Angewandte
Chemie
DOI: 10.1002/anie.201409473
Organocatalysis
Oxidative Enantioselective a-Fluorination of Aliphatic Aldehydes Enabled by N-Heterocyclic Carbene Catalysis** Fangyi Li, Zijun Wu, and Jian Wang* Abstract: Described is the first study on oxidative enantioselective a-fluorination of simple aliphatic aldehydes enabled by N-heterocyclic carbene catalysis. N-fluorobis(phenyl)sulfonimide serves as a an oxidant and as an “F” source. The CF bond formation occurs directly at the a position of simple aliphatic aldehydes, thus overcoming nontrivial challenges, such as competitive difluorination and nonfluorination, and proceeds with high to excellent enantioselectivities.
O
rganofluorine compounds display a wide range of distinct physical properties which often render them valuable to the pharmaceutical companies and agrochemical industries.[1] In particular, fluorine atom incorporation has become an effective tool for medicinal chemists to alter the bioactivity of drug candidates.[2] Despite the broad-spectrum utility of such CF bond containing compounds, it is remarkable to consider that only a few catalytic methods exist for the asymmetric installation of fluorine onto carbogenic frameworks[3] and that most of these methods have focused on the generation of non-enolizable products such as a-alkyl-bketoesters. Given that chiral a-fluoro carbonyl compounds have been identified as high-value synthons for chemical synthesis,[4] great progress has been made by employing chiral metal complexes for electrophilic fluorination of activated ketones,[3a,b,e] nucleophilic fluorination of ketenes, and using nucleophilic fluorine sources for enantioselective allylic fluorination.[3k,l] Enamine catalysis has furnished a number of protocols for highly enantioselective a-fluorination of aldehydes[5a–d] and ketones.[5e] Cinchona alkaloids have been effective for fluorination of carbon nucleophiles[6] and in a dual catalysis mechanism to enable the fluorination of acyl chlorides.[7] Recently, a combination of chiral-anion phasetransfer catalysis and enamine catalysis has been reported to generate a-branched a-fluoroketones.[8] Surprisingly, despite the availability of a variety of N-heterocyclic carbene (NHC) catalysts (e.g., catalysts A–F in Table 1),[9] the utility of simple aldehydes in NHC-catalyzed a-fluorination reactions is still comprehensively elusive. In contrast to the NHC-catalyzed a-CC bond formation reaction (Scheme 1 a),[10] the disclosure of enantioselective a-fluorination of simple aliphatic aldehydes catalyzed by chiral NHC catalysts has not yet been [*] F.-Y. Li, Z.-J. Wu, Prof. Dr. J. Wang Department of Pharmacology and Pharmaceutical Sciences School of Medicine, Tsinghua University, Beijing, 100084 (China) E-mail: [email protected] [**] The project described was supported by grant from the Tsinghua University and the “Thousand Plan” Youth program of China. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201409473.
reported.[11] Herein, we report the first example of oxidative enantioselective a-fluorination of simple aliphatic aldehydes catalyzed by an NHC catalyst. It is noteworthy that NFSI is disclosed not only as an electrophilic fluorinating resource[12] but also as an oxidant[13] in asymmetric organocatalysis (Scheme 1 b). Key results on optimization of the reaction conditions are summarized in Table 1. The reaction of the aliphatic aldehyde 1 a (0.2 mmol) with cyclohexanol (2 a; 0.6 mmol) was chosen as a model reaction. Studies on chiral NHC catalysts revealed that when the indanol-derived catalysts C and D,[14] with an N-2,4,6-trichloro- and N-2,4,6-tribromophenyl substituent, respectively, were used, the desired a-fluorinated product 3 aa was efficiently formed, albeit with a high enantioselectivity (entry 3 and 4). Notably, only a trace amount of the nonfluorinated ester 4 and difluorinated ester 5 was dectected under these reaction conditions. To further improve the enantiocontrol, we turned our attention to screening solvents (entries 6–9). The results indicate that the use of 1,4-dioxane consistently afforded the desired product with a reliable chemical yield and a slightly enhanced ee value (entry 9). A switch of base from K2CO3 to NaOAc led to a slightly higher ee value and comparable yield (entry 13). At last we conducted experiments to test the effect of “F” resources. Surprisingly, all other commonly used fluorinating reagents (G1–G5) gave either no reaction (entries 14–16) or low conversion (entry 17 and 18). The high reactivity of NFSI (versus that of G1–G5) can probably be attributed to two factors: 1) NFSI has a higher oxidation potential (0.78 V) and 2) NFSI has a better solubility in organic solvents.[4a] Consequently, NFSI was selected as the most efficient
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Ü Ü
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
Scheme 1. Oxidative NHC catalysis of aliphatic aldehydes.
These are not the final page numbers!
. Angewandte Communications Table 1: Optimization of the reaction conditions.[a]
Table 2: Scope with respect to the alcohol.[a–d]
Entry NHC Base
Solvent
“F” 3 aa 3 aa 4 rea- Yield ee Yield gent [%][a] [%][b] [%][c]
[a] Reactions were carried out with aldehyde 1 a (0.2 mmol), alcohol 2 b– g (0.4 mmol), cat. D (0.02 mmol), NFSI (0.5 mmol), and NaOAc (0.8 mmol) in 1,4-dioxane (2 mL) for 24 h at RT. [b] Yield is that of product isolated after column chromatography. [c] MeOH and EtOH gave a trace amount of a-fluoroester determined by GC-MS. [d] Unfortunately, tBuOH gave no desired a-fluoroester.
1 2 3 4 5 6 7 8 9 10 11 12 13[e] 14 15 16 17 18
toluene toluene toluene toluene toluene toluene CH2Cl2 THF 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G1 G2 G3 G4 G5
A B C D E F D D D D D D D D D D D D
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 PhCO2Na K3PO4 NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc
n.r.[f ] 66 84 86
Chemie
DOI: 10.1002/anie.201409473
Organocatalysis
Oxidative Enantioselective a-Fluorination of Aliphatic Aldehydes Enabled by N-Heterocyclic Carbene Catalysis** Fangyi Li, Zijun Wu, and Jian Wang* Abstract: Described is the first study on oxidative enantioselective a-fluorination of simple aliphatic aldehydes enabled by N-heterocyclic carbene catalysis. N-fluorobis(phenyl)sulfonimide serves as a an oxidant and as an “F” source. The CF bond formation occurs directly at the a position of simple aliphatic aldehydes, thus overcoming nontrivial challenges, such as competitive difluorination and nonfluorination, and proceeds with high to excellent enantioselectivities.
O
rganofluorine compounds display a wide range of distinct physical properties which often render them valuable to the pharmaceutical companies and agrochemical industries.[1] In particular, fluorine atom incorporation has become an effective tool for medicinal chemists to alter the bioactivity of drug candidates.[2] Despite the broad-spectrum utility of such CF bond containing compounds, it is remarkable to consider that only a few catalytic methods exist for the asymmetric installation of fluorine onto carbogenic frameworks[3] and that most of these methods have focused on the generation of non-enolizable products such as a-alkyl-bketoesters. Given that chiral a-fluoro carbonyl compounds have been identified as high-value synthons for chemical synthesis,[4] great progress has been made by employing chiral metal complexes for electrophilic fluorination of activated ketones,[3a,b,e] nucleophilic fluorination of ketenes, and using nucleophilic fluorine sources for enantioselective allylic fluorination.[3k,l] Enamine catalysis has furnished a number of protocols for highly enantioselective a-fluorination of aldehydes[5a–d] and ketones.[5e] Cinchona alkaloids have been effective for fluorination of carbon nucleophiles[6] and in a dual catalysis mechanism to enable the fluorination of acyl chlorides.[7] Recently, a combination of chiral-anion phasetransfer catalysis and enamine catalysis has been reported to generate a-branched a-fluoroketones.[8] Surprisingly, despite the availability of a variety of N-heterocyclic carbene (NHC) catalysts (e.g., catalysts A–F in Table 1),[9] the utility of simple aldehydes in NHC-catalyzed a-fluorination reactions is still comprehensively elusive. In contrast to the NHC-catalyzed a-CC bond formation reaction (Scheme 1 a),[10] the disclosure of enantioselective a-fluorination of simple aliphatic aldehydes catalyzed by chiral NHC catalysts has not yet been [*] F.-Y. Li, Z.-J. Wu, Prof. Dr. J. Wang Department of Pharmacology and Pharmaceutical Sciences School of Medicine, Tsinghua University, Beijing, 100084 (China) E-mail: [email protected] [**] The project described was supported by grant from the Tsinghua University and the “Thousand Plan” Youth program of China. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201409473.
reported.[11] Herein, we report the first example of oxidative enantioselective a-fluorination of simple aliphatic aldehydes catalyzed by an NHC catalyst. It is noteworthy that NFSI is disclosed not only as an electrophilic fluorinating resource[12] but also as an oxidant[13] in asymmetric organocatalysis (Scheme 1 b). Key results on optimization of the reaction conditions are summarized in Table 1. The reaction of the aliphatic aldehyde 1 a (0.2 mmol) with cyclohexanol (2 a; 0.6 mmol) was chosen as a model reaction. Studies on chiral NHC catalysts revealed that when the indanol-derived catalysts C and D,[14] with an N-2,4,6-trichloro- and N-2,4,6-tribromophenyl substituent, respectively, were used, the desired a-fluorinated product 3 aa was efficiently formed, albeit with a high enantioselectivity (entry 3 and 4). Notably, only a trace amount of the nonfluorinated ester 4 and difluorinated ester 5 was dectected under these reaction conditions. To further improve the enantiocontrol, we turned our attention to screening solvents (entries 6–9). The results indicate that the use of 1,4-dioxane consistently afforded the desired product with a reliable chemical yield and a slightly enhanced ee value (entry 9). A switch of base from K2CO3 to NaOAc led to a slightly higher ee value and comparable yield (entry 13). At last we conducted experiments to test the effect of “F” resources. Surprisingly, all other commonly used fluorinating reagents (G1–G5) gave either no reaction (entries 14–16) or low conversion (entry 17 and 18). The high reactivity of NFSI (versus that of G1–G5) can probably be attributed to two factors: 1) NFSI has a higher oxidation potential (0.78 V) and 2) NFSI has a better solubility in organic solvents.[4a] Consequently, NFSI was selected as the most efficient
1
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Ü Ü
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
Scheme 1. Oxidative NHC catalysis of aliphatic aldehydes.
These are not the final page numbers!
. Angewandte Communications Table 1: Optimization of the reaction conditions.[a]
Table 2: Scope with respect to the alcohol.[a–d]
Entry NHC Base
Solvent
“F” 3 aa 3 aa 4 rea- Yield ee Yield gent [%][a] [%][b] [%][c]
[a] Reactions were carried out with aldehyde 1 a (0.2 mmol), alcohol 2 b– g (0.4 mmol), cat. D (0.02 mmol), NFSI (0.5 mmol), and NaOAc (0.8 mmol) in 1,4-dioxane (2 mL) for 24 h at RT. [b] Yield is that of product isolated after column chromatography. [c] MeOH and EtOH gave a trace amount of a-fluoroester determined by GC-MS. [d] Unfortunately, tBuOH gave no desired a-fluoroester.
1 2 3 4 5 6 7 8 9 10 11 12 13[e] 14 15 16 17 18
toluene toluene toluene toluene toluene toluene CH2Cl2 THF 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G6 G1 G2 G3 G4 G5
A B C D E F D D D D D D D D D D D D
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 PhCO2Na K3PO4 NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc
n.r.[f ] 66 84 86
