Novel 1,2,3,4‐Tetrahydroquinazolinones via Reaction of 2‐Amino‐N‐substituted Benzamides and Dimethyl Acetylenedicarboxylate

Reaction of 2‐amino‐N‐substituted benzamides and dimethyl acetylenedicarboxylate (DMAD) in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in H₂O at room temperature led to the formation of novel 1,2,3,4‐tetrahydroquinazolinones.     

Insight into 6π Electrocyclic Reactions of 1,8‐Dioxatetraene

A variety of benzofuranone‐based spiroisochromenes were originally designed and synthesized to gain insight into the oxa‐6π electrocyclic reaction of cis,cis‐1,8‐dioxatetraene for the first time. The stability of the 1,8‐dioxatetraene intermediate is governed by its steric congestion and can be fine‐tuned through modification of the backbone structure, leading to the reactivity differences in the 6π electrocyclic reaction and the emergence of photochromic properties.     

Dimethyl Acetylenedicarboxylate in Reactions with Substituted 3‐(2‐aminophenyl)‐6‐R1‐1,2,4‐triazin‐5‐(2H)‐ones: Structure and Properties of the Products

The article describes unusual [5 + 1]‐cyclocondensations of dimethyl acetylenedicarboxylate (DMAD), in which this reagent uncharacteristically acts as a 1,1‐biselelectrophilic agent. Reactions of DMAD with 1,5‐bisnucleophilic 3‐(2‐aminophenyl)‐6‐R¹‐1,2,4‐triazin‐5(2H)‐ones yielded triazinoquinazoline‐derived diesters. The latter was shown to react with nucleophiles: hydrazine cleaved the pyrimidine ring of the diesters to give anilines, while ester hydrolysis furnished corresponding carboxylic acids.     

Experimental and Theoretical Insight into the Kinetics and Mechanism of the Synthesis Reaction of 2,3‐Dihydro‐2‐phenylquinazolin‐4(1H)‐one Catalyzed in Formic Acid

An efficient and simple method has been developed for the synthesis of 2,3‐dihydro‐2‐phenylquinazolin‐4(1H )‐one catalyzed in formic acid. Also, the synthesis reaction between benzaldehyde and 2‐aminobenzamid was monitored spectrally. On the basis of the kinetic data obtained by the UV–vis spectrophotometry, both the first and second steps of the speculative five steps mechanism were enabled to be a rate‐determining step and also reaction showed second‐order kinetics. Considering information obtained by the stopped‐flow technique indicated that the first step is certainly a fast step. Moreover, the reaction was energetically and thermodynamically evaluated using theoretical methods and results were profoundly compared with the experimental approaches. Herein, theoretical rate constants were obtained using potential energy surfaces and the transition state theory at the B3LYP/6–311+G** level of theory. The Winger method was also applied to describe the tunneling effects. Calculations showed that the second step was the rate‐determining step in accordance with the experimental data. It is also found that the oxidation step was the fastest step in the proposed mechanism. For all five steps, two possibilities were considered for generating the probable product by using the thermodynamic parameters and kinetic data. Thermodynamic parameters also showed an exothermic reaction.     

The Reactivity of Dimethyl Acetylenedicarboxylate and Heterocyclization of Hydrazinecarbothioamides to 1,3‐Thiazolidin‐4‐ones

2‐Substituted hydrazinecarbothioamides and N,2‐disubstituted hydrazinecarbothioamides react, in high yields with dimethyl acetylenedicarboxylate to give 4‐oxo‐Z‐(thiazolidin‐5‐ylidene)acetate derivatives. Several mechanistic options involving interaction are presented. The structures of thiazolidin‐4‐ones have been unambiguously confirmed by single crystal X‐ray crystallography.     

Insight into the Reaction Mechanism of α‐Amino Phosphonate Synthesis Using Succinic Acid as a Catalyst: Computational Kinetic Approach

The reaction mechanism in the synthesis of particular α‐amino phosphonates from 4‐methyl benzaldehyde, aniline, and trimethyl phosphite in the presence of succinic acid is theoretically investigated. The profile of the potential energy surface is constructed at both HF /6‐31 + G(d,p) and B3LYP /6‐31 + G(d,p) levels of theory for evaluating all the steps involved in the reaction mechanism. In order to investigate the effect of the structure on reactivity, some para ‐substituted benzaldehydes are subjected to kinetic examination. The overall reaction in the presence of electron‐withdrawing groups is thermodynamically much more favorable than in the presence of the electron‐donating groups; similarly, the reaction is kinetically more favorable and much easier in the presence of electron‐withdrawing groups. Moreover, step 2 (imine formation) is recognized as the rate‐determining step at both levels of theory. Also, step 1 is diffusion‐controlled with both electron‐withdrawing and electron‐donating groups, while the other steps are chemically controlled in the reaction mechanism.     

Efficient Synthesis of [1,3]Oxazino[3,2‐f]phenanthridine Derivatives by a Novel 1,4‐Dipolar Cycloaddition Involving a Phenanthridine–Dimethyl Acetylenedicarboxylate Zwitterion and Aromatic Aldehydes

An efficient synthesis of [1,3]oxazino[3,2‐f]phenanthridine derivatives via a three‐component reaction of phenanthridine, dimethyl acetylenedicarboxylate (DMAD), and aromatic aldehydes is described. This novel method is complementary to the classical Huisgen 1,4‐dipolar cycloaddition in that it is well‐suited to the preparation of [1,3]oxazino[3,2‐f]phenanthridines.     

Experimental and Theoretical Study of an Intramolecular CF3‐Group Shift in the Reactions of α‐Bromoenones with 1,2‐Diamines

The reactions of trifluoromethylated 2‐bromoenones and N,N′‐dialkyl‐1,2‐diamines have been studied. Depending on the structures of the starting compounds, the formation of 2‐trifluoroacetylpiperazine or 3‐trifluoromethylpiperazine‐2‐ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting α‐bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated.     

Structural Snapshots of α‐1,3‐Galactosyltransferase with Native Substrates: Insight into the Catalytic Mechanism of Retaining Glycosyltransferases

Glycosyltransferases (GTs) are a key family of enzymes that catalyze the synthesis of glycosidic bonds in all living organisms. The reaction involves the transfer of a glycosyl moiety and can proceed with retention or inversion of the anomeric configuration. To date, the catalytic mechanism of retaining GTs is a topic of great controversy, particularly for those enzymes containing a putative nucleophilic residue in the active site, for which the occurrence of a double‐displacement mechanism has been suggested. We report native ternary complexes of the retaining glycosyltransferase α‐1,3‐galactosyltransferase (α3GalT) from Bos taurus , which contains such a nucleophile in the active site, in a productive mode for catalysis in the presence of its sugar donor UDP‐Gal, the acceptor substrate lactose, and the divalent cation cofactor. This new experimental evidence supports the occurrence of a front‐side substrate‐assisted S_Ni‐type reaction for α3GalT, and suggests a conserved common catalytic mechanism among retaining GTs.     

Further Insight into the Mechanism of the Irreversible Inhibition of Histidine Ammonia‐Lyase by L‐Cysteine and Dioxygen

Histidine ammonia‐lyase (HAL) was irreversibly inhibited by L ‐cysteine at pH 10.5 under aerobic conditions. The inhibited enzyme, still in its intact conformation, showed an absorption maximum at 338 nm. Upon denaturation, followed by pronase digestion, two main chromophoric products 1 and 2 (Figs. 4 and 5, resp.) could be isolated with absorption maxima at 335 and 332 nm, respectively. As determined by MALDI‐TOF mass spectrometry and ¹H‐NMR spectroscopy, in product 1 one of the methylidene H‐atoms of the 3,5‐dihydro‐5‐methylidene‐4H‐imidazol‐4‐one (formerly called 4‐methylideneimidazol‐5‐one; MIO) prosthetic group was substituted by one of the amino groups of L ‐ cystine, while in product 2 the ε‐amino group of L ‐lysine was the analogous substituent. Acid‐catalyzed hydrolysis of product 1 gave compound 3 whose chromophore (λ_max 310 nm) was that of 3,5‐dihydro‐5‐(4‐hydroxymethylidene)‐4H‐imidazol‐4‐one, i.e., of a vinylogous acid. These results support our previous proposal that, in the first step, the L ‐cysteine S‐atom attacks the prosthetic electrophile (Scheme 2). The resulting nucleophilic enolate captures O₂ to form a peroxide. On the basis of the present results, we postulate that the observed products 1 – 3 arise from a vinylogous thioester 4 , which is formed in the conformationally intact inhibited enzyme by an electrocyclic reaction eliminating H₂O₂.     

Divergent Pathways and Competitive Mechanisms of Metathesis Reactions between 3‐Arylprop‐2‐ynyl Esters and Aldehydes: An Experimental and Theoretical Study

Mechanistic studies of the reaction between 3‐arylprop‐2‐ynyl esters and aldehydes catalyzed by BF₃ ? Et₂O were performed by isotopic labeling experiments and quantum chemical calculations. The reactions are shown to proceed by either a classical alkyne–carbonyl metathesis route or an unprecedented addition–rearrangement cascade. Depending on the structure of the starting materials and the reaction conditions, the products of these reactions can be Morita–Baylis–Hillman (MBH) adducts that are unavailable by traditional MBH reactions or E‐ and Z‐α,β‐unsaturated ketones. ¹⁸O‐Labeling studies suggested the existence of two different reaction pathways to the products. These pathways were further examined by quantum chemical calculations that employed the DFT(wB97XD)/6‐311+G(2d,p) method, together with the conductor‐like screening model for realistic solvation (COSMO‐RS). By using the wB97XD functional, the accuracy of the computed data is estimated to be 1–2 kcal mol^?1, shown by the careful benchmarking of various DFT functionals against coupled cluster calculations at the CCSD(T)/aug‐cc‐pVTZ level of theory. Indeed, most of the experimental data were reproduced and explained by theory and it was convincingly shown that the branching point between the two distinct mechanisms is the formation of the first intermediate on the reaction pathway: either the four‐membered oxete or the six‐membered zwitterion. The deep mechanistic understanding of these reactions opens new synthetic avenues to chemically and biologically important α,β‐unsaturated ketones.     

Synthesis of New Stable Phosphorus Ylides and 1,4‐Diionic Organophosphorus Compound from a Reaction between Hexamethyl Phosphorous Triamide and Dimethyl Acetylenedicarboxylate in the Presence of CH‐Acids

A simple and efficient one‐pot three‐component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate (DMAD) in the presence of CH‐acids, such as acetylacetone, 1,3‐indandione, dibenzoylmethane, anthrone, and N,N‐dimethylbarbituric acid, has been studied. In all cases, new and stable phosphorus ylides are obtained in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond, resulting from conjugation of the ylide moiety with the adjacent carbonyl group. From the reaction of N,N‐dimethylbarbituric acid with DMAD in the presence of hexamethyl phosphorous triamide, a 1,4‐diionic organophosphorus compound is obtained. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:84–89, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21067     

Ruthenium‐Catalyzed Multicomponent Reactions: Access to α‐Silyl‐β‐Hydroxy Vinylsilanes,Stereodefined 1,3‐Dienes,and Cyclohexenes

The synthesis of densly functionized α‐silyl‐β‐hydroxyl vinylsilanes via ruthenium‐catalyzed multicomponent reaction (MCR) is reported herein. Exceptionally high regio‐ and diastereoselectivity was achieved by employing an unprecedented hydrosilylation of bifunctional silyl‐propargyl boronates. The simple protocol, mild reaction conditions, and unique tolerability of this method make it a valuable tool for the synthesis of highly elaborated building blocks. The one‐pot synthesis of stereodefined olefins, the generation of a valuable cyclohexene building block through a four‐component MCR, and further functionalization in an abundance of diastereoselective reactions is disclosed herein.