A contribution of Physical Organic Chemistry to systematizing Organic Synthesis. Cordial congratulations on the occasion of the Golden Anniversary of Synthesis.
Enolate equivalents are among the most important reagents in organic and biochemistry.[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11] In organic synthesis, they are commonly employed as metal enolates or as their synthetic equivalents, enamines or enol ethers, depending on the electrophilicity of the corresponding reaction partners. The qualitative ranking of reactivity — metal enolate > enamine > enol ether — is well known. A quantitative comparison has been hampered by the fact, however, that electrophiles, which are suitable for kinetic studies with enolate ions, have such low electrophilicities that they do not react with enamines and enol ethers. On the other hand, electrophiles, suitable for studying the kinetics of their reactions with enamines or enol ethers, are so reactive that they will generally undergo unselective diffusion-controlled reactions with alkali enolates. How can this dilemma be overcome?
In previous years, we have established a series of colored reference electrophiles covering a reactivity range of 32 orders of magnitude, which are suitable for studying the reactivities of nucleophiles of widely differing reactivity.[12]
[13]
[14]
[15] By using equation 1, in which electrophiles are characterized by one parameter E, and nucleophiles are characterized by the solvent-dependent nucleophilicity parameter N and susceptibility s
N, we have so far parameterized more than 300 electrophiles and 1100 nucleophiles.[16]
Equation 1
We now report on the reactivities of the enolate equivalents depicted in Figure [1], which allow us to quantitatively compare the previously reported nucleophilicities of potassium enolates with those of structurally analogous enamines and enol ethers. We will furthermore demonstrate that the combination of nucleophilicity parameters for enolates, enamines, and silyl enol ethers with the reactivity parameters E of electrophiles provides an ordering principle for enolate chemistry.
Figure 1 Structures of silyl enol ethers 1a–d and enamines 2a,b investigated as enolate equivalents in this work
Table [1] lists the indolylbenzylium ions 3a–c, benzhydrylium ions 3d–l, and quinone methides 3m–o, which were employed as reference electrophiles for the kinetic measurements.
Table 1 Indolylbenzylium Ions 3a–c, Benzhydrylium Ions 3d–l and Quinone Methides 3m–o Employed as Reference Electrophiles in this Study
|
Electrophile
|
|
|
E
a
|
|
R = H
R = Me
R = OMe
|
3a
3b
3c
|
–1.80
–2.19
–3.02
|
|
R = OMe
R = N(Me)CH2CF3
R = N(CH2CH2)2O
R = N(Me)2
R = N(CH2)4
|
3d
3e
3f
3g
3h
|
0.00
–3.85
–5.53
–7.02
–7.69
|
|
n = 2
n = 1
|
3i
3j
|
–8.22
–8.76
|
|
n = 2
n = 1
|
3k
3l
|
–9.45
–10.04
|
|
R = H
R = OMe
R = N(Me)2
|
3m
3n
3o
|
–11.87
–12.18
–13.39
|
a Electrophilicity parameters E were taken from refs 12, 13, 17, and 18.
Product Studies
The reactions of the silyl enol ethers 1a, 1c, and 1d with benzhydrylium or indolylbenzylium tetrafluoroborates initially yielded siloxy-substituted carbenium ions 4. Fast subsequent desilylation then afforded ketones 5a–c (Scheme [1]), which were purified by column chromatography and characterized by NMR spectroscopy and mass spectrometry. 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).
Electrophilic attack of the benzhydrylium tetrafluoroborate 3g on the enamine 2b led to formation of the iminium salt 6. Its hydrolysis gave the ketone 5d, which was purified by column chromatography and isolated in moderate yield (Scheme [2]).
Scheme 1 Reactions of silyl enol ethers 1a, 1c, and 1d with reference electrophiles. Yields refer to isolated products
Scheme 2 Reaction of the enamine 2b with reference electrophile 3g-BF4 (NMR chemical shift δ in ppm, CD3CN, 100 MHz)
The reaction of the enamine 2a with the quinone methide 3m furnished the zwitterion 7, which tautomerized, and within 30 minutes, quantitatively yielded the product 8 as determined by NMR spectroscopy (Scheme [3]).
Scheme 3 Reaction between enamine 2a and quinone methide 3m
Structure–Reactivity Relationships
The narrow range of the nucleophile-specific susceptibilities (0.82 < s
N < 0.94) for the silyl enol ethers 1 indicates that the relative reactivities of these π-systems depend only slightly on the nature of the attacking electrophiles. Therefore, the reactivities towards any of the carbenium ions 3a–l reflect general structure–reactivity trends.
Table [2] shows that the reactions of 1a with 3a and 3c 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.
Figure [4] compares the reactivities of the silyl enol ethers 1a and 1b towards indolylbenzylium ion 3b with the previously reported reactivity of the acetophenone-derived silyl 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 introduction of a phenyl group at this position (9a → 1a) reduces nucleophilic reactivity by three orders of magnitude.
Figure 4 Structural effects on the nucleophilic reactivities of silylated enol ethers at 20 °C. a Calculated by applying N and s
N from ref 12 in equation 1 (for 9a in CH2Cl2: N = 6.22, s
N = 0.96). b Second-order rate constant in MeCN from Table [2]
Benzoannulation of the cyclic enol ether 9b increases its reactivity towards 3g by a factor of 3.9 (9b → 1c) (Figure [5]), whereas benzoannulation of 1-(trimethylsiloxy)cyclohexene (9c) does not have a significant effect on the reactivity (9c → 1d). As a consequence, the previously reported reactivity preference of the cyclopentenyl over the cyclohexenyl silyl enol ether by a factor of 20 increases to almost two orders of magnitude for the benzoannulated analogs (1c vs 1d). As mentioned above, the small reactivity difference of 1a in acetonitrile and dichloromethane (Table [2]) allows us to neglect the fact that the data for 9b and 9c in Figure [5] refer to dichloromethane whereas those for 1c and 1d refer to acetonitrile solutions.
Figure 5 Effect of benzoannulation on the nucleophilic reactivities of 1-(trimethylsiloxy)cycloalkenes at 20 °C. a Second-order rate constant (in dichloromethane) from ref 12. b Second-order rate constant in MeCN from Table [2]. c Calculated for the reaction 1d + 3g (in MeCN) from data in Tables 1 and 2 by using equation 1
Figure [6] compares the nucleophilic reactivities of enamines, which are structural analogs of the silylated enol ethers in Figure [5]. As in the enol ether series, the cyclopentene 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 effect on nucleophilic reactivity, benzoannulation of the corresponding cyclohexene derivative 10b (→ 2b) reduces the nucleophilicity by a factor of 69 (in acetonitrile). Due to steric effects, coplanarity of the pyrrolidino ring with the C=C double bond of the enamine is more disturbed in 2b than in 2a.[20]
Figure 6 Effect of benzoannulation on the nucleophilic reactivities of enamines at 20 °C. a Second-order rate constant (in dichloromethane) from ref 19. b Second-order rate constant (in MeCN) from Table [2]. c Second-order rate constant (in MeCN) from ref 21
With the newly determined nucleophilicity parameters, it is now possible to compare directly the nucleophilic reactivity of the enolate ion 11
[22] with the reactivities of its structurally related equivalents 1a and 10c
[23] (Figure [7]). When the N and s
N parameters of 1a and 10c are used to calculate the rate constants of their reactions with quinone methide 3o (E = –13.39), the most reactive electrophile used for the characterization of the enolate ion 11, one finds that the enamine 10c is 107 times less reactive than 11 and that the enol ether 1a is another 107 times less reactive than the enamine 10c. In a dilute solution, in which the reaction of the enolate ion 11 would proceed within one second, the corresponding reaction of the enamine 10c would require one year, and the silyl enol ether 1a would reach the same degree of conversion after ten million years.
Figure 7 Comparison of the nucleophilic reactivities (at 20 °C) of the deprotonated deoxybenzoin 11 with its synthetic equivalents 1a and 10c. a In MeCN, from ref 23. b In DMSO, from ref 22
Applications
The nucleophilicity parameters determined in this investigation can now be combined with previously reported reactivity indices[16] to rationalize the use of enolate ions and their synthetic equivalents in organic synthesis. Figure [8] depicts enolates, enamines, and silyl enol ethers with increasing nucleophilicity from bottom to top and electrophiles with increasing reactivities from top to bottom. Nucleophiles and electrophiles at the same level (E + N ≈ –3) react with a rate constant of ca. 0.004 M–1 s–1 at 20 °C (from equation 1 for a typical value of s
N = 0.8), which corresponds to a half reaction time of about 20 minutes for 0.2 M solutions. If enolate ions and enamines are intermediates of catalytic processes, their lower concentration has to be taken into account when estimating the reaction times.
Reactions of Enolate Ions
Reactions of enolate ions with C-centered electrophiles represent important methods for generating new carbon–carbon bonds.[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
,
[24]
[25]
[26]
[27]
[28]
[29] The non-stabilized enolate ions at the top of Figure [8] react with all electrophiles shown on the right. Due to their high reactivity, lithium enolates are useful reagents for cross-aldol reactions with ketones and aldehydes (as shown for 12 in Scheme [4a]).[30] In reactions with Michael acceptors (e.g., with 13), they may be used as preformed anions or may be generated in situ by treatment of the corresponding CH acids with catalytic amounts of Brønsted bases (Scheme [4b]).[31]
[32] Acceptor-substituted enolate ions, such as cyano-, acetyl-, alkoxycarbonyl- and phenylsulfonyl-substituted enolate ions, react at or slightly above room temperature with a large variety of Michael acceptors with E > –23 (as exemplified for the combination 14 + 15 in Scheme [4c]),[33]
[34]
[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).
Scheme 4 Enolate ions: (a) in a cross-aldol reaction with benzaldehyde (12) (from ref 30), (b) generated from 11-H in a reaction with the Michael acceptor 13 (from ref 31), and (c) generated from 14-H in a reaction with ethyl acrylate (15) (from refs 34 and 35)
Pyridinium-substituted enolate ions (that is, acyl-substituted pyridinium ylides) readily react with Michael acceptors of E > –25 to give zwitterions, which usually cyclize with formation of 1,2,3,8a-tetrahydroindolizines (Scheme [5a])[36]
[37] or cyclopropanes.[38]
[39]
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)
Scheme 5 Reactions of pyridinium ylides with Michael acceptors: (a) from ref 37, (b) from ref 40
Monitoring the reaction of equimolar amounts of a 4-(dimethylamino)-substituted pyridinium ylide with p-methoxybenzylidene malononitrile by NMR spectroscopy showed the quantitative formation of a betaine, which did not cyclize under the reaction conditions due to the stabilizing effect of the two cyano groups at the carbanionic center (Scheme [5b]).[40]
Reactions of Enamines
Pyrrolidine-derived enamines, such as 1-(cyclopent-1-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]
[42]
[43] Whereas the reaction with the weakly electrophilic acrylonitrile (19) required 12 hours refluxing in dioxane,[41] the reactions with more electrophilic nitroalkenes[42] and the strong electrophile 20 proceed rapidly at room temperature.[43] The nucleophilic attack of enamines at the carbonyl group of aromatic and aliphatic aldehydes yields α,β-unsaturated ketones through condensation and subsequent aqueous workup (Scheme [6b]).[44]
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)
Enamines (for example, 2b or 10b) react with preformed iminium salts such as 21a and 21b in high yields under mild conditions to give the Mannich bases of α-tetralone or cyclohexanone, respectively (Scheme [7]).[45]
[46]
Scheme 7 Formation of Mannich bases through reactions of enamines with preformed iminium salts (from ref 45)
Fast F+ transfer reactions to colored enamines, such as 10c, were used to quantify the reactivity of electrophilic fluorinating N–F reagents with –10.5 < E < –5 [such as NSFI (22) in Scheme [8a]].[47] The same types of enamines were used to characterize F3CS+ and F2CHS+ transfer agents, such as the saccharin derivative 23 (Scheme [8b]).[48]
Scheme 8 Reactions of enamine 10c with electrophilic: (a) fluorinating (from ref 47), and (b) trifluoromethylthiolating reagents (from ref 48)
Enamine activation has emerged as a widely applicable organocatalytic method for the α-functionalization of carbonyl compounds.[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56] List et al. discovered that enantioselective aldol reactions between acetone and various aldehydes proceed through conversion of the ketone into the corresponding proline-derived enamine intermediate (Scheme [9a]).[57,58] Subsequently proline-catalyzed three-component Mannich reactions with N-arylimines[59] and Michael additions to nitroolefins, such as 24 (Scheme [9b]),[60] were developed (at r.t., several hours of reaction time).
Scheme 9 Proline-catalyzed: (a) aldol reactions (from ref 57), and (b) Michael additions (from ref 60)
In particular, diarylprolinol silyl ethers introduced by Hayashi and Jørgensen have proven to be versatile catalysts for the stereoselective introduction of substituents at the α-position of aldehydes.[54]
[61]
[62] As indicated by the position of the 2-phenylacetaldehyde-derived enamine 10d (N = 10.56, s
N = 1.01 in MeCN) in Figure 8,[63] structurally analogous enamines are such strong nucleophiles that they react with β-nitrostyrene (24) at 0 °C with excellent control of the stereoselectivity (Scheme [10a]).[64]
[65] The diphenylprolinol silyl ether-catalyzed reaction of 3-phenylpropanal with the less electrophilic methyl vinyl ketone (18) delivered only a moderate yield of the 1,5-dicarbonyl product with high enantioselectivity, even when a higher catalyst loading was used (Scheme [10b]).[64]
[66]
Scheme 10 Michael additions via Hayashi–Jørgensen-catalyst-derived enamines (from ref 64)
Cozzi and coworkers rationally designed enantioselective 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 10e in Figure [8]) derived from aldehydes and MacMillan’s imidazolidinone catalysts.[67]
[68]
[69]
[70] The position of enamine 10e
[63] in Figure [8] is also in line with the observation that NFSI (22)[71] and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one (25) are suitable reagents for imidazolidinone-catalyzed α-halogenations of aldehydes (Scheme [11]).[72]
[73]
Reactions of Enol Ethers
Alkyl enol ethers have similar nucleophilic reactivities as structurally analogous silyl enol ethers (Scheme [12a]),[74] but are considerably less nucleophilic than enamines (see Figure [8]). The use of alkyl enol ethers as enolate anion equivalents is rather limited, however, because of their tendency to undergo polymerization. In an extensive review, Hall demonstrated that highly electrophilic ethylene derivatives can initiate the ionic polymerization of alkyl enol ethers.[75] Polymerization is avoided when 1,4-zwitterions are formed, which cyclize with formation of cyclobutanes, as studied in detail by Huisgen (Scheme [12b]).[76]
Lewis acid catalyzed additions of alkyl halides, acetals, and orthoesters to alkyl enol ethers only give 1:1 products when the reactants ionize more readily than the products.[77]
[78]
[79] Though ZnCl2-catalyzed additions of α,β-unsaturated acetals to ethyl vinyl ether are key steps in Isler’s technical β-carotin synthesis,[80] the choice of reactants, which ionize faster than the resulting α-haloethers or acetals, is limited,[81] as shown by the examples depicted in Scheme [13].
Scheme 11 Organocatalytic α-functionalizations of aldehydes via enamine intermediates according to (a) Cozzi (refs 67–70), and (b) MacMillan (ref 72)
Scheme 12 (a) Comparison of the nucleophilicities of alkyl and silyl enol ethers, and (b) formation of cyclobutanes in the reaction of methyl vinyl ether with tetracyanoethene (from ref 76)
Scheme 13 Lewis acid catalyzed additions of alkoxycarbenium precursors to alkyl vinyl ethers: Example (a) from ref 82, example (b) from ref 78, and example (c) from ref 80
Silyl enol ethers, which are readily accessible from carbonyl compounds with high regio- and stereoselectivity, are more versatile reagents.[83] Since α-siloxy-carbenium ions generated by electrophilic attack at silyl enol ethers are rapidly desilylated to give carbonyl compounds, the problem of polymerization encountered with alkyl enol ethers is largely eliminated. However, only highly electrophilic Michael acceptors, like the bis(benzenesulfonyl)-substituted ethylene 20, undergo uncatalyzed reactions with silylated enol ethers (Scheme [14]).[43]
Scheme 14 Reaction of 1,1-bis(benzenesulfonyl)ethylene (20) with the silyl enol ether 9b (from ref 43)
Reactions of silyl enol ethers with less reactive electrophiles, such as carbonyl compounds, α,β-unsaturated ketones or alkyl acrylates, require activation.[83] For example, Lewis acids can be employed to enhance the reactivity of carbonyl compounds for their reactions with silyl enol ethers. This concept is widely used in Mukaiyama-type cross-aldol[84] and Michael reactions[85] of silyl enol ethers as shown for the reactions of 9b in Scheme [15].[86]
[87]
[88]
Scheme 15 Titanium tetrachloride promoted Mukaiyama reactions of 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 E, no reaction is expected in the absence of the Lewis acidic catalyst
Alternatively, Lewis base catalysis[89] was used to activate the nucleophile in Mannich-type reactions of silyl enol ethers with Schiff bases, such as PhCH=NTs (26).[90]
[91] In these reactions, coordination of phthalimide or carboxylate anions at silicon is assumed to enhance the nucleophilicity of the silyl enol ether through the formation of hypervalent silicon species (Scheme [16a]).[91–93] Similarly, acetate ions triggered the Michael reactions of 1b and 1-(trimethylsiloxy)cyclohexene (9c) with chalcone (13) (Scheme [16b]).[94]
[95]
[96]
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 94). In line with the reactivity parameters N and E, no reaction is expected in the absence of the Lewis basic catalyst
Reetz reported the synthesis of α-tert-alkyl-substituted carbonyl compounds by Lewis acid mediated reactions of silyl enol ethers with tert-alkyl chlorides or acetates (Scheme [17]).[97]
[98]
[99]
Scheme 17 Lewis acid mediated tert-butylation of the silyl enol ether 9c
As expected from their nucleophilicity parameters, silyl enol ethers react with iminium ions under mild conditions to give Mannich bases as illustrated in Scheme [18a].[100]
[101]
[102]
[103] Important variants of this reaction are chiral-imidazolidinone-catalyzed reactions of α,β-unsaturated aldehydes with silyl enol ethers to give δ-ketoaldehydes in high yields and enantioselectivities (Scheme [18b]).[104,105]
Scheme 18 Formation of (a) a Mannich base through the reaction of iminium ions with the silyl enol ether 9c (from ref 100), and (b) δ-ketoaldehydes through iminium-activated reactions of cinnamaldehyde with the silyl enol ethers 9a and 1d (from ref 104) (DNBA = 2,4-dinitrobenzenesulfonic acid)
Silyl enol ethers readily react with the (tricarbonyl)iron-complexed cyclohexadienylium (27) and the 2-phenyl-[1,3]-dithian-2-ylium ion (28), which are positioned below most enol ethers in Figure 8 (Scheme [19]).[106]
[107]
[108] Highly reactive Co2(CO)6-complexed propargyl cations (with E in the range of +1 to –1,[16] generated from the corresponding propargyl methyl ethers or acetates by BF3·OEt2-mediated ionization) have been reported to react with the silyl enol ethers 1b and 9c even at 0 °C in dichloromethane to yield, after aqueous workup, α-substituted ketones.[109]
Scheme 19 Formation of α-substituted ketones through reactions of silyl enol ethers with (a) (tricarbonyl)iron-stabilized cyclohexadienylium ions (from ref 106), and (b) [1,3]-dithian-2-ylium ions (from ref 108) (yields of isolated products after aqueous workup)
Silyl enol ethers have also been used for the synthesis of α-heteroatom-substituted carbonyl compounds. Slow reactions of silyl enol ethers 9a–c with diethyl diazocarboxylate (29)[110] are predicted by equation 1. The observation that α-amino ketones formed slightly faster than predicted by equation 1 may be due to the fact that the electrophilic attack of the azodicarboxylate at the silylated enol ether is assisted by the interaction of the second nitrogen with silicon, thus giving rise to a concerted sila-Alder-ene reaction (Scheme [20]).[111]
[112]
Scheme 20 Uncatalyzed α-amination of the silyl enol ether 9b by diethyl diazocarboxylate (29) (from ref 112)
Reactions of the N-fluoropyridinium triflate with silyl enol ethers are sluggish at room temperature and deliver α-fluorinated products only after heating the reaction mixtures to reflux for several hours,[113] in accord with the significantly lower nucleophilicities of silyl enol ethers compared to those of the structurally analogous enamines. The more electrophilic fluorinating and chlorinating reagents NFSI (22)[114] and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one (25),[73] respectively, with E > –9, are effective for the α-halogenation of silyl enol ethers at ambient temperature (Scheme [21]).
Scheme 21 Formation of α-haloketones by reactions of silyl enol ethers with the electrophilic reagents (a) NFSI (22) (from ref 114), and (b) 25 (from ref 73)
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 recognized that the lower nucleophilicities of these enolate equivalents enabled synthetic transformations that were not possible with enolate anions. While the qualitative ordering of reactivities of these compounds has long been known, we have now used the method of overlapping correlation lines for a quantitative comparison.
Kinetic investigations of -O–, -N(CH2)4- and -OSiMe3-substituted stilbenes with C-centered electrophiles have shown that these structurally analogous enolate anions, enamines, and silyl enol ethers have relative reactivities of 1014:107:1. Since the measured second-order rate constants followed equation 1, we were able to derive their nucleophile-specific parameters N and s
N. In combination with the more than 300 reported electrophilicity parameters E,[16] equation 1 can now be used to predict the rates for a large variety of reactions of enolate anions and their synthetic equivalents with electrophiles. Of course, the concentrations of the enolate ions and enamines have to be considered when they are formed as intermediates in catalyzed reactions. Since the susceptibilities s
N of enolate anions, enamines, and enol ethers do not differ significantly, the synthetic potential of these reagents can be illustrated as shown in Figure [8]: Enolate ions and their synthetic equivalents can be expected to react at room temperature with all electrophiles located below them in Figure [8].
