Selective,C-3 Friedel-Crafts acylation to generate functionally diverse,acetylated Imidazo[1,2-a]pyridine derivatives

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, CC bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance CC bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl₃. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.     

Phosphinate selective hosts and importance of CH hydrogen bonding for affinity modulation toward anion guests

Even though phosphinate and its analogs are very important guests in nature, the artificial receptors which are capable of selective recognition of phosphinate are rare. Here, we report a series of acetate and phosphinate selective hosts (1, 2 and 3) which utilize amide NH and aliphatic CH groups as hydrogen bonding donors. In this series of receptors, even though the amide NH hydrogen bonding element was found to be the most significant, by varying the polarity of CH group, the magnitude of recognition could be modulated considerably. The affinities of host 3 against all the tested anion guests showed significantly higher affinities compared with those of hosts 1 and 2, and this could be attributed to the difference of CH group polarities among the receptors 1, 2 and 3. C_α-H hydrogen in host 3 is the most highly polarized by the charged pyridinium group. Therefore, it is the strongest host in this series of hosts. From the experiments shown here, we demonstrated the importance of CH hydrogen bonding element as a decisive modulating moiety for anionic recognition.     

Rh(III)-catalyzed, 1,2,3-triazole-assisted directed CH coupling with diazo diphosphonates

A mild and efficient procedure was developed for the [Cp1Rh(III)]-catalyzed, 1,2,3-triazole directed CH coupling with diazomethylene-diphosphonates. This protocol provided a step- and atom-economical protocol for CC bond formation and led to structurally diverse 2-(1,2,3-triazol-2-yl)benzyl diphosphonates in good to excellent yields.     

Palladium-catalyzed [5+2] oxidative annulation of N-Arylhydrazones with alkynes through CH activation to synthesize Benzo[d][1,2]diazepines

An efficient and novel method using palladium catalyst for the synthesis of benzo[d][1,2]diazepines by [5 + 2] annulation of N-arylhydrazones with alkynes has been developed. This methodology undergoes through eight membered palladacycle serving as a backbone for the formation of CC/CN bond to provide benzodiazepine derivatives in moderate to good yield.     

Selective synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines via copper-catalyzed tandem annulation of alkynylbenzonitriles with 2-Iodoanilines

An efficient copper-catalyzed cascade cyclization reaction for selectively synthesizing a variety of benzo[4,5]imidazo[2,1-a]isoquinoline derivatives has been developed. The reaction features the formation of three different CN bonds in sequence. In the presence of Cu(OAc)₂ and KO^tBu, o-alkynylbenzonitriles and 2-iodoanilines proceeded smoothly to obtain the corresponding benzo[4,5]imidazo[2,1-a]isoquinolines in moderate to good yields.     

Photocatalytic anion oxidation achieves direct aerobic difunctionalization of alkenes leading to β-thiocyanato alcohols

A novel visible light-driven oxidative cascade reaction for the synthesis of β-thiocyanato alcohols via difunctionalization of alkenes is described for the first time. In this protocol inorganic ion thiocyanate was successfully converted into radical through photocatalysis by employing Rose Bengal as a photocatalyst to mediate the single-electron transfer. This hydroxylation process did not need extra reducing agent and the new CS and CO bonds could be constructed in one pot. Molecular oxygen not only was used as an excellent terminal oxidant, but also served as a green oxygen source, which is one of the most ideal processes to realize CH bond oxidation functionalization. Moreover, the reaction also proceeded very well under irradiation of sunlight.     

A visible-light-promoted cross-dehydrogenative-coupling reaction of N-arylglycine esters with imidazo[1,2-a]pyridines

A mild and convenient visible-light-promoted cross-dehydrogenative-coupling reaction between N-arylglycine esters and imidazo[1,2-a]pyridines for the construction of CC bond was developed. A range of N-arylglycine esters and imidazo[1,2-a]pyridines were able to undergo the CDC reaction readily to afford α-heteroaryl substituted α-amino acid derivatives in good to excellent yields. A tentative mechanism for the photoredox reaction was also proposed. Importantly, the use of copper(II) salt as the sole catalyst in this visible-light-promoted transformation makes this reaction sustainable and practical.     

Morita-Baylis-Hillman enal-based triple cascade strategy for anti-selective synthesis of highly functionalized tetrahydropyridines using iminium-enamine catalysis

A novel and efficient three-component coupling strategy for stereoselective synthesis of highly substituted tetrahydropyridines (THP) is reported in high yield (83–94%) with excellent diastereoselectivity (95–99%) in favor of anti-isomer. The reaction proceeds via sequential iminium-iminium-enamine mediated formation of three consecutive CC, CC and CN bonds in one-pot through reaction of [E]-α-cyano/nitro unsaturated aldehyde, activated methylene and aldimine/phenyl-N-tosyl-methanimine and opens up a new aspect for the utility of Morita-Baylis-Hillman (MBH) adducts in THP synthesis.     

Rhodium-catalyzed NH-indole-directed ortho CH coupling of 2-arylindoles with diazo compounds via metal carbene migratory insertion

A high regioselective rhodium-catalyzed ortho CH coupling of 2-arylindoles with diazo compounds via NH-indole-directed CH bond activation has been developed. The catalytic reaction features mild reaction conditions, broad substrate scope and good functional group tolerability.     

Visible-light-mediated cascade difunctionalization/cyclization of alkynoates with acyl chlorides for synthesis of 3-acylcoumarins

A new visible-light-mediated radical cyclization of alkynoates with acyl chlorides is described for the one-pot construction of diverse 3-acylcoumarins with high efficiency and selectivity. This method is successful by sequential difunctionalization of an alkynes CC triple bond with the CCl bonds of acyl chloride and aromatic C(sp²)H bonds. The cyclization is proposed to simultaneously form two new carbon–carbon bonds, and involves radical acylation, 5-exo-trig cyclization, and ester migration.     

Influence of sulfur groups on carboxylic acid strengths

The relative acid strength for a series of monocarboxylic acids of the general formula RX(CH₂)_nCOOH and related dicarboxylic acids of the general formula HOOC(CH₂)_nX(CH₂)_nCOOH, where R?=?Ph or Me, X?=?CH₂, S, SO, or SO₂; and n?=?1 or 2 as appropriate; have been studied as a function of X. It is found that sulfur containing acids have lower pKa values than the corresponding carbon analogues, that the pK_a is highest for the thioacids and lowest for the sulfonyl acids, that the pK_as increase as n increases, and that for the dicarboxylic acid systems only the thio members show a significant reduction in pK_a (2) – pK_a (1) differences upon changing n from 1 to 2.     

Recent advance in radical fluoroalkylation with sulfinate salts

In the last few years, the incorporation of a fluoroalkyl moiety into an organic molecule has been extensively studied. Especially, radical fluoroalkylation, involving the formation of CC and Cheteroatom bonds, presents its valuable synthetic potential to achieve fluoroalkylated compounds. This digest paper highlights recent progress on fluoroalkylation with sulfinate salts, and focuses on radical tri-/di-/monofluoromethylation during the last five years.     

Synthesis of cyclic olefins via Mitsunobu C-alkylation followed by Ramberg-Bäcklund ring contraction

Cyclic olefins were prepared via a novel synthetic approach that involves the formation of two CC bonds in a potentially stereoselective fashion. The first bond is formed by employing a Mitsunobu dehydrative C-alkylation; the second CC bond involves a ring contraction via Ramberg-Bäcklund rearrangement.     

Transition-metal-free,atom-economical cascade synthesis of novel 2-sulfonated-benzo[f][1,7]naphthyridines and their cytotoxic activities

An efficient, transition-metal-free cascade synthetic method has been developed for new 2-aryl/heteroaryl sulfonated benzo[f][1,7]naphthyridines. It is tert-butyl hydroperoxide (TBHP) mediated highly regioselective sulfonylation?cyclization?aromatization process between N-(3-aryl/heteroarylprop-2-yn-1-yl)quinolin-3-amines and aryl/heteroaryl sulfonylhydrazides. This synthetic protocol offers one-step strategy for CS and CC bond formations with a broad range of functional group tolerance. It is a simple, mild, and atom-economical route for the synthesis of various valuable functionalized 1, 2-aryl/heteroaryl sulfonated benzo[f][1,7]naphthyridines in moderate yields. Since the core motif of 2-sulfonated benzo[f][1,7]naphthyridines are biologically and pharmaceutically important (TLR activity 7, 8 modulators). Additionally, the synthesized derivatives were evaluated for their in vitro cytotoxic activities against six human cancer cell lines including lung (NCIH23), colon (HCT15), gastric (NUCG-3), renal (ACHN), prostate (PC-3), and breast (MDA-MB-231) cell lines. These compounds displayed significant cytotoxic activities against all tested human cancer cell lines.     

Synthesis and structural investigation of 4,4′-dimethyl-[3,3′-bi(1,2,5-oxadiazole)] 5,5′-dioxide

The oxidation of hexane-2,3,4,5-tetraone tetraoxime with dinitrogen tetroxide was studied in different solvents. The primary furoxan ring closure was found to occur involving either two central or two terminal oxime groups to form 4,7-dimethyl[1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide and the previously unknown 4,4′-dimethyl-[3,3′-bi(1,2,5-oxadiazole)] 5,5′-dioxide. The structure of the latter compound was established by X-ray diffraction.     

Experimental and theoretical studies on rhodium-catalyzed direct CH benzoxylation reaction

An efficient Rh(III)-catalyzed, chelation assisted CH benzoxylation reaction has been developed, releasing H₂O as the single byproduct. The reaction proceeded under mild conditions, with controllable mono- and dioxygenation selectivity, thus providing a good complement to previous CH oxygenation reactions. DFT calculations support that a nucleophilic addition pathway is most likely involved in the current reaction system.     

Concept of Ir-catalyzed CH bond activation/borylation by noncovalent interaction

Noncovalent interactions play a fundamental role in molecular biology, crystal engineering, supramolecular chemistry, drug design, sensing applications, and many other research fields in the chemical sciences. Because of this importance, thorough research efforts have been focused on the interpreting and quantifying these interactions, which include H-bonding, electrostatic effects, ππ interaction, cation-π interaction, hydrophobic-hydrophobic interaction, van der Waals forces, and other such type of interactions. However, on the synthetic standpoint, use of these noncovalent interactions are rare, although might be beneficial for the site-selective CH bond activation and functionalization by transition metal catalysis. In this context, iridium-catalyzed CH borylation has gained immense popularity due to the versatility conferred to the CB bonds. Very recently, researchers have started employing these interactions as a governing factor for attaining regioselectivity in arene CH borylation. In this perspective, we will focus on the advancements made so far by the use of various noncovalent interactions in Ir-catalyzed borylations.     

Synthesis of 3,4-diarylsubstituted hexahydro-1H-indoles

Efficient syntheses of 3,4-diarylsubstituted hexahydro-1H-indoles in good yields with excellent diastereoselectivities were achieved with a two-step protocol comprising an allylic cation mediated nucleophilic addition and an intramolecular cyclization reaction. The N-aryl sulfonyl protecting groups of cyclization products were readily removed to furnish free amines with retention of halogen substitutions and CC double bonds.     

Potassium tert-butoxide-mediated generation of arynes from o-bromoacetophenone derivatives

o-bromoacetophenone derivatives as new versatile aryne precursors are induced to selectively eliminate the C_ArBr and C_ArC_(Ac) bonds in the help of t-BuOK. Furthermore, the active aryne intermediates are successfully applied in a substantial set of reactions including N-arylation and copper-catalyzed coupling with various terminal alkynes. It is important to note that the generation of benzyne intermediate is demonstrated through cycloadditon reaction experiment with furan.     

Concise synthesis of 3,4-dihydro-1,4-benzoxazines by three-component reactions of acyl chlorides, o-aminophenols and 1,2-dichloroethane

The Cu(OAc)₂-catalyzed three-component reactions of o-aminophenols, acyl chlorides and 1,2-dichloroethane (DCE) have been established for the efficient synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazines (3,4-dihydro-1,4-benzoxazines). This method features advantages of the one-pot operation enabling N-acylation, CCl bond amidation and etherification, as well as the structural divergence of the synthesized products.