Palladium mediated coupling

In the synthesis of Win 57,273 the attachment of the group, a 2,6-dimethylpytidinyl group, involves formation of a carbon-carbon bond rather than a carbon-nitrogen bond. The method for the attachment of this group is a palladium mediated coupling reaction (77,78) of 4-tributylstarmyl-2,6-dimethylpyridine [122033-61 -8] with a 7-halo quinolone (26). 

Stille cross coupling reactions usually proceed under mild neutral conditions. 2-Substituted thiazoUnes can be obtained by the cross coupling reaction of 2-bromothiazolines with various tributylstannyl compounds. Previous attempts at a palladium mediated coupling of 2-trimethylstannylthiazoUne led to only decomposition of the substrate <96TL4857>. 

Unfortunately, it quickly became apparent that a shortfall in this proposal was an inability to prepare the desired vinyl halide 25 in a straightforward and selective manner [19]. In contrast, we reasoned that the selective formation of an enol sulfonate, such as the enol triflate 26a, could be controlled by judicious tuning of enolization conditions starting from the corresponding ketone, and that such an enol sulfonate would possibly be a substrate for a palladium-mediated coupling (Scheme 9.17). In this way a common intermediate from the previously defined synthesis, that is, the racemic ketone rac-13 or its cyano equivalent rac-5 could be used to generate the required enamide. 

Another compound 9 with three heterocyclic rings linearly fused (5 5 5) with two heteroatoms has been prepared from 1,1 -carbonyl diindole 297 <2001T5199>. Palladium-mediated coupling of the 2- and 2 -positions of 297 afforded the 1,1 -carbonyl-2,2 -biindolyl 9. 1,1 -Carbonyl diindole 297 was in turn obtained in 41% yield from 1,1 -carbonyldiimidazole 296 by reaction with indole in DMSO at 125 °C. The palladium-catalyzed coupling step afforded the desired product 9 in low yield and required a stoichiometric amount of palladium acetate. Therefore, it was felt prohibitively expensive. Addition of various co-oxidants (Ac20, Mn02, and Cu(OAc)2, etc) to make the reaction catalytic in palladium did not result in any improvement of the yield of 18 (Scheme 53). 

Young and DeVita have shown that 1,2,4-oxadiazoles can be prepared by a new route in a novel one-pot procedure by the palladium-mediated coupling of an aryl iodide with an amidoxime in the presence of carbon monoxide (Equation 40) <1998TL3931>. 

Another Suzuki coupling reaction was described by Zhang et al., to produce arylindoles 116a and b, using solid-phase synthesis [76]. The synthesis was achieved by palladium-mediated coupling/intramolecular indole cycli-zation of resin-bound 2-trimethylsilylindole 117, Scheme 29. 

A convenient direct route has recently been described for obtaining regioregular polyalkylthiophenes using a tandem iridium-catalyzed borylation to produce the monomer, and a palladium-mediated coupling to produce the polymer [68]. The treatment of substituted thiophenes with B2pin2 in the presence of [lrCl2(COD)]2/ 4,4 -di-tert-butyl-2,2 -bipyridine (DTBPY) provided the expected monomer in 97% yield (Scheme 7.35). 

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

Palladium-catalyzed alkenylation reactions involving pyrimidines can be achieved with hydrozirconated terminal alkynes, although the reaction is carried out in the presence of zinc chloride, so transmetallation to the zinc species is presumed to occur prior to the palladium-mediated coupling <1996ACS914, B-2002MI409>. Selective reaction at the 4-position of both 2,4-dichloropyrimidine and 2,4-dichloroquinazoline can be achieved. 

Polystyrene-bound trialkylboranes, which can be prepared by hydroboration of support-bound alkenes with 9-BBN, undergo palladium-mediated coupling with alkyl, vinyl, and aryl iodides (Suzuki coupling Entries 1 and 2, Table 5.3 for vinylations, see Section 5.2.4). Because boranes are compatible with many functional groups and do not react with water, these coupling reactions could become a powerful tool for solid-phase synthesis. To date, however, few examples have been reported. 

Linkers that enable the preparation of y-lactones by cleavage of hydroxy esters from insoluble supports are discussed in Section 3.5.2. Resin-bound y-lactones have been prepared by Baeyer-Villiger oxidation of cyclobutanones [39], by intramolecular addition of alkyl radicals to oximes [48], by electrophilic addition of resin-bound sele-nenyl cyanide or bromide to 3,y-unsaturated acids (Figure 9.2 [100]), and by palladium-mediated coupling of resin-bound aryl iodides with allenyl carboxylic acids (Entry 10, Table 5.7 [101]). 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

Following Ellman s pioneering work on benzodiazepines,2 another study from the same laboratory illustrated the vast potential of combining a variety of chemical reactions on drug-like heterocycles. In this case a preformed heterocycle was grafted as a whole onto the solid phase to be subsequently derivatized via a three-component palladium-mediated coupling reaction followed by a reductive alkylation or an acylation (Fig. 12).34... 

Fig. 12. Versatile derivatization scheme of a tropane template, including palladium-mediated coupling, (a) TsOH, CH2C12 (b) aryl bromide, Pd(PPh3)4, THF, 66° (c) arylboronic acid, 2 N Na2C03, PPh3, THF, or anisole, 66° (d) formic acid, Et3N, PPh3, DMF, 66° (e) phenylacetylene, Cul, B114NCI, DMF, 66° (f) B114NF, THF, 50° (g) aldehyde, NaBH(OAc)3, DMF (h) HATU, Et3N, benzoic acid, HOAt, DMF (i) TFA/H2Q (20 1).

H.-C. Zhang, M. Brakta, and G. D. Daves, Preparation of l-(tri-n-butylstannyl)furanoid glycals and their use in palladium-mediated coupling reactions, Tetrahedron Lett., 34 (1993) 1571-1574. 

An expedient method for synthesis of 2,3-disubstituted 1-benzoselenophenes (91) by the electrophilic cyclization of various 1 -(1 -alkynyl)-2-(methylseleno)arenes (90) has been reported recently (Scheme 24). This method tolerates a wide of variety of functional groups, and proceeds under exceptionally mild reaction conditions [141], Moreover, an efficient solid phase synthesis of 91 based on a combination of palladium-mediated coupling and iodocyclization protocols has been developed [142],... 

Scheme 3. Palladium-mediated coupling reactions between olefins and alcohols or carboxylic acids.

Oxidative coupling was used to form alkyl- and alkoxy-substituted phenanthrenedione products lOOa-d (Table 22) [73]. These compounds can be obtained by other methods, albeit in much lower yields. In this instance, oxidative coupling proceeds even with carbonyl-substituted arenes, and VOF3 gives much better results than thallium- or palladium-mediated coupling procedures. 

Another interesting tandem Michael initiated sequence was developed in our laboratory by combining the conjugate addition of unsaturated alkoxides to alkylidene malonates with a palladium-mediated coupling reaction with an organic halide. In this cydization reaction, an organopalladium species acts as the electrophilic partner of the cydization. This reaction results in the trans addition of the organopalladium species and of the nucleophile across the unsaturation, and therefore, in overall difunctionalization of the unsaturated substrates [66,67]. 

Another example of palladium-mediated coupling is provided by the Suzuki reaction of the pyrimidodiazocine 134, which gave the arylated derivative 135 in nearly quantitative yield (Equation 5) <2005BMC5717>. 

Mn(0Ac)3 2H20 <03EJ01410> <03S1977>. Muller, on the other hand, investigated the enantioselective rhodium-catalyzed reactions between 2-diazocyclohexane-l,3-diones and alkenes, which led to products with similar structures <03HCA3164>. Palladium-mediated coupling of alkenes and a 1,3-dicarbonyl derivative was utilized in the total synthesis of ( )-brevione B <03TL5235>. 

The organomercury compounds formed in such reactions are not of great synthetic importance, although they do undergo nitrosation reactions with nitrosyl chloride, NOCl. They can also be used as the organometallic component in certain palladium-mediated coupling processes. 

Transition metal catalyzed coupling reactions 4.02.5.5.4(i) Palladium mediated coupling of N-protected imidazole halides 4.02.5.5.4(i)(a) Heck coupling... 

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