respectively.
Ph
N
Ph
N
Ph
H
H
H
1N
TFA (1 equiv.)
MeOH, r.t.
7
2 N
N
N
6
7a
OMe
+
OMe
4a
O
O
EtO2C
EtO2C
O 5
3
EtO2C
H
4
12a
16b 13%
16a 13 %
TFA (1 equiv.)
DCM, r.t., 5 h
H
H+
Ph
Ph
N
Ph
OR
N
Ph
N
N
N
H
N
N
OR
N
O
O
O
EtO2C
EtO2C
OH
EtO2C
O
EtO2C
H
R = H or Me
15 20%
Scheme 2. Reactivity of tetrahydrofuro[3,2-c]pyridazine 12a derived from furan in the presence of TFA.
Open-chain hydrazone 13b was obtained in good yield when furo-pyridazine 12e,
derived from 2-methylfuran, was treated with TFA (1 equiv.) in dichloromethane at
room temperature (Scheme 3). Interestingly, using TFA as solvent, furo-pyridazine 12e
was readily converted into a mixture of pyrazoles 17 and 18 in 26% overall yield (1:1
ratio).
Structural assignment of compounds 17 and 18 was supported by two-dimensional
1
spectra (COSY, NOESY, HSQC and HMBC). In the H NMR spectrum of the mixture
it is possible to observe the vinylic protons at 5.81 (H-7, dd) and 6.12 ppm (H-6, d) and
a multiplet at 4.90-4.93 ppm (H-8) expected for compound 17. On the other hand, the
13C NMR spectrum shows a signal at 206.2 ppm corresponding to the carbonyl carbon
C-8 of compound 18. The cis configuration of the double bond of compound 17 was
established by the cross peaks observed in the NOESY spectrum, between the proton of
the pyrazole ring (H-4), a singlet at 6.96 ppm, with methyl group protons (H-9) and H-
8.
6
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
Ph
N
Ph
TFA
(1 equiv.)
NH
N
N
DCM
r.t., 6 h
O
O
EtO2C
EtO2C
Ph
13b 67%
12e
Ph
N
TFA
r.t., 15 min.
O
6
7
8
6
N
N
N
+
17:18 26% (1:1)
8
7
9
4
4
EtO2C
9
EtO2C
OH
17
18
Scheme 3. Reactivity of tetrahydrofuro[3,2-c]pyridazine 12e derived from 2-methylfuran in the presence
of TFA.
The synthesis of allylic alcohol 17 can be explained considering the in situ generation of
hydrazone 13b, protonation of the furan at C-5 followed by intramolecular nucleophilic
attack by the amine moiety at furan C-2, producing the spirocyclic intermediate 19.
Subsequent furan ring-opening reaction leads to 1H-pyrazolyl allylic alcohol 20. Acid-
catalysed rearrangement of the allylic alcohol moiety of 1H-pyrazole leads to 1H-
pyrazole 18, bearing a 3-oxobutyl side-chain (Scheme 4). This type of acid-catalysed
rearrangement of allylic alcohol into the corresponding saturated ketone has been
previously reported.[2f,9-13]
Ph
Ph
N
Ph
N
H
NH
N
TFA
12e
N
N
O
O
EtO2C
HO
EtO2C
EtO2C
13b
19
H
20
Ph
N
Ph
N
OH
O
N
N
EtO2C
EtO2C
21
18
Scheme 4. Mechanism proposal for the acid-catalysed rearrangement of furo-pyridazine 12e leading to
pyrazole 18.
Cycloadducts 12b-d were converted into the corresponding open-chain hydrazones 22
on reacting with trifluoroacetic acid (1 equiv.) at room temperature using
dichloromethane as solvent. Functionalized furans 22a and 22c were obtained in 48%
and 57% yield, respectively, whereas furan 22b could only be obtained in low yield
(14%). On the other hand, furo-pyridazine 12b underwent acid-catalyzed rearrangement
to afford pyrazole derivatives 24 when TFA was used as solvent.
7
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
The rational for the synthesis of compound 24a is based on the generation of spirocyclic
intermediate 23, followed by furan ring-opening reaction leading to 1H-pyrazolyl allylic
alcohol 24a (36%), as previously described by Gilchrist et al.[4] From this reaction the
trifluoroacetic acid ester 24b was also isolated in 12% yield, which could be converted
quantitatively into 1H-pyrazole 24a by treatment with Al2O3 (Scheme 5).
NO2
NH
NO2
O2N
Ar
O2N
Ar
22a Ar = Ph
22b Ar = p-NO2C6H4
22c Ar = p-FC6H4
48%
14%
57%
N
TFA (1 equiv.)
DCM, r.t.
N
N
19-28 h
O
O
12b Ar = Ph
12c Ar = p-NO2C6H4
12d Ar = p-FC6H4
DNP
NO2
NH
NO2
N
N
TFA
Ph
O2N
Ph
r.t., 2 h
OH
O2N
Al2O3
CH2Cl2
(quant.)
Ar = Ph
DNP
N
24a 36%
N
N
N
O
O
N
Ph
22a
23
Ph
OCOCF3
24b 12%
Scheme 5. Reactivity of tetrahydrofuro[3,2-c]pyridazines 12b-d derived from furan in the presence of
TFA.
Open-chain hydrazones 25a-25c were also obtained in good to excellent yields when
furo-pyridazines 12f-h, derived from 2-methylfuran, were efficiently converted into the
corresponding open-chain hydrazones 25a-25c upon treatment with TFA (1 equiv.) at
room temperature, using dichloromethane as solvent (Scheme 6). However, using TFA
as solvent, complex mixtures were obtained.
Ar2
N
N
Ar1
O
12f-h
TFA
(1 equiv.)
DCM
r.t., 2-6 h
Ar2
NH
N
Ar1
O
25a Ar1 = Ph, Ar2 = o,p-(NO2)2C6H3
25b Ar1 = p-NO2C6H4, Ar2 = o,p-(NO2)2C6H3
25c Ar1 = p-FC6H4, Ar2 = o,p-(NO2)2C6H3
89 %
90%
52%
8
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
Scheme 6. Reactivity of tetrahydrofuro[3,2-c]pyridazines 12f-12h derived from 2-methylfuran in the
presence of TFA.
Mackay et al. reported the efficient TFA-catalysed isomerization of one 4a,6-dimethyl-
1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine derivative into the corresponding acetonyl-
dihydropyridazine by carrying out the reaction in refluxing bromobenzene .[3] However,
attempts to promote this type of isomerization starting from tetrahydrofuro[3,2-
c]pyridazines 12i-12l led only to complex mixtures.
Unexpectedly, using chloroform as solvent in the presence of HCl (2 M in Et2O) at
room temperature for 6 h, tetrahydrofuro[3,2-c]pyridazines 12j-12l were converted into
stereoisomeric hexahydrofuro[3,2-c]pyridazines 26 and 27 (Scheme 7). This result is in
contrast with the reactivity previously observed for tetrahydrofuro[3,2-c]pyridazines
which, under these reaction conditions, were converted into 6-(2-oxobutyl)-1,6-
dihydropyridazine derivatives (see Scheme 1) in a process having as its key step a furan
ring-opening reaction. In the case of pyridazine 12j the corresponding
hexahydrofuro[3,2-c]pyridazines were isolated in 78% overall yield. The synthesis of
these products can be explained considering the in situ generation of ethanol, resulting
from ethyl ether cleavage by hydrogen chloride via a SN2 pathway, which would trap
the protonated 2,3-dihydrofuran ring as described above for the synthesis of
hexahydrofuro[3,2-c]pyridazines 16. Interestingly, treatment of compounds 26 or 27
with TFA at room temperature, using toluene as solvent, led to the formation of the
corresponding starting bicyclic heterocycle 12 via an elimination reaction.
Ar2
N
Ar2
N
Ar2
N
H
H
HCl 2 M
in Et2O
N
N
OEt
N
OEt
+
CHCl3
r.t., 4 h
Ar1
O
Ar1
Ar1
O
O
12j-12l
26
27
26
27
a Ar1 = Ph, Ar2 = o,p-(NO2)2C6H3
b Ar1 = p-NO2C6H4; Ar2 = o,p-(NO2)2C6H3
c Ar1 = p-FC6H4); Ar2 = o,p-(NO2)2C6H3
53% 25%
13%
50%
7%
4%
Scheme 7. Reactivity of tetrahydrofuro[3,2-c]pyridazines 12j-12l derived from 2,5-dimethylfuran in
presence of HCl.
The structure of bicyclic heterocycle 26a was unambiguously established by X-ray
crystallography (Figure 1). The compound 26a crystallizes in the centrosymmetric,
9
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
monoclinic, space group P21/c. Each unit cell contains 4 independent molecules (2
enantiomeric pairs). The conformation of the pyradizine ring is close to a boat form, as
shown by the Cremer and Pople[14] puckering parameters Q= 0.587(3) Å,  =88.8(3)º,
=180.3(3)º calculated taking N1–N2 as the reference bond. The furan ring has a
twisted half-chair conformation with puckering parameters Q2 = 0.290(3) Å,
2=121.1(6)º, corresponding to pseudorotation parameters[15] P=109.9(3)º, M=32.6(2)º
for reference bond C(7)–C(7A). The phenyl and dinitrophenyl substituents are
equatorial to the pyridazine ring. The ethoxy group and one methyl group of the furan
ring are in axial positions, while the other methyl group is in bissectional position. The
dihedral angle between the least-squares planes of the furan and pyridazine rings is
75.1(2)º. Bond lengths and valence angles are within the expected range of values. No
classical hydrogen bonds are found in the crystal packing of the molecules. However,
two relatively short intramolecular interactions can be spotted C(8)–H(8A)...O(10)
[3.156(4) Å] and C(11) –H(11B)...O(5) [2.894(5) Å].
Figure 1. X-ray structure of compound 26a. Anisotropic displacement ellipsoids are drawn at the
50% probability level.
Hetero-Diels-Alder reaction of furans with nitrosoalkenes
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
The study of hetero-Diels-Alder reaction towards furan derivatives was extended
to nitrosoalkenes 29, generated by base-mediated dehydrohalogenation of
-
bromooximes 28 (Scheme 8). Starting from oximes 28a and 28b the expected
furo-oxazines 30 were obtained in 92% and 53% yield, respectively. However,
the reaction of 4-methoxyphenyl-oxime 28c with furan in the presence of sodium
carbonate gave cycloadduct 30c in only 7% yield. Clearly the efficiency of the
reaction of nitrosoalkenes 29 towards furan depends on the electron withdrawing
ability of aryl group and is the one expected for inverse electron demand Diels-
1
Alder reactions. However, the H and 13C NMR spectra of cycloadduct 30c
showed evidence of two isomeric 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines in
79:21 ratio, the bicyclic cis- and trans-fused systems. Thus, in this particular case
the results indicated that furo-oxazines 30c are formed via a conjugate addition of
furan to nitrosoalkene 29c, rather than a Diels-Alder reaction, followed by a
cyclization reaction. Evidence for the reaction of nitrosoalkenes to pyrrole and
dipyrromethanes via conjugate addition has been previously reported.[16]
2,2-Difuranylpropane (3) was prepared by a known synthetic procedure involving the
acid-catalyzed condensation of acetone with furan under solvent free conditions.[17] The
generation of nitrosoalkenes 29a and 29b in the presence of bis(furan-2-yl)methane (3)
afforded furan derivatives 30d and 30e in 81% and 41% yield, respectively. It was again
observed that nitrosoalkene 29a leads to the corresponding cycloadducts in higher
yields than the less activated nitrosoalkene 29b (Scheme 8).
11
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European Journal of Organic Chemistry
O
O
O
NOH
N
N
Na2CO3, r.t.
DCM
Br
23-41 h
Ar
O
Ar
Ar
30a-30c
29
28a Ar = p-NO2C6H4
28b Ar = p-FC6H4
28c Ar = p-MeOC6H4 44-46 h
O
O
3
O
N
O
Ar
O
30d Ar = p-NO2C6H4
30e Ar = p-FC6H4
Entry
1
Oxime
Product
30a 92%
30b 53%
28a
28b
28c
28a
28b
2
3
4
5
30c 7%
30d 81%
30e 41%
Scheme 8. Reaction of nitrosoalkenes with furan and 2,2-difuranylpropane leading to the synthesis of
4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines 30.
Dehydrohalogenation of -bromooximes 28a and 28b in the presence of 2-methylfuran
led to the generation of the expected cycloadducts 31 but these compounds underwent
ring-opening reactions leading to open-chain oximes 32, isolated in high yields (Scheme
9). The Diels-Alder reaction of oximes 28a and 28b was also explored using 2,5-
dimethylfuran as dienophile. In this case, cycloadducts 33 could be characterized by
NMR spectroscopy but proved to be very unstable. Nevertheless, they underwent a ring-
opening reaction to give the corresponding 6H-1,2-oxazines which were fully
characterized (see Scheme 15).
O
O
OH
N
N
Na2CO3, DCM
r.t., 45 h
O
O
Ar
Ar
31
32a Ar = p-NO2C6H4 91%
NOH
32b Ar = p-FC6H4 68%
Br
Ar
28a Ar = p-NO2C6H4
28b Ar = p-FC6H4
O
O
N
Na2CO3, DCM
r.t., 17.5-22 h
O
Ar
33a Ar = p-NO2C6H4 97%
33b Ar = p-FC6H4 46%
Scheme 9. Reaction of nitrosoalkenes with 2-methylfuran and 2,5-dimethylfuran leading to the synthesis
of open-chain oximes 32 and 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines 33, respectively.
12
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Reactivity of furo-oxazines
The treatment of furo-oxazines 30a-b with TFA led to isoxazoles 35, together with the
open-chain oximes 34 (Scheme 10). The structure of compound 35b was established
1
based on H NMR and two-dimensional spectra (COSY, NOESY, HSQC and HMBC).
1
In the H NMR spectrum vinylic protons H-7 and H-6 were observed at 6.18 and 6.41
ppm, respectively. On the other hand, protons of the methylene group (H-8) appear as a
multiplet at 4.70 ppm and at 1.75 ppm the proton of the hydroxyl group could be
1
observed. Recording the H NMR after the addition of D2O leads to the disappearance
of the latter signal confirming the assignment of the hydroxyl proton. Furthermore, the
multiplet corresponding to the methylene group becomes a double doublet. In the
NOESY spectrum, cross peaks were observed between the pyrazole ring proton (H-4)
and the protons of the methylene group (H-8) allowing to establish the cis configuration
of the double bond.
6
O
O
OH
i) TFA, r.t.
N
N
N
7
+
4
ii) Al2O3, DCM
O
O
Ar
Ar
8
HO
Ar
30a Ar = p-NO2C6H4
30b Ar = p-FC6H4
35
34
Reaction
conditions
Furo-oxazine
Isolated yield
30a
30b
i) 0.5 h; ii) 47 h
i) 1.5 h; ii) 29 h
34a 30% + 35a 21%
34b 34% + 35b 26%
Scheme 10. Reactivity of 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines 30a-b derived from furan in the
presence of TFA.
Isoxazoles 35 were obtained in better yields when the synthetic procedure was split into
two steps. First, 2-(2-aryl-2-hydroxyiminoethyl)furans 34 were obtained in good yields
from furo-oxazines 30a-b on reacting with TFA (1 equiv.) in dichloromethane.
Treatment of these oximes with TFA afforded isoxazolyl allylic alcohol 35 in good
yields (Scheme 11). A similar transformation, involving the generation of spirocyclic
intermediates, has been previously reported for 3-phenyl-4a,7a-dihydro-4H-furo[2,3-
e][1,2]oxazine.[4]
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
O
OH
TFA (1 equiv.)
N
N
DCM, r.t., 2-4 h
O
O
Ar
Ar
34a 98%
34b 83%
30a Ar = p-NO2C6H4
30b Ar = p-FC6H4
i) TFA, r.t., 3.5-4 h
O
N
O
ii) Al2O3, DCM
N
O
HO
Ar
Ar
35a Ar = p-NO2C6H4 60%
35b Ar = p-FC6H4
44%
Scheme 11. Synthesis of isoxazoles 35 from 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines.
The acid-catalyzed reaction of oximes 32 was also explored (Scheme 12). From the
reaction of oxime 32a with TFA, isoxazoles 36a and 37a were isolated in 60% and 15%
yield, respectively. Under similar reaction conditions oxime 32b led to isoxazoles 36b-
38b in moderate yields. It’s noteworthy that isoxazole 37b isomerizes in a TFA solution
to give isoxazole 38b. The configuration of the double bond was established based on
NMR data. Signals for vinylic protons H-6 and H-7 of compounds 37b and 38b showed
values for the coupling constants of 12.8 and 16.4 Hz, respectively, indicating that
compound 37b has cis configuration and compound 38b has trans configuration. On the
other hand, in the NOESY spectrum of compound 38b cross peaks were observed
between protons H-4 and H-7, which is in agreement with the assigned configuration.
OH
N
32a Ar = p-NO2C6H4
O
Ar
32b Ar = p-FC6H4
TFA, r.t.
(from 32a, 1.5 h)
(from 32b, 6 h)
O
O
6
6
O
O
O
N
N
N
7
8
9
7
4
4
8
O
Ar
Ar
Ar
9
38a ---
38b 22%
36a 60%
36b 36 %
37a 15%
37b 15%
TFA, r.t.
Scheme 12. Reactivity of 2-(2-aryl-2-hydroxyiminoethyl)furans 32 in the presence of TFA.
The synthesis of isoxazoles 36-38 can be explained as outlined in Scheme 13. The acid-
catalysed rearrangement of 2-(2-aryl-2-hydroxyiminoethyl)furans 32 leads to
spirocyclic intermediates 39, which can then follow two different pathways. It can
14
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
undergo furan ring-opening to afford allylic alcohol 40, followed by acid-catalysed
rearrangement into the corresponding ketone 36, a similar transformation to the one
described for the synthesis of pyrazole 18 (see Scheme 4). On the other hand,
spirocyclic intermediates 39 can also undergo ring-opening to give 5-(3-oxobut-1-enyl)-
4,5-dihydroisoxazole 43, followed by aromatization leading to isoxazole 38.
H
OH
OH
O
O
O
O
N
N
N
N
O
O
Ar
HO
Ar
Ar
Ar
32
39
H
41
36
40
H
O
O
O
N
N
Ar
42
43
Ar
O
O
N
Ar
O
O
O
N
N
O
Ar
Ar
38
37
Scheme 13. Mechanistic proposal for the synthesis of isoxazoles 36-38 from 2-(2-aryl-2-
hydroxyiminoethyl)furans 32.
When cycloadducts 30d-e were treated with TFA (1 equiv.) the corresponding open-
chain oximes 44 were obtained in high yield (Scheme 14). In the presence of a catalytic
amount of p-toluenesulfonic acid (PTSA), 4H-furo[2,3-e][1,2]oxazine 30d was also
converted into bis(furan-2-yl)methane 44a.
OH
O
N
TFA (1 equiv.)
N
DCM
r.t., 2.5-4 h
O
O
Ar
Ar
O
O
30d Ar = p-NO2C6H4
30e Ar = p-FC6H4
44a Ar = p-NO2C6H4 93%
44b Ar = p-FC6H4 84%
Scheme 14. Synthesis of functionalized 2,2-difuranylpropanes 44 from 4a,7a-dihydro-4H-furo[2,3-
e][1,2]oxazines 30.
Finally, furo-oxazines 33, derived from 2,5-dimethylfuran, were converted efficiently
into 6H-1,2-oxazines 45 in refluxing chloroform in the presence of a catalytic amount of
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PTSA (Scheme 15). Thus, bicyclic heterocyles 33 underwent an elimination reaction
followed by the consequent furan ring-opening reaction leading to 6H-1,2-oxazines 45.
O
CHCl3
Reflux, 19-22 h
O
N
N
O
O
PTSA (cat.)
R
R
33
45a R = p-NO2C6H4 54%
45b R = p-FC6H4 71%
Scheme 15. Reactivity of 4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazines 33 in the presence of PTSA.
CONCLUSION
Hetero-Diels–Alder reaction of furans with nitroso- and azoalkenes afforded 4a,7a-
dihydro-4H-furo[2,3-e][1,2]oxazines and 1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazines.
The chemical behaviour of these bicyclic heterocyclic compounds in the presence of
trifluoroacetic acid and p-toluenesulfonic acid was explored, affording a diversity of
heterocycles, namely, furans bearing side-chains incorporating oxime and hydrazone
groups, 1H-pyrazoles and isoxazoles functionalized with 3-oxobutyl and allylic alcohol
side-chains and 6H-1,2-oxazines. On the other hand, tetrahydrofuro[3,2-c]pyridazines
react with alcohols or water in the presence of TFA to give 6-substitued-
hexahydrofuro[3,2-c]pyridazines.
EXPERIMENTAL SECTION
General Information
1H and 13C NMR spectra were recorded on an instrument operating at 400 and 100
MHz, respectively. The solvent is deuteriochloroform except where indicated otherwise.
Chemical shifts are expressed in parts per million related to TMS, and coupling
constants (J) are in Hz. Infrared spectra (IR) were recorded on an ATR spectrometer.
High-resolution mass spectra (HMRS) were obtained on an electrospray (ESI) or
electronic impact (EI) TOF mass spectrometer. Melting points were determined in open
glass capillaries and are uncorrected. Elemental analyses were carried out on an
Elemental Vario Micro Cube analyser. Thin-layer chromatography (TLC) analyses were
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European Journal of Organic Chemistry
performed using precoated silica gel plates. Flash column chromatography was
performed with silica gel 60 as the stationary phase.
2,2'-(Propane-2,2-diyl)difuran
(3),[17]
(10b),[18]
1-(2-Bromo-1-phenylethylidene)-2-(2,4-
dinitrophenyl)hydrazone
1-(2,4-Dinitrophenyl)-3-phenyl-1,4,4a,7a-
tetrahydrofuro[3,2-c]pyridazine (12b)[19] and 1-(2,4-dinitrophenyl)-4a,6-dimethyl-3-
phenyl-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine 2-Bromo-1-(4-
(12j),[19]
nitrophenyl)ethanone oxime (28a),[20] 2-Bromo-1-(4-fluorophenyl)ethanone oxime
(28b),[21] 2-Bromo-1-(4-methoxyphenyl)ethanone oxime (28c),[20] were prepared as
described in the literature.
Ethyl 3-bromo-2-(2-phenylhydrazono)propanoate (10a): To a stirred solution of
ethyl bromopyruvate (2.33 mL, 18.52 mmol) in dry diethyl ether (50 mL),
phenylhydrazine (2 mL, 20.35 mmol) and four drops of glacial acetic acid were added.
The reaction mixture was stirred at room temperature for 4 h. The mixture was washed
with water, dried with anhydrous Na2SO4 and the solvent evaporated off. The crude
product was triturated with diethyl ether and filtered, giving compound 10a (1.99 g,
37%) as a beige solid. m.p. 95.6-96.2 ºC (from diethyl ether); ν̃
(ATR) 692, 756,
max
-1
1
1022, 1177, 1306, 1534, 1674 and 3193 cm ; H NMR: δ = 1.40 (t, J = 7.1 Hz, 3H),
4.35 (q, J = 7.1 Hz, 2H), 4.46 (s, 2H), 7.02-7.05 (m, 1H), 7.22-7.24 (m, 2H), 7.30-7.34
13
(m, 2H), 12.38 (s, 1H). C NMR: δ = 14.3, 33.0, 61.3, 76.8, 77.2, 77.5, 114.7, 123.4,
124.4, 129.5, 142.5, 163.0. HRMS (EI-TOF): calcd. for C11H13N2O2Br, 248.0160 [M+];
found, 248.0160.
General procedure for the synthesis of hydrazones 10c and 10d: To a solution of the
appropriate α-halogenated carbonyl compound (0.75 equiv.) in the minimum volume of
diethyl phosphite, a solution of 2,4-dinitrophenylhydrazine (25% H2O, 1 equiv.) in
diethyl phosphite (20 mL) was added. The reaction mixture was stirred at room
temperature for the time indicated in each case. The precipitate formed was filtered off
and washed with petroleum ether.
1-(2-bromo-1-(4-nitrophenyl)ethylidene)-2-(2,4-dinitrophenyl)hydrazone
(10c):
Obtained from the appropriate α-halogenated carbonyl compound (458 mg, 1.875
mmol) and 2,4-dinitrophenylhydrazine compound (495 mg, 2.5 mmol) following the
general procedure (reaction time: 1 h) giving compound 10c (700 mg, 88%) as a yellow
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solid. Decomposition at 183.5 ºC (from petroleum ether); ν̃
(ATR) 855, 1137, 1337,
max
-1
1
1490, 1591, 1613 and 3278 cm . H NMR: δ = 4.46 (s, 2H), 7.68 (s, 1H), 8.00 – 8.06
(m, 2H), 8.15 (d, J = 9.4 Hz, 1H), 8.31 – 8.37 (m, 1H), 8.47 (dd, J = 9.5 e 2.6 Hz, 1H),
9.21 (d, J = 2.6 Hz, 1H), 11.67 (s, 1H). 13C NMR: δ = 18.1, 117.2, 123.4, 124.4, 127.2,
130.5, 140.1, 140.8, 142.5, 144.2, 146.2, 148.8.
1-(2-Bromo-1-(4-fluorophenyl)ethylidene)-2-(2,4-dinitrophenyl)hydrazone (10d):
Obtained from the appropriate α-halogenated carbonyl compound (1.5 g, 0.692 mmol)
and 2,4-dinitrophenylhydrazine compound (1.823 g, 9.21 mmol) following the general
procedure (reaction time: 1 h) giving compound 10d (2.62 g, 95%) as an orange solid.
p.f. 200.2-200.7 ºC (from petroleum ether); ν̃
(ATR) 835, 1114, 1309, 1327, 1493,
max
-1
1
1590, 1612 and 3287 cm . H NMR: δ = 4.41 (s, 1H), 7.19 (t, J = 8.6 Hz, 1H), 7.86
(dd, J = 8.9 and 5.2 Hz, 1H), 8.11 (d, J = 9.5 Hz, 1H), 8.41 (dd, J = 9.4 and 2.5 Hz, 1H),
13
9.19 (d, J = 2.5 Hz, 1H), 11.55 (s, 1H). C NMR: δ = 18.6, 116.3 (d, J = 22 Hz, 1C),
117.1, 123.5, 128.5 (d, J = 8 Hz, 2C), 130.3, 130.9, 131.1, 139.4 (d, J = 2 Hz, 1C),
144.7, 148.1, 164.4 (d, J = 251 Hz, 1C). HRMS (ESI-TOF): calcd. for C14H11BrFN4O4,
396.99422 [M+ + H]; found, 396.99459.
General procedure for the hetero-Diels-Alder reactions of Azoalkenes:
Method A:
The appropriate α-bromohydrazone 10 (1 equiv.) was added stepwise to a suspension of
sodium carbonate (5 equiv.) and a furan derivative (10-100 equiv.) in dry
dichloromethane (30 mL). The reaction mixture was stirred at room temperature for the
time indicated in each case, monitored by TLC until complete and filtered through a
Celite pad, which was washed with dichloromethane. The solvent was evaporated and
the product was purified as indicated in each case.
Method B:
The appropriate α-bromohydrazone 10 (1 equiv.) was added stepwise to a suspension of
sodium carbonate (5 equiv.) and a furan derivative (15-17 equiv.) in dry
dichloromethane (30 mL). The reaction mixture was stirred at room temperate for the
time indicated in each case. The reaction was monitored by TLC until complete and
filtered through a Celite pad, which was washed with ethyl acetate. The solvent was
evaporated off and the product was purified as indicated in each case.
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Method C:
The appropriate α-bromohydrazone 10 (1 equiv.) was added stepwise to a suspension of
sodium carbonate (5 equiv.) and a furan derivative (40-80 equiv.). The reaction mixture
was stirred at room temperature for the time indicated in each case, and monitored by
TLC until complete. The reaction mixture was filtered through a Celite pad and washed
with dichloromethane. The solvent was evaporated off and the product was purified as
indicated in each case.
2-(2'-Ethoxycarbonyl-2'-phenylhydrazonoethyl)furan (13a) and Ethyl 1-phenyl-
1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine-3-carboxylate (12a): Obtained from
hydrazone 10a (151 mg, 0.53 mmol) and furan [Method A (3.85 mL, 53 mmol), Method
C (3.08 mL, 42.4 mmol)] as described in the general procedure A (reaction time: 18h)
and method C (reaction time: stepwise addition of hydrazone 10a during 2.5 h and then
stirring for an additional 16.5 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:2) gave by order of elution compound 13a
[Method A (9 mg, 6%)] as a yellow oil and compound 12a [Method A (104 mg, 72%),
Method C (123 mg, 87%)] as a beige solid.
Compound 12a: m.p. 95.2-96.1 ºC (from ethyl acetate/hexane); ν̃
(ATR) 748, 1119,
max
-1
1
1571, 1592, 1686 and 1690 cm . H NMR: δ = 1.38 (t, J = 7.1 Hz, 3H), 2.49 (dd, J =
16.5 and 4.7 Hz, 1H), 3.24 (dd, J = 16.5 and 3.1 Hz, 1H), 4.33 (qd, J = 7.1 and 1.6 Hz,
2H), 5.16 (d, J = 9.6 Hz, 1H), 5.20 (t, J = 2.1 Hz, 2H), 5.25 – 5.32 (m, 1H), 6.41 – 6.44
13
(m, 2H), 7.04 (t, J = 8.4 Hz, 1H), 7.32 – 7.37 (m, 5H). C NMR: δ = 14.4, 24.1, 59.7,
61.4, 79.1, 101.1, 116.2, 122.6, 129.2, 136.4, 145.9, 150.0, 164.6. HRMS (EI-TOF):
calcd. for C15H16N2O3, 272.1161 [M+]; found, 272.1160.
1
Compound 13a: H NMR: δ = 1.39 (t, J = 7.1 Hz, 3H), 4.03 (s, 2H), 4.33 (q, J = 7.1
Hz, 2H), 6.17 (d, J = 3.1 Hz, 1H), 6.29 – 6.34 (m, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.17 (d,
J = 7.6 Hz, 2H), 7.28 – 7.36 (m, 3H), 8.43 (s, 1H).
1-(2,4-Dinitrophenyl)-3-(4-nitrophenyl)-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine
(12c): Obtained from hydrazone 10c (250 mg, 0.589 mmol) and furan (4.28 mL, 58.9
mmol), as described in the general procedure A (stepwise addition of hydrazone 10c
during 6 h and then stirring for an additional 1.5 h). Diethyl ether was added to the
crude, and the yellow solid was filtered, giving compound 12c (176 mg, 73%). m.p.
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187.9-188.5 ºC (the compound changed colour to orange at 175 ºC) (from ethyl
-1
acetate/hexane); ν̃
(ATR) 854, 1064, 1141, 1150, 1252, 1328, 1508 and 1601 cm .
max
1H NMR: δ = 2.17 (d, J = 1.8 Hz, 1H), 2.66 (d, J = 15.9 Hz, 1H), 3.48 (d, J = 14.9 Hz,
1H), 5.19 (s, 1H), 5.44 (d, J = 10.0 Hz, 1H), 5.61 (d, J = 10.5 Hz, 1H), 6.53 (s, 1H),
7.35 (dd, J = 9.4 and 1.6 Hz, 1H), 7.78 – 7.84 (m, 2H), 8.27 (dd, J = 8.9 and 1.9 Hz,
13
2H), 8.39 (dt, J = 9.4 and 2.2 Hz, 1H), 8.61 (t, J = 2.3 Hz, 1H). C NMR: δ = 28.1,
31.1, 62.3, 80.9, 98.5, 116.6, 122.7, 124.2, 126.9, 127.2, 140.5, 141.2, 144.3, 148.9,
152.3, 157.0. HRMS (EI-TOF): calcd. for C18H13N5O7, 411.0815 [M+]; found,
411.0811.
1-(2,4-Dinitrophenyl)-3-(4-fluorophenyl)-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine
(12d): Obtained from hydrazone 10d (250 mg, 0.629 mmol) and furan (4.57 mL, 62.9
mmol), as described in the general procedure A (stepwise addition of hydrazone 10d
during 8 h and then stirring for an additional 40 h). Diethyl ether was added to the
crude, and the orange-yellow solid was filtered, giving compound 12d (196 mg, 81%).
m.p. 153.2-154.4 ºC (from diethyl ether); ν̃
(ATR) 842, 1142, 1226, 1322, 1492,
max
1497 and 1599 cm -1. 1H NMR: δ = 2.59 (ddd, J = 15.1, 3.7 and 1.1 Hz, 1H), 3.40 – 3.47
(m, 1H), 5.12 – 5.19 (m, 1H), 5.42 (dt, J = 10.3 and 1.6 Hz, 1H), 5.56 (dt, J = 10.2 and
3.2 Hz, 1H), 6.51 (dd, J = 2.6 and 1.3 Hz, 1H), 7.10 (t, J = 8.7 Hz, 2H), 7.28 (d, J = 9.3
Hz, 1H), 7.60 – 7.70 (m, 2H), 8.35 (dd, J = 9.3 and 2.6 Hz, 1H), 8.59 (d, J = 2.6 Hz,
1H). 13C NMR: δ = 28.5, 62.1, 80.9, 98.1, 115.9, 116.1 (d, J = 22 Hz, 2C), 122.8, 127.1,
128.3 (d, J = 9 Hz, 2C), 131.7 (d, J = 3 Hz, 1C), 139.6, 140.0, 144.7, 152.2, 159.6,
164.5 (d, J = 249 Hz, 1C). Anal. Calcd for C18H13FN4O5: C, 56.25; H, 3.41; N, 14.58.
Found: C, 55.93; H, 3.65; N, 14.63.
2-(2'-Ethoxycarbonyl-2'-phenylhydrazonoethyl)-5-methylfuran (13b) and Ethyl 6-
methyl-1-phenyl-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine-3-carboxylate
(12e):
Obtained from hydrazone 10a (200 mg, 0.706 mmol) as described in the general
procedure C (stepwise addition of hydrazone 10a during 8 h and then stirring for an
additional 16 h). Purification of the crude product by flash chromatography (ethyl
acetate/hexane, 1:3) gave by order of elution compound 13b (6 mg, 3%) as a yellow oil,
and compound 12e (110 mg, 54%) as a yellow solid.
Compound 12e: 1H NMR δ 1.38 (t, J = 7.1 Hz, 3H), 1.74 (t, J = 1.3 Hz, 3H), 2.47 (dd,
J = 16.6 and 4.7 Hz, 1H), 3.22 (dd, J = 16.6 and 3.2 Hz, 1H), 4.33 (qd, J = 7.1 and 2.9
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European Journal of Organic Chemistry
Hz, 2H), 4.91 (s, 1H), 5.09 (d, J = 9.3 Hz, 1H), 5.29 (ddd, J = 9.4, 4.9 and 3.1 Hz, 1H),
7.02 (ddt, J = 6.4, 4.9 and 2.4 Hz, 1H), 7.34 (d, J = 4.7 Hz, 4H). This cycloadduct
underwent ring-opening reaction to give the corresponding open-chain hydrazone 13b,
which was fully characterized.
-1
Compound 13b: ν̃
(cm ) (ATR) 747, 790, 1019, 1092, 1166, 1234, 1369, 1495,
max
1546, 1699, 3282; 1H NMR δ 1.39 (t, J = 7.1 Hz, 3H), 2.25 (d, J = 1.0 Hz, 3H), 3.97 (s,
2H), 4.33 (q, J = 7.1 Hz, 2H), 5.87 (dd, J = 3.1 and 1.2 Hz, 1H), 6.03 (d, J = 3.1 Hz,
1H), 6.97 (tt, J = 7.3 and 1.2 Hz, 1H), 7.14 – 7.19 (m, 2H), 7.30 (dd, J = 8.5 e 7.3 Hz,
2H), 8.55 (s, 1H); 13C NMR δ 13.65, 14.48, 24.58, 61.53, 106.67, 108.08, 114.17,
122.34, 129.47, 131.83, 143.40, 147.11, 151.72, 165.04. HRMS (EI-TOF): calcd. for
C16H18N2O3, 286.1317 [M+]; found, 286.1319.
1-(2,4-Dinitrophenyl)-6-methyl-3-phenyl-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine
(12f): Obtained from hydrazone 10b (250 mg, 0.659 mmol) and 2-methylfuran [Method
A (0.99 mL, 11.20 mmol), Method C (2.33 mL, 26.36 mmol)] as described in the
general procedure A (reaction time: 26 h stepwise addition and then 6 h) and method B
(stepwise addition of hydrazone 10b during 26 h and then stirring for an additional 5
h). Diethyl ether was added to the crude product, and the yellow solid was filtered,
giving compound 12f [Method A (158 mg, 63%), Method C (233 mg, 93%)] as a
yellow solid. m.p. 172.2-173.9 ºC (the compound changed colour to orange at 172.2 ºC)
(from diethyl ether); ν̃
(ATR) 740, 933, 1144, 1266, 1320, 1500, 1529, 1602 and
max
-1
1669 cm . 1H NMR: δ = 1.72 (t, J = 1.3 Hz, 3H), 2.57 (dd, J = 15.1 and 3.7 Hz, 1H),
3.45 (dd, J = 15.1 and 2.8 Hz, 1H), 4.83 (s, 1H), 5.34 – 5.40 (m, 1H), 5.56 (d, J = 10.0
Hz, 1H), 7.25 (d, J = 10.5 Hz, 1H), 7.43 (dd, J = 5.0 and 1.9 Hz, 3H), 7.62 – 7.69 (m,
13
2H), 8.33 (dd, J = 9.3 and 2.6 Hz, 1H), 8.59 (d, J = 2.7 Hz, 1H). C NMR: δ = 13.7,
28.9, 63.5, 81.1, 93.6, 115.9, 122.9, 126.3, 127.0, 129.0, 130.6, 135.8, 139.3, 139.9,
144.9, 160.6, 162.5. HRMS (EI-TOF): calcd. for C19H16N4O5, 380.1121 [M+]; found,
380.1123. HRMS (EI-TOF): calcd. for C19H16N4O5, 380.1121 [M+]; found, 380.1123.
1-(2,4-Dinitrophenyl)-3-(4-nitrophenyl)-6-methyl-1,4,4a,7a-tetrahydrofuro[3,2-
c]pyridazine (12g): Obtained from hydrazone 10c (250 mg, 0.589 mmol) and 2-
methylfuran (0.89 mL, 10.01 mmol), as described in the general procedure B (stepwise
addition of hydrazone 10c during 7 h and then stirring for an additional 17 h). Diethyl
ether was added to the crude, and the orange-yellow solid was filtered, giving
21
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
compound 12g (228 mg, 91%). m.p. 129.2 ºC (decomposition, from diethyl ether); ν̃
max
-1
1
(ATR) 741, 1140, 1309, 1330, 1491, 1510 and 1593 cm . H NMR: δ = 1.74 (s, 3H),
2.63 (dd, J = 15.3 and 3.8 Hz, 1H), 3.45 (dd, J = 15.0 and 2.7 Hz, 1H), 4.87 (s, 1H),
5.36 (dt, J = 10.1 and 1.6 Hz, 1H), 5.59 (dt, J = 10.0 and 3.2 Hz, 1H), 7.30 (d, J = 9.3
Hz, 1H), 7.76 – 7.83 (m, 2H), 8.24 – 8.31 (m, 2H), 8.36 (dd, J = 9.3 and 2.6 Hz, 1H),
8.58 (d, J = 2.6 Hz, 1H). 13C NMR: δ = 28.4, 31.1, 63.5, 80.9, 94.0, 116.4, 122.7, 124.2,
126.9, 127.1, 140.1, 140.3, 141.5, 144.3, 148.8, 156.7, 162.6. HRMS (EI-TOF): calcd.
for C19H15N5O7, 425.0971 [M+]; found, 425.0988.
1-(2,4-Dinitrophenyl)-3-(4-fluorophenyl)-6-methyl-1,4,4a,7a-tetrahydrofuro[3,2-
c]pyridazine (12h): Obtained from hydrazone 10d (375 mg, 0.944 mmol) and 2-
methylfuran (1.42 mL 16.05 mmol), as described in the general procedure A (stepwise
addition of hydrazone 10d during 8 h and then stirring for an additional 17 h). Diethyl
ether was added to the crude product, and the yellow solid was filtered, giving
compound 12h (305 mg, 61%). m.p. 156.3-157.2 ºC (from ethyl acetate/hexane); ν̃
max
-1
(ATR) 734, 1036, 1227, 1311, 1337, 1493, 1509, 1587, 1600 and 1672 cm . 1H NMR:
δ = 1.73 (s, 3H), 2.56 (dd, J = 15.1 and 3.6 Hz, 1H), 3.41 (dd, J = 15.1 and 2.8 Hz, 1H),
4.84 (s, 1H), 5.36 (dt, J = 10.0 and 1.7 Hz, 1H), 5.55 (dt, J = 10.0 and 3.2 Hz, 1H), 7.06
– 7.15 (m, 2H), 7.24 (d, J = 9.4 Hz, 1H), 7.60 – 7.69 (m, 2H), 8.33 (dd, J = 9.3 and 2.6
13
Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H). C NMR: δ = 13.7, 28.9, 63.4, 81.0, 93.7, 115.8,
116.1 (d, J = 22 Hz, 2C), 122.9, 127.0, 128.3 (d, J = 9 Hz, 2C), 132.0 (d, J = 3 Hz, 1C),
139.4, 139.9, 144.7, 159.5, 162.5, 164.4 (d, J = 250 Hz, 1C). Anal. Calcd for
C19H15FN4O5: C, 57.29; H, 3.80; N, 14.06. Found: C, 57.30; H, 3.83; N, 14.00.
Ethyl
4a,6-dimethyl-1-phenyl-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazine-3-
carboxylate (12i): Obtained from hydrazone 10a (200 mg, 0.706 mmol) and 2,5-
dimethylfuran (1.13 mL, 10.59 mmol), as described in the general procedure A (reaction
time: 9.5 h stepwise addition and then 14.5 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 12i (177 mg, 84%) as a
beige solid. m.p. 110.1-110.9 ºC (from ethyl acetate/hexane); ν̃
(ATR) 759, 1153,
max
-1
1232, 1492, 1574, 1590 and 1689 cm . 1H NMR: δ = 1.38 (t, J = 7.1 Hz, 3H), 1.58 (s,
3H), 1.71 (t, J = 1.3 Hz, 3H), 2.20 (d, J = 15.9 Hz, 1H), 3.28 (dd, J = 15.9 and 0.8 Hz,
1H), 4.33 (qd, J = 7.1 and 5.0 Hz, 2H), 4.73 (qt, J = 1.5 Hz, 1H), 4.81 (dt, J = 2.2 and
13
1.1 Hz, 1H), 6.99 – 7.04 (m, 1H), 7.32 – 7.35 (m, 4H); C NMR: δ = 27.0, 31.0, 61.4,
22
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European Journal of Organic Chemistry
67.4, 86.6, 96.0, 116.1, 122.3, 129.2, 138.0, 146.1, 159.2, 164.6. HRMS (EI-TOF):
calcd. for C17H20N2O3, 300.1474 [M+]; found, 300.1479.
1-(2,4-Dinitrophenyl)-3-(4-nitrophenyl)-4a,6-dimethyl-1,4,4a,7a-tetrahydrofuro
[3,2-c]pyridazine (12k): Obtained from hydrazone 10c (250 mg, 0.589 mmol) and 2,5-
dimethylfuran (0.94 mL, 8.84 mmol), as described in the general procedure B (stepwise
addition of hydrazone 10c during 7 h and then stirring for an additional 17 h). Cold
ethyl acetate was added to the crude product, and the yellow solid was filtered, giving
compound 12k (153 mg, 59%). m.p. 221.8-222.6 ºC (the compound changed colour to
brown at 220 ºC) (from ethyl acetate); ν̃
(ATR) 741, 1313, 1326, 1491, 1501, 1588,
max
-1
1
1664 and 1735 cm . H NMR: δ = 1.70 (t, J = 1.2 Hz, 3H), 1.72 (s, 3H), 2.45 (d, J =
14.8 Hz, 1H), 3.40 (d, J = 14.7 Hz, 1H), 4.79 (s, 1H), 4.94 (s, 1H), 7.31 (d, J = 9.4 Hz,
1H), 7.75 – 7.83 (m, 2H), 8.27 (d, J = 8.9 Hz, 2H), 8.36 (dd, J = 9.3 and 2.6 Hz, 1H),
13
8.60 (d, J = 2.6 Hz, 1H). C NMR: δ = 13.9, 26.5, 31.1, 34.8, 69.8, 89.0, 93.3, 116.5,
122.7, 124.2, 127.0, 127.1, 140.1, 140.4, 141.3, 144.5, 148.8, 158.3, 161.8. Anal. Calcd
for C20H17N5O7: C, 54.67; H, 3.90; N, 15.94. Found: C, 54.27; H, 3.83; N, 15.92.
1-(2,4-Dinitrophenyl)-3-(4-fluorophenyl)-4a,6-dimethyl-1,4,4a,7a-tetrahydrofuro
[3,2-c]pyridazine (12l): Obtained from hydrazone 10d (500 mg, 1.258 mmol) and 2,5-
dimethylfuran (2.01 mL, 18.87 mmol), as described in the general procedure A
(stepwise addition of hydrazone 10d during 6 h and then stirring for an additional 17
h). Diethyl ether was added to the crude, and the orange-yellow solid was filtered,
giving compound 12l (485 mg, 94%). m.p. 192.2-192.6 ºC (from ethyl acetate/hexane);
-1
1
ν̃
max
(ATR) 739, 1066, 1141, 1316, 1491, 1510, 1589 and 1599 cm . H NMR: δ =
1.69 (d, J = 1.5 Hz, 6H), 2.40 (d, J = 14.6 Hz, 1H), 3.35 (d, J = 14.6 Hz, 1H), 4.76 (s,
1H), 4.92 (s, 1H), 7.10 (t, J = 8.7 Hz, 2H), 7.25 (d, J = 10.0 Hz, 1H), 7.60 – 7.68 (m,
13
2H), 8.32 (dd, J = 9.3 and 2.6 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H). C NMR: δ = 13.8,
26.3, 35.1, 69.4, 88.8, 92.8, 115.8, 115.9 (d, J = 22 Hz, 2C), 122.7, 126.9, 128.2 (d, J =
8 Hz, 2C), 131.6, 139.2, 139.8, 144.7, 160.6, 161.6, 163.5 (d, J = 395 Hz, 1C); Anal.
Calcd for C20H17FN4O5: C, 58.25; H, 4.16; N, 13.59. Found: C, 58.22; H, 4.06; N,
13.53.
General procedure for the synthesis of open-chain hydrazones: To a stirred solution
of the appropriate tetrahydropyridazine 12 in dry dichloromethane (20 mL) two drops of
trifluoroacetic acid were added. The reaction mixture was stirred at room temperature
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
for the time indicated in each case, and monitored by TLC until complete. The solvent
was evaporated off, and the crude product was purified by flash chromatography.
2-(2'-Phenyl-2'-(2,4-dinitrophenyl)hydrazonoethyl)furan (22a): Obtained from
tetrahydropyridazine 12b (100 mg, 0.273 mmol) as described in the general procedure
(reaction time: 28 h). Purification of the crude product by flash chromatography (ethyl
acetate/hexane, 1:3) gave compound 22a (48 mg, 48%) as an orange solid. m.p. 179.1
ºC (decomposition, from diethyl ether); ν̃
(ATR) 737, 1106, 1337, 1508, 1584, 1614
max
and 3303 cm -1. 1H NMR: δ = 4.25 (s, 2H), 6.33 (d, J = 1.4 Hz, 2H), 7.38 (d, J = 1.5 Hz,
1H), 7.45 – 7.53 (m, 3H), 7.92 – 7.99 (m, 2H), 8.14 (d, J = 9.5 Hz, 1H), 8.36 (ddd, J =
13
9.6, 2.6 and 0.7 Hz, 1H), 9.15 (d, J = 2.6 Hz, 1H), 11.58 (s, 1H). C NMR: δ = 27.7,
108.4, 110.8, 117.1, 123.5, 127.0, 129.0, 130.1, 130.4, 136.9, 138.6, 142.9, 145.2,
147.0, 151.4. HRMS (EI-TOF): calcd. for C18H14N4O5, 366.0964 [M+]; found,
366.0963.
2-(2'-p-Nitrophenyl-2'-(2,4-dinitrophenyl)hydrazonoethyl)furan (22b): Obtained
from tetrahydropyridazine 12c (150 mg, 0.365 mmol) as described in the general
procedure (reaction time: 96 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 22b (21 mg, 14%) as an
orange solid. m.p. 180.9 ºC (decomposition, from ethyl acetate/hexane); ν̃
(ATR)
max
-1
1
741, 1110, 1311, 1333, 1507, 1592, 1608, 3081 and 3280 cm . H NMR: δ = 4.27 (s,
2H), 6.36 (d, J = 1.9 Hz, 1H), 6.39 (s, 1H), 7.38 (d, J = 1.2 Hz, 1H), 8.13 (t, J = 9.7 Hz,
3H), 8.30-8.35 (m, 2H), 8.42 (dd, J = 9.5 and 2.5 Hz, 1H), 9.17 (d, J = 2.6 Hz, 1H). 13C
NMR: δ = 27.5, 108.9, 111.0, 117.1, 123.5, 124.2, 127.7, 130.4, 143.3, 144.8, 146.1,
148.5, 148.6. HRMS (EI-TOF): calcd. for C18H13N5O7, 411.0815 [M+]; found,
411.0810.
2-(2'-p-Fluorophenyl-2'-(2,4-dinitrophenyl)hydrazonoethyl)furan (22c): Obtained
from tetrahydropyridazine 12d (100 mg, 0.260 mmol) as described in the general
procedure (reaction time: 19 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 22c (57 mg, 57%) as an
orange solid. m.p. 169.7-170.6 ºC (from ethyl acetate/hexane); ν̃
(ATR) 742, 1107,
max
-1
1
1232, 1306, 1498, 1587, 1612 and 3311 cm . H NMR: δ = 4.23 (s, 2H), 6.34 (d, J =
1.4 Hz, 2H), 7.16 (dd, J = 9.5 and 7.7 Hz, 2H), 7.38 (t, J = 1.4 Hz, 1H), 7.91 – 7.97 (m,
24
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European Journal of Organic Chemistry
2H), 8.11 (d, J = 9.6 Hz, 1H), 8.37 (dd, J = 9.5 and 2.6 Hz, 1H), 9.16 (d, J = 2.6 Hz,
13
1H), 11.56 (s, 1H). C NMR: δ = 27.7, 108.5, 110.9, 116.0 (d, J = 22 Hz, 2C), 117.0,
123.6, 129.0 (d, J = 8 Hz, 2C), 130.2, 133.1 (d, J = 4 Hz, 1C), 138.7, 143.0, 145.2,
146.8, 150.3, 164.2 (d, J = 250 Hz, 1C). HRMS (EI-TOF): calcd. for C18H13N4O5F,
384.0870 [M+]; found, 384.0873.
(E)-Ethyl
3-(5-methylfuran-2-yl)-2-(2-phenylhydrazono)propanoate
(13b):
Obtained from tetrahydropyridazine 12e (100 mg, 0.349 mmol) as described in the
general procedure (reaction time: 6 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 13b (67 mg, 67%) as a
yellow oil. See characterization data above.
2-(2'-Phenyl-2'-(2,4-dinitrophenyl)hydrazonoethyl)-5-methylfuran (25a): Obtained
from tetrahydropyridazine 12f (200 mg, 0.470 mmol) as described in the general
procedure (reaction time: 4 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 25a (178 mg, 89%) as an
orange solid. m.p. 191.7-192.9 ºC (from ethyl acetate/hexane); ν̃
(ATR) 741, 834,
max
-1
1
1109, 1314, 1331, 1513, 1594, 1614, 3105 and 3292 cm . H NMR: δ = 2.25 (s, 2H),
4.19 (s, 2H), 5.89 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 3.0 Hz, 1H), 7.45-7.50 (m, 3H), 7.95
(dd, J = 6.5 and 3.3 Hz, 2H), 8.14 (d, J = 9.6 Hz, 1H), 8.36 (d, J = 9.5 and 2.5 Hz, 1H),
13
9.16 (d, J = 2.6 Hz, 1H). C NMR: δ = 13.7, 27.9, 106.6, 109.1, 117.1, 123.6, 127.0,
128.9, 130.1, 130.2, 130.3, 137.0, 138.5, 145.0, 145.3, 152.0, 152.8. HRMS (EI-TOF):
calcd. for C19H16N4O5, 380.1121 [M+]; found, 380.1127.
2-(2'-p-Nitrophenyl-2'-(2,4-dinitrophenyl)hydrazonoethyl)-5-methylfuran
(25b):
Obtained from tetrahydropyridazine 12g (100 mg, 0.235 mmol) as described in the
general procedure (reaction time: 2 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 25b (90 mg, 90%) as an
orange solid. m.p. 214.5 ºC (decomposition, from diethyl ether); ν̃
(ATR) 743, 808,
max
-1
1
1108, 1312, 1332, 1503, 1591, 1607, 3087 and 3286 cm . H NMR: δ = 2.24 (s, 3H),
4.21 (s, 2H), 5.92 (d, J = 2.2 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 8.12 (t, J = 9.1 Hz, 3H),
8.32 (d, J = 8.9 Hz, 2H), 8.42 (dd, J = 9.5 and 2.4 Hz, 1H), 9.17 (d, J = 2.5 Hz, 1H),
11.68 (s, 1H). 13C NMR: δ = 13.7, 27.8, 106.8, 109.6, 117.1, 123.5, 124.1, 127.7, 130.3,
25
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European Journal of Organic Chemistry
130.8, 134.4, 139.3, 142.9, 144.1, 144.8, 148.6, 149.0. HRMS (EI-TOF): calcd. for
C19H15N5O7, 425.0971 [M+]; found, 425.0977.
2-(2'-p-Fluorophenyl-2'-(2,4-dinitrophenyl)hydrazonoethyl)-5-methylfuran (25c):
Obtained from tetrahydropyridazine 12h (75 mg, 0.188 mmol) as described in the
general procedure (reaction time: 2 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave compound 25c (39 mg, 52%) as an
orange solid. m.p. 167.9-169.2 ºC (from ethyl acetate/hexane); ν̃
(ATR) 792, 831,
max
-1
1
1101, 1311, 1332, 1499, 1590, 1615, 3110 and 3288 cm . H NMR: δ = 2.25 (s, 3H),
4.16 (s, 2H), 5.90 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 3.0 Hz, 1H), 7.16 (dd, J = 11.9 and
5.3 Hz, 2H), 7.91-7.98 (m, 2H), 8.10 (d, J = 9.6 Hz, 1H), 8.36 (dd, J = 9.5 and 2.4 Hz,
13
1H), 9.16 (d, J = 2.6 Hz, 1H), 11.58 (s, 1H). C NMR: δ = 13.7, 27.9, 106.6, 109.2,
116.0 (d, J = 22 Hz, 2C), 117.0, 123.6, 129.0 (d, J = 8 Hz, 2C), 130.1, 130.2, 133.2 (d, J
= 3 Hz, 1C), 138.6, 144.8, 145.2, 150.9, 152.9, 164.2 (d, J = 250 Hz, 1C). HRMS (EI-
TOF): calcd. for C19H15N4O5F, 398.1026 [M+]; found, 398.1022.
(4aS,6R,7aS)-
and
(4aR,6S,7aR)-Ethyl
6-hydroxy-1-phenyl-1,4,4a,6,7,7a-
hexahydrofuro[3,2-c]pyridazine-3-carboxylate (15): To a stirred solution of
tetrahydropyridazine 12a (150 mg, 0.550 mmol) in dry dichloromethane (15 mL) two
drops of trifluoroacetic acid were added. The reaction mixture was stirred at room
temperature for 5 h, and monitored by TLC until complete. The solvent was evaporated
off and the crude product purified by flash chromatography (ethyl acetate/hexane, 1:3)
giving compound 15 (32 mg, 20%) as a yellow solid. m.p. 192.5 – 193.8 ºC (from ethyl
acetate/hexane); ν̃
(ATR) 691, 743, 977, 1126, 1180, 1256, 1490, 1577, 1593, 1693
max
1
and 2984 cm -1. H NMR: δ = 1.37 (t, J = 7.1 Hz, 3H), 2.19 (dt, J = 13.9 e 5.4 Hz, 1H),
2.46 (ddd, J = 13.9, 6.6 e 1.6 Hz, 1H), 2.62 (dd, J = 17.5 e 4.7 Hz, 1H), 2.77 (dd, J =
17.5 e 4.3 Hz, 1H), 4.31 (qd, J = 7.1 e 1.5 Hz, 2H), 4.52 (q, J = 5.9 Hz, 1H), 4.64 (q, J =
4.7 Hz, 1H), 5.45 (d, J = 4.1 Hz, 1H), 7.04 (qt, J = 4.2 Hz, 1H), 7.35 (d, J = 4.2 Hz,
13
4H). C NMR: δ = 14.5, 24.3, 39.9, 54.6, 61.3, 72.0, 99.0, 116.4, 122.6, 129.2, 132.3,
145.2, 164.9. HRMS (EI-TOF): calcd. for C15H18N2O4, 290.1267 [M+]; found,
290.1264.
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European Journal of Organic Chemistry
(4aS,6R,7aS)-
hexahydrofuro[3,2-c]pyridazine-3-carboxylate (16a) and (4aS,6S,7aS)- and
(4aR,6R,7aR)-ethyl 6-methoxy-1-phenyl-1,4,4a,6,7,7a-hexahydrofuro[3,2-
and
(4aR,6S,7aR)-ethyl
6-methoxy-1-phenyl-1,4,4a,6,7,7a-
c]pyridazine-3-carboxylate (16b): To a stirred solution of tetrahydropyridazine 12a
(76 mg, 0.279 mmol) in methanol (8 mL) two drops of trifluoroacetic acid were added.
The reaction mixture was stirred at room temperature for 43 h, the solvent was
evaporated and the crude product was purified by flash chromatography (ethyl
acetate/hexane, 1:3) giving by order of elution compound 16a (11 mg, 13%) as a brown
oil, and compound 16b (11 mg, 13%) as a brown oil.
Compound 16a: ν̃
(ATR) 691, 749, 1031, 1167, 1252, 1492, 1574, 1697 and 2907
max
cm -1. 1H NMR: δ = 1.37 (t, J = 7.1 Hz, 3H), 2.13 (dt, J = 14.0 e 5.3 Hz, 1H), 2.43 (ddd,
J = 14.0, 6.7 e 1.8 Hz, 1H), 2.63 (dd, J = 17.5 e 4.3 Hz, 1H), 2.82 (dd, J = 17.5 e 4.3 Hz,
1H), 3.36 (s, 3H), 4.31 (qd, J = 7.1 e 1.1 Hz, 2H), 4.51 (d, J = 6.2 Hz, 1H), 4.63 – 4.70
(m, 1H), 5.01 (dd, J = 5.4 e 1.6 Hz, 1H), 7.03 (tt, J = 5.3 e 3.0 Hz, 1H), 7.30 – 7.37 (m,
13
4H). C NMR: δ = 14.5, 24.3, 40.1, 54.6, 55.3, 61.3, 71.6, 103.9, 116.3, 122.5, 129.2,
132.3, 145.2, 165.0. HRMS (EI-TOF): calcd. for C16H20N2O4, 304.1423 [M+]; found,
304.1434.
Compound 16b: ν̃
(ATR) 691, 748, 1032, 1170, 1251, 1492, 1571, 1692 and 2917
max
cm -1. 1H NMR: δ = 1.38 (t, J = 7.1 Hz, 3H), 1.90 (ddd, J = 14.1, 7.2 e 3.8 Hz, 1H), 2.69
– 2.83 (m, 2H), 3.00 (ddd, J = 17.8, 6.1 e 1.6 Hz, 1H), 3.37 (s, 23), 4.30 – 4.42 (m, 4H),
5.10 (dd, J = 6.0 e 3.8 Hz, 1H), 7.03 (ddt, J = 6.4, 4.5 e 1.9 Hz, 1H), 7.31 – 7.39 (m,
13
4H). C NMR: δ = 14.5, 25.9, 37.8, 54.6, 55.7, 61.2, 70.4, 104.5, 115.6, 122.5, 129.3,
131.7, 145.8, 165.0. HRMS (EI-TOF): calcd. for C16H20N2O4, 304.1423 [M+]; found,
304.1424.
(E)-Ethyl 5-(3-hydroxybut-1-en-1-yl)-1-phenyl-1H-pyrazole-3-carboxylate (17) and
Ethyl 5-(3-oxobutyl)-1-phenyl-1H-pyrazole-3-carboxylate (18): A solution of
tetrahydropyridazine 12e (104 mg, 0.363 mmol) in trifluoroacetic acid (10 mL) was
stirred at room temperature for 15 min, and monitored by TLC until complete. The
solvent was evaporated off, the crude product was dissolved in dichloromethane (10
mL) and a catalytic amount of alumina was added. The reaction mixture was stirred for
6 h, the alumina filtered and washed with ethyl acetate. The crude product was purified
by flash chromatography (ethyl acetate/hexane, 1:3) giving a mixture of compounds 17
and 18 [25 mg, 24% (50:50)].
27
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
1
Compound 17: H NMR δ 1.36 (s, 3H), 1.37 – 1.43 (m, 3H), 4.41 (dq, J = 12.9 e 7.2
Hz, 2H), 4.81 – 4.94 (m, 1H), 5.80 (dd, J = 11.7 e 8.8 Hz, 1H), 6.10 (d, J = 11.7 Hz,
1H), 6.94 (s, 1H), 7.40 – 7.50 (m, 5H).
Compound 18: 1H NMR δ 1.37 – 1.43 (m, 3H), 2.13 (s, 3H), 2.74 (dd, J = 8.0 e 6.6 Hz,
2H), 2.88 (t, J = 7.3 Hz, 2H), 4.41 (dq, J = 12.9 e 7.2 Hz, 2H), 6.70 (s, 1H), 7.40 – 7.50
(m, 5H).
General procedure for the reactivity of tetrahydrofuropyridazines with HCl 2M in
Et2O: To a stirred solution of the appropriate tetrahydropyridazine 12 (1 equiv.) in
chloroform (20 mL) hydrochloric acid (2 M in Et2O; 2 equiv.) was added. The reaction
mixture was stirred at room temperature for the time indicated in each case, and
monitored by TLC until complete. The solvent was evaporated off and the crude
product purified by flash chromatography.
(4aS,6S,7aS)- and (4aR,6R,7aR)-1-(2,4-Dinitrophenyl)-6-ethoxy-4a,6-dimethyl-3-
phenyl-1,4,4a,6,7,7a-hexahydrofuro[3,2-c]pyridazine (26a) and (4aS,6R,7aS)- and
(4aR,6S,7aR)-1-(2,4-Dinitrophenyl)-6-ethoxy-4a,6-dimethyl-3-phenyl-1,4,4a,6,7,7a-
hexahydrofuro[3,2-c]pyridazine (27a):
Obtained from tetrahydropyridazine 12j (200 mg, 0.507 mmol) as described in the
general procedure (reaction time: 4 h). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:3) gave by order of elution compound 26a
(118 mg, 53%) as a yellow solid, and compound 27a (57 mg, 25%) as an orange solid.
Compound 26a: m.p. 166.4 – 168.2 ºC (from ethyl acetate/hexane); ν̃
(ATR) 768,
max
-1
1
1060, 1097, 1336, 1509, 1604 and 2974 cm . H NMR: δ = 1.20 (t, J = 7.1 Hz, 3H),
1.36 (s, 3H), 1.62 (s, 3H), 1.92 (dd, J = 13.2 and 8.4 Hz, 1H), 2.47 (d, J = 15.5 Hz, 1H),
2.74 (dd, J = 13.2 and 7.6 Hz, 1H), 3.02 (d, J = 15.5 Hz, 1H), 3.46 – 3.55 (m, 1H), 3.59
– 3.67 (m, 1H), 4.62 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 7.39 – 7.45 (m , 3H),
13
7.63 – 7.66 (m, 2H), 8.32 (dd, J = 9.3 and 2.6 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H). C
NMR: δ = 15.7, 22.5, 28.5, 36.8, 44.5, 56.7, 64.3, 84.0, 107.2, 116.4, 122.7, 126.2,
127.0, 128.9, 130.5, 135.6, 139.6, 140.3, 145.4, 159.3. HRMS (EI-TOF): calcd. for
C22H24N4O6, 440.1696 [M+]; found, 440.1693.
Compound 27a: m.p. 187.5 – 188.2 ºC (from ethyl acetate/hexane); ν̃
(ATR) 766,
max
-1
1
1040, 1268, 1317, 1501, 1592 and 2970 cm . H NMR: δ = 1.08 (t, J = 7.0 Hz, 3H),
1.55 (d, J = 1.6 Hz, 6H), 2.25 (dd, J = 13.7 and 8.6 Hz, 1H), 2.60 – 2.72 (m, 2H), 3.36
28
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10.1002/ejoc.201700453
European Journal of Organic Chemistry
(d, J = 17.4 Hz, 1H), 3.44 – 3.53 (m, 1H), 3.57 – 3.64 (m, 1H), 4.10 (t, J = 8.3 Hz, 1H),
7.15 (d, J = 9.3 Hz, 1H), 7.38 – 7.43 (m, 3H), 7.61 – 7.67 (m, 2H), 8.29 – 8.34 (m, 1H),
13
8.55 (d, J = 2.6 Hz, 1H). C NMR: δ = 15.6, 25.4, 27.2, 33.6, 43.6, 57.5, 61.9, 78.1,
106.7, 116.3, 122.7, 125.7, 127.0, 128.8, 130.0, 136.1, 139.5, 139.9, 144.6, 150.0.
HRMS (EI-TOF): calcd. for C22H24N4O6, 440.1696 [M+]; found, 440.1698.
(4aS,6S,7aS)- and (4aR,6R,7aR)-1-(2,4-Dinitrophenyl)-6-ethoxy-3-(4-nitrophenyl)-
4a,6-dimethyl-1,4,4a,6,7,7a-hexahydrofuro[3,2-c]pyridazine
(26b)
and
(4aS,6R,7aS)- and (4aR,6S,7aR)-1-(2,4-Dinitrophenyl)-6-ethoxy-3-(4-nitrophenyl)-
4a,6-dimethyl-1,4,4a,6,7,7a-hexahydrofuro[3,2-c]pyridazine (27b): Obtained from
tetrahydropyridazine 12k (100 mg, 0.227 mmol) as described in the general procedure
(reaction time: 4 h). Purification of the crude product by flash chromatography (ethyl
acetate/hexane, 1:3) gave by order of elution compound 26b (13 mg, 13%) as an orange
solid with low melting point, and compound 27b (8 mg, 7%) as an orange solid.
Compound 26b: ν̃
(ATR) 731, 832, 854, 1060, 1264, 1326, 1514, 1600 and 2975
max
-1
1
cm . H NMR: δ = 1.20 (t, J = 7.1 Hz, 1H), 1.39 (s, 1H), 1.61 (s, 1H), 1.93 (dd, J =
13.2 and 8.3 Hz, 1H), 2.55 (d, J = 15.9 Hz, 1H), 2.78 (dd, J = 13.2 and 7.4 Hz, 1H),
2.97 (d, J = 15.9 Hz, 1H), 3.56 – 3.47 (m, 1H), 3.67 – 3.58 (m, 1H), 4.62 (t, J = 7.8 Hz,
1H), 7.34 (d, J = 9.3 Hz, 1H), 7.81 – 7.74 (m, 1H), 8.29 – 8.23 (m, 1H), 8.36 (dd, J =
9.2 and 2.6 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H). 13C NMR: δ = 15.7, 22.8, 28.3, 36.1, 45.0,
56.9, 64.0, 82.6, 107.1, 117.0, 122.5, 124.2, 126.7, 127.1, 140.5, 140.9, 141.5, 144.7,
148.7, 154.0 HRMS (EI-TOF): calcd. for C22H23N5O8, 485.1547 [M+]; found, 485.1548.
Compound 27b: m.p. 206.8 – 207.9 ºC (from ethyl acetate/hexane); ν̃
(ATR) 743,
max
1
822, 854, 1266, 1331, 1505, 1589, 1608 and 2921 cm-1; H NMR: δ = 1.10 (t, J = 7.1
Hz, 3H), 1.45 (s, 3H), 1.56 (s, 3H), 2.25 (dd, J = 13.7 and 8.6 Hz, 1H), 2.63 – 2.71 (m,
2H), 3.37 (d, J = 17.6 Hz, 1H), 3.46 – 3.55 (m, 1H), 3.56 – 3.64 (m, 1H), 4.13 (t, J = 8.2
Hz, 1H), 7.22 (d, J = 9.3 Hz, 1H), 7.74 – 7.79 (m, 2H), 8.23 – 8.28 (m, 2H), 8.36 (dd, J
= 9.2 and 2.6 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H); 13C NMR δ 15.7, 25.4, 27.2, 29.9, 31.4,
33.4, 38.3, 43.8, 57.7, 59.7, 62.0, 106.8, 117.1, 122.5, 124.1, 126.3, 127.2, 140.4, 142.1,
144.1, 146.5, 148.3. HRMS (EI-TOF): calcd. for C22H23N5O8, 485.1547 [M+]; found,
485.1545.
29
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