New pyridazine derivatives: Synthesis, chemistry and biological activity

Article abstract of DOI:10.1016/j.bmc.2009.02.028

In this paper we report a feasible study concerning synthesis, structure and biological activity of some new pyridazine derivatives. Syntheses have been done both under classical conditions and microwave [in liquid phase and interphasic transfer catalysis

Full text of DOI:10.1016/j.bmc.2009.02.028

Bioorganic & Medicinal Chemistry 17 (2009) 2823–2829
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
New pyridazine derivatives: Synthesis, chemistry and biological activity
*
Roxana M. Butnariu, Ionel I. Mangalagiu
‘Al. I. Cuza’ University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, 700506 Iasi, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper we report a feasible study concerning synthesis, structure and biological activity of some
new pyridazine derivatives. Syntheses have been done both under classical conditions and microwave
[in liquid phase and interphasic transfer catalysis (PTC)]. The MW induced a remarkable acceleration
for the [3+2] dipolar cycloaddition reaction of pyridazinium ylides to activated alkenes and alkynes,
the yields were increased in some cases, and the amount of used solvents decrees in liquid phase (while
PTC do not use solvents). Consequently, these types of reactions could be considered environmentally
friendly. The in vitro antibacterial and antifungal activities of the newly obtained diazine compounds
were tested, some of the compounds have proved to have a remarkable activity against Gram positive
germs, the results on Sarcinia luteea being spectacular.
Received 19 January 2009
Revised 11 February 2009
Accepted 15 February 2009
Available online 21 February 2009
Keywords:
Pyridazine
Cycloadditions
Microwaves
Biological activities
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
dition leading to fused pyridazine. When dipolarophiles are N-
phenylmaleimide (NPMI, symmetrical cyclic Z-alkenes) and maleic
Pyridazine derivatives have been reported1 to posses a wide
range of biological activities, these include antiviral and antican-
cer,2 antituberculosis,3 antihypertensive4 and antimicrobial5 activ-
ity. One of the strategies adopted for the synthesis of the
pyridazine derivatives involves nitrogen ylides, as reactive species
in organic chemistry.6–8 The reaction pathway involves, in the
most frequent cases, a Huisgen [3+2] dipolar cycloaddition of
ylides to dipolarophiles (activated alkenes and alkynes). During
the last decades microwave irradiation (MW) has became an
increasingly valuable tool in organic chemistry, since it offers a
versatile and facile pathway in a large variety of syntheses.9 Fur-
thermore, PTC reactions under MW conditions have the great
advantage of using small amounts of or no organic solvents (‘sol-
vent free’), thus such reactions are more environmentally friendly
and generate less side products.9,10 So far, few studies have been
reported regarding dipolar cycloaddition reactions of pyridazinium
ylides and most of these have been conducted by our group.5a,10
The aim of this work was to perform a thorough study concern-
ing synthesis, structure and biological activity of some new pyrid-
azine derivatives and to establish correlation MW/classical heating
(both in liquid phase and PTC conditions).
and fumaric esters (symmetrically cis–trans olefins), cycloadducts (
4–6) are obtained (Scheme 1). The Huisgen 3+2 cycloaddition oc-
curs with high stereospecificity and no formation of other isomers
was observed.
The reaction of ylides (3) with non-symmetrical dipolarophiles
such as acrylonitrile and methyl acrylate (activated alkenes) and
ethyl propiolate (activated alkynes) lead to a single isomer (regio-
specific reactions), the saturated tetrahydropyrrolo pyridazine ad-
ducts (7–8) or the aromatized pyrrolopyridazine adducts (9). The
reaction of ylides (3) with dimethyl acetylendicarboxylate (DMAD,
symmetrical activated alkynes), lead to aromatized pyrrolopyrid-
azine, (10). As to the mechanism, the formation of compounds
(9) and (10), could be explained by oxidative dehydrogenation of
saturated intermediaries (i) and (ii), which allow formation to
the more stable aromatized cycloadducts (Scheme 2).
The structure of the new compounds (4–10) has been proved by
elemental and spectral analysis (IR, MS, 1H NMR, 13C NMR, 2D-
COSY, 2D-HETCOR (HMQC), long range 2D-HETCOR (HMBC).
Influence of MW irradiation (both in liquid phase and PTC con-
ditions) concerning the cycloaddition reactions was also studied.
Table 1 lists the optimized conditions, under MW and classical
heating (liquid phase, chloroform). Using MW irradiation, in liquid
phase, the best results were obtained applying a constant irradia-
tion power (25% from the full power of the magnetron, 800 W)
and varying the temperature (the so-called ‘power control’). Atten-
tion was then focused on PTC reactions. In this study, the solid
phase was a mixture of potassium fluoride and N-(p-R-phenacyl)-
pyridazinium bromides; the liquid phase was dipolarophiles dis-
solved in trioctyl-methyl-ammonium chloride-Aliquat 336 (tensio-
active compound which acts as transfer catalyst). The resultant
2. Results and discussion
Pyridazinium ylides (3) [generated in situ from the correspond-
ing cycloimmonium salts (2), in alkaline medium (Et3N)], react
with symmetrically substituted Z-alkene via a 3+2 dipolar cycload-
* Corresponding author.
E-mail address: ionelm@uaic.ro (I.I. Mangalagiu).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.02.028

2824
R. M. Butnariu, I. I. Mangalagiu / Bioorg. Med. Chem. 17 (2009) 2823–2829
BrCH2COC6H4R-4
R = F, Cl, CH3
N
N
N
Br
N
N
N
N
6
N
1
CH2
CH
COC6H4R-4
CH
COC6H4R-4
1
O
7
2.a. R = F
2.b. R = Cl
C
9
2.c. R = CH3
3.a. R = F
3.b. R = Cl
3.c. R = CH3
R
12
O
R
14
12
C6H5
N
10
O
CO2CH3
H
H3CO2C
H
C
H
H
H
H3CO2C
O
N
H4
N
H
O
CO2H3
3a
1
H
O
8
3
9a
9
9b
N
15
16
R
R
2
O
O
C
7
11
10
C
11
1
H
1
N
H
10
4.a. R=F
4.b. R=Cl
4.c. R=CH3
N
7
CO2CH3
N
CO2CH3
N
H
H
5.a. R=F
5.b. R=Cl
5.c. R=CH3
6.a. R=F
6.b. R=Cl
6.c. R=CH3
6
6
5
H
5
H
4a
4
4a
4
H
H3CO2C
CO2CH3
H
Scheme 1. Reaction pathway of pyridazinium ylides with symmetrically substituted Z-alkene.
R
O
7.a. Z=CN, R=F
7.b. Z=CN, R=Cl
7.c. Z=CN, R=CH3
8.a. Z=CO2CH3, R=F
8.b. Z=CO2CH3, R=Cl
8.c. Z=CO2CH3, R=CH3
1
N
C
Ha
H
N
7
11
10
Z
H
H
6
Hb
4a
Z = CN, CO2CH3
5
4
Z
N
N
R
CH
COC6H4R-4
O
COC6H4R-4
1
C
11
N
N
10
CO2Y
N
N
3.a-c. R= F, Cl, CH3
6
Y = C2H5
5
4
CO2Y
CO2Y
9.a. Y=CO2C2H5, R=F
9.b. Y=CO2C2H5,R=Cl
9.c. Y=CO2C2H5,R=CH3
i
CO2CH3
CO2CH3
R
O
COC6H4R-4
CO2CH3
1
C
11
N
N
10
N
N
CO2CH3
10.a. R=F
10.b. R=Cl
10.c. R=CH3
6
5
4
CO2CH3
CO2CH3
ii
Scheme 2. Reaction pathway of pyridazinium ylides with non-symmetrically substituted dipolarophiles and DMAD.
biphasic system undergoes the action of the MW using the mono-
mode reactor at 800 W. The best results have been obtained by
applying a constant temperature (130 °C) and varying the irradia-
tion power (the so-called ‘temperature control’).
Considering the pyridazine–acetophenone skeleton (10) as the
pharmacophoric group for the activity,1,5 in this work we aimed
to obtain new pyridazine derivatives with antimicrobial activity,
having in mind two structural modifications: introduction of a
As indicated in Table 1, MW induced a remarkable acceleration
for reactions, the reaction times decreasing dramatically, from
hours to minutes (5 min for liquid phase and 15 min for PTC). Con-
sequently, the consumed energy decrease considerably. In the
some cases, under MW irradiation the yields are higher, sometimes
substantially. Moreover, the amount of used solvents is two times
less (see experimental) in liquid phase, while PTC do not use sol-
vents, these types of reactions being considered as environmen-
tally friendly.
pyrrolo (I) ring, and a classical isosteres substituient R
(R = Me, F, Cl) in the para-position of the benzoyle ring. The
in vitro antibacterial and antifungal activities of the compounds
were determinate by using diffusion technique on agar.11 Six
bacterial strains were included in this study: Staphylococcus
aureus ATCC 25923, Sarcinia luteea ATCC 9341, Bacillus subtillis,
Pseudomonas aeruginosa, Escherichia coli ATCC 25922, and
fungus Candida albicans ATCC 10231. The results are listed in
Table 2.

R. M. Butnariu, I. I. Mangalagiu / Bioorg. Med. Chem. 17 (2009) 2823–2829
2825
Table 1
Cycloaddition reactions for some pyridazinium ylides with activated alkenes and alkynes under MW heating and classical conditions
Compd.
Classical (chloroform, reflux)
Reaction time (min) Yield (%)
Microwaves
Liquid phase (chloroform, reflux)
PTC (KF-Aliquat)
Reaction time (min)
15
Reaction time (min)
5
Yield (%)
Yield (%)
4.a. (R = F)
180
180
180
180
180
180
180
180
180
180
180
180
180
180
180
120
120
120
120
120
120
85
81
45
36
43
35
9
22
14
29
76
38
21
20
32
25
83
38
10
82
12
70
76
60
23
27
56
31
21
28
23
84
46
9
10
13
12
87
20
14
93
12
28
30
21
17
43
Trace
5
4.b. (R = Cl)
4.c. (R = CH3)
5.a. (R = F)
5.b. (R = Cl)
5.c. (R = CH3)
6.a. (R = F)
6.b. (R = Cl)
6.c. (R = CH3)
7.a. (R = F)
7.b. (R = Cl)
7.c. (R = CH3)
8.a. (R = F)
8.b. (R = Cl)
8.c. (R = CH3)
9.a. (R = F)
9.b. (R = Cl)
9.c. (R = CH3)
10.a. (R = F)
10.b. (R = Cl)
10.c. (R = CH3)
21
7
10
15
27
12
12
15
12
62
26
6
65
6
Table 2
Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial and antifungal activities for some dazine derivatives described in the text
Strain?product and reference drug ;
S. aureus ATCC25923
S. luteea ATCC 9341
B. subtillis
P. aeruginosa
E. coli ATCC 25922
Candida albicans ATCC 10231
Chloramphenicol 30 mcg/disc
Nysatin, 100 mcg/disc
2.a. (R = F)
2.b. (R = Cl)
2.c. (R = CH3)
4.a. (R = F)
4.b. (R = Cl)
4.c. (R = CH3)
5.a. (R = F)
5.b. (R = Cl)
5.c. (R = CH3)
6.a. (R = F)
6.b. (R = Cl)
6.c. (R = CH3)
7.a. (R = F)
7.b. (R = Cl)
7.c. (R = CH3)
9.a. (R = F)
9.b. (R = Cl)
9.c. (R = CH3)
10.a. (R = F)
10.b. (R = Cl)
10.c. (R = CH3)
30
—
40
—
26
—
19
—
25
—
—
29
19
29
27
25
34
29
24
25
30
27
27
29
23
35
30
22
30
28
21
24
29
38
36
47
27
28
31
29
33
41
29
23
47
26
30
46
27
25
40
27
30
46
61
57
81
63
54
73
60
56
62
51
54
59
50
57
67
48
48
56
52
57
65
31
32
40
28
28
37
37
39
39
35
36
38
27
29
39
22
25
37
23
26
26
20
20
20
16
18
18
18
18
19
17
15
17
14
14
19
20
20
18
15
18
19
31
36
25
25
28
24
35
32
37
35
31
37
20
28
23
23
33
25
21
31
25
– there is a certain influence of the isosters substituent R from the
para- position of the benzoyle ring, compounds with R = Me
being more active that those one with R = F, Cl;
N
N
I
O
– the influence of pyrrolo (I) moiety seems to be negligible. How-
ever, it can be noticed that the saturated tetrahydropyrrolo-pyr-
idazine derivatives (5) and (6) are more active as compared with
the others, most probably, because of the complementary action
of the two carbomethoxy groups existing on the pyrrolo-moiety;
– only two pyridazine derivatives (4b, 7b) have a significant activ-
ity against fungus C. albicans.
R
1'
The comparative analysis for the obtained data leads to the
conclusions:
– all the pyridazine derivatives have a spectacular antimicrobial
activity against Gram positive germ S. luteea;
– the pyridazine salts (2) have an excellent antimicrobial activity
(non-selective) against Gram positive and Gram negative germs.
It could be also noticed that, the pyridazine salts (2) are signifi-
cant more active as comparative as the corresponding cycload-
3. Conclusions
In conclusion, a thorough study concerning synthesis, structure
and biological activity of some new pyridazine derivatives is
reported. Syntheses have been done both under classical and
ducts (3–10).
A
reasonable explication could be the
complementary actions of the counter anion, Brꢀ, in salts;

2826
R. M. Butnariu, I. I. Mangalagiu / Bioorg. Med. Chem. 17 (2009) 2823–2829
microwave (MW), in liquid phase and interphasic transfer catalysis
(PTC). The MW induced a remarkable acceleration for the [3+2]
dipolar cycloaddition reaction of pyridazinium ylides to activated
alkenes and alkynes, the yields were increased in some cases,
and the amount of used solvents decrees in liquid phase (while
PTC do not use solvents). Consequently, these types of reactions
could be considered environmentally friendly. The in vitro antibac-
terial and antifungal activities of the newly obtained diazine com-
pounds were tested, some of the compounds have proved to have a
remarkable activity against Gram positive germs, the results on
S. luteea being spectacular. Against fungus C. albicans pyridazine
derivatives have no significant activity. Correlation structure-bio-
logical activity have been done.
flash chromatography (silica, CH2Cl2–MeOH) and than crystallized
from an appropriate solvent.
4.2.1. 4-(4-Fluorobenzoyl)-2-phenyl-9a,9b,3a,4-tetrahydro-
pyrrolo[30,40:3,4]pyrrolo[1,2-b]pyridazine-1,3-dione (4a)
White crystals (85%), mp 166–168 °C. IR (cmꢀ1): 1708 (C@O
imide), 1681(C@O keto). 1H NMR (400 MHz, CDCl3): d = 3.58–
3.54 (dd, J = 8.0, 8.0 Hz, 1H, H9b), 4.08–4.06 (d, J = 8.0 Hz, 1H,
H3a), 4.24–4.20 (t, J = 8.0, 5.6 Hz, 1H, H9a), 5.94 (s, 1H, H4), 5.96–
5.95 (dd, J = 8.0, 3.6 Hz, 1H, H8), 6.29–6.25 (m, J = 5.6, 3.6 Hz, 1H,
H9), 6.87–6.85 (dd, J = 3.2 Hz, 1H, H7), 7.21–7.16 (m, J = 8.0, 4.4
Hz, 2H, H16), 7.42–7.38 (t, J = 7.2, 3.6 Hz, 1H, H18), 7.49–7.45
(t, J = 7.6 Hz, 2H, H17), 8.27–8.23 (dd, J = 8.4, 5.2 Hz, 2H, H12). 13C
NMR: 44.60 (C3a), 50.32 (C9b), 57.40 (C9a), 76.20 (C4), 174.21 (C3,
keto imide), 176.70 (C1, keto imide), 192.97 (C10, keto). Anal.
C22H16N3O3F: C, 67.86; H, 4.14; N, 10.79. Found: C, 67.78; H,
4.12; N, 10.74.
4. Experimental
The 1H and 13C NMR spectra and two-dimensional 2D-COSY,
2D-HETCOR (HMQC), long range 2D-HETCOR (HMBC) experiments
were recorded on a Bruker Avance 400 DRX spectrometer operat-
ing at 400/100 MHz. Chemical shifts are given in ppm (d-scale),
coupling constants (J) in hertz. The IR spectra were recorded on a
FTIR Shimadzu Prestige 8400s spectrophotometer in KBr. Melting
points were determined on a MELTEMP II apparatus and are uncor-
rected. For the microwave irradiation we used a 800 W STAR SYS-
TEM-2 monomode reactor (CEM Corporation).
4.2.2. 4-(4-Chlorobenzoyl)-2-phenyl-9a,9b,3a,4-tetrahydro-
pyrrolo[30,4’:3,4] pyrrolo[1,2-b]pyridazine-1,3-dione (4b)
White crystals (81%), mp 193–195 °C. IR (cmꢀ1): 1713 (C@O
imide), 1684 (C@O keto). 1H NMR: 3.57–3.53 (dd, J = 8.0, 8.0 Hz,
1H, H9b), 4.07–4.05 (d, J = 8.0 Hz, 1H, H3a), 4.21–4.18 (t, J = 8.0,
5.6 Hz, 1H, H9a), 5.92 (s, 1H H4), 5.95–5.93 (m, J = 2.4 Hz,1H, H8),
6.28–6.25 (dd, J = 9.0, 5.6 Hz, 1H, H9), 6.86–6.85 (d, J = 3.2 Hz, 1H,
H7), 7.21–7.19 (d, J = 7.2 Hz, 2H, H16), 7.41–7.38 (dd, J = 7.2, 3.6
Hz, 1H, H18), 7.49–7.45 (m, 4H, 2H13, 2H17), 8.16–8.13 (d, J = 8.8
Hz, 2H, H12). 13C NMR: 44.76 (C3a), 51.39 (C9b), 56.61 (C9a), 75.90
4.1. General procedure for syntheses of diazine salts (2a–c)
A solution of 2-bromo-40-R-acetophenone (R = F, Cl, CH3) (10
mmol, dissolved in 15 ml of anhydrous benzene) and pyridazine
(10 mmol, dissolved in 10 ml of anhydrous benzene), was stirred
for 3 h at room temperature to give the corresponding cycloimmo-
nium salt (2). The obtained salts were filtered off and dried in va-
cuo. No purification required.
(C4), 174.45 (C3, keto imide), 176.64 (C1, keto imide), 192.61 (C10
,
keto). Anal. Calcd for C22H16N3O3Cl: C, 65.11; H, 3.97; N, 10.35.
Found: C, 65.02; H, 3.92; N, 10.30.
4.2.3. 4-(4-Methylbenzoyl)-2-phenyl-9a,9b,3a,4-tetrahydro-
pyrrolo[30,40:3,4] pyrrolo[1,2-b]pyridazine-1,3-dione (4c)
White crystals (60%), mp 180–181 °C. IR (cmꢀ1): 1708 (C@O
imide), 1677 (C@O keto). 1H NMR (400 MHz, CDCl3): d = 2.43 (s,
3H, CH3 from 14 position), 3.57–3.52 (dd, J = 8.0, 8.4 Hz, 1H, H9b),
4.06–4.04 (d, J = 8.0, Hz, 1H, H3a), 4.27–4.24 (t, J = 8.0, 5.6 Hz, 1H,
H9a), 5.94–5.91 (m, J = 8.0, 5.6 Hz, 1H, H8), 5.98 (s, 1H, H4), 6.28–
6.23 (m, J = 5.6, 4.0 Hz, 1H, H9), 6.85–6.84 (dd, J = 3.2 Hz, 1H, H7),
7.24–7.21 (m, J = 6.4 Hz, 2H, H16), 7.32–7.30 (d, J = 8.4 Hz, 2H,
H13), 7.41–7.37 (m, J = 8.0, 4.4 Hz, 1H, H18), 7.49–7.45 (t, J = 16.0,
5.6 Hz, 2H, H17), 8.12–8.10 (d, J = 8.4 Hz, 2H, H12). 13C NMR (400
MHz, CDCl3): d = 21.78 (CH3 from 14 position), 44.99 (C3a), 51.41
(C9b), 56.62 (C9a), 75.79 (C4), 174.61 (C3, keto imide), 176.79 (C1,
keto imide), 193.35 (C10, keto). MS (ES): 408 (M++Na+). Anal. Calcd
for C23H19N3O3: C, 71.67; H, 4.97; N, 10.90. Found:C, 71.60; H, 4.93;
N, 10.83.
4.1.1. 1-[2-(4-Methylphenyl)-2-oxoethyl] pyridazinium
bromide (2c)
White crystals, (94%), mp 235–237 °C. IR (cmꢀ1): 1687 (C@O
keto). 1H NMR (400 MHz, CDCl3): d = 2.45 (s, 3H, CH3 from 12 posi-
tion), 6.80 (s, 2H, CH2 from 7), 7.49–7.47 (d, J = 8.0 Hz, 2H, H11), 8.02–
8.00 (d, J = 8.0 Hz, 2H, H10), 8.79–8.75 (dtd, J = 12.0, 8.0, 5.2 Hz, 1H,
H4), 8.94–8.89 (dtd, J = 12.0, 4.0 Hz, 1H, H5), 9.76–9.75 (dd, J = 4
Hz, 1H, H3), 10.0–9.98 (d, J = 5.6 Hz, 1H, H6). 13C NMR (400 MHz,
CDCl3): d = 21.34 (CH3 from 12 position), 70.13 (CH2 from 7 posi-
tion), 128.55 (C10), 129.67 (C11), 130.81 (C9), 135.91 (C5), 137.43
(C4), 145.74 (C12), 151.79 (C6), 154.63 (C3), 189.69 (C8, keto).
4.2. General procedure for obtaining [3+2] dipolar cycloadducts
The corresponding cycloimmonium salt (2) (2 mmol) was sus-
pended in 50 ml of chloroform. A solution of an activated alkene
or alkyne (2 mmol) and triethylamine (2.2 mmol) in the same sol-
vent (5 ml) was then added. The solution was refluxed for 2 h (al-
kynes) and for 3 h (alkenes). Under microwave heating, in liquid
phase the solution was exposed to microwave irradiation for 5
min (25% magnetron power), and the amount of solvent was half
(10 ml). The resulting mixture was washed thoroughly three times
with water (50 ml), dried with sodium sulfate, filtered and evapo-
rated. In interphasic transfer catalysis we exposed to microwave
for 15 min a mixture of potassium fluoride (1 mmol) and cycloim-
monium salt (2) (1 mmol), the dipolarophile (1.1 mmol) and trio-
4.2.4. 7-(4-Fluorobenzoyl)-4a,5,6,7-tetrahydropyrrolo[2,1-b
]pyridazine-5,6-cis-dicarboxylic acid dimethyl ester (5a)
Yellow crystals (36%), mp 119–120 °C. IR (cmꢀ1): 1737 (C@O es-
ter from 5), 1728 (C@O ester from 6), 1687 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 3.45–3.42 (dd, J = 7.6, 5.2 Hz, 1H, H5), 3.65
(s, 3H, CH3 from 5 position), 3.70 (s, 3H, CH3 from 6 position),
3.99–3.96 (dd, J = 7.6, 7.2 Hz, 1H, H6), 4.42–4.39 (ddd, J = 1.6, 5.2,
5.6 Hz, 1H, H4a), 5.78–5.75 (ddd, J = = 10.0, 3.2, 1.6 Hz, 1H, H3),
5.84–5.82 (ddd, J = 4.0, 1.6 Hz, 1H, H4), 5.87–5.85 (d, J = 7.2 Hz,
1H, H7), 6.53–6.52 (dd, J = 1.6, 3.2 Hz, 1H, H2), 7.19–7.14 (dd,
J = 2.0 Hz, 2H, H11), 8.37–8.33 (dd, J = 20.0, 2H, H10). 13C NMR:
(400 MHz, CDCl3): 42.65 (C6), 51.95 (C5), 52.41 (CH3, COOMe from
5), 52.70 (CH3, COOMe from 6), 59.27 (C4a), 70.19 (C7), 115.59 (C11),
132.71 (C10). Anal. Calcd for C18H17N2O5F: C, 60.00; H, 4.76; N, 7.77.
Found: C, 59.91; H, 4.72; N, 7.73.
ctylmethylammonium chloride-Aliquat 336 (0.5 mmol);
a
mechanical stirrer was used to mix the resulted slurry. After cool-
ing, 15 ml chloroform was added. The solution was filtered and the
solvent evaporated. In all cases, the crude product was purified by

R. M. Butnariu, I. I. Mangalagiu / Bioorg. Med. Chem. 17 (2009) 2823–2829
2827
4.2.5. 7-(4-Chlorobenzoyl)-4a,5,6,7-tetrahydropyrrolo[2,1-b
]pyridazine-5,6-cis-dicarboxylic acid dimethyl ester (5b)
4.2.9. 7-(4-Methylbenzoyl)-4a,5,6,7-tetrahydropyrrolo[2,1-b
]pyridazine-5,6-trans-dicarboxylic acid dimethyl ester (6c)
Yellow crystals (43%), mp 119–120 °C. IR (cmꢀ1): 1729 (C@O es-
ter from 5), 1720 (C@O ester from 6), 1681 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 3.45–3.41 (dd, J = 7.6, 5.6 Hz, 1H, H5), 3.65
(s, 3H, CH3 from 5 position), 3.69 (s, 3H, CH3 from 6 position),
3.99–3.96 (t, J = 7.6, 7.2 Hz, 1H, H6), 4.40–4.37 (ddd, J = 1.2, 5.2,
5.6 Hz, 1H, H4a), 5.77–5.74 (ddd, J = 10.0, 3.2, 1.6 Hz, 1H, H3),
5.84–5.82 (dd, J = 4.4 Hz, 1H, H4), 5.86–5.84 (d, J = 7.2 Hz, 1H,
H7), 6.53–6.52 (dd, J = 1.6, 4.0 Hz, 1H, H2), 7.49–7.45 (dd, J = 2.0
Hz, 2H, H11), 8.37–8.33 (dd, J = 2.0 Hz, 2H, H10). 13C NMR: 400
MHz, CDCl3): 42.20 (C6), 52.19 (CH3, COOMe from 6), 52.69 (CH3,
COOMe from 5), 52.99 (C5), 60.02 (C4a), 69.82 (C7), 128.89 (C11),
131.41 (C10), 192.46 (C8, keto). Anal. Calcd for C18H17N2O5Cl: C,
57.38; H, 4.55; N, 7.43. Found: C, 57.31; H, 4.52; N, 7.40.
Yellow crystals (28%), mp 170–171 °C. IR (cmꢀ1): 1739 (C@O es-
ter from 5), 1732 (C@O ester from 6), 1666 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 2.41 (s, 3H, CH3 from 12 position), 3.61 (s,
3H, CH3 from 5 position), 3.70 (s, 3H, CH3 from 6 position), 3.72–
3.69 (dd, J = 9.2 Hz, 1H, H6), 3.80–3.76 (dd, J = 9.2, 7.6 Hz, 1H,
H5), 4.32–4.29 (dd, J = 9.2, 5.2 Hz, 1H, H4a), 5.83–5.80 (ddd, J = 6.8
Hz, 1H, H3), 5.86–5.84 (dd, J = 7.2 Hz, 1H, H7), 5.96–5.92 (ddd,
J = 7.2, 1.6 Hz, 1H, H4), 6.78–6.77 (dd, J = 1.2, 3.2 Hz, 1H, H2),
7.28–7.26 (d, J = 8.0 Hz, 2H, H11), 8.03–8.01 (d, J = 8.0, 2H, H10).
13C NMR: (400 MHz, CDCl3): 21.78 (CH3, from 12 position), 46.61
(C6), 52.11 (CH3, COOMe from 6), 52.60 (CH3, COOMe from 5),
55.41 (C4a), 73.49 (C7), 128.98 (C11), 130.80 (C10), 171.08 (C5, keto
ester), 172.87 (C6, keto ester), 193.55 (C8, keto). MS (ES): 379
(M++Na+). Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, 63.99; H, 5.64; N, 7.83.
4.2.6. 7-(4-Methylbenzoyl)-4a,5,6,7-tetrahydropyrrolo[2,1-b
]pyridazine-5,6-cis-dicarboxylic acid dimethyl ester (5c)
Yellow crystals (56%), mp 136–137 °C. IR (cmꢀ1): 1730 (C@O es-
ter from 5), 1724 (C@O ester from 6), 1670 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 2.42 (s, 3H, CH3 from 12 position), 3.45–
3.42 (dd, J = 7.6, 5.6 Hz, 1H, H5), 3.64 (s, 3H, CH3 from 5 position),
3.69 (s, 3H, CH3 from 6 position), 3.99–3.96 dd, J = 7.6, 7.2 Hz, 1H,
H6), 4.43–4.41 (ddd, J = 1.2, 5.2, 5.6 Hz, 1H, H4a), 5.76–5.72 (ddd,
J = 10.0, 3.2, 1.6 Hz, 1H, H3), 5.84–5.80 (ddd, J = 10.0, 4.4, 1.2 Hz,
1H, H4), 5.91–5.89 (d, J = 7.2 Hz, 1H, H7), 6.52–6.50 (dd, J = 1.6,
3.2 Hz, 1H, H2), 7.31–7.29 (dd, J = 8.0 Hz, 2H, H11), 8.21–8.19 (dd,
J = 8.0 Hz, 2H, H10). 13C NMR: (400 MHz, CDCl3): 21.75 (CH3 from
12 position), 46.70 (C6), 52.03 (CH3, COOMe from 5), 52.74 (CH3,
COOMe from 6), 55.40 (C5), 60.01 (C4a), 73.57 (C7), 129.35 (C11),
129.55 (C10), 194.26 (C8, keto). MS (ES): 379 (M++Na+). Anal. Calcd
for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 63.98; H, 5.64;
N, 7.81.
4.2.10. 7-(4-Fluorobenzoyl)-4a,5,6,7-tetrahydro pyrrolo[2,1-
b]pyridazine-5-carbonitrile (7a)
Dark white crystals (29%), mp 148–150 °C. IR (cmꢀ1): 2242
(CN), 1697 (C@O keto). 1H NMR (400 MHz, CDCl3): d = 2.14–2.08
(dtd, J = 12.8, 3.6, 2.8 Hz, 1H, H6b), 2.81–2.74 (dtd, J = 12.8, 9.6,
6.8, Hz, 1H, H6a), 3.26–3.20 (m, J = 7.2, 4.8 Hz, 1H, H5), 4.00–4.97
(t, J = 12.0, 6.0 Hz, 1H, H4a), 5.55–5.53 (dd, J = 8.4, 2.8 Hz, 1H, H7),
6.04–6.01 (m, J = 10.0, 6.4 Hz, 1H, H4), 6.15–6.11 (m, J = 10.0, 3.6
Hz, 1H, H3), 6.88–6.85 (dd, J = 3.2 Hz, 1H, H2), 7.18–7.14 (dd,
J = 8.8 Hz, 2H, H11), 8.20.8.16 (dd, J = 8.8 Hz, 2H, H10). 13C NMR:
400 MHz, CDCl3): 27.60 (C6), 35.37 (C5), 55.83 (C4a), 70.69 (C7),
116.02 (C11), 120.40 (CN), 131.22 (C10), 164.90 (C12), 194.00 (C8,
keto). Anal. Calcd for C15H12N3OF: C, 66.91; H, 4.49; N, 15.61.
Found: C, 66.88; H, 4.46; N, 15.57.
4.2.11. 7-(4-Chlorobenzoyl)-4a,5,6,7-tetrahydro pyrrolo[2,1-
b]pyridazine-5-carbonitrile (7b)
4.2.7. 7-(4-Fluorobenzoyl)-4a,5,6,7-tetrahydropyrrolo[2,1-b
]pyridazine-5,6-trans-dicarboxylic acid dimethyl ester (6a)
Yellow crystals (31%), mp 147–148 °C. IR (cmꢀ1): 1728 (C@O es-
ter from 5), 1721 (C@O ester from 6), 1674 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 3.62, (s, 3H, CH3 from 5 position), 3.70 (s,
3H, CH3 from 6 position), 3.74–3.72 (dd, J = 6.8, 7.2 Hz, 1H, H6),
3.79–3.75 (dd, J = 7.2, 8.4 Hz, 1H, H5), 4.30–4.27 (dd, J = 5.2, 9.2
Hz, 1H, H4a), 5.83–5.81 (d, J = 6.8 Hz, 1H, H7), 5.86–5.85 (ddd,
J = 1.2, Hz, 1H, H3), 5.96–5.92 (ddd, J = 1.2, 5.2, 10.6 Hz, 1H, H4),
6.80–6.78 (dd, J = 1.6, 3.2 Hz, 1H, H2), 7.28–7.26 (dd, J = 8.8, Hz,
2H, H11), 8.18–8.14 (dd, J = 8.8, 2H, H10). 13C NMR: 400 MHz,
CDCl3): 52.11 (C5), 52.62 (C6), 55.41 (C4a), 115.93 (C11), 118.13
(C7), 132.27 (C10), 171.12 (C5, keto ester), 172.91 (C6, keto ester),
193.08 (C8, keto). Anal. Calcd for C18H17N2O5F: C, 60.00; H, 4.76;
N, 7.77. Found: C, 59.94; H, 4.73; N, 7.74.
Brown crystals (84%, mp 156–158 °C. IR (cmꢀ1): 2242 (CN),
1692 (C@O keto). 1H NMR (400 MHz, CDCl3): d = 2.15–2.08 (dtd,
J = 12.8, 3.2, 2.8, 1H, H6b), 2.80–2.74 (dtd, J = 12.8, 8.4, 7.0, 1H,
H6a), 3.26–3.20 (m, J = 7.2, 6.4 Hz, 1H, H5), 3.98–3.96 (t, J = 11.6,
6.0, 1H, H4a), 5.47–5.51 (dd, J = 8.4, 2.8, 1H, H7), 6.07–6.03 (dd,
J = 9.6, 6.0, 1H, H4), 6.14–6.11 (dd, J = 9.6, 3.2, 1H, H3), 6.88–6.87
(d, J = 3.2, 1H, H2), 7.49–7.47 (d, J = 8.8, 2H, H11), 8.11–8.10 (d,
J = 8.8, 2H, H10). 13C NMR: 27.49 (C6), 35.25 (C5), 55.83 (C4a),
70.70 (C7), 120.36 (CN), 129.06 (C11), 130.85 (C10), 133.08 (C12),
194.39 (C8, keto). Anal. Calcd for C15H12N3OCl: C, 63.05; H, 4.23;
N, 14.71. Found: C, 62.97; H, 4.19; N, 14.65.
4.2.12. 7-(4-Methylbenzoyl)-4a,5,6,7-tetrahydro pyrrolo[2,1-
b]pyridazine-5-carbonitrile (7c)
Yellow crystals (46%), mp 170–171 °C. IR (cmꢀ1): 2235 (CN), 1685
(C@O keto). 1H NMR (400 MHz, CDCl3): d = 2.15–2.09 (m, J = 4.8,
12.8, Hz, 1H, H6b), 2.41 (s, 3H, CH3 from 12 position), 2.75–2.68
(dtd, J = 6.4, 9.6, 12.4 Hz, 1H, H6a), 3.24–3.19 (m, J = 7.2 Hz, 1H, H5),
4.06–4.03 (t, J = 6.8, 11.6 Hz, 1H, H4a), 5.58–5.55 (dd, J = 8.4, 2.8 Hz,
1H, H3), 6.04–6.01 (dd, J = 6.8 Hz, 1H, H4), 6.12–6.09 (dd, J = 8.0, 3.6
Hz, 1H, H7), 6.86–6.85 (dd, J = 16.0, 3.2 Hz, 1H, H2), 7.29–7.26 (d,
J = 8.0 Hz, 2H, H11), 8.03–8.01 (d, J = 8.0, 2H, H10). 13C NMR: (400
MHz, CDCl3): 21.74 (CH3 from 12 position), 28.06 (C6), 35.25 (C5),
55.84 (C4a), 70.44 (C7), 120.48 (CN), 129.43 (C11), 132.24 (C10),
144.88 (C12), 1995.31 (C8, keto). Anal. Calcd for C16H15N3O: C,
72.43; H, 5.70; N, 15.84. Found: C, 72.38; H, 5.67; N, 15.79.
4.2.8. 7-(4-Chlorobenzoyl)-4a,5,6,7-tetrahydropyrrolo[2,1-b
]pyridazine-5,6-trans-dicarboxylic acid dimethyl ester (6b)
Yellow crystals (22%), mp 160–161 °C. IR (cmꢀ1): 1731 (C@O es-
ter from 5), 1729 (C@O ester from 6), 1683 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 3.62, (s, 3H, CH3 from 5 position), 3.70 (s,
3H, CH3 from 6 position), 3.75–3.72 (dd, J = 7.2 Hz, 1H, H6), 3.79–
3.75 (dd, J = 7.6 Hz, 1H, H5), 4.30–4.26 (dd, J = 5.6 Hz, 1H, H4a),
5.81–5.79 (ddd, J = 6.8 Hz, 1H, H7), 5.85–5.82 (dd, J = 7.2 Hz, 1H,
H3), 5.96–5.92 (dd, J = 5.2 Hz, 1H, H4), 6.79–6.78 (dd, J = 3.2, 1.2
Hz, 1H, H2), 7.46–7.44 (d, J = 8.8, Hz, 2H, H11), 8.07–8.05 (d,
J = 8.8, 2H, H10). 13C NMR: (400 MHz, CDCl3): 46.70 (C6), 52.07
(CH3, COOMe from 6), 52.74 (CH3, COOMe from 5), 55.40 (C4a),
73.57 (C7), 129.35 (C11), 129.55(C10), 173.05 (C5, keto ester),
194.26 (C8, keto). Anal. Calcd for C18H17N2O5Cl: C, 57.38; H, 4.55;
N, 7.43. Found: C, 57.30; H, 4.51; N, 7.38.
4.2.13. 7-(4-Fluorobenzoyl)-4a,5,6,7-tetrahydro pyrrolo[2,1-
b]pyridazine-5-carboxylic acid ethyl ester (8a)
Brown crystals (21%), mp 170–171 °C. IR (cmꢀ1): 1689 (C@O
keto). 1H NMR (400 MHz, CDCl3): d = 2.35–2.32 (t, 2H, H6a and

2828
R. M. Butnariu, I. I. Mangalagiu / Bioorg. Med. Chem. 17 (2009) 2823–2829
H6b), 3.22–3.17 (m, J = 6.4, 6.8 Hz, 1H, H5), 3.68 (s, 3H, CH3 from 5 po-
sition), 4.26–4.23 (dd, J = 6.8, 12.0 Hz, 1H, H4a), 5.59–5.56 (t, J = 6.4
Hz, 1H, H7), 5.84–5.81 (m, J = 3.2, 7.6, 8.0, Hz, 1H, H3), 5.96–5.92
(ddd, J = 3.2, 12.0 Hz, 1H, H4), 6.68–6.67 (dd, J = 2.8, 12.0 Hz, 1H,
H2), 7.17–7.12 (t, J = 8.8 Hz, 2H, H11), 8.20–8.17 (dd, J = 8.8, 5.6 2H,
H10). 13C NMR: (400 MHz, CDCl3): 25.73 (C6), 50.20 (C5), 51.32
(CH3, COOMe from 5), 57.40 (C4a), 70.72 (C7), 173.74 (C5, keto ester),
195.39 (C8, keto). MS (ES): 288 (M++Na+). Anal. Calcd for C16H15
N2O3F: C, 63.57; H, 5.00; N, 9.27. Found: C, 63.52; H, 4.97; N, 9.24.
4.2.18. 7-(4-Methylbenzoyl)pyrrolo[2,1-b]pyridazine-5-
carboxylic acid ethyl ester (9c)
Dark white crystals (14%), mp 105–107 °C. IR (cmꢀ1): 1706
(C@O ester), 1631 (C@O keto). 1H NMR (400 MHz, CDCl3):
d = 1.42–1.39 (t, J = 7.2 Hz, 3H, CH3 from 5 position), 2.46 (s, 3H,
CH3 from 12 position), 4.41–4.36 (q, J = 7.2 Hz, 2H, CH2 from 5 po-
sition), 7.15–7.12 (dd, J = 9.2, 4.4 Hz, 1H, H3), 7.32–7.30 (d, J = 8.0
Hz, 2H, H11), 7.74 (s, 1H, H6), 7.84–7.82 (d, J = 8.0 Hz, 2H, H10),
8.53–8.51 (dd, J = 16.0, 4.4 Hz, 1H, H2), 8.67–8.65 (dd, J = 16.0, 9.2
Hz, 1H, H4). 13C NMR: (400 MHz, CDCl3): 14.48 (CH3 from 5 posi-
tion), 21.66 (CH3 from 12 position), 60.40 (CH2 from 5 position),
105.20 (C5), 124.56 (C6), 129.11 (C11), 129.77 (C10), 133.29 (C4a),
136.30 (C12), 163.62 (C5, keto ester), 184.15 (C8, keto). Anal. Calcd
for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.08; H,
5.20; N, 9.03.
4.2.14. 7-(4-Chlorobenzoyl)-4a,5,6,7-tetrahydro pyrrolo[2,1-
b]pyridazine-5-carboxylic acid ethyl ester (8b)
Yellow crystals (20%), mp 100–102 °C. IR (cmꢀ1): 1682 (C@O
keto). 1H NMR (400 MHz, CDCl3): d = 2.35–2.32 (t, 2H, H6a and
H6b), 3.22–3.17 (m, J = 6.4 Hz, 1H, H5), 3.68 (s, 3H, CH3 from 5 posi-
tion), 4.26–4.23 (dd, J = 5.2, 6.8 Hz, 1H, H4a), 5.59–5.55 (t, J = 6.8 Hz,
1H, H7), 5.84–5.81 (dd, J = 3.2, 7.6, 8.0Hz, 1H, H3), 5.95–5.91 (ddd,
J = 3.2, 12.0 Hz, 1H, H4), 6.68–6.67 (dd, J = 2.8, 16.0 Hz, 1H, H2),
7.30–7.28 (t, J = 8.8 Hz, 2H, H11), 8.05–8.03 (dd, J = 8.8, 5.6 2H,
H10). 13C NMR: 400 MHz, CDCl3): 25.54 (C6), 50.20 (C5), 51.81
(CH3, COOMe from 5), 57.31 (C4a), 70.89 (C7), 173.79 (C5, keto es-
ter), 195.89 (C8, keto). Anal. Calcd for C16H15N2O3Cl: C, 60.29; H,
4.74; N, 8.79. Found: C, 60.23; H, 4.70; N, 8.76.
4.2.19. 7-(4-Fluorobenzoyl)pyrrolo[1,2-b]pyridazine-5,6-
dicarboxylic acid dimethyl ester (10a)
White crystals (14%), mp 156–158 °C. IR (cmꢀ1): 1739 (C@O es-
ter from 5), 1708 (C@O ester from 6), 1652 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 3.65 (s, 3H, CH3 from 6 position), 3.92 (s,
3H, CH3 from 5 position), 7.10–7.06 (dd, J = 9.2, 4.4 Hz, 1H, H3),
7.15–7.10 (t, J = 8.8, 8.4 Hz, 2H, H11), 7.72–7.70 (dd, J = 8.8, 5.2
Hz, 2H, H10), 8.32–8.31 (dd, J = 16.0, 4.8 Hz 1H, H2), 8.63–8.60
(dd, J = 16.0, 9.2 Hz 1H, H4). 13C NMR: 400 MHz, CDCl3): 51.92
(CH3 from 5 position), 52.63 (CH3 from 6 position), 115.51 (C5),
117.33 (C6), 128.79 (C7), 130.91 (C11), 132.41 (C10), 130.41 (C4a),
162.90 (C5, keto ester), 164.51 (C6, keto ester), 184.01 (C8, keto).
MS (ES): 375 (M++Na+). Anal. Calcd for C18H13N2O5F: C, 60.68; H,
3.68; N, 7.86. Found: C, 60.62; H, 3.65; N, 7.82.
4.2.15. 7-(4-Methylbenzoyl)-4a,5,6,7-tetrahydro pyrrolo[2,1-
b]pyridazine-5-carboxylic acid ethyl ester (8c)
White crystals (32%), mp 75–76 °C. IR (cmꢀ1): 1679 (C@O keto).
1H NMR (400 MHz, CDCl3): d = 2.32–2.27 (dtd, J = 8.4, 12.4 Hz, 1H,
H6b), 2.41–2.36 (dtd, J = 8.4, 12.8 Hz, 1H, H6a), 2.43 (s, 3H, CH3 from
12 position), 3.22–3.17 (m, J = 4.4, 8.0, 12.4 Hz, 1H, H5), 3.69 (s, 3H,
CH3 from 5 position), 4.33–4.30 (dd, J = 5.6, 7.2 Hz, 1H, H4a), 5.63–
5.60 (dd, J = 3.6, 8.4 Hz, 1H, H7), 5.85–5.81 (m, J = 4.4, 5.6, 12.0 Hz,
1H, H3), 5.95–5.91 (m, J = 3.6, 4.4, 12.0 Hz, 1H, H4), 6.68–6.67 (dd,
J = 3.2, 16.0 Hz, 1H, H2), 7.30–7.28 (d, J = 8.0 Hz, 2H, H11), 8.05–8.03
(d, J = 8.0, 2H, H10). 13C NMR: (400 MHz, CDCl3): 21.69 (C6), 26.21
(CH3, COOMe from 12), 50.06 (C5), 51.77 (C4a), 57.40 (C7), 173.82
(C5, keto ester), 196.77 (C8, keto). Anal. Calcd for C17H18N2O3: C,
68.44; H, 6.08; N, 9.39. Found: C, 68.40; H, 6.05; N, 9.34.
4.2.20. 7-(4-Chlorobenzoyl)pyrrolo[1,2-b]pyridazine-5,6-
dicarboxylic acid dimethyl ester (10b)
White crystals (93%). mp 178–179 °C. IR (cmꢀ1): 1744 (C@O es-
ter from 5), 1707 (C@O ester from 6), 1648 (C@O keto). 1H NMR:
3.66 (s, 3H, CH3 from 6 position), 3.92 (s, 3H, CH3 from 5 position),
7.11–7.08 (dd, J = 8.8, 3.2 Hz, 1H, H3), 7.44–7.42 (d, J = 8.0 Hz, 2H,
H11), 7.74–7.72 (d, J = 8.4 Hz, 2H, H10), 8.33–8.32 (d, J = 3.2 Hz,
1H, H2), 8.63–8.60 (d, J = 8.8 Hz, 1H, H4). 13C NMR: 51.95 (CH3 from
5 position), 52.69 (CH3 from 6 position), 103.44 (C5), 126.18 (C6),
126.28 (C7), 128.74 (C11), 130.78 (C10), 131.00 (C4a), 136.21 (C12),
162.86 (C5, keto ester), 164.52 (C6, keto ester), 184.24 (C8, keto).
Anal. Calcd for C18H13N2O5Cl: C, 58.00; H, 3.52; N, 7.52. Found: C,
57.92; H, 3.48; N, 7.45.
4.2.16. 7-(4-Fluorobenzoyl)pyrrolo[2,1-b]pyridazine-5-
carboxylic acid ethyl ester (9a)
Brown crystals (34%), mp 116–118 °C. IR (cmꢀ1): 1708 (C@O es-
ter), 1647 (C@O keto). 1H NMR (400 MHz, CDCl3): d = 1.43–1.39 (t,
J = 7.2 Hz, 3H, CH3 from 5 position), 4.42–4.37 (q, J = 7.2 Hz, 2H,
CH2 from 5 position), 7.17–7.14 (dd, J = 4.4, 9.2 Hz, 1H, H3), 7.22–
7.20 (dd, J = 8.4 Hz, 2H, H11), 7.73 (s, 1H, H6), 7.96–7.93 (dd, J = 8.4,
5.6 Hz, 2H, H10), 8.54–8.52 (dd, J = 1.6, 4.4 Hz, 1H, H2), 8.69–8.66
(dd, J = 1.6, 9.2 Hz, 1H, H4). 13C NMR: (400 MHz, CDCl3): 14.72 (CH3
from 5 position), 60.67 (CH2 from 5 position), 115.48 (C5), 124.61
(C6), 128.03 (C11), 132.09 (C10), 133.53 (C4a), 144.35 (C12), 164.23
(C5, keto ester), 182.35 (C8, keto). Anal. Calcd for C17H13N2O3F: C,
65.38; H, 4.20; N, 8.97. Found: C, 65.35; H, 4.18; N, 8.95.
4.2.21. 7-(4-Methylbenzoyl)pyrrolo[1,2-b]pyridazine-5,6-
dicarboxylic acid dimethyl ester (10c)
Yellow crystals (12%), mp 176–178 °C. IR (cmꢀ1): 1720 (C@O es-
ter from 5), 1704 (C@O ester from 6), 1652 (C@O keto). 1H NMR
(400 MHz, CDCl3): d = 2.42 (s, 3H, CH3 from 12 position), 3.59 (s,
3H, CH3 from 6 position), 3.92 (s, 3H, CH3 from 5 position), 7.07–
7.04 (dd, J = 9.2, 4.4 Hz, 1H, H3), 7.26–7.24 (d, J = 6.8 Hz, 2H, H11),
7.72–7.70 (d, J = 8.4 Hz, 2H, H10), 8.32–8.31 (dd, J = 16.0, 4.4 Hz
1H, H2), 8.62–8.59 (dd, J = 16.0, 7.6 Hz 1H, H4). 13C NMR: (400
MHz, CDCl3): 21.98 (CH3, COOMe from 5), 51.37 (CH3 from 12 po-
sition), 53.69 (CH3 from 6 position), 101.37 (C6), 103.21 (C5),
129.15 (C10), 129.62 (C11), 143.22 (C12), 163.24 (C7), 184.26 (C8,
keto). MS (ES): 331 (M++Na+). Anal. Calcd for C19H16N2O5: C,
64.77; H, 4.58; N, 7.95. Found: C, 64.70; H, 4.56; N, 7.88.
4.2.17. 7-(4-Chlorobenzoyl)pyrrolo[2,1-b]pyridazine-5-
carboxylic acid ethyl ester (9b)
Light blue crystals (88%), mp 109–110 °C. IR (cmꢀ1): 1705 (C@O
ester), 1640 (C@O keto). 1H NMR: 1.43–1.39 (t, J = 7.2 Hz, 3H, CH3
from 5 position), 4.42–4.37 (q, J = 7.2 Hz, 2H, CH2 from 5 position),
7.19–7.15 (dd, J = 9.2, 4.0 Hz, 1H, H3), 7.50–7.48 (d, J = 8.4 Hz, 2H,
H11), 7.73 (s, 1H, H6), 7.86–7.84 (d, J = 8.4 Hz, 2H, H10), 8.55–8.53
(d, J = 4.0 Hz, 1H, H2), 8.69–8.66 (dd, J = 9.2 Hz, 1H, H4). 13C NMR:
14.49 (CH3 from 5 position), 60.53 (CH2 from 5 position), 105.53
(C5), 124.81 (C6), 126.30 (C7), 128.77 (C11), 130.92 (C10), 133.62
(C4a), 137.31 (C12), 163.44 (C5, keto ester), 183.00 (C8, keto). Anal.
Calcd for C17H13N2O3Cl: C, 62.11; H, 3.99; N, 8.52. Found: C,
62.06; H, 3.97; N, 8.50.
4.3. Microbiology
Antibacterial and antifungal activities of the compounds were
determined by using diffusion technique on agar.11 The bacteria
and fungi were maintained on nutrient Mueller Hinton agar
(Oxoid). The agar media were incubated with different microor-

R. M. Butnariu, I. I. Mangalagiu / Bioorg. Med. Chem. 17 (2009) 2823–2829
2829
4. (a) Demirayak, S.; Karaburn, A. C.; Beis, R. Eur. J. Med. Chem. 2004, 39, 1089; (b)
Gokçe, M.; Dogruer, D.; Fethi Sahin, M. Il Farmaco 2001, 56, 223.
ganisms culture tested. After 24 h of incubation at 30 °C for bacte-
ria and 48 h of incubation at 28 °C for fungi, the diameter of inhi-
bition zone (mm) was measured (Table 2). Chloramphenicol and
nysatin were purchased from the market and used in a concentra-
tion of 30 mcg/disc and 100 mcg/disc, respectively, as references
for antibacterial and antifungal activities.
5. (a) Butnariu, R.; Caprosu, M.; Bejan, V.; Ungureanu, M.; Poiata, A.; Tuchilus, C.;
Florescu, M.; Mangalagiu, I. I. J. Heterocycl. Chem. 2007, 44, 1149; (b) Caprosu,
M.; Butnariu, R.; Mangalagiu, I. I. Heterocycles 2005, 65, 1871; (c) Ungureanu,
M.; Mangalagiu, I. I.; Grosu, G.; Petrovanu, M. Ann. Pharm. Fr. 1997, 55, 69.
6. Padwa, A. (Ed.). 1,3-Dipolar Cycloaddition Chemistry, Vol. 2, Chapter 12, ed. by A.
Padwa, pp 277–406 and Chapter 13, ed. by K. N. Houk, K. Yamaguchi, pp 407–
450 and the references cited therein, John Wiley & Sons: New York, 1984.
7. Klamann, D.; Hagen, H.. In Organische Stickstoff-Verbindungen mit einer CN-
Doppelbindung; Houben-Weyl, Ed.; Thieme: Stuttgart, 1991; Vol. E14b, Teil 1, pp
1–160. and the references cited therein.
Acknowledgements
To CNCSIS Bucuresti, Grants No. 1155/2006 and Grant TD No.
457/2006, for financial support.
8. (a) Caprosu, M.; Zbancioc, Ghe.; Moldoveanu, C.; Mangalagiu, I. I. Collect. Czech.
Chem. C 2004, 69, 426; (b) Mangalagiu, I. I.; Mangalagiu, G.; Deleanu, C.;
Drochioiu, G.; Perovanu, M. Tetrahedron 2003, 59, 111; (c) Tsuge, O.; Kanemasa,
S.; Takenaka, S. Bull. Chem. Soc. Jpn. 1985, 58, 3137.
9. (a) Van der Eycken, E.; Kappe, O. C. In Microwave-Assisted Synthesis of
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Stadler, A. In Microwaves in Organic and Medicinal Chemistry; Wiley-VCH:
Weinheim, Germany, 2005; (c) Loupy, A. In Microwaves in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2002.
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