Introducing substituents

There are only few reactions known introducing substituents to the H-bearing nitrogen of oxaziridines. (V-Alkylation of l-oxa-2-azaspiro[2.5]octane (3,3-pentamethylene-oxaziridine 52) with r-butyl chloride to give (53) was carried out for structure proof of (52). This reaction is of no preparative importance, since N-alkylated oxaziridines are easily obtained by ring synthesis. 

At the end of the nineteenth century, Claisen described the cyclization of P-keto esters with hydroxylamine to provide 3-hydroxyisoxazoles. Substituents Ri and R2 in the P-keto ester make it possible to introduce substituents in the 4- and 5-position of the heterocyclic ring. 

As is apparent at a glance, cortisone is an intricate molecule with a wealth of functionality. Steroid transformations in the corticoid series require serious strategic planning in order to provide the appropriate protecting groups and to introduce substituents in the proper order. It is therefore easy in a discussion of this chemistry to get lost in a welter of detail. 

Cotton linters and viscose grade wood pulp were partially acetylated and carboxymethylated. The samples were grafted under the same conditions with acrylamide. Grafting yield and efficiency depend on several factors, such as the kind of pulp, chemical and physical structure, type of the introduced substituent, and degree of substitution (DS). 

Nitration differs from halogenation since here the strongly electron-withdrawing effects of the nitro substituents first introduced influence the reactivity and the positions of further introduced substituents. Therefore, it is possible to prepare under carefully controlled reaction conditions different substitution products.100 103 The preparation of the tetrasubstituted product cannot be achieved since the deactivating effects of three nitro groups are too strong.104... 

Of great importance for porphyrin chemistry is the introduction of carbon substituents by Vilsmeier formylation100 or Friedel-Crafts acylation.100 The introduced substituents allow further carbon-chain elongations and other transformations so that interesting porphyrin derivatives can be synthesized. The Vilsmeier formylation of copper octaethylporphyrin (5) takes place at themethine position. The copper can then be easily removed by treatment with acid.105... 

The chlorosilanes are available from classical synthetic routes [108]. In most cases the products can be obtained from SiCl4 and the lithium salts of the introduced substituents with sufficient selectivity and in high yield. This is particularly true for the alcoholates and the thiolates. The exchange problems R vs. Cl which arise with the t-butylthiochlorosilanes will not be discussed in detail here. These problems are overcome by an appropriate choice of the reaction conditions. 

Fig. 5. Mixed cyclization reaction using two kinds of porphyrins. The introduced substituents of 7 and 8 are omitted for clarity and the structures of 9-13 are roughly drawn...

It is possible to introduce substituents that can influence the conformational equilibria to favor a particular product. In the reactions shown below, the addition of the trimethylsilyl substituent leads to a single stereoisomer in 85% yield, whereas in the unsubstituted system two stereoisomers are formed in ratios from 4 1 to 8 1.124... 

At present, the difficulties described in 7-9 can be solved. The use of MAO can be avoided by the use of non-MAO catalysts such as cationic Group 4 metallocenes or neutral Group 3 metallocenes. It has been found that the molecular weight of the resulting polymer can be increased by introducing substituents at the 2,5-position in the cyclopentadienyl group of the... 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

Another advantage of this approach is that it allows the possibility of introducing substituent effects. Substituents which alter the energies of allyl n orbitals relative to the S orbital will increase the chances of interaction either with /[ or with /3. 

Introducing substituents into the pigment molecule which reduce the solubility of their host structure. 

Acylation of 1-aminoanthraquinone affords 1-acylaminoanthraquinones. The carbonamide function renders these compounds very fast to migration. The migration fastness may be improved further by introducing substituents which carry additional carbonamide groups, or by molecular dimerization using aromatic dichlorides. 

The upfield shift of signals of carbon atoms in 7-position to a newly introduced substituent was recognized very early. Grant and Paul (169) found a 7-parameter of —2.5 in linear and branched alkanes. Later this group studied various other classes of hydrocarbons (33,88,100,101,170-172) and developed an interpretation of the 7-effects in terms of a polarization of the bond between the carbon concerned and an adjacent, sterically perturbed hydrogen atom (33,88) that has come to be called the Grant-Cheney approach. ... 

Upfield shifts of multiply heterosubstituted carbon atoms are well known in the 13C NMR literature. Some representative examples are shown in Figure 9 and Table 16, where the actual l3C chemical shifts and individual a-SCSs, respectively, for each newly introduced substituent in methane derivatives are compiled. The ICSs can be calculated by subtracting any a-SCS from its respective predecessor within a given row in Table 16. The general trend is toward a distinct decrease of a-SCS with progressive substitution that is, all the ICSs are negative. 

More powerful directing groups such as those based on amides and sulphonamides are successful with pyridines as with carboxylic rings, and will not be discussed separately. The enhanced acidity of pyridine ring protons makes the simple carboxylate substituent an ideal director of lithiation in pyridine systems . The pyridinecarboxylic acids 232-234 are deprotonated with BuLi and then lithiated with an excess of LiTMP all the substitution patterns are lithiated nicotinic acid 233 is lithiated in the 4-position (Scheme 113). The method provides a valuable way of introducing substituents into the picolinic, nicotinic and isonicotinic acid series. 

Instead of introducing substituent groups into a molecule we may dissolve a reactant in a solvent and the energy of activation of decomposition of the complex reactant-solvent will vary in a similar manner as we alter the solvent as exemplified by the data of von Halban (Zeit. Phys. Ohem. lxxvii. 129, 1909) on the decomposition of triethylsulphine bromide, the energies of activation being calculated without correction for the possible alterations with the temperature of the concentration of the complex undergoing reaction. 

In order to introduce substituent variation on the amino group at the pyrazolo[l,5- 7]pyridine 7-position, a modified procedure was investigated where a 7-chloro substituent was carried through the synthesis. However, this procedure was compromised by the fact that dimethylamine displacement of the chlorine also occurred during formation of the enamino ketone 1000, giving the dimethylamino compound 1001 as a major by-product <2003X9001, 2005BMC5346>. 

More recently the same behavior was found with the bi- and tricyclic thioacetals cu-1,5-dimethyl-2,4-dithiabicyclo[3.1.0]hexane (1) and 3a,7a-methano-l,3-benzodithiole (2)58. A deprotonation-alkylation reaction gave a single alkylated product 3, with the introduced substituent in an aw/i-position relative to the three-membered ring. 

The diastereoselectivity is reversed in the alkylation of the enolate derived from the structurally very similar bicyclic lactam, tetrahydro-3-phenyl-l//.577-pyrrolof 1,2-c]oxazol-5-one (3). Thus, the major diastereomer 4 produced has the tram relationship between the newly introduced substituent in the pyrrolidine ring and the fused oxazolidine ring residue11,12. Only active electrophiles such as iodomethane, 3-halopropenes or (halomethyl)benzenes react11,12. Base-catalyzed equilibration of the product obtained by reaction with 3-bromocyclohexene gives a 50 50 mixture of the cis- and rra s-diastereomers11. 

Conjugate addition to (35 ,7a/ )-3,7a-dihydro-3-phenyl-l//,5f/-pyrrolof1,2-r ]oxazol-5-onc (8) yields the saturated -substituted bicyclic lactams 9 with complete diastereoselectivity13. Treatment of the latter with 2.2 equivalents of lithium diisopropylamide in tetrahydrofuran at — 78 °C, followed by alkylation with a haloalkane, furnishes the a,/i-dialkylatcd products 10 with excellent selectivity (d.r. >98.5 1.5, determined by H and 13CNMR)13. In this case the major diastereomer has the cw-relationship between the newly introduced substituent (R2) in the pyrrolidine ring and the fused oxazolidinc ring rcsiduc13. 

The C,-synthon is usually a carboxylic acid or a derivative of a carboxylic or carbonic acid and introduces substituent R . An example is the reaction of 4-oxo-6-methyl-HP (16) and formic acid in Scheme 9 (59JOC787). 

In the synthesis of disubstituted benzenes, the first substituent present determines the position of the incoming second. Therefore the order of introducing substituents must be carefully planned to yield the desired isomer. 

Frequently used methods for introducing substituents into the various positions of the pyridine nucleus include the following ... 

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