Decyanation reductive

Keywords Cyanohydrin acetonide alkylations. Reductive decyanations, Oxocarbenium ions. Reductive lithiation... 

Though the syn-l,3-diol relationship is ultimately established in the reductive decyanation vide infra), the alkylation is itself highly selective. Selectivities are typically greater than 100 1 in favor of the axial nitrile. This selectivity can be rationalized by a chair-like intermediate 15 (Scheme 3) for which equatorial alkylation is highly favored on steric grounds. Approach of the electrophile from an axial trajectory leads to a syu-pentane-like interaction. 

The syn-l,3-diol acetonide is ultimately established by reductive decyanation. These reactions proceed with exceptionally high selectivity. The selectivity observed in reductive decyanations could in principle have two origins ... 

Rychnovsky demonstrated that the latter explanation is correct in reductive decyanations, the intermediate radical equilibrates to the most stable (axial) radical, and this equilibration determines the stereochemical outcome. Reductive decyanation of a 52 48 mixture of cyanohydrin acetonides 22 provided the 5yn-product 25 with 99 1 selectivity (Scheme 4). Ab initio calculations revealed a ca. 3.5 kcal/mol enthalpy difference between the axial and equatorial radical... 

Alternative conditions for reductive decyanations can be used. The allylic ether in compound 26, an intermediate in a total synthesis of (-)-roxaticin, was prone to reduction when treated with lithium in liquid ammonia. Addition of the substrate to an excess of lithium di-ferf-butylbiphenylide in THF at -78°C, and protonation of the alkyllithium intermediate provided the reduced product 27 in 63% yield, as a single diastereomer (Eq. 7). a-Alkoxylithium intermediates generated in this manner are configurationally stable at low temperature, and can serve as versatile synthons for carbon-carbon bond forming processes (see Sect. 4). 

During the course of the development of our group s alkylation/reductive decyanation strategy, a very reliable method for distinguishing between syn-and anfz-l,3-diols was discovered [17,18]. The acetonide methyl groups reliably display diagnostic C-NMR chemical shifts, allowing for stereochemistry to be determined simply by inspection (Fig. 1). Evans later extended the C-NMR chemical correlation to polypropionate chains [19,20]. 

Khadilrar, B.M. Bendale, P.M. in Microwave assisted reductive decyanation of alkyldiphenylmethanes, OR 24, presented at the Int. Conf. Microwave Chemistry, Prague, Czech Republic, Sept. 6-11,1998. 

In practice, the equivalent synthon of 2 was l-cyano-4,5-dimethoxybenzocyclobutene 22 (Scheme 3.7) which on heating generates a reactive o-quinodimethane by a conrotatory electrocyclic ring opening process (Cf. Scheme 3.7) and reacts, at 150-160 °C, with the 3,4-dihydroisoquinoleine 23 to give 80-88%yield of 13-cyanoprotoberberine 24. A simple reductive decyanation with lithium in liquid ammonia in the presence of isopropyl alcohol afforded xylopinine (19) in 84.6% yield [19]. 

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive de-cyanation (596) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH4 in MeOH led to predominant (8 2) formation of the trans isomer (232) which was then debenzylated to ( )-solenopsin A (Id). The cis product (Ic) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by de-benzylation (Scheme 10). 

The reductive decyanation of cyanopyrazine using H2 and Pt/C under acidic conditions has been reported <2002TL6747>, that is, 2-amino-3-cyano-5-phenylpyrazine 1-oxide 73 is hydrogenated to 2-amino-5-phenylpyra-zine 74 in 90% yield (Equation 11). The double reduction has also been shown to be realized with sodium dithionite. 

Reductive decyanations of 2-cyanotetrahydropyran derivatives with sodium in ammonia yield predominantly axially protonated products. The observations are consistent with the reductive decyanation proceeding via the pyramidal, axial radical which accepts a second electron to give a configurationally stable carbanion, which in turn abstracts a proton from ammonia with retention of configuration (Rych-novsky, S. D. Powers, J. P. LePage, T. J., J. Am. Chem. Soc., 1992, 114, 8375-8384). Provide an explanation for the axial preference of the intermediate free radical on the basis of orbital interactions. Hint The title of the paper by Rychnovsky et al. is Conformation and Reactivity of Anomeric Radicals. ... 

Reductive decyanation. K-A1203 reduces alkyl nitriles in hexane at 25° in 70-90% yield. The reaction is rapid for secondary and tertiary nitriles but requires about 1 hour for primary nitriles. Potassium alone is less efficient. The reaction was useful in a synthesis of the sex pheromone 1. 

Bendale, P.M., Chowdhury, B.R. and Khadilkar, B.M., Polyethylene glycol mediated reductive decyanation of diphenylacetonitrile moderately enhanced by microwave heating, Indian]. Chem., Sect. B, 2001,40,433—435. 

Reductive decyanation. This reaction is a key step in a route to syn-l,3-diol acetonides from P-trimethylsilyloxy aldehydes (1). Reaction of 1 with trimethylsilyl cyanide followed by acetonation gives a 1 1 mixture of a protected cyanohydrin (2). This mixture is converted into a single isomer (3) on alkylation of the anion of the cyanohydrin acetonide. Reductive decyanation with Na-NH3 at -78° produces a syn-diol acetonide (4). The apparent retention of configuration in the reduction results from preferential formation of an intermediate axial anion. 

Ar- 7/-Butoxycarbonyl-2-cyanopiperidines such as 277 undergo reductive decyanation-lithiation with lithium di- v/-butylbiphenylidc (LiDBB) to give a-lithiopiperidines which can then undergo addition of numerous electrophiles, to give 2-substituted piperidines. The addition of aldehydes and ketones results in formation of bicyclic carbamates such as 278. Transmetalation of the initial lithiate, with hexynylcopper, forms the cuprate which results in the formation of the 1,4-addition product 279 upon addition of enones, such as cyclohexenone, while the lithiate gives only 1,2-addition product 280 (Scheme 66) <2004OL2745>. 

Marshall has applied the reductive decyanation-elimination of /3, -y-epoxy-nitriles to allylic alcohols212 in a synthesis of cis- and trans-pulegol (Scheme 11) which is converted into ( )-pulegone.213... 

Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin III [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin III (1) (Scheme I). The bifunctional cyanohydrin acetonide 2, prepared by ruthenium/BINAP catalyzed enantioselective hydrogenation of the corresponding ) -keto ester (BINAP = [ 1,1 -binaphthyl]-2,2 -diylbis(diphenylphosphane)), is deprotonated with LiNEt2 and alkylated with 2-benzyloxy-l-iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second... 

Scheme 2. Reductive decyanation of the cyanohydrin acetonide 9 according to Rychnovsky et al.

Oecyanation. Aliphatic nitriles undergo reductive decyanation in good yield when treated with potassium in HMFF and ether. If the nitrile is tertiary, a protic cosolvcnt (alcohol) is not necessary. Yields are in the range 60-90%. 

---