New data on the molecular compounds of stereoisomeric ditertiary glycols of the series 1,4-di-(α-hydroxy-sec-alkyl)-cyclohexanes

Summary 1¹,4¹-Dihydroxy-1¹,4¹-diethyl-1,4-dipropylcyclohexanes, like the previously described 1¹,4¹-dihydroxy-1¹,4¹-dimethyl-1,4-diethylcyclohexanes, give a molecular compound of three molecules of cis- and one molecule of trans-form.     

A Near‐Infrared Dye That Undergoes Multiple Interconversions through Acid–Base Equilibrium and Reversible Redox Processes

A near‐infrared (NIR) polymethine dye ( 1 ), consisting of a cyclohepta[1,2‐b ;4,3‐b′ ]dithiophene and two phenol moieties, was synthesized. This dye exhibited pH‐responsive changes in its photophysical properties due to a two‐step acid–base equilibrium that produced a protonated cation ( 1H⁺ ) and an anion ( 1⁻ ). While 1H⁺ showed an intense fluorescence in the red region of the visible spectrum, 1⁻ exhibited a strong absorption in the NIR region. The tropylium ion character in 1H⁺ induces high pK _a1 and pK _a2 values for 1 . Moreover, a stable radical ( 1^. ) was prepared, which showed a NIR absorption band with a maximum at circa 1600 nm. The cyclic voltammogram of 1^. revealed a two‐step reversible redox process that produced 1⁻ and the cation 1⁺ , which is different from 1H⁺ . These redox processes accompany drastic electrochromic changes in the vis–NIR region. Overall, 1 is susceptible to multiple interconversions between five forms, due to the multifaceted character of the cycloheptadithiophene skeleton.     

A Novel Entry into a New Class of Spiro Heterocyclic Framework: A Facile Synthesis of Dispiro[oxindole-1,2,3,4-tetrahydro-naphthalen-1-one]pyrrolidines and Spiro[1,2,3,4-tetrahydro-naphthalen-1-one]pyrrolidines

Abstract

2-Arylidene-1,2,3,4-tetrahydro-naphthalen-1-ones undergo regioselective 1,3-dipolar cycloaddition reaction with the azomethine ylide derived from isatin and sarcosine by decarboxylative route affording a series of 1-N-methyl-spiro[2.3¹]oxindole-spiro[3.2¹¹]1¹¹, 2¹¹,3¹¹,4¹¹, -tetrahydro-naphthalen-1¹¹-one-4-aryl-pyrrolidines. 2-Arylidene-1,2,3,4-tetrahydro-naphthalen-1-ones also undergo cycloaddition reaction with azomethine ylide derived from paraformaldehyde and sarcosine affording a series of 1-N-methyl-spiro[3.2¹]1¹,2¹,3¹,4¹-tetrahydro-naphthalen-1¹-one-4-aryl-pyrrolidines. The structures of the compounds were established by spectroscopic techniques.     

Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters

A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.

Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.¹ Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).² Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).³ However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,⁴ substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.^5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.⁶ In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)^9,10 as well as the synthesis of chiral tetraarylmethanes,⁸ we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag₂O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)₃ (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO₂ gave only 60% conversion (entry 10).Evaluation of oxidants

A Near-Infrared Dye That Undergoes Multiple Interconversions through Acid–Base Equilibrium and Reversible Redox Processes

A near-infrared (NIR) polymethine dye ( 1 ), consisting of a cyclohepta[1,2-b;4,3-b′]dithiophene and two phenol moieties, was synthesized. This dye exhibited pH-responsive changes in its photophysical properties due to a two-step acid–base equilibrium that produced a protonated cation ( 1H⁺ ) and an anion ( 1⁻ ). While 1H⁺ showed an intense fluorescence in the red region of the visible spectrum, 1⁻ exhibited a strong absorption in the NIR region. The tropylium ion character in 1H⁺ induces high pK_a1 and pK_a2 values for 1 . Moreover, a stable radical ( 1^. ) was prepared, which showed a NIR absorption band with a maximum at circa 1600 nm. The cyclic voltammogram of 1^. revealed a two-step reversible redox process that produced 1⁻ and the cation 1⁺ , which is different from 1H⁺ . These redox processes accompany drastic electrochromic changes in the vis–NIR region. Overall, 1 is susceptible to multiple interconversions between five forms, due to the multifaceted character of the cycloheptadithiophene skeleton.     

ORGANISCHE PHOSPHORVERBINDUNGEN 80 HERSTELLUNG VON TRIAZOLYLMETHYL-PHOSPHONATEN UND VON TRIAZOLYL-METHYLPHOSPHONIUMSALZEN UND DEREN VERWENDUNG IN DER WITTIG-HORNER REAKTION

Abstract

Attempts to prepare 1H-1,2,4-triazol-1-ylmethylphosphonates (4 and 5) by a Mannichtype reaction or by transesterification of 1-hydroxymethyl-1H-1,2,4-triazol 1 with tertiary phosphites failed. On the other hand 4 and 5 are obtained by a Michaelis-Becker reaction from 1-chloromethyl-1H-1,2,4-triazol 3 and sodium phosphites in high yield. The Michaelis-Arbuzov reaction is less suited for the preparation of 4 and 5. 3 is obtained in good yield as a water clear liquid, b.p. 52–54°C/0.2 torr, from the interaction of 1 with thionyl chloride followed by treatment with a base. On standing at 0° or 20°C it decomposes within hours and yields the unsymmetrical methylen-bis(triazol) 3a in addition to other products. However an acetonitrile solution of 3 is stable for months. Heating this solution with tertiary phosphines gives triazolylsubstituted phosphoniumsalts 6 to 8. The Wittig-Horner reaction with 4 to 6 gives the olefinically substituted triazols 9–12 as a Z/E mixture in high yield. Alkylation of 4 with methyl-and ethyl iodide gives the corresponding alkylated diethyl-1H-1,2,4-triazol-1-yl-ethyl-1-and-propyl-1-phosphonates 14 and 15 which on hydrolysis with HCI yield 1H-1,2,4-triazol-1-yl-ethyl-1-and propyl-1-phosphonic acids 17 and 18, respectively. Hydrolysis of 4 gives the unsubstituted 1H-1,2,4-triazol-1-ylmethyl-phosphonic acid, 16.     

Polycyclic heteroaromatics via hydrazine-catalyzed ring-closing carbonyl–olefin metathesis

The use of hydrazine-catalyzed ring-closing carbonyl–olefin metathesis (RCCOM) to synthesize polycyclic heteroaromatic (PHA) compounds is described. In particular, substrates bearing Lewis basic functionalities such as pyridine rings and amines, which strongly inhibit acid catalyzed RCCOM reactions, are shown to be compatible with this reaction. Using 5 mol% catalyst loadings, a variety of PHA structures can be synthesized from biaryl alkenyl aldehydes, which themselves are readily prepared by cross-coupling.

Hydrazine catalysis enables the ring-closing carbonyl–olefin metathesis (RCCOM) to form polycyclic heteroaromatics, especially those with basic functionality.

Polycyclic heteroaromatic (PHA) structures comprise the core framework of many valuable compounds with a diverse range of applications (Fig. 1A).¹ For example, polycyclic azines (e.g. quinolines) are embedded in many alkaloid natural products, including diplamine² and eupolauramine³ to name just a few. These types of structures are also of interest for their biological activity, such as with the inhibitor of the Src-SH3 protein–protein interaction shown in Fig. 1A.⁴ Many nitrogenous PHAs are also useful as ligands for transition metal catalysis, as exemplified by the widely used ligand 1,10-phenanthroline.⁵ Meanwhile, chalcogenoarenes⁶ such as dinaphthofuran⁷ and benzodithiophene⁸ have attracted high interest for both their medicinal properties⁹ and especially for their potential use as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), and organic field-effect transistors (OFETs).¹⁰ These and numerous other examples have inspired the development of a wide variety of strategies to construct PHAs.^1,11–14 Although these approaches are as varied as the structures they target, the wide range of molecular configurations within PHA chemical space and the challenges inherent in exerting control over heteroatom position and global structure make novel syntheses of these structures a topic of continuing interest.Open in a separate windowFig. 1(A) Examples of PHAs. (B) RCCOM strategy for PHA synthesis. (C) Lewis base inhibition for Lewis acid vs. hydrazine catalyzed RCCOM. (D) Hydrazine-catalyzed RCCOM for PHA synthesis.One potentially advantageous strategy for PHA synthesis is the use of ring-closing carbonyl–olefin metathesis¹⁵ (RCCOM) to forge one of the PHA rings, starting from a suitably disposed alkenyl aldehyde precursor 2 that can be easily assembled by cross-coupling (Fig. 1B). In related work, the application of RCCOM to form polycyclic aromatic hydrocarbons (PAHs) was reported by Schindler in 2017.¹⁶ In this case, 5 mol% FeCl₃ catalyzed the metathesis of substrates to form phenanthrenes and related compounds in high yields at room temperature. This method was highly attractive for its efficiency, its use of an earth-abundant metal catalyst, and the production of benign acetone as the only by-product. Nevertheless, one obvious drawback to the use of Lewis acid activation is that the presence of any functionality that is significantly more Lewis basic than the carbonyl group can be expected to strongly inhibit these reactions (Fig. 1C). Such a limitation thus renders this method incompatible with a wide swath of complex molecules, especially PHAs comprised of azine rings. This logic argues for a mechanistically orthogonal RCCOM approach that allows for the synthesis of PHA products with a broader range of ring systems and functional groups.We have developed an alternative approach to catalytic carbonyl–olefin metathesis that makes use of the condensation of 1,2-dialkylhydrazines 5 with aldehydes to form hydrazonium ions 6 as the key catalyst–substrate association step.^17–19 This interaction has a much broader chemoorthogonality profile than Lewis acid–base interactions and should thus be much less prone to substrate inhibition than acid-catalyzed approaches. In this Communication, we demonstrate that hydrazine-catalyzed RCCOM enables the rapid assembly of PHAs bearing basic functionality (Fig. 1D).For our optimization studies, we chose biaryl pyridine aldehyde 7 as the substrate (20 salt 11 was also productive (entry 2), albeit somewhat less so. Notably, iron(iii) chloride generated no conversion at either ambient or elevated temperatures (entries 3 and 4). Trifluoroacetic acid (TFA) was similarly ineffective (entry 5). Meanwhile, a screen of various solvents revealed that, while the transformation could occur in a range of media (entries 6–9), THF was optimal. Finally, by raising the temperature to 90 °C (entry 10) or 100 °C (entry 11), up to 96% NMR yield (85% isolated yield) of adduct 8 could be obtained in the same time period.Optimization studies^a

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI^†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a

Threshold energies for production of CH2(3B1) and CH2(1A1) from ketene photolysis. The CH2(3B1) ↔ CH2(1A1) energy splitting

By measuring the relative CO quantum yields from ketene photolysis as a function of photolysis wavelength we have determined the threshold energy at 25° for CH₂CO(¹A₁) → CH₂(³B₁) + CO(¹Σ⁺) to be 75.7 ± 1.0 kcal/mole. This corresponds to a value of 90.7 ± 1.0 kcal/mole for ΔH_f298⁰[CH₂(³B₁)]. By measuring the relative ratio of CH₂(¹A₁)/CH₂(³B₁) from ketene photolysis as a function of photolysis wavelength we have determined the threshold energy at 25°C for CH₂CO(¹A₁) → CH₂(¹A₁) + CO(¹Σ⁺) to be 84.0 ± 0.6 kcal/mole. This corresponds to a value of 99.0 ± 0.6 kcal/mole for ΔH_f298⁰[CH₂(¹A₁)]. Thus a value for the CH₂(³B₁) ? CH₂(¹A₁) energy splitting of 8.3 ± 1 kcal/mole is determined, which agrees with three other recent independent experimental estimates and the most recent quantum theoretical calculations.     

The potentials of zero charge of Pd(1 1 1) and thin Pd overlayers on Au(1 1 1)

The potential of zero charge (pzc) of Pd(1 1 1) has been determined in dilute NaF solutions by measuring the Gouy–Chapman minimum of the double-layer capacity. For a massive Pd(1 1 1) single crystal electrode a pzc of −0.12 V vs. SCE has been found. The corresponding values for thin Pd(1 1 1) overlayers on Au(1 1 1) have also been determined. While the pzc of the first, pseudomorphic Pd layer on Au(1 1 1) is −0.09 V vs. SCE, the pzc of a five monolayers thick Pd film on Au(1 1 1) is practically identical to the pzc of the massive Pd(1 1 1) electrode. By comparing pzc's and work functions for Au(1 1 1) and Pd(1 1 1), the dipole contribution to the potential drop across the Pd(1 1 1)/water interface is estimated.     

Synthesis and Circular Dichroism of Both Enantiomers of 2-deuterofluoroacetic acid ( Fluoro[2H1]acetic acid)

Sharpless epoxidation of (E)-1-(trimethylsilyl)[1-²H₁]oct-1-en-3-o1 ( 3a ) yielded (1S,2S,3S)- and (1R,2R,3R)-1-(trimethylsilyl)-1,2-epoxy[1-²H₁]octan-3-ols ( 4a and 4b , resp.) which were converted in three steps into (S)- and (R)-fluoro[ ²H₁]acetic acid ( 7a and 7b , resp.) in good yields. Their high isotopic and optical purity was established by ¹H- and ¹⁹F-NMR, mass, and circular-dichroism spectroscopy.     

Conformation and Aromaticity Switching in a Curved Non-Alternant sp2 Carbon Scaffold

A curved sp² carbon scaffold containing fused pentagon and heptagon units ( 1 ) was synthesized by Pd-catalyzed [5+2] annulation from a 3,9-diboraperylene precursor and shows two reversible oxidation processes at low redox potential, accompanied by a butterfly-like motion. Stepwise oxidation produced radical cation 1 ^.+ and dication 1 ²⁺. In the crystal structure, 1 exhibits a chiral cisoid conformation and partial π-overlap between the enantiomers. For the radical cation 1 ^.+, a less curved cisoid conformation is observed with a π-dimer-type arrangement. 1 ²⁺ adopts a more planar structure with transoid conformation and slip-stacked π-overlap with closest neighbors. We also observed an intermolecular mixed-valence complex of 1 ⋅( 1 ^.+)₃ that has a huge trigonal unit cell [( 1 )₇₂(SbF₆)₅₄⋅(hexane)₁₀₁] and hexagonal columnar stacks. In addition to the conformational change, the aromaticity of 1 changes from localized to delocalized, as demonstrated by AICD and NICS(1)_zz calculations.     

Ligand design for Rh(iii)-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones

We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(iii) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cp^t affords product with excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.C–H activation mediated processes have provided a unique retrosynthetic approach to access a variety of substituted heterocycles.¹ One tactic that has received increased attention is the coupling of π-components with heteroatom containing molecules.² A variety of transition metals are capable of catalyzing this type of transformation, providing access to dozens of heterocyclic motifs.^1–3 A challenge for these methods is controlling the regioselectivity of migratory insertion across alkenes and alkynes after the metallacycle forming C–H activation (eqn 1).Steric and electronic effects are understood to control migratory insertion of unsymmetrical alkynes in Rh(iii) catalyzed isoquinolone syntheses (eqn 1). When the substituents are electronically similar, the larger group resides β- to Rh in the metallacycle to avoid unfavorable steric interactions (selectivity is generally >10 : 1).⁴ When the substituents are electronically different, the more electron-donating group prefers being α- to rhodium in the metallacycle, presumably to stabilize the electron poor metal.^5,6 The type of C–H bond being activated also plays an important role in the regioselectivity of migratory insertion; aromatic substrates typically provide synthetically useful regioselectivities when electronically different alkynes are used (>10 : 1) but alkenyl C–H activation leads to products with lower regioselectivities, presumably due to minimal steric interactions during migratory insertion.^7,8 We found that sterically bulky di-tert-butylcyclopentadienyl ligand (Cp^t) enhances the regioselectivity of the alkyne migratory insertion event in these cases, delivering regioselectivities (>10 : 1) modestly above those achievable by Cp* ligated Rh complexes (<6 : 1). However, when the alkyne migratory insertion was poorly selective with RhCp* (<3 : 1), RhCp^t complex was ineffective at providing synthetically useful levels of selectivity. Furthermore, the Cp^t ligand was only effective with aryl substituted alkynes, presumably because of strong steric interactions between the ligand and alkyne in the insertion event. Migratory insertion of alkenes to access heterocycles using C–H activation chemistry is still relatively rare, with seminal studies by Glorius and Fagnou reporting the synthesis of dihydroisoquinolones.^9–11 Similar to alkynes, alkenyl electron-donating groups favor the position adjacent to the metal in the metallacycle delivering high regioselectivity. In contrast to alkynes, aliphatic alkenes afford product with poor regioselectivity (2 : 1) (eqn 2).^5h,12 We hypothesized competing steric and electronic effects cause the low regioselectivity, with steric effects favoring the formation of a 4-substituted product and electronics favoring the formation of a 3-substituted product.¹³ As a temporary solution to this problem, our group and others have employed tethering strategies to increase the regioselectivity of the migratory insertion event (eqn 3).^14,15 Of course, regioselectivity controlled by the ligand on Rh would be the optimal solution to the selectivity problem (eqn 4).¹⁶ Consequently, we focused our attention toward developing an intermolecular variant of this reaction that would provide product with improved regioselectivity.As a model system, we explored the impact ligands have on the coupling of O-pivaloyl-benzhydroxamic acid 1a with 1-decene 2a to provide dihydroisoquinolones 3a and 3a′. When Cp* is used as a ligand, the desired products are isolated in excellent yield but poor selectivity (2.4 : 1 3a : 3a′) ( a

Mono- and oligosaccharide sensing by phenylboronic acid-appended 5,15-bis(diarylethynyl)porphyrin complexes

Porphyrin derivatives bearing a pair of boronic acid groups (1, 1·Zn, and 1·Cu) were designed and synthesized from 2 to construct a saccharide sensing system. Compounds 1, 1·Zn, and 1·Cu have a diethynyl porphyrin rotational axis, which is expected to act as a saccharide-binding modulator. Saccharide binding studies were conducted by UV-vis, fluorescence, and circular dichroism (CD) spectroscopies. In a water-methanol 1:1 (v/v) mixed solvent, we have found that 1·Zn can bind mono- and oligosaccharides including Lewis oligosaccharides to produce 1:1 host-saccharide complexes with the association constants of 10²−10³ M⁻¹ range. This paper thus demonstrates a new principle to design a boronic acid-based saccharide receptor.     

Azimine IV. Kinetik und Mechanismus der thermischen Stereoisomerisierung von 2,3-Diaryl-1-phthalimido-aziminen

Azimines IV. Kinetics and Mechanism of the Thermal Stereoisomerization of 2,3-Diaryl-1-phthalimido-azimines¹) Mixtures of (1E, 2Z)- and (1Z, 2E)-2-phenyl-1-phthalimido-3-p-tolyl-azimine ( 3a and 3b , resp.) and (1E, 2Z)- and (1Z, 2E)-3-phenyl-1-phthalimido-2-p-tolylazimine ( 4a and 4b , resp.) were obtained by the addition of oxidatively generated phthalimido-nitrene (6) to (E)- and (Z)-4-methyl-azobenzene ( 7a and 7b , resp.). Whereas complete separation of the 4 isomers 3a, 3b, 4a and 4b was not possible, partial separation by chromatography and crystallization led to 5 differently composed mixtures of azimine isomers. The spectroscopic properties of these mixtures (UV., ¹H-NMR.) were used to determine the ratios of isomers in the mixtures, and served as a tool for the assignment of constitution and configuration to those isomers which were dominant in each of these mixtures, respectively. Investigation of the isomerization of the azimines 3a, 3b, 4a and 4b within the 5 mixtures at various concentrations by ¹H-NMR.-spectroscopy at room temperature revealed that only stereoisomers are interconverted ( 3a ? 3b; 4a ? 4b) and that the (1E, 2Z) ? (1Z, 2E) stereoisomerization is a unimolecular reaction. These observations exclude an isomerization mechanism via an intermediate 1-phthalimido-triaziridine (2) or via dimerization of 1-phthalimido-azimines (1) , respectively. The 3-p-tolyl substituted stereoisomers 3a and 3b isomerized slightly slower than the 3-phenyl substituted ones 4a and 4b , an effect which is consistent with the assumption that the rate determining step of the interconversion of (1E, 2Z)- and (1Z, 2E)-1-phthalimido-azimines (1a ? 1b) is the stereoisomerization of the stereogenic center at N(2), N(3), either by inversion of N(3) or by rotation around the N(2), N(3) bond. The total isomerization process is assumed to occur via the thermodynamically less stable (1Z, 2Z)- and (1E, 2E)-isomers 1c and 1d , respectively, as intermediates in undetectably low concentrations which stay in rapidly established equilibria with the observed, thermodynamically more stable (1E, 2Z)- and (1Z, 2E)-isomers 1a and 1b , respectively. At higher temperatures, the azimines 3 and 4 are transformed into N-phenyl-N,N′-phthaloyl-N′-p-tolyl-hydrazine (8) with loss of nitrogen.     

Untersuchungen zum elektronischen Einfluß von Organoliganden. XIII. Synthese und Charakterisierung von 2-funktionalisierten Vinylrhodoximen

Studies on the Electronic Influence of Organoligands. XIII. Synthesis and Characterization of 2-Functionalized Vinyl Rhodoximes 2-Functionalized vinyl rhodoximes [Rh(dmgH)₂ (PPh₃)cis/trans-CH = CHZ] ([Rh]? CH = CHZ) ) ( 1 ) can be prepared with a wide variation of the substituent Z (cis: OEt ( 1 a ), OPh ( 1 b ), Cl ( 1 c ), Me ( 1 j ), Ph ( 1 k ), SMe ( 1 l ), SPh ( 1 m ); trans: SPh ( 1 d ), Me ( 1 e ), Ph ( 1 f ), CMe₃ ( 1 g ), SiMe₃ ( 1 h )) by oxidative addition of XCH = CHZ and/or by nucleophilic addition of HC?CZ and Me₃SiC?CZ, respectively, to [Rh]^?. 1 a is converted to [Rh]? CH₂CHO ( 2 ) already in a weakly acid medium. 1 l is isomerized to trans-[Rh]? CH = CHSMe ( 1 n ) in the presence of acids. The complexes 1 are characterized by microanalysis and by ¹H, ¹³C and ³¹P NMR spectroscopy. The magnitude of the coupling constants ¹J(¹⁰³Rh, ³¹P) reveals only a small effect of Z on the (NMR) trans influence of the vinyl ligands CH = CHZ. The molecular structures of cis-[Rh]? CH = CHSPh ( 1 m ) and trans-[Rh]? CH = CHSPh ( 1 d ) show a distorted octahedral coordination of Rh with a mutual trans position of triphenyl-phosphine and the 2-phenylmercaptovinyl ligands. Van der Waals interactions exist between the sulfur and the equatorial dimethylglyoximato ligands in the cis complex 1 m .     

Redox-neutral manganese-catalyzed synthesis of 1-pyrrolines

This report describes a manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functional 1-pyrrolines. In this redox-neutral process, the oxime ethers function as internal oxidants and H-donors. The reaction involves sequential rupture of C–C, C–H and N–O bonds and proceeds under mild conditions. This intermolecular protocol provides an efficient approach for the synthesis of structurally diverse 1-pyrrolines.

Described herein is a novel manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functionalized 1-pyrrolines.

Pyrroline and its derivatives appear frequently as the core of the structure of natural products and biologically active molecules (Fig. 1A).¹ Such compounds also serve as versatile feedstocks in various transformations, such as 1,3-dipolar cyclization, ring opening, reduction and oxidation, leading to diverse and valuable compounds.^2–4 Over the past few decades, great effort has been devoted to the preparation of pyrrolines. This has resulted in several elegant approaches that rely on photoredox catalysis (Fig. 1B).⁵ The groups of Studer,^5a,b Leonori,^5c and Loh^5d–f disclosed intramolecular addition of the intermediate iminyl radical to alkenes to construct pyrrolines. Generally, the synthetic value of a method can be further improved by using an intermolecular reaction pattern. For example, Alemán et al. recently reported a radical-polar cascade reaction involving the addition to ketimines of alkyl radicals formed in hydrogen atom transfer (HAT) reactions.^5g That the existence of benzylic C–H bonds in the substrates is requisite for the HAT, compromises the substrate scope. Despite the appealing photochemical processes, development of new redox approaches to enrich the product diversity of pyrrolines, especially with inexpensive transition-metal catalysts, is still in demand.Open in a separate windowFig. 1(A) Importance of pyrrolines, and (B and C) synthetic approaches to pyrrolines.Prompted by extensive applications of cyclopropanols in synthesis⁶ and our achievements in manganese-catalyzed ring-opening reactions,⁷ we conceived a radical [3 + 2] cyclization using cyclopropanol as a C3 synthon and oxime ethers as a nitrogen source (Fig. 1C). Hypothetically, single-electron oxidation of cyclopropanol by Mnⁿ generates the β-keto radical (I), which undergoes a radical [3 + 2] cascade reaction with an oxime ether to give the alkoxy radical species (II). Conversion of II to the intermediate (III), the pyrroline precursor, requires an extra H-donor to support a HAT process and an oxidant for recovery of Mnⁿ to perpetuate the catalytic cycle. In this scenario, the strategic inclusion of oxime ether is crucial to the overall transformation. The oxime ether is not only an internal oxidant and H-donor, but should also be subject to in situ deprotection by cleaving the N–O bond during the reaction. The choice of a proper Mnⁿ/Mnⁿ⁻¹ pair with suitable redox potentials is also vital to the catalytic cycle.Herein, we provide proof-of-principle studies for this hypothesis. The desired radical [3 + 2] cyclization of cyclopropanols and O-benzyl oxime ethers is accomplished with manganese catalysis. This redox-neutral process involves sequential rupture of C–C, C–H, and N–O bonds under mild conditions. The intermolecular protocol provides an ingenious approach to the synthesis of multi-functionalized 1-pyrrolines.With these considerations in mind, phenylcyclopropanol (1a) and oxime ether (2a) were initially chosen as model substrates to evaluate reaction parameters in the presence of manganese salt ( N bond of 2a (entry 2). The optimization of organic solvents was then conducted (entries 3–8), and it was found that the use of fluorinated alcohols, such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents provided excellent yields (entries 7 and 8). Decreasing the amount of Mn(acac)₃ to 1.2 equiv. gave a comparable yield (entry 9), but further reducing the amount compromised the yield (entry 10). Replacing Mn(acac)₃ with Mn(OAc)₃ or MnCl₂ significantly decreased the reaction yield (entries 11 and 12). However, the use of Mn(acac)₂ gave a similar yield to Mn(acac)₃ (entries 13 vs. 9). The above results prompted us to think over the counteranion effect that the acetylacetone (acac) anion may be requisite to the reaction. Indeed, the synergistic use of stoichiometric MnCl₂ and acetylacetone led to a good yield of the desired product (entry 14). More importantly, a comparable yield was obtained with only 0.2 equiv. of MnCl₂ and added acetylacetone, realizing this reaction under a catalytic amount of Mn salts (entry 15). Given that the low solubility of the Mn salt may lead to poor efficiency, a reaction with 0.067 M concentration was carried out and gave a 89% yield (entry 16). Further reducing the amount of acetylacetone to 1.0 equiv. had no influence on the outcome of the reaction (entry 17), but the reaction efficiency slightly decreased when 0.6 equiv. of acetylacetone was used as the additive (entry 18). Use of a decreased amount (1.0 equiv.) of acetic acid led to the best yield (91%, entry 19), whereas the reaction in the presence of 0.5 equiv. acetic acid (entry 20) or without acetic acid (entry 21) also gave high yields. It is noted that acetic acid is not crucial to the reaction using MnCl₂ as catalyst, as the reaction could generate cat. HCl in situ. The reaction with substoichiometric amount (0.6 equiv.) of acac gave a decreased but also good yield (entry 22). Reducing the catalytic loading of MnCl₂ to 10 mol% slightly compromised the yield (entry 23).Optimization of the synthesis of 1-pyrrolines

Entrya	Mn salt (equiv.)	Additive (equiv.)	Solvent	Yield (%)
1	Mn(acac)3 (1.7)	None	CH3CN	33
2b	Mn(acac)3 (1.7)	None	CH3CN	Trace
3	Mn(acac)3 (1.7)	None	DCM	31
4	Mn(acac)3 (1.7)	None	Acetone	25
5	Mn(acac)3 (1.7)	None	DMSO	Trace
6	Mn(acac)3 (1.7)	None	DMF	Trace
7	Mn(acac)3 (1.7)	None	TFE	80
8	Mn(acac)3 (1.7)	None	HFIP	82
9	Mn(acac)3 (1.2)	None	HFIP	83
10	Mn(acac)3 (0.9)	None	HFIP	55
11	Mn(OAc)3·2H2O (1.2)	None	HFIP	36
12	MnCl2 (1.2)	None	HFIP	Trace
13	Mn(acac)2 (1.2)	None	HFIP	88
14	MnCl2 (1.2)	acac (3.6)	HFIP	80
15	MnCl2 (0.2)	acac (3.6)	HFIP	81
16c	MnCl2 (0.2)	acac (3.6)	HFIP	89
17c	MnCl2 (0.2)	acac (1.0)	HFIP	89
18c	MnCl2 (0.2)	acac (0.6)	HFIP	83
19c,d	MnCl2 (0.2)	acac (1.0)	HFIP	91
20c,e	MnCl2 (0.2)	acac (1.0)	HFIP	83
21c,b	MnCl2 (0.2)	acac (1.0)	HFIP	80
22c,d	MnCl2 (0.2)	acac (0.6)	HFIP	82
23c,d	MnCl2 (0.1)	acac (1.0)	HFIP	81

Open in a separate window^aReaction conditions: 1a (0.45 mmol), 2a (0.3 mmol), AcOH (2.0 equiv.), and Mn salt (as shown) in solvent (2.0 mL), at room temperature (rt) under N₂, for 16 h.^bWithout AcOH.^c0.067 M reaction.^d1.0 equiv. AcOH.^e0.5 equiv. AcOH. acac = acetylacetone.With the optimized conditions in hand for the synthesis of 1-pyrrolines, the compatibility of various cyclopropanols was inspected (Scheme 1). Common functional groups on the phenyl ring, including halides (3b–3d), ester (3f), ether (3j), were compatible under the reaction conditions. Regardless of the presence of electron-withdrawing or -donating substituents at the para-position of this phenyl ring, the reactions readily proceeded with generally high yields (3b–3j). The cyclopropanol (1k) with an ortho-methyl substituent underwent a cyclization reaction with excellent yield, demonstrating that steric effects had little effect on product of the reaction (3k). By replacing the phenyl group with a naphthyl or thienyl group, the corresponding products (3l and 3m) were produced with slightly lower yields. When 2-substituted cyclopropanols were utilized, these reactions gave rise to a portfolio of trisubstituted 1-pyrrolines (3n–3u).The relative configuration of 3u was determined by comparison with a reported structure.⁸ Remarkably, this protocol provided a convenient method for the construction of an N-containing spiro skeleton (3t). The reaction with alkyl cyclopropanols could also furnish the desired products (3v–3x) smoothly and with good yields.Open in a separate windowScheme 1Scope of cyclopropanols. Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), AcOH (0.2 mmol), MnCl₂ (0.04 mmol), and acac (0.2 mmol) in HFIP (3.0 mL), at rt under N₂. The d.r. values were determined by ¹H NMR analysis with crude reaction mixture, and major isomers are shown with relative configurations. ^aThe reaction is scaled up for 10 times.Next, we studied the scope of oxime ethers (Scheme 2). Steric hindrance from the ester moiety in the oxime ethers appeared not to influence the reaction outcome. Oxime ethers bearing various esters, such as phenyl (3y), biphenyl (3z and 3ab), 2-naphthyl (3aa), 2,4-di-tert-butylphenyl (3ac and 3ad), and 2,6-dimethylphenyl (3ae) esters all reacted smoothly. In addition, the substrate with tert-butyl ester also readily underwent cyclization to afford the desired product 3af with excellent yield. Remarkably, the trifluoromethyl-substituted pyrroline (3ag) was afforded almost quantitatively from the corresponding ketoxime ether. However, if the trifluoromethyl group was replaced by a methyl or phenyl group, the reaction failed to give rise to the desired product (3ah or 3ai), and this might be attributed to poorer electrophilic nature of the methyl or phenyl substituted substrate.Open in a separate windowScheme 2Scope of oxime ethers. Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), AcOH (0.2 mmol), MnCl₂ (0.04 mmol), and acac (0.2 mmol) in HFIP (3.0 mL), at rt under N₂. The d.r. values were determined by ¹H NMR analysis with crude reaction mixture, and major isomers are shown with relative configurations.To illustrate the utility of this protocol, we carried out a set of synthetic applications using 1-pyrroline (3a) (Scheme 3). Upon treatment with acetyl chloride and pyridine at 42 °C, 1-pyrroline (3a) could be readily converted into the acyclic amino acid derivative (4). The reaction between 3a and LiAlH₄ gave rise smoothly to the corresponding alcohol (5). In the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquin-4-one (DDQ) and triethylamine, the 2,5-disubstituted pyrrole (6) was obtained. Moreover, treatment of 3a with MeOTf and NaBH₄ delivered the N-methyl proline derivative (7).⁹Open in a separate windowScheme 3Synthetic applications. Reaction conditions: (a) AcCl, pyridine, dry DCE, 42 °C, 63% yield; (b) LiAlH₄, THF, reflux, 90% yield; (c) DDQ, Et₃N, DCM, rt, 53% yield; (d) MeOTf, DCM, and then NaBH₄, THF, 40% yield, cis : trans = 6.6 : 1.To probe the mechanistic pathways, we performed a radical trapping experiment in the presence of 2.0 equiv. of radical scavenger TEMPO. The radical trapping product (8) was detected by high-resolution mass spectrometry (HRMS) (Scheme 4A, top). In addition, the reaction was obviously suppressed when 1,1-diphenylethylene was added under standard condition (Scheme 4A, bottom). These results suggested that this process engaged in a radical pathway. Kinetic studies illustrated that the reaction immediately started with 20 mol% Mn(acac)₂ but an approximate 15 min of induction period was appeared by using Mn(acac)₃, which probably indicated that the reaction was initiated with Mn(ii) rather than Mn(iii), and the Mn(ii)/Mn(i) cycle might be involved in the transformation (Scheme 4B, for details see ESI^†).Open in a separate windowScheme 4(A and B) Mechanistic studies, and (C) proposed mechanism.On the basis of these results, a plausible mechanism for this radical process was proposed in Scheme 4C. Initially, the interaction between cyclopropanol (1a) and Mn(ii) salt gives rise to the alkoxy manganese species (I), which undergoes a ligand-to-metal charge transfer (LMCT) process, leading to the alkoxy radical (II).^5f Subsequent ring-opening of the alkoxyl radical (II) provides the alkyl radical (III). The addition of intermediate (III) to the oxime ether, possibly activated by HFIP or HOAc, furnishes the N-centered radical (IV), which intramolecularly attacks the ketone to afford a new alkoxy radical (V).¹⁰ The subsequent 1,5-hydrogen atom transfer (HAT) process delivers the alkyl radical (VI) at the α-position adjacent to the O atom, thus driving N–O bond cleavage to generate the N-centered radical (VII),^5b,11 and benzaldehyde which was detected by TLC. This radical intermediate (VII) undergoes a single electron transfer (SET) mediated by the reduced-state Mn(i) species, and protonation to yield the cyclic pyrrolidine (VIII). Finally, dehydration of this intermediate produces 1-pyrroline (3a).     

Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution

β-Difluoroalkylborons, featuring functionally important CF₂ moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.

Organofluorine compounds have been widely applied in medicinal chemistry and materials science.^1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.^2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,^3a,b photoredox difluorination,⁴ radical difluorination,⁵ and cross-coupling reactions with suitable CF₂ carriers^6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.^7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).^7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.^7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.^7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.⁷ⁱOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates^8a–c as starting materials.^9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.^9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).¹⁰ While extending the scope of our previous work,^9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.^11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,¹⁰ could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.^12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et₃N·HF in association with PhI(OAc)₂ (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions

On the Heterogeneous Nature of Cisplatin-1-Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH3 Ligands as Likely Explanation

The conversion of the 1 : 1-complex of Cisplatin with 1-methyluracil (1MeUH), cis-[Pt(NH₃)₂(1MeU-N3)Cl] ( 1 a ) to the aqua species cis-[Pt(NH₃)₂(1MeU-N3)(OH₂)]⁺ ( 1 b ), achieved by reaction of 1 a with AgNO₃ in water, affords a mixture of compounds, the composition of which strongly depends on sample history. The complexity stems from variations in condensation patterns and partial loss of NH₃ ligands. In dilute aqueous solution, 1 a , and dinuclear compounds cis-[(NH₃)₂(1MeU-N3)Pt(μ-OH)Pt(1MeU-N3)(NH₃)₂]⁺( 3 ) as well as head-tail cis-[Pt₂(NH₃)₄(μ-1MeU-N3,O4)₂]²⁺ ( 4 ) represent the major components. In addition, there are numerous other species present in minor quantities, which differ in metal nuclearity, stoichiometry, stereoisomerism, and Pt oxidation state, as revealed by a combination of ¹H NMR and ESI-MS spectroscopy. Their composition appears not to be the consequence of a unique and repeating coordination pattern of the 1MeU ligand in oligomers but rather the coexistence of distinctly different condensation patterns, which include μ-OH, μ-1MeU, and μ-NH₂ bridging and combinations thereof. Consequently, the products obtained should, in total, be defined as a heterogeneous mixture rather than a mixture of oligomers of different sizes. In addition, a N₂ complex, [Pt(NH₃)(1MeU)(N₂)]⁺ appears to be formed in gas phase during the ESI-MS experiment. In the presence of Na⁺ ions, multimers n of 1 a with n=2, 3, 4 are formed that represent analogues of non-metalated uracil quartets found in tetrastranded RNA.