Electrochemical Oxidative Clean Halogenation Using HX/NaX with Hydrogen Evolution.

Organic halides (R-X) are prevalent structural motifs in pharmaceutical molecules and key building blocks for the synthesis of fine chemicals. Although a number of routes are available in the literature for the synthesis of organic halides, these methods often require stoichiometric additives or oxidants, metal catalysts, leaving or directing groups, or toxic halogenating agents. In addition, the necessity of employing different, often tailor-made, catalytic systems for each type of substrate also limits the applicability of these methods. Herein, we report a clean halogenation by electrochemical oxidation with NaX/HX. A series of organic halides were prepared under metal catalyst- and exogenous-oxidant-free reaction conditions. It is worth noting that this reaction has a broad substrate scope; various heteroarenes, arenes, alkenes, alkynes, and even aliphatic hydrocarbons could be applied. Most importantly, the reaction could also be performed on a 200-mmol scale with the same efficiency (86%, 50.9 g pure product).

Introduction

Organic halides (R-X) are compounds of high practical utility, which are not only important structural motifs in many pharmaceutical molecules and natural products (Hernandez et al., 2010; Jeschke, 2010, Butler and Sandy, 2009) but also key building blocks for the synthesis of fine chemicals via transition-metal-catalyzed oxidative/reductive cross-coupling reactions (Yue et al., 2018, Fairlamb, 2007, Nicolaou et al., 2005, Meijere and Diederich, 2004, Liu et al., 2017a). Consequently, practical and efficient methods to access this class of compounds are highly valuable. Extensive efforts have been made, and great achievement has been reached (Ye et al., 2018, Mo et al., 2010, Petrone et al., 2016, Rafiee et al., 2018, Liu et al., 2017b, Fu et al., 2017a, Wang et al., 2012, Wallentin et al., 2012, Liu and Groves, 2010, Murphy et al., 2007, Smith et al., 2002), such as the electrophilic aromatic substitutions (Barluenga et al., 2007, Prakash et al., 2004, David, 1976) and the directed C-H halogenations (Teskey et al., 2015, Schröder et al., 2015, Schröder et al., 2012, Bedford et al., 2011, Kakiuchi et al., 2009, Mei et al., 2008, Whitfield and Sanford, 2007, Wan, 2006). Although these methods have been widely used for the synthesis of organic halides (R-X), they still have one or more of the following limitations: (1) the use of hazardous and toxic X2 (X = Br, Cl) as halogenating agents; (2) the need of stoichiometric amount of additives/exogenous oxidants; (3) the need of a metal salt as the catalyst; (4) the need of custom-built substrate bearing leaving or directing groups; (5) the necessity of employing different, often tailor-made, catalytic systems for each types of substrate; and (6) the harsh reaction conditions. Therefore, exploring an efficient and versatile method for the synthesis of various organic halides (R-X) with non-toxic and green halogenating agents under environmentally benign metal-catalyst-free and exogenous-oxidant-free reaction conditions would be highly desirable.

Electrochemical anodic oxidation presents the prospect of the efficient and environmentally benign synthesis of complex molecules and has attracted considerable interest (Tang et al., 2018a, Yoshida et al., 2018, Jiang et al., 2018, Yan et al., 2017, Pletcher et al., 2018, Francke and Little, 2014, Jutand, 2008, Sperry and Wright, 2006, Qiu et al., 2018, Xiong et al., 2017, Gieshoff et al., 2017, Fu et al., 2017b, Yang et al., 2017, Horn et al., 2016, Badalyan and Stahl, 2016, Kärkäs, 2018, Liu et al., 2018, Lyalin and Petrosyan, 2013, Raju et al., 2006, Kulangiappar et al., 2016, Tan et al., 2017). As part of our continuing studies in the area of electrochemical oxidative C-C and C-heteroatom bonds formation (Yuan et al., 2019, Tang et al., 2018b, Gao et al., 2018, Yuan et al., 2018a, Yuan et al., 2018b, Yuan et al., 2018c), we herein report a clean halogenation by exogenous-oxidant-free electrochemical oxidation. A series of significant organic halides (R-X) were prepared under metal-catalyst-free and exogenous-oxidant-free reaction conditions with commercially available, nontoxic, and atom-efficient NaX/HX (aq.). It is worth noting that this electrochemical oxidative synthetic protocol has a broad substrate scope. Various heteroarenes, arenes, alkenes, alkynes, and even aliphatic hydrocarbons were suitable for this transformation.

Results and Discussion

Imidazopyridines (Dyminska, 2015, Enguehard-Gueiffier and Gueiffier, 2007), especially C-3-substituted imidazopyridines, are often used as commercially available drugs including alpidem (Okubo et al., 2004), zolpidem (Langer et al., 1990), necopidem (Depoortere and George, 1991), and saripidem (Sanger, 1995). The introduction of a halogen moiety into the C-3 position of imidazopyridines has been considered to be important because the generated C-3 halogenated imidazopyridines are key intermediates for the synthesis of these drugs. Our investigation included 2-phenylimidazo[1,2-a]pyridine (1a) and sodium chloride (2a) as the starting materials for the synthesis of these class of significant C-3 halogenated imidazopyridines. As shown in Table 1, by employing a two-electrode system with carbon rod as the anode and platinum plate as the cathode, the desired C-H chlorination product 3a was produced in 81% yield with a 12 mA constant current in an undivided cell (entry 1). A range of other chlorides were investigated, but all displayed lower effectiveness than sodium chloride (entries 2–6). Both decreasing the operating current to 6 mA and increasing the operating current to 18 mA led to slightly decreased reaction yields (entries 7–8). Then different electrode materials were surveyed, employing either carbon cloth as cathode or platinum plate as anode led to decreased reaction efficiency (entries 9–10). The effect of solvent was explored as well. When N,N-dimethylformamide was used as the sole solvent, 69% yield of 3a could still be obtained (entry 11). However, when the reaction was performed using acetonitrile instead of N,N-dimethylformamide, an obvious loss of the yield was observed (entry 12). As was expected, no reaction could be observed in the absence of electric current (entry 13).

Table 1

Optimization of Electrochemical Oxidative C-H Chlorination

Entry	Variation from the Standard Conditions	Yield (%)a
1	None	81
2	HCl (aq.) instead of NaCl	49
3	LiCl instead of NaCl	34
4	KCl instead of NaCl	75
5	MgCl2 instead of NaCl	44
6	CaCl2 instead of NaCl	51
7	6 mA, 7 h	75
8	18 mA, 2.3 h	70
9	Carbon cloth cathode	61
10	Platinum plate anode	53
11	Without H2O	69
12	MeCN instead of DMF	48
13	No electric current	ND

Reaction conditions: carbon rod anode, platinum plate cathode, constant current = 12 mA, 1a (0.3 mmol), 2a (2.0 equiv.), DMF (10.5 mL), H2O (0.5 mL), 80oC, N2, 3.5 h (5.2 F/mol).

ND, not detected.

Isolated yields.

With the optimized reaction conditions in hand, the scope and generality of this clean halogenation was explored (Figure 1). With respect to the C-H chlorination (Figure 1A), diverse heteroarenes/arenes served as effective reaction partners with 2a to form C-Cl bond. The phenyl- and naphthyl-substituted imidazo[1,2-a]pyridines showed good reactivity and gave the corresponding products in 81% and 76% yields (Figure 1A, 3a-b), respectively. 2-Arylimidazo[1,2-a]pyridines bearing halogen substituents on the phenyl ring delivered the C-H chlorination products in good to high yields (Figure 1A, 3d-f). Delightfully, strong electron-withdrawing groups such as trifluoromethyl and cyano at the para position of the phenyl ring of 2-phenylimidazo[1,2-a]pyridines nearly did not affect the reaction efficiency (Figure 1A, 3g-h). By contrast, 2-phenylimidazo[1,2-a]pyridines bearing electron-rich group showed decreased reaction efficiency (Figures 1A, 3i). It is worth noting that the substrates bearing tert-butyl, trifluoromethyl, and -H groups at the C-2 position of imidazo[1,2-a]pyridines also reacted smoothly and delivered the desired products in moderate to good yields (Figure 1A, 3j-l). Moreover, imidazo[1,2-a]pyridines bearing various substituents such as methyl, chlorine, and trifluoromethyl groups at different positions of the pyridine ring all furnished the C-H chlorination products in high yields (Figure 1A, 3m-p). Besides various imidazo[1,2-a]pyridines, 1-phenylpyrazole, benzo[d]-imidazo[2,1-b]thiazole derivatives, and very-electron-rich 1,3,5-trimethoxybenzene were also suitable substrates for this transformation, affording the desired products in 62%–90% yields (Figure 1A, 3q-t).

Figure 1

Substrate Scope for Electrochemical Oxidative C-H Halogenation

(A) Substrate scope of C-H chlorination.

(B) Substrate scope of C-H bromination.

(C) Gram-scale synthesis.

Reaction conditions: carbon rod anode, platinum plate cathode, constant current = 12 mA, 1 (0.3 mmol), 2a (2.0 equiv.) or 2b (4.0 equiv.), DMF (10.5 mL), H2O (0.5 mL), 80°C, N2, 3.5 h (5.2 F/mol), isolated yields.

CH3CN (10.5 mL), H2O (0.5 mL), 75°C.

1 (2.0 equiv.), 2 (0.3 mmol).

7.0 h.

We subsequently turned our attention to the C-H bromination (Figure 1B). To our delight, imidazo[1,2-a]pyridines bearing various substituents such as alkyl, alkoxy, halogen, cyano, and trifluoromethyl groups at different positions of the phenyl ring or pyridine ring all underwent clean transformations to generate the C-H bromination products in good to excellent yields (Figure 1B, 4a-o). Notably, besides various imidazo[1,2-a]pyridines, other kinds of heteroarenes and arenes were also suitable for this transformation. For example, 2-aminopyridine, benzo[d]-imidazo[2,1-b]thiazole derivative, 1-phenylpyrazole, 3-phenylpyrazole, 8-aminoquinoline, and 2-aminopyridine derivatives all delivered the corresponding C-H bromination products in moderate to high yields (Figure 1B, 4p-v). It is worth noting that for 3-phenylpyrazole and 8-aminoquinoline, the double C-H bromination products were the major products (Figure 1B, 4r-s). In the case of electron-rich arenes, p-chloroaniline and p-bromoaniline afforded the corresponding C-H bromination products in good yields (Figure 1B, 4w-x). The very-electron-rich arenes, such as 1,3,5-trimethoxybenzene and 3,5-dimethoxytoluene, gave the C-Br bond formation products in 85% and 83% yields (Figure 1B, 4y-z), respectively. To examine the scalability of the exogenous-oxidant-free electrochemical oxidative C-H halogenation, reactions on the 15- and 50-mmol scale were performed (Figure 1C). The corresponding C-H halogenation products were afforded in 81% and 70% isolated yield, respectively (see Supplemental Information for details).

To shed light on the reaction mechanism for this electrochemical oxidative C-H halogenation, a series of control experiments were conducted. First, voltammograms of the substrates were recorded (see Figure S160 of the Supplemental Information for details). The oxidation peak of 1a was observed in N,N-dimethylformamide (DMF)/H2O at 1.59 V, whereas the oxidation peak of NaCl and NaBr were observed at 1.55 V and 1.40 V, respectively, which indicated that NaCl or NaBr was likely to be first oxidized under the electrolytic conditions. Moreover, under the standard optimized conditions, no homo-coupling product of 1a was observed in either C-H chlorination or bromination (Figures 2A and 2B). These results further indicated that NaCl and NaBr are readily oxidized than 1a in this electrochemical oxidative C-H halogenation. The reaction of 1a with molecular Cl2 and Br2 in the absence of electricity was also investigated (Figures 2C–2E). When 1.0 equiv. of molecular Br2 was added into the reaction system, the desired C-H bromination product could be obtained in high yield and H2O did not affect the efficiency of this reaction, whereas no chlorination product was detected when molecular Cl2 was used as the chlorinating agent. These results suggest that molecular Cl2 might not be involved as the intermediate in C-H chlorination, whereas molecular Br2 ought to be a key intermediate in C-H bromination. Meanwhile, the pathway in which molecular Br2 reacted with H2O yielding the Br+ (HOBr), then attacked by heteroarenes (1) to form the desired product, could be completely ruled out. Last but not least, the reaction of 1a with MeOH in the absence of sodium halides was carried out (Figure 2F); 9% homo-coupling product of 1a was isolated from the reaction system, but the product of radical cation intermediate captured by MeOH was not detected. These results suggest that the pathway in which 1a is oxidized to the corresponding radical cation intermediate and then captured by nucleophile could be ruled out.

Figure 2

Control Experiments

Based on the above-mentioned experimental results, a plausible reaction mechanism for C-H halogention is depicted in Figure 3. For the C-H chlorination, the reaction begins with the anodic oxidation of chlorine ion to generate the chlorine radical. The radical intermediate A could then be formed through a radical addition of chlorine radical to 1a. Finally, further single-electron oxidation and the following deprotonation led to product 3a. Concomitant cathodic reduction of water leads to hydrogen evolution. Different from the C-H chlorination, in C-H bromination, bromide ion is directly oxidized to molecular Br2, which then is attacked by 1a to access the intermediate C. Finally, the following deprotonation led to the product 4a.

Figure 3

Proposed Mechanism of C-H Halogenation

Having successfully demonstrated electrochemical oxidative halogenation of heterocycles/arenes, we subsequently turned our attention to the other type substrates. Indeed, this versatile electrochemical oxidative synthetic protocol was not limited to the heterocycles/arenes; alkenes (5) were identified as amenable substrates as well. As shown in Figure 4A, when the ratio of alkenes to HBr (aq.) was 1:2, various styrenes and aliphatic alkenes were compatible with the reaction conditions, providing the desired C-Br double bond forming products in moderate to high yields (Figures 4A, 6a-6x). Moreover, besides terminal alkenes, internal alkenes were also tolerated in this electrochemical system, and the trans-1,2-dibromides were isolated as the sole diastereomeric products (Figures 4A, 6k, 6r, 6s, 6u). This result suggests that molecular Br2 might be the key intermediate for this transformation. To evaluate the practicability of this method, we conducted the exogenous-oxidant-free electrochemical oxidative dibromination of 1-decene on a 200-mmol scale and finally obtained 50.9 g pure product (Figure 4B; see Supplemental Information for details), which is hard to access traditionally. This indicates that our protocol could be conveniently scaled up in industry.

Figure 4

Substrate Scope for Electrochemical Oxidative Dibromination of Alkenes

(A) Substrate scope of alkenes.

(B) Gram-scale synthesis.

Reaction conditions: carbon rod anode, platinum plate cathode, constant current = 12 mA, 5 (0.5 mmol), 2c (2.0 equiv.), MeCN (10.8 mL), H2O (0.2 mL), Bu4NBF4 (0.1 mmol), RT, N2, 3.0 h (2.7 F/mol), isolated yields.

2c (4.0 equiv.), 6.0 h.

To develop a more general method, we also turned our attention to investigate the dibromination of alkynes (Figure 5). Delightfully, when 4-methoxyphenylacetylene (7a) and 1-phenyl-1-propyne (7b) were employed as the surrogates of alkynes, the desired dibromination products were isolated in 65% and 33% yields (Figure 5), respectively, and E-isomers were isolated as the sole diastereomeric products. This result suggests that molecular Br2 might also be the key intermediate in this dibrominating reaction.

Figure 5

Substrate Scope for Electrochemical Oxidative Dibromination of Alkynes

Reaction conditions: carbon rod anode, platinum plate cathode, constant current = 12 mA, 7 (0.3 mmol), 2b (4.0 equiv.), MeCN (10.5 mL), H2O (0.5 mL), 75°C, N2, 3.5 h, isolated yields.

To further affirm that the alkene and alkyne dibromination involved a molecular Br2 intermediate, the reaction of molecular Br2 with styrene (5a) and 4-methoxyphenylacetylene (7a) in the absence of electricity was investigated (Figure 6), respectively. The reaction results indicate that these two transformations indeed involve a molecular Br2 intermediate.

Figure 6

Mechanism Experiments

The success of the heteroarenes, arenes, alkenes, and alkynes led us to extend this method to aliphatic hydrocarbons because alkyl halides are also powerful substrates. To our delight, when ethyl 2-pyridylacetate (9) and α-menthylstyrene (12) were employed as the surrogates of aliphatic hydrocarbons, the desired alkyl halides 10 and 13 were isolated in 54% and 32% yields (Figure 7), respectively. Moreover, for 2-pyridylacetate (9), when the amount of sodium bromide (2b) was increased to 4.0 equiv. and the reaction time was extended to 3.5 h, the double C-H halogenated product 11 could be isolated in 40% yield.

Figure 7

Electrochemical Oxidative C-H Bromination of Aliphatic Hydrocarbons

Limitations of Study

Substrate scope of alkyne dibromination is limited to the electron-rich alkynes.

Conclusion

We have successfully employed constant current for clean halogenation. A series of significant organic halides (R-X) were prepared under a metal-catalyst-free and exogenous-oxidant-free reaction conditions with commercially available, nontoxic, and atom-efficient NaX/HX (aq.). Remarkably, this electrochemical oxidative synthetic protocol has a broad substrate scope. Besides, various heteroarenes/arenes, alkenes, alkynes, and aliphatic hydrocarbons were also suitable. Most importantly, the reaction could also be performed on a 200-mmol scale with the same efficiency (86%, 50.9 g pure product), which further highlighted the synthetic practicability of this electrochemical oxidative strategy.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.