JACS: synthesis of 1,2-aminoalcohol by carbonyl addition reaction with chromium / photocatalysis

1,2-aminoalcohol unit is an important group, which widely exists in natural products, drug active molecules and ligand structures It is estimated that about 300000 compounds have this unit, including > 2000 natural products, > 80 FDA approved drugs and > 100 candidate drugs (Figure 1) Therefore, the synthesis of this kind of structure has aroused wide interest of chemists In traditional methods, amines can be used to nucleophilic attack the epoxy structure to obtain such products, but the epoxides are too active and difficult to prepare, so the selectivity of this method is not high Another method is to use carbon anion to add carbonyl nucleophile to get such products However, the development of this method is relatively slow, mainly due to the difficulty of synthesis of carbon anion substituted by α - nitrogen (α - nitrogen atom has destabilization effect on carbon anion) At present, the synthesis of a-n-substituted carbon anion mainly depends on tin reagent, but this method is toxic, low atom economy and poor functional group tolerance As a nucleophilic reagent, organic chromium reagent has unique advantages Chromium reagent not only has good functional group tolerance, but also has good selectivity for aldehydes Therefore, the addition reaction of organic chromium reagent to carbonyl, i.e Nozaki Hiyama Kishi (NHK) reaction, is widely used in organic synthesis, Although many chromium reagents can be produced under the conditions of traditional NHK reaction (i.e the reduction metallization of organic halogenated compounds catalyzed by nickel with chromium species), the synthesis of alkyl chromium reagents is difficult Takai, shenvi and Baran groups have developed methods for the synthesis of alkylchromium reagents, which greatly expanded the range of chromium mediated carbonylation substrates However, equivalent chromium salts are still needed in these methods, and α - aminoalkyl chromium species cannot be synthesized by these methods Recently, the frank glorius group at the University of Minster in Germany has developed a catalytic method for the synthesis of α - aminoalkylchromium species, which provides a simple and mild method for the synthesis of 1,2-aminoalcohol Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b12053) (source: J am Chem SOC.) firstly, the author used phenylalanine 1a and α - silylamine 2A as template substrate to optimize the conditions (Table 1) By optimizing the conditions of photosensitizer and chromate, the author determined that the optimal reaction conditions were as follows: IR (CF 3 PPy) 2 (dtbbpy)] [pf 6] (ir-2) as photosensitizer, chromium trichloride as chromate, DMA as solvent, substrate reacted at room temperature under blue light for 2 h, and the final yield was 92% It is worth mentioning that the reaction is sensitive to water, but the light intensity, temperature and reaction concentration have little influence on the reaction system (source: J am Chem SOC.) after determining the optimal reaction conditions, the author then expanded the substrate range of the reaction (Table 2) Many nitrogen heterocyclic structures can participate in the reaction well The size of the ring has little effect on the reaction The amines with ring opening can also get the product in high yield However, the second-order α - aminoalkylchromium reagent can not participate in the reaction effectively For aromatic aldehydes, the product can only be obtained in medium yield, which is mainly due to the pinacol coupling product The reaction has good functional group tolerance, and the third-order amines, alkenes, aryl halides and other groups are compatible with the reaction conditions At the same time, the reaction system has good selectivity for aldehydes and ketones Then, the author realized the challenging process of alkylation of ketones Ring, acyl and acyl silicon structures can participate in the reaction well (source: J am Chem SOC.) finally, through the study of the mechanism of the reaction, the following conclusions are obtained: 1) the reaction is deoxidized and quenched; 2) α - aminoalkylchromium reagent is produced in the reaction system through the σ - bond decomposition process Summary: Frank glorius group has developed a mild and highly selective method to synthesize α - aminoalkylchromium reagent by chromium / photocatalysis, thus realizing the synthesis of 1,2-aminoalcohol.