Intermolecular C-H amination reactions

Fig. 79 Cobalt porphyrin-catalyzed intermolecular C-H amination reactions...

Recently, efficient rhodium-catalyzed intermolecular C—H amination reactions have been reported where a sulfonimidamide is used as the nitrene precursor [46]. The functionalizations of various C—H bonds proceed smoothly in this type of intermolecular amidation reaction (Equation 11.20) [47]. When chiral sulfonimida-mides are used, moderate to excellent diastereoselectivities can be achieved. 

Trichloroethyl-N-tosyloxycarbamate has been designed by Lebel and Huard specifically to achieve intermolecular C—H amination reactions and leads to Troc-protected amines which are easy to cleave [76], The C—H amination of cyclic alkanes proceeds in good yields with 2 equiv of hydrocarbon substrate and 1 equiv of the amination reagent in the presence of 6 mol% of Rh2(tpa)4 (Eq. (5.25)). However, 5 equiv of alkane are usually required to achieve good yields with other substrates, such as aromatic compounds (Eq. (5.26)). In this case, the reaction is run without solvent. 

Bess EN, DeLuca RJ, Tindall DJ, et al. Analyzing site selectivity in Rh2(esp)2-catalyzed intermolecular C-H amination reactions. J Hm Chem Soc. 2014 136 5783-5789. 

Metal nitrene complexes were used in a number of C-H amination reactions (recent reviews [358, 359]). Copper ketiminate complexes react with azides to nitrene complexes, which were isolated [360]. (p-Ketiminate)copper(I) complex 262 (2.5 mol%) serves therefore as an efficient catalyst for the intermolecular C-H amination of alkylarenes, cycloalkanes, or benzaldehydes 260 using adamantyl azide 261 as the nitrogen source ig. 68) [361]. The corresponding adamantyl amines or amides 263 were isolated in 80-93% yield. Copper complex 262 forms initially a dinuclear bridged complex with 261. From this a copper nitrene complex is generated by elimination of nitrogen, which mediates the hydrogen abstraction from 260. 

A recent DFT study has shown that retention of configuration observed for the above reactions is in agreement with the insertion of singlet nitrene and a concerted product formation [150 is the transition state for the reaction shown in Equation (6.135)]. Du Bois and coworkers have performed detailed mechanistic investigations of the intramolecular sulfamate ester C-H amination reaction catalyzed by a dirhodium complex. Reactivity patterns, Hammett analysis, and kinetic isotope effect studies have provided support for the concerted, asynchronous transition structure 151. A similar conclusion was arrived at for an analogous intermolecular process. ... 

Suna developed a one-pot, two-step process for the intermolecular C—H amination of indoles and other electron-rich aromatic systems. Indole 229 is converted to indolyliodonium tosylate 230 (the structure of which was confirmed by X-ray crystallography) the intermediate is stable in MeCN,dichlo-romethane (DCM), and DMSO at room temperature for at least 72 h. Upon exposure to morpholine and catalytic copper salts, aminated indole 231 is isolated in good yield. The scope of competent amines is quite broad alkyl amines, benzylic amines, anilines, and allylic amines are all tolerated.The reaction sequence also works with pyrroles, azaindoles, pyrazoles, and related systems (14JA6920). Gross and colleagues reported the first one-pot synthesis of L-7-iodotryptophan firom 7-iodoindole and serine the biotransformation uses a bacterial cell lysate that can be stored lyophilized for several months and used catalyticaUy (19 examples, 9-81% yield) (140L2622). 

In comparison, intermolecular reaction met high challenges due to both enthalpy and entropy reasons. In 2007, He and coworkers developed a disilver-based new catalyst 11 which showed high efficiency for intramolecular C-H amination reaction (Scheme 10) [32]. Such an intermolecular C-H amination/amidation ran at mild condition. The new catalyst set has successfully been applied to intermolecular amination reaction for the first time (Scheme 11). In the reaction, the catalyst was added in two portions in order to increase the yield. Under typical reaction condition, AgOTf (2 mol%) and ligand (2.4 mol%) were mixed in DCM in a tube for 20 min. Then the substrate (5.0 or 10.0 eqmv.), PhI=NNs (1.0 equiv.) and 4 A molecular sieves (2 g/mmol) were added under N2 atmosphere. The tube was sealed and heated to 50°C for 2 h before another AgOTf (2 mol%) and ligand (2.4 mol%) mixed in DCM were added. The reaction was carried out at 50°C... 

This discovery has tremendously expanded the field of amination reactions, not only to perform intramolecular, but also intermolecular C—H insertion reactions. Today this approach is the most commonly used to prepare metal nitrenes, especially those derived from rhodium catalysts. N-Tosyloxycarbamates are alternative rhodium... 

As mentioned earlier in the review (see Section 3.1.2), the intermolecular C(sp )—H amination reaction is particularly challenging, and, until now, this approach has been very rarely applied in total synthesis.In this context, the important contribution of Movassaghi, which describes the synthesis of aminocyclotryptamines via catalytic intermolecular C—H amination, can be considered as a landmark appHcation. Diversely N-protected cyclotryptamines have, thus, been aminated stereospecificaUy with satisfactory yields by reaction with an arylsulfamate under the reaction... 

Intermolecular Insertions. Singlet carbenes undergo insertion reactions with X H bonds such as O—H (alcohols), N—H (amines), Si H (silanes), and so on. The reactions with alcohols can be extremely fast. Here, however, we focus on the C H insertion reactions of singlet carbenes, in which carbon-carbon bonds are created. ... 

The C—H insertion reaction of nitrenes is a potentially useful way of functionalizing unactivated C—H bonds, converting hydrocarbons into amine derivatives. In its intermolecular form the synthetic utility of the reaction is highly dependent on the substituents on the nitrene, and on the manner in which it is generated. To exemplify these effects, the results for the functionalization of cyclohexane by insertion of various nitrenes (equation 1) are summarized in Table 1. 

This chapter will highlight recent efforts to develop metal-mediated processes for selective C-H amination. Other excellent, comprehensive reviews can be found on this topic [3, 8-10]. To distinguish this discourse from prior works, we have opted to focus attention on the diversity of catalysts that are now known to mediate racemic and asymmetric intra- and intermolecular oxidation reactions. Where possible, mechanistic insights that elucidate the role of the metal catalyst and the details of the defining bond-forming event will be presented. It is our hope that this analysis will serve to inspire additional inventive discoveries in this rapidly progressing field - advances that may change the art and practice of complex molecule assembly. 

---