Practical one-pot synthesis of semicarbazone derivatives via semicarbazide, and evaluation of their antibacterial activity

Article abstract of DOI:10.1007/s11164-015-2235-7

New series of 2-(aryl or alkyl)-N-phenylhydrazine-1-carboxamides 1a-j were synthesized through one-pot reactions of aldehyde or ketones, hydrazine hydrate, and phenylisocyanate in MeOH. The structure of products was confirmed by Fourier transform infrared

Full text of DOI:10.1007/s11164-015-2235-7

Res Chem Intermed
DOI 10.1007/s11164-015-2235-7
Practical one-pot synthesis of semicarbazone
derivatives via semicarbazide, and evaluation
of their antibacterial activity
Nosrat O. Mahmoodi1 Mojtaba Namroudi1
•
•
•
Fateme Ghanbari Pirbasti1 Hossein Roohi1
•
Iraj Nikokar2
Received: 19 May 2015 / Accepted: 17 August 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract New series of 2-(aryl or alkyl)-N-phenylhydrazine-1-carboxamides 1a–j
were synthesized through one-pot reactions of aldehyde or ketones, hydrazine
hydrate, and phenylisocyanate in MeOH. The structure of products was confirmed
by Fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H
NMR), and 13C NMR spectra. Minimum inhibitory concentration (MIC) of
antibacterial activity of 1a–j was screened against five bacterial strains. Compound
1f showed antibacterial activity against Pseudomonas aeruginosa and Staphylo-
coccus aureus.
Keywords Semicarbazone Á Hydrazine hydrate Á Phenyl isocyanate Á
One-pot reaction Á Antibacterial
Introduction
Semicarbazones are urea derivatives and have recently been the subject of a great
number of studies. Semicarbazone derivatives have versatile biological activities,
making their study interesting: anticonvulsant [1–3], antimicrobial [4, 5], antiox-
idant [6], antiangiogenic [7], anticancer [8], antiproliferative [9], antimalarial [10],
and antiprotozoal [11]. In addition, steroidal semicarbazone derivatives have shown
antiproliferative activity [12], indole semicarbazones exhibited antimicrobial
activity [13], and semicarbazone derivatives of calix[4]arene have been used for
removal of Cr(VI) ions [14]. Moreover, semicarbazones have been used as organic
&
Nosrat O. Mahmoodi
mahmoodi@guilan.ac.ir; nosmahmoodi@gmail.com
1
2
Department of Organic Chemistry, Faculty of Sciences, University of Guilan,
PO Box 41335-1914, Rasht, Iran
Laboratory of Microbiology and Immunology of Infectious Diseases, Paramedicine Faculty,
Guilan University of Medical Sciences, PO Box 44715-1361, Guilan, Iran
123

N. O. Mahmoodi et al.
corrosion inhibitors [15]. Metaflumizone, under the brand name ProMeris, is a
semicarbazone derivative with eco-friendly insecticide activity [16] (Fig. 1).
Moreover, semicarbazones behave as chelating ligands due to their N and O atoms
and electron delocalization along the semicarbazone moiety. Various semicarbazone
complexes have been synthesized that exhibit biological activities, for example,
nickel(II) complexes of 3-thiophene aldehyde semicarbazone, 2,3-thiophene dicar-
boxaldehyde bis(semicarbazone) have shown antifungal activity [17]; antioxidant
and anticancer activity of ruthenium(II) complexes of semicarbazone bearing 9,10-
phenanthrenequinone moiety have been studied [18]; anticancer activity of
copper(II), vanadium(IV/V), iron(II)/(III), and gallium(III) complexes of salicy-
laldehyde semicarbazone and its bromo derivative have been reported [19]; Cu(II),
Zn(II), Ni(II) complexes of 3-carbaldehyde-chromone semicarbazone have DNA
binding properties and antioxidant activities [20]; organotin(IV) complexes of
semicarbazone derived from 4-hydroxy-3-methoxybenzaldehyde have shown
antimicrobial activity [21]. In addition, palladium complexes of semicarbazones
have been used as catalysts in Suzuki and Sonogashira cross-coupling reactions [22].
In addition, semicarbazone derivatives are versatile intermediates for synthesis of
heterocyclic compounds. The key feature of these intermediates is obtaining different
products from semicarbazone in acidic or basic media, e.g. oxadiazole derivatives
obtained from 4-substituted phenyl semicarbazones in acidic media [23], while the
reaction of aryl semicarbazones in alkaline media afforded 1,2,4-triazoles [24].
Despite these various properties and applications of semicarbazones, surprisingly
there are limited one-pot straightforward procedures for their synthesis. In the
present work, we planned to produce intermediate semicarbazide 6 [25] in one pot,
and then in the same pot, incorporate it to the several different aliphatic, alicyclic,
and aromatic ketones and aldehydes 4 to produce semicarbazone 1 (route 2)
(Scheme 1). Key intermediate semicarbazides 6 [26, 27] prepared via route 1
involved the reaction of amines with phenyl chloroformate 2 to create the
corresponding carbamates 3, consequently under hydrazinolysis by hydrazine
hydrate to 6 [26–28] (Scheme 1). The newly synthesized 1 were screened for their
antibacterial activity against five bacteria strains, including Bacillus cereus (B.
cereus) ATCC 11778, Enterococcus fecalis (E. fecalis) ATCC 29212, Escherichia
coli (E. coli) ATCC 25922, Pseudomonas aeruginosa (P. aeruginosa) ATCC
27853, and Staphylococcus aureus (S. aureus) ATCC 25923.
The relative stability of salicylaldehyde semicarbazone derivatives has been
previously investigated by Xi et al. [29]. They have compared the theoretic and
experimental results to confirm the stability order of conformers. Accordingly, we
have decided to confirm the stability of our interested compounds using the
theoretical and experimental methods.
OCF3
Fig. 1 Metaflumizone
O
N
F
N
H
N
H
3C
NC
123

Practical one-pot synthesis of semicarbazone derivatives…
R3
H2N NH2 .H2O
NH2
O
2
R3
N
5
C O
Ph
Cl
O
Ph CF3
MeOH
route 1
route 2
O
4
R1
R2
O
O
O
H2N NH2 .H2O
R1
N
R3
R3
R3
Ph
H2N
N
H
N
H
N
H
O
N
N
H
R2
H
6
1
3
Scheme 1 Synthetic routes to one-pot synthesis of semicarbazones
Experimental
1
The H NMR spectra were obtained at room temperature on a Bruker Avance
400-MHz spectrometer.13C NMR spectra were recorded at room temperature on a
Bruker 100 MHz instrument. DMSO-d6 used as solvent. FT-IR spectra were
measured at room temperature with a Shimadzu IR-470 spectrophotometer. Melting
points are uncorrected and were determined using a MettlerFp5 apparatus.
General procedure for synthesis of 1a–j
Hydrazine hydrate (1 mmol) was added dropwise to a methanolic solution of
aldehydes or ketones 4a–i (1 mmol) and stirred for 30 min, then phenylisocyanate 5
(1 mmol) was added dropwise to this mixture. The mixture was stirred well for the
required time. The process of reaction was monitored by TLC (n-hexane:EtOAc
6:3). After completion of the reaction, the solution was kept at room temperature for
evaporation to dryness, then recrystallized with EtOH. All reported yield was
evaluated after recrystallization.
Theoretical
For the synthesized compounds 1a–j, there are more stable conformers on their
internal rotation potential energetic surfaces (PES) about the N–N and C–N single
bonds. These conformers, called cis–cis, cis–trans, and trans–trans, have close
potential energy on their potential energy surface (PES). One target from each
category of compounds (1b, 1f, and 1j) was selected for theoretical calculations.
The structures of selected compounds were optimized at B3LYP/6-311??G(d,p)
level of theory. Vibrational frequency analysis was performed at the previously
mentioned level for stationary states to obtain vibrational zero point vibrational
energy (ZPVE) and to validate that the found structures corresponded to the energy
minima or transition states.
123

N. O. Mahmoodi et al.
2-(3,4-Dihydronaphthalen-1(2H)-ylidene)-N-phenylhydrazine-1-
carboxamide 1a
White solid, yield: 98 %, m.p. 208–210 °C, FT-IR (KBr, m cm-1): 3359, 3201
(stretch N–H), 3109 (stretch C–H Ar.), 2934 (stretch C–H ali.), 1684 (stretch C=O,
amide), 1597, 1528 (stretch C=C), 1442 (bending CH2), 1299, 1129 (stretch C–N),
1
751, 622 (OOP. C–H). H NMR (400 MHz, DMSO-d6): d; 9.72 (s, 1H, NH, He),
8.89 (s, 1H, NH, Hd), 8.29 (d, J = 6.8 Hz, 1H, Hl), 7.64 (d, J = 7.6 Hz, 2H, Hc),
7.32–7.19 (m, 5H, Hb, Hi, Hj, Hk), 7.02 (t, J = 7 Hz, 1H, Ha), 2.74 (s, 2H, Hh), 2.63
(s, 2H, Hf), 1.84 (s, 2H, Hg) ppm. 13C NMR (100 MHz, DMSO-d6): d;. 13C NMR
(100 MHz, DMSO-d6): d; 158.1 (C=O), 142.7 (C=N), 139.0, 138.9, 130.1, 128.0,
128.4, 126.9, 125.7, 122.4, 121.7, 119.5, 119.4 (10 C), 28.0 (Cg), 26.9 (Cf) ppm.
2-(2,3-Dihydronaphthalen-1H-inden-1-ylidene)-N-phenylhydrazine-1-
carboxamide 1b
White solid, yield: 98 %, m.p. 222–224 °C, FT-IR (KBr, m cm-1): 3362, 3193
(stretch N–H), 3085 (stretch C–H Ar.), 2914 (stretch C–H ali.), 1681 (stretch C=O,
amide), 1597, 1537 (stretch C=C), 1442 (bending CH2), 1313, 1127 (stretch C–N),
1
750, 688, 619 (OOP. C–H). H NMR (400 MHz, DMSO-d6): d; 9.69 (s, 1H, NH,
He), 8.91 (s, 1H, NH, Hd), 7.97 (d, J = 7.6 Hz, 1H, Hk), 7.67 (d, J = 8.2, 1.2 Hz,
2H, Hc), 7.38–7.28 (m, 5H, Hb, Hj, Hi, Hh), 7.01 (t, J = 7.4 Hz, 1H, Ha), 3.08 (t,
J = 6.4 Hz, 2H, Hg), 2.82–2.79 (m, 2H, Hf) ppm. 13C NMR (100 MHz, DMSO-d6):
d; 155.1 (C=O), 147.9 (C=N), 139.0, 137.8, 129.9, 128.4, 126.7, 125.5, 122.2,
121.7, 119.4, 119.3 (10 C), 28.0 (Cg), 26.9 (Cf) ppm.
2-Cyclohexylidene-N-phenylhydrazine-1-carboxamide 1c
White solid, yield: 98 %, m.p. 207–208 °C, FT-IR (KBr, m cm-1): 3289, 3135
(stretch N–H), 3086 (stretch C–H Ar.), 2934, 2859 (stretch C–H ali.), 1656 (stretch
C=O, amide), 1601, 1550, 1499 (stretch C=C), 1442 (bending CH2), 1309, 1213
1
(stretch C–N), 758, 642 (OOP. C–H). H NMR (400 MHz, DMSO-d6): d; 9.60 (s,
1H, NH, He), 8.73 (s, 1H, NH, Hd), 7.64 (d, J = 7.6 Hz, 2H, Hc), 7.32 (d,
J = 7.8 Hz, 2H, Hb), 7.03 (t, J = 7.2 Hz, 1H, Ha), 2.42 (s, 2 h, Hf or Hf’), 2.35 (t,
J = 7.4 Hz, 2H, Hf’ or Hf), 1.70 (s, 2H, Hh), 1.62 (m, 4H, Hg) ppm. 13C NMR
(100 MHz, DMSO-d6): d; 153.6 (C=N), 139.2 (C=O), 139.1, 128.4, 122.0, 119.0,
118.9, 34.7, 26.8, 26.5, 25.5, 25.1 ppm.
2-Cyclopentylidene-N-phenylhydrazine-1-carboxamide 1d
White solid, yield: 98 %, m.p. 178–180 °C, FT-IR (KBr, m cm-1): 3348, 3193
(stretch N–H), 3082 (stretch C–H Ar.), 2961, 2874 (stretch C–H ali.), 1677 (stretch
C=O, amide), 1600, 1532 (stretch C=C), 1443 (bending CH2), 1188 (stretch C–N),
1
751, 612 (OOP. C–H). H NMR (400 MHz, DMSO-d6): d; 9.23 (s, 1H, NH, He),
8.65 (s, 1H, NH, Hd), 7.57 (d, J = 7.6 Hz, 2H, Hc), 7.25 (t, J = 8.0 Hz, 2H, Hb),
6.97 (t, J = 7.4 Hz, 1H, Ha), 2.37 (t, J = 7.2 Hz, 2H, Hf or Hi), 2.28 (t, J = 7.2 Hz,
123

Practical one-pot synthesis of semicarbazone derivatives…
2H, Hi or Hf), 1.76 (m, 2H, Hg or Hh), 1.68 (m, 2H, Hh or Hg) ppm. 13C NMR
(100 MHz, DMSO-d6): d; 160.3 (C=N), 153.4 (C=O), 139.2, 128.4, 122.0, 119.0,
118.9 (5C), 32.8, 28.1, 24.5, 24.4 (4C aliphatic) ppm.
2-Cycloheptylidene-N-phenylhydrazine-1-carboxamide 1e
White solid, yield: 97 %, m.p. 185–186 °C, FT-IR (KBr, m cm-1): 3378, 3190
(stretch N–H), 3112 (stretch C–H Ar.), 2916, 2848 (stretch C–H ali.), 1682 (stretch
1
C=O, amide), 1596, 1532 (stretch C=C), 759, 685, 606 (OOP. C–H). H NMR
(400 MHz, DMSO-d6): d; 9.24 (s, 1H, NH, He), 8.72 (s, 1H, NH, Hd), 7.58 (d,
J = 8.2 Hz, 2H, Hc), 7.25 (t, J = 8.0 Hz, 2H, Hb), 6.97 (t, J = 7.4 Hz, 1H, Ha),
2.47 (t, J = 5.4 Hz, 2H, Hf or Hc), 2.38 (t, J = 6 Hz, 2H, Hk or Hf), 1.66–1.53 (m,
8H, Hg, Hh, Hi, Hj) ppm. 13C NMR (100 MHz, DMSO-d6): d; 156.3 (C=N), 153.4
(C=O), 139.1, 128.5, 122.0, 119.0 (4C), 36.3, 30.3, 29.8, 29.8, 27.2, 23.9 (5C
aliphatic) ppm.
1-(2-Oxoindolin-3-ylidene)-4-phenylsemicarbazide 1f
Orange solid, yield: 95 %, m.p. 196–198 °C, reported 193–196 °C [30], FT-IR
(KBr, m cm-1): 3331 (stretch N–H), 3060 (stretch C–H Ar.), 2921, 2867 (stretch C–
H ali.), 1675 (stretch C=O, amide), 1598, 1506 (stretch C=C), 825, 752, 588 (OOP.
C–H).
2-(Anthracen-9-ylmethylene)-N-phenylhydrazine-1-carboxamide 1g
Orange solid, yield: 98 %, m.p. 285–287 °C, FT-IR (KBr, m cm-1): 3391, 3200
(stretch N–H), 3033 (stretch C–H Ar.), 2971, 2890 (stretch C–H ali.), 1691 (stretch
C=O, amide), 1595, 1534 (stretch C=C), 1297, 1150 (stretch C–N), 738, 574 (OOP.
C–H). 1H NMR (400 MHz, DMSO-d6): d; 10.99 (s, 1H, NH, He), 9.13 (s, 1H, NH,
Hd), 8.82 (s, 1H, Hk), 8.71 (s, 1H, Hf), 8.53 (d, J = 8.4 Hz, 2H, Hj), 8.16 (d,
J = 8.0 Hz, 2H, Hg), 7.65–7.58 (m, 6H, Hc, Hh, Hi), 7.28 (t, J = 8.0 Hz, 2H, Hb),
7.00 (d, J = 7.6 Hz, 1H, Ha) ppm. 13C NMR (100 MHz, DMSO-d6): d; 139.7,
139.7, 138.8, 130.8, 129.4, 128.8, 128.7, 128.5, 126.9, 125.9, 125.5, 124.8, 122.4,
119.6, 119.4 ppm.
2-(1-(3-Nitrophenyl)ethylidene)-N-phenylhydrazine-1-carboxamide 1h
Orange solid, yield: 98 %, m.p. 249–251 °C, FT-IR (KBr, m cm-1): 3381, 3197
(stretch N–H), 3098 (stretch C–H Ar.), 1683 (stretch C=O, amide), 1599 (stretch
1
C=C), 1536, 1342 (stretch NO2), 892, 796, 749 (OOP. C–H). H NMR (400 MHz,
DMSO-d6): d; 9.98 (s, 1H, NH, He), 8.99 (s, 1H, NH, Hd), 8.60 (t, J = 2 Hz, 1H,
Hj), 8.41 (d, J = 8.4 Hz, 1H, Hi), 8.23 (d, J = 8.4, 1.4 Hz, 1H, Hg), 7.71 (t,
J = 8.0 Hz, 1H, Hh), 7.61 (d, J = 8.2, 1.2 Hz, 2H, Hc), 7.32 (t, J = 7.4 Hz, 2H,
Hb), 7.04 (t, J = 10 Hz, 1H, Ha), 2.33 (s, 3H, Hf) ppm. 13C NMR (100 MHz,
DMSO-d6): d; 148.0 (C=O), 143.7 (C=N), 139.7, 138.8, 132.6, 129.7, 128.5, 123.1,
122.6, 120.6, 119.9, 119.8 (10C), 13.7 (1C aliphatic) ppm.
123

N. O. Mahmoodi et al.
2-(1-(4-Methoxyphenyl)ethylidene)-N-phenylhydrazine-1-carboxamide 1i
Pale green solid, yield: 96 %, m.p. 163–165 °C, FT-IR (KBr, m cm-1): 3350, 3200
(stretch N–H), 3100 (stretch C–H Ar.), 2950, 2800 (stretch C–H ali.), 1680 (stretch
C=O, amide), 1600, 1540, 1520, 1500 (stretch C=C), 1250, 1030 (stretch C–N), 830,
1
800, 750, 680 (OOP. C–H). H NMR (400 MHz, DMSO-d6): d; 9.68 (s, 1H, NH,
He), 8.82 (s, 1H, NH, Hd), 7.87 (d, J = 9.2 Hz, 2H, Hg), 7.63 (d, J = 8.0 Hz, 2H,
Hc), 7.03 (t, J = 8.0 Hz, 2H, Hb), 7.02 (t, J = 7.4 Hz, 1H, Ha), 6.96 (d, J = 6.8,
2.2 Hz, 2H, Hh), 3.79 (s, 3H, Hi, OCH3), 2.23 (s, 3H, Hf, CH3) ppm. 13C NMR
(100 MHz, DMSO-d6): d; 159.8, 153.5 (C=O), 145.8 (C=N), 139.0, 130.4, 128.4,
127.7, 122.3, 119.6, 119.5, 113.5 (8C), 55.1 (OCH3), 13.6 (CH3) ppm.
2-(1-(Naphthalene-2-yl)ethylidene)-N-phenylhydrazine-1-carboxamide 1j
Pink solid, yield: 87 %, m.p. 200–201 °C, FT-IR (KBr, m cm-1): 3371, 3196 (stretch
N–H), 3098 (stretch C–H Ar.), 1691 (stretch C=O, amide), 1597, 1535 (stretch
1
C=C), 747, 601 (OOP. C–H). H NMR (400 MHz, DMSO-d6): d; 9.87 (s, 1H, NH,
He), 8.94 (s, 1H, NH, Hd), 8.31–8.29 (m, 2H, Hg, Hh), 8.00 (d, J = 5.6, 4.2 Hz, 1H,
Hm), 7.92 (d, J = 9.2, 4.4 Hz, 2H, Hi, Hj), 7.55–7.53 (m, 2H, Hk, Hl), 7.57 (d,
J = 7.6 Hz, 2H, Hc), 7.32 (t, J = 7.8 Hz, 2H, Hb), 7.04 (t, J = 7.4 Hz, 1H, Ha),
2.39 (s, 3H, Hf, CH3) ppm. 13C NMR (100 MHz, DMSO-d6): d; 153.4 (C=O), 145.7
(C=N), 138.9, 135.3, 133.0, 132.7, 128.5, 128.4, 127.5, 127.4, 126.5, 125.8, 124.0,
122.5, 119.9, 119.8 (14C), 13.5 (CH3) ppm.
2,20-(((Butane-1,4-diylbis(oxy))bis(3,1-phenylene))bis(ethan-1-yl-1-
ylidene))bis(N-phenylhydrazine-1-carboxamide) 8
Hydrazine hydrate 5 (2 mmol) was added dropwise to a 10-mL methanolic solution
of bis-ketones 7 (0.374 g, 1 mmol) and stirred for 2 days at 40 °C, then
phenylisocyanate 5 (2 mmol) was added dropwise to this mixture. The mixture
was stirred well for 1 day. The process of reaction was monitored by TLC (n-
hexane:EtOAc 6:3), and after completion of the reaction, the solution was kept at
room temperature for evaporation to dryness, then recrystallized from EtOH. Forty-
two percent (0.25 g) of 8 was recovered.
Pink opaque solid, yield: 42 %, m.p. 204–206 °C, FT-IR (KBr, m cm-1): 33,751,
3199 (stretch N–H), 3072 (stretch C–H Ar.), 2941 (C–H aliphatic), 1684 (stretch
C=O, amide), 16057, 1515 (stretch C=C), 826, 750 (OOP. C–H). 1H NMR
(400 MHz, DMSO-d6): d; 9.78 (s, 1H, NH, He), 8.88 (s, 1H, NH, Hd), 7.62–7.61 (m,
2H, Hg, Hh), 7.47–7.43 (m, 2H, Hm), 7.31–7.29 (m, 3H), 7.01–6.99 (m, 2H),
4.14–4.05 (m, 2H, O–CH2), 2.25 (s, 3H, CH3), 1.99–1.93 (m, 1H, CH2) ppm.
Antibacterial activity using MIC
Minimum inhibitory concentration is defined as the lowest concentration of tested
compound that can inhibit bacterial growth. Cultures were prepared according to
manufacturers’ instructions. Stock solutions of tested compounds were prepared at a
123

Practical one-pot synthesis of semicarbazone derivatives…
concentration of 1000 lg/mL in DMSO. DMSO was used as negative control.
Twofold serial dilutions from stock solutions were used to determine MIC.
Results and discussion
Continuing our studies of the synthesis of novel compounds bearing heteroatoms
[31–36] here, synthesis of a new series of 2-(aryl or alkyl)-N-phenylhydrazine-1-
carboxamide 1a–j via one-pot reaction is completed. The products 1a–j were
obtained through the reaction of anthracene carbaldehyde 4g or cyclic aliphatics 4a–
f, or aromatic ketones 4h–j with hydrazine hydrate and phenyl isocyante 5 in MeOH
under reflux condition (Scheme 2).
For optimization of reaction conditions, the reaction of a-tetralone 4a, hydrazine
hydrate, and phenyl isocyanate 5 was selected as the model reactions. The results
are summarized in Table 1. The lowest yield was obtained in CHCl3 as solvent at
room temperature (Table 1, entry 2); however, MeOH led to the highest yield at
room temperature (Table 1, entry 5). Moreover, while the reaction was performed
under reflux in MeOH the lower yield of product, but in shorter reaction time was
obtained. TLC monitoring shows that reflux conditions also will lead to the
formation of several by-products (Table 1, entry 8). Thus, the product was obtained
in higher yield at 45 °C in MeOH (Table 1, entry 9).
The structure of compounds has been characterized by FT-IR, 1H NMR, and 13
C
NMR spectra. All spectral data are in accordance with the expected structures. In
FT-IR spectra, N–H stretching appeared in 3391–3289 and 3201–3135 cm-1; the
O
H
N
H
N
4a-f
N
Ph
O
or
O
MeOH
1a-f
or
NH2NH2
PhNCO
5
R1
H
4g
H
N
H
N
or
N
Ph
O
O
R1
H
4h-j
R2
CH3
1g
or
H
H
N
N
,
O
,
,
=
,
,
N
Ph
N
H
e
f
c
a
O
b
d
R2
CH3
1h-j
N
O2
R1
=
R2
=
,
,
H
3CO
i
g
h
j
Scheme 2 Synthesis of 2-(aryl or alkyl)-N-phenylhydrazine-1-carboxamide 1a–j
123

N. O. Mahmoodi et al.
Table 1 Optimization of the
reaction condition for synthesis
of 11a
Entry
Solvent
Temperature (°C)
Time (h)
Yield %
1
2
3
4
5
6
7
8
9
EtOH
r.t.
9
12
12
14
12
12
14
6
89
45
59
81
90
87
39
45
96
CHCl3
THF
r.t.
r.t.
DMF
r.t.
MeOH
CH2Cl2
CH3CN
MeOH
MeOH
r.t.
r.t.
r.t.
Reflux
45
6
band in 1691–1659 cm-1 is due to the C=O group of amide, and the other stretching
and bending vibrations appeared in expected frequencies.
1
The H NMR spectral data were consistent with the assigned structures; the
signals of the respective protons of the synthesized compounds 1a–j were confirmed
on the basis of their chemical shifts, multiplicities, and coupling constants. Protons
of C=N–NH and NH–C=O appeared as singlets at 10.99–9.23 and 9.13–8.65 ppm,
respectively. Aromatic protons appeared at 8.82–6.96 ppm. Protons of the HC=N of
compound 1f was observed as a sharp singlet at 8.71 ppm. Aliphatic protons
appeared at 3.79–1.53 ppm.
The 13C NMR spectra of 1a–j are in agreement with their structures. Presence of
chemical shifts of C=N and C=O at low field confirmed the formation of products.
Aromatic carbons, C=N and C=O appeared at 160.3–113.5 ppm, and aliphatic
carbons were observed at 55.1–13.5 ppm.
In the 1H and 13C NMRs of 1c–e different protons and carbons for cyclic
derivatives have been observed. 1H NMR of 1c showed four kinds of protons and in
13C NMR of 1c five kinds of carbon appeared in aliphatic region. Also, for 1d, four
types of protons appeared in the high field of 1H NMR, and four resonances for four
aliphatic carbons in 13C NMR (Fig. 2). 13C NMR of compound 1e showed seven
types of carbons in aliphatic region.
In the other attempt in contribution to our previous bis-synthesis [38–41], 0.5
equivalents of prepared diketone 7, upon reaction with one equivalent of 5 and one
equivalent of H2N–NH2ÁH2O via in situ prepared intermediate 8, in one pot led to
the formation of 2,20-(((butane-1,4-diylbis(oxy))bis(3,1-phenylene))bis(ethan-1-yl-
1-ylidene))bis(N-phenylhydrazine-1-carboxamide) 9 (Scheme 3).
The ZPVE corrected energy of conformers and vibrational frequency for three
categories as depicted in Fig. 3 are given in Table 3. As can be seen in Table 2, the
trans–trans conformer is most stable in each category.
The order of stability of conformers is cis–cis \ cis–trans \ trans–trans. In
addition, the results show that there is a good agreement between the calculated
frequency and experimental one. It is clear that vibrational frequency of the C=O
group increases on going from cis–cis to cis–trans and then trans–trans, with the
exceptional trans–trans form of 1f due to the presence of NH_OC H-bonding.
123

Practical one-pot synthesis of semicarbazone derivatives…
a
b
c
O
NH
d
HN
e
N
f
i or f
f or i
i
g
h or g g or h
h
a
b
c
O
NH
i
d
HN
i or f
f or i
e
f
g or h
N
h
h or g
g
Fig. 2 1H NMR and 13C NMR of aliphatic region for 1d
The in vitro antibacterial activities of compounds 1a–j were screened against five
bacterial strains, including Bacillus cereus (B. cereus) ATCC 11778, Enterococcus
fecalis (E. fecalis) ATCC 29212, Escherichia coli (E. coli) ATCC 25922,
123

N. O. Mahmoodi et al.
O
N
NH2
MeOH
H2N NH2 .H
2O
O
+
O
H2N
N
O
O
O
8
7
5
O
H
H
R3
N
N
H
N
N
N
H
N
R3
O
O
O
9
Scheme 3 Synthetic routes to one-pot bis N-phenylhydrazine-1-carboxamide 9 synthesis
1f
1b
1j
Fig. 3 The B3LYP/6-311??G(d,p) optimized structures of 1f, 1b, and 1J
Table 2 The ZPVE-corrected relative energy and vibrational frequency of C=O group at B3LYP/6-
311??G(d,p) level of theory
Conformer
ZPVE/hartree
E0/hartree
DE0 (kJ/mol)
m(CO)/cm-1
1b
1f
1j
cis–cis
0.28241
0.28239
0.28115
0.25203
0.25232
0.25245
0.32155
0.32187
0.32039
-857.98624
-857.986933
-857.987433
-948.081867
-948.082606
-948.099538
-973.481805
-973.483786
-973.484709
0.00
-1.82
-3.13
0.00
1701.76178
1716.47386
1736.50939
1723.8299
1731.28273
1693.05068
1706.89165
1722.57163
1737.3805
cis–trans
trans–trans
cis–cis
cis–trans
trans–trans
cis–cis
-1.94
-46.35
0.00
cis–trans
trans–trans
-5.20
-7.62
123

Practical one-pot synthesis of semicarbazone derivatives…
Table 3 Antibacterial activity of 1f using MIC
Compound
Microorganisms
B. cereus
E. fecalis
E. coli
P. aeruginosa
S. aureus
1f
–
–
–
512
128
Ciprofloxacin
62.5
62.5
62.5
62.5
62.5
Pseudomonas aeruginosa (P. aeruginosa) ATCC 27853, and Staphylococcus aureus
(S. aureus) ATCC 25923. The minimum inhibitory concentrations (MIC) of
compounds 1a–j were evaluated. MIC values are expressed in lg/mL [33].
Compound 1f showed activity against P. aeruginosa at a concentration of 512 lg/
mL and S. aureus at a concentration of 128 lg/mL, while other compounds showed
no activity against bacterial strains. Ciprofloxacin was used as positive control and
showed antibacterial activity at concentration 62.5 lg/mL against all tested
bacterial strains (Table 3).
Conclusion
New 2-(aryl or alkyl)-N-phenylhydrazine-1-carboxamide derivatives were synthe-
sized in an efficient high yield, and semicarbazone derivatives can be prepared by
this optimized reaction set-up. Synthesized carboxamide derivatives showed no
antibacterial activity against tested bacterial strains except 1-(2-oxoindolin-3-
ylidene)-4-phenylsemicarbazide. The results showed route2 in comparison to other
reported syntheses of (thio)semicarbazones, e.g. route1, was more reliable,
reproducible, economic, produced a high yield, showed no chromatographic
separation, and was time consuming. The ZPVE corrected energy of conformers and
vibrational frequency for three categories indicate that the trans–trans conformer is
the most stable one in each category. The order of stability of conformers is cis–
cis \ cis–trans \ trans–trans. Also, good agreement between the calculated
frequency of C=O group and experimental one was observed.
Acknowledgments The authors are grateful to the Research Council of University of Guilan for
financial support of this work.
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