Catalytic Asymmetric Synthesis of α-Arylpyrrolidines and Benzo-fused Nitrogen Heterocycles.

Herein, we report a practical two-step synthetic route to α-arylpyrrolidines through Suzuki-Miyaura cross-coupling and enantioselective copper-catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium-ring dibenzo-fused nitrogen heterocycles.

The Pauson-Khand reaction using alkynylboronic esters: solving a long-standing regioselectivity issue.

The first intermolecular Pauson-Khand reaction, conducted using internal alkynylboronic esters, allows the installation of the boronic ester moiety at the ß-position of the cyclopentenone with total regio- and stereoselectivity.

Functionalizations of Mixtures of Regioisomeric Aryllithium Compounds by Selective Trapping with Dichlorozirconocene.

The reaction of mixtures of aryllithium regioisomers obtained either by directed lithiation or by Br/Li exchange with substoichiometric amounts of Cp2ZrCl2 proceeds with high regioselectivity. The least sterically hindered regioisomeric aryllithium is selectively transmetalated to the corresponding arylzirconium species leaving the more hindered aryllithium ready for various reactions with electrophiles. As an application, these regioselective transmetalations from Li to Zr were used to prepare all three lithiated regioisomers of 1,3-bis(trifluoromethyl)benzene.

Transition-Metal-Free Cross-Coupling of Aryl and N-Heteroaryl Cyanides with Benzylic Zinc Reagents.

Functionalized 4-benzylated pyridines can be efficiently prepared by a transition-metal-free cross-coupling between various benzylic zinc chlorides and substituted 4-cyanopyridines in THF/DMPU under microwave irradiation (40 °C, 0.5-1.5 h). Selective benzylations on polycyano-aromatics have also been achieved under these mild conditions. We also report a novel oxidative nucleophilic substitution of a hydrogen on 1,3-dicyanobenzene using benzylic zinc reagents.

Asymmetric intermolecular cobalt-catalyzed Pauson-Khand reaction using a P-stereogenic bis-phosphane.

The asymmetric intermolecular and catalytic Pauson-Khand reaction has remained an elusive goal since Khand and Pauson discovered this transformation. Using a novel family of P-stereogenic phosphanes, we developed the first catalytic system with useful levels of enantioselection for the reaction of norbornadiene and trimethylsilylacetylene. The results demonstrate that Co-bisphosphane systems are sufficiently reactive and that they lead to high selectivity in the intermolecular process.

Transition-metal-free BF3-mediated oxidative and non-oxidative cross-coupling of pyridines.

We report a BF3-mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross-coupling). Moreover, we have developed a novel transition-metal-free cross-coupling method between alkylmagnesium reagents and 4-substituted pyridines, such as isonicotinonitrile and 4-chloropyridine, by employing BF3⋅OEt2 as a promoter. The combination of these methods enabled us to efficiently prepare a range of di-, tri-, and tetrasubstituted pyridines.

TMP-magnesium and TMP-zinc bases for the regioselective metalation of the cinnoline scaffold.

A regioselective functionalization of cinnolines in positions 3 and 8 using metalations has been developed. This involves either the use of a frustrated Lewis pair consisting of BF3·Et2O and TMP2Mg·2LiCl or the in situ generated base TMP2Zn·2MgCl2·2LiCl. Successive metalations allow the preparation of 3,8-disubstituted cinnolines. Various functionalizations by acylation, allylation, and cross-coupling reactions with aryl halides or alkenyl iodides were carried out successfully.

Ni-catalyzed carboxylation of C(sp2)- and C(sp3)-O bonds with CO2.

In recent years a significant progress has been made for the carboxylation of aryl and benzyl halides with CO2, becoming convenient alternatives to the use of stoichiometric amounts of well-defined metal species. Still, however, most of these processes require the use of pyrophoric and air-sensitive reagents and the current methods are mostly restricted to organic halides. Therefore, the discovery of a mild, operationally simple alternate carboxylation that occurs with a wide substrate scope employing readily available coupling partners will be highly desirable. Herein, we report a new protocol that deals with the development of a synergistic activation of CO2 and a rather challenging activation of inert C(sp(2))-O and C(sp(3))-O bonds derived from simple and cheap alcohols, a previously unrecognized opportunity in this field. This unprecedented carboxylation event is characterized by its simplicity, mild reaction conditions, remarkable selectivity pattern and an excellent chemoselectivity profile using air-, moisture-insensitive and easy-to-handle nickel precatalysts. Our results render our method a powerful alternative, practicality and novelty aside, to commonly used organic halides as counterparts in carboxylation protocols. Furthermore, this study shows, for the first time, that traceless directing groups allow for the reductive coupling of substrates without extended π-systems, a typical requisite in many C-O bond-cleavage reactions. Taking into consideration the limited knowledge in catalytic carboxylative reductive events, and the prospective impact of providing a new tool for accessing valuable carboxylic acids, we believe this work opens up new vistas and allows new tactics in reductive coupling events.

Stereodivergent SN2@P reactions of borane oxazaphospholidines: experimental and theoretical studies.

The stereodivergent ring-opening of 2-phenyl oxazaphospholidines with alkyl lithium reagents is reported. N-H oxazaphospholidines derived from both (+)-cis-1-amino-2-indanol and (-)-norephedrine provide inversion products in a highly stereoselective process. In contrast, N-Me oxazaphospholidines yield ring-opening products with retention of configuration at the P center, as previously reported by Jugé and co-workers. As a result, from a single amino alcohol auxiliary, both enantiomers of key P-stereogenic intermediates could be synthesized. Theoretical studies of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H substrates react in a single step via preferential backside S(N)2@P substitution with inversion at phosphorus. N-methylated substrates react preferentially via a two-step frontside S(N)2@P, yielding a ring-opened product in which the nucleophilic methyl binds to P with retention of configuration. DFT calculations have shown that the BH3 unit is a potent directing group to which the methyl lithium reagent coordinates via Li in all the reactions studied.

Ni-catalyzed direct carboxylation of benzyl halides with CO2.

A novel Ni-catalyzed carboxylation of benzyl halides with CO(2) has been developed. The described carboxylation reaction proceeds under mild conditions (atmospheric CO(2) pressure) at room temperature. Unlike other routes for similar means, our method does not require well-defined and sensitive organometallic reagents and thus is a user-friendly and operationally simple protocol for assembling phenylacetic acids.

P-stereogenic secondary iminophosphorane ligands and their rhodium(I) complexes: taking advantage of NH/PH tautomerism.

Have a good SIP: P-stereogenic secondary iminophosphorane (SIP) ligands with a sulfonyl group attached to nitrogen have been prepared. In the presence of rhodium, the tautomeric equilibrium is shifted from the favored PH tautomer towards the P(III) tautomer, thereby allowing coordination of the SIP ligand through the P and O atoms. The resulting Rh complexes are effective in the [2+2+2] cycloaddition of enediynes with terminal alkynes.

Stereoselective synthesis of P-stereogenic aminophosphines: ring opening of bulky oxazaphospholidines.

A highly diastereoselective and efficient synthesis of P-stereogenic bulky alkyl and aryl aminophosphines that relies on ring opening of tert-butyl-oxazaphospholidine 2 is described. Ring opening with several organometallic reagents takes place with inversion of configuration at the phosphorus center as it has been demonstrated by X-ray analysis of two ring-opened intermediates. The unprecedented reactivity observed is attributed to the presence of a free NH functionality that facilitates the attack of the organometallic reagent in an S(N)2@P-type process.