Intramolecular nucleophilic substitution ring closure

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

The palladium catalyzed intramolecular nucleophilic substitution of allyl alcohol derivatives (Tsuji-Trost reaction) has successfully been extended to the closure of a seven membered ring. The coupling of the allyl alcohol unit and the enamide was the key step in the preparation of the natural product claviciptic acid (5.14.),14... 

A nice example of this approach has been reported for two-step prodrugs of pilocarpine (47) (Fig. 13.41), aimed at improving ocular delivery (215). The prodrugs were lipophilic diesters of pilocarpic acid (46). The first activation step was enzymatic regiospecific 0-acyl hydrolysis to remove the acyl carrier (reaction A). In a second step, intramolecular nucleophilic substitution-elimination led to loss of the alcohol carrier and to ring closure to pilocarpine (reaction B). Efficient enzymatic hydrolysis was seen in various ocular tissue preparations, confirming the potential of these diesters as prodrugs for ocular delivery. 

A ring closure similar to that yielding a,]3-epoxysulfones (Eq. 13.16) is expected in the phase transfer reaction of phenyl vinyl sulfone with a-chloropropionitrile. Under basic conditions, the nitrile is deprotonated and then adds in the Michael sense to the a,j3-unsaturated sulfone. Protonation of the intermediate a-sulfonylcarbanion yields the simple Michael adduct, (Eq. 13.17), whereas intramolecular nucleophilic substitution would lead to sulfonylcyclopropanes (Eq. 13.18). The former process is favored over the latter to such an extent that less than a 10% yield of cyclopropanes are isolated in this reaction [27]. 

Path B Oxazoline formation by intramolecular nucleophilic substitution of the sulfonyl group by the oxygen atom of an N-acyl group (35, 143, 273, 289). Compounds with an urethane protective group are never observed to undergo this reaction. Polar solvents favour oxazoline formation, strong bases 3-elimination. The course of the reaction is also influenced by the C -H acidity of the substrate, for which reason ring closure to the oxazoline is particularly common with amides of P-tosyloxy-a-acylamino acids. 

The selective oxidation of the activated aromatic ring, substituted with electron-donating hydroxy or methoxy groups, can be perfomed at relatively low electrode potential (Ep = 0.3-1.2 V vs SCE) and ring closure is the result of the intramolecular nucleophilic attack of an amino group on the oxidized aromatic ring. 

When a-substituted JV,iV-dimethylacetamidines are used as the bidentate nucleophiles, the reaction proceeds according to Scheme 6. The primary attack occurs at an a position by the nucleophilic nitrogen to yield the zwitterionic adduct 77 (Amax = 506 nm) and is followed by intramolecular ring closure at the y position leading to a bicyclic adduct (78). In contrast, with the N-oxide of 3,5-dinitropyridine the points of attachment of the reagent are both a to the aza group. 

In the research of potential therapeutics for type II diabetes, Pei et al. synthesized 1,4-thiazepines by performing a nucleophilic substitution to cyclize to the seven-membered ring. Aniline 227 underwent intramolecular ring closure in the presence of potassium carbonate in DMF to form 1,4-thiazepine 228 (Equation 18) <2003JOC92>. 

---