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.

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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.