Palladium nanoparticles immobilized on polyethylenimine-derivatized gold surfaces for catalysis of Suzuki reactions: development and application in a lab-on-a-chip context

Gold surface-bound hyperbranched polyethyleneimine (PEI) films decorated with palladium nanoparticles have been used as efficient catalysts for a series of Suzuki reactions. This thin film-format demonstrated good catalytic efficiency (TON up to 3.4 × 10³) and stability. Incorporation into a quartz crystal microbalance (QCM) instrument illustrated the potential for using this approach in lab-on-a-chip-based synthesis applications.

Gold surface-bound hyperbranched polyethyleneimine (PEI) films decorated with palladium nanoparticles have been used as efficient catalysts for a series of Suzuki reactions in a lab-on-a-chip format.

Metal and metal-oxide nanostructures and nanoparticles are often key features in materials used in separation technology, biomedical devices, and catalysis.^1,2 Poor mechanical strength and a tendency to aggregate, thus reducing the surface to volume ratio, both limit their use in real-time applications.^3,4 To overcome these shortcomings, nanoparticles are often dispersed in a matrix, such as sol–gel, biopolymers, and carbon-based materials without disturbing their innate properties at nano-scale level.^5,6 Functionalized polymers have been explored extensively in this regard due to their robustness, low cost, ease of handling, and their amenability for chemical modification.^7–9Recently, we have demonstrated the immobilization of hyperbranched polyethyleneimine (PEI) hydrogels on metallic surfaces for use as antifouling surfaces.¹⁰ Owing to their hydrogelation properties, polymers of this type have proven useful in therapeutic applications, for e.g. bio-mineralization, and the formation of nanostructures.^11,12 PEI is a hyperbranched polymer containing very high densities of primary, secondary and tertiary amines, in a 1 : 2 : 1 ratio, and are capable of coordination with transition metals to form nanostructures.^13,14 Recent reports on amine functionalized polymer-supported heterogeneous catalysts for C–C coupling reactions (Table 1-SI^†) prompted us to deploy PEI as a matrix for synthesizing surface-bound palladium nanoparticles for use as catalysts of C–C coupling reactions. For catalytic applications, a miniaturized microfluidic setup, such as a lab-on-a-chip device, can significantly reduce the consumption of chemicals, catalysts, process time and be beneficial for on-site analysis.^15,16In this study, we demonstrate the use of the PEI surface-supported nanoparticles for as a support for catalysis of the Suzuki reaction the possibility for using of these Pd-nanoparticle immobilized PEI-derivatized gold surfaces for performing Suzuki reactions in a microfluidics device. Catalytic surface fabrication (Scheme 1) was performed using gold sputtered quartz surfaces (Au/quartz) that were functionalized with 11-mercaptoundecanoic acid (MuDA), and then activated and derivatization with PEI. The polymer attachment was carried out at high ionic strength (150 mM NaCl), which has been found to enhance the thickness and growth of PEI brush-like structures.¹⁰ Optimization of the Pd nanoparticle synthesis procedure was performed by varying incubation times and Pd(OAc)₂ concentrations (Table 1-SI^†). A quartz crystal microbalance (QCM) was used to monitor the amount of Pd deposited on the PEI coated Au/quartz resonators.Open in a separate windowScheme 1Palladium immobilization on polyethyleneimine coated Au/quartz surfaces.The energy dispersive X-ray (EDX) spectrum confirmed the presence of Pd in the PEI film with a distinct band at 2.8 keV (Fig. 1A). XPS spectra of the Pd-bound PEI surfaces revealed the presence of the anticipated proleptic elements (C_1s, N_1s, O_1s, Pd_3d and Au_4f) (Fig. 1A-SI^†). Deconvoluted peaks differentiated the amine N of PEI (399.8 eV) from that of the amide N (–*N–C O–, 400.8 eV) (Fig. 1B-SI^†).^17,18 Bands around 335 and 340 eV in the survey spectra correspond to the 3d_5/2 and 3d_3/2 states of the surface bound Pd.¹⁹ The deconvoluted bands at 335.3 and 338.2 demonstrated the presence of Pd(0) and Pd(ii), respectively (Fig. 1B). Importantly, peak integration showed the immobilized Pd to be predominantly in the Pd(0) state, with less than 5% present as Pd(ii).¹⁹Open in a separate windowFig. 1(A) Energy dispersive X-ray (EDX) analysis and (B) X-ray photoelectron spectra (XPS) of the palladium nanoparticle immobilized PEI coated Au/quartz surface.RAIR spectra confirmed the presence of the PEI on the gold surface based on the discernible vibrational bands of the –N–H–, –CH– and –CN– bending modes of the adsorbed PEI film (Fig. 2). Subtle differences can be observed in the RAIR spectra of the PEI before and after Pd immobilization. The band corresponding to –N–H– bending mode has been significantly red shifted emphasizing the interaction of the Pd particles with the amine moieties of the PEI film (Fig. 2, inset). This, together with the XPS data, provides evidence for the reduction of Pd(ii) to Pd(0) and its incorporation as nanoparticles into the PEI brush layer.Open in a separate windowFig. 2RAIR spectra of PEI coated Au/quartz surface before and after Pd immobilization.SEM images (Fig. 3) showed uniform long-range coating of the palladium nanoparticles on the PEI immobilized surface (PEI/Pd). The crystallinity of the Pd coated PEI surface was evaluated with powder diffraction measurements which showed characteristic peaks for Pd(111), Pd(200) and Pd(220) with Miller indices of 40, 47.2 and 68.3° (JCPDS No. 98-004-7386), respectively, again confirming the presence of Pd nanoparticles in the (0) oxidation state (curve a, Fig. 2-SI^†).Open in a separate windowFig. 3Scanning electron micrographs of (A) gold surface, (B) polyethyleneimine (PEI) film and (C) PEI-supported palladium particles fabricated on Au/quartz surfaces.The possibility of using these surfaces for catalysis of the Suzuki reaction was explored using a series of phenylboronic acids and substituted aryl halides (†). The amount of catalytic nanopalladium loaded was determined by QCM. Au/quartz surfaces coated with PEI/Pd were immersed in the reaction mixtures at 55 °C for 12 h (Section 1.7-SI^†). Reactions of aryl halides with a series of arylboronic acids offered the corresponding products in good to excellent yield (†). This negligible effect on Pd catalyst poisoning confirms the nature of the catalytic Pd exists predominantly in the (0) oxidation state.²⁰ No biphenyl product has been observed when the Suzuki reaction was performed in presence of unmodified Au/quartz surface (without PEI and Pd).Suzuki cross-coupling reactions of aryl halides with arylboronic acids using PEI/Pd as catalysts^a

Palladium catalyst immobilized on functionalized microporous organic polymers for C–C coupling reactions

Two microporous organic polymer immobilized palladium (MOP-Pd) catalysts were prepared from benzene and 1,10-phenanthroline by Scholl coupling reaction and Friedel–Crafts reaction, respectively. The structure and composition of the catalyst were characterized by FT-IR, TGA, N₂ sorption, SEM, TEM, ICP-AES and XPS. MOP-Pd catalysts were found to possess high specific surface areas, large pore volume and low skeletal bone density. Moreover, the immobilized catalyst also had advantages, such as readily available raw materials, chemical and thermal stability, and low synthetic cost. The Pd catalyst is an effective heterogeneous catalyst for carbon–carbon (C–C) coupling reactions, such as the Heck reaction and Suzuki–Miyaura reaction, affording good to high yields. In these reactions, the catalyst was easily recovered and reused five times without significant activity loss.

Two microporous organic polymers were prepared from 1,10-phenanthroline by Scholl coupling reaction and Friedel–Crafts reaction, and applied to Heck reaction and Suzuki–Miyaura reaction as heterogeneous catalysts.

Carbon–carbon (C–C) coupling reactions have become one of the most versatile and utilized reactions for the selective construction of C–C bonds for the formation of functionalised aromatics,¹ natural products,² pharmaceuticals,³ polymers⁴ and advanced materials.⁵ Many transition metals have been used as catalysts in these reactions, aided by a great variety of ligands ranging from simple, commercial phosphines to complex custom-made molecules.⁶ Among these transition metals, palladium plays a significant role in various cross-coupling reactions, such as Suzuki,⁷ Heck,⁸ Sonogashira,⁹ Stille,¹⁰ and Ullmann coupling reactions,¹¹ due to their strong electrical and chemical properties.¹² Over the past decades, various homogeneous catalytic systems have been developed for organic transformations,¹³ which often progress smoothly under the inert atmosphere in organic solvents, for example, toluene or tetrahydrofuran in the presence of soluble palladium complexes as catalysts. However, most homogeneous palladium catalysts suffer from drawbacks such as high-cost of phosphine ligands, use of various additives, difficult separation, metal leaching, recovery, recyclability, and the toxicity of phosphine ligands.Heterogeneous catalysis have attracted increasing attention as they have been proven to be useful for different organic reactions owning to their unique properties, such as high reactivity, stability, easy separation, purification and recyclability.¹⁴ Many active heterogeneous palladium catalysts have been developed and widely applied in the C–C coupling reactions.¹⁵ Palladium has been immobilized on various solid supporting materials, such as zeolite,¹⁶ silica,¹⁷ metal organic frameworks,¹⁸ and functionalized graphene oxide.¹⁹ However, a substantial decrease in activity and selectivity of the heterogeneous palladium catalysts is frequently observed because of their long diffusion pathway to catalytic sites and the difference of electron density on active sites. To address these problems, materials with larger interface and more active site are employed to support palladium as heterogeneous catalysts, such as palladium immobilized on hyper-crosslinked polymers were high activity in Suzuki–Miyaura coupling reaction.²⁰Microporous organic polymers (MOPs) consists of purely organic elements have recently emerged as versatile platforms for heterogeneous catalysts thanks to their unique properties, including superior chemical, thermal and hydrothermal stability, synthetic diversity, low skeletal density and high surface area.^20,21 More importantly, the bottom–up approach of MOPs provides an opportunity for the design of polymer frameworks with a range of functionalities into the porous structure to use as catalysts or ligands.²² Recently, Kaskel reported the incorporation of a thermally fragile imidazolium moiety into MOPs resulted in a heterogeneous organocatalyst active in carbene-catalyzed Umpolung reaction.²³ Wang designed photocatalysts with microporous via the copolymerization from pyrene and dibenzothiophene-S,S-dioxide building blocks and tested the effect of the photocatalytic hydrogen evolution.²⁴ Xu described the synthesis of microporous with N-heterocyclic carbenes by an external cross-linking reaction and applied it in Suzuki reaction.²⁵ Zhou demonstrated for the first time that the microporous structure has a positive effect on controlling selectivities in the hydrosilylation of alkynes.²⁶ Recently, we also reported three pyridine-functionalized N-heterocyclic carbene–palladium complexes and its application in Suzuki–Miyaura coupling reactions.²⁷1,10-phenanthroline is an ideal candidate of ligands due to its structural features such as two N-atom placed in juxta position to provide binding sites for metal cations.²⁸ To utilize the unique structure feature, we employed it in the construction of MOPs via Scholl and Friedel–Crafts reaction, respectively. Therefore, this paper presents our recent studies on the synthesis of two heterogeneous palladium catalysts supported on MOPs through a simple and low-cost procedure. These catalysts displayed remarkable catalytic activity in C–C coupling reactions, including Suzuki–Miyaura reaction and Heck coupling reaction. The properties of simple preparation, wide application of this catalyst and good performance in C–C coupling reactions and adaptability with various substrates make it perfect catalytic option for C–C coupling reactions.The microporous network with 1,10-phenanthroline functional groups and incorporation of Pd metal were confirmed by Fourier transform infrared (FT-IR) spectroscopy. The FT-IR spectra of MOPs and MOPs-Pd (Fig. 1) displayed a series of bands around 2800–3100 cm⁻¹, which were assigned to the C–H stretching band and in-of-plane bending vibrations of the aryl rings. The bands around 1550–1750 cm⁻¹ were attributed to the –C N- stretching band. The bands around 1400–1450 and 850–700 cm⁻¹ were corresponded to the benzene and 1,10-phenanthroline skeletal stretching and the C–H out-of-plane bending vibrations of the aryl rings, respectively. The bond around 1495 cm⁻¹ in MOPs-I and MOPs-Pd-I is assigned to in-of-plane bending vibrations of CH₂, which indicated that 1,10-phenanthroline and benzene were linked by CH₂.Open in a separate windowFig. 1FT-IR spectra of MOPs and MOPs-Pd.The X-ray photoelectron spectroscopy (XPS) analysis of the MOPs-Pd is performed to investigate the coordination states of palladium species (Fig. 2). In Fig. 2, the Pd 3d XPS spectra of the MOPs-Pd-I catalysts reveal that Pd is present in the +2 oxidation state rather than in the metallic state. This is corresponding to the binding energy (B.E.) of 337.4 eV and 342.4 eV, which are assigned to be Pd 3d_5/2 and 3d_3/2 of Pd (+2), respectively. Compared with the PdCl₂ (337.9 eV and 343.1 eV), the Pd²⁺ binding energy in the MOPs-Pd-I catalyst shifts negatively by 0.5 eV and 0.7 eV. This can be attributed to the effect of the coordination with 1,10-phenanthroline in microporous networks. The results show that Pd²⁺ can be immobilized successfully on the MOPs by coordinating to 1,10-phenanthroline rather than by physical adsorption of Pd²⁺ on the surface. XPS graphs of MOPs-Pd-II also reveal that Pd²⁺ is immobilized on MOPs materials.Open in a separate windowFig. 2XPS spectra of the MOPs-Pd.The surface area and pore structure of the MOPs and MOPs-Pd were investigated by nitrogen adsorption analyses at 77.3 K. In Fig. 3, the MOPs-Pd exhibits type I adsorption–desorption isotherms, which is similar to the isotherms exhibited by the parent MOPs polymers. The result implies that these microporous organic polymers and metalized polymers consist of both micropores and mesopores. The apparent Brunauer–Emmett–Teller surface areas (S_BET) of MOPs-Pd are smaller than those of the non-metallized parent networks (Open in a separate windowFig. 3N₂ adsorption–desorption isotherms and corresponding pore size distributions of MOPs and MOPs-Pd.Physical properties of MOPs and MOPs-Pd

Enantioselective bromination of axially chiral cyanoarenes in the presence of bifunctional organocatalysts

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported. Sequential addition of a brominating reagent in several portions at an optimized temperature was effective in accomplishing high enantioselectivities.

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported.

Axially chiral biaryls are privileged structures in pharmaceuticals,¹ asymmetric catalysts,² functional materials,³etc. Thus, the development of efficient methods for their synthesis is desirable to advance research in these scientific fields. Among recent accomplishments on catalytic atroposelective transformations⁴ toward the synthesis of densely substituted axially chiral biaryls, powerful strategies include organocatalytic dynamic kinetic resolution involving ortho-functionalization of existing biaryls via the introduction of additional rotational barriers.⁵ In this method, substrates should in principle have rotational barriers low enough to enable fast rotation about the biaryl axis, leading to their rapid racemization. Therefore, it is difficult to employ biaryl substrates bearing intrinsic rotational barriers, which impede their racemization. In 2015, the Miller group reported an elegant example of this type of dynamic kinetic resolution via bromination of 3-arylquinazolin-4(3H)-ones, the rotational barrier of which is ∼19 kcal mol⁻¹, by slow addition of a brominating agent.^5e Here, we present enantioselective bromination of axially chiral cyanoarenes bearing intrinsic rotational barriers exceeding 18 kcal mol⁻¹ (Scheme 1). To the best of our knowledge, there has been no report of a catalytic asymmetric reaction affording axially chiral cyanoarenes,⁶ despite their prevalence in bioactive agents⁷ and the rich chemistry of cyano compounds as synthetic intermediates.⁸Open in a separate windowScheme 1Enantioselective bromination of axially chiral cyanoarenes using bifunctional organocatalysts. 9 Other catalysts 3d and 3e, bearing a cyclohexanediamine framework, and 3f, bearing a binaphthyl framework, resulted in poor enantioselectivities (10 Using 3a and 3c, lower reaction temperatures were investigated (Fig. 1) were also investigated; NBA (4a) still afforded the best enantioselectivities ( EntryCatalystBrominating reagentSolventTemp. (°C)Yield^b (%)ee (%)13aNBA (4a)CH₂Cl₂25812623bNBA (4a)CH₂Cl₂2587633cNBA (4a)CH₂Cl₂25891843dNBA (4a)CH₂Cl₂2583653eNBA (4a)CH₂Cl₂2585363fNBA (4a)CH₂Cl₂2579373aNBA (4a)CH₂Cl₂−40822083aNBA (4a)CH₂Cl₂−60<1—93cNBA (4a)CH₂Cl₂−408341103cNBA (4a)CH₂Cl₂−60<1—113cNBA (4a)CHCl₃−402154123cNBA (4a)Toluene−4018−10133cNBA (4a)THF−4013−2143cNBA (4a)Et₂O−4046−20153cNBA (4a)EtOAc−4068−4163cNBA (4a)EtOH−40<5—173cDBH (4b)CH₂Cl₂−40791183cNBS (4c)CH₂Cl₂−408220193cNBP (4d)CH₂Cl₂−4079−520^c,d3cNBA (4a)CH₂Cl₂−40854921^c,e3cNBA (4a)CH₂Cl₂−40515922^c,f3cNBA (4a)CH₂Cl₂−40336623^c,g3cNBA (4a)CH₂Cl₂−401771 Open in a separate window^aReactions were run using 1a (0.10 mmol), the brominating reagent (0.30 mmol), and the catalyst (0.010 mmol) in the solvent (10 mL).^bIsolated yields.^cReactions were run using 3c (0.0050 mmol).^dReaction was run for 48 h.^eReaction was run for 24 h.^fReaction was run for 12 h.^gReaction was run for 6 h.Open in a separate windowFig. 1Brominating reagents.Subsequently, to improve the efficiency of dynamic kinetic resolution by retarding the enantiodetermining bromination,^5e4a was added sequentially in five portions (Fig. 2).¹¹ Although the procedure hardly affected the results at −40 °C, the enantioselectivity was greatly improved for reactions carried out at −20 °C and −30 °C. Such effects were smaller at temperatures above −10 °C.Open in a separate windowFig. 2Investigations of temperatures and procedures. Blue bar: reactions were run with 4a added in 1 portion. Red bar: reactions were run with 4a added in 5 portions. Green values represent yields of 2a isolated after silica gel column chromatography. At 0, −10, −20, and −30 °C, reactions were run for 24 h; at −40 °C, reactions were run for 72 h.Next, at −30 °C and −40 °C, respectively, the relationships between enantioselectivity and yield were investigated (Fig. 3). Reactions were carried out using various amounts of 4a. At both temperatures, the enantioselectivity decreased as the yield increased; however, the quantitative reactions also exhibited some enantioselectivity (−30 °C: 99% yield, 50% ee; −40 °C: 99% yield, 47% ee), implying the presence of the characteristics of dynamic kinetic resolution. In addition, although the enantioselectivity was better at −40 °C than −30 °C when the yield was low, the relationship became reversed as the yield increased; hence, the efficiency of dynamic kinetic resolution was revealed to be better at −30 °C than at −40 °C. Furthermore, when 1.5 equiv. of 4a were used at −30 °C affording 2a in 22% yield with 65% ee, the ortho-monobrominated product 1a-Br (Fig. 4) was also obtained with 75% ee (see Scheme S1 in the ESI^† for details). It shows that the bromination at one of the ortho-positions introduces a rotational barrier high enough to set the chiral axis, which is consistent with the rotational barriers calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory (Fig. 4).Open in a separate windowFig. 3Relationships between ee and yield. Red line: reactions were run at −30 °C for 24 h with 4a added in 5 portions. Blue line: reactions were run at −40 °C for 72 h with 4a added in 5 portions. Red and blue values represent amounts of 4a used for each reaction.Open in a separate windowFig. 4Rotational barriers of substrate, intermediate, and product calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory.Under the conditions of using 3c as the catalyst at −30 °C with 3 equiv. of 4a added sequentially in five portions, other substrates bearing substituted phenols were also investigated (Scheme 2).¹² First, substrates 1b–1e bearing a substituent at the meta-position were investigated. While the electron-deficient substrate 1b resulted in poor enantioselectivity, 1c and 1d bearing aliphatic substituents gave improved enantioselectivities; however, substrate 1e with a methoxy group resulted in low enantioselectivity. In addition, substrates 1f–1i bearing substituents at the para-positions of the biaryl axis were then examined; phenol 2h bearing a methyl group resulted in higher enantioselectivities than phenols 2f and 2g bearing electron-withdrawing groups and 2i bearing a methoxy group. These results suggest that aliphatic substituents might efficiently facilitate the racemization of 1 during bromination, leading to dynamic kinetic resolution with greater enantioselectivity. Utilizing this methodology with the characteristics of dynamic kinetic resolution, the reactions of 1c and 1g were also carried out using a sub-stoichiometric amount of 4a (Scheme 3); higher enantioselectivities were accomplished albeit with lower yields.¹³ The absolute configuration of 2c was determined by X-ray crystallography (see the ESI^† for details), and the configurations of all other products were assigned analogously.Open in a separate windowScheme 2Reactions of substrates with substituted phenols. ^aReaction was run for 72 h.Open in a separate windowScheme 3Reactions with a substoichiometric amount of 4a.In summary, we present enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts. The sequential addition of 4a in several portions at the optimized temperature was effective in improving the enantioselectivity. Although the enantioselectivities are still moderate using the current catalytic system, the guidelines for designing catalytic asymmetric syntheses of axially chiral cyanoarenes were established. Further studies on the additional optimization and application of this methodology to the construction of densely substituted axially chiral biaryls are currently underway.     

Enantioselective conjugate hydrosilylation of α,β-unsaturated ketones

Enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones was realized. In the presence of a chiral picolinamide–sulfonate Lewis base catalyst, the reactions provided various chiral ketones bearing a chiral center at the β-position in up to quantitative yields with moderate enantioselectivities.

Enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones was realized.

Chiral ketones are important intermediates for the synthesis of natural products or chiral drugs, and some themselves are useful chiral drugs.¹ Asymmetric conjugate reduction of α,β-unsaturated carbonyl compounds is an attractive and challenging transformation for the construction of chiral ketones. During the past few decades, many groups have devoted considerable efforts to this area and made great improvement, for instance, transition metal catalyzed asymmetric hydrogenation of α,β-unsaturated carbonyl compounds, including palladium,² iridium,³ copper,⁴ ruthenium,⁵ rhodium⁶ and cobalt.⁷ Besides, some organocatalyzed asymmetric conjugate transfer hydrogenations using Hantzsch ester⁸ or pinacolborane⁹ as the hydride source have also been reported. However, very few examples about chiral Lewis base catalyzed conjugate hydrosilylation of α,β-unsaturated carbonyl compounds have been reported and only chiral phosphine oxide Lewis base catalysts were used in these reactions (Scheme 1).¹⁰ Therefore, exploration of the application of other kinds of chiral Lewis base catalysts in this reaction is still highly desirable.Open in a separate windowScheme 1Enantioselective conjugate hydrosilylation of α,β-unsaturated ketones by chiral Lewis base catalysts.Recently, we developed a kind of easily accessible chiral picolinamide–sulfonate Lewis base catalysts and used them in asymmetric hydrosilylation of α-acyloxy-β-enamino esters,¹¹ one of them exhibiting excellent reactivity, diastereoselectivity and enantioselectivity. Herein we present the enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones using this kind of Lewis base as catalysts, leading to various chiral ketones bearing a chiral center at β-position (Fig. 1).Open in a separate windowFig. 1Three typical chiral drugs containing chiral ketone moiety.First, various chiral Lewis base catalysts 2 were screened in the enantioselective hydrosilylation of (E)-1,3-diphenylbut-2-en-1-one 1a in acetonitrile at 0 °C. As shown in Fig. 2, l-piperazine-2-carboxylic acid derived N-formamide 2a,^12aR-(+)-tert-butylsulfinamide derived catalyst 2b^12b and picolinamide 2c^12c were found to be totally inactive for the reaction. Meanwhile picolinamide–tosylate catalyst 2d was highly active to afford the product with excellent yield in moderate ee value. Afterwards, several picolinamide–tosylate catalysts 2f–2h bearing electron-withdrawing group in 4-position of pyridine were employed in the reaction and 4-bromo picolinamide 2f delivered a slightly higher ee value. 5-Methoxy picolinamide 2i gave the product with the same ee value as that of 2d but in much lower yield. Lower enantioselectivities were observed with 4-phenyl picolinamide 2j and 3-methyl picolinamide 2k. When (R)-1-(2-aminonaphthalen-1-yl)naphthalen-2-ol derived catalyst 2l was used, no product was observed. When (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol derived catalyst 2m gave the product in both poor yield and ee value. Moreover, two picolinamide–sulfonamide catalysts 2n and 2o were also used in the reaction and almost racemic products were obtained. Hence, 2f was determined as the optimal catalyst and was used through out our study.Open in a separate windowFig. 2Evaluation of the chiral Lewis base catalysts 2 in conjugate hydrosilylation of (E)-1,3-diphenylbut-2-en-1-one 1a. Unless otherwise specified, the reactions were carried out with 1a (0.1 mmol), trichlorosilane (0.2 mmol) and catalyst 2 (0.02 mmol) in 1 mL of acetonitrile at 0 °C for 24 hours. Isolated yield based on 1a. The ee values were determined by using chiral HPLC.Subsequently, the other reaction conditions were optimized. The results are summarized in Entry^aSolvent T (°C)Time [h]Yield^b [%]ee^c,d [%]1CH₃CN0247751 (R)2CH₃CH₂CN0248450 (R)3C₆H₅CN0248324 (R)4THF0249211 (R)51,4-Dioxane024635 (R)6CHCl₃0249225 (S)7CH₂Cl₂0249638ClCH₂CH₂Cl0249010 (R)9CCl₄0249535 (S)10Toluene0249555 (S)11Xylene024N.R.—12Mesitylene024N.R.—13C₆H₅CF₃0249531 (S)14Toluene−10489764 (S)15Toluene−20609265 (S)16Toluene−4072N.R.—Open in a separate window^aUnless otherwise specified, the reactions were carried out with 1a (0.1 mmol), trichlorosilane (0.2 mmol) and catalyst 2f (0.02 mmol) in 1 mL of solvent.^bIsolated yield based on 1a.^cThe ee values were determined by using chiral HPLC.^dThe absolute configuration of 3a was determined by comparison of the retention times of the two enantiomers on the stationary phase with those in the literatures.With the optimized conditions in hand, the scope and limitations of the reaction were explored. The results are summarized in Fig. 3. In the presence of 20 mol% of chiral Lewis base catalyst 2f and 2 equivalents of trichlorosilane, various α,β-unsaturated ketones were hydrosilylated. We first tested the effect of various 3-aryl groups of 1. 3-(4-Methoxy-phenyl) substrate 3e (Fig. 3) and 3-(naphthalen-2-yl) substrate 3i (Fig. 3) underwent the reaction to give the products with good yields in enantioselectivities close to 3a, while lower ee values were observed with 3b–3d, 3h, 3k and 3l (Fig. 3). No product was obtained with 3-(2-chloro-phenyl) substrate 3f and 3-(naphthalen-1-yl) substrate 3j, perhaps due to the high steric hindrance (Fig. 3). When 3-(2-methoxy-phenyl) substrate 3g was used, by prolonging the reaction time to 60 hours, the product was obtained with good yield but very poor enantioselection (Fig. 3). Trace amount of the product was detected with 3-(pyridin-2-yl) substrate 3m (Fig. 3). Next, some 3-phenyl-but-2-en-1-ones with different 1-aryl groups were also employed in the reaction. The 4-substituted or 3-substituted substrates delivered good yields of the products with similar or slightly lower enantioselectivities (Fig. 3), while much lower ee value was observed with 2-substituted substrate 3s (Fig. 3). For some other 3-alkyl chalcones, moderate to good yields and moderate ee values were obtained (Fig. 3), except for the bulkier tertiary butyl substituted 3w that gave trace amount of the product (Fig. 3). Reaction of 3y with two different 3,3-aryl groups afforded the product with moderate yield in very low enantioselectivity (Fig. 3). Finally, cyclic substrate 3z was subjected in the reaction and provided the product with excellent yield but in poor ee value (Fig. 3).Open in a separate windowFig. 3Substrate scope of the reaction. Unless otherwise specified, the reactions were carried out with 1 (0.1 mmol), trichlorosilane (0.2 mmol) and catalyst 2f (0.02 mmol) in 1 mL of toluene at −10 °C for 48 hours. Isolated yield based on 1. The ee values were determined by using chiral HPLC. The absolute configuration of 3a was determined by comparison of the retention times of the two enantiomers on the stationary phase with the literatures. The absolute configurations of other products were determined in analogy. ^aThe reaction time was 60 hours. ^bThe reaction time was 72 hours.Although detailed structural and mechanistic studies remain to be carried out, based on the absolute configuration of the product 3a, we propose a mechanism shown in Scheme 2. First, the nitrogen atom of the pyridine ring and the carbonyl oxygen atom of catalyst 2f are coordinated to Cl₃SiH to create an activated hydrosilylation species. Substrate 1a may approache the Cl₃SiH-catalyst complex to generate two transition states A and B. In transition state A, the N–H of catalyst 2f activates the carbonyl group of 1a through H-bonding. In addition, there could be π–π stackings between the two aromatic systems of the catalyst and the substrate. Then Si-face conjugate attack of the hydride to 1a generate (S)-product 3a. On the contrary, in transition state B through which (R)-product will be obtained, the carbonyl group of 1a can not be connected with the N–H of catalyst 2f. Thus the fact that (S)-enriched product 3a was obtained is consistent with the suggestion that the hydrosilylation predominantly proceeds through the pathway involving transition state A rather than transition state B.Open in a separate windowScheme 2A plausible reaction mechanism for hydrosilylation of 1a catalyzed by 2f.In conclusion, we have developed a facile, metal-free and mild enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones. By using chiral picolinamide–sulfonate Lewis base as catalyst, the reactions provided various optically active ketones bearing a chiral center at β-position with moderate to good yields in moderate enantioselectivities. Comparing with the chiral phosphine oxide Lewis base catalysts, the chiral picolinamide–sulfonate is cheaper and easier accessible. The absolute configuration of one product was determined by comparison of the retention times of the two enantiomers on the stationary phase with those in the literature.     

Mesoporous PbO nanoparticle-catalyzed synthesis of arylbenzodioxy xanthenedione scaffolds under solvent-free conditions in a ball mill

A protocol for the efficient synthesis of arylbenzodioxy xanthenedione scaffolds was developed via a one-pot multi-component reaction of aromatic aldehydes, 2-hydroxy-1,4-naphthoquinone, and 3,4-methylenedioxy phenol using mesoporous PbO nanoparticles (NPs) as a catalyst under ball milling conditions. The synthesis protocol offers outstanding advantages, including short reaction time (60 min), excellent yields of the products (92–97%), solvent-free conditions, use of mild and reusable PbO NPs as a catalyst, simple purification of the products by recrystallization, and finally, the use of a green process of dry ball milling.

An efficient one-pot multicomponent protocol was developed for the synthesis of arylbenzodioxy xanthenedione scaffolds using mesoporous PbO nanoparticles as reusable catalyst under solvent-free ball milling conditions.

Recently, the ball milling technique has received great attention as an environmentally benign strategy in the context of green organic synthesis.^1a The process of “ball milling” has been developed by adding mechanical grinding to the mixer or shaker mills. The ball milling generates a mechanochemical energy, which promotes the rupture and formation of the chemical bonds in organic transformations.^1b Subsequently, detailed literature^1c and books on this novel matter have been published.^2a,b Several typical examples include carbon–carbon and carbon–heteroatom bond formation,^2c organocatalytic reactions,^2d oxidation by using solid oxidants,^2e dehydrogenative coupling, asymmetric, and peptide or polymeric material synthesis, which have been reported under ball milling conditions.^2e Hence, the organic reactions using ball milling activation carried out under neat reaction environments, exhibit major advantages,^2f including short reaction time, lower energy consumption, quantitatively high yields and superior safety with the prospective for more improvement than the additional solvent-free conditions and clear-cut work-up.^3–5On the other hand, the organic transformations using metal and metal oxide nanoparticles⁶ are attracting enormous interest due to the unique and interesting properties of the NPs.^7,8,9a Particularly, PbO NPs^9b provide higher selectivity in some organic reactions^9c and find applications in various organic reactions, like Paal–Knorr reaction,¹⁰ synthesis of diethyl carbonate,¹¹ phthalazinediones,¹² disproportionation of methyl phenyl carbonate to synthesize diphenyl carbonate,¹³ the capping agent in organic synthesis, and selective conversion of methanol to propylene.¹⁴ In addition, the PbO NPs are also used in many industrial materials.^15,16However, till date, PbO NPs have not been explored in MCRs leading to biologically important scaffolds. Among others, the xanthene scaffolds¹⁷ are one of the important heterocyclic compounds¹⁸ and are extensively used as dyes, fluorescent ingredients for visual imaging of the bio-molecules, and in optical device technology because of their valuable chemical properties.¹⁹ The xanthene molecules have conjointly been expressed for their antibacterial activity,²⁰ photodynamic medical care, anti-inflammatory drug impact, and antiviral activity. Because of their various applications, the synthesis of these compounds has received a great deal of attention.²¹ Similarly, vitamin K nucleus^22,23 shows a broad spectrum of biological properties, like anti-inflammatory, antiviral, antiproliferative, antifungal, antibiotic, and antipyretic.^24a As a consequence, a variety of strategies^24b have been demonstrated in the literature for the synthesis of xanthenes and their keto derivatives, like rhodomyrtosone-B,^25a rhodomyrtosone-I,^25b and BF-6 ^25c as well as their connected bioactive moieties. Few biologically active xanthene scaffolds are shown in (Fig. 1).Open in a separate windowFig. 1Some biologically important xanthenes and their keto derivatives.Due to the significance of these compounds, the synthesis of xanthenes and their keto derivatives using green protocols is highly desirable. Reported studies reveal that these scaffolds are synthesized by three-component condensations using p-TSA²⁶ and scolecite²⁷ as catalysts. However, these methods suffer from the use of toxic acidic catalysts like p-TSA, long reaction times (3 h), harsh refluxing²⁶ or microwave reaction conditions,²⁷ and tedious work-up procedures. The previously reported methods for the synthesis of xanthenediones are shown in Scheme 1.Open in a separate windowScheme 1Previous protocol for the synthesis of xanthenedione derivatives.Herein, we report an economical and facile multicomponent protocol, using ball milling, for the synthesis of 7-aryl-6H-benzo[H][1,3]dioxolo[4,5-b]xanthene-5,6(7H)-dione using PbO NPs as a heterogeneous catalyst (Scheme 2). The PbO NPs are non-corrosive, inexpensive, and easily accessible.Open in a separate windowScheme 2General reaction scheme of PbO NP-catalyzed synthesis of the xanthenedione scaffolds under ball milling conditions.In our protocol,²⁸ the PbO NPs were initially prepared by mixing sodium dodecyl sulphate (2.5 mmol) and sodium hydroxide (10 mL, 0.1 N) with an aqueous methanolic solution of lead nitrate (2 mmol) under magnetic stirring at 30 °C by continuing the reaction for 2 h. Then, the obtained white polycrystalline product was filtered, washed with H₂O, and dried at 120 °C, followed by calcination at 650 °C for 2 h. During this step, the white PbO NPs turned pale yellow in colour. Eventually, the synthesized PbO was then characterized by spectroscopic and analytical techniques.The powder X-ray diffraction (XRD) pattern revealed the crystalline nature of the PbO NPs as the diffraction peaks corresponding to (131), (311), (222), (022), (210), (200), (002), and (111) crystal planes were identified (Fig. 2). The XRD outline of the synthesized PbO NPs was further established for the formation of space group Pca2₁ ²⁹ with a single orthorhombic structure (JCPDS card number 76-1796). The sharp diffraction peaks indicated good crystallinity, and the average particle size of the PbO NPs was estimated to be 69 nm, as calculated using the Debye–Scherer equation.Open in a separate windowFig. 2The powder XRD pattern of PbO NPs.The surface morphology of the PbO NPs was analyzed by scanning electron microscopy (SEM), and the SEM image revealed the discrete and spongy appearance of the PbO NPs (Fig. 3).Open in a separate windowFig. 3The SEM image of PbO NPs.Moreover, the elemental composition obtained from energy dispersive X-ray (EDX) analysis confirmed that the material contains Pb and O elements, and no other impurity was present (Fig. 4).Open in a separate windowFig. 4The EDAX spectrum of crystalline PbO NPs.The transmission electron microscopy (TEM) image shown in Fig. 5 indicated the formation of orthorhombic crystallites of PbO with several hexagon-shaped particles. The dark spot in the TEM micrograph further confirmed the synthesis of PbO NPs, as the selected area diffraction pattern associated with such spots reveals the occurrence of the PbO NPs in total agreement with the X-ray diffraction data (Fig. 6). The average size of the PbO nanocrystals by TEM was approximated to be around 20 nm.Open in a separate windowFig. 5The TEM image of nanocrystalline PbO NPs.Open in a separate windowFig. 6The SAED image of nanocrystalline PbO NPs.The Fourier transform infrared (FT-IR) spectrum (ESI, S6^†) of the PbO NPs displayed peaks at 575, 641, and 848 cm⁻¹, which corresponds to the Pb–O vibrations. Furthermore, the absorption band at ∼3315 cm⁻¹ was due to the presence of the hydroxyl group (–OH) in the NPs.The N₂ adsorption–desorption isotherms of the PbO nanoparticles shown in Fig. 7 was consistent with type IV adsorption–desorption isotherms with H1 hysteresis corresponding to the cylindrical mesoporous structure. Moreover, the surface area, pore-volume, and BJH pore diameter were found to be 32.0 m² g⁻¹, 0.023 cm³ g⁻¹, and 30.9 Å, respectively.Open in a separate windowFig. 7BET surface area and pore size of nanocrystalline PbO catalyst.The catalytic activity of the synthesized PbO NPs was tested in a one-pot multicomponent synthesis of arylbenzodioxoloyl xanthenedione derivative under ball milling condition according to the reaction scheme 2a, with 3,4-dimethoxybenzaldehyde (166.2 mg, 1.0 mmol), 3,4-methylenedioxyphenol (138.0 mg, 1.0 mmol), and 2-hydroxy-1,4-naphthoquinone (174.0 mg, 1.0 mmol) as reactants. The reaction conditions, the ball milling parameters (speed, time, and ball to solids ratio), and the PbO nanocatalyst amount were first optimized to produce the highest yield using experimental design as shown in EntryConditionsRotation (rpm)Catalyst (mol%)Time (min)Yield (%)^a1Ball milling4000050212Ball milling4001050483Ball milling4001560544Ball milling4002070595Ball milling5001050626Ball milling5001550657Ball milling5002060678Ball milling6001070719Ball milling60015507710Ball milling60020608211Ball milling60005709012Ball milling600105091 13 Ball milling ^b 600 15 60 97 14Ball milling60020709715No ball milling^c—1560—Open in a separate window^aIsolated yield; model reaction: 3,4-dimethoxybenzaldehyde (166.2 mg, 1.0 mmol), 3,4-methylenedioxyphenol (138.1 mg, 1.0 mmol), 2-hydroxy-1,4-naphthoquinone (174.1 mg, 1.0 mmol) under ball milling.^bOptimized reaction conditions.^cThe reaction was performed under stirring condition in a RB flask.Next, by utilizing the general experimental procedure (ESI^† for detail experimental procedure; S2) and the aforementioned optimized conditions (29 we also investigated the possible scopes of the reactants as revealed in 26 These data are available in S4 (see ESI^† for the spectroscopic data). The aromatic aldehydes comprising both electron-withdrawing (e.g., nitro group) and electron-donating (e.g., –OMe, –OH, –Cl, –Me, and –Br) groups participated proficiently in the reaction without including any electronic effects. The aromatic aldehyde with electron-donating groups (e.g., –OMe, –OH, –Cl, –Me, and –Br) increased the product yield, while in the case of aryl aldehyde having an electron-withdrawing group (e.g., –NO₂), both the product yield as well as the reaction rate decreased. These findings are depicted in †Scope of the PbO NP-catalyzed synthesis of arylbenzodioxoloyl xanthenedione derivatives

Correction: Base recognition by l-nucleotides in heterochiral DNA

Correction for ‘Base recognition by l-nucleotides in heterochiral DNA’ by Shuji Ogawa et al., RSC Adv., 2012, 2, 2274–2275.

The authors regret that some of the data in the original article were presented incorrectly. Some of the oligonucleotide sequences in the Graphical Abstract, Fig. 2 and Fig. 2 and Open in a separate windowFig. 2Effects of base pair mismatch of d- (a–d) and l-nucleotide (e–h) on duplex stability. Samples contained 6 mM duplex in 10 mM MgCl₂, 100 mM NaCl, and 70 mM MOPS (pH 7.1). Yellow bars denote T_m values of fully matched duplexes, and blue bars denote T_m values of mismatched duplexes.UV-melting points of homo- and heterochiral duplexes^a

Highly dispersed Ni nanoparticles on mesoporous silica nanospheres by melt infiltration for transfer hydrogenation of aryl ketones

Nickel-based catalysts have been applied to the catalytic reactions for transfer hydrogenation of carbonyl compounds. In the present work, highly dispersed nickel particles located at the pores of mesoporous silica spheres (Ni@mSiO₂) were prepared via an optimized melt infiltration route. The nickel nanoparticles of 10 wt% in the Ni@mSiO₂ catalyst could be uniformly loaded with high dispersion of 36.3%, resulting excellent performance for catalytic transfer hydrogenation of aryl ketones.

Nickel-based catalysts have been applied to the catalytic reactions for transfer hydrogenation of aryl ketones.

The reduction of carbonyl compounds has received steady interest as a common transformation in organic synthetic chemistry. Corresponding alcohols are important building blocks for the manufacture of chemicals, pharmaceuticals, and cosmetics.^1,2 The transfer hydrogenation (TH) reaction of ketones has lots of advantages owing to its low cost, simple process, easy handling, and mild conditions.³ Isopropyl alcohol both as a solvent and hydrogen donor provides safe reaction conditions.⁴ Until now, many catalysts have been developed for TH reactions.⁵Among the catalysts for TH reactions, nickel-based catalysts are representative, due to the metallic nickel surface can absorbs hydrogen and easily activates hydrogen in the atomic state.^6–11 In addition, nickel compounds could be the significant catalyst candidate because of the low price, accessibility, and high reactivity.^12,13 Therefore, several works used nickel nanocatalysts for TH reactions.^{14–17,44–51} However, developing the new supported catalyst with the high metal dispersion and narrow particle size distribution is still required, because it can enhance the reactant conversion and improve product yield.¹⁸ Recently, melt infiltration process has been exploited to prepare supported nanocatalysts as a fast and convenient route with no solvent use.^19–21The method which uses highly porous supports with regular porosity and hydrated metal salts with mild melting temperatures, allowed the metal salts to permeate inside the porous support via capillary forces. High performance nanocatalysts based on well-dispersed nanoparticles could be obtained through uniform infiltration of metal precursors and sequential thermal treatment.²² The obtained nanoparticles have narrow size distributions as well as small sizes, enlarging active sites.^23,24Mesoporous silica nanosphere (mSiO₂) as a porous support can be an outstanding platform for the synthesis of metal nanoparticle, owing to the good thermal stability, high surface area, and large pore volume as well as uniform pore structures.^25–29 Herein, we report a new catalyst with highly dispersed Ni nanoparticles at mesoporous silica sphere nanostructures (Ni@mSiO₂) for catalytic TH reactions, which was synthesized through a melt infiltration of hydrated nickel salts and a sequential thermal reduction (Scheme 1). First, mSiO₂ supports could be prepared by a sol–gel method based on a modified Stöber process. More details were described in the ESI.^† The mesopores were formed in the silica nanospheres using the cationic surfactant C₁₆TAB as a self-assembly template. The TEM images show mesoporous silica spheres with an average diameter of 417 ± 20 nm (Fig. 1a and b). Ordered mesoporous channels were generated by removing the long carbon chains of C₁₆TAB by calcination at 500 °C. The corresponding Fourier-transform (FT) pattern showed a ring pattern of polycrystalline (inset of Fig. 1c). The inverse fast Fourier-transform (IFFT) image, calculated by Micrograph TM Gatan software, also demonstrated the existence of hexagonal lattice planes (Fig. 1c).Open in a separate windowScheme 1A brief synthetic scheme of Ni@mSiO₂ nanocatalyst.Open in a separate windowFig. 1(a and b) TEM images, (c) FT pattern for (b) (inset of c) and IFFT image, (d) HRTEM image, (e) N₂ adsorption/desorption isotherms, and (f) pore size distribution diagrams of mSiO₂. The bars represent 1 mm (a), 100 nm (b), and 20 nm (d).The brightest of the rings originated from a two-dimensional hexagonal (p6mm) structure with d100 spacing. The interplanar spacing computed from the brightest FFT diffraction ring was approximately 3 nm, corresponding to the pore sizes shown in the TEM image (Fig. 1d).N₂ sorption experiments for the mSiO₂ nanosphere exhibited type IV adsorption–desorption hysteresis with H4 type hysteresis loop (Fig. 1e). The Brunauer–Emmett–Teller (BET) surface area and pore volume of the mSiO₂ nanosphere were 1501 m² g⁻¹ and 0.70 cm³ g⁻¹, respectively. The average pore size was estimated to be approximately 2 nm from the adsorption/desorption branches of N₂ isotherms by using the Barrett–Joyner-Halenda (BJH) method (Fig. 1f). Scheme 1 illustrated the simple procedure for the synthesis of the Ni@mSiO₂ nanocatalyst. Based on the small pore size (3 nm) of mSiO₂ nanospheres, very tiny nickel nanoparticles (∼2 nm) could be generated via a melt-infiltration process and thermal treatment under hydrogen flow. Using a 0.55 g_{nickel salt}/g_silica support ratio, the hydrated nickel salt (melting point = 56.7 °C) was successfully incorporated in the mSiO₂ nanosphere during the melt infiltration process, driven by the capillary forces. The Ni-loading content after the final thermal treatment was calculated to be nominally 10 wt% on the basis of Ni converted from the nickel nitrate salt. First, the hydrated nickel salt was melt-infiltrated into the mesoporous silica pores of the mSiO₂ nanospheres by physical mixing at room temperature with subsequent aging at 60 °C for 24 h in a tumbling oven. Then, tiny nickel nanoparticles were generated by thermal reduction of the confined hydrated Ni salt in the small pores at 500 °C under hydrogen flow.The low-resolution TEM images of the Ni@mSiO₂ nanostructure show Ni nanoparticles as black dots (Fig. 2a and b). The high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) image showed bright dots of a very small size (average 2.0 nm), which indicates uniform incorporation of the Ni nanoparticles in the porous silica (Fig. 2c and S1 in the ESI^†). In the elemental mapping of silica (green color) and nickel (red color), high dispersion of nickel nanoparticles was observed (Fig. 2d). HRTEM analysis showed lattices of a single Ni nanoparticles in the mSiO₂ pores (Fig. 2e). The inner particle size was observed to be around 2 nm. The Fourier-transform pattern represented a single crystal of metallic nickel with a distance of 0.2 nm between neighboring fringes, which corresponded to the (111) planes of face centered-cubic nickel (Fig. 2e).Open in a separate windowFig. 2(a and b) TEM and (c) HAADF TEM images, (d) scanning TEM image with elemental mapping and (e) HRTEM images, and (f) XRD spectrum of Ni@mSiO₂ nanostructure. The bars represent 200 nm (a), 20 nm (b–d), and 2 nm (e).The X-ray diffraction (XRD) spectrum of Ni@mSiO₂ nanocatalyst has a broad peak at 2θ = 44.5°, which is assigned to the reflections of the (111) plane in the fcc-nickel phase (Fig. 2f, JCPDS No. 04-0850). The average crystal size of the nickel particle was estimated to be 1.8 nm, from the broadness of the (111) peak using the Debye–Scherrer equation, which is well-matched with that observed in the TEM images. The other intense peak around 23° of the Ni@mSiO₂ nanocatalyst indicates the presence of amorphous silica.Using a H₂ chemisorption experiment, the active nickel surface area and average nickel particle size of the Ni@mSiO₂ nanocatalyst could be analyzed, and measured 242 m² g⁻¹ and 2.78 nm, respectively. The obtained Ni dispersion was very high, and was calculated to be 36.3%.The XPS spectrum analysis was carried out to probe the chemical states of Ni@mSiO₂ (Fig. S2^†). The Ni 2p peak of Ni@mSiO₂ showed NiO and Ni peak. The four peaks at 853.9, 855.6, 860.7, and 863.5 eV are assigned to NiO, and the other peak at 852.1 eV is assigned metallic Ni peak. The metallic Ni surface of the small nanoparticles (∼2 nm) was easily oxidized under an ambient condition.N₂ sorption experiments for the Ni@mSiO₂ nanocatalyst showed a type IV isotherm with type H4 hysteresis (Fig. 3a). The BET surface area was calculated to be 636 m² g⁻¹. The total pore volume was found to be 0.3 cm³ g⁻¹, which is about 43% of the initial mSiO₂ nanosphere (0.7 cm³ g⁻¹). The significant decrease in pore volume was attributed to inner nickel nanoparticle occupancy. Applying the BJH method, small pore sizes were obtained by the adsorption/desorption branches (Fig. 3b). Because of the occupancy of tiny nickel particles in the pristine silica pores, the pore size of the Ni@mSiO₂ nanocatalyst was also slightly decreased, and was observed to be 1.8 nm.Open in a separate windowFig. 3(a) N₂ adsorption/desorption isotherms and (b) pore size distribution diagrams of Ni@mSiO₂ nanocatalyst.The Ni@mSiO₂ nanocatalyst was applied to the hydrogen-transfer reaction of acetophenone. Acetophenone is an ideal substrate in the hydrogen transfer reaction, and is generally used as a hydrogen acceptor.³⁰ Among the various products of acetophenone reduction, only 1-phenylethanol resulted from the catalyzed reaction. The metallic Ni on the catalyst surface is the active species and the reaction was promoted by base.¹⁷ The dihydride species referred in this catalyst system to make alcohol from the transfer of the two hydrogen atoms of the donor to the surface of the metal.³¹ However, small amount of various byproduct including hemiacetals and condensation products which is occurred between ketone and alcohol were produced due to basic conditions.³² For optimization, the reaction parameters, such as amount of catalyst and base, temperature, and time, are adjusted. The TH reaction results of acetophenone are summarized in EntryCat. (mol%)Temp. (°C)Time (min)Base (eq.)Conv.^b (%)Yield^b (%)TON1111045110095952111060176737331100602100999941100601100929251100600.562595961906011009696718045158555581806017268689180751100979710180901676565110.58075110096192120.25807511095380130.1807516260603140.05100602806262Open in a separate window^aRxn. condition: acetophenone (2 mmol), i-PrOH (solvent, 10 mL), base (NaOH).^bDetermined by GC-MS spectroscopy.^cnickel-aluminium alloy purchased from Lancaster (10034177) was applied.First, we studied the effect of the base and determined the amount of base required (Entries 3–6, 33,34 Although no reaction was observed without bases, a small amount of base was sufficient to trigger the reaction (Entry 5, 6,15,35 The optimized conditions were applied to extend the scope.To verify the general applicability of Ni@mSiO₂, various aromatic ketones were tested (†).^36–43Catalytic transfer hydrogenation reactions of various aromatic carbonyl compounds with Ni@mSiO₂^a

Continuous flow synthesis of aryl aldehydes by Pd-catalyzed formylation of phenol-derived aryl fluorosulfonates using syngas

This communication describes the palladium-catalyzed reductive carbonylation of aryl fluorosulfonates (ArOSO₂F) using syngas as an inexpensive and sustainable source of carbon monoxide and hydrogen. The conversion of phenols to aryl fluorosulfonates can be conveniently achieved by employing the inexpensive commodity chemical sulfuryl fluoride (SO₂F₂) and base. The developed continuous flow formylation protocol requires relatively low loadings for palladium acetate (1.25 mol%) and ligand (2.5 mol%). Good to excellent yields of aryl aldehydes were obtained within 45 min for substrates containing electron withdrawing substituents, and 2 h for substrates containing electron donating substituents. The optimal reaction conditions were identified as 120 °C temperature and 20 bar pressure in dimethyl sulfoxide (DMSO) as solvent. DMSO was crucial in suppressing Pd black formation and enhancing reaction rate and selectivity.

Pd-catalyzed formylation of aryl fluorosulfonates by using syngas as an atom efficient and sustainable source of carbon monoxide and hydrogen.

Aryl aldehydes are ubiquitous intermediates and building blocks in the chemical and pharmaceutical industry. As such, their convenient and cost-efficient synthesis is of high interest. One of the simplest ways of forming aldehydes is through the Pd-catalyzed formylation of Ar–X (where X = I, Br, or OTf) using syngas (CO and H₂).¹ The main limitations in the case of aryl iodides and bromides are the price and availability of the starting materials. In the case of triflates, trifluoromethanesulfonic anhydride (Tf₂O) is the reagent most commonly employed to prepare triflates from alcohols, but it is relatively expensive, prone to hydrolysis and atom uneconomic.² Fluorosulfonates (–OSO₂F) have been proposed as an alternative leaving group to triflates because their reactivity is considered largely the same,^2,3 or placed in-between bromides and chlorides.⁴ The fluorosulfonate leaving group is an emerging chemical motif⁵ that has been used in many types of chemical transformations including reduction,⁶ metal catalyzed cross-coupling,^3,5,7 deoxyfluorination,⁸ amination,⁹ and methoxycarbonylation.¹⁰ Aryl fluorosulfonates can be conveniently and inexpensively prepared by treating readily available phenols with the commodity chemical sulfuryl fluoride (SO₂F₂) and base.Previously, Beller and co-workers successfully demonstrated the Pd-catalyzed formylation of aryl triflates with syngas as a sustainable and cost effective reagent under batch conditions (Scheme 1a).¹¹ We were interested in the synthesis of aryl aldehydes from aryl fluorosulfonates, which could be derived from their corresponding phenols. Our group previously reported the continuous flow Pd-catalyzed formylation of (hetero)aryl bromides within a continuous flow system.¹² Carbonylation reactions benefit from the highly efficient mixing, enhanced mass and heat transfer characteristics, precise residence time, accessibility to high pressure and temperature regimes, and the high operational safety of continuous flow reactors.^13–16 Herein, we describe the development of a continuous flow protocol for the synthesis of aryl aldehydes from their corresponding aryl fluorosulfonates (Scheme 1b).Open in a separate windowScheme 1Pd-catalyzed reductive carbonylation using syngas for (a) triflates (Beller)¹¹ and (b) fluorosulfonates (this work) as leaving groups.We commenced our investigation by evaluating the catalytic system palladium(ii) acetate (Pd(OAc)₂) and 1,3-bis(diphenylphosphino)propane (dppp), which was utilized by Beller and co-workers for the batch formylation of aryl triflates.^11,17 The reaction was optimized within a continuous flow reactor for 4-methoxyphenyl sulfurofluoridate (1a) as model substrate. We used a Uniqsis FlowSyn flow system consisting of two HPLC pumps and a heated reactor coil (32 mL). Two sample loops were used to deliver the substrate solution (2 mL) and catalyst feed solution (3 mL). The gases, H₂ and CO, were introduced into a four-way mixer by using two mass flow controllers (MFCs). The flow system was pressurized to 10 bar by using a back pressure regulator (BPR). Substrate 1a was mixed with triethylamine (Et₃N) as base and diphenyl ether (Ph₂O) as internal standard for preparation of the substrate feed. Pd(OAc)₂ and dppp were used as the catalyst feed. Initially, we evaluated toluene (PhMe), tetrahydrofuran (THF), acetonitrile (MeCN) and dimethylformamide (DMF) as solvents for the carbonylation reaction ( EntrySolventTemp. [°C]Conv. 1a^b [%]Sel.^b [%]Yield^b2a [%]1PhMe1007.7002PhMe12017.12.20.43THF1009.66.90.74THF12017.04.90.85MeCN10020.73.05.96MeCN12042.75.93.47DMF10067.119.112.88DMF12079.122.117.59DMF^c12050.322.611.410DMF^d12036.759.021.611DMF^d,e12032.850.016.4Open in a separate window^aGeneral conditions: feed 1: 0.2 M 4-methoxy sulfurofluoridate (1a), 1.0 equiv. Et₃N and 0.15 equiv. Ph₂O in solvent; feed 2: 5 mol% Pd(OAc)₂ and 10 mol% dppp in solvent. Feed 1/feed 2/H₂/CO = 0.1 : 0.1 : 5 : 5 mL min⁻¹ resulting in a 27 min residence time (t_res). 10 bar system pressure.^bAnalyzed by GC-FID.^c13.5 min t_res.^d1 equiv. of pyridine as base.^eFlow rates for feed 1/feed 2/H₂/CO = 0.3 : 0.3 : 1.87 : 1.87 mL min⁻¹, t_res 35 min.Higher conversion was typically observed when using 120 °C instead of 100 °C. Using PhMe and THF as solvent gave only minimal conversion and trace amount of product (Fig. 1). The drop in yield and black output solution indicates a well-known phenomenon of Pd⁰ – agglomerating and forming clusters.¹⁸ These clusters then irreversibly precipitate as Pd black particles. These Pd black particles coat the reactor wall and can catalyze further Pd black formation.^12,19 In order to tackle this issue, we looked for an additive or a method to prevent or slow the rate of Pd black agglomeration.Open in a separate windowFig. 1Drop in 4-methoxybenzaldehyde (2a) GC yield after repeated reaction runs without wash runs in-between. Conditions used are provided in 20 When applied to our reaction system using 4-chloro sulfurofluoridate (1b) as substrate, the use of DMSO as co-solvent alleviated the issues associated with Pd black formation (Fig. 2). Furthermore, we could drastically increase the yield of desired product 2b, due to reduced catalyst decomposition. The only side product in all cases was the hydrogenated product 3b, with the loss of the fluorosulfonate group (-OSO₂F). Increased pressure (20 bar) and base (1.5 equiv.) resulted in higher selectivity to the aldehyde product 2b (Fig. S1^†). The fraction of DMSO solvent could be increased to no more than 80% owing to catalyst solubility.Open in a separate windowFig. 2Influence of DMSO on conversion and yield for Pd-catalyzed formylation of 4-chloro sulfurofluoridate (1b) with syngas measured by GC-FID (Ph₂O as internal standard). For 0–80 vol% DMSO, 0.2 M 4-chloro sulfurofluoridate (1b), 1.0 equiv. pyridine and 0.15 equiv. Ph₂O in DMF/DMSO; feed 2: 5 mol% Pd(OAc)₂ and 10 mol% dppp in DMF/DMSO. 120 °C temperature and 10 bar system pressure. Flow rates for feed 1/feed 2/H₂/CO = 0.3 : 0.3 : 1.87 : 1.87 mL min⁻¹, corresponding to t_res 35 min. 100 vol% DMSO experiment was performed using 1.25 mol% Pd(OAc)₂ and 2.5 mol% dppp.The reaction conditions in terms of residence time and catalyst loading were then re-optimized for using DMSO as solvent. The catalyst loading was lowered to 1.25 mol% Pd(OAc)₂ and 2.5 mol% dppp to ensure full dissolution of the catalyst system. A further decrease in loading did not provide satisfactory results, with a drop in yield observed (Fig. S2^†). Under these conditions 40 min of residence time was sufficient to achieve a high yield of 4-chlorobenzaldehyde (2b) (Fig. S3^†). With these new conditions (Scheme 2a), a long run was successfully operated which was stable for 4 hours with no apparent drop in yield, thus demonstrating no or minimal catalyst decomposition (Scheme 2b).Open in a separate windowScheme 2(a) Continuous flow setup for the Pd-catalyzed formylation of 4-chloro sulfurofluoridate (1b) long run. (b) 4-Chlorobenzaldehyde (2b) GC yield at 30 min intervals over 4 h operation time. 0.15 equiv. Ph₂O was used as an internal standard.The applicability of the optimized conditions, shown in Scheme 2a, was demonstrated on a range of substrates. In most cases, substrates bearing an electron withdrawing group (EWG) in the para position underwent full conversion and the corresponding aryl aldehyde was formed in moderate to excellent yields (Fig. 3). The hydrogenated product was the sole side product observed. However, the reaction of substrates 1e and 1f resulted in the formation of a mixture of double formylation and hydrogenated products. The formylation of 4-nitro sulfurofluoridate (1 m) was problematic because of deactivation of the catalyst.Open in a separate windowFig. 3Substrate scope for aryl fluorosulfonates containing electron withdrawing groups. Yields were determined by GC-FID using Ph₂O as internal standard. Yields in parentheses were isolated yield. Conditions are the same as given in Scheme 2a.Less reactive substrates, 1k and 1l, were only fully converted when modified reaction conditions were applied. In these cases, the liquid flow rates were lowered, which prolonged the residence time to approximately 2 h (Fig. 4a). Moreover, the H₂ flow rate was modified to deliver 4.2 equiv. The same modified conditions were also used for substrates containing electron donating groups (EDG). The formation of the hydrogenated side product was not a significant problem for substrates containing EDG substituents with the aldehyde products obtained in good to excellent yields (Fig. 4b). Gratifyingly, 6-methoxy-2-naphthalaldehyde (2p) could be isolated in 82% yield after purification by column chromatography. Substrate 2b is a potential precursor to naproxen, an important non-steroidal anti-inflammatory active pharmaceutical ingredient.Open in a separate windowFig. 4(a) Unreactive substrates containing electron withdrawing groups; (b) substrates containing electron donating groups. For 43 min conditions, see Scheme 2a. Conditions: feed 1: 0.2 M fluorosulfonate, 1.5 equiv. pyridine and 0.15 equiv. Ph₂O in DMSO; feed 2: 1.25 mol% Pd(OAc)₂ and 2.5 mol% dppp in DMSO. 120 °C temperature and 10 bar system pressure. Feed 1/feed 2/H₂/CO = 0.08 : 0.08 : 1.5 : 0.5 mL min⁻¹, corresponding to a t_res = 123 min.Substrates bearing a substituent in ortho position to the fluorosulfonate group afforded the corresponding aldehyde either in low yield, for 1r and 1u, or no yield, for 1d and 1o. The drop in yield could be caused by steric hindrance from the ortho-substituent. The steric block on the catalytic center will favor the addition of the much smaller hydrogen molecule instead of a larger CO molecule, resulting in the hydrogenated product.In conclusion, we have described a continuous flow method for the Pd-catalyzed synthesis of valuable aryl aldehyde building blocks from aryl fluorosulfonates and syngas as an inexpensive, atom-economic, and environmentally friendly source of CO and H₂. The continuous flow approach enabled the precise addition of gas by using mass flow controllers. Meta and para substituted aryl fluorosulfonates could be converted to their corresponding aldehydes in good to excellent yields. Catalyst decomposition was successfully avoided by using DMSO as solvent. DMSO coordinates to Pd⁰ and facilitates the re-oxidation to Pd^II. Additionally, reaction rates and selectivity could be enhanced by the use of DMSO. Starting materials for the reductive carbonylation could be conveniently derived in excellent yields from readily-available phenols and the commodity chemical sulfuryl fluoride. The developed process is especially appealing for the chemical industry, where reagent cost and availability are important factors in process feasibility.     

Palladium catalysed carbonylation of 2-iodoglycals for the synthesis of C-2 carboxylic acids and aldehydes taking formic acid as a carbonyl source

Pd catalyzed carbonylative reaction of 2-iodo-glycals has been developed taking formic acid as a carbonyl source for the synthesis of 2-carboxylic acids of sugars by the hydroxycarbonylation strategy. The methodology was successfully extended to the synthesis of 2-formyl glycals by using a reductive carbonylation approach. Both ester and ether protected glycals undergo the reaction and furnished sugar acids in good yield which is otherwise not possible by literature methods. The C-2 sugar acids were successfully utilized for the construction of 2-amido glycals, 2-dipeptido-glycal by Ugi reaction and C-1 and C-2 branched glycosyl esters.

Pd catalyzed carbonylative reaction of 2-iodo-glycals has been developed taking formic acid as a carbonyl source for the synthesis of 2-carboxylic acids of sugars by the hydroxycarbonylation strategy.

Sugar acids constitute a diverse family of carbohydrates¹ which play a crucial role in cell–cell recognition, cellular adhesion, and virus–host recognition processes, for protection of cells from pathogen attachment, and in the synthesis of biologically active natural products.² α,β-Unsaturated sugar acids such as zanamivir and ianinamivir (Fig. 1) are subjects of particular interest because of their application as inhibitors of different glycoproteins such as hemagglutinin (HA) and neuraminidase (NA),³ the major glycoproteins expressed by influenza viruses. While several reports dealing with the synthesis of carboxylic acids at C-6 and C-1 positions of sugars exist,^4a,b there is no established procedure for the synthesis of C-2 carboxylic acids. In glycals accessing carboxylic group at C-1 position required t-butyl lithium and carbon dioxide treatment at −78 °C.^4c There is only one report available in the literature in which carboxylic group was introduced to the C-2 position of glycals by Furstner et al.^4c,d where the C-2 carboxylic acid was derived from the Pinnick oxidation of 2-formyl glycal obtained by classical Vilsmeier–Haack reaction⁵ and thereafter utilized in the total synthesis of bioactive natural orevactaene (exhibits HIV-1 inhibitory property). This strategy has certain drawbacks like long reaction times with cocktails of oxidants and limited substrate specificity. For example, it works only with ether protected sugars like tri-O-benzyl-d-glycal and fails with other base labile and silyl protecting groups. Further, recovery of 2-formyl glycals after base workup is rather low in our hand. Our experience with glycals^6a–f encouraged us to formulate an attractive way to launch carboxylic acid at C-2 position of glycals as shown in Scheme 1 and apply them in the synthesis of C-2 glycoconjugates.Open in a separate windowFig. 1Glycal based acids in drugs.Open in a separate windowScheme 1Art of launching carboxyl group in sugars.This is pertinent to mention that carbonylation reactions of C-2 glycals have been successfully carried out by using metal carbonyl for the synthesis of C-2 branched glycoconjugates.^7a,b In these reaction stoichiometric amount of costly Mo(CO)₆ is required for such transformation that too ends up with some non-carbonylative side products. CO surrogates^8,9 such as formic acid, formamide, chloroform and anhydride have been explored in recent times obviating metal carbonyls and CO gas. Among all formic acid is an attractive candidate for insertion of CO in an organic molecule,¹⁰ because it liberates one water molecule after releasing one CO molecule thereby making the process environmentally benign. We felt that palladium catalyzed hydroxycarbonylation of stable glycal halides, which are conveniently accessed from glycals in good yield, may prove to be the most effective and environmentally benign method to prepare such molecules. With our continuous interest in synthesis of C-2 branched sugars,¹¹ this time we developed a reagent system for the direct synthesis of C-2 sugar carboxylic acids from 2-iodo glycals using formic acid as carbonyl source. Further, we transformed the synthesized acid for the synthesis of different C-2 branched glycoconjugates.Preliminary experiments were conducted by using 2-iodoglycal 1a, HCOOH as carbonyl source, N,N′-dicyclohexylcarbodiimide, (DCC) as an activator and xantphos as a ligand. When 1a was reacted with 5 mol% Pd(OAc)₂, 10 mol% of xantphos, 1 equiv. of DCC, 2 equiv. of formic acid and 2 equiv. of triethyl amine as base in DMF at 90 °C for 16 h the desired product 3a was obtained along with 3a′ in 60 : 40 ratio with overall 63% yield ( EntryPd sourceLigandTime (h)Conversion (%)(3a : 3a′)Yield^b (overall)%1Pd(OAc)₂L1169060 : 40632Pd(OAc)₂L21699>99 : 1723Pd(OAc)₂L2699>99 : 180 4 Pd(OAc) ₂ L2 1.5 99 >99 : 1 81 5Pd(OAc)₂L2190>99 : 1736Pd(OAc)₂L3164045 : 55237Pd(OAc)₂L4163030 : 70158Pd(OAc)₂L51610—Traces9Pd(OAc)₂L61610—Traces10Pd(PPh)₃L2275>99 : 12111Pd(TFA)₂L2235>99 : 12712PdCl₂L2223>99 : 111Open in a separate window^aReaction conditions: 1a (0.18 mmol), 2a (0.36 mmol), Pd(OAc)₂ (0.009 mmol), L2 (0.018 mmol), N,N′-dicyclohexylcarbodiimide (DCC) (0.18 mmol), triethylamine (0.36 mmol) at 90 °C for 2 h.^bYield of isolated product. Pd 5 mol% and ligand 10 mol% were used. Ratio of 3a and 3a′ and conversion were determined through ¹H NMR.Utilising the optimised reaction condition (l-rhamnal 1b was tested to get a better yield of the product 3b, (85%). The galactal substrate also furnished the desired 2-carboxyl galactal 3c in good yield (76%). In order to broaden the substrate scope the reactivity of glycals protected with different protecting groups was next investigated. Gratifyingly, 2, 3-acetonide protected 2-iodo-d-galactal 1d survived under the reaction condition and yielded the product 3d in good yield (75%). Tri-O-ethyl-2-iodoglucal 1e also reacted well and formed the respective acid derivative 3e in (76%) yield. Next we utilized different glycals having silicon based protection or ester protection. Tri-O-acetyl-2-iodoglucal 1f and di-O-acetyl-2-iodoxylal 1g were also well tolerated under the reaction condition and gave the desired products 3f–3g in reasonable yields (73–75%). 2-Bromo-glucal was next tested under the optimized reaction condition and the desired compound 3a was obtained in good yield although it takes 3 h to complete the reaction.Substrate scope^a

Entry	Substrate	Product	Time (h)	Yieldb (%)
1			1.5	81
2			1.5	85
3			1.5	76
4			1.5	75
5			2	76
6			2.5	73
7			2.5	75

Open in a separate window^aReaction conditions: 1 (1 equiv.), 2a (2 equiv.), Pd(OAc)₂ (5 mol%), L2 (10 mol%), DCC (1 equiv.), triethylamine (2 equiv.) at 90 °C for 1.5 to 2.5 h in 3 mL of DMF.^bYield of isolated product.TBS protected sugars acids are used in the total synthesis of various bioactive natural products by activating the anomeric carbon which is otherwise not possible with other protecting groups. In the literature in order to get such types of acids multiple steps are required along with poor overall yield. By utilizing carbonylation strategy under Pd catalysis we were able to synthesis the TBS protected acids in just 2 h when substrate 1h was reacted with HCOOH under Pd catalysis to generate product 3h in good yield.After successful execution of our strategy for hydroxycarbonylation of 2-iodoglycals, we became interested to apply the same carbonylative approach for the synthesis of 2-formyl glycals. In the literature formylation at C-2 of glycals has been carried out either by Vilsmeier–Haack or XtalFluor-E catalyzed reactions (Scheme 3).^5,12 We utilized the reductive carbonylation approach employing triethylsilyl hydride (1.2 equiv.) as a hydride source keeping other reagents same as for acid synthesis. To our delight, the required 2-formyl glycals were obtained in good to excellent yields (Scheme 3, 3aa–3ae).Open in a separate windowScheme 3Synthesis of 2-formyl glycals.Open in a separate windowScheme 2Synthesis of silyl protected C-2 carboxylic acid.To test the utility of sugar acids in the synthesis of C-2 glycoconjugates, sugar acid 3a was successfully utilized for the synthesis of C-2 linked dipeptides via Ugi reaction (Scheme 4, 5a). The simple amide 5b was also synthesised from 3a using thionyl chloride and ammonium hydroxide; the product is otherwise difficult to synthesize via the existing methods. Where substituted amides are synthesized. The acid chloride of 3a could be successfully coupled with 8-aminoquinoline, leading to the amide 5c in good yield. In order to test the reactivity of the acid 3a, we used it as a glycosyl acceptor in glycosylation reaction by treating with a suitable glycosyl donor like 6, when the pseudodisaccharide 7 was isolated in good yield (63%) with a mixture of anomers. On the other hand, treatment with aryne precursor 8 resulted in the formation of compound 9 in excellent yield (84%) via coupling of aryne with the sugar acid. When sugar acid 3a was treated with thiophenol thioester 11 was isolated in excellent yield (Scheme 5).Open in a separate windowScheme 4Synthesis of amides using 3a. Reaction conditions: (a) 3a (1.5 equiv.), aniline (1 equiv.), anisaldehyde (1 equiv.), cyclohexyl isocyanate (1 equiv.) in ethanol at rt for 48 h; (b) 3a (1.0 equiv.), SOCl₂ (1.5 equiv.), NH₄OH (37%, 2 mL) in THF for 2 h; (c) 3a (1.0 equiv.), PCl₅ (1.2 equiv.), pyridine (6 equiv.), 8-aminoquinoline (1.2 equiv.) in DCM for 5 h.Open in a separate windowScheme 5Utilization of 3a for establishing ester linkages.A plausible reaction mechanism has been proposed for hydroxycarbonylation of 2-iodoglycals (Scheme 6). Initially Pd(0) is generated in situ in the presence of ligand Ln. The catalytic cycle then starts with oxidative addition of Pd(0) to 2-iodoglycal A which produces the pallado complex B.Open in a separate windowScheme 6Plausible mechanism of hydroxycarbonylation reaction.Coordination and insertion of carbon monoxide generated in situ by the combination of DCC and formic acid leads to the formation of acyl Pd(ii) complex C. Formic acid attack on complex Cvia transmetallation affords the intermediate D with release of HI. Pd(0) could be regenerated for the next catalytic cycle after reductive elimination from complex D with formation of anhydride E. Decomposition of the anhydride with release of one molecule of CO generates the desired sugar acid F.In conclusion we have developed an efficient and mild Pd catalysed synthetic strategy for hydroxycarbonylation of 2-iodoglycals using the cheap reagent formic acid as CO source and 1 equiv. of DCC as an activator. The methodology was successfully extended to various glycals with different protecting groups like acetonide, ether, ester and silicon based ones. 2-Formyl glycals were also synthesised by using reductive carbonylation approach. The synthesised sugar acid could be used in the synthesis of glycoconjugates, pseudodisaccharides, for aryl ester and thioester.     

DBU mediated one-pot synthesis of triazolo triazines via Dimroth type rearrangement

Herein we report an efficient one-pot synthesis of [1,2,4]triazolo[1,5 a][1,3,5]triazines from commercially available substituted aryl/heteroaryl aldehydes and substituted 2-hydrazinyl-1,3,5-triazines via N-bromosuccinimide (NBS) mediated oxidative C–N bond formation. Isomerisation of [1,2,4]triazolo[4,3-a][1,3,5]triazines to [1,2,4]triazolo[1,5-a][1,3,5]triazines is driven by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) affording both isomers with good to excellent yields (70–96%).

We demonstrate a simple yet efficient one-pot synthesis of two triazolotriazine isomers via DBU mediated Dimroth type rearrangement with excellent yields.

Purines are nitrogen-containing heterocycles and are structural motifs in the nucleobases adenine and guanine of DNA as well as RNA. Purine nucleotides (ATP, GTP, cAMP, cGMP, NAD, FAD) also act as co-factors, substrates, or mediators in the functioning of numerous proteins.¹ Therefore, bioisosteres of purines are widely explored and exploited by pharmaceutical chemists in developing new drug entities. Heterocycles containig the 1,3,5-triazine ring act as bioisosteres of purine, which exist as two isomers, namely [1,2,4]triazolo[4,3-a][1,3,5]triazine and [1,2,4]triazolo[1,5-a][1,3,5]triazine (Fig. 1), which have been extensively studied as adenosine receptor antagonists,^2,3 as well as for other pharmacological activities^1,4,5 (Fig. 2). Literature reports suggest that [1,2,4]triazolo[1,5-a][1,3,5]triazine has been exploited extensively in drug discovery as compared to its corresponding isomer. Further, from the literature it is evident that symmetrical disubstituted triazines,^6–9 especially morpholine^10–12 substituted, have displayed broad pharmacological activities.Open in a separate windowFig. 1Structure of isomers of triazolo–triazine.Open in a separate windowFig. 2Biologically active molecules of [1,2,4]triazolo[4,3-a][1,3,5]triazine (1) and [1,2,4]triazolo[1,5-a][1,3,5]triazine (2, 3, 4).Various synthetic methods have been reported for the C–N bond formation by employing different starting materials^13–15via oxidative cyclisation,¹⁶ high temperature condition^17–19 and/or metal-catalysed reactions.²⁰ However, the current reported protocols were environmentally unfriendly as they suffered from drawbacks such as, multistep, and tedious procedures, use of carcinogenic solvents, high-temperature, expensive and toxic metal-catalysts, and other hazardous reagents.Furthermore, there is very less reported research on these heterocycles, and that can be because of the unavailability of the efficient and cheaper methods. Thus, there is a need to develop new versatile synthetic method for the synthesis of disubstituted triazolotriazine heterocycles of pharmacological interest.In 1970, for the first time Kobe²¹et al. (scheme a) reported the synthesis of [1,2,4]triazolo[4,3-a][1,3,5]triazine utilizing lead tetraacetate in benzene under reflux conditions (Fig. 3). However, no further Isomerization was carried out and resulted low to moderate yield. Deshpande²²et al. reported (scheme b) the reaction of 2-hydrazinyl-1,3,5-triazine with various substituted benzoic acids. The product formed was treated with P₂O₅, refluxed in xylene for 10h to yield [1,2,4]triazolo[4,3-a][1,3,5]triazine. Further, Isomerization of the resulting product was carried out in 2% methanolic-NaOH solution resulting in poor yields. Recently, Stefano²³et al. (scheme c) reported, a multistep protocol by reacting the intermediate with bis(methyl-sulfanyl)methylenecyanamide at 180 °C under N₂ for 3h resulting in low yield due to the formation of several side products. In addition no isomerization studies were carried out, and only the [1,2,4]triazolo[1,5-a][1,3,5]triazine analogs were reported.Open in a separate windowFig. 3Different approaches for the synthesis of triazolo triazines.Herein, we report an economical one-pot synthesis of [1,2,4]triazolo[1,5-a][1,3,5]triazine analogs via Dimroth type rearrangement of [1,2,4]triazolo[4,3-a][1,3,5]triazine derivatives. This one pot novel methodology was carried out by reacting readily available, inexpensive starting materials such as substituted aryl/heteroaryl benzaldehydes and substituted 2-hydrazinyl-1,3,5-triazine in methanol (a mild solvent)²⁴ at room temperature giving excellent yields of the desired product. For cyclization reaction, an eco-friendly reagent NBS²⁵ was used and the resulting product was treated with DBU to yield its corresponding desired isomer. To the best of our knowledge this is the first report for the greener synthesis of symmetric disubstituted triazolotriazine heterocycles via Dimroth type rearrangement. We believe that this simple, yet novel methodology could be further exploited by the researchers in pharmaceutical industries and academics settings in drug discovery.Formation of the Schiff base was initiated reacting 4,4′-(6-hydrazinyl-1,3,5-triazine-2,4-diyl)dimorpholine 1a and unsubstituted benzaldehyde as shown in Entry no.SolventOxidantBaseBase equiv.Time (hour)Yield%1EtOHNBSDBU1.016682DCMNBSDBU1.01603DMFNBSDBU1.01604MeOHNBSDBU1.016725i-PrOHNBSDBU1.016Trace6H₂ONBSDBU1.01607MeOHNBS——1608MeOHNBS2%NaOH1.016Trace9MeOHNBSK₂CO₃1.016010MeOHNBSTEA1.016011MeOHNBSDABCO1.016012MeOHNBSDBU1.528513MeOHNBSDBU2.01.58014MeOHNCSDBU1.525615MeOHNISDBU1.526116MeOHIBDDBU1.526317MeOHKI/I₂DBU1.525318MeOH/H₂ONBSDBU1.5270Open in a separate window^aConditions: 1a (1 mmol), benzaldehyde (1 mmol), solvent, rt, 20 min, then oxidant (1 mmol), 5 min, rt, then DBU, stir at rt till completion of the reaction.Meanwhile, equivalents of DBU were adjusted (entry 12, 13) to attain the highest yield %. Reaction with 1.5 eq. showed drastic improvement in yields in 2 h whereas 2.0 eq. resulted in good yields with less reaction time. Considering the yield factor (entry 12), the oxidant optimization was achieved (entry 14–17). Using N-chlorosuccinimide (NCS) and N-iodosuccinimide (NIS) (entry 14, 15) offered 56% and 61% yield respectively. When the reaction was performed using phenyliodine(iii) diacetate (PIDA) and KI/I₂ (entry 16, 17) it provided 2a in 63% and 53% yields, respectively. Finally, methanol–water and ethanol–water systems in 3 : 1 were used, which gave approximately 70% yield, concluding that entry 12 gives the best result, demanding alcoholic solvents especially methanol as a key factor for Dimroth type rearrangement. Additionally, it was supported by the observation that reaction goes well in methanol, a little worse in ethanol (Fig. 4. The reaction involves a Schiff base formation (II) by 1a and benzaldehydes, the addition of NBS results in oxidative cyclization reaction to produce isomer 1. The addition of DBU in isomer-1 initiates a famous Dimroth type rearrangement, protonation of III results in ring-opening with the formation of unstable intermediate V. It undergoes tautomerism by 1,3 proton shift, bond rotation and proton abstraction by methoxide ion facilitating the intramolecular cyclization to afford the isomer 2. This reaction mechanism is supported by the formation of the Schiff base, isomer-1, and its conversion to isomer-2, which were easily monitored by TLC, isolated, and characterized (ESI^†). In addition to that, a single crystal of compound 2e was obtained, which further supports the Dimorth type of rearrangement (ESI^†).Open in a separate windowFig. 4Plausible mechanism of the reaction pathway.Having in hand the optimized conditions, the substrate scope was further explored by using different aldehydes (Fig. 5). The reaction was carried out using 1a with benzaldehydes having electron-donating groups (2a-f) followed by NBS and DBU additions. The reaction was allowed to stir at room temperature till reaction completion, as monitored by TLC, which would approximately take 2 h. The reaction could smoothly give final products in excellent reaction yields (79 to 96%). Electron withdrawing groups such as chlorobenzaldehydes (2g-i) despite the position of substitution gave excellent yields (93–95%). With the 4-bromo and different fluoro-benzaldehydes, the reaction resulted in 2j (89%) and 2k-m (84–90%) with very good yields. Also, reaction afforded 70% and 77% yields with heterocyclic aldehydes such as 3-pyridinecarboxyaldehyde (2n) and thiophene-2-carbaldehyde (2o), respectively.Open in a separate windowFig. 5Substrate scope for different aldehydes.The gram scale reaction was performed to further validate this synthetic procedure. The reaction was carried out using 1a (1 g) with benzaldehyde (0.38 g) and stirred for 30 min. The NBS (1.26 g, 1 eq.) was added slowly and stirred till new spot appeared on TLC followed by the slow addition of DBU (1.5 eq.) resulted in isomerisation to give 2a in good yields (1.1 g, 84%) (ESI^†).Encouraged from the potency of the reaction to generate in good to excellent yields [1,2,4]triazolo[1,5-a][1,3,5]triazine analogues, we shifted our investigation to isolate [1,2,4]triazolo[4,3-a][1,3,5]triazine derivatives (isomer-1) as described in Fig. 6. Different aldehydes were reacted with hydrazinyl-1,3,5-triazine analogs (1a, 3a, and 4a) and followed by the addition of NBS, stirred at room temperature till the completion of reaction as monitored by TLC. Compound 1a on reaction with 4-bromobenzaldehyde and NBS resulted in 1b with 90% yield. Similarly, 3a with 4-bromobenzaldehydes and thiophene-2-carbaldehyde afforded 3b and 3c with 84% and 83% yields, respectively. The same reaction was carried out with 4a and 4-bromobenzaldehyde bearing an electron-withdrawing group gave 3d with 87% yield. Further, 4a with aldehydes bearing electron-donating groups resulted 4c and 4d, with 88% and 84% yields, respectively (Fig. 7).Open in a separate windowFig. 6Substrate scope for [1,2,4]triazolo[4,3-a][1,3,5]triazine analogues.Open in a separate windowFig. 7Substrate scope for different disubstituted triazinyl-hydrazine and aldehydes.With these promising results, we explored the scope of aldehydes and 2-hydrazinyl-1,3,5-triazine analogs for the synthesis of [1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives. Compound 3a, when reacted with different aldehydes and employing the optimized protocols gave 5a-e with excellent yields (86–92%) in 2–4 h. Similarly compounds 6a, 6b and 6c, synthesized from 4a also afforded excellent yields 88%, 86% and 90% respectively. Further, substituted cinnamaldehydes were also explored and reacted with 1a followed by the addition of NBS and DBU resulted in 7a and 7b in appreciable yields of 84% and 82%, respectively.Finally, we investigated both the isomers (3b and 5d) spectroscopically, to elucidate the change in proton chemical shifts during rearrangement. Interestingly, it was observed that the proton chemical shift for 5d at the 7th position (Fig. 6) was not affected. However, 5th position of 5d suffers a downfield shift due to change in its electronic environment as compared to its corresponding isomer 3b. In general, the proton chemical shifts for the substitution at 5th position and for the aromatic region was found to be more for isomer-2 as compared to isomer-1.     

Ligand-free Pd/Ag-mediated dehydrogenative alkynylation of imidazole derivatives

A variety of 2-alkynyl(benzo)imidazoles have been synthesized by dehydrogenative alkynylation of (benzo)imidazoles with terminal alkyne in NMP under air in the presence of Ag₂CO₃ as the oxidant and Pd(OAc)₂ as the catalyst precursor. The data obtained in this study support a reaction mechanism involving a non-concerted metalation deprotonation (n-CMD) pathway.

The regioselective synthesis of 2-alkynyl(benz)imidazoles was successfully achieved by Pd(ii)/Ag(i)-mediated dehydrogenative alkynylation of the corresponding (benz)imidazoles with terminal alkynes in an open vessel.

The development of synthetic protocols that enable the direct and selective functionalization of C_sp²–H bonds are of primary importance in the decoration of the imidazole scaffold.^1–10 The presence of two nitrogen atoms in the pentatomic structure of this important azole in fact introduces a differentiation in the chemical behaviour of the three C–H bonds, allowing their selective involvement in carbon–carbon bond-forming reactions as long as appropriate experimental conditions are identified.During our studies dedicated to the synthesis and investigation of azole-based fluorophores featuring a π-conjugated backbone end-capped with electron-donating (EDG) and electron-acceptor (EWG) groups (the so-called “push–pull” systems),^11–15 taking into account the structural characteristics and synthetic versatility of a triple carbon–carbon bond^16–23 that make it an excellent π-spacer, we recently decided to evaluate the possibility of obtaining alkynyl-substituted imidazoles by transition metal-catalyzed C_sp²–C_sp bond-forming reactions. Among the synthetic procedures that allow the selective alkynylation of imidazoles and other five-membered heteroarenes,^5,24 there is no doubt that the possibility of forming the new σ carbon–carbon bond through the double activation of two distinct carbon–hydrogen bonds through a cross-dehydrogenative alkynylation (CDA) represents the best synthetic approach in terms of atom economy and functional group tolerance (eqn (1), Scheme 1).^25–34 In fact, when compared with the transition metal-catalyzed direct C_sp²–H alkynylation protocols involving 1-haloalkynes (the so-called “inverse Sonogashira coupling”) (eqn (2), Scheme 1),^35–45 hypervalent iodine reagents (eqn (3), Scheme 1),^46–48 or α,β-ynoic acids (decarboxylative direct arylation) (eqn (4), Scheme 1),^26,49,50 the CDA methodology makes it possible to use terminal alkynes without the need for preliminary activation.^5,24Open in a separate windowScheme 1Synthetic protocols for the transition metal-catalyzed C_sp²–H alkynylation of heteroarenes.Despite several papers having been dedicated to the dehydrogenative alkynylation of pyrroles,²⁷ indoles,^27,31 oxazoles,^{27,30,32–34} benzoxazoles,^{26,29,30,32,34} thiazoles,^27,30 benzothiazoles,^{26,29,31,32,34} pyrazoles,^25,27 1,3,4-oxadiazoles,³³ imidazopyridines,^27,34 and N-substituted sydnones,²⁸ to the best of our knowledge a study specifically devoted to the dehydrogenative alkynylation of imidazoles has never been reported. However, careful reading the literature where alkynylation reactions involving azoles other than imidazole were described, it emerged that two papers reported the C-2 alkynylation of N-benzylimidazole and N-benzylbenzimidazole with phenylacetylene. In a study mainly devoted to the dehydrogenative alkynylation of imidazo[1,5-a]pyridine, Shihabara, Dohke and Murai employed the commercially unavailable Pd(ii) complex bi(4-nitropyridinyl)Pd(OAc)₂, Ag₂CO₃ as the oxidant and AcOH as additive, in a 95 : 5 mixture of DMF and DMSO for 2 h at 120 °C under argon.³⁴ Due to the propensity of alkynes to give Glaser-type homocoupling side-products in the presence of silver(i) salts,⁵¹ phenylacetylene was slowly added over 90 min to the reaction mixture. In 2015, Likhar, Kantam and co-workers used a synthetic Pd(ii) carbene complex. In this case Ag₂O was used as the oxidant, Cs₂CO₃ base, performing the coupling in DMF at 85 °C under air.²⁶Encouraged by these results but with the intention of developing a simplified procedure that would allow the use of a commercial Pd(ii) pre-catalyst in the absence of any palladium ligands, we decided to review the conditions of reaction and, in this work, we are pleased to summarize the results obtained in the synthesis of 2-alkynylimidazole derivatives by dehydrogenative alkynylation with terminal alkynes (Scheme 2). In particular, a careful screening allowed us to show how the reactivity of C_sp²–H bond of imidazole derivatives and other azoles can be enhanced simply by performing the alkynylation using NMP as the reaction solvent, under air in non-anhydrous conditions, and without the need for palladium ligands.Open in a separate windowScheme 2Pd/Ag-Promoted dehydrogenative alkynylation of imidazole derivatives.We decided to start our synthetic investigations by trying a cross-dehydrogenative coupling between N-methylbenzimidazole (1) and phenylacetylene (2a), chosen as typical coupling partners, under conditions very similar to those proposed by Murai and co-workers for the regioselective C-3 dehydrogenative alkynylation of 1-alkynyl-3-arylimidazo[1,5-a]-pyridines.³⁴Hence, to a mixture of 1.0 mmol 1, 5 mol% Pd(OAc)₂, 1.5 equiv. Ag₂CO₃, and 1.0 equiv. AcOH in a 95 : 5 (v/v) mixture of DMF and DMSO under argon 3.0 equiv. of 2a were added dropwise over 90 min. However, after 2 h at 120 °C a 56% GLC conversion of 1 was recorded, and the required 2-phenylethynyl-N-methylbenzimidazole (3a) was obtained in only 34% GLC yield (entry 1, EntryPd cat. (mol%)Ag(i) salt (equiv.)RCOOHSolventTemp./react. time^b (°C/h)1 GLC conversion^c (%)3a GLC yield^d (%)3a:4 AP%1^ePd(OAc)₂ (5)Ag₂CO₃ (1.5)AcOHDMF/DMSO (95 : 5)120/2563457 : 432Pd(OAc)₂ (5)Ag₂CO₃ (1.5)AcOHDMF/DMSO (95 : 5)100/5.5676632 : 683Pd(OAc)₂ (5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/2737034 : 664Pd(OAc)₂ (5)—AcOHDMF/DMSO (95 : 5)100/3.5NR——5Pd₂(dba)₃ (2.5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5736930 : 706Pd(acac)₂ (5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5676327 : 737PdCl₂ (5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5726835 : 658Pd(OAc)₂ (5)Ag₂CO₃ (2.0)—DMF/DMSO (95 : 5)100/3.5532372 : 289Pd(OAc)₂ (5)Ag₂CO₃ (2.0)—AcOH100/3.50—0 : 10010Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5766930 : 7011Pd(OAc)₂ (2.5)AgOAc (2.0)AcOHDMF/DMSO (95 : 5)100/3.5554825 : 7512Pd(OAc)₂ (2.5)Ag₂O (2.0)AcOHDMF/DMSO (95 : 5)100/3.5666228 : 7213Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)EtCOOHDMF/DMSO (95 : 5)100/3.5807135 : 6514Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)PivOHDMF/DMSO (95 : 5)100/3.5454522 : 7815Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)80/3.5434017 : 8316Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMF100/3.5757034 : 6617Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMA100/3.58175(68)33 : 67 18 Pd(OAc) ₂ (2.5) Ag ₂ CO ₃ (2.0) AcOH NMP 100/3.5 85 81(69) 36 : 64 19^fPd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHNMP100/3.58266(51)40 : 6020^gPd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHNMP100/3.5838036 : 64Open in a separate window^aReaction conditions: 2a (3.0 mmol) in the selected solvent (2.0 mL) was added dropwise over 45 min to a mixture of 1 (1.0 mmol), Pd cat., Ag(i) salt, RCOOH (1.0 mmol) in the selected solvent (2.0 mL) under air, unless otherwise reported.^bAfter the reported reaction time the GLC conversion of 2a was quantitative.^cGLC conversion of 1vs. biphenyl.^dGLC yield vs. biphenyl. In parentheses isolated yield.^eThis reaction was carried out under an argon atmosphere.^fThis reaction was carried out on a 10 mmol scale.^gThis reaction was carried out in the presence of TEMPO (1.0 equiv.) as radical scavenger.Taking note of this unexpected negative result, we decided to re-examine the reaction conditions, starting from the consideration that even if Ag₂CO₃ can theoretically serve as the oxidant, run the reaction in air (open flask) may be critical.²⁸ Gratifyingly, when the coupling was performed under air there was a marked increase in GLC yield, which went from 34% to 66% (entry 2, i) salts different from Ag₂CO₃ gave slightly worse results (entries 11 and 12, 31 the use of the right buffer system may be crucial for the deprotonation of the terminal alkyne, and also for the reoxidation of Pd(0) to Pd(ii).With our delight the chemical yield went up to 69% when the DMF/DMSO mixture was replaced by NMP (entry 18, 34 it should be highlighted that the slow addition of phenylacetylene never avoided in our hands the formation of Glaser side-product 4.Finally, when the reaction was performed in the presence of 1.0 equiv. of TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl as radical scavenger, it still proceeded smoothly to afford 2-alkynylazole 3a in 80% GLC yield (entry 20, Scheme 3).Open in a separate windowScheme 3Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 1-methylimidazole 5 or 1-methylbenzimidazole 1 with terminal alkynes 2a–h.Noteworthy, the reaction outcome was not influenced by the electronic nature of the aromatic moiety on the terminal alkyne. More importantly, several functional groups on the phenyl ring resulted well tolerated, including formyl and hydroxy groups that are potentially sensitive to the oxidative conditions required by dehydrogenative couplings.While good results were obtained when arylacetylenes were used as coupling partners, worse results were observed when TIPS-acetylene 2i or 1-octyne (2j) were reacted with 5. In fact, the expected 2-alkynyl substituted imidazoles 6i and 6j were isolated in 30% and 11% yields, respectively (Scheme 4).^25,31 The low reactivity of these two terminal alkynes in respect to their aryl analogues could be attributed, as already noted,³¹ to the decreased electrophilic nature of the corresponding alkynyl-palladium(ii) intermediates being generated during the reaction. As a further proof of their lower reactivity, the slow addition of 2i and 2j was found to be unnecessary.Open in a separate windowScheme 4Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 1-methylimidazole 5 with terminal alkynes 2i and 2j.Gratifyingly, the optimized Pd(OAc)₂/Ag₂CO₃-promoted coupling conditions proved to be useful also for the C-2 dehydrogenative alkynylation of 4,5-diphenyl-1-methylimidazole 7. In fact, this disubstituted azole gave the expected C-2 alkynylation product 8 in 70% isolated yield when reacted with phenylacetylene (2a) (Scheme 5).Open in a separate windowScheme 5Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 4,5-disubstituted 1-methylimidazole 7 or 9 with terminal alkynes 2a or 2d.One of the main advantages of dehydrogenative cross-coupling reactions is the tolerance, among others, of carbon–halogen bonds that, hence, are available for subsequent transformations. We were please to confirm this tolerance; in fact, 4,5-dibromo-1-methyl-1H-imidazole 9 was efficiently reacted with alkynes 2a and 2d, giving rise to the required 2-alkynyl-4,5-dibromoimidazoles 10a,b in 68 and 75% isolated yields, respectively (Scheme 5). Notably, no conventional Sonogashira-type coupling side-products were observed.Similar satisfactory yields were obtained when 1-benzyl- and 1-phenyl-1H-imidazoles 11 and 12 when reacted with 2a. The corresponding 2-phenylethynylimidazoles 13 and 14 were recovered in 68% and 52% isolated yields, respectively (Scheme 6). In contrast, the C-2 alkynylation of thiazole (15) and oxazole (16) with 2a gave the required products 17 and 18 in somewhat lower yields (48 and 42%, respectively). It is noteworthy, however, that the observed reactivity of 1-substituted imidazole 6, 11 and 12, i.e. 1-methyl > 1-benzyl > 1-phenyl, and that found for the three 1,3-azoles 6, 13 and 14, i.e. 1-methylimidazole > thiazole > oxazole, parallels that reported in the literature for classical SEAr.^52,53 As regards the regioselectivity, when the reaction involved 1-substituted imidazoles 5, 11, and 12, thiazole 15 and oxazole 16 a clean C-2 alkynylation was observed, while the corresponding C-5 or even the less probable C-4 alkynyl-substituted regioisomers were never detected in the crude reaction mixtures.⁵⁴ However, it is worth mentioning that when the alkynylation was tempted on 1,2-dimethyl-1H-imidazole 19, the C-5 alkynylated product 20 was obtained in 42% isolated yield (eqn (1)).1Open in a separate windowScheme 6Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 1-substituted imidazoles 5, 11, 12, thiazole (15), and oxazole (16) with phenylacetylene (2a).Based on earlier reports and our observations, a possible reaction mechanism for this Pd/Ag-promoted dehydrogenative alkynylation of imidazoles is summarized in Fig. 1, using 1-methylimidazole 5 as an example. Initial transmetallation involving a Pd(ii) complex and a (presumed) silver(i) acetylide generates the alkynyl Pd(ii) species A, which then affords the imidazole–Pd–alkyne complex E through a sequence of base-assisted carbanion generation from an azole–Pd complex (B → C), followed by a C-palladation step via carbene D. This particular C–H palladation mechanism, known as non-concerted metalation-deprotonation (n-CMD) pathway, was initially proposed by Hoarau and co-workers to justify the observed C-2 regioselectivity in the copper-free Pd-catalyzed direct arylation of oxa(thia)zoles-4-carboxylate with aryl bromides.^55–57Open in a separate windowFig. 1Proposed n-CMD mechanistic pathway for the Pd(OAc)₂/Ag₂CO₃-promoted dehydrogenative alkynylation of 1-methylimidazole 5.Although the comparison of the reactivity of 1-methylimidazole 5 with both the other two 1-substituted imidazoles 11 and 12, and with thiazole (15) and oxazole (16) suggested a SEAr mechanism (hence via a classic Wheland intermediate),^58–60 it should be noted that the most reactive position should have been C-5, and not the position C-2 that instead has the most acidic C–H bond. Similarly, a pure concerted metalation–deprotonation (CMD) pathway can reasonably be excluded considering that DFT calculations have shown that in the case of 1,3-azoles position C-5 is, again, the most reactive.⁶¹ The n-CMD mechanism hypothesizes that the deprotonation occurs through the formation of an azole–Pd(ii) complex and, therefore, justifies the observed reactivity by the most acidic C–H bond, i.e. the one in position 2 on the azole nucleus. On the other hand, one key step of this mechanism is the formation of N3–Pd complex C, which is the more effective the more the terminal alkyne is electron-poor (hence having the C_sp–H bond more acid). That the steps of the mechanism from A to E are certainly critical for the success of the reaction is also proved by the beneficial effect resulting from the slow addition of the terminal alkyne 2 to the reaction mixture. Finally, reductive elimination involving complex E gave the coupling product 6, and reoxidation of Pd(0) to Pd(ii) by Ag(i) or air closed the catalytic cycle.     

Alkyl coupling in tertiary amines as analog of Guerbet condensation reaction

We report here that C–C coupling in tertiary amines for the synthesis of long chain and hindered amines might be efficiently performed over Pt and Pd catalysts. The mechanism study confirms similarity with the Guerbet reaction through dehydrogenation of the alkyl group and subsequent attack of the α-carbon atom by an alkyl group of another molecule. Finally, secondary amines and tertiary amines with longer alkyl chains are formed.

C–C coupling in tertiary amines for the synthesis of fatty and hindered amines proceeds efficiently over supported Pt and Pd catalysts.

Tertiary amines are important products in the modern chemical industry. Usually applications of tertiary amines include quaternary derivatives, amine oxides and betaines which are used in household, industrial, and institutional cleaners and disinfectants, wood treatment, personal care, oil field, and water treatment end-use markets.¹Different methods have been reported for the synthesis of tertiary amines, for example, (1) reductive alkylation of aldehydes with secondary amines over metal catalysts,² (2) N-alkylation of amines or nitroarenes with alkylhalides or alcohols,³ (3) hydroamination of olefins with amines⁴ and (4) amination of arylhalides.⁵ The main disadvantage of these routes is complex multistep processes and environmental pollution due to the usage of aggressive chemicals like halides. At the same time, these methods often provide low selectivities to desired tertiary amines.There are several classes of tertiary amines, which are especially important. The linear tertiary amines containing alkyl chain between 6 and 20 carbon atoms with two other short chain alkyl or piperidine ring are the commonly referred to fatty tertiary amines which are used for the synthesis of surfactants.⁶ Hindered tertiary amines containing iso-alkyl groups is another important class of tertiary amines which is hard to produce.⁷ These amines are used as a non-nucleophilic base and as a stabilizer for polymers.⁸The problem of increase of the chain length for alcohols and synthesis of isomerized alcohols have been solved by Marcel Guerbet in 1899.⁹ The Guerbet reaction involves coupling of two (or more) alcohol molecules through intermediate aldehyde formation, aldol condensation, dehydration of aldol product and hydrogenation of allylic aldehyde. The reaction proceed over bifunctional catalysts containing usually Cu, Ni metal for dehydrogenation/hydrogenation and base sites like MgO for C–H bond activation and coupling reaction.¹⁰Depending on the types of used alcohols in the reaction like long chain or short chain branched or unbranched products could be formed, respectively.¹¹ This route would be an interesting opportunity for the synthesis of long chain or hindered amines. We have found that transformation of tertiary amines over Pd and Pt metallic catalyst proceed through C–C coupling with formation of heavier amines depending on the type of used tertiary amine.The transformation of non-symmetric tertiary amines over Pd black has been described in 1978 by Murahashi et al.¹² The authors observed fast exchange of alkyls with formation of the mixture of tertiary amines. The reaction has been explained by insertion of palladium into a carbon–hydrogen bond adjacent to the nitrogen, leading to a highly active intermediate complex of an iminium ion. Afterwards a lot of reports have been devoted to C–C coupling of tertiary amines with different compounds like acrylates¹³ and alkynes¹⁴ usually activated by electro and photo-energy.¹⁵ The self-alkylation of triethylamine over noble metal catalysts in CO atmosphere has been described in the patent,¹⁶ however, no mechanism or further applications have been proposed. As far as we know, there are no scientific studies devoted to C–C coupling between tertiary amines. The reaction proceed by transfer of alkyl group from one molecule to another with formation of new C–C bond and increase of the chain length in one tertiary amine and formation of secondary amine from another molecule (Fig. 1).Open in a separate windowFig. 1Scheme of alkyl coupling of tertiary amines.Triethylamine (TEA) has been chosen as a model reagent for the reaction like ethanol in Guerbet reaction. †Catalytic results of transformation of TEA over different catalysts (2 g TEA, p(N₂) = 5 bar, 0.1 g catalyst, 0.24 mol% Pd, 5 h)

Simple and efficient synthesis of bicyclic enol-carbamates: access to brabantamides and their analogues

A novel synthetic approach towards the formation of the unusual bicyclic enol-carbamates, as found in brabantamides A–C, is reported. The bicyclic oxazolidinone framework was obtained in very good yield and with high E/Z selectivity from a readily available β-ketoester under mild reaction conditions using Tf₂O and 2-chloropyridine tandem. The major E isomer was used in the synthesis of the brabantamide A analogue.

A simple and short synthesis of bicyclic enol-carbamates with high E/Z selectivity and the synthesis of brabantamide A analogue are presented.

Brabantamides A–C (1–3) (Fig. 1) were first isolated in 2000 from the culture extracts of Pseudomonas fluorescens.¹ They displayed nanomolar inhibitory activity towards lipoprotein-associated phospholipase A₂ (Lp-PLA₂) and therefore they could be used in the treatment of the inflammatory diseases such as atherosclerosis.^1–3 It was found that the sugar moiety is not necessary for the biological activity against Lp-PLA₂. In contrast, deglycosylated brabantamides A and C showed improved inhibitory activity compared to their natural counterparts.³ Moreover, simplified brabantamide analogues with amide functional group and long alkyl side chains showed even higher inhibitory effect.⁴ Brabantamides A–C also exhibit significant activity against Gram-positive bacteria, fungi, and oomycetes.^5,6 A recent study confirmed that the bicyclic scaffold and the long lipophilic side chain are essential for the antibacterial activity.⁷Open in a separate windowFig. 1Structures of brabantamides A–C (1–3). Rha = rhamnose.Surprisingly, only five reports concerning the synthesis of the bicyclic oxazolidinone with an exocyclic double bond have been reported to date.In 2000, Pinto et al. prepared a series of analogues of brabantamide A where the enol-carbamate 5 was first obtained by direct iodocyclization from acetylene derivative 4 and then converted into key ester 6 by carbonylation of the corresponding vinyl iodide in the presence of 2-(trimethylsilyl)ethanol and PdCl₂ (Scheme 1a).⁴ Another synthesis of the related esters 9 has been reported by Snider et al. in 2006, employing Wittig reaction between stabilized ylides and bicyclic oxazolidindione 8 synthesized from l-proline 7 (Scheme 1b).⁸ Shortly after, bicyclic enol-carbamate 10 with an exocyclic methylene group was synthesized in one step from acetylene derivative 4 using gold(i) catalysts (Scheme 1c).⁹ Very recently, Witte et al. reported the synthesis of series of Z-analogues of brabantamides 12 by cyclization of β-ketoamides 11 using CDI (Scheme 1d).⁷ As a part of our ongoing research program aimed at the utilization of trifluoromethanesulfonic anhydride (Tf₂O)/2-halopyridine (2-XPy) tandem in the synthesis of bioactive natural products and their analogues, we envisioned that similar reaction conditions could be effectively used to form the bicyclic oxazolidinone framework as found in brabantamides.Open in a separate windowScheme 1Literature syntheses of bicyclic enol-carbamates and method proposed herein.The combination of Tf₂O/2-XPy was extensively and successfully used in the amide activation^10,11 as well as in generating isocyanate species from N-Boc and N-Cbz protected amines.¹² We anticipated that the N-Boc-protected β-ketoester 13 could react in its enolate form with in situ generated isocyanate ion by intramolecular 5-endo-dig cyclization to give bicyclic enol-cyclocarbamate 14 (Scheme 1e).At the start of our investigation, model β-ketoester 15, prepared from N-Boc-l-proline,⁷ was chosen as the model substrate to identify optimal reaction conditions (12c the initial using of 1.5 equivalents of Tf₂O and 3 equivalents of 2-ClPy led to a full conversion of the substrate 15 in 15 minutes (monitored by TLC) (13 Any variation of the amount of 2-ClPy did not have any positive impact on the reaction ( EntryTf₂OBaseTime (min)16a : 16b^aYield^b (%)11.5—60—–^c21.5Et₃N60—–^c31.5DMAP60—–^c41.5Pyridine60—–^c51.5^d2,6-Lutidine60—–^c61.5^dDBU6090 : 1041^e,f71.52-ClPy1593 : 753^e 8 1.1 2-ClPy 15 85 : 15 80 ^e 91.12-ClPy (1.5 equiv.)4085 : 1575^e101.12-ClPy (5 equiv.)1587 : 1364^e111.12-FPy1589 : 1171^e121.12-BrPy7086 : 1473^e131.12-IPy9086 : 1468^e14Witte''s protocol^gOvernight50 : 5036^eOpen in a separate window^aRatio determined by ¹H NMR of the crude reaction mixture.^bIsolated combined yield.^cTraces of products.^dReactions performed with 1.1 equiv. of Tf₂O did not lead to full conversion of ester 15.^eReactions were performed on 1 mmol of ester 15.^fReaction mixture contained a large amount of unidentified by-products.^gReaction conditions: (1) TMSOTf (2 equiv.), CH₂Cl₂, 0 °C, 1 h. (2) CDI (1.5 equiv.), CH₂Cl₂, 0 °C – rt, overnight.⁷It is noteworthy that the reaction can be performed on a gram scale without affecting the yield and both isomers are easily separable by FCC (see the ESI^†).The ¹H and ¹³C NMR data of the major E isomer 16a were consistent with those published previously.⁸ Possible racemization in the course of the reaction was dismissed based on the comparing specific optical rotation with the published data for 16a ([α]²²_D = −261.1 (c 1.01, MeOH); ref. 8: [α]²²_D = −207 (c 1.0, MeOH)). Most importantly, X-ray crystallographic analysis of 16a (Fig. 2; see the ESI^† for further details)¹⁴ confirmed its absolute configuration on the C-7a carbon atom.Open in a separate windowFig. 2Molecular structure of the enol-carbamate E-16a confirmed by X-ray crystallographic analysis.The minor Z isomer 16b was isolated for the first time as the pure compound and was fully characterized. Its structure was assigned on the basis of its ¹H, ¹³C, COSY, HSQC, and HMBC NMR spectra.A plausible mechanism of the cyclization of β-ketoester 15 was based upon previous works^12a–c and it is depicted in Scheme 2. Isocyanate cation II, as a key intermediate, can be formed directly from iminium triflate I (path A) or through the formation of carbamoyl triflate III with subsequent elimination of triflate ion spontaneously (path B). Ester enolate moiety IV then reacts as O-nucleophile via 5-endo-dig cyclization and leads predominantly to the formation of the enol-carbamate 16a.Open in a separate windowScheme 2Plausible mechanism of the cyclization β-ketoester 15.Next, the optimized conditions were briefly applied in the synthesis of the brabantamide A analogue 21 (Scheme 3). Starting β-ketoester 18 was synthetized in two steps in a 70% yield using both commercially available N-Boc-d-proline 17 and 2-(trimethylsilyl)ethanol. It ought to be mentioned that previously examined hydrolysis of the corresponding methyl ester 16a under acidic as well as basic conditions failed due to the instability of the bicyclic enol-carbamate.^3,8Open in a separate windowScheme 3Synthesis of the brabantamide A analogue 21.Subsequent cyclization of ester 18 using optimized reaction conditions afforded enol-carbamate 19 in 76% yield as a mixture of E and Z isomers in a ratio of 89 : 11. After isolation of the major isomer E-19a, it was treated with TBAF, providing free acid 20 in 89% yield. Finally, an amidation of 20 with tetradecylamine in the presence of EDCI gave amide 21 in moderate 40% yield. Both free acid 20 and amide 21 were fully characterized for the first time and their structures were assigned on the basis of its ¹H, ¹³C, COSY, HSQC, and HMBC NMR spectra. Moreover, their structures were unambiguously confirmed by X-ray crystallographic analysis (Fig. 3; see ESI^† for further details).¹⁴Open in a separate windowFig. 3Molecular structures of acid 20 (top) and amide 21 (bottom) confirmed by X-ray crystallographic analysis.     

Catalytic enantioselective bromohydroxylation of cinnamyl alcohols

This work describes an effective enantioselective bromohydroxylation of cinnamyl alcohols with (DHQD)₂PHAL as the catalyst and H₂O as the nucleophile, providing a variety of corresponding optically active bromohydrins with up to 95% ee.

Optically active bromohydrins are obtained with up to 95% ee via asymmetric bromohydroxylation of cinnamyl alcohols with H₂O as nucleophile.

Electrophilic halogenation of olefins allows installation of two stereogenic centers onto the C–C double bond and is one of the most important transformations in organic chemistry.¹ Optically active halogen containing products resulting from asymmetric halogenation would serve as versatile chiral building blocks for organic synthesis. As a result, extensive efforts have been devoted to the development of asymmetric halogenation process. In recent years, great progress has been made in both intramolecular^2,3 and intermolecular^4,5 reaction processes with various types of olefins and nucleophiles. However, there are still challenges remaining to be addressed. In many cases, the developed catalytic systems often only apply to certain ranges of substrates and the reaction reactivity as well as selectivity can''t be rationally adjusted. The substrate scope is also often difficult to be logically extended and requires much experimentation, largely due to the complexity of the reaction systems and the lack of clear understanding of the reaction mechanisms.Halohydroxylation of olefins simply with H₂O as nucleophile is a classic electrophilic addition reaction in organic chemistry and produces synthetically useful halohydrins (Scheme 1). Asymmetric version of such process has been challenging with only a few reports.^6,7 As part of our general intertest in asymmetric halogenation,⁸ recently we have been investigating the intermolecular asymmetric reaction processes, particularly with unfunctionalized olefins, which has been a long standing challenging problem. During such studies, we have found that up to 92% ee could be achieved for the bromoesterification of unfunctionalized olefins with (DHQD)₂PHAL (Scheme 2, eqn (a)).⁹ This work represents an early example of asymmetric halogenation for unfunctionalized olefins with high enantioselectivity. To our delight, high enantioselectivity can also be achieved for bromohydroxylation with H₂O upon further investigation, giving optically active bromohydrins with up to 98% ee (Scheme 2, eqn (b)).¹⁰ In our efforts to expand the reaction scope of the asymmetric bromohydroxylation, we have found that cinnamyl alcohols are effective substrates, giving the corresponding bromohydrins with up to 95% ee. Herein, we report our preliminary studies on this subject.Open in a separate windowScheme 1Asymmetric halohydroxylation of olefins.Open in a separate windowScheme 2Asymmetric oxybromination of olefins.Initial studies were carried out with (E)-3-(4-bromophenyl)prop-2-en-1-ol (1a) as substrate. Several bromine reagents were examined with 10 mol% (DHQD)₂PHAL (3a) (Fig. 1) as the catalyst and 10 mol% (−)-camphorsulfonic acid (CSA) as additive in acetone/H₂O (10 : 1) at −30 °C (Open in a separate windowFig. 1Selected examples of catalyst examined.Studies on reaction conditions^a

Base mediated spirocyclization of quinazoline: one-step synthesis of spiro-isoindolinone dihydroquinazolinones

A novel approach for the spiro-isoindolinone dihydroquinazolinones has been demonstrated from 2-aminobenzamide and 2-cyanomethyl benzoate in the presence of KHMDS as a base to get moderate yields. The reaction has been screened in various bases followed by solvents and a gram scale reaction has also been executed under the given conditions. Based on the controlled experiments a plausible reaction mechanism has been proposed. Further the substrate scope of this reaction has also been studied.

A novel approach for the spiro-isoindolinone dihydroquinazolinones has been demonstrated from 2-aminobenzamide and 2-cyanomethyl benzoate in the presence of KHMDS as a base to get moderate yields.

Because of their strong potent biologically activity, heterocyclic compounds have been a constant source of inspiration for the invention of new drugs especially for pharmaceutical and agro chemical industries.¹ Indeed, investigation of novel methods for the synthesis of various natural products and heterocycles has always been a challenging task in modern organic chemistry. Amid all, spiro based scaffolds have been found to be very interesting because of their structural diversity. In spite of their intrinsic structures and immense biological activity there is a tremendous demand for the chemistry of spiro-isoindolinone dihydroquinazolinones.² Indeed, nitrogen containing heterocyclic compounds like spiro-oxindole, spiro-isoindoline, spiro-isoindolinone are playing a significant role in medicinal chemistry and synthetic transformations.³ Moreover these compounds present in many natural products as a core unit like Lennoxamine, Zopiclone, Taliscanine and Pazinaclone (Fig. 1). In addition, many unnatural spiro-isoindolinones show significant biological activities acting as anti HIV-1, antiviral, antileukemic, anesthetic and antihypertensive agents.^4,5 Notably, the spiro-isoindolinone dihydroquinazolinone unit has been found to be a combination of two potent pharmacophore units of dihydroquinazolinone and spiro-isoindolinone. Inspite of their remarkable biological activity afore mentioned, various methods have been developed for their synthesis like lithiation approaches, base mediated protocols, Diels–Alder and Wittig reactions, electrophilic and radical cyclization, metal-catalysed reactions and various electrochemical procedures.⁶Open in a separate windowFig. 1Some biologically active spiro-isoindolinone and quinazolinone units.Previously, a number of metal catalyzed reactions have also been reported for the spiroannulations.⁷ Among all, Nishimura et al. developed an Ir(i) catalyzed [3 + 2] annulation of benzosultam and N-acylketimines with 1,3-dienes via C–H activation for the synthesis of aminocyclopentene derivatives. Further, Xingwei Li et al. developed a Rh(iii)-catalysed [3 + 2] annulation of cyclic N-sulfonyl or N-acyl ketimines with activated alkenes for the preparation of various spirocyclic compounds.⁸ Recently Yangmin Ma et al. developed a one pot nano cerium oxide catalyzed synthesis of spiro-oxindole dihydroquinazolinone derivatives (Scheme 1).^5c However, development of these type of novel compounds is always challenging and more attractive. Indeed, to the best of our knowledge there are no reports for the synthesis of spiro-isoindolinone dihydroquinazolinones. This led us to give more attention to study these compounds.Open in a separate windowScheme 1Different strategies for the synthesis of quinazolinone units.In continuation of our earlier efforts⁹ for the synthesis of various dihydroquinazolinones, herein we would like to report KHMDS mediated synthesis of novel spiro-isoindolinone dihydroquinazolinones. We envisioned the retro synthetic pathway for these compounds, as depicted in Scheme 2. Accordingly these compounds could be synthesised from 2-aminobenzamide and methyl-2-cyanobenzoate or ethyl-2-cyanobenzoate.Open in a separate windowScheme 2Retro synthetic approach for the synthesis of quinazolinone unit.Indeed, in order to understand the reaction conditions, we have commenced the reaction by taking 2-amino-N-hexyl-benzamide (2) and methyl-2-cyanobenzoate (3) as a model substrates. However, in the initial phase of reaction optimisation, we have screened the reaction in different bases (Fig. 2) and to our delight amongst all the bases KHMDS, LiHMDS and NaHMDS were amenable to get moderate yields. However the reaction had not progressed at low temperatures (5 °C) and could improve the yield at room temperature. Moreover the reaction underwent complete conversion with 1.5 equivalents of base. Further, the reaction was also executed with ethyl-2-cyanobenzoate and could replicate the same yield. Incontinuation, the reaction was futile when the reaction was carried out in DIPEA, DBU, K₂CO₃ and Cs₂CO₃. Subsequently, the reaction in NaOMe and ^tBuOK produced exclusively the hydrolysis product (4) of methyl-2-cyanobenzoate (Open in a separate windowFig. 2Base screening in 1,4-dioxane.Optimisation of the base-mediated spiroannulation^a

A formal intermolecular [4 + 1] cycloaddition reaction of 3-chlorooxindole and o-quinone methides: a facile synthesis of spirocyclic oxindole scaffolds

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions. The products could be obtained in excellent yields with numerous types of 3-chlorooxindole. This methodology features mild reaction conditions, high atom-economy and broad substrate scope.

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions.

The structural diversity of spirocyclic oxindole scaffolds is a reason for their frequent occurrence in many relevant natural products and medicinal agents (Fig. 1).¹ In particular, natural spirocyclic-2-oxindole scaffolds have been proven to exhibit a broad range of biological activities and have attracted increasing attention in the synthetic field. For instance, XEN 907 is a novel pentacyclic spirooxindole with excellent activities as sodium channel blockers.² Due to their unique structure and intriguing biological activity, numerous methodologies have been developed for the construction of these privileged frameworks.³ For example, in the past few years, transition-metal catalyzed or organocatalytic [3 + 2] cycloaddition reactions have been developed for the synthesis of spirocyclic oxindole scaffolds.⁴ Despite the emergence of these elegant approaches, exploiting new strategies for the construction of spirocyclic oxindole derivatives is still highly desirable.Open in a separate windowFig. 1Examples of biologically active spirocyclic oxindole scaffolds. Ortho-quinone methides (o-QMs) as highly reactive versatile intermediates have been of great interest to the chemical and biological community.⁵o-QMs react with various classes of reagents by three typical reaction pathways: 1,4-addition of nucleophiles, [4 + 2] cycloaddition with dienophiles and oxa-6π-electrocyclization.⁶ Because most o-QMs are unstable, these reactions generally depend on the reaction conditions used for the generation of o-QMs in situ. Rokita et al. reported that o-silylated phenols when exposed to fluoride could also produce o-QMs under mild reaction conditions.⁷Because of the dual nature (nucleophilic/electrophilic) of the C-3 position, 3-chlorooxindole serves as a highly reactive starting material in the synthesis of spirocyclic oxindole scaffolds. The introduction of a chloro group at the C-3 position of indoles serves as an excellent leaving group in favour of the subsequent cyclization. In addition, this also increases the acidity of the C–H bond for directly entering the C-3 quaternary centers.⁸ Inspired by this reactivity profile, 3-chlorooxindoles have been successfully utilized for [2 + 1]⁹ and [4 + 1]¹⁰ cyclization to synthesize spirocyclic oxindole scaffolds (Fig. 2).Open in a separate windowFig. 2Representation of the synthesis and applications of 3-chlorooxindoles.We designed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindoles via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-QMs, which were generated under mild conditions. In this study, using TBAF as the fluoride source and base ensures that the one-pot domino reaction will occur in mild reaction conditions, with high atom-economy and broad substrate scope.Initially, we carried out optimization studies by examining the reaction between O-silylated phenol 2a and 3-chlorooxindole 1a. Indeed, when TBAF was employed as the fluoride source, a smooth [4 + 1] cyclization reaction occurred, affording the spirocyclic oxindole product 3a with 75% yield (entry 1, EntryF⁻ source X Y SolventTemp (°C)Yield^b1TBAF^c1.24.0DCMrt75%2TBAF1.54.0DCMrt87%3TBAF2.04.0DCMrt85%4CsF1.54.0DCMrt11%5TBAF1.53.0DCMrt80%6TBAF1.54.0CHCl₃rt83%7TBAF1.54.0THFrt94%8TBAF1.54.0Toluenert90%9TBAF1.54.0DMFrt72%10TBAF1.54.0MeCNrt84%11TBAF1.54.0MeOHrtNDOpen in a separate window^aReaction conditions: 1a (0.3 mmol), solvent (3.0 mL), 6 h.^bIsolated yield.^cTBAF (1 M in THF solution).With the optimal conditions known, we next investigated the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenol 2a as a representative ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2a (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.^bIsolated yields.Next, we also explored the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenols 2a′ ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2a′ (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.^bIsolated yields.On the basis of above-mentioned results, a plausible mechanism for this formal [4 + 1] cycloaddition reaction is depicted in Scheme 1. Initially, the highly reactive o-QMs are generated via the desilylation/elimination reaction. Then, 3-chlorooxindole 1a as a nucleophile attacks the external carbon of o-QMs, affording zwitterion Int-1. Finally, the zwitterion Int-1 loses one molecular HCl through a nucleophilic attack, yielding the spirocyclic oxindole product 3a.Open in a separate windowScheme 1Possible mechanism.     

Access to 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed C–H bond aminoimidoylation reaction from functionalized isocyanides

Efficient access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step under redox neutral conditions, employing O-benzoyl hydroxylamines as electrophilic amino sources.

Efficient and practice access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed.

As a class of cyclic amidine compounds, 1-amino-3,4-dihydroisoquinolines are essential six-membered heterocycles which can be found in numerous natural products, functional chemicals and pharmaceutical agents (Scheme 1).¹ For example, piperazine tethered dihydroisoquinoline and benzocyclic amide I was found to be an efficient cardiovascular agent.^1a Phenylalanine-derived and arylamine or cyclic aliphatic-amine-containing 1-amino-3,4-dihydroisoquinolines (II–V) show outstanding BACE-1 inhibition, kinase VEGFR-2 inhibition, phosphodiesterase IV inhibition and hydrogen ion-sodium exchanger NHE-3 inhibition activities, respectively.^1b–e Traditional preparation of such 1-amino-3,4-dihydroisoquinoline scaffolds is mainly based on nucleophilic substitution of readily prepared 3,4-dihydroisoquinolines² and Bischler-Napieralski reaction starting from urea.³ Most of these methods suffer from multiple-step synthesis, harsh conditions or the use of toxic reagents. Thus, developing an efficient and practical method for the construction of 1-amino-3,4-dihydroisoquinoline derivatives remain an attractive synthetic task.Open in a separate windowScheme 1(a) Representative bioactive molecules containing the 1-amino-3,4-dihydroisoquinoline moiety. (b) Traditional synthetic methods.In recent decades, isocyanides have been extensively studied in multicomponent reactions,⁴ imidoyl radical-involved transformations⁵ and transition-metal-catalyzed insertion reactions⁶ due to their diverse and unique reactivities. A variety of acyclic imine derivatives were synthesized via palladium-catalyzed imidoylation reactions.⁷ For the construction of biorelevant nitrogen-containing heterocycles via Pd-catalyzed non-functionalized isocyanide insertion reactions, a nucleophilic group is usually preinstalled to the substrates containing C–X (C–H) bonds, followed by Pd-catalyzed oxidative addition (C–H bond activation)/isocyanide insertion/ligand substitution/reductive elimination sequence.⁸ For example, Maes and coworkers developed an efficient palladium-catalyzed synthesis of 4-aminoquinazolines from N-(2-bromoaryl)amidines using amidine as an internal nucleophile.^8a Access to the same scaffold through palladium-catalyzed amidine-directed C–H bond imidoylation/cyclization reaction was reported by Zhu group.^8c Isocyanide acted as a C1 synthon in these cyclization reactions, with the terminal carbon of isocyanide being used in the ring formation.⁹ Considering the diversity of R group on the nitrogen atom of isocyanide, the so-called functionalized isocyanide strategy was widely developed as well, with various N-heterocycles such as oxazoles,¹⁰ indoles,¹¹ phenanthridines,¹² 9H-pyrido[3,4-b]indoles¹³ and nonaromatic azepines¹⁴ being synthesized efficiently. Zhu and coworkers developed the first asymmetric C–H bond imidoylation reaction from easily accessible α,α-dibenzyl-α-isocyanoacetates with chiral quaternary-carbon-containing 3,4-dihydroisoquinolines being generated (Scheme 2a).¹⁵ Recently, a catalytic system controlled regioselective C–H bond imidoylation was realized for the selective synthesis of 5 or 6-membered cyclic imines (Scheme 2b).¹⁶ Aryl halides were mostly used in these transformations while N–O compounds were rarely reported as electrophiles in Pd-catalyzed isocyanide insertion reactions.¹⁷ Zhu group reported the synthesis of phenanthridin-6-amine derivatives from O-benzoyl hydroxylamines and commonly used biaryl isocyanides.^17c However, a methyl or methoxyl carbonyl group was needed at the ortho position of isocyano group, which critically limited the application of the reaction. Herein, we developed an efficient and practical synthesis of 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation reaction of α-benzyl-α-isocyanoacetates. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds being constructed in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources.Open in a separate windowScheme 2Palladium-catalyzed imidoylative cyclization of α-benzyl-ethylacetates.The reaction conditions were optimized with ethyl 2-benzyl-2-isocyano-3-phenylpropanoate (1a) and morpholino benzoate (2a) as model substrates, and ethyl 3-benzyl-1-morpholino-3,4-dihydroisoquinoline-3-carboxylate (3a) was obtained in 34% yield in the presence of Pd(OAc)₂ (1.5 equiv.), PPh₃ (20 mol%), Cs₂CO₃ (1.0 equiv.) and PivOH (0.6 equiv.) in toluene at 80 °C (entry 1, EntryCatalystLigandSolventYield^b1Pd(OAc)₂PPh₃Toluene342Pd(OAc)₂PPh₃THFTrace3Pd(OAc)₂PPh₃DCE294Pd(OAc)₂PPh₃Dioxane765Pd(OAc)₂PPh₃MeCNTrace6Pd(OAc)₂PPh₃DMSOTrace7Pd(OPiv)₂PPh₃Dioxane318Pd(TFA)₂PPh₃Dioxane269PdCl₂(MeCN)₂PPh₃Dioxane3811Pd(PPh₃)₄Dioxane5612Pd(OAc)₂BINAPDioxane3013Pd(OAc)₂dppbDioxane2614Pd(OAc)₂dpppDioxane2815Pd(OAc)₂XantPhosDioxane4216Pd(OAc)₂SPhosDioxane3417Pd(OAc)₂XPhosDioxane2418^cPd(OAc)₂PPh₃Dioxane84 (80)^d19^cNonePPh₃Dioxane020^cPd(OAc)₂NoneDioxane5621^c,ePd(OAc)₂PPh₃Dioxane022^c,fPd(OAc)₂PPh₃Dioxane4123^c,gPd(OAc)₂PPh₃Dioxane2424^c,hPd(OAc)₂PPh₃Dioxane3125^c,iPd(OAc)₂PPh₃Dioxane61Open in a separate window^aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd-catalyst (0.01 mmol, 10 mol%), ligand (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 80 °C, Ar. A solution of 1a was added via a syringe pump within 1 h.^bNMR yield with 1-iodo-4-methoxybenzene as an internal standard.^c T = 110 °C.^dIsolated yield.^eWithout Cs₂CO₃ and PivOH.^fCsOPiv was used as the base.^gK₂CO₃ was used as the base.^hNa₂CO₃ was used as the base.ⁱ5 mol% of catalyst was used.With the optimized conditions in hand, the scope of functionalized isocyanide was investigated first, using morpholino benzoate 2a as the coupling partner (Scheme 3). Both electron rich and withdrawing substituents such as Me, t-Bu, F, Cl, CF₃, CO₂Me and NO₂ at the para position of aromatic ring can tolerate the reaction conditions, and generate the corresponding products in good to excellent yields (3a–3h). Isocyanides bearing ortho substituents on the phenyl ring underwent the reaction smoothly, generating the products 3i and 3j in 58% and 82% yields respectively. Even substrates bearing two substituents were well suited to the reaction conditions, affording the aminoimidoylation products without loss of efficiency (3k–3l). Compound 3m was delivered with excellent regioselectivity in 63% yield when m-Cl substituted starting material was employed in the reaction, which indicated the hindrance sensitivity of this reaction. Modifying the ester moiety in 1 to a methyl ester or an amide did not impede the reaction, giving 3n and 3o with excellent yields. Changing one of the benzyl groups to alkyl substituents didn''t decrease the reaction efficiency, generating products 3p and 3q in moderate yields.Open in a separate windowScheme 3Scope of isocyanides. Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1 was added via a syringe pump within 1 h. Isolated yields.Then we moved our attention to the investigation of substrate scope of aminating partners (Scheme 4). It was found that various O-benzoyl hydroxylamines derived from piperidines could be smoothly employed in the reaction (4a–4e). Substituents such as Me, CO₂Et, OMe and ketal group on the piperidines were well tolerated (4b–4e). Aminating reagent derived from Boc-protected piperazine was also compatible with this reaction, generating the product 4f in 99% yield. Fortunately, acyclic aminated product 4g was obtained as well in moderate yield.Open in a separate windowScheme 4Substrate scope of aminating agents. Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1a was added via a syringe pump within 1 h. Isolated yields.When ethyl 2-isocyano-2,3-diphenylpropanoate was conducted in the reaction with 2a, the 3,4-dihydroisoquinoline product 6 was generated exclusively, albeit in only 37% yield (Scheme 5a). To examine if isoindoline could be afforded by this aminoimidoylation reaction, ethyl 2-isocyano-4-methyl-2-phenylpentanoate (7) was selected as the substrate with 2a (Scheme 5b). However, no desired product was generated under the standard conditions, showing different site-selectivity with the previous imidoylation reaction developed by Zhu and coworkers.¹⁶Open in a separate windowScheme 5Reaction conditions: 5(7) (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 5(7) was added via a syringe pump within 1 h. Isolated yields.Gram-scale preparation of 3a was carried out smoothly under standard conditions (Scheme 6a). The reduction reaction of 3a was carried out using LiAlH₄ and the corresponding product 8 was generated in 70% yield (Scheme 6b). The ester group was successfully transformed to tertiary alcohol (9) in moderate yield with Grignard reagent.Open in a separate windowScheme 6Gram-scale preparation and diversifications of 3a.In order to get further insight into the reaction mechanism, a radical trapping reaction with 0.1 equivalents of TEMPO was carried out (Scheme 7a). The product 3a was generated without loss of efficiency, which indicated that the radical-involved pathway could be ruled out. A plausible mechanism was then proposed in Scheme 7b. The reaction was initiated with oxidative addition of O-benzoyl hydroxylamine 2a to the in situ generated Pd(0) species. Migratory isocyanide insertion to intermediate B afforded aminoimidoyl Pd(ii) intermediate C. The following intramolecular C–H bond activation and reductive elimination viaE yielded the final product 3a and regenerated Pd(0) to complete the catalytic cycle.Open in a separate windowScheme 7Proposed mechanism.In conclusion, we have developed an efficient and practical method to prepare 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates under redox-neutral conditions. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources. A broad range of substrates were applicable to the reaction in good to excellent yields.     

One-pot reductive amination of carbonyl compounds with nitro compounds over a Ni/NiO composite

Easily prepared Ni/NiO acts as a heterogeneous catalyst for the one-pot reductive amination of carbonyl compounds with nitroarenes to afford secondary amines with H₂ as a hydride source. This catalytic system does not require a special technique to avoid air-exposure, in contrast to the common heterogeneous Ni catalysts.

Easy-to-prepare Ni/NiO acts as an efficient heterogeneous catalyst for one-pot reductive amination of carbonyl compounds with nitroarenes.

Amines are among the most important organic compounds for the chemical, materials, pharmaceutical and agrochemical industries.¹ In particular, aromatic and heteroaromatic amines occupy a privileged position in medicinal chemistry,^1c,2 as exemplified in top-selling drugs such as atorvastatin, hydrochlorothiazide, furosemide and acetaminophen.³ The general methods to prepare aryl and heteroaryl amines are the reductive amination of carbonyl compounds,⁴ direct alkylation of amines with alkyl halides,⁵ Buchwald–Hartwig amination⁶ and Ullman-type C–N bond formation.⁷ These amination systems utilize aniline derivatives which are usually prepared in advance by hydrogenation of nitroarenes.⁸ Direct amine synthesis using nitroarenes is attractive because it eliminates the hydrogenation step, which saves time, energy and cost. Among the amination reactions, reductive amination has been actively investigated due to its high atom economy and ease of industrial application (Scheme 1);⁹ however, reductive amination has frequently been accompanied by unwanted side products due to the reduction of carbonyl compounds to alcohols and/or over-alkylation of product amines. One-pot reductive amination with nitro compounds has been achieved by precious metal catalysis.¹⁰ Recently, precious metal alloy nanoparticles were demonstrated to exhibit high catalytic performance for one-pot reductive amination with nitro compounds, even under mild reaction conditions.¹¹ In the context of economic efficiency and a ubiquitous element strategy, the replacement of precious metals with earth-abundant metals has gained much attention. Although some catalytic systems based on Fe,¹² Cu,¹³ Co ¹⁴ and Mo ¹⁵ have been reported using H₂ as a reductant, severe reaction conditions are typically required (Table S1, ESI^†). It is noteworthy that the nitrogen-doped carbon supported cobalt catalysts were reported to be active for one-pot reductive amination using nitroarenes using formic acid or CO/H₂O as a reductant though high temperature was required (Table S2, ESI^†).¹⁶Open in a separate windowScheme 1One-pot reductive amination using nitroarenes.To develop active catalysts for one-pot reductive amination using nitro compounds, we have focused on nickel catalysts, which are known as active catalysts for many transformation reactions.^17,18 The active species is typically metallic nickel, which is easily oxidized in air and becomes covered with NiO.¹⁹ Therefore, special techniques to avoid air-exposure (i.e., pre-reduction in the reaction vessel, glovebox) are required to achieve high catalytic performance for liquid phase reactions. Herein we report an easily prepared Ni/NiO composite as a heterogeneous catalyst for one-pot reductive amination using nitro compounds. This Ni catalyst can be handled under an air atmosphere, even though the supposedly active species, metallic nickel, is oxidized by air-exposure.Ni/NiO was prepared by the partial reduction of NiO with H₂ in the temperature range from 200 to 500 °C (Ni/NiO-X: X = reduction temperature). X-ray diffraction (XRD) patterns of the prepared Ni catalysts after exposure to air are summarized in Fig. 1(A). When NiO is treated in H₂ at 200 °C, the dominant phase produced is still nickel oxide. Metallic nickel was formed by reduction at ≥250 °C, which is consistent with the H₂-temperature programmed reduction (H₂-TPR) profile of NiO in which the H₂ consumption peak begins to increase at around 250 °C.²⁰ The ratio of Ni to NiO, determined by Rietveld analysis, increased with increasing reduction temperature and no peaks attributed to metallic nickel were evident for Ni/NiO-500 (†) and crystallite diameter estimated from (111) diffraction lines using Scherrer''s equation (Table S3, ESI^†). Fig. 1(C) shows an SEM image of Ni/NiO-300, where the particle size was estimated to be 0.5–3 μm, and the layered structure of NiO was maintained after the reduction treatment (see also Fig. S4, ESI^†).Open in a separate windowFig. 1(A) XRD patterns for Ni/NiO-X; (a) Ni/NiO-500, (b) Ni/NiO-400, (c) Ni/NiO-350, (d) Ni/NiO-300, (e) Ni/NiO-250, and (f) Ni/NiO-200 (♦: Ni, ○: NiO), and (B) SEM images of Ni/NiO-300.Specific surface areas and weight ratios of Ni to NiO

Boron nitride nanochannels encapsulating a water/heavy water layer for energy applications

Water interaction and transport through nanochannels of two-dimensional (2D) nanomaterials hold great promises in several applications including separation, energy harvesting and drug delivery. However, the fundamental underpinning of the electronic phenomena at the interface of such systems is poorly understood. Inspired by recent experiments, herein, we focus on water/heavy water in boron nitride (BN) nanochannels – as a model system – and report a series of ab initio based density functional theory (DFT) calculations on correlating the stability of adsorption and interfacial properties, decoding various synergies in the complex interfacial interactions of water encapsulated in BN nanocapillaries. We provide a comparison of phonon vibrational modes of water and heavy water (D₂O) captured in bilayer BN (BLBN) to compare their mobility and group speed as a key factor for separation mechanisms. This finding, combined with the fundamental insights into the nature of the interfacial properties, provides key hypotheses for the design of nanochannels.

Single layer water (SLW) on BN layer and encapsulated between bilayer BN (BLBN) as nanochannel.

Hexagonal boron nitride (h-BN) is a synthetic material, similar to graphene in structure and layered form,^1,2 but with alternating B and N atoms. Among others properties, h-BN is considered for its hydrophobicity, remarkable chemical and thermodynamic stability (air stable up to 1000 °C),³ and exceptional mechanical⁴ and optical properties.⁵ Thin BN sheets have been fabricated by high-energy electron beam irradiation,⁶ ultrasonication,⁷ Lewis acid–base,⁸ hydrolysis of lithium based materials,⁹ liquid alloys of alkali metals at room temperature¹⁰ and chemical vapor deposition² methods.Nanochannels by design is an appealing idea due to their potential applications in filtration and separation as well as molecular sieving.^11,12 Recently, Agrawal et al.¹³ revealed the water phase transition encapsulated within carbon nanotubes of different radius. Specifically, fabricating artificial capillaries for molecular transport led to emergence of nanofluidics.¹⁴ Shultz et al.¹⁵ studied the local water structure by investigation of local and long-range response of hydrogen-bond network of water with surface. Water is polar due to the high electronegativity of oxygen atom and two weakly electropositive hydrogen atoms besides the buckled structure.¹⁶ Graphene-based materials such as graphene oxide (GO) membranes can have nanometer pores and tunable sieving of ions,¹² indicating low frictional water flow. Sun et al.¹⁷ studied on electro/magneto modulated ion transport through GO membranes. While several experimental works demonstrate promising applications of nanochannels, the fundamental subatomic and electronic phenomena at the heart of such nanochannels are poorly understood.Herein, we present a comprehensive ab initio study to decode the complex interfacial interactions of water and heavy water encapsulated in bilayer BN (BLBN) as a model system. Our findings demonstrated that 2D BN can be used as nanochannels with tunable interlayer distance that is determined by in/out-plane hydrogen bonds of water layers. To discover the mechanism for separating water and heavy water, we further investigate phonon spectrum for water layers between BLBN and for heavy water, deuterium oxide D₂O. This nanometer-scale BN capillaries is a flagship architecture in fabricating atomically channels for nanofluidic technology.¹⁸BN nanosheet could be a good candidate for water cleaning and purification as experimentally has been reported by Lei, et al.¹⁹ Moreover, Hao et al. in their paper²⁰ reported the properties of atomic layer deposition (ALD) boron nitride nanotube, which is relevant for water purification. Li et al.²¹ reported that porous boron nitride nanosheets show an excellent performance for water purification.More recently Falin et al.²² synthesized single crystalline of mono/few layer BN nanosheets. They experimentally measured the Young''s modulus of high quality 1–9 layer BN.²¹ Mechanical properties of BN nanosheets placed them among the strongest insulating materials, indicating the fracture strength of 70.5 ± 5.5 GPa.²¹To obtain fundamental insights on the interfacial interactions, a series of DFT calculations were performed on single layer water (SLW) molecules and double layer water (DLW) molecules settled on BN layers and encapsulated in BLBN (see Methods). We first examined the molecular models of SLW settled on BN layers with and without external field. Fig. 1a and b show SLW/BN, including (H₂O)₁₆, representing 16 water molecules and the substrate containing 120 B, N atoms. In order to take into account the effect of structural boundary conditions and compare the interfacial properties of SLW and DLW on BN surface, we employed the energy minimized structures for the SLW and DLW on BN layer (Fig. 1d and e), containing 32H₂O molecules. The electrical dipole moment (Open in a separate windowFig. 1Optimized single layer water (SLW)/BN and its electronic band structure for different external electric field, (a) E = 0 V Å⁻¹, (b) Total density of states (DOS) and (c) projected DOS for SLW/BN. Optimized double layer water (DLW)/BN and its electronic band structure for different external electric field, (d) E = 0, (e) E = 0.1 V Å⁻¹, (f) total DOS for nanochannels of (a) and (b).DFT results of interfacial properties of optimized SLW and DLW on BN

Efficient synthesis of spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles

A versatile synthesis of spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles is described. A wide range of spirooxindolyl oxazol-2(5H)-ones and other spirocyclic frameworks incorporating the oxazol-2(5H)-one unit can be readily prepared in good to high yields under the optimal conditions.

A versatile synthesis of spirooxindolyl oxazol-2(5H)-ones and derivatives via palladium(ii)-catalyzed addition of arylboronic acids to nitriles is described.

Rapid and efficient construction of pharmaceutical and biologically relevant compounds plays a very important role in modern organic synthesis, and constitutes the original impetus for the development of various novel synthetic approaches. The efficient construction of spirocyclic frameworks has been a topic of great relevance in organic synthesis due to their inherent three-dimensional architectures and the pronounced biological activities.¹ In particular, the spirocyclic oxindoles have emerged as attractive synthetic targets because of their prevalence in numerous natural and unnatural products.² Notably, the enhanced biological activities have been observed by the incorporation of a spiro five-membered azaheterocyclic ring at the C3 position of the oxindole core (Fig. 1).³ Thereby, a variety of synthetic methods have been developed to access analogous compounds possessing such privileged structure moieties.⁴Open in a separate windowFig. 1Examples of spiro oxindoles containing natural products and biological relevant compounds.As one of the important N–O heterocyclic compounds, oxazolidinones and their derivatives have been widely used not only as synthetic building blocks,⁵ but also as pharmaceuticals⁶ and agrochemicals,⁷ owing to a diverse range of biological activities.⁸ Although great contributions have been made to access these valuable scaffolds,⁹ the construction of structurally diverse spirooxindolyl oxazol-2(5H)-ones, characterized by a spiro ring fusion at the C3 position of the oxindole core with oxazol-2(5H)-one motif, has received less attention from synthetic community,¹⁰ despite the fact that these spirocyclic heterocycles could be promising candidates possessing biological responses. In 2017, He and co-workers reported a formal [3 + 2] cycloaddition reaction of in situ generated azaoxyallyl cation with cyclic ketones for the synthesis of spiro-4-oxazolidinones.^11a In 2018, Alla and co-workers described a copper-catalyzed one-pot multicomponent protocol for the synthesis of spiro(indoline-3,5′-oxazolidine)-2,2′-diones starting from ketones, arylacetylenes and isocyanates.^11bRecently, the transition-metal-catalyzed addition of organoboron reagents to nitriles has received remarkable progress,¹² since the elegant works on the addition of arylpalladium species to the cyano group reported by Larock and Lu et al.,¹³ in which nitriles served as C building blocks and provided aryl ketones. In virtue of palladium-catalyzed tandem addition of organoboron reagents to nitriles/cyclization protocol, this approach enabled the combination of organoboron reagents and nitriles to construct a diversity of nitrogen-containing heterocycles such as 2-aminobenzophenones, benzofurans, and indoles, in which nitrile serves as C–N synthon instead and is incorporated into heterocyclic frameworks in an atom-economical fashion.¹⁴ However, the development of transition-metal-catalyzed tandem sequence involving the addition of organoboron reagents to nitriles to construct structural novel three-dimensional architectures such as spirocyclic systems is still undeveloped.We have recently developed both intramolecular and intermolecular cyclization approaches to prepare indole and thiophene fused polycyclic derivatives via Pd-catalyzed direct C–H bond addition to nitriles.¹⁵ Given the promising biological activities of spirooxindoles-containing molecules in medicinal chemistry and our ongoing interest in the development of efficient catalytic processes to prepare diverse aza-heterocyclic frameworks, herein, we report an efficient synthetic approach to prepare spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles.As functionalized nitriles, cyanohydrins which are readily prepared from ketones and aldehydes have demonstrated considerable synthetic potential as useful building blocks.¹⁶ We chose the Pd(ii)-catalyzed reaction of 3-cyano-1-methyl-2-oxoindolin-3-yl ethyl carbonate 1a, which is readily prepared from isatin and ethyl cyanoformate, and phenylboronic acid 2a as a model reaction for the optimization of the reaction conditions (ii) catalyst proven to be essential to this transformation since no reaction happened without them (†). In addition, the reaction also was evaluated with Ni(ii) catalyst system. However, Ni(ii)-catalyzed reaction gave the inferior to that of Pd(ii) catalytic system (†).Effects of reaction parameters^a