Alkyl Isonitriles Research Articles

Photoinduced Nickel-Catalyzed Homolytic C(sp3)-N Bond Activation of Isonitriles for Selective Carbo- and Hydro-Cyanation of Alkynes.

The exploration of strong chemical bonds as synthetic handles offers new disconnection strategies for the synthesis of functionalized molecules via transition metal catalysis. However, the slow oxidative addition rate of these covalent bonds to a transition metal center hampers their synthetic utility. Here, we report a C(sp3)-N bond activation strategy that bypasses thermodynamically challenging 2e- or 1e- oxidative addition via a distinct pathway in nickel catalysis. This strategy leverages a previously unknown activation pathway of photoinduced inner-sphere charge transfer of low-valent nickel(isonitriles), triggering a C(sp3)-N bond cleavage distal to the metal-ligand interaction to deliver nickel(cyanide) and versatile alkyl radicals. Utilizing this catalytic strategy, the selective intermolecular 1,2-carbocyanation reaction of alkynes with alkyl isonitriles as both alkylating and cyanating agents can be achieved, delivering a wide array of trisubstituted alkenyl nitriles with excellent atom-economy, regio-, and stereoselectivity under mild conditions. Furthermore, Markovnikov-selective hydrocyanation of aliphatic alkynes can be accomplished through the synergistic action of a photocatalyst utilizing isonitriles as the cyanation agents. Mechanistic investigations support the photogeneration of low-valent Ni(isonitrile) complexes that undergo photochemical homolysis of the C(sp3)-N bond to engage catalytic cyanation with alkynes.

Iridium-Photocatalyzed Hydrodecyanation of Alkyl Isonitriles with NHC–Borane

Iridium-Photocatalyzed Hydrodecyanation of Alkyl Isonitriles with NHC–Borane

Isonitriles as Alkyl Radical Precursors in Visible Light Mediated Hydro‐ and Deuterodeamination Reactions**

AbstractHerein, we report the use of isonitriles as alkyl radical precursors in light‐mediated hydro‐ and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late‐stage functionalization. Importantly, the method is general for Cα‐primary, Cα‐secondary and Cα‐tertiary alkyl isonitriles. For most examples, high yields were obtained through direct visible‐light irradiation of the isonitrile in the presence of a silyl radical precursor. Interestingly, in the presence of an organic photocatalyst (4CzIPN) a dramatic acceleration was observed. In‐depth mechanistic studies using UV/Vis absorption, steady‐state and time‐resolved photoluminescence, and transient absorption spectroscopy suggest that the excited state of 4CzIPN can engage in a single‐electron transfer with the isonitrile.

Isonitriles as Alkyl Radical Precursors in Visible Light Mediated Hydro- and Deuterodeamination Reactions.

Herein, we report the use of isonitriles as alkyl radical precursors in light-mediated hydro- and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late-stage functionalization. Importantly, the method is general for Cα -primary, Cα -secondary and Cα -tertiary alkyl isonitriles. For most examples, high yields were obtained through direct visible-light irradiation of the isonitrile in the presence of a silyl radical precursor. Interestingly, in the presence of an organic photocatalyst (4CzIPN) a dramatic acceleration was observed. In-depth mechanistic studies using UV/Vis absorption, steady-state and time-resolved photoluminescence, and transient absorption spectroscopy suggest that the excited state of 4CzIPN can engage in a single-electron transfer with the isonitrile.

Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles

Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe2+, and ferric, Fe3+). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species.

Highly Diastereoselective Preparation of Tertiary Alkyl Isonitriles by Stereoinvertive Nucleophilic Substitution at a Nonclassical Carbocation.

A highly efficient SnCl4-catalyzed nucleophilic isocyanation of cyclopropyl ethers has been developed. The reaction proceeds at the quaternary carbon stereocenter of the cyclopropane with a complete inversion of configuration, providing a new avenue for the construction of synthetically challenging tertiary alkyl isonitriles with high diastereopurity. The diversity of the incorporated isocyanide group has been demonstrated by the transformation of tertiary alkyl isonitriles into the corresponding tertiary alkyl amines, amides, and cyclic ketoimines.

A Model Study on the Carbon‐Halogen Activation in Perhalonated Arenes with Isonitrile Under Photoirradiation

AbstractThe mechanisms of the photochemical carbon‐halogen bond activation reactions were investigated theoretically using a model system of hexahalobenzene C6X6 (X=F, Cl, and Br) and phenyl isonitrile (PhN=C:), with the M06‐2X method and the 6–311G(d) basis set. The theoretical findings suggest the photoactivation mechanism should proceed as follows: Rea‐X‐S0 + hν → FC‐X‐T1 → PhNC‐T1 + C6X6 → Int‐X‐T1 → TS‐X‐T1 → T1/S0‐X → Pro‐X‐S0. The present theoretical evidence confirms the reported results by Studer and co‐workers that using UV irradiation, a simple and efficient transition‐metal‐free C‐F activation in various perfluoroarenes with aryl and alkyl isonitriles obtain imidoyl fluorides. Nevertheless, due to the highly vertical Frank‐Condon excitation energy, our theoretical study demonstrates N‐heterocyclic carbene cannot undergo the C‐F bond activation reaction with hexafluorobenzene under photoirradiation, which closely agrees with the available experimental observations. The present theoretical research reveals the spin crossover processes, which lead to a concerted reaction pathway, play a key role in the regioselecitivities of the final photoinsertion products.

Tantallacarborane Mediated Consecutive C–C and C–N Coupling Reactions of Alkyl Isonitriles: A Facile Route to N-Heterocycles

Reactions of tantallacarborane methyl complexes ([η1:η5-(Me2NCH2CH2)C2B9H10]TaMe3 (1) and [η1:η5-(MeOCH2CH2)C2B9H10]TaMe3 (8)) with alkyl isonitriles have been studied. Complex 1 reacted with 1 equiv of RNC (R = TMSCH2, Cy, and iPr) to afford double migratory insertion products [η1:η5-(Me2NCH2CH2)C2B9H10]Ta[η2-C,N-C(Me2)NCH2TMS]Me (2) and [σ:η1:η5-{MeN(CH2)CH2CH2}C2B9H10]Ta[N(iPr)R]Me (R = Cy (3), iPr (4)). However, treatment of 1 or 8 with 4 equiv of alkyl isonitriles gave two fused six-membered N-heterocycles 5–7 and 9 via consecutive C–C/C-N bond-forming reactions. All new complexes were characterized by 1H, 13C, and 11B NMR spectra as well as elemental analyses. Their structures were further confirmed by single-crystal X-ray analyses. The results show that aryl and alkyl isonitriles exhibit significantly different reactivity patterns. This work also offers a very efficient method for the synthesis of N-heterocycles.

C-F Activation in Perfluorinated Arenes with Isonitriles under UV-Light Irradiation.

Due to the great value of fluorinated arenes in agrochemistry, medicinal chemistry and materials science, development of methods for preparation of fluorinated arenes is of high importance. They can be either accessed by arene fluorination or by partial arene defluorination. However, the carbon-fluorine bond belongs to the strongest σ-bonds, which renders C-F activation highly challenging. Here it is shown that aryl and alkyl isonitriles efficiently activate the strong C-F bond in perfluoroarenes by simple UV irradiation under mild conditions. Reactions proceed by formal direct insertion of the isonitrile into the C-F bond without any transition metal. Activation occurs at arene C-F bonds whereas aliphatic C-F bonds remain unreacted. For selected perfluoroarenes C-F activation occurs with high regioselectivity and resulting imidoyl fluorides are transformed into other valuable compounds. Theoretical studies give insights into the reaction mechanism.

Bridging Rhodium–Iron Borataaminocarbyne Complexes Formed by Intramolecular Isonitrile–Borane Coordination

Reaction of [(TXPB)Rh(μ-CO)2Fe(CO)Cp] (1; TXPB = 2,7-di-tert-butyl-5-diphenylboryl-4-diphenylphosphino-9,9-dimethylthioxanthene) with both aryl and alkyl isonitriles formed [(TXPB)Rh(μ-CO)(μ-CNR)Fe(CO)Cp] (R = C6H4Cl-p (2), Xyl (3), nBu (4); Xyl = 2,6-dimethylphenyl), in which the CNRBR3 unit is best described as a borataaminocarbyne ligand with single bonds between carbon and nitrogen and between nitrogen and boron. The carbon atom of the borataaminocarbyne ligand is doubly bound to iron and singly bound to rhodium. For comparison, borane-free [(TXPH)Rh(μ-CO)2Fe(CO)Cp] (5; TXPH = 2,7-di-tert-butyl-4-diphenylphosphino-9,9-dimethylthioxanthene) was prepared from [(TXPH)RhCl(CO)] and K[CpFe(CO)2], and reaction of 5 with either 1 or 2 equiv of CNC6H4Cl-p afforded [(TXPH)Rh(CO)(μ-CNC6H4Cl-p)2Fe(CO)Cp] (6), which contains two μ-isonitrile ligands and two terminal carbonyl ligands: one bound to iron and the other to rhodium. The C–N stretching frequency for 6 is 124 cm–1 higher than that for the TXPB CNC6H4Cl-p complex 2, and the Rh–(μ-CNR) and Fe–(μ-CNR) distances are notably longer than those in 2, and the C–N distance is shorter.

A simple protocol for the synthesis of triazole-linked cyclic glycopeptidomimetics: a sequential Ugi-MCR and azide–alkyne cycloaddition approach

Sequential combination of Ugi-MCR and click chemistry has been employed for the synthesis of triazole linked cyclic glycopeptidomimetics. The protocol employs Poc-amino alkyl isonitriles, sugar-1-amines, azido acids, and simple aldehydes as precursors. The dual nature of the propargyloxycarbonyl (Poc) group was explored for amine protection as well as cycloaddition with an azide. All the cyclic glycopeptidomimetics are isolated and characterized.

ChemInform Abstract: Synthesis of β‐Lactam Peptidomimetics Through Ugi MCR: First Application of Chiral Nβ‐Fmoc Amino Alkyl Isonitriles in MCRs.

Chiral Nβ-Fmoc amino alkyl isonitriles were employed in Ugi multi component reactions (Ugi 4C-3CR) to obtain functionalized β-lactam peptidomimetics with l-aspartic acid α-methyl ester/peptide ester and organic aldehydes. The reactions were carried out in MeOH. Thirteen Ugi products have been prepared in good to moderate yields with good diastereoselectivities.

Chiral Nβ-Fmoc-amino alkyl isonitriles in Ugi-4CR: an assembly of novel 1,1′-iminodicarboxylated peptidomimetics

Enantiopure Nβ-Fmoc-amino alkyl isonitriles and amino acid esters have been employed as building blocks in Ugi four-component reaction (U-4CR) to yield 1,1′-iminodicarboxylated peptidomimetics. By employing trifluoroacetic acid as one of the components, a different outcome has been observed and rationalized. Ugi products are obtained as trifluoroacetamide adducts, which on further reaction under mild acidic conditions lead to the title compounds. The method has also been proven to be useful for the preparation of ethyl, benzyl and tert-butyl esters.

Synthesis of β-lactam peptidomimetics through Ugi MCR: first application of chiral Nβ-Fmoc amino alkyl isonitriles in MCRs

Chiral N β-Fmoc amino alkyl isonitriles were employed in Ugi multi component reactions (Ugi 4C-3CR) to obtain functionalized β-lactam peptidomimetics with l-aspartic acid α-methyl ester/peptide ester and organic aldehydes. The reactions were carried out in MeOH. Thirteen Ugi products have been prepared in good to moderate yields with good diastereoselectivities.

ChemInform Abstract: Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of Nβ‐Fmoc‐Amino Alkyl Isonitriles from Nβ‐Fmoc‐Amino Alkyl Thioformamides.

AbstractAn optimized ultrasound promoted procedure for the synthesis of the thioformamides is developed and their conversion to isonitriles is described briefly (no yields given).

Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of Nβ-Fmoc-Amino Alkyl Isonitriles from Nβ-Fmoc-Amino Alkyl Thioformamides

Synthetically useful NI²-Fmoc amino alkyl isonitriles are prepared conveniently from NI²-Fmoc amino alkyl thioformamides via a cyanogen bromide mediated dehydrosulfurization. The reaction is fast, clean, and yields are good. © Georg Thieme Verlag Stuttgart - New York.

ChemInform Abstract: Chiral N‐Fmoc‐β‐Amino Alkyl Isonitriles Derived from Amino Acids: First Synthesis and Application in 1‐Substituted Tetrazole Synthesis.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.

Chiral N-Fmoc-β-Amino Alkyl Isonitriles Derived from Amino Acids: First Synthesis and Application in 1-Substituted Tetrazole Synthesis

A novel class of optically active N-Fmoc-protected amino isonitriles has been described for the first time. Conversion of the carboxyl group of Fmoc-beta-amino acids into an isocyano group has resulted in a new class of N-urethane-protected amino isonitriles. All the isonitriles have been isolated as stable solids, purified, and completely characterized. A synthetic application of the obtained isonitriles has also been demonstrated through the synthesis of 1-substituted tetrazole analogues of amino acids via a 2 + 3 cycloaddition with trimethylsilyl azide.

Reaction of β‐Lactam Carbenes with Alkyl Isonitriles for a Ready Approach to 4‐Cyano and 4‐Carbamoyl Substituted β‐Lactams.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Reaction of β-lactam carbenes with alkyl isonitriles for a ready approach to 4-cyano and 4-carbamoyl substituted β-lactams

The reaction of β-lactam carbenes with alkyl isonitriles was investigated. Two different types of products, 4-cyano- or 4-carbamoyl-β-lactams, were isolated, depending upon the nature of the alkyl group of the isonitriles. The cyano-β-lactams were derived by a N-to-C 1,3-rearrangement of the ketenimine intermediates, while the carbamoyl-β-lactams were the hydrolysis products of the intermediates. This work extends the application of β-lactam carbenes, and provides a very simple and efficient route to 4-cyano- or 4-carbamoyl-β-lactams, which are versatile synthetic intermediates and new chemical entities of potential biological activity.