Copper-catalyzed three-component synthesis of 5-acetamidoimidazoles from carbodiimides, acyl chlorides and isocyanides

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.

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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

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

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).

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).

Table 1 Substrate scope^a

Entry	R^1	R^2	R^3	Product	Yield^b (%)
a Reaction conditions: carbodiimide (0.5 mmol), RCOCl (1.05 equiv.), 0 °C and then isocyanide (2.0 equiv.), CuI (0.2 equiv.), Et3N (2.5 equiv.), MeCN (c 0.3 M), room temperature, 6 h. b Isolated yield after FCC on silica gel.
1	Cy	Me	CO2Et	10a	77
2	iPr	Me	CO2Et	10b	75
3	iPr	Et	CO2Et	10c	67
4	Cy	nC5H11	CO2Et	10d	67
5	iPr	CH2CMe3	CO2Et	10e	71
6	Cy	(CH2)2CH=CH2	CO2Et	10f	65
7	Cy	iPr	CO2Et	10g	66
8	iPr	Cy	CO2Et	10h	73
9	iPr	Cyclopentyl	CO2Et	10i	61
10	Cy	Bn	CO2Et	10j	41
11	Cy	CH2OPh	CO2Et	10k	22
12	iPr	CH=CHMe	CO2Et	10l	69
13	Cy	Ph	CO2Et	10m	47
14	iPr	4-BrC6H4	CO2Et	10n	25
15	Cy	(CH2)2CH2Cl	CO2Et	10o	68
16	iPr	(CH2)4CH2Br	CO2Et	10p	80
17	iPr	(CH2)2CO2Me	CO2Et	10q	42
18	Cy	Me	CO2tBu	10r	39
19	Cy	Me	Ts	10s	82
20	Cy	(CH2)2CH=CH2	Ts	10t	68

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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.

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

1. (a) N. X. Huang and L. Liu, in Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzy, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Pergamon, Oxford, 2008, vol. 4, pp. 143–364; (b) F. Bellina, S. Cauteruccio and R. Rossi, Tetrahedron, 2007, 63, 4571–4624; (c) S. Kaniyo and Y. Yamamoto, Chem.–Asian J., 2007, 2, 568–578; (d) F. Bellina and R. Rossi, Adv. Synth. Catal., 2010, 352, 1223–1276.
2. Imidazolium-based ionic liquids: J. Dupont, R. F. de Souza and P. A. Suarez, Chem. Rev., 2002, 102, 3667–3692.
3. (a) J. L. Schrimsher, F. J. Schendel and J. Stubbe, Biochemistry, 1986, 25, 4356–4365; (b) J. L. Schrimsher, F. J. Schendel, J. Stubbe and J. M. Smith, Biochemistry, 1986, 25, 4366–4371.
4. B. Estramareix and S. David, Biochem. Biophys. Res. Commun., 1986, 134, 1136–1141.
5. H. R. Samari and P. O. Seglen, J. Biol. Chem., 1998, 273, 23758–23763.
6. K. Kadir, G. Shaw and D. Wright, J. Chem. Soc., Perkin Trans. 1, 1980, 2728–2731.
7. A. Reayi and R. S. Hosmane, J. Med. Chem., 2004, 47, 1044–1050.
8. M. J. Alves, B. L. Booth, M. Fernanda and J. R. P. Proenç, J. Chem. Soc., Perkin Trans. 1, 1990, 1705–1712.
9. (a) Y. L. Lin, H. P. Lee, J. C. On and Y. H. Kuo, Heterocycles, 1996, 43, 781–786; (b) Y.-L. Lin, R.-L. Huang, C.-M. Chang and Y.-H. Kuo, J. Nat. Prod., 1997, 60, 982–985.
10. (a) C. Peinador, J. M. Quintela and M. J. Moreira, Tetrahedron, 1997, 53, 8269–8272; (b) H. Roggen, C. Charnock and L.-L. Gundersen, Tetrahedron, 2009, 65, 5199–5203.
11. (a) J. P. Ferris and L. E. Orgel, J. Am. Chem. Soc., 1966, 88, 1074–1074; (b) T. H. Koch and R. M. Rodehorst, J. Am. Chem. Soc., 1974, 96, 6707–6710.
12. (a) G. Shaw, R. N. Wanener, R. K. Ralph and D. N. Butler, J. Chem. Soc., 1959, 1648–1655; (b) G. Mackenzie, H. A. Wilson, G. Shaw and D. Ewing, J. Chem. Soc., Perkin Trans. 1, 1988, 2541–2546; (c) G. Cristalli, A. Eleuteri, P. Franchetti, M. Grifantini, S. Vittori and G. Lupidi, J. Med. Chem., 1991, 34, 1187–1192; (d) M. J. Alves, L. B. Booth, A. P. Freitas and M. F. J. R. P. Proença, J. Chem. Soc., Perkin Trans. 1, 1992, 913–917; (e) B. L. Booth, A. M. Dias and M. F. Proença, J. Chem. Soc., Perkin Trans. 1, 1992, 2119–2126; (f) P. R. Birkett, H. King, C. B. Chapleo, D. F. Ewing and G. MacKenzie, Tetrahedron, 1993, 49, 11029–11036; (g) F. Corelli, V. Summa, A. Brogi, E. Monteagudo and M. Botta, J. Org. Chem., 1995, 60, 2008–2015; (h) M. McLaughlin, R. M. Mohareb and H. Rapoport, J. Org. Chem., 2003, 68, 50–54.
13. J. T. Hunt and P. Bartlett, Synthesis, 1978, 741–742.
14. Copper-catalyzed condensation of α-isocyanoacetate with aromatic isocyanide leading to imidazole has been reported, see: C. Kanazawa, S. Kamijo and Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662–10663.
15. Van Leusen's three-component synthesis of imidazole using TosMIC as a key substrate: (a) A. M. Van Leusen, J. Wildeman and O. H. Oldenziel, J. Org. Chem., 1977, 42, 1153–1156; (b) J. Sisko, A. J. Kassick, M. Mellinger, J. J. Filan, A. Allen and M. A. Olsen, J. Org. Chem., 2000, 65, 1516–1524; (c) V. Gracias, A. F. Gasiecki and S. W. Djuric, Org. Lett., 2005, 7, 3183–3186; (d) F. de Moliner and C. Hulme, Org. Lett., 2012, 14, 1354–1357.
16. L. Banfi and R. Riva, in Org. React., ed. A. B. Charette, John Wiley & Sons Inc., 2005, vol. 65, pp. 1–140.
17. A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168–3210.
18. For selected reviews on isocyanide-based multicomponent reactions, see: (a) J. Zhu, Eur. J. Org. Chem., 2003, 1133–1144; (b) A. Dömling, Chem. Rev., 2006, 106, 17–89; (c) L. El Kaim and L. Grimaud, Tetrahedron, 2009, 65, 2153–2171; (d) L. Banfi, R. Riva and A. Basso, Synlett, 2010, 23–41; (e) A. V. Gulevich, A. G. Zhdanko, R. V. Orru and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235–5331; (f) G. C. Tron, Eur. J. Org. Chem., 2013, 1849–1859.
19. For selected reviews on carbodiimides chemistry, see: (a) H. G. Khorana, Chem. Rev., 1953, 53, 145–166; (b) A. Williams and I. T. Ibrahim, Chem. Rev., 1981, 81, 589–636; (c) W.-X. Zhang and Z. Hou, Org. Biomol. Chem., 2008, 6, 1720–1730.
20. Multicomponent reactions involving carbodiimides: (a) X. Xu, D. Cheng, J. Li, H. Guo and J. Yan, Org. Lett., 2007, 9, 1585–1587; (b) X. Xu, J. Gao, D. Cheng, J. Li, G. Qiang and H. Guo, Adv. Synth. Catal., 2008, 250, 61–64; (c) Z. Wang, Y. Wang, W.-X. Zhang, Z. Hou and Z. Xi, J. Am. Chem. Soc., 2009, 131, 15108–15109; (d) Y. Wang, W.-X. Zhang, Z. Wang and Z. Xi, Angew. Chem., Int. Ed., 2011, 50, 8122–8126; (e) H. Wang, S. Ye, H. Jin, J. Liu and J. Wu, Tetrahedron, 2011, 67, 5871–5877; (f) F. Zhao, Y. Wang, W.-X. Zhang and Z. Xi, Org. Biomol. Chem., 2012, 10, 6266–6270; (g) G. Qiu, Y. Lu and J. Wu, Org. Biomol. Chem., 2013, 11, 798–802.
21. Selected examples: (a) A. Fayol and J. Zhu, Org. Lett., 2004, 6, 115–118; (b) A. Fayol and J. Zhu, Org. Lett., 2005, 7, 239–242; (c) T. Ngouansavanh and J. Zhu, Angew. Chem., Int. Ed., 2006, 45, 3495–3497; (d) S.-X. Wang, M.-X. Wang, D.-X. Wang and J. Zhu, Org. Lett., 2007, 9, 3615–3618; (e) S.-X. Wang, M.-X. Wang, D.-X. Wang and J. Zhu, Angew. Chem., Int. Ed., 2008, 47, 388–391; (f) T. Yue, M.-X. Wang, D.-X. Wang and J. Zhu, Angew. Chem., Int. Ed., 2008, 47, 9454–9457; (g) J. M. Grassot, G. Masson and J. Zhu, Angew. Chem., Int. Ed., 2008, 47, 947–950; (h) T. Yue, M.-X. Wang, D.-X. Wang, G. Masson and J. Zhu, J. Org. Chem., 2009, 74, 8396–8399; (i) W. Erb, N. Neuville and J. Zhu, J. Org. Chem., 2009, 74, 3109–3115; (j) T. Yue, M.-X. Wang, D.-X. Wang, G. Masson and J. Zhu, Angew. Chem., Int. Ed., 2009, 48, 6717–6721; (k) C. Lalli, M. J. Bouma, D. Bonne, G. Masson and J. Zhu, Chem.–Eur. J., 2011, 17, 880–889; (l) Y. Odabachian, S. Tong, Q. Wang, M.-X. Wang and J. Zhu, Angew. Chem., Int. Ed., 2013, 52, 10878–10882.
22. (a) K. Hartke and E. Palou, Chem. Ber., 1966, 99, 3155–3162; (b) K. Hartke, Chem. Ber., 1966, 99, 3163–3172; (c) W. T. Brady and R. A. Owens, J. Org. Chem., 1977, 42, 3220–3222.
23. Y. Wang, C. Yue, F. Zhano, W.-X. Zhang and Z. Xi, Synthesis, 2013, 347–354.
24. (a) J. U. Nef, Justus Liebigs Ann. Chem., 1892, 270, 267–335; (b) I. Ugi and U. Fetzer, Chem. Ber., 1961, 94, 1116–1121; (c) M. Westling and T. Livinghouse, J. Am. Chem. Soc., 1987, 109, 590–592; (d) L. El Kaim, L. Grimaud and S. Wagschal, Synlett, 2009, 1315–1317; (e) A. dos Santos, L. El Kaim, L. Grimaud and C. Ronsseray, Chem. Commun., 2009, 3907–3909; (f) R. Mossetti, T. Pirali, G. C. Tron and J. Zhu, Org. Lett., 2010, 12, 820–823; (g) R. Mossetti, D. Caprioglio, G. Colombano, G. C. Tron and T. T. Pirali, Org. Biomol. Chem., 2011, 9, 1627–1631 For a review, see: (h) T. Livinghouse, Tetrahedron, 1999, 48, 2209–2222.
25. For a review, see: (a) A. V. Lygin and A. de Meijere, Angew. Chem., Int. Ed., 2010, 49, 9094–9124; (b) G. Qiu, Q. Ding and J. Wu, Chem. Soc. Rev., 2013, 42, 5257–5269.
26. (a) T. Saegusa, Y. Ito, H. Kinoshita and S. Tomita, J. Org. Chem., 1971, 36, 3316–3323; (b) Y. Ito, M. Sawamura and T. Hayashi, J. Am. Chem. Soc., 1986, 108, 6405–6406; (c) Y.-R. Lin, X.-T. Zhou, L.-X. Dai and J. Sun, J. Org. Chem., 1997, 62, 1799–1803; (d) R. Grigg, M. I. Lansdell and M. Thornton-Pett, Tetrahedron, 1999, 55, 2025–2044; (e) H. Takaya, S. Kojima and S. Murahashi, Org. Lett., 2001, 3, 421–424; (f) S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem. Soc., 2005, 127, 9260–9266; (g) N. Elders, E. Ruijter, F. J. J. de Kanter, M. B. Groen and R. V. A. Orru, Chem.–Eur. J., 2008, 14, 4961–4973; (h) Y. Odabachian, Q. Wang and J. Zhu, Chem.–Eur. J., 2013, 19, 12229–12233.
27. It is difficult to record NMR spectra due to the presence of copper salt in the mixture. Therefore, no spectroscopic data were collected to support the involvement of 12 as an intermediate on the way to 5-acetamidoimidazoles 10.
28. The reaction of α-metalated isocyanide with imidoyl chloride has been reported for the synthesis of 4-tosylimidazole: A. M. van Leusen and O. H. Oldenslel, Tetrahedron Lett., 1972, 13, 2373–2374.
29. Exploitation of the enamide and the aza-diene properties of 5-aminooxazoles for the synthesis of macrocycles and heterocycles: (a) G. Zhao, X. Sun, H. Bienaymé and J. Zhu, J. Am. Chem. Soc., 2001, 123, 6700–6701; (b) P. Janvier, X. Sun, H. Bienaymé and J. Zhu, J. Am. Chem. Soc., 2002, 124, 2560–2567.

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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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