Cyclopropane Intermediates Research Articles

Protonated cyclopropane as an intermediate in cation–olefin cyclizations. Ab initio and density functional theory investigations

In order to investigate the mechanism of cation–olefin cyclizations, the model calculations for the cyclization of cis-5,6-dimethyl-5-hexenyl cation were studied with both ab initio and density functional theory methods. The geometry optimization of the cis-5,6-dimethyl-5-hexenyl cation reveals its spontaneous rearrangement into protonated cyclopropane intermediates, for which four conformers were identified on the potential energy surface of C 8H 15 + ions. The present study demonstrates that two of these conformers are suitably preorganized to undergo chair- and boat-like cation–olefin cyclizations. The result is the formation of the chair cyclohexyl cation and the protonated cyclopropane moiety embedded into the cyclohexyl cation in boat conformation. The analysis of the intrinsic reaction coordinates show that the formation of the latter species via the boat-like pathway is preferred by 2.0 kcal/mol. To appreciate the influence of the leaving group, the cyclization reactions of protonated cis-1,2-dimethyl-6-hydroxyhexene were also studied by the MP2 and MP4 methods, using the 6-31G ∗ and 6-311+G ∗ basis sets. In this model system, the neutral water molecule was used to simulate the leaving group during the cyclization step in which the cyclohexyl cation–water complexes were generated. The MP4(SDQ)/6-31G ∗//MP2/6-31G ∗ computed energy barriers are almost identical for the chair- and boat-like cyclization reactions of the appropriately preorganized reactants. The boat-like cyclization pathway, preferred only by 0.2 kcal/mol, again leads to the incorporation of the protonated cyclopropane into the cyclohexyl cation–water complex in boat conformation. To evaluate the cyclization energy barriers when the preorganization of the reactant is not taken into account, the lowest conformer of protonated alcohol has to be considered. In this case, the chair-like cyclization pathway is preferred by a small margin of 0.8 kcal/mol for the formation of the C–C hyperconjugated chair cyclohexyl cation–water complex. The use of a larger basis set and the inclusion of polarization functions has little, if any, effect on the relative stability of cation–water complexes. The MP2 and MP4 methods appear to be well suited for investigations of cation–olefin cyclizations for the model systems proposed in this study. In contrast to intermolecular cation–olefin additions, which are barrier-less processes, the present study demonstrates that the MP2 and, to an even greater extent, the MP4 method, reveal distinct energy barriers for intramolecular cation–olefin cyclizations.

Cyclopropane-derived peptidomimetics. design, synthesis, and evaluation of novel Ras farnesyltransferase inhibitors.

Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.

Formation of Acetylenes by Ring-Opening of 1,1,2-Trihalocyclopropanes

This review describes studies into the conversion of substituted 1,1,2-trihalocyclopropanes into acetylenic acetals and acetylenic ketals by application of alcohols or alkoxides under basic conditions. The acetal/ketal ratio turned out to depend both on the substituents attached to the ring and on the reaction conditions prevailing during the reaction. Under the right conditions, however, completely regioselective ring-opening occurs to give either acetylenic acetals or acetylenic ketals, with formation of either no or only minor amounts of other products. The reactions are thought to involve cyclopropene intermediates, which are consumed by nucleophilic attack of alcohol or alkoxide. In some cases, the cyclopropene intermediates rearrange to the corresponding vinyl carbenes, which undergo insertion reactions with protic species present in the reaction mixture and give various 2-propenal derivatives as by-products.

Formation of Acetylenes by Ring-Opening of 1,1,2-Trihalocyclopropanes

This review describes studies into the conversion of substituted 1,1,2-trihalocyclopropanes into acetylenic acetals and acetylenic ketals by application of alcohols or alkoxides under basic conditions. The acetal/ketal ratio turned out to depend both on the substituents attached to the ring and on the reaction conditions prevailing during the reaction. Under the right conditions, however, completely regioselective ring-opening occurs to give either acetylenic acetals or acetylenic ketals, with formation of either no or only minor amounts of other products. The reactions are thought to involve cyclopropene intermediates, which are consumed by nucleophilic attack of alcohol or alkoxide. In some cases, the cyclopropene intermediates rearrange to the corresponding vinyl carbenes, which undergo insertion reactions with protic species present in the reaction mixture and give various 2-propenal derivatives as by-products.

Intramolecular Carbenoid Insertions: the Reactions of α-Diazoketones Derived from Pyrrolyl and Indolyl Carboxylic Acids with Rhodium(II) Acetate

α-Diazoketones derived from pyrrolyl- and indolyl-carboxylic acids were prepared and their Rh 2(OAc) 4 catalyzed decomposition chemistry was studied. These reactions generally resulted in the alkylation of the heteroaromatic system by the ketocarbenoid and in some instances the systems underwent CH or NH insertions. Evidence that some of these reactions proceed via a cyclopropane intermediate is presented. The methodology described provides facile access to fused pyrrolyl– or indolyl–cycloalkanone systems wherein the carbonyl is beta to the heteroaromatic system.

The Reaction of Chromium Alkenyl Carbene Complexes with Alkenyl Oxazolines: A Diastereoselective [3 + 2] Annulation Route to Cyclopentanones

Pentacarbonyl(alkenylmethoxy)carbene chromium complexes 1 undergo regio- and diastereoselective formal [3 + 2] cycloaddition to electron-deficient alkenes, e.g. alkenyl oxazoline derivatives 2, affording cyclopentanoids 3 and 4, the cis isomer 3 being the major stereoisomer. The cyclopropane intermediates 5/6 were isolated, under appropriate reaction conditions, and further converted into 3 and 4. The cycloadduct 3b was efficiently elaborated into the 3,4-disubstituted cyclopentanones 10 and 11.

Effect of Alumina Fluoridation on Hydroconversion ofn-Heptane on Sulfided NiW/Al2O3Catalysts

Hydroisomerization and hydrocracking ofn-heptane on sulfided NiW catalysts, supported on alumina modified with various amounts of fluoride, have been studied at 673, 698, and 723 K and at a total pressure of 3 MPa. It was found that alumina fluoridation increases the catalytic activity for both hydroisomerization and hydrocracking and provides a higher hydroisomerization selectivity. Differences in product selectivities for the hydroisomerization and hydrocracking ofn-heptane indicate that alumina fluoridation induces also changes in the various contributions of the mechanisms involved in the transformation ofn-heptane. A decrease in the ratio of 3-MC6and 2-MC6monobranched isomers predicted by a branching mechanism via the protonated cyclopropane (PCP) intermediates and a decrease in the dimerization cracking mechanism in favor of the classic bifunctional cracking mechanism were observed with increasing fluoride content. Theses changes are results of a better balance of the (de)hydrogenation and acidity functions of the sulfided catalysts with increasing fluoride content since the incorporation of fluoride increases the (de)hydrogenation function and decreases the strength of the acid sites.

Diazo transfer reaction of 2-(trimethylsilyl)-1,3-dithiane with tosyl azide. Carbenic reactivity of transient 2-diazo-1,3-dithiane

A novel diazo transfer reaction of 2-lithiated 2-(trimethylsilyl)-1,3-dithiane with tosyl azide in a 1:20 HMPA-THF mixture furnishes 2-diazo-1,3-dithiane 2, which decomposes at about 0°C to give in fairly high yield bis(1,3-dithianylidene) 5 through formal dimerization of derived carbene 4. In the presence of dimethyl fumarate, dimethyl maleate, trans- and cis-1,2-bis(benzenesulfonyl)ethylene, the diazodithiane affords only trans-cyclopropane adducts in a stereoselective, but non stereospecific fashion. With dimethyl acetylenedicarboxylate or 1-tosyl-2-(trimethylsilyl)acetylene, no corresponding cyclopropene adducts are observed, but instead bis(ketene-dithioacetal) products, likely arising from further reaction of cyclopropene intermediates with diazodithiane 2 and/or its carbene 4. A related ring-opened dithioacetal product is observed upon treatment of diazodithiane with dimethyl 3,3-dimethylcyclopropene-1,2-dicarboxylate. The above reactions with electrophilic alkenes and alkynes are preferentially explained in terms of primary intervention of somewhat nucleophilic dithiocarbene 4 rather than its diazo precursor. The outcome of the usual reaction of 2-lithio-2-(trimethylsilyl)-1,3-dithiane with tosyl azide, in the presence of dimethyl acetylenedicarboxylate, is profoundly changed when performed in the absence of HMPA cosolvent. Under these circumstances the occurrence of bis(ketene-dithioacetal) product (and the dimer 5) is essentially suppressed in favor of significant formation of the silylated maleate 12; this is believed to arise from preferential trapping by the alkyne of the triazenyl anion 3, the presumable progenitor of diazodithiane. An X-ray crystallographic analysis of maleate 12 is reported.

Cover Picture (Angew. Chem. Int. Ed. Engl. 9/1997)

Angewandte Chemie International Edition in EnglishVolume 36, Issue 9 Cover PictureFree Access Cover Picture (Angew. Chem. Int. Ed. Engl. 9/1997) First published: May 16, 1997 https://doi.org/10.1002/anie.199708971AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract The cover picture shows a model of the binding of a protonated cyclopropane in a cation-binding site of an antibody. The larger circle gives an enlarged view of the actual binding of the organic intermediate. The aromatic and carboxylate groups are yellow, the organic intermediate silver, and the carbon atoms of the protonated cyclopropane red. The image was created with the programs Persistence of Vision and RasMol as well as proprietary software by Dr. Nicholas C. DeMello. More on the stabilization of cyclopropane intermediates is reported by J. K. Lee and K. N. Houk on pages 1003 ff. Volume36, Issue9May 16, 1997 RelatedInformation

Dihydrofurans from α-diazoketones due to facile ring opening – cyclization of donor–acceptor cyclopropane intermediates

A series of α-diazoketones, 8, 25, 28, 31, and 34, have been synthesized and their reaction with ethyl vinyl ether examined under various reaction conditions. In the presence of metal salts (Rh2(OAc)4, Pd(OAc)2, CuCl) the ethoxy-dihydrofurans 12, 37, 39, 41, and 43 are produced. Sensitized irradiation of the α-diazoketone 8 afforded the dihydrofuran 12 plus cyclobutanone 7, while direct photolysis of α-diazoketones 8, 25, 28, 31, and 34 gave the cyclobutanones 7, 38,40,42, and 44, respectively. A sample of the cyclopropylketone 45 was isolated from the rhodium(II) acetate mediated reaction of 34 and its facile rearrangement to dihydrofuran 43 demonstrated. Collectively, these results indicate that the initial product from the reaction of an α-diazoketone with an electron-rich alkene such as ethyl vinyl ether is a cyclopropylketone. The donnor–acceptor substitution pattern of this intermediate results in spontaneous rearrangement to a dihydrofuran. Thus a direct dipolar cycloaddition mechanism is not involved when α-diazoketones react with enol ethers under metal-mediated conditions. Instead, these reactions follow a cyclopropanation rearrangement or, more accurately, cyclopropanation – ring opening – cyciization pathway. Key words: diazoketone, rhodium acetate, dihydrofuran, cyclopropylketone, vinyl ether.

Isomerisation of 1-methylene-2-methyl-2-(2-oxopropyl)-cyclohexanes to 2-methylene-1-methyl-1-(2-oxopropyl)-cyclohexanes by ene and retro-ene reaction

Thermal activation of the normal Claisen products, the enones 4, 7 and 14 in the presence of a catalytic amount of propionic acid generated the isomeric enones 6, 9 and 15 via the sequential intramolecular ene-reaction of the enol tautomer followed by 1,5-hydrogen transfer (or retro ene-reaction) of the resultant acetyl cyclopropane intermediate. Conversion of the enones 9 and 15 into the corresponding cyclohexenones 10 and 16 established the structures of the rearrangement products.

Dihydrofurans from α-diazoketones: Facile rearrangement of donor-acceptor cyclopropanes

The direct synthesis of dihydrofurans 7, 11, and 23–25 from α-diazoketones 3, 8, and 20–22 is described. The cyclopropane intermediates generated upon treatment of the α-diazoketones with metal catalysts in the presence of ethyl vinyl ether rearranged spontaneously. Sensitized of 3 afforded 7 plus cyclobutanone 5 while direct photolysis gave the cyclobutanones 5, and 26–28.

Mechanism-based enzyme inactivation via a diactivated cyclopropane intermediate

Mechanism-based enzyme inactivation via a diactivated cyclopropane intermediate

Intramolecular transfer of sulfonyl oxygen to vinylcarbene generated in the reaction of tris(isopropylthio)cyclopropenyl cation with arylsulfinate salts

Tris(isopropylthio)cyclopropenylium perchlorate 1 reacts with sodium arylsulfinates 2a–d in dry acetonitrile and benzene under reflux to give arylsulfinylpropenethioates 3a–d, accompanied by the formation of arylsulfonylallenes 4a–d, through cyclopropene intermediates 5a–d and then vinylcarbenes 6a–d.

A novel entry to substituted chromones and furochromones through cyclopropane intermediates.

Addition of several carbon nucleophiles to 3-bromochromone 1 and 6-bromofurochromone 2 yield interestingly substituted δ-pyrone ring analogues.

Evidence for branching of long-chain n-alkanes via protonated cycloalkanes larger than cyclopropane

The formation of monobranched isomers from n-alkanes over bifunctional faujasite-type catalysts is explained by proposing the occurrence of alkylcarbenium ions as reaction intermediates and by using the general rules of alkylcarbenium ion chemistry. Methyl branching of n-alkanes occurs mainly via substituted corner-protonated cyclopropane intermediates. Protonated cycloalkanes with larger rings must be invoked in order to explain the primary nature of isomers with side chains larger than methyl groups and to rationalize the observed methyl-, ethyl-, propyl-, and butyl-branching selectivities.

Isomerization and fragmentation of aliphatic ether radical cations: Interconversion of distonic ions and cyclopropane intermediates

AbstractThe reactions of propyl ether radical cations close to threshold are initiated by (reversible) formation of γ‐disitonic isomers, R\documentclass{article}\pagestyle{empty}\begin{document}$ \mathop {\rm O}\limits^ + $\end{document} (H)CH2CH2CH2·. The three methylene groups in these ions lose their positional identity by ring closure/ring opening via [cyclopropane + alcohol]+· intermediates. Extensive hydrogen exchange occurs within the C3‐chain. When R is not methyl the γ‐distonic isomer undergoes further intramolecular hydrogen atom transfer reactions that lead to formation of α‐ and β‐distonic ions. The α‐distonic isomers expel ethyl and propyl radicals by CO bond cleavage.

Ring opening of gem-dihalocyclopropanes: novel types of 1,4-elimination reactions

Upon treatment with tetrabutylammonium fluoride, tert-butyl 2,2-dichloro- and 2-chloro-2-fluoro-3,3-dimethyl-1-cyclopropanecarboxylate (1 and 3, respectively) undergo a chlorine/fluorine exchange via cyclopropene intermediates. As a by-product, tert-butyl 4-methyl-4-penten-2-ynoate ( 6) is formed. The same ring opened compound and, in addition, tert-butyl 4-chloro-4-methyl-2-pentynoate ( 9) are obtained besides the gem-dichlorocyclopropane derivative 1 when tert-butyl 3-methyl 2- butenoate is allowed to react with chloroform in strongly alkaline medium. - 2,2-Difluoro-3,3)-dimethyl-1-cyclopropanecarbaldehyde ( 11) can be generated by oxidation of the corresponding alcohol. In the presence of any base, however, instantaneous ring opening and dehydrofluorination (to give 13) occur. - The solvolysis of 2,2-difluoro-3,3-dimethylcyclopropylmethyl p-tolueaesulfonate ( 14) in boiling aqueous dioxane affords two ring opened products, 3,3-difluoro-2-methyl-l,4-pentadiene ( 17) and 3,3-difluoro-2-methyl-4-penten-2-ol ( 16), besides 2,2-difluoro-3,3-dimethyl-1-cyclopropyl-methanol ( 10).

Isotope label scrambling in alkyl cations. A mechanistic proposal

AbstractThe observation of sharp limits to the chain lengths of alkyl cations derived by low energy collision‐induced dissociation of isotopically labelled trimethyltetradecylammonium cations, as well as the selectively limited scrambling of its isotope label, has prompted the proposal of a new mechanistic model for alkyl cation fragmentation. The model invokes protonated cyclopropane intermediates which may reopen to branched structures, or fragment (if suitably substituted) to form smaller alkyl cations and neutral olefins. The model accounts completely for the absence of daughter ions with fewer than three or more than six carbon atoms, while its semi‐quantitative application provides a reasonable match to the observed isotope scrambling.

ChemInform Abstract: Corner Attack on Cyclopropane by Deuteron and Mercuric Ions: An Example of Stereospecific Formation and Capture of Unsymmetrical Corner‐Deuteriated/Mercurated Cyclopropane Intermediates.

ChemInformVolume 19, Issue 33 Preparative Organic Chemistry ChemInform Abstract: Corner Attack on Cyclopropane by Deuteron and Mercuric Ions: An Example of Stereospecific Formation and Capture of Unsymmetrical Corner-Deuteriated/Mercurated Cyclopropane Intermediates. J. M. COXON, J. M. COXON Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this authorP. J. STEEL, P. J. STEEL Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this authorB. I. WHITTINGTON, B. I. WHITTINGTON Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this authorM. A. BATTISTE, M. A. BATTISTE Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this author J. M. COXON, J. M. COXON Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this authorP. J. STEEL, P. J. STEEL Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this authorB. I. WHITTINGTON, B. I. WHITTINGTON Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this authorM. A. BATTISTE, M. A. BATTISTE Dep. Chem., Univ. Canterbury, Christchurch, N. Z.Search for more papers by this author First published: August 16, 1988 https://doi.org/10.1002/chin.198833106Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume19, Issue33August 16, 1988 RelatedInformation