2,3-Substituted Indole synthesis by Regioselective Electrophilic Trapping

The selective synthesis of indoles is an important area of organic chemistry, largely due to their prevalence in countless natural products, medicines, materials etc. Numerous methods have been described for the synthesis of substituted indoles, with many requiring the pre-instillation of functional groups by incorporating them within the initial starting material. Late stage functionalisation is also possible, but in order for this to be achieved additional steps are often required, with some involving harsh conditions or the use of expensive transition metal catalysts. With this in mind, the report described by Eiichi Nakamura from the University of Tokyo could be of interest to people wishing to make a small library of substituted indoles from one common building block.1


Scheme 1

Within this communication, Nakamura describes the synthesis of indoles via dimetalated intermediates – although the synthesis via 2,3-dimetalloindoles has previously been reported, the selective introduction of electrophiles has, to the best of my knowledge, not previously been achieved. The problem of obtaining such selectively is shown in Scheme 2 – the dimetalated intermediates A and B react without selectivity, and so a mixture of isomers are obtained. In comparison to other dimetalated indoles,2 the Authors show that dizincioindoles are stable and relatively easily formed, suggesting a dimeric structure (shown in Figure 1) to rationalise this stability.


Scheme 2



Figure 1

The Authors show that when using of ZnCl2, electrophiles can be introduced at C-3 when simple electrophiles are used, but this can be switched C-2 when transition metals are introduced. When ZnPhBr is used, reactivity is generally more selective for C-3, unless a stannane is used, with differing reactivity probably due to a change in mechanism from simple nucleophilic reactions to that occurring through charge transfer (please see reference 1 for detailed substrate scope).

Although the above chemistry is not completely selective, it is certainly a good starting point for further investigation, as the selective synthesis of indoles remains and important task within many disciplines. I suppose the next question is – what other heterocyclic systems can this chemistry be applied to next?

Blog by Mark Honey

All Schemes and Figures were taken from J. Am. Chem. Soc. 2017, 139, 23-26


  1. J. Am. Chem. Soc. 2017, 139, 23-26
  2. Organometallics, 1998, 17, 2906


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]



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.