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

Abstract

ARKAT-USA, Inc.However, 2-formylbenzonitriles are not cheap compounds and to our knowledge relatively few methodologies which describe their synthesis have been reported (Figure 2). 2,[5][6][7][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. 2,18 Similar disappointing results are obtained in the reaction of 8 with the toxic CuCN. 2,19 On the other hand, the transformation of gem-dihalo compounds (benzal halides) into benzaldehydes is quite a common method. [20][21][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. 29 Figure 2. Common approaches to 2-formylbenzonitriles.Hydrolysis 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. NaOH) at high temperatures, [25][26] conditions too harsh for the synthesis of 2-formylbenzonitriles, Therefore, the transformation of benzal halides 7 into 2-formylbenzonitriles have been reported under milder conditions only in the presence of the rather expensive AgNO3, used in large excess (> 3 eq.), 5-7 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 2-formylbenzonitriles, 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.

Multifaceted Behavior of 2‐Cyanobenzaldehyde and 2‐Acylbenzonitriles in the Synthesis of Isoindolinones, Phthalides and Related Heterocycles

“…However, considering the narrow scope of the reactions described in scheme 67, the method previously reported by Patelski was reconsidered under different conditions, [46] refluxing easily accessible benzal bromides 162 in a mixture of water and dioxane, leading to a series of 2‐cyanobenzaldehydes in good to high yields, without using the excess of AgNO 3 (Scheme 68). [59] …”

“…[28] However, considering the narrow scope of the reactions described in scheme 67, the method previously reported by Patelski was reconsidered under different conditions, [46] refluxing easily accessible benzal bromides 162 in a mixture of water and dioxane, leading to a series of 2-cyanobenzaldehydes in good to high yields, without using the excess of AgNO 3 (Scheme 68). [59] Emphasis was also given to the synthesis of 2-acetylbenzonitrile because it is rather expensive, and because derivatives substituted on the aromatic ring are not easy to synthesize. In 2012 Gotor, Fernandez and co-workers [38] reported a synthetic pathway to 2-acetyl benzonitriles 95, requiring several steps and employing cyanating agents like NaCN or CuCN in Sandmeyer reactions in rather low yields.…”