Cycloadditions of 4-Alkenyl-2-aminothiazoles with Nitroalkenes in the Formal Synthesis of Pramipexole: An Experimental and Computational Study.

4-Alkenyl-2-dialkylaminothiazoles act as in-out dienes in [4 + 2] cycloaddition reactions with nitroalkenes, furnishing 2-amino-6-nitro-4,5,6,7-tetrahydrobenzothiazoles in moderate to good yields, accompanied by a subsequent 1,3-H migration. These transformations proceed with exquisite site-, regio-, and diastereoselectivity. This strategy is further enriched by revealing a novel route for pramipexole synthesis. The examination of the potential energy surfaces associated with the four possible reaction pathways for the Diels-Alder cycloaddition (relative approach of the diene-dienophile and endo/exo approach of the nitro group) not only aligns with experimental observations but also unveils key mechanistic insights. Specifically, computational analyses uncover the favored pathway yielding 6-nitro-4,5,6,7-tetrahydrobenzothiazoles, with some instances proceeding through a two-step mechanism involving a tandem sequence of chemical processes, and the influence of various factors such as dienophile structure and the approach mode of the nitro group. Additionally, the stabilization of the exo-transition states, particularly facilitated by phenyl substitution in the dienophile, is highlighted. Asynchronicity, dipole moment, and other parameters indicative of polar character further characterize these Diels-Alder reactions. Conceptual DFT calculations underscore the pivotal role of the 1,3-thiazole ring in enhancing dienic activation and dictating regioselectivity, emphasizing interactions between the C5 of the thiazole nucleus and the Cß atom of the nitroalkenes.

A structural analysis of 2,5-diaryl-4H-2,4-dihydro-3H-1,2,4-triazol-3-ones: NMR in the solid state, X-ray crystallography, and GIPAW calculations.

The 1 H, 13 C, 15 N, and 19 F nuclear magnetic resonance (NMR) spectra of 11 2,5-diaryl-2,4-dihydro-3H-1,2,4-triazol-3-ones have been acquired in DMSO-d6 solution and the 13 C, 15 N, and 19 F NMR spectra have also been acquired in the solid state (solid-state nuclear magnetic resonance [SSNMR] and magic angle spinning [MAS]). The X-ray structures of Compounds 3, 5, and 6 have been determined by X-ray diffraction. Theoretical calculations at the gauge-independent atomic orbital (GIAO)/B3LYP/6-311++G(d,p) level have provided a set of 321 chemical shifts that were compared with 310 experimental values in DMSO-d6 . To obtain good agreements, some effects need to be included. The SSNMR chemical shifts have been compared with gauge-including projector-augmented wave (GIPAW) calculations and with the heavy atom-light atom (HALA) effects.

Lewis Acid-Mediated Formation of 1,3-Disubstituted Spiro[cyclopropane-1,2'-indanes]: The Activating Effect of the Cyclopropane Walsh Orbital.

By virtue of its alkylidenecyclopropane moiety, 2-(cyclopropylidenemethyl)benzaldehyde reacts with a range of amines and thiols under Lewis acid catalysis. These reactions yield 1,3-bis(arylamino) and 1,3-bis(arylthio and alkylthio)indanes, respectively, which are spirolinked to the cyclopropane ring at carbon 2. The reaction mechanism, and the peculiar contribution of the cyclopropane ring, have been scrutinized via DFT calculations.

Chemodivergent Conversion of Ketenimines Bearing Cyclic Dithioacetalic Units into Isoquinoline-1-thiones or Quinolin-4-ones as a Function of the Acetalic Ring Size.

C-Alkoxycarbonyl- C-phenyl- N-aryl ketenimines bearing 1,3-dithiolan-2-yl or 1,3-dithian-2-yl substituents at ortho position of the C-phenyl ring, respectively, transform into isoquinoline-1-thiones and quinolin-4-ones under thermal treatment in toluene solution. The formation of isoquinolinethiones involves a rare degradation of the 1,3-dithiolane ring, whereas, in contrast, the 1,3-dithiane ring remains intact during the reaction course leading to quinolin-4-ones. Computational density functional theory results support that the kinetically favorable mechanism for the formation of isoquinoline-1-thiones proceeds through a [1,5]-hydride shift/6π-electrocyclization cascade, followed by a thiirane extrusion process. Alternative mechanistic paths showing interesting electronic reorganization processes have been also scrutinized but resulted not competitive on energetic grounds.

Exploring the Conversion of Macrocyclic 2,2'-Biaryl Bis(thioureas) into Cyclic Monothioureas: An Experimental and Computational Investigation.

Macrocyclic bis(thioureas) derived from 2,2'-biphenyl and binaphthyl skeletons have been synthesized by reaction of 2,2'-diaminobiaryl and 2,2'-bis(isothiocyanato)biaryl derivatives. The splitting of these bis(thioureas) into two units of the respective cyclic monothioureas has been monitored by NMR, shedding some light on the factors that control these processes. Additionally, a computational study revealed up to three mechanistic paths for the conversion of the 2,2'-biphenyl-derived bis(thiourea) into the corresponding monothiourea. The proposed mechanisms account for the participation of a molecule of water as an efficient proton-switch as well as for different classes of putative intermediates. The computational study also supports the ability of the thiourea group to participate in a plethora of processes, such as prototropic equilibria, sigmatropic shifts, heteroene and retro-heteroene reactions, and cis ⇆ trans isomerizations.

Tandem processes promoted by a hydrogen shift in 6-arylfulvenes bearing acetalic units at ortho position: a combined experimental and computational study.

6-Phenylfulvenes bearing (1,3-dioxolan or dioxan)-2-yl substituents at ortho position convert into mixtures of 4- and 9-(hydroxy)alkoxy-substituted benz[f]indenes as result of cascade processes initiated by a thermally activated hydrogen shift. Structurally related fulvenes with non-cyclic acetalic units afforded mixtures of 4- and 9-alkoxybenz[f]indenes under similar thermal conditions. Mechanistic paths promoted by an initial [1,4]-, [1,5]-, [1,7]- or [1,9]-H shift are conceivable for explaining these conversions. Deuterium labelling experiments exclude the [1,4]-hydride shift as the first step. A computational study scrutinized the reaction channels of these tandem conversions starting by [1,5]-, [1,7]- and [1,9]-H shifts, revealing that this first step is the rate-determining one and that the [1,9]-H shift is the one with the lowest energy barrier.

The network simulation method: a useful tool for locating the kinetic-thermodynamic switching point in complex kinetic schemes.

The kinetic-thermodynamic switching point of a multistep process, whose reaction mechanism has been elucidated by DFT calculations, can be calculated by means of an efficient model based on the Network Simulation Method (NSM). This method can solve, fast and effectively, a difficult system of differential equations derived from a complex kinetic scheme by establishing a formal equivalence between the chemical system and an electrical network. The NSM employs very short simulation times to determine the dependence of the switching time on the temperature, a fundamental topic to take control over the product composition which has not been treated exhaustively so far, and that could be applied for synthetic purposes avoiding laborious and costly experimental trials.

Thermal cyclization of phenylallenes that contain ortho-1,3-dioxolan-2-yl groups: new cascade reactions initiated by 1,5-hydride shifts of acetalic H atoms.

A series of 2-(1,3-dioxolan-2-yl)phenylallenes that contained a range of substituents (alkyl, aryl, phosphinyl, alkoxycarbonyl, sulfonyl) at the cumulenic C3 position were prepared by using a diverse range of synthetic strategies and converted into their respective 1-(2-hydroxy)-ethoxy-2-substituted naphthalenes by smooth thermal activation in toluene solution. Electron-withdrawing groups at the C3 position accelerated these tandem processes, which consisted of 1) an initial hydride-like [1,5]-H shift of the acetalic H atom onto the central cumulene carbon atom; 2) a subsequent 6π-electrocyclic ring-closure of the resulting reactive ortho-xylylenes; and 3) a final aromatization step with concomitant ring-opening of the 1,3-dioxolane fragment. If the 1,3-dioxolane ring of the starting allenes was replaced by a dimethoxymethyl group, the reactions led to mixtures of two disubstituted naphthalenes, which were formed by the migration of either the acetalic H atom or the methoxy group, with the latter migration occurring to a lesser extent. Two of the final 1,2-disubstituted naphthalenes were converted into their corresponding naphtho-fused dioxaphosphepine or dioxepinone through an intramolecular transesterification reaction. A DFT computational study accounted for the beneficial influence of the 1,3-dioxolane fragment on the carbon atom from which the H-shift took place and also of the electron-withdrawing substituents on the allene terminus. Remarkably, in the processes that contained a sulfonyl substituent, the conrotatory 6π-electrocyclization step was of lower activation energy than the alternative disrotatory mode.

Alkylammonium Cation Affinities of Nitrogenated Organobases: The Roles of Hydrogen Bonding and Proton Transfer.

Alkylammonium cation affinities of 64 nitrogen-containing organobases, as well as the respective proton transfer processes from the alkylammonium cations to the base, have been computed in the gas phase by using DFT methods. The guanidine bases show the highest proton transfer values (191.9-233 kJ mol-1 ) whereas the cis-2,2'-biimidazole presents the largest affinity towards the alkylammonium cations (>200 kJ mol-1 ) values. The resulting data have been compared with the experimentally reported proton affinities of the studied nitrogen-containing organobases revealing that the propensity of an organobase for the proton transfer process increases linearly with its proton affinity. This work can provide a tool for designing senors for bioactive compounds containing amino groups that are protonated at physiological pH.

Synthesis and molecular structure of beta-phosphinoyl carboxamides: an unexpected case of chiral discrimination of hydrogen-bonded dimers in the solid state.

A series of N,P,P-trisubstituted aminophosphanes react with diphenylcyclopropenone to afford an easily separable mixture of two diastereomeric alpha,beta-diphenyl-beta-phosphinoyl carboxamides in good yields. X-ray crystal structures reveal that these compounds associate into dimers, formed from two enantiomeric units linked by two bifurcated hydrogen bonds, whereby the oxygen atom of the phosphoryl group acts as a dual acceptor for the vicinal NH and CH of a carbonyl group of a neighbouring molecule. Studies on the interconversion between diastereomeric phosphinoyl carboxamides in basic solution show that the thermodynamically most stable isomer depends on the nature of the substituent at the nitrogen atom. Simple computational calculations explain this phenomenon.