Palladium nucleophilic aliphatic

A number of palladium-catalysed reactions of the triflate 61 have been reported but the nucleophilic displacement with primary aliphatic amines was, surprisingly, very slow in refluxing THF (24-92h). However, under microwave irradiation the reactions were very rapid and gave high yields, although even with microwaves, secondary amines and anilines failed to... 

The triflate 125 is formed from the hydroxy precursor (Equation 131) and undergoes a variety of nucleophilic substitution processes <2006TL4437>, including Suzuki and Stille couplings (Equations 132 and 133, respectively). Amination of 125 with aliphatic amines occurs under thermal conditions, using either conventional or microwave heating (Equation 134), but the reactions of 125 with less reactive amines require palladium catalysis (Equation 135). 

Neither the palladium nor nickel catalyst described will promote the carbonylation of saturated aliphatic halides as noted above. However, this reaction can be catalyzed with cobalt (17) or iron (77) and probably with manganese (18) carbonyl anion salts. These carbonyl anions are strongly nucleophilic species and readily displace halide or other good leaving groups from primary or secondary positions giving alkyl metal carbonyl complexes. 

As stated above, aliphatic amines are potent ligands for electrophilic transition metals and are efficient catalyst poisons in attempted alkene animation reactions. However, tosylation of the basic amino group greatly reduces its complexing ability, yet does not compromise its ability to nucleophilically attack complexed alkenes. Thus, a variety of alkenic tosamides efficiently cyclized under palladium(II) catalysis producing N-tosylenamines in excellent yield (equations 17 and 18).32 Again, this alkene amination proceeded through an unstable a-alkylpalladium(II) species, which could be intercepted by carbon monoxide, to result in an overall aminocarbonylation of alkenes. With ureas of 3-hydroxy-4-pentenyl-amines (Scheme 7), this palladium-catalyzed process was quite efficient but it was somewhat less so with... 

Pd(0)/phosphine complexes, or their precursors, in the presence of a suitable co-base, have also been shown to promote, in good yields (66-100%), the formation of allylic carbamates from various primary and secondary aliphatic amines, pressurized C02 and allylic chlorides, in THF, at ambient temperature [87a]. The choice of the added co-base (Base), used for generating the carbamate salt RR NC02 (BaseH)+, was found to be critical for high yields of O-allylic urethanes. The use of a guanidine (CyTMG) or amidine (DBU) base was optimal for this system (see also Section 6.3.1). ft is assumed that this chemistry passes catalytically through a mechanism similar to that illustrated in Scheme 6.19. This involves nucleophilic attack by carbamate anion on a (tt-allyl) palladium species, formed by the oxidative addition of the allylic chloride to a palladium(O) intermediate. 

Palladium-catalyzed tclomcrization of conjugated dienes in the presence of oxygen nucleophiles, such as water, aliphatic alcohols, phenols or acetic acid, represents another example of oxycarborative addition. Similar reactions are achieved with nitrogen, sulfur, or carbon nucleophiles. Depending on the reaction conditions, mixtures of linear and branched regioisotners are obtained, with the linear f-isomer usually prevailing3,24 27,88. 

A microwave-assisted fast and convenient route to palladium-catalyzed car-bonylation reactions has been reported. The microwave-assisted amidation of aryl halides 41 was achieved utilizing in situ generated carbon monoxide from [Mo(CO)6] (see Scheme 24) [46]. Aliphatic non-hindered primary amines 42 were observed to couple easily whereas hindered amines or amines with low nucleophilicity, e.g. anilines, afforded low yields and incomplete conversions. No difference in reactivity among electron-deficient, neutral or electron-rich aryl halides was found. In general, iodides could be coupled with solid Pd/C (or Pd(OAc)2) as catalyst, while bromides required a homogeneous catalyst. Ami-dations were studied in a sealed microwave protocol at 150 for 15 min, which could also be performed in a classical oil bath without any loss of yield. 

Heck carbonylation involving the oxidative addition of aryl halides is not applicable to aliphatic halides, since alkyl halides react directly with nucleophiles. Tsuji developed a process of carbonylating allyl carbonates to form carboxylic esters by palladium-catalyzed carbonylation that is applicable to aliphatic substrates [60]. The process probably involves (a) the oxidative addition of allyl carbonates to Pd(0) species to form r/ -allyl palladium species, (b) CO insertion into the allyl-Pd bond to give acylpalladium species, (c) decarboxylation of the carbonate ligand to give alkoxide, and (d) liberation of butenoate esters by combination with the alkoxides as shown in Scheme 1.21. 

More recently, Trost el al. also examined the ability to use aliphatic alcohols as competent nucleophiles in the palladium-catalyzed DYKAT of MBH adducts. High yield and enantioselectivity were obtained for both the kinetic transformation and dynamic kinetic transformation to alford substituted pyran products. The utility of this method was further demonstrated in the context of a concise total synthesis of the gastrulation inhibitor ( + )-hippospongic acid A (Scheme 3.138). ° ... 

Enantioselective allylic substitutions of cyclic allylic esters have been more challenging to develop than enantioselective reactions of symmetrical, acyclic allylic esters. In one set of reactions, racemic allylic esters react to form non-racemic products by addition of carbon or nitrogen nucleophiles in the presence of palladium catalysts. In these cases, attack at the two termini of the allylic intermediate generates the two enantiomers. Only a handful of ligands have generated catalysts that form products from the substitution of aliphatic. 

The palladium catalysts most frequently employed can be preformed palladium(O) complexes, such as Pd(PPh3)4,f" or complexes made in situ, for example, a combination of Pd(dba)2 or Pd2(dba)3 (dba - dibenzyUdene acetone) with PPhjJ Another common source of palladium is from [Pd(allyl)Cl]2 with a suitable phosphine, typically triph-enylphosphine. [Pd(allyl)Cl]2 is in oxidation state +2 but is reduced to Pd(0) by nucleophilic attack on the aUyl groupJ The standard phosphine is triphenylphosphine but bidentate and aliphatic phosphines can also be used. 

Since an amide nitrogen is far less basic than that of an aliphatic amine, amides do not displace alkene from palladium. The N atom of an amide is thus able to attack alkenes coordinated to Pd(II) to give vinyl amides, according to Scheme 1. Given in Table 1 is an example of the amidation of alkenes. The amidation can be made catalytic by using a combination of CuCl and O2 in the presence or absence of hexamethylphosphoramide (HMPA). The use of O2 alone also makes the reaction catalytic. The amidation does not proceed well with simple alkenes however, electron-deficient alkenes such as methyl acrylate and vinyl ketones undergo an effective catalytic amidation. Note that cyclic carbamates, because of the higher nucleophilicity of the N atom, are more reactive than cyclic amides. 

The aryl ether formation was, until the late 1990s, the domain of copper-catalyzed processes, namely the Ullmann reaction. Around 15 years ago, Hartwig and Buchwald independently discovered the palladium-catalyzed alkoxylation of aryl halides with phenols. Later, these reactions were extended to aliphatic alcohols and to hydroxide as nucleophiles (vide infra. Scheme 5-159). The mechanism of the reductive elimination has been elucidated on isolated complexes. ... 

While palladium-catalyzed alkenylation reactions involving amines as nucleophiles have been extensively explored, the related copper-catalyzed processes are rare and only few examples have been reported in the literature. The first example was described in 2001 and implied the particular use of l,3-dibenzyl-5-iodouracil as electrophilic counterpart for the access of enamine-type products with potential pharmacological activity (Scheme 20) [87]. The authors demonstrated that the conditions previously reported by Buchwald for the arylation of imidazoles [88] were suitable for the vinylation of numerous amines (including primary heteroaromatic substrates and both primary and secondary aliphatic ones) to yield thus the corresponding 5-aminouracil derivatives in yields up to 78%. 

Trost, B.M., Machacek, M.R., and Tsui, H.C. (2005) Development of aliphatic alcohols as nucleophiles for palladium-catalyzed DYKAT reactions Total synthesis of (-l-)-hippospongic add A. J. Am. Chem. Soc., 127, 7014-7024. 

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