Who Needs Lab-Based Synthetic Chemists?

Back in 2013 I was a postdoc at the University of Tokyo – when I wasn’t working hard in the laboratory, eating sushi or participating in karaoke, I encountered a paper that fascinated me; ‘Combining 3D printing and liquid handling to produce user-friendly reactionware for chemical synthesis and purification’ was the title of the article.1 The group of Lee Cronin at The University of Glasgow described the fabrication of a multi-chamber reaction vessel, with each region having different catalysts printed onto its surface – in this case Montmorillonite K10 and Pd/C (Figure 1). Building up around the loaded base layer and subsequent sealing of the entire unit allowed, after 90 degree rotations, the synthesis of 3a and 3b (Figure 3) via an initial acid-catalysed Diels-Alder cyclisation, imine formation and subsequent reduction over palladium on carbon with triethylsilane.


Figure 1: Fabrication of Reaction Vessel1

A schematic of the reaction vessel can be seen in Figures 2 & 3. The first split chamber contains solutions of the initial reactants. When rotated by 90o, the two solutions combine in a second chamber that has been layered with Montmorillonite K10. Once the first reaction is complete (5 h), the box is rotated again by 90o in order to initiate imine formation. A third rotation by 90o passes the solution over a printed surface of palladium on carbon in the presence of triethylsilane, which acts to reduce the imine to the corresponding amine. The crude mixture is finally passed through a silica plug to give the desired final products in yields similar to those utilising traditional glassware (32% vs 40% for 3a, 30% vs 38% for 3b).


Figure 2: Schematic of Reaction Vessel1


Figure 3: Rotation and Reaction in Separated Chambers1


So, with the above in mind, do we really need lab-based synthetic chemists? Probably – the current range of reactions applicable to this technology is rather limited to robust and well established chemistry; mixtures that are happy to be left under atmospheric conditions, in the presence of water and without proper temperature regulation. However, although there are currently quite a few limitations, I do feel that perhaps after optimisation by a trained scientist, people unfamiliar with advanced synthesis techniques or liquid handling will be able to synthesise pure compounds (medicinally relevant or not) by picking up a box from the shelf and following instructions like one might do with piece of flat-packed furniture from one of the world’s favourite Swedish stores – surely nothing can go wrong with that?


Blog written by: Mark Honey



  1. P.J Kitson,   M.D. Symes,   V. Dragone and  L. Cronin  Chem. Sci., 2013,4, 3099-3103





A one-pot copper-catalysed synthesis of all possible stereoisomers of 1,3-amino alcohols from enals and enones

This recent letter produced by the Buchwald group [1] at MIT describes a copper catalysed synthesis of amino alcohols by sequential hydrosilyalation and hydroamination of enals and enones ( Figure 1).yusuffig1

Figure 1. Synthesis of amino alcohols. [1]

The chirality of a drug can have a significant biological impact in drug discovery. The chirality is the ‘handedness’ of a molecule and the various isomers of a chiral compound, known as enantiomers, will exhibit a different 3-dimensional orientation in space and could therefore possess different biological activities as they are different ‘keys’ that could fit into different ‘locks’. The most infamous example of this phenomenon is the sedative thalidomide which resulted 10,000 cases in the 1950s of malformed infants with a 50% survival rate. It was found that (R)-thalidomide possessed sedative effects while (S)-thalidomide was severely teratogenic. Figure 2, taken from the Wikipedia page on thalidomide, clearly shows the differing space occupied by the two enantiomers of thalidomide.yusuffig2

Figure 2. Enantiomers of thalidomide represented as 2D drawings and 3D ball and chain structures

With drug discovery clearly in need of methods to obtain all possible enantiomers of a chiral compound in a relatively easy manner, asymmetric synthesis has come to the rescue over the past few decades with major advancements in enantioselective synthesis. However, what has been lacking are methods that give a unified route to all possible stereoisomers of a given product containing multiple contiguous stereocentres.

The asymmetric hydrosilylation/hydroamination of enals and enones produces optically pure 1,3-amino alcohols which could be required for a target compound or be used as a building block in asymmetric synthesis. The synthesis is a one-pot procedure where the pre-stirred catalytic mixture composed of the copper hydride based catalyst, ligand and silane reagent is added to the enone or enal for 15 minutes followed by addition of the hydroxylamine ester (amine source) which is stirred at 55 °C for 36 h.

The authors show that hydrosilylation occurs regioselectively at the carbonyl over the alkene functionality and that hydroamination also occurs in a regio- and stereoselective manner to ultimately allow all possible amino-alcohols with a high chemo-, regio-, diastereo and enantioselectivity. Catalytic control was achieved by starting from the appropriate choice of enal/enone (E or Z) and ligand enantiomer (R or S).

The method seems to be applicable to a variety of enals/enones and amino –bearing groups with yields above 60 % generally obtained. Yields were generally higher for enals over enones. In all cases diasterometric ratios were >95% and e.e (enantiomeric excess) >99 %. Most notably, it was shown that all 8 possible stereoisomers of the final compound could be achieved in high selectivity from appropriate starting enals and starting enones (Figure 3).



Figure 3. All possible stereoisomers from the reaction of the enone 4 with dibenzylamine aminating reagent [1] (see Figure 1)

This method to synthesise all possible stereoisomers of 1,3-amino alcohols using readily available starting materials in a reliable and easy manner is a good example of asymmetric synthesis methods coming through in the literature in more recent times that allows assembling all possibilities in compounds with multiple sterocentres. I look forward to see further expansion in this particular area of asymmetric synthesis.

Blog writted by Yusuf Ali


[1] Shi SL, Wong ZL, Buchwald SL. Nature. 2016 Mar 28. doi: 10.1038/nature17191 [Epub ahead of print]



One-Pot oxidative Conversion of Alcohols into Nitriles

When looking for a mild synthetic method which could interconvert an alcohol functional group into a nitrile I came across this 2014 paper by Jean-Michel Vatèle published in Synlett. Vatèle has previously published some interesting papers using 2,2,6,6-tetramethylpiperidine-1-oxyl  (TEMPO) with a co-oxidant such as a practical one-pot procedure for the oxidation/olefination of primary alcohols using a TEMPO – Bis(acetoxy)iodobenzene (BIAB) system and stabilized phosphouous ylides.

There have been many publications describing the sequential oxidation-imination-aldimine oxidation of an alcohol to yield a nitrile. However, Vatèle’s metal free method uses cheap reagents and a simple reaction procedure which made it the most appealing of the methods that I looked into.

Vatèle had previously seen that a TEMPO/BIAB system can oxidise aldimines to nitriles and so wanted to investigate, if with the addition of an ammonium salt, the process could be extended to sequentially oxidise an alcohol to a nitrile. A small selection of solvents and ammonium salts were screened (table 1) using TEMPO (5 mol%) and BIAB (2.2 eq) as a co-oxidant. The conditions in entry 1 were chosen to investigate the scope of this reaction.lewis1


There were 22 alcohols subjected to these optimised reaction conditions and they all gave the desired product in >80% yields (summary in table 2). It was observed that in general alkyl alcohols were oxidised faster than benzyl alcohols (entries 1,2,3 vs 4,5). Acid sensitive groups such as TBS, Boc (entry 3), trityl and acetyl groups were stable under the reaction conditions. No racemisation was seen where chiral centres were present (entry 3) and electron withdrawing/donating groups on the aromatic ring had little effect on the oxidation (entry 4 and 5). There was no scrambling of cis or trans (entry 7) double bond geometry and chemoselectivity for a primary over a secondary alcohol was achieved (entry 8).

Table 2 Summary of products (table from Organic Chemistry Portal)


In addition to all of these examples we at the SDDC have used Vatèle’s conditions on a variety of 5 and 6-membered heterocyclic alcohols in which we generally isolated the corresponding nitriles in >80% yields. The only exception was when a quinone like motif was present and in this case a large volume of gas was produced and no starting material or product could be isolated.

In summary this is a very simple, cheap and general method for the oxidation of alcohols to nitriles. The reactions are relatively quick and high yielding. There is a simple work up and as there are minimal by-products the final product isolation is fairly simple. I would fully recommend giving these condition a try the next time you need to synthesise a nitrile.

Blog written by Lewis Pennicott

“Druglike” space – an artefact of the reactions we (medicinal chemists) use?

Scientists from AstraZeneca have recently carried out an analysis of the impact of organic synthesis on medicinal chemistry programs and revealed that, with a few exceptions, the most common reactions used in 1984 are still used in 2014, and that the chemical space generated with those few more frequently used reactions is composed of structurally similar compounds and therefore maybe biasing the drugs that are emerging.

In the article, Brown and Boström compare the most frequent reactions in Medicinal Chemistry in 2014 versus 1984 (see Figure 1) and found out that only a few newer reactions have taken a space in the top 20 list, such as the Suzuki and Buchwald cross-coupling reactions. While the latter was first published in 1994, and therefore could not have been used a decade before, the Suzuki-Miyaura reaction was first published in 1981 but the impact of this reaction was not seen in 1984. Similarly, newly developed synthetic reactions have yet to show an impact in recent drug discovery programmes.


Figure 1. Occurrence of a particular reaction, plotted as percentage of which it shows up in at least one manuscript (Figure taken from DOI: 10.1021/acs.jmedchem.5b01409)

Instead, comparing the reactions used by medicinal chemists to those used by chemists working towards the synthesis of natural products shows a completely different picture (see Figure 2). While the former tend to make amide bonds, aryl-aryl bonds, and amino-aryl bonds, the latter concentrate on functionalising oxygen atoms, set stereocentres and make carbon-carbon bonds.

Although carbon-carbon bond formation is a common practice, the type of reactions used by medicinal chemists and natural product chemists differs significantly. Medicinal chemists tend to used Suzuki coupling reactions while in natural product production it varies with aldol, Wittig and Grignard reactions.


Figure 2. Occurrence of a particular reaction type plotted as percentage of which it shows up in at least one medicinal chemistry manuscript versus natural product papers (Figure taken from DOI: 10.1021/acs.jmedchem.5b01409)

The authors question whether the type of reactions selected by medicinal chemists is done out of convinence (e.g because of efficiency and chemoselectivity of the reaction), therefore leading to libraries of compounds  with similar shape, or whether it is indeed there where the drug space is more abundant. To address this question they examine the frequency of biphenyl fragments (normally achieved through Suzuki reaction) in an AstraZeneca collection and found that over time there has been a 6-fold increase on the appearance of this fragment.  Using an in-house database (IBEX) they further examined the possible substitution patterns of mono– and disubstituted biphenyl structures.   For monosubstituted biphenyl fragments it was found that the para substituion was preferred while for the bisubstituted compounds it was the paraortho arrangement (Fig. 3). These preferences result in a high density of linear and disk shape molecules (see Figure 4 green and blue dots), whether the less frequent substitution patterns lead to more diverse molecular shapes (see Figure 4 red dots).


Figure 3. Frequency population of various biphenyl regioisomers in the IBEX (Figure taken from DOI: 10.1021/acs.jmedchem.5b01409)


Figure 4.Population analysis of representative biphenyl compounds illustrating the geometrical diversity of para-para (green), meta-para(blue), and ortho-ortho (pink) compounds (Figure taken from DOI: 10.1021/acs.jmedchem.5b01409)

Brown and Boström point out that, despite the reactions being used by medicinal chemists today still rely on chemistry discovered decades ago, scientific and technological innovations are still of great influence in medicinal chemistry laboratories. Automation, microwave and supercritical fluid chromatography are just some examples of technological advances  and recent reaction improvements have provided advantages to the classical reactions conditions discovered decades ago. However, the impact of recently developed methodologies, such as ring-closing metathesis, C-H bond activation, selective fluorination, biocatalysis etc… is still to be seen in medicinal chemistry laboratories.


Blog written by Carol Villalonga-Barber

New Year, New Chemistry – “Any-stage functionalisation” via strain-release amination

The Baran group at The Scripps Research Institute (http://www.scripps.edu/baran/html/publications.html) have recently reported an interesting reagent-based methodology to enable “any-stage functionalisation” of both simple and complex amines with small cyclic motifs such as bicyclo[1.1.1] pentanes, azetidines and cyclobutanes [1].

The strategy employs a turbo-amide to break a “spring-loaded” C-C or C-N bond, and in doing so directly aminates a strained species (Fig 1), enabling simpler syntheses and expanding retrosynthetic logic of some traditionally challenging targets.

Scott 01-02-2015 Picture 1

Fig 1. A – Strain-release amination using turbo amide and “strain-release reagent”, propellane, to afford bicyclo[1.1.1]pentan-1-amine on large scale after deprotection. B – Strain-release amination using turbo amide of late stage intermediate and “strain release” reagent, propellane, to afford a “propellerized” tertiary amine. Image taken directly from [1] without permissions

These small heterocyclic and bicyclic motifs can serve as bioisosteres in medicinal chemistry with the potential to bypass structural liabilities and navigate intellectual property space [2]. The incorporation of such structures into molecules using traditional methods (Fig 2), and from a late stage intermediate, can involve multiple FGIs and may involve the synthetic route being altered significantly to accommodate the small cyclic structure.

Scott 01-02-2015 Picture 2

Fig 2. Conventional and ‘new’ retrosynthetic analysis to obtain Pfizer’s precursor, bicyclo[1.1.1]pentan-1-amine. Image adapted from [3] and [1] without permissions

Pfizer’s urgent requirement of the costly precursor, bicyclo[1.1.1]pentan-1-amine (3 kg ~ $150 k)(Fig 2), in kilogram quantities for the synthesis of a clinical candidate, was the driving force behind this innovative methodology. Fortuitously, the strategy developed was then successfully demonstrated on a variety of secondary amines including commercial drugs, highlighting the applicability of strain-release amination. The ‘strain-release reagent’, propellane, used in direct amination was then substituted to include azetidines and cyclobutanes (B and C from Fig 3 respectively).

Scott 01-02-2015 Picture 3

Fig 3. The concept of strain-release amination: using the turbo amide of a lead with “strain-release reagent” A, B or C to append a strained ring system at “any stage” of synthesis onto the lead. Image taken directly from [1] without permissions

It will be interesting to see how this methodology develops; what other “strain-release reagents” can be employed, and how strain-release amination will be realised by academia and industry.

For a more complete account of the development of strain-release amination, further applications and in-depth details of the methodology (> 400 pages of supporting info!) visit http://openflask.blogspot.co.uk/ and read the primary reference [1].

Blog written by Scott Henderson


  1. Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L. R. Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M. Gallego, N. W. Sach, J. E. Spangler, H. Zhu, J. Zhu, P. S. Baran. Science. 351, 6270, 241 (2016)
  2. A. Meanwell. J. Med. Chem. 54, 2529 (2011)
  3. D. Bunker, N. W. Sach, Q. Huang, P.F. Richardson. Org. Lett. 13, 4746 (2011).


Bargellini Reaction

I recently had the opportunity to put into practice the early 20th century work of the Italian chemist Bargellini, when I had to synthesise α-heterocyclic amino carboxylic acids.

The Bargellini reaction typically involves the addition of trichloromethide to a non hindered ketone resulting in a trichloromethyl carbinol. This rapidly forms a gem-dichloroepoxide. Phenols can add to this gem-dichloroepoxide to give α-phenoxyisobutyric acids.

I followed the work of Butcher and Hurst (Tetrahedron Letters 50, 2009, 2497–2500), which extended the range of novel nucleophiles that can add to the gem-dichloroepoxide intermediate with substituted anilines and amino heterocycles.

Using Boc-protected piperidinone, analogues were made using poorly nucleophilic amino heterocycles. Butcher found that weak, sterically hindered nucleophiles still gave products in useful yields, with the nucleophilic atom not restricted to being a substituent on an aromatic ring (pyrazole).

Kam 04-01-2015 Picture 1

Reaction mechanism for the original Bargellini reaction:Kam 04-01-2015 Picture 2

(Phenoxide can be substituted for other nucleophiles such as anilines/amino heterocycles etc)

In summary, the Bargellini reaction offers a way to introduce varying points of diversity, exploring chemical space in a one pot atom efficient approach.

Blog written by Kamlesh Bala

References: Bargellini, Guido (June 4, 1906). “Azione del cloroformio e idrato sodico sui fenoli in soluzione nell’acetone. (Action of chloroform and sodium hydroxide on phenols in acetone solution.)”. Gazzeta chimica Italiana.

Aromatic amines as nucleophiles in the Bargellini reaction; Ken J. Butcher, Jenny Hurst , Tetrahedron Letters 50 (2009) 2497–2500


Aryl Sulfonamides made easy

Sulfonamide moieties are ubiquitous across commercial drugs and have been used in a wide range of therapeutic areas such as antimicrobial, diuretics, antiretrovirals and antiinflammatories. Among the drugs featuring sulfonamides are COX-2 inhibitor Celebrex (1), HIV protease inhibitor Amprenavir (2) and WHO’s list of essential medicine Sulfadiazine (3) (Figure 1).

Michael Fig 1 30-11-2015

Figure 1. Sulfonamide-containing drugs

Synthetically, sulfonamides can be readily accessed from (hetero)aryl or alkyl sulfonyl chlorides and amines. These sulfonyl chlorides have often the tendency to be instable due to their reactivity and their preparation itself can be challenging.

Of the many reported methods for the preparation of aryl sulfonyl chlorides, the main access still remains via aromatic electrophilic substitution. However, this methodology is dependent upon the aromatic characteristic of the arenes employed toward the electrophilic substitutions. Of the other methods available, worth mentioning is the conversion of thiol derivatives under oxidative conditions, often limiting the compatibility with other functional groups.

Mike Willis previously reported the preparation of aryl ammonium sulfinates under palladium-catalysed sulfination of aryl iodides. Based on the understanding that DABSO (Scheme 1) could be used as a convenient surrogate of SO2 gas in a number of transformations, Willis has shown that ammonium sulfinates could be readily obtained from aryl halides (Scheme 1).

Michael Scheme 1 30-11-2015

Scheme 1. Palladium catalysed cross coupling of aryl iodide with DABSO

To evaluate the scope of the reaction, the sulfinates were converted to the corresponding sulfones in situ by reaction with bromo tert-butyl acetate as the electrophile (Figure 2).

Michael Fig 2 30-11-2015

Figure 2. Sulfones from ammonium sulfonates

Shortly after, Willis also reported a simple and efficient one-pot synthesis of (hetero)aryl sulfonamides obtained from magnesium sulfonates prepared in situ with DABSO and a Grignard reagent and a N-chloro-amine as the electrophilic partner, also generated in situ from bleach and the relevant amine (Figure 3).

Michael Fig 3 30-11-2015

Figure 3. Organometallic reagent scope for the one-pot preparation of sulfonamides

In his latest publication, Willis reports a combination of the previous two DABSO-based methodologies where the ammonium sulfonate intermediate obtained from palladium catalysed sulfination of an (hetero)aryl iodide is further reacted with an amine in the presence of sodium hypochlorite (Scheme 2). Both electron withdrawing and donating groups are tolerated on the aryl moiety. More interesting however is the compatibility of the reaction conditions with the presence of other functional groups (esters, nitriles, ketones, phenols) but also thiols, allowing for the presence of sulfur atoms at different oxidative levels in the same molecule.

Michael Scheme 2 30-11-2015

Scheme 2.

The scope of the amines also tolerated was examined and the telescoped two steps, one pot procedure is highly tolerant of vulnerable functional groups. Example 4b in the table below clearly highlights how tolerant the reaction is to sensitive functionalities with both methyl thiol and acetal moieties untouched (Figure 4).

Michael Fig 4 30-11-2015

Figure 4. Reaction scope

Willis clearly exemplifies over a few publications how having access to an easy to handle surrogate of SO2 allows for the rapid development of novel reactions to prepare key functional groups such as sulphonamides.

Blog written by Michael Paradowski


Palladium-Catalyzed Synthesis of Ammonium Sulfinates from Aryl Halides and a Sulfur Dioxide Surrogate: A Gas- and Reductant-Free Process; Edward J. Emmett, Barry R. Hayter, and Michael C. Willis*; Angew. Chem. Int . Ed. 2014, 53, 10204 –10208

Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis; Alex S. Deeming, Claire J. Russell, and Michael C. Willis*; Angew. Chem. Int. Ed. 2015, 54, 1168 –1171

One-Pot Sulfonamide Synthesis Exploiting the Palladium-Catalyzed Sulfination of Aryl Iodides; Emmanuel Ferrer Flegeau, Jack M. Harrison, Michael C. Willis*; Synlett, 2015, DOI: 10.1055/s-0035-1560578.

Copper-Catalyzed Synthesis of Trifluoroethylarenes

Trifluoromethyl groups have found a use in medicinal chemistry for many reasons which include lowering the basicity of a molecule and increase the metabolic stability of alkyl groups.

Lewis 08-10-15 Picture 1A recent paper by Altman et al. expanded on the previous work of Chen in which he published a method for the decarboxylative trifluoromethylation of benzyl bromodifluoroacetates.

Altman noticed that there are currently methods for accessing trifluoroethylarenes via nucleophilic trifluoromethylation of benzyl electrophiles but there were no catalytic methods for this transformation on electron-deficient or heterocyclic substrates.

The current systems for benzylic trifluoromethylation require either stoichiometric copper (1), exclusive transformation of electron-neutral (2) or electron-rich substrates (3)(scheme 1)

Lewis 08-10-15 Picture 2The benefits of Chen’s work was the easy access to substrates derived from benzylic alcohols and the benign and easily separable by-products (CO2 and KBr). This method was not shown to convert a wide variety of substrates which Altman believes is related to the reaction mechanism described by Chen (scheme 2).

Lewis 08-10-15 Picture 3

Chen’s mechanism postulates a free CF3 anion, generated by an outer-sphere decarboxylation, which could react with sensitive carbonyl groups or deprotonate acidic sites. Altman hoped that he could refine the reaction so that an inner-sphere decarboxylation took place which generated Cu-CF3 and therefore making the reaction more tolerant of functional groups.

In this paper Altman investigated the reaction solvent, the catalytic copper source, additives and total quantity of iodide present on the reaction yield and by-product profile (table 1).

Lewis 08-10-15 Picture 4The optimised reaction conditions, 0.2 eq CuI, 0.25 eq KI, 0.4 eq MeO2CCF2Br and 4 eq KF in 1:1 DMF/MeCN, were then used to test if substrates containing a broad range sensitive groups and heterocycles could by trifluoromethylated in reasonable yields (table 2).

Lewis 08-10-15 Picture 5As can be seen from table 2 these reaction conditions tolerated a range of functionalities. The reaction was also conducted on a gram scale (2b) without a decrease in yield. Due to this functional group compatibility with amide (2c) and carbonyls Altman suggested that free CF3 anion (pKa = 27 in water) was not in existence in solution. To reflect the observations from this series of experiments, and previous work, including the absence of the CF3 anion and the importance of iodide in the reaction mixture Altman suggested the reaction sequence in figure 1.

Lewis 08-10-15 Picture 6To demonstrate the utility of this reaction an intermediate of fluorinated tebufenpyrad was synthesised in fewer steps and higher yield compared with a published route and also without the use of manganese or tin (scheme 3).

Lewis 08-10-15 Picture 7This paper has taken a previously published useful reaction for the transformation of benzylic alcohols into trifluoroethylarenes and further optimised it. The reaction can now be used to form trifluoroethylarenes from reagents that contain unactivated electrophiles, reactive carbonyls, acidic protons and heterocycles.

Blog written by Lewis Pennicott

Synthesis of Pyrazoles and Indazoles by Cu/O2 catalysed C-H activation

In a recent paper by Huanfeng Jiang a new practical synthesis of both pyrazoles and indazoles was described. By using a simple copper / oxygen catalytic system direct C-H bond amination was achieved.

Huanfeng started investigating this reaction by varying the copper catalyst, additive, solvent and reaction temperature to attempt to optimise the reaction conditions (table 1).

lp table 1Table 1: Optimisation of reaction conditions

With the optimal condition of Cu(OAc)2 (10 mol %) and DABCO (30 mol %) in DMSO at 100°C under O2 (1 atm) the scope of this reaction was explored (table 2 and 3).

As can be seen in table 2 the reaction gave pyrazoles in a >80 % yield where R1 = aromatic / olefinic, R2 = aromatic / olefinic / alkyl and R3 = aromatic / olefinic / alkyl. A wide range of functionalities were tolerated including fluorides, chlorides, bromides, nitriles, trifluoromethyls, carbonyls, sulphonamides and ethers. The only functionality investigated that was not tolerated was a free NH2. Huanfeng states that the geometry of the hydrazone double bond in the starting material is not important and believes that at elevated temperature in the presence on DABCO this would isomerise.

lp table 2Table 2: Synthesis of Pyrazoles

 After further optimisation of the reaction conditions it was found that the addition of 1 equivalent K2CO3 and an increased temperature of 120°C gave the best yields of indazoles. This reaction, as expected, tolerated the same functionalities as the pyrazole series. However, the potential to produce, presumably difficult to separate, mixtures of regioisomers makes this synthesis less desirable. It was noted that in the case of unsymmetrical aryl group that electron-rich substrates were favoured in the insertion step and that steric factors might also affect the regioselectivity.

lp table 3Table 3: Synthesis of Indazoles

The methodology to synthesise pyrazoles was then extended further to start from an aryl enone (scheme 1). Yields for this one-pot procedure (85 %) were comparable to the one step synthesis from a hydrazone (92 %).

lp scheme 1Scheme 1:  One-pot Pyrazole synthesis

To further the applicability of this chemistry Huanfeng functionalised a pyrazoles with NBS and used this building block in a Sonogashira reaction, Suzuki-Miyaura reaction and an amidation reaction (scheme 2).

lp scheme 2Scheme 2: Pyrazole derivatisation

To probe the mechanism of the C-H amidation several experiments were conducted using stochiometric quantities of an electron-transfer scavenger (1,4-dinitrobenzene), a radical clock (diallyl ether), or a radical inhibitor (hydroquinone, TEMPO) (scheme 3). The reaction proceeded in each case and when using diallyl ether no cyclised product was observed. These results suggest that this is not a radical mediated transformation.

lp scheme 3Scheme 3: Mechanism probing experiments

Based on these preliminary mechanistic studies Huanfeng has postulated the following mechanism (scheme 4). Initially olefinic hydrazone 1 or aryl hydrazone 3 would react with Cu(OAc)2 to form an Cu-N adduct A. The nitrogen from this Cu-N adduct could then undergo an intramolecular electrophilic substitution followed by aromatisation via C to give the pyrazole / indazole. The reduced copper species (Cun-2) could then be reoxidised by oxygen to complete the catalytic cycle.  Alternatively metallacycle B could be formed by electrophilic metalation or C-H bond activation followed by reductive elimination and aromatisation.


lp scheme 4Scheme 4: Proposed catalytic cycle

In conclusion this synthesis uses cheap and readily available reagents and has been shown to proceed in high yields even when preformed in air (72 % yield, table 1 entry 14).  This methodology circumvents the need to prefunctionalise starting materials with (pseudo) halides or directing groups and therefore has the potential to reduce the step count and open up previously more challenging or unavailable pyrazoles or indazoles.

Rotamers- assigned by a simple NMR experiment

Rotamers are conformational isomers where interconversion by rotation around a single bond is restricted and an energy barrier has to be overcome in order to convert one conformer to another.  When this rotation strain barrier is high enough to allow for the isolation of the conformers then the isomers become atropoisomers. Rotamers are however not separable and their existence normally complicates the 1H NMR interpretation. Variable temperature (VT) NMR is the generally preferred method for  studying the equilibration of the rotamers and at low temperatures the spectrum is assigned to the frozen equilibrium and multiple peaks are observed while at higher temperatures the spectrum simplifies as the equivalent peaks are averaged out. Other methods for NMR simplification include the introduction of a complexing agent and solvent switching. All these techniques are inconvenient to the organic synthetic chemist when working on small scale. To overcome this problem, Steve Ley and co-workers have identified that chemical-exchange NMR experiments, such as 1D NOE, can be used to identified resonances corresponding to those protons in chemical exchange processes, therefore distinguishes rotamers form other impurities or even stereoisomers, in a non intrusive way.


In a 1D gradient NOE experiment, a selected peak is irradiated leading to a negative peak at the site of irradiation while those protons connected to the targeted frequency region through space appear as positive peaks (or in the opposite phase to the irradiated peak). On the other hands those protons undergoing chemical exchange with the irradiated protons will appear as negative peaks, (or in the same phase as the irradiated peak). Figure 1 illustrates this, where a chemical-exchange experiment can be used to distinguish sets of rotamers in the presence of diastereoisomers.


Figure 1. (a) 1H NMR spectrum of a sample containing 3 and 4. Four NMR resonances (I, II, III, and IV) are observed corresponding to protons HA and HB in 3, 4, and their respective rotamers. (b) 1D gradient NOE spectrum after selective excitation of the resonance at 4.59 ppm (I) produces a single downfield resonance in the same phase at 4.28 ppm (III), indicating that resonances I and III belong to two rotamers of the same diastereomer (3) and that resonances due to one diastereomer do not transfer spin information via chemical exchange to the other. (c) 1D gradient NOE spectrum after selective excitation of the diastereomeric peak at 4.52 ppm (II) also produces a single downfield peak in the same phase (IV), indicating that resonances II and IV belong to two rotamers of the same diastereomer (4). Only the 5.2−4.1 ppm region is shown for clarity

Recently this technique has been applied by Proksch et al. to unambiguously determine the presence of four rotamers in two new depsipeptides. In this publication, they have also used 2D ROESY or NOESY experiments to find the same results.