Facile one-pot synthesis of 4-substituted semicarbazides

Article abstract of DOI:10.1039/c4ra12425a

A diverse library of twenty-five 4-mono- and disubstituted semicarbazides was prepared in a one-pot two-step approach. The method includes formation of a carbamate from bis(2,2,2-trifluoroethyl)carbonate or 2,2,2-trifluoroethylchloroformate and a primary or secondary amine and subsequent interaction of the carbamate with hydrazine to result in a semicarbazide. The approach allowed to obtain 4-substituted semicarbazides on a large scale in good yield and high purity. This journal is

Full text of DOI:10.1039/c4ra12425a

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PAPER
Facile one-pot synthesis of 4-substituted
semicarbazides†
Cite this: RSC Adv., 2015, 5, 1063
a
ab
ac
Yurii V. Dmytriv,a
*
*
Andrey V. Bogolubsky, Yurii S. Moroz,
Pavel K. Mykhailiuk,
Sergey E. Pipko,b Liudmyla N. Babichenko,ab Anzhelika I. Konovetsad
and Andrey Tolmachevab
A diverse library of twenty-five 4-mono- and disubstituted semicarbazides was prepared in a one-pot two-
step approach. The method includes formation of a carbamate from bis(2,2,2-trifluoroethyl)carbonate or
2,2,2-trifluoroethylchloroformate and a primary or secondary amine and subsequent interaction of the
carbamate with hydrazine to result in a semicarbazide. The approach allowed to obtain 4-substituted
semicarbazides on a large scale in good yield and high purity.
Received 15th October 2014
Accepted 24th November 2014
DOI: 10.1039/c4ra12425a
www.rsc.org/advances
phenyl and p-nitrophenyl carbamates (pKa(phenol) z 10,
pKa(p-nitrophenol) z 7) are very reactive substrates and can
Introduction
easily form symmetrical ureas with active amines during the
synthesis of the carbamate, which complicates a one-pot
A semicarbazide motif is widespread in agrochemistry, drug
discovery, and organic synthesis (Fig. 1).1–5
transformation
semicarbazide.
of
the
carbonate
to
4-substituted
Methods for obtaining 4-substituted semicarbazides,
common building blocks to introduce the semicarbazide motif
into molecules, include reactions of hydrazine with (a) isocya-
nates, (b) N-substituted carbamoyl chlorides, and (c) carba-
mates (Scheme 1).6–26
Several disadvantages, however, can be noted for the existing
synthetic approaches. Isocyanates are toxic and available with
limited number of substituents (less than 300 substances are
listed in eMolecules database), which decreases diversity of the
semicarbazide motifs. N-substituted carbamoyl chlorides are
effective reagents for the synthesis of 4-substituted semi-
carbazides; but they are derived from phosgene or triphosgene
that are toxic, inconvenient in handling, and may result in side
products in the reactions with functionalized amines.
Commonly utilized ethyl, phenyl and p-nitrophenyl carbamates
or “blocked isocyanates”27,28 that are synthesized from the cor-
responding carbonates or chloroformates provide a facile
approach to diverse semicarbazides.
Fig. 1 Drugs and agrochemicals bearing the semicarbazide motif.4,5
Reactivity of the carbamate is related to a pKa value of the
released alcohol:29 ethyl carbamates (pKa(ethanol) z 16) poorly
react with hydrazine resulting in longer time of the reaction;
aEnamine Ltd., 23 Matrosova Street, Kyiv, 01103, Ukraine. E-mail: ysmoroz@mail.
enamine.net; Pavel.Mykhailiuk@mail.enamine.net; Pavel.Mykhailiuk@gmail.com
bChemBioCenter, Kyiv National Taras Shevchenko University, 61 Chervonotkatska
Street, Kyiv, 02094, Ukraine
cDepartment of Chemistry, Kyiv National Taras Shevchenko University, 64
Volodymyrska Street, Kyiv, 01601, Ukraine
dThe Institute of High Technologies, Kyiv National Taras Shevchenko University, 4
Glushkov Street, Building 5, Kyiv, 03187, Ukraine
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of the synthesized compounds. See DOI: 10.1039/c4ra12425a
Scheme 1 Synthetic approaches to 4-substituted semicarbazides.6–26
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Table 1 Synthesized 4-substituted semicarbazides
Amine Semicarbazide
Recently we have successfully employed bis(2,2,2-
triuoroethyl)carbonate
(1)
and
2,2,2-triuoroethyl-
Yielda (%)
chloroformate (2) in the one-pot synthesis of unsymmetrical
ureas30,31 (Scheme 2), where a preformed carbamate 3 interacted
with a primary or secondary alkyl amine to produce a di- or
trisubstituted urea 4, respectively. The moderate reactivity of
the 2,2,2-triuoroethyl carbamates (pKa(2,2,2-triuoroethanol)
z 12) compared with the ethyl and the phenyl carbamates
prevented formation of symmetrical ureas during the carba-
mate synthesis and allowed for rapid interaction of the carba-
mate with the nucleophile resulting in a desirable product and a
volatile and easily separable by-product, 2,2,2-triuoroethanol.
Herein, we present our results on utilization of this strategy
for a one-pot synthesis of 4-substituted semicarbazides.
5.1
5.2
85
83
5.3
5.4
5.5
5.6
81
87
90
73
Results and discussion
To test our approach, we decided to synthesize on a large scale a
diverse library of 4-substituted semicarbizides utilizing 25
amines: alkyl and aryl, primary and secondary, simple and
functionalized (Table 1). The approach consists of two steps: (1)
in situ preparation of the carbamate and (2) the subsequent
interaction of the carbamate with hydrazine (Scheme 3). We
found that bis(2,2,2-triuoroethyl)carbonate (1) smoothly reac-
ted with alkyl amines in the presence of a base at room
temperature producing carbamates 3 but showed no reactivity
with less nucleophilic aryl amines. More active 2,2,2-tri-
uoroethylchloroformate (2), however, formed the carbamates
under similar conditions with aryl amines. Reagents 1 and 2 can
be synthesized simultaneously in the same reaction between
triphosgene and 2,2,2-triuoroethanol31 which makes them
available for both types of amines.
In the rst step, reagent 1 or 2 was mixed with an alkyl or aryl
amine in dichloromethane at 0 ꢀC in the presence of triethyl-
amine. Continuous stirring of the reaction mixture for 3 or
6 hours (for aryl or alkyl amines, respectively) at room temper-
ature gave carbamates 3 in high purity according to the 1H NMR
of the crude material. Aer removing the solvent under vacuum,
by-product 2,2,2-triuoroethanol, and unreacted 1 or 2, an
alcohol solution of hydrazine hydrate was added to the crude
carbamate and the resulting mixture was heated at reux for 1.5
hours.
5.7
5.8
74
86
5.9
78
72
80
49
38
5.10
5.11
5.12
5.13
5.14
5.15
35
57
Our results indicated that the higher nucleophilicity of
hydrazine compared with amines allowed for a direct interac-
tion with the carbamates in cases where a transient isocyanate
5.16
5.17
5.18
53
50
55
5.19
51
Scheme 2 One-pot synthesis of unsymmetrical ureas from reagents 1
and 2.30,31
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Table 1 (Contd.)
The synthesized semicarbazides typically precipitated out
from the solution and were easily separated by ltration. The
products were obtained in moderate to high yields; the identity
Amine
Semicarbazide
Yielda (%)
1
and purity of them were conrmed by means of H, 13C NMR
spectroscopy and LC-MS analysis. The yields for 4-disubstituted
semicarbazides were generally lower than those for the mono-
substituted analogs. H NMR spectra of the compounds recor-
5.20
50
1
ded in DMSO-d6 contained characteristic broad peaks for NH
groups (in most cases three for 5.1–5.11 and 5.15–5.24 and two
for 5.12–5.14 and 5.25) and one set of signals for each alkyl or
aryl group.
5.21
5.22
52
55
The experimental results showed advantages of reagents 1
and 2 over the commonly used reagents. The synthesized
semicarbazides were obtained as solids except for compound
5.3 in high purity with no need for further purication. Semi-
carbazide 5.17 derived from 3,4-(methylenedioxy)aniline was
obtained in good yield utilizing the above procedure, but the
experiment with phenyl chloroformate failed because substan-
tial amount of the symmetrical urea formed. Additional func-
tionalities (hydroxyl in 5.16 and carboxylic in 5.24) were
tolerated under the reaction conditions.
5.23
5.24
52
55
Conclusions
5.25
39
We employed bis(2,2,2-triuoroethyl) carbonate (1) and 2,2,2-
triuoroethyl chloroformate (2) in a facile one-pot synthesis of
twenty ve 4- mono and disubstituted semicarbazides. The
approach allows to prepare the semicarbazides derived from
alkyl and aryl amines in moderate to good yields and high
purity. The developed approach makes possible to generate
diverse 4-substituted semicarbazides under conditions of
parallel synthesis, which would expand availability of the
compounds with the semicarbazide structural motif.
a
Isolated yield in respect to the quantity of the starting amine.
Experimental
Materials and methods
All amines and solvents were obtained from commercially
available sources (Aldrich, Enamine Ltd.) and used without
further purication. Bis(2,2,2-triuoroethyl)carbonate and
2,2,2-triuoroethyl chloroformate were prepared as previously
described.31 IR spectra were recorded on Perkin-Elmer Spec-
trum BX II. NMR spectra were acquired on Bruker Avance DRX
500 spectrometer using CDCl3 or DMSO-d6 as a solvent and
tetramethylsilane (TMS) as an internal standard. Melting points
were determined on a Buchi melting point apparatus and are
uncorrected. LC-MS data were obtained on Agilent 1100 HPLC
equipped with diode-matrix and mass-selective detector Agilent
LC/MSD SL. According to the LC-MS data all the synthesized
compounds have purity over 95%. Elemental analysis was done
on a Vario MICRO Cube (Elementar) Elemental Micro-Analyzer.
Scheme
3 One-pot synthesis of 4-substituted semicarbizides.
Reagents and conditions: (A) (i) alkyl amine, triethylamine, stirring at
room temperature for 6 hours; (ii) hydrazine hydrate, heating under
reflux for 1–2 hours; (B) (iii) aryl amine, triethylamine, stirring at room
temperature for 3 hours; (iv) hydrazine hydrate, heating under reflux
for 1–2 hours.
can't be formed32,33 which resulted in 4-disubstituted semi-
carbazides 5.12–5.14 and 5.25 (Table 1). In the reaction between
disubstituted carbamate and hydrazine, however, secondary
amine, a better leaving group than a primary amine, can be
easily substituted with hydrazine under reaction conditions to
produce carbohydrazide. Therefore, we monitored the progress
of the reaction using 1H NMR to decrease the formation of this
side product.
General procedure for the one-pot synthesis of 4-substituted
alkyl (method A) and aryl (method B) semicarbazides (5)
To a chilled stirred solution of an amine (0.1 mol) and
triethylamine (0.11 mol, method A, 0.2 mol, method B) in
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dichloromethane (70 mL) was added dropwise 0.11 mol of
bis(2,2,2-triuoroethyl)carbonate (1) (method A) or 2,2,2-tri-
uoroethyl chloroformate (2) (method B). Care was taken to
maintain temperature below 0 ꢀC during the addition. The
obtained mixture was stirred for 3 hours (6 hours in case of
method B) at room temperature; then, the solvent, triethyl-
amine and unreacted 1 or 2 were removed under reduced
pressure. To a solution of the crude carbamate 3 in ethanol (100
mL) hydrazine hydrate (0.5 mol, method A and 0.75 mol,
method B) was added. The reaction mixture was heated under
reux for approximately 1.5 hours. For carbamates 5.12–5.14
and 5.25, derived from secondary amines, the reaction was
monitored by 1H NMR to prevent formation of the symmetrical
side product, carbonohydrazide. Most semicarbazides precipi-
tated out upon cooling down the solution to room temperature.
In other cases, the solvent was evaporated under reduced
pressure and the remained crude product 5 was treated with
diethyl ether to form solid or viscous oil (5.3). The product was
separated by ltration and dried in vacuum.
4-(Cyclopenthyl)semicarbazide (5.5). Yield: 12.9 g, 90%,
white solid, Mp 123–125 ꢀC. IR (KBr): 3373, 3306, 3299 (NH),
2958, 2869 (CH), 1631 (C]O) cmꢁ1. 1H NMR (500 MHz, DMSO-
d6): d ¼ 1.33 (m, 2H, CH2), 1.50 (m, 2H, CH2), 1.61 (m, 2H, CH2),
1.78 (m, 2H, CH2), 3.87 (m, 1H, CH), 4.05 (br. s, 2H, NH2), 6.12
(m, 1H, NH), 6.82 (s, 1H, NH) ppm. 13C NMR (125 MHz, DMSO-
d6) d ¼ 23.3, 33.0, 50.7, 160.0 ppm. MS (APCI) m/z [M + H]+
calculated for C6H14N3O 144.1, found 144.2. Anal. calcd for
C6H13N3O: C, 50.33; H, 9.15; N, 29.35; found C, 50.30; H, 9.21; N,
29.32%.
4-(2,2,2-Triuoroethyl)semicarbazide (5.6). Yield: 11.5 g,
73%, whitish solid, Mp 72–74 ꢀC. IR (KBr): 3366, 3311, 3230
(NH), 3007, 2974, 2925 (CH), 1630 (C]O) cmꢁ1 1H NMR
.
(500 MHz, DMSO-d6): d ¼ 3.80 (m, 2H, CH2), 4.22 (br. s, 2H,
NH2), 6.90 (s, 1H, NH), 7.36 (s, 1H, NH) ppm. 13C NMR (125 MHz,
2
1
DMSO-d6) d ¼ 40.8 (q, JC,F ¼ 34 Hz), 125.7 (q, JC,F ¼ 279 Hz),
160.0 ppm. MS (APCI) m/z [M + H]+ calculated for C3H7F3N3O 158.1,
found 158.1. Anal. calcd for C3H6F3N3O: C, 22.94; H, 3.85; N, 26.75;
found C, 22.90; H, 3.90; N, 26.73%.
4-Butyl semicarbazide (5.1). Yield: 11.2 g, 85%, white solid,
Mp 45–47 ꢀC. IR (KBr): 3500, 3358, 3338, 3316, 3215 (NH), 2963,
4-(2-Thiophen-2yl-ethyl)semicarbazide (5.7). Yield: 13.7 g,
74%, yellowish solid, Mp 90–92 C. IR (KBr): 3379, 3355, 3243
ꢀ
2932, 2873, 2861, 2852 (CH), 1662 (C]O) cmꢁ1 1H NMR
.
(NH), 3071, 2969, 2933, 2860 (CH), 1648 (C]O) cmꢁ1. 1H NMR
(500 MHz, DMSO-d6): d ¼ 2.92 (t, 3J ¼ 7.2 Hz, 2H, CH2), 3.29 (q,
3J ¼ 7.0 Hz, 2H, CH2), 4.09 (s, 2H, NH2), 6.49 (s, 1H, NH), 6.88
(m, 1H, Het), 6.96 (m, 1H, Het), 7.00 (s, 1H, NH), 7.33 (m, 1H,
Het) ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 30.9, 41.2, 124.3,
125.5, 127.4, 142.4, 160.6 ppm. MS (APCI) m/z [M + H]+ calcu-
lated for C7H12N3OS 186.1, found 186.3. Anal. calcd for
C7H11N3OS: C, 45.39; H, 5.99; N, 22.68; found C, 45.37; H, 6.05;
N, 22.64%.
(500 MHz, CDCl3): d ¼ 0.87 (t, 3J ¼ 7.2 Hz, 3H, CH3), 1.27 (m, 2H,
3
CH2), 1.36 (m, 2H, CH2), 3.02 (q, J ¼ 6.5 Hz, 2H, NCH2), 4.07
(br. s, 2H, NH2), 6.29 (br. s, 1H, NH), 6.90 (s, 1H, NH) ppm. 13
C
NMR (125 MHz, DMSO-d6) d ¼ 14.2, 20.0, 32.7, 39.0, 160.8 ppm.
MS (APCI) m/z [M + H]+ calculated for C5H14N3O 132.1, found
132.2. Anal. calcd for C5H13N3O: C, 45.78; H, 9.99; N, 32.03;
found C, 45.69; H, 10.08; N, 31.95%.
4-Penthyl semicarbazide (5.2). Yield: 12 g, 83%, white solid,
Mp 66–68 ꢀC. IR (KBr): 3395, 3293, 3220 (NH), 2955, 2930,
2872, 2860 (CH), 1663 (C]O) cmꢁ1. 1H NMR (500 MHz, DMSO-
4-(1,1-Dioxo-tetrahydro-1l6-thiophen-3-yl)semicarbazide
(5.8). Yield: 16.6 g, 86%, yellowish solid, Mp 167–168 ꢀC. IR
(KBr): 3363, 3343, 3295, 3234 (NH), 3007, 2947 (CH), 1666 (C]
O) cmꢁ1. 1H NMR (500 MHz, DMSO-d6): d ¼ 2.11 (m, 1H, CH2),
2.31 (m, 1H, CH2), 3.02 (m, 1H, CH2), 3.12 (m, 1H, CH2), 3.27 (m,
2H, CH2), 4.14 (s, 2H, NH2), 4.38 (m, 1H, CH), 6.79 (br. s, 1H,
NH), 7.18 (s, 1H, NH) ppm. 13C NMR (125 MHz, DMSO-d6)
d ¼ 29.7, 46.8, 51.4, 56.0, 159.9 ppm. MS (APCI) m/z [M + H]+
calculated for C5H12N3O3S 194.1, found 194.2. Anal. calcd for
C5H11N3O3S: C, 31.08; H, 5.74; N, 21.75; found C, 31.05; H, 5.78;
N, 21.72%.
3
d6): d ¼ 0.87 (t, J ¼ 7.2 Hz, CH3), 1.27 (m, 4H, CH2), 1.39 (m,
2H, CH2), 3.01 (q, 3J ¼ 6.7 Hz, CH2), 4.05 (br. s, 2H, NH2), 6.28
(br. s, 1H, NH), 6.85 (s, 1H, NH) ppm. 13C NMR (125 MHz,
DMSO-d6) d ¼ 14.4, 22.4, 29.1, 30.3, 39.3, 160.7 ppm. MS (APCI)
m/z [M + H]+ calculated for C6H16N3O 146.1, found 146.1. Anal.
calcd for C6H15N3O: C, 49.63; H, 10.41; N, 28.94; found C,
49.57; H, 10.50; N, 28.83%.
4-(3-Methoxypropyl)semicarbazide (5.3). Yield: 11.9 g, 81%,
colorless viscous oil. 1H NMR (500 MHz, DMSO-d6): d ¼ 1.62 (m,
2H, CH2), 3.07 (q, 3J ¼ 6.5 Hz, 2H, CH2), 3.22 (s, 3H, OCH3), 3.33
4-(C-(Tetrahydro-furan-2-yl)-methyl)semicarbazide
(5.9).
3
Yield: 12.4 g, 78%, yellowish solid, Mp 80–81 ꢀC. IR (KBr): 3309,
(t, J ¼ 6.2 Hz, 2H, CH2), 3.99 (br. s, 2H, NH2), 6.37 (br. s, 1H,
NH), 6.91 (s, 1H, NH) ppm. 13C NMR (125 MHz, DMSO-d6) d ¼
30.6, 36.9, 58.4, 70.5, 160.8 ppm. MS (APCI) m/z [M + H]+
calculated for C5H14N3O2 148.1, found 148.2%.
3226, 3090 (NH), 2943, 2871 (CH), 1662 (C]O) cmꢁ1. H NMR
1
(500 MHz, DMSO-d6): d ¼ 1.49 (m, 1H, CH2), 1.83 (m, 3H, CH2),
3.03 (m, 1H, CH2), 3.17 (m, 1H, CH2), 3.60 (m, 1H, CH2), 3.80 (m,
2H, CH + CH2), 4.1 (br. s, 2H, NH2), 6.32 (s, 1H, NH), 6.97 (s, 1H,
NH) ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 25.8, 28.7, 43.4,
67.6, 78.3, 160.7 ppm. MS (APCI) m/z [M + H]+ calculated for
C6H14N3O2 160.1, found 160.2. Anal. calcd for C6H13N3O2: C,
45.27; H, 8.23; N, 26.40; found C, 45.23; H, 8.30; N, 26.38%.
4-(C-Furan-2-yl-methyl)semicarbazide (5.10). Yield: 11.2 g;
4-(C-Cyclopropyl-methyl)semicarbazide (5.4). Yield: 11.2 g,
87%, whitish solid, Mp 54–56 ꢀC. IR (KBr): 3370, 3353, 3326,
1
3298 (NH), 3005, 2972, 2929, 2874 (CH), 1660 (C]O) cmꢁ1. H
NMR (500 MHz, DMSO-d6): d ¼ 0.15 (m, 2H, CH2), 0.38 (m, 2H,
CH2), 0.91 (m, 1H, CH), 2.91 (t, 3J ¼ 6.2 Hz, 2H, CH2), 4.10 (br. s,
2H, NH2), 6.36 (br. s, 1H, NH), 6.90 (s, 1H, NH) ppm. 13C NMR
(125 MHz, DMSO-d6) d ¼ 3.1, 11.7, 43.4, 160.3 ppm. MS (APCI)
m/z [M + H]+ calculated for C5H12N3O 130.1, found 130.2. Anal.
calcd for C5H11N3O: C, 46.50; H, 8.58; N, 32.53; found C, 46.47;
H, 8.63; N, 32.48%.
ꢀ
72%, yellowish solid, Mp 88–89 C. IR (KBr): 3403, 3338, 3217,
1
3137 (NH), 3082, 2951, 2930 (CH), 1663 (C]O) cmꢁ1. H NMR
(500 MHz, DMSO-d6): d ¼ 4.14 (s, 2H, NH2), 4.23 (d, 3J ¼ 6.0 Hz,
2H, CH2), 6.19 (m, 1H, Het), 6.37 (m, 1H, Het), 7.01 (m, 1H, NH),
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7.09 (m, 1H, NH), 7.55 (s, 1H, Het) ppm. 13C NMR (125 MHz, OH), 7.08 (d, 3J ¼ 8.0 Hz, 2H, Ar), 7.35 (s, 1H, NH), 7.41 (d,
DMSO-d6) d ¼ 36.5, 106.6, 110.8, 142.2, 154.2, 160.4 ppm. MS 3J ¼ 8.2 Hz, 2H, Ar), 8.54 (s, 1H, NH) ppm. 13C NMR (125 MHz,
(APCI) m/z [M + H]+ calculated for C6H10N3O2 156.1, found DMSO-d6) d ¼ 38.9, 62.9, 118.7, 129.4, 132.9, 138.3, 158.0 ppm.
156.2. Anal. calcd for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08; MS (APCI) m/z [M + H]+ calculated for C9H14N3O2 196.1, found
found C, 46.41; H, 5.90; N, 27.05%.
196.2. Anal. calcd for C9H13N3O2: C, 55.37; H, 6.71; N, 21.52;
4-(3-Triuoromethyl-benzyl)semicarbazide (5.11). Yield: 18.6 found C, 55.32; H, 6.80; N, 21.48%.
g, 80%, whitish solid, Mp 87–90 ꢀC. IR (KBr): 3395, 3364, 3325,
4-(Benzo[1,3]dioxol-5-yl)semicarbazide (5.17). Yield: 9.8 g,
3244 (NH), 3079, 2957, 2928 (CH), 1668 (C]O) cmꢁ1. H NMR 50%, brown solid, Mp 163–165 C. IR (KBr): 3357, 3334, 3222,
(500 MHz, DMSO-d6): d ¼ 4.20 (br. s, 2H, NH2), 4.33 (d, 3J ¼ 6.1 3177 (NH), 3088, 3006, 2937, 2909, 2893 (CH), 1681 (C]O)
Hz, 2H, CH2), 7.07 (s, 1H, NH), 7.15 (s, 1H, NH), 7.57 (m, 4H, Ar) cmꢁ1. 1H NMR (500 MHz, DMSO-d6): d ¼ 4.33 (br. s, 2H, NH2),
ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 42.6, 123.6 (q, 5.94 (s, 2H, CH2), 6.78 (d, 3J ¼ 8.5 Hz, 1H, Ar), 6.88 (d, 3J ¼ 8 Hz,
3JC,F ¼ 4.6 Hz), 124.0 (q, 3JC,F ¼ 4.2 Hz), 124.8 (q, 1JC,F ¼ 272 Hz), 1H, Ar), 7.28 (s, 1H, Ar), 7.34 (br. s, 1H, NH), 8.54 (s, 1H, NH)
1
ꢀ
2
129.4 (q, JC,F ¼ 33 Hz), 129.6, 131.7, 143.3, 160.8 ppm. MS ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 101.1, 101.3, 108.4,
(APCI) m/z [M + H]+ calculated for C9H11F3N3O 234.1, found 111.3, 135.0, 142.1, 147.5, 158.0 ppm. MS (APCI) m/z [M + H]+
234.2. Anal. calcd for C9H10F3N3O: C, 46.36; H, 4.32; N, 18.02; calculated for C8H10N3O3 196.1, found 196.2. Anal. calcd for
found C, 46.32; H, 4.40; N, 17.97%.
C8H9N3O3: C, 49.23; H, 4.65; N, 21.53; found C, 49.18; H, 4.74; N,
N,N-Dimethyl semicarbazide (5.12). Yield: 5.1 g, 49%, white 21.45.
solid, Mp 86–88 ꢀC. IR (KBr): 3424, 3338 (NH), 2936, 2886 (CH),
N-(4-Methoxyphenyl)hydrazinecarboxamide (5.18). Yield: 9.8
1
1641 (C]O) cmꢁ1. H NMR (500 MHz, DMSO-d6): d ¼ 2.85 (s, g, 55%, beige solid, Mp 146–148 ꢀC. IR (KBr): 3363, 3356, 3311,
6H, 2CH3), 3.80 (br. s, 2H, NH2), 6.28 (br. s, 1H, NH) ppm. 13C 3259 (NH), 3156, 3090, 3036, 3005, 2975, 2835 (CH), 1680 (C]O)
NMR (125 MHz, DMSO-d6) d ¼ 35.6, 160.3 ppm. MS (APCI) m/z cmꢁ1. H NMR (500 MHz, DMSO-d6): d ¼ 3.70 (s, 3H, OCH3),
1
[M + H]+ calculated for C3H10N3O 104.1, found 104.2. Anal. calcd 4.32 (br. s, 2H, NH2), 6.83 (d, 3J ¼ 7 Hz, 2H, Ar), 7.29 (s, 1H, NH),
for C3H9N3O: C, 34.94; H, 8.80; N, 40.75; found C, 34.80; H, 8.92; 7.42 (d, J ¼ 7 Hz, 2H, Ar), 8.46 (br. s, 1H, NH) ppm. 13C NMR
3
N, 40.69%.
(125 MHz, DMSO-d6) d ¼ 55.6, 114.3, 120.4, 133.6, 154.7, 158.1
Morpholine-4-carbohydrazide (5.13). Yield: 5.5 g, 38%, ppm. MS (APCI) m/z [M + H]+ calculated for C8H12N3O2 182.1,
yellowish solid, Mp 121–122 ꢀC. IR (KBr): 3320, 3230 (NH), 2987, found 182.2. Anal. calcd for C8H11N3O2: C, 53.03; H, 6.12; N,
2959, 2933, 2917, 2903, 2864 (CH), 1651 (C]O) cmꢁ1. 1H NMR 23.19; found C, 52.94; H, 6.26; N, 23.04%.
(500 MHz, DMSO-d6): d ¼ 3.25 (m, 4H, 2CH2), 3.53 (m, 4H,
N-(2-Chloro-5-methoxyphenyl)hydrazinecarboxamide (5.19).
2CH2), 3.91 (br. s, 2H, NH2), 7.71 (br. s, 1H, NH) ppm. 13C NMR Yield: 11.0 g, 51%, whitish solid, Mp 159–161 ꢀC. IR (KBr): 3345,
(125 MHz, DMSO-d6) d ¼ 44.2, 66.4, 160.4 ppm. MS (APCI) m/z 3319, 3240 (NH), 3117, 3094, 3070, 3037, 2876 (CH), 1675 (C]O)
[M + H]+ calculated for C5H12N3O2 146.1, found 146.2. Anal. cmꢁ1. H NMR (500 MHz, DMSO-d6): d ¼ 3.73 (s, 3H, OCH3),
1
calcd for C5H12N3O2: C, 41.37; H, 7.64; N, 28.95; found C, 41.32; 4.71 (br. s, 2H, NH2), 6.57 (d, 3J ¼ 7.5 Hz, 1H, Ar), 7.32 (d, 3J ¼ 7.5
H, 7.72; N, 28.90%.
Hz, 1H, Ar), 7.92 (s, 1H, Ar), 8.01 (br. s, 1H, NH), 9.15 (br. s, 1H,
Thiomorpholine-4-carbohydrazide (5.14). Yield: 5.6 g, 35%, NH) ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 55.8, 105.2, 108.2,
white solid, Mp 130–131 ꢀC. IR (KBr): 3340, 3332, 3323, 3237 112.7, 129.7, 137.3, 156.9, 159.0 ppm. MS (APCI) m/z [M + H]+
(NH), 2963, 2921, 2910, 2897 (CH), 1646 (C]O) cmꢁ1. 1H NMR calculated for C9H13ClN3O3 246.1, found 246.0. Anal. calcd for
(500 MHz, DMSO-d6): d ¼ 2.50 (m, 4H, 2CH2), 3.57 (m, 4H, 2H2), C9H12ClN3O3: C, 44.00; H, 4.92; N, 17.10; found C, 43.95; H,
3.92 (br. s, 2H, NH2), 7.68 (s. 1H, NH) ppm. 13C NMR (125 MHz, 5.05; N, 17.02%.
DMSO-d6) d ¼ 26.6, 46.7, 159.7 ppm. MS (APCI) m/z [M + H]+
N-(4-Chloro-2,5-dimethoxyphenyl)hydrazinecarboxamide
calculated for C5H12N3OS 162.1, found 162.2. Anal. calcd for (5.20). Yield: 12.3 g, 50%, whitish solid, Mp 168–170 ꢀC. IR
C5H11N3OS: C, 37.25; H, 6.88; N, 26.06; found C, 37.21; H, 6.92; (KBr): 3347, 3304, 3275 (NH), 3110, 3001, 2963, 2936 (CH), 1688,
1
N, 26.03%.
1652 (C]O) cmꢁ1. H NMR (500 MHz, DMSO-d6): d ¼ 3.77 (s,
4-(4-Dimethylamino-phenyl)semicarbazide (5.15). Yield: 3H, OCH3), 3.83 (s, 3H, OCH3), 4.60 (br. s, 2H, NH2), 7.06 (s, 1H,
ꢀ
11.1 g, 57%, beige solid, Mp 141–143 C. IR (KBr): 3351, 3337, Ar), 7.78 (s, 1H, NH), 8.16 (s, 1H, Ar), 8.95 (br. s, 1H, NH) ppm.
3232 (NH), 3083, 3045, 2898, 2861 (CH), 1663 (C]O) cmꢁ1. H 13C NMR (125 MHz, DMSO-d6) d ¼ 56.8, 57.0, 103.3, 112.2,
1
NMR (500 MHz, DMSO-d6): d ¼ 2.81 (s, 6H, NMe2), 4.31 (br. s, 112.9, 129.2, 142.0, 149.0, 157.2 ppm. MS (APCI) m/z [M + H]+
2H, NH2), 6.66 (d, 3J ¼ 8.8 Hz, 2H, Ar), 7.21 (s, 1H, NH), 7.32 (d, calculated for C8H11ClN3O2 216.1, found 216.0. Anal. calcd for
3J ¼ 8.7 Hz, 2H, Ar), 8.30 (s, 1H, NH) ppm. 13C NMR (125 MHz, C8H10ClN3O2: C, 44.00; H, 4.92; N, 17.10; found C, 43.95; H,
DMSO-d6) d ¼ 41.3, 113.6, 120.5, 130.5, 146.7, 158.2 ppm. MS 5.05; N, 17.02%.
(APCI) m/z [M + H]+ calculated for C9H15N4O 195.1, found 195.0.
N-(3-Chlorophenyl)hydrazinecarboxamide (5.21). Yield: 9.6
Anal. calcd for C9H14N4O: elemental analysis: C, 55.65; H, 7.27; g, 52%, whitish solid, Mp 107–109 ꢀC. IR (KBr): 3358, 3225 (NH),
N, 28.85; found C, 55.60; H, 7.33; N, 28.80%.
3096, 2962, 2940, 2909, 2829 (CH), 1679 (C]O) cmꢁ1. 1H NMR
4-(4-(2-Hydroxy-ethyl)-phenyl)semicarbazide (5.16). Yield: (500 MHz, DMSO-d6): d ¼ 4.40 (br. s, 2H, NH2), 6.95 (d, 3J ¼ 7.5
3
3
ꢀ
11.4 g, 53%, white solid, Mp 149–150 C. IR (KBr): 3364, 3320, Hz, 1H, Ar), 7.24 (dd, J ¼ 7.5 Hz, J ¼ 5.5 Hz, 1H, Ar), 7.41 (d,
3247 (NH), 3095, 3040, 2945, 2927, 2883, 2858 (CH), 1668 (C]O) 3J ¼ 5.5 Hz, 1H, Ar), 7.56 (br. s, 1H, NH), 7.81 (s, 1H, Ar), 8.85 (s,
cmꢁ1. 1H NMR (500 MHz, DMSO-d6): d ¼ 2.66 (t, J ¼ 7.0 Hz, 2H, 1H, NH) ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 117.1, 118.0,
CH2), 3.58 (t, J ¼ 6.5 Hz, 2H, CH2), 4.35 (s, 2H, NH2), 4.51 (s, 1H, 121.4, 130.6, 133.5, 142.1, 157.7 ppm. MS (APCI) m/z [M + H]+
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calculated for C7H8ClN3O 186.0, found 186.0. Anal. calcd for
C7H7ClN3O: C, 44.56; H, 4.67; N, 19.49; found C, 44.50; H, 4.75;
N, 19.44%.
6 K. Ichimori, D. J. Stuehr, R. N. Atkinson and S. B. King,
J. Med. Chem., 1999, 42, 1842–1848.
7 K. K. Adkison, D. G. Barrett, D. N. Deaton, R. T. Gampe,
A. M. Hassell, S. T. Long, R. B. McFadyen, A. B. Miller,
L. R. Miller, J. A. Payne, L. M. Shewchuk, K. J. Wells-
Knecht, D. H. Willard and L. L. Wright, Bioorg. Med. Chem.
Lett., 2006, 16, 978–983.
8 R. Soliman and S. A. S. Darwish, J. Med. Chem., 1983, 26,
1659–1663.
9 M. W. Beukers, M. J. Wanner, J. K. Von Frijtag Drabbe
N-(4-Bromo-2-chlorophenyl)hydrazinecarboxamide (5.22).
ꢀ
Yield: 14.5 g, 55%, white solid, Mp 130–131 C. IR (KBr): 3364,
3332, 3220 (NH), 3103, 3046, 2913 (CH), 1702 (C]O) cmꢁ1. MS
(APCI) m/z [M + H]+ calculated for C7H8BrClN3O 264.0, found
264.0. 1H NMR (500 MHz, DMSO-d6): d ¼ 4.73 (br. s, 2H, NH2),
7.46 (d, 3J ¼ 9 Hz, 1H, Ar), 7.67 (s, 1H, NH), 7.98 (s, 1H, Ar), 8.28
(m, 1H, Ar), 9.18 (br. s, 1H, NH) ppm. 13C NMR (125 MHz,
DMSO-d6) d ¼ 113.1, 120.8, 122.3, 131.1, 131.4, 136.2, 156.8
ppm. Anal. calcd for C7H7BrClN3O: C, 31.79; H, 2.67; N, 15.89;
found C, 31.71; H, 2.77; N, 15.82%.
¨
Kunzel, E. C. Klaasse, A. P. IJzerman and G.-J. Koomen,
J. Med. Chem., 2003, 46, 1492–1503.
10 H. Huang, Q. Chen, X. Ku, L. Meng, L. Lin, X. Wang, C. Zhu,
Y. Wang, Z. Chen, M. Li, H. Jiang, K. Chen, J. Ding and
H. Liu, J. Med. Chem., 2010, 53, 3048–3064.
N-(4-(Methylsulfonyl)phenyl)hydrazinecarboxamide (5.23).
ꢀ
Yield: 11.9 g, 52%, white solid, Mp 104–106 C. IR (KBr): 3376,
1
3364, 3260 (NH), 3020, 3003, 2925 (CH), 1684 (C]O) cmꢁ1. H 11 M. V. Vovk, N. V. Mel'nichenko, V. A. Chornous and
NMR (500 MHz, DMSO-d6): d ¼ 3.14 (s, 3H, CH3SO2), 4.45 (br. s,
M. K. Bratenko, Russ. J. Org. Chem., 2001, 37, 1747–1752.
2H, NH2), 7.71 (m, 5H, Ar + NH), 9.15 (s, 1H, NH) ppm. 13C NMR 12 J. G. Zeevaart, L. Wang, V. V Thakur, C. S. Leung, J. Tirado-
(125 MHz, DMSO-d6) d ¼ 117.2, 130.5, 143.1, 158.0, 170.3 ppm.
MS (APCI) m/z [M + H]+ calculated for C8H12N3O3S 230.1, found
Rives, C. M. Bailey, R. A. Domaoal, K. S. Anderson and
W. L. Jorgensen, J. Am. Chem. Soc., 2008, 130, 9492–9499.
230.2. Anal. calcd for C8H11N3O3S: C, 41.91; H, 4.84; N, 18.33; 13 G. D. Probst, S. Bowers, J. M. Sealy, A. P. Truong, R. K. Hom,
found C, 41.85; H, 4.90; N, 18.24%.
R. A. Galemmo, A. W. Konradi, H. L. Sham, D. A. Quincy,
´
4-(4-Carboxy-phenyl)semicarbazide (5.24). Yield: 10.7 g,
H. Pan, N. Yao, M. Lin, G. Toth, D. R. Artis, W. Zmolek,
ꢀ
55%, whitish solid, Mp 198–200 C. IR (KBr): 3336, 3288, 3223
K. Wong, A. Qin, C. Lorentzen, D. F. Nakamura,
K. P. Quinn, J.-M. Sauer, K. Powell, L. Ruslim, S. Wright,
D. Chereau, Z. Ren, J. P. Anderson, F. Bard, T. A. Yednock
and I. Griswold-Prenner, Bioorg. Med. Chem. Lett., 2011, 21,
315–319.
1
(NH), 3044, 2884 (CH), 1677 (C]O) cmꢁ1. H NMR (500 MHz,
DMSO-d6): d ¼ 5.5–6.7 (s, 3H, NH2 + COOH), 7.55 (d, 3J ¼ 8.0 Hz,
3
2H, Ar), 7.83 (d, J ¼ 8.0 Hz, 2H, Ar), 8.0–8.7 (m, 1H, NH), 9.0–
10.0 (s, 1H, NH) ppm. 13C NMR (125 MHz, DMSO-d6) d ¼ 44.5,
118.2, 128.5, 130.1, 145.3, 157.4 ppm. MS (APCI) m/z [M + H]+ 14 P. V. R. Schleyer, D. Lenoir, R. Glaser and P. Mison, J. Org.
calculated for C8H10N3O3 196.2, found 196.1. Anal. calcd for
C8H9N3O3: C, 49.23; H, 4.65; N, 21.53; found C, 49.20; H, 4.70; N, 15 R. Ohme and H. Preuschhof, J. Prakt. Chem., 1971, 313, 626–
21.50%. 635.
Chem., 1971, 36, 1821–1826.
N,N-Diphenyl semicarbazide (5.25). Yield: 8.9 g, 39%, 16 J. D. Chanley, S. Kalichstein and E. M. Gindler, J. Am. Chem.
yellowish solid, Mp 141–143 ꢀC. IR (KBr): 3318, 3281, 3220 (NH),
Soc., 1953, 75, 5113–5114.
1
3090, 3058, 3010 (CH), 1672 (C]O) cmꢁ1. H NMR (500 MHz, 17 C. Sheng, X. Che, W. Wang, S. Wang, Y. Cao, Z. Miao, J. Yao
DMSO-d6): d ¼ 4.42 (br. s, 8H, NH + NH2 + H2O), 7.16 (m, 6H,
and W. Zhang, Eur. J. Med. Chem., 2011, 46, 5276–5282.
Ar), 7.34 (m, 4H, Ar) ppm. 13C NMR (APT, 125 MHz, CDCl3- 18 M. N. Aboul-Enein, A. A. El-Azzouny, M. I. Attia, Y. A. Maklad,
d6): d ¼ 125.9, 127.4, 129.5, 143.6, 158.8 ppm. MS (APCI) m/z
K. M. Amin, M. Abdel-Rehim and M. F. El-Behairy, Eur.
J. Med. Chem., 2012, 47, 360–369.
[M + H]+ calculated for C13H14N3O 228.3, found 228.2. Anal.
calcd for C13H13N3O: C, 68.70; H, 5.77; N, 18.49; found C, 19 H. Rajak, R. Deshmukh, R. Veerasamy, A. K. Sharma,
68.65; H, 5.85; N, 18.42%.
P. Mishra and M. D. Kharya, Bioorg. Med. Chem. Lett.,
2010, 20, 4168–4172.
20 S. Pardeshi and V. D. Bobade, Bioorg. Med. Chem. Lett., 2011,
21, 6559–6562.
21 B. Qi, H. Tao, D. Wu, J. Bai, Y. Shi and P. Gong, Arch.
Pharmacal Res., 2013, 346, 596–609.
22 H. Cerecetto, R. Di Maio, G. Ibarruri, G. Seoane, A. Denicola,
G. Peluffo, C. Quijano and M. Paulino, Farmaco, 1998, 53,
89–94.
Notes and references
1 H. Beraldo and D. Gambino, Mini-Rev. Med. Chem., 2004, 4,
31–39.
2 S. F. Asghar, K. A. Yasin and S. Aziz, Nat. Prod. Res., 2010, 24,
315–325.
ˇ
´
ˇ
´
3 I. Perkovic, S. Trsinar, J. Zanetic, M. Kralj, I. Martin-Kleiner, 23 M. K. Abdel-Hamid, A. A. Abdel-Hafez, N. A. El-Koussi,
J. Balzarini, D. Hadjipavlou-Litina, A. M. Katsori and B. Zorc,
J. Enzyme Inhib. Med. Chem., 2013, 28, 601–610.
N. M. Mahfouz, A. Innocenti and C. T. Supuran, Bioorg.
Med. Chem., 2007, 15, 6975–6984.
4 A. Gaulton, L. J. Bellis, A. P. Bento, J. Chambers, M. Davies, 24 A. Chipeleme, J. Gut, P. J. Rosenthal and K. Chibale, Bioorg.
A. Hersey, Y. Light, S. McGlinchey, D. Michalovich, B. Al- Med. Chem., 2007, 15, 273–282.
Lazikani and J. P. Overington, Nucleic Acids Res., 2012, 40, 25 P. Yogeeswari, J. V. Ragavendran, D. Sriram, Y. Nageswari,
D1100–D1107.
R. Kavya, N. Sreevatsan, K. Vanitha and J. Stables, J. Med.
Chem., 2007, 50, 2459–2467.
5 The Pesticide Manual, ed. C. MacBean, BCPC, 16th edn, 2012.
1068 | RSC Adv., 2015, 5, 1063–1069
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Paper
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˜
26 O. Seitz, A. Gerpe, I. Odreman-Nunez, P. Draper, L. Boiani, 30 A. V Bogolubsky, Y. S. Moroz, P. K. Mykhailiuk, D. S. Granat,
´
J. A. Urbina, M. Gonzalez and H. Cerecetto, Bioorg. Med.
S. E. Pipko, A. I. Konovets, R. Doroschuk and A. Tolmachev,
Chem., 2008, 16, 569–577.
ACS Comb. Sci., 2014, 16, 303–308.
27 D. A. Wicks and Z. W. Wicks, Prog. Org. Coat., 1999, 36, 148– 31 A. V. Bogolubsky, S. V. Ryabukhin, S. E. Pipko, O. Lukin,
172.
A. Shivanyuk, D. Mykytenko and A. Tolmachev,
Tetrahedron, 2011, 67, 3619–3623.
32 S. Azad, K. Kumamoto, K. Uegaki, Y. Ichikawa and
H. Kotsuki, Tetrahedron Lett., 2006, 47, 587–590.
33 F. Saliu and B. Rindone, Tetrahedron Lett., 2010, 51, 6301–
6304.
28 E. Delebecq, J.-P. Pascault, B. Boutevin and F. Ganachaud,
Chem. Rev., 2013, 113, 80–118.
29 I. De Aguirre and J. Collot, Bull. Soc. Chim. Belg., 1989, 98, 19–
30.
This journal is © The Royal Society of Chemistry 2015
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