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M. Eckhardt et al. / Tetrahedron Letters 49 (2008) 1931–1934
a shift of preference for the attachment of residues to N-3
versus N-1: easier accessiblility of N-1 over N-3 may com-
promise the selectivity for the latter derivatized regioiso-
mer.2,3 Hence, we decided to choose for such a scaffold a
more elaborated common intermediate that already
included the properly positioned substituent on the imida-
zole substructure as in 5. Unfortunately, neither compound
2 nor 5 has been described in the literature. Although a few
quite competent syntheses of the 3,5-dihydro-imidazo[4,5-d]-
pyridazin-4-one core have been reported,4–7 none that
would provide the desired scaffolds expediently and quickly
in larger quantities has been delineated. In this Letter, we
describe the convenient and efficient syntheses of the 3,5-
dihydro-imidazo[4,5-d]pyridazin-4-ones 2, 5 and analogs
of 5 and their chemoselective variation at all open sites.
The synthetic route we developed to access scaffold 2 is
outlined in Scheme 1.8 Starting out with the commercial
and inexpensive dicyanoimidazole 6, monoketone 8 was
acquired in 45% yield by the addition of three equivalents
of methylmagnesium halide to the imidazole dissolved in
tetrahydrofuran.9,10 Besides the desired product, diketone
7 was isolated in about 5–10% yield. We did not spend
much effort on optimizing the yield of this transformation
since the product was obtained in high purity after simple
precipitation from ethyl acetate and ether. Subsequently,
monoketone 8 was reacted with hydrazine hydrate in
ethanol at elevated temperature, which resulted in a clean
conversion to compound 9 in nearly quantitative yield.
Diazotization of 9 using sodium nitrite and sulfuric acid
in acetic acid and water followed by hydrolysis of the diazo
intermediate at reflux temperature furnished the 3,5-di-
hydro-imidazo[4,5-d]pyridazin-4-one core 10 in excellent
yield and purity after precipitation from water. Bromina-
tion of compound 10 was conducted in the presence of
potassium carbonate with bromine in acetonitrile. After
the aqueous work-up and precipitation from water, the
desired relay compound 2 was obtained in 70% yield.11
This route appeals by its conciseness and efficiency. All
reaction steps have been carried out on 5–20 g-scale with-
out the use of any chromatographic purification. In addi-
tion, the route may be employable for further C-7 carbon
derivatized 3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones pro-
vided that the selective monoaddition to 6 of carbon
nucleophiles other than methyl is workable.
Opportunely, relay compound 2 could be selectively
derivatized at N-3 and N-5 by reacting with an alkyl elec-
trophile and at C-2 by displacing the bromine with a nitro-
gen nucleophile using the conditions applied in the
variation of xanthine 1 (Scheme 2). Reaction of 2 with
one equivalent of an alkyl halide in the presence of a weak
amine base, such as triethylamine or ethyldiisopropyl-
amine, in dimethylformamide gave the monoalkylated
product selectively derivatized at N-3 in high yield; neither
the competing N-1 nor the N-5 alkylated product was
detected. Alkylation of N-5 was then carried out using
the stronger base potassium carbonate in dimethylformam-
ide affording product 13 in good yield; O-alkylation at C-4
instead of N-alkylation was not observed. Replacement of
the bromine at C-2 for 3-tert-butoxycarbonylaminopiperi-
dine (?14) was accomplished in high yield using sodium
carbonate in dimethylsulfoxide at elevated temperature;
however, dimethylformamide or N-methylpyrrolidinone
could be employed with similar success. The order of intro-
duction of the last two substituents could be reversed
allowing specific variations at either site at a very late stage
of the reaction sequence. However, initial introduction of
the residue at C-2 required longer reaction times for the
nucleophilic displacement to be complete due most likely
to the abstraction of the proton at N-5 by the base that ren-
ders the scaffold less electrophilic. Additionally, it was also
feasible to carry out the last two steps in one pot to stream-
line the reaction sequence. Accordingly, compound 11 was
reacted first with the alkyl halide in the presence of potas-
sium carbonate in dimethylformamide. After complete
consumption of the starting material, determined by HPLC
or TLC, the nucleophile was added and the temperature
increased to 80 °C to deliver the product within 8–10 h in
yields comparable to those obtained for the step-by-step
procedure. In a first trial, we also succeeded in attaching
all three substituents successively to 2 in one pot using
dimethylformamide as the solvent and ethyldiisopropyl-
amine followed by potassium carbonate as the bases
achieving a yield of 56% for the purified product bearing
2-butynyl at N-3, methyl at N-5, and 3-tert-butoxycarbonyl-
aminopiperidinyl at C-2.
NH2
H
N
O
H
H
N
N
a
b
N
N
N
N
N
N
N
N
(45%)
(95%)
6
7
8
9
O
H
N
c
(94%)
O
The syntheses of scaffold 5 and analogs were accom-
plished in four steps from the commercial imidazole 15
(Scheme 3).12 The sequence started with the bromination
of 15 furnishing 16 in excellent yield using either bromine
in combination with potassium carbonate in a solvent mix-
ture of dichloromethane and acetonitrile or N-bromosuc-
cinimide in acetonitrile.13 At this stage, the residue at N-3
of the eventual scaffold 50 was attached via alkylation of
one imidazole nitrogen. Allyl, propargyl, and benzyl resi-
dues were introduced via their corresponding halides by
O
N
O
H
H
N
d
H
N
N
N
HN
N
Br
N
N
(70%)
2
10
Scheme 1. Reagents and conditions: (a) MeMgCl (3 equiv, 3 mol/L in
Et2O), THF, 5–10 °C; (b) H2NNH2ꢀH2O (4 equiv), EtOH, reflux; (c)
NaNO2 (4 equiv), H2SO4 (0.6 equiv), HOAc, H2O, 50 °C (0.5 h), then
95 °C; (d) Br2 (1.1 equiv), K2CO3 (1.2 equiv), MeCN, 60 °C.
Eckhardt, Matthias
