Minisci alkylations of electron-deficient pyrimidines with alkyl carboxylic acids

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

“…Other reagents have indeed been exploited for the selective alkylation of CÀHb onds in electron-deficient heteroarenes:t hey include alcohols, [70][71][72][73] carboxylic acids, [74][75][76][77][78][79][80][81][82][83] peroxides, [84,85] aldehydes, [86][87][88] acyl chlorides, [89] as well as some less common reagents such as pyridinium salts, [90] dihydropyridines, [91] N-tosylhydrazones, [92] N-(acyloxy)phthalimides, [93,94] a-diazocarbonyl derivatives, [95] a-carbonyl alkylsulfones, [96] carboxylic xanthates, [97,98] cycloalkanols, [99,100] and Wittig reagents. [101] Theu se of alcohols as remarkably attractive alkylating agents was elegantly exploited by MacMillan in 2015 for the direct alkylation of pyridine derivatives by using as trategy that combines photoredox catalysis and hydrogen atom transfer catalysis.…”

“…[73] Carboxylic acids have also been utilized extensively as competent alkylating agents for the direct functionalization of nitrogen-containing heterocycles.These processes are usually based on ad ecarboxylation/oxidation sequence for the generation of alkyl radicals that then add to the heteroarenes in aM inisci-type fashion. Fore xample,t he direct C6alkylation of purine nucleosides with primary,s econdary, and tertiary alkyl carboxylic acids could be achieved using an AgNO 3 /(NH 4 ) 2 S 2 O 8 system, [74] which was also found to be efficient for the functionalization of electron-deficient pyrimidines with secondary and tertiary alkyl carboxylic acids, [75] as well as for the direct alkylation of some 3,6-disubstituted pyridazines with amino acids. [76a] (NH 4 ) 2 S 2 O 8 itself was also shown to readily promote the direct alkylation of N-heteroarenes in the absence of metal, photoredox catalyst, and light.…”

Jenseits von Friedel und Crafts: dirigierte Alkylierung von C‐H‐Bindungen in Arenen

“…Auch andere Reagenzien wurden fürd ie selektive Alkylierung von C-H-Bindungen in elektronenarmen Heteroarenen genutzt:H ierzu zählen Alkohole, [70][71][72][73] Carbonsäuren, [74][75][76][77][78][79][80][81][82][83] Peroxide, [84,85] Aldehyde, [86][87][88] Acylchloride [89] sowie…”

“…Diese Verfahren beruhen fürg ewçhnlich auf einer Sequenz aus Decarboxylierung und Oxidation zur Erzeugung von Alkylradikalen, die dann in einer Minisci-Reaktion an die Heteroarene addieren. Beispielsweise gelang so die direkte C6-Alkylierung von Purinnucleosiden mit primären, sekundären und tertiären Alkylcarbonsäuren mithilfe eines AgNO 3 /(NH 4 ) 2 S 2 O 8 -Systems, [74] das sich auch als effizient fürd ie Funktionalisierung elektronenarmer Pyrimidine mit sekundären und tertiären Alkylcarbonsäuren erwies, [75] sowie fürd ie direkte Alkylierung einiger 3,6-disubstituierter Pyridazine mit Aminosäuren. [ [79] Unter diesen Bedingungen konnten diverse Heteroarene mit einem großen Überschuss (10 ¾quivalenten) an primären, sekundären und tertiären Carbonsäuren sowie Amino-und Fettsäuren alkyliert werden, wodurch in ausreichenden bis guten Ausbeuten die gewünschten alkylierten Produkte entstanden (Schema 25).…”

Advances in Radical Oxidative C—H Alkylation of N‐Heteroarenes

“…The electron-deficient pyrimidines with a chloro and a trifluoromethyl group were also suitable for the Minisci reaction (Scheme 17). [27] A variety of readily available alkyl and (hetero)cycloalkyl carboxylic acids underwent the alkylation well with good yields.…”