Tag Archives: Synthesis

On the road to the full control of the stereochemistry of dihalogenation reactions

The dihalogenation reactions of alkenes proceed with almost exclusive anti-diastereoselectivity and opposed to other well-known text book reactions, an enantioselective version seems quite elusive. In the last few years, I have been fascinated by two great advances towards the full control of the stereochemistry in reactions of dihalogenation of alkenes. First the discovery of enantioselective dihalogenation reactions and second the discovery of a catalytic syn-dichlorination of alkenes.

anti mechanism
The development of enantioselective versions is very elusive because racemization can easily occur via olefin-to-olefin halenium transfer and non-regioselective nucleophilic opening of the halonium intermediates. The first successful approach to this problem was done by the group of Scott Snyder who developed a stoichiometric dichlorination reaction using a chiral borane auxiliary that forms an in-situ complex with the substrate[1]. The chlorinated olefin was obtained with 87% e.e. and that was a tremendous success due to the difficulty of the reaction. A catalytic version adds the nonenantioselective background reaction to the existing problems. Later discoveries of catalytic enantioselective dichorinaton, dibromination and heterodihalogenation reactions of olefins by the groups of Nicolau, Burns and more recently Borhan are simply spectacular [2–5]. Nicolau and Borhan approach the problem using Sharpless dihydroxylation catalyst (DHQD)2PHAL while Burns uses a combination of a Titanium salt with a chiral promoter. But all these approaches have in common a wise election of substrates (allyl alcohols and amides) that can serve as an anchor to the catalysts to overcome the regioselectivity problem.

dihalogenation of olefins
The almost set-in-stone mechanism of the dihalogenation of alkenes involves the formation of a cyclic halonium ion followed by a backside nucleophilic opening that leads to the formation of the well stablished anti-product. Overturning the anti-diastereospecificity of this process is a major challenge. The group of Scott Denmark was able to develop the first syn-dichlorination of alkenes with a strategy based on a first step of anti-addition of an in-situ generated PhSeCl3 to an alkene followed by a nucleophilic displacement with a chloride ion source leading to a syn-dichlorination product overall.6
The process is made catalytic by adding an oxidant to the Ph-Se-Se-Ph precatalyst.
All these discoveries are impressive and I cannot help finding certain parallelism with the already Nobel Prize awarded hydrogenation and dihydroxylation reactions by Noyori, Knowles and Sharpless. I am very much looking forward to seeing further advances.

nobel prize2

References:
1. Snyder, S. A., Tang, Z.-Y. & Gupta, R. Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin. J. Am. Chem. Soc. 131, 5744–5745 (2009).
2. Nicolaou, K. C., Simmons, N. L., Ying, Y., Heretsch, P. M. & Chen, J. S. Enantioselective Dichlorination of Allylic Alcohols. J. Am. Chem. Soc. 133, 8134–8137 (2011).
3. Hu, D. X., Shibuya, G. M. & Burns, N. Z. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc. 135, 12960–12963 (2013).
4. Hu, D. X., Seidl, F. J., Bucher, C. & Burns, N. Z. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc. 137, 3795–3798 (2015).
5. Soltanzadeh, B. et al. Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides. J. Am. Chem. Soc. 139, 2132–2135 (2017).
6. Cresswell, A. J., T.-C., E. & Denmark, S. E. Catalytic, stereospecific syn-dichlorination of alkenes. Nat Chem 7, 146–152 (2015).

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Superbases in FLP chemistry

A new post for the series I am crazy about Frustrated Lewis Pairs (FLPs). If you are new to this exciting field I recommend you to read first one of my previous posts: “Frustration to a Good End”.superbases2The extraordinary reactivity of FLPs allows the stoichiometric and catalytic activation of small molecules being the most important application the heterolytic cleavage of hydrogen. The spectrum of Lewis bases used in FLP chemistry is wider compared to the Lewis acid partners. Phosphines, amines, N-heterocyclic carbenes or carbodiphosphoranes have been used, with a few exceptions, combined with boranes such as B(C6F5)3 and derivatives.

strategy

The activation of the strong H-H bond has been commonly achieved using a type of the Lewis bases mentioned above in the presence of strong Lewis acidic boranes. Krempner and co-workers have recently showed that the use of strong Lewis acids is not strictly necessary for the activation of hydrogen. In this new approach denominated as “Inverse” Frustrated Lewis Pairs, organic superbases combined with rather moderate and weak Lewis acids are capable to reversibly cleavage hydrogen. Organic superbases have an enormous proton affinity and are very strong due to the great stability of their conjugated acids once they are protonated. In their recent work Krempner and co-workers activate hydrogen using phosphazene based superbases with BPh3, HBMes2 or 9-BBN and extend the concept of Inverse Frustrated Lewis Pairs to the catalytic hydrogenation of organic molecules using N-Benzylidenaniline as model substrate.catalysisDo you want to know more? Read the original paper

Suresh Mummadi, Daniel K. Unruh Jiyang Zhao, Shuhua Li and Clemens Krempner. “Inverse” Frustrated Lewis Pairs – Activation of Dihydrogen with Organosuperbases and Moderate to Weak Lewis Acids. J. Am. Chem. Soc., 2016, 138 (10), pp 3286–3289.

Are you a newcomer to the topic? Take a look to this papers

Seminal work by Douglas Stephan’s group

Gregory C. Welch, Ronan R. San Juan, Jason D. Masuda, Douglas W. Stephan. Reversible, Metal-Free Hydrogen Activation.Science, 2006, 314, 1124-1126.

A couple of reviews for newcomers to the topic

Stephan, Douglas W. “Frustrated Lewis pairs”: a concept for new reactivity and catalysis Organic & Biomolecular Chemistry (2008), 6(9), 1535-1539.

Stephan, Douglas W.; Erker, Gerhard. Frustrated Lewis Pairs: Metal- free Hydrogen Activation and More. Angewandte Chemie, International Edition (2010), 49(1), 46-76.

An alternative to Brady’s test?

In one of our practicals at the chemistry teaching labs of Queen Mary University of London our students are provided with a mixture of 2 unknown organic compounds that they have to separate and identify with the use of spectroscopic methods and analytical qualitative tests. One of the most common tests during the practical is the Brady’s test for the identification of aldehydes and ketones. In this test a solution of 2,4-Dinitrophenylhydrazine (2,4-DNP) is reacted with the unknown mixture and if there is an aldehyde or a ketone, a yellow to deep red precipitate is observed as a consequence of the formation of the corresponding 2,4-dinitrophenylhydrazone.

Here is a nice video from FranklyChemistry showing examples of how a positive Brady’s test looks like:

For the practical this year I realised we had run out of 2,4-DNP and we needed to buy some more. I tried to buy 2,4-DNP from usual providers such as Sigma Aldrich, Alfa Aesar and VWR among others just to find that the chemical has been discontinued because is explosive.

I thought of alternative tests like Tollen’s and Fehling’s but unfortunately they are not general for carbonyl compounds and they only work for aldehydes easy to oxidise. My next move was to consult with colleagues in the department and in the internet community. Networks like researchgate and projects like #realtimechem on twitter are incredibly useful to connect and exchange knowledge with chemists around the world.

This time, very interesting suggestions as alternatives to 2,4-DNP came from Researchgate, (credit to: Joe Olechno, Matthew Mcgrath and Americo Lemos):

-4-Hydrazino-7-nitro-benzofurazan has been used to make fluorescent derivatives of aliphatic aldehydes including reducing sugars.

-4-Amino-3-hydrazino-5-mercapto-1,2,4-triazole (also known as purpald): Used for the determination of formaldehyde, gives a purple colour with aldehydes and also reacts with ketones but the product is not coloured.

-2,4-dichlorophenylhydrazine as a non-explosive alternative.

I still have to test this alternatives and if successful I hope I can write a post explaining the experience.

Ironically, I have recently found that a suitable alternative to 2,4-DNP is actually 2,4-DNP but as a solution in phosphoric acid. The 2,4-DNP solution in phosphoric acid can be purchased from Sigma Aldrich and it is advertised as an alternative to the explosive 2,4-DNP.

Green Synthesis of Benzene and Pyridine Derivatives

In parallel to the discovery of new reactions there is also a need to develop a more “green attitude”. We, synthetic chemists are often too busy focused on our target molecules to pay much attention to the “costs” of our achievements. Synthesis frequently requires the use of relatively expensive and toxic transition-metals, large amounts of solvents and additives that lead to the generation of waste along with the desired products.

Going green also has an impact in economy. Industry expends important amounts of time (which means money) and money trying to remove metal catalysts and solvents. Some transition metals are toxic even at very low concentrations and that is obviously undesirable for pharma industry. Small amounts of metals can have an undesired influence in the colour or properties of an organic polymer.

It is important to invest time and resources in the development of metal free methodologies. In this post I want to highlight the work published in Green Chemistry by Wei Yi and co-workers toward the metal and solvent free synthesis of benzene and pyridine derivatives.

Green

Pyridine and benzene derivatives are commonly found in organic molecules with interest in material or medicinal sciences. This new methodology describes the synthesis of benzene and pyridine derivatives from ready available ketones and amines using HOTf as catalyst. Wei Yi and co-workers remove any stochiometric or catalytic amounts of metals from the equation together with solvents.The reaction is performed in one pot with no need of other oxidants than air and features excellent yields, chemoselectivity and functional group tolerance.

If you want to know more why don’t you take a look to the original paper:

HOTf-Catalyzed Sustainable One-Pot Synthesis of Benzene and Pyridine Derivatives under Solvent-free Conditions. Xu Zhang, Zhiqiang Wang, Kun Xu, Yuquan Feng, Wei Zhao, Xuefeng Xu, Yanlei Yan and Wei Yib. Green Chem., 2016, Advance Article DOI: 10.1039/C5GC02747K

And my advice to all is that you consider GO GREEN:

12 Principles of Green Chemistry

Quick guide to get your synthetic methodology in a top journal

Nowadays thousands of “gurus” share their expertise to offer guidance in topics ranging from beauty and health to how to succeed in life. Chemistry of course is not an exception, we have our own gurus to seek for a piece of advice on many chemistry-related topics. Well, I am not a guru but still for my post today I would like to write a few lines on how I think you can improve your chances to get your synthetic methodology published in a good journal. I have also included one beautiful Yes-No flow diagram so my post is taken more seriously.

get published

Even in the case you have developed a new methodology to solve a very challenging synthetic problem, you may not get your results published in the top journals if you don’t include all the relevant information. For example, sometimes including a mechanism proposal is as important as getting excellent yields. I have considered two main scenarios:

Your synthetic methodology is new: The best scenario possible. You are the first one that solved the puzzle, but make sure the problem you are working in has relevance. And make sure that you are the first, so you did a good and meticulous literature research. Let’s say your method is good and your research is relevant, now is time to be creative. Select challenging and varied substrates and explore functional groups tolerance. If you are using a catalyst or a reagent developed by you it has to be fully characterized, an X-Ray structure can make the difference to get to the top journals. A new methodology might mean new reaction pathways or mechanisms. In my opinion at least a mechanism proposal should be always included. More and more often publications in synthetic methodology include now theoretical calculations to support mechanistic proposals.

Your methodology is not new but is way better than the others: Now is time to show your muscles. Besides being creative with substrates, having a full characterization or good mechanistic studies, now more than ever you have to include “extra toppings” to strengthen your chemistry. Stablish clear comparisons between your methodology and current methods using tables, explore recyclability or robustness of your catalyst, reagent or conditions. In other words try to highlight all your methodology’s strengths. Show off, put some efforts trying to scale-up to multi-gram levels “I synthesised 500 g at once, why? Because I can”. Apply your methodology to the synthesis of products of interests.

To conclude this post what could be better than showing a very good example of how to get your synthetic methodology in a good journal? This great work by Snyder and co-workers (click the link) speaks for itself: Et2SBr⋅SbCl5Br: An Effective Reagent for Direct Bromonium-Induced Polyene Cyclizations (Angew.Chem.Int.Ed.2009,48, 7899 –7903). In their paper, Snyder and co-workers describe a new reagent for well known reactions of bromocyclization. They describe the synthesis of their reagent with a full characterization including an X-Ray structure and more importantly they don’t hesitate to show muscle. They compare their reagent with the existing methods at that time to clearly show their reagent is in general better than the others, they also explore the scaleability of their methodology and apply it to the synthesis of natural products.

Syn-dichlorination of alkenes

Another post for the series “This blog is obsessed with dihalogenation reactions”. In previous posts I presented some of the reactions I consider of great relevance on the subject of enantioselective dihalogenation reactions (you can take a look here and here as well :D).  All these reactions having in common the synthesis of vicinal halides resulting from anti-addition as an inevitable consequence  of the ionic nature of the addition reaction of elemental halogens and related reagents to alkenes.

In other words, the challenge I’d like to highlight in this post is the difficulty of the development of straightforward methodologies for the syn-halogenation of alkenes. A great contribution to this topic is the first catalytic, syn-stereospecific dichlorination of alkenes developed by Denmark and co-workers.

challenge

The strategy used is based on a first step of anti-addition of an in-situ generated PhSeCl3 to an alkene followed by a nucleophilic displacement with a chloride ion source leading to a syn-dichlorination product overall. The process is made catalytic by adding an oxidant to the Ph-Se-Se-Ph precatalyst.

mechanism syn

This new methodology could be very useful for the synthesis of oligo- and polychlorinated compounds such as chlorosulfolipids, a family of synthetically challenging compounds originally discovered from the membranes of freshwater algae and associated to diarrhetic shellfish poisoning.

fosfolipids

Do you want to know more? Take a look to the original paper:

Catalytic, stereospecific syn-dichlorination of alkenes. Alexander J. Cresswell,              Stanley T.-C. Eey & Scott E. Denmark. Nature Chemistry 7, 146–152 (2015).

Conia-ene Nostalgia

I’ve seen very recently a nice review on the Conia-ene reaction by Dieter Enders and co-workers and I couldn’t avoid feeling some nostalgia. A very important part of my PhD project was related to the Conia-ene reaction so today I felt like wanting to write a few lines in a post…

nostalgia

The Conia-ene reaction was, at its origins, a thermal cyclization reaction of unsaturated carbonyl compounds usually in an exo mode. An intramolecular cousin of the Ene Reaction. This reaction usually required temperatures in excess of 300 oC limiting its utility in the synthesis of complex molecules.

conia mechanism

The potential of the Conia-ene reaction attracted the interest of many groups on the development of milder variants. We can find very encouraging contributions in the literature of Conia-ene reactions catalysed at much lower temperatures by Mo, Sn, Ti, Pd, Hg or Co, however these reactions usually required hard conditions in the presence of acid, bases, photochemical activation and were limited to the exo cyclization mode.

endo vs exo

It wasn’t until the seminal works of Toste’s group using the catalytic system AuPPh3Cl/ AgOTf that we can find a general method at room temperature that can lead to both endo and exo cyclization modes.

It seems natural that the next step in the study of a reaction is an enantioselective variant. Toste and co-workers, always one step ahead, developed in 2005 the first asymmetric version of the Conia-ene reaction. The strategy: Electrophilic activation of the acetylenic moiety of b-Ketoesters with a DTBM-SEGPHOS Palladium complex as chiral promoter in the presence of the Lewis acid Yb(OTf)3.

chiral strategies

A different approach is the generation of a chiral enolate. Dixon and co-workers used this strategy in their work by combining Cu(OTf)2 with a Brønsted base.

enantioselective conia

The Conia-ene reaction has proved to be a very useful synthetic tool toward the synthesis of cyclopentanoid products. Just to name one example (of many), Toste’s group application to the synthesis of (+)-Lycopladine A.

Conia aplicacion sintesis

Do you want to know more? Take a look to these papers:

The review of the nostalgia:

Catalytic Conia-ene and related reactions. Daniel Hack, Marcus Blümel, Pankaj Chauhan, Arne R. Philipps and Dieter Enders, Chem. Soc. Rev., 2015,44, 6059-6093

Where it all begun:

The Thermal Cyclisation of Unsaturated Carbonyl Compounds. J. M. Conia, P. Le Perchec, Synthesis 1975, 1 – 19

Seminal works in gold catalysis

Gold(I)-Catalyzed 5-endo-dig Carbocyclization of Acetylenic Dicarbonyl Compounds. Steven T. Staben, Joshua J. Kennedy-Smith andF. Dean Toste, Angew. Chem. Int. Ed. 2004, 43, 5350 –5352.

Gold(I)-Catalyzed Conia-Ene Reaction of β-Ketoesters with Alkynes. Joshua J. Kennedy-Smith , Steven T. Staben , and F. Dean Toste, J. Am. Chem. Soc., 2004, 126, 4526–4527.

Enantioselective Conia-eno

Catalytic Enantioselective Conia-Ene Reaction. Britton K. Corkey and F. Dean Toste, J. Am. Chem. Soc., 2005, 127,17168–17169.

Brønsted Base/Lewis Acid Cooperative Catalysis in the Enantioselective Conia-Ene Reaction. Ting Yang, Alessandro Ferrali, Filippo Sladojevich, Leonie Campbell and Darren J. Dixon. J. Am. Chem. Soc., 2009, 131 (26), 9140–9141.

And a bonus track, one application in synthesis

Gold(I)-Catalyzed Cyclizations of Silyl Enol Ethers: Application to the Synthesis of (+)-Lycopladine A. Steven T. Staben, Joshua J. Kennedy-Smith, David Huang, Britton K. Corkey, Rebecca L. LaLonde andF. Dean Toste. Angew. Chem., Int. Ed., 2006,45, 5991.

Enantioselective Dihalogenation of Allylic Alcohols

The development of a catalytic enantioselective reaction of bromination of alkenes can be at least as complicated as the corresponding dichlorination variant. The background reaction of bromine and other common dibrominating reagents capable of reacting rapidly with alkenes with no need of catalyst and the fact that bromonium ions can rapidly racemize in the presence of alkene do not make it any easier.

Recently in 2013 Burns and co-workers approached this challenge with a different strategy: to formally separate Br2 into electrophilic and nucleophilic components that are unreactive on their own. Diethyl dibromomalonate as the bromonium source and titanium bromide as the bromide anion source do the trick. To induce enantiocontrol a chiral TADDOL ligand is used as a chiral promoter and allylic alcohols capable to bind to the titanium metal centre are chosen as substrates. The TADDOL-type ligand used in the reaction has been found to induce good levels of enantioselectivity when used stoichiometrically and also lowering its loading to 20 mol%.

dibromacionNot happy with this incredible contribution Burns and co-workers have very recently published a follow up paper extending the methodoly to an enantioslective Bromochlorination version. Same strategy different actors, in this case Chlorotitanium triisopropoxide as the chloride source and N-bromosuccinimide as the bromonium source serve as a non-disproportionating equivalent to bromine monochloride and a tridentate Schiff base is used as chiral promoter.

dihalogenation
These new methodology will enable enantioselective synthesis of a wide variety of polyhalogenated natural products. As a proof of concept the paper also includes a short chemo-, regio-, and enantioselective synthesis of (+)-bromochloromyrcene and model subtrates leading to bromochlorocyclohexane motifs that can be found within several natural products including obtuso and preintricatol.

natural products           Do you want to know more? Why don’t you take a look to these references?

-Dennis X. Hu , Grant M. Shibuya , and Noah Z. Burns. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc., 2013, 135, 12960–12963.

– Dennis X. Hu , Frederick J. Seidl , Cyril Bucher , and Noah Z. Burns. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc., 2015, 137, 3795–3798.

Asymmetric Chlorination of Olefins.

There is no need to argue the relevance of the study of the halogenation reactions. Alkyl halides are common and useful intermediates in organic synthesis and there are thousands of halogenated natural products with potential biological activity. But curiously and despite the chlorination of olefins is a well-known text book reaction, a general enantioselective variant is yet to be discovered. A great contribution to this challenge was the enantioselective olefin dichlorination developed by Snyder and co-workers in their total synthesis of napyradiomycin A1. The reaction requires the use of a stoichiometric chiral borane auxiliary that forms an in-situ complex with the substrate. According to the authors the enantioselectivity of the process can be due to an organizational π-stacking interaction with the substrate favouring the formation of a chloronium ion at the bottom face of the molecule. The chlorinated olefin is obtained with 87% e.e. (95% e.e. only after recrystallization) and that is a tremendous success due to the difficulty of the reaction.

Snyder

If you think that an enantioselective chlorination reaction promoted by a stoichiometric reagent is hard, try to make it catalytic. That can be just madness:

-It is strictly necessary to minimise the background reaction, chlorinating reagents can add to olefins with no need of a catalyst.

-Even in the case you are able to form enantioselectively the corresponding chloronium intermediate, complete loss of enantioselectivity can occur due to:

a) Chloronium transfer to a free olefin or

b) Non-regioselective nucleophilic opening by a chloride.

Racemization

The catalytic reaction challenge was admirably accepted by Nicolau and co-workers. Aryl-substituted allylic alcohols were wisely selected as model substrates in an attempt to overcome the difficulties of the reaction. The reaction is expected to occur via benzylic chloronium species that favour a regiocontrolled chloride attack and the hydroxyl group can serve as an anchor to the catalyst via hydrogen bonding rigidifying the system and providing stereocontrol. The reaction is also performed at low temperatures to slow down the background reaction. The best system to promote the catalytic dichlorination reaction was a combination of the cinchona alkaloid derivative (DHQ) 2PHAL (commonly used as a ligand in Sharplesasymmetric hydroxylation) with p-Ph(C6H4)ICl2 as chlorine source. Although the enantioselectivities obtained were moderate and controlled by substrate design, the work of Nicolaus group meant a great contribution to the field and there is (Im completely sure) much more to come in the future.

Nicolau

Do you want to know more? Take a look to these papers:

-Scott A. Snyder, Zhen-Yu Tang and Ritu Gupta. Enantioselective Total Synthesis of (−)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin. J. Am. Chem. Soc., 2009, 131, 5744–5745.

-K.C. Nicolaou, Nicholas L. Simmons,Yongcheng Ying, Philipp M. Heretsch, and Jason S. Chen. Enantioselective Dichlorination of Allylic Alcohols. J. Am. Chem. Soc. 2011, 133, 8134–8137.

-Mattia R. Monaco and Marco Bella. A Formidable Challenge: Catalytic Asymmetric Dichlorination. Angew. Chem. Int. Ed. 2011, 50, 2–5.

Grignard Goes Inorganic

Great news for the inorganic chemists!!! A classical strategy widely used for decades in organic chemistry is now available for the synthesis of bimetallic species. A new Mn-Mg bonded compound was recently discovered by the group of Cameron Jones in Australia while trying to synthesise new Mn-Mn complexes. The direct comparison with the well known Grignard reagents gives the new Mn-Mg based complex the qualification of “inorganic Grignard reagent”.

inorganic grignard

Normal Grignard reagents, or maybe more correctly now Organic Grignard reagents, are organomagnesium based strong nucleophiles used mainly but not exclusively for the formation of carbon-carbon bonds. Discovered by French chemist François Auguste Victor Grignard who was awarded the 1912 Nobel Prize in Chemistry, Grignard reagents have become an essential tool in organic synthesis.

reacciones_2

The inorganic version, the so called “Inorganic Grignard reagents”, are not a new concept although their use is yet far from been a general tool for the creation of metal-metal bonds. The new Mn-Mg bonded compound discovered by Jones and co-workers was successfully utilised to transfer the Manganese fragment for the preparation of the first two-coordinate manganese(I) dimer, and the related Mn-Cr hetereobimetallic complex.

Do you want to know more? Take a look to the original paper.

Jamie Hicks, Chad E. Hoyer, Boujemaa Moubaraki, Giovanni Li Manni, Emma Carter, Damien M. Murphy, Keith S. Murray, Laura Gagliardi, and Cameron Jones. A Two-Coordinate Manganese(0) Complex with an Unsupported Mn–Mg Bond: Allowing Access to Low Coordinate Homo- and Heterobimetallic Compounds. J. Am. Chem. Soc., 2014, 136, 5283–5286.