A Proposed Cheap Replacement for Quinoline -3-carboxylic acid as a Reversible Tag

 

In 1999, Hélène Perrier and Marc Labelle [J. Org. Chem. 1999, 64 2110-2113 ] proposed using a 3-quinolinecarboxylate protecting group on a growing intermediate substrate to assist in isolating them at each step in a process by precipitating these substances as insoluble quinolinium salts.

The proposal seemed promising but at scale the cost of that protecting group inhibited adoption.

The KiloMentor blog has always aimed to promote and enhance methods that streamline isolation, purification, and workup procedures in synthetic organic chemistry.

In this particular instance, KiloMentor wishes to propose an inexpensive synthesis of a related 6-methyl-3-pyridinecarboxylic acid that might serve in the same way but that could be much cheaper to prepare.

The chemical literature already teaches the high-yield, simple, scalable synthesis of 2-methyl-5-aldehydo-4-pyridone in 75% isolated yield. [ F. Arya, J. Bouquant J. Chuche, Synthesis Communications 1983, 946-948 ] by continuous hot tube pyrolysis from the inexpensive inputs isopropyl amine, ethylformate and dimethylmalonate. 

The conversion of this 2-methyl-5-aldehydo-4-pyridone to  6-methyl-pyridine-3-carboxylic acid has not, as far as I know, been reported; however, it would seem that it might be made simply by the addition of the compound gradually to strong aqueous alkali to oxidize the aldehyde, reduce the ketone (Cannizzaro like) and then dehydrate the ring to aromatize the moiety. The resultant amino acid should be easily separated because of its acid-base properties.

Arylboronic Acid Functionality makes Phase Switching Possible

 

In the thesis of Paul O’Brien working with Professor Organ at York University in Toronto, there is useful information for using molecules containing aryl boronic acids as intermediates that enable a phase switching purification.

 This thesis teaches that phenyl boronates can be extracted into a water solution containing 1.0M D- Sorbitol at pH 11-13 and then after making the pH acidic, the boronate functionalized substrate can be taken back into a water-immiscible organic solvent, thus achieving a solvent switch that can provide a rugged tool for rapid purification.

“Hall demonstrated that aryl boronic acids are stable to reaction conditions such as IBX oxidations (2-iodoxybenzoic acid), DIBAL-H reductions, esterification of alcohols, amidations, Wittig reactions, and Grignard additions [Mothana, S.; Grassot, J.; Hall, D. G. Angew. Chem. Int. Ed. 2010, 49, 2883-2887].This strongly suggests that arylboronic acids may be stable to a range of rather harsh reaction conditions without resorting to protecting groups. 

Arylboronic acid tagging strategies also show good atom economy in contrast with other tagging methods because the tag can be utilized in chemical transformations such as Suzuki cross-coupling, Rhodium cross-coupling (C-N and C-C), chemoselective oxidations, catalytic hydrogenations, selective aerobic oxidative coupling, transition-metal free cross-coupling, and protodeboronation to name just a few.

The use of arylboronic acid moieties as phase-switching handles adds synthetic utility while reducing synthetic steps such as protection protocols for subsequent column chromatography. Purification of most boronic acids is difficult since they are highly polar, like carboxylic acids, and adhere to polar chromatography material such as silica. The degree of lipophilicity of the boronic acid substituent influences chromatographic adhesion, where highly lipophilic substituents decrease retention on silica. Another method to decrease the polarity is boronic acid protection using 1,2-diol such as catechol or pinacol esters to mask the polar -B(OH)₂ functionality as a lipophilic ester.”

I have made what I think are editorial changes in what is almost, but not quite, a quote.

The Quinoline Tag to enable Phase Switching Isolations in Chemical Synthesis Process Development

 

The KiloMentor blog is dedicated to transmitting useful ‘tricks of the trade’ to the synthetic organic chemists who do the actual laboratory experimentation that creates chemical processes that are intended to be performed at scale.

The KiloMentor blog therefore particularly highlights the importance of the workup of chemical reactions with their separations, isolations, and purification operations since it is these that consume the most time in the plant setting. It is also these methods which are most difficult to uncover by electronic database searching.

In 1999, Hélène Perrier and Marc Labelle published a paper titled Liquid-Phase Synthesis with Solid-Phase Workup: Application to Multistep and Combinatorial Syntheses, J. Org. Chem. 1999, 64, 2110-2113 which was designed to make the workup of every step of a reaction sequence a simple filtration until the tagged target molecule was completely assembled whereupon the facilitating functional ‘tag’ could be cleaved off to leave the target molecule itself in practically pure form.

Another way of looking at what they were enabling is an alcohol-protecting group that so long as it remains in process intermediates makes them simple to isolate and purify from their reactions. In the terminology of Dennis P. Curran, it makes phase switching of these intermediates possible. In the terminology of Jun-ichi Yoshida, it introduces tags on these intermediates.

These chemists discovered that if an alcohol functionality in a starting material was made into the ester of 3-quinoline carboxylic acid then other functionalities in that starting material could be used to elaborate some larger assemblage and all the intermediates in that sequence could be easily isolated and purified by first precipitating them from the reaction solvents as insoluble sulphuric acid salts and then reconstituting the free quinoline by neutralizing the salts and extracting the intermediate back into the solvent for the next reaction in the desired synthetic route.

The salts with sulphuric acid were found to be the choice that most dependably crystallized from a wide range of solvents. The original paper should be consulted for the experimental details.

Finally, in their examples, the 3-quinoline carboxylic acid could be recovered at the end of their test sequences and was sufficiently pure to be reused!

Although these authors don’t go that far, KiloMentor concludes that protection groups generally, besides protecting functional groups, should be selected to promote the isolation and purification of the intermediates into which they are introduced.

Phenylboronic Acid: A Functional Tag to Enable Simple Removal of Excess Reagent or Coproduct using Chromotropic Acid

Chromotropic Acid for Extracting Boronates

The KiloMentor Blog articles emphasize ways to make the workup, separation, and purification of the product from organic reactions more cost-effective. Often this is enabled by phase switching methods that quickly take the desired material into one bulk phase and byproducts, coproduces, and the processing chemicals into another.

One way to dot this is to use a reagent or coreactant that has built into its structure some functionality that allows it to be subsequently extracted into an aqueous phase. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is an example of such a reagent. The pendant dimethylamino functional group makes an excess reagent or coproduce or byproduct basic and so soluble in aqueous acid.

A functional fragment that can be used in this way but has rarely been adopted is the p-dihydroxy-boryl benzyl function.  This substructure appears in the Dobz protecting group for peptide synthesis [D.S. Kemp and David C. Roberts, Tet. Lett. 52, 4629-4632, 1975]. The dihydroxyboryl group forms a strong covalent linkage with the sodium salt of chromotropic acid [1,8-dihydroxynaphthalene-3,6-disulfonic acid] which is very soluble in water.

In the absence of complexing species, boronic acids are in reversible equilibrium with their cyclic trimers and water. Other species containing the group may be partially converted to Boronic anhydrides.

Although many reactions can be conducted in the presence of the free Boronic acid function  as a second option the Boronic acid can itself be protected as the N-methyldiethanolamine complex. N-methylethanolamine is of course itself readily taken into water in a workup. 

The 1,2-Diol Functionality as a Possible Phase Separating Tag

In CA2677670, a monoglyceride ester is separated from other impurities by absorbing the mixture on silica gel and washing with hexanes/ethyl acetate 90:10 v/v. This was not a column chromatography as can be determined from the experimental details. The 90:10 mixture of hexanes/ethyl acetate (10 ml) was used to dissolve the approx. 16 g of ester and to this solution 40 g of silica gel was added.  The slurry was put on a fritted funnel and eluted with 150 ml of the mixed solvents to remove the impurities. A second elution with 300 ml of ethyl acetate  removed the monoglyceride which was concentrated in vacuo. This seems to show that diols seem to bind tenaciously to polar solid adsorbants.

It is well known that mono alcohols often form insoluble complexes with CaCl₂, LiCl, LiBr, CaBr₂ and MnCl₂ for example. So it not surprising that diols would form strong complexes with such inorganic salts.  As evidence of this there is a patent, US 3,846,450 titled Purification of Oxygenated Compounds that describes the removal of diols by passing a liquid comprising some of these through solid alkali earth halides. This would trivialize their separation from compounds without this substructure. 

It has been reported that complex steroidal and prostaglandin structures can be purified by precipitating as LiBr complexes [GB2094795]. The prostaglandin structures typically contain more than one alcohol functionality. This should increase the likelihood that metal halide complexes with 1,2-diols are more likely to produce solid precipitates.  Kilomentor has already published a note about using such metal complexes to separate alcohols from non-alcohols and some alcohol mixtures from each other.

I have not found work showing that substances containing two or more non-adjacent alcohol groups dependably form lithium bromide or calcium bromide precipitates even though the work with lithium bromide and prostaglandin intermediates is promising in this respect. What is clear is that neutral 1,2-diols can be separated from other functionalities ruggedly and dependably.The 1,2-diol functionality most probably can be covalently attached to a very wide variety of intermediates as a ‘phase-separating tag’.

 Substrates containing the tag would, perchance, be precipitated by stirring with an inorganic salt in non-polar solvent. It might turn out that the 1,2-diol at the end of a hydrocarbon chain might be a substructure that could control precipitation in a wide variety of intermediates using a standard set of conditions ( a particular salt, precipitating solvent, ethanol catalyst and reaction conditions). It is already known for example that a primary alcohol is preferred to a secondary or tertiary one.

After the terminal 1,2-diol had served its purpose for intermediate isolation/ purification it could be selectively cleaved to an aldehyde or cleaved and reduced to a primary alcohol with one  fewer carbons than the diol. The functional group would be expected to work as a phase-separating tag best when the other functional groups in the intermediate were not polar ones that could also interact strongly with the inorganic salt.

It seems that whether a solid complex is formed may depend upon both the crystal lattice energy of the complex and the energy of the crystal lattice of the salt itself. As Sharpless notes, [K.B. Sharpless, A.O. Chong, and J.A. Scott, Rapid Separation of Organic Mixtures by Formation of Metal Complexes, J. Org. Chem., 40, 1252 (1975)}, whether they form solid complexes or not the alcohols do cause the dissolution of the calcium chloride into the hexane. Another important observation provided by Sharpless et al. was that mixtures of alcohols often dissolved but did not even partially precipitate under the complex forming conditions even when the pure components of the mixture formed solid calcium chloride complexes when treated individually but separately. 

Why some alcohols form solid complexes and others just dissolve the inorganic salt ,but do not precipitate, has been hanging unsolved for a long time. The Sharpless strategy has never become popular. This is because, according to a personal communication from Sharpless himself, the best conditions for forming and precipitating the complexes were unfortunately not those recommended in his article. Not a 2:1 molar alcohol inorganic salt ratio, but a large excess of inorganic salt works best taking into account more cases. Perhaps the alcohols and inorganic salt form oil-in-water or water in-oil emulsions which only occasionally break down to precipitated solid. 

If the problem is emulsion formation it might be important to remove completely any residual water. Using aprotic solvents that have fewer degrees of freedom themselves might help. Cyclohexane and diisopropyl ether might be tried. Diisopropyl ether seems to be the solvent of choice when it is difficult to get regular crystallization. Patent GB1555968 suggests that methyl isobutyl ketone (MIBK)or methyl n-amylketone are preferred candidates to form insoluble complexes, at least when calcium bromide is used.

Clearly solvents must be used that do not themselves dissolve these divalent inorganic salts because such solvents present in so large an excess would easily out compete substrates.  Hexanes, methylene chloride, MIBK and methyl n-amyl ketones would meet the criterion of not dissolving much salt alone.

Besides the equilibrium effect sometimes giving rise to useful precipitation there is probably also a kinetic effect upon whether the precipitation/crystallization provides purification. The limited data could be interpreted as suggesting that small alcohols exchange more rapidly than large alcohols and small alcohols, present catalytically, promote exchanges. 

Using a Sulfur Tag for Separations both in the Lab and At Scale

In 1964, G.M.Badger, N. Kowanko and W.H. F. Sasse submitted a short communication to J. Chromatog. 13, (1964) 234 titled, Chromatography on a column of Raney cobalt. The small experimental section read as follows:

“The freshly prepared Raney cobalt (ca 7.5 g) was mixed with clean sand and packed into a chromatographic column (1.2 cm X 10 cm.). A mixture of isoeugenol (0.5 g) and 2,5-dimethylthiophene (0.5 g) was applied to the column and eluted with methanol ( a 3-ft head of liquid was required). Evaporation of the first fraction 930 ml) gave sulfur-free isoeugenol (0.477 g). Subsequent fractions contained only trace amounts of isoeugenol and were also sulfur-free. The dimethylthiophene was subsequently recovered by Soxhlet extraction of the cobalt-containing solid with methanol.” (my italics).

The discussion pointed out that active cobalt metal binds sulfur-containing compounds by chemisorption; however, unlike Raney nickel, cobalt has a much reduced tendency to desulfurize. Nevertheless, this binding is powerful, much stronger than simple adsorption, as the rigorous conditions described for removing the dimethylthiophene from the solid support attested.

What this suggested to me was that the method would not need to be conducted as a column chromatography. It would probably work simply by stirring the solid with a solution containing the sulfurous material, passing through filter aid, and washing. Thus, the method could separate sulfur-containing from sulfur-free materials by filtration as easily as an insoluble polymer is separated from a solution.

That  desulfurization under the conditions of separation is unlikely is further suggested by another paper [1960] by the same authors which contains the sentence “Desulphurisation with Raney cobalt was similar to that with W7-J Raney nickel in that, although little reaction occurred in boiling methanol, it was complete in diethyl phthalate at 220.”

It would seem that, besides obviously being able to separate the sulfur-containing from sulfur-free compounds, the technology should be adaptable to separate compounds that have been derivatized with a sulfur-containing reagent from compounds without such an appendage.

It might be that the method of recovery of the chemisorbed compound could be improved. Eluting with a solvent containing carbon disulfide or COS might speed the recovery without irreversibly contaminating the eluting solvent.

Also, a chemisorbant simpler to prepare than Raney cobalt might be available by reducing a cobalt salt with sodium borohydride to give a Cobalt boride analogous to the Nickel boride catalysts called P-1 and P-2 developed by H. C.Brown et al. 

A Piperidino Phase Switching Functional Group Tag

KiloMentor blog articles have emphasized of having intermediate substances that are easy to purify in a synthetic scheme.  An intermediate that acts as a base and can be extracted into an aqueous phase as a salt and subsequently taken back into an organic solvent in its free base form will usually be easier to separate and purify. This is consistent with the teaching of Dennis P. Curran who first drew attention to the importance of phase switching in purification and isolation.

R. A. Olofson and Duain E. Abbott wrote a paper, Tests of a Piperidino Mask for the Protection of Functionalized Carbon Sites in Multistep Synthesis, J. Org. Chem., 49, 2795-2799 (1984) which I believe needs more consideration. It teaches that a piperidine functionality attached to carbon at a primary or secondary carbon within a complex structure can be converted, in their respective cases, into a primary chloride or secondary chloride/ alkene in high yield and good selectivity.  To quote from the paper, “…. advantages can be envisioned in schemes using this mask for multistep protection. First, acid-base extraction methods are readily adapted for the isolation of process intermediates. Second, the formation of readily crystallized amine salts can further facilitate the purification of these intermediates.”

The reagent that affects this loss of a piperidine group from a complex molecule and its replacement by chlorine is α-chloroethyl chloroformate {Cl-CO-O—CHCl-CH₃; called ACE-Cl}. The conversion can be pictured as:

The reason the cleavage is so clean with the piperidine ring moiety unopened is that competition between S_N1 (E1) and S_N2 cleavages of the intermediate quaternary salt is occurring with relative rates such that ArCH2, allyl, t-alkyl >> sec-alkyl >methyl > primary 

alkyl >> piperidine ring opening. That is, the piperidino ring 

functionality is cleaved much more slowly than anything else!

Treatment with methanol hydrogen chloride removes the ACE protection liberating the piperidine.

The KiloMentor Approach compared with Yoshida’s Tag Strategy

The KiloMentor philosophy or strategy of process development ranks process schemes not only by the number of reaction steps and their anticipated approximate yields but additionally and with higher priority by the anticipated simplicity of the reaction work-ups and purifications expected as part of the process steps.  A proposed ranking system for isolations is provided in an earlier KiloMentor blog. 

A consequence of this selection principle is that process steps which involve phase switching in the isolation/purification, as taught be D. P. Curran, tend to be preferred over steps in which starting materials, by-products, and co-products are not so easily separated.  In its simplest embodiment, intermediates that are carboxylic acids or amines and that can be separated by acid-base extractions are preferred intermediates as contrasted to neutral substances. However, as readers will discover there are many more robust phase switching techniques.

Compare and Contrast: The Yoshida Teaching

The same philosophy is taught by Jun-ichi Yoshida Kenichiro Itami and coworkers in their article, Chem. Rev. 2002, 102, 3693-3716, Tag Strategy for Separation and Recovery.  The key difference is that these authors are thinking about tagging products, reagents or by-products to simplify the separation in a process that has already been chosen and is just being optimized.  In contrast, KiloMentor would be making the choice among different proposed paper syntheses based, to a fundamental extent, upon whether the intermediates in the process steps are easily separable because they are naturally ‘tagged’ by the functional groups they bear. These naturally tagged intermediates are those intermediates containing (most frequently deployed) acidic and basic functional groups which enable simple acid-base extraction separations.  Put another way, KiloMentor uses the concept of phase tags to select a preferred route, while Yoshida teaches the contribution tagging can make to improving the ease of separation in a previously selected route. Also, while Yoshida’s review encompasses phase tags that are contained within or can be attached to, anyone of reagents, co-products and by-products and not just the desired products,  KiloMentor only looks at whether the desired intermediates themselves contain or could contain some tag.

Yoshida sees tags as being similar modus operandi to protecting groups. Typically a protecting group is introduced into a molecule in one step, protects its corresponding functional group during some transformation(s) and then is removed in still another step.  The protecting group protects a function group from undesired reaction. A tag is introduced intentionally before a process step, simplifies the isolation of pure product from the step and is subsequently removed.  The tag is not an inherent part of the process but a functional add-on. Yoshida does not completely ignore the kind of tagging Kilomentor recommends but calls it the masking of tags. To quote:

“Another approach to this issue is masking of tags (Scheme 7). In some cases, tags are masked so that tagged molecules retain their natural phase affinity. Thus reactions can be conducted under homogeneous conditions in organic solvents. After the reaction, however, the tag is converted into its active form to effect separation of the tagged molecule from untagged molecules. A typical example of this case is acid/base extraction. For example, an ammonium ion tag is unmasked by protonation of the corresponding amine tag and the tagged compound is extracted from the organic phase into acidic aqueous phase. Remasking the tag by neutralization enables reextraction of the tagged compound into the organic phase (phase switching). In such a case, the tag is not a simple tag, but a phase–trafficking tag or “phase shuttle” because it facilitates the back and forth movement of molecules from one phase to another.”

This explanation feels contrived because it makes the simple, complex, but if we must make reference to it, using this nomenclature, what KiloMentor is recommending is that, in making the initial route choice, higher consideration should be given to processes containing intermediates that comprise a “phase-switch.”