Ultrasound assisted site-selective alkynylation of 2,3,5,6-tetrachloropyridines under Pd/C—Cu catalysis

1 Introduction

The 2,6-dialkynyl pyridine derivatives have been explored for their various pharmacological activities. For example, the hydrochloride salts represented by A (Fig. 1) have been explored as inhibitors of tryptase, a serin protease in human mast cells that is associated with airways disorders, interstitial lung disorders, disorders of arthritis type, autoimmune disorders, inflammatory disorders, etc. (Thomas, 2006). The 2,6-bis-phenylethynyl-pyridine (Carvalho et al., 2013) has been assessed for protein binding affinity using human ERG (ether-a-go-go-related gene) K⁺ channel test system (Vilums et al., 2012; Yu et al., 2015a,b; Vandenberg et al., 2012). Very recently, in a follow-up study the same group has explored the Structure–Affinity Relationships (SARs) and Structure–Kinetics Relationships (SKRs) of hERG blockers based on 2,6-dialkynyl pyridine derivatives B and C (Fig. 1) (Yu et al., 2015a,b). In continuation of our work on pyridine derivatives (Pal et al., 2005; Kumar et al., 2012; Reddy et al., 2013; Gade et al., 2013) of potential pharmacological importance we became interested in assaying 2,6-dialkynyl pyridine class of compounds against a number of pharmacological targets. We therefore required a robust and rapid supply of these compounds possessing diverse structural features.

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Figure 1

Examples of bioactive 2,6-dialkynyl pyridine derivatives (A–C).

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The coupling of 2,6-dihalopyridine with an appropriate alkyne in the presence of a Pd-catalyst, popularly known as Sonogashira coupling is the most convenient method for accessing 2,6-dialkynylpyridine derivatives (Takahashi et al., 1980). This methodology has been used by various groups for the preparation of desired 2,6-dialkynylpyridine derivatives for different purposes (Vilums et al., 2012, Furusho et al., 2004; Ng et al., 1998; Isfahani et al., 2014; Jadhav et al., 2015; Shi and Zhang, 2007; Huang et al., 2004; Huynh and Lee, 2013; Bosdet et al., 2007). Generally, 2,6-dibromopyridine is used as a halide component in this coupling reaction that proceeds at room temperature for several hours to give the expected products in moderate to good yields. Yields were found to be poor in some cases (Vilums et al., 2012). Recently, site-selective Sonogashira reactions of 2,3,5,6-tetrachloropyridines have been reported to obtain 2,6-dialkynylpyridine derivatives in good yields (Ehlers et al., 2013; Ehlers et al., 2014). This approach appeared to be attractive as the strategy allowed further functionalization of chloro groups present at C-3 and C-5 position of the pyridine ring (Ehlers et al., 2014). Moreover chloro pyridines are cheaper than their bromo derivatives. However, this method requires heating of the reaction mixture for a long duration i.e. 20 h and involved the use of relatively expensive and air sensitive Pd(PPh₃)₄ as a source of Pd-catalyst. Moreover, the Pd-catalyst used is destroyed during the work-up procedure and therefore cannot be recovered or reused. Thus, development of improved and faster synthetic method for accessing existing and novel 2,6-dialkynylpyridine derivatives is necessary.

The use of Pd/C in Sonogashira reaction has been reported earlier (Pal et al., 2003; Jiang and Cai, 2006; Pal, 2009). As a catalyst Pd/C has advantages over the other Pd-complexes or salts. For example, Pd/C is less expensive, stable, easy to handle and recyclable. The Pd/C catalyst can be separated easily from the product via simple filtration. Moreover, it can be stored for a long time without taking any extra precautions. Indeed, the use of Pd/C as an effective catalyst for the site-selective alkynylation of 2,4-dichloroquinoline to obtain 2-alkynyl quinoline has been reported by us earlier (Reddy et al., 2008; Reddy et al., 2009). Ultrasound assisted reactions on the other hand have attracted considerable attention in modern organic synthesis because of shorter reaction time, mild conditions and high yields of products (Luche, 1998; Li et al., 2003; Mcnulty et al., 1998). These reactions appeared to be more convenient and advantageous compared to the traditional methods. Thus, combination of Pd/C with ultrasound irradiation appeared as an attractive and greener option to us for the site-selective alkynylation of 2,3,5,6-tetrachloropyridines. Herein we report Pd/C-catalyzed one pot and alternative synthesis of 2,6-dialkynylpyridine derivatives (3) from 2,3,5,6-tetrachloropyridines (1) and terminal alkynes (2) under ultrasound irradiation (Scheme 1). To the best of our knowledge, the use of this strategy for the site-selective alkynylation of pyridines or other similar class of heteroarenes has not been explored earlier.

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Scheme 1

Pd/C—Cu catalyzed site-selective alkynylation of 2,3,5,6-tetrachloropyridines under ultrasound irradiation.

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2 Materials and methods

3 Results and discussion

Initially, it was necessary to test the feasibility of the ultrasound based strategy. Accordingly, the commercially available 2,3,5,6-tetrachloropyridine (1a) was chosen as a key reactant that was coupled with a terminal alkyne i.e. 2-methylbut-3-yn-2-ol (2a) under various conditions (Table 1). The reaction was performed in a number of solvents using 10%Pd/C–CuI–PPh₃ as a catalyst system at 60 °C under ultrasound irradiation. The reaction proceeded reasonably well when performed in MeCN, DMF, DME and PEG-400 (entries 1–6, Table 1). The solvent PEG-400 appeared as more attractive because it is known as a green solvent. Because of its high boiling, non-hazardous and polar nature of the use of PEG as a solvent in organic reactions has already been explored earlier. Indeed, due to its easy recovery (from the reaction mixture) and recyclability, PEG has been used as a solvent in several organometallic reactions including Cu-mediated Sonogashira, Heck and Suzuki–Miyaura coupling (Declerck et al., 2006; Colacino et al., 2007; Mao et al., 2008; Chandrasekhar et al., 2002). In the present case, the reaction in PEG-400 was performed for 6 h when the desired product 3a was obtained in 75% yield. To optimize the reaction time the reaction was performed for 4 and 2 hours (entries 7 and 8, Table 1) when 3a was obtained in 74% and 53% yield respectively. It was therefore clear that the reaction had to be performed for a minimum duration of 4 h. We also examined the use of water as a solvent in the present reaction. However, a complex mixture of products was obtained in this case perhaps due to the partial hydrolysis of 1a. While Et₃N was used as a base in all these reactions the use of other base e.g. K₂CO₃ was also examined but found to be less effective (entry 9, Table 1). In fact the reaction did not proceed well in the absence of a base (entry 10, Table 1) indicating its key role in the present reaction. A similar observation was noted when the reaction was performed in absence of PPh₃. The role of Pd-catalyst was also assessed by performing the reaction in the presence of mercury (Hg) (entry 11, Table 1). The reaction did not proceed perhaps due to the accumulation of Hg on the charcoal surface [thereby alloying with Pd through dπ–dπ bonding (the catalyst poisoning) (Dunleavy, 2006)] indicating the role of Pd/C in the present coupling reaction. This was further confirmed by the fact that the reaction did not proceed in the absence of 10%Pd/C (entry 12, Table 1). All these reactions were performed at 60 °C. Lowering of reaction temperature decreased the product yield (entry 13, Table 1). The reaction was also carried out in the absence of ultrasound (entry 14, Table 1) when a slow progress of the reaction was observed affording 3a in 31% yield after 4 h. This clearly highlights the key role of ultrasound in the present reaction. Overall, the conditions of entry 7 appeared to be optimal and were used for further study.

Table 1 Coupling of 1a with 2a under various conditions.^a

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^a All reactions were performed using 1a (1.0 mmol, 217 mg), 2a (2.5 mmol, 210 mg), 10%Pd/C (0.026 mmol), PPh₃ (0.20 mmol, 60 mg), CuI (0.05 mmol, 9.5 mg), and Et₃N (3 mmol, 0.4 mL) in a solvent (7 mL) at 60 °C.

^b Isolated yields.

^c Formation of a number of side products observed.

^d The reaction was performed in the presence of mercury (Hg).

^e The reaction was performed in the absence of 10%Pd/C.

^f The reaction was performed at 50 °C.

^g The reaction was performed in the absence of ultrasound.

To test the recyclability of catalyst the reaction mixture obtained after the completion of the reaction of 1a with 2a under the condition of entry 7 of Table 1 was filtered. The residue was collected, thoroughly washed with EtOAc and EtOH (to remove all the contaminated organic materials) followed by cold water (to remove all the contaminated water soluble materials) and then dried under high vacuum. It was then reused for the reaction of 1a with 2a under the condition of entry 7 of Table 1. This process was repeated for two times when the desired product 3a was obtained in 68% and 60% yield after 1st and 2nd cycle respectively. It is worthy to mention that the recovered catalyst was not tested for its purity that could be the reason for the observed drop in the product yield after 1st and 2nd cycle compared to the 0th cycle.

To extend the scope and generality of this ultrasound assisted Pd/C-based methodology, a number of 2,6-dialkynylpyridine derivatives (3) were synthesized and results are summarized in Table 2. Thus, 2,3,5,6-tetrachloropyridine (1a) and 2,3,5,6-tetrachloro-4-isopropoxypyridine (1b) were treated with a range of terminal alkynes (2) under the conditions of entry 7 of Table 1. The alkynes (2) may contain a hydroxyalkyl, alkyl and aryl group. The aryl ring may carry various substituents such as Me, OMe, F, and ^tBu. The reaction proceeded well in all these cases affording the corresponding products in acceptable to good yields. The alkyne 2b (bp 71–72 °C) was used in excess quantity (entry 2, Table 2) as evaporation of this reactant was observed during the reaction. In general, the halide 1b (entries 7–11, Table 2) afforded slightly better yields of corresponding products than 1a (entries 1–6, Table 2). This perhaps can be explained by the electron-withdrawing effect of OPrⁱ group [the alkoxy group at the position meta to the aryl–halogen bond work as an electron-withdrawing group due to its high electronegativity of the oxygen atom (inductive effect)] that facilitated the oxidative addition of Pd(0) species into the C—Cl bond of compound 1 (see the reaction mechanism). We also examined the use of perchloropyridine (1c) in the present coupling reaction that was treated with the alkyne 2c (entry 12, Table 2). A mixture of products was obtained in this case upon chromatographic separation which afforded 2,3,4,5,6-pentakis(phenylethynyl)pyridine (4a) in low yield (27%). However, the use of 2,4-dichloropyridine (1d) afforded the desired 4-chloro-2-(phenylethynyl)pyridine (4b) in good yield (75%) and selectivity when treated with the alkyne 2c (entry 13, Table 2). Nevertheless, all the products isolated were characterized by spectral and analytical data though most of the alkynylated products are known (Ehlers et al., 2014). For example in case of compounds 3 the ¹³C signals observed near 85 and 95 ppm in the ¹³CNMR spectra of most of the cases indicated the presence of two acetylenic carbons. Additionally, the IR absorption near 2210–2230 cm⁻¹ observed in the IR spectra of all compounds confirmed the presence of —C≡C— moiety.

Table 2 Pd/C-mediated synthesis of 2,6-dialkynylpyridine derivatives (3) under ultrasound irradiation.^a

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Entry	Halide 1; X=	Alkyne 2; R=	Product 3	% yieldb
1.	1a; H	2a; CMe2OH		74
2.	1a	2b; n-Butyl		63c
3.	1a	2c; Ph		69
4.	1a	2d; C6H4F-p		65
5.	1a	2e; C6H4OMe-p		77
6.	1a	2f; C6H4CMe3-p		68
7.	1b; OPri	2c		81
8.	1b	2g; C6H4Me-p		83
9.	1b	2d		85
10.	1b	2e		74
11.	1b	2f		76
12.	1c; Cl	2c		27d
13.		2c		75

a All reactions were performed using 1 (1.0 mmol, 217 mg for 1a and 275 mg for 1b), 2 (2.5 mmol), 10%Pd/C (0.026 mmol), PPh₃ (0.23 mmol, 60 mg), CuI (0.05 mmol, 9.5 mg), and Et₃N (3 mmol, 0.4 mL) in PEG-400 (7 mL) at 60 °C under ultrasound irradiation for 4–5 h.

b Isolated yields.

c 3.0 equiv of alkyne 2b was used.

d A mixture of products was obtained in this case.

A reaction mechanism is proposed for the Pd/C-mediated synthesis of 3 under ultrasound (Scheme 2). The reaction appeared to proceed via (i) the generation of the Pd(0)—PPh₃ complex in solution which seemed to be the actual catalytic species, (ii) oxidative addition of Pd(0) to the halide (1) affording the organo-Pd(II) species E-1, (iii) trans metallation of E-1 with the Cu-acetylide generated from 2 to give E-2 and (iv) reductive elimination of Pd(0) to give the desired product 3. Thus, in the initial step an active Pd(0) species is generated via a Pd leaching process (Chen et al., 2007) from the minor portion of the bound palladium (Pd/C) into the solution followed by interactions with the phosphine ligands. The dissolved Pd(0)—PPh₃ complex then participated in subsequent steps as outlined in Scheme 2. Overall, the catalytic cycle seemed to operate in solution rather than on the surface and Pd was re-precipitated on the charcoal surface at the end of the reaction. To gain evidence on Pd-leaching in the present reaction 10%Pd/C (0.026 mmol), PPh₃ (0.23 mmol, 60 mg), CuI (0.05 mmol, 9.5 mg), and Et₃N (3 mmol, 303.6 mg, 0.4 mL) (all mmol amount was calculated based on 1 mmol of 1a) in PEG-400 (7 mL) were stirred at 60 °C under ultrasound irradiation for 1 h. The mixture was then filtered while hot and the filtrate was used for a new reaction by adding 1a (1.0 equiv) and 2a (2.5 equiv) without adding any additional catalyst. The mixture was then stirred at 60 °C under ultrasound irradiation for 4 h when 77% conversion was observed. Though the precise role of ultrasound in the present reaction was not clearly understood it accelerated the Pd leaching process greatly thereby facilitating the subsequent steps. The ultrasound might have also facilitated the rapid reductive elimination of Pd(0) to give the product 3. Nevertheless, both catalyst and ultrasound played key roles in completing the reaction within 4–5 h.

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Scheme 2

Proposed reaction mechanism for the Pd/C-mediated synthesis of 2,6-dialkynylpyridine derivatives (3) under ultrasound irradiation.

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4 Conclusions

In conclusion, we have developed a faster and convenient synthetic method for accessing 2,6-dialkynylpyridine derivatives in acceptable to good yields. The methodology is based on ultrasound assisted site-selective alkynylation of 2,3,5,6-tetrachloropyridines under Pd/C—Cu catalysis. PEG-400 was found to be an effective solvent in this reaction. A variety of terminal alkynes were employed in this C—C coupling reaction to afford the corresponding 2,6-dialkynylpyridine derivatives. These compounds are amenable for further functionalization by using the chloro groups present at C-3 and C-5 position of the pyridine ring. In general, the methodology does not involve the use of any expensive catalysts, reagents or solvents. Thus the present Pd/C-based methodology appeared to be a useful and cheaper alternative to the existing method. The methodology therefore may find usage in constructing diversity based library of compounds based on 2,6-dialkynylpyridine framework of potential medicinal value.