Enolizable aldehydes

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

Acetamido ketones have been prepared in a multicomponent reaction from aromatic aldehydes, enolizable ketones (acetophenone and propiophenone), and acetyl chloride in acetonitrile over Nafion-H1002 [Eq. (5.363)]. High yields are achieved under mild conditions and the catalyst proved to be recyclable. 

Early attempts to solve this problem focused on the use of weaker bases, such as Cs2C03 or K3P0460. Catalytic aminations conducted with these bases are possible in the presence of esters, aldehydes, enolizable ketones and nitro functional groups on the aryl halide. Alternatively, the functional group tolerance has been shown to be improved... 

BiCla in situ generated from the procatalyst BiOCl was proved to be very efficient in the catalyzed one-pot multicomponent synthesis of P-acetamido ketones from a variety of aromatic aldehydes, enolizable ketones, acetyl chloride, and aceto or benzonitrile (Equation 13) [33cj. 

The modification of the Peterson reaction using an N-trimethylsilylamide anion instead of an a-silyl carbanion offers a promising route to the corresponding imines. Treatment of N-(p-tolyl)-N-trimethylsilylamide anion with carbonyl compounds yields the corresponding ketimines [400]. In particular, LiHMDS has been utilized for the preparation of N-trimethylsilylimines, which are useful as masked imine derivatives in the synthesis of yS-lactam antibiotics [401-407]. Reactions of LiHMDS with non-enolizable aldehydes, enolizable aldehydes, ketones, a diketone, and a-keto esters give the respective imines (Scheme 2.153) [408-413]. Chloro-trimethylsilane is added to convert the generated lithium trimethylsilanolate into hexamethyldisiloxane. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The in situ cyanosilylation of p-an1saldehyde is only one example of the reaction which can be applied to aldehydes and ketones in general. - The simplicity of this one-pot procedure coupled with the use of inexpensive reagents are important advantages over previous methods. The silylated cyanohydrins shown in the Table were prepared under conditions similar to those described here. Enolizable ketones and aldehydes have a tendency to produce silyl enol ethers as by-products in addition to the desired cyanohydrins. The... 

Claisen-Schmidt reaction (Section 18.10) A mixed aldol condensation in which an aromatic aldehyde reacts with an enolizable aldehyde or ketone. 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

The Barbier-type modification17, in which the allyl Grignard reagent is produced in the presence of a carbonyl compound, seems not to be suitable for enolizable aldehydes. Some... 

The present procedure illustrates the facile demethylation of methyl aryl ethers by lithium diphenylphosphide.3 This reaction is specific for methyl ethers and may be carried out in the presence of ethyl ethers in high yield.4 Use of excess reagent allows cleavage in the presence of enolizable ketones.5 In the present case, the cleavage may be performed without protection of the aldehyde, but two equivalents of reagent are required, and the yield is reduced to ca. 60%. 

Enolizable compounds can be used for Meerwein reactions provided that the keto-enol equilibrium is not too far on the side of the ketone for example, P-dicar-bonyl compounds such as acetylacetone are suitable (Citterio and Ferrario, 1983). The arylation of enol esters or ethers (10.12) affords a convenient route for arylating aldehydes and ketones at the a-carbon atom (Scheme 10-48). Silyl enol ethers [10.12, R = Si(CH3)3] can be used instead of enol ethers (Sakakura et al., 1985). The reaction is carried out in pyridine. 

Note. This sequence succeeds with both aldehydes and ketones, but fails with readily enolizable ketones and enones. 

Non-enolizable aldehydes are transformed into N-trimethylsilylaldimines on treatment with lithium hexamethyldisilazide (22) such imines provide valuable routes to N-unsubstituted / -lactams ... 

Corey and Chaykovsky were the first to investigate the reaction of dimethyl sulphoxide anion (dimsyl anion) with aldehydes and ketones400,401. They found that the reaction with non-enolizable carbonyl compounds results in the formation of /1-hydroxyalkyl sulphoxides in good yields (e.g. Ph2CO—86%, PhCHO—50%). However, with enolizable carbonyl compounds, particularly with cycloalkanones, poor yields of hydroxyalkyl products are observed (e.g. camphor—28%, cyclohexanone—17%, but... 

A novel and versatile method for preparing polymer-supported reactive dienes was recently developed by Smith [26]. PS-DES (polystyrene diethyl-silane) resin 28 treated with trifluoromethanesulfonic acid was converted to a polymer-supported silyl triflate 29 and then functionalized with enolizable a,jS-unsaturated aldehydes and ketones to form silyloxydienes 30 and 31 (Scheme 4.4). These reactive dienes were then trapped with dienophiles and the Diels Alder adducts were electrophilically cleaved with a solution of TFA. 

Likewise, enolizable aldehydes such as isobutyraldehyde or 2-phenacetaldehyde are converted by silylated morpholine 294, in the presence of TMSOTf 20, into N,N-acet-als such as 466 in nearly quantitative yield [57]. The thermal and, in particular, Lewis acid-catalyzed conversion of 0,N-acetals such as 124 into N,N-acetals such as 464a obviously proceeds via the intermediate 467 and iminium salts such as 468, which readily add nucleophiles, as discussed in Sections 5.1.3 and 5.2 (Scheme 5.20). 

This enolate can then react with a plethora of electrophiles, setting a new stereocenter by a diastereoface-selective reaction. The simplest electrophile to trap enolate 71 is H" ", which can, for example, originate from methanol [89] or diphenyl acetaldehyde (as a readily enolizable aldehyde) [90] leading to the acy-lated catalyst species (Fig. 38). The free catalyst is regenerated by acyl-group transfer to methanol(ate) or the aldehyde-derived enolate, producing methyl or enolesters 72/73 in good yields and enantioselectivities. 

Allyl vinyl ethers have been prepared using the ylide (101) but only from non-enolizable carbonyl compounds. The ethers rearrange on heating to give a-allyl aldehydes, e.g. (102). 

The reaction, formally speaking a [3 + 2] cycloaddition between the aldehyde and a ketocarbene, resembles the dihydrofuran formation from 57 a or similar a-diazoketones and alkenes (see Sect. 2.3.1). For that reaction type, 2-diazo-l,3-dicarbonyl compounds and ethyl diazopyruvate 56 were found to be suited equally well. This similarity pertains also to the reactivity towards carbonyl functions 1,3-dioxole-4-carboxylates are also obtained by copper chelate catalyzed decomposition of 56 in the presence of aliphatic and aromatic aldehydes as well as enolizable ketones 276). No such products were reported for the catalyzed decomposition of ethyl diazoacetate in the presence of the same ketones 271,272). The reasons for the different reactivity of ethoxycarbonylcarbene and a-ketocarbenes (or the respective metal carbenes) have only been speculated upon so far 276). 

In a similar one-pot synthesis of substituted quinolines, Wang et al. used molecular iodine (1 mol%) to catalyze the reaction between enolizable aldehydes and imines in refluxing benzene. The advantage of this method is that it is metal free, takes place with short reaction times, and produces good yields <06TL3127>. 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

When treated with DBU at elevated temperature, l-[(benzotriazol-l-yl)methyl -2-aminopyridine salts 741 eliminate rather the N-H proton than the C-H one. Intermediates 742 can be trapped with aromatic aldehydes to create betaines 743. The consecutive cyclocondensation and elimination of benzotriazole results in formation of imidazolo[l,2-rz]pyridines 744 in good yields (Scheme 117) <2000JOC9201>. Aldehydes with enolizable a-protons fail to give bicyclic systems 744, producing corresponding enamines instead. 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

In this reaction, the CH2C12/DMF solvent (9 1) suppresses the undesirable Claisen condensation and increases the yield of 2,2-difluoro-3-hydroxyesters. It is notable that high yields are obtained even with ketones and enolizable aldehydes, which do not undergo the Reformatsky reaction. 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

Peterson methylenation (10, 433 11, 581). Methylenation with trimethyl-silylmethyllithium, (CH3),SiCH2Li, is not widely used in synthesis because of lack of selectivity and moderate yields. However, a modified reagent prepared from (CH3)3SiCH2Li and CeCl, adds to aldehydes or ketones (even enolizable ones) to form adducts in generally high yield, particularly in the presence of TMEDA. The 2-hydroxysilanes are converted into methylene compounds by aqueous HF (with or without pyridine).4... 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

The A-trimethylsilylimines 68 (R = t-Bu, Ph, 2-MeCgH4 or 2-BrC6H4), which are prepared by the reaction of non-enolizable aldehydes with lithium bis(trimethylsilyl)amide, followed by trimethylsilyl chloride, undergo pinacolic coupling induced by NbCLt 2THF to yield the vicinal diamines 69 as mixtures of dl- and meso-isomers, in which the former predominate. Another method for the preparation of 1,2-diamines is by the combined action of the niobium tetrachloride/tetrahydrofuran complex and tributyltin hydride on cyanides RCN (R = /-Hu. Ph, cyclopentyl or pcnt-4-en-l-yl) (equation 32)82. 

Trimethylsilylation of enolizable carbonyl compounds and alcohols has also been accomplished by the fluoride ion promoted reaction with hexamethyldisilane and ethyl trimethylsilylacetate [48, 49], with high stereospecificity giving Z-enol ethers from ketones [50]. l-Trimethylsilyl-(l-trimethylsilyloxy)alkanes, produced from the reaction of aldehydes with hexamethyldisilane, undergo acid-catalysed hydrolysis during work up to yield the trimethylsilylcarbinols [51]. In the case of aryl aldehydes, the initially formed trimethylsiloxy carbanion produces the pinacol (Scheme 3.1). 

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