Preparation of 2-Alkoxy-5-methoxybenzaldehydes and 2-Ethoxy-5-alkoxybenzaldehydes

Direct O -alkylation of 2-hydroxy-5-methoxybenzaldehyde (1) with alkyl bromides or iodides gave nine 2-alkoxy-5-methoxybenzaldehydes 2a-i in high yields, six of which are novel compounds. Treatment of 2-ethoxy-5-bromobenzaldehydes (3) with n -BuLi, morpholine and nitrobenzene afforded 2-ethoxy-5-hydroxybenzaldehyde (4), which easily underwent O - alkylation to furnish 2-ethoxy-5-alkoxybenzaldehydes 5a-b in total moderate yields.


Introduction
Dialkoxybenzaldehydes are useful and important precursors for the pharmaceutical industry and for organic synthesis in general.We have recently reported the preparation of three symmetrical 2,5-dialkoxybenzaldehydes (R = CH3CH2, PhCH2 and HC≡CCH2) via the formylation of 1,4diethoxybenzene with hexamethylenetetramine (HMTA) and the alkylation of 2,5-dihydroxybenzaldehyde with benzyl bromide or with 3-bromo-1-propyne.1These two general methods, i.e., the formylation of dialkoxybenzenes with HMTA2 and the alkylation of dihydroxybenzaldehydes with alkyl halides,3 are widely used for the preparation of symmetrical dialkoxybenzaldehydes.However, they are not suitable for the synthesis of unsymmetrical dialkoxybenzaldehydes due to the poor regioselectivity of the formylation or alkylation.
To our knowledge, there are only three reports of the preparation of unsymmetrical 2,5dialkoxybenzaldehydes: 2-ethoxy-5-methoxybenzaldehyde (2a) was prepared by the reaction of
Considering the possible transformation of bromo to alkoxy or hydroxy group, 2-ethoxy-5bromobenzaldehyde (3) was used as a starting material to prepare unsymmetrical 2,5dialkoxybenzaldehydes.Although phenyl tert-butyl ether was reported to be obtained in 42−46% yield by the reaction of bromobenzene and potassium tert-butoxide,7 we found that the treatment of 3 with potassium tert-butoxide removed the formyl group.In addition, potassium alkoxides are difficult to prepare due to their easy oxidation.
In 1969, Bacon et al., reported the conversion of halogen to alkoxy groups by the reaction of aryl halides with sodium alkoxides, using copper(I) salts as catalysts.8However, our efforts to in vacuo, the residue was separated by column chromatography with hexane/EtOAc (from 3:1 to 6:1) as eluent to give the expected product 2a−i.
The reaction time was monitored by gas chromatography.The structures of 2a−i were clearly confirmed by 1H and 13C NMR spectra and elemental analyses or HRMS results.Aliphatic alkyl iodides were used for the preparation of 2a−d; while activated alkyl bromides were used for 2f−i.It also shows that the alkylation of 1 with activated alkyl bromides takes place more easily with shorter reaction time than aliphatic alkyl iodides.As for 2-(2-chloroethoxy)-5-methoxybenzaldehyde (2e), both 1-chloro-2-bromoethane and 1-chloro-2-iodoethane were used and 2e