Facile synthesis of 4-aryl and alkyl substituted, N6-alkylated pyridazine-3,6-diamines

Article abstract of DOI:10.1016/j.tetlet.2015.10.075

Substituted pyridazine-3,6-diamines are attractive but poorly precedented scaffolds in medicinal chemistry and are challenging targets in terms of synthetic tractability. In the following communication we report the use of a Buchwald protocol for the facile synthesis of 4-aryl and alkyl substituted, N⁶-alkylated pyridazine-3,6-diamines. This approach utilises the unreactive nature of the pyridazine 3-amino group, negating the need for an additional protecting group in the transformation. The relevant precursors were prepared by selective Suzuki or Negishi transformations using commercially available 4-bromo-6-chloro-3-pyridazinamine.

Full text of DOI:10.1016/j.tetlet.2015.10.075

Accepted Manuscript
Facile synthesis of 4-aryl and alkyl substituted, N 6-alkylated pyridazine-3,6-
diamines
Joanna Wlochal, Andrew Bailey
PII:
S0040-4039(15)30272-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.075
TETL 46904
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 September 2015
10 October 2015
23 October 2015
6
Please cite this article as: Wlochal, J., Bailey, A., Facile synthesis of 4-aryl and alkyl substituted, N -alkylated
pyridazine-3,6-diamines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.075
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Facile synthesis of 4-aryl and alkyl substituted,
Leave this area blank for abstract info.
N6-alkylated pyridazine-3,6-diamines
Joanna Wlochal, Andrew Bailey.

1
Tetrahedron Letters
Facile synthesis of 4-aryl and alkyl substituted, N6-alkylated pyridazine-3,6-diamines.
Joanna Wlochal, Andrew Bailey*
AstraZeneca Pharmaceuticals, Oncology iMed, Alderley Park, Macclesfield, Cheshire, SK10 4TG.
* a.bailey@redxpharma.com
ARTICLE INFO
ABSTRACT
Substituted pyridazine-3,6-diamines are attractive but poorly precedented scaffolds in medicinal
chemistry and are challenging targets in terms of synthetic tractability. In the following
communication we report the use of a Buchwald protocol for the facile synthesis of 4-aryl and
alkyl substituted, N6-alkylated pyridazine-3,6-diamines. This approach utilises the unreactive
nature of the pyridazine 3-amino group, negating the need for an additional protecting group in
the transformation. The relevant precursors were prepared by selective Suzuki or Negishi
transformations using commercially available 4-bromo-6-chloro-3-pyridazinamine.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Substituted pyridazine-3,6-diamines
3,6-diaminopyridazines
Brettphos precatalyst
Buchwald protocol
2009 Elsevier Ltd. All rights reserved.
The pyridazine-3,6-diamine scaffold has been explored in
multiple drug discovery programs, appearing as a key focus of
several projects1 and resulting in, for example, the marketed
antihypertensive agent, cadralazine.2 Pyridazine-3,6-diamines
have also served as a broad synthetic platform in many patents
and have been used as key intermediates leading to a variety of
other pharmaceutically important compounds.3
As part of an AstraZeneca ongoing interest in the medicinal
chemistry of pyridazine-3,6-diamines, we wished to investigate
the effect of either aryl or alkyl substituents (R1) directly
introduced onto the heterocyclic core. Particularly desirable
targets for our studies were the 4-substituted, N6-alkylated,
analogues of pyridazine-3,6-diamines such as 1
aryl substituents (R1) were very poorly represented. Furthermore,
to the best of our knowledge no route to make these substituted
analogues had been reported.
In our previous publication,6 we had already demonstrated that
transformation of the corresponding unsubstituted analogues
could be accomplished under mild conditions, by utilising a
copper catalysed, Ullmann-type methodology and the appropriate
iodo precursor 2a (Figure 2). Building on this report, we initially
hoped to extend the scope of our work by including suitable R1
substituted substrates to allow access to the corresponding
analogues exemplified by 1.
Figure 2. Displacement routes to pyridazine-3,6-diamines
With this in mind, our initial strategy relied on the application
of commercially available 4-bromo-6-chloro-3-pyridazinamine 4
as a suitable starting material. In order to assess its reactivity
profile in a standard Suzuki coupling reaction, we performed a
tentative experiment with 4, phenylboronic acid, Pd(dppf)Cl2
catalyst and sodium carbonate as a base in refluxing 1,4-dioxane
to access 5 in good yield (71%). To test and further advance this
approach we then subjected the resulting substrate 5 to our
previously developed amination protocol. Using this strategy we
were able to synthesise pyridazine-3,6-diamine 7 in 65% yield by
sequential preparation of the corresponding iodo intermediate 6
followed by copper catalysed Ullmann-type coupling (Scheme
1).
Figure 1. Substituted pyridazine-3,6-diamine targets
However, synthetic entry to targets containing the pyridazine-
3,6-diamine motif is limited. Described methods rely on high
temperature nucleophilic displacement of a halogen atom (X)
from an aminohalopyridazine (Figure 2).4 The poor reactivity of
X in these structures effectively limits the scope of this method to
cyclic secondary amines (where excess or neat amine is often
required and temperatures typically range from 100 to 200 °C).
Similarly, the few reported literature examples of displacements
involving primary amines have necessitated the use of forcing
conditions and resulted in poor yields.5
A search of the literature also revealed that, despite the large
number of publications focussed on pyridazine-3,6-diamines
(where R1 = H), structures such as 1, carrying additional alkyl or

2
Tetrahedron
Scheme 1. Reaction conditions: (i) 1.03 equiv. PhB(OH)2,
Pd(dppf)Cl2.CH2Cl2 (10 mol%), Na2CO3, aq. dioxane, reflux, 71% (ii) HI
(aq., 57 wt%), 127 °C, 94% (iii) 1.3 equiv. 2-ethoxyethanamine, CuI (10
mol%), L-hydroxyproline (20 mol%), 3 equiv. K3PO4, DMSO, 50 °C, 65%.
Scheme 2. Reaction conditions: (i) DMF dimethyl acetal, toluene, reflux,
99% (ii) 1.5 equiv. 2-ethoxyethanamine, BrettPhos (5 mol%), BrettPhos
precatalyst (5 mol%), 2.4 equiv. LHMDS, 60 °C (iii) aq. HCl, MeOH, room
temp (75% 2 steps). (iv) 1.5 equiv. 2-ethoxyethanamine, BrettPhos (5 mol%),
BrettPhos precatalyst (5 mol%), 2.4 equiv. LHMDS, 60 °C, 83%.
Although we had demonstrated the feasibility of the protocol on
the substrate derived from unsubstituted phenylboronic acid, we
were concerned with possible functional group compatibility,
where necessity of a halogen exchange step under the harsh
reaction conditions would preclude the presence of many
functional groups on the adjacent substituent R1. Therefore, in
order to allow a broad scope of substrates, an alternative, more
robust approach to 1 was needed.
Encouraged by this result, we decided to proceed with an
investigation of the scope of this transformation and employed a
selection of primary amines with chloropyridazine 5, under the
same palladium catalysed conditions. Results with isolated yields
are summarised in Table 1. Functional groups such as ether
(entry 1, 83%), nitrile (entry 2, 70%) and alcohol (entry 3, 73%)
were well tolerated, as was 4-methylbenzylamine (entry 4, 85%)
and a tertiary amine (entry 5, 83%). No desired product was
observed for the BOC protected primary amine (entry 6) but
Based on the several literature examples describing the
formation of the desired pyridazine-3,6-diamine targets via
metal-catalysed C-N bond formation reactions using palladium
and the corresponding chloro precursors,7 we were encouraged to
investigate that approach. However, the major drawbacks of the
existing methods were poor yields, limited scope and poor
compatibility with aliphatic amines. Notably however, these
reactions used catalysts and ligands found early on in the
development of cross-coupling methodologies and had not been
evaluated using a more modern catalytic approach. We were
determined therefore, to investigate the possibility of introducing
a range of primary amines to the electron-rich, substituted
pyridazine core by utilising catalytic systems recently published
by Buchwald and co-workers.8 Tentative experiments revealed
that a method based on the ‘first generation’ Brettphos
moderate yields were obtained for
a similarly protected
secondary amine (entry 7, 63%) and the hindered 2-
methylbutylamine (entry 8, 60%).
Table 1
Assessment of scope for primary amines
Yield
(%)
Entry
Amine
Product
1
83
precatalyst9 was
a
favourable means to functionalise
chloropyridazines such as 5 to give the desired structures
represented by 1.
2
3
4
5
70
73a
85
In order to account for the potentially competitive side reactions
arising from the ‘free’ NH2 group in 5 we had initially prepared
its formamidine derivative 8. This was felt to be a necessary
precaution, based on numerous literature examples for palladium
catalysed couplings involving aminopyridazines.10 With the
suitably elaborated substrate 8 we proceeded to the coupling step
using the favoured reaction conditions; 5 mol% BrettPhos ligand,
5 mol% BrettPhos precatalyst, 1.5 equiv. primary amine and 2.4
equiv. of 1.0 M LHMDS in THF, which was then heated to 60
°C. This method afforded the desired product 9, which after final
deprotection delivered 7 in very good 75% overall yield (Scheme
2).
However, it seemed reasonable to hypothesise that the reactivity
of the NH2 group in structures such as 5 could be moderated due
to factors such as sterics and electronics from the neighbouring
aryl ring. Crucially, following further investigations, we found
that ‘unprotected’ chloropyridazine 5 could be directly converted
to target 7 in a single step (step iv in Scheme 2) using the same
BrettPhos precatalyst system and conditions employed for the
protected derivative 8. The direct conversion of 5 to 7 was
achieved in excellent yield (83%) with no side-products arising
from reaction of the unprotected NH2 functionality.
83
6
0a

3
7
8
63
60
3
93a
4
5
6
7
88
81
65
61
9
89
Conditions: 1.5 equiv. amine, BrettPhos (5 mol%), BrettPhos precatalyst (5
mol%), 2.4 equiv. LHMDS. a 3.4 equiv. LHMDS
To further assess the functional group tolerance of this method, a
range of substituents on the aryl ring were then introduced via
use of the appropriate boronic acid in the initial Suzuki step. This
resulted in good yields of the chloropyridazine precursors
(Scheme 3).
8
9
42
75a
Scheme 3. Reaction conditions: (i) 1.03 equiv. ArB(OH)2,
Pd(dppf)Cl2.CH2Cl2 (10 mol%), 2 equiv. Na2CO3, aq. dioxane, reflux. (1H-
indol-5-yl)boronic acid gave a yield of 74%
Conditions: 1.5 equiv. 2-ethoxyethanamine, BrettPhos (5 mol%), BrettPhos
precatalyst (5 mol%), 2.4 equiv. LHMDS, 60 °C. a 3.4 equiv. LHMDS
2-Ethoxyethanamine was selected as the model system amine
which was used to generate a series of functionalised pyridazine-
3,6-diamines (Table 2). Yields for these various, aryl-ring
substituted analogues ranged from 42% to 93% with functional
groups such as arylether (entry 2, 80%), phenol (entry 3, 93%)
and trifluoromethyl (entry 4, 88%) all being very well tolerated.
Similarly, the hindered o-tolyl example gave a pleasing 81%
yield (entry 5) and respectable yields were also obtained for
nitrile (entry 6, 65%) and an N,N-dimethylaniline (entry 7, 61%).
However, the recovery from an amide was low (entry 8, 42%),
which was found to be due to a competing ‘transamination’
reaction at the amide carbonyl centre. Finally, we investigated the
use of an indole as shown in entry 9 and were pleased to obtain a
75% yield for this heterocycle.
In order to extend the scope for substituent R1 we then turned
our attention to the analogous alkyl substituted structures. We
found that it was possible to treat 4-bromo-6-chloro-3-
pyridazinamine 4 under Negishi conditions with the appropriate
alkylzinc halide in order to selectively introduce various alkyl
groups in good yields (Scheme 4).11
Scheme 4. Reaction conditions: (i) 3 equiv. R1ZnBr, Pd(PPh3)2Cl2 (10
mol%), THF, room temp.
Table 2
Assessment of scope for aryl functionality
The resultant intermediates were carried through using the same
BrettPhos catalytic system as previously described (Table 3). All
alkyl examples worked well, apart from the benzyl substrate
(entry 6) which gave a low yield of 14%.
Entry
Product
Yield (%)
1
83
Table 3
Assessment of scope for alkyl substituents
2
80
Entry
Product
Yield (%)

4
Tetrahedron
We would like to thank Jamie Scott for discussions and also
Paul Davey, Scott Boyd, Marta Wylot, Eva Lenz and Steve
Glossop for analytical support.
1
2
3
4
5
81
70
72
86
64
Supplementary Data
Supplementary material (experimental procedures and
1
characterization data, including H NMR, 13C NMR spectra) for
all table compounds and ‘chloro-precursors’ associated with this
article can be found in the online version.
References
1.
See, for example; (a) Khalil, N. A.; Ahmed, E. M.; Mohamed, K.
O.; Nissan, Y. M.; Zaitone, S. A. Bioorg. Med. Chem. 2014, 22,
2080–2089;(b) Abouzid, K. A. M.; Khalil, N. A.; Ahmed, E. M.;
Mohamed, K. O. Arch. Pharm. Res. 2013, 36, 41–50; (c) Yang, S.;
Kuo, G.; Gaul, M. D.; Rano, T. A. WO Patent 2013/085957; Chem.
Abstr. 2013, 159, 118568.
2.
Semeraro, C.; Dorigotti, L.; Banfi, S.; Carpi. C. J. Cardiovasc.
Pharm. 1981, 3, 455-467.
3.
(a) Almario, G. A.; Barrague, M.; Burnier, P.; Enguehard, C.;
Gao, Z.; George, P.; Gueiffier, A.; Li, A. T.; Puech, F.; Vaz,
R.; Zhao, Q. WO Patent 2009/016286; Chem. Abstr. 2009, 150,
168375; (b) Zoller, G.; Strobel, H.; Will, D. W.; Wohlfart, P. WO
Patent 2008/104279; Chem. Abstr. 2008, 149, 307879; (c) Falco, J.
6
14
L.; Palomer, A.; Guglietta, A. WO Patent 2007/110437; Chem. Abstr.
2007, 147, 406830.
(a) Biagetti, M.; Contini, S. A.; Genski, T.; Guery, S.; Leslie,
C. P.; Mazzali, A.; Pizzi, D. A.; Sabbatini, F. M.; Seri, C. WO
Conditions: 1.5 equiv. 2-ethoxyethanamine, BrettPhos (5 mol%), BrettPhos
precatalyst (5 mol%), 2.4 equiv. LHMDS, 60 °C.
4.
Patent 2009/095377; Chem. Abstr. 2009, 151, 245649; (b) Bouchain,
G.; Delorme, D.; Frechette, S.; Gaudette, F.; Isakovic, L.; Leit,
S.; Moradei, O.; Paquin, I.; Raeppel, S.; Vaisburg, A.; Zhou, Z.
Of particular note was the 81% yield for the analogue
containing the methyl group (Entry 1, Table 3), the smallest of
the R1 substituents investigated. The transformations shown in
Scheme 2 and discussed earlier, had led us to speculate that the
unreactive nature of the pyradizine ‘NH2’ in these reactions could
be due to steric hindrance from R1 (thus negating the need for the
formamidine protecting group shown in Scheme 2). However, the
high yield obtained for the methyl substituent in Table 3
suggested that steric hindrance was not a significant factor.
Accordingly, we found that we were also able to extend this
chemistry to the corresponding unsubstituted (R1 = H) analogues.
6-Chloro-3-pyridazinamine 10, for example, gave a respectable
68% yield with 2-ethoxyethanamine under the same conditions
(Scheme 5).
WO Patent 2005/092899; Chem. Abstr. 2005, 143, 367317.
5.
(a) Xing, L.; Ziener, U.; Sutherland, T. C.; Cuccia, L. A. Chem.
Commun. 2005, 5751–5753; (b) Gschwend, H. W.; Kodumuru, V.; Liu,
S.; Kamboj, R. U.S. Patent 8148378; Chem. Abstr. 2012, 156,
477720.
6.
7.
Bethel, P. A.; Roberts, B.; Bailey, A. Tetrahedron Lett. 2014,
55, 5186-5190.
(a) Blench, T.; Goodacre, S.; Lai, Y.; Liang, Y.; Macleod, C.;
Magnuson, S.; Tsui, V.; Williams, K.; Zhang, B. WO Patent
2012/066061; Chem. Abstr. 2012, 157, 12801; (b) Currie, K. S.;
Wang, X.; Young, W. B. WO Patent 2012/031004; Chem. Abstr. 2012,
156, 363058; (c) Cho, Y. S.; Borland, M.; Brain, C.; Chen, C. H.;
Cheng, H.; Chopra, R.; Chung, K.; Groarke, J.; He, G.; Hou, Y.;
Kim, S.; Kovats, S.; Lu, Y.; O’Reilly, M.; Shen, J.; Smith, T.;
Trakshel, G.; Vogtle, M.; Xu, M.; Xu, M.; Sung, M. J. J. Med.
Chem. 2010, 53, 7938–7957.
Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.; Buchwald,
S. L. Chem. Sci., 2011, 2, 57.
8.
9.
BrettPhos first generation precatalyst; Chloro[2-
(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′, 6′-triisopropyl-
1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II). CAS
1148148-01-9
Scheme 5. Reaction conditions: (i) 1.5 equiv. 2-ethoxyethanamine,
10. See, for example; (a) Wagner, P.; Bollenbach, M.; Doebelin, C.;
Bihel, F.; Bourguignon, J.; Salome, C.; Schmitt, M. Green Chem.
2014, 16, 4170-4178; (b) Hu, C. H.; Qiao, J. X.; Han, Y.; Wang,
T. C.; Hua, J.; Price, L. A.; Wu, Q.; Shen, H.; Huang, C. S.;
Rehfuss, R.; Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem.
Lett. 2014, 24, 2481-2485; (c) Loones, K. T. J.; Maes, B. U. W.;
Meyers, C.; Deruytter, J. J. Org. Chem. 2006, 71, 260-264.
11. 6-Chloro-4-methylpyridazin-3-amine precursor was purchased from
Sigma Aldrich.
BrettPhos (5 mol%), BrettPhos precatalyst (5 mol%), 2.4 equiv. LHMDS, 60
°C
In summary, we have reported a convenient and facile synthetic
approach for accessing a desirable medicinal chemistry scaffold
based on 4-aryl and alkyl substituted, N6-alkylated pyridazine-
3,6-diamines. This methodology makes use of selective Suzuki
and Negishi transformations using a low-cost, commercially
available starting material. Introduction of the desired primary
amines was achieved via a Buchwald protocol with BrettPhos
precatalyst on challenging and previously unexplored pyridazine
structures. Moreover, no additional protecting group strategy was
required to aid the desired selectivity.
Acknowledgments