Burgess and Martin Dehydrating Reagents

An understanding of synthetically useful dehydrating reagents for the reduction of hydroxyl groups, various functional group interconversions and other synthetically useful operations.

• Oday Alrifai

Dehydration of alcohols has been a synthetically useful strategy in order to attain olefins in high yields through the treatment of secondary, tertiary and homoallylic alcohols. Martin sulfurane and Burgess dehydrating reagents have been useful because of their mild and selective properties on alcohol containing species. ^[1] Both reagents have made a significant contribution in industrial and academic applications, aiding in the synthesis of natural products and drugs. The Burgess Reagent, known as Methyl-N-(triethylammoniumsulphonyl)carbamate (Figure 1), is an interesting reagent assisting formations of 5-membered heterocycles, initially derived from the acyclic precursor by dehydrative treatment. ^[1] It was first discovered by Edward Meredith Burgess in 1968, but was not given much attention until Peter Wipf proposed the idea of heterocyclic formation. Further research on this reagent, such as the preparation of isocyanides and nitrile oxides from formamides and nitroalkanes, respectively, have been investigated. ^[1]

Figure 1. Structure of Methyl-N-(triethylammoniumsulphonyl)carbamate, also known as Burgess’s dehydrating reagent. ^[1]

Similar to the Burgess reagent, Martin reagent (or Martin sulfurane) is another dehydrating reagent possessing high reactivity to allow the production of alkenes, with diphenyl sulfoxide and a alcohol as minor products, occurring fast (approximately one hour) and at below room temperatures. ^[2] It was James C. Martin who discovered this stable, moisture sensitive sulfurane, also known as bis(α,α-bis[trifluoromethyl]benzyloxy)diphenyl sulfur (Figure 2), in 1971. ^[2][3] Similar to the Burgess reagent, the mechanistic action may be similar, via E1 and/or E2 (or cis) elimination, in order for the treatment of secondary and primary alcohols, respectively. ^[3] Also similar, cyclic heteroatoms have been more favorable in synthesis, due to carbenium ion rearrangement, via alcoholic dehydration. ^[3]

Figure 2. Structure of bis(α,α-bis[trifluoromethyl]benzyloxy)diphenyl sulfur, also known as Martin’s sulfurane or Martin’s dehydrating reagent. ^[10]

Preparation of the Burgess reagent requires the incorporation of two commercially available chemicals, chlorosulfonyl isocyanate (CSI) and trieethylamine (TEA), and ceases in two steps. Figure 3 illustrates the treatment of CSI with anhydrous methanol and dry benzene at temperatures ranging from 25-30°C, for approximately half-hour. This fairly quick reaction gives good yields (88-92%) of methyl (chlorosulfonyl) carbamate (MCC) which exists as white crystals when filtered and washed with hexanes. The generated MCC is then treated with a solution of TEA in anhydrous benzene, at temperatures ranging from 10-15°C, over the course of one hour. The generated salt, Methyl-N-(triethylammoniumsulphonyl)carbamate, precipitates into colorless needles (84-86% yield). ^[1]

Figure 3. Preparation of the inner salt (Burgess reagent) from two commercially available compounds, trieethylamine and chlorosulfonyl isocyanate.

A special type of elimination reaction is believed to occur during the period the Burgess reagent is operational. The simultaneous elimination of two vicinal substituents, forming an alkene framework from an alkane, is the route of an intramolecular (E_i) mechanism or a syn elimination. The mechanistic action taken by the Burgess reagent, illustrated in Figure 4, will first produce a sulfamate ester by the attack of the sulfonyl group as well as the rapid displacement of the TEA group, by oxygen’s lone pair in methanol (pka=15.5). ^[1][4] By heating the sulfamate ester, pyrolysis is initiated, the α-carbon is ionized and bears an ion that rapidly transfers the β-hydrogen from the cationic to the anionic state. ^[1]

Figure 4. Mechanism illustrating treatment of Burgess reagent with ethanol, allowing the extraction of the β-hydrogen and formation of the olefin.

In general, the extraction of the proton and the expulsion of the leaving group will generate the expected olefin, shown in Figure 5. The production of the olefin depends on the geometry of the molecule, therefore the hydrogen must be present in the syn conformation to the leaving group (TEA) in order for the reaction to proceed. In addition, the leaving group has nucleophilic properties that will allow the proton to be extracted readily in low polarity solvents. It also should bear multiple proton acceptor sites to permit favorable proton capture. ^[1] It is possible however that the cis elimination not be observed due to carbonium ion stability, which is stabilized by substituents, and/or a more stable configuration by means of rearrangement. ^[1]

Figure 5. Example of a syn elimination, where the proton adjacent to the carbon bearing the reagent is removed and the deuterium remains a substituent with the olefin formation.

Pertaining to Figure 5, the type of alcohol group (secondary, tertiary and homoallylic), the configuration and the environment are the main factors that affect the process of the reaction. The dehydration of a secondary or tertiary alcohol, in an aprotic solvent, follows Saytzef’s rule to form a more thermodynamically stable alkene, versus the kinetic product. Oppositely, primary alcohols (Figure 5i) will not yield the expected olefins; rather carbamates via an S_N2 pathway as they are energetically more favorable. Steric hindrance is another important factor when treating with the Burgess Reagent.^[1] Such an example holds true in primary sulfamate esters where intramolecular rearrangement occurs when temperatures increase due to the restrictions on bimolecular displacement (Figure 5ii). Depending on the conditions of the reaction, such as solvent polarity and temperature, allylic alcohols can either undergo elimination or S_N1 rearrangement (Figure 5iii), with more favorable approaches of S_N1 reactions providing greater than 90% yields. The same is applicable for tertiary alcohols where they can be subjected to rearrangement even though, under normal conditions, undergo dehydration. ^[1]

Figure 6. Examples illustrating i) primary alcohols will not undergo olefin formation, rather producing a carbamate via S_N2, ii) sterically hindered compounds can proceed with the formation of a thermodynamic product (Saytzef’s rule) and iii) allylic alcohol dehydration via elimination or S_N1. ^[1]

Functional group interconversions (FGI) can aid in many useful syntheses to design versatile compounds. With the assistance of Burgess’s reagent, high yields have been obtained through the transformation of formamides to isocyanides, nitrile oxides from nitroalkanes and nitriles from primary amides, for example. To stimulate the formation of nitriles from primary amides, the Burgess reagent is often employed instead of other reagents. ^[1] The problem arises when particular reagents come in contact with certain functional groups, requiring protecting groups or alternative multi-step syntheses to carry out the production. Burgess reagent is employed due to its chemoselective properties and its ability to form the intermediate in a fast(er) manner. As a result of this quick reaction, the product is kinetically more favored. ^[1] Figure 7 illustrates the interconversion of an amide to allow the Burgess reagent to proceed with dehydrative activities, thus yielding isocyanide with rearrangement.

Figure 7. To allow dehydration of the alcohol, an amide undergoes interconversion to allow the Burgess reagent to proceed, forming isocyanide.

Knowing the environment the alcohol group is in and how its configuration can be altered, the synthesis of natural products in industry, by usage of this reagent, has been of great synthetic value. For example, dihydrooxazoles are important heterocyclic-containing intermediates used in the synthesis of many biologically active natural products. Initially, these compounds have required an extensive multi-step synthesis for their preparation and previous attempts to cyclize have provided low product yields (25%) and an abundance of recovered starting material. ^[5] Wipf and Miller investigated more efficient protocols that would obtain better yields of the β-sulfonate derivatives (Figure 8) of threonine and serine via a more selective intramolecular substitution. Treating the hydroxyl amino acid precursors, threonine and serine, with the reagent allowed the production of dihydrooxazoles because of their high reactivity to stimulate intramolecular cyclization. ^[5] Unlike other reagents removing hydroxyl substituents, Burgess reagent allows stereospecific production of dihydrooxazoles without the formation of minor products like azirdine or β-lactam. ^[5]

Figure 8. Formation of the olefin, via dehydration, and proceeding with intramolecular cyclization to form the 5-membered ring.

A paper by Rigby et al. investigated phenanthridone alkaloids originating from the narciclasine family and their anti-tumor properties. The synthesis of (+)-lycoricidine involved the use of the Burgess reagent in order to selectively deprotect the hydroxyl group and to promote cis elimination. ^[1][6] When dehydrated into an olefin, the compound can exhibit antimitotic activity, which in turn can elicit cytotoxic activities involved in the inhibition of plant growth and regulation, for example. ^[7] Chida et al. reported that synthetic (+)-lycoricidine exhibited strong cytotoxic activity against P-388 lymphocytic leukemia, suggesting stereochemistry was a responsible and an important component for the elevated cytotoxicity. ^[7]

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Other synthetically useful examples of products that are of value are medicinal drugs such as Efrotomycin, which is a new class of antibiotics eliciting anti-bacterial properties that act on gram-positive bacteria, ^[8] and Pravastatin, which is involved in the management of atherosclerosis and is a regulator of blood lipid levels. ^[9] Burgess reagent is either involved in the final step in order to form the olefin or participates in a one or two-step synthesis for the production of the precursor.

Other uses of the Burgess reagent have been investigated by Canadian researchers at Brock University by designing thermally stable versions of the Burgess reagent with an objective to improve reactivity on epoxides, diols and vinyl oxiranes in comparison to the original reagent. ^[17] They tested the reactivity of the Burgess reagent with oxiranes, both in cyclic and acyclic conformations, providing low yields of sulfamidates. Also, epoxidation reactions, which required two equivalents of the Burgess reagent, provided cis-sulfamidates at low yields. ^[17] Since yields were not above their expected 40%, new derivatives created by Metcalf et al. allowed for anion or cation stability in the zwitterion. They tested thermal stability by monitoring the decomposition, in THF-d₈ at 50°C, of four new versions of the Burgess reagent showing stability and reactivity of the original reagent can be improved by inductive components of the zwitterion. ^[17] The inductive effects depress the nucleophilicity of the carbamate anion, reducing formation of the sulfamidates and favouring diamine formation. This allows for the Burgess reagent to be synthetically useful in work other than dehydrative operations. ^[17] Figure 9 illustrates the conversion of a styrene diol to the diamine compound by treating with the modified Burgess reagent 1.

Figure 9. Treatment of the modified Burgess reagent 1 with styrene diol, yielding a diamine compound to demonstrate other uses for this reagent.

Martin sulfurane not only participates in dehydrative reactions but also in several other synthetically useful reactions, such as the production of sulfinimines, epoxidation reactions, cleavage of amides and oxidation. ^[12] Preparation of the diphenylsulfur compound incorporates commercially available 2-phenyl-2-propanol, using potassium hydroxide as the deprotonating agent, bromine and diphenylsulfide. ^[12]

Stereospecificity of a molecule, as a reactant or product, is important in order to carry out biological functions. Under certain conditions, such as varying solvent polarities and reaction temperatures, Martin sulfurane induces stereospecific dehydration that allows for the formation of certain isomers. (E)-isomerism in certain products exists because of trans-E₂ eliminations, whereas the (Z)-isomer is more favored due to the attachment of the sulfurane in the antiperiplanar conformation for the E₂ elimination. ^[2] The mechanistic action first involves the exchange of the alkoxy ligand on either side the sulfurane, producing an alkoxysulfonium ion as a result of ionization and then proceeding through E₁ or E₂ elimination. ^[12] Illustrated in Figure 10, using tertiary-butyl alcohol as an example, Arhart and Martin suggest that all alcohols used in their experimental appeared to exchange rapidly with the alkoxy ligands of the Martin reagent. The cause of this is not definite but it was proposed that a dissociative mechanism was carried out. ^[10][11]

Figure 10. The proposed mechanism illustrating the production of the expected olefin by means of dehydration when Martin sulfurane is used.

Similar to the Burgess reagent, dehydration of secondary and tertiary alcohols yield the expected olefin but treatment of primary alcohols, such as ethanol and neopentyl alcohols with Martin reagent, favors the formation of unsymmetrical ethers due to the absence of structural features that aid in the elevation of β-proton acidity. ^[10][11] Wensley et al. reported that treatment of a secondary alcohol with Martin sulfurane can lead to the production of a ketone by oxidation, in addition to the predicted olefin containing compound during the synthesis of their natural product containing a spiroketal enol ether. They proposed that the intermediate, containing the alkoxysulfonium ion, had proceeded forward via two possible routes, one of which was the deprotontation of the β-proton allowing the olefin (or enol ether) formation and/or the other resulting in oxidation through intermolecular deprotonation by the excess ^–OR_f (R_f = C₆H₅C(CF₃)₂ . ^[13]

A paper written by Moslin and Jamison investigated the synthesis of (+)-acutiphycin, a natural metabolite found in blue-green algae, exhibiting effective antineoplastic activity against Lewis lung carcinoma and a potent cytotoxic agent against KB and N1H/3T3 cell lines. ^[14] The synthesis of (+)-acutiphycin underwent intermolecular condensation, through application of the Reformatsky reaction, affording a β-hydroxy ketone followed by dehydration with the Martin sulfurane. ^[14] Prior to treatment with Martin sulfurane, samarium (II) iodide (SmI₂ or Kagan’s reagent) was used to carry out the intramolecular Reformatsky reaction. ^[14] SmI₂ has its limitations when intermolecular rearrangements occur because of side reaction formation and and oxidative dimerization of the enolate by the samarium therefore when coupled with Martin sulfurane, a 2-step sequence was carried forward to overcome sterically hindered structures (Figure 11). ^[12][14]

Figure 11.

Neurodegenerative disorders such as Parkinson’s disease and Alzheimers are caused by the degradation of the nerve growth factor (NGF) in the neurotrophin family of proteins. Therapeutic potential of NGFs have been extensively studied for the prevention, slow progression and even the reversal of these disorders. ^[15][16] Trzoss et al. have investigated other therapeutic strategies by synthetically mimicking neurotrophins in order to allow their biosynthesis. ^[16] The enantioselective synthesis of (-)-jiadifenin was carried forward with the assistance of Martin sulfurane. Trzoss et al. were unsuccessful when trying to eliminate the secondary alcohol via Barton-McCombie deoxygenation as well as mesylation and treatment with a variety of bases in order to obtain the desired alkene. When treated with Martin sulfurane, the olefin was obtained and was selectively hydrogenated, obtaining a 72% yield in two steps. ^[16]

Geng and Danishefsky recently synthesized the macrolide aigiolamycin D, via Diels-Alder, using disiloxydiene and a 14-membered dienophile also known as the ynolide (or dienophile).^[18] Having two or more of the same functional groups within a system can be difficult when trying to selectively treat one of the targets. Protecting groups are important in unsymmetrical synthesis, in comparison with symmetrical molecules which are chemically equivalent and protecting either side (with functional groups) is simple. Greg and Danishefsky proceeded to protect the diol group to allow the loner –OH unit to participate in the upcoming sequences. The loner –OH was protected via a silyl ether to allow the deprotection of the pivaloyl ester and formation of the –OH group. This –OH group can then be treated with Martin sulfurane, in methylene chloride solution, to form the resulting olefin and then deprotection (or conversion) of the dioxylane to the diol. ^[18]

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