Asymmetric Intermolecular Heck Reaction of Aryl Halides by Pd-histidine Organocatalysts

Extensive studies of asymmetric intermolecular Heck reaction are described and provide a deeper insight into histidine-catalyzed. In particular, aspects of enantioas well as diastereoselectivity of these reactions are discussed. As the first report, we synthesized five histidine-based organocatalyts including histidine as a well-defined and biodegradable natural structure alone and in combination with 2,4,6-trichloro-1,3,5-triazine, benzene-1,3-diamine, dimethyl malonate and dimeric structure applied in the asymmetric intermolecular Heck reaction of aryl halides; their efficiency was compared to each other’s. These phosphine-free palladium catalysts were found as efficient catalytic system which provided the superior efficiency with excellent yields, regioselectivity and enantioselectivity. In these among, histidine with 2,4,6-trichloro-1,3,5-triazine which generate the star like molecule palladium catalyst gave the best activity in asymmetric intermolecular Heck reaction with excellent yields and good regioand enantioselectivity under mild reaction conditions. The asymmetric intermolecular Heck reaction has been limited to aryl and vinyl triflates or aryl iodide in the rare reports of available Pd catalysts. Herein, we extend the reaction to aryl bromides. In addition, the scope of reaction was examined in two different techniques: conventional heating and microwave irradiation and compared. For the first time, microwave irradiation sintering is successfully used for this reaction. Comparison of catalytic activities of our catalyst (Pd/His) with literature examples confirmed our success.


Introduction
In recent years, asymmetric Heck reaction of aryl halides or aryl triflates with 2, 3-dihydrofuran have received considerable attention due to usages of some products in natural synthesis [1][2]. Up to now, numerous chiral catalytic systems for asymmetric Heck reaction of 2, 3-dihydrofuran with phenyl triflate were examined [3][4][5]; but, application of aryl halides, as more available substrates, in this coupling reaction is rare [6].
However, to the best of our knowledge, asymmetric arylation of 2, 3-dihydrofuran employing histidine-based organocatalytst has never been reported.
As a further extension of our ongoing work; [34][35][36][37] Herein we describe efficient and facile methods for Halides by Pd-histidine Organocatalysts intermolecular Heck reaction of aryl halides and 2, 3dihydrofuran which catalyzed by several histidine base Pdcatalytic systems. The structure of organocatalytst's ligands were represented in Scheme 1. The ligand 1 was found as the most efficient compound for asymmetric coupling reaction under thermal and microwave conditions with excellent ragio-and stereoselectivities. As we know, this is the first report of using phosphorus-free palladium catalyst in regioselective intermolecular Heck reaction of aryl halides with 2, 3-dihydrofuran.

Results and Discussion
Firstly, their catalytic efficiency in intermolecular Heck reaction of aryl halides with dihydrofuran were explored. To obtain the optimum experimental conditions, the Heck crosscoupling of 4-methoxyiodobenzene with 2, 3-dihydrofuran was chosen as a model reaction and various reaction conditions was explored. The results are summarized in Table  1. At first, the reaction was done applying different Pd/His catalysts, as can be seen, ligand 1 gave the best results. In continues, various reactions conditions in presented of this ligand were optimized. Different solvents such as acetonitrile, ethanol, dimethyl sulfoxide and tetrahydrofuran were examined. The last one (THF) was found as the most effective solvent in reaction conversion, selectivity and enantioselectivity. After optimization of reaction temperature, 40°C was selected as sufficient heat. Among various base, K 2 CO 3 was found as the most effected. The reaction was performed in THF with K 2 CO 3 at 40 °C for 6 h. a Iodobenzene (0.5 mmol), 2, 3-dihydrofuran (1 mmol), solvent (3 mL) and base (2 mmol), 6 h; b with 0.04 mol% PdCl2; c Conversion percentages and selectivity was determined by GC [29]; d The enantioselectivity was measured by GC equipped with chiral column; e Due to low conversion, ragio-and enantio-selectivity were not detected.
As shown herein, Pd/His exhibits good catalytic activity and enantioselectivity, which is obtained in the mildest reaction conditions (low temperature and relatively shorter reaction times).
Using microwave irradiation, the reaction times was decreased remarkably. So, to further optimize the reaction conditions, the temperature and the MW power were also optimized and the best results were obtained using K 2 CO 3 , THF at 400 W. The optimum temperature was found as 40 °C. No increase in yield was observed at higher temperatures, while lowering the temperature below 40°C reduced the reaction rate. In continuous, the generality and versatility of this asymmetric palladium catalyst in regioselectivty arylation reaction of 2, 3-dihydrofuran cross-coupling of aryl halids was examined in two different techniques: conventional heating (method A) and MW irradiation (method B), were compared. As shown in Table 2, the microwave-assisted reactions were superior to those using conventional heating. It was observed that in both technics, some varieties of aryl halids with either electron-rich or electron-deficient substitutes reacted efficiently with 2, 3dihydrofuran and gave the corresponding products in moderate to good yields, ragio-and enantioselectivity. In general, high yields (80−99%), good regioselectivity and excellent enantioselectivity are observed for aryl iodides and bromide substrates bearing either electron donating or electron-withdrawing substituents (entries 1−9). Actually, founding active substrates is one of the major limitations of this reaction; so, these results can be introduced as a success.
The obtain results was compared to various reported chiral catalysts for the asymmetric intramolecular Heck reaction arylation of 2, 3-dihydrofuran ( Table 3). Almost of reported methods applied palladium catalyst with complex phosphine chiral ligands and in long reaction times.
Phenyl triflates were used as substrates in the typical process of the Heck arylation of 2, 3-dihydrofuran, the main disadvantage of triflate is easily hydrolysis. To the best of our knowledge, a few reports about stereoselective Heck coupling of 2, 3-dihydrofuran with aryl hides are available. Aryl hides are cheaper, more stable and more easily available substrates compared with triflates. Therefore, present procedure can be a valuable for the homochiral catalysts in asymmetric synthesis of derivatives of 2, 5-dihydro-2-phenylfuran.
One of the trends of the catalysis industry and green chemistry in environmental and economical point of view is scale-up synthesis. To gain insight into this issue, the Heck reaction of iodobenzen with 2, 3-dihydrofuran was selected and the scale of the reaction was increased to 10.0 mmol, keeping the reaction stoichiometry intact.

Conclusion
This is the first report of applying oxidant-and phosphinefree catalyst in asymmetric Heck reaction of aryl halides with 2, 3-dihydrofuran. The reaction was found to proceed successfully, the corresponding product was obtained in good yields, high regio-and enantioselectivity at mild reaction conditions without inert atmosphere and phase transfer agents. In this work, we developed a novel palladium catalyst using palladium chloride salt and nitrogen rich histidin-based ligands (Pd/His) with cleaner reaction profiles and simple operation.