Pyridines 4-amino-, hindered

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

Many synthetic applications of Rh-catalyzed hydrogenation of a-dehydroamino acid derivatives have recently been explored (Scheme 26.2). Takahashi has reported a one-pot sequential enantioseiective hydrogenation utilizing a BINAP-Rh and a BINAP-Ru catalyst to synthesize 4-amino-3-hydroxy-5-phenylpentanoic acids in over 95% ee. The process involves a first step in which the dehydroami-no acid unit is hydrogenated with the BINAP-Rh catalyst, followed by hydrogenation of the / -keto ester unit with the BINAP-Ru catalyst [87]. A hindered pyridine substituted a-dehydroamino acid derivative has been hydrogenated by a... 

Di-/m-butyl-4-methy I pyridine (3) is hindered, allows coupling of Fmoc-amino-acid fluorides with weak nucleophiles (see Section 7.12) and is best for minimizing the enantiomerizaton of Fmoc-Cys(tBu)-F (see Section 8.1) during its reaction with the hydroxyl group of a linker-resin. 

More stable iV-acylpyridinium salts can be formed by using 4-(Ar,Ar-dialkyl-amino)pyridines. The salts are less readily hydrolyzed and are effective in the acylation of sterically hindered alcohols (72S619) and in the formation of iV-f-butoxycarbonyl derivatives of a-amino acids in aqueous alkali, for use in peptide synthesis (71CC267). 

The product is 2-amino-5-nitropyridine because substitution occurs preferentially at the sterically less hindered position para to NH,. The conditions are milder than those for nitration of pyridine, because NH is activating. 

These two compounds are superior to pyridine as catalysts for acylation of alcohols, particularly for tertiary and sterically hindered alcohols. Even axial lljS-hydroxyl groups of steroids can be acetylated in yields as high as 80%. Several useful C-acylations have been reported. The reagents catalyze the transformation of amino acids into or-acylamino ketones (equation II). They are superior to pyridine for reaction of isocyanates and carboxylic acids to form amides (equation III). 

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

Pyrazolo[l,5-a]pyridines can be prepared by cycloaddition of pyridinium A -imides (produced by iV-deprotonation of iV-amino-pyridinium salts with base ) with alkynes or A -amination of 2-alkynyl-pyridines. The cycloaddition of 3-benzyloxypyridinium AT-imide involves preferentially the more hindered C-2. ... 

Oxyamination of olefins. This reagent reacts with a variety of olefins to give, after reductive cleavage of intermediate osmate esters, cis-vicinal amino alcohols in fair to high yield. The reaction is regiospecific in that the new C—N bond is formed at the least substituted carbon atom of the olefin. The reagent reacts more rapidly with monosubstituted olefins than with di- and trisubstituted olefins. Diols are obtained as the main products from hindered olefins. Methylene chloride or THF can be used as solvents, but pyridine is the solvent of choice. 

N(3)-Hydroxytriazolo[4,5-b]pyridine plOl, HOAt], as its uronium or phosphonium salts, demonstrated superior performance in solid state peptide synthesis as compared to N-hydroxybenzotriazole [102, HOBt]. This feature enhances the automated synthesis of peptides containing hindered amino acids or hindered amines [94CC201]. 

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