Rapid analogue synthesis of trisubstituted triazolo[4,3-b]pyridazines

Article abstract of DOI:10.1016/S0040-4039(99)02153-X

A rapid analogue synthesis of biologically active 3,6,7-trisubstituted 1,2,4-triazolo[4,3-b]pyridazines was devised to give easy and selective variation of the three substituents through combinations of silicon-directed anion formation, palladium-catalysed couplings and S(N)Ar displacements. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02153-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 781–784
Rapid analogue synthesis of trisubstituted
triazolo[4,3-b]pyridazines
Ian Collins,∗ José L. Castro and Leslie J. Street
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings
Park, Harlow, CM20 2QR, UK
Received 25 October 1999; accepted 17 November 1999
Abstract
A rapid analogue synthesis of biologically active 3,6,7-trisubstituted 1,2,4-triazolo[4,3-b]pyridazines was de-
vised to give easy and selective variation of the three substituents through combinations of silicon-directed
anion formation, palladium-catalysed couplings and SNAr displacements. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: pyridazines; triazoles; coupling reactions; silicon; silicon compounds.
Trisubstituted 1,2,4-triazolo[4,3-b]pyridazines 1 (Fig. 1) have been identified as subtype selective
ligands for the benzodiazepine binding site of GABA-A receptors and as such may provide anxiolytic
drugs with improved side-effect profiles.1,2 As part of our medicinal chemistry program in this area,
we sought an efficient and general synthesis of 1 that would permit easy variation of the pendant
groups. We saw the 6,7-dihalo-1,2,4-triazolo[4,3-b]pyridazine 2 as a desirable intermediate, anticipating
discrimination between the chloroimidate and 7-halo substituent in the final stages of the synthesis
by alkoxide displacements and palladium-catalysed couplings, respectively. Initial attempts to prepare
2 by halogenation of 7-unsubstituted 6-chloro- or 6-hydroxytriazolopyridazines were unsuccessful,
as were metalations of related 6-alkoxytriazolopyridazines, and this led us to consider instead the
early introduction of the 7-halo substituent in a masked form. The well precedented conversion of
trialkylsilylarenes to aryl halides3 suggested the trimethylsilylpyridazine 34 as a suitable starting material.
Although the electrophile-induced ipso desilylation of such electron deficient heteroarylsilanes is not
established, the corresponding reaction of trialkylstannylpyridazines has been described.5
Fig. 1.
∗
Corresponding author. Fax: +44 1279 440187; e-mail: ian_collins@merck.com (I. Collins)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02153-X
tetl 16081

782
Compound 3 was prepared on a large scale by in situ quenching of the 4-lithio-anion of 3,6-
dichloropyridazine4,6 (Scheme 1). Direct conversion of 3 to the triazolopyridazine 6 was possible in
poor yield (6%) under the standard harsh conditions7 (benzoic hydrazide, Et3N·HCl, xylene, 140°C)
accompanied by copious desilylation. A milder approach began with monodisplacement of chloride
from 3 with anhydrous hydrazine to give quantitatively the separable hydrazinopyridazines 4 and 5.
The regiochemistry of the expected major product 5 was confirmed by the observed NOE. The use
of a dry THF solution of hydrazine† was critical since hydrazine hydrate led to extensive desilylation.
Acylation of 5 with aroyl chlorides was clean and high yielding when carried out in Et2O, whereas in
CH2Cl2 substantial diacylation occurred. The cyclisation of the hydrazide to the triazolopyridazine was
accomplished by several means; treatment with Et3N·HCl at 40°C yielded 48% of 6, but competitive
desilylation was again observed. Mitsunobu conditions (DEAD, PPh3, Et3N) gave a low yield (26%) of
the product. Optimum conditions were found with triphenylphosphonium dibromide, generated in situ
from triphenylphosphine and 1,2-dibromotetrachloroethane,9 which gave 6 reliably in excellent yield.
Scheme 1. Reagents and conditions: (i) LiTMP, TMSCl, THF, −78°C (67%); (ii) anhydrous NH2NH2, EtNiPr2, THF,
reflux (99%); (iii) ArCOCl, Et3N, Et2O, 0°C (59–96%); (iv) (BrCl2C)2, PPh3, Et3N, MeCN, 0°C (91–97%); (v) (BrF2C)2,
[Bu4N]+[Ph3SnF2]−, THF, rt (88–98%)
The 7-trimethylsilyltriazolopyridazine 6 proved unreactive towards electrophilic ipso halogenation3
(Br2, ICl), reflecting the strongly electron-deficient nature of the heteroarene. Treatment with alkoxides
displaced the 6-chloro substituent, but was accompanied by protodesilylation. This was reasoned to occur
through generation of an anion equivalent at C-7, presumably a hypervalent silicon complex,10 and this
mode of reactivity was exploited to introduce the desired 7-bromo substituent. Thus the anion formed
on desilylation with fluoride ion was captured by a soft electrophilic source of bromine to give the key
dihaloheteroaromatic 2 in excellent yield.11 Tetrabutylammonium triphenyldifluorostannate12 provided
a convenient, non-hygroscopic source of fluoride ion for this purpose. Multigram quantities of 2 were
readily prepared by this route. To the best of our knowledge, this is the first time such a conversion of a
heteroarylsilane to a heteroaryl bromide has been described.
Selective reaction of the chloroimidate group in 2 was achieved on treatment at low temperature
with alkoxides, such as (2-methyl-2H-[1,2,4]triazol-3-yl)methanol1 (Scheme 2). The resulting 7-bromo-
6-alkoxytriazolopyridazines 7 underwent a variety of palladium-catalysed C–C bond forming reac-
tions to complete the synthesis of the desired trisubstituted targets 1 (Table 1). For example, Stille,13
Sonogashira,14 Suzuki15 and Negishi–Knochel16,17 couplings were all successful. Although the condi-
†
CAUTION: Anhydrous solutions of hydrazine should not be over-concentrated as the neat reagent presents an explosion
hazard.8

783
tions were not optimised, improvements in yields and in the reactivity of the heterocyclic bromide were
seen with more active catalyst combinations (entries 3–5).18 Thus a short and efficient route to the targets
1 was developed with the flexibility to vary the three substituents at will, two of these in the last two
steps, which was of ready applicability to rapid analogue parallel synthesis.‡
Scheme 2. Reagents and conditions: (i) (2-methyl-2H-[1,2,4]triazol-3-yl)methanol,1 KHMDS, THF, 0°C (52–69%)
Table 1
Representative palladium-catalysed couplings to the bromides 7
The use of the trimethylsilyl group as a masked anion was developed further to extend the diversity of
substituents at the 7-position (Scheme 3). Treatment of 6 with stoichiometric fluoride ion in the presence
of methyl cyanoformate gave the ester 8 and the desilylation–protonation product 9. Alternatively,
catalytic fluoride ion was sufficient to promote the reaction of 6 with aldehydes6 to give the alcohols
such as 10. However, with less reactive or readily enolisable carbonyl compounds, e.g. cyclopentanone,
only 9 was isolated. These compounds were elaborated as before to give further analogues of 1.
Scheme 3. Reagents and conditions: (i) [(Me2N)3S]+[Me3SiF2]−, MeO2CCN, THF, rt (8, 21% and 9, 25%); (ii) MeCHO,
[Bu4N]+[Ph3SnF2]− (2×20 mol%), THF, rt (10, 75% and 9, 10%)
Finally, the use of the heterocycle as the nucleophilic component in the palladium-catalysed coupling
reactions was investigated. Transmetalation of the 7-trimethylsilyl group of 6 to the trialkylstannane
11 was achieved using Buchwald’s conditions19 (Scheme 4). The stannane 11 was indeed a competent
‡
All new compounds gave satisfactory 1H NMR and MS data. In addition, compounds in Table 1 and compound 7 (Ar=Ph)
gave satisfactory elemental analyses (C,H,N) and/or had purity of >97% as assessed by HPLC.

784
coupling partner in the Stille reaction with iodobenzene, but this reaction was markedly slower (2 days to
completion) than the corresponding couplings of the heteroaryl bromides 7. In the light of this, no further
optimisation of this sequence was attempted.
Scheme 4. Reagents and conditions: (i) (Bu3Sn)2O, TBAF (3 mol%), THF, 60°C (18%); (ii) PhI, Pd(PPh3)4, DMF, 100°C (35%)
In summary, we have devised a short and flexible rapid analogue synthesis of trisubstituted
triazolo[4,3-b]pyridazines of pharmacological interest that permits easy, selective variation of the three
substituents by exploiting the potential of a heteroarylsilane to act as a masked anion. The biological
activities of the compounds 1 and the application of this synthetic strategy to other heterocyclic systems
will be reported in due course.
Acknowledgements
We gratefully acknowledge Steven Thomas for the NMR experiment on compound 5.
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