N-protected anilines

A new synthetic route to quinazolines from N-protected anilines 895 is available using hexamethylenetetramine (HMTA) in trifluoroacetic acid and potassium ferricyanide in aqueous ethanolic KOH. The method affords substituted quinazolines 897 with good selectivity <2006T12351>, and although only moderate yields were initially achieved, good yields have now been obtained under microwave-assisted conditions <2007TL3229>. The method has also been used to prepare benzoquinazolines <20060L255>. 

N-Protected anilines can be selectively fluorinated at the para-position by bis(tert-butylcarbonyloxy)-iodobenzene, PhI(OPiv)2 and hydrogen fluoride/pyridine. This convenient procedure provides facile access... 

Likewise, the oxidative dearomatization ofpara-methoxy substituted N-protected anilines 288 using (diace-toxyiodo)benzene in the presence of methanol gives p-quinone monoimide ketals 289 (Scheme 3.120) [358]. If the oxidation of aniline derivatives is performed in the presence of water, the final isolated products are the respective / -benzoquinones or p-benzoquinone monoketals resulting from the hydrolysis of initially formed monoimide ketals 289 [358,359]. 

Larock reported his initial results in this area in 1991, in the reaction of ortho-iodoanilines with internal alkynes [58]. This method provides an efficient route to assembly of the 2,3-disubstituted indole core from anilines and alkynes, both of which are easily generalized. This initial report employed N-protected anilines, however, subsequent research demonstrated that the parent aniline moiety can also participate in this chemistry [59]. 

The N-aryl imines 412 as protected anilines can be prepared by Pd-catalysed arylation of benzophenone imine with aryl halides using DPPF and BINAP as ligands, and aniline derivatives are obtained by deprotection [204a],... 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

Our return to amination chemistry was inspired by the mechanistic studies of the Ullman reaction (Scheme 8). Hartwig had shown that the Cu(I)-phthalimide complex (38) could undergo oxidative addition with aryl halides to form a Cu(lll) intermediate (39), which then reductively eliminated to form a C—N bond (40). We hypothesized that a Cu(III)-phthalimide intermediate (42) could also be created by oxidation of 38 and a subsequent C—H metalation, presumably via a CMD mechanism (Scheme 8). Consequently, we synthesized 38 and reacted it with a series of oxidants and arenes in an attempt to discover a synthesis of protected anilines (e.g., 40) via C-H activation. The initial reactions were performed using stoichiometric amoimts of 38, but we intended to lower the catalyst loading once a lead reaction was discovered. 

One strategy to prepare protected anilines is the reaction of diallylamine with aryl halides using the catalysts best suited for reactions of secondary amines. " The formation of N-aryl benzophenone imines by Pd-catalyzed C—N bond formation is a second strategy that allows for straightforward deprotection to the parent aniline. Benzophenone imine is commercially available. 

Cycloisomerization of o-alkynylanUines 114 into multisubstituted N-protected as well as NH-indoles 115 in the presence of various Cu(II) catalysts was extensively investigated by Hiroya et al. (Scheme 9.44) [200, 201). The authors, demonstrated that, in addition to Cu-catalysts, Ti(IV) and Zn(II) salts could also trigger this cyclization to some extent. Further, it was shown that Cu(OTf)2 catalyst displayed good activities in the case of primary aniline derivatives, whereas Cu(OAc)2 was better suited for secondary aniline derivatives. In both cases, moderate to excellent yields of up-to-trisubstituted indoles 115, bearing a variety of labile functional groups, can be synthesized using this procedure. A cascade cydization-intramolecular C3-alkyl-ation leading to C2-C3 fused indoles was also demonstrated. 

However, when electron-rich aryl halides were used in amidations, by-products arising from the exchange of the phenyl group ofXantPhos (11) with the aryl group of the product were observed [123]. Not only amides and enolizable amides, but also urethanes, urea derivatives, and primary and secondary sulfonamides were successfully arylated. The coupling of carbamic acid tert-butyl ester was reported by Hartwig et a. [46] in 1999 and provided N-Boc-protected anilines in one synthetic step (Scheme 13.74). 

Thus, bromoarenes were converted into the N-Boc-protected anilines in moderate to high yields employing the [Pd(dba)2]/P(tBu)3 (26) catalyst system with 2.5-4mol% loading. 

Keywords Aryl bromides, ferf-butyl carbamate, Pd2(dba)3.CHCl3, ligand 1, BuONa, toluene, room temperature, amidation, N-Boc-protected anilines... 

SCHEME 4 Heteroarmulation through heterogeneous additive-free catalysis from N-tosyl protected anilines. 

The syntheses of these three compounds share a common route as described by Brickner et al. [53] and Barbachyn et al. [54]. Namely, the coupling reaction of 3,4-difluoronitrobenzene (82) with piperazine, morpholine, or thiomorpholine to yield the corresponding 4-substituted 3-fluoro-nitrobenzene (83), which upon reduction gives rise to the aniline derivative (84). Carbobenzoxy protection of the active nitrogen of 84 using benzyloxy-carbonyl chloride (CbzCl) results in the formation of carbamates 85a and 85b. Treatment of 85a,b with n-BuLi and (i -glycidyl butyrate yields a 5-(R)-... 

Conversely, activated methylene compounds undergo an addition reaction across the C=N bond of imines. For example, benzylic ketones react with benzylidene anilines to from P-aminoketones [35], whereas the analogous reaction of diphenyl-methylene-protected a-amino esters, and nitriles, produces a disastereomeric mixture of the A-protected a,p-diamino esters, and nitriles [36, 37]. 

A. N-Sulfinylaniline (Note 1). A solution of 82.5 g. (0.69 mole) of pure thionyl chloride (Note 2) in 100 ml. of anhydrous benzene is added slowly to a solution of 46.5 g. (0.5 mole) of freshly distilled aniline in 250 ml. of anhydrous benzene contained in a 1-1. round-bottomed flask, with swirling and occasional cooling in an ice bath (if necessary). An immediate precipitation of aniline hydrochloride occurs. After the addition of the thionyl chloride solution is complete, the mixture is heated to reflux, protected from moisture, on a heating mantle until a clear solution is obtained (2-5 hours). The solvent and excess thionyl chloride are evaporated under reduced pressure (Note 3)... 

The relative importance of N-substituted arylamines for the construction of biologically significant molecules, particularly pharmaceuticals and agrochemicals, prompted the extension of rhodium-catalyzed allylic amination to aniline nucleophiles (Tab. 10.6) [41, 42]. The N-arylsulfonyl-protected anihnes were again optimal for high selectivity, analogous to that observed with the N-toluenesulfonyl-N-aLkylamines. 

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