Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of alpha-trifluoromethylsulfonamido furans

The reaction of alpha-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf(2)O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf(2)O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocyclic systems.     

Nucleophilic ortho allylation of aryl and heteroaryl sulfoxides

Aryl and heteroaryl sulfoxides undergo ortho allylation upon treatment with Tf(2)O and allylsilanes. The method complements the use of sulfoxides to direct ortho-metalation and reaction with electrophiles as it allows allylic carbon nucleophiles to be added ortho to the directing group in a metal-free process. The versatile sulfide adducts can be selectively manipulated using various methods including Kumada-Corriu cross-coupling of the organosulfanyl group.     

Halo substituent effects on intramolecular cycloadditions involving furanyl amides

Intramolecular Diels-Alder reactions involving a series of N-alkenyl-substituted furanyl amides were investigated. Stable functionalized oxanorbornenes were formed in high yield upon heating at 80-110 degrees C. The cycloaddition reactions include several bromo-substituted furanyl amides, and these systems were found to proceed at a much faster rate and in higher yield than without substitution. This effect was observed by incorporating a halogen in the 3- or 5-position of the furan ring and appears to be general. The origin of increased cycloaddition rates for halo-substituted furans has been investigated with quantum mechanical calculations. The success of these reactions is attributed to increases in reaction exothermicities; this both decreases activation enthalpies and increases barriers to retrocycloadditions. Halogen substitution on furan increases reactant energy and stabilizes the product, which is attributed to the preference of electronegative halogens to be attached to a more highly alkylated and therefore more electropositive framework.     

Elimination of benzotriazolyl group in N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides: their self-coupling and cross-coupling reactions with carbonyl compounds

The elimination of benzotriazolyl group from N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling reaction with carbonyl compounds, thus affording the corresponding dimers or α-hydroxyalkylated sulfonamides in moderate yields.     

Transition-metal,organic solvent and base free α-hydroxylation of β-keto esters and β-keto amides with peroxides in water

Without employing any transition metal, organic solvent and base, a facile, economical and environmentally friendly strategy has been developed for the α-hydroxylation of β-keto esters and β-keto amides with peroxides via radical cross-coupling reaction in water under open-air conditions. This protocol allows a convenient access to various α-hydroxy-β-keto esters and α-hydroxy-β-keto amides with up to 92% yield (34 examples). Moreover, the reaction was successfully scaled up to gram quantity and mechanistic studies showed the radical pathway was involved in this hydroxylation.     

Stereoselectivity and regioselectivity in nucleophilic ring opening in derivatives of 3-phenylisoxazolo[2,3-a]pyrimidine. Unpredicted dimerization and ring transformation. Syntheses of derivatives of pyrimidinylmethylamine, pyrimidinylmethylamino acid amides, and alpha-amino-2-pyrimidinylacetamides

The nucleophilic ring opening of the isoxazolone ring in 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidine derivatives by optically active amino acid amides and ephedrine led to pyrimidinylmethylamino acid amides. Using amides of different L-amino acids and (-)-ephedrine resulted in different degrees of stereoselectivity. The degree of streoselectivity depended mostly on the nucleophile used. When applying hydroxy amines such as ephedrine, the attack via the secondary amino group was found as the favored regioselectivity. Upon replacement of the oxo group in position 2 in the phenylisoxazolo[2,3-a]pyrimidine system by an imino group, it was expected that the spontaneous decarboxylation that follows the ring opening would not take place, thus achieving amino acid amide derivatives of 2-pyrimidinylacetamide, which are closely related to pyrimidoblamic acid, an important constituent of Bleomycins, used in cancer therapy. However, by heating 5,7-dimethyl-2-imino-3-phenylisoxazolo[2,3-a]pyrimidine in solution, it underwent an unprecedented dimerization process that involved both the phenyl and the imino group. After protecting the imino group by acetylation, the ring opening by nucleophiles was possible, resulting in the formation of derivatives of 2-pyrimidinylacetamide. 2-Acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]pyrimidine also underwent a ring transformation, yielding an interesting indolone derivative. Selectivity in ring opening and mechanisms of dimerization and ring transformation are discussed.     

Oxidative cross-coupling of acrylates with vinyl carboxylates catalyzed by a Pd(OAc)2/HPMoV/O2 system

Oxidative cross-coupling of acrylates with vinyl carboxylates was first successfully achieved by the use of a Pd(OAc)(2)/HPMoV/O(2) system in fair to good yields. For instance, the reaction of n-butyl acrylate with vinyl acetate in the presence of catalytic amounts of Pd(OAc)(2) and H(4)PMo(11)VO(40).nH(2)O under O(2) in acetic acid at 70 degrees C for 12 h afforded the corresponding cross-coupling product, n-butyl 5-(acetoxy)-2,4-pentadienoate, in 70% yield.     

Pd-catalyzed carbonyl insertion coupling reactions of a hypervalent iodoheterocycle with alcohols and amines

The palladium-catalyzed cross-coupling carbonyl insertion reaction between 3,7-bis(N,N-dimethylamino)-10H-dibenz[b,e]iodinium iodide (1) and alcohols or amines 2 is described. Some new amides and esters 3 containing an active iodo functional group have been prepared in 65-91% yields.     

2-Ethoxy-3-pyridylboronic acid: a versatile reagent for the synthesis of highly-functionalised 3-aryl/heteroaryl-pyridines via Suzuki cross-coupling reactions

This paper describes the commercially-viable synthesis and isolation of 2-ethoxy-3-pyridylboronic acid on a ca. 70 g scale via a directed ortho-metalation reaction on readily-available 2-ethoxypyridine. A range of efficient cross-coupling reactions of 2-ethoxy-3-pyridylboronic acid with selected aryl/heteroaryl halides under palladium-catalysed Suzuki-Miyaura conditions yield novel 2-ethoxy-3-aryl/heteroaryl-pyridines in high yield (heteroaryl=pyridyl, pyrimidyl, pyrazyl). The X-ray crystal structure of 2-ethoxy-3-pyridylboronic acid reveals that the boronic acid group takes part in an intramolecular O-H?O bond with the adjacent ethoxy substituent, and an intermolecular O-H?N bond.     

A general synthetic entry to the pentacyclic strychnos alkaloid family, using a [4 + 2]-cycloaddition/rearrangement cascade sequence

The total synthesis of (+/-)-strychnopivotine, (+/-)-tubifolidine, (+/-)-strychnine, and (+/-)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom causes the reactive s- trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to (+/-)-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of (+/-)-strychnine. The total synthesis of (+/-)-strychnine required only 13 steps from furanyl indole 18 and proceeded in an overall yield of 4.4%.     

Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl bromides. Synthesis of heteroaromatic amine substituted ynamides

A practical cross-coupling of amides with alkynyl bromides using catalytic CuSO(4).5H(2)O and 1,10-phenanthroline is described here. This catalytic protocol is more environmentally friendly than the use of CuCN or copper halides and provides a general entry for syntheses of ynamides including various new sulfonyl and heteroaromatic amine substituted ynamides. Given the interest in ynamides, this N-alkynylation of amides should be significant for the future of ynamides in organic synthesis.     

Formal total synthesis of (+/-)-gamma-lycorane and (+/-)-1-deoxylycorine using the [4+2]-cycloaddition/rearrangement cascade of furanyl carbamates

The total syntheses of gamma-lycorane and (+/-)-1-deoxylycorine were accomplished using an intramolecular Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroindolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)(2) employing the Jeffrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield. Compound 24 was subsequently converted into (+/-)-gamma-lycorane using a four-step procedure to establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu(3)SnH at reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction was used to provide the C(2)(-)C(3)(-)C(12) allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (+/-)-1-deoxylycorine via known synthetic intermediates.     

Synthesis and Crystal Structure of Dicopper(II) Compound Containing Oxalate and Reduced Imino Nitroxide Radicals

1 INTRODUCTION There has been increasing interest in molecular- based magnetic materials, in which the combination of metal ions and organic radicals are used to construct assembled systems[1, 2]. Nitroxide radicals are normally used as spin carriers …     

Synthesis of indeno-fused derivatives of quinolizinium salts, imidazo[1,2-a]pyridine, pyrido[1,2-a]indole, and 4h-quinolizin-4-one via benzannulated enyne-allenes

The benzannulated enediynyl propargylic alcohol 8 was prepared from 1-bromo-2-iodobenzene by two consecutive Sonogashira cross-coupling reactions. The subsequent transformation to mesylate 9 followed by treatment with 4-substituted pyridines 10 then furnished the benzannulated enediynes 11. On exposure of 11 to triethylamine, the indeno-fused quinolizinium salts 15 were produced in quantitative yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement to form the benzannulated enyne-allenes 12, which then underwent either a concerted Diels-Alder reaction or a two-step process involving a Schmittel cyclization reaction to form biradical 13 followed by an intramolecular radical-radical coupling to afford 14. A subsequent prototropic rearrangement then produced 15. Similarly, 21a and 21b were produced from 19a and 19b, respectively. The use of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene (7) and 1-(2-propynyl)-1H-imidazole (25) followed by treatment of the resulting adduct with potassium tert-butoxide gave the indeno-fused imidazo[1,2-a]pyridine 24 in 98% yield. Similarly, the indeno-fused pyrido[1,2-a]indole 32 and 4H-quinolizin-4-one 35 were obtained by starting from 7 for cross-coupling with 1-(2-propynyl)-1H-indole (30) and 1-(2-propynyl)-2(1H)-pyridinone (33), respectively, followed by treatment with potassium tert-butoxide.     

Unusually accelerated silylmethyl transfer from tin in stille coupling: implication of coordination-driven transmetalation

The palladium-catalyzed cross-coupling reaction of 2-PyMe2SiCH2SnBu3 with aryl iodide (Ar-I) exclusively produced the 2-PyMe2SiCH2 transferred product 2-PyMe2SiCH2Ar. The relative transfer ability of organic group from tin was found to be 2-PyMe2SiCH2 > Ph > Me > Bu > PhMe2SiCH2, which implies the beneficial pyridyl-to-palladium coordination effect. Thus, the transfer of the silylmethyl group from tin to palladium was remarkably accelerated by simply appending the 2-pyridyl group on silicon. The pyridyl-to-palladium coordination was validated in the palladium(II) complex 2-PyMe2SiCH2PdClPPh3 by 1H NMR and X-ray crystal structure analysis. The cross-coupling product was used for further transformations. The C-Si oxidation of the cross-coupling product 2-PyMe2SiCH2Ar afforded ArCH2OH in high yield. The fluoride ion-catalyzed 1,2-addition of 2-PyMe2SiCH2Ar to carbonyl compound (RR'C=O) gave ArCH2C(OH)RR' in high yield.     

Palladium-catalyzed synthesis of arylacetamides from arylboronic acids

Aryl amides were synthesized by the palladium catalyzed cross-coupling reaction of α-bromoacetamides with arylboronic acids in good yields. Both electron-donating and electron-withdrawing substituents on the aromatic ring are found to be compatible. The addition of Cu₂O and PPh₃ was found to be essential for good reaction yields.     

Practical Synthesis of Phosphinic Amides/Phosphoramidates through Catalytic Oxidative Coupling of Amines and P(O)−H Compounds

Herein, we report a highly efficient ZnI₂-triggered oxidative cross-coupling reaction of P(O)−H compounds and amines. This operationally simple protocol provides unprecedented generic access to phosphinic amides/phosphoramidate derivatives in good yields and short reaction time. Besides, the reaction proceeds under mild conditions, which avoids the use of hazardous reagents, and is applicable to scale-up syntheses as well as late-stage functionalization of drug molecules. The stereospecific coupling is also achieved from readily available optically enriched P(O)−H compounds.     

trans-Chloro(1-naphthyl)bis(triphenylphosphine)nickel(II)/PCy3 catalyzed cross-coupling of aryl and heteroaryl neopentylglycolboronates with aryl and heteroaryl mesylates and sulfamates at room temperature

trans-Chloro(1-naphthyl)bis(triphenylphosphine)nickel(II) complex/PCy(3) system has been successfully applied as catalyst for the Suzuki-Miyaura cross-coupling of aryl and heteroaryl neopentylglycolboronates with aryl and heteroaryl mesylates and sulfamates in THF at room temperature. This cross-coupling reaction tolerates various functional groups, including keto, imino, ester, ether, and cyano. Together with the nickel-catalyzed, one-pot, two-step neopentylglycolborylation, this bench stable and inexpensive Ni(II)-based catalyst can be utilized as an alternative to Ni(COD)(2)/PCy(3) to provide an inexpensive, robust, and convenient synthesis of biaryl and heterobiaryl compounds.     

NH(4)OAc Promoted Cyclocondensation of 3-(o-Allylphenyl)pentane-1,5-diones: Synthesis of Tetracyclic Benzofused 1-Azahomoisotwistanes

A facile two-step synthetic route for preparing the novel tetracyclic skeleton of benzofused 2,6-diaryl-1-azahomoisotwistanes 2 had been developed. The route was carried out by a one-pot tandem cross-coupling reaction of o-allylbenzaldehydes 1 with aryl methyl ketones 3, and NH(4)OAc mediated the cascade cyclocondensation reaction of the resulting 1,5-diketones 4 with the 3-o-allylphenyl group in good yield in two steps.     

Synthesis and cross-coupling reaction of alkenyl[(2-hydroxymethyl)phenyl]dimethylsilanes

Highly stable alkenyl[2-(hydroxymethyl)phenyl]dimethylsilanes are prepared by stereo- and regioselective hydrosilylation of alkynes catalyzed either by a platinum or ruthenium catalyst using protected [2-(hydroxymethyl)phenyl]dimethylsilanes. Cyclic silyl ether, 1,1-dimethyl-2-oxa-1-silaindan, also serves as a starting material for the alkenylsilanes by the ring-opening reaction with alkenyl Grignard reagents. The resulting alkenylsilanes undergo cross-coupling reaction with various aryl and alkenyl iodides under reaction conditions employing K₂CO₃ as a base at 35–50 °C in highly regio- and stereospecific manners. The reaction tolerates a diverse range of functional groups including silyl protections. The silicon residue is readily recovered and reused on a gram-scale synthesis. Intramolecular coordination of a proximal hydroxyl group is considered to efficiently form pentacoordinate silicates having a transferable group possibly at an axial position and, thus, responsible for the cross-coupling reaction under conditions significantly milder than those reported for the silicon-based reactions.