SEAr reactions

Discovered over a century ago, electrophilic mercuration is probably the oldest known C-H bond-activation reaction with a metal compound. The earliest examples of aromatic mercuration were reported by Volhard (mercuration of thiophene) [1], Pesci (mercuration of aromatic amines) [2], and Dimroth [3], who was the first to mercurate benzene and toluene, generalize the reaction, and assign the correct structures to the products originally observed by Pesci. Since the work of Dimroth electrophilic aromatic metalation reactions with compounds of other metals, for example Tl(III), Pb(IV), Sn(IV), Pt(IV), Au(III), Rh(III), and Pd(II), have been discovered [4], In this chapter, we will focus on intermolecular SEAr reactions involving main-group metal electrophiles and resulting in the formation of isolable metal aryls which find numerous important applications in synthesis [5], Well-known electrophilic cyclometalation reactions, for example cyclopalla-dation can be found in other chapters of this book and will not be reviewed here. 

The mechanisms of the Gattermann and Gattermann-Koch formylation belong to the category of electrophilic aromatic substitution (SEAr) but are not known in detail, since they have a tendency to vary from one substrate to another, and the reaction conditions may also play a role. When carbon monoxide is used, the electrophilic species is believed to be the formyl cation, which is attacked by the aromatic ring to form a -complex. This -complex is then converted to the aromatic aldehyde upon losing a proton. When HCN is used, the initial product after the SEAr reaction is an imine hydrochloride, which is subsequently hydrolyzed to the product aldehyde. 

Abstract Azines, diazines or thiazole (V-oxides are highly reactive substrates in palladium-catalyzed direct arylation reaction. For these reactions, the results are inconsistent with an SEAr reaction pathway and may best fit with a concerted metalation-deprotonation-like (CMD) mechanism. 

There are few general methods for the direct functionalization of quinazolines and quinazolinones because of their deactivated nature. TTierefore, these compounds are more commonly constructed from acyclic precursors. For those examples that do exist, SeAr reactions generally take place on the benzene ring, while nucleophilic substitution reactions generally occur on the diazine ring and are selective for the C4 position due to the electropositive nature of this position. Reactions can take place at the C2 position, but generally only if the C4 position is already occupied. 

Numerous classical isoquinoline syntheses utilize intramolecular SeAr reactions for the construction of the hetero ring. Among them are the Bischler-Napiehaiski synthesis, the Pictet-Gams and Pictet-Spengler syntheses, and the Pomeranz-Fritsch synthesis. 

Electrophilic substitutions of acridine often result in disubstitution at the 2- and 7-positions (e.g., nitration giving 3), whereas at phenanthridine, SeAr reactions occur at different positions (e.g., nitration mainly at the 1- and 10-position yielding 4 and 5) ... 

In the case of a diketone (e.g., 3-tosyloxypentane-2,4-dione), the formation of 5-acetyl-4-methyl-2-aryl-l,3-thiazole derivatives can be realized in very good yields (86-89%) (Scheme 7). All these experiments where performed in a Sears Kenmore unmodified household microwave oven (990 W) equipped with a turntable. The average bulk temperature was estimated by inserting a thermometer in the alumina bath housing the reaction vessel. 

The reaction is believed to begin with the metalation of the substrate via aromatic electrophilic substitution (SEAr) followed by CO insertion and nucleophilic displacement by water or another protic nucleophile such as tri-fluoroacetic acid (TFFA) to give, respectively, the aromatic carboxylic acid or its mixed anhydride derivative, from which the acid is freed by hydrolysis (Scheme 24). 

Chiral selenenylating reagents have been developed and shown to be capable of effecting enantiselective additions and cyclizations. For example the reagent show below (SeAr ) achieves >90% enantioselectivity in typical reactions.79... 

In some instances, especially with the oxygen and sulfur heterocycles, the overall reaction leading to a substituted product does not involve an SEAr mechanism but proceeds by an addition followed by elimination sequence, as outlined for the bromination of coumarin in equation (4). The choice of experimental conditions can affect the outcome of the reaction, as illustrated in the formation of (114) and (115) in Section 3.2.1.4.7. 

Aromatic mercuration (Scheme 1), the oldest SEAr metalation reaction known, has been the subject of several reviews and monographs [7-11]. 

Let us go back to radical brominations (cf. Section. 1.7.3). The bromination of alkyl aromatics takes place completely regioselectively only the benzylic position is bromi-nated. The intermediates are the most stable radicals that are available from alkyl aromatics, namely, benzylic radicals. Refluxing orf/zo-xylene reacts with 2 equiv. of bromine to give one monosubstitution per benzylic position. The same transformation occurs when the reactants are irradiated at room temperature in a 1 2 ratio (Figure 1.22, right). The rule of thumb SSS applies to the reaction conditions that afford these benzylic substitutions chemoselectively. SSS stands for searing heat + sunlight —> side chain substitution. ... 

On the other hand Price and Sears [107] studied the reactions of nitryl chloride with various aromatic compounds in the presence of aluminium chloride, and found that phenol, anisole and naphthalene tended to undergo oxidative degradation. In the case of naphthalene they obtained a 31% yield of a- nitronaphthalene, whereas with anisole and phenol they were able to isolate only traces of nitro compounds without any evidence of chlorination. 

These re sear ches, which are due to iiichael, show that in all probability the reactions between iiiany 0(, -dibromides and sodium malonic ester should be interpreted as follows the dibromide first loses hydro-bromic acid under the influence of the alkaline reagent (sodium alcoholate,as the reaction is usually carried out in the presence of dlcohol)>an oi-brom unsatuxated compound is thus formed which reacts with the L.alonlc ester in the manner outline above for... 

Sears, P. G., Wolford, R. K., and Dawson, L. R. (1956). Conductances of some acids, bromides, and picrates in dimethylformamide at 25°C. J. Electrochem. Soc. 103, 633-636. Senesi, N. (1981). Free radicals in electron donor-acceptor reactions between a soil humic acid and photosynthesis inhibitor herbicides. Z. Pflanzenernahr Dung. Bodenkd. 144, 580-586. Senesi, N., Chen, Y., and Schnitzer, M. (1977a). Hyperfine splitting in electron spin resonance spectra of fulvic acid. Soil Biol. Biochem. 9, 371-372. 

Shown in Fig. 9.9 are water-composition ranges for some humid-climate streams (in New Jersey), a dilute, freshwater lake (Lake Huron) and lake-bottom muds from the Great Lakes (Sutherland 1970), and deep-soil moisture from Pennsylvania (Sears 1976 Sears and Langmuir 1982). Lake Huron and the Delaware River are dilute, humid-climate waters. They both plot near the kaolinite-gibbsite boundary. Their composition can be described as water dominated. In other words, their chemistries are controlled chiefly by dilution with fresh rainfall and runoff, not by reactions with geological materials. In a study of acid rain (water-dominated) control of soil moisture and ground-water chemistry of a sandy aquifer in Denmark, Hansen and Postma (1995) found that pore waters were close to equilibrium with gibbsite and supersaturated with kaolinite (Fig. 9.9). Precipitation pH = 4.34 at the site, and log([K+]/lH+]) = -0.95. 

The first part of this chapter deals with the effects of high pressure on cycloaddition reactions, particularly the Diels-Alder reaction, which is the most important cycloaddition reaction. The second part will illustrate applications of pressure to nucleophilic substitutions, condensations and other reactions (miscellaneous reactions), such as Mannich, Heck, ene, SeAr, Wittig, Horner-Wadsworth Emmons and multicomponent Strecker reactions. 

An indication that non-SEAr-type reactivity could be at play has emerged from cyclizations. In these reactions, the effect of a wfa-substituent on regioselectivity was evaluated and, in the majority of cases, reaction was observed at the more sterically accessible para-position (Scheme 5) [67]. In contrast, an inversion in selectivity was found to occur when a fluorine substituent was present, leading to preferential orlho-diiect arylation. 

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