Synthesis, characterization and applications of densely functionalized pyridazines and fulvene-type compounds containing azulene moiety

Article abstract of DOI:10.1016/j.tet.2013.04.034

Ethyl 4-ethoxyazulene-1-carboxylate (1) is highly efficient and novel substrate for electrophilic substitution reactions. These derivatives (2-4) were treated with NH₂NH₂/PhNHNH₂ in ethanol to produce pyridazine, and fulve

Full text of DOI:10.1016/j.tet.2013.04.034

Tetrahedron 69 (2013) 4953e4963
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, characterization and applications of densely
functionalized pyridazines and fulvene-type compounds containing
azulene moiety
,
a
a
Badugu Devendar a, Chi-Phi Wu a , Chi-Yuan Chen , Hung-Chang Chen ,
*
Chung-Hao Chang a, Chien-Kuo Ku b , Cheng-Yin Tsai , Chieh-Yuan Ku
,
b
b
*
a Department of Chemistry, Chung Yuan Christian University, Chungli 32023, Taiwan
b Department of Applied Physics and Chemistry, Taipei Municipal University of Education, Taipei 10042, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2012
Received in revised form 28 March 2013
Accepted 8 April 2013
Available online 12 April 2013
Ethyl 4-ethoxyazulene-1-carboxylate (1) is highly efficient and novel substrate for electrophilic sub-
stitution reactions. These derivatives (2e4) were treated with NH2NH2/PhNHNH2 in ethanol to produce
pyridazine, and fulvene derivatives with azulene frameworks (5, 6, 17, 19) via intramolecular cyclization.
The substrates 5e8, 11, and 19 were effectively converted into densely functionalized heterocyclic
molecules via VilsmeiereHaack, FriedeleCrafts, and Michael addition reactions.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Azulene
VilsmeiereHaack formylation
FriedeleCrafts reaction
Michael addition reaction
Intramolecular cyclization
1. Introduction
reported the highly efficient intramolecular FriedeleCrafts type
cyclization methodology on azulene derivatives at 3-position, and
Azulene and its derivatives are interesting and structurally
challenging carbocyclic moieties1 because of the presence of azu-
lene ring system as a centerpiece of number of bioactive natural
products, such as orientalol F,2a purbinernoid,2b guaiane,2c pseu-
dolaric acids A, B, F, and H,2d guanacastepene A, and heptemerone
G,2e englerin A,2f (ꢀ)-9-deoxyenglerin A.2g Several azulene de-
rivatives, in fact, have been known to exhibit various biological
activities, such as insect anti-feeding agent,3a anti-fungal infections
of skin and nails,2d anti-inflammatory agents,3b anti-oxidant ther-
apeutics,3c and anti-microbial agents.3d,e Subsequently, azulenes
and their derivatives have attracted the attention of chemists’5aec
due its abnormal properties and interesting modern applications.
The electrophilic substitution method is one of the most im-
portant methodologies for the functionalization of aromatic com-
pounds.4 There are several reports of electrophilic substitution
reactions for functionalizing azulenes these including Vils-
meiereHaack formylations6aef and FriedeleCrafts acylations,7a,b of
azulene derivatives at 1- and/or 3-positions. Recently, we have
the applications of corresponding derivatives toward thermal and
photo-chemical reactions (Scheme 1).7b In continuing of our re-
search program7b,8 in carbo- and heterocyclic molecules with
azulene framework, we herein report the synthesis of pyridazine,
and fulvene type of products with azulene moiety.
Scheme 1. Syntheses of vinyl azulene derivatives.7b
2. Results and discussion
Ethyl 4-ethoxyazulene-1-carboxylate (1) was prepared from
commercially available tropolone in four steps.8 Compound 1 was
subjected to VilsmeiereHaack formylation conditions (POCl3/DMF,
0
ꢁC, 3 h) to obtain ethyl 4-ethoxy-3-formylazulene-1-carboxylate
* Corresponding authors. Tel.: þ886 32653333; fax: þ886 32653399; e-mail
addresses: bdevendar@yahoo.com (B. Devendar), chiphi@cycu.edu.tw (C.-P. Wu),
Kuo@tmue.edu.tw (C.-K. Ku).
(2), and with FriedeleCrafts acylation methodology (Ac2O,
BF3$Et2O, 0 ꢁC, 2 h and (CF3CO)2O/CH2Cl2, room temperature,
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.034

4954
B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
30 min) to produce ethyl 3-acetyl-4-ethoxyazulene-1-carboxylate
(3a), and ethyl 4-ethoxy-3-(2,2,2-trifluoroacetyl)azulene-1-
carboxylate (3b) with excellent yields (Scheme 2). We also ex-
tended our synthetic strategy toward the applications of Michael
addition reactions.9 The best results in this approach were obtained
when ethyl 4-ethoxyazulene-1-carboxylate (1) was treated with
methyl vinyl ketone (MVK) in the presence of p-toluenesulfonic acid
(p-TSA) in ethanol at room temperature for 40 min, thus providing
the desired ethyl 4-ethoxy-3-(3-oxobutyl)-azulene-1-carboxylate
(4a), in 90% isolated yield (Scheme 2); the reaction proceeds more
selectively at 3-position, which was confirmed from spectral analy-
sis. To examine the scope of this reaction, we employed various ac-
tivated cyclic enones, i.e., cyclopentenone, cyclohexenone, and
cycloheptenone with the compound 1 (Scheme 2). A variety of cyclic
enones have been proved to be very efficient substrates under these
conditions.
followed by intramolecular condensation reactions. The structures
of 5aec were confirmed from 1H NMR, 13C NMR, IR, and MS data
analyses, while that of 5b was further confirmed with single-crystal
X-ray diffraction analysis (CCDC # 882109),10 see Fig. 1 for the
ORTEP diagram.
Fig. 1. ORTEP diagram of compound 5b.
With a view to understand the generality of this methodology,
we further investigated the reactions of 3a and 3b with phenyl
hydrazine at room temperature for 2 h. Interestingly we obtained
fulvene type products (6a and 6b) with the
p-electron de-
localization within the ring system, in 88% and 90% yields, re-
spectively (Scheme 3). All these products were well characterized
from spectral analysis.
Scheme 3. Syntheses of fulvene type of products (6a, b).
Scheme 2. Selective VilsmeiereHaack, FriedeleCrafts, and Michael addition reactions
on ethyl 4-ethoxyazulene-1-carboxylate (1).
Encouraged by these promising and interesting results, we fur-
ther transformed 5a and 5b, by treatment with methyl/ethyl iodide
with and/or without a base, into a mixture of N-alkylated pyr-
idazines and/or fulvene type of products (7aed, 8aed). We noticed
that the compound 5c did not convert to N-methylated or fulvene
type of products (7e, 8e) in the presence of methyl iodide in the
absence of a base. Interestingly, with methyl iodide/ethyl iodide
and NaH, we obtained exclusively the compounds 7e (96%), and 7f
in 90% yield (Table 2); all these products were well characterized
from the analysis of their spectral data. Particularly, with the help of
After successful syntheses of VilsmeiereHaack and Friedele-
Crafts products, we found that ethyl 1H-azuleno[8,1-cd]-pyridazine-
5-carboxylate (5a) was readily prepared in excellent yield (95%)
from 2 and hydrazine in ethanol at room temperature for 30 min;
the reaction presumably proceeded via a substitution reaction and
a subsequent intramolecular condensation (Table 1, entry 1). En-
couraged by these results, we successfully transformed represen-
tative FriedeleCrafts products 3a,b into the desired ethyl 3-methyl-
1H-azuleno[8,1-cd]pyridazine-5-carbo-xylate (5b) and ethyl 3-(tri-
fluoromethyl)-1H-azuleno[8,1-cd]-pyridazine-5-carboxylate (5c) in
excellent yields after purification by column chromatography
(Table 1). The reactions apparently produced via a substitution
Table 2
N-Alkylation of azuleno[8,1-cd]pyridazine-5-caboxylate derivatives (5)a
Table 1
Syntheses of azuleno[8,1-cd]pyridazine-5-carboxylate derivatives (5)a
Entry
Reactants 5
Reagents
(1.2 equiv)
R1
Products
Products
7/yieldb (%)
8/yieldb (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5b
5b
5c
5c
5c
CH3I
CH3
7a/15
7b/e
7b/35
7c/13
7d/14
7e/e
8a/56
8b/39
8b/54
8c/37
8d/41
8e/e
CH3CH2I
CH3CH2I/NaH
CH3I
CH3CH2I
CH3I
CH3CH2
CH3CH2
CH3
CH3CH2
CH3
Entry
Reactants 2, 3
R
Products 5
R1
Yieldb (%)
1
2
3
2
3a
3b
CHO
COCH3
COCF3
5a
5b
5c
H
CH3
CF3
95
92
85
CH3I/NaH
CH3CH2I/NaH
CH3
CH3CH2
7e/96
7f/90
8e/e
8f/e
a
a
All the reactions were carried out with 1 mmol scale of 2, and 3.
Isolated yields after silica gel column chromatography.
All the reactions were carried out with 1 mmol scale of 5.
Isolated yields after silica gel column chromatography.
b
b

B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
4955
1H NMR spectral data, easily we can differentiate N-alkylated pyr-
idazines from fulvene type of products; principally, we noticed
a large difference (w1.00 ppm) at the H6 proton chemical shift of
the N-alkylated pyridazine and fulvene type of products. In com-
parison, the 1H NMR spectral data of the compound 5a is similar to
that of the compounds 7, but different from that of the compounds
8 (Table 3). We also obtained single crystals for compounds 7d, 7f,
and 8b, whose structure were further confirmed with single-crystal
X-ray diffraction analysis (CCDC # 887649; 887650; 844733),10 see
Fig. 2 for the ORTEP diagrams.
Table 4
Scope of the VilsmeiereHaack formylation reaction on azuleno[8,1-cd]pyridazine-5-
caboxylate derivatives (5, 6, 7, 8)a
Entry
1
Reactants 5, 6, 7, 8
Products 9
Yieldb (%)
81
Table 3
1H NMR studies of compounds 5, 7, and 8a
2
3
79
90
5a
7a
7c
8a
8c
H3
H4
H6b
H7
H8
H9
7.77
7.05
8.02
5.75
6.53
6.06
7.68
7.21
8.25
5.83
6.59
5.82
7.47
6.96
7.37
5.30
5.87
5.63
7.21
8.30
5.88
6.62
5.91
6.88
7.37
5.28
5.85
5.62
4
5
84
86
a
1H NMR chemical shift in ppm.
b
Large difference (e1.00 ppm) at the H6 proton chemical shift of the N-alkylated
pyridazine and fulvene type of products.
After successful syntheses of various N-alkylated pyridazine
derivatives, we focused our attention toward the synthetic appli-
cations of VilsmeiereHaack formylation reactions on ethyl 1H-
azuleno[8,1-cd]pyridazine-5-carboxylate (5a) and their various
substituted products (5c, 6a, 6b, 7b, 8b). At first, for a model study
we selected 5a, which was treated with POCl3 (1.2 equiv)/DMF
(3 mL) at 0 ꢁC for 10 min, and the reaction continued at 90 ꢁC for 2 h,
thus providing ethyl 4-formyl-1H-azuleno[8,1-cd]pyridazine-5-
carboxylate (9a) in 81% isolated yield after purification by column
chromatography (Table 4, entry 1). In order to understand the
generality of this reaction, we subjected various substituted and N-
alkylated ethyl azuleno[8,1-cd]-pyridazine-5-carboxylates (5c, 6a,
6b, 7b, 8b) into the desired chemoselectively substituted formyl
azuleno[8,1-cd]pyridazine-5-carboxylates (9bef) in excellent
yields (Table 4, entries 2e6).
6
88
a
All the reactions were carried out with 1 mmol scale of reactants.
Isolated yields after silica gel column chromatography.
b
(prop-1-en-2-yl)-2H-azuleno[8,1-cd]pyridazine-5-carboxylate (12)
and its derivative 13, which were synthesized from ethyl 4-(2-
(propan-2-ylidene)hydrazinyl)azulene-1-carboxylate (11a) and its
derivative ethyl 4-(2-(4-ethoxy-4-oxobutan-2-ylidene)hydrazinyl)
azulene-1-carboxylate (11b), which in turn were prepared from
ethyl 4-hydrazinylazulene-1-carboxylate (10) and ethyl 4-
ethoxyazulene-1-carboxylate (1) with 2.5 equiv of POCl3/DMF
Alternatively, we have also obtained very promising and in-
teresting results in one-pot operation with consecutive formation of
products via VilsmeiereHaack formylation, such as ethyl 4-formyl-2-
Fig. 2. ORTEP diagrams of compounds 7d, 7f, and 8b.

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B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
(3 mL) at 0 ꢁC for 4 h. Interestingly, in the presence of 1.2 equiv of
POCl3/DMF (3 mL) at 0 ꢁC for 2 h, ethyl 2-(4-ethoxy-4-oxobut-2-en-
2-yl)-2H-azuleno[8,1-cd]pyridazine-5-carboxylate (14) was ob-
tained in 85% isolated yield, presumably formed via the Vils-
meiereHaack formylation followed by cyclization (Scheme 4). The
structures of 12, 13, and 14 were confirmed with spectral analyses. A
plausible mechanism is presented in Scheme 5.
a Isolated yields after silica gel column chromatography.
Scheme 4. Tandem VilsmeiereHaack reactions on 11.
Scheme 6. Applications of Michael adducts 4a and 4c.
the compound 18 in hand, we subjected our synthetic methodology
(NH2NH2/EtOH at reflux temperature for 2 h) to produce densely
functionalized nitrogen heterocyclic molecule ethyl 3-(4-
oxopentyl)-1H-azuleno[8,1-cd]pyridazine-5-carboxylate (19) in
78% yield (Scheme 6); the reaction presumably proceeded via
substitution, intramolecular condensation, and a subsequent ring
opening reactions (Scheme 7). The compound 19 is the key pre-
cursor for the intramolecular FriedeleCrafts reaction and the gen-
eration of secondary alcohols of ethyl 1H-azuleno[8,1-cd]
pyridazine-5-carboxylate derivative. At first, the compound 19 was
Scheme 5. Plausible mechanism for the formation of VilsmeiereHaack products (12,
13, 14).
Subsequently, we focused our attention toward the syntheses of
highly functionalized nitrogen heterocyclic molecules from the
Michael adducts, which are readily prepared from ethyl 4-
ethoxyazulene-1-carboxylate (1). The Michael adduct 4a was
treated with NaBH4 in ethanol at room temperature for 40 min to
obtain the compound 15 in 98% yield. Then upon oxidation with
DDQ in presence of water/acetone, we accomplished the required
key intermediate 16 for the formation of nitrogen heterocyclic
molecule. Further, the compound 16 was subjected to hydrazine in
ethanol under reflux for 2 h to attain ethyl (2-hydroxypropyl)-1H-
azuleno[8,1-cd]pyridazine-5-carboxylate (17); the reaction appar-
ently proceeded via a substitution reaction and a subsequent
intramolecular condensation (Scheme 6).
Encouraged by these attractive results, we have extended the
similar strategy to the compound 4c, which was obtained from
ethyl 4-ethoxyazulene-1-carboxylate (1) and cyclohexenone in
presence of p-TSA in ethanol. Ethyl 4-ethoxy-3-(3-oxocyclo-hexyl)
azulene-1-carboxylate (4c) was treated with DDQ in refluxing tol-
uene for 2 h to obtain the dehydrogenated product 18. After having
Scheme 7. Plausible mechanism for the compound 19.

B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
4957
readily converted for intramolecular FriedeleCrafts reaction in
presence of p-TSA in ethanol to obtain heterocyclic molecule 20.
The product was well characterized with the spectral data analysis.
Later, the compound 19 was further transformed into ethyl 3-(4-
hydroxypentyl)-1H-azuleno[8,1-cd]pyridazine-5-carboxylate (21)
in 95% yield in presence of NaBH4 in EtOH (Scheme 6).
We also extended our Michael addition reaction strategy to
ethyl 1H-azuleno[8,1-cd]pyridazine-5-carboxylate (5a), which was
treated with MVK in presence of p-TSA in ethanol at room tem-
perature for 1 h to attain ethyl 4-(3-oxobutyl)-1H-azuleno [8,1-cd]
pyridazine-5-carboxylate (22a) as a major product in 47% isolated
yield and 22b as a minor product in 23% yield; the latter may be
produced from the former via further Michael addition at the
2-position (Scheme 8). The structures of 22a and 22b were con-
firmed with 1H NMR, 13C NMR, IR, and MS data analyses, while that
of 22a was further confirmed with single-crystal X-ray diffraction
analysis (CCDC # 844734),10 see Fig. 3 for the ORTEP diagram.
after flash column chromatography. 1H NMR and 13C NMR spectra
were recorded on Bruker ACE-300 M Hz FT-NMR. 19F NMR spectra
were recorded on a Bruker AMX-400 (376.5 MHz). Chemical shifts
were reported as
d values referenced to CDCl3. Coupling constants
were reported in Hertz, and multiplicities are indicated as follows: s
(singlet); d (doublet); dd (doublet of doublet); t (triplet); m (mul-
tiplet). IR spectra were recorded as thin film on KBr plates on a Jasco
FT/IR-460 and reported in wave number (n). Elemental analyses
were recorded on a Thermo Finnigan Flash EA 1112 analyzer. Mass
spectra are measured on Agilent 7890A GC-5975C MSD and
Shimadzu-LCMS-2010 A mass spectrometers.
4.2. Procedure for the preparation of VilsmeiereHaack
product ethyl 4-ethoxy-3-formylazulene-1-carboxylate (2)
To
a
solution of ethyl 4-ethoxyazulene-1-carboxylate
(1, 1 mmol, 0.244 g), in DMF (3 mL) at 0 ꢁC was added POCl3
(1.2 mmol, 0.1 mL) slowly for 10 min and the reaction continued
for 3 h. Then the reaction mixture was diluted with water (10 mL),
quenched with aqueous KOH solution, and was extracted with
EtOAc. The combined organic layers were dried over MgSO4,
concentrated, and chromatographed on silica gel column chro-
matography (Hexane/EtOAc¼2:1) to afford the compound 2. Yield
80%; colorless solid (mp: 156e157 ꢁC); 1H NMR (CDCl3, 300 MHz):
d
1.40 (t, 3H, J¼7.1 Hz), 1.65 (t, 3H, J¼7.0 Hz), 4.37 (q, 2H,
J¼14.2 Hz), 4.50 (q, 2H, J¼14.0 Hz), 7.39 (d, 1H, J¼11.5 Hz), 7.50 (t,
1H, J¼9.8 Hz), 7.86 (t, 1H, J¼10.6 Hz), 8.77 (s, 1H), 9.80 (d, 1H,
Scheme 8. Michael addition reaction on ethyl 1H-azuleno-[8,1-cd]pyridazine-5-
carboxylate (5a) with MVK.
J¼10.2 Hz), 10.85 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d 14.4, 14.7,
60.0, 66.2, 115.0, 118.1, 126.1, 127.5, 131.6, 138.7, 138.8, 140.2, 142.4,
165.2, 165.7, 189.7; IR (KBr):
n 2360, 1684, 1644, 1235, 1214, 1050,
785 cmꢀ1. Anal. Calcd for C16H16O4: C, 70.57; H, 5.92. Found: C,
70.51; H, 5.90.
4.2.1. Procedure for the preparation of FriedeleCrafts product ethyl 3-
acetyl-4-ethoxyazulene-1-carboxylate (3a). To a stirred solution of
ethyl 4-ethoxyazulene-1-carboxylate (1, 1 mmol, 0.244 g), in
CH2Cl2 (3 mL) at 0 ꢁC were added Ac2O (1.0 mL) and BF3$Et2O
(1.0 mL), and the reaction continued for 2 h. Then the reaction
mixture was diluted with water (10 mL), quenched with aqueous
NaHCO3 solution, and was extracted with EtOAc. The combined
organic layers were dried over MgSO4, concentrated, and chro-
matographed on silica gel column chromatography (Hexane/
EtOAc¼2:1) to afford the compound 3a. Yield 85%; red solid (mp:
Fig. 3. ORTEP diagram of compound 22a.
124e125 ꢁC); 1H NMR (CDCl3, 300 MHz):
d
1.38 (t, 3H, J¼7.1 Hz),
3. Conclusion
1.51 (t, 3H, J¼7.1 Hz), 2.57 (s, 3H), 4.37 (m, 4H), 7.20 (d, 1H,
J¼11.1 Hz), 7.35 (t, 1H, J¼10.2 Hz), 7.71e7.79 (m, 1H), 8.14 (s, 1H),
9.67 (d, 1H, J¼10.2 Hz); 13C NMR (CDCl3, 75 MHz):
d 14.0, 14.5,
In summary, we have successfully developed a new substrate
ethyl 4-ethoxyazulene-1-carboxylate (1) for the electrophilic sub-
stitution reactions. These derivatives (2e4) were effectively applied
in the syntheses of pyridazine, and fulvene type of products with
azulene moiety (5, 6, 17, 19), and further applications were made
toward the syntheses of densely functionalized heterocyclic mol-
ecules via the VilsmeiereHaack, FriedeleCrafts, and Michael addi-
tion reactions. The utilization of this methodology for the synthesis
of biological important molecules is in progress.
32.5, 59.7, 66.0, 113.4, 116.0, 124.1, 124.9, 127.8, 129.7, 136.3, 138.5,
139.7, 164.1, 165.2, 201.9; IR (K Br):
n 2360, 1709, 1681, 1241, 1221,
1212, 1192, 742 cmꢀ1. Anal. Calcd for C17H18O4: C, 71.31; H, 6.34.
Found: C, 71.29; H, 6.33.
4.2.2. Ethyl 4-ethoxy-3-(2,2,2-trifluoroacetyl)azulene-1-carboxylate
(3b). To
a
stirred solution of ethyl 4-ethoxyazulene-1-
carboxylate (1, 1 mmol, 0.244 g), in CH2Cl2 (3 mL) at room tem-
perature was added (CF3CO)2O (1.0 mL), and the reaction contin-
ued for 2 h. Then the reaction mixture was diluted with water
(10 mL), quenched with aqueous NaHCO3 solution, and was
extracted with EtOAc. The combined organic layers were dried
over MgSO4, concentrated, and chromatographed on silica gel
column chromatography (Hexane/EtOAc¼2:1) to afford the com-
pound 3b. Yield 90%; dark red solid (mp: 104e105 ꢁC); 1H NMR
4. Experimental section
4.1. General experimental procedures
Unless stated otherwise, reagents were obtained from com-
mercial sources and used without further purification. Thin layer
chromatography (TLC) was performed by using Merck 5735 DC-
Alufolien Kiesegel 60 F254. Flash column chromatography was
performed by using 230e400 mesh silica gel from Merck Art.9385
Kiesegel 60H. Except as otherwise indicated, yields were calculated
(CDCl3, 300 MHz):
d
1.41 (t, 3H, J¼7.1 Hz), 1.51 (t, 3H, J¼6.9 Hz),
4.35e4.47 (m, 4H), 7.35 (d, 1H, J¼11.1 Hz), 7.48 (t, 1H, J¼9.7 Hz),
7.87 (t, 1H, J¼9.7 Hz), 8.33 (s, 1H), 9.76 (d, 1H, J¼10.1 Hz); 13C NMR
(CDCl3, 75 MHz):
d 13.8, 14.5, 60.0, 66.4, 115.1, 115.5, 117.0, 117.8,

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B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
119.0, 125.9, 130.7, 138.1, 139.5, 140.3, 141.0, 164.9, 181.9; 19F NMR
(32), 279 (22), 255 (15), 223 (19), 199 (7). Anal. Calcd for C22H26O4:
C, 74.55; H, 7.39. Found: C, 74.48; H, 7.39.
(376.5 MHz, CDCl3):
d
ꢀ73.9; IR (KBr):
n 2360, 2341, 1709, 1681,
1241, 1221, 1212, 1192, 742 cmꢀ1. Anal. Calcd for C17H15F3O4: C,
60.00; H, 4.44. Found: C, 60.02; H, 4.46.
4.4. Typical procedure for the preparation of ethyl 1H-azu-
leno[8,1-cd]pyridazine-5-carboxylate derivatives (5 and 6)
4.3. Typical procedure for the preparation of Michael addi-
tion products (4aed)
To a solution of 2 or 3 (1 mmol), in ethanol (3 mL) was added
NH2NH2/PhNHNH2 (1.2 mmol) at room temperature and stirred
for 30 min/2 h, the reaction mixture was quenched with water
and extracted with EtOAc. The combined organic layers were
dried over anhydrous MgSO4, filtered, and stripped off solvent to
give crude product, which was purified by silica gel column
chromatography.
To a stirred solution of ethyl 4-ethoxyazulene-1-carboxylate 1
(1 mmol, 0.244 g) in EtOH (4 mL) were added methyl vinyl ketone or
cyclopentenone or cyclohexenone or cycloheptenone (1.2 mmol),
and p-TSA (1.1 mmol, 0.189 g) at room temperature, and the reaction
continued for 40 min (4aec) to 1 h (4d). Aqueous KOH solution was
added slowly to neutralize the reaction and the reaction mixture
was extracted with EtOAc; the combined organic layers were dried
over anhydrous MgSO4, filtered, and stripped off solvent to give
mixture of crude products were isolated by silica gel column
chromatography.
4.4.1. Ethyl 1H-azuleno[8,1-cd]pyridazine-5-carboxylate (5a). Yield
95%; green solid (mp: 146e147 ꢁC); 1H NMR (CDCl3, 300 MHz):
d
1.31 (t, 3H, J¼3.5 Hz), 4.23 (q, 2H, J¼6.0 Hz), 5.75 (t, 1H, J¼9.8 Hz),
6.06 (d, 1H, J¼11.7 Hz), 6.53 (dd, 1H, J¼8.7, 11.7 Hz), 7.05 (s, 1H), 7.77
4.3.1. Ethyl 4-ethoxy-3-(3-oxobutyl) azulene-1-carboxylate
(s, 1H), 8.00 (d, 1H, J¼11.1 Hz), 11.00 (s, 1H); 13C NMR (CDCl3,
(4a). Yield 90%; purple solid (mp: 160e161 ꢁC); 1H NMR (CDCl3,
75 MHz): d 19.0, 64.2, 117.9, 123.2, 123.4, 124.9, 133.1, 138.9, 144.6,
300 MHz):
d
1.43 (t, 3H, J¼7.2 Hz), 1.57 (t, 3H, J¼6.9 Hz), 2.16 (s, 3H),
146.6, 149.8, 158.6, 170.4; IR (KBr): n 3270, 1665, 1442, 1422, 1118,
2.87 (t, 2H, J¼7.1 Hz), 3.46 (t, 2H, J¼7.8 Hz), 4.33e4.44 (m, 4H), 7.01
1082, 1034, 750 cmꢀ1; GCeMS (m/z): 240 (Mþ, 100), 212 (80), 195
(40), 167 (30), 140 (20). Anal. Calcd for C14H12N2O2: C, 69.99; H,
5.03; N, 11.66. Found: C, 70.01; H, 5.00; N, 11.65.
(d, 1H, J¼11.1 Hz), 7.16 (t, 1H, J¼9.7 Hz), 7.60 (t, 1H, J¼10.3 Hz), 7.96
(s, 1H), 9.60 (d, 1H, J¼9.9 Hz); 13C NMR (CDCl3, 75 MHz):
d 14.3, 14.6,
25.7, 29.8, 46.1, 59.4, 65.0, 111.4, 115.2, 121.5, 128.3, 128.7, 137.4,
137.8, 137.9, 139.5, 164.9, 165.3, 208.4; IR (KBr):
n
1671, 1109, 1043,
4.4.2. Ethyl 3-methyl-1H-azuleno[8,1-cd]pyridazine-5-carboxylate
1083, 1003 cmꢀ1; GCeMS (m/z): 314 (Mþ, 77), 257 (100), 229 (5),
201 (3), 183 (7). Anal. Calcd for C19H22O4: C, 72.59; H, 7.05. Found: C,
72.62; H, 7.01.
(5b). Yield 92%; green solid (mp: 151e152 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.38 (t, 3H, J¼7.1 Hz), 2.18 (s, 3H), 4.33 (q, 2H, J¼7.2 Hz),
5.80e5.90 (m, 2H), 6.47e6.56 (m, 1H), 7.18 (s, 1H), 8.15 (d, 1H,
J¼9.9 Hz), 9.08 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d 14.5, 18.5, 59.8,
4.3.2. Ethyl 4-ethoxy-3-(3-oxocyclopentyl) azulene-1-carboxylate
113.8, 117.1, 118.2, 119.1, 119.9, 129.0, 139.8, 140.9, 151.6, 152.4, 166.2;
(4b). Yield 94%; purple solid (mp: 157e158 ꢁC); 1H NMR (CDCl3,
IR (KBr): n
3205, 3050, 2977, 1693, 1430, 1230 cmꢀ1; GCeMS (m/z):
300 MHz):
d
1.40 (t, 3H, J¼6.9 Hz), 1.56 (t, 3H, J¼6.9 Hz), 2.05e2.35
254 (Mþ, 100), 226 (80), 209 (50), 181 (30), 152 (20). Anal. Calcd for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.83; H, 5.56; N,
11.00.
(m, 2H), 2.40e2.50 (m, 3H), 2.71 (dd, 1H, J¼6.9, 10.8 Hz), 4.28e4.51
(m, 5H), 7.00 (d, 1H, J¼11.1 Hz), 7.14 (t, 1H, J¼9.6 Hz), 7.58 (t, 1H,
J¼10.3 Hz), 8.04 (s, 1H), 9.60 (d, 1H, J¼9.9 Hz); 13C NMR (CDCl3,
75 MHz):
d
14.5, 14.7, 31.8, 37.9, 38.6, 47.3, 59.7, 65.3, 111.9, 115.7,
4.4.2.1. Crystal data for 5b. Empirical formula¼C15H14N2O2; for-
mula weight¼254.28; temperature¼296 (2) K; wavelength¼
122.1, 128.3, 131.1, 134.3, 137.8, 138.5, 139.9, 165.3, 165.4, 219.8; IR
1682, 1175, 1076, 1039 cmꢀ1; GCeMS (m/z): 326 (Mþ, 100),
0.71073 A; crystal system¼triclinic; space group¼Pꢀ1; unit cell
ꢀ
(KBr):
n
ꢀ
ꢀ
ꢀ
297 (23), 270 (27), 253 (45), 225 (17), 197 (10). Anal. Calcd for
C20H22O4: C, 73.60; H, 6.79. Found: C, 73.62; H, 6.77.
dimensions, a¼7.4962 (2) A; b¼9.9488 (2) A; c¼10.2979 (2) A;
a
¼63.5800 (10)ꢁ;
b
¼86.1730 (10)ꢁ;
g
¼84.2410 (10)ꢁ; vol-
3
3
ꢀ
ume¼684.10 (3) A ; Z¼2; density (calculated)¼1.322 Mg/m ; ab-
4.3.3. Ethyl 4-ethoxy-3-(3-oxocyclohexyl) azulene-1-carboxylate
sorption coefficient¼0.093 mmꢀ1
;
F(000)¼288; crystal size¼
(4c). Yield 89%; purple solid (mp: 165e166 ꢁC); 1H NMR (CDCl3,
0.02ꢂ0.02ꢂ0.02 mm3; theta range for data collection¼2.21e
28.32ꢁ; index ranges¼ꢀ9ꢃhꢃ9, ꢀ12ꢃkꢃ13, ꢀ12ꢃlꢃ13; reflections
collected¼12,328; independent reflections¼3386 [R(int)¼0.0445];
completeness to theta¼28.32ꢁ¼99.7%; absorption correc-
tion¼semi-empirical from equivalents; max. and min. trans-
mission¼0.9981 and 0.9981; refinement method¼full-matrix
least-squares on F2; data/restraints/parameters¼3386/0/191;
300 MHz):
d
1.42 (t, 3H, J¼6.9 Hz), 1.60 (t, 3H, J¼6.9 Hz), 1.73e1.89
(m, 1H), 1.95e2.10 (m, 1H), 2.16e2.35 (m, 2H), 2.40e2.63 (m, 3H),
2.81 (d, 1H, J¼15.3 Hz), 4.14e4.25 (m, 1H), 4.35e4.46 (m, 4H), 7.06
(d, 1H, J¼11.1 Hz), 7.20 (t, 1H, J¼9.9 Hz), 7.64 (t, 1H, J¼10.3 Hz), 8.13
(s, 1H), 9.65 (d, 1H, J¼9.9 Hz); 13C NMR (CDCl3, 75 MHz):
d 14.6, 14.7,
26.1, 33.4, 39.8, 41.5, 50.7, 59.7, 65.4, 111.8, 116.0, 122.1, 127.5, 132.9,
134.6, 137.7, 138.6, 139.6, 165.3, 165.5, 211.9; IR (KBr):
n
1679, 1100,
goodness-of-fit on F2¼1.017; Final
R
indices [I>2sigma(I)]¼
1047 cmꢀ1; GCeMS (m/z): 340 (Mþ, 100), 297 (30), 281 (23), 270
(13), 239 (13), 207 (15). Anal. Calcd for C21H24O4: C, 74.09; H, 7.11.
Found: C, 74.11; H, 7.09.
R1¼0.0542, wR2¼0.1156;
R
indices (all data)¼R1¼0.1352,
ꢀꢀ3
wR2¼0.1426; largest diff. peak and hole¼0.164 and ꢀ0.168 e A
.
Detailed X-ray crystallographic data is available from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK (for compound 5b CCDC # 882109).
4.3.4. Ethyl 4-ethoxy-3-(3-oxocycloheptyl) azulene-1-carboxylate
(4d). Yield 97%; purple solid (mp: 173e174 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.41 (t, 3H, J¼7.2 Hz), 1.54 (t, 3H, J¼6.9 Hz), 1.70e1.88
4.4.3. Ethyl 3-(trifluoromethyl)-1H-azuleno[8,1-cd]pyridazine-5-
carboxylate (5c). Yield 85%; green solid (mp: 233e234 ꢁC); 1H
(m, 2H), 1.95e2.10 (m, 2H), 2.31 (d, 2H, J¼13.5 Hz), 2.55e2.65 (m,
2H), 2.78e3.00 (m, 2H), 4.18 (t, 1H, J¼11.1 Hz), 4.26e4.42 (m, 4H),
6.96 (d, 1H, J¼11.1 Hz), 7.12 (t, 1H, J¼9.6 Hz), 7.54 (t, 1H, J¼10.3 Hz),
NMR (DMSO-d6, 300 MHz):
d
1.38 (t, 3H, J¼6.9 Hz), 4.29 (q, 2H,
J¼6.9 Hz), 5.96 (m, 1H), 6.23 (d, 1H, J¼9.1 Hz), 6.70e6.78 (m, 1H),
8.04 (s, 1H), 9.60 (d, 1H, J¼9.6 Hz); 13C NMR (CDCl3, 75 MHz):
d 14.6,
7.19 (s, 1H), 8.15 (d, 1H, J¼11.0 Hz); 13C NMR (DMSO-d6, 75 MHz):
14.7, 24.3, 29.8, 36.8, 40.0, 44.30, 52.8, 59.6, 65.3, 111.7, 116.0, 121.9,
d 14.3, 59.7, 111.1, 111.5, 118.5, 119.3, 121.8, 128.3, 135.8, 138.7, 142.8,
126.9, 134.9, 135.4, 137.5, 138.4, 139.4, 165.3, 165.5, 214.2; IR (KBr):
n
153.3, 164.7; 19F NMR (376.5 MHz, CDCl3):
3260, 3184, 3077, 2984, 1660, 1601 cmꢀ1; GCeMS (m/z): 308 (Mþ,
d
ꢀ70.2; IR (KBr):
n 3358,
1688, 1208, 1093, 1037 cmꢀ1; GCeMS (m/z): 354 (Mþ, 100), 297

B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
4959
100), 289 (60), 279 (16), 273 (15). Anal. Calcd for C15H11F3N2O2: C,
(CDCl3, 75 MHz):
d
12.2, 14.4, 49.8, 59.6, 113.6, 115.8, 117.6, 119.1,
58.45; H, 3.60; N, 9.09. Found: C, 58.41; H, 3.62; N, 9.10.
119.4, 128.5, 136.3, 141.2, 141.9, 144.9, 152.4, 166.0; IR (KBr): n 1670,
1109, 1093, 1030 cmꢀ1; LCeMS (m/z): 291.2 (Mþ23, 100), 270.2
(14.46), 269.2 (Mþ1, 100, 92.33), 240.2 (9.11). Anal. Calcd for
C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.60; H, 6.02; N,
10.39.
4.4.4. Ethyl 3-methyl-2-phenyl-2H-azuleno[8,1-cd]pyridazine-5-
carboxylate (6a, with PhNHNH2). Yield 88%; green solid (mp:
189e190 ꢁC); 1H NMR (CDCl3, 300 MHz):
d
1.37 (t, 3H, J¼7.2 Hz),
2.13 (s, 3H), 4.32 (q, 2H, J¼7.2 Hz), 5.41 (dd, 1H, J¼8.1, 12.0 Hz), 5.79
(d, 1H, J¼12.0 Hz), 5.96 (dd, 1H, J¼8.1, 12.0 Hz), 7.16 (s, 1H),
4.5.4. Ethyl 2-ethyl-2H-azuleno[8,1-cd]pyridazine-5-carboxylate
7.32e7.55 (m, 6H); 13C NMR (CDCl3, 75 MHz):
d
14.5, 16.9, 59.8,
(8b). Yield 54%; green solid (mp: 149e150 ꢁC); 1H NMR (CDCl3,
112.6,120.1, 121.3, 123.3, 125.1,125.8, 128.7,129.6,129.8, 132.4, 136.1,
300 MHz):
d
1.33 (t, 3H, J¼6.9 Hz), 1.41 (t, 3H, J¼7.2 Hz), 3.70 (q, 2H,
137.0, 142.4, 150.7, 159.6, 166.0; IR (KBr):
n
2296, 1680, 1610,
J¼7.2 Hz), 4.28 (q, 2H, J¼7.2 Hz), 5.27 (dd, 1H, J¼3.3, 8.1 Hz), 5.64 (d,
1H, J¼12.3 Hz), 5.85 (ddd,1H, J¼6.6, 8.4, 8.6 Hz), 6.96 (s,1H), 7.36 (d,
1066 cmꢀ1; GCeMS (m/z): 330 (100), 302 (60), 285 (24). Anal. Calcd
for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.36; H, 5.50;
N, 8.50.
1H, J¼11.4 Hz), 7.51 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d 14.4, 14.7,
55.7, 59.6, 111.3, 119.2, 121.0, 123.1, 124.2, 128.9, 134.0, 136.5, 137.4,
139.2, 161.9, 166.0; IR (KBr):
n ;
1671, 1115, 1043, 1063, 1018 cmꢀ1
4.4.5. Ethyl
idazine-5-carboxylate (6b, with PhNHNH2). Yield 90%; yellow-green
solid (mp: 202e203 ꢁC); 1H NMR (CDCl3, 300 MHz):
1.38 (t, 3H,
2-phenyl-3-(trifluoromethyl)-2H-azuleno[8,1-cd]-pyr-
LCeMS (m/z): 291.2 (Mþ23, 81.28), 279.2 (17.92), 271.3 (15.73),
270.1 (15.19), 269.2 (Mþ1, 100), 240.1 (19.95). Anal. Calcd for
C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.63; H, 6.00; N,
10.42.
d
J¼7.1 Hz), 4.33 (q, 2H, J¼7.2 Hz), 5.34 (dd,1H, J¼8.1,12.0 Hz), 5.61 (d,
1H, J¼12.0 Hz), 5.86 (dd, 1H, J¼8.1, 12.0 Hz), 7.32e7.52 (m, 7H); 13C
NMR (CDCl3, 75 MHz):
d
14.4, 60.2, 113.5 (q, J¼34.5 Hz), 116.5, 117.9,
4.5.4.1. Crystal data for 8b. Empirical formula¼C16H16N2O2; formula
ꢀ
121.7,122.9, 125.4, 125.9,126.9, 128.8, 129.3, 130.1,136.1,138.5,139.7
weight¼268.31; temperature¼296 (2) K; wavelength¼0.71073 A;
(q, J¼283.2 Hz), 142.4, 161.1, 165; 19F NMR (376.5 MHz, CDCl3):
crystal system¼monoclinic; space group¼P 1 21/c 1; unit cell di-
d
ꢀ59.0; IR (KBr):
n
2293, 1686, 1600 cmꢀ1; GCeMS (m/z): 384
mensions, a¼10.4209 (2) A; b¼14.9495 (2) A; c¼9.3605 (2) A;
a
¼90ꢁ;
ꢀ
ꢀ
ꢀ
3
ꢀ
ꢁ
(100), 356 (45), 339 (20). Anal. Calcd for C21H15F3N2O2: C, 65.62; H,
3.93; N, 7.29. Found: C, 65.65; H, 3.96; N, 7.30.
b
¼110.4120 (10)ꢁ;
g
¼90 ; volume¼1366.68 (4) A ; Z¼4; density
(calculated)¼1.304 Mg/m3; absorption coefficient¼0.087 mmꢀ1
;
F(000)¼568; crystal size¼0.2ꢂ0.15ꢂ0.1 mm3; theta range for data
collection¼2.09e28.29ꢁ; index ranges¼ꢀ12ꢃhꢃ13, ꢀ19ꢃkꢃ14,
ꢀ12ꢃlꢃ12; reflections collected¼12,024¼independent reflections¼
3367 [R(int)¼0.0441]; completeness to theta¼28.29ꢁ¼99.4%; ab-
sorption correction¼semi-empirical from equivalents; refinement
method¼full-matrix least-squares on F2; data/restraints/parame-
4.5. Typical procedure for the preparation of N-alkylated
products (7 and 8)
To a solution of 5 (1 mmol), in DMF (3 mL) was added methyl
iodide/ethyl iodide (1.2 mmol) at room temperature and refluxed at
100 ꢁC for 30 min, then the reaction mixture was allowed to cool to
room temperature. The reaction mixture was quenched with water
and extracted with EtOAc. The combined organic layer was dried
over anhydrous MgSO4, filtered, and the solvent was removed to
give crude product, which was purified by silica gel column
chromatography.
ters¼3367/0/184; goodness-of-fit on F2¼0.978; final
R indices
indices (all data)¼
[I>2sigma(I)]¼R1¼0.0496, wR2¼0.1060;
R
R1¼0.1298, wR2¼0.1355; extinction coefficient¼0.0043 (11); largest
ꢀꢀ3
diff. peak and hole¼0.167 and ꢀ0.154 e A . Detailed X-ray crystal-
lographic data is available from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK (for compound 8b
CCDC # 844733).
4.5.1. Ethyl 1-methyl-1H-azuleno[8,1-cd]pyridazine-5-carboxy-late
(7a). Yield 15%; dark blue solid (mp: 105e106 ꢁC); 1H NMR (CDCl3,
4.5.5. Ethyl 1,3-dimethyl-1H-azuleno[8,1-cd]pyridazine-5-
carbo-xylate (7c)
300 MHz):
d
1.38 (t, 3H, J¼7.2 Hz), 3.41 (s, 3H), 4.33 (q, 2H, J¼7.2 Hz),
5.82 (d, 1H, J¼12.0 Hz), 5.83 (dd, 1H, J¼8.7, 12.0 Hz), 6.59 (dd, 1H,
J¼8.7, 12.0 Hz), 7.21 (s, 1H), 7.68 (s, 1H), 8.25 (d, 1H, J¼10.8 Hz); 13C
Yield 13%; dark blue solid (mp: 123e124 ꢁC); 1H NMR (CDCl3,
NMR (CDCl3, 75 MHz):
d 14.5, 43.1, 59.8, 113.9, 115.9, 117.6, 119.2,
300 MHz):
d
1.39 (t, 3H, J¼7.2 Hz), 2.18 (s, 3H), 3.44 (s, 3H), 4.35 (q,
119.3, 128.6, 136.3, 141.5, 142.2, 144.5, 153.2, 166.1; IR (KBr): n 1673,
2H, J¼7.2 Hz), 5.88 (dd, 1H, J¼8.7, 10.8 Hz), 5.91 (d, 1H, J¼12.0 Hz),
1107, 1083, 1049 cmꢀ1; GCeMS (m/z): 254 (100), 226 (83), 209 (39).
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.86; H, 5.53; N, 11.00.
6.62 (ddd, 1H, J¼0.6, 8.7, 12.0 Hz), 7.21 (s, 1H), 8.30 (d, 1H,
J¼10.8 Hz); 13C NMR (CDCl3, 75 MHz):
d 14.5, 18.4, 43.0, 59.7, 113.3,
115.8, 118.3, 118.8, 118.9, 128.7, 134.6, 140.9, 141.3, 151.8, 151.9, 166.2;
IR (KBr):
n
1671, 1109, 1058, 1006 cmꢀ1; GCeMS (m/z): 268 (100),
4.5.2. Ethyl 2-methyl-2H-azuleno[8,1-cd]pyridazine-5-carboxy-late
240 (71), 223 (25). Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N,
10.44. Found: C, 71.60; H, 6.03; N, 10.40.
(8a). Yield 56%; green solid (mp: 109e110 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.33 (t, 3H, J¼7.2 Hz), 3.53 (s, 3H), 4.27 (q, 2H, J¼7.2 Hz),
5.30 (dd, 1H, J¼8.1, 11.5 Hz), 5.63 (d, 1H, J¼12.2 Hz), 5.87 (ddd, 1H,
J¼0.8, 8.1, 12.2 Hz), 6.96 (s, 1H), 7.37 (d, 1H, J¼11.5 Hz), 7.47 (s, 1H);
4.5.6. Ethyl 2,3-dimethyl-2H-azuleno[8,1-cd]pyridazine-5-
carbo-xylate (8c)
13C NMR (CDCl3, 75 MHz):
d
14.5, 47.5, 59.8, 111.8, 119.1, 121.3, 123.2,
124.6, 128.6, 133.8, 136.7, 137.7, 140.5, 161.7, 166.0; IR (KBr):
n 1669,
1110, 1083, 1013 cmꢀ1; GCeMS (m/z): 254 (100), 226 (90), 209 (22).
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.84; H, 5.57; N, 11.03.
Yield 37%; green solid (mp: 130e131 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.33 (t, 3H, J¼7.2 Hz), 2.17 (s, 3H), 3.47 (s, 3H), 4.26 (q,
2H, J¼7.2 Hz), 5.28 (dd, 1H, J¼7.8, 11.4 Hz), 5.62 (d, 1H, J¼12.0 Hz),
5.85 (dd, 1H, J¼7.8, 12.0 Hz), 6.87 (s, 1H), 7.37 (d, 1H, J¼11.4 Hz); 13C
4.5.3. Ethyl
(7b). Yield 35%; dark blue solid (mp: 138e139 ꢁC); 1H NMR (CDCl3,
300 MHz):
1-ethyl-1H-azuleno[8,1-cd]pyridazine-5-carboxy-late
NMR (CDCl3, 75 MHz): d 14.5, 15.6, 43.6, 59.6, 111.5, 120.4, 120.5,
121.8, 124.3, 128.7, 132.6, 136.1, 136.5, 150.0, 159.7, 166.2; IR (KBr):
n
d
1.30 (t, 3H, J¼7.2 Hz), 1.37 (t, 3H, J¼7.2 Hz), 3.79 (q, 2H,
1675,1119,1083,1003 cmꢀ1; GCeMS (m/z): 268 (100), 240 (82), 223
(22). Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found:
C, 71.59; H, 6.00; N, 10.44.
J¼7.2 Hz), 4.32 (q, 2H, J¼6.9 Hz), 5.77e5.87 (m, 2H), 6.52e6.62 (m,
1H), 7.18 (s, 1H), 7.72 (s, 1H), 8.23 (d, 1H, J¼10.5 Hz); 13C NMR

4960
B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
4.5.7. Ethyl 2-ethyl-3-methyl-2H-azuleno[8,1-cd]pyridazine-
5-carboxylate (7d)
J¼7.2 Hz), 4.34 (q, 2H, J¼7.2 Hz), 5.85e5.96 (m, 2H), 6.65 (dd, 1H,
J¼9.0, 9.8 Hz), 7.36 (s, 1H), 8.33 (d, 1H, J¼10.8 Hz); 13C NMR (CDCl3,
75 MHz): d 12.0, 14.4, 50.4, 59.9, 77.4, 112.0, 113.6, 115.2, 118.7, 120.2,
Yield 14%; dark blue solid (mp: 141e142 ꢁC); 1H NMR (CDCl3,
122.3, 129.3, 139.0, 141.1, 142.6, 152.2, 165.6; 19F NMR (376.5 MHz,
300 MHz):
d
1.31 (t, 3H, J¼7.2 Hz), 1.39 (t, 3H, J¼7.2 Hz), 2.19 (s, 3H),
CDCl3):
d
ꢀ73.3; IR (KBr):
n
1677, 1100, 1083, 1010 cmꢀ1; LCeMS (m/
3.84 (q, 2H, J¼7.2 Hz), 4.35 (q, 2H, J¼7.2 Hz), 5.87 (dd, 1H, J¼8.7,
z): 359.2 (Mþ23, 100), 337.2 (Mþ1, 97.58), 309.2 (26.83), 264.1
(19.16). Anal. Calcd for C17H15F3N2O2: C, 60.71; H, 4.50; N, 8.33.
Found: C, 60.72; H, 4.48; N, 8.35.
10.8 Hz), 5.95 (d, 1H, J¼12.0 Hz), 6.61 (dd, 1H, J¼8.7, 12.0 Hz), 7.19 (s,
1H), 8.29 (d, 1H, J¼10.8 Hz); 13C NMR (CDCl3, 75 MHz):
d 12.5, 14.6,
16.5, 49.8, 59.7,113.1,115.8,118.4,118.8,118.9,128.7,134.7,140.7,141.1,
151.1,152.3,166.2;IR(KBr):
n
1672,1116,1086,1002cmꢀ1;GCeMS(m/
4.5.10.1. Crystal data for 7f. Empirical formula¼C17H14F3N2O2; formula
ꢀ
z): 282 (100), 254 (45), 226 (71). Anal. Calcd for C17H18N2O2: C, 72.32;
H, 6.43; N, 9.92. Found: C, 72.31; H, 6.43; N, 9.93.
weight¼335.30; temperature¼298 (2) K; wavelength¼0.71073 A;
crystal system¼monoclinic; space group¼P 21/m; unit cell di-
ꢀ
ꢀ
ꢀ
mensions, a¼10.4078ꢁ(3) A; b¼6.8160 (2) A; c¼10.9689 (4) A;
a
¼90ꢁ;
3
ꢀ
4.5.7.1. Crystal data for 7d. Empirical formula¼C17H18N2O2; for-
mula weight¼282.33; temperature¼298 (2) K; wavelength¼
b
¼92.845 (2)ꢁ;
¼90 ; volume¼777.17 (4) A ; Z¼2; density (calcu-
g
lated)¼1.433 Mg/m3; absorption coefficient¼0.119 mmꢀ1; F(000)¼
346; crystal size¼0.15ꢂ0.13ꢂ0.11 mm3; theta range for data
collection¼1.86e28.28ꢁ; index ranges¼ꢀ12ꢃhꢃ13, ꢀ8ꢃkꢃ9, ꢀ14ꢃl
ꢃ13; reflections collected¼7477; independent reflections¼2077
[R(int)¼0.0431]; completeness to theta¼28.28ꢁ¼99.5%; absorption
correction¼semi-empirical from equivalents; max. and min. trans-
mission¼0.9870 and 0.9824; refinement method¼full-matrix least-
squares on F2; data/restraints/parameters 2077/0/143; goodness-of-
ꢀ
0.71073 A; crystal system¼orthorhombic; space group¼P c a 21;
ꢀ
ꢀ
3
ꢀ
unit cell dimensions¼a¼22.ꢁ6357 (11) A; b¼8.8938 (4) A; c¼7.2615
ꢀ
(3) A;
a
¼90ꢁ;
b
¼90ꢁ;
¼90 ; volume¼1461.87 (11) A ; Z¼4; den-
g
sity
(calculated)¼1.283
Mg/m3;
absorption
coefficient¼
0.085 mmꢀ1; F(000)¼600; crystal size¼0.25ꢂ0.15ꢂ0.11 mm3; theta
range for data collection¼2.29e28.30ꢁ; index ranges¼ꢀ30ꢃhꢃ28,
ꢀ11ꢃkꢃ11, ꢀ9ꢃlꢃ9; reflections collected¼9516; independent
reflections¼3626 [R(int)¼0.0263]; completeness to theta¼
28.30ꢁ¼99.9%; absorption correction¼semi-empirical from equiv-
alents; max. and min. transmission¼0.9907 and 0.9790; refinement
method¼full-matrix least-squares on F2; data/restraints/parame-
ters¼3626/1/193; goodness-of-fit on F2¼1.007; final R indices
fit on F2¼1.052; Final
R
indices [I>2sigma(I)]¼R1¼0.0600,
wR2¼0.1586; R indices (all data)¼R1¼0.1236; wR2¼0.1939; extinc-
tion coefficient¼0.012 (5); largest diff. peak and hole¼0.359 and
ꢀꢀ3
ꢀ0.246 e A . Detailed X-ray crystallographic data is available from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
[I>2sigma(I)]¼R1¼0.0451, wR2¼0.1127;
R
indices (all data)¼
bridge CB2 1EZ, UK (for compound 7f CCDC # 887650).
R1¼0.0617, wR2¼0.1243; absolute structure parameter¼0.3 (15);
ꢀꢀ3
largest diff. peak and hole¼0.190 and ꢀ0.195 e A . Detailed X-ray
4.6. Typical procedure for the preparation of Vils-
meiereHaack products (9aef, 12e14)
crystallographic data is available from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (for
compound 7d CCDC # 887649).
To a stirred solution of 5a or 5c or 6a or 6b or 7b0 or 8b or 11a or
11b (1 mmol), in DMF (3 mL) at 0 ꢁC was added POCl3 (1.2 mmol,
0.1 mL) slowly for 10 min and the reaction continued at 90 ꢁC/0 ꢁC
for 2 h. Then the reaction mixture was allowed to cool to
room temperature and diluted with water (10 mL). The reaction
mixture was quenched with aqueous KOH solution, and was
extracted with EtOAc. The combined organic layers were dried over
MgSO4, concentrated, and chromatographed on silica gel column
chromatography.
4.5.8. Ethyl 2-ethyl-3-methyl-2H-azuleno[8,1-cd]pyridazine-
5-carboxylate (8d)
Yield 41%; green solid (mp: 145e146 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.33 (t, 3H, J¼7.2 Hz), 1.34 (t, 3H, J¼7.2 Hz), 2.25 (s, 3H),
3.79 (q, 2H, J¼7.2 Hz), 4.27 (q, 2H, J¼7.2 Hz), 5.30 (dd, 1H, J¼8.1,
11.4 Hz), 5.68 (d, 1H, J¼12.3 Hz), 5.87 (dd, 1H, J¼8.1, 12.3 Hz), 6.94 (s,
1H), 7.39 (d,1H, J¼11.4Hz);13C NMR (CDCl3, 75MHz):
d 14.1,14.5,15.0,
50.9, 59.6, 111.5, 120.4, 120.5, 122.0, 124.3, 128.8, 132.5, 136.1, 136.5,
4.6.1. Ethyl 4-formyl-1H-azuleno[8,1-cd]pyridazine-5-
carboxylate (9a)
149.0,160.1,166.2;IR (KBr):
n
1676, 1109, 1093, 1010 cmꢀ1; GCeMS(m/
z): 282 (100), 254 (44), 226 (79). Anal. Calcd for C17H18N2O2: C, 72.32;
H, 6.43; N, 9.92. Found: C, 72.32; H, 6.44; N, 9.90.
Yield 81%; dark green solid (mp: 108e109 ꢁC); 1H NMR
(CD3COCD3, 300 MHz):
d
1.39 (t, 3H, J¼7.2 Hz), 4.39 (q, 2H,
4.5.9. Ethyl 1-methyl-3-(trifluoromethyl)-1H-azuleno
[8,1-cd]pyridazine-5-carboxylate (7e)
J¼7.2 Hz), 5.95 (dd, 1H, J¼8.7, 11.7 Hz), 6.31 (d, 1H, J¼11.7 Hz), 6.67
(dd, 1H, J¼8.7, 11.7 Hz), 7.93 (d, 1H, J¼11.7 Hz), 8.77 (s, 1H), 10.6 (s,
1H); 13C NMR (CD3COCD3, 75 MHz):
d 13.8, 60.2, 119.7, 120.2, 120.5,
Yield 96%; yellow-green solid (200e201 ꢁC); 1H NMR (CDCl3,
121.9, 128.3, 128.7, 132.5, 138.8, 141.8, 144.7, 153.5, 165.0, 189.2; IR
300 MHz):
d
1.39 (t, 3H, J¼7.2 Hz), 3.43 (s, 3H), 4.35 (q, 2H,
(KBr):
n
2308, 1702, 1104 cmꢀ1; GCeMS (m/z): 268 (48), 239 (100).
J¼7.2 Hz), 5.81 (d, 1H, J¼12.0 Hz), 5.94 (dd, 1H, J¼1.5, 9.0 Hz), 6.65
Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C,
67.19; H, 4.50; N, 10.42.
(dd, 1H, J¼3.3, 8.7 Hz), 7.37 (s, 1H), 8.30 (d, 1H, J¼10.8 Hz); 13C NMR
(CDCl3, 75 MHz):
d 14.4, 43.5, 59.9, 112.0, 113.9, 115.1, 120.1, 120.3,
122.3, 129.3, 138.9, 141.4, 142.7, 152.8, 165.6; 19F NMR (376.5 MHz,
4.6.2. Ethyl 7-formyl-3-(trifluoromethyl)-1H-azuleno[8,1-cd]-
pyridazine-5-carboxylate (9b)
CDCl3):
d
ꢀ70.3; IR (KBr):
n
1670, 1109, 1080 cmꢀ1; LCeMS (m/z):
345.2 (Mþ23,100), 323.2 (Mþ1, 28.48), 309.2 (24.03). Anal. Calcd
for C16H13F3N2O2: C, 59.63; H, 4.07; N, 8.69. Found: C, 59.61; H,
4.09; N, 8.70.
Yield 79%; yellow-green solid (mp: 126e127 ꢁC); 1H NMR
(CD3COCD3, 300 MHz):
d
1.38 (t, 3H, J¼7.2 Hz), 4.36 (q, 2H,
J¼7.2 Hz), 6.42 (d, 1H, J¼12.0 Hz), 7.22 (dd, 1H, J¼1.4, 12.0 Hz), 7.35
4.5.10. Ethyl 1-ethyl-3-(trifluoromethyl)-1H-azuleno
[8,1-cd]pyridazine-5-carboxylate (7f)
(q, 1H, J¼1.8 Hz), 8.70 (d, 1H, J¼1.4 Hz), 9.45 (s, 1H); 13C NMR
(CD3COCD3, 75 MHz):
d 13.7, 60.2, 114.4, 115.6, 117.7, 119.6, 122.3,
125.0, 129.6, 136.2, 137.9, 142.4, 148.9, 153.3, 164.4, 190.9; 19F NMR
(376.5 MHz, CDCl3):
ꢀ68.1; IR (KBr):
2310, 1706, 1104 cmꢀ1
GCeMS (m/z): 336 (100), 308 (49), 291 (40). Anal. Calcd for
Yield 90%; yellow-green solid (207e208 ꢁC); 1H NMR (CDCl3,
d
n
;
300 MHz):
d
1.32 (t, 3H, J¼7.2 Hz), 1.39 (t, 3H, J¼7.2 Hz), 3.84 (q, 2H,

B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
4961
C16H11F3N2O3: C, 57.15; H, 3.30; N, 8.33. Found: C, 57.17; H, 3.32; N,
8.30.
135.0, 137.2, 138.6, 146.1, 159.4, 165.1, 189.3; IR (KBr):
n
1680, 1110,
1057 cmꢀ1; GCeMS (m/z): 308 (95), 279 (100), 239 (56). Anal. Calcd
for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.12; H, 5.20;
N, 9.10.
4.6.3. Ethyl 1-ethyl-7-formyl-1H-azuleno[8,1-cd]pyridazine-
5-carboxylate (9c)
4.6.8. Ethyl 2-(4-ethoxy-4-oxobut-2-en-2-yl)-4-formyl-2H-
azulen-[8,1-cd]pyridazine-5-carboxylate (13)
Yield 90%; dark green color viscous liquid; 1H NMR (CDCl3,
300 MHz):
d
1.35e1.44 (m, 6H), 3.98 (q, 2H, J¼14.4 Hz), 4.37 (q, 2H,
J¼14.4 Hz), 6.03 (d, 1H, J¼12.6 Hz), 7.25 (dd, 1H, J¼11.4, 12.1 Hz),
Yield 78%; green solid (mp: 155e156 ꢁC); 1H NMR (CDCl3,
7.34 (s, 1H), 7.95 (s, 1H), 8.74 (d, 1H, J¼1.2 Hz), 9.43 (s, 1H); 13C NMR
300 MHz):
d
1.34 (t, 3H, J¼7.2 Hz), 1.42 (t, 3H, J¼7.2 Hz), 2.67 (s, 3H),
(CDCl3, 75 MHz):
d
12.7, 14.3, 50.9, 60.3, 115.1, 116.3, 121.1, 124.5,
4.26 (q, 2H, J¼7.2 Hz), 4.41 (q, 2H, J¼7.2 Hz), 5.60 (dd, 1H, J¼8.1,
11.7 Hz), 5.98 (d, 1H, J¼12.3 Hz), 6.10 (dd, 1H, J¼8.1, 12.3 Hz), 6.52 (s,
1H), 7.35 (d, 1H, J¼11.7 Hz), 9.10 (s, 1H), 10.45 (s, 1H); 13C NMR
127.5, 128.0, 136.1, 138.1, 145.1, 151.0, 152.1, 165.4, 191.5; IR (KBr):
n
2312, 1712, 1104 cmꢀ1; LCeMS (m/z): 297 (Mþ1, 59.81), 298 (11.22),
319 (Mþ23, 100), 320 (17.36). Anal. Calcd for C17H16N2O3: C, 68.91;
H, 5.44; N, 9.45. Found: C, 68.94; H, 5.43; N, 9.45.
(CDCl3, 75 MHz):
d 14.1, 14.3, 15.6, 60.8, 60.9, 113.9, 121.5, 121.6,
123.8,127.4,127.9,129.5,134.1,134.9,137.5,139.1,153.6,159.5,164.9,
165.3, 189.3; IR (KBr):
n
1680, 1106, 1039 cmꢀ1; GCeMS (m/z): 380
4.6.4. Ethyl 4-formyl-3-methyl-2-phenyl-2H-azuleno
[8,1-cd]pyridazine-5-carboxylate (9d)
(100), 351 (49), 239 (62). Anal. Calcd for C21H20N2O5: C, 66.31; H,
5.30; N, 7.36. Found: C, 66.31; H, 5.32; N, 7.35.
Yield 84%; green solid (mp: 207e208 ꢁC); 1H NMR (CDCl3,
4.6.9. Ethyl 2-(4-ethoxy-4-oxobut-2-en-2-yl)-2H-azuleno[8,1-
cd]-pyridazine-5-carboxylate (14)
300 MHz):
d
1.39 (t, 3H, J¼7.2 Hz), 2.57 (s, 3H), 4.40 (q, 2H, J¼7.2 Hz),
5.52 (dd, 1H, J¼7.8, 11.7 Hz), 5.90 (d, 1H, J¼12.3 Hz), 6.02 (dd, 1H,
J¼7.8, 12.3 Hz), 7.08 (d, 1H, J¼11.7 Hz), 7.32e7.56 (m, 5H), 10.30 (s,
Yield 85%; green solid (mp: 124e125 ꢁC); 1H NMR (CDCl3,
1H); 13C NMR (CDCl3, 75 MHz):
d
14.4, 21.5, 61.1, 120.8, 122.5, 124.9,
300 MHz):
d
1.28 (t, 3H, J¼7.2 Hz), 1.33 (t, 3H, J¼7.2 Hz), 2.54 (s, 3H),
125.6, 128.8, 129.9, 130.8, 134.0, 134.2, 136.6, 143.1, 153.5, 158.1,
4.18 (q, 2H, J¼7.2 Hz), 4.26 (q, 2H, J¼7.2 Hz), 5.35 (dd, 1H, J¼8.0,
11.2 Hz), 5.73 (d, 1H, J¼12.0 Hz), 5.87 (dd,1H, J¼8.0,12.0 Hz), 6.47 (s,
1H), 7.09 (s, 1H), 7.28 (d, 1H, J¼11.2 Hz), 7.83 (s, 1H); 13C NMR
165.9, 187.6; IR (KBr):
n
2306, 1708, 1110 cmꢀ1; GCeMS (m/z): 358
(3), 329 (100). Anal. Calcd for C22H18N2O3: C, 73.73; H, 5.06; N, 7.82.
Found: C, 73.71; H, 5.04; N, 7.84.
(CDCl3, 75 MHz):
d 14.2, 14.4, 14.8, 60.0, 60.5, 110.4, 115.9, 120.2,
122.9, 126.0, 126.4, 129.9, 132.9, 135.6, 137.0, 137.3, 152.4, 160.1,
4.6.5. Ethyl 7-formyl-2-phenyl-3-(trifluoromethyl)-2H-azu-
leno-[8,1-cd]pyridazine-5-carboxylate (9e)
165.5, 166.2; IR (KBr):
(100), 240 (40), 212 (60). Anal. Calcd for C20H20N2O4: C, 68.17; H,
5.72; N, 7.95. Found: C, 68.15; H, 5.71; N, 7.95.
n
1672, 1109, 1052 cmꢀ1; GCeMS (m/z): 352
Yield 86%; yellow-green solid (mp: 223e224 ꢁC); 1H NMR
(CDCl3, 300 MHz):
5.85 (d, 1H, J¼12.6 Hz), 6.59 (dd, 1H, J¼1.5, 12.6 Hz), 7.39e7.54 (m,
6H), 8.08 (s, 1H), 9.18 (s, 1H); 13C NMR (CDCl3, 75 MHz):
14.3, 60.8,
d
1.41 (t, 3H, J¼7.2 Hz), 4.37 (q, 2H, J¼7.2 Hz),
4.7. Typical procedure for the preparation of compounds 17
and 19
d
115.6 (q, J¼33.0 Hz), 117.8, 119.0, 121.5, 121.9, 125.7, 128.1, 129.5,
To a solution of 16 or 18 (1 mmol) in ethanol (3 mL), was added
NH2NH2 (1.2 mmol) at room temperature and the reaction con-
tinued at reflux temperature for 2 h, then the reaction mixture was
allowed to cool to room temperature and diluted with water
(10 mL) and extracted with EtOAc. The combined organic layers
were dried over anhydrous MgSO4, filtered, and stripped off solvent
to give crude product, which was purified by silica gel column
chromatography.
130.6, 131.9, 133.4, 137.0, 140.1 (q, J¼288.0 Hz), 142.2, 150.1, 159.7,
164.9, 191.6; 19F NMR (376.5 MHz, CDCl3):
d
ꢀ70.0; IR (KBr):
n 2318,
1702, 1114 cmꢀ1; GCeMS (m/z): 412 (100), 384 (39). Anal. Calcd for
C22H15F3N2O3: C, 64.08; H, 3.67; N, 6.79. Found: C, 64.10; H, 3.68; N,
6.78.
4.6.6. Ethyl 2-ethyl-4-formyl-2H-azuleno[8,1-cd]pyridazine-
5-carboxylate (9f)
4.7.1. Ethyl 3-(2-hydroxypropyl)-1H-azuleno[8,1-cd]pyr-
idazine-5-carboxylate (17)
Yield 88%; green color viscous liquid; 1H NMR (CDCl3, 300 MHz):
d
1.40 (t, 3H, J¼7.2 Hz), 1.52 (q, 3H, J¼7.2 Hz), 4.01 (q, 2H, J¼7.5 Hz),
4.39 (q, 2H, J¼6.9 Hz), 5.56 (dd, 1H, J¼3.6, 8.1 Hz), 5.96 (dd, 1H,
J¼3.6, 8.1 Hz), 6.08 (dd, 1H, J¼4.2, 8.1 Hz), 7.41 (d, 1H, J¼11.7 Hz),
Yield 75%; blue solid (mp: 201e202 ꢁC); 1H NMR (CD3OD,
300 MHz):
d
1.23 (t, 3H, J¼6.3 Hz), 1.37 (t, 3H, J¼7.2 Hz), 2.56 (q, 1H,
8.89 (s, 1H), 10.43 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d
14.3, 14.9,
J¼6.6 Hz), 2.69 (q, 1H, J¼6.6 Hz), 4.20e4.34 (m, 3H), 4.80e4.50 (m,
2H), 5.78 (t, 1H, J¼10.9 Hz), 6.01 (d, 1H, J¼11.5 Hz), 6.51 (t, 1H,
J¼11.5 Hz), 7.13 (s, 1H), 7.97 (d, 1H, J¼10.9 Hz); 13C NMR (CD3OD,
57.0, 60.5, 119.2, 122.1, 122.8, 124.9, 126.7, 129.0, 134.2, 135.4, 137.2,
140.4, 160.5, 165.2, 189.3; IR (KBr):
(m/z): 297 (Mþ1, 22.70), 309 (15.55), 319 (Mþ23, 100), 320 (19.92),
381 (21.78). Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45.
Found: C, 68.90; H, 5.44; N, 9.43.
n
2316, 1705, 1104 cmꢀ1; LCeMS
75 MHz): d 13.4, 21.9, 41.5, 59.4, 65.0, 112.3, 117.7, 118.2, 118.4, 119.4,
128.3, 132.8, 138.5, 140.4, 152.0, 153.0, 166.5; IR (KBr): n 3432, 3357,
1674, 1178, 1035 cmꢀ1; GCeMS (m/z): 298 (Mþ, 100), 281 (12), 254
(30), 226 (31), 209 (20), 181 (24). Anal. Calcd for C17H18N2O3: C,
68.44; H, 6.08; N, 9.39. Found: C, 68.45; H, 6.09; N, 9.40.
4.6.7. Ethyl 4-formyl-2-(prop-1-en-2-yl)-2H-azuleno
[8,1-cd]pyridazine-5-carboxylate (12)
4.7.2. Ethyl 3-(4-oxopentyl)-1H-azuleno[8,1-cd]pyridazine-5-
carboxylate (19)
Yield 82%; green solid (mp: 116e117 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.39 (t, 3H, J¼7.2 Hz), 2.23 (s, 3H), 4.37 (q, 2H,
J¼14.4 Hz), 5.08 (s, 1H), 5.52 (dd, 1H, J¼8.1, 11.7 Hz), 5.58 (s, 1H),
5.92 (d, 1H, J¼12.3 Hz), 6.04 (dd, 1H, J¼8.1, 12.3 Hz), 7.33 (d, 1H,
J¼11.7 Hz), 8.99 (s, 1H), 10.39 (s, 1H); 13C NMR (CDCl3, 75 MHz):
Yield 78%; blue solid (mp: 190e191 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.39 (t, 3H, J¼7.2 Hz), 1.94e2.05 (m, 2H), 2.13 (s, 3H),
2.50e2.58 (m, 4H), 4.35 (q, 2H, J¼11.5 Hz), 5.80e5.94 (m, 2H), 6.52
d
14.3, 19.2, 60.7, 109.2, 120.5, 121.7, 123.3, 126.3, 127.0, 129.3, 134.0,
(t, 1H, J¼11.5 Hz), 7.19 (s, 1H), 8.14 (d, 1H, J¼10.8 Hz); 13C NMR

4962
B. Devendar et al. / Tetrahedron 69 (2013) 4953e4963
(CDCl3, 75 MHz):
d
14.5, 20.1, 30.0, 31.5, 42.8, 59.8, 113.4, 117.3, 117.6,
Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.64; H,
5.83; N, 9.00.
119.5, 120.1, 129.0, 133.2, 139.8, 141.0, 151.7, 154.7, 166.1, 208.8; IR
(KBr):
n
3446, 1687, 1135, 1073, 1037 cmꢀ1; GCeMS (m/z): 324 (Mþ,
91), 281 (50), 237 (11), 206 (100), 146 (13). Anal. Calcd for
C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.34; H, 6.23; N,
8.62.
4.10.1.1. Crystal data for 22a. Empirical formula¼C18H18N2O3; formula
ꢀ
weight¼310.34; temperature¼295 (2) K; wavelength¼0.71073 A;
crystal system¼monoclinic; space group¼C2/c; unit cell dimensions,
ꢀ
ꢀ
ꢀ
a¼15.9841 (17) A; b¼ꢁ 16.5867 (18) A; c¼13.1061 (14) A;
a
¼90ꢁ;
3
ꢀ
b
¼116.264 (3)ꢁ;
¼90 ; volume¼3116.0 (6) A ; Z¼8; density (calcu-
g
4.8. Procedure for the preparation of compound 20
lated)¼1.323 Mg/m3; absorption coefficient¼0.091 mmꢀ1; F(000)¼
1312; crystal size¼0.15ꢂ0.15ꢂ0.04 mm3; theta range for data
collection¼1.88e28.36ꢁ; index ranges¼ꢀ21ꢃhꢃ14, ꢀ20ꢃkꢃ22,
ꢀ17ꢃlꢃ16; reflections collected¼14,020; independent reflections¼
3897 [R(int)¼0.0644]; completeness to theta¼28.36ꢁ¼99.7%; ab-
sorption correction¼semi-empirical from equivalents; max. and min.
transmission¼0.9964 and 0.9865; refinement method¼full-matrix
least-squares on F2; data/restraints/parameters¼3897/0/208; goodn-
ess-of-fit on F2¼0.980; Final R indices [I>2sigma(I)]¼R1¼0.0584,
wR2¼0.1226; R indices (all data)¼R1¼0.1601, wR2¼0.1574; largest
To a solution of ethyl 3-(4-oxopentyl)-1H-azuleno[8,1-cd]-pyr-
idazine-5-carboxylate (19, 1 mmol) in EtOH (3 mL), was added
p-TSA (1.2 mmol) at room temperature and refluxed at 100 ꢁC for
2 h. Then the reaction mixture was allowed to cool to room tem-
perature, and quenched with water and extracted with EtOAc. The
combined organic layer was dried over anhydrous MgSO4, filtered,
and stripped off solvent to give crude product, which was purified
by silica gel column chromatography to afford the compound 20.
Yield 85%; blue solid (mp: 200e201 ꢁC); 1H NMR (CDCl3, 300 MHz):
ꢀꢀ3
diff. peak and hole¼0.209 and ꢀ0.246 e A . Detailed X-ray crystal-
d
1.37 (t, 3H, J¼7.2 Hz), 2.10 (s, 3H), 2.40 (t, 2H, J¼6.9 Hz), 2.57 (t, 2H,
lographic data is available from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK (for compound 22a
CCDC # 844734).
J¼6.9 Hz), 4.37 (q, 2H, J¼7.2 Hz), 5.65e5.74 (m, 2H), 5.87 (t, 1H,
J¼11.7 Hz), 6.39 (m, 1H), 7.37 (d, 1H, J¼10.9 Hz); 13C NMR (CDCl3,
75 MHz): d 14.3, 23.4, 25.1, 34.7, 60.9, 116.1, 116.9, 119.3, 121.0, 125.1,
127.3, 128.3, 132.0, 133.2, 137.5, 140.1, 151.1, 157.2, 168.6; IR (KBr):
n
3459, 1676, 1178, 1104, 1076 cmꢀ1; GCeMS (m/z): 306 (Mþ, 94), 263
(29), 207 (100), 177 (7), 147 (13). Anal. Calcd for C19H18N2O2: C,
74.49; H, 5.92; N, 9.14. Found: C, 74.50; H, 5.93; N, 9.12.
4.10.2. Ethyl 2,4-bis(3-oxobutyl)-2H-azuleno[8,1-cd]pyr-
idazine-5-carboxylate (22b)
Yield 23%; green solid (mp: 138e139 ꢁC); 1H NMR (CDCl3,
300 MHz):
d
1.29 (t, 3H, J¼7.2 Hz), 2.00 (s, 3H), 2.13 (s, 3H), 2.64
4.9. Procedure for the preparation of ethyl 3-(4-hydroxy-
pentyl)-1H-azuleno[8,1-cd]pyridazine-5-carboxylate (21)
(t, 2H, J¼6.0 Hz), 2.90e2.98 (m, 4H), 3.83 (t, 2H, J¼6.0 Hz), 4.23 (q,
2H, J¼7.2 Hz), 5.13 (dd, 1H, J¼8.2, 11.4 Hz), 5.47 (d, 1H, J¼12.3 Hz),
5.72 (dd, 1H, J¼8.2, 12.3 Hz), 7.15 (d, 1H, J¼11.4 Hz), 7.75 (s, 1H); 13C
To a solution of ethyl 3-(4-oxopentyl)-1H-azuleno[8,1-cd]-pyr-
idazine-5-carboxylate (19, 1 mmol) in EtOH (3 mL), was added
NaBH4 (1.2 mmol) at room temperature and heated at 50 ꢁC for
40 min. Then the reaction mixture was allowed to cool to room
temperature, and quenched with water (10 mL) and extracted with
EtOAc. The combined organic layer was dried over anhydrous
MgSO4, filtered, and stripped off solvent to give crude product,
which was purified by silica gel column chromatography to afford
the compound 21. Yield 95%; blue solid (mp: 195e196 ꢁC); 1H NMR
NMR (CDCl3, 75 MHz):
d 14.3, 20.3, 30.1, 30.2, 41.4, 44.8, 54.7, 59.7,
119.1, 120.3, 120.7, 124.3, 126.4, 128.9, 132.8, 136.7, 137.2, 141.0, 161.8,
166.3, 205.5, 209.0; IR (KBr):
GCeMS (m/z): 380 (100), 302 (58). Anal. Calcd for C22H24N2O4: C,
69.46; H, 6.36; N, 7.36. Found: C, 69.48; H, 6.35; N, 7.38.
n
2320, 1702, 1490, 1476, 1180 cmꢀ1
;
Acknowledgements
(CD3OD, 300 MHz):
d
1.14 (d, 3H, J¼6.0 Hz), 1.36 (t, 3H, J¼6.9 Hz),
We gratefully acknowledge Professor Chun-Chen Liao for help-
ful discussions. The financial support is from the CYCU distinctive
research area project as grant CYCU-99-CR-CH and National Science
Council (NSC) of Taiwan (Grant No.: NSC 100-2119-M-033-001).
B.D. thanks NSC of Taiwan (Grant No.: NSC 100-2811-M-033-008)
for a postdoctoral fellowship.
1.50e1.55 (m, 2H), 1.67e1.86 (m, 2H), 2.46 (t, 2H, J¼7.5 Hz),
3.70e3.80 (m,1H), 4.30 (q, 2H, J¼6.9 Hz), 4.61 (s, 1H), 5.75e5.82 (m,
1H), 6.00 (d, 1H, J¼11.7 Hz), 6.47e6.54 (m, 1H), 7.11 (s, 1H), 7.97 (d,
1H, J¼10.9 Hz); 13C NMR (CD3OD, 75 MHz):
d 13.5, 22.1, 22.5, 32.0,
38.4, 59.4, 66.8, 112.2, 117.6, 117.7, 118.3, 119.4, 128.3, 132.7, 138.5,
140.3, 152.2, 155.4, 166.6; IR (KBr):
n 3330, 1667, 1184, 1080,
1031 cmꢀ1; GCeMS (m/z): 326 (Mþ, 93), 207 (100), 185 (24), 147
(14). Anal. Calcd for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58. Found: C,
69.91; H, 6.80; N, 8.59.
Supplementary data
Copies of 1H NMR, 13C NMR, DEPT, and 19F NMR spectra are
available. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.04.034.
4.10. Procedure for the preparation of 22a and 22b
Similar to the general procedure of Section 4.3.
References and notes
4.10.1. Ethyl 4-(3-oxobutyl)-1H-azuleno[8,1-cd]pyridazine-5-
carboxylate (22a)
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d
1.34 (t, 3H, J¼7.2 Hz), 2.06 (s, 3H), 2.68 (t, 2H, J¼7.2 Hz),
3.08 (t, 2H, J¼7.2 Hz), 4.29 (q, 2H, J¼7.2 Hz), 5.65 (dd, 1H, J¼8.8,
11.0 Hz), 5.74 (d, 1H, J¼11.6 Hz), 6.32 (dd, 1H, J¼8.8, 11.6 Hz), 7.70 (s,
1H), 7.86 (d, 1H, J¼11.0 Hz), 10.19 (br s, 1H); 13C NMR (CDCl3,
75 MHz): d 14.4, 20.9, 30.1, 44.7, 59.8, 116.8, 117.0, 117.5, 120.1, 128.6,
129.2, 133.5, 139.8, 141.0, 143.6, 152.7, 166.4, 209.6; IR (KBr):
n 2300,
1690, 1480 cmꢀ1; GCeMS (m/z): 310 (110), 253 (61), 221 (76). Anal.

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