Transition metal-catalyzed transformations

Fig. 3. Correlation diagram for the transition metal catalyzed transformation of two ethene molecules into cyclobutane according to the forbidden-to-allowed concept.

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

The previous sections have described methods to obtain 2-pyridone scaffolds. Both in the construction of new materials and especially in drug design and development, there is a desire to be able to derivatize and optimize the lead structures. In the following sections, some recent developments using MAOS to effectively substitute and derivatize 2-pyridone heterocycles are described. The reaction types described range from electrophilic-, and nucleophilic reactions to transition metal-catalyzed transformations (Fig. 7). To get an overview of how these systems behave, their characteristics imder conventional heating is first described in brevity. 

To date, only a few examples are known where a domino reaction starts with an electrocydic reaction, although the value of this approach is clearly demonstrated by the beautiful synthesis of estradiol methyl ether 4-319 through a domino elec-trocyclic/cycloaddition process. There is also an impressive example of a double thermal electrocyclization being used however, the starting material for this domino reaction was prepared in situ by a transition metal-catalyzed transformation, and is therefore discussed in Chapter 6. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

The main reason for the rapid development of metathesis reactions on a laboratory scale (the reaction itself had been known for quite a long time) has been the development of active and robust second-generation ruthenium catalysts (6/3-14 to 6/3-16), which usually provide better yields than the first-generation Grubbs catalysts (6/3-9 or 6/3-13) (Scheme 6/3.2). This also reflects the huge number of domino processes based on ruthenium-catalyzed metathesis, which is usually followed by a second or even a third metathesis reaction. However, examples also exist where, after a metathesis, a second transition metal-catalyzed transformation or a pericyclic reaction takes place. 

Transition Metal-Catalyzed Transformations other than Pd, Rh, and Ru... 

A few years later, the same group extended this strategy in order to access metabolically stable C-glycosyl clusters containing long-arm spacers via a sequence of transition metal-catalyzed transformations (Scheme 11).93 In this context, crossmetathesis reactions of various C-glycosyl compounds with alkenes having available... 

There are many other examples in the literature where sealed-vessel microwave conditions have been employed to heat water as a reaction solvent well above its boiling point. Examples include transition metal catalyzed transformations such as Suzuki [43], Heck [44], Sonogashira [45], and Stille [46] cross-coupling reactions, in addition to cyanation reactions [47], phenylations [48], heterocycle formation [49], and even solid-phase organic syntheses [50] (see Chapters 6 and 7 for details). In many of these studies, reaction temperatures lower than those normally considered near-critical (Table 4.2) have been employed (100-150 °C). This is due in part to the fact that with single-mode microwave reactors (see Section 3.5) 200-220 °C is the current limit to which water can be safely heated under pressure since these instruments generally have a 20 bar pressure limit. For generating truly near-critical conditions around 280 °C, special microwave reactors able to withstand pressures of up to 80 bar have to be utilized (see Section 3.4.4). 

Compared to the previously described transition metal-catalyzed transformations in this chapter, microwave-assisted Stille reactions [74] involving organotin reagents as coupling partners are comparatively rare. A few examples describing both inter- and intramolecular Stille reactions in heterocyclic systems are summarized in Scheme 6.38 [47, 75-77]. Additional examples involving fluorous Stille reactions are described in Section 7.3. 

In more recent work by other researchers, sealed-vessel microwave technology has been utilized to access valuable medicinally relevant heterocyclic scaffolds or intermediates (Scheme 6.120) [240-245]. Additional examples not shown in Scheme 6.120 can be found in the most recent literature (see also Scheme 6.20) [246-249]. Examples of nucleophilic aromatic substitutions in the preparation of chiral ligands for transition metal-catalyzed transformations are displayed in Scheme 6.121 [106,108]. 

In a recent study, the group of Van der Eycken described the decoration of polymer-bound 2(lH)-pyrazinone scaffolds by performing various transition metal-catalyzed transformations [42]. The readily prepared pyrazinone was specifically decorated at the C3 position by employing microwave-mediated Suzuki, Stille, Sonogashira, and Ullmann protocols (Scheme 7.24), thereby introducing additional diver-... 

An analysis of the processes listed in Table 37.2 shows that asymmetric hydrogenation of C=C and C=0 functions is by far the predominant transition metal-catalyzed transformation applied for industrial processes, followed by epoxida-tion and dihydroxylation reactions. On the one hand, this is due to the broad scope of catalytic hydrogenation, and on the other hand it could be attributed to... 

Keyword Carbocycles a Cascade Reactions a Cycloadditions a Combinatorial Chemistry a Domino Reactions a Enantioselective Transformations a Ene Reactions a Eieterocydes a Natural products a Preservation of Resources and Environment a Sigmatropic Rearrangements a Tandem Reactions a Transition Metal-Catalyzed Transformations... 

Most of the above reactions occur via a mechanism involving intermediates with a metal-silicon bond (i.e. silicometallics) and a metal-hydrogen bond, accompanied (or sided) only occasionally by compounds containing metal-carbon bonds (i.e. organometallics) that are characteristic of the key intermediates of transition-metal-catalyzed transformations of organic compounds (for recent reviews, see Refs [11, 13]). 

The use of this classification might help to identify the ways a selected compound might participate in late transition metal catalyzed transformations, and might also help to establish potential reaction partners. Although Table 2 suggests that there is an abundance of potential reactions for a given substrate, we have to emphasize that certain classes are well represented in the synthetic literature (e.g. 3, 8, 11, 17), while for other classes there are only a very limited number of examples. 

The alternate reaction sequence, starting from o-iodobenzaldehye imine and carrying out two subsequent transition metal catalyzed transformations was also reported Roesch, K. R. Larock, R. C. Org. Lett. 1999,1, 553. 

One of the most frequently studied transition metal catalyzed transformations of azoles and indole is their participation in cross-coupling reactions. Due to the abundance of examples in this field we only present some representative examples of the different reaction classes. In this chapter reactions where a halogenated azole is used to introduce the five membered ring onto the palladium in the oxidative addition and processes,... 

Probably the most thoroughly studied transition metal catalyzed transformation of six membered systems is their participation in crosscoupling reactions. Due to the vastness of this field we present only some representative examples for the different reaction types. In this chapter... 

This chapter discusses the transition metal catalyzed functionalization of such systems that fall outside the topic of Chapters 6 and 7, as well as certain other compound classes (e.g. purines, pyrones). In contrast to the abundant literature of the chemistry of five and six membered systems, the transition metal catalyzed transformations of other heterocycles have not been studied so far in the same depth, probably due to the limited availability of their halogen derivatives compared to haloazines and haloazoles. Purine compounds and their structural analogues constitute an exception, since their biological importance proved to be a strong drive for synthetic chemist worldwide.1... 

Much less information is available about [2 + 2]-cycloadditions. These allow the formation of cyclobutane derivatives in the reaction between two alkenes, or that of cyclobutenes from alkenes and alkynes. The reaction can be achieved thermally via biradical intermediates,543 by photoreaction,544 and there are also examples for transition-metal-catalyzed transformations. An excellent example is a ruthenium-catalyzed reaction between norbomenes and alkynes to form cyclobutenes with exo structure ... 

One of the most important applications of microwave reactions is for transition-metal-catalyzed transformations [28]. The Curran and Hallberg... 

Several examples of heterocyclic BINAP analogues have been reported which sometimes offer an improved performance in a variety of transition-metal-catalyzed transformations when compared to standard BINAP ligands. In this review, we survey the efforts of developing atropisomeric biheteroaryl backbone-containing bisphosphines, their designing concept, synthetic approaches and some of their important applications. 

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