C-H amination in synthesis

Xie Z, Peng J, Zhu Q (2016) Copper-mediated C(sp ) C-H amination in a multiple C-N bond-forming strategy for the synthesis of N-heteiocycles. Org (Them Front 3(l) 82-86... 

Preliminary efforts to examine the mechanism of C-H amination proved inconclusive with respect to the intermediacy of carbamoyl iminoiodinane 12. Control experiments in which carbamate 11 and PhI(OAc)2 were heated in CD2CI2 at 40°C with and without MgO gave no indication of a reaction between substrate and oxidant by NMR. In Hne with these observations, synthesis of a carbamate-derived iodinane has remained elusive. The inability to prepare iminoiodinane reagents from carbamate esters precluded their evaluation in catalytic nitrene transfer chemistry. By employing the PhI(OAc)2/MgO conditions, however, 1° carbamates can now serve as effective N-atom sources. The synthetic scope of metal-catalyzed C-H amination processes is thus expanded considerably as a result of this invention. Details of the reaction mechanism for this rhodium-mediated intramolecular oxidation are presented in Section 17.8. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

Oxidative C-H amination has been an area of intensive research since the publication of CHEC-II(1996). This methodology has been applied to the synthesis of a variety of 1,2-thiazine 1,1-dioxides. In the simple cases, substrates containing an aromatic C-H can be cyclized in the presence of hypervalent iodine. For instance, the reaction of A-methoxy(2-arylethane)sulfonamide 202 with [hydroxyl(tosyloxy)iodo]benzene rapidly affords benzenesulfon-amide 203 in excellent yield (Equation 30) <20030BC1342> see also <2000JOC926> and <2000JOC8391>. 

Park, W K C, Auer, M, Jaksche, H, Wong, C-H, Rapid combinatorial synthesis of aminoglycoside antibiotic mimetics Use of a polyethylene glycol-linked amine and a neamine-derived aldehyde in multiple component condensation as a strategy for the discovery of new inhibitors of the HIV RNA Rev responsive element, J. Am. Chem. Soc., 118, 10150-10155, 1996. 

The use of substrate control in rhodium catalyzed C H aminations is covered in detail in Espino and Du Bois recent review of rhodium catalyzed oxidative amina tion [51]. A brief summary of relevant material is provided here, leading to a discussion of recent advances in the synthesis of chiral amines from achiral substrates. Rhodium catalyzed C H amination proceeds via a concerted insertion process rendering it a stereospecific transformation. Thus, the appropriate choice of an enantioenriched starting material can facilitate the synthesis of enantioenriched amines, which would often be particularly difficult to access in any other manner. As exemplified in Scheme 12.9, the C H insertion reaction of enantiomerically pure carbamate 9 was accomplished with complete retention of configuration providing the chiral oxazolidinone 10 in greater than 98% ee [13]. 

The history of C-H amination can be traced to the earliest work of Hofmann involving the reactivity of /V-bi omoamines. chemistry later recognized by Loffler and Freytag for its potential to facilitate pyrrolidine synthesis from simple acyclic precursors [11]. The intermediacy of both haloamine and aminyl radical in this stepwise oxidation reaction is now generally accepted, as is the hyper-reactivity of... 

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). 

Another intramolecular synthesis of carbazoles 270 employed amino biaryls 269 as the starting materials with 2-picolinic acid as a directing group to facilitate a net C—H amination reaction under copper catalysis in the presence of Mn02 and acetic acid. The directing group is removed spontaneously after the initial amination (140L2892). 

Zhu and Chiba applied a TEMPO-mediated allylic C—H amination involving alkenyl hydrazones to the synthesis of tetrahydropyridazines 8 and dihydrophthalazines 9 (Scheme 5) (140BC4567). Optimal reaction conditions were found to be treatment of the respective hydrazone with 3 equivalents of TEMPO in A/,N-dimethylformamide (DMF) at 130°C, giving the corresponding products in moderate-to-high yields. 

Chair-like transition states minimizing gauche interactions between the substituents with metal nitrene insertion into the equatorial C-H bond are used to explain the stereochemical outcome. Such an intramolecular C-H amination with sulfamates was used in a few syntheses, including the total synthesis of (-l-)-sax-itoxin [66, 67]. 

Davies has recently developed a chiral rhodium dimer derived from adamantane glycine, Rh2[(S)-tcptad]4 [75]. He demonstrated that this was the most efficient catalyst for the enantioselective synthesis of oxazolidinones via C—H amination, using N-tosyloxycarbamates as nitrene precursors (Eq. (5.24)). Enantioselectivities up to 82% are observed in this case. 

In conclusion, the recent developments towards more practical reagents and catalysts to perform C—H amination reactions have provided a variety of new synthetic tools to prepare various nitrogen derivatives. Furthermore, a number of stereoselective methods have been recently disclosed. All this progress should promote the use of C—H amination reactions in total synthesis of natural products and biologically active compounds. 

A convenient and clean water-mediated synthesis of a series of indolo[l,2-c] quinazoline derivatives was reported using alternative nonconventional energy sources. The products are obtained in shorter times with excellent yields (78-89 %) from the MCR of 2-arrrinobenzimidazole, malononitrile, and carbonyl compourtds [55]. In their research, 2-(2-halophenyl)-lH-indoles arrd (aryl)methanamines were adopted as raw rrraterials to generate corresponding Schiff base via the Ullrrrarm reaction. Thert, gas as oxidarrt, 3 equiv K COj as base, and 10 mol% Cu(OAc)2 as catalyst were revealed as the optimum conditions to conduct aerobic oxidative C-H amination under solvent-free conditions or water (Scheme 13.14). 

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