Preparation of 2,6-dialkoxybenzaldehydes

Lithiation of 1,3-dialkoxybenzenes with n -BuLi, followed by formylation with DMF, furnished solely 2,6-dialkoxybenzaldehydes with high regioselectivity. Using this key step, different approaches have been developed for novel symmetrical and unsymmetrical 2,6-dialkoxybenzaldehydes.


Introduction
Dialkoxybenzaldehydes are useful and important precursors for pharmaceutical industry and for organic synthesis in general.−4 However, this route is not appropriate for the preparation of 2,6-dialkoxybenzaldehydes due to lack of the commercially available 2,6dihydroxybenzaldehyde.Even if 2,6-dihydroxybenzaldehyde is available, its alkylation with alkyl halides is not expected to generate unsymmetrical 2,6-dialkoxybenzaldehydes because of poor regioselectivity.Although the direct formylation of an aromatic ring with hexamethylenetetramine (HMTA) in acetic acid and/or trifluoroacetic acid is a known method to introduce a formyl group into an aromatic ring, 5−10 the formylation of 1,3-dialkoxybenzenes with HMTA is not appropriate for preparation of 2,6-dialkoxybenzaldehydes due to poor regioselectivity (one example will be discussed in this paper).A very recent paper reported the formylation of phenol derivatives with formaldehyde in the presence of KSF−Et3N, but the substituents attached to the benzene ring are limited to alkyl groups. 11To our knowledge, no general method has previously been reported to prepare 2,6-dialkoxybenzaldehydes. In this paper, we develop several approaches for the title compounds.
Our first approach was to use the ability of certain 1,3-substituents on aromatic systems to direct metallation at a position ortho to both of these groups using organolithium reagents.This phenomenon is of synthetic importance since electrophilic attack on aryllithium intermediates is a useful method for the functionalization of aromatic compounds.Therefore, many papers have reported the factors which control the regioselectivity and efficiency of lithiation of aromatic substrates. 12Numerous functional groups are known to promote ortho-lithiation. 13,14 owever, with many of these groups, difficulties may arise due to lack of discrimination between nonequivalent ortho positions or between the ring positions and other acidic sites within the substrates. 15n early investigation revealed that lithiation can occur selectively at the common ortho site of 1,3-dialkoxybenzenes. 15 Encouraged by these results, we first synthesized symmetrical 2,6dialkoxybenzaldehydes 3a and 3b in two steps by O-alkylation of benzene-1,3-diol (1) in the presence of potassium carbonate with an excess alkyl iodide, followed by the lithiation and subsequent formylation of the corresponding intermediate symmetrical 1,3-dialkoxybenzenes 2a and 2b (Scheme 1).The 1 H NMR spectra (no singlet proton peak in the aromatic region) and 13 C NMR spectra (four aromatic carbon peaks determining the molecular symmetry) clearly prove that the formyl group is introduced into the desired position with high regioselectivity between the two ortho directing alkoxy groups.No regio-isomers with the formyl group at other positions of the benzene ring were detected.
For unsymmetrical 2-methoxy-6-alkoxybenzaldehydes, we used commercially available 3methoxyphenol (7) as the starting material.O-Alkylation of 7 with the alkyl iodides readily produced 1-methoxy-3-alkoxybenzenes 8a−c, which were subsequently lithiated and formylated as described above to generate 2-methoxy-6-alkoxybenzaldehydes 9a−c in moderate yields (Scheme 3 and Table 1).The structures of 9a−c were confirmed by their 1 H NMR (no singlet peak in the aromatic region) and 13 C NMR spectra.Notably, entry d in Table 1 shows that although the alkylation of 7 with benzyl bromide gave 75% yield of 1-methoxy-3benzyloxybenzene (8d), treatment of 8d with n-BuLi/DMF did not furnish the desired product 2benzyloxy-6-methoxybenzaldehyde (9d).This could be rationalized by the high acidity of the benzyl hydrogens, which can be competitively deprotoned by n-BuLi, thus causing the formation of unexpected by-products.Therefore, another strategy was developed for preparation of 9d.The prerequisite starting material for preparation of 9d is obtained by methodology from Zacharie's work. 162-Hydroxy-6-methoxybenzaldehyde (12) was obtained from 3methoxyphenol (7) in three steps in overall 44% yield (reported yield 16 : 45%) (Scheme 4).Treatment of 12 with benzyl, allyl and propargyl bromide and ethyl 2-bromoacetate in the presence of potassium carbonate produced unsymmetrical 2-alkoxy-6-methoxybenzaldehydes 9d−g in 63%−75% yields.The structures of 9d−g were confirmed by their 1 H, 13 C NMR spectra and elemental analyses or HRMS results.The method is therefore useful for preparation of 2-alkoxy-6methoxybenzaldehydes with substituents containing acidic hydrogens.However, there is an obvious limitation that the 6-position has to be occupied by a methoxy group due to the starting material 3-methoxyphenol (7).

Scheme 5
In summary, several approaches have been developed for the preparation of symmetrical and unsymmetrical 2,6-dialkoxybenzaldehydes. The key step is the highly regioselective introduction of the formyl group into the desired position between two ortho directing alkoxy groups by the lithiation of 1,3-dialkoxybenzenes with n-BuLi, followed by formylation with DMF.

Experimental Section
General Procedures.THF was distilled from sodium-benzophenone prior to use.Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1H and 13 C NMR spectra (300 MHz and 75 MHz respectively) were recorded on a Gemini 300 NMR spectrometer in CDCl 3 (with TMS for 1 H and CDCl 3 for 13 C as the internal reference).Elemental analyses were performed on a Carlo Erba-1106 instrument.Column chromatography was performed on silica gel.All of the reactions were carried out under N 2 .