Amino palladation

Utilization of heteropalladation (halopalladation ox5q>alladation amino-palladation acetyloxypalladation) of unsaturated hydrocarbons in organic synthesis, particularly, in s5mthesis of heterocycles 07CJO819. 

Several examples of Pd°-catalyzed carboamination reactions between allenes and aryl or alkenyl halides have been reported [50[. For example, treatment of allene 52 with iodobenzene in the presence of K2CO3 and 2mol% Pd(PPh3)4 afforded pyrrolidine 53 in 78% yield (Eq. (1.25)) [50a]. Mechanisms involving aikene amino-palladation (similar to the reactions of alkynes and alkenes noted above) have occasionally been invoked to explain these reactions. However, in many instances these transformations may involve intermediate Ji-allylpalladium complexes. Due to this mechanistic ambiguity, these transformations have been included in this section for comparison with the related reactions of alkenes and alkynes. Similar reactions involving allylic halides have also been described (Eq. (1-26)) [51]. 

A mucii different strategy was developed by Shi for the conversion of 1,3-dienes or trienes to cyclic ureas [66]. As shown below, treatment of conjugated diene 84 with di-t-butyldiaziridinone 83 and in the presence of Pd(PPh3)4 as catalyst led to the formation of 85 in 94% yield with >20 1 dr (Eq. (1.38)). This reaction is beUeved to occur via oxidative addition of 83 to Pd° to generate 86, which undergoes amino-palladation to afford allylpalladium complex 87. Reductive elimination from 87 affords the urea product. An asymmetric variant of this transformation that provides products with up to 95% ee has also been reported [67]. 

The synthesis of a-benzofuranylacetamides and indolylacetamides has been achieved through a palladium-catalyzed process (Scheme 3.61 and Example 3.10) [67]. The overall reaction consisted of an intramolecular oxy/amino-palladation/isocyanide insertion process starting from functionalized propargyl alcohols. Although a vast array of compounds were successfully generated using this approach, the conversion of nitrated anilines was unsuccessful under the reaction conditions. 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

Alkenes can be palladated to yield a complex which can be opened trans by an amine nucleophile. The resulting o-pidladium species can be woiked up oxidatively to yield an amino alcohol (as its acetate ester). This depalladation occurs with inversion, yielding overall cis stereochemistry (Scheme 54). If the acetic acid in step iii is replaced with phenol, a -phenoxyamine is produced. 

Diamino-2-phenyltriazole and nitrosobenzene, stirred in an emulsion of benzene and 12 N sodium hydroxide, gave 4-amino-2-phenyl-5-phenylazotriazole (60°C, 10 min, 72%) (70BCJ3587). Potassium permanganate in dilute acetic acid oxidized 4-amino-3,5-diphenyltriazole to 3,3, 5,5 -tetraphenyl-4,4 -azotriazole (25 °C, 30%). This product, stirred with hydrazine hydrate and palladized carbon in chloroform, gave 4-amino-3,5-diphenyltriazole (25°C, 1 hr, 91%) (70JOC2215). 

According to mechanistic considerations of Scheme 8, benzylamine arylation should also be feasible. The palladation of benzylamines in strong acid might be retarded due to protonation of the directing amino group. Employing a limited amount of trifluoroacetic acid solvent allowed efficient benzylamine arylation [63], Specifically, the benzylamine arylation reactions are the fastest if about five equivalents of trifluoroacetic acid solvent are used. A number of benzylamines and A-methy lbenzy I am i n e s were shown to be reactive under these conditions (Scheme 16). The reactions proceed well with both electron-rich and moderately electron-poor benzylamines. For unsubstituted or 4-substituted benzylamines, 2,6-diarylation is observed. Benzylamines substituted at the 3-position are monoarylated. As in the case of pyridine and anilide arylation, bromine is tolerated on the substrate, and even iodide is compatible with the reaction conditions, although the yield is reduced. The products are acylated after the reaction to facilitate isolation. 

Carbonylation of alkenes having an amino or hydroxy group (AH or BH = OH or NHR) 140, 142 and 144 offers interesting synthetic methods for cyclic compounds. The 4-pentenylamine or alcohol 140 is converted to 141 via amino or oxypalladation, followed by carbonylation. The amino alcohol 142 gives 143 by palladation and carbonylation by path a. The homoallylic amine or alcohol 144 is converted to lactone or lactam ester 145 by path c [60]. 

Intramolecular reaction of allenes is known to proceed mainly by palladation at the central carbon to generate alkenylpalladium 235, which undergoes further reactions. Also TT-allylpalladium 236 is formed when a nucleophile attacks the central carbon. The intramolecular aminopalladation of the 6-aminoallene 237, followed by CO insertion, afforded the unsaturated amino ester 238. The reaction has been applied to the enantioselective synthesis of pumiliotoxin [103]. Oxycarbonylation of the allenyl alcohol 239 afforded the unsaturated ester 240 in 83 % yield using a catalytic amount of PdCl2 and 3 equivalents of CuCb in MeOH and is used for the synthesis of rhopaloic acid [104]. 

A variety of Lewis-basic nonbonding electron donors including amino, imino, azo, amido, phosphino, and sufldo groups readily participate in the arene palladation, as indicated by the results shown in Scheme 1.[ H12] Ethers and other oxygenated groups... 

NMR spectroscopy was applied in the enantiomeric excess determination of (iV,iV-dimethyl-(2,2,2-trifluoro-l-phenylethyl)amine-C,A)palladium complexes of a-amino acids.Dunina et al. used NMR spectroscopy and a P -chiral phosphapalladacycle for the enantiomeric purity determination of a-amino acids. P NMR spectroscopy was also used in the enantiomeric excess determination of N,C o///5< -palladated complexes of P-chiral phosphines. A ferrocene-based reagent (i p,successfully designed for the chiral recognition of /3-hydroxyphosphines and the discrimination of ( )-bis(diphenylphosphino)-1,1 -binaphthyl. 

Indenols, and ultimately indanones, can be prepared via a nucleophilic vinyl pallad-ation of o-bromobenzaldehyde. Stereoselective addition of a -amino-organometallics to aldehydes have been reviewed (62 references). " Diastereoselective additions of MeMgX and MeLi to an oxo-sugar have been reported. ... 

A suspension of palladized charcoal in a freshly prepared soln. of dry HCl in acetic acid equilibrated with Hg, a soln. of ethyl a-(N-acetylphenylhydra-zono)-/ -oxobutyrate in acetic acid added, and hydrogenated 1 hr. ethyl a-amino-/ -oxobutyrate hydrochloride (Y 83%) and acetanilide (Y 94%).— With a platinum-palladium catalyst, also reduction of the keto to a sec. alcohol group occurs. W. G. Laver, A. Neuberger, and J. J. Scott, Soc. 1959, 1474. 

Enantiopure unsaturated amino acids are ideally suited for further selective transformations. In this section some selected examples are given. Radical additions will lead to enantiopure sulfur-containing amino acids. Ring-closing olefin metathesis will give cyclic amino acids, whereas Pd-catalyzed oxy palladation, amido palladation, and cross-coupling will lead to a vast array of enantiopure heterocyclic compounds. 

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