Work-Up Conditions

The synthesis of hydroxy-3-aminoethane thiosulfuric acid (AETSAPPE) is shown in Scheme II. The same basic conditions used for the polymer synthesis were employed to synthesize the model compound (AETSAPPE) although the work-up conditions were less stringent. The structure was confirmed by carbon-13 NMR and elemental analysis. 

Kinetic studies of alkene-phosphorus pentachloride reactions in benzene show the effects of substituents when the double bond is terminal.88 When the alkene is conjugated, the standard work-up conditions (using sulphur dioxide) produce alk-1-enylphosphonyl dichlorides (103), instead of 2-chloroalkylphosphonyl dichlorides (104).87... 

The Dotz benzannulation reaction yields either arene chromium tricarbonyl complexes or the decomplexed phenols, depending on the work-up conditions. Because of the instability of hydroxy-substituted arene chromium tricarbonyl complexes, yields of the latter tend to be low. High yields of arene complexes can, however, be obtained by in situ silylation of the crude product of the benzannulation reaction [336]. Oxidative work-up yields either decomplexed phenols or the corresponding quinones. Treatment of the benzannulation products with phosphines also leads to decomplexed phenols [272]. 

The immediate products of additions between carbonyl substrates and allylic boranes 1 or boronate derivatives 2 are borinate or borate esters, respectively. To cleave the covalent B-O bond in these intermediates (structme 6, Scheme 1) and to obtain the desired free alcohol, a hydrolytic or oxidative work-up is required. This issue is discussed in detail in the section Work-Up Conditions . In the interest of simplifying chemical equations, specific work-up conditions are not inclnded in most of the examples highlighted in this chapter. 

The addition of allylic boron reagents to carbonyl compounds first leads to homoallylic alcohol derivatives 36 or 37 that contain a covalent B-O bond (Eqs. 46 and 47). These adducts must be cleaved at the end of the reaction to isolate the free alcohol product from the reaction mixture. To cleave the covalent B-0 bond in these intermediates, a hydrolytic or oxidative work-up is required. For additions of allylic boranes, an oxidative work-up of the borinic ester intermediate 36 (R = alkyl) with basic hydrogen peroxide is preferred. For additions of allylic boronate derivatives, a simpler hydrolysis (acidic or basic) or triethanolamine exchange is generally performed as a means to cleave the borate intermediate 37 (Y = O-alkyl). The facility with which the borate ester is hydrolyzed depends primarily on the size of the substituents, but this operation is usually straightforward. For sensitive carbonyl substrates, the choice of allylic derivative, borane or boronate, may thus be dictated by the particular work-up conditions required. 

Additions of allylic boron reagents are typically performed under experimentally simple conditions, and under a wide range of temperatures that is dictated by the reactivity of the particular reagent employed. Work-up conditions are discussed in a previous section. For the reaction itself, uncatalyzed additions can be performed in a wide variety of aprotic solvents. Non-coordinating solvents usually lead to shorter reactions times, but the identification of an optimal solvent in stereoselective additions is rather unpredictable and may require coordinating... 

Work-up becomes a major consideration in designing processes for preparation of all phases of drug development after Phase 1, as 60 to 80% of both capital expenditures and operating costs go to separations. (Eckert, 2000) Work-up conditions can limit the selection of reagents and routes. Simple work-ups with a minimal number of transfers decrease the number of opportunities for physical losses and contamination. 

The results of some of the many aminations of pyridine and its derivatives that have been carried out appear in Table 14. Yields are quoted where possible but these should not be used for quantitative comparisons as reaction and work up conditions vary widely. 2-Alkylpyridines aminate at the vacant a-position, except when the substituent is very large. 2-f-Butylpyridine does not undergo the Chichibabin reaction, probably because the bulky 2-f-butyl group prevents adsorption on to the sodamide surface. In contrast, 2-phenylpyridine undergoes amination in very good yield. Aminations of 2- and 4-methyl-pyridines do not involve attack on the anhydrobases in aprotic solvents, but some ionization does take place in liquid ammonia. 4-Benzylpyridine forms a carbanion (148) which is only aminated with difficulty by a second mole of sodamide (equation 103). 

Depending upon the work-up conditions good yields of either of two stable 19... 

Depending on the work-up conditions, Vilsmeier-Haack formylation of 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidines gave various 9-sub-stituted pyrido[l,2-a]pyrimidines (240 -242).284,319 The 9-aminomethylene derivatives (240) were transformed by hydrolysis in 0.5 N hydrochloric acid to the 9-formyl compounds (241 R3 = H), by ethanolic hydrogen chloride to... 

We could prepare a-alkoxy-y-phenylselenenyl aldehydes as "stable" equivalents of a-alkoxy-P,y-unsaturated aldehydes but their reaction with boron enolates did not lead to the expected condensation products, probably due to inadequate work up conditions. 

The electrochemical behavior of malonyl-a-aminopyridines 661 was investigated by Gullu et al. in acetonitrile or a mixture of trifluoroacetic acid and dichloromethane containing tetrabutylammonium tetrafluoro-borate or triethylammonium trifluoroacetate in a water-jacketed, two-compartment glass cell equipped with a platinum disk anode at 1.50 V (Ag/ Ag+) and a carbon-rod secondary electrode (91T675). Controlled potential anodic oxidation of 661 afforded labile coupled carboxylic acids 662 (R2 = COOH), which easily decarboxylated to compounds 662 (R2 = H) under the work-up conditions. Sometimes, the carboxylic acid 662 (R2 = COOH) could be isolated or when the reaction mixture was treated with methanol, methyl ester 662 (R = H, R1 = Bu, R2 = COOMe) was obtained in 40% yield. 

Techniques of chromatographic analysis continue to develop and for up-to-date methods, the specialist literature should be consulted [62, 63]. In all cases, reaction samples have to be taken at known time intervals and quenched by an appropriate method (sudden cooling, change of pH, dilution, etc.) before chromatographic analysis. It is important to check the stability of the reaction component to the chromatographic and work-up conditions. For example, are the compounds to be analysed thermally stable to the GC conditions (Conditions inside a GC injection port and, indeed, within the column are not unlike those of a heterogeneous catalytic reactor ) Are they stable to the pH of the HPLC eluent An obvious restriction is that chromatographic component analysis does not lend itself to the study of fast reactions. 

In cases where there is an exocyclic double bond at the 3-position, e.g. 24, reductive C2—C3 ring opening (25 -+ 26) under the work-up conditions (gas chromatography) has been observed. 

Prolonged exposure to work-up conditions should be avoided to prevent hydrolysis at phosphorus at this step. 

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