First synthesis of the N (1)-bulky substituted imidazole 3-oxides and their complexation with hexafluoroacetone hydrate

Synthesis of new 2-unsubstituted imidazole 3-oxides bearing bulky substituents at the N(1) atom, based on the condensation of appropriate alkylamines, formaldehyde, and corresponding  - (hydroxyimino)ketone, is described. Treatment of imidazole 3-oxides with hexafluoroacetone hydrate (HFAH) yields crystalline 1:1 complexes in nearly quantitative yields. Heating of isolated complexes possessing phenyl ring at the C(4) atom of imidazole ring, results in their isomerization into imidazol-2-ones in fair yields. The formation of analogous complexes of HFAH with other azole N -oxides is also described.

Recently we reported on reactions of some imidazole 3-oxides of type 1 with electron deficient 2,2-bis(trifluoromethyl)ethylene-1,1-dicarbonitrile (BTF) (Scheme 1).1d The corresponding malonodinitriles 2 and/or already known imidazol-2-ones 3 were obtained in different ratios, depending on the solvent used.In the case of 1-benzyl-4,5-diphenyl-3-oxido-1Himidazole hydrate (1a, R 1 = CH2Ph, R 2 = Ph), the reaction, carried out in methanol, yielded corresponding 2a accompanied by small amount of complex 4a.The latter, unexpected product, formed after reaction of 1a with in situ generated hexafluoroacetone hydrate (HFAH), was isolated in a trace yield (8%).The X-ray diffraction analysis proved the structure of 4a as a centrosymmetric tetramer (2:2 complex) with four hydrogen bonds closing a 12-atom loop (Figure 1).Since the azaaromatic N-oxides display a significant nucleophilic and basic character, they react with acidic agents yielding the corresponding salts.For example, some of pyridine Noxides were tested as Lewis bases towards p-toluic acid 7a and hydroquinone 7b to give corresponding 1:1, and 2:1 complexes, respectively.On the other hand, smooth transformation into hydrochlorides is a general and useful method for the isolation/purification of crude imidazole and oxazole N-oxides during the workup procedures.2b,3a,8 Similarly, (+)-(R)-(tertbutyl)(phenyl)phosphonothioic acid is used as a chiral solvating agent in order to determine the enantiopurity of the in situ formed, corresponding salts of chiral imidazole N-oxides.2b,3a However, to the best of our knowledge, a systematic study on the reactions of azaaromatic Noxides with HFAH was not described in literature so far.
The first goal of the present paper was focused on preparation of N-bulky substituted imidazole 3-oxides using extremely hindered primary amines such as tert-butylamine and 1aminoadamantane; less hindered isopropylamine was also included for the first time in the study.In extension of the preliminary observation made with 1a a series of analogous imidazole 3oxides complexes with hexafluoroacetone hydrate were prepared and studied with respect to their physico-chemical and chemical properties.For comparison, other heteroaromatic N-oxides, derived from diphenylquinoxaline, 1,2,4-triazole and oxazole were also tested in their reactivities towards hexfluoroacetone hydrate.

Results and Discussion
For the present study, new N-bulky substituted imidazole 3-oxides 1b-e were prepared starting with sterically hindered 1-aminoadamantane, tert-butylamine and iso-propylamine, respectively.The amines were converted into formaldimines (R 1 = Ad, t-Bu) (monomeric forms) or hexahydro-1,3,5-triazine (R 1 = i-Pr) using either paraformaldehyde or aqueous formaldehyde solution (formalin) (Scheme 2). 9Isolated products were reacted with diacetyl monooxime or benzil monooxime giving the expected imidazole 3-oxides 1b-e in satisfactory yields.Preliminary test experiment was carried out using the most bulky N-methylidene-1aminoadamantane and diacetyl monooxime in boiling ethanol, following the general procedure.4b However, after 4h heating no expected product was found in the reaction mixture.Thus, the reaction was repeated at room temperature using glacial acetic acid as a solvent, and in this case, the desired imidazole 3-oxide 1b was isolated in 47% yield.Other, N-bulky substituted products 1c-e were prepared in analogous manner and isolated as crystalline, stable solids in 54-75% yields.The 1 H-NMR (600 MHz) spectra of all new imidazole 3-oxides 1b-e revealed the presence of the low-field shifted singlets located between 8.18 and 7.78 ppm, characteristic for the C(2)H atoms.In the case of adamantan-1-yl derivatives 1b and 1c, H-atoms attached to adamantane skeleton formed three groups of signals identified in both cases as a broad singlet (3H), doublet (6H) and an AB-like system (6H), respectively.
Additionally, five known imidazole 3-oxides 1f-j, selected for further studies with HFAH, were prepared by heating of ethanolic solutions of corresponding 1,3,5-trialkylhexahydro-1,3,5triazines with diacetyl monooxime (product 1f), benzil monooxime (product 1h) or 1-(hydroxyimino)-1-phenylpropan-2-one (products 1g,i,j), respectively (Figure 2).The reaction of 1b with hexafluoroacetone sesquihydrate (1.5 H2O) was carried out at room temperature in dichloromethane solution, and after 30 min.the expected complex 4b was isolated in 95% yield (Scheme 3).The same result was achieved using hexafluoroacetone trihydrate, and again 4b was obtained nearly quantitatively after standard workup (drying, solvent removal).In analogous manner, 2-unsubstituted imidazole 3-oxides 1d-j were converted into crystalline, solid complexes 4d-j in excellent yields (Table 1).In selected examples 1g,h,j, pure products spontaneously crystallized from reaction solutions.In the 1 H-NMR (600 MHz) spectrum of complex 4b, registered in CDCl3, the characteristic singlet of C(2)H was down-field shifted (8.02 ppm) in comparison to the starting 1b (7.86 ppm) and analogous tendency was observed for all complexes 4. The 13 C-NMR spectra of 4b revealed the presence of quartet ( 1 JC-F = 288.0Hz) and heptet ( 2 JC-F = 32.0Hz) located at 121.7 and 91.1 ppm, respectively.These two characteristic signals found also in the spectra of complexes 4d-j prove the presence of (CF3)2C(OH)2 molecule in the isolated products.Because of the unique character of the hydrogen bond in complexes 4, 1d the IR spectroscopy data deserve a short comment.In the case of 4b, the IR spectrum registered in solid KBr showed a set of strong and broad absorption bands located between 3432 and 2507 cm -1 which are attributed to the associated -OH groups.Additionally, strong bands at 1214 and 1206 cm -1 resulting from stretch vibrations of the C-F bonds were observed in all cases.
In order to test if other azole N-oxides are also able to form corresponding complexes, two 2,4,5-trisubstituted oxazole 3-oxides 5a,b (Figure 2) were prepared following the literature protocol. 8Both compounds were tested in reactions with HFAH under standard conditions and the desired salts 6a,b were isolated as crystalline materials in 92 and 66% yield, respectively (Scheme 3).Surprisingly, neither 2,3-diphenylquinoxaline bis-N,N'-oxide 7 nor 3ethoxycarbonyl-1-phenyl-1,2,4-triazole N-oxide 8 (Figure 3) gave the expected complexation products.On one hand, a likely explanation of this fact is the more basic character of the O atom present in the N→O unit of the azoles than in the 6-membered azaaromatic N-oxides.This effect results from advantageous stabilization of the positive charge within 5-membered azole rings.On the other hand, the presence of electron withdrawing ester moiety induces certain decrease of the electron density in heterocyclic ring what is reflected by a reduced basicity of the O-atom in the tested 1,2,4-triazolecarboxylate.
In the series of HFAH complexes 4b,d-f, derived from 4,5-dimethylimidazole 3-oxides, determined melting points can be considered as a qualitative measure of their stability.It depends clearly on the bulkiness of the substituent attached to the N(1)-atom and decreases in the following order: Ad > cHex ≈ t-Bu > i-Pr (decomposition points: 147-149, 120-121, 114-116 and 97-98 °C, resp., Table 1).However, replacement of Me group to Ph substituent at C(5) or/and C(4) atoms (complexes 4g-j) does not lead to significant change of decomposition point.
Unexpectedly, isolated complexes 4 possesing Ph ring attached to the C(4)-atom, decompose at melting points under extrusion of a gaseous product and yield imidazol-2-ones 3 as main products.Similarly, they undergo the same transformation while heating in boiling CHCl3 solution (or suspension).For instance, heating of 4h gave after 0.5 h desired 1-cyclohexyl-1,3dihydro-4,5-diphenyl-2H-imidazol-2-one 3h in 53% yield.According to the general method, heating of complexes 4h-j in neat furnished corresponding 3h-j in acceptable yields (49-72%).In the case of 4d and 4e, bearing Me groups at the C(4)-atom, decomposition yielded complex mixtures and the expected imidazol-2-ones could not be detected in the registered IR spectra of crude materials.*The observed facts suggest, that in analogy to Beckmann type rearrangement of nitrones, 10 hexafluoroacetone hydrate is a prone acidic inductor (with pK1 = 6.58 [H2O, 25 °C]) 11 for the isomerisation of the Ph-C(4)-substituted imidazole 3-oxides 1 into corresponding imidazol-2-ones 3; the proposed reaction pathway is presented in Scheme 4.

Scheme 4. Mechanism of Brönstedt acid catalysed isomerisation of complexes 4 into imidazol-2-ones 3.
In the initial step HFAH is proposed to undergo addition onto imidazole 3-oxide yielding the intermediate adduct A. Next, rearomatization of imidazole ring leads to elimination of water molecule and hemiacetal B is probably formed.The latter undergoes further conversion via 1,5-H shift into imidazol-2-one 3 and hexafluoroacetone as a side product.It is noteworthy, that in the CI-MS spectrum of 4i, one of the four main mass peaks is 355 (8%, [M-H2O+1] + ) which can be attributed to the hemiacetal structure of type B. Analogous fragmentation was observed in the case of 4g.These observations support the mechanism presented in Scheme 4.
Conversions of 2-unsubstituted imidazole 3-oxides with cycloaliphatic thioketones are considered as a straightforward method for preparation of imidazole-2-thiones via so called 'sulfur transfer reaction'.1a,f, 12 Now, the question arises if complexes 4 are also able to undergo the same transformation under typical conditions (room temperature, dichloromethane or chloroform as a solvent).In order to answer this question, a test experiment with the complex 4f and 2,2,4,4-tetramethylcyclobutane-1,3-dithione 1a was carried out in chloroform solution.In contrast to the parent 3-oxide 1f, which was completely converted into 1-cyclohexyl-4,5dimethylimidazole-2-thione within 30 min., 1a complex 4f reacts sluggishly and the conversion was completed only after 3 days (TLC monitoring).Apparently, complexes 4 dissociate in the solution and exist in an equilibrium with little amount of 'free' N-oxide and hexafluoroacetone hydrate.

Conclusions
The study showed, that the N-bulky substituted imidazole 3-oxides 1b-d, bearing at the N(1)atom extremely large groups, like 1-adamantanyl or tert-butyl, can be prepared in satisfactory yields using a simple and efficient protocol for condensation of -(hydroxyimino)ketones with corresponding monomeric formaldimines in glacial acetic acid at room temperature.The alternative method based on the heating of the same substrates in ethanolic solution turned out completely useless for preparation of these type of products.The obtained imidazole 3-oxides 1b-d are potentially attractive starting materials for the synthesis of new, stable nucleophilic carbenes (NHC) via three step deoxygenation-quaternization-elimination procedure.Imidazole 3-oxides 1, irrespectively of the substitution pattern, easily react with hexafluoroacetone hydrate yielding stable, crystalline 1:1 complexes 4 in nearly quantitative yields.Similar complexes displaying the same stoichiometry were obtained with oxazole 3oxides 5. To the best of our knowledge this is the first example of successful exploration of commercially available hexafluoroacetone hydrate for complexation of azaaromatic N-oxides.The 4-phenyl-substituted complexes 4h-j decompose at melting point temperature, as well as upon heating in CHCl3 solutions, to afford the corresponding imidazol-2-ones 3h-j, isomeric with the starting imidazole 3-oxides 1.In analogy to parent 3-oxides 1, their complexes 4 can be transformed into corresponding imidazole-2-thiones via 'sulfur transfer reaction' with 2,2,4,4-tetramethylcyclobutane-1,3dithione.However, reaction is significantly slower and according to the test experiment with 4f requires ca. 3 days at room temperature.

Experimental Section
General.Melting points were determined in a capillary using a Mel-Temp.II apparatus (Aldrich) and are uncorrected.The IR spectra were recorded on a NEXUS FT-IR spectrophotometer in KBr; absorptions ( ) in cm -1 .The 1 H-, 13 C-, and 19 F-NMR spectra were measured on a Bruker Avance III (600 and 150 MHz, resp.) or Bruker AC 300 (300 and 75.5 MHz, resp.)instruments using CDCl3 or CD3OD as solvents.Chemical shifts (δ) are given in ppm ( TMS = 0 ppm) and coupling constants J in Hz.The multiplicity of the 13 C signals was deduced from DEPT or multidimentional spectra.The MS spectra were measured on Varian 500-MS or Finnigan MAT-95 instruments.Elemental analyses were performed in the laboratory of Polish Academy of Sciences in Łódź.

General procedure for preparation of complexes (4 and 6)
To the solution of azole N-oxide (1.0 mmol) in 2 ml of CH2Cl2, hexafluoroacetone trihydrate (HFAH, 1.0 mmol, 0.22 g) was added at 0 °C.Resulting mixture was magnetically stirred for 30 min and next diluted with CH2Cl2 (ca. 10 ml) (in the case of 4g, 4h and 4i amount of 20-30 ml was necessary in order to dissolve the precipitated product).Organics were separated, dried with anhydrous MgSO4, filtered, and the solvent was removed in vacuo from cold water bath to give crude product (4 or 6) as a colorless solid.Analytically pure samples were obtained by recrystallization from appropriate solvents.