Diastereoselective synthesis of dimethyl (4R*,4a′R*, 7a′R*)-1-Aryl-6′-benzoyl- 4a′-methyl-5-oxo-1,4′, 4a′,5,5′,6′-hexahydrospiro[pyrazole-4,7′-pyrrolo[3,4-c] pyridazine]-3′,7a′(1′H)-dicarboxylates

Article abstract of DOI:10.1055/s-0028-1083291

Methyl (Z)-2-(benzoylamino)-3-(dimethylamino)prope- noate (1) reacted with trimethylenemethane (2) to produce methyl (Z)-2-[benzoyl(2-methylallyl)amino]-3- (dimethylamino)propeno- ate (3), which was then converted into pyrazole derivatives 11a-h by a cons

Full text of DOI:10.1055/s-0028-1083291

PAPER
217
Diastereoselective Synthesis of Dimethyl (4R*,4a¢R*,7a¢R*)-1-Aryl-6¢-benzoyl-
4a¢-methyl-5-oxo-1,4¢,4a¢,5,5¢,6¢-hexahydrospiro[pyrazole-4,7¢-pyrrolo[3,4-c]
pyridazine]-3¢,7a¢(1¢H)-dicarboxylates
F
ormation of Spiro
r
[pyrazo
o
le-4,7
¢
-pyrro
š
c
]
pyridaz
i
U
nes] ršič, Uroš Grošelj, Anton Meden, Jurij Svete, Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: branko.stanovnik@fkkt.uni-lj.si
Received 3 June 2008; revised 5 September 2008
Dedicated to Professor Volker Jäger on the occasion of his 65th birthday
3¢H-spiro[bicyclo[2.2.1]heptane-2,2¢-furans] and further
Abstract: Methyl (Z)-2-(benzoylamino)-3-(dimethylamino)prope-
noate (1) reacted with trimethylenemethane (2) to produce methyl
(Z)-2-[benzoyl(2-methylallyl)amino]-3-(dimethylamino)propeno-
ate (3), which was then converted into pyrazole derivatives 11a–h
reductions of these cycloadducts yielding novel non-
racemic amines, diamines, and amino alcohols.4 Further
[4+2] cycloaddition reactions of dimethyl 1,2,4,5-tetra-
by a consecutive exchange of the dimethylamino group with hydra- zine-3,6-dicarboxylate to systems possessing an exocy-
clic C=C bond leads to the formation of
zine derivates 9a–h and cyclization to the ester group. Reactions of
pyrazoles 11a–g with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate
(6) resulted in the diastereoselective formation of 1-aryl-6¢-ben-
plicability of 1,2,4,5-tetrazines as useful electron-poor
zoyl-4a¢-methyl-5-oxo-1,4¢,4a¢,5,5¢,6¢-hexahydrospiro[pyrazole-
4,7¢-pyrrolo[3,4-c]pyridazine]-3¢,7a¢(1¢H)-dicarboxylates 12a–g.
This represents a simple new pathway to novel heterocyclic sys-
spirodihydropyridazines,5–7 thus expanding the wide ap-
dienes in inverse-demand [4+2] cycloadditions to various
electron-rich dienophiles.
tems. On the other hand, when (dimethylamino)propenoate 3 react-
ed with aniline hydrochloride (4), followed by the cycloaddition of
1,2,4,5-tetrazine 6, dimethyl (E)- and (Z)-4-({benzoyl[1-(methoxy-
cyclic systems,8 including some natural products and their
carbonyl)-2-(phenylamino)vinyl]amino}methyl)-4-methyl-1,4-di-
hydropyridazine-3,6-dicarboxylates (7) and (8) were formed,
respectively.
So far, 3-(dimethylamino)propenoates have been shown
to be widely applicable in the synthesis of various hetero-
analogues, such as aplysinopsins,9 meridianines,10 and di-
podazines and tryprostatins.11 Recently, we have reported
on regiospecific [2+2] cycloadditions of electron-poor
Key words: spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazine], 1,2,4,5-
tetrazine, heterocycles, diastereoselectivity, cycloadditions
acetylenes to (Z)-2-(acylamino)-3-(dimethylamino)pro-
penoates.12 On the other hand, no attempt has been report-
ed on employing 3-(dimethylamino)propenoates in
cycloadditions with the trimethylenemethane precursor.
There have been only a few reports of the synthesis of sys-
When methyl (Z)-2-(benzoylamino)-3-(dimethylami-
no)propenoate (1) reacted with trimethylenemethane (2)
in the presence of palladium(II) acetate and triisopropyl
phosphite, the reaction proceeded by attaching a 2-meth-
ylallyl moiety on to the nitrogen atom of the benzoylami-
no group resulting in the formation of methyl (Z)-2-
[benzoyl(2-methylallyl)amino]-3-(dimethylamino)prope-
noate (3) (Scheme 1), the structure of which was con-
firmed by X-ray crystal structure analysis (Figure 1).13
tems with a similar heterocyclic backbone to that of
spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazine], which is
reported in this paper. A well-reported route to similar
spiro systems is to employ a consecutive Pschorr–Sandm-
eyer reaction. In this manner, racemic epimers
(3¢S*,4¢R*)- and (3¢S*,4¢S*)-4¢-hydroxy-2,5¢-dimethyl-2¢-
phenyl-2¢,4-dihydrospiro[isoindoline-1,3¢-[3H]pyrazol]-
3-ones,1 and (3S*,4R*)- and (3S*,4S*)-4-chloro-2,4-di-
hydro-1¢,3¢,5,5¢-tetramethyl-2-phenylspiro[3H-pyrazole-
3,4¢-[1H]pyrrolo[3,4-c]pyrazol]-6¢(5¢H)-one2 have been
prepared.
In the last decades, 2-[(trimethylsilyl)methyl]allyl acetate
has proven to be a very useful reagent in palladium-cata-
lyzed reactions with alkenes possessing an adjacent ester
group to produce methylenecyclopentane derivatives,
while reactions with ketones result in 3-methylenetetrahy-
drofurans.3 Within this context, we have recently reported
highly stereoselective [3+2] cycloadditions of trimethyl-
enemethane
lo[2.2.1]heptan-2-ones leading to 4¢-methylenedihydro-
to
3-(arylamino)-1,7,7-trimethylbicyc-
SYNTHESIS 2009, No. 2, pp 0217–0226
x
x
.
x
x
.2
0
0
8
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083291; Art ID: T09308SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 ORTEP view of compound 3

218
U. Uršič et al.
PAPER
COOMe
NCOPh
δ = 9.51; 9.62 ppm
H
O
H
O
COOMe
i
Me2N
Ph
N
OMe
Ph
N
OMe
84%
Me2N
NHCOPh
NCOPh
NCOPh
1
3
1'
COOMe
H
5
δ = 5.72; 6.01 ppm
4
6
H
N
MeOOC
COOMe
3
NH
N
2
NH
1
2
MeOOC
δ = 7.91; 8.02 ppm
7'
7
Scheme 1 Reagents and conditions: (i) trimethylenemethane (2)
{from 2-[(trimethylsilyl)methyl]allyl acetate}, Pd(OAc)2, (i-
PrO)3PO, anhyd toluene, anhyd THF, reflux.
COOMe
COOMe
NCOPh
δ = 7.40 ppm
Ph NH
δ = 5.64; 6.01 ppm
The dimethylamino group of the (dimethylamino)prope-
noate 3 exhibits the same reactivity as in other (dimethyl-
amino)propenoates reported previously. In this manner, it
was easily exchanged by aniline 4 in an acid-catalyzed re-
action, producing methyl (Z)-2-[benzoyl(2-methylal-
lyl)amino]-3-(phenylamino)propenoate (5). Reacting
propenoate 5 with 1,2,4,5-tetrazine 6 gave two products
(Scheme 2) that were successfully separated by column
chromatography. The 1H NMR spectra of the two isolated
products revealed that each contains a mixture of two iso-
mers, which are in both cases in approximately the same
ratio. It appears that the two separated products are the
isomers (E)-7 and (Z)-8, where the NH protons of the E-
isomer 7 appear at a lower field (d = 9.51 and 9.62) due to
hydrogen bond formation with the carbonyl oxygen of the
ester group, while those of the Z-isomers 8 appear at high-
er field (d = 7.40), because in this case no hydrogen bond
can be formed.
The two sets of signals in the 1H NMR of E-isomer 7 and
Z-isomer 8 appear to be due to rotational restrictions
around the C4–C1¢ bond, resulting in the observation of
rotamers 7 and 7¢, and 8 and 8¢. The possibility of tautom-
erism of the dihydropyridazine was ruled out by the pres-
ence of characteristic chemical shifts for N1–H (E-
isomers: d = 7.91 and 8.02; Z-isomers: d = 7.75 and 7.91)
and C5–H (E-isomers: d = 5.72 and 6.01; Z-isomers: d =
5.64 and 6.01), thus confirming the 1,4-dihydro form in
all cases. Additionally, the nature of the signals for N1–H
has been, in all cases, established by addition of D2O
where these signals disappeared (Figure 2).
Ph NH
MeOOC
NCOPh
H
COOMe
COOMe
H
N
N
NH
NH
8
MeOOC
8'
δ = 7.75; 7.91 ppm
Figure 2 1H NMR chemical shifts of certain protons in 7 and 8, and
their rotamers 7¢ and 8¢
10¢a–e,g, and 10¢¢a–e,g. Further cyclization to the ester
group did not take place under these conditions. In most
cases the products appeared as mixtures of three forms:
the hydrazono form 10, the (Z)-hydrazino form 10¢ and the
(E)-hydrazino form 10¢¢. In the reaction with hydrazines
9f and 9h only the hydrazono forms 10f,h were isolated.
The structures of the tautomeric forms of intermediates
10a–h, 10¢a–e,g, and 10¢¢a–e,g were determined by
1
HRMS and H NMR spectra. These intermediates were
cyclized into pyrazole derivatives 11a–h in the presence
of triethylamine by heating to reflux in ethanol. When the
pyrazole derivatives 11a–g reacted with 1,2,4,5-tetrazine
6 an unexpected type of products was formed. Namely,
[4+2] cycloaddition of 1,2,4,5-tetrazine 6 to the C=C bond
of the 2-methylallyl moiety was followed by intramolecu-
lar cyclization resulting in the formation of dimethyl
(4R*,4a¢R*,7a¢R*)-1-aryl-6¢-benzoyl-4a¢-methyl-5-oxo-
1,4¢,4a¢,5,5¢,6¢-hexahydrospiro[pyrazole-4,7¢-pyrro-
lo[3,4-c]pyridazine]-3¢,7a¢(1¢H)-dicarboxylates
12a–g
(Scheme 3). In these reactions, three new stereogenic cen-
ters are formed, therefore, four diastereomeric pairs of
enantiomers can be formed. In fact these reactions pro-
ceeded with a relatively high diastereoselectivity, produc-
ing only two diasteromeric pairs of enantiomers, of which
In the next step of this research (dimethylamino)prope-
noate 3 reacted with a series of hydrazines 9a–h. Under
the conditions of acidic catalysis the dimethylamino
group was exchanged by hydrazines to afford 10a–h,
COOMe
NCOPh
Ph NH
COOMe
NCOPh
CO2Me
N
N
N
COOMe
NCOPh
COOMe
NCOPh
Ph NH
MeOOC
N
i, PhNH2⋅HCl (4)
ii,
MeO2C
(6)
+
Me2N
Ph NH
68%
COOMe
MeOOC
COOMe
3
5
N
NH
N
NH
8
7
47%
47%
Scheme 2 Reagents and conditions: (i) EtOH, reflux; (ii) toluene, reflux.
Synthesis 2009, No. 2, 217–226 © Thieme Stuttgart · New York

PAPER
Formation of Spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazines]
219
COOMe
NCOPh
COOMe
NCOPh
HN NH
Ar
COOMe
NCOPh
COOMe
NCOPh
i, ArNHNH2⋅HCl (9a–e) or
ArNHNH2 (9f–h), 37% HCl
HN
Ar
N
HN NH
Ar
Me2N
79–96%
10a–h
10'a–h
10''a–h
3
Ar
1N
Ar
2N
N
CO2Me
5
N
N
N
Ar
O
O
N
4
3
COOMe
COOMe
N
N
1'
+
OH
7'
PhOCN
PhOCN
N
MeO2C
iii,
(6)
7a' NH
ii
6'
NH
N
N2'
4a'
5'
49–86%
(relative
to 3)
64–88%
NCOPh
3'
4'
12a–g
COOMe
12'a–g
COOMe
major diastereomer
(4R*,4a'R*,7a'R*)
minor diastereomer:
(4R*,4a'R*,7a'S*),
(4R*,4a'S*,7a'R*) or
(4R*,4a'S*,7a'S*)
11a–h
9-12: a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-FC6H4, d Ar = 4-MeOC6H4, e Ar = 3-ClC6H4,
f Ar = 4-O2NC6H4, g Ar = 4-HO2CC6H4, h Ar = 6-phenylpyridazin-3-yl
Scheme 3 Reagents and conditions: (i) EtOH, reflux; (ii) Et3N, EtOH, reflux; (iii) MeCN, reflux.
the major diastereomers 12a–g were formed with a dia- In the last stage, the nucleophilic attack of the pyrazole
stereomeric ratio ranging between 75:25 and 85:15. The takes place on the opposite side from the methyl group,
structure of the major isomers was determined by X-ray pushing the carboxylate to the side of the methyl group. In
diffraction of product 12a (Figure 3).14 This proved that other words, (S)-14 undergoes nucleophilic attack from
(4R*,4a¢R*,7a¢R*)-diastereomers are formed. While the Si face, while in the case of (R)-14 the attack takes
the minor isomer 12¢ formed is one of the three other place from the Re face (Scheme 4).
possible
diastereomers:
the
(4R*,4a¢R*,7a¢S*)-,
N
N
N
N
(4R*,4a¢S*,7a¢R*)-, or (4R*,4a¢S*,7a¢S*)-isomer. In all
cases the major diastereomers 12a–g can be obtained in a
pure form by crystallizing the reaction mixture once or
twice from a mixture of ethyl acetate and petroleum ether.
Ar
1'
N
MeOOC
COOMe
5'
2'
OH
6
N
COOMe
N2
3
3'
4'
Ar
N
N1
4
N
6
PhOC
OH
N
5
COOMe
(S)-13
– N2
N
Ar
PhOC
N
N
OH
11a–g
COOMe
N
N
N
N
N
N
N
MeOOC
COOMe
PhOC
COOMe
6
(R)-13
Ar
Ar
N
Si face
N
N
N
O
O–
COOMe
NH
COOMe
PhOCN
NH+
N
N
N
PhOC
Figure 3 ORTEP view of compound 12a
COOMe
COOMe
(4S,4a'S,7a'S)-12a–g
(S)-14
To explain the predominant formation of the major
(4R*,4a¢R*,7a¢R*)-diastereomers 12a–g an easy mecha-
nistic route can be envisioned. In the first stage, the [4+2]
cycloaddition of 1,2,4,5-tetrazine 6 can proceed from both
sides of the C=C bond, resulting in the formation of
racemic dimethyl 4-{[(1-aryl-5-hydroxy-1H-pyrazol-
4-yl)benzoylamino]methyl}-4-methyl-4,5-dihydropyrid-
azine-3,6-dicarboxylates 13. The transfer of a proton from
the acidic hydroxy group to the dihydropyridazine nitro-
gen atom makes the pyrazole C4¢ atom more nucleophilic.
Ar
N
Ar
Re face
N
O
N
N
O–
COOMe
COOMe
PhOCN
NH
N
NH+
N
N
PhOC
COOMe
COOMe
(4R,4a'R,7a'R)-12a–g
(R)-14
Scheme 4 Proposed mechanism of the formation of 12a–g
Synthesis 2009, No. 2, 217–226 © Thieme Stuttgart · New York

220
U. Uršič et al.
PAPER
Dimethyl (E)-4-[({Benzoyl[1-(methoxycarbonyl)-2-(phenylami-
no)vinyl]amino)methyl]-4-methyl-1,4-dihydropyridazine-3,6-
dicarboxylate (7), Dimethyl (Z)-4-[({Benzoyl[1-(methoxycarbo-
nyl)-2-(phenylamino)vinyl]amino)methyl]-4-methyl-1,4-dihy-
dropyridazine-3,6-dicarboxylate (8), and Their Rotamers 7¢
and 8¢
Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (6, 0.163 g, 0.825
mmol) was added to a soln of 5 (0.263 g, 0.75 mmol) in toluene (5
mL). The mixture was refluxed for 2 h. Volatile components were
evaporated in vacuo and the residue was purified by column chro-
matography (silica gel, EtOAc–PE, 1:1) isolating two products.
Fractions containing individual products were evaporated in vacuo
to obtain E- and Z-isomers as mixtures of two rotamers. Experimen-
tal, analytical, and spectral data for compounds 7, 7¢, 8, and 8¢ are
given in Tables 1– 4.
In conclusion, a new type of (dimethylamino)propenoate
reagent 3 has been prepared, which gave rise to the syn-
thesis of new pyrazole derivatives 11a–h and additionally
a synthetic route to a new heterocyclic systems,
spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazines] 12, has
been developed by [4+2] cycloaddition reactions of di-
methyl 1,2,4,5-tetrazine-3,6-dicarboxylate (6) to pyra-
zoles 11.
Melting points were determined on a Kofler micro hot stage. NMR
spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for
1H, and 75.5 MHz for 13C nucleus, using DMSO-d6 and CDCl3 as
solvents and TMS as the internal standard. Microwave irradiations
were performed on CEM Corporation Discover microwave unit.
Mass spectra were recorder on an AutoSpecQ and Qtof-premier
spectrometers, IR spectra on a Perkin-Elmer Spectrum BX FTIR
spectrophotometer. Microanalyses were performed on a Perkin-
Elmer CHN Analyzer 2400 II. Column chromatography (CC) was
performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm). Petro-
leum ether = PE.
N-(1-Aryl-5-hydroxy-1H-pyrazol-4-yl)-N-(2-methylallyl)benz-
amides 11a–h through Methyl 3-(2-Arylhydrazono)-2-[ben-
zoyl(2-methylallyl)amino]propenoates 10a–h, Methyl (Z)-3-(2-
Arylhydrazinyl)-2-[benzoyl(2-methylallyl)amino]propenoates
10¢a–h, and Methyl (E)-3-(2-Arylhydrazinyl)-2-[benzoyl(2-
methylallyl)amino]propenoates 10¢¢a–h; General Procedure
Hydrazine hydrochloride 9a–e (2.4 mmol) or hydrazine 9f–h (2.4
mmol) and 37% aq HCl (6 drops, ca. 2 mmol) was added to a soln
of 3 (0.604 g, 2 mmol) in EtOH (6 mL). The mixture was refluxed
for 2–16 h. Volatile components were evaporated in vacuo and the
residue was purified by column chromatography (silica gel). Frac-
tions containing the product were combined and evaporated in
vacuo to give a crude mixture of 3-(2-arylhydrazono)propenoate
10a–h and 3-(2-arylhydrazinyl)propenoates 10¢a–h and 10¢¢a–h.
2-[(Trimethylsilyl)methyl]allyl acetate (2), aniline hydrochloride
(4) and hydrazines 9a–h are commercially available (Sigma-
Aldrich). Methyl (Z)-2-(benzoylamino)-3-(dimethylamino)pro-
penoate15 (1) and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate16 (6)
were prepared according to literature procedures.
Methyl (Z)-2-[Benzoyl(2-methylallyl)amino]-3-(dimethylami-
no)propenoate (3)
A soln of methyl (Z)-2-(benzoylamino)-3-(dimethylamino)prope-
noate (1, 7.448 g, 30 mmol) and 2-[(trimethylsilyl)methyl]allyl
acetate [precursor of trimethylenemethane (2)] (6.85 mL, 33 mmol)
in anhyd toluene (60 mL) was heated to boiling point. Then a soln
of (i-PrO)3P (4.44 mL, 18 mmol) and Pd(OAc)2 (0.680 g, 3 mmol)
in anhyd THF (30 mL) was added through the condenser. The mix-
ture was refluxed for 100 min. Volatile components were evaporat-
ed in vacuo and the residue was purified by column
chromatography (silica gel, EtOAc–PE, 2:1). Fractions containing
the product were combined and evaporated in vacuo. The product
was recrystallized (EtOAc–PE). Experimental, analytical, and spec-
tral data for compound 3 are given in Tables 1– 4.
No further purification of such a mixture was undertaken. Et3N
(0.420 mL, 3 mmol) was added to a soln of a crude mixture of 10,
10¢, and 10¢¢ in EtOH (5 mL). The mixture was refluxed for 1–8 h
and at the end acidified with 1 M HCl (3.5 mL). The precipitated
products 11a–f,h were collected by filtration. Product 11g did not
precipitate. In order to isolate product 11g volatile components
were evaporated in vacuo, the residue was dissolved in 1 M
NaHSO4 and the product extraction with EtOAc. Experimental, an-
alytical, and spectral data for compounds 10a–h, 10¢a–h, 10¢¢a–h,
and 11a–h are given in Tables 1– 4.
Dimethyl (4R*,4a¢R*,7a¢R*)-1-Aryl-6¢-benzoyl-4a¢-methyl-5-
oxo-1,4¢,4a¢,5,5¢,6¢-hexahydrospiro[pyrazole-4,7¢-pyrrolo[3,4-
c]pyridazine]-3¢,7a¢(1¢H)-dicarboxylates 12a–g; General Proce-
dure
Methyl (Z)-2-[Benzoyl(2-methylallyl)amino]-3-(phenylami-
no)propenoate (5)
Aniline hydrochloride (4, 0.129 g, 1 mmol) was added to a soln of
3 (0.302 g, 1 mmol) in EtOH (2 mL). The mixture was refluxed for
4.5 h. H2O (10 drops) was added and the soln cooled to 4 °C. The
precipitated product was collected by filtration. Experimental, ana-
lytical, and spectral data for compound 5 are given in Tables 1– 4.
Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (6, 0.178 g, 0.9 mmol)
was added to a soln of 11a–g (0.75 mmol) in MeCN (4 mL). The
mixture was refluxed for 3–5 h. Volatile components were evapo-
rated in vacuo and the residue was crystallized EtOAc–PE). The
precipitated products 12a–g were collected by filtration. Experi-
mental, analytical, and spectral data for compounds 12a–g are given
in Tables 1– 4.
Table 1 Experimental and Physical Data for Compounds 3, 5, 7, 8, 10, 11, and 12
Compound
Ar
Time Isolationa
(h)
Yield Ratio of
drc
Mp (°C)
(solvent)
(%)
84
68
47
47
91
isomersb (%)
3
–
1.67 CC: EtOAc–PE (2:1)
–
–
–
–
–
–
117–118 (EtOAc–PE)
164–166 (EtOH–H2O)
71–74 (EtOAc–PE)
192–198 (EtOAc–PE)
–
5
Ph
Ph
Ph
4.5
2
crystallization: EtOH–H2O
CC: EtOAc–PE (1:1)
CC: EtOAc–PE, (1:1)
CC: EtOAc–PE, (1:2)
–
7, 7¢
8, 8¢
72:28
70:30
48:25:27
2
10a, 10¢a, 10¢¢a Ph
2
Synthesis 2009, No. 2, 217–226 © Thieme Stuttgart · New York

PAPER
Formation of Spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazines]
221
Table 1 Experimental and Physical Data for Compounds 3, 5, 7, 8, 10, 11, and 12 (continued)
Compound
Ar
Time Isolationa
(h)
Yield Ratio of
drc
Mp (°C)
(solvent)
(%)
95
96
89
92
91
79
79
isomersb (%)
10b, 10¢b, 10¢¢b 4-MeC6H4
10c, 10¢c, 10¢¢c 4-FC6H4
10d, 10¢d, 10¢¢d 4-MeOC6H4
10e, 10¢e, 10¢¢e 3-ClC6H4
2
CC: EtOAc–PE, (1:2)
42:35:23
53:24:23
37:37:26
64:19:17
100:0:0
50:36:14
100:0:0
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5
CC: EtOAc–PE, (1:2)
CC: EtOAc–PE, (1:2)
CC: EtOAc–PE, (1:2)
CC: EtOAc–PE, (2:3)
CC: EtOAc–PE, (2:1)
CC: EtOAc–PE, (2:1)
–
2
–
2
–
10f, 10¢f, 10¢¢f
4-O2NC6H4
3
–
10g, 10¢g, 10¢¢g 4-HO2CC6H4
16
2
–
10h, 10¢h, 10¢¢h 6-phenylpyridazin-3-yl
–
11a
11b
11c
11d
11e
11f
Ph
8
crystallization: EtOH–1 M HCl 76d
crystallization: EtOH–1 M HCl 70d
crystallization: EtOH–1 M HCl 68d
crystallization: EtOH–1 M HCl 78d
crystallization: EtOH–1 M HCl 86d
crystallization: EtOH–1 M HCl 75d
extraction: EtOAc–1 M NaHSO4 49d
crystallization: EtOH–1 M HCl 64e
188–192 (toluene)
183–185 (toluene)
182–185 (toluene)
178–180 (toluene)
188–190 (toluene)
186–188 (toluene)
4-MeC6H4
4-FC6H4
6
–
4.5
5.5
3
–
4-MeOC6H4
3-ClC6H4
–
–
4-O2NC6H4
4-HO2CC6H4
6-phenylpyridazin-3-yl
Ph
1
–
11g
11h
12a
12b
12c
12d
12e
12f
7
–
186–189 (toluene–DMF)
235–238 (toluene)
1
–
4
crystallization: EtOAc–PE
crystallization: EtOAc–PE
crystallization: EtOAc–PE
crystallization: EtOAc–PE
crystallization: EtOAc–PE
crystallization: EtOAc–PE
crystallization: EtOAc–PE
85e
74e
79e
70e
88e
87e
64e
85:15
84:16
83:17
82:18
83:17
81:19
75:25
85:15 204–206 (toluene)
84:16 217–220 (toluene–DMF)
83:17 207–211 (toluene)
82:18 194–197 (toluene)
83:17 178–180 (EtOAc–PE)
81:19 197–200 (toluene)
75:25 180–183 (toluene–DMF)
4-MeC6H4
4-FC6H4
4
3
4-MeOC6H4
3-ClC6H4
4.5
4.5
4
4-O2NC6H4
4-HO2CC6H4
12g
5
a CC = column chromatography.
b Determined by 1H NMR of the crude reaction mixture or after CC.
c Determined by 1H NMR of the crude reaction mixture.
d Determined relative to 3 used in the reaction.
e Isolated yield after one crystallization (EtOAc–PE) resulting in higher to 100% de.
Table 2 Analytical, MS, and IR Data for Compounds 3, 5, 7, 8, 10, 11, and 12a
Compound MS (m/z)
HRMS (m/z)
IR (cm–1)
3
MS (EI): 302 [M+]
MS (FAB): 303 [M + H+]
2912, 1685, 1646, 1631, 1434, 1396, 1374, 1301, 1212, 1185, 1163, 1113, 1102, 1052,
900, 726, 705
5
–
3445, 3236, 1703, 1640, 1624, 1599, 1490, 1435, 1402, 1247, 1139, 1058, 897, 779,
762, 715
7, 7¢
MS (EI): 520 [M+]
3359, 2953, 1714, 1680, 1630, 1601, 1587, 1505, 1438, 1399, 1348, 1290, 1226, 1198,
HRMS (EI): calcd: 520.195800; found: 1103, 757, 700
520.195800
8, 8¢
MS (EI): 520 [M+]
3376, 3250, 2951, 1709, 1645, 1627, 1601, 1576, 1499, 1436, 1403, 1370, 1349, 1295,
HRMS (EI): calcd: 520.197250; found: 1243, 1200, 1102, 761, 718, 696
520.195800
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Table 2 Analytical, MS, and IR Data for Compounds 3, 5, 7, 8, 10, 11, and 12a (continued)
IR (cm–1)
Compound MS (m/z)
HRMS (m/z)
10a, 10¢a,
10¢¢a
MS (EI): 365 [M+]
HRMS (EI): calcd: 365.173942; found:
365.173020
–
10b, 10¢b,
10¢¢b
MS (EI): 379 [M+]
HRMS (EI): calcd: 379.189592; found:
379.188350
–
–
–
–
–
–
–
10c, 10¢c,
10¢¢c
MS (EI): 383 [M+]
HRMS (EI): calcd: 383.164520; found:
383.165000
10d, 10¢d,
10¢¢d
MS (EI): 395 [M+]
HRMS (EI): calcd: 395.184507; found:
395.185300
10e, 10¢e,
10¢¢e
MS (EI): 399 [M+]
HRMS (EI): calcd: 399.134970; found:
399.135500
10f
MS (ESI): 411.2 [M + H+]
HRMS (ESI): calcd: 411.1668; found:
411.1662
10g, 10¢g,
10¢¢g
MS (EI): 409 [M+]
HRMS (EI): calcd: 409.163771; found:
409.164550
10h
11a
MS (ESI): 444.2 [M + H+]
HRMS (ESI): calcd: 444.2036; found:
444.2038
MS (ESI): 334.2 [M + H+]
HRMS (ESI): calcd: 334.1556; found:
334.1557
3444, 3105, 2734, 1651, 1625, 1600, 1579, 1500, 1457, 1446, 1398, 1357, 1290, 1233,
916, 776, 751, 699
11b
11c
–
–
3446, 3095, 2921, 1645, 1620, 1579, 1515, 1493, 1400, 1344, 1318, 1246, 924, 808,
767, 698
3446, 3103, 1648, 1624, 1600, 1576, 1509, 1445, 1406, 1355, 1291, 1231, 832, 768,
698
11d
11e
–
–
3447, 3096, 1651, 1621, 1578, 1513, 1399, 1358, 1301, 1249, 1028, 826, 766, 700
3446, 3108, 1652, 1630, 1598, 1584, 1485, 1434, 1394, 1358, 1231, 918, 877, 792,
777, 748, 703
11f
–
3445, 3094, 1645, 1633, 1597, 1514, 1497, 1404, 1342, 1239, 1114, 850, 774, 749,
698
11g
MS (ESI): 378.1 [M + H+]
HRMS (ESI): calcd: 378.1454; found:
378.1448
3445, 3093, 1689, 1630, 1607, 1577, 1515, 1428, 1402, 1348, 1287, 1245, 1177, 855,
771, 698
11h
MS (ESI): 412.2 [M + H+]
HRMS (ESI): calcd: 412.1774; found:
412.1773
3447, 3102, 1652, 1592, 1452, 1428, 1382, 1366, 1286, 1223, 1106, 923, 744, 694
12a
12b
12c
–
3338, 2956, 1747, 1736, 1707, 1639, 1620, 1499, 1399, 1365, 1314, 1270, 1237, 1194,
1147, 1125, 1080, 765, 692
–
3434, 3310, 1752, 1723, 1690, 1640, 1614, 1516, 1437, 1392, 1372, 1314, 1270, 1193,
1166, 1139, 1125, 825, 720
MS (ESI): 522.2 [M + H+]
HRMS (ESI): calcd: 544.1608 [M + Na+]; 1156, 1143, 1124, 839, 722
found: 544.1603
3308, 1755, 1728, 1690, 1639, 1613, 1510, 1439, 1393, 1372, 1314, 1269, 1216, 1194,
Synthesis 2009, No. 2, 217–226 © Thieme Stuttgart · New York

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Formation of Spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazines]
223
Table 2 Analytical, MS, and IR Data for Compounds 3, 5, 7, 8, 10, 11, and 12a (continued)
IR (cm–1)
Compound MS (m/z)
HRMS (m/z)
12d
12e
12f
12g
MS (ESI): 534.2 [M + H+]
HRMS (ESI): calcd: 534.1989; found:
534.1984
3399, 3309, 1750, 1731, 1712, 1645, 1624, 1512, 1445, 1390, 1311, 1270, 1249, 1188,
1149, 1127, 1028, 832, 722
MS (ESI): 538.2 [M + H+]
HRMS (ESI): calcd: 538.1493; found:
538.1508
3315, 1733, 1728, 1707, 1640, 1594, 1483, 1438, 1398, 1358, 1311, 1273, 1243, 1190,
1127, 1078, 782, 719
MS (ESI): 549.2 [M + H+]
HRMS (ESI): calcd: 549.1734; found:
549.1726
3299, 1749, 1730, 1706, 1635, 1594, 1516, 1497, 1399, 1334, 1270, 1195, 1129, 1112,
846, 751
MS (ESI): 548.2 [M + H+]
HRMS (ESI): calcd: 548.1781; found:
548.1775
3448, 3338, 2958, 1729, 1701, 1682, 1670, 1637, 1606, 1515, 1395, 1356, 1315, 1276,
1250, 1183, 1131, 1086, 860, 720
a Anal. 3, 5, 7, 7¢, 8, 8¢, 11a–h, 12a–d, C 0.29, H 0.21, N 0.31 except, 12e: Calcd for C26H24ClN5O6·0.5 C4H8O2 (EtOAc): C, 57.78; H, 4.85;
N, 12.03. Found: C, 58.16; H, 4.76; N, 12.11; 12f: Calcd for C26H24N6O8·0.5 C7H8 (toluene): C, 59.59; H, 4.75; N, 14.13. Found: C, 59.80; H,
4.80; N, 14.22; and 12g: Calcd for C27H25N5O8·C3H7NO (DMF): C, 58.06; H, 5.20; N, 13.54. Found: C, 58.45; H, 5.10; N, 13.29.
Table 3 1H NMR Data for Compounds 3, 5, 7, 8, 10, 11, and 12a
Compound 1H NMR d (CDCl3)b, J (Hz)
3
5
1.90 (s, 3 H, CH3), 3.03 (s, 6 H, NMe2), 3.55 (s, 3 H, COOMe), 3.69 (d, J = 13.6, 1 H, CHHa), 4.63 (d, J = 13.6, 1 H, CHHb), 4.87
(s, 2 H, C=CH2), 7.03 (s, 1 H, CH), 7.23–7.32 (m, 3 H, Ph), 7.40–7.45 (m, 2 H, Ph)
1.92 (s, 3 H, CH3), 3.58 (s, 3 H, COOMe), 3.73 (d, J = 15.1, 1 H, CHHa), 4.64 (d, J = 15.1, 1 H, CHHb), 5.01 (s, 1 H, C=CHHa),
5.05 (s, 1 H, C=CHHb), 6.92–6.97 (m, 2 H, Ph), 7.03–7.09 (m, 1 H, Ph), 7.15 (br d, J = 13.7, 1 H, NH), 7.21–7.28 (m, 2 H, Ph),
7.29–7.37 (m, 3 H, Ph), 7.40–7.46 (m, 2 H, Ph), 7.72 (d, J = 13.6, 1 H, CH)
7
1.47 (s, 3 H, CH3), 3.61 (s, 3 H, COOMe), 3.81 (s, 3 H, COOMe), 3.87 (s, 3 H, COOMe), 3.96 (d, J = 14.1, 1 H, CHHa), 4.44 (d,
J = 14.4, 1 H, CHHb), 6.01 (d, J = 2.1, 1 H, H5), 6.68–6.72 (m, 2 H, Ph), 6.91 (d, J = 13.1, 1 H, CHNH), 6.97–7.03 (m, 1 H, Ph),
7.13–7.32 (m, 7 H, Ph), 8.02 (d, J = 2.0, 1 H, H1), 9.51 (d, J = 13.0, 1 H, CHNH)
7¢
8
1.51 (s, 3 H, CH3), 3.49 (d, J = 14.2, 1 H, CHHa), 3.59 (s, 3 H, COOMe), 3.61 (s, 3 H, COOMe), 3.72 (s, 3 H, COOMe), 4.82 (d,
J = 14.0, 1 H, CHHb), 5.72 (d, J = 1.8, 1 H, H5), 6.79–6.84 (m, 2 H, Ph), 7.01–7.07 (m, 2 H, CHNH, Ph), 7.13–7.32 (m, 7 H, Ph),
7.91 (d, J = 1.9, 1 H, H1), 9.62 (d, J = 12.1, 1 H, CHNH)
1.42 (s, 3 H, CH3), 3.79 (s, 3 H, COOMe), 3.80 (s, 3 H, COOMe), 3.84 (d, J = 14.4, 1 H, CHHa), 3.88 (s, 3 H, COOMe), 4.49 (d,
J = 14.6, 1 H, CHHb), 6.01 (d, J = 1.7, 1 H, H5), 6.64–6.72 (m, 2 H, Ph), 6.96–7.02 (m, 1 H, Ph), 7.09 (d, J = 13.8, 1 H, CHNH),
7.15–7.34 (m, 7 H, Ph), 7.40 (d, J = 13.5, 1 H, CHNH), 7.91 (d, J = 1.8, 1 H, H1)
8¢
1.42 (s, 3 H, CH3), 3.33 (d, J = 14.4, 1 H, CHHa), 3.63 (s, 3 H, COOMe), 3.69 (s, 3 H, COOMe), 3.91 (s, 3 H, COOMe), 4.90 (d,
J = 14.3, 1 H, CHHb), 5.64 (d, J = 2.2, 1 H, H5), 6.80–6.85 (m, 2 H, Ph), 7.00–7.04 (m, 1 H, Ph), 7.11 (d, J = 13.5, 1 H, CHNH),
7.15–7.34 (m, 7 H, Ph), 7.40 (d, J = 13.5, 1 H, CHNH), 7.75 (d, J = 2.2, 1 H, H1)
10a
1.71 (s, 3 H, CH3), 3.81 (s, 3 H, COOMe), 3.89 (d, J = 17.7, 1 H, CHHa), 3.97 (d, J = 17.7, 1 H, CHHb), 4.57 (d, J = 6.3, 1 H,
H2), 5.11 (s, 1 H, C=CHHa), 5.38 (s, 1 H, C=CHHb), 7.20–7.58 (m, 11 H, Ph, H3), 7.66 (s, 1 H, NH)
10¢a
10¢¢a
10b
1.90 (s, 3 H, CH3), 3.63 (s, 3 H, COOMe), 4.61 (d, J = 15.0, 1 H, CHHb), 4.99 (s, 1 H, C=CHHa), 5.80 (s, 1 H, C=CHHb), 6.30
(d, J = 11.4, 1 H, CHNH), 6.56 (s, 1 H, NHAr)
1.80 (s, 3 H, CH3), 3.54 (d, J = 14.6, 1 H, CHHa), 3.75 (s, 3 H, COOMe), 4.85 (s, 1 H, C=CHHa), 5.87 (s, 1 H, C=CHHb), 6.54
(s, 1 H, NHAr), 6.74 (d, J = 10.7, 1 H, H3), 8.58 (d, J = 10.5, 1 H, CHNH)
1.71 (s, 3 H, CH3), 2.27 (s, 3 H, PhCH3), 3.80 (s, 3 H, COOMe), 3.88 (d, J = 19.2, 1 H, CHHa), 3.96 (d, J = 18.5, 1 H, CHHb),
4.57 (d, J = 5.7, 1 H, H2), 5.10 (s, 1 H, C=CHHa), 5.38 (s, 1 H, C=CHHb), 6.85–6.91 (m, 2 H, H3¢, H5¢), 7.28–7.44 (m, 5 H, Ph),
7.48–7.54 (m, 3 H, H2¢, H6¢, H3), 7.58 (s, 1 H, NH)
10¢b
1.89 (s, 3 H, CH3), 2.27 (s, 3 H, PhCH3), 3.62 (s, 3 H, COOMe), 4.58 (d, J = 14.7, 1 H, CHHb), 4.98 (s, 1 H, C=CHHa), 5.72 (s,
1 H, C=CHHb), 6.29 (d, J = 11.0, 1 H, CHNH), 6.49 (s, 1 H, NHAr)
10¢¢b
1.80 (s, 3 H, CH3), 2.27 (s, 3 H, PhCH3), 3.53 (d, J = 14.5, 1 H, CHHa), 3.74 (s, 3 H, COOMe), 4.85 (s, 1 H, C=CHHa), 5.79 (s,
1 H, C=CHHb), 6.46 (s, 1 H, NHAr), 6.75 (d, J = 10.8, 1 H, H3), 8.56 (d, J = 10.6, 1 H, CHNH)
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Table 3 1H NMR Data for Compounds 3, 5, 7, 8, 10, 11, and 12a (continued)
Compound 1H NMR d (CDCl3)b, J (Hz)
10c
1.71 (s, 3 H, CH3), 3.80 (s, 3 H, COOMe), 3.89 (d, J = 16.2, 1 H, CHHa), 3.97 (d, J = 16.7, 1 H, CHHb), 4.54 (d, J = 5.8, 1 H,
H2), 5.11 (s, 1 H, C=CHHa), 5.37 (s, 1 H, C=CHHb), 6.85–6.95 (m, 2 H, H3¢, H5¢), 7.30–7.45 (m, 5 H, Ph), 7.47–7.53 (m, 2 H,
H2¢, H6¢), 7.55 (d, J = 6.7, 1 H, H3), 7.68 (s, 1 H, NH)
10¢c
1.89 (s, 3 H, CH3), 3.64 (s, 3 H, COOMe), 4.57 (d, J = 13.4, 1 H, CHHb), 4.97 (s, 1 H, C=CHHa), 5.75 (s, 1 H, C=CHHb)
10¢¢c
1.80 (s, 3 H, CH3), 3.53 (d, J = 14.3, 1 H, CHHa), 3.76 (s, 3 H, COOMe), 4.84 (s, 1 H, C=CHHa), 5.82 (s, 1 H, C=CHHb), 6.71
(d, J = 10.7, 1 H, H3), 8.58 (d, J = 10.9, 1 H, CHNH)
10d
1.71 (s, 3 H, CH3), 3.77 (s, 3 H, OMe), 3.80 (s, 3 H, COOMe), 3.88 (d, J = 18.1, 1 H, CHHa), 3.96 (d, J = 17.3, 1 H, CHHb), 4.56
(d, J = 5.9, 1 H, H2), 5.11 (s, 1 H, C=CHHa), 5.38 (s, 1 H, C=CHHb), 6.79–6.85 (m, 2 H, H3¢, H5¢), 7.29–7.55 (m, 9 H, Ph, H2¢,
H6¢, H3, NH)
10¢d
10¢¢d
10e
1.88 (s, 3 H, CH3), 3.62 (s, 3 H, COOMe), 3.77 (s, 3 H, OMe), 4.55 (d, J = 14.7, 1 H, CHHb), 4.96 (s, 1 H, C=CHHa), 5.66 (s, 1
H, C=CHHb), 6.31 (d, J = 11.2, 1 H, CHNH), 6.54 (s, 1 H, NHAr)
1.80 (s, 3 H, CH3), 3.53 (d, J = 14.3, 1 H, CHHa), 3.74 (s, 3 H, COOMe), 3.76 (s, 3 H, OMe), 4.85 (s, 1 H, C=CHHa), 5.73 (s, 1
H, C=CHHb), 6.51 (s, 1 H, NHAr), 6.75 (d, J = 10.8, 1 H, H3), 8.56 (d, J = 10.3, 1 H, CHNH)
1.72 (s, 3 H, CH3), 3.80 (s, 3 H, COOMe), 3.89 (d, J = 17.3, 1 H, CHHa), 3.97 (d, J = 17.3, 1 H, CHHb), 4.53 (d, J = 6.3, 1 H,
H2), 5.12 (s, 1 H, C=CHHa), 5.38 (s, 1 H, C=CHHb), 6.75 (ddd, J = 0.9, 2.1, 8.2, 1 H, H4¢ or H6¢), 6.79 (ddd, J = 0.9, 1.9, 7.8, 1
H, H4¢ or H6¢), 7.02 (t, J = 2.0, 1 H, H2¢), 7.11 (t, J = 8.1, 1 H, H5¢), 7.30–7.54 (m, 5 H, Ph), 7.59 (d, J = 6.2, 1 H, H3), 7.91 (s,
1 H, NH)
10¢e
10¢¢e
10f
1.91 (s, 3 H, CH3), 3.63 (s, 3 H, COOMe), 4.59 (d, J = 15.1, 1 H, CHHb), 4.99 (s, 1 H, C=CHHa), 5.87 (s, 1 H, C=CHHb), 6.42
(d, J = 10.8, 1 H, CHNH)
1.80 (s, 3 H, CH3), 3.53 (d, J = 14.3, 1 H, CHHa), 3.75 (s, 3 H, COOMe), 4.86 (s, 1 H, C=CHHa), 5.93 (s, 1 H, C=CHHb), 6.52
(t, J = 2.0, 1 H, H2¢), 6.62 (s, 1 H, NHAr), 6.69 (d, J = 10.6, 1 H, H3), 8.59 (d, J = 10.6, 1 H, CHNH)
1.74 (s, 3 H, CH3), 3.81 (s, 3 H, COOMe), 3.92 (d, J = 17.0, 1 H, CHHa), 4.00 (d, J = 17.0, 1 H, CHHb), 4.53 (d, J = 6.3, 1 H,
H2), 5.14 (s, 1 H, C=CHHa), 5.37 (s, 1 H, C=CHHb), 6.81–6.87 (m, 2 H, H2¢, H6¢), 7.36–7.54 (m, 5 H, Ph), 7.84 (d, J = 6.4, 1 H,
H3), 8.02–8.09 (m, 2 H, H3¢, H5¢), 9.12 (s, 1 H, NH)
10g
1.72 (s, 3 H, CH3), 3.79 (s, 3 H, COOMe), 3.90 (d, J = 17.0, 1 H, CHHa), 3.98 (d, J = 18.3, 1 H, CHHb), 4.55 (d, J = 6.2, 1 H,
H2), 5.13 (s, 1 H, C=CHHa), 5.37 (s, 1 H, C=CHHb), 6.90–6.97 (m, 2 H, H2¢, H6¢), 7.35–7.56 (m, 5 H, Ph), 7.89–7.96 (m, 2 H,
H3¢, H5¢), 7.68 (d, J = 6.1, 1 H, H3), 8.40 (s, 1 H, NH), COOH exchanged
10¢g
1.90 (s, 3 H, CH3), 3.65 (s, 3 H, COOMe), 4.43 (d, J = 14.4, 1 H, CHHb), 4.98 (s, 1 H, C=CHHa), 6.21 (s, 1 H, C=CHHb)
10¢¢g
1.79 (s, 3 H, CH3), 3.54 (d, J = 14.4, 1 H, CHHa), 3.78 (s, 3 H, COOMe), 4.85 (s, 1 H, C=CHHa), 6.23 (s, 1 H, C=CHHb), 6.66
(d, J = 10.7, 1 H, H3), 8.66 (d, J = 10.9, 1 H, CHNH)
10h
1.71 (s, 3 H, CH3), 3.84 (s, 3 H, COOMe), 3.90 (d, J = 17.0, 1 H, CHHa), 4.01 (d, J = 16.9, 1 H, CHHb), 4.63 (d, J = 6.3, 1 H,
H2), 5.11 (s, 1 H, C=CHHa), 5.37 (s, 1 H, C=CHHb), 7.35–7.57 (m, 9 H, Ph, Hpyridazine), 7.78 (d, J = 9.34, 1 H, Hpyridazine), 7.84 (d,
J = 6.1, 1 H, H3), 7.98–8.04 (m, 2 H, Ph), 9.46 (br s, 1 H, NH)
11a
11b
11c
11d
11e
11f
1.64 (s, 3 H, CH3), 4.22 (s, 2 H, CH2), 5.02 (s, 1 H, C=CHHa), 5.05 (s, 1 H, C=CHHb), 7.27–7.32 (m, 1 H, Ph), 7.40–7.56 (m, 8
H, H3, Ph), 7.79–7.88 (m, 2 H, Ph), OH exchanged
1.63 (s, 3 H, CH3), 2.38 (s, 3 H, Me), 4.21 (s, 2 H, CH2), 5.02 (s, 1 H, C=CHHa), 5.05 (s, 1 H, C=CHHb), 7.22–7.27 (m, 2 H, H3¢,
H5¢), 7.38–7.56 (m, 6 H, H3, Ph), 7.64–7.70 (m, 2 H, H2¢, H6¢), 10.56 (br s, 1 H, OH)
1.64 (s, 3 H, CH3), 4.21 (s, 2 H, CH2), 5.01 (s, 1 H, C=CHHa), 5.06 (s, 1 H, C=CHHb), 7.08–7.17 (m, 2 H, H3¢, H5¢), 7.38–7.56
(m, 6 H, H3, Ph), 7.74–7.82 (m, 2 H, H2¢, H6¢), 10.71 (br s, 1 H, OH)
1.63 (s, 3 H, CH3), 3.84 (s, 3 H, OMe), 4.21 (s, 2 H, CH2), 5.01 (s, 1 H, C=CHHa), 5.05 (s, 1 H, C=CHHb), 6.94–7.00 (m, 2 H,
H3¢, H5¢), 7.38 (s, 1 H, H3), 7.40–7.56 (m, 5 H, Ph), 7.64–7.72 (m, 2 H, H2¢, H6¢), 10.53 (br s, 1 H, OH)
1.63 (s, 3 H, CH3), 4.21 (s, 2 H, CH2), 5.00 (s, 1 H, C=CHHa), 5.06 (s, 1 H, C=CHHb), 7.22–7.27 (m, 1 H, H4¢), 7.36 (t, J = 8.1,
1 H, H2¢), 7.40–7.56 (m, 6 H, H3, Ph), 7.77–7.81 (m, 1 H, H6¢), 7.89–7.93 (m, 1 H, H2¢), 10.84 (br s, 1 H, OH)
1.64 (s, 3 H, CH3), 4.23 (s, 2 H, CH2), 5.01 (s, 1 H, C=CHHa), 5.08 (s, 1 H, C=CHHb), 7.43–7.58 (m, 6 H, H3, Ph), 8.12–8.18
(m, 2 H, H2¢, H6¢), 8.28–8.34 (m, 2 H, H3¢, H5¢), 11.24 (br s, 1 H, OH)
11gc
1.78 (s, 3 H, CH3), 4.24 (s, 2 H, CH2), 4.88 (s, 2 H, C=CH2), 7.24–7.42 (m, 6 H, H3, Ph), 7.74–7.82 (m, 2 H, H2¢, H6¢), 7.94–
8.02 (m, 2 H, H3¢, H5¢), 12.19 (br s, 1 H, COOH), 12.91 (br s, 1 H, OH)
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Formation of Spiro[pyrazole-4,7¢-pyrrolo[3,4-c]pyridazines]
225
Table 3 1H NMR Data for Compounds 3, 5, 7, 8, 10, 11, and 12a (continued)
Compound 1H NMR d (CDCl3)b, J (Hz)
11h
12a
1.85 (s, 3 H, CH2), 4.43 (s, 2 H, CH2), 4.89–4.94 (m, 2 H, C=CH2), 7.21–7.31 (m, 3 H, Ph), 7.45–7.51 (m, 2 H, Ph), 7.51–7.59
(m, 4 H, Ph, H5¢), 7.97–8.04 (m, 2 H, Ph), 8.05 (s, 1 H, H3), 8.11 (d, J = 9.5, 1 H, H4¢), 12.13 (br s, 1 H, OH)
1.01 (s, 3 H, CH3), 2.71 (d, J = 17.5, 1 H, H4¢a), 3.29 (d, J = 17.6, 1 H, H4¢b), 3.68 (d, J = 10.1, 1 H, H5¢a), 3.83 (s, 3 H, COOMe),
3.94 (s, 3 H, COOMe), 4.03 (d, J = 10.4, 1 H, H5¢b), 7.17–7.24 (m, 1 H, Ph), 7.32 (s, 1 H, H3), 7.34–7.50 (m, 6 H, Ph, NH), 7.52–
7.58 (m, 2 H, Ph), 7.70–7.77 (m, 2 H, Ph)
12¢a
1.23 (s, 3 H, CH3), 2.47 (d, J = 19.0, 1 H, H4¢a), 3.86 (s, 3 H, COOMe), 3.91 (s, 3 H, COOMe)
12b
1.02 (s, 3 H, CH3), 2.34 (s, 3 H, Me), 2.70 (d, J = 17.5, 1 H, H4¢a), 3.28 (d, J = 17.4, 1 H, H4¢b), 3.67 (d, J = 10.0, 1 H, H5¢a), 3.83
(s, 3 H, COOMe), 3.93 (s, 3 H, COOMe), 4.00 (d, J = 9.6, 1 H, H5¢b), 7.14–7.22 (m, 2 H, H3¢, H5¢), 7.30 (s, 1 H, H3), 7.38–7.50
(m, 4 H, Ph, NH), 7.50–7.56 (m, 2 H, Ph), 7.56–7.62 (m, 2 H, H2¢, H6¢)
12¢b
1.22 (s, 3 H, CH3), 2.52 (d, J = 18.1, 1 H, H4¢a), 3.55 (d, J = 9.9, 1 H, H5¢a), 3.86 (s, 3 H, COOMe), 3.90 (s, 3 H, COOMe), 4.21
(d, J = 9.8, 1 H, H5¢b)
12c
1.00 (s, 3 H, CH3), 2.71 (d, J = 17.5, 1 H, H4¢a), 3.29 (d, J = 17.5, 1 H, H4¢b), 3.68 (d, J = 10.0, 1 H, H5¢a), 3.83 (s, 3 H, COOMe),
3.95 (s, 3 H, COOMe), 4.04 (d, J = 10.1, 1 H, H5¢b), 7.02–7.11 (m, 2 H, H3¢, H5¢), 7.30 (s, 1 H, H3), 7.35 (br s, 1 H, NH), 7.40–
7.50 (m, 3 H, Ph), 7.52–7.58 (m, 2 H, Ph), 7.67–7.74 (m, 2 H, H2¢, H6¢)
12¢c
1.23 (s, 3 H, CH3), 2.47 (d, J = 19.1, 1 H, H4¢a), 3.56 (d, J = 9.8, 1 H, H5¢a), 3.86 (s, 3 H, COOMe), 3.91 (s, 3 H, COOMe), 4.19
(d, J = 9.7, 1 H, H5¢b)
12d
1.02 (s, 3 H, CH3), 2.69 (d, J = 17.5, 1 H, H4¢a), 3.28 (d, J = 17.8, 1 H, H4¢b), 3.67 (d, J = 10.0, 1 H, H5¢a), 3.81 (s, 3 H, OMe),
3.83 (s, 3 H, COOMe), 3.93 (s, 3 H, COOMe), 4.00 (d, J = 10.2, 1 H, H5¢b), 6.88–6.95 (m, 2 H, H3¢, H5¢), 7.29 (s, 1 H, H3), 7.39–
7.50 (m, 4 H, Ph, NH), 7.50–7.57 (m, 2 H, Ph), 7.57–7.64 (m, 2 H, H2¢, H6¢)
12¢d
1.22 (s, 3 H, CH3), 2.46 (d, J = 19.0, 1 H, H4¢a), 2.77 (d, J = 19.2, 1 H, H4¢b), 3.55 (d, J = 9.7, 1 H, H5¢a), 3.86 (s, 3 H, COOMe),
3.91 (s, 3 H, COOMe), 4.20 (d, J = 9.6, 1 H, H5¢b), 7.14 (s, 1 H, H3)
12e
0.99 (s, 3 H, CH3), 2.72 (d, J = 17.5, 1 H, H4¢a), 3.28 (d, J = 17.4, 1 H, H4¢b), 3.69 (d, J = 10.1, 1 H, H5¢a), 3.84 (s, 3 H, COOMe),
3.95 (s, 3 H, COOMe), 4.06 (d, J = 10.2, 1 H, H5¢b), 7.14–7.19 (m, 1 H, H4¢), 7.26–7.34 (m, 3 H, H2¢, H3, NH), 7.40–7.58 (m, 5
H, Ph), 7.67–7.72 (m, 1 H, H6¢), 7.81–7.85 (m, 1 H, H2¢)
12¢e
1.24 (s, 3 H, CH3), 2.46 (d, J = 19.0, 1 H, H4¢a), 3.57 (d, J = 9.8, 1 H, H5¢a), 3.86 (s, 3 H, COOMe), 3.91 (s, 3 H, COOMe), 4.19
(d, J = 10.1, 1 H, H5¢b)
12f
0.98 (s, 3 H, CH3), 2.75 (d, J = 17.5, 1 H, H4¢a), 3.29 (d, J = 17.4, 1 H, H4¢b), 3.72 (d, J = 10.1, 1 H, H5¢a), 3.85 (s, 3 H, COOMe),
3.99 (s, 3 H, COOMe), 4.12 (d, J = 10.1, 1 H, H5¢b), 7.24 (br s, 1 H, NH), 7.39 (s, 1 H, H3), 7.42–7.59 (m, 5 H, Ph), 7.99–8.05
(m, 2 H, H2¢, H6¢), 8.22–8.29 (m, 2 H, H3¢, H5¢)
12¢f
1.27 (s, 3 H, CH3), 2.48 (d, J = 19.4, 1 H, H4¢a), 2.78 (d, J = 19.1, 1 H, H4¢b), 3.61 (d, J = 9.8, 1 H, H5¢a), 3.87 (s, 3 H, COOMe),
3.90 (s, 3 H, COOMe), 4.18 (d, J = 9.9, 1 H, H5¢b), 7.18 (br s, 1 H, NH), 7.28 (s, 1 H, H3)
12gc
0.79 (s, 3 H, CH3), 2.64 (d, J = 17.1, 1 H, H4¢a), 3.00 (d, J = 17.1, 1 H, H4¢b), 3.67 (s, 3 H, COOMe), 3.72 (d, J = 10.1, 1 H, H5¢a),
3.94 (s, 3 H, COOMe), 4.15 (d, J = 10.4, 1 H, H5¢b), 7.48–7.62 (m, 5 H, Ph), 7.82 (s, 1 H, H3), 7.82–7.87 (m, 2 H, H2¢, H6¢),
7.99–8.05 (m, 2 H, H3¢, H5¢), 9.06 (br s, 1 H, NH), 12.89 (br s, 1 H, COOH)
12¢gc
1.31 (s, 3 H, CH3), 3.66 (s, 3 H, COOMe), 3.71 (s, 3 H, COOMe), 9.33 (s, 1 H, NH), 12.75 (br s, 1 H, COOH)
a The 1H NMR spectra of 10¢a–e,g, 10¢¢a–e,g and 12¢a–g are part spectra.
b Unless otherwise stated.
c DMSO-d6.
Table 4 13C NMR Data for Compounds 3, 11a–f, and 12a–f
Compound Solvent
13C NMR d, J (Hz)
3
CDCl3
21.6, 42.0, 50.9, 56.5, 102.3, 115.0, 127.0, 127.7, 129.3, 137.3, 141.4, 145.7, 168.0, 172.9
20.0, 53.8, 112.4, 120.5, 120.6, 125.7, 126.9, 127.5, 128.8, 129.0, 131.1, 136.7, 138.1, 140.7, 170.7
20.1, 20.4, 53.8, 112.4, 120.5, 120.7, 127.0, 127.5, 129.0, 129.3, 135.2, 135.9, 136.8, 137.6, 140.8, 170.7
11a
11b
11c
DMSO-d6
DMSO-d6
DMSO-d6
20.1, 53.8, 107.9, 112.5, 115.7 (d, J = 22.8), 122.7 (d, J = 7.1), 127.0, 127.6, 129.0, 134.7, 136.8, 138.1, 140.7, 159.9
(d, J = 243), 170.7
11d
DMSO-d6
20.1, 53.9, 55.4, 112.5, 114.1, 122.7, 127.0, 127.6, 129.1, 131.5, 136.8, 137.5, 140.8, 157.4, 170.8
Synthesis 2009, No. 2, 217–226 © Thieme Stuttgart · New York

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U. Uršič et al.
PAPER
Table 4 13C NMR Data for Compounds 3, 11a–f, and 12a–f (continued)
13C NMR d, J (Hz)
Compound Solvent
11e
11f
12a
DMSO-d6
DMSO-d6
CDCl3
20.0, 53.7, 108.4, 112.6, 118.4, 119.6, 125.4, 127.0, 127.6, 129.1, 130.7, 133.3, 136.7, 138.9, 139.4, 140.7, 170.7
20.0, 53.6, 108.9, 112.8, 119.6, 124.9, 127.0, 127.7, 129.2, 136.6, 140.3, 140.7, 143.3, 144.0, 170.7
20.7, 29.9, 36.3, 52.4, 53.8, 60.9, 71.4, 75.6, 119.9, 125.9, 127.6, 128.7, 128.9, 131.3, 133.6, 133.8, 137.7, 146.7,
164.8, 167.9, 168.5, 169.3
12b
12c
12d
12e
12f
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
20.9, 21.2, 29.9, 36.5, 52.5, 53.8, 60.9, 71.3, 75.3, 120.3, 127.7, 128.7, 129.5, 131.3, 133.6, 134.0, 135.3, 135.8,
146.4, 164.9, 167.9, 168.5, 169.3
20.8, 29.9, 36.4, 52.5, 53.9, 61.0, 71.5, 75.6, 115.7 (d, J = 22.7), 122.0 (d, J = 8.2), 127.7, 128.7, 131.4, 133.8, 133.9,
134.0, 146.8, 160.6 (d, J = 245), 164.8, 168.0, 168.5, 169.4
20.9, 29.9, 36.4, 52.5, 53.8, 55.7, 60.9, 71.3, 75.2, 114.3, 122.4, 127.7, 128.7, 131.1, 131.3, 133.6, 134.0, 146.4,
158.0, 164.9, 168.0, 168.5, 169.4
20.7, 29.9, 36.3, 52.5, 53.9, 61.0, 71.6, 75.9, 117.4, 119.5, 125.7, 127.7, 128.7, 130.0, 131.4, 133.6, 133.9, 134.7,
138.9, 147.1, 164.7, 167.9, 168.5, 169.4
20.7, 30.0, 36.3, 52.7, 54.1, 61.1, 72.0, 76.3, 118.6, 124.9, 127.8, 128.8, 131.7, 133.3, 134.4, 142.9, 144.6, 148.1,
164.7, 168.1, 168.6, 169.5
(10) (a) Jaške, R.; Svete, J.; Stanovnik, B.; Golobič, A.
Tetrahedron 2004, 60, 4601. (b) Časar, Z.; Bevk, D.; Svete,
Acknowledgment
Financial support from the Slovenian Research Agency through
grants P1-0179 and J1-6689-0103-04 is gratefully acknowledged.
We thank the pharmaceutical companies Krka d.d. (Novo mesto,
Slovenia) and Lek d.d., a Sandoz company (Ljubljana, Slovenia) for
the financial support. Crystallographic data were collected on a
Kappa CCD Nonius diffractometer in the Laboratory of Inorganic
Chemistry, Faculty of Chemistry and Chemical Technology, Uni-
versity of Ljubljana, Slovenia. We acknowledge with thanks the fi-
nancial contribution of the Ministry of Science and Technology,
Republic of Slovenia through grant Packet X-2000 and PS-511-102,
which made the purchase of the apparatus possible.
J.; Stanovnik, B. Tetrahedron 2005, 61, 7508.
(c) Stanovnik, B.; Svete, J. Mini-Rev. Org. Chem. 2005, 2,
211.
(11) (a) Wagger, J.; Bevk, D.; Meden, A.; Svete, J.; Stanovnik, B.
Helv. Chim. Acta 2006, 89, 240. (b) Wagger, J.;
Golič Grdadolnik, S.; Grošelj, U.; Meden, A.; Stanovnik, B.;
Svete, J. Tetrahedron: Asymmetry 2007, 18, 464.
(c) Wagger, J.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik,
B. Tetrahedron 2008, 64, 2801. (d) Wagger, J.; Svete, J.;
Stanovnik, B. Synthesis 2008, 1436.
(12) Uršič, U.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik, B.
Tetrahedron Lett. 2008, 49, 3775.
(13) Crystallographic data for compound 3 in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
689402. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, CB2 1EZ, UK
[fax: +44(1223)336033 or e-mail:
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Synthesis 2009, No. 2, 217–226 © Thieme Stuttgart · New York