Arylation of Ammonia

Copper source Ligand Base Reaction conditions Yield (%) ReT. 

Arylation and Vinylation of N-Heteroqrdes 9.2.2.1 Coupling of Aryl Halides and N-Heterocydes 

A stoichiometric quantity of 1,10-phenanthroline (L13) was the first ligand used for copper-catalyzed arylation of imidazole with aryl iodides (Table 9.4, entry 1) [18]. As an ejctension of this methodology, Cu2O/4,7-dimethoxy-l,10-phenanthroline (LI4) was found to be more effective, the coupling reaction occur-ing at 80-110 °C in the presence of CS2CO3 and using n-PrCN as a solvent (entry 2 ) [19, 20]. 

Entry Copper source Ligand N-heterocycle Reaction conditions Ref. 

Taillefer and coworkers found that Salox (L7) and Chxn-Py-Al (L16) were efficient ligands for the Cu20-catalyzed N-arylation of pyrazoles and imidazoles as well as pyrroles, indoles and triazoles (entry 5) [25, 26). Both aryl iodides and bromides as substrates gave good results. 

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So far no arylation of ammonia has been reported, and it is difficult to prepare aniline derivatives directly by the Pd-catalyzed reaction of aryl halides with ammonia. Aniline derivatives are prepared indirectly by the reaction of ammonia surrogates (ammonia equivalents). The reaction of the ammonia surrogates with aryl halides, followed by deprotection affords aniline derivatives. As one of them, LiN(TMS)2 (61) reacts with aryl bromides and chlorides. P(t-Bu)3 is the best ligand, and the coupled products are converted easily to anilines by treatment with aq. HCl. 

Recently, the arylation of ammonia as the simplest amine was accompHshed by Hartwig [169] (Scheme 3.4). In the same pubhcation, the use of lithium amide for the synthesis of anilines under similar reaction conditions was described this constitutes a user-friendly protocol for small-scale settings, whereas the direct use of ammonia is attractive within an industrial environment Subsequently, Buch-wald also reported the arylation of ammonia using biphenyl-based ligands [170]. 

Kwong and coworkers utilized amino phosphines L47-L48 for the amination of aryl mesylates [29]. The use of air-stable phenyl-bridged PJSl-ligands L49-L56 has been subsequently danon-strated for the arylation of ammonia with aiyl chlorides (Scheme 20.15) [30]. 

Figure 2.4 A cross-section of results for the Buchwald-Hartwig arylation of ammonia with arylchlo-rides developed by Stradlotto and coworkers [28a, b],...

The arylation of ammonia remains one of the most attractive entry points for the synthesis of arylamines. Ammonia is inexpensive and readily available however, it is a gas at room temperature under atmospheric pressure. This significantly increases the operational complexity of its use and requires high-pressure reaction vessels. To address these issues, a range of ammonia alternatives have been used in the synthesis of arylamines. While some were more successful than others, many tended to suffer from an additional complication due to a competing diarylation reaction that led to the formation of diarylamines. A practical solution to the selective synthesis of aniline derivatives was reported by Hartwig... 

Scheme 6 Palladium-Catalyzed N-Arylation of Ammonia Using Josiphos Ligands...

The action of ammonia on N-(5-aryl-l,3-oxathioI-2-ylidene) tertiary iminium salts (7) affords linear intermediates that cyclize to 2-amino-4-phenylthiazoles (Scheme 7) (45). 

The action of ammonia on N-(aryl-i,3-oxathiol-2-ylidine) tertiary im-inium salts (254) yields linear intermediates (255) that cyclize to 2-amino-4-phenyl thiazoles (256) on crystallization from acetic acid (Scheme 129) (730). 

Amines are derivatives of ammonia in which one or more of the hydrogens is replaced with an alkyl, aryl, cycloalkyl, or heterocycHc group. When more than one hydrogen has been replaced, the substituents can either be the same or different. Amines are classified as primary, secondary, or tertiary depending on the number of hydrogens which have been replaced. It is important to note that the designations primary, secondary, and tertiary refer only to the number of substituents and not to the nature of the substituents as in some classes of compounds. 

Reductive amination (Section 22.10) Reaction of ammonia or an amine with an aldehyde or a ketone in the presence of a reducing agent is an effective method for the preparation of primary, secondary, or tertiary amines. The reducing agent may be either hydrogen in the presence of a metal catalyst or sodium cyanoborohy-dride. R, R, and R" may be either alkyl or aryl. 

Heating of an aryl hydrazone 1 in the presence of a catalyst leads to elimination of ammonia and formation of an indole 2. This reaction is known as the Fischer indole synthesisy and is somewhat related to the Benzidine rearrangement. 

Alkyl and aryl nitriles 151 react with thiosemicarbazide 138 under acidic conditions to give 1,3,4-thiadiazoles (Scheme 14 and Table 8) <1995BML1995, 1996IJB273, 1997IJB394>. The acidic conditions promote the elimination of ammonia from the intermediate iminothioacylhydrazine 152. 

Photochemical addition of ammonia and primary amines to aryl olefins (equation 42) can be effected by irradiation in the presence of an electron acceptor such as dicyanoben-zene (DCNB)103-106. The proposed mechanism for the sensitised addition to the stilbene system is shown in Scheme 7. Electron transfer quenching of DCNB by t-S (or vice versa) yields the t-S cation radical (t-S)+ Nucleophilic addition of ammonia or the primary amine to (t-S)+ followed by proton and electron transfer steps yields the adduct and regenerates the electron transfer sensitizer. The reaction is a variation of the electron-transfer sensitized addition of nucleophiles to terminal arylolefins107,108. 

When the reaction with substituted benzaldehydes is conducted in the presence of ammonia, the a-amino carboxylic acids are formed [11], The corresponding reaction involving bromoform is less effective and, for optimum yields, the addition of lithium chloride, which enhances the activity of the carbonyl group, is required. In its absence, the overall yields are halved. The reaction of dichlorocarbene with ketones or aryl aldehydes in the presence of secondary amines produces a-aminoacetamides [12, 13] (see Section 7.6). 

Amines can be considered as derivatives of ammonia, obtained by replacement of one, two or all the three hydrogen atoms by alkyl and/or aryl groups. 

Intermolecular N-C-C transfragment replacement occurs less widely than the N-C-N replacement. A synthesis of alkyl(aryl)pyrimidines has been published that was based on the replacement of the N-C-C fragment of the pyrimidine ring by an identical sequence of atoms derived from a ketone in the presence of ammonia [94H(38)249]. Heating a solution of 3-methyl-5-nitropyrimidin-4(3//)-one (120) in acetonitrile with cyclohexanone and ammonia gas in a sealed tube at 100°C for 3 hours gave tetrahy-... 

The arylation of organyl tellurolates, restricted first to aryl halides activated by electron-withdrawing groups,2 or requiring special conditions such as heating in HMPA in the presence of Cul, or photostimulation in liquid ammonia,ijggjj achieved successfully with non-activated aryl halides under normal conditions. ... 

The double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

As mentioned earlier, the synthesis of primary amides is rather challenging due to technical difficulty in handling gaseous ammonia. Thus, the use of ammonia substitutes such as HMDS and formamide has been studied (see Schemes 21 and 22). With the use of microwave irradiation, however, it has been shown that it is possible to generate both CO and ammonia at the same time for the synthesis of primary amides from aryl bromides. This protocol is very useful for laboratory organic syntheses, especially combinatorial syntheses. As Scheme 29 illustrates, the Pd-catalyzed aminocarbonylation of aryl bromides 200 with formamide (33.5 equiv.) in the presence of KOBu (1.5 equiv.) and imidazole (1 equiv.) with microwave irradiation for 400 s (6.7 min) gave the corresponding benzamides... 

When arylhydrazones of aldehydes or ketones are treated with a catalyst, elimination of ammonia takes place and an indole is formed, in the Fischer indole synthesis.515 Zinc chloride is the catalyst most frequently employed, but dozens of others, including other metal halides, proton and Lewis acids, and certain transition-metals have also been used. Arylhydrazones are easily prepared by the treatment of aldehydes or ketones with phenylhydrazine (6-2) or by aliphatic diazonium coupling (2-7). However, it is not necessary to isolate the arylhy-drazone. The aldehyde or ketone can be treated with a mixture of phenylhydrazine and the catalyst this is now common practice. In order to obtain an indole, the aldehyde or ketone must be of the form RCOCH2R (R = alkyl, aryl, or hydrogen). 

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