Nitrile stabilization

Addition and substitution reactions of nitrile-stabilized carbanions S. Arseniyadis, K. S. Kyler and D. S. Watt, Organic Reactions 31,1 (1984). Note. Includes ArC (OTMS)CN, and HetAr (OTMS)CN. 

Insertion of phenyl, trimethylsilyl, and nitrile-stabilized metalated epoxides into zircona-cyclcs gives the product 160, generally in good yield (Scheme 3.37). With trimethylsilyl-substituted epoxides, the insertion/elimination has been shown to be stereospecific, whereas with nitrile-substituted epoxides it is not, presumably due to isomerization of the lithiated epoxide prior to insertion [86]. With lithiated trimethylsilyl-substituted epoxides, up to 25 % of a double insertion product, e. g. 161, is formed in the reaction with zirconacyclopentanes. Surprisingly, the ratio of mono- to bis-inserted products is little affected by the quantity of the carbenoid used. In the case of insertion of trimethylsilyl-substituted epoxides into zirconacydopentenes, no double insertion product is formed, but product 162, derived from elimination of Me3SiO , is formed to an extent of up to 26%. 

A nitrile-stabilized carbanion is also involved in a synthesis of a fused pyranone system (81S225). A range of 2-ureidomethylenecyclohexane-l,3-diones, e.g. (308), react with activated acetonitriles in the presence of a strongly basic catalyst to produce 5-oxo-5,6,7,8-tetrahydrocoumarins (309). Since the substrates are readily available from cyclohexane-1,3-diones by reaction with triethyl orthoformate and a urea, the synthesis is attractive (Scheme 88). Furthermore, it has been applied to a pyran-2,4-dione, whereupon the 2,5-dioxopyrano[4,3-6]pyran (310) is formed. 

The same study shows that with the complex of A W-dimethyl-o-toluidine (38), the selectivity depends on time, temperature and the nature of the anion (Table 4 and equation 34).87 Again, equilibration occurs with the tertiary nitrile-stabilized anion, favoring the C-4 substitution product, while lithioacetonitrile favors addition at C-3. The 2-methyl-1,3-dithianyl anion gives precisely the same product mixture at -78 °C and at -30 C there is no evidence for equilibration with this anion. 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

The reaction of aryl and hetaryl halides with the nitrile-stabilized carbanions (RC -CN) leads to derivatives of the type ArCH(R)CN. Sometimes, however, dimeric products of the type ArCH(R)CH(R)Ar are formed (Moon et al. 1983). As observed, 1-naphthyl, 2-pyridyl, and 2-quinolyl halides give the nitrile-substituted products, while phenyl halides, as a rule, form dimers. The reason consists of the manner of a surplus electron localization in the anion radical that arises upon replacing halogen with the nitrile-containing carban-ion. If the resultant anion radical contains an unpaired electron within LUMO covering mainly the aromatic ring, such an anion radical is stable, with no inclination to split up. It is oxidized by the initial substrate and gives the final product in the neutral form, Scheme 1-7 ... 

Nitrile-stabilized anions, generated for example by lithiation of benzyl cyanide and propionitrile, have been added diastereoselectively to aromatic aldimines.50 Acid workup gives /5-cyano amines. Alternatively, addition of RX gives /3-R-substituted-/3-cyanoamines. The factors determining des in both reaction versions have been investigated. 

Quantum yields of photoinitiated reactions have been used as a qualitative measure of the chain length. The quantum yields for substitution of haloarenes with nitrile-stabilized carbanions range from 7 to 31 in liquid ammonia [24]. Quantum yields from 20 to 50 have been determined for the substitution of iodobenzene by (EtO)2PO ions [25]. 

Nitrile-stabilized anions are so nucleophilic that they will react with alkyl halides rather well even when a crowded quaternary centre (a carbon bearing no H atoms) is being formed. In this example the strong base, sodium hydride, was used to deprotonate the branched nitrile completely and benzyl chloride was the electrophile. The greater reactivity of benzylic electrophiles compensates for the poorer leaving group. In DMF, the anion is particularly reactive because it is not solvated (DMF solvates only the Na+ cation). 

Armstrong et al. studied the electrophilic amination of carbanions with A -carboxamido-oxaziridines <2000TL2247>. A range of 3-aryl-A -carboxamido oxaziridines was evaluated and the 3-(2-cyanophenyl) oxaziridine 108 gave optimum yields of the amination products. A variety of ketone, ester, and amide enolates, as well as sulfone-, phosphonate-, and nitrile-stabilized carbonions underwent the desired amination (Table 6). 

Radicals may be generated by thermal means using, as initiators, compounds which possess either a weak 0-0 bond such as a peroxide, or which, on fragmentation, generate a stabilized radical and a strongly bonded product such as nitrogen gas. Azobisisobutyronitrile (1.59) falls into this class. After the loss of the nitrogen, the nitrile stabilizes the adjacent carbon radical by delocalization. 

Three examples of nitrile-stabilized enolates have been described by Boche et al. Two of these structures incorporate the anion of phenylacetonitrile. Hie TMEDA-solvated dimer (178) crystallizes out of benzene solution however, the mixed nitrile anion LDA-(TMEDA)2 complex (179) is obtained when excess LDA is present. This latter complex has often been mistaken as a geminal d anion since it frequently gives products that appear to arise from a dianion. The crystal structure of the anion l-cyano-2,2-dimethylcyclopropyllithium (180) consists of an infinite polymer (181) that is solvated by THF. Interestingly, there are C— Li contacts in this structure and the carbanionic carbon remains tetrahedral. 

The crystal structures of both Na Xr(CN)3 and K+C(CN)3 are known for comparison. In all examples of the nitrile-stabilized carbanions except the dianion (182), the metal coordination to the organic anion is through the nitrogen. No evidence of interaction between the metal and the nucleophilic carbon atom is seen. Lithiated imine (184) is somewhat analogous to dimer (150), although this species is not derived fiom an enolizable substrate. 

Let s take each radical in turn, and look at its selectivity. Clearly bond strength has something to do with it, but how do you explain the opposing selec-tivities of R and the nitrile-stabilized radicals We will see that the origins of the selectivities impose some restrictions on the type of starting material that can be used for these C-C bondforming reactions. 

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. 

Little work could be found on the electrophilic amination of simple nitrile-stabilized carbanions. The lithium anion of propionitrile reacts normally with an N-substituted oxaziridine (Eq. 141).158 The amination of nitriles with a camphor-derived N-unsubstituted oxaziridine was discussed earlier (Eq. II).151 Aminoma-lononitrile is formed from malononitrile anion and 0-(mesitylenesulfonyl)hydro-xylamine (Eq. 142).463... 

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