Diethylaluminum Cyanide Research Articles

ChemInform Abstract: Diasteroselective Conjugate Addition of Diethylaluminum Cyanide to a Conjugated N‐Enoyl System: An Alternative Synthesis of (S)‐Pregabalin (X).

ChemInform Abstract: Diasteroselective Conjugate Addition of Diethylaluminum Cyanide to a Conjugated N‐Enoyl System: An Alternative Synthesis of (S)‐Pregabalin (X).

Diasteroselective conjugate addition of diethylaluminum cyanide to a conjugated N-enoyl system: an alternative synthesis of (S)-pregabalin

We have explored in this work the conjugate addition of diethylaluminum cyanide (Nagata’s reagent) to an N-enoyl system bearing the (R)-4-phenyl-2-oxazolidinone chiral auxiliary. Since this method provided a practical synthesis of γ-amino acids, we report the conjugate addition of diethylaluminum cyanide as the key step in the synthesis of (S)-pregabalin 1 in a five-step sequence of reactions from commercially available starting materials.

The GAP chemistry for chiral N-phosphonyl imine-based Strecker reaction

Chiral N-phosphonyl imines were found to be efficient electrophiles for reaction with diethylaluminium cyanide, a non-volatile and inexpensive cyanide source. The reaction produced chiral Strecker adducts, α-aminonitriles, in excellent chemical yields (94–98%) and diastereoselectivities (95 : 5 to >99%). This synthesis was confirmed to follow the GAP chemistry (group-assistant-purification chemistry) process, which can avoid traditional chromatography and recrystallization purifications, i.e., the pure chiral α-aminonitriles bearing a chiral N-phosphonyl group can be simply obtained by washing the solid crude products with hexane. The chiral N-phosphonyl auxiliary can be easily cleaved under mildly acidic conditions and quantitatively recycled by a one-time extraction with n-butanol.

ChemInform Abstract: Reissert Compound Studies. Part 63. Preparation of Reissert Compounds Using Diethylaluminum Cyanide.

ChemInform Abstract: Reissert Compound Studies. Part 63. Preparation of Reissert Compounds Using Diethylaluminum Cyanide.

ChemInform Abstract: Regio- and Stereocontrolled Nucleophilic Ring Opening of Chiral Oxazolidines by Diethylaluminum Cyanide. A Short and Efficient Route to Enantiomerically-Enriched α-Amino Esters.

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ChemInform Abstract: Ring-Opening of Epoxyalcohols by Diethylaluminum Cyanide. Regio- and Stereoselective Synthesis of 1-Cyano-2,3-diols.

ChemInform Abstract: Ring-Opening of Epoxyalcohols by Diethylaluminum Cyanide. Regio- and Stereoselective Synthesis of 1-Cyano-2,3-diols.

Ring-opening reaction of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents

Ring-opening reactions of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents, using trans-1-benzyl-3-(3,4-methylenedioxyphenyl)aziridine-2-carboxylate as a typical aziridine substrate, were examined. Formation of azomethine ylide by C2–C3 bond cleavage was observed when the aziridine was treated with trimethylsilyl cyanide under thermal conditions. On the other hand the use of bromine cyanide (BrCN) and diethylaluminum cyanide (Et 2AlCN) led to N–C3 bond cleavage and the stereospecificity was found to be dependent on the reagent used. Additional aluminum-catalyzed ring-opening reactions disclosed that the potential cationic character of the C3 benzylic position and stereochemical requirements of substituents in the arylaziridine system control the reactivity. Furthermore, the synthetic utility of the ring-opening reaction was demonstrated not only by application to the cyclization of a ring-opened cyanopropanoate to an isoquinoline skeleton but also by the extension of other carbon nucleophile from nitrile (C1) to a ketene acetal (C2).

Theoretical investigation on isomerization of Et 2AlCN to Et 2AlNC and cyanation of aldimine

The chemical fixation of diethylaluminum cyanide (Et 2AlCN) reacting with N-benzylideneaniline to produce 2-phenyl-2-(phenylamino)acetonitrile has been investigated by using DFT/B3LYP methods. The solvent effect is assessed using the continuum solvent model based on the SCRF/PCM method at the PCM/B3LYP/6-31G∗ level. Our results reveal that based on isomerization of Et 2AlCN to Et 2AlNC and their ambidextrous CN groups which will result in C-attack or N-attack to imine center carbon, there are four possible reaction paths to be found. The analysis of activation barriers shows the carbon atom in Et 2AlNC firstly attacking the imine C atom in N-benzylideneaniline to afford the five-membered-ring transition state 4′a is favorable in the gas phase and in solvent toluene. The changing geometries and Wiberg bond indices with NBO analysis indicate the reaction process and the overall reaction is exothermic.

Formal Synthesis of (-)-Frontalin through Diastereoselective Hydrocyanation of a β-Keto Sulfoxide

The diastereoselective synthesis of (S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)butan-1-ol (9), an intermediate in the asymmetric synthesis of the pine beetle pheromone (-)-frontalin [(1S,5R)-1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane] (1), has been accomplished starting from the β-keto sulfoxide 2, derived from glutaric anhydride. The key step of the synthetic sequence is the diastereoselective hydrocyanation of 2 by diethylaluminum cyanide.

Conjugate hydrocyanation of 17-acetyl-11-carbomethoxygona-1,3,5(10),13(17)-tetraenes

The conjugate hydrocyanation of 17-acetylgona-11-carbomethoxy-1,3,5(10),13(17)-tetraenes using diethylaluminum cyanide (Nagata reaction) is reported. This methodology has allowed the introduction of an angular cyano group at the C-13 position of the steroid skeleton. Subsequent reduction of the nitrile group yielded various functionalized steroids. One of them, 22 bears the natural trans/ anti/ trans stereochemistry and possesses an hydroxyl and aminomethyl functionalities in the positions 11β and 13β, respectively. The characteristic 1H and 13C NMR spectroscopic features of the synthesized steroids are reported.

An improved synthesis of piperazino-piperidine based CCR5 antagonists with flexible variation on pharmacophore sites

An improved and efficient synthetic route towards piperidino-piperazine based CCR5 antagonists was developed. The new approach was flexible for introducing various substituents in the pharmacophore sites via Grignard reagent addition and reductive amination. l-Amino acids were used as a chiral pool to introduce and then induce the desired stereochemistries, meanwhile rendering the variable substitution. The efficient construction of the piperazino-piperidine nucleus was achieved in a highly convergent manner with a key building block of N 1-Boc-4-substituent-4-aminopiperidine, exhibiting significant advantages in terms of concise synthetic route and environmental-friendly reagents over the previously described stepwise synthesis, in which a modified Strecker reaction was involved with highly toxic reagents such as diethylaluminum cyanide.

Facile Synthesis of 4‐Substituted‐4‐aminopiperidine Derivatives, the Key Building Block of Piperazine‐Based CCR5 Antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building block of piperazine-based CCR5 antagonists

4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An efficient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent yield using N′-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors.

Synthesis of the 7α-cyano-(17α,20 E/ Z)-[ [formula omitted]]iodovinyl-19-nortestosterones: potential radioligands for androgen and progesterone receptors

We report the preparation of the 7α-cyano derivative of the isomeric (17α,20 E/ Z)-[ 125 I ]iodovinyl-19-nortestosterones (IVNT) together with their binding affinity for the androgen receptor (AR) and their biodistribution in two different animal models. The cyano group was introduced at the 7α-position by hydrocyanation of 4,6-estradien-17β-ol-3-one with diethylaluminum cyanide. Selective protection of the A-ring enone system as the dienol ether followed by ethynylation and deprotection under base and acid hydrolysis condition gave 7α-cyano-17α-ethynyl-19-nortestosterone. The stannyl derivatives were prepared by addition of tri- n-butylstannyl hydride and converted stereospecifically to the corresponding [ 125 I ]iodovinyl analog using [ 125 I ]NaI and H 2O 2. The [ 125 I ]iodovinylsteroids were intravenously administered to male rats and estrogen-primed immature female rats and tissue uptake was measured up to 6 h post-injection. Co-administration of NLP-004 or ORG-2058, highly selective ligands for the progesterone receptor, to the female rats did not affect uterus uptake of the 125 I -ligands. However co-injection of testosterone to DES-primed male rats induced a marked increase in prostate uptake of the 20 Z-isomer of 7α-cyano-[ 125 I ]-IVNT. The relative binding affinity (RBA) of either 7α-cyano-(17α,20 E/ Z)-IVNT isomer for the AR is low (RBA=4 and 3, respectively, versus 100 for 5α-dihydrotestosterone (DHT)), suggesting the absence of a possible role of the AR in the localization process. These findings contrast previously reported data for the analogous 7α-methyl-[ 125 I ]-IVNT where co-administration of testosterone was shown to result in a 50% drop in prostate uptake. These data indicate that the addition of an electron withdrawing 7α-cyano group to 123 I -labeled nortestosterone derivatives does not improve their potential to serve as SPECT agents for the imaging of AR densities in the prostate.

Addition of Metal Cyanides to Tosylhydrazones of Aldehydes in Aprotic Solvents: A New Method for One‐Carbon Homologation of Aldehydes and for the Synthesis of α‐(N2‐Tosylhydrazino)nitriles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Neighboring-group participation in benzylidene acetal ring-opening of a 2-cyano-2-deoxypyranoside derivative by diethylaluminum cyanide

The oxirane ring-opening of an anhydro sugar with diethylaluminum cyanide (Et 2AlCN) is a direct approach for obtaining a cyano derivative. Methyl 2,3-anhydro-4,6- O-benzylidene-α- d-allopyranoside showed anomalous chemical behavior when treated with Et 2AlCN. The reaction afforded the corresponding β-cyanohydrin as the minor component from a mixture of compounds resulting from the benzylidene acetal ring-opening caused by the attack of ethyl or cyano groups.

A Comparative Study of the Stereoselective Addition of Trimethylsilyl Cyanide and Diethylaluminum Cyanide to Chiral Cyclic Nitrones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Val‐Ala Dipeptide Isosteres by Hydrocyanation of α′‐Amino α,β‐Unsaturated Ketones − Control of Stereoselectivity by the N‐Protecting Group

AbstractThree diastereoisomeric hydroxyethylene isosters of the Val‐Ala dipeptide were synthesized from α,β‐unsaturated ketones 1 derived from N‐Boc‐ and N,N‐dibenzyl‐L‐valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β‐cyano ketones with the stereoselectivity depending on the protecting group. N‐Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N‐dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N‐Boc and N,N‐dibenzyl compounds. The cyano alcohols thus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val‐Ala dipeptide. In the first series the hydroxy group and the N‐terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C‐terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4‐hydroxy‐5‐amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach. (© Wiley‐VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003)

A comparative study of the stereoselective addition of trimethylsilyl cyanide and diethylaluminum cyanide to chiral cyclic nitrones

The mild cyanating agent trimethylsilyl cyanide adds with total stereoselectivity to α-alkoxy cyclic nitrones to afford the corresponding trans-hydroxyaminonitriles. The addition of Lewis acids to precomplexing the nitrones does not affect the stereoselectivity of these additions significantly. In all of the cases examined, excellent yields of diastereomerically homogeneous products were obtained. On the other hand, the use of diethylaluminum cyanide as cyanating agent leads to low diastereoselectivities. Both NMR studies and theoretical calculations show that whereas the addition of trimethylsilyl cyanide takes place through a concerted mechanism, in the addition of diethylaluminum cyanide, a complex is formed prior to the intramolecular delivery of the cyanide ion.

Addition of Metal Cyanides toTosylhydrazones of Aldehydes in Aprotic Solvents: A NewMethod for One-Carbon Homologation of Aldehydes and forthe Synthesis of α-(N 2-Tosylhydrazino)nitriles

One-carbon homologation of aldehydes to nitriles via reaction of the respective tosylhydrazones with trimethylsilyl cyanide, tributyltin cyanide and diethylaluminum cyanide with or without Lewis acid-type catalysts was examined. Representative tosylhydrazones on treatment with trimethylsilyl cyanide in the presence of trimethylsilyl triflate or scandium triflate afforded α-(N 2-tosylhydraziono)nitriles in excellent yields. The same adducts were also obtained using tributyltin cyanide/scandium triflate system or diethylaluminum cyanide at room temperature. Treatment of tosylhydrazones with trimethylsilyl cyanide/scandium triflate or with diethylaluminum cyanide in appropriate solvent at higher temperatures afforded the respective one-carbon extended nitriles in good yields. Some examples of the application of these reactions to polyfunctional compounds are given.