RESUMO
A transition-metal-free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4-quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro-type reduction followed by an Evans-Tishchenko reaction. When isoquinolines featuring a proton at the 4-position are used, a tandem methylation-hydroxymethylation occurs, leading to the formation of 2 new C-C bonds in one pot.
RESUMO
A four-step protocol for the synthesis of pyrazolo[1,5-a]pyrazines has been developed. Commercially available pyrazoles were alkylated and formylated in a regiocontrolled manner to give pyrazole-5-aldehydes bearing 2,2-dialkoxyethyl substitution on N-1. Efficient conditions for the subsequent deprotection and cyclization of these intermediates allowed access to pyrazolo[1,5-a]pyrazines with multiple substitution patterns. The versatility of the pyrazole-5-aldehyde intermediates was further demonstrated through a deprotection and double-reductive amination sequence to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines.
RESUMO
The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium-catalysed dearomative functionalisation of a range of electronically diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. A noteworthy feature of this work is that paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. Removal of the activating group can be achieved readily, furnishing the free NH compound in only 2 steps. The synthetic utility of the method was illustrated with a synthesis of (±)-Paroxetine.
RESUMO
Pyridines are ubiquitous aromatic rings used in organic chemistry and are crucial elements of the drug discovery process. Herein we describe a new catalytic method that directly introduces a methyl group onto the aromatic ring; this new reaction is related to hydrogen borrowing, and is notable for its use of the feedstock chemicals methanol and formaldehyde as the key reagents. Conceptually, the C-3/5 methylation of pyridines was accomplished by exploiting the interface between aromatic and non-aromatic compounds, and this allows an oscillating reactivity pattern to emerge whereby normally electrophilic aromatic compounds become nucleophilic in the reaction after activation by reduction. Thus, a set of C-4 functionalised pyridines can be mono or doubly methylated at the C-3/5 positions.
RESUMO
Aromatic rings are ubiquitous in organic chemistry and form the basis of many commercial products. Despite the numerous routes available for the preparation of aromatic compounds, there remain few methods that allow their conversion into synthetically useful partially saturated derivatives and even fewer that allow new C-C bonds to be formed at the same time. Here we set out to address this problem and uncover a unique catalytic partial reduction reaction that forms partially saturated azaheterocycles from aromatic precursors. In this reaction, methanol and formaldehyde are used for the reductive functionalization of pyridines and quinolines using catalytic iridium; thus, inexpensive and renewable feedstocks are utilized in the formation of complex N-heterocycles. By harnessing the formation of a nucleophilic enamine intermediate, the C-C bond-forming process reverses the normal pattern of reactivity and allows access to the C3 position of the arene. Mechanistic investigations using D-labelling experiments reveal the source of hydride added to the ring and show the reversible nature of the iridium-hydride addition.