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How Do Enolate Equivalents Differ in Nucleophilic Reactivity?

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How Do Enolate Equivalents Differ in Nucleophilic Reactivity? SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2019, 51, 1157–1170 feature 1157 en Syn thesis A. I. Leonov et al. Feature Metal Enolates – Enamines – Enol Ethers: How Do Enolate Equivalents Differ in Nucleophilic Reactivity? Artem I. Leonov1 Daria S. Timofeeva OSiMe3 N O K Armin R. Ofial* 0000-0002-9600-2793 Ph Ph Herbert Mayr* 0000-0003-0768-5199 Ph Ph Ph Ph Department Chemie, Ludwig-Maximilians-Universität München, increasing nucleophilicity Butenandtstraße 5–13, 81377 München, Germany 7 14 krel 1 1.3 × 10 3.5 × 10 [email protected] τ 6 [email protected] 1/2 10 × 10 years 1 year 1 s A contribution of Physical Organic Chemistry to systematizing Organic Synthesis. Cordial congratulations on the occasion of the Golden Anni- versary of Synthesis. Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue Received: 23.11.2018 they will generally undergo unselective diffusion-con- Accepted after revision: 27.11.2018 trolled reactions with alkali enolates. How can this dilem- Published online: 08.01.2019 DOI: 10.1055/s-0037-1611634; Art ID: ss-2018-z0787-fa ma be overcome? License terms: In previous years, we have established a series of col- ored reference electrophiles covering a reactivity range of Abstract The kinetics of the reactions of trimethylsilyl enol ethers and 32 orders of magnitude, which are suitable for studying the enamines (derived from deoxybenzoin, indane-1-one, and α-tetralone) reactivities of nucleophiles of widely differing reactivity.12–15 with reference electrophiles (p-quinone methides, benzhydrylium and By using equation 1, in which electrophiles are character- indolylbenzylium ions) were measured by conventional and stopped- ized by one parameter E, and nucleophiles are characterized flow photometry in acetonitrile at 20 °C. The resulting second-order rate constants were subjected to a least-squares minimization based on by the solvent-dependent nucleophilicity parameter N and the correlation equation lg k = sN(N + E) for determining the reactivity susceptibility sN, we have so far parameterized more than 16 descriptors N and sN of the silyl enol ethers and enamines. The relative 300 electrophiles and 1100 nucleophiles. reactivities of structurally analogous silyl enol ethers, enamines, and enolate anions towards carbon-centered electrophiles are determined lg k = s (E + N) (1) as 1, 107, and 1014, respectively. A survey of synthetic applications of 20 °C N enolate ions and their synthetic equivalents shows that their behavior Equation 1 can be properly described by their nucleophilicity parameters, which therefore can be used for designing novel synthetic transformations. We now report on the reactivities of the enolate equiva- Key words alkylation, enols, kinetics, linear free energy relationship, reactivity scales lents depicted in Figure 1, which allow us to quantitatively compare the previously reported nucleophilicities of potas- sium enolates with those of structurally analogous enam- Enolate equivalents are among the most important re- ines and enol ethers. We will furthermore demonstrate that agents in organic and biochemistry.2–11 In organic synthesis, the combination of nucleophilicity parameters for enolates, they are commonly employed as metal enolates or as their enamines, and silyl enol ethers with the reactivity parame- synthetic equivalents, enamines or enol ethers, depending ters E of electrophiles provides an ordering principle for on the electrophilicity of the corresponding reaction part- enolate chemistry. ners. The qualitative ranking of reactivity — metal enolate > enamine > enol ether — is well known. A quantitative com- parison has been hampered by the fact, however, that elec- OSiMe3 OSiMe3 N R trophiles, which are suitable for kinetic studies with eno- Ph late ions, have such low electrophilicities that they do not H n n react with enamines and enol ethers. On the other hand, electrophiles, suitable for studying the kinetics of their re- 1a (R = Ph) 1c (n = 1) 2a (n = 1) 1b (R = Me) 1d (n = 2) 2b (n = 2) actions with enamines or enol ethers, are so reactive that Figure 1 Structures of silyl enol ethers 1a–d and enamines 2a,b inves- tigated as enolate equivalents in this work Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1157–1170 1158 Syn thesis A. I. Leonov et al. Feature Table 1 lists the indolylbenzylium ions 3a–c, benzhy- sequent desilylation then afforded ketones 5a–c (Scheme drylium ions 3d–l, and quinone methides 3m–o, which 1), which were purified by column chromatography and were employed as reference electrophiles for the kinetic characterized by NMR spectroscopy and mass spectrome- measurements. try. Electrophilic attack of the prochiral carbocation 3a led to a mixture of two diastereomers of 5c in a ratio of ca. 1:1.33 (determined by NMR spectroscopy). Product Studies Electrophilic attack of the benzhydrylium tetrafluoro- borate 3g on the enamine 2b led to formation of the imini- The reactions of the silyl enol ethers 1a, 1c, and 1d with um salt 6. Its hydrolysis gave the ketone 5d, which was pu- benzhydrylium or indolylbenzylium tetrafluoroborates ini- rified by column chromatography and isolated in moderate tially yielded siloxy-substituted carbenium ions 4. Fast sub- yield (Scheme 2). Biographical Sketches Artem I. Leonov obtained a doctoral degree in the group of opment of the Munich reactivi- diploma in chemical engineer- Dr. Ofial on physical organic ty scale. In 2018, he joined the ing at the Mendeleev University chemistry. His research focused group of Prof. Lee Cronin in of Chemical Technology of Rus- on kinetic and mechanistic Glasgow (UK) to work on an au- sia (Moscow) before moving to studies of carbon nucleophiles tomatic synthetic platform and Ludwig-Maximilians-Universität such as Grignard reagents, the implementation of kinetic München (LMU) (Germany) in carbanions, enol ethers and analysis for reaction optimiza- 2013, where he received his enamines for the further devel- tion. Daria S. Timofeeva received mone total synthesis conducted where her work has focused on her diploma in chemical engi- at the All-Russian Plant Quaran- the study of the reactivity of neering at the Mendeleev Uni- tine Center. In 2014, she started enamines and electrophilic fluo- versity of Chemical Technology her doctoral studies in the rinating reagents. of Russia (Moscow), with her fi- group of Prof. Herbert Mayr at nal research project on phero- the LMU München (Germany), Armin R. Ofial studied chem- 1997, he moved as a research ests include reactions of imini- istry at the Technical University associate to the Ludwig-Maxi- um ions, kinetics, and selective of Darmstadt (Germany), where milians-Universität München C–H bond functionalizations. he graduated with Prof. Alarich (Germany). In 2009, he estab- He received the Thieme Chem- Weiss in 1991 (diploma) and re- lished his research group at the istry Journals Award in 2012. ceived his doctoral degree with LMU München and habilitated Prof. Herbert Mayr in 1996. In in 2013. Armin’s research inter- Herbert Mayr obtained his LMU München in 1996. He re- of Sciences. His research inter- Ph.D. in 1974 (Prof. R. Huisgen, ceived the Alexander von Hum- ests comprise quantitative ap- LMU München). After postdoc- boldt Honorary Fellowship of proaches to organic reactivity toral studies (Prof. G. A. Olah, the Foundation for Polish Sci- including mechanisms of or- Cleveland, USA), he completed ence (2004) and the Liebig ganocatalytic reactions and the his habilitation in 1980 (Prof. P. Denkmünze (GDCh, 2006). He theory of polar organic reac- von R. Schleyer, Erlangen). After is a member of the Bavarian tions. professorships in Lübeck and Academy of Sciences and the Darmstadt, he returned to the Leopoldina - National Academy Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1157–1170 1159 Syn thesis A. I. Leonov et al. Feature Table 1 Indolylbenzylium Ions 3a–c, Benzhydrylium Ions 3d–l and NMe2 BF NMe2 Quinone Methides 3m–o Employed as Reference Electrophiles in this 4 Study H+/H O N δ 2 3g-BF4 C 184.8 N O – pyrrolidine Electrophile Ea MeCN, r.t. NMe2 R = H 3a –1.80 2b NMe2 R R = Me 3b –2.19 65d, 37% N R = OMe 3c –3.02 Scheme 2 Reaction of the enamine 2b with reference electrophile 3g- Me BF4 (NMR chemical shift δ in ppm, CD3CN, 100 MHz) R = OMe 3d 0.00 R = N(Me)CH2CF3 3e –3.85 R = N(CH2CH2)2O 3f –5.53 The reaction of the enamine 2a with the quinone R = N(Me) 3g –7.02 R R 2 R = N(CH2)4 3h –7.69 methide 3m furnished the zwitterion 7, which tautomeri- zed, and within 30 minutes, quantitatively yielded the n n n = 2 3i –8.22 product 8 as determined by NMR spectroscopy (Scheme 3). N N n = 1 3j –8.76 Me Me N N Ph n = 2 3k –9.45 Ph N N N n = 1 3l –10.04 3m ~H+ Ph n n Ph CD3CN, r.t. Ph Ph OH R = H 3m –11.87 Ph O R = OMe 3n –12.18 2a 78 R O R = N(Me)2 3o –13.39 Ph Scheme 3 Reaction between enamine 2a and quinone methide 3m a Electrophilicity parameters E were taken from refs 12, 13, 17, and 18. Me3SiO O Ph Ph OSiMe3 Ph Ph 3d-BF4 BF4 Ph Ph CH2Cl2, r.t. – FSiMe3 – BF3 MeO OMe MeO OMe 1a 4a 5a, 95% Me Me N N CF3 CF3 O OSiMe3 Me3SiO 3e-BF4 BF4 MeCN, r.t. – FSiMe3 – BF3 CF3 CF3 1c4b N 5b, 80% N Me Me BF4 OSiMe 3 Me3SiO Ph O Ph 3a-BF4 – FSiMe MeCN, r.t. N 3 N – BF3 Me Me 1d 4c 5c, 71% (dr 57/43) Scheme 1 Reactions of silyl enol ethers 1a, 1c, and 1d with reference electrophiles. Yields refer to isolated products Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1157–1170 1160 Syn thesis A.
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