β‐Amino Alcohol Properfumes

Amino‐alcohol derivatives of fragrant, volatile aldehydes and ketones were synthesized in a one‐pot procedure by sequential cyanohydrin formation with trimethylsilyl cyanide and reduction with lithium aluminium hydride, or by ammonolysis of epoxide precursors. The amino alcohols are nonvolatile, stable properfumes releasing fragrant carbonyls by oxidation with sodium periodate or sodium bismuthate. Examples include amino alcohol properfumes of citronellal, Lilial^®, lauryl aldehyde, menthone, benzaldehyde, and anisaldehyde.     

Internal oxidation-reduction of quinoxaline-2- carboxaldehyde 1,4-dioxide

Reaction of carboxaldehyde 1 with acetone cyanohydrin gives carboxylic acid 2. Reaction of 1 with acetone cyanohydrin in methanol affords the methyl ester 3. The structural assignment for 2 is supported by ¹³C nmr data and by the decarboxylation of deuterated 2 to give 4b. The internal oxidation-reduction upon going from 1 to 2 is explained in terms of a mechanism whereby 1 is converted into its cyanohydrin 5 and then to acyl cyanide 6. Acyl cyanide 6 then reacts with either water or methanol to give 2 or 3.     

Development of a New α‐Aminonitrile Synthesis

Abstract

α‐Aminonitriles are prepared upon reaction of aryl carboxaldehydes with LiHMDS and acetone cyanohydrin. This new method provides a general route to the synthesis of various substituted α‐amino‐arylacetonitriles in high yield and purity, and avoids the use of the highly toxic cyanide salts.     

A novel synthesis of α-fluoroacetonitriles. Application to a convenient preparation of 2-fluoro-2-phenethylamines

α-Fluorophenylacetonitriles (3) are readily prepared by the treatment of the corresponding benzaldehyde cyanohydrin trimethylsilylethers (2) with diethylaminosulfur trifluoride (DAST). This method for the introduction of fluorine alpha to a cyano group is also applicable to the cyanohydrin trimethylsilylethers of aromatic ketones. Diborane reduction of the α-fluorophenylacetonitriles (3) yields 2-fluoro-2-phenethylamines (4).     

Highly efficient trialkylsilylcyanation of aldehydes, ketones and imines catalyzed by a nucleophilic N-heterocyclic carbene

The synthetic utility of N-heterocyclic carbenes was demonstrated by the trialkylsilylcyanation of aldehydes, ketones and imines. In the presence of a catalytic amount of 3a, the reactions with Me₃SiCN proceeded smoothly to give the corresponding cyanohydrin trimethylsilyl ethers or amino nitrile derivatives in good to excellent yields.     

Catalytic asymmetric synthesis of O-acetyl cyanohydrins from KCN,Ac2O and aldehydes

A (salen)titanium catalyst has been found to induce the asymmetric addition of potassium cyanide and acetic anhydride to aldehydes, giving enantiomerically enriched cyanohydrin esters with up to 92% enantiomeric excess using just 1 mol% of the catalyst. This is the first report of the asymmetric synthesis of cyanohydrin derivatives using a cyanide source which is non-volatile and inexpensive.     

Crown Ether Catalysis in the Synthesis of Cyanohydrin Derivatives

Carbonyl compounds react with cyanide ion under phase transfer catalysis (18-crown-6) to give cyanohydrin anions which are trapped by acid chlorides, anhydrides or alkylating agents to give cyanohydrin derivatives.     

CO2-Enabled Cyanohydrin Synthesis and Facile Iterative Homologation Reactions**

Thermodynamic and kinetic control of a chemical process is the key to access desired products and states. Changes are made when a desired product is not accessible; one may manipulate the reaction with additional reagents, catalysts and/or protecting groups. Here we report the use of carbon dioxide to accelerate cyanohydrin synthesis under neutral conditions with an insoluble cyanide source (KCN) without generating toxic HCN. Under inert atmosphere, the reaction is essentially not operative due to the unfavored equilibrium. The utility of CO₂-mediated selective cyanohydrin synthesis was further showcased by broadening Kiliani–Fischer synthesis under neutral conditions. This protocol offers an easy access to a variety of polyols, cyanohydrins, linear alkylnitriles, by simply starting from alkyl- and arylaldehydes, KCN and an atmospheric pressure of CO₂.     

IMPROVED SYNTHESIS OF CYANOHYDRIN PHOSPHATES AND ITS REACTION MECHANISM

Cyanohydrin phosphates 2a–2c were prepared in high yield from ketones (or aldehyde), diethyl phosphorochloridate, and sodium cyanide by using acetonitrile as solvent. GC analysis proved that the two reactions of cyanohydrin sodium with diethyl phosphorochloridate and with diethyl phosphorocyanidate resulted in the formation of cyanohydrin phosphates.     

Synthesis of the new ring system,Pyrazolo[3,4-d][1,3]diazepine. A novel route for the synthesis of azolo[1,3]diazepines

A reduction of the nitrile group of 5-amino-4-cyano-1-methylpyrazole ( 3 ) has provided the very versatile compound 5-amino-1-methylpyrazole-4-carboxaldehyde ( 4 ). The amino group of 4 was protected using di-methylformamide dimethylacetal and the aldehyde group was then reacted with trimethylsilyl cyanide to afford the moisture sensitive compound 5-[[(dimethylamino)methylene]amino]-4-[cyano(trimethylsiloxy)-methyl]-1-methylpyrazole ( 10 ). The cyano group of the cyanohydrin 10 was reduced using a cobalt boride catalyst to afford an intermediate aminomethyl group which was involved in an in situ annulation. This reaction provided 1-methyl-1,4,5,6-tetrahydropyrazolo[3,4-d][1,3]diazepin-4-ol, a derivative of the new ring system, pyrazolo[3,4-d][1,3]diazepine.     

Chiral lithium binaphtholate aqua complex as a highly effective asymmetric catalyst for cyanohydrin synthesis

A highly enantioselective cyanohydrin synthesis with aromatic aldehydes using chiral lithium binaphtholate aqua or alcohol complexes has been developed and is a simple and inexpensive catalyst suitable for process chemistry to give gram-scale cyanohydrins successfully. Dramatic improvements in enantiomeric excess have been realized along with an interesting changeover in absolute stereochemistry of cyanohydrin product against the thoroughly "dry" catalytic systems.     

Stereocontrolled access to orthogonally protected anti,anti-4-aminopiperidine-3,5-diols through chemoselective reduction of enantiopure beta-lactam cyanohydrins

The cyanosilylation of enantiopure 4-oxoazetidine-2-carbaldehydes with tert-butyldimethylsilyl cyanide was promoted by either molecular sieves or catalytic amount of sodium carbonate to give O-silylated beta-lactam cyanohydrins with good yield and diastereoselectivity. In contrast, Lewis acids did not effectively promote the cyanosilylation under different experimental conditions, and instead hydrocyanation took place affording the corresponding free cyanohydrins in variable yield and selectivity. Starting from beta-lactam cyanohydrin hybrids, two concise, complementary stereocontrolled routes to optically pure orthogonally protected anti,anti-4-amino-3,5-piperidine diols were achieved. Key features of the first approach include chemoselective reductive opening of the beta-lactam ring with LiBH4 to a 3-amino-5-hydroxy pentanenitrile followed by reductive cyclization of a conveniently functionalized cyanomesylate derivative with NaBH4/NiCl2. The second approach involves LiAlH4 reduction of protected anti,anti-4-amino-3,5-dihydroxypiperidin-2-ones, which were easily obtained by chemoselective reduction of the cyano group in the beta-lactam cyanohydrin hybrids with NaBH4/NiCl2 and subsequent intramolecular rearrangement of the resulting amino beta-lactams. Both routes make use of an oxidative N-dearylation with diacetoxyiodobenzene of a 4-methoxyphenylamino group as a common synthetic step. Specifically, the utility of this novel reaction sequence has been demonstrated by the synthesis of fully orthogonally protected sialidase inhibitors.     

Reactions of Trimethylsilyl Cyanide with α-Keto Esters: Selective Preparation of Either Methyl 4-(Trimethyl-silyl) oxy-4-cyano-2-oxopentanoate or Methyl 2-(Trimethylsilyl) Oxy-2-cyano-4-oxopentanoate

The reaction of methy1 2,4-dioxopentanoate (3) with TMSCN in the presence of zinc iodide affords the TMS protected cyanohydrin enol ether 4, from which the TMS protected cyanohydrin 1 can be obtained. Treatment of 3 with TMSCN alone gives the isomeric cyanohydrin 2. Reactions of two other α-keto esters with TMSCN are shown to proceed without a catalyst.     

Total synthesis of (-)-5,6,11-trideoxytetrodotoxin and its 4-epimer

[reaction: see text] The first total synthesis of 5,6,11-trideoxytetrodotoxin (1) and its 4-epimer were achieved. The synthesis is characterized by the stereoselective construction of the quaternary amino carbon center at C8a by an asymmetric transferring Strecker synthesis and the highly efficient conversion of cyanohydrin 4 to 1 via intramolecular cyclization reactions.     

2-(o-Hydroxyanilido)alkylnitriles vs. 2-[1-(o-hydroxyanilido)alkyl]-benzoxazoles as products from o-aminophenol and cyanohydrins

The reaction of o-aminophenol with cyanohydrins leads to the formation of novel benzoxazoles 2 or the expected 2-(o-hydroxyanilido)alkylnitriles 3 or mixtures of these two, depending on the alkyl substituents on the cyanohydrin. The formation of benzoxazoles 2 was found to be due to the intrinsic instability of the corresponding 2-(o-hydroxyanilido)alkylnitriles, such as 4 .     

DBU catalyzed cyanoacylation of ketones with acyl cyanides

The reaction of cyclohexanone with benzoyl cyanide catalyzed by amines provides the corresponding O-benzoyl cyanohydrin adducts in moderate to good yields under mild conditions. Among the catalysts, DBU was found to be the most effective promoter allowing the reaction to proceed smoothly at room temperature and to give the corresponding O-acyl cyanohydrin adducts in higher yields for a variety of substituted cyclohexanones, cyclopentanone, acetone or pentan-3-one and various acyl cyanides.     

Practical Oxirane Ring Opening with In Situ Prepared LiCN; Synthesis of (2S,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1-butanenitrile

Trisubstituted oxirane 1 was regiospecifically opened with LiCN in situ prepared from acetone cyanohydrin and LiH to provide the corresponding β-hydroxy nitrile 2 in satisfactory yield, enabling us to manufacture a key intermediate for a new antifungal agent on a multi-kg scale. Some applications of this method to the ring opening of other oxiranes and nucleophilic substitution are also described.     

Syntheses and reactions of functional polymers. XCVII. Chemical activation and functionalization of poly(γ-methyl-L-glutamate)

To enhance its solubility in common solvents poly(γ-methyl-L -glutamate) (PMG) was transesterificated with ethylene chlorohydrin, ethylene cyanohydrin, and β,β,β-trichloroethanol, respectively. The aminolyses of the resulting polymers proceeded easily in pendant ester groups to give the corresponding amides in reasonable yields without main chain fission. By these procedures the incorporation of functional groups such as azide, amino acid, and thiol into PMG is successfully performed.     

The chemistry of acylals. 3. Cyanohydrin esters from acylals with cyanide reagents

[reaction: see text] When treated with KCN in DMSO at room temperature, acylals from aliphatic aldehydes gave the corresponding cyanohydrin esters in good to excellent yields. Acylals from aromatic aldehydes were less reactive and gave several byproducts in addition to fair yields of cyanohydrin under the same conditions. Trimethylsilyl cyanide mixed with titanium(IV) chloride afforded cyanohydrin esters in good to excellent yields from both aliphatic and aromatic aldehydes.     

A New,Specific Synthesis of β-Cyclocitral

A new specific synthesis of ρ-cyclocitral is presented. The key step is the dehydration of the trans 2.2.6-trimethylcyclohexanone cyanohydrin by thionyl chloride.