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.


C-H activation showcase

C-H activation has been a hot subject for the last few years with many groups investing much effort in removing the need for organo-metallic derivatives that can prove a challenge of their own to generate. Despite many efforts in what sometimes looks more like ‘black art’ than planned selectivity, the direct arylation of pyrazoles has been one of the toughest challenges of the past 10 years. The likes of Daugulis and Sames have established methodologies involving Cu catalysis and SEM directing groups to enable the direct arylation onto pyrazoles.

 A recent publication from Doucet’s group at the Université de Rennes showcases the introduction of a sacrificial heteroatom to address the selectivity of aryl moieties onto pyrazoles by direct arylation.


The initial C-H activation is worth a few words here as the reaction is catalysed by a phosphine free palladium used in very low loading (0.1%). A considerable advantage over the typical conditions, especially as such processes find their way into pilot plants and commercial routes. No mention however as to why the reaction undergoes C-H activation with such a system. Also of interest, the authors claims the arylation proceeds via a Concerted Metalation Deprotonation (CMD) mechanism. Although there are no explanations, it is interesting to note that in this case pivalic acid, normally added to lower the energy of the C-H bond cleavage, is not used in this CMD reaction.

The reaction prefers para- and meta- electron withdrawing aryl bromide substituents with yields mostly ranging in the 70 to 80%.


Of most interest is the direct arylation of pyridyls, quinolones and isoquinolines, all obtained in high yield. A real ‘tour de force’ if you have ever tried to introduce a boron to either a pyridyl or a pyrazole without suffering subsequent protodeborylation during the cross coupling.

Dehalogenation in the presence of 5% Pd/C enables the further direct arylation at the C-5 position, this time using a palladium with a phosphine ligand.


Overall, a good example of how powerful the C-H activation methodology can be in coupling hetero aromatics moieties together

This article can only lead to a comparison to the excellent Sames’ article published in JACS (previously mentioned in my introduction and to which the author also refers to) a few years ago. Sames used nitrogen protected SEM group to direct the selectivity to the adjacent carbon.



Borylation feast

I have always found boron chemistry exciting. Maybe the result of too many Suzuki reactions (and reactivity issues) from a previous life in the pharma world. With the recent advances of catalytic borylations, boron is quickly becoming a very versatile element to build on and not any longer just for cross coupling methodologies.

With the advent of C-H activation for C-C bond formation, the scope has expanded to other metal catalysed C-H functionalisations, including C-H borylation under a variety of iridium and rhodium catalysed conditions.

A case in point are 2 recent communications published in JACS.

The first from Tobisu et al (J. Am. Chem. Soc., 2012, 134 (1), pp 115–118) looks at the rhodium catalysed borylation of nitriles through the cleavage of the carbon-nitrile bond (scheme 1).

Scheme 1

According to the author, this is the first example of a rhodium catalysed C-CN bond cleavage other than Ni(0) or silyl metal complex. After an extensive screening of various bases and ligands, a range of boronate esters were obtained in reasonable to excellent yields and excellent compatibility with a range of functionalities (Table 1). Worth noting is the reaction tolerance to esters, amino acids and amines.


Table 1. Rh-catalysed borylation of nitrile

Bulky ortho-substituted aryl nitriles proceed efficiently under less bulky phosphine ligands (PPh3 instead of Xantphos in these cases).

Tobisu makes an attempt at a proposed mechanism involving a boryl rhodium intermediate and iminylrhodium isomerisation prior to β-aryl elimination (Scheme 2).

 Scheme 2

Overall a very unusual but efficient C-CN bond activation promoted by borylrhodium complex.

The second publication from Yu at the Scripps institute (J. Am. Chem. Soc., 2012, 134 (1), pp 134–13) looks at the Palladium oxidative ortho aryl borylation (Scheme 3).

Scheme 3. Palladium catalysed borylation of N-Arylbenzamides

The conditions are so far fairly specific, relying on a very strong ortho directing group  (4-CF3)C6F4, modified dba ligand and a strong oxidant (K2S2O8). After extensive screening conditions, Yu demonstrates some efficient ortho borylation obtained in good yield (Scheme 4).

Scheme 4

At this stage, the aryl substituents are limited but it will be interesting to see if future improvements of this methodology allow for a more diverse range of functionalities.

Both these methodologies are a great addition to the now very versatile and sterically controlled Ir catalysed C-H borylation conditions. The example from Keith James et al (Pfizer & Scripps; Org. Letters, 2010, 12 (17), 3870-3873) is just an illustration of how powerful this methodology has become (Scheme 5)

Scheme 5. Steric Ir catalysed CH borylation

The conclusion from Yu’s communication (Scheme 6) is just a reminder of how versatile C-H borylated compounds have become in accessing new chemical space often difficult to reach via more traditional chemistry methods.

Scheme 6