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Issue 23 March 2008

What's New in Process Chemistry?

Reduction of Tertiary Amides without the use of Hydrides

The reduction of amides to amines is well-documented and there are many publications in the literature and choices of reagent for this important transformation but many involve the use of highly reactive species such as hydrides of aluminium or boron. These reagents offer high-yielding processes, but work-up can be problematic with significant waste streams. More recently silanes have emerged in conjunction with transition metal catalysts, which although they offer advantages over the `metal hydrides' there remain some drawbacks including catalyst and silane cost and issues over chemoselectivity. A recent publication (G Barbe and A B Charette, J Am Chem Soc, 2008, 130, 18) reported the use of the Hantzsch ester as a reducing agent for tertiary amides. The reaction involves the formation of an iminium ion by reaction with triflic anhydride and the Hantzsch ester completes the reduction to the amine, as indicated in the scheme below. The reaction is selective for tertiary amides, leaving ketones, esters, unsaturated esters, nitrile, epoxide and acetylenes all intact when these functional groups were present in the molecules with a tertiary amide. It should be noted that previous publications have reported the use of the Hantzsch ester for reduction of ,-unsaturated aldehydes, imines, and pyridines (Org Lett, 2005, 7, 3781 and Synlett, 2005, 2367). In conclusion, the procedure offers an interesting and potentially scalable means to selectively reduce a tertiary amide without recourse to `metal hydrides' or transition metal catalysts.

John Knight n

N-amino Hantzsch ester in the hydroamination of alkenes

The authors describe the use of an N-aminated Hantzsch ester for the radical transfer hydroamination of alkenes, including the stereoselective transfer into an alkene appended to an Evans auxiliary. The authors propose the following pathway for the reaction:

The hydroamination reagent is prepared thus:


Mild and Simple Conversion Work Up of Borane of Primary Amines to Reductions of Amides N-Substituted Glycines and Imides

During an attempted imidazolidinone synthesis researchers at the University of Cardiff discovered a simple way to prepare N-substituted glycine derivatives. Treatment of a primary amine, such as benzylamine, with two equivalents of glyoxylic acid produces N-formyl-Nbenzylglycine in 79% yield. The reaction works best in water or dichloromethane, but the advantage of using water in this case is that addition of 2M HCl after formation of the initial product allows for the direct onepot conversion to N-benzylglycine hydrochloride. The initial product of the borane reduction of an amide or imide is not usually the desired amine, but the amine:borane complex. Cleaving these complexes can be problematic and if carried out with acids or inorganic bases hydrogen is liberated which creates potential fire and explosion hazards. If the next step in the synthetic sequence is another reduction then the borane complex can be used as a source of hydrogen for catalytic hydrogenation / hydrogenolysis (see M. Couturier et al (Pfizer), Org. Lett., 2001, 3, 465; Org. Proc. Res. Dev., 2002, 6, 42; Tet. Letts., 2001, 42, 2285). Alternatively addition of an excess of a simple amine can break the complex forming a different amine:borane complex that can be separated by partitioning between the organic layer and an aqueous layer. For example, addition of excess piperazine hydrate generates a piperazine:borane complex, which can be extracted into the aqueous layer, leaving the product in the organic layer. Alternatively use of excess dimethylamine or diethylamine produces and dimethylamine:borane complex (or diethylamine:borane), which is soluble in the organic layer allowing the product amine to be extracted in to aqueous acid. Will Watson n

Secondary amines and tertiary amines do not react and so this method also allows selective conversion of a primary amine to the glycine derivative in the presence of a secondary amine. Yields are typically 40-60% for this conversion.

The authors showed that the chemistry can be carried out in DCM or toluene, using optimally about 0.1-0.15 molar equivalents of thiophenol in the presence of a radical initiator such as AIBN or triethylborane/ air mixture. The major products are those of antiMarkovnikov addition and yields are currently modest at around 50-60%th, but the chemistry offers the potential to provide a scalable process for preparation of amines from alkene precursors (see J Guin, R Fröhlich and A Studer, Angew Chem Int Ed, 2008, 47, 779).

John Knight n


Youknowyou'veworked toolonginthelabwhen... are strangely proud of the collection of junk you have stolen from vendors at trade shows

T.K. Gibbs, M. Boomhoff, and N.C.O. Tomkinson,* Synlett, 2007, 1573. Will Watson n


Issue 23 March 2008

What's New in Process Chemistry?

It's Not What You Do ... ... It's the Way That You Do It

British tea-drinking scientists know that when you put milk in tea, the resultant brew is different depending on whether the tea is added to the milk (best mode) or the milk is added last (as in the US when hot water is added to a tea bag in a cup, and milk added later). We could go on about other critical process parameters involved in tea-making but now is not the time. As in tea-making, the order of addition of reagents in chemistry can result in major changes in product distribution. A recent example (Hajra S et al, Chem Commun, 2007, 2408-2410) examined normal and inverse modes of addition of reagents in the asymmetric aldol reaction. In one case syn products were obtained and in the other anti. The normal sequence is to add TiCl4, then base followed by the aldehyde, whereas in the inverse method the aldehyde is added after the TiCl4 with base last. The latter gives excellent yields of anti-aldol product with high selectivity, in contrast to the normal method which gives syn-adduct.

Trevor Laird n


Medicinal Chemistry 9 - 11 April 2008, London, UK An Introduction to Organic Chemistry

For Chemical Engineers & Other Scientists

16 - 18 April 2008, London, UK Understanding Polymorphism & Crystallisation Issues in the Pharmaceutical Industry 23 - 25 April 2008, Basel, Switzerland Industrial Biotransformations

Designer Enzymes for a New Era

24 - 25 April 2008, San Francisco, California, USA Chemical Development & Scale-Up in the Fine Chemical & Pharmaceutical Industries

Principles and Practice

29 April - 1 May 2008, Boulder, CO, USA 17 - 19 June 2008, Dublin, Ireland Secrets of Batch Process Scale-Up

Ensuring Effective Translation of Laboratory Processes to Pilot Plant Scale

3 - 5 June 2008, Edinburgh, UK EssentialReading

Process Chemistry in the Pharmaceutical Industry: Challenges in an Ever Changing Climate by Kumar Gadamasetti and Tamim Braish. The second volume of this book has now been published and contains a large number of interesting case studies in process R&D. It is a must-buy for all process chemistry departments. Published by CRC Press, 2007, 520pp $249.95

Trevor Laird n


Did you know that iodylarenes explode when heated above 2000C? Bretherick's Reactive Chemical Hazard Database reports that they also may explode on impact or by heating under confinement, especially in the absence of solvent. In a letter to Chemical & Engineering News, workers at the Medical University of Warsaw, Poland, reported that a violent explosion occurred when attempting to recrystallise 3-iodotoluene from boiling water. However, later on they give the formula as ArIO2, which of course is much more unstable than ArI and they talk about the oxidation process itself in the letter (C&E News, Jan 23, 2006). The authors suggested that poor stirring and local overheating were contributing causes to the explosion, but fundamentally, when working with compounds with a halogen oxygen bond, one has to know the temperature limits within which safe operation can be guaranteed.

Trevor Laird n

Too Much Analysis Leads To Paralysis I've never believed the little rhyme above, particularly when it refers to analysis of impurities in drug substances or products. In fact the opposite is true ­ the more you look, the more you find. If you wish to know more about analysis of drug impurities, you should read a book of the same name by Richard Smith and Mike Webb, both of GSK. They haven't actually written all the chapters, just edited them. They have called on colleagues from GSK and other companies to provide a unique industrial overview of the subject. I would particularly recommend the chapter on "Low-level Measurement of Potential Toxins (particularly alkylating agents)". Analysis of Drug Impurities edited by R J Smith and M L Webb, 275pp, 2007 ISBN 978-1-4051-3358-6 Pharmaceutical Analysis edited by D C Lee and M L Webb, 384pp, 2006 ISBN 978-1841-27335-8 Both published by Blackwell Publishing

Trevor Laird n


Informex 2008 - Continuous Processes

We recently hosted 4 networking roundtable sessions at Informex in New Orleans, January 2008 ­ one of which focussed on continuous processes and discussed the advantages and disadvantages of trying to apply continuous process technology to fine chemicals and pharmaceuticals. After a 20 minute presentation by Trevor Laird, questions were invited. An enthusiastic, though critical, audience then kept discussion going for a further 40 minutes. Key issues were equipment design and compatibility; capital costs and economics; what type of chemistry can be used; solids handling; cleaning and cross-contamination; continuous work-ups and isolations, particularly crystallisation etc. For those needing further information, details of the discussions at Informex and at other events on this topic will be the subject of an article in `Speciality Chemicals' in 2008, as well as a special issue of `Organic Process Research & Development'. More on continuous flow reactors can be found in a review by Professor Watts at Hull University, UK in a recent Eur. J. Org. Chem. article, published online in Jan 2008, DOI: ejoc.200701041. An article on continuous crystallisation can be found in The Chemical Engineer (2008, Feb, pp 36-38). Trevor Laird n

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