Old Selenium Heterocycles Revisited: Synthesis,Spectroscopic, and Structural Characterization of N‐Acyl‐1,3‐selenazol‐2(3H)‐imines and 5‐Acyl‐1,3‐selenazol‐2‐amines from Acylselenourea Derivatives

A series of five‐membered selenium heterocycles was prepared from the reaction of various selenoureas and phenacyl bromides. In the case of 1‐acyl‐3‐arylselenoureas N‐acyl‐1,3‐selenazol‐2(3H)‐imines are formed, whereas the analogous reaction with 3,3‐disubstituted 1‐acylselenoureas affords 5‐acyl‐1,3‐selenazol‐2‐amines. The compounds were characterized by NMR spectroscopy and mass spectrometry. In addition, the proposed structures were unambiguously confirmed by X‐ray diffraction studies.     

Synthesis of Novel Pyrazole–sucrose Derivatives by 1,3‐dipolar Cycloaddition

The syntheses of an important class of enantiopure five‐membered glyconjucates containing furan unit are described. The regioselective synthesis of a series of sugar‐fused pyrazole heterocycles was achieved by the Huisgen cyclization of aryl diazomethanes with propargyl O‐glycoside derivatives in good yields. The cycloaddition regioselectivity was confirmed by NMR.     

Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

Herein, we describe the synthesis of molecular scaffolds consisting of medium‐sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid‐phase peptide synthesis, and cyclization was carried out through acid‐mediated tandem endocyclic N‐acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven‐, eight‐, and nine‐membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases.     

Asymmetric Cycloaddition: An Efficient Synthesis of Enantiopure Isoxazolines Substituted with Carbohydrate Analogues

A simple and convenient method for the synthesis of heterocycles substituted with carbohydrate analogs is described. The chiral optically pure five‐membered glycoconjugates containing the isoxazoline unit were obtained by an aromatic nitrile oxides cycloaddition with 1‐phenyl‐1,2‐dihydro‐pyridazine‐3,6‐dionyl N‐glycoside derivatives.     

A comparison of 2,7‐di­hydro‐2,2,7,7‐tetra­methyl‐3,6‐di­phenyl‐1,4,5‐thiadiazepine and the corresponding 1,1‐­dioxide

The structures of the highly substituted title heterocycles, C₂₀H₂₂N₂S and C₂₀H₂₂N₂O₂S, have been determined at 123 (1) K. Both mol­ecules possess exact C₂ symmetry and the seven‐membered rings have very similar twist‐boat conformations. The magnitudes of the C—S—C bond angles, 107.13 (6) and 108.27 (7)°, respectively, are influenced significantly by the four substituent methyl groups on the seven‐membered rings.     

Vindoline and 16‐de­methoxy­vin­doline: two catharanthus‐derived alkaloids

Vindoline, C₂₅H₃₂N₂O₆, and 16‐de­methoxy­vindoline, C₂₄H₃₀N₂O₅, both of which are naturally occurring biologically active products derived from plants, are important as possible starting materials for the synthesis of valuable anticancer antibiotics, viz. vincristine and vinblastine, and other pharmaceuticals. The vindoline framework consists of two five‐ and three six‐membered condensed rings. One of the six‐membered rings adopts a boat conformation, one adopts a sofa conformation and the third is planar. Both five‐membered rings have envelope structures. The intramolecular hydrogen bonds present in the structures are characteristic of vinca alkaloids.     

Synthesis of Anionic Phosphorus‐Containing Heterocycles by Intramolecular Cyclizations Involving N‐Functionalized Phosphinecarboxamides

We report that the 2‐phosphaethynolate anion (PCO^?) reacts with propargylamines in the presence of a proton source to afford novel N‐derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five‐ and six‐membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5‐exo‐dig or 6‐endo‐dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus‐containing heterocylic systems that are closely related to known organic molecules with interesting bio‐active properties.     

Synthesis of Imidazole Derivatives Using 2‐Unsubstituted 1H‐Imidazole 3‐Oxides

The reaction of 1,4,5‐trisubstituted 1H‐imidazole 3‐oxides 1 with Ac₂O in CH₂Cl₂ at 0 – 5° leads to the corresponding 1,3‐dihydro‐2H‐imidazol‐2‐ones 4 in good yields. In refluxing Ac₂O, the N‐oxides 1 are transformed to N‐acetylated 1,3‐dihydro‐2H‐imidazol‐2‐ones 5 . The proposed mechanisms for these reactions are analogous to those for N‐oxides of 6‐membered heterocycles (Scheme 2). A smooth synthesis of 1H‐imidazole‐2‐carbonitriles 2 starting with 1 is achieved by treatment with trimethylsilanecarbonitrile (Me₃SiCN) in CH₂Cl₂ at 0 – 5° (Scheme 3).     

Aluminiumhydrazide. Bildung eines dimeren Di(tert‐butyl)aluminiumhydrazids mit viergliedrigem Al2N2‐Heterozyklus und Umsetzung eines Dialkylaluminiumchlorids mit Dilithium‐bis(trimethylsilyl)hydrazid

Aluminium Hydrazides – Formation of a Dimeric Di( tert ‐butyl)aluminium Hydrazide Containing a Four‐Membered Al₂N₂ Heterocycle and Reaction of Dialkylaluminium Chloride with Dilithium Bis(trimethylsilyl)hydrazide The reaction of di(tert‐butyl)aluminium chloride with tert‐butylhydrazine yielded an adduct ( 1 ) which was isolated in a pure form and characterized by crystal structure determination. 1 reacted with n‐butyllithium by deprotonation and salt elimination to give the corresponding di(tert‐butyl)aluminium hydrazide ( 2 ), which is a dimer in solution and in the solid state and possesses a four‐membered Al₂N₂ heterocycle with two exocyclic N–N bonds. The structure of 2 differs from that of other di(tert‐butyl)aluminium hydrazides which have four‐ or five‐membered heterocycles. Treatment of impure samples of 1 with n‐butyllithium yielded by the cleavage of the N–N bonds a mixture of several unknown products, from which the dimeric, centrosymmetric aluminium amide [(Me₃C)₂AlN(H)CMe₃]₂ ( 3 ) was isolated. A similar product ( 4 ) was obtained in a low yield by the reaction of (Me₃SiCH₂)₂AlCl with the dilithium hydrazide Li₂N₂(SiMe₃)₂. An intact N–N bond was neither found in the second product isolated from this reaction. Instead a tricyclic compound was formed by C–H activation which has two five‐membered AlNSiC₂ heterocycles bridged by Al–N bonds.     

Regioselective Synthesis of N‐Heteroaromatic Trifluoromethoxy Compounds by Direct O−CF3 Bond Formation

The first one‐step method for the synthesis of ortho‐N‐heteroaromatic trifluoromethoxy derivatives by site‐specific O?CF₃ bond formation using hydroxylated N‐heterocycles and Togni's reagent is described. The approach enables the unprecedented syntheses of a wide range of six or five‐membered N‐heteroaromatic trifluoromethoxy compounds containing one or two heteroatoms from most commonly used hydroxylated N‐heterocycles. Notable advantages of this method include its simplicity and mild conditions, avoidance of the need for metals or toxic reagents, and compatibility with a variety of functional groups. Furthermore, this method is especially suitable for the larger scale application.     

Catalytic Asymmetric Inverse‐Electron‐Demand Hetero‐Diels−Alder Reactions

In this review, the recent developments in catalytic asymmetric inverse‐electron‐demand hetero‐Diels−Alder reaction, which is recognized as one of the most powerful routes to construct highly functionalized and enantioenriched six‐membered heterocycles, are described. The article is organized on the basis of different kinds of electron‐deficient heterodienes, including α,β‐unsaturated ketones/aldehydes, o‐benzoquinones, α,β‐unsaturated imines, N‐aryl imines, o‐benzoqinone imides, and other aza‐olefins.     

N‐Alkylsulfonylimines as Dipolarophiles in Cycloaddition Reactions

First described in the late 1960s, N‐alkylsulfonylimines are heterocumulenes that participate in reactions with a range of 1,3‐dipoles to afford interesting 3‐, 4‐, 5‐, and 6‐membered heterocycles. The distribution of adducts obtained suggests that multistage, stepwise mechanistic pathways rather than a concerted process are in operation.     

Dimethyl Carbonate as a Sacrificial Molecule for the Synthesis of 5‐Memebered N‐ and O‐Heterocycles

In the last twenty years DMC has been employed as an efficient methylating and methoxycarbonylating agent with several monodentate and bidentate nucleophiles, showing great selectivity and unexpected results. In this short review we report on yet another application of DMC chemistry i.e. the synthesis of 5‐membered N‐ and O‐heterocycles. In these reactions DMC acts as a sacrificial molecule since it is not present in the final products, but only in the reaction intermediates as an halogen‐free leaving group. This DMC‐based synthesis of heterocycles resulted of general application, as it is effective for aliphatic and aromatic 1,4‐diols, incorporating several functionalities (primary, secondary, tertiary, allylic, phenolic), as well as, for bifunctional compounds i.e. 4‐amino‐1‐butanol. This synthetic procedure was also employed for industrially relevant compounds such as (‐)‐norlabdane oxide and isosorbide showing to maintain the chiral integrity of the substrate. In one case intramolecular cyclisation of isosorbide was also observed to achieve a strained tricyclic derivative. Comparing this reaction methodology with a chlorine based procedure, the DMC‐mediated pathway is quantitative, occurs in one step, does not require any chlorine‐based chemical or strong acid and does not produce any chlorinated waste material.     

3‐Benzyl­oxy‐16‐[(N‐methyl‐N‐phenyl­amino)­methyl­idene]­estra‐1,3,5(10)‐trien‐17‐one

In the title compound, C₃₃H₃₅NO₂, the five‐membered ring adopts a half‐chair conformation. The N‐methyl‐N‐phenyl‐substituted keto–enamine moiety shows a comparatively long Csp²—N bond.     

Low Catalyst Loading in Ring‐Closing Metathesis Reactions

An efficient procedure is described for ring‐closing metathesis reactions. A conversion of 95 % for diethyl diallylmalonate in dilute solution could be achieved within a few minutes, reaching TOF=4173 min^?1, with very low loading of commercially available Ru catalysts that contained unsaturated NHC ligands. In general, only 50 to 250 ppm of the catalyst is required to achieve near‐quantitative conversion into a broad variety of 5–16‐membered heterocyclic compounds. The practicality of this procedure was illustrated in the synthesis of 5–8‐membered N‐tert‐butoxycarbonyl (N‐Boc)‐ and N‐para‐toluenesulfonyl (N‐Ts)‐protected cyclic amines and 9–16‐membered lactones. The synthesis of macrocyclic proline‐based lactams required slightly higher catalyst loadings. Along with monocyclic products, oligomeric byproducts, mostly cyclodimers, were isolated and characterized.     

Cover Picture: Journal of the Chinese Chemical Society 11/2012

The use of DMC chemistry for the synthesis of 5‐membered N‐ and O‐heterocycles is reported. In these one‐pot reactions DMC act as a sacrificial molecule providing the selected substrates with an halogen‐free leaving group which is then expelled to form the 5‐membered cyclic by intramolecular cyclisation. For more information on this figure, turn to pp 1375—1384 in this issue.     

Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

An approach to cyclic nitrones from N‐hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N‐OSEM [SEM=2‐(trimethylsilyl)ethoxymethyl] lactam forms a five‐membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one‐pot process. When combined with the N‐oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio‐pure form, enabling the concise total synthesis of cylindricine C.     

Enantioselective Synthesis of Pyrrole‐Based Spiro‐ and Polycyclic Derivatives by Iridium‐Catalyzed Asymmetric Allylic Dearomatization and Controllable Migration Reactions

The first highly diastereo‐ and enantioselective synthesis of five‐membered spiro‐2H‐pyrroles was achieved using an Ir‐catalyzed asymmetric allylic dearomatization reaction. The spiro‐2H‐pyrrole derivatives readily undergo a controllable and stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values. Additionally, the novel Ir‐complex K1 , derived from [Ir(cod)Cl]₂ (cod=1,5‐cyclooctadiene) and N‐benzhydryl‐N‐phenyldinaphthophosphoramidite (BHPphos), showed excellent control of both diastereo‐ and enantioselectivities.     

Unanticipated formation of a novel octaazacyclodecane ring upon oxidation of a 1,1‐bis‐urazole

Tetrahydrotetrazoles are a little‐explored class of five‐membered heterocycles with four contiguous singly‐bonded N atoms. Recent work in our labs has demonstrated that urazole radicals are amenable to N—N bond formation via radical combination to form such a chain of four N atoms. Previously described 1,1‐bis‐urazole compounds appeared to be convenient precursors to the target tetrazoles via their oxidation to intermediate urazole diradicals, which upon N—N bond formation would complete the tetrazole framework. While oxidation proceeded smoothly, the novel 10‐membered octaaza heterocycle 7,7,18,18‐tetraacetyl‐4,10,15,21‐tetraphenyl‐1,2,4,6,8,10,12,13,15,17,19,21‐dodecaazapentacyclo[17.3.0.0^2,6.0^8,12.0^13,17]docosan‐3,5,9,11,14,16,20,22‐octone, C₄₂H₃₂N₁₂O₁₂, was obtained (36% yield) instead of the expected tetrazole product, as confirmed by X‐ray crystallography. Calculations at the (U)B3LYP/6‐311G(d,p) level of theory suggest that the desired tetrazoles have weak N—N bonds connecting the two urazole units.     

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Allenes

The rhodium‐catalyzed asymmetric intramolecular hydroamination of sulfonyl amides with terminal allenes is reported. It provides selective access to 5‐ and 6‐membered N‐heterocycles, scaffolds found in a large range of different bioactive compounds. Moreover, gram scale reactions, as well as the application of suitable product transformations to natural products and key intermediates thereof are demonstrated.