DOI:
10.1039/C4QO00034J
(Research Article)
Org. Chem. Front., 2014,
1, 240-246
Copper-catalyzed three-component synthesis of 5-acetamidoimidazoles from carbodiimides, acyl chlorides and isocyanides†
Received
31st January 2014
, Accepted 23rd February 2014
First published on 28th February 2014
Abstract
Only very limited methods are available for the synthesis of 5-amino imidazoles. We report in this paper that three-component reaction of acyl chlorides, carbodiimides and α-isocyanoacetates or TosMIC took place smoothly in the presence of Et3N (2.5 equiv.) and a catalytic amount of copper iodide (0.2 equiv.) to afford 1,4-disubstituted 5-acetamidoimidazoles in good yields.
Introduction
Functionalized imidazole-containing compounds have found a broad range of applications in pharmaceuticals and in organic synthesis.1,2 Among them, the 5-aminoimidazole, a sub-class of this important family of heterocycles, is present in some biologically important natural products and medicinally relevant synthetic compounds. For example, 5-aminoimidazole ribonucleotide (AIR) (1) is an essential intermediate in the de novo biosynthesis of purine ribonucleotides3 and thiamin.4 5-Amino-4-carboxamide-1-β-D-ribofuranoside (AICAR) (2) is a commonly used AMP-kinase activator employed to treat and protect against cardiac ischemic injury.5 The arabinosyl amidine 3 is a synthetic precursor and potential prodrug of 9-β-D-arabinofuranosyladenine (4, Ara-A), a valuable anti-tumor drug.6 The amino-imidazole motif is also found in important natural products such as coformycin (5), a potent inhibitor of adenosine deaminase with anticancer and antiviral properties (Fig. 1).7 Obviously, substituted 5-aminoimidazoles are also useful intermediates in the synthesis of purine,8 and the purine-derived natural products. For example, heteromine A (6a) and B (6b),9 cytotoxic against several cancer cell lines, have been synthesized from 5-amino-4-cyanoimidazole.10 Additionally, it is interesting to note that condensation of 5-amino-4-cyanoimidazole with formamidine has been proposed as a possible prebiotic pathway to adenine.11
![image file: c4qo00034j-f1.tif](/image/article/2014/QO/c4qo00034j/c4qo00034j-f1.gif) |
| Fig. 1 5-Acetamidoimidazole-containing compounds. | |
In light of the importance of the functionalized imidazoles, many synthetic methods have been developed for the construction of this heterocycle as well as for the regio-selective functionalization of the imidazole ring.1 However, only very limited methods are currently available for the synthesis of 5-aminoimidazoles. Among them, the three-step synthesis from α-aminomalonitriles, orthoformates and primary amines developed by Shaw and co-workers has been widely adopted by synthetic and medicinal chemists.6,8,12 Alternatively, Bartlett developed an elegant synthesis of 5-amino-imidazole-4-carboxylic ester by condensation of isothioureas with the pre-formed enolate of ethyl isocyanoacetate (five examples with yields ranging from 30 to 75%).13
The lack of synthetic methodologies to 5-amino-imidazole stimulated our interest in developing a one-pot synthesis of this important heterocycle. We report herein a CuI-catalyzed three-component reaction of carbodiimides 7, acyl chlorides 8 and isocyanides 9 for the synthesis of 1,4-disubstituted 5-acetamidoimidazoles 10 in good yields (Scheme 1).14,15
![image file: c4qo00034j-s1.tif](/image/article/2014/QO/c4qo00034j/c4qo00034j-s1.gif) |
| Scheme 1 Three-component synthesis of substituted 5-acetamidoimidazoles. | |
Results and discussion
By virtue of the carbene-like reactivity of its divalent carbon, isocyanides are key components used in the development of classic Passerini-3CR,16 Ugi-4CR17 and their variants thereof.18 On the other hand, carbodiimides19 have only scarcely been exploited in multicomponent reactions, although they are also capable of reacting with both nucleophiles and electrophiles.20 In connection with our ongoing project on the development of isocyanide-based multicomponent reactions,21 we became interested in investigating the reaction of isocyanides, carbodiimides in the presence of external electrophiles and as a prelude, acyl chlorides were chosen for the present study.
N,N′-Dicyclohexylcarbodiimide (DCC, 7a), acetyl chloride (8a) and ethyl α-isocyanoacetate (9a) were selected as test substrates to survey the reaction conditions. It is known that carbodiimides can be pre-activated by acyl chlorides,22 facilitating the subsequent nucleophilic addition. Recent work from Zhang and Xi has provided convincing evidence that the reaction between 7 and 8 afforded isolable N-acyl chloroformamidine 11 that is susceptible to react with a range of nucleophiles including water, 1,3-dicarbonyls, terminal alkynyl, (thio)urea, sodium hydrosulfide etc.23 Since isocyanide can also react with acyl chloride spontaneously,24 the addition order of substrates is therefore an important factor that will determine the outcome of the reaction. In the present study, a protocol involving first mixing of 7a and 8a followed by addition of 9a was adopted. While 7a and 8a reacted spontaneously to produce 11a, conditions for its subsequent reaction with 9a needed to be carefully optimized. Reaction of the isolated N-acyl chloroformamidine 11a with the pre-formed enolate of 9a afforded the desired heterocycle in only low to moderate yield (≤40%) regardless of the nature of the base (Et3N, DBU, K2CO3, Li2CO3, Cs2CO3, CsF, NaH, BuLi, LHMDS, KHMDS) and the solvent (DCM, MeCN, THF, DMSO) used. We then turned our attention to the Lewis acid-catalyzed (mediated) conditions.25,26 After having screened the metal salts (AgOTf, Ag3PO4, CuO, CuSO4, Cu(OAc)2, CuCl, CuBr, CuI), the solvents (DCM, MeCN, THF, DMSO), the additives (TMEDA, DABCO, HMPA, 18-C-6) and the temperature, the optimum conditions found consisted of mixing 7a and 8a at 0 °C for 20 min followed by addition of ethyl isocyanoacetate (9a) in MeCN (c = 0.3 M), CuI (0.2 equiv.) and Et3N (2.5 equiv.) at room temperature. Under these conditions, we were able to isolate 10a in 77% yield (Scheme 2).
![image file: c4qo00034j-s2.tif](/image/article/2014/QO/c4qo00034j/c4qo00034j-s2.gif) |
| Scheme 2 Optimized conditions for the three-component synthesis of 5-acetamidoimidazole. | |
The scope of the reaction was next investigated (Table 1). Both DCC and DIC can be successfully used for this reaction. Primary and secondary aliphatic acid chlorides incorporating a variety of functional groups (alkyl halides, conjugated or isolated double bond, ester) were well-accepted substrates furnishing the imidazoles in good yields. However, the aromatic acid chlorides provided the imidazoles with reduced yields (entries 13, 14). t-Butyl α-isocyanoacetate participated also in this reaction (entry 18) giving 10r in moderate yield. p-Toluenesulfonylmethyl isocyanide (TosMIC) participated in this 3CR as well to afford the corresponding 1-alkyl-4-tosyl-5-acetamidoimidazoles (entries 19, 20).
Upon mixing an equal molar of 11a with CuI, we observed a rapid disappearance of 11a leading to a polar compound that we assumed to be the N-acylimminium salt 12.27 Addition of ethyl α-isocyanoacetate 9a to the reaction mixture led to the formation of 10a. Based on this control experiment, we proposed the following reaction pathway to account for the formation of 1,4-disubstituted 5-acetamidoimidazoles 10 (Scheme 3). Reaction of carbodiimide 7 with acyl chloride 8 gave the N-acyl chloroformamidine 11 that was converted to a hypothetic N-acylimminium salt 12 upon addition of CuI. On the other hand, deprotonation of the copper(I)-coordinated ethyl α-isocyanoacetate yielded enolate 13. Nucleophilic addition of 13 to 12 afforded an intermediate 14.28 Deprotonation of the remaining α-protons followed by intramolecular attack of the resulting secondary amine to the isonitrile carbon provided, after protonation, the observed imidazole 10.
![image file: c4qo00034j-s3.tif](/image/article/2014/QO/c4qo00034j/c4qo00034j-s3.gif) |
| Scheme 3 Plausible reaction pathway. | |
Conclusion
In summary, we developed a novel CuI-catalyzed three-component reaction of isocyanides, carbodiimides and acyl chlorides for the synthesis of 5-acetamidoimidazoles. To the best of our knowledge, this represented the first examples of one-pot synthesis of this type of imidazole. We are further exploiting the reactivity of these unique heterocycles for accessing other more complex heterocyclic scaffolds.29
Experimental
Mass spectra were determined with a Waters ACQUITY H-class UPLC/MS ACQ-SQD by electron ionisation (EI positive and negative) or with a Finnigan TSQ7000 by electrospray ionization (ESI+). The accurate masses were calculated by the mass spectrometry service of the EPFL by ESI-TOF using a QTOF Ultima from Waters. NMR spectra were recorded on a Brüker Avance III-400, Brüker Avance-400 or Brüker DPX-400 spectrometer at room temperature, the 1H frequency is at 400.13 MHz, and the 13C frequency is at 100.62 MHz. Chemical shifts δ) are reported in parts per million (ppm) from tetramethylsilane. NMR experiments were carried out in deuterochloroform (CDCl3). The following abbreviations are used for the multiplicities: s: singlet, d: doublet, m: multiplet for proton spectra. Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a Jasco FT/IR-4100 spectrometer outfitted with the PIKE technology. Melting points were determined using a Stuart SMP30 and were uncorrected. Flash column chromatography was performed using Silicycle silica gel: 230–400 mesh (40–63 μm). Reactions were monitored using Merck Kieselgel 60 F254 on aluminium sheets. TLCs were visualized by UV fluorescence (254 nm) and then with one of the following: KMnO4, ninhydrin, pancaldi, p-anisaldehyde or vanillin. All reagents were obtained from commercial suppliers unless otherwise stated.
General procedure for the three-component synthesis of 1,4-disubstituted 5-acetamidoimidazoles
Acyl chloride 8 (1.05 equiv.) was added dropwise to carbodiimide 7 (0.5 mmol) under Ar and the mixture was stirred at 0 °C for 20 min. To the reaction mixture were added a solution of α-isocyanoacetate 9 (2.0 equiv.) in acetonitrile (c, 0.3 M), CuI (0.2 equiv.) and Et3N (2.5 equiv.), successively. After being stirred at room temperature for 2–6 h, the reaction was quenched by addition of aqueous NH4OH (2.0 M) and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (DCM–EtOAc) to afford 5-acetamidoimidazole 10.
Ethyl 1-cyclohexyl-5-(N-cyclohexylacetamido)-1H-imidazole-4-carboxylate (10a).
Yellow solid, yield 77%; m.p. 163.9–166.2 °C; IR (neat): ν 3106 (w), 2937 (w), 2926 (m), 2856 (w), 1699 (m), 1666 (s), 1567 (m), 1493 (m), 1367 (m), 1224 (s), 1177 (s), 1040 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 4.39–4.24 (m, 3H), 3.89–3.79 (m, 1H), 2.10–1.87 (m, 5H), 1.79 (s, 3H), 1.77–1.67 (m, 5H), 1.65–1.53 (m, 2H), 1.46–1.21 (m, 5H), 1.33 (t, J = 7.1 Hz, 3H), 1.07–0.83 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 161.7, 133.6, 132.5, 127.8, 60.2, 57.0, 53.3, 35.0, 33.9, 31.5, 29.7, 25.4 (3C), 25.3, 25.0, 24.5, 22.5, 13.9; HRMS (ESI) calcd for C20H32N3O3+ [M + H]+ 362.2438; found 362.2435.
Ethyl 1-isopropyl-5-(N-isopropylacetamido)-1H-imidazole-4-carboxylate (10b).
Yellow solid, yield 75%; m.p. 162.4–163.3 °C; IR (neat): ν 3110 (w), 2974 (w), 2936 (w), 2163 (w), 1723 (s), 1659 (s), 1554 (w), 1498 (m), 1369 (m), 1313 (s), 1155 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 4.62–4.46 (m, 1H), 4.32–4.19 (m, 3H), 1.75 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.5 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 161.8, 133.3, 132.6, 127.9, 60.4, 49.6, 45.8, 24.4, 23.2, 22.7, 21.1, 19.9, 14.0; HRMS (ESI) calcd for C14H24N3O3+ [M + H]+ 282.1812; found 282.1810.
Ethyl 1-isopropyl-5-(N-isopropylpropionamido)-1H-imidazole-4-carboxylate (10c).
Yellow solid, yield 67%; m.p. 159.9–161.7 °C; IR (neat): ν 3105 (w), 2980 (w), 2938 (w), 2170 (w), 1724 (s), 1663 (s), 1554 (w), 1498 (m), 1418 (w), 1380 (s), 1241 (s), 1154 (s), 1111 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 4.67–4.58 (m, 1H), 4.39–4.23 (m, 3H), 2.19–2.08 (m, 1H), 1.85–1.75 (m, 1H), 1.55 (d, J = 6.9 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.11–1.00 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 174.6, 162.0, 133.4, 132.5, 128.1, 60.5, 49.9, 45.8, 27.9, 24.5, 23.5, 21.3, 20.1, 14.2, 9.0; HRMS (ESI) calcd for C15H26N3O3+ [M + H]+ 296.1969; found 296.1963.
Ethyl 1-cyclohexyl-5-(N-cyclohexylhexanamido)-1H-imidazole-4-carboxylate (10d).
Yellow oil, yield 67%; IR (neat): ν 3105 (w), 2918 (m), 2853 (w), 1735 (s), 1660 (s), 1562 (w), 1496 (m), 1396 (m), 1260 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 4.39–4.24 (m, 3H), 3.86–3.75 (m, 1H), 2.11–2.01 (m, 3H), 1.99–1.87 (m, 3H), 1.83–1.47 (m, 9H), 1.32–1.06 (m, 13H), 0.98–0.85 (m, 3H), 0.78–0.74 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 173.9, 162.0, 133.9, 132.6, 128.1, 60.5, 57.5, 53.5, 35.4, 34.5 (2C), 31.7, 31.4, 30.1, 25.7 (3C), 25.6, 25.4, 24.9, 24.5, 22.4, 14.2, 13.8; HRMS (ESI) calcd for C24H40N3O3+ [M + H]+ 418.3064; found 418.3067.
Ethyl 1-isopropyl-5-(N-isopropyl-3,3-dimethylbutanamido)-1H-imidazole-4-carboxylate (10e).
Yellow solid, yield 71%; m.p. 158.9–160.5 °C; IR (neat): ν 3106 (w), 2980 (w), 2943 (w), 2870 (w), 1724 (s), 1667 (s), 1554 (w), 1498 (m), 1463 (w), 1401 (m), 1370 (m), 1267 (m), 1171 (s), 1153 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 4.60–4.48 (m, 1H), 4.37–4.20 (m, 3H), 1.99 (d, J = 16.1 Hz, 1H), 1.67 (d, J = 16.0 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.49 (d, J = 6.8 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.99 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.6, 162.0, 133.3, 132.9, 128.1, 60.7, 49.9, 46.6, 45.7, 30.9, 29.7, 24.6, 23.9, 21.6, 20.1, 14.3; HRMS (ESI) calcd for C18H32N3O3+ [M + H]+ 338.2438; found 338.2435.
Ethyl 1-cyclohexyl-5-(N-cyclohexylpent-4-enamido)-1H-imidazole-4-carboxylate (10f).
Yellow oil, yield 65%; IR (neat): ν 3108 (w), 2929 (m), 2857 (w), 1737 (s), 1666 (s), 1560 (w), 1493 (m), 1444 (w), 1374 (m), 1223 (m), 1150 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 5.66–5.59 (m, 1H), 4.87–4.81 (m, 2H), 4.25–4.17 (m, 3H), 3.75–3.69 (m, 1H), 2.30–2.20 (m, 2H), 2.14–2.07 (m, 1H), 1.98–1.81 (m, 5H), 1.76–1.50 (m, 8H), 1.31–1.16 (m, 5H), 1.24 (t, J = 7.1 Hz, 3H), 1.01–0.78 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0, 162.0, 137.1, 133.9, 132.3, 128.1, 115.2, 60.5, 57.6, 53.4, 35.3, 34.4, 33.9, 31.6, 30.1, 28.8, 25.6 (3C), 25.5, 25.3, 24.8, 14.1; HRMS (ESI) calcd for C23H36N3O3+ [M + H]+ 402.2751; found 402.2753.
Ethyl 1-cyclohexyl-5-(N-cyclohexylisobutyramido)-1H-imidazole-4-carboxylate (10g).
Yellow oil, yield 66%; IR (neat): ν 3108 (w), 2932 (m), 2855 (w), 1712 (s), 1676 (s), 1553 (w), 1498 (m), 1452 (m), 1382 (s), 1359 (m), 1224 (s), 1170 (s), 1133 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 4.42–4.16 (m, 3H), 3.89–3.64 (m, 1H), 2.11–1.60 (m, 15H), 1.42–1.36 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.30–1.25 (m, 2H), 1.11–1.03 (m, 1H), 1.02 (d, J = 4.1 Hz, 3H), 1.00 (d, J = 4.0 Hz, 3H), 0.98–0.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 178.3, 162.1, 133.9, 132.6, 128.0, 60.6, 57.7, 53.4, 35.2, 34.9, 32.6, 31.9, 30.2, 25.84, 25.80, 25.7, 25.6, 25.5, 24.9, 20.4, 19.4, 14.3; HRMS (ESI) calcd for C22H36N3O3+ [M + H]+ 390.2751; found 390.2750.
Ethyl 1-isopropyl-5-(N-isopropylcyclohexanecarboxamido)-1H-imidazole-4-carboxylate (10h).
Yellow solid, yield 73%; m.p. 172.5–174.8 °C; IR (neat): ν 3102 (w), 2932 (m), 2854 (w), 1722 (s), 1655 (s), 1551 (w), 1498 (m), 1380 (s), 1338 (m), 1152 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 4.60–4.48 (m, 1H), 4.36–4.27 (m, 2H), 4.26–4.18 (m, 1H), 1.78–1.40 (m, 8H), 1.54 (d, J = 6.7 Hz, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.17–1.13 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 0.98–0.88 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 176.9, 161.8, 133.3, 132.6, 127.8, 60.4, 49.7, 45.5, 43.1, 30.2, 28.6, 25.3 (2C), 25.0, 24.1, 23.9, 21.5, 19.8, 14.1; HRMS (ESI) calcd for C19H32N3O3+ [M + H]+ 350.2438; found 350.2435.
Ethyl 1-isopropyl-5-(N-isopropylcyclopentanecarboxamido)-1H-imidazol-4-carboxylate (10i).
Yellow solid, yield 61%; m.p. 166.7–168.8 °C; IR (neat): ν 3337 (w), 3106 (w), 2962 (w), 2924 (w), 2872 (w), 2189 (w), 1723 (s), 1658 (s), 1557 (m), 1495 (m), 1382 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 4.57–4.50 (m, 1H), 4.36–4.21 (m, 3H), 2.21–2.13 (m, 1H), 1.83–1.62 (m, 6H), 1.55 (d, J = 6.8 Hz, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.43–1.36 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.1, 161.9, 133.4, 133.0, 128.1, 60.6, 50.2, 45.8, 43.1, 31.7, 31.4, 26.4, 26.1, 24.4, 23.8, 21.6, 20.2, 14.3; HRMS (ESI) calcd for C18H30N3O3+ [M + H]+ 336.2208; found 336.2287.
Ethyl 1-cyclohexyl-5-(N-cyclohexyl-2-phenylacetamido)-1H-imidazole-4-carboxylate (10j).
Yellow oil, yield 41%; IR (neat): ν 2934 (w), 2855 (w), 1725 (m), 1676 (s), 1564 (w), 1495 (w), 1452 (w), 1356 (m), 1224 (s), 1174 (s), 1132 (s), 1032 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.28–7.18 (m, 3H), 7.09–7.08 (m, 2H), 4.26–4.17 (m, 3H), 3.78–3.68 (m, 1H), 3.40 (d, J = 15.3 Hz, 1H), 3.30 (d, J = 15.3 Hz, 1H), 2.16–1.93 (m, 3H), 1.83–1.54 (m, 8H), 1.39–1.26 (m, 7H), 1.21–0.98 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 171.9, 162.1, 134.6, 134.1, 132.8, 129.1, 128.5, 126.8, 60.7, 58.7, 53.8, 41.5, 35.1, 34.9, 31.7, 30.1, 25.9, 25.88, 25.82, 25.7, 25.6, 24.9, 14.3; HRMS (ESI) calcd for C26H36N3O3+ [M + H]+ 438.2678; found 438.2757.
Ethyl 1-cyclohexyl-5-(N-cyclohexyl-2-phenoxyacetamido)-1H-imidazole-4-carboxylate (10k).
Yellow solid, yield 22%; m.p. 183.5–185.1 °C; IR (neat): ν 3108 (w), 2942 (w), 2851 (w), 1730 (s), 1683 (s), 1599 (w), 1496 (m), 1398 (m), 1261 (m), 1225 (s), 1172 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.23 (t, J = 7.9 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 8.1 Hz, 2H), 4.51 (d, J = 14.7 Hz, 1H), 4.36 (q, J = 6.9 Hz, 2H), 4.28–4.18 (m, 1H), 4.12 (d, J = 14.7 Hz, 1H), 3.96–3.83 (m, 1H), 2.16–2.03 (m, 2H), 1.98–1.85 (m, 3H), 1.82–1.72 (m, 5H), 1.69–1.59 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.33–0.96 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 169.1, 162.3, 158.3, 134.6, 131.1, 129.5, 128.6, 121.7, 114.9, 67.1, 61.1, 59.0, 53.9, 35.5, 34.8, 31.4, 29.9, 25.9, 25.8, 25.79, 25.72, 25.5, 24.9, 14.4; HRMS (ESI) calcd for C26H36N3O4+ [M + H]+ 454.2700; found 454.2703.
(E)-Ethyl 1-isopropyl-5-(N-isopropylbut-2-enamido)-1H-imidazole-4-carboxylate (10l).
Yellow oil, yield 69%; IR (neat): ν 2977 (w), 2934 (w), 2875 (w), 2356 (w), 1720 (s), 1673 (s), 1635 (s), 1568 (m), 1495 (m), 1383 (s), 1342 (s), 1235 (s), 1183 (s), 1026 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.03–6.89 (m, 1H), 5.47 (d, J = 14.4 Hz, 1H), 4.73–4.59 (m, 1H), 4.35–4.21 (m, 3H), 1.73 (d, J = 6.9 Hz, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (d, J = 6.7 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 161.9, 143.0, 133.5, 132.1, 128.7, 122.4, 60.6, 49.9, 46.2, 24.6, 23.3, 21.3, 20.3, 17.9, 14.2; HRMS (ESI) calcd for C16H26N3O3+ [M + H]+ 308.1969; found 308.1972.
Ethyl 1-cyclohexyl-5-(N-cyclohexylbenzamido)-1H-imidazole-4-carboxylate (10m).
Yellow solid, yield 47%; m.p. 142.9–144.5 °C; IR (neat): ν 3122 (w), 2935 (m), 2856 (w), 1719 (s), 1670 (s), 1551 (w), 1499 (m), 1448 (m), 1383 (m), 1307 (s), 1171 (s), 1032 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41–7.27 (m, 3H), 7.25–7.08 (m, 3H), 4.40–4.30 (m, 2H), 4.30–4.20 (m, 1H), 3.64–3.52 (m, 1H), 2.03–1.50 (m, 10H), 1.35 (t, J = 7.1 Hz, 3H), 1.32–1.11 (m, 8H), 1.06–0.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7, 162.4, 136.1, 133.2, 133.1, 130.2, 128.3, 128.0, 127.3, 60.7, 59.9, 53.7, 35.3, 34.2, 30.9, 30.3, 25.98, 25.91, 25.8, 25.7, 25.5, 24.9, 14.3; HRMS (ESI) calcd for C25H34N3O3+ [M + H]+ 424.2522; found 424.2600.
Ethyl 5-(4-bromo-N-isopropylbenzamido)-1-isopropyl-1H-imidazole-4-carboxylate (10n).
Yellow solid, yield 25%; m.p. 152.7–154.8 °C; IR (neat): ν 3118 (w), 2981 (w), 2926 (w), 2853 (w), 1715 (s), 1658 (s), 1594 (w), 1497 (m), 1409 (m), 1378 (m), 1317 (s), 1166 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.34 (d, J = 7.1 Hz, 2H), 7.24 (d, J = 7.3 Hz, 2H), 4.63–4.45 (m, 1H), 4.43–4.33 (m, 2H), 4.18–4.08 (m, 1H), 1.48 (d, J = 6.6 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.34–1.27 (m, 6H), 1.12 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 162.3, 134.9, 132.9, 131.3, 129.1, 128.2, 124.9, 60.9, 53.0, 46.0, 24.6, 23.7, 20.8, 20.4, 14.4; HRMS (ESI) calcd for C19BrH25N3O3+ [M + H]+ 422.1074; found 422.1074.
Ethyl 5-(4-chloro-N-cyclohexylbutanamido)-1-cyclohexyl-1H-imidazole-4-carboxylate (10o).
Yellow oil, yield 68%; IR (neat): ν 3110 (w), 2932 (m), 2856 (w), 1725 (s), 1676 (s), 1566 (w), 1494 (m), 1450 (m), 1405 (m), 1382 (m), 1224 (s), 1175 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 4.31–4.17 (m, 3H), 3.81–3.70 (m, 1H), 3.60–3.51 (m, 1H), 3.46–3.41 (m, 1H), 2.23–2.13 (m, 1H), 2.02–1.81 (m, 8H), 1.75–1.52 (m, 7H), 1.35–1.19 (m, 8H), 1.04–0.83 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 162.1, 134.1, 132.2, 128.1, 60.6, 57.8, 53.6, 44.5, 35.4, 34.6, 31.7, 31.2, 30.0, 27.3, 25.7 (3C), 25.6, 25.4, 24.9, 14.2; HRMS (ESI) calcd for C22ClH35N3O3+ [M + H]+ 424.2361; found 424.2357.
Ethyl 5-(6-bromo-N-isopropylhexanamido)-1-isopropyl-1H-imidazole-4-carboxylate (10p).
Yellow oil, yield 80%; IR (neat): ν 3421 (w), 2976 (w), 2935 (w), 2190 (w), 1726 (s), 1678 (s), 1592 (w), 1558 (w), 1496 (w), 1462 (m), 1421 (m), 1380 (s), 1243 (s), 1204 (s), 1114 (s), 1087 (m), 1023 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 4.60–4.52 (m, 1H), 4.35–4.20 (m, 3H), 3.34 (t, J = 6.6 Hz, 2H), 2.13–2.06 (m, 1H), 1.81–1.57 (m, 5H), 1.53 (d, J = 6.9 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.36–1.28 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.6, 162.1, 133.5, 132.6, 128.3, 60.7, 50.2, 45.9, 34.6, 33.6, 32.6, 27.8, 24.7, 23.9, 23.8, 21.4, 20.2, 14.4; HRMS (ESI) calcd for C18H31N3O3Br+ [M + H]+ 416.1471; found 416.1550.
Ethyl 1-isopropyl-5-(N-isopropyl-4-methoxy-4-oxobutanamido)-1H-imidazole-4-carboxylate (10q).
Brown oil, yield 42%; IR (neat): ν 3105 (w), 2979 (w), 2937 (w), 1727 (s), 1662 (s), 1497 (w), 1436 (w), 1404 (m), 1367 (m), 1275 (m), 1234 (s), 1159 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 4.59 (m, 1H), 4.45–4.26 (m, 3H), 3.66 (s, 3H), 2.84 (ddd, J = 16.2, 9.9, 4.6 Hz, 1H), 2.37 (dt, J = 17.4, 5.2 Hz, 1H), 2.31 (dt, J = 16.8, 5.2 Hz, 1H), 2.12 (ddd, J = 16.0, 9.6, 4.8 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.54 (d, J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5, 172.4, 162.2, 133.7, 132.3, 128.4, 60.8, 51.8, 50.3, 46.2, 29.9, 28.8, 24.8, 23.9, 21.4, 20.1, 14.4; HRMS (ESI) calcd for C17H28N3O5+ [M + H]+ 354.2023; found 354.2026.
tert-Butyl 1-cyclohexyl-5-(N-cyclohexylacetamido)-1H-imidazole-4-carboxylate (10r).
Yellow oil, yield 39%; IR (neat): ν 2931 (w), 2854 (w), 1722 (m), 1676 (s), 1562 (w), 1493 (w), 1452 (w), 1393 (m), 1365 (m), 1299 (m), 1148 (s), 1131 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 4.30–4.22 (m, 1H), 3.89–3.77 (m, 1H), 2.12–2.07 (m, 1H), 1.98–1.86 (m, 4H), 1.80 (s, 3H), 1.77–1.69 (m, 4H), 1.67–1.59 (m, 2H), 1.53 (s, 9H), 1.41–1.29 (m, 5H), 1.07–0.86 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.7, 161.4, 133.8, 131.9, 129.7, 81.6, 57.4, 53.6, 35.5, 34.5, 32.0, 30.4, 28.4, 25.9, 25.8 (2C), 25.7, 25.6, 25.1, 23.2; HRMS (ESI) calcd for C22H36N3O3+ [M + H]+ 390.2751; found 390.2739.
N-Cyclohexyl-N-(1-cyclohexyl-4-tosyl-1H-imidazol-5-yl)acetamide (10s).
Yellow solid, yield 82%; m.p. 83.4–85.2 °C; IR (neat): ν 3098 (w), 2934 (w), 2855 (w), 1688 (m), 1598 (w), 1545 (w), 1486 (w), 1454 (w), 1365 (m), 1322 (s), 1296 (s), 1147 (s), 1087 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.21–4.07 (m, 1H), 3.78–3.66 (m, 1H), 2.33 (s, 3H), 2.32–2.08 (m, 2H), 1.98–1.79 (m, 5H), 1.67 (s, 3H), 1.64–1.48 (m, 4H), 1.35–1.17 (m, 6H), 1.00–0.82 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 144.4, 137.6, 135.3, 134.3, 130.3, 129.6, 128.1, 57.9, 53.8, 35.0, 34.4, 31.9, 30.3, 25.62, 25.59, 25.57, 25.50, 25.48, 24.7, 23.1, 21.6; HRMS (ESI) calcd for C24H34N3O3S+ [M + H]+ 444.2315; found 444.2323.
N-Cyclohexyl-N-(1-cyclohexyl-4-tosyl-1H-imidazol-5-yl)pent-4-enamide (10t).
Yellow solid, yield 68%; m.p. 159.7–161.2 °C; IR (neat): ν 2929 (w), 2854 (w), 1676 (m), 1542 (w), 1488 (w), 1450 (w), 1376 (w), 1324 (s), 1292 (m), 1215 (m), 1147 (s), 1087 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 5.70 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 4.98–4.88 (m, 2H), 4.24 (ddd, J = 12.0, 8.6, 3.5 Hz, 1H), 3.76 (ddd, J = 12.1, 8.9, 3.5 Hz, 1H), 2.41 (s, 3H), 2.38–2.28 (m, 2H), 2.26–2.17 (m, 2H), 1.96–1.67 (m, 9H), 1.62–1.51 (m, 2H), 1.42–1.23 (m, 6H), 1.10–0.93 (m, 3H); 13C NMR (100 MHz, CDCl3) 172.7, 144.6, 137.8, 137.3, 135.8, 134.4, 129.9, 129.8, 128.4, 115.5, 58.4, 53.9, 35.3, 34.8, 34.3, 32.2, 30.5, 29.0, 25.85, 25.81 (2), 25.7, 25.6, 24.9, 21.8; HRMS (ESI) calcd for C27H38N3O3S+ [M + H]+ 484.2628; found 484.2631.
Acknowledgements
We thank Merck Serono, EPFL (Switzerland) for financial support.
Notes and references
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Footnotes |
† Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra. See DOI: 10.1039/c4qo00034j |
‡ Current address: UCB S.A., Chemin du Foriest, 1420 Braine l'Alleud, Belgium. |
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