*2.3. Sonogashira and Related Reactions*

Since the first report by Sonogashira in 1975 [121], the metal complex-catalysed coupling of terminal alkynes with haloorganics has developed into an essential tool for the synthetic organic chemist (Scheme 24) [1,5,9]. Palladium or copper complexes are generally employed to facilitate this reaction and some very efficient systems have been reported for a wide variety of halides. Reports of the use of thiosemicarbazone complexes for this reaction have appeared only relatively recently. Representative metal complexes are shown in Figure 5; see also Figures 1, 3 and 4.

Although it is not a normal Suzuki–Miyaura reaction, we may also mention here the application of the palladium thiosemicarbazonato complex **27** as a catalyst for the synthesis of diaryl ketones via the C–C coupling reaction between aryl aldehydes and aryl boronic acids reported by Prabhu and Ramesh (Scheme 23) [120]. Optimal conditions were found to be 110 °C in toluene in the presence of Cs2O<sup>3</sup> and using 5 mol% of the complex. The scope of the reaction was demonstrated by the synthesis of diaryl ketones from the reaction of a wide variety of aromatic and heteroaromatic aldehydes with phenyl boronic acid as well as from the reaction of a selection of aryl boronic acids with

Table 2 summarises representative conditions and yields for Suzuki–Miyaura reactions

**Scheme 23.** Synthesis of diaryl ketones by carbon–carbon coupling reaction between aryl aldehydes

Since the first report by Sonogashira in 1975 [121], the metal complex-catalysed coupling of terminal alkynes with haloorganics has developed into an essential tool for the synthetic organic chemist (Scheme 24) [1,5,9]. Palladium or copper complexes are generally employed to facilitate this reaction and some very efficient systems have been reported for a wide variety of halides. Reports of the use of thiosemicarbazone complexes for this reaction have appeared only relatively recently.

Reports of the use of thiosemicarbazone complexes for this reaction have appeared only relatively recently. The few studies that have been made concern Pd and Ni complexes and are often subsidiary to studies of other coupling reactions. Thus there have been no significant studies on the

Representative metal complexes are shown in Figure 5; see also Figures 1, 3 and 4.

benzaldehyde. Satisfactory to excellent isolated yields were obtained.

catalysed by thiosemicarbazone complexes.

and aryl boronic acids.

*2.3. Sonogashira and Related Reactions*

**Scheme 24.** Sonogashira reaction. **Scheme 24.** Sonogashira reaction. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 19 of 42

**Figure 5.** Representative metal complexes of thiosemicarbazones as catalysts for the Sonogashira **Figure 5.** Representative metal complexes of thiosemicarbazones as catalysts for the Sonogashira reaction.

reaction. **Table 2.** Suzuki–Miyaura reactions catalysed by thiosemicarbazone complexes: representative conditions and yields <sup>1</sup> . **Metal <sup>T</sup> (°C) Solvent Time Yield**  Reports of the use of thiosemicarbazone complexes for this reaction have appeared only relatively recently. The few studies that have been made concern Pd and Ni complexes and are often subsidiary to studies of other coupling reactions. Thus there have been no significant studies on the nature of the active species in these reactions or of other features which may confer advantages over previously reported complexes. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 20 of 42 <sup>1</sup> conditions refer to reactions involving aryl bromides and phenyl or aryl boronic acids. 2 ligand donor atoms. <sup>3</sup> microwave irradiation <sup>4</sup> aryl chlorides were used. <sup>5</sup> Aryl aldehydes used instead of aryl halides.

**(h) Ligand <sup>2</sup> Base Catalyst (mol%) (%) Ref.** Pd 100 DMF/H2O 24 O,N,S Na2CO<sup>3</sup> 0.1 40–88 [16] Pd <sup>100</sup>– <sup>157</sup> DMF/H2<sup>O</sup> 0.25–<sup>1</sup> O,N,S Na2CO<sup>3</sup> 0.001–0.1 <sup>25</sup>–<sup>85</sup> [100] 3 Pd 25–95 EtOH/toluene 9–20 N,S NaOH 0.001 >99 [102] Pd 140 DMF 24 O,N,S K2CO<sup>3</sup> 2.0 46–78 [103] In 2011, Paul et al. in their study described above in connection with the use of thiosemicarbazone complexes of palladium in the Mizoroki–Heck or Suzuki–Miyaura couplings also examined their application to the Sonogashira reaction (see complexes **3** and **4** in Figure 1) [95]. Moderate to good conversions were obtained for the coupling of a limited number of aryl bromides with phenyl acetylene using either toluene-ethanol or PEG as solvent in the presence of Cu(I) and NaOH at 75–110 ◦C (Scheme 25). Catalyst loadings of 0.5 mol% were employed giving TONs of up to 200 and TOFs of up to 20 h–1 . In 2011, Paul et al*.* in their study described above in connection with the use of thiosemicarbazone complexes of palladium in the Mizoroki–Heck or Suzuki–Miyaura couplings also examined their application to the Sonogashira reaction (see complexes **3** and **4** in Figure 1) [95]. Moderate to good conversions were obtained for the coupling of a limited number of aryl bromides with phenyl acetylene using either toluene-ethanol or PEG as solvent in the presence of Cu(I) and NaOH at 75–110 °C (Scheme 25). Catalyst loadings of 0.5 mol% were employed giving TONs of up to 200 and TOFs of up to 20 h–<sup>1</sup> .

Pd 25–95 EtOH/toluene 9–20 N,S NaOH 0.001 98–100 [108] Pd 25–95 EtOH/toluene 3–14 C,N,S NaOH 0.001 100 [108] **Scheme 25.** Sonogashira reaction of aryl bromides with phenylacetylene catalysed by complex **3** or **4**. **Scheme 25.** Sonogashira reaction of aryl bromides with phenylacetylene catalysed by complex **3** or **4**.

Pd 130 DMF 24–48 C,N,S K3PO<sup>4</sup> 0.5 31–99 [109] Pd reflux DMF 3 O,N,S K2CO<sup>3</sup> 0.001 78–99 [110] Pd <sup>25</sup> EtOH 0.5–1.5 N,S <sup>K</sup>2CO<sup>3</sup> 0.2 <sup>76</sup>–<sup>98</sup> [111] 4 Pd 100 DMF 24 N,S K2CO<sup>3</sup> 0.05 60–99 [112] Pd 70 H2O 24 O,N,S Na2CO<sup>3</sup> 1.0 25–98 [113] Pd 28 H2O 2–12 N,S K2CO<sup>3</sup> 1.18 65–90 [114] In addition to the Suzuki–Miyaura reaction, Verma et al*.* also applied their carbohydrate derived thiosemicarbazone Pd complex **18**, shown in Figure 3, to the Sonogashira reaction between phenylacetylene and chlorobenzene, *p*-nitrobromobenzene or iodobenzene in triethylamine at 80 °C [111]. Moderate conversions of about 65% were obtained with 0.5 mol% catalyst loadings. In order to avoid the use of copper compounds in the Sonogashira reaction, a number of attempts have been made to develop complexes that are active under copper-free conditions. The first instance of a such a catalyst containing a thiosemicarbazone ligand was reported by Prabhu and Pal who synthesised a pyrenealdehyde thiosemicarbazonide palladium complex **28** (Figure 5) containing a Ph3P supporting ligand [122]. Single crystal X-ray diffraction indicated bidentate *N*,*S*-coordination of the ligand. The complex is air stable and was shown to catalyse the Sonogashira reaction between phenylacetylene In addition to the Suzuki–Miyaura reaction, Verma et al. also applied their carbohydrate derived thiosemicarbazone Pd complex **18**, shown in Figure 3, to the Sonogashira reaction between phenylacetylene and chlorobenzene, *p*-nitrobromobenzene or iodobenzene in triethylamine at 80 ◦C [111]. Moderate conversions of about 65% were obtained with 0.5 mol% catalyst loadings. In order to avoid the use of copper compounds in the Sonogashira reaction, a number of attempts have been made to develop complexes that are active under copper-free conditions. The first instance of a such a catalyst containing a thiosemicarbazone ligand was reported by Prabhu and Pal who synthesised a pyrenealdehyde thiosemicarbazonide palladium complex **28** (Figure 5) containing a Ph3P supporting ligand [122]. Single crystal X-ray diffraction indicated bidentate *N*,*S*-coordination of the ligand. The complex is air stable and was shown to catalyse the Sonogashira reaction between

bromides) or 24 h (for the chlorides).

complex **28**.

Ni 140 DMF 24 O,N,S Cs2CO<sup>3</sup> 2.0 40–99 [118] Ni 90 DMA 7 O,N,S K2CO<sup>3</sup> 1.0 28–64 [119]

Pd <sup>110</sup> toluene <sup>12</sup> N,S Cs2CO<sup>3</sup> 5.0 <sup>62</sup>–<sup>97</sup> [120]

**Scheme 26.** Copper-free Sonogashira reaction of aryl halides with phenylacetylene catalysed by

The octahedral nickel complexes **26** (Figure 4) prepared by Anitha et al*.* derived from 9,10 phenanthrenequinone thiosemicarbazone, 9,10-phenanthrenequinone *N*-methylthiosemicarbazone and 9,10-phenanthrenequinone *N*-phenylthiosemicarbazone described briefly above in connection with the Suzuki–Miyaura reaction were also examined for their activity in the Sonogashira reaction of phenyl acetylene with aryl halides [119]. Using catalyst loadings of 0.5 mol%, they were found to give good to very good conversions after 4 h in MeOH and in the presence of Cu(I) and pyridine (Scheme 27). Heteroaromatic chlorides also entered into the reaction as did ortho-substituted aromatics, albeit in lower yields. The authors concluded that steric effects in the ligands play a more important role than electronic effects in the catalytic activity of the complexes. Very good conversions were observed by Prabhu and Ramesh with a square-planar nickel complex NiL<sup>2</sup> **(29)** (Figure 5)

5

complex **28**.

occurs before coupling.

occurs before coupling.

arylboronic acids.

arylboronic acids.

to 200 and TOFs of up to 20 h–<sup>1</sup>

.

phenylacetylene and a range of aryl chlorides and bromides at room temperature in DMF/Et3N using a 0.5 or 1 mol% catalyst loading (Scheme 26). Moderate to very good conversions were obtained after 12 h (for the bromides) or 24 h (for the chlorides). and a range of aryl chlorides and bromides at room temperature in DMF/Et3N using a 0.5 or 1 mol% catalyst loading (Scheme 26). Moderate to very good conversions were obtained after 12 h (for the bromides) or 24 h (for the chlorides).

complex is air stable and was shown to catalyse the Sonogashira reaction between phenylacetylene

**Scheme 25.** Sonogashira reaction of aryl bromides with phenylacetylene catalysed by complex **3** or **4**.

In addition to the Suzuki–Miyaura reaction, Verma et al*.* also applied their carbohydrate derived thiosemicarbazone Pd complex **18**, shown in Figure 3, to the Sonogashira reaction between phenylacetylene and chlorobenzene, *p*-nitrobromobenzene or iodobenzene in triethylamine at 80 °C [111]. Moderate conversions of about 65% were obtained with 0.5 mol% catalyst loadings. In order to avoid the use of copper compounds in the Sonogashira reaction, a number of attempts have been made to develop complexes that are active under copper-free conditions. The first instance of a such a catalyst containing a thiosemicarbazone ligand was reported by Prabhu and Pal who synthesised a

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 20 of 42

atoms. <sup>3</sup> microwave irradiation <sup>4</sup> aryl chlorides were used. <sup>5</sup> Aryl aldehydes used instead of aryl halides.

In 2011, Paul et al*.* in their study described above in connection with the use of thiosemicarbazone complexes of palladium in the Mizoroki–Heck or Suzuki–Miyaura couplings also examined their application to the Sonogashira reaction (see complexes **3** and **4** in Figure 1) [95]. Moderate to good conversions were obtained for the coupling of a limited number of aryl bromides with phenyl acetylene using either toluene-ethanol or PEG as solvent in the presence of Cu(I) and NaOH at 75–110 °C (Scheme 25). Catalyst loadings of 0.5 mol% were employed giving TONs of up

2

ligand donor

<sup>1</sup> conditions refer to reactions involving aryl bromides and phenyl or aryl boronic acids.

**Scheme 26.** Copper-free Sonogashira reaction of aryl halides with phenylacetylene catalysed by **Scheme 26.** Copper-free Sonogashira reaction of aryl halides with phenylacetylene catalysed by complex **28**.

The octahedral nickel complexes **26** (Figure 4) prepared by Anitha et al*.* derived from 9,10 phenanthrenequinone thiosemicarbazone, 9,10-phenanthrenequinone *N*-methylthiosemicarbazone and 9,10-phenanthrenequinone *N*-phenylthiosemicarbazone described briefly above in connection with the Suzuki–Miyaura reaction were also examined for their activity in the Sonogashira reaction of phenyl acetylene with aryl halides [119]. Using catalyst loadings of 0.5 mol%, they were found to give good to very good conversions after 4 h in MeOH and in the presence of Cu(I) and pyridine (Scheme 27). Heteroaromatic chlorides also entered into the reaction as did ortho-substituted aromatics, albeit in lower yields. The authors concluded that steric effects in the ligands play a more important role than electronic effects in the catalytic activity of the complexes. Very good conversions were observed by Prabhu and Ramesh with a square-planar nickel complex NiL<sup>2</sup> **(29)** (Figure 5) The octahedral nickel complexes **26** (Figure 4) prepared by Anitha et al. derived from 9,10 phenanthrenequinone thiosemicarbazone, 9,10-phenanthrenequinone *N*-methylthiosemi carbazone and 9,10-phenanthrenequinone *N*-phenylthiosemicarbazone described briefly above in connection with the Suzuki–Miyaura reaction were also examined for their activity in the Sonogashira reaction of phenyl acetylene with aryl halides [119]. Using catalyst loadings of 0.5 mol%, they were found to give good to very good conversions after 4 h in MeOH and in the presence of Cu(I) and pyridine (Scheme 27). Heteroaromatic chlorides also entered into the reaction as did ortho-substituted aromatics, albeit in lower yields. The authors concluded that steric effects in the ligands play a more important role than electronic effects in the catalytic activity of the complexes. Very good conversions were observed by Prabhu and Ramesh with a square-planar nickel complex NiL<sup>2</sup> (**29**) (Figure 5) where ligand L is derived from the reaction of 4-phenyl-3-thiosemicarbazide with 3-methyl-thiophene-2-carboxaldehyde [123]. The structure was confirmed by X-ray diffraction studies. Very promising results were obtained in the reaction of a range of aryl bromides and iodides with phenyl acetylene in the presence of the nickel complex together with Cu(I) in Et3N at 80 ◦C (Scheme 28). Very good yields of the coupled products (79–99%) with good TONs were obtained after 2 h in the case of iodides (TONs of up to 1980 and TOFs of up to 990 h–1) or 8 h in the case of the bromides (TONs of up to 990 and TOFs of up to 124 h–1). Aryl halides with ortho-substitution also coupled readily. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 21 of 42 where ligand L is derived from the reaction of 4-phenyl-3-thiosemicarbazide with 3-methylthiophene-2-carboxaldehyde [123]. The structure was confirmed by X-ray diffraction studies. Very promising results were obtained in the reaction of a range of aryl bromides and iodides with phenyl acetylene in the presence of the nickel complex together with Cu(I) in Et3N at 80 °C (Scheme 28). Very good yields of the coupled products (79–99%) with good TONs were obtained after 2 h in the case of iodides (TONs of up to 1980 and TOFs of up to 990 h–<sup>1</sup> ) or 8 h in the case of the bromides (TONs of up to 990 and TOFs of up to 124 h–<sup>1</sup> ). Aryl halides with ortho-substitution also coupled readily. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 21 of 42 where ligand L is derived from the reaction of 4-phenyl-3-thiosemicarbazide with 3-methylthiophene-2-carboxaldehyde [123]. The structure was confirmed by X-ray diffraction studies. Very promising results were obtained in the reaction of a range of aryl bromides and iodides with phenyl acetylene in the presence of the nickel complex together with Cu(I) in Et3N at 80 °C (Scheme 28). Very good yields of the coupled products (79–99%) with good TONs were obtained after 2 h in the case of iodides (TONs of up to 1980 and TOFs of up to 990 h–<sup>1</sup> ) or 8 h in the case of the bromides (TONs of up to 990 and TOFs of up to 124 h–<sup>1</sup> ). Aryl halides with ortho-substitution also coupled readily.

**Scheme 27.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complexes **26**. **Scheme 27.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complexes **26**. **Scheme 27.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complexes **26**.

**Scheme 28.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complex **29**. **Scheme 28.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complex **29**.

**Scheme 28.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complex **29**. It is also appropriate to mention here a reaction related to the Sonogashira reaction, which involves coupling between aryl boronic acids with alkynes or alkynyl carboxylic acids (Scheme 29) reported by Lu et al*.* [124] using tridentate salicylaldiminato-thiosemicarbazone palladium catalysts It is also appropriate to mention here a reaction related to the Sonogashira reaction, which involves coupling between aryl boronic acids with alkynes or alkynyl carboxylic acids (Scheme 29) reported by Lu et al*.* [124] using tridentate salicylaldiminato-thiosemicarbazone palladium catalysts **2** (Figure 1), which had previously been shown to catalyze the Mizoroki–Heck coupling [94]. The best It is also appropriate to mention here a reaction related to the Sonogashira reaction, which involves coupling between aryl boronic acids with alkynes or alkynyl carboxylic acids (Scheme 29) reported by Lu et al. [124] using tridentate salicylaldiminato-thiosemicarbazone palladium catalysts **2** (Figure 1), which had previously been shown to catalyze the Mizoroki–Heck coupling [94]. The best yield was

steric hindrance was present (in the case of 1-naphthyl boronic acid and ortho-substituted aryl boronic acids) as well as for 2-pyridyl boronic acid. When carboxylic acids are used, decarboxylation

boronic acids) as well as for 2-pyridyl boronic acid. When carboxylic acids are used, decarboxylation

**Scheme 29.** Alkynylation coupling reaction between alkynes or alkynyl carboxylic acids and

**Scheme 29.** Alkynylation coupling reaction between alkynes or alkynyl carboxylic acids and

Additionally related to coupling reactions involving alkynes is the A3 coupling reaction, which is particularly useful in asymmetric synthesis [125]. This is a three-component reaction with an aldehyde, an amine and a terminal alkyne as the substrates. The reaction has been shown to be catalysed by a number of transition metal systems, including the thiosemicarbazone complex [Pd(PPh3)L] **30** where L is a dianionic tridentate *O*,*N*,*S*-coordinating ligand derived from pyridoxal thiosemicarbazone or pyridoxal *N*-methylthiosemicarbazone as reported by Manikandan et al. (Scheme 30) [126]. In this case an ionic liquid, [emim]BF<sup>4</sup> (emim = 1-ethyl-3-methylimidazolium) was used as the reaction medium. After optimisation runs, a number of substrates were subjected to the

Additionally related to coupling reactions involving alkynes is the A3 coupling reaction, which is particularly useful in asymmetric synthesis [125]. This is a three-component reaction with an aldehyde, an amine and a terminal alkyne as the substrates. The reaction has been shown to be catalysed by a number of transition metal systems, including the thiosemicarbazone complex [Pd(PPh3)L] **30** where L is a dianionic tridentate *O*,*N*,*S*-coordinating ligand derived from pyridoxal thiosemicarbazone or pyridoxal *N*-methylthiosemicarbazone as reported by Manikandan et al. (Scheme 30) [126]. In this case an ionic liquid, [emim]BF<sup>4</sup> (emim = 1-ethyl-3-methylimidazolium) was used as the reaction medium. After optimisation runs, a number of substrates were subjected to the

and yields <sup>1</sup>

Pd <sup>75</sup>– 110 .

*2.4. Kumada–Tamao–Corriu Reaction*

**Metal T (°C) Solvent Time** 

EtOH/toluene or

Ni <sup>70</sup> MeOH <sup>4</sup> O,N,S pyridi

reaction between arylboronic acids and phenylacetylene.

<sup>1</sup> conditions refer to reactions involving aryl bromides and phenylacetylene. <sup>2</sup>

obtained by complex **2a**. Using mild conditions (CH2Cl2, KOAc, Ag2O, 24 h, under argon) and a 2 mol% catalyst loading very good yields of coupled products were obtained except where steric hindrance was present (in the case of 1-naphthyl boronic acid and ortho-substituted aryl boronic acids) as well as for 2-pyridyl boronic acid. When carboxylic acids are used, decarboxylation occurs before coupling. yield was obtained by complex **2a**. Using mild conditions (CH2Cl2, KOAc, Ag2O, 24 h, under argon) and a 2 mol% catalyst loading very good yields of coupled products were obtained except where steric hindrance was present (in the case of 1-naphthyl boronic acid and ortho-substituted aryl boronic acids) as well as for 2-pyridyl boronic acid. When carboxylic acids are used, decarboxylation occurs before coupling.

**2** (Figure 1), which had previously been shown to catalyze the Mizoroki–Heck coupling [94]. The best

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 21 of 42

where ligand L is derived from the reaction of 4-phenyl-3-thiosemicarbazide with 3-methylthiophene-2-carboxaldehyde [123]. The structure was confirmed by X-ray diffraction studies. Very promising results were obtained in the reaction of a range of aryl bromides and iodides with phenyl acetylene in the presence of the nickel complex together with Cu(I) in Et3N at 80 °C (Scheme 28). Very good yields of the coupled products (79–99%) with good TONs were obtained after 2 h in the case of

**Scheme 27.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complexes **26**.

**Scheme 28.** Sonogashira reaction of aryl halides with phenylacetylene catalysed by Ni complex **29**.

It is also appropriate to mention here a reaction related to the Sonogashira reaction, which

) or 8 h in the case of the bromides (TONs of

). Aryl halides with ortho-substitution also coupled readily.

iodides (TONs of up to 1980 and TOFs of up to 990 h–<sup>1</sup>

up to 990 and TOFs of up to 124 h–<sup>1</sup>

$$\begin{array}{rcl} \mathsf{Ar^{\mathsf{I}}} \mathsf{Ar^{\mathsf{I}}} \mathsf{c} \, \overline{\mathsf{xxx}} \mathsf{c} \, \mathsf{ } & \mathsf{Ar^{2}} \mathsf{B} \, \mathsf{(O\mathsf{H})\_{2}} & \mathsf{\mathsf{A}g\_{2} \mathsf{O}, \mathsf{K} \mathsf{O} \mathsf{Ac}} \\ \mathsf{Ar} = \mathsf{H}, \mathsf{COOH} & & \\ \end{array} \\ \begin{array}{rcl} \mathsf{complex} \, \mathsf{2a} \, \mathsf{(2 \mathsf{mol}\mathsf{V}\mathsf{s})} \\ \mathsf{Ag} \, \mathsf{2o}, \mathsf{K} \mathsf{O} \mathsf{Ac} \\ \mathsf{C} \mathsf{H}\_{2} \mathsf{Cl}\_{2}, \mathsf{35} \, \mathsf{C}, \mathsf{24} \, \mathsf{h}, \mathsf{Ar} \\ \end{array} \\ \begin{array}{rcl} \mathsf{Ar^{\mathsf{I}}} \mathsf{c} \, \mathsf{K} \mathsf{T} \mathsf{c} \, \mathsf{- } \mathsf{Ar^{2}} \\ \mathsf{Ar^{\mathsf{I}}} \mathsf{c} \, \mathsf{K} \mathsf{T} \, \mathsf{- } \mathsf{Ar^{2}} \\ \end{array}$$

**Scheme 29.** Alkynylation coupling reaction between alkynes or alkynyl carboxylic acids and arylboronic acids. **Scheme 29.** Alkynylation coupling reaction between alkynes or alkynyl carboxylic acids and arylboronic acids.

Additionally related to coupling reactions involving alkynes is the A3 coupling reaction, which is particularly useful in asymmetric synthesis [125]. This is a three-component reaction with an aldehyde, an amine and a terminal alkyne as the substrates. The reaction has been shown to be catalysed by a number of transition metal systems, including the thiosemicarbazone complex [Pd(PPh3)L] **30** where L is a dianionic tridentate *O*,*N*,*S*-coordinating ligand derived from pyridoxal thiosemicarbazone or pyridoxal *N*-methylthiosemicarbazone as reported by Manikandan et al. (Scheme 30) [126]. In this case an ionic liquid, [emim]BF<sup>4</sup> (emim = 1-ethyl-3-methylimidazolium) was used as the reaction medium. After optimisation runs, a number of substrates were subjected to the Additionally related to coupling reactions involving alkynes is the A3 coupling reaction, which is particularly useful in asymmetric synthesis [125]. This is a three-component reaction with an aldehyde, an amine and a terminal alkyne as the substrates. The reaction has been shown to be catalysed by a number of transition metal systems, including the thiosemicarbazone complex [Pd(PPh3)L] **30** where L is a dianionic tridentate *O*,*N*,*S*-coordinating ligand derived from pyridoxal thiosemicarbazone or pyridoxal *N*-methylthiosemicarbazone as reported by Manikandan et al. (Scheme 30) [126]. In this case an ionic liquid, [emim]BF<sup>4</sup> (emim = 1-ethyl-3-methylimidazolium) was used as the reaction medium. After optimisation runs, a number of substrates were subjected to the reaction at 80 ◦C, 8 h reaction time with a 1 mol% catalyst loading. Phenyl acetylene was used as the terminal alkyne together with a range of aromatic or heteroaromatic aldehydes, formaldehyde or cyclohexyl carboxaldehyde and piperidine, morpholine, pyrrolidine or diethylamine as the amine component. In all cases, very good yields of the coupled products were obtained. Importantly, the catalyst could be recovered readily and retained its activity for at least five further cycles. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 22 of 42 reaction at 80 °C, 8 h reaction time with a 1 mol% catalyst loading. Phenyl acetylene was used as the terminal alkyne together with a range of aromatic or heteroaromatic aldehydes, formaldehyde or cyclohexyl carboxaldehyde and piperidine, morpholine, pyrrolidine or diethylamine as the amine component. In all cases, very good yields of the coupled products were obtained. Importantly, the catalyst could be recovered readily and retained its activity for at least five further cycles.

**Scheme 30.** A3 coupling reaction for the synthesis of propargylamines. **Scheme 30.** A3 coupling reaction for the synthesis of propargylamines.

**Table 3.** Sonogashira reactions catalysed by thiosemicarbazone complexes: representative conditions

Sonogashira-type reactions catalysed by thiosemicarbazone complexes are summarised in Table 3. Sonogashira-type reactions catalysed by thiosemicarbazone complexes are summarised in Table 3.

**(h) Ligand <sup>2</sup> Base Catalyst** 

PEG <sup>10</sup>–<sup>15</sup> N,S NaOH 0.5 <sup>68</sup>–<sup>99</sup> [95]

ne

**(mol%)**

**Yield** 

0.5 55–85 [119]

ligand donor atoms. <sup>3</sup>

**(%) Ref.**

Pd rt DMF 12 N,S Et3N 0.5 67–99 [122]

Ni 80 DMF 8 N,S Et3N 0.1 79–99 [123] Pd 35 CH2Cl<sup>2</sup> 24 O,N,S KOAc 2.0 30–99 [124] <sup>3</sup>

The use of organometallic reagents to form carbon–carbon bonds is a standard procedure in organic synthesis but there are still many instances where the simple stoichiometric reaction is unsuccessful for one or more reasons. A number of transition metal catalysts have been developed for specific cases such as the Negishi coupling of organozinc reagents with aryl or alkenyl halides [127], or the related Kumada–Tamao–Corriu reaction involving the analogous coupling with Grignard reagents (Scheme 31) [8]. There are a number examples of the latter involving thiosemicarbazone complexes although the majority of the reports describe only one instance of a coupling of an aryl bromide and aryl magnesium bromide and thus do not permit a good assessment


**Table 3.** Sonogashira reactions catalysed by thiosemicarbazone complexes: representative conditions and yields <sup>1</sup> .

1 conditions refer to reactions involving aryl bromides and phenylacetylene. <sup>2</sup> ligand donor atoms. <sup>3</sup> reaction between arylboronic acids and phenylacetylene.
