Nitrogen arylation

In the general preparation of quinolones by forming the nitrogen aryl bond a in the ring closure, typical precursors are prepared as shown in Figure 2. The ring closure involves nucleophilic displacement of a halogen, usually a chlorine or fluorine (76) eg, (29) and (30) lead to (31) [86483-54-7] and (32) [123942-15-4] respectively. 

A 2-phenethyltetrahydroisoquinoline with hydroxyl groups as substituents leads to an ortho, p ra-coupled spiro compound (Table 7, number 17) with alkoxy groups a tetracyclic compound by nitrogen-aryl coupling is obtained (Table 7, number 18). The intramolecular aryl coupling of XLIII has been used in a synthesis of colchicine [171]. 

When an aqueous solution of a diazonium salt is added to an alkaline solution of a phenol, coupling occurs with formation of an azo-compound (p. 188). If ho vc cr the ntiueous solution of the diazonium salt, t. . ., />-bromohenzene diazonium chloride, is mixed with an excess of an aromatic hydrocarbon, and aqueous sodium hydroxide then added to the vigorously stirred mixture, the diazotate which is formed, e.g., BrC,H N OH, dissolves in the hydrocarbon and there undergoes decomposition with the formation of nitrogen and two free radicals. The aryl free radical then reacts with the hydrocarbon to give a... 

Many organolithium compounds may be prepared by the interaction of lithium with an alkyl chloride or bromide or with an aryl bromide in dry ethereal solution In a nitrogen atmosphere ... 

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

Acetylation of 2-phenyl-4-amino-5-benzoylthiazole takes place on the exocyclic nitrogen (49). This exocyclic nitrogen remains the reactive center even with 2-imino-3-aryl-4-amino-5-carboxamido-4-thiazoline (111). Its acetylation with acetic anhydride gives the 4-acetamido derivative (112), which reacts further on heating to yield 2-(acetylimino)-(3H)-3-aryl-5-methylthiazolo[4,5-d]pvrimidin-7-(6H)-one (113) (Scheme 76) (276). 

In 1880, Liebermann and Voltzkow (40), and then Voltzkow (41), condensing chloroacetic acid with both ethyl N-phenylthiocarbamate and p-tolylisothiocyanate obtained homologous compounds to which they attributed formulas 40 and 41, whereas their structure probably derives from that of 38 by substituting an aryl group on the cyclic nitrogen. 

Thiazolium salts can be obtained successfully by a modification of the Hantzsch s thiazole synthesis. This method is particularly valuable for those thiazolium compounds in which the substituent on the ring nitrogen cannot be introduced by direct alkylation, for example, aryl or heteroaryl thiazolium salts (Scheme 42). 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

The groups attached to nitrogen may be any combination of alkyl or aryl groups... 

Arylamines contain two functional groups the amine group and the aromatic ring they are difunctional compounds The reactivity of the amine group is affected by its aryl substituent and the reactivity of the ring is affected by its amine substituent The same electron delocalization that reduces the basicity and the nucleophilicity of an arylamme nitrogen increases the electron density in the aromatic ring and makes arylamines extremely reactive toward electrophilic aromatic substitution... 

Primary arylamines like primary alkylammes form diazonium ion salts on nitro sation Aryl diazonium 10ns are considerably more stable than their alkyl counterparts Whereas alkyl diazonium 10ns decompose under the conditions of their formation aryl diazonium salts are stable enough to be stored m aqueous solution at 0-5°C for a rea sonable time Loss of nitrogen from an aryl diazonium ion generates an unstable aryl cation and is much slower than loss of nitrogen from an alkyl diazonium ion... 

A reaction of aryl diazonium salts that does not involve loss of nitrogen takes place when they react with phenols and arylamines Aryl diazonium ions are relatively weak elec trophiles but have sufficient reactivity to attack strongly activated aromatic rings The reaction is known as azo coupling two aryl groups are joined together by an azo (—N=N—) function... 

Amide (Sections 4 1 and 20 1) Compound of the type RCNR2 Amine (Chapter 22) Molecule in which a nitrogen containing group of the type —NH2 —NHR or —NR2 is attached to an alkyl or aryl group... 

Arylamine (Section 22 1) An amine that has an aryl group at tached to the amine nitrogen... 

Quantum (Section 13 1) The energy associated with a photon Quaternary ammonium salt (Section 22 1) Salt of the type R4N X The positively charged ion contains a nitrogen with a total of four organic substituents (any combination of alkyl and aryl groups)... 

Tertiary amine (Section 22 1) Amine of the type R3N with any combination of three alkyl or aryl substituents on nitrogen Tertiary carbon (Section 2 13) A carbon that is directly at tached to three other carbons... 

Dimethylsulfoxide Acyl and aryl halides, boron compounds, bromomethane, nitrogen dioxide, magnesium perchlorate, periodic acid, silver difluoride, sodium hydride, sulfur trioxide... 

This is the branch-poiat differentiatiag phenylalanine (25, R = H) from tyrosiae (25, R = OH). Both phenylalanine and tyrosiae contain an aryl ring, a three-carbon side chain (a Cg—Cg fragment), and a nitrogen. Decarboxylation yields a two-carbon side chain (a Cg—Cg fragment), eg, 2-phenethylamine (59, R = H) from phenylalanine and tyramine (59, R = OH) from tyrosiae, although it is not certain that ia all cases decarboxylation must precede use ia alkaloid constmction. 

The Balz-Schiemaim reaction is a useful laboratory and industrial method for the preparation of fluoroaromatics. The water-insoluble diazonium fluoroborate is filtered, dried, and thermally decomposed to give the aryl fluoride, nitrogen, and boron trifluoride (28—30). 

The synthesis of a new class of inorganic polymers (21) with a backbone consisting of alternating sulfur(VI) and nitrogen atoms, and with variable alkyl or aryl substituents as well as a fixed oxygen substituent on sulfur, has recentiy been accompHshed (83—85). These polymers are stmcturaHy analogous to poly(alk5l/arylphosphazenes). 

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