Intermediates as starting materials

Much of our work in this field has been devoted to the search for more suitable natural intermediates as starting materials. 

The reduction in mathematical complexity of non-simple networks is mainly of value in modeling. For network elucidation, a better approach usually is to study as many portions of the network separately, say, by experiments that use synthesized intermediates as starting materials or by appropriate lumping, as the following example will illustrate (see also Section 7.3.3). 

If the pathway or segment of a portion producing a non-trace intermediate is irreversible, no subsequent portion of the overall network feeds back into it. As a rule, this allows the subsequent portion or portions to be studied independently by using the separately synthesized non-trace intermediate as starting material. It also allows the portion yielding the non-trace intermediate to be studied independently For this purpose, all subsequent intermediates and products are lumped with the intermediate produced by the portion (i.e., the concentrations are added) to obtain the total production of the portion. Alternatively, before analysis, all intermediates are converted to end products, and only these then need to be analyzed for and lumped. 

The problems inherent to these two processes are not only the production of corrosive salts, but also the possibiUty of product contamination by 2-chloroethylamine [689-98-5] as starting material or intermediate. This substance can initiate polymerisation of ethyleneimine with the elimination of HCl. 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

Carboxylic acid, 161, also serves as starting material for a substituted pyrazine that has proven to be an important diuretic agent. As the first step in the synthesis the acid is converted to the corresponding amide (165). Treatment with a single equivalent of hypobromous acid effects Hoffmann rearrangement of only one of the amide groups. Ethanolysis of the intermediate carbamate leads directly to the amino ester (166). Exposure of the... 

An intermediate used in the preparation of the antihistamine, propiomazine, serves as starting material for a 2-substi-tuted major tranquilizer as well. Thus, reaction of the phosgene... 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

The retrosynthetic analysis presented in Scheme 6 (for 1, 2, and 16-19) focuses on these symmetry elements, and leads to the design of a strategy that utilizes the readily available enantiomers of xylose and tartaric acid as starting materials and/or chiral auxiliaries to secure optically active materials.14 Thus by following the indicated disconnections in Scheme 6, the initially generated key intermediates 16-19 can be traced to epoxide 23 (16,19 =>23),... 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

When quinazolines are used as starting materials, [4 + 2] cycloadducts are obtained as intermediates, which cleave off hydrogen cyanide by cycloreversion to provide quinolines (see Houben-Weyl, Vol. E9b/Part 2, p 157). 

To support the 2,3-allenol as an intermediate in this reaction, 2,3-allenols were employed in test experiments as starting materials (Scheme 10, route F). The crossover aldol product was obtained as the sole product, when the reaction was run in the presence of the suitable aldehyde. In the absence of an aldehyde the corresponding ( )-a,p-unsaturated ketone was obtained (Scheme 24) [37]. 

Employing ketones or aldehydes as starting materials, the corresponding silylethers are obtained. Thereafter, the oxidation or hydrolysis of the obtained silylethers gives the corresponding alcohols (Scheme 17). In most cases, a hydride (silyl) metal complex H-M-Si (M = transition-metal), which is generated by an oxidative addition of H-Si bond to the low-valent metal center, is a key intermediate in the hydrosilylation reaction. 

The lH-l,2,4-triazole compounds possess important pharmacological activities such as antifimgal and antiviral activities [18-20]. In the present study, the reactive intermediates 45a-c, prepared in situ from the dichlorides 44a-c, were reacted via the cycloaddition reaction with ethyl cyanoacetate 40 to give, after spontaneous rearrangement, the triazole hydrazides 41a-c. These compoimds were used as starting materials for the synthesis of the... 

The initial step in creating a synthetic plan involves a retrosynthetic analysis. The structure of the molecule is dissected step by step along reasonable pathways to successively simpler compounds until molecules that are acceptable as starting materials are identified. Several factors enter into this process, and all are closely interrelated. The recognition of bond disconnections allows the molecule to be broken down into key intermediates. Such disconnections must be made in such a way that it is feasible to form the bonds by some synthetic process. The relative placement of potential functionality strongly influences which bond disconnections are preferred. To emphasize that these disconnections must correspond to transformations that can be conducted in the synthetic sense, they are sometimes called antisynthetic transforms, i.e., the reverse of synthetic steps. An open arrow symbol, = , is used to indicate an antisynthetic transform. 

With a 13C label at the methide center, the presence of reactive methide intermediate can be verified and complex reaction products can be inventoried and eventually identified. The only limitations are the synthesis and cost involved in incorporation of the 13C label. As a rule we, only use 13C-labeled dimethylformamide and NaCN as starting materials because of their low cost and availability. Another limitation of enriched 13C-NMR monitoring is dilution of the enriched label to natural abundance levels. Currently, we are developing isotope-editing techniques that utilize unnatural 13C double labels to solve this problem. 

Although thiosalicylaldehyde 46a (R2 = H) was first synthesized by Friedlander and Lenk (Scheme 23),95 it is an unstable intermediate and should be stored in solution below 0°C. Alternate synthetic procedures utilizing o-chlorobenzaldehyde or salicylaldehyde, as starting materials, are shown in Scheme 24.96 The preferred method for the synthesis of substituted thiosalicylaldehydes 46 is via salicylaldehyde. 

An alternative route to anthraquinone, which involves Friedel-Crafts acylation, is illustrated in Scheme 4.3. This route uses benzene and phthalic anhydride as starting materials. In the presence of aluminium(m) chloride, a Lewis acid catalyst, these compounds react to form 2-benzoyl-benzene-1-carboxylic acid, 74. The intermediate 74 is then heated with concentrated sulfuric acid under which conditions cyclisation to anthraquinone 52 takes place. Both stages of this reaction sequence involve Friedel-Crafts acylation reactions. In the first stage the reaction is inter-molecular, while the second step in which cyclisation takes place, involves an intramolecular reaction. In contrast to the oxidation route, the Friedel-Crafts route offers considerable versatility. A range of substituted... 

DAS (11.7) is synthesised from 4-nitrotoluene-2-sulphonic acid (11.6) by the route outlined in Scheme 11.1. An important factor in the preparation of DAST brighteners in the purity necessary for good performance is the purity of the DAS used as starting material. At one time DAS made in this way contained significant amounts of yellow azoxy compounds similar to 11.8, which formed the main components of the obsolescent dye Sun Yellow (Cl Direct Yellow 11) made by the partial reduction and self-condensation of intermediate 11.6. Today the major manufacturers supply DAS essentially free from these undesirable impurities [37]. 

A facile synthesis of cyclic five-, six-, and seven-membered oxonitriles 7-35 by a combination of an ozono lysis and an aldol reaction has been described by the Fleming group [17]. As starting material the unsaturated oxonitriles 7-33 are used, which are easily accessible by reaction of unsaturated esters 7-32 with LiCHjCN (Scheme 7.11). It can be assumed that 7-34 acts as an intermediate. 

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

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