Safe azide or oxymoron?


The Huisgen cycloaddition or ‘click chemistry’ could certainly take part of the blame for the resurgence of one of the bad boys of organic chemistry: azide. Coming from a large – Risk averse – pharma, I have always tried to avoid such fragments, possibly due to the implications and paperwork if (or more likely when) it goes wrong. So when an article with ‘Azide’, ‘Facile’ and ‘Safe’ is published it’s certainly worth reading.

The article from Wang’s group is looking at the diazotransfer reaction converting a primary amine to the corresponding azide.

The pre-Goddard-Borger and Stick era was using triflate azides as diazotransfer reagents which proved to be prone to explosion (Figure 1).

azide1Figure 1

The Wang article here is looking at a safe protocol to the imidazole-1-sulfonyl azide (compound 4, Figure 2) reagents developed and optimised over the last 6 years.

azide2Figure 2

Key requirements to the described ‘safe’ route were to avoid the presence of NaN3 with strong acids, minimise the excess of NaN3 and avoid the formation of explosive intermediates.  Previously reported procedures to prepare diazotransfer reagents such as those depicted in Figure 2 all seem to engage sulfonyl chloride, leading to the generation of (N3)2SO2 as a highly explosive byproduct. Wang starts from sulfuryl diimidazole which after mono methylation is treated with NaN3 to give the  imidazole sulfuryl azide reagent (Figure 3).

azide3

Figure 3

Worth noting that dimethylation of the sulfuryl diimidazole is not observed, so no highly explosive (N3)2SO2 species were observed and that sulfuryl diimidazole itself proved unreactive with NaN3 (Figure 4).

azide4Figure 4

Furthermore, Wang report that the aqueous conditions the reaction is performed in prevent the formation of the explosive (N3)2SO2 intermediate from the diazotransfer reagent itself (Figure 5).

azide5

Figure 5

Does that make the whole process safe? What about stability and storage? Wang et al. prepared the  imidazole-1-sulfonyl azide (compound 4, Figure 2) in over 100g scale but seems to have used it in-situ….

Imidazole-1-sulfonyl azide (the preferred diazotransfer reagent from the Figure 2 bunch) is usually prepared as a HCl salt. The ‘safety update’ from Goddard-Borger and Stick, published in 2011 as a follow up to their original 2007 ‘shelf-stable’ imidazole-1-sulfonyl azide, reports that ‘imidazole-1-sulfonyl azide hydrochloride is hygroscopic and reacts slowly with water to produce hydrazoic acid. Concentration of the mother liquors from which imidazole-1-sulfonyl azide hydrochloride crystallised has resulted in an explosion. This solution may contain sulfonyl diazides and/or hydrazoic acid byproducts which are both extremely sensitive, explosive substances’.

 

The Sejer group seems to work regularly with such diazotransfer reagents and reports that ‘rigorous drying of the HCl salt of imidazole-1-sulfonyl azide followed by storage at -20⁰C makes it stable for >1 year’ and that tetrafluoroborate and hydrogensulfate salts of imidazole-1-sulfonyl azide were found to be much better with respect to shelf life.

 

Back to Wang et al.’s conclusion that the protocol can be applied to large scale preparation in both academia and industry…. I will ensure it’s on my day off!

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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.

Decarboxylative Esterification of Carboxylic Acids with Dialkyl Dicarbonates


To continue on from the esterification theme of our recent blog (Palladium catalyzed oxidative esterifications of aldehydes and benzylic alcohols) I would like to highlight 2 papers on the subject of decarboxylative esterification of carboxylic acids from professor Gooßen’s group at the Max-Planck-Institut für Kohlenforschung.

Gooßen’s first paper (Adv. Synth. Catal., 2005, 345, 943-947) describes the exploration of conditions for the optimisation of Lewis acid catalysed decarboxylative esterification of carboxylic acids with dialkyl dicarbonates (Scheme 1).

Scheme 1

Gooßen showed that in the presence of Bronsted acids almost no ester formation was observed and that DMAP only yielded a modest catalytic activity using the conditions previously described by Takeda. In contrast to these results it was shown that the all the Lewis acids investigated gave the desired ester with a catalyst loading of only 1 mol % (Table 1).

Table 1

Gooßen’s selected nitromethane as the solvent to further explore the generality of the chemistry, due to the carboxylic acids being readily soluble in it, but the reaction works equally well in methanol, dichloromethane or acetonitrile.

Both magnesium perchlorate and copper triflate are mild enough Lewis acids that transesterification of the sensitive phenol ester did not occur (table 1, entries 25 and 26) but they were both still able to convert the carboxylic acid into a methyl ester in a quantitative yield. Based on these results coupled with both environmental and economical considerations it was decided that magnesium perchlorate was the superior choice of Lewis acids for this reaction.

With these variables fixed the scope of this reaction was further explored with a range of carboxylic acid and dialkyl dicarbonates (table 2). All of the reactions produced the desired esters in high yield except for amino ester 8c. Both the methyl ester 8a and benzyl ester 8b were produced as expected but the t-butyl ester was unstable under the reaction conditions, producing isobutene and the carboxylic acid starting material.

Table 2

Gooßen believes that the reaction proceeds via an intramolecular decarboxylation due to methyl ester 18a (table 2) being formed in a high yield (92%). If only an intermolecular reaction of the mixed anhydride occurred then a statistical mixture of the methyl ester, lactone and oligomeric esters should be formed.  In an attempt to confirm this hypothesis Gooßen reacted phenylpropionic acid with dimethyl dicarbonate and Mg(ClO4)2 in the presence of 1 equivalent of n-butanol. The desired methyl ester formed (81%) but also a quantity of the n-butyl ester (19%).  Gooßen is investigating the mechanism of this reaction and will report his finding in due course.

In Gooßen’s second paper (Synlett 2004, 263–266) he describes a convenient protocol for the esterification of carboxylic acids with alcohols in the presence of di-t-butyl dicarbonate (Boc2O). By using a stoichiometric amount of a carboxylic acid, a primary or secondary alkyl alcohol and Boc2O, in the presence of a catalytic amount of N,N-dimethylaminopyridine (DMAP), gave high yields of the corresponding esters (Scheme 2).

Scheme 2

Gooßen investigated a range of catalysts (Hf(OTf)4, Mg(ClO4)2, Sc(OTf)3, Yb(OTf)3 and DMAP) as well as a selection of solvents (nitromethane, THF, toluene, DMF and MeCN) before arriving at his standard conditions (1.0 mmol 3-phenylpropionic acid, 1.3 mmol Boc2O, 1.3 mmol benzyl alcohol, 5 % DMAP, 4 mL nitromethane, 50°C, 16 h). It was observed that the reaction gave the same yield regardless of the solvent used to run the reaction in.

Scheme 3

Gooßen exemplified this procedure by using a selection of alcohols that he coupled with 3-phenylpropionates (Scheme3, Table 3). The reaction produced the desired products in high yields with both primary and secondary alcohols. Groups including cyano, keto, ester and less reactive alcohols were tolerated.

Table 3

Gooßen then chose a selection of carboxylic acids that he then coupled to benzyl alcohol (Table 4). The reaction was able to be performed on aryl, alkyl, vinyl and heterocyclic carboxylic acids which contain ester, ketone, amide, ether and nitrile functional groups. Unfortunately the reaction failed to yield the desired product and resulted in decomposition of the starting material for o-fluorobenzoic acid and m-NO2-benzoic acid.

This procedure presents an advantage over the use of alkylating reagents such as alkyl halides for esterifications due to the relative costs of reagents and the larger range of alcohols that are available.

Table 4

In summary both papers offer alternative approaches for synthesising esters from carboxylic acids. The reactions are mild enough to tolerate a large range of functional groups and use cheap, readily available starting materials. The work up of these reactions is also simplified by the fact that most of the by-products are either volatile or water-soluble and this make these methods very practical for a synthetic chemist to use.

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.

Image

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%.

Image

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.

Image

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.

Image

Image

One-Pot Synthesis of Substituted Ureas Directly from Primary Alcohols


Publications that describe novel and unusual transformations or interesting one-pot procedures always grab my attention and the latest paper by Chi Zang et al. in Synthesis eFirst is a prime example of this.

Zang set out to develop a phosgene and transition metal free, easily handled, and mild method to synthesise substituted ureas. In this paper Zang describes a one-pot transformation of primary alcohols and amines into unsymmetrical ureas (scheme 1). This work builds on and optimises some previous work from Zang’s group where they use iodobenzenedichloride and sodium azide in acetonitrile to convert primary alcohols into carbamoyl azides, albeit in low yields.

After screening a selection of solvents, hypervalent iodine reagents and the number of equivalents of reagents required Zang’s best conditions used 5 equivalents of iodobenzenedichloride and 10 equivalents of sodium azide in ethyl acetate.

To test the generality of these conditions a variety of primary alcohols were converted to their respective carbamoyl azides (table 1). It was found that, regardless of the electronic or steric properties of the alcohols, all of the reactions proceeded smoothly. It is also noteworthy that no racemisation was observed with chiral alkyl alcohol 1h (table 1, entry 8).

With the synthesis of the first stage of the reaction optimised Zang proceeded to test his hypothesis that both symmetrical and unsymmetrical ureas could be synthesised from alcohols. Zang chose 4-methylbenzyl alcohol (1b) and aniline as the model substrates and as expected, 1-phenyl-3-p-tolylurea (3a) was isolated in high yields (table 2). It was also shown that by increasing the number of equivalents of aniline a small improvement in the yield could be achieved as well as a reduction in the reaction time.

Utilising these reaction conditions Zang explored the range of anilines to gage the generality for this new one-pot procedure (table 3). Satisfyingly all of the anilines examined, which included electron poor, electron rich and sterically hindered molecules, produced the desired products in good to excellent yields. Alkyl amines (table 3, entries 11-13) also gave the desired ureas in good yields. Zang acknowledges that 8 equivalents of the amine coupling partner is not ideal but he does explain that a majority of this excess can be recovered by a simple workup and gave the example that 4-bromo-aniline was recovered in a 78% yield (table 3, entry 4).

On the basis of the above experimental results and his previous related work, a stagewise reaction mechanism for the present one-pot transformation of primary alcohols to substituted ureas is proposed: i) oxidation of the primary alcohols to the corresponding aldehydes, ii) conversion of the aldehydes into acyl azides, iii) formation of carbamoyl azides from the acyl azides via Curtius rearrangement and subsequent addition of hydrazoic acid, and iv) transformation of the carbamoyl azides with amines to the corresponding ureas (scheme 2).

 

With this proposed mechanism Zang wanted to understand why the reaction gave higher yields when run in ethyl acetate compared to acetonitrile. He used benzyl alcohol to investigate the kinetic formation of benzaldehyde and benzoyl azide. The studies showed that the benzyl alcohol was completely oxidised to benzaldehyde within 30 minutes at 0 °C in both acetonitrile and ethyl acetate with only trace amounts of benzoyl azide observed. After stirring for a further 4 hours all of the benzaldehyde in ethyl acetate was converted to benzoyl azide but even after stirring for 5 hours only a small proportion of the benzaldehyde in acetonitrile was converted to benzoyl azide. [Bis(azido)iodo]benzene, the active intermediate generated when sodium azide is added iodobenzenedichloride, has been shown to be unstable at 0 °C and to decompose to iodobenzene and nitrogen gas. It was seen that in contrast to the reaction in ethyl acetate when the reaction was run in acetonitrile a large amount of gas was generated from the reaction mixture. A ligand-exchange experiment was undertaken to attempt to understand these differences. These results showed that the speed of the ligand-exchange reaction between iodobenzenedichloride and sodium azide is faster in acetonitrile than that in ethyl acetate; consequently, the concentration of the reactive intermediate [bis(azido)iodo]benzene would be higher in acetonitrile and thus kinetically result in the faster decomposition of [bis(azido)iodo]benzene.

 

In conclusion this paper demonstrates a phosgene and transition metal free, easily handled, and mild one-pot method to synthesise substituted ureas. It also includes a good explanation for the differences in yields that were observed when the reaction was run in different solvents. I believe that this methodology could be modified to synthesise carbamates in one-pot by the addition of an excess of an alcohol (instead of the amine) to the carbamoyl azide intermediate.

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

Michael