Carbonyl group, nucleophilic addition cyclization

The 1,3-bond formation by electrolysis has been successfully applied for 1,3-disulfonates and 3-phenylthio-l-sulfonates as well as 1,3-dihalides. The electrolysis of a,a -dibromoketones in the presence of nucleophiles gives cyclopropanol derivatives resulting from the addition of the nucleophile to the carbonyl group . The electrolytic cyclization of 1,3-dibromides has been shown to be non-stereospecific. ... 

Chlorobenzotrifluoride provides an example of nucleophilic aromatic substitution with Me SO CH2, and < -aminobenzophenone gives 3-phenylindole through nucleophilic addition to the carbonyl group followed by cyclization. Methylation of 2-methylstilbene with Me-SO-CHg" can be controlled to produce either a- or a -methyl homologue, while the more hindered 2,6-dimethylstilbene produces the (Z)-form of the a-methyl homologue (114). The course of the... 

Design of Enamine-Enamine Cascades Three possible active sites (e.g., carbonyl group, nucleophilic a- and Y-positions) of enamine catalysis product 4 or 6 (Figure 1.1) can be further functionalized via a second enamine process in a cascade manner. Taking advantage of the electrophilic carbonyl in 4 and 6, intermolecular enamine-enamine (Scheme 1.3a) and enamine-enamine cyclization (Scheme 1.3b) cascades could be possible. In addition, the a-position of the same (Scheme 1.3c) or different (Scheme 1.3d, e.g., Robinson annulation) carbonyl group can be subjected to a second enamine process. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Dunitz (180) has collected X-ray crystallographic data for carbonyl compounds that possess nucleophilic atoms in proximity to C=0, and has postulated that such molecules can be used as models for the incipient transition state (reaction coordinate) for the nucleophilic addition to carbonyl compounds. Atrop-isomeric compounds have the potential, by providing a variety of such data, for understanding the incipient transition states. For example, the interaction found in the 1,4-dimethoxy-9-(2-acyloxyethyl)triptycenes (130) can be viewed as a model for SN2 type reactions where the acyloxy group is the leaving group and the methoxy is the nucleophile. In an extreme case of this sort, cyclization actually takes place. Such an example has been reported (181). 

A. Cyclizations proceeding by nucleophilic additions to carbonyl groups 571... 

A. Cyclizations Proceeding by Nucleophilic Additions to Carbonyl Groups... 

The allenic ether (204) cyclizes to spiro compounds in the presence of potassium r-butoxide and dicyclohexano-18-crown-6. Acid hydrolysis yields the dihydrofuranone (205). The new carbonyl compound l-oxaspiro[4,4]nonan-4-one can be subjected to another spiroannela-tion sequence. The carbonyl group in (206) has two faces available for addition of a nucleophilic species. Only one product is formed, a cyclopentyl[3]helixane (207). One can in principle continue this reiterative reaction (Scheme 53) (B-81MI31200). 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

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. 

This principle is often applied to molecules. If a nucleophile is joined to the carbonyl group it is to attack by a short chain of covalent bonds, it may be able to reach only one side of the carbonyl group. An example from a familiar reaction concerns the Robinson annelation. The first step, Michael addition, creates a stereo genic centre but no relative stereochemistry. It is in the second step—the aldol cyclization—that the stereochemistry of the ring junction is decided. 

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