Synthesis, characterization and antibacterial activity of some new ferrocenyl selenazoles and 3,5-diferrocenyl-1,2,4-selenadiazole

Article abstract of DOI:10.1016/j.jorganchem.2014.10.007

New ferrocenyl containing selenazole derivatives were synthesized from reactions of aryl selenocarboxamide (i.e. Ar-CSe(NH₂); ArC₆H₅ (1), 4-Br-C₆H₄ (2), 4-PhC₆H₄ (3), 4-CH_3<

Full text of DOI:10.1016/j.jorganchem.2014.10.007

Accepted Manuscript
Synthesis, Characterization and Antibacterial Activity of Some New Ferrocenyl
Selenazoles and 3, 5-Diferrocenyl-1, 2, 4-Selenadiazole
Ali Z. Al-Rubaie, Shaker A.S. Al-Jadaan, Salah K. Muslim, Eman A. Saeed, Eman T.
Ali, Amer K.J. Al-Hasani, Hussien N.K. Al-Salman, Sabaa. A.M. Al-Fadal
PII:
S0022-328X(14)00471-9
10.1016/j.jorganchem.2014.10.007
JOM 18749
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 8 July 2014
Revised Date: 30 September 2014
Accepted Date: 4 October 2014
Please cite this article as: A.Z. Al-Rubaie, S.A.S. Al-Jadaan, S.K. Muslim, E.A. Saeed, E.T. Ali,
A.K.J. Al-Hasani, H.N.K. Al-Salman, S.A.M. Al-Fadal, Synthesis, Characterization and Antibacterial
Activity of Some New Ferrocenyl Selenazoles and 3, 5-Diferrocenyl-1, 2, 4-Selenadiazole, Journal of
Organometallic Chemistry (2014), doi: 10.1016/j.jorganchem.2014.10.007.
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The graphical abstract synopsis
New ferrocenyl containing selenazole derivatives, ferrocenyl selenocarboxamide and 3,5-
diferrocenyl-1,2,4-selenadiazole were prepared and characterized by several spectroscopic
techniques. The new compounds were screened as antibacterial agents against S. aureus, E. coli
and P. aeruginosa and showed promising properties.

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Synthesis, Characterization and Antibacterial Activity of Some New
Ferrocenyl Selenazoles and 3, 5-Diferrocenyl-1, 2, 4-Selenadiazole
Ali Z. Al-Rubaie*1, Shaker A. S. Al-Jadaan2, Salah K. Muslim2, Eman A. Saeed2, Eman T. Ali2,
Amer K. J. Al-Hasani2, Hussien N. K. Al-Salman2 and Sabaa. A. M. Al-Fadal2
1Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
2Department of Chemistry, College of Pharmacy, University of Basrah, Basrah, Iraq
ABSTRACT:
New ferrocenyl containing selenazole derivatives were synthesized from reactions of aryl
selenocarboxamide (i.e. Ar-C=Se(NH2); Ar= C6H5 (1), 4-Br-C6H4 (2), 4-PhC6H4 (3), 4-
CH3OC6H4 (4), 4-CH3SC6H4 (5) , 6-MeO-naphyl (6), 4-MeO-naphthyl (7), 4-C2H5OC6H4 (8),
3,4-(CH3O)2C6H3 (9), and 3,5-(CH3O)2C6H3 (10) ) with (2-bromoacetyl)ferrocene. The
1
13
structures of the new compounds were determined by elemental analyses, IR, H and C NMR
and mass spectroscopic data.
Reaction of 1-cyanoferrocene with sodium hydrogen selenide (NaHSe) in methanol gave the new
ferrocenyl selenocarboxamide (11) in 27% yield. Treatment of compound 11 with a catalytic
amount of Na2[PdCl4] gave 3,5-diferrocenyl-1,2,4-selenadiazole in 35% yield. Both compounds
were characterized elemental analyses and spectroscopic techniques.
Compounds 1 - 10 and 12 were screened as antibacterial agents against S. aureus, E. Coli and P.
aeruginosaand showed promising properties.
Keywords: ferrocenyl selenazoles, 3,5-diferrocenyl-1,2,4-selenadiazole, (2-bromoacetyl)
ferrocene, selenocarboxamide, sodium hydrogen selenide.
*Corresponding author. E-mail: alrubaie49@yahoo.com ; Phone: +9647801951550
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1. Introduction
The interest in selenazoles has been growing during the last decades not only for their
importance in synthetic chemistry only but also for their biological properties [1].
1,3-Selenazoles were found to be of pharmacological importance due to their antibiotic and
cancerostatic activity [2]. Selenazole heterocycles, namely C-glycosylselenazole (selenafurin),
are being studied because of its anti-bacterial activities [2a] while 2-aminoselenazoles because of
their superoxide anion-scavengers [3].
A number of synthetic routes have been developed for the synthesis of selenium-
containing interesting heterocyclic compounds because of their unique reactivity [4, 5]. It is
worth noting that [1,2,3]-selenadiazole-4-yl-ferrocene, di-[1,2,3]-selenadiazole-4-yl-ferrocene
and their sulfur analog were prepared from the reaction of ketones with semicarbazones or
hydrazones [6a]. The synthesis and evaluation of ferrocenyl thiazole derivatives as anticancer
agents have been reported [6b]. On the other hand, ferrocene and its derivatives have received
considerable attention for their biological activity [7]. Ferrocifen which is a ferrocene derivative
of tamoxifen was submitted to clinical trial as breast anti-cancer drug [8].
However, to the best of our knowledge, there is no report described the synthesis and
evaluating biological activities of ferrocene derivatives that contains selenazoles or
selenadiazoles. Thus, herein we described the synthesis and biological activities of some new
ferrocenyl containing selenazole or selenadiazole moieties.
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2. Results and Discussion
Arylselenocarboxamides were prepared by treatment of arylnitriles with NaHSe in
ethanol according to a reported method [9], Scheme 1. All these compounds were obtained as
1
yellow or orange solids and were characterized by their melting points, IR and H NMR
spectroscopic data, which agrees well with previously reported data [9, 10].
(2-Bromoacetyl) ferrocene was prepared as a red needle in 35% yield by treatment of ferrocene
with bromoacetyl bromide in presence of AlCl3, Scheme 1.
Reaction of the primary aryl selenocarboxamides with (2-bromoacetyl) ferrocene gave the
corresponding 2-diaryl-4-ferrocenyl-1,3-selenazoles (1-10) in fair to good yields (Experimental
section, Scheme 1).
Ar = C6H5, 4-BrC6H4, 4-PhC6H4, 4-CH3C6H4, 4-CH3SC6H4, 6-CH3O-Naphthyl, 4-CH3O-
Naphthyl, 4-EtOC6H4, 3,4-(CH3O)2C6H3 and 3,5-(CH3O)2C6H3
Scheme 1. Methods of preparation of compounds 1-10.
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All 2-diaryl-4-ferrocenyl-1,3-selenazole derivatives (1-10) are red or orange solids with sharp
melting point which are soluble in common organic solvents. The IR spectra of all compounds
show an absorption band between1580-1630 cm-1 due to ν(C=N) and an absorption band in
range 595-560 cm-1 may assigned to ν(Se-C) [9,11, 12]. The characteristic frequencies
observed of the compounds 1-10 around 3081, 1442, 1105, 830, 5 03 and 482 cm-1 are
attributed to the ferrocenyl moieties ν(C-H), ν(C-C), ν(C-H), ν(C-H) and ν(Fe-ring),
respectively[12,13]. Furthermore, the (C-H) vibrations for the selenazole ring in compounds 1-
10 is observed in the region 3070-3011 cm-1, which is characteristic of heteroaromatic
compounds [13].
1H NMR spectra of compounds 1-10 were recorded in CDCl3 and gave a further support for the
formation of these compounds. The 1H NMR spectra consist of, in addition to SCH3, OCH3 and
OCH2CH3, low field signals of aryl protons at the range 6.98-8.89 ppm. The 1H NMR spectra of
compounds 1-10 exhibited triplet for substituted Cp ring around 4.92 and 4.78 ppm and a
singlet for unsubstituted Cp ring around 4.23 ppm. Furthermore, all spectra showed one
singlet signal downfield between 8.75 and 8.89 ppm due to the H-selenazole ring, which agrees
well with the literature values [10].
13C NMR data are in good agreement with the formulation of these compounds. In general, the
13C NMR spectra of all compounds (1-10) showed the characteristic signals of the 1,3-selenazole
ring skeleton carbons, signals for the carbons of the mono and unsubstituted cyclopentadienyl
rings and signals for the aryl groups. For example, the 13C spectrum of compound 5 shows
signals at 75.1, 69.9, 68.8 and 68.6 ppm for the carbons of mono and unsubstituted
cyclopentadienyl rings, and signals at 168.3, 163.8 and 121.2 ppm for C2, C4 and C5 for
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selenazole ring, respectively. Furthermore, signal at 17.2 ppm due to SCH3 group was observed.
All 13C data are presented in the experimental section.
The mass spectra of compounds 1, 2, 3, 5, 10 and 12 show the molecular ion with a
correct isotope pattern for compounds containing selenium. The base peak of each spectrum was
based on ArCN+ which is corresponding to the loss of FcC=CHSe+ ion. In general, the mass
spectra of these compounds show the characteristic features of selenazole compounds and the
exact fragmentation patterns. Furthermore, fragments at 186, 121 and 56 were observed in all
spectra due to ferrocene moiety.
The synthetic method for 3,5-diferrocenyl-1,2,4-selenadiazole(12) based on the
preparation of cyanoferrocene which was treated with NaHSe (prepared in situ) to afford the new
ferrocenyl selenocarboxamide (11) in 27% yield as a red solid, Scheme 2.
Scheme 2. Methods of preparation of compounds 11and 12.
The IR spectrum of compounds 11 showed the appearance of bands due to NH2 asymmetrical
and symmetrical stretching at 3314 and 3215 cm-1, respectively. The spectrum showed strong
band at 1623 cm-1 due to the deformation of N-H. Furthermore, the spectrum showed intense
band at 620 cm-1 and a medium band at 380 cm-1 assigned to the C-Se stretching contribution [9,
11, 14].
1H NMR spectrum of compound 11 showed two broad singlet signals at 9.45 and 10.34 ppm
due to the -C(=Se)NH2 group, which agrees well with the literature values [9,14]. The spectrum
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showed singlet signal at 4.18 ppm for unsubstituted cyclopentadienyl ring and two triplets at 4.62
and 4.42 ppm for monosubstituted cyclopentadienyl ring with the proper intensity ratio
(Experimental Section).
Compound 11 was treated with a catalytic amount of Na2PdCl4 to give the new 3,5-
diferrocenyl-1,2,4-selenadiazole(12) as orange-red crystals in 35% yield, Scheme 2. The IR
spectrum of 12 indicates clearly the absence of ν(NH2) and ν(C=Se) and the appearance of
medium band at 1680 cm-1 for ν(C=N) and at 515 cm-1 corresponding to ν(C-Se)[10-12].
1H NMR spectrum of compound 12 showed all the expected peaks with the proper intensity
ratio, see Experimental Section. 13C NMR spectrum of compound 12 showed signals at 173.6
and 166.2 for C4 and C5 carbons of the selenadiazole ring with the expected signals for the
carbons of mono and unsubstituted cyclopentadienyl rings, Experimental Section.
2.1 Antibacterial activity
It is worth noting that ferrocenyl thiazole derivatives showed some degree of biological activity
[15]. This prompted us to evaluate the antimicrobial activity of some synthesized compounds
(i.e. compounds 1-10 and 12) against different strains of bacteria.
The antimicrobial activity of tested compounds against E. coli, S. aureus and P. aeruginosa is
shown in Table 1.
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Table 1
Antibacterial activity expressed as inhibition diameter zone in millimeter (mm) of
compounds 1-10 and 12 at 40 ug/ ml.
Compounds
Zone of Inhibition (mm)
S. aureus
E. coli
P. aeruginosa
17 ± 0.33
1
17 ± 0.33
16 ± 0.33
2
19 ± 0.33
16 ± 0.33
19 ± 0.33
21± 0.33
15 ± 0.33
16 ± 0.33
19 ± 0.33
18 ± 0.33
20 ± 0.33
19 ± 0.33
35 ± 0.01
20 ± 0.33
15 ± 0.33
20 ± 0.33
23± 0.33
16 ± 0.33
15 ± 0.33
20 ± 0.33
19 ± 0.33
18± 0.33
21± 0.33
33± 0.00
19 ± 0.33
15 ± 0.33
19 ± 0.33
19 ± 0.33
13 ± 0.33
13 ± 0.33
20± 0.33
18 ± 0.33
17 ± 0.33
20 ± 0.33
32 ± 0.33
3
4
5
6
7
8
9
10
12
Chloramphenicol
All the values are expressed as men ± SEM triplicate
From Table 1, it can be concluded that all the compounds have displayed some activity against
bacteria. Compound 5 is highly active against E. coli which may due to the combined activity of
sulfur and selenium in this compound. Compound 8 also showed good activity toward the three
bacteria. This increase in activity may due to presence of ethoxy groups in this compound.
Compounds 3, 6 and 7 showed minimum activity against all strains. This may be attributed to the
presence of a bulky naphthyl and phenyl groups, which makes slow diffusion through the cell
membrane. In general, the antibacterial study shows some promising results compare to the
standard drug, Table 1.
The minimum inhibitory concentration (MIC) values of the studied compounds against these
bacteria are reported in Table 2. Compound 5 (MIC = 0.5 ꢀg/ ml) was found to have a very good
activity against E. coli when compared with chloramphenicol and good activity against S. aureus
and P. aeruginosa.
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Table 2
Antibacterial activity (MIC ꢀg/ ml) of compounds 1 - 10 and 12
Compounds
S. aureus
E. coli
P. aeruginosa
20
30
30
10
5
30
30
20
10
10
10
0.1
5
5
20
5
0.5
30
20
10
10
10
5
5
5
20
5
1
2
3
4
5
6
7
8
5
20
30
10
10
5
9
10
12
5
0.1
0.1
Chloramphenicol
Compounds 1, 2, 4 and 12 were found to be equally potent to against E. coli and P. aeruginosa.
In general, compounds 1-10 and 12 showed some promising activity against the growth of the
tested bacterial strains. In comparing the biological activity of these newly synthesized with
those previously reported data on ferrocene derivatives [16-18], we may conclude that the
combination of ferrocene and selenazoles/selenadiazoles is favourable for the biological activity.
3. Conclusion
In conclusion, the objective of the present work was to synthesize some novel ferrocene
derivatives containing selenazole moieties and the new 3,5-diferrocenyl-1,2,4-selenadiazole in
hope of discovering new compounds as antimicrobial agents. Some of these compounds showed
potential biological activity against different strains of bacteria.
4. Experimental
4.1 Physical measurements
All melting points were determined on a Gallenkamp melting point apparatus and are
uncorrected. The 1H and 13C NMR spectra were measured on a Bruker Ultra-300 spectrometer in
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CDCl3 solution with TMS as internal standard. Elemental analyses were determined on an MT-3
elemental analyzer within ±5 % of the theoretical values. Mass spectra were recorded on a HP-
598 8A MS instrument at 70 eV.
4.2. Synthesis
All materials were obtained from Sigma-Aldrich and solvents were purified and dried prior
to use according to conventional methods. All reactions were carried out under nitrogen
atmosphere and monitored by TLC using aluminium-backed plates coated with silica gel
(Merck Kieselgel 60 F254). Acetyl ferrocene [19] and (2-bromoacetyl) ferrocene [20,21] were
prepared by literature methods.
Phenylselenocarboxamide, 4-bromophenylseleno-carboxamide, 4-phenylphenylselenocarbox-
amide, 4-methoxyphenylselenocarboxamide, 4-methylthiophenylselenocarboxamide, 6-
methoxynaphthyl-1-selenocarboxamide,
4-methoxynaphthyl-2-selenocarboxamide,
3,4-dimethoxyphenylselenocarboxamide and
4-
ethoxyphenylselenocarboxamide,
3,5-
dimethoxyphenyl-3,5-selenocarboxamide were prepared according to a literature method [10].
All compounds were characterized by their melting points, IR and 1H NMR spectroscopic data.
1-Cyanoferrocene was prepared by a literature method [22, 23] as golden-yellow plates in 28%
yield, m.p: 105-107°C (Lit. [19] 106-107oC; Lit[23] 106.4-106.7oC). IR (KBr disc): 3050, 2980,
2252, 1600, 1450, 870 cm-1.
2-Ary-4-ferrocenyl-1,3-selenazoles were prepared from the reaction of the corresponding aryl
selenocarboxames with (2-bromoacetyl)ferrocene by the following procedure:
A solution of (2-bromoacetyl)ferrocene (10 mmol) in of ethanol (10 mL) was added
dropwise to a hot solution of aryl selenocarboxamides (10 mmol) in ethanol (20 mL). The
reaction mixture was refluxed for 60 min (the end of the reaction was monitored by TLC). The
mixture is then concentrated by a rotary evaporator and the residue neutralized with dilute
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aqueous ammonia solution (10%). The precipitate was deposited, collected by filtration and then
washed several times with cold ethanol. Recrystallization from ethanol gave the corresponding
2-ary-4-ferrocenyl-1,3-selenazoles in fair to good yields.
4.2.1. 2-Phenyl-4-ferrocenyl-1,3-selenazole (1).
Yield: 66%, mp. 119-121oC.
Anal. Calc. for C19H15FeNSe: C, 58.20; H, 3.86; N, 3.57. Found: C, 58.12; H, 3.91; N, 3.35.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.75(s, 1H, selnazole), 7,87(m,2H, Ar-H), 7.47(m, 3H, Ar-
H), 4.64(t, 2H, J=1.82Hz, Cp), 4.36(t, 2H, J=1.83Hz, Cp), 4.06(s, 5H, Cp).
13C-NMR (75 MHz, CDCl3, δ / ppm): 165.1, 160.3, 131.5, 123.6, 115.3, 78.2, 71.2, 68.6.
MS: m/z: 392(M+).
4.2.2. 2-(4-bromophenyl)-4-ferrocenyl-1,3-selenazole (2 ).
Yield: 55%. Mp. 146-148oC.
Anal. Calc. for C19H14BrFeNSe: C, 48.45; H, 3.00; N, 2.97. Found: C, 48.26; H, 3.11; N, 3.05.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.82(s, 1H, selnazole), 7,97(d, 2H, J= 7,8Hz, Ar-H), 7.65(d,
2H, J= 7.65Hz, Ar-H), 4.60(t, 2H, J=1.82Hz, Cp), 4.30(t, 2H, J=1.83Hz, Cp), 4.03(s, 5H, Cp).
13C-NMR (75 MHz, CDCl3, δ / ppm): 169.1, 163.6, 131.7, 131.4, 129.8, 125.5, 81.1, 70.2, 69.7,
58.1. MS: m/z: 470/472/544(M+).
4.2.3. 2-(4-phenyphenyl)-4-ferrocenyl-1,3-selenazole (3 ).
Yield: 61%, mp. 181-182oC.
Anal. Calc. for C25H19FeNSe: C, 64.13; H, 4.09; N, 2.99. Found: C, 64.23; H, 3.95; N, 2.87.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.79(s, 1H, selnazole), 8.07(d,2H, J= 7,5Hz, Ar-H), 7.84(d,
2H, J= 7.85Hz, Ar-H), 7.64(m,2H, Ar-H), 7.37-7,47(m, 3H, Ar-H), 4.65(t, 2H, J=1.84Hz, Cp),
4.32(t, 2H, J=1.82Hz, Cp), 4.11(s, 5H, Cp).
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13C-NMR (75 MHz, CDCl3, δ / ppm): 165.3, 159.7, 144.2, 140.8, 131.3, 129,1, 128.0, 127.9,
127.6, 129.4, 81.5, 70,5, 69.6, 67.9.
MS: m/z: 468(M+).
4.2.4. 2-(4-(Methoxy)phenyl)-4-ferrocenyl-1,3-selenazole (4)
Yield: 72%, mp. 215-217oC.
Anal. Calc. for C20H17FeNOSe: C, 56.90; H, 4.06; N, 3.32. Found: C, 57.22; H, 3.96; N, 3.35.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.80(s, 1H, selnazole), 7.77(d,2H, J= 7.6Hz, Ar-H), 7.01(d,
2H, J= 7.74Hz, Ar-H), 4.65(t, 2H, J=1.82Hz, Cp), 4.32(t, 2H, J=1.83Hz, Cp), 4.27(s, 3H,
OCH3), 4.02(s, 5H, Cp).
13C-NMR (75 MHz, CDCl3, δ / ppm): 168.3, 163.9, 162.8, 130.2, 123.8, 118.4, 114.7, 81.7, 73.3,
69.7, 67.8, 55.2.
4.2.5. 2-(4-(Methylthio)phenyl)-4-ferrocenyl-1,3-selenazole (5)
Yield: 58%, mp. 175-177oC.
Anal. Calc. for C20H17FeNSSe: C, 54.82; H, 3.91; N, 3.20. Found: C, 54.75; H, 3.86; N, 3.35.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.79(s, 1H, selnazole), 7.77(d, 2H, J= 7, 6Hz, Ar-H),
7.42(d, 2H, J= 7.85Hz, Ar-H), 4.73(t, 2H, J=1.81Hz, Cp), 4.36(t, 2H, J=1.85Hz, Cp), 4.11(s, 5H,
Cp), 2.57(s, 3H, SCH3).
13C-NMR (75 MHz, CDCl3, δ / ppm): 168.6, 163.8, 141.5, 128.8, 129.0, 126.1, 121.2, 75.1, 69.9,
68.8, 68.6, 17.2.
MS: m/z: 438(M+).
4.2.6. 2-(6-Methoxy-2-naphthyl)-4-ferrocenyl-1,3-selenazole (6)
Yield: 43%, mp. 107-109oC.
Anal. Calc. for C24H19FeNOSe: C, 61.04; H, 4.06; N, 2.97. Found: C, 60.78; H, 3.94; N, 3.12.
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1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.75(s, 1H, selnazole), 8.26(s,1H, Ar-H), 7.81-7.97(m, 2H,
Ar-H), 7.56(d,1H, J=7.5Hz, Ar-H), 7.2(d,1H, J= 1.5Hz, Ar-H). 6.84(dd, 1H, J=1.6Hz, J=7.76Hz,
Ar-H), 4.71(t, 2H, J=1.81Hz, Cp), 4.37(t, 2H, J=1.85Hz, Cp), 4.27(s, 3H, OCH3), 4.12(s, 5H,
Cp).
13C-NMR (75 MHz, CDCl3, δ / ppm): 165.6, 160.1, 157.2, 141.8, 129.9, 129.6, 129.3, 127.4,
127.0, 126.2, 119.6, 118.8, 106.9, 78.9, 72.1, 69.2, 67.7, 56.7.
3.2.7. 2-(4-Methoxy-1-naphthyl)-4-ferrocenyl-1,3-selenazole (7)
Yield: 37%, mp. 91-93oC.
Anal. Calc. for C24H19FeNOSe: C, 61.04; H, 4.06; N, 2.97. Found: C, 60.99; H, 3.97; N, 2.87.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.81(s, 1H, selnazole), 7.81(d,2H, J= 7.6Hz, Ar-H), 7.58-
7.73 (m, 2H, Ar-H), 7.24-7.38(m, 2H, Ar-H), 7.04(d,1H, J= 7.8Hz, Ar-H). 4.71(t, 2H, J=1.81Hz,
Cp), 4.41(t, 2H, J=1.85Hz, Cp), 4.27(s, 3H, OCH3), 4.00(s, 5H, Cp).
13C-NMR (75 MHz, CDCl3, δ / ppm): 167.4, 160.4, 157.1, 135.2, 127.6, 126.7, 125.4, 125.0,
123.5, 122.6, 119.4, 118.9, 104.6, 81.4, 78.4, 69.5, 68.2, 56.2.
4.2.8. 2-(4-Ethoxyphenyl)-4-ferrocenyl-1,3-selenazole (8)
Yield: 62%, mp. 126-128oC.
Anal. Calc. for C21H19FeNOSe: C, 57.82; H, 4.39; N, 2.21. Found: C, 57.88; H, 3.97; N, 2.14.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.82(s, 1H, selenazole), 7.77(d, 2H, J= 7.82Hz, Ar-H),
7.24(d, 2H, J= 1.7Hz, Ar-H), 4.83(q, 2H, CH2), 4.72(m, 2H, Cp), 4.38(m, 2H, Cp), 4.10(s, 5H,
Cp), 1.89(t, 3H, CH3).
13C-NMR (75 MHz, CDCl3, δ / ppm): 167.6, 161.5, 159.7, 129.6, 121.5, 119.1, 115.2, 78.4, 69.6,
58.7, 66.9, 65.4, 15.1.
MS: m/z: 436(M+).
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4.2.9. 2-(3,4-Dimethoxyphenyl)- 4-ferrocenyl-1,3-selenazole (9)
Yield: 51%, mp. 141-143oC.
Anal. Calc. for C21H19FeNO2Se: C, 55.78; H, 4.24; N, 3.10. Found: C, 55.58; H, 3.98; N, 3.12.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.65(s, 1H, selenazole), 7.31(s, 1H, Ar-H), 7.34(d, 1H, J=
1.86Hz, Ar-H), 6.91(d, 1H, J= 8.21Hz, Ar-H), 4.73(t, 2H, J= 1.84Hz, Cp), 4.54(t, 2H, J=
1.83Hz, Cp), 4.27(s, 3H, OCH3), 4.26(s, 3H, OCH3), 4.21(s, 5H, Cp).
4.2.10. 2-(3,5-Dimethoxyphenyl)-4-ferrocenyl-1,3-selenazole (10)
Yield: 57%, mp. 158-160oC.
Anal. Calc. for C21H19FeNO2Se: C, 55.78; H, 4.24; N, 3.10. Found: C, 55.57; H, 4.15; N, 3.04.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 8.89(s, 1H, selenazole), 6.98(s, 2H, Ar-H), 6.55(s, 1H, Ar-
H), 4.66(t, 2H, J= 1.83Hz, Cp), 4.33(t, 2H, J= 1.78Hz, Cp), 4.31(s, 3H, OCH3), 4.27(s, 3H,
OCH3), 4.22(s, 5H, Cp).
MS: m/z: 452(M+).
4.2.11. Ferrocenyl selenocarboxamide (11)
Sodium borohydride (1.02g, 27 mmol)was added dropwise over 30 min to a suspension
of selenium powder(1.98g, 25mmol) in dry ethanol (30 mL) under nitrogen atmosphere while
hydrogen evolved vigorously. The resulting solution stirred for additional 30 min. Pyridine
(4.1mL, 50 mmol) and 1-cyanoferrocene (2.74g; 13 mmol) were added to the resulting solution
at room temperature. The solution was heated under reflux while hydrochloric acid (20 mL, 2M)
was added dropwise over 2h. The solution was refluxed for 30 min then filtered hot. The filtrate
was cooled to room temperature. Crushed ice was added in small portions with continuous
stirring until the precipitation of ferrocenyl selenocarboxamide was completed. The red
precipitate was recrystallized from benzene to give an orange solid in 27% yield, mp. 121-123oC.
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Anal Cacld. for C11H11NFeSe: C,45.24, H, 3.89, N, 4.80. Found: C, 45.12, H, 4.05, N, 4.68.
1H-NMR (300 MHz,CDCl3,δ/ ppm): 4.62(t, J =1.82Hz, 2H, Cp), 4.42(t, J =1.84Hz, 2H, Cp),
4.18(s, 5H, Cp), 9.45(sb, 1H, NH), 10.34(sb, 1H, NH).
3.2.12. 3,5-Diferrocenyl-1,2,4- selenadiazole (12)
To a solution of ferrocenyl selenocarboxamide (1.17g; 4 mmol) in acetone (20 mL) an
aqueous solution of Na2PdCl4 (0.2mg; 1x10-4 mmol) was added. The solution was stirred
at room temperature for 6 h. The resulting solution was filtered and the filtrate evaporated at
room temperature to give 3,5-diferrocenyl-1,2,4-selenadiazole as a yellow-orange solid in 35%
yield, mp. 111-113oC.
Anal. Calc. for C22H18Fe2N2Se: C, 52.74; H, 3.62; N, 5.59; Found: C, 52.83; H,3.59; N,5.36.
1H-NMR(300 MHz,CDCl3,δ/ ppm): 4.73(t, J =1.82Hz, 2H, Cp), 4.62(t, J =1.8Hz, 2H, Cp),
4.42(t, J =1.84 Hz, 2H, Cp), 4.33 (t, J = 1.82Hz, 2H, Cp), 4.11(s, 5H, Cp), 4.08 (s, 5H, Cp).
13C-NMR(75MHz,CDCl3,δ/ppm):173.6(C-Fc),166.2(C-Fc), 84.25(Cp), 72.72(Cp), 71.31(Cp),
69.42(Cp).
4.3. Antibacterial activity
Compounds 1-10 and 12 were screened for their antibacterial activity in vitro following
the protocol described previously [24]. The antibacterial effect was assayed against Gram
positive bacteria viz., S. aureus and Gram negative E. coli and P. aeruginosa by the agar well
diffusion method. The compounds were dissolved in DMF at different concentrations of 0.1, 0.5,
5, 10, 20, 30, 40, 50, 80 and 100 µg/ ml. Mueller Hinton-agar plates were prepared and inoculum
size for test strain was adjusted to 108 CFU/ ml (colony forming unit per milliliter) by comparing
the turbidity. Wells (9 mm) were made in the agar petri dishes. DMF was used as the negative
control. The plates were incubated at 37oC for 24 h. Zone of inhibition of bacterial growth
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around each well was measured in mm. The results were compared with the activity of
chloramphenicol identical concentrations. The experiment was performed three times to
minimize the errors. The minimum inhibitory concentration (MIC), defined as the lowest
concentration of the test compound, which inhibits the visible growth, was determined visually
after incubation for 24 h at 37oC.
ACKNOWLEDGMENTS
The financial support of this work by Ministry of Higher Education and Scientific Research/
Research and Development (Grant No. 595) is hereby gratefully acknowledged.
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Table 1. Antibacterial activity expressed as inhibition diameter zone in
millimeter (mm) of compounds 1-10 and 12 at 40 ug mL-1.
Compounds
Zone of Inhibition (mm)
S. aureus
E. coli
P. aeruginosa
17 ± 0.33
1
17 ± 0.33
16 ± 0.33
2
19 ± 0.33
16 ± 0.33
19 ± 0.33
21± 0.33
15 ± 0.33
16 ± 0.33
19 ± 0.33
18 ± 0.33
20 ± 0.33
19 ± 0.33
35 ± 0.01
20 ± 0.33
15 ± 0.33
20 ± 0.33
23± 0.33
16 ± 0.33
15 ± 0.33
20 ± 0.33
19 ± 0.33
18± 0.33
21± 0.33
33± 0.00
19 ± 0.33
15 ± 0.33
19 ± 0.33
19 ± 0.33
13 ± 0.33
13 ± 0.33
20± 0.33
18 ± 0.33
17 ± 0.33
20 ± 0.33
32 ± 0.33
3
4
5
6
7
8
9
10
12
Chloramphenicol
All the values are expressed as men ± SEM triplicate
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Table 2. Antibacterial activity (MIC µg mL-1) of compounds 1 - 10 and 12
MIC µg mL-1
Compounds
S. aureus
E. Coli
P. aeruginosa
20
30
30
10
5
30
30
20
10
10
10
0.1
5
5
20
5
0.5
30
20
10
10
10
5
5
5
20
5
1
2
3
4
5
6
7
8
5
20
30
10
10
5
9
10
12
5
0.1
0.1
Chloramphenicol

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•
•
•
A new series of novel ferrocene derivatives containing selenazole-moiety were
synthesized.
Ferrocenyl selenocarboxamide and 3,5-diferrocenyl-1,2,4-selenadiazole were
synthesized.
The new compounds showed potential biological activity against S. aureu, E. coli and P.
aeruginosa strains.