A highly efficient copper and ligand free protocol for the room temperature Sonogashira reaction

Abstract

A mild and efficient catalytic system based on PdCl₂ and Na₂SO₄ has been developed for the Sonogashira reaction of aryl iodides at room temperature. The system provides a simple route to obtain polyfunctional alkynes under ligand and copper free conditions. The procedure is equally efficient for aliphatic alkynes and aryl bromides.

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Introduction

The Pd-catalyzed Sonogashira reaction of a terminal alkyne with an aryl halide is found to be a reliable tool for the construction of polyfunctional alkynes, which find extensive applications ranging from pharmaceuticals to agrochemicals and in materials chemistry.¹ This method was developed by Sonogashira, Tohda, and Hagihara in 1975 and since its discovery, various modifications have been made to the reaction conditions.^2,3 Initially these reactions were performed in an organic solvent with the concomitant addition of ligand and a Cu-salt as co-catalyst.^2a Although the addition of copper is advantageous in terms of reaction efficiency, the formation of undesired Glaser type homocoupling from the alkyne is one of the major obstacles associated with this reaction.⁴ So to address this issue several other additives were used to maintain the reaction efficiency such as Ag,⁵ Zn,⁶ Al,⁷ Sn,⁷ tetrabutyl ammonium salts⁸ etc. On the other hand ligand plays a key role in the Sonogashira reaction which is generally used to stabilize the active palladium species in the reaction. Among the ligands designed for this reaction significant amount of success have been achieved with phosphine based ligands such as electron rich bulky phosphanes,⁹ water soluble phosphanes such as TPPTS and TXPTS,¹⁰ nitrogen based ligands such as N-heterocyclic carbenes,^1c,11 oxime palladacycles,¹² amines¹³ etc. Although complex containing such ligands show excellent reactivity, however in majority of cases principal drawbacks are the availability, stability, and cost of the palladium complexes and related ligands. In addition they also lead to waste disposal which have severe effect on the environment. So regarding the principles of Green chemistry it is the necessity to design catalytic system using cheap and non toxic reagents under mild reaction conditions. Thus the development of a protocol under ligand and copper free condition for Sonogashira reaction is highly desirable. For many years simple inorganic salts are often use are as an activator in different organic transformation.¹⁴ The innocuous nature and rate enhancing effect of these salts makes them a suitable alternate for ligands in the Pd-catalyzed Suzuki–Miyaura cross coupling reaction.^15,16 Recently our group has reported the efficiency of Na₂SO₄ as an activator in the Suzuki–Miyaura cross coupling reaction.¹⁶ In order to extend the scope of this protocol herein we reported the efficiency of same catalytic species in Sonogashira cross coupling reaction of aryl iodides with aryl acetylenes at room temperature.

Results and discussion

The enhancing effect of non-toxic salt particles in Suzuki–Miyaura cross coupling reaction is well known.¹⁶ However to the best of our knowledge; there is no report available on the effect of non-toxic salt particles in Pd catalysed Sonogashira reaction. Therefore we wish to study the effect of different metal salts in the Sonogashira reaction of aryl iodides. For that purpose iodobenzene (0.5 mmol) and phenyl acetylene (0.6 mmol) was considered as model substrate. The preliminary investigation for reaction optimization was performed with 2 mol% of PdCl₂ and three equivalent of K₂CO₃ (1.5 mmol) in MeOH (2 mL) at room temperature under aerobic condition. The results obtained are highlighted in Table 1. It was found that MnCl₂ has no effect in the cross coupling reaction (Table 1, entry 1). The yield of cross coupling product was slightly increased when ZnCl₂ was used as an additive (Table 1, entry 2). Similar observations were also noticed in case of ferrous and ferric salts (Table 1, entries 3 and 4). Then we thought to incorporate alkali metal salts in the reaction. It is interesting to observe that Na₂SO₄ can enhance the efficiency of Sonogashira reaction and provide excellent yield of isolated cross coupling product (Table 1, entry 5).

Table 1 Effect of salts on Sonogashira reaction of aryl iodides^a

Entry	Catalyst (2 mol%)	Additive	Yield^b (%)
a Reaction conditions: iodobenzene (0.5 mmol), phenyl acetylene (0.6 mmol); additive (10 mol%), K2CO3 (1.5 mmol), MeOH (3 mL) at room temperature unless otherwise noted.b Isolated yield.c 1 mol% PdCl2 was used.d 1 mol% of PdCl2 and 20 mol% of Na2SO4 was used.
1	PdCl2	MnCl2	54
2	PdCl2	ZnCl2	70
3	PdCl2	FeSO4·7H2O	72
4	PdCl2	FeCl3	76
5	PdCl2	Na2SO4	91
6	PdCl2	LiCl	78
7	PdCl2	NaCl	81
8	PdCl2	NaOAc	69
9	PdCl2	—	54
10	Pd(OAc)2	—	56
11	Na2PdCl4	—	82
12	Pd(OAc)2	Na2SO4	87
13^c	PdCl2 (1 mol%)	Na2SO4	59
14^d	PdCl2 (1 mol%)	Na2SO4	65

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Compared with the efficiency of Na₂SO₄, other alkali metal salts viz. LiCl, NaCl and NaOAc showed slightly lower activity (Table 1, entries 6–8). However the yield of the cross coupling product decreased significantly when the reaction was performed in absence of Na₂SO₄ (Table 1, entries 9 & 10) which clearly confirms the role of Na₂SO₄ in the reaction. The use of in situ generated complex Na₂PdCl₄ results 82% of isolated cross coupling product (Table 1, entries 11). It is important to mention here that the amount of Glaser type homo-coupling product in case of Na₂SO₄ is minimized to only 1%. A typical reaction with Pd(OAc)₂ and Na₂SO₄ results 87% of desired product (Table 1, entries 12). In order to check the effect of amounts of PdCl₂ and Na₂SO₄, reactions were performed with various amounts of catalyst and additive. Finally we observed that 2 mol% of PdCl₂ was necessary for optimum yield (Table 1, entries 5 vs. 13 & 14). Recently PdCl₂/Na₂SO₄ system has been found to be very effective for the Suzuki–Miyaura coupling reaction.^16,17 Although the exact role of Na₂SO₄ is not clear, it is believed that the addition of sodium sulfate, could provide soluble ate complex of palladium, Na₂Pd(SO₄)₂, which is the actual catalytic species.^16,17

Our next goal was to identify a suitable solvent which can accelerate the reaction at good rate. A myriad number of aqueous and non-aqueous solvents were examined. The results are listed in Table 2. It has been observed that alcoholic solvents viz. MeOH, EtOH and i-PrOH are most suited for the reaction as excellent yield of cross coupling product was obtained in all cases (Table 2, entries 1–3). However, the yield dramatically falls when aqueous alcoholic solvents were used (Table 2, entries 4 & 5). The reaction fails to complete when water was used as a solvent (Table 2, entry 6). On the other hand moderate to good yield were obtained in case of other organic solvents such as DMF, DMSO, PEG-300, MeCN (Table 2, entries 7–10). So we have considered EtOH for further optimization process. Next we thought to examine the effect of bases in the Sonogashira reaction of iodobenzene (0.5 mmol) with phenyl acetylene (0.6 mmol) in presence of 2 mol% PdCl₂ with 10 mol% Na₂SO₄ at room temperature. Among the bases tested maximum yield was noted with K₂CO₃ (Table 2, entry 1). Similar yields can be also obtained from Cs₂CO₃ and Na₃PO₄ (Table 2, entries 11 & 12). But considering the cost factor and hygroscopic nature of Cs₂CO₃ and Na₃PO₄, we choose K₂CO₃ for the further optimization process. Whereas, poor yields were recorded with bicarbonate, hydroxide and organic bases (Table 2, entries 13–16). Further optimization confirms that 3 equivalent of K₂CO₃ was optimum for efficient coupling (Table 2, entries 1 vs. 17 & 18).

Table 2 Effect of solvent and base on Sonogashira reaction^a

Entry	Solvent (3 mL)	Base	Yield^b (%)
a Reaction conditions: iodobenzene (0.5 mmol), phenyl acetylene (0.6 mmol); Na2SO4 (10 mol%), base (1.5 mmol), solvent (3 mL) at room temperature unless otherwise noted.b Isolated yield.c 1 : 1 (MeOH : H2O) was used.d 1 : 1 (EtOH : H2O) was used.e 2 equivalent of K2CO3 was used.f 4 equivalent of base was used.
1	MeOH	K2CO3	91
2	EtOH	K2CO3	90
3	i-PrOH	K2CO3	87
4^c	MeOH : H2O	K2CO3	70
5^d	EtOH : H2O	K2CO3	79
6	H2O	K2CO3	57
7	DMF	K2CO3	80
8	DMSO	K2CO3	76
9	PEG-300	K2CO3	59
10	CH3CN	K2CO3	68
11	EtOH	Cs2CO3	90
12	EtOH	Na3PO4·12H2O	83
13	EtOH	NaHCO3	69
14	EtOH	KOH	46
15	EtOH	NaOH	39
16	EtOH	Et3N	68
17^e	EtOH	K2CO3	63
18^f	EtOH	K2CO3	90

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To verify the scope and limitation of the present system we have tested several electronically diverse aryl iodide and aryl acetylene under the optimized condition and the results obtained are highlighted in Table 3. It was noticed that presence of electron donating or withdrawing group at the para position of aryl iodide furnishes excellent yield of isolated cross coupling product (Table 3, entries 2–5). The sterically demanding 2-nitroiodobenzne also affords good yield with phenyl acetylene (Table 3, entries 6). The reaction also proceeds well in case of meta substituted electron rich and electron deficient aryl iodides (Table 3, entries 7 & 8). We also investigated the reaction of substituted aryl acetylenes and aliphatic alkynes. In all cases good to acceptable yield of cross coupling product was observed (Table 3, entries 9–11).

Table 3 Sonogashira coupling of aryl iodides using PdCl₂/Na₂SO₄ system^a

	R1	R2	X	Yield^b (%)
a Reaction conditions: aryl halide (0.5 mmol), aryl/alkyl acetylene (0.6 mmol); Na2SO4 (10 mol%), K2CO3 (1.5 mmol), EtOH (3 mL) at room temperature unless otherwise noted. Isolated yields.b Isolated yields.c Reaction conducted at 60 °C.d Reaction conducted at 100 °C.
1	H	H	I	91
2	4-Me	H	I	92
3	4-OMe	H	I	86
4	4-NO2	H	I	99
5	4-COCH3	H	I	97
6	2-NO2	H	I	91
7	3-NO2	H	I	95
8	3-Me	H	I	90
9	H	4-Me	I	89
10	4-Me	4-Me	I	90
11	4-NO2	C10H21C≡CH	I	86
12	4-Me	H	Br	61, 87^c
13	4-Me	4-Me	Br	81^c
14	4-OMe	H	Br	65^c, 82^d
15	4-Me	4-OMe	Br	79^d
16	4-OMe	4-OMe	Br	50^d

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We next explored the activity of our present system to the coupling of aryl bromides. However, at room temperature low conversion was observed for 4-bromotolyl (Table 3, entry 12). Hence it was decided to perform the reactions for aryl bromides at high temperature. Aryl bromides having electron donating substituent's viz. 4-Me and 4-OMe rendered good yield of isolated cross coupling products (Table 3, entries 12–16).

Conclusion

In summary we have developed a Na₂SO₄ promoted efficient procedure for the Sonogashira cross coupling reaction of aryl iodides with aryl acetylenes at room temperature. The main advantages of the protocol are that it operates at mild condition under ligand and copper free condition. Further the protocol is also suitable for the aliphatic alkynes.

Experimental section

General procedure for the Sonogashira reaction of aryl iodides/aryl bromides

In a 50 mL round bottomed flask aryl halide (0.5 mmol), aryl/alkyl acetylene (0.6 mmol), PdCl₂ (2 mol%; 1.77 mg), Na₂SO₄ (10 mol%; 7.1 mg) and K₂CO₃ (1.5 mmol; 207 mg) in 3 mL EtOH was stirred at room temperature under aerobic condition. The progress of the reaction was monitored by TLC. After completion of the reaction the mixture was diluted with H₂O (20 mL) and extracted with diethyl ether (3 × 20 mL). The ether part dried over by Na₂SO₄. After evaporation under reduced pressure, the residue was purified by flash chromatography (silica gel, hexane) to give the pure product. Formation of the product was confirmed by comparing FTIR spectra, ¹H NMR spectra, ¹³C NMR spectra, melting point measurement and high resolution GC-MS with authentic compounds.

Acknowledgements

We wish to thank UGC, New Delhi for financial support of this Project (no. 41 254/2012 (SR)).

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