Modern Pummerer-type reactions

Ken S. Feldman

Research output: Contribution to journalReview article

145 Citations (Scopus)

Abstract

Who discovered the Pummerer reaction? A simple, if not rhetorical, question that belies a straightforward answer. Ultimately, provenance for this well-known transformation depends on a second question: what chemical process actually constitutes a Pummerer reaction? Perhaps the original candidate for this role was reported by Fromm and Achert in 1903,1 who described the decomposition of dibenzylsulfoxide (1) upon attempted distillation to furnish the suite of products 2-5 (Scheme 1). This study did not include the deliberate treatment of the sulfoxide with an electrophile (i.e., H+, Ac2O), a precondition of the modern version of the Pummerer reaction, and so it is likely that adventitious and unacknowledged acid autocatalyzed the decomposition. No mechanistic discussion attended this observation, and the surprising formal oxidative transposition that was observed caused the authors to doubt the structure of their starting material: "Der merkwürdige Zerfall des Benzylsulfoxyds bei 210°, insbesondere die Bildung von Benzaldehyd bei dieser Zersetzung, liess Zweifel darüber autkommen, ob die dem Sulfoxyd zugeschriebene Constitutions-formel: (C6H5·CH2)2S:O, die richtige sei. Es musste in diesem Falleja eine Wanderung des Sauerstoffs vom Schwefel an den Kohlenstoff stattgefunden haben. Eine solche Wanderung konnte man ausschliessen, wenn man dem Benzylsulfoxyd die folgende Constitutions-formel, in welcher der Sauerstoff von vornherein an Kohlenstoff gebunden ist, zuschrieb: C6H5·CH2·S· O·CH2·C6H5."1 (The unusual decomposition of benzylsulfoxide at 210°, in particular the formation of benzaldehyde upon this decomposition, raises concerns about whether the constitutional formula assigned to the sulfoxide, (C6H5·CH2)2S:O, is correct. If it is so, then migration of the oxygen from sulfur to carbon must have taken place. Such a migration can be excluded if one assigns the following constitutional formula, in which the oxygen is bound at carbon from the outset, to the benzylsulfoxide: C6H5·CH2·S· O·CH2·C6H5.) Six years later in early 1909, Smythe picked up this train of research and described the products detected upon exposing 1 to the undeniable Pummerer activators HCl and Ac2O.2 Smythe observed formation of the characteristic Pummerer reaction product benzaldehyde (2) (and its derived thioacetal 7), and his mechanistic speculation started out in a productive vein by suggesting that the hydroxysulfide 9 preceded the aldehyde. However, Smythe was apparently at a loss to rationalize the intermediacy of this alcohol, and he resorted to invoking what he termed 'dynamic isomerism' between 1 and 9, by analogy with known keto-enol tautomerizations, to justify its presence. Later in that same year, in a paper that cites the work of Smythe, Rudolph Pummerer authored his now famous report on the consequences of treating the sulfinyl acetic acid 10 with HCl.3a Pummerer meticulously characterized the product distribution, which included the aldehyde 13 and thiophenol. Once again, a formal oxidation at carbon required explanation, and Pummerer rose to this challenge by invoking the intermediacy of the sulfurane 11 and then its formal 1,2-chloride shift product, the sulfide 12. The similarity of Pummerer's sulfurane to the currently adopted thionium ion intermediate, Ph(+)S=CH-, should not be overlooked (simple chloride ionization from 11), and this hypothesis provided for the first time a rational mechanistic framework for discussing sulfoxide decomposition chemistry. Pummerer evaluated and then rejected Smythe's dynamic isomerism explanation, noting that "Auf die ausführlichen Desmotropie-Betrachtungen des Verfassers kann ich nicht näher eingehen, sie stehen in beträchtlichem Gegensatz zur heutigen Kenntnis derartiger Probleme."3a (I don't want to elaborate further on the author's detailed discussion of 'desmotropy', as it stands in considerable contrast to modern understanding of such problems.) Thus, while Pummerer was perhaps not the first researcher to observe his eponymous reaction, he appears to be the first to understand what he was observing. It is unclear whether Pummerer appreciated the significance of his (or Smythe's) discovery. He published only one follow-up report on the topic in 1910,3b which did, however, describe the reaction of a sulfoxide 10a with acetic anhydride in the classical Pummerer sense, before embarking on a long and distinguished career in the general area of industrial organic chemistry. In fact, Pummerer's biographer, R.E. Oesper, wrote a 1951 encomium that noted Pummerer's many contributions to both industrial chemistry and organic mechanistic studies, but failed even to mention the sulfoxide chemistry that now bears his name!4 So, why is the Pummerer reaction called 'The Pummerer reaction'? Perhaps the genesis of this term can be traced to a 1960 supplement for a 1959 article by Horner and Kaiser from Universität Mainz,5a who christened the reaction thusly: "Die Analogie zur POLONOVSKI-Reaction liegt auf der Hand. Die Reaktion zwischen Sulfoxyden und Säureanhydriden wollen wir in Zukunft als 'Pummerer-Reaktion' bezeichnen."5b (The analogy to the POLONOVSKI reaction is obvious. In the future, we would like to designate the reaction between sulfoxides and acid anhydrides as the 'Pummerer reaction'.). Research into the electrophile-promoted decomposition of sulfoxides proceeded only fitfully for the 50 years following Pummerer's initial observation, Figure 1. Sporadic reports of Pummerer-like chemistry appeared, but no systematic efforts to explore the process were documented until the 1959 Horner and Kaiser work. Perhaps the Mainz groups' attention to this obscure reaction, coupled with their elevation of the chemistry to 'named reaction' status, piqued the interest of other researchers, as the 1960s saw the beginning of an upsurge of research work that continues unabated to the present day. Early studies largely focused on mechanistic issues and attempted to explore the scope of the process, leading to elucidation of a detailed reaction mechanism. Other milestones include the first use in a natural product synthesis (illudin M by Matsumoto et al.6), the first example of C-C bond formation,7 and the first claim for asymmetric synthesis from a chiral sulfoxide.8. The mechanistic course of the Pummerer rearrangement has been explored through judicious use of deuterium- and O18-labeling experiments, kinetic analysis, and product identification studies.9 The confluence of results from these studies provides a self-consistent mechanistic picture, Scheme 2. A chiral sulfoxide is invoked to illustrate some of the mechanistic subtleties uncovered by the labeling studies, as the observation of significant levels of asymmetric induction would otherwise be at odds with passage through the commonly cited achiral thionium ion intermediate 20. Treatment of sulfoxide 16 with Ac2O rapidly provides the chiral sulfonium salt 17, which can racemize under certain circumstances (e.g., high acetate concentration) via the intermediacy of a sulfurane PhS(OAc)2CH2R. To limit this undesirable outcome, the effective acetate trap DCC has been introduced into the Pummerer mixture, albeit at some sacrifice in yield.10 If acetate acts as a base with 17 instead, ylide 18a will be formed, itself a resonance form of the sulfurane 18b. This ylide preserves the chirality at sulfur under standard Pummerer conditions, and it is postulated to serve as a direct precursor to (chiral) α-acetoxysulfide 21 via either intramolecular S-to-C transposition of the acetate group,11 or by intermolecular addition of exogenous acetate.12 Ejection of acetate from 18 competes with product formation, and this process can lead first to a tight ion pair 19 and then to a solvent separated ion pair 20. Both 19 and 20 can serve as precursors to α-acetoxysulfide 21, although the stereochemical consequences for each path may differ. The broader utility of the Pummerer reaction in organic synthesis stems, at least in large part, from the capability of the electrophilic intermediate 20 to combine productively with carbon π-nucleophiles and fashion new C-C bonds. The question then can be raised, 'How good of an electrophile is thionium ion 20?' Many studies have shown that electron rich arenes and alkenes are effective partners for 20. Some qualitative measure of sulfur-stabilized carbocation 20's electrophilicity can be gleaned from the seminal contributions of Mayr, who measured/calculated the electrophilicity parameter E for the species 22-24.13 By this scale, the doubly sulfur-stabilized carbocation ion 23 reacts with Mayr's reference π-type carbon nucleophiles a few orders of magnitude slower than the phenyl/oxygen stabilized carbocation 22, but significantly faster than the iminium ion 24. The energetics that govern the various competitive pathways that extend from 18 seem to be finely balanced, as variations of substrate structure/functionality, solvent, additives, etc. appear sufficient to steer the reaction down one channel or another. Oxygen-18 labeling studies provide evidence for the predominant or exclusive operation of each of these pathways under differing circumstances.9b.

Original languageEnglish (US)
Pages (from-to)5003-5034
Number of pages32
JournalTetrahedron
Volume62
Issue number21
DOIs
StatePublished - May 22 2006

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Carbon
Sulfur
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Aldehydes
Chlorides
Chemical Phenomena
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Cite this

Feldman, Ken S. / Modern Pummerer-type reactions. In: Tetrahedron. 2006 ; Vol. 62, No. 21. pp. 5003-5034.
@article{985ac0f14d10430e959b6f13f0e50eae,
title = "Modern Pummerer-type reactions",
abstract = "Who discovered the Pummerer reaction? A simple, if not rhetorical, question that belies a straightforward answer. Ultimately, provenance for this well-known transformation depends on a second question: what chemical process actually constitutes a Pummerer reaction? Perhaps the original candidate for this role was reported by Fromm and Achert in 1903,1 who described the decomposition of dibenzylsulfoxide (1) upon attempted distillation to furnish the suite of products 2-5 (Scheme 1). This study did not include the deliberate treatment of the sulfoxide with an electrophile (i.e., H+, Ac2O), a precondition of the modern version of the Pummerer reaction, and so it is likely that adventitious and unacknowledged acid autocatalyzed the decomposition. No mechanistic discussion attended this observation, and the surprising formal oxidative transposition that was observed caused the authors to doubt the structure of their starting material: {"}Der merkw{\"u}rdige Zerfall des Benzylsulfoxyds bei 210°, insbesondere die Bildung von Benzaldehyd bei dieser Zersetzung, liess Zweifel dar{\"u}ber autkommen, ob die dem Sulfoxyd zugeschriebene Constitutions-formel: (C6H5·CH2)2S:O, die richtige sei. Es musste in diesem Falleja eine Wanderung des Sauerstoffs vom Schwefel an den Kohlenstoff stattgefunden haben. Eine solche Wanderung konnte man ausschliessen, wenn man dem Benzylsulfoxyd die folgende Constitutions-formel, in welcher der Sauerstoff von vornherein an Kohlenstoff gebunden ist, zuschrieb: C6H5·CH2·S· O·CH2·C6H5.{"}1 (The unusual decomposition of benzylsulfoxide at 210°, in particular the formation of benzaldehyde upon this decomposition, raises concerns about whether the constitutional formula assigned to the sulfoxide, (C6H5·CH2)2S:O, is correct. If it is so, then migration of the oxygen from sulfur to carbon must have taken place. Such a migration can be excluded if one assigns the following constitutional formula, in which the oxygen is bound at carbon from the outset, to the benzylsulfoxide: C6H5·CH2·S· O·CH2·C6H5.) Six years later in early 1909, Smythe picked up this train of research and described the products detected upon exposing 1 to the undeniable Pummerer activators HCl and Ac2O.2 Smythe observed formation of the characteristic Pummerer reaction product benzaldehyde (2) (and its derived thioacetal 7), and his mechanistic speculation started out in a productive vein by suggesting that the hydroxysulfide 9 preceded the aldehyde. However, Smythe was apparently at a loss to rationalize the intermediacy of this alcohol, and he resorted to invoking what he termed 'dynamic isomerism' between 1 and 9, by analogy with known keto-enol tautomerizations, to justify its presence. Later in that same year, in a paper that cites the work of Smythe, Rudolph Pummerer authored his now famous report on the consequences of treating the sulfinyl acetic acid 10 with HCl.3a Pummerer meticulously characterized the product distribution, which included the aldehyde 13 and thiophenol. Once again, a formal oxidation at carbon required explanation, and Pummerer rose to this challenge by invoking the intermediacy of the sulfurane 11 and then its formal 1,2-chloride shift product, the sulfide 12. The similarity of Pummerer's sulfurane to the currently adopted thionium ion intermediate, Ph(+)S=CH-, should not be overlooked (simple chloride ionization from 11), and this hypothesis provided for the first time a rational mechanistic framework for discussing sulfoxide decomposition chemistry. Pummerer evaluated and then rejected Smythe's dynamic isomerism explanation, noting that {"}Auf die ausf{\"u}hrlichen Desmotropie-Betrachtungen des Verfassers kann ich nicht n{\"a}her eingehen, sie stehen in betr{\"a}chtlichem Gegensatz zur heutigen Kenntnis derartiger Probleme.{"}3a (I don't want to elaborate further on the author's detailed discussion of 'desmotropy', as it stands in considerable contrast to modern understanding of such problems.) Thus, while Pummerer was perhaps not the first researcher to observe his eponymous reaction, he appears to be the first to understand what he was observing. It is unclear whether Pummerer appreciated the significance of his (or Smythe's) discovery. He published only one follow-up report on the topic in 1910,3b which did, however, describe the reaction of a sulfoxide 10a with acetic anhydride in the classical Pummerer sense, before embarking on a long and distinguished career in the general area of industrial organic chemistry. In fact, Pummerer's biographer, R.E. Oesper, wrote a 1951 encomium that noted Pummerer's many contributions to both industrial chemistry and organic mechanistic studies, but failed even to mention the sulfoxide chemistry that now bears his name!4 So, why is the Pummerer reaction called 'The Pummerer reaction'? Perhaps the genesis of this term can be traced to a 1960 supplement for a 1959 article by Horner and Kaiser from Universit{\"a}t Mainz,5a who christened the reaction thusly: {"}Die Analogie zur POLONOVSKI-Reaction liegt auf der Hand. Die Reaktion zwischen Sulfoxyden und S{\"a}ureanhydriden wollen wir in Zukunft als 'Pummerer-Reaktion' bezeichnen.{"}5b (The analogy to the POLONOVSKI reaction is obvious. In the future, we would like to designate the reaction between sulfoxides and acid anhydrides as the 'Pummerer reaction'.). Research into the electrophile-promoted decomposition of sulfoxides proceeded only fitfully for the 50 years following Pummerer's initial observation, Figure 1. Sporadic reports of Pummerer-like chemistry appeared, but no systematic efforts to explore the process were documented until the 1959 Horner and Kaiser work. Perhaps the Mainz groups' attention to this obscure reaction, coupled with their elevation of the chemistry to 'named reaction' status, piqued the interest of other researchers, as the 1960s saw the beginning of an upsurge of research work that continues unabated to the present day. Early studies largely focused on mechanistic issues and attempted to explore the scope of the process, leading to elucidation of a detailed reaction mechanism. Other milestones include the first use in a natural product synthesis (illudin M by Matsumoto et al.6), the first example of C-C bond formation,7 and the first claim for asymmetric synthesis from a chiral sulfoxide.8. The mechanistic course of the Pummerer rearrangement has been explored through judicious use of deuterium- and O18-labeling experiments, kinetic analysis, and product identification studies.9 The confluence of results from these studies provides a self-consistent mechanistic picture, Scheme 2. A chiral sulfoxide is invoked to illustrate some of the mechanistic subtleties uncovered by the labeling studies, as the observation of significant levels of asymmetric induction would otherwise be at odds with passage through the commonly cited achiral thionium ion intermediate 20. Treatment of sulfoxide 16 with Ac2O rapidly provides the chiral sulfonium salt 17, which can racemize under certain circumstances (e.g., high acetate concentration) via the intermediacy of a sulfurane PhS(OAc)2CH2R. To limit this undesirable outcome, the effective acetate trap DCC has been introduced into the Pummerer mixture, albeit at some sacrifice in yield.10 If acetate acts as a base with 17 instead, ylide 18a will be formed, itself a resonance form of the sulfurane 18b. This ylide preserves the chirality at sulfur under standard Pummerer conditions, and it is postulated to serve as a direct precursor to (chiral) α-acetoxysulfide 21 via either intramolecular S-to-C transposition of the acetate group,11 or by intermolecular addition of exogenous acetate.12 Ejection of acetate from 18 competes with product formation, and this process can lead first to a tight ion pair 19 and then to a solvent separated ion pair 20. Both 19 and 20 can serve as precursors to α-acetoxysulfide 21, although the stereochemical consequences for each path may differ. The broader utility of the Pummerer reaction in organic synthesis stems, at least in large part, from the capability of the electrophilic intermediate 20 to combine productively with carbon π-nucleophiles and fashion new C-C bonds. The question then can be raised, 'How good of an electrophile is thionium ion 20?' Many studies have shown that electron rich arenes and alkenes are effective partners for 20. Some qualitative measure of sulfur-stabilized carbocation 20's electrophilicity can be gleaned from the seminal contributions of Mayr, who measured/calculated the electrophilicity parameter E for the species 22-24.13 By this scale, the doubly sulfur-stabilized carbocation ion 23 reacts with Mayr's reference π-type carbon nucleophiles a few orders of magnitude slower than the phenyl/oxygen stabilized carbocation 22, but significantly faster than the iminium ion 24. The energetics that govern the various competitive pathways that extend from 18 seem to be finely balanced, as variations of substrate structure/functionality, solvent, additives, etc. appear sufficient to steer the reaction down one channel or another. Oxygen-18 labeling studies provide evidence for the predominant or exclusive operation of each of these pathways under differing circumstances.9b.",
author = "Feldman, {Ken S.}",
year = "2006",
month = "5",
day = "22",
doi = "10.1016/j.tet.2006.03.004",
language = "English (US)",
volume = "62",
pages = "5003--5034",
journal = "Tetrahedron",
issn = "0040-4020",
publisher = "Elsevier Limited",
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}

Feldman, KS 2006, 'Modern Pummerer-type reactions', Tetrahedron, vol. 62, no. 21, pp. 5003-5034. https://doi.org/10.1016/j.tet.2006.03.004

Modern Pummerer-type reactions. / Feldman, Ken S.

In: Tetrahedron, Vol. 62, No. 21, 22.05.2006, p. 5003-5034.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Modern Pummerer-type reactions

AU - Feldman, Ken S.

PY - 2006/5/22

Y1 - 2006/5/22

N2 - Who discovered the Pummerer reaction? A simple, if not rhetorical, question that belies a straightforward answer. Ultimately, provenance for this well-known transformation depends on a second question: what chemical process actually constitutes a Pummerer reaction? Perhaps the original candidate for this role was reported by Fromm and Achert in 1903,1 who described the decomposition of dibenzylsulfoxide (1) upon attempted distillation to furnish the suite of products 2-5 (Scheme 1). This study did not include the deliberate treatment of the sulfoxide with an electrophile (i.e., H+, Ac2O), a precondition of the modern version of the Pummerer reaction, and so it is likely that adventitious and unacknowledged acid autocatalyzed the decomposition. No mechanistic discussion attended this observation, and the surprising formal oxidative transposition that was observed caused the authors to doubt the structure of their starting material: "Der merkwürdige Zerfall des Benzylsulfoxyds bei 210°, insbesondere die Bildung von Benzaldehyd bei dieser Zersetzung, liess Zweifel darüber autkommen, ob die dem Sulfoxyd zugeschriebene Constitutions-formel: (C6H5·CH2)2S:O, die richtige sei. Es musste in diesem Falleja eine Wanderung des Sauerstoffs vom Schwefel an den Kohlenstoff stattgefunden haben. Eine solche Wanderung konnte man ausschliessen, wenn man dem Benzylsulfoxyd die folgende Constitutions-formel, in welcher der Sauerstoff von vornherein an Kohlenstoff gebunden ist, zuschrieb: C6H5·CH2·S· O·CH2·C6H5."1 (The unusual decomposition of benzylsulfoxide at 210°, in particular the formation of benzaldehyde upon this decomposition, raises concerns about whether the constitutional formula assigned to the sulfoxide, (C6H5·CH2)2S:O, is correct. If it is so, then migration of the oxygen from sulfur to carbon must have taken place. Such a migration can be excluded if one assigns the following constitutional formula, in which the oxygen is bound at carbon from the outset, to the benzylsulfoxide: C6H5·CH2·S· O·CH2·C6H5.) Six years later in early 1909, Smythe picked up this train of research and described the products detected upon exposing 1 to the undeniable Pummerer activators HCl and Ac2O.2 Smythe observed formation of the characteristic Pummerer reaction product benzaldehyde (2) (and its derived thioacetal 7), and his mechanistic speculation started out in a productive vein by suggesting that the hydroxysulfide 9 preceded the aldehyde. However, Smythe was apparently at a loss to rationalize the intermediacy of this alcohol, and he resorted to invoking what he termed 'dynamic isomerism' between 1 and 9, by analogy with known keto-enol tautomerizations, to justify its presence. Later in that same year, in a paper that cites the work of Smythe, Rudolph Pummerer authored his now famous report on the consequences of treating the sulfinyl acetic acid 10 with HCl.3a Pummerer meticulously characterized the product distribution, which included the aldehyde 13 and thiophenol. Once again, a formal oxidation at carbon required explanation, and Pummerer rose to this challenge by invoking the intermediacy of the sulfurane 11 and then its formal 1,2-chloride shift product, the sulfide 12. The similarity of Pummerer's sulfurane to the currently adopted thionium ion intermediate, Ph(+)S=CH-, should not be overlooked (simple chloride ionization from 11), and this hypothesis provided for the first time a rational mechanistic framework for discussing sulfoxide decomposition chemistry. Pummerer evaluated and then rejected Smythe's dynamic isomerism explanation, noting that "Auf die ausführlichen Desmotropie-Betrachtungen des Verfassers kann ich nicht näher eingehen, sie stehen in beträchtlichem Gegensatz zur heutigen Kenntnis derartiger Probleme."3a (I don't want to elaborate further on the author's detailed discussion of 'desmotropy', as it stands in considerable contrast to modern understanding of such problems.) Thus, while Pummerer was perhaps not the first researcher to observe his eponymous reaction, he appears to be the first to understand what he was observing. It is unclear whether Pummerer appreciated the significance of his (or Smythe's) discovery. He published only one follow-up report on the topic in 1910,3b which did, however, describe the reaction of a sulfoxide 10a with acetic anhydride in the classical Pummerer sense, before embarking on a long and distinguished career in the general area of industrial organic chemistry. In fact, Pummerer's biographer, R.E. Oesper, wrote a 1951 encomium that noted Pummerer's many contributions to both industrial chemistry and organic mechanistic studies, but failed even to mention the sulfoxide chemistry that now bears his name!4 So, why is the Pummerer reaction called 'The Pummerer reaction'? Perhaps the genesis of this term can be traced to a 1960 supplement for a 1959 article by Horner and Kaiser from Universität Mainz,5a who christened the reaction thusly: "Die Analogie zur POLONOVSKI-Reaction liegt auf der Hand. Die Reaktion zwischen Sulfoxyden und Säureanhydriden wollen wir in Zukunft als 'Pummerer-Reaktion' bezeichnen."5b (The analogy to the POLONOVSKI reaction is obvious. In the future, we would like to designate the reaction between sulfoxides and acid anhydrides as the 'Pummerer reaction'.). Research into the electrophile-promoted decomposition of sulfoxides proceeded only fitfully for the 50 years following Pummerer's initial observation, Figure 1. Sporadic reports of Pummerer-like chemistry appeared, but no systematic efforts to explore the process were documented until the 1959 Horner and Kaiser work. Perhaps the Mainz groups' attention to this obscure reaction, coupled with their elevation of the chemistry to 'named reaction' status, piqued the interest of other researchers, as the 1960s saw the beginning of an upsurge of research work that continues unabated to the present day. Early studies largely focused on mechanistic issues and attempted to explore the scope of the process, leading to elucidation of a detailed reaction mechanism. Other milestones include the first use in a natural product synthesis (illudin M by Matsumoto et al.6), the first example of C-C bond formation,7 and the first claim for asymmetric synthesis from a chiral sulfoxide.8. The mechanistic course of the Pummerer rearrangement has been explored through judicious use of deuterium- and O18-labeling experiments, kinetic analysis, and product identification studies.9 The confluence of results from these studies provides a self-consistent mechanistic picture, Scheme 2. A chiral sulfoxide is invoked to illustrate some of the mechanistic subtleties uncovered by the labeling studies, as the observation of significant levels of asymmetric induction would otherwise be at odds with passage through the commonly cited achiral thionium ion intermediate 20. Treatment of sulfoxide 16 with Ac2O rapidly provides the chiral sulfonium salt 17, which can racemize under certain circumstances (e.g., high acetate concentration) via the intermediacy of a sulfurane PhS(OAc)2CH2R. To limit this undesirable outcome, the effective acetate trap DCC has been introduced into the Pummerer mixture, albeit at some sacrifice in yield.10 If acetate acts as a base with 17 instead, ylide 18a will be formed, itself a resonance form of the sulfurane 18b. This ylide preserves the chirality at sulfur under standard Pummerer conditions, and it is postulated to serve as a direct precursor to (chiral) α-acetoxysulfide 21 via either intramolecular S-to-C transposition of the acetate group,11 or by intermolecular addition of exogenous acetate.12 Ejection of acetate from 18 competes with product formation, and this process can lead first to a tight ion pair 19 and then to a solvent separated ion pair 20. Both 19 and 20 can serve as precursors to α-acetoxysulfide 21, although the stereochemical consequences for each path may differ. The broader utility of the Pummerer reaction in organic synthesis stems, at least in large part, from the capability of the electrophilic intermediate 20 to combine productively with carbon π-nucleophiles and fashion new C-C bonds. The question then can be raised, 'How good of an electrophile is thionium ion 20?' Many studies have shown that electron rich arenes and alkenes are effective partners for 20. Some qualitative measure of sulfur-stabilized carbocation 20's electrophilicity can be gleaned from the seminal contributions of Mayr, who measured/calculated the electrophilicity parameter E for the species 22-24.13 By this scale, the doubly sulfur-stabilized carbocation ion 23 reacts with Mayr's reference π-type carbon nucleophiles a few orders of magnitude slower than the phenyl/oxygen stabilized carbocation 22, but significantly faster than the iminium ion 24. The energetics that govern the various competitive pathways that extend from 18 seem to be finely balanced, as variations of substrate structure/functionality, solvent, additives, etc. appear sufficient to steer the reaction down one channel or another. Oxygen-18 labeling studies provide evidence for the predominant or exclusive operation of each of these pathways under differing circumstances.9b.

AB - Who discovered the Pummerer reaction? A simple, if not rhetorical, question that belies a straightforward answer. Ultimately, provenance for this well-known transformation depends on a second question: what chemical process actually constitutes a Pummerer reaction? Perhaps the original candidate for this role was reported by Fromm and Achert in 1903,1 who described the decomposition of dibenzylsulfoxide (1) upon attempted distillation to furnish the suite of products 2-5 (Scheme 1). This study did not include the deliberate treatment of the sulfoxide with an electrophile (i.e., H+, Ac2O), a precondition of the modern version of the Pummerer reaction, and so it is likely that adventitious and unacknowledged acid autocatalyzed the decomposition. No mechanistic discussion attended this observation, and the surprising formal oxidative transposition that was observed caused the authors to doubt the structure of their starting material: "Der merkwürdige Zerfall des Benzylsulfoxyds bei 210°, insbesondere die Bildung von Benzaldehyd bei dieser Zersetzung, liess Zweifel darüber autkommen, ob die dem Sulfoxyd zugeschriebene Constitutions-formel: (C6H5·CH2)2S:O, die richtige sei. Es musste in diesem Falleja eine Wanderung des Sauerstoffs vom Schwefel an den Kohlenstoff stattgefunden haben. Eine solche Wanderung konnte man ausschliessen, wenn man dem Benzylsulfoxyd die folgende Constitutions-formel, in welcher der Sauerstoff von vornherein an Kohlenstoff gebunden ist, zuschrieb: C6H5·CH2·S· O·CH2·C6H5."1 (The unusual decomposition of benzylsulfoxide at 210°, in particular the formation of benzaldehyde upon this decomposition, raises concerns about whether the constitutional formula assigned to the sulfoxide, (C6H5·CH2)2S:O, is correct. If it is so, then migration of the oxygen from sulfur to carbon must have taken place. Such a migration can be excluded if one assigns the following constitutional formula, in which the oxygen is bound at carbon from the outset, to the benzylsulfoxide: C6H5·CH2·S· O·CH2·C6H5.) Six years later in early 1909, Smythe picked up this train of research and described the products detected upon exposing 1 to the undeniable Pummerer activators HCl and Ac2O.2 Smythe observed formation of the characteristic Pummerer reaction product benzaldehyde (2) (and its derived thioacetal 7), and his mechanistic speculation started out in a productive vein by suggesting that the hydroxysulfide 9 preceded the aldehyde. However, Smythe was apparently at a loss to rationalize the intermediacy of this alcohol, and he resorted to invoking what he termed 'dynamic isomerism' between 1 and 9, by analogy with known keto-enol tautomerizations, to justify its presence. Later in that same year, in a paper that cites the work of Smythe, Rudolph Pummerer authored his now famous report on the consequences of treating the sulfinyl acetic acid 10 with HCl.3a Pummerer meticulously characterized the product distribution, which included the aldehyde 13 and thiophenol. Once again, a formal oxidation at carbon required explanation, and Pummerer rose to this challenge by invoking the intermediacy of the sulfurane 11 and then its formal 1,2-chloride shift product, the sulfide 12. The similarity of Pummerer's sulfurane to the currently adopted thionium ion intermediate, Ph(+)S=CH-, should not be overlooked (simple chloride ionization from 11), and this hypothesis provided for the first time a rational mechanistic framework for discussing sulfoxide decomposition chemistry. Pummerer evaluated and then rejected Smythe's dynamic isomerism explanation, noting that "Auf die ausführlichen Desmotropie-Betrachtungen des Verfassers kann ich nicht näher eingehen, sie stehen in beträchtlichem Gegensatz zur heutigen Kenntnis derartiger Probleme."3a (I don't want to elaborate further on the author's detailed discussion of 'desmotropy', as it stands in considerable contrast to modern understanding of such problems.) Thus, while Pummerer was perhaps not the first researcher to observe his eponymous reaction, he appears to be the first to understand what he was observing. It is unclear whether Pummerer appreciated the significance of his (or Smythe's) discovery. He published only one follow-up report on the topic in 1910,3b which did, however, describe the reaction of a sulfoxide 10a with acetic anhydride in the classical Pummerer sense, before embarking on a long and distinguished career in the general area of industrial organic chemistry. In fact, Pummerer's biographer, R.E. Oesper, wrote a 1951 encomium that noted Pummerer's many contributions to both industrial chemistry and organic mechanistic studies, but failed even to mention the sulfoxide chemistry that now bears his name!4 So, why is the Pummerer reaction called 'The Pummerer reaction'? Perhaps the genesis of this term can be traced to a 1960 supplement for a 1959 article by Horner and Kaiser from Universität Mainz,5a who christened the reaction thusly: "Die Analogie zur POLONOVSKI-Reaction liegt auf der Hand. Die Reaktion zwischen Sulfoxyden und Säureanhydriden wollen wir in Zukunft als 'Pummerer-Reaktion' bezeichnen."5b (The analogy to the POLONOVSKI reaction is obvious. In the future, we would like to designate the reaction between sulfoxides and acid anhydrides as the 'Pummerer reaction'.). Research into the electrophile-promoted decomposition of sulfoxides proceeded only fitfully for the 50 years following Pummerer's initial observation, Figure 1. Sporadic reports of Pummerer-like chemistry appeared, but no systematic efforts to explore the process were documented until the 1959 Horner and Kaiser work. Perhaps the Mainz groups' attention to this obscure reaction, coupled with their elevation of the chemistry to 'named reaction' status, piqued the interest of other researchers, as the 1960s saw the beginning of an upsurge of research work that continues unabated to the present day. Early studies largely focused on mechanistic issues and attempted to explore the scope of the process, leading to elucidation of a detailed reaction mechanism. Other milestones include the first use in a natural product synthesis (illudin M by Matsumoto et al.6), the first example of C-C bond formation,7 and the first claim for asymmetric synthesis from a chiral sulfoxide.8. The mechanistic course of the Pummerer rearrangement has been explored through judicious use of deuterium- and O18-labeling experiments, kinetic analysis, and product identification studies.9 The confluence of results from these studies provides a self-consistent mechanistic picture, Scheme 2. A chiral sulfoxide is invoked to illustrate some of the mechanistic subtleties uncovered by the labeling studies, as the observation of significant levels of asymmetric induction would otherwise be at odds with passage through the commonly cited achiral thionium ion intermediate 20. Treatment of sulfoxide 16 with Ac2O rapidly provides the chiral sulfonium salt 17, which can racemize under certain circumstances (e.g., high acetate concentration) via the intermediacy of a sulfurane PhS(OAc)2CH2R. To limit this undesirable outcome, the effective acetate trap DCC has been introduced into the Pummerer mixture, albeit at some sacrifice in yield.10 If acetate acts as a base with 17 instead, ylide 18a will be formed, itself a resonance form of the sulfurane 18b. This ylide preserves the chirality at sulfur under standard Pummerer conditions, and it is postulated to serve as a direct precursor to (chiral) α-acetoxysulfide 21 via either intramolecular S-to-C transposition of the acetate group,11 or by intermolecular addition of exogenous acetate.12 Ejection of acetate from 18 competes with product formation, and this process can lead first to a tight ion pair 19 and then to a solvent separated ion pair 20. Both 19 and 20 can serve as precursors to α-acetoxysulfide 21, although the stereochemical consequences for each path may differ. The broader utility of the Pummerer reaction in organic synthesis stems, at least in large part, from the capability of the electrophilic intermediate 20 to combine productively with carbon π-nucleophiles and fashion new C-C bonds. The question then can be raised, 'How good of an electrophile is thionium ion 20?' Many studies have shown that electron rich arenes and alkenes are effective partners for 20. Some qualitative measure of sulfur-stabilized carbocation 20's electrophilicity can be gleaned from the seminal contributions of Mayr, who measured/calculated the electrophilicity parameter E for the species 22-24.13 By this scale, the doubly sulfur-stabilized carbocation ion 23 reacts with Mayr's reference π-type carbon nucleophiles a few orders of magnitude slower than the phenyl/oxygen stabilized carbocation 22, but significantly faster than the iminium ion 24. The energetics that govern the various competitive pathways that extend from 18 seem to be finely balanced, as variations of substrate structure/functionality, solvent, additives, etc. appear sufficient to steer the reaction down one channel or another. Oxygen-18 labeling studies provide evidence for the predominant or exclusive operation of each of these pathways under differing circumstances.9b.

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U2 - 10.1016/j.tet.2006.03.004

DO - 10.1016/j.tet.2006.03.004

M3 - Review article

VL - 62

SP - 5003

EP - 5034

JO - Tetrahedron

JF - Tetrahedron

SN - 0040-4020

IS - 21

ER -