Heteroannulation Reaction of α-Aminoketones for the Efficient Synthesis of 4-Imidazolin-2-ones and 2-Thiones

The hydrogenation of α-oximinoketones in methanol/HCl afforded α-aminoketones, which were applied without purification to the synthesis of 4-imidazolin-2-ones and 2-thiones, including chiral derivatives. The latter two series were obtained in high yields by a heteroannulation reaction of α-aminoketones with isocyanates and isothiocyanates, respectively. A double condensation of the α-aminoketones with two mol equivalents of the isocyanates produced a series of 4,5-dialkyl-N,3-diaryl-2-oxo-2,3-dihydro-1H-imidazole-1-carboxamides. With isothiocyanates, a single condensation reaction furnished a series of 4,5-dialkyl-1-aryl-1H-imidazole-2(3H)-thiones, which underwent alkylation with alkyl halides to form the corresponding 1-aryl-2-thioalkyl-1H‑imidazoles in high yields.

Through Pd(0)-catalyzed hydrogenolysis in the presence of hydrochloric acid, 33 α-oximinoketones 1a-1d were converted into α-aminoketones 5a-5d, their corresponding chlorhydrates (Scheme 2), in almost quantitative yields, as shown by the 1 H nuclear magnetic resonance (NMR) spectra of the crude mixtures. The isolation of the respective hydrochloride salts was necessary to avoid the dimerization of the free α-aminoketone. 49,50 Without purification, α-aminoketones 5a-5d were thermally reacted with isocyanates 9a-9i to furnish the series of 2-oxo-2,3-dihydro-1H-imidazole-1-carboxamides 10-13 in moderate to good yields (Scheme 2, Table 1). Unexpectedly, the formation of imidazol-2-one 14 was not observed, 36 even when using a sub-equimolar amount of 9 (Scheme 3). Compound 14 was probably an intermediate in the formation of 10-13 via an N-addition of the unsubstituted nitrogen atom to another molecule of isocyanate. Considering that 14 was not detected in the crude reaction mixtures, the last step of the process is likely faster than the first step, which is the addition of the α-aminoketones 5a-5d to arylisocyanates 9a-9i to afford the carbamate intermediate I and the subsequent cyclization step to give hemiaminal II. However, it is also possible that the competitive intermolecular addition to 9 occurred from the internal urea moiety of I to generate intermediate III, followed by cyclization to provide 10-13. 36 There was no significant difference in efficiency between the products derived from alkyl or aryl isocyanates. Interestingly, the optically active 1H-imidazol-1-carboxamides 11g and 13 were also prepared in good yields. Actually, the relatively modest yields observed for the derivatives from α-aminoketone 5c were probably due to a lower conversion during the hydrogenolysis of the α-oximinoketone 1c or a higher decomposition of the product 5c, judging by the byproducts observed in the reaction crude mixtures by thin layer chromatography (TLC) analysis.
is due to the formation of an N−H⋅⋅⋅O (1.941 Å) hydrogen bond between the exocyclic urea proton atom and the oxygen atom of the imidazol-2-one carbonyl group. Hence, the carboxamide carbonyl group is oriented toward the C-5 alkyl group and has a quasi-coplanar conformation (dihedral angle C5−N1−C1'−O2 = 2.6º) with respect to the plane of the heterocycle. This is probably the reason why the protons of the C-5 alkyl substituent undergo a deshielding effect and their signal is shifted downfield in comparison with the protons of the C-4 alkyl group. However, a shielding effect of the N-3 aryl ring on the latter alkyl group cannot be discarded. 51 The plausible formation of 4-imidazolin-2-ones 14 and their attack on the isocyanates 9 to afford the respective 2-oxo-2,3-dihydro-1H-imidazole-1-carboxamides 10-13 is a large part due to the high reactivity of the isocyanates themselves. 52 This is in contrast to the lower reactivity of isothiocyanates, as was demonstrated in the reaction of α-hydroxyketones. 53 Therefore, the reactivity of α-aminoketones 5a-5b with isothiocyanates 15a-15c was evaluated under reaction conditions similar to those used for isocyanates 9 (Table 2). Indeed, 4-imidazolin-2-thiones 16-17 were obtained as the main products in good yields.
The structure of 4-imidazole-2-thiones 16-17 was examined by 1 H and 13 C NMR spectroscopy, HRMS and elemental analysis. Interestingly, in the 1 H NMR spectra of derivatives 16, the C-5 methyl group is shifted upfield with regard to the C-4 methyl group, which is probably due to the shielding effect of the aryl ring located at the vicinal nitrogen atom. The X-ray crystallography of 16a confirmed its structure (Figure 2), showing that the aryl ring adopts an almost orthogonal conformation in relation to the plane formed by the heterocyclic ring (dihedral angle C5−N1−C1'−C2' = −117.1º), similar to the descriptions of analogous heterocycles. [53][54][55][56][57] Unlike other five-membered heterocycles, in which the C-4 and C-5 substituents adopt a nonplanar conformation, 56 the C-4 and C-5 methyl groups are quasi-eclipsed from each other (dihedral angle C6−C4−C5−C7 = −0.8º), as was observed in the case of its analog, 4,5-dimethyl-4-oxazolin-2-thione 19. 53 Hence, 4-imidazolin-2-thiones 16-17 were obtained in the absence of the respective carboxamides 18. The presence of the latter compound would have derived from Scheme 3. Plausible reaction mechanisms for the formation of 2-oxo-2,3-dihydro-1H-imidazole-1-carboxamides 10-13. Figure 1. Structure of 12c as determined by single-crystal X-ray diffraction (ellipsoids at the 30% probability level). a subsequent attack of heterocycles 16-17 on a second molecule of the isothiocyanates 15a-15c. The results may indicate that a second addition to 15a-15c was impeded by the lower reactivity of the isothiocyanates, as well as the lower nucleophilicity of the N-3 nitrogen atom of 4-imidazole-2-thiones 16-17. The observed behavior can be associated with the size of the sulfur atom and its 3d orbitals, 58 its high polarizability, as well as the hyperconjugation and inductive effect. 59,60 These factors induce the delocalization of the N-3 nitrogen lone-pair toward the C-2 carbon atom, and thus generate the aromatic character of the heterocycle of 16 and 17. This occurs despite the lower electronegativity of the sulfur (2.58 D) versus nitrogen atom (3.05 D).
Our hypothesis is supported by the X-ray of compound 16a. The distance of the N-3 and C-2 bond (1.343(2) Å) is shorter than that between N-1 and C-2 (1.361(3) Å), indicating a certain double bond character of the former. At the same time, a lengthening of the C2=S double bond should be expected. Indeed, the observed distance of C2=S was in fact longer (1.695(2) Å) than that for a known carbon disubstituted by nitrogen atoms (Y) 2 C=S (1.671 Å), 61 but shorter than a single C(sp 2 )−S bond (1.751 Å). 61 Consequently, the polarization of the electronic density of the N-3 nitrogen lone pair toward the C2=S bond should increase the electronic density at the sulfur atom, stabilizing a formal or incipient negative charge, then increasing its nucleophilicity. 59,60 The latter explains the attack of the sulfur atom on diverse electrophiles (20a-20c) to generate the imidazole-containing products 21a-21c (Scheme 4). Of course, the N-3 nitrogen lone-pair polarization toward the heterocyclic ring reduces its nucleophilic effect, decreasing its reactivity with another molecule of the isothiocyanate and impeding the formation of compound 18.
The greater capacity of the sulfur atom versus the nitrogen atom (or the enamine-like double bond) to react with electrophiles appears to stem from not only by its Table 2. Preparation of the series of 4-imidazolin-2-thiones 16-17 by the reaction of α-aminoketones 5a-5b with isothiocyanates 15a-15c a entry 5 15 Under N 2 atmosphere, with α-aminoketones 5a-5b (1.0 mol equiv) and isothiocyanates 15a-15c (2.5 mol equiv) in anhydrous toluene, at 100 °C for 24 h. b Yields were determined after column chromatography.

Figure 2.
Structure of 16a as determined by single-crystal X-ray diffraction (ellipsoids at the 30% probability level).
nucleophilicity, but also by the polarization of the electron density of the nitrogen atom toward the thiocarbonyl group. 11,53 Of course, this effect is also favored by the stability resulting from the formation of a neutral aromatic heterocyclic ring.

General
Melting points were determined on a Krüss KSP 1N capillary melting point apparatus. IR spectra were recorded on a PerkinElmer 2000 spectrophotometer. 1 H and 13 C NMR spectra were captured on Varian Mercury (300 MHz) and Varian VNMR (500 MHz) instruments, with CDCl 3 as the solvent and tetramethylsilane (TMS) as internal standard. Signal assignments were based on 2D NMR spectra (HMQC and HMBC). Mass spectra (MS) were recorded on Thermo Polaris Q-Trace GC Ultra and Hewlett-Packard 5971A spectrometers. High-resolution mass spectra (HRMS) were obtained (in electron impact mode) on a Jeol JSM-GCMateII spectrometer. Elemental analyses were performed on a CE-440 Exeter Analytical instrument. Analytical thin-layer chromatography was carried out by using E. Merck silica gel 60 F254 coated 0.25 plates, visualized with a long-and short-wavelength UV lamp. Flash column chromatography was conducted over Natland International Co. silica gel (230-400 and 230-400 mesh). All air moisture sensitive reactions were achieved under N 2 using oven-dried glassware. Prior to use, toluene was freshly distilled over sodium, as was CH 2 Cl 2 over CaH 2 . MeOH were distilled over sodium. K 2 CO 3 was dried overnight at 200 °C prior to use. All other reagents (Sigma-Aldrich, St. Louis, MI, USA) were employed without further purification. Compounds 1a-1d were prepared as described. 21

4-Aminohexan-3-one hydrochloride (5b)
Following the method of preparation for 5a, 1b (0.500 g, 3.88 mmol) and Pd/C (5%) (0.039 g, 0.388 mol) were mixed under H 2 atmosphere to afford 5b as a reaction crude, which was used in the next step without previous purification.

3-Aminopentan-2-one hydrochloride (5c)
Following the method of preparation for 5a, 1c (0.500 g, 4.35 mmol) and Pd/C (5%) (0.044 g, 0.435 mol) were mixed under H 2 atmosphere to furnish 5c as a reaction crude, which was used in the next step without previous purification.

2-Aminopentan-3-one hydrochloride (5d)
Following the method of preparation for 5a, 1d (0.500 g, 4.35 mmol) and Pd/C (5%) (0.044 g, 0.435 mol) were mixed under H 2 atmosphere to provide 5d as a reaction crude, which was used in the next step without previous purification.

Supplementary Information
Crystallographic data (excluding structure factors) for the structure in this work were deposited in the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 2045892 (for 12c) and CCDC 2045895 (for 16a). Copies of the data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. E-mail: deposit@ccdc.cam.ac.uk.
Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.