Synthesis of highly functionalized 2,2'-bipyridines by cyclocondensation of β-ketoenamides – scope and limitations

The scope of a flexible route to unsymmetrically functionalized bipyridines is described. Starting from 1,3-diketones 1a–e, the corresponding β-ketoenamines 2a–e were converted into different β-ketoenamides 3a–g by N-acylation with 2-pyridinecarboxylic acid derivatives. These β-ketoenamides were treated with a mixture of TMSOTf and Hünig’s base to promote the cyclocondensation to 4-hydroxypyridine derivatives. Their immediate O-nonaflation employing nonafluorobutanesulfonyl fluoride provided the expected 4-nonafloxy- substituted bipyridine derivatives 5a–g in moderate to good overall yields. The bipyridyl nonaflates are excellent precursors for palladium-catalyzed reactions as demonstrated by representative Suzuki and Sonogashira couplings. Thus, a library of specifically substituted bipyridine derivatives was generated, showing the versatility of the simple 1,3-diketone-based approach to this important class of ligands

One-pot nucleophilic substitution–double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives

The nucleophilic substitution of benzylic bromides with sodium azide was combined with a subsequent copper-catalyzed (3 + 2) cycloaddition with terminal alkynes. This one-pot process was developed with a simple model alkyne, but then applied to more complex alkynes bearing enantiopure 1,2-oxazinyl substituents. Hence, the precursor compounds 1,2-, 1,3- or 1,4-bis(bromomethyl)benzene furnished geometrically differing bis(1,2,3-triazole) derivatives. The use of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) as ligand for the click step turned out to be very advantageous. The compounds with 1,2-oxazinyl end groups can potentially serve as precursors of divalent carbohydrate mimetics, but the reductive cleavage of the 1,2-oxazine rings to aminopyran moieties did not proceed cleanly with these compounds

Alkoxyallenes as building blocks for organic synthesis

Alkoxyallenes are unusually versatile C3 building blocks in organic synthesis. Hence this tutorial review summarizes the most important transformations, including subsequent reactions and their applications in the synthesis of relevant compounds, e.g. natural products. The reactivity patterns involved and the synthons derived from alkoxyallenes are presented. Often alkoxyallenes can serve as substitutes of acrolein or acrolein acetals, utilisation of which has already led to interesting products. Most important is the use of lithiated alkoxyallenes which smoothly react with a variety of electrophiles and lead to products with unique substitution patterns. The heterocycles or carbocycles formed are intermediates for the stereoselective synthesis of natural products or for the preparation of other structurally relevant compounds. The different synthons being put into practice by the use of lithiated alkoxyallenes in these variations will be discussed

Samarium(II)-Promoted Cyclizations of Nonactivated Indolyl Sulfinyl Imines to Polycyclic Tertiary Carbinamines

Samarium(II)-promoted cyclizations of N-acylated indolyl sulfinyl imines without electron-withdrawing groups at C-3 furnished tertiary carbinamines in good yield. Screening of the reaction conditions revealed that application of an excess of samarium diiodide in the presence of water and lithium bromide provided the cleanest reactions and the highest yields. The most striking observation during this investigation was the reductive detachment of the sulfur functional group, which most likely precedes the cyclization step. As consequence no enantioselectivity could be observed if enantiopure sulfinyl imines were employed. The mechanisms of the N−S cleavage and of the cyclization of the intermediate imines as well as the role of the additives are discussed. The presented method generates interesting polycyclic indoline derivatives; a cascade reaction involving an ethoxycarbonyl-substituted side-chain provided unique tetracyclic spiro-γ-lactams

Multivalent Aminoseptanose Mimetics by Copper-Catalyzed (3+2) Cycloadditions of Azidomethyl-Substituted Bicyclic 1,2-Oxazines

Starting from readily available enantiopure azidomethyl-substituted bicyclic 1,2-oxazine derivatives and mono-, di- or trialkynes, their copper-catalyzed (3+2) cycloadditions furnished a series of 1,2,3-triazolyl-linked compounds in good yields. These click reactions proceeded smoothly at room temperature when copper iodide as catalyst was used in the presence of triethylamine and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine as ligand. Generally, the unprotected bicyclic 1,2-oxazine derivatives seemed to show slightly higher reactivity and provided better yields compared with their silyl-protected counterparts. Exhaustive hydrogenolysis with cleavage of the 1,2-oxazine N-O bonds in the presence of palladium on charcoal as promotor is feasible but was found to be capricious. Reasonable results were obtained when acetic acid employed as cosolvent. By applying these conditions, several of the bicyclic 1,2-oxazine derivatives were successfully converted into the expected mono- or divalent aminooxepine derivatives which can be regarded as aminoseptanose mimetics

The Boekelheide Rearrangement of Pyrimidine-N-oxides as a Case Study of Closed or Open Shell Reactions – Experimental and Computational Evidence for the Participation of Radical Intermediates

In a case study, the acetic anhydride-promoted reaction of a model pyrimidine-N-oxide to the corresponding 4-acetoxymethyl-substituted pyrimidine derivative (Boekelheide rearrangement) was investigated in detail by experiment and quantum chemical calculations. The reaction conditions were varied and several side products formed in low to moderate yields were identified. These experiments indicate that a (pyrimidin-4-yl)methyl radical is one of the key species of the rearrangement. This interpretation was supported by the fact that rearrangements performed in solvents which can easily lose hydrogen atoms, afford considerable quantities of products incorporating the solvent. With TEMPO the key radical could be trapped. Other carboxylic acid anhydrides confirm the conclusion that the Boekelheide rearrangement of the model pyrimidine-N-oxide proceeds, at least in part, via radical intermediates. The high level closed and open shell quantum chemical calculations show that concerted [3,3]-sigmatropic rearrangements or stepwise processes, either via ion pairs or via radicals, are energetically feasible

an Experimental and Computational Study

To gain a deeper understanding of the formation of the synthetically important 3,6‐dihydro‐2H‐1,2‐oxazines, the 6‐endo‐trig cyclization of allenyl‐substituted hydroxylamines was experimentally investigated in detail employing a model compound. The solvent effect was moderate with respect to the rate, but crucial to suppress side‐product formation. Surprisingly, acids or bases had no big influence on the cyclization rate. With O‐deuterated allenyl hydroxylamine a high primary isotope effect was found, indicating that the proton transfer is crucial in the rate‐determining step. DFT calculations evidence that the allenyl‐substituted hydroxylamine is converted into an energetically similar zwitterionic intermediate with an allyl cation subunit. It cyclizes to the 1,2‐oxazine as the most stable species. Alternative pathways starting from the zwitterion were computationally investigated. Interestingly, it can also undergo a fragmentation to give a pentadiene derivative and a nitroso compound. The hetero Diels–Alder reaction of these components may also deliver the 1,2‐oxazine. To evaluate an alternative mechanistic scenario, calculations of the protonated allenyl‐substituted hydroxylamine were also performed

Multivalent 1,2,3‐Triazole‐Linked Carbohydrate Mimetics by Huisgen–Meldal‐Sharpless Cycloadditions of an Azidopyran

Starting from an enantiopure 3‐azido‐substituted pyran derivative and various oligo‐alkynes a series of multivalent 1,2,3‐triazole‐linked carbohydrate mimetics was synthesized. The copper‐catalyzed Huisgen–Meldal‐Sharpless cycloaddition (CuAAC) served as key coupling reaction. Cu/C in the presence of triethylamine proved to be a good catalytic system in most cases. Tri‐, tetra‐, hexa‐, and octavalent compounds with typical rigid or flexible core units were prepared. The most complex compound contains a C60‐fullerene center leading to a dodecavalent carbohydrate mimetic. Only a few of the multivalent target compounds could be converted into pure O‐sulfated derivatives that are required for their evaluation as L‐ and P‐selectin ligands. Nevertheless, preliminary experiments suggest that the dodecavalent C60‐derived compound may be a promising ligand of these biologically important proteins with IC50 values in the low nanomolar range

Multivalent interaction and selectivities in selectin binding of functionalized gold colloids decorated with carbohydrate mimetics

Colloidal gold particles with functionalized organic shells were applied as novel selectin binders. The ligand shell was terminated with different monocyclic carbohydrate mimetics as simplified analogs of the sLe(x) unit found in biological selectin ligands. The multivalent presentation of the sulfated selectin binding epitopes on the gold particles led to extremely high binding affinities towards L- and P-selectin and IC(50) values in the subnanomolar range. Depending on the ring size of the sulfated carbohydrate mimetic, its substitution pattern and its configuration, different selectivities for either L-selectin or P-selectin were obtained. These selectivities were not found for gold particles with simple acyclic sulfated alcohols, diols and triols in the ligand shell. In addition, the influence of the particle size and the thickness of the hydrophobic organic shell were systematically investigated