H-Cube

An automated H-Cube platform was designed, constructed and validated by Clapham et al. [26], to perform deprotection reactions and produce compound libraries. This special instrument includes 48 starting material vials for automated injection into the flow reactor. In producing the Cbz deprotected library, complete conversions and a 93% average crude yield were obtained over Pd/C catalyst at 60°C using full hydrogen mode. For the second library, 4-benzyloxy benzoic acid was coupled with a series of amides. The deprotection performed in H-Cube resulted in eomplete conversions to the products and 88% average crude yield. 

The use of eontinuous-flow for rapid optimization followed by seale up was demonstrated by Steven Ley s group [66]. Imine reductions were performed in the presenee of Pd/C as eatalyst on the H-Cube flow hydrogenation system. After optimization of eonditions on small quantities, 1.0 g of desired product was synthesized within 70 min with quantitative yield and exeellent purity. Worth noting is that the reactions progressed quantitatively without the need for further purifieation. 

The sequence includes several synthetic steps over polymer-supported catalysts in directly coupled commercially available Omnifit glass reaction columns [41] using a Syrris Africa microreactor system [14], Thales H-Cube flow hydrogenator [32] and a microfluidic chip. The process affords the alkaloid in 90% purity after solvent evaporation, but in a moderate 40% yield. After a closer investigation it was concluded that this is due to the poor yield of 50% in the phenolic oxidation step. On condition that this is resolved with the use of a more effective supported agent, the route would provide satisfactory yields and purities of the product. 

This process could also be applied to the synthesis of tripeptides. A Cbz-protected dipeptide (Cbz-Ala-Gly-OEt) was deprotected in flow using the H-Cube system, and using the above procedure the tripeptide Cbz-Phe-Ala-Gly-OEt was obtained in 59% overall yield and in only 6-7 h, based on the longest linear sequence from glycine. 

The synthesis of 2-aminochromes by Vaddula and Gonzalez [77] is an example of a multicomponent reaction performed within a single pass of a continuous-flow ThalesNano H-Cube Pro reactor. Using this reactor the authors demonstrated that various chromene derivatives could be obtained with a simple and rapid one-step continuous-flow synthesis route from the reaction of aromatic aldehydes, a-cyano-methylene compounds, and naphthols. The efficient, safer, faster, and modular reaction proceeded to completion with very high yields and residence times of less than 2 min at a slightly elevated pressure of approximately 25 bar. 

ThalesNano Nanotechnology produces nanotechnology solutions for pharmaceutical and biochemical companies. Their products include the H-CUBE and the CATC ART. 

Ponceau 4GB. Solochrome black. Alizarin red S H - cube/octahedron 14101... 

Hydrogenations were done with a H-cube hydrogen reactor equipped with 10 % Pd on charcoal cartridges as catalyst [43]. 

A 0.05 M solution of NO2HL2 (130 mg) in methanol was cycled twice in an H-cube Hydrogen reactor equipped with a palladium cartridge (full H2 mode, 1 mL/ min flow) at room temperature and atmospheric pressure. After one cycle the orange color of the solution had faded to yellow. After removal of the solvent the desired product was obtained as yellow oil (105 mg, 85 %). 

Table 7.1 Commercially available catalyst cartridges for the H-Cube .

Midi or H-Cube Maxi. This permits the use of another gas molecule in place of hydrogen - such as carbon monoxide, ethylene, nitric oxide, or oxygen - at up to 100 bar by adding an optional gas module, which ensures a variety of metal-catalyzed reactions under the flow conditions [60],... 

The first report using the H-Cube system appeared in 2005. AThalesNano team reported the reduction of nitro compounds into the corresponding amines under flow conditions using a Pd/C cartridge [61]. They also demonstrated the flow reduction of a variety of functional groups (Scheme 7.15) [62]. 

Scheme 7.15 Hydrogenation conducted on H-Cube as demonstrated bytheThalesNano group.

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