Nucleophilic cyclization ring-formation

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Most syntheses of naturally occurring phenazines, though, are based on a two-step elaboration of the central heterocycle of the phenazine [78]. The first key step involves the generation of orf/zo-monosubstituted 88 or orf/zo, ortho -disubstituted diphenylamines 89-91 via nucleophilic aromatic substitution. Ring formation is then achieved by means of reductive or oxidative cyclization, for which a number of efficient methods are available. The main flaw of this approach is the synthesis of the substituted diphenylamines via nucleophilic aromatic substitution, as this reaction often can only be performed under strongly basic reaction conditions and at high temperatures. In addition, the diphenylamines required may only be achieved with certain substitution patterns with high yields. 

The above reactions are relatively straightforward in terms of mechanism. There are, however, a number of important transformations based on 1,3,5-triazine as starting material, and which result in formation of either pyridine or pyrimidine derivatives. 1,3,5-Triazine reacts very readily with nucleophiles, probably as outlined in equation (197) if X in (31) is a suitable electrophile, cyclization can take place. Thus, when X = CN, 4-amino-5-cyanopyrimidine is obtained, and other illustrative examples are shown in equation (198). This procedure is particularly useful for the preparation of 2-unsubstituted pyrimidines, a class of compound which is not readily accessible by other types of ring formation. The reverse type of transformation, i.e. of pyrimidines to 1,3,5-triazines, is also an important synthetic method, and one which has been studied in detail. Two types of substituted... 

Fructose can cyclize into a fivc-membered ring known as a furanose. The hydroxyl group on which carbon of fructose behaves as a nucleophile during the formation of a furan ... 

The only common mode of cyclization is formation of the O—C(2) bond, usually by nucleophilic attack of the carbonyl oxygen of an amide group at the carbon atom which becomes C-2 in the 1,3,4-oxadiazole ring (Scheme 12). 

The product of Michael addition of an enolate to an a,p-unsaturated carbonyl compound will normally be a 1,5-dicarbonyl compound. The two reactive carbonyl groups separated from one another by three carbon atoms present the opportunity for ring formation by intramolecular aldol condensation. If one of the carbonyls acts as an electrophile while the other forms a nucleophilic enolate, this cyclization gives a six-membered ring. 

Reaction of 1,1,2-trifluorovinyl ether 166 with 2,2 -iminodiethanol leads to 1,4,7-dioxazocane system 168 (Scheme 43 <1999ZPK1345, 2000JFC13>). The proposed mechanism involves addition of amine to substrate, formation of oxazolinium intermediate 167 via intramolecular nucleophilic cyclization and fluoride a-elimination, and final intramolecular O-alkylation/ring expansion. 

The functionalization of a double bond promoted by an electrophile is one of the most utilized reactions in organic synthesis1. The term cyclofunctionalization 2 denotes a process where the addition of an electrophile to an alkene containing an internal nucleophile promotes a cyclization in which a carbon of the double bond involved in the ring formation becomes attached to a group specifically chosen to allow further modifications. 

The reaction sequence of Scheme 3 might well be classified as an imidazole synthesis from other heterocycles, but it seems more logical to treat this as a cyclization involving formation of the 1,5-bond. The enaminoketone condensation products (12) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds are cyclized by base to imidazoles (13) in 60-80% yields." Such a reaction makes use of the well-established general attack of a nucleophilic center in the side chain on N-2 of the oxadiazole ring. Benzamidine combines with 2-amino-3-phenacyl-l,3,4-oxadiazolium bromides to produce 1-acyl-amino-2-benzimidoylamino-4-arylimidazoles. ... 

Proton elimination is the most common teimination mode for tertiary cations and also for secondary cations when the cyclizing reagent is a Lewis acid. With protonic acids, nucleophilic attack is often observed and is usually stereoselective in many cases, due to the electron deficiency of the double bonds involved, nucleophilic attack may be concerted with ring formation. Cyclization of the acids (11) is in... 

The biosynthesis is accomplished by several ATP-driven reactions. Ring formation (cyclization) is achieved by incorporating nucleophilic amino groups and electrophilic carbonyl groups at the appropriate positions. 

---