Protection amines

Methyl acetoacetate (MAA) and ethyl acetoacetate (EAA) are the most widely used esters they are found ia the pharmaceutical, agricultural, and allied industries. Both esters are used extensively as amine protecting agents ia the manufacture of antibiotics and synthetic sweeteners (Dane Salts) (147). Principal outiets for MAA are the manufacture of the organophosphoms insecticide dia2inon [33341-5] (148,149) and the uracil herbicides bromacil [31440-9] and terbacil [5902-51-2] (150,151) (see Insect conztiol technology Herbicides). 

Fig. 1. Synthesis of C-3 side chain analogues of monobactams, where P is an amine protecting group and other terms are defined in text.

TtM use of vinyl chloroformate tor N-dealkytatlon of tertiary amines, protection of amino groups, protection of hydroxyl groups or formation of Z-ketoimidazoles. Synthesis of vtnyl cartxjnates by means of fluoro or chiorofonnates. 

The first, and still widely used, polymer-supported ester is formed from an amino acid and a chloromethylated copolymer of styrene-divinylbenzene. Originally it was cleaved by basic hydrolysis (2 N NaOH, FtOH, 25°, 1 h). Subsequently, it has been cleaved by hydrogenolysis (H2/Pd-C, DMF, 40°, 60 psi, 24 h, 71% yield), and by HF, which concurrently removes many amine protective groups. Monoesterification of a symmetrical dicarboxylic acid chloride can be effected by reaction with a hydroxymethyl copolymer of styrene-divinylbenzene to give an ester a mono salt of a diacid was converted into a dibenzyl polymer. ... 

The BOC group is used extensively in peptide synthesis for amine protection. It is not hydrolyzed under basic conditions and is inert to many other nucleophilic reagents. 

Derivatization of cyclic urethanes with (B0C)20 makes the urethane carbonyl susceptible to hydrolysis under mild conditions and leaves the amine protected as a BOC derivative."... 

A number of imine derivatives have been prepared as amine protective groups, but few of these have seen extensive use. The most widely used are the benzylidene... 

A primary amine, protected by reaction of the amine with cyclopentadiene and formaldehyde (H2O, rt, 3 h), is cleaved by trapping cyclopentadiene with A -methylmaleimide (H2O, 2.5 h, 23-50°, 61-97% yield), CUSO4 (EtOH or MeOH, 70°, 74-99%), or Bio-Rad AG 50W-X2 acid ion-exchange resin, 82-98% yield. ... 

A number of imine derivatives have been prepared as amine protective groups, but most of these have not seen extensive use. The most widely used are the ben-zylidene and diphenylmethylene derivatives. The less used derivatives are listed, for completeness, with their references at the end of this section. For the most part, they are prepared from the aldehyde and the amine by water removal cleavage is effected by acid hydrolysis. 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

Zanoni MVB, Stradiotto NR (2005) Electrochemical behaviour of aromatic amines protected by nitrobenzenesulfonyl group. Electroanalysis 7(4) 365-369... 

To create the free secondary amine group (N-H) fulleropyrrolidine, an amine-protected starting material can be used in the reaction (Cai et al., 2006). For instance, a trityl-oxazolidinone (using either triphenylmethyl- or better, 4-methoxytriphenylmethyl-protecting groups) can be reacted with C60 to yield the trityl-protected pyrrolidine (Figure 15.5). 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

De Visser PC, van Helden M, Filippov DV, van der Marel GA, Drijfhout JW, van Boom JH, Noort D, Overkleeft HS (2003) A novel, Base-Labile Fluorous Amine Protecting Group Synthesis and Use as a Tag in the Purification of Synthetic Peptides. Tetrahedron Lett 44 9013-9016... 

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