Heterocyclic substrates, reactivity

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

Since the classic papers by Ingold and his co-workers,110, 111 nitration has for a long time been considered as the standard electrophilic substitution. Many orientation and relative rate data on the nitration of both carbocyclic and heterocyclic substrates have been accumulated and the results have been generalized as valid for all electrophilic substitutions. As a matter of fact, this popularity is partially undeserved nitration is a complicated reaction, which can occur by a multiplicity of parallel mechanisms.112 In particular, in the case of the very reactive substrates that five-membered heterocycles are, two complications may make meaningless both kinetic measurements and competitive experiments.113 (i) Due to the great reactivity of both partners the encounter limiting rate may be achieved in this case, of course, all the substrates react at the same rate and the effect of structure on the reactivity cannot be studied. (ii) Nitrous acid, always present in traces, may exert an anticatalytic effect in some cases and a markedly catalytic effect in others with a very reactive substrate, nitration may proceed essentially via nitrosa-tion, followed by oxidation. For these reasons, the nitration data must be handled with much caution. 

The analogous six-membered heterocyclic substrates also exhibit a complex behavior. Aminomethylation of the uracils 71 occurs on the N atom in position 3, although the reaction with formaldehyde alone shows an equilibrium constant for hydroxyme-thylation in position 1 which is about twice as much as the value obtained for the reaction at position 3. By contrast, in barbituric acid derivatives 72 (X = O), po.sition 5 is the most reactive when unsubstituted. Otherwi.se, the reaction is directed toward the 1 or the 3 position. " When present, the imine NH group (72, X = NH) is the last moiety to undergo attack. 

Remarkable enantiocontrol was obtained using N heterocyclic substrates such as protected indole 34 and pyrazole 38, showing the potential of this method in the synthesis of biologically active chiral amines. Another striking element of this catalyst is its reactivity toward alkene substrates. While rhodium tetracarboxylate catalysts tend to promote both C H insertion and aziridination, the Rh2(S nap)4 (32) is particularly selective for C H insertion, cis Olefins were well tolerated, providing the aminated product in good yield and enantioselectivity (39, 41). However, the use of trans isomers resulted in reduced yield and selectivity (e.g., 40). 

Complex 15 illustrates the importance of incorporating an N, 0-chelate of sufficient steric bulk on an electrophilic metal center to achieve overall improved reactivity. While these room temperature transformations are promising, this complex is not thermally robust and thus displays limited substrate scope. In particular, heating to promote reactivity with unstrained internal alkenes or challenging N-heterocyclic substrates results in no appreciable product formation and catalyst decomposition, as noted by NMR spectroscopy. 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

When more than one reactive position is available in a heterocyclic substrate, as is often the case for pyridines for example, there are potential problems with regioselectivity or/and disubstitution (since the product of the first substitution is often as reactive as the starting material). Regioselectivity is dependent to a certain extent on the nature of the attacking radical and the solvent, but may be difficult to control satisfactorily. ... 

Heteroarene Functionalization Innate Functionalization of Simple Systems. Zinc isopropylsulfinate can functionalize heteroarenes in one step under oxidizing conditions (using TBHP) to add steric hulk and lipophilicity where desired. Since the innate reactivity of the heterocyclic substrate dictates the regiochemistry of the product, the regioselectivity is good for some substrates (eq 2) but is poor for others (eq 3). Furthermore, the isopropyl substituent can serve as an activating group for pyridine substrates, and therefore polysubstitution can occur. ... 

Six-membered heterocycles with two heteroatoms are prepared by reaction of diketene with a substrate containing a C—O or C—N multiple bond. With carbonyl compounds diketene reacts in the presence of acids to give l,3-dioxin-4-ones. The best known is 2,2,6-trimethyl-4H-l,3-dioxin-4-one [5394-63-8] (15), the so-called diketene—acetone adduct, often used as a diketene replacement that is safer to handle and to transport, albeit somewhat less reactive than diketene itself (103,104), forming acetylketene upon heating. 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

Our previous treatment (76AHCS1, p. 12) contained a section called Chemical Methods to Study Tautomerism where the relationship between tautomerism and reactivity was discussed. Today, nobody uses chemical methods to study tautomerism. However, a great many reactions are carried out on tautomeric heterocycles, although few papers contain new insights on that topic. Authors desiring to explain reactivity results based on tautomerism must take great care to verify that the substrate is in the neutral form AH and not as a conjugated anion A or cation HAH, which are usually devoid of tautomerism. They must also realize that most frequently the reaction path from tautomers to products in-... 

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