N-Amino Groups

A-Amino groups are replaced by hydrogen on treatment with nitrous acid (e.g. 729— 730) (80AHC(27)24l) or phosphorus trichloride (1,2,4-triazole-4-acylimines are converted into triazoles (74AHC(17)213)). A-Alkylaminoazoles form stable AT-nitroso compounds, normally existing as a mixture of E- and Z-rotamers (98T9677). 

Reactivity of Five-membered Rings with Two or More Heteroatoms 

Oxidation of 1-aminobenzimidazoles with manganese dioxide or lead tetraacetate can give either 1,1 -azobenzimidazoles (735) or 3-substituted benzo-l,2,4-triazines (736). Electrochemical measurements have shown that the first step in this reaction is removal of an electron from a ir-orbital of benzimidazole rather than from the A-amino group. Because the cation radical which is formed must be stabilized by loss of a proton, for (736) to form the 2-substituent must contain an NH or OH group. This is unnecessary for the formation of the azo product (735) which may form via a nitrene intermediate. 

Oxidation of 1,2-diaminobenzimidazole, leading to the formation in high yield of 3-aminobenzo-1,2,4-triazine (739), is thought to proceed through recyclization of an intermediate C-nitrene (737) 

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The pathway for the degradation of metribuzin that has been used as a herbicide has been established, and attention has been directed to the occurrence of the metabolites in leachate from agricultural soil in Denmark. Although the parent metribuzin was not found, the metabolites produced by loss of the N-amino group and the thiomethyl groups were produced and contributed to ground-water contamination (Kjaer et al. 2005). 

Hydrazination of 4-aryl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine (66) also affords a rearranged product, 4-amino-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (81JHC953). This replacement of the A-aryl group by the N-amino group requires the intermediacy of the ring-opened compound 67. This intermediate could be isolated under mild conditions and its structure was proven by an independent synthesis. From this structure it can be concluded unequivocally that the ring transformation involves initial addition of the hydrazine at C-5 and not at C-3 (Scheme III.37). 

Heterobactin A and B (30) are produced by Rhodococcus erythropolis (59). They are based on the sequence Om-Gly-cOHOm. The N -amino group of Om is substituted by a DHB group. In heterobactin B, the a-amino group of Om is free (R = H) in heterobactin A, R is probably a 2-hydroxybenzoxazolyl-carbonyl group. 

Rhodobactin (31) was isolated from Rhodococcus rhodochrous (86). A sequence of four Om units derivatized in different ways is linked together. The nitrogen atoms of the N-terminal Om are substituted with DHB groups, the N-terminal Om is followed by two Om moieties, for which the N -amino groups are transformed into urea units (NH2CONH-), and the C-terminus is cOHOm. The stereochemistry of the Orn units was not determined. Rhodobactin forms a 1 1 Fe /Lig complex. Iron uptake was studied with Fe ". ... 

Thermobifida fusca, belonging to the Actinomycetales, produces three closely related siderophores, namely, the fuscachelins (92). Fuscachelin B starts with the sequence DHB - Arg-Gly-Gly-Ser, which is bound to the hydroxylated N -amino group of Om. Its N -amino group (the carboxyl group is free) is bound to the C-terminus of the sequence Gly-Gly-Arg-DHB (32). Fuscachelin A is considered to be the genuine metabolite, with B and C degradation products. 

Amino acid 1 with n-amino group protected by Fmoc group... 

Cyclization of an N-amino group with an a-methyl substituent in 7V-aminoazinium salts or in N-aminoazoles is the most frequently used route to pyrazolo-fused systems (92AHC(53)85). Thus, (V-amino-imidazolium and -thiazolium salts (23 Z = NR, S) on heating with anhydrides in the presence of a base, are cyclized to give (25 Z = NR, S). The acyl group in (25) results from acylation of the initially formed pyrazoloazole (24). 

Amino substituents also behave normally with electrophiles, being acylated and converted to benzylidene derivatives. N-Amino groups have also been converted to benzylidene derivatives and are removed on treatment with AT-nitrosodiphenylamine (79JHC249). 

The direct a-amination of aldehydes by azodicarboxylates as the electrophilic nitrogen source can be catalyzed by, for example i-proline 3a, to give the a-hydrazino aldehydes 4 having (R -configuration in moderate to good yields and with excellent enantioselectivities (89-97% ee) (Scheme 2.27) [4]. The optically active a-hydrazino aldehydes 4 are prone to racemization, and it was found beneficial to reduce them directly with NaBFU to stereochemical stable compounds which, by treatment with NaOH, can cyclize to form the N-amino oxazolidinones 5 in a one-pot process. The N-amino group in 5 could be cleaved with Zn/acetone to give the oxazolidinone 6 (Scheme 2.27). 

The de novo discovery synthesis of capecitabine (1) was reported by the Nippon Roche Research Center scientists9,19 and was followed up with a preparation invented by a team at the Hoffinann-La Roche laboratories in New Jersey for the conversion to 1 from 5 -DFCR (10).2° In the first route, 5-fluorocytosine (15) was mono-silated using one equivalent of hexamethyldisilazane in toluene at 100 °C followed by stannic chloride-catalyzed glycosidation with known 5-deoxy-l,2,3-tri-0-acetyl-p-D-ribofuranoside (17) in ice-cooled methylene chloride. While this procedure provided the 2, 3 -di-0-acetyl 5-fluorocytidine 18 in 76% yield on a 25-g scale, an alternative method was also devised using in situ-generated trimethylsilyl iodide in acetonitrile at 0°C to provide a 49% yield of 18 on smaller scale. Acylation of the N -amino group of the bis-protected 5 -DFCR derivative was accomplished by the slow addition of two equivalents of -pentyl chloroformate to a solution of 18 in a mixture of pyridine and methylene chloride at -20 °C, followed by a quench with methanol at room temperature to provide the penultimate intermediate 19 on 800-g scale. The yield of intermediate 19 was assumed to be quantitative and was subjected to the final deprotection step, with only a trituration to... 

In an early work, neurotensin was derivatized with histidine either through an amide bond to the carboxylic acid to produce a bidentate NN chelator or through alkylation at the N -amino group under retention of the tripodal coordinating feature [ 107]. Labelling of neurotensin comprising the tripodal his-... 

N-Amino groups have little -interaction with the imidazole ring, and only small inductive effects are apparent when the pAa values are examined. By contrast, the hetero ring has a strong base-weakening effect on an exocyclic amino group. Protonation of 1-aminobenzimidazole, for example, occurs at N(3), the basicity of which is reduced by the amino substituent (p/v, — 4.95 ). As an NH-acid, 1-aminobenzimidazole has a pAa of 28.4 (DMSO, 20 C) (cf. pAa = 30.7 for aniline). 

N-Amino groups can be alkylated and acylated by way of their anions, and they take part in the usual reactions with carbonyl compounds, with carbodiimides, and in aza-Wittig reactions. 1-Aminobenzimidazoles and their quaternary salts react similarly, and the Schiff bases formed can lead to cyclized products. 

Proteins and peptides are amino acid polymers in which the individual amino acids, called residues, are linked together by amide bonds, or peptide bonds. i n amino group from one residue forms an amide bond with the carboxyl of a second residue, the amino group of the second forms an amide bond with Ihc carboxyl of a third, and so on. For example, alanylscrine is the dipeptidc that... 

Since silk fibroin of cultured silkworms contains relatively large amount of achiral glycine residue, silk fibroin cS wild lkworms with a h er content of chiral alanine residue was examined as the carrier of palladium and optical yields of S<+) 14.4% and R-(+) 32.1% were obtained in reaaions (1) and (2), re ctively (3). l n amino groups of silk fibroin of cultured silk worm were acetylated and used as the carrier, the optical yield in reaction (2) was R-(+) 65,9%. 

Modifications of other proteins by ascorbate have been reported on the N -amino group of lysine to produce NS-(carboxymethyl)lysine which has a mass of 58amu (Dunn et al., 1990 Ortwerth et al., 1992). The mass of the difference peptide was determined using LC-MS (see Fig. 4 and Table I). The lower panel shows the spectrum of the modified peptide with a mass of 1055,2amu and the upper panel shows the spectrum of the P-globin N-terminal peptide with a mass of 983.5amu to produce a difference of 71.7amu. 

With a-di ketones 1- and 2-amino- and 1,2- and 1,5-diaminoimidazoles condense to give fused-ring heterocycles, with initial attack at the C-amino function. An N-amino group can be removed by treatment with nitrous acid. Oxidation of quaternary salts of 1-aminoimidazoles gives azoimidazolium salts, while manganese dioxide converts 1,2-di-aminoimidazoles into triazoles and triazines (see Section IV,D). 

Since the Fmoc procedure uses a base for protection of the N-amino group, acid-labile compounds are used to protect the side chains. Side chain protecting compounds generally use a t-butyl moiety such as t-butyl ethers for Ser, Thr, and Tyr t-butyl esters for Asp and Glu and the t-BOC group for His and Lys, respectively. Also, the trityl group is used to protect Cys, Asn, and Gin the 4-methoxy 2,3,6,-trimethylbenzenesulphonyl or the 2,2,5,7,8,-pentamethylChroman-6-sulfonyl... 

Cyclizations from N-Amino Group on Ring Atom. 183... 

An interesting feature of this reaction is that the N-amino group does not take part in the cyclization. This is also observed in other cases. Thus, cyanogenbromide and 4-amino-3-(o-aminophenyl)-5-triazoles (216) give the condensed 7V-aminotriazoles (217), whereas the reaction of 216 with orz/io-esters proceeds with participation of both amino groups and results in triazepine 218 (73TL1643). 

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