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Richard P Hsung - One of the best experts on this subject based on the ideXlab platform.
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a silver i catalyzed intramolecular ficini s 2 2 cycloaddition employing Ynamides
Tetrahedron Letters, 2015Co-Authors: Xiao-na Wang, Jun Deng, Richard P HsungAbstract:We reported the first examples of Ficini’s [2 + 2] cycloaddition, or the Ficini reaction, employing Ynamides in 2010 after a 13-year long attempt.1 This final success came more than 40 years after Ficini2–5 had disclosed perhaps the most useful carbon-carbon bond forming reaction involving ynamines.2,6 The Ficini reaction3 entails a stepwise and thermally driven [2 + 2] cycloaddition7 of ynamines with α,β-unsaturated ketones, while our reaction1 with Ynamides 1 were promoted with Cu(II)/Ag(I) salts, leading to the formation of cyclobutenamides 3 via the proposed zwitter ionic intermediate 2 [Scheme 1]. Mezzetti8 subsequently reported a beautiful account of asymmetric Ficini [2 + 2] cycloadditions using a chiral dicationic Ru(II) complex. However, an intramolecular variant of the Ficini reaction has remained untapped using Ynamides.9 Given that Ynamides have become a powerful and versatile functional group in organic synthesis in the last 20 years,10,11 a successful intramolecular Ficini reaction using Ynamides tethered with an enone motif as shown in 4 could prove to be a tantalizing possibility for constructing complex polycycles. We wish to communicate here our success in establishing the concept of an intramolecular [2 + 2] cycloaddition employing Ynamides and its current limitations. Scheme 1 Ficini’s [2 + 2] Cycloaddition Using Ynamides. Our work commenced first with a new finding experimentally for the intermolecular [2 + 2] cycloaddition. We observed that it is not necessary to use both Cu(II) and Ag(I) catalysts to promote the intermolecular reaction. As shown in Table 1, the initial keys to render the [2 + 2] cycloaddition successful are that Ynamides cannot be terminally unsubstituted as in 7 [entries 1 and 2], and that 20 mol% CuCl2 and 60 mol% AbSbF6 were found to be the most suitable catalytic system1 to afford the desired cycloadduct 10 in high yield from Ynamide 9 [entry 3]. However, our efforts post publication reveal that either Cu(II) or Ag(I) salt alone could catalyze this cycloaddition, and that silver is actually more superior. More specifically, AgNTf2 in 10 mol% appears to be the best catalyst overall [entries 9 and 10]12 in providing comparable outcome as those promoted by both CuCl2 and AbSbF6. While AgBF4 also worked quite effectively [entry 6], the reaction took a much longer time [entries 6–8]. Table 1 The Effectiveness of Silver Salts. The discovery of Ag(I) catalyst proves out to be essential, as it turned out that the presence of 20 mol% CuCl2 and 60 mol% AbSbF6 were completely ineffective for the intramolecular [2 + 2] cycloaddition of Ynamides 11a–d.13–15 Consequently, we focused on the silver catalyst and quickly found that AgNTf2 again was the best silver salt [entries 1–3 versus entry 4 in Table 2]. In addition, yields were better when the reaction was carried out in CH2Cl2 [entry 4 versus entries 6–9] and at higher concentrations [entries 4 and 12 versus entries 10 and 11].16 Lastly, the nature of the electron withdrawing group on the nitrogen atom did not appear to have a significant impact on the reaction [entry 4 versus entries 13–15]. Table 2 A Ag(I)-Catalyzed Intramolecular Cycloaddition. Relative stereochemistry was assigned using nOe experiments performed using cycloadduct 12a [Figure 1], and the scope of this cycloaddition is showcased in Figure 2. It is noteworthy that when the nitrogen atom is substituted with an alkene, yields of the cycloaddition are lower [see 13–16]. This is likely due to competing complexation of the olefin with the silver catalyst followed by decomposition pathways. Only when there is sufficient distance between the olefin and the nitrogen atom, the cycloaddition could be improved [see 16]. Figure 1 Stereochemical Assignment of 12a via nOe Experiment. Figure 2 Scope of the Intramolecular Cycloaddition. Unfortunately, when we turned to Ynamide 20 in hope of obtaining cycloadduct 21, we found instead only the half-cycloaddition product 22 after numerous attempts [Scheme 2]. While the relative stereochemistry is unassigned, isolation of 22 is most likely a result of direct hydrolysis of the zwitter ionic intermediate 23 after the first bond formation, although the desired cycloaddition could have taken place, and that a subsequent hydrolytic ring-opening of the desired cycloadduct 21 could lead to 22. On the other hand, only when utilizing AgOTf as the catalyst, did we find the corresponding half-cycloaddition product 24 from Ynamide 11a. In all other cases, cycloadducts in which the cyclobutenamide is fused to a 6-membered ring could be prepared without problem. This distinct contrast suggests that the ring strain in the anticipated cycloadduct 21, where the cyclobutenamide is fused to a 5-membered ring, could be responsible in deterring the cycloaddition pathway.17 Scheme 2 Observations of the Half-Cycloaddition Products. We then examined electrocyclic ring-opening of these [2 + 2] cycloadducts.18 As shown in Scheme 3, a highly torquoselective conrotatory ring-opening of cyclobutenamides 12a and 12d could take place effectively at 100 °C to afford 2-amidodienes 25a and 25d, respectively. Likewise, 2-amidodienes 26 and 27 could also be obtained in high yields from their respective starting cyclobutenamides 15 and 16. The high level of torquoselectivity is predictably a result of the ring-junction hydrogen [in blue] rotating inwardly with respect to the cyclobutene ring to avoid the formation a trans-cyclohexene ring. This rotational preference trumps the inward rotation favored from the electron withdrawing carbonyl group based on Houk’s prediction,19 and leads to the exclusive formation of Z-vinylogous amide, which was assigned using nOe experiments. Scheme 3 Pericyclic Ring-Opening of the [2 + 2] Cycloadducts. In addition, it is noteworthy that these 2-amidodienes favor the S-trans conformation with ∆E being 4.03 kcal mol−1 for 25a from B3LYP/6-31G* [Spartan™] calculations. Such conformational preference for S-trans is likely to avoid allylic strain. Consequently, our preliminary attempts to carry out an obvious application in the form of [4 + 2] cycloadditions were not successful using 2-amidodienes 26 and 27, with the latter as an attempt for a possible intramolecular [4 + 2] cycloaddition.20 We are currently exploring other possible applications that can distinctly showcase synthetic potential of these highly functionalized unique dienes. We have described here an intramolecular [2 + 2] cycloaddition using N-sulfonyl substituted Ynamides tethered to an enone motif. This intramolecular Ficini reaction could be effectively catalyzed using AgNTf2. Our work represents the first examples of an intramolecular variant of Ficini’s original ynamine–[2 + 2] cycloaddition. Efforts are underway in further development of this new cycloaddition and its applications.
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Novel Ynamide structural analogues and their synthetic transformations.
ARKIVOC : free online journal of organic chemistry, 2014Co-Authors: Richard P HsungAbstract:This Highlight accounts for a recent phenomenon in which a series of novel Ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these de novo Ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses.
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synthesis of de novo chiral γ amino Ynamides using lithiated Ynamides observation of a unique 5 endo dig cyclization with an inversion of s center
Heterocycles, 2014Co-Authors: Xiao-na Wang, Richard P Hsung, Mingcan Lv, Rui QiAbstract:We describe herein details of our efforts in developing a highly stereoselective synthesis of de novo chiral γ-amino-Ynamides through additions of lithiated Ynamides to Ellman-Davis chiral N-tert-butanesulfinyl imines. While additions of Ynamides could be highly stereoselective even without Lewis acids, the use of BF3-OEt2 completely reversed the stereoselectivity. On the other hand, additions of oxazolidinone-substituted, oxazinanone-substituted and tetrahydropyrimidinone-substituted Ynamides behaved quite differently and functioned better with BF3-OEt2. The chirality of the oxazolidinone ring exerts no impact on the selectivity. This work also features a unique 5-endo-dig cyclization of oxazolidinone-substituted γ-amino-Ynamides that could be promoted with acid, leading to isothiazoles and 2,3-dihydro-isothiazole S-oxides.
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Ynamides a modern functional group for the new millennium
Chemical Reviews, 2010Co-Authors: Kyle A. Dekorver, Andrew G Lohse, Ryuji Hayashi, Yu Zhang, Richard P HsungAbstract:An Overview on Ynamines Alkynes represent one of the most important and versatile building blocks in organic synthesis. Heteroatom-substituted alkynes, which can be considered as subgroups of alkynes, have also been vastly utilized in developing synthetic methods. In particular, ynamines [1-amino-alkynes or N-alkynyl amines] became the most valuable subgroup of alkynes after the establishment of their practical synthesis in the 1960's. The first attempt at preparation of an ynamine was reported by Bode1,2 in 1892. While well-characterized ynamines were reported in 19583 and 1960,4 a practical synthesis was not achieved until the effort led by Viehe5 in 1963 in addition to other subsequent works. In the ensuing twenty years, the synthetic significance of ynamines in organic and organometallic chemistry was firmly established by the work of many creative synthetic chemists. These elegant pioneer works have been informatively and carefully reviewed by Viehe in 19676 and 1969;7 Ficini in 1976;8 Pitacco and Valentin9 in 1979; Collard-Motte and Janousek10 in 1986; Himbert11 in 1993; and most recently by us12,13 and Katritzky14. Open in a separate window The synthetic eminence of ynamines is well merited because of the predicable regioselectivity in their transformations as shown by the generalization in Scheme i, and more importantly, because they are inherently highly reactive. However, this latter attribute is also the source of the limitation that has seriously hampered the development of ynamine chemistry, thereby shortening the period of its prominence in synthesis. Ynamines are very sensitive toward hydrolysis, as protonation of the electron-rich alkynyl motif affords reactive keteniminium intermediates, which upon trapping with water leads to simple amides in a rather expensive manner (Scheme i). This hydrolytic instability has caused much difficulty in the experimental preparation and general handling of ynamines, and more detrimentally, rendered ynamine chemistry inaccessible. Open in a separate window Scheme i Consequently, the synthetic utility of ynamines has suffered a dramatic decline during the last thirty years.15 The most glaring limitations have been in the development of intramolecular and stereoselective reactions.7–14 The only reported intramolecular reaction of ynamines was Genet and Kahn's acid catalyzed addition of a hydroxyl group to an ynamine [i→ii in Scheme ii] in 1980,16 and although clever, it constitutes a hydrolytic process. Open in a separate window Scheme ii Besides Reinhoudt's17 sole account in 1987 reporting hetero-[4 + 2] cycloadditions of chiral ynamine iii with nitroalkenes that led to cycloadducts iv in modest de, the only other notable studies were reported ten years later by Fischer18 showcasing [2 + 2] cycloadditions of chiral Ynamides v and vi with vinylidene chromium carbene complexes, and another three years later by Pericas19 in their Pauson-Khand cycloadditions using chiral ynamines vii.
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Synthesis of Amidines Using N-Allyl Ynamides. A Palladium-Catalyzed Allyl Transfer Through an Ynamido-π-Allyl Complex
Organic letters, 2009Co-Authors: Yu Zhang, Yanshi Zhang, Kyle A. Dekorver, Andrew G Lohse, Jian Huang, Richard P HsungAbstract:A de novo transformation of N-allyl-N-sulfonyl Ynamides to amidines is described featuring a palladium-catalyzed N-to-C allyl transfer via ynamido-palladium-π-allyl complexes.
Yuanhong Liu - One of the best experts on this subject based on the ideXlab platform.
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nickel catalyzed β regioselective amination cyclization of Ynamide nitriles with amines synthesis of functionalized 3 aminoindoles and 4 aminoisoquinolines
Organic Letters, 2021Co-Authors: Xin Xie, Yi Gan, Gaonan Wang, Yuanhong LiuAbstract:A highly regioselective nickel/Lewis acid catalyzed amination/cyclization of Ynamide-nitriles with amines involving β-addition has been developed. The reaction offers an attractive and efficient route for the synthesis of 3-aminoindoles and 4-aminoisoquinoline derivatives. The Ts-group on the Ynamide acts as a directing group to produce the alkenyl nickel species with high regioselectivity.
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gold i catalyzed formal intramolecular dehydro diels alder reaction of Ynamide ynes synthesis of functionalized benzo b carbazoles
Organic Letters, 2018Co-Authors: Gaonan Wang, Xin Xie, Yuanhong LiuAbstract:A gold-catalyzed cycloisomerization of Ynamide-ynes via a formal dehydro-Diels–Alder reaction has been developed, providing an attractive route to diversely substituted benzo[b]carbazoles. The reaction likely proceeds via regioselective attack of the pendant alkyne moiety to a keteniminium ion intermediate followed by benzannulation. The method offers several advantages such as high efficiency, mild reaction conditions, and wide functional group tolerance and serves as a highly useful complement to the thermal DDA reactions of Ynamide-ynes.
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Gold(I)-Catalyzed Formal Intramolecular Dehydro-Diels–Alder Reaction of Ynamide-ynes: Synthesis of Functionalized Benzo[b]carbazoles
2018Co-Authors: Gaonan Wang, Xin Xie, Yuanhong LiuAbstract:A gold-catalyzed cycloisomerization of Ynamide-ynes via a formal dehydro-Diels–Alder reaction has been developed, providing an attractive route to diversely substituted benzo[b]carbazoles. The reaction likely proceeds via regioselective attack of the pendant alkyne moiety to a keteniminium ion intermediate followed by benzannulation. The method offers several advantages such as high efficiency, mild reaction conditions, and wide functional group tolerance and serves as a highly useful complement to the thermal DDA reactions of Ynamide-ynes
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gold i catalyzed 1 2 acyloxy migration 3 2 cycloaddition of 1 6 diynes with an Ynamide propargyl ester moiety highly efficient synthesis of functionalized cyclopenta b indoles
ChemInform, 2015Co-Authors: Jun Liu, Ming Chen, Liangwei Zhang, Yuanhong LiuAbstract:A gold-catalyzed cycloisomerization of 1,6-diynes containing an Ynamide propargyl ester or carbonate moiety is developed that provides an attractive route to diverse-substituted 3-acyloxy-1,4-dihydrocyclopenta[b]indoles.
Nan Zheng - One of the best experts on this subject based on the ideXlab platform.
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Rhodium-Catalyzed Highly Regioselective and Stereoselective Intermolecular Hydrosilylation of Internal Ynamides under Mild Conditions
2018Co-Authors: Nan Zheng, Wangze Song, Tiexin Zhang, Yubin Zheng, Lingyue ChenAbstract:A rhodium-catalyzed highly regio- and stereoselective intermolecular hydrosilylation of internal Ynamides has been developed. With the neutral rhodium complex [Rh(CO)2Cl]2 as a catalyst and the bulky silanes as reactants, various Ynamides underwent hydrosilylation smoothly at room temperature with an excellent β-regioselectivity and anti-stereoselectivity. The synthetically versatile β-silyl (Z)-enamide products could be further transformed to diverse useful building blocks. Several possible mechanisms are proposed to rationalize this unique formal trans-addition-type selectivity
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iridium catalyzed highly regioselective azide Ynamide cycloaddition to access 5 amido fully substituted 1 2 3 triazoles under mild air aqueous and bioorthogonal conditions
Organic Letters, 2017Co-Authors: Wangze Song, Nan ZhengAbstract:A highly regioselective method to access 5-amido fully substituted 1,2,3-triazoles by iridium-catalyzed azide-Ynamide cycloaddition under mild, air, aqueous, and bioorthogonal conditions is reported. The excellent regioselectivities may derive from the strong coordination between the carbonyl oxygen of Ynamide and the π-acidic iridium. Since the iridium ion is insensitive to oxygen/water and exhibits low cytotoxicity, it could catalyze this reaction in both organic and biological environments efficiently. Preparation in gram-scale and application in carbohydrates highlight this method.
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Iridium-Catalyzed Highly Regioselective Azide–Ynamide Cycloaddition to Access 5‑Amido Fully Substituted 1,2,3-Triazoles under Mild, Air, Aqueous, and Bioorthogonal Conditions
2017Co-Authors: Wangze Song, Nan ZhengAbstract:A highly regioselective method to access 5-amido fully substituted 1,2,3-triazoles by iridium-catalyzed azide–Ynamide cycloaddition under mild, air, aqueous, and bioorthogonal conditions is reported. The excellent regioselectivities may derive from the strong coordination between the carbonyl oxygen of Ynamide and the π-acidic iridium. Since the iridium ion is insensitive to oxygen/water and exhibits low cytotoxicity, it could catalyze this reaction in both organic and biological environments efficiently. Preparation in gram-scale and application in carbohydrates highlight this method
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gold catalyzed intramolecular tandem cyclization of indole Ynamides diastereoselective synthesis of spirocyclic pyrrolidinoindolines
Chemistry-an Asian Journal, 2016Co-Authors: Nan Zheng, Yuanyuan Chang, Lijie Zhang, Jianxian Gong, Zhen YangAbstract:A gold-catalyzed intramolecular tandem cyclization of indole-Ynamide affords tetracyclic spirocyclic pyrrolidinoindoline bearing an all-carbon quaternary stereocentre in a single step; however, when the reaction was carried out in the presence of BF3 ⋅Et2 O, the corresponding tricyclic spirocyclic pyrrolidinoindoline-based enones are produced through a key 1,5-hydride shift. The developed chemistry provides a diastereoselective and straightforward entry to structurally diverse polycylic pyrrolidinoindolines from indole-Ynamides in one-pot reactions under mild conditions.
Zhen Yang - One of the best experts on this subject based on the ideXlab platform.
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gold catalyzed intramolecular tandem cyclization of indole Ynamides diastereoselective synthesis of spirocyclic pyrrolidinoindolines
Chemistry-an Asian Journal, 2016Co-Authors: Nan Zheng, Yuanyuan Chang, Lijie Zhang, Jianxian Gong, Zhen YangAbstract:A gold-catalyzed intramolecular tandem cyclization of indole-Ynamide affords tetracyclic spirocyclic pyrrolidinoindoline bearing an all-carbon quaternary stereocentre in a single step; however, when the reaction was carried out in the presence of BF3 ⋅Et2 O, the corresponding tricyclic spirocyclic pyrrolidinoindoline-based enones are produced through a key 1,5-hydride shift. The developed chemistry provides a diastereoselective and straightforward entry to structurally diverse polycylic pyrrolidinoindolines from indole-Ynamides in one-pot reactions under mild conditions.
Akhila K. Sahoo - One of the best experts on this subject based on the ideXlab platform.
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Ring Expansion and 1,2‐Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies
Chemistry an Asian journal, 2019Co-Authors: Rajeshwer Vanjari, Shubham Dutta, B. Prabagar, Vincent Gandon, Akhila K. SahooAbstract:Demonstrated herein is an AuI -catalyzed annulation of sulfonyl-protected Ynamides with substituted 1,2-benzisoxazoles for the synthesis of E-benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold-activated Ynamide, ring expansion of the benzisoxazole fragment to provide an α-imino vinylic gold intermediate, and 1,2-migration of the sulfonamide motif to the masked carbene center to deliver the respective ring-expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α-imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.
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Alkyne Versus Ynamide Reactivity: Regioselective Radical Cyclization of Yne-Ynamides.
Angewandte Chemie (International ed. in English), 2019Co-Authors: Shubham Dutta, Vincent Gandon, Rajendra K. Mallick, Rangu Prasad, Akhila K. SahooAbstract:Ynamides are typically more reactive than simple alkynes and olefins. However, a serendipitous observation revealed a rare case where the reactivity of simple alkynes exceeds that of Ynamides. This led to the development of a unique sulfur-radical-triggered cyclization of yne-tethered Ynamides, which involves attack of the alkyne by a thiyl radical followed by cyclization with the Ynamide. A wide range of novel 4-thioaryl pyrroles that could tolerate common functional moieties and N-protecting groups were expediently constructed by this strategy. The current method contrasts with the typical cyclization of yne-Ynamides, which involves the attack of the alkyne moiety by the Ynamide core. Control experiments and DFT calculations supported the participation of the sulfur radical in the reaction and the regioselective cyclization. The synthetic potential of the substituted pyrroles is also discussed.
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Gold-Catalyzed syn-1,2-Difunctionalization of Ynamides via Nitrile Activation.
Organic letters, 2018Co-Authors: Rajeshwer Vanjari, Shubham Dutta, Vincent Gandon, Manash Protim Gogoi, Akhila K. SahooAbstract:Developed is an unprecedented Au(I)-catalyzed syn-1,2-difunctionalization of Ynamides with 2-aminobenzonitriles via nitrile activation. The coupling between Ynamides and 2-aminobenzonitriles is explicitly regioselective, providing a straightforward access to 2,4-diamino-substituted quinolines. Density functional theory (DFT) study provides insightful information and rationalizes the reaction pathway. It shows how the synergy between Ynamide π-activation and nitrile σ-coordination by the Au(I) catalyst makes the cyclization viable.
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gold catalyzed cyclization and cycloisomerization of yne tethered Ynamide the significance of a masked enol equivalent of an amide
Organic and Biomolecular Chemistry, 2016Co-Authors: Sanatan Nayak, B. Prabagar, Akhila K. SahooAbstract:This perspective briefly describes the conceptual manifestation of a Bronsted acid promoted Au-catalyzed cyclization of yne-tethered Ynamides for the construction of novel N-heterocycles. A hetero-atom assisted intramolecular 6-endo-dig cyclization of a transient ketene N,O-acetal (a masked enol-ether of an amide), generated from an ambivalent Ynamide through the attack of p-TsOH, with a Au-activated yne-motif creates dihydropyridinones and benzo[f]dihydroisoquinolones. The Au(I)-catalyzed cycloisomerization of an alkyne-tethered ketene N,N-acetal to manufacture unusual cyclobutene-fused azepine scaffolds is also highlighted.
