Multicomponent Reaction toward Benzothiazoles

Multicomponent reaction was my research topic when I was finishing my master’s degree. While I was browsing the Journal of Organic Chemistry, I stumbled upon a multicomponent reaction reported by Abu Khan from Indian Institute of Technology Guwahati, Nahid Ali from Indian Institute of Chemical Biology, and their co-workers. They combined 2-aminothiophenols, oxalyl chloride, and thiols to form benzothiazoles with a thioester moiety at the 2-position. Tetra-n-butylammonium iodide (10 mol%) was used as a catalyst, and the optimal reaction conditions were found in acetonitrile at 60 °C. With this protocol, various benzothiazoles could be prepared in fair to good yields within four to six hours. Maximum yields were observed when both 2-aminothiophenols and thiols possessed electron-donating groups. Oxalyl chloride, tetra-n-butylammonium iodide, and different 2-aminothiophenols and thiols are commercially available.

In vitro analyses by the investigators indicated that benzothiazoles below were active against Leishmania donovani, the protozoan causing visceral leishmaniasis, also known as black fever because of the darkening of the skin noticed on infected people in India.

Teleportation gates:

• Article: Dar, A. A.; Shadab, M.; Khan, S.; Ali, N.; Khan, A. T. J. Org. Chem. 2016, 81, 3149–3160. DOI: 10.1021/acs.joc.6b00113.
• Indian Institute of Technology Guwahati.
• Abu Khan’s research group.
• Indian Institute of Chemical Biology.
• Nahid Ali’s research group.
• Leishmania donovani on Wikipedia.
• Visceral leishmaniasis on Wikipedia.

Ureas from Boc-Protected Amines

In the Journal of Organic Chemistry, Christoforos Kokotos and his student, Constantinos Spyropoulos, from National and Kapodistrian University of Athens described a one-pot synthesis of ureas from amines protected by tert-butyloxycarbonyl (Boc) group. Treating a Boc-protected amine with 2-chloropyridine (3 equivalents) and triflic anhydride in dichloromethane at room temperature for 50 minutes led to an isocyanate that generated a urea upon addition of 9 equivalents of another amine. This mechanism was proposed after the researchers could isolate the isocyanate intermediate in one reaction, but I doubt whether the secondary amines protected by the Boc group, for example, for the urea with a piperidine motif below, form isocyanates. Various ureas were formed within 1 to 20 hours after the addition of the second amine. The ureas below show the idea of the substrate scope.

No strong base was required and no epimerization occurred in this methodology so that the use of chiral substrates like amino acids is tolerated. The problem is that 9 equivalents of the amine nucleophile were necessary so that the excess had to be recycled via acid-base extraction. Kokotos and Spyropoulos recovered 78% to 85% of the amine.

Boc-protected amines either are commercially available or can be synthesized. 2-Chloropyridine and triflic anhydride can be bought from the market.

Teleportation gates:

• Article: Spyropoulos, C.; Kokotos, C. G. J. Org. Chem. 2014, 79, 4477–4483. DOI: 10.1021/jo500492x.
• National and Kapodistrian University of Athens.
• Christoforos Kokotos’s research group.

Biaryls: Copper-Catalyzed Suzuki Coupling

In Angewandte Chemie International Edition, M. Kevin Brown and co-workers from Indiana University Bloomington reported a type of Suzuki coupling where 10% (Xantphos)CuCl catalyzed reactions between arylboronic esters and aryl iodides to provide biaryls. As in Suzuki coupling, a base was used, and in this case, the choice fell to sodium tert-butoxide. Optimally, the reaction proceeded in toluene at 80 ºC in 15 hours. Both electron-rich and electron-poor iodides and boronic esters were suitable for this process, but steric hindrance in one of the two starting materials needed Cy₃PCuCl as the catalyst.

The arylboronic esters can be synthesized from the corresponding arylboronic acids and neopentyl glycol as reported by Aiwen Lei and colleagues from Wuhan University, and (Xantphos)CuCl can be made from CuCl and Xantphos as described by the laboratory of Yasushi Tsuji from Kyoto University. (See the scheme below.) Sodium tert-butoxide can be purchased from chemical companies.

Teleportation gates:

• Article: Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew. Chem., Int. Ed. 2014, 53, 3475–3479. DOI: 10.1002/anie.201310275.
• Indiana University Bloomington.
• M. Kevin Brown’s research group.
• Suzuki coupling on Wikipedia.
• Syntheses of arylboronic esters: Liu, Q.; Li, G.; He, J.; Liu, J.; Li, P.; Lei, A. Angew. Chem., Int. Ed. 2010, 49, 3371–3374. DOI: 10.1002/anie.201000460.
• Synthesis of (Xantphos)CuCl: Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Adv. Synth. Catal. 2012, 354, 1542–1550. DOI: 10.1002/adsc.201200200.

Biaryls: Chromium-Catalyzed Cross-Coupling between (Hetero)aryl Halides and Grignard Reagents

There has been no activity in this blog for quite a while. I had family issues requiring me to stay in my fatherland for some time. I was also busy with the last phase of my study, but I have finally graduated. I am going to receive the beautiful pieces of paper in the coming months, but you can say that I am now a Master of Science. I am sure that you know the feeling to finally reach the finish line of one phase of your life!

Fall has arrived, and I think I need to pack my summer clothes and put coats and thicker clothes in my linen cupboard. In my opinion, however, this blog can do with at least one new post.

We have another article about biaryls. This one resembles the well-known Kumada coupling, except that chromium is used as the catalyst. Paul Knochel and co-workers at the LMU Munich, in collaboration with Novartis, reported in Journal of the American Chemical Society that 3% chromium(II) chloride catalyzed coupling reaction between (hetero)aryl halides and (hetero)arylmagnesium halides at 25 °C to produce bi(hetero)aryls. Tetrahydrofuran was the solvent under the optimized conditions. Most reactions were complete within 15 minutes to 2 hours although two examples with benzothiophene- and thiophene-containing Grignard reagents needed a higher temperature or a longer reaction time. A few examples below show the scope of this procedure.

For years, Knochel and colleagues have developed handy ways to make (hetero)arylmagnesium halides. One example is starting with a (hetero)aryl bromide and exchanging the bromide with magnesium using complex i-PrMgCl·LiCl, made by stirring isopropyl chloride with magnesium turnings and lithium chloride in tetrahydrofuran at room temperature for 12 hours to obtain a yield of 95–98%. Another instance is stirring magnesium turnings and lithium chloride (with diisobutylaluminum hydride to activate the magnesium) in tetrahydrofuran for five minutes before adding a (hetero)aryl chloride or bromide; here, lithium chloride helps the insertion of magnesium into the carbon–halide bond.

Chromium(II) chloride is commercially available.

Teleportation gates:

• Article: Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D.; Knochel, P. J. Am. Chem. Soc. 2013, 135, 15346–15349. DOI: 10.1021/ja409076z.
• Kumada coupling on Wikipedia.
• LMU Munich.
• Paul Knochel’s research group.
• Preparation of Grignard reagents via bromide–magnesium exchange: Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336. DOI: 10.1002/anie.200454084.
• Preparation of Grignard reagents via lithium chloride-assisted magnesium insertion: Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P. Chem.—Eur. J. 2009, 15, 7192–7202. DOI: 10.1002/chem.200900575.

Hafnium-Catalyzed Enantioselective Epoxidation of Tertiary Allylic and Homoallylic Alcohols

My notebook traveled between the Netherlands and Germany and underwent a motherboard replacement twice. The precious equipment is now back, and so am I. Let’s look at what the chemistry community has had to offer in recent weeks.

In a communication to Journal of the American Chemical Society, Hisashi Yamamoto and co-workers at the University of Chicago reported a hafnium-catalyzed strategy to enantioselectively epoxidize the olefin group in tertiary allylic and homoallylic alcohols. The optimum reaction conditions involved 10 mol% hafnium(IV) tert-butoxide as the precatalyst, 11 mol% of chiral bis(hydroxamic acid) L1 or L2 as the ligand, and 20 mol% magnesium oxide as an additive. (See the scheme above.) Acid L2 was excellent for more sterically demanding tertiary allylic alcohols. Cumene hydroperoxide (2 equivalents) was the oxidizing agent, and the protocol was performed in toluene at 0 °C for 48 hours. Various tertiary allylic and homoallylic alcohols could be epoxidized with high enantioselectivity in good yield. No such alcohols with a tri- or tetrasubstituted-olefin moiety were, however, tested.

The chiral bis(hydroxamic acid)s were first designed by Yamamoto and colleagues themselves and can be synthesized from a readily available diamine tartrate salt in six steps. (See the scheme below.) Hafnium(IV) tert-butoxide, magnesium oxide, and cumene hydroperoxide are purchasable.

Teleportation gates:

• Article: Olivares-Romero, J. L.; Li, Z.; Yamamoto, H. J. Am. Chem. Soc. 2013, 135, 3411–3413. DOI: 10.1021/ja401182a.
• University of Chicago.
• Hisashi Yamamoto’s research group.
• Synthesis of chiral bishydroxamic acids L1 and L2: Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 4389–4391. DOI: 10.1002/anie.200500938.

Benzimidazoles and Quinazolinones: Palladium-Catalyzed Amination and Aminocarbonylation

Many drugs and natural products around us contain benzimidazole scaffolds, for example, albendazole (Albenza, GlaxoSmithKline) and tiabendazole (Mintezol, Merck & Co.), and quinazolinone ones, for instance, febrifugine and halofuginone. Michael Willis and co-workers at the University of Oxford in a collaboration with Pfizer have developed a microwave-assisted palladium-catalyzed benzimidazole synthesis with carboximidoyl chlorides and amines as substrates. (See the scheme above.) The reaction condition involved 5 mol% palladium(II) acetate as the precatalyst, 7 mol% Ad₂Pn-Bu, also known as cataCXium A, as the ligand, and sodium tert-butoxide as the base in trifluorotoluene as the solvent. The procedure tolerated a wide range of substituents, but aromatic amines rendered benzimidazoles in more moderate yields. Carboximidates could replace the carboximidoyl chlorides although a higher reaction temperature and a longer reaction time were necessary and only anilines could be applied. The method still permited diverse functional groups. The reaction mechanism begins with nucleophilic substitution by the amine at the carboximidoyl or carboximidate carbon to give the corresponding imidine as the reaction intermediate, followed by intramolecular palladium-catalyzed amination.

The chemists have also conceived a palladium-catalyzed quinazolinone synthesis with carboximidates having bromide on the ortho position of the benzene ring and amines as precursors. The reaction condition this time comprised a slightly higher precatalyst loading and a higher concentration of the ligand under 1 atm of carbon monoxide. Cesium carbonate and toluene replaced sodium tert-butoxide as the base and trifluorotoluene as the solvent respectively, and conventional heating substituted the microwave irradiation. The reaction mechanism now starts with palladium-catalyzed aminocarbonylation to create an amide intermediate that then undergoes cyclization under basic environment. This synthetic approach also allowed a variety of substituents even though incorporation of alkylamines needed a higher temperature.

The carboximidoyl chlorides can be prepared from the commercially available corresponding anilines by synthesis of the amides with acyl chlorides and conversion of these amides to carboximidoyl chlorides by applying phosphorus pentachloride. (See the scheme below.) The carboximidates can be synthesized from the anilines and orthoesters with an acid catalyst or by heating. Palladium(II) acetate, cataCXium A, sodium tert-butoxide, and cesium carbonate are all in the market.

Teleportation gates:

• Article: Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. J. Org. Chem. 2012, 77, 9473–9486. DOI: 10.1021/jo301805d.
  
• University of Oxford.
• Michael Willis’s research group.
• Microwave chemistry on Wikipedia.

Biaryls: Gold-Catalyzed Arylation

Biaryls are moieties we often see in natural products, pharmaceuticals, agrochemicals, and organic materials. Guy Lloyd-Jones, Christopher Russell, and their student, Liam Ball, at the University of Bristol reported gold-catalyzed arylation of simple arenes by trimethylsilyl-substituted ones. In the typical condition, the three chemists used 1 or 2 mol% Ph₃PAuOTs as the precatalyst and an oxidant formed in situ from iodobenzene diacetate and camphorsulfonic acid. The solvent was 2% methanol in chloroform, and most reactions were complete at room temperature between 20 and 40 hours. The arylation was regioselective, and its position followed the trends of the electrophilic aromatic substitution, which are also consistent with the results that reactions with sterically hindered or less electron-rich arenes and electron-deficient arylsilanes needed higher temperatures or longer reaction times. The synthetic strategy showed little or no double arylation or homocoupling and tolerated a wide variety of functional groups.

Trimethylsilyl-substituted arenes can be synthesized via silylation methods known in the literature. Ph₃PAuOTs can be prepared according to work by Hubert Schmidbaur and co-workers at the Technical University of Munich based on two commercially available precursors: treatment of Ph₃PAuCl with AgOTs in tetrahydrofuran at –70 °C for 2 hours gave Ph₃PAuOTs in a yield of 95%. Both iodobenzene diacetate and camphorsulfonic acid are commercially accessible.

Lloyd-Jones, Russell, and Ball applied their synthetic protocol to the preparation of diflunisal, a generic anti-inflammatory drug Merck & Co. developed in 1971.

Teleportation gates:

• Article: Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Science 2012, 337, 1644–1648. DOI: 10.1126/science.1225709.
• University of Bristol.
• Guy Lloyd-Jones’s research group.
• Christopher Russell’s research group.
• Electrophilic aromatic substitution on Wikipedia.
• Syntheses of arylsilanes on Organic Chemistry Portal.
• Preparation of Ph₃PAuOTs: Römbke, P.; Schier, A.; Schmidbaur, H. J. Chem. Soc., Dalton Trans. 2001, 2482–2486. DOI: 10.1039/b104001b.
• Diflunisal on Wikipedia.

Welcoming Words

Hello and welcome to Organic Times Syndicate. Before you are overly excited by, in my opinion, an amazing name for a blog, I must say that I decide to write here because one of the forms of my personal happiness lies in writing. At this moment, I am doing some chemistry, organic chemistry to be precise, in a university laboratory in the Netherlands. I am, however, not a fully specialized man in this particular field since I also did various multiple-month projects in other branches of chemistry in the past. On the other hand, I think it will be the best idea for myself to write about organic chemistry as a tool to keep up with the daily development in this area across the oceans as well as to learn something new on a regular basis.

As the tagline states, Organic Times Syndicate will deliver news about recent synthetic methods in the literature. It seems quite simple, but the complicity is certain because a massive number of synthetic protocols is published in a great number of scientific journals every week. I wish I could compile all procedures, but the task will need more than an ordinary student in myself. All synthetic methodologies posted here are thus just arbitrarily selected. Of course, I am glad to receive ideas about which current article deserves to be highlighted.

I have been grown up during the era of “The Learning Revolution”, and I believe it is a good point that someone can be a lifelong learner. I thank you for visiting Organic Times Syndicate, it is my hope that you enjoy your stay, and it is my pleasure to read and perhaps response to your comments, especially when I make mistakes here and there. I am grateful to Automattic for providing me with the beautiful theme.