JACS: Dong guangbin group of the University of Chicago realized the double carbon ring expansion of 1-indanone by inserting ethylene into the C-C bond

The ring extension reactions of carbonyl compounds such as Baeyer Villiger oxidation, Beckmann rearrangement and various carbon insertion reactions are often used in complex molecular synthesis, but most of them can only insert one atom Compared with the existing scheme 1a, there are few studies on the double carbon ring expansion of ketones Proctor's research group initially found that β - keto ester of carbon ring can be cycloaddition with activated alkyne, and then the double carbon ring expanding product (scheme 1b) can be obtained by rapid reverse 4 π cyclization; kuninobu and Takai et al Found a rhenium catalyzed insertion reaction of terminal alkyne with β - keto ester, but not suitable for the preparation of seven membered ring; caubere and Stoltz A scheme 1b method was reported, which was inserted by phenylyne Through transition metal catalyzed C-C activation, the unsaturated unit can be directly inserted into the CYCLOKETONE, and polyatomic ring expansion can be carried out without by-products The reaction involves the addition of C-C bond to the low-cost transition metal, and then the insertion of 2 π to obtain the expanded metal ring and the elimination of C-C reduction, that is, the "cutting and sewing" process, which has been widely proved in the tension ternary and quaternary ring systems (scheme 1c) However, for non tension system, its application scope is limited Ethylene as a bicarbonate coupling partner and ethylene as a 2 π unit of "cut and splice" reaction are challenging for tension or non tension systems In addition, the transition metal catalysts tend to cut off the strong aryl carbonyl bond to provide complementary selectivity for the conventional or free radical mediated C-C cracking reaction Recently, Dong guangbin group of the University of Chicago initially developed a RH catalyzed scheme 1D of 1-indanone by inserting ethylene into the C-C bond The result was published in J am Chem SOC (DOI: 10.1021 / JACS 9b07445) (photo source: J am Chem SOC.) firstly, the author used the unsubstituted 1-indanone (1a) as the model substrate, and optimized the reaction conditions such as different aminopyridine, ligands, solvents, additives, temperature and pressure of ethylene, etc Finally, the expected benzocyclohexanone product 1B (76%) was obtained under THF conditions of 100 psi ethylene, 5 mol% [Rh (C 2H 4) 2Cl] 2, 10 mol% imes, 20 mol% TsOH · H 2O, 100 mol% DG-1 and 100 mol% H 2O Among them, Rh catalyst, TsOH · H 2O and DG-1 are very important for the conversion, and when they do not exist, they can not get the expected products After determining the optimal reaction conditions, the author explored the substrate range of ethylene insertion reaction (chart 1) Firstly, the substrate of 1-indanone substituted at C6 position was investigated, and it was found that the electrical properties of the substituent at C6 position had little effect on the reaction The reaction has a wide range of functional group tolerance, including free phenol, sulfonamide, chloride, ester, methyl ketone, methylsilyl group, borate ester and free hydroxyl group For the substrate containing two keto carbonyls, C-C activation occurs only at the ninhydrin site 1-indanone with substituents at C4 or C5 showed similar reactivity When the C7 position is replaced, the steric hindrance around the carbonyl group is increased and the reactivity is reduced In addition, disubstituted 1-indanone or naphthyl fused cyclopentanone is also a suitable substrate (photo source: J am Chem SOC.) next, the authors studied the substituent effect on the fatty chain of 1-indanone Under the standard reaction conditions, the reactivity of 3-methyl-1-indanone was significantly reduced, while the yield was increased when imes ligand was not present and water content (50 mol%) was reduced Under the new reaction conditions, 3-phenyl-1-indanone can also get the expected product When there is an additional substituent in the benzene ring, the reaction efficiency is significantly improved In addition to methyl and phenyl, other alkyl substituents at position 3 can also be tolerated However, the C2 position of 1-indanone was replaced and the reactivity was lost Finally, the reaction can also be used in the natural product derived indanone, such as indanone 44a, which is linked to cholesterol, and androsterone 45A, which is linked to ether The unique 7-6-6-6-5 pentacyclic structure 46b can be obtained by introducing sevenform ketone 46a, which is confirmed by X-ray diffraction analysis In addition, the limiting condition of the reaction, i.e good synthesis efficiency (scheme 2a) can still be obtained by using the lowest catalyst loading / temperature, was also investigated When the loading amount of Rh / imes is reduced to 5 mol% and DG-1 to 50 mol%, the reaction efficiency is the best; at a lower temperature (130 ℃), when 5 mol% RH / ligand is used, the reaction can still proceed smoothly The reaction can also be scaled up to gram scale 1-indanone containing donor or acceptor groups still has good yield, and DG-1 can be recycled (scheme 2b) In addition, the enantiomeric enrichment of 5-substituted benzocycloheptanone (scheme 2C) can be achieved by using chiral 1-indanone r-35a (photo source: J am Chem SOC.) benzocycloheptanone is often used to synthesize bioactive compounds containing seven membered rings, but its conventional preparation method is very inefficient (scheme 3) The double carbon ring expanding method developed by the author greatly shortens the synthesis route of related complex molecules For example, benzocycloheptanone (8B), a key intermediate for the synthesis of weight-loss drug 50, can be prepared in one step by this method (scheme 3a) Cep-28122 shows potential antitumor activity The key structural fragment of cep-28122 is that benzocycloheptene can be synthesized by methoxy substituted benzocycloheptene 24b, and 24B can be directly prepared by the commercial 4-methoxy-1-indanone 24a through the "cut and splice" method (scheme3b) The key intermediate 10B for the synthesis of NMDA receptor amine53 for the treatment of various neurological disorders can be obtained by one-step synthesis of relatively cheap 6-chloro-1-indanone 10A (scheme 3C) In addition, benzocycloheptanone can be transformed into useful synthesis framework such as benzocycloheptanone 1b, and tetracycline 54 can be obtained by Fischer indole synthesis method in 88% yield; conjugated heptanone 55 can be obtained by ketone desaturation; octagonal lactam 56 or tetrazole 57 can be obtained by sodium azide treatment under different conditions, and its structure can be obtained by X Scheme 3D (photo source: J am Chem SOC.) conclusion: Dong guangbin's research group developed a double carbon ring expanding method by inserting ethylene into the relatively unstressed C-C bond of 1-indanone, which provides a direct and efficient synthesis method for the preparation of benzocycloheptanone The reaction is chemically selective and can be used to amplify the synthesis and simplify the synthesis of benzocycloheptene derived active compounds.