Reactions of tetrachloropyridazine with aliphatic nitrogen nucleophiles

Article abstract of DOI:10.1002/jhet.5570450114

(Chemical Equation Presented) Nucleophilic aromatic substitution reactions of tetrachloropyridazine with a series of aliphatic primary and secondary amines led selectively to products arising from replacement of chlorine at the 4-position in all cases. Th

Full text of DOI:10.1002/jhet.5570450114

Jan-Feb 2008
143
Reactions of Tetrachloropyridazine with Aliphatic Nitrogen
Nucleophiles
Graham Pattison,a Graham Sandford,a* Emma V.B. Wallace,a Dmitry S. Yufit,b Judith
A.K. Howard,b John A. Christopherc and David D. Millerc
a Department of Chemistry, University of Durham, South Road, Durham, UK DH1 3LE
b Chemical Crystallography, Department of Chemistry, University of Durham, South Road, Durham, UK DH1 3LE
c GlaxoSmithKline, R&D Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire,
SG1 2NY, U.K.
Received March 20, 2007
N
N
Cl
R2
R1
H
N
N
N
Cl
N
N
Cl
N
+
N
H
Cl
Cl
Cl
Cl
Cl
Cl
R1R2NH
N
N
N
Cl
Cl
N
N
N
Nucleophilic aromatic substitution reactions of tetrachloropyridazine with a series of aliphatic primary
and secondary amines led selectively to products arising from replacement of chlorine at the 4-position in
all cases. The structures of the products were unambiguously confirmed by X-ray crystallography.
Substitution occurs at the most activated site para to ring nitrogen, despite the possible steric hindrance to
substitution by adjacent chlorine atoms, reflecting the activating influence of ring nitrogen meta to the site
of attack. N,N'-Dimethylethylene diamine gave a mixture of [6,6] ring fused products following initial
substitution at the 4-position.
J. Heterocyclic Chem., 45, 143 (2008).
excellent scaffolds for the synthesis of many pyridazine
derivatives. For example, all four chlorine atoms attached
to the pyridazine ring could, potentially, be displaced by a
sequence of, for instance, nucleophilic substitution,
dechlorolithiation, and palladium catalysed coupling
processes. However, the utility of tetrachloropyridazine,
and, indeed, all other perchlorinated heteroaromatic
systems, as a scaffold has been hampered by the almost
total lack of chemistry reported for this system. At first
sight this is perhaps surprising for such a simple and
potentially valuable molecule, but the chemistry of
perchlorinated derivatives has, in general, not been
developed to any great extent because of a previous lack
of effective, definitive structural probes. However, the
advent of rapid X-ray crystallography should now allow
the field to make significant progress.
Tetrachloropyridazine should react efficiently with
nucleophiles because of the presence of the four chlorine
atoms that decrease electron density in the ring. In this
paper, we aim to unambiguously establish the outcome of
reactions between tetrachloropyridazine and a represen-
tative sample of aliphatic nitrogen centred nucleophiles
with varying steric demands to make an initial assessment
of the potential utility of tetrachloropyridazine as a
scaffold for wider synthetic application and to establish
fundamental principles of nucleophilic substitution
reactions of perchloro-heteroaromatic systems.
INTRODUCTION
Although pyridazines are a structurally simple class of
heterocycles, many derivatives possess very useful
biological activity and the life science industries have
employed various polysubstituted pyridazine systems for
applications ranging from herbicides to anthelmintic agents
[1]. In general, pyridazine systems are synthesized from
reaction of hydrazine with an appropriate acyclic dicarbonyl
derivative [1-3] which, although very successful, can limit
the range of functionalities present on the pyridazine ring.
There is great interest in developing efficient and selective
methodology for the synthesis of low molecular weight poly-
functional heterocyclic systems for use in drug discovery
programmes [4-6]. The application of polyfunctional 'core
scaffolds' [7,8], that is, a heterocycle bearing several
functional groups, to the synthesis of many analogues of a
particular biologically active heterocyclic molecule using
Rapid Analogue Synthesis (RAS) techniques [7,8], is an
established part of the 'hit-to-lead' medicinal chemistry
process. Furthermore, the concept that small heterocycles
are 'privileged structures' [9,10] and generally fall within the
Lipinski parameters [11], has provided further stimulus for
the development of methodology for the synthesis of
multisubstituted small-ring heterocycles.
In this context, perchlorinated heterocycles [12], such
as tetrachloropyridazine, could, in principle, act as

144
G. Pattison, G. Sandford, E. V. B. Wallace, D. S. Yufit, J. A. K. Howard,
J. A. Christopher and D. D. Miller
Vol 45
RESULTS AND DISCUSSION
confirmed that in all cases substitution occurs selectively
at the 4-position.
Reaction between tetrachloropyridazine 1 and a range
of aliphatic nitrogen centred nucleophiles 2a-f (2
equivalents) was carried out in acetonitrile and the results
are collated in Table 1.
In all cases, GC/MS and NMR analysis of the crude
product mixture showed that only one product 3a-f was
formed although only good yields of isolated products
were obtained due to the sometimes difficult separation
by column chromatography. X-ray analysis of products
3b and 3d (Figure 1), arising from displacement of
chlorine by a primary and secondary amine respectively,
The geometrical parameters of molecules 3b and 3d are
close to expected values. (Figure 1) The aromatic rings in
molecule 3b are almost perpendicular to each other, the
dihedral angle between their planes being 99.2º. The
molecules 3b in the crystal are linked together by N-
H…N hydrogen bonds (N…N 2.922(1)Å) into unusual
tubular chains (Figure 2) along the c-axis and the ꢀ…ꢀ
interactions between the phenyl rings connect the adjacent
chains. The packing of the molecules 3d is more typical
with their aromatic rings arranged in anti-parallel stacks
with alternating interplanar distances of 3.27 and 3.87Å.
Table 1
R1
R2
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
R1R2NH 2
N
CH3CN
N
N
3
1
Product (yield%)
R1R2NH
H
CH3
N
N
CH3NH2
Cl
Cl
Cl
3a
43%
2a
N
H
H
N
NH2
Figure 1. X ray structures of 3b and 3d.
Cl
Cl
Cl
Cl
Cl
3b
54%
N
N
N
N
N
2b
Cl
Cl
3c
45%
NH2
2c
N
N
Cl
Cl
3d
49%
N
H
N
N
2d
Cl
Cl
Cl
3e
25%
N
H
N
N
O
2e
Figure 2. Packing of the molecules 3b in a crystal.
N
N
O
3f
47%
Cl
Cl
Cl
It is well established that nitrogen para to the site of
nucleophilic attack is very activating in perhalogenated
heteroaromatic systems and, consequently we would
N
H
N
2f

Jan-Feb 2008
Reactions of Tetrachloropyridazine with Aliphatic Nitrogen Nucleophile
145
expect substitution to occur predominantly at the 4-
position in the case of tetrachloropyridazine. However,
the regiospecificity is surprising because, in related
processes involving substitution reactions of pentachloro-
pyridine, substitution at the less sterically hindered 2-
position competes significantly and, in the case of
diethylamine, substitution occurs almost exclusively at the
2-position rather than the electronically most favoured 4-
position (Scheme 1) [12,13]. Consequently, in the
tetrachloropyridazine case, ring nitrogen meta to the site
of nucleophilic attack is far more activating than chlorine
substituents at the same position and activation of the 4-
position outweighs any steric factors.
Scheme 1
Cl
N
Cl
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
+
+
Et2NH
NEt2
Figure 3. X ray structure of 5a.
exclusively
NEt2
Molecules in the crystal of 5a are located at a special
position on a 2-fold axis. The conformation of the
piperazine ring is a half-chair with a pyramidal bond
configuration at both nitrogen atoms. The anti-parallel
ꢀ…ꢀ stacking of the heterocycles in a crystal of 5a is
typical for similar compounds and the mean interplanar
distance between adjacent molecules in the stacks is
3.67Å, the shortest inter-atomic distance being 3.571Å
(Cl…C).
In summary, reactions of primary and secondary
nitrogen nucleophiles with tetrachloropyridazine proceed
very efficiently and regiospecifically to give products
arising from substitution of the most activated 4-position.
The surprising regiospecificity of the reactions makes the
use of tetrachloropyridazine as a scaffold for library
synthesis possible.
Cl
N
Cl
Cl
Cl
Cl
Cl
Cl
Et2NH
N
N
N
exclusively
Reaction of tetrachloropyridazine with a difunctional
nitrogen nucleophile, N,N'-dimethylethylene diamine 4,
gave a mixture of [6,6] ring fused products 5a and 5b in
an 8:3 ratio arising from initial substitution at the 4-
position followed by cyclisation onto the 5- and 3- sites
respectively (Scheme 2).
Scheme 2
H
Cl
N
N
N
N
N
N
H
Cl
Cl
Cl
N
Cl
Cl
Cl
N
+
N
N
N
MeCN, r.t.
N
EXPERIMENTAL
Cl
5a, 32%
5b, 17%
General. All starting materials were obtained commercially
(Aldrich, Lancaster or Fluorochem) All solvents were dried
using literature procedures. NMR spectra were recorded in
deuteriochloroform, unless otherwise stated, on a Varian VXR
400S NMR spectrometer operating at 400 MHz (1H n.m.r.) and
100 MHz (13C n.m.r.) with tetramethylsilane as internal
standards. Mass spectra were recorded on a Fisons VG-Trio
1000 Spectrometer coupled with a Hewlett Packard 5890 series
II gas chromatograph using a 25m HP1 (methyl-silicone)
The product distribution reflects the slightly higher
activity of the 5-position which is also para to activating
ring nitrogen and, again, X-ray crystallography confirmed
the structure of the major product (Figure 3).
Molecules in the crystal of 5a are located at a special
position on a 2-fold axis. The conformation of the
piperazine ring is a half-chair with a pyramidal bond
configuration at both nitrogen atoms. The anti-parallel
ꢀ…ꢀ stacking of the heterocycles in a crystal of 5a is
typical for similar compounds and the mean interplanar
distance between adjacent molecules in the stacks is
3.67Å, the shortest inter-atomic distance being 3.571Å
(Cl…C).
column. Elemental analyses were obtained on
a Exeter
Analytical CE-440 elemental analyser. Melting points and
boiling points were recorded at atmospheric pressure unless
otherwise stated and are uncorrected. Column chromatography
was carried out on silica gel (Merck no. 109385, particle size
0.040-0.063mm) and TLC analysis was performed on silica gel
TLC plates (Merck).

146
G. Pattison, G. Sandford, E. V. B. Wallace, D. S. Yufit, J. A. K. Howard,
J. A. Christopher and D. D. Miller
Vol 45
X-ray crystallography. The single crystal X-ray data were
1.49 (s, 9H, CH3), 4.82 (br s, 1H, NH); 13C nmr: ꢁ 31.4 (s, CH3),
57.2 (s, CCH3), 121.7 (s), 142.9 (s), 148.4 (s), 155.0 (s); ms
(70eV, electron impact m/z 255 (2%, [M]+), 253 (2, [M]+), 242
(4, [M-CH3]+), 240 (9, [M – CH3]+), 238 (9, [M - CH3]+), 201 (5,
collected on a Bruker SMART CCD 6K (3b and 5a) and Bruker
Proteum M CCD (3d) at 120 (3b and 3d) and 200K using
graphite monochromated Mo-K radiation (ꢀ = 0.71073 Å). All
structures were solved by direct methods and refined by full-
matrix least squares analysis on F2 for all data using SHELXL
software. All non-hydrogen atoms were refined with anisotropic
displacement parameters, H-atoms were found in the difference
Fourier maps and refined isotropically. CCDC 641086 and
641088 contains the supplementary crystallographic data for this
paper. These data can be viewed free of charge via
http://www.ccdc.cam.ac.uk/cont/retrieving.html or from the
CCDC, 12 Union Road, Cambridge, CB2 1EZ; fax: +44-1223-
336033. E-mail: deposit@ccdc.cam.ac.uk.
t
t
t
[M - Bu]+), 199 (13, [M - Bu]+), 197 (15, [M - Bu]+), 57 (100,
[tBu]+); Anal. Calcd. for C8H10Cl3N3: C, 37.9; H, 3.8; N, 16.3.
Found: C, 37.8; H, 4.0; N, 16.5.
3,5,6-Trichloro-N,N-diethylpyridazin-4-amine (3d).
1
(1.00g, 4.59mmol) and diethylamine 2d (0.95ml, 9.18mmol)
in acetonitrile (25ml) gave a crude red-brown product (1.04g)
which after recrystallisation gave 3d (0.57g, 49%) as a yellow
solid; mp 52 – 54 °C from hexane; 1H nmr: ꢁ 1.09 (t, 6H, CH3,
3
3JHH = 7.2 Hz), 3.37 (q, 4H, CH2 , JHH = 7.0 Hz); 13C nmr: ꢁ
13.9 (s, CH2), 45.9 (s, CH3), 133.2 (s), 146.4 (s), 155.1 (s),
155.4 (s); ms (70eV, electron impact m/z 257 (3%, [M]+), 255
(9, [M]+), 253 (12, [M]+), 242 (22, [M-CH3]+), 240 (63, [M-
CH3]+), 238 (60, [M-CH3]+), 214 (15, [M-CH2CH3]+), 212 (45,
[M-CH2CH3]+), 210 (48, [M-CH2CH3]+), 29 (100,
[CH2CH3]+); Anal. Calcd. for C8H10N3Cl3: C, 37.7; H, 4.0; N,
16.4. Found: C, 37.8; H, 4.0; N, 16.5. Crystals suitable for X-
ray diffraction were obtained by recrystallisation from
hexane. Crystal data for 3d: C8H10Cl3N3 , M = 254.54,
monoclinic, space group P 21/c, a = 9.8565(3), b = 7.2922(3),
c = 15.0344(5) Å, ꢂ = 94.56(1)°, U = 1077.18(7)Å3, F(000) =
520, Z = 4, Dc = 1.570 mg m-3, μ = 0.814 mm-1. 11707
reflections (2.72 ꢃ ꢄ ꢃ 29.50°) were collected yielding 2978
unique data (Rmerg = 0.0397). Final wR2(F2) = 0.0787 for all
data (167 refined parameters), conventional R (F) = 0.0274
for 2622 reflections with I ꢅ 2ꢆ, GOF = 1.097.
General Procedure for the reaction of Tetrachloropyri-
dazine with Nitrogen Nucleophiles. Tetrachloropyridazine 1
was dissolved in acetonitrile (25ml) under argon with stirring.
The amine 2 was added and the mixture stirred at rt or heated at
reflux until TLC indicated complete conversion to products.
After this period water (20ml) was added and the solution
acidified with 10% HCl, followed by extraction with ethyl
acetate (3 x 20ml). The combined organic extracts were dried
(MgSO4), filtered and evaporated under vacuum to yield a crude
product which was purified by recrystallisation.
3,5,6-Trichloro-N-methylpyridazin-4-amine (3a). 1 (1.00g,
4.59mmol) and methylamine (2a) (4.6ml, 9.18mmol, 2.0M in
EtOH) in acetonitrile (25ml) gave a crude yellow product
(0.62g) which after recrystallisation gave 3a (0.42g, 43%) as a
pale yellow solid; mp 113 – 114 °C (from hexane/ethyl acetate,
2:3); 1H nmr: ꢁ 3.41 (d, 3H, CH3, 3JHH = 5.5 Hz), 5.26 (br s, 1H,
NH); 13C nmr: ꢁ 33.2 (s, Me), 115.8 (s), 142.1 (s), 143.6 (s),
154.8 (s); ms (70eV, electron impact m/z 215 (4%, [M]+), 213
(15, [M]+), 211 (18, [M]+), 187 (4, [M-NHMe]+), 185 (15, [M-
NHMe]+), 183 (16, [M-NHMe]+); Anal. Calcd. for C5H4Cl3N3:
C, 28.6; H, 1.9; N, 19.5. Found: C, 28.3; H, 1.9; N, 19.8.
3,4,6-Trichloro-5-piperidine-1-yl-pyridazine (3e). 1 (2.00g,
9.17mmol) and piperidine 2e (1.8ml, 18.31mmol) in acetonitrile
(50ml) gave a crude yellow solid (1.48 g) which after
recrystallisation gave 3e (0.60g, 25%) as a yellow solid; mp 76.3
1
- 78.3 °C from ethyl acetate; H nmr: ꢁ 1.73 (m, 6H, CH2), 3.33
(t, 4H, NCH2, 3JHH = 5.27 Hz); 13C nmr: ꢁ 23.7 (s, C-4'), 26.2 (s,
C-3'), 51.9 (s, C-2') 129.7 (s), 146.8 (s), 152.8 (s) 155.5 (s); ms
(70eV, electron impact m/z 271 (3%, [M]+), 270 (5%, [M-H]+),
269 (18%, [M]+), 268 (48%, [M-H]+) 267 (53%, [M]+), 266
(100%, [M-H]+), 265 (53%, [M]+), 264 (100%, [M-H]+), 55
(35%, [C4H7]+); Anal. Calcd. for C9H10Cl3N3: C, 40.6; H, 3.8; N,
15.6. Found: C, 40.6; H, 3.8; N, 15.8.
N-Benzyl-3,5,6-trichloropyridazin-4-amine (3b). 1 (1.00g,
4.59mmol) and benzylamine (2b) (1.0ml, 9.18mmol) in
acetonitrile (25ml) gave a crude yellow product (0.86g)
which after recrystallisation gave 3b (0.71g, 54%) as yellow
1
crystals; mp 75 – 77 °C from hexane/ethyl acetate (2:1); H
nmr: ꢁ 4.95 (d, 2H, NHCH2Ph, 3JHH = 5.9 Hz), 5.42 (br s, 1H,
NHCH2Ph), 7.29 – 7.40 (m, 5H, ArH); 13C nmr: ꢁ 49.6 (s,
NHCH2Ph), 116.8 (s), 127.3 (s, Ph), 128.2 (s, Ph), 129.1 (s,
Ph), 137.2 (s), 141.4 (s), 144.1 (s, NHPh), 154.8 (s); ms
(70eV, electron impact m/z 291 (3%, [M]+), 289 (12, [M]+),
287 (11, [M]+), 91 (100, [CH2Ph]+), 77 (11), 65 (63); Anal.
Calcd. for C11H8N3Cl3: C, 46.0; H, 2.9; N, 14.5. Found: C,
45.8; H, 2.8; N, 14.6. Crystals suitable for X-ray diffraction
were obtained from slow evaporation of ethyl acetate.
Crystal data for 3b: C11H8Cl3N3, M = 288.55, monoclinic,
space group P 21/c, a = 8.9251(3), b = 12.4466(5), c =
10.8975(4) Å, ꢂ = 100.70(1)°, U = 1189.52(8)Å3, F(000) =
584, Z = 4, Dc = 1.611 mg m-3, μ = 0.748 mm-1. 18653
reflections (2.32 ꢃ ꢄ ꢃ 29.50°) were collected yielding 3314
unique data (Rmerg = 0.0269). Final wR2(F2) = 0.0852 for all
data (186 refined parameters), conventional R (F) = 0.0296
for 2973 reflections with I ꢅ 2ꢆ, GOF = 1.030.
4-(3,5,6-Trichloro-pyridazine-4-yl)-morpholine (3f).
1
(2.00g, 9.17mmol) and morpholine 2f (1.60ml, 18.34mmol) in
acetonitrile (50ml) gave a crude yellow product which after
recrystallisation gave 3f (1.15g, 47%) as yellow crystals; mp
1
100.8-102.8 °C (from hexane / ethyl acetate, 1:1); H nmr: ꢁ
3
3
3.43 (t, 4H, Ha, JHH = 4.4 Hz), 3.86 (t, 4H, Hb, JHH = 4.6 Hz);
13C nmr: ꢁ 50.6 (s, C-2'), 67.1 (s, C-3'), 103.3 (s), 145.5 (s),
152.7 (s), 155.7 (s); ms (70eV, electron impact m/z 273 (2%,
[M]+), 272 (2%, [M-H]+), 271 (15%, [M]+), 270 (7%, [M-H]+),
269 (43%, [M]+), 268 (10%, [M-H]+), 267 (46%, [M]+), 266
(6%, [M-H]+), 234 (30, [M-Cl]+), 232 (69, [M-Cl]+), 211 (95,
[M-C3H6O]+), 209 (100, [M-C3H6O]+), 148 (36, [M-
C4H8NOCl]+), 146 (54, [M-C4H8NOCl]+), 117.9 (32), 85 (23,
[C4H8NO]+), 77 (34); Anal. Calcd. for C8H8N3OCl3: C, 35.9; H,
3.0; N, 15.4. Found: C, 35.8; H, 3.0; N, 15.7.
Reaction with N,N'-Dimethylethylene diamine (4). 1
(1.00g, 4.59mmol) and N,N'-dimethylethylene diamine (4)
(0.54ml, 5.05mmol) in acetonitrile (100ml) gave a crude red-
brown product (0.98g). Purification by flash column chroma-
tography using hexane:ethyl acetate as eluant, 5,8-dichloro-
1,2,3,4-tetrahydro-1,4-dimethylpyrazino[2,3-d]pyridazine (5a)
N-tert-Butyl-3,5,6-trichloropyridazin-4-amine (3c). 1
(1.00g, 4.59mmol) and tert-butylamine 2c (0.96ml, 9.18mmol)
in acetonitrile (25ml) gave a crude yellow product (0.67g) which
after recrystallisation gave 3c (0.52g, 45%) as a yellow-orange
solid; mp 64 – 66 °C from hexane/ethyl acetate (2:3); 1H nmr: ꢁ

Jan-Feb 2008
Reactions of Tetrachloropyridazine with Aliphatic Nitrogen Nucleophile
147
1
REFERENCES
(0.34g, 32%) as a cream solid; mp 143.5 – 146 °C; H nmr: ꢀ
3.05 (s, 6H, CH3), 3.07 (s, 4H, CH2CH2); 13C nmr: ꢀ 42.7 (s,
CH2CH2), 46.1 (s, CH3), 135.7 (s), 146.0 (s); ms (70eV,
electron impact m/z 233 (0.4%, [M]+), 231 (1.6, [M]+), 91
(100); Anal. Calcd. for C8H10N4Cl2: C, 41.2; H, 4.3; N, 23.8.
Found: C, 41.2; H, 4.3; N, 24.0. Crystals suitable for X-ray
diffraction were obtained from slow evaporation of ethyl
acetate; Crystal data for 5a: C8H10Cl2N4 , M = 233.10,
monoclinic, space group C 2/c, a = 8.8096(4), b = 14.0969(7),
c = 7.9734(4) Å, ꢁ = 93.02(2)°, U = 988.82(8)Å3, F(000) =
480, Z = 4, Dc = 1.566 mg m-3, μ = 0.620 mm-1. 5535
reflections (2.73 ꢂ ꢃ ꢂ 29.49°) were collected yielding 1371
unique data (Rmerg = 0.0204). Final wR2(F2) = 0.1091 for all
data (85 refined parameters), conventional R(F) = 0.0378 for
1249 reflections with I ꢄ 2ꢅ, GOF = 1.004; and, 3,4-dichloro-
5,6,7,8-tetrahydro-5,8-dimethylpyrazino[2,3-c]pyridazine (5b)
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Zhong, Y. L.; Sarabia, F. J. Am. Chem. Soc. 2002, 124, 5718.
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1
(0.18g, 17%) as a cream solid; mp 121 – 123 °C; H nmr: ꢀ
3.40 (m, 2H, CH2), 3.35 (m, 2H, CH2), 3.20 (s, 3H, CH3), 3.16
(s, 3H, CH3); 13C nmr: ꢀ 36.9 (s, CH2), 41.8 (s, CH2), 45.4 (s,
CH3), 50.1 (s, CH3), 134.4 (s), 136.9 (s), 145.5 (s), 150.5 (s),
153.9 (s); ms (70eV, electron impact m/z 217 ([M-Me]+, 1%),
106 (28), 85 ([C5H9N2]+, 29), 71 ([C3H7N2]+, 34), 49 (32), 47
(100), 35 (72); Anal. Calcd. for C8H10N4Cl2: C, 42.5; H, 4.7; N,
22.7. Found: C, 41.2; H, 4.3; N, 24.0.
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Compounds, Suschitzky, H., Ed., Plenum, London, 1974, pp 197.
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Acknowledgement. We thank GlaxoSmithKline and EPSRC
for funding.