New Palladacycle-Derived Acylhydrazones as Pre-catalysts in Mirozoki-Heck Coupling and Oxyarylations

New acylhydrazone-based palladacycles are prepared and evaluated as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.


INTRODUCTION
Palladacycles were discovered in the mid-1960s as intermediates in palladium-mediated transformations and have been employed as active intermediates in cascade transformations leading to complex molecular architectures (Beletskaya andCheprakov 2004, Dupont et al. 2005).
Since the preparation of the cyclopalladate trio-tolyl-phosphine complex reported by Herman (Hermann et al. 1995(Hermann et al. , 1999) ) and its use as a precatalyst for palladium-catalyzed Mirozoki-Heck and other cross-coupling reactions, the use of palladacycles has experienced tremendous growth (Beletskaya andCheprakov 2004, Dupont et al. 2005).
Their high thermal stability in the solid state, easy preparation and ready modulation of both steric and electronic properties make them affordable tools in organic synthesis.In fact, a large number of new palladacycles have been prepared and used as pre-catalysts (Alonso et al. 2000, Nájera 2016).
Despite some suggestion of a mechanism involving Pd(II) and Pd(IV) species (Shaw et al. 1998a, Shaw 1998), they are considered as a source of in situ formed Pd(0) nanoparticles, which have been successfully used in several coupling reactions in low catalytic loading.In addition, palladacycles can be prepared in water and do not require the presence of ligands, making their use very attractive (Beletskaya andCheprakov 2004, Dupont et al. 2005) Although some hydrazone-based palladacycles are known in the literature and promote Suzyki-Miyaura and Mirozoki-Heck coupling reactions (Cardenas andEchavarren 1995, Nagy et al. 2005), herein we describe the first synthesis and application of acyl-hydrazone-based paladacycles as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.

DISCUSSION AND RESULTS
Acylhydrazones (1a-c) are easily prepared by the reaction of acylhydrazines with aromatic aldehydes and have been extensively used as a platform to construct interesting biologically active compounds (Fraga and Barreiro 2006).
The new palladacycles 2a-c were prepared by electrophilic C-H activation of acylhydrazones 1a-c with Li 2 PdCl 4 in methanol in the presence of NaOAc as the base at room temperature (Figure 1) (Alonso et al. 2002).Compounds 2a-c precipitated from the reaction medium and were obtained as yellowish stable solids after filtration.
Once 1 H NMR spectra are complex to analyze the structures of 2a-c were determined by indirect way.Palladacycles 2a and 2c were reduced with NaCNBD 3 in THF/MeOH (Figure 2) (Alonso et al. 2002) leading to the respective deuterated acylhydrazones 3a and 3c, which were characterized by GC/MS and 1 H NMR. Also, the palladacycle 2b was reduced under the same conditions, yielding the acylhydrazone 3b (GC/MS).
A fragment of the oxonium ion at m/z = 105 was the base peak in all three cases (Figure 3).Since this fragment does not present deuterium in its structure, the Pd-C bond in palladacycles 2a-c must be located at the B ring.Deuterated acylhydrazones 3a and 3c led to a deuterated fragment at m/z = 224, while for 3b a fragment was observed at m/z = 147, by releasing a deuterated phenyl group.These analyses clearly indicate that the deuterium is located in the B-ring, in accordance with the proposed structures of 2a-c.
To demonstrate the efficiency of these new acylhydrazone-based palladacycles, they were evaluated in the Mirozoki-Heck reaction between iodobenzene (4) and methyl acrylate (5).The yield of methyl cinnamate (6) and the major reaction conditions studied are shown in Figure 4 and Table I.Triethylamine was used as the base and after 10 h at 110 o C in the presence of 0.1 mol% Pd source, 6 was obtained in excellent yield, regardless of the pre-catalyst used (entries 1-3, Table I).Similar yields were obtained in the presence of 0.001 mol% of 2a-c, but using a more prolonged reaction time (entries 3-6, Table I).Similar results were obtained when DIPEA was used as the base (entries 7 and 8, Table I) but yields decreased in the presence of Na 2 CO 3 (entries 9-11, Table I).The yields were still good when MeCN or NMP were employed as solvents (entries 12-16, Table I).However, no reaction was observed when the reaction was  conducted in the mixture DIPEA-water (data not shown).
Next, we studied the Mirozoki-Heck reaction between 4 and styrene (7), shown in Figure 5 and Table II.Stilbene (8) was obtained in reasonable yield when 0.1 mol% 2b or 2c were used as precatalyst (entries 1 and 2, Table II) but the yield decreased when 0.001 mol% of pre-catalyst was employed (entries 3 and 4, Table II).
Finally, we turned our attention to a more challenging transformation, the oxyarylation reaction.The first catalytic version of the oxyarylation reaction was reported (Larock 1998) under conditions that favored the neutral pathway.Kiss et al. (2003) reported the use of silver carbonate as base, conditions where the cationic mechanism is favored.
The scope of this reaction in the presence of Ag 2 CO 3 was studied by our group and a cationic palladacycle formed in the migratory insertion step could be intercepted by ESI-MS and characterized by ESI-MS/MS (Buarque et al. 2010).As the carbopalladation step occurs with the attachment of the aryl group and the palladium atom in the same face of the olefin, the cis-stereoselectivity observed in oxyarylation reaction can be understood by    The Najera's palladacycle also catalyzed these reactions, but the mechanism was not studied under these conditions (Leão et al. 2011).The use of PEG-400 as solvent and additive was also reported (de Moraes et al. 2015).
The oxyarylation reaction of dihydronaphthalene 10 with ortho-iodophenols 9a-c was used in order to evaluate the efficiency of the palladacycles 2a-c.(Figure 6 and Table III).Interestingly, these reactions did not proceed when performed in DMF.However, compounds 11a-c were obtained in reasonable yields using the mixture MeCN-H 2 O (MeCN-H 2 O =1/3), irrespective of the pre-catalyst used (entries 1-5, Table III).Yields for 11a are higher than that obtained with Najera's palladacycle (35% under thermal conditions, data not shown) (Leão et al. 2011).In contrast, for reactions using silver carbonate as base (de Moraes et al. 2015) the yields did not depend on the pattern of substitution in 9.

CONCLUSIONS
In summary, we describe the synthesis of new acylhydrazone-based palladacycles and their application as efficient pre-catalysts in Mirozoki-Heck and oxyarylation reactions in reasonable to good yield using low catalytic load.

GENERAL
All the reagents and solvents were purchased from Aldrich Chem.Co. and used without purification.Melting points were determined with a Thomas-Hoover apparatus.Column chromatography was performed on flash silica 0.035-0.070mm (Acros).IR spectra were obtained in an IR Prestige-21 Shimadzu.NMR spectra were recorded on a Varian 400 (400 MHz) spectrometer.Low-resolution mass spectra were obtained from a GCMS-QP 5000 Plus Shimadzu.

TABLE II Yields and main conditions for the reaction shown in
Figure 5.

Figure 3 -
Figure 3 -Proposed mechanism for the fragmentation of 3a-c.