Bimolecular reduction of carbon dioxide: double synthons for alkynes trifunctionalization

Carbon dioxide reduction, as a sustainable and versatile strategy for the access of chemical fuels, has attracted increasing attention and enormous efforts have been devoted to it in recent years. However, employing carbon dioxide as double synthons via bimolecular reduction remains challenging. Here, by leveraging the bimolecular reduction of carbon dioxide to carbonyl and methyl respectively, we describe a Pd-catalyzed trifunctionalization of alkynes with aryl iodide for the first time and showcase its advantages on the formation of various β-diketones and their application in the constructing of heterocyclic compounds with important biological activity, including pyrimidine, oxazole, pyrazole.

Diastereodivergent formal[4+1]cycloaddition of azoalkenes as one-carbon synthons

The first diastereodivergent formal[4+1]cycloaddition reactions of azoalkenes with p-quinone methides(pQMs)have been accomplished.The reported reaction occurred via a domino oxa-1,4-addition/1,6-addition process,allowing the use of common azoalkenes as C1 synthons.A broad range of 2,3-dihydrobenzofurans was smoothly prepared in good yields and with reversible diastereoselectivities.The steric hindrance and hydrogenbonding interaction were proposed to account for the two different modes of diastereo-control.The projected reaction features the employment of azoalkene as carbene-like C1 synthon,mild conditions,broad substrate scope and tunable diastereoselectivity.

Multi-component Hydrogen-bonding Organic Salts Formed from 1-Methylpiperazine with Aromatic Carboxylic Acids： Synthons Cooperation and Crystal Structures

1-Methylpiperazine was employed to crystallize with 2,4-dihydroxybenzoic acid and 1,8-naphthalene acid, affording two multi-component hydrogen-bonding salts [（C5H14N2）^2＋-（C7H5O4）2^·H2O]（1） and [（C5H14N2）^2＋（C12H6O4）^2-.2H2O]（2）. These two forms of salts are both monoclinic systems with space group P21/c（14）. The lattice parameters of salts 1 and 2 are a=1.32666（10） nm, b=0.90527（7） nm, c=1.67107（13） nm, β=103.125（1）° and a=1.4950（2） nm, b=0.75242（15） nm, c=1.6563（3） nm, β=92.834（2）°, respectively. Expected classical hydrogen bonds N-H...O and O-H...O appear in the chargetransfer salts, and asymmetric units of these two forms both contain water molecules which play a significant role in building novel supramolecular architectures. Robust hydrogen-bond interactions between 1-methylpiperazine and aromatic acid provide sufficient driving force to direct the two crystals to three-dimensional structures. Weak interactions C-H-O emerging in salts 1 and 2 further enhance their crystal structures. As a consequence, hydrogen-bonding interactions in these compounds afford diverse 3D net supramolecular architectures. Thermal stability of these compounds was investigated by thermogravimetric analysis（TGA）.

Syntheses, Crystal Structures and Hydrogen-bonding Motif of Two Glycoluril Derivatives

The synthesis and aggregation behavior of two glycoluril derivatives were descrybed.The crystal of compound 1 belongs to the triclinic system,space group P1,with a=8.946(1),b=13.445(2),c=20.361(3)?,α=89.517(3),β=84.405(3),γ=86.325(3)°,Z=2,V=2432.1(6)?3,Dc=1.293 g·cm-3,C48H34N6O6·2DMSO,Mr=947.07,F(000)=992,μ=0.170 mm-1,the final R=0.1606 and wR=0.2410 for 4382 observed reflections(Ⅰ>2σ(Ⅰ)).The crystal of compound 2belongs to the monoclinic system,space group P21/c,with a=9.500(3),b=24.522(8),c=17.997(6)A,Z=2,V=4054(2)A^3,Dc=1.296 g·cm^-3,C48H34N6O6,Mr=790.81,F(000)=1648,μ=0.087mm-1,the final R=0.2146 and wR=0.2535 for 2878 observed reflections(Ⅰ>2σ(Ⅰ)).Unlike the highly conserved R22(8)hydrogen-bonding amide···amide homosynthon,the structural analysis indicated that compound 1 selected the C(20)hydrogen-bonding motif and 2 selected the R22(34)hydrogen-bonding motif,which revealed the competition from remote solvent molecule and the interference of the molecular hydrocarbon core in crystal packing.The supramolecular structure revealed molecule 1 is further linked into a one-dimensional chain and 2 into a two-dimensional interwoven plane by N–H···N hydrogen bonds.

Synthesis of Asymmetric Propanetriol Analogues

From natural tartaric acid, (R)-2-benzyloxy-3-(2-tetrahydropyranyloxy) propanol 3 was designed and synthesized, and (R)-2-benzyloxy-3-(4-methoxybenzyloxy) propanol 7 was prepared in a new method. They can be used as chiral synthons of lysophosphatidic acid and other compounds with asymmetric propanetriol backbone.

Construction of a Self-assembling Intertwined Spiral Solvent Channel Based on Interactions between Macrocycles and CH_2Cl_2

The construction of an unprecedented intertwined spiral solvent channel is driven by weak C–Cl…O and C–H…N interactions based on extraordinary parallel spirals which were structured from supramolecular synthon macrocycle 1（C44H44N4O4） with a propargylamine backbone. The product is characterized by ^1H NMR, ^13C NMR, IR and HRMS, and further confirmed by single-crystal X-ray diffraction. It crystallizes in the monoclinic system, space group C2/c, with a = 28.922（3）, b = 8.5069（9）, c = 21.687（2）A^°, β = 130.6320（10）°, V = 4049.4（7） A^°3 and Z = 8. A total of 11874 reflections were collected, of which 4942 were independent（Rint = 0.0590） and 2937 were observed with I 〉 2σ（I）. The final full-matrix least-squares refinement gave R（I 〉 2s（I）） = 0.069 and w R = 0.167, S = 1.05,（Δρ）max = 0.20 and（Δρ）min =-0.22 e·A^1-3. The fluorescence of the product is discussed.

SYNTHESIS OF A POTENTIAL ANTIFEEDANT SESOUITERPENE INTERMEDIATE FROM A NEW TERPENOID A, B-RING SYNTHON BY TANDEM NICHAEL REACTION

An efficient synthesis of functionalized 6-decalone 16, starting from a dienolate anion 3a via a tandem Michael reaction, is described. 16 could be used as a potential intermediate for synthesis of drimane related sesquiterpenes.

A New Method for the Synthesis of C/D Ring Synthon of Vitamin D

A C/D ring synthon of vitamin D is readily obtained from cholesteryl acetate via oxidation, elimination of acetoxy group and Norrish type II photochemical reaction.

Recent advances of versatile reagents as controllable building blocks in organic synthesis

Diversity-oriented synthesis is a powerful and interesting synthetic tool for the rapid construction of structurally complex and privileged scaffolds from readily accessible starting materials.To date,diversity-oriented synthesis mostly relies on the employment of versatile reagents.Versatile reagents can be regulated as controllable and flexible building blocks for multipurpose utilizations.Over the past decade,a variety of multifunctional reagents have been developed.However,most versatile reagents usually need multi-step synthesis,thus restricting their wide application to a large extent.In terms of the practicalities and universalities,we prefer to pay more attention to the utilization of simple and practical versatile reagents with multiple reactivities,mainly including atropaldehyde acetals,aryl methyl ketones,vinylene carbonate,vinyl azides,aryldiazonium salts,rongalite,halodifluoromethyl compounds.Most importantly,these versatile reagents can also play different roles simultaneously in the same reaction,in which their different reactivities are converged into the final target products.Such strategy can not only offer more possibilities for the synthesis of several active pharmaceutical ingredients,but also minimize the occurrence of some side reactions by lessening the varieties of materials.Also,a perspective is given at the end of this review.

Theoretical and experimental cocrystal screening of temozolomide with a series of phenolic acids, promising cocrystal coformers

The virtual cocrystal screening approach based on molecular electrostatic potential surface(MEPS)maps is a fast and feasible computational method to estimate the probability of cocrystal formation by calculating the difference in the interaction site pairing energies of monomers and that of their assemblies prior to experimental screening.In this paper,we report 12 cocrystal forms of temozolomide with mono-,di-,and trihydroxy benzoic acids,namely,3-hydroxy-,2,4-dihydroxy-,2,5-dihydroxy-,2,6-dihydroxy-,3,4-dihydroxy-,and 3,4,5-trihydroxy-benzoic acids,as well as benzoic acid,as pharmaceutical coformers for the first time.10 single crystals out of the 12 cocrystal forms were obtained and unequivocally determined by single-crystal X-ray diffraction,which clarified spatial arrangements,molecular conformations,and supramolecular synthons.MEPS further gains some insights into the sites of hydrogen bonding interactions for exploring combination patterns in these assemblies.Modulated stability of TMZ was successfully achieved by cocrystallization with these acids.

Recent advances in chemical fixation of CO_(2)based on flow chemistry

Carbon dioxide(CO_(2))is an attractive C1 building block in chemical synthesis due to its abundance,availability and sustainability.However,the low reactivity and high stability generally limits its transformations under mild conditions to value added chemicals.Recent advances in flow chemistry provide effective means for the chemical transformation of CO_(2),and many new methods and techniques that fully utilized the advantages of continuous flow platforms for the chemical fixation of CO_(2)have been realized.In view of the rapid development and the urgent need for continuous transformation of CO_(2),herein we wish to present an update of the recent advances in this research area.

Co-crystals of non-steroidal anti-inflammatory drugs(NSAIDs):Insight toward formation,methods,and drug enhancement

Pharmaceutical co-crystals have been explored by many researchers as a strategy to optimize physicochemical properties of solid-state drugs.Their improvements of solubility,bioavailability,and the reduced tendency for phase transformation occurrence,are factors that highlight benefits of pharmaceutical co-crystals among other solid forms.According to the Biopharmaceutical Classification System(BCS),non-steroidal anti-inflammatory drugs(NSAIDs)are class Ⅱ drugs,which have low aqueous solubility and therefore co-crystallization has the potential to optimize NSAID product properties.In this review,we highlight the recent progress made on NSAIDs co-crystals,their co-formers,synthesis,methods and use,while we underline some promising results on in vitro and in vivo co-crystal properties.A celecoxib-tramadol co-crystal reaches phase Ⅲ clinical trials,showing greater analgesic activity than both individual APIs.The aqueous solubility of the co-crystal formed between l-proline and diclofenac is very high in comparison with the pure drug.Naproxen co-crystals with urea and thiourea have an increase of drug release of almost 60%.Co-crystal design brings a new perspective in drug development since the co-former used can also be a biologically active component allowing to combine different anti-inflammatory drugs,which have an incredible spectrum of application due to the analgesic,anti-pyretic and anti-inflammatory properties.

Highly efficient enantioselective synthesis of bispiro[benzofuran-oxindole/benzofuran-chromanone]s through organocatalytic inter-/intramolecular Michael cycloaddition

A quinine-derived thiourea-catalyzed inter-/intramolecular Michael cycloaddition of chromoneoxindole/benzofuranone synthons with 3-substituted methylenebenzofuranones has been established,which constructed enantiomerically pure bispiro[benzofuran-oxindole/benzofuran-chromanone]s bearing five consecutive stereocenters including two spiro quaternary carton centers in good yields(up to 93%) with high diastereoselectivities(up to>20:1 dr) and good enantioselectivities(up to>99% ee).Moreover,this is the first example of bifunctional chromone-benzofuranone synthon directed organocatalytic tandem reaction,and also the first example of the bispiro[benzofuran-oxindole] and bispirobenzofuranone,potentially useful in medicinal chemistry.

Toward Rational and Modular Molecular Design in Soft Matter Engineering

This essay discusses some preliminary thoughts on the development of a rational and modular approach for molecular design in soft matter engineering and proposes ideas of structural and functional synthons for advanced functional materials. It echoes the Materials Genome Initiative by practicing a tentative retro-functional analysis （RFA） scheme. The importance of hierarchical structures in transferring and amplifying molecular functions into macroscopic properties is recognized and emphasized. According to the role of molecular segments in final materials, there are two types of building blocks： structural synthon and functional synthon. Guided by a specific structure for a desired function, these synthons can be modularly combined in various ways to construct molecular scaffolds. Detailed molecular structures are then deduced, designed and synthesized precisely and modularly. While the assembled structure and property may deviate from the original design, the study may allow further refinement of the molecular design toward the target function, The strategy has been used in the development of soft fullerene materials and other giant molecules. There are a few aspects that are not yet well addressed： （1） function and structure are not fully decoupled and （2） the assembled hierarchical structures are sensitive to secondary interactions and molecular geometries across different length scales. Nevertheless, the RFA approach provides a starting point and an alternative thinking pathway by provoking creativity with considerations from both chemistry and physics. This is particularly useful for engineering soft matters with supramolecular lattice formation, as in giant molecules, where the synthons are relatively independent of each other.

Dichloromethane as a methylene synthon for regioselective linkage of diverse carboxylic acids:Direct access to methylene diesters under metal-free conditions

A metal-free cross coupling between common CH2Cl2 and carboxylic acids has been achieved with K2CO3 as the sole additive. This simple protocol is a convenient and cost-effective route to synthesize methylene diesters from a wide scope of carboxylic acids substrates with good functional group tolerance. Several gram-scale reactions have been performed to evaluate the effectiveness and practicality of this protocol.

New Crystalline Forms of Mebendazole with n-Alkyl Carboxylic Acids Neutral and Ionic Status

Structural information on the crystalline forms of mebendazole, an anti-parasitic drug, is limited, although three polymorphic forms of this drug have been reported. The present work investigates the structures and properties of different crystalline forms of mebendazole with a series of n-alkyl carboxylic acids, including trifluroacetic acid （1）, formic acid （2）, acetic acid （3）, propanoic acid （4）, butanoic acid （5）, valeric acid （6） and hexanoic acid （7）. These compounds were characterized by thermogravimetric analysis, IR spectra, as well as powder and single-crystal X-ray diffraction analysis. The R22（8） structural motif was detected in all the seven products, which was formed by a pair of N--H…O/O--H…N hydrogen bonds between mebendazole and carboxylic acid. Forms 3--7 were found to be neutral solvate, while in forms 1 and 2, proton transfer was observed from carboxylic acid to mebendazole.

Approach to synthesis of novel chiral 3-chloro-2(5H)- furanone and its application in asymmetric reactions

The synthetic method of the novel chiral synthon, 5-/-menthyloxy-3-chloro-2-(5H)-furanone 5a and its application in asymmetric reactions were investigated. 5a is easily obtained in highly optical purity, and acts as a stable acceptor of Michael addition with oxygen nucleophiles in tandem double Michael addition / internal nucieophilic substitution to offer the spiro-cyclopropane derivative containing four stereogenic centers 8, which it is difficult to obtain by routine methods. The synthetic methods for 5a and 8 are reported in detail and the new compounds are identified on the basis of their analytical data and spectroscopic data, such as UV, IR, H NMR,13 C NMR, MS and elementary analysis. The absolute configuration of the interesting spiro-cyclopropanes, spiro [1-chloro-4-(/-menthyloxy)-5-oxo-6-oxa-biscyclo[3.1.0]hexane-2,3i(4’-/-menthyloxy-5’-/-menthyloxy- butyrolactone)] 8 was established by X-ray crystallography. This result can provide important synthetic strategy in synthesis of some complex

Ring opening [3+2] cyclization of azaoxyallyl cations with benzo[d]-isoxazoles:Efficient access to 2-hydroxyaryl-oxazolines

A selective ring-opening [3+2] cyclization reaction of benzo[d]isoxazoles with 2-bromo-propanamides has been developed.The azaoxyallyl cation intermediates are employed as C^O 3-atom synthon to build oxa-heterocycles via the selectivity of suitable cyclization partners.This transformation provides rapid access to highly functionalized 2-hydroxyaryl-oxazolines under mild conditions and excellent regioselectivity.

TMSCF_(2)Br as both a C1 synthon and a F1 reagent

This highlight summarizes a recent development of KF-promoted three-component fluorinationaminocarbonylation reaction of aldehydes,tertiary amines,and TMSCF_(2)Br for the synthesis of structurally importantα-fluoroamide derivatives.The key to the success of this method could be attributed to the multiple functions of difluorocarbene precursor(TMSCF_(2)Br)as both a C1 synthon and a F1 reagent through the process of C-F bond cleavage and C-F bond re-formation.