Ultrasound assisted Mizoroki–Heck coupling/C–H amination in a single pot: Direct synthesis of indole derivatives

1 Introduction

The 2-substituted indole ring is prevalent in various naturally occurring alkaloids, bioactive compounds and drugs (Gribble, 1996; Young et al., 2001; Mackman et al., 2002; Chai et al., 2003). Consequently numerous synthetic methods including transition metal catalyzed reactions have been developed for the construction of indole ring (Gribble, 2000; Li and Gribble, 2000; Cacchi and Fabrizi, 2005; Humphery and Kuethe, 2006; Chen et al., 2009; Oskooie et al., 2007; Palimkar et al., 2006). One of the commonly used methods for the synthesis of 2-substituted indoles involves two steps e.g. Sonogashira coupling of 2-aminoaryl halide with a terminal alkyne followed by cyclization of the resulting 2-alkynylanilines. Alternatively, 2-substituted indoles can be prepared directly via a single step method using Pd-mediated coupling-cyclization of o-iodoanilides with terminal alkynes (Layek et al., 2009; Pal et al., 2004) (Eq. (1), Scheme 1). The C–H amination of 2-alkenylanilines is another straightforward and useful strategy for the construction of indole ring. Two different approaches have been developed for this purpose that involved (i) Pd(II)-catalysis or (ii) nitrogen radical (cation) formation, respectively (Eq. (2), Scheme 1). Indeed, the Pd(II)-catalyzed aminopalladation has been developed as one of the attractive and efficient methods for the construction of indole ring (Hegedus et al., 1978; Harrington and Hegedus, 1984; Harrington et al., 1987; Krolski et al., 1988; Larock et al., 1996; Tsvelikhovsky and Buchwald, 2010; Youn et al., 2011). The methodology has found wide applications in organic synthesis though substrate scope was limited. Recently, a strategy based on intramolecular oxidative amination of alkenes has been reported for the synthesis of indole derivatives (Liwosz and Chemler, 2013). The reaction followed a mechanism that involved nitrogen-radical addition to the alkenes. The involvement of a nitrogen-centered radical cation generated from N-p-alkoxy-phenyl-2-alkenylanilines during the photocatalytic synthesis of indoles has also been reported (Maity and Zheng, 2012). Prompted by these reports we became interested in exploring a similar strategy based on intramolecular oxidative amination of alkenes toward the development of a straightforward synthesis of indoles.

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Scheme 1

Reported strategies for the construction of indole ring.

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As a well known and widely used Pd catalyst for hydrogenation reactions the Pd/C has found applications in Mizoroki–Heck reaction too (Hagiwara et al., 2001; Xie et al., 2004; Perosa et al., 2004). In fact in comparison with other Pd catalysts the Pd/C is a less expensive, stable, easy to handle and recyclable catalyst. Consequently, the use of Pd/C has advantages over the other Pd-complexes or salts. Indeed, the combination of Pd/C with ionic liquid as a recyclable catalyst system for the Mizoroki–Heck coupling is known in the literature (Hagiwara et al., 2001; Perosa et al., 2004). Moreover, acceleration of these reactions using microwave irradiation is documented in the literature (Perosa et al., 2004). The Mizoroki–Heck reaction of iodobenzene with methyl acrylate has also been studied using Pd/C as a catalyst in the presence of ultrasound (Ambulgekar et al., 2005). Like microwave, ultrasound enhanced the reaction rate as expected and was found to be essential for the reaction to proceed at room temperature. While the effect of base, solvent and recyclability of catalyst was studied in the presence and absence of ultrasound, the application and scope of this ultrasound based methodology in organic synthesis has not been explored. Only one and simple example was studied in this case. It was therefore necessary to explore this strategy as a general and efficient method not only for the C–C bond forming reaction but also as a key step in the construction of heteroarene ring such as indole. Herein we report a one-pot and faster method based on Pd/C mediated Mizoroki–Heck coupling of 2-iodosulfanilides (1) (Layek et al., 2009; Inamoto et al., 2012) with various alkenes (2) under ultrasound irradiation leading to indoles (Scheme 2). The formation of indole ring was facilitated by the use of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) (Bhattacharya et al., 1989; Cheng and Bao, 2008; Li and Bao, 2009; Mo and Bao, 2009; Jin et al., 2010; Wang et al., 2012), an oxidant that has been used previously for oxidation of olefins and dehydrogenative cross-coupling reactions.

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Scheme 2

Constructing indole ring via Mizoroki–Heck coupling/C–H amination strategy in a single pot under ultrasound irradiation.

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2 Materials and methods

3 Results and discussion

To assess the feasibility of Mizoroki–Heck coupling/C–H amination in a single pot we began our study with the reaction of N-(2-iodophenyl)benzenesulfonamide (1a) with styrene (2a). The reaction was performed initially under Pd/C-PPh₃ catalyzed Mizoroki–Heck reaction conditions and then in the presence of DDQ in the same pot. A number of solvents e.g. Et₃N, DMF, MeCN and 1,4-dioxane were examined to identify the appropriate reaction media for the first as well as second steps. Under the traditional heating condition the reaction did not afford the desired product 3a when performed in Et₃N (entry 1, Table 1) that was used as a solvent as well as base. Indeed, the compound 4 that appeared to be the precursor of 3a was obtained in low yield in this case. The change of solvent (without changing the base) though afforded the desired product 3a in low yield but a substantial amount of compound 4 was also isolated in these cases (entries 2–4, Table 1). Since better yield of 3a was obtained in 1,4-dioxane (entry 4, Table 1) subsequent studies were performed using this solvent. The first step of all these reactions was performed at a refluxing temperature of the respective solvent used except DMF. However, in search of a milder reaction condition at the same time improved yield of 3a we performed the reaction under ultrasound irradiation (using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz) instead of conventional heating (entry 5, Table 1). Indeed, the reaction proceeded at lower temperature (50 °C) and reached to the completion within 2 h as indicated by TLC (thin layer chromatography) for the first step. While the compound 4 was also isolated as a side product in this case overall, the reaction afforded 3a in 77% yield. This prompted us to continue our study further. To assess the role of catalyst, ligand and base in the initial step of this one-pot reaction the coupling reaction was performed in the absence of Pd/C (entry 6, Table 1), PPh₃ (entry 7, Table 1) and DBU or K₂CO₃ in place of Et₃N (entry 8 and 9, Table 1) separately. The reaction either did not proceed or afforded low to poor yield of 3a in these cases. All these observations clearly indicated the key role played by the Pd/C, PPh₃ and Et₃N in the present reaction whereas the use of ultrasound allowed a faster reaction at a lower temperature with improved yield of 3a. Overall, the condition of entry 5 appeared to be the best for synthesizing 3a and was used for the preparation of other indole derivatives.

Table 1 Effect of reaction conditions on the coupling of 1a with 2a.^a

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Entry	Solvent/base	Temp (°C)/Time (h)	% yieldb
			3a	4
1.	Et3N	90/12	0	27
2.	DMF/Et3N	100/12	10	69
3.	MeCN/Et3N	80/12	12	47
4.	1,4-Dioxane/Et3N	100/12	31	32
5.	1,4-Dioxane/Et3N	50/2	77c	7
6.	1,4-Dioxane/Et3N	50/2	0c,d	0
7.	1,4-Dioxane/Et3N	50/2	Tracec,e	0
8.	1,4-Dioxane/DBU	50/2	49c	0
9.	1,4-Dioxane/K2CO3	50/2	28c	66

a All reactions were performed using iodoarene 1a (0.3 mmol, 1.0 equiv.), alkene 2a (0.36 mmol, 1.2 equiv.), 10% Pd/C (0.05 equiv), PPh₃ (0.10 equiv), and Et₃N (0.6 mmol, 2.0 equiv.) in 1,4-dioxane (5.0 mL) in the presence of nitrogen and then DDQ (0.6 mmol, 2 equiv) at 50 °C in the presence of nitrogen for 4 h.

b Isolated yield.

c The reaction was carried out under ultrasound irradiation.

d The reaction was carried out without Pd/C.

e The reaction was carried out without PPh₃.

A large number of indole derivatives were prepared by using the present Mizoroki–Heck coupling/C–H amination strategy in a single pot under ultrasound irradiation (Table 2). A variety of iodoarenes (1) and a number of terminal alkenes (2) were employed in this reaction. The corresponding desired product was generally obtained in good to acceptable yield. The R¹ and R² groups of iodoarenes (1) may include substituents such as H, Me, Cl, NO₂, OMe, and CF₃ whereas it’s R³ group may include moieties such as Ph, C₆H₄Me-p, C₆H₄NO₂-p and Me. Generally, aryl and heteroaryl alkenes were used in the present reaction. However, the use of other terminal alkenes such as methyl acrylate or 3-ethoxyprop-1-ene or alkenes possessing substituent at both ends [e.g. (E)-ethyl but-2-enoate] was not successful. The use of acrolein was also not successful due to its quick polymerization under the condition studied. The use of other haloarenes e.g. the corresponding chloro and bromoarene in place of 1 was examined. While bromoarene was less effective the reaction did not proceed in case of chloroarene. All the indole derivatives prepared were well characterized by spectral (¹H NMR, ¹³C NMR and MS) data. For example appearance of a singlet in the range δ 6.5–6.6 in the ¹HNMR and a peak near 113 ppm in the ¹³C NMR spectra clearly indicated the presence of indole C-3 hydrogen and carbon atom respectively.

Table 2 Preparation of indole derivatives.^a

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Entry	Iodoarene (1); R1, R2, R3=	Alkene (2); R4=	Product (3)	% yieldb
1.	1a; H, H, Ph	2a; Ph		77
2.	1b; H, H, C6H4Me-p	2a		75
3.	1b; H, H, C6H4Me-p	2b; C6H4Me-o		81
4.	1b; H, H, C6H4Me-p	2c; C6H4Me-m		79
5.	1b; H, H, C6H4Me-p	2d; C6H4Me-p		63
6.	1b; H, H, C6H4Me-p	2e; C6H4Cl-p		79
7.	1b; H, H, C6H4Me-p	2f; C6H4NO2-p		71
8.	1b; H, H, C6H4Me-p	2g; C6H4CF3-m		80
9.	1b; H, H, C6H4Me-p	2h; C6H4OMe-m		72
10.	1b; H, H, C6H4Me-p	2i; 1-naphthyl		76
11.	1b; H, H, C6H4Me-p	2j; 3-thienyl		79
12.	1c; H, H, C6H4Cl-p	2a		71
13.	1d; H, H, C6H4NO2-p	2a		73
14.	1e; H, H, Me	2a		72
15.	1f; H, Me, C6H4Me-p	2a		63
16.	1g; H, Cl, C6H4Me-p	2a		60
17.	1h; H, NO2, C6H4Me-p	2a		68
18.	1i; Me, H, C6H4Me-p	2a		71
19.	1j; Cl, H, C6H4Me-p	2a		74
20.	1k; OMe, H, C6H4Me-p	2a		69
21.	1l; NO2, H, C6H4Me-p	2a		70
22.	1m; CF3, H, C6H4Me-p	2a		77

a All reactions were performed using iodoarene 1 (0.3 mmol, 1.0 equiv.), alkene 2 (0.36 mmol, 1.2 equiv.), 10% Pd/C (0.05 equiv), PPh₃ (0.10 equiv), and Et₃N (0.6 mmol, 2.0 equiv.) in 1,4-dioxane (5.0 mL) at 50 °C under ultrasound in the presence of nitrogen for 2 h and then DDQ (0.6 mmol, 2 equiv) at 50 °C under ultrasound in the presence of nitrogen for 4 h.

b Isolated yield.

While the mechanism of the second step of this one-pot method is not clearly understood a plausible reaction mechanism for the present ultrasound assisted construction of indole ring via Mizoroki–Heck coupling/C–H amination strategy is presented in Scheme 3. The initial step of this reaction involves in situ generation of an active palladium(0) species (Pal, 2009; Rambabu et al., 2013; Chen et al., 2007) via a Pd leaching process from the minor portion of the bound palladium (Pd/C) (Köhler et al., 2002). The leached Pd in the solution then interacts with the ligand PPh₃ to afford a dissolved Pd(0)–PPh₃ complex which is the actual catalytic species. It should be noted that the generation of active species from supported Pd catalyst under Heck reaction conditions has been studied earlier (Reimann et al., 2011). Nevertheless, this complex on oxidative addition with the deprotonated species generated from 1 affords the organo-palladium(II) species E-1. Subsequent formation of a π-complex of E-1 with the alkene 2 followed by syn addition of Pd-carbon bond of E-1 across the double bond of 2 affords E-2. A torsional strain relieving rotation around the C–C bond of E-2 gives E-3 which then undergoes a syn β-hydride elimination to give E-4 and H-Pd^II-I species. The regeneration of Pd(0) via reductive elimination of Pd from H-Pd^II-I species completes the catalytic cycle which continues till the complete consumption of 1. Overall, it appears that the catalytic cycle operates in solution instead of on the surface and at the end of the reaction and re-precipitation of Pd occurs on the surface of the charcoal. Nonetheless, once formed the alkene intermediate E-4 then undergoes intramolecular cyclization aided by DDQ via formation of an intramolecular C–N bond (between the sulfonamide anion and the C–C double bond) and intermolecular C–O bond (between the benzylic carbon and DDQ) leading to the adduct E-5. The aromatization of E-5 via the loss of proton and the attached DDQ moiety affords the desired product 3. To gain further evidence on intermediacy of E-4 in the present reaction the compound 4 was treated with 2 equivalents of DDQ and Et₃N in 1,4-dioxane at 50 °C under ultrasound irradiation for 4 h when compound 3a was isolated in 79% yield. This observation clearly indicated that the reaction proceeded via E-4 to give the desired indole 3.

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Scheme 3

The proposed reaction mechanism for the ultrasound assisted construction of indole ring via Mizoroki–Heck coupling/C–H amination strategy.

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While it is not clear if one or more steps of Scheme 3 were influenced by the ultrasound irradiation the results of Table 1 clearly suggest that the intramolecular cyclization via C–H amination in the second step of this one-pot process was particularly facilitated by the ultrasound. Possibly the force created due to the cavitational collapse provided a positive effect on this step. Indeed, the cavitational collapse is known to create drastic conditions inside the medium within an extremely short period of time. For example, the temperature of 2000–5000 K and pressure up to 1800 atmosphere can be produced inside the collapsing cavity under sonic conditions (Luche, 1998; Suslick and Flannigan, 2008; Mason, 1997). Also, strong physical effects including shear forces, jets, and shock waves are caused by this collapse outside the bubble. Thus, it is possible that the key steps of this process including the oxidative addition, rotation, and C–H amination (Scheme 3) along with several other steps were driven by the force created due to the cavitational collapse. It is also possible that the in situ generation of active Pd(0) species via Pd leaching process was accelerated under sonic conditions. It is worthy to mention that the ultrasound may facilitate the generation of Pd(0) nanoparticles which may serve as a reservoir of “homogeneous” catalytic active species (Cassol et al., 2005). The role of Pd nanoparticles in Heck and other coupling reactions (e.g. Suzuki–Miyaura reaction) has been studied earlier (Baumann et al., 2014; Ellis et al., 2010).

4 Conclusion

In conclusion, a one-pot method based on coupling-cyclization strategy has been developed for the construction of indole ring leading to 2-substituted indole derivatives. The methodology involved ultrasound assisted Mizoroki–Heck coupling in the initial step followed by C–H amination in the same pot. The C–C bond forming reaction in the first step was catalyzed by Pd/C-PPh₃ catalyst system whereas the C–N bond formation in the second step was mediated by DDQ. A large number of indoles were prepared in good to acceptable yield by treating 2-iodosulfanilides with various terminal alkenes under this condition. Various substituents such as Me, Cl, NO₂, OMe, and CF₃ present on the benzene ring of the iodosulfanilides used were well tolerated. However, the use of terminal alkenes other than aryl and heteroaryl alkenes was not successful. Overall, merit and demerit of this methodology along with the possible reaction mechanism have been discussed. Since the rapid conversions along with the use of inexpensive catalyst as well as oxidant are key features of this method hence the methodology may find applications in preparing indole based library of molecules.