Palladium-catalyzed amination secondary amines

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

Until recently, alkylphosphines had been used less often than arylphosphines in crosscoupling chemistry. However, several studies pointed to the potential of such ligands in the palladium-catalyzed amination of aryl halides. Alkylphosphines in combination with palladium catalyst precursors have now been shown to allow milder conditions for the amination of aryl bromides, to improve yields with acyclic secondary amines, to give high turnover numbers, and to induce mild aminations of inexpensive aryl chlorides and tosylates. 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

In a detailed investigation of the mechanism and scope of palladium catalyzed amination of five-membered heterocycles, the 1-methyl-3-bromoindole 145 was aminated with secondary amines to the 3-aminoindoles 146. Similar results were obtained for l-methyl-2-bromoindole <03JOC2861>. Rhodium-catalyzed cyclopropanation reactions involving 1-methyl-3-diazooxindole and exocyclic alkenes provided novel dispirocyclic cyclopropanes <03SL1599>. New applications of palladium-mediated cross-coupling reactions have been utilized to prepare a variety of functionalized indoles. Suzuki-Miyaura coupling reactions of indole-3-boronates <03H(59)473> and indole-5-boronates <03H(60)865> were utilized to prepare inhibitors of lipid peroxidation and melatonin analogues, respectively. 

Hartwig s group has developed chelating ferrocene ligands for this animation.21 They demonstrated that readily available DPPF serves as a competent ligand for the palladium catalyzed amination of primary aliphatic and aromatic amines. The coupling is conducted in THF and works equally well for both aryl iodides and bromides. Secondary amines were not extensively reported. 

Buchwald s XPhos ligand (L7) works well to catalyze the amination of 5-bromopyrimidine with anilines and secondary cyclic amines.67 Buchwald also found that ligands L20 and L21 were the best ligand for the palladium-catalyzed amination of benzothiazoles with secondary amines and anilines. Hartwig reports that (r-Bu)3P was excellent for the catalytic amination of 2-chloroheteroaryl compounds with secondary amines and anilines.35,68 As with other examples using bulky mono-dentate phosphines, primary aliphatic amines were not reported. 

Particularly for small-scale apphcations, Fu s report on the use of the tetrafluo-roborate salt of P( Bu)3 constitutes a viable alternative [73]. P( Bu)3 has been used in many areas of palladium-catalyzed amination, such as the arylations of piperazines [74], couphngs of secondary amines at ambient temperature [75] and triaryl-amine syntheses [75, 76]. PCy3 was used for the palladium[Pg.76]

Nolan reported several examples of palladium-catalyzed aminations using imidazolium salts as precursors to an unsaturated NHC ligand (Figure 3.5). AppUca-tions include arylations of piperidine [63] and couplings of aryl chlorides with additional secondary amines. 

Ackermann HASPO Ligands Ackermann presented two new ligand families, named heteroatom-substituted secondary phosphine oxides (HASPO) and the corresponding phosphine chlorides. The development of the former ligand class is related to studies of Li (DuPont), who described the use of dialfeylphosphine oxides with electronically distinct properties as active and easily accessible ligands for palladium-catalyzed aminations (Figure 3.10) [107]. 

Fort and co-workers first reported that [(IPr)2Ni] (formed in situ from [Ni(acac)2], SIPr-HCl, and base) allowed for the efficient amination of various aryl chlorides under mild conditions (Equation (10.6)). Both electron-poor and electron-rich substituents were supported as well as pyridinic core. A great variety of anilines and secondary amines were easily introduced in good to excellent yields. Primary amines also reacted in moderate yields with activated aryl chlorides. The catalytic cycle was presumably similar to that postulated for the palladium-catalyzed amination of aryl halides using NHC-Pd systems. ... 

For the preparation of a-ketoamides, palladium-catalyzed double carbonylation of aryl halides with carbon monoxide and secondary amines is also a useful reaction Kobayashi, T. Tanaka, M. J. Organomet. Chem. 1982, 233, C64 Ozawa, F. Soyama, H. Yamamoto, T. Yamamoto, A. Tetrahedron Lett. 1982, 23, 3383. 

The reaction of an orf/io-ester, e.g., HC(OEt)3, with a secondary bisamine in the presence of an anunonium salt yields imidazolidinium salts (Scheme The necessary secondary diamines can be generated by a classical condensation-reduction sequence or by applying the palladium-catalyzed Buchwald-Hartwig amination." The latter reaction offers convenient access to imidazolidinium salts with chiral backbones starting from chiral diamines, a number of which are commercially available. ... 

Palladium-catalyzed, Allylic Amination. Allylic substitution of mono-saccharidic hex-2-enopyranoside 4-acetates with secondary amines in the presence of tetrakis (triphenylphosphine)palladium(O) liad led to a large variety of 4-aminated 2-enosides, with retention of configuration (56-58). The method was applied to the disaccaridic enoside 1 to give, with benzylmethylamine or dibenzylamine, the 4-amino sugar derivatives g in yields of 92 and 67% (46). Studies concerning hydrox-ylation of t)ie double bond and subsequent deprotection are incomplete. 

The chemo- and regiospecific palladium-catalyzed four-component reaction of aryl iodides followed by incorporation of carbon monoxide, a polymer-supported allene, and a range of secondary cyclic amines has been reported as a short and high-yielding route to complex heterocycles with three points of diversity, such as 7 <2000CC2241>. 

A palladium-catalyzed amidation of halo(hetero)aromatics substituted in the ortAo-position by a carbonyl function with a primary or secondary amine has been introduced as an alternative to the Friedlander condensation for the synthesis of naphthyridinones (and quinolinones) (Scheme 32) <2004OL2433>. 

Amides are produced from the palladium-catalyzed carbonylation of organic halides if primary or secondary amines are present rather than only an alcohol (/5) ... 

Another variation of the palladium-catalyzed carbonylation reaction occurs when hydrogen is added rather than an alcohol or a primary or secondary amine. This variation leads to aldehyde formation the hydrogen reduces the acylpalladium intermediate to aldehyde and metal hydride (76). A basic tertiary amine is also added as in the ester-forming reaction to neutralize the hydrogen halide formed in the dissociation of the hydride ... 

Ammonia fails to act as an effective nucleophile for 7r-allylpalladium complexes. Some examples of primary amines81-181-183 have been reported, although diallylation is often a problem in these reactions. Secondary amines are, however, excellent substrates for palladium-catalyzed allylation.81-84,181-183-195 Amides,176-196 sulfonamides,196-197 azides198 and magnesium amides199 have also been shown to be effective nucleophiles. 

Fig. 10. Multiple derivatization of purines including palladium-catalyzed reaction at the poorly reactive C2 position, (a) NaBH(OAc)3, 1% HOAc, THF (b) 59 (0.5 equiv.), 2,6-dichloropurine (1 equiv.), DIEA (1.5 equiv.), BuOH 80° (c) R2OH, PPh3, DiAD (1.5 2 1.3) in excess, THF, RT (d) boronic acids (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, Cs2C03 (6 equiv.), 1,4-dioxane, 90°, 12 h (e) anilines (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, KO Bu (6 equiv.), 1,4-dioxane, 90°, 12 h (f) phenols (5 equiv.), 7% Pd2(dba)3, 28% phosphine ligand, K3P04 (7 equiv.), toluene, 90°, 12 h (g) primary or secondary amines (5 equiv.), 90°, 12 h.

Early findings by Heck and co-workers [56] have shown that the palladium-catalyzed coupling of aromatic halides, non-conjugated 1,3 dienes and secondary amines gives the corresponding arylallylated amines. A representative example is given in Scheme 8.20. 

Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or pseudohalides (for example triflates) and primary or secondary amines. 

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