Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon

Abstract A robust and practical difluoroalkylation synthon, α,α‐difluoroenol species, which generated in situ from trifluoromethyl diazo compounds and water in the presence of dirhodium complex, is disclosed. As compared to the presynthesized difluoroenoxysilane and in situ formed difluoroenolate under basic conditions, this difluoroenol intermediate displayed versatile reactivity, resulting in dramatically improved enantioselectivity under mild conditions. As demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine‐derived urea, and chiral phosphoric acid (CPA), respectively, this relay catalysis strategy provides an effective platform for applying asymmetric fluorination chemistry. Moreover, this method features a novel 1,2‐difunctionalization process via installation of a carbonyl motif and an alkyl group on two vicinal carbons, which is a complementary protocol to the metal carbene gem‐difunctionalization reaction.


Introduction
The growing interest in selective synthesis of fluorinated compounds is evident based on their prevalence in natural products, agrochemicals, and pharmaceuticals. [1]Thus, a variety of catalytic methods have been disclosed, [2,3] including radical processes, [4] nucleophilic [5] or electrophilic additions, [6] and other transformations. [7]In this area, an appealing task is the introduction of a difluoromethylene unit, [8] which has demonstrated broad applications in medicinal chemistry and material science. [9]Especially, the ,-difluoroketone moiety has been found in a broad spectrum of bioactive molecules with unique physicochemical properties that are useful for DOI: 10.1002/advs.202307520developing pharmaceuticals and probes for chemical biology. [10]However, the difluoroalkylation has rarely been documented, which might be mainly due to the limited accessibility of fluorinated reagents that could be used as practical precursor/synthon for the difluoroalkylation. [11][15] Although relatively stable, the prepreparation, acidsensitivity, and moderate reactivity are the key obstacles in this method.By contrast, difluoroenolates are much more reactive species, which could be generated in situ from different types of prenucleophiles (Figure 1A, right), [16] however, the reaction of difluoroenolates with carbonyl compounds has proved to be complicated and the asymmetric induction has remained a major challenge in this area. [17]In this context, it is highly desirable to develop an effective catalytic method with practical difluoroalkylation precursors to overcome the above mentioned limitations, especially enabling the catalytic asymmetric difluorocarbonylation with a robust difluorinated synthon.
Recently, Bi's group has disclosed a novel C─F bond functionalization protocol using trifluoromethyl hydrazone as the fluorinated reagent (Figure 1B). [18]In the presence of metal catalyst under basic conditions, these reactions initially form the metal carbene species, then C─F bond cleavage occurs to give the difluoroenol or its analog, and terminated by protonation (path a) [18a] or intramolecular rearrangement (path b) [18b,c] providing the ,-difluoroketone derivatives through a controllable mono─C─F bond functionalization process.Inspired by these advances [13][14][15][16][17][18] and in line with our ongoing interest in metal carbene gem-difunctionalization via interception of in situ formed intermediates (Figure 1C), [19,20] we wondered whether a novel difluoroalkylation reaction using ,-difluoroenol (Figure 1A, middle) as the key synthon could be designed via an intermolecular electrophilic trapping process (Figure 1B, path c).If realized, such an unprecedented interception process might represent a complementary 1,2-difunctionalization method for direct assembly of difluoromethylene incorporated architectures by installing a carbonyl motif and an alkyl group sequentially.Herein, we disclose the successful establishment of this goal, culminating in a practical and robust enantioselective difluoroalkylation method using an in situ formed difluoroenol species as the key fluoridated synthon under mild conditions (Figure 1D).This species has shown versatile reactivity and dramatically im-proved enantioselectivity as demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine-derived urea and chiral phosphoric acid CPA, respectively.In comparison to our previous studies on metal carbene gem-difunctionalization reaction, [21] this method features a novel 1,2-difunctionalization process by introducing two different functionalities on the two vicinal carbons (Figure 1C vs 1D).a) The reaction was carried out on a 0.1 mmol scale: to the mixture of Rh 2 (OAc) 4 (0.45 mg, 2.0 mol%), 2a (0.1 mmol), 3a (0.1 mmol), and organocatalyst (10 mol%) in the indicated solvent (1.0 mL), was added a solution of diazo compound 1a (0.1 mmol) in the same solvent (1.0 mL) via syringe pump over 1 h under an argon atmosphere at 30 °C, and the reaction mixture was stirred for an additional 1 h under these conditions; b) Isolated yields; c) Determined by chiral HPLC analysis, see SI for detail; d) The reaction was conducted with 1a (0.15 mmol, 1.5 equiv.)and 2a (0.15 mmol, 1.5 equiv.);e) The reaction was conducted with reduced catalyst loading: 1.0 mol% of Rh 2 (OAc) 4 and 2.0 mol% of Q8; f) The reaction was conducted with triethylsilanol 2b instead of water, which formed the desilylation product 4a.DCM = dichloromethane; EA = ethyl acetate; TBME = methyl tert-butyl ether.

Results and Discussion
We commenced our studies using trifluoromethyl diazo compound 1a, water 2a, and isatin 3a as model substrates for the optimization of reaction conditions (Table 1).20a] Tetrahydrofuran (THF) was identified as the better solvent in term of stereoselectivity, forming the difluoroalkylated product 4a in 68% yield with 65% ee (entry 2), and higher yield was obtained when the reaction was conducted in ethyl acetate (entry 3, 85% yield).Then, the screening of a variety of quinine-derived chiral organocatalysts Q2-Q6 in THF found that 3,5-di-CF 3 substituted aniline derived catalysts gave better results in terms of both yield and enantioselectivity (entries 6-10, and see Figure S1 and Table S2, Supporting Information).
Further optimization of the organocatalysts by replacing the quinine or squaramide parts with chiral cyclohexanediamine or urea motifs (entries 11 and 12) resulted in that the quinine-derived urea catalyst Q8 giving the desired product 4a in 72% yield with 93% ee (entry 12).The yield was improved to 95% by increasing the ratio of diazo compound 1a and water to 1.5 equivalents (entry 13), while the excellent reactivity and stereoselectivity was retained by reducing the loading of both the dirhodium tetraacetate and organocatalyst Q8 (see Table S3, Supporting Information for details).Only inferior results were observed when other metal catalysts were used instead of Rh 2 (OAc) 4 (see Table S3, Supporting Information for details).The best results were obtained by using 1.0 mol% of Rh 2 (OAc) 4 and 2.0 mol% of Q8 in THF at 30 °C, which delivered the difluoroalkylated product 4a in 95% yield with 93% ee (entry 14).Moreover, this reaction could also be conducted with triethylsilanol 2b instead of water 2a, which formed the desilylation product 4a in 95% yield with 94% ee (entry 15).Under the optimized conditions, the substrate scope with respect to the isatins 3 was explored and the results were shown in Table 2.A variety of N-substituted isatins 3a-3e were found to provide the aldol addition products 4a-4e in 88%-95% yields with ≥90% ee.Notably, when non-protected isatin (3f) was used, the desired product 4f was obtained in high yield with elegant enantioselectivity (95% ee).Furthermore, the reaction with isatins containing an electron-donating or electronwithdrawing group on the different positions of the aryl motif all proceeded smoothly, delivering the corresponding products 4g-4v in high yields with excellent enantioselectivity (92%-96% ee).With electron-deficient isatins, 10 mol% of chiral organocatalyst loading was used to retain the excellent stereoselectivity, whereas, 20 mol% of catalyst loading was used in previous studies when only 78% ee was achieved for the nitro-substituted product 4r through a decarboxylative aldol reaction [17c] (vs our results in 95% ee).The absolute stereochemistry of 4a was determined as S using X-ray crystallography, and the other products were similarly assigned by analogy. [22]hen, a series of trifluoromethyl diazo compounds 1 with different substitutions at para-substitution of the phenyl ring, including F, Br, Me, OMe, or CF 3 all proceeded smoothly to afford the products 5a-5e in 82%-92% yields with 91%−95% ee (Table 3).The meta-and ortho-substituted aryl diazo compounds also gave products 5f and 5 g in high yields with 94% and 91% ee, respectively.For the formation of 5 g, 10 mol% of organocatalyst loading was used to retain its excellent stereoselectivity.In addition, 2-naphthyl or 5-benzofuranyl substituted diazo compounds were well tolerated under current conditions, producing 5 h and 5i in high yields and excellent enantioselectivities. Notably, the alkyl substituted products 5j and 5k, which are a challenge to be obtained with high reactivity and selectivity by using reported method with the corresponding difluoroenoxysilane as a) The reaction was carried out on a 0.1 mmol scale: to the mixture of Rh 2 (OAc) 4 (0.45 mg, 1.0 mol%), water 2a (2.7 μL, 0.15 mmol), 3 (0.1 mmol), and Q8 (1.2 mg, 2.0 mol%) in THF (1.0 mL), was added a solution of diazo compound 1a (27.9 mg, 0.15 mmol) in THF (1.0 mL) via syringe pump over 1 h under an argon atmosphere at 30 °C, and the reaction mixture was stirred for an additional 1∼2 h under these conditions; b) The reaction was conducted with 10 mol% of Q8 loading.
Table 4. Substrate scope for the synthesis of 7. a) a) The reaction was carried out on a 0.1 mmol scale: to the mixture of Rh 2 (esp) 2 (0.76 mg, 1.0 mol%), 2a (2.7 μL, 0.15 mmol) and CPA-1 (1.8 mg, 2.0 mol%) in EA (1.0 mL), was added a solution of diazo compound 1a (27.9 mg, 0.15 mmol) and imine 6 (0.1 mmol) in EA (1.0 mL) via syringe pump over 2 h under an argon atmosphere at 30 °C, and the reaction mixture was stirred for an additional 1∼2 h under these conditions; b) The reaction was conducted with 10 mol% of CPA-1 loading.
Encouraged by above promising results, we turned our attention into the evaluation of asymmetric difluorocarbonylation with imines.After optimization of conditions (see Table S4, Supporting Information for details), this protocol was extended to Mannich-type addition by using Rh 2 (esp) 2 (1.0 mol%) as the metal catalyst, chiral phosphoric acid CPA-1 (2.0 mol%) as the organo cocatalyst, delivering the difluoroalkylated amino product 7a in 95% yield with 94% ee (Table S4, Supporting Information, entry 4).Under these optimized conditions the substrate scope with respect to the imines 6 was investigated (Table 4).A variety of substituents at different positions of two aryl rings were all well tolerated, leading to the corresponding products 7a--7j in 81%-95% yields with 90%-95% ee.When the imines 6k and 6l were used, in which the oxygen of the reactant (X in 6) was replaced with a sulfur atom or a methylene unit as linkage, leading to the products 7k and 7l were formed in 95% and 78% yields, respectively, also with high enantioselectivity has been maintained well.The absolute stereochemistry of 7a was determined as R using X-ray crystallography, and the other products were assigned by analogy. [22]ubsequently, the scope of this three-component reaction with respect to other types of cyclic imine derivatives was examined (Figure 2).Under optimized conditions, the Aldol-type addition with linear ketones, methyl (E)−2-oxo-4-phenylbut-3-enoate (3w) and ethyl 2-oxoacetate (3x), proceeded smoothly, giving the products 4w and 4x in 95% and 85% yields with 91% and 87% ee, respectively (Figure 2A,B).15b,d] Notably, the generally inert phenanthridine 12 delivered the corresponding product 13 smoothly in high yield and enantioselectivity under slightly modified conditions (Figure 2E). [24]o demonstrate the synthetic utility of this strategy, the reaction was scaled up to a gram scale, and the corresponding product 5 h was obtained in 90% yield with 95% ee (Figure 2F).Then, the synthetic transformations of these generated products were performed.The product 4b, bearing a terminal alkyne unit, was subjected to catalytic [3+2]-cycloaddition with benzyl azide in the presence of copper(I) thiophene-2-carboxylate hydrate (CuTC), yielding the triazole 14 in 90% yields with 93% ee after separation by crystallization in DCM (Figure 2G).The Wittig reaction of 7a proceeded smoothly, affording the terminal alkene product 15 in 85% yield without decreasing the ee (Figure 2H, 93% ee).The difluorocarbonylation adduct 5c was converted to the tricyclic structure 16 through a sequential Baeyer-Villiger oxidation and reductive cyclization procedure, which could potentially be used in the synthesis of the difluorinated analogues of (+)madindoline (Figure 2I). [25]Moreover, this robust method might also be used for the modification of bioactive molecules and natural products.For example, 1,1,1-trifluoro-6-phenylhexan-2one, which is an inhibitor of GIVA cPLA 2 and GVIA iPLA 2 , [26] was used as the starting material for the synthesis of trifluoromethyl diazo compound 1j, and then converted to the isatin hybrid product 17 through this three-component reaction in 74% yield with 90% ee (Figure 2J).Difluoromethyl 4-pyrazolyl ketone motif, which is the key unit of an anti-malarial molecule, [27] was decorated with isatin through an asymmetric aldol-type addition using diazo compound 1k as difluorination reagent, leading to adduct 18 in 80% yield with 90% ee after separation by crystallization in DCM (Figure 2K).In addition, the current protocol was also found to be feasible for the synthesis of the difluoro analogues of YK-4-279, which could potentially be used for the treatment of high-risk and relapsing neuroblastoma, [28] affording the difluorinated adduct 19 in 90% yield with 85% ee (Figure 2L, and after recrystallization, the ee was enhanced to 97% with 79% yield).
To gain insight into the mechanism of this reaction, control experiments with -CF 2 H ketone 20 and isatin 3a were conducted under the optimal conditions or in the presence of base Et 3 N instead of Q8, and no reaction occurred (Figure 3A; see Figures S2 and S3, Supporting Information for details).This result suggests that a stepwise pathway is not the case in this reaction for the formation of difluorinated adduct.Furthermore, only decomposition of diazo compound 1a was observed when the reaction was conducted in absent of water under the otherwise identical conditions, and the most of isatin 3a was retained (see Figure S4, Supporting Information for details).Based on these results and previous studies, [18][19][20][21] a plausible reaction pathway is proposed in Figure 3B.Initially, the carbene intermediate A is formed followed by the generation of ylide intermediate B by addition with water 2a.18a] The electrophilic reagent isatin 3 intercepts this species with the assistance of a bifunctional urea catalyst Q8, delivering the aldol addition products 4 or 5 [21] and regenerates the organocatalyst simultaneously.The elegant enantioselectivity is achieved in this transformation through a dual H-bonding catalysis model [23,29] with chiral organocatalyst through a re-face addition via TS-I according to the observed absolute stereochemistry of products 4a.The asymmetric difluoroalkylation reaction with imine is realized through an analogous catalytic process via TS-II with the assistance of CPA-1, [15b,30] giving the Mannich addition product 7 with excellent enantiocontrol.

Conclusion
In summary, we are reporting an asymmetric difluoroalkylation method using a robust ,-difluoroenol species, which is generated in situ from trifluoromethyl diazo compounds and water in the presence of a dirhodium complex.The reaction proceeds under mild conditions with low chiral organocatalyst loading and broad substrate scope.Dramatically improved enantioselectivity has been realized as demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine-derived urea and chiral phosphoric acid CPA, respectively.In comparison to welldocumented studies on metal carbene gem-difunctionalization reaction, this method features a novel 1,2-difunctionalization process by introduction of two different functionalities on the two vicinal carbons, and the disclosed relay catalysis strategy provides an effective platform for expanding asymmetric fluorination chemistry.

Experimental Section
General Procedure for the Asymmetric Aldol-Type Three-Component Reaction: To a 10-mL oven-dried vial containing a magnetic stirring bar, isatin 3 (0.1 mmol), H 2 O (0.15 mmol, 2.7 μL, 1.5 equiv.),Rh 2 (OAc) 4 (0.45 mg, 1.0 mol%), and organocatalyst Q8 (1.2 mg, 2.0 mol%) in tetrahydrofuran (THF, 1.0 mL), was added a solution of diazo compound 1 (0.15 mmol, 1.5 equiv.) in 1.0 mL THF via syringe pump over 1 h under argon atmosphere at 30 °C.After addition, the reaction mixture was stirred for additional 1-2 h under these conditions until consumption of the material (monitored by TLC).Then the reaction mixture was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc = 5:1 to 2:1) to give the pure products 4 and 5 in good to high yields and excellent enantioselectivity.
General Procedure for the Asymmetric Mannich-Type Three-Component Reaction: To a 10-mL oven-dried vial containing a magnetic stirring bar, H 2 O (0.15 mmol, 2.7 μL, 1.5 equiv.),Rh 2 (esp) 2 (0.76 mg, 1.0 mol%), and chiral phosphoric acid CPA-1 (1.8 mg, 2.0 mol%) in ethyl acetate (EA, 1.0 mL), was added a solution of diazo compound 1 (0.15 mmol, 1.5 equiv.)and imine 6 (0.1 mmol) in 1.0 mL EA via syringe pump over 2 h under argon atmosphere at 30 °C.After addition, the reaction mixture was stirred for additional 1-2 h under these conditions until consumption of the material (monitored by TLC).Then the reaction mixture was purified by column chromatography on silica gel without any additional treatment (Hexanes : EtOAc = 50:1 to 20:1) to give the pure products 7 in good to high yields and excellent enantioselectivity.

Figure 1 .
Figure 1.General synthons for the difluoroalkylation and our tactic for asymmetric C-F bond functionalization.A) General nucleophilic difluoroalkylation synthons.B) C─F Bond functionalization via carbene intermediate & our design.C) Catalytic metal carbene gem-difunctionalization. D) This work: Asymmetric difluoroalkylation via a C─F bond fragmentation and electrophilic addition sequence.

Figure 2 .
Figure 2. Synthetic applications and gram-scale reaction.A) Synthesis of compound 4w.B) Synthesis of compound 4x.C) Synthesis of compound 9. D) Synthesis of compound 11.E) Synthesis of compound 13.F) Gram-scale reaction for the synthesis of compound 5 h.G) Synthesis of compound 14.H) Synthesis of compound 15.I) Synthesis of compound 16.J) Synthesis of compound 17.K) Synthesis of compound 18.L) Synthesis of compound 19.

Figure 3 .
Figure 3.Control experiment and proposed reaction mechanism.A) Control experiment of ketone 20 with 3a under optimal conditions.B) Proposed reaction mechanism.