Reagents metal acetylide

Reaction of estrone with a metal acetylide affords 17a-ethynyl-173-hydroxy-estradiol (etbynylestradiol, 30a EE). This compound is equipotent with estradiol by subcutaneous administration, but it is 15 to 20 times as active when administered orally. Ethynylation of the methyl ether of estradiol analogously affords mestranol (30b), It should be noted that the same factors apply in these reactions as in previously discussed reductions at 17 almost the sole products of these reactions are those which result from attack of reagent from the least hindered a side of the steroid. Ethynylestradiol and mestranol are of special commercial significance since the majority of the oral contraceptives now on sale incorporate one or the other of the compounds as the estrogenic component. 

Especially in the early steps of the synthesis of a complex molecule, there are plenty of examples in which epoxides are allowed to react with organometallic reagents. In particular, treatment of enantiomerically pure terminal epoxides with alkyl-, alkenyl-, or aryl-Grignard reagents in the presence of catalytic amounts of a copper salt, corresponding cuprates, or metal acetylides via alanate chemistry, provides a general route to optically active substituted alcohols useful as valuable building blocks in complex syntheses. 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

Owing to their stability and low nucleophilicity, metal acetylides are less reactive toward Cjq than other lithium organyls or Grignard reagents [11]. Though the reaction is slower and higher reaction temperatures are necessary, various acetylene derivatives of Cjq could be obtained. The first acetylene Cjq hybrids were (trimethyl-silyl)ethynyl- and phenylethynyl-dihydro[60]fullerene, synthesized simultaneously... 

Sodium acetylides are the most common reagents, but lithium, magnesium and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylene diamine complex. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. 1,4-Diols can be prepared by treatment of aldehyde with dimetalloacetylenes. 

Terminal alkynes are acidic, and the end hydrogen can be removed as a proton by strong bases (e.g. organolithiums, Grignard reagents and NaNH2) to form metal acetylides and alkynides. They are strong nucleophiles and bases, and are protonated in the presence of water and acids. Therefore, metal acetylides and alkynides must be protected from water and acids. 

Zinc(II) halide mediated Gaudemar/Normant-type allylmetallation to metal acetylide is also an efficient route. As shown in Scheme 38, the obtained. sp2-gcminated organodizinc reagent reacts with various electrophiles83. 

Hiickel band calculations, rigid-rod transition metal-acetylide polymers, 12, 371-372 Human health, tin toxic effects, 12, 637 Hybrid magnets, metallocene-containing bimetallic M(II)—Cr(II) oxalates, 12, 427 bimetallic M(II)-Fe(III) oxalates, 12, 432 bimetallic M(III)-Ru(III) oxalates, 12, 435 materials, 12, 437 properties, 12, 425 trimetallic oxalates, 12, 436 Hydantoins, with lead reagents, 3, 888 Hydration... 

Asymmetric alkynyl additions to aldehydes by prior, separate generation of the alkynylides (e.g. dialkylzinc reagents) have recently been reviewed and are a topic of current research [10], They will not be covered in the context of this chapter. Instead, in line with the theme of this book, this chapter will focus on the metala-tion of terminal alkynes by activation of the terminal C-H and the use of the corresponding metal acetylides in aldehyde and ketone addition reactions. 

Metallation of alkynylcyclopropanes at the acetylenic end is accomplished either by deprotonation or via metal-halide exchange reaction with strong bases. Metallation of ethynylcyclopropane may be affected by KOH in DMF, ethereal EtMgBr or preferably BuLi in THF (equation 151) All three metal acetylides react with methyl ketones to give the corresponding alcohols. However, the instability of cyclopropyl ketones towards bases, especially at the reaction conditions required by KOH (20 °C, 6h), and the sensitivity of cyclopropenyl double bonds in cyclopropenyl ketone derivatives towards addition reactions of alkylmagnesium compounds, make the alkyllithium (-78 °C, instant reaction) superior to the other reagents. 

Acetylenic carbinols are prepared by the interaction of sodium acety-lides or acetylenic Grignard reagents with aldehydes. The formation and reaction of the metallic acetylide may be combined into a single operation. For example, an alkylacetylene in ether solution is treated successively with ethylmagnesium bromide and formaldehyde to give the acetylenic alcohol such as 2-heptyn-l-ol (82%). ... 

The ring opening of epoxides with carbon nucleophiles represents a Scheme 2.21 useful way of making C-C bonds. Grignard, organolithium and organocopper reagents and alkali metal acetylides have all been used for this purpose. This type of reaction has been used to form carbocyclic systems. 

Several organometallic acetylene compounds are prepared by the replacement of acetylenic Grignard reagents or alkalimetal acetylides with metal halides (MX) where M is B, AI, Si, Ge, Sn, P, As, Sb, Cu, or Ag [128-131]. They are also synthesized by metallation of metal halides and R3AI or R2Hg (see Table 4, entries 40 and 41). Metal acetylides of the type (RC C)3B or (RC C)3A1 are unstable and are isolated as complex with amines or ethers. Note that many of the precious metal acetylides are extremely explosive, and the appropriate precautions should be taken for their handling and storage. 

The most important organometallic reagents used for the carbon-carbon bond formation in carotenoid synthesis are the metal acetylides, metal alkenyls and the Gngnard reagents. However the Reformatsky reaction has also been applied and recently also transition metals such as Pd, Ni, Cu and especially low valent Ti have been used. The application of organometallic reactions for the synthesis of carotenoids and retinoids has recently been reviewed [39]. 

Vinylidene (3), as well as related vinylidenes, have been obtained in good yields via the addition of electrophiles to acetylide complexes. The procedure below allows one to make these vinylidenes without the use of alkali metal acetylide reagents. Solid vinylidene 3 is not sensitive to air or water making it an attractive starting material. 

The Huisgen 1,3-dipolar cycloaddition of azides to alkynes or nitriles as dipolaro-philes, resulting in 1,2,3-triazoles or tetrazoles, is one of the most powerful click reactions . A limitation of this approach, however, is the absence of regiospecificity normally found in thermal 1,3-cycloaddition of nonsymmetrical alkynes this leads to mixtures of the different possible regioisomers. In other reports, classical 1,3-dipolar cycloadditions of azides to metal acetylides, alkynic Grignard reagents, phosphonium salts and acetylenic amides have been described. Extended reaction times and high temperatures are required in most of the reactions, but they can also be performed more effectively with the aid of microwave irradiation. The main results reported are reviewed in this section. 

By the judicious choice of reaction conditions, it is possible to control the regioselectivity and stereoselectivity of acetylide addition to a keto group. For instance, the reaction of the diketone 14 with lithium acetylide in THF at low temperatures gives the C(9)-acetylenic alcohol 75 (Scheme 4) [10], and a stereospecific synthesis of the acetylenic triol 16 is achieved by the condensation of the lithium reagent 77 derived from the isopropenylmethyl (IPM) ether of ( j-3-methylpent-2-en-4-yn-l-ol (18) with the optically active ketone 19, followed by acid-catalysed removal of the protecting groups [11]. Only 3% of the C(6)-diastereoisomer of 16 was detected (Scheme 5). The preparation of 16 is described in Worked Example 2. Table 1 lists a selection of a-hydroxyalkynes that have been prepared from metal acetylides. 

The condensation of alkali metal acetylides or of allylic or benzylic organoalkalis generally occurs smoothly with alkyl iodides and to some extent also with alkylbromides. For one thing, this has to do with the lower basicity of such reagents. The permanent menace to promote dehydrohalogenation of the substrate by p-elimination is thus obviated or at least diminished. Furthermore, the concentrated and sterically well-accessible electron density at an acetylenic terminus is as advantageous for a controlled Sw2-like attack on the electrophile as is the diffuse ("soft") but mobile electron density at the metal-binding carbon of resonance-delocalized species. 

The last isomerization is remarkable in that the triple bond can shift through a long carbon chain to the terminus, where it is fixed as the (kinetically) stable acetylide. The reagent is a solution of potassium diami no-propyl amide in 1,3-di-aminopropane. In some cases alkali metal amides in liquid ammonia car also bring about "contra-thermodynamic" isomerizations the reactions are successful only if the triple bond is in the 2-position. 

Alkynyl anions are more stable = 22) than the more saturated alkyl or alkenyl anions (p/Tj = 40-45). They may be obtained directly from terminal acetylenes by treatment with strong base, e.g. sodium amide (pA, of NH 35). Frequently magnesium acetylides are made in proton-metal exchange reactions with more reactive Grignard reagents. Copper and mercury acetylides are formed directly from the corresponding metal acetates and acetylenes under neutral conditions (G.E. Coates, 1977 R.P. Houghton, 1979). 

It occurs with the alkyls, aryls or acetylides of metals more electropositive than magnesium, but including Grignard reagents, and is often carried out by adding a solution of the organometallic compound in an inert solvent to a large excess of powdered, solid C02 it is a particularly useful method for the preparation of acetylenic acids. The Kolbe-Schmidt reaction (p. 291) is another example of carbanion carbonation. 

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