Mechanistic intermolecular amination

Scheme 47 Mechanistic rationale of sequential intramolecular amination-insertion-intermolecular aminations [102]...

Dirhodium tetracarboxylate complexes are among the most successful and well-studied catalysts for C-H amination. Early work by Miiller provided support for a concerted asynchronous reaction mechanism for intermolecular amination reactions using Rh2(OAc)4 and NsN=IPh [22-24]. Du Bois and coworkers have shown that carbamate and sulfamate esters can engage in oxidative cyclization reactions promoted by these same types of Rh complexes using PhI(OAc)2 as the terminal oxidant [93-96]. Mechanistic studies, which include Hammett analysis (p = 0.55... 

While the majority of Rh-catalyzed C-H amination processes employ hyperva-lent iodine oxidants and sulfonamide derivatives, Lebel and coworkers have demonstrated that /V-tosyloxycarbamates will engage with catalytic Rh2(02CCPh3)4 and K2CC>3 to afford products of intramolecular C-H insertion (Fig. 22) [104, 5, 105]. Similar to Du Bois earlier work involving oxidative cyclization with 1 ° carbamates [94], the /V-tosyloxy derivatives display a strong bias for oxazolidinone formation. Selectivity trends and other mechanistic data support a reaction pathway involving a Rh-nitrene oxidant. Intermolecular amination of simple benzylic substrates... 

Despite these mechanistic and theoretical studies, intermolecular amine-catalyzed aldolizations have only rarely been used on a preparative scale. A few note vorthy exceptions in vhich aldehydes are used as donors are sho vn in Scheme 4.6 [51-55]. These reactions are often performed neat or in the presence of small amounts of an organic solvent. The catalyst usually used is either a primary or secondary amine, a combination of an amine vith a carboxylic acid, or simply an amino acid. These catalyst systems have previously been used in the Knoevenagel condensation and it is apparent that synthetic amine-catalyzed aldolizations originate from Knoevenagel s chemistry [56]. 

Fiori KW, Du Bois J. Catalytic intermolecular amination ofC—H bonds method development and mechanistic studies. JHm Chem Soc. 2007 129 562-568. 

Intermolecular Nucleophilic Substitution with Heteroatom Nucleophiles. A patent issued in 1965 claims substitution for fluoride on fluorobenzene-Cr(CO)3 in dimethyl sulfoxide (DMSO) by a long list of nucleophiles including alkoxides (from simple alcohols, cholesterol, ethylene glycol, pinacol, and dihydroxyacetone), carboxylates, amines, and carbanions (from triphenyhnethane, indene, cyclohexanone, acetone, cyclopentadiene, phenylacetylene, acetic acid, and propiolic acid). In the reaction of methoxide with halobenzene-Cr(CO)3, the fluorobenzene complex is ca. 2000 times more reactive than the chlorobenzene complex. The difference is taken as evidence for a rate-limiting attack on the arene ligand followed by fast loss of halide the concentration of the cyclohexadienyl anion complex does not build up. In the reaction of fluorobenzene-Cr(CO)3 with amine nucleophiles, the coordinated aniline product appears rapidly at 25 °C, and a carefiil mechanistic study suggests that the loss of halide is now rate limiting. 

In view of the hydride-donating potential of (23), one might anticipate similar reactivity for adducts derived from, for example, amines and thiols. Intermolecular demonstrations of such reactivity are scarce on the other hand intramolecular examples are well known, although they may be mechanistically ambiguous. The prototype reaction is the intramolecular disproportionation of glyoxal (31) to glycolic acid (32), shown in equation (19). This reaction may be induced by hydroxide. With the aid of ab initio and MNDO-SCF-MO calculations a highly bent transition state has been calculated for hydride transfer. ... 

Organo-/-element-catalyzed hydroaminations have been extensively investigated for more than 10 years.1034-1038 Lanthanide metallocenes catalyze the regiospecific intermolecular addition of primary amines to acetylenic, olefinic, and diene substrates at rates which are —1/1000 those of the most rapid intramolecular analogs. Kinetic and mechanistic data argue for turnover-limiting C=C/C=C insertion into an Ln-N bond, followed by protonolysis of... 

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. ... 

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. 

A variety of aryl and diarylalkene radical cations have been generated in solution and characterized using transient absorption spectroscopy. Many of these are sufficiently long-lived for detailed kinetic studies of their intermolecular reactivity under conditions that are comparable to those used in mechanistic and synthetic studies. Reactions with nucleophiles typically occur by either addition or electron transfer, with the latter dominating in cases where the oxidation potential of the nucleophile is lower than that of the alkene. The data summarized herein indicate that most arylalkene radical cations are unseleclive in their additions to anionic nucleophiles in nonprotic solvents. By contrast, the additions to neutral nucleophiles such as alcohols and amines cover a range of timescales and clearly demonstrate the... 

Based on early mechanistic experiments, we propose that aminoester 139 and palladium(II)-n-allyl conplex 140 establish an unfavorable equilibrium with palladium(0) and ammonium salt 141 (Scheme 1 S.3ST As soon as this unstable ammonium intermediate is formed, it undergoes a rapid deprotonation to generate ammonium ylide 142, which is transformed into the observed [2,3]-rearrangement product 143 through an exo transition state. An unfavorable equilibrium for the palladium-catalyzed ammonium salt formation, in conjunction with the facile conversion of ammonium salts into the [2,3]-rearrangement products, could explain the difficulty in observing any ammonium intermediates. This mechanistic proposal also accounts for why catalytic intermolecular allylic amination with tertiary amines has never been reported before. 

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

While early efforts in rare earth systems focused on cyclohydroamination, pioneering contributions in group 4 catalyzed hydroamination catalysis focused on intermolecular reactions [8]. However, owing to the aforementioned thermodynamic problems associated with intermolecular alkene hydroamination and mechanistic hmitations (see later discussion), early efforts focused on alkyne hydroamination with a variety of primary amines. 

Interestingly, the Schafer group [34] has established that group 4 complexes can indeed be used for the intermolecular hydroamination of alkynes with secondary amines consistent with a shift in mechanism from the established [2+2] cycloaddition pathway. Specifically, a Zr ureate catalyst 5 has been developed to realize this shift in mechanism. For example, entry 20 shows that morpholine can be used at elevated temperatures to give enamine products that can be characterized in situ. Using the ureate catalyst 5, mechanistic analyses [35] and subsequent computational investigations [36] support a proton-assisted C-N bond formation (see later discussion). 

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