Copper-Catalyzed Amide Synthesis

The utility of the method was demonstrated with a variety of electron-rich and electron-poor aryl aldehydes, but the method was not suitable for aliphatic aldehydes. No racemization was observed in the copper-catalyzed oxidative amidation reaction when an optically active amine, (S)-valine methyl ester, was employed. 

---

Parco et al. described a copper-catalyzed amidation of vinyl iodide 115 to give 116 (Scheme 20).28e Enhanced conversions were attained using copper(i) thiophenecarboxylate (GuTG) in a polar aprotic solvent such as NMP. The total synthesis of the antitumor natural product, lobatamide G, has been accomplished by using this reaction.28f Buchwald et al. developed a general and efficient copper-catalyzed method using N,N -dimethyl ethylenediamine L8. The double-bond geometry of the alkenyl halides was retained under the reaction conditions. 

Novel imidazolidinone tetrahydropyrroloindole. During the attempted total synthesis of roquefortine C, a fungal metabolite of Penicillium roqueforti, an essential fungus in the production of Roquefort cheese, the copper catalyzed amidation of the vinyl bromide 34 in Scheme 1 was envisioned to lead to the requisite diketopiperazine ring contained in 35. " Preliminary spectroscopic data, however, suggested that the amidation had not gone as anticipated and that an unknown cyclization product had instead formed. 

Overman and Tomasi applied the copper-catalyzed amidation of compound 658 (Scheme 3.262) in the key step of the enantioselective total synthesis of the natural tetracyclic spermidine alkaloid (-)-hispidospermidin [805],... 

In recent years, cross-coupling methodology has emerged as a viable tool for enamide synthesis, and, indeed, there are a number of published protocols which employ palladium- or copper-catalyzed stereospecific amidations of vinyl halides [17]. For example, Buchwald and coworkers had recently shown that a copper-catalyzed cross-coupling of vinyl bromides or iodides proceeded with retention of stereochemistry (Scheme 9.16), though the only example using a tetrasubstituted vinyl halide, 23, lacked the need for any stereochemical control in the halide portion [18]. Based on this it seemed feasible that the desired enamide 22 could potentially be assembled via a comparable coupling between amide 24 and a stere-odefined vinyl halide such as 25. 

Tandem azidination- and hydroazidination-Hiiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3-triazoles <06OBC2679>. A series of diversely l-substituted-4-amino-l,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. 

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

A new copper-catalyzed reaction involving imines, acid chlorides, and alkynes has been applied to the synthesis of propargyl amides 160 in a single operation by Arndtsen and co-workers. The same method allows the synthesis of N-carbamate-protected propargylamines [149]. a-Substituted amides 161 may also be prepared under palladium catalysis by substituting alkynes for vinyltin (Scheme 8.71) [150]. 

Llewellyn DB, Arndtsen BA (2005) Synthesis of a library of chiral a-amino acid-based borate counteranions and their application to copper catalyzed olefin cyclopropanation. Tetrahedron Asymmetry 16 1789-1799 Makino T, Baba N, Oda J, Inouye Y (1977) Asymmetric reduction of alpha, beta-unsaturated iminuum salt with A-glucopyranosyl-l,4-dihydronicotin-amides. Chemlnd 1977 277-278... 

Indazoles were prepared by many different methods. Indazoles 41 were synthesized from nitroaromatics 39 and N-tosylhydrazones 40 with bases (14CC5061). A rhodium(III)-catalyzed oxidative olefination of 1,2-di-substi-tuted arylhydrazines with alkenes via sp C-H bond aaivation followed by an intramolecular aza-Michael reaction yielded indazoles (140L2494). Copper-catalyzed C-H amidation with aromatic imines 42 with tosyl azide provided a route to 3-substituted indazoles 43 (14OL4702). 4,5,6,7-Tetrahydro-lH-inda-zol-3-(2fJ)-one derivatives were prepared in two-step one-pot process (14SC1076). A regioselective synthesis of 2H-indazoles 45 was achieved using... 

General procedure for the copper-catalyzed synthesis of primary arylamines via amidation/hydrolysis ... 

Ackermann engineered a copper-catalyzed process to achieve the A-arylation/hydroamination synthesis of indoles (Scheme 4, equation 1) [35], In similar fashion, A-acylindoles and NH-indoles were made available using A-unsubstituted amides and carbamates in place of anilines. In these latter reactions, a vicinal diamine ligand improved the cyclizations. Miura and Hirano reported a... 

In this domino process, benzylamine was reacted with 2-halobenzamides through UUman-type coupling to yield the N-arylated intermediate 144 (Scheme 9.26). Then, a copper-catalyzed aerobic oxidation of 144 afforded the intermediate 145, which underwent an intramolecular nucleophilic addition of the amide to provide 146. Under the used reaction conditions, the intermediate 146 was oxidized to provide the desired products 147 in excellent yield. This protocol was also utilized by Fu et al. [80] by employing easily available a-amino adds instead of benzylamines to synthesize similar analogs. Very recently, the same method was applied for the synthesis of pyrimido[4,5-b]carbazoles by Nagarajan et al. [81]. 

As early as 1985, a palladium-catalyzed carbonylative procedure for the synthesis of 1,4-benzodiazepines was reported. Starting from 2-haloanilines and amino acids, the desired seven-membered heterocycles were formed in moderate yields. More recently, an efficient, one-pot method for the synthesis of dibenzodiazepinone derivatives involving copper-catalyzed tandem C-N bond formation was reported. Using various halo amide and 2-iodoaniline derivatives as substrates, an array of dibenzcxliazepinone... 

Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water, (b) M. P. Cassidy, J. Raushel, V. V. Fokin, Angew. Chem. Int. Ed. 2006,4, 3154-3157. Practical synthesis of amides from in situ generated copper(I) acetyhdes and sulfonyl azides, (c) S. H. Cho, S. Chang, Angew. Chem. Int. Ed. 2007, 46, 1897-1900. Rate-accelerated nonconventional amide synthesis in water a practical catalytic aldol-surrogate reaction. 

A facile access to A-sulfonylimidates and their synthetic utility for the transformation to amidines and amides, (b) E. J. Yoo, S. H. Park, S. H. Lee, S. Chang, Org. Lett. 2009, 11, 1155-1158. A new entry of copper-catalyzed four-component reaction facile access to a-aryl P-hydroxy imidates. (c) R. Husmann, Y. S. Na, C. Bohn, S. Chang, Chem. Commun. 2010, 46, 5494—5496. Copper-catalyzed one-pot synthesis of a-functionalized imidates. (d) W. Song, W. Lu, J. Wang, P. Lu, Y. Wang, J. Org. Chem. 2010, 75, 3481-3483. A facile route to y-nitro imidates via four-component reaction of alkynes with sulfonyl azides, alcohols, and nitroolefins. (e) G. Murugavel, T. Punniyamurthy, Org. Lett. 2013, 15, 3828—3831. Novel copper-catalyzed multicomponent cascade synthesis of iminocoumarin aryl methyl ethers. 

A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphi-noylimines has been developed for the synthesis of chiral a,a,a-trifluoromethyl-amides (249). Ketimines (250), generated in situ from the corresponding hemiaminals, led to the chiral amides in high yields and excellent enantiocontrol (Scheme 101). ... 

A sequential one-pot synthesis of unsymmetrical aryl urea derivatives was developed by arylation of N-substituted cyanamides under metal-free conditions, followed by a second N-arylation under copper-catalyzed conditions [96]. Chen and Chen devised the arylation of pyridine N-oxides with At21X via initial O-arylation followed by a 1,3-radical rearrangement to o-pyridinium phenolates, and arylation of pyridine N-amidates delivered o-pyridinium anilines (Scheme 5d) [97]. 

In 2014, Ohno and co-workers reported the synthesis of the more complex ynamides 68 based on the copper-catalyzed alkynylation of tosyl amide 66 using aryl EBX reagent 67 (Scheme 34) [158]. Interestingly, this constituted the first example of a copper-catalyzed reaction with an EBX reagent in which the alkyne group is kept in the product. Although alkynyl bromides have traditionally been used in copper catalysis for the synthesis of ynamides, they were not successful in this case. 

SCHEME 3.115 Copper-catalyzed synthesis of enamides from primary amides [121]. 

Song Q, Feng Q, Yang K (2014) Synthesis of primary amides via copper-catalyzed aerobic decarboxylative ammoxidation of phenylacetic acids and a-hydroxyphenylacetic acids with ammonia in water. Org Lett 16(2) 624-627... 

Ghosh SC, Ngiam JSY, Seayad AM, Tuan DT, Chai CLL, Chen A (2012) Copper-catalyzed oxidative amidation of aldehydes with amine salts synthesis of primary, secondary, and tertiary amides. J Org Chem 77(18) 8007-8015... 

Double N-arylation can also be conducted by using copper catalysts. In 2007, Martin, Li, and co-workers independently reported pyrrole synthesis via copper-catalyzed C—N bond formation between l,4-dihalo-l,3-dienes and amines [13]. They applied this methodology to carbazole synthesis (Scheme 23.9). In general, diiodobiaryl gave better results than dibromobiaryls. As a nitrogen source, carbamates and amides were investigated in their reports. 

---