Intramolecular reaction epoxide alkylation

Scheme 4.16 Intramolecular reactions of alkyl azides with epoxides.

Alkyl azides have been involved in the synthesis of indolizidinone derivatives in several ways. One example (Scheme 7) is the intramolecular Schmidt reaction between alkyl azides and ketones which can be used to transform azidoketone 24 into the corresponding indolizidinones 26 through intermediate 25 <2001JOC886> or with epoxides to obtain the indolizidine 27 <2004JOC3093>. 

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

Recently, a new intramolecular hydroxyl sulfide (325) catalyzed MBH reaction, using alkyl halides or epoxides 327 as electrophiles and lactams or lactones 326 as substrates, was performed successfully under the basic conditions (Scheme 2.178). However, the procedure failed for aldehydes when a conventional acid (TiCU)-catalyzed procedure was used. ... 

A new synthesis of chiral cyclopentanoid intermediates involves the stereospecific reaction of the carbanion (30) with the tartaric acid derived epoxide (31). An intramolecular enolate anion alkylation, induced by a Michael reaction, has been utilized in the preparation of cyclopentanes (Scheme 6). Additionally, variation... 

Applications Based on Deprotonation of Selenoketals R Se CHB — alkyl) and Seleno-orthoesters. Deprotonation, usually with KDA, of selenoketals (PhSe)2CHR (R = alkyl) gives carbanions that react efficiently with common electrophiles [primary alkyP - and benzyl halides, aldehydes, ketones, and (for R = alkyl or H) epoxides ]. A few of the resulting selenoketals have been hydrolysed under very mild conditions. Carbanions derived from selenoketals undergo intramolecular reactions [e.g. (49)] when appropriately substituted, and can be used in the synthesis of silyl enol ethers, e.g. (50). ... 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

Until 1968, not a single nonenzymic catalytic asymmetric synthesis had been achieved with a yield above 50%. Now, barely 15 years later, no fewer than six types of reactions can be carried out with yields of 75-100% using amino acid catalysts, i.e., catalytic hydrogenation, intramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosilylation, and epoxidations. 

Stable epoxides of op -unsaturated carbonyl and nitro compounds have been obtained. For example, compound 24 reacts with hydrogen peroxide or alkyl hydroperoxides in the presence of a base to give 25.63 The reaction is believed to proceed by Michael addition of the hydroperoxide anion to 24, and subsequent intramolecular displacement of hydroxide by the anion of the carbon atom that bears the nitro group (Scheme 10). 

The structure of the titanium-tartrate derivatives has been determined,25,26,31 37 and based on these observations together with the reaction selectivity, a mechanistic explanation has been proposed (Scheme 9.3).38 The complex 1 contains a chiral titanium atom through the appendant tartrate ligands. The intramolecular hydrogen bond ensures that internal epoxidation is only favored at one face of the allyl alcohol. This explanation is in accord with the experimental observations that substrates with an a-substituent (b = alkyl a = alkyl or hydrogen) react much slower than when this position is not substituted (b = hydrogen). 

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