A Simple and Efficient Palladium Catalyst of Nitrogen-Based Ligand for Cu(I)- and Amine-Free Sonogashira Reaction

Abstract Glycine, as a kind of commercially available and inexpensive ligand, is used to prepare an air-stable and water-soluble catalyst used in Sonogashira reaction in our study. In the presence of 1% [PdCl2(NH2CH2COOH)2] as catalyst, excellent catalytic activity towards the Sonogashira coupling of aryl iodides with terminal alkynes without using any additive such as Cu(I)-cocatalyst is observed in a mixture of water and acetone (3/3 mL) under air at 60 °C with NaOH as a base, giving products in good to excellent yields. GRAPHICAL ABSTRACT


INTRODUCTION
The synthesis of alkynyl compounds has attracted considerable interest because of their appearance in many biologically active natural products (such as panaxynol, panaxydol, panaxytriol, which show certain anticancer effects [1] ) and because they serve as key intermediates of pharmaceuticals or drug-like molecules [2,3] and can even be monomers of polymer materials [4,5] and liquid-crystalline material, [6,7] which show great application potential and have considerable economic value in the fields of medicine, organic synthesis, and materials chemistry. Thus, much attention has been focused on the development of efficient and selective methods for the synthesis of alkynes.
Transition-metal-catalyzed cross-coupling reactions can be considered as cornerstones in organic synthesis for the formation of carbon-carbon bonds. In these reactions, the coupling of aryl or alkenyl halides with terminal alkynes catalyzed by palladium in the presence of Cu(I) cocatalyst or not, commonly known as Sonogashira cross-coupling reaction, is one of the most powerful methods for straightforward sp 2 -sp carbon-carbon bond formation reaction to prepare arylalkynes and conjugated enynes encountered frequently in natural products, [8,9] bioactive molecules, [10,11] molecular electronics, [12,13] and dendrimeric and polymeric materials. [14,15] Therefore, considerable effort has been directed to the development of new and efficient palladium catalytic systems for Sonogashira cross-coupling reaction. [16][17][18][19][20][21] Generally, the Sonogashira reaction is performed with palladiumphosphane ligand complex, such as Pd(PPh 3 ) 2 Cl 2 , Pd(dppe)Cl 2 , and Pd(dppf)Cl 2 , in the presence of Cu(I) salt as cocatalyst and an amine as a solvent, such as triethylamine, under homogeneous conditions. When these palladium species are employed, they often require high loading of palladium (usually up to 5 mol%) and a larger amount of the Cu(I) salt. Additionally, many phosphine ligands are air sensitive and not environmentally friendly, significantly limiting their synthetic applications. [22,23] Besides, the presence of Cu(I) salt can result in the formation of oxidative homocoupling reaction of alkynes. [24] In past decades, although significant developments from the original palladium-phosphorus complexes [25] to palladium-P,N or palladium-P,O complexes, [26] palladium-nitrogen complexes [27] and N-heterocyclic carbene palladium complexes, [28] palladacycle patalysts, [29] and even the use of ligand-free palladium catalysts [30] have helped achieve the Sonogashira reaction with moderate to excellent yields, [31][32][33][34] most systems still require high reaction temperatures in organic solvents under an inert atmosphere and even need the presence of Cu(I) salt and an amine as solvent. Therefore, achieving a more active catalyst for simpler, milder, and more effective reaction conditions with the Cu(I)-, amine-, and phosphine-free catalytic system becomes more significant and challenging for chemistry researchers.
Taking stability and safety into consideration and from an economic and environmental viewpoint, recently we selected glycine as water-soluble nitrogen-based ligand to synthesize a catalyst with palladium chloride and found that glycine was a highly efficient ligand for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction, giving excellent yields for aryl bromides and moderate yields for aryl chlorides, [35,36] so that we expected to extend the use of this catalyst to other palladium-catalyzed transformations. In this article, we report a highly efficient [PdCl 2 (NH 2 CH 2 COOH) 2 ]-catalyzed Sonogashira cross-coupling reaction of aryl halides with terminal alkynes to form internal alkynes. In our studies, [PdCl 2 (NH 2 CH 2 COOH) 2 ], as a catalyst for the Sonogashira coupling reaction, has several advantages compared with those reported. [37][38][39] First, the ligand of the catalyst is glycine, which possesses lots of properties, such as solubility, stability, and safety.
Because of the properties of the ligand, the catalyst is also water-soluble, stable, and safe, which provides the possibility of catalyzing Sonogashira reaction in water under air. Second, synthesis of the catalyst is extremely easy and it is obtained only by stirring glycine with palladium chloride (PdCl 2 ) in ethanol and acetic acid for 24 h at room temperature under air. Third, from an economic point of view, glycine is commercially available and inexpensive, which creates feasible conditions for industrial production. Finally, the catalyst shows high efficiency to Sonogashira reaction in a mixture of water and acetone (3/3 mL) under air at 60°C with 1% catalyst and NaOH as a base in 2 h with the Cu-, amine-, and phosphine-free catalytic system, giving products in moderate to good yields.

Optimization of the Coupling Reaction Conditions
Initially, moderate yield (Scheme 1; Table 1, entries 1 and 2) was observed when iodobenzene and phenyl acetylene were selected to test the activity of the catalyst in a mixture of water and ethanol or PEG-400 under air at 60°C with NaOH (2.0 mmol) as a base for 2 h. Thus, the two compounds were chosen to establish guidelines for the optimization of our protocol as the model reaction. Because of good solubility of the catalyst in water, we continued to explore solvent systems consisting of water and another organic solvent. As shown in Table 1, when 1,4-dioxane or tetrahydrofuran (THF) was selected to be the mixed solvent with water (Table 1, entries 3 and 4), poor yield was observed. However, relatively high yield (Table 1, entry 5) was observed when acetone was chosen as solvent with water in the proportion of 3/ 3 mL. Next, different proportions of acetone and water were studied but the reaction did not perform well under other proportions (Table 1, entries 6-9) so that the mixed solvent of water and acetone (3/3 mL) was found to be the best reaction solvent.
After the best reaction solvent was found, other reaction conditions, such as reaction temperature or time, were studied in detail. Results of this preliminary survey are shown in Table 2 and Scheme 2. As shown in Table 2, when the effect of the amount of the catalyst on the coupling reaction was studied, we could see that lowering the amount of Pd from 2% mol to 1% mol did not affect the reaction performance ( Table 2, entries 4 and 5). When the amount of the catalyst was reduced to 0.5%, it gave products in moderate yield ( Table 2, entry 3), and when reduced to 0.1%, the coupling reaction could hardly be performed ( Table 2, entries 1 and 2). So, 1% mol catalyst was optimal for the system. Next, we found that reaction temperature had also an important role on the coupling reaction. When increasing the reaction temperature from 30 to 60°C (Table 2, entries 6-8), the yield also increased remarkably. It was worth noting that poor yield (34%) was obtained when reaction temperature was up to 80°C (Table 2, entry 9), indicating that high temperature was not suitable for the reaction under this system. In addition, prolonging the reaction time from 0.5 to 2 h (Table 2, entries 10-12), the yield increased from 86% to 93%. To further optimize the reaction condition, with the amount of catalyst fixed as 1% mol, the reaction proceeded well when inorganic base NaOH was used, affording the desired coupling product in excellent yield (Table 2, entry 12) under air at 60°C for 2 h. However, NEt 3 and K 3 PO 4 used in this reaction gave moderate yield ( Table 2, entries 13 and 14). In contrast, K 2 CO 3 and pyridine slightly promoted the reaction ( Table 2, entries 15 and 16) and organic base 1,2-propanediamine scarcely promoted the reaction ( Table 2, entry 17).

Scheme 2.
Optimization of other reaction conditions. in moderate to good yields (Table 3, entries 1-8). On the other hand, the terminal alkynes also have a significant effect on the coupling reaction. As shown in Table  3, the reaction of phenylacetylene, 1-hexyne, and 3-butyn-1-ol with aryl halides gave superior yields of the products to 3,3-dimethyl-1-butyne, indicating that terminal alkynes with steric hindrance, such as 3,3-dimethyl-1-butyne, gave products in moderate yields, significantly being less than 1-hexyne or 3-butyn-1-ol without steric hindrance. Moreover, the relatively poor activity was obtained when aryl bromides coupled with various terminal alkynes.

Possible Mechanism of the Catalyst for Sonogashira Reaction
The mechanism of the copper-free Sonogashira reaction is still not well known. The possible mechanism is as follows. The first step would be the oxidative addition of aryl halides to the palladium(0) complex. However, the second step is under debate. The base employed usually makes it hard to deprotonate the alkyne for the reaction with the oxidative addition palladium(0) complex (trans-R 1 PdXL 2 ) so that complexation of the alkyne to the complex is supposed to proceed first with displacement of one ligand to give intermediate complex (RCCH)-PdXL 2 . The ligated alkyne would be more easily deprotonated by base such as NaOH used in the reaction, forming the new complex R 1 Pd-(CCR 2 )L 2 , which gives the coupling product R 1 -CC-R 2 by reductive elimination.

Reagents and Machines
All reagents employed in the reaction were analytical grade, obtained commercially from J&K China Chemical Ltd. and used without further purification. 1 H and 13 C NMR spectra were recorded on a Bruker Avance III (400-MHz) spectrometer using tetramethylsilane (TMS) as the internal standard and CDCl 3 as the solvent. Elemental analyses (C, H, N) were carried out on a Perkin-Elmer model 240 C automatic instrument. Electrospray mass spectra (ES-MS) were recorded on a Finnigan LCQ mass spectrometer.

Recovery and Recycling of the Catalyst
The palladium catalyst can be easily recovered by simple extraction. Because the catalyst is water soluble and the reaction solvent consists of water and acetone, the catalyst can be separated from products and recovered by simple extraction. In addition, the catalyst used in the reaction is recyclable, but the catalytic efficiency decreases gradually with recycling time, from 93% to 53%. From Table 4, the recycling of catalyst was investigated using iodobenzene and phenyl acetylene as model substrates. We can see that the efficiency of catalyst recycling decreases apparently, even with prolonging the reaction time.

General Procedure for the Synthesis
The aryl halides (1.0 mmol), terminal alkynes (1.2 mmol), catalyst (1% mol, 0.003268 g), NaOH (2.0 mmol, 0.08 g), and water/acetone (3/3 mL) were added to a flask and stirred under air at 60°C for 2 h. Then, the 5 mL brine was added to quench the reaction and the mixture was extracted with ethyl acetate (3 × 15 ml). The combined organic phase was dried with Na 2 SO 4 for 3 h. Next, the organic phase was filtrated and removed on a rotary evaporator. Finally, the product was isolated by thin-layer chromatography (TLC) and the purified products were identified by 1 H and 13 C NMR.

CONCLUSION
In summary, it has been shown that the use of [PdCl 2 (NH 2 CH 2 COOH) 2 ] as catalysts in a mixture of water and acetone (3/3 mL) under air at 60°C with NaOH as a base is a very convenient way to carry out Sonogashira coupling reaction with the Co-, amine-, and phosphine-free catalytic system, which gives an extremely fast, highly efficient, and much more green approach to obtain alkynyl compounds found easily in natural products, bioactive molecules, and dendrimeric and polymeric materials, demonstrating great industrial application perspective and considerable economic value in the field of medicine, organic synthesis, and material chemistry.

SUPPORTING INFORMATION
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