Nitroimidazoles Part 8. Synthesis and anti-HIV activity of new 4-nitroimidazole derivatives using the Suzuki cross-coupling reaction

Article abstract of DOI:10.5560/ZNB.2012-0185

The development of new HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating structures of increased potency. To this end, a series of 1-(1-benzyl-2-ethyl-4-nitro-1 H-imidazol-5-yl)-4-(1,1'- biaryl)-4-yl-piperazine derivatives (6a-l) was synthesized via the Suzuki coupling reaction. Analogously, coupling of the acid derivative 5, prepared from 4, with various amino acid methyl esters in the presence of HOBt/DCC reagents afforded the benzamide derivatives 8-11. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. All compounds are inactive, except compound 6f which showed inhibition of HIV-1 with EC₅₀ = 2.60μgmL^-1 with a selectivity index (SI) of 9.

Full text of DOI:10.5560/ZNB.2012-0185

Nitroimidazoles Part 8. Synthesis and Anti-HIV Activity of New
4-Nitroimidazole Derivatives Using the Suzuki Cross-Coupling Reaction
Yaseen A. Al-Souda, Najim A. Al-Masoudib, Hossam H. Al-Suoda, and
Christophe Pannecouquec
a
Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
b
c
Reprint requests to Prof. Dr. N. A. Al-Masoudi. E-mail: najim.al-masoudi@gmx.de or
Prof. Dr. Y. A. Al-Soud. E-mail: alsoud@aabu.edu.jo
Z. Naturforsch. 2012, 67b, 925 – 934 / DOI: 10.5560/ZNB.2012-0185
Received July 7, 2012
The development of new HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the
possibility of generating structures of increased potency. To this end, a series of 1-(1-benzyl-2-ethyl-
4-nitro-1H-imidazol-5-yl)-4-(1,10-biaryl)-4-yl-piperazine derivatives (6a–l) was synthesized via the
Suzuki coupling reaction. Analogously, coupling of the acid derivative 5, prepared from 4, with
various amino acid methyl esters in the presence of HOBt/DCC reagents afforded the benzamide
derivatives 8–11. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-
4 cells. All compounds are inactive, except compound 6f which showed inhibition of HIV-1 with
EC50 = 2.60µg mL−1 with a selectivity index (SI) of 9.
Key words: Anti-HIV Activity, Nitroimidazoles, NNRTIs, Piperazine Derivatives, Suzuki
Cross-Coupling Reaction
Introduction
to reach the stage of clinical trials [7]. For this reason
RT remains a central target in the development of anti-
Since the first case of acquired immunodeficiency HIV-1 drugs, and of new classes of NNRTIs having
syndrome (AIDS) was reported in 1981, the hu- high potency as well as being effective against resis-
man immunodeficiency virus (HIV)/AIDS has always tant mutants [8, 9].
been a global health threat and the leading cause
Several potent heterocyclic NNRTIs have been syn-
of deaths [1]. Therefore, the rapid worldwide spread thesized with high anti-HIV inhibitory activity, some
of AIDS has prompted an intense research effort of which have an imidazole scaffold (for example,
to discover compounds that could effectively inhibit capravirine; S-1153, (1) (Fig. 1) [10].
HIV. In the past two decades, 25 drugs, including
Several nitroimidazoles were reported to possess
nucleoside/nucleotide viral reverse transcriptase in- a number of biological activities, with possible appli-
hibitors (NRTIs), non-nucleoside RT inhibitors (NNR- cations as, e. g., antibacterial agents [11 – 13], potential
TIs), protease inhibitors (PIs), integrase inhibitors radiosensitizers [14], anticancer agents [15, 16] such
R
ꢀ
(INIs) and fusion (or entry) inhibitors (FIs) were ap- as Dacarbazine (DTIC) [17] and misonidazole [18],
proved for clinical use [2]. Three NNRTIs, nevirap- fungicides and/or as antiprotozoal agents such as
ine [3], delaviridine [4, 5] and efavirenz [6], have been clotrinazole [1-(2-chlorotrityl)-1H-imidazole] [19, 20]
approved by the Food and Drug Administration (FDA) and metronidazole (Flagyl) (2) [21].
for the treatment of HIV infection. However, these
Some arylpiperazine derivatives possess anti-
drugs have only limited or transient clinical benefit. enterovirus activity [22, 23], such as atevirdine (3)
Therefore, the rapid emergence of resistant mutants (Fig. 1) [24] and vicriviroc, which are currently in
against the NNRTIs allowed only a few compounds Phase II clinical trials [25].
c
ꢀ 2012 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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926
Y. A. Al-Soud et al. · Nitroimidazoles
Fig. 1. Chemical structures of capravirine
(1), metronidazole (Flagyl) (2) and ateviri-
dine (3).
In our recent work, we have reported new 4- tentially active analogs. Scheme 1 depicts the chem-
nitroimidazoles with their anti-HIV activity [26 – 32]; istry employed in the preparation of this series of
meanwhile the efforts have been focused on de- 5-substituted piperazinyl-4-nitroimidazole derivatives
veloping inhibitors based on novel scaffolds, via starting from 4 by replacement of the bromo sub-
a regioselective palladium(0)-catalyzed cross-coupling stituent by 1-(4-bromophenyl)piperazine in hot DMF
reaction [33, 34]. As a result of this strategy, furnishing 5 (79%). The Suzuki coupling reaction
new 4-nitroimidazole derivatives bearing substituted has been employed by using the bromo deriva-
biphenylpiperazine and phenylbenzamide residues tive 5 as a key intermediate for the synthesis of
have been selected as a lead template in our present our target molecules and the appropriate arylboronic
study which might lead to the optimization of HIV-1 acids (e. g. phenyl-, 3-cyanophenyl-, 4-methylphenyl-,
RT inhibitory activity.
3-methoxyphenyl-, 4-methoxyphenyl-, 4-fluoro-3-me-
thoxyphenyl-, 3-fluoro-4-methoxyphenyl-, 3-amino-
phenyl-, 4-hydroxyphenyl-, 3-chloro-4-hydroxyphe-
nyl-, pyrimidine-5-, and 5-indole boronic acid) in the
Results and Discussion
Our recent work [26 – 31] has focused on the syn- presence of Pd(PPh3)4 and Na2CO3 as catalysts to give
thesis of 5-alkyamino, alkylsulfanyl and 2-alkylthio- 6a–l in 42 – 73% yield. Compounds 6a–l were pre-
1-piperazinyl derivatives of 4-nitroimidazoles as po- pared in a parallel way using a conventional method
Scheme 1. Reagents and conditions: a) 1-(4-bromophenyl)piperazine, DMF, 70 – 80 ◦C; b) Na2CO3, Pd(PPh3)4, DMF, MWI,
30 min.
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Y. A. Al-Soud et al. · Nitroimidazoles
927
(longer reaction time, 3 – 7 days), giving moderate
yields and purity.
1
The structures of 6a–l were identified by H, and
1
13C NMR and mass spectra. The H and 13C NMR
spectra of all prepared compounds are in agree-
ment with the suggested structures. DEPT experi-
ments were employed to differentiate secondary and
quaternary carbons from primary and tertiary car-
bons. The 1H NMR spectra showed rather similar
patterns for the benzylic and ethyl protons. The two
broad singlets at δ = 3.81 – 3.52 and 2.98 – 2.66 ppm
were assigned to eight piperazine protons. The ben-
zylic protons resonated at δ = 5.18 – 5.14 ppm. In
the 1H NMR spectrum of 5, the protons 30-H and
50-H of the aromatic group at C(4)imidazole appeared
Fig. 2. JC,H correlations in the HMBC NMR spectrum of 6b.
as a doublet at δ = 6.99 ppm (J = 6.9 Hz), while 20- Additionally, a 3JC,H coupling between methylene pro-
H and 60-H of the same group resonated as a dou- tons of piperazine at δ = 3.82 ppm and C-10 of the
blet at δ = 6.74 ppm (J = 6.9 Hz). The signals of aromaic ring attached to the piperazine moiety at
the biaryl protons were further identified by DFQ- δ = 141.9 ppm was observed (Fig. 2).
COSY spectra [35]. The 13C NMR spectra of 5
Additional support for the proposed structures
and 6a–l showed signals at δ = 150.6 – 145.1 ppm, comes from mass spectra which showed the correct
attributed to C(2) of the imidazole ring, while the molecular ions, (M+), as suggested by their molecular
carbon atoms C(4) and C(5) of the same ring res- formulas.
onated at δ = 145.4 – 138.6 and 139.3 – 135.5 ppm, re-
Next, treatment of 4 with 4-carboxy phenylboronic
spectively. The piperazine carbon atoms resonated at acid in the presence of Pd(PPh3)4 and Na2CO3 as cat-
δ = 50.5 – 49.1 and 49.4 – 48.8 ppm, whereas the sig- alysts, using a Suzuki cross-coupling reaction and by
nals of the benzylic CH2 carbon atoms appeared at following the method of Vanelle et al. [37], afforded 5
δ = 46.6 – 46.1 ppm. Compound 6b has been selected in 72% yield (Scheme 2).
for further NMR studies, and its HMBC spectrum [36]
Our work was modified by selecting 5 as a pre-
revealed a 3JC,H coupling between the methylene pro- cursor for the synthesis of new benzamide derivatives
tons of piperazine at δ = 2.63 ppm and C(5) of the im- to examine their antiviral activity in comparison to
idazole ring at δ = 138.6 ppm, as well as a 2JC,H cou- the biaryl analogs 6a–l. Thus, treatment of 7 with
pling with the carbons of piperazine at δ = 49.6 ppm. the acylated amino acid derivatives (glycine, L-serine,
Scheme 2. Synthesis of carboxylic esters; i: 1-(4-bromophenyl)piperazine, DMF, 70 – 80 ◦C; ii: Na2CO3, Pd(PPh3)4, DMF,
MWI, 30 min.
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928
Y. A. Al-Soud et al. · Nitroimidazoles
L-methionine, L-alanine and L-valine acetates) in the matic residue at δ = 8.08 ppm. Similarly, C=O of the
presence of HOBT and DCC as coupling reagents gave amide group at δ = 166.8 ppm was identified from its
3
8–11 in 74% – 67% yield (Scheme 2).
a JC,H correlations to 30-H and 50-H of the aromatic
3
The structures of 8–11 were determined by their residue at δ = 7.96 ppm (Fig. 3), as well as a JC,H
1H, 13C NMR and mass spectra. The H NMR spec- correlation to the CHCH2OH proton at δ = 3.58 ppm.
1
2
tra of 8–11 showed a similar pattern of benzylic and Additionally, The latter proton showed a JC,H cor-
ethyl protons of the nitroimidazole scaffold. The low- relation to the CH2OH carbon atom at δ = 67.1 ppm
field doublets at δ = 8.32 – 8.11 (JNH,CH ∼ 5.5 Hz) (Fig. 3). The mass fragmentation patterns were consis-
were assigned to NH signals. The CH2 and CH tent with the suggested structures; however, the FAB-
protons of the amino acid residues (CONHCH) ap- MAS spectra showed the protonated molecular ions of
peared as doublet, doublet of doublets, or multiplet at these compounds.
δ = 4.39 (JNH,CH2 = 5.8 Hz), 4.51 (JNH,CH = 5.5 Hz,
JCH,Me = 7.2 Hz), 3.38 (multiplet), and 4.40 ppm In-vitro anti-HIV assay
(JNH,CH = 5.1 Hz, JCH,CHMe2 = 9.5 Hz), respectively.
Compounds 5, 6a–l and 8–11 were tested for their
in-vitro anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain
ROD) activity in human MT-4 cells using the MT-4/
MTT assay [38]. The results are summarized in Ta-
ble 1, in which the data for azidothymidine (AZT) [39]
and nevirapine (BOE/BIRG587) [40] are included for
comparison purposes.
Compound 6f was found to be the only compound
of the series inhibiting HIV-1 and HIV-2 replication in
a cell culture, with an EC50 value of > 2.60 µg mL−1
with a selectivity index (SI) of 9. Compound-induced
cytotoxicity was also measured in MT-4 cells parallel
with the antiviral activity.
The other protons of the amino acid moieties were fully
analyzed (cf. Experimental Section). In the 13C NMR
spectra of 8–11, the carbon atoms of the carboxylate
groups resonated in the range δ = 172.9 – 171.1 ppm,
while the carbonyl (NHC=O) carbon atoms of
the amino acid residues resonated in the range
δ = 167.1 – 166.6 ppm. The resonances at δ = 39.6,
56.6, 54.8, and 56.8 ppm were atrributed to the carbon
atoms of CH2-glycine, CHMe-alanine, CHCH2OH-
serine, and CHCHMe2-valine moieties. The CHMe,
CH2OH and CHMe2 carbon signals of 10–11 appeared
at δ = 18.2, 67.1 and 30.9 ppm, while the dimethyl
carbon atoms of 11 resonated at δ = 30.9 ppm. C-2
and C-4 of the imidazole ring resonated in the range
δ = 149.5 – 148.2 and 145.8 – 145.2 ppm, respectively,
while C-5 of the same ring appeared in the range
δ = 140.3 – 139.6 ppm, and the benzylic CH2 carbon
atoms resonated at δ = 46.5 – 46.3 ppm. A gradient-
selected HMBC spectrum of 10 allowed the identifi-
cation of C-5 of the imidazole ring at δ = 140.0 ppm
from the 3JC,H correlations to 20-H and 60-H of the aro-
Based on the chemical structure of compound 6f,
this molecule can be proposed to act as non-nucleoside
reverse transcriptase inhibitor (NNRTI).
6f
In conclusion, the data in Table 1 suggest that sub-
stitution of the bromo residue at position 4 of the ni-
troimidazole ring by a methoxy-fluoro-biphenyl group
may engender an inhibitory activity on HIV-1.
Conclusion
In summary, a series of 5-(substituted-biphenyl-
Fig. 3. JC,H correlations in the HMBC NMR spectrum of 10. 4-yl)piperazine (6a–l) and phenylbenzamide (8–11)
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Y. A. Al-Soud et al. · Nitroimidazoles
929
Table 1. In-vitro anti-HIV-1a and -HIV-2b activity of new 4- methoxyphenyl ring. Otherwise, compounds that were
nitroimidazioles 5, 6a–l and 8–11.
substituted at the aromatic ring by amino, cyano,
Compound Virus
strain
EC50
(µg mL−1
CC50
SIe
hydroxy, methoxy, or methyl residues did not show
any activity. Therefore, 6f is a promising agent for
further structural modification and pharmacological
evaluation.
c
d
)
(µg mL−1
)
5
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>79.7
>79.7
>22.41
>23.34
>9.23
>9.43
>125
>79.7
>79.7
22.41
23.34
9.23
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
9
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
6a
6b
6c
6d
6e
6f
Experimental Section
9.43
>125
>125
63.5
General
>125
>63.5
>67.0
>17.89
>17.97
>2.6
Melting points were measured on a Mettler FP1 melt-
67.0
1
ing point apparatus and are uncorrected. H NMR and 13C
>17.89
>17.97
23.2
23.2
106
115
64.7
61.1
11.1
12.3
87.4
93.1
80.1
70.1
103
102
3.26
NMR spectra were measured on a Bruker AM500 spectro-
meter (500 MHz) at 300 K.
NMR spectra were recorded on 400 and 500 MHz (1H)
and on 150.91 MHz (13C) spectrometers (Bruker, Germany)
with TMS as internal standard and on the δ scale in ppm.
Signal assignments for protons were performed by selective
proton decoupling or by COSY spectra. Heteronuclear as-
signments were verified by 1H-13C COSY or HMBC experi-
ments. All coupling constants (J) are given in Hz. Mass spec-
tra (ESI) were recorded on a TSQ Quantum (Thermo Fisher)
instrument and a MAT 8200 spectrometer (Finnegan MAT,
USA). Microwave-assisted reactions were carried out in
a CEM focused microwave synthesis system (100 – 150 W).
Purification of products was performed by preparative thin-
layer chromatography (TLC) using 1 mm SIL G-100 UV254
glass plates (Macherey-Nagel), and the progress of the re-
action was monitored by TLC on Alugram SIL G UV254
(Macherey-Nagel).
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>23.2
>106
>115
6g
6h
6i
>64.7
>61.1
>11.1
>12.3
>87.4
>93.1
>80.1
>70.1
>103
6j
6k
6l
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>102
8
>3.26
>3.26
>4.69
>4.70
>3.26
>3.26
>21.24
>21.24
0.0022
0.00094
0.050
3.26
4.69
4.70
3.26
9
10
11
AZT
3.26
21.24
21.24
>25
>25
>4.00
>4.00
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)4-
(4-bromophenyl)piperazine (5)
ROD
IIIB
ROD
<1
>11 363
>26 596
>80
<1
Nevirapine IIIB
ROD
To a stirred solution of 4 (3.10 g, 10.0 mmol) in DMF
(25 mL) was added 1-(4-bromophenyl)piperazine (1.03 g,
12.0 mmol), and the solution was heated at 70 – 80 ◦C for
6 h. The solution was evaporated to dryness, the residue
was washed with diethyl ether and purified by TLC us-
ing CHCl3 as eluent to give 5. Yield: 3.71 g (79%) as
>4.00
a
Anti-HIV-1 activity measured with strain IIIB; b anti-HIV-2 activ-
c
ity measured with strain ROD; compound concentration required
to achieve 50% protection of MT-4 cells from the HIV-1 and -2-
d
induced cytopathogenic effect; compound concentration that re-
duces the viability of mock-infected MT-4 cells by 50%; e SI: selec-
1
a brown powder; m. p. 153 – 156 ◦C (dec). − H NMR
tivity index (CC50/EC50).
(CDCl3): δ = 7.36 – 7.32 (m, 5H, Ar-H), 6.99 (d, J = 6.9 Hz,
2H, H(3)arom−Br + H(5)arom−Br), 6.74 (d, J = 6.9 Hz,
2H, H(2)arom−Br + H(6)arom−Br), 5.15 (s, 2H, CH2Ph),
4.12 – 2.70 (br s, 8H, Hpiperazine), 2.62 (q, J = 7.5 Hz, 2H,
CH2CH3), 1.30, (t, 3H, CH2CH3). – 13C NMR (CDCl3):
δ = 150.2 (C-2), 145.0 (N-C(1)arom), 139.9 (C-4), 138.7
(C-5), 135.5 (CH2-C(1)arom), 131.9, 129.2, 128.2, 125.8
(Carom), 118.0 (N-C(2)arom + N-(C6)arom), 112.3 (C-Br),
49.6, 49.1 (Cpiperazine), 46.1 (CH2Ph), 21.1 (CH2CH3), 11.3
derivatives of 1-benzyl-2-ethyl-4-nitroimidazole (4)
were synthesized and evaluated in-vitro for their anti-
HIV activity. Compound 6f exhibited moderate anti-
HIV activity with SI = 9. Compound 6f, with a 4-
fluoro-3-methoxyphenyl substituent, generally showed
higher potency, and a dramatic change in activity
was observed with congener 6g bearing a 3-fluoro-4- (CH2CH3). – MS ((+)-FAB): m/z = 469/471 [M+H]+. −
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930
Y. A. Al-Soud et al. · Nitroimidazoles
C22H24BrN5O2 (470.36): calcd. C 56.18, H 5.14, N 14.89; 1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
found C 56.27, H 5.30, N 15.05.
4-(40-methyl-[1,10-biphenyl]-4-yl)piperazine (6c)
From 3-methylphenylboronic acid (95 mg). Yield:
0.10 gm (42%), light-brown crystals; m. p. 145 – 148 ◦C
(dec.). − 1H NMR (CDCl3): δ = 7.51 (d, 2H, J = 8.6
Hz, Ar-H), 7.38 – 7.28 (m, 7H, Ar-H), 7.15 – 7.06 (m,
2H, Ar-H), 7.00 (d, 2H, J = 7.2 Hz, Ar-H), 5.16 (s, 2H,
CH2Ph), 3.70 – 2.79 (br s, 8H, Hpiperazine), 2.63 (q, 2H,
J = 7.5 Hz, CH2CH3), 2.40 (s, 3H, CH3), 1.31 (t, 3H, J =
7.5 Hz, CH2CH3). – 13C NMR (CDCl3): δ = 145.1 (C-2
+ N-C(1)arom), 140.3 (C(10)arom), 138.9 (C-4 + C(40)arom),
136.9 (C-5 + CH2-C(1)arom), 129.4, 129.2, 129.1, 128.9,
128.6, 128.2, 128.0, 127.9, 127.5, 127.4, 127.1, 126.0, 125.8,
123.7 (Carom), 50.5, 48.9 (Cpiperazine), 46.4 (CH2Ph), 21.5
(CH2CH3), 11.3 (CH2CH3). – MS ((+)-FAB): m/z = 482
[M+H]+. − C29H31N5O2 (481.59): calcd. C 72.33, H 6.49,
N 14.54; found C 72.50, H 6.32, N 14.80.
General procedure for preparation of 1-(1-benzyl-2-ethyl-4-
nitro-1H-imidazol-5-yl)-4-(1,10-biaryl-4-yl)piperazines 6a–l
A suspension of 5 (235 mg, 0.50 mmol), substituted
arylboronic acid (0.70 mmol), tetrakis(triphenylphosphane)-
palladium (Pd(Ph3)4) (22 mg, 5% mmol), and Na2CO3
(212 mg, 2.00 mmol) in DMF-water 1 : 1 (40 mL) was heated
at 70 – 80 ◦C for 6 h or under MWI for 30 min. After cool-
ing, the mixture was evaporated to dryness, and the residue
was partitioned between ethyl acetate (3 × 30 mL) and wa-
ter (30 mL). The combined organic extracts were dried
(Na2SO4) and filtered. The filtrate was evaporated to dry-
ness, and the crude product was purified by preparative TLC.
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
(1-[1,10-biphenyl]-4-yl)piperazine (6a)
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
From phenylboronic acid (85 mg). Yield: 170 mg (73%),
orange crystals; m. p. 189 – 191 ◦C (dec.). – 1H NMR
(CDCl3): δ = 7.67 – 7.63 (m, 1H, Ar-H), 7.53 – 7.50 (m, 4H,
Ar-H), 7.46 – 7.26 (m, 7H, Ar-H), 6.99 (d, 2H, J = 7.2 Hz,
Ar-H), 5.15 (s, 2H, CH2Ph), 3.93, 2.63 (2 × br s, 8H,
Hpiperazine), 2.61 (q, 2H, J = 7.5 Hz, CH2CH3), 1.29 (t, 3H,
J = 7.5 Hz, CH2CH3). – 13C NMR (CDCl3): δ = 145.1 (C-
2 + N-C(1)arom), 138.7 (C-5 + C(10)arom+ C-4), 135.5
(CH2-C(1)arom), 132.1, 132.0, 131.9, 129.2, 128.7, 128.5,
128.4, 128.2, 127.9, 126.7, 126.6, 125.8 (Carom), 50.1,
48.9 (Cpiperazine), 46.3 (CH2Ph), 21.1 (CH2CH3), 11.3
(CH2CH3). – MS ((+)-FAB): m/z = 468 [M+H]+. −
C28H29NO2 (467.23): calcd. C 71.93, H 6.25, N 14.98; found
C 71.77, H 6.39; N 15.08.
4-(30-methoxy-[1,10-biphenyl]-4-yl)piperazine (6d)
From 3-methoxyphenylboronic acid (106 mg). Yield:
120 mg (48%), dark-brown crystals; m. p. 144 – 147 ◦C
(dec.). − 1H NMR (CDCl3): δ = 7.50 (d, 2H, J = 8.8 Hz,
Ar-H), 7.38 – 7.73 (m, 4H, Ar-H), 7.15 – 7.13 (m, 1H, Ar-H),
7.08 (t, 1H, J = 1.9 Hz, Ar-H), 7.00 (d, 2H, J = 7.0 Hz, Ar-
H); 6.95 (d, 2H, J = 8.8 Hz, Ar-H), 6.86 – 6.83 (m, 1H, Ar-
H), 5.15 (s, 2H, CH2Ph), 3.85 (s, 3H, OCH3), 3.76 – 2.76 (br
s, 8H, Hpiperazine), 2.63 (q, 2H, J = 7.5 Hz, CH2CH3), 1.31 (t,
3H, J = 7.5 Hz, CH2CH3). – 13C NMR (CDCl3): δ = 159.9
(C(30)arom-OMe), 150.6 (C-2), 145.0 (N-C(1)arom), 142.3
(C(10)arom), 138.8 (C-4), 135.5 (CH2-C(1)arom+ C-5), 132.6,
129.9, 129.7, 129.2, 128.2, 127.8, 125.8 (Carom), 119.1
(C(60)arom), 112.3 (C(20)arom+ C(40)arom), 111.9 (C(2)arom
+
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
4-(30-isocyano-[1,10-biphenyl]-4-yl)piperazine (6b)
C(6)arom), 55.3 (OCH3); 49.6, 49.2 (Cpiperazine), 46.1
(CH2Ph), 21.1 (CH2CH3), 11.3 (CH2CH3). – MS ((+)-
FAB): m/z = 498 [M+H]+. − C29H31N5O3 (497.59): calcd.
C 70.00, H 6.28, N 14.07; found C 70.19, H 6.50, N 13.89.
From 3-cyanophenylboronic acid (103 mg). Yield:
160 mg (65%), dark-brown crystals; m. p. 153 – 156 ◦C
(dec.). – 1H NMR (CDCl3): δ = 7.81 (s, 1H, Ar-H), 7.76
(t, 1H, J = 1.3 Hz, Ar-H), 7.56 – 7.55 (m, 1H, Ar-H),
7.51 – 7.32 (m, 6H, Ar-H), 7.03 – 7.00 (m, 4H, Ar-H), 5.17
(s, 2H, CH2Ph), 3.82, 2.82 (2 × br s, 8H, Hpiperazine), 2.63
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
4-(40-methoxy-[1,10-biphenyl]-4-yl)piperazine (6e)
From 4-methoxyphenylboronic acid (106 mg). Yield:
(q, 2H, J = 7.5 Hz, CH2CH3), 1.31 (t, 3H, J = 7.5 Hz, 140 mg (56%), yellow crystals; m. p. 216 – 219 ◦C (dec.).
CH2CH3). – 13C NMR (CDCl3): δ = 145.4 (C-2 + N-
–
1H NMR (CDCl3): δ = 7.46 – 7.44 (m, 4H, Ar-H),
C(1)arom), 141.9 (C(10)arom), 139.8 (C-4), 138.6 (C-5), 7.36 – 7.30 (m, 3H, Ar-H), 6.99 (d, 3H, J = 7.1 Hz, Ar-H),
135.5 (CH2-C(1)arom), 130.7, 130.0, 129.9, 129.5, 129.3, 6.93 (d, 3H, J = 8.8 Hz, Ar-H), 5.14 (s, 2H, CH2Ph), 3.82 (s,
128.2, 127.8, 125.3 (Carom), 118.9 (CN), 116.7, 116.6 3H, OCH3), 3.81 – 2.66 (br s, 8H, Hpiperazine), 2.61 (q, 2H,
(C(1)arom), 112.9 (C(40)arom-CN), 49.6, 48.9 (Cpiperazine), J = 7.5 Hz, CH2CH3), 1.29 (t, 3H, J = 7.5 Hz, CH2CH3). –
46.2 (CH2Ph), 21.1 (CH2CH3), 11.3 (CH2CH3). – MS 13C NMR (CDCl3): δ = 159.1 (C(4)arom-OMe), 147.8 (C-
((+)-FAB): m/z = 493 [M+H]+. − C29H28N6O2 (492.57): 2), 145.1 (N-C(1)arom), 140.9 (C-4), 139.3 (N-C(10)arom),
calcd. C 70.71, H 5.73, N 17.06; found C 70.53, H 5.66, N 138.8 (CH2-C(1)arom), 135.5 (C-5), 134.4, 129.3, 128.3,
17.30.
127.6, 127.4, 125.8 (Carom), 117.0, 116.9 (C(2)arom+
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C(6)arom), 114.2 (C(30)arom+ C(50)arom), 55.4 (OCH3), 50.2, (t, 1H, J = 7.8 Hz, Ar-H), 6.98 (d, 2H J = 7.1 Hz, Ar-H),
49.1 (Cpiperazine), 46.2 (CH2Ph), 21.2 (CH2CH3), 11.4 6.94 – 6.90 (m, 3H, Ar-H), 6.84 (t, 1H, J = 1.9 Hz, Ar-H),
(CH2CH3). – MS ((+)-FAB): m/z = 498 [M+H]+. − 6.61 – 6.59 (m, 1H, Ar-H), 5.14 (s, 2H, CH2Ph), 3.68
C29H31N5O3 (497.59): calcd. C 70.00, H 6.28, N 14.07; (br s, 2H, NH2), 3.63 – 2.65 (br s, 8H, Hpiperazine), 2.61
found C 70.21, H 6.43, N 14.26.
(q, 2H, J = 7.5 Hz, CH2CH3), 1.29 (t, 3H, J = 7.5 Hz,
CH2CH3). – 13C NMR (CDCl3): δ = 150.4 (C(40)-NH2),
146.7 (C-2), 145.0 (N-C(1)arom), 142.0 (C(10)arom), 138.9
(C-4), 135.9 (C-5 + CH2-C(1)arom), 133.0, 129.6, 129.2,
128.2, 127.8, 127.7, 125.8 (Carom), 117.1 (C(60)arom), 116.4
(C(50)arom), 113.5 (C(20)arom), 113.3 (C(2)arom+ C(6)arom),
49.6, 49.2 (Cpiperazine), 46.1 (CH2Ph), 21.1 (CH2CH3),
11.3 (CH2CH3). – MS ((+)-FAB): m/z = 483 [M+H]+. −
C28H30N6O2 (482.58): calcd. C 69.69, H 6.27, N 17.41;
found C 69.55, H 6.40, N 17.20.
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
4-(40-fluoro-30-methoxy-[1,10-biphenyl]-4-yl)piperazine (6f)
From 4-fluoro-3-methoxyphenylboronic acid (119 mg).
Yield: 180 mg (70%), light-brown crystals; m. p.
126 – 129 ◦C (dec.).
−
1H NMR (CDCl3): δ = 7.46
(d, 2H, J = 8.4 Hz, Ar-H), 7.40 – 7.28 (m, 4H, Ar-H),
7.11 – 7.07 (m, 3H, Ar-H), 7.05 – 7.03 (m, 1H, Ar-H), 7.01
(d, 2H, J = 7.1 Hz, Ar-H), 5.17 (s, 2H, CH2Ph), 3.93 (s,
3H, OCH3), 3.73 – 2.82 (br s, 8H, Hpiperazine), 2.62 (q, 2H,
J = 7.5 Hz, CH2CH3), 1.31 (t, 3H, J =7.5 Hz, CH2CH3 ). –
40-[4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
piperazin-1-yl]-[1,10-biphenyl]-4-ol (6i)
13C NMR (CDCl3): δ = 153.8, 151.7 (d, JC4 ,F = 250 Hz,
0
C(40)arom-F), 147.7 (C-2), 147.6 (N-C(1)arom), 145.2
(C(10)arom), 138.6 (C-4 + CH2-C(1)arom), 135.8 (C-5 +
C(10)arom), 129.4, 129.2, 128.7, 128.2, 127.8, 127.1, 126.0,
125.8 (Carom), 116.2, 116.1 (C(30)arom+ C(50)arom), 112.1
(C(2)arom+ C(6)arom), 56.3 (OCH3), 50.4, 48.8 (Cpiperazine),
46.3 (CH2Ph), 21.1 (CH2CH3), 11.3 (CH2CH3). – MS
((+)-FAB): m/z = 514/516 [M+H]+. − C29H30FN5O3
(515.58): calcd. C 67.65, H 5.86, N 13.58; found C 67.42, H
5.98, N 13.37.
From 4-hydroxyphenylboronic acid (97 mg, 0.70 mmol.
Yield: 120 mg (50%), colorless crystals; m. p. 219 – 221 ◦C
(dec.). − 1H NMR ([D6]DMSO): δ = 9.42 (s, 1H, OH),
7.43 – 7.30 (m, 7H, Ar-H), 7.11 (d, 2H, J = 7.2 Hz, Ar-H),
6.95 (d, 2H, J = 8.9 Hz, Ar-H), 6.79 (d, 2H, J = 8.7 Hz, Ar-
H), 5.17 (s, 2H, CH2Ph), 3.55 – 2.95 (br s, 8H, Hpiperazine),
2.58 (q, 2H, J = 7.4 Hz, CH2CH3), 1.14 (t, 3H, CH2CH3). −
13C NMR ([D6]DMSO): δ = 156.7 (C(40)-OH), 150.0 (C-2),
145.2 (N-C(1)arom), 140.0 (C-4), 139.1 (C-5), 136.8 (CH2-
C(1)arom), 131.6, 129.3, 128.0, 127.3, 126.9, 126.7 (Carom),
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
4-(30-fluoro-40-methoxy-[1,10-biphenyl]-4-yl)piperazine (6g)
116.6, 116.1 (C(30)arom+ C(50)arom), 113.7 (C(2)arom
+
C(6)arom), 49.1, 48.8 (Cpiperazine), 46.2 (CH2Ph), 20.7
(CH2CH3), 11.1 (CH2CH3). – MS ((+)-FAB): m/z = 484
[M+H]+. − C28H29N5O3 (483.56): calcd. C 69.55, H 6.04,
N 14.48; found C 69.78, H 6.23, N 14.77.
From 3-fluoro-4-methoxyphenylboronic acid (119 mg).
Yield: 0.130 mg (50%), gray crystals, m. p. 126 – 129 ◦C
(dec.). – 1H NMR (CDCl3): δ = 7.42 (d, 2H, J = 8.6 Hz,
Ar-H), 7.35 – 7.24 (m, 6H, Ar-H), 7.00 – 6.98 (m, 4H, Ar-H),
5.15 (s, 2H, CH2Ph), 3.89 (s, 3H, OCH3), 3.70 – 2.75 (br s,
8H, Hpiperazine), 2.61 (q, 2H, J = 7.5 Hz, CH2CH3), 1.29 (t,
3H, J = 7.5 Hz, CH2CH3). – 13C NMR (CDCl3): δ = 153.6,
40-[4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-
1-yl]-3-chloro-[1,10-biphenyl]-4-ol (6j)
From 3-chloro-4-hydroxyphenylboronic acid (121 mg,
0.70 mmol). Yield: 150 mg (58%), light-yellow crystals;
m. p. 207 – 210 ◦C (dec.). − 1H NMR (CDCl3): δ = 7.49
(d, 1H, J = 2.0 Hz, Ar-H), 7.41 (d, 2H, J = 8.8 Hz, Ar-H),
7.36 – 7.33 (m, 4H, Ar-H), 7.05 (d, 1H, J = 8.5 Hz, Ar-H),
7.00 (d, 1H, J = 7.0 Hz, Ar-H), 6.93 (d, 2H, J = 8.7 Hz, Ar-
H), 5.71 (br s, 1H, OH), 5.16 (s, 2H, CH2Ph), 3.81 – 2.76 (br
s, 8H, Hpiperazine), 2.63 (q, 2H, J = 7.5 Hz, CH2CH3), 1.30
(t, J = 7.5 Hz, CH2CH3). − 13C NMR (CDCl3): δ = 150.4
(C(40)-OH), 150.2 (C-2), 145.1 (N-C(1)arom), 138.8 (C-
4), 135.7 (C-5 + CH2-C(1)arom), 134.5 (C(10)arom), 129.2,
128.7, 128.2, 127.8, 127.3, 126.8 (Carom), 125.8 (C-Cl),
120.2 (C(50)arom), 113.5, 113.2 (C(2)arom+ C(6)arom), 49.6,
151.6 (d, JC3 −F = 250 Hz, C(30)arom-F), 146.6 (C-2),
0
146.5 (N-C(1)arom), 145.1 (C(10)arom), 139.7 (C-4), 138.7
(CH2-C(1)arom), 135.7 (C-5), 134.0, 129.2, 128.2, 127.4,
125.8 (Carom), 122.0, 116.4, 115.5, 114.3 (m, C(30)arom
+
C(40)arom), 113.8 (C(2)arom+ C(6)arom), 56.4 (OCH3), 50.0,
49.0 (Cpiperazine), 46.2 (CH2Ph), 21.1 (CH2CH3), 11.3
(CH2CH3). – MS ((+)-FAB): m/z = 514/516 [M+H]+. −
C29H30FN5O3 (515.58): calcd. C 67.65, H 5.86, N 13.58;
found C 67.71, H 5.75, N 13.34.
40-[4-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-
1-yl]-[1,10-biphenyl]-3-amine (6h)
From 3-aminophenylboronic acid (96 mg, 0.70 mmol). 49.2 (Cpiperazine), 46.1 (CH2Ph), 21.1 (CH2CH3), 11.3
Yield: 150 mg (62%), dark-yellow crystals; m. p. (CH2CH3). − MS ((+)-FAB): m/z = 517/519 [M+H]+. −
209 – 212 ◦C (dec.). − 1H NMR (CDCl3): δ = 7.45 (d, C28H28ClN5O3 (518.01): calcd. C 64.92, H 5.45, N 13.52;
2H, J = 8.8 Hz, Ar-H), 7.36 – 7.30 (m, 3H, Ar-H), 7.17 found C 65.15, H 5.61, N 13.73.
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932
Y. A. Al-Soud et al. · Nitroimidazoles
4-(4-(4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
piperazin-1-yl)phenyl)pyrimidine (6k)
(CH2Ph), 21.2 (CH2CH3), 11.6 (CH2CH3). – MS ((+)-
FAB): m/z = 352 [M+H]+. − C19H17N3O4 (351.36): calcd.
C 64.95, H, 4.88, N 11.96; found C 64.69, H 4.77, N 11.74.
From pyrimidine-5-boronic acid (87 mg, 0.70 mmol).
Yield: 130 mg (55%), orange oil. – 1H NMR (CDCl3):
δ = 9.10 (s, 1H, Ar-H), 8.29 (br s, 2H, Ar-H), 7.69 – 7.10
(m, 9H, Ar-H), 5.18 (s, 2H, CH2Ph), 3.52 – 2.98 (br s, 8H,
Hpiperazine), 2.64 (q, 2H,J = 7.5 Hz, CH2CH3), 1.32 (t, 3H,
CH2CH3). – 13C NMR (CDCl3): δ = 156.8 (C(10)pyrimidine),
154.4 C(30)pyrimidine), 153.2 (C(50)pyrimidine), 148.2 (C-2),
145.4 (N-C(1)arom), 138.8 (C-4), 135.7 (C-5 + CH2-
C(1)arom), 132.3, 129.5, 128.7, 128.7, 128.5, 128.0, 126.0
(Carom), 113.6, 113.2 (C(60)pyrimidine+ C(2)arom+ C(6)arom),
49.4, 49.2 (Cpiperazine), 46.4 (CH2Ph), 21.4 (CH2CH3),
11.6 (CH2CH3). – MS ((+)-FAB): m/z = 470 [M+H]+. −
C26H27N7O2 (469.54): calcd. C 66.51, H 5.80, N 20.88;
found C 66.30, H 5.66, N 20.59.
Synthesis of 4-nitroimidazoles bearing amino acid esters
(8–11)
General procedure. – To a cold solution of the amino
acid ester (2.0 mmol) at −5 ◦C in MeCN (20 mL), 7
(703 mg, 2.0 mmol), hydroxybenzotriazole (HOBt) (270 g,
2.0 mmol) and N,N0-dicyclohexyl-carbodiimide (DCC)
(412 mg, 2.00 mmol) were added successively. The reac-
tion mixture was stirred at 0 ◦C for 1 h, at 5 ◦C for 1 h,
and at 23 ◦C for 16 h. Dicyclohexylurea (DCU) was filtered
off, and the filtrate was evaporated to dryness. The residue
was dissolved in ethyl acetate, and the solution was fil-
tered and washed successively with saturated NaCl solution,
5% NaHCO3 solution, 1 M HCl, followed by washing with
saturated NaCl solution and finally with water. The solu-
tion was dried (Na2SO4), filtered, evaporated to dryness and
the residue purified on a SiO2 column to give the desired
products.
5-(4-(4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
piperazin-1-yl)phenyl)-1H-indole (6l)
From 5-indoleboronic acid (113 mg, 0.70 mmol). Yield:
110 mg (43%), dark-brown crystals; m. p. 103 – 106 ◦C
(dec.). – 1H NMR (CDCl3): δ = 8.28 (br s, 1H, NH),
7.80 (s, 1H, Ar-H), 7.69 – 7.65 (m, 2H, Ar-H), 7.61 – 7.53
(m, 2H, Ar-H), 7.48 – 7.43 (m, 4H, Ar-H), 7.40 – 7.37
(m, 3H, Ar-H), 7.35 – 7.32 (m, 1H, Ar-H), 7.29 – 7.26 (m,
1H, Ar-H), 5.16 (s, 2H, CH2Ph), 3.52 – 2.87 (br s, 8H,
Hpiperazine), 2.64 (q, 2H, J = 7.5 Hz, CH2CH3), 1.32 (t, 3H,
CH2CH3). − 13C NMR (CDCl3): δ = 150.6 (C-2 ), 145.0
(N-C(1)arom), 138.6 (C-4), 135.8 (C-5 + CH2-C(1)arom),
134.1 (C(7a)indole), 131.9, 129.3, 128.7, 128.6, 128.5,
128.3, 127.8, 127.5, 125.8 (Carom), 124.9 (C(2)indole), 121.6
(C(4)indole), 115.5 (C(6)indole), 113.2 (C(2)arom+ C(6)arom),
111.6 (C(7)indole), 100.9 (C(3)indole), 50.1, 49.4 (Cpiperazine),
46.3 (CH2Ph), 21.2 (CH2CH3), 11.5 (CH2CH3). – MS ((+)-
FAB): m/z = 507 [M+H]+. − C30H30N6O2 (506.60): calcd.
C 71.13, H, 5.97, N 16.59; found C 71.29, H 6.09, N 16.80.
Methyl 2-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
benzamido)acetate (8)
From glycine methyl ester (178 mg). Yield: 565 mg
(67%); m. p. 138 – 140 ◦C. – 1H NMR ([D6]DMSO):
δ = 8.11 (d, 1H, JNH,CH2 = 5.8 Hz, NH); 8.02 (d, 2H,
J = 7.1 Hz, H(2)arom+ H(6)arom), 7.89 (d, 2H, J = 7.1 Hz,
H(3)arom+ H(5)arom), 7.26 – 7.21 (m, 5H, Harom), 5.33
(s, 2H, CH2Ph), 4.39 (d, 2H, JNH,CH2 = 5.8 Hz, CH2-
glycine), 3.70 ( s, 3H, CO2Me), 2.65 (q, 2H, J = 7.3 Hz,
2H, CH2CH3), 1.25, (t, 3H, CH2CH3). − 13C NMR
([D6]DMSO): δ = 171.8 (CO2Me); 167.1 (NCglycine =O);
149.2 (C-2); 145.2 (C-5), 139.8 (C-4), 137.1 (CH2-
C(1)arom), 135.9 (C(10)arom), 134.5, 131.9, 129.2, 128.2,
127.2, 125.5 (Carom), 51.6 (CO2Me); 46.3 (CH2Ph), 39.6
(CH2-glycine), 21.0 (CH2CH3), 11.4 (CH2CH3). –MS ((+)-
FAB): m/z = 445 [M+Na]+. − C22H22N4O4 (422.16):
calcd. C 62.55, H 5.25, N 13.26; found C 62.32, H 5.16, N
12.97.
4-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)benzoic
acid (7)
Methyl 2-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
benzamido)propanoate (9)
This compound was prepared according to the proce-
dure for the preparation of 5 from 4 (618 mg, 2.00 mmol)
and 4-carboxylphenylboronic acid (398 mg, 2.40 mmol).
From L-alanine methyl ester (206 mg). Yield: 628 mg
Yield: 506 mg (72%); m. p. 161 – 164 oC (dec.). – 1H (72%); m. p. 143 – 147 ◦C. – 1H NMR ([D6]DMSO):
NMR ([D6]DMSO): δ = 8.02 (d, 2H, J = 7.1 Hz, H(2)arom
+
δ = 8.28 (d, 1H, JNH,CH2 = 5.5 Hz, NH); 8.11 (d, 2H,
(H(6)arom), 7.89 (d, 2H, J = 7.1 Hz, H(3)arom+ H(5)arom), J = 7.0 Hz, H(2)arom+ H(6)arom), 7.91 (d, 2H, J = 7.0 Hz,
7.26 – 7.21 (m, 3H, Harom), 5.36 (s, 2H, CH2Ph), 2.69 (q, H(3)arom+ H(5)arom), 7.29 – 7.24 (m, 5H, Harom), 5.38 (s,
2H, J = 7.4 Hz, 2H, CH2CH3), 1.26, (t, 3H, CH2CH3). – 2H, CH2Ph), 4.51 (dd, 1H, JNH,CH = 5.5 Hz, JCH,Me = 7.2
13C NMR (CDCl3): δ = 168.4 (CO2H), 148.9 (C-2), 145.5 Hz, CH-alanine), 3.73 ( s, 3H, CO2Me), 2.67 (q, 2H,
(C-5), 140.7 (C-4), 137.5 (C(1)arom+ CH2-C(1)arom), 129.9, J = 7.5 Hz, 2H, CH2CH3), 1.39 (d, 3H, JCH,Me = 7.2 Hz,
128.8, 128.5, 127.9, 127.7, 127.6, 127.4, 125.1 (Carom), 46.3 CHalanine-Me), 1.24 (t, 3H, CH2CH3). − 13C NMR
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Y. A. Al-Soud et al. · Nitroimidazoles
933
([D6]DMSO): δ = 172.9 (CO2Me); 166.6 (NCalanine =O); Methyl 2-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
149.5 (C-2); 145.4 (C-4), 139.6 (C-5), 137.1 (CH2- benzamido)-3-methylbutanoate (11)
(C(1)arom), 135.9 (C(10)arom), 134.5, 131.9, 129.2, 128.2,
From L-valine methyl ester (262 mg). Yield: 641 mg
127.2, 125.5 (Carom), 46.5 (CH2Ph), 56.6 (CH-alanine), 52.0
(69%); m. p. 145 – 18 ◦C.
–
1H NMR ([D6]DMSO):
(CO2Me), 21.3 (CH2CH3), 18.2 (CHMe), 11.5 (CH2CH3).
–MS ((+)-FAB): m/z = 437 [M+H]+. − C23H24N4O4
(436.46): calcd. C 63.29, H 5.54, N 12.84; found C 62.98,
H 5.44, N 12.65.
δ = 8.32 (d, 1H, JNH,CH = 5.1 Hz, NH); 8.12 (d, 2H,
J = 7.4 Hz, H(2)arom + H(6)arom), 7.97 (d, 2H, J = 7.4 Hz,
H(3)arom + H(5)arom), 7.29 – 7.24 (m, 5H, Harom), 5.45
(s, 2H, CH2Ph), 4.41 (dd, 1H, JCH,CHMe2 = 9.5 Hz,
JNH,CH = 5.1 Hz, CHCHCMe2), 3.66 (s, 3H, CO2Me), 2.09
(m, 1H, CHMe2), 2.71 (q, 2H, J = 7.5 Hz, 2H, CH2CH3),
1.23 (t, 3H, CH2CH3), 0.83, 0.80 (2× s, 6H, 2× Me).
Methyl 2-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
benzamido)-3-hydroxypropanoate (10)
-
13C NMR ([D6]DMSO): δ = 171.8 (CO2Me), 166.6
From L-serine methyl ester (238 mg). Yield: mg (74%);
m. p. 156 – 157 ◦C. – 1H NMR ([D6]DMSO): δ = 8.16 (br s,
1H, NH); 8.08 (d, 2H, J = 7.2 Hz, H(2)arom+ H(6)arom), 7.96
(d, 2H, J = 7.2 Hz, H(3)arom+ H(5)arom), 7.27 – 7.23 (m, 5H,
Harom), 5.41 (s, 2H, CH2Ph), 4.53 (m, 2H, CH2OH), 4.10 (t,
1H, JOH,CH2 = 5.5 Hz, CH2OH), 3.58 (m, 1H, CH-serine),
3.70 (s, 3H, CO2Me), 2.69 (q, 2H, J = 7.4 Hz, CH2CH3),
1.25 (t, 3H, CH2CH3). – 13C NMR ([D6]DMSO): δ = 171.1
(CO2Me), 166.8 (NCserine =O), 148.6 (C-2), 145.3 (C-
4), 140.0 (C-5), 137.3 (CH2-C(1)arom), 135.8 (C(10)arom),
134.1, 131.2, 129.0, 128.2, 127.5, 127.2, 125.7 (Carom),
46.4 (CH2Ph), 67.1 (CH2OH), 54.8 (CHCH2OH), 51.7
(NCvaline =O), 148.2 (C-2), 145.8 (C-4), 140.3 (C-5), 137.4
(CH2-(C(1)arom), 135.8 (C(10)arom), 134.4, 131.1, 129.2,
129.1, 127.7, 127.5, 125.7 (Carom), 46.7 (CH2Ph), 56.8
(CHCHMe2), 52.1 (CO2Me), 46.5 (CH2Ph), 30.9 (CHMe2),
20.9 (CH2CH3), 18.8, 17.7 (2× Me), 11.3 (CH2CH3). – MS
((+)-FAB): m/z = 487 [M+Na]+. − C25H28N4O5 (464.51):
calcd. C 64.64, H 6.08, N 12.06; found C 64.42, H 5.98, N
11.87.
Acknowledgement
Prof. Y. Al-Soud thanks the Deanship of Scientific Re-
(CO2Me), 21.2 (CH2CH3), 11.3 (CH2CH3). – MS ((+)- search, University of Al al-Bayt for financial support. Prof.
FAB): m/z = 426 [M+H]+. − C23H24N4O6 (425.46): calcd. N. Al-Masoudi would like to thank Basrah University for the
C 61.05, H 5.35, N 12.38; found C 61.24, H 5.26, N 12.49.
sabbatical leave.
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