Davis–Beirut reaction

Davis–Beirut reaction
Named after	University of California, Davis American University of Beirut
Reaction type	Ring forming reaction

The Davis–Beirut reaction is N,N-bond forming heterocyclization that creates numerous types of 2H-

The Davis–Beirut reaction is named after Mark Kurth and Makhluf Haddadin's respective universities; University of California, Davis and American University of Beirut, and is appealing because it uses inexpensive starting materials and does not require toxic metals.^[3][6][7]

Mechanism in base

The current proposed mechanism for the Davis–Beirut reaction in base was first published in 2005 by Kurth, Olmstead, and Haddadin. The reaction occurs when a N-substituted 2-nitrobenzylamine is heated in the presence of base, such as NaOH and KOH, and an alcohol and includes the formation of a

(8) is extracted by the base, the flow of electrons creates two new carbon-nitrogen bonds and causes the loss of the protonated hydroxyl group as a molecule of water. The final product produced by this mechanism is therefore a 3-oxy-substituted 2H-indazole.

Slight variations of this mechanism exists depending on the starting materials and the conditions (acid or base) of the reaction.^[2][1] In instances of intramolecular oxygen attack (i.e. step 5 of the proposed mechanism is intramolecular) an o-nitrobenzylidene imine intermediate is formed compared to the secondary imine of the displayed mechanism.^[2]

Furthermore, Davis–Beirut reactions in acids form a carbocation as one of its transition states instead of the proposed carbanion one when the reaction occurs in base.^[3]

Other variants of the Davis–Beirut reaction

By manipulating the starting materials of the Davis–Beirut reaction, researchers can create a large number of 2H-indazoles derivatives, many of which can be utilized for further synthesis.^[1][6] In 2014, Thiazolo-, Thiazino-, and Thiazipino-2H-indazoles were synthesized utilizing o-nitrobenzaldhydes or o-nitrobenzyl bromides and S-trityl-protected primary aminothiol alkanes with a base, such as KOH, in alcohol.^[1] Creating Thiazolo-, Thiazino-, and Thiazipino-2H-indazoles is beneficial since they are generally more stable than the oxo-2H-indazoles formed without the S-trityl-protected group, and they can easily be oxidized to sulfones.^[1]

Creating 2H-indazoles via the Davis–Beirut reaction can also help in producing 1H-indazoles, naturally occurring and synthetically made molecules with known pharmaceutical uses such as anti-inflammatories and anti-cancer drugs.^[6][8] By creating 2H-indazoles via the Davis–Beirut reaction, the product can subsequently be reacted with electrophiles, such as anhydrides, to create disubstituted 1H-indazoles that can be utilized for pharmaceutical and other industrial purposes.^[6]

Applications

Heterocycles, especially those containing nitrogen atoms, are highly prevalent in many pharmaceutical drugs currently on the market.^[4] Some, like those coming from 1H-indazoles, contain naturally occurring molecules, while others are purly synthetic.^[8] 2H-indazoles, though, are very rare in nature compared to 1H-indazole compounds, most likely due to the complex nature of a heterocycle including a nitrogen-nitrogen bond and an ether side chain.^[9] The discovery of the Davis–Beirut reaction therefore provides any easy and cost effective way to synthetically create 2H-indazoles.^[4] Breakthroughs, including the success of introducing thioether moiety at C3 of the 2H-indazole structure, has aided in creating drug treatments for a variety of ailments, including cystic fibrosis, with the use of myeloperoxidase inhibitors.^[4][6][10] Due to the recentness of the discovery of this reaction, though, most research is primarily headed by Haddadin, Kurth, or both, therefore causing a currently limited scope.^[3]

References