Hans-Ulrich Reissig

It has been long known that hexamethylphosphoric acid triamide ( HMPA ) may cause genetic defects and cancer. Nevertheless, it is frequently used as highly polar aprotic solvent and as very strong Lewis base in synthetic organic chemistry as well as in other applications. Several attempts of replacing this hazardous compound by alternative strong Lewis bases have been reported in the literature, but the knowledge about these useful compounds and their properties does not receive the deserved attention of potential applicants. In the current computational study, we compare the Brønsted and Lewis basicity of HMPA , the already established replacement compound tripyrrolidino phosphoric acid triamide ( TPPA ) and of two conformationally restricted phosphoric acid triamides. The density functional theory study also includes N , N ′ ‐ dimethyl‐ N , N ′ ‐ propylene urea ( DMPU ) as known Lewis basic additive in a few transformations of lithium organic compounds. The Gibbs free energies of the reactions of these Lewis bases with protons, with lithium cations and with samarium(II) as well as samarium(III) species, were calculated including THF as solvent sphere. The results reveal that TPPA and one of the newly designed phosphoric acid triamides ( HAPO‐2 ) are stronger bases than HMPA in all computed reactions and are excellent substitutes of hazardous HMPA .

Levoglucosenone (LGO) smoothly undergoes microwave-assisted hetero-Diels–Alder reactions with thiochalcones in THF solution at 60 °C. The studied reactions are completed after 10 min, and the expected tricyclic 2,3-dihydro-4H-thiopyran derivatives are formed in a highly regio- and moderately stereoselective manner via competitive exo- and endo-attacks of the 1-thiadiene moiety onto the activated C=C bond of dienophile LGO. Although eight isomers are possible, only the formation of exo,exo- (major) and exo,endo- (minor) cycloadducts was observed. In most cases, isomeric products were separated by preparative layer chromatography and identified by means of spectroscopic methods. Some of the cycloadducts were obtained as single crystalline solids, and X-ray analyses enabled unambiguous confirmation of their structures. In order to explain the observed selectivity of the studied hetero-Diels–Alder reactions, DFT studies were carried out to determine the thermodynamic and kinetic properties of all regio- and stereoisomers. The results of these calculations predict the preferred formation of the two experimentally observed isomers. In addition, remarkable details on the electronic structure of E-1,3-diphenylprop-2-en-1-thione and on involved and hypothetical transition states could be elucidated.

The carbonyl group of two diastereomeric 1,2-oxazin-4-ones was employed to study routes to new enantiopure amino polyols. Addition of nucleophiles to the syn-configured diastereomer occurred with high stereoselectivity, whereas the reactions of the anti-configured 1,2-oxazine are less selective. Grignard reagents and an ester enolate were examined as nucleophiles. The carbonyl group of the 1,2-oxazin-4-ones could also be converted into an exo-methylene group by a Wittig reaction. The β-hydroxy esters derived from the ester enolate additions were treated with acid and provided bi- and tricyclic δ-lactones. Again, the configuration of the precursor compounds was crucial for the selectivity. Representative derivatives of the obtained products were either subjected to hydrogenolysis under palladium catalysis or treated with samarium diiodide as an N–O bond cleaving reagent. These reductions mostly provide the expected amino polyols. Two chain-elongated diastereomeric 1,2-oxazine derivatives bearing three contiguous stereogenic centers were also subjected to acidic conditions, which afford unique di- and tricyclic amino polyol derivatives.

With the motivation to expand the compound library of specifically substituted pyrimidine derivatives, we prepared several pyrimidine-4-carbaldehydes. In most cases, the chemoselective oxidation of 4-hydroxymethyl-substituted pyrimidine derivatives could be achieved in good yields to provide the desired compounds. Alternatively, the aldehydes were prepared by Riley oxidation with selenium dioxide from the corresponding 4-methylpyrimidines. The formyl group of these compounds was employed as handle to generate alkynyl, cyano, oxazol-5-yl or β-ketoester substituents. Furthermore, two methods were found to prepare furo[3,2-d]pyrimidines. A serendipitously discovered reaction to a 6-(pyrimidin-4-yl)furo[3,2-d]pyrimidin-7-ol derivative involves a mechanistically interestingly ‘dimerization’ process with a benzoin addition as key step. Other compounds in this series contain amino, azido, or 1,2,3-triazol-1-yl groups. All these transformations to highly substituted pyrimidine derivatives demonstrate the synthetic versatility of pyrimidine-4-carbaldehydes and similar compounds.

This study analyzes the samarium diiodide‐promoted cyclizations of 5‐arylpentan‐2‐ones to dearomatized bicyclic products utilizing density functional theory. The reaction involves a single electron transfer to the carbonyl group, which occurs synchronously with the rate determining cyclization event, and a second subsequent proton‐coupled electron transfer. These redox reactions are accurately computed employing small core pseudo potentials explicitly involving all f‐electrons of samarium. Comparison of the energies of the possible final products rules out thermodynamic control of the observed regio‐ and diastereoselectivities. Kinetic control via appropriate transition states is correctly predicted, but to obtain reasonable energy levels the influence of the co‐solvent hexamethylphosphortriamide has to be estimated by using a correction term. The steric effect of the bulky samarium ligands is decisive for the observed stereoselectivity. Carbonyl groups in para‐position of the aryl group change the regioselectivity of the cyclization and lead to spiro compounds. The computations suggest again kinetic control of this deviating outcome. However, the standard mechanism has to be modified and the involvement of a complex activated by two SmI₂ moieties is proposed in which two electrons are transferred simultaneously to form the new C−C bond. Computation of model intermediates show the feasibility of this alternative+ mechanism.

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‐gbenzyl‐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 was 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 synthesis of three enantiopure 1,2-oxazine-derived azides was optimized and the reductions of these compounds to amino alcohols were studied. As a primary aim of this study, the copper-catalyzed (3+2)-cycloadditions of the azides were investigated, employing a series of alkynes, dialkynes, and trialkynes, which afforded the corresponding mono-, di-, and trivalent triazole derivatives with different rigid and flexible core elements. The expected click products were generally obtained in good to excellent yields when copper iodide was employed in presence of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) as ligand in acetonitrile at room temperature. Several of the products were subjected to exhaustive hydrogenolysis reactions, leading to enantiopure compounds with aminopyran substructures, which can be regarded as carbohydrate mimetics.

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.

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.

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.