Catalytic, Enantioselective 1,2-Difluorination of Cinnamamides

Abstract

We report the enantio- and diastereoselective synthesis of 1,2-difluorides via chiral aryl iodide-catalyzed difluorination of cinnamamides. The method uses HF-pyridine as a fluoride source and mCPBA as a stoichiometric oxidant to turn over catalyst, and affords compounds containing vicinal, fluoride-bearing stereocenters. Selectivity for 1,2-difluorination versus a rearrangement pathway resulting in 1,1-difluorination is enforced through anchimeric assistance from a N-tert-butyl amide substituent.

Graphical Abstract

The stereocontrolled introduction of fluorine atoms into organic molecules is a long-standing challenge in synthetic chemistry driven, to a significant extent, by the beneficial properties fluorination can impart to the physical and biological properties of organic molecules.¹ Due to their known preference for adopting gauche conformations, vicinal difluorides represent a particularly interesting subset of organofluorine compounds.² The direct, enantioselective 1,2-difluorination of alkenes represents a most appealing approach to this class of compounds, but no general methods have yet been identified for accomplishing such a transformation.³ Reported examples of enantiocontrolled synthesis of vicinal difluorides most often involve deoxyfluorination of 1,2-fluoroalcohols derived from stereodefined epoxides or diols.⁴ However, these reactions are prone to competitive elimination pathways and are often low-yielding.⁵ New methods for direct, enantioselective vicinal difluorination could enable a more thorough exploration of the gauche effect on molecular structure and function.

There has been remarkable progress over the past decade in the development of enantioselective alkene difunctionalization reactions using hypervalent iodine reagents and catalysts.⁶ In that context, the Gilmour lab and our group recently developed catalytic variants of the alkene 1,2-difluorination first reported by Hara.^3n,6g-h Our system engaged HF-pyridine as a nucleophilic fluoride source and meta-chloroperbenzoic acid (mCPBA) as the stoichiometric oxidant,⁷ and included a single example of an enantioselective variant in the 1,2-difluorination of trisubstituted cinnamamide 2q catalyzed by chiral aryl iodide 1b (Scheme 1).⁸ However, in subsequent work, we found that the scope of that reaction was severely limited due to competing rearrangement pathways. Here we address that selectivity challenge through a systematic study of the factors influencing product distribution, leading to the development of a protocol for the highly chemo- and enantioselective 1,2-difluorination of trisubstituted cinnamamide substrates. These reactions provide versatile synthetic building blocks bearing contiguous secondary and tertiary fluorine-bearing stereocenters. Concurrent with our efforts, Gilmour and coworkers reported a complementary method for the enantioselective 1,2-difluorination of simples, electron-deficient styrenes.⁹

Scheme 1.

Product Selectivity in Aryl Iodide-Catalyzed Difluorination of Cinnamamides

Styrenyl substrates are susceptible to rearrangement pathways under electrophilic fluorination conditions, thereby affording 1,1-difluorinated products^.10,11 For example, in the attempted difluorination of trisubstituted cinnamamide 2a promoted by aryl iodide 1b, a mixture of 1,2- and 1,1-difluoride products was obtained unselectively (Scheme 1A). Product partitioning is proposed to arise from the initial fluoroiodination adduct A, which can undergo aryl iodide displacement either by the amide carbonyl oxygen or by the aryl group (Scheme 1B).^6g,6j The basis for enantioinduction is likely common to both pathways, and was explored computationally in a recent collaborative study.^11e We hypothesized that the amide anchimeric assistance pathway leading to the 1,2-product might be enhanced through judicious introduction of N-substituents, since substitution has been demonstrated to lower the strain energy in small rings in specific cases.¹²

We evaluated a series of N-substituted amides as model substrates for the enantioselective 1,2-difluorination reaction with catalyst 1b (Table 1). While tertiary amide derivatives of 2 displayed poor reactivity, secondary amides underwent reaction more efficiently than the primary amide 2a. Thus, the difluorination of N-methyl amide 2b (entry 2) proceeded with improved yield and enantioselectivity, although without any change in product ratio. Decreasing the HF-pyridine concentration led to a modest improvement in selectivity for the 1,2-product 3b, with optimal yields obtained using 5.6 equivalents (entry 3). The dependence of product ratio on HF-pyridine loading might be attributable to attenuation of amide nucleophilicity by hydrogen bonding between the amide and HF^.13 Increasing the size of the secondary amide N-substituent resulted in increased selectivity for formation of 1,2-difluoride products (entries 3–6), with the N-tert-butyl amide 2f affording the desired 1,2-difluoride 3f almost exclusively (entry 7). Notably, the reaction of 2f proceeded with significantly diminished chemoselectivity when 11 equiv. of HF-pyridine were used (entry 8^).14

Table 1.

Optimization of the 1,2-Difluorination Reaction

entry	substrate	R	pyr·9HF (equiv.)	3 : 4	yield of 3 (%)	e.e. of 3 (%)
1a	2a	H	11	1.1 : 1.0	17	91
2a	2b	Me	11	1.1 : 1.0	38	95
3	2b	Me	5.6	3.3 : 1.0	51	94
4	2c	Et	5.6	4.3 : 1.0	61	95
5	2d	i-Pr	5.6	4.8 : 1.0	56	95
6	2e	n-Bu	5.6	6.9 : 1.0	63	94
7	2f	t-Bu	5.6	39 : 1.0	81	96
8a	2f	t-Bu	11	5.9 : 1.0	65	96

Unless noted otherwise, reactions were conducted on a 1.00 mmol scale and isolated yields of 3 are listed. Reported ratios of 1,2-difluoride to 1,1-difluoride were determined by 19F NMR analysis of crude product mixtures.

^aReaction conducted on 0.10 mmol scale, with yields of 1,2-difluoride determined by 1H NMR against an internal standard.

Under the optimized conditions, a variety of tert-butyl cinnamamide derivatives were found to undergo highly diastereo- and enantioselective formation of the corresponding 1,2-difluorination products (Figure 1A^).15 Substrates bearing electron-withdrawing and mildly electron-donating substituents (2g–i) were particularly effective. The electron-rich cinnamamide 2j underwent reaction with only modest chemoselectivity to generate a 2.2:1.0 ratio of the desired 1,2-difluoride to the 1,1-difluoride, with the 1,2-difluoride isolated in 40% yield and 98% e.e. This result is nonetheless notable because it overturns the overwhelming selectivity for 1,1-difluoride observed for the analogous primary amide substrate (see Supporting Information). A further increase in chemoselectivity for the 1,2-product was obtained by increasing the ratio of pyridine to HF from 1:9 to 1:4.5. Although we have not performed a systematic investigation of the effect of the reaction medium on product distribution, Gilmour and coworkers have demonstrated clearly that 1,2:1,1 product ratios are dependent on amine concentrations in difluorninations of electron deficient styrenes.⁹ Chemoselectivity for 1,2- vs. 1,1-difluorination was observed to be correlated directly to the nucleophilicity of the arene, as evidenced by the positive linear correlation (ρ⁺ = 4.34) between the Hammett substituent σ⁺ constants and log(3:4) for substrates 2f and 2h–j (Figure 1B). The α-alkyl substituent of the cinnamamide could also be varied (Figure 1A). Substrate 2l, which bears an ethyl substituent at the α-position of the cinnamamide, undergoes 1,2-difluorination exclusively. Indene 2m, which is not susceptible to an aryl migration pathway, afforded 3m in moderate yield and enantioselectivity. Non-styrenyl unsaturated amides display poor reactivity under the reaction conditions.

Figure 1.

(A) Scope of the enantioselective 1,2-difluorination of N-tert-butyl cinnamamides. Reactions were conducted on 1.00 mmol scale with 5.6 equiv. HF. Ratios of 1,2-difluoride to 1,1-difluoride were determined by ¹⁹F NMR analysis of crude product mixtures. Isolated yields of diastereomerically pure 1,2-difluoride are reported. The relative and absolute configurations of all 1,2-difluorination products were assigned by analogy to those of 3q (ref 16) ^a Reaction conducted with 2.8 equiv. HF. ^b Reaction conducted with 2.8 equiv. HF and added pyridine (pyr:HF = 1:4.5). (B) Hammett plot of σ⁺ values of the aryl substituents in 2f and 2h–j versus the product ratio (log(1,2 : 1,1)) obtained for each substrate.

We sought to elucidate the basis for the significant impact of amide N-substituent on product ratio. A strong linear free-energy correlation was observed between the 1,2- vs. 1,1-product ratios and the Charton values (ν) of the amide N-substituents for 2a–f (Figure 2A), indicating that the effect is primarily steric in nature.¹⁷ Larger substituents thus appear to enhance amide anchimeric assistance relative to aryl migration, thereby favoring the 1,2-difluorination pathway.

Figure 2.

(A) Plot of Charton values (ν) for amide N-substituents of 2a–f versus the product ratio (ln(1,2 : 1,1)) obtained for each substrate. (B) Plot of amide carbonyl stretching absorptions for 2c and 2n–p versus the product ratio (ln(1,2 : 1,1)) obtained for each substrate. Reactions were conducted on a 1.00 mmol scale. Reported ratios of 1,2-difluoride to 1,1-difluoride were determined by ¹⁹F NMR analysis of the crude mixture.

The electronic effect of the amide N-substituent on the competition between the aryl migration and amide trapping pathways was probed by examining substrates bearing fluorinated N-substituents (2n–p). Substrates bearing electron-withdrawing N-alkyl substituents underwent difluorination with lower product selectivity for the 1,2-difluoride (Figure 2B, top). The experimentally measured infrared stretching frequencies of the amide carbonyls of 2c and 2n–p correlate to ln(3:4) (Figure 2B, bottom). As might be anticipated, decreased nucleophilicity of the amide oxygen disfavors anchimeric assistance relative to phenonium ion formation.

The products of the difluorination reaction can be derivatized to access versatile, enantioenriched vicinal difluoride building blocks (Figure 4). Treatment of 3f with a solution of hydrogen bromide in acetic acid resulted in efficient cleavage of the tert-butyl group to afford primary amide 3a. The arene of 3f can be degraded oxidatively to give carboxylic acid 5, thereby providing a 1,4-dicarbonyl bearing a second functional handle off the stereodefined difluoride framework.

In conclusion, we have developed a catalytic, enantioselective 1,2-difluorination of cinnamamides. The competing 1,1-difluorination resulting from phenonium rearrangement was suppressed through enhancement of anchimeric assistance by a proximal tert-butyl amide. The resulting products and their derivatives may serve as versatile building blocks for the preparation of 1,2-difluoride-containing compounds, enabling further study of this interesting motif. Efforts are underway to extend the scope of this methodology to other enantioselective fluorofunctionalization reactions.

Scheme 2.

Product Derivatization