Multisubstituted compounds

For multisubstituted compounds, the ring carbon atom connected to the functional group with the greatest effects on solubility, based on fragmental coefLdents determined in a previous study (Hu, 1990), was selected as the prime atom and assigned as position 1. 

In some multisubstituted compounds, the lack of additivity needs to be noted. Proximal effects are operative and tend to distort electronic contributions. For example,... 

A very important use of this technique is determining the relative electron affinities of multisubstituted compounds for which little data are available. For hexa-fluorobenzene and petafluorobenzene the READS (hexaF/pentaF) = (0.611/0.389), while the value for READS (p-diF/FBz) = (0.595/0.405) and READS(s-triF/ p-diF) = (0.595/0.405). The sequential addition of a fluorine increases the Ea, and the READS values are relatively constant. The charge distributions are shown in Figure 7.9 for hexafluorobenzene and petafluorobenzene. The pentafluorobenzene value is 0.389q. The value for the hexafluorobenzene is the complement or 0.61 lq. 

Moving on to multisubstituted aromatic systems, the real value of Table 5.4 soon becomes apparent. In dealing with such systems, it will not be long before you encounter a 1,4 di-substituted benzene ring. This substitution pattern (along with the 1,2 symmetrically di-substituted systems) gives rise to an NMR phenomenon that merits some explanation - that of chemical and magnetic equivalence and the difference between them. Consider the 1,4 di-substituted aromatic compound shown in Structure 5.1. 

Fifolt [ 130] reported this chemical shift additivity method for fluorobenzenes in two deuterated solvents d6 acetone and d6 dimethyl sulfoxide (DMSO) Close correlations between experimental and calculated fluorine chemical shifts were seen for 50 compounds Data presented in Table 18 result from measurements in deuterochloroform as (he solvent [56] Fluorine chemical shifts calculated by this additivity method can be used to predict approximate values for any substituted benzene with one or more fluorines and any combination of the substituents, to differentiate structural isomers of multisubstituted fluorobenzenes [fluoromtrotoluenes (6, 7, and 8) in example 1, Table 19], and to assign chemical shifts of multiple fluorines in the same compound [2,5 difluoroamline (9) in example 2, Table 19] Calculated chemical shifts can be in error by more than 5 ppm (upfield) in some highly fluonnated systems, especially when one fluonne is ortho to two other fluorines Still, the calculated values can be informative even in these cases [2,3,4,6-tetrafluorobromobenzene (10) in example 3, Table 19]... 

Although various transition-metal complexes have reportedly been active catalysts for the migration of inner double bonds to terminal ones in functionalized allylic systems (Eq. 3.2) [5], prochiral allylic compounds with a multisubstituted olefin (Rl, R2 H in eq 2) are not always susceptible to catalysis or they show only a low reactivity [Id]. Choosing allylamines 1 and 2 as the substrates for enantioselective isomerization has its merits (1) optically pure citronellal, which is an important starting material for optically active terpenoids such as (-)-menthol, cannot be obtained directly from natural sources [6], and (2) both ( )-allylamine 1 and (Z)-allylamine 2 can be prepared in reasonable yields from myrcene or isoprene, respectively, The ( )-allylamine 1 is obtained from the reaction of myrcene and diethylamine in the presence of lithium diethylamide under Ar in an almost quantitative yield (Eq. 3.3) [7], The (Z)-allylamine 2 can also be prepared with high selectivity (-90%) by Li-catalyzed telomerization of isoprene using diethylamine as a telomer (Eq. 3.4) [8], Thus, natural or petroleum resources can be selected. 

The reaction of the multisubstituted pyridine (329) with excess carbon disulfide in the presence of triethylamine at room temperature gave a product identified as the tricyclic compound (330) (Scheme 33) <90JMC656>. To block one mode of cyclization, the hydrazone (331) was prepared and condensed with one equivalent of carbon disulfide in the presence of triethylamine. In this case, no tricyclic product was formed but the products (332) and (333) were isolated in 15 and 36% yields, respectively. 

In their studies of multisubstituted aromatic compounds, Hansch and co-workers have generally summed ir and a values for individual substituents to obtain estimates of tt and a characterizing the multisubstituted derivative (10). Although tr and o- constants for ortho substituents may not be well represented by the corresponding values for para substituents, let us assume that tt(2-C1) = 7r(4-Cl) and o-(2-Cl) = o-(4-Cl) for our predictive calculation. For the disubstituted TFMS derivatives, we obtain from Table IV (in the absence of surfactant) ... 

Multisubstituted five-membered aromatic heterocycles are synthesized via this cascade protocol (equation 34). The cycloadditions of a-acyloxyketones 78a with lithium ynolates afford /3-lactone lithium enolates 79a, which spontaneously cyclize to give bicyclic compounds 80a. These intermediates, which are stable enough to be isolated, are treated with TsOH under heating to provide substituted furans 81a via decarboxylation and dehydration. Thiophenes (e.g. 81b) are also synthesized by the analogous scheme via intermediate 80b using a-acylthioketones (78b) as a substrate. In the synthesis of pyrroles using a-acylaminoketones as a substrate, the cyclization proceeded at —20 °C, and the -lactone was subsequently ring-opened via /3-elimination to furnish pyrroles in one-pot (equation 35). ... 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

Fluorine-activated aromatic nucleophilic substitutions are highly useful for the syntheses of functionalized and multisubstituted aromatic compounds via both inter- and... 

The only compound in this series to have been formed by synthesis of the pyrazine ring is the multisubstituted derivative 36, formed from the appropriate diaminopyrrole and diacetyl. Oxidation of this compound with chromium trioxide in acetic acid gave 2,3-dimethyl-5,6-dibenzoylpyrazine. 

Reduction of a multisubstituted aromatic compound is functional group selective, where selectivity is based on the reduction potentials. For example, the aldehyde group is reduced in p-cyanobenzaldehyde and p-acetobenzal-dehyde, whereas cyano and aceto groups are not. The nitro group, however, is reduced more readily than the aldehyde group when p-nitrobenzaldehyde is employed as a substrate [23]. The reduction efficiency for an aliphatic aldehyde is much less than that for an aromatic one because of the difference in reduction potentials. 

Claisen reported the first preparation of a pyridine derivative from an enaminone in 1897 with the synthesis of diethyl 2,6-dimethyl-3,5-pyridinedicarboxylate 390 from ethyl 3-aminocrotonate 388 and ethyl ethoxymethyleneacetoacetate 389, Scheme 108 (1897LA1). Since then this method has been applied to the preparation of many multisubstituted pyridines a few examples are presented in Table IV. ,)8-Unsaturated carbonyl compounds are also excellent substrates for this type of reaction some examples are shown in Table IV (entries 5, 6, and 8). 

Design syntheses that use the influence of substituents to generate the correct isomers of multisubstituted aromatic compounds. 

As follows from Fig. 4-1 and Fig. 4-2, the separation characteristics of graphitized thermal carbon black are unique. Graphitized carbon blacks are useful for analyzing cis-trans double bond isomers and positional isomers of multisubstituted aromatic (homo- and hetero-nuclear) compounds. Many examples of the separations are given in [36]. 

The particular interest under this heading lies in current studies of sulphuranes, both as synthetic objectives and as reaction intermediates. While the numerous papers dealing with compounds that are multisubstituted at Se and Te atoms are summarized only briefly in this section, the growing interest in Se and Te analogues of reactions of organosulphur compounds will depend more and more on this work. 

Cyclopropanation. Pd(PhCN)2Cl2 may also efficiently catalyze the cyclopropanation reaction of alkenes, dienes, or allenes with diazo compounds forming multisubstituted cyclopropanes (eqs 128-133) or alkylidenecyclopropanes(eqs 134 and 135). ... 

The AgNOs-mediated debromination of benzylic dibromides in hot aqueous ethanol affords benzaldehydes in high yields. However, poor to moderate yields of ketones are obtained from the corresponding gem-dibromides.Silver nitrate is used as the HI scavenger in the synthesis of multisubstituted pyrroles from the condensation of a-iodoketones, primary amines, and -dicarbonyl compounds under high-speed vibration milling conditions. ... 

C-C bond-formation afforded ketimines in good yields (Scheme 49). Subsequent treatment of ketimines with dia-rylalkynes in the presence of catalytic amoxmt of Pd-catalyst, afforded the multisubstituted isoquinolines via the annulation reaction. Notably, multisubstituted isoquinolines constitute a vital class of biologically active compounds including berberine, palmatine, and papaverine. 

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