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Article

Imidazole-based Potential Bi- and Tridentate Nitrogen Ligands: Synthesis, Characterization and Application in Asymmetric Catalysis

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, nám. Čs. legií 565, Pardubice, CZ-532 10, Czech Republic
*
Author to whom correspondence should be addressed.
Molecules 2008, 13(9), 2326-2339; https://doi.org/10.3390/molecules13092326
Received: 2 September 2008 / Revised: 10 September 2008 / Accepted: 12 September 2008 / Published: 25 September 2008

Abstract

Twelve new imidazole-based potential bi- and tridentate ligands were synthesized and characterized. Whereas in the first series the α-amino acid and imidazole moieties were linked by an amino bond, in the second series the tridentate ligands, containing two imidazole groups, were separated by an amide bond. The first series was obtained by the reductive amination of 2-phenylimidazole-4-carboxaldehyde with α-amino acid esters. The tridentate ligands were prepared from 2-phenylimidazole-4-carboxylic acid and chiral amines. In the Henry reaction, the amines were revealed as a more reactive species than the less nucleophilic amides, however the enantiomeric excesses were generally poor.
Keywords: Imidazole; Nitrogen ligands; Asymmetric catalysisq Imidazole; Nitrogen ligands; Asymmetric catalysisq

Introduction

A remarkable effort has been devoted by organic chemists over the past 10 years to the design, synthesis, characterization and applications of diverse chiral imidazole-based derivatives [1,2,3,4,5,6,7,8,9,10,11]. These five-membered heterocyclic compounds are mainly being explored for their interesting physicochemical and biological properties, thermal and chemical robustness, acid-base character and possible tautomerism, and last but not least, for their easy synthesis and possible manifold functionalization. Imidazole is frequently found as part of a large number of biologically and medicinally significant substances [12,13] e.g. histidine and its derivatives or as part of the purine skeleton [14]. More recently, imidazole and its derivatives became of interest due to their ability to bind various transition metals [15,16]. In such complexes, the imidazole with its two nitrogen atoms serves as a coordination part of the molecule whereas the chiral auxiliaries at positions 1, 2, 4 or 5 provide an overall asymmetrical environment. This way, designed complexes were able to perform as promising candidates for application in a wide range of asymmetric reactions involving e.g. the Henry reaction [17], conjugate addition [18], addition of dialkylzinc to aldehydes [19], allylation [20], epoxidation and cyclopropanation [21], oxidation [22] or transfer hydrogenation [23].
Several readily available enantiopure precursors such as α-amino acids [2,4,5,7], chiral amines [9], 1,2-amino alcohols [6,10] or α-(acetyloxy)aldehydes [8] were already utilized as a convenient starting material in the synthesis of the chiral imidazole derivatives. Recently, we reported on the synthesis and application of the 2-phenylimidazolecarboxamides 1 featuring an amino acid motive [24], as well as on the tridentate ligands 2 prepared from α-amino acids containing two imidazole groups linked through an amino bond [17] (Scheme 1). Having established the synthesis and catalytic activity of these two classes of compounds bearing either amino or amide bonds and featuring motives from essential α‑amino acids, we turned our attention to the synthesis and investigation of their counterparts. Structures of the two newly proposed ligand series are also depicted in Scheme 1. Whereas the first class of compounds 3 comprises molecules bearing an amino acid residue linked by an amino bond, the second 4 contains two imidazole groups linked by an amide bond. Here we report the synthesis of the two new ligand classes 3 and 4, thus allowing a systematical investigation of the amino vs. amide linkers between the α-amino acid residues and the chelating imidazole moiety (ie. comparing series 1 vs. 3 and 2 vs. 4, respectively) and their influence on the catalytic activity in chosen asymmetric reactions.
Scheme 1. Known and newly proposed imidazole-based ligands.
Scheme 1. Known and newly proposed imidazole-based ligands.
Molecules 13 02326 g003

Results and Discussion

Ligand synthesis

Our synthetic approach to the first series 3 resembles those used for the synthesis of the precedent tridentate ligands [17]. This reaction involves a simple condensation between 2-phenylimidazole-4-carboxaldehyde and free amines (α-amino acid esters) affording unstable imines that were directly reduced in‑situ using the H2/Pd/C system (Scheme 2, Table 1). The starting 2‑phenylimidazole-4-carboxaldehyde is accessible via condensation of dihydroxyacetone with benzamidine in liquid ammonia and oxidation of the resulting hydroxymethyl intermediate with concentrated nitric acid [25]. The amino acid esters hydrochlorides were prepared by a known method [26], whereas the free amino bases were liberated in-situ using triethylamine.
Scheme 2. The reductive amination leading to ligands 3a-f.
Scheme 2. The reductive amination leading to ligands 3a-f.
Molecules 13 02326 g004
Table 1. Bidentate ligands 3a-f.
Table 1. Bidentate ligands 3a-f.
Comp.R / Source of chiralityYield [%]e.e. [%][α]D20 (c 0.05, CH3OH)
3aCH3 / (S)-Alanine56> 95-8.9
3bCH(CH3)2 / (S)-Valine73> 95-22.8
3cCH2CH(CH3)2 / (S)-Leucine34> 95-22.0
3dCH(CH3)CH2CH3 / (S)-Isoleucine38> 95-9.2
3eCH2Ph / (S)-Phenylalanine66> 95-13.4
3fPh / (R)-Phenylglycine23> 95-16.7
Synthesis of the second series 4 started from 2-phenyl-4-carboxylic acid 5 and its activation through acylchlorides (Method A) or mixed anhydrides (Method B, see the Experimental section for more details). Although alternative and more convenient methods for activation of the carboxylic function are well known (e.g. transformation into esters or in-situ activation using DCC or CDI), we found these methods unfeasible for 5 [24]. Thus, only 5 activated in the two ways mentioned could be condensed with the chiral amines 6a-e (Scheme 3, Table 2) obtained from the corresponding N‑Cbz-α-amino acids and their transformation into the corresponding α‑diazoketones and α‑bromoketones, respectively, followed by condensation with benzamidine. Finally, Cbz-group removal afforded the desired free amines 6a-e [4]. In addition, the commercially available (S)‑1‑phenylethanamine 6f was employed as the starting chiral amine as well as affording the bidentate ligand 4f.
Scheme 3. Synthesis of tridentate ligands 4a-e and ligand 4f.
Scheme 3. Synthesis of tridentate ligands 4a-e and ligand 4f.
Molecules 13 02326 g005
Comparing both methods, Method B utilizing mixed anhydrides was operationally simpler, providing also higher yields, while the yields were solely affected by the undesired formation of the carbamic function on the imidazole nitrogen. Both the activating or condensing steps require careful pH control. Triethylamine as a base maintained the free reactive amino group while scavenging the hydrogen chloride produced during both reactions. The optimal pH value was revealed to be about 9 (possible risk of racemization at higher pH values).
Table 2. Tridentate 4a-e and bidentate ligand 4f.
Table 2. Tridentate 4a-e and bidentate ligand 4f.
Comp.R / Source of chiralityYield[a] [%]e.e. [%][α]D20 (c 0.05, CH3OH)
4aCH3 / (S)-Alanine23/24> 95+95.6
4bCH(CH3)2 / (S)-Valine30/35> 95+48.0
4cCH2CH(CH3)2 / (S)-Leucine16/25> 95+48.8
4dCH(CH3)CH2CH3 / (S)-Isoleucine13/34> 95+36.0
4eCH2Ph / (S)-Phenylalanine17/22> 95+33.0
4fCH3 / (S)-1-Phenylethanamine44/42> 95+142.0
[a] Isolated yields for Methods A/B

Asymmetric catalysis

Enantioselectivities of the ligands prepared were examined in the Henry reaction [27]. Its asymmetric version involves a reaction between aldehyde and nitroalkane catalyzed by the chiral ligands chelating mainly copper (II) [28,29], zinc [30] or rare earth metal salts [31] (Scheme 4).
Scheme 4. Asymmetric version of the Henry reaction.
Scheme 4. Asymmetric version of the Henry reaction.
Molecules 13 02326 g006
This reaction serves as a basic screening of the enantioselectivity giving the first insight into the catalytic behaviour of the studied ligands. The yields and enantiomeric excesses (ee) achieved for ligands 3a-f and 4a-f as well as for the precedent ligands 1a-f [24] and 2a-c, 2e [17] are summarized in Table 3. When comparing the attained chemical yields for series 1 and 3, we can deduce that the amines (series 3) are more efficient catalysts/bases than less nucleophilic amides (series 1).
Table 3. The Henry reaction – yields and enantiomeric excesses.
Table 3. The Henry reaction – yields and enantiomeric excesses.
Molecules 13 02326 i001 Molecules 13 02326 i002
Lig.R Molecules 13 02326 i003Yield [%]ee [%]Lig.R Molecules 13 02326 i004Yield [%]ee [%]
3aCH3H, H98104aCH3O9410
3bCH(CH3)2H, H9674bCH(CH3)2O916
3cCH2CH(CH3)2H, H94154cCH2CH(CH3)2O9414
3dCH(CH3)CH2CH3H, H97104dCH(CH3)CH2CH3O898
3eCH2PhH, H95144eCH2PhO9915
3fPhH, H9394fsee Scheme 3O915
1a[a]CH3O7912a[b]CH3H, H9413
1b[a]CH(CH3)2O8432b[b]CH(CH3)2H, H9513
1c[a]CH2CH(CH3)2O8582c[b]CH2CH(CH3)2H, H9615
1d[a]CH(CH3)CH2CH3O9142d[c]CH(CH3)CH2CH3H, H--
1e[a]CH2PhO9032e[b]CH2PhH, H9619
1f[a]PhO704
[a] Taken from Ref. [24] [b] Taken from Ref. [17] [c] No available data.
Although the enantiomeric excesses for both series are poor, the attained ee values have the same trend as those for the chemical yields. As a general trend, the attained ee’s increase throughout the data in Table 3 along with an increased bulk of the substituent R (e.g. the highest ee measured for derivatives with bulky benzyl group – ligands 3e and 4e). Comparison of the chemical yields for series 2 and 4 is less straightforward. The catalytic activity/basicity of the tridentate ligands is most likely given by the presence of two imidazole moieties. However, the attained enantiomeric excesses were slightly higher for the amines (series 2).

Conclusions

We have synthesized two new classes of compounds bearing either amino or amide bonds. The first series 3, where an imidazole ring and α-amino acid ester auxiliaries were linked via an amine, was obtained by the simple reductive amination. The second series 4 was comprised of tridentate ligands containing two 2-phenylimidazole groups bonded through an amide bond. Tridentate ligands 4e-f were prepared from the corresponding 2-phenyl-4-carboxylic acid employing two activation methods followed by condensation with either synthetically accessible or commercially available amines. The method of activation utilizing benzylchloroformate (Method B) proved to be more efficient than the method proceeding through the corresponding acylchloride (Method A). The optical purities of compounds 3af as well as 4a-f preserve those from the starting α-amino acids or amines used (as determined by 1H-NMR spectra measured with Mosher’s acid; for representative 1H-NMR spectra see Figure 1 and Figure 2 ).
Figure 1. 1H-NMR spectra of (S)-4b measured with (R)-Mosher’s acid (d6-acetone) used for the ee’s determination.
Figure 1. 1H-NMR spectra of (S)-4b measured with (R)-Mosher’s acid (d6-acetone) used for the ee’s determination.
Molecules 13 02326 g001
Figure 2. 1H-NMR spectra of (rac)-4b measured with (R)-Mosher’s acid (d6-acetone) used for the ee’s determination (compare in particular the 2-H signals with (S)-4b on the Figure 1).
Figure 2. 1H-NMR spectra of (rac)-4b measured with (R)-Mosher’s acid (d6-acetone) used for the ee’s determination (compare in particular the 2-H signals with (S)-4b on the Figure 1).
Molecules 13 02326 g002
The enantioselectivity of both ligand series were examined in the Henry reaction. Whereas the amines as well as the amides were able to catalyze the reaction, both compared amine series (2 and 3) revealed to be more efficient catalysts (stronger bases), while higher yields were observed. In general, the attained enantiomeric excesses were poor nevertheless higher ee’s were measured for the amines as well as for the ligands bearing bulkier substituents.

Experimental

General

The 2-phenylimidazole-4-carbaldehyde [25], α-amino acid esters [26], 2-phenylimidazole-4-carboxylic acid (5) [24] and chiral amines 6a-e [4] were synthesized according to literature procedures. (R)‑Mosher’s acid refers to (R)-(+)-α-methoxy-α-trifluoromethylphenylacetic acid (Aldrich). The Henry reaction was carried out under the conditions given in [17]. Reagents and solvents (reagent grade) were purchased from Aldrich or Fluka and used as received. THF was freshly distilled from Na/benzophenone under N2. Evaporation and concentration in vacuo were performed at water aspirator pressure. The reductive aminations were carried out in a ROTH pressure vessel. Column chromatography (CC) was carried out with SiO2 60 (particle size 0.040-0.063 mm, 230-400 mesh; Merck) and commercially available 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 (M.p.) were measured on a Büchi B-540 melting-point apparatus in open capillaries and are uncorrected. 1H- and 13C-NMR spectra were recorded in CD3OD at 500 MHz or 125 MHz, respectively, with Bruker AVANCE 500 instrument at 20 °C. Chemical shifts are reported in ppm relative to the signal of Me4Si. Residual solvent signals in the 1H and 13C-NMR spectra were used as an internal reference (CD3OD – 3.31 and 49.15 ppm for 1H- and 13C-NMR, respectively). Coupling constants (J) are given in Hz. The apparent resonance multiplicity is described as s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). 2-Phenyl protons in compounds 3a-f and 4a-f were marked as ArH. 5-Imidazole protons in compounds 4a-e were marked as HImL/HImR (left/right imidazole ring according to the scheme in Table 3). Additional NMR techniques such as 1H-1H COSY, HMBC, and HMQC spectra were further used for regular signal assignment (especially for distinguishing HImL and HImR signals in compounds 4a-f, and for regular carbon assignment). 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 [α] values [17].

General method for reductive amination. Preparation of 3a-f

Catalyst - Pd/active carbon (0.05 g; 10%, Aldrich®) was added to a solution of 2-phenylimidazole-4-carbaldehyde (0.40 g; 2.3 mmol) and α‑amino acid ester (2.3 mmol) in dry methanol (15 mL) and triethylamine (0.35 mL; 2.4 mmol). The solution was degassed and saturated with hydrogen in an autoclave at 1 MPa at 55 °C for 2 h. The catalyst was filtered off, washed with methanol and the filtrate concentrated in vacuo. The crude product was purified by CC (SiO2; ethyl acetate/methanol 4:0.7).
(2S)-Methyl 2-[(2-phenyl-1H-imidazol-4-yl)methylamino]propanoate (3a). Prepared from (S)-alanine methyl ester hydrochloride in 56% yield; m.p. 145-146 ºC; [α]D20 = -8.9 (c 0.05, CH3OH); 1H-NMR: δ = 1.34 (3H, d, J = 7.0, CH3), 3.50 (1H, q, J = 7.0, CHNH), 3.70 (3H, s, OCH3), 3.77 (1H, d, J = 13.8, CH2NH), 3.83 (H, d, J = 13.8, CH2NH), 7.07 (1H, s, HIm), 7.37 (1H, t, J = 7.4, ArH), 7.44 (2H, t, J = 7.4, ArH,), 7.85 (2H, d, J = 7.4, ArH); 13C-NMR: δ = 18.5 (CH3), 44.5 (CH2NH), 52.7 (OCH3), 56.60 (CHNH), 122.1 (C5Im), 126.5 (ArH), 130.0 (ArH), 130.1 (ArH), 131.4 (Arq), 137.6 (C4Im), 148.3 (C2Im), 176.4 (COOCH3); Elemental analysis (%) calcd. for C14H17N3O2: C 64.85, H 6.61, N 16.20; found: C 64.90, H 6.58, N 16.23.
(2S)-Methyl 3-methyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]butanoate (3b). Prepared from (S)-valine methyl ester hydrochloride in 73% yield; m.p. 141-142 ºC; [α]D20 = -22.8 (c 0.05, CH3OH); 1H-NMR: δ = 0.91 (3H, d, J = 6.9, (CH3)2), 0.94 (3H, d, J = 6.9, (CH3)2), 1.91-1.97 (1H, m, CH(CH3)2), 3.11 (1H, d, J = 5.8, CHNH), 3.65 (3H, s, OCH3), 3.67 (1H, d, J = 14.0, CH2NH), 3.77 (1H, d, J = 14.0, CH2NH), 6.99 (1H, s, HIm), 7.36 (1H, t, J = 7.5, ArH), 7.42 (2H, t, J = 7.5, ArH), 7.84 (2H, d, J = 7.5, ArH); 13C-NMR: δ 19.3 ((CH3)2), 32.7 (CH(CH3)2), 45.3 (CH2NH), 52.4 (OCH3), 67.5 (CHNH), 122.2 (C5Im), 126.4 (ArH), 129.8 (ArH), 130.1 (ArH), 131.6 (Arq), 138.2 (C4Im), 148.1 (C2Im), 176.5 (COOCH3); Elemental analysis (%) calcd. for C16H21N3O2: C 66.88, H 7.37, N 14.62; found: C 66.91, H 7.33, N 14.60.
(2S)-Methyl 4-methyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]pentanoate (3c). Prepared in 34% yield from (S)-leucine methyl ester hydrochloride; m.p. 115-117 °C; [α]D20 = -22.0 (c 0.05, CH3OH); 1H-NMR: δ = 0.85 (3H, d, J = 6.6, (CH3)2), 0.92 (3H, d, J = 6.6, (CH3)2), 1.47-1.52 (2H, m, CH2CH), 1.66-1.70 (1H, m, CH(CH3)2), 3.38 (1H, t, J = 7.2, CHNH), 3.67 (3H, s, OCH3), 3.68 (1H, d, J = 13.9, CH2NH), 3.79 (1H, d, J = 13.9, CH2NH), 7.01 (1H, s, HIm), 7.37 (1H, t, J = 7.5, ArH), 7.44 (2H, t, J = 7.5, ArH), 7.84 (2H, d, J = 7.2, ArH); 13C-NMR: δ = 23.0 (CH3)2), 23.1 (CH3)2), 26.2 (CH(CH3)2), 43.7 (CH2CH), 45.0 (br, CH2NH), 52.4 (OCH3), 60.2 (CHNH), 122.2 (C5Im), 126.5 (ArH), 129.9 (ArH), 130.1 (ArH), 131.6 (Arq), 148.2 (C2Im), 177.2 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C17H23N3O2: C 67.75, H 7.69, N 13.94; found: C 67.73, H 7.72, N 13.98.
(2S,3S)-Methyl 3-methyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]pentanoate (3d). Prepared from (2S,3S)-isoleucine methyl ester hydrochloride in 38% yield; m.p. 93-98 °C; [α]D20 = -9.2 (c 0.05, CH3OH); 1H-NMR: δ = 0.87-0.93 (6H, m, CHCH3 and CH2CH3), 1.17-1.24 (1H, m, CH2CH3), 1.50-1.55 (1H, m, CH2CH3), 1.70-1.72 (1H, m, CHCH3), 3.23 (1H, d, J = 5.7, CHNH), 3.65 (3H, s, OCH3), 3.67 (1H, d, J = 14.0, CH2NH), 3.77 (1H, d, J = 14.0, CH2NH), 6.99 (1H, s, HIm), 7.36 (1H, t, J = 7.4, ArH), 7.43 (2H, t, J = 7.4, ArH), 7.84 (2H, d, J = 7.8, ArH); 13C-NMR: δ = 12.0 (CH2CH3), 15.9 (CHCH3), 27.1 (CH2CH3), 39.7 (CHCH3), 45.3 (CH2NH), 52.1 (OCH3), 66.1 (CHNH), 122.2 (C5Im), 126.7 (ArH), 129.9 (ArH), 130.1 (ArH), 131.6 (Arq), 148.2 (C2Im), 176.4 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C17H23N3O2: C 67.75, H 7.69, N 13.94; found: C 67.72, H 7.73, N 13.96.
(2S)-Methyl 3-phenyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]propanoate (3e). Prepared from (S)-phenylalanine methyl ester hydrochloride in 66% yield; m.p. 165-166 °C; [α]D20 = -13.4 (c 0.05, CH3OH); 1H-NMR: δ = 2.94 (2H, 2, J = 9.7, CH2Ph), 3.58 (3H, s, OCH3), 3.61 (1H, t, J = 7.1, CHNH), 3.68 (1H, d, J = 14.0, CH2NH), 3.78 (1H, d, J = 14.0, CH2NH), 6.92 (1H, s, HIm), 7.14-7.30 (5H, m, Ph), 7.36 (1H, t, J = 7.0, ArH), 7.43 (2H, t, J = 7.7, ArH), 7.81 (2H, d, J = 7.3, ArH); 13C-NMR: δ = 40.4 (CH2Ph), 45.2 (br, CH2NH), 52.3 (OCH3), 63.3 (CHNH), 122.3 (C5Im), 126.5 (ArH), 127.9 (Ph), 129.6 (Ph), 129.9 (ArH), 130.1 (ArH), 130.4 (Ph), 131.5 (Arq), 138.6 (Phq), 148.2 (C2Im), 176.0 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C20H21N3O2: C 71.62, H 6.31, N 12.53; found: C 71.65, H 6.25, N 12.59.
(2S)-Methyl 2-phenyl-2-[(2-phenyl-1H-imidazol-4-yl)methylamino]ethanoate (3f). Synthesized from (S)-glycine methyl ester hydrochloride in 23% yield; m.p. 157-158 °C; [α]D20 = -16.7 (c 0.05, CH3OH); 1H-NMR: δ = 3.63 (3H, s, OCH3), 3.73 (2H, s, CH2NH), 4.47 (1H, s, CHNH), 7.00 (1H, s, HIm), 7.28-7.44 (8H, m, ArH and Ph), 7.84 (2H, d, J = 7.4, ArH); 13C-NMR: δ = 44.3 (CH2NH), 52.8 (OCH3), 65.7 (CHNH), 122.4 (C5Im), 126.5 (ArH), 129.7 (Ph), 129.5 (Ph), 129.9 (Ph), 130.0 (ArH), 130.1 (ArH), 131.5 (Arq), 139.1 (Phq), 148.3 (C2Im), 174.6 (COOCH3), C4Im is missing; Elemental analysis (%) calcd. for C19H19N3O2: C 71.01, H 5.96, N 13.08. Found: C 71.07, H 6.03, N 12.99.

General procedure for the preparation of 4a-f

Method A 

Thionyl chloride (5 mL; 69 mmol) was added dropwise to a stirred and ice-cooled suspension of 5 (1.0 g; 5.3 mmol) in dry THF (200 mL). The reaction mixture was refluxed for 6 h, all of the volatiles evaporated in vacuo and the crude acylchloride used in the next step without further purification. A solution of the amine 6a-f (4.7 mmol) in dry THF (30 mL) was added dropwise to a stirred and ice-cooled solution of the above acylchloride (1 g; 4.8 mmol) in dry THF (180 mL), followed by gradual addition of triethylamine (1.5 mL, 10.7 mmol) as rapidly as pH doesn’t exceed 7. The reaction mixture was stirred for 12 h at 25 ºC, the precipitated triethylamine hydrochloride filtered off, the filtrate concentrated in vacuo and the residue purified by CC (SiO2; ethyl acetate/methanol 4:0.7).

Method B 

Benzylchlorofomate (0.97 mL 6.8 mmol) was added dropwise to a solution of 5 (1.0 g; 5.3 mmol) and triethylamine (1.5 mL; 10.8 mmol) in dry THF (200 mL) under N2 at -10º. The reaction mixture was stirred for an additional 30 min whereupon a solution of amine 6a-f (5.2 mole) in dry THF (30 mL) was added. The reaction was stirred for 12 h at 25 ºC, the precipitated triethylamine hydrochloride filtered off, the filtrate concentrated in vacuo and the crude product purified by CC (SiO2; ethyl acetate/methanol 4:0.7).
(1S)-2-Phenyl-N-[1-(2-phenyl-1H-imidazol-4-yl)ethyl]-1H-imidazole-4-carboxamide (4a). This compound was synthesized from amine 6a in yields of 23 (method A) and 24% (method B), respectively; m.p. 134-135 °C; [α]D20 = +95.6 (c 0.05, CH3OH). 1H-NMR: δ = 1.62 (3H, d, J = 6.9, CH3), 5.32 (1H, q, J = 6.9, CHNH), 7.08 (1H, s, HImR), 7.31-7.43 (6H, m, ArH), 7.73 (1H, s, HImL), 7.84 (2H, d, J = 7.3, ArH), 7.89 (2H, d, J = 7.1, ArH). 13C-NMR: δ = 21.2 (CH3), 44.1 (CHNH), 118.4 (C5ImR), 123.4 (C5ImL), 126.7 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.0 (Arq), 131.4 (Arq), 137.2 (C4ImL), 143.1 (C4ImR), 148.4 (C2ImR), 148.9 (C2ImL), 164.2 (CONH). Elemental analysis (%) calcd. for C21H19N5O: C 70.57, H, 5.36; N, 19.59. Found: C, 70.55; H, 5.40; N, 19.54.
(1S)-N-[2-Methyl-1-(2-phenyl-1H-imidazol-4-yl)propyl]-2-phenyl-1H-imidazole-4-carboxamide (4b). This compound was synthesized from amine 6b in yields of 30 (method A) and 35% (method B), respectively; m.p. 127-128 °C; [α]D20 = +48.0 (c 0.05, CH3OH). 1H-NMR: δ = 0.95 (3H, d, J = 6.7, (CH3)2), 1.06 (3H, d, J = 6.7, (CH3)2), 2.29-2.35 (1H, m, CH(CH3)2), 5.04 (1H, d, J = 5.8, CHNH), 7.09 (1H, s, HImR), 7.30-7.44 (6H, m, ArH), 7.74 (1H, s, HImL), 7.85 (2H, d, J = 7.3, ArH), 7.91 (2H, d, J = 7.2, ArH). 13C-NMR: δ = 19.4 ((CH3)2), 20.4 ((CH3)2), 34.2 (CH(CH3)2), 54.1 (CHNH), 119.2 (C5ImR), 123.1 (C5ImL), 126.4 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.1 (Arq), 131.5 (Arq), 137.5 (C4ImL), 141.1 (C4ImR), 148.2 (C2ImR), 148.8 (C2ImL), 164.6 (CONH). Elemental analysis (%) calcd. for C23H23N5O: C 71.67, H 6.01, N 18.17. Found: C 71.66, H 5.97, N 18.20.
(1S)-N-[3-Methyl-1-(2-phenyl-1H-imidazol-4-yl)butyl]-2-phenyl-1H-imidazole-4-carboxamide (4c). This compound was synthesized from amine 6c in yields of 16 (method A) and 25% (method B), respectively; m.p. 155-157 °C; [α]D20 = +48.8 (c 0.05, CH3OH). 1H-NMR: δ = 0.99 (6H, deceptively t, J = 6.2, (CH3)2), 1.66-1.71 (1H, m, CH(CH3)2), 1.87 (2H, t, J = 6.9, CH2CH), 5.35 (1H, t, J = 7.5, CHNH), 7.07 (1H, s, HImR), 7.31-7.45 (6H, m, ArH), 7.73 (1H, s, HImL), 7.85 (2H, d, J = 7.2, ArH), 7.90 (2H, s, J = 7.2, ArH). 13C-NMR: δ = 22.8 ((CH3)2), 23.3 ((CH3)2), 26.4 (CH(CH3)2), 45.4 (CH2CH), 46.4 (CHNH), 118.7 (C5ImR), 123.0 (C5ImL), 126.6 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.1 (Arq), 131.6 (Arq), 138.1 (C4ImL), 142.3 (C4ImR), 148.4 (C2ImR), 148.8 (C2ImL), 165.1 (CONH). Elemental analysis (%) calcd. for C24H25N5O: C 72.16, H 6.31, N 17.53. Found: C 72.15, H 6.36, N 17.50.
(1S,2S)-N-[2-Methyl-1-(2-phenyl-1H-imidazol-4-yl)butyl]-2-phenyl-1H-imidazole-4-carboxamide (4d). This compound was synthesized from amine 6d in yields of 13 (method A) and 34% (method B), respectively; m.p. 144-145 °C; [α]D20 = +36.0 (c 0.05, CH3OH). 1H-NMR: δ = 0.93 (3H, d, J = 6.7, CHCH3), 0.96 (3H, t, J = 7.5, CH2CH3), 1.25-1.30 (1H, m, CH2CH3), 1.68-1.73 (1H, m, CH2CH3), 2.09-2.14 (1H, m, CHCH3), 5.09 (1H, d, J = 8.2, CHNH), 7.09 (1H, s, HImR), 7.30-7.46 (6H, m, ArH), 7.73 (1H, s, HImL), 7.85 (2H, d, J = 7.4, ArH), 7.92 (2H, d, J = 7.3, ArH). 13C-NMR: δ = 11.8 (CH3CH), 16.6 (CH3CH2), 26.6 (CH2CH3), 40.4 (CHCH3), 52.8 (CHNH), 119.0 (C5ImR), 123.6 (C5ImL), 126.6 (ArH), 126.9 (ArH), 129.9 (ArH), 130.0 (ArH), 130.1 (ArH), 130.5 (ArH), 131.1 (Arq), 131.5 (Arq), 137.8 (C4ImL), 141.3 (C4ImR), 148.2 (C2ImR), 148.8 (C2ImL), 165.0 (CONH). Elemental analysis (%) calcd. for C24H25N5O: C 72.16, H 6.31, N 17.53. Found: C 72.23, H 6.25, N 17.61.
(1S)-2-Phenyl-N-[2-phenyl-1-(2-phenyl-1H-imidazol-4-yl)ethyl]-1H-imidazole-4-carboxamide (4e). This compound was synthesized from amine 6e in yields of 17 (method A) and 22% (method B), respectively; m.p. 187-188 °C; [α]D20 = +33.0 (c 0.05, CH3OH). 1H-NMR: δ = 3.23-3.35 (2H, m, CH2Ph), 5.49 (1H, t, J = 7.3, CHNH), 6.97 (1H, s, HImR), 7.11 (1H, t, J = 7.3, Ph), 7.19 (2H, t, J = 7.3, Ph), 7.22 (2H, d, J = 7.2, Ph), 7.32-7.44 (6H, m, ArH), 7.69 (1H, s, HImL), 7.86 (2H, d, J = 7.4, ArH), 7.89 (2H, d, J = 7.2, ArH). 13C-NMR: δ = 42.5 (CH2Ph), 50.1 (CHNH), 118.6 (C5ImR), 123.7 (C5ImL), 126.6 (ArH), 126.9 (ArH),, 127.6 (Ph), 129.4 (ArH), 129.9 (Ph), 130.0 (ArH), 130.1 (ArH), 130.5 (Ph), 131.1 (Arq), 131.5 (Arq), 137.9 (C4ImL), 139.5 (Phq), 141.6 (C4ImR), 148.4 (C2ImR), 148.8 (C2ImL), 164.5 (CONH). Elemental analysis (%) calcd. for C27H23N5O: C 74.81, H 5.35, N 16.16. Found: C 74.78, H 5.41, N 16.14.
(1S)-2-Phenyl-N-(1-phenylethyl)-1H-imidazole-4-carboxamide (4f). This compound was synthesized from commercially available (S)-1-phenylethanamine (6f) in yields of 44 (method A) and 42% (method B), respectively; m.p. 163-164 °C; [α]D20 = +142.0 (c 0.05, CH3OH). 1H-NMR: δ = 1.55 (3H, d, J = 7.0, CH3), 5.21 (1H, q, J = 7.0, CHNH), 7.22 (1H, t, J = 7.4, Ph), 7.31 (2H, t, J = 7.4, Ph), 7.39-7.48 (5H, m, ArH and Ph), 7.72 (1H, s, HIm), 7.91 (2H, d, J = 7.1, ArH). 13C-NMR: δ = 22.7 (CH3), 50.2 (CHNH), 122.8 (C5Im), 126.9 (ArH), 127.3 (ArH), 128.3 (Ph), 129.7 (Ph), 130.2 (ArH), 130.6 (Ph), 131.1 (Arq), 145.2 (Phq), 148.6 (C2Im), 164.2 (CONH). Elemental analysis (%) calcd. for C18H17N3O: C 74.20, H 5.88, N 14.42. Found: C 74.17, H 5.85, N 14.46.

Acknowledgements

This research was supported by the Ministry of Education, Youth and Sport of the Czech Republic (MSM 0021627501).

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  • Sample Availability: Samples of compounds 3a-f and 4a-f are available from the authors.
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