Microwave-promoted Heck reaction

Similarly, the Tietze group has described an intramolecular microwave-promoted Heck reaction for the construction of the B ring in the synthesis of enantiopure B-nor-estradiol analogues (Scheme 6.10 a) [29]. The Heck coupling took place from below, anti to the angular methyl group, to form a single diastereoisomer. The best... 

Scheme 8 Microwave-promoted Heck reactions using ultralow palladium concentrations...

Microwave-promoted Heck reactions are another recent development. It was shown that Heck reactions of common substrates hke p-iodoanisol and methyl acrylate, which under standard conditions need several hours for reasonable conversions, can be carried out in just a few minutes if DMF is used as a solvent and microwave irradiation is apphed [97]. 

Microwave-promoted Heck reactions in water using ultra-low concentrations of palladium catalyst have also been performed. Different catalyst concentrations... 

Microwave-assisted Heck reactions have also been carried out with triflates as coupling partners, involving some very complex molecules. Winterfeld and coworkers have reported a multigram synthesis of a complex non-symmetrical bis-steroidal diene by microwave-promoted coupling of the corresponding alkene and triflate steroidal moieties (Scheme 6.8) [27]. 

The imidazo-benzazepine 43 was prepared in moderate yield by a combination reaction sequence involving an initial van Leusen reaction to prepare the imidazole 42 followed by a microwave-promoted intramolecular Heck reaction <06TL3225>. 

A series of potent, linear C2-symmetric HIV-1 protease inhibitors with K, values in the nanomolar range was prepared from a diaryl bromide precursor emanating from a carbohydrate scaffold, by application of Heck, Suzuki, Stille, and cyanation reactions. Included in this series was the first reported microwave-promoted Suzuki coupling with an alkyl borane [41]. A very high-yielding Suzuki coupling is presented... 

This review attempts to provide an overview of microwave-promoted metal-catalyzed transformations of aryl and vinyl halides (or pseudo halides), providing a personal selection of both pioneering and very recently published work. Covered areas include carbonylative transformations, Heck and Sono-gashira reactions, nucleophilic substitutions and cross-couplings. Because of the diversity of the microwave systems used, the reader should consult the original references for detailed descriptions of settings and instrumentation. 

Wang, J.-X., Liu, Z., Hu, Y., Wei, B., Bai, L. Microwave-promoted palladium-catalyzed Heck cross-coupling reaction in water. J. Chem. 

Erdelyi, M., Gogoll, A. Rapid Microwave Promoted Sonogashira Coupling Reactions on Solid Phase. J. Org. Chem. 2003, 68, 6431-6434. Najera, C., Gil-Molto, J., Karlstroem, S., Falvello, L. R. Di-2-pyridylmethylamine-Based Palladium Complexes as New Catalysts for Heck, Suzuki, and Sonogashira Reactions in Organic and Aqueous Solvents. Org. Lett. 2003, 5,1451-1454. 

Heck reaction and other couplings. The Heck reaction has been promoted by microwave irradiation in DMF or in water at high temperature (225°). In the intramolecular reaction leading to spirocyclic products, the double bond migration can be... 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins organohalides or pseudohalides are frequently used as organopalladium precursors [143]. One of the strengths of the method is that it enables direct mono-functionalization of a vinylic carbon, which is difficult to achieve by other means. The Heck arylation in Scheme 15.74, reported in 1996, was the first example of a microwave-promoted, palladium-catalyzed C-C bond formation [18]. The power... 

Table 5.4), prepared from reduction of Pd(II) salts with potassium graphite. The results suggested that this catalyst was not very active. However, some years later Jikei and Kakimoto [73] prepared a more active Pd/CGr based on a smaller crystallite size. In 2002, Kohler et al. [74] studied a variety of Pd/C catalysts with different properhes (Pd dispersion, oxidation state, water content, conditions of catalysts preparation etc.) in the Heck reaction of aryl bromides with olefins (entry 4, Table 5.4). The authors pointed out the hypothesis that the leached Pd from the support is the active species and the solid Pd/C catalyst acts as a reservoir that delivers catalytically active Pd species into solution. All catalysts were obtained by wet impregnation (5% Pd loading). The Heck reaction can also be conducted in ionic liquids through promotion by microwave irradiation. Moreover the reaction of iodobenzene with methylacrylate in NMP was reported to be accelerated by ultrasound [75]. The ionic liquid containing the catalyst system was used five consecutive times with only a slight loss of activity (entry 5, Table 5.4) [76]. Perosa [77] reported the addition of a phase transfer catalyst to an ionic liquid as a method to accelerate the C-C coupling reaction. As far as we know, only by using ionic liquids has Pd on carbon been recovered and reused with success.

As chemical synthesis moves from discovery to production, scales increase and the use of catalytic rather than stoichiometric quantities of reagents is increasingly advantageous from both the economic and environmental standpoints. The vast majority of fluorous catalysts prepared to date are best classified as heavy fluorous catalysts, and they are removed from the reaction mixture by liquid/liquid separation techniques. On the one hand, fluorous silica gel provides another option for these catalysts, which is to use a solid/liquid separation instead. On the other hand, fluorous silica gel enables the use of light fluorous catalysts, such as the palladium catalyst shown in Scheme 36. Mizoroki-Heck reactions are promoted by standard conductive heating (oil bath) or microwave heating. After cooling and solid-phase extraction. 

The Mizoroki-Heck reaction promoted by microwave irradiation was first described by Laihed and Hallberg [205]. For easy catalyst recovery, solid-supported systems were often used. An a-heteroatom-substituted carbonyl linker has been utilized in solid-phase approaches to oxinolines by Pummerer cyclization [206]. The reaction performed with s/c = 20 in the presence of phosphine ligands (ratio ligand/palladium-precursor = 1 1) in 88-99% yield at 7 h reaction time. 

A variety of other reaction variables, such as the solvent, base and various additives, can have profound effects on asymmetric Mizoroki-Heck cyclizations. These factors have been discussed in recent reviews [3]. The reaction temperature can also play an important role. At temperatures above 100 °C, catalyst decompositiou can contribute to deterioration of enantioselectivity [23, 24], Nonetheless, there are numerous examples of successful asymmetric Mizoroki-Heck cyclizations at higher temperature. Carrying out palladium-catalysed reactions in microwave reactors is now common [25], with several examples of microwave-accelerated asymmetric Mizoroki-Heck reactions being reported [26, 27]. Under microwave heating conditions, reaction times can be reduced and rigorous exclusion of oxygen is often not required. This technology was used to promote an asymmetric Mizoroki-Heck cyclization in the recent total synthesis of minliensine (see Section 16.4.4). 

More recently, a microwave-promoted palladium-catalyzed aminocarbonyla-tion of (hetero)aryl halides (X = I, Br, Cl) using Mo(CO)e and allylamine as a nucleophile was also described [190, 191]. Remarkably, no side products resulting from the competing Heck reaction were detected. Importantly, this was the achievement that aminocarbonylation was realized on a larger laboratory scale (25 mmol) starting from 4-iodoanisole (Scheme 2.18). 

Example 6.6 The Heck reaction, coupling aryl halides with a vinyl group, is promoted by microwaves and in situ prepared Pd(II) complex with V(ortho-to y )j, ligand in ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmim) [30]. 

Scheme 6.10 Heck reaction promoted by microwave radiation...

Recently, a wide range of organic reactions have been promoted by microwave irradiation," but in the field of Heck chemistry only a limited number of papers have appeared. " " "" Two types of microwave heating equipment have been used, a multimode reactor or a monomode reactor.The latter is more expensive but allows the placement of the reaction mixture at a fixed position of much higher continuous electric field strength than can be obtained in a multimode reactor." This is particularly important with Pd-catalyzed reactions since the reaction mixture must be heated to a high temperature in a reproducible and homogeneous fashion. 

In 2007, Larhed and co-workers reported a palladium-catalyzed cyclization of o-halobenzyl cyclohexenyl ethers. " A number of new spiro[cyclohexane-l,l -isobenzofuran]-based compounds were synthesized by palladium(O)-catalyzed S-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of... 

---