Na₂SO₃-Promoted Heck Coupling and Homo-Coupling of Arylhydrazines at Room Temperature

Abstract

A novel protocol facilitated by Na₂SO₃ that enhances the efficiency of palladium-catalyzed Heck coupling and the homo-coupling reactions of arylhydrazines. This innovative method enables the effective construction of a diverse array of cinnamate derivatives and biphenyl compounds. Notably, these transformative reactions proceed smoothly at room temperature, leveraging the activation of C-N bonds. This technique not only streamlines the synthesis process but also expands our understanding and expertise in the realm of coupling reactions.

1. Introduction

The synthesis of Csp²–Csp² bonds is pivotal in the realm of organic synthesis [1,2]. These bonds represent a prevalent structural motif that is prevalent among natural products [3], pharmaceuticals [4], and materials [5]. These compounds include arylalkenes and biaryls, which can typically be prepared through palladium-catalyzed Heck coupling [6,7] and homo-coupling reactions [8], respectively. Though a diverse array of aryl sources, such as aryl halides [9], aryl sulfonates [10], and aryl sulfonyl chloride [11], alongside their derivatives, have proven to be effective in coupling reactions, the expansion of the electrophilic coupling partners continues to hold substantial importance in the field of organic synthesis.

In recent years, the activation and cleavage of C–N bonds to facilitate coupling reactions have attracted significant interest, with arenediazonium salts being extensively utilized [12,13]. However, the instability of these salts and their susceptibility to side reactions have limited their application in broader contexts. Traditional applications of arylhydrazines have centered around the creation of colorants, medicinal compounds, and diagnostic imaging agents, while also serving as indispensable detectors for a range of carbonyl and sugar compounds [14]. Recently, arylhydrazines have emerged as a novel and promising alternative for a variety of coupling transformations, offering significant advantages such as affordability, ready availability, and exceptional versatility [15].

Teck-Peng Loh’s pioneering research [16] established a novel arylhydrazine-based Heck reaction mechanism, marked by the crucial involvement of phenanthroline ligands and the essential use of atmospheric oxygen and acetic acid for a productive chemical process. In 2014, Xu et al. [17] reported on the Suzuki cross-coupling reaction between arylhydrazines and arylboronic acids under acidic conditions, catalyzed by palladium. Furthermore, Wang and colleagues [18] have illuminated the field with their report on the palladium-catalyzed Hiyama cross-coupling reaction, efficiently coupling arylhydrazines with arylsilicon reagents. Nonetheless, the reaction schemes mentioned above are confined to acidic environments, which require the employment of an excess of acidic reagents. Our research team has also made significant strides in the field of catalysis by pioneering the use of sulfonyl chloride to activate arylhydrazines, thereby facilitating the palladium-catalyzed Suzuki and Heck cross-coupling reactions of arylhydrazines [19,20,21,22,23]. In this work, we propose an innovative method that employs Na₂SO₃ as a diazonium salt stabilizer, effectively facilitating the coupling of phenylhydrazine hydrochloride and demonstrating its capacity to enhance the Heck and homo-coupling reactions of arylhydrazines at ambient temperature.

2. Results and Discussion

In the preliminary phase of our research, phenylhydrazine hydrochloride (1a) and ethyl acrylate (2a) were chosen as the benchmark substrates for the Heck model reaction. An extensive screening of reaction conditions was conducted, with the outcomes compiled in

Table 1. Optimization of the reaction conditions ^a.

Entry	[Pd]	Base (Equiv.)	Additive	Solvent	Yield of 3a b (%)
1	Pd(OAc)2	Et3N	Na2SO3	DMF	64
2	Pd(OAc)2	Et3N	—	DMF	36
3 b	Pd(OAc)2	Et3N	Na2SO3	DMF	60
4 c	Pd(OAc)2	Et3N	Na2SO3	DMF	83
5 d	Pd(OAc)2	Et3N	Na2SO3	DMF	80
6	Pd(OAc)2	Et3N	Na2SO3	THF	53
7	Pd(OAc)2	Et3N	Na2SO3	EtOH	48
8	Pd(OAc)2	Et3N	Na2SO3	CH3CN	64
9	Pd(OAc)2	Et3N	Na2SO3	H2O	Trace
10	Pd(OAc)2	Et3N	Na2SO3	DMSO	70
11	Pd(OAc)2	Et3N	Na2SO3	Acetone	35
12	Pd(OAc)2	DMAP	Na2SO3	DMF	70
13	Pd(OAc)2	K2CO3	Na2SO3	DMF	51
14	Pd(OAc)2	Cs2CO3	Na2SO3	DMF	31
15	Pd(OAc)2	Et3N	Na2S2O8	DMF	48
16	Pd(OAc)2	Et3N	NaHSO3	DMF	73
17	Pd(OAc)2	Et3N	Na2S2O3	DMF	Trace
18	Pd(OAc)2	Et3N	Na2S	DMF	Trace
19	Pd(TFA)2	Et3N	Na2SO3	DMF	46
20	PdCl2	Et3N	Na2SO3	DMF	59
21	—	Et3N	Na2SO3	DMF	Trace
22 e	Pd(OAc)2	Et3N	Na2SO3	DMF	66
23 f	Pd(OAc)2	Et3N	Na2SO3	DMF	75
24 g	Pd(OAc)2	Et3N	Na2SO3	DMF	79
25 h	Pd(OAc)2	Et3N	Na2SO3	DMF	76

^a Reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol), [Pd] (5 mol%), base (2 equiv.), solvent (2 mL), 20 h. ^b Na₂SO₃ (0.6 eq.). ^c Na₂SO₃(1.2 eq.). ^d Na₂SO₃(1.4 eq.). ^e [Pd] (2.5 mol%). ^f [Pd] (10 mol%). ^g O₂. ^h N₂.

. Initially, the model reaction was conducted at room temperature with 5 mol% Pd(OAc)₂ as the catalyst, 2.0 equivalents of Et₃N as the base, and 1.0 equivalents of Na₂SO₃ as an additive in dimethylformamide (DMF). To our delight, the desired product, ethyl cinnamate (3a), was obtained with a 64% yield (Entry 1). Upon comparison without Na₂SO₃, a stark difference in yield was observed (Entry 2). Building on these initial observations, we conducted a further optimization of the sodium sulfite equivalents (entries 3–5) and determined that the reaction yield reached a maximum of 83% when the equivalents of sodium sulfite were equimolar with those of phenylhydrazine (entry 4). Consequently, for subsequent condition screenings, we selected the use of 1.2 equivalents of sodium sulfite as the additive to continue our investigation. We explored alternative solvents, including EtOH, CH₃CN, acetone, DMSO, and THF (Entries 6–11), but found that DMF remained the most effective medium. Subsequently, the impact of various bases on the reaction was assessed (Entries 12–14). Et₃N proved superior to other bases such as Cs₂CO₃ and DMAP. Additionally, we tested Na₂S₂O₈, Na₂S₂O₃, and Na₂S as substitutes for Na₂SO₃, revealing that only the +4 valence sulfide exhibited optimal performance, with other valence states showing weaker promotion or even inhibition (Entries 15–18). Furthermore, other Pd-catalysts were evaluated, with Pd(OAc)₂ emerging as the most effective (Entries 19 and 20). In the absence of a palladium catalyst, the reaction was inert (Entry 21); reducing the equivalents of the catalyst led to a decrease in yield (Entry 22), while increasing the equivalents of the catalyst did not result in a significant improvement in yield (Entry 23). Ultimately, when nitrogen (N₂) and oxygen (O₂) were introduced into the reaction environment, the process demonstrated minimal sensitivity to additional oxidants, with yields remaining largely unaffected (Entries 24 and 25).

Subsequently, the scope of the palladium-catalyzed Heck coupling reaction between arylhydrazine hydrochlorides and acrylates was investigated (Scheme 1). When phenylhydrazine hydrochloride was substituted with a methyl group, both the mono-methylated and di-methylated substrates were reactive in the coupling process, yielding good yields (3b–3c). The introduction of other electron-withdrawing groups into the aryl group, such as halogens, trifluoromethyl, and nitro groups (3d–3h), resulted in a slight decrease in yields. Furthermore, the range of acrylates including methyl acrylate (3i) and tert-butyl acrylate (3j) was explored, with results indicating no significant influence on the reaction yields. Switching from acrylates to unactivated styrenes, such as 4-methylstyrene (3k) and 4-methoxystyrene (3l), resulted in a sharp reduction in yields to 22% and 28%, respectively. Unfortunately, the electron-rich substituted arylhydrazine hydrochlorides, such as p-methoxyphenylhydrazine hydrochloride, did not yield the expected product when used in the reaction. This lack of expected product may be attributed to the high reactivity of these electron-rich arylhydrazines, which are prone to decomposition.

During the aforementioned study of the Heck coupling reaction, it was observed that the homo-coupling reaction of arylhydrazines was inevitable. Consequently, the homo-coupling of arylhydrazine hydrochlorides was investigated under conditions similar to the Heck coupling reaction, with the findings summarized in Scheme 2. To our delight, the yield of the homo-coupled product, biphenyl (4a), could reach up to 76%, and the introduction of additional methyl substituents did not cause significant fluctuations in yield (4b–4d). Moreover, the incorporation of other electron-withdrawing groups into the aryl group, such as halogens (4e), trifluoromethyl (4f), and trifluoromethoxy (4g), resulted in a reduction of yield to varying extents. Regrettably, the introduction of a nitro group did not yield the corresponding product. Additionally, because of steric hindrance, the desired product could not be obtained when 2,6-dimethylhydrazine hydrochloride was used as the substrate.

To gain a deeper understanding of the intrinsic mechanism behind the coupling reactions involving arylhydrazines promoted by sodium sulfite, we conducted a series of inorganic chemistry experiments to meticulously investigate the transformation pathway of sodium sulfite. After the reaction, we performed a post-treatment of the solution by adding dichloromethane and water. To check for the possible formation of sodium sulfate, we added saturated BaCl₂ solution to the upper aqueous phase, where only a slight turbidity was observed. Subsequently, we added dilute hydrochloric acid dropwise to the system and noticed the gradual dissolution of the precipitate. This change indicated the presence of a small amount of sodium sulfite, but not sodium sulfate, in the aqueous phase. This finding is of significant importance in revealing the role of sodium sulfite in the coupling reaction mechanism.

Based on the aforementioned experimental outcomes and the research findings from other groups, we have postulated a probable mechanism for the coupling reactions of arylhydrazines promoted by sodium sulfite. As depicted in Figure 1, under the oxidation by Pd(II), phenylhydrazine is transformed into a diazonium salt, with sodium sulfite playing a crucial role in stabilizing this intermediate. With the aid of a palladium catalyst, the diazonium salt then participates in a homo-coupling reaction, or alternatively, it can undergo a classic Heck coupling reaction with acrylate. These reactions, respectively, result in the synthesis of biphenyl and cinnamate products. Throughout this catalytic cycle, sodium sulfite not only stabilizes the diazonium salt but also acts as a ligand to coordinate with the palladium catalyst, ensuring the smooth progression of the reaction.

3. Materials and Methods

3.1. General Information

Unless otherwise noted, all of the reagents were purchased from commercial suppliers and used without purification. The purification of products was conducted by flash chromatography on silica gel (200–300 mesh). Nuclear magnetic resonance (NMR) spectra were measured on a Bruker Avance III 400 (400 MHz). The ¹H NMR (400 MHz) chemical shifts were obtained relative to CDCl₃ as the internal reference (CDCl₃: δ 7.26 ppm). The ¹³C NMR (101 MHz) chemical shifts were given using CDCl₃ as the internal standard (CDCl₃: δ 77.16 ppm). Chemical shifts are reported in ppm using tetramethylsilane as the internal standard (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet). Compounds described in the literature were characterized by the comparison of ¹H and/or ¹³C NMR spectra to the previously reported data.

3.2. General Method for the Na₂SO₃-Promoted Heck Coupling and Homo-Coupling of Arylhydrazines

Arylhydrazine hydrochloride 1 (0.36 mmol), ethyl acrylate 2 (0.3 mmol), Et₃N (0.6 mmol), Pd(OAc)₂ (5 mmol%), and Na₂SO₃ (0.36 mmol) were combined in DMF (2 mL) and the mixture was stirred at room temperature for 20 h. After the reaction was complete, saturated sodium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate in three portions (15 mL each). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography to yield product 3.

Arylhydrazine hydrochloride 1 (0.36 mmol), Et₃N (0.6 mmol), Pd(OAc)₂ (5 mmol%), and Na₂SO₃ (0.36 mmol) were combined in DMF (2 mL) and the mixture was stirred at room temperature for 20 h. After the reaction was complete, saturated sodium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate in three portions (15 mL each). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was then purified by column chromatography to yield product 4.

3.3. Characterization Data for Products 3a–4g

The following NMR spectra of compounds 3a–4g are shown in Supplementary Materials.

• Ethyl cinnamate (3a) [24]. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 16.0 Hz, 1H), 7.56–7.48 (m, 2H), 7.41–7.34 (m, 3H), 6.44 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.03, 144.62, 134.45, 130.26, 128.90, 128.08, 118.26, 60.53, 14.36.

• Ethyl (E)-3-(p-tolyl)acrylate (3b) [25]. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.35–1.32 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.26, 144.64, 140.66, 131.72, 129.63, 128.07, 117.15, 60.45, 21.49, 14.37.

• Ethyl (E)-3-(3,4-dimethylphenyl)acrylate (3c) [26]. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 16.0 Hz, 1H), 7.29–7.23 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.25 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.30, 144.83, 139.41, 137.11, 132.14, 130.17, 129.30, 125.71, 116.95, 60.39, 19.83, 19.77, 14.38.

• Ethyl (E)-3-(2-bromophenyl)acrylate (3d) [25]. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (dd, J = 15.9, 3.4 Hz, 1H), 7.66–7.54 (m, 2H), 7.26 (ddd, J = 17.9, 7.5, 2.0 Hz, 2H), 6.46–6.32 (m, 1H), 4.29 (qd, J = 7.1, 3.6 Hz, 2H), 1.37–1.33 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.42, 142.92, 134.51, 133.41, 131.15, 127.72 127.61, 125.30, 121.10, 60.72, 14.30.

• Ethyl 3-(4-bromophenyl)acrylate (3e) [24]. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.42 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 166.77, 143.22, 133.36, 132.14, 129.44, 124.48, 118.96, 60.68, 14.33.

• Ethyl (E)-3-(4-chlorophenyl)acrylate (3f) [24]. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 16.0 Hz, 1H), 7.47–7.42 (m, 2H), 7.39–7.31 (m, 2H), 6.41 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.79, 143.16, 136.12, 132.93, 129.22, 129.17, 118.84, 60.66, 14.32.

• Ethyl (E)-3-(4-nitrophenyl)acrylate (3g) [24]. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 8.8 Hz, 2H), 7.70 (dd, J = 15.9, 8.7 Hz, 3H), 6.57 (d, J = 16.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 166.06, 148.44, 141.64, 140.58, 128.64, 124.18, 122.57, 61.04, 14.27.

• Ethyl (E)-3-(4-(trifluoromethyl)phenyl)acrylate (3h) [24]. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 16.0 Hz, 1H), 7.63 (d, J = 1.9 Hz, 4H), 6.51 (d, J = 16.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.45, 142.71, 137.82, 131.68, 131.68, 128.16. 125.83, 120.82, 60.82, 14.26. 19F NMR (377 MHz, CDCl3) δ −62.88.

• Methyl cinnamate (3i) [22]. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 16.0 Hz, 1H), 7.56–7.46 (m, 2H), 7.43–7.36 (m, 3H), 6.44 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.50, 144.93, 134.36, 130.3, 128.92, 128.11, 117.78, 51.76.

• Tert-butyl cinnamate (3J) [22]. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 16.0 Hz, 1H), 7.50 (dd, J = 6.5, 3.1 Hz, 2H), 7.36 (dd, J = 5.0, 1.9 Hz, 3H), 6.37 (d, J = 16.0 Hz, 1H), 1.54 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 166.38, 143.59, 129.99, 128.85, 128.42, 127.98, 120.18, 80.53, 28.22.

• (E)-1-Methyl-4-styrylbenzene (3k) [22]. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 7.4 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.23 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 2.6 Hz, 2H), 2.34 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 137.60, 137.57, 134.60, 129.49, 128.75, 128.68, 127.76, 127.50, 126.52, 126.49, 21.36.

• (E)-1-Methoxy-4-styrylbenzene (3l) [27]. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.7 Hz, 4H), 7.34 (t, J = 7.6 Hz, 2H), 7.23 (dd, J = 9.1, 5.5 Hz, 1H), 7.07 (d, J = 16.3 Hz, 1H), 6.97 (d, J = 16.3 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 159.31, 137.66, 130.15, 128.69, 128.22, 127.76, 127.26, 126.62, 126.29, 114.15, 55.37.

• 1,1′-Biphenyl (4a) [28]. ¹H NMR (400 MHz, CDCl₃) δ 7.69–7.63 (m, 4H), 7.50 (t, J = 7.5 Hz, 4H), 7.40 (t, J = 7.3 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 141.30, 128.85, 127.30.

• 4,4′-Dimethyl-1,1′-biphenyl (4b) [28]. ¹H NMR (400 MHz, CDCl₃) δ 7.25–7.21 (m, 4H), 7.10 (d, J = 7.9 Hz, 4H), 2.32 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 131.06, 129.94, 129.82, 128.52, 21.11.

• 3,3′,5,5′-Tetramethyl-1,1′-biphenyl (4c) [28]. ¹H NMR (400 MHz, CDCl₃) δ 7.13 (s, 4H), 6.86 (s, 2H), 2.29 (s, 12H). ¹³C NMR (101 MHz, CDCl₃) δ 138.77, 136.80, 129.03, 125.09, 21.31.

• 3,3′,4,4′-Tetramethyl-1,1′-biphenyl (4d) [28]. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (s, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 6.8 Hz, 2H), 2.27 (s, 6H), 2.24 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 138.99, 136.88, 135.39, 130.08, 128.36, 124.45, 20.06, 19.54.

• 4,4′-Dibromo-1,1′-biphenyl (4e) [28]. ¹H NMR (400 MHz, CDCl₃) δ 7.59–7.54 (m, 4H), 7.45–7.38 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 138.92, 132.05, 128.54, 121.97.

• 4-(Trifluoromethyl)-biphenyl (4f) [28]. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 8.5 Hz, 4H), 7.69 (d, J = 8.5 Hz, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 143.25, 130.28 (q, J = 32.7 Hz), 127.65, 125.97 (q, J = 3.8 Hz). 124.13 (q, J = 272.1 Hz). ¹⁹F NMR (377 MHz, CDCl₃) δ −62.56.

• 4,4′-Bis(trifluoromethyl)-1,1′-biphenyl (4g) [23]. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J = 8.4 Hz, 4H), 7.29 (d, J = 8.5 Hz, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 148.95, 138.59, 128.49, 121.38, 120.52 (q, J = 257.4 Hz). ¹⁹F NMR (377 MHz, CDCl₃) δ −57.85.

4. Conclusions

In conclusion, we have successfully developed an innovative catalytic system that employs sodium sulfite as a promoter to facilitate the palladium-catalyzed C-N bond activation, enabling the Heck coupling and homo coupling of arylhydrazine hydrochloride salts. This approach utilizes commercially available arylhydrazine hydrochloride salts as the starting coupling agents and pairs them with the cost-effective and user-friendly activation reagent, sodium sulfite, rendering the entire synthesis not only cost-efficient but also straightforward to perform. This economical, eco-friendly, and efficient method enriches the repertoire of classical Heck coupling and homo-coupling reactions.