Synthesis of fused bicyclic pyridines with microwave-assisted intramolecular hetero-Diels-Alder cycloaddition of acetylenic pyrimidines

A series of acetylenic pyrimidines was synthesized and subjected to microwave irradiation. In contrast to conventional heating, the microwave irradiations generally gave clean conversion to fused bicyclic pyridines for all substrates reported with shorter reaction time. This method has been successfully applied to the synthesis of both fused lactones and lactams.     

o-Fluoranil chemistry: Diels-Alder versus hetero-Diels-Alder cycloaddition

The title quinone undergoes [4 + 2] cycloadditions in two ways, Diels-Alder on the ring and hetero-Diels-Alder by attack at the oxygens. The latter mode of reaction is strongly favored thermodynamically, but there is a kinetic bias favoring the normal Diels-Alder addition that often prevails, especially with cycloaddends that are not electron-rich.     

An unusual intramolecular Diels-Alder reaction

The diene-ester (2) on heating undergoes an intramolecular Diels-Alder reaction via the intermediate (3). The β-alkyl furan moiety in 3 reacts as the dienophile adding to the cyclohexadiene unit to give 4.     

Expeditious synthesis of the aromatic spiroketal skeleton using hetero-Diels-Alder cycloaddition

The hetero-Diels-Alder reactions of enolic ethers generated from methylenation of various esters are described, which allow for the rapid synthesis of various substituted [6,6] aromatic spiroketal skeletons.     

Light-induced hetero-Diels-Alder cycloaddition: a facile and selective photoclick reaction

2-Napthoquinone-3-methides (oNQMs) generated by efficient photodehydration (Φ=0.2) of 3-(hydroxymethyl)-2-naphthol undergo facile hetero-Diels-Alder addition (k(D-A)～ 4×10(4) M(-1) s(-1)) to electron-rich polarized olefins in an aqueous solution. The resulting photostable benzo[g]chromans are produced in high to quantitative yield. The unreacted oNQM is rapidly hydrated (k(H2O) ～145 s(-1)) to regenerate the starting diol. This competition between hydration and cycloaddition makes oNQMs highly selective, since only vinyl ethers and enamines are reactive enough to form the Diels-Alder adduct in an aqueous solution; no cycloaddition was observed with other types of alkenes. To achieve photolabeling or photoligation of two substrates, one is derivatized with a vinyl ether moiety, while 3-(hydroxymethyl)-2-naphthol is attached to the other via an appropriate linker. The light-induced Diels-Alder "click" strategy permits the formation of either a permanent or hydrolytically labile linkage. Rapid kinetics of this photoclick reaction (k=4×10(4) M(-1) s(-1)) is useful for time-resolved applications. The short lifetime (τ ～7 ms in H(2)O) of the active form of the photoclick reagent prevents its migration from the site of irradiation, thus, allowing for spatial control of the ligation or labeling.     

An unusual substitution reaction directed by an intramolecular re-arrangement

Secondary amines and thiols undertake a substitution reaction on the side chain of 2-bromoethyl-pyridinium derivatives ‘directed’ by an intramolecular re-arrangement. Experimental investigations strongly indicate that the reaction is initiated by an alpha addition of the nucleophile onto the iminium moiety of the N-heteroaromatic cation, followed by a cyclisation and an oxidative ring opening. This novel substitution process is able to occur with less reactive nucleophiles that would not undergo conventional substitution with ‘isolated’ bromoethyl moieties.     

Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes to alkynes

Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes (MCPs) to arkylalkynes via proximal bond cleavage is reported. The reaction provides a facile route for the preparation of cyclopenta[a]indene derivatives.     

beta-Acyloxysulfonyl tethers for intramolecular Diels-Alder cycloaddition reactions

[reaction: see text]. beta-Hydroxy sulfone-based tethers were employed for the first time to achieve thermally mediated intramolecular Diels-Alder cycloaddition. The reactions proceeded with complete regioselectivity and high (10/1) to complete endo/exo-selectivity and resulted in the preferential formation of one of the two possible endo-cycloadducts. The yields and stereoselectivities were proportional to the bulk of the R(1) substituent on the beta-acyloxysulfonyl tether.     

Anion radical chain cycloaddition of tethered enones: intramolecular cyclobutanation and Diels-Alder cycloaddition

[reaction: see text] The anion radicals of certain bis(enones), generated by cathodic reduction, are observed to participate in intramolecular cyclobutanation, yielding bicyclo[3.2.0]heptane derivatives through an anion radical chain mechanism. Evidence for stepwise cycloaddition involving distonic anion radical intermediates is presented. In addition to the novel anion radical cyclobutanations, an unprecedented intramolecular anion radical Diels-Alder product is observed. Parallel trends in substrate scope vis-à-vis the Co-catalyzed bis(enone) cyclobutanation are discussed.     

Syntheses of enantiomeric dihydropyrans through stereocontrolled intramolecular cycloaddition

Reaction of the cyclic 1, 3-dicarboxylic acid derivatives ($\text{1}$), ($\text{2}$) and ($\text{3}$) with (R)- or (S)-citronellal ($\text{4}$/$\text{5}$) gives the enantiomeric tricyclic dihydropyrans ($\text{10}$), ($\text{11}$), ($\text{12}$) and ($\text{13}$), probably via a 100% stereocontrolled intramolecular cycloaddition.     

Phenylethynyl-pendant polyphenylquinoxalines curable by an intramolecular cycloaddition reaction

Polyphenylquinoxalines containing 2,2′-bis(phenylethynyl)diphenylene moieties along the polymer backbone have been synthesized. As anticipated, these polymers were found to undergo a novel curing reaction consisting of an intramolecular cycloaddition (IMC) of pendant groups to a dibenzoanthracene backbone structure. The IMC reduces chain mobility, and the fused ring structure increases the glass transition temperature of the polymer. The potential of this approach to curing high-temperature polymers was demonstrated in the processing of one such polymer having an initial T_g of 215°C. Curing at 245°C with no evolution of volatiles produced a T_g of 365°C. This very significant increase in potential use temperature via a volatiles-free IMC cure provides promise for a tough phenyiquinoxaline resin system which can be used to fabricate reinforced composites that have use temperatures far exceeding processing temperatures.     

N-烯基硝酮分子内环加成反应区域选择性的理论研究I. N-3-丁烯基硝酮分子内环加成反应的区域专一性

n-烯基硝酮的分子内环加成反应可能得到氧桥和碳桥的两种产物, 但N-3-丁烯基硝酮却只有单一的氧桥产物, 已被用来合成一系列新的区域专一性人化合物。弄清此反应机理是很有意义的。本文用过渡状理论和AM1方法进行研究, 结果表明,虽然存在得到两种产物的平行反应, 但由于这两个反应的速率常数之比很大, 基本上只得到单一的氧桥产物。生成氧桥产物的反应活化焓比较小, 活化熵比较大。活化熵对反应速率常数比值的贡献是不可忽略的。     

N-烯基硝酮分子内环加成反应区域选择性的理论研究IV. N-4-己烯基硝酮分子内环加成反应的区域选择性

本文用AM1 MO方法和过渡状态理论研究N-4-己烯基硝酮分子内环加成反应的机理, 计算两个平行反应(a, b)的速率常数的比值, 得到与实验吻合的结果。计算结果还表明, 由于N-5-甲基的电子效应, 使得反应b的活化焓降低, 同时, N-5-甲基引起的构型变化, 使得反应b的活化熵增高(绝对值变小), 这使得K~b/K~a值明显增长, 是区域选择性发生较大改变的原因。     

An intramolecular [2 + 2] cycloaddition of ketenimines via palladium-catalyzed rearrangements of N-allyl-ynamides

A cascade of Pd-catalyzed N-to-C allyl transfer-intramolecular ketenimine-[2 + 2] cycloadditions of N-allyl ynamides is described. This tandem sequence is highly stereoselective and the [2 + 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene substitutions, leading to bridged and fused bicycloimines.     

Ionic liquid accelerated intramolecular hetero-Diels-Alder reactions: a protocol for the synthesis of octahydroacridines

2-Azadienes derived in situ from arylamines and (R)-(+)-citronellal/3-methylcitronellal undergo intramolecular [4+2] hetero-Diels-Alder reactions in the air and moisture stable ionic liquid [bmim]BF₄ in the absence of any acid catalyst to afford 1,2,3,4,4a,9,9a,10-octahydroacridine derivatives in high to quantitative yields.     

An unusual formal migrative cycloaddition of aurone-derived azadienes: synthesis of benzofuran-fused nitrogen heterocycles

Aurone-derived azadienes are well-known four-atom synthons for direct [4 + n] cycloadditions owing to their s-cis conformation as well as the thermodynamically favored aromatization nature of these processes. However, distinct from this common reactivity, herein we report an unusual formal migrative annulation with siloxy alkynes initiated by [2 + 2] cycloaddition. Unexpectedly, this process generates benzofuran-fused nitrogen heterocyclic products with formal substituent migration. This observation is rationalized by less common [2 + 2] cycloaddition followed by 4π and 6π electrocyclic events. DFT calculations provided support to the proposed mechanism.

A HNTf₂-catalyzed formal migrative cycloaddition of aurone-derived azadienes with siloxy alkynes has been developed to provide access to benzofuran-fused dihydropyridines.

Benzofuran is an important scaffold in biologically important natural molecules and therapeutic agents.¹ Among them, benzofuran-fused nitrogen heterocycles are particularly noteworthy owing to their broad spectrum of bioactivities for the treatment of various diseases (Fig. 1).² Consequently, the development of efficient methods for their assembly has been a topic receiving enthusiastic attention from synthetic chemists.³ Notably, aurone-derived azadienes (e.g., 1) have been extensively employed as precursors toward these skeletons owing to their easy availability and versatile reactivity (Scheme 1a).³ The polarized conjugation system, combined with the preexisting s-cis conformation, has enabled them to serve as ideal annulation partners for the synthesis of nitrogen heterocycles of variable ring sizes. Moreover, the aromatization nature of these processes by forming a benzofuran ring provides additional driving force for them to behave as a perfect four-atom synthon for [4 + n] cycloaddition.³ In contrast, the use of such species as a two-atom partner for [2 + n] cycloaddition has been less developed.^3c,k,4 Herein, we report a new migrative annulation leading to benzofuran-fused dihydropyridines of unexpected topology (Scheme 1b, with formal R² migration), which is initiated by the less common [2 + 2] cycloaddition.Open in a separate windowFig. 1Benzofuran-fused N-heterocyclic natural and bioactive molecules.Open in a separate windowScheme 1Synthesis of benzofuran-fused nitrogen heterocycles.Siloxy alkynes are another important family of building blocks in organic synthesis.^5–8 The presence of a highly polarized C–C triple bond enables such molecules to serve as versatile two-carbon cycloaddition partners in various annulation reactions.^5–7 In the above context and in continuation of our interest in the study of such electron-rich alkynes,⁷ we envisioned that the reaction between aurone-derived azadienes 1 and siloxy alkynes 2 should lead to facile electron-inversed [4 + 2] cycloaddition to form benzofuran-fused dihydropyridine products (Scheme 1b). Interestingly, the expected product 3′ from direct [4 + 2] cycloaddition was not observed. Instead, a dihydropyridine product 3 with formal R² migration was observed. Careful analysis of the mechanism suggested that a [2 + 2] cycloaddition followed by 4π and 6π electrocyclic steps might be responsible for this unexpected product topology (vide infra).We began our investigation with the model substrates 1a and 2a, which were easily prepared in one step from aurone and 1-hexyne, respectively.⁸ Various Lewis acids were initially examined as potential catalysts for this cycloaddition (Table 1). Unfortunately, common Lewis acids (e.g., TiCl₄, BF₃·OEt₂, Sc(OTf)₃, In(OTf)₃, and AgOTf) were all ineffective (entries 1–5). Substrate decomposition into an unidentifiable mixture was typically observed. However, further screening indicated that AgNTf₂ served as an effective catalyst, leading to benzofuran-fused dihydropyridine 3a in 44% yield (entry 6). Careful analysis by X-ray crystallography confirmed that it was not formed by simple [4 + 2] cycloaddition, as the positions of the phenyl and the siloxy groups were switched (vs. the expected topology). The distinct catalytic performance of AgNTf₂ (vs. AgOTf) suggested that the triflimide counter anion Tf₂N⁻ might be important. However, further screening of various metal triflimide salts did not improve the reaction efficiency (entry 7). Instead, we were delighted to find that the corresponding Brønsted acid HNTf₂ served as a better catalyst (57% yield, entry 8). However, triflic acid (TfOH) led to no desired product in spite of complete conversion (entry 9). After considerable efforts in the optimization of other reaction parameters, an improved yield of 75% was obtained with 2.5 mol% of HNTf₂ and 2.5 equivalents of 2a at 60 °C (entry 10). Solvent screening indicated that the reaction proceeded faster in DCE with comparable yield (entry 11). However, other solvents were all inferior (entries 12–15). Finally, with a reversed order of addition of the two reactants, the yield was slightly improved (entry 16). We believe that this might be related to the relative decomposition rates of the substrates.Reaction conditions^a

Ruthenium-catalyzed (2 + 2) intramolecular cycloaddition of allenenes

We report a ruthenium-catalyzed (2 + 2) intramolecular cycloaddition of allenes and alkenes. We have found that the use of the ruthenium complex RuH(2)Cl(2)(P(i)Pr(3))(2), which has previously gone unnoticed in catalytic applications, is crucial for the observed reactivity. The reaction proceeds under mild conditions and is fully diastereoselective, providing a practical entry to a variety of bicyclo[3.2.0]heptane skeletons featuring cyclobutane rings.