Synthesis of polynuclear heterocycles via the reaction of α-ester carbanions with quaternized nicotinamide salts. A facile stereoselective synthesis of sesbanine

α-Ester carbanions add to N-benzylnicotinamide salts to give C-4 and C-6 substituted primary products. The C-4 substituted dihydronicotinamides undergo a further reaction involving nucleophilic attack of the amide nitrogen on the carbonyl group of the ester. The resulting cyclization products can be oxidized and debenzylated to 1,2-dioxo-1,2,3,4-tetrahydro-2,7-naphthyridine derivatives. The sequence of reactions has been utilized in the synthesis of several heterocycles and in the stereoselective synthesis of the alkaloid sesbanine.     

Novel chiral bridged azepanes: stereoselective ring expansion of 2-azanorbornan-3-yl methanols

The reaction of 2-azanorbornan-3-yl methanols under Mitsunobu or mesylation conditions with various nucleophiles led to a series of chiral-bridged azepanes with configuration at C-4 dependent on the configuration of the starting alcohol. High yielding, stereoselective ring expansion to novel 2-azabicyclo[3.2.1]octane system occurred via aziridinium intermediates, which were specifically opened by nucleophilic attack at the more substituted carbon.     

Hydrolysis of 2-aryl-4h-3, 1-benzoxazin-4-ones

2-Aryl-4H-3, 1-benzoxazin-4-ones were subjected to alkaline hydrolysis in O¹⁸-enriched water. It was established on the basis of data from mass-spectrometric analysis of the hydrolysis products that the C-2 and C-4 atoms of the benzooxazinone ring undergo nucleophilic attack. The primary direction of attack depends on the nature and position of the substituent.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 641–644, May, 1976.     

Derivatives and reactions of glutaconaldehyde—XIII: Regiospecific ring opening of 3-substituted pyridines

A number of nucleophilic ring openings of 3-substituted pyridinium salts have been reinvestigated and summarized. The structure of the resulting stable glutaconaldehyde derivatives was investigated in detail by ¹H NMR. It has been concluded that in general nucleophilic pyridinium ring openings are highly regiospecific. In each case investigated to date a single product was isolated, as a result of attack by the nucleophile at only one of the pyridine α-positions. With the OH ion as the only nucleophile, attack occurs at the pyridine C-2, while larger nucleophiles such as amines and carbanions attack at the pyridine C-6. This was found to be the case for a variety of 3-substituted pyridines such as 3-methyl, 3-methoxy-, 3-cyano-, 3 chloro-pyridine.     

Nucleophilic reactions of fluoroolefins. II. Regioselectivity and elimination-addition competition in the reaction of 1-phenylpentafluoropropenes with sodium ethoxide

1-Phenylpentafluoropropene and its para-substituted analogs $\text{1}$ are susceptible to nucleophilic attack at both vinylic carbon atoms C-1 and C-2. They react with ethanolio sodium ethoxide to give predominantly substitution products, 1-ethoxy-1-phenyltetrafluoropropenes $\text{2}$ and 2-ethoxy-1-phenyltetrafluoropropenes $\text{3}$, with only little formation of adducts, $\text{viz}$. 2-ethoxy-1H-1-phenylpentafluoropropanes $\text{4}$. Alkenes $\text{1}$, where the para-substituent X  H,Cl,and CF₃ give additionally 1,2-diethoxy-1-phenyltrifluoropropenes $\text{5}$ and, where X = CF₃ also 2,2-diethoxy-1H-1-phenyltetrafluoropropane $\text{6}$. Overall regioselectivity of nucleophilic attack of the ethoxide ion on alkenes $\text{1}$ exhibits the Hammett type correlation with Ó_p values of substituents X: CH₃O and CH₃ groups favour the attack on the vinylic carbon C-1, while CF₃ and Cl substituents direct the attack on the C-2 carbon of alkenes $\text{1}$. The E and Z isomers of 1-ethoxy and 1,2-diethoxy substituted alkenes $\text{2}$ and $\text{5}$ were formed in comparable amounts, while the E isomers of 2-ethoxy substituted alkenes $\text{3}$ were always formed with a 93 – 97 % selectivity.     

Probing the intestinal α-glucosidase enzyme specificities of starch-digesting maltase-glucoamylase and sucrase-isomaltase: synthesis and inhibitory properties of 3'- and 5'-maltose-extended de-O-sulfonated ponkoranol

The synthesis and glucosidase inhibitory activities of two C-3'- and C-5'-β-maltose-extended analogues of the naturally occurring sulfonium-ion inhibitor, de-O-sulfonated ponkoranol, are described. The compounds are designed to test the specificity towards four intestinal glycoside hydrolase family 31 (GH31) enzyme activities, responsible for the hydrolysis of terminal starch products and sugars into glucose, in humans. The target sulfonium-ion compounds were synthesized by means of nucleophilic attack of benzyl protected 1,4-anhydro-4-thio-D-arabinitol at the C-6 position of 6-O-trifluoromethanesulfonyl trisaccharides as alkylating agents. The alkylating agents were synthesized from D-glucose by glycosylation at C-4 or C-2 with maltosyl trichloroacetimidate. Deprotection of the coupled products by using a two-step sequence, followed by reduction afforded the final compounds. Evaluation of the target compounds for inhibition of the four glucosidase activities indicated that selective inhibition of one enzyme over the others is possible.     

Synthesis of 2-heterosubstituted 1,3-oxathianes and their reaction with sec- butyllithium

A series of 2-heterosubstituted 1,3-oxathianes were synthesized and their reactivity toward a strong base, sec-butyllithium, was studied. It was shown that sec-butyllithium attacked 2-heterosubstituted 1,3-oxathianes in three different ways depending upon the heteroatom at C-2; the removal of the proton at C-2, the nucleophilic attack at the heteroatom, or the nucleophilic attack at C-2 took place.     

Photochemistry of some steroidal bicyclo[3.1.0]hexenones

The photochemistry of five 11-hydroxy-1,5-cyclopregn-3-en-2-ones (‘lumi’ products from the corresponding pregna-1,4-dien-3-ones) has been investigated. In all cases the photoproducts were 1,11-oxy derivatives, resulting from intramolecular attack of the hydroxyl group to the incipient positive charge at C-1. When a fluorine atom was present at C-6, HF elimination took place concurrently with the nucleophilic addition and led to linearly conjugated dienones, rather than the enones obtained in the other cases. Quantum yields were in the range 0.06-0.2, the lower values applying when a fluorine atom was present in position 6 (not in position 9). The results add new evidence on the role of zwitterionic intermediates in the photochemistry of cross-conjugated dienones and the corresponding lumi photoproducts.     

On the reaction of α-(2-hydroxyphenoxy)alkylketones with dimethylsulphoxonium methylide. A novel route to 2-substituted-2,3-dihydro-2-hydroxymethyl-1,4-benzodioxins

A new route to 2-substituted-2,3-dihydro-2-hydroxymethyl-1,4-benzodioxins 3 based on the reaction of α-(2-hydroxyphenoxy)alkylketones 1 with dimethylsulphoxonium methylide in dimethylsulphoxide is reported. Besides the desired compounds 3 , the isomeric 2H-3,4-dihydro-1,5-benzodioxepines 4 were also isolated, generally as minor products. The concurrent formation of 3 and 4 has been interpreted as occurring through the intermediate oxiranes 2 , which can undergo intramolecular nucleophilic attack at either of the carbon atoms of the epoxy ring.     

Studies of the Factors Controlling Regioselective Nucleophilic Addition to Dienylium-Iron Complexes

Tricarbonyl(4-alkoxyl-1-alkylcyclohexadienylium)iron complexes (I) react with metal-cation enolate nucleophiles to give in most cases a mixture of products (II) and (III), resulting from attack at the C-1 and C-5 termini of the dienylium ring. Factors that control the regioselectivity of nucleophilic addition, including the steric and electronic effects of the 4-alkoxyl and 1-alkyl substituents, the degree of association between the enolate nucleophiles and their counterions, and the polarity of the solvents, were investigated.     

Highly stereoselective palladium-catalyzed dithiocarbonylation of propargylic mesylates with thiols and carbon monoxide

Highly stereoselective dithiocarbonylation of propargylic mesylates with thiols and carbon monoxide has been developed by the use of tetrakis(triphenylphosphine)palladium(0) as the catalyst at 90 degrees C in THF. The reaction affords the corresponding dithioesters in good to excellent yields. For some secondary and tertiary propargylic alcohols with a terminal or internal triple bond, the reaction stereoselectively produces E-dithioesters as products. The dithiocarbonylation is believed to proceed via allenylpalladium and allenyl ester intermediates, and the high stereoselectivity might be rationalized by a mechanism where nucleophilic attack of a Pd(0)L(n) species on the allenyl sp carbon occurs from the less hindered side of an alkyl substituent.     

Stereocontrolled synthesis of iminocyclitols with an ether bridge

Nor-tropane related bicyclic (6+5) iminocyclitols with an ether bridge and different substituents (hydroxymethyl, aminomethyl, and aminoethyl) on C-1 are prepared starting from a β-d-psicofuranosyl cyanide. The method involves an internal nucleophilic attack of a stabilized amide ion on a 5-mesyloxy derivative. The intermediate N-acetyl O-protected iminocyclitols present atropoisomerism due to restricted rotation of the N-CO amido bond. Conformational aspects of the prepared compounds are discussed.     

Stereoselective C9 arylation and vinylation of Cinchona alkaloids

A simple and efficient method for the highly stereoselective C-9 arylation and vinylation of Cinchona alkaloids was developed. Both 9S- and 9R-chloroquinine with PhMgBr yielded 9S-phenylquinine (X-ray structure). The reactions with various aryl and vinyl Grignard reagents resulted in the series of 9S-aryl and vinyl alkaloid derivatives. The stereochemical outcome was rationalized by coordination of the magnesium atom to the quinuclidine nitrogen, thus directing the nucleophilic attack at the C-9 stereogenic center.     

Nucleophilic addition to substituted 1H-4,5-dihydroimidazolium salts

1H-4,5-Dihydroimidazolium salts 1 react readily with nucleophilic reagents originating cyclic products which may be stable or become transformed into acyclic compounds maintaining the structural ethylenediamine unit. With methylmagnesium iodide compound 1e affords the expected imidazolidine, but in the case of substituted 1-aryl-3-methyl-2-phenyl salts 1b-d the N-aryl-N′-methylethylenediamines 3b-d and acetophenone ( 4 ) were isolated, the process representing the transfer of the C-2 unit to a nucleophilic carbon. With alkaline cyanides salts 1 react efficiently affording α,α-diaminonitriles 5 . In these compounds the cyano group may be readily substituted by nucleophiles (hydroxyl anion, species with nucleophilic carbon and reagents that act by hydride ion transfer), in a way similar to the salts but with better yields.     

Reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide heterocyclic system: a combined experimental and theoretical study

The reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide (or beta-amino-gamma-sultone) heterocyclic system has scarcely been studied. Here we describe the reactivity of this system towards electrophiles and amines on readily available model substrates differently substituted at the C-5 position. A variety of C-electrophiles, carbonyl electrophiles (such as acyl chlorides, isocyanates, or aldehydes) and halogen or nitrogen electrophiles have been explored. Both the C-3 and 4-amino positions of the beta-amino-gamma-sultone system are able to undergo electrophilic reactions, and the reaction products depend on the electrophile used and on the reaction conditions. On the other hand, nucleophilic attack of amines occurs at the C-4 position of the beta-amino-gamma-sultone system only in spiranic substrates bearing alicyclic substituents at the C-5 position. A comparative computational study between spiranic and non-spiranic substrates suggests that conformational changes, undergone on intermediate compounds, account for the observed reactivity differences. Moreover, these conformational changes seem to bring about an increase of electron density on the N-4 and C-3 atoms of the enaminic system, and a possible enhancement in the reactivity of spiranic substrates towards electrophiles in the presence of amines. Experimental data consistent with this predicted enhanced reactivity is also presented.     

Ring opening of 2,3-epoxy phenyl ketones upon reaction with nitric oxide

Epoxide rings of 2,3-epoxy phenyl ketones were cleaved by nitric oxide, affording regioselectively the C-3 ring-opened products, erythro-α-hydroxyl nitrates (2), in a highly syn-selective manner (isolated yield of the erythro products up to 91%). Products were identified by NMR, MS, and X-ray crystallography. The reaction is assumed to be initiated by NO₂, unlike a nucleophilic attack.     

Tertiary alcohols by tandem β-carbolithiation and N→C aryl migration in enol carbamates

Enol carbamates (O-vinylcarbamates) derived from aromatic or α,β-unsaturated compounds and bearing an N-aryl substituent undergo carbolithiation by nucleophilic attack at the (nominally nucleophilic) β position of the enol double bond. The resulting carbamate-stabilized allylic, propargylic, or benzylic organolithium rearranges with N→C migration of the N-aryl substituent, creating a quaternary carbon α to O. The products may be readily hydrolyzed to yield multiply branched tertiary alcohols in a one-pot tandem reaction, effectively a polarity-reversed nucleophilic β-alkylation-electrophilic α-arylation of an enol equivalent.     

High 1,3-trans stereoselectivity in nucleophilic substitution at the anomeric position and β-fragmentation of the primary alkoxyl radical in 3-amino-3-deoxy-ribofuranose derivatives: application to the synthesis of 2-epi-(-)-jaspine B

The high inverse stereoselectivity in the nucleophilic substitution at the anomeric position of 3-amino-3-deoxy-ribofuranose derivatives is reported. This unprecedented stereoselectivity is explained in terms of preferential nucleophilic attack on the "inside face" of the respective five-membered ring oxocarbenium ion that orients pseudoequatorially to the benzylamine group placed at the C-3 position. In addition, an unusual β-fragmentation of a primary alkoxyl radical generated from its corresponding N-phthalimide derivative was achieved, and thus taking advantages of both reactions, the total synthesis of 2-epi-(-)-jaspine B was completed.     

Pentatomie heteroaromatic cations. Note II. Chemical properties of 2-phenyl-1,3-benzoxathiolium perchlorate

The reactions of 2-phenyl-1,3-benzoxathiolium perchlorate with common nucleophilic reagents (water, sodium hydroxide, ethanol, thiophenol, morpholine, phenylmagnesium bromide), with reducing agents (zinc, lithium aluminium hydride) and with manganese dioxide, were studied. In every case the reactions proceed by attack of the reagents at the C-2 position of the cationic system, giving rise either to 1,3-benzoxathiole derivatives or to ring-opening products. The 1,3-benzoxathiolium salts were shown to be suitable intermediates for converting the carboxylic acids into aldehydes and ketones.     

Practical approach for the stereoselective introduction of beta-arabinofuranosides

A practical approach for the stereoselective introduction of beta-arabinofuranosides has been developed on the basis of locking an arabinosyl donor in a conformation in which nucleophilic attack from the beta face is favored. The new glycosyl donor was designed by analyzing optimized geometries of low-energy conformers of the arabinofuranosyl oxacarbenium ion. The Newman projection of the E(3) conformer indicated that nucleophilic attack from the alpha face is disfavored because an eclipsed H-2 will be encountered. On the other hand, an approach from the beta face was expected to be more favorable, because it will experience only staggered substituents. The arabinofuranosyl oxacarbenium ion could be locked in the E(3) conformation by employing a 3,5-O-di-tert-butylsilane protecting group, which places C-5 and O-3 in a pseudoequatorial orientation, resulting in a perfect chair conformation of the protecting group. The new glycosyl donor gave excellent beta selectivities in a range of glycosylations with glycosyl acceptors having primary and secondary alcohols. The attractiveness of the new methodology was demonstrated by the chemical synthesis of a fragment of arabinogalactan, which is an important constituent of the primary plant cell wall.