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The Balz-Schiemann Reaction

Aryl- and heteroaryl- diazonium tetrafluoroborate salts, prepared by diazotization of an aniline in the presence of HBF4, are unique in that in many cases they are sufficiently stable to isolate. Thermal decomposition of these salts at elevated temperatures results in fluoro-dediazoniation and formation of the corresponding aryl or heteroaryl fluoride- the Balz-Schiemann reaction.1a,bRadiolabelled 18F compounds

Selective N-methylation of amides using (chloromethyl)dimethylchlorosilane/ fluoride: Application to the large scale synthesis of a pyrimidone intermediate for Raltegravir

Raltegravir (free base) Selective N- v’s O- alkylation of an amide can be challenging and somewhat unpredictable- the outcome being highly dependent on the structure of the substrate. A good example of this is the N-methylated pyrimidone intermediate (5) en route to Merck’s antiretroviral drug Raltegravir.1 Direct methylation of amide (4) (Figure 1) using MeI gives significant

All about the base- or lack of it! Base-free nickel catalysed decarbonylative Suzuki-Miyaura coupling of acid fluorides

Figure 1: Suzuki-Miyaura Coupling   It’s a reaction that most organic chemists have run at some stage in their careers and is almost certainly in the running for the most widely used C-C bond forming reaction. First reported in 1979, the Suzuki-Miyaura cross-coupling between an organoboron nucleophile and an aryl halide electrophile is still ubiquitous in

Heterocyclic phosphonium salts- powerful intermediates for pyridine coupling

Heterocyclic phosphonium salts- powerful intermediates for pyridine coupling:- I’ve always had a keen interest in phosphorus chemistry and have followed the work of the McNally group at Colorado state on heterocyclic phosphonium salts closely. In late 2016 a paper describing synthesis and application of the so called HetPhos salts for C4 (or C2) functionalisation of

Reagent of the month: N-((Methylsulfonyl)oxy)acetimiodyl chloride (The Fier reagent)

Figure 1 I guess to qualify as a reagent of the month the material has to fulfil certain criteria and commercial availability, though not essential, is very desirable. N-((Methylsulfonyl)oxy)acetimiodyl chloride (henceforth known, at least by me, as Fier’s reagent) is now available to buy from Sigma Aldrich (CAS: 1433887-06-9). The compound is an air and

Intrinsically safe and shelf stable diazo transfer reagent for fast synthesis of diazo compounds

At the Scientific Update OPRD conference in Milan earlier this month, Xiaohu Deng from Kura Oncology discussed a pyrimidine-derived diazo intermediate that exists predominantly in the tautomeric ‘tetrazole’ form at equilibrium in solution.[1] The compound was shown as a putative retrosynthetic building block for synthesis of a J&J P2X7 antagonist (Figure 1).[2] I’d not come

A concise total synthesis of Quinine and analogues via C-H activation

                    The naturally occurring cinchona alkaloids, and Quinine in particular, have been of interest to synthetic chemistry practitioners for many years, due ostensibly to its antimalarial activity, particularly against resistant strains of the disease. The original synthesis, by Woodward and Doering in 1944 was heralded as

The Chichibabin amination reaction

         2-Aminopyrides are useful synthetic intermediates and pharmacophores in a number of drugs.[1] The Chichibabin reaction, developed in the 1900’s gives a direct method for the amination of pyridine and pyridine derivatives (azines and azoles) using sodium or potassium amides. Intramolecular amination reactions are also known. The reaction can be run either

Cyanomethylene trimethylphosphorane (CMMP)- a safer reagent for Mitsunobu couplings

The Mitsunobu reaction is a powerful coupling method for alkylation of various nucleophiles (H-A) with alcohols (R-OH).[1] The classical conditions use a redox system comprising of an azodicarboxylate (such as diethylaziodicarboxylate, DEAD) and a phosphine (normally triphenylphosphine, TPP). The alcohol is essentially activated in situ and coupling occurs with the generation of the phosphine oxide