MCRs unions

Usually, the higher MCRs are unions of the U-4CR and further chemical reactions or MCRs. However, these procedures are the rare exceptions. The majority of MCR unions proceeds only well if at least one of its participating MCRs belongs to type II. In these exceptional cases, an irreversible final step of MCR unions takes place, although all of the participating subreactions of MCRs are reversible. 

In 1993 the first MCR composed of seven educts was introduced, and it was soon recognized that such higher MCRs are usually unions of the U-4CR and additional reactions. In the first 7-CR, the intermediate 63 was formed by an A-4CR and underwent with the equilibrating product 67 the a-addition of the cations and ions onto the isocyanide 27. Finally, this a-adduct, 69, rearranges into the final product, 71 (Scheme 1.17). 

MCR also tolerates the aliphatic isocyanide functionality [150], thus allowing the union with various IMCRs. Finally, we developed the first example of a triple MCR process (SCR toward 83) based on our 2//-2-imidazoline (65) and W-(cyano-methyl)amide (32) MCRs united with the Ugi-4CR (Fig. 25). 

In practice there are different approaches to the development of new MCRs. These are random discovery or chance, combinatorial chemistry, rational and computer-assisted design and the concept of unions of MCRs, and these will be described in the following sections. 

Another concept towards novel MCRs was established in 1993 by us the union of MCRs [23], Our objective was to find reactions with maximal numbers of participating starting materials. Thus we considered combining several MCRs, since a single MCR already contains a high number of educts. Two MCRs can be combined if the product or an advanced intermediate of the first MCR is a intermediate or starting material of the second MCR. The starting materials should ideally not have the possibility for irreversible side reactions under the reaction conditions used. Scheme 3.16 illustrates this approach. 

Scheme 3.16. Schematic representation of the union of MCRs. An Asinger 4CR (A-4CR) is combined with an Ugi 5CR (U-5CR) and a Mannich 3CR (M-3CR) resulting in the union of these three MCRs.

Another example of the strategy of union of MCRs was performed by Ugi et al. This involved the union of a U-5C-4CR with a P-3CR (Scheme 3.18). Glutaric acid or aspartic acid reacts in methanol with one equivalent of aldehyde and isocyanide to form the corresponding Ugi product, which in a second step without isolation of the intermediate reacts with the remaining carboxylic acid functionality and one equivalent of isocyanide and aldehyde to yield the Passerini product [25],... 

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

The Union of MCRs (MCR, Fig. 9) is a fourth strategy for the rational design of novel MCRs that combines two (or more) different types of MCRs in a one-pot... 

The presence of orthogonal reactive groups in the product of the primary MCR (which is either formed during the primary MCR or present in one of the inputs) allows the union with the secondary MCR [17,99]. By varying the secondary MCR (e.g., by addition of inputs E/F or G/H), diverse (and complex) scaffolds will be available, making this strategy excellent for application in DOS. 

Fig. 9 Schematic representation of the union of MCRs (MCR ) to scaffold diversity...

The two early types of MCRs remained separate entities for a whole century [7,8], but in January 1959 [11] they were combined [12] and became the U-4CR (U = Ugi) [2-4,8]. This soon also included the libraries of combinatorial chemistry [8,13a]. The educts and products of the U-4CR and its unions with other chemical reactions are by many orders of magnitude more variable than those of any other chemical reactions, and even of the entire spectrum of other MCRs. Under suitable reaction conditions, the U-4CR may produce almost quantitative yields of pure product, and with minimal preparative work [4,8,10]. Nevertheless, this profound preparative progress was of no general chemical interest until early 1995 [2-5,14], when almost overnight the one-pot MCR chemistry of the isocyanides and their libraries became one of the most intensely used areas of industrial chemical research. The technique is used not only to find new chemical products, but also to produce them far more conveniently and in higher yields than might other multistep syntheses. 

Several one-pot syntheses are closely related to MCRs that have irreversible final steps, although they are unions of two usually reversible M-3CRs, since their products are rather stable polyheterocyclic compounds. The first such procedure was introduced by Robinson in 1917 [48a], who synthesized the tropinone 59 from succindialdehyde 56, methylamine 2b and the methyl ester of acetonedicarbocylic acid 57 (Scheme 4.28). Two decades later, Schopf et al. accomplished some progress with a closely related synthesis [48b],... 

The even more sophisticated stereospecific formation of the chiral alkaloid 63 by Stevens and Lee [49], and the previous synthesis of 58 and related procedures have in common their essential ring-closing steps corresponding to unions of M-3CRs.The a-amino-alkylating MCRs of type I [4,7] correspond to collections of equilibrating subreactions. Such positive formation of polyheterocyclic products correspond to almost irreversible cyclocondensations. These elegant syntheses correspond to an area of preparative chemistry whose products can be formed successfully, and where unions of reversible MCRs can have virtually irreversible final steps. 

In 1993 it was realized that one-pot MCRs of five and more educts can take place as unions of the U-4CR and other reactions or MCRs. A great variety of their educts and products can participate, if the irreversible U-4CR can be combined with a great variety of further types of participating chemical compounds. 

In the early studies relating to anions of acid components in the U-4CR, it was also found that cyanic acid and thiocyanic acid can participate [113,114] in the U-4CR. It was then realized that products of the type 67 can also be formed directly via A-3(4)CRs [36, 37]. Such 5CRs and 6CRs [115, 116] correspond to the union of the A-MCRs and the U-4CR [2,3],... 

The chemistry of even higher MCRs began when the concept of unions was fully realized [2], and when it was shown that higher unions of one-pot reactions can succeed if their last procedures are MCRs of type II. The first 7CRs were accomplished in 1993 [116, 117]. In Britain [118] and the USA [119], it was soon recognized that such MCRs were the start of a new era of MCR chemistry and their libraries. The first 7CR took place via the a-addition of 69b and 6b onto 13c, forming 70. This corresponds to the isocyanide 13c a-adduct 3h of 4a + 8 and the intermediate A-4CR product 68a of Id, 2a, 66b and 68 rearranges into 70, as its last event, just like an U-4CR (Scheme 4.32). 

Until now, all MCRs of more than five different educts have been unions of MCRs, in whose last steps isocyanides have participated. 

Recently, many new types of chemical products have been described that were produced by one-pot MCRs of by-functional educts [6], Since then, further progress has been made. In particular, those MCRs will be mentioned here which are unions of the U-4CR and related chemical reactions, and that have been developed recently by several chemical companies. 

Scheme 5.5 Union of Asinger and Ugi MCRs leading to a seven-component reaction.

Petra 140 (Allied Signal) is a 40 percent glass-reinforced polyethylene tereph-thalate from recycled soda bottles. It has a tensile strength of 26,000 psi and a heat-deflection temperature of 225°C at 264 psi. PC23MS-200 (MCR Polymers) contains at least 25 percent recyclate from personal computer compact disks and polyethylene terephthalate beverage bottles. DMDA-1343NT polyethylene (Union Carbide) contains 28 percent color-sorted recyclate and has physical properties similar to those of virgin stock. Encore resins (Hoechst Celanese) are a family of plastics based on 100 percent reclaimed thermoplastics such as acetal, polyester, polyphenylene sulfide, nylon 6/6, and liquid crystal polymer. 

---