Tetrahedron report number 964Dual super-electrophilic and Diels–Alder reactivity of neutral 10π heteroaromatic substrates
Graphical abstract
Introduction
Nucleophilic aromatic substitutions (SNAr reactions) together with the formation of the related anionic σ-bonded adducts—the so-called Meisenheimer complexes (MCs)—represent reactions of overwhelming importance in organic synthesis.1, 2, 3, 4, 5, 6 Eq. 1 describes a model representative process where Nu−: is an anionic nucleophile reacting with a benzenoid aromatic activated by electron-withdrawing group(s) (EWG), e.g., NO2, and bearing a potential leaving group, LG. Following the pioneering work of Bunnett1 and Miller,2 research has developed continuously,3, 4, 5, 6 aimed at understanding the factors governing the formation of the intermediate MC7, 8 and extending the field of applicability of Eq. 1 in organic synthesis. In fact, varying the protocols in combining a judicious choice of the solvent, including room temperature ionic liquids9, 10(a) and the use of cavitands,10b with the use of methodologies, such as microwave,11, 12, 13, 14, 15 ultrasonic,12, 16, 17 high-pressure techniques,18, 19 as well as organometallic activation,20, 21, 22 has extended the range of feasible SNAr C–O, C–N, C–S, C–P and/or C–C couplings.3, 23 In this regard, an important landmark has been the discovery by Makosza24, 25 that the overall substitution process of Eq. 1 can also be achieved with substrates bearing H as the leaving group, even though H− departure is virtually precluded by the very poor nucleofugality of the hydride anion. The so-called vicarious nucleophilic substitution (VNS)24, 25, 26 and oxidative nucleophilic aromatic substitution26, 27 are now recognized as valuable tools for synthetic chemists.
In the last two decades, new developments in SNAr substitution have derived from the finding that neutral electron-deficient 10π heteroaromatics exhibit such high electrophilic reactivity (super-electrophilicity) that they define a new category of SNAr substrates that display a wide range of versatile behaviour.28 Compared to 1,3,5-trinitrobenzene (TNB, 1), 4,6-dinitrobenzofuroxan (DNBF, 2) serves as the benchmark super-electrophile and Eq. 2 complements Eq. 1 in describing the reactivity of such 10π heteroaromatics in σ-complexation and SNAr substitution.
Thus, two different classes of electrophile have been defined in Meisenheimer complexation: (a) normal, generally 6π electron-deficient benzenoid aromatics and (b) super-electrophilic (mostly) 10π heteroaromatics.3, 7, 8 Scheme 1 illustrates MC formation: both for 6π electron-deficient aromatics and for 10π heteroaromatics. The regioselectivity shown on the left-hand side of Scheme 1 (dashed box, MC-1 vs MC-3 or MC-5) has been reviewed by us previously8 and will not be considered further, although it is still an area of investigation both for 6π29 and 10π systems.30 For the general scheme involving reaction with an anionic nucleophile (Nu:−), the substrate ring substituents, X, Y and Z, are typical electron-withdrawing groups, such as nitro or cyano, while LG represents a potential leaving group. Thus, X=Y=Z=NO2, LG=H, represents the classic normal Meisenheimer electrophile, 1,3,5-trinitrobenzene (TNB, 1), while replacement of the poor leaving group by a much better one (LG=Cl) would give picryl chloride (Pi-Cl). On the super-electrophile side of the spectrum, X=Y=NO2, n=1, Q=O, LG=H, represents the benchmark super-electrophile, 4,6-dinitrobenzofuroxan (DNBF, 2), while 7-chloro-4-nitrobenzofurazan (NDB chloride) could be constructed from the general super-electrophile structure when X=NO2, n=0, Y=H, LG=Cl. The latter two electrophiles, Pi-Cl and NDB chloride, undergo SNAr displacement, an area of active interest in its own right.30, 31, 32
A major recent finding for the heteroaromatic super-electrophiles is that these also display a wide range of versatile cycloaddition behaviour,33, 34, 35, 36, 37 that offers new structure–reactivity relationships and new avenues for synthetic exploitation (Eq. 3). For example, DNBF, 2, reacts quantitatively with 1-trimethylsilyloxybuta-1,3-diene (4π partner) to yield the Diels–Alder cycloadduct, 3 (as a racemic mixture; the diastereomer shown is the thermodynamically stable product). The residual nitroolefinic moiety of 3 is inert to further reaction with this silylated diene, but undergoes cycloaddition with vinyl ethyl ether (2π contributor),33b permitting synthesis of ‘unsymmetrical’ diadducts. In contrast, benzenoid compounds (e.g., 1) have not shown this rich range of reactivity.
In this review, we probe the origin of super-electrophilicity found in the electron-deficient 10π substrates studied thus far, and we shall consider cycloaddition reactivity and show that super-electrophilicity in Meisenheimer complexation shares a common origin with this substrate, Diels–Alder reactivity providing predictive power for cycloaddition behaviour in other heteroaromatics. A key question arising from our consideration of the Diels–Alder reactivity of the electron-deficient 10π heteroaromatics that we have studied is whether these reactions proceed by pericyclic or stepwise routes. Further, under what conditions will a stepwise path be preferred over the single-step concerted path? Global and local electrophilicity parameters, derived from density functional theory (DFT), form a theoretical framework for elucidating these results. Insights into the concerted versus stepwise modes of cycloaddition are illuminated by the DFT calculational studies but also by stereochemical and spectroscopic analysis.
Section snippets
Water as nucleophile in Meisenheimer complex (MC) formation: hydration behaviour
Species considered super-electrophilic in Meisenheimer complexation, typified by DNBF, 2, add water as a nucleophile (to ultimately form MC-7 with LG=H, Nu=OH: Scheme 1) as a major pathway, whereas normal electrophiles, such as TNB, do not; the corresponding complex (MC-1, with LG=H, Nu=OH) requires the more potent OH− nucleophile.3, 7(b), 32(b) Further, the OH− MC-7 (Nu=HO) of DNBF is 1010–fold more stable than the corresponding MC-1 of TNB.3, 7(b) Determination of the equilibrium constant for
Enhanced MC stabilization inherent in the structure and/or decreased aromaticity
Two main factors (or their combination) have been proposed to account for the super-electrophilicity outlined: (1) improved stabilization of the MC ascribed to the heteroannelated five-membered ring that assists the other electron-withdrawing groups present, e.g., nitro or trifluoromethanesulfonyl groups, and (2) decreased aromaticity of the neutral heteroaromatic 10π systems relative to the electron-deficient normal 6π aromatics.28
If the degree of substrate aromaticity is the key determinant
Diels–Alder reactions with DNBF, 2
Cycloadditions, including those that formally fall under the rubric of Diels–Alder (4+2) or Huisgen (3+2) dipolar reactions, have provided organic chemists with multiple avenues for the synthesis of natural products, pharmaceuticals and their precursors, notably heterocyclic compounds. Such cycloaddition reactions may be incorporated in sequences of tandem reactions46 and the appeal of such ‘one-pot’ syntheses is illustrated by a recent report of ‘SNAr-click’ synthesis.47
Although DNBF had been
Mayr E scale
Since its introduction, the electrophilicity (E) parameter and the nucleophilicity (N) parameter, defined by Mayr and co-workers59 from the three-parameter Eq. 7, have proven useful in delving into numerous nucleophile–electrophile combination reactions.59, 60 Kinetic measurements on MC formation between a set of 10 neutral electrophiles, mostbeing analogues of DNBF and a series of reference carbon nucleophiles (N-methylpyrrole, indole, N-methylindole and a range of enamines),
Conclusions
1. In the arsenal of the synthetic organic chemist, Diels–Alder and related cycloadditions, as well as nucleophilic aromatic substitutions, define a chief set of tools for rational construction of molecules. In this article, we have shown the striking versatility of DNBF and related 10π heteroaromatics in cycloaddition (see Fig. 1). Moreover, products of these cycloadditions or of Meisenheimer complexations retain untapped reactivity that may also be exploited synthetically.
2. Notably, we have
Acknowledgements
We acknowledge funding by CNRS and the Ministry of Research (France) (F.T.), NSERC (E.B.) and Grenfell Campus, Vice-President’s Research Fund (J.M.D.). Helpful discussions with Profs. Régis Goumont (Versailles), J.-M. Nunzi (Queen’s) and D.-R. Parkinson (Grenfell Campus, MUN) are gratefully acknowledged. We particularly wish to thank all of our students and collaborators without whose efforts this work could not have been completed.
Erwin Buncel received his Ph.D. from University of London (Prof. Alwyn Davies) in the School of Sir Christopher Ingold. After postdoctoral fellowship at the University of North Carolina (Bunnett), McMaster University (Bourns), and as a research chemist (American Cyanamid), he was appointed at Queen’s University, reaching a full professor (1970). Investigations in physical organic, bioorganic and bioinorganic chemistry, and now environmental and materials chemistry, with 70 graduate students and
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Erwin Buncel received his Ph.D. from University of London (Prof. Alwyn Davies) in the School of Sir Christopher Ingold. After postdoctoral fellowship at the University of North Carolina (Bunnett), McMaster University (Bourns), and as a research chemist (American Cyanamid), he was appointed at Queen’s University, reaching a full professor (1970). Investigations in physical organic, bioorganic and bioinorganic chemistry, and now environmental and materials chemistry, with 70 graduate students and PDFs, have led to 350 research papers and book chapters, reviews and books. He was awarded the Syntax and R.U. Lemieux Awards. He has been editor of the Canadian Journal of Chemistry (CJC) and the Journal of Labelled Compounds and Radiopharmaceuticals; he was honoured by CJC with a Special Issue (Festschrift).
Julian M. Dust, was educated at University of Waterloo (B.Sc. Hons), Dalhousie University, (Halifax; M.Sc.) and Queen’s University at Kingston (Ph.D., 1987) under the guidance of Prof. E. Buncel. He then undertook a PDF at University of Alabama in Huntsville (J. Milton Harris). He is Associate Professor of Chemistry and Environmental Science at Grenfell Campus, Memorial University of Newfoundland in Corner Brook, NL, Canada. Other research interests include the preparation and reactions of electrophilic derivatives of water-soluble polymers, environmental physical organic chemistry and the abiotic breakdown of pesticides, as well as aspects of materials chemistry. With Prof. Buncel he coauthored ‘Carbanion chemistry: structures and mechanisms’, ACS Books-Oxford University Press, Washington (2003).
François Terrier received his Ph.D. from the University of Paris (UPMC). After a PDF with Claude Bernasconi (UC-Santa Cruz), he became Professor at the University of Rouen (1976). In 1991 he joined the University of Versailles as Head of the Chemistry Department and Head of the SIRCOB Laboratory (UMR CNRS 8086). His research interests deal with various fields of organic reactivity. These include σ-complexation and related nucleophilic aromatic substitutions, proton transfer at carbon, and exalted reactivity of α-nucleophiles. He has published over 220 research papers as well as review articles and book chapters. He is the author of ‘Nucleophilic aromatic displacements: the role of the nitro group’, VCH, New York (1991).