Reactions of vicinal aliphatic bis(hydroxylamines) with trifunctionalized methane derivatives

The reactions of cis -1,2-bis(hydroxylamino)cyclohexane and 2,3-bis(hydroxylamino)-2,3-dimethylbutane with polyelectrophilic carbonyl compounds in ethanol were studied. It has been shown that such reactions result in the formation of predominantly five-membered heterocyclic rings with one or two nitrogen atoms. A nitronylnitroxide radical of 2-imidazoline type bearing a 1,3-dicarbonyl function was synthesized.


Introduction
Aliphatic 1,2-bis(hydroxylamines) (BHAs) were regarded as a suitable precursors in the synthesis of heterocyclic compounds such as 1,2-diazetes 1 , imidazoles 2 , pyrazines 3 , 1,4diazepines 4 bearing N-oxide-, N-hydroxy-, hydroxamic, N-alkoxy-moieties.Many of such compounds possess wide diversity of biological activity.1,2-Diazete derivatives has been shown as effective NO-donors 5 , 2-imidazolidine carboxylic acids and 2,3-piperazinedione derivatives revealed potent antiaggregatory properties 6 .Furthermore, 1,3-dihydroxyimidazolidines are key intermediates for the synthesis of stable nitronyl-and iminonitroxide radicals which are widely used to design organic and hybrid magnetic materials 7 .On the other hand, the recent observations that C2-symmetric bishydroxamic acids and dinitrones serve as effective ligands and catalysts for enantioselective epoxidation of allylic and homoallylic alcohols 8 , oxidation of sulfides and disulfides 9 and asymmetric allylation of aldehydes 10 , correspondingly, have drawn special attention to new chiral BHAs 11 .Therefore, systematic study of chemical behavior of these BHAs is of particular interest due to their both theoretical and practical application.This paper is aimed at studying the reactions of BHAs 1a,b with polyelectrophilic carbonyl compounds 2a-e, derivatives of trifunctionalized methane.The latter compounds containing aldehyde, ketone, alkoxycarbonyl, nitrile groups, etc. as it was shown by Nishiwaki, Ariga et al. are effective synthetic blocks for the construction of heterocycles with desired functional group(s). 12

Results and Discussion
We have found that the reactions of carbonyl containing compounds with symmetric BHAs 1a,b lead predominantly to the formation of 5-membered rings.Thus the reaction of cis-1,2bis(hydroxylamino)cyclohexane 1a with ethyl ester of ethoxymethylenecyanoacetic acid 2а in ethanol at room temperature give 1-hydroxyimidazol-2-ylidene 3a (Scheme 1).NMR 13 С Spectrum of 3a contains characteristic signals of carbon atoms from exocyclic C=C bond at 171.2 and 76.6 ppm, whereas the singlets of ester and amide carbon atoms appeared at 168.0 and 167.1 ppm respectively.Spectral characteristics of compound 3a are similar to those for the earlier prepared derivative 3b 13 .Scheme 1. Reaction of BHA 1a,b with ether 2a and 3a,b cyclization.
It seems relevant to note that in the course of reaction nitrile function in 2a undergoes hydrolysis both in case of 1a with secondary hydroxylamino groups and 1b with sterically hindered tertiary hydroxylamino groups. 13aking into consideration the synthesis of physiologically active barbituric acid derivatives, compounds 3a,b were treated with carbamide and thiocarbamide.However, the desired pyrimidine derivatives 4a,b were not observed in this reaction.It was shown that independent refluxing of 3a,b in methanol with MeONa led to imidazo [1,2-b]isoxazoles 5a,b.High downfield shift of NH proton of enamine group in NMR 1 Н spectrum at 9.43÷9.50ppm can be explained either by the existence of strong intramolecular hydrogen bonding between NH proton and oxygen atom of amide group or fast equilibrium between tautomeric forms A and B. An attempt of oxidation of bicycle 5b in H2O2/Na2WO4 medium has led to 100% conversion of initial compound, but none of the paramagnetic species such as 6 were observed in the reaction mixture.
Reaction of BHA 1a with a masked form of diethyl 2-formylmalonate, compound 2b in the presence of ~10 eq HCl gave a fine crystalline precipitate of product with elemental formula C12H21ClN2O6 in 47% yield.Spectral data of the compound does not correspond to either neither imidazolidine 7 or diazepine 8 structures.In fact, according to NMR 1 H spectrum only one set of protons with relative intensity 5 was observed for the еthyl group, whereas the IR spectrum of this product contains a strong band at 1776 cm -1 which is not typical for carbonyl group in cyclic hydroxamic acids.The crystals of isolated compound suitable for X-ray analysis were grown by slow vaporization of its ethanol solution and the structure was determined as isoxazolin-5-one hydrochloride hydrate 9a. Figure 1 depicts the solid-state molecular structure.Isoxazol cycle is plane within ±0.013(1) Å, with bond lengths being close to the corresponding ones in 4-(2methoxybenzyl)-3-phenyl-2H-isoxazol-5-one 14 .The O2, O4 and C10 atom deviations from isoxazol ring plane equal to 0.065(4), 0.012(4) and 0.012(4) Å respectively.Cyclohexyl ring adopts chair conformation.The torsional angle C2C1N1O1 characterizing orientation of izoxazol ring to cyclohexyl one is 63.6(3)°.The shortened intramolecular contact O2…O4 equal to 3.021(2) Å and weak intramolecular hydrogen bond C3-H3A…O1 with parameters: C-H 0.96(2), H…O 2.55(2), C…O 3.144(3) Å, C-H…O 120(2) were observed.The crystal structure of compound under investigation is characterized by a big number of hydrogen bonds due to water molecules and chlorine anion (Table 1).
Plausible explanation of such unexpected result of this reaction is the initial formation of acylic nitrone 11 followed by tautomeric shift to hydroxylamine 12 and final intramolecular ring closure (Scheme 2).The formation of hydrochloride salt has obviously stopped any further transformations.We did not succeed in performing intramolecular cyclization of 9a into tricycle 10 at the presence of tetramethylguanidine (TMG).
Again, the increase of electronegative character of polycarbonyl compound has led to the unusual result in the reaction with BHAs.When 3-ethoxymethylene-2,4-pentanedione 2c was involved in condensations with BHAs 1a,b neither the expected cyclic ketenaminals 13a,b nor isoxazoline derivatives 14a,b were obtained.The synthesized substances proved to be identical with the products prepared earlier in the reaction of acetoacetaldehyde diethylacetal with BHA 1a,b in acidic medium 13 , i.e. acetylimidazolidine-2-ylidenes 15a,b (Scheme 3).When optimizing this reaction, we found that heating of the components in the mixture of HCl and EtOH affords 15a quantitatively.Thus, ketenaminal 15a was isolated with 95% yield applying the above mentioned conditions, while running this reaction in neutral medium led to a dramatic drop in yield of 15a down to 41%, which is supposed to make 2c a useful alternative of 4,4diethoxybutan-2-one for efficient preparation of acetylated imidazolidin-2-ylidenes.

Scheme 3. Reaction of BHA 1a,b with ether 2c.
The similar deacylation reactions with ketene aminals were described earlier in literature.Thus, Huang et al. has observed monodeacetylation process for diacetylmethylene derivatives of imidazolidine, oxazolidine, hexahydropyrimidine by treatment of the listed heterocycles with alkali 15 .At the same time, the related process was registered when dibenzoylmethyleneimidazolidine was subject to hydrolysis furnished to monobenzoylated product 16 .
Reaction of BHA 1a with 2-ethoxymethylene derivative of ethyl acetoacetate 2d in ethanol at room temperature led to the precipitation of white solid.IR-spectrum of a product reveals an intensive absorption at 1716 cm -1 that is specific for ester's group valent vibrations.The analysis of NMR spectra of an isolated compound reveals that this product consists of the mixture of diastereomers of imidazo[1,2-b]isoxazole 16a.Likewise, BHA 1b reacted with 2d, giving isoxazole 16b (Scheme 4).Besides, the synthesis of nitronyl nitroxides (NNR) possessing 1,3-dicarbonyl functionality oxidation of 16b was studied.When treating the solution of imidazo[1,2-b]isoxazole 16b with an excess of PbO2 (or aqueous NaIO4) in a few minutes, there is a deep coloration of organic phase in the red-purple color due to the formation of radical 18.Despite the fact that only a single product was formed in this reaction (as monitored by TLC), obtaining NNR 18 in its pure form seems to be quite problematic since it is a strong CH-acid which is very labile.In particular, the color of the mixture changed from dark purple to a dirty-yellow upon standing of NNR solution at room temperature for 12 h.To obtain nitronyl nitroxide in a persistent form of freshly prepared solution of 18 was treated with alkali solutions (MeONa, LiOH and KOH were used) in MeOH.As a result, a deep violet sodium salt 19Na as well as other salts were isolated and characterized by IR, UV and ESR-spectroscopy.To illustrate, UV-spectrum of 19Na is represented by two absorption maxima at 314 and 573 nm (characteristic for π→π* and n→π* transitions).In ESR spectrum there is a characteristic quintet with relative intensities as 1:4:6:4:1 and with hyperfine coupling constant for two equivalent imidazoline nitrogen nuclei aN1=aN2=0.750mT, giso=2.0065,which is typical of nitronylnitroxides (Figure 2).
Crystallization of NNR 18 with the salt of nickel has led to an unexpected formation of red paramagnetic crystals, which, as it turned out, are known as NNR 17 17 , unsubstituted at the 2position of the heterocycle.The same results were obtained when Cu(OAc)2 was used.Complexation of radical salt 19Na with Mn(hfac)2 or Cu(hfac)2 has led to noncrystalline material with nonconstant chemical composition.In order to study the elimination of acyl fragment in the reaction of BHAs with polycarbonyl compounds we synthesized cyclic 1,3-ketoaldehyde -2-formyl-3-ketosulpholane 2e by acylation of useful synthetic block, 3-sulpholanone 20 19 according to Claisen procedure 18. .We assumed that the structural rigidity of molecule 2e will prevent the rupture of the C-C bond in the reagent, so that the reaction product will be imidazolidinylidene with two electron-withdrawing substituents at the terminal atom of enamine fragment.
However, the reaction of 1,3-ketoaldehyde 2e with BHA 1a in acid containing media has led to the compound with molecular formula С16Н22N2O8S2, which corresponds to the adduct of one molecule of 1,2-bishydroxylamine with two molecules of ketosulpholane.Indeed, the set of spectral data allowed us to assign the structure of a symmetric dinitrone 22 for separated compound.
According to NMR spectra, dinitrone 22 exists in DMSO solution in a conjugated tautomeric form 22C rather than in the enamine form 22B or alternative form of ketonitrone 22A.In NMR 1 Н spectrum of 22, the singlet signal from aldonitrone proton appears at 7.79 ppm while the corresponding signal from carbon atom in NMR 13 C spectra has a chemical shift of 138.2 ppm that agrees with the spectra of conjugated nitrones.Also, the signals from carbon atoms of cyclohexane CH-groups appear at 66.3 ppm which points at their coupling to sp 2 -nitrogen atom.The formation of dinitrone in this reaction is likely to occur due to the preferential attack of the second molecule of carbonyl compound by hydroxylamino group in acyclic tautomeric form 21.

Conclusions
Thus, we have investigated the reactivity of two different aliphatic symmetric BHAs with respect to various acyclic polycarbonyls containing electrophilic moieties, with5-membered heterocyclic rings being the dominant products in these reactions.For the first time, we have synthesized nitronyl nitroxide radical bearing 1,3-dicarbonyl function and studied some of its complexationabilities.The reaction of BHA with cyclic 2-formyl-3-ketosulpholane leads to the formation of open-chain dinitrone.

Experimental Section
General.BHAs -cis-1,2-bis(hydroxylamino)cyclohexane 20 1a and 2,3-bis(hydroxyamino)-2,3dimethylbutane 21 1b were synthesized as described in literature.Polycarbonyl compounds 2c and 2d were prepared by formylation of acetylacetone 22a and ethyl acetoacetate 22b .Other reagents and solvents from commercial sources were of the highest purity available and were used as received.Silufol UV 254 and Merck Kieselgel 60 F254 plates were used for TLC monitoring.Chromatography was carried out with the use of "Merck" silica gel (0.063-0.100 mm) for column chromatography.C, H, N, Cl and S elemental analyses were carried out by the Chemical Service Center of the Novosibirsk Institute of Organic Chemistry.The melting points were determined on a Boethius type apparatus and not corrected.IR spectra were recorded on Bruker IFS-66 in KBr pellets (conc.0.25%, d=1 mm).UV spectra were registered on Specord M-40.NMR 1 H and 13 С spectra were obtained on Bruker AC-200, AV-300 and АМ-400.X-Band CW ESR spectra were recorded in dilute degassed CHCl3 solutions at room temperature on a Bruker EMX spectrometer.