Flow Syntheses

Although Lehn and his coworkers prepared a large number of cryptands and derived complexes over the years, the synthetic approach to these compounds remained essentially similar for most of them. Details are presented for a number of such compounds in ref. 26. The essential features of these syntheses were use of amide-forming reactions in the absence of templating ions with reliance on a high dilution step to form the second ring. An alternative approach for the synthesis of cryptands was developed by Dye and his coworkers. Their approach involved the use of a flow synthesis to replace the high dilution step. 

Boleininger, J., Kurz, A., Reuss, V. and Sonnichsen, C. (2006) Microfluidic continuous flow synthesis of rod-shaped gold and silver nanocrystals. Physical Chemistry Chemical Physics, 8, 3824-3827. 

Disadvantages of the Ultrasonic Bath. The major disadvantage of the bath as a source of ultrasonic waves is the low acoustic intensity. This translates into less than optimum reaction rates and, for some reluctant systems, no rate enhancements at all. Companion to this is variability (often on a day-to-day basis) of the intensity and its focal point, which makes precise rate measurements a formidable challenge. Ultrasonic baths are not easily adapted to flow synthesis as are immersion horns. 

Nikbin N, Watts P (2004) Solid-supported continuous flow synthesis in micro-reactors using electroosmotic flow. Org Process Res Dev 8 942 Overbeek JTG (1952) Electro chemistry of double layer. In Kruyt HR (ed) Colloid science, Vol. 1. Elsevier, Amsterdam... 

Solid Supported Reagents in Multi-Step Flow Synthesis... 

Scheme 7. Continuous flow synthesis of the natural product Oxomaritidine...

Baumann M, Baxendale IR, Ley SV, Smith CD, Tranmer GK (2006) Fully Automated Continuous Flow Synthesis of 4,5-Disubstituted Oxazoles. Org Lett 9 1521-1524... 

Dye JL, Lok MT, Tehan FJ, Creaso JM, Voorhees KJ (1973) Flow synthesis. Substitute for the high-dilution steps in cryptate synthesis. J Qrg Chem 38 1773-1775... 

Figure 25. Schematic illustrating the continuous flow synthesis of 2-phenyl-l,3-dithiane [41],...

Nikbin, N. and Watts, P. (2004). Solid-Supported Continuous Flow Synthesis in Microreactors Using Electroosmotic Flow. OPRand D, 8, 942-944. 

Scheme 17 Flow synthesis of terminal alkynes using the Bestmann-Ohira reagent [42]...

Nagaki A, Tomida Y, Usutani H et al (2007) Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes. Chem Asian J 2(12) 1513-1523... 

The fact that macroporous, highly cross-linked polystyrene does not swell makes this support particularly interesting for continuous-flow synthesis in columns. This support has also been successfully used as an alternative to CPG for the solid-phase synthesis of oligonucleotides [90,91]. Furthermore, because reagents do not need to penetrate into the polystyrene network, enzyme-mediated reactions should also proceed smoothly on macroporous polystyrene [85]. 

Different forms of silicon dioxide have been used as supports for solid-phase organic synthesis. Silica gel is a rigid, insoluble material, which does not swell in organic solvents. Commercially available silica gel differs in particle size, pore size (typically 2-10 nm), and surface area (typically 200-800 m2/g). Like macroporous, highly cross-linked polystyrene, silica gel enables efficient and rapid transfer of solvents and reagents to its entire surface. Because the synthetic intermediates are only located on the surface of the support, enzyme-mediated reactions can be realized on silica [189,190], Silica gel is particularly well suited for continuous-flow synthesis because its volume stays constant and diffusion rates are high. 

Employing a staked plate microreactor (channel dimensions = 100 pm, total volume = 2 ml), Acke and Stevens (2007) reported the continuous flow synthesis of a series of chromenones via a multicomponent route consisting of a sequential Strecker reaction-intramolecular nucleophilic addition and tautomerization, as depicted in Scheme 2. 

Scheme 32 Schematic illustrating the general reaction conditions employed for the continuous flow synthesis of thiazoles and imidazoles.

Table 30 Summary of the results obtained for the continuous flow synthesis of a spiro lactone 201...

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