Nucleophilic substitution and lipophilicity - Structure relations in methylazolopyridazines

Article abstract of DOI:10.1135/cccc20051372

Syntheses of methyl[1,2,4]triazolo- or methyltetrazolopyridazine isomers, their separation and nucleophilic substitution with morpholine, dimethylamine and hydrazine have been described. The lipophilicity of the azolopyridazines has been measured and rela

Full text of DOI:10.1135/cccc20051372

1372
Katrusiak, Ratajczak-Sitarz, Skierska, Zinczenko:
NUCLEOPHILIC SUBSTITUTION AND LIPOPHILICITY – STRUCTURE
RELATIONS IN METHYLAZOLOPYRIDAZINES
b
a2
Anna KATRUSIAKa1,*, Małgorzata RATAJCZAK-SITARZ , Urszula SKIERSKA and
a3
Wiktoria ZINCZENKO
a
Department of Pharmacy, Poznań University of Medical Sciences,
Grunwaldzka 6, 60-780 Poznań, Poland; e-mail: akatrus@amp.edu.pl, uskiersk@amp.edu.pl,
1
2
3
wzinczen@amp.edu.pl
b
Department of Crystal Chemistry, Adam Mickiewicz University,
Grunwaldzka 6, 60-780 Poznań, Poland; e-mail: sitarz@amu.edu.pl
Received February 23, 2005
Accepted Jun e 2, 2005
Syn th eses of m eth yl[1,2,4]triazolo- or m eth yltetrazolopyridazin e isom ers, th eir separation
an d n ucleoph ilic substitution with m orph olin e, dim eth ylam in e an d h ydrazin e h ave been
described. Th e lipoph ilicity of th e azolopyridazin es h as been m easured an d related to th e
n um ber an d sites of th e m eth yl substituen ts. Th e structures of n ew m eth ylated azolo-
pyridazin es h ave been ch aracterized by 1H NMR, MS spectra, an d X-ray diffraction .
Keywords: Nitrogen h eterocycles; Triazolopyridazin es; Tetrazolopyridazin es; Azolopyridazin es;
Lipoph ilicity; X-ray diffraction .
Azolopyridazin es possess a versatile biological activity. Th ey are applied as
m edicin es, for exam ple in th erapy of bron ch ial diseases1. Th e pyridazin e
rin g is in m olecules of m an y biologically active com poun ds of broad activi-
ties, such as in an ticon vulsan ts or sedatives2. Our prelim in ary tests on rats
sh owed a positive effect of a series of azolopyridazin es for lowerin g blood
pressure with out affectin g th e h eart rate3. Meth yl substituen ts can ch an ge
ph arm aceutical activity (cf. m orph in e an d codein e). It is also kn own th at
th e an tih yperten sive activity of 5-m eth ylpyridazin on e derivatives is con sid-
erably stron ger th an th eir lower h om ologues with out 5-m eth yl, wh ich are
used as vasodilator/β-adren oceptor an tagon ists4. In fact th e decreased size
of on e alkyl group an d in creased size of an oth er are likely to en h an ce th e
required property. Such m odification s of m olecular structure are term ed
m eth ylen e sh uffle an d h ave been used to m odify th e h ydroph obicity of
com poun ds. In creased lipoph ilicity facilitates pen etration of drugs in to th e
cen tral n ervous system , e.g. h exobarbiton e with h ypn otic an d an tiepileptic
activity5. Meth yl substituen ts in pyridazin e or azole rin g in azolopyrid-
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20051372

Structure Relations in Methylazolopyridazines
1373
azin es in crease th eir stability. In our search for n ew active ph arm aceutical
drugs based on azolopyridazin es, th eir m eth yl derivatives were syn th esized.
In X-ray diffraction study of five m eth ylpyridazin e derivatives th eir crystal
structures h ave been determ in ed to establish th e site of th e m eth yl substi-
tuen t in th e pyridazin e rin g, th eir in teraction s an d association .
RESULTS AND DISCUSSION
Syntheses and Molecular Structures of Methyl Derivatives of Azolopyridazine
6-Ch loro-7-m eth yl- (3), 6-ch loro-8-m eth yl- (4), 6-ch loro-3,7-dim eth yl- (5)
an d 6-ch loro-3,8-dim eth yl[1,2,4]triazolo[4,3-b]pyridazin e (6) as well as
6-ch loro-7-m eth yl- (7) an d 6-ch loro-8-m eth yltetrazolo[1,5-b]pyridazin e (8)
h ave been obtain ed by m ultistep syn th eses startin g from citracon ic an -
h ydride wh ich , con den sed with h ydrazin e h ydrate an d ch lorin ated with
POCl3, gave 3,6-dich loro-4-m eth ylpyridazin e (1). Th e presen ce of th e m eth yl
group at C-4 differen tiates th e ch lorin e atom s at C-3 an d C-6. Th e reaction
of com poun d 1 with a 50% aqueous solution of h ydrazin e h ydrate, givin g
th e 6-ch loro-3-h ydrazin o-4-m eth ylpyridazin e (2b) as th e m ain product, h as
already been described6. We h ave n oticed th at th e treatm en t of 1 with
eth an olic solution of 99% h ydrazin e h ydrate in m olar ratio 1:1 yields
3-ch loro-6-h ydrazin o-4-m eth ylpyridazin e (2a) as a precipitate. Th e filtrate
was used in th e reaction with an excess of h ydrazin e h ydrate an d a m ixture
of com poun ds 2a an d 2b was obtain ed. Th e routin e separation of th ese
NH2
N N
HN
RCOOH or
NaNO2
X
H3C
H3C
N
N
N
N
R = H, CH3
Cl
H3C
Cl
Cl
N
N
4, 6, 8
2b
Cl
Cl
Cl
1
H3C
RCOOH or
NaNO2
H3C
N
N
N
N
R = H, CH3
X
Compound
3, 4
X
HN
NH2
N N
CH
CCH3
N
5, 6
3, 5, 7
2a
7, 8
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1374
Katrusiak, Ratajczak-Sitarz, Skierska, Zinczenko:
a
b
FIG. 1
a A fragm en t of th e O–H···N h ydrogen -bon ded ch ain of m olecules 2a an d water; b arran ge-
m en t of m olecules 2a in th e crystal lattice projected alon g th e crystal [100] direction . Th e h y-
drogen bon ds are sh own as dash ed lin es. Th e th erm al ellipsoids h ave been drawn at 50% prob-
ability level
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Structure Relations in Methylazolopyridazines
1375
com poun ds by colum n ch rom atograph y proved un successful. By applyin g
th e best m obile solution ph ase (aceton e–h exan e) 3-ch loro-6-(isopropyl-
iden eh ydrazin o)-5-m eth ylpyridazin e (2c) was isolated. So a m ixture of
com poun ds 2a an d 2b was used for cyclization reaction s by treatm en t with
form ic acid, acetic acid or sodium n itrite. On ly 6-ch loro-7-m eth yltetrazolo-
[1,5-b]pyridazin e (7), wh ich precipitated directly from th e reaction m ixture,
could be isolated, wh ile th e m ixture of 7-m eth yl (7) an d 8-m eth yl (8) deriv-
atives rem ain ed in solution . Th e m ixtures of th e correspon din g m eth yl-
azolopyridazin es (3 an d 4, 5 an d 6, 7 an d 8) were separated by colum n
ch rom atograph y (Sch em e 1).
a
b
FIG. 2
a On e of two sym m etry-in depen den t m olecules 4; b th e arran gem en t of m olecules 4 in th e
crystal lattice, projected alon g th e crystal [100] direction . Th e th erm al ellipsoids are plotted at
50% probability level
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1376
Katrusiak, Ratajczak-Sitarz, Skierska, Zinczenko:
Com poun d 2a crystallizes as a m on oh ydrate, wh ere two water-m ediated
h ydrogen bon ds (N(4)···O(1W) 2.892(8) Å an d N(1)···O(1Wi) 2.898(2) Å; su-
perscript “i” den otes th e sym m etry code for obtain in g th e in teractin g atom
from th e origin al atom ic list: 2 – x, y – 1/2, 3/2 – z) form ch ain s alon g crys-
tal axis (y), sh own in Fig. 1. As expected, th e pyridazin e rin g an d attach ed
atom s form a plan ar system . Th e pyridazin e rin g an d th e azolopyridazin e
fragm en t are plan ar with in experim en tal errors (root m ean square devia-
tion s of th e fitted atom s are 0.0023–0.0079 an d 0.0057–0.0103 Å, respec-
tively).
Th e m olecular structure of com poun d 4 h as been determ in ed by X-ray
diffraction . Th e fused pyridazin e–triazole system is plan ar with in m easure-
m en t error (Fig. 2), an d th e m olecular strain s due to th e fusion affect th e
bon d len gth an d valen cy an gles (see Table I).
Isolated com poun ds 3–8 (iden tified by NMR, m ass spectroscopy, an d
X-ray diffraction ) were subjected to n ucleoph ilic substitution s. Th e treat-
m en t of com poun ds 3–8 with m orph olin e, dim eth ylam in e or h ydrazin e
h ydrate in eth an ol gave products (9–26) as precipitates (Sch em e 2). Th e
1
structure of com poun ds 9–26 was con firm ed by H NMR an d MS spectra. It
N
N
N
N
R2
R1
R2
R1
X
X
N
N
Nu/EtOH
N
N
Nu
Cl
9–26
3–8
Com p. R1
R2
H
X
Nu
Com p. R1
R2
X
Nu
9
10
11
12
13
14
15
16
17
CH3
CH
C4H8NO
C4H8NO
C4H8NO
C4H8NO
C4H8NO
C4H8NO
C2H6N
18
19
20
21
22
23
24
25
26
H
CH3
CCH3
N
C2H6N
C2H6N
C2H6N
N2H3
H
CH3 CH
CH3
H
H
CH3
H
H
CCH3
CH3
H
N
CH3 CCH3
CH3
H
CH
CH
CCH3
CCH3
N
CH3
H
H
N
CH3
H
N2H3
CH3
H
N
CH3
H
N2H3
CH3
H
CH
CH3
H
N2H3
CH3 CH
CCH3
C2H6N
CH3
H
N2H3
CH3
H
C2H6N
CH3
N
N2H3
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Structure Relations in Methylazolopyridazines
1377
TABLE I
Bon d len gth s (in Å) an d an gles (in °). Th e atom labellin g is sh own in Figs 1a, 2a, 3a, an d 4a.
Bold values in dicate n arrower en docyclic valen cy an gles at m eth yl substituted atom s
2a
4
4′
5
7
C11–C3
1.734(7)
1.423(11)
1.335(8)
1.400(8)
1.336(9)
1.366(7)
1.305(8)
1.512(9)
1.355(9)
1.722(2)
1.414(3)
1.355(3)
1.424(3)
1.375(3)
1.357(3)
1.305(3)
1.494(3)
1.317(3)
1.377(3)
1.296(4)
1.362(3)
114.0(2)
119.1(2)
111.9(2)
126.9(2)
119.9(2)
115.8(2)
118.2(2)
127.3(2)
1.730(2)
1.417(3)
1.359(3)
1.424(3)
1.369(3)
1.371(3)
1.294(3)
1.486(4)
1.320(3)
1.390(3)
1.302(3)
1.351(3)
114.2(2)
118.9(2)
111.8(2)
126.9(2)
120.3(2)
115.3(2)
118.5(2)
127.2(2)
1.723(3)
1.433(4)
1.367(4)
1.406(4)
1.389(4)
1.366(3)
1.303(4)
1.501(4)
1.311(4)
1.397(4)
1.304(4)
1.361(4)
113.1(2)
119.1(3)
113.1(3)
127.8(3)
116.1(3)
119.6(3)
117.4(3)
126.0(3)
121.9(3)
122.0(3)
1.713(2)
1.433(4)
1.348(4)
1.396(3)
1.343(3)
1.345(3)
1.294(3)
1.494(3)
1.324(3)
1.342(3)
1.295(3)
1.344(3)
113.8(2)
118.9(2)
112.2(2)
127.3(2)
116.0(3)
119.5(2)
117.1(2)
128.0(2)
121.2(3)
122.8(3)
C3–C4
C4–C5
C5–C6
C6–N1
N1–N2
N2–C3
C4(C5)–C7
C6–N3
N3–N4
N4–C8(N5)
C8(N5)–N1
C11–C3–N2
C11–C3–C4
N1–N2–C3
N2–C3–C4
C3–C4–C5
C4–C5–C6
C5–C6–N1
C6–N1–N2
C3–C4–C7
C5–C4–C7
C4–C5–C7
C6–C5–C7
C5–C6–N3
N1–C6–N3
C6–N3–N4
N3–N4–C8(N5)
N4–C8(N5)–N1
C8(N5)–N1–C6
C8(N5)–N1–N2
N1–C8–C9
N4–C8–C9
115.2(6)
120.0(6)
119.5(7)
124.8(7)
115.1(7)
119.7(7)
123.1(6)
117.8(6)
121.6(7)
123.3(7)
123.9(2)
120.3(2)
132.0(2)
109.8(2)
106.4(2)
108.6(2)
109.9(2)
105.3(2)
127.4(2)
125.3(2)
119.4(2)
131.9(2)
109.5(2)
106.8(2)
108.1(2)
110.2(2)
105.4(2)
127.4(2)
119.4(6)
117.5(6)
124.0(7)
133.3(3)
109.3(3)
106.6(3)
109.0(3)
109.0(3)
106.1(3)
128.0(3)
123.5(3)
127.5(3)
135.7(3)
107.2(2)
106.0(2)
112.3(2)
104.7(2)
109.8(2)
122.2(2)
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

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Katrusiak, Ratajczak-Sitarz, Skierska, Zinczenko:
h as been observed th at in th e 1H NMR spectrum of 7-m eth ylazolopyrid-
azin es th e sign al of proton at C-8 appears at ca. 8.00 ppm , wh ereas in th e
1H NMR spectrum of 8-m eth ylazolopyridazin es th at at C-7 gave a sign al at
ca. 7.00 ppm . Th is sh ift facilitates th e iden tification of th e respective iso-
m ers. In each 1H NMR spectrum a lon g-ran ge couplin g between th e
C-m eth yl group an d h ydrogen atom at n eigh bourin g C-7(C-8) h as been ob-
served (see Experim en tal). Th e m agn itude of th is couplin g is of about
0.8–1.4 Hz. Com poun ds 3–12 an d 21–26 were described, an d th eir ch arac-
teristics h as been com pared with th e literature data in th e Experim en tal.
Th e h ypoten sive activity of th e 6-m orph olin o derivatives of 7- an d
8-m eth ylazolopyridazin es (9–14) are bein g in vestigated, wh ereas th e
6-h ydrazin o derivatives (21–26) h ave been used for furth er syn th eses,
aim ed at fusion of a secon d azole rin g, an d for studyin g th e azide-tetrazole
tautom erism con version s7.
Th e crystal structures of com poun ds 5 an d 7 are sh own in Figs 3 an d 4,
respectively. Again , th e triazolopyridazin e an d tetrazolopyridazin e rin g sys-
tem s are plan ar; bon d an gles m ain ly accom m odate th e strain s due to th e
fusion of pyridazin e with a five-m em bered rin g (Table I). It can be observed
th at sm aller, but equally system atic ch an ges of th e bon d an gles are in duced
by th e m eth yl substituen t. Th e m eth yl substitution decreases th e en do-
cyclic bon d an gle at th e substituted atom by about 4° (Table I).
Lipophilicity Measurement8
Th e lipoph ilicity of m eth ylazolopyridazin es 3–8 h as been m easured an d
com pared with th ose of th e azolopyridazin es with out m eth yl substituen t at
C-7 or C-8: 6-ch loro[1,2,4]triazolo[4,3-b]pyridazin e (A), 6-ch loro-3-m eth yl-
[1,2,4]triazolo[4,3-b]pyridazine (B) and 6-chlorotetrazolo[1,5-b]pyridazine (C).
Th e results are listed in Table II. Th e RM values h ave been calculated from
th e experim en tal Rf values accordin g to th e form ula RM = log [(1/Rf) – 1].
TABLE II
Lipoph ilicities of azolopyridazin es (A, C) an d th eir m eth yl derivatives (B, 3–8)
Com poun d
A
B
3
4
5
6
C
7
8
Rf
0.71
0.70
0.68
0.63
0.59
0.61
0.72
0.62
0.59
RM
–0.39
–0.35
–0.33
–0.23
–0.16
–0.19
–0.41
–0.21
–0.16
A, 6-ch loro[1,2,4]triazolo[4,3-b]pyridazin e; B, 6-ch loro-3-m eth yl[1,2,4]triazolo[4,3-b]pyrid-
azin e; C, 6-ch lorotetrazolo[1,5-b]pyridazin e
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Structure Relations in Methylazolopyridazines
1379
a
b
FIG. 3
a A perspective ORTEP drawin g of m olecule 5 viewed perpen dicularly to th e azolopyridazin e
fragm en t; b th e arran gem en t of m olecules 5 in th e crystal lattice, projected alon g th e crystal
[100] direction . Th e th erm al ellipsoids h ave been drawn at 50% probability level
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1380
Katrusiak, Ratajczak-Sitarz, Skierska, Zinczenko:
a
b
FIG. 4
a A perspective ORTEP drawin g of m olecule 7 viewed perpen dicularly to th e least-squares
plan e; b th e arran gem en t of m olecules 7 in th e crystal structure, projected alon g th e crystal
[100] direction . Th e th erm al ellipsoids are sh own at 50% probability level; th e h ydrogen atom s
are represen ted as sm all circles
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Structure Relations in Methylazolopyridazines
1381
High er an d/or positive RM values in dicate com poun ds m ore lipoph ilic th an
th ose com poun ds ch aracterized by th e lower an d/or n egative RM values.
A correlation between th e lipoph ilicity an d th e n um ber of m eth yl substitu-
en ts in th e azolopyridazin e is apparen t. Th e un m eth ylated com poun ds A
an d C h ave th e lowest RM m agn itudes, an d th e h igh est RM m agn itudes are
th ose of dim eth ylated 5 an d 6 an d m on om eth ylated 7 an d 8.
EXPERIMENTAL
X-ray Diffraction
Th e diffraction data h ave been collected on a Kum a KM4-CCD diffractom eter, λ = 0.71073 Å
(5, 7, 2c) an d on a Kum a KM4 diffractom eter, λ = 1.54178 Å (2a, 4), at room tem perature.
Th e structures of four com poun ds (2a, 4, 5, 7) h ave been solved by direct m eth ods9 an d re-
fin ed on F2 by program SHELXL97 10. Th e H atom s at N(3) an d N(4) in 2a, an d all H atom s
in 4 were located usin g differen ce Fourier m aps an d refin ed with isotropic tem perature fac-
tors, all th e oth er H atom s were calculated from th e m olecular geom etry an d th eir Uiso h ave
been related to th erm al vibration s of th eir carriers. Th e crystals of com poun d 2c h ad th e
form of very sm all th in n eedles an d were of low quality. Neverth eless, we m an aged to col-
lect diffraction data an d to solve th e structure10
. Th e skeleton s of two sym m etry-
in depen den t m olecules h ave been obtain ed, but th e m easured in ten sities were n ot accurate
en ough to refin e th e structure. Th e crystal data an d details of th e X-ray an alysis are given in
Table III. CCDC 262568 (for 2a), 262569 (for 4), 262570 (for 5), an d 262571 (for 7) con tain
th e supplem en tary crystallograph ic data for th is paper. Th ese data can be obtain ed free of
ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from th e Cam bridge Crystallo-
graph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam .ac.uk).
Ch em ical Syn th eses
Meltin g poin ts were determ in ed on a Boetius apparatus an d were un corrected. 1H NMR spec-
tra were recorded on a Varian MH-300 spectrom eter in CDCl3 or trifluoroacetic acid (TFA),
with TMS as a in tern al stan dard. Th e lipoph ilicity m easurem en t was don e accordin g to th e
literature8. Separation was carried out on precoated RP-TLC plates of RP-18 F 254s (Merck,
Darm stadt, Germ an y). Th e polar m obile ph ase was a m ixture m eth an ol–water (8:2). Each
com poun d was dissolved in m eth an ol (1 m g/m l) an d th e solution (5 µl) was applied on to
th e plate with aid of a HAMILTON syrin ge. After developm en t th e plates were dried an d th e
spots were localized in UV 254 n m . Citracon ic h ydrazide was obtain ed from citracon ic an -
h ydride an d h ydrazin e h ydrate11. 3,6-Dich loro-4-m eth ylpyridazin e was obtain ed from
citracon ic h ydrazide usin g POCl3 11. 3-Ch loro-6-h ydrazin o-4(5)-m eth ylpyridazin es (2b an d
2a) were syn th esized from 3,6-dich loro-4-m eth ylpyridazin e (1) an d h ydrazin e h ydrate6.
3-Chloro-6-(isopropylidenehydrazino)-5-methylpyridazine (2c). M.p. 142–143 °C (aceton e). For
C8H11ClN4 (198.7) calculated: 48.37% C, 5.58% H, 28.20% N; foun d: 48.25% C, 5.62% H,
28.05% N. 1H NMR (CDCl3): 2.11 (s, 3 H, CH3-C=N); 2.16 (s, 3 H, CH3-C=N); 2.39 (d, 3 H,
J = 0.9, CH3-C=C); 8.06 (q, 1 H, J = 0.9, H-4). MS, m/z: 198.4.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

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Katrusiak, Ratajczak-Sitarz, Skierska, Zinczenko:
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Structure Relations in Methylazolopyridazines
1383
3-Chloro-6-hydrazino-4-methylpyridazine (2a). Com poun d 1 (1.63 g, 0.01 m ol) an d h ydra-
zin e h ydrate (0.5 g, 0.01 m ol; 99%) were stirred at room tem perature for 24 h . Th e precipi-
tate was recrystallized from eth an ol, m .p. 158–160 °C (lit.6 gives 158 °C), yield 63%.
Triazolopyridazin es 3–6. Gen eral Procedure
A solution of 15.86 g (0.1 m ol) of a m ixture 2a an d 2b was refluxed in 100 m l of form ic or
acetic acid for 1 h . Th e reaction m ixture was cooled, poured in to water an d extracted with
ch loroform . Th e extracts were wash ed with water, dried (an h ydrous MgSO4) an d evaporated.
Th e azolopyridazin es 3–6 were separated by colum n ch rom atograph y usin g th e 3:2 aceton e–
h exan e m ixture as a m obile ph ase. Th e colum n (ID 2 cm , len gth 50 cm ) was filled with
silica gel (0.040–0.063 m m , 230–400 m esh ASTM, Merck).
6-Chloro-7-methyl[1,2,4]triazolo[4,3-b]pyridazine (3). In form ic acid. Wh ite crystals, yield
87%, m .p. 158–160 °C (eth an ol) (lit.6 gives 157.5–158 °C). For C6H5ClN4 (168.6) calculated:
42.75% C, 2.99% H, 33.23% N; foun d: 42.69% C, 3.01% H, 33.18% N. 1H NMR (CDCl3):
2.52 (d, 3 H, J = 1.374, CH3-C=C); 7.98 (q, 1 H, J = 1.4, H-8); 9.03 (s, 1 H, H-3). MS, m/z:
168.5.
6-Chloro-8-methyl[1,2,4]triazolo[4,3-b]pyridazine (4). In form ic acid. Ligh t beige crystals,
yield 62%, m .p. 135–136 °C (eth an ol) (lit.6 gives 134–134.5 °C). For C6H5ClN4 (168.6) calcu-
lated: 42.75% C, 2.99% H, 33.23% N; foun d: 42.71% C, 3.06% H, 33.25% N. 1H NMR
(CDCl3): 2.77 (d, 3 H, J = 1.4, CH3-C=C); 6.98 (q, 1 H, J = 1.4, H-7); 9.03 (s, 1 H, H-3). MS,
m/z: 168.5.
6-Chloro-3,7-dimethyl[1,2,4]triazolo[4,3-b]pyridazine (5). In acetic acid. Ligh t brown crystals,
yield 90%, m .p. 188–189 °C (eth an ol) (lit.12 gives 183–184 °C). For C7H7ClN4 (182.6) calcu-
lated: 46.04% C, 3.86% H, 30.68% N; foun d: 46.10% C, 3.92% H, 30.70% N. 1H NMR
(CDCl3): 2.48 (d, 3 H, J = 1.1, CH3-C=C); 2.79 (s, 3 H, CH3-C=N); 7.89 (q, 1 H, J = 1.1, H-8).
MS, m/z: 182.0.
6-Chloro-3,8-dimethyl[1,2,4]triazolo[4,3-b]pyridazine (6). In acetic acid. Ligh t brown crystals,
yield 68%, m .p. 166–168 °C (eth an ol) (lit.12 gives 170–171 °C). For C7H7ClN4 (182.6) calcu-
lated: 46.04% C, 3.86% H, 30.68% N; foun d: 46.00% C, 3.82% H, 30.71% N. 1H NMR
(CDCl3): 2.09 (d, 3 H, J = 1.1, CH3-C=C); 2.72 (s, 3 H, CH3-C=N); 6.92 (q, 1 H, J = 1.1, H-7).
MS, m/z: 182.0.
6-Ch loro-7-m eth yltetrazolo[1,5-b]pyridazin e (7) an d
6-Ch loro-8-m eth yltetrazolo[1,5-b]pyridazin e (8)
To a solution of 15.86 g (0.1 m ol) of a m ixture of 2a an d 2b in 100 m l of water an d 150 m l
of acetic acid, a solution of 4.5 g of sodium n itrite in 70 m l of water was added dropwise at
0 °C. Com poun d 7 precipitated durin g th e addition . Beige crystals, yield 93%, m .p. 139 °C
(eth an ol) (lit.6 gives 140.5 °C). For C5H4ClN5 (169.6) calculated: 35.41% C, 2.38% H,
41.30% N; foun d: 35.40% C, 2.33% H, 41.28% N. 1H NMR (CDCl3): 2.64 (d, 3 H, J = 1.4,
CH3-C=C); 8.23 (q, 1 H, J = 1.4, H-8). MS, m/z: 169.0.
Th e residue (m ixture of com poun ds 7 an d 8) was poured in to water an d extracted with
ch loroform . Th e extracts were wash ed with water, dried (an h ydrous MgSO4) an d evaporated.
Th e tetrazolopyridazin es 7 an d 8 were separated by colum n ch rom atograph y usin g th e 3:2
aceton e–h exan e m ixture as a m obile ph ase. Th e colum n (ID 2 cm , len gth 50 cm ) was filled
with silica gel (0.040–0.063 m m , 230–400 m esh ASTM, Merck). Com poun d 8: beige crystals,
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yield 61%, m .p. 100–101 °C (eth an ol) (lit.6 gives 107 °C). For C5H4ClN5 (169.6) calculated:
35.41% C, 2.38% H, 41.30% N; foun d: 35.38% C, 2.35% H, 41.32% N. 1H NMR (CDCl3):
2.45 (d, 3 H, J = 0.8, CH3-C=C); 7.43 (q, 1 H, J = 0.8, H-7). MS, m/z: 169.0.
6-Substituted Azolopyridazin es 9–26. Gen eral Procedure
Azolopyridazin e (0.01 m ol) with a th reefold excess of m orph olin e (9–14), dim eth ylam in e
(15–20) or 99% h ydrazin e h ydrate (21–26) in 30 m l of an h ydrous eth an ol was refluxed for
8 h . After coolin g, th e precipitate was filtered off an d recrystallized from eth an ol.
7-Methyl-6-morpholino[1,2,4]triazolo[4,3-b]pyridazine (9). Beige crystals, yield 79%, m .p.
157–158 °C (lit.13 gives 172 °C). For C10H13N5O (219.2) calculated: 54.78% C, 5.98% H,
31.94% N; foun d: 54.76% C, 6.01% H, 31.92% N. 1H NMR (CDCl3): 2.51 (d, 3 H, J = 1.1,
CH3-C=C); 3.28–4.05 (m , 8 H, m orph olin e); 7.83 (q, 1 H, J = 1.1, H-8); 8.88 (s, 1 H, H-3).
MS, m/z: 219.0.
8-Methyl-6-morpholino[1,2,4]triazolo[4,3-b]pyridazine (10). Beige crystals, yield 65%, m .p.
172–174 °C (lit.14 gives 177–180 °C). For C10H13N5O (219.2) calculated: 54.78% C, 5.98% H,
31.94% N; foun d: 54.74% C, 5.96% H, 31.91% N. 1H NMR (CDCl3): 2.65 (d, 3 H, J = 1.1,
CH3-C=C); 3.22–3.88 (m , 8 H, m orph olin e); 6.74 (q, 1 H, J = 1.1, H-7); 8.88 (s, 1 H, H-C3).
MS, m/z: 219.0.
3,7-Dimethyl-6-morpholino[1,2,4]triazolo[4,3-b]pyridazine (11). Beige crystals, yield 82%,
m .p. 197–199 °C (lit.13 gives 160–174 °C). For C11H15N5O (233.3) calculated: 56.64% C,
6.48% H, 30.02% N; foun d: 56.60% C, 6.51% H, 30.11% N. 1H NMR (CDCl3): 2.40 (d, 3 H,
J = 1.1, CH3-C=C); 2.72 (s, 3 H, CH3-C=N); 3.23–3.87 (m , 8 H, m orph olin e); 7.71 (q, 1 H, J =
1.1, H-8). MS, m/z: 233.0.
3,8-Dimethyl-6-morpholino[1,2,4]triazolo[4,3-b]pyridazine (12). Beige crystals, yield 88%,
m .p. 215–216 °C (lit.14 gives 212–213 °C). For C11H15N5O (233.3) calculated: 56.64% C,
6.48% H, 30.02% N; foun d: 56.66% C, 6.53% H, 30.09% N. 1H NMR (CDCl3): 2.60 (d, 3 H,
J = 1.1, CH3-C=C); 2.67 (s, 3 H, CH3-C=N); 3.02–3.56 (m , 8 H, m orph olin e); 6.71 (q, 1 H, J =
1.1, H-7). MS, m/z: 233.0.
7-Methyl-6-morpholinotetrazolo[1,5-b]pyridazine (13). W h ite crystals, yield 64%, m .p.
163–165 °C. For C9H12N6O (220.2) calculated: 49.08% C, 5.49% H, 38.16% N; foun d:
49.10% C, 5.53% H, 38.19% N. 1H NMR (CDCl3): 2.54 (d, 3 H, J = 1.4, CH3-C=C); 3.39–3.93
(m , 8 H, m orph olin e); 7.99 (q, 1 H, J = 1.4, H-8). MS, m/z: 220.0.
8-Methyl-6-morpholinotetrazolo[1,5-b]pyridazine (14). W h ite crystals, yield 61%, m .p.
142–145 °C. For C9H12N6O (220.2) calculated: 49.08% C, 5.49% H, 38.16% N; foun d:
49.12% C, 5.43% H, 38.14% N. 1H NMR (CDCl3): 2.32 (d, 3 H, J = 1.4, CH3-C=C); 3.39–3.93
(m , 8 H, m orph olin e); 6.99 (q, 1 H, J = 1.4, H-7). MS, m/z: 220.0.
6-Dimethylamino-7-methyl[1,2,4]triazolo[4,3-b]pyridazine (15). Wh ite crystals, yield 79%,
m .p. 83–85 °C. For C8H11N5 (177.2) calculated: 54.22% C, 6.26% H, 39.52% N; foun d:
54.20% C, 6.25% H, 39.58% N. 1H NMR (CDCl3): 2.43 (d, 3 H, J = 1.4, CH3-C=C); 2.93 (s,
6 H, (CH3)2-N); 7.71 (q, 1 H, J = 1.4, H-8); 8.82 (s, 1 H, H-3). MS, m/z: 177.1.
6-Dimethylamino-8-methyl[1,2,4]triazolo[4,3-b]pyridazine (16). Wh ite crystals, yield 79%,
m .p. 208–210 °C. For C8H11N5 (177.2) calculated: 54.22% C, 6.26% H, 39.52% N; foun d:
54.26% C, 6.21% H, 39.50% N. 1H NMR (CDCl3): 2.64 (d, 3 H, J = 1.4, CH3-C=C); 3.16 (s,
6 H, (CH3)2-N); 6.66 (q, 1 H, J = 1.4, H-7); 8.77 (s, 1 H, H-3). MS, m/z: 177.1.
6-Dimethylamino-3,7-dimethyl[1,2,4]triazolo[4,3-b]pyridazine (17). Wh ite crystals, yield 84%,
m .p. 139–141 °C. For C9H13N5 (191.2) calculated: 56.53% C, 6.85% H, 36.62% N; foun d:
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Structure Relations in Methylazolopyridazines
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56.59% C, 6.80% H, 36.58% N. 1H NMR (CDCl3): 2.41 (d, 3 H, J = 1.1, CH3-C=C); 2.70 (s,
3 H, CH3-C=N); 2.93 (s, 6 H, (CH3)2-N); 7.66 (q, 1 H, J = 1.1, H-8). MS, m/z: 191.2.
6-Dimethylamino-3,8-dimethyl[1,2,4]triazolo[4,3-b]pyridazine (18). Wh ite crystals, yield 80%,
m .p. 69 °C. For C9H13N5 (191.2) calculated: 56.53% C, 6.85% H, 36.62% N; foun d: 56.57% C,
6.81% H, 36.65% N. 1H NMR (CDCl3): 2.62 (d, 3 H, J = 1.4, CH3-C=C); 2.68 (s, 3 H,
CH3-C=N); 3.13 (s, 6 H, (CH3)2-N); 6.62 (q, 1 H, J = 1.4, H-C7). MS, m/z: 191.2.
6-Dimethylamino-7-methyltetrazolo[1,5-b]pyridazine (19). Wh ite crystals, yield 60%, m .p.
143–145 °C. For C7H10N6 (178.2) calculated: 47.18% C, 5.66% H, 47.16% N; foun d: 47.21% C,
5.68% H, 47.23% N. 1H NMR (CDCl3): 2.54 (d, 3 H, J = 1.4, CH3-C=C); 3.08 (s, 6 H,
(CH3)2-N); 7.90 (q, 1 H, J = 1.4, H-8). MS, m/z: 178.0.
6-Dimethylamino-8-methyltetrazolo[1,5-b]pyridazine (20). Wh ite crystals, yield 61%, m .p.
142–144 °C. For C7H10N6 (178.2) calculated: 47.18% C, 5.66% H, 47.16% N; foun d: 47.23% C,
5.60% H, 47.19% N. 1H NMR (CDCl3): 2.31 (d, 3 H, J = 1.1, CH3-C=C); 3.14 (s, 6 H,
(CH3)2-N); 6.61 (q, 1 H, J = 1.1, H-7). MS, m/z: 178.0.
6-Hydrazino-7-methyl[1,2,4]triazolo[4,3-b]pyridazine (21). Wh ite crystals, yield 90%, m .p.
278–280 °C (lit.6 gives 265 °C). For C6H8N6 (164.2) calculated: 43.90% C, 4.91% H, 51.19% N;
foun d: 43.95% C, 4.98% H, 51.21% N. 1H NMR (CF3COOH-d6): 2.46 (d, 3 H, J = 1.4,
CH3-C=C); 4.23 (2 H, NH2); 6.58 (q, 1 H, J = 1.4, H-7); 8.28 (1 H, NH); 9.12 (s, 1 H, H-3).
MS, m/z: 164.0.
6-Hydrazino-8-methyl[1,2,4]triazolo[4,3-b]pyridazine (22). Wh ite crystals, yield 68%, m .p.
245–248 °C (lit.15 gives 242 °C). For C6H8N6 (164.2) calculated: 43.90% C, 4.91% H, 51.19% N;
foun d: 43.94% C, 4.95% H, 51.14% N. 1H NMR (CDCl3): 2.43 (d, 3 H, J = 1.1, CH3-C=C);
3.83 (2 H, NH2); 7.72 (q, 1 H, J = 1.1, H-8); 8.28 (1 H, NH); 8.92 (s, 1 H, H-3). MS, m/z:
164.0.
6-Hydrazino-3,7-dimethyl[1,2,4]triazolo[4,3-b]pyridazine (23). Ligh t brown crystals, yield
88%, m .p. 313–314 °C (lit.15 gives 256 °C). For C7H10N6 (178.2) calculated: 47.18% C, 5.66% H,
47.16% N; foun d: 47.21% C, 5.69% H, 47.19% N. 1H NMR (CDCl3): 2.17 (d, 3 H, J = 1.4,
CH3-C=C); 2.56 (s, 3 H, CH3-C=N); 3.36 (2 H, NH2); 7.72 (q, 1 H, J = 1.4, H-8); 8.08 (1 H,
NH). MS, m/z: 178.0.
6-Hydrazino-3,8-dimethyl[1,2,4]triazolo[4,3-b]pyridazine (24). Ligh t brown crystals, yield
72%, m .p. 238–239 °C (lit.15 gives 243 °C). For C7H10N6 (178.2) calculated: 47.18% C, 5.66% H,
47.16% N; foun d: 47.23% C, 5.68% H, 47.13% N. 1H NMR (CDCl3): 2.41 (d, 3 H, J = 1.1,
CH3-C=C); 2.66 (s, 3 H, CH3-C=N); 3.87 (2 H, NH2); 6.52 (q, 1 H, J = 1.4, H-7); 8.38 (1 H,
NH). MS, m/z: 178.0.
6-Hydrazino-7-methyltetrazolo[1,5-b]pyridazine (25). Ligh t pin k crystals, yield 83%, m .p.
274–277 °C (lit.16 gives 285–287 °C). For C5H7N7 (165.2) calculated: 36.36% C, 4.27% H,
59.37% N; foun d: 36.30% C, 4.31% H, 59.39% N. 1H NMR (CF3COOH-d6): 2.67 (d, 3 H, J =
1.4, CH3-C=C); 4.11 (2 H, NH2); 8.42 (q, 1 H, J = 1.4, H-8). MS, m/z: 165.0.
6-Hydrazino-8-methyltetrazolo[1,5-b]pyridazine (26). Ligh t pin k crystals, yield 58%, m .p.
247–248 °C (lit.16 gives 247–248 °C). For C5H7N7 (165.2) calculated: 36.36% C, 4.27% H,
59.37% N; foun d: 36.32% C, 4.33% H, 59.31% N. 1H NMR (CDCl3): 2.48 (d, 3 H, J = 0.9,
CH3-C=C); 4.01 (2 H, NH2); 7.43 (q, 1 H, J = 0.9, H-7); 8.23 (1 H, NH). MS, m/z: 165.0.
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