Hydroxycarboxamide

Aldol derivative synthesis Kitagawa and Taguchi group have shown a rearrangement of a-alkoxycarboxamides 41 which proceeds with a high level of retention at the migrating center to give optically active /3-hydroxycarboxamides 42 (equation 22). ... 

The A-hydroxycarboxamide group is a key fragment of many siderophores so that a convenient synthesis of this group is crucial for further progress. A variety of methods have been attempted for the preparation of hydroxamic acids starting from carboxylic acids. Although some of these methods are quite efficient for the preparation of substituted hydroxamic acids, the preparation of the parent compound is still a problem and yields are often moderately unacceptable, in part due to the low solubility of the parent hydroxylamine hydrochloride in organic solvents. 

The cyclizations of /3-hydroxycarboxamides with aldehydes, ketones, or their equivalents results in l,3-oxazin-4-one derivatives <1996CPB734, 2006BMC584, 2006BMC1978>. In the acid-catalyzed condensation of salicylamide 422 with (—)-menthone, a 2 1 mixture of C-2-epimeric 27/-l,3-benzoxazin-4(37r)-ones 202 and 423 was formed, the equilibrium of which could be shifted toward the (23 )-enantiomer 202 by base-catalyzed isomerization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in A -methyl-2-pyrrolidone (NMP) to yield a 14 1 mixture of 202 and 423 (Equation 44) <1996TL3129>. 

Passerini, M., Formation of a-hydroxycarboxamides on treatment of an isonitrile with a carboxylic acid and an aldehyde or ketone, Gazz. Chim. Ital, 1921, 51, 126. 

A cyclic hydroxamic acid is formed when an amino-(iV-hydroxycarboxamide) is heated with an acylating agent such as an anhydride or acid chloride [2399]. 

Synthesis of a-hydroxycarboxamides by add catalyzed reaction of an isocyanide with an aldehyde or ketone (see 1st edition)... 

Aqueous inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and, preferentially, sulfuric acid, as well as some Lewis acids, e.g. boron trifluoride etherate and titanium tetrachloride, catalyze the a-addition of the isocyanides, yielding the a-hydroxycarboxamides (24) in 12-88% The catalysis of this reaction by acids is due to an enhancement of the electrophilic reactivity of the carbonyl compound (4). 

A great variety of carbonyl compounds has been used in this reaction in order to produce the respective a-hydroxycarboxamides, but to the best of our knowledge, formaldehyde had never been reported in the literature as the carbonyl component in the synthesis of (24). We wondered whether or not formaldehyde displays any abnormal behavior in the preparation of (24), but we noticed that in dilute sulfuric acid paraformaldehyde reacted with isocyanides to form (24 R, = H R = Bu, Oct , c-Hex and 0-CIC6H4)... 

When Lumma synthesized a series of a-hydroxycarboxamides (6) as intermediates for analogs of isoproterenol, he observed the formation of (27), an unusual reaction of 2-pyridinecarbaldehyde (25) with (26) in the presence of hydrochloric acid. 

The TiCU-mediated synthesis of (24) from (4) and (5) by Seebach et alP proceeds particularly well, as has been demonstrated by many examples yields of up to 98% are encountered. This variant of the a-hydroxycarboxamide synthesis proceeds via an a-adduct (28) of TiCU and presumably a species (29) with pentacoordinated Ti. 

The Passerini reaction and the formation of a-hydroxycarboxamides (24) may compete with the Ugi reaction. When carboxylic acids (3) and carbonyl compounds (4) with electron-withdrawing groups are subjected to 4CC in nonpolar solvents such as dichloromethane, the Passerini reaction may compete strongly. Also, with bulky components the Passerini reaction becomes a serious side reaction of the Ugi reaction. ... 

Kinetic resolution. Various situations that dynamic kinetic resolution applies are reviewed. Resolution by enantioselective benzoylation of 2-benzoylamino-l,3-propanediols is accomphshed in the presence of the CuCl2-complex of ligand lA. Selective esterification catalyzed by 2 is for dynamical kinetic resolution of hemiaminals and aminals, whereas tosylation of a-hydroxycarboxamides proceeds well under the influence of Cu(OTf)2 -... 

P-Hydroxycarboxamides. Selective amidation of 3-hydroxyalkanoic acids is easily performed via formation and aminolysis of 2,2-bis(trifluoromethyl)-l,3-dioxan-4-ones/ The heterocycles are obtained from condensation of the hydroxy acids with hexafluoroacetone in the presence of iV,iV -diisopropylcarbodiimide. 

Aldehydes and isonitriles undergo hydrative condensation. Depending on the hydro-philicity of the isonitriles, either a-hydroxycarboxamides or a-acyloxycarboxamides are formed. 

DMFCl has been used to prepare carboxylic esters (eq 3), fV-hydroxycarboxamides and 0,A-dimethylcarboxamides, and a-hydroxycarboxamides (eq 4), via a one pot process. 

The resulting a-hydroxycarboxamides have been interestingly employed as intermediate for the synthesis of more complex scaffolds, hi fact, as in Ugi reaction (Chapter 7), the combination of these MCRs with a further transformation has gained much attention in the last years for the preparation of structurally diverse complex molecules. Many... 

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