Bulky Nucleophiles Research Articles

Sequential nucleophilic substitution of pseudorotaxanes forms rotaxanes with various linking functionalities and recycling of the surrogate stopper.

A sequential nucleophilic substitution method produces rotaxanes from anion-sensitive pseudorotaxanes. First, a nucleophilic bulky tertiary aniline interlocks a pseudorotaxane to form a surrogate rotaxane; this unit then functions as a leaving group for a set of bulky nucleophiles, affording rotaxanes with various linking functionalities, along with the bulky aniline recovered in its original form.

Update of the Imine-Anion-Mediated Smiles Rearrangement: Application to Migration of Electron-Neutral/Rich Aromatic Groups

AbstractWe have revisited the imine-anion-mediated Smiles rearrangement for the synthesis of ortho-hydroxyphenyl arylketimines. Detailed examinations revealed that migration of various aromatic groups, previously considered to be unsuited to SNAr-type reactions, such as electron-rich or sterically hindered aromatic groups, can be accomplished by introducing bulky 9-anthryllithium as a nucleophile. Among the aromatic groups examined, naphthyl groups (1- and 2-naphthyl groups) exhibited an excellent performance, and their migration ability was well illustrated by the reaction with less bulky nucleophiles.

Atroposelective Construction of Axially Chiral Alkene‐Indole Scaffolds via Catalytic Enantioselective Addition Reaction of 3‐Alkynyl‐2‐indolylmethanols†

Main observation and conclusionAtroposelective construction of axially chiral alkene‐heteroaryl scaffolds is highly desired but challenging. In this work, we established an atroposelective construction of axially chiral alkene‐indole scaffolds via the strategy of catalytic enantioselective addition reaction of 3‐alkynyl‐2‐indolylmethanols with bulky nucleophiles. In this strategy, α‐amido sulfones were used as competent nucleophiles and chiral phosphoric acid (CPA) acted as suitable chiral catalyst for this addition reaction. By this strategy, a new class of axially chiral acyclic alkene‐indoles was synthesized in overall high yields (up to 86%), excellent (E/Z)‐selectivity (all > 95 : 5) and good enantioselectivities (up to 92 : 8 er). This reaction represents the first catalytic enantioselective construction of axially chiral alkene‐indole frameworks, which will add a new member to the family of atropoisomeric heterocycles, especially the family of axially chiral indole compounds.

A tris(benzyltriazolemethyl)amine-based cage as a CuAAC ligand tolerant to exogeneous bulky nucleophiles.

The archetypal tris(benzyltriazolemethyl)amine (TBTA) ligand was equipped with a bowl-shaped cap in the cage Hm-TBTA. Hm-TBTA accelerates CuAAC reactions without suffering from product inhibition. Furthermore, this shielded ligand efficiently protects the copper center from deactivation by the CuI-chelator glutathione, opening the way to novel approaches for efficient CuAAC reactions in complex media.

Chemistry of Tertiary Carbon Center in the Formation of Congested C−O Ether Bonds

Nucleophilic substitutions, including SN 1 and SN 2, are classical and reliable reactions, but a serious drawback is their intolerance for both bulky nucleophiles and chiral tertiary alkyl electrophiles for the synthesis of a chiral quaternary carbon center. An SRN 1 reaction via a radical species is another conventional method used to carry out substitution reactions of bulky nucleophiles and alkyl halides, but chiral tertiary alkyl electrophiles cannot be used. Therefore, a stereospecific nucleophilic substitution reaction using chiral tertiary alkyl electrophiles and bulky nucleophiles has not yet been well studied. In this paper, we describe the reaction of tertiary alkyl alcohols and non-chiral or chiral α-bromocarboxamides as a tertiary alkyl source for the formation of congested ether compounds possessing two different tertiary alkyl groups on the oxygen atom with stereoretention.

Chemistry of Tertiary Carbon Center in the Formation of Congested C−O Ether Bonds

AbstractNucleophilic substitutions, including SN1 and SN2, are classical and reliable reactions, but a serious drawback is their intolerance for both bulky nucleophiles and chiral tertiary alkyl electrophiles for the synthesis of a chiral quaternary carbon center. An SRN1 reaction via a radical species is another conventional method used to carry out substitution reactions of bulky nucleophiles and alkyl halides, but chiral tertiary alkyl electrophiles cannot be used. Therefore, a stereospecific nucleophilic substitution reaction using chiral tertiary alkyl electrophiles and bulky nucleophiles has not yet been well studied. In this paper, we describe the reaction of tertiary alkyl alcohols and non‐chiral or chiral α‐bromocarboxamides as a tertiary alkyl source for the formation of congested ether compounds possessing two different tertiary alkyl groups on the oxygen atom with stereoretention.

Synthesis and Characterization of Fatty Acid Furfuryl Ester Mixtures: Biodiesel from Furfuryl Alcohol

Synthesis and Characterization of Fatty Acid Furfuryl Ester Mixtures: Biodiesel from Furfuryl Alcohol Amanda L. Raley, Jenny P. Beldin, Russell J. Franks Abstract The synthesis of biodiesel fuels from triacylglycerols and common alcohols such as methanol and ethanol has been reported using a variety of methods and catalysts. As part of an effort to explore the properties of biodiesel fuels made from novel feedstocks, furfuryl alcohol is used as the alcohol component in biodiesel synthesis. Commercially-available cooking oils were transesterified using furfuryl alcohol and K2CO3 in the presence of a room-temperature ionic liquid catalyst. The resulting product is a fatty acid furfuryl ester (FAFurE) mixture. After purification, the FAFurE product mixtures were analyzed using 1H-NMR spectroscopy. Percentage conversion values were calculated using integration data from the NMR spectra. Percent conversion values ranged from 19 to 75%. The wide range in percent conversion has been attributed to steric interactions between the bulky nucleophile and polyunsaturated fatty acid chains in the oils used. This work represents a proof-of-concept that furfuryl alcohol can serve as an alternative alcohol source for biodiesel fuels or biodiesel additives. Full Text: PDF DOI: 10.15640/jcb.v7n1a3

Transetherification of 2,4-dimethoxynitrobenzene by aromatic nucleophilic substitution.

In view of the few reports concerning aromatic nucleophilic substitution reactions featuring an alkoxy group as a leaving group, the aromatic nucleophilic substitution of 2,4-dimethoxynitrobenzene was investigated with a bulky t-butoxide nucleophile under microwave irradiation. The transetherification of 2,4-dimethoxynitrobenezene with sodium t-butoxide under specific conditions, namely for 20 min at 110°C in 10% dimethoxyethane in toluene, afforded the desired product in 87% yield with exclusive ortho-selectivity. A variety of reaction conditions were screened to obtain the maximum yield. The aromatic nucleophilic substitution of 2,4-dimethoxynitrobenzene with t-butoxide should be carried out under controlled conditions in order to avoid the formation of byproducts, unlike that of dihalogenated activated benzenes. Among the formed byproducts, a major compound was elucidated as 2,4-dimethoxy-N-(5-methoxy-2-nitrophenyl)aniline by X-ray crystallography.

Synthesis of Poly(glycidyl 2-ylidene-acetate) and Functionalization by Nucleophilic Ring-Opening Reactions

Rhodium-mediated C1 polymerization of glycidyl 2-diazoacetate resulted in the novel functional polymethylene poly(glycidyl 2-ylidene-acetate), the first functional polymethylene suitable for a subsequent controlled post-polymerization modification at moderate reaction conditions via nucleophilic ring-opening of the epoxide. Nucleophilic ring-opening reactions with water, various amines, and thiols were examined. Even bulky nucleophiles such as α-aminodiphenylmethane reacted quantitatively, resulting in densely packed functional polymers. The obtained results were compared with previously published results on post-polymerization modification of poly(glycidyl methacrylate). Contradictory to the expectations, epoxide ring-opening with primary amines led to soluble products when the C1 polymer poly(glycidyl 2-ylidene-acetate) was employed, while the same reaction with the C2 polymer poly(glycidyl methacrylate) resulted in gelation.

Tricarbonyliron(0) complexes of bio-derived η4 cyclohexadiene ligands: An approach to analogues of oseltamivir

We have prepared novel [η4] and [η5]+ tricarbonyliron complexes from an unusual enantiopure cyclohexadiene ligand that possesses a quaternary stereocentre; this in turn is prepared through biotransformation of an aromatic ring. The cyclohexadiene ligand initially possessed two hydroxyl groups, both of which could be substituted with other functionality by means of an overall [η4] → [η5]+ → [η4] → [η5]+ → [η4] sequence. From six novel tricarbonyliron complexes which have been prepared, three have been characterised by x-ray crystallography. The reaction sequence we describe is potentially of relevance to the synthesis of analogues of the anti-influenza drug oseltamivir. In addition, the failure of an attempted addition of a bulky nitrogen nucleophile to an [η5]+ complex sheds light on the limits of reactivity for such additions. Thus, two bulky nucleophiles which are each known to add successfully to unencumbered [η5]+ complexes seemingly cannot be added sequentially to adjacent positions on the cyclohexadiene ligand.

ChemInform Abstract: Nucleophilic Aromatic Substitution of Bis(pentafluorophenyl)mercury with Various Bulky Nucleophiles and the Structures of [Hg(C6F4X‐4)2] (X = cyclo‐C5H10N, OCH(CH3)2, OC(CH3)3).

Reactions of bis(pentafluorophenyl)mercury with piperidine, sodium iso-propoxide or sodium tert-butoxide have yielded the corresponding 4-substituted tetrafluorophenylmercurials, [Hg(C6F4X-4)2] (X = cyclo-C5H10N (1), OCH(CH3)2 (2), OC(CH3)3 (3)), in reasonable yields but the bulkier nucleophiles, cis-2,6-dimethylpiperidine and 2,6-di-iso-propylphenolate (from sodium 2,6-di-iso-propylphenolate) decomposed the mercurial into pentafluorobenzene. Treatment of bis(pentafluorophenyl)mercury with another bulky nucleophile, 2,6-diphenylphenolate (from sodium 2,6-diphenylphenolate), in methanol, resulted in the unexpected formation of [Hg(C6F4(OMe)-4)2] (4). The structures of all the mercurials have linear C–Hg–C stereochemistry with two coplanar aryl rings. Amongst a complex series of supramolecular interactions, Hg⋯O bonding is observed for the alkoxy substituted mercurials but there are no Hg⋯N interactions in the structure of bis(2,3,5,6-tetrafluoro-4-piperidinophenyl)mercury.

Nucleophilic Aromatic Substitution of Bis(pentafluorophenyl)mercury with Various Bulky Nucleophiles and the Structures of [Hg(C6F4X-4)2] (X=cyclo-C5H10N, OCH(CH3)2, OC(CH3)3)

Reactions of bis(pentafluorophenyl)mercury with piperidine, sodium iso-propoxide or sodium tert-butoxide have yielded the corresponding 4-substituted tetrafluorophenylmercurials, [Hg(C6F4X-4)2] (X = cyclo-C5H10N (1), OCH(CH3)2 (2), OC(CH3)3 (3)), in reasonable yields but the bulkier nucleophiles, cis-2,6-dimethylpiperidine and 2,6-di-iso-propylphenolate (from sodium 2,6-di-iso-propylphenolate) decomposed the mercurial into pentafluorobenzene. Treatment of bis(pentafluorophenyl)mercury with another bulky nucleophile, 2,6-diphenylphenolate (from sodium 2,6-diphenylphenolate), in methanol, resulted in the unexpected formation of [Hg(C6F4(OMe)-4)2] (4). The structures of all the mercurials have linear C–Hg–C stereochemistry with two coplanar aryl rings. Amongst a complex series of supramolecular interactions, Hg⋯O bonding is observed for the alkoxy substituted mercurials but there are no Hg⋯N interactions in the structure of bis(2,3,5,6-tetrafluoro-4-piperidinophenyl)mercury.

Methimazole-disulfide as an Anti-Thyroid Drug Metabolite Catalyzed the Highly Regioselective Conversion of Epoxides to Halohydrins with Elemental Halogens

The regioselective ring opening of epoxides using elemental iodine and bromine in the presence of methimazole (MMI, a anti-thyroid drug) and its metabolite methimazole-disulfide as new catalysts are studied. MMI easily converted in vitro to MMI-disulfide without any double activation presented in vivo. FT-Raman and UV spectroscopies are used to study the interaction of iodine with these catalysts. The results indicate that both catalysts are efficient in polyiodide formation, but MMI-disulfide can catalyze this reaction in higher yield and regioselectivity. The complex [(MMI-disulfide)I]+.I3- is considered to be formed initially which could be bulkier by addition of excess of iodine in the course of the reaction. These bulky nucleophiles have a fundamental role in the high regioselectivity by attacking the less sterically hindered epoxide carbon. In this study we suggest that MMI is readily converted to MMI-disulfide by interaction with iodine or activated iodine in thyroid gland, and this process is responsible for high anti-thyroid activity of MMI.

Ambident Electrophilicity of 5-Membered Ring Phosphate Triesters

The reactions of 2-alkoxy-1,3,2-dioxaphospholane 2-oxide with various nucleophiles were studied both experimentally and theoretically. These studies show that 5-membered ring phosphate triesters act as ambident electrophiles: hard and bulky nucleophiles attack at the phosphorus while soft nucleophiles attack at the ring carbon.

Mo-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation of 3-Aryloxindoles

A highly regio-, diastereo-, and enantioselective allylic alkylation reaction mediated by a chiral molybdenum catalyst has been developed as a novel entry into synthetically versatile 3-alkyl-3-aryloxindoles. Extremely bulky nucleophiles were employed to form a quaternary center and an adjacent tertiary center asymmetrically concurrently. The regio- and diastereoselectivity of the reaction is dependent upon the steric and electronic nature of the nucleophiles to an unusual degree. A reaction mechanism based on the bonding modes of molybdenum enolate complexes was discussed.

Reaction with alcohols of 1-bromo(chloro)-1,2-epoxyheptafluorobutanes and 1,2-epoxyperfluorobutane. Preparation of α-bromo-, α-chloro-, and α-alkoxyhexafluorobutyric acids esters

1-Bromo(chloro)-1,2-epoxyheptafluorobutanes reacted with primary and secondary alcohols by two concurrent routes giving a mixture of esters of α-alkoxy-and α-bromo(chloro)-hexafluorobutyric acids with growing content of the latter on increasing the bulk of the nucleophilic agent. 1,2-Epoxyperfluorobutane under the same conditions was converted into α-alkoxyhexafluorobutyric acid esters. Reaction of 1-bromo-1,2-epoxyheptafluorobutane and 1,2-epoxyperfluorobutane with potassium tert-butylate in tert-butanol resulted in tert-butyl α-bromohexafluorobutyrate and heptafluorobutyrate respectively due to the forced attack of the bulky nucleophile on the terminal carbon atom of the epoxy ring.

Regio‐ and Diastereoselective Conjugate Addition to 4,4‐Dimethylcyclohexadienones

AbstractConjugate addition of vinyl cuprate and dimethyl malonate to 4,4‐dimethylcyclohexa‐2,5‐dienones has allowed facile access to mono‐ and bis‐adducts in satisfactory yields. While the high diastereoselectivity of such processes to afford trans‐bis‐adducts was predictable, an unprecedented regioselectivity was observed with 2,4,4‐trimethylcyclohexa‐2,5‐dienone, with the first addition occurring exclusively at the C‐5 carbon atom (distal from the methyl group) and with the second addition of a bulky nucleophile such as dimethyl malonate even prevented. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

O‐Phenylenediamine as a New Catalyst in the Highly Regioselective Conversion of Epoxides to Halohydrins with Elemental Halogens.

AbstractFor Abstract see ChemInform Abstract in Full Text.

O-Phenylenediamine as a New Catalyst in the Highly Regioselective Conversion of Epoxides to Halohydrins with Elemental Halogens

The regioselective ring opening of epoxides using elemental iodine and bromine in the presence of o-phenylenediamine as a new catalyst affords vicinal iodo alcohols and bromo alcohols in high yields. The major advantages of this method are versatility, high regioselectivity, a cheap and commercially available catalyst, mild and neutral reaction conditions, and short reaction times. Fourier transform Raman spectroscopy was used to study the reaction of iodine with o-phenylenediamine. The results indicate that the complex [(Diamine)I]+·I5− is formed, and we suggest that the major nucleophile is the pentaiodide ion. This bulky nucleophile has a fundamental role in the high regioselectivity observed attacking the less sterically hindered epoxide carbon.

Diastereoselective total synthesis of both enantiomers of epolactaene.

A stereocontrolled total synthesis of both the (+)- and (-)-epolactaene ((+)- and (-)-1) enantiomers from tetrahydropyran-2-ol is described. The following reactions in this synthesis are particularly noteworthy: (1) the stereoselective construction of the conjugated (E,E,E)-triene by a combination of kinetic deprotonation and thermodynamic equilibration, (2) the E-selective Knoevenagel condensation of beta-ketonitrile 33 with a chiral 2-alkoxyaldehyde, (3) a diastereoselective epoxidation achieved using a bulky nucleophile (TrOOLi) and an appropriate protecting group, (4) the mild hydrolysis of an alpha-epoxy nitrile by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular assistance.