Regioselective, catalytic 1,1-difluorination of enynes

Fluorinated small molecules are prevalent across the functional small-molecule spectrum, but the scarcity of naturally occurring sources creates an opportunity for creative endeavour in developing routes to access these important materials. Iodine(I)/iodine(III) catalysis has proven to be particularly well-suited to this task, enabling abundant alkene substrates to be readily intercepted by in situ-generated λ3-iodanes and processed to high-value (di)fluorinated products. These organocatalysis paradigms often emulate metal-based processes by engaging the π bond and, in the case of styrenes, facilitating fluorinative phenonium-ion rearrangements to generate difluoromethylene units. Here we demonstrate that enynes are competent proxies for styrenes, thereby mitigating the recurrent need for aryl substituents, and enabling highly versatile homopropargylic difluorides to be generated in an operationally simple manner. The scope of the method is disclosed, together with application in target synthesis (>30 examples, up to >90% yield).

The synergistic interplay of precision synthesis 1,2 and functional smallmolecule design 3 continues to be a major driver of innovation in both disciplines.In the vanguard of enabling technologies, fluorination has a venerable history in tailoring the physiochemical traits of promising active pharmaceutical ingredients (APIs), and the societal impact of Fried's seminal work on fluorinated steroids is a compelling exemplar 4 .Function-driven synthesis thus continues to provide a powerful incentive to expand the current methodological arsenal under the auspices of atom and step efficiency 5 .In particular, the success of the geminaldifluoromethylene group in leading pharmaceuticals has stimulated much interest in the development of main group catalysis-based strategies to facilitate installation from readily available precursors [6][7][8] .
The prominence of fluorination patterns in contemporary drug discovery [9][10][11][12][13][14] disguises the comparative scarcity of naturally occurring organofluorines in marine and terrestrial environments 15,16 .Although more than 5,000 halogen-containing natural products have been described so far 17,18 , and fluorine sources are accessible, it is manifest that nature has not been compelled to evolved fluorine biochemistry to any substantial degree 19,20 .This fluorous juxtaposition between natural and synthetic functional small molecules continues to provide opportunities for the conception and development of new molecular entities with geometries and physiochemistries that are not encountered in biology [21][22][23] , and it logically follows that this continues to expand the chemical space available for function-driven synthesis.A compelling exemplar is the bond-angle distortion that results from CH 2 to CF 2 replacement 24 , which renders the difluoromethylene group a validated bioisostere of oxygen in phosphate mimics 25,26 .This motif is finding increasing application in the small-molecule drug repertoire, with prominent examples including lubiprostone (Amitiza), tafluprost (Taflotan) and various 5-HT1D agonists (Fig. 1a) 27 .Motivated by the demand for new fluorinated modules for medicinal chemistry 12,14 , and cognizant of the emergent importance of alkyne-containing APIs such as efavirenz (Estiva) and levonorgestrel (PlanB One-Step), it was envisaged that a route to homopropargylic difluorides would address a gap in the discovery portfolio: this would provide isosteric surrogates of propargylic ethers and alcohols in which the electronegativity of the fluorine atoms would emulate the non-bonding electron pairs 28 .

Article
https://doi.org/10.1038/s41557-023-01344-5 A catalytic cycle was conceived based on the in situ generation of an ArIF 2 species, via a process of ligand exchange, that would promote an alkene-activation and fluorination sequence.Should the key rearrangement be successful, then the product cation would benefit from fluorine as a stabilizing auxiliary 49 .This would provide a facile route to homopropargylic difluorides, in which the alkyne handle would facilitate downstream functionalization.

Results and discussion
To validate the working hypothesis delineated in Fig. 1c, enyne S1 was prepared and exposed to catalysis conditions using various inexpensive aryl iodides, oxidants and HF sources (Table 1).Initially, p-TolI was combined with Selectfluor and amine•HF (1:7 ratio) in chloroform at ambient temperature.This enabled the desired homopropargylic fluoride 1 to be generated in 88% yield.Importantly, the vicinal regioisomer was not formed under these conditions, as determined by 19 F NMR (<5%).However, in the absence of the catalyst, the vicinal difluoride was formed in 13% yield.A screen of electronically modulated catalysts confirmed the superiority of p-TolI, and revealed the following trend: p-Me > p-H > p-CO 2 Me > p-OMe.Modifying the amine:HF ratio or the oxidant were found to have a detrimental effect on the reaction outcome (Table 1).
Having identified optimized conditions for the title reaction, the scope and limitations of the transformation were investigated.In the course of this process, reactivity differences were noted in response to subtle changes in the amine:HF ratio.This is in line with early observations related to the impact of trifluoroacetic acid on the reactivity of iodobenzene dichloride 50 .For that purpose, a gradient of amine:HF ratios was considered starting from 1:4.5 and increasing to 1:7.0 (denoted A-F).For simplicity, only the most effective conditions are indicated in Table 2. Initially, the impact of modifying the capping aryl group was investigated while keeping the alkene substituent constant (R = Me).This enabled a series of gem-difluorides to be generated, and demonstrated functional-group compatibility with electron-withdrawing groups, halogens and small alkyl fragments (1-10, up to 83%).In the case of product 2, it was possible to rigorously establish the molecular connectivity by single-crystal X-ray diffraction (Table 2; CCDC 2256836).Gratifyingly, the method also proved to be compatible with medicinally relevant heterocycles such as pyridines, quinolines and morpholines (11-13, up to 56%).Furthermore, it was possible to replace R = Me with R = CH 2 X (X = Br and Cl) to create linchpins that could be functionalized at the proximal C(sp 3 ) position (15 and 16, up to 91%).Finally, the compatibility of the method with more complex natural-product-derived scaffolds was validated (17-19).
To advance the scope of the transformation beyond aryl-substituted enynes, aliphatic derivatives were then explored with a view to applying the method to target synthesis (Table 3).Simple alkyl and cycloalkyl derivatives were tolerated (20 and 21, up to 63%) and it was possible to introduce functionality in the form of phthalimides (22, 50%) and ethers (23, 71%).Substrates with potentially challenging benzylic/propargylic positions such as 24 were smoothly converted to the desired product.The transformation was found to be chemoselective for the enyne versus cinnamoyl motifs (25, 64%), and alkynoic esters (26, 63%), tosylates (27, 56%) and alcohols (28, 41%) were compatible.Modifying the alkyl substituent was possible (29,  30) and enabled the 1,2,2-trifluoro motif to be generated in a facile manner.The introduction of more complex heterocycles, such as in febuxostat (Adenuric) derivative 32, is an encouraging validation of the method in a drug-discovery setting.With a view to accessing the parent motif derived from the unsubstituted enyne, the triisopropylsilyl (TIPS)-acetylene 33 was prepared in 67% yield.
To demonstrate the synthetic utility of this geminal difluorination of enynes, two representative experiments were validated on a 4.0 mmol scale (Fig. 2a), and a series of product derivatization reactions were conducted (Fig. 2b).Initially, alkyne 20 was fully and partially reduced 51 to the alkane and alkene products 34 and 35, respectively.To demonstrate the value of the homopropargylic fluorides in hetero cycle formation, compound 4 was converted to the quinoxaline 36 through Ru-catalysed oxidation of the alkyne and concomitant condensation with 1,2-phenylendiamine 52,53 .Desilylation of compound 33 with tetrabutylammonium fluoride (TBAF) furnished the terminal alkyne 37 in 85% yield: this could then be processed further to triazole 38 via a copper-catalysed click reaction 54 .In situ deprotection of 33 and subsequent Sonogashira cross-coupling proved facile, enabling the electron-rich aryl alkyne 39 to be generated in 64% yield.Because electron-rich enynes undergo uncatalysed side reactions with the Selectfluor 55 , this approach enables the geminal difluorination products to be generated by an alternative route.Finally, the compatibility of the motif under Suzuki-Miyaura conditions was demonstrated through the generation of compound 40 (93% yield) 56 .
A concise route to the CF 2 -modified palmitic acid 44 was conceived to validate the method in target synthesis (Fig. 2c).Initially reported by O'Hagan and co-workers in the context of a wider study of the conformational preferences of palmitic acids and nonadecane containing CF 2 groups 57 , this molecule remains a benchmark in difluorination method development 58 .With the aim of complementing the existing reagent-based approaches, enyne 41 was exposed to the catalytic geminal-difluorination conditions: this furnished the key intermediate 42 in 51% yield.Chemoselective reduction of the alkyne and saponification of the methyl ester enabled the desired compound 44 to be generated in 98% yield over two steps.
Finally, control reactions were performed to establish that deletion of the alkyl substituent was tolerated (Fig. 3).Interest in the difluoromethyl group as a surrogate of primary alcohols 28 renders such products appealing in the wider context of molecular design on account of their hydrogen-donor character 59 .Pleasingly, both the aryl-and alkyl-substituted enynes 45 and 47 could be processed to their Standard reaction conditions: enyne S1 (0.1 mmol), catalyst (20 mol%), amine•HF 1:7.0 (0.25 ml), CHCl 3 (0.25 ml) and Selectfluor (0.15 mmol).Yields were determined by 19 F NMR using ethyl fluoroacetate as an internal standard.a meta-Chloroperoxybenzoic.b Amine•HF ratio changed to 1:7.5.
The isolation of compound 50 as the sole product of the reaction (40% yield) is consistent with the 1,2-shift out-competing phenonium-ion rearrangement.The skeletal rearrangement that is central to the working hypothesis was supported by deuterium labelling to generate 29-d (56%, 76% D incorporation; Fig. 3c).

Conclusions
The direct, geminal difluorination of alkenes under the auspices of hypervalent iodine catalysis remains a powerful paradigm to expand organofluorine chemical space for contemporary drug discovery.In situ-generated λ 3 -iodanes regulate regiocontrol by inducing C(sp 3 )-F bond-forming/rearrangement sequences with exquisite efficiency: the latter step is conditional on substrates that are predisposed to undergo a phenonium-ion rearrangement.To circumvent this limitation, enynes have been validated as competent substrates that deliver the desired 1,1-selectivity, where the phenonium-ion rearrangement can be replaced by a formal 1,2-shift of the alkyne.Computational support for the tentative mechanism outlined in Fig. 1 is available in Supplementary section 1.7.Utilizing the alkyne as a phenyl proxy, it has been possible to achieve the title reaction and deliver homopropargylic difluorides that are highly amenable to downstream functionalization.A broad substrate scope is demonstrated (>30 examples) together with selected derivatization protocols, as well as a short, catalysis-based synthesis of CF 2 -modified palmitic acid.
It is envisaged that this enabling method will find application in the conception of new drug-discovery modules.
c Amine:HF = 1:5.0.d Amine:HF = 1:4.5.e19 F NMR yield using ethyl fluoroacetate as an internal standard.23% of the vicinal difluorination product was formed due to an uncatalysed background reaction (details are provided in Supplementary section 1.3).f Reaction performed on a 0.10 mmol scale.g Thermal ellipsoids are shown at 50% probability.Care should be exercised during isolation due to the volatility of many of the products.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.

Fig. 1 |
Fig. 1 | Development of a catalytic gem-difluorination of enynes.a, Bioisostere design and examples of bioactive molecules containing a CF 2 or alkyne moiety.b, Hypervalent iodine-catalysed gem-difluorination of alkenes and the phenonium-ion rearrangement.c, Reaction blueprint to enable catalysis-based fluorinative alkyne-migration.The electron-rich alkyne is envisaged to be a competent proxy for phenyl, enabling the phenonium-ion rearrangement to be replaced by a formal 1,2-alkynyl shift via a stabilized vinyl cation.
crystal structure of compound 2 g

Fig. 3 |
Fig. 3 | Control experiments.a, Removal of the alkyl group.Enynes 45 and 47 could be converted to 46 and 48, containing the difluoromethyl group, respectively.b, Investigation of regioselectivity.Compound 50 was obtained as the sole product.c, Deuterium labelling experiment.Deuterium atom incorporated exclusively at the propargylic position, unambiguously demonstrating that 1,2-alkynyl migration took place.Isolated yields are given.

Table 3 | Expanding the scope to alkyl and silyl alkynes
19nthesis of CF 2 -modified palmitic acid.Isolated yields are given.19FNMRyieldsare given in parentheses and determined by19F NMR using ethyl fluoroacetate as an internal standard.