Hindered dialkyl ether synthesis with electrogenerated carbocations.

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

Modular Approach to Highly Substituted 3-Methylpyridones.

A method has been developed for the rapid synthesis of highly substituted 3-methylpyridones via the condensation of Baylis-Hillman amines and ketones under benzoic acid catalysis. The process features readily available starting materials, broad substrate scope, high functional group tolerance, excellent regioselectivity, and gram-scale synthesis. We envision that this on-demand construction of 3-methylpyridones will provide exciting opportunities in biological research, therapeutics, and material sciences.

Catalyst-Free α-Allylation of Dihydroisoquinolines with Morita-Baylis-Hillman Carbonates and Its Applications in the Construction of Benzo[a]quinolizidines.

In this work, a mild and efficient catalyst-free α-allylation of 3,4-dihydroisoquinoline imines with Morita-Baylis-Hillman (MBH) carbonates was reported. The scopes of 3,4-dihydroisoquinolines and MBH carbonates as well as gram-scale synthesis were investigated, and densely functionalized adducts were obtained in moderate to good yields. The synthetic utility of these versatile synthons was further demonstrated by the facile synthesis of diverse benzo[a]quinolizidine skeletons.

Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors.

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.

Modular and Stereoselective Approach to Highly Substituted Indole/Pyrrole-Fused Diazepanones.

A one-pot synthetic method for indole/pyrrole-fused 1,4-diazepanone scaffolds has been developed. This method involves a sequential amide coupling/intramolecular aza-Michael addition of 1H-indole/pyrrole-2-carboxylic acids with Morita-Baylis-Hillman-derived allylamines. The readily available starting materials, good stereoselectivity, and gram-scale synthesis make this method valuable for the construction of highly substituted fused heterocycles containing the 1,4-diazepanone moiety.

Direct C(sp3)-H allylation of 2-alkylpyridines with Morita-Baylis-Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement.

A base- and catalyst-free C(sp3)-H allylic alkylation of 2-alkylpyridines with Morita-Baylis-Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2' type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated in the reaction to give the allylation products in 26-91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives.

Electrochemical γ-Selective Deuteration of Pyridines.

Herein, we first report a γ-selective deuteration reaction of pyridines via H/D exchange without the need for preinstalled directing groups and transformable functional groups. The electrochemical process offers an attractive approach to producing γ-deuterated pyridines under gentle conditions. The broad substrate scope, excellent deuterium incorporation, and remarkable selectivity of the electrochemical method make it applicable for the late-stage modification of pharmaceutical molecules.

Synthesis of novel 4H-pyrimido[1,6-a]pyrimidines via a one-pot three-component condensation.

Highly substituted novel 4H-pyrimido[1,6-a] pyrimidines were prepared by a trifluoromethanesulfonic acid catalyzed one-pot three-component condensation of 4-aminopyrimidines, aldehydes, and ß-ketoesters. A preliminary feasibility study was undertaken on these compounds, to assess the potential production of a library of further diversified compounds by nucleophilic replacement of Cl(R(1)) or by reaction of electrophiles with the NH(2)(R(2)) group.

Electrooxidative Dearomatization of Inactive Biphenyls to Cyclohexadienones.

An efficient electrooxidative dearomatization of inactive biphenyls has been developed under mild and easy-to-operate conditions. The protocol provides a powerful tool for the rapid synthesis of cyclohexadienones in moderate to high yields with wide substrate scope and good functional group compatibility even to oxidation-sensitive motifs. This method provides an environment-friendly and direct approach for the construction of C-O bonds with high regioselectivity.

Catalyst-Controlled Regiodivergent Synthesis of α/ß-Dipeptide Derivatives via N-Allylic Alkylation of O-Alkyl Hydroxamates with MBH Carbonates.

A controllable and regiodivergent N-allylation reaction involving readily available O-alkyl hydroxamates derived from natural α-amino acids has been developed, allowing regiospecific access to α/ß-dipeptides containing α-unsaturated ß-amino acids moieties in moderate to good yields. The regioselectivity could be conveniently switched by alternation of the catalysts and solvents.

Synthesis of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, amines and aldehydes.

A practical strategy was developed for the preparation of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, primary amines, and aldehydes. The key step for this synthesis entails a cyclization reaction involving an intramolecular amide addition to an iminium intermediate formed in situ from 4-amino-pyrimidine-5-carboxamide 2 and aldehydes to form the pyrimido[4,5-d]pyrimidine core with a strategically placed 5-Cl group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 27-membered library of representative 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones in moderate to good yields.

Electroselective and Controlled Reduction of Cyclic Imides to Hydroxylactams and Lactams.

An efficient and practical electrochemical method for selective reduction of cyclic imides has been developed using a simple undivided cell with carbon electrodes at room temperature. The reaction provides a useful strategy for the rapid synthesis of hydroxylactams and lactams in a controllable manner, which is tuned by electric current and reaction time, and exhibits broad substrate scope and high functional group tolerance even to reduction-sensitive moieties. Initial mechanistic studies suggest that the approach heavily relies on the utilization of amines (e.g., i-Pr2NH), which are able to generate α-aminoalkyl radicals. This protocol provides an efficient route for the cleavage of C-O bonds under mild conditions with high chemoselectivity.

Stereochemistry as a tool in deciphering the processes of a tandem iminium cyclization and Smiles rearrangement.

To understand the detailed mechanism of a recently reported tandem iminium cyclization and Smiles rearrangement, the reaction processes of a chiral substrate were investigated by monitoring its stereochemical courses. Under the tandem reaction conditions, chiral aldehyde 1 derived from l-prolinol led to two surprising results. First, the iminium cyclization gave a diastereomeric mixture with the cis-configured product as the predominant one. Second, Smiles rearrangement of both cis- and trans-2 led to the same product 3a directly derived from the trans isomer. The former was rationalized by the postulation of a Cram's chelate transition state leading to the cis product as kinetically favored. The latter was due to the equilibration between the trans/cis pair involving a carbocation intermediate and the steric hindrance, which prevented the cis isomer from undergoing the intramolecular nucleophilic substitution. This hypothesis was further supported by the results of a competition experiment in which the addition of 1 equiv of p-methoxyaniline in the rearrangement step led to a significant amount of anilinyl-exchanged rearrangement product.

Synthesis of hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines via an intramolecular hetero-Diels-Alder reaction.

Method development was completed for a strategy to access a novel pyrimidine-fused heterocyclic scaffold. The key step for this synthetic route entails an intramolecular inverse electron demand hetero-Diels-Alder reaction of imines or iminiums formed in situ from allylaminopyrimidinealdehydes 3 and anilines. The reactions provided exclusively cis-configuration products 6. Products 6 were readily precipitated in the reaction solution in good to excellent yields. Further transformations of the phenylthio group were demonstrated by an oxidation and subsequent nucleophilic substitution sequence. The synthetic strategy provides an efficient way to access libraries of the tetracyclic pyrimidine-fused heterocycles that can be explored for potential pharmaceutical or biological activities.

Synthesis of novel 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones.

Practical and efficient methods have been developed for the synthesis of 4,6,8,9-tetrasubstituted 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones from 4,6-dicholoropyrimidine aldehyde, N-substituted amino acid esters, and amines in five steps. This synthetic strategy is based on suitably substituted pyrimidines as bis-electrophilic species reacting with various amines to construct the pyrimido[4,5-e][1,4]diazepine core with a strategically anchored functional group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 33-membered library of representative 8,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)-ones in good to excellent yields.

Nickel-Catalyzed Electrochemical Phosphorylation of Aryl Bromides.

A nickel-catalyzed electrochemical cross-coupling reaction of aryl bromides with dialkyl phosphites, ethyl phenylphosphinate, and diphenylphosphine oxide has been developed. This reaction utilizes a simple undivided cell with inexpensive carbon electrodes to synthesize aryl phosphonates, aryl phosphinates, and arylphosphine oxides at room temperature. This protocol provides a mild and efficient route for the construction of C-P bond in moderate to high yields with broad substrate scope.

Single-Electron Oxidation/Alterable C3- and C10-Arylation of 9-MeO-phenanthrene.

A reactivity pattern for C3-arylation of 9-MeO-phenanthrene has been established for the first time by using 2-naphthyl amines as coupling partners. A series of phenanthrene- and naphthalene-based multifunctionalized polycyclic aromatic hydrocarbons have been obtained in good to excellent yields. Alternative C10-arylation of 9-MeO-phenanthrene has also been accomplished, using 2-naphthalenol derivatives as coupling partners. Trifluoroacetic acid is found crucial for the regioselectivity. Density functional theory calculations and electrochemical analyses have been performed to rationalize the reaction mechanism.

A cascade reaction consisting of Pictet-Spengler-type cyclization and Smiles rearrangement: application to the synthesis of novel pyrrole-fused dihydropteridines.

[reaction: see text] Tandem Pictet-Spengler-type cyclization and Smiles rearrangement have been discovered in the synthesis of pyrimidine-fused heterocycles. The reaction of 4-chloro-5-pyrrol-1-ylpyrimidine amino aldehyde with an amine under an acidic condition yielded the Pictet-Spengler-type cyclization product diazepine, which readily underwent Smiles rearrangement to give a novel pyrrolo[1,2-f]pteridine derivative.

Synthesis and Evaluation of 2-Alkylthio-4-(N-substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti-myeloma Agents.

A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti-cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities.

Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach.

An efficient discovery strategy by combining diversity-oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 µM), which exhibits much less toxicity toward normal cells (EC50 > 100 µM against normal human fibroblasts). The most active hits also exhibited drug-like properties suitable for further preclinical research. This redeployment of antidepressing compounds for anticancer applications provides promising future prospects for treating drug-resistant tumors with fewer side effects.