Substitutions at the 4-Position

Phenyl substituents (visible) (nm) A OD Steady-state FadeTin (s) 

Substituents on the phenyl groups of 3,3-diphenyl-3//-naphtho[2,l-6]pyran can have substantial effects on color, intensity, and fade. Electron-donating groups in the para position(s) result in a bathochromic shift in the visible spectrum, a lower equilibrium intensity, and a somewhat more rapid fade (Table 3.1). An additional 

In this sequence29,30 a (substituted or unsubstituted) benzophenone (15) is reacted witb sodium acetylide (16) in an etber solvent at room temperature to yield a 1,1-diaiyl-2- propyn-l-ol (17). This intermediate can be condensed with a P-naphthol in the presence of an acid catalyst at 30 to 50°C to yield the pyran. 

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The structure was established on the basis of substitution at the 3-position (11CB2409), optical investigations (26LA(437)162), dipole moment (3.06 D) (44MI41600) and IR measurements (57MI41600, 66DIS(B)102). The first 2,1-benzisoxazole to be synthesized was 5,6-dimethoxy-2,l-benzisoxazole-4-carboxylic acid in 1881 (1881JPR353). 

Another illustration of the structural changes that may result as a consequence of alkyl substitution at the 3-position of the pyrazolyl group is provided by the structures of the dimeric copper(I) complexes [Tp]Cu 2 (36), [TpMe2]Cu 2 (36), [TpPh2]Cu 2 (37), and [TpBut]Cu 2 (37), which differ in the manner in which the tris(pyrazo-lyDhydroborato ligand bridges the two copper centers (Fig. 16). 

The use of substitution at the 3-position to modify the steric environment about the metal center has been described in Section II,D,1. In a similar vein, substitution at the remote 5-position has been used with the specific goal of providing steric protection for the B-H moiety in attempts to inhibit ligand degradation. Indeed, as will be described, the steric protection that is provided by the methyl groups of the... 

Chlorine substitution at the 3-position leads to CF3 carbon chemical shifts at a progressively higher field (Scheme 5.7), whereas the proton and carbon chemical shifts for the CH2 group of CF3CH2C1 are affected more by the chlorine substituent than by the CF3 group. 

By contrast, the synthesis of syndiotactic PP, s-PP, is generally catalyzed by Cs-symmetry ansa- metallocenes. For example, (16)/MAO affords PP with a pentad (rrrr) content of 86% at 25 °C.77 The stereoselectivity is highly sensitive to ligand variation. For example, substitution at the 3-position of the Cp ring with a methyl group affords heterotactic PP,78 whilst the Bu analog favors i-PP production.50,75,79... 

The substitution at the 3-position in the acyl side chains is important for the agonistic activity of AHLs, but so far no clear prediction on the antagonistic effect of a modification at this position can be made [57]. Recently however, the biological impact of chain length variation and hydroxylation of C6-HSL was investigated [70]. Based on the halofuranone 26 from Deliseapulchra, a small... 

Kim s group in Seoul report the application of another of the E. coli ATs, the aromatic l-AAT encoded by the tyrB gene, to enrich the D-component of racemic preparations of alanine substituted at the /3-position with pyrazole, triazole, and imidazole. They also carried out an in silico investigation based on the crystal structure (PDB 3TAT) providing a reasonable rationalization (and therefore also potentially prediction) of substrate specificities. 

Moderate to good enantioselectivities were obtained for nearly all examples, but the products from 83a-c could be recrystallized to higher enantiomeric purity. Addition of iodine was critical for catalysis as was the use of a ligand with electron-poor para-fluorophenyl groups on the phosphorous atom. Substitution at the 3 position of the pyridine ring was described as being difficult for both the quinolines and pyridine systems. The resulting hydrazine derivatives could be easily converted to piperdines by reduction with Raney nickel or under Birch conditions. 

Electrophilic aromatic substitution of other benzo-fused v-deficient systems generally follows predictable pathways. Thus, benzopyrylium salts are in general resistant to electrophilic substitution even in the benzo-fused ring. Chromones behave somewhat similarly, although substitution can be effected under forcing conditions. Coumarins, on the other hand, undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

Stabilized carbanions will substitute a- and y-halogenopyridines and their benzo analogues. Substitution at the /3-position is much less common and requires the presence of suitable activating groups, e.g. Scheme 140 (73BCJ3144). 

The nature and position of substitution has a profound influence upon the oxepin-arene oxide equilibrium position. The effect of substituents on the relative energies of each valence tautomer has been calculated (80JA1255) and these theoretical results are in accord with the limited experimental data which are available. In general terms, oxepins substituted at the 3-position are less favored than the corresponding arene oxides, while the reverse obtained for 2- and 4-substituted oxepins. This substituent effect has been rationalized in terms of a preference for the maximum number of alternative resonance contributors. The influence of both 7r donating and v withdrawing substituents oh the oxepin contribution is summarized in Scheme 2. This latter effect may be considered as an electronic substituent effect. 

The preferred position for electrophilic substitution in the pyridine ring is the 3 position. Because of the sluggishness of the reactions of pyridine, these are often carried out at elevated temperatures, where a free radical mechanism may be operative. If these reactions are eliminated from consideration, substitution at the 3 position is found to be general for electrophilic reactions of coordinated pyridine, except for the nitration of pyridine-N-oxide (30, 51). The mercuration of pyridine with mercuric acetate proceeds via the coordination complex and gives the anticipated product with substitution in the 3 position (72). The bromina-tion of pyridine-N-oxide in fuming sulfuric acid goes via a complex with sulfur trioxide and gives 3-bromopyridine-N-oxide as the chief product (80). In this case the coordination presumably deactivates the pyridine nucleus in the 2 and... 

Coumarins undergo nitration readily in the 6-position while bromination results in substitution at the 3-position as a consequence of addition-elimination. 

A radical ipso substitution at the 3-position of 2,3-disubstituted indoles has also been reported in their reaction with benzoyl-r-butyl nitroxide leading to (227) or, with the 2-substituted indole, the dimer (228) (cf. Section 3.05.1.4) (81CC694). In contrast with the benzoyloxylation reactions the nitroxide radical initially abstracts the hydrogen atom at the 1-position to form the indolyl radical. This mechanism is supported by the failure of the corresponding 1 -methylindole to undergo an analogous oxidation. 

A kinetic study of the nitration and nitrosation of l-methyl-2-phenylindolizine revealed that substitutions at the 3-position derive from an attack on the indolizine base while substitutions elsewhere involve attack on the conjugate acid (79JCS(P2)312>. 

In contrast to thiophene, benzo[6]thiophene is preferentially substituted at the /3-position. The /3 a reactivity ratios and partial rate factors for the electrophilic substitutions of benzo[6]thiophene have been summarized. The reactivity ratio varies over a wide range, depending on the nature of the electrophile and the temperature of the reaction in the case of acetylation, the percentage of the a-substituted product increases with temperature. Also in contrast to thiophene, the extended selectivity treatment applied to the reactions at the a- and /3-positions of benzo[6]thiophene gives a non-linear plot. The effect of fusion of a benzene ring to thiophene is to decrease the reactivity of the a-position and increase the reactivity of the /3-position. 

Heterocyclic Components. The most important compounds in this range are the 5- pyrazolones substituted at the 3-position. 

An early significant example is the coupling of 1-substituted indoles with 2-chloro-3,6-dialkylpyrazines (Eq. 1) [5, 6]. Depending on the 1-substituents, the reaction occurs selectively at 2- or 3-position. Substitution at the 3-position is a rare occurrence and seems to be caused by the electron-withdrawing tosyl group, although the precise mechanism is still not clear. 

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