Nitroimidazoles, part 1. An unexpected reactivity during the cyclization of 3-(4-amino-1-benzyl-2-ethyl-1H-imidazol-5-ylsulphanyl)-propionic acid methyl ester

Article abstract of DOI:10.1080/00397910500184735

Nucleophilic substitution of the 5-bromo group in 1 by methyl 3-mercaptopropionate gave the 5-alkyl-mercapto derivative 2. Reduction of 2 with H₂/Pd led to the amine 3, meanwhile reduction with Fe/HOAc afforded the 5-acetamido derivative 4 and

Full text of DOI:10.1080/00397910500184735

This article was downloaded by: [Georgetown University]
On: 06 October 2013, At: 05:35
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Nitroimidazoles, Part 1.
An Unexpected Reactivity
During the Cyclization of
3‐(4‐Amino‐1‐benzyl‐2‐ethyl‐1H‐im
Acid Methyl Ester
Yaseen A. Al‐Soud a & Najim A. Al‐Masoudi b
a Department of Chemistry, College of Science,
University of Al al‐Bayt, Al‐Mafraq, Jordan
b Formerly Fachbereich Chemie, Universität
Konstanz, Konstanz, Germany
Published online: 18 Aug 2006.
To cite this article: Yaseen A. Al‐Soud & Najim A. Al‐Masoudi (2005)
Nitroimidazoles, Part 1. An Unexpected Reactivity During the Cyclization of
3‐(4‐Amino‐1‐benzyl‐2‐ethyl‐1H‐imidazol‐5‐ylsulphanyl)‐propionic Acid Methyl Ester,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:17, 2259-2264
To link to this article: http://dx.doi.org/10.1080/00397910500184735
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,

or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 2259–2264, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500184735
Nitroimidazoles, Part 1. An Unexpected
Reactivity During the Cyclization of
3-(4-Amino-1-benzyl-2-ethyl-1H-imidazol-
5-ylsulphanyl)-propionic Acid Methyl Ester
Yaseen A. Al-Soud
Department of Chemistry, College of Science, University of Al al-Bayt,
Al-Mafraq, Jordan
Najim A. Al-Masoudi
¨
Formerly Fachbereich Chemie, Universitat Konstanz, Konstanz,
Germany
Abstract: Nucleophilic substitution of the 5-bromo group in
1 by methyl
3-mercaptopropionate gave the 5-alkyl-mercapto derivative 2. Reduction of 2 with
H2/Pd led to the amine 3, meanwhile reduction with Fe/HOAc afforded the 5-
acetamido derivative 4 and not the cyclized derivative 1,3,8-triaza-azulen-7-one 6,
as expected. Treatment of 3 with NaOMe/MeOH furnished the racemic mixture
5a and 5b via an unexpected reactivity.
Keywords: Cyclization, 4-nitroimidazole, nucleophilic substitution, meso-product
INTRODUCTION
4-Nitrohaloimidazoles are of considerable pharmacological significance,
particularly as antibacterial agents,[1,2] potential radiosensitizers,[3] and in
cancer chemotherapy.[4] Furthermore, because of the facile replacement of
Received in the U.K. December 15, 2004
Address correspondence to Najim A. Al-Masoudi, P.O. Box 10 05 52,
D-78405 Konstanz, Germany. Fax: þ49 7531 34435; E-mail: najim.al-masoudi@
gmx.de
2259

2260
Y. A. Al-Soud and N. A. Al-Masoudi
halogen[5] and the reduction of the nitro group,[5] 4-nitrohaloimidazoles are
intermediates in syntheses of a variety of biologically active imidazoles.
Several benzodiazepines are known as antidepressant agents. Some
analogues, such as ‘Diltiazamw,[6] show potent coronary vasodilatory
activities as calcium antagonists. Our efforts for the synthesis of the
imidazole 6 bearing thialactam, the 3-benzyl-2-ethyl-3,5,6,8-tetrahydro-4-
thia-1,3,8-triaza-azulen-7-one, as a potential antitumor or coronary vaso-
dilator agent resulted in an unexpected rearrangement of the imidazole
derivative.
RESULTS AND DISCUSSION
Treatment of 1 with methyl 3-mercapto-propionate in THF with K2CO3 at
238C under argon afforded, after purification, the crystalline sulfide 2 in
80% yield. Recently, Erker et al.[8,9] have reported the reduction of some thio-
phenes carrying a propionylthio substituent, vicinal to a nitro group, resulting
in the formation of the thienothialactams. Moreover, hydrogenation[5] of 2 in
the presence of a molar amount of 5% Pd/C as a catalyst in anhyd. EtOH at
238C gave methyl ester 3 in 70% yield as oil and not the expected cyclized
product 6. The structure of 3 was confirmed by the homo- and heteronuclear
NMR studies and by its mass spectrum [m/z: C16H21N3O2S (319, Mþ)]. The
1H–13C HSQC spectrum of 3 showed, unexpectedly, two methylene groups
[(CH2)-2, (CH2)-3] as a singlet at dH 2.46, which are cross-linked to their
carbons C-2 and C-3 at dC 34.0 and 32.0, respectively. Reduction[9] at 708C
for 24 h of 2 with Fe/AcOH furnished the 5-acetamido derivative 4 in 55%
yield, as an oil [m/z: C18H23N3O3S (361, Mþ)].
In an attempt to obtain 6 by cyclization of 3, the latter compound was
stirred at 238C h in 0.2 M NaOMe/MeOH. However, the isolated product
turned out to be a racemic mixture of the 5a and 5b (78%) (Scheme 1).
A possible mechanism for the formation of 5a,b is depicted in Scheme 1,
depending on the observation of Kulkarani et al.[10] during the reaction of
sodium methoxide with 5-iodo-4-nitroimidazole. The structure 5 was
1
assigned by NMR and mass spectra. The CH2Ph signal in the H NMR
spectrum appeared as an AB system at dH 4.87 with a large coupling
constant (J ¼ 14.4 Hz), indicative of diastereotopic protons. The
methylene protons of the ethyl group at C-2 showed the pattern of an
ABX3 system (dH 2.02 and 1.78, J ¼ 7.3 Hz). The broad singlet at
dH 6.38 was assigned to the NH2 group, exchangable with D2O. In the
13C NMR of 6 a signal at dC 182.9 was assigned to the C55S group.
Irradiation of the CH2CH3 signal at dH 0.61 resulted in collapsing of the
two multiplets of the diastereotopic CH2 protons at dH 2.02 and 1.78 into
an AB-quartet (Figure 1). Furthermore, the IR spectrum of 5 showed
strong absorptions at 1655 and 1235 cm21, indicative for the C55N, and
C55S resonances, respectively.

Nitromidazoles, Part 1.
2261
Scheme 1. Reagents and conditions: (i) SH(CH2)2CO2Me, K2CO3, THF, rt, 18 h,
under argon; (ii) H2/Pd-C, anhydr. EtOH, rt; (iii) Fe/AcOH, 708C, 24 h; (iv) NaOMe/
MeOH, rt, 4 h.
Figure 1. 1H NMR (CDCl3, 600 MHz) of 5, showing irrradiation experiment.

2262
Y. A. Al-Soud and N. A. Al-Masoudi
EXPERIMENTAL
General
Melting points are uncorrected. NMR spectra are at 300 and 600 MHz (1H) and
at 62.9MHz (13C) with TMS as internal standard and on d scale in ppm. The
signal assignments for protons were verified by selective proton decoupling
or by COSY spectra. Heteronuclear assignments were verified by 1H–13C cor-
relation spectroscopy (COSY)[11] or heteronuclear multiple quantum coherence
(HMQC) experiments.[12] IR spectra (KBr disks) were measured with an FTIR
Bomen MB-120 spectrophotometer. 3-Nitrophenol (NBOH) or glycerol were
used in the EI and FAB mass measurements as matrices. Some molecular
ions were detected by doping the sample with Naþ ions.
3-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylsulfanyl)propionic
Acid Methyl Ester (2)
A suspension of potassium carbonate (0.90 g, 8.05 mmol) and methyl
3-mercaptopropionate (0.47 g, 3.91 mmol) was stirred in dry THF (20 mL)
under argon at rt. To this suspension, 1 (1.0 g, 3.22 mmol) was added
slowly and was stirred for 18 h, until the disappearance of the starting
material as monitored by TLC. The mixture was poured into ice water, and
the precipitate filtered off and recrystallized from EtOH to give 2 (0.90 g,
1
80%), mp: 94–958C. H NMR (600 MHz, CDCl3): d 7.36–7.26 (m, 3H,
Ar); 6.95 (d, 2H, J ¼ 7.1 Hz, Ar); 5.33 (s, 2H, CH2Ph); 3.62 (s, 3H, OMe);
3.12 [t, 2H, J ¼ 6.8 Hz, (CH2)-2]; 2.65 (q, 2H, J ¼ 7.5 Hz, CH2CH3); 2.53
[t, 2H, J ¼ 6.8 Hz, (CH2)-3]; 1.26 (t, 3H, CH2CH3). 13C NMR (CDCl3):
d 171.4 (C55O); 150.5 (C-20); 134.8 (C-40); 129.2, 128.3, 125.9, (Ar); 124.1
(C-50); 51.9 (COCH3); 47.6 (CH2Ph); 34.2, 31.4 (C-2, C-3); 21.2
(CH2CH3); 11.2 (CH2CH3). MS (70 eV, EI): m/z 349 (Mþ): elemental
analysis calcd. (%) for C16H19N3O4S (349.4): C, 55.00; H, 5.48; N, 12.03;
found: C, 54.75; H, 5.08; N, 11.92.
Reduction of 2
a) with H2/Pd: A solution of 2 (0.50 g, 1.43 mmol) in anhyd. EtOH (10 mL)
was hydrogenated in the presence of 5% palladium oxide (0.60 g) on charcoal
at atmospheric pressure and rt until the absorption of H2 has ceased. The
catalyst was filtered and the filtrate was concentrated to give an oily product
(0.32 g) that was identified as 3-(4-amino-1-benzyl-2-ethyl-1H-imidazol-5-
ylsulfanyl)-propionic acid methyl ester (3) (70%). 1H NMR (600 MHz,
CDCl3): d 7.33–7.25 (m, 3H, Ar); 6.98 (d, 2H, J ¼ 7.0 Hz, Ar); 5.13
(s, 2H, CH2Ph); 4.05 (br s., 2H, NH2); 3.56 (s, 3H, OMe); 2.55 (q, 2H,

Nitromidazoles, Part 1.
2263
J ¼ 7.6 Hz, CH2CH3); 2.47 [s, 4H, (CH2)-2, (CH2)-3]; 1.28 (t, 3H, CH2CH3).
13C NMR (CDCl3): d 172.1 (C55O); 151.6 (C-20); 148.8 (C-50); 137.0 (C-40);
128.7, 127.4, 125.8 (Ar); 51.6 (COCH3); 46.3 (CH2Ph); 34.0, 32.0 (C-2, C-3);
20.8 (CH2CH3); 11.6 (CH2CH3). MS (70 eV, EI): m/z 320 (MHþ). Analysis
calcd. for C16H21N3O3S (319.43): C, 60.16; H, 6.63; N, 13.15; found: C,
60.01; H, 6.57; N, 12.92.
b) with iron/HOAc: To a stirred suspension of 2 (0.40 g, 1.14 mmol) in
glacial HOAc (10 mL) and water (1.0 mL) at 708C was added iron powder
(0.60 g) in small portions. The reaction mixture was heated at 708C for 24 h,
filtered hot, and then cooled down. No precipitate was formed, instead the
solution was evaporated to dryness and the residue was partitioned between
water (20 mL) and CHCl3 (3 ꢀ 20 mL). The combined organic extracts
were dried (Na2SO4), filtered, and evaporated to dryness to give syrup. The
syrup was poured on flash SiO2 column (6 g), using CHCl3–MeOH (4 : 1)
as eluent, and the produce was tentatively identified as 3-(4-acetamido-1-
benzyl-2-ethyl-1H-imidazol-5-ylsulfanyl)propionic acid methyl ester (4)
1
(0.20 g, 55%). H NMR (600 MHz, CDCl3): d 8.95 (br s., 1H, NH); 7.55–
7.25 (m, 3H, Ar); 7.00 (d, 2H, J ¼ 6.0 Hz, Ar); 5.26 (s, 2H, CH2Ph); 3.70
(s, 3H, OMe); 2.61 (q, 2H, J ¼ 7.5 Hz, CH2CH3); 2.57, 2.46 [2d, 4H,
J ¼ 6.5 Hz, (CH2)-2, (CH2)-3]; 1.28 (t, 3H, CH2CH3). 13C NMR (CDCl3):
d 172.4 (C55O); 169.4 (NHCOMe); 150.4 (C-20); 141.5 (C-50); 136.5
(C-40); 128.9, 127.7, 125.9 (Ar); 51.9 (COCH3); 46.8 (CH2Ph); 33.9, 32.6
(C-2, C-3); 29.6 (NHCOMe); 21.2 (CH2CH3); 11.5 (CH2CH3). MS (70 eV,
FAB) (C18H23N3O3S): m/z 384 (MNa)þ.
Reaction of 3 with Sodium Methoxide
A solution of 3 (0.30 g, 0.94 mmol) in 0.2 M NaOMe solution (10 mL) was
stirred at rt for 4 h. The solution was neutralized with HOAc and then evapor-
ated to dryness. The residue was partitioned between water (10 mL) and
CHCl3 (3 ꢀ 10 mL), and the combined organic extracts were dried
(Na2SO4), filtered, and evaporated to give a solid that was identified as the
racemic mixture (R),(S)-4-amino-1-benzyl-2-ethyl-1,2-dihydro-2-methoxyi-
midazol-5-thione (5) (0.19 g, 78%), mp: 136–1378C decomp. nmax (cm21):
3360, 3250 (NH); 1655 (C55N), 1580, 1517, 1513, 1505, 1350 (Ar, C-N);
1
1235 (C55S). H NMR (600 MHz, CDCl3): d 7.51 (m, 2H, Ar); 7.32–7.20
(m, 3H, Ar); 6.38 (br s., 2H, NH2); 4.87 (AB q, 2H, J ¼ 14.4 Hz, 2H,
CH2Ph); 2.75 (s, 3H, OMe) 2.02 (dt, 1H, J ¼ 7.3 Hz, CH2CH3, diastreotopic
protons); 1.78 (dt, J ¼ 7.3 Hz, CH2CH3, diastereotopic protons); 0.61 (t, 3H,
CH2CH3). 13C NMR (CDCl3): d 182.9 (C55S); 158.2 (C-5); 129.1, 128.5,
128.1 (Ar); 114.7 (C-2); 49.6 (OMe), 48.1 (CH2Ph); 30.5 (CH2CH3); 7.2
(CH2CH3). MS: m/z (FAB) (264) (MHþ). Anal. calcd. for C13H17N3OS
(263.36): C, 59.29; H, 6.51; N, 15.96. Found: C, 59.08; H, 6.43; N, 15.68.

2264
Y. A. Al-Soud and N. A. Al-Masoudi
ACKNOWLEDGMENT
¨
¨
¨
We thank U. Beifuß, Fakultat fur Chemie at the Universitat Hohenheim,
Germany, for assisting in the NMR experiment and mass spectra
measurements.
REFERENCES
1. Grimmett, M. R. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Oxford: Pergamon, 1984; Vol. 4, p. 498.
2. Winkelmann, E.; Raether, S. Arzneim.-Forsch./Drug Res. 1978, 28 (1), Heft 3,
351.
3. Walts, M. E.; Hodgkinss, R. H.; Sehmi, D. S.; Woodcock, M. Int. J. Radiot. Biol.
1980, 38, 673.
4. Morgenstern, J.; Otto, R.; Scheithauer, S. Ger. East. DD 260 062 1988, Chem.
Abstr. 1989, 110, 231634r.
5. Kochergin, P. M.; Reznichenko, L. A.; Gireva, R. N.; Aleksandrova, E. V. Chem.
Heterocycl. Chem. 1998, 34, 1142.
6. Saunders, J. Top Drugs—Top Synthetic Routes, Ch. 3; Suander, J., Ed.; Oxford
University Press: Oxford, U.K., 2000; p. 19, references therein.
7. Al-Masoudi, N. A.; Al-Soud, Y. A. Chem. Biodiver. 2005, submitted.
8. Puschmann, I.; Erker, T. Heterocycles 1993, 36, 1323.
9. Erker, T. Arch. Pharm. 1995, 328, 313, and references therein.
10. Kulkarani, S.; Grimmett, M. R. Aust. J. Chem. 1987, 40, 1399.
11. Piantini, U.; Sorensen, O. W.; Ernst, R. R. J. Am. Chem. Soc. 1982, 104, 6800.
12. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn. Reson. Chem.
1993, 31, 287, and references therein.