Stereoselective Synthesis of Fluoroalkanes via FLP Mediated Monoselective C─F Activation of Geminal Difluoroalkanes

Abstract

A method of desymmetrization of geminal difluoroalkanes using frustrated Lewis pair (FLP) mediated monoselective C–F activation where a chiral sulfide is the Lewis base component is reported. The stereoselective reaction provides generally high yields of diastereomeric sulfonium salts with dr of up to 95:5. The distribution of diastereomers is found to be thermodynamically controlled via facile sulfide exchange. The use of enantiopure chiral sulfides allows for high stereospecificity in nucleophilic substitution reactions and the formation of stereoenriched products.

Introduction

Fluorocarbons are exceedingly rare in biology.^[1] Nonetheless, fluorine has had a significant impact on modern biological systems through synthetic compounds.^[2] Importantly, fluorine and fluorine containing groups act as bioisosteres, allowing simple access to chemical antagonists and agonists. Fluorine (or a fluorine containing group) is known to emulate hydrogen, alkyl, hydroxyl, and amide groups (inter alia).^[2] In a biological context, apart from chemical isostericity, stereochemistry is intrinsically important to the design of effective antagonists/agonists. Thus, it is surprising that methods for stereoselective installation of fluorine into organic molecules are belatedly undeveloped.^[3]

Methods that generate chiral centers at C─F positions rely upon the stereoselective introduction of fluorine via proton substitution with electrophilic fluorine, stereoselective addition of nucleophilic fluoride (commonly across unsaturated bonds), or stereoselective elaborations of monofluorides (Figure 1A). Stereoselective fluorination often suffers from the need to use toxic/hazardous fluorine sources, to employ starting materials with either acidic hydrogen positions (normally subtended by electron withdrawing groups) or starting materials with unsaturated bonds (across that HF can add), and a high incompatibility of electrophilic fluorine with many functional groups, while stereoselective elaborations are generally restricted to hydro- or bromo-functionalization at α-fluorocarbonyl positions.^[3a] Notably, despite the synthesis of benzyl fluorides being routine,^[4] the stereoselective generation of enantioenriched benzyl fluorides remains challenging.^[5]

Figure 1. A) Examples of current methods to access chiral C─F centers. B) We have shown that FLP mediated monoselective C─F activation can generate racemic fluorocarbon products. We propose the use of chiral Lewis bases to generate diastereomeric products in a stereoselective manner.

As part of our contribution to the field of Lewis acid mediated C─F bond activatrion,^[6] we previously reported frustrated Lewis pair (FLP) mediated monoselective activation of gem-difluoromethyl groups generating chiral carbon centers in racemic mixtures.^[7] The stereoselective functionalization of an enantiotopic fluorine allows access to a wide variety of enantio and/or diastereo enriched products from a common precursor (Figure 1B).^[8]

Previously, stereoselective FLP catalysis has been largely restricted to reductions of imines, ketones, and enones, and it has focused on employing a chiral Lewis acid to impart stereoselectivity to products.^[9] Generally, because the FLP base partners used in the activation of the reducing agent are (or compete with) the achiral substrates.^[10] In contrast, FLP mediated C─F bond activation relies upon capture of the activated fragment by a suitable Lewis base, and the substrates do not commonly act as FLP components. As such, we saw an opportunity to utilize affordable, stable, and easily accessible (or commercially available) chiral sulfide Lewis bases to induce stereoselectivity. Such an approach is a departure from pre-existing approaches to FLP enantioselective catalysis and represents the first example of FLP stereoselective activation of C─F bonds.

Results and Discussion

To provide proof-of-principle for this concept, we utilized the enantiopure base (R,R)−2,5-dimethylthiolane (A)^[11] with previously reported catalytic conditions.^[7b] Application of such conditions to 1-Br-2-(CF₂H)-C₆H₄ (1a) resulted in diastereomeric products 2a-[A] with distinct ¹⁹F NMR signals at δ_F −173.5 (d, ²J_HF = 45.6 Hz) and −152.2 (q, ³J_HF = 46.5 Hz) in 83% yield and a diastereomeric ratio (dr) of 40:60 after 2 h. The reaction was monitored over 6 days to determine the change in yield and dr. After 24 h the reaction yield had improved to 98% and the dr had improved to 30:70. The dr continued to increase to 15:85 after 6 days, with the product still present in 98% (Figure 2).

Figure 2. FLP mediated monoselective C─F activation of 1a utilizing the enantiopure thiolane A as the Lewis base partner. The dr of the reaction improves from q = 1.5 (2 h) to q = 5.7 (144 h).

With the aid of theoretical analysis, we sought to understand how diastereoselectivity arose so we might improve upon our initial results. DFT calculations for the C─F activation event in substrate 1a suggested an S_N1 pathway proceeding via a common benzylium intermediate, similar to the calculated activation profile using tetrahydrothiophene (THT) as a base partner (see Figure S143, Supporting Information).^[12] It was calculated that the addition of sulfide A to this intermediate was barrierless, precluding the likelihood that differential kinetic barriers existed capable of giving rise to the observed dr in our products.

Indeed, a thermodynamic equilibrium is suggested by the improvement in dr over time in Figure 2, and evidence for facile exchange of A leading to a thermodynamic product distribution was also obtained via reaction of A with preformed 2a-[THT] (Figure 3). Addition of 2.5 equivalents of A to a solution of 2a-[THT] resulted in the slow formation of 2a-[A] with the ratio of 2a-[THT] to 2a-[A] being 1:1.3 after 36 h with 2a-[A] having a dr of 15:85 (see Figure S50, Supporting Information).

Figure 3. Generation of 2a-[A] from 2a-[THT] demonstrating facile exchange of sulfide nucleofuges and establishing that stereoselectivity is induced via a thermodynamic equilibrium between diastereomers.

In silico, carbocation [2a]⁺ was found to remain kinetically accessible at only 22.5–24.8 kcal mol⁻¹ above the most stable diastereomer conformers of 2a-[A] (Figure 4). An S_N2 isomerization pathway was located with a higher barrier (as compared to the S_N1 pathway) of 25.7–28.0 kcal mol⁻¹ above 2a-[A], suggesting that dr arises from a thermodynamic equilibrium that operates via an S_N1 isomerization pathway. Indeed, the addition of excessive A failed to improve the rate of isomerization between diastereomers but instead promoted the isomerization of A from its (R,R) isomer into a meso form, giving rise to a new enantiomeric product 2a-[A_meso].

Figure 4. Calculated SN1 and SN2 pathways for isomerization of the C─F chiral center in 2a from R to S configuration.

With this knowledge in-hand, we proceeded to optimize the reaction. We found that gentle heating at 40 ˚C and increasing the reaction concentration from 0.12 to 0.60 mm (Table 1, entry 2) generated 2a-[A] in 98% with a dr of 85:15 after only 24 h (cf. 6 days, Figure 2), demonstrating practical access to stereoenriched monofluorides via FLP mediated C─F bond activation. Continued heating for 48 h only improved the dr to 86:14 indicating that the equilibrium point of the reaction was likely approached. Under this assumption, a lower experimental estimate of ΔG⁰ = 1.1 kcal mol⁻¹ can be derived between the two epimers of 2a-[A] (cf. ΔG⁰ = 2.3 kcal mol⁻¹, computationally derived value).

Table 1 Exploration of yield and diastereoselectivity for the stereoselective C─F activation reaction using sulfides A-D with substrates 1a-b. Yields based on ¹⁹F NMR analysis.

[IMAGE OMITTED. SEE PDF.]
entry	R group	chiral sulfide	temp	conc. [mm]	time
					2 h	24 h
1	Br (1a)	A	25 °C	0.12	83% dr 60:40	98% dr 70:30
2	Br (1a)	A	40 °C	0.60	-	99% dr 85:15
3	Br (1a)	B	25 °C	0.12	70% dr 52:48	-
4	Br (1a)	B	40 °C	0.60	-	54% dr 57:43
5	Br (1a)	C	25 °C	0.12	0%	-
6	Br (1a)	D	25 °C	0.12	0%	-
7	H (1b)	A	25 °C	0.12	98% dr 52:48	98% dr 55:45
8	H (1b)	A	40 °C	0.60	-	99% dr 62:38
9	H (1b)	B	25 °C	0.12	72% dr 52:48	-
10	H (1b)	C	25 °C	0.12	27% dr 62:38	0%
11	H (1b)	D	25 °C	0.12	21% dr 73:27	0%

Testing the related thiolane B^[13] with 1a failed to improve upon the yield or selectivity observed using sulfide A, while employing thiolane C^[14] and sulfide D^[15] led to no desired products. However, it was found that selective activation of PhCF₂H (1b) with C and D led to products 2b-[C] and 2b-[D] in low yield but improved dr as compared to that observed in 2b-[A]. These products proved much less stable than 2b-[A], precluding the generic use of C and D for practical syntheses.

Overall, it was deemed that Lewis base A gave the best combination of high yield and diastereoselectivity. As such, A was utilized to explore substrate scope (Figure 5). Compounds 2-[A] could be generated in moderate to high yield from difluorides 1. 1,1-diflouoromethylaryl substrates that feature substituents in the 2-position gave very good stereoselectivity, with all examples (except 2f-[A]) demonstrating dr of greater than 75:25, with 2g-[A] having a dr of 95:5 (albeit with a reduced yield of 39%).

Figure 5. Scope of stereoselective C─F activation reaction. a) [Al(C6F5)3•C7H8] and PhCl used in place of B(C6F5)3 and DCM. b) Run at r.t. for 2 h. c) 10 mol.% B(C6F5)3 used. See Supporting Information for crystallographic details for structures of 2h-[B] and 2x-[B]. Yields based on 19F NMR analysis.

Internal difluorides (i.e., difluoromethylene) in benzylic positions {2o-[A] – 2s-[A]} were also found to give moderate to good stereoselectivity, with 2q-[A] generated in 86% yield with a dr of 80:20. Difluoromethoxy groups demonstrated moderate stereoselectivity, despite the absence of any ortho substituents in products 2t-[A] and 2u-[A], while other non-benzylic supports tested (silyl, sulfide, alkyl) gave poor selectivity. This can be attributed to less stabilized carbocation intermediates raising the kinetic barrier for isomerization. This was exemplified by 2x-[A] and 2x-[B] that could only be generated in a dr of 50:50.

Pleasingly, we were able to isolate compounds 2a-[A], 2c-[B], 2h-[A], 2h-[B], 2i-[A], 2i-[B], 2x-[A], and 2x-[B] in 59–88% yield (see Supporting Information). Molecular structures for single diastereomers of 2h-[B] and 2x-[B] showed that the substitution of enantiotopic fluorides with the chiral sulfide B had indeed led to the formation of chiral centers at the C─F position (Figure 5). Further, crystallisation of 2i-[B] led to a single diastereomer (see Figure S16, Supporting Information). It was found that the isolated diastereomer slowly isomerized in solution (over hours) to give the original mixture of two diastereomers, suggesting an S_N1 isomerization process. The isolation of 2i-[B] provides proof-of-principle for chiral resolution of sulfonium salts 2-[SR₂*].

Given that A is an enantiopure base, products 2-[A] represent epimers and optically enriched products can be generated with the stereospecific transfer of the chiral fluorocarbon fragment. This was demonstrated by the reaction of enantiopure amine (S)-N,N-dimethyl-1-phenylethylamine (N_S) with 2-[A] to generate epimeric products 2-[N_S] in high diastereospecificity (Figure 6). For example, addition of N_S to a solution of 2a-[A] resulted in the formation of 2a-[N_S] in 91% yield with a diastereospecificity (ds) of 100%. Similarly, ds for products 2c-[N_S], 2e-[N_S], 2h-[N_S], 2i-[N_S], and 2u-[N_S] were all over 96%. A control reaction of N_S with racemic 2a-[THT] resulted in 2a-[N_S] with a dr of 50:50, precluding diastereoselective induction through exchange of N_S (additionally, the barrier for exchange of N_S was found to be kinetically inaccessible, see Pages S37–S39, Supporting Information). (Figure 6)

Figure 6. Transfer of fluorocarbon fragment to enantiopure chiral amine NS with high stereospecificity. Yields based on 19F NMR analysis. Isolated yields in brackets. See Supporting Information for reaction conditions.

High enantiospecificity (es) of the S_N2 transfer also allowed for the generation of enantioenriched products (Figure 7). For example, the reaction of 2a-[A] with [NⁿBu₄][SCN] resulted in 2a-[SCN] in 88% isolated yield with an enantiomeric ratio (er) of 85:15 (ee 70%) and es of 100%. Similarly, 2a-[OBz] was generated in 76% isolated yield with er of 83:17 and 2a-[Pth] was generated in 41% isolated yield with er of 78:22. Importantly, enantioenriched benzylfluorides in the absence of α-carbonyls are difficult to generate using existing synthetic technologies.^[3,5]

Figure 7. A) Generation of enantioenriched products via stereospecific reaction of 2a-[A] with achiral nucleophiles. B) Access to an enantioenriched fluoro-analog of benzyltriazole motifs present in current and potential pharmaceuticals.[12] Absolute configuration determination revealed the product 2a-[Trz] to be the R-enantiomer. C) Hydrodebromination of 2a-[OBz] to give 2b-[OBz]. See SI for reaction conditions.

Further functionalization possibilities were also demonstrated by installing an azide group to generate 2a-[N₃], which could then be employed in a copper catalyzed azide-alkyne cycloaddition (CuAAC) to generate 2a-[Trz] in 55% yield with er of 83:17 (Figure 7B). Absolute configuration of 2a-[Trz] revealed the product to be the R-enantiomer, in agreement with an inversion of the (calculated) thermodynamically preferred epimer 2a^R-[A] (Figure 4). 2a-[Trz] represents an enantioenriched fluoro-analog of benzyltriazole motifs that are present in current and potential pharmaceuticals.^[16]

Lastly, the superior stereoselectivity in 1,1-difluoromethylarene substrates with ortho substituents presents an opportunity for further functionalization. For example, the removal of silyl and halo groups is prevalent in the literature (i.e. hydrodesilylation and hydrodehalogenation) and allows for traceless enhanced stereoselectivity.^[17] The veracity of such an approach was demonstrated through the hydrodebromination of 2a-[OBz] in 40% generating 2b-[OBz] with an er or 78:22 (Figure 7C).

Conclusion

In summary, we have shown that chiral Lewis bases can be utilized to induce stereoselectivity in the FLP selective C─F activation of geminal difluorides (1). The sulfonium products, 2-[SR₂*], exhibit moderate to good diastereoselectivity (up to dr 95:5 for 2g-[A]) that arises from facile isomerization of 2-[SR₂*] via a calculated S_N1 pathway. As such, substrates that prevent the facile exchange of sulfide and substrates that do not sterically impede the bound sulfide (e.g., benzyl groups without ortho substituents) give limited stereoselectivity. The use of enantiopure chiral Lewis bases allows for the transfer of the chiral fluorocarbon fragment with high stereospecificity leading to diastereo and enantioenriched products that are difficult to generate using current stereoselective methodologies.

Acknowledgements

The authors thank the Singapore Agency for Science, Technology and Research (A*STAR grant No. M21K2c0111) and the Australian Research Council (FT220100738) for funding.

Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians.

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.