The kinetics of epoxide formation by Darzens condensation of aliphatic ketones 1 with arylsulfonyl-substituted chloromethyl anions 2 (ArSO2CHCl–) have been determined photometrically in DMSO solution ...at 20 °C. The reactions proceed via nucleophilic attack of the carbanions at the carbonyl group to give intermediate halohydrin anions 4, which subsequently cyclize with formation of the oxiranes 3. Protonation of the reaction mixture obtained in THF solution at low temperature allowed the intermediates to be trapped and the corresponding halohydrins 4-H to be isolated. Crossover experiments, i.e., deprotonation of the halohydrins 4-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted chloromethyl anions 2, provided the relative rates of backward (k –CC) and ring closure (k rc) reactions of the intermediates. Combination of the kinetic data (k 2 exptl) with the splitting ratio (k –CC/k rc) gave the second-order rate constants k CC for the attack of the carbanions 2 at the ketones 1. These k CC values and the previously reported reactivity parameters N and s N for the arylsulfonyl-substituted chloromethyl anions 2 allowed us to use the linear free energy relationship log k 2(20 °C) = s N(N + E) for deriving the electrophilicity parameters E of the ketones 1 and thus predict potential nucleophilic reaction partners. Density functional theory calculations of the intrinsic reaction pathways showed that the reactions of the ketones 1 with the chloromethyl anions 2 yield two rotational isomers of the intermediate halohydrin anions 4, only one of which can cyclize while the other undergoes retroaddition because the barrier for rotation is higher than that for reversal to the reactants 1 and 2. The electrophilicity parameters E correlate moderately with the lowest unoccupied molecular orbital energies of the carbonyl groups, very poorly with Parr’s electrophilicity indices, and best with the methyl anion affinities calculated for DMSO solution.
The monoalkylation of
N
-methoxypyridinium salts with alkyl radicals generated from alkenes (
via
hydroboration with catecholborane), alkyl iodides (
via
iodine atom transfer) and xanthates is ...reported. The reaction proceeds under neutral conditions since no acid is needed to activate the heterocycle and no external oxidant is required. A rate constant for the addition of a primary radical to
N
-methoxylepidinium >10
7
M
−1
s
−1
was experimentally determined. This rate constant is more than one order of magnitude larger than the one measured for the addition of primary alkyl radicals to protonated lepidine demonstrating the remarkable reactivity of methoxypyridinium salts towards radicals. The reaction has been used for the preparation of unique pyridinylated terpenoids and was extended to a three-component carbopyridinylation of electron-rich alkenes including enol esters, enol ethers and enamides.
N
-Methoxypyridinium salts are exceptionally reactive radical traps that can be used in efficient radical chain reactions with organoboranes.
The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa values of functionalized N‐, S‐, ...and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.
Metalation site prediction: The use of simple pKa calculations allowed a reliable prediction of metalation sites in various heterocycles, arenes, olefins, and alkanes, employing the mild base TMPZnCl⋅LiCl. Using this predictive model, also unexplored N‐heterocycles were investigated, and the obtained deprotonation sites rationalized readily.
Simple monocyclic diketopiperazine (DKP)‐derived alkoxyamines exhibit unprecedented activation of a remote C−O bond for homolysis by amide distortion. The combination of strain‐release‐driven amide ...planarization and the persistent radical effect (PRE) enables a unique, irreversible, and quantitative trans→cis isomerization under much milder conditions than typically observed for such homolysis‐limited reactions. This isomerization is shown to be general and independent of the steric and electronic nature of both the amino acid side chains and the substituents at the DKP nitrogen atoms. Homolysis rate constants are determined, and they significantly differ for both the labile trans diastereomers and the stable cis diastereomers. To reveal the factors influencing this unusual process, structural features of the kinetic trans diastereomers and thermodynamic cis diastereomers are investigated in the solid state and in solution. X‐ray crystallographic analysis and computational studies indicate substantial distortion of the amide bond from planarity in the trans‐alkoxyamines, and this is believed to be the cause for the facile and quantitative isomerization. Thus, these amino‐acid‐derived alkoxyamines are the first examples that exhibit a large thermodynamic preference for one diastereomer over the other upon thermal homolysis, and this allows controlled switching of configurations and configurational cycling.
Strain release drives isomerization: Amide pyramidalization in diketopiperazine‐derived trans‐alkoxyamines is the reason for facile homolytic bond cleavage at mild temperatures and quantitative isomerization into cis isomers with nearly planar amide geometry. PRE=persistent radical effect.
Two fused N‐heterocyclic scaffolds were selectively functionalized giving access to novel pharmaceutical targets that offer a better life to the whole world. More information can be found in the ...Research Article by P. Knochel and co‐workers (DOI: 10.1002/chem.202200733).
DFT‐calculations allow prediction of the reactivity of uncommon N‐heterocyclic scaffolds of pyrazolo1,5‐apyrimidines and imidazo1,2‐bpyridazines and considerably facilitate their functionalization. ...The derivatization of these N‐heterocycles was realized using Grignard reagents for nucleophilic additions to 5‐chloropyrazolo1,5‐apyrimidines and TMP2Zn ⋅ 2 MgCl2 ⋅ 2 LiCl allowed regioselective zincations. In the case of 6‐chloroimidazo1,2‐bpyridazine, bases such as TMP2Zn ⋅ MgCl2 ⋅ 2 LiCl, in the presence or absence of BF3 ⋅ OEt2, led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta‐substitution). X‐ray analysis confirmed the regioselectivity for key functional heterocycles.
N‐heterocycles, pyrazolopyrimidines and imidazopyridazines were reliably functionalized with the support of DFT ‐ calculations using Grignard reagents as nucleophilic partners and TMPZn‐mediated zincations for 5‐chloropyrazolo1,5‐apyrimidine. Successive regioselective magnesiations with TMPMgCl⋅LiCl or TMP2Zn⋅MgCl2 ⋅ 2 LiCl in the presence or absence of BF3 ⋅ OEt2 for the 6‐chloroimidazo1,2‐bpyridazine scaffold provided a range of highly functionalized new N‐heterocycles of pharmaceutical interest.
Radikalkettenreaktionen werden normalerweise durch die thermische oder photochemische Aktivierung von Radikalinitiatoren, durch die photochemische Aktivierung der Substrate selbst oder durch gezielte ...Redoxprozesse eingeleitet. Woher Radikale in der Abwesenheit dieser Initiierungsstrategien kommen, ist oft wenig bekannt und wird daher auf das Vorhandensein unbekannter Verunreinigungen zurückgeführt. In dieser Situation bieten sich Molekül‐induzierte Radikalbildungs (MIRF)‐Reaktionen als wohldefinierte alternative Initiierungsmechanismen an. In ihrer allgemeinsten Definition reagieren in MIRF‐Reaktionen zwei geschlossenschalige Moleküle unter Bildung eines Radikalpaars oder Diradikals. Der genaue Charakter dieses Prozesses hängt von den σ‐ oder π‐Bindungen ab, die an der MIRF‐Reaktion beteiligt sind, und dieser Kurzaufsatz konzentriert sich besonders auf Reaktionen, in denen zwei σ‐Bindungen in zwei Radikale und ein geschlossenschaliges Produkt umgewandelt werden.
Bimolekulare Radikalbildung: Die Molekül‐induzierte Radikalbildung (MIRF), bei der ein geschlossenschaliges Molekül einem zweiten bei der Dissoziation assistiert, stellt eine wichtige Alternative zur unimolekularen Bindungshomolyse dar.
The first ferrocenes with a persulfurated cyclopentadienyl ring C5(SR)5, (R= Me, Ph), were prepared. Their crystal structures show all sulfur substituents in axial positions and iron–sulfur distances ...significantly shorter than the sum of the van der Waals radii. Cyclovoltammetry of the C5(SPh)5 compound shows a high oxidation potential of 651 mV versus FcH/FcH. DFT calculations show the expected reductions of the HOMO–LUMO gap for both compounds with respect to ferrocene, however, with stabilizations of both HOMO and LUMO levels. More information can be found in the Communication by K. Sünkel et al. on page 12684.
Persulfurated arenes are a fascinating class of functional molecules with a wide range of potential applications. Ferrocenes are also a multifaceted class of aromatic compounds that can easily be ...finetuned for an enormous variety of desired properties. A combination of both substance classes might yield an even wider field of applications. Herein, we describe the synthesis of two ferrocenes with one persulfurated cyclopentadienyl ring C5(SR)5, with R=Me or Ph, together with their crystal structures, optical, and electrochemical properties. Both crystal structures show significant intramolecular sulfur‐iron interactions as well as weak intermolecular sulfur– contacts. Cyclovoltammetry of the C5(SPh)5 compound shows a high oxidation potential of 651 mV vs. FcH/FcH+.
Metalation: Ferrocenes with one persulfurated cyclopentadienyl ring C5(SR)5FeCp have been prepared from monobromoferrocene by a sequence of deprotonations and electrophilic thiolations. In their crystal structures, all cyclopentadienyl rings have their thiolate substituents in axial positions away from the iron atom. Cyclovoltammetric studies show that the sulfur substituents lead to significantly enhanced oxidative stability (see figure).
A convenient and efficient strategy for the synthesis of 3-pyrrolines containing an amino quaternary stereogenic center
via
phosphine-catalyzed formal 3 + 2 annulation of 2-aminoacrylates with ...allenoates is disclosed. A wide range of substrates underwent this reaction smoothly, affording a series of 3-pyrrolines in good to excellent yields, and it could be extended to a gram-scale reaction. The kinetic profiles and the calculated methyl anion affinity (MAA) values were employed to explain the reactivities of different allenoates used in the reaction, which provides deep understanding for the catalytic mechanism of this type of reaction.
A phosphine catalyzed formal 3 + 2 annulation was disclosed, affording 3-pyrrolines containing an amino quaternary stereogenic center in good to excellent yields. The catalytic mechanism was investigated by DFT and kinetic studies.
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