Professor Dong guangbin, University of Chicago, re issued JACS: direct β - alkylation of ketones and aldehydes

The author: it is an important strategy for danyan to construct carbon carbon bond by alkylation of carbonyl compounds The usual method is to treat ketones with strong base and then add haloalkanes to obtain α - alkylation products; however, it is more challenging to alkylate the unactivated β position directly Recently, Macmillan and his colleagues [1,2] reported a simple method of β - alkylation, i.e β - alkylation of the substrate was realized by the combination of enamine catalyst and photo oxidation-reduction catalyst, in which Michael receptor or ketone and imine can be used as the source of alkylation (scheme 1a) In addition, Newhouse and his colleagues [3,4] realized the β - alkylation (scheme 1b) of the substrate by palladium catalyzed dehydrogenation of ketones and addition of organocopper nucleophiles Recently, Professor Dong guangbin of the University of Chicago reported on J am Chem SOC That the direct β - alkylation of ketone and aldehyde was realized by palladium catalyzed redox cascade reaction (scheme 1C, DOI: 10.1021 / JACS 8b03530) (photo source: J am Chem SOC.) the hypothesis of β - alkylation pathway proposed by the author is shown in the figure (scheme 2): electronic rich PD (0) excites alkyl halides to form free radicals, which then react with ketene intermediates to generate new free radicals, and then the carbonyl α position combines with PD (I) - x to produce β - alkylated PD (II) enol products If the unstable alkyl radicals can not react with ketene in time, many side reactions will occur In addition, it is also a question whether palladium catalyzed double electron dehydrogenation can occur in the presence of active radicals (photo source: J am Chem SOC.) the main problem in the catalytic cycle proposed by the author is the instability of alkyl radicals, so additional catalysts, such as copper salt, which can produce alkyl radicals reversibly, need to be added In addition, the α - radicals produced by conjugated addition may recombine with Cu (I) (instead of PD (I)) to form Cu (II) enol, which can minimize the β - H elimination reaction before enol formation; Pd (I) species can be oxidized by Cu (II) to form PD (II) catalyst In order to test this hypothesis, we used cyclohexanone (1a) and 2-bromopropane (2a) as model substrates and Pd (OAC) 2 / P (i-pr) 3 / Cu (opiv) 2 as catalyst to obtain the target β - alkylation product (3a) in 65% yield In this reaction, the author did not find a-alkylation product, only a small amount (< 3%) of excessive dehydrogenation product 3-isopropyl-2-cyclohexanone was observed Subsequently, the author designed a series of control experiments to illustrate the effect of each reactant (Table 1) When the reaction is carried out in the dark, the yield is the same as before, indicating that light is not needed to produce free radicals in the reaction The reactivity of alkyl iodide and alkyl chloride is not as good as that of alkyl bromide Palladium catalyst is necessary in the reaction, and ligands play a key role in the conversion P (i-pr) 3 is better than PCY 3, P (t-Bu) 3 and PPH 3 In addition, the catalytic efficiency of bidentate ligands is low Adding Cu (opiv) 2 cocatalyst can significantly increase the yield (from 20% to 65%); at the same time, reducing the copper load, using Cu (OAC) 2 or Cu (I) pre catalyst, the catalytic efficiency slightly decreased It is found that the mixed solvent of benzene and methyl acetate is the best solvent The addition of CS 2CO 3 can neutralize the HBr produced in the reaction, and it can be used as a halide scavenger due to the low solubility of CSBR, while the effect of other bases is poor Finally, it was found that the Hoac of the catalytic amount was also critical, although the exact reason was not clear (photo source: J am Chem SOC.) after obtaining the best reaction conditions, the author first used cyclohexanone and phenylacetone to screen the application scope of alkyl halide (scheme 3) All kinds of secondary and tertiary alkyl bromine substrates can carry out this transformation In addition to isopropyl bromide, four to eight membered cycloalkane bromine can produce expected products in medium to good yields The functional groups in the substrate have good tolerance to reaction conditions, including ether, BOC protected amine, ester, nitrile, cyclopropyl, benzoyl, TBS - or mom protected alcohol, amide, electron rich olefin and ketone Tert alkyl bromide has good reactivity to both cyclic and linear ketones, but excessive dehydrogenation occurs Cholesterol, androsterone, pentoxifylline and α - tocopherol, which are derived from natural products, can also be successfully obtained When phenylacetone was used as the substrate, the ortho-c-h bond on the aryl group remained intact (photo source: J am Chem SOC.) next, the author further explored the applicability of carbonyl substrate (scheme 4) Cyclic ketones such as cyclopentanone, polysubstituted cyclohexanone and benzocycloheptanone have weak reactivity; 1,4-dione can obtain the target product; simple linear ketones such as pentanone and 2-butanone show high reactivity In addition, phenylacetone with trifluoromethyl or methoxy substituent in p-position can obtain the target β - alkylation product in high yield Aldehydes with α - substituents can also react smoothly, and α - substituents are very important to inhibit aldol condensation In addition, both secondary and tertiary alkyl bromines can be coupled with α - aryl or alkyl substituted aldehydes In addition, it was found that aldehydes with ring structure were mainly trans products (photo source: J am Chem SOC.) the β - alkylation method developed by the author can be effectively applied to the synthesis of zanapezil (scheme 5) Ketone 6 and bromide 7 are used as coupling substrates, and the connection between them can be realized by β - alkylation (photo source: J am Chem SOC.) conclusion: the author has developed a new method for direct β - alkylation of simple ketones and α - substituted aldehydes by palladium catalyzed redox cascade reaction Different from the existing β - functionalization methods, this strategy can use easily available alkyl bromide as the source of alkyl, and has a relatively wide substrate range and high functional group tolerance This method can also be applied to the synthesis of complex molecules 137, 8404 [2] For β-alkylation of cyclopentanones using a tungsten photo-redox catalyst,see: Okada, M.; Fukuyama, T.; Yamada, K.; Ryu, I.; Ravelli, D.; Fagnoni, M Chem.Sci 2014 , 5 , 2893 [3] Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T R Angew Chem Int Ed 2017 , 56 , 8258 [4] For examples of using such a strategy to introduce other functional groups,see: (a) Hayashi, Y.; Itoh, T.; Ishikawa, H Angew Chem Int Ed 2011 , 50 , 3920 (b) Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li,J.; Wang, W Nat Commun 2011 , 2 , 211 (c) Jie, X.;Shang, Y.; Zhang, X.; Su, W J Am Chem Soc 2016 , 138, 5623.