Oxygen nucleophiles formation

Nucleophilic addition of oxygen nucleophiles formation of hydrates and acetals... 

The Johnson group began by examing the solvolysis of 5-hexenyl nosylate (65) in formic acid. This reaction gave only small amounts of cyclohexanol and cyclohexene, but illustrated that that cyclization was possible. Solvolysis of diene 66 gave cyclohexanol 67 as the major product. This product results from addition of the electrophilic carbon (Ci) and oxygen nucleophile (formate) across the fm r-olefin. Decalins 68-70 were produced in low yields, but it was notable that only fm -fused decalins were produced. This observation was consistent with an addition of electrophilic carbon (Ci) and nucleophilic carbon (Cio) across the af-olefin (see B in Steroids-12). 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

With Oxygen Nucleophiles Aziridine ring-opening of 111 (Scheme 3.42) with water in the presence of a catalytic amount of TsOH gave the corresponding (3-hydrox-yphenylalanine derivative 121 in 72% yield as the major isomer [74], Treatment of N-(p-tolylsulfmyl) aziridine-2-carboxylates with TFA and subsequent aqueous workup resulted in the formation of j3-substituted serine derivatives [62, 63, 101]. Under these reaction conditions, not only was the aziridine ring opened, but also the N-sulfmyl group was removed treatment of 122 (Scheme 3.43) with TFA at 73 °C, for example, afforded 123 in 75% yield [101],... 

G. Other Oxygen Nucleophiles 10-31 Formation of Oxonium Salts... 

Sections D through H of Scheme 3.2 involve oxygen nucleophiles. The hydrolysis reactions in Entries 12 and 13 both involve benzylic positions. The reaction site in Entry 13 is further activated by the ERG substituents on the ring. Entries 14 to 17 are examples of base-catalyzed ether formation. The selectivity of the reaction in Entry 17 for the meta-hydroxy group is an example of a fairly common observation in aromatic systems. The ortho-hydroxy group is more acidic and probably also stabilized by chelation, making it less reactive. 

Although transition metal-catalyzed allylic alkylation has become one of the most powerful methods in chemical synthesis, the formation of ether bonds using this process has been slow to evolve.119-121 The main reasons for this disparity are the lower nucleophilicity and higher basicity of oxygen nucleophiles, particularly those derived from aliphatic alcohols, compared to their carbon or nitrogen analogs. However, this notion has rapidly been revised, as recent advances in the O-allylation area have largely addressed the issue of the reactivity mismatch between the hard alkoxide and the soft 7r-allylmetal species to provide a considerable body of literature. 

While the alkoxymetallation process has typically been affected by highly electrophilic metal salts, high-valent metal species generated by an oxidative addition have also been used to activate alkynes through the formation of 7r-complexes. In such cases, the metal-carbon emerging from the attack of an oxygen nucleophile may enter a reaction manifold that leads to an additional C-G bond formation rather than a simple protic quench. This approach, pioneered by Arcadi and Cacci, has proved to be a powerful strategy for the synthesis of structurally diverse substituted... 

Like alkynes, a variety of mechanistic motifs are available for the transition metal-mediated etherification of alkenes. These reactions are typically initiated by the attack of an oxygen nucleophile onto an 72-metalloalkene that leads to the formation of a metal species. As described in the preceding section, the G-O bond formation event can be accompanied by a wide range of termination processes, such as fl-H elimination, carbonylation, insertion into another 7r-bond, protonolysis, or reductive elimination, thus giving rise to various ether linkages. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

Peptide bond formation involves activation of the carboxyl group of an amino acid residue, followed by aminolysis of the activated residue by the amino group of a second amino acid residue. Two types of activated molecules are recognized those that are not detectable but are postulated and those that are detectable and can be isolated. Postulated intermediates are necessary to account for the formation of the detectable intermediates. The postulated intermediates are consumed as fast as they are formed, either by aminolysis by an amino group or by nucleophilic attack by an oxygen nucleophile, which produces activated molecules that are also immediate precursors of the peptide. More than one activated compound may be generated by a postulated intermediate. Activated esters, acyl halides and azides, and mixed and symmetrical anhydrides are isolatable activated compounds that are generated from postulated intermediates. Peptides are produced by one of three ways ... 

Carbon-Oxygen Bond Formation Hydroxyl or carboxylate groups can participate in a ring-closure reaction by an intramolecular nucleophilic attack to a generated electrophilic center as already described in Schemes 1 and 3. 

A wide range of carbon, nitrogen, and oxygen nucleophiles react with allylic esters in the presence of iridium catalysts to form branched allylic substitution products. The bulk of the recent literature on iridium-catalyzed allylic substitution has focused on catalysts derived from [Ir(COD)Cl]2 and phosphoramidite ligands. These complexes catalyze the formation of enantiomerically enriched allylic amines, allylic ethers, and (3-branched y-8 unsaturated carbonyl compounds. The latest generation and most commonly used of these catalysts (Scheme 1) consists of a cyclometalated iridium-phosphoramidite core chelated by 1,5-cyclooctadiene. A fifth coordination site is occupied in catalyst precursors by an additional -phosphoramidite or ethylene. The phosphoramidite that is used to generate the metalacyclic core typically contains one BlNOLate and one bis-arylethylamino group on phosphorus. 

Baldwin, J. E. Thomas, R. C. Kruse, L. I. Silberman, L. Rules for ring-closure Ring formation by conjugate addition of oxygen nucleophiles. J. Org. Chem. 1977, 42, 3846-3852. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

The exchange of a halogen to a classical nitrogen or oxygen nucleophile usually proceeds readily on the purine skeleton, without the necessity of using a transition metal catalyst. There are certain cases, however, where the palladium catalyzed carbon-heteroatom bond formation might take preference over noncatalysed methods. Inosine derivatives, for example,... 

Whichever method is employed, the key step is the formation of an alkoxy-sulfonium salt, 7, by a displacement reaction involving dimethyl sulfoxide as an oxygen nucleophile. (Notice that the S—O bond, like the C=0 bond, is... 

Cyclizations of substrates in which internal oxygen nucleophiles have been attached to unsaturated alcohols provide a method for stereoselective formation of acyclic 1,2- and 1,3-diol functionalities, as outlined in Scheme 2. 

The addition of oxygen nucleophiles (peroxides) to a,(i-unsaturated ketones is also catalyzed by the lanthanoid catalysts, leading to the formation of the corresponding epoxides with up to 96% ee (Scheme 8D.19) [41]. This reaction shall be reviewed in another chapter. 

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