Domino catalytic reactions

The N-alkylation of amines with alcohols [63] can also be carried out with Ir catalysts through a similar domino sequence reaction. In this case, the aldehyde/ketone resulting from oxidation is condensed with an amine to the corresponding imine, which is hydrogenated to the alkylated amine [63]. By way of example, the reaction of benzyl alcohol with aniline in toluene afforded benzylaniline in a 88% isolated yield by using catalytic amounts of [ lr(/z-Cl)Cp Cl 2]/K2C03. 

The catalytic domino Michael reaction of oxophorone and its derivatives 148 with various electron-poor olefins was promoted by Af-methylaminopropylated silica (NMAP) combined with butyllithium that converts the surface silanols into the basic SiOLi groups (NMAP-Li) 147 (Scheme 3.43)/ ... 

Since very few synthetic strategies employing hydroformylation have been developed, the major part of our research activities have focused on this catalytic reaction. Our effort in this area is directed at developing new strategies involving hydroformylation either in short reaction sequences consisting essentially of atom economic reactions or as a reaction triggering a domino process. 

New synthetic methods should be designed in concert with new concepts of modem chemistry. These key concepts involve atom and step economies and the use of highly efficient catalytic reactions. The hydroformylation reaction follows these guidelines. It requires a low catalyst loading, allows the creation of three new chemical bonds, and introduces a highly reactive aldehyde. We have already demonstrated that its combination with other chemical reactions in well-developed domino sequences shows its potential in the synthesis of complex molecules. The few previously synthesized natural molecules demonstrated that the robustness of the catalyst system and other domino reactions are possible to create even more complexity and diversity. 

The same group extended this methodology to incorporate a Sonogashira reaction into the domino sequence [14]. As a result, oxindole 40 could be synthesized from propiolamide 38 and 2 equiv of aryl iodide 39 in the presence of catalytic Pd(PPh3)4/CuI via a domino Sonogashira reaction/carbopaUadation/C-H activation sequence (Scheme 3.10). Overall three C-C bonds were formed from distinct catalytic cycles using only one catalyst. UnsymmetricaUy substituted oxindoles were also synthesized by a one-pot/two-step protocol where the second aryl iodide was simply added to the same reaction vessel after the Sonogashira reaction of the first aryl iodide. 

The Heck-Mizoroki reaction has also been heavily applied in one-pot sequential reaction sequences. The topic of sequential, domino, consecutive, or tandem catalytic reactions is a very timely subject, as at its core is efficiency, economy, and waste minimization in organic synthesis. In 2010 [59], one of us published a review of this topic which explains the current state of play and includes relevant references on the subject. However, the topic is still rather murky in terms of definitions, and this is something that we feel needs urgent attention. The Heck-Mizoroki is a very suitable transformation for inclusion in a sequential catalytic process, given that it leads to the formation of C=C units, a common functionality for further catalytic transformation. 

Smith and co-workers have employed NHC 81 to catalyse the 0- to C-carboxyl transfer of a range of oxazolyl carbonates 80, forming 82 with the generation of a C-C bond at a quaternary centre with good catalytic efficiency [27], This transformation presumably proceeds via the generation of an intermediate carboxyazolium species, and has been utihsed as a component of domino multi-component reactions [28], as well as the rearrangement of indolyl and benzofuranyl carbonates (Scheme 12.15) [29]. 

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

In addition to aldehydes and a-diketones, a-ketoesters can also be used in the domino process, as shown by Tietze and coworkers [396]. Reaction of methyl pyruvate 2-791 with dimethylbarbituric acid (2-747) and the enol ether 2-792 in the presence of trimethyl orthoformate (TMOF) and a catalytic amount of EDDA gave the cycloadduct 2-793 in 84% yield (Scheme 2.176). 

The domino reaction of (IS)-2-808, Meldmm s acid (2-801) and enol ether 2-802b in the presence of EDDA, followed by treatment with K2C03/Me0H and a catalytic amount of Pd/C in methanol under a nitrogen atmosphere for 50 min and subsequently under a H2-atmosphere for 2 h at r.t. gave the benzoquinolizidine 2-809 with the correct stereochemistry at all stereogenic centers as in emetine (2-798) and tubulosine (2-799), together with two diastereomers (Scheme 2.180) [406]. Further manipulations of 2-808 led to emetine (2-798) and tubulosine (2-799). 

In a similar way, Carreaux and coworkers [53] used 1-oxa-l,3-butadienes 4-155 carrying a boronic acid ester moiety as heterodienes [54], enol ethers and saturated as well as aromatic aldehydes. Thus, reaction of 4-155 and ethyl vinyl ether was carried out for 24 h in the presence of catalytic amounts of the Lewis acid Yb(fod)3 (Scheme 4.33). Without work-up, the mixture was treated with an excess of an aldehyde 4-156 to give the desired a-hydroxyalkyl dihydropyran 4-157. Although this is not a domino reaction, it is nonetheless a simple and useful one-pot procedure. 

In transition metal-catalyzed domino reactions, more than one catalyst is often employed. In Tietze s definition and the classification of domino reactions, no distinction has been made between transformations where only one or more transition metal catalyst is used for the different steps, provided that they take place in a chronologically distinct order. Poli and coworkers [13] differentiated between these processes by calling them pure-domino reactions (which consisted of a single catalytic cycle driven by a single catalytic system) or pseudo-domino reactions . The latter type was subdivided into ... 

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. 

In an approach towards a total synthesis of the marine ascidian metabolite pero-phoramidine (6/1-96) [55], Weinreb and coworkers developed a domino Heck/car-bonylation process [56]. This allowed construction of the C,E,F-ring system of 6/1-96, together with the C-20 quaternary center and the introduction of a functionality at C-4 (Scheme 6/1.25). Thus, reaction of 6/1-97 in the presence of catalytic amounts of Pd(OAc)2 and P(oTol)3 under a CO atmosphere in DMA/MeOH led to 6/1-98 in 77% yield. 

As described in the preceding sections, many domino reactions start with the formation of vinyl palladium species, these being formed by an oxidative addition of vinylic halides or triflates to Pd°. On the other hand, such an intermediate can also be obtained from the addition of a nucleophile to a divalent palladium-coordinated allene. Usually, some oxidant must be added to regenerate Pd11 from Pd° in order to achieve a catalytic cycle. Lu and coworkers [182] have used a protonolysis reaction of the formed carbon-palladium bond in the presence of excess halide ions to regenerate Pd2+ species. Thus, reaction of 6/1-386 and acrolein in the presence of Pd2+ and LiBr gave mainly 6/1-388. In some reactions 6/1-389 was formed as a side product (Scheme 6/1.98). 

A domino RCM of an ene-yne was also used by Granja and coworkers [250] for their synthesis of the B-bishomo-steroid analogue 6/3-70. Reaction of the substrate 6/3-69 with the ruthenium catalyst 6/3-13 led to 6/3-70 in 48% yield as a 6.5 l-mix-ture of the two C-10-epimers (Scheme 6/3.20). The aim of this study was to prepare haptenes for the production of catalytic monoclonal antibodies that could be used to study the mechanism of the physiologically important transformation of previtamin D3 into vitamin D3 [251]. 

Scheme 10.30. Domino Knoevenagel condensation/catalytic hydrogenation reaction in ionic liquid.

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