Continuous-flow reactors synthesis

Catalytic Testing for NMP Synthesis - Continuous Flow Reactor... 

Saaby S, Knudsen KR, Ladlow M, Ley SV (2005) The Use of a Continuous Flow-Reactor Employing a Mixed Flydrogen-Liquid Flow Stream for the Efficient Reduction of Imines to Amines. Chem Commun 23 2909-2911 Seebach D, Overhand M, Kilhnle FNM, Martinoni D, Oberer L, Hommel U, Widmer H (1996) Beta-Peptides Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a Beta-Hexapeptide in Solution and its Stability Towards Pepsin. Helv Chim Acta 79 913-941... 

One of the major advantages of flow reaetors is the short residence time of reaetions in the reaetor. This allows seleetive reaetions to pass through the system and out again before any side reaetion ean take plaee. This is very well illustrated in the synthesis of dithioketal and -aeetals, where the seleetive reaetion resulted in superior conversion using eontinuous flow when eompared to bateh synthesis. A dramatic increase of yield was noted in the hydrogenation reaetion performed by Kobayashi et al. when a residence time of less than 1 min was used. The yield inereased from 1% to 97% using the continuous-flow reactor. 

Having confirmed that the immobilization strategy was robust enough to be used in conjunction with a continuous flow reactor, the authors evaluated the immobilization of a second Hisg-tag enzyme, BsubpNBE, and employed the synthesis of 6-O-acetyl-D-glucal 162 (Scheme 44) as a model reaction. 

With numerous researchers investigating the advantages associated with thermally or biocatalytically controlled asymmetric syntheses, some of which have been performed in continuous flow reactors, few have considered the prospects of photochemical asymmetric synthesis, an idea... 

Employing a stainless-steel continuous flow reactor, Zhang et al. (2004) described the synthesis of gram to kilogram quantities of material for use in early clinical studies. One reaction reported by the authors was the exothermic synthesis of N-methoxycarbonyl-L-ferf-leucine 210, as illustrated in Scheme 61. By continuously adding a solution of methyl chlor-oformate 211 to i-tod-leucine 212, in the presence of aq. NaOH 26, at a reactor temperature of —40°C afforded the target compound 210 in 91% yield with a throughput of 83.0 gh... 

As indicated in the introduction of Section 2.2.2, continuous flow reactors (generally fixed bed reactors) are not frequently used in the investigation of the liquid phase zeolite catalysed synthesis of Fine Chemicals. However, fixed bed reactors present some significant advantages on batch reactors ... 

The reaction proceeds through initial Diels-Alder reaction of 2-pyrazinones 4 with an acetylene forming bicyclic intermediate 5. This is followed by spontaneous elimination of cyanogen chloride or an isocyanate to obtain 2-pyridone 6 and pyridine 7, respectively. Additionally, continuous flow reactors have been designed for microwave reactions, which improve the energy efficiency. The eontinuous flow microwave reaction was illustrated using a mierowave assisted Bohlmann-Rahtz pyridine synthesis <05JOC7003>. 

Although photochemical transformations provide the synthetic chemist with an attractive, atom-efficient approach to the synthesis of complex molecules, the inability to increase the scale of reactions beyond the bench-scale has hampered the adoption of this technique. As can be seen from the examples described below, the use of continuous flow reactors affords a facile means of increasing the throughput of photochemical reactions while employing laboratory-scale light sources such as low-energy LEDs. 

Table 14.3 Synthesis of a,(5-unsaturated compounds in a continuous flow reactor.

Traditional Friedel-Crafts synthesis uses low temperatures and long reaction times to control the reaction. In many cases, reactions are performed over 24-72 h, which nevertheless produces a mixture of products that need separation to recover the desired product with appropriate purity. In the case of continuous flow reactors, however, higher temperatures are required than in a batch reactor because the residence time within small-volume reactors is comparatively low even so, high selectivities and conversions have still been achieved at these temperatures [48]. 

Fig. 11 (A) Schematic of conventional batch synthesis setup and (B) a dual-stage continuous flow reactor setup with precursor A and B. Reproduced from ref. 106 with permission from the American Chemical Society.

Several other newer indolization techniques completely unknown to Fischer and his contemporaries are cited here. The synthesis of indoles using continuous flow reactors has been described by the groups of Watts [79] and Cosford [80], The latter group synthesized a series of biologically active 2-(l/7-indol-3-yl)thiazoles 5 as shown in Scheme 6. 

The wide variety of ILs and reaction conditions makes it difficult to extract a trend, but clearly the presence of both acid and base sites are crucial for the cyclic carbonate synthesis. Outstanding results were reported by Takahashi et al. [78] using phosphoniiun quaternary salts as phospho-niiun halides immobilized on SiO (e.g. CO SiO -CjHg-Pfn-BuljBr)) for the synthesis of PC from PO and CO using a continuous fixed-bed reactor. As far as we know it is best catalytic performance ever reported for the synthesis of PC using a continuous flow reactor with a PO conversion... 

Recently Cosford and co-workers used a one-step continuous flow Hantzsch synthesis to prepare a series of A -substituted pyrrole-3-carboxylic acids as part of their ongoing efforts to develop efficient and high-yielding flow chemistry methods for multistep transformations. Reaction of /-butyl acetoacetate 32 and a-bromoacetophenone 34 with amines 33,36,38,40,42, and 44 using diisopropylethyl amine (DIPEA) and DMF at 200 "C in a continuous flow reactor gave the corresponding A-substituted pyrroles in modest yields (40-62%). The authors found the optimal reaetion conditions were 2.2 equiv of /-butyl acetoacetate, 1 equiv of amine and 0.5 equiv of DIPEA in a 0.5M solution of a-bromoacetophenone predissolved in DMF. In addition, the authors noted that the HBr produced as a byproduct of the reaction simultaneously hydrolyzed the ester to give the free acid. Several additional P-ketoesters and a-bromoketones were explored in their report with similar success. 

Nucleophilic substitution reactions are highly important in organic synthesis. By conducting these within continuous flow reactors, it is observed that the products are generated in higher yield and selectively compared to the corresponding batch reactions. It is evident from the literature examples cited in this chapter that the reactions can be easily scaled within commercial micro reactor systems to enable kg quantities of product to be readily produced. 

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