Tag Archives: Impressive Reactions

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.

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

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.

Two-step Sequence Strategy for the Synthesis of ortho-OCF3 Anilines.

The chemistry of molecules containing fluorine atoms has grown in interest and in consequence a great increase of the number of papers on synthetic strategies to introduce fluorine atoms in molecules has been observed during the last years. Fluor is known to improve the biological activity of drugs by enhancing properties such as the solubility, stability and lipophilicity of molecules. The OCF3 moiety in particular presents one of the highest lipophilicity values favouring  in vivo uptake and transport in biological systems.

orto OCF3 migration

Ngai and co-workers describe a useful procedure for the synthesis of ortho-trifluoromethoxylated anilines through a two-step sequence of O-trifluoromethylation of alkyl hydroxylamines followed by OCF3 migration. The methodology allows the formation o a wide range of ortho-OCF3 aniline derivatives with high regioselectivity and can be performed one-pot. One of the drawbacks is that the migration step requires higher temperatures than the initial trifluoromethylation making  almost unavoidable the removal of solvent and further re-dissolution to achieve the whole sequence.

Do you want to know more? You can find here the paper:

Katarzyna N. Hojczyk, Dr. Pengju Feng, Chengbo Zhan andProf. Ming-Yu Ngai. Trifluoromethoxylation of Arenes: Synthesis of ortho-Trifluoromethoxylated Aniline Derivatives by OCF3 Migration. Angew, Chem. Int. Ed. 2014, 53, 14559-14563.

A Catalytic Wittig Reaction.

The Wittig reaction was discovered by Georg Wittig and co-workers in 1953 and for which Wittig was awarded the chemistry Nobel Prize in 1979.  Since its discovery, the Wittig reaction has probably been the preferred choice of synthetic chemists towards the synthesis of alkenes. The formation of the alkene proceeds through the reaction of an aldehyde or ketone with a phosphonium ylide. The success of the reaction is due first to its regioselectivity, as the double bond of the alkenes is formed only between the reacting carbon of the ylide and the carbonylic partner, and second to its stereoselectivity to the formation of one of the two possible geometric isomers. The major drawback of the reaction is the generation of stoichiometric amounts of undesired triphenylphosphine oxide, a byproduct that frequently complicates the purification of the desired product.

wittig

In a very smart approach to overcome the problem of generating such a big amount of phosphine oxide waste, O’Brien and co-workers from the University of Texas designed a catalytic version of the Wittig reaction. The challenges: to generate in situ the reactive ylide and to reduce the phosphine oxide without reducing the carbonyl compounds involved in the reaction. The solution: the utilization of a cyclic phosphine that is reduced by Ph2SiH2, a reducing agent mild enough to leave the carbonyl  coupling partners intact. The catalytic version has proved effective with a series of aldehydes and stabilised or semi-stabilised ylides. The reaction represents an important first step to a general catalytic Wittig reaction and more research will be needed to achieve the same degree of effectiveness as the stoichiometric variant in terms of the scope of substrates and regioselectivity.

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

Christopher J. OBrien, Jennifer L. Tellez, Zachary S. Nixon, Lauren J. Kang, Andra L. Carter, Stephen R. Kunkel, Katherine C. Przeworski, and Gregory A. Chass. Recycling the Waste: The Development of a Catalytic Wittig Reaction. Angew. Chem. Int. Ed. 2009, 48, 6836 –6839.

Frustration to a Good End.

Frustration: “The feeling of being upset or annoyed as a result of being unable to change or achieve something”. It sounds like a very negative feeling that every researcher has felt at some point at their careers. It is not the case for the topic of Frustrated Lewis Pairs, where frustration is actually a good thing. But, what is a Frustrated Lewis Pair (usually abbreviated as FLP)?, well not that fast, let’s start for the beginning.

frustration

One of the basics of chemistry reactivity is that the combination of a Lewis acid and a Lewis base leads to the formation of a classical Lewis adduct as exemplified by the combination of borane with ammonia to form the ammonia-borane adduct NH3.BH3. But, what happens if we introduce steric impediments in both the Lewis acid and the Lewis base? Then, it comes “the frustration” of the adduct. Do not mistake this with the actual frustration of a chemist attempting a reaction that does not work. In this situation, the steric demands preclude formation of simple Lewis acid-base adducts and then is when we have a Frustrated Lewis Pair.

pubications in FLP

In this very particular scenario where both acidity and basicity remain unquenched, FLPs have an extraordinary reactivity towards the cleavage and activation of small molecules such as hydrogen, alkenes, alkynes or CO2 among others. Unarguably the most important and more developed applications are within the fields of activation of hydrogen and catalytic hydrogenations. The number of publications and citations in Frustrated Lewis Pairs chemistry has been increasing since the first  publication in 2006 by Douglas Stephan, one of the “fathers” and most active researchers of the topic.

hydrogenacion

In my opinion there is still a long way to walk and we’ll see in the next years new developments in catalytic asymmetric hydrogenation along with applications in areas such as hydrogen storage, CO2 capture and fuel cells.

If you want to know more there are many good articles and reviews on the topic, these could be a starting point:

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.