An improved synthesis of various racemic polyphenolic tetrahydroisoquinoline alkaloids

An improved and straightforward synthesis of (±)-coclaurine (Va), (±)-isococlaurine (Vb), (±)-reticuline (VIIIa) as well as an alternate route to an intermediate in the synthesis of (±)-multifloramine, the (±)-diphenol (VIIIb), is described.     

Synthesis of functionalized 1,4-cyclohexadienes through intramolecular anionic dearomatization of N-alkyl-N-benzyldiphenylphosphinamides. Insight into the reaction mechanism

A generalization of the intramolecular nucleophilic dearomatization-electrophilic alkylation reactions of N-alkyl-N-benzyldiphenylphosphinamide anions is presented. The process has been optimized by analyzing the effects of metalation and quench times, additives, the nature of the electrophiles used (MeI, CF(3)SO(3)Me, Me(3)O(+)BF(4)(-), AllylBr, PhCH(2)Br, BrCH(2)CO(2)Me, and RCH=O, where R = Ph, 4-Cl-C(6)H(4), 4-MeO-C(6)H(4), and (i)()Pr), and the alkyl substituent linked to the nitrogen of the phosphinamide. Both HMPA and DMPU act as catalysts. The latter proved to be much more efficient for obtaining high yields of substituted tetrahydrobenzo[c][1,2]-1lambda(5)-phospholes containing a 1,4-cyclohexadiene system with very high regio- and diastereoselectivity. Steric effects in the neighborhood of the benzylic anion tend to decrease the stereoselectivity of the anionic cyclization. The optimization study also served to shed light on the reaction mechanism of the dearomatization process by identifying several intermediate species and showing the reversibility of the anionic cyclization step as well as of the reaction with aldehydes.     

Regio- and stereoselective lithiation of 2,3-diphenylaziridines: a multinuclear NMR investigation

The alpha-lithiation-trapping sequence of trans-N-alkyl-2,3-diphenylaziridines (s-BuLi or s-BuLi/TMEDA), taking place with a stereochemistry which dramatically depends on the solvent coordinating ability (inversion of configuration in THF and retention in toluene), has been carefully investigated. 1H,13C, and 7Li multinuclear NMR investigations at low temperature suggest that two differently configured lithiated aziridines (monomeric cis-1-Li in THF and dimeric trans-1-Li in toluene) are involved.     

Li- and P NMR spectra of cyclopentanone lithium enolate in ethereal solvents: identification of the HMPA-coordinated aggregate structures

The structures of cyclopentanone lithium enolate under HMPA titration in 0.04-0.8 M diethyl ether and dimethyl ether solvents have been investigated using the low-temperature ⁷Li, ³¹P, and ¹³C NMR. The progressive solvation by HMPA occurs for the tetra- and dimeric enolates, and upon addition of >2 equiv. of HMPA, the lithium enolate has been converged on a mixture of tetra-HMPA coordinated tetramer and bis-HMPA coordinated dimer with the ratio of 5:95 and <1:99 in diethyl ether and dimethyl ether, respectively. Neither monomeric nor trimeric enolate is detectable under such HMPA titration.     

Synthesis and spectroscopic studies of phenyllead halide and thiocyanate adducts with hexamethylphosphoramide

Hexamethylphosphoramide (HMPA) adducts of the type Ph₃PbX·HMPA (X=Cl, Br, I, and NCS), Ph₂PbX₂·2HMPA (X=Cl, Br, and I), and Ph₂PbX₂·HMPA (X=Br and I), have been prepared and characterized by infrared, Raman, mass, and ³¹P nmr spectroscopy. Molecular weight and infrared solution data show that Ph₃PbX·HMPA adducts dissociate in benzene, the degree of dissociation being NCS«Cl<Br<I. The thiocyanate adducts Ph₃PbNCS·HMPA and Ph₂Pb(NCS)₂·2HMPA have v(CN) and v(CS) frequencies in the solid state, and v(CN) frequencies and absorptivities in benzene solution consistent with N-bonded thiocyanate in the solid state and in benzene solution. Vibrational frequencies are reported in the range 260 to 80 cm⁻¹ and assignments are made for v(Pb-X), v(Pb-O0, and v(Pb-NCS) modes. The 1:1 adducts Ph₃PbX·HMPA are monomeric and trigonal bipyramidal, whereas the 1:2 adducts Ph₂PbX₂·2HMPA are monomeric and cis-octahedral and the Ph₂PbX₂·HMPA appear to be halogen bridged polymers with lead six-coordinate. Coordination of HMPA causes a small upfield change in ³¹P chemnical shift values, and ²J(Pb-P) values vary with X in the order: NCS>I-Br>Cl for Ph₃PbX·HMPA adducts. Corresponding tin and lead adducts are compared with respect to mode of adduct formation.     

Synthesis of Asymmetric 4H-1, 3, 2-Benzodioxaphosphorin 2-Sulfides from Intramolecular Cyclization Reaction

Avarietyofbiologicalactivitiesofsome4H-l,3,2-benzodioxaphosphorin2-sulfideshavebeenreported,forexampletheinsecticideSalithionl.Thecyclicphosphonothionateshavebeenpreparedbyintermolecularcondensationofphosphorodichloridothioateswithsalicylalcoholoritsderivativesinthepresenceofabase=,andbyintramolecularcyclizationreactionofthesalicylalasthestartingmaterial3.However,theintramolecularcyclizationreactionofthe2-hydrobenzophenonesandstereochemicalstudieshavenotbeenreported.Wenowdescribeanewsynthesis…     

Nearly planar nonsolvated monomeric silyl- and germyllithiums as a result of an intramolecular CH-Li agostic interaction

Pale-yellow crystals of the nonsolvated monomeric silyl- and germyllithiums, tris[di-tert-butyl(methyl)silyl]silyllithium 2a and tris[di-tert-butyl(methyl)silyl]germyllithium 2b, were obtained by one-electron reduction of the corresponding silyl and germyl radicals with lithium in hexane. The crystal structure analysis of both 2a and 2b showed almost planar geometry around the anionic centers, due to both intramolecular CH-Li agostic interactions and steric reasons. However, the free anions [(tBu2MeSi)3Si-][Li+(THF)4] 3a and [(tBu2MeSi)3Ge-][Li+(THF)n] (n = 3, 4) 3b no longer showed a planar geometry, because of the absence of the intramolecular CH-Li agostic interaction. A temperature-dependent 1H NMR study of 2a showed that the CH-Li interaction is weak.     

Dearomatizing anionic cyclization of phosphonamides. A route to phosphonic acid derivatives with antitumor properties

Deprotonation of bis(N-benzyl-N-methyl)-P-arylphosphonic diamides with s-BuLi in THF at -90 degrees C takes place selectively at the benzylic position. The anions undergo intramolecular attack to the P-aryl ring leading to dearomatized species that were trapped with a series of electrophiles (MeOH, ArOH, BnBr, aliphatic and aromatic aldehydes, and benzophenone) in very high yield, and with high regio- and stereocontrol. The dearomatized products were smoothly transformed into gamma-aminophosphonic acids under acidic conditions. Preliminary screening for antitumor activity showed promising levels of activity.     

Ortho-selective nucleophilic aromatic substitution reactions of polyhaloanilines with potassium/sodium o-ethyl xanthate: a convenient access to halogenated 2(3H)-benzothiazolethiones

Polyhaloanilines bearing an ortho halogen atom undergo smooth nucleophilic aromatic substitution reactions with anionic sulfur nucleophiles at relatively mild temperatures (95-120 degrees C). These reactions are very efficient and highly ortho-selective. With potassium/sodium O-ethyl xanthate as a nucleophile, subsequent cyclization follows to afford halogenated 2(3H)-benzothiazolethiones (2-mercaptobenzothiazoles) in high yields.     

Indolizidine synthesis by transannular cyclization

Beckmann rearrangement of alkylcyclooctenone oximes VIa and VIb gave corresponding nine-membered lactams 1,3,4,5,8,9-hexahydro-3-methyl-2H-azonin-2-one (VIIIa) and 1,3,4,5,8,9-hexahydro-3-butyl-2H-azonin-2-one (VIIIb), respectively. A stereospecific transannular cyclization was induced by mercuric acetate leading to alkyl indolizinones Xa and Xb. Temperature and solvent dependent nmr spectra of the medium ring lactams indicates the stereochemical control is caused by steric interactions of the alkyl side chain. Lithium aluminum hydride reduced Xa/Xb to cis-octahydro-6-methylindolizidine (XIa) and cis-octahydro-3-n-butylindolizidine (XIb).     

Reaction of Isocyanates and Isothiocyanates with Butyraldazine; Formation of 1-Substituted 2-Pyrazolines

Phenyl isothiocyanate reacts with butyraldazine in presence of acidic catalysts to form a 2-pyrazoline (IV) whereas phenyl or benzyl isocyanates under similar conditions yield a mixture of the two isomeric 2-pyrazolines XIa and XII. On reaction with Ac₂O, IV gave the 1-acetyl derivative V. Reduction with LiAlH₄ led to the corresponding pyrazolidines. Reexamination of Kost's three step preparation of a 1-phenylthiocarbamoyl 2-pyrazoline [19] such as X via formic acid cyclization [18] of butyraldazine revealed that his first step product was apparently a mixture of two stereoisomeric 1-formyl-2-pyrazolines VIIIa and VIIIb. A mechanism for the formation of these pyrazolines is proposed.     

From the tetra(amino) phosphonium cation, [P(NHPh)4]+, to the tetra(imino) phosphate trianion, [P(NPh)4]3-, two-faced ligands that bind anions and cations

The tetraanilino phosphonium cation, [P(N(H)Ph)4]+, 1+, is sequentially deprotonated by Bu(n)Li in thf. The deprotonation reaction of the chloride derivative, Cl, was monitored by (31)P NMR, which revealed the successive formation of the neutral [P(N(H)Ph)3(NPh)], 2, the monoanionic [P(N(H)Ph)2(NPh)2]-, 3-, the dianionic [P(N(H)Ph)(NPh)3]2-, 4(2-), and finally the trianionic species [P(NPh)(4)](3-), (3-). Considering the isoelectronic relationship of oxo, =O, and imino groups, =NR, as well as hydroxy, -OH, and amino groups, -N(H)R, the neutral complex corresponds to phosphoric acid, H3PO4, whereas the anions 3-, 4(2-) and 5(3-) are analogues of dihydrogen phosphate, H2PO4-, monohydrogenphosphate, HPO4(2-), and orthophosphate ions, PO4(3-), respectively. Solid state structures were obtained of 1Cl, 2LiCl(thf)(2), 3Li(thf)(3.5), 3Li(2)Cl(thf)(4.25), 3Li(2)Cl(thf)(6) and 5Li(4)Cl(thf)(4). All systems provide two separate N-P-N chelation sites at opposite ligand faces, either consisting of the di(amino) arrangement P(NH)(2), acting as a double H-bond donor, the di(imino) arrangement PN(2), donating two electron pairs, or the mixed amino imino arrangement P(N)(NH), which supplies both electron pair and H-donor site. Interesting in this aspect is the mixed amino imino derivative 3- which has the ability to chelate a Lewis acid, such as a metal ion, at one face and a Lewis base, such as an anionic or neutral donor at the opposite ligand face. The formation of 1-D aggregates and the entrapment of lithium chloride are key characteristics of the supramolecular structures of the discussed complexes.     

Electrochemical reduction and radical anions of benzo[b]thioxanthene-6,11,12-trione and thioxanthene-1,4,9-trione

The electrochemical reduction of benzo[b]thioxanthene-6,11,12-trione and thioxanthene-1,4,9-trione in DMSO, MeCN and HMPA is an EE process, which is characterized by two separate one electron reversible peaks on cyclic voltammograms, first peak retains reversibility in DMSO–H2O mixtures, corresponding radical anions were obtained by one electron reduction of the above compounds and characterized by EPR and DFT calculations at the (U)B3LYP/6-31+G* level of theory.     

Nucleophilic de-coordination and electrophilic regeneration of "hemilabile" pincer-type complexes: formation of anionic dialkyl, diaryl, and dihydride Pt(II) complexes bearing no stabilizing pi-acceptors

Novel anionic dialkyl, diaryl, and dihydride platinum(II) complexes based on the new "long-arm" hemilabile PCN-type ligand C6H4[CH2P(tBu)2](CH2)2N(CH3)2 with the general formula Li+[Pt(PCN)(R)2]- (R=Me (4), Ph (6) and H (9)) were prepared by reaction of [Pt(PCN)(R)] complexes (obtained from the corresponding chlorides) with an equivalent of RLi, as a result of the opening of the chelate ring. Alkylating agents based on other metals produce less stable products. These anionic d8 complexes are thermally stable although they bear no stabilizing pi acceptors. They were characterized by 1H, 31P[1H], 13C, and 7Li NMR spectroscopy; complex 9 was also characterized by single crystal X-ray crystallography, showing that the Li+ ion is coordinated to the nitrogen atom of the open amine arm and to the hydride ligand (trans to the P atom) of a neighboring molecule (H--Li=2.15 A), resulting in a dimeric structure. Complexes 4 and 9 exhibit high nucleophilic reactivity, upon which the pincer complex is regenerated. Reaction of 4 with water, methyl iodide, and iodobenzene resulted in the neutral complex [Pt(PCN)(CH3)] (3) and methane, ethane, or toluene, respectively. Labeling studies indicate that the reaction proceeds by direct electrophilic attack on the metal center, rather than attack on the alkyl ligand. The anionic dihydride complex 9 reacted with water and methyl iodide to yield [Pt(PCN)(H)] (8) and H2 or methane, respectively.     

Photoinduced electron-transfer reactions with quinolinic and trimellitic acid imides: experiments and spin density calculations(1)

The regioselectivity of photoinduced electron-transfer (PET) reactions of unsymmetrical phthalimides is controlled by the spin density distribution of the intermediate radical anions. ROHF ab initio calculations were found to be most suitable for atomic spin density analysis. Intramolecular PET reactions of quinolinic acid imides were studied with the potassium butyrate and hexanoate 1a,b and a cysteine derivative 3. The photocyclizations products 2a,b and 4 were formed with moderate regioselectivities (68:32, 57:43, and 81:19) showing preferential ortho cyclization. The intermolecular reaction of potassium propionate and potassium isobutyrate with N-methylquinolinic acid imide (5) yielded as addition products the dihydropyrrolo[3,4-b]pyridines 6a,b with slight ortho regioselectivity (55:45). In contrast to these low regioselectivities, the PET reaction of potassium propionate with the methyl ester of N-methyltrimellitic acid imide (9) yielded solely the para addition product 10. Likewise, the intramolecular photoreaction of the cysteine derivative 7 gave a 75:25 (para/meta) mixture of regioisomeric cyclization products 8. The regioselectivity originates from donor-acceptor interactions prior to electron transfer and differences in spin densities in the corresponding imide radical anions. The results of DFT and ab initio calculations for the radical anions of the quinolinic acid imide (11(*)(-)) and the methyl ester of trimellitic acid imide (12(*)(-))( )()were in agreement with the latter assumption: spin densities in 11(*)(-) were higher for the imido ortho carbon atoms (indicating preferential ortho coupling); for 12(*)(-) the spin densities were higher for the imido para carbon atoms (indicating preferential para coupling). These correlations became more significant when the additional spin densities at the carbonyl oxygen and the adjacent carbon atoms were taken into account. The cyclization selectivities for 2, 4, and 8 deviate from the intermolecular examples probably because of ground-state and solvent effects.     

7Li,31P Shift correlation. Application to the structural assignment of benzyllithium complexes of N-methyl-N-benzylphosphinamide

A correlation experiment between (7)Li and (31)P nuclei through scalar coupling is described for the first time. The utility of the method is demonstrated by identifying the species formed in the benzylic lithiation of N-benzyl-N-methyldiphenylphosphinamide in Et(2)O solution.     

Mechanism of anionic dearomatizing reactions of diphenylphosphinamide derivatives: a theoretical and experimental study

The mechanism of the anionic dearomatisation of phosphinamide derivatives has been investigated both theoretically and experimentally. The potential-energy surface of model reactions was studied at the Becke3LYP/6-31+G* level of theory, and according to this study, a pre-reactive complex is formed between the alkyllithium and the phosphinamide. This complex evolves preferentially through NC(alpha)-metalation of the phosphinamide. The intramolecular nucleophilic addition of the carbanion to the ortho position of the aromatic ring leads to the dearomatised products, in a reaction that has been shown to be under thermodynamic control. Coordinating co-solvents, such as hexamethyl phosphoramide (HMPA) or N,N'-dimethyl-N,N'-propylene urea (DMPU), appear to influence the reaction by favouring the formation of solvent-separated ion pairs. The cyclisation reaction of allylphosphinamide derivatives was also studied. It was found that both the alpha- and gamma-attack of the allyl anion can take place, however the formation of the seven-membered ring products derived from the gamma-attack are clearly favoured.     

Snytheses of analgesics. Part XXXVII. An alternative synthesis of 1,2,3,4, 5, 6-hexahydro-8-hydroxy-2,6-methano-6, h-dimethyl-3-phenethyl-3-benzazoeine [studies on the syntheses of heterocyclic compounds. Part DXXI]

Acid treatment of the alkylated products of (Va, Vb, and VIII) of piperidinols IVa and IVb, and tetrahydropyridine VII with β-bromoethylbenzene, afforded 1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,1 1-dimethyl-3-phenethyl-3-benzazocine (la) in good yield. Piperidinols Va and Vb were also obtained from the reaction of N-(3-methyl-3-pentenyl)-β-phenethylamine (IIb) with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate.     

Mechanistic study of samarium diiodide-HMPA initiated 5-exo-trig Ketyl-Olefin coupling: the role of HMPA in post-electron transfer steps

The mechanistic importance of HMPA and proton donors (methanol, 2-methyl-2-propanol, and 2,2,2-trifluoroethanol) on SmI2-initiated 5-exo-trig ketyl-olefin cyclizations has been examined using stopped-flow spectrophotometric studies. In the presence of HMPA, the rate order of proton donors was zero and product studies showed that they had no impact on the diastereoselectivity of the reaction. Conversely, reactions were first-order in HMPA, and the additive displayed saturation kinetics at high concentrations. These results were consistent with HMPA being involved in a rate-limiting step before cyclization, where coordination of the intermediate ketyl to the sterically congested Sm(III)HMPA both stabilizes the intermediate and inhibits cyclization. Liberation of the contact ion pair through displacement by an equivalent of HMPA provides a solvent-separated ion pair releasing the steric constraint to ketyl-olefin cyclization. The mechanism derived from rate studies shows that HMPA is important not only in increasing the reduction potential of Sm(II) but also in enhancing the inherent reactivity of the radical anion intermediate formed after electron transfer through conversion of a sterically congested contact ion pair to a solvent-separated ion pair. The mechanistic complexity of the SmI2-HMPA-initiated ketyl-olefin cyclization is driven by the high affinity of HMPA for Sm(III), and these results suggest that simple empirical models describing the role of HMPA in more complex systems are likely to be fraught with a high degree of uncertainty.     

Samarium(II)-promoted radical spirocyclization onto an aromatic ring

Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of methyl 4-(4-oxoalkyl)benzoates with SmI(2) in the presence of i-PrOH and HMPA, yielding methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this chemistry, spiro[3.5] and -[5.5] systems, and sterically congested spiro[4.5] systems, were easily synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven to be extremely important: while an ester or amide functionality on the aromatic ring can promote the spirocyclization, a sulfonamide substituent causes ortho cyclization.