Tag Archives: Oxidation

Uncovering alkenes: complex products from all-carbon substrates

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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.

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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.

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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.

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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.

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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.

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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

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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

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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.

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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.

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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.

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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].

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

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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 transformation of alcohols to carboxylic acid salts and hydrogen using water as the oxygen atom source

Ekambaram Balaraman, Eugene Khaskin, Gregory Leitus and David Milstein
Nature Chem.
DOI: 10.1038/nchem.1536

milstein1

We’ve discussed ruthenium-catalysed oxidative cross-coupling before, and the area appears to developing rapidly. Milstein and co-workers have reported dimerisation of alcohols (to esters)1 and coupling of alcohols with amines (to amides)2 previously, and now report a remarkable oxidation of alcohols to acids using water as the terminal oxidant.

The reported reaction is operationally straightforward, requiring only the alcohol substrate, catalyst, a slight excess of hydroxide and water at reflux. Alcohols are oxidised with high tolerance and high yield, though any present alkenes are subsequently hydrogenated.

The ruthenium catalyst operates with a bipyridyl ligand that can oxidise the metal centre through dearomatising loss of a proton. The proposed mechanism of the reaction cycles this dearomatising/aromatising process with a bound alochol and water to give the acid and two equivalents of hydrogen.

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The authors comment on the important role hydroxide plays in the mechanism. Without it, only trace product is observed. They conclude that hydroxide is necessary to scavenge the acid (as the salt) in order to regenerate the active catalyst.

Direct oxidations from alcohols to acids are uncommon, yet, obviously, very useful. Not only does this report address a general synthetic problem, it does so with an incredibly mild and accessible method.

1. J. Am. Chem. Soc. 2005, 127, 10840
2. Science 2007, 317, 790

Palladium-Catalyzed Aerobic Dehydrogenative Aromatization of Cyclohexanone Imines to Arylamines

Alakananda Hajra, Ye Wei, and Naohiko Yoshikai
Org. Lett.
DOI:10.1021/ol302568b

Substituted anilines are common core structures for a wide range of molecules. They are usually synthesised by SNAr chemistry, transition metal-catalysed C-N bond forming couplings or the reduction of nitroarene precursors. The common feature of these methodologies is that the aryl ring is already present in the starting material.

A recent report outlines a more indirect way of preparing such molecules employing a Pd-catalysed dehydrogenative aromatisation of cycloheximines. Rather than sourcing the aryl ring from the starting material, this methodology forms the substituted arene by a dual dehydrogenative catalytic cycle that leads to aromatisation of the cycloheximine substrate.

The use of expensive or wasteful stoichiometric by-products is avoided by using an oxygen atmosphere to achieve successive oxidations. The authors demonstrate the applicability of their method by preparing a variety of substituted anilines.

This method provides an expedient preparation of anilines that complements traditional methods by bypassing possible problems embodied in aromatic substitutions.

Catalytic Functionalisation of Unactivated sp3 C−H Bonds via exo-Directing Groups: Synthesis of Chemically Differentiated 1,2-Diols

Zhi Ren, Fanyang Mo, and Guangbin Dong
J. Am. Chem. Soc.
DOI: 10.1021/ja3082186

Selective C-H oxidation of unactivated alkyl groups is a remarkably powerful way of installing new functionality in simple substrates. We’ve featured some developments in this area previously.

C-H oxidation at the β-carbon of an unactivated alcohol has, so far, been inaccessible due to the deactivating inductive effect of the proximal oxygen. Dong and co-workers have overcome this problem in a method that allows the selective preparation of orthogonally protected 1,2-diols from simple alcohol precursors.

Their method employs a neat oxime derivative of the alcohol to direct palladium C-H insertion β to oxygen. Oximes are known to direct palladation of C-H bonds on the ‘other side’ of the oxime moiety; by removing appropriate C-H bonds from the oxime directing group, palladation in this case occurs on the desired oxygen ‘side’.

The authors note that reaction concentration is critical to the success of the oxidation process. The optimised process uses a concentration of 0.2 M. At lower concentration (0.1 M) the reaction does not go to completion; at higher concentration (0.4 M) decomposition products are observed. Whether or not this narrow range of optimal conditions is variable by substrate is not discussed, but the scope of the reaction is exemplified in a number of substrates with consistently good conversion.

Selective preparation of 1,2 diol derivatives is critical to any application of this methodology in synthesis. The oxime directing group can be removed as a protecting group in the presence of the adjacent acetate. Similarly, the oxime is stable under conditions for acetate cleavage, allowing selective differentiation between the two masked hydroxyl groups.

Interestingly, the reaction gives better yields on larger scale. A test example showed an improvement from 61% yield on 0.1 mmol scale to 80% yield from a 5 mmol reaction.

In one example, a substrate derived from menthol was subjected to the reaction conditions. Instead of observing the expected 1,2 oxidation product, a postulated intermediate undergoes an interesting skeletal rearrangement to give an unusual substituted cyclopentane scaffold.

Catalytic C–H oxidation by a triazamacrocyclic ruthenium complex

Eric McNeill and Justin Du Bois Chemical Science
DOI: 10.1039/c2sc20118f

Transition metal-catalysed methods for the chemoselective oxidation of C-H bonds have been widely developed over the past 15 years. DuBois and co-workers report a new ruthenium-based catalyst for carrying out teriary and benzylic C-H oxidations. Previous work in this area has focused on developing precatalysts that generate the active ruthenium tetroxide in situ. However, the group have taken a different approach, introducing a tridentate Me3tacn ligand to the precatalyst and generating a cis-dioxoruthenium catalytic species.

The catalyst carries out C-H oxidations selectively in a number of polyfunctional molecules at the most electron rich tertiary or benzylic C-H bond. Interestingly, the group observed that this catalytic system is more efficient than a system generating ruthenium tetroxide.

Moreover, introducing a ligand system to ruthenium-mediated oxidations raises the possibility of ligand design optimising for chemoselectivity or perhaps stereoselectivity.

Towards a Green Process for Bulk-Scale Synthesis of Ethyl Acetate: Efficient Acceptorless Dehydrogenation of Ethanol

Martin Nielsen, Henrik Junge, Anja Kammer and Matthias Beller Angew. Chem. Int. Ed.

Innovation in bulk feedstock synthesis is fairly uncommon and usually modestly incremental. As such, it is rare to find new techniques for the synthesis of common simple molecules in the chemical literature.

Matthias Beller, however, reports a catalytic dehydrogenative bulk synthesis of ethyl acetate from ethanol with several distinct advantages over current production protocols.

Ethyl acetate is usually made in bulk by one of three processes: Fischer esterification of acetic acid with ethanol; Tischenko dimerisation of acetaldehyde; or addition of acetic acid to ethylene. This synthesis builds on the work of Gerard van Koten in applying pincer complexes of iridium and ruthenium in dehydrogenative coupling of alcohols.

The groups most interesting result shows that 50 ppm loading of a PNP/Ru complex with a catalytic quantity of ethoxide (0.6 mol%) can give a 77% yield of ethyl acetate with a turnover number exceeding 15000.

The strength of the method lies in lack of undesired byproducts; only hydrogen gas is evolved, and is itself a desirable feedstock. No hydrogen acceptor species is required. Also, both oxidations occur in the same process, requiring only one feedstock for dimerisation.

DOI: 10.1002/anie.201200625