Trifluoroacetic acid-mediated

The preparation of purine derivatives substituted at the C-2 position via amine displacement of a halogen is known as a difficult reaction step requiring several days of reaction time. However, Al-Obeidi and coworkers have recently prepared 2,6,9-trisubstituted purines on soUd-phase by employing a synthetic route in which the critical step was performed with microwave irradiation (Fig. 37) [62]. PS resin-bound 2-iodosubstituted purine was treated with diethanolamine or propanolamine in NMP with microwave irradiation at 200 °C for 30 min. Trifluoroacetic acid-mediated cleavage resulted in the 2-amino substituted purines in 45-59% yields and 77-89% purities. 

Scheme 6.234 Trifluoroacetic acid-mediated Pictet-Spengler reactions.

The resin-bound perfluoroalkylsulfonyl linker is compatible with many common solid-phase reactions, such as tin dichloride-mediated aromatic nitro group reduction, trifluoroacetic acid-mediated tBoc deprotection, reductive amination reactions, acylation, and sulfonation. It is possible to perform several sequential synthetic reactions on the nonflate resin so that multistep syntheses can be carried out. The solid-phase approach provides an operationally simple, inexpensive, and general protocol for the cleavage... 

Trifluoroacetic acid-mediated cyclization of an co-guanidino a-ketoacid affords a good yield of the 1,3-diazocine (9) <83LA1623> however, this route is far from general, as the analogous derivative bearing an N—H in place of the N—Me group cyclized instead to diazabicyclic products (Scheme 9). 

Scheme 2.60) (Luo and De Brabander 2015). These adducts 329 were transformed into chiral 3-suhstituted 3,4-dihydroquinoxalin-2(l//)-ones 330 (Scheme 2.61) upon trifluoroacetic acid-mediated Boc deprotection/in situ cyclodehydration. Importantiy, the entire two-step procedure occurs without racemization, even with racemization-prone arylglycine substrates. This approach uniquely avoids potential symmetry-related limitations in the substrate scope compared to previous approaches to enantiomerically pure 3-aryl-3,4-dihydroquinoxalin-2(lfl)-ones that emanate from symmetrical dianilines. 

The Meerwein-Ponndorf-Verley (MPV) reduction is generally mediated by aluminum triiso-propoxide, Al(01Pr)3. In MPV reduction, reversible hydride transfer occurs via a six-membered transition state (Scheme 67). By removing acetone from the reaction system, the reversible reaction proceeds smoothly. The advantages of the reduction are the mildness of the reaction conditions, chemoselectivity, safety, operational simplicity, and its applicability to large-scale synthesis. It is reported that the addition of trifluoroacetic acid, significantly accelerates the reduction (Scheme 68) 304,305 in which case a catalytic amount of Al(0 Pr)3 is enough to complete the reaction. 

Combs and coworkers have presented a study on the solid-phase synthesis of oxa-zolidinone antimicrobials by microwave-mediated Suzuki coupling [38], A valuable oxazolidinone scaffold was coupled to Bal resin (PS-PEG resin with a 4-formyl-3,5-dimethoxyphenoxy linker) to afford the corresponding resin-bound secondary amine (Scheme 7.18). After subsequent acylation, the resulting intermediate was transformed to the corresponding biaryl compound by microwave-assisted Suzuki coupling. Cleavage with trifluoroacetic acid/dichloromethane yielded the desired target structures. 

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

The same group reported a palladium-mediated oxidation of methane to a methanol derivative employing a CuCl2 and Pd/C-based catalyst system and dioxygen in a trifluoroacetic acid/water mixture.18 A system was also described, which mediated the oxidation of ethane (Equation (10)). 

The next residues were attached successively by dicyclohexylcarbodiimide-mediated coupling of Boc-amino acids with the free amino groups. The use of excess Boc-amino acid eliminated the need for capping after coupling. The last Boc-group and the benzyl-based side chain and carboxy-terminal protectors were removed at the end of the synthesis by acidolysis with hydrogen bromide in trifluoroacetic acid the latter was used instead of acetic acid to avoid acetylation of hydroxymethyl side chains (see Section 6.6). Catalytic hydrogenolysis of the peptide removed the nitro... 

An unusual [1,3]-rearrangement of aryl 2-halocyclohexenylmethyl ethers promoted by trifluoroacetic acid has been observed. Products due to a Claisen rearrangement were not formed and the proposed pathway for the process is outlined in Scheme 7. It has been shown that AICI3-mediated decomposition of A-phenoxybenzamide... 

A rapid synthesis of cyclodepsipeptides containing sugar moieties was reported by Zhu and coworkers (Scheme 20) [88]. A three-component reaction of a sugar amino acid derivative 20a, an aldehyde b, and a dipeptide isocyanide c, followed by saponification and trifluoroacetic acid-promoted macrocyclization was employed to afford the cyclic amino sugar cyclopeptides d. This approach allows to systematically modify the amino acids and the carbohydrate residue, as well as the size of the macrocycle. Again, the only reagents used to mediate the formation of the... 

Pinacol rearrangement driven by the release of the ring strain of a cyclobutane ring has been employed in an extremely efficient manner to form cyclopentanone derivatives. Experimentally. the Lewis acid mediated aldol condensation of benzaldehyde with l,2-bis(trimethyl-siloxy)cyclobutcne at —78 C gave the pinacol 1 in its silylated form.35,36 Subsequent treatment of this pinacol with trifluoroacetic acid at room temperature afforded 2-phenyl-cyclopentane-l,3-dione (2) in 97% yield.35,36... 

Many continuous processes are used to prepare early pharmaceutical intermediates, but Pfizer recently presented a continuous process to prepare the API itself. A continuous process to prepare the anti-inflammatory drug celecoxib was described (Scheme 11.3) [6]. The batch process for celecoxib consists of two steps (1) a base-mediated Claisen reaction between 4-methylacetophenone and ethyl trifluoroacetate, and (2) an acid-mediated pyrazole condensation between enolate intermediate 8 and hydrazine 9 giving celecoxib (Scheme 11.4) [7]. Continuously flowing the Claisen reaction step 1 into the pyrazole condensation step 2 offers the advantages of directly telescoping continuous processing steps, as described in the introduction to this chapter. 

Palladium-mediated addition of silyl stannane reagents to alkynyl ethers has been employed for the synthesis of aliphatic acyl silanes in very good yields via the intermediate a-alkoxy-/J-stannyl vinyl silanes (enol ethers of acyl silanes)82. In a second palladium-catalysed step, the vinyl stannane moiety could be coupled to suitable halides before hydrolysis to the acyl silanes with trifluoroacetic acid (Scheme 11). 

Ethyl enol ethers of acyl silanes have been prepared by the palladium-mediated addition of silyl stannanes to alkynyl ethers. Hydrolysis using trifluoroacetic acid gave very high yields of acyl silanes (vide supra, Section m.A.4)82. 

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