Alkenylation, of aromatics

Similar to mercuration, Pd(OAc)2 undergoes facile palladation of aromatic com-povmds. The palladation product 162 is an unstable intermediate. It can be isolated only when stabilized by chelation. The palladation products of aromatics as reactive intermediates undergo three reactions. The reaction with alkenes to afford styrene derivatives 164 is the first one. Pd(II)-promoted alkenylation of aromatic compovmds, discovered by Fujiwara, is a stoichiometric Heck reaction. The second one is homocoupling to form biaryls. The acetoxylation of aromatic rings is the third reaction. These latter two reactions are treated in Chapter 2.7. 

The direct alkenylation of aromatics tolerates a variety of alkenes. Besides the alkenes mentioned above, lower alkenes (e.g. 1-butene, propene) [6], alkenes containing polar groups (e.g. acrylonitrile) [4b] and cychc alkenes such as cyclooctene [7] all participate in the palladium(II)-promoted substitution of arenes. In most cases, however, the yields of these reactions were prohibitively low (less than 20%). 

Importantly, one can effect a chemoselective direct alkenylation of aromatic halides without reacting with the carbon-halogen bond [11]. Murakami and coworkers [12] reported a chemoselective C-3 alkenylation of 4-bromo-l-tosylindole (17) with methyl 2-ferf-butoxycarbamoylacrylate (18) in the presence of stoichiometric Pd(OAc)2 and 1 equiv chloranil. The reaction smoothly generated 4-bromodehydrotryptophan derivative... 

The palladium(II)-assisted alkenylation of aromatic compounds has also been applied to the synthesis of heterocycles. A novel synthesis of pyrido[3,4-d] pyrimidines, pyrido[2,3-d]pyrimidines and quinazolines was developed by Hirota et al. [18] employing the palladium(ll)-promoted oxidative coupling of uracil derivatives and alkenes. l,3-Dimethyluracil-6-carboxaldehyde dimethylhydrazone (22), 6-dimethylaminomethylenamino-l,3-dimethyluracil (24) and ( )-6-(2-dimethylaminovinyl) uracil (26) all reacted with methyl acrylate in the presence of stoichiometric Pd(OAc)2, producing pyrido[3,4-ii]pyrimidine 23, pyrido[2,3-if]pyrimidine 25 and quinazoline 27, each apparently arising from direct arylation, 6ti electrocycliza-tion, and elimination of dimethylamine, in 67%, 89% and 64% yields respectively (Scheme 9.3). 

H. (1981) Palladium-catalyzed alkenylation of aromatic heterocycles with olefins. Synthesis of functionalized aromatic heterocycles. J. Org. Chem., 46, 851-5. 

Figure 4.35 A cross-section of results for the Ru-catalyzed orfho-alkenylation of aromatic ketones as described by Padala and Jeganmohan [69].

Reoxidant in Palladium-Catalyzed Reactions. Cu(OAc)2 has been used as a reoxidant in the Wacker oxidation (CH2=CH2 + 02- CHsCHO) and in the Pd(OAc)2-catalyzed alkenylation of aromatic compounds with alkenes (eq 17). Pd(OAc)2 and Cu(OAc)2 are effective catalysts for the reactions... 

In order to find alternative routes to functimial olefins via the very useful Heck reaction [52] oxidative dehydrogenative cross-coupling of sp C-H bonds with (alkene) C-H bond was first discovered using Pd(II) catalyst and an oxidant, by Moritani and Fujiwara [25,53], This oxidative alkenylation of aromatic C-H bonds profitably performed using cheap and stable mthenium(ll) catalysts was shown for the first time in 2011 successively by the groups of Satoh and Miura [54], Ackermann [55], Bruneau and Dixneuf [56], and Jegaiunohan [57] [(Eq. 2)]. This Ru(n)-catalysed alkenylation reaction offers a potential to reach a large variety of functional alkenes at low cost and has been extended to annulation reactions with alkynes for a fast access to heterocycles. 

Alkenylation of aromatic C-H bonds was initially observed in several examples by Chae S. Yi using [RuH(CO)(PCy3)(CgH6)]BF4 as catalyst precursor with a strong acid HBF4 OEt2 as catalyst precursor. The reaction of the naphthylketone with styrene led preferentially to the orf/io-alkenylation product with low yield (35%) [(Eq. 50)1 [139]. 

Interestingly, the ort/io-alkenylation of aromatic aldehydes allowed the access to four-membered cyclic ketones and to polysubstituted isochromanone derivatives by an irradiation in benzene of the alkenylated product [(Eq. 62)] [144]. 

Lim S-G, Lee JH, Moon CW, Hong J-B, Jun C-H (2003) Rh(I)-catalyzed direct ortho-alkenylation of aromatic ketimines with alkynes and its application to the synthesis of isoquinoline dtnivatives. Org Lett 5(15) 2759-2761... 

Hydrogenolysis of aryl and alkenyl halides and triflates proceeds by the treatment with various hydride sources. The reaction can be explained by the transmetallation with hydride to form palladium hydride, which undergoes reductive elimination. Several boro hydrides are used for this purpose[680], Deuteration of aromatic rings is possible by the reaction of aryl chlorides with NaBD4681]. 

Tetrahalobenzynes, however, react with a variety of aromatic compounds to afford tetrahalobenzobarrelene derivatives in good yields, frequently in the range of 55 to 75%. The dehalogenation of a variety of alkenyl chlorides with alkali metals in tetrahydrofu-ran containing tert-butyl alcohol suggested this approach to the dechlorination of tetrachlorobenzobarrelenes. 

This section will describe the Friedel-Crafts alkylation reactions of aromatic hydrocarbons with alkenylchlorosilanes containing short chain alkenyl groups such as allyl and vinyl. The reaction will be discussed in terms of the substituent effect on silicon and the arene rings. 

A second group of aromatic substitution reactions involves aryl diazonium ions. As for electrophilic aromatic substitution, many of the reactions of aromatic diazonium ions date to the nineteenth century. There have continued to be methodological developments for substitution reactions of diazonium intermediates. These reactions provide routes to aryl halides, cyanides, and azides, phenols, and in some cases to alkenyl derivatives. 

Electrochemically generated nickel is very selective for the reduction of aromatic nitro compounds into anilines, in which alkenyl, alkynyl, halo, cyano, formyl, and benzyloxy groups are not affected.84 Sodium sulfide has been used for the selective reduction of aromatic nitro group in the presence of aliphatic nitro groups (Eq. 6.44).85... 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

Nitrogen functionality also assists the alkylation of ortho-Cr-H bonds of aromatics, as shown in Equations (10)—(12). In the case of aromatic imines, Ru3(GO)i2 exhibits a high catalytic activity.8-10 This reaction gives the alkylation product together with the alkenylation product in the reaction with triethoxyvinylsilane. Rhodium catalysts show the same activity to give the alkylation product.11,12,12a For example, the Rh(i)-catalyzed reaction of the imine of aromatic ketones with methyl acrylate... 

Similarly, ketimines (benzylimines of aromatic ketones) undergo the rhodium-catalyzed ortho-alkenylation with alkynes to give or/ o-alkenylated aromatic ketones after hydrolysis.61 This method is applied to an efficient one-pot synthesis of isoquinoline derivatives by using aromatic ketones, benzylamine, and alkynes under Rh catalysis (Equation (55)). 

Intramolecular process with rhodium catalyst has been described for the syntheses of indane, dihydroindoles, dihydrofurans, tetralins, and other polycyclic compounds. Wilkinson catalyst is efficient for the cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered to the K z-position of the imine-directing group. 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

The palladium-catalyzed arylation and alkenylation of terminal alkynes with aryl or alkenyl hahdes in presence of a copper(l) co-catalyst is called Sonogashira reaction. In the same way as in the other cross-coupling reactions described before, it is possible to immobihze the alkyne or the aromatic bromides, iodides or triflates on sohd supports (Scheme 3.15). 

The improved activity of 3 -alkyl and 3 -alkenyl taxoids described above clearly establishes the dispensability of aromatic character at the C-3 position. Next, we investigated the effects of C-2 modification on cytotoxicity by replacing the C-2 benzoate moiety with nonaromatic ester groups. Replacement of the 2-benzoate with simple alkyl and alkenyl esters in conjunction with modification at C-3 provides a series of novel taxoids devoid of all the aromatic groups of paclitaxel and docetaxel.44... 

This C-H/olefin coupling can be extended to coupling with acetylenes [6], The reaction of aromatic ketones with internal acetylenes gives the ortho alkenylated product in high yield (Scheme 2), but reaction with terminal acetylenes does not afford the coupling product. With terminal acetylenes, dimerization of acetylenes occurs as a predominant reaction. 

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