Boronate carboxylic acid formation

The reaction is proposed to proceed from the anion (9) of A/-aminocatbonylaspattic acid [923-37-5] to dehydrooranate (11) via the tetrahedral activated complex (10), which is a highly charged, unstable sp carbon species. In order to design a stable transition-state analogue, the carboxylic acid in dihydrooronate (hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) [6202-10-4] was substituted with boronic acid the result is a competitive inhibitor of dibydroorotase witb a iC value of 5 ]lM. Its inhibitory function is supposedly due to tbe formation of tbe charged, but stable, tetrabedral transition-state intermediate (8) at tbe active site of tbe enzyme. 

Although there are several reports in the literature on boron-mediated amide formations, the boron reagents had to be used in stoichiometric amounts.1-4-5-6-7-8-9 Recently, Yamamoto et al. presented the first truly catalytic method allowing for a direct amide formation from free carboxylic acids and amines as the reaction partners.10-1112 Best results were obtained by using phenylboronic acids bearing electron withdrawing substituents in the meta- and/or para-positions such as 3,4,5-trifluorophenylboronic acid or 3,5-bis(trifluoromethyl)boronic acid as the catalysts. 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

TRIFLUOROPHENYL)BORONIC ACID-CATALYZED AMIDE FORMATION FROM CARBOXYLIC ACIDS AND AMINES N-BENZYL-4-PHENYLBUTYRAMIDE [Benzenebutanamide, N-(phenylmethyl)-]... 

TRIFLUOROPHENYL)BORONIC ACID-CATALYZED AMIDE FORMATION FROM CARBOXYLIC ACIDS AND AMINES ... 

Reactions between a representative range of alkyl- and aryl-amines and of aliphatic and aromatic acids showed that the direct formation of amides from primary amines and carboxylic acids without catalyst occurs under relatively low-temperature conditions (Scheme 1). The best result obtained was a 60% yield of N-bcnzyl-4-phenylbutan-amide from benzylamine and 4-phenylbutanoic acid. For all these reactions, an anhydride intermediate was proposed. Boric and boronic acid-based catalysts improved the reaction, especially for the less reactive aromatic acids, and initial results indicated that bifunctional catalysts showed even greater potential. Again, anhydride intermediates were proposed, in these cases mixed anhydrides of carboxylic acids and arylboronic acids, e.g. (I).1... 

The use of a classical anode such as Pt in anodic oxidation usually leads to a partial mineralization of wastewaters containing aromatics due to the formation of final short-chain carboxylic acids, as oxalic acid, that hardly react with OH. Overall mineralization is feasible with a boron-doped diamond (BDD) anode that possesses a much greater 02 overpotential compared to Pt, thus producing a higher amount of... 

Other methods that can be used to prepare thiol esters from carboxylic acids include the use of aryl thiocyanates,12 thiopyridyl chloroformate,13 2-fIuoro- V-methylpyridinium tosylate,14 1-hydroxybenzotriazole, 5 and boron thiolate.16 Direct conversion of 0-esters to 5-esters can also be effected via aluminum and boron reagents.17 However, the applicability of these 1217 and other more recent methods18 to the selective thiol ester formation discussed above has not been clearly defined. 

The rapid reaction between carboxylic acids and borane is related to the electrophilicity of the latter. The carbonyl group of the initially formed acyloxyborane intermediate, which is essentially a mixed anhydride, is activated by the Lewis acidity of the trivalent boron atom. Addition of 1/3 equiv of the Borane-Tetrahydrofuran complex to acrylic acid in dichloromethane followed by addition of a diene at low temperature results in the formation of Diels-Alder adducts in good yield (eq 1). Further, the reaction is successful even with a catalytic amount of borane. 

Until about 1950, reduction of carboxylic acids and their derivatives to aldehydes was not straightforward, and even one of the best methods, the Rosenmund hydrogenation of acid chlorides, required very careful control of both the reaction conditions and preparation of catalyst. The advent of aluminum and boron hydrides and their ready commercial availability transformeKl the situation to such an extent that the formation of aldehydes from carboxylic acids, acid chlorides, esters, amides, nitriles and similar groups in the presence of other reducible functional groups has become a relatively easy operation on both small and large scale. 

Dihydro-1,4-benzothiazines are generally more reactive, and direct N-alkylation has been reported, but this reaction is not always straightforward.21 Funke et al. could not alkylate 2-phenyldihydro-l,4-benzothiazine with co-chloramines, even under forcing conditions.90 However, later work showed that this reaction was possible in toluene solution,37 and other workers have also reported direct alkylations.143 The l,4-benzothiazin-3-ones are, however, more easily alkylated, and reduction of the N-alkyl derivatives of these compounds, usually with lithium aluminum hydride, affords the corresponding N-alkyldihydro-1,4-benzothiazines.52,56 70 90,154 These products can also be prepared in one step from the corresponding 1,4-benzothiazines, e.g., Ill - 112, presumably via intermediate dihydro-1,4-benzothiazines, by sodium borohydride in the presence of a carboxylic acid. Boron derivatives, such as Na[(RCOO)3BH] and Na[(RCOO)4B] are suggested as the species responsible for N—C bond formation.155... 

Heinze proposed a convenient synthetic route starting from ferrocene to give 1-aminofer-rocene-1 -carboxylic acid hydrochloride 45.54 Scheme 12.8 summarizes the reaction sequence. The key synthon in this synthesis is 1-aminoferrocene provided by the Gabriel synthesis from IV-ferrocenylphthalimide. However, this route requires the synthesis of 1-haloferrocene or ferrocene boronic acid as precursors of IV-ferrocenylphthalimide. In addition, the reaction is accompanied by the formation of biferrocenes due to a copper-mediated C—C coupling reaction, even in the presence of excess phthalimide.55,56 57... 

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

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