Beatriz Iglesias

Carbon Dioxide as a Carbonylating Agent in the Synthesis of 2-Oxazolidinones, 2-Oxazinones, and Cyclic Ureas: Scope and Limitations

Carbon dioxide can be used as a convenient carbonylating agent in the synthesis of 2-oxazolidinones, 2-oxazinones, and cyclic ureas. The transient carbamate anion generated by treating a primary or secondary amine group in basic media can be activated with phosphorylating agents such as Diphenylphosphoryl azide (DPPA) and Diphenyl chlorophosphate (DPPCl) but also with other types of electrophiles such as SOCl(2), TsCl, or AcCl. The intramolecular trapping of the activated carbamate by a hydroxyl group leads to the formation of 2-oxazolidinones or 2-oxazinones in good to excellent yields. This methodology was successfully applied to the synthesis of cyclic ureas up to 7-membered rings from the corresponding diamines.

Regioselective palladium-catalyzed cross-coupling reactions in the synthesis of novel 2,3-disubstituted thiophene derivatives

Abstract A reactivity optimization study of the palladium-catalyzed cross-coupling reactions of 2,3-dibromothiophene and organometallic reagents has been conducted. Regioselective coupling at the C2 position, accomplished most notably by Suzuki coupling, was combined with a Stille reaction at C3 using Fus modification, to afford the 2,3-disubstituted thiophene derivatives.

A COMPREHENSIVE SURVEY OF STILLE-TYPE CSP2-CSP2 SINGLE BOND FORMING PROCESSES IN THE SYNTHESIS OF RETINOIC ACID AND ANALOGS

Abstract The synthesis of the retinoid skeleton has been exhaustively explored using the Stille coupling for the formation of the side-chain single bonds. On employing the experimental catalytic conditions developed by Farina [Pd 2 (dba) 3 , AsPh 3 , NMP] we have modified the electronic and steric requirement of the coupling parters, alkenyl stannanes and electrophiles (alkenyl iodides and triflates). The comprehensive survey afforded appropriately matched components for every bond formation considered. Moreover, from the comparison of the reactivities of different coupling partners with different degrees of steric hindrance, the sensitivity of the Stille coupling to steric effects was confirmed. Besides providing a variety of building blocks for retinoid synthesis, the study highlights some trends that might be useful for the application of the Stille reaction to the synthesis of unsubstituted conjugated polyenes.

Stereocontrolled synthesis of all-(E)- and (8Z)-anhydroretinol

Abstract Convergent syntheses of hexaenes anhydroretinol and its (8 Z )-isomer are described. Despite the mild reaction conditions for the final step in both cases, a Stille coupling reaction between trienyl triflates and trienyl stannanes, the stereochemical integrity of anhydroretinol is not maintained, due to its intrinsic instability.

Insights into the mechanism of the site-selective sequential palladium-catalyzed cross-coupling reactions of dibromothiophenes/dibromothiazoles and arylboronic acids. Synthesis of PPARβ/δ agonists

A reactivity study, aided by NMR spectroscopy, allowed a mechanistic rationale to be postulated for the palladium-catalyzed regioselective coupling of arylboronic acid (and arylstannane where feasible) at the position next to the sulfur atom in functionalized dibromothiophenes and dibromothiazoles. The analysis of the NMR spectra (using 19F from the boronic acid CF3 group and 31P from the phosphine of the catalyst as probes) of the entire reaction starting from the dibromoheterocycles allowed the qualitative proposal that the transmetalation is the rate-limiting step for both sequential substitution processes. The extremely facile oxidative addition at the C–Br bond next to the sulfur atom of the heterocycle instead determines the positional selectivity. An additional Stille reaction then replaced the second halogen, providing the trisubstituted heterocyclic scaffolds of PPAR ligands, which displayed PPARβ/δ agonist activity, as revealed by reporter assays in living cells.

A general synthesis of alkylpyridines

Abstract The hydroboration of alkenes, followed by the coupling of the B -alkyl-9-borabicyclo[3.3.1]nonane derivatives with bromopyridines constitutes an efficient procedure for the attachment of functionalized alkyl chains to the pyridine nucleus.

Functionalized alkylidenecyclopentenes by acid-catalyzed electrocyclic ring closure of (2Z)-(di)vinylallene acetals

Acid-induced electrocyclic ring-closure of (2Z)-4-tert-butyl-3-methyl-2,4,5,7-tetraene acetals 3 afforded a mixture of alkylidenecyclopentene dioxanes Z-4 and E-4. The lack of torquoselective effects on the electrocyclization suggested the transition state structures for the two alternative conrotatory modes to have similar energies. The results of an ab initio study of a model system at the DFT B3LYP/6-31G∗ level were consistent with this hypothesis.

Different Reactivity of Hydroxylamine with Carbamoyl Azides and Carbamoyl Cyanides: Synthesis of Hydroxyureas and Carbamoyl Amidoximes

The carbamoylating agents carbamoyl azides and carbamoyl cyanides (aka cyanoformamides) react with hydroxylamine in different ways, leading in the first case to N-hydroxyureas and, in the case of carbamoyl cyanides, to carbamoyl amidoxime derivatives. The synthetic procedure developed for the latter type of compound, which represents an interesting precursor for heterocyclic structures, allowed the highly efficient preparation of a wide selection of examples. The Z configuration of the double bond in the amidoxime moiety was proposed on the basis of comparison between experimental and calculated (13)C and (15)N NMR chemical shift values for the isopropyl and benzyl derivatives.

STEREOCONTROLLED SYNTHESIS OF RETINOIDS FUNCTIONALIZED AT C-13 BY SUZUKI COUPLING REACTIONS

Abstract The retinal analogues (13Z)-13-bromo-13-desmethylretinal (3) and (13E)-20,20,20-trifluororetinal (4) have been efficiently synthesized using the palladium-catalyzed cross-coupling of boronic acid 8 and electrophiles 9 and 10, respectively. For the first analogue, the coupling of 8 and the gem-dibromide 9 took place with high stereoselectivity. The configuration of the C13-C14 double bond in 4 relied on the stereoselective preparation and coupling of alkenyltriflate Z-10 from β-ketoester 15.

Semicarbazones from N-Hydroxyureas and Amines: A Novel Entry in the Reactivity of the Acyl Nitroso Group

The condensation of carbamoyl nitroso compounds, obtained by oxidation of N-hydroxyureas, with amines unexpectedly afforded semicarbazones (aka carbamoyl hydrazones). Although the substitution of the nitrosyl moiety might compete to afford the corresponding urea, an excess of amine led to the semicarbazone as the major product, which is presumably formed via isomerization of an initially generated acyl azo compound.