Internal Nucleophile Research Articles

Synthesis of bridged bicyclic hydrazines via endocyclic N-acylhydrazonium intermediates: A novel route to the 1-Azatropane skeleton

Bicyclic molecules with the 1,7-diaza-6,6-dimethylbicyclo[2.2.1]heptane and 1,8-diaza-7,7-dimethylbicyclo[3.2.1]octane (1-aza-7,7-dimethyltropane) skeleton are shown to be efficiently synthesized via cyclization reactions of endocyclic N-acylhydrazonium intermediates. By using a protected β-ketoester as the internal nucleophile, azacocaine analogues are also accessible via this methodology.

Ozonolysis of Amino Alkenes Derived From Labda-8(17),14-dien-13-ol

A series of amino alkenes was synthesized from manool [labda-8(17),14-dien-13-ol] as substrates for an investigation of the ability of an amino group to act as an internal nucleophile during ozonolysis. A 10-membered ring keto lactam (20) was produced from amino. alkene (4) but the C8-C9 bond remained intact during the ozonolysis of amino alkene (18). Substrates with an unfavourable relationship of the amino group to the olefin, (7), (10) and (16), gave no products resulting from intramolecular participation.

Polyene cyclizations using mercury (II) triflate-N,N-dimethylaniline complex - participation by internal nucleophiles

The cyclization of a number of functionalized polyenes with mercuric triflate - N,N-dimethylaniline complex (Nishizawa's reagent) to give bicyclic or tricyclic products has been studied. Suitably positioned internal nucleophiles, such as carbonyl, hydroxy and β-ketoester groups were found to participate to varying extent, in the termination of these cyclizations.

Communication: The Reductive Coupling of Carbohydrate Radicals with Diazonium Ions: a New Access to 2-Amino-2-Deoxy Glycosides

The oxidative coupling of glycals with alcohols is an efficient procedure for creating an α-glycosidic bond. It can be triggered by an “I+”-reagent (iodonium di-sym-collidine perchlorate1 or N-iodosuccinimide2) and occurs in a 1,2-diaxial fashion through a presumed 1,2-iodonium ion intermediate leading to 2-deoxy-2-iodo-α-glycosides. This iodoglycosylation allows the preparation of 2-deoxy-α-glycosides by reductive deiodination with tributylstannane3 or nickel boride.4 Considering the behavior of good leaving groups at C-2 of α-D-mannopyranosides,5 the displacement of iodine by oxygen or nitrogen functions through SN2-type reactions would be difficult or impossible, unless performed with internal nucleophiles.6 In contrast, a C-2 radical can be easily trapped by electron-deficient olefins7 or nitrogen monoxide8 giving access to C-2 branched carbohydrates and oximes, respectively. Nucleophilic radicals have also been trapped by aryldiazonium ions in a reversible manner to give azo radical cations.9 In the presence of a reducing agent (Ti3+, Fe2+, Cr2+, V2+), the equilibrium is shifted towards the azo compound:

Transformation of cyclic α-phenylthio aldehydes by stereoselective aldol reactions and phenylthio migration into spirocyclic lactones and ethers, and E-allylic alcohols with 1,4-related chiral centres

syn- and anti-Selective aldol reactions between enolates of propionate esters and three α-phenylthio cycloalkanecarbaldehydes give single diastereoisomers of phenylthio alcohols which rearrange in acid with 5-hydroxy or 5-CO2H participation to give spirocyclic ethers or lactones. In the absence of internal nucleophiles, allylic sulphides are formed which are used to make allylic alcohols with an E double bond exo to the ring and two stereochemically defined 1,4-related chiral centres.

ChemInform Abstract: Heterocyclisations Induced by Thallium(III) Acetate. Effect of Varying the Internal Nucleophile.

AbstractTreatment of the hex‐4‐en‐1‐ol (I) with Tl(OAc)3 in acidic aqueous acetone affords the trans‐2,5‐disubstituted tetrahydrofuran (II).

Heterocyclisations induced by thallium(III) acetate. Effect of varying the internal nucleophile

The stereochemistry of the 2,5-disubstituted tetrahydrofuran formed on treating 5-methyl-1-phenylhex-4-en-1-ol [6] with thallium(III) acetate in appropriate solvents has been established as trans by means of nuclear Overhauser experiments. Replacement of the hydroxy group of [6] by ether, ester, amide or carbamate functionalities suppresses intramolecular nucleophilic participation during oxythallation. Instead, products of acetoxythallation followed by solvolysis of the C-Tl bond or by methyl group migration are isolated.

ChemInform Abstract: Carbopalladation of Alkylidenecyclopropanes. Part 2. Intramolecular Capture of the Organo‐Palladium Intermediate.

AbstractIn the presence of Ph‐I (II) and Pd(0) complex the alkylidenecyclopropanes (I), (IV), (VI) and (VIII) form a π‐allylic Pd complex which is attacked by an internal nucleophile to give the cyclization products (III), (V), (VII) and (IX), respectively.

ChemInform Abstract: Conjugate Addition of Internal Nucleophile to Chiral Vinyl Sulfoxides with Stereogenic Center at the Allylic Carbon. “Intramolecular” Double Asymmetric Induction.

Abstract The intramolecular conjugate addition of allylically situated carbamoyloxy nitrogen to chiral vinyl sulfoxides displays diastereoselectivity governed by cooperation or competition of two controlling factors. These factors have been evaluated.

Carbopalladation des alkylidenecyclopropanes-II capture intramoleculaire de l'organopalladique intermediaire

Resume The reaction of an alkylidenecyclopropane of type 1, bearing an Internal nucleophile(β-diester , β-keto-ester, β-sulfonyl-ester , amine) with lodobenzene in the presence of catalytic amounts of a palladium (o) complex leads to cyclic compounds 3 and (or) 4 depending on the number of carbon atoms between the nucleophilic moeity and the double bond. These compounds result from the intramolecular attack of a II-allyl-palladium formed by isomerisation of the initial α-cyclopropanic σ-palladic species. This isomerisation does not occur when n = 4 and the product then results from the direct attack of the carbon nucleophile on the Csp3-palladium bond of the cyclopropanic σ-complex.

Conjugate addition of internal nucleophile to chiral vinyl sulfoxides with stereogenic center at the allylic carbon. “intramolecular” double asymmetric induction

The intramolecular conjugate addition of allylically situated carbamoyloxy nitrogen to chiral vinyl sulfoxides displays diastereoselectivity governed by cooperation or competition of two controlling factors. These factors have been evaluated.

Protic acid-induced intramolecular reactions of 2-cyclopropylazobenzenes

Treatment of 2-cyclopropylazobenzenes with concentrated sulfuric acid affords the intramolecular N- and C-alkylation products. Treatment of azobenzenes with trifluoroacetic acid results in quantitative rearrangement to arylindazoles via the intermediate formation of acid-stable indazolium ions. It is suggested that the formation of indazolium ions in trifluoroacetic acid results from the synchronous opening of the cyclopropane ring and stabilization of the developing carbocation by an internal nucleophile (the azo-group).

Modeling chemical reactivity. 7. The effect of a change in rate-limiting step on the stereoselectivity of electrophilic addition to allylic alcohols and related chiral alkenes

The stereoselectivities of electrophilic additions to acyclic allylic alcohols with and without internal nucleophiles have been assessed with use of previously developed chemical reactivity modeling techniques. Reactions normally assumed to proceed via onium-type intermediates have been investigated. The diastereofacial selectivity of attack by I/sub 2/, Br/sub 2/, PhSeCl, Hg(OAc)/sub 2/, and related electrophiles, known to be opposite for substrates containing an internal nucleophile compared with those without, is explained in terms of a change in the rate-limiting step for the reaction. Specifically, where intramolecular nucleophilic attack is possible, cyclizations proceed via a transition state that resembles a (reactant-like) ..pi.. complex, whereas reactions that involve intermolecular addition of the nucleophile are governed by one that resembles an onium ion, e.g., iodonium. Calculations show that these two extremes should exhibit opposite diastereofacial selectivity of attack on the acyclic allylic ..pi.. bond by the electrophile, in agreement with available experimental results.

Hydrolysis of N-methylnicotinyl and N-methylisonicotinyl esters and some n-participating derivatives under micellar conditions

Hydrolysis rate of two types of compounds, A and B were studied in the presence of variable concentrations of an anionic surfactant (sodium dodecylsulfate, SDS). Class A of compounds consists of substances which hydrolyze by the S N1 mechanism and which are structurally related to cationic surfactants. The second class (B) contains an internal nucleophile and thus solvolyzes under anchimeric assistance. It was found that compounds of class A are forming an effective micelle and show a rate retardation relative to solvolysis in pure water. The hydrolysis rates of compounds of class B are relatively unaffected by the presence of the micelle forming surfactant. The merits of a N-methylnicotinoic and N-nethylisonicotinoic esters as a new type of leaving groups are discussed.

Deamination of endo- and exo-bicyclo[3.2.1]octan-3-ylamines and their derivatives

Bicyclo[3.2.1] octan-3-ylamines have been deaminated in acetic acid by nitrous acid and via their N-phenyltriazenes; their ethyl N-nitrosocarbamates have also been solvolysed in ethanol. The exo-isomers give mainly unrearranged substitution, some elimination, and very little rearrangement. The unrearranged substitution, is derived from both the solvent (the external nucleophile, either acetic acid or ethanol) and the internal nucleophile liberated in the deaminative fragmentation step (water from the nitrous acid reaction, aniline from the triazene, and ethyl carbonate from the nitrosocarbamate). It is of predominantly retained configuration in all three reactions with the solvent, and, as demonstrated in the nitrosocarbamate solvolysis, with the internal nucleophile. The endo-isomers give mainly elimination, some unrearranged substitution, and appreciable rearrangement. The solvent-derived unrearranged substitution is with predominant inversion of configuration in all three reactions whereas that from the internal nucleophile, established by the nitrosocarbamate solvolysis, is predominantly with retention. Rearrangement from both endo- and exo-compounds is best explained in terms of hydride shift from the first formed carbonium ions (in nitrogen-separated complex ion-pairs with hydrogen-bonded anions) produced in the deaminative fragmentation. This gives rearranged classical bicyclo[3.2.1]octan-2-yl carbonium ions which, in competition with nucleophilic capture and proton loss, undergo further stepwise rearrangemnt to a common unsymmetrical non-classical carbonium ion. The non-classical cation and its classical precursors (which, from exo- and endo- substrates, differ in the location of the counter-anion) give rise to substitution products derived from solvent and the internal nucleophile. The non-classical carbonium ion also gives some tricyclo[3.2.1.02,7] octane. The high yields of internal substituion products from both endo- and exo-compounds rule out long lived intermediates such as diazonium ions.

Mercury(II)-mediated opening of cyclopropanes. Effects of proximate internal nucleophiles on stereo- and regioselectivity

Etude des effets de moities acide carboxylique et ester internes sur les regio- et stereoselectivites inherentes au clivage induit par le mercure(II) de cyclopropanes non actives. Bien que les cyclisations fournissent classiquement des lactones avec une forte stereoselectivite, des pertes surprenantes de selectivite sont occasionnellement observees

Iodocyclization of allylic alcohol derivatives containing internal nucleophiles. Control of stereoselectivity by substituents in the acyclic precursors

La reaction d'acides hydroxy-3 alcene-4oiques avec l'iode en milieu biphasique neutre donne une cyclisation stereoselective habituellement en cis-hydroxy-3 iodo-4 lactone. Effet des substituants

Electron-transfer photooxygenation, 8. trapping of internal nucleophiles

Irradiation of 5,5-diphenylpent-4-en-1-ol, sensitized by 9,10-dicyanoanthracene under N 2, leads to 2-(diphenylmethyl)-tetrahydrofuran ( 7 ). Under O 2, a related oxidation product, 2-(diphenylhydroxymethyl)-tetrahydrofuran is produced.

Classical carbonium ions. Part 12. The deamination of 1- and 4-amino-n-octane

The deamination products of 1- and 4-amino-octane in acetic acid were examined. The amines were treated with sodium nitrite directly, and also converted into alkylaryltriazenes derived from several arenediazonium cations, which were then acetolysed. N-Nitrosobutyramides were acetolysed, and N-nitrosoacetamides were butyrolysed, to allow the separate analysis of rearranged and unrearranged products from internal and external nucleophiles. It is concluded that the primary alkylamine is converted by all these different methods in high yield into a primary alkane diazonium ion RN2+, the properties of which are independent of its method of preparation in that the alkyl cation formed by its decomposition does not capture the leaving group which accompanies its formation, but reacts with solvent to give a constant set of products. The secondary alkylamine behaves differently. Its diazo-derivatives, RN2X, usually undergo effectively concerted decomposition to carbonium ions, nitrogen, and leaving group X. The cations show differing degrees of hydride shift, and capture the internal nucleophile X to a considerable but variable extent, after as well as before rearrangement. The acetolysis of 4-diazo-octane proceeds via a much less reactive intermediate, possibly an intimate ion-pair, giving mainly unrearranged 4-acetoxyoctane, plus an olefin mixture in which the substantial proportion of cis-isomers reflects the conformational preference of the starting material.

Ouverture de dichlorocyclopropanes en présence d'un nucléophile interne. Absence de participation intramoléculaire. Réarrangement concerté en chlorures allyliques

It is shown that a conveniently placed internal nucleophile (carboxyl group) is not involved with the rearrangement of a dichlorocyclopropane into an allylic chloride. This result appears to support a concerted mechanism of a σs2 + σa2 type for this rearrangement. In the products obtained, the allylic chloride may undergo displacement either by solvent (H2O), leading to alcohols, or by the internal carboxyl group, leading to a lactone. [Journal translation]