Functional substituents

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Fischer indole cyclizations incorporating functionalized substituents... 

Chapters III to VII discuss the general properties of thiazoles having hydrocarbon and functional substituents, respectively. A special chapter (Chapter VIII) is devoted to mcso-ionic thiazoles, and Chapter IX describes the thiazolium salts and their numerous cyanine dyes derivatives. The last chapter concerns the monocyclic selenazoles. 

This method has mainly been used to prepare thiazoles nonsubstituted in the 2-position and involves the replacement of a functional substituent (amino, halo, mercapto, hydroxy, or carboxy) by a hydrogen. In this way the often delicate cyclization of thioformamide can be avoided. 

The reactivity of alkylthiazoles possessing a functional group linked to the side-chain is discussed here neither in detail nor exhaustively since it is analogous to that of classical aliphatic and aromatic compounds. These reactions are essentially of a synthetic nature. In fact, the cyclization methods discussed in Chapter II lead to thiazoles possessing functional groups on the alkyl chain if the aliphatic compounds to be cyclized, carrying the substituent on what will become the alkyl side chain, are available. If this is not the case, another functional substituent can be introduced on the side-chain by cyclization and can then be converted to the desired substituent by a classical reaction. 

Effect of Structure. The rate at which different alcohols and acids are esterified as weU as the extent of the equiHbrium reaction are dependent on the stmcture of the molecule and types of functional substituents of the alcohols and acids. Specific data on rates of reaction, mechanisms, and extent of reaction are discussed in the foUowing. More details concerning stmctural effects are given in References 6, 13—15. 

When the pyrazole ring bears two adjacent functional substituents, it reacts like an o-substituted benzene. For example, 4,5-diaminopyrazoles behave similarly to... 

Most parent structures consist essentially of an assembly of rings and/or chains, the degree of hydrogenation of which is defined (usually completely saturated or containing the maximum number of non-cumulative double bonds in cyclic portions), and having no attached functional substituents (the carbohydrates are a notable exception to this). The stereochemistry at all (or most) chiral centres is defined thus such parent structures are sometimes referred to as stereoparents . Some examples are shown (77)-(83). 

As mentioned above, it is usually most convenient to employ as parent structure a skeleton from which all functional substituents have been removed. However, there are many substituted parent names in common use, either with or without implied stereochemistry (see examples 102-106). 

Since l-heterobut-l-en-3-ynes are readily alkylated and functionalized at the terminal acetylenic carbon atom, their reaction with hydrazines makes it possible to introduce diverse (including functional) substituents into the pyrazole ring. For instance, from benzylated methoxybutenyne 112, isomeric 2-phenylethylpyrazoles 113 were obtained in 74% yield (81H146). 

As with other electrophilic substitution reactions, there is practically no work available on the halogenation of isoxazoles with functional substituents. The only instance that indicates that the general pattern holds true here is the extremely rapid bromination of 3-anilino-5-phenylisoxazole (65), in which the isoxazole ring is the first to react with 1 mole of bromine, yielding... 

The nucleophilic substitution of a halogen atom at C-5 in the isoxazole nucleus without further functional substituents is so far unknown, but recently reports appeared on the nucleophilic substitution reactions at C-5 in isoxazole derivatives with benzoyl (78 79), ester, and cyano groups (81—>80, 82) in the 4-position. ... 

The reactivity of T4R4 species remains largely unexplored because of the lack of compounds available for study but the T4[OR]4 (R = Ft, Pr, iPr, mBu, CgH4Me, C18H37) compounds are reported to be reactive under the hydrolysis conditions under which they are prepared, probably to give Tg and T12 species (Figure 4). The reactions of T4 derivatives with functionalized substituents are likely to be dominated by the reactivity of the substituents as has been found in the case of the Tg derivatives described in Section V. 

With functionally substituted, alkyltin compounds, the functional substituent may become involved in the cleavage process, resulting in an intramolecular reaction, e.g.. 

The synthesis of new heterocyclic derivatives under conservation of a preformed cyclic structure is not only of particular importance for the synthesis of ionic 1,3,2-diazaphosphole or NHP derivatives but has also been widely apphed to prepare neutral species with reactive functional substituents. The reactions in question can be formally classified as 1,2-addition or elimination reactions involving mutual interconversion between 1,3,2-diazaphospholes and NHP, and substitution processes. We will look at the latter in a rather general way and include, beside genuine group replacement processes, transformations that involve merely abstraction of a substituent and allow one to access cationic or anionic heterocycle derivatives from neutral precursors. 

A large part of the chemical reactions of 1,3,2-diazaphosphole and NHP derivatives reported to date include transformations under substitution of functional substituents at the C, N, or P ring atoms. The interest in several of these displacement processes was mainly directed by the desire to develop synthetic pathways for specifically... 

Unsaturated groups are very interesting for application development because this specific functionality opens up a broad range of possibilities for further (chemical) modification of the polymer structure, and therefore its physical and material properties. The direct microbial incorporation of other functional substituents to the polymer side chains, e.g. epoxy-, hydroxy-, aromatic-, and halogen functional groups, influences the physical and material properties of poly(HAMCL) even further [28,33,35,39-41]. This features many possibilities to produce tailor-made polymers, depending on the essential material properties that are needed for the development of a specific application. 

Cycloaddition reactions are used to prepare organolead compounds with functionalized substituents. (Triphenylplumbyl)pyrazole, 95, can be prepared from triorganoplumbylalkynes by 1,3-dipolar cycloadditions with diazomethane196 ... 

Synthesis of 5,6-Dihydro-4H-Oxazines Containing Functionalized Substituents at the C-3 Atom Unlike BENAs, six-membered cyclic nitroso acetals do not form quaternary ammonium salts in the reactions with StX/Nu. ... 

Reduction of the Oximino Fragment in Substituted 5,6-Dihydro-4H-Oxazines Catalytic hydrogenation of substituted dihydro-477-oxazines (552), as well as their reduction with sodium cyanoborohydride (553), were studied in sufficient detail and were used in several total syntheses. However, the use of silylation of six-membered cyclic nitronates enables the synthesis of previously unknown dihydrooxazines containing functionalized substituents at the C-3 and C-4 atoms from easily available precursors. 

This cyclopropanol formation proceeds smoothly with alkenyl- (except ethenyl) [74], cycloalkyl- [58—60,72], and arylcarboxylates [56,58], as well as with carboxylates containing a P- [65,75] or y-halogen [66], an acetal [71,76], and quite a number of other functional substituents, including dialkoxyphosphonyl groups [69] (see Table 11.1). 

With a functional substituent in the alkyl group, the self-association may be intramolecular. Thus, in the tu-hydroxyalkyltin trihalides, HO(CI I2) SnGI3, when n 3 or 4, the molecules are intramolecularly coordinated, whereas when n = 5, they form a linear polymer.336 Similarly, MeC02(CH2) SnCl3 forms a cyclic monomer when n = 3, but a cyclic dimer when 11 = 2, and an oligomer when n = 4.337... 

Bis(tribuyltin) oxide reacts with carboxylic esters in ether at room temperature to give the corresponding tributyltin carboxylate and tributyltin alkoxide, and this reaction is recommended for removing protecting ester groups in the presence of other functional substituents.358-360... 

This group has examples of many types of acids derived from aliphatic, aromatic and heterocyclic radicals, with carboxylic, phenolic or sulfonic or related functional substituents. Individually indexed acids are ... 

The second example is the electro-oxidative polymerization of phenols bearing functional substituents. It is known that salicylic acid forms a stable chelate with copper ion, thus the copper catalyst is deactivated and the polymerization does not occur. On the other hand, salicylic acid was electro-oxidatively polymerized to produce the poly(phenyleneoxide) bearing carboxylic group. 

AspAT has been shown to display a broad substrate spectrum. This chemoenzymatic procedure is, therefore, a very convenient way to prepare a variety of L-2,4-syn Glu analogues substituted at the 4-position by alkyl or functionalized substituents. Moreover, this catalyst has been used for the preparation of 4,4-disubstituted ° and (25,3R)-3-methyl Glu derivatives, as well as the cyclobutane analogues LCBG II-IV. The different Glu analogues prepared to date using this methodology are reported in Figure 10.1. 

Schemes 9 and 10 show the synthesis of triphosphanes with functional substituents in the 1,2-position. Additional reaction proceeds with elimination of MejSiCl and the formation of the corresponding cyclotetraphosphane in which the P(CMe3)2 groups are adjacent. The reaction progresses with the formation of the P=P double bond, which can be proved by the addition of cyclopentadiene (Scheme 10). The...

Recent investigations have demonstrated that electron withdrawing substituents at the a-position increase the rate of this reaction strongly (12.). This reaction would have great potential for natural product syntheses provided that additional electron donating functional substituents could be introduced in the p- and a-positions, that enol ethers, enediol ethers, ketene acetals could react as dienophiles (see route E in Scheme 1). In addition. 

---