A protocol for the Pd-catalyzed C5(sp 3 )-H arylation of readily available 1-Boc-3-(picolinoylamino)piperidine with iodo-(hetero)arenes is reported. The substrate can be obtained from a biorenewable feedstock, namely L-arginine. The use of the right N1 protective group is decisive to get arylation. The addition of a catalytic amount of 2,6-dimethylbenzoic acid and performing the reaction at high concentration are important to achieve a high conversion and yield. The procedure gives arylated 1-Boc-3-(picolinoylamino)piperidines in a regiospecific (C5) and stereospecific (cis) manner. Orthogonal cleavage of the amide over the carbamate group allows one to further selectively derivatize the amino moieties of the piperidine scaffold.
A catalytic system for ruthenium-catalyzed CA C H T U N G T R E N N U N G (sp 3) À H a-alkylation of piperidines with dioxolaneprotected alkenones is reported. Dioxolane protection of the ketone proved crucial to obtain alkylation products. A diverse set of highly substituted piperidines was readily prepared in moderate to good yields via this methodology from easily accessible starting materials (C-2, C-3 and C-4 substituted piperidines). When the methodology is applied to C-3 substituted piperidines, featuring two a positions, only monoalkylated products (2,5-disubstituted) are observed. Even bicyclic amines, which feature a fused piperidine moiety, can be used. The successful directing group as well as protecting group (ketal) removal is also demonstrated. The methodology thus allows one to further derivatize and access hitherto unknown functionalized cyclic amine derivatives and will be useful in molecular library synthesis.
An ew three-component reductive arylation of amides with stable reactants (iPrOH and arylboronate esters), making use of a2 -pyridinyl (Py) directing group,i s described. The N-Py-amide substrates are readily prepared from carboxylic acids and PyNH 2 ,a nd the resulting N-Py-1arylalkanamine reaction products are easily transformed into the corresponding chlorides by substitution of the HN-Py group with HCl. The 1-aryl-1-chloroalkane products allow substitution and cross-coupling reactions.Therefore,ageneral protocol for the transformation of carboxylic acids into avariety of functionalities is obtained. The Py-NH 2 by-product can be recycled.
Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site‐ and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd‐catalyzed γ‐C(sp3)‐H olefination of aminocyclohexane with gem‐dibromoalkenes, followed by a consecutive intramolecular Cu‐catalyzed amidation of the 1‐bromo‐1‐alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza‐ and oxa‐analogues. The Cu catalyst of the Ullmann‐Goldberg reaction additionally avoids off‐cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7‐alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio‐ and diastereoselective Pd‐catalyzed γ‐C(sp3)‐H olefination is achieved.
An efficient strategy for the cleavage
of the picolinamide directing
group (DG) and recycling of the byproduct generated has been developed.
In this protocol, picolinamides were first Boc activated into tertiary N-Boc-N-substituted picolinamides. These
were then cleaved via a Ni-catalyzed esterification reaction with
EtOH to give valuable N-Boc protected amines. Ni(cod)2 was used as a catalyst without any ligands or base additives.
The byproduct, ethyl 2-picolinate can be used to install the picolinamide
DG in a direct or indirect manner on amines. The protocol exhibits
a broad functional group tolerance and high yields. To demonstrate
the utility of this approach, it was applied on many selected examples
from the recent C–H functionalization literature featuring
2-picolinamide as a DG.
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