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An efficient construction of oxazoline-containing polycyclic scaffolds is presented through a Pd-catalyzed addition/cyclization of (hetero)arenes tethered O-acyl cyanohydrin units and arylboronic acids. A diversity of oxazoline-containing polycyclic compounds can be prepared in good to high yields under the mild reaction conditions. This method can be extended to prepare multi-substituted polycyclic heterocyclic compounds via a Pd-catalyzed addition/cyclization/arylation tandem sequence by using arylboronic acid and different heteroarene scaffolds such thiophene, pyrrole and furan analogues.

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.

A new porous metal–organic framework (MOF) with the chemical formula [Y5L6(OH)3(DMF)3]·5H2O (1) (where L = 3-amino-4-hydroxybenzoate) has been prepared by a solvothermal procedure. The structural characterization reveals that this material consists of a robust three-dimensional metal–organic framework (MOF) grown with clusters formed by Y(III) and hydroxide anions joined to one another by the ligand, giving rise to an open structure with interconnected microchannels with variable dimensions. This assembled set has shown to possess a fascinating catalytic activity for the cyanosilylation of a broad range of aldehydes and ketones with exceptional recyclability, a solvent-free medium, and one order of magnitude lower catalyst loading compared to all related lanthanide-based MOFs described so far in the literature.

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 .

Hydroxynitrile lyases (HNLs) are sought-after, stereo-selective biocatalysts used in the agrochemical, pharmaceutical and fine chemical industries to produce cyanohydrin enantiomers. There ...

Despite widespread use as a synthetic method, as well as rapid expansion of substrate scope, the precise mechanism and kinetics of photoredox coupled hydrogen atom transfer (HAT) reactions remain poorly understood. This results from a lack of detailed kinetic information, as well as the identification of side reactions and products. In this report, a mechanistic study of a prototypical tandem photoredox/HAT reaction coupling cyclohexene and 1,4-Dicyanobenzene (DCB) using an Ir(ppy)3 photocatalyst and thiol HAT catalyst is reported. Through a combination of electrochemical, photochemical, and spectroscopic measurements, key unproductive pathways and side products are identified and rate constants for main chemical steps are extracted. The reaction quantum yield was found to decline rapidly over the course of the 20-hour reaction. A previously unreported cyanohydrin side product was identified and thought to play a key role as proton acceptor in the reaction. Transient absorption spectroscopy (TAS) suggested a reaction mechanism that involves trapping of the DCB radical anion by cyclohexene with HAT occurring as the final step via a cooperative HAT step. Kinetic modeling of the reaction, using rate constants derived from TAS, demonstrates that the efficiency of the reaction is limited by parasitic absorption and unproductive quenching between excited Ir(ppy)3 and the cyanohydrin photoproduct.

The cyanosilylation was performed by using metavanadate catalysts, and in situ measurements revealed the formation of [VO2(CN)3]2− and [VO4TMS2]− under reaction conditions. The reaction of [VO2(CN)3]2−, trimethylsilyl cyanide (TMSCN), and water afforded [VO4TMS2]− and CN−, which reacted with ketones to yield the corresponding cyanohydrin trimethylsilyl ethers over [VO2(CN)3]2−. Compound [VO2(CN)3]2− showed high catalytic performance for cyanosilylation of various carbonyl compounds. In the case of n-hexanal, turnover frequency reached up to 250 s−1.

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)., This research was funded by the Spanish Ministry of Science, Innovation and Universities (MICINN), State Research Agency (AEI) and the European Regional Development Funds (ERDF) (PGC2018-094503-B-C21)

The catalytic enantioselective addition of glyoxylate cyanohydrin to imines to afford α-keto-β-amino acid equivalents is reported. Sterically tuned aminobenzothiadiazine catalysts provided high yields and stereoselectivities (up to 100% yield, 99% ee, >99:1 dr) for both aromatic and aliphatic imines, and the stereodivergent synthesis of both diastereomers was achieved. The optimal catalytic system was scalable, even with a low catalyst loading. The resulting adducts were converted into various chiral building blocks, including β-amino acid analogues, which are important motifs in medicinal chemistry, while maintaining a high enantiomeric excess.

A new Ni(II)-based metal–organic framework with the chemical formula of (Me2NH2)[Ni3(L)2(μ3-OH)(H2O)]·2DMF (1) have been designed and synthesized by the reaction of 3-phenylpyridine polycarboxylic (H3L) ligands and Ni(NO3)2·6H2O in a mixed solvent of DMF and water under the solvothermal conditions. The resulting solvent-free 1a was found to be catalytically active for the cyanosilylation reaction of aromatic aldehydes with nitro substituent in varying positions in the presence of trimethylsilyl cyanide to afford cyanohydrin trimethylsilyl ethers in a shape and size selective manner. The as-prepared 1 did not exhibit catalytic activities for the same reaction. Based on the experimental results, a possible catalytic mechanism has also been proposed. We next examined the cell viability with CCK-8 assay and the cell proliferation with plate colony formation assay. Both experiments suggested the inhibitory effect of compound 1a on human promyelocytic leukemia cancer HL-60 cells. For the mechanism exploration, the ROS content in HL-60 cancer cells was measured with detection kit, results also indicated the compound 1a increased the level of ROS in HL-60 cells, which may the reason of the compound’s anti-cancer activity.

Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C(10)N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed late-stage decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C(10)N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.

Thermodynamic and kinetic control of a chemical process is the key to access desired products and states. Changes are made when 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 direct reaction pathways in order to selectively afford desired products in high reaction rates while avoiding the formation of byproducts. The utility of CO2-mediated selective cyanohydrin synthesis was further showcased by broadening Kiliani-Fischer synthesis to offer an easy access to variety of polyols, cyanohydrins, linear alkylnitriles, by simply starting from alkyl- and arylaldehydes, KCN and atmospheric pressure of CO2.

The liquid-phase hydrogenation of the aromatic cyanohydrin mandelonitrile (MN, C6H5CH(OH)CN) over a carbon-supported Pd catalyst to produce the primary amine phenethylamine (PEA, C6H5CH2CH2NH2) is investigated with respect to the transition from operation in single-batch mode to repeat-batch mode. While a single-batch reaction returns a complete mass balance, product analysis alongside mass balance measurements for a six-addition repeat-batch procedure shows an attenuation in the rate of product formation and an incomplete mass balance from the fourth addition onward. This scenario potentially hinders possible commercial operation of the phenethylamine synthesis process, so it is investigated further. With reference to a previously reported reaction scheme, the prospects of sustained catalytic performance are examined in terms of acid concentration, stirrer agitation rate, catalyst mass, and hydrogen availability. Gas-liquid mass transfer coefficient measurements indicate efficient gas → liquid transfer kinetics within the experimental constraints of the Henry's law limitation on hydrogen solubility in the process solvent (methanol). Deviations from the optimized product selectivity are attributed to mass transport constraints, specifically the H2(solv) → 2H(ads) transition, which is ultimately restrained by the availability of H2(solv). Finally, in an attempt to better understand the deactivation pathways, inelastic neutron scattering measurements on a comparable industrial-grade catalyst operated in an analogous reaction in fed-batch mode indicate the presence of an oligomeric overlayer postreaction. This overlayer is thought to be formed via oligomerization of hydroxyimine or imine species via specific pathways that are identified within a postulated global reaction scheme.

Granulicella tundricolahydroxynitrile lyase (GtHNL) is a manganese dependent cupin which catalyses the enantioselective synthesis of (R)-cyanohydrins. TheGtHNL triple variant A40H/V42T/Q110H, previously reported to exhibit a high activity and stability, was immobilised on Celite R-633 by adsorption. The synthesis of (R)-mandelonitrile catalysed by immobilised enzyme in a rotating bed reactor was compared to a continuous flow reactor. A batch reaction was used as reference system and organic solvent (MTBE) was used as reaction medium to suppress the chemical background reaction, ensuring the synthesis of enantiopure cyanohydrin. The rotating bed reactor, designed to boost conversion rates due to enhanced mass transfer, did not greatly enhance the reaction displaying a rate 1.7 times higher than the reference batch model. Moreover, similar conversion (96% after 4 hours) and recyclability were observed as compared to the reference system. The continuous flow reactor displayed rates 2 and 3 times higher than the rotating bed and the reference batch systems, respectively. Good conversions were achieved within minutes (97% conversion in 4 minutes at 0.1 mL min−1). The immobilised enzyme displayed excellent enantioselectivity and high operational stability under all evaluated conditions. Overall,GtHNL triple variant A40H/V42T/Q110H immobilised on Celite R-633 is an excellent catalyst for the synthesis of (R)-mandelonitrile with a great potential for continuous flow production of cyanohydrins.

Nitrile hydration provides access to amides that are indispensable to researchers in chemical and pharmaceutical industries. Prohibiting the use of this venerable reaction, however, are (1) the dearth of biphasic catalysts that can effectively hydrate nitriles at ambient temperatures with high turnover numbers and (2) the unsolved challenge of hydrating cyanohydrins. Herein, we report the design of new “donor–acceptor”-type platinum catalysts by precisely arranging electron-rich and electron-deficient ligands trans to one other, thereby enhancing both the nucleophilicity of the hydroxyl group and the electrophilicity of the nitrile group. Leveraging a high-throughput, automated workflow and evaluating a library of bidentate ligands, we have discovered that commercially available, inexpensive DPPF [1,1′-ferrocenendiyl-bis(diphenylphosphine)] provides superior reactivity. The corresponding “donor–acceptor”-type catalyst 2a is readily prepared from (DPPF)PtCl_2, PMe_2OH, and AgOTf. The enhanced activity of 2a permits the hydration of a wide range of nitriles and cyanohydrins to proceed at 40 °C with excellent turnover numbers. Rational reevaluation of the ligand structure has led to the discovery of modified catalyst 2c, harboring the more electron-rich 1,1′-bis[bis(5-methyl-2-furanyl)phosphino] ferrocene ligand, which demonstrates the highest activity toward hydration of nitriles and cyanohydrins at room temperature. Finally, the correlation between the electron-donating ability of the phosphine ligands with catalyst efficiencies of 2a, 2c, 2d, and 2e in the hydration of nitrile 7 are examined, and the results support the “donor–acceptor” hypothesis.

Two known lanthanide complexes, [KLa(HL 1 ) 2 {(CH 3 ) 2 NCHO} 2 (H 2 O) 3 ] ( 1 ) and [Sm(H 2 O) 9 ]( E -H 2 L 2 ) 3 ·2H 2 O ( 2 ) were prepared by reaction of lanthanum(III) and samarium(III) nitrates with potassium 3-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)-2-hydroxy-5-nitrobenzenesulfonate (KH 2 L 1 ) and potassium ( E,Z )-5-chloro-3-(2-(1,3-dioxo-1-phenylbutan-2-ylidene)hydrazinyl)-2-hydroxybenzenesulfonate (KH 2 L 2 ), respectively. Catalytic activities of 1 and 2 were evaluated in the cyanosilylation of aldehydes with trimethylsilyl cyanide in different solvents such as tetrahydrofuran, dichloromethane or methanol. Complex 1 was found to be efficient catalyst for the cyanosilylation reaction in methanol medium at room temperature, producing cyanohydrin trimethylsilyl ethers with good yields (76–99%).

A chemoselective phosphine-catalyzed cyanoacylation of α-dicarbonyl compounds is reported. Under the catalysis of P(NMe2)3, the cyanoacylation of α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with acyl cyanides exclusively proceeds under very mild conditions, affording a wide range of cyanohydrin esters bearing one quaternary stereocenter in moderate to excellent yields. It represents the first phosphine-catalyzed cyanoacylation of α-dicarbonyl compounds and also provides a general method to prepare fully substituted cyanohydrin esters.

A series of known metal complexes, [LaL2(NO3)(H2O)2]·5H2O (1), [Zn(μ-L)(NO3)(H2O)]n (2), {[Cd2(μ-HL)(μ-L)(NO3)3(H2O)]·H2O}n (3) and [Hg(μ-L)(N3)]n·nH2O (4), were synthesized from the corresponding metal salts and 2-pyridinecarboxaldehyde isonicotinoylhydrazone (HL), and demonstrated high activity and selectivity in the cyanosilylation of aldehydes. Although all the complexes are derived from the same HL hydrazone ligand, the catalytic activity of 1–4 is different and relates to the metal center and coordination environment, whereas complex 1 being the most effective homogeneous Lewis acid-base catalyst towards the synthesis of cyanohydrin trimethylsilyl ethers from both aliphatic and aromatic aldehydes with yields up to 96.3 % in 6 h in methanol solution and at room temperature. According to the proposed mechanism, both coordination and noncovalent interactions (hydrogen and tetrel bonds) play a significant role and account for the higher catalytic activity of complex 1.

Reactions of pyrazine-2,3-dicarboxylic acid (H2pzdc), cobalt nitrate and lanthanide (Ln) oxide under hydrothermal conditions result in four new 3d-4f heterometal coordination polymers, namely, [Ln2Co(pzdc)4(H2O)6]·2H2O [Ln = La (1), Pr (2), Eu (3) and Gd (4)]. All compounds were characterized by elemental analysis, infrared spectroscopy, thermal gravimetric analysis, and X-ray diffraction. The compounds exhibit a three-dimensional (3D) brick-like structure with rectangular-shaped nano-scale channels along a axis direction, made up of wave-like layers containing [Ln(pzdc)]+ units, which are connected by one-dimensional (1D) chain of [Co(pzdc)2]2–. The catalytic properties of compounds 1 and 3 were investigated in the synthesis of cyanohydrins at room temperature under solventless conditions. They showed similar catalytic activities with very high conversions of benzaldehyde and high selectivity towards cyanohydrin. The control experiment without addition of the coordination polymers only reached 16 % conversion. Other aldehydes could also be converted totally under shorter reaction times also with very high selectivities for the corresponding cyanohydrins. Compound 1 could also be recycled in another catalytic cycle.

Two known organotin(IV) complexes, [Sn(C6H5)3HL1] (1) and [Sn(C2H5)2(1κO,2κO-H3L2) (1κO2-H3L2) (μ3-O)]2 (2), were prepared upon interaction of Ph3SnCl and Et2SnO with 2-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)benzoic acid (H2L1) and 2-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) hydrazinyl)benzoic acid (H4L2), respectively, in toluene solution. Both complexes are applied as catalysts in cyanosilylation of aldehydes. Complex 2 shows a high catalytic activity in the cyanosilylation reaction of a variety of aliphatic and aromatic aldehydes with trimethylsilyl cyanide yielding to the corresponding cyanohydrin trimethylsilyl ethers (yields up to 99%) in methanol and at room temperature.

The new trinuclear [Co II (H 2 O) 2 (Me 2 NCHO) 2 {Co III (1κ NOO′ :2κ O″ -μ-HL)} 2 (1κ NOO′ )]·2H 2 O ( 1 ) and polymeric [Co II (1κ NOO′ :2κ O″ -μ-HL)(MeOH) 2 ] n ( 2 ) complexes were isolated by the reaction of ( Z )-2-(2-(1,3-dioxo-1-(phenylamino)butan-2-ylidene)hydrazinyl)benzoic acid (H 3 L) with CoCl 2 ·6H 2 O and Co(ClO 4 ) 2 ·6H 2 O, respectively, in a mixture of DMF/MeOH (1/10, v/v), in the presence of Et 3 N at room temperature, and characterized by IR and ESI-MS spectroscopies, elemental and X-ray crystal structural analyses. In both structures the cobalt centres display distorted octahedral geometries. The structural units in 1 and 2 are connected via intermolecular hydrogen bonds involving the coordinated HL 2− and the bound and non-bound water molecules (in 1 ) or the methanol ligands (in 2 ) which provides supramolecular networks. 1 and 2 are catalyst precursors for the cyanosilylation reaction of a variety of both aromatic and aliphatic aldehydes with trimethylsilyl cyanide leading to the corresponding cyanohydrin trimethylsilyl ethers in high yields (up to 89%) in methanol and at room temperature.

We prepared a magnetically recoverable imidazolium hydrogen carbonate by immobilizing an imidazolium hydrogen carbonate on magnetite and applied it as an N-heterocyclic carbene catalyst to the cyanosilylation of aldehydes and ketones. By employing the magnetite-supported imidazolium hydrogen carbonate as a catalyst, the cyanosilylation proceeded at 60 °C to provide the corresponding trimethylsilylated cyanohydrin in a fair chemical yield. Moreover, after the reaction, the magnetic catalyst was readily recovered by use of an external magnet and could be reused up to five times.

A carbon supported Pd catalyst is used in the liquid phase hydrogenation of the aromatic cyanohydrin mandelonitrile (C6H5CH(OH)CH2CN) to afford the primary amine phenethylamine (C6H5CH2CH2NH2). Employing a batch reactor, the desired primary amine is produced in 87% selectivity at reaction completion. Detection of the by-product 2-amino-1-phenylethanol (C6H5CH(OH)CH2NH2) accounts for the remaining 13% and closes the mass balance. The reaction mechanism is investigated, with a role for both hydrogenation and hydrogenolysis processes established.

The novel Ag(I) and Cu(II) coordination polymers [Ag(&mu, 3-1&kappa, O, 2:3&kappa, O&prime, 4&kappa, N-HL)]n∙n/2H2O (1) and [Cu(en)2(&mu, 1&kappa, 2&kappa, N-L)]n∙nH2O (2) [HL&minus, = 2-(2-(1-cyano-2-oxopropylidene)hydrazinyl)benzene sulfonate] were synthesized and characterized by IR and ESI-MS spectroscopies, elemental and single crystal X-ray diffraction analyses. Compounds 1 and 2 as well as the already known complex salt [Cu(H2O)2(en)2](HL)2 (3) have been tested as homogenous catalysts for the cyanosilylation reaction of different aldehydes with trimethylsilyl cyanide, to provide cyanohydrin trimethylsilyl ethers. Coordination polymer 2 was found to be the most efficient one, with yields ranging from 76 to 88% in methanol, which increases up to 99% by addition of the ionic liquid [DHTMG][L-Lactate].

Synthesis of the valuable unsymmetric 1,8-dicarbonyl compounds remains underexplored currently. Herein, we disclose a new strategy for the synthesis of 1,8-diketones through the coupling of cyclopropanols and cyanohydrins under visible-light irradiation. The protocol features a cascade of intriguing ring opening of cyclopropanols and remote cyano migration. The unfavorable addition of an alkyl radical to an electron-rich alkene is facilitated by the intramolecular cyanohydrin interception. A variety of multiply functionalized 1,8-diketones are furnished in useful yields. The products could be further transformed into other valuable compounds, manifesting the utility of this method.

Enantiopure &beta, amino alcohols constitute one of the most significant building blocks for the synthesis of active pharmaceutical ingredients. Despite the availability of a range of chiral &beta, amino alcohols from a chiral pool, there is a growing demand for new enantioselective synthetic routes to vicinal amino alcohols and their derivatives. In the present study, an asymmetric 2-step catalytic route that converts 4-anisaldehyde into a &beta, amino alcohol derivative, (S)-tembamide, with excellent enantiopurity (98% enantiomeric excess) has been developed. The recently published initial step consists in a concurrent biocatalytic cascade for the synthesis of (S)-4-methoxymandelonitrile benzoate. The O-benzoyl cyanohydrin is then converted to (S)-tembamide in a hydrogenation reaction catalyzed by Raney Ni. To achieve hydrogenation of the nitrile moiety with highest chemoselectivity and enantioretention, various parameters such as nature of the catalyst, reaction temperature and hydrogen pressure were studied. The reported strategy might be transferrable to the synthesis of other N-acyl-&beta, amino alcohols.

The first example of Pd-catalyzed intramolecular C-H addition of indoles bearing cyanohydrin components at the C(3), C(2), and N(1) positions to nitriles is described. A wide range of functionalized partially saturated carbazoles, tetrahydropyrido[1,2-a]indole, and carbazoles can be prepared in good to excellent yields under the optimal conditions. In addition, fused polycyclic indoles with seven- or eight-membered rings can also be formed smoothly.

GtHNL from Granulicella tundricola is a Mn(II) containing hydroxynitrile lyase with a cupin fold. The quasi-octahedral manganese is pentacoordinated by the enzyme. It catalyzes the enantioselective addition of HCN to aldehydes, yielding R-cyanohydrins. On the Lewis acidic vacant coordination site the Mn binds either substrate or the product, leading to a hexacoordinated 17 electron complex. EPR spectra of the active enzyme are unusually wide with a zero-field splitting approximately equal to the X-band microwave energy. A spectral change is induced by incubation with either one of the substrates/products HCN, benzaldehyde, and/or mandelonitrile. This points toward Mn(II) catalyzed cyanohydrin synthesis.

An active nickel catalyst prepared in situ from a Ni(II) compound, phosphine ligand, and zinc powder was found to be an efficient catalyst system for the hydrocyanation of various alkenes using acetone cyanohydrin as a safer cyano source. The combination of NiCl2·6H2O and 1,3-bis(diphenylphosphino)propane was the most efficient catalyst precursor in DMF. Under the optimized conditions, various styrenes, heterocyclic alkenes, and aliphatic alkenes were converted to their corresponding nitriles in excellent yields.

The absolute stereochemistry of cyanohydrins, derived from ketones and aldehydes, is obtained routinely, in a microscale and derivatization-free manner, upon their complexation with Zn-MAPOL, a zincated porphyrin host with a binding pocket comprised of a biphenol core. The host-guest complex leads to observable exciton-coupled circular dichroism (ECCD), the sign of which is easily correlated to the absolute stereochemistry of the bound cyanohydrin. A working model, based on the ECCD signal of cyanohydrins with known configuration, is proposed.

Hydroxynitrile lyases (HNLs) are increasingly finding application in synthesis of enantiomerically pure cyanohydrins. Cyanohydrins are important intermediates in the production of pharmaceuticals and agrochemicals. In the present studies seeds of wild apricot (Prunus armeniaca L.) have emerged as potential source of hydroxynitrile lyase. The HNL of wild apricot (ParsHNL) was purified 8.1 fold and 18.2 % yield with a specific activity of 141 units mg−1 protein. The SDS-PAGE of the enzyme revealed that it consists of subunits of 40 and 37 kDa. However, the molecular weight of holoenzyme was assessed to be 360 kDa. The enzyme showed maximum activity in 0.1 M sodium-citrate buffer having pH 4.75 at 25 °C. Thermostability studies revealed that this HNL showed activity up to 70 °C temperature and quite stable up to 50 °C. Activation energy of ParsHNL was calculated to be 37.83 kJ mol−1. This enzyme has K m of 3.76 mM, V max of 188.4 µmol mg−1 min−1 and k cat of 1130.4 s−1 using mandelonitrile as substrate while for reverse reaction using benzaldehyde as substrate it showed K m of 16.1 mM, V max of 7.21 µmol mg−1 min−1 and k cat of 43.3 s−1. Synthesis of mandelonitrile was carried out using ParsHNL and finally 8.88 mmole (1.184 g) of mandelonitrile was recovered which corresponded to 89 % molar conversion with 96 % ee for R-mandelonitrile. The yield of mandelonitrile was 411 µmol mg−1h−1. These results indicated that ParsHNL has very high potential for synthesis of cyanohydrins and can be used for the production of enantiopure cyanohydrins.

Three-dimensional (3D) cobalt(II) and cadmium(II) metal–organic frameworks (MOFs) bearing rigid 1,4-naphthalenedicarboxylate (1,4-NDC) linkers were prepared and their solid-state structures were characterized by X-ray crystallography. Both Co-MOF and Cd-MOF exhibited isostructural frameworks. 1,4-NDC ligands bridge the metal ions in chelating/bridging and simple bridging modes to form a 1D chains, and these 1D chains are interconnected by 1,4-NDC to form 3D frameworks with the formula of [M2(1,4-NDC)2(DMF)2] (M = CoII or CdII). The as-prepared Cd-MOF was found to be catalytically active for the cyanosilylation reaction of aromatic aldehydes with nitro substituent in varying positions in the presence of trimethylsilyl cyanide to afford cyanohydrin trimethylsilyl ethers in a shape and size selective manner. The catalytic reaction is thought to have mainly occurred inside the Cd-MOF micropores which were generated through the partial dissociation of DMF ligands near the surfaces of Cd-MOF, where openly accessible coordination sites are available once the labile DMF ligands dissociate from CdII ions. The as-prepared Co-MOF did not exhibit catalytic activities for the same reaction.

By reacting copper(II) or nickel(II) salts with sodium 2-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl) benzenesulfonate (NaHL) in an EtOH/H2O solvent mixture and in the presence of ethylenediamine (en), [Cu(HL)2(en)2] (1) or {[Ni(en)3](HL)2}·C2H5OH·6H2O (2) were synthesized, respectively. In MeOH, the coordination polymer [Cu(μ-L1-1κO,NN′N′′:2κO′)]n (3) was obtained, where L1 refers to a dianionic ligand species attained via Schiff-base condensation of NaHL with en on the Cu(II) metal centre, whereas no reaction was obtained in the case of Ni(II). All the compounds were characterised by IR spectroscopy, ESI-MS, elemental and single-crystal diffraction. The Cu(II) compounds 1 and 3 act as effective homogenous catalysts for the cyanosilylation reaction of a variety of aldehydes with trimethylsilyl cyanide affording the corresponding cyanohydrin trimethylsilyl ethers in high yields (up to 93%) and at room temperature.

A convenient one-pot, two-step procedure for the synthesis of ketone cyanohydrin esters in aqueous media is reported using N -acylbenzotriazoles as the acylating agents. In saturated aqueous sodium bicarbonate containing a catalytic amount of tetrabutylammonium bromide, the reaction of ketones with potassium cyanide and N -acylbenzotriazoles proceeded readily at room temperature to provide the corresponding O -acyl cyanohydrin derivatives in good to excellent yields.

Three known multinuclear Zn(II)-arylhydrazone complexes, [Zn{(CH3)2SO}(H2O)(L1)] (1), [Zn2(CH3OH)2(μ-L2)2] (2) and [Zn4(μ-OH)2(1κO:2κO-HL3)4(κO-HL3)2(H2O)4] (3) were prepared upon reaction of ZnCl2 or Zn(CH3COO)2·2H2O with 3-(2-(2-hydroxy-4-nitrophenyl) hydrazineylidene) pentane-2,4-dione (H2L1), 3-(2-(2-hydroxyphenyl)hydrazineylidene)pentane-2,4-dione (H2L2) and 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzoic acid (H2L3), respectively, in methanol solution. Compounds 1–3 were tested as catalysts for the cyanosilylation reaction of a diversity of both aliphatic and aromatic aldehydes with trimethylsilyl cyanide yielding the corresponding cyanohydrin trimethylsilyl ethers in high yields (72–98%) in methanol and at room temperature.

A mechanistic exploration of the liquid phase hydrogenation of the aromatic cyanohydrin mandelonitrile (C6H5CH(OH)CH2CN) over a carbon supported Pd catalyst to produce the primary amine, phenethylamine (C6H5CH2CH2NH2) is conducted. Prior examination showed the reaction to involve the production of the ketone intermediate 2-aminoacetophenone (C6H5C(O)CH2NH2), formed as a consequence of the presence of an acid catalysed tautomeric side reaction. The corresponding deuteration reaction, reported here and analysed by multinuclear NMR spectroscopy and mass spectrometry, is employed to further investigate accessible pathways. Examination of the resultant product distribution of the deuteration, and the location of deuterium incorporation establishes the role of a hydroxy-imine species as a key reaction intermediate. In addition, the acid catalysed tautomerism to the ketone is shown to be a reversible side reaction, but also a contributor to desired product formation. Moreover, an order for the three critical hydrogen consuming steps in phenethylamine formation is established. Hydrogenation of the nitrile functionality to afford the hydroxy-imine precedes hydrogenolysis of the hydroxyl group, with the final step being hydrogenation of the imine to form the target product, phenethylamine.

Two transition-metal containing heteropolyniobates, H[Ni(en)3]5[VNb12O40(VO)2]·15H2O (1) and H3[Cu(en)2]4[VNb12O40(VO)2]·13H2O (2) (en = ethylenediamine), based on dicapped vanadium keggin polyoxoniobates have been synthesized by using ethylene glycol and water as a mixed solvent and characterized by various means. Due to the synergy between polyoxoniobate anions and transition-metal chelates, 1 and 2 showed remarkable catalytic performance for cyanosilylation of various aldehydes and ketones, giving the corresponding cyanohydrin trimethylsilyl ethers with high yields in short time. In particular, with 0.1 mol% loading of 1, the turnover frequency (515.5 h−1) for the cyanosilylation of benzaldehyde was higher than those of previously reported heterogeneous polyoxometalates catalysts.

A highly regio- and stereospecific rhodium-catalyzed allylic alkylation of tertiary allylic carbonates with alkenyl cyanohydrin pronucleophiles is described. This protocol offers a fundamentally novel approach toward the synthesis of acyclic quaternary-substituted α,β-unsaturated ketones and thereby provides a new cross-coupling strategy for target directed synthesis. A particularly attractive feature with this process is the ability to directly couple di-, tri- and tetrasubstituted alkenyl cyanohydrin pronucleophiles to prepare the corresponding α,β-unsaturated ketone derivatives in a highly selective manner. Additionally, the chemoselective 1,4-reduction of the enone products provides rapid access to acyclic enantiomerically enriched α,α'-dialkyl-substituted ketones, which are challenging motifs to prepare using conventional enolate alkylation.

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Here we present a systematic investigation of the cyanosilylation of aldehydes with trimethylsilyl cyanide (TMSCN) by using metal–organic frameworks (MOFs) as catalysts. Four types of thermally stable MOFs (MIL-47 (V), MIL-53 (Al), MIL-101 (Cr), and UiO-66 (Zr)) constructed with the same organic linker, terephthalic acid, were studied, among which MIL-101 (Cr) exhibits the highest catalytic activity. Experimental results revealed that the catalytic activities are in close relation with the types of coordinatively unsaturated metal ions, pore sizes as well as solvents. Using MIL-101 (Cr) as the catalyst, both aliphatic and aromatic aldehydes were efficiently transformed to cyanohydrin trimethylsilyl ether, meanwhile significant size selectivities and electronic effects have also been observed. The solvent-free reaction conditions not only provide a high TON for MOF catalyzed cyanosilylation, but also render the current protocol more attractive to industrial applications.

Hydroxynitrile lyases (HNLs) catalyse the reversible cleavage of cyanohydrins to carbonyl compounds and HCN. The recent discovery of bacterial HNLs with a cupin fold gave rise to a new promising class of these enzymes. They are interesting candidates for the synthesis of cyanohydrins on an industrial scale owing to their high expression levels in Escherichia coli. The activity and enantioselectivity of the manganese-dependent HNL from Granulicella tundricola (GtHNL) were significantly improved by site-saturation mutagenesis of active site amino acids. The combination of beneficial mutations resulted in a variant with 490-fold higher specific activity in comparison to the wild-type enzyme. More importantly, GtHNL-A40H/V42T/Q110H is a highly competitive alternative for the synthesis of chiral cyanohydrins, such as 2-chlorobenzaldehyde cyanohydrin, (R)-2-hydroxy-4-phenylbutyronitrile, and (R)-2-hydroxy-4-phenyl-3-butene nitrile, which serve as intermediates for the synthesis of pharmaceuticals.

Cyanide ions are shown to interact with lanthanide complexes of phenacylDO3A derivatives in aqueous solution, giving rise to changes in the luminescence and NMR spectra. These changes are the consequence of cyanohydrin formation, which is favored by the coordination of the phenacyl carbonyl group to the lanthanide center. These complexes display minimal affinity for fluoride and can detect cyanide at concentrations less than 1 μm. By contrast, lanthanide complexes with DOTAM derivatives display no affinity for cyanide in water, but respond to changes in fluoride concentration.

This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling.The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-Lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen complex with a tertiary amine as a catalytic system in the enantioselective synthesis of O-acylated cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step.The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of O-acylated and O-formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved.