Copper catalyzed processes

Formally copper catalyzed couplings are analogous to palladium and nickel catalyzed reactions. Carbon-carbon and carbon-heteroatom bonds can be formed in such transformations alike. From the mechanistic point of view there is a significant difference between nickel, palladium and copper catalyzed processes however. While in the former cases the catalyst usually oscillates between the 0 and +2 oxidation states, in copper mediated transformations the common oxidation numbers are +1, +2 and +3. 

In certain cases copper catalyzed processes might also be used for the N-alkynylation of azoles. Methyl indole-3-carboxylate was coupled with 1-bromo-2-triisopropylsilyl-acetylene in the presence of a copper-phenantroline catalyst to give the desired 1-ethynylindole derivative in excellent yield (6.74.),105... 

Studies aimed at the comparison of Rh(II) and Cu(II)-catalyzed onium ylide reactions of diazoketones 449 using 3 mol% of the former and 15 mol% of the latter led to the conclusion that the copper-catalyzed process provides the better yields and selectivities for [1,2]-rearrangement products 450 (Fig. 107) [490, 491]. In the rhodium-catalyzed process, 1,5-C-H insertion may compete. The diastereo-selectivity with both catalysts is in some cases similar, in others the Rh-catalyzed process is more selective. Analogous reactions of acetal 451 provided a mixture of stereoisomers 452a and 452b at the benzylidene position, supporting a stepwise process. The authors proposed that the involved intermediate was either a 1,6-biradical or the corresponding ion pair. 

The commercial bioconversion process employs the enzyme nitrile hydratase, which catalyzes the same reaction as the chemical process (Figure 31.15). The bioconversion process was introduced using wild-type cells of Rhodococcus or Pseudomonas, which were grown under selective conditions for optimal enzyme induction and repression of unwanted side activities. These biocatalysts are now replaced with recombinant cells expressing nitrile hydratase. The process consists of growing and immobilizing the whole cell biocatalyst and then reacting them with aqueous acrylonitrile, which is fed incrementally. When the reaction is complete the biocatalyst is recovered and the acrylamide solution is used as is. The bioconversion process runs at 10°C compared to 70°C for the copper-catalyzed process, is able to convert 100 percent of the acrylonitrile fed compared to 80 percent and achieves 50 percent concentration... 

Copper catalysis has been shown to have a dramatic effect on regioselectivity in the protection of sugar derivatives as the acetonide [33]. Compound 47 afforded the acet-onide 48 upon treatment with dimethoxypropane and CUSO4 in acetone. In contrast, the acid-catalyzed acetalization afforded 49 in 90 % yield (Sch. 12). It is suggested that the acid-catalyzed reaction occurs first at the primary alcohol and subsequently migrates to the secondary alcohols to afford 49 whereas the copper-catalyzed process is not reversible. 

Aromatic amines are found in biologically active natural products, common pharmaceuticals, dyestuffs, materials with conductive and emissive properties, and ligands for transition-metal-catalyzed reactions. For these reasons much effort has been spent for more than a century on methods to prepare aromatic amines. The synthetic methods to obtain these materials range from classical methods, such as nitration and reduction of arenes, direct displacement of the halogens in haloarenes at high temperatures, or copper-mediated chemistry, as well as modem transition-metal-catalyzed processes and improved copper-catalyzed processes. The following sections describe each of these synthetic routes to aromatic amines, including information on the scope and mechanism of most of these routes to anilines and aniline derivatives. 

For copper-catalyzed processes, see (a) Tamura M, Kochi J (1971) Synthesis 1971 303 ... 

In a similar manner,benzo[6]pyrido[3,2 [l,4]oxazepinones 115 were prepared using a ligand-free, copper-catalyzed process (14RA55640). An intramolecular 1,3-dipolar cycloaddition reaction of 6-azido-4-0-propargyl glucopyranosides generated aryl-substituted hexahydro-4H-pyrano[2,4 [l,2,3]triazolo[5,l-c][l,4]oxazepines 116 (14RA63962). 

The potential for sequential copper-catalyzed processes can also be illustrated in the case of formation of fully substituted 1,2,3-triazoles. In this sequence, the same copper catalyst is promoting two distinct types of catalysis [3+2]-cycloaddition and arylation via C-H activation. Each reaction type tolerates both electron-rich and -poor substrates, as well as steric hindrance, adding noteworthy breadth to this scheme. A 4-component sequence using NaNs, rather than an alkyl azide, is shown below. The diamine DMEDA (W.W -dimethylethylenediamine) is used to stabilize the copper catalyst. 

Several investigators have uncovered additional copper-catalyzed indole syntheses from 2-ethynylanilines accompanied by in situ indole functionahzation. Yamamoto and colleagues reported the synthesis of Af-(alkoxybenzyl) indoles from the copper-catalyzed tandem reaction between 2-alkynyl-Af-arylideneanihnes and alcohols (Cul, toluene, 100°C, 55%-83%) [26], Ohno, Fujii, and coworkers employed a domino three-component copper-catalyzed process to prepare 2-(aminomethyl)indoles [27, 28] and... 

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... 

The rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to a, 3-unsaturated carbonyl compounds is one of the most versatile and robust methods for the stereoselective introduction of aryl groups (Scheme 8.17). In contrast, copper-catalyzed processes generally transfer alkyl groups with high selectivities, but perform only poorly in aryl transfer [43]. 

Anhyd copper sulfate is also an excellent catalyst for the formation of acetonides from glycols and acetone (eq 2). Either 2,2-dimethoxypropane or 2-methoxypropene can sometimes improve the efficiency. The regiochemistry of the copper-catalyzed process is different from that found in the proton-catalyzed reaction. 

A number of preparations of different types of imidazoquinoxalines were reported in 2013. Ma and coworkers devised an efficient one-pot synthesis of benzo[4,5]imidazo[l,2-a]quinoxalines via a copper-catalyzed process... 

In a single-step copper-catalyzed process, l-azido-3-(2-iodobenzyloxy) propan-2-ol 215 underwent two different reactions, an azide-alkyne cycloaddition and a C-O bond forming reaction, to produce 1,2,3-triazole appended 1,4-benzodioxepines 216 (13OBC7350). 

Recently, a copper-catalyzed process for the construction of pyrrolobenzoxazepinones from 2-(2-iodopheno3gr)-l-(l//-pyrrol-2-yl)ethanones was described. A variety of pyrrolobenzoxazepinone derivatives were synthesized from the corresponding substrates by intramolecular Cu-catalyzed Ullmann N-aiylations in good to excellent yields (Scheme 4.8). 

Other reactions that have been applied in the Ugi postmodification strategy are the aza-Wittig reaction [80-84] and copper-catalyzed processes [85, 86], More recently, Domling and coworkers have developed a new approach for the synthesis of polycyclic compounds via Ugi MCR followed by a Pictet-Spengler reaction [87-89]. In 2011, apro-tocol for the rapid access to quinolin-2-(l//)-one scaffold was reported by a sequential 4-component Ugi-Knoevenagel condensation [90]. Hulme et al. have introduced a one-pot, two-step protocol for large-scale production of libraries of novel peptidomimetic-like fcM-pyrrolidinone tetrazoles via the Ugi-3CR-azide reaction of tethered keto ester methyl... 

DSM also have been interested in this type of transformation and, in 2005, filed a patent on the application of this copper-catalyzed process in the synthesis of enantiomerically enriched indoline-2-carboxylic acids [76]. In this protocol, (5)-2-bromophenylalanine was cydizedto the corresponding indoline-2-carboxylic acid using 0.01 - 2 mol% CuCl. 

Scheme 6.49 A copper-catalyzed process for the coupling of aldehydes, amines, and boronic acids (a) and a proposed mechanism (b), as described by Bergin and coworkers [68].

Aryl bromides and iodides are usually prepared from diazonium salts by a copper-catalyzed process, a reaction commonly known as the Sandmeyer reaction. Under the classic conditions of the Sandmeyer reaction, the diazonium salt is added to a hot acidic solution of the cuprous halide.It is also possible to convert anilines to aryl halides by generating the diazonium ion in situ. Reaction of anilines with alkyl nitrites and cuprous halides in acetonitrile gives good yields of aryl bromides by a copper-mediated process which is mechanistically similar to that occurring under the usual Sandmeyer conditions. Diazonium salts can also be converted to... 

The cyano and azido groups are also readily introduced via diazonium ions. The former reaction occurs by a copper-catalyzed process analogous to the Sand-meyer reaction. Reaction of diazonium salts with azide ion gives adducts which smoothly decompose to nitrogen and the azide. Scheme 8.6 gives some representative examples of substitution reactions proceeding via diazonium salts. 

A copper-catalyzed process converts aryl iodides and bromides into phenols in pure water using TBAB as a phase-transfer catalyst [48]... 

A copper-catalyzed process is perhaps the most operationally simple since several versions can be carried out under air [75]... 

Secondary alkyl halides are often challenging to successfully use in coupling reactions however, a light-assisted copper-catalyzed process has successfully coupled primary amides with secondary alkyl halides [7]... 

Indazoles can be generated through a copper-catalyzed process using TsNj as the amino source (Scheme 3.87) [45], Using CuTc as the catalyst for the reaction, moderate yields of the indazoles were obtained. The chemistry was tolerant to several functional groups including halogens and ethers. 

This is perhaps the most popular starting point for the preparation of ynamides. This copper-catalyzed process typically uses a bromoalkyne and a secondary amide as substrates and mineral bases sueh as Cs COj. The process was attractive since it does not require the use of strong bases [166, 170-175]... 

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