Four-membered Heterocycles Research Articles

Synthesis, Structure, and Chemistry of New, Mixed Group 14 and 16 Heterocycles: Nucleophile-Induced Ring Contraction of Mesocyclic Dications

More than 40 new 4- to 12-membered ring heterocycles containing various combinations of Group 14 and 16 elements Si, Sn, S, Se, and Te have been synthesized and fully characterized. Synthesis of these small-ring as well as medium-ring (mesocyclic) heterocycles from alpha,omega-dihalides is facilitated by the presence of gem-dialkylsilyl and gem-dialkylstannyl groups in the precursors. Conformations of several of the new ring systems in the solid state have been determined by X-ray crystal structure analysis. Oxidation of mixed S(Se, Te)/Si eight-membered ring mesocycles with NOPF6 or Br2 gives dications or a bicyclic dibromide, respectively, which can be characterized by NMR methods. On treatment with nucleophiles, mesocyclic dications, or the corresponding radical cations undergo ring contraction, giving five- or six-membered ring heterocycles. Photolysis of a S/Se four-membered ring heterocycle gives selenoformaldehyde, trapped in 80% yield with 2,3-dimethyl-1,3-butadiene.

Stable four-pi-electron, four-membered heterocyclic cations and carbenes.

Replacement of halide from N-(haloboryl)formamidines for the weakly coordinating anion [B(C(6)F(5))(4)](-), using [Et(3)Si(toluene)](+)[B(C(6)F(5))(4)](-), induces a ring closure leading to the cationic four-pi-electron four-membered heterocycles [HC(N-2,6-diisopropylphenyl)(2)BR](+) [R = N(i-Pr)(2), Ph]. Subsequent deprotonation of the B-amino derivative affords the corresponding N-heterocyclic carbene, which has been isolated as yellow crystals. According to single-crystal x-ray diffraction studies, both the carbene and its conjugate acid precursor have a planar structure, with no pyramidalization of the ring atoms. The structural parameters indicate that the four pi electrons are mostly distributed over the N-C-N fragment with little involvement of the boron center, and therefore both types of heterocycles escape from antiaromaticity. However, considering the ring strain and the presence of the Lewis acid center, the thermal stability of the carbene (mp 98 degrees C without decomposition) is rather surprising. These results clearly suggest that the backbone of N-heterocyclic carbenes can be modified at will, without preventing their isolation.

Structures of (S)-(−)-4-oxo-2-azetidinecarboxylic acid and 3-azetidinecarboxylic acid from powder synchrotron diffraction data

The crystal structures of the four-membered heterocycles (S)-(-)-4-oxo-2-azetidinecarboxylic acid (I) and 3-azetidinecarboxylic acid (II) were solved by direct methods using powder synchrotron X-ray diffraction data. The asymmetry of the oxoazetidine and azetidine rings is discussed, along with the hydrogen bonding.

Aluminum and Gallium Hydrazides Derived from N-Aminopyrrole and N-Aminopiperidine

The heterocyclic hydrazine derivatives N-aminopyrrole, H2N-NC4H4, and N-aminopiperidine, H2N-NC5H10, reacted with the hydrides H-Al(CMe3)2 or GaH3NMe2Et by the release of elemental hydrogen and the formation of the corresponding aluminum and gallium hydrazides. These products are dimerized in the solid state via Al-N-Al or Ga-N-Ga bridges and possess four-membered E2N2 heterocycles with two exocyclic N-N bonds.

Microwaves in organic and medicinal chemistry

Preface. Personal Foreword. 1. Introduction: Microwave Synthesis in Perspective. 1.1 Microwave Synthesis and Medicinal Chemistry. 1.2 Microwave: Assisted Organic Synthesis (MAOS) - A Brief History. 1.3 Scope and Organization of the Book. 2. Microwave Theory. 2.1 Microwave Radiation. 2.2 Microwave Dielectric Heating. 2.3 Dielectric Properties. 2.4 Microwave Versus Conventional Thermal Heating. 2.5 Microwave Effects. 2.5.1 Thermal Effects (Kinetics). 2.5.2 Specific Microwave Effects. 2.5.3 Non-Thermal (Athermal) Microwave Effects. 3. Equipment Review. 3.1 Introduction. 3.2 Domestic Microwave Ovens. 3.3 Dedicated Microwave Reactors for Organic Synthesis. 3.4 Multimode Instruments. 3.4.1 Milestone s.r.1. 3.4.2 CEM Corporation. 3.4.3 Biotage AB. 3.4.4 Anton Paar GmbH. 3.5 Single-Model Instruments. 3.5.1 Biotage AB. 3.5.2 CEM Corporation. 3.6 Discussion. 4. Microwave Processing Techniques. 4.1 Solvent-Free Reactions. 4.2 Phase-Transfer Catalysis. 4.3 Reactions Using Solvents. 4.3.1 Open-versus Closed-Vessel Conditions. 4.3.2 Pre-Pressurized Reaction Vessels. 4.3.3 Non-Classical Solvents. 4.4 Parallel Processing. 4.5 Scale-Up in Batch and Continuous-Flow. 5. Starting with Microwave Chemistry. 5.1 Why Use Microwave Reactors? 5.2 Translating Conventionally Heated Methods. 5.2.1 Open and Closed Vessels? 5.2.2 Choice of Solvent. 5.2.3 Temperature and Time. 5.2.4 Microwave Instrument Software. 5.3 Reaction Optimization and Library Generation - A Case Study. 5.3.1 Choice of Solvent. 5.3.2 Catalyst Selection. 5.3.3 Time and Temperature. 5.3.4 Reinvestigation by a Design of Experiments Approach. 5.3.5 Optimization for Troublesome Building Block Combinations. 5.3.6 Automated Sequential Library Production. 5.4 Limitations and Safety Aspects. 6. Literature Survey Part A: General Organic Synthesis. 6.1 Transition Metal-Catalyzed Carbon-Carbon Bond Formations. 6.1.1 Heck Reactions. 6.1.2 Suzuki Reactions. 6.1.3 Sonogashira Reactions. 6.1.4 Stille Reactions. 6.1.5 Negishi, Kumada, and Related Reactions. 6.1.6 Carbonylation Reactions. 6.1.7 Asymmetric Allylic Alkyations. 6.1.8 Miscellaneous Carbon-Carbon Bond-Forming Reactions. 6.2 Transition Metal-Catalyzed Carbon-Heteroatom Bond Formations. 6.2.1 Buchwald-Hartwig Reactions. 6.2.2 Ullmann Condensation Reactions. 6.2.3 Miscellaneous Carbon-Heteroatom Bond-Forming Reactions. 6.3 Other Transition Metal-Mediated Processes. 6.3.1 Ring Closing Metathesis. 6.3.2 Pauson-Khand Reactions. 6.3.3 Carbon-Hydrogen Bond Activation. 6.3.4 Miscellaneous Reactions. 6.4 Rearrangement Reactions. 6.4.1 Claisen Rearrangements. 6.4.2 Domino/Tandem Claisen Rearrangements. 6.4.3 Squaric Acid-Vinylketene Rearrangements. 6.4.4 Vinylcyclobutane-Cyclohexene Rearrangements. 6.4.5 Miscellaneous Rearrangements. 6.5 Diels-Alder Cycloaddition Reactions. 6.6 Oxidations. 6.7 Catalytic Transfer Hydrogenations. 6.8 Mitsunobu Reactions. 6.9 Glycosylation Reactions and Related Carbohydrate-Based Transformations. 6.10 Multicomponent Reactions. 6.11 Alkylation Reactions. 6.12 Nucleophilic Aromatic Substitutions. 6.13 Ring-Opening Reactions. 6.13.1 Cyclopropane Ring-Opening. 6.13.2 Aziridine Ring-Openings. 6.13.3 Epoxide Ring-Opening. 6.14 Addition and Elimination Reactions. 6.14.1 Michael Additions. 6.14.2 Addition to Alkenes. 6.14.3 Addition to Alkenes. 6.14.4 Addition to Nitriles. 6.15 Substitution Reactions. 6.16 Enamine and Imine Formations. 6.17 Reductive Aminations. 6.18 Ester and Amide Formation. 6.19 Decarboxylation Reactions. 6.20 Free Radical Reactions. 6.21 Protection/Deprotection Chemistry. 6.22 Preparation of Isotopically Labeled Compounds. 6.23 Miscellaneous Transformations. 6.24 Heterocycle Synthesis. 6.24.1 Three-Membered Heterocycles with One Heteroaton. 6.24.2 Four-Membered Heterocycles with One Heteroatom. 6.24.3 Five-Membered Heterocycles with One Heteroatom. 6.24.4 Five-Membered Heterocycles with Two Heteroatom. 6.24.5 Five-Membered Heterocycles with Three Heteroatom. 6.24.6 Five-Membered Heterocycles with Four Heteroatom. 6.24.7 Six-Membered Heterocycles with One Heteroatom. 6.24.8 Six-Membered Heterocycles with Two Heteroatom. 6.24.9 Six-Membered Heterocycles with Three Heteroatom. 6.24.10 Larger Heterocyclic and Polycyclic Ring Systems. 7. Literature Survey Part B: Combinatorial Chemistry and High-Throughput Organic Synthesis. 7.1 Solid-Phase Organic Synthesis. 7.1.1 Combinatorial Chemistry and Solid-Phase Organic Synthesis. 7.1.2 Microwave Chemistry and Solid-Phase Organic Synthesis. 7.1.3 Peptide Synthesis and Related Examples. 7.1.4 Resin Functionalization. 7.1.5 Transition Metal Catalysis. 7.1.6 Substitution Reactions. 7.1.7 Multicomponent Chemistry. 7.1.8 Microwave-Assisted Condensation Reactions. 7.1.9 Rearrangements. 7.1.10 Cleavage Reactions. 7.1.11 Miscellaneous. 7.2 Soluble Polymer-Supported Synthesis. 7.3 Fluorous Phase Organic Synthesis. 7.4 Grafted Ionic Liquid-Phase-Supported Synthesis. 7.5 Polymer-Supported Reagents. 7.6 Polymer-Supported Catalysts. 7.6.1 Catalysts on Polymeric Supports. 7.6.2 Silica-Grafted Catalysts. 7.6.3 Catalysts Immobilized on Glass. 7.6.4 Catalysts Immobilized on Carbon. 7.6.5 Miscellaneous. 7.7 Polymer-Supported Scavengers. 8. Outlook and Conclusions. Index.

H-atom abstraction dynamics of reactions between Cl atoms and heterocyclic organic molecules

The HCl(v' = 0, J') rotational state distributions produced in the photoinitiated reactions of ground spin-orbit state Cl(2P3/2) atoms with the organic heterocycles oxirane (c-C2H4O), thiirane (c-C2H4S) and oxetane (c-C3H6O) have been measured using the technique of 2 + 1 resonance-enhanced multiphoton ionization in a time-of-flight mass spectrometer. In contrast to previous studies of H-atom abstraction dynamics by Cl atoms with linear functionalized molecules, the nascent HCl(v' = 0, J') products of the reactions of the three-membered heterocycles oxirane and thiirane are formed rotationally cold, with mean rotational energies <Erot> of (0.28 ± 0.02) kcal mol-1 and (0.31 ± 0.02) kcal mol-1, respectively. The reaction of Cl atoms with the four-membered heterocycle oxetane, however, results in more rotationally excited HCl(v' = 0, J') products for which <Erot> = (0.78 ± 0.03) kcal mol-1. Ab initio calculations were performed at the G2//MP2/6-311G(d,p) level to characterize molecular complexes and transition states on the reactive pathways. In all cases, the reactions were calculated to be barrierless, and weakly bound pre- and post-reaction complexes were located on the potential energy surfaces. The observed distributions and calculated reaction profiles are compared with previous studies of the reactions of Cl atoms with linear functionalized organic molecules and the consequences of the constrained molecular geometry on the HCl(v' = 0, J') rotational distribution discussed in terms of the dipole-dipole interaction model proposed previously.

A Surprisingly Stable 1‐(Chlorosilyl)‐2‐phosphaethenyllithium Compound, RCl2SiC(Li)=PMes*

AbstractRCl2Si–C(Li)=PMes* (1) (R = 9‐methylfluoren‐9‐yl, Mes* = 2,4,6‐tri‐tert‐butylphenyl), considered as a key intermediate in the synthesis of the heteroallene RClSi=C=PMes*, was obtained from RCl2Si–C(Cl)=PMes* by lithium/chlorine exchange with nBuLi and evidence for its identity was obtained by hydrolysis. Remarkably, however, it failed to undergo a lithium salt elimination to form the corresponding chlorophosphasilaallene, RClSi=C=PMes*, even under prolonged heating in toluene. As shown by theoretical studies (RHF/3‐21G* and RHF/6‐31G**//RHF/3‐21G* level), interactions between the lithium ion and the π‐systems of the substituents at the phosphorus and silicon atoms could partly account for this stability. The lithium compound 1 reacts with methanol or chlorotrimethylsilane leading to new silylphosphaalkenes. The reaction of the lithium derivative 1 with benzaldehyde gave a four‐membered heterocycle with an exocyclic P=C bond which virtually corresponds to the product of a [2+2] cycloaddition between the Si=C and C=O double bonds. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)

Reactions of a Germacyclopropabenzene with Elemental Chalcogens: Syntheses and Structures of a Series of Stable 2H-Benzo[c][1,2]chalcogenagermetes

Thermal reactions of a stable germacyclopropabenzene, Tbt(Dip)GeC6H4 (Tbt = 2,4,6-tris[bis(trimethylsilyl)methyl]phenyl, Dip = 2,6-diisopropylphenyl), with elemental chalcogens in C6D6 at 130 °C resulted in the formation of novel Ge-containing four-membered heterocycles, 2H-benzo[c][1,2]chalcogenagermete derivatives. This is the first example of a ring expansion reaction of cyclopropabenzene derivatives using elemental chalcogen, while several types of ring-opening reactions have been explored for cyclopropabenzene so far. In addition, the 2H-benzo[c][1,2]telluragermete is the first stable compound as a tellurete derivative. Structures of the chalcogenagermetes obtained here were elucidated by X-ray crystallographic analysis, and the experimentally obtained structural parameters were supported by theoretical calculations. The skeletons of chalcogenagermetes have very little strain in their four-membered rings annelated with a benzene ring.

Varied Reactivity of the Germene Mes2GeCR2 toward Nitriles

The germene Mes 2 Ge=CR 2 (1, CR 2 = fluorenylidene) shows varied behavior toward nitriles. It reacts as a 1,2-dipole with t-BuCN giving a four-membered ring heterocycle, 2-aza-3-germacyclobut-1-ene, as a 1,4-dipole with PhCN, leading to a six-membered ring heterocycle, 3,4-dihydro-3-germaisoquinoline, and as a base, abstracting the α-H of R'CH 2 CN to give α-cyanogermanes (R' = H, 2-thienyl, 2-FC 6 H 4 , 4-FC 6 H 4 ).

Benzylbis(dimethylamino)methylsilyl-kappa2C,N](N,N,N',N'-tetramethylethylenediamine-kappa2N,N)lithium(I).

The title compound, [Li(C12H21NSi)(C6H16N2)], is an intermediate in the synthesis of the corresponding organometallic compounds. The molecule has an unusual C-Si-N-Li four-membered heterocycle which adopts a folded conformation, with the coordination around the Li, N, C and Si atoms being distorted tetrahedral. Its structure is strongly supported by 1H NMR, 13C NMR and 13C-1H correlation spectra. The compound has potential for application in the synthesis of other novel organometallic compounds.

Generic synthesis of β-sultams via domino alkylation of bromomethanesulfonamides

Reaction of N-substituted bromomethanesulfonamides with 2 equiv of potassium carbonate and an α-halo ketone, ester, or nitrile leads directly to 3-substituted β-sultams. The first step is intermolecular and is followed by an intramolecular alkylation. The process is particularly efficient when diethyl bromomalonate and 3-chloro-2-butanone are involved. In the latter example, no competitive cyclization to form a six-membered ring is seen. The functional groups in certain of the β-sultam products can be subsequently manipulated to give bicyclic products.Key words: β-sultams, intramolecular SN2 displacement, sulfonamides, ring closing metathesis, four-membered heterocycles.

13C-13C Spin-Spin Coupling Constants in Structural Studies: XXXIV. Nonempirical Calculations: Small Heterocycles

An ab initio calculation was carried out for 13C-13C spin-spin coupling constants in a series of saturated three- and four-membered heterocycles within a framework of second order perturbation theory using an approximation of second order polarization propagator. The accounting for electron correlation effects and the use of correlation-consistent basis sets with addition of functions allowing for internal correlation and of dense functions on nuclei permitted to obtain good quantitative agreement with experimental data.

Benzyldimethyl(dimethylamino)silyl-κ2C,N](N,N,N,N-tetramethylenediamine-κ2N,N)lithium(I)

The molecule of the title compound, [Li(C11H18NSi)(C6H16N2)] contains a four-membered heterocycle with a folded conformation. The coordination around the Li, N, C and Si atoms in this ring is distorted tetrahedral.

(1-tert-Butyl-2-phenylvinylamino)(dimethylamino)dimethylsilyl-κ2N,N′] (N,N,N′,N′-tetramethylenediamine-κ2N,N′)lithium(I)

The crystal structure of the title compound, [Li(C16H27N2Si)(C6H16N2)], contains the N—Si—N—Li four-membered heterocycle. The heterocycle contains a planar three-coord­inated N-atom centre, a four-coordinated N-atom centre, a four-coordinate Li-atom centre and a four-coordinated Si-atom centre, and adopts a folded conform­ation. There are two molecules in the asymmetric unit.

Diphosphetanes, Dihydrodiphosphetes, and Diphosphetes

Publisher Summary This chapter discusses four-membered rings with two phosphorous atoms. It begins by reviewing existing literature, and mentions the reviews previously provided by Fluck and Neumuller, Afarinkia, Regitz and Binger, Nixon, and Weber. A monography by Dillon et al. is also mentioned. Theoretical methods using ab-initio and semi-empirical methods are then described. Experimental structural methods include information on the structural aspects, spectroscopic, and thermodynamic aspects of diphosphetes. Reactivity studies are enumerated in details. They discuss reactivity of certain diphosphetes, cyclic addition reactions, addition reactions, reactivity of nonconjugated rings, reactivity of ring heteroatoms and substituents attached to ring heteroatoms, σ-complexation of transition metals, oxidation of ring hetereoatoms, reactions with reducing agents, and other reactions. Synthesis of four-membered heterocycles with two P-atoms is the next topic. The chapter also consists of a description of synthesis from acylic compounds by formation of one P—C or P—P bond, formation of two C—P bonds, ring formation by organic cyclic addition reactions, ring formation by cyclic addition reactions in the co-ordination sphere of a transition metal, various routes, and ring synthesis by transformation to another ring. An overview of the synthesis of particular classes of compounds, such as, 1,2- and 1,3- diphosphetes, 1,3- dihydro and 1,3-diphosphetes, and 1,2- and 1,3- disphosphetanes are also present. It concludes with a description of diphosphetanes as parts of polycyclic compounds.

Formation of Four-Membered Heterocycles through Electrophilic Heteroatom Cyclization

This review demonstrates the feasibility of the formation of cyclobutane heterocycles through 4-endo and 4-exo electrophile-induced processes. Cyclizations are usually observed upon treatment of linear substrates with electrophiles such as halogens (chlorine, bromine, iodine), haloreagents {NBS, [bis(collidine)X+]Y−, ...}, and more rarely with seleno reagents and metallic salts. Results show that the formation of β-lactones, oxetanes, and β-lactams can be viewed as a general process useful for synthetic purposes. Formation of azetidines and thietanes appears more limited and has been reported in only a few cases. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Novel small organo-P-S/Se heterocycles.

Oxidative addition of elemental sulfur and selenium to cyclomonocarbatetraphosphines (PhP)4CR2 (R = H, Me) afforded novel five- and four-membered heterocycles PhP(E)CH2PhP(E)E2(E = S, Se) and PhP(Se)CMe2-PhP(Se)Se.

Synthesis, crystal structure, and thermolysis of the first tetracoordinate 1lambda4,2-selenazetidines: aziridine formation reaction from a four-membered heterocycle bearing highly coordinate selenium.

[structure: see text]. The first tetracoordinate 1lambda4,2-selenazetidines were synthesized by taking advantage of the Martin ligand and characterized by X-ray crystallographic analysis. The selenazetidines gave the corresponding aziridine and the cyclic selenenate on their thermolysis, which indicates the possibility that a highly coordinate 1,2-heterachalcogenetane may provide the corresponding heteracyclopropane regardless of the heteroatoms.

ChemInform Abstract: Chemistry of Dithiiranes, 1,2-Dithietanes, and 1,2-Dithietes

Publisher Summary This chapter reviews the chemistry of three- and four-membered ring compounds containing an S–S bond in their ring. Dithiiranes; 1,2-dithietanes; and 1,2-dithietes are the compounds of this type. Although 1,3- dithietanes are four-membered heterocycles that are prepared easily and are seemingly familiar, they have no S–S bond in the ring. The S–S bond preferentially adopts a 90o torsional orientation to minimize the S–S lone pair energy interactions. Any deviation from 90o can exert a profound weakening effect on the S–S bond. When an S–S bond is a part of a three- or four-membered ring, it is inevitably forced to adopt cisoid geometry where repulsive interactions of the lone pair electrons reach a maximum. This, along with the angle strain, renders the S–S bond much weaker and makes the synthesis very difficult. The considerations described explains the very reason that makes the synthetic, reactivity, structural, and theoretical chemistry of these heterocycles highly attractive and challenging.

Rhodium-catalyzed rearrangement of alpha-diazo thiol esters to thio-substituted ketenes. Application in the synthesis of cyclobutanones, cyclobutenones, and beta-lactams.

Exposure of alpha-diazo thiol esters (1) to the action of catalytic rhodium(II) acetate leads to a remarkably facile "thia-Wolff rearrangement", producing thio-substituted ketenes which combine with a variety of ketenophiles to provide access to alpha-thiocyclobutanones, cyclobutenones, and beta-lactams. Reductive desulfurization of these cycloadducts takes place under mild conditions and in excellent yield, and this sequence thus represents a useful new alternative to the existing dichloroketene-based methodology for the synthesis of four-membered carbocycles and heterocycles.