Aryl (β,β′,β″-Trifluoro)-tert-butyl: A Candidate Motif for the Discovery of Bioactives

The (β,β′,β″-trifluoro)-tert-butyl (TFTB) group has received very little attention in the literature. This work presents a direct synthesis of this group and explores its properties. The TFTB group arises when the methyl groups of a tert-butyl moiety are exchanged for fluoromethyl groups. Sequential fluoromethylations result in a decrease of Log P (increasing hydrophilicity), ultimately by 1.7 Log P units in the TFTB group relative to that of tert-butyl benzene itself. A focus is placed on synthetic transformations, conformational analysis, and metabolism of the TFTB group in the context of presenting a favorable profile as a motif for the discovery of bioactives.

T he selective fluorination of aromatic rings has a tendency to increase their lipophilicity.This phenomenon has been widely articulated for aryl−F or aryl−CF 3 fluorinations, and it is an important concept in medicinal chemistry. 1However, the opposite effect is found when aliphatics are selectively fluorinated, and this concept is perhaps less widely embedded in the culture of the discovery of bioactives. 1,2This concept has been explored across a range of structural motifs, and we have explored the phenomenon in the context of partially fluorinated cyclohexanes. 3In this Letter, a focus is placed on selective fluorination of the aryl tert-butyl group.The tert-butyl group is a ubiquitous motif in organic chemistry; however, its high lipophilicity mitigates against its wide utility in medicinal chemistry. 4For example, only a handful of the top 200 selling drugs of 2021 contain a tert-butyl group.Examples are ventolin (salbutamol), 5 ivacaftor formulations, 6 bupropion formulations (e.g., Wellbutrin), 7 and timolol formulations (e.g., Combigan). 8The lipophilicity of the tert-butyl group exposes any drug candidate to the pharmacokinetic challenges associated with increasing Log P (low solubility, membrane and albumin association, increased metabolism, etc.). 9The tert-butyl group is represented more widely in agrochemical products where higher lipophilicities are tolerated to a greater extent (e.g., chromafenozide (Matric), isouron, and tebufloquin). 10Recognizing that fluorinations of aliphatic motifs can decrease Log P, it became an objective to explore selective fluorinations of the tert-butyl group, specifically replacing the methyl substituents with fluoromethyl groups, anticipating Log P reductions.Only two papers have been reported 11,12 in the literature regarding this (β,β′,β″-trifluoro)-tert-butyl substituent (TFTB), and these are confined exclusively to amine 5 as a building block; the most recent report 11 was over two decades ago.These papers outline different synthetic approaches to amine 5, as summarized in Scheme 1.
In the first route, 12 β,β′,β″-tribromopivalic acid 1 was converted to the corresponding trifluoroacyl fluoride 3 to enable a Curtius rearrangement to amine 5.The free base was then progressed to fluoroquinolone 6, as one of a range of variants exploring antibiotic structure−activity relationships.A more convoluted route to amine 5 was reported a decade later. 11Although not an obvious improvement, it avoided "the distillation of labile fluorinated pivaloyl fluorides and isocyanates".Amine 5 is the only TFTB building block reported so far, and no particular properties of the TFTB motif were described.We report a synthesis of the aryl-TFTB motif for the first time.A conformational analysis is explored, and Log P comparisons are made, measured progressively from the tert-butyl group through mono-, di-, and tri-fluoromethyl substituents.Given the current concern regarding persistent organofluorine compounds, 13 metabolism of the aryl-TFTB substituent is also explored.
A direct synthetic approach to the TFTB motif was envisaged through the formal deoxyfluorination of an appropriate precursor triol such as 16, and the route that developed is summarized in Scheme 2. Intermediate triol 16 was prepared via a Cannizzaro-type reaction on phenylacetaldehyde 15 as previously reported, 14 and then the triol was activated to tritosylate 17.These reactions proved straightforward, and 17 could be readily purified by recrystallization.
Optimization of the trifluorination reaction of 17 to 18 was explored with both cesium (CsF) and potassium (KF) fluorides and with polar aprotic solvents (DMF and DMSO), as summarized in Table 1.KF was not suitable even with 18crown-6, and in the event the most efficient transformations were achieved with CsF in DMSO at 120 °C, which showed a modest improvement over DMF.TBAF addition improved the DMF reaction; however, there was no particular advantage in TBAF addition to DMSO.Lower temperatures led to more sluggish reactions.
The route was adapted too to the para-bromoaryl substitution such that acetaldehyde 19 was progressed to aryl bromide 22, which was explored for cross-coupling reactions 15,16 to generate products 23−35, as summarized in Scheme 3.
An X-ray structure of Suzuki product 29 was determined, as illustrated in Figure 1.This gave the first insight into the preferred conformation of the aryl-TFTB motif.
The structure indicates a preference for each of the C−F bonds to lie approximately on an xyz-axis relative to each other in a propeller arrangement, essentially with each fluorine atom Scheme 1.Previous Routes to the TFTB Motif in Amine 5 12,11 Scheme 2. Synthesis of (β,β′,β″-Trifluoro)-tert-butyl Benzenes 18 and 22  The conformational space for the aryl-TFTB substituent was explored using a Grimme's iterative workflow approach with static metadynamics simulations as implemented in CREST software 17 for the parent compound 18.The global minimum was used to explore the energetic minima and maxima along the full rotation coordinate of one C−CH 2 F bond, and each stationary point was optimized at the M06-2X/def2-TZVP theory level. 18Thermal corrections were obtained from frequency calculations at standard temperatures and pressures and also at the M06-2X/def2-TZVP level.
The rotational energy profile in Figure 2a illustrates that there are three eclipsing barriers, the highest of which has ΔG ‡ = 6.5 kcal mol −1 .The TFTB motif conformation from the global minimum C is similar to that observed from the X-rayderived crystal structure of 29, showing good agreement between experimental and calculated C−F•••HC contact distances (Figure 2b).Given the calculated relative Gibbs free energies between the minima A-C it is estimated that conformer C will dominate (96%) while conformers A (1%) and B (3%) will be minor contributors.The tendency toward a clearly preferred conformer reflects favorably on the potential of the TFTB substituent in the discovery of bioactives.
It was of interest too to explore the effects of fluorination on Log P. To this end.Log P values were evaluated experimentally for phenyl derivative 18 by reverse-phase HPLC (MeCN/ water, C 18 column) 3 and compared with those of the corresponding aryl tert-butyls 36 and 37 with two and one fluoromethyl groups, respectively, and also relative to tert-butyl benzene 38.The outcomes are summarized in Figure 4.
The replacement of one methyl of tert-butylbenzene 38 for a fluoromethyl group in 37 results in significant decrease of Log    Figure 4. Log P and molecular dipole values for progressively fluorinated tert-butylbenzenes determined by reverse-phase HPLC. 3 P, in this case by an order of magnitude (ΔLog P = 1.07), as illustrated in Figure 4. Log P reductions in changing −CH 3 to −CH 2 F in molecular matched pairs are well-known, 21 and there is good evidence that the effect is supported significantly by an increase in overall molecular dipole moment.21b Exchange of the second and third methyl groups for fluoromethyls in 36 and 18, respectively, continues the trend toward increasing hydrophilicity (lower Log P), although notably there is no longer a consistent increase in the molecular dipole moment.The difluoro analogue 36 is more polar again (μ = 2.3 D calculated for its minimum energy conformation; see Figure S10); however, the aryl-TFTB 18 becomes less polar as the individual C−F dipoles cancel each other, and there are compensating electrostatic interactions between the coaligned C−F and C−H bonds as discussed above.Nonetheless, 18 has the lowest Log P value and is the most hydrophilic of the series, presumably because there are six geminal and polarized hydrogens that can make electrostatic interactions with water.Solubility was not addressed comprehensively here; however, the TFTB-biphenyl ether 23 was soluble (11 mg mL −1 ) in water than its corresponding tert-butyl analog (6 mg mL −1 ) [see SI].
There is a growing concern regarding persistent fluorochemicals, 13 and it is becoming increasingly important that any new motifs that contain fluorine should be able to metabolize. 22To this end we have explored the metabolism of both tertbutylbenzene 38 as a control and then 18 in cultures of Cunninghamella elegans, a fungus that has been used to model human metabolism, as it is rich in P-450 activity. 23Aliquots of 38 and 18 were subject to incubations with C. elegans under previously established protocols (see the SI).After up to three days of incubation, the fungal culture supernatants were extracted into ethyl acetate.tert-Butylbenzene 38 was completely metabolized after three days.Aryl-TFTB 18 was more slowly, but significantly, metabolized (∼60%), and the organofluorine metabolite profile was assessed by 19 F NMR and GC-MS.The major metabolite was determined to be alcohol 41, the identity of which was confirmed by independent synthesis (see the SI).Alcohol 41 could clearly arise after P-450 hydroxylation of a fluoromethyl group to generate 39 and then collapse to aldehyde 40, with HF elimination followed by biocatalytic reduction, as illustrated in Scheme 4. Consistent with this hypothesis, a metabolite with the mass of aldehyde 40 was identified as a minor metabolite by GC-MS (Figure S3).This study indicates that the TFTB motif is amenable to metabolism and should not present a persistence concern.
Finally, a synthesis of an aryl-TFTB analog 49 of the tertbutyl containing pesticide pyridaben 50 24 was demonstrated and is illustrated in Scheme 5. Pyridaben is among the most widely used acaricides globally.24b One objective in developing this route was to establish a protocol to benzyl bromide 47, as this offers an intermediate for the more general introduction of the aryl-TFTB motif.Several approaches were explored for the benzylic bromination of 46, and the most efficient conditions used the method previously described by Golding et al. 25 Benzyl bromide 47 was then combined with thiol 48 to generate 49.
In conclusion, we present an amenable route to the aryl (β,β′,β″-trifluoro)-tert-butyl (TFTB) motif and explore Pdcross coupling reactions on bromoaryl derivatives.An analogue 49 of the pesticide pyridaben 50 is prepared to exemplify an additional approach to incorporating TFTB through benzyl bromide 47.X-ray structure analysis and DFT computation indicate that the aryl tert-(β,β′,β″-trifluoro)butyl (TFTB) substituent is found to have a favored conformation, which is dictated by electrostatic repulsion between the fluorines and also stabilized by compensating electrostatic interactions between polarised C−F and C−H bonds hydrogen.The progressive switch of methyl for fluoromethyl groups in going from tert-butylbenzene 38 to the analogous TFTB benzene 18 resulted in over an order of magnitude reduction in Log P. In addition, it is demonstrated that the aryl-TFTB group is significantly metabolized in cultures of C. elegans and will not be a persistent organofluorine.Collectively, these aspects should be attractive for the exploration of the aryl-TFTB motif more widely in the discovery of bioactives.

Figure 1 .
Figure 1.X-ray structure of 29 showing a propeller arrangement of the aryl-TFTB motif and a graphic illustrating attractive CH•••FC interactions.
The parallel alignment of C−F and C−H bonds in C results in a total of four CF•••HC electrostatic contacts, each accounting for −8.9 kcal mol −1 of electrostatic stabilization as calculated by the classic Coulomb equation using NPA-derived atomic charges from NBO analysis. 19Upon rotation of the C−CH 2 F bond, repulsive contacts from the alignment of C−F bonds start to emerge in conformers A and B and lead to electrostatically destabilizing CF•••FC interactions of +10.0 kcal mol −1 in each contact.Non-covalent interaction analysis (NCI) 20 also reveals the attractive and repulsive nature of the CF•••HC and CF•••FC interactions, respectively, as illustrated in Figure 3.In the CF••• HC contact, the region characterized by sin(λ 2 )ρ ∼ −0.015 au indicates the presence of an attractive interaction between F and H atoms, which are weaker in conformer A than in C, as indicated by the higher values of the reduced density gradient (s) for the CF•••HC contact in A. On the other hand, the CF••• FC contact is characterized by a region of sin(λ 2 )ρ ∼ +0.025 au, which indicates the presence of repulsive interactions between F atoms.In conformer A, the reduced density gradient approaches zero for the CF•••FC contact, indicating stronger repulsive interactions compared to those in conformer C. Overall, NCI analysis is in accordance with NBO and reinforces the importance of the electrostatic CF•••HC and CF•••FC interactions in determining the conformational equilibria between A, B, and C.

Figure 2 .
Figure 2. (a) Calculated rotational energy profile of 18 rotating around one of the C−CH 2 F bonds.(b) Comparison of C−F•••H− C contact distances (Å) between the calculated structure for 18 and the X-ray derived structure of the analogue 29.(c) Thermodynamic parameters calculated for minima and maxima of the rotational energy profile in panel a in kcal mol −1 ; minima are labeled from A to C in decreasing relative energies.Calculations were carried out at the M06-2X/def2-TZVP theoretical level.17,18

17
Figure 2. (a) Calculated rotational energy profile of 18 rotating around one of the C−CH 2 F bonds.(b) Comparison of C−F•••H− C contact distances (Å) between the calculated structure for 18 and the X-ray derived structure of the analogue 29.(c) Thermodynamic parameters calculated for minima and maxima of the rotational energy profile in panel a in kcal mol −1 ; minima are labeled from A to C in decreasing relative energies.Calculations were carried out at the M06-2X/def2-TZVP theoretical level.17,18 Figure 2. (a) Calculated rotational energy profile of 18 rotating around one of the C−CH 2 F bonds.(b) Comparison of C−F•••H− C contact distances (Å) between the calculated structure for 18 and the X-ray derived structure of the analogue 29.(c) Thermodynamic parameters calculated for minima and maxima of the rotational energy profile in panel a in kcal mol −1 ; minima are labeled from A to C in decreasing relative energies.Calculations were carried out at the M06-2X/def2-TZVP theoretical level.17,18