Catalytic C-H Functionalisation

This is a really hot area of organic chemistry and promises to be of use to process chemists in providing new routes to molecules. In 2009, a collaboration known as the Center for Selective C-H Functionalisation was set up with funding from the National Science Foundation in USA. 6 chemists (5 synthetic and 1 computational) were involved at that time. Phase II which began in 2012/3 comprises 23 research groups in 15 universities (for a full list see Angew Chem Int Ed, 2014, 53, 10256 which gives more details of the collaborations which are all in USA).

Enantioselective Formation of Beta-Lactams

An interesting article from the group of Nicolai Cramer at Lausanne (Angew Chem Int Ed, 2014, 53, 9064) describes the conversion of alpha-chloro amides, which have an additional feature of a benzylic or similar active methylene group on the nitrogen, into beta-lactams by carbon-carbon bond formation and loss of HCl. The reaction takes place under palladium catalysis in toluene at reflux with base present, the enantioselectivity being induced when a chiral phosphoramidite ligand is present.

Alkylating agents

During the Scientific Update conference 'Organic Process Research and Development' in Cologne in September, amongst the many great talks was a tip I had not previously come across. Thomas Allmendinger (Novartis) was describing efforts to scale-up the hydrogenolysis of the benzylic hydroxyl by first forming the carbonate with methyl chloroformate. A really interesting talk within which was a single slide describing how they used a simple colour test to monitor for residual methyl chloroformate. The reaction is shown below. They could calibrate the colour of test solutions with the residual chloroformate and although on this occasion they had to use visual comparison, in principle at least a photometric method of analysis is feasible.

Book Review: Greene’s “Protective Groups in Organic Synthesis
5th Edition, by Peter G M Wuts, Wiley, 2014, ISBN 9781118905074. 1360 pages, price 66-95

The long-awaited 5th Edition of this extremely valuable work has now been published covering the literature to mid-2013 and including a further 2800 new references.This fills in the gaps from the previous edition of 2006 and so covers a tremendous amount of new material. As before the material is organised in a reader-friendly fashion as in an encyclopedia so that the reader can easily locate a particular protecting group. But at the end of the book there are reactivity charts which list the best protecting groups for each functional group. Peter Wuts has done a fantastic job in collating all this useful information and putting it together in a readable fashion. Highly recommended and incredible value for money.

Chemical Process Technology

By J.A.Moulijn, M. Makkee and A.E. van Diepen

Wiley, 2013, 2nd edition (softback) ISBN 978-1-444-32025-1 (552 pp)

The first edition of this textbook appeared about 12 years earlier so this new edition, with 35% new material, is particularly welcome.

Workers at Merck wanted to hydrolyse nitrile (20) to acid (2), so they chose to heat the nitrile in 5N HCl at 40°C.  They were somewhat surprised to obtain the desired acid (2) contaminated with isomer (21) formed in up to 15% yield or a ratio of 89:11.

J.Y.L. Chung,* Y.-L. Zhong,* K.M. Maloney,* R.A. Reamer, J.C. Moore, H. Strotman, A. Kalinin, R. Feng, N.A. Strotman, B. Xiang, and N. Yasuda, Org. Lett., 2014, 16, 5890-5893.

This paper describes a Boc removal method using TMS iodide (TMSI) which is ideal for producing zwitterionic products. The substrate is treated with TMSI in acetonitrile at 0°C. At the end of the reaction a limited amount of water is added and the product crystallises directly in high purity.