Base-mediated Cyclization Research Articles

Synthesis of N-Alkyl-1,3-dihydro-2,1-benzisoxazoles.

We describe a practical method for the synthesis of various substituted N-alkyl-1,3-dihydro-2,1-benzisoxazoles and their 2,1-benzisoxazolone precursors starting from readily available methyl 2-nitrobenzoates. The method entails partial nitro reduction with hydrazine and rhodium on carbon to give the hydroxylamines, followed by base-mediated cyclization to give the corresponding benzisoxazol-3(1H)-ones. Subsequent alkylation is conducted under basic conditions and is followed by reduction to the target 1,3-dihydrobenzisoxazoles, achieved with lithium aluminum hydride in the presence of trimethylsilyl chloride.

Expedient synthesis of 8-membered azasultams: A combined synthetic, DFT, and in vitro study

Herein we describe the novel approach to the synthesis of functionalized ind(az)olo-fused 1,2,4-thiadiazocine 1,1-dioxides through the CSIC (Carbanion-mediated Sulfonate (Sulfonamide) Intermolecular Coupling (Intramolecular Cyclization) reaction strategy. 1,2,4-Thiadiazocine 1,1-dioxides (put simply 8-membered azasultams) are increasingly popular but quite underrepresented in the literature compounds, were prepared in two simple steps and good yield from readily available reagents. Particularly, the alkylation of 7-functionalized ind(az)oles with N-(chloromethyl)-N-methylmethanesulfonamide gave the corresponding N-((1H-ind(az)ol-1-yl)methyl)-N-methylmethane-sulfonamides which underwent base-mediated cyclization affording the target 8-membered azasultams. The method worked well and provided azasultams decorated with a set of synthetically valuable handles. The conducted DFT calculations explained and rationalized the experimental data thus allowing us to formulate the rules of the structure‒activity relationship. Despite the prepared compounds showing weak cytotoxicity against the MDA-MB-231 breast cancer cell line, they are considered novel building blocks and perspective pharmacological templates prone to further optimization.

Base-Mediated Synthesis of 2-Bromobenzoheterocycles

AbstractA base-mediated cyclization to synthesize 2-bromobenzoheterocycles is reported. This transformation was demonstrated with 16 examples to access a broad range of brominated benzoheterocycles. Mechanistic studies support the reaction proceeds through a bromoalkyne, and revealed an exchangeable proton at C3 of the indole products.

Anionic aza 8π-electrocyclization as an unprecedented pathway versus 7-endo-dig: DFT study on the mechanism of base-catalyzed benzofuroazepine synthesis via cyclization of (2-alkynylbenzyl)oxy nitriles.

DFT calculations are used to disclose the mechanism of Brønsted base-mediated cyclization of (2-alkynylbenzyl)oxy nitriles for the synthesis of benzofuroazepines. In 2015, the synthesis of substituted benzofuroazepines was reported by Zeni et al. via a stepwise mechanism known as 7-endo-dig. However, DFT calculations revealed that the anionic aza 8π-electrocyclization is more favorable than the proposed 7-endo-dig mechanism.

Synthesis of fused-pyran derivatives via a base-mediated annulation of bis-allenoates followed by auto-oxidation in air.

We introduce, for the first time, an inorganic base-mediated cyclization and auto-oxidation of bisallenones/bisalkynones. This reaction is realized under mild conditions through precise control of the base and atmosphere, providing a wide range of structurally diverse fused-pyran derivatives with moderate to excellent yields. Utilizing KOH as the initiator under a nitrogen atmosphere, a series of novel cyclohexane-fused pyran derivatives was obtained as the primary product. In contrast, under aerobic conditions with Na2S as the catalyst, oxidative cyclization predominantly occurred, yielding cyclohexanone-fused pyran derivatives. The protocol also exhibits significant regioselectivity, particularly when asymmetric bisallenones/bisalkynones are selected as substrates.

Dirhodium-Catalyzed Transannulation of N-Sulfonyl-1,2,3-triazoles to 2,3-Dehydropiperazines.

The dirhodium(II)-catalyzed synthesis of a range of C2-substituted 2,3-dehydropiperazines using 1-mesyl-1,2,3-triazoles and β-haloalkylcarbamates is reported. The reaction is proposed to proceed through an α-imino rhodium carbene 1,3-insertion into N-H followed by a base-mediated cyclization. C-Substituted dehydropiperazines can also be conducted directly from terminal alkynes in a three-step, one-pot operation, forming the triazole in situ. This methodology has also been expanded to afford several 2,5-disubstituted 2,3-dehydropiperazines as well as a larger 4,5,6,7-tetrahydro-1H-1,4-diazepine derivative.

Unlocking Kuhn Verdazyls: New Synthetic Approach and Useful Mechanistic Insights.

An optimized synthetic protocol toward the assembly of Kuhn verdazyls based on an azo coupling of arenediazonium salts with readily available hydrazones followed by the base-mediated cyclization of in situ formed formazans with formalin was developed. The scope and limitations of the presented method were revealed. Some new mechanistic insights on the formation of Kuhn verdazyls were also conducted. It was found that in contradiction with previously assumed hypotheses, the synthesis of verdazyls was accomplished via an intermediate formation of verdazylium cations which were in situ reduced to leucoverdazyls. The latter underwent deprotonation under basic conditions to generate corresponding anions which coproportionate with verdazylium cations to furnish the formation of Kuhn verdazyls. The spectroscopic and electrochemical behavior of the synthesized verdazyls was also studied. Overall, our results may serve as a reliable basis for further investigation in the chemistry and applications of verdazyls.

Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol-Ene/Cyclization Sequence in Continuous Flow.

A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol–ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1–0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.

2,2′-(1,4-Phenylene)bis(7-nitro-1H-benzimidazole 3-oxide)

Bis(benzimidazol-2-yl-3-oxide)benzene derivatives have potential applications as energetic or photoactive materials. By using a two-step one-pot approach employing microwave heating as a tool, 2,2′-(1,4-phenylene)bis(7-nitro-1H-benzimidazole 3-oxide) (1) has been prepared in 94% yield. In the first step an SNAr reaction is performed using p-xylylenediamine as the central building block. Without isolating the intermediate, a base-mediated cyclization reaction follows in the second step. The product was isolated in analytically pure form by means of a pH-controlled precipitation.

Phosphazene superbase mediated cyclization and annulation reactions of functionalized alkynes for the synthesis of heterocyclic compounds

Base-mediated cyclization and annulation reactions are very useful methods in the heterocyclic synthesis. Different types of conventional bases, i.e., inorganic bases or organometallic bases have been traditionally used for carrying out these reactions in the past. Over the years, the phosphazene organic superbases have emerged as effective alternatives to inorganic and organometallic bases. The phosphazene superbase was first used for alkyne cyclization in 2008, and its use has become quite popular over the last decade. This review is aimed to provide an analysis of the use of phosphazene superbase, especially P4–t-Bu as a robust and highly efficient catalyst/reagent in various intra- or intermolecular reactions of substituted alkynes for the synthesis of O,N-heterocycles such as isoindolin-1-ones, benzofurans, isobenzofurans, proline derivatives, pyrroles, etc.

Application of a Dual Catalytic Nickel/Iridium-Based Photoredox Reaction to Synthesize 2-Alkyl-N-Arylindoles in a Continuous Flow.

A versatile one-pot procedure for the preparation of 2-alkyl-substituted N-arylindoles is described. The method combines a visible light-mediated Ni/Ir-photoredox dual catalytic N-arylation of alkynyl anilines under continuous flow conditions with a subsequent base-mediated cyclization to afford the desired substituted indoles. The initial Ni/Ir photoredox-promoted N-arylation of alkynylanilines proceeds efficiently in a continuous flow to afford the desired products in moderate to excellent yields with a short residence time (20 min) and mild conditions at ambient temperature and without the exclusion of air. The methodology was amenable for a multi-gram scale-up to deliver 2-alkyl-N-arylindoles in high yields followed with only a single purification step.

A Route to Triazole-Fused Sultams via Metal-Free Base-Mediated Cyclization of Sulfonamide-Tethered 5-Iodotriazoles.

An efficient direct approach to triazole-fused sultams has been developed. The key step of the proposed strategy is base-mediated cyclization of sulfonamide-tethered 5-iodo-1,2,3-triazoles which are readily available via an improved protocol for Cu-catalyzed 1,3-dipolar cycloaddition. The annulation of the sultam fragment to the triazole ring proceeds smoothly under transition-metal-free conditions in the presence of Cs2CO3 in dioxane at 100 °C and affords fused heterocycles in high yields up to 99%. The favorability of an SNAr-like mechanism for the cyclization was supported by DFT calculations. The applicability of the developed procedure to modification of natural compounds was demonstrated by preparation of a deoxycholic acid derivative.

Asymmetric total synthesis of (+)-isocryptotanshinone and formal synthesis of (−)-cryptotanshinone

The first asymmetric total synthesis of (+)-isocryptotanshinone was achieved in 12 linear steps with 12% overall yield from commercially available dihydrobenzopyrone. The key step was a base-mediated cyclization reaction. In addition, the synthetic strategy included the formal synthesis of (−)-cryptotanshinone.

Adventures in Atropisomerism: Development of a Robust, Diastereoselective, Lithium-Catalyzed Atropisomer-Forming Active Pharmaceutical Ingredient Step

The final step in the route to BMS-986142, a reversible inhibitor of the BTK enzyme, involves the diastereoselective construction of a chiral axis during the base-mediated cyclization of the quinazolinedione fragment. Optimization of the reaction to minimize formation of the undesired atropisomer led to the discovery that the amount of base and nature of the counterion play a vital role in the diastereoselectivity of the reaction. The highest diastereoselectivities were observed with a catalytic amount of LiOt-Bu. Development of a crystallization to selectively purge the undesired atropisomer is reported. Interestingly, ripening of the crystalline API was observed and further investigated, leading to a significant increase in the purity of the active pharmaceutical ingredient.

Annulation-Induced Cascade Transformation of 5-Iodo-1,2,3-triazoles to 2-(1-Aminoalkyl)benzoxazoles.

Base-mediated cyclization of (5-iodo-1,2,3-triazolyl)phenols was proposed as a new synthetic strategy for the in situ generation of diazoimines via electrocyclic ring opening of the fused heterocycle. Cu-catalyzed amination of the intermediate diazoalkanes was employed to develop an efficient cascade approach to functionalized benzoxazoles.

Transition-Metal-Free Cyclization of Propargylic Alcohols with Aryne: Synthesis of 3-Benzofuranyl-2-oxindole and 3-Spirooxindole Benzofuran Derivatives ⊥.

An unprecedented base-mediated cyclization of propargylic alcohols with aryne is reported, providing a novel method for the synthesis of 3-benzofuranyl-2-oxindole and 3-spirooxindole benzofuran scaffolds via a propargyl Claisen rearrangement/cycloaddition pathway. The nature of the substituent on acetylene group of propargylic alcohol influences the outcome of the reaction. The protocol offers a transition-metal-free and operationally simple methodology with broad substrate scope as a ready access to complex oxindole-linked heterocyclic compounds.

Pd-Catalyzed One-Pot Stepwise Synthesis of Benzo[b][1,6]naphthyridines from 2-Chloroquinoline-3-carbonitriles Using Sulfur and Amines As Nucleophiles.

A palladium-catalyzed one-pot stepwise coupling-annulation reaction of 2-chloroqunoline-3-carbonitriles enabled the direct synthesis of sulfur-substituted benzo[b][1,6]naphthyridines via multiple bond formation. The reaction provided an unusual mode for cyclization as sodium sulfide, a soft nucleophile, preferred to attack on the carbon of the nitrile group rather than on the C-C triple bond. The developed chemistry was extended with the secondary amines as nucleophiles to afford nitrogen-substituted benzo[b][1,6]naphythyridines while primary amines afforded hydroamination products . The hydromination products were transformed to benzo[b][1,6]naphthyridones via a base-mediated cyclization reaction. The developed protocol features inexpensive and easily synthesizable starting materials, easy operations, and a high efficiency and tolerance to a broad range of substrates.

Regioselective Base-Mediated Cyclizations of Mono-N-acylpropargylguanidines.

A regioselective base-mediated cyclization of mono-N-acylpropargylguanidines is reported. A related Ag(I)-catalyzed hydroamination strategy was recently employed to yield N3-Cbz-protected ene-guanidines, which found utility in the synthesis of naamidine A. Herein, we report the base-catalyzed hydroamination of mono-N-acylpropargylguanidines, which proceeds with the opposite regiochemistry to deliver isomerized N2-acyl-2-aminoimidazoles with broad substrate scope, circumventing the problematic regiospecific acylation of free 2-aminoimidazoles.

Synthesis of Partially Reduced Imidazo[1,2-a]pyridines through an Unprecedented Base-Mediated (4+2) Cyclization

A water-mediated regioselective synthesis of 6,7-diaryl-5-oxo-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine-6-carbonitriles was performed by the reaction of 2-[1-cyano-2,2-bis(methylsulfanyl)vinyl]benzonitrile with 1-aryl-2-(imidazolidin-2-ylidene)ethanones under basic conditions. This reaction involves an unprecedented (4+2) annulation.

Alkoxy base-mediated selective synthesis and new rearrangements of 1,2,4-triazolodipyrimidinones

A versatile approach for the synthesis of [1,2,4]triazolodipyrimidinones with various annulations of the triazole and pyrimidine rings was developed. The isomeric triazolodipyrimidinones were obtained by the stepwise condensation of partially hydrogenated [1,2,4]triazolo[1,5-a]pyrimidin-2-amines with β-ketoesters or diethyl ethoxymethylenemalonate, alkoxy base-mediated cyclization of the enamines, and subsequent cascade rearrangement of the 10-oxo-[1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidines.