Heteroaromatics Heck reaction

The same group [38] also developed a double Heck reaction which was then terminated by a Friedel-Crafts alkylation to give 6/1-54 from 6/1-53 (Scheme 6/1.12) this involved an attack of an alkylpalladium(II) intermediate on an aryl or heteroaryl moiety. Noteworthy is the finding that the formal Friedel-Crafts alkylation occurs on both electron-rich and electron-poor heteroaromatic rings, as well as on substituted phenyl rings. Single Heck/Friedel-Crafts alkylation combinations have also been performed. 

As mentioned previously, the partially reduced forms of five membered heteroaromatic systems might act as olefins in insertion reactions. This behaviour is characteristic particularly of dihydrofuranes. The olefin insertion and the following / hydride elimination should in principle lead to a trisubstituted olefin, which is rarely observed, however. Typical products of this reaction are 2-aryl-2,3-dihydrofuranes. A characteristic example of such a reaction is presented in 6.54. The coupling of 4-iodoanisole and dihydrofurane led to the formation of the chiral 2-anisyl-2,3-dihydrofurane in excellent yield.83 The shift of the double bond, which leads to the creation of a new centre of chirality in the molecule, opens up the way for enantioselective transformations. Both intermolecular and intramolecular variants of the asymmetric Heck reaction have been studied extensively.84... 

The heteroaryl Heck reaction is an efficient tool for the introduction of other five membered heteroaromatic systems too (for more details see Chapter 6.4.). Chloropyrazines reacted readily with oxazole to give the coupled product (7.57.), consisting solely of the 5-oxazolyl isomer.77 Extension of the reaction to imidazole led to a similar observation,78 and the expected 5-pyrazyl-imidazole derivative was isolated in acceptable yield. Reactions using thiophene as the masked olefin gave similar results. Under forcing conditions the 2,5-diarylation of fiiran was also observed.77... 

As noted for the Heck reaction, aryl, alkenyl, and alkynyl bromides, iodides, and triflates are best for the oxidative addition. However, aromatic, heteroaromatic, alkenyl, and even alkyl boronic acids and esters can be coupled effectively. The reaction appears almost oblivious to other functional groups present ... 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Halofurans and halobenzofurans readily participate in Heck reactions with alkenes, and it is possible to synthesize benzofurans via intramolecular Heck reactions of aryl vinyl ethers. The heteroaromatic behavior of furans enable them to undergo heteroaryl Heck reactions to provide substituted furans. 

Coupling reactions. Scopes of many well-established reactions continue to be explored. The Heck reaction of alkenyl(2-pyridyl)dimethylsilanes is benefited by the direction of the heteroaromatic group during carbopalladation and the expediency in product purification and catalyst recovery. ... 

Nonconventional methodologies for Heck reaction, particularly, with participation of heteroaromatics 05T11771. 

This concept was proven to be viable using the example of 4-nitrophenyl esters in the presence of a palladium(II) chloride/lithium chloride/isoquinoline catalyst system, the 4-nitrophenyl esters 3c of various aromatic, heteroaromatic and vinylic carboxylic acids were converted to the corresponding vinyl arenes 5k along with 4-nitrophenol (Figure 4.17). The latter was demonstrated to react with benzoic acid at the same temperature as required for the vinylation step (160 °C) to regenerate the corresponding ester [28], thus demonstrating that at least a two-step waste-minimized Mizoroki-Heck reaction is feasible. 

According to Baldwin s rules [4], 5-endo-tiig cyclizations are normally disfavoured nevertheless, this reaction mode can be realized by Mizoroki-Heck reactions. Although they were outshone by the many 5- and 6-exo-type transformations, quite a number of examples following this cyclization mode were reported. This was mostly for the construction of five-membered heteroaromatic compounds (Chapter 6), but in these cases an alternative mechanistic scenario sometimes seems likely [39]. However, a few syntheses of carbocycles via (formal) 5-o Mizoroki-Heck cyclization were disclosed as well. 

Scheme 35).P],[44],[52] jy[ajjy heteroaromatic chlorides such as 88 can, however, react quite readily. This situation has changed rapidly in the past few years. For example, in the case of the Heck reaction, noteworthy advances in the use of aryl chlorides have been described by Ohff et al., Herrmann et al., and Shaw et al. Recent work by Littke and Fu has established that certain Pd-catalyzed coupling reactions of aryl chlorides can be accomplished efficiently in the presence of sterically hindered, electron-rich phosphines such as PTlu3. However, there are no examples of utilization for the coupling reaction of chloroarene with terminal acetylenes. 

The scientific contributions from the Ph.D. work of Thomas M. Gdgsig falls specifically into this category. Thomas M. Gdgsig has worked in a very competitive area of expertise dealing with the discovery or improvement of a number of transition metal-catalyzed transformations, including (a) studies on Pd-catalyzed 1,2-migra-tion reactions, (b) Pd-catalyzed Heck reactions employing heteroaromatic tosylates, (c) Ni-catalyzed Heck reactions, and (d) Pd-catalyzed carbonylation reactions... 

In Chap. 5, a presentation of the related regioselective Heck reaction of heteroaromatic tosylates is given. The work was conducted in collaboration with Dr. Anders Thyboe Lindhardt, Dr. Mouloud Dekhane from AstraZeneca, and B.Sc. Julie Groulefif. 

In the following, the regioselective Heck reaction of heteroaromatic tosylates and electron rich olefins will be presented and discussed. This protocol constitutes the first general strategy for the palladium catalyzed olefination of pyridyl tosylates obtaining perfect a-regioselectivity. 

Next, tosylated hydroxypyrimidines were tested in the regioselective Heck reaction using NVA and n-butyl vinyl ether in order to investigate the influence of the heteroaromatic core system on the catalytic outcome (Scheme 5.3). Similar yields of the vinylated pyrimidines compared to the pyridine equivalents were achieved indicating a robust catalytic system. Even a double Heck reaction could be accomplished yielding 56 in 36 % corresponding to an average of 60 % yield of each vinylation. 

In conclusion, the first general protocol describing the palladium catalyzed Heck reaction of heteroaromatic tosylates and electron rich olefins has been established based on a catalyst derived from conventional bisphosphine ligands. Furthermore,... 

The Heck coupling reaction appeared to be a route of choice to achieve the synthesis of the modified-DIOP ligands. We previously studied the palladium-catalyzed coupling of acrolein and acrolein acetals with several polyaromatic and heteroaromatic bromides either in the presence of homogeneous or heterogeneous catalytic systems (6, 7). After optimization of the reaction conditions, high conversions and selectivities were achieved except with anthracenyl derivatives (8). Based on these results, we developed the synthesis of the desired ligands. The... 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

---