**3.1. Nitro reductions**

of contained pyrophoric catalysts, replacement of hydrogen reservoirs with in situ hydrogen generation, improved temperature control, and smaller solvent volumes all contribute to an increase in hydrogenation safety [4]. Flow technologies have improved hydrogenation outcomes by increasing substrate-gas-catalyst interactions and permitting stringent control of reaction parameters (temperature, flow rate, and pressure) with a commensurate reduction in undesirable side product and improved selectivity. Combined with optimised reaction conditions, this generally means very little or no further purification is required after the

This chapter details key recent development in functional group transformation, multistep

Unlike batch reactions where gas-solvent contact is limited by diffusion of gas into the bulk solvent, flow hydrogenation rapidly saturates the solvent with hydrogen using two different approaches [5]. The first, used by the ThalesNano H-cube®, employs in-line mixing of hydrogen with the solvent under pressure, which prevents outgassing and rapid solvent stream saturation (**Figure 1A**) [6]. The second approach, used by the Vapourtec Gas/Liquid reactor (**Figure 1B**) and Gastropod Gas Liquid Module, employs gas permeable membranes in a tubein-tube reactor. These systems enable solvent stream saturation by passing hydrogen gas under

**Figure 1.** Schematic of the mechanical mixing setup in (**A**) the ThalesNano H-Cube® and (**B**) schematic of the gas per-

The Thalesnano H-cube® was the first commercial flow hydrogenator. Together with the use of in-line gas mixing, the H-cube uses exchangeable 30 or 70 mm heterogeneous catalyst cartridges and a HPLC pump. Hydrogen gas is generated in situ through water electrolysis. The system is capable of heating to 100°C and 150 bar, with a flow rate range from 0.5 to 5.0

synthesis utilising flow hydrogenation and technology advances [1, 3].

270 New Advances in Hydrogenation Processes - Fundamentals and Applications

pressure through a gas porous polymer and into the solvent [7–10].

reaction [1].

**2. Instrumentation**

meable membrane (tube-in-tube) technology [1].

Flow nitro reductions, using palladium, platinum, and Raney Ni catalysts, under optimised conditions have been shown to provide both increased yield and simplified work up [1, 3]. Abdel-Hamid et al's recent synthesis of 1,8-naphthalimide derivatives illustrates this with an increase in yield (86–98%) and purification simplification (chromatographic to extractive) (**Figure 2**) [13].

**Figure 2.** Synthesis of 1,8-naphthalimide derivatives. Reagents and conditions: (i) ThalesNano H-Cube®, 10% Pd/C, THF, 40°C, 10 bar, 1 mL min−1, 2 cycles; (ii) SnCl2, HCl, ethanol, reflux 2 h; (iii) (a) fuming sulfuric acid, 50°C, 3 h; (b) saturated aq. KCl, room temperature.

The utility of the flow nitro reduction extends across pyrrolidine, carboxylate ester, phenyl propanoate, benzothiopene, benzofurans, and indole-carboxylate scaffolds. These reactions employed either Raney Ni or 10% Pd/C catalysts from 25 to 65°C and atmospheric (atm)—20 bar, respectively, providing excellent reaction outcomes (**Table 1**).

#### **3.2. Alkene reductions**

Flow hydrogenation is particularly useful in the reduction in alkene and alkyne bonds as is evident from the examples shown in **Table 2**. Gericke et al. developed ruthenium-nitrogendoped carbon nanotubes (NCNT) and ruthenium-hyperbranched polystyrene-supported (HPS) catalysts, providing a more sustainable process [24]. Gericke et al. suggested that HPSand NCNT-supported catalysts are a suitable alternative to Raney Ni and have an increased production rate per mole of catalyst compared to Raney Ni. Multiple similar alkene and alkyne reductions have been reported (**Table 2**). These hydrogenation catalysts were found not to be limited to the hydrogenation of alkenes and alkynes and have been applied in the reduction in glucose **4** to sorbitol **5**, which traditionally has relied on expensive catalysts such as Raney Ni (**Figure 3**).


**Table 1.** Flow nitro reduction of selected analogues.


**Table 2.** Flow reduction of selected alkenes and alkynes.

**Figure 3.** Reaction scheme for the hydrogenation of D-glucose (**4**).

**Starting material Product Yield Catalyst Conditions References**

**Starting material Product Yield Catalyst Conditions References**

86% 10%

21% 5%

98% 10%

84% 10%

Quant. 10%

Pd/C

Pd/C

Rh/C

Pd/C

Pd/C

99% RaNi 60°C, 60 bar,

**Table 1.** Flow nitro reduction of selected analogues.

272 New Advances in Hydrogenation Processes - Fundamentals and Applications

**Table 2.** Flow reduction of selected alkenes and alkynes.

90% Ra-Ni 65°C, 20 bar, 1.0 mL min−1 [14]

100% 10% Pd/C 25°C, 1–30 bar [15]

100% 10% Pd/C 50°C, 1 bar, 1.0 mL min−1 [16]

88–98% 10% Pd/C 40–60°C, 1 bar, 0.5–1.0 mL min−1 [17]

25°C, 10 bar, recirculate 2 h

70°C, 1 bar,

30°C, 40 bar, 1 mL min−1, 2 cycles

1 mL min−1, 24 h

50°C, 1 bar [23]

40°C, 1 mL min−1

1.5 mL min−1, 3 cycles

[18]

[19]

[20]

[21]

[22]

Initial attempts by Yadav et al. under batch reaction conditions to access alcohol **6** afforded an 8:2 mixture of **6** and ketone **7** [20]. The use of the H-cube® and relatively mild reducing conditions (10% Pd/C, 40°C, and 6 bar) gave exclusively **6** in a near-quantitative yield (**Figure 4**).

**Figure 4.** Synthesis of the marine macrolide sanctolide **6** via batch and flow hydrogenation. Reagents and conditions: (i) H2, Pd/C (10%), EtOAc, rt, 8 h; (ii) H-cube®, Pd/C (10%), MeOH, 40°C, 6 bar.

Trobe and Breinbauer highlighted the use of flow methodologies to improve reaction yields (**Figure 5**) [22]. The trifluoroether **11** was accessed through a conventional traditional Witting/ hydrogenation approach in a 32% yield. A modified access via a Claisen rearrangement and flow hydrogenation was developed leading to **11** in a 71% yield.

**Figure 5.** Improving the yield of a synthetic route from 32% to 71% with the aid of flow hydrogenation. Reagents and conditions: (i) salicylaldehyde, toluene, 80°C, 8 h; (ii) H2, Pd/C, MeOH, 22°C, 3 h; (iii) DMAc, 190°C, 5 d; (iv) H-cube®, Ra-Ni, 60°C, 60 bar; (v) (i) ICl, AcOH, 22°C, 24 h; (ii) Tf2O, pyridine, 0°C, 2 h.

#### **3.3. Reductive amination**

Traditionally, borohydride reagents such as NaCNBH3, NaBH(OAc)3, or pyridine-BH3 have been used for reductive amination [25]. However, flow hydrogenation offers considerable advantages over transfer hydrogenation, such as improved atom economy, reduced environmental impact, simple reaction workups, and reduced exposure to toxic or reactive starting materials [26].

Flow reductive aminations are generally conducted using 10% Pd/C or 20% Pd(OH)2/C, with the temperatures and pressures used substrate-dependent [1]. However, the use of an Au/ Al2O3 catalyst has facilitated a cascade nitro reduction and direct reductive amination to afford secondary amine **16** (**Figure 6**). Unlike many conventional Pd- and Ni-based catalysts, the Au/Al2O3 catalyst showed selective reduction in the nitrobenzene **14** over benzaldehyde **15**, aiding imine formation and subsequent reductive amination. Under optimised conditions (1:1.5 nitrobenzene **14**: benzaldehyde **15**, 80°C and 50 bar), the desired *N*-benzylaniline **16** was generated in a 91% yield (**Figure 6**) [27].

**Figure 6.** Flow reductive amination to afford *N*-benzylaniline **16**. Reagents and conditions: H-cube® Pro, 0.05 M **15** in EtOH, Au/Al2O3 (70 mm), 125°C, 10 bar, 0.3 mL min−1.

Treatment of phenethylamine (**18**) and levulinic acid (**17**) in 2-methylfuran under the hydrogenation conditions of 85 bar H2 pressure, 150°C and carbon-supported Fe/Ni yielded pyrrolidine **19** with a 91% conversion via a sequential reductive amination and cyclisation process (**Figure 7**) [28].

**Figure 7.** Flow reductive amination with carbon-supported Fe/Ni (C-Fe/Ni) to form pyrrolidine **19**. Reagents and conditions: H-cube® Pro, 0.025 M **18** in 2-methylfuran, C-Fe/Ni alloy (70 mm), 150°C, 85 bar, 0.3 mL min−1.

#### **3.4. Protecting group manipulation**

The synthesis of carbohydrate and nucleoside mimics has led to the development of Cnucleosides and C-glycosides as antibiotic, anticancer, and antiviral agents [29]. Using flow chemistry, Redpath et al. were able to access the deprotected 2-deoxy-C-galac-topyranosylbenzoic acid **26** (**Figure 8**) [29]. The final stage of the multistep reaction, including the hydrogenation, provided **26** in a 39% yield over five steps. This route was found to provide access to galactoside and mannoside type C-nucleosides incorporating functionality analogous to the biologically important benzamide riboside through the use of an oxazoline protecting group, which had been previously inaccessible using a transmetallation/inter molecular Sakura condensation approach.

**Figure 8.** Synthesis of (D/L)-deoxy-β-galactopyranosyl-benzoic acid (**26**). Reagents and conditions: (i) SOCl2, toluene; (ii) H2NC(CH3)2CH2OH, CH2Cl2; (iii) *sec*-BuLi, TMEDA, Et2O; (iv) Ti(O*<sup>i</sup>* Pr)4; (v) crotonaldehyde, BF3·OEt2, CH2Cl2; (vi) MsCl, Net3, CH2Cl2; (vii) O3, CH2Cl2/MeOH then Me2S; (viii) NaBH4; (ix) LiAlH4, THF; (x) BnBr, TBAI, NaH, 15 crown-5, THF; (xi) MeI, MeNO2; (xii) 20% KOH, MeOH; (xiii) H2, 10% Pd/C, MeOH.

Pd-catalysts and mild (RT, 1 bar) to moderate (45°C, 10 bar) conditions have been employed for the removal of benzyloxy carbamate (CBz) and benzyl (Bn) protecting groups (**Table 3**).
