Coupling couplings with ethyl acrylate

Haloindoles and indolyl triflates are also known to undergo Heck coupling both in the 2- and 3-position. In a typical example the protected 3-indolyl triflate was coupled with ethyl acrylate in excellent yield (6.57.).87... 

Further investigations into the palladium(ll)-catalysed cross-couphng of olefins with iodopyrimidines have been published. As previously reported,2-iodo-4,6-dimethylpyrimidine and its 4-iodo-2,6-dimethyl isomer do not couple with ethyl acrylate if a reagent mixture of Pd(OAc)2, PhaP, and EtaN is used however, omission of the triphenylphosphine permits the coupling to proceed in reasonable yields. Palladium black can also be used as the catalyst. ... 

Heck reactions can be carried out in the absence of phosphine ligands.141 These conditions usually involve Pd(OAc)2 as a catalyst, along with a base and a phase transfer salt such as tetra-n-butylammonium bromide. These conditions were originally applied to stereospecific coupling of vinyl iodides with ethyl acrylate and methyl vinyl ketone. 

Isayama described the coupling reaction of N-methylimine 157 and ethyl crotonate catalyzed by Co(acac)2 and mediated by PhSiH3 to produce Mannich product 158 in 82% with syn-selectivity (Scheme 41) [71]. The (i-laclam 159 was readily synthesized by heating 158. In 2002, Matsuda et al. reported cationic Rh complex [Rh(COD) P(OPh)3 2]OTf (1 mol%) as an active catalyst for the reductive Mannich reaction [72]. N-Tosylaldiminc 160 was coupled with methyl acrylate and Et2MeSiH (200 mol%) at 45 °C to give the b-amino ester 161 in 96% with moderate anti-selectivity 68%. 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

In contrast, Tsuji s group coupled 2-methylfuran with ethyl acrylate to afford adduct 6 via a Pd-catalyzed reaction using tm-butyl peroxybenzoate to reoxidize Pd(0) to Pd(II) [16]. The palladation of 2-methylfuran took place at the electron-rich C(5) in a fashion akin to electrophilic aromatic substitution. The perbenzoate acted as a hydrogen acceptor. 

The reaction of alkenyltriphenylbismuthonium salt with ethyl acrylate in the presence of Pd(OAc)2 (2 mol%) afforded both alkenylated and phenylated products in low yields (Scheme 4) [13]. In addition, ligand coupling products of the bismuthonium salt were also formed. 

Heteropolyoxametalates are often used in combination with palladium salts as catalysts in oxidation processes using dioxygen as the oxidant. Indeed, the oxidative coupling reaction of benzenes with alkenes was also successfully achieved by use of the Pd(OAc)2/molybdovanadophosphoric acid (HPMoV)/02 system [14a]. For example, reaction of benzene with ethyl acrylate using this catalytic system in acetic acid afforded ethyl cinnamate as a major product in satisfactory yield. Typically, the reaction is conducted in acetic acid at 90 °C under 1 bar of 02. After 6 h the TON is 15. This number was recently improved to 121 [14b]. 

For example, coupling of complexed aldehyde 31 with ethyl acrylate gave lactone 32 with complete diastereocontrol.52 Furthermore, Lewis acid-mediated epimerisation of lactone 32 allowed for the isolation of the alternative diastereoisomer 33. Subsequent decomplexation with iodine liberated the two enantiomerically pure lactones.52... 

Pd-catalysed oxidative heterocyclisation features in a synthesis of substituted dihydropyran-4-ones from P-hydroxy-ynones. The process involves domino Wacker - Heck coupling of the ynones with ethyl acrylate and, although yields are only moderate, the stereochemistry of the ynone is retained in the product (Scheme 24) <06JOC8390>. 

A later report demonstrated similar chemistry under milder conditions. The apparently reduced effectiveness of the PTA in the previous work was noted, as was a further report where Pd/MjCOj/PTA had been demonstrated to catalyze the Heck reaction in water in excellent yield under mild conditions. This chemistry was therefore adapted to the solid phase. After tethering 4-iodobenzoic acid to TentaGel resin, the reaction with ethyl acrylate was examined and found to be successful with the conditions shown in Scheme 2. Initial attempts to run the reaction in neat water failed to convert starting material to product in much more than about 50% yield, but introduction of a DMF-water solvent mixture solved this problem. The chemistry was adapted for the coupling of a number of olefins (generally those with attached electron-withdrawing groups). In contrast to the previous report, where these reactions were shown with reversal of polarity (i.e., the reaction of solution-phase iodides and bromides with resin-bound 4-vinylbenzoic acid), no products were obtained in these reversed cases. 

Yamanaka s group reported the Heck reactions of 4-bromo- and 5-bromo-4-methylox-azoles 72 and 73 with ethyl acrylate and acrylonitrile, giving the coupled products 93 and 94, respectively [50]. 

Contrary to the results with ethyl acrylate, which affords 5-carbofunctional pyrimidines, palladium-catalyzed C-C coupling with ethyl methacrylate or ethyl crotonate directly gives the corresponding pyrido[2,3-r/]pyrimidin-2(l//)-ones l.139... 

Ethyl 4-chloro-2,6-dimethylpyrimidine-5-acrylate (32), prepared either by coupling 4-chloro-5-iodo-2.4-dimethylpyrimidine with ethyl acrylate in the presence of palladium(IT) aeelale/Lri-ethylamine or by treatment of ethyl 2,6-dimethyl-4-oxo-3,4-dihydropyrimidine-5-acrylate with phosphoryl chloride, when treated with ammonia in ethanol at 120°C gives 2,4-dimethylpyri-do[2,3-rf]pyrimid in-8(77/)-one (33).139... 

The coupling of homoallylic iodide with a,) -unsaturated esters and nitriles is valuable in obtaining simple addition products with ethyl acrylate and acrylonitrile. While tributyltin hydride gives the sequential cyclization products 46 and 48 as the major products [17], the BER-Ni2B system yields the simple addition compounds 45... 

Coupling 971 and 973 with ethyl acrylate, acrylonitrile, and styrene produced 975a-c and 976a-c, respectively, albeit in lower and more variable yields. Finally, the authors were unsuccessful in their efforts to couple a 2-halooxazole with a terminal acetylene or an olefin. In these cases, they encountered significant decomposition that was attributed to ring cleavage of the 2-palladated oxazole. 

An early example of this arene coupling was reported by Ames and BuU,t who noted the formation of benzofuro[3,2-c]cinnoline in the reaction of 3-bromo -phenoxycinnohne with ethyl acrylate in the presence of a catalytic amount of paUadium(n) acetate (Scheme 2, Eq. 1). Subsequent studies showed that ethyl acrylate is not necessary, and the arylation reaction was achieved by using 0.1 equiv of palladium acetate, 0.2 equiv of triphenylphosphine, and 3 equiv of sodium acetate in DMA at 170 °C (Scheme 2, Eq. 

Itahara et al. [9] found that A-2,6-dichlorobenzoylindole (13) was oxidatively coupled with methyl acrylate (4b) in the presence of stoichiometric Pd(OAc)2 in acetic acid, affording the 3-alkenylated product 14 in 25% yield. Similarly, A-tosylindole (15) reacted with ethyl acrylate (4c) to generate the 3-alkenylated indole 16 in 48% yield (Scheme 9.2) [10]. Unlike what Fujiwara et al. [8b] had observed in the reaction with A-acetylindole (8) and methyl acrylate (4b), both cases did not produce any 2-alkenylated indoles, presumably due to the steric hindrance of the relatively bulky 2,6-dichlorobenzoyl and tosyl groups. 

The heterogeneous catalyst Pd/C (10 wt%, 3.0 mol% relative to the olefin) was used in [BMImjPFe to couple various iodobenzenes with ethyl acrylate in up to 95% yield [45]. The corresponding bromobenzenes could be coupled with yields of up to 85%. After the reaction, the product was extracted with -hexane. Dissolution of palladium once reported by Earle and coworkers [46] was not observed according to analysis with induced coupled plasma emission spectroscopy. 

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