Intramolecular homolytic substitution of sulfinates and sulfinamides--a computational study

Ab initio and density functional theory (DFT) calculations predict that intramolecular homolytic substitution by alkyl radicals at the sulfur atom in sulfinates proceeds through a smooth transition state in which the attacking and leaving radicals adopt a near collinear arrangement. When forming a five-membered ring and the leaving radical is methyl, G3(MP2)-RAD//ROBHandHLYP/6-311++G(d,p) calculations predict that this reaction proceeds with an activation energy (ΔE(1)(?)) of 43.2 kJ mol(-1). ROBHandHLYP/6-311++G(d,p) calculations suggest that the formation of five-membered rings through intramolecular homolytic substitution by aryl radicals at the sulfur atom in sulfinates and sulfinamides, with expulsion of phenyl radicals, proceeds with the involvement of hypervalent intermediates. These intermediates further dissociate to the observed products, with overall energy barriers of 45-68 kJ mol(-1), depending on the system of interest. In each case, homolytic addition to the phenyl group competes with substitution, with calculated barriers of 51-78 kJ mol(-1). This computational study complements and provides insight into previous experimental observations.     

Selenofonsartan analogues: novel selenium-containing antihypertensive compounds

2-Butyl-4-(methylseleno)-1-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (4) and 2-butyl-4-(phenylseleno)-1-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (5) have been prepared and tested for AT₁ receptor antagonist properties. Both compounds proved to be potent AT₁ receptor antagonists, with pK_b estimates indicating that these selenides are very effective at blocking AT₁ receptor mediated responses.     

Aromatic homolytic substitution using solid phase synthesis

Solid phase synthesis has been used to carry out intramolecular aromatic homolytic substitution with benzoimidazole precursors. The protocol attaches the radical precursors to the resins via the radical leaving groups (in the aromatic homolytic substitution). When the radical reactions are complete, the leaving group, unaltered starting material and reduced uncylised products remain attached to the resin, which facilitates easy separation of the cyclised products. Novel use of focussed microwave irradiation in solid phase radical reactions drastically shortens the reactions times. Tributylgermanium hydride has been used to replace the toxic and troublesome tributyltin hydride in the radical reactions.     

Intramolecular homolytic substitution at the sulfur atom: an alternative way to generate phosphorus- and sulfur-centered radicals

Two efficient procedures involving tin hydride or thiophenol-mediated intramolecular homolytic substitution at the sulfur atom are reported. They lead to the generation of varied P(V)-centered radicals from the corresponding aryl or alkyne thiophosphorus substrates. The radical formed can be trapped by an olefin via an intermolecular addition, leading to the construction of C-P bonds. Thiophosphination of triple bonds was also achieved using a radical cycloisomerization process. Extension of the methodology to sulfur-containing species was examined.     

Preparation of novel selenopenams by intramolecular homolytic substitution

Photolyses of the thiohydroximate ester derivatives 13 and 21 of the 4- (benzyl-seleno)-2-azetidinoines 7 and 20, afford the 1-aza-7-oxo-4-selenabicyclo- [3.2.0]heptane ring systems 14 and 21 in good to moderate yield in processes that presumably involve intramolecular homolytic substitution at selenium with expulsion of benzyl radical. Extension of this methodology to the preparation of derivatives 24 of 12,2a-dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (22) is also described.     

Synthesis of novel selenium-containing donors as selenium analogues of diiodo(ethylenedithio)diselenadithiafulvalene (DIETS)

Novel selenium analogues of diiodo(ethylenedithio)diselenadithiafulvalene (DIETS) have been successfully derived from 1,3-diselenole-2-thione, which could be synthesized without the use of the highly toxic reagent CSe(2).     

Intramolecular homolytic aromatic substitution of alkyl 2-benzimidazolyl sulfones as a means of entry into alkyl radicals for organic synthesis

The intramolecular radical aromatic substitution of heteroaryl sulfones by tethered aryl radicals has been investigated as a source of alkyl radicals. The 1-(2-iodobenzyl)benzimidazole-2-sulfonyl system was found to be the most effective, while a tetrazole-based system did not undergo the desired radical aromatic substitution at all. Application of the benzimidazole-based system to the generation of alkyl radical and their subsequent use in radical cyclizations was demonstrated.     

Generation of phosphorus-centered radicals via homolytic substitution at sulfur

A novel radical domino process relying on the homolytic cleavage of P-S bonds allows the preparation of phosphorus-containing molecules through addition of P-centered radicals onto olefins. The key step of this reaction is a homolytic substitution on a sulfur atom. The scope of the reaction is broad. Diaminophosphonyl radicals whose reactivity was unknown react smoothly with olefins. Use of tin hydride can be avoided. A radical thiophosphinoylation of triple bonds has been uncovered. [reaction: see text]     

Intramolecular nucleophilic substitution at an sp carbon: synthesis of substituted thiazoles and imidazole-2-thiones

The nucleophilic substitution reactions of vinylic bromides with intramolecular thioamide or thiourea moieties proceed to give a series of substituted thiazoles and imidazole-2-thiones.     

Stereoselective synthesis of new selenium-containing heterocycles by cyclocarbonylation of aminoalkynes with carbon monoxide and selenium

The reaction of 3-aminoalkynes 2 with carbon monoxide and selenium yielded 5-alkylideneselenazolin-2-ones 3 stereoselectively via cycloaddition of in situ generated carbamoselenoates to the carbon-carbon triple bond. 4-Aminoalkyne 7 also afforded the corresponding six-membered selenium-containing heterocycle with the aid of CuI.     

Design,synthesis, molecular docking,and biological evaluation of novel selenium containing lumefantrine analogues

A new series of 1-(9-benzylidene-2,7-dichloro-9H-fluoren-4-yl)-2-(methylselanyl)ethanol was synthesized by a simple Knoevenagel condensation of 1-(2,7-dichloro-9H-fluoren-4-yl)-2-(methylselanyl)ethanol with different substituted aromatic aldehydes in basic media. These synthesized compounds were confirmed on the basis of their elemental analyses, infrared (IR), ¹H NMR, ¹³C NMR, and mass spectral data and screened for the antibacterial and antifungal activity. The preliminary antibacterial and antifungal screening revealed that the compounds 8c (dichloro), 8d (fluoro), 8e (chloro), 8i (methoxy), and 8l (methyl) displayed moderate to good activity. The antibacterial results of these compounds were further supported by in silico molecular docking studies, for the inhibition of Escherichia coli MurB enzyme (PDB code: 2MBR), wherein they showed higher binding energy and good affinity towards the active pocket of the enzyme compared with that of the standard drug Ciprofloxacin. Thus, the plausible mechanism of their antibacterial activity was owed to their inhibitory action of the bacterial MurB enzyme.     

Mechanism of titanocene-mediated epoxide opening through homolytic substitution

The mechanism of titanocene-mediated epoxide opening was studied by a combination of voltammetric, kinetic, computational, and synthetic methods. With the aid of electrochemical investigations the nature of a number of Ti(III) complexes in solution was established. In particular, the distribution of monomeric and dimeric Ti(III) species was found to be strongly affected by the exact steric conditions. The overall rate constants of the reductive epoxide opening were determined for the first time. These data were employed as the basis for computational studies of the structure and energies of the epoxide-titanocene complexes, the transition states of epoxide opening, and the beta-titanoxy radicals formed. The results obtained provide a structural basis for the understanding of the factors determining the regioselectivity of ring opening and match the experimentally determined values. By employing substituted titanocenes even more selective epoxide openings could be realized. Moreover, by properly adjusting the steric demands of the catalysts and the substrates the first examples of reversible epoxide openings were designed.     

Intramolecular SN'-type aromatic substitution of benzylic carbonates at their para-position

The benzylic carbonates, which connect with an active methine through an o-phenylene tether at their meta-position, are cyclized by Pd(η(3)-C(3)H(5))Cp-S-Phos catalyst, yielding 3-methyl-9,10-dihydrophenanthrenes. In the catalytic cyclization, the internal nucleophile attacks not the ortho-carbon but the para-carbon of the benzylic ester. The [3 + 2] cycloaddition of m-(silylmethyl)benzyl carbonates with alkylidene malonates was developed from the palladium-catalyzed intramolecular S(N)'-type aromatic substitution.     

Parallel synthesis of prostaglandin E1 analogues

The first demonstration of the rapid parallel synthesis of diverse prostaglandin derivatives is reported. Upper (alpha-) side chain diversity was introduced to core 1 via the parallel Suzuki coupling of hydroborated alkenes. Conversion to the enones 3 and 9 was followed by the addition of the lower (omega-) side chains as higher-order cuprates 4. Upper side chains incorporating an N-acylsulfonamide protecting group were further transformed into prostaglandin amide analogues. Cleavage from support with HF/pyridine followed by scavenging provided 26 prostaglandin E1 analogues in high purity.     

Selenoimidoylation of alcohols with selenium and isocyanides and its application to the synthesis of selenium-containing heterocycles

The reaction of alcohols with selenium and isocyanides in the presence of DBU gave oxyimidoylselenoates 6. Trapping of 6 with BuI resulted in high-yield formation of selenocarbonimidates 4. When alk-2-yn-1-ols 9 were allowed to react with selenium and isocyanides under similar conditions, new selenium-containing heterocycles 10, 2-imino-4-alkylidene-1,3-oxaselenolanes, were obtained via cycloaddition of oxyimidoylselenoates 13 generated in situ by intramolecular addition of selenolates to carbon-carbon triple bonds.     

Intramolecular 1,3-dipolar cycloaddition strategy for enantioselective synthesis of FR-900482 analogues

[reaction: see text] Enantioselective synthesis of FR-900482 analogues is described. The key reaction of the synthesis is intramolecular 1,3-dipolar cycloaddition of a highly functionalized nitrile oxide with complete stereo- and regioselectivities to construct the eight-membered benzazocine ring.