Chemical Communications Blog

Methods of allylic etherification are usually involved synthetic procedures, due to the need for activation of the starter aliphatic alcohol. By contrast, no such problems exist in analogous reactions to form allylic amines. 

Significant steps have been made in this synthetic area, but limitations remain. Iridium catalysis has been successfully employed for this reaction but usually requires the use of a glove box. Derivatisation of starting materials to incorporate suitable leaving groups has also been explored, as has the use of various bases to deprotonate the alcohol nucleophile.

Tertiary butyl alcohol has been extensively investigated for its reactivity also, but it appears that the more conditions you put on this reaction the more limited its scope and applicability become. Add to this the effect of each modification on product regio- and stereoselectivity and you can appreciate the challenge. Each new ‘improvement’ can leave you, figuratively speaking, one step up, and two steps back.

With this situation in mind, the Lee group from Heriot-Watt University report a considerable breakthrough in the catalysis of the allylic etherification of unactivated alcohols, using a gold(I) salt. Well chosen controls and an extensive optimisation of the reaction parameters has yielded a robust strategy, effective for a wide range of substrates and aliphatic alcohols, with very good to excellent regio- (S_N2 vs S_N2′) and stereoselectivity (cis/trans). An inert atmosphere is not even required.

The use of Lewis acidic gold(I) for this reaction seems to provide a reliable activation of the olefin of the allyl group, to nucleophilic attack from the external alcohol nucleophile, all helped along by the possible involvement of a six-membered transition state. It would appear that it is this activation and plausibly reliable mechanism, that has allowed this usually difficult process to be controlled, both chemically and stereochemically.

A large variety of alcohol nucleophiles, (including primary, secondary, tertiary, and functionalised examples) and allyl alcohol electrophiles have been screened. Overall trans- products with S_N2′ regiochemistry are highly favoured. An interesting selection of control reactions were performed, including the use of a hindered proton sponge to prove absolutely the effect of the gold(I) catalyst as well as the sole use of the acidic bis-trifluoromethylsulfonimide (HNTf₂) as catalyst, which resulted in a conversion of less than 5%.

The authors report a breakthrough in the allylic etherification of aliphatic alcohols, the application of which should be substantial, as the team now turns its attention to possible applications in asymmetric synthesis.

Read the ‘HOT’ Chem Comm article today (Free to access until the 14th of December):

Gold(I)-catalysed direct allylic etherification of unactivated alcohols

Paul C. Young , Nina A. Schopf and Ai-Lan Lee
Chem. Commun., 2012, 48, Advance Article
DOI: 10.1039/C2CC36760B

Published on behalf of Kevin Murnaghan, Chemical Communications web science writer. 

Researchers at the University of Münster have developed an unusual variant of the Staudinger reaction which takes advantage of frustrated Lewis pair (FLP) frameworks to provide internal stabilisation.

The Staudinger reaction represents an important tool for the generation of iminophosphoranes, which can be subsequently utilized in the synthesis of a wide range of functional motifs, including amines, imines, and amides. Additionally, with the variation of the phosphorus compound, the Staudinger reaction can be employed in bio-ligation processes under mild conditions.

Traditionally, the iminophosphorane product (3) is generated from the reaction of an organic azide (1) with a trivalent phosphorus compound. This is thought to proceed via transition state 2, from which elimination of dinitrogen yields the iminophosphorane (3). In the variation developed by the Erker group, such elimination of dinitrogen is avoided, generating products such as 4.

This unusual reactivity was cleverly obtained through the incorporation of the phosphorus moiety in an FLP; specifically, vicinal phosphane–borane FLPs (5). Upon reaction with mesityl azide, these FLPs led to the formation of 5-membered heterocycles (6). Following thermolysis or photolysis, phosphinimines (7) were obtained which benefit from internal stabilisation from borane. The by-product of this formation is indazole 8. While the mechanism of this unusual variation has yet to be confirmed, the authors propose a pathway proceeding via the ion pair 9.

This work contributes to the broadening utility of the Staudinger reaction, and illustrates the potential of FLP chemistry in the development of new reactivity.

Read the ‘HOT’ Chem Comm article today (Free to access until the 7th of December):

Anomalous Staudinger reaction at intramolecular frustrated P–B Lewis pair frameworks

Annika Stute , Lukas Heletta , Roland Fröhlich, Constantin G. Daniliuc, Gerald Kehr and Gerhard Erker
Chem. Commun., 2012, 48, 11739-11741
DOI: 10.1039/C2CC36782C

Published on behalf of Ruth Gilligan, Chemical Communications web science writer.

Synthetic organic chemists have long regarded the Wittig reaction as one of the most significant methods for the creation of new C–C bonds. Now, researchers at Peking University have reported that this time-honoured reaction can be used for the modification of proteins in a bioorthogonal process.

Bioorthogonal processes represent a growing area of interest, encompassing reactions which can take place under physiological conditions. That is, the reaction must proceed at neutral pH in an aqueous solvent at ambient temperature and low concentrations, with high selectivity. Given these challenging parameters, the range of bioorthogonal processes remains limited.

The Ye group, based at the Key State Laboratory of Natural and Biomimetic Drugs, have contributed to the expansion of this fascinating area of chemistry by successfully applying the Wittig reaction to their one-pot site-selective protein modification. The first step involves the incorporation of an aldehyde at the N-terminus of a peptide chain (1). This could be achieved by the periodate oxidation of N-terminal serine or threonine residues, or by PLP (pyridoxal-5-phosphate) oxidation of N-terminal glycines. The resulting aldehyde (2), without the need for isolation or purification, could be reacted with an ylide (3) to form a wide variety of functionalised peptide products (4). Di-, penta- and hexa-peptide substrates could be functionalised in this manner, using water and t-butanol as co-solvents at room temperature.

The strength of this site-selective reaction was further demonstrated by modifying myoglobin. Crucially, this was achieved with no damage to the protein’s secondary or tertiary structure and, furthermore, Prof. Ye’s group established that myoglobin’s oxygen storage and release function was unaffected.

The functionality introduced offers the potential for further structural modification, or for use in medical imaging. With protein-based pharmaceuticals becoming widely used, greater insight into protein function and behaviour is of paramount importance. This methodology has the potential to be a valuable tool in that understanding. 

Read the ‘HOT’ Chem Comm article today:

Enabling Wittig reaction on site-specific protein modification

Ming-Jie Han, De-Cai Xiong and Xin-Shan Ye
Chem. Commun., 2012, 48, 11079-11081
DOI: 10.1039/C2CC35738K

Published on behalf of Ruth Gilligan, Chemical Communications web science writer.

Luminescence from lanthanide-based compounds is currently exploited in electroluminescent devices ranging from glucose monitoring sensors to thin-film displays. Triarylboron groups are known to greatly enhance the fluorescence or phosphorescence of transition metal complexes, but such compounds are very sensitive to oxygen quenching and are unsuitable for use as sensors under ambient conditions.  The combination of these groups with lanthanides may offer enhanced luminescence in more ambient-friendly lanthanide-based materials.

The Wang group from Queen’s University, Canada have synthesised the first examples of triarylboron functionalized Tb(III) and Eu(III) compounds, and have shown that the BMes₂ group is extremely effective at activating lanthanide emissions.  The new compounds have been tested as sensors, showing that such triarylboron functionalized lanthanides may be promising new CN^– and F^– anion sensors.

To find out more, download this HOT article now (free to access until the 5th of December 2012).

Selective activation of lanthanide luminescence with triarylboron-functionalized ligands and visual fluoride indicators

Maria Varlan, Barry A. Blight and Suning Wang