Heterocyclic Merging of Stereochemically Diverse Chiral Piperazines and Morpholines with Indazoles.

We report a heterocyclic merging approach to construct novel indazolo-piperazines and indazolo-morpholines. Starting from chiral diamines and amino alcohols, novel regiochemically (1,3 and 1,4) and stereochemically diverse (relative and absolute) cohorts of indazolo-piperazines and indazolo-morpholines were obtained within six or seven steps. The key transformations involved are a Smiles rearrangement to generate the indazole core structure and a late-stage Michael addition to build the piperazine and morpholine heterocycles. We further explored additional vector diversity by incorporating substitutions on the indazole aromatic ring, generating a total of 20 unique, enantiomerically pure heterocyclic scaffolds.

Annulation of Enals with Carbamoylpropiolates via NHC-Catalyzed Enolate Pathway: Access to Functionalized Maleimides/Iso-maleimides and Synthesis of Aspergillus FH-X-213.

Herein we report the N-heterocyclic carbene (NHC)-catalyzed [3 + 2] annulation of α,ß-unsaturated aldehydes with carbamoylpropiolates via an unusual enolate pathway leading to the construction of highly functionalized maleimides or isomaleimides. The electronic effect imposed by the alkyl/aryl group present on the amide nitrogen of carbamoylpropiolates plays a crucial role in the selective formation of these important five-membered heterocyclic building blocks. The developed protocol is mild and tolerates a wide range of substituents on both substrates. The application of this protocol in the synthesis of the antibacterial natural product Aspergillus FH-X-213 has also been demonstrated.

para-Selective copper-catalyzed C(sp2)-H amidation/dimerization of anilides via a radical pathway.

Copper-catalyzed amidation/dimerization of anilides via regioselective C(sp2)-H functionalization is achieved. The para-selective amidation is accomplished on the anilide aromatic ring via a radical pathway leading to C-N bond formation in the presence of ammonium persulfate as a radical source/oxidant for the copper catalyst. The developed protocol tolerates a wide range of anilide substrates. The regioselectivity is confirmed by single-crystal X-ray studies.

Ruthenium-Catalyzed Regioselective Alkenylation/Tandem Hydroamidative Cyclization of Unmasked Quinazolinones Using Terminal Alkynes.

Ruthenium-catalyzed amide directed Csp2-H activation of the quinazolinone scaffold has been demonstrated, leading to the selective mono- or dialkenylation in moderate to good yields to achieve medicinally important stilbene containing quinazolinones. The terminal alkyne is utilized as a coupling partner, which resulted in the selective trans-alkene formation. Electron-deficient phenylacetylenes facilitate alkenylation followed by tandem hydroamidation of the newly generated trans-double bond to provide novel quinazolinone alkaloids related to the Luotonine class of natural products.

Pd-Catalyzed Regioselective Mono-Arylation: Quinazolinone as the Inherent Directing Group for C(sp2)-H Activation.

The Pd-catalyzed quinazolinone-directed regioselective monoarylation of aromatic rings by C-H bond activation is developed. A broad substrate scope is demonstrated for both quinazolinone as well as diaryliodonium triflates. The use of a base was found to be crucial for this transformation, unlike for the known nitrogen-directed arylations. All of the novel quinazolinones of biological interest were synthesized by using the operationally simple Pd(II)-catalyzed arylation reaction.