Selective Methylation of NH-Containing Heterocycles and Sulfonamides Using N,N-Dimethylformamide Dimethylacetal Based on Calculated pKa Measurements

Abstract

The use of N,N-dimethylformamide dimethylacetal (DMF-DMA) as a suitable methylating agent for the methylation of NH-containing groups and heterocycles has been investigated. Use of ReactArray and calculated pK a measurements have allowed additional helpful information to be collated to determine optimum reaction conditions for a variety of substrates.

Photophysical and Photochemical Properties of 3‐methylpterin as a New and More Stable Pterin‐type Photosensitizer

“…Accordingly, as shown in Scheme 1, the synthesis of 3‐Mep was carried out by the selective methylation of N ‐3 with DMF‐DMA in anhydrous 1,4‐dioxane. Under the reaction conditions, compound 1 undergoes N ‐methylation and its amino moiety suffers a concomitant nucleophilic substitution by DMF‐DMA, followed by a twofold elimination of methanol, to afford the N,N ‐dimethylformimidamido derivative 2 . In turn, this was submitted to amino group deprotection by ammonolysis with concentrated ammonia in methanol.…”

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…at AstraZeneca used DMF‐DMA for the methylation of NH‐containing groups in heterocycles. They discovered that the optimal reaction temperature varied according to the calculated p K a values of substrates (Table ) …”

“…They discovered that the optimal reaction temperature varied according to the calculated pK a values of substrates (Table 1). [25] The pK a -temperature correlation provides au seful guide for applying the appropriate methylation conditions for the indole derivatives. For instance,a t6 0 8C, the mono N-methylated 7 was isolated at 83 %y ield.…”

First N‐Heterocyclic Carbenes Relying on the Triazolone Structural Motif: Syntheses, Modifications and Reactivity

“…For the synthesis of triazolonium salt 1·BF 4 ,4-phenylsemicarbazide was cyclizedw ith formamidinium acetate in DMF according to ap rocedurer ecently reported by Zhang and Yao. [14] The resultingn eutral triazole was alkylated in two steps;f irst it was treated with iodomethane in the presence of potassium carbonatet og ive the methylated amide backbone intermediate, [15] whichw as then further methylated using trimethyloxonium tetrafluoroborate to afford the amidinium cation (1·BF 4 ) in 74 %y ield (Scheme1). 1·BF 4 was fully characterized by mass spectrometry,e lemental analysis, 1 Ha nd 13 C{ 1 H} NMR spectros- [a] M. Jonek,J.Diekmann, Prof. Dr.C.G anter Institut für Anorganische und Strukturchemie Heinrich-Heine UniversitätD üsseldorf Universitätsstrasse 1, 40225 Düsseldorf (Germany) E-mail:christian.ganter@uni-duesseldorf.de copy.N otably,a 4 J HH coupling between the amidinium proton and the methyl group was observed as evidenced by the appearance of aq uartet andadoublet, respectively,i nt he 1 HNMR spectrum with 4 J HH = 0.9 Hz.…”

“…In the 1 HNMR spectrumo f7,t he signals for C2ÀHa nd N4ÀHw ere detected at d = 10.2 ppm and 9.3 ppm, respectively.W ef ound no indication that betaine 7 is in at automeric equilibriumw ith its neutralc arbene tautomer 7a,a sn or eac- (4),N1 ÀC2 1.322(4), C2ÀN3 1.374(4), C1ÀN2 1.359(4);N 1-C2-N3 105.5(3); 5b:Ir1ÀC11 1.8336 (16), Ir1ÀC121.8896(13), Ir1ÀC2 2.0657(11), Ir1ÀCl1 2.3591(5), O1ÀC1 1.2181 (15), N1ÀC2 1.3271(16),C 2 ÀN3 1.3682 (15), O2ÀC111.145(2), O3ÀC12 1.1364 (17);N1-C2-N3105.28 (10).…”