Letter Cite This: Org. Lett. 2018, 20, 8073−8076
pubs.acs.org/OrgLett
Catalytic Geminal Difluorination of Styrenes for the Construction of Fluorine-rich Bioisosteres Felix Scheidt, Jessica Neufeld,† Michael Schäfer,† Christian Thiehoff,† and Ryan Gilmour* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany
Org. Lett. 2018.20:8073-8076. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 12/21/18. For personal use only.
S Supporting Information *
ABSTRACT: A geminal difluorination of alkenes based on I(I)/I(III) catalysis is disclosed, which is compatible with a range of electronically and substitutionally diverse styrenes (27 examples, up to 89% yield). Employing inexpensive p-TolI as the organocatalyst, turnover is enabled by Selectfluor-mediated oxidation to generate the ArIF2 species in situ. Extension to include α-substituted styrenes bearing fluorine-containing groups is disclosed and provides an expansive platform for the generation of fluorine-rich architectures. of the fluorine atoms to emulate the oxygen lone pairs, while rendering the methane proton acidic and a competent hydrogen bond donor.7 This alcohol surrogate is resistant to oxidation, and 1,1-fluorination renders the immediate locality lipophilic.8 Consequently, efforts to achieve the direct, geminal difluorination of π-bonds under catalyst control have been intensively pursued.9 Hypervalent iodine reagents and I(I)/I(III) catalysis manifolds where the λ3-iodane species is generated in situ10 are synonymous with the development of this direct, programmed alkene oxidation.10−16 However, since regioselection to bias geminal (1,1-) in favor of vicinal (1,2-) difluorination17 is conditional on efficient phenonium ion rearrangement, electron-deficient styrenes often prove recalcitrant (Scheme 1). Herein, we report a broadly applicable, catalytic difluorination of styrenes to address this limitation and illustrate the utility of the method in constructing fluorine-rich architectures. Since Hara and Yoneda’s seminal report that internal alkenes undergo facile, fluorinative ring contraction to generate the geminal difluoromethyl group when exposed to Et3N·5HF and stoichiometric amounts of p-TolIF2,11 a plenum of methods have been reported to construct this privileged motif (Scheme 2). These include stoichiometric geminal difluorination of electron-rich styrenes employing an analog of the Togni reagent,12 and catalytic processes that are compatible with electron-rich substrates.13 A catalytic, asymmetric 1,1-difluorination of alkenes to generate difluoromethylated stereocenters from β-substituted styrenes using a chiral resorcinol-based
F
luorine introduction is inimitable in developing structural algorithms that encode for bespoke properties in small molecule drug discovery.1 Juxtaposing the scarcity of fluorinated organic molecules in nature2 and their abundance in the pharmaceutical and agrochemical sectors are therefore instructive.1,3 The high electronegativity of fluorine coupled with its minimal steric demand constitute the basis of structural mimesis whereby seemingly innocent substitution of C−H(δ+) by C−F(δ−) allows for localized partial charge inversion.4 The introduction of specific fluorination patterns, often translates into striking electronic and conformational behaviors that can be harnessed to tailor the pharmacokinetic and dynamic profiles of small molecule drug candidates.5 A logical consequence has been the establishment of fluorine-containing bioisosteres for metabolically vulnerable sites.6 A pertinent example is the replacement of the OH group by the 1,1-difluoromethyl motif (Scheme 1). This simultaneously harnesses the electronegativity Scheme 1. 1,1-Difluorination of Styrenes
Received: November 27, 2018 Published: December 11, 2018 © 2018 American Chemical Society
8073
DOI: 10.1021/acs.orglett.8b03794 Org. Lett. 2018, 20, 8073−8076
Letter
Organic Letters
effect of reaction medium on efficiency (entries 1−6). Halogenated solvents proved to be most effective with chloroform slightly outperforming DCE and DCM (entries 1−3). Switching to acetonitrile or toluene proved highly detrimental to the reaction (entries 4 and 5). Consequently, the remainder of the study was conducted with CHCl3. A screen of common oxidants (see Supporting Information (SI) for full details) confirmed Selectfluor as being optimal. While hydrogen peroxide, sodium hypochlorite, and Oxone proved ineffective, Selectfluor and m-CPBA yielded the desired geminal difluoride in 61% and 51% yield, respectively (entries 3 and 6). However, in contrast to Selectfluor, reactions with m-CPBA generated byproducts that could be identified as the fluorohydrin18 and the vicinal difluorinated product.17e This translates to a drastic reduction in the regioselectivity from >20:1 (gem:vic) when employing Selectfluor, to 2:1 with m-CPBA. To investigate the effect of Brønsted acidity, the amine/HF ratio was adjusted (entries 7−9). In the case of amine/HF 1:4.5, no geminal difluorination product was observed by 19F NMR spectroscopy (entry 7). Instead, the vicinal difluoride was formed exclusively.17e While improved regioselectivity was observed when employing an amine/HF ratio of 1:7.5, the desired geminal difluoride was only formed in 13% yield (entry 8). Having demonstrated that a ratio of 1:9.23 is optimal for catalysis, the catalyst loading was reduced to 10 mol % with no detrimental effect on efficiency (entry 9). Finally, the control reaction in the absence of p-TolI did not yield product thereby indicating that catalysis is operative (entry 10). Having established general catalysis conditions (Table 1, entry 9), the scope and limitations of the reaction were probed. Initially, electron-deficient styrenes were investigated due to the limited number of methods available (Scheme 3). Gratifyingly, a range of substrates bearing electron withdrawing groups in the para or meta positions were smoothly transformed to the corresponding 1,1-difluorinated products (vide inf ra). Both para- and meta-nitrostyrenes proved to be viable substrates for the transformation delivering 2a and 2b in 61% and 58% yield, respectively. Similarly, para- and meta-cyanostyrenes were smoothly converted to products 2c (41%) and 2d (44%), as were the para- and meta-methylsulfonylstyrenes (54% and 53% for 2e and 2f, respectively). Gratifyingly, all three triflate regioisomers (m-, p-, and o-OTf, respectively) could be converted to the corresponding geminal difluorinated products in good to high yields (2g, 2h, and 2i, 80%, 81%, and 52% yield, respectively). Interestingly, the bis-triflimide group was also tolerant of the reaction conditions, and 2j was isolated in 57% yield. Trifluoromethyl ketones are also viable substrates allowing 2k and 2l to be generated in 59% and 57% yield, respectively. To validate the catalytic difluorination conditions with electronically diverse substrates, a range of substituted styrenes was investigated (Scheme 4). For the most part, these comparatively electron-rich substrates could be smoothly converted to the difluorinated products using an amine/HF ratio of 1:4.5. Both the m-Br and p-Cl products 4a and 4b were generated smoothly (46% and 50%, respectively). In comparison to the acetylated vinylaniline, which proved to be tolerant of the conditions delivering 4c in 35% yield, the more electron-deficient phthalimide derivative performed better (4d, 47%). The 4nitrobiphenyl system was transformed to the desired product 4e in 50% yield. In a demonstration of chemoselectivity, compound 4f was produced (47%) where only the electron-rich alkene undergoes oxidation. Since α-substituted styrenes are com-
Scheme 2. Strategies for the 1,1-Difluorination of Styrenes
catalyst has also been reported.14 Furthermore, geminal difluorination of phenylallenes can be achieved using stoichiometric amounts of p-TolIF2 under Lewis acidic conditions,15 and the difluorination of alkenyl N-methyliminodiacetyl boronates can be achieved.16 Often, catalysis is predicated on generating p-TolIF2 in situ via m-CPBA mediated oxidation of p-TolI in the presence of a Pyr· (HF)x source. To complement these methods, catalysis conditions were sought that would be compatible with a broad spectrum of electronically diverse styrenes, and mitigate the possibility of fluorohydrin formation resulting from m-CPBA/ HF mixtures.18 It was envisaged that in situ generation of pTolIF2 via oxidation of p-TolI using Selectfluor in the presence of an amine·HF complex would be a logical starting point for catalysis development.17c−e,19−21 The conversion of p-nitrostyrene (1a) to 2a was selected as a model reaction for optimization using p-TolI (20 mol %), Selectfluor (1.5 equiv), and Pyr·(HF)x (amine/HF, 1:9.23) (Table 1). Initially, a solvent screen was conducted to assess the Table 1. Reaction Optimizationa
entry
solvent
amine/HF ratio
conversionb (%)
yieldc (%)
1 2 3 4 5 6d 7 8 9e 10f
DCE DCM CHCl3 MeCN toluene CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
1:9.23 1:9.23 1:9.23 1:9.23 1:9.23 1:9.23 1:4.5 1:7.5 1:9.23 1:9.23
>95 >95 >95 >95 >95 >95 87 >95 >95 20
57 51 61 (61) 8 11 51
