Efficient and selective N-alkylation of amines with alcohols catalysed by manganese pincer complexes

Abstract

Borrowing hydrogen (or hydrogen autotransfer) reactions represent straightforward and sustainable C-N bond-forming processes. In general, precious metal-based catalysts are employed for this effective transformation. In recent years, the use of earth abundant and cheap non-noble metal catalysts for this process attracted considerable attention in the scientific community. Here we show that the selective N-alkylation of amines with alcohols can be catalysed by defined PNP manganese pincer complexes. A variety of substituted anilines are monoalkylated with different (hetero)aromatic and aliphatic alcohols even in the presence of other sensitive reducible functional groups. As a special highlight, we report the chemoselective monomethylation of primary amines using methanol under mild conditions.

Figure 1. Different methods of C–N bond formation.

(a) Traditional approach using alkyl halides and (b) greener pathway using borrowing hydrogen methodology.

Figure 2. N-alkylation of amines.

(a) General mechanism and (b) recent examples of non-noble metal complexes catalysing the N-alkylation of amines.

Figure 3. Selected examples for nitrogen containing pharmaceuticals.

(a) Examples with methylated amine functionalities and (b) examples with alkylated amine functionalities.

Figure 4. N-alkylation of aniline with benzyl alcohol: optimization with different Mn complexes.

Reaction conditions: aniline (0.5 mmol), benzyl alcohol (0.6 mmol), [Mn] (0.01 mmol), t-BuOK (1 equiv.) and toluene (1 ml), 80 °C. Conversion and yield were determined by GC analysis using hexadecane as an internal standard.

Figure 5. Selective N-alkylation of various aromatic amines with benzyl alcohol.

(a) General reaction conditions: aniline derivative (1 mmol), benzyl alcohol (1.2 mmol), 1 (3 mol%), t-BuOK (0.75 equiv.) and toluene (2 ml), 80 °C, 24 h. (b) Reaction of different aniline derivatives with alcohols. Conversion was determined by GC (isolated yield in parentheses). *Traces of reduction (<2%) of double bond were observed. **11% of N, 9-dibenzyl-9H-fluoren-2-amine was detected.

Figure 6. N-alkylation of (hetero)aromatic amines using (hetero)aromatic and aliphatic alcohols.

(a) General reaction conditions: aniline derivative (1 mmol), benzyl alcohol (1.2 mmol), 1 (3 mol%), t-BuOK (0.75 equiv.) and toluene (2 ml), 80 °C, 24 h. (b) Conversion was determined by GC (isolated yield in parentheses). 6o–6s 48 h. *22% of the corresponding imine was observed. **2 equiv. of ethanol was used.

Figure 7. Synthesis of resveratrol derivatives.

Reaction conditions: 4-aminostilbene (1 mmol), alcohol (1.2 mmol), 1 (0.03 mmol), t-BuOK (0.75 equiv.) and toluene (2 ml), 80 °C, 24 h.

Figure 8. Alternative synthesis route for indole.

Alternative synthesis of indole via an intramolecular reaction of 2-aminophenethyl alcohol.

Figure 9. N-methylation of primary anilines using methanol.

(a) General reaction conditions: aniline derivative (1 mmol), 1 (3 mol%), t-BuOK (1 equiv.), and toluene (2 ml), 100 °C, 24 h. (b) Conversion was determined by GC (isolated yield in parentheses). *Traces of reduction of double bond. **15% dehalogenation was observed.