Ketones cross-coupling with

Trapping experiments with electron deficient olefins such as acrylonitrile and 3-buten-2-one gave the expected 1,4-adducts from the proposed acylnickel intermediates. This provides strong support for the proposed mechanism. It was also demonstrated that allylic, vinylic and pentafluorophenyl halides could be cross-coupled with acid chlorides to give the corresponding ketones in good yields. 

Pyridylstannanes have been cross-coupled with numerous aryl- and heteroaryl halides as well as various other electrophiles. For example, an extension of Stille s original methodology to 3-trimethylstannylpyridine and acid chloride 73 gave the corresponding ketone 74, which was then converted to 2S-(+)-nicotinylalanine 75, a neuroprotection agent [62],... 

Both vinyl- and aryl triflates have been cross-coupled with 2-furylzinc chloride [26-28]. Since vinyl triflates are easily obtained from the corresponding ketones, they are useful substrates in Pd-catalyzed reactions. In the following example, a Negishi coupling of 2-furylzinc chloride and indol-5-yl triflate (22) provided an expeditious entry to 2-(5 -indolyl)furan (23). Protection of the NH in the indole ring was not required. A similar reaction was successful with pyridyl- and quinolinyl triflates. 

Fluorosilylsubstituted aryl derivatives were found to be useful reagents for carbon-carbon bond formation via palladium-catalyzed cross-coupling with aryl halides in the presence of fluoride anions as Si—C bond activator in dimethylformamide (DMF), as well as rhodium-catalyzed 1,4-addition to a, 3-unsaturated ketones in the presence of a fluoride anion source (Equation 14.11) [66, 69, 70],... 

Alkyl halides possessing / -hydrogens are usually poor substrates for carbonylative cross-coupling due to competitive / -hydride elimination/ Allyl chlorides can be used in carbonylative cross-coupling with allylstannanes/ phenyl-, 3-furyl, or vinylstannanes " to afford allylketones in modest to good yields. Divinylketones can be accessed through the reaction of vinylstannanes with vinyl iodides or vinyl triflates, with the latter requiring the addition of LiCl. Synthetic potential of this method has been proved in the formation of macrocyclic ketone jatrophone. In the reaction of vinyl triflates with tetramethyltin or aryltrimethylstannanes the additional activation by ZnCle is required. 

Bromination of the enol ether product with two equivalents of bromine followed by dehydrobromination afforded the Z-bromoenol ether (Eq. 79) which could be converted to the zinc reagent and cross-coupled with aryl halides [242]. Dehydrobromination in the presence of thiophenol followed by bromination/dehydrobromination affords an enol thioether [243]. Oxidation to the sulfone, followed by exposure to triethylamine in ether, resulted in dehydrobromination to the unstable alkynyl sulfone which could be trapped with dienes in situ. Alternatively, dehydrobromination of the sulfide in the presence of allylic alcohols results in the formation of allyl vinyl ethers which undergo Claisen rearrangements [244]. Further oxidation followed by sulfoxide elimination results in highly unsaturated trifluoromethyl ketonic products (Eq. 80). 

The Reformatsky reagents, i.e. zinc enolates of esters, undergo Ni catalysed cross-coupling with aryl halides.53 The Ni catalysed reaction of arylzincs with a-bromoacetates also permits a-arylation of esters54 (Scheme 11.13). However, a-alkenylation of enolates of ketones, aldehydes, and esters has been less satisfactory. Its further development is clearly desirable. Alternatively, a-alkenylation of a-iodoenones in conjunction with conjugate reduction discussed earlier should be considered. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Sugino 448 obtained the crossed coupling product 147 in 70% yield and current efficiency on coelectrolysis of acrylonitrile and acetone in aqueous sulfuric acid at a mercury cathode. At lead and cadmium mixed couplingwas suppressed and hydrocarbon formation increased. With methyl ethyl ketone and diethyl ketone crossed coupling was achieved in 60% and 30% yield, respectively. With acetone and maleic acid 10% terebic acid (148) was obtained. Tomilov 449- coupled acetone and acrylic acid in 95% yield (70% current efficiency) to... 

Allenyl ketones can also be cross-coupled with allenoic acids to give 2,4-disubstituted furans <2002AGE1775> or with allenamides to yield 4-(3 -furanyl)-2(5//)-furanimines <2005JOC6291>. With chiral allenoic acid derivatives, 4-(3 -furanybbutenolides can be synthesized stereoselectively with complete chirality transfer (Equation 47) <2004CEJ2078>. 

For the ketone synthesis via the present protocol, acid chlorides are useful precursors, in deed. Nevertheless, carbonylative cross coupling with organic halides is strategically the most simple and direct way to this purpose. The palladium-catalyzed carbonylative cross-coupling reaction with various organic halides has been extensively investigated, because of its merits from synthetic as well as phenomenal point of view. Acid chlorides are not always readily available, and their preparation is not always compatible with many sensitive functionalities. Therefore the development of this type of reaction widens the scope of the ketone synthesis in the present protocol because of the ready availability and storability of organic halides and pseudohalides. 

Rieke and coworkers have found that a special type of activated metallic nickel, available through reduction of nickel(II) iodide with lithium metal, suffers oxidative addition of benzylic and allylic halides. The resulting nickel(Il) complexes readily undergo cross-coupling with acid chlorides to form ketones. Once again it was difficult to obtain, y-unsaturated ketones from this method. Moderate to good yields of simple ketones may be prepared by this method. 

Z. Hou, K. Takamine, Y. Fujiwara and H. Taniguchi, Chem. Lett., 1987, 2061 aromatic ketones can be cross-coupled with aliphatic ketones using this method, see ref. 190. 

Hindered ketones. Dimethylcopperlithium (and related reagents) undergo cross-coupling with a-bromoketones such as (1) to give sterically hindered ketones such as (2). Even tertiary lithium cuprates can be employed.11... 

Thioesters are readily accessible and have recently been shown to undergo Pd-catalyzed cross coupling with boronic acids to prepare ketone products. This chemistry has expanded to Stille cross coupling. The key to the reaction is the addition of stoichiometric amounts of Cu -diphenylphosphinate [60]. Stille coupling of thioester 142 with 2-tributylstannylpyrimidine affords the desired product 143 in 61% isolate yield. 

In the presence of 5-10% palladium catalyst 34,20-45% Nal, and 4-6 equiv K2CO3, various boronic acids underwent cross-coupling with thio esters 32 in dimethylacetamide at 90-95 °C for 12-24 h to give the desired ketones in moderate to high yields. Tetrahydrothiophene, detected by GC/MS, was formed by intramolecular nucleophilic attack at the terminal carbon by a sulfur atom. Interestingly, in the absence of Nal, the bromobutyl thiol ester 32a gave only a trace amount of benzophenone when treated with phenylboronic acid in the presence of 34 in DMA at 95 °C for 22 h. In the presence of Nal, the bromide atom at the terminal carbon is replaced by an iodide atom, leading to sulfonium formation via intramolecular S-alkylative activation. 

Arylboronic and alkenylboronic acids undergo transition metal complex-catalyzed synthetic organic reactions such as cross-coupling with organic halides [58-60], 1,4-addition to a,/I-unsaturated ketones [61-63], and ring-opening addition to vinyl oxirane [64]. Scheme 5.8 depicts the mechanism proposed for the... 

Homoallyl bromide 314, prepared from readily available non-racemic ester 313, was converted to the Grignard reagent, which reacted with non-racemic epoxide, derived from D-maUc acid, to afford the alcohol 305. Ozonolysis of the alkene gave a ketone, which was converted into enol tri-flate 316. Ni-catalyzed cross coupling with trimethylsilylmethyl magnesium chloride afforded the allyl silane, which was converted into the allyl stan-nane 317. The asymmetric allylation of 313 with 317 provided 304 with a ration of 8.5 1. Methyl etherification and oxidative cleavage of exo-methylene... 

Aromatic aldehydes, Ar CHO, have been cross coupled with diarylbromomethanes, Ar Ar CHBr, to give diaryl acetophenone derivatives, Ar COCHAr Ar, using NHC catalysis. A benzoin can be used as a masked aldehyde in the reaction, indicating that the formation of the Breslow intermediate is reversible. The utility of the reaction has been extended on the halide side a-halo ketones and esters can serve in place of diarylmethyl bromides. 

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