Electrophilic aromatic synthesis

Sometimes the orientation of two substituents m an aromatic compound precludes Its straightforward synthesis m Chloroethylbenzene for example has two ortho para directing groups m a meta relationship and so can t be prepared either from chloroben zene or ethylbenzene In cases such as this we couple electrophilic aromatic substitution with functional group manipulation to produce the desired compound... 

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution reaction. 

Arenes, on complexdQon with Cr, Fe, Mn, and so forth, acquire strongly electrophilic character, such complexes m reactions with nucleophiles behave as electrophilic tutroarenes. Synthesis of aromatic tutnles via the temporary complexanon of rutroarenes to the catiotuc cyclopentadienyhron moiety, cyarude addition, and oxidative demetalation v/ith DDQ has been reported fEq. 9.43 ... 

The general approaches for the synthesis of poly(arylene ether)s include electrophilic aromatic substitution, nucleophilic aromatic substitution, and metal-catalyzed coupling reactions. Poly(arylene ether sulfone)s and poly(arylene ether ketone)s have quite similar structures and properties, and the synthesis approaches are quite similar in many respects. However, most of the poly(arylene ether sul-fone)s are amorphous while some of the poly(arylene ether)s are semicrystalline, which requires different reaction conditions and approaches to the synthesis of these two polymer families in many cases. In the following sections, the methods for the synthesis of these two families will be reviewed. 

Figure 7.6 Mechanism of novolac synthesis via electrophilic aromatic substitution.

A combination of 2,3 sigmatropic rearrangement (Pummerer-type reaction) followed by an electrophilic aromatic substitution of the intermediate sulfenium ion, the formation of an iminium ion and, finally, a second electrophilic aromatic substitution, was used by Daich and coworkers for the synthesis of iso-indolo-isoquinolinones as 4-314 (Scheme 4.68) [106]. Thus, reaction of the two diastereo-meric sulfoxides 4-313, easily obtainable from 4-312 by a Grignard reaction and oxidation, led to 4-314 as a single product after crystallization in 42% yield. 

In 2011, Hartwig and coworkers reported the total synthesis of taiwaniaquinol B (55, Scheme 11.9), a member of a family of diterpenoids that are derived from the abietane skeleton [36]. A key aspect of the Hartwig synthesis of taiwaniaquinol B was the use of the iridium-catalyzed borylation reaction to accomplish the C(5) functionalization of resorcinol derivative 53. This regioselectivity for the overall bromination is complementary to that which would be obtained using a standard electrophilic aromatic substitution (EAS) reaction. In the transformation of 53 to 54, a sterically controlled borylation was first accomplished, which was then followed by treatment of the boronic ester intermediate with cupric bromide to... 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

An interesting example of a triple electrophilic aromatic substitution between an oxonium ion, generated from a trisubstituted dihydrofuran, and phloroglucinol was exploited for the total synthesis of the C3-symmetric xyloketal A, as depicted in the scheme below C06OL1427 06JOC1620>. 

The synthesis of 3-aryltetrahydroisoquinolines was accomplished by electrophilic aromatic substitution of polysubstituted phenols and phenyl ethers with Lewis acid-generated tosyliminium ions of 2-tosyl-3-methoxytetrahydroisoquinoline derivatives <00SL801>. In addition isoquinoline was reported to react with N-tosylated (R)- or (S)-amino acid fluorides to afford optically active dihydroimidazoisoquinolinones. The reaction proceeds via acylation followed by attack of the tosylamino group at Cl of the intermediate 2-tosylaminoacylisoquinolinium salt <00TL5479>. 

Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids using this method is limited due to the moderate yields for the oxidative cyclization [88,90]. In this respect, the molybdenum-mediated oxidative coupling of an arylamine and cyclohexene 2a represents a complementary method. The construction of the carbazole framework is achieved by consecutive molybdenum-mediated C-C and C-N bond formation. The cationic molybdenum complex, required for the electrophilic aromatic substitution, is easily prepared (Scheme 23). 

The most common way to modify aromatic polymers for application as a PEM is to employ electrophilic aromatic sulfonation. Aromatic polymers are easily sulfonated using concentrated sulfuric acid, fuming sulfuric acid, chlorosulfonic acid, or sulfur trioxide (or complexs thereof). Postmodification reactions are usually restricted due to their lack of precise control over the degree and location of functionalization, the possibility of side reactions, or degradation of the polymer backbone. Regardless, this area of PEM synthesis has received much attention and may be the source of emerging products such as sulfonated Victrex poly (ether ether ketone). 

An interesting variation of this quinoxaline synthesis is outlined by the synthesis of sydnoquinoxalines shown in Scheme 103. The starting material is phenylsydnone 288 with an iminophosphorane group in an o-position. With isocyanate or isothiocyanate carbodiimide intermediates 289 are formed by an electrophilic aromatic substitution at the sydnone ring (4 position), the 4-(arylamino)sydno[3,4-a]quinoxalines (290) are obtained (91S745). 

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

C-H activation at a primary benzylic site was the key step in very short syntheses of lig-nans 206 and 207 (Scheme 14.27) [138]. Even though both the substrate 203 and the vinyl-diazoacetate 204 contain very electron-rich aromatic rings, C-H activation to form 205 (43% yield and 91% ee) is still possible because the aromatic rings are sterically protected from electrophilic aromatic substitution by the carbenoid. Reduction of the ester in (S)-205 followed by global deprotection of the silyl ethers completes a highly efficient three-step asymmetric total synthesis of (-i-)-imperanene 206. Treatment of (R)-205 in a more elaborate synthetic sequence of a cascade Prins reaction/electrophilic substitution/lacto-nization results in the total synthesis of a related lignan, (-)-a-conidendrin 207. 

The synthesis of DDT is a good example of an electrophilic aromatic substitution. The chloral is protonated and attacks the aromatic ring to generate a carbocation. Loss of a proton regenerates the aromatic ring. 

Aromatic donble bonds may also be nsed effectively to trap the electrophilic intermediate (electrophilic aromatic snbstitntion). The Beckmann rearrangement-cyclization seqnence has fonnd ntihty in the synthesis of the isoquinoline nucleus . ... 

Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C-C and C-N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). 

Electrophilic aromatic substitution of the arylamine 780a using the iron-complex salt 602 afforded the iron-complex 785. Oxidative cyclization of complex 785 in toluene at room temperature with very active manganese dioxide afforded carbazomycin A (260) in 25% yield, along with the tricarbonyliron-complexed 4b,8a-dihydro-3H-carbazol-3-one (786) (17% yield). The quinone imine 786 was also converted to carbazomycin A (260) by a sequence of demetalation and O-methylation (Scheme 5.86). The synthesis via the iron-mediated arylamine cyclization provides carbazomycin A (260) in two steps and 21% overall yield based on 602 (607-609) (Scheme 5.86). 

The construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (614). Reaction of the iron complex salt 602 with the fully functionalized arylamine 814 in air provided the tricarbonyliron-coordinated 4b,8a-dihydrocarbazole complex 819 via sequential C-C and C-N bond formation. This one-pot annulation is the result of an electrophilic aromatic substitution and a subsequent iron-mediated oxidative cyclization by air as the oxidizing agent. The aromatization with concomitant demetalation of complex 819 using NBS under basic reaction conditions, led to the carbazole. Using the same reagent under acidic reaction conditions the carbazole was... 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

An equally important general type of synthesis which proceeds via heterocyclization with formation of a ring bond y to the heteroatom involves acid-catalyzed intramolecular electrophilic aromatic substitution, especially those in which a carbonyl group functions as the electrophile. The most common structural requirements are summarized in (18)-(2l) ... 

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