Borohydride Reagents Research Articles

AMD070, a CXCR4 Chemokine Receptor Antagonist: Practical Large-Scale Laboratory Synthesis

An efficient and convergent four-step synthetic route to the CXCR4 chemokine receptor antagonist AMD070 (1) has been developed which employs only a single chromatographic step in the entire sequence. Novel reductive amination methods have been developed for the coupling of 2 and 3 in which a dehydrative imine formation is followed by reduction with an attenuated borohydride reagent (zinc chloride and sodium borohydride). Selective extraction methods were employed to purify synthetic intermediates and remove reagents and impurities. A procedure has also been developed to isolate 1 in a pure crystalline form.

Direct Reductive Amination of Aldehydes and Ketones with 2,4-Ionene-Based Borohydride Exchange Resin as a Novel Polymer-Supported Reducing Agent

Direct reductive amination of aldehydes and ketones were accomplished efficiently using high-capacity, ionene-based, polymer-supported borohydride reagent in isopropyl alcohol at reflux under neutral conditions. The reagent is easily prepared by mixing aqueous solution of 2,4-ionene bromide with an alkaline solution of sodium borohydride at room temperature. The generality of reaction was established using both aliphatic and aromatic aldehydes, ketones, and amines.

Synthetic methods : Part (ii) Oxidation and reduction methods

This Report highlights advances in some of the most commonly used oxidation and reduction reactions, focusing on the literature from 2007. Significant advances in oxidation chemistry include enantioselective Ti-catalysed epoxidation of unactivated alkenes (Scheme 1),Fe-catalysed epoxidation of alkenes that uses H2O2 as terminal oxidant (Scheme 2), the first effective and catalytic chiral peracid epoxidation reaction (Scheme 3), and organocatalytic aziridinations (Scheme 4). Significant advances in reduction chemistry include enantioselective hydrogenation of unactivated tetrasubstituted alkenes (Scheme 7), a new practical chiral borohydride reagent (Scheme 8), and conjugate reductions of nitro olefins and vinyl sulfones (Scheme 12).

Ionene-Bound Borohydrides: Efficient, Selective, and Versatile Polymer-Supported Reducing Agents

Reduction of structurally different carbonyl compounds, such as aldehydes, ketones, α,β-unsaturated enals and enones, acid chlorides, and imines was accomplished efficiently using high capacity ionene based borohydride reagents. Aldehydes and imines were reduced to the corresponding alcohols and amines in excellent yields in methanol at ambient temperature while ketones and acid chlorides were reduced in iso-propanol and THF-MeOH at reflux. Chemoselective reduction of aldehydes over ketones was achieved successfully with these reagents. Complete regioselectivity was also observed in the reduction of α,β-unsaturated aldehydes and ketones.

Lithium Amino Borohydrides (LABs)

Lithium amino borohydride reagents (LABs) are a new class of powerful and selective reagents that were first ­introduced by Singaram et al. in 1992. [1a] The reactivity of these reagents is comparable to lithium aluminium ­hydride. However, they have several advantages over ­lithium aluminium hydride, e.g., they are air-stable, non-pyrophoric, thermally stable and hydrolyse only slowly in protic solvents above pH 4. Thus LABs can perform in air virtually all of the transformations for which LAH is commonly used and offer significant advantages in safety, ­selectivity, and ease of handling and simple work-up ­procedures. In short, LAB is an attractive alternative to LAH or super hydride reduction.

Synthesis of Deoxygenated Disaccharide Precursors for Modified Lipid II Synthesis

AbstractThe synthesis of novel deoxygenated disaccharide precursors for modified lipid II synthesis is described. The 3‐ and 4‐deoxy‐GlcNAc donors were obtained, respectively, by radical reduction of the iodo derivative by TBTH/AIBN and hydrogen reduction of the triflate using a borohydride reagent (nBu4NBH4). O‐Glycosylation of the acceptor, promoted by NIS/TMSOTf, led to the 3‐ and 4‐deoxygenated disaccharides. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Electronic Structure of Bis(imino)pyridine Iron Dichloride, Monochloride, and Neutral Ligand Complexes: A Combined Structural, Spectroscopic, and Computational Study

The electronic structure of a family of bis(imino)pyridine iron dihalide, monohalide, and neutral ligand compounds has been investigated by spectroscopic and computational methods. The metrical parameters combined with Mössbauer spectroscopic and magnetic data for ((i)PrPDI)FeCl(2) ((i)PrPDI = 2,6-(2,6-(i)Pr(2)C(6)H(3)N=CMe)(2)C(5)H(3)N) established a high-spin ferrous center ligated by a neutral bis(imino)pyridine ligand. Comparing these data to those for the single electron reduction product, ((i)PrPDI)FeCl, again demonstrated a high-spin ferrous ion, but in this case the S(Fe) = 2 metal center is antiferromagnetically coupled to a ligand-centered radical (S(L) = (1)/(2)), accounting for the experimentally observed S = (3)/(2) ground state. Continued reduction to ((i)PrPDI)FeL(n) (L = N(2), n = 1,2; CO, n = 2; 4-(N,N-dimethylamino)pyridine, n = 1) resulted in a doubly reduced bis(imino)pyridine diradical, preserving the ferrous ion. Both the computational and the experimental data for the N,N-(dimethylamino)pyridine compound demonstrate nearly isoenergetic singlet (S(L) = 0) and triplet (S(L) = 1) forms of the bis(imino)pyridine dianion. In both spin states, the iron is intermediate spin (S(Fe) = 1) ferrous. Experimentally, the compound has a spin singlet ground state (S = 0) due to antiferromagnetic coupling of iron and the ligand triplet state. Mixing of the singlet diradical excited state with the triplet ground state of the ligand via spin-orbit coupling results in temperature-independent paramagnetism and accounts for the large dispersion in (1)H NMR chemical shifts observed for the in-plane protons on the chelate. Overall, these studies establish that reduction of ((i)PrPDI)FeCl(2) with alkali metal or borohydride reagents results in sequential electron transfers to the conjugated pi-system of the ligand rather than to the metal center.

The Synthetic Versatility of Acyloxyborohydrides

Acyloxyborohydrides are unsurpassed in their versatility as reagents in organic synthesis. In addition to their superior ability in effecting reductive amination of aldehydes and ketones, acyloxyborohydrides can reduce nitrogen heterocycles (indoles, quinolines, isoquinolines), imines, enamines, oximes, amides, nitriles, benzylic alcohols, aryl ketones, aldehydes (but not ketones), acetals, β-hydroxy ketones, and other substrates. The ability to control chemoselectivity, regioselectivity, and stereoselectivity by adjusting the carboxylic acid, borohydride reagent, stoichiometry, and temperature has no parallel in the repertoire of the organic chemist.

Direct Access to Marine Pyrrole-2-aminoimidazoles, Oroidin, and Derivatives, via New Acyl-1,2-dihydropyridin Intermediates

[reaction: see text] A short synthesis of the C(11)N(5) oroidin derivatives is reported. The key step of the strategy is a one-pot oxidative bromine-mediated addition of protected guanidines to the N-acyl-1,2-dihydropyridines 9a-c. The new N-acyl-1,2-dihydropyridines were prepared directly from pyridine and pyrrole-2-carbonyl chloride by reduction with borohydride reagent in one step.

Facile Syntheses of Quater-, Penta-, and Sexipyrroles

alpha,alpha-Linked oligopyrroles are attractive precursors for both expanded porphyrin and conducting polymer chemistry. We demonstrate facile methods for synthesizing quater-, penta-, and sexipyrroles from more readily available bi- and terpyrrole intermediates. These products demonstrate stability in their brightly colored oxidized forms, while reduction using borohydride reagents gives the corresponding all-pyrrole oligomers, which oxidize readily in air. The oxidized quater- and sexipyrroles were characterized by single-crystal X-ray diffraction analysis.

Chemoselective and Stereoselective Reductions with Modified Borohydride Reagents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Application of microgels as polymer supports for organic synthesis: preparation of a small phthalide library, a scavenger, and a borohydride reagent.

Microgel polymers containing a series of functional groups have been prepared. These microgels were composed of cross-linked poly(styrene) and were prepared by radical polymerization in solution. The microgel polymers exhibit good solubility in an array of different organic solvents, and in addition, they can be efficiently precipitated by the addition of methanol and isolated by filtration. A nine-member phthalide library was synthesized using an aminomethyl-functionalized microgel 5. To further demonstrate the versatility of these microgel polymers, tris(2-aminoethyl)amino microgel 11 was examined as a scavenger reagent to remove unreacted isocyanate after a urea synthesis. Finally, a microgel-supported ammonium borohydride reagent 14 was successfully prepared and used as a reducing agent. Notable features of these microgels are that in all applications the progress of the reaction could be monitored by standard NMR techniques and their preparation is performed using common glassware and techniques found in all organic laboratories.

Some aspects of NaBH4 reduction in NMP

In our solvent optimization study of NaBH4 reduction, NMP was found to enhance the reactivity. A chemoselective debromination of the bromide and sulfonates can be attained in the new borohydride reagent system: NaBH4-LiOTf-NMP. This mixed system worked as an alternative to NaBH3CN and Bu3SnH for the SN2 type displacement of alkylbromide and sulfonate. Also mentioned is an expedient reduction of an azide group into amine by NaBH4 in NMP without any additive, which offers a convenient protocol for the direct transformation of halides into amines via azide in one flask. Some examples of other reductions were also presented.

Facile reduction of coordinated α-imino acids to amino acids by dithionite and borohydride

Sodium dithionite was found to reduce a range of α-iminoacidato ligands, chelated to cobalt(III), to the related α-aminoacidato species. For the bis(1,2-ethanediamine) system, the distribution of the products showed a small stereoselectivity towards the ΛR,ΔS diastereoisomers. The most significant selectivity was exhibited in the preparation of the valinato complex, via reduction of the related imine, [(en)2Co(Vim)]2+, where ΛR,ΔS/ΛS,ΔR = 4.2. Smaller selectivities (≈1.5) were observed in reductions using borohydride reagents. Reduction of the α-imino acid by sodium dithionite is optimised under acidic conditions (pH 3.5–5.5) in a dinitrogen atmosphere, whilst the corresponding reduction by sodium borohydride is optimised under mildly alkaline conditions (pH 9–10). Reduction conditions are therefore available to suit molecules with either acid or base sensitive functional groups. A mechanism for the reduction of the chelated imino acids by dithionite is proposed.

Reactivity of 3-Ethoxycarbonyl Isoquinolinium Salts Towards Various Nucleophilic Reagents: Applications to the Synthesis of New 1,2-Dihydroisoquinoline-3-carboxylates

Different types of novel 1,2-disubstituted 1,2-dihydro isoquinolines were synthesized by addition reactions of organolithium, alcoholates and borohydride reagents with various isoquinolinium salts. The leaving group character of the isoquinoline moiety was also evidenced.

Facile Synthesis of o- and p-(1-Trifluoromethyl)-alkylated Phenols via Generation and Reaction of Quinone Methides

Several ortho- and para-(1-chloro-2,2,2-trifluoroethyl)phenols were prepared from the corresponding alcohols and thionyl chloride in the presence of pyridine. They reacted smoothly with sodium borohydride and Grignard reagents under mild conditions, forming 2,2,2-trifluoroethyl- or 1-trifluoromethylalkylphenols in high yields.

Remote stereocontrol in acyclic systems. Hydride addition to 1,5- and 1,6-hydroxy ketones mediated by metal chelation

Acyclic 1,6-hydroxy amino ketones can be reduced to either the anti or syn diols with high 1,6 diastereoselectivity by sequential treatment with a Lewis acid and a borohydride reagent, with the direction of stereocontrol depending on the Lewis acid complexant used. For example, with 1a anti:syn ratios of >100:1 [Ti(OiPr) 4/K-Selectride] and 1:7 [Al(OEt) 3/K-Selectride] were realized. 1,5-Hydroxy amino ketone 4a was reduced with high syn 1,5 diastereoselectivity [ anti: syn = 1:18 with Al(OEt) 3/K-Selectride].

A novel decomplexation of π-allyltricarbonyliron lactone complexes using borohydride reagents: a new route to stereodefined acyclic 1,5-diols and 1,5,7-triols

π-Allyltricarbonyliron lactone complexes undergo a highly stereoselective decomplexation reaction on treatment with sodium triacetoxyborohydride to afford acyclic alcohols in excellent yields.

Tritium and deuterium labelling studies of alkali metal borohydrides and their application to simple reductions

Simple and facile syntheses of highly deuterated and tritiated LiBH4, NaBH4 and KBH4 were achieved by hydrogen isotope exchange with deuterium or tritium gas at elevated temperatures. The exchange products were characterized by boron, proton and deuterium or tritium NMR spectroscopy. The extent of isotope (2H or 3H) incorporation was calculated from the patterns of 11B NMR spectra. Several samples of tritiated NaBH4 were treated with BF3-Et2O to produce tritiated borane-THF complex, which is an electrophilic reducing agent. The utility of both the borohydride reagents and borane-THF complex in labelling reactions was confirmed by exemplary reductions leading to specifically labelled products. The extent and orientation of labelling in the reduction products was assessed by a combination of radio-HPLC analysis, 1H, 2H or 3H NMR and mass spectrometry.

Stereoselective Synthesis of Erythro α-Amino Epoxides

The stereoselective reduction of bromomethyl ketones derived from leucine, phenylalanine, alanine and valine is described using borohydride reagents. The Boc-amino alcohol product has erythro stereochemistry at the carbinol center as deduced by conversion to Boc-amino epoxides. These oxiranes are useful for the preparation of hydroxyethylene peptide isosteres.