Synthesis and properties of alkylthioethanals

A method, allowing alkylthioethanals to be synthesized in 80-93% yields, has been developed. It comprises the hydrolysis of bis-1,1-alkoxy-2-alkylthioethanes using two-phase system water - organic solvent. The method is applicable for both common aldehydes bearing lower radicals (R = Pr, Bu) and hitherto unknown highly boiling aldehydes (R = C 7 H 15 , C 8 H 17 , PhCH 2 ). It has been found that alkylthioethanals can spontaneously trimerize into 2,4,6-alkylthiotrioxanes. In basic media (1N NaOH, KF/Si(OEt) 4 /EtOH), alkylthioethanals affords the products of aldol self-condensation in up to 60% yield ( 1 H NMR). In competitive interaction (cross-aldol condensation) of butylthio-and alkoxyethanals with furan-or thiophen-2-carbaldehydes, the reactivity of sulfur-containing carbanions was shown to be more than six times higher than that of the alkoxy analogs.


Introduction
2][3] Alkylthioethanals are generated by oxidative decarboxylation of natural Salkylcysteines (Strecker degradation). 1For example, propylthioethanal, possessing a smell of freshly mowed grass, has been prepared as one of the main volatile components, by thermal degradation of equimolar mixtures of S-propyl-L-cysteine and glucose (in 1.34% yield). 3olatile sulfur compounds are essential for the aroma of many fermented food products like cheese or beverages (wine, beer). 4Several unnatural fragrant compositions containing alkylthioethanals have been claimed. 5he interest in chemistry of 2-alkylthioethanals is sustained by their application in organic synthesis either as carbonyl compounds, 6,7 or carbanions. 8,9,10For instance, alkylthioethanals were previously studied as СН-acids in aldol condensation 8 (equation 1, Scheme 1) or in the Mannich reaction performed in water using formaldehyde as methylenating component, 9,10 (equation 2).When the Mannich reaction proceeds in anhydrous medium in the presence of CH2Br2 as methylenating reagent, alkylthioethanals 1 show high activity as Michael donors that results in the formation of 2,4-dialkylthiopentanedials as the only products of new domino sequence (equation 3) in up to 87% yield ( 1 Н NMR).Alkylthioethanals have found many applications in the synthesis of compounds possessing antihypertensive, 12 antibacterial, [13][14][15] bio-antimutagenic, 15 fungicide, 16 and herbicide activities. 17hey are also employed for the preparation of RS-substituted indoles, 18 and azapeptides, 19 to study a proteolytic enzyme associated with Alzheimer , s disease.
The yields of alkylthioethanals isolated from natural compounds are negligible.The known protocols for the synthesis of alkylthioethanals concern mainly the aldehydes bearing lower RSradicals (MeS, EtS, BuS). 14,20,21,22The target products are often formed in low yields (21-47%), 20,22 and synthetic procedures require a strictly limited set of catalysts and solvents, the absence of which leads to the drop of aldehydes yield up to zero. 23Recently, a novel method for the synthesis of hexylthioethanal via the reaction of hexyl allyl thioether with OsO4 and NaIO4, 15 has been reported.However, the former reagent is quite expensive and starting thioether needs to be specially pre-synthesized.
Previously, we obtained alkylthioethanals by the hydrolysis of the corresponding alkylthioacetals, the yields of the target products being 43-59%. 9The purpose of the study was to raise the yields of the reaction and to widen the application area of the protocol for previously unreported high boiling alkylthioethanals, as well as investigate their most typical reaction (sometimes spontaneous).
In this work, the alkylthioacetal 2 hydrolysis selectivity was increased and the yields of alkylthioethanals 1 reached 80-93% due to the introduction of certain amount of organic solvent, benzene or toluene, into the reaction mixture.This allowed the reaction to be performed at a higher temperature and not only propylthio-and butylthioethanals but also hitherto unknown highly boiling heptylthio-, octylthio-and benzylthioethanals to be prepared in high yields.Besides, usual side reactions accompanying the hydrolysis of acetals 2 such as dealcoholysis to ethenes 3, aldol condensation of aldehydes 1 to enals 4 and polymerization were not observed (Scheme 2).When butylthioethanal 1а was synthesized via the hydrolysis of its acetal (non-optimized conditions), the aldol self-condensation of aldehyde 1а could reach 28%.The latter process represents a side reaction in cross-aldol condensation, 8 (equation 1) and in the Mannich reaction, 11 (equation 3).It was reported that similar self-condensation of ethylthioethanal occurred completely even in the absence of a catalyst on storage of aldehyde during one year without air oxygen and water. 20The higher proneness of alkylthioethanals to aldol selfcondensation in acidic or alkaline media prompted us to search for the optimized conditions of direct synthesis of these poorly studied RS-functionalized enals on the example of aldehyde 4а.It turned out that the application of alcohol solutions of MeONa, EtONa or two-phase system NaOH-DMF, 8 led to deep resinification of the reaction mixture.When a solution of 1N NaOH was used as a catalyst and the reaction temperature increased up to 70 °С, the yield of aldehyde 4а attained 44% ( 1 H NMR). The employment of KF in the presence of Si(OEt)4 afforded the target aldehyde 4а in 60% yield ( 1 H NMR).
A capability of the neat alkylthioethanals 1 for spontaneous cyclotrimerization appeared to be a surprising property of them.The works related to cyclotrimerization of aldehydes to the corresponding 2,4,6-trialkyl-1,3,5-trioxanes are abundant in the literature. 24The latter compounds find numerous applications in, for example, color photography, 25 as fumigants, 26 repellents, deodorants, 27 and insecticides. 28Commonly, the synthesis of trioxanes requires usage of the acidic catalysts such as Broensted, 29 and Lewis, 24,30 acids, clay, 31 and ionic liquids, 24c,d though spontaneous cyclotrimerization of propanals in water was recently documented. 32But neither spontaneous nor catalytic cyclotrimerization of alkylthioethanals was previously observed.We have found for the first time that propylthio-, butylthio-and hexylthioethanals undergo spontaneous cyclotrimerization on storage in refrigerator (-6 °C) without a solvent during from 7 days to several months (Scheme 3).In one of the experiments, propylthioethanal 1b was almost completely transformed into a trimer 5b (3 months), which could be easily characterized by 1 H NMR technique.In this sample, the signal of carbonyl proton of the initial aldehyde 9.43 ppm has minimal value, while the signal of trimer acetal proton appears as triplet at 5.01 ppm (the signals ratio is 1 : 4.4).Similar triplets of acetal protons in trimers of ethanal (4.92 ppm), chloroethanal (5.05 ppm), 3-chloropropanal (5.08 ppm), 3-cyanopropanal (5.15 ppm) were observed.24f The same picture was observed by us in the 1 H NMR spectrum of butylthioethanal 1a (6 months), though the monomer : trimer ratio was 1 : 2.3.The trimerization of hexylthioethanal 1c made up 21% on its storage at -6 °C for three years in a sealed ampoule.But the ratio trioxane 5c : aldehyde 1c in the equilibrium system raised up to 47 : 53 in one month upon keeping hexylthioethanal in a flask at room temperature.Apparently, spontaneous trimerization at lower temperatures can be rationalized by slight oxidation of aldehydes with air oxygen (dissolved in them) to give the corresponding acid, 33 which catalyzes the trimerization.
Unlike monomers, trimers of aldehydes did not participate in the reactions (1) and ( 3), performed in alkaline medium.Therefore, the conditions of the starting alkylthioacetaldehydes should be strictly controlled before the application.The trimer of propylthioethanal was detrimerized by distillation in the presence of water and trace amounts of an acid, the yield of the aldehyde reaching 92%.Previously, on the example of ketones, it was shown that the introduction of sulfur substituent into the α-position of the carbonyl moiety increased thermodynamic acidity of a neighbor proton by ~ 10 3 as compared to simple ketone and stabilized carbon anion adjacent to sulfur atom. 34Since the comparative activity of alkylthioacetic aldehydes as CH-acids was not earlier studied, we accomplished the cross-aldol condensation reactions, where furan-2carbaldehyde 6а and thiophene-2-carbaldehyde 6b acted as carbonyl components and competitive ethoxy-and butylthioethanals played a role of the methylene counterparts (Scheme 4).Two-phase system NaOH-DMF was employed as a catalyst.The ratio of the starting reagents 6 : 1а : 7 was 1 : 1.2 : 1.2.The reaction was controlled using 1 H NMR and GC-MS techniques.In the case of aldehyde 6а, the reaction mixture in 2 h contained products 8а and 9а in a ratio of 6 : 1 ( 1 H NMR), aldehyde 6а being completely converted.In the reaction with aldehyde 6b, the conversion of the starting aliphatic aldehydes (2 h) reached 100%.2-Butylthio-3-(2-thienyl)propenal 8b ( ~ 50%) was identified as a major reaction product.The expected 2-ethoxy-3-(2-thienyl)propenal 9b was absent in the reaction mixture that was supported by the comparison of 1 H NMR spectral data of mixture with those of authentic sample.To compare spectral data ( 1 H NMR and GC-MS), this aldehyde was synthesized by two-component cross-aldol condensation according to the protocol. 8Among the reaction products, two compounds with molecular weight 202 ( ~ 13% of each) were detected (GC-MS).These were likely the products of cross-aldol condensation of the starting aliphatic aldehydes.

Conclusions
A convenient and effective method is developed to synthesize alkylthioethanals in the yield 80-93%, using commercially available initial reagents.The conditions for their aldol selfcondensation in the presence of basic catalyst have been demonstrated.The spontaneous cyclotrimerization of the neat alkylthioethanals during storing them at the temperature from -6 °C to 20 °C has been discovered for the first time.Regeneration of the alkylthioethanals out of the corresponding 2,4,6-alkylthiomethyl-1,3,5-trioxanes (in the yield 92%) is possible by their distillation in the presence of an acid in trace amounts.By the example of cross-aldol condensation, the introduction of a sulfur-containing substituents into α-position of the aldehyde group is shown to raise the alkylthioethanals reaction rates as compared with alkoxyethanals by factor of 6 and more.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on a Bruker DPX 400 spectrometer (400.13 and 100.61MHz accordingly) using CDCl3 as a solvent, and HMDS as an internal standard.GC -MS analysis was performed using Hewlett-Packard 5971A mass-selective detector (electron impact, 70 eV) coupled with an HP 5890 gas chromatograph (Ultra-2 column, 5% of phenylmethylsilicone; injector temperature 250 °C; oven temperature 70 to 280 °C; at rate of 20 °C min -1 ).IR spectra were recorded in a film on a Bruker Vertex 70 spectrophotometer.Elemental analysis were carried out in a Thermo Finnigan automatic analyzer 1112 ser.Column chromatographic separations were done on silica gel 60 (70-200 mesh).