Acetone Cyanohydrin Research Articles

Multicomponent Cyanation of 2‐Amino‐3‐cyano‐4H‐chromenes in Aqueous Media

AbstractChromenes represent a pivotal molecular structure found in a diverse range of biologically active compounds. Specifically, derivatives of 2‐amino‐3‐cyano‐4H‐chromene have demonstrated pharmacological applications, displaying potential antioxidant and anticancer activities. This has heightened interest in the exploration of new and more efficient methods for their synthesis. In recent years, few examples have emerged, focusing on the organocatalytic and enantioselective synthesis of 2‐amino‐3‐cyano‐4H‐chromene derivatives, although the overall number of works to date is limited. In this study, we present the results of the synthesis of 2‐amino‐4H‐chromen‐3,4‐dicarbonitriles through a Michael addition of cyanide to 2‐iminochromenes. To achieve this, we utilized a mild source of cyanide (acetone cyanohydrin), green solvents and catalytic conditions at room temperature, via a multicomponent approach. Furthermore, we initiated the enantioselective study of this process using chiral organocatalysts obtaining promising preliminary results.

Ligand-Enabled Gold-Catalyzed Cyanation of Organohalides.

Herein, we disclose the first report on gold-catalyzed C(sp2)-CN cross-coupling reaction by employing a ligand-enabled Au(I)/Au(III) redox catalysis. This transformation utilizes acetone cyanohydrin as a nucleophilic cyanide source to convert simple aryl and alkenyl iodides into the corresponding nitriles. Combined experimental and computational studies highlighted the crucial role of cationic silver salts in activating the stable (P,N)-AuCN complex towards the oxidative addition of aryl iodides to subsequently generate key aryl-Au(III) cyanide complexes.

Ligand‐Enabled Gold‐Catalyzed Cyanation of Organohalides

Herein, we disclose the first report on gold‐catalyzed C(sp2)‐CN cross‐coupling reaction by employing a ligand‐enabled Au(I)/Au(III) redox catalysis. This transformation utilizes acetone cyanohydrin as a nucleophilic cyanide source to convert simple aryl and alkenyl iodides into the corresponding nitriles. Combined experimental and computational studies highlighted the crucial role of cationic silver salts in activating the stable (P,N)‐AuCN complex towards the oxidative addition of aryl iodides to subsequently generate key aryl‐Au(III) cyanide complexes.

Energy-saving design of azeotropic distillation for the separation of methanol–methyl methacrylate azeotrope from industrial effluent

For the purpose of separating the binary methanol–methyl methacrylate (MMA) azeotrope in light boiling residues and preventing MMA polymerization from acetone cyanohydrin process, low pressure heterogeneous azeotropic distillation (HAD) with process intensification was adopted. The binary interaction parameters of the azeotrope were obtained by correlating and regressing the experimental data of isobaric vapor–liquid equilibrium at low pressures (75, 50 and 26 kPa for methanol-MMA and 26 kPa for cyclohexane-MMA). The residue curve map at 26 kPa was plotted under the UNIQUAC model, and the optimal parameters of its conventional process were achieved through sequential iterative optimization procedure. The purity of MMA and methanol was 99.99 wt% and 99.90 wt%, respectively. Subsequently, in order to further reduce costs and energy consumption, dividing wall column (ADWC), heat pump distillation (HP-AD), and heat pump assisted azeotropic dividing wall column (HP-ADWC), three technical approaches were explored and compared. Total annual cost (TAC), total energy consumption (TEC), and CO2 emissions were used as evaluation indicators. Among them, ADWC reduced its annual capital investment by 14.48 % through special structural design. HP-AD effectively reduced TEC by 27.30 %. HP-ADWC combined the advantages of both, effectively reducing costs and saving energy (12.88 % in TAC). At present, the purity and energy saving of the product meet industrial expectations, providing valuable insights for enhanced methanol-MMA azeotrope recovery from industrial effluent.

Structure-Based Site-Directed Mutagenesis of Hydroxynitrile Lyase from Cyanogenic Millipede, Oxidus gracilis for Hydrocyanation and Henry Reactions.

Hydroxynitrile lyase (HNL) from the cyanogenic millipede Oxidus gracillis (OgraHNL) is a crucial enzyme in the cyanogenesis pathway. Here, the crystal structures of OgraHNL complexed with sulfate, benzaldehyde (BA), (R)-mandelonitrile ((R)-Man), (R)-2-chloromandelonitrile ((R)-2-Cl-Man), and acetone cyanohydrin (ACN) were solved at 1.6, 1.7, 2.3, 2.1, and 2.0 Å resolutions, respectively. The structure of OgraHNL revealed that it belonged to the lipocalin superfamily. Based on this structure, positive variants were designed to further improve the catalytic activity and enantioselectivity of the enzyme for asymmetric hydrocyanation and Henry reactions.

Ring-opening of oxazolidines with acetone cyanohydrin: A short and effective pathway to 2-((2-hydroxyethyl)amino)acetonitriles from carbonyl compounds

Herein we describe a mild and efficient two step-approach for the construction of 2-((2-hydroxyethyl)amino)acetonitriles in high yields via the reaction of readily available 5-aryl(alkyl)oxazolidines and acetone cyanohydrin.

Water‐Mediated C−H Cyanation of Quinoxalin‐2(1H)‐ones and Quinoxalines Under Visible‐Light Conditions

AbstractRegioselective cyanation of quinoxalin‐2(1H)‐ones and quinoxalines with acetone cyanohydrin under aqueous aerobic visible‐light conditions at room temperature is described. Acetone cyanohydrin is utilized as a safe source for cyanation. In both cases, good functional group tolerance was observed with very good to quantitative yields of products under metal/base/ligand‐free conditions. Several control experiments revealed that, water and oxygen from air are crucial for the efficiency of the present transformation. These reactions proceed through a radical pathway as confirmed by radical scavengers. To validate the feasibility of the process for commercial syntheses, three products were synthesized at gram scale under the optimized conditions. The conversion of cyanated products into corresponding amides and acid was also performed and the pure products were obtained without column chromatographic separation.

Preparation of enantiopure pregabalin intermediate using cross linked enzyme aggregates (CLEAs) in basket reactor

Route to the synthesis of enantiomerically pure ethyl (S)-3-cyano-5-methylhexanoate, (S)-5, a key chiral intermediate for Pregabalin has been improved. The racemic β-cyano diester, 3 was prepared in 98% purity via gelatine catalysed Knoevenagel condensation of diethylmalonate with isovaleraldehyde followed by hydrocyantion of α,β-unsaturated diester 14 using acetone cyanohydrin and K2CO3. Racemic diethyl 2-(1-cyano-3-methylbutyl)malonate, rac-3, has been resolved using lipase from Thermomyces lanuginosus immobilised in form of crosslinked enzyme aggregates, CLEAs. The CLEAs were made by employing commercial soymilk as an additional protein source and a reaction was carried out in a moving basket reactor. The immobilised enzyme was found to be stable in many organic solvents and temperature up to 50 °C. The resolution reaction was studied in a basket reactor at 50% substrate loading in calcium acetate buffer, pH 7.5 at 30 °C by using 20% w/w enzyme loading. The apparent kinetic parameters were V max,app = (8.74 ± 0.43) mM/h/g and K m,app = (1.5 ± 0.07) M (correlation coeff. r = 0.98). The desired ethyl (S)-3-cyano-5-methylhexanoate, (S)-5 is obtained in 90-92% theoretical yield and e.e > 99%. The advantages of this improved process are mild reaction conditions; an alternate method for hydrocyanation step avoiding the use of highly toxic potassium cyanide at large scale operation and an immobilised enzyme that can be reused for at least 11 recycles.

Structural characterization of Linum usitatissimum hydroxynitrile lyase: A new cyanohydrin decomposition mechanism involving a cyano-zinc complex

Hydroxynitrile lyase from Linum usitatissimum (LuHNL) is an enzyme involved in the catabolism of cyanogenic glycosides to release hydrogen cyanide upon tissue damage. This enzyme strictly conserves the substrate- and NAD(H)-binding domains of Zn2+-containing alcohol dehydrogenase (ADH); however, there is no evidence suggesting that LuHNL possesses ADH activity. Herein, we determined the ligand-free 3D structure of LuHNL and its complex with acetone cyanohydrin and (R)-2-butanone cyanohydrin using X-ray crystallography. These structures reveal that an A-form NAD+ is tightly but not covalently bound to each subunit of LuHNL. The restricted movement of the NAD+ molecule is due to the “sandwich structure” on the adenine moiety of NAD+. Moreover, the structures and mutagenesis analysis reveal a novel reaction mechanism for cyanohydrin decomposition involving the cyano-zinc complex and hydrogen-bonded interaction of the hydroxyl group of cyanohydrin with Glu323/Thr65 and H2O/Lys162 of LuHNL. The deprotonated Lys162 and protonated Glu323 residues are presumably stabilized by a partially desolvated microenvironment. In summary, the substrate binding geometry of LuHNL provides insights into the differences in activities of LuHNL and ADH, and identifying this novel reaction mechanism is an important contribution to the study of hydroxynitrile lyases.

Cyanogenic compounds removal and characteristics of non- and pregelatinized traditional detoxified wild yam (Dioscorea hispida) tuber flour

The presence of cyanide compounds restricts the utilization of wild yam (Dioscorea hispida) tubers for food or food ingredients. Traditional detoxification, usually used in wild yam chips processing, has not been evaluated for its effectiveness in reducing cyanogenic compounds. Processing into flour will increase wild yam tubers utilization and pregelatinization usually improve flour functional properties. This study aimed to evaluate the effect of 4 traditional detoxification methods and pregelatinization on cyanogenic compounds removal and wild yam tuber flour characteristics. The different methods were in rubbing ash, soaking time, and pregelatinization methods by boiling or steaming. The duration of a particular step was also different. The results showed that traditional detoxification methods reduced total cyanides 97%, cyanogenic glycosides 98-100%, acetone cyanohydrin 89-97%, and HCN 94-95%; also affected degree of cyanogenic compounds removal. Pregelatinization also reinforced the degree of cyanogen removal. Tuber flour physicochemical properties were affected by detoxification methods and pregelatinization. Modification of starch might occur due to the presence of SiO2 and calcium in rubbing ash and affected functional properties of wild yam tuber flour. Starch granule morphology appeared not to be affected by detoxification methods. Traditional detoxification methods could be used to make a safe wild yam tuber flour.

Comparison of cyanide content in arbila beans (Phaseolus lunatus l) of East Nusa Tenggara using picrate and acid hydrolysis methods

Arbila beans contains cyanogenic compounds in the form of linamarin (cyanoglucosides), acetone cyanohydrin, and free cyanide, all together constitute total cyanide content. The objective of this study was to compare the cyanide content in arbila beans analyzed by picrate and acid hydrolysis methods. Picrate method measures total cyanide only. Cyanide content was identified by using a picrate paper, which turned into yellow. The absorbance was measured by a spectrophotometer at 510 nm. Acid hydrolysis method measures cyanide in arbila beans in the form of linamarin, acetone cyanohydrin, and free cyanide. Linamarin wa hydrolyzed in H3PO4 solution. Estimated cyanide levels was measured by using a colorimetric procedure. Data was analyzed using Independent sample t-test (SPSS v.16). The results showed that, there was no difference in the total level of cyanide in both methods. Total cyanide measured by picrate and acid hydrolysis method was 2705.17 ppm and 2693.29 ppm, respectively. In addition, the three forms of cyanide content were as follows: linamarin 926.22 ppm, cyanohydrin 556.01 ppm, and free cyanide 1211.06 ppm. Based on the results, both methods can be used for total cyanide analysis. To determine the form of cyanide other than total cyanide, it is recommended to use the acid hydrolysis method.

Programmed Formation of HCN Oligomers through Organosulfur Catalysis.

An efficient, inexpensive, and reliable synthesis of diaminomaleonitrile (DAMN, 1) is described starting from readily available acetone cyanohydrin as the source of hydrogen cyanide (HCN). Diaminomaleonitrile (DAMN) is known to be an important intermediate in heterocyclic and medicinal chemistry as well as being a possible precursor for the origin of life's hypothesis within prebiotic chemistry. The mechanism of its formation through organosulfur catalysis has been investigated by electrospray ionization mass spectrometry (ESI-MS) using two newly synthesized cationic "marker" molecules as a tool that allows for sensitive detection. As a result, the proposed mechanism of a thiocyanate-mediated synthesis of the HCN tetramer DAMN starting from organic disulfides was confirmed.

Cyanovinylation of Aldehydes: Organocatalytic Multicomponent Synthesis of Conjugated Cyanomethyl Vinyl Ethers.

A novel organocatalytic multicomponent cyanovinylation of aldehydes was designed for the synthesis of conjugated cyanomethyl vinyl ethers. The reaction was implemented for the synthesis of a 3-substituted 3-(cyanomethoxy)acrylates, using aldehydes as substrates, acetone cyanohydrin as the cyanide anion source, and methyl propiolate as the source of the vinyl component. The multicomponent reaction is catalyzed by N-methyl morpholine (2.5 mol%) to deliver the 3-(cyanomethoxy)acrylates in excellent yields and with preponderance of the E-isomer. The multicomponent reaction manifold is highly tolerant to the structure and composition of the aldehyde (aliphatic, aromatic, heteroaromatics), and it is instrumentally simple (one batch, open atmospheres), economic (2.5 mol% catalyst, stoichiometric reagents), environmentally friendly (no toxic waste), and sustainable (easy scalability).

Tris(pentafluorophenyl)borane-Catalyzed Formal Cyanoalkylation of Indoles with Cyanohydrins.

Despite the significant achievements related to the C3 functionalization of indoles, cyanoalkylation reactions continue to remain rather limited. We herein report on the formal C3 cyanoalkylation of indoles with cyanohydrins in the presence of a tris(pentafluorophenyl)borane (B(C6F5)3) catalyst. It is noteworthy that cyanohydrins are used as a cyanoalkylating reagent in the present reaction, even though they are usually used as only a HCN source. Mechanistic investigations revealed the unique reactivity of the B(C6F5)3 catalyst in promoting the decomposition of a cyanohydrin by a Lewis acidic activation through the coordination of the cyano group to the boron center. In addition, a catalytic three-component reaction using indoles, aldehydes as a carbon unit, and acetone cyanohydrin that avoids the discrete preparation of each aldehyde-derived cyanohydrin is also reported. The developed methods provide straightforward, highly efficient, and atom-economic access to various types of synthetically useful indole-3-acetonitrile derivatives containing α-tertiary or quaternary carbon centers.

Cyanide detoxification methods in food: A review

Cyanide is a toxic substance found in several tubers such as cassava (Manihot esculenta), wild yam (Dioscorea hispida Dennts), some cerealia and legumes. In the plants, it can be in the form of cyanogenic glycosides, acetone cyanohydrin, and hydrogen cyanide (HCN). Cyanogenic glycosides such as linamarin and lotaustralin belong to the product of secondary metabolism. The characteristic of cyanogenic glycosides is intermediately polar, water-soluble, and often accumulated in the vacuoles of plant cells. Acetone cyanohydrins are intermediates product from cyanogenic glycosides and cyanide acid in plant tissues. HCN, hydrogen cyanide, is a volatile and water-soluble compound. The toxic effect of cyanide in humans is inactivation of cytochrome oxidase, respiratory disorders, sore throat, dizziness, limpness, convulsions, and lethal effects. Cyanide can be removed by several processes before consumption. Methods such as peeling, washing, heating, drying, fermenting and chemical treatment are used to remove or reduce cyanide. The treatment can damage the structure of the cell and hydrolyzed the cyanogenic glycosides to acetone cyanohydrin and glucose by endogenous enzyme like linamarase. A second enzyme, hydroxynitril lyase, can dissociate acetone cyanohydrins to HCN, ketone and aldehyde compound. The maximum safe level for total cyanide in food is 10 ppm. This review aims at updating the available knowledge on the various detoxification cyanide in food.

Asymmetric Hydrocyanation of N‐Phosphinoyl Aldimines with Acetone Cyanohydrin by Cooperative Lewis Acid/Onium Salt/Brønsted Base Catalysis

Abstractα‐Amino acids are of fundamental importance for life. Both natural and artificial α‐amino acids also play a crucial role for pharmaceutical purposes. The catalytic asymmetric Strecker reaction still provides one of the most attractive strategies to prepare scalemic α‐amino acids. Here we disclose a new concept for Strecker reactions, in which an achiral Brønsted base cooperates with a Lewis acid and an aprotic ammonium salt, which are both arranged in the same chiral catalyst entity. The described method could successfully address various long‐standing practical issues of this reaction type. The major practical advantages are that (1) the N‐protecting group is readily removable, (2) acetone cyanohydrin is attractive as cyanation reagent in terms of atom economy and cost efficiency, (3) an excess of the cyanation reagent is not necessary, (4) the new method does not require additives and (5) is performed at ambient temperature.

Facile Amberlyst A-21 catalyzed access of β-hydroxynitriles via epoxide opening in water

β-Hydroxynitriles are essential intermediates in the synthesis of diverse bioactive compounds and clinical drugs. One of the precursor reactions to these intermediates is the opening of an epoxide ring with a cyanide nucleophile. In the present study, we report a milder and safer route to β-hydroxynitriles employing recyclable, Amberlyst A-21 resin in the ring-opening of epoxides with acetone cyanohydrin in water. A diverse range of substrates (fifteen), including aromatic epoxides, phenoxy epoxides, non-terminal, and terminal aliphatic epoxides, are investigated under the optimized conditions to afford the desired β-hydroxynitriles in good to excellent yield. In addition to this, the recyclability of the Amberlyst A-21 resin is also successfully demonstrated. This relatively safer methodology has the potential to be explored in other organic transformations.

Methods for the Synthesis of Methacrylic Acid and Methacrylates

The review provides an analysis of the literature on the existing processes for obtaining an important organic product – methacrylic acid and its ester – methyl methacrylate. The main methods of their industrial production are the synthesis from acetone and hydrocyanic acid (the acetone cyanohydrin method) and catalytic syntheses from petrochemical raw materials –ethylene, propylene and isobutylene.

Increasing Health Benefit of Wild Yam (Dioscorea hispida) Tuber by Red Mold (Angkak) Fermentation

Detoxification of cyanogen is very important in cyanide containing tubers such as wild yam (Dioscorea hispida). Principally, cyanogen detoxification is by converting cyanogenic glycoside into acetone cyanohydrin and further converted into free HCN that is easily removed by heating or soaking. Conversion of cyanogenic glycoside into free HCN is catalyzed by beta glucosidase enzyme (linamarase) in linamarin deglycosilation and a- hydroxyinitril liase (HNL) in acetone cyanohydrin degradation into free HCN and acetone. Endogen linamarase is found in the tubers and exogenous linamarase might be from microbes. It is supposed that fermentation of wild yam by angkak will reduce cyanide level. Angkak or Red Mold Rice (RMR) is a product of rice fermentation using Monascus sp mainly M. purpureus. Beside red pigment, angkak fermentation also produces a variety of secondary metabolites such as lovastatin, mevinolin, and citrinin. Monacolin K (lovastatin) from Monascus purpureus is an inhibitor for HMG-CoA reductase in cholesterol biosynthesis. Monacolin K production is higher in Dioscorea substrate compared to rice. RMD (Red Mold Dioscorea) reveals higher anti-cholesterol activity and anti-hypertension than red mold rice. RMD also exhibits antioxidant, anti-diabetic, anti-obesity, and induces cancer sell apoptosis and does not reveal mutagenic and toxicity. In RMD, monascin and ankaflavin have a role in reducing cholesterol. It is expected that wild yam fermentation by angkak will reduce cyanide level and produce health beneficial secondary metabolites.

Study on the Reaction of Acetone Cyanohydrin with 3,5-Dimethyl-N-α,β-unsaturated Acyl Pyrazole

Study on the Reaction of Acetone Cyanohydrin with 3,5-Dimethyl-<i>N</i>-<i>α,β</i>-unsaturated Acyl Pyrazole