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EtO
OEt
NH 2CN
NH 2
AcOH
EtO
OEt
Scheme-1.10.2 Lawson’s synthesis.
H
N
NH
NH 2
HCl
H 2O
N
H
N
NH 2.HCl
Kruetzberger found that condensation of 1,2-hydrazinedicarboxamidine with benzoin
derivatives in alkali media will yield symmetrically substituted azoimidazoles after
spontaneous oxidation of the bis-imidazolhydrazine (Scheme-1.10.3). 86 Reductive
cleavage of the azo group by hydrogenolysis gives two mole equivalents of the 2aminoimidazole.
This methodology is useful but limited to the preparation of 4,5diaryl
substituted 2-aminoimidazoles.
H 2N
HN
HN NH
NH
NH 2
Ar
O
OH
Ar
NaOH
Scheme-1.10.3 Kruetzberger’s condensation.
Ar
In 1966, Lancini and Lazzari successfully expanded Lawson’s strategy to include α -
aminoketones, including the use of N-alkylamines (Scheme-1.10.4). 87-88 They were
the first to observe the strict pH dependence of this condensation. At very low pH the
cyanamide is quickly converted to urea. At high pH, dimerization of the aminoketone
to the piperazine competes with cyanamide condensation. Having established the
optimum pH of the reaction to be ~4.5, these conditions are now routinely adopted. In
1925 Pyman and Burtles had reported the reaction of α-bromoacetone and guanidine
to give a mixture of uncharacterizable compounds, leading them to abandon this
approach and develop their diazonium coupling described below. 89 Seventy years
later, Weber discovered that N-acetylguanidine smoothly undergoes displacement and
condensation with α -haloketones and aldehydes. 90
O
H
N
NH 2CN
pH = 4.5
N
N
N
NH
Ar
HN
N
N
Ar
N
Ar
NH 2
H 2
Pd/C
Scheme-1.10.4 Lancini and Lazzari’s expanded strategy
Ph
Ar
HN
Ar
N
NH 2