Ketones, reaction with isonitriles

As with the aryl compounds the reaction scheme is simplified for the sake of clarity. The reactions observed are various and include reductive coupling (ketones, nitriles), insertion (diphenylacetylene, isocyanate, isonitrile, CO2 and CO), and disproportionation (diphenylacetylene, CS2). The course of the reactions and the complexity of the product mixtures strongly depend on the nature of the alkyl groups and the substituents on the substrate molecule. As examples we will discuss reactions with ketones, acetylenes and CO. The reaction with ketones strongly resembles the coupling of nitriles R C=N on Cp2TiR (R = aryl). The coupling proceeds more slowly when R, R and R" increase in size. 

A very common combination in Pd-catalyzed domino reactions is the insertion of CO as the last step (this was discussed previously). However, there is also the possibility that CO is inserted as the first step after oxidative addition. This process, as well as the amidocarbonylation, the animation, the arylation of ketones, the isomerization of epoxides, and the reaction with isonitriles will be discussed in this section. 

The synthetic utility of the carbonylation of zirconacycles was further enhanced by the development of a pair of selective procedures producing either ketones or alcohols [30] and has been extensively applied to the synthesis of cyclic ketones and alcohols, most extensively by Negishi [22—27,29—33,65,87,131—134], as detailed below in Section I.4.3.3.4. The preparation of unsaturated aldehydes by carbonylation with CO is not very satisfactory. The use of isonitriles in place of CO, however, has provided a useful alternative [135], and this has been applied to the synthesis of curacin A [125]. Another interesting variation is the cyanation of alkenes [136]. Further developments and a critical comparison with carbonylation using CO will be necessary before the isonitrile reaction can become widely useful. The relevant results are shown in Scheme 1.35. 

The steroid may be bifunctionalized with any of the functional groups participating in the Ugi reaction, i.e., isonitrile, amine, aldehyde (ketone), and carboxylic acid, and having two different functionalities on one steroid building block even increases the possibilities. 

With excess HFA a dioxolaneimine 99a is formed from a typical isonitrile reaction mentioned in previous sections. Acidification yields the unsubstituted five-membered ring 99, which is the parent compound of alkylated dioxolanes 99b-e available from isonitriles (R = Me, Et, t-Bu, c-CgHu) 111, 188). Whether the imine structure 99 or the ketone structure 101 has to be assigned to the hydrolysis product is not known. The Chapman rearrangement has been proved in the following system [Eq. (86)] 190). Treatment of 98 with strong bases like l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) yields a spirocyclic compound 100 with elimination of HCN the structure of 100 has been derived by spectroscopic methods 193). The reaction of 98 with HFA X HjO (91) in sulfuric acid produces a l,3-dioxolan-(4)one 112). 

Summary The thermally stable silylene Si[ N(CH2tBu) 2C6H4-l,2] 1 readily undergoes addition reactions with compounds containing CO and CN multiple bonds (e g., ketones, imines, nitriles or isonitriles). The products, most of them characterized by their X-ray structures, contain novel skeletal frameworks SiCOSi, SiOSiCCC, SiCNSi, CSi(CN),... 

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],... 

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. 

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... 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Cyclohexylisonitrile inserts selectively into the endocyclic vinyltitanium bond of a-methylenetitanacyclobutene complexes 37, although the reaction fails for many other isonitriles (Equation 12) <19960M1176>. No insertion occurs upon treatment with nitriles or ketones, in contrast to the established reactivity of typical titanacyclobutenes <1996CHEC-II(lb)887>. The reaction of fert-butylisonitrile with 1,9-anthracenediyl-zirconocene complex 38 proceeds exclusively by insertion into the terminal ring zirconium-carbon bond, presumably due to steric considerations (Equation 13) <2000JA9880>. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

The chemistry of 2 and 3 has been investigated over the past ten years. Thus, for example, reactions of these species with nitriles, isonitriles, ketones, 1,4-dihetero-1,3-dienes, and many other multiple bond systems have been realized [2], However, the important groups of the alkenes and 1,3-dienes were missing from this series. The objective of the present work was to rectify this omission. 

Tosylmethyl isocyanide (TsMIC) (120) is an easily prepared sulfone with a wide repertoire of useful reactions thus, TsMIC may be converted to ketones (121), alkanes (122) and alicyclic ketones (123) and (124), as shown in Scheme 52. The alicyclic compounds formed may be either small rings, e.g. cyclobutanone (123), or medium-sized rings like the 10-membered compound (124). In these reactions, the utility of TsMIC (120) is dependent on the good leaving group capacities of the tosyl and isonitrile moieties. The reagent (120) can also be used to synthesise heterocycles, e.g. oxazoles (125) (Scheme 53). 

Passerini reaction The formation of an a-acyloxyamide when an isonitrile is treated with a carboxylic acid and an aldehyde or ketone. Related to the Ugi reaction. 

A series of diaza-titanacyclopentene and related complexes (Scheme 221) can be generated by coupling reactions of mono-Cp derivatives with imines, followed by the incorporation of a second substrate, such as ketone or isonitrile. In these reactions a chiral center is generated at the coupled imine carbon atom with potential applications to generate further chiral centers.601,602... 

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