Methyl Cyanoformate Research Articles

Repurposing Mander's reagent for the first direct carbonyl deoxycyanation: Synthesis of oxoalkenenitriles from 1,3-diketones

The deoxycyanation of ketones is an uncommon reaction. Recently, we demonstrated that alkyl cyanoformates, such as methyl cyanoformate (Mander's reagent) or ethyl cyanoformate, can perform deoxycyanation on 1,3-diketones to deliver oxoalkenenitriles directly. This represents a significant departure from the typical reactivity of these reagents, which are predominantly used for the synthesis of β-ketoesters (α-acylation). By transitioning from lithium bases to amine-based bases, the selectivity of the acylation shifts from carbon to oxygen, yielding an enol carbonate intermediate. Density Functional Theory (DFT) investigations and in vitro experiments corroborate the synthetic outcome, namely, the synthesis of oxonitriles via deoxycyanation. The reaction mechanism was studied, revealing a series of sequential additions and eliminations consistent with the mechanistic proposal for the generation of a major byproduct, which poses one of the main drawbacks of this method. Although this approach was proven to be non-general, it represents the first direct synthesis of oxoalkenenitriles through a deoxycyanation process, thereby deviating from the conventional C-selective applications of alkyl cyanoformates.

Dissipative Cyclic Reaction Networks: Mechanistic Insights into a Minor Enantiomer Recycling Process

AbstractAn analysis of an out‐of‐equilibrium cyclic reaction network which continuously converts a minor undesired product enantiomer to the desired major enantiomer by irreversible addition of chemical fuel and irreversible elimination of spent fuel is presented. The reaction network is maintained as long as fuel is added; interrupted fuel addition drives the system towards equilibrium, but the cyclic process restarts upon resumed fuel addition, as demonstrated by three consecutive fuel cycles. The process is powered by the hydrolysis of methyl cyanoformate to HCN and monomethyl carbonic acid, which decomposes to CO2 and MeOH. The time it takes to reach steady state depends on the rate of conversion of the fuel and decreases with increased conversion rate. Three catalysts, one metal catalyst and two enzymes, together constitute an efficient regulation system allowing control of the forward, backward and waste‐forming steps, thereby assuring the production of high yields of products with high enantiopurity.

Enantioselective Formal Total Synthesis of Damsin

AbstractEnantioselective formal total synthesis of damsin, which was isolated from Compositae Ambrosia maritima L., is described. The highly enantio- and diastereoselective catalytic Mukaiyama–Michael reaction and subsequent highly stereoselective epimerization shorten the synthetic steps. It is also reported that the enolate, which was formed by the reaction of β-keto sulfone with lithium naphthalenide, reacted with methyl cyanoformate to form a quaternary stereogenic center in high yield with high stereoselectivity. This finding extends the synthetic chemistry starting from β-keto sulfones.

Mander’s Reagent for the Deoxycyanation of β-Diketones: A Direct Synthesis of Oxoalkenenitriles

AbstractEthyl cyanoformate and methyl cyanoformate (Mander’s reagent) are both routinely used to perform C-selective ketone alkoxycarbonylations. Interestingly, both reagents were found to yield oxoalkenenitriles through an unprecedented deoxycyanation of 1,3-dicarbonyl compounds (e.g., 2-methylcyclohexane-1,3-dione). Although this method is not general, this is the first time that both Mander’s reagent and ethyl cyanoformate have been used for the deoxycyanation of 1,3-dicarbonyl compounds for the preparation of synthetically useful oxoalkenenitriles. Limitations on the substrate scope of the present method are discussed.

Solid-phase synthetic method for N-alkyl-4-alkylamino-6-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives

Abstract Herein, we describe a solid-phase synthetic method for synthesizing N-alkyl-4-alkylamino-6-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The derivatives consist of the biologically active 6-phenylthieno[3,2-d]pyrimidine scaffold. The template mediated synthetic strategy involving Suzuki coupling reactions between methyl 3-amino-5-bromothiophene-2-carboxylate and arylboronic acids afforded methyl 3-amino-5-arylthiophene-2-carboxylates. Cyclocondensation reactions involving methyl 3-amino-5-arylthiophene-2-carboxylates and methyl cyanoformate afforded esters, that when subjected to hydrolysis reactions yielded 6-aryl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-carboxylic acids (template compounds). These carboxylic acid templates were coupled with primary alkylamine-loaded acid-sensitive methoxybenzaldehyde (AMEBA) resins. The amide coupling reactions were followed by direct amination reactions mediated by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). The compounds were subsequently cleaved from the solid support, purified using the reverse phase-high performance liquid chromatography technique (RP-HPLC), and passed through a strong anion exchange (SAX) resin pretreated with water to yield the N-alkyl-4-alkylamino-6-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The reaction conditions for the solid-phase transformations were optimized using a solution-phase model using 2,4-dimethoxybenzyl-protected isobutylamine as a reactant. 2,4-Dimethoxybenzyl-protected isobutylamine, and not AMEBA resin-loaded isobutylamine was used during the process. Substituent variation experiments were performed using 6-aryl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-carboxylic acids and a variety of primary and secondary amine building blocks. Additionally, we could include the Suzuki coupling step in a modified solid-phase synthetic sequence.

Large amplitude vibrations of acetyl isocyanate, methyl cyanoformate, and acetyl cyanate.

The far infrared region of three detectable molecules sharing the empirical formula C3H3O2N, acetyl isocyanate CH3CONCO (AISO), methyl cyanoformate NC-COOCH3 (MCN) and acetyl cyanate CH3COOCN (ACN), is explored using explicitly correlated coupled cluster ab initio methods and a variational procedure designed for non-rigid species and large amplitude motions. The three isomeric forms display two conformers, cis and trans, of Cs symmetry that intertransform through the torsion of the central bond. This internal rotation interacts with the methyl group torsion generating a ground electronic state potential energy surface of six minima. Accurate rotational constants, centrifugal distortion constants, potential energy barriers, and surfaces, as well as, the low energy levels and their splittings, are provided. Far infrared energies are calculated up to 600 cm-1 which represent excitations of the torsional and the skeletal bending modes. Below 410 cm-1, 28, 14 and 20 vibrational energy levels and their splittings have been identified and classified for acetyl isocyanate, methyl cyanoformate, and acetyl cyanate, respectively. All the methyl torsion barriers are relatively low (∼300 cm-1) generating relevant tunneling effects. Computed spectroscopic parameters can help further interpretation and assignments of experimental rotational spectra using effective Hamiltonians.

Photochemistry of metallaborane: A novel method for functionalized carborane synthesis

The photointeractions of a stable 10-vertex manganadecaborane [nido-6-Mn(CO)3B9H13][NMe4] (1) and various unsaturated moleculars were studied. The investigated unsaturated molecules include nitriles (1,5-dicyanopentane, acetonitrile, methyl cyanoformate), ketones (4-heptanone, 1-indanone, ethyl pyruvate), aldehyde (benzaldehyde), imines (N-benzylidenemethylamine), alkene (methyl acrylate), isocyanates (phenyl isocyanate) and various alkynes. The manganadecaborane was found to photoreact with both terminal and internal alkynes to afford the carborane with general formula [7-R-8-R′-7,8-nido-C2B9H10][NMe4] (2) in good yield. This not only represents a novel method for generating the substituted nido-C2B9 complex but also implies photochemical approach can be an alternative methodology for metallaborane and metallacarborane chemistry.

Synthesis and kinetic resolution of substituted tetrahydroquinolines by lithiation then electrophilic quench.

Treatment of N-Boc-2-aryl-1,2,3,4-tetrahydroquinolines with n-butyllithium in THF at -78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products. Variable temperature NMR spectroscopy gave kinetic data that showed that the rate of tert-butoxycarbonyl (Boc) rotation was fast (ΔG‡ ≈ 45 kJ mol-1 at -78 °C) and in situ ReactIR spectroscopy showed fast lithiation at -78 °C. By carrying out the lithiation in the presence of the chiral ligand sparteine, kinetic resolutions with very high levels of enantioselectivity were achieved. The resulting enantioenriched N-Boc-2-aryltetrahydroquinolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Most electrophiles add at the 2-position and the chemistry provides a way to access tetrahydroquinolines that are fully substituted alpha to the nitrogen atom. Notably, either enantiomer of the 2,2-disubstituted tetrahydroquinolines can be obtained with high selectivity from the same enantiomer of the chiral ligand. Unusually, when methyl cyanoformate was used as the electrophile, substitution occurred in the ortho position of the aryl ring attached at C-2. This change in regioselectivity on changing the electrophile was probed by deuterium isotope studies and by DFT calculations which suggested that the binding of the cyanoformate altered the structure of the intermediate organolithium. Secondary amine products can be prepared by removing the Boc group with acid or by inducing the Boc group to rearrange to the 2-position in the presence of triethylborane and this carbonyl N-to-C rearrangement occurs with retention of configuration from the intermediate enantiomerically enriched organolithium species.

Is Photolytic Production a Viable Source of HCN and HNC in Astrophysical Environments? A Laboratory-based Feasibility Study of Methyl Cyanoformate

Motivated by the possibility that cyano-containing hydrocarbons may act as photolytic sources for HCN and HNC in astrophysical environments, we conducted a combined experimental and theoretical investigation of the 193 nm photolysis of the cyano-ester, methyl cyanoformate (MCF). Experimentally, nanosecond time-resolved infrared emission spectroscopy was used to detect the emission from nascent products generated in the photolysis reaction. The time-resolved spectra were analyzed using a recently developed spectral reconstruction analysis, which revealed spectral bands assignable to HCN and HNC. Fitting of the emission band shape and intensity allowed determination of the photolysis quantum yields of HCN, HNC, and CN (A22 Π1)and an HNC/HCN ratio of ∼0.076 ± 0.059. Additionally, multiconfiguration self-consistent field calculations were used to characterize photoexcitation-induced reactions in the ground and four lowest singlet excited states of MCF. At 193 nm excitation, dissociation is predicted to occur predominantly on the repulsive S 2 state, with minor pathways via internal conversion from S 2 to highly excited ground state. An automated transition-state search algorithm was employed to identify the corresponding ground-state dissociation channels, and Rice-Ramsperger-Kassel-Marcus and Kinetic Monte Carlo simulations were used to calculate the associated branching ratios. The proposed mechanisms were validated using the experimentally measured and quasi-classical trajectory-deduced nascent internal energy distributions of HCN and HNC. This work, along with previous studies, illustrates the propensity for cyano-containing hydrocarbons to act as photolytic sources for astrophysical HCN and HNC and may help explain the observed overabundance of HNC in astrophysical environments.

A novel solid-phase synthetic method for production of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide library

This work describes a solid-phase synthetic method for building a compound library of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide derivatives, that are based on the biologically active 1-aryl-1H-pyrazolo[3,4-d]pyrimidine scaffold. In the first step of this synthetic sequence, condensation reactions of ethyl 5-amino-1-aryl-1H-pyrazole-4-carboxylates with methyl cyanoformate resulted in the formation of esters that underwent hydrolysis to give 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylic acids. The coupling reaction of these carboxylic acids with primary alkylamine-loaded acid-sensitive methoxybenzaldehyde (AMEBA) resins was followed by amination reactions mediated by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). Subsequent cleavage from the solid support resulted in the formation of the target N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide derivatives. The reaction conditions for solid-phase transformations were optimized using a solution-phase model study with 2,4-dimethoxybenzyl-protected isobutylamine as a reactant in place of the AMEBA resin-loaded isobutylamine. The progress of the solid-phase reactions was monitored by on-bead ATR-FTIR spectroscopy. Diversification experiments were performed by using 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylic acids and a variety of primary and secondary amine building blocks to build the target compound library.

TBD- or PS-TBD-Catalyzed One-Pot Synthesis of Cyanohydrin Carbonates and Cyanohydrin Acetates from Carbonyl Compounds.

Cyanation reactions of carbonyl compounds with methyl cyanoformate or acetyl cyanide catalyzed by 5 mol % of 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) were examined. Using methyl cyanoformate, the corresponding cyanohydrin carbonates were readily obtained in high yield for aromatic and aliphatic aldehydes and ketones. Similar results were obtained when acetyl cyanide was used as the cyanide source. The polymer-supported catalyst, PS-TBD, also acted as a good catalyst for this reaction. PS-TBD was easily recovered and reused with minimal activity loss.

The molecular mechanism of palladium-catalysed cyanoesterification of methyl cyanoformate onto norbornene.

Potential energy surface mapping was completed for the entire catalytic cycle of palladium-catalysed cyanoesterification onto norbornene (NBE) using density functional theory calculations. We found that after the oxidative addition step of the reagent methyl cyanoformate, the reaction proceeds through an insertion of olefin into a Pd(II)-COOMe bond first. Subsequently, reductive elimination occurs by transferring the cyanide group from the Pd center to NBE. This rearrangement is triggered by the rotation of the ester group into a π-interaction with the Pd(II) centre. The regioselectivity of olefin insertion is controlled by ionic and covalent interactions in the precursor π-complex formation step. Importantly, all of the intermediates and transition states along the exo pathway were found to be more stable than the corresponding structures of the endo pathway without any sign of crossing over between the two surfaces via isomerization. The rate-determining step is the reductive elimination despite the fact that the corresponding activation barrier is reduced by conformational changes via the rotation of a MeOOC-C(NBE) bond.

ChemInform Abstract: Chemoselective Alkylations with N‐ and C‐Metalated Nitriles.

AbstractThe reaction of N‐lithiated cyclohexanecarbonitrile with bifunctional electrophiles or a 1:1 mixture of methyl cyanoformate and benzyl bromide proceeds chemoselectively to afford 1‐alkylated cyclohexanecarbonitriles (III), (VI), and (XI), whilst the reaction of C‐magnesiated nitriles gives rise to 1‐acylated products such as (IV), (VIII), and (XII).

Chemoselective Alkylations with N- and C-Metalated Nitriles.

Metalated nitriles exhibit complementary chemoselectivities in electrophilic alkylations. N-Lithiated or C-magnesiated nitriles can be prepared from the same nitrile precursor and selectively reacted with a 1:1 mixture of methyl cyanoformate and benzyl bromide or bifunctional electrophiles through chemoselective attack onto either an alkyl halide or a carbonyl electrophile. A mechanistic explanation for the chemoselectivity preferences is provided that rests on the structural and complexation differences between N- and C-metalated nitriles.

Reactivity and Mechanistic Studies of the Reactions of Chlorodiphenylphosphine and Its Oxide with Methyl Glyoxylate, Glyoxylate Oximes, and Methyl Cyanoformate

ABSTRACTIn this work, we describe the reactivity of chlorodiphenylphosphine and its oxide, as well as diphenylphosphine, with some glyoxylate derivative systems: methyl glyoxylate, methyl or 8‐phenylneomenthyl glyoxylate oximes, and methyl cyanoformate. By analyzing the reactions outcomes and with the aid of computational chemistry, we propose some reaction mechanisms and molecular rearrangements.

The origin of exo-selectivity in methyl cyanoformate addition onto the C=C bond of norbornene in Pd-catalyzed cyanoesterification.

A computational investigation has been carried out to elucidate the origin of the exclusive exo-selectivity in the Pd-catalyzed cyanoesterification of strained cyclic olefins, norbornene and norbornadiene. A hybrid density functional was selected for the level of theory with a triple-ζ quality basis set, which was proposed in an earlier study to provide an experimentally sound ground state electronic structure description for palladium(ii) and palladium(iv) complexes from multi-edge X-ray absorption spectroscopic measurements. Given that the product of oxidative addition can be isolated, we focused on the olefin coordination as the earliest possible origin of exo-selectivity. The calculated geometric structure for the trans-Pd(CN)(COOR)(PPh3)2 complex at the BHandHLYP/def2TZVP/PCM(toluene) level is in an excellent agreement with its experimental structure from crystallographic measurements. Upon dissociation of one of its phosphane ligands, the coordinatively unsaturated trans-isomer is only 17 kJ mol(-1) away from the isomerization transition state, leading to the 14-electron cis-isomers that are 17 to 37 kJ mol(-1) lower in energy than the trans-isomers. Regardless of the initial complex for olefin coordination, the exo-isomer for the norbornene complex is at least 8 kJ mol(-1) lower than the corresponding endo-isomer. The origin of this considerable difference in Gibbs free energy can be attributed to the remarkably different steric and agostic hydrogen interactions between the methylene and the ethylene bridges of the norbornene and the adjacent cis-ligands at the Pd(II) center.

ChemInform Abstract: Synthesis of β‐ and γ‐Carbolines via Ruthenium and Rhodium Catalyzed [2 + 2 + 2] Cycloadditions of Yne‐Ynamides with Methylcyanoformate.

AbstractThe direction of the [2 + 2 + 2] cycloaddition of yne‐ynamides with methyl cyanoformate leading to β‐ and/or γ‐carbolines depends on the structure of the yne‐ynamide and the type of catalyst used.

A Novel Synthesis of Carboxylic Esters from 2-Methyl-4,6-pyrimidyl Dicarbonates and Grignard Reagents

The carboxylic esters are mostly prepared by the reaction of carboxylic acids or their derivatives with alcohols and a large number of methods have been known. However, a few methods have been reported on the derivation of carboxylic esters from the alkoxycarbonylation of organometallics via σ bond formation between α-carbon and carbonyl carbon. Among them, the reaction of alkynyllithiums with methyl chloroformate or 2,2,2-trichloroethyl chloroformate affords the corresponding α,β-alkynoic esters at low temperature, but it requires an excess of chloroformate reagents to avoid competing side reactions. Although the treatment of ethyl chloroformate with organomanganates or organocopper reagents associated with magnesium salt under Pd catalysis produces the corresponding ethyl esters, these organometallics are prepared by an additional step and the scope is limited to primary and alkenyl group, respectively. The direct alkoxycarbonylation of Grignard reagents with dialkyl carbonates or alkyl chloroformates affords the corresponding esters, but the former requires 2 equiv of dialkyl carbonates and the latter is limited to the preparation of α-diazo esters at −78 C. Instead, the alkoxycarbonylation of Grignard reagents proceeds well with 1 equiv of 2-pyridyl carbonates, but the yield of 2,2,2-trichloroethyl ester depends on reaction temperature. Recently, alkyl cyanoformates have been utilized for the alkoxycarbonylation of organometallics. Thus, the alkoxycarbonylation of alkynyllithiums or allenyllithiums with 2 equiv of methyl or ethyl cyanoformate provides methyl akynoates or ethyl allenates, respectively. The reaction of heteroaromatic magnesium halides with an excess of alkyl cyanoformates also affords carboxylic esters in moderate to high yields. Furthermore, the treatment of methyl cyanoformate with magnesium metalated nitriles, derived from αbromonitriles and isopropylmagnesium chloride, at −78 C affords methyl α-cyanoates in moderate to high yields. Thus, the success of carboxylic esters synthesis by the alkoxycarbonylation of organometallics depends largely on the nature/amount of alkoxycarbonylating reagents and metals employed. However, there are no reports of alkoxycarbonylating reagents that can produce 2 equiv of carboxylic esters with organometallics. Inspired by our previous reports on ketones synthesis using pyrimidyl diesters, we investigated the synthesis of carboxylic esters from 2-methyl-4,6pyrimidyl dicarbonates and Grignard reagents. In choosing 2-methyl-4,6-pyrimidyl group as active moiety, we considered i) chelation effect between nitrogen atom and magnesium atom ii) thermal stability and storage of 2-methyl-4,6-pyrimidyl dicarbonates rather than other pyrimidyl dicarbonates. 2-Methyl-4,6-pyrimidyl dicarbonates 3 were newly prepared by the addition of 2 equiv of alkyl chloroformates 2 to a suspended solution of 4,6-dihydroxy-2-methylpyrimidine 1 and 2 equiv of triethylamine in THF at room temperature (Scheme 1). The nucleophilic acyl substitution of 2 with 1 was completed in 2-10 h at room temperature because 1 was slightly soluble in THF. After completion of the reaction, the resulting triethylamine hydrochloride precipitate was filtered off. After usual workup, the residue was subjected to silica gel (Davisil, pH = 7) or recystallized to afford 3 in 67-89% yields. During the synthesis of 2-methyl-4,6-pyrimidyl diisobutyl dicarbonate 3a, a small amount (~10%) of N,Ndiethyl isobutyl carbamate was produced by the nucleophilic acyl substitution of isobutyl chloroformate with triethylamine, which was distilled out under vacuum. However, 2-

ChemInform Abstract: Nucleophilic Reaction with Methyl Cyanoformate: A Novel α- Cyanomethylation and Hydrocyanation of α,β-Unsaturated Carbonyl Compounds.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective cyanoformylation of aldehydes organocatalyzed by recyclable cinchonidine ammonium salts

Enantiomerically enriched O-methoxycarbonyl cyanohydrins were obtained using an enantioselective addition of methyl cyanoformate to aldehydes organocatalyzed by a dimeric anthracenyldimethyl-derived cinchonidine ammonium salt (1 mol % catalyst loading) in the presence of substoichiometric amounts of triethylamine (20 mol %). Aromatic and heteroaromatic aldehydes usually afford high enantioselectivities (up to 96%) and quantitative yields of the corresponding O-methoxycarbonyl cyanohydrins, whereas aliphatic and α,β-unsaturated aldehydes give lower enantioselectivities (up to 60%) in high yields. The observed sense of the enantioselection was always the same, and the organocatalyst was almost quantitatively recovered by ether-promoted precipitation without any loss of activity. The use of resin-supported cinchonidine-derived ammonium salts as an organocatalyst in this transformation was also explored.