3.2 Nucleophiles
67
Et 3 N, THF
rt, 6 d
69 %
N
Cl
NH
Ph
HO
SH
N
NH
Ph
OH
S
THF
rt, 2 h
85 %
DCC
O
O
N
N
Ph
S
O
O
O
O
Scheme 3.48 The application of thiol nucleophilicity in the synthesis of sulfur-containing
heterocycles
Et 3 N, MeCN
rt, 2 h
72 %
N
Cl
NH
EtO 2 C
S
N
N
EtO 2 C
S
N
N
EtO 2 C
S
Scheme 3.49 The high reactivity of sulfides with NIs can often lead to unexpected rearrangement
products when attempting a 1,3-dipolar cycloaddition
amine is utilised as a nucleophile, a pendant carboxylic acid or ester moiety typically
serves as a means of cyclisation, following on from the nucleophilic addition of the
thiol (Scheme 3.48) [152, 155–158].
The addition reaction of thiols to NIs has been shown to be highly efficient, and as a
result has been responsible for the generation of multiple unexpected by-products in a
number of reports. This is typically observed in attempted 1,3-dipolar cycloadditions
using compounds that also contain either sulfides or thiols (Scheme 3.49) [142,
159, 160]. In some instances, control experiments have shown that the desired
cycloaddition products are formed almost exclusively when exchanging the sulfur
for an oxygen atom [159]. Thiols have also been shown to out-compete both amines
and carboxylic acids in reactions with NIs throughout the literature [141, 156].
However, more recent studies have suggested that the order of reactivity of NIs
with nucleophiles can be established as acids ≈ thiols > amines [142].
3.2.4 Carboxylic Acids
First reported in 1961, [82] the reaction of carboxylic acids and NIs serves as another
example where the primary nucleophilic adduct was not isolated as part of the initial
study, with a bis-hydrazide formed in 83% yield (Scheme 3.50). Huisgen proposed
a similar mechanism as that of the alcohol rearrangement, with a 1,4-acyl shift
furnishing a stable product with two amide bonds.
However, unlike the reaction between an NI and an alcohol, the use of a carboxylic
acid as a reaction partner is extremely favourable, and in many cases has been shown
67
Et 3 N, THF
rt, 6 d
69 %
N
Cl
NH
Ph
HO
SH
N
NH
Ph
OH
S
THF
rt, 2 h
85 %
DCC
O
O
N
N
Ph
S
O
O
O
O
Scheme 3.48 The application of thiol nucleophilicity in the synthesis of sulfur-containing
heterocycles
Et 3 N, MeCN
rt, 2 h
72 %
N
Cl
NH
EtO 2 C
S
N
N
EtO 2 C
S
N
N
EtO 2 C
S
Scheme 3.49 The high reactivity of sulfides with NIs can often lead to unexpected rearrangement
products when attempting a 1,3-dipolar cycloaddition
amine is utilised as a nucleophile, a pendant carboxylic acid or ester moiety typically
serves as a means of cyclisation, following on from the nucleophilic addition of the
thiol (Scheme 3.48) [152, 155–158].
The addition reaction of thiols to NIs has been shown to be highly efficient, and as a
result has been responsible for the generation of multiple unexpected by-products in a
number of reports. This is typically observed in attempted 1,3-dipolar cycloadditions
using compounds that also contain either sulfides or thiols (Scheme 3.49) [142,
159, 160]. In some instances, control experiments have shown that the desired
cycloaddition products are formed almost exclusively when exchanging the sulfur
for an oxygen atom [159]. Thiols have also been shown to out-compete both amines
and carboxylic acids in reactions with NIs throughout the literature [141, 156].
However, more recent studies have suggested that the order of reactivity of NIs
with nucleophiles can be established as acids ≈ thiols > amines [142].
3.2.4 Carboxylic Acids
First reported in 1961, [82] the reaction of carboxylic acids and NIs serves as another
example where the primary nucleophilic adduct was not isolated as part of the initial
study, with a bis-hydrazide formed in 83% yield (Scheme 3.50). Huisgen proposed
a similar mechanism as that of the alcohol rearrangement, with a 1,4-acyl shift
furnishing a stable product with two amide bonds.
However, unlike the reaction between an NI and an alcohol, the use of a carboxylic
acid as a reaction partner is extremely favourable, and in many cases has been shown