Thanks to the Fu group retreats, we have the opportunities to brainstorm new projects and pursue them in the lab. Next, I would like to thank every single person who has worked in the Fu Group for the past five and a half years. A number of previous graduate students and postdocs who worked in the Fu group but did not overlap with me deserve a very special acknowledgment.
My friends in the greater Boston area, including Wen Sang (MIT), Lei Sun (MIT), Zhe Wang (MIT), Chi Zhang (MIT).
An Overview An Overview
- Nickel-Catalyzed Cross-Coupling Methods Developed in the Fu Group: Recent Developments Developments
- Carbon–Carbon Bond-Forming Strategy for the Synthesis of Organofluorine Compounds Compounds
- Overview of Individual Chapters
- Notes and References
- Introduction
- Optimization
Lundgren was able to provide a novel enantioconvergent cross-coupling using a racemic alkyl metal reagent and unactivated secondary electrophiles (equation 1.5).11. We tried to use fluorine- and fluoroalkyl-substituted electrophiles in the cross-coupling methods and generate fluorine-containing compounds as targets. On the other hand, these new methods also help to enrich cross-coupling chemistry.
This method serves as the first example of enantioselective cross-coupling using germline alkyl dihalides as substrates.
Effect of Nucleophiles
Effect of Ligands
Scope
With optimized conditions, we began to explore the scope of this new method. Highly enantioselective cross-coupling can be uniformly achieved regardless of whether the aryl group (Ar) is para-, meta-, or ortho-substituted and whether it is electron-rich or electron-deficient (Table 2.3). Several failed electrophiles and nucleophiles under our optimized conditions (entry 1 in Table 2.1) are shown in Figure 2.1.
The cross-linking product was stable (no cleavage or erosion of the C-F bond at ee) under our optimized conditions and its ee value was constant.
Derivatization of Cross-Coupling Products
A major side reaction is the hydrodebromination of electrophiles and the products are formed as racemates. No kinetic resolution of the electrophile (<5% ee) was observed during the course of the reaction. Moreover, regioselective Baeyer-Villiger oxidation of the related products can be achieved (eqs 2.13 and 2.14, HFIP hexafluoro-2-propanol).17 The relative migratory abilities of the ketone substituents can determine the regioselectivity of the reaction.18 to our knowledge, these reactions serve as the first asymmetric synthesis of acylated fluorohydrins19 and an indirect method for the enantioselective catalytic synthesis of tertiary α-fluoroesters.20.
Conclusions
2-Bromo-2-fluoro-1,3-diphenylpropan-1-one (307 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-2-fluoro-1-phenylpent-4-en-1-one (257 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-2-fluoro-1-(4-methoxyphenyl)-3-phenylpropan-1-one (337 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used.
2-Bromo-1-(4-(tert-butyl)phenyl)-4-chloro-2-fluorobutan-1-one (336 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-4-chloro-2-fluoro-1-(4-fluorophenyl)butan-1-one (298 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-2-fluoro-1-(3-methoxyphenyl)butan-1-one (275 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used.
2-Bromo-2-fluoro-1-(3-fluorophenyl)-3-phenylpropan-1-one (325 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-1-(3,5-dimethylphenyl)-2-fluorobutan-1-one (273 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-2-fluoro-1-(2-methoxyphenyl)butan-1-one (275 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used.
2-Bromo-2-fluoro-1-(naphthalen-2-yl)butan-1-one (295 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used. 2-Bromo-2-fluoro-1,3-diphenylpropan-1-one (307 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from (4-bromophenoxy)(tert-butyl)dimethylsilane were used. 2-Bromo-2-fluoro-1-phenylbutan-1-one (245 mg, 1.00 mmol) and the aryl zinc chloride reagent prepared from 1-bromo-4-isopropylbenzene were used.
2-Bromo-2-fluoro-1,3-diphenylpropan-1-one (307 mg, 1.00 mmol) and arylzinc chloride reagent prepared from (3-bromophenoxy)(tert-butyl)dimethylsilane were used. 2-Bromo-2-fluoro-1-phenylbutan-1-one (245 mg, 1.00 mmol) and arylzinc chloride reagent prepared from 1-bromo-3-isopropylbenzene were used. 2-Chloro-2-fluoro-1,3-diphenylpropan-1-one (263 mg, 1.00 mmol) and the arylzinc chloride reagent prepared from bromobenzene were used.
Notes and References
For selected examples of the catalytic asymmetric synthesis of other families of tertiary alkyl fluorides, see: (a) Phipps, R. 7). For a recent review on the topic of enantioselective and enantiospecific cross-coupling reactions, see: Cherney, A. 11) When we began our studies in 2011, we were not aware of any precedent for selective nickel-catalyzed cross-couplings. of α-halo-α-fluoro compounds. For a review of the effect of a fluorine substituent on the conformation of molecules, see: Hunter, L. 16) At this stage we are unable to determine the relative stereochemistry of this alcohol.
For examples of the use of this class of compounds see: (a) rye, C. 5-halo-4-fluoro-4,7,7-trimethyl-3-oxabicyclo[4.1.0]heptan-2-ones, method for their production and their use in the production of cyclopropane carboxylic acids.
Introduction
To construct this type of structure, a commonly used strategy is to perform an alkyl–alkyl cross-coupling reaction with a perfluoroalkyl nucleophile (Scheme 3.1a). However, only stoichiometric cross-coupling methods have been reported when unactivated alkyl electrophiles are used as substrates.6 In addition, the reluctance of a fluoroalkyl group to participate in the reductive elimination step may also add difficulty to adopting this strategy.7.
Two Types of Cross-Coupling Strategies
Optimization
We chose to start our study by choosing alkylzinc reagents as the nucleophilic cross-coupling partners due to their easy accessibility and high functional group tolerance.9 In 2003, our group achieved the first Ni-catalyzed Negishi alkylation method with unactivated secondary alkyl electrophiles as substrates.10 Using these conditions applied to the cross-coupling of an alkyl electrophile bearing a perfluoroalkyl group, we obtained promising results (eq 3.1). Although this catalytic system was able to provide the CF3-substituted product in moderate yield, the efficiency of the reaction with the C2F5-substituted electrophile is very disappointing. In order to develop a general method that can cross-couple electrophiles bearing all kinds of perfluoroalkyl groups, we decided to optimize the reaction conditions using the C2F5-substituted alkyl bromide as a model substrate.
After extensive screening, we finally found a suitable condition that can give both cross-coupling products in good yield (Eq. 3.2). As shown in Table 3.1, in the absence of nickel source, no product is formed (entry 2). The addition of a small amount of water or the changes in temperature have no significant effect on the outcome of the reaction, whereas carrying out the reaction under air leads to reduced yields (entries 6 to 9).
Several other related additives have been tested under optimized conditions and NaBr is found to be the best (Table 3.2). Possible explanations for the beneficial effects of NaBr include, but are not limited to, increased ionic strength of the reaction medium and activation of alkylzinc reagents through the formation of those complexes.11. LiBr, instead of NaBr KBr, instead of NaBr CsBr, instead of NaBr (n-Bu)4NBr, instead of NaBr NaI, instead of NaBr.
Several tridentate and bidentate chiral or achiral ligands have been investigated under our optimized conditions (Scheme 3.2).
Effect of Ligands
Scope
Next, we are pleased to note that this method can also be applied to electrophiles containing higher order perfluoroalkyl groups without any modification (Table 3.4). Considering the unique properties of the trifluoromethyl (CF3) group, the construction of molecules containing C-CF3 moieties has attracted much attention recently. Although several methods have been developed to generate targets that include a trifluoromethyl group attached to a tertiary carbon, a general method that provides products with good efficiency is still desirable.4,12 As shown in Table 3.5 and Table 3.6, Method can be directly used to access these targets and the functional group tolerance is very satisfactory.
Under the same conditions, a fluorinated alkyl iodide can also cross-couple with an alkylzinc reagent with moderate efficiency (Eq. 3.3). To investigate the scalability of this method, we perform a large-scale experiment using a trifluoromethyl-containing electrophile (eq 3.4). Although we initially optimized the reaction conditions with α-bromo-α-perfluoroalkyl secondary electrophiles, we were also pleased to observe that an α-bromo-α-difluoromethyl secondary electrophile can react with alkylzinc reagents under related conditions (eqs 3.5 and 3.6).
It thus offers us an efficient way to generate difluoromethyl-substituted compounds, which is complementary to other strategies.13,14. A number of low-yielding electrophiles under our optimized conditions (Equation 3.2) are summarized in Figure 3.2.
Competition Experiments
As shown in Table 3.7, the trifluoromethyl-substituted electrophile is indeed more reactive than partially fluorinated electrophiles and non-fluorinated electrophiles under our standard condition. Although we are not sure about the origin of this selectivity, it is not uncommon for fluorine atoms to play important roles in determining the reactivity of organofluorine compounds.15. In addition, we also performed a similar competition experiment using a pentafluoroethyl-substituted electrophile and a trifluoromethyl-substituted electrophile.
Mechanistic Studies
This cross-coupling reaction can be inhibited by the addition of a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as shown in equation 3.8. This by-product can be independently synthesized and isolated according to the conditions shown in equation 3.10.
Conclusions
The reaction mixture was stirred at 0 °C for 15 min, and then allowed to warm to r.t. After the addition was complete, the mixture was stirred at 0 °C for 30 min, and then allowed to warm to r.t. The mixture was extracted with CH2Cl2 (3 × 50 mL) and the combined organic layers were dried over Na2SO4 and concentrated.
Then an aqueous solution of 1 N HCl (30 mL) was added and the mixture was allowed to stir at r.t. General Procedure C: Synthesis of Electrophiles with a CF3 Group The first two steps are the same as in General Procedure B. The title compound was synthesized according to General Procedure A using 2,2,3,3,3-pentafluoro-N-methoxy -N-methylpropanamide and a Grignard reagent made from (2-bromomethyl)benzene.
The title compound was synthesized according to general procedure A using 2,2,3,3,3-pentafluoro-N-methoxy-N-methylpropanamide and a Grignard reagent prepared from 1-bromo-5-chloropentane. The title compound was synthesized according to general procedure A using heptafluoro-N-methoxy-N-methylbutanamide and a Grignard reagent prepared from (2-bromomethyl)benzene. The title compound was synthesized according to general procedure A using nonafluoro-N-methoxy-N-methylpentanamide and a Grignard reagent prepared from (2-bromomethyl)benzene.
The title compound was synthesized according to General Procedure A, using 2,2,2-trifluoro-N-methoxy-N-methylacetamide and a Grignard reagent prepared from (2-bromomethyl)benzene. The title compound was synthesized according to General Procedure A, using 2,2,2-trifluoro-N-methoxy-N-methylacetamide and a Grignard reagent prepared from 1-bromooctane.
![Table 2.12. Bond Lengths [Å] and Angles [°] for Crystal_002.](https://thumb-ap.123doks.com/thumbv2/123dok/10401990.0/113.918.157.482.154.1027/table-12-bond-lengths-å-angles-crystal-002.webp)
