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 colored 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 comparison 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

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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

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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

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Kinetic Investigations Table 2 Second-Order Rate Constants k2 for the Reactions of the Silyl Enol Ethers 1 and Enamines 2 with Reference Electrophiles 3 in MeCN at The reactions of the silyl enol ethers 1a–d and enamines 20 °C 2a,b with the reference electrophiles 3a–n were investigat- a b –1 –1 ed in either acetonitrile or dichloromethane at 20 °C and Nucleophile N (sN) Electrophile λ (nm) k2 (M s ) monitored by UV-Vis spectroscopy at or close to the absorp- 1a 3.00 (0.83) 3a 425 1.00 × 101 tion maxima of the electrophiles (Table 2). To simplify the 3b 431 4.77 –1 evaluation of the kinetic experiments, the nucleophiles 3c 474 9.63 × 10 1 were used in large excess (usually 8 equiv or more) to keep 1a (in CH2Cl2) 3.13 (0.82) 3a 425 1.24 × 10 3c 492 1.23 their concentrations almost constant throughout the reac- 1b 5.18 (0.94) 3a 413 1.32 × 103 tions. The first-order rate constants kobs were derived by 3b 434 7.26 × 102 2 least-squares fitting of the exponential function At = 3c 471 1.00 × 10 A0·exp(–kobst) + C to the time-dependent absorbances At of 1c 7.32 (0.82) 3a 413 2.59 × 104 3b 434 1.39 × 104 the electrophile. The second-order rate constants k2, listed 3c 471 4.94 × 103 in Table 2, were obtained as the slopes of the linear correla- 3e 586 8.94 × 102 1 tions between kobs and the concentrations of the nucleo- 3f 612 3.39 × 10 philes as exemplified in Figure 2 for the reaction of the silyl 3g 605 1.36 enol ether 1a with the indolylbenzylium ion 3a. 1d 5.06 (0.91) 3a 413 8.41 × 102 3b 434 3.53 × 102 3c 471 9.29 × 101 3f 612 3.48 × 10–1 2a 15.27 (0.93) 3k 635 2.53 × 105 3l 632 7.73 × 104 3m 384 1.57 × 103 3n 414 7.00 × 102 2b 14.09 (0.66) 3g 605 4.34 × 104 3h 612 1.75 × 104

3i 620 8.87 × 103 3j 616 3.03 × 103 3k 635 1.14 × 103

a From the second-order rate constants k2 in this Table by using equation 1 and the electrophilicity parameters E listed in Table 1. b Monitored wavelength. Figure 2 (a) Exponential decay of the absorbance A (at 425 nm) during the reaction of 3a (9.27 × 10–5 M) with 1a (8.82 × 10–4 M) in acetonitrile

at 20 °C. (b) Correlation of the first-order rate constants kobs with the 3m concentrations of the nucleophile 1a 6 3n 3l 3k 3g 3f 3e 3c 3b 3a 1c 5 3h 1b 4 3j Correlation Analysis 3i 1d

2 3 k

lg 2 2a 2b The rate constants (lg k2) for the reactions of the silyl 1a enol ethers 1 and enamines 2 with indolylbenzylium ions 1 3a–c, benzhydrylium ions 3e–l, and quinone methides 3m– 0 n correlate linearly with the electrophilicity parameters E –1 of 3a–n (Figure 3). Therefore, equation 1 is applicable, and –14 –12 –10 –8 –6 –4 –2 0 Electrophilicity E the N and sN parameters for the nucleophiles 1 and 2 (Table 2) were derived from the intercepts and slopes of these cor- Figure 3 Correlations of the second-order rate constants (lg k2) for the reactions of the enolate equivalents 1 and 2 with the electrophiles 3 in relations. acetonitrile at 20 °C with the electrophilicity parameters E of 3

Structure–Reactivity Relationships slightly on the nature of the attacking electrophiles. There- fore, the reactivities towards any of the carbenium ions 3a– The narrow range of the nucleophile-specific suscepti- l reflect general structure–reactivity trends. bilities (0.82 < sN < 0.94) for the silyl enol ethers 1 indicates Table 2 shows that the reactions of 1a with 3a and 3c that the relative reactivities of these π-systems depend only proceed only 1.3 times faster in dichloromethane than in acetonitrile. Because of this small difference, solvent effects will be neglected in the following discussions.

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Figure 4 compares the reactivities of the silyl enol ethers steric effects, coplanarity of the pyrrolidino ring with the 1a and 1b towards indolylbenzylium ion 3b with the previ- C=C double bond of the enamine is more disturbed in 2b ously reported reactivity of the acetophenone-derived silyl than in 2a.20 enol ether 9a towards the same electrophile.12 Introduction of a methyl group at the site of electrophilic attack (9a → 1b) decreases the reactivity by a factor of 10, whereas intro- N N N N duction of a phenyl group at this position (9a → 1a) reduces nucleophilic reactivity by three orders of magnitude.

10a2a 10b 2b OSiMe3 OSiMe3 OSiMe3 –1 –1 5,a 5,b 4,a 3,b H Me Ph k2(3k) (M s ) 3.3 × 10 2.5 × 10 4.6 × 10 1.1 × 10 Ph Ph Ph (7.6 × 104)c 9a 1b 1a krel 1 1/1.3 1/7.2 1/300 (1/4.3) –1 –1 3,a 2,b b k2(3b) (M s ) 7.4 × 10 7.3 × 10 4.8 Figure 6 Effect of benzoannulation on the nucleophilic reactivities of krel 1 1/10 1/1520 enamines at 20 °C. a Second-order rate constant (in dichloromethane) Figure 4 Structural effects on the nucleophilic reactivities of silylated from ref 19. b Second-order rate constant (in MeCN) from Table 2. c Sec- a enol ethers at 20 °C. Calculated by applying N and sN from ref 12 in ond-order rate constant (in MeCN) from ref 21 b equation 1 (for 9a in CH2Cl2: N = 6.22, sN = 0.96). Second-order rate constant in MeCN from Table 2 With the newly determined nucleophilicity parameters, Benzoannulation of the cyclic enol ether 9b increases its it is now possible to compare directly the nucleophilic reac- reactivity towards 3g by a factor of 3.9 (9b → 1c) (Figure 5), tivity of the enolate ion 1122 with the reactivities of its whereas benzoannulation of 1-(trimethylsiloxy)cyclohex- structurally related equivalents 1a and 10c23 (Figure 7). ene (9c) does not have a significant effect on the reactivity When the N and sN parameters of 1a and 10c are used to (9c → 1d). As a consequence, the previously reported reac- calculate the rate constants of their reactions with quinone tivity preference of the cyclopentenyl over the cyclohexenyl methide 3o (E = –13.39), the most reactive electrophile silyl enol ether by a factor of 20 increases to almost two or- used for the characterization of the enolate ion 11, one ders of magnitude for the benzoannulated analogs (1c vs finds that the enamine 10c is 107 times less reactive than 1d). As mentioned above, the small reactivity difference of 11 and that the enol ether 1a is another 107 times less reac- 1a in acetonitrile and dichloromethane (Table 2) allows us tive than the enamine 10c. In a dilute solution, in which the to neglect the fact that the data for 9b and 9c in Figure 5 reaction of the enolate ion 11 would proceed within one refer to dichloromethane whereas those for 1c and 1d refer second, the corresponding reaction of the enamine 10c to acetonitrile solutions. would require one year, and the silyl enol ether 1a would reach the same degree of conversion after ten million years. OSiMe3 OSiMe3 OSiMe3 OSiMe3

OSiMe3 N O K Ph 9b1c 9c 1d Ph Ph Ph Ph Ph –1 –1 a b –2,a –2,c k2(3g) (M s ) 0.36 1.4 1.9 × 10 1.6 × 10 1a 10c 11 krel 1 3.91/19 1/22 N (sN) 3.00 (0.83) 11.66 (0.82)a 23.15 (0.60)b Figure 5 Effect of benzoannulation on the nucleophilic reactivities of k (3o) (M–1 s–1) 2.4 × 10–9 3.8 × 10–2 7.2 × 105 1-(trimethylsiloxy)cycloalkenes at 20 °C. a Second-order rate constant 2 7 14 (in dichloromethane) from ref 12. b Second-order rate constant in krel 1 1.6 × 10 3.0 × 10 τ 6 MeCN from Table 2. c Calculated for the reaction 1d + 3g (in MeCN) 1/2 10 × 10 years 1 year 1 s from data in Tables 1 and 2 by using equation 1 Figure 7 Comparison of the nucleophilic reactivities (at 20 °C) of the deprotonated deoxybenzoin 11 with its synthetic equivalents 1a and Figure 6 compares the nucleophilic reactivities of enam- 10c. a In MeCN, from ref 23. b In DMSO, from ref 22 ines, which are structural analogs of the silylated enol ethers in Figure 5. As in the enol ether series, the cyclopen- Applications tene derivative 10a is one order of magnitude more reactive than the cyclohexene derivative 10b.19 While benzoannulation of the cyclopentenylamine 10a (→ 2a) has a negligible The nucleophilicity parameters determined in this in- effect on nucleophilic reactivity, benzoannulation of the vestigation can now be combined with previously reported corresponding cyclohexene derivative 10b (→ 2b) reduces reactivity indices16 to rationalize the use of enolate ions and the nucleophilicity by a factor of 69 (in acetonitrile). Due to their synthetic equivalents in organic synthesis. Figure 8 depicts enolates, enamines, and silyl enol ethers with in-

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Syn thesis A. I. Leonov et al. Feature creasing nucleophilicity from bottom to top and electro- Pyridinium-substituted enolate ions (that is, acyl-sub- philes with increasing reactivities from top to bottom. Nuc- stituted pyridinium ylides) readily react with Michael ac- leophiles and electrophiles at the same level (E + N ≈ –3) re- ceptors of E > –25 to give zwitterions, which usually cyclize act with a rate constant of ca. 0.004 M–1 s–1 at 20 °C (from with formation of 1,2,3,8a-tetrahydroindolizines (Scheme 36,37 38,39 equation 1 for a typical value of sN = 0.8), which corre- 5a) or cyclopropanes. sponds to a half reaction time of about 20 minutes for 0.2 M a) solutions. If enolate ions and enamines are intermediates of O O catalytic processes, their lower concentration has to be tak- 1. DMSO, 20 °C, 1 h N + en into account when estimating the reaction times. 2. chloranil (2 equiv) N 18 DMSO, 20 °C, 1 h COPh (E = –16.8) COPh Reactions of Enolate Ions 17 74% (N = 19.5) O via Reactions of enolate ions with C-centered electrophiles N represent important methods for generating new carbon– COPh carbon bonds.2–11,24–29 The non-stabilized enolate ions at the top of Figure 8 react with all electrophiles shown on the b) right. Due to their high reactivity, lithium enolates are use- NMe2 NMe2 ful reagents for cross-aldol reactions with ketones and alde- 30 CN hydes (as shown for 12 in Scheme 4a). In reactions with N N CN + Michael acceptors (e.g., with 13), they may be used as pre- Ph CN DMSO-d6 Ph formed anions or may be generated in situ by treatment of 20 °C, 5 min CN O O the corresponding CH acids with catalytic amounts of Brøn- sted bases (Scheme 4b).31,32 Acceptor-substituted enolate (N = 21.6) OMe ions, such as cyano-, acetyl-, alkoxycarbonyl- and phenyl- OMe sulfonyl-substituted enolate ions, react at or slightly above (E = –10.8) quant. (NMR) room temperature with a large variety of Michael acceptors Scheme 5 Reactions of pyridinium ylides with Michael acceptors: (a) with E > –23 (as exemplified for the combination 14 + 15 in from ref 37, (b) from ref 40 Scheme 4c),33–35 but we are not aware of reactions of such stabilized enolate ions with weak electrophiles, such as the cinnamic ester 16 (E = –24.5). Monitoring the reaction of equimolar amounts of a 4- (dimethylamino)-substituted pyridinium ylide with p-me- a) OLi O OH O OH thoxybenzylidene malononitrile by NMR spectroscopy PhCHO (12) H H showed the quantitative formation of a betaine, which did (E = –12.9) Ph Ph + not cyclize under the reaction conditions due to the stabi- THF, –78 °C lizing effect of the two cyano groups at the carbanionic cen- (N > 23) (85:15) 40 98% ter (Scheme 5b). b) O Reactions of Enamines Ph O NaOH (10%) Ph Ph Ph O + O Ph Ph DMSO, r.t., 30 min Ph Ph Pyrrolidine-derived enamines, such as 1-(cyclopent-1- 11-H 13 (for 11: N = 23.2) (E = –19.4) 73% en-1-yl)pyrrolidine (10a) or 10b, have been reported to react with a large variety of Michael acceptors with E > –20 (Scheme 6a).41–43 Whereas the reaction with the weakly c) CO2Et electrophilic acrylonitrile (19) required 12 hours refluxing K CO 2 3 41 + CO2Et in dioxane, the reactions with more electrophilic ni- O O 37 °C, 12 h troalkenes42 and the strong electrophile 20 proceed rapidly 4 equiv neat 14-H 15 O O at room temperature.43 The nucleophilic attack of enamines (for 14: N = 17.6) (E = –19.1) 96% at the carbonyl group of aromatic and aliphatic aldehydes Scheme 4 Enolate ions: (a) in a cross-aldol reaction with benzaldehyde yields α,β-unsaturated ketones through condensation and (12) (from ref 30), (b) generated from 11-H in a reaction with the Mi- subsequent aqueous workup (Scheme 6b).44 chael acceptor 13 (from ref 31), and (c) generated from 14-H in a reaction with ethyl acrylate (15) (from refs 34 and 35)

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N O 24.99 Ph Me O Ph 23.15 Ph 23 –26 11

22 –25 –24.69 Ts –24.52 CO2Et Ph Ph 16 21 –24 O –23.59 CO Et O 20.24 2 Ph

Enolates (in DMSO) N –23.01 20 –23 O 19.46 CO2Et –22.77 –22.30 N O OEt O 18.82 Ph 19 –22 17 O O O CO2Et Ph –21.00 18 –21 O O 17.64 –20.55 CO2Et 14 CN O 17.19 O Ph CO Et 13 SO2Ph 17 –20 2 O 16.55 Ph Ph Ph –19.49 CO2Et –19.39 O –19.07 Ph O 16.03 CO Et 16 –19 2 –18.60 15.91 N –19.05 15 Cl 15.27 CN N MeO N 10a 14.91 15 –18 19 –17.79 CO2Et N (in CH Cl ) EtO C 2 2 2a 2 14.09 O 14 –17 N –16.76 –16.63 SO2F 18 N Ph

10b –16.19 O O (in CH2Cl2) 13 –16 –15.71 CN NC Ph O –15.25 Boc 2b N N 12 –15 Enamines 11.66 Ph H Ph Ph –14.22 NO Ph 11 2 Pd(PPh3)2 Ph N –14 –13.85 NO2 –14.14 10c Ph OSiMe3 10.56 24 Ph Ph –13.19 10d O 10 –13 –12.90 Ph O O N NO Ph 12 2 2 SO F N O 2 Ph Ph Me Cl –12.09 Ts Cl N 9 –12 N N 26 10e –11.52 –11.50 OSiMe3 N O –11.24 Ph H Ph Cl –11.31 O 8 –11 Me O OSiMe3 7.32 9b 7.20 O 1c N Ph –10.15 (in CH Cl ) BF4 2 2 7 –10 –9.80 6.57 –9.89 EtO C N OSiMe3 –9.42 2 –9.27 N N CO2Et OSiMe3 Ph N 29 Ph 6.22 6 –9 F CN 9a Ph 21b Ph (in CH Cl ) 5.41 1b –8.44 2 2 PhO2S SO2Ph 5.18 N CN OSiMe3 OSiMe3 5.21 5 –8 22 5.06 –7.76 F SO2Ph Silyl Enol Ethers Fe(CO)3 O –7.50 (in CH Cl ) 2 2 27 Cl 20 Cl SO Ph 4 –7 –6.75 Cl 2 OSiMe3 1d –6.69 N –6.48 O2 OSiMe3 S 9c 21a Cl Cl 3.00 –6.43 (in CH Cl ) Ph 3 –6 N SCF3 2 2 Ph Cl 25 1a S 23 O E Ph S 28

Figure 8 Ranking of C-nucleophiles on the nucleophilicity scale and the scope of their reactions with electrophiles. Enolate ions and their synthetic equivalents (on the left-hand side) can be expected to react with all electrophiles (on the right-hand side) located at the same level of the respective nucleophile or below (nucleophilicity parameters N in acetonitrile if not mentioned otherwise, N and E were taken from ref 16)

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O a) a) SO2Ph reflux, dioxane CN F N 22 N 12 h + CN SO2Ph aq workup (E = –8.4) Ph Ph Ph 19 80% (E = –19.1) Ph MeCN, 20 °C Ph Ph N O + O 10b then FF (N = 14.9) aq workup F 77/23 O 10c 55% SO Ph (N = 11.7) 2 MeCN, r.t. SO2Ph isolated yield 10b + aq workup (N = 14.9) SO2Ph SO2Ph

20 O Ph 63% b) 2 (E = –7.5) S MeCN, r.t., 5 min Ph O N SCF3 + 10c then (N = 11.7) SCF3 b) O aq workup O O O 23 91% N – H2O (E = –6.5) + H in benzene Scheme 8 Reactions of enamine 10c with electrophilic: (a) fluorinating reflux 84% (from ref 47), and (b) trifluoromethylthiolating reagents (from ref 48)

(N = 13.4 (E = –12.9) in CH2Cl2) Scheme 6 Reactions of enamines with (a) Michael acceptors (for 19 from ref 41; for 20 from ref 43), and (b) aldehydes (from ref 44a) corresponding proline-derived enamine intermediate (Scheme 9a).57,58 Subsequently proline-catalyzed three- component Mannich reactions with N-arylimines59 and Mi- Enamines (for example, 2b or 10b) react with pre- chael additions to nitroolefins, such as 24 (Scheme 9b),60 formed iminium salts such as 21a and 21b in high yields were developed (at r.t., several hours of reaction time). under mild conditions to give the Mannich bases of α-tetralone or cyclohexanone, respectively (Scheme 7).45,46 a) CO2H Ph O N 12 H L-proline O OH 30 mol% + N AlCl4 O THF, –70 °C O DMSO, r.t. Ph 1 h + N NMe2 then 62% aq workup as co-solvent (20 vol%) (60% ee)

2b 21a 76% (N = 14.1) (E = –6.7) b) 24 (E = –13.9) Ph Ph NO NO2 L-proline 2 Ph O Ph 15 mol% O N CH2Cl2, –80 °C + DMSO, r.t. + 3 h N NMe2 O Cl then aq workup CO2R via 94% (dr > 20:1, 23% ee) N 10b 21b 94% (N = 14.9) (E = –9.3) (R = H) Scheme 7 Formation of Mannich bases through reactions of enamines for R = Me: N = 14.96 with preformed iminium salts (from ref 45) sN = 0.68 (in MeCN) + Fast F transfer reactions to colored enamines, such as Scheme 9 Proline-catalyzed: (a) aldol reactions (from ref 57), and (b) 10c, were used to quantify the reactivity of electrophilic Michael additions (from ref 60) fluorinating N–F reagents with –10.5 < E < –5 [such as NSFI (22) in Scheme 8a].47 The same types of enamines were In particular, diarylprolinol silyl ethers introduced by + + used to characterize F3CS and F2CHS transfer agents, such Hayashi and Jørgensen have proven to be versatile catalysts as the saccharin derivative 23 (Scheme 8b).48 for the stereoselective introduction of substituents at the α- Enamine activation has emerged as a widely applicable position of aldehydes.54,61,62 As indicated by the position of organocatalytic method for the α-functionalization of car- the 2-phenylacetaldehyde-derived enamine 10d (N = 10.56, 49–56 63 bonyl compounds. List et al. discovered that enantiose- sN = 1.01 in MeCN) in Figure 8, structurally analogous lective aldol reactions between acetone and various alde- enamines are such strong nucleophiles that they react with hydes proceed through conversion of the ketone into the β-nitrostyrene (24) at 0 °C with excellent control of the ste-

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1157–1170 1165

Syn thesis A. I. Leonov et al. Feature reoselectivity (Scheme 10a).64,65 The diphenylprolinol silyl O O ether-catalyzed reaction of 3-phenylpropanal with the less N N electrophilic methyl vinyl ketone (18) delivered only a reactions via Bn Bn moderate yield of the 1,5-dicarbonyl product with high en- N or N antioselectivity, even when a higher catalyst loading was used (Scheme 10b).64,66 R R for R = Ph: N = 5.80 N = 7.20 sN = 0.87 sN = 1.14 Ph (in MeCN) (in MeCN) Ph N reactions via OSiMe3 a) O X N

R R = Me, CH2Ph Bn N H for R = Ph: N = 10.56, sN = 1.01 2 CHO 20 mol% R' CHO + R'-OH * a) Ph R – H2O 24 (E = –13.9) Ph R Ph N NO H R = Me, iPr 2 OSiMe3 high ee 5 mol% Ph + NO2 b) O O in hexane O 23 °C N

85% Bn N (syn/anti 96:4, 99% ee) CHO O H Cl CHO Cl ·CF3CO2H Cl Cl 5 mol% b) Ph + acetone, –30 °C, 8 h 18 (E = –16.8) Ph Cl Cl N O H OSiMe O Cl 3 87% (94% ee) 30 mol% 25 O + (E = –6.8)

neat O Ph Ph Scheme 11 Organocatalytic α-functionalizations of aldehydes via enamine intermediates according to (a) Cozzi (refs 67–70), and (b) 52% (97% ee) MacMillan (ref 72) Scheme 10 Michael additions via Hayashi–Jørgensen-catalyst-derived enamines (from ref 64) a) OEt OSiMe3 Cozzi and coworkers rationally designed enantioselec- N = 4.23 N = 3.94 tive α-alkylation reactions of aldehydes, in which in situ generated carbocations R'+ with electrophilicities E between –1.5 and –7 were intercepted by enamines (e.g., by b) OMe OMe 10e in Figure 8) derived from aldehydes and MacMillan’s OMe C H 67–70 + imidazolidinone catalysts. The position of enamine NC CN 25 °C NC CN 63 NC C CN 10e in Figure 8 is also in line with the observation that NC NC CN CN NFSI (22)71 and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien- NC CN 1-one (25) are suitable reagents for imidazolidinone-cata- Scheme 12 (a) Comparison of the nucleophilicities of alkyl and silyl lyzed α-halogenations of aldehydes (Scheme 11).72,73 enol ethers, and (b) formation of cyclobutanes in the reaction of methyl vinyl ether with tetracyanoethene (from ref 76) Reactions of Enol Ethers Lewis acid catalyzed additions of alkyl halides, acetals, Alkyl enol ethers have similar nucleophilic reactivities and orthoesters to alkyl enol ethers only give 1:1 products as structurally analogous silyl enol ethers (Scheme 12a),74 when the reactants ionize more readily than the prod- 77–79 but are considerably less nucleophilic than enamines (see ucts. Though ZnCl2-catalyzed additions of α,β-unsatu- Figure 8). The use of alkyl enol ethers as enolate anion rated acetals to ethyl vinyl ether are key steps in Isler’s tech- equivalents is rather limited, however, because of their ten- nical β-carotin synthesis,80 the choice of reactants, which dency to undergo polymerization. In an extensive review, ionize faster than the resulting α-haloethers or acetals, is Hall demonstrated that highly electrophilic ethylene deriv- limited,81 as shown by the examples depicted in Scheme 13. atives can initiate the ionic polymerization of alkyl enol Silyl enol ethers, which are readily accessible from car- ethers.75 Polymerization is avoided when 1,4-zwitterions bonyl compounds with high regio- and stereoselectivity, are formed, which cyclize with formation of cyclobutanes, are more versatile reagents.83 Since α-siloxy-carbenium as studied in detail by Huisgen (Scheme 12b).76 ions generated by electrophilic attack at silyl enol ethers are

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Syn thesis A. I. Leonov et al. Feature

a) MeO MeO a) OSiMe3 O OH Ph OEt O TiCl4, CH2Cl2 (N = 3.9) Cl + Ph Ph r.t., 18 h Ph OEt ZnBr2·Et2O Cl 9b 61% CH Cl 2 2 (N = 6.6) (E < –20) –78 20 °C

b) OSiMe MeO MeO 3 O Ph O (for carbocation: E = 0.0) O TiCl4, CH2Cl2 + Ph Ph Ph –78 °C b) OEt 45 min ZnCl ·Et O 9b 13 85% Ph Cl 2 2 Ph OEt (N = 6.6) (E = –19.4) CH2Cl2, 20 °C OMe Cl 68% OMe Scheme 15 Titanium tetrachloride promoted Mukaiyama reactions of (for carbocation: E = 3.0) silyl enol ether 9b with (a) 1,3-diphenylacetone (from ref 84), and (b) chalcone (13) (from ref 85). In line with the reactivity parameters N and c) OEt E, no reaction is expected in the absence of the Lewis acidic catalyst OEt OEt ZnCl2

OEt AcOEt OEt OEt 45 °C (for carbocation: E > 3) 91% a) 10 mol% NTs O NHTs OSiMe3 K-phthalimide Scheme 13 Lewis acid catalyzed additions of alkoxycarbenium precur- + sors to alkyl vinyl ethers: Example (a) from ref 82, example (b) from ref Ph Ph DMF, 3 h, r.t. Ph Ph 78, and example (c) from ref 80 1b 26 72% (N = 5.2) (E = –11.5)

b) OSiMe rapidly desilylated to give carbonyl compounds, the prob- 3 O Ph O O 10 mol% LiOAc lem of polymerization encountered with alkyl enol ethers is + Ph largely eliminated. However, only highly electrophilic Ph Ph DMF, 8 h, 70 °C Michael acceptors, like the bis(benzenesulfonyl)-substitut- 9c 13 75% ed ethylene 20, undergo uncatalyzed reactions with silylat- (N = 5.2) (E = –19.4) ed enol ethers (Scheme 14).43 Scheme 16 Lewis base catalyzed reactions of silyl enol ethers: (a) with imines (from ref 91), and (b) with α,β-unsaturated ketones (from ref

OSiMe3 O 94). In line with the reactivity parameters N and E, no reaction is ex- SO2Ph 1. MeCN, r.t. SO2Ph pected in the absence of the Lewis basic catalyst + SO2Ph 2. aq workup SO2Ph

9b 20 71% Reetz reported the synthesis of α-tert-alkyl-substituted (in MeCN: N = 6.4) (E = –7.5) carbonyl compounds by Lewis acid mediated reactions of Scheme 14 Reaction of 1,1-bis(benzenesulfonyl)ethylene (20) with silyl enol ethers with tert-alkyl chlorides or acetates the silyl enol ether 9b (from ref 43) (Scheme 17).97–99

TiCl4, –40 °C, CH2Cl2 Reactions of silyl enol ethers with less reactive electro- OSiMe3 + tBu–Cl O philes, such as carbonyl compounds, α,β-unsaturated ke- 85% tones or alkyl acrylates, require activation.83 For example, ZnI2, r.t., CH2Cl2 Lewis acids can be employed to enhance the reactivity of + tBu–OAc 9c 92% carbonyl compounds for their reactions with silyl enol (N = 5.2) ethers. This concept is widely used in Mukaiyama-type Scheme 17 Lewis acid mediated tert-butylation of the silyl enol ether 84 85 cross-aldol and Michael reactions of silyl enol ethers as 9c shown for the reactions of 9b in Scheme 15.86–88 Alternatively, Lewis base catalysis89 was used to activate the nucleophile in Mannich-type reactions of silyl enol As expected from their nucleophilicity parameters, silyl ethers with Schiff bases, such as PhCH=NTs (26).90,91 In enol ethers react with iminium ions under mild conditions these reactions, coordination of phthalimide or carboxylate to give Mannich bases as illustrated in Scheme 18a.100–103 anions at silicon is assumed to enhance the nucleophilicity Important variants of this reaction are chiral-imidazolidi- of the silyl enol ether through the formation of hypervalent none-catalyzed reactions of α,β-unsaturated aldehydes silicon species (Scheme 16a).91–93 Similarly, acetate ions with silyl enol ethers to give δ-ketoaldehydes in high yields triggered the Michael reactions of 1b and 1-(trimethylsi- and enantioselectivities (Scheme 18b).104,105 loxy)cyclohexene (9c) with chalcone (13) (Scheme 16b).94–96

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Syn thesis A. I. Leonov et al. Feature

a) OSiMe3 a) OSiMe3 O O CH2Cl2 'instantaneously' MeCN Fe(CO) N PF 3 + NMe2 + 6 I then aq workup r.t. Fe(CO)3 9c 18a 87% 9c 27 69% (N = 5.2) (E = –6.7) (N = 5.2) (E = –7.8) b) CHO b) OSiMe 3 Ph O Ph OSiMe 100 mol% 3 O S S CHO CH2Cl2 Ph Ph + SS O –30 °C Ph 9a NMe at 0 °C: 75% (90% ee) ( )n BF4 ( ) Ph n (N = 6.2) Bn N tBu H 30 mol% 9b (N = 6.6) 28 from 9b (n = 1): 56% OSiMe 9c (N = 5.2) (E = –6.4) from 9c (n = 2): 67% 3 DNBA 30 mol% O Ph CHO Scheme 19 Formation of α-substituted ketones through reactions of tBuOH/iPrOH (5/1) silyl enol ethers with (a) (tricarbonyl)iron-stabilized cyclohexadienylium 12 h ions (from ref 106), and (b) [1,3]-dithian-2-ylium ions (from ref 108) 1d at –20 °C: 87% (yields of isolated products after aqueous workup) (N = 5.1) Ph Bn O (85% ee, dr 30:1) via N NMe

tBu (E = –5.5) OSiMe3 O 9b (N = 6.6) SiMe3 Scheme 18 Formation of (a) a Mannich base through the reaction of Et2O, 3 h, 0–5 °C + N N iminium ions with the silyl enol ether 9c (from ref 100), and (b) δ-ke- then 2 h at r.t. EtO2C CO2Et toaldehydes through iminium-activated reactions of cinnamaldehyde EtO C N 2 68% with the silyl enol ethers 9a and 1d (from ref 104) (DNBA = 2,4-dinitro- N CO2Et 29 benzenesulfonic acid) aq workup (E = –10.2)

O Silyl enol ethers readily react with the (tricarbonyl)iron- H complexed cyclohexadienylium (27) and the 2-phenyl- N N [1,3]-dithian-2-ylium ion (28), which are positioned below EtO2C CO2Et most enol ethers in Figure 8 (Scheme 19).106–108 Highly reac- 58% (72% from 9c, 56% from 9a) tive Co2(CO)6-complexed propargyl cations (with E in the range of +1 to –1,16 generated from the corresponding prop- Scheme 20 Uncatalyzed α-amination of the silyl enol ether 9b by diethyl diazocarboxylate (29) (from ref 112) argyl methyl ethers or acetates by BF3·OEt2-mediated ion- ization) have been reported to react with the silyl enol ethers 1b and 9c even at 0 °C in dichloromethane to yield, Reactions of the N-fluoropyridinium triflate with silyl after aqueous workup, α-substituted ketones.109 enol ethers are sluggish at room temperature and deliver α- fluorinated products only after heating the reaction mix- tures to reflux for several hours,113 in accord with the sig- Silyl enol ethers have also been used for the synthesis of nificantly lower nucleophilicities of silyl enol ethers com- α-heteroatom-substituted carbonyl compounds. Slow reac- pared to those of the structurally analogous enamines. The tions of silyl enol ethers 9a–c with diethyl diazocarboxylate more electrophilic fluorinating and chlorinating reagents (29)110 are predicted by equation 1. The observation that α- NFSI (22)114 and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien- amino ketones formed slightly faster than predicted by 1-one (25),73 respectively, with E > –9, are effective for the equation 1 may be due to the fact that the electrophilic at- α-halogenation of silyl enol ethers at ambient temperature tack of the azodicarboxylate at the silylated enol ether is as- (Scheme 21). sisted by the interaction of the second nitrogen with silicon, thus giving rise to a concerted sila-Alder-ene reaction (Scheme 20).111,112 Conclusion

While studies on the chemistry of enolate anions started in the 19th century, it was only in the second half of the 20th century, particularly through the pioneering work of Stork and Mukaiyama, that the synthetic potential of enamines and silyl enol ethers became obvious. It was soon rec-

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1157–1170 1168

Syn thesis A. I. Leonov et al. Feature

a) OSiMe3 O Supporting Information F F SO2Ph 1. CH2Cl2, r.t., 24 h N Supporting information for this article is available online at + SO2Ph 2. aq workup https://doi.org/10.1055/s-0037-1611634. Supporting InformationSupporting Information

9c 22 46% (N = 5.2) (E = –8.4) References

b) O (1) Current affiliation: School of Chemistry, Joseph Black Building, OSiMe3 Cl O Cl University of Glasgow, University Avenue, Glasgow, G12 8QQ, 1. CH Cl , r.t., 2 h Cl 2 2 Cl + UK. Cl Cl 2. aq workup (2) Caine, D. Alkylations of Enols and Enolates, In Comprehensive Cl Organic Synthesis, Vol. 3;Vo l. 3 Trost, B. M.; Fleming, I.; Pattenden, G., 9b 25 55% Ed.; Chap. 1.1; Pergamon Press: Oxford, 1991, 1–63. (N = 6.6) (E = –6.8) (3) Stolz, D.; Kazmaier, U. Metal Enolates as Synthons in Organic Scheme 21 Formation of α-haloketones by reactions of silyl enol Chemistry, In The Chemistry of Metal Enolates Part 1; Zabicky, J., ethers with the electrophilic reagents (a) NFSI (22) (from ref 114), and Ed.; Wiley: Chichester, 2009, Chap. 7, 355-410. (b) 25 (from ref 73) (4) Bruckner, R. Chemistry of the Alkaline Earth Metal Enolates, In Organic Mechanisms – Reactions, Stereochemistry and Synthesis; Harmata, M., Ed.; Springer-Verlag: Berlin, 2010, Chap. 13, 519- ognized that the lower nucleophilicities of these enolate 593. equivalents enabled synthetic transformations that were (5) Bates, R. B.; Ogle, C. A. Carbanion Chemistry; Springer: Berlin, not possible with enolate anions. While the qualitative or- 1983. dering of reactivities of these compounds has long been (6) Brandsma, L. Preparative Polar Organometallic Chemistry, Vol. 2; Springer: Berlin, 1990, 1–13. known, we have now used the method of overlapping cor- (7) Jung, M. E. Stabilized Nucleophiles with Electron Deficient Alkenes relation lines for a quantitative comparison. and Alkynes, In Comprehensive Organic Synthesis, Vol. 4;Vo l. 4 Trost, B. – Kinetic investigations of -O , -N(CH2)4- and -OSiMe3- M.; Fleming, I.; Semmelhack, M. F., Ed.; Chap. 1.1; Pergamon substituted stilbenes with C-centered electrophiles have Press: Oxford, 1991, 1–67. shown that these structurally analogous enolate anions, (8) Snieckus, V. Advances in Carbanion Chemistry;Vo l. 1 Snieckus, V., Ed.; enamines, and silyl enol ethers have relative reactivities of JAI Press: Greenwich (CT), 1992. 1014:107:1. Since the measured second-order rate constants (9) Buncel, E.; Dust, J. M. Carbanion Chemistry; Oxford University Press: Oxford, 2003. followed equation 1, we were able to derive their nucleop- (10) Smith, M. B. In March’s Advanced Organic Chemistry: Reactions, hile-specific parameters N and sN. In combination with the Mechanisms, and Structure; John Wiley & Sons: Hoboken, 2013, more than 300 reported electrophilicity parameters E,16 7th Ed., 221–233. equation 1 can now be used to predict the rates for a large (11) Minko, Y.; Marek, I. Chem. Commun. 2014, 50, 12597. variety of reactions of enolate anions and their synthetic (12) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; equivalents with electrophiles. Of course, the concentra- Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500. tions of the enolate ions and enamines have to be consid- (13) Lucius, R.; Loos, R.; Mayr, H. Angew. Chem. Int. Ed. 2002, 41, 91; ered when they are formed as intermediates in catalyzed Angew. Chem. 2002, 114, 97. reactions. Since the susceptibilities sN of enolate anions, (14) Mayr, H. Tetrahedron 2015, 71, 5095. enamines, and enol ethers do not differ significantly, the (15) Mayr, H.; Ofial, A. R. SAR QSAR Environ. Res. 2015, 26, 619. synthetic potential of these reagents can be illustrated as (16) For a freely accessible database of E, N, and sN parameters, see: shown in Figure 8: Enolate ions and their synthetic equiva- http://www.cup.lmu.de/oc/mayr/DBintro.html (accessed Dec lents can be expected to react at room temperature with all 12, 2018). (17) Richter, D.; Hampel, N.; Singer, T.; Ofial, A. R.; Mayr, H. Eur. J. electrophiles located below them in Figure 8. Org. Chem. 2009, 3203. (18) Follet, E.; Berionni, G.; Mayer, P.; Mayr, H. J. Org. Chem. 2015, 80, Funding Information 8643. (19) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003, 9, 2209. Deutsche Forschungsgemeinschaft (SFB 749, project B1).Deutsche Forschungsgemeinschaft (SFB (20) Derived from molecular geometries calculated using the 749) SMD(acetonitrile)/M06-2X/6-31+g(d,p) level of theory. (21) Kanzian, T.; Lakhdar, S.; Mayr, H. Angew. Chem. Int. Ed. 2010, 49, Acknowledgment 9526. (22) Corral Bautista, F.; Appel, R.; Frickel, J. S.; Mayr, H. Chem. Eur. J. We are grateful to Nathalie Hampel for synthesizing the reference 2015, 21, 875. electrophiles and to Robert J. Mayer for quantum chemical calcula- (23) Timofeeva, D. S.; Mayer, R. J.; Mayer, P.; Ofial, A. R.; Mayr, H. tions. We thank Professor Hans-Ulrich Reißig and Dr. Sami Lakhdar Chem. Eur. J. 2018, 24, 5901. for helpful discussions. (24) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.

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