A novel approach to functionalised pyridazinone arrays

Article abstract of DOI:10.1039/b613223e

An efficient route to 3,6-dichloro-1 H-pyridazine-4-ones undergoing regioselective C-O, C-S and C-C bond forming reactions was investigated. A series 3,6-dichloro-1 H-pyridazine-4-ones have been prepared through the cycloaddition of 3,6-dichlorotetrazine with alkynylboronates and their employment. Pyridazine represent an important class of bioactive compounds and they have been particularly widely exploited as crop protection pharmaceuticals. It was investigated that the cycloaddition of alkynyl boronates with dichlorotetrazine will provide a pyridazine boronic ester that can be elaborated to a pyridazinone with the option of functionalizing at C-3 or C-6. Substitution of n-protected substrates were investigated and it was found that it took place in good yield and with complete regiocontrol for addition at C-6 to give products.

Full text of DOI:10.1039/b613223e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A novel approach to functionalised pyridazinone arrays†
Matthew D. Helm,a Andrew Plantb and Joseph P. A. Harrity*a
Received 12th September 2006, Accepted 17th October 2006
First published as an Advance Article on the web 26th October 2006
DOI: 10.1039/b613223e
A series of 3,6-dichloro-1H-pyridazin-4-ones have been pre-
pared via the cycloaddition of 3,6-dichlorotetrazine with
alkynylboronates, and their employment as useful synthetic
intermediates was highlighted through a selection of highly
regioselective C–O, C–S and C–C bond forming reactions.
may contain incompatible functionality. An alternative route that
allows heavily functionalised pyridazines to be readily accessed
is through the Carboni–Lindsey cycloaddition reaction.5 In this
context we have shown that highly functionalised pyridazine
boronic esters can be accessed by the cycloaddition of tetrazines
with alkynylboronates.6,7 Additionally, and in the context of this
study, we further demonstrated that these intermediates could be
elaborated to pyridazinones by oxidation, albeit in a single exam-
ple. In an effort to broaden this technique to include pyridazinone
scaffolds, we envisaged that the cycloaddition of alkynylboronates
with dichlorotetrazine would provide a pyridazine boronic ester
that could be elaborated to a pyridazinone with the option of
functionalising at C-3 or C-6. Notably, a crucial goal in this study
was the realisation of conditions that would allow a number of
groups to be incorporated into these intermediates with high levels
of regiocontrol (Scheme 1).
Pyridazinones represent an important class of bioactive com-
pounds, and they have been particularly widely exploited as crop
protection agents and as pharmaceuticals.1 For example, the anal-
gesic anti-inflammatory agent emorfazone 12 and the herbicide
norflurazon 23 are founded on this motif, whilst Stevenson and co-
workers found that the structurally related 3 also showed good her-
bicidal activity (Chart 1).4 Recent work in our labs has uncovered
an efficient route to pyridazines that we felt would be amenable to
the preparation of a range of pyridazinone scaffolds that would
represent useful intermediates in agrochemical discovery research.
Specifically, we hoped to prepare a series of heterocycles 4 that
would allow flexible introduction of functionality around the
ring and that provided a functional group at C-6 for late stage
modification. We report herein a flexible route to this motif and
some representative functionalisation reactions of the C–Cl bond.
Scheme 1 Alkynylboronate cycloaddition route to pyridazinones.
We began our studies by investigating the cycloaddition reac-
tion of 3,6-dichlorotetrazine 58,9 with a representative series of
alkynylboronates. Pleasingly, this technique delivered the key 2,6-
dichloropyridazines 6 in good yield in all cases examined. We
found that the reaction proceeded most efficiently in xylenes;
running the reaction at similar temperatures in non-refluxing
solvent gave lower yields due to sublimation of the volatile
tetrazine from the reaction medium. Furthermore, oxidation of
substrates 6b–d proceeded rapidly to provide the corresponding
pyridazinones 7 in good yield within a short reaction time
(Scheme 2).
With the pyridazinones in hand, we turned our attention
to the regioselective functionalisation reactions (Scheme 3).10
Preliminary attempts to add oxygen based nucleophiles invariably
led only to recovery of the starting compound. We surmised
that this poor reactivity was probably due to the generation
of an electron rich pyridazin-4-olate via deprotonation of the
Chart 1 Representative bioactive pyridazinones.
The synthesis of pyridazines is most commonly carried out by
condensation of hydrazine with an appropriately functionalized
dicarbonyl compound (or equivalent).1 This approach can be
rather limited if more heavily functionalised heterocycles are
required because the starting substrate may be inaccessible or
aDepartment of Chemistry, University of Sheffield, Brook Hill, Sheffield,
UK S3 7HF. E-mail: j.harrity@sheffield.ac.uk; Fax: +44 (0114) 222 9346;
Tel: +44 (0114) 222 9496
bResearch Chemistry, Syngenta, Jealott’s Hill International Research Centre,
Bracknell, Berkshire, UK RG42 6EY
† Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all new compounds. See DOI:
10.1039/b613223e
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products 11a and 12a respectively (entries 1 and 2). Further studies
demonstrated that substitution of the chloride at C-6 could also
be performed by a base mediated thiolate substitution to give
13a (entry 3). In contrast however, the Suzuki coupling reaction
with phenylboronic acid proceeded with complete reversal of
regiochemistry to provide isomer 14b in 62% yield (entry 4). This
divergence in regiochemistry was unexpected but may be due to
the greater steric congestion around C-6 in comparison to that
at C-3.11 Finally, the employment of the remaining chloride to
introduce further diversity was demonstrated in a single case in
this series by the substitution of the C-3 chloride in 12a by thiolate
to give 15 (Scheme 4).
Scheme 2 Synthesis of 3,6-dichloro-1H-pyridazin-4-ones.
Scheme 4 Thiolate substitution at C-3.
With the methodology in hand for the selective functionalisation
of the dichloropyridazinones, we set about employing this ap-
proach to the synthesis of analogues of the herbicidal core reported
by Dupont chemists (4 in Chart 1).4 We prepared compound 10
as before, although sequential cycloaddition, oxidation and N-
methylation without intermediate purification gave this compound
in higher overall yield (84% over three steps). We next investigated
the chloride substitution of 10 by methoxide and were surprised to
find this to be poorly regioselective and to favour displacement of
the 3-Cl-substituent.12 However, modification of the reaction con-
ditions allowed to us once again to achieve a highly regioselective
substitution at the C-6 position (Scheme 5).
Scheme 3 Pyridazinone protection.
acidic NH. Accordingly we carried out the N-protection of these
substrates and found that both methylation and benzylation
proceeded in modest to excellent yield.
Substitution of the N-protected substrates 8 and 9 were next
investigated and the results are outlined in Table 1. Substitution
of chloride for phenoxide was found to take place in good
yield and with complete regiocontrol for addition at C-6 to give
Table 1 Regioselective chloride substitution
Scheme 5 Methoxide substitution studies.
Finally, Pd-catalysed dechlorination and demethylation pro-
vided an analogue of the Stevenson compound 17. Moreover, the
potential exploitation of the chloride in 16a for further elaboration
was demonstrated by Suzuki cross-coupling to provide 18 after
demethylation (Scheme 6).
In conclusion, we have developed an efficient route to 3,6-
dichloro-1H-pyridazin-4-ones and demonstrated that they un-
dergo regioselective C–O, C–S and C–C bond forming reactions.
We are grateful to the EPSRC and Syngenta for a studentship
(M.D.H.) and to H. Adams for help in obtaining the X-ray
diffraction data.
Entry R1
Conditions
R2
Yield
1
2
3
4
Ph 8
NaOPh, THF, 40 ◦
NaOPh, THF, 40 ◦
NaS(p-ClC6H4), THF, RT S(p-ClC6H4) 13a; 96%
PhB(OH)2, 3% Pd(PPh3)4, Ph
Na2CO3, tol., reflux
C
C
OPh
OPh
11a; 77%a
12a; 70%b
Bu 9
Bu 9
Bu 9
14b; 62%
a 16% of bis-phenoxide was also isolated. b 11% of bis-phenoxide was also
isolated.
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Org. Lett., 2005, 7, 251; (e) M. W. Davies, R. A. J. Wybrow, C. N.
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8 We have developed a modified route to this compound that avoids the
use of chlorine gas. See Supplementary Information† for experimental
details.
9 For the participation of dichlorotetrazine in other alkyne cycloaddi-
tions see: T. J. Sparey and T. Harrison, Tetrahedron Lett., 1998, 39,
5873.
Scheme 6 Reagents and conditions: (a) HCO2NH4, 5% Pd/C, EtOH;
100%. (b) TMSCl, NaI, MeCN. 17; 90%. 18; 100%. (c) PhB(OH)2, 2.5%
Pd(PPh3)4, Na2CO3, tol.; 71%.
10 For related studies on the displacement reactions of 4,5-
dichloropyradizin-3(2H)-ones see: J.-W. Park, J.-J. Kim, H.-K. Kim,
H.-A. Chunh, S.-D. Cho, S. G. Lee, M. Shiro and Y.-J. Yoon,
Tetrahedron, 2005, 61, 5389.
11 The regiochemistry of compound 12a was established by X-ray crystal
structure of the debenzylated compound, the regiochemistry of 16a
was therefore based on the assumption that phenoxide addition to 4
followed the same regiochemistry pattern. The regiochemistry of 13a
was established by NOE spectroscopy and that of 14b was established
by X-ray crystal structure after debenzylation and formation of the
O-4-nitrobenzoate ester. X-Ray crystallography data for debenzylated
Notes and references
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C. Maqueda, J. M. Gine´s and E. Morillo, Chemosphere, 2005, 60, 656.
4 T. M. Stevenson, B. A. Crouse, T. V. Thieu, C. Grebreysus, B. L.
Finkelstein, M. R. Sethuraman, C. M. Dubas-Cordery and D. L.
Piotrowski, J. Heterocycl. Chem., 2005, 42, 427.
5 R. A. Carboni and R. V. Lindsey, Jr., J. Am. Chem. Soc., 1959, 81, 4342;
D. L. Boger, Chem. Rev., 1986, 86, 781.
6 M. D. Helm, J. E. Moore, A. Plant and J. P. A. Harrity, Angew. Chem.,
Int. Ed., 2005, 44, 3889.
7 For alternative alkynylboronate cycloadditions see: (a) G. Hilt and P.
Bolze, Synthesis, 2005, 13, 2091; (b) G. Hilt, W. Hess and F. Schmidt,
Eur. J. Org. Chem., 2005, 2526; (c) G. Hilt and K. I. Smolko, Angew.
Chem., Int. Ed., 2003, 42, 2795; (d) G. Hilt, S. Luers and K. I. Smolko,
12a: C14H15ClN2O2, M = 278.73, ◦monoclinic, a = 9.227(2), b =
3
˚
˚
12.144(3), c = 12.904 A, b = 91.550 , U = 1445.5(6) A , space group
P2(1)/c, Z = 4, l = 0.264 mm−1, 11 319 reflections measured, 1865
independent reflections, R1 = 0.0916 and wR2 = 0.1266 for all data. X-
Ray crystallography data for O-4-nitrobenzoate ester of debenzylated
14b: C21H18ClN3O4, M = 411.83, tetragonal, a = 25.7394(10), b =
3
˚
˚
25.7394(10), c = 5.9168(6) A, U = 3920.0(5) A , space group P4/n,
Z = 8, l = 0.228 mm−1, 53 474 reflections measured, 2407 independent
reflections, R1 = 0.0801 and wR2 = 0.1143 for all data. CCDC reference
numbers 620790 and 620791. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b613223e. See Supplementary
Information† for NOE spectroscopy of 13a.
12 The regiochemistry of 16a was established by NOE spectroscopy, see
Supplementary Information† for details.
4280 | Org. Biomol. Chem., 2006, 4, 4278–4280
This journal is
The Royal Society of Chemistry 2006
©