Functionalized heteroarylpyridazines and pyridazin-3(2H)-one derivatives via palladium-catalyzed cross-coupling methodology

Article abstract of DOI:10.1021/jo702420q

(Chemical Equation Presented) A general method for the synthesis of functionalized pyridazinylboronic acids/esters is described involving a directed ortho metalation (DoM)-boronation protocol (Schemes 1 and 2). A comprehensive study of the reactivity of t

Full text of DOI:10.1021/jo702420q

Functionalized Heteroarylpyridazines and Pyridazin-3(2H)-one
Derivatives via Palladium-Catalyzed Cross-Coupling Methodology
Kate M. Clapham,† Andrei S. Batsanov,† Ryan D. R. Greenwood,† Martin R. Bryce,*,†
Amy E. Smith,†,‡ and Brian Tarbit‡
Department of Chemistry, Durham UniVersity, Durham, DH1 3LE, England, and
Vertellus Specialties UK Ltd., Seal Sands Road, Middlesbrough, TS2 1UB, England
m.r.bryce@durham.ac.uk
ReceiVed NoVember 9, 2007
A general method for the synthesis of functionalized pyridazinylboronic acids/esters is described involving
a directed ortho metalation (DoM)sboronation protocol (Schemes 1 and 2). A comprehensive study of
the reactivity of the C-B bond in palladium-catalyzed cross-couplings with aryl/heteroaryl halides is
presented. Aryl-/heteroarylpyridazines are thereby obtained in synthetically viable yields (typically 40-
75%) although in some cases competing protodeboronation has been observed. A series of pyridazin-
3(2H)-one derivatives, including 4,6-diaryl/heteroaryl derivatives, have been obtained from the
corresponding 3-methoxypyridazines in straightforward procedures (Schemes 3 and 4). Several X-ray
crystal structures of aryl-/heteroarylpyridazines and derived pyridazin-3(2H)-one derivatives are reported.
These multi-ring systems are of considerable interest in contemporary N-heterocyclic chemistry.
Introduction
inhibitors, thereby acting as anti-inflammatory drugs,1c,d and
show strong affinity for R1-adrenergic receptors.3 Several
6-arylpyridazin-3(2H)-ones are active cardiotonic agents and
platelet aggregation inhibitors, notably 6-(3,4-dialkoxyphenyl)-
pyridazin-3(2H)-ones, such as zardaverine.1a Structures are
shown in Chart 1.
The pyridazine nucleus and derived 3-oxo derivatives [py-
ridazin-3(2H)-ones] are versatile pharmacophores in many
biologically active molecules of contemporary interest.1 For
example, aryl-/heteroarylpyridazine derivatives have been used
in the treatment of dementia, and others are selective GABAA
antagonists.2 Pyridazinone derivatives are cyclooxygenase-2
Examples of the pyridazine moiety in palladium-catalyzed
cross-coupling reactions are restricted to the use of halopy-
ridazines.4 An organozinc pyridazine has been prepared and
reacted in situ to synthesize heteroarylpyridazine derivatives in
good yields.5 Recently, Harrity et al. reported the preparation
of substituted pyridazinylboronic esters through the [4 + 2]
cycloaddition reaction of an alkynylboronic ester with disub-
* Address correspondence to this author.
† Durham University.
‡ Vertellus Specialties UK Ltd.
(1) (a) Sotelo, E.; Ravin˜a, E. Synlett 2003, 8, 1113 and references cited
therein. (b) Barbaro, R.; Betti, L.; Botta, M.; Corelli, F.; Giannaccini, G.;
Maccari, L.; Manetti, F.; Strappaghetti, G.; Corsano, S. J. Med. Chem. 2001,
44, 2118. (c) Chintakunta, V. K.; Akella, V.; Vedula, M. S.; Mamnoor, P.
K.; Mishra, P.; Casturi, S. R.; Vangoori, A.; Rajagopalan, R. Eur. J. Med.
Chem. 2002, 37, 339. (d) Li, C. S.; Brideau, C.; Chan, C. C.; Savoie, C.;
Claveau, D.; Charleson, S.; Gordon, R.; Greig, G.; Gauthier, J. Y.; Lau, C.
K.; Riendeau, D.; The´rien, M.; Wong, E.; Prasit, P. Bioorg. Med. Chem.
Lett. 2003, 13, 597. (e) Betti, L.; Corelli, F.; Floridi, M.; Giannaccini, G.;
Maccari, L.; Manetti, F.; Strappaghetti, G.; Botta, M. J. Med. Chem. 2003,
46, 3555. (f) Coelho, A.; Sotelo, E.; Novoa, H.; Peeters, O. M.; Blaton, N.;
Ravina, E. Tetrahedron Lett. 2004, 45, 3459. (g) Tamayo, N.; Liao, L.;
Goldberg, M.; Powers, D.; Tudor, Y.-Y.; Yu, V.; Wong, L. M.; Henkle,
B.; Middleton, S.; Syed, R.; Harvey, T.; Jang, G.; Hungate, R.; Dominguez,
C. Bioorg. Med. Chem. Lett. 2005, 15, 2409. (h) Pu, Y.-M.; Ku, Y.-Y.;
Grieme, T.; Henry, R.; Bhatia, A. V. Tetrahedron Lett. 2006, 47, 149.
(2) Maes, B. U. W.; Lemie`re, G. L. F.; Dommisse, R.; Augustyns, K.;
Haemers, A. Tetrahedron 2000, 56, 1777 and references cited therein.
(3) (a) Review: Manetti, F.; Corelli, F.; Strappaghetti, F.; Botta, M. Curr.
Med. Chem. 2002, 9, 1303. (b) For references to the biological activity of
arylpyridazinones see: Salives, R.; Dupas, G.; Ple´, N.; Que´guiner, G.; Turck,
A.; George, P.; Servin, M.; Frost, J.; Almario, A.; Li, A. J. Comb. Chem.
2005, 7, 414.
(4) For reactions of halopyridazines with arylboronates see: (a) Aldous,
D. J.; Bowe, S.; Moorcroft, N.; Todd, M. Synlett 2001, 150. (b) Parrot, I.;
Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163. (c) Sotelo, E.; Ravin˜a, E.
Synlett 2002, 223. (d) Parrot, I.; Ritter, G.; Wermuth, C. G.; Hibert, M.
Synlett 2002, 1123. With aryl/vinylstannanes see: (e) Draper, T. L.; Bailey,
T. R. J. Org. Chem. 1995, 60, 748. (f) Reference 2.
(5) Turck, A.; Ple´, N.; Lapreˆtre, A.; Que´guiner, G. Heterocycles 1998,
49, 205.
10.1021/jo702420q CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/23/2008
2176
J. Org. Chem. 2008, 73, 2176-2181

Heteroarylpyridazines and Pyridazin-3(2H)-one DeriVatiVes
TABLE 1. Palladium-Catalyzed Cross-Coupling Reactions of 2a
CHART 1. Examples of Biologically Active Arylpyridazines
and Arylpyridazinones
SCHEME 1. General Route to 10-16a
a Reagents and conditions: (i) n-BuLi, HNi-Pr2, -78 °C, THF; (ii) B(Oi-
Pr)3, -78 °C then H2O/HBr; (iii) Het-Br, Pd(OAc)2/D-t-BPF, 1,4-dioxane,
Na2CO3 (1 M), reflux.
stituted 1,2,4,5-tetrazines.6 Further transformations of the py-
ridazinylboronic esters provided access to extensively function-
alized pyridazine derivatives.
In this paper we present a route to heteroaryl-substituted
pyridazines using Suzuki-Miyaura palladium-catalyzed cross-
coupling reactions and describe the synthesis of derived
pyridazinones. In particular, there are two key aspects to our
methodology. (i) We report a series of pyridazinylboronic acids
prepared via lithiation/boronation techniques7 and (ii) we report
the facile conversion of substituted 3-methoxypyridazines into
the corresponding pyridazin-3(2H)-ones with good functional
group tolerance: this constitutes an attractive route to substituted
pyridazin-3(2H)-ones.
a Reagents and conditions: (a) (i) Pd(OAc)2 (5 mol %)/D-t-BPF (5 mol
%), 1,4-dioxane, Na2CO3 (1 M), reflux, 65 h. (b) (i) Pd(PhCN)2Cl2 (5 mol
%)/t-Bu3P (5 mol %), 1,4-dioxane, Na2CO3 (1 M), reflux, 65 h. (c) (i)
Pd(PPh3)2Cl2 (5 mol %), 1,4-dioxane, Na2CO3 (1 M), reflux, 65 h.
the catalyst system,10 1,4-dioxane, Na2CO3, reflux]11 to yield
products 10-16, respectively, thereby providing expedient
access to highly functionalized heteroarylpyridazine derivatives,
which would be very difficult to obtain by alternative methodol-
ogy. The results are collated in Table 1. The reactions proceeded
in moderate to high yields with a variety of heteroaryl bromides
as coupling partners (viz. pyridyl, pyrimidyl, pyrazyl, thienyl,
and quinolyl derivatives) including those bearing nitro (entries
1, 2, and 8) and primary amine substituents (entries 2, 4, and
5). The efficient reactions in the presence of a primary amine
Results and Discussion
Directed ortho-lithiation of 3,6-dimethoxypyridazine 18 with
LDA in THF at -78 °C followed by addition of triisopropy-
lborate and aqueous workup afforded the boronic acid derivative
2 as an air-stable solid in 88% yield (Scheme 1). Suzuki-
Miyaura cross-coupling reactions9 of 2 were carried out with a
range of heteroaryl halides 3-9 under standard conditions [Pd-
(OAc)2/1,1′-bis(di-tert-butylphosphino)ferrocene (D-t-BPF) as
(9) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(b) Stanforth, S. P. Tetrahedron 1998, 54, 263. (c) Suzuki, A. In Boronic
Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Chapter
3, pp 123-170.
(10) Itoh, T.; Mase, T. Tetrahedron Lett. 2005, 46, 3573.
(11) Pd(OAc)2/D-t-BPF was selected based on the Suzuki-Miyaura
cross-couplings of unprotected amines reported in ref 10. These workers
found D-t-BPF to be superior to other bidentate ferrocenyl ligands,
concluding that this was due to the increased ability of the chelating bis-
(phosphine) ligand to inhibit the formation of bis(amine) complexes. Other
Pd/P catalyst systems were screened [Pd(PPh3)2Cl2/t-Bu3P; Pd(PhCN)2/t-
Bu3P; and Pd(OAc)2/t-Bu3P]. In most cases Pd(OAc)2/D-t-BPF gave the
highest yields.
(6) (a) Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A. Angew.
Chem., Int. Ed. 2005, 44, 3889. (b) Helm, M. D.; Plant, A.; Harrity, J. P.
A. Org. Biomol. Chem. 2006, 4, 4278. (c) Gomez-Bengoa, E.; Helm, M.
D.; Plant, A.; Harrity, J. P. A. J. Am. Chem. Soc. 2007, 129, 2691.
(7) Review of heterocyclic boronic acids: Tyrrell, E.; Brookes, P.
Synthesis 2003, 469.
(8) Review of directed metalation of diazines: Turck, A.; Ple´, N.;
Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489.
J. Org. Chem, Vol. 73, No. 6, 2008 2177

Clapham et al.
SCHEME 2. Synthesis of 21-32a
a Reagents and conditions: (i) ArB(OH)2, Pd(PPh3)2Cl2, 1,4-dioxane, Na2CO3 (1 M), reflux, 65 h; (ii) n-BuLi, HNi-Pr2, -78 °C, THF or Et2O; (iii)
B(Oi-Pr)3, -78 °C then H2O/H+; (iv) pinacol, toluene, rt, 19 h; (v) Ar′Br 4, 5 or 33, Pd catalyst, 1,4-dioxane, base, reflux; (vi) KHF2, H2O/MeOH, rt, 1 h
f 0 °C, 1 h; (vii) ZnCl2, THF, Pd(PPh3)4, 5 or 33, reflux.
substituent are notable as new examples of Suzuki reactions
where protection of the amino group is not necessary.12
When 2 was dissolved in refluxing ethanol, protodeboronation
rapidly occurred and X-ray analysis showed that the crystals
obtained were a 1:1 molecular complex of 1 and boric acid,
1‚B(OH)3 (see the Supporting Information). Protodeboronation
was not observed in Suzuki-Miyaura cross-couplings of 2.
In a further development that has led to more highly func-
tionalized systems, we explored an alternative cross-coupling
protocol. Reaction of commercial 3-chloro-6-methoxypyridazine
17 with the readily available benzene-, 4-methoxybenzene-,
2-methoxy-5-pyridyl-,13 and 2-fluoro-5-pyridylboronic acids14
[Pd(PPh3)2Cl2, 1,4-dioxane, Na2CO3, reflux] gave products
18a-d, respectively, in high yields, providing the first example
of the 3-(pyridin-5-yl)pyridazine system.15 Treatment of py-
ridazines 18a-d with the standard lithiation-boronation tech-
nique used for the preparation of boronic acid 2 yielded boronic
acids 19a-d in 61-96% yields (Scheme 2). Electron-deficient
heterocyclic boronic acids are known to be susceptible to proto-
deboronation both during their synthesis (where careful neu-
tralization is required) and during their subsequent reactions.6a,16
Initial cross-couplings of 19a with 2-bromopyridine, 33, showed
protodeboronation occurring under a variety of Suzuki-Miyaura
conditions. In some cases boronic esters are regarded as being
more stable than their boronic acid derivatives,17 consequently
we converted boronic acids 19a-d into their pinacol ester
derivatives 20a-d in good yields after stirring with pinacol and
magnesium sulfate in toluene at room temperature (Scheme 2).18
It is pleasing to note that despite the presence of a second
directing metalation group (DMG) in 18b-d lithiation occurred
regioselectively on the more electron-deficient pyridazine ring.
Compounds 18b and 18c are of particular interest in this regard.
To our knowledge there are no literature reports which compare
the effect of the same DMG (i.e., methoxy for 18b and 18c) on
different rings in a biaryl/heteroaryl system.19 The substitution
pattern in the boronated products was confirmed unequivocally
by X-ray crystal structure determinations of 20b and 20d (see
the Supporting Information).
Suzuki-Miyaura cross-coupling reactions of 19a,b and
20a-d were carried out with heteroaryl bromides 4, 5, and 33
under standard conditions [Pd2(dba)3/PCy3, 1,4-dioxane, K3PO4
(1.27 M), reflux]20 to yield products 21-32; the results are
collated in Table 2. In every case competing protodeboronation
occurred yielding pyridazines 18a-d as byproducts, and in some
cases as the major isolated product. In attempts to overcome
the protodeboronation reaction solid K3PO4 was used;21 how-
ever, this led to decreased yields of the coupling products (Table
2, conditions b, entries 1 and 3). The catalyst system was
changed to Pd2(dba)3/[t-Bu3PH]BF4 (entry 1, conditions c),
which had been used by Harrity et al. for reactions of their
pyridazinylboronic esters.6a However, this gave no improvement
(cf. entry 1, conditions a). Microwave conditions (entry 10,
conditions d) did increase the yield of cross-coupling product
25; however, protodeboronation was again obtained. In some
cases the reactivity of trifluoroborates in coupling reactions is
superior to that of the corresponding boronic acids.22 19a was
converted to the potassium trifluoroborate derivative 34 in 97%
yield by using the established protocol with KHF2 in aqueous
methanol. However, 34 was less efficient than 19 in cross-
(19) (a) Regioselectivity of DMG on 3- and 3,6-disubstituted py-
ridazines: Turck, A.; Ple´, N.; Ndzi, B.; Que´guiner, G. Tetrahedron 1993,
49, 599. (b) Relative ortho directing power of DMG in the diazine series:
Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489.
Toudic, F.; Turck, A.; Ple´, N.; Que´guiner, G.; Darabantu, M.; Lequeux,
T.; Pommelet, J. C. J. Heterocycl. Chem. 2003, 40, 855. (c) Examples of
regioselective DoM on DMG-substituted pyridines: Mallet, M. J. Orga-
nomet. Chem. 1991, 406, 49. Comins, D. L.; Baevsky, M. F.; Hong, H. J.
Am. Chem. Soc. 1992, 114, 10971.
(20) Palladium catalyst and phosphine ligand systems were initially
screened with the reaction between 19a or 20a and 33; Pd2(dba)3/PCy3 gave
the highest yields and was subsequently used as the standard catalyst system.
Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282.
(21) Protodeboronation is partially base promoted and can be strongly
dependent on the base used. In our case other bases were not tried as the
thermal instability of the boronic acids was established; when 19a was heated
in 1,4-dioxane (in the absence of base and palladium catalyst), protodebo-
ronation was observed through TLC monitoring at temperatures >50 °C.
Other workers have found, for example, dicyclohexylamine to be an
excellent base for the Suzuki cross-coupling of a 2-boronic acid derivative
of indole, at the same time preventing protodeboronation: Payack, J. F.;
Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. J. Org. Chem. 2005,
70, 175.
(12) Thompson, A. E.; Hughes, G.; Batsanov, A. S.; Bryce, M. R.; Parry,
P. R.; Tarbit, B. J. Org. Chem. 2005, 70, 388.
(13) Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. J.
Org. Chem. 2002, 67, 7541.
(14) Parry, P. R.; Bryce, M. R.; Tarbit, B. Synthesis 2003, 1035.
(15) For previous Suzuki arylation reactions on halopyridazines see: (a)
Reference 2. (b) Reference 3b. (c) Goodman, A. J.; Stanforth, S. P.; Tarbit,
B. Tetrahedron 1999, 55, 15067. (d) Maes, B. U. W.; Kosmrlj, J.; Lemie`re,
G. L. F. J. Heterocycl. Chem. 2002, 39, 535.
(16) (a) Gronowitz, S.; Bobosik, V.; Lawitz, K. Chem. Scr. 1984, 23,
120. (b) Coudret, C.; Mazenc, V. Tetrahedron Lett. 1997, 38, 5293. (c)
Alessi, M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.;
Snieckus, V. J. Org. Chem. 2007, 72, 1588.
(17) Cailly, T.; Fabis, F.; Bouillon, A.; Lemaˆıtre, S.; Sopkova, J.; de
Santos, O.; Rault, R. Synlett 2006, 53.
(18) The direct preparation of pinacol esters 20c,d by trapping the
lithiated species from 18c,d with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane was less efficient than the two-step route via 19c,d.
(22) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
2178 J. Org. Chem., Vol. 73, No. 6, 2008

Heteroarylpyridazines and Pyridazin-3(2H)-one DeriVatiVes
TABLE 2. Cross-Coupling Reactionsa
a Reagents and conditions: (a) Pd2(dba)3 (1 mol %)/PCy3 (2.4 mol %), 1,4-dioxane, K3PO4 (1.27 M), reflux, 24 h. (b) Pd2(dba)3 (1 mol %)/PCy3 (2.4 mol
%), 1,4-dioxane, K3PO4(s), reflux, 24 h. (c) Pd2(dba)3 (5 mol %)/(t-Bu3PH)BF4 (12 mol %),MeCN, K3PO4(s), 85 °C, 1 h. (d) Pd2(dba)3 (1 mol %)/PCy3 (2.4
mol %), 1,4-dioxane, K3PO4 (1.27 M), µW 120 °C, 1 h. (e) Pd2(dba)3 (1 mol %)/PCy3(2.4 mol %), DMF, K3PO4‚2H2O, µW 160 °C, 5 min. (f) Pd(OAc)2
(5 mol %)/D-t-BPF (5 mol %), 1,4-dioxane, Na2CO3 (1 M), reflux, 5 h.
coupling reactions.23 This may be anticipated as the formation
of such an “ate” complex polarizes the C-B bond leading to
facile protodeboronation in some R-heteroaryltrifluoroborates.22
As can be observed in Table 2, we have successfully prepared
novel highly functionalized (hetero)arylpyridazine derivatives
in synthetically useful yields. Protodeboronation of these
pyridazinylboronic species dominates Suzuki-Miyuara cross-
coupling especially when less reactive coupling partners are
applied. In general the overall yields of the cross-coupled
products from the two-step protocol via the pyridazinylboronic
esters are comparable to the one-step procedure from the boronic
acid derivatives. X-ray diffraction studies confirmed the struc-
tures of compounds 22 and 24 (see the Supporting Information).
organozincate derivatives from 18a and 18c (Scheme 2).24 The
overall yields of the cross-coupling products 21, 22, and 27
(based on the starting pyridazines 18a and 18c) were improved
to 77%, 44%, and 73%, respectively, compared to the overall
yields of 64%, 33%, and 32% via the boronic acid 19a or ester
20c. Nevertheless, the boronic acid/ester route may be more
practical due to the isolation and stability of boronic acids/esters
compared to organozincate derivatives.
To increase the structural diversity of heteroarylpyridazines,
the reaction of 18c with phosphorus oxychloride/DMF under
standard Vilsmeier-Haack conditions did not give the dichlo-
robiheteroaryl product: instead compound 35 was obtained in
60% yield, representing a new route into the pharmacologically
important 6-substituted-pyridazin-3(2H)-one motif (Scheme
3).1,3 While the standard methoxy f chloro transformation
occurred at the pyridine ring of 18c,25 this was not the case at
the pyridazine ring where demethylation of the methoxy group
occurred in preference to chlorination. One explanation is that
As an alternative route in the preparation of heteroarylpy-
ridazines we have explored the formation and reactions of
(23) Cross-couplings of 34 with 2-bromopyridine 33 to yield 21 were
attempted under different reaction conditions. In each case 34 was found
to be highly insoluble at reflux temperature and no cross-coupling was
observed by TLC analysis. On the addition of water to make the reaction
mixture homogeneous, protodeboronation occurred yielding 18a as the major
product: Pd(dppf)Cl2‚CH2Cl2, Et3N, EtOH, reflux gave 21 in 47% yield;
Pd(dppf)Cl2‚CH2Cl2, Et3N, MeCN, reflux gave predominantly deboronated
species 18a; Pd2(dba)3/PCy3, Et3N, 1,4-dioxane, reflux gave 21 in 33% yield;
(24) (a) Transmetalation of the lithio derivative of 3,6-dimethoxypy-
ridazine 1 to the zincate species, followed by Negishi coupling has been
reported: see ref 5. (b) Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin,
F. J. Org. Chem. 2007, 72, 6602.
(25) For the conversion of 2-methoxypyridine to 2-chloropyridine under
Vilsmeier-Haack conditions see: Lai, L.-L.; Lin, P.-Y.; Hwu, J.-R.; Shiao,
M.-J.; Tsay, S.-C. J. Chem. Res. (S) 1996, 194.
Pd2(dba)3/PCy3, K3PO4
DMF, 110 °C gave (by LCMS analysis)
(s),
deboronated boronic species 70%, 21 26% LCMS yield.
J. Org. Chem, Vol. 73, No. 6, 2008 2179

Clapham et al.
SCHEME 3. Synthesis of 35
Experimental Section
Preparation of 3,6-Dimethoxy-4-pyridazinylboronic Acid (2).
Diisopropylamine (13.4 mL, 0.10 mol) was added to n-butyllithium
(2.5 M in hexane, 41.0 mL, 0.10 mol) in anhydrous THF (400 mL)
at -78 °C under argon. The mixture was warmed to 0 °C and left
to stir for 0.5 h. The reaction was then cooled to -78 °C and a
solution of 3,6-dimethoxypyridazine 1 (6.73 g, 48 mmol) in
anhydrous THF (100 mL) was added over 1 h. The reaction was
stirred for a further 0.5 h. Triisopropylborate (33.2 mL, 0.144 mol)
was added at -78 °C and the mixture was stirred for 1.5 h. The
mixture was warmed to -10 °C and quenched with deionized water
(100 mL). The organic solvent and most of the water were removed
in vacuo. The resulting slurry was then dissolved in water and
filtered. The filtrate was washed with diethyl ether (2 × 150 mL)
and acidified to pH 4 with HBr (48% aq solution) to precipitate 2
SCHEME 4. Synthesis of 36-39a
1
as a white solid (7.78 g, 88%): mp 152.1-153.2 °C; H NMR
(400 MHz, DMSO-d6) δ 8.50 (2H, s), 7.13 (1H, s), 3.95 (6H, s);
13C NMR (100 MHz, DMSO-d6) δ 164.0, 162.5, 125.4, 55.0, 54.8.
11B NMR (128 MHz, DMSO-d6) δ 28.9. Anal. Calcd for C6H9-
BN2O4: C, 39.17; H, 4.93; N, 15.23. Found: C, 39.00; H, 4.93;
N, 15.11.
Typical Procedure for the Cross-Coupling Reactions in Table
1. The boronic acid 2 (1.0 equiv), the aryl halide (0.9 equiv), and
the catalyst (ca. 5 mol %) were sequentially added to degassed
1,4-dioxane (10 mL) and the mixture was stirred at 20 °C for 30
min. Degassed aqueous Na2CO3 solution (1 M, 3.0 equiv) was
added and the reaction mixture was heated under argon at reflux
for 65 h. Solvent was removed in vacuo, then ethyl acetate was
added and the organic layer was washed with brine, separated, and
dried over MgSO4. The mixture was purified by chromatography
on a silica gel column followed if needed by recrystallization.
Representative Procedure for the Synthesis of 18a-d: 3-Meth-
oxy-6-(4-methoxyphenyl)pyridazine27 (18b). 4-Methoxyphenyl-
boronic acid (2.38 g, 0.016 mol), 3-chloro-6-methoxypyridazine
17 (2.0 g, 0.014 mol), and Pd(PPh3)2Cl2 (0.55 g, 0.78 mmol) were
sequentially added to degassed 1,4-dioxane (100 mL) and the
mixture was stirred at 20 °C for 30 min. Degassed aqueous Na2-
CO3 solution (1 M, 37 mL) was added and the reaction mixture
was heated under argon at reflux for 65 h. Solvent was removed in
vacuo then ethyl acetate (50 mL) was added and the organic layer
was washed with brine (50 mL), separated, and dried over MgSO4.
Recrystallization from toluene yielded 18b as a white solid (2.59
a Reagents and conditions: (i) POCl3/DMF, 110 °C, 19 h; (ii) BBr3,
DCM, reflux, 4 h; (iii) HBr (48% aq soln), AcOH, 80 °C, 3.5 h; (iv) 36,
BnBr, K2CO3, Bu4NCl, MeCN, reflux, 1 h; (v) 36, HBF4, MeOH.
the Vilsmeier-Haack reagent is acting as an acylating agent,
forming the pyridazinone, which is more stable than the
pyridazinol tautomer26 and consequently is not susceptible to
nucleophilic attack from chloride ions. Alternatively, the 3-chlo-
ropyridazine derivative may be formed and hydrolyzed to 35
during aqueous workup. The 2-chloropyridine function would
be relatively more hydrolytically stable.
To investigate the expedient conversion of methoxypy-
ridazines to their pyridazin-3(2H)-one derivatives we developed
the demethylation protocol further (Scheme 4). Compound 21
was treated with POCl3/DMF to give pyridazinone derivative
36 in 55% yield. An improved yield of 84% was obtained when
21 was treated with BBr3 in DCM at reflux. The attempted
conversion of 22 to 37 with use of BBr3 was unsuccessful;
however, using HBr (48% aq soln) in acetic acid at 80 °C gave
37 in 77% yield. Compound 36 was N-benzylated to yield 38
(93% yield) and 36 was converted into its pyridinium salt 39.
X-ray diffraction studies confirmed the structures of 38 and 39
(see the Supporting Information).
In conclusion, we have reported that lithiation/boronation of
pyridazines provides an efficient entry into a series of new
pyridazinylboronic acid/ester derivatives which are stable to
storage under ambient conditions. We have shown that these
species undergo palladium-catalyzed cross-coupling reactions
to provide aryl/heteroarylpyridazines in synthetically viable
yields, although in some cases competing protodeboronation has
been observed. Substituted 3-methoxypyridazines have been
converted into the corresponding pyridazin-3(2H)-ones with
good functional group tolerance. These functionalized hetero-
cycles are attractive candidates as new pharmacophores and
scaffolds for drug discovery. Moreover, they offer scope for
further synthetic transformations.
1
g, 87%): mp 137.4-139.0 °C (lit. mp27 134 °C); H NMR (400
MHz, CDCl3) δ 7.95 (2H, d, J ) 8.8 Hz), 7.71 (1H, d, J ) 9.2
Hz), 7.00 (3H, m), 4.16 (3H, s), 3.85 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 164.1, 160.9, 155.0, 128.9, 127.9, 126.7, 117.8, 114.5,
55.5, 54.9; MS (ES+) m/z 217.1 ([M + 1]+, 100%). Anal. Calcd
for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.75;
H, 5.62; N, 13.10.
Representative Procedure for the Synthesis of 19a-d: 3-Meth-
oxy-6-(4-methoxyphenyl)-4-pyridazinylboronic Acid (19b). Di-
isopropylamine (0.65 mL, 4.6 mmol) was added to n-butyllithium
(2.5 M in hexane, 1.8 mL, 4.6 mmol) in anhydrous ether (20 mL)
at -78 °C under argon. The mixture was warmed to 0 °C and left
to stir for 0.5 h. The reaction was then cooled to -78 °C and a
solution of 3-methoxy-6-(4-methoxyphenyl)pyridazine 18b (0.5 g,
2.3 mmol) in anhydrous ether (40 mL) was added over 1 h. (The
solid did not completely dissolve in ether at room temperature.)
The reaction was stirred for a further 1 h. Triisopropylborate (1.6
mL, 6.9 mmol) was added at -78 °C and the mixture was stirred
for 1.5 h. The mixture was warmed to room temperature and stirred
for 0.5 h before quenching with deionized water (50 mL) and then
left to stir at room temperature for 1 h. The organic solvent was
removed in vacuo. The resulting aqueous phase was then washed
with diethyl ether (3 × 50 mL) and treated with NaOH to obtain
pH 10, then acidified to pH 6 with HBr (48% aq solution) to
(26) (a) Katrusiak, A.; Katrusiak, A. J. Mol. Struct. 2004, 694, 85. (b)
Jones, R. A.; Whitmore, A. ARKIVOC, 2007, 11, 114 and references cited
therein.
(27) Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163.
2180 J. Org. Chem., Vol. 73, No. 6, 2008

Heteroarylpyridazines and Pyridazin-3(2H)-one DeriVatiVes
precipitate a white solid. The mixture was stirred overnight at pH
6. On further acidification to pH 2 more precipitate formed; after
filtration and drying 19b was obtained as a white solid (0.53 g,
was heated at 110 °C for 19 h. The reaction was cooled to 0 °C
and quenched with saturated NaOAc solution (60 mL). The mixture
was transferred to a separating funnel with the addition of deionized
water (25 mL). The mixture was extracted with EtOAc (3 × 200
mL) and washed with deionized water (3 × 150 mL). The organic
layer was dried over MgSO4 and evaporated to dryness. The solid
was recrystallized from EtOAc to give 35 as a beige solid (249
mg, 60%): mp 262.4-263.0 °C; 1H NMR (400 MHz, DMSO-d6)
δ 13.40 (1H, s), 8.89 (1H, s), 8.29 (1H, dd, J ) 8.9 Hz, J ) 1.3
Hz), 8.10 (1H, d, J ) 10.4 Hz), 7.64 (1H, d, J ) 8.3 Hz), 7.05
(1H, d, J ) 9.9 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.6,
151.1, 147.6, 141.2, 137.2, 131.8, 130.8, 130.4, 124.9; MS (ES+)
m/z 208.1 ([M + 1]+, 100%). Anal. Calcd for C9H6ClN3O: C,
52.07; H, 2.91; N, 20.24. Found: C, 52.10; H, 2.95; N, 20.06.
Preparation of 6-Phenyl-4-(pyridin-2-yl)pyridazin-3(2H)-one
(36). Boron tribromide (1 M in DCM, 3.6 mL, 3.6 mmol) was added
dropwise to a solution of 21 (232 mg, 0.89 mmol) in anhydrous
DCM (30 mL) at -78 °C. The reaction mixture was stirred at -78
°C for 15 min before warming to room temperature. The reaction
mixture was then heated at reflux for 4 h. The reaction was cooled
and deionized water (40 mL) added. The mixture was neutralized
with a saturated NaHCO3 solution to pH 7, before being extracted
with DCM (2 × 50 mL). The combined organic phase was dried
over Na2SO4, evaporated to dryness, and recrystallized from
chloroform/petroleum ether (bp 40-60 °C) to give 36 as a yellow
1
88%): mp 170.4-171.3 °C; H NMR (400 MHz, DMSO-d6) δ
8.51 (2H, s), 8.05 (1H, s), 8.01 (2H, d, J ) 8.4 Hz), 7.07 (2H, d,
J ) 8.4 Hz), 4.04 (3H, s), 3.82 (3H, s); 13C NMR (100 MHz,
DMSO-d6) δ 164.7, 160.2, 153.6, 130.5, 128.6, 127.5, 114.3, 55.2,
54.2; 11B NMR (128 MHz, DMSO-d6) δ 28.9. Anal. Calcd for
C12H13BN2O4: C, 55.42; H, 5.04; N, 10.77. Found: C, 55.39; H,
5.03; N, 10.56.
Representative Procedure for the Synthesis of 20a-d: 3-Meth-
oxy-6-(4-methoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)pyridazine (20b). A solution of 19b (1.0 g, 3.85 mmol),
pinacol (0.45 g, 3.85 mmol), and MgSO4 (2.0 g) in toluene (25
mL) was stirred for 20 h at room temperature (TLC monitoring).
The suspension was filtered and the resulting solution was washed
with brine (3 × 20 mL) and the organic phase dried over MgSO4,
filtered, and evaporated to give 20b as a white solid (1.1 g, 85%):
mp 176.4-177.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.03 (1H, s),
7.98 (2H, d, J ) 8.8 Hz), 6.97 (2H, d, J ) 8.8 Hz), 4.17 (3H, s),
3.82 (3H, s), 1.35 (12H, s); 13C NMR (100 MHz, CDCl3) δ 165.8,
160.7, 154.4, 133.2, 128.9, 127.8, 114.3, 84.8, 55.4, 55.2, 24.8;
11B NMR (128 MHz, CDCl3) δ 30.2; MS (ES+) m/z 343.4 ([M +
1]+, 100%). Anal. Calcd for C18H23BN2O4: C, 63.18; H, 6.77; N,
8.19. Found: C, 63.10; H, 6.82; N, 8.21. Crystals for X-ray
diffraction analysis were grown from hexane.
1
solid (186 mg, 84%): mp 247.6-248.5 °C; H NMR (400 MHz,
Typical Procedure for the Cross-Coupling Reactions in Table
2. The boronic ester 20a-d or acid 19a,b (1.1 equiv), the aryl halide
(1.0 equiv), Pd2(dba)3 (ca. 1 mol %), and PCy3 (ca. 2.4 mol %)
were sequentially added to degassed 1,4-dioxane (2.7 mL) and the
mixture was stirred at 20 °C for 30 min. Degassed aqueous K3PO4
solution (1.27 M, 1.7 equiv) was added and the reaction mixture
was heated under argon at reflux for 24 h. Solvent was removed in
vacuo then ethyl acetate was added and the organic layer was
washed with brine, separated, and dried over MgSO4. The mixture
was purified by chromatography on a silica gel column followed
if needed by recrystallization.
Representative Procedures for the Synthesis of Pyridazinone
Derivatives: 6-(6-Chloropyridin-3-yl)pyridazin-3(2H)-one (35).
Phosphorus oxychloride (1.86 mL, 20 mmol) was added dropwise
to a stirred solution of 18c (434 mg, 2.0 mmol) in anhydrous DMF
(40 mL) at 0 °C. Stirring was continued for 1 h then the mixture
DMSO-d6) δ 13.57 (1H, s), 8.72 (3H, m), 7.92 (3H, m), 7.51 (4H,
m); 13C NMR (100 MHz, DMSO-d6) δ 159.8, 150.2, 149.7, 144.5,
136.7, 135.8, 134.8, 129.2, 129.0, 127.7, 125.6, 124.64, 124.57;
MS (ES+) m/z 250.2 ([M + 1]+, 100%). Anal. Calcd for
C15H11N3O: C, 72.28; H, 4.45; N, 16.86. Found: C, 71.99; H, 4.38;
N, 16.77.
Acknowledgment. We thank Vertellus Specialties UK Ltd.
and EPSRC for funding.
Supporting Information Available: Synthetic procedures and
characterization data for new compounds and X-ray crystallographic
data for compounds 20b, 20d, 22, 24, 38, 39, and 1‚B(OH)3. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702420Q
J. Org. Chem, Vol. 73, No. 6, 2008 2181