Organic & BiomolecularChemistry

Base-catalyzed, C-alkylation of potassium (K) enolates with styrenes (CAKES) has recently emerged as a highly practical and convenient method for elaboration or synthesis of pharmaceutically-relevant cores. K enolate-type precursors such as alkyl-substituted heterocycles (pyridines, pyrazines and thiophenes), ketones, imines, nitriles and amides undergo C-alkylation reactions with styrene in the presence of KO t Bu or KHMDS. Surprisingly, no studies have probed the reaction mechanism beyond the likely initial formation of a K enolate. Herein, a synergistic approach of computational (DFT), kinetic and deuterium labelling studies rationalizes various experimental observations and supports a metal – ene-type reaction for amide CAKES. Moreover, our approach explains experimental observations in other reported C-alkylation reactions of other enolate-type precursors, thus implicating a general mechanism for CAKES.


Introduction
The addition of simple pre-made alkyllithium compounds to styrenes is a known reaction 1 and is used in anionic polymerization chemistry. 2 While the addition of alkylpotassiums to styrenes is rare, in recent years, C-Alkylation of K Enolates with Styrenes (CAKES) is emerging as a practical, convenient, highyielding method for elaboration or synthesis of pharmaceutically-relevant cores. 3-5 KOtBu-catalyzed CAKES of alkyl-substituted heterocycles ( pyridines, pyrazines, thiophenes) were reported around five decades ago (Fig. 1A) 6 and the scope of alkylpyridine CAKES was recently extended by Guan et al., using KHMDS and elevated temperatures (ca. 100°C). 4 KOtBucatalyzed ketone, imine and nitrile CAKES was reported two decades ago by Knochel et al. (Fig. 1B), but no mechanistic rationale was available at that time. 3 Pines first reported KOtBu-catalyzed amide CAKES; 7 using N-methyl-2-pyrrolidinone (NMP) and N-methyl-2-piperidone (NMPI) as substrates. Historically, C-alkylation of most aforementioned substrates is accomplished via initial deprotonation employing a strong base (NaH, LDA, sec-BuLi). 8 Such reactions require an inert atmosphere, moisture-free conditions and cryogenic temperatures. In contrast, KOtBu-mediated amide CAKES are performed successfully at elevated temperatures (>80°C), under air and ambient moisture if stoichiometric base is used (Fig. 1C), 5 and are applicable to a variety of amides beyond NMP and NMPI (including acyclic alkylamides). Kobayashi et al. recently reported successful amide CAKES at rt with catalytic quantities (5-6 mol%) of base (KHMDS) and 18-crown-6 as a promotor under inert (Ar) atmosphere. 9 The term 'CAKES' is coined due to the general requirement for potassium bases; sodium bases succeed under certain conditions but reactions are sluggish, requiring higher temperatures or complexing additives. 4,5 Base-catalyzed CAKES reactions have been proposed to proceed via initial formation of a K enolate, [4][5][6][7]9 yet little evidence has actually been presented for this species. 10 This is especially curious given that the pK a values of K enolate precursors like 4-methylpyridine, 11 acetonitrile 12 and N,N-dimethylacetamide 13 are considerably higher ( pK a = 31-35 in DMSO) than those of the conjugate acids of bases employed like HOtBu 14 and HMDS ( pK a = 26-29 in DMSO). 14 Previous studies have then proposed the formal nucleophilic addition of the K enolate to styrene, 7,9 the direct outcome of which is a strongly basic benzylic alkylpotassium which appears to be considerably higher in energy than its K enolate and styrene precursors (the pK a of PhMe is ca. 43 in DMSO). 15 Despite this, no evidence for a transition state (T.S.) or even rationale, to explain how such an endergonic process might occur, has been presented. The free energy barrier to such a T.S. would have to be low enough to be accessible at rt or the somewhat elevated temperatures often employed. Oligomers are not observed, suggesting the benzylic alkylpotassium is stabilized and cannot undergo addition to a second styrene. This implicates the heteroatom of the K enolate precursor (for example, the O atoms of alkylamides or N atoms of alkylpyridines) in coordinating a closed-type T.S. and in stabilizing the benzylic alkylpotassium as recently proposed by us (Fig. 2).
To our knowledge, computation has not yet been undertaken to probe the T.S. and energetics of CAKES reactions. Herein, we disclose a detailed mechanistic model constructed by a synergy of computational (DFT), kinetic and deuterium labelling studies, revealing a metal-ene T.S. in N-alkylamide CAKES. Various experimental observations are rationalized; such as the bisadduct/monoadduct (B/M) selectivity, the effect of styrene electronics, the roles of additives (18-crown-6) and bases (NaOtBu vs. KOtBu) in the reaction and the reactivity differences between acyclic vs. cyclic amide substrates. Moreover and importantly, our mechanistic picture accords with observations in other (ketone and alkylpyridine) CAKES, thus implicating our model as a general mechanism for each class of compound.

Results and discussion
Investigation of bisadduct/monoadduct selectivity In our recent study, 5 we found that the B/M selectivities of less-reactive acyclic amides such as N,N-dimethylacetamide (DMA, 1) were heavily influenced by the styrene electronics (3, 11-17). Monoadduct 6 is the expected main product because (i) a larger concentration of DMA (as solvent) than 6 occurs throughout the reaction and (ii) the rate of bisadduct 10 formation is limited by the concentration of 6 which is zero at T = 0 and increases during the reaction. Notwithstanding this, we reasoned the influence of styrene electronics on B/M selectivity could be rationalized by the free energy difference (ΔΔG rel ) between the respective T.S. free energies leading to bisadduct (ΔG rel {B}) and monoadduct products (ΔG rel {M}) relative to their initial starting materials. 16 This was deemed a more robust method than comparing the difference in formal T.S. energy barriers relative to their respective K enolate precursors (ΔΔG ‡ = ΔG ‡ {B} − ΔG ‡ {M}), because the second (monoadduct) deprotonation step is affected by the nature of the styrene and contributes to the overall bisadduct formation rate.
DFT calculations used the M06-2X functional 17 with a 6-31++G(d,p) basis set 18 on all atoms (except Br atoms, to which a pseudo-potential was applied). 19 The C-PCM implicit solvent model, 20 as implemented in Gaussian09, 21 assumed DMA, DMSO or PhH, depending on the reactions investigated. This was more appropriate than modelling explicit solvation in order to build a general model which could be applied to several different reaction classes. Results were compared to those from the B3LYP (unrestricted) functional 22 with a 6-31+G (d,p) basis set (see ESI †). 23  It was assumed that KOtBu deprotonates 1 and is regenerated by deprotonation of HOtBu by monoadduct K benzylate 5 to afford 6 (likewise for the pathway to 10). Since benzylic alkylpotassium 5 (and 9) are more potent bases than KOtBu, it was proposed their deprotonation of 1 (or 6) propagates a catalytic cycle. 5,9 Yet the stark pK a difference between 1/6 and HOtBu is likely more important than their available concentration difference and favors the reaction pathway regenerating KOtBu. In support of this, computation found the T.S. for deprotonation of 1 by 5 (ΔG ‡ deprot = 15.9 kcal mol −1 ) was less accessible than that of deprotonation of 1 by KOtBu (ΔG ‡ deprot = 13.1 kcal mol −1 ); deprotonation of HOtBu was a much more kinetically accessible pathway for 5 (ΔG ‡ deprot = 0.3 kcal mol −1 ). Reactions of 1 with various styrenes were all exergonic with accessible free energy barriers (ΔG ‡1 = 16.2-22.0 kcal mol −1 ) at the previously applied 5 reaction temperatures (Table 1). 24 A larger ΔΔG rel (= ΔG rel {B} − ΔG rel {M}) means slower relative kinetics of the reaction of monoadduct (6) to give bisadduct (10) would direct styrene consumption towards the reaction of 1 to form 6, hence decreasing the B/M ratio. Conversely, a smaller ΔΔG rel would encourage bisadduct (10) formation and would increase the B/M ratio. Gratifyingly, a strong negative correlation was found between (i) the free energy difference between the transition states for formation of bisadducts and monoadducts (ΔΔG rel ) and (ii) the B/M selectivity determined experimentally (Fig. 5). The outlier to this trend (not plotted) was 13, which gave a relatively large ΔΔG rel for its high B/M selectivity.
To probe further, we computed the free energy difference in the barriers for deprotonation (formation of amide K enolate vs. monoadduct K enolate), ΔΔG ‡ deprot , which affects the overall rate by controlling the available concentrations of reacting K enolate. For the reaction of 13, ΔΔG ‡ deprot was notably lower

Investigation of styrene electronics and kinetics
We then proceeded to measure the kinetic profiles of reactions of DMA with the same selection of styrenes by in situ NMR spectroscopy using a variable temperature probe fixed at 80°C ( Table 2). As opposed to our previous study where reactions were prepared under ambient air/moisture, 5 herein kinetic study reactions were prepared within an N 2 glovebox in NMR tubes using commercial KOtBu (sublimed grade 99.99%), DMSO-d 6 solvent (D, 99.9%) and degassed (3× freeze/pump/ thaw) reagents (NMP/DMA/DMP) that had been dried overnight over activated 4 Å molecular sieves. Otherwise, KOtBu/ amide equivalents (relative to styrene) and order of addition accorded with the previous study. 5 Reactions were first order with respect to styrene, with Fig. 6 showing a non-linear positive relationship between the ratio of experimental (initial) 25 rate constants, (Ln(k)/Ln(k 0 ); k and k 0 refer to the reactions of styrene derivative and styrene, respectively) and the ratio of computed free energy barriers for the first metal-ene T.S. (ΔG″ ‡ {M}/ΔG′ ‡ {M}; superscripts ″ and ′ refer to the reactions of styrene derivative and styrene, respectively).
Here, the free energy barriers (ΔG ‡ , not ΔG rel ) are examined on the logical assumption that the initial rates correspond to the formation of the monoadduct and are unaffected by formation of the bisadduct. Fig. 6 identifies the initial metal-ene reaction (T.S.{M}) as a rate-determining step (RDS) for styrene conversion, strengthening the computational mechanistic model. Although a catalytic loading of KOtBu (20 mol%) failed to deliver products under previously-reported ambient air/ moisture conditions, 5 we confirm catalytic activity under air-and moisture-free conditions herein, 26 consistent with previous reports. 6,9 In fact, the reaction rate is unchanged (Table 2, entry 7 vs. entry 4). DMP (18) gave a notably faster reaction rate than DMA (1), despite a similar T.S. free energy barrier difference (entry 9 vs. entry 4). The effect of styrene electronics on the rate of reaction was clearly depicted by a linear Hammett plot (Fig. 7), 27 demonstrating that all substrates proceed through the same T.S. and follow the same RDS. Notably, the configuration/bond distances of T.S.{M} (Fig. 4) for the reaction of DMA with styrene resemble those     previously reported for an analogous intramolecular reaction of an anionic oxime with a pendant styrene. 23e

Investigation of cyclic amides
Next, we proceeded to examine the reactions of cyclic amides, such as NMP (19), with styrene as the 'electrophile' in DMSO solvent (Fig. 8). Compared to acyclic amides, cyclic amides like 19 give greater conversions over time and lower B/M selectivities (B/M = 20b/20a = 0.13 for 19). 5,28 Under similar 29 conditions, sarcosine anhydride (21) gave perfect monoadduct (22a) selectivity as previously reported. 5 Although the second reaction with styrene could take place at the alternative α-carbon to that of the first reaction, formation of 22a and 22b was assumed for fair computational comparison with 19. The ΔΔG rel (and ΔΔG deprot ) value was more positive for reaction of 21 than reaction of 19. Unfortunately, the reaction of sarcosine anhydride was not amenable to kinetic analysis by 1 H NMR under the standard conditions employed herein due to solubility issues. Next, we examined the previously-reported reactions of NMP with styrenes 3, 15 and 17 (Fig. 9). 5 As opposed to DMA, the B/M selectivity of NMP's reactions with various styrenes was not influenced by styrene electronics. Computation (assuming DMSO solvent) resulted in a smaller difference in the range of ΔΔG rel values (= 0.2 to 0.7) for all three styrene partners (Fig. 9), compared to that observed for DMA (ΔΔG rel values = 2.3 to 4.2). Interestingly, ΔΔG ‡ deprot values were very similar, allowing reassurance to directly compare the differences in free energy barriers for mono-vs. bisadduct formation (ΔΔG ‡ ), which were also similar. Kinetic profiles found the reaction of NMP faster than DMA, entirely consistent with a lower ΔG ‡ {M} for NMP (together with a slightly lower ΔG ‡ deprot {M} and lower ΔG rel {M}) as found by computation. The free energy barriers for monoadduct formation (ΔG ‡ {M}) were in the order 3 ≤ 15 ≪ 17 (Fig. 10), entirely consistent with the order of rate constants. The aforementioned relationship between Ln(k)/Ln(k 0 ) and ΔG″ ‡ {M}/ ΔG′ ‡ {M} holds, confirming the overall rate of acyclic amides CAKES is determined by ΔG ‡ {M}. Counterintuitively, for 3, 15 and 17, the values of ΔΔG rel are smaller for NMP than for DMA, yet NMP gives lower B/M selectivity. Here, ΔΔG ‡ deprot (which determines the relative concentrations of available reacting amide K enolate and monoadduct K enolate) clearly     33 Therefore, to further investigate the role of deprotonation in amide CAKES, NMP and NMP-d 9 were compared in parallel under conditions demonstrated affording incomplete conversion (10 min at 0°C gave a 40% yield of 20a) and were quenched after an identical time (Fig. 11A). Quantitative deuteration at the benzylic position confirmed the presence of a benzylic alkylpotassium. The decreased yield of 20a-d 9 highlighted the importance of deprotonation at the α-amido position, consistent with the observation of 20a-d 8 which likely formed via deprotonation of 20a-d 9 . 34 We then compared reactions of NMP and NMP-d 9 in parallel under slightly modified conditions using DMSO-d 6 solvent, 35 which allowed the reaction progress to be monitored over time by 1 H NMR spectroscopy. The initial rates of styrene conversion (k H and k D ) were used to determine the KIE (KIE = 2.2). 25 This moderate primary KIE identifies one of two possibilities: (1) deprotonation is irreversible and is the RDS or (2) deprotonation is reversible and occurs before the RDS, such that an observed KIE results from an equilibrium isotope effect on that deprotonation step. The latter situation is likely considering the aforementioned (i) pK a difference between HOtBu and amides and (ii) influence of styrene electronics on the reaction rate.
After completion of the reactions by 1 H NMR (28 min for NMP + styrene vs. 51 min for NMP-d 9 + styrene), the yields and B/M selectivities for each reaction were similar. Although the reaction of NMP-d 9 + styrene in DMSO-d 6 was essentially complete after 51 min at 0°C (see ESI †), it was left for extended time at rt prior to quenching. After quenching, workup and purification, the product ultimately isolated from the reaction was 20a-d 10 (which contained low abundances of 20a-d 9 and 20a-d 7 by mass spectrometry, see ESI †). The deuteration of benzylic positions in the presence of KOtBu and deuterium sources (NMP-d 9 or DOtBu) is feasible. 37 Investigation of base, 18-crown-6, ambient air/moisture conditions and DMSO co-solvent The moderate primary KIE observed is entirely consistent with the fact that C-alkylation reactions of amides with styrenes are dependent on the strength of base employed, with strong sodium/potassium bases such as KHMDS, NaHMDS, KOtBu, KOtAm and KOH all giving successful reactions, while weak potassium bases KF, K 2 CO 3 and weak organic bases DABCO and DBU gave no reaction under the same conditions. 5 Under the previously reported conditions (ambient air/moisture), NaOtBu alone led to successful reaction of NMP but 18-crown-6 was required for successful reaction of DMA at 80°C. 5 In addition, 18-crown-6 appeared to increase reactivity of DMA and NMP in the presence of KOtBu (and NaOtBu). 5 These observations are consistent with other reports of C-alkylation of weakly-acidic compounds with styrene 4,9 showing the rateenhancing effects of 18-crown-6.
We elected to measure the kinetic profiles of reactions of NMP + styrene under different conditions (nature and equivalents of base, 18-crown-6 as an additive, use of ambient air/ moisture) by in situ NMR spectroscopy (Table 3). Under the standard (air-and moisture-free) conditions herein, the reac- KOtBu. The reaction was significantly retarded by preparing under ambient air/moisture with non-degassed and non-dried solvents (as supplied), such that 25°C was required to observe a similar rate constant to the reaction under standard conditions at 0°C (entry 4 vs. entry 1). In line with the observed KIE, these observations confirm the deprotonation steps in the reaction mechanism (e.g. Fig. 12, pathway A) do influence the overall kinetics of amide CAKES. While styrenes are known as common radical acceptors at the terminal position, 39 amide CAKES proceeded successfully in air and in the presence of TEMPO (1 eq.) as reported previously, 5 and no radical species were detected by EPR spectroscopy studies herein (see ESI †). The reaction rate was too fast to measure in the presence of 18-crown-6 (entry 5 vs. entry 1), confirming that 18-crown-6 promotes the reaction. Presumably, sequestering of potassium cation enhances the basicity of the tert-butoxide anion as is previously reported, 40 giving rise to a lower barrier for the transition state of deprotonation (Fig. 12, pathway B vs. A). Computationally, this was found to be the case (entry 5 vs. entry 1); ΔG ‡ deprot was negative (barrierless) and the combined relative energy of products (ΔG rel {Enolate}) was markedly lower for pathway B, even exothermic. Substitution of KOtBu with NaOtBu significantly retarded the reaction; the use of NaOtBu required 80°C to observe a comparable rate constant (Table 3, entry 6 vs. entry 1) consistent with a higher ΔG ‡ deprot . Promotion of the NaOtBu-mediated reaction by 18-crown-6 as disclosed previously 5 is rationalized by the reaction of the "naked" tert-butoxide anion with NMP and an 18-crown-6/Na + complex having a lower ΔG ‡ deprot (entry 7 vs. entry 6). That an exotherm was observed when KOtBu and 18-crown-6 were mixed in NMP (before styrene addition), but not in the case of NaOtBu, is consistent with ΔG rel values in pathway B. Alternative scenarios, like deprotonation of an 18-crown-6/M cation/NMP complex by "naked" tert-butoxide anion, or deprotonation of NMP by an 18-crown-6/MOtBu complex, were investigated computationally (see ESI †). Although such scenarios cannot be ruled out, the former could not account for the experimentally observed exotherm while the latter gave a T.S. too hindered to be computed. Rate enhancement in a mechanistic step following the initial deprotonation cannot be ruled out at this stage. While computation of a metal-ene-type T.S. involving co-ordination of 18-crown-6 was too sterically encumbered and led to dissociation, the reversibility of K + /Na + complexation by 18-crown-6 increases markedly in DMSO/amide-based solvents 41 such that solvated K + /Na + may still be available to construct the metal-ene-type T.S. A non-cyclic, open T.S. in which potassium cation is absent cannot be ruled out (see ESI † and later discussion on 4-alkylpyridine). Nonetheless, a strong argument can be made for rate acceleration via pathway B due to the observed KIE. It is possible that other rate-enhancing additives (LiCl/PMDTA) 31,42 used in these types of reactions function via a similar mechanism.
DMSO has been employed as a co-solvent in previous reports of C-alkylations with styrene, allowing the K-enolate precursor substrate loading to be lowered. 3,5,7 For the purposes of kinetic NMR studies herein, DMSO-d 6 was employed as a co-solvent. Therefore, we desired to probe the role of DMSO-d 6 . When reactions in DMSO-d 6 co-solvent were compared to reactions using the amide substrate (DMA or NMP) as solvent (quenched after a given time), we found higher product yields in the former case. 26,38 Elsewhere, it is known that solvation of  DFT calculations were performed 17-22 with details as in ESI. † a Experimentally-determined rate constant (s −1 ) for conversion of styrene. b Free energy ΔG rel or free energy barrier ΔG ‡ deprot relative to the initial starting materials for the deprotonation of styrene (e.g. amide + 2x styrene + KOtBu for entry 1), see ESI † for further details. c Rate constant determined by extrapolating an Arrhenius plot (see ESI † for details). d The reaction was prepared under ambient air/moisture with non-degassed and non-dried fresh reagents. e For purposes of computation, the 18-crown-6/M + complex as an innocent bystander and formation of the "naked" amide enolate from tert-butoxide anion and NMP were assumed (see ESI †). f Styrene was fully converted at 0°C before the first NMR scan (2 min); lower temperatures could not be employed due to reaction mixture freezing. Free energies given in kcal mol −1 .

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KOtBu in DMSO increases the basicity of the tert-butoxide anion. 43 Deuterated products were not observed in any reactions of non-deuterated DMA or NMP using DMSO-d 6 as solvent. Given the similar B/M selectivity with vs. without DMSO solvent (Fig. 11) and previous literature results that have used DMSO/NMP interchangeably, 3,5,7 there is no reason to suspect a role for DMSO/dimsyl anion 44 in the reaction mechanism beyond promoting base reactivity or stabilizing intermediates/T.S.es.

A general mechanism for C-alkylation with styrenes
Based on the fact that monoadduct and bisadduct products have been observed in other previously reported C-alkylation reactions, 3,4 we postulated that the previously-mentioned metal-ene-type mechanism may be a general pathway for this recently trending class of reaction and applied our computational model accordingly. The C-alkylation of cyclohexanone (25) with styrene reported by Knochel gave good selectivity for the monoadduct 26a (60% yield) and some bisadduct 26b (B/M = 0.15), 45 whereas the reaction of α-tetralone (27) gave monoadduct 28a (68% yield) and no bisadduct (28b) was reported. In order to confirm whether the bisadduct 28b was formed or not, the reaction of 27 was repeated. In our hands, the reaction gave 28a (85% yield) and 28b (11% yield) as determined by NMR analysis of the crude reaction products by comparison to an internal standard. Thus, a marginally higher selectivity for monoadduct 28a was observed in the reaction of α-tetralone (B/M = 0.13). 46 The reactions were then computed according to our model which successfully found metal-ene T.S.es for each reaction. In line with the B/M selectivity difference, α-tetralone gave both a more positive ΔΔG rel than 25 and a more positive ΔΔG ‡ deprot (Fig. 13). The free energy barriers for the first metal-ene T.S. (ΔG ‡ {M}) were almost identical for 25 and 27. That ΔG ‡ deprot {M} was more positive for 27 contrasted with the faster kinetics of 27, revealing a limitation in the current model which could not account for the known acidifying effect of the arene on the α-carbon of the ketone. 47 Overall, Fig. 11 Deuterium labelling experiments. Unless otherwise stated, yields were determined by 1 H NMR by comparison to 1,3,5-trimethoxybenzene (1.0 eq.) as an internal standard. Structures of deuterated products were established by MALDI and ESI-MS (see ESI †). a Abundances of partially-deuterated compounds 20a-d 8 and 20a-d 6 were determined relative to the ionization of 20a-d 9 at 100%. 36 b Reaction was deemed complete (<5% styrene) at this time. c KIE was determined based on the conversion of styrene over time and by comparison to 1,3,5-trimethoxybenzene (1.0 eq.) as an internal standard (see ESI †). d Following 1 h of reaction time at 0°C the reaction was allowed to warm to rt and product 20a-d 10 isolated after extended time (see ESI †). e Abundances of partially-deuterated compounds 20a-d 9 and 20a-d 7 were determined relative to the ionization of 20a-d 10 at 100%. 36  . This led Guan to propose an interaction between the pyridyl N atom and the catalyst (KHMDS) facilitated the catalytic C-H alkylation reaction. Herein, computation showed that the potassium cation interacted strongly with the pyridyl N atom as well as the π-system of styrene in the T.S. of the 2-methylpyridine (29) reaction. The consequence of this interaction was a more hindered T.S. in the case of the bisadduct formation. As expected, the ΔΔG rel for 2-methylpyridine reaction was more positive than that of the 4-methylpyridine reaction and accorded with the change in B/M selectivity (Fig. 14). This was reinforced by a more positive ΔΔG ‡ deprot in the 2-methylpyridine reaction. A substituted, cyclic 2-alkylpyridine (33) gave perfect monoadduct selectivity, 4 in accordance with decreased B/M selectivity observed for cyclic/substituted vs. acyclic/unsubstituted amides (such as DMA vs. NMP observed earlier) and in accordance with both its more positive ΔΔG rel and more positive ΔΔG ‡ deprot than 29. The reaction of 2-methylquinoline (35), which gave slightly lower B/M selectivity vs. 29, 4 had a marginally more positive ΔΔG rel value (despite a less positive ΔΔG ‡ deprot value). The reaction of monoadduct 30a gave exclusively 30b when compared to the reaction of 29, while the B/M selectivity in the reaction of monoadduct 32a decreased (but was not exclusive for 32b) compared to the reaction of 31. 4    ium cation is absent (is bound to the pyridine lone pair instead), hence the T.S. suffers a significantly higher free energy barrier ΔG ‡ . This can be seen when comparing ΔG ‡ or ΔG rel values in the reactions of 29 vs. 31, or 30a vs. 32a. While the heteroatom-stabilized metal-ene-type T.S. is favored, the open T.S. is accessible at high enough temperatures/with strong enough base. 48 A moderate primary KIE (2.7-3.3) was observed by Guan for this KHMDS-catalyzed reaction of alkylpyridines with styrene and it was concluded that the C-H cleavage step was the RDS. 4 However, since the reactivity therein similarly was influenced by the electronics of the styrene (this was also reported by Knochel 3 ) and since the moderate primary KIE is similar to that observed herein, it is postulated that the mechanistic picture for alkylpyridine CAKES reflects the scenario of NMP (19) herein: a reversible C-H cleavage step which influences the concentration of reacting alkylpotassium species and is subject to a KIE, followed by a higher energy, rate-determining metal-ene-type transition state. Based on the results of this study, we propose a general working mechanism for CAKES ( Fig. 15). Deprotonation of the enolate precursor by the potassium base proceeds via an equilibrium to generate a low concentration of K enolate. Although K enolates could not be observed previously 4 or herein by 1 H NMR, we tentatively propose their detection by UV-vis spectroscopy analysis of the colored reaction mixture (see ESI †). This deprotonation step is a minor contributor to the overall rate by controlling the available equilibrium concentration of K enolate and it can be influenced by the choice and loading of base as well as co-ordinating additives. The K enolate then undergoes addition to the styrene via a metalene reaction, which is the RDS (major contributor to the overall rate) and the turnover-limiting step. Deprotonation of the in situ-formed conjugate acid by the K benzylate is kinetically favoured, completing the CAKES catalytic cycle. The metal-ene-type reaction involving K enolates is in accordance with expectations from intramolecular magnesium-ene reactions of Grignard reagents (or those of alkyllithium or alkylzinc reagents) 49 first reported by Lehmkuhl 50 and popularized by Oppolzer 51 in the 1980s. To our knowledge, this study confirms the first example of a metal-ene-type reaction involving K enolates.

Conclusions
Base-catalyzed amide CAKES have been studied using a synergistic approach of computation and experimental kinetic studies. A mechanism proceeding through metal-ene-type transition states sufficiently explains experimental selectivity and reactivity (rate) differences when different styrene partners or different amide partners are used. The role of additives 18-crown-6 is rationalized. Computational barriers are accessible at the reaction temperatures employed and agree with rate constants obtained by kinetic data, thus corroborating a pathway proceeding through a benzylic alkylpotassium species. Notably, our mechanistic picture explains the experimental observations in other (ketone and alkylpyridine) CAKES, hence gathering all these reaction classes under the umbrella of a general reaction mechanism. We hope that this study might shed light on related reactivity 31,52 in this field. Further investigations are ongoing in our laboratory.

Conflicts of interest
There are no conflicts to declare.