Uncovering alkenes: complex products from all-carbon substrates

Molecules containing simple alkene functionality are attractive substrates in synthesis. Carbon-carbon double bonds are relatively stable groups, lacking polarisation, they can be carried through synthetic processes involving acid, base, mildly oxidative and reductive conditions. But, the availability of the π-electrons for reaction embodies remarkable potential for constructing substituted contiguous stereocentres and the possibility of introducing complex functionality to an all-carbon system.

In recent years, functionalisation of unactivated alkenes has blossomed with developments in robust metal-catalysed processes and new oxidating agents. In the last few weeks several reports of new alkene functionalisations have been published that cover many aspects of this broad area, and show the diverse utility of alkenes in synthesis.

Hayashi and co-workers have published an elegant cyclising difunctionalisation of dienes.[1] The process is an iridium-catalysed C-H activation of cyclic aryl N-sulfonyl ketimines and gives spirocyclic aminoindane scaffolds with high diastereoselectivity.

We’ve already discussed an asymmetric cyclising aminofluorination reaction carried out by a chiral hypervalent iodine fluoride oxidant.[2] The reaction is endo-selective and prepares fluoropiperidine-based systems. Extension of the reaction to a racemic intermolecular process with styrene substrates was also demonstrated.

In a similar example of intermolecular alkene difunctionalisation, Zhang reports aminocyanation and diamination of (predominantly) styrene substrates.[3] The principle reagent for functionalisation is NFSI (N-fluorobenzenesulfonimide), which aminates the terminal end of the double bond. Subsequent reaction with TMSCN gives the aminonitrile product. Alternatively, an alkylnitrile may be used to give the Ritter product of the second addition.

The authors suggest a copper(I)-catalysed radical mechanism, generating a carbon-centered radical intermediate after amination by •N(SO₂Ph)₂. This reaction gives some idea of the kind of complex functionality that can be introduced to all-carbon alkene substrates by oxidative processes.

Hydrofunctionalisation of alkenes doesn’t provide the same high degree of complexity as oxidative difunctionalisation processes, but reactions in this category do offer a great deal of diversity in synthetic options while still providing regio- and stereocontrol of sp3 carbon centres. A report from Qing and co-workers describes a general and high yielding hydrotrifluoromethylation of unactivated alkenes.[4] Trifluoromethyl groups are useful moieties in pharmaceutical development of lead compounds. The group apply the method to a wide scope of unactivated alkene substrates showing tolerance to many other functionalities.

Hartwig’s group in Berkeley have developed an asymmetric hydroheteroarylation of bicycloalkenes.[5] The reaction is catalysed by an iridium DTBM-Segphos complex and tolerates various heteroaromatic coupling partners.

Alkenes offer chemists widely available, stable and highly tolerant substrates for synthesis. Careful application of modern reactions allows the uncovering of diverse and complex functionality from a carbon-carbon double bond, and new developments provide ever more effective methods for the preparation of desirable adducts.

References:
1. DOI: 10.1021/ja311968d
2. DOI: 10.1002/anie.201208471
3. DOI: 10.1002/anie.201209142
4. DOI: 10.1002/anie.201208971
5. DOI: 10.1021/ja312360c

Regio- and Enantioselective Aminofluorination of Alkenes

Wangqing Kong, Pascal Feige, Teresa de Haro, and Cristina Nevado
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208471

Multisubstituded, saturated 5-, 6- and 7- membered heterocycles are part of many bio-active molecules. Fluorinated derivatives of such structures have also been shown to display better pharmacological properties such as solubility and metabolic stability. Hence their enantioselective preparation in a facile and efficient manner is of great interest for synthetic chemists.

Classical approaches involve cycloadditions such as inverse-electron demand Diels-Alder or [2,3] azomethine ylide reactions¹, whereas more modern approaches focus on transition metal catalysed aminoalkylations². Cristina Nevado’s group in Zurich, have recently reported a metal-free regio- and enantioselective aminofluorination for the preparation of 6- and 7-membered fluorinated heterocyclic compounds.

The reaction is highly regioselective yielding the 6-endo-cyclisation product only. Using their newly discovered conditions they investigated the scope of the intramolecular aminofluorination.

From the data presented in the supporting information, aromatic substituents seem to have a positive influence on enantioselective induction. The preparation of 7-membered rings was also performed. However it required the addition of a catalytic amount of [(Ph₃P)AuNTf₂].

The authors also investigated the scope of intermolecular aminofluorinations in a non-asymmetric manner, using p-xyleneIF₂ as the fluorine source.

This method provides a facile route to fluorinated surrogates of saturated heterocyclic compounds. It would be interesting to see it applied for the preparation of morpholine or piperazine containing compounds in the future.

References:

1. a) Geraldine Masson et al. Org. Bio. Chem. 2012 ; b) Marco Potowski et al. Angew. Chem. Int. Ed. 2012.

2. a) Josephine S. Nakhla et al. Org. Let. 2007 ; b) Matthew L. Leathen et al. J. Org. Chem. 2009.

Catalytic Asymmetric C–N Bond Formation: Phosphine-Catalyzed Intra- and Intermolecular γ-Addition of Nitrogen Nucleophiles to Allenoates and Alkynoates

Rylan J. Lundgren, Ashraf Wilsily, Nicolas Marion, Cong Ma, Ying Kit Chung, and Gregory C. Fu
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208957

A carbonyl group provides a pivot point for the functionalisation of its proximal positions – α and β. This can be demonstrated by the reactivity of classical enolates as α-functionalisation nucleophiles and Michael acceptors as β-functionalisation electrophiles, as well as their corresponding reactivities in enamine and imminium organocatalysis.

In a recent report Lundgren et al. have successfully demonstrated that γ-functionalisation of carbonyl compounds is also achievable, both intra- and inter- molecularly. Using a spirophospine ligand to induce stereoselectivity, the group has demonstrated the feasibility of asymmetric C-N bond formation with nitrogen nucleophiles and alkynoates or allenoates as electrophiles.

Investigating the scope of the reaction revealed that a good range of functional groups can be accommodated in either intramolecular reactions with alkynoates or intermolecular reactions with allenoates.

The process provides access to novel reactivity and it may even prove complementary to the classical α- and β- asymmetric functionalisation of carbonyl compounds. It would be interesting to see if a γ-, β-, α-cascade addition would be possible.

Highly Diastereoselective Multicomponent Cascade Reactions: Efficient Synthesis of Functionalized 1-Indanols

Jun Jiang, Xiaoyu Guan, Shunying Liu, Baiyan Ren, Xiaochu Ma, Xin Guo, Fengping Lv, Xiang Wu, and Wenhao Hu
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208391

Wenhao Hu has been reporting remarkable reactions of transition metal-generated oxonium ylides for some time now. Oxonium ylides formed from alcohol insertion into carbenoids tend to undergo rapid 1,2-proton shift to give ethers (path A). However, Hu and coworkers report reactions where this process is delayed long enough for the ylide to react as a carbon nucleophile with electrophilic coupling partners (path B).

Recently, these oxonium ylides have been shown to undergo a cascade reaction with a dielectrophilic compound containing an unsaturated ester and an aldehyde. The ylide adds selectively to the Michael acceptor, which is followed by intramolecular aldol-type addition to the aldehyde to generate a complex indanyl adduct. The product is formed as a single diastereoisomer.

The group also report an asymmetric variant of the reaction using a chrial auxiliary on the diazo substrate.

Subsequent studies into the reaction attempted an intermolecular multicomponent cascade. Unfortunately, the product of 1,2-proton shift was preferred and no 4-component products were observed. More interestingly, the product of addition of the ylide into the unsaturated ester was only observed in 13% yield. This suggests that trapping of the oxonium ylide by the unsaturated ester in the dielectrophilic compound above is synergistically promoted by the presence of the aldehyde and subsequent aldol cyclisation.

Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones

Naoki Ishida, Yasuhiro Shimamoto, and Masahiro Murakami
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201206166

Preparation of cyclic carbonates by incorporation of CO₂ into strained cyclic systems is well known and widely exploited. A standard synthesis of these compounds is through addition of epoxide into CO₂ followed by ring expansion. Murakami and co-workers take a similar approach in cyclic carbonate synthesis in order to demonstrate a process involving 2 goals in green chemistry: CO₂ incorporation, and sunlight activation.

The authors show that azetidine derivatives can be prepared from α-methylaminoketones through irradiation with sunlight alone. These high energy intermediates are relatively stable and their stored solar energy can be released in reaction with CO₂ under mild conditions. The reaction can tolerate various aryl groups, but chain length is fixed as a hydroxypyrrolidine derivative is too stable to undergo ring opening.

Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3-Fluoropyrazoles

Kohei Fuchibe, Masaki Takahashi, and Junji Ichikawa
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201206946

We don’t often consider the trifluoromethyl group as a reactive centre. But it is, of course, a highly polarised moiety and, under the right conditions, fluoride can act as a competent leaving group. Ichikawa and coworkers employ hydrazines as nucleophiles in two successive displacements of fluoride from vinyl trifluoromethyl adducts to give 3-fluoropyrazole scaffolds.

After testing other possible reaction pathways, they postulate that the reactive intermediate in the cyclisation step, after loss of the tosyl anion, is an azomethine ylide.

Septulene: The Heptagonal Homologue of Kekulene

Bharat Kumar, Ruth Viboh, Margel Bonifacio, William Thompson, Jonathan Buttrick, Babe Westlake, Min-Soo Kim, Robert Zoellner, Sergey Varganov, Philipp Mçrschel, Jaroslav Teteruk, Martin Schmidt, and Benjamin T. King
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201203266

Both Kekulé and Clar representations of aromatic systems are commonplace in organic chemistry notation. The use of one or the other is usually dependent upon convention or preference. In most cases, neither one is wrong. Very rarely do the differing conventions predict differing physical properties of a molecule.

Kekulene is a well known cyclic polyaromatic hydrocarbon (PAH) consisting of 12 fused benzene rings. It’s structure can be described consistently by both Kekulé and Clar representations. However, not all PAHs exhibit the same consistency.

King and coworkers report a new PAH, dubbed septulene, which they synthesise, characterise and compare to the properties of the related kekulene molecule.

Unlike kekulene, septulene has an odd number of carbon atoms in both the inner and outer carbon rings. Because of this, the only way to resolve the Kekulé structure of septulene is to include a radial π-bond. This π-bond is fundamentally different from all the other bonds in the molecule and breaks the symmetry present in the structure described by the Clar representation. As such, if the Kekulé representation is consistent with reality, septulene will present very different physical properties to kekulene.

The authors studies do, in fact, show that septulene has very similar properties to those of kekulene. The NMR chemical shifts of the inner protons are particularly characteristic. The crystal structure also reveals that there are only 6 unique bonds in the molecule, matching kekulene, highlighting the symmetry of the system. The authors conclude that the similarity in properties between septulene and kekulene cannot follow from the Kekulé representation of the molecule and that only the Clar representation is correct in describing septulene’s, and, indeed, all PAHs’, structure.

Of course, the use of Clar representation for all molecules is not prescribed, the authors suggest that chemists understand the subtle differences between the two representations and use the most appropriate to describe each molecule.

[For anyone up for a challenge, can you ChemDraw the structure of septulene less haphazardly than me?]

Highly Enantioselective Catalytic [6+3] Cycloadditions of Azomethine Ylides

Marco Potowski, Jonathan Bauer, Carsten Strohmann, Andrey Antonchick, Herbert Waldmann
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201204394

Cycloaddition reactions are very useful for generating multiple stereocentres in one step. The fact that they also provide enantiocontrol with the use of chiral Lewis acids or auxiliaries makes these reactions very attractive in most aspects of organic synthesis.

Waldmann and co-workers have reported an enantioselective [6+3] cycloaddition of azomethine ylides with fulvenes using a metal salt with a chiral ferrocene-derived ligand to provide stereocontrol.

Azomethine ylides are readily formed by β-carbonyl imines, which can be prepared simply by condensation between an amino acid ester and an aldehyde.

Waldmann’s group took things a step further; they used the product of the enantioselective [6+3] cycloaddition in a subsequent [4+2] cycloaddition. The second cycloaddition proceeds diastereoselectively allowing the construction of eight stereocentres – up to 98:2 er – in one pot.

A remarkable degree of complexity can be achieved in a single process from three simple starting materials.

“Black Swan Events” in Organic Synthesis

William Nugent
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201202348

The moral of this article can be summarised in three words of folk wisdom: never say never. This article provides a refreshing insight into the misplaced preconceptions of chemists working in previous decades, and how these preconceptions were overturned.

The author lays out a series of dogmatic statements which over the past two decades have been proven incorrect. These statements are classed into two categories depending whether they were brought down by a single publication – “Change through revolution”, or a series of reports – “Change through evolution”.

A selected few are:

“Gold compounds are simply to unreactive to be useful as homogeneous catalysts”

A report by Teles et al. in 1998 demonstrated that a cationic Au(I) complex catalyses the addition of oxygen nucleophiles to acetylenes:

“Olefin metathesis is an ill-defined reaction of olefinic hydrocarbons and unlikely to find any use in organic synthesis”

For students studying organic synthesis today, it’s hard to imagine a time before ubiquitous olefin metathesis, more so that it was considered so far out of reach. R.H. Grubbs ultimately shared the Nobel Prize in Chemistry in 2005 for his research on ruthenium catalysed olefin metathesis.

“Efficient enantioselective catalysis requires the use of a metal complex”

And then came one of the most elegant and sophisticated aspects of catalysis in organic synthesis: organocatalysis, with the work of MacMillan, List, Barbas and others.

As the author points out, a common characteristic of the above overruled statements is that often, the scientific literature contained hints that the “common belief” was incorrect. However, these hints were not picked up on until a report was published proving that the original discounted phenomenon was in fact achievable.

The discovery of something completely new and revolutionary is often preceded by flashes of insights or moments of wisdom that will most probably be ignored until three or four decades later when someone has the curiosity to move it forwards.

So what assumptions about the behavior of molecules do we make today that will populate a surrogate of this article in 50 years?

Olefination of Carbonyl Compounds through Reductive Coupling of Alkenylboronic Acids and Tosylhydrazones

M. Carmen Perez-Aguilar and Carlos Valdes
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201200683

Due to the expense, complexity and, often, toxicity of transition metal catalyst systems, transition metal-free coupling carbon-carbon bond forming reactions are a highly attractive target in synthetic methodology. The difficulty in achieving these processes comes in requiring strong activation of at least one of the coupling partners. In the case of carbon addition to carbonyls, this activation is usually achieved by generating an anionic nucleophile. But addition of weaker nucleophiles, such as boronic acids, can be achieved by activation of the carbonyl species by condensation with tosylhydrazine.

Previous studies have shown that aryl and alkyl boronic acids can arylate and alkylate tosylhydrazones effectively. However, additions of alkenes to hydrazones give mixtures of products varying in both the position and geometry of the double bond. This problem has been solved in a recent report, which demontrates that the presence of two equivalents of CsF in the reaction gives high product selectivity.

When arylvinylbronic acids are used, the product of gamma-protodeboronation is observed as the only product of reaction. This process can be employed with a wide range of arylvinylboronic acids and tosylhydrozones.

In contrast, the addition of alkylvinylboronic acids is marginally less effective and affords selectively the product of alpha-protodeboronation.

This difference in selectivity is postulated to be due to the stabilisation of electron density at the benzylic position of arylvinylboronic acids, thus promoting the gamma-protodeboronation pathway in those cases. Similarly, the presence of electron-withdrawing groups in the hydrazone coupling partner are shown to bias selectivity in favour of the alpha-protodeboronation pathway.