Cycloalkano[1″,2″:4,5;4″,3″:4′,5′] bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines): Synthesis, structure and mechanism of their formation

Article abstract of DOI:10.1016/j.tet.2005.10.008

Reactions of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)- diones with cyclohexyl- and cycloheptylamines in the presence of AgPy ₂MnO₄ produce novel cycloalkano[1″,2″:4, 5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e

Full text of DOI:10.1016/j.tet.2005.10.008

Tetrahedron 62 (2006) 652–661
Cycloalkano[100,200:4,5;400,300:40,50]bis(pyrrolo[2,3-c]pyrimido-
[5,4-e]pyridazines): synthesis, structure and mechanism
of their formation
a
Olga V. Serduke,a Anna V. Gulevskaya,a, Alexander F. Pozharskii,
*
Zoya A. Starikovab and Irina A. Profatilovac
aDepartment of Chemistry, Rostov State University, Zorge 7, 344090 Rostov-on-Don, Russian Federation
bA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova 28, 119991 Moscow, Russian Federation
cDepartment of Physical and Organic Chemistry, South Scientific Centre of Russian Academy of Sciences, Chekhova 41, 344006
Rostov-on-Don, Russian Federation
Received 19 July 2005; revised 20 September 2005; accepted 6 October 2005
Available online 28 October 2005
Abstract—Reactions of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with cyclohexyl- and cycloheptylamines
in the presence of AgPy2MnO4 produce novel cycloalkano[100,200:4,5;400,300:40,50]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines). Detailed
information concerning the scope and mechanism of these transformations is discussed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
with cyclohexylamine in the presence of an oxidant
(AgPy2MnO4) resulted in formation of cyclohexabis(pyrrolo-
Recently, we reported1 that the interaction of 3-alkylamino-
6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones 1
pyrimidopyridazines)
(Scheme 1).
2
along with imidazolines 3
Me
Me
H
O
O
N
N
O
O
O
O
N
D'
D
N
N
N
Me
O
NH R
Me
O
NH2
R
Me
Me
A
N
N
+
C
B
C'
B'
N
N
N
N
AgPy2MnO4
N
N
N
N
N
N
N
N
Me
Me
R
R
2
1
3
H
Me
Me
N
O
O
O
N
N
O
O
N
N
Me
Me
N
N
N
N
N
R
N
N
R
N
O
CH3
MeO
OH
4
5
Scheme 1.
Keywords: 3-Alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones; Nucleophilic substitution of hydrogen; Cycloalkylamines; Cyclo-
alkano[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines; Cycloalkano[100,200:4,5; 400,300:40,50]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines).
*
Corresponding author. Tel./fax: C7 863 2975146; e-mail: agulevskaya@chimfak.rsu.ru
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.008

O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
653
H
H
H
2N
O
:
N
HN
N
N
Me
O
R
N
H R
R
[O]
[O]
N
R
N
N
-NH3
N
N
-H2O
-H2O
N
N
N
N
N
Me
7
1
8
6
H
H
N
N
N
R
N
[O]
-H2O
[O]
N
1
N
H
N
R
2
N
R
N
:
-H2O
N
N
R
N
N
R
N
N
10
9
Scheme 2.
NH R1
N
NH2
AgPy2MnO4
R
+
N
N
N
N
N
N
N
N
N
N
R1
R
2
8
1
Scheme 3.
10
11
9
Me
N13
8
Me
N
NH2
12
16
O
O
14
O
O
O
O
2
3
12
15
17
7
1
7
R
N
4 N
5
N
N11
H R
Me
O
N
Me
N2
1
N
Me
Me
6N
+
10
3
8
6
4
N
5
N
9
N
N
AgPy2MnO4
N
N
R
N
N
O
N
N
R
Me
Me
1a R=Pr
1b R=Bu
1c R=PhCH2
12a R=Pr (6%)
12b R=Bu (10%)
12c R=PhCH2 (7%)
11a R=Pr (10%)
11b R=Bu (11%)
11c R=PhCH2 (13%)
Scheme 4.
10
11
9
NH2
12
13
9
8
8
10
O
O
O
7 N
7
Pr
Pr
N
Me
H Pr
N
Me
Me
O
1
1
N2
3
N2
3
N
6N
6N
5
N
4
N
5
N
4
N
N
AgPy2MnO4
rt, 72h
O
O
N
N
Me
Me
Me
1a
11e
11d
Scheme 5.
(CH2)n
O
O
H
C
H
R
N
Me
NH R
AgPy2MnO4
Me
O
N
N
N
Pr
+
N
(CH2)n
N
O
N
N
N
N
Me
Me
11a R=Pr, n=2 (61%)
1a R=Pr
1b R=Bu
1c R=PhCH2
11b R=Bu, n=2 (55%)
11c R=PhCH2, n=2 (36%)
11d R=Pr, n=3 (21%)
11e R=Pr, n=1 (50%)
Scheme 6.

654
O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
Figure 1. 1H NMR spectrum of compound 12a. (a) 1H NMR spectra of compound 12a (CDCl3, 300 MHz); (b) 1H–1H COSY NMR spectra of compound 12a.
The proposed pathway of the conversion 1/2 is shown in
Scheme 2. It involves a preliminary oxidation of cyclo-
hexylamine into cyclohexanone imine, followed by:
(i) addition of 3-alkylaminopyridazine 1 across the C]N
bond of cyclohexanone imine; (ii) ammonia departure from
gem-diamine 6 producing enamine 7; (iii) cyclization of 7
into tetrahydroindole 8; (iv) oxidation of the latter into
alkene 9; (v) addition of the starting compound 1 to C]C
bond of 9 and (vi) final cyclization 10/2. The participation
of pyrrole 8 as a key intermediate in this process has been

O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
655
confirmed experimentally: the treatment of authentic
compounds 82 with 1 equiv of 3-alkylaminopyridazines 1
in the cyclohexylamine/oxidant system resulted in a full
conversion of the former into polycycles 2 (Scheme 3).
carried out in cycloheptylamine (rt, 72 h), cyclohepta-
pyrroles 11a–c, together with the desired cycloheptabis-
(pyrrolopyrimidopyridazines) 12a–c were obtained in
comparable amounts (Scheme 4). Treating 1a with
cyclooctylamine and AgPy2MnO4 gave cyclooctapyrrole
11d as a single product in 14% yield (Scheme 5). The use of
cyclopentylamine led to complete consumption of 1a, but
we failed to isolate any product except a trace amount of
cyclopentapyrrole 11e.
Besides an unusual cascade mechanism including two
intramolecular stages of nucleophilic substitution of
hydrogen3,4 (namely (iii) and (vi)), two more points of
this transformation should be indicated. Firstly, compounds
2 can be easily oxidized into benzobis(pyrrolopyrimido-
pyridazines) 4, which are fully conjugated p-electron
analogues of an yet unknown aromatic hydrocarbon
dibenzo[a,o]pycene.5 Secondly, the arrangement of five
central nuclei A, B, B0, C and C0 in compounds 2 and 4 has a
remarkable similarity with the skeleton of the indolo-
carbazole antibiotics, for example, K252a 5.6
The structures of pyrroles 11a–e have been confirmed by
their independent synthesis from 3-alkylamino-
pyrimidopyridazines 1 in accordance with earlier described
procedure (Scheme 6).2
The structure assignment for cycloheptabis(pyrrolo-
pyrimidopyridazines) 12, apart from elemental analysis,
was based on the following evidence. Like 2, polycycles 12
are high melting (O300 8C), yellow crystalline substances,
having two long-wavelength peaks at 385 and 435 nm with
a shoulder at 459 nm in their UV spectra. The mass spectra
of all samples show the corresponding molecular ion of a
low intensity. In the IR spectra there are two characteristic
bands of the carbonyl stretching vibration in the
1660–1700 cmK1 region. The 1H NMR spectra of 12
are rather complicated (Fig. 1, a) but 1H–1H COSY
experiments have provided an unambiguous discrimination
between all signals (Fig. 1, b). Interestingly, the a-CH2
protons of N(7 or 8)-substituent are non-equivalent
and reveal themselves as two different signals at 4.1
and 5.1 ppm (for 12a,b) or 5.4 and 6.3 ppm (for 12c).
This seems to reflect the hindered rotation around N(7 or
8)–C(a) bond. The peaks from the axial and equatorial
hydrogens of the 15- and 17-CH2 units are observed at
2.3–2.4 and 4.3–4.5 ppm, respectively, while that of the
16-CH2 protons is at 1.9–2.2 ppm.
With this in mind, our aims were: (1) to collect additional
information on the mechanism of the above transformation,
and (2) to expand its scope. In particular, we report on our
attempts to synthesize cyclopenta-, cyclohepta- and
cycloocta-fused analogues of compounds 2.
2. Results and discussion
As it follows from Scheme 2, cyclohexylamine works here
as a building block for the central ring A of compounds 2.
Therefore, to obtain other cycloalkano-based polycycles of
this type other cycloalkylamines ought to be taken as a
starting material.
We have found that the interaction of 3-alkylamino-
pyrimidopyridazines 1a–c with cyclopentyl-, cycloheptyl-
and cyclooctylamines in the presence of AgPy2MnO4
proceeds specifically in each case. When the reaction was
O
O
N
R
N
H R
Me
O
Me
O
NH2
N
N
+
N
N
N
N
N
N
AgPy2MnO4
rt, 120h
Me
Me
11a-c
1a-c
Me
Me
Me
11
O
N
O
O
O
N
O
N
2
O
3
N4
1
10
12
R
N
N
N
9
N
Me
Me
+
Me
8
N
N
N5
7
N
6
N
N
Me
O
N
R
N
R
N
N
N
N
R
O
12a R=Pr
12b R=Bu
12c R=PhCH2
13a R=Pr
Me
13b R=Bu
13c R=PhCH2
R
Pr
Bu
PhCH2
Total yield of 12 and 13, %
Ratio 12:13
9:1
3:1
1.13:1
27
11
13
Scheme 7.

656
O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
1.525
1.527
1.518
O
1.514
1.392
1.560
1.570
N
1.399
1.440
1.416
1.507
1.410
1.423
1.419
O
1.383
1.367
1.416
1.396
N
1.470
N
1.378
1.319
1.345
N
N
1.361
Selected bond lengths (A)
O
118.4
119.4
124.2
106.6
116.3
128.6
139.0
N
124.6
128.1
121.6
115.8
125.1
125.2
120.5
110.1
116.2
119.7
O
106.6
114.3
114.8
107.6
123.3
117.3
123.2
N
119.2
109.0
N
129.0
128.6
126.4
123.0
114.4
122.4
118.7
N
119.4
116.6
N
Selected bond angles (degree)
Figure 2. The molecular structure of 13a with crystallographic numbering scheme (hydrogens are omitted for clarity).
We believe that the isolation of cycloalkanopyrroles 11 in
the above experiments provides an additional proof in favor
of the mechanism suggested in Scheme 2, at least for its
initial steps. Following this, we attempted to get cyclo-
alkano-fused analogues of 2 directly from pyrroles 11 in a
manner shown in Scheme 3.
the displacement thermal ellipsoids drawn at the 30%
probability level. The molecule adopts a pincer-like
shape (Fig. 3) with the C(15)–C(15A) bond between the
two chair-like cycloheptane rings being the longest
˚
(1.57 A). The distances between centers of the uracil
˚
termini and the pyrrole rings is 7.69 and 3.72 A,
It has been found that prolonged stirring of equimolar
amounts of cyclooctapyrrole 11d and compound 1a in the
cyclooctylamine/AgPy2MnO4 system results in a gradual
disappearance of 1a and an accumulation of 11d. Under
similar conditions, cyclopentapyrrole 11e reacts with
3-propylaminopyrimidopyridazine 1a to give a complex
mixture of inseparable products. Contrary to this, the
reaction of cycloheptapyrroles 11a–c with 1a–c leads to
expected polycycles 12a–c together with dimers 13a–c in
11–27% overall yield (Scheme 7).
The ratio of 12a–c:13a–c is strongly influenced by the alkyl
substituent at the pyrrolic nitrogen: the larger the N-alkyl
group is, the greater is the content of dimer 13. Owing to the
very similar properties of both products, including their
retention factors, in no cases were the corresponding
mixtures separated. Only in the case of 12a and 13a did a
great predominance of 12a over dimer 13a allow us to get
the former in a pure state by crystallization from ethanol.
As for dimers 13a–c, we prepared them in a pure state
by simple oxidation of cycloheptapyrroles 11a–c with
AgPy2MnO4 in cycloheptylamine without addition of
compound 1, though the yields were not higher than 8–10%.
Figure 3. View on the molecule 13a, showing anti-periplanar orientation
of the cycloheptyl rings respectively the C(15)–C(15A) bond (without
hydrogen atoms).
We were able to obtain suitable crystals of dimer 13a for
X-ray study. Figure 2 shows its molecular structure with

O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
657
respectively. Interestingly, the orientation of both N-propyl
substituents reminds us of Scorpion tails turning down to the
pyrrole rings. The crystal packing of compound 13a
includes the alternated layers of ‘pincers’ oriented in the
opposite sides (Fig. 4).
faster (k1[k2). For its seven-membered counterpart 15
(nZ2), k1 is approximately equal to k2, and a radical pairing
into dimer 13 becomes possible. The appearance of
carbocation 16 seems to be a key factor in further
developing of the process towards polycycles 2 and 12.
Going back to Scheme 2, which postulates that the
conversion of 8/2 proceeds via alkenes 9, we hoped to
prepare the latter by oxidation of cycloalkanopyrroles 8 and
11b. However, in both these cases we were unable to stop the
process of monoalkene formation. Thus, upon treatment of
cyclohexapyrrole 8a1 with DDQ in benzene, only indole 18
was obtained as a single product in 41% yield (Scheme 9).
Under similar conditions, cycloheptapyrrole 11b gave
cycloheptatriene derivative 19 (48%). From this, the
explanation of the reaction mechanism as proceeding via
carbocation 16, not alkene 9, seems to be more preferable.
For a deeper insight into regularities of the oxidation of
pyrroles 8 and 11, their half-wave oxidation potentials have
been measured in CH2Cl2 by differential pulse voltammetry.
The following values of Eo⁄x for their one-electron oxidation
Figure 4. The cut of the crystal packing of compound 13a (without
hydrogen atoms).
1
2
were obtained: 1.32 (11e), 1.34 (8a), 1.37 (11a) and 1.65 V
(11d). It is seen that the potential for cyclooctapyrrole 11d is
The isolation of dimers 13 somewhat clarifies the
mechanism of the conversions of 8/2 and 11/12. From
the known data7 on electrooxidation of pyrroles and indoles,
it evidently involves the generation of radical cation 14 as a
starting species, with subsequent loss of a proton from the
a-methylene unit (Scheme 8). Thus, forming benzyl type
radical 15 may be either further oxidized into carbocation 16
or dimerized into 13. Since no signs of dimerization have
been noticed for cyclohexano derivative 15 (nZ1), one can
assume that in this case the first reaction proceeds much
sharply increased, explaining why this compound is inert to
further oxidation with AgPy2MnO4. Three other pyrroles
1
display nearly the same E ⁄ values and actually undergo
ox
2
oxidative conversions. The most difficult question is how to
explain a lack of success in the case of cyclopentapyrrole
11e. One can assume that the latter, like 8a and 11a, also
produces polycyclic compound 20, which in the presence of
amine, silver and permanganate ions8 is converted via
cyclopentadienyl anion 21 into a mixture of unidentified
oxidation products (Scheme 10).
H
H
H
( )n
H
H
H
( )n
( )n
O
.
.
.
+
N
N
.
+
N
R
Me
O
R
R
-e
N
-H+
N
N
N
N
N
N
N
Me
14
8 or 11
H
H
.
( )n
( )n
.
N
N
k
R
R
2
13
N
N
N
N
15
k
-e
1
H
N
N
H
N
( )n
( )n
R
N
N
R
R
1
12 or 2
N
N
N
N
17
16
Scheme 8.

658
O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
9
Al2O3 (III–IV activity of Brockman) was used for
chromatographic separations.
10
11
8
O
O
7 N
X-ray structure determination. Crystallographic data for
13a at 163 K crystals of C72H84N20O8 are monoclinic, space
N
Pr
Me
O
Pr
Me
O
1
N
N2
3
DDQ
6N
5
4
N
N
˚
˚
benzene
group C2/c, aZ12.404(4) A, bZ12.393(4) A, cZ
N
N
N
˚
21.360(8) A, aZ908, bZ93.61(3)8, gZ908, VZ
Me
Me
3277(2) A , ZZ2, MZ1357.59, dcalcdZ1.376 mg mK3
,
3
˚
8a
18
m(Mo Ka)Z0.094 mmK1, F(000)Z1440. Intensities of
2705 reflections were measured with a SMART diffracto-
meter at 163 K and 2578 independent reflections (RintZ
0.1285) were used in further refinement. The structures were
solved by direct method and refined by the full-matrix least
squares against F2 in the anisotropic–isotropic approxi-
mation. Hydrogen atoms were located from the Fourier
synthesis and refined in the isotropic approximation. The
refinement converged to wR2Z0.1104 and GOFZ0.991 for
all independent reflections [R1Z0.0516 was calculated
against F for observed 1270 reflections with IO2s(I)].
10
9
11
8
O
O 12
7
N
N
Bu
Bu
Me
O
Me
O
1
N
N2
3
DDQ
6N
5
4
N
benzene
N
N
N
N
Me
Me
11b
19
Scheme 9.
"oxidation products"
Me
Me
Me
O
Me
O
N
O
O
O
N
N
N
N
O
O
O
N
Me
Me
H2
C
N
N
Me
Me
amine
-H+
11e
N
N
N
N
N
N
N
N
N
R
N
N
R
N
R
R
20
21
Scheme 10.
In conclusion, we have shown that the reactions
of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-
5,7(6H,8H)-diones 1 with cyclocyclohexyl-, cycloheptyl-
and cyclooctylamines in the presence of AgPy2MnO4
follow the same course up to cycloalkanopyrroles 8 or 11.
Further development of the process depends on the
cycloalkylamine nature. When using cyclooctylamine,
compound 11 (nZ2) is a final product. In two other cases,
cycloalkanopyrroles act only as intermediates, which
undergo further transformation into polycycles 2 or 12.
This conversion seems to proceed via a radical species that
is evidenced by isolation of dimers 13. Despite low yields, a
clear advantage of the present methodology is that the whole
series of complex consequent reactions is conducted as a
one-pot procedure. We believe that along with compounds 2
and 12 it may be promising for the synthesis of some other
multi-nuclear heterocyclic systems.
All calculations were performed using SHELXTL-97 on a
IBM PC AT. Atomic coordinates, bond lengths, bond angles
and thermal parameters have been deposited at the
Cambridge Crystallographic Data Centre (CCDC) and
allocated the deposition number CCDC 277965.
The differential pulse voltammograms were measured on a
PA-2 potentiostat in three-compartment cell. The working
electrode was platinum disk with diameter 2 mm. The
reference electrode was saturated calomel electrode; the
auxiliary electrode was wolfram wire. The scan rate of
polarizing voltage was 5 mV/s. The pulse amplitude and
pulse duration were 12.5 mV and 20 ms correspondingly.
The concentration of studying compounds in CH2Cl2 was
5!10K3 M. The supporting electrolyte was 0.5 M
Bu4NClO4.
3.1. Synthesis of 11a and 12a from 3-propylamino-
pyrimidopyridazine 1a
3. Experimental
Proton (1H) nuclear magnetic resonance (NMR) spectra
were recorded on Bruker-250 (250 MHz) and Unity-300
(300 MHz) spectrometers with CDCl3 as a solvent. Infrared
(IR) spectra were recorded on a Specord IR-71 spectrometer
using nujol. Ultraviolet absorption (UV) spectra were
registered on a Specord M-40 spectrophotometer with
CHCl3 as a solvent. Mass spectra were measured on
a Varian MAT-311A spectrometer. Melting points
were determined in glass capillaries and are uncorrected.
To a stirred solution of 1a (0.2 g, 0.8 mmol) in cycloheptyl-
amine (25 mL), AgPy2MnO4 (0.385 g, 1 mmol) was added
in portions at 5 8C. After stirring for 1 week at 20 8C, the
liquid phase was concentrated to dryness. The residue was
extracted with boiling CHCl3 (30 mL). The extract was
chromatographed on a column with Al2O3 (eluent—CHCl3/
CCl4, 10:1). The fraction with Rf 0.8 gave 11a. The fraction
with Rf 0.68 gave 12a. Recrystallyzation from EtOH yielded
11a (0.028 g, 10%) and 12a (0.015 g, 6%).

O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
659
3.1.1. 2,4-Dimethyl-7-propyl-7,8,9,10,11,12-hexahydro-
3.3. Synthesis of 11c and 12c from 3-benzylamino-
pyrimidopyridazine 1c
cyclohepta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]pyridazine-
1,3(2H,4H)-dione (11a). Compound 11a was obtained in
10% yield as bright yellow crystals, mp 178–180 8C; H
1
Synthesis of 11c and 12c from 1c was carried out similarly.
NMR (CDCl3, 250 MHz) d 0.93 (t, JZ7.5 Hz, 3H,
CH2CH2Me), 1.69–1.90 (m, 8H, CH2CH2Me and 9-, 10-,
11-CH2), 3.00 (m, 2H, 8-CH2), 3.50 (s, 3H, 2-Me), 3.59 (m,
2H, 12-CH2), 3.90 (s, 3H, 4-Me), 4.44 (t, JZ7.5 Hz, 2H,
CH2CH2Me); IR (nujol) 1653, 1700 cmK1 (C]O); UV
(CHCl3, lmax (log 3)) 239 (3.99), 350 (3.96), 424 nm (3.86);
MS (m/z) 341 (MC). Anal. Calcd for C18H23N5O2: C, 63.34;
H, 6.74; N, 20.53. Found: C, 63.50; H, 6.81; N, 20.31.
3.3.1. 7-Benzyl-2,4-dimethyl-7,8,9,10,11,12-hexahydro-
cyclohepta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]pyridazine-
1,3(2H,4H)-dione (11c). Compound 11c was obtained in
1
13% yield as bright yellow crystals, mp 175–176 8C; H
NMR (CDCl3, 250 MHz) d 1.61–1.86 (m, 6H, 9-, 10-,
11-CH2), 2.93 (m, 2H, 8-CH2), 3.52 (s, 3H, 2-Me), 3.59 (m,
2H, 12-CH2), 3.94 (s, 3H, 4-Me), 5.74 (s, 2H, CH2Ph),
7.06–7.27 (m, 5H, Ph); IR (nujol) 1646, 1700 cmK1
(C]O); UV (CHCl3, lmax (log 3)) 340 (3.99), 349 (3.98),
421 nm (3.84). Anal. Calcd for C22H23N5O2: C, 67.87; H,
5.91; N, 17.99. Found: C, 67.63; H, 5.82; N, 18.01.
3.1.2. 2,4,11,13-Tetramethyl-7,8-dipropyl-7,8,15,16,
17-pentahydrocyclohepta[100,200:4,5;400,300:40,50]bis- (pyr-
rolo[2,3-c]pyrimido[5,4-e]pyridazine)-1,3,12,12-
(2H,4H,11H,13H)-tetraone (12a). Compound 12a was
1
obtained in 6% yield as yellow crystals, mpO340 8C; H
3.3.2. 7,8-Dibenzyl-2,4,11,13-tetramethyl-7,8,15,16,
17-pentahydrocyclohepta[100,200:4,5;400,300:40,50]bis-
(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazine)-1,3,12,12-
(2H,4H,11H,13H)-tetraone (12c). Compound 12c was
NMR (CDCl3, 300 MHz) d 0.57 (t, JZ7.3 Hz, 6H, 7(8)-
CH2CH2Me), 1.56 (m, 4H, 7(8)-CH2CH2Me), 2.20 (m, 2H,
16-CH2), 2.43 and 4.45 (both m, 4H, 15(17)-CH2), 3.56 (s,
6H, 2(13)-Me), 3.99 (s, 6H, 4(11)-Me), 4.10 and 5.12 (both
m, 4H, 7(8)-CH2CH2Me); IR (nujol) 1660, 1700 cmK1
(C]O); UV (CHCl3, lmax (log 3)) 484 (4.42), 436 (4.34),
459 nm (4.27); MS (m/z) 584 (MC). Anal. Calcd for
C29H32N10O4: C, 59.59; H, 5.48; N, 23.97. Found: C, 59.47;
H, 5.61; N, 23.81.
1
obtained in 7% yield as yellow crystals, mpO340 8C; H
NMR (CDCl3, 250 MHz) d 1.85 (m, 2H, 16-CH2), 2.25 and
4.27 (both m, 4H, 15(17)-CH2), 3.54 (s, 6H, 2(13)-Me), 3.99
(s, 6H, 4(11)-Me), 5.36 and 6.32 (both d, JZ14.8 Hz, 4H,
7(8)-CH2Ph), 6.79–7.13 (m, 10H, Ph); IR (nujol) 1660,
1700 cmK1 (C]O); UV (CHCl3, lmax (log 3)) 386 (4.30),
434 (4.24), 458 nm (3.72); MS (m/z) 680 (MC). Anal. Calcd
for C37H32N10O4: C, 65.29; H, 4.71; N, 20.59. Found: C,
65.31; H, 4.65; N, 20.63.
3.2. Synthesis of 11b and 12b from 3-butylamino-
pyrimidopyridazine 1b
Synthesis of 11b and 12b from 3-butylamino-
pyrimidopyridazine 1b was carried out similarly.
3.4. General procedure for synthesis of 11a–e
from N-alkylaminopyrimidopyridazines 1 and
N-propylketone imines
3.2.1. 7-Butyl-2,4-dimethyl-7,8,9,10,11,12-hexahydro-
cyclohepta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]pyridazine-
1,3(2H,4H)-dione (11b). Compound 11b was obtained in
To a stirred solution of 1 (1 mmol) in N-propylketone imine
(15 mL), AgPy2MnO4 (0.385 g, 1 mmol) was added in
portions at 5 8C. After 3 days of stirring at 20 8C the liquid
phase was concentrated to dryness. The residue was
extracted with boiling CHCl3 (30 mL). The extract was
chromatographed on a column with Al2O3 (eluent—
CHCl3). Recrystallization from EtOH gave 11a in 61%
yield, 11b—55%, 11c—36%, 11d—21%, 11e—50%.
1
11% yield as bright yellow crystals, mp 171–173 8C; H
NMR (CDCl3, 250 MHz) d 0.93 (t, JZ7.1 Hz, 3H,
CH2CH2CH2Me), 1.28–1.43 (m, 2H, CH2CH2CH2Me),
1.70–1.93 (m, 8H, CH2CH2CH2Me and 9-, 10-, 11-CH2),
2.99 (m, 2H, 8-CH2), 3.50 (s, 3H, 2-Me), 3.59 (m, 2H,
12-CH2), 3.91 (s, 3H, 4-Me), 4.48 (t, JZ7.5 Hz, 2H,
CH2CH2CH2Me); IR (nujol) 1660, 1700 cmK1 (C]O); UV
(CHCl3, lmax (log 3)) 239 (3.97), 350 (3.93), 424 nm (3.83).
Anal. Calcd for C19H25N5O2: C, 64.23; H, 7.04; N, 19.72.
Found: C, 64.31; H, 7.11; N, 19.50.
3.4.1. 2,4-Dimethyl-7-propyl-7,8,9,10,11,12,13-hepta-
hydrocycloocta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]pyri-
dazine-1,3(2H,4H)-dione (11d). Compound 11d was
obtained as bright yellow crystals, mp 186–188 8C; 1H
NMR (CDCl3, 250 MHz) d 0.96 (t, JZ7.5 Hz, 3H,
CH2CH2Me), 1.23–1.55 (m, 4H, 10-, 11-CH2), 1.78 (m,
4H, 9-, 12-CH2), 1.86 (m, 2H, CH2CH2Me), 3.00 (m, 2H,
8-CH2), 3.35 (m, 2H, 13-CH2), 3.50 (s, 3H, 2-Me), 3.92 (s,
3H, 4-Me), 4.40 (t, JZ7.5 Hz, 2H, CH2CH2Me); IR (nujol)
1653, 1700 cmK1 (C]O); UV (CHCl3, lmax (log 3)) 260
(4.32), 335 (3.92), 350 (3.78), 427 nm (3.77); MS (m/z) 355
(MC). Anal. Calcd for C19H25N5O2: C, 64.23; H, 7.04; N,
19.72. Found: C, 64.11; H, 7.00; N, 19.81.
3.2.2.
7,8-Dibutyl-2,4,11,13-tetramethyl-7,8,15,16,
17-pentahydrocyclohepta[100,200:4,5;400,300:40,50]bis- (pyr-
rolo[2,3-c]pyrimido[5,4-e]pyridazine)-1,3,12,12-
(2H,4H,11H,13H)-tetraone (12b). Compound 12b was
1
obtained in 10% yield as yellow crystals, mpO340 8C; H
NMR (CDCl3, 300 MHz) d 0.66 (t, JZ7.3 Hz, 6H,
7(8)-CH2CH2CH2Me), 0.95 (m, 4H, 7(8)-CH2CH2CH2Me),
1.60 (m, 4H, 7(8)-CH2CH2CH2Me), 2.20 (m, 2H, 16-CH2),
2.38 and 4.47 (both m, 4H, 15(17)-CH2), 3.56 (s, 6H,
2(13)-Me), 3.99 (s, 6H, 4(11)-Me), 4.10 and 5.13 (both m,
4H, 7(8)-CH2CH2CH2Me); IR (nujol) 1660, 1700 cmK1
(C]O); UV (CHCl3, lmax (log 3)) 384 (4.30), 435 (4.30),
458 nm (4.20); MS (m/z) 612 (MC). Anal. Calcd for
C31H36N10O4: C, 60.78; H, 5.88; N, 22.88. Found: C, 60.69;
H, 5.83; N, 22.90.
3.4.2. 2,4-Dimethyl-7-propyl-7,8,9,10-tetrahydrocyclo-
penta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]pyridazine-1,3-
(2H,4H)-dione (11e). Compound 11e was obtained as
1
bright yellow crystals, mp 184–185 8C; H NMR (CDCl3,
250 MHz) d 0.93 (t, JZ7.3 Hz, 3H, CH2CH2Me), 1.87–1.96

660
O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
(m, 2H, CH2CH2Me), 2.50–2.60 (m, 2H, 9-CH2), 3.01 (t,
JZ7.3 Hz, 2H, 8-CH2), 3.27 (t, JZ7.1 Hz, 2H, 10-CH2),
3.49 (s, 3H, 2-Me), 3.90 (s, 3H, 4-Me), 4.32 (t, JZ7.1 Hz,
2H, CH2CH2Me); IR (nujol) 1660, 1700 cmK1 (C]O); UV
(CHCl3, lmax (log 3)) 266 (4.34), 331 (3.79), 437 nm (3.78).
Anal. Calcd for C16H19N5O2: C, 61.34; H, 6.07; N, 22.36.
Found: C, 61.21; H, 6.12; N, 22.51.
3.7.2. 8,80-Bis[7-butyl-2,4-dimethyl-7,8,9,10,11,12-hexa-
hydrocyclohepta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]-
pyridazine-1,3(2H,4H)-dione] (13b). Compound 13b was
obtained in 8% yield as bright yellow crystals, mpO340 8C;
1H NMR (CDCl3, 300 MHz) d 0.93 (t, JZ7.3 Hz, 6H,
CH2CH2CH2Me), 1.31 (m, 6H, CH2CH2CH2Me, 10-H),
1.60–1.88 (m, 12H, CH2CH2CH2Me, 9-CH2, 10-H0 and
11-H), 2.04 (m, 2H, 11-H0), 2.79 (m, 2H, 8-H), 3.55 (s, 6H,
2-Me), 3.97 (s, 6H, 4-Me), 4.10 and 4.70 (both m, 4H,
12-CH2), 4.28 and 5.13 (both m, 4H, CH2CH2CH2Me); IR
(nujol) 1660, 1700 cmK1 (C]O); UV (CHCl3, lmax (log 3))
346 (4.32), 356 (4.34), 425 (4.18), 450 nm (4.04); MS (m/z)
354 (1⁄2 MC). Anal. Calcd for C38H48N10O4: C, 64.41; H,
6.78; N, 19.77. Found: C, 64.38; H, 6.75; N, 19.81.
3.5. Synthesis of 11d from 1a
To a stirred solution of 1a (0.100 g, 0.4 mmol) in
cyclooctylamine (15 mL), AgPy2MnO4 (0.193 g,
0.5 mmol) was added in portions at 5 8C. After 3 days of
stirring at 20 8C the liquid phase was concentrated to
dryness. The residue was extracted with boiling CHCl3
(30 mL). The extract was chromatographed on a column
with Al2O3 (eluent—CHCl3/CCl4, 5:1). The fraction with Rf
0.8 gave 11d (0.020 g, 14%).
3.7.3. 8,80-Bis[7-benzyl-2,4-dimethyl-7,8,9,10,11,12-
hexahydrocyclohepta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]-
pyridazine-1,3(2H,4H)-dione] (13c). Compound 13c was
obtained in 8% yield as bright yellow crystals, mpO340 8C;
1H NMR (CDCl3, 250 MHz) d 1.24–2.30 (m, 12H, 9-, 10-,
11-CH2), 2.75 (m, 2H, 8-H), 3.54 (s, 6H, 2-Me), 3.96 (s, 6H,
4-Me), 4.20 and 4.67 (both m, 4H, 12-CH2), 5.17 and 6.50
(both d, JZ16.0 Hz, 4H, CH2Ph), 6.80–7.70 (m, 10H, Ph);
IR (nujol) 1660, 1700 cmK1 (C]O). Anal. Calcd for
C44H44N10O4: C, 68.04; H, 5.67; N, 18.04. Found: C, 68.11;
H, 5.65; N, 18.10.
3.6. General procedure for synthesis of 12a–c and 13a–c
from pyrroles 11 and N-alkylaminopyrimidopyridazines 1
To a stirred solution of 11a (0.200 g, 0.586 mmol) and
AgPy2MnO4 (0.460 g, 1.2 mmol) in cycloheptylamine
(20 mL), a solution of 1a (0.146 g, 0.586 mmol) in
cycloheptylamine (20 mL) was added at 5 8C. After
17 days of stirring at 20 8C the liquid phase was
concentrated to dryness. The residue was extracted with
boiling CHCl3 (50 mL). The extract was chromatographed
on a column with Al2O3 (eluent—CHCl3/CCl4, 5:1). The
fraction with Rf 0.68 gave 12a and 13a (9:1). Subsequent
recrystallization from EtOH yielded 12a (0.081 g, 24%).
3.8. Oxidation of 8a and 11b
3.8.1. 2,4-Dimethyl-7-propyl-7H-pyrimido[50,40;5,6]-
pyridazino[3,4-b]indole-1,3(2H,4H)-dione (18). A stirred
suspension of 8a (0.050 g, 0.15 mmol) and DDQ (0.068 g,
0.3 mmol) in benzene (20 mL) was heated at reflux for 40 h.
The resulting mixture was concentrated to dryness. The
residue was extracted with boiling CHCl3 (20 mL). The
extract was chromatographed on a column with Al2O3
(eluent—CHCl3/CCl4, 10:1). Recrystallization from EtOH
gave 18 (0.020 g, 41%) as dark yellow crystals, mp
3.7. General procedure for synthesis of 13a–c from
pyrroles 11
To a stirred solution of 11a (0.196 g, 0.575 mmol) in
cycloheptylamine (15 mL), AgPy2MnO4 (0.221 g,
0.575 mmol) was added at 5 8C. After 10 days of stirring
at 20 8C the liquid phase was concentrated to dryness. The
residue was extracted with boiling CHCl3 (50 mL). The
extract was chromatographed on a column with Al2O3
(eluent—CHCl3/CCl4, 3:1). The fraction with Rf 0.8 gave
11a (0.020 g, 10%). The fraction with Rf 0.68 gave 13a.
Subsequent recrystallization from EtOH yielded 13a
(0.015 g, 8%).
1
227–230 8C; H NMR (CDCl3, 250 MHz) d 0.98 (t, JZ
7.3 Hz, 3H, CH2CH2Me), 1.99 (m, 2H, CH2CH2Me), 3.58
(s, 3H, 2-Me), 3.95 (s, 3H, 4-Me), 4.58 (t, JZ7.1 Hz, 2H,
CH2CH2Me), 7.34 (m, 1H, 9-H), 7.50 (d, JZ8.5 Hz, 1H,
8-H), 7.75 (m, 1H, 10-H), 9.49 (d, JZ8.1 Hz, 1H, 11-H);
UV (CHCl3, lmax (log 3)) 279 (4.45), 317 (3.86), 341 (4.16),
354 (4.10), 451 nm (3.52); MS (m/z) 323 (MC). Anal. Calcd
for C17H17N5O2: C, 63.16; H, 5.26; N, 21.67. Found: C,
63.15; H, 5.22; N, 21.70.
3.7.1. 8,80-Bis[2,4-dimethyl-7-propyl-7,8,9,10,11,12-
hexahydrocyclohepta[4,5]pyrrolo[2,3-c]pyrimido[5,4-e]-
pyridazine-1,3(2H,4H)-dione] (13a). Compound 13a was
3.8.2. 7-Butyl-2,4-dimethyl-7,10-dihydrocyclohepta[4,5]-
pyrrolo[2,3-c]pyrimido[5,4-e]pyridazine-1,3(2H,4H)-
dione (19). A stirred suspension of 11b (0.085 g,
0.242 mmol) and DDQ (0.113 g, 0.5 mmol) in benzene
(20 mL) was refluxed and after 40 h of refluxing DDQ
(0.050 g, 0.22 mmol) was added. After 40 h of refluxing
the reaction mixture was concentrated to dryness. The
residue was extracted with boiling CHCl3 (20 mL). The
extract was chromatographed on a column with Al2O3
(eluent—CHCl3/CCl4, 10:1). The following recrystalliza-
tion from EtOH gave 19 (0.040 g, 48%) as dark yellow
1
obtained as bright yellow crystals, mpO340 8C; H NMR
(CDCl3, 300 MHz) d 0.92 (t, JZ7.4 Hz, 6H, CH2CH2Me),
1.29 (m, 4H, 9-H and 10-H), 1.74 (m, 10H, CH2CH2Me,
9-H0, 10-H0 and 11-H), 2.05 (m, 2H, 11-H0), 2.80 (m, 2H,
8-H), 3.55 (s, 6H, 2-Me), 3.97 (s, 6H, 4-Me), 4.11 and 4.69
(both m, 4H, 12-CH2), 4.25 and 5.10 (both m, 4H,
CH2CH2Me); IR (nujol) 1660, 1700 cmK1 (C]O); UV
(CHCl3, lmax (log 3)) 346 (4.28), 356 (4.30), 425 (4.13),
450 nm (3.97); MS (m/z) 340 (1⁄2 MC). Anal. Calcd for
C36H44N10O4: C, 63.53; H, 6.47; N, 20.59. Found: C, 63.55;
H, 6.51; N, 20.61.
1
crystals, mp 272–274 8C; H NMR (CDCl3, 250 MHz) d
1.03 (t, JZ7.3 Hz, 3H, CH2CH2CH2Me), 1.24 (m, 2H,
CH2CH2CH2Me), 1.97 (m, 4H, CH2CH2CH2Me and

O. V. Serduke et al. / Tetrahedron 62 (2006) 652–661
661
3. Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
2631–2666.
10-CH2), 3.58 (s, 3H, 2-Me), 4.00 (s, 3H, 4-Me), 4.80 (t,
JZ7.1 Hz, 2H, CH2CH2CH2Me), 6.92 (d, JZ12.9 Hz, 1H,
11-CH), 7.32 (d, JZ11.8 Hz, 1H, 9-CH), 7.65 (d, JZ
11.8 Hz, 1H, 8-CH), 9.85 (d, JZ12.9 Hz, 1H, 12-CH); IR
(nujol) 1647, 1686 cmK1 (C]O); UV (CHCl3, lmax
(log 3)) 280 (4.32), 332 (4.31), 351 (4.12), 370 (4.15),
389 (4.21), 463 (3.72), 487 nm (3.67); MS (m/z) 351 (MC).
Anal. Calcd for C19H21N5O2: C, 64.96; H, 5.98; N, 19.94.
Found: C, 64.90; H, 6.00; N, 20.00.
4. Chupakhin, O. N.; Beresnev, D. G. Russ. Chem. Rev. 2002, 71,
707–720.
5. Rachin, E. Izvestiya po Khimiya 1988, 21, 69–77.
6. Wood, J. L.; Stoltz, B. M.; Goodman, S. N.; Onwueme, K.
J. Am. Chem. Soc. 1997, 119, 9652–9661.
7. Bobbitt, J. M.; Kulkarni, C. L.; Willis, J. P. Heterocycles 1981,
15, 495–516.
8. The exact nature of oxidative species in reactions under con-
sideration is still questionable. In principle, it can be either AgC
or MnOK4 ions, since both have comparable reductive potentials
[Lide, D. R. CRC Handbook of Chemistry and Physics; 74th ed.,
CRC, 1993–1994; tabl. 8.21–8.23]. Anyway, an appearance of
‘silver mirror’ in the reaction mixtures may serve as indirect
evidence of the participation of AgC ions in the oxidative
processes.
References and notes
1. Gulevskaya, A. V.; Serduke, O. V.; Pozharskii, A. F.; Besedin,
D. V. Tetrahedron 2003, 59, 7669–7679.
2. Gulevskaya, A. V.; Besedin, D. V.; Pozharskii, A. F.; Starikova,
Z. A. Tetrahedron Lett. 2001, 42, 5981–5983.