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Transition-Metal Free Oxidative Alkynylation of 2-Oxindoles with Ethynylbenziodoxolone (EBX) Reagents
Abstract
We report an efficient direct alkynylations of 3-alkyl/aryl 2-oxindoles employing Waser’s ethynyl-1,2-BenziodoXol-3(1H)-one (EBX) to afford a wide variety of 3-alkynyl-3-alkyl/aryl 2-oxindole under transition-metal free condition. In addition to activated carbonyl compounds viz. 2-oxindole-3-alkylcarboxylates, this direct alkynylations protocol works efficiently on 3-alkyl/aryl 2-oxindols as well thereby widening the scope even further. Eventually, a Pd(0)-catalyzed asymmetric decarboxylative allylation of few products is shown to furnish synthetically viable enantioenriched 2-oxindoles with C-3 quaternary stereocenters.
... Numerous works were dedicated to the alkynylation of activated carbonyl compounds with the use of EBXs [67,68,[148][149][150]. In the pioneering work [67], Waser et al. proposed the ethynylation of keto, cyano, and nitroesters 142 with H-EBX 146, which is generated in situ from alkynylbenziodoxole 51c by TBAF treatment at low temperature (Scheme 29a). ...
... In their next work [68], an alkynylation method of cyclic keto esters was improved, as well as the scope of starting EBX reagents. Further reports concern the variations of reaction conditions (changing the base, additives, and temperature) and either carbonyl compounds or EBXs and, consequently, the scope of obtained products [148][149][150]. Stereoselective electrophilic α-alkynylation of α,α-disubstituted N-tert-butanesulfinyl ketimines 147 using TMS-EBX 51c in the presence of fluoride have been proposed (Scheme 29b) [151]. ...
Hypervalent iodine reagents are in high current demand due to their exceptional reactivity in oxidative transformations, as well as in diverse umpolung functionalization reactions. Cyclic hypervalent iodine compounds, known under the general name of benziodoxoles, possess improved thermal stability and synthetic versatility in comparison with their acyclic analogs. Aryl-, alkenyl-, and alkynylbenziodoxoles have recently received wide synthetic applications as efficient reagents for direct arylation, alkenylation, and alkynylation under mild reaction conditions, including transition metal-free conditions as well as photoredox and transition metal catalysis. Using these reagents, a plethora of valuable, hard-to-reach, and structurally diverse complex products can be synthesized by convenient procedures. The review covers the main aspects of the chemistry of benziodoxole-based aryl-, alkynyl-, and alkenyl- transfer reagents, including preparation and synthetic applications.
... Alkynyliodonium and alkynylbenziodoxolone reagents have also been employed in alkynyl transfer to other heterocycles. Kerwin demonstrated that the iodonium reagents 47c and 49a can be used to access the N-alkynylimidazoles 53a,b (Scheme 14) by reaction with the anion of 2-iodoimidazole (52), albeit in modest yields [31,32]. As part of a study on the oxidative alkynylation of 2-oxindoles, Bisai and co-workers prepared the N-alkynylindole 56 using the ethynylbeziodoxolone 55 (Scheme 15) [33]. ...
... In contrast, when the thermolysis was carried out in chlorobenzene containing 1,4-CHD, the imidazolopyridine 271 was isolated. Based upon these results and a subsequent study demonstrating the generality of these transformations [32], it was proposed that these products are the result of an unprecedented aza-Bergman/retro-aza-Bergman cascade involving initial formation of the diradical 272 which undergoes collapse to the cyclic cumulene 273. Cyclization of 273 to the carbene 275 followed by trapping with 1,4-CHD leads to the products 269a,b and 270, while an alternative cyclization to the benzyne 274 and trapping by solvent leads to 271. ...
Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These N-alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of N-alkynyl azoles mirrors that of the more extensively studied N-alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these N-alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of N-alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting N-alkynyl azoles in synthesis.
The stereoselective mechanochemical synthesis of Z‐enaminones and bis‐enaminones was achieved without any solid component in most cases, reacting 1,3‐dicarbonyl compounds with aliphatic/aromatic primary/secondary amines, which demonstrates the viability of reacting exclusively liquid reagents. The scale‐up was robust, from five to fifty and five hundred mmol without reduction in the reaction yield. The mechanochemical telescopic synthesis of β,γ‐unsaturated butyrolactams was achieved by formal [3+2] azaanulation reaction of intermediate enaminone with maleic anhydride, boosting the access of this potentially bioactive class of compound. The mechanochemical approach revealed its sustainable face in both syntheses, avoiding solid grinding auxiliary and purification by column chromatography. A symbol was suggested to differentiate the representation of the planetary ball mill from other mechanochemical reactors, wherein three spheres are surrounded by two curved arrows representing the two inherent movements of planetary trajectories of the reaction vessel of this equipment.
We developed a modular synthesis for 3,3-disubstituted oxindoles, utilizing readily accessible nitrones and acrylic acids. This approach facilitates the preparation of a diverse array of oxindoles through the variation of...
This review summarizes the structural and synthetic aspects of heterocyclic molecules incorporating an atom of a hypervalent main-group element. The term "hypervalent" has been suggested for derivatives of main-group elements with more than eight valence electrons, and the concept of hypervalency is commonly used despite some criticism from theoretical chemists. The significantly higher thermal stability of hypervalent heterocycles compared to their acyclic analogs adds special features to their chemistry, particularly for bromine and iodine. Heterocyclic compounds of elements with double bonds are not categorized as hypervalent molecules owing to the zwitterionic nature of these bonds, resulting in the conventional 8-electron species. This review is focused on hypervalent heterocyclic derivatives of nonmetal main-group elements, such as boron, silicon, nitrogen, carbon, phosphorus, sulfur, selenium, bromine, chlorine, iodine(III) and iodine(V).
In conjugated π systems, π-extended enolates generated in situ from unsaturated pronucleophiles through suitable HOMO-raising strategies tend to proceed via stereoselective vinylogous reactions that sterically favored remote functionalization (γ-, ε-,...
We report herein that a copper catalyst catalyzed efficient cross-coupling of aryl and alkenyl boronic acids with alkynyl-1,2-benziodoxol-3(1H)-ones to afford diaryl alkynes and enynes under mild visible light irradiation conditions using a catalytic amount of base or even in the absence of base. The reaction applies copper as the catalyst and tolerates a variety of functional moieties including aryl bromide and iodide.
Although alkynes are one of the smallest functional groups, they are among the most versatile building blocks for organic chemistry, with applications ranging from biochemistry to material sciences. Alkynylation reactions have traditionally relied on the use of acetylenes as nucleophiles. The discovery and development of ethynyl hypervalent iodine reagents have allowed to greatly expand the transfer of alkynes as electrophilic synthons. In this feature article the progress in the field since 2018 will be presented. After a short introduction on alkynylation reactions and hypervalent iodine reagents, the developments in the synthesis of alkynyl hypervalent iodine reagents will be discussed. Their recent use in base-mediated and transition-metal catalyzed alkynylations will be described. Progress in radical-based alkynylations and atom-economical transformations will then be presented.
With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.
Herein, we present a general electrochemical method to access unsymmetrical 3,3-disubstituted oxindoles by direct C–H functionalization where the oxindole fragment behaves as an electrophile. This Umpolung approach does not rely on stoichiometric oxidants and proceeds under mild, environmentally benign conditions. Importantly, it enables the functionalization of these scaffolds through C–O, and by extension to C–C or even C–N bond formation.
A general strategy for asymmetric approach to the hexahydropyrrolo[2,3-b]indole alkaloids sharing a vicinal quaternary-tertiary centers has been disclosed via Pd(0)-catalyzed N-deacylative allylations (N-DaA) (dr > 20:1). Utilizing this strategy, asymmetric total syntheses of pseudophrynamines 270 (3c) and 272A (3b) have been achieved from a 3-substituted N-acyl indole 8 (pro-nucleophile) with allyl alcohol (pro-electrophile).
α,α-Difluoroarylacetic acids are stable, inexpensive and readily available building blocks, which have been recently utilized as synthons to access various difluoromethylated aryl motifs via decarboxylative functionalization, such as alkylation, allylation, alkynylation, arylation, fluorination and the formation of carbon-heteroatom (O, S) bonds. In this review, we systematically summarize the decarboxylative functionalization of α,α-difluoroarylacetic acids and salts, and their mechanisms are also discussed.
Palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) provides an efficient and powerful strategy to construct quaternary stereocenters, which are widely present in biologically active natural products and approved drugs. In this short review, we summarize recent developments (since 2018) in the facile synthesis of quaternary stereocenters via DAAA methods. Several representative examples of the use of DAAA strategies for the total synthesis of complex natural products further demonstrate its synthetic potential in the realm of organic and medicinal chemistry.
1 Introduction
2 Construction of Quaternary Stereocenters via Palladium Catalyzed DAAA
3 Construction of Quaternary Stereocenters via Pd-Catalyzed Interceptive DAAA
4 Application of DAAA in Natural Product Synthesis
5 Conclusion
An efficient oxidative direct cyanations of 3-alkyl/aryl 2-oxindoles employing Cyano-1,2-BenziodoXol-3(1H)-one (CBX) (2a) has been reported under ‘transition-metal free’ condition to furnish a wide variety of 3-cyano 3-alkyl/aryl 2-oxindoles sharing an...
We report here a highly efficient method for direct alkynylations of 3‐alkyl/aryl/indolyl 2‐oxindoles using a series of 5‐(alkynyl)dibenzothiophenium triflates (3 a–e) under transition‐metal‐free conditions. This direct electrophilic alkynylation method gave access to a variety of 2‐oxindoles having quaternary center at the benzylic position in an operationally simple and inexpensive procedure. Further, chemoselective alkynylations could be realized in case of N−H free 2‐oxindoles and 3‐(indolyl)‐2‐oxindoles to afford a number of 3,3‐disubstituted‐2‐oxindoles. This methodology was then employed in the total synthesis of (±)‐deoxyeseroline (1 a) as well as C(3a)‐indolyl furoindoline moiety (31).
Late stage functionalization (LSF) through direct X-H manipulations (X = C, N) enable synthetic chemists to accelerate the diversification of natural products, agrochemicals and pharmaceuticals allowing rapid access to novel bioactive molecules without resorting to arduous de novo synthesis. LSF does not only allow to tap the hitherto unexplored chemical space but also renders the synthetic sequence more straight forward, atom-economic and cost-effective. In this regard, recent decade has witnessed the emergence of hypervalent iodine(III) reagents as a powerful synthetic tool owing to their easy availability, mild reaction conditions, remarkable oxidizing properties and high functional group tolerance. Iodine(III) reagents have received tremendous applications in the regio- and chemo-selective late-stage functionalization of a diverse variety of heterocycles through an exciting range of transformations, such as, oxidative amination, cross-dehydrogenative coupling (CDC), fluoroalkylation, azidation, halogenation and oxidation. The present review, classified according to the types of synthetic method involved, encompasses all these recent developments in the field of transition-metal-free iodine(III)-catalyzed/mediated direct functionalizations of heterocycles with representative examples and insightful mechanistic discussions.
Quaternary carbon stereocenters are common structural motifs in organic synthesis. The construction of these stereocenters in a catalytic and enantioselective manner remains a prominent synthetic challenge. In particular, methods for the synthesis of alkyne-substituted quaternary carbon stereocenters are very rare. Previous catalytic systems for hydroalkynylation of alkenes create tertiary stereocenters. We describe here an iridium catalyzed asymmetric hydroalkynylation of non-activated trisubstituted alkene. The hydroalkynylation of β,γ-unsaturated amides occurs with high regio- and enantio-selectivities to afford alkyne-substituted acyclic quaternary carbon stereocenters. Computational and experimental data suggest that the enantioselectivity is not only determined by the facial selectivity of the alkene but also by an alkene isomerization process. This strategy provides an efficient method to access alkyne-substituted acyclic quaternary carbon stereocenters with minimally functionalized starting materials.
Different 1,2-migration and cyclization of a variety of alkynylbenziodoxolones (EBXs) and amidoximes under one-base conditions are described. This process provides an efficient protocol for the divergent synthesis of two oxadiazine derivatives via switchable selectivity of EBXs controlled by simply varying the substituents of the amidoximes, which features transition metal-free conditions, simple execution, and high chemoselectivity.
A facile and efficient cyclization of homotryptamines and their derivatives has been established for the construction of 4a‐chlorotetrahydropyrido[2,3‐b]indoles and 3,3‐spirocyclic 3H‐indoles using hypervalent iodine (1‐chloro‐1,2‐benziodoxol‐3‐one) under mild conditions. The broad substrate scope and successful gram‐scale experiment grant this metal‐free transformation great potential for further application. image John Wiley & Sons, Ltd.
A novel phosphine sequentially catalyzed domino 1, 6-addition/annulation process has been developed using p-quinone methides ( p-QMs) and α-substituted allenoates which generates a series of chroman and tetrahydroquinoline derivatives containing an ethynyl-substituted all-carbon quaternary center with up to 97% yield and 20:1 dr. value. In this reaction, allenoates act as C2 synthons.
We describe the synthesis of α-alkynyl-β-substituted cyclic ketones and analogue chromanones via one-pot Michael addition/hypervalent iodine-based α-alkynylation. Cu(I)-catalyzed Michael addition using either alkyl-aluminum or Grignard reagents, followed by diastereoselective electrophilic alkynylation of the resulting enolate by 1-ethynyl-1λ3,2-benziodoxol-3(1H)-one (EBX) resulted in the α-alkynyl-β-substituted cyclic ketones or chromanones within 34-89% yield (16 examples). The reaction was successfully upscaled to the 5 mmol scale and further functionalization of a model alkynylated ketone was demonstrated.
The in-situ-generated zwitterionic allylic ylides between Morita–Baylis–Hillman carbonates from isatins and chiral tertiary amine catalysts underwent highly regioselective and enantioselective 1,3-oxo-ethynylation or 1,3-amino-sulfenylation reactions with silyl ethynyl-1,2-benziodoxol-3(1H)-ones or N-(aryl or alkylthio)imides, respectively, giving densely functionalized products bearing a quaternary stereogenic center. An array of diversely structured scaffolds were efficiently constructed from the products, showing the synthetic versatility of the current catalytic strategy.
An expeditious approach to catalytic enantioselective total syntheses of crinine-type Amaryllidaceae alkaloids has been accomplished via a Pd-catalyzed enantioselective decarboxylative allylation of allylenol carbonates as a key step (up to 96% ee). Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (−)-epi-elwesine (1b), (−)-crinine (1c), (−)-epi-crinine (1e), (−)-oxocrinine (1f), and (−)-buphanisine (1d) have been accomplished. Gratifyingly, naturally occurring Amaryllidaceae alkaloids such as (+)-vittatine (1g), (+)-epi-vittatine (1h), and (+)-epi-elwesine (1i) [enantiomers of (−)-1c, (−)-1e, and (−)-1b, respectively] have also been achieved by switching the antipode of ligand used in the catalytic enantioselective step.
The synthesis of a variety of 2-oxindoles bearing an all-carbon quaternary center at the pseudo benzylic position has been achieved via a 'transition-metal-free' intramolecular dehydrogenative coupling (IDC). The construction of 2-oxindole moieties was carried out through formation of carbon-carbon bonds using KOt-Bu-catalyzed one pot C-alkylation of β-N-arylamido esters with alkyl halides followed by a dehydrogenative coupling. Experimental evidences indicated toward a radical-mediated path for this reaction.
A highly enantioselective decarboxylative allylation of a mixture of enol carbonates and allyl esters has been achieved. The strategic viability of this methodology has been demonstrated through the total synthesis of cyclotryptamine alkaloids (-)- and (+)-folicanthine (1 a) and the formal total synthesis of (-)-chimonanthine (1 b), (+)-calycanthine (1 c), and (-)-ditryptophenaline (1 d).
A 'transition-metal-f ree' oxidative coupling of 2-oxindoles has been demonstrated in the presence of 1.2 equiv each of potassium tert-butoxide and iodine. The method yields a diverse range of structurally different homo-and heterodimerized 2-oxindoles bearing vicinal all-carbon quaternary centers of great synthetic importance. A radical-driven pathway has been tentatively proposed. C 2-Symmetric 1 dimeric cyclotryptamine alkaloids (1a−c, Figure 1) with a labile C 3a −C 3a′ σ-bond possess a diverse array of biological activities. 2 It is the presence of two vicinal all-carbon quaternary stereocenters in these alkaloids which are a challenge to the synthetic community, and hence they are attractive synthetic targets. 3 One of the plausible biogenetic pathways to achieve this involves a direct C−C bond formation via oxidative coupling 4,5 of two C−H bonds. Synthetic approaches in this direction are mainly concentrated toward the dimerization of 2-oxindoles such as 3a 6a,b and 3b 6c (Figure 1). However, these methods generally afford dimeric 2-oxindole products in poor to moderate yields, which might be due to the associated difficulty in the formation of a C−C bond containing a vicinal all-carbon quaternary center. Other approaches to dimeric cyclotryptamine alkaloids include direct oxidative dimerization of 3-substituted indoles. 7a−c,8
Organocatalytic alkynylation of various nitrogen- and/or sulphur-containing heterocyclic comounds using hypervalent iodine TMS-EBX by catalysis of tertiary amines under mild conditions is described. Developed metal-free methodology enables to obtain corresponding alkynylated heterocycles bearing quaternary carbon in high yields.
We report a catalytic stereoconvergent construction of vicinal all-carbon quaternary centers via double stereoablative enantioselective alkylation of a mixture having racemic and meso diastereomers of esters to afford exceptional levels of diastereo- (up to 17 : 1) and enantioselectivity (up to >99% ee). The strategy offers an efficient and general approach to dimeric cyclotryptamine alkaloids sharing a labile C3a-C3a' σ-bond in the hexahydropyrroloindoline core.
An effective transition-metal-free approach for the synthesis of 3-alkynyl-2-oxindoles through a radical-radical coupling process was developed. The reaction was general with respect to 2-oxindoles and iodoalkynes and provided the desired products bearing a quaternary center at C3 in good to excellent yields, making this method synthetically viable and attractive for the synthesis of spiro and fused 2-oxindole derivatives.
A direct enantioselective C-acylation of 3-substituted benzofuran-2(3H)-ones (with up to 97% ee) was developed using a chiral bicyclic imidazole catalyst OAc-DPI and an achiral tertiary amine additive DIPEA. The reaction mechanism for the direct C-acylation has been investigated using both experimental and theoretical studies.
The development of an efficient method for the site-selective substitution of unprotected phenols has long been considered as an attractive but challenging task. Herein, we describe a highly chemo- and ortho-selective substitution reaction of phenols with α-aryl α-diazoacetates with commercially available (C6 F5 )3 B as the catalyst. This reaction proceeds under simple and mild conditions with high efficiency, it features a wide substrate scope and can be easily scaled up.
Alkynes have found widespread applications in synthetic chemistry, biology, and materials sciences. In recent years, methods based on electrophilic alkynylation with hypervalent iodine reagents have made acetylene synthesis more flexible and efficient, but they lead to the formation of one equivalent of an iodoarene as side-product. Herein, a more efficient strategy involving a copper-catalyzed oxy-alkynylation of diazo compounds with ethynylbenziodoxol(on)e (EBX) reagents is described, which proceeds with generation of nitrogen gas as the only waste. This reaction is remarkable for its broad scope in both EBX reagents and diazo compounds. In addition, vinyl diazo compounds gave enynes selectively as single geometric isomers. The functional groups introduced during the transformation served as easy handles to access useful building blocks for synthetic and medicinal chemistry.
The alkynylation of thiols with EthynylBenziodoXolone (EBX) reagents is a fast and chemoselective method for the synthesis of thioalkynes. Combined experimental and computational studies are reported, which led to the identification of a new mechanism for this reaction, proceeding via an initial sulfur-iodine interaction followed by β-addition, α-elimination, and a 1,2-shift. Depending on the substituent on the alkyne, this mechanism can be favored over the previously disclosed concerted α-addition pathway.
The first enantioselective total syntheses of architecturally interesting prenylated pyrroloindole alkaloids, (-)-pseudophrynamines 272A (3d) and 270 (3b), have been achieved starting from enantioenriched 2-oxindoles having all-carbon quaternary stereocenters. A common strategy involving a thio-urea catalyzed aldol reaction is employed for the total synthesis of both spiro(pyrrolidinyl-oxindole) and hexahydropyrrolo[2,3-b]indole alkaloids.
Alkynes are used as building blocks in synthetic and medicinal chemistry, chemical biology, and materials science. Therefore, efficient methods for their synthesis are the subject of intensive research. Herein, we report the direct synthesis of alkynes from readily available carboxylic acids at room temperature under visible-light irradiation. The combination of an iridium photocatalyst with ethynylbenziodoxolone (EBX) reagents allowed the decarboxylative alkynylation of carboxylic acids in good yields under mild conditions. The method could be applied to silyl-, aryl-, and alkyl- substituted alkynes. It was particularly successful in the case of α-amino and α-oxo acids derived from biomass.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
This chapter discusses the chemistry and reactions of cyclic tautomers derived from tryptamines in the broad sense. There are many naturally occurring indole alkaloids that have substituents at the benzene moiety of the indole ring. The reactivity of cyclic tautomers differs from that of the open chain isomers, the indolic forms, and the 5 and 6 positions of cyclic tautomers are reactive sites for electrophilic substitution and oxidation. Biological oxidation of tryptophan to 5-hydroxytryptophan by a monooxygenase is well known, which suggests that cyclic tautomers play an important role in the enzymatic reaction, although the detailed mechanism is not established. Rhazidine is isolated from the bark of Aspidosperma quebrancho blanco as a major alkaloid, and is an example of indolenine–pyrroloindole tautomerism. The dye-sensitized photooxygenation of tryptophan gives different products depending on the various media.
We have investigated several oxindole derivatives in the pursuit of a 5-HT7 PET ligand. Herein the synthesis, chiral separation and pharmacological profiling of two possible PET candidates towards a wide selection of CNS-targets are detailed. Subsequent 11C-labeling and in vivo evaluation in Danish land race pigs showed that both ligands displayed high brain uptake. However, neither of the radioligands could be displaced by the 5-HT7-selective inverse agonist SB-269970.
Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene-ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinum-catalyzed cyclization/alkynylation domino process to selectively obtain C5- or C6-functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The selective reverse prenylation of 3-substituted-1H-indoles at C3 is described. The iridium-catalyzed reaction proceeds with high branched to linear selectivity (>20:1) for a variety of indoles. In addition, diastereoselective reverse prenylation of tryptophan methyl ester is disclosed, and its synthetic utility is demonstrated in syntheses of (+)-aszonalenin and (-)-brevicompanine B.
A new general three-stage strategy to access polycyclic ring systems bearing all-carbon quaternary centers with high enantioselectivity is reported. The required starting materials were readily accessed in racemic form through the α-alkynylation of ketoesters with EBX (EthynylBenziodoXolone) hypervalent iodine reagents. A Pd-catalyzed asymmetric decarboxylation allylation was then achieved in high yields and enantioselectivities with Trost's biphosphine ligands. Finally, transition-metal catalyzed cyclization of the obtained chiral enynes gave access to fused and spiro polycyclic ring systems constituting the core of many bioactive natural products.
Highly efficient protocols for the alkynylation of H-phosphi(na)tes and secondary phosphine oxides with silyl, aryl and alkyl ethynyl-benziodoxolone (EBX) reagents are reported. Alkynyl phosphorus compounds were obtained in 69–93% yield without the need for a transition metal catalyst at room temperature under open flask conditions.
A palladium(II) catalyst promotes condensation of an N-aryl imine and an alkynylbenziodoxolone derivative to afford a multisubstituted furan, whose substituents are derived from the alkynyl moiety (2-position), the imine (3- and 4-positions), and the 2-iodobenzoate moiety (5-position), along with an N-aryl formamide under mild conditions. The 2-iodophenyl group of the furan product serves as a versatile handle for further transformations. A series of isotope-labeling experiments shed light on the bond reorganization process in this unusual condensation reaction, which includes cleavage of the C-C triple bond and fragmentation of the carboxylate moiety.
Efficient asymmetric synthesis of spiro-2(3H)-furanones was achieved via phase-transfer-catalyzed highly enantioselective alkynylation of cyclic β-keto esters with hypervalent iodine reagents.
A new method for the electrophilic α-alkynylation of ketones was developed using hypervalent iodine under mild and metal-free conditions. Carbonyl compounds containing an α-acetylene group were obtained in good to excellent yields for several ketones using 1-[(trimethylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TMS-EBX) as an alkynylation agent in the presence of t-BuOK and TBAF in THF as solvent. Under the same conditions, an aldehyde was alkynylated.
An efficient electrophilic alkynylation of azlactones (oxazol-5(4H)-ones) is developed using alkynyl(phenyl)iodonium salts as the electrophilic alkyne source. After remarkably short reaction times, the desired alkyne functionalized azlactones are obtained in 60-97% yield and can be transformed easily into a variety of quaternary α-amino acid derivatives.
The addition of lead tetraacetate to a chloroform solution of alk-l-ynyltrimethylstannane results in the rapid formation of trimethylstannyl acetate and an unstable species, believed to be the corresponding alk-l-ynyllead triacetate, which can effect the rapid α-alkynylation of β-dicarbonyl compounds and nitronate salts.
Methods involving zinc–lead exchange for the one-pot
conversion of terminal acetylenes into alk-1-ynyllead(IV)
triacetates have been developed, and examples of the in situ
C-alkynylation of a number of carbon nucleophiles are reported.
An attempt to extend the reaction to phenols by treating
2,4,6-trimethylphenol with phenylethynyllead triacetate led to formation
of the spiro dienone 16, the structure of which was determined by X-ray
diffraction.
Hydrogen fluoride-induced protiodetrimethylsilylation of trimethylsilylethynyl(phenyl)iodonium tetrafluoroborate (5), prepared from bis(trimethylsilyl)ethyne (4), affords ethynyl(phenyl)iodonium tetrafluoroborate (1), a reagent for α-ethynylation of β-dicarbonyl compounds under mild conditions.
A twofold Pd-DAAA Pd-catalyzed decarboxylative allylic alkylation was used to construct two vicinal all-carbon quaternary stereocenters (marked in red) in a diastereo- and enantioselective fashion. The products of the Pd-DAAA were further elaborated to complete the formal syntheses of cyclotryptamine alkaloids. The twofold Pd-catalyzed transformation proceeds through an initial matched allylation followed by a second mismatched allylation to deliver the desired product.
[GRAPHICS] The asymmetric addition of terminal alkynes to a-keto ester was carried out using a catalytic amount of (11 S,2S)-3-(tert-butyldimethylsilyloxyl)2-N,N-(dimethylamino)-l-(p-nitrophenyl)-propane-1-ol in the presence of Zn(OTf)(2) to give the corresponding tertiary propargylic alcohols in high yields with up to 94% ee. N-Methylephedrine and Zn(OSO2CHF2)(2) were also examined in this reaction.
A thiol-alkynylation procedure utilizing the hypervalent iodine alkyne transfer reagent TIPS-ethynyl-benziodoxolone has been developed. This scalable reaction proceeds in five minutes at room temperature in an open flask using commercially available reagents. The scope of the reaction is broad, with a variety of phenolic, benzylic, heterocyclic, and aliphatic thiols undergoing alkynylation in excellent yield. The method is highly chemoselective as a vast array of functional groups are tolerated. The utility of the thiol-alkynylation in postsynthetic elaboration has been demonstrated through the facile installment of a fluorophore tag on a cysteine-containing peptide.
The highly Z-selective asymmetric conjugate addition of 3-substituted oxindoles to alkynyl carbonyl compounds has been developed by using scandium complexes of chiral N,N′-dioxides under mild conditions. The thermodynamically unstable Z-olefin derivatives were obtained in excellent yields and high enantiomeric and geometric control. The catalyst was also found to be effective in the asymmetric acetylenic substitution reaction of 3-substituted oxindoles, giving excellent enantioselectivities. A highly Z-selective asymmetric conjugate addition of alkynyl carbonyl compounds with 3-substituted oxindoles has been developed by using scandium complexes of chiral N,N′-dioxides (L) under mild conditions. The products were obtained in excellent yields and high enantiomeric and geometric control. The catalyst was also found to be effective in the asymmetric acetylenic substitution reaction of 3-substituted oxindoles, giving excellent enantioselectivities (see scheme).
Chemical Matching: C2- or C3-alkynylated furans were selectively synthesized by using gold catalysis. Direct C-H alkynylation of furans was achieved with C2 selectivity, and a domino cyclization/alkynylation process starting from allenes gave C3-alkynylated products. The exact matching of the structure of the gold catalyst and an electrophilic hypervalent iodine reagent was essential for success.
The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions, as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.
An intramolecular-dehydrogenative-coupling (IDC) using "transition-metal-free" oxidation conditions has been achieved to synthesize a variety of 2-oxindoles bearing an all-carbon quaternary stereogenic center at the benzylic position. The methodology involves a one-pot C-alkylation of β-N-arylamido esters (3, 6) with alkyl halides using potassium tert-butoxide concomitant with a dehydrogenative coupling. A radical-mediated pathway has been tentatively proposed for the oxidative process.
Phenyl(β-phenylethynyl)iodonium chloride, from iodosobenzene dichloride and lithium phenylacetylide, decomposes at room temperature to iodobenzene and chlorophenylacetylene. In solution this salt adds hydrogen chloride to give a new salt, phenyl(α-chlorostyryl)iodonium chloride. The latter cation has been isolated as the stable fluoroborate and chloride and as the much less stable iodide. The acetylenic and ethylenic iodonium salts react with the anion of 2-phenyl-1,3-indandione to give 2-phenyl-2-phenylethynyl-1,3-indandione and 2-phenyl-2-(α-chlorostyryl)-1,3-indandione, respectively, in good yield.
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The 3,3′-disubstituted oxindole structural motif is a prominent feature in many alkaloid natural products, which include all kinds of tetrasubstituted carbon stereocenters, spirocyclic or not, all-carbon or heteroatom-containing. The catalytic asymmetric synthesis of the tetrasubstituted carbon stereocenter at the C-3 position of the oxindole framework integrates new synthetic methods and chiral catalysts, reflects the latest achievements in asymmetric catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes. This review summarizes the recent progress in this area, and applications in the total synthesis of related bioactive compounds.
In addition to the well-established nucleophilic alkynylation, the use of electrophilic alkynes can expand tremendously the scope of acetylene transfer reactions. The use of metal catalysis has recently led to a rebirth of this research area. Halogenoalkynes, hypervalent alkynyliodoniums, acetylene sulfones and in situ oxidized terminal acetylenes are the most often used reagents for electrophilic alkynylation. Heteroatoms such as N, O, S and P can be now efficiently alkynylated. For C-C bond formation, electrophilic acetylenes can be coupled with different organometallic reagents. Recently, the first breakthrough in direct C-H and C[double bond, length as m-dash]C bond alkynylation has also been reported. Finally, sulfonyl acetylenes are efficient for alkyne transfer on carbon-centered radicals.
This report describes a full study of the gold-catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3- and 6-position of triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2-pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a π activation or an oxidative mechanism are most probable for the alkynylation reaction.
A method for the para-selective alkynylation of anilines is reported using AuCl as catalyst and triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) as an electrophilic acetylene equivalent. Para-alkynyl anilines substituted at positions 2 or 3 were obtained in one step from simple anilines under mild conditions (room temperature to 60 °C) under air. The methodology could also be extended to the alkynylation of trimethoxybenzenes.
Symmetrical and unsymmetrical diaryliodonium triflates have been synthesized from both electron-deficient and electron-rich arenes and aryl iodides with mCPBA and triflic acid. A thorough investigation of the optimization, scope and limitations has resulted in an improved one-pot protocol that is fast, high-yielding, and operationally simple. The reaction has been extended to the direct synthesis of symmetrical iodonium salts from iodine and arenes, conveniently circumventing the need for aryl iodides.
The Pd-catalyzed asymmetric allylic alkylation (AAA) is one of the most useful and versatile methods for asymmetric synthesis known in organometallic chemistry. Development of this reaction over the past 30 years has typically relied on the use of an allylic electrophile bearing an appropriate leaving group to access the reactive Pd(π-allyl) intermediate that goes on to the desired coupling product after attack by the nucleophile present in the reaction. Our group has been interested in developing alternative approaches to access the reactive Pd(π-allyl) intermediate that does not require the use of an activated electrophile, which ultimately generates a stoichiometric byproduct in the reaction that is derived from the leftover leaving group. Along these lines, we have demonstrated that allenes can be used to generate the reactive Pd(π-allyl) intermediate in the presence of an acid cocatalyst, and this system is compatible with nucleophiles to allow for formation of formal AAA products by Pd-catalyzed additions to allenes. This article describes our work regarding the use of oxindoles as carbon-based nucleophiles in a Pd-catalyzed asymmetric addition of oxindoles to allenes (Pd-catalyzed hydrocarbonation of allenes). By using the chiral standard Trost ligand (L1) and 3-aryloxindoles as nucleophiles, this hydrocarbonation reaction provides products with two vicinal stereocenters, with one being quaternary, in excellent chemo-, regio-, diastereo-, and enantioselectivities in high chemical yields.
Pd-catalyzed asymmetric prenylation of oxindoles to afford selectively either the prenyl or reverse-prenyl product has been demonstrated. Control of the regioselectivity in this transformation is governed by the choice of ligand, solvent, and halide additive. The resulting prenylated and reverse-prenylated products were transformed into ent-flustramides and ent-flustramines A and B. Additionally, control of the regio- and diastereoselectivity was obtained using π-geranylpalladium complexes.
Studies conducted in the field of homogeneous catalysis of decarboxylative allylation and benzylation reactions are presented. Shimizu and Ishii utilized the regiospecificity of decarboxylative coupling to allylate an α-fluoro ketone that proceeds via a fluorinated enolate. Behenna and Stoltz and later Trost and co-workers demonstrated the ability to control the stereochemistry at the R-carbon via enantioselective decarboxylative allylation of enol carbonates. Trost et al. have circumvented the sluggish transformations of ester enolate derivatives by utilizing 2-acyl imidazoles as surrogates for ester enolates. company utilized DcA of a dienol carbonate in their synthesis of trospectomycin sulfate, an aminocyclitol antibiotic. In 2009, Recio and Tunge published an improved synthetic protocol for decarboxylative allylations of α-cyanoacetic esters.
Azonazine, a unique hexacyclic dipeptide, was isolated from a Hawaiian marine sediment-derived fungus eventually identified as Aspergillus insulicola. Its absolute configuration, 2R,10R,11S,19R, was established using NMR, HRESIMS, and CD data plus insights derived from molecular models. A possible route for its biogenesis is proposed, and biological properties were explored against cancer cell lines and in an NFκB inhibition assay.
In the last decades, hypervalent iodine reagents have raised from chemical curiosities to mainstream reagents in organic synthesis. The use of benziodoxole-derived reagents has been especially successful in oxidation methods, whereas non-cyclic iodinanes have been used both for oxidation and atom-transfer reactions. On the other hand, the exceptional properties of benziodoxole reagents for atom-transfer reactions have only started to attract the attention of the synthetic community more recently. In this review, progress in the use of these compounds for C-X and C-C bond formations will be presented. In particular, recent breakthroughs in trifluoromethylation and alkynylation reactions have been realized since 2006 based on benziodoxole-derived reagents and these results are the main focus of this article.
Gemeinsam sind wir stark! Die kooperative Aktivierung des hypervalenten Iodreagens TIPS-EBX mit einem Goldkatalysator und einer Brønsted-Säure ermöglichte die erste direkte Ethinylierung von Thiophenen bei Raumtemperatur (siehe Schema; TFA=Trifluoressigsäure). Die erhaltenen Ethinylthiophene sind wichtige Bausteine für organische Farbstoffe und elektronische Materialien.
Hot alkyne! The in situ generation of Ethynyl-1,2-BenziodoXol-3(1H)-one (EBX) from the corresponding silyl protected reagent using TBAF is reported. EBX displayed exceptional acetylene transfer ability to stabilized enolates, even at –78 °C. The mild reaction conditions allowed the first ethynylation reactions of linear keto, cyano and nitro esters in high yields to give all-carbon quaternary centers or non-natural amino acids after selective reduction of the nitro group.