Regioselective hydroamination

Hydroamination of activated alkenes has been reported with complexes 91-93 (Fig. 2.15). For example, 91 catalyses the hydroamination of methacrylonitrile (X = CN in Scheme 2.13) by a range of secondary amines (morpholine, thiomorpholine, piperidine, iV-methylpiperazine or aniline) in good to excellent conversions (67-99%) and anfi-Markovnikov regioselectivity (5 mol%, -80°C or rt, 24-72 h). Low enantioselectivies were induced ee 30-50%) depending on the amine used and the reaction temperature [79]. 

The stoichiometric hydroamination of unsymmetrically disubstituted alkynes is highly regioselective, generating the azametaUacycle with the larger alkyne substituent a to the metal center [294, 295]. In others words, the enamine or imine formed results from an anti-Markovnikov addition. Unfortunately, this reaction could not be applied to less stericaUy hindered amines. 

Hydroamination of terminal alkynes with primary amines has been performed using organoactinides as catalysts [301, 302]. The organouranium complex Cp 2UMe catalyzes the regioselective formation of imines in fair to high yields (Eq. 4.82). 

In order to account for the high regioselectivities observed in the rhodium-catalyzed hydroboration of styrenes, Hayashi proposed a modified mechanism which proceeds through 73-benzyl-rhodium complex 22 as a key intermediate (Scheme 7). Reductive elimination from this 73-benzyl-rhodium complex 22 produces the secondary alkylborane regioselectively.12 A related 73-benzyl-palladium complex was recently isolated by Hartwig in studies of hydroamination.75... 

Highly regioselective intramolecular hydroamination of a y-aminoallenes has been achieved using a titanium bis (sulfonamide) as a precatalyst (Scheme 16.102) [107]. 

Alkene hydroamination has been known for many years, but has been little used as a method in organic synthesis. Tobin Marks of Northwestern recently published a series of three papers that will make this transformation much mote readily accessible. In the first (J. Am. Chem. Soc. 125 12584,2003) he describes the use of a family of lanthanide-derived catalysts for intermolecular hydroamination of alkynes (to make imines, not illustrated) and alkenes. With aliphatic amines, the branched (Markownikov) product is observed, 1 — 2. With styrenes, the linear product is formed. When two alkenes are present, the reaction can proceed (3 —> 4) to form a ring, with impressive regioselectivity. 

Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13).80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion. 

The mechanism does not proceed through a direct hydroamination of one of the diastereotopic alkenes, but involves a series of very selective processes including a deprotonation of (22), diastereoselective protonation of (26), intramolecular addition of lithium amide (27) to the 1,3-diene moiety, and final regioselective protonation of the allyl anion (28), all mediated by a substoichiometric amount of n-BuLi. 

The intermolecular hydroamination of alkynes, catalysed by the aquapalladium complex [(dppe)Pd(H20)2](0Tf)2, has been reported. The reaction is believed to proceed through the equilibrium between the hydroxopalladium and the amidopalladium complexes, followed by aminopalladation of alkynes.76 Regioselective 1,2-diamination of 1,3-dienes by dialkylureas, catalysed by (MeCN)2PdCl2 in the presence of 1 equiv. of / -benzoquinone, has been developed as a highly efficient method.77... 

Iridium(ni) hydrides, such as (98), proved to be air-stable active catalysts for intramolecular hydroalkoxylation and hydroamination of internal alkynes with proximate nucleophiles (e.g. 96). The cyclization follows the 6-endo-dig pathway with high preference (when regioselectivity is an issue).125... 

Ru3(CO)12 [28]. Furthermore, the Pd-catalyzed solvent free arsination of aryl triflates (Scheme 9) [29], and the hydroamination of phenylacetylene with aniline in the presence of [Ru3(CO)12]/NH4PF6 proceeds with high regioselectivity giving the product by simple distillation with greater than 99% purity in 92% yield (Scheme 10) [30],... 

A number of additional cyclizations involving alkynes have been reported. For instance, it has been shown that indoles may also be accessed from 2-bromo- or 2-chloroanilines, as illustrated by the regioselective preparation of the carbinol 373 in the presence of the ferrocene 374 (Equation 104) <20040L4129>, whereas a one-pot sequence featuring titanium catalyzed hydroamination of 2-chloroanilines with acetylenes, followed by intramolecular Heck cyclization in the presence of an imidazol-2-ylidene palladium complex, has also been reported <2004CC2824>. A set of aryl-2-indolyl carbinols have been prepared in high enantiomeric purity by palladium-catalyzed annulation of... 

Palladium-catalyzed regioselective hydroamination of 2,3-dihydrofuran under ligand-free and neutral conditions was found to be general with secondary alkyl amines, as exemplified in Equation (119) <2001T5445>. 

For indole synthesis, the best additive both for yield and regioselectivity was found to be the anilinium hydrochloride (PhNH2- HCl). The formation of the indole product can be explained by the isomerization of the hydroamination product, in which it has been clearly shown that the ruthenium catalyst is not involved. 

Type 4 metallocene complexes catalyze the regioselective mtermolecular addition of primary amines to acetylenic, olefinic, and diene substrates at rates which are = 1/1000 those of the most rapid intramolecular analogues [165]. Variants such as the intramolecular hydroamination/cyclization of aminoallenes [166] and the intra- and intermolecular tandem C-N and C-C bond-forming processes of aminodialkenes, aminodialkynes, aminoallenynes, and aminoalkynes [167] were applied as new regio- and stereoselective approaches to naturally occurring alkaloids. For example, bicyclic pyrrolizidine intermediate E... 

Organolanthanide-catalyzed intermolecular hydrophosphination is a more facile process than intermolecular hydroamination. The reaction of alkynes, dienes, and activated alkenes with diphenylphosphine was achieved utilizing the ytterbium imine complex 9 (Fig. 8) as catalyst [185-188]. Unsymmetric internal alkynes react regioselectively, presumably due to an aryl-directing effect (48) [186]. 

Scheme 9 Regioselective hydroamination of terminal alkynes promoted by precatalyst 13...

The reaction involves initial formation of the zirconium-imido species, followed by [2-1-2] cycloaddition with the C—C unsaturation (Scheme 13). This is consistent with the observation that bis(amidate) complexes do not mediate hydroamination with secondary amine containing substrates. The cyclic transition state of the intramolecular reaction determines the regioselectivity of the reaction followed by successive protonation of the intermediate metallacycle and release of product to regenerate the catalyticaUy active imido species. 

Doye s group [81] showed that a dinuclear titanium-sulfonamidate complex (Scheme 21), with a tetrahedral sulfur in the ligand backbone, can be used for intermo-lecular hydroaminoalkylation as well. This system gives mixtures of branched and linear products, although to date there has been no mechanistic rationale provided for the reduced regioselectivity of group 4 metal complexes in this transformation. There has been one report by Zi s group [44] that describes axially chiral bis(sulfonamidate) tantalum and niobium complexes for application as precatalysts for hydroamination and hydroaminoalkylation. Unfortunately, these complexes did not show any reactivity for either of these reactions. 

A novel one-pot domino process was developed to synthesize substituted 1,2-dihydroquinoline derivatives 102 with high regioselectivity using a silver catalyst <05OL2675>. Scheme 29 shows the proposed pathway, which starts with the hydroamination of alkyne 103 and aniline 104. This is followed by C-H addition with another alkyne 103 and C-H addition cyclization to give intermediate 105. The final step is another C-H addition with alkyne 103 yielding the desired product 102. The scope and mechanism of this one-pot process is still under investigation. 

Addition and cycloaddition. Styrenes are transformed into benzylatnine derivatives by hydroamination with TsNH2/" More unusual is the regioselective addition of arenes across the triple bond of an alkynylarene, as catalyzed by FeCls. ... 

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