Purines, pyrimidines, and related fused systems: 19.* Use of S NH methodology for the synthesis of a new heterocyclic system, pyrrolo[3′,2′:3,4]pyrimido[4,5-c]pyridazine

Article abstract of DOI:10.1023/A:1023431504814

Sonogashira cross-coupling of 3-chloro-6,8-dimethylpyrimido[4,5-c] pyridazine-5,7(6H,8H)-dione with terminal alkynes afforded the corresponding 3-(alkyn-1-yl) derivatives. Oxidative animation of the latter compounds with primary alkylamines was accompanie

Full text of DOI:10.1023/A:1023431504814

Russian Chemical Bulletin, International Edition, Vol. 52, No. 2, pp. 441—446, February, 2003
441
Purines, pyrimidines, and related fused systems
19.* Use of SNH methodology for the synthesis
of a new heterocyclic system, pyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridazine
V. V. Gorunenko, A. V. Gulevskayaꢀ, and A. F. Pozharskii
Rostov State University,
7 ul. Zorge, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863 2) 22 3958. Eꢀmail: AGulevskaya@chimfak.rsu.ru
Sonogashira crossꢀcoupling of 3ꢀchloroꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdione with terminal alkynes afforded the corresponding 3ꢀ(alkynꢀ1ꢀyl) derivaꢀ
tives. Oxidative amination of the latter compounds with primary alkylamines was accompaꢀ
nied by heterocyclization to give 6,8ꢀdimethylpyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridazineꢀ
7,9(6H,8H )ꢀdiones.
Key words: 3ꢀchloroꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ5,7(6H,8H)ꢀdione, 1ꢀalkynes,
crossꢀcoupling, Sonogashira reaction, catalysis, palladium complexes, 3ꢀ(alkynꢀ1ꢀyl)ꢀ6,8ꢀ
dimethylpyrimido[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdiones, oxidative amination, 6,8ꢀdimethylꢀ
pyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridazineꢀ7,9(6H,8H )ꢀdiones.
Recently,2 we have reported a new procedure for
Scheme 1
annelation of the pyrrole ring to neutral azines based on
the tandem SNH—SNH process involving the formation of
the C—C and C—N bonds between the πꢀdeficient subꢀ
strate and bifunctional C,Nꢀnucleophile. In particular,
the reaction of 6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdione (1) with aliphatic imines in the presꢀ
ence of an oxidant afforded 1ꢀR1ꢀ2ꢀR2ꢀ3ꢀR3ꢀ6,8ꢀdiꢀ
methylpyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridazineꢀ
7,9(6H,8H )ꢀdiones (2) (Scheme 1). In the present study,
H
we applied the SN methodology3 to the synthesis of deꢀ
rivatives of a previously unknown isomeric heterocyꢀ
clic system, viz., pyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridꢀ
azine 3.
One would expect that 3ꢀalkynylꢀ4ꢀaminopyrimidoꢀ
pyridazines 4 would serve as direct precursors of comꢀ
pounds 3 since it is known that such compounds undergo
cyclization to form the pyrrole ring under the action of
bases4,5 and other catalysts.6—8 We chose 3ꢀchloroꢀ6,8ꢀ
dimethylpyrimido[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdione
(5) as the starting compound for the synthesis of pyridꢀ
azines 4.9 Then we intended to use successively
Sonogashira crossꢀcoupling10 and oxidative amination
because the Cl atom in compound 5 can be replaced with
a CHꢀacid residue,11 whereas pyrimidopyridazinedione 1
is readily aminated at the C(4) atom in an RNH2—oxiꢀ
dant system.12
presence of palladium complexes and catalytic amounts
of CuI and K2CO3 to give 3ꢀ(alkynꢀ1ꢀyl) derivatives 8a—e
in 22—74% yields. The reaction of compound 5 with
volatile trimethylsilylacetylene (7f) was carried out in a
sealed tube in the absence of a solvent with the use of the
Pd2dba3—PPh3 system (dba is dibenzylideneacetone as
the ligand) as the catalyst and Et3N as the base.
It is known that additives of CuI make it possible to
perform such transformations at room temperature.13,14
However, the reaction of compound 5 with alkynes proꢀ
ceeds at a noticeable rate only at 90—100 °C. Apparently,
the reason is that the Cl atom in molecule 5 is insuffiꢀ
We found that chloropyridazine 5 (Scheme 2) reacted
with terminal alkynes 7a—e in DMF under argon in the
* For Part 18, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 422—427, February, 2003.
1066ꢀ5285/03/5202ꢀ441 $25.00 © 2003 Plenum Publishing Corporation

442
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Gorunenko et al.
Scheme 2
Scheme 3
X = Cl (5), OTf (6)
7, 8: R = Ph (a), 4ꢀClC6H4 (b), CH2OH (c), CH2OTHP (d),
nꢀC6H13 (e), TMS (f)
Reagents and conditions: Pd(PPh3)4 or Pd2dba3—PPh3, K2CO3,
CuI, DMF, 90—100 °C, Ar.
Table 1. Characteristics of 3ꢀ(alkynꢀ1ꢀyl)ꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ5,7(6H, 8H )ꢀdiones 8a—f
a
Comꢀ
pound
R
Synthesis Rf
method
τ
Yield
(%)
M.p.
/°С
1H NMR (CDCl3),
IR,
ν/cm–1
UV,
max/nm (logε)
/h
δ (J/Hz)
λ
N—Me H(4)
R
Ring C=O C≡C
8a Ph
A, B, 0.6
C
1
5
74—80 175—176 3.49, 8.22 7.39 (m, 3 Н, Ph);
3.90 7.62 (m, 2 Н, Ph)
1558, 1666, 2218
1585, 1787
1599
1573, 1660, 2270
1586, 1713
1600
295 (4.46);
357 (3.47)
8b 4ꢀClC6H4
A
0.6
22
317—319 3.40,b 7.96 7.67 (d, 2 Н, C6H4,
365 (4.45)
3.79
J = 8.7);
8.19 (d, 2 Н, C6H4,
J = 8.6)
8c CH2OH
A, C 0.1
8
2
32—38 203—205 3.48, 8.13 4.58 (s, 2 H, CH2)
3.88
1554, 1675, 2238
1594, 1728
1648
1558, 1665, 2250
1598 1718
276 (4.30);
349 (3.53)
8d CH2OTHP
B
B
0.5
46
103—105 3.48, 8.14 1.50—2.95 (m, 8 Н,
276 (4.35);
350 (3.54)
3.89
THP); 4.56 (d, 2 Н,
CH2, J = 1.9);
4.90 (m, 1 H, THP)
8e C6H13
0.65 1
47
76—77
3.47, 8.06 0.89 (t, 3 Н, Me,
1572, 1679, 2237
1612 1732
269 (4.29);
355 (3.44)
3.87
J = 6.7);
1.28—1.38 (m, 4 H,
(CH2)3(CH2)2Me);
1.41—1.52 (m, 2 H,
(CH2)2CH2C3H7);
1.60—1.72 (m, 2 H,
CH2CH2C4H9);
2.49 (t, 2 Н,
CH2C5H11, J = 7.0)
8f
TMS
—
0.65 1
71
120—121 3.47, 8.21 0.28 (s, 9 H, SiMe3)
3.87
1572, 1679, 2184
1612 1732
281 (4.37);
347 (3.64)
a Reaction time.
b DMSOꢀd6 was used as the solvent.

Use of SNH methodology for heterocyclization
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
443
ciently mobile because of the electronꢀreleasing effect of
the N atom at position 8. Product 8b was obtained in low
yield due, probably, to its further crossꢀcoupling with the
starting arylacetylene.
compound remained unconsumed). Compounds 8a,d also
did not react with KNH2 under these conditions.
The physicochemical characteristics of paleꢀyellow
compounds 11a—h,j (λmax 365—372 nm) are given in
Table 2. Their IR spectra have absorption bands at
The use of aryl iodides or aryl triflates as the electroꢀ
philic component in the catalytic crossꢀcoupling gave the
best results.15,16 Hence, we prepared triflate 6 by condenꢀ
sation of hydrazinouracil 9 with glyoxylic acid followed
by acylation of pyrimidopyridazinetrione 10 with trifluoroꢀ
methanesulfonic anhydride (Scheme 3). However, crossꢀ
coupling of compound 6 with phenylacetylene and propꢀ
argyl alcohol under the aboveꢀmentioned conditions afꢀ
forded the products in only slightly higher yields (80 and
38%, respectively, compared to 74 and 32% obtained in
the reactions with compound 5).
1
1650—1720 cm–1 (νC=O). The H NMR spectra of these
compounds show a signal for the H(3) proton of the pyrꢀ
role ring at δ 6.81—7.06, which is characteristic of fused
pyrroles.17 It should be noted that the protons of the
αꢀCH2 and αꢀCH groups of the substituent at the N(1)
atom in compounds 11 are deshielded by the C(9)=O
group and are observed at low field (δ 4.73—5.55), whereas
the protons of the terminal Me group of pyrroles 11b,d are,
apparently, shielded by the benzene ring (δ 0.50—0.59).
It is reasonable to assume that the transformation
8 → 11 occurs through spontaneous heterocyclization of
intermediate oꢀaminohetarylacetylenes 4. An analogous
tandem process involving SNHꢀamination followed by inꢀ
tramolecular cyclization under the conditions of the clasꢀ
sical Chichibabin reaction has been described earlier for
3ꢀethynylpyridine.18 However, we do not rule out that the
reaction proceeds through enamine intermediate 12, beꢀ
cause an attempt to perform oxidative amination of
hetarylacetylene 8a with piperidine (Scheme 5) led to the
formation of ketone 15 in 20% yield instead of the exꢀ
pected amino derivative 13. The formation of ketone 15
can be explained only as a result of hydrolysis of enamiꢀ
ne 14. The ability of acetylenes to add amines at the triple
bond giving rise to enamines is well known.19
The structures of substituted acetylenes 8 were conꢀ
1
firmed by UV, IR, and H NMR spectroscopy (Table 1).
Compounds 8 are virtually colorless (λmax 347—365 nm).
Their IR spectra have a band at 2180—2270 cm–1 (νC≡C).
The 1H NMR spectra show singlets of two NMe groups at
δ 3.5 and 3.9 and signals for H(4) at δ 8.0—8.2.
Oxidative amination of 3ꢀ(alkynꢀ1ꢀyl)pyrimidopyridꢀ
azinediones 8a,d—f with primary alkylamines in the presꢀ
ence of AgPy2MnO4 at 0—20 °C afforded 1ꢀR1ꢀ2ꢀR2ꢀ6,8ꢀ
dimethylpyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridaziꢀ
neꢀ7,9(6H,8H )ꢀdiones (11a—i) in 22—85% yields
(Scheme 4). Treatment of trimethylsilylethynyl derivative
8f with propylamine and an oxidant gave not the expected
pyrrole 11i but the product of its desilylation 11j in 22%
yield. An attempt to prepare pyrrole 11k by the reaction of
compound 8f with KNH2 in liquid ammonia and KMnO4
at the temperature from –60 to –55 °C failed (the starting
To summarize, we prepared a series of derivatives of
the new heterocyclic system, viz., pyrrolo[3´,2´:3,4]pyrꢀ
imido[4,5ꢀc]pyridazine 11. Evidently, hetarylacetylenes 8
Scheme 4
11:
R1
R2
a
Et
Ph
b
Pr
Ph
c
Pri
Ph
d
Bu
Ph
e
cycloꢀC6H11
Ph
f
Pr
g
Pr
h
Bu
i
Pr
TMS
j
Pr
H
k
H
H
CH2OTHP nꢀC6H13 nꢀC6H13

Table 2. Characteristics of 1,2ꢀdisubstituted 6,8ꢀdimethylpyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridazineꢀ7,9(6H,8H)ꢀdiones 11a—h,j
Comꢀ
pound
R1
R2
Rf
Yield M.p.
(%) /°С
1H NMR (CDCl3), δ (J/Hz)
IR,
UV,
max/nm
ν/cm–1
λ
N—Me H(3)
R1
R2
(logε)
NCH2(NCH)
Other
Ring C=O
11а
11b
Et
Pr
Ph
Ph
0.45
0.50
62 214—216
61 175—178
3.53
3.98
7.05
7.05
4.86 (q, 2 Н,
J = 7.0)
0.98 (t, 3 Н, Me,
J = 7.0)
7.52 (s, 5 Н, Ph)
7.52 (s, 5 Н, Ph)
1526, 1673, 266 (4.50),
1573, 1700, 325 (3.83),
1633
372 (3.63)
3.53
3.99
4.79 (t, 2 Н,
J = 7.2)
0.50 (t, 3 Н, Me,
J = 7.4);
1545, 1652, 267 (4.53),
1572, 1705, 327 (3.85),
1.37 (m, 2 Н,
СH2СH2Me)
1.32 (d, 6 Н,
CНMe2,
J = 7.0)
0.59 (t, 3 Н, Me,
J = 7.2);
1599
373 (3.65)
11c
11d
Pri
Bu
Ph
Ph
0.43
0.52
41 221—222
85 145—146
3.53
3.97
6.97
7.04
5.55 (sept, 1 Н,
J = 7.0)
7.46—7.48 (m, 3 Н, Ph);
7.55—7.58 (m, 2 Н, Ph)
1545, 1665, 266 (4.50),
1585, 1718, 325 (3.80),
1612
1532, 1652, 267 (4.51),
1572, 1705 328 (3.85),
365 (3.58)
3.53
3.98
4.82 (t, 2 Н,
J = 7.2)
7.52 (s, 5 Н, Ph)
0.80—0.95 (m, 2 Н,
(CH2)2CH2Me);
1.23—1.35 (m, 2 Н,
CH2CH2Et)
1599
372 (3.64)
11e cycloꢀC6H11
Ph
0.40
47 207—209
23 122—123
3.54
3.98
3.56
3.95
6.96
7.06
5.04 (m, 1 Н)
0.80—2.00 (m, 10 Н, 7.44—7.49 (m, 3 Н, Ph);
cycloꢀC6H11 7.53—7.56 (m, 2 Н, Ph)
1545, 1665, 267 (4.51),
1572 1718 327 (3.83)
)
11f
Pr
Pr
CH2OTHP 0.35
0.90 (t, 3 Н, Me, J = 7.3); 1.50—2.00 (m, 8 Н, CH2CH2Me and ТНР); 1573 1660, 325 (3.78)
3.65—3.89 (m, 2 Н, OCH2 ТНР); 4.66—4.96 (m, 5 Н, CH2Et,
OCH ТНР and C(2)CH2)
4.73 (t, 2 Н,
J = 7.2)
1700
11g
C6H13
0.40
59
42
80—81
85—86
3.51
3.94
6.81
6.81
0.90 (t, 3 Н, Me,
0.88 (t, 3 Н, Me,
1545, 1665, 324 (3.75),
1572, 1705, 366 (3.48)
J = 7.2);
J = 7.2); 1.20—1.70
1.75—1.80 (m, 2 Н, (m, 8 H, CH2(CH2)4Me); 1585
CH2CH2Me)
2.76 (t, 3 Н,
CH2(CH2)4Me, J = 7.6)
0.85—0.95 (m, 6 Н, (CH2)3Me and (CH2)5Me); 1585, 1678, 324 (3.77),
11h
11j
Bu
Pr
nꢀC6H13 0.40
3.50
3.93
4.77 (t, 2 Н,
J = 7.6)
1.27—1.37 (m, 6 Н, (CH2)2CH2Me and
(CH2)3(CH2)2Me); 1.40—1.58 (m, 4 Н,
CH2CH2Et and (CH2)2CH2Pr); 1.80
(m, 2 Н, CH2CH2Bu); 2.75 (t, 2 Н,
CH2C5H11, J = 7.6)
1599, 1718 68 (3.50),
1619 464 (2.68)
H
0.20
22 139—140
3.51
7.04
4.78 (t, 2 Н,
0.73 (t, 3 Н, Me,
J = 7.4);
—
1545, 1665, 322 (3.73),
1599 1705 362 (3.49)
3.96 (d, 1 Н, J = 7.2)
J = 3.5);
1.79 (m, 2 Н,
CH2CH2Me)
7.39 a
(d, 1 Н,
J = 3.5)
a The chemical shift of H(2).

Use of SNH methodology for heterocyclization
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
445
Scheme 5
Table 3. Results of elemental analysis of compounds 8a—f
and 11a—h,j
Comꢀ
pound
Molecular
formula
Found
Calculated
(%)
C
H
N
8a
C16H12N4O2
65.90
65.75
58.78
58.81
53.90
53.65
58.35
58.18
64.23
64.00
54.30
54.17
64.54
64.48
65.29
65.33
65.50
65.33
66.34
66.12
67.83
67.87
58.85
58.91
63.60
63.87
64.81
64.69
57.05
57.14
4.05
4.11
3.10
3.37
4.01
4.07
5.70
5.45
6.70
6.67
5.70
5.56
5.09
5.07
5.42
5.44
5.27
5.44
5.57
5.79
5.88
5.91
6.25
6.46
7.45
7.56
7.55
7.82
5.61
5.49
18.97
19.18
17.31
17.15
22.58
22.76
17.04
16.97
18.54
18.67
19.24
19.44
20.76
20.90
20.30
20.06
20.17
20.06
19.17
19.28
17.96
17.99
18.13
18.09
19.73
19.61
18.95
18.87
25.44
25.64
8b
C16H11N4O2Cl
8c
C11H10N4O3
8d
C16H18N4O4
C16H20N4O2
8e
8f
C13H16N4O2Si
11a
11b
11c
11d
11e
11f
11g
11h
11j
C18H17N5O2
C19H19N5O2
C
19H19N5O2
C20H21N5O2
C22H23N5O2
can also be used in the synthesis of other fused polyꢀ
nuclear systems based on pyrimidopyridazinedione 1.
C
19H25N5O4
C19H27N5O2
20H29N5O2
C13H15N5O2
Experimental
C
The IR spectra were recorded on a Specord IRꢀ71 instruꢀ
ment in Nujol mulls. The 1H NMR spectra were measured on
Brukerꢀ250 (250 MHz) and Unityꢀ300 (300 MHz) spectrometers
with Me4Si as the internal standard. The UV spectra were reꢀ
corded on a Specord Mꢀ40 instrument in CHCl3. Chromatoꢀ
graphy was carried out on Al2O3 (Brockmann activity III—IV)
using CHCl3 as the eluent; visualization was carried out with
iodine vapor. The melting points were measured in glass tubes
on a PTP instrument and were not corrected.
90—100 °C under argon (reaction times are given in Table 1)
and then treated as described in the method A.
C. A mixture of compound 6 (0.5 mmol), alkyne 7 (1 mmol),
K2CO3 (1 mmol), Pd(PPh3)4 (0.01 mmol), and CuI (0.01 mmol)
in anhydrous DMF (3 mL) was stirred at 90—100 °C under
argon (reaction times are given in Table 1) and then treated as
described in the method A.
6,8ꢀDimethylꢀ3ꢀ(trimethylsilylethynyl)pyrimido[4,5ꢀc]pyridꢀ
azineꢀ5,7(6H,8H )ꢀdione (8f). A mixture of compound 5 (227 mg,
1 mmol), trimethylsilylacetylene (0.2 mL, 1.2 mmol), Pd2dba3
(20 mg, 0.02 mmol), CuI (10 mg, 0.05 mmol), PPh3 (42 mg,
0.16 mmol), and Et3N (5 mL) was heated in a sealed tube under
argon at 100 °C for 1 h and then treated as described above for
compounds 8a—e.
6,8ꢀDimethylpyrimido[4,5ꢀc]pyridazineꢀ3,5,7(2H,6H,8H )ꢀ
trione (10). A mixture of compound 9 (138 mg, 1 mmol) and
glyoxylic acid (111 mg, 1 mmol) in MeOH (5 mL) was refluxed
for 2 h and concentrated to dryness. The residue was exꢀ
tracted with CHCl3. The extract was concentrated to ∼5 mL
The physicochemical characteristics of the resulting comꢀ
pounds are given in Tables 1 and 2. The results of elemental
analysis are presented in Table 3.
3ꢀ(Alkynꢀ1ꢀyl)ꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdiones (8a—e) (general procedure). A. A mixture of
compound 5 (1 mmol), alkyne 7 (1.5 mmol), K2CO3 (1.5 mmol),
Pd(PPh3)4 (0.02 mmol), and CuI (0.05 mmol) in anhydrous
DMF (3 mL) was stirred at 90—100 °C under argon (reaction
times are given in Table 1) and then concentrated to dryness.
The residue was extracted with CHCl3. The extract was concenꢀ
trated to ∼5 mL and chromatographed on a column with Al2O3
using CHCl3 as the eluent. The paleꢀyellow fraction was colꢀ
lected (Rf are given in Table 1). The product was recrystallized
from MeOH (compound 8b was recrystallized from DMSO).
Compounds 8 were obtained as colorless crystals.
B. A mixture of compound 5 (1 mmol), alkyne 7 (1.5 mmol),
K2CO3 (1.5 mmol), Pd2dba3 (0.02 mmol), PPh3 (0.16 mmol),
and CuI (0.05 mmol) in anhydrous DMF (3 mL) was stirred at
and chromatographed on
a column with Al2O3 using
a CHCl3—MeOH mixture (20 : 1) as the eluent. The colorless

446
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 2, February, 2003
Gorunenko et al.
fraction with Rf 0.5 was collected and concentrated to obtain
compound 10 as colorless crystals in a yield of 112 mg (53%),
m.p. 238—240 °C (from MeCN). IR, ν/cm–1: 3300—3600 (NH);
1782, 1728, 1662 (C=O). 1H NMR (DMSOꢀd6), δ: 3.20 (s, 3 H,
N(8)Me); 3.51 (s, 3 H, N(6)Me); 7.41 (s, 1 H, H(4)); 13.2 (br.s,
disappeared after deuteration, 1 H, NH). Found (%): C, 46.32;
H, 3.59; N, 27.12. C8H8N4O3. Calculated (%): C, 46.15; H, 3.85;
N, 26.92.
6,8ꢀDimethylꢀ3ꢀ(trifluoromethylsulfonyl)pyrimiꢀ
do[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdione (6). Trifluoromethaneꢀ
sulfonic anhydride (0.2 mL, 1.2 mmol) was added portionwise
to a solution of compound 10 (207 mg, 1 mmol) in pyridine
(3 mL) cooled to 0 °C. The reaction mixture was stirred at 0 °C
for 1 h and then at 20 °C for 48 h. Then the reaction mixture was
diluted with water (3 mL) and the precipitate that formed was
filtered off. Compound 6 was obtained as colorless crystals in a
yield of 210 mg (68%), m.p. 159—160 °C (from PriOH). IR,
ν/cm–1: 3106 (C—H arom.); 1772, 1720 (C=O). 1H NMR
(CDCl3), δ: 3.50 (s, 3 H, N(8)Me); 3.89 (s, 3 H, N(6)Me); 8.06
(s, 1 H, H(4)). Found (%): C, 32.00; H, 2.06; N, 16.34.
C9H7F3N4O5S. Calculated (%): C, 31.76; H, 2.05; F, 16.76;
N, 16.47; S, 9.41.
1,2ꢀDisubstituted 6,8ꢀdimethylpyrrolo[3´,2´:3,4]pyrimiꢀ
do[4,5ꢀc]pyridazineꢀ7,9(6H,8H )ꢀdiones (11a—h,j) (general
procedure). A solution of compound 8 (1 mmol) in amine
(30—40 mL) was stirred at 20 °C for 15 min (in the case of
EtNH2, at 0 °C) and then AgPy2MnO4 (1 mmol) was added.
The completion of the reaction was determined chromatographiꢀ
cally. The reaction mixture was concentrated to dryness and the
residue was extracted with CHCl3. The extract was concenꢀ
trated to ∼5 mL and chromatographed on a column with
Al2O3 using CHCl3 as the eluent. The first yellow fraction
was collected and concentrated. The residue was recrystalꢀ
lized from PriOH and compound 11 was obtained as yellow
crystals.
3ꢀBenzoylmethylꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdione (15). A solution of compound 8a (292 mg,
1 mmol) in piperidine (25 mL) was stirred at 20 °C for 15 min
and then AgPy2MnO4 (385 mg, 1 mmol) was added. The reacꢀ
tion mixture was kept at 20 °C for one week and concentrated to
dryness. The residue was extracted with CHCl3. The extract was
concentrated to ∼5 mL and chromatographed on a column with
Al2O3 using CHCl3 as the eluent. The yellow fraction was colꢀ
lected and concentrated to obtain compound 15 as darkꢀyellow
crystals in a yield of 62 mg (20%), m.p. 236—238 °C (from
PriOH). IR, ν/cm–1: 3062 (C—H arom.); 1718, 1692, 1678
(C=O). 1H NMR (DMSOꢀd6), δ: 3.36 (s, 3 H, N(8)Me); 3.73
(s, 3 H, N(6)Me); 4.89 (s, 2 H, CH2); 7.54—8.10 (m, 5 H, Ph);
8.16 (s, 1 H, H(4)). Found (%): C, 62.10; H, 4.36; N, 18.15.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
32338).
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Received April 18, 2002;
C
16H14N4O3. Calculated (%): C, 61.93; H, 4.52; N, 18.06.
in revised form September 11, 2002