Conversion multi-step

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

In processes involving whole cells the required product can often be formed in a single step, although the cells essentially carry out a multi-step synthesis. This means that only a single product purification is necessary. Conversely, in chemical synthesis of compounds, each step in the synthesis is usually carried out separately. Thus the product of one reaction must often be purified before it can be used in the next step in the synthetic sequence. This multi-step approach is expensive, time consuming and can require a complex process plant to handle the individual steps on an industrial scale. 

Under certain condition, however, reactions are still preferably conducted in solution. This is the case e.g., for heterogeneous reactions and for conversions, which deliver complex product mixtures. In the latter case, further conversion of this mixture on the solid support is not desirable. In these instances, the combination of solution chemistry with polymer-assisted conversions can be an advantageous solution. Polymer-assisted synthesis in solution employs the polymer matrix either as a scavenger or for polymeric reagents. In both cases the virtues of solution phase and solid supported chemistry are ideally combined allowing for the preparation of pure products by filtration of the reactive resin. If several reactive polymers are used sequentially, multi-step syntheses can be conducted in a polymer-supported manner in solution as well. As a further advantage, many reactive polymers can be recycled for multiple use. 

The above-mentioned targets refer to general advantages of micro reactors [42, 80, 100, 114, 119]. Enhanced transfer and better controlled residence time improve conversion and selectivity. The tools have small internal volumes, allowing one to generate flexibly a multitude of samples in serial or parallel fashion. Synthesis can be combined with a multi-step procedure. The economy of micro-reactor processes has not really been analyzed so far however, it is clear that as laboratory tools they allow in a number of cases technical expenditure, personnel and costs to be reduced. 

Fine and specialty chemicals can be obtained from renewable resonrces via multi-step catalytic conversion from platform molecules obtained by fermentation. An alternative method decreasing the processing cost is to carry out one-pot catalytic conversion to final product without intermediate product recovery. This latter option is illustrated by an iimovative oxidation method developed in our laboratory to oxidize native polysaccharides to obtain valuable hydrophilic end-products useful for various technical applications. 

Rj-S-Hexadecanolide (27) is the pheromone produced by the queens of the oriental hornet (Vespa orientalis). Yamamoto synthesized (R)-27 by employing an interesting asymmetric process (A—>B) followed by a multi-step conversion of B to (R)-27 via C (Scheme 40) [65]. 

Substituted furan formation by an indirect cyclization of 1,4-dicarbonyl derivatives has also been adopted as a key step in the synthesis of 3-oxa-guaianolides. Although 1,4-dicarbonyl compounds have been traditionally considered as the direct precursors for furans, treatment of 1,4-dicarbonyl compounds having a tertiary acetoxy group with p-toluenesulfonic acid leads to only 11% yield of an alkenylfurans as derived from a cyclization/acetoxy-elimination route. The following scheme shows an alternative multi-step conversion of the 1,4-dicarbonyl that leads to a more acceptable yield of the acetoxyfuran . 

Cascade Catalysis and Multi-step Conversions in Concert... 

Special attention is given to the integration of biocatalysis with chemocatalysis, i.e., the combined use of enzymatic with homogeneous and/or heterogeneous catalysis in cascade conversions. The complementary strength of these forms of catalysis offers novel opportunities for multi-step conversions in concert for the production of speciality chemicals and food ingredients. In particular, multi-catalytic process options for the conversion of renewable feedstock into chemicals will be discussed on the basis of several carbohydrate cascade processes that are beneficial for the environment. 

Full exploitation of cascade catalysis and multi-step conversions in concert will require the development of novel, mutually compatible, organic and biosynthetic methods and procedures. Eventually, a full integration of organic synthesis and biosynthesis can be envisaged. 

A major aspect to be overcome in the integration of biocatalysis and chemocatalysis through cascade conversions is the lack of compatibility of the various procedures, both mutually for the many chemocatalytic reactions and between the chemocatalytic and biocatalytic conversions. This is in contrast to biocatalytic reactions, which are, by far, more mutually compatible and can be much more easily combined in a multi-step cascade, as will be shown below. 

A major cause of this problem in organic synthesis is the fact that many of the synthetic tools were developed without knowledge of how nature was performing its chemistry. We now have the heritage of many powerful chemical conversion procedures with a great variety in reaction conditions such as temperature, pressure, solvent, air and moisture sensitivity. In other words, procedures that as such are of great value but lack the possibility to be combined in a cascade mode of conversion for the multi-step syntheses frequently required for specialities. 

Fig. 13.3 The potential power of cascade conversions to overcome thermodynamic hurdles in multi-step syntheses. Dotted circles are compounds in the reaction medium, closed circles are isolated, pure compounds [3, 4].

Up to the late 1990s, combined multi-step chemo-chemo conversions were restricted to a few catalytic examples. Apparently, there has been little effort or interest in developing a toolkit of chemocatalytic reactions that are mutually compatible with respect to reaction conditions. Consequently, chemocatalysts have not yet reached the same level of mutual compatibility as biocatalysts. Some recent examples prove, however, the potential power of chemo-chemo catalytic cascades. 

A substantial part of these savings arises from the novel fermentation process for 7-ADCA that replaces the former multi-step chemical conversion of penicillin (Fig. 13.15). 

Apart from new catalytic methods, cascade conversions require new process technologies, such as in situ product recovery, reactor design, and compartmental-ization. In the long term, part of the present-day stoichiometric chemistry as well as bio- and chemocatalytic conversions in multi-step syntheses will gradually be replaced by cascade catalysis in concert, and full fermentations by cell factory design, or combinations thereof (Fig. 13.17). 

Apart from the chemical technology developments mentioned above, metabolic pathway and flux engineering will have an increasing impact on the way multi-step organic syntheses are carried out in the fine-chemicals industry. For the next generation of microbial conversions, the challenge of molecular biology is to ... 

Selenoxides and telluroxides also function as mild oxidants for the conversion of thiols to disulfides as shown in equations (16) and (17) for the reaction of thiophenol with diphenylselenoxide (47) and diphenyltelluroxide (48). Mechanistically, the oxidation of thiols to disulfides with selenoxides and telluroxides is a multi-step process, which takes advantage of the ease with which tellurium(IV) and selenium(IV) species form trigonal bipryamidal... 

This multi-step, one-pot process was taken further by integration of a third supported reagent for the sequential preparation of 3,5-diphenylpyrazole (Scheme 2.17). Following the previously established procedure, acetophenone was deprotonated and acylated to afford the 1,3-dicarbonyl species. This intermediate was easily separated from the spent polymers by filtration and passed without isolation into a suspension of the resin bound hydrazine salt (9), affording the desired pyrazole in 91% yield. In a subsequent publication, the authors reported that the depleted polymeric reagents from the first step of the conversion (i.e. (7) and (8)) were recovered and separated via a selective flotation procedure, enabhng them to... 

This more involved multi-step process can be used for both iron phosphate and zinc phosphate conversion coating processes. 

An alternative approach for the utilization of biomass resources for energy applications is the production of dean-buming liquid fuels. In this respect, current technologies to produce liquid fuels from biomass are typically multi-step and energy-intensive processes. Aqueous phase reforming of sorbitol can be tailored to produce selectively a clean stream of heavier alkanes consisting primarily of butane, pentane and hexane. The conversion of sorbitol to alkanes plus CO2 and water is an exothermic process that retains approximately 95% of the heating value and only 30% of the mass of the biomass-derived reactant [278]. 

Noteworthy is a recent multi-step method for the production of molecular [ F]F2 of considerable higher specific radioactivity (100-925 Ci/mmol or 3.7-34 TBq/ mmol) starting from aqueous [" Fjfluoride produced with the 0(p,n) F reaction [38], The dried and activated [ F]fluoride is reacted with methyl iodide to yield methyl [ F]fluoiide (CHsf FjF) which is isolated by gas chromatography. The latter is then subjected to an electrical discharge (20-30 kV, 280 pA, 10 s) in the presence of small amounts of carrier fluorine (150 nmol) resulting in about 30% conversion of the original [ F]fluoride into molecular [ F]F2. 

The volatility of difunctional isocyanates (such as tolylene diisocyanates, hexamethylene diisocyanate, etc.) creates many environmental problems in the urethane industry. These difficulties can be overcome by preparation of NCO-terminated oligomers with low vapor pressure. One approach is the preparation of NCO-ter-minated oligomers by partial cyclotrimerization of difunctional isocyanates. Usually this is achieved by a multi-step process which includes also deactivation of the catalyst at a certain conversion. During our work on cyclotrimerization of isocyanates we found that cyclic sulfonium zwitterions are very active cyclotrimerization catalysts (2). Recently we found that cyclic sulfonium zwitterions under certain reaction conditions act as anionic initiators. This behavior of cyclic sulfonium zwitterions permits preparation of isocyanate oligomers containing isocyanurate rings by a one-step procedure, eliminating the deactivation step. 

The conversion of an alcohol to the amine is often a multi-step procedure. Jonathan MJ. Williams of the University of Bath has described (Chem. Commun. 2004, 1072) a direct Ir-catalyzed procedure for this transformation. The reaction probably involves oxidation of the alcohol to the aldehyde, imine formation, and then reduction of the imine to the amine. No secondary examples were reported. 

The suitability of this model, at least for a non-too-wide conversion range, has been confirmed by several authors. However, a correct description of the maleic anhydride production obviously demands splitting of kB into individual rate coefficients for maleic anhydride formation and for combustion, while in fact a separate equation should be added for maleic anhydride combustion. Such multi-step redox models have not been reported in the literature. Sets of first-order rate equations, however, are widely used,... 

The same concept is applicable to allylic alcohols, ketones, or ketoximes. Enol acetates or ketones were successfully converted in multi-step reactions to chiral acetates in high yields and optical yields through catalysis by Candida antarctica lipase B (CALB, Novozyme 435) and a ruthenium complex. 2,6-Dimethylheptan-4-ol served as a hydrogen donor and 4-chlorophenyl acetate as an acyl donor for the conversion of the ketones (Jung, 2000a). 

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