Primary Addition Products Research Articles

Reaction of Lithiated Propargyl Ethers with Carbonyl Compounds – A Regioselective Route to Furan Derivatives

AbstractThe deprotonation of 3-aryl-substituted alkyl propargyl ethers with n-butyllithium provides an ambident anion that reacts with carbonyl compounds to provide mixtures of γ-substituted products with alkoxyallene substructure and of α-substituted propargyl ethers. The ratio of the two product types strongly depends on the solvent: in diethyl ether the γ-substituted products predominate whereas the more polar tetrahydrofuran favors the α-adducts. The primary addition products undergo 5-endo-trig or 5-endo-dig cyclizations under various reaction conditions to afford isomeric furan derivatives. The highest selectivity in favor of α-substituted products was achieved by employing a MOM-protected propargyl ether. During the protonation step no evidence for a proton shift leading to an isomeric allenyl anion was found. A brief mechanistic discussion tries to rationalize the observed regio­selectivities.

Alkoxyallenes as Starting Materials for the Syntheses of Natural Products

Alkoxyallenes are easily available and versatile building blocks for the preparation of a variety of natural products (terpenes, polyketides, alkaloids, amino acids, carbohydrates etc.) originating from different classes. The synthetic use of the three allene carbon atoms frequently follows the “normal” reactivity pattern showing that alkoxyallenes can be regarded as special enol ethers. Additions of alcohols or amines to alkoxyallenes form vinyl-substituted O,O- or N,O-acetals that are frequently used in ring-closing metathesis reactions. This methodology delivers crucial heterocyclic units of the target compounds. Enantioselective additions provide products with high enantiopurity. Alternatively, an “Umpolung” of reactivity of alkoxyallenes is achieved by lithiation at C-1 and subsequent reaction with electrophiles, such as alkyl halides, carbonyl compounds, imines or nitrones. High stereoselectivity of the addition step can be achieved by substrate control or auxiliary control. The high diastereo- or enantioselectivity is transferred to the subsequent acyclic or cyclic products. The cyclization of primary addition products occurs efficiently under mild conditions and provides functionalized dihydrofuran, dihydropyrrole or 1,2-oxazine derivatives. These are valuable intermediates for the synthesis of a variety of heterocyclic natural products. Nazarov cyclizations or gold catalyzed rearrangements allow the synthesis of five- and six-membered carbocyclic compounds that are also used for natural product synthesis. Dedicated to Dr. Reinhold Zimmer, a pioneer of alkoxyallene chemistry, on the occasion of his 60th birthday.

Cyclizations of Alkoxyallenes: Mechanisms, Intermediates, Products – A Personal Account on Solved and Unsolved Problems with Unique Allene Building Blocks

The additions of lithiated alkoxyallenes to electrophiles, such as carbonyl compounds, thioketones, imines, and nitrones, provide the expected primary addition products. These alkoxyallene intermediates undergo ring-closure reactions under quite different conditions. Whereas allenyl hydroxylamine derivatives spontaneously cyclize to 1,2-oxazine derivatives, the related allenyl amines, thiols, and alcohols require, with distinct exceptions, promotion by acids, base, silver(I), or gold(I). The different mechanisms of these processes are discussed in this account. The serendipitous discovery of a novel three-component reaction of lithiated alkoxyallenes, nitriles, and carboxylic acids followed by a cyclization to pyridine derivatives is also reported and the mechanism involved is illustrated. This account also compiles exemplary examples of natural products and other compounds prepared by subsequent reactions of alkoxyallene-based cyclization products, but the fascinating ring-closing event of the allenyl intermediates is the main focus of this report. 1 Introduction 2 Cyclizations of Allenyl Hydroxylamines to 1,2-Oxazine Derivatives 3 Cyclizations of Allenyl Amines to Dihydropyrrole Derivatives 4 Cyclizations of Allenyl Imines to Pyrroles – Discovery of a New Three-Component Synthesis of Pyridines 5 Cyclizations of Allenyl Thiols to Vinylthiiranes and Dihydrothiophene Derivatives 6 Cyclizations of Allenyl Alcohols to Dihydrofuran Derivatives 7 Conclusions

Cyclizations of Alkoxyallenes: Mechanisms, Intermediates, ­Products – A Personal Account on Solved and Unsolved Problems with Unique Allene Building Blocks

The additions of lithiated alkoxyallenes to electrophiles, such as carbonyl compounds, thioketones, imines, and nitrones, provide the expected primary addition products. These alkoxyallene intermediates undergo ring-closure reactions under quite different conditions. Whereas allenyl hydroxylamine derivatives spontaneously cyclize to 1,2-oxazine derivatives, the related allenyl amines, thiols, and alcohols require, with distinct exceptions, promotion by acids, base, silver(I), or gold(I). The different mechanisms of these processes are discussed in this account. The serendipitous discovery of a novel three-component reaction of lithiated alkoxyallenes, nitriles, and carboxylic acids followed by a cyclization to pyridine derivatives is also reported and the mechanism involved is illustrated. This account also compiles exemplary examples of natural products and other compounds prepared by subsequent reactions of alkoxyallene-based cyclization products, but the fascinating ring-closing event of the allenyl intermediates is the main focus of this report.1 Introduction2 Cyclizations of Allenyl Hydroxylamines to 1,2-Oxazine Derivatives3 Cyclizations of Allenyl Amines to Dihydropyrrole Derivatives4 Cyclizations of Allenyl Imines to Pyrroles – Discovery of a New Three-Component Synthesis of Pyridines5 Cyclizations of Allenyl Thiols to Vinylthiiranes and Dihydrothiophene Derivatives6 Cyclizations of Allenyl Alcohols to Dihydrofuran Derivatives7 Conclusions

ChemInform Abstract: N‐Alkyl‐2‐halo‐ and 2,2‐Dihaloaldimines in the Pudovik Reaction

AbstractReview: 35 refs.

N-alkyl-2-halo- and 2,2-dihaloaldimines in the Pudovik reaction

The use of N-alkyl-2-haloaldimines in the imine version of the Pudovik reaction, namely, in the reaction of imines with acid esters of phosphorus acids, much extended the synthetic potential of this reaction due to the fact that the primary addition and protonation product, having quite a mobile single hylogen atom, can undergo both spontaneous transformations and transformations involving other reagents. The reduction of the С–Hlg bond in N-alkyl-2-halo- and -2,2-dihaloaldiminium salts with О,О-dialkyl phosphorodithioic acids was observed for the first time.

π‐Excess Aromatic σ2P Ligands: Formation of a Heterocyclic 1,2‐Diphosphine by the Addition of tBuLi and Subsequent Inverse Addition of the Product at the P=C Bonds of Two Molecules of 1‐Neopentyl‐1,3‐benzazaphosphole

ABSTRACTThe reactivity of tBuLi (pentane) toward the N‐neopentyl‐substituted π‐excess P=CH–N heterocycle 1 depends on the solvent (tetrahydrofuran, diethyl ether, hexane, and toluene) and reaction conditions. Trapping of the resulting organolithium compounds with CO2/ClSiMe3, ClSiMe3, or EtI led to various products indicating CH lithiation (1a,b), normal addition of tBuLi at the P=C bond (E/Z‐2a,b), inverse addition of the primary addition product 2Li at the P=C bond of a second molecule 1, affording 3‐tert‐butyl‐2,2’‐bis(1,3‐benzazaphospholines) 3, or inverse addition of tBuLi (4b,c). The formation of 3 demonstrates a novel route to asymmetric heterocyclic 1,2‐diphosphine ligands. The structure elucidation of the new compounds is based on their 31P and 13C NMR data with conclusive chemical shifts and P–C coupling constants, that of the isolated PH‐functionalized diphosphine 3 on crystal structure analysis.

Nucleophilic difluoro(trimethylsilyl)methylation of arylidene Meldrum's acids

A reaction of arylidene Meldrum's acids with difluoro(trimethylsilyl)methylzinc bromide in the presence of copper cyanide (10 mol%) is described. The primary addition products are hydrolized and decarboxylated followed by esterification of intermediate carboxylic acids affording β-Me3SiCF2-substituted esters. Protodesilylation of Me3SiCF2-group can be performed under mild conditions affording CHF2-fragment.

Synthesis of Unexpected Bifunctionalized Thiazoles by Nucleophilic Attack on Allenyl Isothiocyanate

AbstractTreatment of allenyl isothiocyanate with a variety of nucleophiles leads to 5‐methylthiazoles with a functional group at the 2‐position. The same pattern of reactivity is also seen with N‐aminophthalimide. In the presence of azide salt, hydrazoic acid, or N,N‐disubstituted hydroxylamines, however, allenyl isothiocyanate is converted into bifunctionalized thiazoles. We explain the formation of these products by nucleophilic addition at the isothiocyanato moiety followed by ring closure and an N–N or N–O cleavage reaction to generate short‐lived 2‐imino‐5‐methylidenethiazole or 5‐methylidenethiazol‐2‐one. Such intermediates are trapped by addition reactions to give the final heterocyclic compounds. In the case of N,N‐disubstituted hydroxylamines, the primary addition products with allenyl isothiocyanate can be detected as unstable intermediates by IR and NMR spectroscopy.

Reactions between chlorine atom and acetylene in solid para-hydrogen: Infrared spectrum of the 1-chloroethyl radical

We applied infrared matrix isolation spectroscopy to investigate the reactions between Cl atom and acetylene (C₂H₂) in a para-hydrogen (p-H₂) matrix at 3.2 K; Cl was produced via photodissociation at 365 nm of matrix-isolated Cl₂ in situ. The 1-chloroethyl radical (·CHClCH₃) and chloroethene (C₂H₃Cl) are identified as the main products of the reaction Cl + C₂H₂ in solid p-H₂. IR absorption lines at 738.2, 1027.6, 1283.4, 1377.1, 1426.6, 1442.6, and 2861.2 cm⁻¹ are assigned to the 1-chloroethyl radical. For the reaction of Cl + C₂D₂, lines due to the ·CDClCH₂D radical and trans-CHDCDCl are observed; the former likely has a syn-conformation. These assignments are based on comparison of observed vibrational wavenumbers and ¹³C- and D-isotopic shifts with those predicted with the B3LYP/aug-cc-pVDZ and MP2/aug-cc-pVDZ methods. Our observation indicates that the primary addition product of Cl + C₂H₂, 2-chlorovinyl (·CHCHCl) reacts readily with a neighboring p-H2 molecule to form ·CHClCH₃ and C₂H₃Cl. Observation of ·CDClCH₂D and trans-CHDCDCl from Cl + C₂D₂ further supports this conclusion. Although the reactivity of p-H₂ appears to be a disadvantage for making highly reactive free radicals in solid p-H₂, the formation of 1-chloroethyl radical indicates that this secondary reaction might be advantageous in producing radicals that are difficult to prepare from simple photolysis or bimolecular reactions in situ.

Addition of lithiated methoxyallene to aziridines – a novel access to enantiopure piperidine and β-amino acid derivatives

Addition of lithiated methoxyallene to aziridine derivatives provided the expected primary addition products. The less substituted carbon of the aziridine ring was attacked selectively. The primary adducts could be converted to enantiopure piperidine derivatives or β-amino acid derivatives. The unexpected reactions lead to a tricyclic sulfonamide and to alkynyl-substituted aminoethers. The efficient two-step conversion of a piperidone derivative to a benzomorphan demonstrates the potential of this approach to biologically active compounds.

Reaction of Malonic Acid Derivatives with Acetylenic Diphosphonates

The primary addition products in the reactions of malonic esters, cyanoacetic esters, and malononitrile with acetylenediphosphonates in acetonitrile in the presence of anhydrous potassium carbonate are potassium derivatives, viz. esters and nitriles of the corresponding 2-alkoxycarbonyl(or 2-cyano) -3,4-bis(di-alkoxyphosphinoyl)-2-potassiobut-3-enoic acid. Further hydrogen replacement for potassium in the nitriles is accompanied by isomerization involving double-bond shift and geometry change. (E)- and (Z)-3,4-bis(dial-koxyphosphinoyl)-2-cyano-2-potassiobut-3-enenitriles (the alkoxy groups are CH3O and C2H5O) are crystalline compounds; they were isolated and characterized.

Theoretical Study of the Mechanism and Kinetics of Gas-Phase Ozone Additions to Ethene, Fluoroethene, and Chloroethene: A Multireference Approach

Ab initio multiconfigurational CASSCF and CASPT2 methods were employed in studying the reaction mechanisms and kinetics of the gas-phase ozone additions to ethene, fluoroethene, and chloroethene up to the formation of the primary addition products (primary ozonides). Reactants, transition-state structures, and products were optimized, and harmonic vibrational frequencies were calculated at the CASSCF/cc-pVTZ level. For kinetic calculations, the electron energies of all the stationary points were further refined by utilizing the CASPT2 method with the optimized CASSCF/cc-pVTZ wave functions taken as the zeroth order. The rate constants and Arrhenius kinetic parameters were finally calculated in terms of the conventional transition-state theory. The favorable conformations of the ozone approach to the two asymmetrically substituted haloalkenes are at first governed by the electrostatic repulsion in the transition-state structures and later by the gradually predominating anomeric effect. The bond formation i...

Lithiated Dimethoxymethyl Diphenyl Phosphine Oxide, A Versatile Formiate Carbanion Equivalent

Aldehydes are homologated to the corresponding α-hydroxy methyl esters using lithiated dimethoxymethyl diphenyl phosphine oxide. The primary addition product of this Horner-Wittig process collapses to the corresponding α-hydroxy ester under proton-catalyzed conditions.

On the regioselectivity of nucleophilic additions to anisole-Cr(CO)3 and related complexes: a density functional study

The meta regioselectivity of the nucleophilic addition to methoxy-substituted arene-Cr(CO)3 complexes has been investigated by theoretical methods using density functional calculations employing the hybrid-DFT approach Becke3LYP and a flexible all-electron basis set. By calculating the relative energies and conformational preferences of the competing reactive intermediates (regioisomeric primary addition products) it was, among other things, demonstrated that the preferred reaction pathway proceeds ia the most stable intermediate. Based on the theoretical results a refined mechanistic picture for a synthetically important metallorganic process was derived.

Solvation of radical cations in water--reactive or unreactive solvation?

The solvation and reaction of ethylene radical cation in aqueous solution has been studied with Car-Parrinello molecular dynamics simulations. All ab initio simulations were performed using a system of 56 water and one ethylene molecule. Using a favorable symmetrically solvated radical cation as the starting point of the simulation a fast addition of water (within 90 fs) to the radical cation is observed. The primary addition product is rapidly deprotonated (within 100 fs) to yield the ethanol-2-yl radical. A second simulation was initiated through vertical ionization of neutral hydrated ethylene, representing a significantly less favorable situation for the addition process. No addition of water can be observed in this second simulation over a time span of 1.7 ps. Taken together the two simulations are indicative of a rearrangement of the solvent shell which represents the major part of the overall reaction barrier. Under these circumstances, the reaction rate of an otherwise spontaneous reaction is limited by the intrinsic solvent relaxation time. This interpretation of the reactivity of hydrated radical cations reconciles previously conflicting experimental condensed phase and theoretical gas phase studies.

Reactivity of Cp*Rh 16e Half-Sandwich Complexes Containing a Chelating 1,2-Dicarba-closo-dodecaborane-1,2-dichalcogenolato Ligand. Intermediates in the Catalyzed Trimerization of Methyl Acetylene Carboxylate and Phenylacetylene

Reactions of the 16-electron (16e) half-sandwich complexes Cp*Rh[E2C2(B10H10)] [E = S (1S), Se (1Se)] with methyl acetylene carboxylate and phenylacetylene were studied in order to obtain information on both the primary addition products and the potential catalyzed oligomerization of the alkynes as a function of reaction conditions. Both rhodium complexes 1S and 1Se reacted with HC⋮C−CO2Me under mild conditions to give in low yield the dimers 2S and 2Se, of which 2Se could be characterized by X-ray structural analysis. Both 1S and 1Se act as catalysts for the cyclotrimerization of HC⋮C−CO2Me and HC⋮C−Ph to give the respective 1,3,5- and 1,2,4-trisubstituted benzenes in a 1:1 ratio, if the reaction is carried out at 70 °C in toluene. In boiling chloroform or at room temperature in dichloromethane, trimerization is of minor importance. In the case of 1Se and methyl acetylene carboxylate, an intermediate 3Se, formed in the course of the trimerization process, could be characterized by X-ray structural analysis. The dimer 2Se catalyzes trimerization in the same way as 1Se. In the absence of HC⋮C−CO2Me, 2Se rearranges upon heating in toluene at 70 °C completely into the known carborane-substituted complex 8Se. One of the final products of the reaction of 1S with HC⋮C−CO2Me, the 16e complex 4S, also catalyzes the trimerization of HC⋮CCO2Me.

Controlled Hydrolysis of Tripodal Titanium Amido Halides: The Influence of the Ligand Periphery upon the Basicity of the Amido‐N Functions

AbstractHydrolysis of the tripodal amidotitanium halides H3CC(CH2NSiMe3)3TiX (X = Cl: 1a; Br: 1b) in the presence of Et3N affords the linear μ‐oxo‐bridged complex [H3CC(CH2NSiMe3)3Ti]2 (μ‐O) (3) which was characterized by X‐ray crystallography. Treatment of H3CC(CH2NiPr)3TiX (X = Cl: 2a; Br: 2b), obtained in low yields, under the same conditions only leads to decomplexation of the amido ligand. Under conditions of very slow exposure to H2O the primary addition product of water across two Ti–N bonds in 2a could be isolated and was characterized as [H3CC(CH2‐i(μ‐Cl)]2(μ‐O) (4), the crystal structure analysis establishing a triply bridging central Ti(μ‐O)(μ‐Cl)2 Ti unit. Deprotonation with two molar equivalents of nBuLi and subsequent LiCl elimination afforded the μ‐oxo complex [H3CC(CH2NiPr)3Ti]2(μ‐O) (5).

Carbenes in matrices: reactions and rearrangements

Carbenes and silylenes with a variety of substituents have been isolated and characterized in low temperature matrices. Reactions of these species with small molecules, especially 3O 2, have been studied. The structure of the primary addition products as well as the reactivity as a function of the spin-state (triplet T or singlet S) is discussed.

Structures and reactivities of sulfonium salts in relation to their lewis-acidity

Either by F--abstraction from ψ-pentacoordinated sulfuranes or by alkylation of ψ-tetracoordinated imino derivatives, various amino fluoro trifluoromethyl sulfonium hexafluoroarsenates were prepared (e.g. CF3SF2+, Me2NSF2+, (CF3)2SNME2+, (CF3)S(NME2)2+). X-ray-structures of these compounds and nmr-investigations show a similar influence of CF3 and F on the Lewis acidity of the sulfur centers. One amino group (e.g. in Me2NSF2+ causes that anion-cation-interactions in the crystal are rather weak, when two Me2N-groups are present, these interactions are negligible.In isocyanato derivatives SX2NCO+ (x = Cl, F) Lewis acids primarily attack the carbon of the isocyanato group, not the sulfonium center. The primary addition products with silylamines decompose complete. With S4N4 stable adducts are isolated.