Dr. Enrica Alberti and Dr. Marta Brucka are acknowledged for the collection and registration of the NMR spectra. We thank Dr. Francesco Tibiletti and Dr. Gabriella Ieronimo for helpful discussions and experimental assistance.

1. Preliminary preparation of the Jones Reagent
<ol>
	<li>Add 25 g (0.25 mol) of chromium trioxide using a spatula in a 500 mL beaker that contains a magnetic stirring bar.</li>
	<li>Add 75 mL of water and keep the solution under magnetic stirring.</li>
	<li>Add slowly 25 mL of concentrated sulfuric acid with careful stirring and cooling in an ice-water bath. 
	NOTE: Now the solution is ready and is stable and usable for many oxidation procedures; the concentration of the solution prepared by this procedure is 2.5 M.</li>
</ol>
2. Synthesis of 1-phenyl-2-propyne-1-one
<ol>
	<li>Add 75 mL of acetone in an open-air round bottom flask that contains a magnetic stirring bar.</li>
	<li>Add 2.0 g (15.13 mmol) of 1-phenyl-2-propyne-1-ol via a glass Pasteur pipette.</li>
	<li>Keep the reaction mixture at 0 &#176;C and under magnetic stirring.</li>
	<li>Add a solution of Jones reagent dropwise till the presence of a persistent orange color.</li>
	<li>Add 2-propanol dropwise till the excess of Cr(VI) reactant is consumed to the point of a green color.</li>
	<li>Filter the solution through a pad of diatomaceous earth.</li>
	<li>Concentrate the washings by rotary evaporation obtaining an oil.</li>
	<li>Dissolve the oil in 100 mL of CH2Cl2 and put in a separatory funnel.</li>
	<li>Wash this organic phase with a saturated solution of NaHCO3 (2 x 125 mL).</li>
	<li>Wash the organic layer with brine (125 mL).</li>
	<li>Dry the organic solution over anhydrous Na2SO4 and filter it.</li>
	<li>Evaporate the solution obtaining 1.77 g of 1-phenyl-2-propyne-1-one as a yellow solid (quantitative yield).</li>
	<li>Leave the solid to dry in vacuum.</li>
	<li>Analyze and characterize by 1H-NMR.</li>
</ol>
3. Preparation of 4-nitronitrosobenzene
<ol>
	<li>Add 16 g of potassium peroxymonosulfate (2KHSO5&#183;KHSO4&#183;K2SO4) (26 mmol) using a spatula in a beaker, open to air that contains a magnetic stirring bar.</li>
	<li>Add 150 mL of water and keep the solution at 0 &#176;C under magnetic stirring.</li>
	<li>Add 3.6 g of 4-nitroaniline (26 mol) using a spatula.</li>
	<li>Stir the suspension at room temperature.</li>
	<li>Check the reaction by TLC till the complete conversion of 4-nitroaniline (Rf4-Nitroaniline = 0.44, Rf4-Nitronitrosobenzene = 0.77; CH2Cl2 as eluent).</li>
	<li>Filter the crude reaction mixture on a Buchner after 48 h.</li>
	<li>Put the solid in a one-neck round bottom flask.</li>
	<li>Recrystallize the solid in methanol (50 mL).</li>
	<li>Warm the suspension using a heat gun till boiling point of methanol and filter immediately the hot suspension.</li>
	<li>Discard the solid and reuse it eventually for another recrystallization.</li>
	<li>Filter the second precipitate formed in the Erlenmeyer flask when the solution reaches room temperature.</li>
	<li>Leave the solid to dry in vacuum on a Buchner funnel.</li>
	<li>Characterize the solid by 1H-NMR.</li>
</ol>
4. Synthesis of 3-benzoyl-1-hydroxy-5-nitroindole
<ol>
	<li>Connect all the oven dried glassware (a 250 mL two neck round bottom flask containing a magnetic stirring bar, a stopcock, a refrigerant and a joint to connect to vacuum/nitrogen system) and put under vacuum for 30 min.</li>
	<li>At room temperature, after some cycles of vacuum/nitrogen, flush all the glassware with nitrogen and leave it under inert atmosphere.</li>
	<li>Add 1.52 g (10 mmol) of 4-nitronitrosobenzene under inert atmosphere.</li>
	<li>Add 1.30 g (10 mmol) of 1-phenyl-2-propyne-1-one.</li>
	<li>Add 80 mL of toluene via a syringe and keep the reaction mixture under magnetic stirring at 80 &#176;C.</li>
	<li>After few minutes, check the complete solubilization of the reactants.</li>
	<li>Verify the formation of an orange precipitate after about 30-40 min at 80 &#176;C.</li>
	<li>After the complete precipitation of an orange solid (about 2.5 h), turn off the heating and leave the reaction to reach room temperature.</li>
	<li>Filter the mixture and collect 3-benzoyl-1-hydroxy-5-nitroindole as an orange solid on a Buchner funnel.</li>
	<li>Keep under vacuum to dryness.</li>
	<li>Analyze and characterize the solid product by 1H- and 13C-NMR, FT-IR, and HRMS.</li>
</ol>

The authors have nothing to disclose.

The reaction for the indole synthesis between nitrosoarenes and alkynones shows a very high versatility and a strong and wide application. In a previous report, we could generalize our synthetic protocol working with different C-nitrosoaromatics and substituted terminal arylalkynones or heteroarylalkyones72. The procedure shows a deep substrate survey and a high functional group tolerance and both electron-withdrawing groups and electron-donor groups were present both in nitrosoarene and ...

Aromatic C-nitroso compounds1 and alkynones2 are versatile reactants that are continuously and deeply used and studied as starting materials for the preparation of high valuable compounds. Nitrosoarenes play an ever-growing role in the organic synthesis. They are used for many different purposes (e.g., hetero Diels-Alder reaction3,4, Nitroso-Aldol reaction5,6, Nitroso-Ene reaction7, synthesis of azocompounds8,9,10). Very recently they were even used as starting materials to afford different heterocyclic compounds11,12,13. In the last decades, conjugated ynones were investigated for their role as very interesting and useful scaffolds in the achievement of many high valuable derivatives and heterocyclic products14,15,16,17,18. C-Nitrosoaromatics can be afforded by oxidation reactions of the corresponding and commercially available anilines using different oxidizing agents as potassium peroxymonosulfate (KHSO5&#183;0.5KHSO4&#183;0.5K2SO4)19, Na2WO4/H2O220, Mo(VI)-complexes/H2O221,22,23, selenium derivatives24. Alkynones are easily prepared by the oxidation of the corresponding alkynols using various oxidants (CrO325 even known as Jones&#39; reagent or mild reactants as MnO226 and Dess-Martin periodinane27). The alkynols can be achieved by direct reaction of ethynylmagnesium bromide with commercially available arylaldehydes or heteroarylaldehydes28.
Indole is probably the most studied heterocyclic compound and indole derivatives have wide and various applications in many different research fields. Both medicinal chemists and material scientists produced many indole-based products that cover different functions and potential activities. Indole compounds have been investigated by many research groups and both naturally occurring products and synthetic derivatives containing the indole framework show relevant and peculiar properties29,30,31,32. Among the plethora of indole compounds, the 3-aroylindoles have a relevant role among molecules that show biological activities (Figure 1). Different indole products belong to diverse classes of pharmaceutical candidates to become potential novel drugs33. Synthetic and naturally occurring 3-aroylindoles are known to play a role as antibacterial, antimitotic, analgesic, antiviral, anti-inflammatory, antinociceptic, antidiabetic and anticancer34,35. The &#39;1-hydroxyindole hypothesis&#39; was provocatively introduced by Somei and coworkers as an interesting and stimulating supposition to support the biological role of N-hydroxyindoles in the biosynthesis and functionalization of indole alkaloids36,37,38,39. This assumption was recently reinforced by the observation of many endogen N-hydroxy heterocyclic compounds that show relevant biological activities and an interesting role for many purposes as pro-drugs40. In the recent years, the search for novel active pharmaceutical ingredients revealed that different N-hydroxyindole fragments were detected and discovered in natural products and bioactive compounds (Figure 2): Stephacidin B41 and Coproverdine42 are known as antitumor alkaloids, Thiazomycins43 (A and D), Notoamide G44 and Nocathacins45,46,47 (I, III, and IV) are deeply studied antibiotics, Opacaline B48 is a natural alkaloid from ascidian Pseudodistoma opacum and Birnbaumin A and B are two pigments from Leucocoprinus birnbaumii49. New and efficient N-hydroxyindole-based inhibitors of LDH-A (Lactate DeHydrogenase-A) and their ability to reduce the glucose to lactate conversion inside the cell were developed50,51,52,53,54,55,56. Other researchers repeated that indole compounds, that did not show biological activities, became useful pro-drugs after the insertion of a N-hydroxy group57.
A motif of debate was the stability of N-hydroxyindoles and some of these compounds gave easily a dehydrodimerization reaction that leads to the formation of a class of novel compounds, subsequently renamed as kabutanes58,59,60,61, by the formation of a new C-C bond and two new C-O bonds. Due to the importance of stable N-hydroxyindoles the study of different synthetic approaches for the easy preparation of such compounds becomes a fundamental topic. In a previous research by some of us, an intramolecular cyclization by a Cadogan-Sundberg-type reaction was reported using nitrostyrenes and nitrostilbene as starting materials62. In the last decades we developed a novel cycloaddition between nitro- and nitrosoarenes with different alkynes in an intermolecular fashion affording indoles, N-hydroxy- and N-alkoxyindoles as major products (Figure 3).
At the beginning, using aromatic and aliphatic alkynes63,64,65,66,67 the reactions were carried out in large excess of alkyne (10 or 12-fold) and sometimes under alkylative conditions to avoid the formation of kabutanes. 3-Substituted indole products were achieved regioselectively in moderate to good yields. Using electron poor alkynes, like 4-ethynylpyrimidine derivatives as privileged substrates we could carry out the reactions for this one-pot synthetic protocol using a 1/1 nitrosoarene/alkyne molar ratio68. With this protocol, an interesting class of kinase inhibitors as meridianins, marine alkaloids isolated from Aplidium meridianum69, was prepared showing a different approach to meridianins through an indolization procedure (Figure 4)68. Meridianins were generally produced so far with synthetic tools starting from preformed indole reactants. To the best of our knowledge, only a couple of methodologies reported the total synthesis of meridianins or meridianin derivatives through an indolization procedure68,70.
In a more recent development on the use of electron poor alkynes it was worthwhile to test the employ of terminal alkynones as substrates for the indolization procedure and this led us to disclose an intermolecular synthetic technique to afford 3-aroyl-N-hydroxyindole products71,72. Analogously to the process studied for the preparation of meridianins, using terminal arylalkynone compounds the 1/1 Ar-N=O/Ar-(C=O)-C&#8801;CH molar ratio was used (Figure 5). Working with alkynones as privileged starting materials, the general indole synthesis was performed with different reactants exploring a wide substrate survey and changing the nature of the substituents both on nitrosoarenes and on the aromatic ynones. Electron-withdrawing groups on the C-nitrosaromatic compound led us to observe an improvement both in reaction times and in products yields. An interesting synthetic approach that makes easily available a stable library of these compounds could be very useful and, after a preliminary study, we optimized our synthetic protocol using this stoichiometric reaction between alkynones and 4-nitronitrosobenzene to afford stable 3-aroyl-N-hydroxy-5-nitroindoles. Basically, this easy access to N-hydroxyindoles led us to evidence as the cycloaddition reaction between nitrosoarene and alkynone is a very atom-economical process.

<table><tbody><tr><td>4-Nitroaniline</td><td>TCI Chemicals</td><td>N0119</td><td></td></tr><tr><td>Acetone</td><td>TCI Chemicals</td><td>A0054</td><td></td></tr><tr><td>1-Phenyl-2-propyne-1-ol</td><td>TCI Chemicals</td><td>P0220</td><td></td></tr><tr><td>Celite 535</td><td>Fluorochem</td><td>44931</td><td></td></tr><tr><td>Dichloromethane</td><td>TCI Chemicals</td><td>D3478</td><td></td></tr><tr><td>Sodium hydrogen carbonate</td><td>Sigma Aldrich</td><td>S5761</td><td></td></tr><tr><td>Sodium chloride</td><td>Sigma Aldrich</td><td>746398</td><td></td></tr><tr><td>Sodium sulfate anhydrous</td><td>Sigma Aldrich</td><td>239313</td><td></td></tr><tr><td>Oxone</td><td>TCI Chemicals</td><td>O0310</td><td></td></tr><tr><td>Methanol</td><td>TCI Chemicals</td><td>M0628</td><td></td></tr><tr><td>Toluene</td><td>TCI Chemicals</td><td>T0260</td><td></td></tr><tr><td>Chromium Trioxide</td><td>Sigma Aldrich</td><td>236470</td><td></td></tr><tr><td>Dichloromethane anhydrous</td><td>TCI Chemicals</td><td>D3478</td><td></td></tr><tr><td>Hexane anhydrous</td><td>TCI Chemicals</td><td>H1197</td><td></td></tr></tbody></table>

a direct, regioselective and atom-economical synthesis of 3-aroyl-n-hydroxy-5-nitroindoles by cycloaddition of 4-nitronitrosobenzene with alkynones

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.

The preparation of 4-nitronitrosobenzene 2 was achieved by oxidation of 4-nitroaniline 1 by reaction with potassium peroxymonosulfate as reported in Figure 6. The product 2 was obtained in 64% yield after recrystallization in MeOH (twice) with 3-5% contamination of 4,4&#39;-bis-nitro-azoxybenzene 6. The structure of product 2 was confirmed by 1H-NMR (Figure 7). 1...

Watch this Scientific Journal Video about A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones at JoVE.co

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

3-Aroyl-N-hydroxy-5-nitroindoles were synthesized by cycloaddition of 4-nitronitrosobenzene with a conjugated terminal alkynone in a one-step thermal procedure. Preparation of the nitrosoarene and of the alkynones were adequately reported and respectively through oxidation procedures on the corresponding aniline and on the alkynol.

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ...

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8.0K Views.  Università degli Studi dell'Insubria. Deze nieuwe techniek kan worden gebruikt om n-hydroxy 3-aroyl indoolverbindingen voor te bereiden. Deze producten zijn bijzonder interessant voor het gebruik ervan als antibiotica, antinociceptica, antidiabeten en geneesmiddelen tegen kanker. Hoewel n-hydroxyindoles vaak worden beschouwd als onstabiele en ongrijpbare producten, hebben we een zeer stabiele bibliotheek van n-hydroxyindoolderivaten verworven.De reactie van de cycloaddition van nitrosaminen met alkynes kan worden gebruikt ...

Video: A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

Synthesis of Indoxyl-glycosides for Detection of Glycosidase Activities

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are rapidly oxidized, for example by atmospheric oxygen, to indigo type dyes. This reaction enables fast and easy screening in vivo without isolation or purification of enzymes, as well as rapid tests on agar plates or in solution (e.g., blue-white screening, micro-wells) and is used in biochemistry, histochemistry, bacteriology and molecular biology. Unfortunately the synthesis of such substrates proved to be difficult, due to various side reactions and the low reactivity of the indoxyl hydroxyl function. Especially for glucose type structures low yields were observed. Our novel approach employs indoxylic acid ester as key intermediates. Indoxylic acid esters with varied substitution patterns were prepared on scalable pathways. Phase transfer glycosylations with those acceptors and peracetylated glycosyl halides can be performed under common conditions in high yields. Ester cleavage and subsequent mild silver mediated glycosylation yields the peracetylated indoxyl glycosides in high yields. Finally deprotection is performed according to Zempl&#233;n.

Indoxyl glycosides are well-established and widely used tools for enzyme screening and enzyme activity monitoring. Especially for glucose type structures previous syntheses proved to be challenging and low yielding. Our novel approach employs indoxylic acid esters as precious intermediates to yield a considerable number of indoxyl glycosides in good yields.

Indoxyl glycosides proved to be valuable and versatile tools for monitoring glycosidase activities. Indoxyls are released by enzymatic hydrolysis and are ...

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 &#176;C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.

Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

Cycloaddition Reactions: Overview

Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new &#963; bonds formed at the expense of &#960; bonds. The [4 + 2] cycloaddition, known as the Diels&#8211;Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.
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The feasibility of cycloaddition reactions under thermal and photochemical conditions can be predicted using a set of selection rules. If the total number of &#960; electrons involved in the rearrangement is a multiple of 4n, the reaction is photochemically allowed. The reaction is thermally allowed if the total number of &pi; electrons involved is 4n + 2.

Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two ...

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

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