Isolation, of intermediates

The success of the last reaction depends upon the inertness of the ester carbonyl groups towards the organocadmium compound with its aid and the use of various ester acid chlorides, a carbon chain can be built up to any reasonable length whilst retaining a reactive functional group (the ester group) at one end of the chain. Experimental details are given for l-chloro-2-hexanone and propiophenone. The complete reaction (formation of ketones or keto-esters) can be carried out in one flask without isolation of intermediates, so that the preparation is really equivalent to one step. 

Various ways of overcoming the PTA oxidation problem have been incorporated into commercial processes. The predominant solution is the use of high concentrations of manganese and cobalt ions (2,248—254), optionally with various cocatalysts (204,255,256), in the presence of an organic or inorganic bromide promoter in acetic acid solvent. Operational temperatures are rather high (ca 200°C). A lesser but significant alternative involves isolation of intermediate PTA, conversion to methyl/)-toluate, and recycle to the reactor. The ester is oxidized to monomethyl terephthalate, which is subsequentiy converted to DMT and purified by distillation (248,257—264). 

AIkyl-Ai,A/-diaLkyl-l-naphthalenecarboxamides are useful herbicides (86) and the 2,2-dimeth5lhydra2ide of 1-naphthalenecarboxyhc acid has been patented as a plant growth regulator (87). 2-Propynyl-2-naphthalenecarboxylate [53548-27-9] and similar esters are insecticides (88). 1-Naphthaleneacetic acid, the plant growth regulator, has been prepared from naphthalene, concentrated HCl, and paraformaldehyde without isolation of intermediate 1-chloromethylnaphthalene or l-naphthaleneacetonitnle (89). 

The overall transformation can be carried out without isolation of intermediates, or alternatively, each compound can be purified before being carried on. Although the 17-acetyl-eneamine is isolable, it is quite sensitive to hydrolysis by either acid or base. ... 

A rather special procedure for the preparation of 21-hydroxy-20-ketopreg-nanes starts with the 17a-ethoxyethynyl-17 -hydroxy steroids described earlier. Free radical addition of ethanethiol to the triple bond, followed by acid-catalyzed hydrolysis and dehydration gives the 20-thioenol ether 21-aldehyde. This can be reduced with lithium aluminum hydride to the C-21 alcohol and then hydrolyzed to the C-20 ketone in the presence of mercuric chloride. The overall yield, without isolation of intermediates, is in the order of 50% ... 

The mechanism of the Hurd-Mori reaction has been discussed extensively in the review by Stanetty. The mechanism of the reaction was initially postulated by Hurd-Mori based on the isolation of intermediate 10. This intermediate was shown to transform into the desired thiadiazole upon heating in ethanol, either with or without acid. The reaction was thought to proceed via the four-membered intermediate 11, which would release the volatile ethylformate as a by-product. In 1995, Kobori and co-workers were able to isolate and determine crystallographically a very similar intermediate structure to 10 in their mechanistic studies of the reaction. ... 

Quaternary hydrazonium salts (derived from aldehydes) give nitriles when treated with OEt or DBU (p. 488, 1337) as do dimethylhydrazones RCH— NNMe2 when treated with Et2NLi and HMPA. All these are methods of converting aldehyde derivatives to nitriles. For the conversion of aldehydes directly to nitriles, without isolation of intermediates, see 16-21. 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

The degradation of acenaphthene is initiated by benzylic monooxygenation, and the pathway was determined using [l- C]acenaphthene by the isolation of intermediate metabolites (Selifonov et al. 1998). Importantly, the method proved applicable even when only limited biotransformation of the substrates had taken place by partial oxidation. 

Iterative procedures hold the potential of automated production as employed reliably and frequently in the case of the Merrifield synthesis. Furthermore, the specific isolation of intermediates and the precise insertion of substituents compensates the enhanced preparative effort compared to polymer syntheses. 

The combined information gathered from kinetic studies,184 in situ high-pressure NMR experiments,184,185,195 and the isolation of intermediates related to catalysis, leads to a common mechanism for all the hydrogenolysis reactions of (102)-(104) and other thiophenes catalyzed by triphos- or SULPHOS-rhodium complexes in conjuction with strong Bronsted bases. This mechanism (Scheme 41) involves the usual steps of C—S insertion, hydrogenation of the C—S inserted thiophene to the corresponding thiolate, and base-assisted reductive elimination of the thiol to complete the cycle.184 185 195-198... 

Isolation of intermediate 119 appeared to be impossible, since the formation of a more stable betaine structure (120) was observed. The interaction of compound (120) with a second molecule of boric acid ester in the presence of triethylamine or pyridine gave rise to spirobicycle 121 [Eq. (79)]. 

An attractive feature of this dehydrative coupling approach is that it avoids the need for isolation of intermediate glycosyl donors. This can be desirable if a glycosyl donor is not stable to isolation or purification. Moreover, the use of a hemiacetal donor reduces the number of synthetic manipulations of the carbohydrate donor by avoiding hemiacetal derivatization to alternative donor types. In this way, the approach has the potential to streamline time and labor-intensive multiglycosylation sequences. Although there increasingly have been reports of these direct dehydrative... 

Unsubstituted or 2,3-disubstituted stannoles can be prepared from the palladium-catalyzed reaction of an alkyne with the stable stannylenes [(Me3Si)2CH]2Sn and CH2C(SiMe3)2 2Sn . The mechanism has been traced by the isolation of intermediates,235 and by ab initio calculations (Equation (78)).236... 

The amide functionality plays an important role in the physical and chemical properties of proteins and peptides, especially in their ability to be involved in the photoinduced electron transfer process. Polyamides and proteins are known to take part in the biological electron transport mechanism for oxidation-reduction and photosynthesis processes. Therefore studies of the photochemistry of proteins or peptides are very important. Irradiation (at 254 nm) of the simplest dipeptide, glycylglycine, in aqueous solution affords carbon dioxide, ammonia and acetamide in relatively high yields and quantum yield (0.44)202 (equation 147). The reaction mechanism is thought to involve an electron transfer process. The isolation of intermediates such as IV-hydroxymethylacetamide and 7V-glycylglycyl-methyl acetamide confirmed the electron-transfer initiated free radical processes203 (equation 148). 

SC1293) (Scheme 56). A similar approach provides 3-phenylthia-zolo[3,2-a]benzimidazole (205) via isolation of intermediate 204 [92JCS(P1)707] (Scheme 57). 

In summary, the combination of enzymes is advantageous from an enzymol-ogy and reachon engineering point of view. Reaction yields can be increased by avoiding product inhibition of single enzymatic reachons. Product decomposihon (e.g. by hydrolysis) can be overcome by further enzymatic transformahons. Tedious isolation of intermediate products is not necessary. However, both strategies - combinatorial biocatalysis and combinatorial biosynthesis - have their disadvantages. The in vitro approach needs every enzyme to be produced by recombinant techniques and purified in high amounts, which is in some cases difficult to achieve. On the other hand, product isolation from a biotransformation with permeabilized or whole host cells can be tedious and results in low yields. 

Strictly speaking a catalytic cascade process is one in which all of the catalysts (enzymes or chemocatalysts) are present in the reaction mixture from the outset. A one-pot process, on the other hand, is one in which several reactions are conducted sequentially in the same reaction vessel, without the isolation of intermediates. However, not all of the reactants or catalysts are necessarily present from the outset. Hence, a cascade process is by definition a one-pot process, but the converse is not necessarily true. Clearly a cascade process is a more elegant solution, but a one-pot process that is not, according to the strict definihon, a cascade reaction may have equal practical uhlity. In this chapter we shall be primarily concerned with enzymatic cascade processes, but the occasional chemocatalytic step may be included where relevant and sometimes a sequential one-pot procedure may slip through the net. 

Synthesis of glycopeptides in solution has been successfully applied in the preparation of glycopeptides of moderate lengths (see Sections 6.3.2 and 6.3.3). However, yields in solution synthesis are often only modest and isolation of intermediates makes the approach inconvenient. 

Sato and Narita provided an improved synthesis of various halopyrazines in which hydroxypyrazines 160 were activated with TMSCl to give silyl ethers 161 <99JHC783>. Subsequent treatment of 161 with the appropriate phosphorus-based halogen source provided halopyrazines 162 in 46-94% overall yield. This two-step process was accomplished without isolation of intermediate 161 and provides a milder, more convenient approach than the traditional heating of hydxoxypyrazines with PX directly. 

All the syntheses of this type give piperid-4-ones or pyrid-4-ones. Errera reported that diethyl acetonedicarboxylate condensed with triethyl orthoformate in hot acetic anhydride, and that treatment of the product with ammonia gave a poor yield of the pyrid-4-one (644) (1898CB1682). It is certain that the intermediate is the di(ethoxyvinyl) ketone (643), so that this is perhaps better classified as a [5 + 1] synthesis, but most developments from this beginning do not involve isolation of intermediates. An arylamine has been used to obtain an A-arylpyrid-4-one (645) (46JA1253). 

An alternative, though less efficient, method for the synthesis of furo[3,2-. pyrimidines commences with a furan with adjacent amino and ester functionalities. Compound 329 serves as this precursor (Scheme 29). The amino group was remarkably resistant to guanylation using standard methodology. The more reactive l,3-bis(carbomethoxy)-2-methyl-2-thiopseudourea 330 effected condensation to give the adduct 331. While 331 could be isolated, it was found to be more convenient to carry out both cyclization and hydrolysis steps without isolation of intermediates to provide the desired 332 <1999JHC423>. 

Following are further examples of reversed reactivity order. The formation of 5-oxo-TPs is achieved by means of condensations of AT (in the presence of sodium ethoxide) with ethyl 3,3-diethoxypropionate or 3-ethoxyacrylate (64ZOB499), propiolic acid (70CB3266), and cyanoacetate (61CPB801 64CB1373, 64IZV1475), respectively. In the last case (formation of 12), the fusion of reactants without catalyst allows the isolation of intermediate amide 11 (Scheme 5). 

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