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R. Hron, B. S. Jursic / Tetrahedron Letters 55 (2014) 1540–1543
Figure 3. NMR experiment showing reaction progress under optimized conditions for the preparation of semicarbazide 3c.
H
N
H
N
R1
N
O
R
R1HNNHR2
2
N
H
4-methylmorpholine or K2CO3 in CH3CN
sonicate for 1-3 hrs. ~90%
O
O
C2H5O2C
C2H5O2C
2c
4
4a: R1 = CH3, R2 = H; 4b: R1 = H, R2 = C6H5; 4c: R1 = H, R2 = 2,4-(O2N)2C6H3; 4d: R1 = H, R2 = COC6H5;
4e
4f
4g
: R1 = H, R2 = COC6H4-p-NO2; : R1 = H, R2 = O2SC6H4-p-CH3; : R1 = H, R2 = COO-cholesteryl
Scheme 3. Preparation of multi-substituted semicarbazides.
Table 2
The preparation of substituted semicarbazides is almost as sim-
ple and straightforward as the preparation of phenyl carbamates.
However, the general procedure varies depending on the nature
of the particular phenyl carbamate and hydrazine. Simple reaction
conditions outlined in Figure 3 are applicable for the preparation of
a wide variety of arylsemicarbazides from corresponding arylcar-
bamates 2a–2r (Table 1). The reaction is complete after sonication
for one hour at room temperature. It is important to note that
hydrazine hydrate must be present in excess (2.5 equiv) because
it serves as both a base and a nucleophile. Hydrazine hydrate is
not fully soluble in acetonitrile, so in order to make the reaction
mixture homogenous, a few drops of water can be added. Alterna-
tively, DMF and THF can also be used as reaction solvents; how-
ever, acetonitrile is preferred due to the simplicity of isolation
and purification of the product. The presence of functional groups
such as hydroxyl, carbethoxy, carboxy, nitro, or halogens does not
alter the reaction.
When the same reaction conditions were applied to phenyl 4-
alkylcarbamates, there was no detectable product. However, the
reaction can be completed by minimal heating in all three studied
solvents. Again, the best isolated yields were obtained when the
acetonitrile solution was sonicated at 60 °C overnight (12 h). In this
way, this approach can be used to selectively transform arylcarba-
mates into arylsemicarbazide in the presence of alkylcarbamate
moiety.
Isolated yields of semicarbazides 4 with potassium carbonate as base
R1
R2
Semicarbazide 4
Yield of 4 (%)
Me
H
H
H
H
H
Ph
4a
4b
4c
4d
4e
4f
91
98
92
97
91
93
90
2,4-(NO2)2Ph
CHOPh
4-NO2CHOPh
4-MeSO2Ph
CO2-cholesteryl
H
H
4g
In theory, it is possible to form two different products in the
reaction with mono-substituted hydrazines. However, under the
conditions shown in Scheme 3, we obtained almost quantitative
yields of only one product (Table 2). We propose that this is due
to the mild reaction conditions, which favor the formation of one
product. This is because the product which is formed has a nitro-
gen attached to the carbonyl group with the higher electron den-
sity in the starting hydrazine or hydrazide.
In conclusion, we have developed an exceptionally simple, high
yield, and economical procedure for the preparation of substituted
semicarbazides from readily available amines and hydrazines via
phenyl carbamates. This condensation reaction can even be per-
formed with hydroxyl, carboxylic, nitro, or heterocyclic groups.
Not only is this approach applicable to large scale industrial syn-
theses, but also to the synthesis of semicarbazides with a variety
of functional groups, with the exception of amines.
For mono-substituted hydrazines, the reaction can be per-
formed under identical conditions but with equivalent amounts
of hydrazine and either N-methylmorpholine or anhydrous potas-
sium carbonate as a base (Scheme 3). Although both bases gave
excellent isolated yields, we prefer potassium carbonate over
N-methylmorpholine because it is easier to handle in larger
amounts. For larger molecules that are known to entrap water,
such as steroids,22 partial hydrolysis of ester groups may occur.
In this case, N-methylmorpholine is the favored base over potas-
sium carbonate.
Supplementary data
Supplementary data associated with this article can be found, in