Derivatization reaction sequence

Alkali metal derivatives of 2-(trimethylsilyl)aminopyridines can be further derivatized by insertion of 1,3-dicyclohexylcarbodiimide. Functionalized guani-dinates are formed in this reaction via a 1,3-silyl shift. Scheme 170 illustrates the reaction sequence as well as the preparation of an aluminum complex of the modified ligand, which exhibits pseudo jS-diketiminate binding of the metal center, thus exemplifying the coordinative versatility of this new multi-N-donor system. ... 

The examples that are treated below are those sequences where all steps - except the last — are preparations for a color or fluorescence derivatization reaction which is carried out in the last step, i. e. they can be regarded as a sort of selective in situ pretreatment for a final detection reaction. Such reaction sequences are frequently necessary because all the reagents cannot be mixed together in a single solvent, or because it is necessary to dry, heat or irradiate with UV light between the individual reaction steps. The detection of aromatics by the reaction sequence nitration — reduction — diazotization - couple to form an azo dye is an example of this type (Fig 21). 

Figure 5.21 The reaction sequence of crosslinking with sulfo-SANPAH involves first derivatizing an amine-containing molecule using its NHS ester end to create an amide bond. Exposure to UV light then causes ring expansion to the dehydroazepine derivative, which can couple with amines to form the final conjugate.

The peptide mixture on the MALDI target can be exposed to a chemical derivatization to confirm the identity of a peptide by the mass shift associated with the sequence-specific derivatization. A large number of possible derivatization reactions can be combined with the MALDI-TOF analysis. Their usefulness depends critically on the kinetics of the derivatization reaction, whether the reaction is complete with small amounts of peptides and whether only one product is generated. A visible MALDI signal can be generated from low atomole of peptide present under the laser beam (Vorm et al., 1994), but these amounts are often not sufficient... 

The reaction sequence starts by anchoring 2,6-dichloropurine onto the sohd-phase PAT, -amine at the more reactive C6 position with exclusive regioselectivity. A multitude of PAL-amine resins 59 can be prepared ahead by reductive amination of commercial (4-formyl-3,5-dimethoxyphe-noxy)-methylpolystyrene. The N9 position of the purine (60) may be modified by Mitsunobu alkylation. The final derivatization step involves a palladium-catalyzed cross-coupling reaction in position 2. This reaction... 

In these investigations, the authors subjected PAF to direct derivatization with pentafluorobenzoyl chloride (PFB) or heptafluorobutyric anhydride (HFB). Using a 16 0 PAF, the resulting reaction sequence is presented in Figure 6-3. The reaction mixture is evaporated under a stream of nitrogen, and the residue is partitioned between hexane and water. The derivatives noted above are found in the hexane layer, and the polar head group is located in water-soluble fraction. 

Dihydroxylation of the stilbene double bond in the trans isomers of Combretastatin A-1 and A-4 produced diols which by treatment with boron trifluoride in ethyl ether [44] or with trifluoroacetic acid [17] resulted in pinacolic rearrangement to produce an aldehyde. The aldehyde was converted in a variety of derivatives, as illustrated in the Scheme 20, via the following reaction sequence reduction with sodium borohydride to primary alcohol which was derivatized to the corresponding mesylate or tosylate, substitution with sodium azide and final reduction to amine with lithium aluminum hydride. Alternatively the aldehyde was converted to oxime which was catalitically hydrogenated to amine [17]. 

A similar approach of fluorous quasi-racemic synthesis [20] was used to synthesize both enantiomers of mappicine at the same time in a coded mixture. The pyridine derivative 41 was split, and the carbonyl group was reduced enantioselectively by (+)- and (-)-DIP-Cl, respectively. The resulting enantiomerically pure alcohols were subsequently derivatized - the (1 ) enantiomer with BrSi(iPr)2CH2CH2QFi3 to yield (Ji)-4-2 and the (S) enantiomer with BrSi(iPr)2CH2CH2CgFi7 to yield the quasi-enantiomer (S)-43. The mixture of both quasi-enantiomers was then subjected to the reaction sequence leading to the fluorous mappicines (R)-44 and (S)-4S. These were separated by fluorous chromatography and deprotected to yield the two mappicine enantiomers (Scheme 3.21). 

The use of reaction sequences is also common in the analysis of pharmaceuticals. For example, for the purity test for hydrochlorothiazide (HCT) the DAB specifies a nitration reaction followed by reaction with naphthylethylenediamine dihydrochloride, in which the reaction sequence is performed as in the example given below. HCT is a diuretic which is often used in combination with beta-blockers for the treatment of hypertension (high blood pressure). Diuretics of this type are also abused in sport (doping) and appear on the list of banned substances prepared by the IOC (International Olympic Committee). In the quantitative determination of HCT in urine, the red azo dyes formed in the derivatization (parent substance and metabohtes) is regarded as a doping-positive result [111]. The complete specification for this analytical method, known as Application A-43.2, can be obtained from CAM AG. 

Example of a reaction sequence for derivatization detection limit test for known and unknown compounds in the purity testing of ambroxol hydrochloride... 

From carbohydrates, several diphosphines have been derived and used as ligands in hydroformy-lation reactions (Section D.l. 5.8.). a,a -TREDFP (a,a -40) is prepared from commercially available a, a -trehalose (39) by the reaction sequence outlined42,43 similarly, the / ,/f-anomer is obtained from / ,/ -trehalose44. L-Iditol is commercially available but expensive, but may be prepared by catalytic reduction of L-sorbose and separation from the isomeric L-sorbitol by fractionated crystallization of the hexaacetate45. Conversion to the diphosphine 42 involves a further fractional crystallization for the separation of isomeric ditosylates46. The reactions for the synthesis of the precursors employ techniques described in Section 4.4. for the derivatization of carbohydrates. 

Apart from racemization or other types of isomerizations, a large number of other types of substrate accesses (e.g., by synthesis via carbon-carbon bond formation) are conceivable with respect to the combination with their further chemical derivatization steps. For the minimum number of two-step one-pot processes based on this concept, the biotransformation can be set as the initial or subsequent reaction step of the one-pot reaction sequence. For both types of reaction sequences, which are shown in Scheme 19.1, concept (b) (sequence types I and II), one-pot processes were developed however, when choosing the biotransformation as the... 

Octa(phenyl)silsesquioxane is prepared by hydrolysis and condensation of phenyltrichlorosilane and the subsequent rearrangement reaction catalyzed by benzyltrimethylammonium hydroxide [22]. For further derivatization this precursor has to be activated, for example, by halogenation of the phenyl rings. This complex reaction sequence is necessary because halogenated precursors such as bromophenyl silanes of the type X3SiCgH4Br may be readily accessible from Grignard reactions between the benzene derivative and either SiCU or Si(OR)4, but the following hydrolysis and condensation step results in only low yields of... 

A.ldehyde Syntheses. Aromatic (Ar) carboxylic acids are reduced to the corresponding aldehydes by a sequence of steps known as the McFadyen-Stevens reaction. The acid is converted to the hydrazide, derivatized with benzenesulfonylchloride, then decomposed to the aldehyde in hot glycol in the presence of a base ... 

Analogous techniques facilitating sequencing from a polypeptide s C-terminus remain to be satisfactorily developed. The enzyme carboxypeptidase C sequentially removes amino acids from the C-terminus, but often only removes the first few such amino acids. Furthermore, the rate at which it hydrolyses bonds can vary, depending on what amino acids have contributed to bond formation. Chemical approaches based on principles similar to the Edman procedure have been attempted. However, poor yields of derivatized product and the occurrence of side reactions have prevented widespread acceptance of this method. 

PITC has been used extensively in the sequencing of peptides and proteins and reactions under alkaline conditions with both primary and secondary amino acids. The methods of sample preparation and derivatization follow a stringent procedure which involves many labour-intensive stages. However, the resulting phenylthio-carbamyl-amino acids (PTC-AA s) are very stable, and the timing of the derivatization step is not as critical as when using OPA. 

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