Scope and Mechanism

Shortly after the initial discovery of native chemical ligation, a number of studies were subsequently conducted with the aim of establishing the scope of the ligation methodology and deciphering the subtleties of the reaction mechanism. In particular, the dependence of the rate of ligation oti the nature of the C-terminal peptide thioester moiety has been extensively studied. 

6MQn HCI, 0.1 M sodium phosphate, pH = 7.5 4vol% PhSH or benzylmercaptan 

---

The reduction of iminium salts can be achieved by a variety of methods. Some of the methods have been studied primarily on quaternary salts of aromatic bases, but the results can be extrapolated to simple iminium salts in most cases. The reagents available for reduction of iminium salts are sodium amalgam (52), sodium hydrosulfite (5i), potassium borohydride (54,55), sodium borohydride (56,57), lithium aluminum hydride (5 ), formic acid (59-63), H, and platinum oxide (47). The scope and mechanism of reduction of nitrogen heterocycles with complex metal hydrides has been recently reviewed (5,64), and will be presented here only briefly. 

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

Introductory discussion of the scope and mechanism of each reaction has been kept to a minimum. Many excellent texts and reviews exist that provide thorough and accurate discussion of the more theoretical aspects of organic synthesis, and the student is referred to these sources and to the original literature frequently. Since it is the purpose... 

This reaction, similar in scope and mechanism to 10-55, can be carried out with ammonia or primary or secondary amines. Amino acids can be N-acylated using... 

Sulfonium compounds (—C— SR2) undergo elimination similar to that of their ammonium counterparts (17-6 and 17-7) in scope and mechanism but this reaction is not of great synthetic importance. These syn-elimination reactions are related to the Cope elimination (17-8) and the Hofmann elimination (17-6). ... 

The scope and mechanism of the isomerization of arylamines to methyl-substituted aromatic heterocycles have been studied. Aniline, toluidines, naphthylamines and m-phenylenediamine all gave the corresponding ortho-methyl-substituted aza-aromatics when exposed to high NHj pressure and elevated temperature in the presence of acid catalysts, e.g., zeolites. The yiel of pyridines formed by this process range from low to moderate <95JC(155)268>. 

Nieto-Oberhuber, C., Perez-Galan, P., Herrero-Gomez, E., Lauterbach, T, Rodriguez, C., Lopez, S., Bour, C., Rosellon, A., Cardenas, D.J. and Echavarren, A.M. (2008) Gold(I)-Catalyzed Intramolecular [4+ 2] Cycloadditions of Arylalkynes or 1,3-Enynes with Alkenes Scope and Mechanism. Journal of the American Chemical Society, 130, 269-279. 

The synthesis of phthalimidines by dicobalt octacarbonyl-catalyzed carbonylation of Schiff bases was first described by Pritchard78 and the scope of the reaction was evaluated by Murahashi et a/.79 Later Rosenthal et al.80-83 subjected a variety of related compounds to carbonylation, and also achieved a phthalimidine synthesis directly from benzonitrile under the conditions of the oxo process.84 An example illustrating the formation of a phthalimidine is shown in Scheme 49 a comprehensive review of the scope and mechanism of reactions of this type is available.85... 

S. Kitahata, C. F. Brewer, D. S. Genghof, T. Sawai, and E. J. Hehre, Scope and mechanism of carbohydrase action. Stereocomplementary hydrolytic and glu-cosyl-transferring actions of glucoamylase and glucodextranase with alpha- and beta-D-glucosyl fluoride, J. Biol. Chem., 256 (1981) 6017-6026. 

The scope and mechanism of carboxylic acid homologation is examined here in relation to the structure of the carboxylic acid substrate, the concentrations and composition of the ruthenium catalyst precursor and iodide promoter, synthesis gas ratios, as well as 13C labelling studies and the spectral identification of ruthenium iodocarbonyl intermediates. 

Methods for indirect oxidation have also been developed. The combination of KF/ wCPBA in acetonitrile and water has been used to generate KOF CH3CN reagent, a mild and selective oxidant that reacts at 0 °C with no overoxidation [78]. This reagent functions by providing a fluorosulfonium ion intermediate, which is hydrolyzed in the presence of water to the desired sulfoxides. As a result of the indirect oxidation method, the typical stereoselectivity of mCPBA-type oxidations is not observed here. The KOFCH3CN oxidant is similar in scope and mechanism to 1-fluoropyridinium triflates, Selectfluor [302] and the more classical t-butyl hypochlorite [288]. 

As a result of our previous work on the scope and mechanism of tertiary amine nitrosation (X), we became interested in the behavior of N-alkylaziridines toward nitrous acid. Possible modes of reaction are illustrated in Scheme 1. The operation of either path A or C would be consistent with our previous studies of oxidative dealkylation of tertiary amines (1 ), while pathway B would be akin to the observed cheleotropic transformation of N-nitroso-aziridines (2). 

In this chapter, the recent advances in amidocarbonylations, cyclohydrocarbonylations, aminocarbonylations, cascade carbonylative cyclizations, carbonylative ring-expansion reactions, thiocarbonylations, and related reactions are reviewed and the scope and mechanisms of these reactions are discussed. It is clear that these carbonylation reactions play important roles in synthetic organic chemistry as well as organometallic chemistry. Some of the reactions have already been used in industrial processes and many others have high potential to become commercial processes in the future. The use of microwave irradiation and substitutes of carbon monoxide has made carbonylation processes suitable for combinatorial chemistry and laboratory syntheses without using carbon monoxide gas. The use of non-conventional reaction media such as SCCO2 and ionic liquids makes product separation and catalyst recovery/reuse easier. Thus, these processes can be operated in an environmentally friendly manner. Judging from the innovative developments in various carbonylations in the last decade, it is easy to anticipate that newer and creative advances will be made in the next decade in carbonylation reactions and processes. 

Leung, D.H., Bergman, R.G. and Raymond, K.N. (2006) Scope and mechanism of the C—H bond activation reactivity within a supramolecular host by an iridium guest A stepwise ion pair guest dissociation mechanism. J. Am. Chem. Soc., 128 (30), 9781-9797. 

This reaction, also called the Sandmeyer reaction, is similar to 4-25 in scope and mechanism. It is usually conducted in neutral solution to avoid liberation of HCN. 

R. Madsen and B. Fraser-Reid, Acetal transfer via halonium-ion induced reactions of di-pent-4-enyl acetals Scope and mechanism. J. Org. Chem. 60 772 (1995). 

The photocyclization of stilbene and its simple derivatives to phenanthrene and substituted phenanthrenes is now a well-documented and useful synthetic reaction the scope and mechanism of this reaction have been thoroughly reviewed by Stermitz.344 There... 

Hartwig, J.F., Transition metal catalysed synthesis of arylamines and aryl ethers from aryl halides and triflates scope and mechanism, Angew. Chem., Int. Ed. Engl, 1998, 37, 2047-2067. 

Christen, P., and D. E. Metzler, (eds.), Transaminases. New York John Wiley and Sons, 1985. A series of review chapters describing in detail the scope and mechanisms of transamination reactions. 

Recent advances in the scope and mechanisms of Pummerer-type reactions have been reviewed.133... 

Duran Pachon, L., Elsevier, C.J. and Rothenberg, G. (2006) Electroreductive palladium-catalysed Ullmann reactions in ionic liquids scope and mechanism. Adv. Synth. Catal., 348, 1705. 

The scope and mechanism of ionic hydrogenation of iminium cations have been investigated for a CpRuH catalyst bearing a chelating diphosphine.64 The mechanism involves three steps hydride transfer (from the catalyst) to form an amine, coordination of H2 to the resulting ruthenium cation, followed by proton transfer from the dicoordinated H2 to the amine. The cationic intermediate [e.g. CpRu(dppm)( 72-H2)+] can be used to hydrogenate enamines provided that the latter are more basic than the product amine. The relative reactivity of C=C and C=N bonds in a, ft -unsaturated iminium cations has also been investigated. 

The A-chloroacetyl derivatives of amines appropriately substituted with electron-rich arenes often give intramolecular alkylation and not solvolysis upon irradiation in aqueous solution. These photocyclizations have proven to be quite useful and versatile methods to synthesize a variety of novel and natural aza-heterocyclic compounds. The reader is referred to Reference 13 for a comprehensive review of the scope and mechanism of these reactions. 

---