Guidelines for Sonogashira cross-coupling reactions

As a synthetic organic chemist you will have built many carbon-carbon bonds and most probably in some occasions this will have been between sp2 and sp carbons. The so called Sonogashira cross-coupling reaction (Scheme 1), the most important of the latter carbon-carbon bond formations, is the reaction between an aryl or vinyl halides with a terminal acetylene catalysed generally by a palladium catalyst.

sono1Scheme 1.

 However, if one is to perform such reaction, the search for the ideal conditions can be difficult as addressed by a recent review (Chem. Soc. Rev. 2011, 40, 5084) where a search in SciFinder with the topic ‘Sonogshira’ revealed more than 1500 hits for the period 2007-2010.

Some general rules have previously been published by Hartwig in 2007 (Inorg. Chem. 2007, 46, 1936) which were derived from studies of the electronics and the bulkiness of the substrates and catalysts:

  1. The oxidative addition in Ar-X is promoted by electron-withdrawing groups at the aryl halide.
  2. Steric bulk of phosphines or NHC ligands coordinated to Pd promote the formation of a monoligated complex, which turns out to be highly active for oxidative addition.
  3. There is a pronounced steric effect in the transmetalation, while the ligand bite angle and the electronic effect are less important.
  4. Reductive elimination tends to be favoured by less electron donating ligands and steric bulk.

More recently Plentio has presented a guide on the performance of the Sonogashira cross-coupling (J. Org. Chem. 2012, 77, 2798) based on about 200 reactions (Scheme 2), where he correlates the stereoelectronic properties of the substituents in aryl bromides, acetylenes and phosphines.

 sono2Scheme 2.

  His conclusions can be summarized:

  •  The most important factor for choosing the ideal Pd/phosphine catalyst is the steric bulk of the phenylacetylene and Plentio reaches an ideal combination for the optimum steric bulk on the acetylene and phosphine. In short, the higher the steric bulk on the arylacetylene and the lower is the bulk of the phosphine ligand will promote the most efficient transformations.
  • Electron-withdrawing groups on the arylacetylene also increases the reactivity and this effect is more pronounced when the electron-withdrawing group is located on the acetylene rather than on the aryl bromide.
  • The more electron-rich the phosphine is, the higher the reactivity is.
  • The steric bulk on the aryl bromide, alpha to the bromo substituent, is more detrimental for the reaction than steric bulk on the acetylene.


Trifluoromethylation of arylboronic acids by Cu-mediated CF3 radicals

The incorporation of fluorine atoms into pharmaceutical molecules has long been in the medicinal chemist’s book of tricks to improve metabolic stability. The number of recent publications focusing on development of new methodologies for novel fluorination  and trifluoromethyl reactions only reflect the importance of such transformations.

Despite significant progress in the development of trifluoromethylation methodologies, and more recently with the Cu-catalysed trifluoromethylation of boronic acids, many transformations are still limited by either the cost of reagents, high temperature, strong acids / bases or limited scope.

Following on Melanie Sanford’s excellent JACS communication earlier this year, Melanie is back with a further publication addressing the scope and methodology of the trifluoromethylation of arylboronic acids with CF3 radicals. Key advantages to the publication is the generation of a practical source of CF3 radicals under mild conditions.

The CF3 radicals are generated in situ from of readily available NaSO2CF3 (Langlois’ reagent) and tert-butyl hydroperoxide (TBHP) and can undergo Cu-mediated trifluoromethylation with a range of boronic acids.

After an extensive evaluation of copper salts, CuCl proved to work well on reactions with no protodeborylation observed under the mild reaction conditions (Figure 2)

Figure 2

Both electron-rich and electron-neutral boronic acids are tolerated under the conditions described in the publication. However, Melanie reports that electron-deficient boronics acids led to moderate to poor yields. Further Cu screening for electron-deficient boronic acids led to the substitution of CuCl for (MeCN)4CuPF6 and addition of NaHCO3 (acceleration of the transmetalation rate) resulting in an improved yield (Figure 3).

Figure 3

From the scope of the reaction, it is worth noting that sterically hindered boronic acids are tolerated and the reaction compatible with a range of functional groups (esters, ketones, phenols).

Overall, a very mild and general approach for the Cu-catalysed trifluoromethylation of arylboronic acids, demonstrating the feasibility of a radical pathway.

Palladium catalyzed oxidative esterifications of aldehydes and benzylic alcohols

Over the past 10 years there has been a successful effort on the direct esterification of aldehydes with alcohols  using palladium catalysts mainly using molecular oxygen as the oxidant as the most environmentally friendly variation.

The common proposed mechanism for the transformation is shown below

The first step is the reduction of the Pd(II) species to Pd(0) and recently Xu and co-workers (Chem. Com. 2012, 48, 8592-8594) have taken this in consideration and added hydrosilanes to the reaction mixture in order to accelerate the first catalytic step in the aerobic oxidation of benzylic acohols.


Polymethylhydrosiloxane (PMHS) was found to be the best performing hydrosilane and gave high chemoselective oxidation for benzyl alcohol.  However, the reaction was found to be substrate dependent and for other substituted benzylic alochols, the aldehyde was the major product (Table 1)

Further attempts to improve the conversion and selectivity on o-tolylmethanol lead to the discovery that addition of BiCl3 as co-catalyst resulted in complete conversion and excellent ester selectivity and reduction of the reaction time. The optimized bimetallic Pd/Bi catalyst in the presence of PMHS proceeded in high yield and excellent selectivities also on different benzylic alcohols (Scheme 1).

Scheme 1.

 In the former oxidative esterification there was no reported issue of dimeric esterification presumably because methanol is used as solvent and therefore in large excess.  A highly selective cross-oxidative esterification was reported earlier this year by Lei (Angew. Chem. Int. Ed. 2012, 51, 5662) where the esterification of an aldehyde with a benzylic alcohol occurred before any alcohol oxidation. This selective transformation was achieved by using benzyl chloride as the oxidant. Other organohalides selectively converted the benzylic alcohol to the corresponding aldehyde without any ester formation. (Table 2) The use of aryl halides for the oxidation of alcohols is well documented and Lei’s paper cites a review by Muzart from 2003 (Tetrahedron 2003, 59, 5789), although there have been more recent publications improving this reaction  (J. Org. Chem. 2011, 76, 1390; Org. Lett. 2003, 5, 2485)…but not cited.

The use of 2-chloroactophenone as oxidant of alcohols has not been reported before but a similar reactivity with a-bromo sulfoxide has been previuosly described by Asensio (Adv. Synth. Catal. 2007, 349, 987-991). Lei, however, describes the alcoholisis step to generate I2 in Scheme 1 to occcur at the Pd-enolate bond of I1 (A-B = Cl-enolate) whereas Asensio proposes the alcoholisis to occur at the Pd-Cl bond. In the case of benzyl chloride, the alcoholysis is proposed to occur at the Pd-Cl bond by Lei, and he confirms it by isotopic labeling experiments.

The benzyl group seems therefore to be the key for the selective esterification of aldehydes with alcohols and Lei proposes that it forms a n3-coordination to palladium and facilitates dissociation of one of the triphenyphosphine ligands favouring the coordination of the aldehyde to the palladium.

The high selectivity of this reaction allows the authors to use the reagents (aldehyde and alcohol) in a 1:1 ratio, rather than using the alcohol in excess as originally described by the authors who first described the oxidative esterification using benzyl chloride (Tetrahedron Lett. 2011, 52, 5319). By the way…no proper citation (again) to this reference in Lei’s paper!!.

As the original publication (Table 3), Lei’s procedure is suitable for electron-rich and electron-deficient aromatic aldehydes and also aliphatic aldehydes and a,b-unsaturated aldehyes, their novelty, however, is the use of various aliphatic, benzylic and allylic alcohols  without alcohol oxidation observed (Table 4), making this piece of work a general and selective oxidative esterification of aldehyde with alcohol in a 1:1 ration.


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