Palladium-catalyzed cross coupling reactions

To the best of our knowledge, the first example of a Suzuki coupling reaction in the synthesis of a PUFA-derived natural product was disclosed in the synthesis of prostaglandin 

The MIDA-protected boronate esters developed by Burke and coworkers allow iterative Suzuki cross coupling reactions under mild conditions to give polyenes [64,65]. The MIDA-protected boronate esters are stable and easily handled, and deprotection occurs readily at room temperature under mild basic conditions to provide the corresponding boronic acids. 

SCHEME 3.17 Synthesis of 3-parinaric acid (59) by Burke and coworkers[66]. 

SCHEME 3.18 Synthesis of methyl (5Z8Z,10E,12E,14Z)-eicosapentanoate (66) by Hansen and Mohammed [67]. 

SCHEME 3.19 Synthesis of (55,15S)-dihydroxy-6,13-frafw-8,ll-cw-eicosatetraenoic acid (73) by Nicolaou and Webber [69], 

As the examples illustrate, the synthesis of biaryls has received much attention. One reason is because they are difficult to synthesize, another is that they are often candidates for new drugs. The product in the Suzuki coupling, for example, is an intermediate in the synthesis of atazanavir, a protease inhibitor used in the treatment of HIV-AIDS. Numerous other classes of compounds are accessible by appropriate choices of reactants. 

The 2010 Nobel Prize in Chemistry was awarded to Richard F. Heck (University of Delaware), Ei-ichi Negishi (Purdue University), and Akira Suzuki (Hokkaido University) for their work on paiiadium-cataiyzed cross-coupiing reactions. Eariy and important contributions were made by John Stille (Colorado State University) before his untimely death in a 1989 plane crash. 

The reactions tolerate many functional groups, including OH, C=0, and NO2 elsewhere in the molecule and as shown in the Heck example, the stereochemistry of the double bond is retained when cross-coupling involves an i p -hybridized carbon. 

It should also be noted that various sources of palladium are given in the examples. The active oxidation state is Pd(0) in all these reactions, even when the source is Pd as in the Heck reaction example that uses palladium acetate. 

Give the structure including stereochemistry of the product of each of the following reactions. 

Aryl or heteroaryl organozincs and alkenyl organozincs behave rather similarly in Pd-catalyzed coupling reactions. For clarity, however, given the huge volume of research devoted to these transformations, they will be discussed separately. 

1 Cross-Coupling Reactions of Aryl- and Heteroarylzinc Reagents 

Notably, the presence of iPrI in the reaction medium (generated during the arylzinc preparation or included as an additive) accelerates the cross-coupling reaction, possibly by radical catalysis ]130]. Aromatic and heteroaromatic bromides react with diarylzinc reagents at 25 °C within minutes to yield the corresponding biaryl compounds, as shown with the preparation of 144 from 142 with 143. 

Palladium-phosphinous acids (POPds), either isolated or generated in situ, are also able to catalyze the cross-coupling of aromatic organozinc reagents and aryl chlorides [134]. It is assumed that deprotonation of the hydroxy group by the zinc 

I 4 Carbon-Carbon Bond Forming Reactions Mediated by Organozinc Reagents 

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These zinc reagents are useful precursors for stereocontrolled palladium-catalyzed cross-coupling reactions, as illustrated in equations 73-80 [100, 101, 102, 103, 104, 105, 106, 107, 108] This methodology has been used to prepare new fluorinated analogues of codlemone [I09. ... 

Heck reaction, palladium-catalyzed cross-coupling reactions between organohalides or triflates with olefins (72JOC2320), can take place inter- or intra-molecularly. It is a powerful carbon-carbon bond forming reaction for the preparation of alkenyl- and aryl-substituted alkenes in which only a catalytic amount of a palladium(O) complex is required. 

Z)-3-(Tributylstannyl)allylamine participates in a palladium-catalyzed cross-coupling reaction with 2-bromobenzaldehyde (73, R = H) to give 3//-2-benzazepine (75, R = H). A similar reaction with the corresponding acetophenone 73 (R = Me) produces 1 -methyl-3//-2-benzazepine (75 R = Me), whereas with ethyl 2-bromobenzoate (73, R = OMe), 3//-2-benzazepin-(12/7)-one (74) is formed.237... 

SYNTHESIS OF N-( -BUTOXYCARBONYL)-P-IODOALANINE METHYL ESTER A USEFUL BUILDING BLOCK IN THE SYNTHESIS OF NONNATURAL a-AMINO ACIDS VIA PALLADIUM CATALYZED CROSS COUPLING REACTIONS... 

Palladium catalyzed cross-coupling reactions of arylhalides or halide equivalents with various nucleophiles have been shown to be highly effective and practical... 

King AO, Yasuda N (2004) Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals. 6 205-246 King NP, see Nicolaou KC, He Y (1998) 1 73-104... 

Over the last decade, the chemistry of the carbon-carbon triple bond has experienced a vigorous resurgence [1]. Whereas construction of alkyne-con-taining systems had previously been a laborious process, the advent of new synthetic methodology based on organotransition metal complexes has revolutionized the field [2]. Specifically, palladium-catalyzed cross-coupling reactions between alkyne sp-carbon atoms and sp -carbon atoms of arenes and alkenes have allowed for rapid assembly of relatively complex structures [3]. In particular, the preparation of alkyne-rich macrocycles, the subject of this report, has benefited enormously from these recent advances. For the purpose of this review, we Emit the discussion to cychc systems which contain benzene and acetylene moieties only, henceforth referred to as phenylacetylene and phenyldiacetylene macrocycles (PAMs and PDMs, respectively). Not only have a wide... 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Palladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 NicolaouKC, KingNP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natural Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

Table 1 Air-stable palladium-catalyzed cross-coupling reactions.

Deoxyvariolin B 149 has been synthesized by a palladium-catalyzed cross-coupling reaction of iodo derivative 147 with tin compound 148 (Equation 5) <2001TL315, 2003JQC10020, 2003TL6191, 2004JOC4974>. 

The palladium-catalyzed cross-coupling reaction featured in this procedure occurs under neutral conditions in the presence of many synthetically useful functional groups (e.g. alcohol, ester, nitro, acetal, ketone, and aldehyde). The reaction works best in N,N-dimethylformamide with bis(triphenylphosphine)palladium(ll) chloride, PdCI2(PPh3)2, as the catalyst. Lithium chloride is added to prevent decomposition of the catalyst.143 13 It is presumed that conversion of the intermediate aryl palladium triflate to an aryl palladium chloride is required for the transmetallation step to proceed.9... 

Chlorophenyl)-4-phenyl-l,2,5-thiadiazole 128 was prepared from 3-trifluoromethylsulfonyloxy-4-phenyl-1,2,5-thiadiazole 127 by palladium-catalyzed cross-coupling reaction with the tributyl(4-chlorophenyl)stannane (Equation 20) <1996H(43)2435>. The addition of lithium chloride improves the yield. The 3-chloro- and 3-bromo-l,2,5-thiadiazole derivatives were also reactive, but only the bromo compound gave the product in comparable yield (see Section 5.09.7.6). 

Dipolar cycloaddition reaction of trimethylstannylacetylene with nitrile oxides yielded 3-substituted 5-(trimethylstannyl)isoxazoles 221. Similar reactions of (trimethylstannyl)phenylacetylene, l-(trimethylstannyl)-l-hexyne, and bis (trimethylsilyl)acetylene give the corresponding 3,5-disubstituted 4-(trimethyl-stannyl)isoxazoles 222, almost regioselectively (379). The 1,3-dipolar cycloaddition reaction of bis(tributylstannyl)acetylene with acetonitrile oxide, followed by treatment with aqueous ammonia in ethanol in a sealed tube, gives 3-methyl-4-(tributylstannyl)isoxazole 223. The palladium catalyzed cross coupling reaction of... 

The scope of this remarkable regioselectivity imparted by the TMS group was further advanced by replacement of the TMS group with a benzyldimethylsilyl (BDMS) group.43 Trost has shown that the BDMS group functions as a synthon and is suitable for palladium-catalyzed cross-coupling reactions (Scheme 6). 

It is well known that alkenylzirconocenes are transmetalated to zinc and conveniently undergo further palladium-catalyzed cross-coupling reactions [7k,8a,32]. Although the transmetalation of zirconacyclopentadienes to zinc is not yet well developed, some interesting reactions that take place in the presence of ZnCl2 have already been described (Eq. 2.30) [9]. 

Recent contributions from Vogel s group have shown that, under CO atmosphere and in the presence of Pd2(dba)3 and Ph3As, 1-stannyl glycals can be carbonylated and coupled to organic halides (Scheme 6a),38 or vinyl triflates (Scheme 6b),39 in carbonylative Stifle cross-coupling processes.40 Also of interest is the palladium catalyzed cross-coupling reaction of... 

Palladium catalyzed cross-coupling reactions of 1-substituted glycals have not only been limited to tributylstannyl derivatives. In fact, the versatility of this approach is significantly enhanced by the fact that C-l zinc-, indium-, or iodine-substituted glycals (easily accesible from glycals, see Scheme 7)... 

Palladium-catalyzed cross-coupling reactions of 123 with aryl halides 124 proceeded via the allenylzinc isomers and afforded 1,1-diarylallenes 125 exclusively (Scheme 3.63). 

The catalytic asymmetric synthesis of allenes was first achieved by Elsevier and co-workers in 1989 [104]. A palladium-catalyzed cross-coupling reaction of an allenyl-metal compound 250 (M = ZnCl, MgCl or Cu) with iodobenzene in the presence of DIOP 251 gave 252 in 25% ee (Scheme 4.65). The synthesis of 252 by the reaction of 250 (M = Br) with phenylzinc chloride in the presence of a chiral palladium catalyst gave a quantitative conversion but very low enantiomeric excesses (3-9% ee). 

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