Regioselective aluminium chloride induced heteroarylation of pyrrolo[1,2-b]pyridazines: Its scope and application

Article abstract of DOI:10.1016/S0040-4020(02)01352-2

We describe a detailed study on the novel synthesis of 6,7-disubstituted pyrrolo[1,2-b]pyridazines through AlCl₃ induced C-C bond formation reactions. A wide variety of 6-aryl substituted azolopyridazines was reacted with 3,6-dichloropyridazine to give 7-pyridazinyl substituted pyrrolopyridazines regioselectively in good to excellent yield. The mechanism and regiochemistry of the reaction along with applications of the methodology are discussed.

Full text of DOI:10.1016/S0040-4020(02)01352-2

Tetrahedron 58 (2002) 9933–9940
Regioselective aluminium chloride induced heteroarylation of
pyrrolo[1,2-b]pyridazines: its scope and applicationq
*
Manojit Pal, Venkateswara Rao Batchu, Smriti Khanna and Koteswar Rao Yeleswarapu
*
Chemistry Discovery Research, Dr Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500050, India
Received 4 October 2001; revised 23 September 2002; accepted 17 October 2002
Abstract—We describe a detailed study on the novel synthesis of 6,7-disubstituted pyrrolo[1,2-b]pyridazines through AlCl3 induced C–C
bond formation reactions. A wide variety of 6-aryl substituted azolopyridazines was reacted with 3,6-dichloropyridazine to give
7-pyridazinyl substituted pyrrolopyridazines regioselectively in good to excellent yield. The mechanism and regiochemistry of the reaction
along with applications of the methodology are discussed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
tase9b and secretory phospholipase A2 (s PLA2)9c along
with their antimicrobial activity.2b,9d
The pyridazine nucleus, which has been known for more
than a century, is of considerable interest because of its
many synthetic1 and biological uses.2 This six membered
heterocycle has been found to be an integral part of many
polynuclear heterocycles. An example of this class is
pyrrolo[1,2-b]pyridazine or 5-azaindolizine 1 (Fig. 1).
Several nitrogen heterocycles related to 1 have attracted
particular attention due to their potential therapeutic
usefulness.3 – 9 Amongst them adenosine A1 receptor
antagonist 2 (FK 838),4 anti-inflammatory agent 36 and
anti-platelet agent8 (KC-764) are of particular interest (Fig.
1). Compound 2 has been described as a potent and selective
non-xanthine adenosine A1 receptor antagonist related to
both diuretic and antihypertensive effects, whereas 3 has
been developed as a highly selective cyclooxygenase-2
(COX-2) inhibitor for pain management. Several deriva-
tives of 1 have been reported as inhibitors of lipid
peroxidation,9a hydroxymethylglutaryl (HMG) CoA reduc-
As part of our continuing interest in the development of
various diaryl heterocycles10 for biological testing in
different therapeutic areas,10c we decided to explore
the biological and pharmacological properties of a
combinatorial library based on the scaffold of pyrrolopyri-
dazines 1. We thought that due to the structural similarity
with the pyrazolopyridine nucleus of 2 this could be an
alternative template for the development of potent and water
soluble adenosine A1 receptor antagonists. We therefore
postulated that introduction of an aryl group and a
pyridazinone moiety (in which the double bond and
carbonyl group of acrylolylamide were mimicked by a
ring system)4 at position 6 and 7 of this template,
respectively, may lead to a novel class of pyrrolopyridazines
(4) of potential biological interest (Fig. 2).
Over a period of more than a century, only few methods
Figure 1. Some nitrogen containing fused heterocycles.
q 5-Azaindolizine or pyrrolo[1,2-b]-pyridazine has been named as azolopyridazine according to IUPAC nomenclature; DRF Publication No. 173.
Keywords: pyridazines; aluminium chloride; regioselective heteroarylation; C–C bond formation.
*
Corresponding authors. Fax: þ91-40-3045438/3045007; e-mail: manojitpal@drreddys.com; koteswarraoy@drreddys.com.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01352-2

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M. Pal et al. / Tetrahedron 58 (2002) 9933–9940
Crafts arylation and palladium-catalyzed cross-coupling
reaction14d,f including Suzuki coupling are the most
popular. In view of cost effectiveness and availability of
starting materials, we chose the AlCl3 induced arylation
reaction15 to generate a combinatorial library based on
pyrrolopyridazines 4. To the best of our knowledge no
successful heteroarylation of the pyrrolopyridazine system
using a similar methodology has hitherto been described in
the literature.
Figure 2. Design of novel adenosine A1 receptor antagonists.
have been reported for the synthesis of pyrrolopyridazine
and its derivatives. They are prepared by (i) the reaction of
dimethylpyridazine with a-bromoketones followed by
cyclization in the presence of alkali,11 (ii) reaction of
pyridazines with diphenylcyclopropenone9a,12 or (iii) 1,3-
dipolar cycloaddition reactions13 of pyridazinium dicyano-
methylides, obtained from pyridazine and tetracyano-
ethylene oxide, with dipolarophiles such as dimethyl
acetylenedicarboxylate or cyanoacetylene.13c On the other
hand the synthesis of 6-(hetero)aryl substituted pyridazin-3-
one proceeds via three steps procedure involving conden-
sation of hydrazine with appropriately substituted 1,4-
dicarbonyl compounds.1b,2e,4 However, these synthetic
routes to obtain 4 are either inappropriate (due to the non-
availability of the required starting material) or unattractive
due to the lengthy synthetic procedure.
2. Results and discussion
The regioselective heteroarylation reaction of pyrrolo[1,2-
b]pyridazines was carried out successfully under the
Friedel–Crafts reaction condition according to Scheme 1.
When 5.6 equiv. of 6-aryl substituted pyrrolo[1,2-b]pyrida-
zines 5 (Ar¼aryl group) were reacted with 6.04 equiv. of
3,6-dichloropyridazine 6 in the presence of 6.06 equiv. of
AlCl3 using dichloroethane as solvent, 7-pyridazinylpyr-
rolo[1,2-b]pyridazines 7 were formed as the exclusive
products in good yields. The results are summarized in
Table 1.
As can be seen from Table 1, the heteroarylation reaction
was well tolerated in the presence of various substituted aryl
groups at position 6 of the pyrrolopyridazine moiety. An
alkyl group at the p-position of the aryl ring was found to be
effective in terms of yield (see entries 1, 11 and 12). A
fluorine substituent at the o-position to the alkyl group
enhanced the yield (entry 11), whereas branching of the
We focused on the methods available in the literature14 that
could be utilized for the straightforward preparation of 4 via
C–C bond formation as the key synthetic step. Among the
methods available for aryl–aryl bond formation Friedel–
Scheme 1. Reagents and conditions: (a) AlCl3, dichloroethane, 50–608C, 48 h.
Table 1. AlCl3 induced heteroarylation of pyrrolo[1,2-b]pyridazine
Entry
Starting material 5; Ar¼
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Isobutylphenyl
4-Chlorophenyl
2,4-Dimethoxyphenyl
4-Fluorophenyl
4-Fluorophenyl
3-Fluoro-4-methylphenyl
4-Ethylphenyl
4-(N-Methylsulfonyl) aminophenyl
4-Methoxyphenyl
4-Nitrophenyl
Product
Temperature (8C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7ab
7b
7c
7d
7e
7e
7f
60
rt
48
48
12
24
48
48
48
48
48
48
48
48
48
48
48
48
65
–
28
33
–
42
50
60
71
12
89
76
4
60
60
60
60
55
60
50
rt
55
60
60
55
60
60
9
10
11
12
13
14
15
16
7g
7h
7i
93
72
20
7j
4-Methylphenyl
8c
a
Yield of isolated products.
Reaction was carried out in the absence of AlCl3.
3-Chloro-6-methoxypyridazine was used in place of 6.
b
c

M. Pal et al. / Tetrahedron 58 (2002) 9933–9940
9935
Scheme 2. Reagents and conditions: (a) CH3COONa, CH3COOH, reflux, 5 h; (b) ethylbromoacetate, DMF, K2CO3; (c) MeOH–H2O, K2CO3.
alkyl group led to lowering of the yield (entry 6). A halogen
at the p-position was well tolerated (entries 7 and 9). An
excellent yield of product was observed when a strong
electron donating group such as methoxy occupied the
p-position (entry 14), while no significant effect was
observed when a strong electron withdrawing group (entry
15) was present at the same position. The N-methylsul-
fonylamino group was found to be a poor substituent in our
heteroarylation reaction (entry 13).
moiety was attached with it. On the other hand C-7 of 5
appeared at dC 120–126 ppm, and was shifted to dC 140–
155 ppm in the case of product 7.
6-Arylpyrrolopyridazines 5, key substrates for the hetero-
arylation reaction, were prepared by an established
procedure.11,18,19
We have described an efficient and practical method for the
synthesis of 6,7-disubstituted pyrrolopyridazines through an
AlCl3 induced coupling reaction. Interestingly, little is
known about either Friedel–Crafts or AlCl3 induced
reactions on nitrogen containing heterocycles.20 The nitro-
gen containing heterocycles, e.g. pyridine derivatives, due
to the enhanced electron deficiency of the six membered
ring as well as their complexation with AlCl3,21 have been
identified as poor substrates for AlCl3 mediated alkylation/
acylation reactions. We did not encounter this problem,
probably due to the poor availability of the lone pair of
electrons on either of the nitrogen atoms of the pyrrolo-
pyridazine ring. This was supported by the observation that
like pyridine none of 5a–j generated the corresponding salt
when treated with hydrochloric acid under protic con-
ditions.20b However, it is the same feature in the case of 3,6-
dichloropyridazine, which actually promotes its reaction
with nucleophilic pyrrolopyridazine derivatives.
3,6-Dichloropyridazine 6 was used as heteroaryl halide in
most of the arylation reactions. However, use of 3-chloro-6-
methoxypyridazine was also found to be satisfactory albeit
in lower yield (entry 16) and 3-chloro-1,6-dihydro-6-
pyridazinone failed to react under the conditions employed
in the reaction. The reaction was found to be moisture
sensitive as 6 was hydrolyzed to the corresponding
pyridazinedione (maleic hydrazide) in the presence of
AlCl3 upon exposure to the moisture.
The molar ratio of reagents, reaction time and temperature
was optimized to achieve maximum yield and was found to
be a 1:1.08:1.08 ratio of 5 and 6 with AlCl3 as reagent. No
reaction occurred without AlCl3 (entry 5). The reactions
were usually carried out at 50–608C (entries 2 and 10) for
48 h. Either lower yields (10–15%) or the formation of no
products were observed when the reaction was carried out at
room temperature. Dicholoroethane was the solvent of
choice. Use of other chlorinated solvents such as dichloro-
methane was also investigated and was found to be
ineffective.
We have extended the scope of our AlCl3 induced
methodology to the synthesis of a compound having
potential biological interest (Scheme 2). Compound 7g
was hydrolyzed to pyridazinone derivative 9 using sodium
acetate in acetic acid under reflux. The resulting compound
was treated with ethylbromoacetate in the presence of
potassium carbonate in DMF at room temperature to afford
the ester 10 that was finally hydrolyzed to give the expected
product 4g (Ar¼C6H4C2H5-p) in good yield.
The heteroarylation reaction was found to be highly
regioselective. The structures of the products isolated
were established from analytical and spectroscopic
data.16–17 In the 1H NMR spectra the pyridazinyl hydrogens
were at d 7.80^0.30 and d 7.30^0.50 as two doublets.
Regioselective substitution at the 7-position of 7 was
1
confirmed by analysis of the H NMR and 13C NMR17
3. Conclusion
spectra of starting material and product. A singlet at d
1
7.90^0.30 in the H NMR spectra of starting materials 5
In conclusion, we have applied the AlCl3 mediated reaction
to develop a general and convenient method for the
synthesis of diaryl nitrogen containing heterocycles. Our
method involves use of readily available starting materials,
inexpensive reagents and mild reaction conditions. The
method offers an adaptable and single step procedure to
introduce the pyridazinyl group at position 7 of the
pyrrolo[1,2-b]pyridazine nucleus having a wide range of
was assigned as the proton at position 7. This disappears in
the corresponding spectra of products 7. Moreover the
signal at d 6.6 due to the hydrogen at the 5-position of 5 was
1
found to remain unchanged in the H NMR spectra of 7.
Similarly the unsubstituted C-5 could be seen at dC 95–
105 ppm in 13C NMR spectra17 of 5 and 7 which would have
appeared in a more down field region if the pyridazine

9936
M. Pal et al. / Tetrahedron 58 (2002) 9933–9940
aryl residues at position 6. Thus the protocol could be a
useful alternative to the Suzuki coupling and other transition
metal catalyzed reactions when applied to similar type of
nitrogen containing heterocyclic systems. The method has
been utilized for synthesis of compounds of possible
biological importance. Application of this methodology to
other heterocyclic systems in order to open new avenues
towards the synthesis of biologically active compounds is
under active investigation.
diluting with water (100 mL) the mixture was extracted with
chloroform (3£50 mL). Organic layers collected, combined,
washed with water (2£75 mL), dried (Na2SO4) and
concentrated under vacuum to give the desired product.
4.2.1. 6-(4-Methylphenyl)-2-methylpyrrolo[1,2-b]pyri-
dazine (5a). Yield¼0.81 g (61%); mp 138–1398C; dH
(200 MHz, CDCl3) 7.92 (s, 1H), 7.66–7.53 (m, 3H), 7.21 (d,
J¼7.8 Hz, 2H), 6.67 (s, 1H), 6.40 (d, J¼8.8 Hz, 1H), 2.45
(s, 3H, Me), 2.37 (s, 3H, Me); nmax (KBr) 1595 cm21; m/z
(CI, i-butane) 223 (100, MHþ); found C, 81.15; H, 6.34; N,
12.58; C15H14N2 requires C, 81.05; H, 6.35; N, 12.60%.
4. Experimental
4.2.2. 6-(4-Isobutylphenyl)-2-methylpyrrolo[1,2-b]pyri-
dazine (5b). The title compound was prepared from
2-bromo-1-(4-isobutylphenyl)-1-ethanone (prepared by
brominating19e 4-isobutylacetophenone19f) according to
the procedure described earlier. Yield¼0.49 g (31%); low
melting; dH (200 MHz, CDCl3) 7.93 (s, 1H), 7.61–7.54 (m,
3H), 7.17 (d, J¼8.3 Hz, 2H), 6.68 (s, 1H), 6.40 (d,
J¼9.3 Hz, 1H), 2.53 (d, J¼8.3 Hz, 2H, CH2CHMe2), 2.45
(s, 3H, Me), 1.92–1.85 (m, 1H, CH2CHMe2), 0.93 (d,
J¼6.8 Hz, 6H, 2Me); nmax (KBr) 1590 cm21; m/z (CI, i-
butane) 265 (100, MHþ); found C, 81.75; H, 7.64; N, 10.57;
C18H20N2 requires C, 81.78; H, 7.62; N, 10.60%.
4.1. General methods
Unless stated otherwise, reactions were performed in dried
glassware under nitrogen atmosphere. All the solvents used
were commercially available and distilled before use.
Reactions were monitored by thin layer chromatography
(TLC) on silica gel plates (60 F254; Merck), visualizing
with ultraviolet light or iodine spray. Flash chromatography
was performed on silica gel (SRL 230–400 mesh) using
distilled petroleum ether, ethyl acetate, dichloromethane,
chloroform and methanol. H and 13C NMR spectra were
1
determined in CDCl3, DMSO-d6 or MeOH-d4 solution on
Varian Gemini 200 MHz spectrometers. Proton chemical
shifts (d) are relative to tetramethylsilane (TMS, d¼0.00) as
internal standard and expressed in ppm. Spin multiplicities
are given as s (singlet), d (doublet), t (triplet) and m
(multiplet) as well as b (broad). Coupling constants (J) are
given in hertz. Infrared spectra were recorded on a Perkin–
Elmer 1650 FT-IR spectrometer. UV spectra were recorded
on Shimadzu UV 2100S UV–Vis recording spectro-
photometer. Melting points were determined using Buchi
melting point B-540 apparatus and are uncorrected. Thermal
analysis data was generated with the help of Shimadzu
DSC-50 detector. MS spectra were obtained on a HP-5989A
mass spectrometer. Purity was determined by HPLC
(AGIL-AUTO) using the condition specified in each case:
column, mobile phase (range used), flow rate (ranges used),
detection wavelength, retention times. Microanalyses were
performed using Perkin–Elmer 2400 CHNS/O analyzer.
Acetophenones and their bromo derivatives were either
purchased or prepared according to the procedure described
in the literature.19 4-isobutylacetophenone19f was bromi-
nated according to the procedure described in the litera-
ture.19e 3,6-dichloropyridazine is commercially available
and 3-chloro-6-methoxypyridazine was prepared according
to the procedure described in the literature.22
4.2.3. 2-Bromo-1-(4-isobutylphenyl)-1-ethanone. Low
1
melting solid, yield 68%; H NMR (CDCl3): d 7.89 (dd,
J¼5.8, 5.8 Hz, 2H), 7.25 (dd, J¼6.3, 6.3 Hz, 2H), 4.44 (s,
2H, CH2CO), 2.56–2.51 (m, 2H, CH2CHMe2), 1.94–1.84
(m, 1H, CH2CHMe2), 0.91 (d, J¼6.35 Hz, 6H, 2Me); MS
(CI, i-butane): 256 (100, MHþ), 255 (100). Elemental
analysis found C, 56.39; H, 5.90; C12H15BrO requires C,
56.49; H, 5.93%.
4.2.4. 6-(4-Chlorophenyl)-2-methylpyrrolo[1,2-b]pyrida-
zine (5c). Yield¼0.68 g (47%); mp 146–1488C; dH
(200 MHz, CDCl3) 7.91 (s, 1H), 7.62–7.51 (m, 3H), 7.36
(d, J¼8.3 Hz, 2H), 6.66 (s, 1H), 6.43 (d, J¼9.3 Hz, 1H),
2.45 (s, 3H, Me); nmax (KBr) 1594 cm21; m/z (CI, i-butane)
243 (100, MHþ); found C, 69.25; H, 4.56; N, 11.59;
C14H11ClN2 requires C, 69.28; H, 4.57; N, 11.54%.
4.2.5. 6-(2,4-Dimethoxyphenyl)-2-methylpyrrolo[1,2-
b]pyridazine (5d). Yield¼1.10 g (69%) (gum); dH
(200 MHz, CDCl3) 7.90 (s, 1H), 7.59 (d, J¼9.3 Hz, 1H),
7.27–7.17 (m, 2H), 6.92 (d, J¼8.3 Hz, 1H), 6.65 (d,
J¼1.5 Hz, 1H), 6.42 (d, J¼9.3 Hz, 1H), 3.96 (s, 3H, OMe),
3.92 (s, 3H, OMe), 2.46 (s, 3H, Me); nmax (KBr) 1598 cm21
;
m/z (CI, i-butane) 269 (100, MHþ); found C, 71.64; H, 6.00;
N, 10.41; C16H16N2O2 requires C, 71.62; H, 6.01; N,
10.44%.
4.2. General procedure for preparation of 5
Step 1.
A mixture of 2-bromo-1-aryl-1-ethanone
(13.21 mmol) and dimethylpyridazine18 (26.38 mmol) in
ethyl acetate (10 mL) was stirred at 708C for 12 h. The
reaction mixture was cooled to room temperature and
the solvent was decanted out from the separated mass. The
residue was dried and used for the next step without further
purification.
4.2.6. 6-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyrida-
zine (5e). Yield¼0.79 g (59%); mp 147–1488C; dH
(200 MHz, CDCl3) 7.89 (s, 1H), 7.62–7.56 (m, 3H),
7.13–7.04 (m, 2H), 6.64 (s, 1H), 6.43 (d, J¼9.3 Hz, 1H),
2.46 (s, 3H, Me); 13C NMR (CDCl3, 50 MHz) d 164.35,
159.48, 150.40, 131.09, 127.52, 127.36, 126.81, 126.48,
115.84, 115.41, 113.55, 112.09, 96.47, 21.69; nmax (KBr)
1590 cm21; m/z (CI, i-butane) 227 (100, MHþ); found C,
74.43; H, 4.91; N, 12.30; C14H11FN2 requires C, 74.32; H,
4.90; N, 12.38%.
Step 2. A mixture of salt (5.97 mmol) as obtained above and
sodium bicarbonate (17.85 mmol) in ethanol (10 mL) was
heated to reflux with vigorous stirring for 12 h. After

M. Pal et al. / Tetrahedron 58 (2002) 9933–9940
9937
4.2.7. 6-(3-Fluoro-4-methylphenyl)-2-methylpyrrolo[1,2-
b]pyridazine (5f). Yield¼0.76 g (53%); mp 153–1558C; dH
(200 MHz, CDCl3) 7.85 (s, 1H), 7.57 (d, J¼8.8 Hz, 1H),
7.44–7.39 (m, 2H), 7.04–7.00 (m, 1H), 6.61 (d, J¼1.5 Hz,
1H), 6.39 (d, J¼9.3 Hz, 1H), 2.43 (s, 3H, Me), 2.31 (d,
J¼1.5 Hz, 3H, Me); nmax (KBr,) 1592 cm21; m/z (CI,
i-butane) 241 (100, MHþ); found C, 74.95; H, 5.44; N,
11.68; C15H13FN2 requires C, 74.98; H, 5.45; N, 11.66%.
(200 MHz, CDCl3) 7.87 (d, J¼9.3 Hz, 1H), 7.70 (d,
J¼8.8 Hz, 1H), 7.48 (d, J¼8.8 Hz, 1H), 7.28 (d,
J¼8.8 Hz, 2H), 7.12 (d, J¼7.8 Hz, 2H), 6.66 (s, 1H), 6.58
(d, J¼9.3 Hz, 1H), 2.44 (s, 3H, Me), 2.34 (s, 3H, Me); nmax
(KBr) 1591 cm21; m/z (CI, i-butane) 335 (100, Mþ); found
C, 68.50; H, 4.57; N, 16.45; C19H15ClN4 requires C, 68.16;
H, 4.52; N, 16.73%; UV (EtOH, nm) 284.60, 246.00;
HPLC: 97.46%. INERTSIL ODS 3V, H2O/acetonitrile
(30:70), 1.0 mL/min, 210 nm, retention time: 7.888 min.
4.2.8. 6-(4-Ethylphenyl)-2-methylpyrrolo[1,2-b]pyrida-
zine (5g). Yield¼1.20 g (85%); mp 143–1448C; dH
(200 MHz, CDCl3) 7.92 (s, 1H), 7.61–7.56 (m, 3H), 7.24
(d, J¼8.3 Hz, 2H), 6.68 (s, 1H), 6.40 (d, J¼9.3 Hz, 1H),
2.73–2.61 (m, 2H, CH2CH3), 2.45 (s, 3H, Me), 1.26 (t,
J¼7.5 Hz, 3H, CH2CH3); nmax (KBr) 1593 cm21; m/z (CI,
i-butane) 237 (100, MHþ); found C, 81.36; H, 6.80; N,
11.80; C16H16N2 requires C, 81.32; H, 6.82; N, 11.85%.
4.3.2. 7-(6-Chloro-3-pyridazinyl)-6-(4-isobutylphenyl)-2-
methyl pyrrolo[1,2-b]pyridazine (7b). Yield¼0.88 g
(42%); light yellow powder, mp .2508C; dH (200 MHz,
CDCl3) 8.02 (d, J¼9.3 Hz, 1H), 7.79 (d, J¼8.8 Hz, 1H),
7.67 (d, J¼9.3 Hz, 1H), 7.25 (d, J¼7.8 Hz, 2H), 7.07 (d,
J¼7.8 Hz, 2H), 6.70 (s, 1H), 6.67 (d, J¼8.8 Hz, 1H), 2.58
(m, 2H, CH2CHMe2), 2.44 (s, 3H, Me), 1.92–1.85 (m, 1H,
CH2CHMe2), 0.91 (d, J¼6.8 Hz, 6H, 2Me); nmax (KBr)
1590 cm21; m/z (CI, i-butane) 377 (100, Mþ); found C,
70.41; H, 5.61; N, 14.77; C22H21ClN4 requires C, 70.11; H,
5.62; N, 14.87%; UV (EtOH, nm) 246.60; HPLC: 97.76%.
INERTSIL ODS 3V, H2O/acetonitrile (20:80), 1.0 mL/min,
245 nm, retention time: 14.970 min.
4.2.9. N-[4-(2-Methylpyrrolo[1,2-b]pyridazin-6-yl)-
phenyl]methanesulphonamide (5h). The title compound
was prepared from N-(4-acetylphenyl)methanesulfon-
amide19e according to the procedure described earlier.
Yield¼0.90 g (50%); mp 178–1798C; dH (200 MHz,
CDCl3) 7.90 (s, 1H), 7.64–7.55 (m, 3H), 7.21 (d,
J¼7.8 Hz, 2H), 6.64 (s, 1H), 6.43–6.33 (m, 2H), 3.01 (s,
4.3.3. 7-(6-Chloro-3-pyridazinyl)-6-(4-chlorophenyl)-2-
methylpyrrolo[1,2-b]pyridazine
3H, NHSO2Me), 2.44 (s, 3H, Me); nmax (KBr) 1590 cm21
;
(7c).
Yield¼0.99 g
m/z (CI, i-butane) 302 (100, MHþ); found C, 59.75; H, 5.00;
N, 14.00; C15H15N3O2S requires C, 59.78; H, 5.02; N,
13.94%.
(50%); light yellow powder, mp 239–2408C; dH
(200 MHz, CDCl3) 8.02 (d, J¼8.8 Hz, 1H), 7.72 (d,
J¼9.3 Hz, 1H), 7.53 (d, J¼8.8 Hz, 1H), 7.37–7.30 (m,
4H), 6.66 (s, 1H), 6.62 (d, J¼8.8 Hz, 1H), 2.45 (s, 3H, Me);
13C NMR (CDCl3, 50 MHz): d 164.38, 159.8, 155.50,
153.0, 150.87, 150.00, 133.74, 133.02, 130.70, 130.61,
129.23, 128.49, 127.29, 126.79, 126.70, 114.19, 101.28,
21.95; nmax (KBr) 1592 cm21; m/z (CI, i-butane) 355 (100,
Mþ); found C, 60.96; H, 3.40; N, 15.39; C18H12Cl2N4
requires C, 60.86; H, 3.40; N, 15.77%; UV (EtOH, nm)
280.00, 146.80; HPLC: 94.87%. INERTSIL ODS 3V,
H2O/acetonitrile (30:70), 1.0 mL/min, 210 nm, retention
time: 9.218 min.
4.2.10. 6-(4-Methoxyphenyl)-2-methylpyrrolo[1,2-
b]pyridazine (5i). Yield¼0.79 (56%); mp 133–1348C; dH
(200 MHz, CDCl3) 7.96–7.88 (m, 2H), 7.58 (d, J¼8.8 Hz,
2H), 6.95–6.92 (m, 2H), 6.63 (s, 1H), 6.39 (d, J¼9.3 Hz,
1H), 3.83 (s, 3H, OMe), 2.44 (s, 3H, Me); nmax (KBr)
1601 cm21; m/z (CI, i-butane) 239 (100, MHþ); found C,
75.64; H, 5.90; N, 11.78; C15H14N2O requires C, 75.61; H,
5.92; N, 11.76%.
4.2.11. 6-(4-Nitrophenyl)-2-methylpyrrolo[1,2-b]pyrida-
zine (5j). Yield¼0.78 g (52%); mp 197.5–1988C; dH
(200 MHz, CDCl3) 8.25 (d, J¼8.8 Hz, 2H), 8.01 (s, 1H),
7.76 (d, J¼7.8 Hz, 2H), 7.64 (d, J¼9.3 Hz, 1H), 6.75 (s,
1H), 6.48 (d, J¼9.3 Hz, 1H), 2.47 (s, 3H, Me); nmax (KBr)
1595 cm21; m/z (CI, i-butane) 254 (100, MHþ); found C,
66.45; H, 4.35; N, 16.50; C14H11N3O2 requires C, 66.40; H,
4.38; N, 16.59%.
4.3.4. 7-(6-Chloro-3-pyridazinyl)-6-(2,4-dimethoxy-
phenyl)-2-methylpyrrolo[1,2-b]pyridazine (7d). Yield¼
1.26 g (60%); light brown solid, dH (200 MHz, CDCl3) 7.57
(d, J¼9.3 Hz, 1H), 7.54–7.47 (m, 2H), 7.27–7.17 (m, 2H),
6.92 (d, J¼8.3 Hz, 1H), 6.65 (s, 1H), 6.43 (d, J¼9.3 Hz,
1H), 3.97 (s, 3H, OMe), 3.93 (s, 3H, OMe), 2.47 (s, 3H, Me);
nmax (KBr) 1590 cm21; m/z (CI, i-butane) 377 (100, Mþ);
found C, 63.19; H, 4.54; N, 14.52; C20H17ClN4O2 requires
C, 63.08; H, 4.50; N, 14.71%.
4.3. General procedure for preparation of 7
A mixture of 6-(4-aryl)-2-methylpyrrolo[1,2-b]pyridazine 5
(5.6 mmol), 3,6-dichloropyridazine (6.04 mmol) and AlCl3
(0.81 g, 6.06 mmol) in dichloroethane (10 mL) was stirred
under nitrogen atmosphere at 50–608C for 48 h. The
reaction mixture was poured into ice (10 g) and extracted
with chloroform (3£20 mL). Organic layers combined,
washed with water (2£30 mL), dried over anhydrous
Na2SO4 and concentrated under vacuum to give the required
product.
4.3.5. 7-(6-Chloro-3-pyridazinyl)-6-(4-fluorophenyl)-2-
methylpyrrolo[1,2-b]pyridazine
(7e).
Yield¼1.36 g
(72%); light yellow powder, mp 237–2388C; dH
(200 MHz, CDCl3) 7.99 (d, J¼9.3 Hz, 1H), 7.72 (d,
J¼9.3 Hz, 1H), 7.52 (d, J¼9.3 Hz, 1H), 7.42–7.35 (m,
2H), 7.01 (t, J¼8.8 Hz, 2H), 6.65 (s, 1H), 6.61 (d, J¼9.3 Hz,
1H), 2.45 (s, 3H, Me); 13C NMR (CDCl3, 50 MHz): d
164.54, 159.65, 154.35, 152.94, 150.93, 150.74, 132.2,
131.02, 130.86, 130.72, 129.44, 127.25, 126.72, 115.41,
114.98, 114.12, 101.30, 21.92; nmax (KBr) 1588 cm21; m/z
(CI, i-butane) 339 (100, Mþ); found C, 63.44; H, 3.49;
N, 16.63; C18H12ClFN4 requires C, 63.82; H, 3.57; N,
16.54%; UV (EtOH, nm) 282.00, 244.20; HPLC: 99.05%.
4.3.1. 7-(6-Chloro-3-pyridazinyl)-6-(4-methylphenyl)-2-
methylpyrrolo[1,2-b]pyridazine (7a). Yield¼1.22 g
(65%); light yellow powder, mp 248–2498C; dH

9938
M. Pal et al. / Tetrahedron 58 (2002) 9933–9940
INERTSIL ODS 3V, H2O/acetonitrile (30:70), 1.0 mL/min,
245 nm, retention time: 10.876 min.
RPB, H2O/acetonitrile (40:60), 1.0 mL/min, 240 nm,
retention time: 11.176 min.
4.3.6. 7-(6-Chloro-3-pyridazinyl)-6-(3-fluoro-4-methyl-
phenyl)-2-methylpyrrolo[1,2-b]pyridazine (7f). Yield¼
1.76 g (89%); white powder, mp 228–2298C; dH
(200 MHz, CDCl3) 7.96 (d, J¼8.8 Hz, 1H), 7.71 (d,
J¼9.3 Hz, 1H), 7.51 (d, J¼8.8 Hz, 1H), 7.23–7.11 (m,
2H), 6.97–6.88 (m, 1H), 6.63 (s, 1H), 6.60 (d, J¼9.3 Hz,
1H), 2.45 (s, 3H, Me), 2.25 (s, 3H, Me); nmax (KBr)
1590 cm21; m/z (CI, i-butane) 353 (100, Mþ); found C,
64.78; H, 4.12; N, 15.58; C19H14ClFN4 requires C, 64.69; H,
4.00; N, 15.88%; UV (EtOH, nm) 244.60; HPLC: 95.75%.
INERTSIL ODS 3V, H2O/acetonitrile (30:70), 1.0 mL/min,
210 nm, retention time: 8.076 min.
4.3.11. 7-(6-Methoxy-3-pyridazinyl)-2-methyl-6-(4-
methylphenyl)pyrrolo[1,2-b]pyridazine (8). The title
compound was prepared from 6-(4-methylphenyl)-2-
methylpyrrolo[1,2-b]pyridazine (5a) and 3-chloro-6-
methoxypyridazine22 according to the procedure described
earlier. Yield¼0.37 g (20%); pale yellow solid, mp 288–
2898C; dH (200 MHz, CDCl3) 7.81 (d, J¼9.2 Hz, 1H), 7.65
(d, J¼9.3 Hz, 1H), 7.37–7.17 (m, 4H), 7.00 (d, J¼7.8 Hz,
1H), 6.66 (s, 1H), 6.53 (d, J¼9.3 Hz, 1H), 4.18 (s, 3H,
OMe), 2.44 (s, 3H, Me), 2.34 (s, 3H, Me); nmax (KBr)
1589 cm21; m/z (CI, i-butane) 330 (100, Mþ); found C,
72.32; H, 5.37; N, 17.16; C20H18N4O requires C, 72.71; H,
5.49; N, 16.96%.
4.3.7. 7-(6-Chloro-3-pyridazinyl)-6-(4-ethylphenyl)-2-
methylpyrrolo[1,2-b]pyridazine, (7g). Yield¼1.48 g
(76%); pale yellow powder, mp 227–2288C; dH
(200 MHz, CDCl3) 7.87 (d, J¼8.8 Hz, 1H), 7.70 (d,
J¼8.8 Hz, 1H), 7.49 (d, J¼8.8 Hz, 1H), 7.31 (d,
J¼8.3 Hz, 2H), 7.14 (d, J¼8.3 Hz, 2H), 6.66 (s, 1H), 6.58
(d, J¼8.8 Hz, 1H), 2.70–2.58 (m, 2H, CH2CH3), 2.44 (s,
3H, Me), 1.24 (t, J¼7.6 Hz, 3H, CH2CH3); nmax (KBr)
1593 cm21; m/z (CI, i-butane) 349 (100, Mþ); found C,
68.56; H, 4.94; N, 16.27; C20H17ClN4 requires C, 68.86; H,
4.91; N, 16.06%; UV (EtOH, nm) 245.80; HPLC: 98.52%.
HICHROM RPB, H2O/acetonitrile (30:70), 1.0 mL/min,
210 nm, retention time: 10.347 min.
4.3.12. 3-[6-(4-Ethylphenyl)-2-methylpyrrolo[1,2-b]pyri-
dazin-7-yl]-1,6-dihydro-6-pyridazinone (9). A mixture of
350 mg (1.004 mmol) of 7-(6-chloro-3-pyridazinyl)-6-(4-
ethylphenyl)-2-methlypyrrolo[1,2-b]pyridazine 7g and
164 mg (2 mmol) of sodium acetate in 15 mL of acetic
acid was heated to reflux under nitrogen atmosphere for
5 h with stirring. The mixture was then poured into
150 mL of cold water with stirring. Solid separated was
filtered, washed with water (2£10 mL) and dried under
vacuum to give the required product as a white powder,
1
yield¼0.28 g (85%); mp 214–2158C; DSC 214.478C; H
NMR (DMSO-d6): 13.15 (s, 1H, NH, exchangeable with
D2O), 7.96 (d, J¼8.8 Hz, 1H), 7.70 (d, J¼9.8 Hz, 1H),
7.31–7.17 (m, 4H), 6.98 (d, J¼7.8 Hz, 1H), 6.75 (d,
J¼8.8 Hz, 1H), 2.65–2.57 (m, 2H, CH2CH3), 2.39 (s, 3H,
Me), 1.19 (t, J¼7.6 Hz, 3H, CH2CH3); nmax (KBr): 3419,
1648 cm21; UV (MeOH, nm) 366.00, 249.50; m/z (CI,
i-butane) 331 (100, MHþ); HPLC: 98.58%. HICHROM
RPB, H2O/acetonitrile (30:70), 1.0 mL/min, 250 nm,
retention time: 7.554 min. Elemental analysis found
C, 72.75; H, 5.47; C20H18N4O requires C, 72.71; H,
5.49%.
4.3.8. N-{4-[7-(6-Chloro-3-pyridazinyl)-2-methylpyr-
rolo[1,2-b]pyridazin-6-yl]phenyl}methanesulfonamide
(7h). Yield¼0.09 g (4%); Off white powder, mp 242–
2448C; dH (200 MHz, CDCl3) 9.79 (s, 1H), 8.22 (d,
J¼9.3 Hz, 1H), 8.05–8.01 (m, 2H), 7.29 (d, J¼8.3 Hz,
2H), 7.14 (d, J¼8.8 Hz, 2H), 6.84–6.80 (m, 2H), 3.33 (s,
3H, NHSO2Me), 2.50 (s, 3H, Me); nmax (KBr) 1589 cm21
;
m/z (CI, i-butane) 414 (100, Mþ); found C, 55.04; H, 3.87;
N, 17.19; C19H16ClN5O2S requires C, 55.14; H, 3.90; N,
16.92%; UV (EtOH, nm) 254.40; HPLC: 97.84%.
INERTSIL
ODS
3V,
H2O/acetonitrile
1.0 mL/min, 245 nm, retention time: 5.288 min.
(30:70),
4.3.13. Ethyl 2-(3-[6-(4-ethylphenyl)-2-methylpyrrolo-
[1,2-b]pyridazin-7-yl]-6-oxo-1,6-dihydro-1-pyridazinyl)-
acetate (10). A mixture of 500 mg (1.51 mmol) of 3-[6-(4-
Ethylphenyl)-2-methylpyrrolo[1,2-b]pyridazin-7-yl]-1,6-
dihydro-6-pyridazinone 9, 300 mg (1.79 mmol) of ethyl
bromoacetate and 540 mg (3.91 mmol) of potassium
cabonate in 10 mL DMF was stirred at room temperature
for 48 h. The mixture was poured into 50 mL of cold water
with stirring. The separated solid was filtered washed with
water (2£10 mL) and dried under vacuum to give the
required product as a pale yellow powder, yield¼0.27 g
(43%); mp 149–1508C; DSC 150.268C; 1H NMR (CDCl3):
d 7.70–7.63 (m, 2H), 7.35 (d, J¼7.8 Hz, 2H), 7.15 (d,
J¼8.3 Hz, 2H), 6.97 (d, J¼9.8 Hz, 1H), 6.63 (s, 1H), 6.53
(d, J¼8.8 Hz, 1H), 4.80 (s, 2H, CH2COOCH2CH3), 4.21–
4.17 (m, 2H, OCH2CH3), 2.66–2.62 (m, 2H, CH2CH3), 2.45
(s, 3H, Me), 1.24 (t, J¼7.3 Hz, 6H, 2Me); nmax (KBr): 1730,
1670, 1590 cm21; UV (MeOH, nm) 369.50, 251.50; m/z
(CI, i-butane): 417 (100, MHþ); HPLC: 96.59%.
HICHROM RPB, H2O/acetonitrile (30:70), 1.0 mL/min,
250 nm, retention time: 8.779 min. Elemental analysis
found C, 69.27; H, 5.80; C24H24N4O3 requires C, 69.21;
H, 5.81%.
4.3.9. 7-(6-Chloro-3-pyridazinyl)-6-(4-methoxyphenyl)-
2-methylpyrrolo[1,2-b]pyridazine (7i). Yield¼1.83 g
(93%); white powder, mp 242–2438C; dH (200 MHz,
CDCl3) 7.86 (d, J¼9.3 Hz, 1H), 7.67 (d, J¼9.3 Hz, 1H),
7.46 (d, J¼8.8 Hz, 1H), 7.33–7.23 (m, 2H), 6.83 (d,
J¼8.3 Hz, 2H), 6.61 (s, 1H), 6.56 (d, J¼9.3 Hz, 1H), 3.78
(s, 3H, OMe), 2.42 (s, 3H, Me); nmax (KBr) 1590 cm21
;
m/z (CI, i-butane) 351 (100, Mþ); found C, 65.35; H, 4.34;
N, 15.61; C19H15ClN4O requires C, 65.05; H, 4.31; N,
15.97%.
4.3.10. 7-(6-Chloro-3-pyridazinyl)-6-(4-nitrophenyl)-2-
methylpyrrolo[1,2-b]pyridazine
(7j).
Yield¼1.47 g
(72%); light brown powder, mp 288–2898C; dH
(200 MHz, CDCl3) 8.25–8.16 (m, 3H), 7.77 (d, J¼8.8 Hz,
1H), 7.62–7.54 (m, 3H), 6.74 (s, 1H), 6.67 (d, J¼9.3 Hz,
1H), 2.49 (s, 3H, Me); nmax (KBr) 1591 cm21; m/z (CI,
i-butane) 366 (100, Mþ); found C, 59.47; H, 3.39; N, 19.01;
C18H12ClN5O2 requires C, 59.11; H, 3.31; N, 19.15%; UV
(EtOH, nm) 288.50, 242.50; HPLC: 98.74%. HICHROM

M. Pal et al. / Tetrahedron 58 (2002) 9933–9940
9939
6. Beswick, P.; Campbell, I.; Naylor, A. World Patent
WO9912930-A1; Chem Abstr. 1999, 130, 223286.
´
7. Almansa, C.; de Arriba, A. F.; Cavalcanti, F. L.; Gomez, L. A.;
4.3.14. 2-{3-[6-(4-Ethylphenyl)-2-methylpyrrolo[1,2-
b]pyridazin-7-yl]-6-oxo-1,6-dihydro-1-pyridazinyl}ace-
tic acid (4g). A mixture of 200 mg (0.48 mmol) of ethyl
2-(3-(6-(4-ethylphenyl)-2-methylpyrrolo[1,2-b]pyridazin-
7-yl)-6-oxo-1,6-dihydro-1-pyridazinyl)acetate 10 and
330 mg (2.39 mmol) of potassium carbonate was stirred in
15 mL of methanol and 3 mL of water for 24 h at room
temperature. After removal of methanol under low vacuum
the reaction mixture was poured into the 50 mL of cold
water and then acidified by 33% HCl solution. Solid
separated was filtered and washed with water (2£10 mL) to
give the title compound as a light brown powder,
´
Miralles, A.; Merlos, M.; Garcıa-Rafanell, J.; Forn, J. J. Med.
Chem. 2001, 44, 350.
8. Nakashima, M.; Kanamaru, M.; Uematsu, T.; Nagashima, S.;
Mizuno, A.; Toriumi, C.; Hotta, M.; Komuro, M.; Ishida, R.;
Uchida, H. Eur. J. Pharmacol. 1990, 2, 183. Abst P.mo.375.
9. (a) Nasir, A. I.; Gundersen, L.-L.; Rise, F.; Antonsen, Ø;
Kristensen, T.; Langhelle, B.; Bast, A.; Custers, I.; Haenen,
¨
G. R. M. M.; Wikstrom, H. Bioorg. Med. Chem. Lett. 1998, 8,
1829. (b) Matsuo, M.; Manabe, T.; Okumura, H.; Matsuda, H.;
Fujii, N. World Patent WO 9118903 A1, 12 December 1991;
Chem. Abstr. 1992, 130, 151782. (c) Ohtani, M.; Fuji, M.;
Fukui, Y.; Adachi, M. World Patent WO 9959999 A1, 25
November 1999; Chem. Abstr. 2000, 132, 12318.
(d) Ungureanu, M.; Mangalagiu, I.; Grosu, G.; Petrovanu,
M. Ann. Pharm. Fr. 1997, 55(2), 69. Chem. Abstr. 1997, 126,
303587.
1
yield¼0.16 g (86%); DSC 208.558C; H NMR (CDCl3): d
7.67 (dd, J¼9.3 Hz, 1.46 Hz, 2H), 7.34 (d, J¼7.8 Hz, 2H),
7.16 (d, J¼7.8 Hz, 2H), 7.02 (d, J¼9.7 Hz, 1H), 6.63 (s,
1H), 6.57 (d, J¼9.3 Hz, 1H), 4.88 (s, 2H, CH2COOH), 3.86
(bs, 1H, COOH, exchangeable with D2O), 2.70–2.59 (m,
2H, CH2CH3), 2.46 (s, 3H, Me), 1.23 (t, J¼7.3 Hz, 3H,
CH2CH3); nmax (KBr): 3407 (b, s), 2899, 1723, 1639,
1576 cm21; UV (MeOH, nm) 369.00, 251.50; m/z (CI,
i-butane): 389 (100, MHþ); HPLC: 98.91%. HICHROM
RPB, 0.01 M KH2PO4/acetonitrile (55:45), pH¼3.5,
1.2 mL/min, 250 nm, retention time: 16.943 min. Elemental
analysis found C, 68.33; H, 5.20; C22H20N4O3 requires C,
68.03; H, 5.19%.
10. (a) Pal, M.; Rao, Y. K.; Rajagopalan, R.; Misra, P.; Kumar,
P. M.; Rao, C. S. World Patent WO 01/90097, 29 November
2001; Chem. Abstr. 2002, 136, 5893. (b) Pattabiraman, V. R.;
Padakanti, P. S.; Veeramaneni, V. R.; Pal, M.; Yeleswarapu,
K. R. Synlett 2002, 947. For a brief overview see: (c) Scrip
2002, 112, 43.
11. Fraser, M. J. Org. Chem. 1971, 36, 3087.
12. (a) Weidner, C. H.; Michaels, F. M.; Beltman, D. J.;
Montgomery, C. J.; Wadsworth, D. H.; Briggs, B. T.; Picone,
M. L. J. Org. Chem. 1991, 56, 5594. (b) Lown, J. W.;
Matsumoto, K. Can. J. Chem. 1971, 49, 1165.
Acknowledgements
The authors would like to thank Dr A. Venkateswarlu, Dr
R. Rajagopalan and Professor J. Iqbal for their constant
encouragement and the Analytical Department specially Dr
J. Moses Babu for spectral support. V. R. B. also thanks to
the Department of Chemistry, Regional Engineering
College, Warangal, Andhra Pradesh, India for allowing
him to pursue part of this work as MSc project-assignment.
13. (a) Kobayashi, Y.; Kutsuma, T.; Morinaga, K. Chem. Pharm.
Bull. 1971, 19, 2106. (b) Masaki, Y.; Otsuka, H.; Nakayama,
Y.; Hioki, M. Chem. Pharm. Bull. 1973, 21, 2780. (c) Sasaki,
T.; Kanematsu, K.; Yukimoto, Y.; Ochiai, S. J. Org. Chem.
1971, 36, 813.
14. (a) Kundu, N. G.; Pal, M. J. Chem. Soc., Chem. Commun.
1993, 86. (b) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De, M.
J. Chem. Soc., Perkin Trans. 1 1997, 2815. (c) Roesch, K. R.;
Larock, R. C. Org. Lett. 1999, 1, 1551. (d) Østby, O. B.;
Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G. R.
M. M. Eur. J. Org. Chem. 2000, 3763. (e) For an excellent
review see: Undheim, K.; Benneche, T. Adv. Heterocycl.
Chem. 1995, 62, 304. (f) Maes, B. U. W.; Kosmrlj, J.; Lemiere,
G. L. F. J. Heterocycl. Chem. 2002, 39, 535 and references
cited therein.
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