Pt-catalyzed cyclization/1,2-migration for the synthesis of indolizines, pyrrolones, and indolizinones

Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles from readily available substrates. [reaction: see text]     

Ti‐Catalyzed Straightforward Synthesis of Exocyclic Allenes

Exocyclic allenes constitute useful building blocks in organic synthesis and have recently been identified as key intermediates in the synthesis of natural products. Here the first general method for the most straightforward synthesis of exocyclic allenes reported to date is presented. This method is based on the Barbier‐type cyclization of propargyl halides catalyzed by titanium; a safe, abundant, and ecofriendly metal. The reaction proceeds under mild conditions compatible with different functional groups and provides good yields of five‐, six‐, and seven‐membered carbocycles and nitrogen‐containing heterocycles bearing an exocyclic allene group. Experimental evidence supporting the proposed reaction mechanism is also provided. Moreover, this procedure can be carried out in an enantioselective manner by using chiral titanocene(III) catalysts. The utility of this method has been proved in the synthesis of the natural alkaloid stemoamide.     

Synthesis of 2H-1,2-oxaphosphorin 2-oxides via Ag2CO3-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters

[reaction: see text]. Six new 2-ethoxy-2H-1,2-oxaphosphorin 2-oxides were synthesized with high regioselectivity in good yields via Ag(2)CO(3)-catalyzed cyclization of (Z)-2-alken-4-ynylphosphonic monoesters in CH(2)Cl(2) at room temperature. This cyclization of P-OH to substituted alkynes is reported for the first time. The products are a class of phosphorus heterocycles with potential use and are heretofore prepared with difficulty.     

Studies directed toward the synthesis of the scabrosins: validation of a tandem enyne metathesis approach

A synthetic approach to the scabrosin family of antibiotics using a ruthenium carbene-catalyzed tandem metathesis and a Pd(II)-catalyzed cyclization is described. The chiral propargyl amino acid is furnished through enantioselective phase-transfer propargylation. The synthesis of the cyclohexadiene ring system is achieved through ring synthesis using tandem enyne metathesis, previously developed in our lab. The complementary methods of methylene-free and 1,5-hexadiene-alkyne metatheses are compared. The indoline heterocycles are formed using a two-step chloroacetoxylation (Bäckvall reaction) with subsequent nucleophilic attack by an amide nucleophile. The indoline subunits were joined and cyclized to furnish the core diketopiperazine ring. The stereochemical assignment of intermediates is also discussed.     

Palladium(0)-catalyzed tandem cyclization of allenenes: direct construction of tricyclic heterocycles through aromatic C--H activation

Palladium(0)-catalyzed tandem cyclization of allenenes is described. Treatment of allenenes with an aryl halide, potassium carbonate, and catalytic [Pd(PPh(3))(4)] in dioxane afforded tri- or tetracyclic heterocycles in moderate to good yields through insertion of arylpalladium(II) halide into the allenic moiety, intramolecular carbopalladation, and aromatic C--H bond activation. The substituent on the olefin terminus has proven to be essential for the success of the tandem cyclization. The reaction with heterocyclic aryl halides such as iodopyrazine or 4-bromo-1-methylindole afforded tri- or tetracyclic heteroaromatic products in good yields.     

Palladium mediated C-H activation in the field of terpenoids: synthesis of rostratone

We present results, which indicate that Pd-mediated C-H bond activation can be used under mild conditions for the remote functionalization of C-4 methyl groups of molecules with different terpenoid-like skeletons containing six- or seven-membered A rings. This procedure has allowed us to complete a novel strategy for the synthesis of γ-dioxygenated terpenoids in three stages: (i) selective epoxidation of commercial polyenes, (ii) titanium(III)-catalyzed cyclization of epoxypolyprenes, and (iii) Pd-mediated remote functionalization of equatorial methyl groups. This strategy has proved to be useful for the synthesis of the natural labdane rostratone (1).     

Exploiting PdII and TiIII chemistry to obtain gamma-dioxygenated terpenoids: synthesis of rostratone and novel approaches to aphidicolin and pyripyropene A

In nature there are several terpenoids with a characteristic gamma-dioxygenated system on the A ring, and many of them show interesting pharmacological properties. We have developed a novel strategy for the synthesis of these terpenoids involving three stages: (a) the selective epoxidation of commercial polyenes, (b) titanium(III)-catalyzed cyclization of the epoxypolyprenes thus obtained, and (c) Pd-mediated remote functionalization of the equatorial methyl group attached at C-4 on ring A of the cyclic terpenoid thus formed. This strategy has proved to be useful for the synthesis of the natural labdane rostratone (1) and related terpenoids, as well as for advanced synthetic approaches toward the pharmacologically active products aphidicolin (2) and pyripyropene A (3).     

A modular, one-pot, four-component synthesis of polysubstituted 1,3-oxazolidines

A modular, one-pot, two-step, four-component synthesis of polysubstituted 1,3-oxzolidines is described. The method comprises two linked domino processes: an organocatalyzed domino reaction of alkyl propiolate and an aliphatic aldehydes and a microwave-assisted amine addition cyclization domino process. An alternative modular, one-pot, three-step, four-component synthesis has also been developed by linking the organocatalyzed domino process to a sequential amine addition/Yb(OTf)(3)-catalyzed enamine cyclization reaction.     

Intercepted-Knoevenagel condensation for the synthesis of unsymmetrical fused-tricyclic 4H-pyrans

4H-Pyrans (4H-Pys) and 1,4-dihydropyridines (1,4-DHPs) are important classes of heterocyclic scaffolds in medicinal chemistry. Herein, an indium(III)-catalyzed one-pot domino reaction for the synthesis of highly functionalized 4H-Pys, and a model of 1,4-DHP is reported. This alternative approach to the challenging Hantzsch 4-component reaction enables the synthesis of fused-tricyclic heterocycles, and the mechanistic studies underline the importance of an intercepted-Knoevenagel adduct to achieve higher chemoselectivity towards these types of unsymmetrical heterocycles.     

The synthesis of phosphaisocoumarins by Cu(I)-catalyzed intramolecular cyclization of o-ethynylphenylphosphonic acid monoesters

Cu(I)-catalyzed intramolecular cyclization of o-ethynylphenylphosphonic acid monoethyl esters was examined, and a new class of six-membered phosphorus heterocycles was formed with high regioselectivity and good yields. The present reaction is the first example of intramolecular addition of P-OH to alkynes, which provides a convenient way to synthesize novel phosphorus heterocycles having potential bioactivities.     

Rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles

The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III)-catalyzed C–H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions.     

Synthesis of phosphaisoquinolin-1-ones by Pd(II)-catalyzed cyclization of o-(1-alkynyl)phenylphosphonamide monoesters

A Pd(II)-catalyzed intramolecular cyclization of o-(1-alkynyl)phenylphosphonamide monoethyl esters was examined, and a new class of six-membered phosphorus heterocycles (phosphaisoquinolin-1-ones) were formed with high regioselectivity and good yields. The present reaction is the first example of intramolecular addition of P-NH to substituted alkynes, which provides a valuable way to synthesize novel phosphorus heterocycles with potential bioactivities.     

Rh(III)-catalyzed annulation of azobenzenes and α-Cl ketones toward 3-acyl-2H-indazoles

Rhodium(III)-catalyzed [4 + 1] cyclization of azobenzenes with α-Cl ketones has been developed. 3-Acyl-2H-indazoles could be easily afforded in up to 97% yields for more than 30 examples. The obtained products are potentially valuable in organic synthesis and drug discovery. This protocol featured with high efficiency, extensive functional group tolerance and mild reaction conditions. The one-step efficient construction of an anti-inflammatory agent confirms the practicability of this procedure.     

一价铜催化的N-对甲基苯磺酰腙与3-丁炔-1-醇的串联反应:一种四氢呋喃类化合物的新合成方法

最近几年来,利用稳定的重氮类化合物和N-对甲基苯磺酰腙类化合物作为金属卡宾前体,在过渡金属催化下通过形成金属卡宾的偶联反应引起了人们广泛的兴趣.金属卡宾前体与有机金属物种反应,可以生成金属卡宾中间体,并发生金属上基团的转移插入过程,得到新的有机金属物种,从而实现丰富的偶联反应.这类经由金属卡宾转移插入过程的交叉偶联反应为构建C?C键,C?N键以及许多环状化合物和不饱和有机分子结构提供了可靠而强有力的工具.本课题组一直致力于研究该类经由金属卡宾中间体的催化转化和偶联反应,报道了在铜催化下,对甲苯磺酰腙以及重氮类化合物可以与端炔反应,通过所形成的炔基铜卡宾中间体的转移插入过程,可高效得到联烯类化合物.该类反应条件相对温和,并且有很好的底物普适性.不仅各种多取代的联烯类化合物,而且苯并呋喃,菲以及呋喃等结构都可由这类铜催化的腙和炔烃的偶联反应来得到.在这些反应中,通过炔基铜卡宾中间体上炔基的转移插入过程,在形成了C(Sp3)-Cu键以后,通过铜的1,3-迁移过程,可以得到联烯结构,随后发生分子内杂原子的亲核进攻或者6π电子环化过程来实现苯并呋喃,菲等杂环类结构的构建.另一方面,该类反应进一步拓展和研究,可望得到其他有价值的有机分子骨架.环状的醚类结构,如四氢呋喃结构,也是有机化合物中常见的结构类型,我们希望从目前已经发展成熟的卡宾前体与炔烃生成联烯的偶联反应出发,通过分子内的串联过程来高效地构建取代的环状醚类结构.我们设想,在炔烃上引入氧原子作为亲核试剂,在形成联烯化合物以后,通过分子内氧原子对联烯基的亲核进攻,来实现串联的分子内关环反应,从而构建环状醚类结构.本文以CuI为催化剂,3-丁炔-1-醇为炔烃偶联组分,采用二芳基对甲苯磺酰腙作为金属卡宾前体,实现了取代四氢呋喃的合成.在对甲苯磺酰腙与3-丁炔-1-醇类化合物发生偶联反应生成二芳基联烯基化合物以后,采用一锅法实现分子内的关环反应,从而生成亚烯基取代的四氢呋喃化合物.该串联反应不仅具有原料易得和操作较为简便等优点,而且底物普适性和官能团耐受性都较好,多种取代的二芳基腙类化合物都能以较好的收率得到目标产物,从而为四氢呋喃类化合物的合成提供了一种新的方法.该反应进一步展示了经由金属卡宾中间体的交叉偶联反应的普遍性,将在有机化学和有机合成领域具有广泛的研究和应用价值.     

Ag(I)-catalyzed cyclization reaction of ethyl o-hydroxyphenylethynylphosphinates to phosphachromones

An Ag(I)-catalyzed intramolecular cyclization of ethyl o-hydroxyphenylethynylphosphinate to phosphachromones has been developed with high regioselectivity and good yields. The present reaction represents the first example of intramolecular addition of phenol to 1-alkynylphosphonates, which provides an approach to synthesize new phosphorus heterocycles. The resulting phosphachromones could have potential bioactivities.     

Rhodium(III)-catalyzed C-H alkylation of heterocycles with allylic alcohols in water: A reusable catalytic system for the synthesis of β-aryl ketones

A highly efficient, green and sustainable protocol for rhodium(III)-catalyzed C-H alkylation of heterocycles with allylic alcohols has been achieved, which affords a series of β-aryl ketones in high yields. The reaction proceeds smoothly in water under air, and works well with heterocycles such as indoles, indolines, pyrroles and carbazoles. Notably, the expensive rhodium catalyst in water could be easily separated from the organic products, and reused for at least five times without loss of its catalytic activity and selectivity, which is a promising, green and sustainable pathway for the synthesis of β-aryl ketones. To the best of our knowledge, this is the first example for the reuse of expensive rhodium catalyst in water.     

Application of the Rh(II) cyclization/cycloaddition cascade for the total synthesis of (+/-)-aspidophytine

[Structure: see text] A new strategy for the synthesis of (+/-)-aspidophytine has been developed and is based on a Rh(II)-catalyzed cyclization/dipolar cycloaddition sequence. The resulting [3+2]-cycloadduct undergoes an efficient Lewis acid mediated cascade that rapidly provides the complete skeleton of aspidophytine. The synthesis also features a mild decarbomethoxylation reaction.     

Au(III)-catalyzed tandem amination-hydration of alkynes: synthesis of α-(N-2-pyridonyl)ketones

A new Au(III)-catalyzed tandem amination-hydration reaction has been discovered, leading to the formation of α-(N-2-pyridonyl)ketones and heterocyclic analogues in good to excellent yields (14 examples, 48-90%). This reaction demonstrates the unusual use of a heterocyclic sp(2) nitrogen nucleophile in a gold-catalyzed 6-endo-dig cyclization. The tandem process allows rapid access to α-(N-2-pyridonyl)ketones, making them a convenient building block for the synthesis of more complex N-alkyl pyridone targets.     

Ruthenium-catalyzed diyne hydrative cyclization: synthesis of substituted 1,3-diene synthons

[reaction: see text]. A novel and versatile strategy for the synthesis of highly functionalized substituted 3-sulfolenes based on [CpRu(CH3CN)3]PF6-catalyzed hydrative cyclization has been developed. A marked ketone directing effect in ruthenium-catalyzed cyclization was observed for the first time. This provides complementary chemoselectivity for the synthesis of 3-sulfolenes and other cyclic enones. The utility of this method has been demonstrated by SO2 extrusion of 3-sulfolenes to afford 1,3-dienes and the subsequent inter- and intramolecular Diels-Alder reaction.     

Cu(I)-catalyzed cascade reaction of N-tosylhydrazones with 3-butyn-1-ol: A new synthesis of tetrahydrofurans

The Cu(I)-catalyzed cascade coupling/cyclization reaction of N-tosylhydrazones with 3-butyn-1-ol has been explored. This new strategy represents a simple platform for the synthesis of tetrahydrofurans in moderate to good yields.