Suzuki couplings allylic alkylation

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

A less extensive study of the reaction of boronic acids with different structural characteristics - aryl, vinyl, allyl, and alkyl- with iodobenzene on Pd-KF/Al203 was also undertaken (eq. 3) (Table 4), Only the allylic boronic acid, 3-propenylboronic acid, did not undergo the Suzuki coupling although it was largely consumed. 

A similar situation prevails in other C-C and C-N coupling reactions since they also contain a PdL key intermediate. It is therefore no surprise that mixed NHC/phosphane ligand systems have been employed for the Mizoroki-Heck, Suzuki-Miyaura and StiUe reactions [238,255-258]. In all these cases, the incorporation of a phosphane ligand instead of the second NHC ligand improves the activity of the catalytic reaction. Similar results are reported for the allylic alkylation of dimethylmalonate using mixed NHC/phosphane palladium catalysts [252]. 

We will now proceed by looking into the Suzuki reaction and the allylic alkylation reaction in more detail as key examples for the influence of mixed NHC/phosphane hgand systems on the performance of catalytic coupling reactions. 

Alkylboronic acids are coupled to aryl halides using a palladium catalyst, " analogous to the Suzuki reaction in 13-12. Conversely, arylboronic acids can be coupled to aliphatic halides Arylboronic acids can be coupled to allylic alcohols as well. " Arylboronic acids (12-28) were shown to react directly with benzene in the presence of Mn(OAc)3. " Arylboronic acids also couple with alkyl halides in... 

The Suzuki reaction was described in the presence of various [Pd(7 -allyl)Cl]2 (l)/ligand systems as well. The efficiency of the tetraphosphine ligand Tedicyp was demonstrated for various Suzuki couplings, and more recently for the reaction of alkenyl-boronic acids with arylbromides. 7i The preparation of various stryrene derivatives (eq 81) has been performed in the presence of vinylboronic acid and substituted alkenyl boronic acids. The catalyst system was tolerant of electronic variation in the aryl-bromide component. Tum-over numbers of 3100-8600 could be achieved for activated substrates such as 4-bromoacetophenone. The coupling of alkyl tosylates was described either in the presence of Pd(OAc)2 or dimer (1) as precursor. 7 a fiber-supported catalyst prepared from 1 was found to be efficient for Suzuki coupling between activated aryl bromides and phenylboronic acid. 

Macrocyclic furanyl pyrimidine SB1578 (2) was also synthesized via a convergent route using a RCM as the key step, starting from 2,4-dichlorop)T-imidine (99) as shown in Scheme 5.6. Suzuki coupling of 99 with boronic acid 113 proceeded smoothly to furnish biaryl aldehyde 114 in moderate yield followed by reduction in the presence of sodium borohydride to furnish an almost quantitative yield of alcohol 115. Alkylation of benzyl alcohol 115 with allyl bromide 94 under phase transfer conditions provided the key left-hand fragment 116. 

The scope of the Negishi reaction is broad, similar to that of Stille and Suzuki cross-coupling. The reaction seems to work if R = aryl, vinyl, alkynyl, acyl, allyl, benzyl, homoallyl (-CH2-CH2-CH=CH2) and homobenzyl (-CH2-CH2-Ph), or even primary alkyl, and if X = I, Br, or OTf (Cl works, but often sluggishly). Correspondingly, R = aryl, vinyl, alkynyl, allyl, benzyl, and primary alkyl. The organozinc reagent may either be used as a preformed compound, such as R2Zn... 

Many organic chemical transformations have been carried out in ionic liquids hydrogenation [4, 5], oxidation [6], epoxidation [7], and hydroformylation [8] reactions, for example. In addition to these processes, numerous synthetic routes involve a carbon-carbon (C-C) bond-forming step. As a result, many C-C bond-forming procedures have been studied in ambient-temperature ionic liquids. Among those reported are the Friedel-Crafts acylation [9] and alkylation [10] reactions, allylation reactions [11, 12], the Diels-Alder reaction [13], the Heck reaction [14], and the Suzuki [15] and Trost-Tsuji coupling [16] reactions. 

Nevertheless, it must be pointed out that the formation of such transient species has never been spectroscopically observed. Native CDs are effective inverse phase-transfer catalysts for the deoxygenation of allylic alcohols, epoxydation,or oxidation " of olefins, reduction of a,/ -unsaturated acids,a-keto ester,conjugated dienes,or aryl alkyl ketones.Interestingly, chemically modified CDs like the partially 0-methylated CDs show a better catalytic activity than native CDs in numerous reactions such as the Wacker oxidation,hydrogenation of aldehydes,Suzuki cross-coupling reaction, hydroformylation, " or hydrocarboxylation of olefins. Methylated /3-CDs were also used successfully to perform substrate-selective reactions in a two-phase system. 

Reactions of arylboronic acids with allyl esters have also been found to proceed smoothly in water to give allylic arylation products via a Ti-allylic intermediate with net inversion of configuration (Scheme 22) [90]. It was reported that the secondary allyl esters (alkyl vinyl carbinol esters) undergo j0-hydrogen elimination of the Ti-allylpalladium intermediates forming conjugated dienes under the standard Suzuki-Miyaura coupling conditions due to the relatively lower reactivity of arylboronic acids. 

For the synthesis of the non-diene analogue 65, which bears a benzyl group in the terminal position (Scheme 17), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) cleavage of the p-methoxybenzyl (PMB) ether at the C15-position did not proceed in the presence of the benzyl moiety (oxidation of the methylene in allylic-benzylic-position in C23-position). Therefore, we inverted the order of the first two steps (1) DDQ deprotection on 44 and (2) nickel-catalyzed cross-coupling reaction performed on a free primary alcohol in C15 position. After this minor modification, completion of the synthesis followed the established route Suzuki-Miyaura crosscoupling reaction between alkyl iodide 73 (via its trialkylboronate species) and vinyl iodide 60 to yield 74 selective carbamate installation and final deprotection to afford DDM analogue 65. 

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