Thermal transformations of 7-aryl-1,6-diazabicyclo[4.10]heptanes and 6,13-diarylperhydrodipyridazino-[1,2-a: 1′,2′-d]-1,2,4,5-tetrazines

Article abstract of DOI:10.1007/s10593-008-0120-7

The thermolysis of 7-aryl-1,6-diazabicyclo[4.1.0]heptanes in the absence of 1,3-dipolarophiles leads to dimers of the initially formed azomethineimines, namely, 6,13-diaryloctahydrodipyridazino[1,2-a:1′,2′.

Full text of DOI:10.1007/s10593-008-0120-7

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
THERMAL TRANSFORMATIONS OF
7-ARYL-1,6-DIAZABICYCLO[4.10]HEPTANES
AND 6,13-DIARYLPERHYDRODIPYRIDAZINO-
[1,2-a:1',2'-d]-1,2,4,5-TETRAZINES*
Yu. B. Koptelov and A. I. Ukolov
The thermolysis of 7-aryl-1,6-diazabicyclo[4.1.0]heptanes in the absence of 1,3-dipolarophiles leads to
dimers of the initially formed azomethineimines, namely, 6,13-diaryloctahydrodipyridazino[1,2-a:1',2'-
d]-1,2,4,5-tetrazines The thermolysis of such diaziridines in the presence of N-arylmaleimides leads
predominantly to the trans cycloaddition adducts. The trans adducts are the only products of the
thermolysis in the presence of 2,6-disubstituted N-phenylmaleimides. The cis adducts predominated in
the thermolysis of 6,13-diaryloctahydrodipyridazino[1,2-a:1',2'-d]-1,2,4,5-tetrazines in the presence of
N-arylmaleimides without substituents in the ortho position of the benzene ring.
Keywords: azomethineimine, N-arylmaleimide, 1,6-diazabicyclo[4.1.0]heptane, tetrazine, 1,3-dipolar
cycloaddition.
Azomethineimines are a convenient synthone for obtaining five-membered heterocycles with two
nitrogen atoms. These reagents undergo 1,3-dipolar cycloaddition, permitting the formation of polyfunctional
pyrazole derivatives, including polycyclic systems already with several new chiral sites in a single synthetic step
[1]. Readily available 1,(n+2)-diazabicyclo[n.1.0]alkanes serve as precursors for reactive azomethineimines: the
thermal opening of the diaziridine fragment, for example, in 1,5-diazabicyclo[3.1.0]hexanes, which occurs above
100°C at the carbon–nitrogen bond, leads to unstable cyclic azomethineimines. Under the reaction conditions, these
cyclic species may either isomerize to give the corresponding 2-pyrazolines [2] or, in the presence of active
1,3-dipolarophiles, give products of 1,3-dipolar cycloaddition [3-5]. The steric interactions between the reagent
and substrate in the endo or exo approach of the 1,3-dipolarophile are probably the determining factor in the
steric selectivity of the cycloaddition leading to trans isomers as the major products [6].
In the present work, we studied possible changes in the reactivity and direction of stabilization of the
intermediate labile azomethineimines as well as the steric selectivity of the cycloaddition of N-arylmaleimides
with increasing size of the N,N'-polymethylene bridge in going from 6-aryl-1,5-diazabicyclo[3.1.0]hexanes
studied in our previous work to 7-aryl-1,6-diazabicyclo[4.1.0]heptanes 1a-c obtained according to Kuznetsov
et al. [7].
_______
* Dedicated to the memory of A. A. Potekhin.
__________________________________________________________________________________________
St. Petersburg State University, St. Petersburg 198504, Russia; e-mail: koptelov@JK7283.spbu.edu.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1062-1070, July, 2008. Original article
submitted October 10, 2007.
852
0009-3122/08/4407-0852©2008 Springer Science+Business Media, Inc.

The thermolysis of diaziridines 1a,b in p-xylene for 1 h gave good yields of 6,13-diarylocta-
hydrodipyridazino[1,2-a:1',2'-d]-1,2,4,5-tetrazines 2a,b instead of 1-arylmethyl-1,4,5,6-tetrahydropyridazines
3a and 3b expected by analogy to the thermolysis of 1,5-diazabicyclo[3.1.0]hexanes. Nevertheless, the 1H NMR
spectrum of the reaction mixture obtained in the thermolysis of 1b shows signals for benzylic protons
(4.17 ppm) and imino group protons (6.74 ppm) of 3b present in trace amounts [8]; these signals correspond to
the literature values.
R
R
R
R
N
N
138°C
N
+
–
N
+
N
N
N
N
N
N
R
1a,b
2a,b
3a,b
traces
1–3 а R = Me, b R = H
The stabilization of the azomethineimines formed in the thermal opening of the diaziridine ring in 1a
and 1b by dimerization rather than a [1,4-H] shift was somewhat unexpected since we observed dimerization for
1,5-diazabicyclo[3.1.0]hexanes only in the catalytic opening of the diaziridine fragment [9, 10]. According to
literature data [11, 12], dimer 2b has been obtained in the reaction of benzaldehyde with hexahydropyridazine.
We should note that, under conditions similar to those used for obtained 1a-c, a dimer of the corresponding
azomethineimine, namely, 6,13-bis(4-methoxyphenyl)octahydrodipyridazino[1,2-a:1'2'-d]-1,2,4,5-tetrazine (2c,
R = OMe) was also obtained from anisaldehyde instead of the diazabicycloheptane.
Carrying out the thermolysis of diazabicycloheptanes 1a-c for 40 min in p-xylene at reflux in the
presence of an equimolar amount of N-arylmaleimides 4a-g gave adducts 5a-m and 6a-d in total preparative
yields of 66-91%.
R
R
R
–
O
N
Ar
O
O
138°C
O
1a–c
+
N
+
N
N Ar
N Ar
N
N
4a-g
N
N
O
O
trans-
5a-m
cis-
6a-d
1 a R = Me, b R = H, c R = Br; 4–6 a Ar = 4-MeOC6H4, b Ar = 4-MeC6H4, c Ar = Ph,
d Ar = 4=BrC6H4; 4, 5 e Ar = 2,6-Me2C6H3, f Ar = 2,6-Cl2C6H3, g Ar = 2,4,6-Me3C6H2;
5 h, k Ar = 2,6-Me2C6H3, i, l Ar = 2,6-Cl2C6H3, j, m Ar = 2,4,6-Me3C6H2; 5 a–g R = Me,
h–j R = H, k–m R = Br; 6 a–d R = Me
The relative trans configuration of adduct 5m was established using the NOESY 2D 1H NMR spectrum.
The major through-space interactions between the protons of this compound seen as the corresponding cross
peaks are given in the scheme below. The most important such peak here is observed for the interaction between
the proton at 3.60 ppm and the methyl protons at 2.16 ppm, which is possible only for the trans isomer.
853

The configuration of the remaining cycloaddition products 5a-l and 6a-d was also determined using the
assignments for the 1H NMR signals for adduct 5m. 1H NMR spectroscopy shows that the ratio of the trans and
cis isomers 5a-d/6a-d in the reaction mixture was about 3-4:1 but only 1.5-3:1 for the 6-aryl-1,5-diaza-
bicyclo[3.1.0]hexanes in the presence of the same maleimides [4, 10], which indicates a slight increase in the
steric selectivity with increasing size of the N,N'-polymethylene bridge. On the other hand, the time required for
the complete conversion of starting compounds 1a-c is virtually the same as for the 6-aryl-1,5-diaza-
bicyclo[3.1.0]hexanes.
Br
2.16
H3C
7.38
H
CH3
O
3.34
H
7.38
N
3.60
H
H
H
2.89
CH3
N
O
3.68
N
H
H
2.66
H
2.21
H
3.55
The thermolysis of diaziridines 1a-c in the presence of 2,6-disubstituted N-arylmaleimides 4e-g led to
the exclusive formation of the trans products of 1,3-dipolar cycloaddition. The planes of the benzene and
pyrrole rings in these maleimides are virtually orthogonal. Thus, steric hindrance may arise as the
ortho substituents in the maleimide benzene ring approaches the cyclic azomethinimine. In the case of
Z-configuration of the virtually planar azomethineimine formed, the strong steric interactions between the
ortho substituents in the maleimide and the benzene ring of the azomethineimine upon exo approach of the
dipolarophile should hinder the formation of the cis adduct, while such hindrance probably does not obtain in
the formation of the trans adduct upon endo approach of the dipolarophile (from the side of the polymethylene
bridge), such that the only products of the cycloaddition are the trans adducts.
The thermolysis of azomethineimine dimers 2a-c in the presence of N-arylmaleimides in p-xylene also
lead to products of the 1,3-dipolar cycloaddition but requires more prolonged heating (12 h instead of 40 min).
Inversion of the steric selectivity is noted for the N-arylmaleimides lacking substituents in the ortho position of
the benzene ring. The 1H NMR spectra of the reaction mixtures obtained in the thermolysis of dimers 2a and 2c
in the presence of maleimide 4a indicated predominance of the corresponding cis adducts. On the other hand,
the exclusive formation of trans adduct 5n (R = OMe, Ar = 2,4,6-Me3C6H2) was found in the thermolysis of
dimer 2c in the presence of N-mesitylmaleimide 4g.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Bruker DPX-300 spectrometer at 300 and 75 MHz,
respectively, in CDCl3. The chemical shifts are given relative to the signal of the residual chloroform proton
(7.26 ppm for 1H NMR) or the CDCl3 signal (77.16 for 13C NMR) [13]. The C, H, N analysis was carried out on
a Hewlett-Packard 185B analyzer. The thin-layer chromatographic analysis was carried out on Silufol UV-254
plates with development by UV light or in an iodine chamber. A sample of p-xylene was heated at reflux using a
Dean-Stark trap, then for 2 h with sodium, and distilled. A sample of t-BuOCl was obtained according to Mintz
and Walling [14]. The melting points of diazabicycloheptanes 1b and 1c coincided with the literature data [7].
854

7-(4-Tolyl)-1,6-diazabicyclo[4.1.0]heptane (1a). t-BuOCl (22 mmol) in methanol (10 ml) was added
slowly dropwise to a solution of 1,4-diaminobutane (0.04 mol) in methanol (60 ml) cooled to -10°C. Then,
p-tolualdehyde (20 mmol) was added dropwise over 30 min. The mixture was stirred for an additional 1 h, left
for 24 h in a refrigerator, and filtered through 1 cm Merck 60 (35-70 µm) silica gel. Methanol was removed in
vacuum and 100 ml water was added. The mixture was extracted with three ether portions (30 ml) after
saturating the solution with NaCl. Ether was evaporated off and the residue was recrystallized from ether to give
3.1 g (82%) 1a, mp 72°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.78 (4H, m, (CH2)2); 2.32 (3H, s, CH3); 2.88 (2H,
m, CHN); 3.47 (1H, s, NCHN); 3.50 (2H, m, CHN); 7.13 (2H, d, J = 8, H arom); 7.21 (2H, d, J = 8, H arom).
13C NMR, δ, ppm: 24.7 (CH3); 23.4 (2C, CH3); 51.1 (2C, CH2); 53.8 (CH); 121.3 (2C); 125.0 (2C); 136.7,
137.5. Found, %: C 76.07; H 8.51; N 14.76. C12H16N2. Calculated, %: C 76.55; H 8.57; N 14.88.
Thermolysis of 7-Aryl-1,5-diazabicyclo[4.1.0]heptanes in the Absence of Dipolarophiles (General
Method). A solution of diazabicycloheptane (0.8 mmol) in absolute p-xylene (3 ml) was heated for 1 h at
140°C in an argon stream. The solvent was distilled off in vacuum and the residue was recrystallized from ether.
6,13-Bis(4-methylphenyl)octahydrodipyridazino[1,2-a:1',2'-d]-1,2,4,5-tetrazine (2a) was obtained in
55% yield (77 mg); mp 197°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.48 (8H, m, CH2CH2); 2.14 (4H, m, CHN);
2.35 (6H, s, CH3); 2.46 (4H, m, CHN); 4.03 (2H, s, NCHN); 7.13 (4H, m, H arom); 7.56 (4H, m, H arom).
Found, %: C 76.41; H 8.50; N 14.80. C24H32N4. Calculated, %: C 76.55; H 8.57; N 14.88.
6,13-Diphenyloctahydrodipyridazino[1,2-a:1',2'-d]-1,2,4,5-tetrazine (2b) [11, 12] was obtained in
1
57% yield (65 mg); mp 187°C (244°C [11]). H NMR spectrum, δ, ppm (J, Hz): 1.39 (8H, m, CH2CH2); 2.17
(4H, m, CHN); 2.45 (4H, m, CHN); 4.06 (2H, s, NCHN); 7.31 (8H, m, H arom); 7.69 (2H, m, H arom).
6,13-Bis(4-methoxyphenyl)octahydrodipyridazino[1,2-a:1',2'-d]-1,2,4,5-tetrazine (2c) was obtained
by a procedure similar to the preparation of 1b but the addition of the solution of 4-methoxybenzaldehyde in
methanol (30 ml) to the solution of 1,4-diaminobutane cooled to -12°C was carried out over 1.5 h. After
treatment of the reaction mixture and removal of the solvent, the residue was recrystallized from methanol to
1
give 2.08 g (51%) 2c; mp 210°C. H NMR spectrum, δ, ppm (J, Hz): 1.38 (8H, m, CH2CH2); 2.16 (4H, m,
CHN); 2.46 (4H, m, CHN); 3.81 (6H, s, OCH3); 3.97 (2H, s, NCHN); 6.86 (4H, m, H arom); 7.15 (2H, m,
H arom), 7.58 (2H, m, H arom). Found, %: C 70.58; H 7.93; N 13.69. C24H32N4O2. Calculated, %.: C 70.56;
H 7.90; N 13.71
Thermolysis of 7-aryl-1,6-diazabicyclo[4.1.0]heptanes in the Presence of N-Arylmaleimides
(General Method). N-Arylmaleimide 4a-g (0.75 mmol) was added to a solution of diazabicycloheptane 1a-c
(0.8 mmol) in absolute p-xylene (3 ml) and heated for 1 h at 140°C in an argon stream. The solvent was
removed in vacuum and the residue was subjected to chromatography on a column packed with Merck 60 silica
gel (35-70 µm) using 2:1 hexane–ethyl acetate as the eluent. The reaction was monitored by thin-layer
chromatography; the trans isomers have higher Rf values.
(3aR,10R,10aS)-2-(4-Methoxyphenyl)-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo-
[1,2-a]pyridazine-1,3(2H,3aH)-dione (5a) was obtained in 65% yield (208 mg); mp 159°C. 1H NMR spectrum,
δ, ppm (J, Hz): 1.49-1.69 (4H, m, CH2CH2); 2.23 (1H, t, J = 10, CHN); 2.37 (3H, s, CH3); 2.68 (1H, t, J = 8,
CHN); 2.88 (1H, t, J = 10, CHN); 3.36 (1H, t, J = 7.2, CHC=O); 3.50 (1H, d, J = 3.6, CHN); 3.58 (1H, d,
J = 10, CHN); 3.65 (1H, d, J = 8, CHN); 3.84 (3H, s, OCH3); 6.99 (2H, d, J = 8, H arom); 7.19 (2H, d, J = 7.2,
13
H arom); 7.27 (2H, d, J = 7.2, H arom); 7.38 (2H, d, J = 8, H arom). C NMR spectrum, δ, ppm: 21.5 (CH3);
24.1 (2C, CH2); 53.3 (CH2); 55.6 (CH2); 55.9 (CH); 66.5 (CH); 71.9 (CH); 114.8 (OCH3); 124.7, 128.1 (2C);
129.9 (2C); 135.9 (2C); 138.3 (2C); 159.9; 174.1 (C=O); 176.1 (C=O). Found, %: C 70.42; H 6.85; N 10.56.
C23H25N3O3. Calculated, %.: C 70.57; H 6.44; N 10.73.
(3aR,10S,10aS)-2-(4-Methoxyphenyl)-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo-
[1,2-a]-pyridazine-1,3(2H,3aH)-dione (6a) was obtained in 21% yield (48 mg); mp 139°C. 1H NMR spectrum,
δ, ppm (J, Hz): 1.46-1.79 (4H, m, CH2CH2); 2.06 (1H, m, CHN); 2.34 (3H, s, CH3); 3.02 (1H, d, J = 10, CHN);
855

3.19 (1H, t, J = 10, CHN); 3.40 (1H, d, J = 6.5, CHN); 3.50 (1H, d, J = 6.5, CHN); 3.63 (1H, m, CHN); 3.82
(3H, s, OCH3); 4.25 (1H, m, CHC=O); 6.99 (2H, d, J = 8, H arom); 7.19 (2H, d, J = 7.2, H arom); 7.27 (2H, d,
J = 7.2, H arom); 7.38 (2H, d, J = 8, H arom). 13C NMR spectrum, δ, ppm: 21.7 (CH3); 24.9 (CH2); 50.6 (CH2);
55.9 (CH2); 114.8 (OCH3); 124.6, 127.8 (2C); 129.7 (2C); 132.8 (2C); 138.5 (2C); 159.7; 173.9 (C=O); 174.4
(C=O). Found, %: C 70.20; H 6.00; N 10.79. C23H25N3O3. Calculated ,%: C 70.57; H 6.44; N 10.73.
(3aR,10R,10aS)-2,10-Bis(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyridazine-
1
1,3(2H3aH)-dione (5b) was obtained in 41% yield (69 mg) as an oil. H NMR spectrum, δ, ppm (J, Hz):
1.46-1.79 (4H, m, CH2CH2); 2.06 (1H, m, CHN); 2.34 (3H, s, CH3); 2.19 (3H, s, CH3); 2.69 (1H, t, J = 10,
CHN); 2.89 (1H, d, J = 10, CHN); 3.37 (1H, t, J = 7.2, CHN); 3.63 (1H, m, CHN); 3.80 (1H, m, CHC=O); 4.25
(1H, m, CHC=O); 7.20 (2H, d, J = 8, H arom); 7.28 (2H, d, J = 8.7, H arom); 7.37 (2H, d, J = 8, H arom); 7.62
(2H, d, J = 8.7, H arom).
(3aR,10S,10aS)-2,10-Bis(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyridazine-
1
1,3(2H,3aH)-dione (6b) was obtained in 29% yield (49 mg); mp 148°C. H NMR spectrum, δ, ppm (J, Hz):
1.46-1.79 (4H, m, CH2CH2); 2.06 (1H, m, CHN); 2.19 (3H, s, CH3); 2.34 (3H, s, CH3); 3.02 (1H, d, J = 10,
CHN); 3.18 (1H, t, J = 10, CHN); 3.41 (1H, d, J = 6.5, CHN); 3.63 (1H, m, CHN); 3.80 (1H, m, CHC=O); 4.25
(1H, m, CHC=O); 7.20 (2H, d, J = 8, H arom); 7.28 (2H, d, J = 8.7, H arom); 7.37 (2H, d, J = 8, H arom); 7.62
(2H, d, J = 8.7, H arom). 13C NMR spectrum, δ, ppm: 21.6 (CH3); 21.7 (CH3); 24.9 (CH3); 31.3 (CH2); 50.3
(CH2); 50.6 (CH2); 126.4, 129.3 (2C); 129.7 (2C); 130.1 (2C); 132.7 (2C); 138.2, 138.5, 138.9, 173.8 (C=O);
174.3 (C=O). Found, %: C 73.57; H 6.71; N 11.19. C23H25N3O2. Calculated, %: C 73.43; H 6.56; N 11.33.
(3aR,10R,10aS)-10-(4-Methylphenyl)-2-phenylhexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyridazine-
1
1,3(2H,3aH)-dione (5c) was obtained in 66% yield (190 mg); mp 154°C. H NMR spectrum, δ, ppm (J, Hz):
1.49-1.69 (4H, m, CH2CH2); 2.24 (1H, t, J = 10, CHN); 2.38 (3H, s, CH3); 2.69 (1H, t, J = 8, CHN); 2.90 (1H, d,
J = 10, CHN); 3.38 (1H, t, J = 7.2, CHC=O); 3.60 (1H, d, J = 10, CHN); 3.66 (1H, d, J = 8, CHN); 3.77 (1H, d,
J = 7.2, CHC=O); 7.20 (2H, d, J = 8, H arom); 7.35-7.43 (5H, m, H arom); 7.47-7.52 (2H, m, H arom).
13C NMR spectrum, δ, ppm: 21.6 (CH3); 24.2 (2C, CH2); 53.2 (CH2); 53.4 (CH2); 55.5 (CH); 66.5 (CH); 71.9
(CH); 126.8, 128.2 (2C); 128.9 (2C); 129.9 (2C); 132.0 (2C); 132.0 (2C); 135.9; 138.2; 138.3; 173.8 (C=O);
175.9 (C=O). Found, %: C 73.18; H 6.39; N 11.64. C22H23N3O2. Calculated, %: C 73.11; H 6.41; N 11.63.
(3aR,10S,10aS)-10-(4-Methylphenyl)-2-phenylhexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]-pyridazine-
1
1,3(2H,3aH)-dione (6c) was obtained in 15.6% yield (37 mg); mp 152°C. H NMR spectrum, δ, ppm (J, Hz):
1.49-1.69 (4H, m, CH2CH2); 2.24 (1H, m, CHC=O); 2.34 (3H, s, CH3); 3.03 (1H, d, J = 10, CHN); 3.19 (1H, t,
J = 10, CHN); 3.36 (1H, d, J = 6.5, CHN); 3.47 (1H, d, J = 6.5, CHN); 3.65 (1H, m, CHN); 3.72-3.96 (1H, m,
CHC=O); 7.20 (2H, d, J = 8, H arom); 7.35-7.43 (5H, m, H arom); 7.47-7.52 (2H, m, H arom). 13C NMR
spectrum, δ, ppm: 21.7 (CH3), 24.0 (CH2); 24.9 (CH2); 50.3 (CH2); 50.6 (CH2); 54.8 (CH); 64.7 (CH); 73.2
(CH); 126.6; 128.4 (2C); 128.8 (2C); 129.4 (2C); 129.7 (2C); 131.9, 132.7, 138.5; 173.7 (C=O); 174.2 (C=O).
Found, %: C 73.08; H 6.39; N 11.64. C22H23N3O2. Calculated, %: C 73.11; H 6.41; N 11.63.
(3aR,10R,10aS)-2-(4-Bromophenyl)-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]-
1
pyridazine-1,3(2H,3aH)-dione (5d) was obtained in 68% yield (237 mg); mp 140°C. H NMR spectrum, δ,
ppm (J, Hz): 1.49-1.69 (4H, m, CH2CH2); 2.24 (1H, t, J = 10, CHN); 2.38 (3H, s, CH3); 2.69 (1H, t, J = 8,
CHN); 2.88 (1H, t, J = 10, CHN); 3.40 (1H, t, J = 7.2, CHC=O); 3.57 (1H, d, J = 10, CHN); 3.62 (1H, d,
J = 7.2, CHN); 3.77 (1H, d, J = 8, CHC=O); 7.20 (2H, d, J = 8, H arom); 7.28 (2H, d, J = 8.7, H arom); 7.37
(2H, d, J = 8, H arom); 7.62 (2H, d, J = 8.7, H arom). 13C NMR spectrum, δ, ppm: 21.6 (CH3); 24.0 (CH2); 24.2
(CH2); 53.1 (CH2); 53.3 (CH2); 55.6 (CH), 66.4 (CH); 71.9 (CH); 122.8; 128.2 (2C); 128.4 (2C); 129.9 (2C);
131.0 (2C); 132.6, 135.7, 138.4, 173.4 (C=O); 175.5 (C=O). Found, %: C 60.14; H 5.36; N 9.89. C22H22BrN3O2.
Calculated, %: C 60.01; H 5.04; N 9.54.
(3aR,10S,10aS)-2-(4-Bromophenyl)-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo-
1
[1,2-a]pyridazine-1,3(2H,3aH)-dione (6d) was obtained in 24% yield (66 mg); mp 154°C. H NMR spectrum,
δ, ppm (J, Hz): 1.62 (4H, m, CH2CH2); 2.06 (1H, m, CHN); 2.34 (3H, s, CH3); 3.02 (1H, d , J = 10, CHN); 3.16
856

(1H, t, J = 10, CHN); 3.42 (1H, m, CHN); 3.64 (1H, m, CHN); 3.82 (1H, m, CHC=O); 4.26 (1H, m, CHC=O);
7.20 (2H, d, J = 8, H arom); 7.28 (2H, d, J = 8.7, H arom); 7.37 (2H, d, J = 8, H arom); 7.62 (2H, d, J = 8.7,
13
H arom). C NMR spectrum, δ, ppm: 21.6 (CH3); 24.0 (CH2); 24.2 (CH2); 53.1 (CH2); 53.3 (CH2); 55.6 (CH);
66.4 (CH); 71.9 (CH); 122.8; 128.2 (2C); 128.4 (2C); 129.9 (2C); 131.0 (2C); 132.6; 135.7; 138.4; 173.4 (C=O);
175.5 (C=O). Found, %: C 60.33; H 5.19; N 9.76. C22H22BrN3O2, Calculated, %: C 60.01; H 5.04; N 9.54.
(3aR,10R,10aS)-2-(2,6-Dimethylphenyl)-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo-
[1,2-a]pyridazine-1,3(2H,3aH)-dione (5e) was obtained in 66% yield (205 mg), mp 137°C. 1H NMR spectrum,
δ, ppm (J, Hz): 1.46-1.79 (4H, m, CH2CH2); 2.09 (3H, s, CH3); 2.24 (3H, s, CH3); 2.27 (1H, m, CHN); 2.36 (3H,
s, CH3); 2.68 (1H, t, J = 8, CHN); 2.93 (1H, t, J = 10, CHN); 3.42 (1H, t, J = 7.2, CHC=O); 3.57 (1H, d, J = 10,
CHN); 3.63 (1H, d, J = 7.2, CHN); 3.72 (1H, d, J = 7.2, CHC=O); 7.15 (2H, t, J = 7, H arom); 7.19 (2H, d,
J = 8, H arom); 7.23 (1H, d, J = 8, H arom); 7.39 (2H, d, J = 8, H arom). 13C NMR spectrum, δ, ppm: 18.1
(CH3); 18.2 (CH3); 21.5 (CH3); 24.1 (CH2); 24.3 (CH2); 51.2 (CH2); 53.7 (CH2); 55.3 (CH); 66.8 (CH); 72.3
(CH); 128.2 (2C); 128.8 (2C); 128.9 (2C); 129.8 (2C); 136.0; 136.3; 136.7; 138.3 (2C); 173.8 (C=O); 175.9
(C=O). Found, %: C 74.20; H 7.00; N 10.79. C24H27N3O2. Calculated, %: C 74.01; H 6.99; N 10.79.
(3aR,10R,10aS)-2-(2,6-Dichlorophenyl)-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo-
[1,2-a]pyridazine-1,3(2H,3aH)-dione (5f) was obtained in 70% yield (240 mg), mp 150°C. 1H NMR spectrum,
δ, ppm (J, Hz): 1.49-1.69 (4H, m, CH2CH2); 2.24 (1H, m, CHN); 2.32 (3H, s, CH3); 2.67 (1H, t, J = 8, CHN);
2.91 (1H, t, J = 10, CHN); 3.36 (1H, t, J = 7.2, CHC=O); 3.56 (1H, d, J = 10, CHN); 3.62 (1H, d, J = 7.2,
CHC=O); 3.69 (1H, d, J = 7.2, CHN); 7.19 (2H, d, J = 7.2, H arom); 7.37 (1H, t, J = 3, H arom); 7.39 (2H, d,
13
J = 2, H arom); 7.45 (1H, d, J = 7.2, H arom); 7.47 (1H, d, J = 8, H arom). C NMR spectrum, δ, ppm: 21.5
(CH3); 24.1 (CH2); 24.3 (CH2); 53.6 (CH2); 53.8 (CH2); 55.3 (CH); 66.7 (CH); 71.7 (CH); 122.4; 127.3 (2C);
129.3 (2C); 129.7 (2C); 129.8, 129.9 (2C); 132.3 (2C); 136.2, 138.3, 173.6 (C=O); 175.9 (C=O). Found, %:
C 61.42; H, 4.85; N 9.56. C22H21Cl2N3O2. Calculated, %: C 61.40; H 4.92; N 9.76.
(3aR,10R,10aS)-2-Mesityl-10-(4-methylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyrida-
1
zine-1,3(2H,3aH)-dione (5g) was obtained in 74% yield (238 mg); mp 142°C. H NMR spectrum, δ, ppm
(J, Hz): 1.46-1.79 (4H, m, CH2CH2); 2.05 (3H, s, CH3); 2.20 (3H, s, CH3); 2.22 (1H, m, CHN); 2.32 (3H, s,
CH3); 2.37 (3H, s, CH3); 2.68 (1H, t, J = 8, CHN); 2.93 (1H, t, J = 10, CHN); 3.41 (1H, t, J = 7.2, CHC=O);
3.57 (1H, d, J = 10, CHN); 3.63 (1H, d, J = 7.2, CHN); 3.70 (1H, d, J = 7.2, CHC=O); 6.97 (2H, m, H arom);
13
7.19 (2H, d, J = 8, H arom); 7.30 (2H, d, J = 8, H arom). C NMR spectrum, δ, ppm: 18.1 (CH3); 21.5 (CH3);
24.1 (CH3); 24.4 (CH3); 53.7 (CH2); 55.3 (CH); 66.8 (CH); 72.3 (CH); 127.4 (2C); 128.2; 129.6 (2C); 129.8;
135.9 (2C); 136.3; 138.2 (2C); 139.7; 173.9 (C=O); 176.1 (C=O). Found, %: C 74.20; H 7.00; N 10.79.
C25H29N3O2. Calculated, %: C 74.41; H 7.24; N 10.41.
(3aR,10R,10aS)-2-(2,6-Dimethylphenyl)-10-phenylhexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyrida-
1
zine--1,3(2H,3aH)-dione (5h) was obtained in 72% yield (216 mg); mp 139°C. H NMR spectrum, δ, ppm
(J, Hz): 1.49-1.69 (4H, m, CH2CH2); 2.09 (3H, s, CH3); 2.22 (1H, t, J = 10, CHN); 2.25 (3H, s, CH3); 2.69 (1H,
t, J = 8, CHN); 2.95 (1H, d, J = 10, CHN); 3.44 (1H, t, J = 7.2, CHC=O); 3.57 (1H, d, J = 10, CHN); 3.68 (1H,
d, J = 7.2, CHN); 3.72 (1H, d, J = 7.2, CHC=O); 7.16 (2H, t, J = 6.5); 7.25 (2H, d, J = 8, H arom); 7.32 (1H, d,
J = 7.2, H arom); 7.39 (2H, t, J = 7.2, H arom); 7.51 (2H, d, J = 6.5, H arom). 13C NMR spectrum, δ, ppm: 18.1
(CH3); 18.2 (CH3); 24.1 (CH2); 24.3 (CH2); 53.7 (CH2); 55.3 (CH); 66.8 (CH); 72.4 (CH); 128.5; 128.8 (2C);
129.0 (2C); 129.2 (2C); 129.8 (2C); 136.3; 136.7; 139.2; 173.6 (C=O); 175.9 (C=O). Found, %: C 73.59; H
6.79; N 10.91. C23H25N3O2. Calculated, %: C 73.57; H 6.71; N 11.19.
(3aR,10R,10aS)-2-(2,6-Dichlorophenyl)-10-phenylhexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyrida-
1
zine-1,3(2H,3aH)-dione (5i) was obtained in 75% yield (249 mg); mp 131°C. H NMR spectrum, δ, ppm
(J, Hz): 1.49-1.69 (4H, m, CH2CH2); 2.25 (1H, t, J = 8, CHN); 2.68 (1H, t, J = 8, CHN); 2.91 (1H, d, J = 10,
CHN); 3.47 (1H, t, J = 7.2, CHC=O); 3.57 (1H, d, J = 10, CHN); 3.68 (1H, d, J = 7.2, CHN); 3.76 (1H, d,
J = 7.2, CHC=O); 7.19 (2H, d, J = 8, H arom); 7.37 (2H, d, J = 8, H arom); 7.39 (2H, d, J = 8, H arom);
857

13
7.46 (2H, t, J = 8, H arom). C NMR spectrum, δ, ppm: 23.5 (CH2); 23.7 (CH2); 52.9 (CH2); 53.2 (CH2); 54.9
(CH); 66.3 (CH); 71.3 (CH); 127.7, 128.4 (2C); 128.5 (2C); 129.3 (2C); 130.9 (2C); 134.4; 134.8; 135.1; 171.7
(C=O); 173.6 (C=O). Found, %: C 60.68; H 4.84; N 9.92. C21H19Cl2N3O2; Calculated, %: C 60.59; H 4.60;
N 10.09.
(3aR,10R,10aS)-2-Mesityl-10-phenylhexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyridazine-
1
1,3(2H,3aH)- dione (5j) was obtained in 75% yield (233 mg); mp 130°C. H NMR spectrum, δ, ppm (J, Hz):
1.49-1.69 (4H, m, CH2CH2); 2.05 (3H, s, CH3); 2.20 (3H, s, CH3); 2.25 (1H, t, J = 10, CHN); 2.32 (3H, s, CH3);
2.69 (1H, t, J = 8, CHN); 2.94 (1H, t, J = 10, CHN); 3.42 (1H, t, J = 7.2, CHC=O); 3.67 (1H, d, J = 7.2, CHN);
3.71 (1H, d, J = 7.2, CHC=O); 6.97 (2H, m, H arom); 7.33 (1H, d, J = 7.2, H arom); 7.38 (2H, t, J = 7.2,
13
H arom); 7.51 (2H, d, J = 7.2, H arom). C NMR spectrum, δ, ppm: 17.4 (CH3); 17.5 (CH3); 20.9 (CH3); 23.6
(CH2); 23.8 (CH2); 53.1 (CH2); 53.2 (CH2); 54.7 (CH); 66.2 (CH); 71.8 (CH); 126.8; 127.7 (2C); 128.6 (2C);
129.0 (2C); 129.2; 135.3; 135.7; 173.2 (C=O); 175.5 (C=O). Found, %: C 74.09; H 6.97; N 10.71. C24H27N3O2.
Calculated, %: C 74.01; H 6.99; N 10.79.
(3aR,10R,10aS)-10-(4-Bromophenyl)-2-(2,6-dimethylphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo-
[1,2-a]pyridazine-1,3(2H,3aH)-dione (5k) was obtained in 73% yield (265 mg); mp 146°C. 1H NMR spectrum,
δ, ppm (J, Hz): 154-1.79 (4H, m, CH2CH2); 2.23 (3H, s, CH3); 2.24 (3H, s, CH3); 2.68 (1H, t, J = 8, CHN); 2.91
(1H, t, J = 10, CHN); 3.37 (1H, t, J = 7.2, CHC=O); 3.52 (1H, d, J = 10, CHN); 3.63 (1H, d, J = 7.2, CHN);
3.71 (1H, d, J = 7.2, CHC=O); 7.16 (2H, m, H arom); 7.17 (2H, d, J = 6, H arom); 7.24 (1H, d, J = 8, H arom);
13
7.51 (2H, d, J = 8, H arom). C NMR spectrum, δ, ppm: 18.1 (CH3); 18.2 (CH3); 24.0 (CH2); 24.2 (CH2); 53.6
(CH); 53.8 (CH2); 55.3 (CH2); 66.7 (CH); 71.7 (CH); 122.4; 128.8 (2C); 129.0 (2C); 129.9 (2C); 132.3 (2C);
136.2; 136.5; 138.2; 173.4 (C=O); 173.4 (C=O). Found, %: C 60.70; H 5.95; N 9.15. C23H24BrN3O2. Calculated,
%: C 60.80; H 5.32; N 9.25.
(3aR,10R,10aS)-10-(4-Bromophenyl)-2-(2,6-dichlorophenyl)hexahydropyrrolo[3'4':3,4]pyrazolo-
[1,2-a]pyridazine-1,3(2H,3aH)-dione (5l) was obtained in 74% yield (293 mg); mp 151°C. 1H NMR spectrum,
δ, ppm (J, Hz): 1.46-1.79 (4H, m, CH2CH2); 2.27 (1H, m, CHN); 2.68 (1H, t, J = 8, CHN); 2.90 (1H, t, J = 10,
CHN); 3.42 (1H, t, J = 7.2, CHC=O); 3.57 (1H, d, J = 10, CHN); 3.69 (1H, d, J = 7.2, CHN); 3.77 (1H, d,
J = 7.2, CHC=O); 7.35 (2H, d, J = 8, H arom); 7.41 (2H, d, J = 8, H arom); 7.45 (2H, d, J = 8, H arom); 7.50
(2H, d, J = 6.5, H arom); 7.53 (2H, d, J = 8, H arom). 13C NMR spectrum, δ, ppm: 24.0 (CH2); 24.2 (CH2); 53.6
(CH); 55.5 (CH); 66.7 (CH); 122.5; 128.2 (2C); 129.0 (2C); 129.1 (2C); 130.0 (2C); 131.6; 132.3 (2C); 134.9;
135.2 (2C); 137.9; 172.0 (C=O); 174.0 (C=O). Found, %: C 50.62; H 3.78; N 8.16. C21H18BrCl2N3O2.
Calculated, %: C 50.93; H 3.66; N 8.49.
(3aR,10R,10aS)-10-(4-Bromophenyl)-2-mesitylhexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyrida-
1
zine-1,3(2H,3aH)-dione (5m) was obtained in 77% yield (288 mg); mp 147°C. H NMR spectrum, δ, ppm
(J, Hz): 1.49-1.69 (4H, m, CH2CH2); 2.02 (3H, s, CH3); 2.16 (3H, s, CH3); 2.21 (1H, m, CHN); 2.30 (3H, s,
CH3); 2.66 (1H, t, J = 8, CHN); 2.89 (1H, t, J = 10, CHN); 3.34 (1H, t, J = 7.2, CHC=O); 3.55 (1H, d, J = 10,
CHN); 3.60 (1H,d , J = 7.2, CHC=O); 3.68 (1H, d, J = 7.2, CHN); 6.94 (1H, s, H arom); 6.96 (1H, s, H arom);
13
7.38 (2H, d, J = 8, H arom); 7.49 (2H, d, J = 8, H arom). C NMR spectrum, δ, ppm: 18.0 (CH3); 18.1 (CH3);
21.5 (CH3); 24.1 (CH2); 24.3 (CH2); 53.6 (CH); 66.7 (CH); 71.7 (CH); 122.4 (2C); 129.8 (2C); 129.9; 132.3;
135.8 (2C); 136.2 (2C); 138.3; 139.8; 173.6 (C=O); 175.9 (C=O). Found, %: C 61.66; H 5.70, N 8.73.
C24H26BrN3O2. Calculated, %: C 61.54; H 5.60; N 8.97.
Thermolysis of Tetrazines 2a-c in the Presence of N-Arylmaleimides. N-Arylmaleimide (0.8 mmol)
was added to a solution of tetrazine (0.4 mmol) in absolute p-xylene (3 ml) and heated for 12 h at 140°C in an
argon stream. After removal of the solvent, the residue was recrystallized from ether.
(3aR,10R,10aS-2-Mesityl-10-(4-methoxyphenyl)hexahydropyrrolo[3',4':3,4]pyrazolo[1,2-a]pyridazine-
1
1,3(2H,3aH)-dione (5n) was obtained in 85% yield (284 mg); mp 125°C. H NMR spectrum, δ, ppm (J, Hz):
1.46-1.79 (4H, m, CH2CH2); 2.05 (3H, s, CH3); 2.19 (3H, s, CH3); 2.22 (1H, t, J = 10, CHN); 2.32 (3H, s, CH3);
2.67 (1H, t, J = 8, CHN); 2.92 (1H, t, J = 10, CHN); 3.39 (1H, t, J = 7.2, CHC=O); 3.57 (1H, d, J = 10,
858

CHN); 3.63 (1H, d, J = 7.2, CHN); 3.70 (1H, d, J = 7.2, CHC=O); 3.83 (3H, s, OCH3); 6.91 (2H, d, J = 8,
13
H arom); 6.94 (1H, s, H arom); 6.96 (1H, s, H arom); 7.42 (2H, d, J = 8, H arom). C NMR spectrum, δ, ppm:
18.0 (CH3); 18.1 (CH3); 21.5 (CH3); 24.13 (CH3); 24.36 (CH2); 24.9 (CH2); 50.3 (CH2); 50.6 (CH2); 54.8 (CH);
64.7 (CH); 73.2 (CH); 126.6; 128.4 (2C); 128.8 (2C); 129.4 (2C); 129.7 (2C); 131.9; 132.7; 138.5; 173.9 (C=O);
176.2 (C=O). Found, %: C 72.01; H 6.49; N 10.34. C25H29N3O3, Calculated, %: C 71.57; H 6.97; N 10.02.
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