Chem: Nuno maulide group realizes direct asymmetric arylation of amides by chemically selective α - oxidative sulfonation

The classical method of direct nucleophilic substitution of alcohols is to convert them to pseudo halides by sulfonation Although sulfonylation of carbonyl compounds by oxidation is an ideal way to directly introduce halophilic functional groups, the process is still challenging So far, carbonyl compounds are still limited to ch acid active methylene compounds and ketones (Figure 1a) On the other hand, the direct oxidation sulfonation of ester or amide is still difficult to achieve, which can only be achieved by sulfonation of α - hydroxyamide precursor (Figure 1b) The steps of the above method are lengthy and difficult to synthesize In particular, the hydroxylation of amides is more difficult to achieve than that of esters or ketones because of their lowest C-H acidity In addition, the oxidation functionalization method based on the formation of enols by strong bases also has some problems, such as the poor compatibility of functional groups, the narrow application range of substrates (not applicable to ketones) Recently, the research team of Professor Nuno maulide of the University of Vienna in Austria solved the above problems They realized the direct α - trifluoromethylsulfonylation of amide for the first time, and further functionalized it into valuable α - arylated amide Relevant research results were published on chem (DOI: 10.1016 / j.champr 2019.05.006) (source: Chem) in the early stage, the author completed the α - arylation of amides via TF 2O mediated activation (angelw Chem Int ed 2017, 56, 5921-5925), so he devoted himself to developing the asymmetric form of the reaction (scheme 1a) The authors speculate that the addition of allylimide a, which is produced in situ by amide 1a, to chiral nitrone (OX1), will produce the addition product B ideally, intermediate B will undergo [3,3] - sigatropic rearrangement, and at the same time, it will be transferred to the desired enantiomerically enriched α - arylamide C However, unexpectedly, trifluoromethylsulfonate 2a was formed in extremely high yield The reason is that the intermediate B releases the imine, then attacks the weak nucleophilic trifluoromethane sulfonate equilibrium ion, and produces the α - trifluoromethane sulfonated amide In order to further understand this process, the author screened a variety of nitrogen or sulfur oxides (OX1 - Ox6), and found that pyridine nitrogen oxides or dimethylpyridine nitrogen oxides had the best effect, and could almost quantitatively form unstable trifluoromethylsulfonate It should be noted that compound 2a is an unstable intermediate, and it can obtain pure trifluoromethane sulfonate in 80% yield by passing through the column rapidly at - 30 ℃ The results show that indoleamide 1C is the most suitable substrate for the synthesis of trifluoromethylsulfonate (scheme 1c) in a very clean and quantitative yield (source: Chem) in order to avoid purification of the product, and trifluoromethylsulfonate has high chemical reaction activity, the author expects that α - OTF amides can be further functionalized to realize asymmetric α - arylation of amides Inspired by the aromatization of α - halocarbonyl compounds with aryl nucleophiles (such as 9-BBN, ArZnX and armgx), the author initially tried to generate in situ α - OTF amides for aromatization under the cross coupling conditions developed by the Fu research group However, the response did not go smoothly (source: Chem) fortunately, tetraethyl ammonium bromide (net 4Br) was added directly to the mixture of trifluoromethylsulfonic acid esterification at room temperature Nucleophilic substitution took place rapidly (< 10 minutes), and the corresponding α - bromoamide was formed in a very high yield, and the pure bromide was obtained by filtration The cross coupling reaction of α - bromoamide with Fu was investigated (J am Chem SOC 2010, 132, 11027-11029) After optimizing the conditions, the author found that the solvent is very important for the reaction When heptane ether is used as the mixed solvent, the desired α - arylamide can be obtained with good yield and enantiomer ratio Then, under the optimal conditions, the universality of the amide substrate (scheme 2) was investigated Simple alkylated amides (3a-3f) or heteroatom substituted amides (3G and 3H) with good overall yield and excellent Dr are worthy of α - oxidative sulfonation products The reaction is also compatible with highly active alkene and alkyne functional groups (3I and 3j) α - arylated amides (3K and 3L) can be selectively generated from amides with ester and ketone carbonyl groups In addition, a variety of borane nucleophiles were screened, and the corresponding products (3m - 3T) were always obtained in good yields (source: Chem) in order to prove the practicability of this method, the author used DDQ to oxidize amide into corresponding indole derivatives, which were further cracked into acid, and the enantiomeric purity was not affected In addition, C2-C3 of indole is decomposed by ozone to form 2-aminobenzaldehyde 6 Aldehyde 6 was oxidized by pinnick and treated by AC 2O, and α - chiral benzoxazinone 7 was obtained in excellent yield The yield of quinazoline 8 can be obtained by simply stirring aldehyde 6 in ammonia water Alternatively, amide (±) - 5 can be converted to N - (2-phenylpropyl) indole 9 by catalytic reduction, while C-2 aromatization by PD can yield 10 (source: Chem) in summary, the direct α - trifluoromethylsulfonation of amides has been realized for the first time In the presence of more electrophilic carbonyl functional groups and other active functional groups, amides can be chemically selective, and the reaction has good functional group tolerance The sensitive trifluoromethylsulfonate is formed in the form of high purity and can be functionalized directly in situ to complete the direct asymmetric arylation of amides The direct oxidation sulfonation of the amide provides a convenient way to develop other useful transformations.