A Domino Oxidation/Arylation/Protodecarboxylation Reaction of Salicylaldehydes: Expanded Access to meta‐Arylphenols

Abstract A method that allows salicylaldehydes to be efficiently transformed into meta‐arylated phenol derivatives through a cascade oxidation/arylation/protodecarboxylation sequence is presented. We demonstrate that the aldehyde functional group can be used as a convenient removable directing group to control site selectivity in C−H activation. Aldehydes are easily introduced into the starting materials and the group is readily cleaved after the C−H functionalization event.

Transition metal catalyzedC ÀHa ctivation providesa na tomand step-economical alternative to the formation of CÀC, CÀX, CÀO, and CÀNb onds. [1] Site-selective functionalization of ubiquitous CÀHb onds is ah ighly attractive strategy as it allows efficient and reliable access to target molecules. There have been tremendous advances in this field, in particular for the functionalization of aromatic compounds. [2] In these cases, aregioselectivec ontrolling group is usually required owing to the similar reactivity of the CÀHb onds in benzene derivatives. The most popular strategy is the use of directing groups,w hich offer site-selective functionalization through chelation assistance, and dozens of methods for ortho-functionalization based on this strategy have been reported in recent years. [3,4] However,i tb ecomes more challenging to apply this type of strategyw hen the target CÀHb ond is distant from the directing group;t he development of direct meta-selective functionalizationr emains as ignificant challenge. [5] Additionally,i fadirecting group functionality is not present in the startingm ate-rial, furthers ynthetic steps are required to install, and possibly remove, the directing group, which is as ubstantial drawback for synthetic applications.S ignificant research effort has therefore been focusedo nt he development of directing groups that are easily introduced and removed, and so are applicable to the synthesis of aw ider range of target molecules. We recently developed an ovel strategy using at ransient carboxyl group that facilitates ap alladium-catalyzed cross-coupling reaction ortho-to the carboxylic acid (meta-t ot he hydroxyl substituent) which,f ollowed by decarboxylation of the arene, affords meta-arylated phenol derivatives (Scheme 1a). [6,7] This methoda llowed the synthesis of meta-arylphenolsf rom cheap phenolsinasingle synthetic operational step, and substituents including electron-donating and electron-withdrawing groups are tolerated. However,t he carboxyl group is installed by aK olbe-Schmitt carboxylation, requiring high CO 2 pressure (20-100 atm) and high temperature (120-300 8C), [8] which can limit the synthetic applicationso ft he method.
To avoid the use of harsh conditions, it is key to find ar emovabled irecting group that:( 1) can be easily installed under mild conditions; ( 2) can facilitatea northo-functionalization; (3) can be easily cleaved,r evealing the desired meta-arylated products.S alicylaldehyde motifsa re widely found in natural products as well as being key precursors to av ariety of useful molecules. [9] Importantly,t he aldehyde group can be easily and efficiently introduced into phenol derivatives under mild conditions by as imple ortho-selective formylation (Scheme 1b). [10,11] However, due to its sensitivity under commonC ÀHa rylation reaction conditions, the aldehyde group has rarely been used as ad irecting group before. [12] In this report, we describe how aldehydes can be used as efficient traceless directing groups, allowing the synthesis of meta-arylated phenol derivatives under ap alladium-catalyzed system.
Interestingly,1 7% of the desired product was obtained. The amount of Ag 2 CO 3 proved crucial, and 1.0 equivalent of Ag 2 CO 3 performed best (Table 1, entry 2). The source of the Pd catalystw as found to be important,w ith PEPPSI-IPr (from the pyridine enhanced precatalyst preparation stabilization and initiation family) leading to the best yield (Table 1, entry 4). Moreover,t he addition of K 2 CO 3 significantly improved the yields (Table 1, entries 5a nd 7). Finally, increasing the amount of Pd to 5mol %l ed to 72 %y ield (Table 1, entry 7). Further efforts aiming to facilitatet he oxidation of the formyl group in situ by the addition of stronger oxidants, were unsuccessful. It was envisagedt hat oxidationt os alicylic acid may be required before ortho-metalation. [13] However, the addition of p-benzoquinone and m-CPBA (m-chloroperoxybenzoic acid) completely shut down the reaction (Table 1, entries 8and 9).
[c] 1.0 equiv of m-CPBAwas added into the reaction.
Scheme2.Scopeo ft he domino oxidation/arylation/protodecarboxylation process on substituted iodoarenes. 3.0 equiv of 2 with respect to 1a were used. Yields are of isolatedpure material.
Chem. Asian J. 2016, 11,347 -350 www.chemasianj.org aminationo ft he crude reactionm ixtures revealed that no ortho-arylated salicylaldehyde intermediate was observed, with 20 %o fs alicylic acid being obtained instead (Scheme 5a), thus indicating that pathway three may be in operation. To probe this mechanism further, we heated salicylaldehyde in the presence of Ag 2 CO 3 but only starting materials were recovered (Scheme 5b). However,4 2% of salicylica cid was obtained when salicylaldehyde was submitted to the standard arylation conditions in the absence of iodoarene. AW acker-type oxidation process might be the explanation of this Pd-catalyzedo xidation of salicylaldehyde. [18] Finally,t he use of the iodide abstractor NMe 4 OAc, which has been shown to be an efficient replacementf or AgOAc when oxidation is not required, [19] resulted in no arylation reaction. These experimentss uggest that this transformation of salicylaldehydes to meta-arylatedp henol derivatives proceeds througha no xidation/arylation/proto-decarboxylation process.
In summary,w eh ave described am ethod for the preparation of meta-arylated phenols from salicylaldehyde derivatives. Importantly,u nlike most directing groups, the aldehyde group can be easily introduced into the starting material andr emoved after CÀHf unctionalization in at andemf ashion.Apreliminary mechanistic study indicates that the reactiono ccurs throught hree steps involving ap alladium-catalyzed oxidation of the salicylaldehyde followed by ortho-arylation of the salicylic acidi ntermediate and subsequent protodecarboxylation of the arylatedp roduct. Remarkably,t hese three steps occur in ac ascade process, allowing for as imple and efficient synthetic operation.

Experimental Section General Information
All chemicals used in this work were obtained from commercial sources and used without further purification. Salicylaldehyde starting materials were prepared by Skattebø's procedure [11b,f] except 1a and 1e,w hich were purchased from Sigma Aldrich. Analytical thin-layer chromatography was performed on pre-coated Merck silica gel F254 plates and visualized under UV light. Melting points were obtained using aB ibby Stuart Scientific apparatus and are uncorrected. IR spectra were recorded using aB ruker Te nsor 37 FTIR machine and are quoted in cm À1 . 1 HNMR spectra, recorded at 400 MHz, are referenced to the residual solvent peak at 7.26 ppm (CDCl 3 ). 13 CNMR spectra, recorded at 101 MHz, are referenced to the residual solvent peak at 77.0 ppm (CDCl 3 ).