Electrophilic reactions derivatives

Reactions of the Aromatic Ring. The aromatic ring of hydroxybenzaldehydes participates in several typical aromatic electrophilic reactions. Ha.logena.tlon, Chlorination and bromination yield mono- and dihalo derivatives, depending on reaction conditions. Bromination of / -hydroxy-benzaldehyde in chloroform yields 65—75% of the product shown (39). 

Other Electrophilic Reactants. ReversibHity of the electrophilic reactions enables substituted dye derivatives to be obtained. Thus, the halogenation of cyanines, oxonoles, and merocyanines has been studied (3,65,66). Halogen atoms are mobHe in the polymethine chain, and the derivatives themselves can function as halogenation reagents. 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

All of the above mentioned examples of vinyl cation intermediates have involved electrophilic additions to triple bonds or allenes or participation in solvolyses of such multiple bonds. In a sense, these reactions derive from analogies in normal... 

The synthetic utility of the mercuration reaction derives from subsequent transformations of the arylmercury compounds. As indicated in Section 7.3.3, these compounds are only weakly nucleophilic, but the carbon-mercury bond is reactive to various electrophiles. They are particularly useful for synthesis of nitroso compounds. The nitroso group can be introduced by reaction with nitrosyl chloride73 or nitrosonium tetrafluoroborate74 as the electrophile. Arylmercury compounds are also useful in certain palladium-catalyzed reactions, as discussed in Section 8.2. 

The discovery of carbene and carbenoid additions to olefins was the major breakthrough that initiated the tapping of this structural resource for synthetic purposes. Even so, designed applications of cyclopropane chemistry in total syntheses remain limited. Most revolve around electrophilic type reactions such as acid induced ring opening or solvolysis of cyclopropyl carbinyl alcohol derivatives. One notable application apart from these electrophilic reactions is the excellent synthesis of allenes from dibromocyclopropanes 2). 

As the last point in Sect. IV, we discuss briefly the reactions of chiral sulfur compounds with electrophilic reagents. In contrast to nucleophilic substitution reactions, the number of known electrophilic reactions at sulfur is very small and practically limited to chiral tricoordinate sulfur compounds that on reacting with electrophilic reagents produce more stable tetracoordinate derivatives. It is generally assumed that the electrophilic attack is directed on the lone electron pair on sulfur and that the reaction is accompanied by retention of configuration. As typical examples of electrophilic reactions at tricoordinate sulfur, we mention oxidation, imination, alkylation, and halogenation. All these reactions were touched on in the section dealing with the synthesis of chiral tetracoordinate sulfur compounds. 

Fig. 2.20. Reaction of heteroatom-substituted carbene complexes with nucleophilic and electrophilic tin derivatives.

In a similar manner, A-Cbz-a-Lys-OMe reacted with an electrophilic cyclopropane derivative, and a mixture of diastereomeric y-lactams was isolated. The reaction is postulated to proceed by an attack of the amino group on the methylene group with subsequent cyclization (Scheme 4) (85JOC3631). 

As discussed in Section 4.10.6.1, due to low electron density at the carbon atoms, electrophilic reactions such as acylation, sulfonation, and nitration do not occur readily. In the presence of an amino group at C(2), the 5-bromo derivative can be prepared <84CHEC-I(4)545>. 

For example, the fluorination with [ F]F2 of diazepam, a 1,4-benzodiazepine (Scheme 18), gives the 3-fluoro derivative in up to 60% radiochemical yield [100]. The mechanism proposed is the electrophilic reaction of [ F]F2 with the enol form of the amide (stabilised by conjugation) yielding, after fluorine attachment and reformation of the carbonyl group, the a-fluoroketo derivative. 

Dithiin and 1,3-Dithiane Derivatives Thermal and Photochemical Reactions Reactions with Electrophiles Reactions with Nucleophiles... 

The reaction of 3,6-di-/ftt-butyl-l,4-dihydropyrrolo[3,2-. ]pyrrole 58 with chlorosulfonyl isocyanate (CSI) giving 59 was investigated (Scheme 1) <1996H(43)2361>. The higher reactivity for electrophilic reaction demonstrated the remarkably electron excessive nature of the system when compared with indole and pyrrole derivatives. 

General Order of Rate Constants. The rate constants of electrophilic reactions of aromatic ligands and their metal complexes fall in the order fo, > kML > kffL. The difference between these rate constants becomes greater as the activity of the attacking reagent decreases. When L is a phenolate, HL is the phenol when L is an amine, HL is the corresponding ammonium derivative. The possible synthetic applications of this sequence can be appreciated from the fact that 8-hydroxyquinoline is usually sulfonated with 15 to 30% oleum, while its copper (II) complex can be readily sulfonated in 70% sulfuric add (5). 

The electrophilic reaction of magnesium cyclopropylidene (113) with Ai-lithioaryl-amines was reported (equation 31) . Thus, electrophilic reaction of magnesium cyclopropylidene (113) derived from 112 with iV-lithio iV-methyl p-anisidine resulted in the formation of a-amino-substituted cyclopropylmagnesium (119) in good yield. Methanol-ysis of the reaction mixture with CH3OD gave a-deuteriated Af-cyclopropyl-Af-methyl-p-anisidine (120) in 82% yield with 98% D-content. 

The electrophilic reaction of magnesium alkylidene carbenoids with other nucleophiles than the original Grignard reagent can also be carried out. For example, treatment of magnesium alkylidene carbenoid 157, derived from 147, with a-sulfonyl lithium carbanion afforded allenes 159 in moderated yields (equation 39/. ... 

The equimolar mixture of bromine trifluoride and bromine can be employed for the bro-mofluorination of fluorine-free alkcncs such as (Z)- and( )-l,2-dichloroethene, methyl acrylate and its a-substituted derivatives.1 The reactions are carried out in l,l,2-trichoro-l,2,2-tri-fluoroethane (CFC-113) using a 25-35 % excess of bromine trifluoridc/ bromine. The direction of the bromine monofluoride" addition to multiple bonds in the esters, much as in other electrophilic reactions, depends on the electronic nature of the substituent R. 

The positional reactivity of dibenzofuran in electrophilic substitution reactions depends on the electrophile. Reaction occurs mostly at the 2- and 3-positions but the ratio of the two products varies (91JOC4671). The reaction of cyanogen bromide catalyzed by aluminum chloride gives an 80% yield of the 2-substituted product together with 15% of the 3-cyano-derivative (92ACS312). Oxidative acetoxylation of dibenzofuran occurs predominantly at the 3-position ( 60%) together with attack at the 1-position ( 30%) (92ACS802). In this latter reaction, the attack by acetate is on the dibenzofuranium radical cation. 

The partial rate factors af and /3f for the a- and /3-positions of thiophene have been calculated for a wide range of electrophilic reactions these have been tabulated (71 AHC(13)235, 72IJS(C)(7)6l). Some side-chain reactions in which resonance-stabilized car-benium ions are formed in the transition states have also been included in this study. A correspondence between solvolytic reactivity and reactivity in electrophilic aromatic substitution is expected because of the similar electron-deficiency developed in the aromatic system in the two types of reactions. The plot of log a or log /3f against the p-values of the respective reaction determined for benzene derivatives, under the same reaction conditions, has shown a linear relationship. Only two major deviations are observed mercuration and protodemercuration. This is understandable since the mechanism of these two reactions might differ in the thiophene series from the benzene case. 

Only a few electrophilic reactions of selenolopyridines have been reported. In deuteriodeprotonation of selenolo[3,2-6]pyridine the 3-position is the preferred site of attack (78JCS(P2)86l>. In selenolo[3,2-6]pyridine and thieno[3,2-6]pyridine the C-2/C-3 reactivity ratio is ca. 10-3 whereas for furo[3,2-6]pyridine a value of ca. 10-5 has been determined. Logarithmic partial rate factors (Figure 13) show that seleno o[3,2-6 ]pyridine is the most reactive compound. As in the case of (9) and (261), the deuteriodeprotonation of (426) takes place on the protonated species. Both se enolo[2,3-6]- and [3,2-6]pyridine (423, 426) on treatment with potassium nitrate and concentrated sulfuric acid give yield the corresponding 3-nitro derivatives in 50% yield (10 °C, 3 h). 

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