Ethylenation of aldehydes to 3-propanal, propanol and propanoic acid derivatives

Methodology has been developed for the synthesis of 3-propanaldehydes through a five-step process in 11–67% yield from aldehydes. Aldehydes were reacted with Meldrum’s acid through a Knoevenagel condensation to give materials that upon reduction with sodium borohydride and subsequent hydrolysis decarboxylation generated the corresponding 3-propanoic acid derivatives. The -propanoic acid derivatives were reduced to give 3-propanol derivatives, which were readily oxidised to target 3-propanal derivatives.

A literature reported method for the synthesis of 3n was used 17 , for which we carried out minor solvent modifications to avoid the use of benzene (Fig. 2   products. The same procedure also yielded the novel pentafluorophenyl derivative (3o, Fig. 2, entry 20), Both the para-trifluoromethyl (3n) and pentafluoro (3o) derivatives were not purified at this stage due to instability of the substrates during attempted purification protocol, which included recrystallisation and flash column chromatography. Instead, when full conversion was determined to have been reached by 1 H NMR spectroscopic analysis of the crude reaction mixtures for these reactions, they were taken forward to the next step 18 .
With alkene containing compounds 3a-o in hand, the next step was reduction of the conjugated double bonds introduced through the Knoevenagel condensation. This was successfully carried out according to the method reported for the synthesis of 4d by Andrews et al. 16 giving high yields (87-99%) for 4a,c-h,j-l,n-o. The 4-dimethylamino derivative (4b) gave a lower than expected yield of 75%, minor decomposition was observed. In the case of compounds 4c (Fig. 3, entry 3) and 4h (Fig. 3, entry 8) methanol led to ring opening of the Meldrum's moiety to the dimethyl malonate, whereas under otherwise identical conditions the use of ethanol furnished the desired compounds. Therefore, ethanol was selected as the preferable solvent for manipulation of 3 to 4 from this point.
The hydrolysis and decarboxylation of derivatives 4 was required in order to synthesise 5, this was achieved with the method reported for the synthesis of 5d by Andrews et al. 16 in acceptable to good yields (48-98%, Fig. 4) for 5a-h,j-l,n-o.
For the synthesis of the para-methyl (5h) and para-methoxy (5c) derivatives from 4h and 4c, respectively, undesired side-products were detected. In order to minimise the formation of the side-products, the reaction was run initially at room temperature for one hour, followed by heating to reflux for a further 4 hours. The desired compounds were obtained after work-up without requiring further purification. Furthermore, under the standard reaction conditions the synthesis of 2-furyl derivative 5e from 4e led to the formation of the desired compound alongside a minor undesired side-product, the desired compound was poorly soluble in common laboratory solvents and therefore this impurity was taken through to the LiAlH 4 reduction. The low yield for the synthesis Scientific RepoRts | 7: 1720 | DOI:10.1038/s41598-017-01950-7 of 3-indole derivative 5l was most likely due to product loss during reaction work-up because of the probable zwitterionic nature of 5l having some water solubility.
In order to synthesis 7, isolated 5a-h,j-l,n-o should first be converted to the corresponding primary alcohols 6a-h,j-l,n-o before oxidation to aldehydes 7a-h,j-l,n-o. The reduction of 5b-d, f-h,j-l to 6b-d, f-h,j-l was carried out with lithium aluminium hydride (LiAlH 4 ) in THF to give the primary alcohols in 83% to 99% yields (Fig. 5). The reduction of 5e to 6e was attempted with lithium aluminium hydride (LiAlH 4 ) in THF led to the formation of a number of unidentified decomposition products.
The reduction of 5n and 5o to 6n and 6o was attempted with lithium aluminium hydride (LiAlH 4 ) however partial fluorine displacement was observed. Pentafluoro derivative 5o underwent a nucleophilic aromatic substitution (S N Ar) displacing one of the fluorine substituents to give 8o in an approximate 4:1 ratio 6o:8o (Fig. 6), similar observations are reported in the literature with related substrates 19 . When para-trifluoromethyl derivative 6n was exposed to LiAlH 4 it underwent a hydride-fluorine exchange to give the para-difluoromethyl compound 8n (Fig. 6) in an approximate 1:1 ratio 6n:8n by 1 H NMR spectroscopic analysis. Fluorine substitution by hydride within trifluoromethyl groups has been previously reported with related substrates 20 . Reduction of 5a and 5k to 6a and 6k was carried out using borane to give the desired compounds in 86% and 74%, respectively (Fig. 7). This procedure provides an alternative, milder, method to reduce carboxylic acids when incompatible with LiAlH 4 . Thus, this procedure should also be applicable to fluorinated derivatives 5n and 5o and has previously been demonstrated in the literature 21,22 .
Hydrocinnamyl alcohol derivatives 6 a,c,d,f-h,j,k,o were converted to aldehydes 7a,c,d,f-h,j,k,o using a Swern oxidation in 29-89% yield (Fig. 8). The oxidation of 4-dimethylamino derivative 6b to 7b and 3-indole derivative 6l to 7l was unsuccessful, a complex mixture of unidentifiable by-products alongside the desired compound precluded satisfactory synthesis and isolation. Oxidation of a mixture of 6o and 8o led to the formation of the desired aldehyde 7o in acceptable yield (29%) and the by-product from the oxidation of 8o could be separated with column chromatography.    The outlined five-step synthesis of aldehydes 7 was successful in providing a range of derivatives in acceptable yields (11-67%, Fig. 9). Our studies found that a single set of conditions were not applicable to all substrates but tailoring of reaction conditions can give a diverse range of derivatives. By-products were observed in the LiAlH 4 reduction of 6n and 6o, the decarboxylation of 4d and 4h but modifications to the synthetic procedure can minimise their formation 23 . Experimental procedures are detailed in the Supplementary Information.