Design and synthesis of optically active 2-phenylimidazolecarboxamides featuring amino acid motive

Article abstract of DOI:10.1002/jhet.5570450611

(Chemical Equation Presented) Overall sixteen new, optically active carboxamides 1-3 have been synthesized. These compounds based on the 2-phenylimidazole and featuring amino acid residues are linked on the 4-position by an amidic bond. Two general methods were used for their construction. Whereas the first method employs acylchlorides as a reactive species, the second one involves a condensation of mixed anhydrides with the amino acid counterparts. Actually, the second method proved to be more efficient than the first one. Carboxamides 1-3 were preliminarily tested as N-chelating ligands with an application in the Henry or Aldol reactions affording either poor yields or enantiomeric excesses.

Full text of DOI:10.1002/jhet.5570450611

Nov-Dec 2008
1621
Design and Synthesis of Optically Active
2-Phenylimidazolecarboxamides Featuring Amino Acid Motive
Roman Sívek, Oldꢀich Pytela and Filip Bureꢁ*
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice,
nám. ꢂs. Legií 565, Pardubice, 532 10, Czech Republic
e-mail: Filip.Bures@upce.cz
Received February 26, 2008
R
Z
Z
H2N
O
X
O
COY
N
N
R
N
N
HN
THF
Ph
Ph
H
H
COY
Z = H, COOCH3
X = Cl, OCOOEt
Z = H, COOCH3
Y = OCH3, NH2
R = amino acid residue
Overall sixteen new, optically active carboxamides 1-3 have been synthesized. These compounds based
on the 2-phenylimidazole and featuring amino acid residues are linked on the 4-position by an amidic
bond. Two general methods were used for their construction. Whereas the first method employs
acylchlorides as a reactive species, the second one involves a condensation of mixed anhydrides with the
amino acid counterparts. Actually, the second method proved to be more efficient than the first one.
Carboxamides 1-3 were preliminarily tested as N-chelating ligands with an application in the Henry or
Aldol reactions affording either poor yields or enantiomeric excesses.
J. Heterocyclic Chem., 45, 1621 (2008).
O
INTRODUCTION
N
R
N
HN
Ph
H
Heterocyclic compounds incorporating the imidazole
nucleus and their functionalization steadily attract
considerable interest from organic chemists [1-2]. These
compounds possess many attractive properties, in
particular diverse biological and pharmacological [3-6] or
antibacterial, antifungal and antiviral activities [3,7].
Miscellaneous naturally occurring alkaloids, e.g. the
alkaloids isolated from marine sponge, soft corals,
microorganisms and plants [8-10] or diverse ionic liquids
[11], bear an imidazole ring as well. However, the most
widely known imidazole structural motif comes from an
essential amino acid – histidine and its analogs or
derivatives such as a neurotransmitter histamine and
ligands selective to the histamine receptors [3,12-13]. A
report on the imidazole based receptors for the chiral
recognition is known as well [14].
COOCH3
1
O
N
R
N
HN
Ph
H
CONH2
2
COOCH3
O
N
R
N
HN
Ph
H
COOCH3
3
Figure 1
In the past several decades, the chemistry of transition
metals and their coordination on diverse N-chelating
ligands became an exponentially growing area of organic
chemistry. Prospective applications of complexes such as
organometallic catalysts [15] is considerably stimulating
efforts of chemists to design and synthesize novel
nitrogen ligands. The complexing ability of the imidazole
ring to bind transition metals [16-19] as well as the
application in some asymmetric reactions [20] has already
been proven. Considering these findings, here we report
on the synthesis, characterization and preliminary
catalytic activity of the imidazole carboxamides having
general formulas 1-3 (Figure 1). Whereas the imidazole
ring should perform as a coordinating auxiliary, the amino
acid chain (ester or amide) linked by an amidic bond
bears the chiral center. Considering the practical
applicability and ability to scale up the entire synthesis,
our retro-synthetic strategy involves only the reasonable
synthetic steps that particularly employ the commercially
available amino acids (according to R). Several
approaches to synthesizing such compounds already exist.
Veronese et al. condense the 2-oximinoacetoacetamides
and various benzyl amines to afford 4-carboxamido-5-
methyl-2-phenylimidazoles [21].
Starting from the

1622
R. Sívek, O. Pytela and F. Bureꢀ
Vol 45
Meldrum’s and amino acids, Gopalsamy and Shi have
synthesized similar carboxamides in four step
may be basically enhanced by several known methods
[30]. In general, we can divide these methods into two
main groups: i) derivatization of the carboxylic acid into
the intermediates capable of isolation e.g. esters or
acylhalogenides and ii) carboxylic function in situ
activation into reactive intermediates used directly in the
next reaction step e.g. DCC/CDI activation or activation
via (mixed) anhydrides. Considering this elemental
knowledge, we examined first the simplest and best
known method of activation via DCC. To our great
a
transformation [22]. Rather than adopt these two
strategies, and in view of a recent report by Baures and
co-workers [23], we turned our attention to a direct
condensation of the amino acids with the appropriate
imidazole-4(5)-(di)carboxylic acid derivatives [24-25].
RESULTS AND DISCUSSION
The synthetic aspect of our work comprises of the synthesis
of three ligands series (1-3). The first two series were
generated from a 2-phenylimidazole-4-carboxylic acid (4) and
its derivatization by amino acid esters (1a-f) and amides (2a-
d), respectively. The starting carboxylic acid 4 was prepared
via the HNO3 oxidation of the 2-phenyl-4-hydroxy-
methylimidazole, generated from dihydroxyacetone [26].
Since this methodology of oxidation was mainly developed for
the synthesis of 2-phenylimidazole-4-carbaldehyde, particular
attention should be paid to the conditions of this reaction step.
Whereas an oxidation using either fuming or concentrated
nitric acid led only to the nitration of the phenyl ring at the
2-position or the formation of the undesired 2-phenyl-
imidazole-4-carbaldehyde, a catalytic amount of FeCl3
directed the oxidation to the 2-phenylimidazole-4-carboxylic
acid 4 in an 85% yield. A third series of carboxamides was
gained by the condensation of the activated monomethyl ester
of the 2-phenylimidazole-4,5-dicarboxylic acid (5) with amino
acid esters. The starting 2-phenylimidazole-4,5-dicarboxylic
acid was synthesized in a two step reaction sequence from
tartaric acid involving its transformation into the appropriate
dinitrate and, subsequently, a condensation with benzaldehyde
in the presence of ammonia afforded the desired acid [27]. A
directed acid-catalyzed esterification of the 2-phenyl-
imidazole-4,5-dicarboxylic acid with methanol furnished the
desired mono- and diesters 5 and 9 in 36% and 81% yields,
respectively. The condensation counterparts (Scheme I),
amino acid esters and amides, were prepared by known
methods [28-29].
surprise, both carboxylic acids 4 and
5 remained
unattached and no traces of the desired products 1-3 could
be isolated either. For a second attempt, we tried a
condensation between the methyl esters 7 and 9 and the
amino acid counterparts achieving, unfortunately, the
same result. On the other hand, the transformation of the
acid
4 in the appropriate acylhalogenide 6 using
convenient SOCl2 and followed by condensation with the
amino acid counterparts, afforded the target carboxamides
in moderate to good yields (see Table I, Method A).
Unfortunately, we found a similar transformation of 5 into
the corresponding acylhalogenide infeasible. Acylhalo-
genides are overall a reactive species, however, in our
case the main insufficiency of this activating method lies
in difficult purification, physicochemical characterization
and moisture sensitivity (possible hydrolysis). Hence, we
turned our attention to the in situ activation using mixed
anhydrides as reactive intermediates (see Table I, Method
B). This known method [31] involves the reaction of free
carboxylic acid with chloroformates at low temperature in
the presence of triethylamine as a base, followed by the
addition of amino acid counterparts. To our great delight,
this method was synthetically simpler than method A
affording comparable results and in some cases even
higher yields. The optical purities of carboxamides 1-3
synthesized this way resemble those from starting amino
acids. The yields of the activating steps are solely lowered
due to the undesired formation of a carbamic function on
the imidazole nitrogen. The formed side products were
isolated and characterized. However, an attempted basic
hydrolysis of such side products to the desired
carboxamides 1-3 proceeded with partial racemization.
The prepared carboxylic acids themselves are not
capable of condensing with the amino acid esters or
amides to afford the desired carboxamides. Hence, an
activation of the carboxylic function was necessary. The
carboxylic acid function reactivity towards nucleophiles
Scheme 1
R
Z
Z
Z
carboxylic function
activation
H2N
.HCl
O
O
O
X
COY
N
N
N
R
N
N
N
HN
OH
Method A or B
THF
Ph
Ph
Ph
H
H
H
COY
6 - Z = H, X = Cl
1a-f - Z = H, Y = OCH3
2a-d - Z = H, Y = NH2
3a-f - Z = COOCH3, Y = OCH3
4 - Z = H
5 - Z = COOCH3
7 - Z = H, X = OCH3
8 - Z = H, X = OCOOCH2Ph
9 - Z = COOCH3, X = OCH3
10 - Z = COOCH3, X = OCOOCH2Ph

Nov-Dec 2008
2-Phenylimidazolecarboxamides Featuring Amino Acid Motive
1623
Table 1
Synthetic Methods, Yields and Basic Physical Data for Target Carboxamides 1-3 (Scheme I).
20
[ꢀ]D
(c 0.05, CH3OH)
Compound
R
Z
Y
Method
Yield
[%]
Mp
[°C]
[starting amino acid]
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
B
B
B
B
B
B
38
38
49
53
64
40
51
24
73
23
76
33
4
41
35
42
17
24
25
75
41
56
25
32
18
28
1a
1b
1c
1d
1e
1f
CH3- [(S)-Ala]
(CH3)2CH- [(S)-Val]
(CH3)2CHCH2- [(S)-Leu]
CH3CH2CH(CH3)- [(S)-Ile]
Ph- [(R)-PheGly]
H
H
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
NH2
187-188
75-77
+35.2
+39.0
+17.9
+29.6
+57.1
+38.1
+80.8
+23.6
-35.1
-37.7
146-147
125-127
177-179
130-132
211-215
135-137
144-146
165-167
PhCH2- [(S)-Phe]
CH3- [(S)-Ala]
2a
2b
2c
2d
(CH3)2CHCH2- [(S)-Leu]
Ph- [(R)-PheGly]
NH2
NH2
PhCH2- [(S)-Phe]
NH2
3a
3b
3c
3d
3e
3f
CH3- [(S)-Ala]
(CH3)2CH- [(S)-Val]
(CH3)2CHCH2- [(S)-Leu]
CH3CH2CH(CH3)- [(S)-Ile]
Ph- [(R)-PheGly]
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
186-187
139-141
112-113
oil
103-104
137-139
+20.9
+16.8
+10.8
+30.3
+99.8
+15.6
PhCH2- [(S)-Phe]
Thus the hydrolysis did not lead to the optically pure
compounds.
Aldol condensation [32-33]. Whereas the Henry reaction
involves the reaction of an aldehyde with a nitroalkane
(Scheme II), the asymmetric Aldol condensation employs
an additional ketone as a nucleophile (Scheme III). These
two reactions are widely applied as a basic screening of the
enantioselectivity giving the first insight into the catalytical
behaviour of the studied ligands. The attained yields and
enantiomeric excesses (ee) of the Henry reaction and Aldol
The condensation of the activated carboxylic acids with
amino acids esters and amides hydrochlorides required
careful pH maintenance. Triethylamine as a base liberates
the free amino acids and eventually scavenges the
hydrogen chloride produced during the reaction. The
optimal pH value revealed to be about 9.
condensation are summarized in Table
2 and 3,
When comparing both methods of activation, method A,
utilizing acylchloride 6, afforded moderate to good yields,
almost no side products were observed but the method is
limited by the synthesis of acylchlorides. On the contrary,
the method B is operationally simple, applicable on both
carboxylic acids 4 and 5, affords yields comparable to
method A and there is no need to isolate and purify the
intermediates. Nevertheless we observed the formation of a
side product. The optical purities of the carboxamides 1-3
synthesized by both methods correspond to each other and
respectively. From the measured values we can only
suggest that, in general, the prepared carboxamides 1-3
revealed to be poor catalysts for these two selected
reactions. Whereas they are able to catalyze the Henry
reactions as bases, the enantiomeric excesses are poor
varying from 1.1 to 13.3 %. The attained yields and ee's of
the Aldol condensation are even worse than those for the
Henry reaction.
However, an application of the synthesized
carboxamides 1-3 as small molecules inhibiting protein-
protein interactions, as has been shown by Baures [23],
remains a challenge.
1
also H NMR measurements using Mosher acid do not
reveal a racemization. The molecular structures of the final
1
compounds have been determined by the H-, 13C-NMR
spectroscopy and elemental analysis while the optical
rotations have been measured as well. Additional NMR
EXPERIMENTAL
1
techniques such as H-1H COSY, HMBC and HMQC
spectra were further used for regular signal assignment. The
prepared chiral carboxamides were examined as ligands in
the asymmetric versions of the Henry reaction [20] and
Reagents and solvents were reagent-grade and were purchased
from Aldrich and used as received. THF was freshly distilled
from Na/benzophenone under N2. The starting 2-phenyl-4-

1624
R. Sívek, O. Pytela and F. Bureꢀ
Vol 45
solvents. Thin-layer chromatography (TLC) was conducted on
aluminium sheets coated with SiO2 60 F254 obtained from Merck,
with visualization by UV lamp (254 or 360 nm). Melting points
(mp) were measured on a Büchi B-540 melting-point apparatus
in open capillaries and are uncorrected. 1H- and 13C-NMR
spectra were recorded in CDCl3, DMSO-d6 or CD3OD at
360/500 MHz and 90/125 MHz, respectively, with Bruker AMX
360 or Bruker AVANCE 500 instrument at 25°. Chemical shifts
are reported in ppm relative to the signal of Me4Si. Residual
Scheme 2
CH3NO2/"Cu2+ cat.
EtOH
O
NO2
O2N
O2N
OH
Table 2
Henry reaction [a]
1
solvent signals in the H- and 13C-NMR spectra were used as an
Compound
Yield
[%]
ee
[%]
internal reference (CDCl3 – 7.25 and 77.23, DMSO-d6 – 2.55
1
and 39.51 and CD3OD – 3.31 and 49.51 ppm for H- and 13C-
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
79
84
85
91
70
90
82
93
88
91
88
95
91
93
90
91
1.1
3.1
8.4
4.3
3.6
3.2
13.3
6.2
1.9
8.4
2.6
5.4
6.4
4.8
3.9
4.1
NMR, respectively). Coupling constants (J) are given in Hz. The
apparent resonance multiplicity is described as s (singlet), br s
(broad singlet), d (doublet), dd (doublet of doublet), t (triplet), q
(quartet) and m (multiplet). 2-Phenyl protons are marked as
1
ArH. H-1H COSY, HMBC and HMQC NMR techniques were
also used. Some of the imidazole carbons were not observed in
13C-NMR spectra, most likely due to the hindered imidazole
tautomerism or amide rotation(s). Optical rotation values were
measured on a Perkin Elmer 341 instrument, concentration c is
given in g/100 mL CH3OH. The enantiomeric excesses were
determined by chiral HPLC analysis on a Daicel Chiracel OB
column and simultaneously deduced from [ꢀ] values [20, 33].
2-Phenyl-1H-imidazole-4-carboxylic acid (4). A mixture of
2.0 g (0.0115 mole) of the 2-phenyl-4-hydroxymethylimidazole
in 7 mL of fuming nitric acid and 0.02 g (0.12 mmole) of FeCl3
were heated for 2 h at 140º. After being stand overnight at 5º, the
yellowish crystals were collected by filtration, rinsed with water
and crystallized form ethanol-water (1:1) to yield 1.84 g (85%),
[a] For the reaction condition see Ref. [20]
Scheme 3
1
mp 238-240º (lit.[34] mp 239º); H nmr (360 MHz, DMSO-d6):
ꢁ 7.45 (t, 1H, ArH, J =7.2 Hz), 7.52 (t, 2H, ArH, J = 7.6 Hz),
7.91 (s, 1H, CHim), 8.07 (d, 2H, ArH, J = 7.2 Hz); 13C nmr (90
MHz, DMSO-d6): ꢁ 126.5, 127.3, 128.9, 129.5, 131.3, 144.7,
174.5 (1C missing); Anal. Calcd. for C10H8N2O2: C, 63.82; H,
4.28; N, 14.89. Found: C, 63.92; H, 4.21; N, 14.82.
O
O
O
O2N
O2N
Ligands 1-3
OH
Table 3
5-(Methoxycarbonyl)-2-phenyl-1H-imidazole-4-carboxylic
acid (5). To a solution of 5.0 g (0.0215 mole) of 2-phenyl-
imidazole-4,5-dicarboxylic acid in 150 mL (3.70 mole) of dry
methanol one drop of sulphuric acids was added. The reaction
mixture was refluxed for 6 h, concentrated in vacuo and the
residue crystallized from ethyl acetate to yield the title
compound as off-white solid, 1.9 g (36%), mp 155-156º; 1H nmr
(360 MHz, DMSO-d6): ꢁ 3.92 (s, 3H, -OCH3), 7.50-7.56 (m, 3H,
ArH), 8.17 (d, 2H, ArH, J = 7.6 Hz), 13.64 (br s, 1H, -COOH);
13C nmr (90 MHz, DMSO-d6): ꢁ 51.3, 127.3, 128.4, 129.9,
134.7, 136.5, 137.8, 147.7, 167.4, 172.9; Anal. Calcd. for
C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C, 58.53; H,
4.12; N, 11.36.
Aldol condensation [a]
Compound
Yield
[%]
ee
[%]
1a
1b
1c
1d
1e
1f
2a
2b
2c
3a
3b
3c
3f
8
5
10
13
7
4
8
15
13
7
3.7
2.1
5.2
3.9
1.9
1.8
5.5
4.9
3.7
3.7
2.9
4.9
3.7
Methyl 2-Phenyl-1H-imidazole-4-carboxylate (7). The title
compound was synthesized from 5.0 g (0.0266 mole) of 4
following the procedure as described for 5 and refluxing the
reaction mixture for 10 h. Yield 3.6 g (67%), mp 144-145º
9
7
5
1
[a] For the reaction condition see Experimental
(lit.[35] mp 219-221º); H nmr (500 MHz, CDCl3): ꢁ 3.89 (s,
3H, -OCH3), 7.38-7.42 (m, 3H, ArH), 7.78 (s, 1H, CHim), 7.90
(d, 2H, ArH, J = 7.5 Hz); 13C nmr (125 MHz, CDCl3): ꢁ 52.2,
126.1, 129.1, 129.2, 130.1, 149.2, 162.2 (2C missing); Anal.
Calcd. for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C,
65.30; H, 5.02; N, 13.82.
Dimethyl 2-Phenyl-1H-imidazole-4,5-dicarboxylate (9).
The title compound was synthesized following the same
procedure as described for 5 refluxing the reaction mixture for
hydroxymethylimidazole [26] and 2-phenylimdiazole-4,5-
dicarboxylic acid [27] were synthesized according to literature
procedures. Evaporation and concentration in vacuo were
performed at water aspirator pressure. Column chromatography
(CC) was carried out with SiO2 60 (particle size 0.040-0.063
mm, 230-400 mesh; Merck) and commercially available

Nov-Dec 2008
2-Phenylimidazolecarboxamides Featuring Amino Acid Motive
1625
50 h. Yield 4.5 g (81%), mp 134-135º (lit.[27] mp 157-158º); 1H
nmr (360 MHz, DMSO-d6): ꢀ 3.90 (s, 6H, -OCH3), 7.47-7.56
(m, 3H, ArH), 8.15-8.20 (m, 2H, ArH), 13.85 (br s, 1H, NHim).
General Procedure for Method A. Into a stirred and ice-
cooled suspension of 1.0 g (0.0053 mole) of 4 in 200 mL of dry
THF 5 mL (0.069 mole) of thionylchloride was added dropwise.
The reaction mixture was refluxed for 6 h and all of the volatiles
evaporated in vacuo. The crude acylchloride 6 was used in the
next step without further purification. Into a stirred and ice-
cooled solution of 1 g (0.0048 mole) of 6 in dry THF a
suspension of the amino acid ester or amide hydrochloride
(0.0047 mole) in 30 mL of THF containing 0.74 mL (0.0053
mole) of triethylamine was added. Another portion of 1.49 mL
(0.0107 mole) of triethylamine was added gradually at 0º
maintaining the pH value about 9. The reaction mixture was
stirred for 12 h at 25º, precipitated triethylamine hydrochloride
filtered off, filtrate concentrated in vacuo and the residue
purified on CC (SiO2; ethyl acetate).
General Procedure for Method B. Into a solution of 4 or 5
(0.0053 mole) in 200 mL of dry THF and 1.5 mL (0.0108 mole)
of triethylamine 0.97 mL (0.0068 mole) of the benzylchloro-
formate was added dropwise under N2 at -10º. The reaction
mixture was stirred for additional 30 min whereupon a
suspension of the amino acid ester or amide hydrochloride
(0.0052 mole) in 30 mL of dry THF containing 0.74 mL (0.0053
mole) of triethylamine was added. The reaction was stirred for
12 h at 25º, precipitated triethylamine hydrochloride filtered off,
filtrate concentrated in vacuo and the residue purified on CC
(SiO2; ethyl acetate).
C17H21N3O3: C, 64.74; H, 6.71; N, 13.32. Found: C, 64.73; H,
6.74; N, 13.30.
(2S,3S)-Methyl 3-Methyl-2-{[(2-phenyl-1H-imidazol-4-yl)-
carbonyl]amino}pentanoate (1d). This compound was
obtained as off-white solid, mp 125-127°; [ꢁ]D20 = +29.6 (c 0.05,
CH3OH); 1H nmr (500 MHz, CD3OD): ꢀ 0.92 (t, 3H, -CH2CH3, J
= 7.5 Hz), 0.96 (d, 3H, -CHCH3, J = 7.0 Hz), 1.25-1.34 (m, 1H,
-CH2-), 1.50-1.58 (m, 1H, -CH2-), 1.95-2.00 (m, 1H, -CHCH2-),
3.72 (s, 3H, -OCH3), 4.62 (d, 1H, -CH-, J = 6.0 Hz), 7.37 (t, 1H,
ArH, J = 7.5 Hz), 7.43 (t, 2H, ArH, J = 7.5 Hz), 7.77 (s, 1H,
CHim), 7.9 (d, 2H, ArH, J = 7.5 Hz); 13C nmr (125 MHz,
CD3OD): ꢀ 11.9, 16.2, 26.5, 38.8, 52.7, 58.0, 126.8, 124.6,
130.1, 130.5, 130.9, 136.5, 148.8, 164.9, 173.6; Anal. Calcd. for
C17H21N3O3: C, 64.74; H, 6.71; N, 13.32. Found: C, 64.72; H,
6.68; N, 13.35.
(2R)-Methyl 2-Phenyl-2-{[(2-phenyl-1H-imidazol-4-yl)car-
bonyl]amino}ethanoate (1e). This compound was obtained as
20
off-white solid, mp 177-179°; [ꢁ]D = +57.1 (c 0.05, CH3OH);
1H nmr (500 MHz, CDCl3): ꢀ 3.71 (s, 3H, -OCH3), 5.72 (d, 1H,
-CH-, J = 7.2 Hz), 7.28-7.39 (m, 6H, ArH+Ph), 7.43 (d, 2H, Ph,
J = 8.0 Hz), 7.54 (s, 1H, CHim), 7.93 (d, 2H, ArH, J = 7.0 Hz),
8.22 (d, 1H, NH, J = 7.2 Hz), 11.80 (br s, 1H, NHim); 13C nmr
(90 MHz, CDCl3): ꢀ 52.7, 56.5, 120.8, 125.6, 127.3, 128.5,
128.7, 128.9, 129.1, 129.4, 135.5, 136.0, 147.2, 163.1, 171.0;
Anal. Calcd. for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53.
Found: C, 68.10; H, 5.09; N, 12.52.
(2S)-Methyl 3-Phenyl-2-{[(2-phenyl-1H-imidazol-4-yl)car-
bonyl]amino}propanoate (1f). This compound was obtained as
20
off-white solid, mp 129-133°; [ꢁ]D = +38.1 (c 0.05, CH3OH);
1H nmr (500 MHz, CDCl3): ꢀ 3.18 (m, 2H, -CH2-), 3.63 (s, 3H,
-OCH3), 5.01 (q, 1H, CH, J = 8.0 Hz), 7.14-7.22 (m, 5H, Ph),
7.32 (t, 1H, ArH, J = 7.5 Hz), 7.37 (t, 2H, ArH, J = 8.0 Hz), 7.50
(s, 1H, CHim), 7.84 (d, 1H, NH, J = 7.5 Hz), 7.96 (d, 2H, ArH, J
= 7.5 Hz), 12.33 (br s, 1H, NHim); 13C nmr (125 MHz, CDCl3): ꢀ
38.4, 52.3, 53.4, 120.3, 125.7, 127.1, 128.6, 128.7, 129.0, 129.2,
129.6, 135.9, 147.3, 163.6, 171.8, (1C missing); Anal. Calcd. for
C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found: C, 68.77; H,
5.44; N, 12.02.
(2S)-Methyl 2-{[(2-Phenyl-1H-imidazol-4-yl)carbonyl]-
amino}propanoate (1a). This compound was obtained as off-
20
1
white solid, mp 187-188º; [ꢁ]D = +35.2 (c 0.05, CD3OD); H
nmr (500 MHz, DMSO-d6): ꢀ 1.47 (d, 3H, -CH3, J = 7.3 Hz),
3.70 (s, 3H, -OCH3), 4.57 (m, 1H, -CH-), 7.45 (t, 1H, ArH, J =
7.5 Hz), 7.53 (t, 2H, ArH, J = 7.5 Hz), 7.84 (s, 1H, CHim), 8.07
(d, 2H, ArH, J = 7.5 Hz), 8.26 (br s, 1H, NH), 13.08 (br s, 1H,
NHim); 13C nmr (90 MHz, DMSO-d6): ꢀ 17.3, 47.4, 52.0, 122.9,
125.4, 128.8, 129.9, 136.4, 145.6, 162.5, 173.2, (1C missing);
Anal. Calcd. for C14H15N3O3: C, 61.53; H, 5.53; N, 15.38.
Found: C, 61.58; H, 5.54; N, 15.38.
(1S)-N-[1-Carbamoylethyl]-2-phenyl-1H-imidazole-4-car-
boxamide (2a). This compound was obtained as off-white solid,
20
1
mp 211-215°; [ꢁ]D = +80.8 (c 0.05, CH3OH); H nmr (360
MHz, DMSO-d6): ꢀ 1.39 (d, 3H, -CH3, J = 6.8 Hz), 4.50 (m, 1H,
-CH-), 7.23 (s, 1H, -NH2), 7.45 (t, 1H, ArH, J = 7.2 Hz), 7.53 (t,
2H, ArH, J = 7.4 Hz), 7.62 (s, 1H, -NH2), 7.84 (s, 1H, CHim),
7.89 (d, 1H, NH, J = 7.9 Hz), 8.04 (d, 2H, ArH, J = 7.2 Hz),
13.06 (br s, 1H, NHim); 13C nmr (90 MHz, DMSO-d6): ꢀ 17.5,
54.4, 126.7; 127.8, 128.9, 129.9, 130.3, 136.9, 145.7, 162.4,
174.4; Anal. Calcd. for C13H14N4O2: C, 60.45; H, 5.46; N, 21.69.
Found: C, 60.45; H, 5.46; N, 21.66.
(2S)-Methyl 3-Methyl-2-{[(2-phenyl-1H-imidazol-4-yl)car-
bonyl]amino}butanoate (1b). This compound was obtained as
1
off-white solid, mp 75-77°; [ꢁ]D20 = +39.0 (c 0.05, CH3OH); H
nmr (500 MHz, CDCl3): ꢀ 0.99 (d, 6H, -(CH3)2, J = 7.0 Hz),
2.24-2.30 (m, 1H, -CH(CH3)2), 3.70 (s, 3H, -OCH3), 4.70 (dd,
1H, -CH-, J = 5.5, 9.5 Hz), 7.34 (t, 1H, ArH, J = 7.5 Hz), 7.40 (t,
2H, ArH, J = 7.5 Hz), 7.60 (s, 1H, CHim), 7.83 (d, 1H, NH, J =
8.5 Hz), 8.02 (d, 2H, ArH, J = 8.0 Hz), 12.50 (br s, NHim); 13C
nmr (125 MHz, CDCl3): ꢀ 18.1, 19.1, 31.4, 52.1, 57.3, 120.4,
125.8, 128.7, 129.1, 129.6, 135.9, 147.4, 163.9, 172.1; Anal.
Calcd. for C16H19N3O3: C, 63.77; H, 6.36; N, 13.94. Found: C,
63.72; H, 6.34; N, 13.96.
(1S)-N-[1-Carbamoyl-3-methylbutyl]-2-phenyl-1H-imidaz-
ole-4-carboxamide (2b). This compound was obtained as off-
20
1
white solid, mp 135-137°; [ꢁ]D = +23.6 (c 0.05, CH3OH); H
nmr (500 MHz, CD3OD): ꢀ 0.97 (d, 3H, -(CH3)2, J = 3.0 Hz ),
0.98 (d, 3H, -(CH3)2, J = 3.0 Hz), 1.67-1.79 (m, 3H, -CH2CH-),
4.64-4.67 (m, 1H, -CH-), 4.90 (br s, 4H, NH+NHim+NH2), 7.40 (t,
1H, ArH, J = 7.5 Hz), 7.46 (t, 2H, ArH, J = 7.5 Hz), 7.75 (s, 1H,
CHim), 7.92 (d, 2H, ArH, J = 7.05 Hz); 13C nmr (125 MHz,
CD3OD): ꢀ 22.2, 23.7, 26.2, 42.7, 52.8, 123.1, 126.9, 130.2, 130.6,
131.2, 134.5, 148.9, 165.1, 177.9; Anal. Calcd. for C16H20N4O2: C,
63.98; H, 6.71; N, 18.65. Found: C, 63.98; H, 6.68; N, 18.64.
(1R)-N-[1-Carbamoyl-1-phenylmethyl]-2-phenyl-1H-imid-
azole-4-carboxamide (2c). This compound was obtained as off-
(2S)-Methyl 4-Methyl-2-{[(2-phenyl-1H-imidazol-4-yl)car-
bonyl]amino}pentanoate (1c). This compound was obtained as
20
off-white solid, mp 146-147°; [ꢁ]D = +17.9 (c 0.05, CH3OH);
1H nmr (500 MHz, CDCl3): ꢀ 0.90-0.95 (m, 6H, -(CH3)2), 1.69-
1.76 (m, 3H, -CH2CH-), 3.69 (s, 3H, -OCH3), 4.79-4.83 (m, 1H,
-CH-), 7.35 (t, 1H, ArH, J = 7.5 Hz), 7.41 (t, 2H, ArH, J = 7.5
Hz), 7.59 (s, 1H, CHim), 7.66 (d, 1H, NH, J = 8.0 Hz), 8.0 (d,
2H, ArH, J = 8.0 Hz), 12.28 (br s, 1H, NHim); 13C nmr (125
MHz, CDCl3): ꢀ 22.6, 23.8, 39.8, 50.1, 53.2, 126.8, 127.4,
127.9, 129.5, 129.9, 136.9, 147.8, 163.5, 173.5; Anal. Calcd. for

1626
R. Sívek, O. Pytela and F. Bureꢀ
Vol 45
20
1
white solid, mp 144-146°; [ꢀ]D = -35.1 (c 0.05, CH3OH); H
nmr (500 MHz, CD3OD): ꢁ 5.65 (s, 1H, -CH-), 7.31-7.47 (m,
6H, ArH+Ph), 7.55 (d, 2H, Ph, J = 7.5 Hz), 7.74 (s, 1H, CHim),
7.91 (d, 2H, ArH, J = 7.5 Hz); 13C nmr (125 MHz, CD3OD): ꢁ
58.2, 123.2, 126.9, 128.7, 129.5, 130.0, 130.2, 130.6, 131.0,
136.3, 139.5, 149.0, 164.5, 175.0; Anal. Calcd. for C18H16N4O2:
C, 67.49; H, 5.03; N, 17.49. Found: C, 67.47; H, 5.01; N, 17.49.
(1S)-N-[1-Carbamoyl-2-phenylethyl]-2-phenyl-1H-imidaz-
ole-4-carboxamide (2d). This compound was obtained as off-
8.5 Hz), 7.43-7.44 (m, 3H, ArH), 7.97-7.99 (m, 2H, ArH), 10.64
(d, 1H, NH, J = 8.0 Hz), 11.81 (br s, 1H, NHim); 13C nmr (125
MHz, CDCl3): ꢁ 13.8, 16.3, 24.7, 33.5, 51.2, 53.3, 64.6, 127.9,
129.3, 129.8, 130.9, 139.9, 147.6, 164.3, 176.9 (2C missing);
Anal. Calcd. for C19H23N3O5: C, 61.11; H, 6.21; N, 11.25.
Found: C, 61.08; H, 6.26; N, 11.24.
(1R)-Methyl 5-{[1-(Methoxycarbonyl)-1-phenylmethyl]-
carbamoyl}-2-phenyl-1H-imidazole-4-carboxylate (3e). This
20
compound was obtained as off-white solid, mp 103-104°; [ꢀ]D
1
20
1
= +99.8 (c 0.05, CH3OH); H nmr (360 MHz, CDCl3): ꢁ 3.73 (s,
white solid, mp 165-167°; [ꢀ]D = -37.7 (c 0.05, CH3OH); H
nmr (500 MHz, DMSO-d6): ꢁ 3.07-3.20 (m, 2H, -CH2-), 4.75-
4.79 (m, 1H, -CH-), 7.21-7.33 (m, 6H, Ph+NH), 7.44 (t, 1H,
ArH, J = 7.5 Hz), 7.53 (t, 2H, ArH, J = 7.5 Hz), 7.70 (s, 1H,
NH2), 7.80 (s, 1H, CHim), 7.83 (d, 1H, NH2, J = 8.5 Hz), 8.02 (d,
2H, ArH, J = 7.5 Hz), 13.06 (br s, 1H, NHim); 13C nmr (125
MHz, DMSO-d6): ꢁ 38.1, 53.0, 120.7, 125.3, 126.4, 128.1,
128.8, 128.9, 129.3, 129.9, 136.6, 137.6, 145.6, 161.6, 172.9;
Anal. Calcd. for C19H18N4O2: C, 68.25; H, 5.43; N, 16.76.
Found: C, 68.26; H, 5.43; N, 16.72.
3H, -OCH3), 4.06 (s, 3H, -OCH3), 5.72 (q, 1H, -CH-, J = 7.2
Hz), 7.32-7.43 (m, 8H, Ar+Ph), 7.94-7.97 (m, 2H, ArH), 11.22
(d, 1H, NH, J = 7.3 Hz), 11.43 (br s, 1H, NHim); 13C nmr (90
MHz, CDCl3): ꢁ 50.9, 51.7, 52.9, 122.8, 125.6, 127.9, 128.1,
128.7, 128.9, 129.1, 130.4, 136.8, 147.9, 163.7, 176.3 (2C
missing); Anal. Calcd. for C21H19N3O5: C, 64.12; H, 4.87; N,
10.68. Found: C, 64.10; H, 4.80; N, 10.73.
(1S)-Methyl 5-{[1-(Methoxycarbonyl)-2-phenyl-ethyl]car-
bamoyl}-2-phenyl-1H-imidazole-4-carboxylate (3f). This
20
compound was obtained as off-white solid, mp 137-139°; [ꢀ]D
(1S)-Methyl 5-{[1-(Methoxycarbonyl)ethyl]carbamoyl}-2-
phenyl-1H-imidazole-4-carboxylate (3a). This compound was
obtained as off-white solid, mp 186-187°; [ꢀ]D20 = +20.9 (c 0.05,
CH3OH); 1H nmr (360 MHz, DMSO-d6): ꢁ 1.49 (d, 3H, CH3, J =
6.6 Hz), 3.74 (s, 3H, -OCH3), 3.96 (s, 3H, -OCH3), 4.60-4.62 (m,
1H, -CH-), 7.49-7.51 (m, 3H, ArH), 8.21 (d, 2H, ArH, J = 7.5
Hz), 10.20 (br s, 1H, NH), 13.73 (br s, 1H, NHim); 13C nmr (90
MHz, DMSO-d6): ꢁ 17.5, 49.5, 52.4, 57.6, 127.4, 128.1, 129.6,
129.9, 147.4, 150.4, 167.1, 169.5, 177.2 (1C missing); Anal.
Calcd. for C16H17N3O5: C, 58.0; H, 5.17; N, 12.68. Found: C,
57.98; H, 5.15; N, 12.75.
1
= +15.6 (c 0.05, CH3OH); H nmr (500 MHz, CDCl3): ꢁ 3.07-
3.11 (dd, 1H, -CH2-, J = 7.5, 14.0), 3.20-3.24 (dd, 1H, -CH2-, J =
5.5, 13.5 Hz), 3.72 (s, 3H, -OCH3), 4.01 (s, 3H, -OCH3), 4.93 (q,
1H, -CH-, J = 7.0 Hz), 7.12-7.23 (m, 6H, ArH+Ph), 7.44-7.46
(m, 2H, Ph), 7.95-7.99 (m, 2H, ArH), 10.63 (d, 1H, NH, J = 8.0
Hz), 11.34 (br s, 1H, NHim); 13C nmr (125 MHz, CDCl3): ꢁ 39.4,
51.8, 51.9, 53.8, 120.8, 126.7, 127.3, 128.6, 128.9, 129.1, 129.3,
129.6, 134.7, 136.7, 140.9, 147.2, 163.9, 176.8; Anal. Calcd. for
C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.88; H,
5.17; N, 10.35.
General Procedure for the Aldol Condensation. A mixture
of 0.6 g (4.0 mmole) of 4-nitrobenzaldehyde, 6 mL of acetone
and 0.4 mmole of tested ligand were stirred 3 days at 25º. The
solvent was evaporated in vacuo and the residue purified on CC
(SiO2; ethyl acetate/cyclohexane 2:3). 1H nmr (500 MHz,
CDCl3): ꢁ 2.19 (s, 3H, -CH3), 2.82-2.84 (m, 2H, -CH2-), 3.61 (d,
1H, J=2.8 Hz, OH), 5.23 (m, 1H, -CH-), 7.50 (d, 2H, ArH, J =
8.8 Hz), 8.17 (d, 2H, ArH J = 8.8 Hz).
(1S)-Methyl 5-{[1-(Methoxycarbonyl)-2-methylpropyl]car-
bamoyl}-2-phenyl-1H-imidazole-4-carboxylate (3b). This
compound was obtained as off-white solid, mp 139-141°; [ꢀ]D
20
= +16.8 (c 0.05, CH3OH); 1H nmr (500 MHz, CDCl3): ꢁ 0.84 (d,
3H, -(CH3)2, J = 6.5 Hz), 0.90 (d, 3H, -(CH3)2, J = 6.5 Hz), 2.13-
2.20 (m, 1H, -CH(CH3)2), 3.64 (s, 3H, -OCH3), 3.95 (s, 3H,
-OCH3), 4.52-4.55 (dd, 1H, -CH-, J = 5.0, 8.5 Hz), 7.36-7.38 (m,
3H, ArH), 7.98-8.00 (m, 2H, ArH), 10.66 (d, 1H, NH, J = 8.5
Hz), 12.49 (br s, 1H, NHim); 13C nmr (125 MHz, CDCl3): ꢁ 21.6,
22.9, 41.7, 51.5, 52.1, 127.1, 128.7, 129.4, 136.6, 144.4, 150.7,
167.9, 171.6, 176.9 (1C missing); Anal. Calcd. for C18H21N3O5:
C, 60.16; H, 5.89; N, 11.69. Found: C, 60.12; H, 5.92; N, 11.65.
(1S)-Methyl 5-{[1-(Methoxycarbonyl)-3-methylbutyl]car-
bamoyl}-2-phenyl-1H-imidazole-4-carboxylate (3c). This
Acknowledgement. We thank The Ministry of Education,
Youth and Sports of the Czech Republic for financial support
(MSM 0021627501).
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20
compound was obtained as off-white solid, mp 112-113°; [ꢀ]D
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