WCl₆/DMF as a new reagent system for the phosphine-free Pd(0)-catalyzed aminocarbonylation of aryl halides

Abstract

WCl₆ in dimethyl formamide (DMF) is introduced as a new reagent system for aminocarbonylation of aryl halides in the presence of PdCl₂ as pre-catalyst without any phosphorous ligand. Aryl iodides, bromides as well as chlorides were efficiently converted to their corresponding N,N-dimethyl amides in good to high yields. In this protocol, WCl₆/DMF is responsible for the generation of both Pd(0) catalyst as well as the formation of a Vilsmeier imminium type intermediate.

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Introduction

The carbonylation reaction is among the effective transformations for the synthesis of esters, amides, and heterocyclic compounds. Among the carbonyl compounds, amides are one of the important functional groups, due to their wide ranging biological activities as antibacterial and antifungal agents.¹ The synthesis of amides from aryl halides in the presence of transition metal catalysts is an important reaction in organic synthesis. Regarding this synthesis, Heck has reported the first preparation of aryl and alkenyl amides from their corresponding halides in the presence of palladium catalyst, CO gas, and primary amines.² After this report, some other metal catalyzed methods were developed for aminocarbonylation of aryl halides in the presence of CO gas.^3,4 In order to remove the handling problem of carbon monoxide, the use of Mo(CO)₆,⁵ Cr(CO)₆,⁵ W(CO)₆,⁵ carbamoylstannanes⁶ and carbamoylsilanes,⁷ as sources for the in situ generation of carbon monoxide was considered as a practical method. However, the use of metal carbonyls, still have some handling problem due to the generation of CO gas, and in the other hand carbamoylstannane and carbamoylsilanes have thermal instability and are not commercially available.

The use of DMF as source of carbonyl group in transition metal catalyzed aminocarbonylation reaction of aryl halides with amines can be considered as an alternative reagent system for amide formation.^8–10 This reaction in strongly basic condition has been reported both under thermal⁸ and microwave irradiation.⁹ Hallberg et al. reported the Pd-catalyzed aminocarbonylation using DMF as source of CO and an amine.⁹ However, in this reaction, imidazole was added as an additive and the reaction temperature was very high (180–190 °C). The use of excess POCl₃ in DMF was also reported as an example of CO-free aminocarbonylation of aryl and alkenyl halides.¹⁰ Later on, this reagent system was used for aminocarbonylation reaction of aryl halides in the presence of Pd/C catalyst.¹¹ The main disadvantage of the mentioned methods is their limited application to only aryl iodides. Most recently, the use of Pd(OAc)₂/xantphos as catalyst for CO-free aminocarbonylation of aryl halides in the presence of POCl₃ has been reported for preparation of different formamides.¹²

Recently, we have reported the aminocarbonylation of aryl halides using the in situ generated Mo(CO)₄NBD¹³ and also the use of POCl₃/DMF in the presence of nano-palladium catalyst Pd(0)/SDPP (SDPP = silicadiphenylphosphinite) for amide formation.¹⁴ In continuation of our recent studies on the amidation of aryl halides, herein, we introduce a new palladium-catalyzed aminocarbonylation of aryl halides using WCl₆/DMF as a new combinatorial carbonylation reagent system.

Results and discussion

In order to obtain appropriate conditions for the aminocarbonylation of aryl halides using DMF as CO source, we decided to use different metal halides such as WCl₆, MoCl₅, ZrOCl₂, ZrCl₄, TiCl₄, and FeCl₃ in the presence of Pd(II) as pre-catalyst. The effect of different factors on aminocarbonylation of iodobenzene are demonstrated in Table 1. As shown in this table, among the studied metal halides, WCl₆ is the most efficient one and gave quantitative conversion within 5 h. The use of Pd(OAc)₂ instead of PdCl₂ as a pre-catalyst was also examined and the obtained result showed that the reaction time is nearly the same as using PdCl₂ (Table 1, entry 4). Since, PdCl₂ is cheaper than Pd(OAc)₂, it was selected as the Pd precursor. The influence of parameters such as temperature and catalyst loading was also examined on the model reaction.

Table 1 Study of different parameters on the aminocarbonylation of iodobenzene with metal halides at 140 °C^a

Entry	Metal halide	Pd(II) (mol%)	Time (h)	Yield^b (%)
a Reaction conditions: iodobenzene (0.5 mmol), metal halide (1.0 mmol), DMF (5.0 mL).b Conversion yield was based on GC analysis.c Biphenyl was obtained as the product.d Pd(OAc)2 was used instead of PdCl2.e The reaction was performed at 120 °C.f One equimolar of WCl6 was used.g 2.0 mg of PPh3 was used.
1	WCl6	None	24	0
2	None	2.5	24	30^c
3	WCl6	2.5	5	100
4	WCl6	2.5	4.5	100^d
5	MoCl5	2.5	8.5	100
6	ZrOCl2	3.5	12	100
7	ZrCl4	5	24	70
8	FeCl3	5	24	None
9	TiCl4	5	24	None
10	WCl6	2.5	18	45^e
11	WCl6	2.5	12	90^f
12	WCl6	2.5	12	100^g

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Running the reaction with optimized 2.5 mol% of PdCl₂ in the presence of WCl₆ as the reagent at 120 °C showed that the yield of the desired product was too low after 18 h (45% GC conversion) (Table 1, entry 10).

As a controlled reaction, we also checked the aminocarbonylation reaction in the absence of Pd catalyst and once in the absence of metal halide. In the absence of Pd catalyst, the reaction did not proceed even after 24 h (Table 1, entry 1). In the absence of WCl₆, most of the starting material was remained intact after 24 h and biphenyl wao obtained as by-product in 30% yield (Table 1, entry 2). From these experiments, it was concluded that the presence of both Pd catalyst and WCl₆ are essential to produce the corresponding product. When the amounts of WCl₆ was reduced from two equivalents to one, the reaction time was increased from 5 to 12 h (Table 1, entry 11). In order to see the effect of phosphorous ligand on the process of the reaction, the model reaction was conducted in the presence of PPh₃ (Table 1, entry 12). In comparison with the ligand-free reaction (Table 1, entry 3), the presence of PPh₃ not only didn't improve the progress of the reaction, but also increased the reaction time. The elongation of reaction time could be possibly due to the complexation of PPh₃ with WCl₆.

Since it was the first time that WCl₆/DMF is used for this reaction, we decided to find out its scope and applicability for aminocarbonylation of aryl halides. We therefore, studied the possibility of performing this new aminocarbonylation reaction in the presence of WCl₆ as the most efficient metal halide and apply this ligand-free reaction to other aryl halides. Under our optimized reaction conditions (0.5 mmol of aryl halide, 1.0 mmol of WCl₆ 5.0 mL of DMF, 4.4 mg (2.5 mol%) of PdCl₂ under nitrogen at 140 °C), the desired products were obtained in moderate to excellent yields for a wide array of aryl halides (Scheme 1).

Scheme 1 Ligand-free aminocarbonylation of aryl halides in the presence of WCl₆. Reaction conditions: aryl halide (0.5 mmol), PdCl₂ (4.4 mg, 2.5 mol%), WCl₆ (1.0 mmol), DMF (5.0 mL) at 140 °C under N₂. All yields are isolated compounds.

As shown in Scheme 1, different aryl halides can be converted to their corresponding amid derivatives under our optimized conditions in the presence of WCl₆/DMF reagent system. Aryl iodides reacted faster than bromides and chlorides counterparts. The reaction conditions are more effective for aryl halides containing electron-withdrawing groups so that electron-poor substrates reacts faster than electron-rich ones.

Steric hindrance in some substrates such as 1-iodonaphthalene, 1-iodo-2-methylbenzene and 1-iodo-2-methyl-4-nitrobenzene caused a decrease in the yield of the desired product (Scheme 1, compounds 2e–g). This catalytic system was also efficient for the electron-deficient aryl bromides and aryl chlorides (Scheme 1, compounds 2h–i).

In order to see if the reaction can be applied to other formamides, we used N,N-diethylformamide (DEF) instead of DMF for aminocarbonylation of some aryl iodides under optimized conditions. Unfortunately, we couldn't obtain any product from this reaction. Interestingly, the presence of PPh₃ as ligand is required for occurrence of the reaction. Using DEF, iodobenzene and 4-methoxy iodobenzene reacted efficiently to give their corresponding N,N-diethylamides in high yields under optimized conditions, but in the presence of PPh₃ ligand (Scheme 1, compounds 2j, k).

In order to study the pathway of Pd(II) reduction under phosphine-free condition, we studied the following experiments. First, we added PdCl₂ to the solution of WCl₆ in DMF and heated it at 140 °C for 1 h or 80 °C for 3 h. Then we studied the UV-spectrum of both solutions. Disappearance of the band around 400 nm was indicative of the absence of Pd(II) under these conditions. In the other experiment in order to see the effect of DMF, a combination of PdCl₂ and DMF was stirred at 140 °C for 3 h in the absence of WCl₆. The UV-spectrum of this mixture showed that no reduction of Pd(II) to Pd(0) has been occurred (Fig. 1a).

Fig. 1 (a) UV-spectrum of PdCl₂ in the presence of DMF and WCl₆. (b) UV-spectrum of PdCl₂ in the presence of DMF and MoCl₅. (c) UV-spectrum of PdCl₂ in the presence of DMF and ZrOCl₂.

In order to have a comparison with other metal halides, we also performed a similar experiment sing MoCl₅ in DMF at 140 °C. The UV spectrum of the mixture showed that Pd(II) was completely converted to Pd(0) after 2 h which is slightly slower than using WCl₆ (Fig. 1b). When we studied ZrOCl₂ for the same purpose, it was observed that after 2 h, Pd(II) was still present in the media, which shows that the reduction of Pd(II) to Pd(0) is much slower in the case of ZrOCl₂ (Fig. 1c). This study clearly shows that the reduction of Pd(II) to Pd(0) occurs more efficiently in WCl₆/DMF.

According to the reported results in the literature, DMF has been shown to act as reducing agent for the conversion of Ag(I) to Ag(0).¹⁵ On this basis, it can be suggested that DMF can act as a reducing agent for the conversion of W(VI) to W(IV) as shown in Fig. 2. In the following, the produced W(IV) acts as a reducing agent for the reduction of Pd(II) to Pd(0). Detection of dimethyl amine by gc analysis in the reaction mixture is an evidence for the proposed mechanism.

Fig. 2 Conversion of W(VI) to W(IV) in the presence of DMF.

In order to show that the formation of dimethyl amine occurs through the reduction processes and is not a thermic decomposition product of DMF, the mixture of WCl₆ in DMF was also heated at 80 °C in a sealed tube and its gc analysis was compared with a blank solution of DMF under similar condition. The formation of dimethyl amine in the mixture of WCl₆/DMF and its absence in the blank solution confirms the proposed pathway for the generation of dimethyl amine.

Since formation of Pd(0) from Pd(II) was not observed in DEF, it can be concluded that DEF can not act as a reducing agent for the conversion of Pd(II) to Pd(0), thus we needed to add PPh₃ as a phosphine ligand to the reaction mixture for the reduction of Pd(II) to generate the Pd(0) catalyst.

Although the mechanism for this reaction is not clear at this time, we propose a plausible reaction pathway according to our findings and also the litrature as shown in Scheme 2.^10,15 In the first step, reduction of WCl₆ in DMF is occurred and W(IV) is possibly formed. Then this compound can reduce Pd(II) to Pd(0). The Vilsmeier imminium salt reagent [Me₂N⁺ = CHCl] is also produced from the reaction of DMF and WCl₆. The Intermediate I which is produced from the oxidative addition of aryl halide to Pd(0) reacts with the Vilsmeier imminium salt. Then the reaction proceeds via the Heck-type addition of aryl halides to the imminium species as shown in Scheme 2.

Scheme 2 The proposed mechanism.

Since formation of the Vilsmeier imminium salt reagent [Me₂N⁺ = CHCl] is the required step in this catalytic cycle, the use of at least stoichiometric amount of WCl₆ is required to generate this intermediate through the reaction with DMF.

In order to show the formation of Vilsmeier imminium reagent proposed in the mechanism, in an experiment, indole (1.0 mmol) was reacted with WCl₆ (1.0 mmol) in DMF (2 mL) at 80 °C. After 2 h, indol 3-carbaldehyde was obtained in 75% isolated yield. This experiment strongly confirms the generation of Vilsmeier imminium reagent under our optimized conditions (Scheme 3).

Scheme 3 Synthesis of indole-3-carbaldehyde representing the formation of Vilsmeier imminium reagent from DMF/WCl₆ system.

Conclusions

In this study, we have introduced a new method for aminocarbonylation of aryl halides in the presence of WCl₆ as an efficient metal halide in the presence of catalytic amounts of PdCl₂ as precatalyst in the absence of any phosphine ligand. For this transformation, N,N-dimethylformamide (DMF) has been used as the source of carbonyl group. Among the studied metal halides, WCl₆ showed to be the most efficient one. A possible reason for the more efficiency of WCl₆ was shown to be due to the easier reduction of Pd(II) to Pd(0) in WCl₆/DMF compared with those reagent systems using MoCl₅, ZrOCl₂ or ZrCl₄ in DMF. The reaction of aryl iodides in DEF can also occure to give the corresponding N,N-diethyl amides but in the presence of PPh₃ as a reducing ligand.

Experimental section

The progress of reactions was followed by TLC on silica gel SILG/UV 254 plates or GLC analysis on a Shimadzu model GC-10A instrument. IR spectra were run on a Shimadzu FTIR-8300 spectrophotometer. The ¹H NMR and ¹³C NMR spectra were recorded on a Bruker-Avance DPX 250 FT-NMR spectrometer.

General procedure for aminocarbonylation of aryl halides with WCl₆ in the presence of PdCl₂ as catalyst in DMF

WCl₆ (1.0 mmol, 0.415 g) and dry DMF (5.0 mL) were added to a flask containing a magnetic stirring bar. The resulting mixture was stirred for 15 min at room temperature under nitrogen. Then aryl halide (0.5 mmol), and PdCl₂ (2.5 mol%, 4.4 mg) were added to the reaction mixture. After 15 min, the mixture was heated at 140 °C for the appropriate time. After the consumption of the starting material (monitored by TLC or GC analysis), the reaction mixture was cooled down to room temperature. The resulting mixture was added to a saturated aqueous solution of NaHCO₃ (25 mL). The organic layer was extracted with ethyl acetate (25 mL × 4) and then the solvent was evaporated to obtain the desired product. Further purification was performed by silica gel column chromatography [60 Merck (230–240 mesh)] using n-hexane/ethyl acetate (4 : 1) as the eluent to give the pure product in moderate to excellent yields.

General procedure for aminocarbonylation of aryl halides with WCl₆ in the presence of PdCl₂/PPh₃ as catalyst in N,N-diethylformamide

WCl₆ (1.0 mmol, 0.396 g) was dissolved in N,N-diethylformamide (5.0 mL). Then, aryl halide (0.5 mmol), PdCl₂ (2.5 mol%, 4.4 mg) and PPh₃ (2.0 mg) were added to the vessel containing the mixture of DEF and WCl₆. After 15 min, the mixture was stirred for the specified time at 140 °C under nitrogen (Table 1). After consumption of the starting material (TLC or GC), the reaction mixture was cooled down to room temperature. Saturated solution of NaHCO₃ (25 mL) was added to the reaction mixture and was then extracted with ethyl acetate (25 × 4 mL). Evaporation of the solvent gave the desired pure amide. Further purification, if was necessary, was performed by silica gel column chromatography using n-hexane/EtOAc as the eluent to give the pure product in high to excellent yield.

Acknowledgements

The authors would like to acknowledge the support of this work by Shiraz University Research Council and the grant from Iran National Elite Foundation. Technical assistance of Dr S. Motevalli is also acknowledged.

Notes and references

1. (a) K. J. Pradhan, P. S. Variyar and J. R. Bandekar, Lebensm.-Wiss. Technol., 1999, 32, 121–123; (b) E. Aki-Sener, K. K. Bingol, I. Oren, O. Temiz-Arpaci, I. Yalcin and N. Altanlar, Farmaco, 2000, 55, 469–476; (c) I. Kobayashi, H. Muraoka, M. Hasegawa, T. Saika, M. Nishida, M. Kawamura and R. J. Ando, J. Antimicrob. Chemother., 2002, 50, 129–132; (d) J. M. Humphrey and A. R. Chamberlin, Chem. Rev., 1997, 97, 2243–2266.
2. A. Schoenberg and R. F. Heck, J. Org. Chem., 1974, 39, 3327–3331.
3. Z. S. Qureshi, S. A. Revankar, M. V. Khedkar and B. M. Bhanage, Catal. Today, 2012, 198, 148–153.
4. (a) M. Beller, B. Cornils, C. D. Frohning and C. W. Kohlpaintner, J. Mol. Catal. A: Chem., 1995, 104, 17–85; (b) A. Yamamoto, Y. Kayaki, K. Nagayama and I. Shimizu, Synlett, 2000, 925–937.
5. (a) N. F. K. Kaiser, A. Hallberg and M. Larhed, J. Comb. Chem., 2002, 4, 109–111; (b) J. Wannbeg and M. Larhed, J. Org. Chem., 2003, 68, 5750–5753.
6. C. M. Lindsay and D. A. Widdowson, J. Chem. Soc., Perkin Trans. 1, 1988, 569–573.
7. (a) R. F. Cunico and B. C. Maity, Org. Lett., 2002, 4, 4357–4359; (b) R. F. Cunico and B. C. Maity, Org. Lett., 2003, 5, 4947–4949.
8. J. Ju, M. Jeong, J. Moon, H. M. Jung and S. Lee, Org. Lett., 2007, 9, 4615–4618.
9. Y. Wan, M. Alterman, M. Larhed and A. Hallberg, J. Org. Chem., 2002, 67, 6232–6235.
10. K. Hosoi, K. Nozaki and T. Hiyama, Org. Lett., 2002, 4, 2849–2851.
11. P. J. Tambade, Y. P. Patil, M. J. Bhanushali and B. M. Bhanage, Tetrahedron Lett., 2008, 49, 2221–2224.
12. D. N. Sawant, Y. S. Wagh, K. D. Bhatte and B. M. Bhanage, J. Org. Chem., 2011, 76, 5489–5494.
13. N. Iranpoor, H. Firouzabadi, S. Motevalli and M. Talebi, Tetrahedron, 2013, 69, 418–426.
14. N. Iranpoor, H. Firouzabadi and S. Motevalli, J. Mol. Catal. A: Chem., 2012, 355, 69–74.
15. I. Pastoriza-Santos and L. M. Liz-Marzán, Pure Appl. Chem., 2000, 72, 83–90.

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Footnote

† Electronic supplementary information (ESI) available: Copy of ¹H NMR and ¹³C NMR spectra of compounds. See DOI: 10.1039/c4ra04673k

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