Synthesis, antimicrobial activity, and 77Se NMR of some new pyrrole derivatives containing a diphenyl selenide moiety

Article abstract of DOI:10.1080/104265090917763

A simple and mild synthesis for pyrrolyl and pyrrolo[2,3-d]pyrimidinyl diphenyl selenides is described based on the reaction of active methylene compounds with 4′-nitro-4-acetylaminodiphenyl selenide. The sensitivity of ⁷⁷Se NMR spectra allowed

Full text of DOI:10.1080/104265090917763

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Phosphorus, Sulfur, and Silicon
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Synthesis, Antimicrobial
Activity, and 77Se NMR of
Some New Pyrrole Derivatives
Containing a Diphenyl Selenide
Moiety
Sh. H. Abdel-Hafez a , H. W. Anthonsen b , H.-R.
Sliwka b & V. Partali b
a Department of Chemistry, Assiut University, Assiut,
Egypt
b Department of Chemistry, Norwegian University of
Science and Technology, Trondheim, Norway
Version of record first published: 22 Aug 2006.
To cite this article: Sh. H. Abdel-Hafez , H. W. Anthonsen , H.-R. Sliwka & V.
Partali (2005): Synthesis, Antimicrobial Activity, and 77Se NMR of Some New Pyrrole
Derivatives Containing a Diphenyl Selenide Moiety, Phosphorus, Sulfur, and Silicon and
the Related Elements, 180:10, 2217-2224
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Phosphorus, Sulfur, and Silicon, 180:2217–2224, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090917763
Synthesis, Antimicrobial Activity, and 77Se NMR
of Some New Pyrrole Derivatives Containing
a Diphenyl Selenide Moiety
Sh. H. Abdel-Hafez
Department of Chemistry, Assiut University, Assiut, Egypt
H. W. Anthonsen
H.-R. Sliwka
V. Partali
Department of Chemistry, Norwegian University of Science and
Technology, Trondheim, Norway
A simple and mild synthesis for pyrrolyl and pyrrolo[2,3-d]pyrimidinyl diphenyl
selenides is described based on the reaction of active methylene compounds with
77
4ꢀ-nitro-4-acetylaminodiphenyl selenide. The sensitivity of Se NMR spectra al-
lowed differentiating the rather similar pyrrole compounds. The synthesized com-
pounds were screened for their antifungal and antibacterial activities.
Keywords 77Se NMR; antibacterial activity; antifungal activity; diphenyl selenide; keto
enol tautomers; pyrrole
INTRODUCTION
The pyrrole nucleus plays a vital role in many compounds with
biological activities1−5 and, consequently, pyrrolo[2,3-d]pyrimidine
derivatives6,7 are insecticides, microbicides,8 pro-oxidants,9 and an-
timycobacterial agents.10 Likewise, organo-selenium compounds are
known to react as antioxidants11 and as anticancerogens.12−14 In view
of these findings and in continuation of our work15−17 on the synthesis of
novel heterocyclic systems containing diaryl sulfide and diary selenide,
we undertook the synthesis of some new pyrrole derivatives including
the diphenyl selenide moiety.
Received October 22, 2004; accepted November 11, 2004.
Address correspondence to Sh. H. Abdel-Hafez, Assiut University, Department of
Chemistry, Faculty of Science, Assiut 71516, Egypt. E-mail: shams@acc.aun.edu.eg
2217

2218
Sh. H. Abdel-Hafez et al.
RESULTS AND DISCUSSION
The starting material 4ꢀ-nitro-4-chloroacetylaminodiphenyl selenide (2)
was synthesized16 from the reaction of 1 with chloroacetyl chloride in
dioxane at 40◦C. When 2 was refluxed with malononitrile in absolute
ethanol in the presence of anhydrous potassium carbonate according to
the Gewald method,18 compound 3 was obtained. A 77Se NMR peak at
463.8 ppm confirmed the presence of Se. The formation of 3 is assumed
to proceed via alkylation of malononitrile followed by intramolecular
cyclization.19 The reaction of 3 with formamide yielded pyrrolo [2,3-
d]pyrimidine derivative 4 (Scheme 1).
SCHEME 1 (a) ClCOCH2Cl/dioxane; (b) CH2(CN)2/K2CO3; (c) HCONH2.
The relative stability of the tautomers 3a and 3b were estimated from
the calculated formation energies20 (Figure 1). The keto form 3a (ꢀE =
48.2 kcal/mol) is more stable than enol form 3b (ꢀE = 57.2 kcal/mol),
which is in agreement with 1H NMR spectra, showing only a singlet of
two protons from the CH2 group of the pyrrole ring in 3a.
FIGURE 1 Tautomer energy calculation of Compound 3.

Synthesis for Pyrrole Derivatives
2219
When compound 2 was reacted with ethyl acetoactate in refluxing
DMF in the presence of anhydrous potassium carbonate, two possible
structures, 5 and 6, could be predicted. The structure of 5 was ex-
1
cluded on the basis of analytical and spectral data. In the H NMR
spectrum the OC2H5 fragment was not detected; only the singlet of
the acetyl group was seen, which was also detected in the IR spec-
trum. The formation of compound 6 can be explained on the basis of an
initial alkylation of ethyl acetoacetate followed by intramolecular cy-
clization to the intermediate dihydropyrrole, which is then oxidized21
under the reaction condition to yield the novel pyrrole derivative 6
(Scheme 2).
SCHEME 2 (a)
.
In a similar manner, the reaction of ethyl cyanoacetate with com-
pound 2 gave the pyrrole derivative 8. The other possible compound 7
was discarded on the basis of analytical and spectral data (Scheme 3).
The presence of selenium in 8 was detected at δ 453.9 ppm in the 77Se
NMR spectrum.
Despite the structural similarities of compound 2, 3, and 8, the high
sensitivity of 77Se-NMR allowed an exact distinction of the compounds,
(Table I).22

2220
Sh. H. Abdel-Hafez et al.
SCHEME 3 (a)
.
BIOLOGICAL STUDIES
The newly synthesized compounds were screened for their antibacterial
activity against Bacillus cereus and Staphylococcus aureus and for an-
tifungal activity against Candida albicans, Tricophyton rubrum, and
Chrysosporium tropicum. We used Chloramphenicol 5% for bacteria
and Terbinafine 5% in the case of fungi as reference compounds. Com-
pounds 2, 3, 6, and 8 were tested using the disc-diffusion method23,24
TABLE I 77Se NMR of Compounds 2, 3, and 8
Compound structure
77Se NMR (ppm)
455.7
463.8
453.9

Synthesis for Pyrrole Derivatives
2221
TABLE II Antimicrobial Sensitivity Test of Chemical Compounds
(Expressed as Inhibition Zone in mm)
Microbial species
G +ve bacteria
Fungal species
Bacillus Staphylococcus Candida Tricophyton Chrysosporium
Chemical compounds
cereus
aureus
albicans
rubrum
tropicum
2
3
6
8
8
8
—
10
52
9
10
—
10
54
—
—
—
—
11
—
—
—
—
50
—
—
—
—
52
∗Reference compounds
∗Reference compounds: Chloramphenicol 5% (bacteria), Terbinafine 5% (fungi).
All compounds were inactive against the three species of fungi tested and 6 was
also inactive against bacteria. Compounds 2 and 3 showed weak activity against Bacil-
lus cereus. Compound 3 showed moderate activity only against Staphylococcus aureus,
whereas compound 8 showed moderate activity against two species of bacteria, Bacillus
cereus and Staphylococcus aureus. The presence of the cyano group in compound 8 in
addition to compound 3 is probably responsible for the moderate antibacterial activity.
by dissolving the individual compounds in DMSO to a solution of 5%.
The results of the antibacterial and antifungal screening are presented
in Table II.
CONCLUSION
The synthesized diphenyl selenide pyrrole derivatives 3, 6, and 8 and
the diphenyl selenide derivative 2 have no antimycotic activity, whereas
compounds 2, 3, and 8 act moderately against bacteria.
EXPERIMENTAL
The progress of reaction and the purity of the compounds were mon-
itored by TLC. Melting points (uncorrected) were determined on a
Fisher-Johns melting point apparatus. Elemental analysis was per-
formed on a Perkin Elmer 240C elemental analyzer; all of the results
were in the range 0.4%. IR spectra were recorded on a Pye-Unicam
SP3-100 spectrophotometer using KBr wafer technique and MS spectra
were recorded on a MS 902 instrument with EI ionization at 70 eV. 1H
NMR, 13C NMR, and 77Se NMR spectra (95 MHz) H decoupled, com-
pound concentration 1% in CDCl3 or DMSO with diphenyl diselenide
8% in CDCl3 or DMSO as external standard (δ = 485) corresponding to
dimethylselenide (δ = 0) were recorded on a Bruker Avance DRX 500

2222
Sh. H. Abdel-Hafez et al.
spectrometer at 25◦C. The energy calculation of ground state equilib-
rium geometry was performed with AM1 in Spartanꢀ02.20
4ꢀ-Nitro-4-chloroacetylaminodiphenyl Selenide (2)
4ꢀ-Nitro-4-chloroacetylaminodiphenyl selenide (2) was prepared as pre-
viously described16 C14H11ClN2O3Se (369.5) MS: m/z 370 [M+, Se
isotope pattern], IR: υ´ = 3290 (NH); 1690 (C O) cm−1
;
1H NMR
(CDCl3): δ = 4.2 (s, 2H, CH2); 7.3–8.0 (m, 8H, Ar-H); 8.5 (s, 1H, NH);
13C NMR (CDCl3): 42.84, 120.98, 121.27, 121.57, 122.70, 123.98, 129.19,
129.37, 137.10, 137.21, 137.94, 144.07, 146.13, and 164.01. 77Se NMR:
δ = 455.7 ppm.
4ꢀ-Nitro-4-(2-amino-3-cyano-4,5-dihydro-5-oxo-pyrrol-1-yl)-
diphenyl Selenide (3)
4ꢀ-Nitro-4-(2-amino-3-cyano-4,5-dihydro-5-oxo-pyrrol-1-yl)-diphenyl
selenide (3) was synthesized as described16 C17H12N4O3Se (399) MS:
m/z 400 [M+, Se isotope pattern]. IR: υ´ = 3490–3380 (NH2); 2200 (CN);
1710 (C O) cm−1; 1H NMR (DMSO-d6): δ = 3.5 (s, 2H, CH2); 6.8 (s, 2H,
NH2); 7.10–7.40 (m, 8H, Ar-H). 77Se NMR: δ = 463.8 ppm.
4ꢀ-Nitro-4-(4-amino-5,6-dihydro-6-oxo-pyrrolo[2,3-d]pyrimidin-
7-yl)-diphenyl Selenide (4)
A solution of 3 (1 g, 0.0025 mol) in formamide (5 mL) was refluxed
for 4 h. The solid obtained was recrystallized from dioxane, 0.55 g
(52%); C18H13N5O3Se (426), m.p. 250◦C. IR: υ´ = 3420–3350 (NH2); 1690
(C O) cm−1
;
1H NMR (DMSO-d6): δ = 3.45 (s, 2H, CH2); δ = 5.1 (s,
2H,NH2); δ = 7.10–7.45 (m, 8H, Ar-H), 8.5 (s, 1H, pyrimidine-H).
4ꢀ-Nitro-4-(3-acetyl-2,5-dihydro-2,5-dioxo-pyrrol-1- yl)-
diphenyl Selenide (6)
A mixture of 2 (1 g, 0.0027 mol) and ethyl acetoacetate (0.34 g,
0.0026 mol) in dimethylformamide (20 mL), containing anhydrous
potassium carbonate (0.5 g), was heated under reflux for 2 h, left to
cool, poured on to ice water, and neutralized by conc. HCl (pH = 7). Yel-
low crystals precipitated, recrystallized from ethanol, 0.7 g (56%); m.p.
140◦C; C18H12N2O5Se (415); MS: m/z 416 [M+, Se isotope pattern]. IR:
υ´ = 1710 (C O); 1720 (COCH3) cm−1; 1H NMR (DMSO-d6): δ = 3.42 (s,
3H, CH3); 6.8 (s, 1H, CH-pyrrole); 7.10–8.0 (m, 8H, Ar-H).

Synthesis for Pyrrole Derivatives
2223
4ꢀ-Nitro-4-(3-cyano-2,5-dihydro-2,5-dioxo-pyrrol-1-yl)-diphenyl
Selenide (8)
The compound was prepared in the same way as 6 using ethyl cyanoac-
etate instead of ethyl acetoacetate. Recrystallization from dioxane gave
0.53 g (50%); m.p. 120◦C; C17H9N3O4Se (398) MS: m/z 399 [M+, Se
isotope pattern]. IR: υ´ = 1710 (C O); 2200 (CN) cm−1
δ = 453.9 ppm.
.
77Se NMR:
ANTIMICROBIAL SCREENING
The compounds were tested using the disc-diffusion method23,24 with
a 5% compound solution in DMSO. Filter paper discs (Whatman No.
3 filter paper, 5 mm diameter) were saturated with these solutions.
The saturated filter paper discs were placed on the surface of solidified
Nutrient agar dishes seeded by the test bacteria and Czapek,s Dox agar
dishes seeded by the test fungi. The inhibition zones were measured in
mm at the end of an incubation period of 48 h (at 37◦C for the bacteria
and 28◦C for the fungi).
REFERENCES
[1] A. Almerico, P. Diana, P. Barraja, G. Dattolo, F. Mingoia, A. Loi, et al., Farmaco, 53,
33 (1998).
[2] J. Obniska, K. Kuling, and A. Zejc, Acta Pol. Pharm., 55, 223 (1998).
[3] D. Baucke, U. Lange, H. Mack, W. Seitz, T. Zierke, H. W. Hoffken, et al., WO 98 06
741 (1998) [Chem. Abstr., 128, 192 940n (1998)].
[4] T. Iihama, K. Hagiwara, S. Maruge, S. Sano, S. Shimoda, and Y. Horikoshi, JP 10
324 687 (1998) [Chem. Abstr., 130, 81399q (1999)].
[5] R. A. Farlow and B. L. Reed, EP0895839 (1999) [Chem. Abstr., 130, 169743 (1999)].
[6] Y. Mizuno, M. J. Ikehara, K. A. Watanbe, S. Suzaki, and T. Itoh, J. Org. Chem., 28,
3329 (1963).
[7] R. L. Tolman, R. K. Robins, and L. B. Townsend, J. Am. Chem. Soc., 91, 2102 (1969).
[8] M. Koketsu, T. Senda, and H. Ishihara, JP2000119263 [Chem. Abstr., 132, 293768]
(2000).
[9] S. Janzsu, G. Hoppert, J. Shodiere, and J. C. Yerdon, JP1140067 [Chem. Abstr., 131,
32054] (1999).
[10] M. Koketsu, K. Tanaka, Y. Takenaka, C. D. Kwong, and H. Ishihara, Eur. J. Pharm.
Sci., 15, 307 (2002).
[11] C. M. Andersson, A. Hallberg, M. Linden, R. Brattsand, P. Moldeus, and I. Cotgreave,
Free Rad. Biol. Medicine, 16, 17 (1994).
[12] J. A. Woods, J. A. Hadfield, A. T. McGown, and W. Brian, Bioorg. Med. Chem., 1, 333
(1993).
[13] Ip. Clement, D. J. Lisk, H. Ganther, and H. J. Thompson, Anticancer Research, 17,
3195 (1997).
[14] Ip. Clement, D. J. Lisk, H. Ganther, and H. E. Ganther, Anticancer Research, 18,
4019 (1998).

2224
Sh. H. Abdel-Hafez et al.
[15] Sh. H. Abdel-Hafez, Phos., Sulf., and Silicon, 178, 2563 (2003).
[16] M. A. Abbady and Sh. H. Abdel-Hafez, Phos., Sulf., and Silicon, 160, 121 (2000).
[17] M. A. Abbady, Sh. H. Abdel-Hafez, M. M. Kandeel, and M. I. Abdel-Monem,
Molecules, 8, 622 (2003).
[18] H. Scha¨fer and K. Gewald, Monatsh. Chem., 120, 315 (1989).
[19] U. P. Basu and J. Sikdar, J. Ind. Chem. Soc., 466 (1947).
[20] Spartan ’02, Wavefunction Inc., Irvine, CA, USA 2002.
[21] G. H. Elgemeier, A. H. H. Elghandour, H. A. Ali, and H. M. Abdel-Azzez, J. Chem.
Res.(S), 6 (1999).
[22] W. Nakanishi and S. Hayashi, J. Phys. Chem. A, 103, 6074 (1999).
[23] L. P. Carrod and F. D. Grady, Antibiotic and Chemotherapy, 3rd ed., Edinburgh:
Churchill Livingston (1972).
[24] A. Cremer, Antibiotic Sensitivity and Assay Tests, 4th ed., London: Butterworth
(1980).