66
3 The Reactivity of Nitrile Imines
BnNH 2
Ph
N
H
N
NH
Ph
185
o C, 2h
49 %
N
N
N
N
Ph
Ph
Ph
Scheme 3.45 Huisgen’s initial work in the use of amines as NI nucleophiles
Et 3 N, THF, MeOH
rt, 15 h
71 %
CO 2 H
H
N N
Cl
CO 2 H
H
N N
N
H
Me
O
Me
Me
O
Me
H 2 N
H
N N
N
Me
O
Me
O
CDI
THF
rt, 3 h
73 %
CsF, 18-crown-6 (1:1)
MeCN
0
o C, 20 min
85 %
NH
N
Cl
Ph
S
Ph
Ts
N CN
NPh
S
N
Ph
N
NH
N
Ph
S
N
NH
N
Ph
Scheme 3.46 Two examples of the cyclisation of primary products of nucleophilic amine addition
competency of nitrogen as an NI nucleophile, as the 1,3-dipolar cycloaddition adduct
of the NI with the C–N double bond is often out-competed [151].
3.2.3 Thiols
Thiols react with NIs through the classic addition mechanism outlined above to yield
α-mercaptohydrazones as the primary addition product. This was first discovered by
Huisgen in 1959 through the reaction of diphenyl NI with thiophenol, and further
elucidated by the same author in 1961 (Scheme 3.47) [31, 82].
The reactivity of thiols with NIs can be considered analogous to amines. While
facile, the reaction of thiols with NIs does not furnish an addition product of particular
synthetic value. As a consequence, the main application of this reaction is the
synthesis of sulfur-containing heterocycles. Employing a similar strategy as when an
PhSH
Ph
SPh
N
NH
Ph
170
o C, 2.5 h
87 %
N
N
N
N
Ph
Ph
Scheme 3.47 Huisgen’s initial example of thiol as a NI nucleophile