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Versatile and Direct Transformation of Secondary Amides into Ketones by Deaminative Alkylation with Organocerium Reagents

Amides are a class of easily available and highly stable compounds. Secondary amides also serve as powerful directing groups in C H activation. Ketones are also a class of extremely versatile molecules that enable a number of fundamental transformations in organic synthesis. Hence the transformation of amides into ketones is of high relevance in organic synthesis. However, because of the high stability of amides, their direct transformation into more reactive ketones presents a formidable challenge. Although a limited number of specially designed amides, such as Weinreb amides (N-methoxy-N-methylamides), have been prepared as intermediates for the conversion of carboxylic acids/esters into ketones, such methods cannot be used for the transformation of simple amides into ketones. Herein, we report a general one-pot method for the direct conversion of secondary amides into ketones by using organocerium species as the alkylating reagents. On the basis of carbonyl activation with trifluoromethanesulfonic anhydride (Tf2O), [6] we have recently reported the direct conversion of tertiary lactams/amides into tertiary alkyl amines by sequential reductive alkylation with Grignard and organolithium reagents. As a continuation of this study, and in connection with our general interest in the development of step-economical synthesis, we investigated the Tf2O-activated reductive alkylation of secondary amides. We discovered that cerium complexes generated in situ from RMgX and CeCl3, and organocerium reagents (RCeCl2) generated in situ from RLi and CeCl3 [10] were effective for the direct conversion of secondary amides into ketones by activation with Tf2O and 2-fluoropyridine (Scheme 1). The conversion of N-butylbenzamide (1a) into ketone 2a was selected as a model reaction. An investigation of the influence of the base revealed that the use of a base was necessary, and 2-fluoropyridine gave the best results. The influence of the organometallic reagent was then explored in combination with 2-fluoropyridine (1.2 equiv) as the base. Organocerium reagents (RCeCl2) [12] generated in situ from RLi and CeCl3 and cerium complexes generated in situ from RMgX and CeCl3 [13] are more efficient than organomagnesium, organolithium, and organozinc species for this reaction. Optimal yields were achieved by using the cerium complex nBuMgBr/CeCl3 (3.0 equiv). The optimal protocol for one-pot transformation of secondary amides into ketones was identified as successive treatment of a solution of the amide in dichloromethane and 2-fluoropyridine (1.2 equiv) with Tf2O (1.1 equiv, 78 8C, then 0 8C), and RM/CeCl3 (3.0 equiv, 78 8C), then hydrolysis with aqueous HCl. Under the optimized conditions, the scope of the transformation was studied. As shown in Table 1, this method of converting secondary amides into ketones by deaminative alkylation with organocerium reagents has a wide scope and broad functional group tolerance. A wide array of aroyl (Table 1, entries 1–16), alkanoyl (Table 1, entries 17–25), and alkenoyl amides (Table 1, entry 26) were converted into the corresponding ketones in high yields. The substituents on the N atom of the secondary amides, regardless of whether they are N-n-alkyl (Table 1, entries 1–9, 15-18, 24–26), N-s-alkyl (Table 1, entries 10–14, 21–23) or N-aryl (Table 1, entry 19), do not have much influence on the reactivity. The reaction also went smoothly with hindered amides, such as 1o (Table 1, entry 24). The reaction is compatible with many functional groups on the amides, including ethers (Table 1, entry 12), aromatic bromides (Table 1, entry 13), tertiary aromatic amines (Table 1, entry 14), thiophene (Table 1, entry 16), terminal C=C bonds (Table 1, entry 25), and even conjugated C=C bonds (Table 1, entry 26). For a,b-unsaturated amide 1q, only the 1,2-addition product 2u was obtained, which provides an alternative approach to enones (Table 1, entry 26). With regard to the organocerium complexes, alkyl (Table 1, entries 1–4, 9–17, 19, 22, 24, 26), benzyl (Table 1, entries 20, 21, 23, 25), aryl (Table 1, entries 6 and 7), and alkenyl cerium complexes (Table 1, entry 18) generated from [a] K.-J. Xiao, Dr. A.-E. Wang, Y.-H. Huang, Prof. Dr. P.-Q. Huang Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology College of Chemistry and Chemical Engineering, Xiamen University Xiamen, Fujian 361005 (P. R. China) Fax: (+86)592-2186400 E-mail : pqhuang@xmu.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ajoc.201200066. Scheme 1. Direct transformation of secondary amides into ketones. Tf2O= trifluoromethanesulfonic anhydride; 2-F-Py=2-fluoropyridine.