Pd/xantphos

An interesting double amination of 2-chloro-3-iodo-pyridine (16) with 2-aminopyridine (17) catalyzed by Pd/BINAP or Pd/Xantphos, which gives dipyridoimidazoles (18), was described by B. U. W. Maes and co-workers. 2-Aminopyrazine was also found to be a capable coupling partner.70 The mechanism is most likely an initial amination at the 3-iodo position followed by an intramolecular amination at the 2-chloro position. 

Scheme 55 Proposed mechanism for Pd(Xantphos)-catalyzed allylation of an H-phosphinic acid...

A related Pd-catalyzed allylation relied on the excellent leaving group ability of the H-phosphinate anion. Instead of the allyl acetate shown in Scheme 53, unfunctionalized allyl alcohol was used directly. Transesterification yields an allyl phos-phonate, whose oxidative addition to a Pd(Xantphos) catalyst yields a tt-allyl complex, with the H-phosphinate group present as a counter ion or bound to Pd. P-C bond formation might then take place either by nucleophilic attack, or by P-C reductive elimination (Scheme 55) [91]. A similar mechanism was suggested for cross-coupling of H3PO2 with benzylic alcohols [92]. 

In related Pd(Xantphos)-catalyzed cross-couplings of benzyl halides, reductive elimination was proposed as the slow step, since the overall rate increased with large bite angle ligands [98], P-C bond formation with isolated diastereomers of dinucleoside H-phosphonates was stereospecific, likely with retention of configuration at phosphorus, as above (Scheme 58). 

Scheme 6.13 Palladium-catalyzed carbonylation of diaryl ethers Pd(xantphos)Cl2, TBP...

Arylative cyclization of propargyl-substituted malonate esters RC=CCH2CH-(C02Me)2 with aryl halides, catalysed by the Pd-xantphos complex, has been reported to afford alkylidenecyclopropanes. The reaction proceeds via an initial flnft-carbopalladation of the C C bond, which controls the configuration of the resulting C=C in the product. ° ... 

Several derivatives of 4-aryl-l,5-disubstituted-1,2,3-triazole 51 were synthesized in good yields via 1,3-dipolar cycloaddition of aryl azides 48 and alkynylzinc species 49 followed by Negishi reaction of 50 under new conditions." Of all the combinations screened, Pd/xantphos was found to be superior. Kumada coupling was not as effective as the Negishi coupling in this reaction. 

Alkyl C-H bonds have been shown to be activated towards aminocarbo-nylation, leading to the synthesis of 2-atylacetamides including ibuprofen derivatives. An external oxidant of tert-hutyl hydroperoxide (TBP) with a Pd-Xantphos catalyst-ligand combination yielded a variety of substituted secondary and tertiary 2-arylacetamides (Scheme 17.49). By using the aryl substrates in a 10-fold excess, no additional solvent was required for the reaction in the majority of cases. 

Several studies have explored the influence of modified reaction conditions or special techniques to facilitate Pd-catalyzed iV-arylation reactions. For example, Buchwald has demonstrated that water can be used to preactivate Pd(OAc)2/ biarylphosphine catalyst systems, which leads to enhanced reactivity in N-arylations [118]. The addition of small amounts of water has been shown to accelerate Pd/Xantphos-catalyzed A -arylations of amide nucleophiles when CS2CO3 is used as base [119]. Particle size, shape, and molar excess also have a large influence on reaction rates for Cs2C03-mediated reactions [120]. The use of microwave irradiation to facilitate A -arylation has been explored [121-124], and transformations have been conducted in continuous flow microreactors [125], or with supercritical CO2 as solvent [126]. 

Palladium complexes like Pd/xantphos are known to efficiently catalyze addition of alkyl phosphinates to terminal olefins to give linear adducts as the major products [25]. When the reaction of (—)-8-phenylmenthyl phosphinate with olefins is run using the Pd/xantphos catalyst, enantioselective addition proceeds to give diastereomeric mixtures of P-chiral (—)-8-phenylmenthyl alkylphosphinates (Scheme 55). Stereoselectivities up to 66% and 71% de are observed for 1-octene... 

The intermolecular coupling of lactams and acyclic amides has also been reported. Reactions of carbamates with aryl halides occurred in the presence of catalysts ligated by P(/-Bu)3.78 Both carbamates and amides coupled with aryl halides in the presence of a catalyst bearing Xantphos.90 In addition, the coupling of lactams with aryl halides has been successful. A combination of Pd(OAc)2 and DPPF first formed A-aryl lactams in good yields from 7-lactams, but the arylation of amides was improved significantly by the use of Xantphos (Equations (20) and (21)).90 91 The reaction of aryl halides with vinyligous amides has also been reported 92... 

In line with the above mechanism, catalyst deactivation by formation of palladium black can be retarded by increasing the [P]/[Pd] ratio, however, only on the expense of the reaction rate. Bidentate phosphines form stronger chelate complexes than TPPMS which may allow at working with lower phosphine to palladium ratios. Indeed, the palladium complex of sulfonated XANTPHOS (51) proved to be an effective and selective catalyst for hydroxycarbonylation of propene, although at [51]/[Pd] < 2 formation of palladium black was still observed. The catalyst was selective towards the formation of butyric acid, with 1/b = 65/35 [41]. 

Prior to the recent paper by Buchwald, an intermolecular version of the arylation of carbamates was published by Hartwig et al. (Eq. (22)) [163]. His group showed that reactions catalyzed by a combination of Pd(OAc)2 and P(tBu)3 formed N-aryl carbamates from aryl bromides or chlorides and tert-butyl carbamate, but that this system was inactive for reactions of amides or sulfonamides. Again, the reaction conditions were not as mild as those used for animation, but they were similar to those employed in the reactions with Xantphos. For the intermolecular reactions, the use of sodium phenoxide as base was crucial. 

N- A ry I - 3 - (ary lmethy 1 )i soxazol id i nes were prepared from O-homoallylhydroxylamines by a Pd-catalyzed domino A-arylation/carboamination process. Optimized reaction conditions used catalytic amounts of Pd(dba)2 and of the bis(phosphine) ligand Xantphos in the presence of an excess of NaO -Bu as a base in toluene. Generally, the substituted isoxazolidines such as 86 were obtained with complete diastereoselectivity and good yields <07JOC3145>. 

Commercially available aminophosphine 4 provided even better yields in the coupHng of acycHc secondary amines [42]. The resulting catalyst was found to be so active that the reaction could often be conducted at room temperature. For example, Di- -butylamine was efficiently reacted with 4-bromotoluene in 96% isolated yield at room temperature, Eq. (27). In addition, electron-rich, electronically neutral, and electron-deficient aryl bromides were effectively utihzed with this new system. The 4/Pd-based catalysts also mediate the coupling of J -alkylanihnes that bear electron-donating substituents on the amine partner. A Xantphos/Pd-catalyst is effective in the coupling of electron-poor alkylaryl-amines with electron-poor aryl bromides. 

The Xantphos (9)/Pd-system also mediates the coupling of aryl bromides and carbamates [117]. The coupling of benzyl carbamate below proceeds in quantitative yield when CS2CO3 is used as base, Eq. (141). 

In 1998, the Buchwald group reported the arylation of benzophenone hydrazone with several aryl bromides [121]. The desired reaction could be effected with the BINAP/Pd-catalyst, however, the Xantphos/Pd-system proved particularly well-suited for this transformation, Eq. (147). 

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