Aldehydes, reaction with isonitriles

Isonitrile complexes, having a similar electronic structure to carbonyl complexes, can also react with nucleophiles. Amino-substituted carbene complexes can be prepared in this way (Figure 2.6) [109-112]. Complexes of acceptor-substituted isonitriles can undergo 1,3-dipolar cycloaddition reactions with aldehydes, electron-poor olefins [113], isocyanates [114,115], carbon disulfide [115], etc., to yield heterocycloalkylidene complexes (Figure 2.6). 

By carrying out the Ugi-reaction with a large number of isonitrils, aldehydes, carboxylic acids, and amines, it was found that formation of different products of the reaction occurred depending on the structure of the amines used. Thus, 3-aminoimidazoles 88 were isolated when aldehyde reacted with isocyanide and heterocyclic aromatic 2-aminoazine as primary amine (Scheme 38). 

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

A multicomponent reaction of aldehyde acid 234 with isonitriles and amines in methanol at 40 °C leads to novel pyrrolo[l,2-fl][l,4]diazepines 235 in 75-85% yields (Equation (28), 2005JCX71478). 

The Ugi reaction produces a-amino acid amides from four components (isonitrile, carboxylic acid, aldehyde, and amine) in a one-pot reaction. With glycosylamines and ZnCl2 as promoting Lewis acid, a-amino acid amides are obtained [13,45] with excellent stereoselectivity in these reactions. For example, the galactosylamine 2 gave Ugi product 30 with formic acid as carboxylic component and various aldehydes and isonitriles in high yields and a diastereoselectivity of 19 1 in favor of the D-amino acid amides 30 (Scheme 20). 

Oxazoles. Oxazoles are formed using this building block on reaction with aldehydes and acid chlorides. The isonitrile is prepared from the corresponding formamide by dehydration with POClj-EtjN. 

Thus a support-bound benzylpiperazine (282) was allowed to undergo a Man-nich reaction with formaldehyde and a-keto-aldehyde hydrazones. Upon addition of 1,2-dibromo-ethane (388) the support-bound piperazine tether is N, N -dialky-lated to give a quinuclidinium species (389). Subsequent Hoffmann elimination released a diazaalkadiene (390) from the polymeric support, allowing it to react with isonitriles to give pyrazoles (395). With electron-rich dienophiles, HDA reactions were also reported to have been performed to yield compound (393) (Scheme 80). 

Different novel resin-bound isonitriles have been prepared in order to perform Ugi multicomponent reactions on the solid phase. Thus, Kennedy et al. [346] prepared a novel resin-bound carbonate convertible isonitrile (CCI) that was applied in the preparation of constrained 2,5-diketopiperazine and l,4-benzodiazepine-2,5-dione libraries in parallel 80-well format The first step of the synthetic strategy was a Ugi reaction with a wide variety of amines, aldehydes, and carboxylic acids. Further manipulations of the Ugi MCR products were achieved after basic cleavage from the resin. 

In acyclic systems, reductions of the ketone group of 1.155 (Y = COR) give poor selectivities. Reactions of o-substituted aldehydes 1.155 (Y = CHO) with organomagnesium reagents, perfluoroalkyllithiums or nitromethane [540] or chloracetophenone [540, 544] anions are very selective. Such is also the case for their reactions with functionalized isonitriles [540], silyl enolethers or thioketene acetals in the presence of Lewis acids [545, 546], or in B aylis-Hillmann reactions [547],... 

Chlorination of phosphines. Both trialkyl- and triarylphosphines afford the dichlorides on reaction with triphosgene, which can then be used to convert epoxides to 1,2-dichloroalkanes, aldehydes to gem-dichlorides, amides to nitriles, formamides to isonitriles, ureas to carbodiimides, and amines to triphenylphosphoranylimines. 

The procedures in Sect. 4 give some representative examples of metallation of nitriles and isonitriles and reactions of the anionic intermediates with alkylating agents, epoxides, aldehydes, and ketones. Syntheses involving the generation of anionic intermediates (mostly in small concentrations) and their immediate further reaction with an electrophile present in the medium during this generation fall beyond the scope of this book. 

Our historical account would be incomplete without a few words about the surprisingly original four center condensation (4CC) method of Ivar Ugi [60]. The reaction of an acylamino acid, or peptide with an amine, an aldehyde and an isonitrile leads to a peptide derivative... 

Ganem and co-workers have developed the use of a Zn(OTf)2/TMSCl system to promote a variety of Passerini-type processes. The combination is active even for a,P-unsaturated aldehydes and usually problematic ketones. The promoter system was developed around a strategy of tethering nucleophilic functional groups to the isonitrile component to intercept the transient nitrilium species internally. Depending on the attached functionality either the a-hydroxy amide or a substituted oxazole could be obtained in high yield. For 1-isocyano-(2-morphilino)ethane (28), the reaction with... 

Scheme 3.63 depicts a proposed mechanism where amine 164 and aldehyde react to generate the expected Pictet-Spengler product 202 via the iminium species 205. Evidence for the intermediate formation of 202 was observed through LC/MS monitoring, and the reaction with the protonated isonitrile 203 affords the final exocyclic amidine moiety 204. 

Unsaturated ketones and aldehydes reacted with arylisonitrile in the presence of a GaCls catalyst giving imino lactones (Scheme 7.23) [45]. The reaction was triggered by the carbonyl activation with the Lewis acid. Although the use of stoichiometric Et2AlCl was previously reported for this transformation, GaCla could be recycled. Acetals also reacted with isonitrile giving the insertion products (Scheme 7.24) [46]. 

In a notable exception, Yudin has described the use of amphoteric aldehydes (178) in an Ugi MCR with isonitriles and linear peptides (179) to prepare a series of modified peptidomimetie macrocycles (180) with ring sizes from 9 to 18 atoms (Scheme 11.24). These compounds, via nucleophilic attack on the aziridine, also can be employed as intermediates for further reactions and, hence, provide access to additional structural diversity suitable for library production. Towards this end, the sequence was successfully transferred to an automated mierofluidies platform. The process did not need to be performed under high dilution eonditions (0.2 M). More recently, this approach was applied sueeessfully to the synthesis of bityclic peptidomimetie derivatives, for example 181, in whieh macrocyclization and then disulfide formation were best eondueted in solution after the solid phase MCR to avoid side reaetions. ... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

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