TMSCF3-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism

As reported by Zhao, the TBAT ([Ph3SiF2]−[Bu4N]+)-initiated reaction of ethyl salicylate with TMSCF3 in THF generates α,α-difluoro-3-coumaranones via the corresponding O-silylated ethoxy ketals. The mechanism has been investigated by in situ 19F and 29Si NMR spectroscopy, CF2-trapping, competition, titration, and comparison of the kinetics with the 3-, 4-, 5-, and 6-fluoro ethyl salicylate analogues and their O-silylated derivatives. The process evolves in five distinct stages, each arising from a discrete array of anion speciations that modulate a sequence of silyl-transfer chain reactions. The deconvolution of coupled equilibria between salicylate, [CF3]−, and siliconate [Me3Si(CF3)2]− anions allowed the development of a kinetic model that accounts for the first three stages. The model provides valuable practical insights. For example, it explains how the initial concentrations of the TMSCF3 and salicylate and the location of electron-withdrawing salicylate ring substituents profoundly impact the overall viability of the process, how stoichiometric CF3H generation can be bypassed by using the O-silylated salicylate, and how the very slow liberation of the α,α-difluoro-3-coumaranone can be rapidly accelerated by evaporative or aqueous workup.


INTRODUCTION
1.1.Trifluoromethyltrimethylsilane.Since its introduction in 1984, TMSCF 3 (1) has been a reagent of choice for the addition of CF 3 to electrophiles. 1,2−6 The majority of the reactions of TMSCF 3 (1) require the addition of a silaphilic anion, and a growing body of evidence indicates that this liberates a transient trifluoromethylcarbanion(oid) "[CF 3 ] − " from the TMS group. 2,3Through kinetic and NMR spectroscopic studies, we recently established that reactions of TMSCF 3 initiated by [Ph 3 SiF 2 ] − [Bu 4 N] + ("TBAT"), a readily handled surrogate for "[F] − ", proceed via anionic chain reactions, Scheme 1. 3 In these reactions, the identity of the chain carrier, [Z] − , is determined by whether the [CF 3 ] − reacts with an electrophile, e.g., a ketone, Scheme 1a, a fluorophile, e.g., a TMS group, Scheme 1b, or an acid, e.g., an arene bearing suitably electronwithdrawing substituents, Scheme 1c.For an efficient process, the chain carrier, [Z] − , must be stable enough to be generated but also sufficiently silaphilic to react with TMSCF The identity of which of the step(s) governs the chain reaction velocity and thus the kinetic influence of [CF 3 ] − and [Z] − is highly substrate dependent.Consequently, the rate of the overall process is dictated by (i) the initiator concentration, [TBAT] 0 , (ii) the carrier speciation, i.e., the dynamic distribution of [CF 3 ] − and [Z] − , and (iii) the presence of endogenous or exogenous inhibitors, or chain terminators, that reduce the net carrier concentration [CF 3 + Z] − .Taken together, these factors can lead to unusual temporal− concentration profiles, including delayed or progressive rate accelerations.Thus, in the absence of kinetic insight into the species controlling the rate and evolution of the process, scaleup of reactions using TMSCF 3 (1) should be conducted with caution.

Synthesis of Difluoro-3-coumaranones.
There is a growing interest in annelation reactions proceeding via the formal insertion of CF 2 , 6 and in 2021, Zhao reported using TMSCF 3 (1) and TBAT in THF to convert salicylate esters (2 H ) into α,α-difluoro-3-coumaranones (4), Scheme 2. 5 As part of these developments, Zhao identified that the TMSCF 3 reagent (1) plays a "multifunctional role", 5 and that an Osilylated ethoxy ketal (3 TMS , Scheme 2) is an intermediate that accumulates before being converted into coumaranone (4).Zhao's method 5 provides a broad range of new α,α-difluoro compound 4 as prospective bioisosteres to the potent range of 3-coumaranones employed in drug discovery 7 and is thus of considerable interest.However, the complexity of the process evident from Zhao's preliminary investigations 5 warrants a more detailed analysis of the chain carrier speciation and sequence of steps that convert salicylates (2 H ) into coumaranones (4). 8erein, we report on the in situ 19 F and 29 Si NMR spectroscopic analysis of the TBAT-initiated reaction of ethyl salicylate (2a H , Scheme 2) and its 3-, 4-, 5-, and 6-fluoroarene analogues (2b−e H , Chart 1) with TMSCF 3 (1) in THF.While the study confirms several aspects of the prior mechanistic proposals, 5 it also elucidates and explains several anomalies, 8 as well as providing a general kinetic model for the absolute and relative rates of evolution of the ketals (3 TMS ) from the salicylates (2).The evolution of ketone 4 from ketal 3 TMS was found to vary extensively between experiments, and alternative methods to stimulate this process (3 TMS → 4) are also presented.

RESULTS AND DISCUSSION
2.1.Preliminary Observations.We began by identifying conditions under which the conversion of ethyl salicylates 2a− e H to coumaranones 4a−e could be effectively and safely monitored in situ by 19 F NMR spectroscopy. 9 This required several further adjustments to the preparative methodology reported by Zhao. 5 First, in addition to reducing the scale of the process from 5 to 0.5 mL, the concentration of the TBAT was reduced from 110 to 15 mM so that the full sequence of steps in the overall reaction could be analyzed in detail over a suitable time frame.Second, the concentration of the salicylate 2a−e H was reduced to avoid the development of hazardous overpressures of fluoroform (CF 3 H) in the sealed NMR tubes.
Single pulse 19 F NMR spectra, acquired at 15 s intervals after the addition of TBAT (0.075 equiv) to a solution of the parent salicylate 2a H (0.2 M) and TMSCF 3 (0.5 M) in THF, identified that the overall process evolves in five distinct stages, beginning with CF 3 H generation (stage I, Figure 1).The ketal, The Journal of Organic Chemistry 3a TMS , is generated in stage II in concert with trimethylsilyl fluoride, TMSF.This process diverges in stage III, with significant acceleration in the generation of TMSF and a cessation in ketal 3a TMS production.After a short period, TMSF generation then ceases abruptly, and the process enters stage IV.This sustained period of apparent stasis eventually leads to the conversion of ketal 3a TMS into ketone 4a in stage V.
Analogous behavior was found for the aryl-fluorinated salicylates (2b−e H , Chart 1) that were explored under these standard conditions ([1] 0 0.5 M; [2a−e H ] 0 0.2 M; and [TBAT] 0 0.015 M), but in some cases, the induction period (stage IV) lasted many hours, and in others there were competing side reactions in stages II and III, see Section 2.7.

Stage I:
Aryl O-Silylation.Fluoroform (CF 3 H) is generated immediately after the addition of TBAT to a mixture of TMSCF 3 + 2a H and before any significant accumulation of the ketal, 3a TMS .Quantitative 19 F NMR spectroscopy shows that the amount of CF 3 H generated corresponds to the initial concentration of the salicylate, i.e., [CF 3 H] Analysis of the fluorinated substrates (2b−e H ) identified that the salicylate is completely consumed in stage I to generate the corresponding aryl-O-silyl ether, 2b−e TMS .The analogous reaction of the sterically more hindered reagent TESCF 3 with 2e H proceeded slowly enough for the parallel evolution of equimolar CF 3 H and the aryl-O-triethylsilane (2e TES ) in stage I to be monitored by in situ 19 F NMR, see Section S4.2 in the Supporting Information.
The identities of the aryl-O-trimethylsilyl ethers, 2a−e TMS , were confirmed by independent synthesis, see Section S3.2 in the Supporting Information.Importantly, the silyl ethers undergo conversion to the corresponding ketals, 3a−e TMS , and ketones, 4a−e, when reacted with TMSCF 3 and TBAT.They do this without generating CF 3 H, thus bypassing stage I to directly enter stage II.A key observation in all the reactions, beginning from the phenolic (2a−e H ) or silylated (2a−e TMS ) forms of the salicylate, is that the 19 F NMR signals arising from fluoroaryl substituents on the silylated substrates (2b−e TMS ) undergo a progressive increase in line width and decrease in chemical shift during stages II and III. 19F NMR analysis of the titration of the 5-fluoroarene silyl ether 2d TMS with TBAT, in the absence of TMSCF 3 , shows that the process generates equimolar TMSF, salicylate anion, [2d] − , and Ph 3 SiF, see Section S3.4 in the Supporting Information. 10There is a significant line-broadening and progressive migration in the chemical shifts of all of the species, except the Ph 3 SiF, through the titration.
Overall, the data indicate that there is a dynamic equilibrium between the silyl ethers 2a−e TMS and their salicylate anions, [2a−e] − , with the rate, k 1 , and speciation, K 1 , dependent on the aryl ring substituents (H, F), the concentration of TMSCF 3 (1), and the total anion concentration, [TBAT] 0 , Scheme 3.
Under the standard conditions of the reaction, the exchange, k 1 and k −1 , between 2b−e TMS and [2b−e] − is fast enough to coalesce their 19 F NMR resonances into a broad time-averaged, concentration-weighted peak.At the start of the reaction, the speciation is dominated by 2 TMS , and as the reaction progresses and both 2b−e TMS and TMSCF 3 are consumed, the weighted chemical shift of the signal migrates upfield toward that of [2b−e] − , see Section S3.1 in the Supporting Information. 102.3.Stage II: Ketal 3 TMS Generation.Two distinct general pathways (A and B) can be envisaged for the process that converts 2a−e TMS to 3a−e TMS , Scheme 4. One begins by nucleophilic attack of the ester carbonyl in 2a−e TMS by [CF 3 ] − , followed by various silyl transfer(s) and intramolecular displacement(s). 11The second general pathway begins with equilibrium between the silyl ether 2a−e TMS and the salicylate anion, [2a−e] − (1/K 1 ), with the latter being trapped by CF 2 . 8he ester then undergoes intramolecular nucleophilic attack by [−OCF 2 ] − , and the resulting ketal oxy-anion [3a−e] − is silylated by TMSCF 3 .Both pathways require [CF 3 ] − and both pathways generate TMSF in a 1:1 ratio with ketal 3a−e TMS during stage II, Figure 1.
The pentacoordinate siliconate [5] − , Scheme 5, is a key indicator for trace concentrations of the carbanion(oid), [CF 3 ] − [Bu 4 N] + , in a medium containing TMSCF 3 (1).2c,d,3 The siliconate does not react directly with electrophiles but instead acts as a dynamic and dominant anion reservoir (K 2 ) to a metastable (k F and k C ) system. 3 The rates of reactions of carbonyl species with TMSCF 3 (1) [ are powerfully attenuated by this equilibrium and thus accelerate with conversion when Scheme 3. Stage I Silylation and Anionic Equilibrium, K 1 a a Equilibrium, K 1 , between silyl ethers 2a−e TMS and salicylate anions, [2a−e] − , is rapid relative to the 19 F NMR (376 MHz) time scale.Scheme 4. Potential Routes "A" and "B" from Silyl Ether 2a−e TMS to Ketal 3a−e TMS , in Stage II a a Various alternative related silyl transfer(s) and intramolecular displacement(s) can be envisaged for route A.

The Journal of Organic Chemistry
there is a substoichiometric TMSCF 3 reagent: [1] 0 /[carbonyl] 0 < 1. 3a Conversely, rate-limiting generation of CF 2 by reaction of [CF 3 ] − with TMSCF 3 (1), Scheme 5, is not significantly influenced by the siliconate equilibrium (K 2 ), due to the near-cancelation of the effects of [TMSCF 3 ] (1) concentration on the competing steps (K 2 , k F ). 3b However, both processes (K 2 and k F ) are sensitive to the steric hindrance of the silyl reagent.For example, using TESCF 3 leads to higher [CF 3 ] − concentrations (K 2 TMS /K 2 TES ≈ 20) and overall faster CF 3 -addition to carbonyl species, but slower generation of CF 2 . 3he above features inform tests to probe and distinguish the two general pathways of [CF 3 ] − addition (A) versus CF 2 addition (B), Scheme 4. The presence of [5] − , and by implication [CF 3 ] − , 3 was confirmed by the appearance of a broad signal at δ F ≈ −64.2 ppm 3 during stage II of the in situ 19 F NMR analysis of the conversion of silyl ether 2a TMS to ketal 3a TMS on cooling the sample to 275 K, see Section S1.4 in the Supporting Information.Moreover, on using TESCF 3 , the rate of generation of ketals 3c,d,e TES is strongly suppressed compared to identical conditions when employing TMSCF 3 (1), see Section S1.3 in the Supporting Information.These results weigh strongly against a mechanism in which the silyl ethers 2a−e R3Si undergo nucleophilic attack by [CF 3 ] − , i.e., pathway A in Scheme 4. 3a The addition of α-methyl-pfluorostyrene (6) to the reaction of preformed silyl ether 2a TMS resulted in no detectable attenuation in the rate of generation of ketal 3a TMS but did produce a small quantity of difluorocyclopropane 7, the product of the addition of the electrophilic carbene CF 2 to the alkene, 3b,12 Figure 2.
The majority of 7 is generated at the point of transition from stage II to III, when 2a TMS is near fully consumed and the concentration of salicylate [2] − becomes acutely reduced (K 1 , Scheme 3).This behavior is consistent with stage II proceeding via rate-limiting generation (k F ) of CF 2 , Scheme 5, and then rapid trapping (k O ) of this by the salicylate anion [2a] − to generate [3a] − (B), Scheme 4; 8,13 see Section 2.8 for discussion of the overall anion speciation and kinetics in stage II.
2.4.Stage III: Accelerating TMSF Generation.The primary process in stage III is the conversion of excess TMSCF 3 into TMSF and perfluoroalkenes, C n F 2n .The latter are evident from the broad and complex array of multiplets that accumulate in the in situ 19 F NMR spectra, see Section S1.3 in the Supporting Information.We have previously shown that the hierarchical growth of C n F 2n species in difluorocyclopropanation reactions 12 involving TMSCF 3 arises from a cascade of formal CF 2 oligomerizations initiated by addition (k C ) of [CF 3 ] − and elimination of fluoride, Scheme 5. 3b,d The process can be monitored by the accumulating TMSF coproduct, and in all previous cases, it has been found to undergo progressive deceleration due to anion sequestration in larger oligomers to generate perfluorocarbanions such as [C 11 F 23 ] − .2e,3b,d In stark contrast, during stage III of the reactions of TMSCF 3 (1) with salicylates, TMSF generation accelerates, and in some cases, profoundly, vide infra.The magnitude of the acceleration is dependent on the identity of the ketal 3 TMS , suggesting the latter can act as a surrogate fluoride acceptor (k SF ) to accelerate the overall conversion of TMSCF 3 into TMSF and C n F 2n , 14 Scheme 6.
The anionic chain reaction then propagates via resilylation of ketal oxy-anion The Journal of Organic Chemistry broadening of the diastereotopic fluorine atoms in the α,αdifluoro unit in 3e TMS during stage III and an accompanying contraction in their 19 F NMR chemical shift separation, see Section S5.1 in the Supporting Information, supports the conclusion that 3a−e TMS undergo rapid interconversion with traces of [3a−e] − .Kinetic modeling, see Section 2.9, shows that 3a−e TMS do not need to be better fluoride (k SF ) acceptors than TMSCF 3 (k F ) for there to be substantial acceleration in TMSF generation in stage III, provided that 3a−e TMS do not exergonically complex [CF 3 ] − to generate a siliconate (Scheme 5).2c,d,3 2.5.Stage IV: TMSCF 3 Depletion.After the vigorous TMSF evolution of stage III, the reaction enters a variable and sometimes prolonged period of near-stasis.During this, there is a slow but progressive reduction in the concentration of any remaining TMSCF 3 by several processes, including formal exchange with Ph 3 SiF (a coproduct from anionic initiation by TBAT, Scheme 1) to generate Ph 3 SiCF 3 and TMSF, see Section S1.3 in the Supporting Information.The behavior suggests that TMSCF 3 is a powerful inhibitor of the chain reaction that releases the coumaranone 4, vide infra, and must fall below a critical concentration for the transition from stage IV to stage V to occur.A variety of tests were conducted to support this conclusion; see Sections S7.1−3 in the Supporting Information.For example, briefly bubbling CO 2 gas through the NMR sample at stage IV rapidly converts residual TMSCF 3 into CF 3 CO 2 TMS/[CF 3 CO 2 ][Bu 4 N] + and stimulates the conversion of ketal 3 TMS to coumaranone 4. Removing the volatiles (CF 3 H, TMSF, THF, and TMSCF 3 ) in vacuo and then redissolving the residue in THF also elicits a transition to stage V. 15 2.6.Stage V: In Situ 29 Si NMR Analysis of the Liberation of Coumaranone 4 from Ketal 3 TMS .For many of the salicylates studied, the duration of the stage IV induction period can be so extensive that stage V is not reached, even after prolonged in situ NMR reaction monitoring.To study stage V, we thus employed salicylates 2a H and 2e H , which reliably liberate the corresponding coumaranones, 4a,e, in a reasonable time scale without requiring triggering by additives or physicochemical manipulations, vide supra.To determine the fate of the TMS group derived from ketal 3a TMS in its conversion to ketone 4a, we analyzed the full evolution of the reaction of 2a H by in situ 29 Si NMR spectroscopy, Figure 3.
The insensitivity and slow relaxation of the 29 Si nuclei required the process to be monitored at 285 K, with data acquired under a semiquantitative regime. 9Nonetheless, the temporal intensity profiles report on the mechanistic sequences of the process and correlate well with the general trends determined by quantitative in situ 19 F NMR spectroscopy.The Si NMR spectroscopic analysis, Figure 3, shows that, in contrast to Scheme 2, 8 the TMS is cleaved from ketal 3a TMS by ethoxide in stage V, with the chain reaction being initiated by elimination in anion [3a] − .If anion [3a] − , resulting from TMS cleavage in ketal 3a TMS , has sufficient lifetime to eliminate the ethoxide anion, then this will propagate the chain reaction and generate ketone 4a.Conversely, if [3a] − is resilylated (Scheme 6), the chain is terminated and the process remains at stage IV until the TMSCF 3 has been consumed, physically removed, or quenched in workup. 15.7.Influence of Electron-Withdrawing Aryl-Ring Substituents on Side Reactions.Salicylates 2c,d H/TMS undergo significant side reactions, as identified by in situ 19 F NMR spectroscopy, and these are associated with the nucleophilicity and basicity of the carbanion(oid) [CF 3 ] − , 2,3 Scheme 7.There is a nonlinear growth in the concentration of [CF 3 ] − through stages II and III, as modulated by the coupled equilibria, K 1 and K 2 , see Section 2.8.The position of the fluorine on the aryl ring in the salicylate substrate impacts not only the inherent propensity of intermediates 2c,d TMS and 3c,d TMS to undergo side reactions with [CF 3 ] − but also the [CF 3 ] − concentration, via K 1 , vide infra.
The carbonyl ester group is susceptible to nucleophilic attack by [CF 3 ] − , 16 as confirmed by in situ 19 F NMR spectroscopic analysis of the reaction of ethylbenzoate with TMSCF 3 + TBAT to generate the O-silylated CF 3 -addition product.However, the O-TMS group in silyl ethers 2a−e TMS appears to exert considerable steric shielding and electronic deactivation of the ester unit, with little evidence for CF 3addition in 2b,c,e TMS .An analogous deactivating effect is observed in methyl ether.For the case of silyl ether 2d TMS , however, the meta position of the electron-withdrawing fluorine substituent relative to the ester is sufficiently activating to induce the generation of moderate quantities of what was assigned as the O-silylated CF 3 -addition product 8d TMS , Scheme 7a, see Section S8.3 in the Supporting Information.Under the standard conditions, approximately 15% of 2d TMS is converted to 8d TMS during stage II. 17or salicylate 2c TMS , the dominant side reaction is again related to the dynamic concentration of [CF 3 ] − , but instead arises from aryl deprotonation-silylation of the ketal 3c TMS during stages II and III, see Section S8.1 in the Supporting Information.This general reaction class has been extensively Figure 3.In situ 29 Si NMR (INEPT) spectroscopic analysis of the conversion of salicylate 2a H into ketone 4a at 285 K.The data indicates that desilylation of ketal 3a TMS in stage V proceeds via an anionic chain reaction with [EtO] − as the carrier, with no further generation of TMSF. 8The 29 Si signal intensities have not been corrected for the differing effects of magnetization transfer (INEPT) or relaxation at the three sites, and the analysis is only semiquantitative.Analogous results were obtained on analysis of the reaction of salicylate 2e H at ambient temperature; see Section S7.3 in the Supporting Information.The identity of the EtOTMS coproduct was confirmed by synthesis from EtOH and 29 Si NMR (INEPT) analysis in THF.
The Journal of Organic Chemistry developed by Kondo 4 for a range of (hetero) arenes and requires suitably electron-withdrawing substituents to proceed on simple benzene ring systems.In the Zhao process, it becomes feasible in ketal 3c TMS because C(3)−H is located between two electron-withdrawing groups, C(4)−F and C(2)−OCF 2 , and is sufficiently C−H acidic to be deprotonated by [CF 3 ] − , to generate CF 3 H and a transient aryl anion.3c,d The latter is rapidly silylated by TMSCF 3 , thus propagating the chain reaction, 3c and under the standard conditions, >50% conversion of 3c TMS into 9c TMS has occurred by the end of stage III.On applying the standard workup, 4,15 the C(3)-TMS group in 9c TMS undergoes protonolysis, and ketone 4c is obtained.Thus, any Kondo-silylation 4 that occurs under Zhao's conditions 5 is 'traceless' in the absence of in situ analysis.By increasing the ratio [TMSCF 3 ] 0 /[2c TMS ] 0 to extend the duration of stage III, the conversion of 3c TMS into Ar-silylated 9c TMS was increased to >98%, and on addition of D 2 O, coumaranone 3-[ 2 H]-4c (>98% D) was generated, Scheme 7b, see Section S8.2 in the Supporting Information.A series of approximations can be applied to derive the relationship between the concentrations of the reaction components, i.e., the three major anions (

Anion Speciation and Rates of Conversion of
), and the substrate [2 TMS ] t , with the dynamic concentration of [CF 3 ] − , as determined by the coupled equilibria, K 1 and K 2 , Scheme 9.
Because siliconate generation (K 2 ) is exergonic, the preequilibrium and steady state approximations can be combined and simplified to eq 1, when Σ SR ≈ 0 and f ≈ 1; see Section S11.3 in the Supporting Information for a full derivation Equation indicates that lower phenolate stability (larger K 1 ), higher reagent concentration ([1] 2 ), and lower silyl ether concentration ([2 TMS ]) all increase the rate of CF 2 generation in stage II toward a rate maximum of (k F [TBAT] 0 /K 2 ), i.e., kinetic saturation.Two of the salicylates (2b,e TMS ) cleanly convert to the ketals 3b,e TMS in near-parallel with TMSF generation, indicative that Σ SR ≈ 0 and f ≈ 1. 18 These features allow eq 1 to be tested experimentally, as shown in Figure 4, across a variety of initial conditions.
Inclusion of an additional term in eq 1 for CF 2 generation by transfer of fluoride from [CF 3 ] − to 2b,e TMS (analogous to k SF for 3 TMS in Scheme 6) attenuated the correlation in Figure 4, indicative that TMSCF 3 is the dominant (>95%) acceptor (k F , Scheme 8) in stage II.The kinetic approximation shown in eq 1 was then further explored in the analysis of the relative rates of conversion of pairs of salicylates (i and ii) into their ketals (3 TMS ) in stage II, eqs 2 and 3; see Section S11.3 in the Supporting Information for full derivation Scheme 7. Side Reactions Arising from Nucleophilicity (a) and Basicity (b) of the Carbanion(oid) [CF 3 ] −a a Inset in (b) shows the generation of CF 3 H and an aryl anion(oid).The latter is rapidly silylated to give 9c TMS .The deuterium incorporation 3-[ 2 H]-4c/4c was estimated as 65/1 by 19 F NMR spectroscopy, see Section S8.2 in the Supporting Information., where, 2 The relative rates (k rel (i), (ii)) are compared under the two regimes.In the first, the initial rates of independent reactions were estimated under otherwise identical conditions, eq 2, and the substrate with the electron-withdrawing F-substituent closer to the phenolic position (lower K 1 , eq 2) was found to react slower, 2b TMS and 2c TMS , Chart 2. Conversely, when the relative rates of reactions were estimated in competition reactions, eq 3, the substrates with the electron-withdrawing Fsubstituent closer to the phenolic position (lower K 1 , eq 3) were found to react faster, 2b TMS and 2c TMS , Chart 2.
The relative rates, Chart 2, are opposite in independent versus competition reactions, as modulated by the K 1 values of the substrates, eqs 2 and 3, but are qualitatively inverted.This arises from the additional effects of the concentrations ([1], [2 TMS ]) and thus the values for r on the relative absolute rates, eq 2, and the effects of relative efficiencies of carbene trapping (k O ) by the salicylate anions, [2] − , eq 3, on the competitive rates.The overall kinetic behavior of stage II, eqs 1−3 is thus consistent with the rate-limiting generation (k F ) of the singlet carbene CF 2 , and its rapid trapping (k O ) by salicylate anions, [2] − , as modulated by the coupled equilibria K 1 and K 2 (Schemes 8 and 9).
2.9.Overarching Reaction Network for Stages I−V in the Anion-Initiated Conversion of Salicylates (2 H ) to Coumaranones (4) by TMSCF 3 .Having elucidated the dominant anion-speciations, and the interconnecting equilibria and reactions that govern the net conversion of ethyl salicylates 2a−e H into the corresponding coumaranones (4a−e), 5 an overarching, albeit simplified, reaction network can be proposed, for the reactions of ethyl salicylates 2 H in general, Figure 5.After initiation by TBAT (stage I), there are two productive anion-chain processes that convert 2 H → 4.These proceed via two discrete kinetic regimes (2 H → [2] − → [3] − → 3 TMS , in stage II; then 3 TMS → 4, in stage V).These are separated by stage III, which consumes the majority of the remaining TMSCF 3 (1), and stage IV, during which the TMSCF 3 (1) concentration falls low enough to allow ethoxide elimination from anion [3] − and the onset of the chain reaction that releases the coumaranone 4 in stage V. Progression through the five stages leads to the complex temporal evolution of the overall process, Figure 1.

Kinetic Simulations of Stages I−III.
Considerable effort was made to analyze and simulate the kinetics of the overall process. 9A key issue is the complexity of stage IV and its transition to sigmoidal growth of ketone 4 in stage V, neither of which was found to be experimentally reproducible.We thus focused on the generation of a model for kinetic simulation of stages I−III that responds with reasonable fidelity to experimental data obtained at various initial concentrations of TMSCF 3 ([1] 0 ), salicylate ([2e H ] 0 ), silyl ether ([2e TMS ] 0 ), and [TBAT] 0 .The final model and an example of its application to an experimental dataset are shown in Figure 6.For further examples and discussion of this and other models, see Section S11.1 in the Supporting Information.As the concentration of the salicylate 2 TMS decays, the concentration of [CF 3 ] − rises (K 1 ), leading to a surge in surrogate fluoride acceptance by 3 TMS , k SF , and the system transitions from stage II to stage III.
Chart 2. Examples of Relative Rates (k rel ) of Conversion of 2 TMS to 3 TMS , Evaluated Independently and in Competition a a For the factors controlling k rel , see eqs 2 and 3.
The Journal of Organic Chemistry been investigated by in situ 19 F/ 29 Si NMR spectroscopy and analysis of the absolute and relative kinetics as a function of concentrations and identities of reactants and reagents.The process is found to evolve in five stages, as shown in Figure 1.Each stage has a discrete speciation of anions (Figure 5) that modulates the required sequence of silyl-transfer chain reactions. 8The distinction of the five stages allows four important practical conclusions to be drawn about the inherent behavior of different salicylate esters, 2 H , and how conditions can be selected to favor their effective and efficient conversion to the corresponding α,α-difluoro-3-coumaranones, 4.
(1) Stage I necessarily consumes 1 equiv of TMSCF 3 (1) and can be bypassed by directly employing silyl ether, 2 TMS , which is readily prepared from salicylate 2 H using TMSCl, see Section S12 in the Supporting Information.
Starting at stage II allows the reaction to be safely run at much higher concentrations without risk of overpressure arising from the evolution of 1 equiv of the greenhouse gas CF 3 H. (2) The two key productive steps are the rate-limiting generation of the singlet carbene CF 2 in stage II and the desilylation of ketal 3e TMS by [EtO] − in stage V, and these have opposing requirements in terms of concen-tration of TMSCF 3 (1).The kinetic dependencies in stage II, eq 1, mean that the generation of ketal 3 TMS is disproportionately accelerated by high reagent (1) and low substrate (2 TMS ) concentrations.Reactions run at scale may thus benefit from the slow addition of 2 TMS to  The Journal of Organic Chemistry TMSCF 3 (1) in stage II, at a rate that holds concentrations of the two components in ratios for which the system is most productive.
(3) Electron withdrawing groups, e.g., fluorine, on the aryl ring of 2 TMS not only inherently inhibit stage II (K 1 , Scheme 3) but also accelerate side reactions such as nucleophilic attack at the ester in 2 TMS and Kondo silylation 4 of the aromatic ring in 3 TMS (Scheme 7).These substrates benefit from being run with a significantly raised TMSCF 3 (1) concentration, not only to accelerate the conversion of 2 TMS to 3 TMS but also to suppress (K 2 , Scheme 5) 3 the concentration of [CF 3 ] − and thus attenuate undesired side reactions.
(4) TMSCF 3 (1) is rapidly but unproductively consumed in stage III by conversion to C n F 2n + TMSF, 14 a process that is accelerated by ketal 3a TMS .The presence of even low concentrations of TMSCF 3 (1) powerfully inhibits stage V, leading in some cases, to the system remaining for a prolonged period at stage IV.Aqueous quenching of the reaction at the onset of stage III bypasses stages IV and V, leading to rapid hydrolysis of ketal 3a TMS .Alternatively, excess TMSCF 3 (1) can be removed in vacuo or by distillation, and residual anion is then allowed to mediate the chain-reaction that converts ketal 3a TMS into ketone 4 + EtOTMS under anhydrous conditions. 15
While CF 3 H is soluble in THF, in our experience, it begins to evolve from solution at concentrations above 0.3 M. The use of sealed reaction vessels or employing salicylate 2 H at concentrations in excess of 0.3 M can therefore lead to hazardous overpressures or spontaneous gaseous eruptions on opening the vessel.The initiation step is also considerably exothermic, and the use of the readily prepared silyl ether, 2 TMS , instead of the phenolic form 2 H is advisible.The anionic chain processes inherently generate superstoichiometric TMSF (bp 19 °C), and with some substrates, the rate of TMSF generation in stage III accelerates considerably, potentially leading to uncontrolled exothermic events.Reactions involving anionic initiation of TMSCF 3 (1) invariably cogenerate a complex range of perfluoroalkenes, C n F 2n , some of which are volatile and toxic. 19For all of the above reasons, caution should be exercised in the use of these processes, especially on scale-up.

Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.lation of 3 TMS before conversion to 4, are supported by the data reported herein.However, the overall sequence for these is inconsistent with both the stoichiometry and the temporal evolution of the coproducts reported in preliminary in situ 19 F NMR studies of the reaction of isobutyl salicylate at an unreported temperature. 5For example, 3a TMS would need to be liberated in concert with CF 3 H, and 3a TMS converted to 4a by cogenerating TMSF.Moreover, anion inventory, i.e., where Σ anions = [TBAT] 0 , of the proposed sequence, 5 shows that stoichiometric TBAT would be required to fully convert 2a

The Journal of Organic Chemistry
3 to regenerate [CF 3 ] − and propagate the chain.Examples of efficient chain carriers are [Z] − = [RO] − , [F] − , and [R] − .Conversely, if [Z] − does not react efficiently with TMSCF 3 , for kinetic or thermodynamic reasons, the chain is terminated, and a stoichiometric initiator will be required.Examples of this are for [Z] − = [Cl] − or [RS] − .
Figure6.Numerical methods kinetic simulation 9 of a simplified model for stages I−III in the conversion of salicylate 2e H into ketal 3e with acceleration on transition from stage II to stage III as salicylate 2e TMS becomes depleted.Data from in situ19 F NMR (376 MHz)