JACS: synthesis of ketones, alcohols and amines by carboxylic acid derived radicals

Grignard reaction is one of the basic reactions in organic synthesis, which is widely used in the synthesis of ketones, alcohols and amines Although it has the advantages of strong practicability and wide range of substrates, there are also some problems that some functional groups are incompatible with strong alkaline and strong nucleophilic reagents In addition, compared with other functional groups such as alkenes and carboxylic acids, the starting material alkyl halides are usually not easy to obtain Therefore, organic chemists have been looking for Grignard reaction which is more tolerant and easy to obtain In terms of practicability and availability, alkyl carboxylic acids are the most suitable starting materials, because they can be diversified by the substitution of anions at the α position, then decarboxylate to obtain carbon center free radicals, and then use the free radicals to add the C = x bond to realize the synthesis of ketones, alcohols and amines (Figure 1) Although the research on the synthesis of ketones, alcohols and amines from free radicals can be traced back to the late 1970s and has laid a strategic and mechanism foundation for the current research, the early synthesis work in this field focuses on the use of electrochemical technology, which greatly limits its application Recently, Professor Phil S Baran, Department of chemistry, Scripps Institute, reported the strategy and reaction mechanism of free radical synthesis of ketone, alcohol and amine derived from carboxylate The study was published in J am Chem SOC (DOI: 10.1021 / JACS 9b02238) (photo source: J am Chem SOC.) epoxy ketone 1 is a key intermediate in the synthesis of anamarine (2) The author obtained two synthesis routes based on 2E strategy through reverse synthesis analysis, but the anions obtained by reverse synthesis are not feasible In contrast, based on 1E - strategy, a simple method using chiral cell as raw material (Figure 3a) is proposed Then, the reaction conditions were optimized with 3 and 4 as model substrates (Figure 3B) The results show that ketone 5 can be obtained in 76% yield with benzoic anhydride as carboxylic acid activator, Zn powder as reducing agent, MgCl 2 and LiBr as metal reagents When the conditions are changed properly, the yield of the reaction will decrease by 5-15% When acyl chloride is used instead of the combination of carboxylic acid and anhydrides, the reaction yield is higher (entry 16) (photo source: J am Chem SOC.) based on the optimal reaction conditions, the applicability of carboxylic acid substrate was investigated (Table 1) The results showed that the reaction could tolerate 1 °, 2 °, 3 ° and aromatic carboxylic acids, and the carboxylic acids with ester, ketone, N-Boc or N-TOS functional groups such as amine, amide, ether and halogen could also obtain the corresponding products in excellent yields In addition, the functionalization of Fenbufen, indomethacin and biotin was successfully realized by this strategy, and the corresponding products (19, 22, 23, 41) were obtained in good yields The reaction can achieve gram scale synthesis, and the product can be obtained in excellent yield (photo source: J am Chem SOC.) the author's previous research focused on the synthesis of enantiomeric amino acids with glyoxal derived chiral acetamide imine reagent 90, but the product can only be obtained in 5% yield using aromatic or alkyl imines with weak electrophilicity (Figure 5a) Therefore, the author optimized the reaction conditions, and finally determined NHPI, Zn nano powder and NiCl2 Glyme as the optimal reaction conditions (photo source: J am Chem SOC.) under the optimal conditions, the author investigated the application scope of RAE and imine (Table 3) The results showed that the Raes derived from 1 °, 2 ° and 3 ° carboxylic acids with ether, ester, pyridine and aryl groups were all tolerant under these conditions However, the reaction of RAE derived from n-ts amines with aliphatic imines only resulted in a low yield (106) (photo source: J am Chem SOC.) the addition of aldehydes to nucleophiles based on 2E strategy usually has competitive enolization / polymerization problems This problem can be solved by the reaction of alkyl NHK, but the precursor of alkyl halide is still needed However, it seems to be a feasible method (Figure 6a) to use Rae instead of alkyl halide to add C = O bond to get alcohol The reaction conditions of RAE 4 and aldehyde 107 were optimized The results showed that TMS protected alcohol 108 (Figure 6B, entry 1) could be obtained in the highest yield (88%) under the conditions of CrCl 2, tmscl and THF / DMF But the reaction is sensitive to air (entry 3), and Cr is necessary for the reaction (entry 5) Unlike the alkylnhk reaction using alkyl halides, transition metal media such as COPC or Ni have no effect on the reaction (entry 7 and 8) Under the optimal conditions, the author investigated the application scope of the above reaction substrate (Table 4) The results showed that the alkylnhk reaction based on Rae had good functional group tolerance N-Boc amines, halogens, alkenes and heterocycles (azaindoles and benzimidazoles) were all tolerated under the reaction conditions However, only the first-order Raes can yield the product (114) in an effective yield In addition, the substrate with pyridine structure is not suitable for the reaction (121) (photo source: J am Chem SOC.) (photo source: J am Chem SOC.) finally, the author proposes the following reaction mechanism (Figure 7a): firstly, Ni (0) complex I and anhydride a are oxidized to obtain Ni (II) carboxylic acid complex II; II is catalyzed by MgCl 2 to obtain Ni (II) acyl complex III; III Ni (III) intermediate IV was obtained by capturing R 2 · derived from Rae (R 2-conhpi), which was reduced to ketone product and Ni (I) complex v Then, the resulting Ni (I) complex V combines with Rae to make the cycle permanent and produce Ni (II) complex VI, and Zn reduces Ni (II) complex VI to obtain complex I and complete the cycle (photo source: J am Chem SOC.) Summary: Professor Phil S Baran, Department of chemistry, Scripps Institute, reported the strategy and reaction mechanism of free radical synthesis of ketone, alcohol and amine derived from carboxylic acid The strategy can be used to prepare ketones, alcohols and amines by the reaction of Raes derived from carboxylic acid with mixed anhydrides, acyl halides, imines or aldehydes The reaction conditions are mild, the raw materials are easy to obtain and suitable for parallel synthesis, which greatly promotes the development of Grignard reaction and expands its application scope.