Organocatalytic γ-oxidation of α , β-unsaturated aldehydes

Direct, organocatalytic γ-oxidation of α,β-unsaturated aldehydes via dienamine catalysis has been developed. The reaction of 2-hexenal with dibenzoyl peroxide (BPO) catalyzed by the MacMillan catalyst gave desired γ-benzoyloxy aldehyde in a moderate yield, notably the formation of α-substituted product was greatly suppressed. γ-Benzoyloxy-α,β-unsaturated aldehyde turned out to be a useful building block in the synthesis of highly functionalized molecules.


Introduction
Asymmetric organocatalysis has recently emerged as a powerful tool in organic synthesis. 1,2eginning from the discovery of the L-proline-catalyzed aldol reaction, [3][4][5] over the years, it evolved into a general strategy for the activation of carbonyl compounds.Ten years ago, this mode of activation was limited to the formation of enamines and iminium ions as intermediates (Scheme 1).][8] In 2006 Jørgensen disclosed a dienamine concept by showing the direct γ-functionalization of α,β-unsaturated aldehydes. 9Pentenal reacts with diethyl azodicarboxylate (DEAD) in the presence of 2-[bis (3,5)-bistrifluoromethylphenyl)-trimethylsilanyloxymethyl]pyrrolidyne (silyl protected diarylprolinol) and benzoic acid furnishing the γ-amino substituted product in 56% yield.It was proposed that the reaction proceeds via a [2+4]-cycloaddition pathway.
α,β-Unsaturated aldehydes react with secondary amines generating dienamines as reactive species.As such, their electrophilic character is transformed into the nucleophilic one enabling the reaction with electrophiles at αand γ-positions.A chiral catalyst not only forms dienamine but also differentiates between the two faces of the double bond providing an enantioselective process.
The γ-nucleophilic character of dienamine was exploited in the vinylogous aldol, [10][11][12] and Michael 13,14 reactions.For example, the reaction of allyl ketones with isatins catalyzed by Lvaline-derived bifunctional tertiary amine/thiourea catalyst gave E-configured vinylogous aldol adducts in high yield and ee up to 99%. 11In the Michael reaction, 9-amino cinchona alkaloids were used as catalysts.This mode of activation was also applied in the elegant synthesis of tocopherol 10 and chromenes. 12The organocatalytic formal [4+2] cycloaddition reaction of α,βunsaturated aldehydes was applied in the synthesis of (+)-palitantin. 14ienamines are electron-rich dienes and can react in Diels-Alder reactions, for example in cyclization of unsaturated dicarbonyl compounds. 15Vicario and co-workers developed an efficient method for the synthesis of isochromenes via a cascade [4+2] cycloaddition/elimination process starting from α,β-unsaturated aldehydes. 168][19] Stabilized carbocations act as electrophiles in the diphenylprolinol silyl ether-catalyzed reaction with unsubstituted enals furnishing γ-alkylated products. 17Linear unbranched and β-substituted α,βunsaturated aldehydes favor γ-substitution while γ-disubstituted react at the α-position.Nevertheless, in the presence of cinchona-derived catalyst branched enals afford the desired γproduct. 18,19espite an increased number of reports on dienamine catalysis, to the best of our knowledge, only nitrogen and carbon electrophiles were studied in intermolecular substitution reactions.To further develop the potential of dienamine catalysis, an oxygen based electrophile was studied in the synthesis of γ-oxygenated aldehydes.

Results and Discussion
There are numerous organocatalytic procedures for α-oxygenation of aldehydes and ketones. 20,21or this purpose various electrophilic oxidizing agents were employed including benzoyl peroxide (BPO), [22][23][24][25] molecular oxygen, 26,27 hydroperoxides, 28 o-quinones, 29,30 oxaziridine, 31 iodosobenzene, 32,33 and iodoarenes/MCPBA. 32,333][24] Maruoka's group used tritylpyrrolidine as a catalyst with hydroquinone as an additive. 22As the reaction proceeded in the presence of a radical scavenger the ionic pathway for this reaction was proposed.Similar results were obtained when diphenylprolinol silyl ether was employed with no radical scavenger added. 23Hayashi et al. found that in their reaction both basic and acidic additives cause a decrease in yield.While, in Tomkinson's established conditions for this reaction the MacMillan catalyst worked best when used with p-nitrobenzoic acid. 24nspired by these reports we envisaged that electrophilic BPO could, in a similar manner, react with dienamines.Since various organocatalysts have been used to generate dienamine from α,β-unsaturated aldehydes we tested a broad range of amino acids 1-6 and their derivatives 7-9 as organocatalysts in the reaction of (E)-2-hexenal (10) with dibenzoyl peroxide (Figure 1).Quickly it was established that most of the catalysts studied led to either low conversion or gave a complex mixture of products.Only in imidazolidinone 11 (MacMillan catalyst) catalyzed reaction performed in toluene two products 12 and 13 were easily distinguished.

Scheme 2. Synthesis of γ-benzoyloxy-aldehyde 13.
Desired product 13 was isolated in 11% yield.The position of the benzyloxy group was unambiguously established based on one-and two-dimensional NMR spectroscopy ( 1 H, 13 C, COSY, HMBC, HSQC).The resonance from the aldehyde group was clearly seen at δ = 9.60 ppm.This dublet signal correlates to one proton signal at δ = 6.30ppm in COSY, which in turn possesses a characteristic cross-peak for C4 in HMBC.Carbon 4 produces cross-peak (HMBC) with protons at 2, 3, 5 and 6 positions and has a HSQC correlation for a proton present at δ = 5.73 ppm.The C4 proton then correlates to protons present at C3 and C5 in COSY, thus proving the structure of product 13.
The formation of product 13 was accompanied by a more polar by-product which upon treatment with NEt 3 transformed into αsubstituted benzoyloxy-2-hexenal 12. Unfortunately, at the same time desired γ-benzoyloxy-aldehyde 13 slowly converted into product 12.We assumed that in the presence of NEt 3 compound 13 rearranged into α-benzoyloxy substituted Z-hexenal 12 (30%) (Scheme 3).Furthermore, to avoid possible radical reactions involving BPO we have tested TEMPO as a radical scavenger.In our case, contrary to Maruoka's observation for the diphenylprolinol silyl ether-catalyzed reaction, a decrease in yield was observed (5%).However, when it was used in combination with benzoic acid the yield remained the same.Thus both additives were applied for further studies, followed by an investigation into various solvents.Most of the solvents studied, this included hexane, CH 2 Cl 2 , CHCl 3 , DMF, MeOH and H 2 O, furnished only traces of product 13.A twofold increase in the yield was obtained in toluene (25%).In this case α-benzoyloxysubstituted 2-hexenal 12 was formed in 7%.Similar results were obtained in tBuOMe but the reaction mixture was more complex.
the absence of an acidic co-catalyst the reaction in toluene gave product 13 in 18% yield.It has been already established that in organocatalyzed reactions the type of acid co-catalyst used may influence the yield and stereoselectivity of the reaction.With the goal of finding a correlation between pK a of the acid and outcome of the benzoyloxylation reaction we studied both organic and inorganic acids (Table 1).a conditions: aldehyde 10 (1 mmol), acid (0.2 eq.), TEMPO (0.2 eq.), MacMillan catalyst (0.2 eq.), BPO (1.2 eq.), toluene (1 ml).b isolated yields, the reaction conversion was full.c no by-product of similar polarity formed.d reaction in a diluted solution (0.5 M).
The data presented in Table 1 show that the weaker the acid the higher the yield of the reaction.The use of tartaric acid as a co-catalyst not only eliminated substitution at the αposition but also suppressed the formation of unwanted by-products (entry 5).The yield further increased when the reaction was conducted at lower concentration -0.5 M. The use of THF instead of toluene simplified the purification of the reaction mixture; only desired product 13 was formed.
Disappointingly all reactions studied gave racemic product 13 or with very low enantiomeric excess.Unfortunately, the reaction in the presence of simple secondary amine -pyrrolidyne failed to furnish desired product 13.Further studies aiming at improving the direct γbenzoyloxylation process are in progress.
While we were working on γ-oxygenation of carbonyl compounds, List and co-workers reported that treatment of α-branched α,β-unsaturated aldehydes with BPO in the presence of quinine-derived amine and trichloroacetic acid as a co-catalyst led predominantly to benzoyloxylation at the α-position. 25The α/γ ratio was high for acyclic substrates but in some cases it diminished by a silica gel mediated allylic rearrangement of α-benzoyloxy products to their γ-counterparts. 34

Conclusions
In conclusion, we have described direct γ-benzoyloxylation of α,β-unsaturated aldehydes and proved their usefulness in the synthesis of highly functionalized molecules.List's and our observations on the benzoyloxylation reaction of α,β-unsaturated aldehydes suggest that the regioselectivity of this reaction is governed by the type of amine catalyst and by the substitution pattern on the starting material.Though, the reaction of 2-hexenal (10) with BPO gave desired product 13 in moderate yield it is the first example of the successful direct γ-benzoyloxylation of α,β-unsaturated aldehydes.

Experimental Section
General.High resolution ESI mass spectra were recorded on a Mariner and SYNAPT spectrometer. 1 H and 13 C NMR spectra were recorded at 25 o C on Bruker 500 and Varian 500 MHz instruments with TMS as an internal standard.Elemental analyses were obtained from the Institute of Organic Chemistry PAS.Flash chromatography was performed using Merck Silica Gel (230-400 mesh).Thin layer chromatography (TLC) was performed using Merck Silica Gel GF254, 0.20 mm thickness.All solvents and chemicals used in the syntheses were of reagent grade and were used without further purification.