The synthesis of heterocyclic derivatives from pyran-2-ones and hydrazine hydrate. Ammonium cerium(IV) nitrate as an efficient oxidant in pyridazine chemistry

Article abstract of DOI:10.1016/j.tet.2006.07.061

A novel reaction of 3-amino-2H-pyran-2-ones and their fused derivatives with hydrazine hydrate leading to the corresponding pyridazine derivatives is reported. Further oxidation with ammonium cerium(IV) nitrate (CAN, from Cerium(IV) Ammonium Nitrate) yiel

Full text of DOI:10.1016/j.tet.2006.07.061

Tetrahedron 62 (2006) 9718–9725
The synthesis of heterocyclic derivatives from pyran-2-ones and
hydrazine hydrate. Ammonium cerium(IV) nitrate as an
efficient oxidant in pyridazine chemistry
*
ꢀ
ꢀ
Franc Pozgan, Slovenko Polanc and Marijan Kocevar
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asꢀkercꢀeva 5, SI-1000 Ljubljana, Slovenia
Received 24 April 2006; revised 4 July 2006; accepted 20 July 2006
Available online 10 August 2006
ˇ
Dedicated to Professor Miha Tisler on the occasion of his 80th birthday
Abstract—A novel reaction of 3-amino-2H-pyran-2-ones and their fused derivatives with hydrazine hydrate leading to the corresponding
pyridazine derivatives is reported. Further oxidation with ammonium cerium(IV) nitrate (CAN, from Cerium(IV) Ammonium Nitrate)
yields a collection of pyridazine-3-carboxylates.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Many transformations of pyran-2-ones with nucleophilic
reagents yielding different types of products have been
investigated.10 As part of our continuing interest in the
transformations of pyran-2-one derivatives with hydrazine
and its derivatives11 we preliminarily reported on a new
conversion of pyrano[3,2-c]azepines with hydrazine hydrate
into representatives of pyridazino[4,3-c]azepines.11e The
presence of a free amino group at position 3 in the starting
pyran-2-ones was found to be crucial for the synthesis of
pyridazine derivatives, because all other fused pyran-2-
ones, possessing a benzoyl-protected amino group, led in
the reaction with hydrazine hydrate (or its derivatives) to
different products: to fused pyridine derivatives,11a,b in
some cases the reaction took place at the side group,11b,d,g,h
in other cases b-heteroaryl-a,b-didehydro-a-amino acid
derivatives were obtained.11c,h,i In this paper we report on
the exploration of the scope and limitations of the reaction
starting from a variety of 2H-pyran-2-ones and fused
pyran-2-ones, bearing a free amino group at position 3,
with hydrazine hydrate into representatives of the pyrida-
zine system, which were further oxidized by CAN toward
different types of pyridazines.
Pyridazines and fused pyridazines are of considerable
interest because of their synthetic utility1 and important
pharmacological activities,2 many of them related to the
cardiovascular system. 1,4-Dihydropyridazine derivatives
including their carboxylic esters can be obtained in the
cycloaddition reactions of 1,2,4,5-tetrazines with different
dienophiles,3 by the reaction of aminocarbonylazoalkenes
with b-tricarbonyl compounds,4 via the cycloaddition of
diazomethane to cyclopropenes,5 etc. Since the 1,4-dihydro-
pyridazine system represents an intermediate for aromatized
pyridazines, a plethora of inorganic and organic oxidants
have been found to readily dehydrogenate dihydropyridazi-
nes.3c,d,4,5,6 Among them, CAN,7 a powerful one-electron
oxidant, which has already shown great utility in carbon–
carbon7a or carbon–heteroatom7b bond-forming reactions,
was previously used as a reagent for the cleavage of the hy-
drazine moiety of carbohydrazides.8 Recently, we have also
reported on its applicability as an oxidant for 1,4,6,7,8,9-
hexahydro-5H-pyridazino[4,3-c]azepine-3-carboxylic acid
hydrazides in the presence of an alcohol, where both
the pyridazine moiety and the carbohydrazido group were
successfully oxidized, resulting in the corresponding aro-
matic pyridazine esters.9 The main advantages of CAN
are its experimental simplicity, easy handling, non-toxicity,
and solubility in many common organic solvents.
2. Results and discussion
In the first stage we examined the preparation of 1,4-di-
hydropyridazines 2, containing a fused polymethylene
chain, by the reaction of fused pyran-2-ones 1 with hydra-
zine hydrate (Scheme 1). The reaction of cyclooctene-fused
pyran-2-one 1b with hydrazine hydrate, when using similar
conditions to those that we preliminarily applied for the
Keywords: Heterocycles; Pyridazine-3-carbohydrazides; Esters; Dehydro-
genation; Oxidation; Ammonium cerium(IV) nitrate.
* Corresponding author. Tel.: +386 1 2419230; fax: +386 1 2419220;
e-mail: marijan.kocevar@fkkt.uni-lj.si
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.061

F. Poꢀzgan et al. / Tetrahedron 62 (2006) 9718–9725
9719
transformation of pyrano[3,2-c]azepines,11e was not com-
plete after 9 h, as indicated by TLC. On the other hand,
when the reactions of 1a,b were carried out in boiling hydra-
zine hydrate, which served as the reagent and as a solvent,
pure dihydropyridazine derivatives 2a,b were isolated after
a short reaction time (20 min) with good-to-excellent yields
(up to 88%).
the 9a-hydroxypyridazino[3,4-c]azepine derivative 8 with
a high yield (Scheme 2).
O
O
H
N
H
N
N2H4
2 -NH3
OH
CONHNH
•
5 N2H4 H2O
O
O
O
EtOH, ∆, 5 h
NH2
NH
5
6
OH
O
O
H
H
NH2
H
H
N
O
O
N
•
N
N2H4 H2O
N8
9
N
N
N
2N
1
9a
7
6
3
4a
, 20 min
4
5
( )n
NH2
( )
CONHNH2
CONHNH2
n
CONHNH2
7
8: 83%
2a: 51%
1a (n = 1)
2b: 88%
6 CAN/ROH
1b (n = 2)
HCl(aq)/EtOH
CH2Cl2
or MeOH
rt, 24 h
rt, 0.5 h
∆, 0.5 h
O
6 CAN/MeOH
H
N
O
N
H
N
rt, 15 min
H
6 CAN/MeOH
rt, 0.5 h
N
N
N
N
N
N
CONHNH2
CO2R
9: 91%
( )n
CO2Me
( )
CONHNH2
10a (R = Me) from 8: 59%
10a from 9: 51%
n
4a: 85%
3a,b: quantitatively
4b: 98%
10b (R = Et) from 8: 55%
Scheme 1. Synthesis of cycloalkene-fused pyridazines.
Scheme 2. Pyrano[2,3-c]azepine 5 as a synthon for pyridazino[3,4-c]aze-
pines.
1H NMR spectra of 2a and 2b in DMSO-d6 solutions re-
vealed that these compounds have the 1,4-dihydropyridazine
structure and no trace of any other tautomer was observed.
In fact, a characteristic two-proton signal appeared at
w2.85 ppm (A2 system) for methylene protons at position
4, whereas 1-H protons showed a resonance around 9 ppm.
Compounds 2 are sensitive to oxidation from the air in solu-
tion, as well as in the crystalline form, and readily trans-
formed into their aromatic analogues 3. Thus, stirring of
the compounds 2a,b for 24 h in methylene chloride (or meth-
anol) at room temperature in the presence of air afforded 3a,b
in a quantitative yield, whereas in the crystalline form after
24 h anw90% aromatization of the compound 2b took place.
This transformation can be considerably reduced by storing
compounds 2 in an argon atmosphere at low temperature.
For example, with the compound 2b, after three months at
approximately ꢀ30 ꢁC in a closed bottle under argon atmo-
sphere only an approximately 5% conversion into 3b was
observed. It has been reported that dihydropyridazines are
reactive toward molecular oxygen, normally forming the cor-
responding aromatic pyridazines;12 however, in certain cases
they gave hydroperoxides and endoperoxides.12a With our
compounds, though, we were not able to detect or isolate
any other intermediate: only pyridazine derivatives 3 were
obtained as the final products. Additionally, we could accel-
erate the above dehydrogenation by bubbling oxygen into the
refluxed mixture of 2b in methanol; in this particular case the
reaction was completed within 4 h to give 3b. When bubbling
oxygen in the presence of 50 mass % of activated carbon
(DARCOÒ KB)13 the reaction was finished in 3 h to give
quantitatively 3b. Compounds 2 can also be smoothly oxi-
dized with CAN in a methanolic solution to give the pyrida-
zine esters 4 in 85% (4a) and 98% (4b) yields. In the course
of this reaction the formation of the ester from the hydrazide
is accompanied by a concomitant aromatization of the 1,4-
dihydropyridazine ring.
The structure of the compound 8 was established on the basis
of its NMR spectroscopic data. The two- and three-bond H,
C connectivities, obtained from the HMBC measurement,
strongly support the 9a-hydroxy-4,4a,5,6,7,8,9,9a-octa-
hydro-1H-pyridazino[3,4-c]azepine structure; namely, 1-H,
8-H, the methylene protons at position 4 (4-CHaHb protons
not being chemically and magnetically equivalent), and the
hydroxy group correlate with 9a-C (78.7 ppm) in the
HMBC spectrum, whereas the 1-H and 4-CHaHb protons
correlate with 3-C (135.5 ppm), thus revealing an azepine-
fused pyridazine skeleton and not an open-ring intermediate
7 (or its tautomer) (Fig. 1).
Compound 8 has been found to readily eliminate a water
moleculewhen treated with aqueous HCl in absolute ethanol,
thus giving the 4,5,6,7,8,9-hexahydro-1H-pyridazino[3,4-
c]azepine derivative 9. Treatment of the compound 8 with
6 equiv of CAN in an alcoholic solution led to the isolation
of the fused pyridazine esters 10 in moderate yields (55–
59%). Alternatively, the esters 10 can also be prepared by
the oxidation of the compound 9 with CAN, as shown in
OH
4-Hb
1-H
8-H
4-Ha
9a-C
80
90
100
110
120
130
3-C
140
ppm
In contrast to our previous observation of the behavior of pyr-
ano[3,2-c]azepines in a reaction with hydrazine hydrate,11e
the reaction of the isomeric pyrano[2,3-c]azepine derivative
5 with 5 equiv of hydrazine hydrate in boiling ethanol led to
8.0
7.0
6.0
5.0
4.0
3.0
2.0
ppm
Figure 1. A part of the 1H–13C HMBC spectrum of the compound 8.

9720
F. Poꢀzgan et al. / Tetrahedron 62 (2006) 9718–9725
the case of the methyl ester 10a. On the basis of the above
results we can assume that an acidic medium catalyzes the
elimination of a water molecule from the compound 8 during
the oxidation with CAN, thus initially giving the 1,4-dihydro-
pyridazine intermediate, which is further dehydrogenated
and transformed to the aromatic pyridazine esters 10 as the
final products. The described method is very convenient for
the preparation of pyridazino[3,4-c]azepines for which, to
our knowledge, only two representatives have been previ-
ously described.14
(17%) of the 1,4-dihydropyridazine derivative 15b. On the
other hand, after refluxing the 2H-pyran-2-one 11c in the
presence of 5 equiv of hydrazine hydrate using ethanol or
butanol as a solvent, we isolated the 1,4-dihydropyridazine
derivative 15c, which in ethanol was accompanied by the
aromatic pyridazine 16c (entries 3 and 4, Table 1). Com-
pounds 14a,b can easily eliminate a hydrazine molecule,
when applying acidic conditions (10 mol % of TsOH in
aqueous solution), to give 15a,b in 90 and 71% yields,
respectively. Compounds 15 have been found to be sensitive
to the oxygen in air. For example, if 15b was stirred in
methylene chloride for 24 h at room temperature, a conver-
sion into the aromatic pyridazine 16b was observed in more
than 95% (according to the 1H NMR spectrum). On the other
hand, 1,4-dihydropyridazine 15c was found to be more
resistant toward such oxidation in air; 72-h-stirring of its
methanolic solution at room temperature resulted only in
negligible formation of the aromatic analogue 16c (as indi-
cated by TLC). Aromatization was successfully accom-
plished by 7-h-bubbling of oxygen into the refluxed
mixture of 15c and 50 mass % of activated carbon
(DARCOÒ KB) in methanol. For comparison, in the absence
of activated carbon, but just bubbling oxygen into the re-
fluxed mixture for 10 h, a conversion of about 40% of 15c
took place.
Bearing in mind the above results of the fused pyran-2-ones,
we decided to focus our attention on studies of the suscepti-
bility of non-fused 2H-pyran-2-ones 11 to nucleophilic
attack by a hydrazine molecule (Scheme 3, Table 1).
R2
O
O
R2
O
CONHNH2
NH
•
N2H4 H2O
∆
NH2
R1
11
R1
12
R2
N
H2NN
R2
R1
NH
CONHNH2
NNH2
NHNH2
CONHNH2
R1
14
+
13
10% TsOH/H2O
∆, 15 min
The structures of the compounds 14 were determined on the
basis of microanalyses, mass spectra, and NMR data. The
mass spectra of the compounds 14a and 14b only showed
peaks after the elimination of a hydrazine molecule
(MH+ꢀN2H4 or M+ꢀN2H4), thus indicating that they con-
tain in their structure a labile hydrazine moiety. In the
HMBC spectrum of the compound 14a, the ortho protons
of the phenyl group and the 2-H correlate with the 6-C of
the pyridazine ring, thus supporting the 2,3,4,5-tetrahydro-
pyridazine structure (Fig. 2).
H
R2
N
N
a: R1 = H, R2 = Ph
b: R1 = H, R2 = t-Bu
c: R1 = Me, R2 = 2-Pyridyl
CONHNH2
CONHNH2
R1
15
+
O2
MeOH
R2
N
N
R1
16
Additionally, it has been reported previously that the imine
fragments of 2,3,4,5-tetrahydro-3-pyridazine carboxylic
acid derivatives show characteristic signals at dCz
140 ppm.15 This is in agreement with our observation for
the compound 14a, where the resonance signal for 6-C
appears at 140.9 ppm. Furthermore, the 2-H as well as the
methylene protons at positions 4 and 5 of the pyridazine
Scheme 3. Reaction of 2H-pyran-2-ones 11 with hydrazine.
Due to the absence of a fused ring in the compounds 11, after
the opening of the lactone ring with hydrazine the formation
of a more flexible intermediate might be expected; this might
then open up possibilities for different reactions. For exam-
ple, one might expect that such an open-ring system would
not be prone to cyclization, thus allowing an attack of addi-
tional hydrazine molecule(s). Indeed, when 6-substituted
2H-pyran-2-ones 11a and 11b were allowed to react with
boiling hydrazine hydrate for 20 min the products 14a and
14b were isolated in 76 and 67% yields, respectively. The
product 14b was also accompanied by a small quantity
2-H, 6-H (Ph)
2-H
135.0
Table 1. Reaction of 2H-pyran-2-ones 11 with hydrazine
140.0
Products (yield, %)a
6-C
Entry
Starting 11
t
1
2
3
4
11a
11b
11c
11c
20 minb
20 minb
22 hc
14a (76)
14b (67)+15b (17)
15c (41)d+16c (7)d
15c (71)d
4.5 he
145.0
ppm
a
Yields of isolated products are given.
Hydrazine hydrate used as a solvent.
Five equivalents of N2H4$H2O in ethanol.
Yield after isolation by column chromatography.
Five equivalents of N2H4$H2O in butanol.
b
c
d
e
7.80
ppm
7.70
7.60
7.50
7.40
7.30
7.20
7.10
Figure 2. A part of the 1H–13C HMBC spectrum of the compound 14a.

F. Poꢀzgan et al. / Tetrahedron 62 (2006) 9718–9725
9721
ring in compound 14a correlate with the 3-C. This carbon
atom shows a resonance at 71.9 ppm, which is consistent
with the chemical shift of a quaternary sp3 carbon atom
deshielded by the neighboring heteroatoms.16
produced and further transformed to the aromatized deriva-
tive 22.
H
H
R2
N
R2
R2
R2
N
Ce (IV)
-Ce (III)
+
N
H
-H
COX
N
H
The formation of the products 14 and 15 from 11 might be
explained as follows. We assume that after the opening of
the lactone ring of the 2H-pyran-2-ones 11 with hydrazine,
yielding the intermediate 12, the attack of two additional
hydrazine molecules at the electrophilic C]O and C]N
groups of 12 takes place, thus leading to the a,d-dihydrazono-
hydrazide derivative 13 as an intermediate. Furthermore,
compounds 14 could be formed from 13 by the cyclization
of the amino group of the d-hydrazone moiety with the
C]N group of a-hydrazone. After the elimination of a
hydrazine molecule from 14 the dihydropyridazine 15 is
finally formed in a 1,4-dihydro tautomeric form.
COX
R1
19
R1
18
H
N
H
R2
N
+
Ce (IV)
-Ce (III)
+
N
N
-H
COX
COX
R1
20
R1
21
N
N
X = NHNH2, OMe
COX
R1
22
Scheme 4. Dehydrogenation of the 1,4-dihydropyridazine ring with Ce(IV).
To demonstrate the utility of the compounds 14 and 15, we
treated them with 6–8 equiv of CAN in the presence of
methanol and, after isolation by extraction, pyridazine-3-
carboxylic esters 17a–c were obtained as the sole products
in a 79–93% yield (Table 2). It is obvious that an oxidation
of the hydrazide function was accompanied by an acid-
catalyzed elimination of hydrazine from compounds 14
(as mentioned above), and the dehydrogenation of a 1,4-di-
hydropyridazine ring.
3. Conclusion
We have presented a new transformation of a variety of
2H-pyran-2-ones and fused pyran-2-ones with hydrazine
hydrate into the corresponding 1,4-dihydropyridazine deriv-
atives. We found that different pyran-2-ones required differ-
ent reaction conditions for successful transformation to the
pyridazine system. We have also shown that CAN is able
to serve as a very useful oxidant for the carbohydrazide
moiety as well as for the dehydrogenation of the 1,4-di-
hydropyridazine ring. Since it was previously shown that
representatives of 2,3,4,5-tetrahydropyridazine-3-carbox-
ylic acids and their derivatives possess a variety of biological
activities,2,15 the reported method and transformation might
be of interest for the further design of similar novel
compounds.
In all the above transformations with CAN a 1,4-dihydropyr-
idazine ring was dehydrogenated in addition to the oxidation
of the carbohydrazide moiety. The latter reaction toward the
corresponding esters proceeds probably via acyl diimides as
intermediates and eventually also via the formation of the
acyl cation as discussed previously.8
On the other hand, to our knowledge, the oxidation of the
1,4-dihydropyridazine ring has not yet been rationalized. It
seems reasonable to propose a tentative pathway related to
those depicted for oxidations of 1,4-dihydropyridines.17
Oxidation of a 1,4-dihydropyridazine 18 with CAN is pre-
sumably initiated by a single electron transfer to Ce(IV) gen-
erating a resonance stabilized radical cation 19 (Scheme 4),
which then loses a proton to give a stabilized radical 20. In
the subsequent oxidation the protonated pyridazine 21 is
4. Experimental
4.1. General
Compounds 1 and 11 were prepared from 3-benzoylamino-
substituted pyran-2-one derivatives by a known method.18,19
Compound 5 was prepared as described in the literature.11d
All other reagents and solvents were used as obtained from
Table 2. Oxidation of compounds 14 and 15 with CAN in the presence of
methanol
1
commercial suppliers. Melting points are uncorrected. H
NMR spectra were recorded at 29 ꢁC using TMS as an inter-
nal standard. 13C NMR spectra are referenced against the
central line of DMSO-d6 at d¼39.5 ppm and CDCl3 at
d¼77.0 ppm. TLC was carried out on silica-gel TLC cards.
Column chromatography was carried out with silica-gel 60
(220–440 mesh).
R2
N
6-8 CAN/MeOH
rt, 0.5 ha
N
14, 15
CO2Me
R1
17
a: R1 = H, R2 = Ph
b: R1 = H, R2 = t-Bu
c: R1 = Me, R2 = 2-Pyridyl
Entry
Starting 14 or 15
Product (yield, %)b
4.2. General procedure for the preparation of
pyridazines 2a,b, 14a,b, and 15b
1
2
3
4
14a
14b
15b
15c
17a (93)c
17b (89)c
17b (84)d
17c (79)d
A mixture of 1a,b18 or 11a,b18 (2 mmol) and hydrazine hy-
drate (1.5 g, 98%, 29.36 mmol) was refluxed for 20 min and
then evaporated under reduced pressure. A mixture of water/
methanol (5:1) (3 mL) in the case of 2a or water (3 mL) in
the case of 2b was added to the residue. Upon cooling, the
precipitated yellow solid was filtered off and washed with
a
Reaction time after the addition of the entire amount of compound 14 or
15 to the mixture of CAN in methanol.
Yields of isolated products are given.
Eight equivalents of CAN used.
Six equivalents of CAN used.
b
c
d

9722
F. Poꢀzgan et al. / Tetrahedron 62 (2006) 9718–9725
a small amount of water to give 2a (or 2b). For 14a,b, meth-
anol (3 mL) was added to the residue, and upon cooling the
white solid product 14a,b was filtered off. After the separa-
tion of 14a the filtrate was concentrated to 50% of its volume
under reduced pressure to give an additional quantity of 14a.
The filtrate after the filtration of 14b was evaporated to
dryness, and diethyl ether (1.5 mL) was added to the residue.
Upon cooling, a yellow solid 15b was filtered off.
2, 8, 9, 14 or 15 (1 mmol) was added over a period of 10–
20 min. The stirring was continued for 0.25–0.5 h, then the
solvent was evaporated under reduced pressure, the solid
residue was treated with water (10 mL), and the aqueous
mixture was extracted with methylene chloride (6ꢂ10 mL).
The collected organic layers were dried over anhydrous
Na2SO4 and evaporated to give 4, 10 or 17. In the case of
4a, further purification by column chromatography (CHCl3/
MeOH 25:1) was applied.
4.3. General procedure for the preparation of
pyridazines 8, 15c, and 16c
4.8. Analytical and spectroscopic data of products
A mixture of 511d or 11c18 (2 mmol), hydrazine hydrate
(511 mg, 98%, 10 mmol), and absolute ethanol (8 mL) was
refluxed for 5 h (for 8) or for 22 h (for 15c/16c). For the prep-
aration of pure 15c the solution of 11c and hydrazine hydrate
in butanol (8 mL) was refluxed for 4.5 h. The solvent was
evaporated under reduced pressure. For 8, methanol (4 mL)
was added to the solid residue and, upon cooling, a white
solid was filtered off and washed with a small amount of
methanol. For the separation of the mixture 15c/16c column
chromatography (ethyl acetate/MeOH 25:1) of the solid
residue was applied. For the isolation of pure 15c (in the
case where butanol was used as a solvent) column chromato-
graphy (ethyl acetate/MeOH 25:1) was applied.
4.8.1. 4,5,6,7,8,9-Hexahydro-1H-cyclohepta[c]pyrida-
zine-3-carbohydrazide (2a). Mp 80–84 ꢁC (MeOH/H2O).
1
IR (KBr): 3376, 2918, 1648, 1608, 1504 cmꢀ1. H NMR
(300 MHz, DMSO-d6): d 1.47 (m, 4H), 1.63 (m, 2H), 1.99
(m, 2H), 2.12 (m, 2H), 2.86 (s, 2H), 4.20 (s, 2H), 8.74 (s,
1H), 8.96 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6):
d 25.5, 26.3, 26.9, 28.9, 30.8, 32.3, 103.0, 131.6, 135.5,
164.5. EI-MS: m/z (%) 208 (M+, 15), 192 (100). Anal. Calcd
for C10H16N4O: C, 57.67; H, 7.74; N, 26.90. Found: C,
57.69; H, 8.01; N, 27.25.
4.8.2. 1,4,5,6,7,8,9,10-Octahydrocycloocta[c]pyridazine-
3-carbohydrazide (2b). Mp 93–94 ꢁC (MeOH/H2O). IR
(KBr): 3356, 2920, 2849, 1626, 1497 cmꢀ1 1H NMR
.
4.4. Transformation of 8 to 9
(300 MHz, DMSO-d6): d 1.44 (m, 8H), 2.03 (m, 2H), 2.15
(m, 2H), 2.83 (s, 2H), 4.20 (s, 2H), 8.74 (s, 1H), 9.04 (s,
1H). 13C NMR (75.5 MHz, DMSO-d6): d 24.3, 25.8, 25.9,
26.0, 27.2, 28.9, 29.1, 100.6, 131.4, 133.0, 164.6. EI-MS:
m/z (%) 222 (M+, 15), 206 (100). Anal. Calcd for
C11H18N4O: C, 59.44; H, 8.16; N, 25.20. Found: C, 59.64;
H, 8.34; N, 25.50.
A mixture of 8 (241 mg, 1 mmol), aqueous hydrochloric
acid (200 mg, 9%), and absolute ethanol (5 mL) was re-
fluxed for 0.5 h. The reaction mixture was evaporated, water
(5 mL) was added to the residue and the mixture was neutral-
ized with solid NaHCO3. Upon cooling, the precipitate was
filtered off and washed with water to give 9 (203 mg, 91%)
as a yellow solid.
4.8.3. 6,7,8,9-Tetrahydro-5H-cyclohepta[c]pyridazine-3-
carbohydrazide (3a). Mp 172.8–173.4 ꢁC (EtOAc). IR
(KBr): 3307, 3256, 3206, 2935, 2923, 2854, 1682, 1668,
4.5. Transformation of 14 to 15
1
1632, 1585, 1501 cmꢀ1. H NMR (300 MHz, DMSO-d6):
A mixture of 14a,b (1 mmol), p-toluenesulfonic acid
(19 mg, 0.1 mmol), and water (3 mL) was refluxed for
15 min. Upon cooling, the precipitate was collected by filtra-
tion and washed with a small amount of water, affording
15a,b as yellow solids. Yields: 15a (194 mg, 90%), 15b
(139 mg, 71%).
d 1.63 (m, 4H), 1.84 (m, 2H), 2.90 (m, 2H), 3.24 (m, 2H),
4.64 (s, 2H), 7.88 (s, 1H), 10.23 (s, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 25.9, 26.7, 31.3, 33.4, 35.8,
124.4, 143.8, 151.7, 161.7, 166.7. EI-MS: m/z (%) 206
(M+, 99.5), 148 (100). Anal. Calcd for C10H14N4O: C,
58.24; H, 6.84; N, 27.16. Found: C, 58.54; H, 7.00; N, 26.89.
4.6. Aromatization of 1,4-dihydropyridazine derivatives
2 and 15
4.8.4. 5,6,7,8,9,10-Hexahydrocycloocta[c]pyridazine-3-
carbohydrazide (3b). Mp 168–171 ꢁC (EtOAc). IR (KBr):
1
3310, 3248, 3202, 2931, 2858, 1679, 1631, 1505 cmꢀ1. H
A solution of 2 or 15b (1 mmol) in MeOH or CH2Cl2 (4 mL)
was stirred at room temperature in the presence of air for 24 h.
The solvent was evaporated in vacuo to afford 3 in a quantita-
tive yield. In the case of 15b, over 95% conversion to 16b oc-
curred as indicated on the basis of 1H NMR spectrum of the
crude product. By bubbling oxygen into the refluxed mixture
of 15c (50 mg, 0.216 mmol) and activated charcoal
DARCOÒ KB (Aldrich) (25 mg) in methanol (4 mL) for
7 h a complete conversion to 16c was observed.
NMR (300 MHz, DMSO-d6): d 1.31 (m, 4H), 1.73 (m,
4H), 2.87 (m, 2H), 3.16 (m, 2H), 4.69 (br s, 2H), 7.91 (s,
1H), 10.22 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6):
d 25.1, 25.2, 30.0, 30.5, 30.9, 31.6, 124.7, 142.1, 151.6,
161.7, 165.3. EI-MS: m/z (%) 220 (M+, 100). Anal. Calcd
for C11H16N4O: C, 59.98; H, 7.32; N, 25.44. Found: C,
59.94; H, 7.56; N, 25.60.
4.8.5. Methyl 6,7,8,9-tetrahydro-5H-cyclohepta[c]pyri-
dazine-3-carboxylate (4a). Mp 58.5–59.2 ꢁC (Et2O). IR
1
4.7. General procedure for the oxidation of the pyrida-
zine derivatives 2, 8, 9, 14, and 15 with CAN
(KBr): 3045, 2920, 2848, 1729 cmꢀ1. H NMR (300 MHz,
DMSO-d6): d 1.65 (m, 4H), 1.86 (m, 2H), 2.90 (m, 2H),
3.26 (m, 2H), 3.94 (s, 3H), 7.97 (s, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 25.8, 26.5, 31.3, 33.2, 35.9,
52.6, 126.7, 143.4, 150.0, 164.5, 167.5. EI-MS: m/z (%)
To a stirred mixture of CAN (6–8 mmol; see Schemes 1 and
2, and Table 2) in methanol (10–15 mL) at room temperature

F. Poꢀzgan et al. / Tetrahedron 62 (2006) 9718–9725
9723
1
206 (M+, 18), 148 (100). Anal. Calcd for C11H14N2O2: C,
64.06; H, 6.84; N, 13.58. Found: C, 64.31; H, 7.01; N, 13.41.
IR (KBr): 3306, 3264, 3164, 1667, 1603, 1498 cmꢀ1. H
NMR (300 MHz, DMSO-d6): d 1.90 (m, 2H), 2.50 (m,
2H), 3.31 (br s, 2H), 4.10 (br s, 1H), 4.26 (br s, 2H), 7.29
(m, 4H), 7.62 (m, 2H), 9.03 (br s, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 19.5, 24.9, 71.9, 123.9, 127.2,
128.0, 138.3, 140.9, 171.2. FABMS: m/z (%) 217
(MH+ꢀN2H4, 52), 185 (100). HRMS (EI) calcd for
C11H12N4O (M+ꢀN2H4) 216.1011, found 216.1017. Anal.
Calcd for C11H16N6O: C, 53.21; H, 6.50; N, 33.85. Found:
C, 53.49; H, 6.68; N, 33.54.
4.8.6. Methyl 5,6,7,8,9,10-hexahydrocycloocta[c]pyrida-
zine-3-carboxylate (4b). Mp 60–62 ꢁC (Et2O). IR (KBr):
2940, 2911, 2859, 1715 cmꢀ1
.
1H NMR (300 MHz,
DMSO-d6): d 1.31 (m, 4H), 1.73 (m, 4H), 2.87 (m, 2H),
3.19 (m, 2H), 3.94 (s, 3H), 8.00 (s, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 25.0, 25.2, 29.8, 30.4, 30.8,
31.7, 52.6, 127.1, 141.7, 149.8, 164.5, 166.1. EI-MS: m/z
(%) 220 (M+, 30), 162 (100). Anal. Calcd for
C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C,
65.18; H, 7.53; N, 13.01.
4.8.12. 6-tert-Butyl-3-hydrazino-2,3,4,5-tetrahydropyri-
dazine-3-carbohydrazide (14b). Mp 108–109 ꢁC (pyri-
dine). IR (KBr): 3305, 3267, 3170, 2962, 1666, 1608,
4.8.7. 9a-Hydroxy-9-oxo-4,4a,5,6,7,8,9,9a-octahydro-1H-
pyridazino[3,4-c]azepine-3-carbohydrazide (8). Mp 166–
169 ꢁC (MeOH/DMF). IR (KBr): 3318 br, 1678, 1656, 1616,
1507 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): d 1.24 (m, 1H),
1.38 (m, 1H), 1.64 (m, 1H), 1.79 (m, 3H), 2.56 (dd, J¼17.3,
4.7 Hz, 1H), 2.95 (m, 1H), 3.42 (m, 1H), 4.16 (br s, 2H), 6.24
(s, 1H), 7.72 (s, 1H), 8.05 (dd, J¼ca. 3.7 and 7.6 Hz, 1H),
8.77 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6): d 24.3,
28.9, 31.4, 31.9, 41.0, 78.7, 135.5, 163.9, 172.7. EI-MS:
m/z (%) 241 (M+, 30), 163 (100). Anal. Calcd for
C9H15N5O: C, 44.81; H, 6.37; N, 29.03. Found: C, 45.06;
H, 6.43; N, 29.32.
1507 cmꢀ1 1H NMR (300 MHz, DMSO-d6): d 1.02 (s,
.
9H), 1.67 (m, 2H), 2.07 (m, 2H), 3.20 (br s, 2H), 3.93 (br
s, 1H), 4.21 (br s, 2H), 6.44 (s, 1H), 8.91 (br s, 1H). FABMS:
m/z (%) 197 (MH+ꢀN2H4). HRMS (EI) calcd for C9H16N4O
(M+ꢀN2H4) 196.1324, found 196.1330. Anal. Calcd for
C9H20N6O: C, 47.35; H, 8.83; N, 36.81. Found: C, 47.09;
H, 8.83; N, 37.10.
4.8.13. 6-Phenyl-1,4-dihydropyridazine-3-carbohydra-
zide (15a). Mp 162–164 ꢁC (EtOAc/MeOH). IR (KBr):
3368, 3318, 3203, 1670, 1653, 1628, 1506 cmꢀ1. H NMR
1
(300 MHz, DMSO-d6): d 3.06 (d, J¼3.9 Hz, 2H), 4.31 (s,
2H), 4.89 (dt, J¼2.3, 3.9 Hz, 1H), 7.38 (m, 3H), 7.50 (m,
2H), 8.93 (s, 1H), 9.75 (d, J¼2.3 Hz, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 21.1, 92.0, 125.3, 128.3, 128.4,
132.8, 133.8, 138.5, 164.0. EI-MS: m/z (%) 216 (M+, 26),
200 (100). Anal. Calcd for C11H12N4O: C, 61.10; H, 5.59;
N, 25.91. Found: C, 61.09; H, 5.79; N, 25.62.
4.8.8. 9-Oxo-4,5,6,7,8,9-hexahydro-1H-pyridazino[3,4-
c]azepine-3-carbohydrazide (9). Mp 196–198 ꢁC (MeOH/
DMF). IR (KBr): 3392, 3333, 3317, 3291, 3212, 1659,
1640 cmꢀ1. H NMR (300 MHz, DMSO-d6): d 1.82 (m,
1
2H), 2.34 (m, 2H), 2.90 (s, 2H), 3.09 (m, 2H), 4.27 (s, 2H),
8.15 (dd, J1zJ2z5.0 Hz, 1H), 8.92 (s, 1H), 9.02 (br s,
1H). 13C NMR (75.5 MHz, DMSO-d6): d 27.1, 27.7, 33.1,
40.2, 113.6, 127.5, 132.5, 163.2, 164.2. EI-MS: m/z (%)
223 (M+, 29), 163 (100). Anal. Calcd for C9H13N5O2: C,
48.42; H, 5.87; N, 31.37. Found: C, 48.42; H, 6.16; N, 31.66.
4.8.14. 6-tert-Butyl-1,4-dihydropyridazine-3-carbo-
hydrazide (15b). Mp 144–146.5 ꢁC (EtOAc/light petro-
leum). IR (KBr): 3391, 3372, 3304, 3274, 3205, 2961,
1672, 1621, 1499 cmꢀ1; H NMR (300 MHz, DMSO-d6):
1
d 1.07 (s, 9H), 2.85 (d, J¼3.6 Hz, 2H), 4.24 (br s, 2H),
4.30 (dt, J¼2.6, 3.6 Hz, 1H), 8.72 (s, 1H), 9.17 (d,
J¼2.6 Hz, 1H). 13C NMR (75.5 MHz, DMSO-d6): d 20.6,
27.9, 32.6, 87.0, 132.0, 147.0, 164.2. EI-MS: m/z (%) 196
(M+, 33), 180 (100). Anal. Calcd for C9H16N4O: C, 55.08;
H, 8.22; N, 28.55. Found: C, 54.95; H, 8.45; N, 28.80.
4.8.9.
Methyl
9-oxo-6,7,8,9-tetrahydro-5H-pyrida-
zino[3,4-c]azepine-3-carboxylate (10a). Mp 206–208 ꢁC
(EtOH). IR (KBr): 3196, 3075, 1742, 1665, 1584 cmꢀ1. 1H
NMR (300 MHz, DMSO-d6): d 1.93 (m, 2H), 2.92 (m,
4H), 3.98 (s, 3H), 8.24 (s, 1H), 8.63 (dd, J1zJ2z5.7 Hz,
1H). 13C NMR (75.5 MHz, DMSO-d6): d 27.0, 28.3, 37.4,
53.0, 127.9, 138.9, 151.4, 158.3, 164.0, 166.5. EI-MS:
m/z (%): 221 (M+, 27), 163 (100). Anal. Calcd for
C10H11N3O3: C, 54.29; H, 5.01; N, 19.00. Found: C,
54.36; H, 5.18; N, 19.16.
4.8.15. 4-Methyl-6-(pyridin-2-yl)-1,4-dihydropyridazine-
3-carbohydrazide (15c). Mp 130–132.5 ꢁC (EtOAc/light
petroleum). IR (KBr): 3385, 3314, 3202, 1660, 1634,
1594 cmꢀ1 1H NMR (300 MHz, DMSO-d6): d 0.96 (d,
.
J¼6.5 Hz, 3H), 3.60 (dq, J¼6.5, 6.5 Hz, 1H), 4.32 (s, 2H),
5.71 (dd, J¼2.2, 6.5 Hz, 1H), 7.37 (ddd, J¼1.4, 4.9,
7.0 Hz, 1H), 7.80 (ddd, J¼1.4, 1.4, 7.6 Hz, 1H), 7.85 (ddd,
J¼1.8, 7.0, 7.6 Hz, 1H), 8.57 (ddd, J¼1.4, 1.8, 4.9 Hz,
1H), 9.00 (s, 1H), 9.71 (d, J¼2.2 Hz, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 19.5, 24.8, 100.4, 119.1, 123.3,
135.8, 137.1, 137.2, 148.4, 149.8, 163.5. EI-MS: m/z (%)
231 (M+, 36), 216 (100). Anal. Calcd for C11H13N5O:
C, 57.13; H, 5.67; N, 30.28. Found: C, 57.20; H, 5.69; N,
29.91.
4.8.10.
Ethyl
9-oxo-6,7,8,9-tetrahydro-5H-pyrida-
zino[3,4-c]azepine-3-carboxylate (10b). Mp 210–212 ꢁC
(EtOH). IR (KBr): 3200, 3090, 2931, 1720, 1668 cmꢀ1. 1H
NMR (300 MHz, DMSO-d6): d 1.39 (t, J¼7.1 Hz, 3H),
1.95 (m, 2H), 2.93 (m, 4H), 4.46 (q, J¼7.1 Hz, 2H), 8.23
(s, 1H), 8.64 (dd, J1zJ2z5.9 Hz, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 14.0, 27.0, 28.3, 37.5, 61.9,
127.8, 138.9, 151.5, 158.3, 163.5, 166.5. EI-MS: m/z (%)
235 (M+, 4), 163 (100). Anal. Calcd for C11H13N3O3:
C, 56.16; H, 5.57; N, 17.86. Found: C, 56.03; H, 5.74; N,
17.94.
4.8.16. 6-tert-Butylpyridazine-3-carbohydrazide (16b).
Mp 109–111 ꢁC (Et2O). IR (KBr): 3387, 3325, 2962,
1
4.8.11. 3-Hydrazino-6-phenyl-2,3,4,5-tetrahydropyrida-
zine-3-carbohydrazide (14a). Mp 108–111 ꢁC (pyridine).
1671, 1601, 1515 cmꢀ1. H NMR (300 MHz, DMSO-d6):
d 1.42 (s, 9H), 4.68 (br s, 2H), 7.96 (d, J¼8.9 Hz, 1H),

9724
F. Poꢀzgan et al. / Tetrahedron 62 (2006) 9718–9725
8.08 (d, J¼8.9 Hz, 1H), 10.30 (br s, 1H). 13C NMR
(75.5 MHz, DMSO-d6): d 29.6, 36.9, 124.7, 125.3, 151.1,
161.6, 171.2. EI-MS: m/z (%) 194 (M+, 100). Anal. Calcd
for C9H14N4O: C, 55.65; H, 7.27; N, 28.85. Found: C,
55.83; H, 7.42; N, 28.85.
References and notes
1. (a) Coates, W. J. Comprehensive Heterocyclic Chemistry II:
Pyridazines and their Benzo Derivatives; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
ˇ
Vol. 6, pp 1–91; (b) Kolar, P.; Tisler, M. Adv. Heterocycl.
Chem. 1999, 75, 167–241; (c) Matyus, P.; Maes, B. U. W.;
4.8.17. 4-Methyl-6-(pyridin-2-yl)pyridazine-3-carbo-
hydrazide (16c). Mp 177.5–180 ꢁC (MeOH). IR (KBr):
ꢁ
ꢁ
ꢂ
Riedl, Z.; Hajos, G.; Lemiere, G. L. F.; Tapolcsanyi, P.;
Monsieurs, K.; Elias, O.; Dommisse, R. A.; Krajsovszky, G.
ꢁ
3314 br, 1661, 1626, 1580, 1503 cmꢀ1
.
1H NMR
ꢁ
ꢁ
(300 MHz, DMSO-d6): d 2.56 (d, J¼1 Hz, 3H), 4.69 (s,
2H), 7.59 (ddd, J¼1.1, 4.8, 7.7 Hz, 1H), 8.05 (ddd, J¼1.8,
7.7, 7.9 Hz, 1H), 8.47 (q, J¼1 Hz, 1H), 8.57 (ddd, J¼1.1,
1.1, 7.9 Hz, 1H), 8.78 (ddd, J¼1.1, 1.8, 4.8 Hz, 1H), 10.06
(s, 1H). 13C NMR (75.5 MHz, DMSO-d6): d 18.1, 121.3,
125.3, 126.2, 137.7, 138.1, 149.7, 152.4, 154.9, 157.7,
163.8. EI-MS: m/z (%) 229 (M+, 100). Anal. Calcd for
C11H11N5O: C, 57.63; H, 4.84; N, 30.55. Found: C, 57.91;
H, 5.04; N, 30.24.
Synlett 2004, 1123–1139; (d) Haider, N.; Holzer, W. Science
of Synthesis; Yamamoto, Y., Ed.; Thieme: Stuttgart, 2004;
Vol. 16, pp 125–249; (e) Haider, N.; Holzer, W. Science of
Synthesis; Yamamoto, Y., Ed.; Thieme: Stuttgart, 2004; Vol.
16, pp 251–313; (f) Groziak, M. P. Progress in Heterocyclic
Chemistry; Gribble, G. W., Joule, J. A., Eds.; Elsevier:
Amsterdam, 2004; Vol. 16, pp 347–384; (g) Groziak, M. P.
Progress in Heterocyclic Chemistry; Gribble, G. W., Joule,
J. A., Eds.; Elsevier: Amsterdam, 2005; Vol. 17, pp 304–336.
2. (a) Heinisch, G.; Kopelent-Frank, H. Progress in Medicinal
Chemistry: Pharmacologically Active Pyridazine Derivatives.
Part 2; Ellis, G. P., Luscombe, D. K., Eds.; Elsevier Science
B.V.: Amsterdam, 1992; Vol. 29, pp 141–183; (b) Gelain, A.
J. Heterocycl. Chem. 2005, 42, 395–400.
4.8.18. Methyl 6-phenylpyridazine-3-carboxylate (17a).
Mp 194–197 ꢁC (MeOH/H2O). IR (KBr): 3062, 2952,
1717, 1575, 1442, 1409 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): d 4.10 (s, 3H), 7.56 (m, 3H), 8.00 (d, J¼8.9 Hz,
1H), 8.17 (m, 2H), 8.24 (d, J¼8.9 Hz, 1H). 13C NMR
(75.5 MHz, CDCl3): d 53.2, 123.9, 127.6, 128.0, 129.2,
130.9, 135.4, 150.0, 160.7, 164.7. EI-MS: m/z (%) 214
(M+, 45), 156 (100). Anal. Calcd for C12H10N2O2: C,
67.28; H, 4.71; N, 13.08. Found: C, 67.15; H, 4.84; N, 12.88.
3. (a) Avram, M.; Dinulescu, I. G.; Marica, E.; Nenitzescu, C. D.
ꢁ
Chem. Ber. 1962, 95, 2248–2253; (b) Kotschy, A.; Novak, Z.;
ꢁ
Vincze, Z.; Smith, D. M.; Hajos, G. Tetrahedron Lett. 1999,
40, 6313–6316; (c) Balci, M.; Sarac¸oglu, N.; Menzek, A.
˘
ꢁ
ꢁ
J. Org. Chem. 2003, 68, 7009–7015; (d) Gonzalez-Gomez,
J. C.; Santana, L.; Uriarte, E. Tetrahedron 2005, 61, 4805–4810.
4. Attanasi, O. A.; Filippone, P.; Fiorucci, C.; Foresti, E.;
Mantellini, F. J. Org. Chem. 1998, 63, 9880–9887.
4.8.19. Methyl 6-tert-butylpyridazine-3-carboxylate
(17b). Mp 115–116.5 ꢁC (MeOH/H2O). IR (KBr): 2963,
1
1721, 1576, 1448, 1359, 1298 cmꢀ1. H NMR (300 MHz,
5. Razin, V. V.; Yakovlev, M. E.; Shataev, K. V.; Selivanov, S. I.
Russ. J. Org. Chem. 2004, 40, 1027–1032.
DMSO-d6): d 1.42 (s, 9H), 3.97 (s, 3H), 7.98 (d, J¼8.9 Hz,
1H), 8.14 (d, J¼8.9 Hz, 1H). 13C NMR (75.5 MHz,
DMSO-d6): d 29.5, 37.0, 52.7, 124.3, 127.7, 149.4, 164.3,
171.9. EI-MS: m/z (%) 194 (M+, 15), 152 (100). HRMS calcd
for C10H14N2O2 194.1055, found 194.1060. Anal. Calcd for
C10H14N2O2: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.56;
H, 7.39; N, 14.85.
€
6. (a) Seitz, G.; Kampchen, T.; Overheu, W. Arch. Pharm. 1978,
311, 786–795; (b) Stetter, H.; Jonas, F. Chem. Ber. 1981, 114,
564–580; (c) Ban, T.; Nagai, K.; Miyamoto, Y.; Harano, K.;
Yasuda, M.; Kanematsu, K. J. Org. Chem. 1982, 47, 110–
116; (d) Heinisch, G.; Waglechner, R. J. Heterocycl. Chem.
1984, 21, 1727–1731; (e) Hoferichter, R.; Seitz, G.;
Waßmuth, H. Chem. Ber. 1989, 122, 711–714; (f) Pippich, S.;
Bartsch, H. Heterocycles 1996, 43, 1967–1979; (g) Klindert,
T.; Seitz, G. Synth. Commun. 1996, 26, 2587–2596; (h)
4.8.20. Methyl 4-methyl-6-(pyridin-2-yl)pyridazine-3-
carboxylate (17c). Mp 106.5–108 ꢁC (EtOAc/light petro-
1
leum). IR (KBr): 1719, 1579, 1441, 1379 cmꢀ1. H NMR
€
Gorlitzer, K.; Behrje, H. Pharmazie 1996, 51, 528–536.
(300 MHz, DMSO-d6): d 2.58 (d, J¼0.8 Hz, 3H), 3.99 (s,
3H), 7.60 (ddd, J¼1.1, 4.8, 7.7 Hz, 1H), 8.07 (ddd, J¼1.8,
7.7, 7.9 Hz, 1H), 8.53 (q, J¼ca. 0.8 Hz, 1H), 8.60 (ddd,
J¼1.1, 1.1, 7.9 Hz, 1H), 8.79 (ddd, J¼1.1, 1.8, 4.8 Hz,
1H). 13C NMR (75.5 MHz, DMSO-d6): d 18.5, 52.7,
121.6, 125.5, 126.3, 137.7, 139.2, 149.8, 152.0, 152.5,
158.1, 165.2. EI-MS: m/z (%) 229 (M+, 35), 171 (100).
Anal. Calcd for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33.
Found: C, 62.66; H, 5.02; N, 18.25.
7. (a) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. Rev. 1997,
26, 127–132; (b) Nair, V.; Panicker, S. B.; Nair, L. G.; George,
T. G.; Augustine, A. Synlett 2003, 156–165; (c) Dhakshina-
moorthy, A. Synlett 2005, 3014–3015.
ˇ
8. Stefane, B.; Kocevar, M.; Polanc, S. Tetrahedron Lett. 1999, 40,
ꢀ
4429–4432.
ꢀ
ꢀ
9. Pozgan, F.; Polanc, S.; Kocevar, M. Synthesis 2003, 2349–
2352.
10. (a) Ellis, G. P. Comprehensive Heterocyclic Chemistry: Pyrans
and Fused Pyrans: (ii) Reactivity; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3, pp 647–736;
(b) Ram, V. J.; Srivastava, P. Curr. Org. Chem. 2001, 5,
571–599; (c) Hepworth, J. D.; Heron, B. M. Progress in
Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.;
Elsevier: Amsterdam, 2005; Vol. 17, pp 33–62.
Acknowledgements
We thank the Ministry of Higher Education, Science, and
Technology of the Republic of Slovenia as well as the Slove-
nian Research Agency for financial support (P1-0230-0103).
ꢀ
ˇ
11. For selected examples, see: (a) Kocevar, M.; Polanc, S.; Tisler,
M.; Vercek, B. Heterocycles 1990, 30, 227–230; (b) Trebse, P.;
ˇ
Dr. B. Kralj and Dr. D. Zigon (Center for Mass Spectroscopy,
‘Joꢀzef Stefan’ Institute, Ljubljana, Slovenia) are gratefully
acknowledged for mass measurements.
ˇ
ꢀ
ˇ
ꢀ
Polanc, S.; Kocevar, M.; Solmajer, T.; Golic Grdadolnik, S.
Tetrahedron 1997, 53, 1383–1390; (c) Vranicar, L.; Polanc,
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ꢀ

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