High four-component transformation

An excellent high-pressure domino reaction is shown by the four-component transformation of 2-methoxybuta-l,3-diene 172 with fS-nitrostyrene 174 and 2 equiv of N-phenyhnaleimide 173, as reported by Scheeren and coworkers (Scheme 12.71) [99]. The reaction was completed within 42 h at 15 kbar to give a mixture of the two diastereomeric nitroso acetals rac-175 and roc-176 in yields of 84%. The domino process consists of a [4+2]/[4+2]/[3- -2] cycloaddition and leads to the products 175/176 with the formation of six new bonds and eight stereogenic centers in good yield and high stereoselectivity just forming only the two diastereomers in a ratio of7 3. 

In particular, the consecutive one-pot four-component reaction of (hetero)aroyl chlorides 7, aUcynes 4, tryptamine derivatives 73 as primary amines and a,p-unsam-rated acid chlorides 71 to form tetrahydro-p-carbolines 74 most clearly demonstrates the potential of this concept and methodology for the rapid construction of highly-substituted, complex heterocycles. Five new CT-bonds and four new stereocenters can be installed in a sequence of consecutive one-pot transformations (Scheme 42). 

Finally, other reactions can be performed directly using water as a solvent. Ugi s four components reaction, for example, provides an expedient access to peptidic scaffolds starting from an isocyanide, an amine, an aldehyde and a carboxylic acid. However, in competition to Ugi s reaction, Passerini ester formation often pollutes the reaction mixture and it is of great interest to perform this type of highly complex transformation in supported versions. Indeed, when an ammonium chloride supported aldehyde, similar to those used in Grieco s multicomponent reactions, are dissolved in water in the presence of an amine, the imine formation occurs within 15 min and isocyanide and acid can subsequently be added to the mixture. After 24 h at room temperature, amides were isolated in high yield with no other purification than washing with diethyl ether [135] (Fig. 44). 

In recent years, higher orders of the DK transformation were formulated and explored in benchmark calculations on small molecules. Furthermore, it was shown that highly accurate transformed two-component Hamiltonians can be generated via the DK transformations of higher orders. These Hamiltonians converge quite well for the known elements of the periodic table limits of accuracy become noticeable only for elements with Z > 120. Higher orders of DK transformed Hamiltonians yield only small corrections for molecular observables thus, for most applications with normal demands of accuracy, DK2 is a reasonable, efficient, and well established choice. A valuable alternative is provided by the ZORA scheme, as comparison of available results shows. On the other hand, in the near future, accurate four-component approaches are expected to be essentially restricted to benchmark calculations due to their computational requirements. 

The effect of small components on the properties of molecules have been studied by Schwarz to a high order using the Foldy-Wouthuysen transformation. Schwarz has demonstrated that the contribution of the small components to chemical properties can be ignored. Thus one can ignore the small components if one is considering chemical properties. Examples of four-component atomic spinors are shown in the review paper by Pitzer. ... 

Figure 13 WT-based smoothing has four steps (1) Transform the signal, (2) isolate the wavelet coefficients corresponding to the high-frequency components, (3) zero-out or reduce these coefficients, and (4) apply a reverse W T to the signal. Compare this with the denoising routine illustrated in Figure 14.

Since the two-electron terms have not been transformed in the DKH, X2C, and BSS calculations, the exact-decoupling results differ trom the four-component DC reterence data. For the DKH Hamiltonian, a sufficiently high order has been applied to ensure exact decoupling for the accuracy reached in the SCF calculations it was chosen to be ot 35th order, i.e., DKH refers to DKH35. All energies are given in Hartree atomic units. 

Because of the huge importance of pyridine derivatives, a considerable amoimt of effort has been directed to the development of multicomponent routes for their synthesis, including reactions performed in water. For instance, a one-pot four-component condensation of aldehydes, malononitrile and thiophenols in the presence of boric acid as catalyst in aqueous medium afforded high yields of 2-amino-3,5-dicaibonitrile-6-thiopyridines 46 [29], either by conventional heating or under ultrasound-aided conditions (Scheme 1.21). This reaction can also be performed in an aqneons snspension of basic almnina [30] or in water with microporous mo-lecnlar sieves as catalysts [31]. Mechanistically, this transformation involves an initial Knoevenagel condensation of the aldehyde with a molecule of malononitrile, followed by the Michael addition of the second molecule of malononitrile, reaction of one of the nitrile groups with the thiol, cyclization and a final air oxidation step. 

More interestingly, a sequential four component synthesis, with in situ generation of aryl azide is also possible. In this remarkable transformation, one C-C bond and three C-N bounds are formed in a highly regioselective fashion (Scheme 45). A related approach, using CuCl as a precatalyst, has also been reported [100]. 

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