Transformations of halocyclopropanes—VII : Reactions of 7,7-dichlorobicyclo[4.1.0] heptane with carbanions

The reactions of 7,7-dichlorobicyclo[4.1.0] heptane 1 were carried out with C-H acids in the presence of t- BuOK in DMSO. The respective syn-7-chlorobicyclo[4.1.0] heptane derivatives 3 were the major products of the reactions with diethyl malonate and ethyl cyanoacetate. The dehydrochlorinated material α-bicyclo[4.1.0] hepten-5-yl-α-phenylpropionitrile 5c, was obtained in good yield in the reaction with α-phenylpropionitrile.     

Stereoselective synthesis of new (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-one derivatives

A procedure was developed for the stereoselective synthesis of aminated derivatives of (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-one. The configuration of the side-chain chiral center in (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-ol was determined by X-ray analysis. Diketene and Meldrum’s acid were proposed as initial compounds for the synthesis of, respectively, 3-oxobutanoic and malonic acid esters having a 1-ethyl-4,7,7-trimethylbicyclo[4.1.0]hept-4-ene fragment.     

Reaction of gem-dibromocyclopropanes with diphenylphosphide ion

Diphenylphosphide ion undergoes a photostimulated reaction with 7,7-dibromobicyclo[4.1.0]heptane and 1,1-dibromo-2,2,3,3-tetramethylcyclopropane involving both ionic and radical steps to afford cyclopropyldiphenylphosphines resulting from substitution and reduction.     

Synthesis and Chemistry of Bicyclo[4.1.0]hept-1,6-ene

Bicyclo[4.1.0]hept-1,6-ene has been generated by elimination of 1-chloro-2-(trimethysilyl)bicyclo[4.1.0]heptane in the gas phase over solid fluoride at 25 degrees C. The cyclopropene dimerizes by a rapid ene reaction forming two diastereomeric cyclopropenes. In tetrahydrofuran or chloroform the ene dimers couple to form a single crystalline triene tetramer, whereas a mixture of tricyclohexane tetramers is formed when the neat dimers are allowed to warm to room temperature. Oxidation by dimethyldioxirane or dioxygen gives carbonyl products. Quantum mechanical calculations yielded an increase in strain of approximately 17 kcal/mol over that for 1,2-dimethylcyclopropene. The potential enegy barrier to flexing (folding) along the fused double bond of bicyclo[4.1.0]hept-1,6-ene is only approximately 1 kcal/mol at the highest level of theory investigated.     

Contraction de cycle a partir de la tosyloxy-8 bicyclo[4.2.0]octanone-7 cis

Cis 8-endo tosyloxybicyclo[4.2.0]oct-3-en-7-one treated with H₄AlLi undergoes a stereospecific ring contraction to give endo 7-formyl bicyclo[4.1.0]hept-3-ene and endo 7-hydroxymethyl bicyclo[4.1.0]hept-3-ène. On the contrary, the same compound treated with MeONa in ether or methanol (conditions of the Favorski rearrangement) gives, beside solvolysis products when CH₃OH is solvent, the two epimeric esters 7-endo and 7-exo carbomethoxybicyclo[4.1.0]hept-3-ène. Several pathways are postulated for the rearrangement.     

Electronic and Steric Structure of Thermal Isomerization Products of 1-Methyltricyclo[4.1.0.02,7]heptane Radical Cation

Distributions of the positive charge and unpaired electron in stable conformers of the thermal isomerization products of 1-methyltricyclo[4.1.0.02,7]heptane radical cation, having bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[3.2.0]hept-6-ene, and 1,3-cycloheptadiene skeletons, were estimated by the PM3 semiempirical method.     

Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N′-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons-Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald-Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK_a of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74±0.05, which is 1.3 pK_a units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules.     

Ein neuer Zugang zu Bicyclo[4.1.0]heptan-Derivaten

A New Approach to Bicyclo[4.1.0]heptane Derivatives The reaction of the dienone 1 with ethyl α-bromoacetate does not furnish the expected glycidic acid ester 2 but leads to the bicyclo[4.1.0]heptenone derivative 3 . The structure of this new compound has been proved by means of spectroscopic methods (1R, ¹H-NMR, ¹³C-NMR, MS). The elucidation of the configuration at C(7) could be realized by measuring a NOE effect. Other α-alkylated α-bromoacetates react with 1 in the same manner.     

PtCl2-mediated cycloisomerization of unsaturated propargylic carboxylates

The PtCl₂-mediated cycloisomerization of unsaturated propargylic carboxylates yields differently functionalized bicyclo[4.1.0]heptane enol esters from moderate to good yield, in a very diastereoselective manner. We have prepared and submitted to PtCl₂-catalyzed cycloisomerization a series of differently substituted hept-1-en-6-ynes with different O-acyl (acetyl, trichloroacetyl, 3,4,5-trimethoxybenzoyl, etc.) protecting groups at propargylic positions, investigating also the effect of the geometry at the double bond, as well as the effect of the number of substituents at the alkene moiety. As a result, we have found that the O-acetyl migrating group is the best one in terms of simplicity and chemical yields. In this reaction we have isolated mixtures of compounds formed by minor 1-acetoxy-allenes and major bicyclo[4.1.0]heptane derivatives. Major products are the result of a sequential process involving steps of cycloisomerization plus cyclopropanation, followed by acyl migration. The basic methanolysis (K₂CO₃, MeOH) of these intermediates gave mixtures of cis and trans-caran-2-ones. This two-step protocol (cycloisomerization plus basic methanolysis) for the syntheses of α,β-unsaturated cyclopropyl ketones constitutes a synthetic alternative to the usual unfriendly, intramolecular cyclopropanation of unsaturated α-diazocarbonyl derivatives. The formation of these bicyclo[4.1.0]heptane derivatives is a simple, but efficient entry into the skeleton of the ‘carane’ family of natural products.     

三乙醇胺催化合成7,7—二氯双环[4,1,0]庚烷

报道了三乙醇胺催化二氯卡宾与环己烯的加成反应，考察了催化剂用量、氯仿用量、氢氧化钠浓度，反应时间、反应温度对产品７，７－二氯双环「４，１，０」庚烷收率的影响，在优化条件下，产品收率可达９０．０％     

Development of diversified methods for chemical modification of the 5,6-double bond of uracil derivatives depending on active methylene compounds

The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5- and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21), and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane (15) and 2,4-diazabicyclo-[4.1.0]nonane (16) via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents.     

Heavy-Atom Tunneling in Bicyclo[4.1.0]hepta-2,4,6-trienes

Heavy-atom tunneling limits the lifetime and observability of bicyclo[4.1.0]hepta-2,4,6-triene, a key intermediate in the rearrangement of phenylcarbene. Bicyclo[4.1.0]hepta-2,4,6-triene had been proposed as the primary intermediate of the rearrangement of phenylcarbene, but despite many efforts evaded its characterization even in cryogenic matrices. By introducing fluorine substituents into the ortho-positions of the phenyl ring of phenylcarbene, the highly strained cyclopropene 1,5-difluorobicyclo[4.1.0]hepta-2,4,6-triene becomes stable enough to be characterized in argon matrices. However, even at 3 K this cyclopropene is only metastable and rearranges via heavy-atom tunneling to the corresponding cycloheptatetraene. Calculations suggest that fluorination is necessary to slow down the tunneling rearrangement of the bicycloheptatriene. The parent bicycloheptatriene rapidly rearranges via heavy-atom tunneling and therefore cannot be detected under matrix isolation conditions.     

1,5-Diazabicyclo[3.1.0]hexanes and 1,6-diazabicyclo[4.1.0]heptanes: a new method for the synthesis,quantum-chemical calculations,and X-ray diffraction study

A new method was developed for the synthesis of 6-substituted 1,5-diazabicyclo[3.1.0]hexanes and 7-substituted 1,6-diazabicyclo[4.1.0]heptanes by condensation of N-monohalotrimethylene- and N-monohalotetramethylenediamines with carbonyl compounds in the presence of bases. X-ray diffraction studies and quantum-chemical B3LYP/6-31G* calculations demonstrated that the conformations of the resulting bicyclic systems are stabilized by stereoelectronic interactions. As a result, a boat conformation prevails in 1,5-diazabicyclo[3.1.0]hexanes, whereas the energies of chair, half-chair, and boat conformations of 1,6-diazabicyclo[4.1.0]heptanes are equalized.     

Catalytic Oxidation of Cyclohexene by Dendrimer-bond Metal Catalysts

Since Tomalia and Dovornic discussed the promising outlook of surface-functionalized dendrimer catalysts in 1994, [1] dendritic catalysts have been proposed to many kinds of catalysis.These well-defined macromolecular structures enable the construction of precisely controlled catalyst structures. The large number of the peripheral functionalities enhanced their activity in many processes. [2,3] We report herein a new method of using the dendritic catalysts in the oxidation of cyclohexene. The reactions give some interesting results.In short, the synthesis of the dendritic catalysts was initiated from the well-known PAMAM dendrimers by using their peripheral ammonia groups. The condensation reactions of these ammonia groups and salicyaldehyde (SA) offer the ligands PAMAMSA with different generation (G) numbers.dendrimer-bond PAMAMSA-Ni(Ⅱ) complexes.In the presence of the dendritic PAMAMSA-Ni(Ⅱ) catalysts, cyclohexene was fully oxidized under 1 atm of molecular oxygen at 70℃. All the oxidations give 7-oxabicyclo[4.1.0]heptane 1,2-cyclohexen-l-ol 2, 2-cyclohexen-1-one 3 and 7-oxabicyclo [4.1.0]heptan-2-one 4 as the major products. The results of the oxidation are shown in the table below (table 1):Table 1 Oxidation of cvclohexene bv PAMAMSA-Ni2+ catalysts** Reaction condition: cat. 2mg, cyclohexene 5mL, 1atm O2, 6hat 70℃.**Oxygen absorption (mL) per mol catalyst.It can be seen from table that the oxidations give a new product 7-oxabicyclo[4.1.0]heptan-2-one 4, which is the first reported product in this oxidation. Meanwhile, product 4possesses relatively high selectivity in the six oxidation processes. It will arise much more emphasison the optimizing of these reactions.     

Stereocontrolled approach to 1-azabicyclo[4.1.0]heptanes: application to the synthesis of trans-2,6-disubstituted piperidines

Stereocontrolled synthesis of a 1-azabicyclo[4.1.0]heptane is achieved by formation of an NH aziridine from the corresponding 1,2-azido alcohol and subsequent intramolecular conjugate addition onto a tethered α,β-unsaturated ester. Regioselective ring opening of the product at C-7 by heteroatom based nucleophiles yields trans-2,6-disubstituted piperidines in moderate to good yields.     

Synthesis of a Chiral Bicyclo[4.1.0] Allylic Nitrile Via Reductive Cyclization of a Dienyl Nitrile

(1R, 6S)-7,7-dimethylbicyclo[4.1.0]Hept-2-ene-3-acetonitrile 8 was synthesized from (S)-(-)-Perillaldehyde in 5 steps and 65% overall yield via Mg[0] reductive cyclization.     

Intramolecular photochemical [2 + 1]-cycloadditions of nucleophilic siloxy carbenes

Visible light induced singlet nucleophilic carbenes undergo rapid [2 + 1]-cycloaddition with tethered olefins to afford unique bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane scaffolds. This cyclopropanation process requires only visible light irradiation to proceed, circumventing the use of exogenous (photo)catalysts, sensitisers or additives and showcases a vastly underexplored mode of reactivity for nucleophilic carbenes in chemical synthesis. The discovery of additional transformations including a cyclopropanation/retro-Michael/Michael cascade process to afford chromanones and a photochemical C–H insertion reaction are also described.

Visible light induced singlet nucleophilic carbenes undergo rapid [2 + 1]-cycloaddition with tethered olefins to afford unique bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane scaffolds.     

Strained enamines as versatile intermediates for stereocontrolled construction of nitrogen heterocycles

This contribution assesses the synthetic utility of molecules that impose conformational constrains onto aziridine-derived enamines. Synthetically versatile [3.1.0] and [4.1.0] bicyclic enamines have been prepared by intramolecular oxidative cycloamination of aziridine-containing olefins. This process is initiated by N-bromosuccinimide followed by base-mediated elimination of HBr to afford highly strained exo-bicyclic enamines. In addition, intramolecular aziridine addition to aldehyde functionality was found to afford the [3.1.0] and [4.1.0] bicyclic hemiaminals. These routes highlight possibilities for chemoselective oxidative transformations of aziridine-containing precursors without nitrogen protection/deprotection steps. The resulting products provide straightforward synthetic entries into a wide range of pyrrolidine- and piperidine-containing heterocycles that are positioned toward subsequent transformations via aziridine ring opening.     

Bicyclo[3.1.0]hex-(1,5)-ene and bicyclo[4.1.0]hept-(1,6)-ene

The formation and trapping of bicyclo[3.1.0]hex-(1,5)-ene and bicyclo[4.1.0]hept-(1,6)-ene from the corresponding vicinal dibromides is described.     

Gold(I)-catalysed cycloisomerisation of 1,6-cyclopropene-enes

The gold(I)-catalysed cycloisomerisation of appropriately substituted 1,6-cyclopropene-enes proceeds through regioselective electrophilic ring opening of the three-membered ring to generate an alkenyl gold carbenoid that achieves the intramolecular cyclopropanation of the remote olefin. This strategy allows straightforward, highly efficient and diastereoselective access to a variety of substituted 3-oxa- and 3-azabicyclo[4.1.0]heptanes, as well as to bicyclo[4.1.0]heptan-3-ol derivatives. Since the isopropylidene group in the resulting cycloisomerisation products can be subjected to ozonolysis, 3,3-dimethylcyclopropenes behave as interesting surrogates for α-diazoketones.