Nitriles intramolecular alkylation

Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

Sequential Mannich reaction of ester 210a or nitrile 210b, alkylation and displacement of quaternary ammonium salt affords azides 211. Further hydrogenation can be followed by intramolecular cyclization under basic conditions into pyrrolo-benzodiazepinone 212 (Scheme 44 (1994JHC1317, 1994S164)). 

Ring closure of enamines and acid chlorides39, esters601 or nitriles (equation 40) or intramolecular alkylation of enaminone602,603 (equation 41) are general methods for the preparation of cyclic enaminones. 

Alicyclic nitriles are prepared by the intramolecular alkylation of halo nitriles. For example, cyclopropyl cyanide is obtained in 75-90% yield by the action of sodium amide on y-chlorobutyronitrile in ether or liquid... 

An intramolecular alkylation of a-thionitrile (58) leads to a macrocycle, an intermediate for the synthesis of the sesquiterpene (-)-dihydrogermacrene D (Scheme 29). Alkylation of an a-cyanosulfone followed by reduction gave a-substituted acetonitriles. Cyclization of a 1,3-dibromoalkane with (methylthio)acetonitrile yields a l-cyano-l-(methylthio)cyclobutane, a precursor for the synthesis of cyclopentanones. Reaction of a-(arylthio)nitriles with aryl halides in the presence of LDA and BusP at -78 C affords cyanostilbenes. ... 

Intramolecular alkylations of nitrile-stabilized carbanions have been used to synthesize large rings such as those with 10 and 14 members. Tsuji and coworkers carried out a synthesis of the macrocy-clic antibiotic zearalenone by this route. As shown in Scheme 70, conversion of either of the protected cyanohydrins (144) or (145) to the corresponding dianions, resulting from deprotonation at the benzylic positions and a to the nitrile groups, gave the same cyclization product (146) in excellent yields. Dianion formation (i) provided control of the conformation of the side chain (ii) protected the ester from nucleophilic attack and (iii) appeared to increase the rate of the intramolecular cyclization. 

If employed in the cold and in stoichiometric quantities, DIBAH leads to the iminoaluminate, which is hydrolyzed to aldehyde [K2, Wl, YGl] (Figure 4.8). Toluene or hexane are usually the best solvents for this transformation. The reaction proceeds with aliphatic, aromatic, a,p-unsaturated (see Section 4.4), or cyclopropane nitriles [HH3, WYl] and is compatible with N-BOC groups [KN3] (Figure 4.8). The iminoaluminate thus formed can undergo an intramolecular alkylation, as... 

Reissert compounds of the type 33 (n = 330,49 and 430) undergo an intramolecular alkylation on treatment with sodium hydride in dimethyl-formamide to give the tricyclic compounds (34). A similar reaction also takes place in the quinoline series.30 When 33 (n = 3) and isopropyl bromide are treated with sodium hydride, cyclization to 34 (n = 3) takes place rather than alkylation with the isopropyl bromide however, treatment of 33(n = 3) and carbon disulfide-methyl iodide with sodium hydride gives 35 rather than cyclization.30 Alkaline peroxide converts the nitrile 34 (n = 3) into an amide, and acid or base hydrolysis gives 4-(l-isoquinolyl)butyric acid.30... 

Alicyclic nitriles may be formed by intramolecular alkylation of halo nitriles, e.g., cyclopropyl cyanide from 4-chlorobutyronitrile (yields 74-79%)414... 

Intramolecular alkylation accompanying desilylation of a silyl enol ether is expected in the case that a cis-decalin is formed. For acquiring the trans-isomer the cyclization must rely on activation by the nitrile group alone. 

Viagra) was built up by the PS-BEMP promoted intramolecular alkylation of nitriles [49],... 

If the electrophile and the nitrile are in the same molecule and the spacing between them is appropriate, then intramolecular alkylation entails cyclization to form rings. The preparation of a cyclopropane is shown using sodium hydroxide as the base and chloride as a leaving group. With an intramolecular alkylation, the base and the electrophile necessarily have to be present together, but the cyclization is so fast that competing 5 2 substitution of Cl" by HO" is not a problem. 

The key reaction of the second synthesis of (+)-104 by Inoue-Hirama s group [75-79] was intramolecular alkylation of nitrile-epoxide 168 to form the G-ring, and dithiane coupling and olefin metathesis [80-82] with BCD-ring fragment 169 for macrocyclization (Scheme 17). 

Tetrazoles. Aryl nitriles and alkyl nitriles are converted into the corresponding tetrazoles in the presence of dibutyltin oxide or trimethylaluminum in moderate to good yields. Amides or thioamides also react with TMSA to form tetrazoles. Reaction of a,/3-unsaturated ketones with TMSA can be catalyzed by TMSOTf in dichloromethane. A tandem strategy for fused tetra-zole formation has also been reported a [3-1-2] cycloaddition between a nitrile and TMSA in presence of dibutyltin oxide is followed by an intramolecular allylation to form a fused tetrazole in 60-82% yields. 

Lithium diethylamide (x-Metalation of nitriles Intramolecular C-alkylation... 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

An unusual solvent effect was observed in cycloadditions of aromatic nitrile N-oxides with alkyl-substituted p-benzoquinones in ethanol-water (60 40) the reaction rates were 14-fold greater than those in chloroform (148). The use of ion pairs to control nitrile oxide cycloadditions was demonstrated. A chiral auxiliary bearing an ionic group and an associated counterion provides enhanced selectivity in the cycloaddition the intramolecular salt effect controls the orientation of the... 

To form the stereocenter at C-3 a direct reduction-alkynylation sequence was applied, that provided the diastereomeric homopropargylic alcohols 83 in a ratio of syn anti=76l2A, The major isomer syn-S3 was isolated in 55% yield. The key step of the synthesis was an intramolecular imidotitanium-al-kyne [2+2] cycloaddition/acyl cyanide condensation. With this sequence the pyrrolidine ring was formed and all the carbon atoms of the alkyl side chain were established in acrylonitrile 84. The reduction of the imine double bond proceeded stereoselectively and the nitrile group was removed reductively en route to the target compound. 

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