Palladium catalyzed reaction

SCHEME 20.6 Pd-catalyzed C—N cross-coupling of aryl halides with organotin compound. 

SCHEME 20.7 Examples using bidentate phosphorous hgands. 

Ligand Bite angle (deg) P-BUC6H4NHBU (p-BuC5H4)2NHBu 

SCHEME 20.8 Effect of bite angle in C—N cross-couphng reaction. 

TRANSITION METAL-MEDIATED CARBON-HETEROATOM CROSS-COUPLING 

Palladium-catalyzed coupling reactions are very efficient for the introduction of new carbon- carbon bonds onto molecules attached to solid support. The mild reaction conditions and compatibility with a broad range of functionalities and high reaction yields, have made this kind of transformation a very common tool for the combinatorial synthesis of small organic molecules. The literature for synthetic methods of palladium-catalyzed reactions on solid supports has recently been reviewed [237-239]. 

The intramolecular Heck reaction is useful for the construction of complex natural products [241] and for the synthesis of indoles [242] benzofurans [243] quinolines [244] and benzazepines [245]. 

Recently, this methodology has been extended to the couphng of alkyl, allyhc, 1-alkenyl and 1-alkynyl halides with 1-alkenyl and even alkyl boron reagents. 

This reaction and some variations have been successfully used for the synthesis of heterocycles as indoles [253] or for the preparation of precursors necessary for the synthesis of cinnohnes by Richter reaction [140] as mentioned in Section 3.4.2.1. 

For purposes of completeness, palladium-catalyzed reactions for the synthesis of biaryls using zincates and arylhalides (Negishi Couplings) [254] or using sihcon compounds [255, 256] need to be mentioned. 

Other Metal-Catalyzed Coupling Reactions 6.2.2.1 Palladium-Catalyzed Reactions 

Some palladium-catalyzed reactions of organotins, such as carbostannylations, are not related to the Stille cross-coupling. The history of the transition-metal-cata-lyzed carbostarmylation [148] began with alkynylstannylation of alkynes catalyzed by a palladium-iminophosphine complex [149]. Thus, alkynylstannanes added to a carbon-carbon triple bond of various acetylenes, conjugated ynoates and propar-gyl amines and ethers in the presence of a catalytic amount of a palladium-iminophosphine complex [150]. The reaction also proceeded with arynes to afford ortho-substituted arylstannanes, which could further be converted into 1,2-substituted arenes via carbon-carbon bond-forming reactions [151]. 

MejSnSnMcj reacted with allenes and aryl iodides in a three-component palladium-catalyzed carbostarmylation to afford the corresponding aUylstannanes [152]. Finally, Pdjdbaj-catalyzed allylstarmylations of various alkynes by an a-methyl-allylstannane were reported [153]. 

3 Transition Metal-promoted Reactions 9.07.2.3.1 Palladium-catalyzed reactions 

With the aid of a fluoride ion source, alkynyltrimethylsilanes work as effective alkynyl donors in the Pd-catalyzed cross-coupling with alkenyl iodides.43,43a Recent studies have revealed that the alkynylsilanes react smoothly with aryl iodides and triflates, alkenyl triflates, or alkynyl chlorides under co-catalysis by a Cu or Ag salt.45 46a The use of a Pd/imidazolium chloride system in the presence of Cs2CC 3 and a Cu co-catalyst enables an efficient coupling between alkynyltrimethylsilanes and aryl bromides.47 In some cases, this catalytic system works well under Cu-free conditions. Alkynylsilanols also can be used as alkynyl donors in the coupling with aryl iodides.48 49 When TBAF is employed as activator, the coupling proceeds efficiently without co-catalyst.48 

Hiyama and co-workers have reported that the Mizoroki-Heck-type reaction of aryl- and alkenylsilanols is efficiently promoted by a Pd(OAc)2/Cu(OAc)2/LiOAc system (Equation (9)).50 50a in contrast, a dicationic Pd(ll) complex prepared in situ from Pd(dba)2, a diphosphine (dppe or dppben), and Cu(BF4)2 catalyzes 1,4-addition of aryltrialkoxysilanes to a-enones and a-enals in aqueous media (Equation (10)).51 The Pd-catalyzed 1,4-addition of the arylsilanes can be achieved also by using excess amounts of TBAF 3H20, SbCl3, and acetic acid.52 

alkenyl SiR(OH)2SiR2(OH) Aryl, benzyl Ag20 337-339 

Alkenyl 1 -Me-1 -sila-cyclobutyl Aryl, alkenyl TBAF 341,356,357 

It is important to note that there are successful examples of biaryl coupling using electron-rich and sterically-hindered phosphine ligands on palladium(O).  

In an effort to synthesize a series of trisubstituted pyrazines to study their kinase inhibition activity, a series of regioselective substitution reaction was accomplished under two separate pathways. The first was more amenable to rapid structure activity relationships at the Ni position. At this position a wide variety of benzylic, alkyl and amide fiinctionalities were 

To fiuther illustrate the broad biological activity that pyrazines can display. Sharpies and Seitz synthesized the similar intermediates toward 

This reaction displays a diverse functional group tolerance. This reaction showed no significant differences in yields when comparing electron-donating groups and electron-withdrawing groups. The substitution pattern of the aryl halide displayed minimal effects on the isolated yields of the products. 

After the coupling was completed, the oxidized nitrogen can be manipulated in many different ways to provide a variety of different structural motifs. These reactions display a high-degree of regioselectivity and moderate to high yields. 

It has been suggested that intermolecular incorporation, i.e. oxidative addition and complexation of a substrate by a metal should be favored, intramolecular reactions, i.e. insertion, migration and deinsertion reactions should be invariant, and extmsion reactions such as reductive elimination or decomplexation should be disfavored by pressure [13], However, decomplexation reactions are in most cases ligand exchange reactions, which can proceed by associative mechanisms, and indeed, there is ample evidence that ligand exchange reactions can be accelerated by pressure [2]. 

Alkerre Pressure [kbar] Time [h] Temperature [ Cl Product Yield [%] 

Another effect of pressure in these coupling reactions is a dramatic increase in the lifetime of the catalyst (Table 7.1), which is reflected in turnover numbers (TON) of up to 770,000 [17]. Moreover, even in the absence of stabilizing ligands the coupling reactions proceeded with considerable higher TON (7500) than can be reached with the catalyst Pd(OAc)2/PPh3 at normal pressure. 

A similar pressure effect on regioselectivity was reported for palladium-catalyzed [3-I-2]-cycloadditions [19]. In the reaction of the trimethylenemethane (TMM) precursor 61 with the alkene 62 the two regioisomeric cycloadducts 63 and 64 are possible while 64 is mainly formed at 1 bar, the only product observed at 10 kbar is 63. A possible explanation of this dramatic change in selectivity could be the increased rate of the bimolecular reaction of 65 and 62 to give 63 compared to the unimolecular isomerization of the TMM complexes 65 and 66. Thus, the kineti-cally formed complex 65 is effectively trapped under pressure by the alkene 62. 

The combination of pressure and catalysis can also be used to design a new domino process. The alkenylation of aldehydes with phosphonates (Horner-Wadsworth-Emmons (HWE) reaction) is readily accomplished at room temperature under pressure in the presence of triethylamine as a base. These mild con- 

The mechanism of the reactions catalyzed by complexes of these other metals is less well understood than the mechanism of the reactions catalyzed by complexes of palladium. This discrepancy in mechanistic understanding results, in part, from the accessibility of the allylpalladium intermediates and the detailed studies of the chemistry and dynamics of these complexes. Fewer allyl complexes relevant to the allylations catalyzed by other metals have been isolated. °  

The oxidative addition of allylic esters to paUadium(O) complexes is a common route to allylpalladium complexes. This reaction occurs to form cationic allylpalladium(II) complexes containing an acetate or other carboxylate derivative as the counterion. These reactions were described in Chapter 7. They likely occur by coordination of the olefinic unit of the allylic ester to the metal center, followed by ionization of the coordinated allylic ester to form the allylpalladium intermediate. These reactions occur with inversion of configuration, as shown explicitly by the reaction in Equation 20.20.  

The mechanism of the nucleopliilic attack on the allyl intermediate has been studied in deptli, and this process was discussed in Chapter 11. In general, stabilized carbon nucleophiles containing two electron-withdrawing groups on the methylene carbon, as well as 

The dynamics of the allyl intermediates can have a large effect on the regioselectivity and stereoselectivity of the catalytic reactions.The dynamics of allyl complexes have been studied extensively by variable-temperature NMR spectroscopy. Allyl complexes can undergo rearrangements by the 

Stereochemistry is preserved during a change from an Tfi to Ti binding mode when R and R are different 

In Section 8.2.3.2, we discussed arylation of enolates and enolate equivalents using palladium catalysts. Related palladium-phosphine combinations are very effective catalysts for aromatic nucleophilic substitution reactions. For example, conversion of aryl iodides to nitriles can be done under mild conditions with Pd(PPh3)4 as a catalyst. 

A stable palladacycle 7 derived from biphenyl is also an active catalyst.1 

In addition to bromides and iodides, the reaction has been successfully extended to chlorides,163 triflates,164 and nonafluorobutanesulfonates (nonaflates).165 These reaction conditions permit substitution in both electron-poor and electron-rich aryl systems by a variety of nitrogen nucleophiles, including alkyl or aryl amines and heterocycles. These reactions proceed via a catalytic cycle involving Pd(0) and Pd(II) intermediates. 

Some of the details of the mechanism may differ for various catalytic systems. There have been kinetic studies on two of the amination systems discussed here. The results of a study of the kinetics of amination of bromobenzene using Pd2(dba)3, BINAP, and sodium r-amyloxide in toluene were consistent with the oxidative addition occurring after addition of the amine at Pd. The reductive elimination is associated with deprotonation of the animated palladium complex.166 

Transition Metal-Catalyzed Aromatic Substitution Reactions 

Hiyama and Mori introduced the Mizoroki-Heck-type reaction of aryl- and vinyl- 

The Perkin reaction is an organic reaction developed by William Henry Perkin that can be used to make cinnamic adds by the aldol condensation of aromatic aldehydes and acid anhydrides in the presence of an alkali salt of the acid [65, 66). 

The observation of a simultaneous condensation-decarboxylation leading to the unusual formation of hydroxystilbenes in lieu of a-phenylcinnamic acid reveals an interesting facet of the classical Perkin reaction. 

Synthesis of polyhydroxylated ester analogues of the stilbene resveratrol was accomplished using decarbonylative Heck couplings [73]. Levulinate- and 

Convenient methods for highly stereoselective synthesis of unsymmetrical stil-benoids were accomplished [82]. Cross-metathesis of 4-chlorostyrene with (vinyl) 

Horner-Wadsworth-Emmons and Wittig-Horner Olefination Reactions 

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PALLADIUM-CATALYZED REACTION OF ORGANOLITHIUM COMPOUNDS AND ALKENYL HALIDES ... 

Epoxides are normally hydrogenated in preference to saturated ketones but double bonds are usually reduced under these conditions. It is possible in some cases to selectively cleave an epoxide without saturating double bonds by the use of the deactivated catalysts recommended for the partial reduction of acetylenes (see section IV) or by the addition of silver nitrate to the palladium-catalyzed reaction mixture. " ... 

They have also developed a route to 2-allenylindole derivatives (98T13929). When prop-2-ynyl carbonates (76) are reacted with 73 in the presence of palladium catalyst, a cross-coupling reaction occurs to give 77a (46%) and 77b (45%). Under a pressurized carbon monoxide atmosphere (10 atm), the palladium-catalyzed reaction of 73 with 78 provides 79a (60%) and 79b (60%) (2000H2201). In a similar reaction, when the substrate is changed to aryl halides (80), 2-aryl-1-methoxyindoles such as 81a (70%) and 81b (60%) are prepared (97H2309). 

The palladium-catalyzed reaction of o-iodoanilides with terminal acetylenic carbinols provides a facile route to the synthesis of quinolines using readily available starting materials (93TL1625). When o-iodoanilide 126 was stirred with acetylenic carbinol 127 in the presence of bis-triphenyl phosphine palladium(ll) chloride in triethylamine at room temperature for 24 h, the substituted alkynol 128 was obtained in 65% yield. On cyclization of 128 with sodium ethoxide in ethanol, 2-substituted quinoline 129 was obtained in excellent yield. 

In summary, palladium-mediated reactions, especially cross-coupling reactions have found many applications in quinoline synthesis. It is noteworthy that due to the a and S activation for the C(2) and C(4) positions, even 2-chloro- and 4-chloro-quinolines are viable substrates for palladium-catalyzed reactions under standard conditions. With the advent of the palladium chemistry and more commercially available organometallic substrates, more palladium-mediated quinoline syntheses are to be added to the repertoire of quinoline chemistry. 

The Heck reaction is considered to be the best method for carbon-carbon bond formation by substitution of an olefinic proton. In general, yields are good to very good. Sterically demanding substituents, however, may reduce the reactivity of the alkene. Polar solvents, such as methanol, acetonitrile, N,N-dimethylformamide or hexamethylphosphoric triamide, are often used. Reaction temperatures range from 50 to 160 °C. There are various other important palladium-catalyzed reactions known where organopalladium complexes are employed however, these reactions must not be confused with the Heck reaction. 

Together with reactions named after Heck and Suzuki, the Stille reac-tion belongs to a class of modern, palladium-catalyzed carbon-carbon bond forming reactions. The palladium-catalyzed reaction of an organotin compound 2 with a carbon electrophile 1 is called Stille coupling. 

As in case of other palladium-catalyzed reactions, the general mechanism of the Stille reaction is best described by a catalytic cycle—e.g. steps a) to c) ... 

The N-substituted aminoacids required could be prepared by microwave-assisted reductive amination of aminoacid methyl esters with aldehydes, and although in the Westman report soluble NaBH(OAc)3 was used to perform this step, other reports have shown how this transformation can be performed in using polymer-supported borohydrides (such as polymer-supported cyanoborohydride) under microwave irradiation [90]. An additional point of diversity could be inserted by use of a palladium-catalyzed reaction if suitably substituted aldehydes had been used. Again, these transformations might eventually be accomplished using supported palladium catalysts under microwave irradiation, as reported by several groups [91-93]. 

The dechlorination of the C-3 and C-5 position of the pyrazinone system was described to be fast under microwave irradiation [29]. Contrary to the reported de-chlorination [26] via palladium-catalyzed reaction with sodium formate 100 °C for 2-4 h and at the C-5 position in 2-3 days, a dramatic rate enhancement was observed under microwave irradiation (Scheme 12). The mono-reduction at C-3 was performed at 190 °C in DMF in merely 5 min, and the reduction of C-5, starting from the mono-reduction product, was performed in n-butanol in 55 min to afford the fois-reduction product in good overall yield. 

Alkyl halides or alkyl sulfates, treated with the salts of sulfinic acids, give sulfones. A palladium catalyzed reaction with a chiral complexing agent led to sulfones with modest asymmetric induction. Alkyl sulfinates (R SO—OR) may be side products. Sulfonic acids themselves can be used, if DBU (p. 1337) is... 

Sodium or potassium phenoxide can be carboxylated regioselectively in the para position in high yield by treatment with sodium or potassium carbonate and carbon monoxide. Carbon-14 labeling showed that it is the carbonate carbon that appears in the p-hydroxybenzoic acid product. The CO is converted to sodium or potassium formate. Carbon monoxide has also been used to carboxylate aromatic rings with palladium compoimds as catalysts. In addition, a palladium-catalyzed reaction has been used directly to prepare acyl fluorides ArH —> ArCOF. ... 

Palladium-catalyzed reaction of alkyne 47 with a variety of aryl and vinyl halides afforded alkenes 48 in good yield. Cyclization to quinolines 49 was performed by treating 4 8 with TsOH in EtOH <96T(52)10225>. 

Chiral phosphinous amides have been found to act as catalysts in enantio-selective allylic alkylation. Horoi has reported that the palladium-catalyzed reaction of ( )-l,3-diphenyl-2-propenyl acetate with the sodium enolate of dimethyl malonate in the presence of [PdCl(7i-allyl)]2 and the chiral ligands 45 gave 46 in 51-94% yields and up to 97% ee (Scheme 38). It is notorious that when the reaction is carried out with the chiral phosphinous amide (S)-45a, the product is also of (S) configuration, whereas by using (R)-45b the enantiomeric (R) product is obtained [165]. 

Volume 2, Catalytic Reactions. An account of palladium-catalyzed reactions involving formation of C—C, C—O, C—H, C-halogen, C—N, C—S, or C—Si bonds, and heterogeneous reactions. 

Ketones can also be prepared by palladium-catalyzed reactions of boranes or boronic acids with acyl chlorides. Both saturated and aromatic acyl chlorides react with trialkylboranes in the presence of Pd(PPh3)4.233... 

The synthetic utility of the mercuration reaction derives from subsequent transformations of the arylmercury compounds. As indicated in Section 7.3.3, these compounds are only weakly nucleophilic, but the carbon-mercury bond is reactive to various electrophiles. They are particularly useful for synthesis of nitroso compounds. The nitroso group can be introduced by reaction with nitrosyl chloride73 or nitrosonium tetrafluoroborate74 as the electrophile. Arylmercury compounds are also useful in certain palladium-catalyzed reactions, as discussed in Section 8.2. 

C. Palladium-catalyzed reactions with oxygen nucleophiles. 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

Many palladium-catalyzed reactions are initiated by the reaction of a palladium(O) complex with an acidic derivative.367 The catalytic cycle is considered to be induced by a hydridopalladium complex. When the acidic derivatives are strong acids (e.g., HBF4, HC1, CF3C02H, HOTs), the hydridopalladium formation may be regarded as the protonation of basic Pd° to afford complexes HPdL3 +368-374 or IIPdL2.S +,375 in which S = solvent (see Equation (1)) ... 

The study on 2,7-di-rerf-butylthiepin has recently been extended to explore more simply substituted thiepins 58). The palladium-catalyzed reaction of the diazo compound 107 lacking a 4-methyl substituent gives exclusively the exo-methylene compound 108 whereas the acid-catalyzed reaction of the same precursor 107 resulted in the formation of 2,7-di-/er/-butyl-4-ethoxycarbonylthiepin (109)58). Due to the substantial thermal stability of 109 it is possible to transform the ethoxy-carbonyl group into the hydroxymethyl (110), trimethylsilyloxymethyl (111) and formyl group (112)58). 

The double-Heck-approach can also be employed for the preparation of novel heterocyclic compounds as 6/1-25 and 6/1-26 (Scheme 6/1.4) [24]. Thus, the palladium-catalyzed reaction of 6/1-21 and the cyclic enamide 6/1-22 gave a Oil-mixture of 6/1-23 and 6/1-24, which in a second Heck reaction using the palladacene 6/1-15 led to 6/1-25 and 6/1-26 in an overall yield of 44—49%. The synthesis can also be performed as a domino process using a mixture of Pd(OAc)2 and the palladacene 6/1-15. 

It is well known that minor changes in conditions can have dramatic effects on the products obtained. For example, Heck s group [31] described the palladium-catalyzed reaction of iodobenzene 6/1-42 and 2 equiv. of diphenylacetylene 6/1-43 in... 

Another recent development in the field of palladium-catalyzed reactions with alkynes is a novel multicomponent approach devised by the Lee group. Starting from a-bromovinyl arenes and propargyl bromides, the assembly ofeight-membered car-bocycles can be realized via a cross-coupling/[4+4] cycloaddition reaction. The authors also presented the combination of a cross-coupling and homo [4+2], hetero [4+2], hetero [4+4] or [4+4+1] annulation leading to various cyclic products [147]. 

Benzo-fused pyrrolizines can be prepared from the palladium-catalyzed reaction of alkynes with imines of 2-halogenoanilines. Pyrimidine-substituted alkynes react in the same way, to produce the pyrimidine-fused pyrrolizines 161 <2001JOC412> (Scheme 48). 

Palladium-catalyzed reactions have been used for the formation of thienoindolizines the following reaction, which is carried out in presence of a mild base, gives different ratios of the endo- (thienopyridone) and exo- (thienoindolizine) products according to the specific catalyst and base used (Equation 36). The latter is almost exclusively formed when the base used is sodium formate or piperidine <1997TL1057>. For the conditions favoring the 5 6 6-fused product, see Section 11.17.4.1.1.3. 

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