Alkyne-aldehyde additions

Activation of sp C—H Bonds The activation of sp C—H bonds has been extensively studied for many years. However, asymmetric additions of sp C—H bonds to unsaturated bonds have been studied only since 2003 or so. Since the work of Yamaguchf and later Carreira, the use of stoichiometric (and more recently catalytic) Lewis acids in the presence of an excess amount of base for alkyne-aldehyde additions has also been investigated extensively these studies... 

Unlike previous alkyne-aldehyde additions [23], the generation of an alkynyl carbanion is unlikely owing to the large pK, difference between the terminal acetylene and the solvent water [24]. A mechanism was proposed involving the simultaneous activation of the C-H bond of alkyne by the ruthenium catalyst and the aldehyde carbonyl by the indium ion. The ruthenium intermediate then underwent Grignard-type addition followed by an in situ hydrolysis in water to give the desired carbonyl addition product and regenerated the ruthenium and indium catalysts to catalyze further reactions (Fig. 3). 

Enynes 71 react with aldehydes 61 in the presence of the [Ni(COD)J/SIPr catalytic system to afford two distinct products 72 and 73 (Scheme 5.20) [20b], The enone 72 is derived from aldehyde addition with the alkyne moiety while the adduct 73 arises from the aldehyde addition with the alkene moiety. The product distribution is dependent on the substituent on either the alkyne or alkene moieties. The reaction between 71 and ketones 74 led to the unprecedented formation of pyrans 75 (Scheme 5.20). The reaction showed to be highly regioselective in aU the cases, the carbonyl carbon was bound to the olefin. 

Because organophosphorus compounds are important in the chemical industry and in biology, many methods have been developed for their synthesis [1]. This chapter reviews the formation of phosphorus-carbon (P-C) bonds by the metal-catalyzed addition of phosphorus-hydrogen (P-H) bonds to unsaturated substrates, such as alkenes, alkynes, aldehydes, and imines. Section 5.2 covers reactions of P(lll) substrates (hydrophosphination), and Section 5.3 describes P(V) chemistry (hydrophosphorylation, hydrophosphinylation, hydrophosphonylation). Scheme 5-1 shows some examples of these catalytic reactions. 

This system also worked well in ionic liquids.518 Li etal. found silver-phosphine complexes to promote aldehyde-alkyne coupling in water. When triphenylphosphinesilver chloride was used as a catalyst in water, the only detected product was the aldehyde addition product instead of the adduct derived from imine (Scheme 111).519... 

Closely related to both allyl carbenoids and the allenyl carbenoids discussed above, propargyl carbenoids 101 are readily generated in situ and insert into zirconacycles to afford species 102 (Scheme 3.27), which are closely related to species 84 derived from allenyl carbenoids [65], Protonation affords a mixture of allene and alkyne products, but the Lewis acid assisted addition of aldehydes is regioselective and affords the homopropargylic alcohol products 103 in high yield. Bicydic zirconacyclopentenes react similarly, but there is little diastereocontrol from the ring junction to the newly formed stereocenters. The r 3-propargyl complexes derived from saturated zirconacycles are inert towards aldehyde addition. 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

In addition to alkynes, aldehydes can undergo silylformylation (Equation (27)). Although this reaction pattern was previously carried out with cobalt catalysts, the most important merit in the use of [Rh(cod)Gl]2 or [Rh(GO)2Gl]2 is that the reaction proceeds under far milder conditions. Since such mild conditions make it possible to discriminate starting aldehydes 121 from resultant sterically demanding a-silyloxyaldehydes 122, adjustment of molar ratios of the starting substrates is unnecessary for isolation of product aldehydes. ... 

Metallation of alkyne, nucleophilic addition x to aldehyde (9), oxidation... 

Other nucleophiles that have been used in this context are acetylides (alkynes). The addition of those to iminium cations generated in situ from aldehydes and secondary amines accomplishes a gold(III)-catalyzed three-component coupling for the synthesis of propargylamines, as can be observed in equation (124). The reactions are performed in water or in tetrahydrofuran (THF) when supported catalysts are employed.Chiral prolinol derivatives as... 

Alkenyl, Alkynyl, Aryl and Related Acids. Vinylphosphonates are an important group of compounds that have found use in organic transformations. They are also useful reagents for the synthesis of biologically active systems. The synthesis of vinylphosphonates is varied. However additional convenient routes to them are always welcome. Four recent reports demonstrated that zirco-nacycles (180), readily available from diethyl 1-alkynylphosphonates, are very useful precursors of different vinylphosphonates. They react with alkynes, aldehydes, ketones acyl chlorides and nitriles to produce, in a highly stereo- and regio-selective manner, substituted vinylphosphonates (181), (182), (183) (184) and (185) respectively (Scheme 46). 

There are several attractive methods for the constmction of macrolides (Scheme 22). An intramolecular alkenylzinc/aldehyde addition from w-alkynal ester 144 in the presence of (-)-DAIB furnished 18-membered lactone 145, which led to (-(-)-aspicilin (146) [102]. In the total synthesis of 10-deoxymethynolide... 

Most unsaturated substances such as alkenes, alkynes, aldehydes, acrylonitrile, epoxides, isocyanates, etc., can be converted into polymeric materials of some sort—either very high polymers, or low-molecular-weight polymers, or oligomers such as linear or cyclic dimers, trimers, etc. In addition, copolymerization of several components, e.g., styrene-butadiene-dicyclo-pentadiene, is very important in the synthesis of rubbers. Not all such polymerizations, of course, require transition-metal catalysts and we consider here only a few examples that do. The most important is Ziegler-Natta polymerization of ethylene and propene. 

The synthesis of 252 began with Brown s asymmetric crotylation to aldehyde 261. The resulting homoallyl alcohol was converted benzyl ester 262, which was reduced to give lactol acetate 263. Axial allylation to 263 formed 2,6-trans-tetrahydropyran 264, which was subjected to ozonolysis to give an aldehyde. Addition of alkenylzinc, prepared by hydrozircona-tion of an alkyne 265, to the aldehyde mediated by chiral ligand 266 yielded allyl alcohol 267 with a 5.1 1 diastereoselectivity [110]. The stereochemistry of the major isomer was found, unexpectedly, to be the S-form at Cl7, which rendered the macrolactonization to adopt the Mitsunobu reaction. The iodide 252, prepared from 267 in three steps, reacted with... 

The retrosynthesis of an alkane TM generally begins with an FGI that adds a functional group of your choice (an alkyl halide, alkene, alkyne, aldehyde, or ketone), and continues with a disconnection consistent with that functional group. Addition of the functional group at a branch point will likely lead to a good disconnection, but its precise location is not critical since it will ultimately be removed. 

Formation of C-N bond has raised of interest in the scientific community in the last 10 years. In this context, the formation of enamides is a valuable protocol. In addition to conventional approaches that include condensation of amides and aldehydes, addition of amides to alkynes, acylation of imines, Curtius rearrangement of a,jS-unsaturated acyl azides, amide Peterson olefination, and Wittig and Horner-Wadsworth-Emmons reactions, several transition metal-catalyzed methods have been developed that allow the synthesis of enamides.Inspired by the analogous arylation of amines catalyzed by palladium or copper complexes (Buchwald-Hartwig reaction), a new approach for the synthesis of enamides has been published recently, which allows to prepare enamides from readily available starting materials (amides and vinyl halides) proceeding under very mild conditions. Thus, we decided to test the Porco-Buchwald amidation of vinyl halides in our synthesis [144-146]. 

Wipf and coworkers have used the Zr-Zn transmetalation, aldehyde addition methodology for the rapid, stereocontrolled preparation of a//-(E)-poly-enes [82] in the total syntheses of (+)-curacin A [83] and ( )-nisamycin [84]. Synthesis of the eastern side chain of ( )-nisamycin was accomplished in two steps from alkyne 79 (Scheme 17). Hydrozirconation of 79 followed by addition to cyclohexylcarboxaldehyde in the presence of dimethylzinc afforded the allylic alcohol 80. Elimination of the newly formed hydroxyl group was accomplished via the corresponding trifluoroacetate. Addition of alkenylzirconocenes... 

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). 

Interesting formation of the fulvene 422 takes place by the reaction of the alkenyl bromide 421 with a disubstituted alkyne[288]. The indenone 425 is prepared by the reaction of o-iodobenzaldehyde (423) with internal alkyne. The intermediate 424 is formed by oxidative addition of the C—H bond of the aldehyde and its reductive elimination affords the enone 425(289,290]. 

Diaryl disulfides and diselenides add to alkynes to afford the (Z)-l, 2-bis(ar-ylthio)alkenes 193 and (Z)-l,2-bis(arylseleno)alkenes 194. Under CO pressure, carbonylative addition takes place to give thio esters and the selenoketones 195[I07], The selenoketones are converted into the /J-seleno-a, 3-unsaturated aldehydes 196 by Pd-catalyzed hydrogenolysis with HSnBu3[108,109],... 

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