Diborane amides

Synthesis by high-dilution techniques requires slow admixture of reagents ( 8-24 hrs) or very large volumes of solvents 100 1/mmol). Fast reactions can also be carried out in suitable flow cells (J.L. Dye, 1973). High dilution conditions have been used in the dilactam formation from l,8-diamino-3,6-dioxaoctane and 3,6-dioxaoctanedioyl dichloride in benzene. The amide groups were reduced with lithium aluminum hydride, and a second cyclization with the same dichloride was then carried out. The new bicyclic compound was reduced with diborane. This ligand envelops metal ions completely and is therefore called a cryptand (B. Dietrich, 1969). 

Bell and Hall have incorporated an organometallic unit into a crown by using the ferrocenyl unit as part of the ring or as a third strand. The unit is incorporated either as the 1,1 -diformylferrocene or the corresponding acid. In the former case, the bis-imine is prepared and reduced to give the saturated crown (see structure 24). In the latter case, the acid is converted into its corresponding chloride and thence into the diamide by reaction with a diamine. Diborane reduction affords the saturated amino-crown. Structure 24 could be prepared by either of these methods but the dialdehyde approach was reported to be poor compared to the amide approach which afforded the product in ca. 60% yield . 

Condensation of adipic acid derivative 17 with phenylethylamine in the presence of carbo-nyldiimidazole affords the bis-adipic acid amide 18. The synthesis is completed by reduction of the carbonyl groups with diborane followed by demethylation of the aromatic methoxy groups with hydrogen bromide the afford dopexamine (19) [3]. 

Mit komplexen Hydriden konnen auch Alkohole und Amine erhalten werden, vor-teilhafter ist das selektivere Diboran. Komplexe Borhydride reduzieren Carbonsaure-amide nur in einigen Fallen. 

Bei der Reduktion mit Diboran verbrauchen unsubstituierte Carbonsaure-amide sie-ben, monosubstituierte sechs und disubstituierte ftinf Hydrid-Aquivalente. Die gegeniiber den komplexen Metallhydriden mehr verbrauchten Hydrid-Aquivalente werden vom Amin-Stickstoff-Atom als Amin-Boran (R3N BH3, s. S. 7ff.) gebunden. Man fiihrt die Reaktion in siedendem THF oder in Bis-[2-methoxy-athyl]-ather durch. Mono- und disubstituierte Carbonsaure-amide werden in einer Stunde, unsubstituierte aliphatische in zwei, aromatische in acht Stunden reduziert1. 

Auch Aluminiumhydrid reduziert Carbonsaure-amide ohne Nebenreaktionen zu Aminen. Es kann vorteilhaft zur selektiven Reduktion ungesattigter Verbindungen an-gewendet werden, da es im Gegensatz zu Diboran C,C-Mehrfachbindungen unter den iib-lichen Reaktionsbedingungen nicht angreift. 

Lithiumalanat reduziert l-Alkyl-indolyl-(3)-glyoxylsaure-amide nur zu den 3-(2-Amino-1-hydroxy-athyl)-1- alkyl-in dolen (vgl. a. S. 241), wahrend mit Diboran die vollige Reduktion der Seitenkette moglich ist. Allerdings werden meist Gemische gebildet z. B.5 ... 

Diborane also reduces amides to amines (see Section 5.3.1.2). 

Diborane permits the selective reduction of amides in the presence of ester and nitro groups. 

Diborane is also a useful reagent for reducing amides. Tertiary and secondary amides are easily reduced, but primary amides react only slowly.59 The electrophilicity of diborane is involved in the reduction of amides. The boron coordinates at the carbonyl oxygen,... 

Amides require vigorous reaction conditions for reduction by LiAlH4 so that little selectivity can be achieved with this reagent. Diborane, however, permits the reduction of amides in the presence of ester and nitro groups. 

Cobalt hydrocarbonyl, diborane, and aluminum hydrides add, I think, to all of these carbonyl compounds. Of course, there is the well known Grignard reagent and the alkyllithium additions to carbonyl compounds. Aluminum alkyls add, and we could have listed all the other alkali metal alkyls. Recent work has shown that the tin alkoxides add readily to all these derivatives, and similarly, a tin amide adds to most of these carbonyl compounds. 

There are several reports of methods that will selectively reduce a tertiary amide in the presence of a secondary amide[59]. The secondary lactam of 101 was protected as the lactim ether 107 and treated with diborane however, the spectral characteristics of the major products isolated were consistent with reduction of both the tertiary amide and the lactim ether. In 1991 Martin et al. [60] successfully used alane to reduce a tertiary amide in the presence of an oxindole (secondary amide) relying on the known rate difference for reduction between these two groups [61]. 

To avoid the production of diastereomers during reductive alkylation of Pro residues, the corresponding dipeptide should be first synthesized and the central amide bond subsequently selectively reduced with diborane (see Section 10.7.1.2.1). 

Direct reduction of a peptide bond with diborane 59 or a thioamide bond with several reductive procedures 60 is an alternative route for the production of a reduced peptide bond in a peptide. In some cases the reductive amination does not give satisfactory results. As described earlier, preparation of Boc-Pher )[CH2N]Pro-OH by reductive amination yields two diastereomers (Scheme ll). 57 In this case treatment of Boc-Phe-Pro-OBzl by diborane yielded the reduced pseudodipeptide Boc-Pher )[CH2N]Pro-OBzl without epimerization (Scheme 12). However, in some cases diborane is not entirely selective for the amide bond and can reduce ester functions when they are present. Another procedure is to prepare endothiopeptides directly from protected dipeptides 61-66 followed by their selective reduction. 60 ... 

When 2//-chromene-3-carboxamide (208) is treated with LAH, the amide and the pyran double bond are reduced (68BRP1043857). The ester group of the chromene (209) is similarly reduced by diborane during hydroboration (73SC231). 

Reduction of esters, nitriles, and amides. These groups are rapidly reduced by horanc-dimcthyl sulfide in refluxing THF (b.p. 67°) if the dimethyl sulfide (b.p. 38°) is removed as liberated. Under these conditions, the reagent is comparable to uncomplexed diborane. Reduction of secondary and tertiary amides is best effected in the presence of boron trifluoride etherate otherwise, excess reagent is utilized for formation of complexes with the products. 

The bicyclization step is accomplished under identical conditions to the first macrocyclization step, the base being in this case added triethylamine. The reduction of the bicyclic amide 6 has to be realized with diborane (LiAlH4 cleaves the macrobicyclic system). Note that there is no need to isolate the intermediate aminoborane 7 the crude mixture obtained after... 

Redaction of amides to amines, Primary, secondary, and especially tertiary amides are reduced by diborane to the corresponding amines rapidly and almost quantitatively. The reaction is carried out at 25° in the case of tertiary amines, and at reflux for primary and secondary amines. The method is not suitable for unsaturated... 

Sodium cyanoborohydride (10) produces mainly 1,4-dihydropyridines (11) in the reduction of 3,5-di-cyano- and 3,5-diethoxycarbonyl-pyridines, diborane produces more of the 1,2-isomer. With NBH, mixtures of 1,2- and 1,4-dihydro adducts are produced, the latter predominating when carried out in pyridine solution. Nicotinamide (13) in ethanol can be reduced to (8) in moderate yield at 140 C in diglyme the tetrahydropyridine (8) was isolated in admixture with the piperidine (14), presumably via dehydration of the amide. 3-Nitropyridine affords 3-nitropiperidine in moderate yield when reduced in ethanol. The carboxylic acid and halo derivatives of pyridine are generally not reactive toward NBH. 

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