Amine-aldehyde components

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

The rapid synthesis of 4-thiazolidinones by the MCR of an amine, aldehyde and mercaptoacetic acid has been developed under microwave-assisted conditions [73-75]. Irradiation of the three components in ethanol at 120 °C in the presence of molecular sieves [73] or in toluene at reflux under atmospheric conditions [74] in a single-mode microwave synthesizer gave the... 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The generation of a library of 2-aminoquinoline derivatives has been described by Wilson and colleagues (Scheme 6.240) [423]. The process involved microwave irradiation of the secondary amine and aldehyde components to form an enamine (1,2-dichloroethane, 180 °C, 3 min) and subsequent addition of the resulting crude enamine to a 2-azidobenzophenone derivative (0.8 equivalents) and further micro-wave heating for 7 min at the same temperature. 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

Primary nitramines react with amines in the presence of an aldehyde to form 1,3-amino-nitramines in a reaction analogous to the Mannich condensation. In these reactions the amine and aldehyde component combine to form an intermediate imine which is then attacked by the nitramine nucleophile. 

Citrus oils readily form oxygenated products that are likely to congregate at oil/water interfaces and thereby cause a detectable change in IFT. The aldehydic components of citrus oil could react with the amine groups of the gelatin molecules present in the aqueous phases formed by complex coacervation and thereby affect IFT. In addition to chemical reactions, physical changes can occur at an interface and alter IFT. A visible interfacial film can form simply due to interfacial interactions that alter the interfacial solubility of one or more components. No chemical reactions need occur. An example is the formation of a visible interfacial film when 5 wt. per cent aqueous gum arabic solutions are placed in contact with benzene (3). Interfacial films or precipitates can also form when chemical reactions occur and yield products that congregate at interfaces. 

Amino acids are generally not considered to be important flavor components of several varieties of cheese, although they are important precursors of a variety of flavor components volatile sulfur compounds, amines, aldehydes, and ammonia (Adda et al. 1982 Aston and Dulley 1982 Forss 1979 Langsrud and Reinbold 1973). Free proline levels in Swiss cheese are important in producing the typical sweet cheese flavor. Cheeses with a proline content of < 100 mg/100 g cheese lacked the sweet flavor, while levels of >300 mg/100 g produced a cheese of excessive sweetness (Mitchell 1981). 

Thus, in a second example [29], we investigated the known Doebner three-component reaction using various aromatic amines, aldehydes and a-keto acids. While the reaction is known in textbooks to give quinolines, we found a rather... 

Enamine Dyes are obtained by condensation of heterocyclic methylene- a) -aldehydes with aromatic amines in an acid medium. Technically important dyes contain 1,3,3-trimethyl-2-methyleneindoline-a)-aldehyde as aldehyde component [7], C.I. Basic Yellow 11, the condensation product formed with 2,4-dimethoxyan-iline, is of particular importance (see 3.8.4). This compound dyes polyacrylonitrile a lightfast, brilliant, greenish-yellow shade. 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

A recent paper by Kiselyov et al. (91) reported the synthesis of two small SP discrete libraries of tetrahydroquinolines LI and L2 inspired by a three-component condensation reaction in solution (92-94) as depicted in Eig. 6.8. The scope of this condensation had been expanded by other groups (95-97), and the use of polymer-supjxMted metal catalysts had also been reported (98, 99) however, an SP route with a broad tolerance for different amines, aldehydes, and olefins had still not been defined prior to this work. 

The authors first considered the attachment of the aldehyde component to the SP using the AMEBA (acid-sensitive methoxy benzaldehyde) PS resin (100). 4-Carboxy-benzaldehyde and two different amines were reacted to produce the resin-bound intermediates 6.1 and 6.2 on a 100-g scale according to the reaction scheme shown in Pig. 6.9, with good yields resulting from an optimization of the reaction conditions. Resin-bound 6.1 was reacted with the standard olefin (cyclopentadiene, 6.3) and an aromatic amine (aniline, 6.9) and, after optimization of the reaction conditions, the desired tetrahydroquinoline 6.14 was obtained in good yield and purity after cleavage. 

It was also found that in the presence of a catalytic amount of Sc(OTf)3 benzoylhydrazones reacted with tetraallyltin to afford the corresponding homoallylic hydrazines these were readily converted to homoallylic amines. Three-component reactions of aldehydes, benzoylhydrazine, and tetraallyltin also proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3 [15]. 

Multicomponent reactions offer the possibility to introduce structural variations at more than two positions of a basic scaffold in a single step (for recent reviews, see [37]). In many cases at least some classes of components are commercially available in great numbers and reasonable structural diversity, e.g., in the case of the Ugi reaction, primary amines, aldehydes, and carboxylic acids. For these reasons, multicomponent reactions provide, at least in principle, one of the most economical tools for synthesizing large libraries. 

To a large extent the substitution pattern of the amine is variable (24, 52-54). There are more restrictions for the aldehyde component. For the piperidone synthesis, most five- or six-ring aromatic or heteroaromatic aldehydes, as well as their ring-substituted derivatives, can be used (53, 55-57), but so far only a few aliphatic mono- and dialdehydes (e.g., formaldehyde, acetaldehyde, isobutyr-, glutar-, and succinaldehyde) have found their way into the bispidine preparation. 

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