Cyanides cycloadditions

Thus, Dondoni et aV synthesized a new class of tetrazole-tethered C-glycosyl a-amino acids using serine and cysteine as nncleophiles based on Demko s and Sharpless aforementioned Click azide-sulfonyl cyanide cycloaddition/snlfonyl substitution route (Scheme 9.8). 

Reaction of ethyl (V-(cyanoacetyl)urethane with trifluoroacetonitrile gave 5-cyano-6-trifluoromethyluracil (85JOC4642). Trifluoroacetonitrile reacted with benzyl cyanide (86JOU1408) and diethyl malonate (89JHC7) to yield 2,6-bis(trifluoromethyl)pyrimidines. Cycloaddition of trifluoroacetonitrile with enamines having a /3-H offered a general route to 2,4-bis(trifluoromethyl)pyrimidines (84LA991). 

Conjugate addition, 34-5, 51-2,53, 132, 133 Conjugate hydroxymethylation, 59-60 Copper(n) bromide, 54 Copper([) chloride, 120 Copper(n) chloride, 120 Copper(i) cyanide, 7,52, 53 Copper(i) iodide, 54 Corey s internal quench, 104 Cyanohydrin trimethylsilyl ether, 137 Cycloaddition. 34,112 Cydobutane-l,2-dione, 135 Cyclohept-2-dione, 135 Cyclohex-2-enone, 52,123 Cyclohcxa-1,3-diene, 26 Cyclohexane carboxaldehyde, 22-3,69 73,78... 

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [49], Typically, the conversion from halide to nitrile takes at least 5 h by this route and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

Cycloaddition to give heterocycles IV. ADDITION TO IMINES AND CYANIDES... 

Cycloadditions to a cyano group are comparatively rare. The high-temperature reactions of 1,3-dienes, e.g. butadiene, isoprene and 2-chloro-l,3-butadiene, with dicyanogen, propionitrile or benzonitrile result in formation of pyridines (equation 80)70. Sulfonyl cyanides 147, obtained by the action of cyanogen chloride on sodium salts of sulfinic acids, add to dienes to give dihydropyridines 148, which are transformed into pyridines 149 by oxidation (equation 81)71. 

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. 

In contrast, the 5-phenyliminothiatriazoline (323) reacts as a masked 1,3-dipole with a variety of electrophilic nitriles. Tosyl cyanide and ethyl cyanoformate both react with (323) in refluxing chloroform to give initially (324) which then isomerizes to (325) as the reaction proceeds (Scheme 71) <91JHC333>. When the solvent is changed to acetone the reaction with the nitriles proceeds faster due to the formation of the adduct (326) which is capable of undergoing cycloaddition/elimination reactions at 20 °C. Trichloroacetonitrile does not react with (323) in chloroform solution in acetone,... 

The 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles yields 3,5-disubstituted 1,2,4-thiadiazoles of unequivocal structure. This method has received considerable attention in recent years. Electron deficient nitriles such as tosyl cyanide afford high yields of 5-tosyl derivatives (341) (Equation (53) see also Scheme 61) <93JHC357). 

In view of the multicomponent nature of the tandem [4 + 2] / [3 + 2] cycloaddition, the potential for a combinatorial approach to the synthesis of nitroso acetals has been investigated on solid-phase supports. The incorporation of either the dipolarophile or the starting nitroalkene on a Wang-type resin is compatible with the tandem cycloaddition promoted at high pressures (Schemes 2.28 and 2.29). The solid-supported nitroso acetals are subsequently liberated (in moderate yields from the staring nitroalkene) upon the addition of a catalytic amount of potassium cyanide in triethylamine and methanol or by reduction with lithium aluminum hydride (LAH) (261,264). 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

Cyanides can react with 1-aminopyridinium salts to give 2-substituted triazolopyridines, possibly via the pyridinium ylide. With 1-aminopyridinium iodide and cyanide ion the intermediate 4-cyanopyridine reacts with the aminopyridinium salt to give 2-(4-pyridyl)triazolopyridine (45).51 When acetonitrile or benzonitrile are used, 2-methyl- and 2-phenyltriazolo-pyridines are obtained.58 60 The reaction is thought to involve a dipolar cycloaddition of the N- mi nopyridine with the nitrile, as shown in Eq. (4). 

Kinetically stabilized azetes also show a high tendency for cycloaddition with a variety of other reagents. Cycloaddition of (47) with triplet oxygen produced a fully characterized dioxetan adduct (48), which decomposed at 25°C into t-butyl cyanide and the a-dione fragment (88AG(E)272). 

Considerable variation is also possible in the carbonyl function, and in addition to simple aldehydes and ketones, acetyl cyanide,292 diethyl oxomalonate,293 diethyl oxalate,294 and ethyl cyanoformate 295 [Eq. (77)] will all undergo cycloaddition to alkenes to form the corresponding oxetanes. Oxetanes are also formed in certain circumstances from both a,j8-unsaturated aldehydes298 and acetylenic ketones.297... 

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