Pd cross-coupling

Of all the palladium-catalyzed coupling reactions, the Kumada coupling has been applied least often in indole chemistry. However, this Grignard-Pd cross-coupling methodology has been used to couple l-methyl-2-indolylmagnesium bromide with iodobenzene and a-bromovinyltrimethylsilane to form l-methyl-2-phenylindole and l-methyl-2-(l-trimethyl-... 

The selectivity, functional group tolerance, and mild reaction conditions of the various Pd° cross-coupling reactions have made them invaluable tools for carbon-carbon bond formation. Intramolecular variations to construct macrocycles have also been described. 

Other Pd cross-coupling reactions such as Heck [52] and Suzuki [53] reactions have also been used for macrocyclizations. The main drawback for Pd catalyzed macrocylization is the yield, that is often somewhat disappointing if compared with other established methods. Also, the introduction of the required coupling components (e.g., trialkyltin group, vinylic iodide) can be difficult in some compounds. In other cases, Pd-catalyzed side reactions such as double bond migration or allylic activation can occur. 

Pd cross-coupling reactions Lewis acids (e.g., A1C13, BC13, TfOH)... 

Figure 2.10 A cross-section of results for the Pd cross-coupling of aryl bromides with thioacetates as reported by Park et al. [52].

The synthetic routes into p-trifluoromethylated corroles are significantly different from those used to prepare the p-fluorinated derivatives (Fig. 4). Direct trifiuoro-methylation of the p-position by halogen substitution in octabromocorroles was accomplished using Pd cross-coupling chemistry [37] identical to methodology used to isolate trifluoromethylated porphyrins (Scheme 14) [29,38]. The p-octakis-(trifluoromethyl)corrole was shown to be one the most electron-poor trivalent ligands ever reported for copper, as was gauged by cyclic voltammetry. 

Pd cross-coupling ( Nozaki-Hiyama-Kishi coupling Reveromycin B (79)... 

Pd cross couplings [134, 140], oxidations and oxidative couplings [135], carbene transfer reactions from diazo compounds into 0-H, N-H, and C-H bonds, hydroalk-oxylationof allenes andenyne cyclizations [138]. A more detailed discussion of the properties of l,3,4-trisubstituted-l,2,3-triazol-5-ylidenes can be found in a recent review of the field [141]. 

In a final example, Denmark has described a detailed study on a tandem RCM/Si-assisted Pd cross-coupling reaction sequence that led to unsaturated macrolactones 128 (Scheme 11.15) through the intermediacy of siloxane 127 233 typically difficult 11- to 14-membered ring sizes could be accessed under the optimized conditions, which included a hydrated fluoride ion activator. High dilution conditions were not required and this process was adapted to provide benzo-fused products as well. 

The thioboration of terminal alkynes with 9-(alkylthio)-9-borabicyclo[3.3.1]-nonanes (9-RS-9-BBN) proceeds regio- and stereoselectively by catalysis of Pd(Ph,P)4 to produce the 9-[(Z)-2-(alkylthio)-l-alkeny)]-9-BBN derivative 667 in high yields. The protonation of the product 667 with MeOH affords the Markownikov adduct 668 of thiol to 1-alkyne. One-pot synthesis of alkenyl sulfide derivatives 669 via the Pd-catalyzed thioboration-cross-coupling sequence is also possible. Another preparative method for alkenyl sulfides is the Pd-catalyzed cross-coupling of 9-alkyl-9-BBN with l-bromo-l-phe-nylthioethene or 2-bromo-l-phenylthio-l-alkene[534]. 

The ester 870 is prepared by the cross-coupling of the chloroformate 869 with an organotin reagent. Some chloroformates are easily decomposed by a Pd catalyst, and hence the reaction should be carried out by slow addition of the chloroformates. Similarly, the amide 872 is prepared by the reaction of the carbamoyl chloride 871 [742]. The coupling of alkylcopper with ethyl chloroformate catalyzed by Pd affords esters[743]. 

The cis thioboration of terminal alkynes with 9-(arylthio)-9-BBN is catalyzed by Pd(Pli3P)4 in the presence of styrene. The product 136 is converted into the vinyl sulfides 137 and 138 by the treatment with MeOH or by Pd-catalyzed cross-coupling with aryl or alkenyl halides using K3PO4 in DMF[68]. No thioboration takes place with internal alkynes. 

There are also palladium-catalysed procedures for allylation. Ethyl 3-bromo-l-(4-methylphenylsulfonyl)indole-2-carboxylate is allylated at C3 upon reaction with allyl acetate and hexabutylditin[27], Ihe reaction presumably Involves a ir-allyl-Pd intermediate formed from the allyl acetate, oxidative addition, transmetallation and cross coupling. 

Vinylation can also be done by Pd-catalysed cross-coupling in which one component is used as a halide or triflate and the other as a stannane (Stille reaction) or boronic acid (Suzuki reaction). Entry 9, Table 11.3, is an example of the use of a vinylstannane with a haloindole. lndole-3-boronic acids, which can be prepared by mcrcuration/boration, undergo coupling with vinyl triflates (Entry 10). 

Alkyl- and aryl-pyridazines can be prepared by cross-coupling reactions between chloropyridazines and Grignard reagents in the presence of nickel-phosphine complexes as catalysts. Dichloro[l,2-bis(diphenylphosphino)propane]nickel is used for alkylation and dichloro[l,2-bis(diphenylphosphino)ethane]nickel for arylation (78CPB2550). 3-Alkynyl-pyridazines and their A-oxides are prepared from 3-chloropyridazines and their A-oxides and alkynes using a Pd(PPh3)Cl2-Cu complex and triethylamine (78H(9)1397). 

KUMADA NEGISHI Cross coupling Stsreospecific alkenyl aluminum-alkenyl halide cross coupling catalyzed by Pd or Ni... 

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

Scheme 5.2-18 Pd-catalyzed Suzuki cross-coupling reaction in a [BMIM][BF4] ionic liquid.

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