Name: a direct, regioselective and atom-economical synthesis of 3-aroyl-n-hydroxy-5-nitroindoles by cycloaddition of 4-nitronitrosobenzene with alkynones
Uploaded: 2020-01-21T13:00:00
Description: 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

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...

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 border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<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 ...

This novel technique can be used to prepare n-hydroxy 3-aroyl indole compounds. These products are particularly interesting for their use as antibiotics, antinociceptics, antidiabetes and anticancer drugs. Although n-hydroxyindoles are frequently considered unstable and elusive products, we have acquired a very stable library of n-hydroxyindole derivatives.The reaction of the cycloaddition of nitrosamines with alkynes can be used to selectively prepare a wide library of free substituted indole products. This method provides a simple and to potentially bioactive products. We consider this protocol to be an interesting improvement and advancement in the field of synthetic organic chemistry.For 1-phenyl-2-propyne-1-one synthesis, first add 75 milliliters of acetone and two grams of 1-phenyl-2-propyne-1-ol into an open air round bottom flask containing a magnetic stirring bar. Place the reaction mixture at zero degrees Celsius with stirring and add a solution of Jones reagent drop wise until a persistent orange color is observed. Add 2-propanol drop wise until the excess of hexavalent chromium reactant is consumed and the solution exhibits a green color and filter the solution through a pad of diatomaceous Earth.Concentrate the washings by rotary evaporation until an oil is obtained and dissolve the oil in 100 milliliters of dichloromethane. Add the solution to a separatory funnel and wash the organic phase two times with 125 milliliters of a saturated solution of sodium bicarbonate per wash. After the second wash, wash the organic layer with 125 milliliters of brine before drying the organic solution over n-hydro sodium sulfate.After filtering, evaporate the solution to yield a yellow 1-phenyl-2-propyne-1-one solid and dry the solid under vacuum. For 4-nitronitrosobenzene preparation, first add 16 grams of potassium peroxy monosulfate and 150 milliliters of water to a beaker and stir the solution at zero degrees Celsius. When the potassium peroxy monosulfate has completely dissolved, add 3.6 grams of 4-nitroaniline to the beaker with a spatula and stir the suspension at room temperature.To check the reaction by thin layer chromatography, after 48 hours, filter the crude reaction mixture on a Buchner funnel into a one neck round bottom flask and recrystallize the solid in 50 milliliters of methanol. Use a heat gun to warm the suspension until it reaches the boiling point of methanol and immediately filter the hot suspension into an Erlenmeyer flask. When the solution reaches room temperature, filter the second precipitate onto a Buchner funnel and dry the solid in a vacuum.For a 3-benzoyl-1-hydroxy-5-nitroindole synthesis, first place a 250 milliliter two neck round bottom flask under vacuum before flushing the flask with nitrogen. Leave the flask inert under atmosphere and add 1.52 grams of 4-nitronitrosobenzene and 1.3 grams of 1-phenyl-2-propyne-1-one to the flask. Use a syringe to add 80 milliliters of toluene and keep the reaction mixture under magnetic stirring at 80 degrees Celsius.After a few minutes, check the complete solubilization of the reactants. After 30 to 40 minutes, verify the formation of an orange precipitate. After the complete precipitation of the orange solid, turn off the heat to allow the reaction to reach room temperature.Then filter the mixture to collect the 3-benzoyl-1-hydroxy-5-nitroindole on a Buchner funnel and dry the orange solid under vacuum. Here the preparation of 4-nitronitrosobenzene two as achieved by oxidation of 4-nitroaniline one by reaction with potassium peroxy monosulfate is shown. The product two can be obtained in a 64%yield after recrystallization in methanol two times with a 3-5%contamination of four 4'bis-nitroazoxybenzene-6 and the structure of the product can be confirmed by proton NMR.Here preparation of 1-phenyl-2-propyne-1-one four as afforded by oxidation of 1-phenyl-2-propyne-1-ol three with Jones reagent is shown. The product four can be isolated as a yellow solid in 90%yield and the structure can be confirmed by proton NMR. The synthesis of 3-benzoyl-1-hydroxy-5-nitroindole is accomplished by thermal reaction of 4-nitronitrosobenzene two and 1-phenyl-2-propyne-1-one four in toluene at 80 degrees Celsius.After isolation of the azoxy derivative six in 22%yield as the major product of the mother liquor after chromatography, the structure of product six can be confirmed by proton NMR. The structure of compound five can then be determined by proton NMR, carbon-13 NMR, and high resolution mass spectrometry. The two most delicate aspects of this procedure are the purification of the 4-nitronitrosobenzene by recrystallization and the synthesis of the indole product under an inert atmosphere.Following this procedure, many different indole products can be achieved. Working with electron-rich nitroaromatic derivatives, the target compounds are generally isolated by chromatographic purification techniques. An interesting mechanistic study will be developed in the near future to study any of the redox steps which are not clearly understood.The Jones reagent is very stable, but it is necessary to handle all of the chromium reagents with care.

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