Reaction of benzal bromides in water/dioxane system for easy access to benzaldehydes and 2-formylbenzonitriles (2-cyanobenzaldehydes)

A convenient method of synthesis of substituted benzaldehydes and 2-formylbenzonitriles has been described by reaction of the easily available benzal dibromides in a dioxane/water system


Introduction
2-Formylbenzonitriles 1 are useful starting materials for the preparation of phthalides 1 or nitrogencontaining heterocycles such as isoindolinones [2][3][4][5][6][7][8][9][10][11][12] and isoindoles [13][14] (compounds 2-5, Figure 1), which have been shown to possess a wide range of biological activities.15][16][17] In addition, many of the existing synthetic methods suffer from certain limitations with respect to yield, reaction conditions and toxicity.In particular, the formylations of 6, performed under strongly basic conditions, usually lead to 1 in rather low yields. 2,18Similar disappointing results are obtained in the reaction of 8 with the toxic CuCN. 2,191][22][23][24][25][26][27][28][29][30] In this case solvolytic displacement of halogen with successive replacement by hydroxyl followed by formal loss of HBr to generate the corresponding aldehyde, is favored by resonance stabilization offered by the aromatic ring. 29ydrolysis of the benzal halides to the corresponding aldehydes is often conducted in the presence of strong acids (e.g., 95% H2SO4) or strong bases (aq.6][7] with severe limitations concerning the scale of the synthetic procedure, the necessity of additional tedious purification operations and eventual metal contamination.In our ongoing project on large-scale reaction of 2formylbenzonitriles, we came across these problems and we realized that not much attention has been devoted to the development of simple and effective methods for the synthesis of these valuable aldehydes.Thus, in this article, we have reconsidered the reactivity of benzal bromides 7, developing a convenient approach to 2-formylbenzonitriles, and then we have extended the method to the synthesis of other model benzaldehydes.

Results and Discussion
During our investigations into the large-scale synthesis of 2-formylbenzonitrile 1a by hydrolysis of the respective benzal bromide, instead of using the classical procedure based on large amounts of AgNO3 in refluxing CH3CN/H2O, [5][6][7] we investigated the simple water/dioxane mixture, a system with high boiling temperature in which the substrate 7a is well soluble.Under the conditions of Scheme 1, we were pleased to observe the formation of the desired 2-formylbenzonitrile (X=H) in very high yield in a reasonable reaction time (Table 1, entry 1).The reaction was also performed at 10 mmol scale with similar efficiency, particularly useful for preparative purposes, since 1a can be recovered from the workup in high purity after a short chromatographic purification (Table 1, entry 2).

Scheme 1
In addition, in a control experiment, we tried the hydrolysis of 6a only in refluxing CH3CN/H2O.However, we observed low conversion (about 50%), low yield (30%) and decomposition products (Entry 3), pointing out both the necessity to use the silver salts in large excess, as required by the literature procedure, 5 and at the same time highlighting the efficacy of our methodology.Then, in order to enlarge the scope of the method, we focused on the hydrolysis of other benzal bromides, easily obtained in high yields by radical dibromination of different 2methylbenzonitriles 9. [5][6][7] The 2-methylbenzonitriles 9a, 9c, 9d and 9i (X=H, 5-Cl, 5-F and 4-NO2) are commercially available.Other substrates 9b, 9e-h bearing different groups, like 5-nitro, methoxy, halogens (Br and I) and 3,4-dimethoxyphenyl were conveniently obtained according to the synthetic route shown in Scheme 2, giving access to a range of starting materials which were submitted to the radical dibromination.With the collection of benzal bromides 7b-i now available, we performed the respective hydrolysis under the developed conditions, which afforded the corresponding formyl benzonitriles in moderate to good yields (Table 1).The reaction rates were dependent upon the substituent.6][7] In addition, the methodology herein described allows the access to several new 2formylbenzonitriles (products 1b,c,f-i).Only the benzal bromides bearing the 5-NO2 and 4-NO2 substituents (7b and 7i) were less reactive, giving the respective aldehydes in rather low yields (Entry 4 and 11).In these cases, we recovered a large amount of the starting materials (about 50%) and we observed the formation of smaller amount of a byproduct corresponding to the 3hydroxyphthalide (about 10%), 31,32 as a consequence of the competitive cyclization on 1b at the cyano group and the hydrolysis of the obtained imidate.For comparison, a control experiment performed on 7b in the presence of AgNO3 gave only decomposition products, and 1b was not detected.
Next, we investigated the hydrolysis of some well-known model benzal bromides in order to further determine the scope and limitations of the approach, and for comparison with other methods reported in the literature for the same transformation. 27,28Under the described conditions, the hydrolysis was also effective in the synthesis of the benzaldehyde and of other monosubstituted benzaldehydes bearing different substituents (Table 2).All pure products were isolated in very high yields from the workup without any further chromatographic purification, the results being somewhat better than or comparable with those reported in the literature. 27,28Only the dibromide bearing the strongly electron-withdrawing nitro group was less reactive, and unreacted starting material was recovered (Entry 4).

Conclusions
In this paper we report that the simple water/dioxane system easily transforms benzal bromides into their corresponding benzaldehydes in good to high yield under refluxing conditions.The method is particularly convenient in comparison with others reported in the literature, especially for the synthesis of 2-formylbenzonitriles and for large scale applications.

Experimental Section
General.All reactions were performed using commercially available compounds without further purification.Column chromatographic purification of products was carried out using silica gel 60 (70-230 mesh, Merck Compounds 7a, 7d, 9b, 9e, 10 and 13a were prepared according to the literature. 5,33][36][37][38][39][40] Spectroscopic data are given only for compounds never previously described.5-Iodo-2-methylbenzonitrile (9f). 34Water (10 mL) and concentrated HCl solution 37% (3 mL) were cooled to 0 °C in an ice bath.5-Amino-2-methylbenzonitrile 10 (1.00 g, 7.5 mmol) was dissolved in this mixture and sodium nitrite (0.573 g, 7.2 mmol) in water (2.5 mL) was added.The solution was allowed to stir at 0°C until all of the starting material dissolved (30 minutes).A solution of potassium iodide (1.81 g, 11.2 mmol) in water (2.5 mL) was added and allowed to stir for an additional 30 minutes at 0°C.Diethyl ether (20 mL) was added before stirring an additional 30 min.The reaction mixture was loaded into a separatory funnel, and the organic layer was isolated.The aqueous layer was extracted with additional diethyl ether, then the organic extracts were washed with saturated aqueous sodium thiosulfate solution, saturated NaHCO3, water, and brine.The organic layer was dried over MgSO4, filtered, and concentrated, leaving an orange crystalline residue.Purification by chromatography (ethyl acetate/hexane 5/95) gave the product as a white solid (0.  35 5-Amino-2-methylbenzonitrile 10 (1 g, 7.5 mmol) was dissolved in a solution of H2SO4 (4 mL, conc.) in H2O (12 mL).Crushed ice (10 g) was added.
Then, a solution of NaNO2 (0.650 g, 9.25 mmol) in H2O (4 mL) was added dropwise below 5 °C.Five minutes later, cold water (5 mL), urea (0.070 g, 1.17 mmol) and ice (5 g) were added in sequence.The reaction mixture was added into a refluxed solution of Na2SO4 (5 g, 41mmol) and conc.H2SO4 (10 mL) in H2O (5 mL).The resulting mixture was refluxed for 2 h, then extracted with ethyl acetate for three times.Combined organic parts were dried over Na2SO4, filtered and concentrated affording the title product as a brown waxy solid (0.550 g, 4. General procedure for dibromination 5 A solution of substituted benzonitriles or substituted toluenes (1 mmol) in CCl4 (15 mL) was treated with N-bromosuccinimide (2.5 mmol) and benzoyl peroxide (0.1 mmol).The solution was refluxed for 24 h, cooled to r.t. and filtered to remove succinimide.The filtrate was concentrated and purified by column chromatography.

Table 1 .
2-Formyl benzonitriles synthesized in water/dioxane system (seeScheme 1) a Reaction carried out on 0.6 mmol scale; b Isolated yield; c reaction carried out on 10 mmol scale; d reaction performed in refluxing mixture of CH3CN/H2O (5 mL, 1/1); e in parentheses yield of the recovered starting materials

Table 2 .
Application of the method in the synthesis of model benzaldehydes a Isolated yield, b yield of the recovered starting materials.
).The NMR spectra were recorded on Bruker DRX 400, 300, 250 spectrometers (400 MHz, 300 MHz, 250 MHz, 1 H; 100 MHz, 75 MHz, 62.5 MHz 13 C).Spectra were referenced to residual CHCl3 (7.26 ppm, 1 H, 77.23 ppm, 13 C).Coupling constants J are reported in Hz.Yields are given for isolated products showing one spot on a TLC plate and no impurities detectable in the NMR spectrum.Mass spectral analyses were carried out using an electrospray spectrometer Waters 4 micro quadrupole or Agilent GC-MSD 5975C with triple axis detector.Elemental analyses were performed with FLASHEA 1112 series-Thermo Scientific for CHNS-O apparatus.