Anomeric stereoauxiliary strategy enables efficient synthesis of wide-ranging imidazo[1,5-α]pyridines

Imidazo[1,5-α]pyridines are one of the most important groups of N-heterocyclic compounds, with wide applications in pharmaceutics, chemical science and material science. Despite tremendous progress in their synthesis over the past decade, a number of important imidazo[1,5-α]pyridines as intermediate products remain inaccessible, such as 1-alkylimidazo[1,5-α]pyridines. Herein, we report a novel anomeric stereoauxiliary approach for the preparation of this important class of compounds. It strongly expands the scope of readily accessible imidazo[1,5-α]pyridines well beyond the existing state-of-the-art methods. More than 80 products with a substantial number of deemed unattainable ones were synthesized. With the first time accessibility to alkyl(pyridine-2-yl)methanone substrates, a group of important deuterated imidazo[1,5-α]pyridines derivatives were also efficiently achieved. The mechanism containing a key seven-membered ring transition state via α-anomeric stereoauxiliary for this new synthetic pathway is provided in great detail and supported by electronic structure calculations. In total, this novel synthetic approach for a broad range of imidazo[1,5-α]pyridines involving the native stereochemistry will open a new window for research endeavors in diverse fields, encompassing organic synthesis, biomass conversion via cleavage of C-N bonds and medicinal chemistry.

Why Is THCA Decarboxylation Faster than CBDA? an in Silico Perspective

Tetrahydrocannabinol acid (THCA) and cannabidiol acid (CBDA), the two crucial organic components in cannabis and hemp, decarboxylate at different rates to their more active neutral forms. Theoretical calculations are used herein to analyze how the remote annulated ring or pendant substituent influences the rate determining steps of the decarboxylation processes. The uncatalyzed keto-enol tautomerization that precedes decarboxylation is found to be extremely slow in both cases albeit with a ten-fold preference for CBDA. A single molecule of methanol dramatically enhances the reaction rates by allowing for tautomerization through a more favorable six-membered ring transition state. Methanol-catalyzed tautomerization is found to be faster in THCA than in CBDA. This difference results from both the larger dipole moment of the THCA scaffold as well as its greater rigidity relative to CBDA. The greater dipole moment leads to a somewhat better binding of methanol. The lower entropic penalty in THCA towards tautomerization leads to faster decarboxylation.

Why Is THCA Decarboxylation Faster than CBDA? an in Silico Perspective

Tetrahydrocannabinol acid (THCA) and cannabidiol acid (CBDA), the two crucial organic components in cannabis and hemp, decarboxylate at different rates to their more active neutral forms. Theoretical calculations are used herein to analyze how the remote annulated ring or pendant substituent influences the rate determining steps of the decarboxylation processes. The uncatalyzed keto-enol tautomerization that precedes decarboxylation is found to be extremely slow in both cases albeit with a ten-fold preference for CBDA. A single molecule of methanol dramatically enhances the reaction rates by allowing for tautomerization through a more favorable six-membered ring transition state. Methanol-catalyzed tautomerization is found to be faster in THCA than in CBDA. This difference results from both the larger dipole moment of the THCA scaffold as well as its greater rigidity relative to CBDA. The greater dipole moment leads to a somewhat better binding of methanol. The lower entropic penalty in THCA towards tautomerization leads to faster decarboxylation.

An Alternate Energy-Conserved Pathway for the Morita-Baylis-Hillman (MBH) Reaction

An new overall lower energy pathway for the amine-catalysed Morita-Baylis-Hillman reaction is proposed from computations at the M06-2X/6-311++G(d,p) level. The pathway involves proton-transfer from the ammonium ion to the alkoxide formed from the aldol reaction through a seven-membered ring transition state (TS) structure followed by highly exothermic Hofmann<i> </i>elimination through a five-membered ring TS structure to form the product and also release the catalyst to carry on with the process all over again.

An Alternate Energy-Conserved Pathway for the Morita-Baylis-Hillman (MBH) Reaction

An new overall lower energy pathway for the amine-catalysed Morita-Baylis-Hillman reaction is proposed from computations at the M06-2X/6-311++G(d,p) level. The pathway involves proton-transfer from the ammonium ion to the alkoxide formed from the aldol reaction through a seven-membered ring transition state (TS) structure followed by highly exothermic Hofmann<i> </i>elimination through a five-membered ring TS structure to form the product and also release the catalyst to carry on with the process all over again.

An Alternate Energy-Conserved Pathway for the Morita-Baylis-Hillman (MBH) Reaction

An new overall lower energy pathway for the amine-catalysed Morita-Baylis-Hillman reaction is proposed from computations at the M06-2X/6-311++G(d,p) level. The pathway involves proton-transfer from the ammonium ion to the alkoxide formed from the aldol reaction through a seven-membered ring transition state (TS) structure followed by highly exothermic Hofmann<i> </i>elimination through a five-membered ring TS structure to form the product and also release the catalyst to carry on with the process all over again.

Oxidation of geraniol using niobia modified with hydrogen peroxide

Nb2O5 bulk and Nb2O5 modified with H2O2 were studied in the epoxidation of geraniol at 1 bar and room temperature. The structural and morphological properties for both catalysts were very similar, indicating that the peroxo-complex species were not formed. The order of the reaction was one respect to geraniol and close to zero respect to H2O2, these values fit well with the kinetic data obtained. The geraniol epoxidation is favored by the presence of peroxo groups, which is reached using an excess of H2O2. Moreover, the availability of the geraniol to adopt the three-membered-ring transition state was found as the best form for this type of compound.

DFT studies on the mechanism of acetylene hydrochlorination over gold-based catalysts and guidance for catalyst construction

In the presence of both HCl and C2H2, the linear structure of AuCl is proposed to form a tetracoordinated five-membered ring transition state, along with the oxidation of the Au center from Au(i) into Au(iii).

A DFT study on the mechanism of reaction between 2, 4-diisocyanatotolune and cellulose

The reaction mechanisms between 2, 4-Diisocyanatotolune (2, 4-TDI) and cellulose have been investigated using the density functional theory at the B3LYP/6-31[Formula: see text]G (d, p) level. The calculations show that the direct addition of 2, 4-TDI and cellulose possesses an unrealistically high barrier of 32–34[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. With a neighboring [Formula: see text]-d-glucose serving as a proton transporter by forming a flexible six-membered ring transition state, the energy barrier of the reaction is significantly reduced to 16–18 kcal[Formula: see text]mol[Formula: see text], which is in a good accordance with the experimental activation energy of 13.9–16.7[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. It is indicated that the reaction between 2, 4-TDI and cellulose is auto-catalyzed with a neighboring [Formula: see text]-d-glucose acting as a reactive catalyst.