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Subtitle: 1,1-Disubstituted olefin oxidative rearrangement synthetic ketones
In the chemical industry, the Wake process for converting ethylene to acetaldehyde is one of the important industrial processes based on transition metal catalysis. At the same time, chemists have also developed an efficient method for converting monosubstituted terminal olefin 1 to methylketone 2 based on the aerobic PdII catalytic oxidation process, and widely used it in the total synthesis of bioactive molecules (Figure 1A). Mechanistically, the process mainly involves PdII coordination with olefins, Markovnikov hydroxypalladination, β-hydrogen elimination and tautomerization. To date, most studies have worked to reverse regional selectivity of hydroxypalladylation and reported the conversion of terminal olefin 1 to aldehyde 3, which may involve anti-Markovnikov hydroxypalladylation. In addition, there are also groups that have studied the related reactions of endoolefins, usually resulting in a mixture of two regional isomer ketones. In contrast, there are few reports of Wacker reactions for 1,1-disubstituted olefins, such as: Grigg et al. converted methylcyclobutane to cyclopentanone under typical Wacker conditions (PdCl2-CuCl2-O2-H2O) (Figure 1B); Wahl et al. used tert-butyl nitrite as the terminal oxidant to realize the ring expansion reaction from methylcyclobutane to cyclopentanone. However, since Pd is free of β-hydrides in complex 4, they believe that semi-pinacol-type rearrangements are a possible pathway for the formation of ring expansion products. Similarly, highly toxic reagents (e.g., lead tetraacetate, thallium nitrate) can be used as stoichiometric oxidants to perform the same conversion, but the substrate range is very limited. In addition, cyanogen azide is also used in the ring expansion reaction of methylene naphthenic hydrocarbons, while hydroxyl (tosyloxy)iodobenzene (Koser reagent) is limited to α-substituted styrene derivatives.
Recently, Professor Zhu Jieping (click to view introduction) of the Swiss Federal Institute of Technology in Lausanne (EPFL) has successfully developed a universal method for converting 1,1-disubstituted olefins to ketones by designing the PdII/PdIV catalytic cycle and combining 1,2-alkyl/PdIV dyotropic rearrangement as a key step (Figure 1C). Specifically: Hydroxypalladation of olefin 5 based on Markovnikov rule produces stable neopentyl σ-PdII complexes, which are oxidized in situ to PdIV species 6 in the presence of oxidants, followed by 1,2-alkyl/PdIV rearrangement by dyotropic to obtain species 7, and then reduced elimination to form C-X bond 8. If X is a fairly good off-nuclear body, then 8 will further eliminate HX to get ketone 9; Alternatively, PdIV species 6 were rearranged to obtain ketone 9 directly. To simplify the above sequence of reactions, the authors suggest that oxidants must meet two criteria: 1) chemically selective oxidation of in situ generated alkyl PdII species, not PdII salts; 2) The generated alkyl PdIV-X species 6 should be relatively stable to avoid premature reduction, elimination, and formation of C-X bonds or SN2 substitution reactions. The results were published in Science.
Figure 1. Oxidative functionalization of olefins. Image source: Science
First, the authors selected 7-methylenetridecane (11a, R=nC6H13) as the template substrate to optimize the reaction conditions and obtain the best reaction conditions: that is, ketone 12a could be obtained at 75% at room temperature under the condition of Pd(MeCN)4(BF4)2 (10 mol%). Controlled experiments have shown that the anti-anion BF4- in Selectfluor plays an important role in determining the response pathway of PdIV species, while Pd(MeCN)4(BF4)2 has high Lewis acidity, which in turn promotes the coordination of metals with double bonds and subsequent hydroxypalladylation. The authors then examined the substrate range (Figure 2A), which revealed symmetric 1,1-disubstituted olefins (12a-12i), methylenecyclobutane (13a-13c), functionally clustered methylenecyclohexane (15a, 15b) and methyleneadamantone (17a-17d) and even 7-methylenebenzocycloheptane (19), 1- Methylenecyclododecane (21) and 1-methylenecyclopentadecane (23) are compatible with this reaction to obtain the corresponding ketone products with good yield. Similarly, this conversion can be successfully achieved by asymmetric 1,1-disubstituted olefins (Figure 2B), but due to the selective migration of more substituted carbons, 1-alkyl-2-methylenecycloalkanes obtain C3-substituted cyclopentanone (26), cyclohexanone (28), cycloheptone (30), and cyclooctanone (34) by ring expansion. In addition, trans-1-methylenedehydronaphthalene (31) was selectively converted to the corresponding ketone 32 at a yield region of 57%, while the linear asymmetric terminal olefin (35) was rearranged to ketone-36 with low selectivity.
Figure 2. Substrate expansion (i). Image source: Science
Given the low regional selectivity of linearly asymmetric terminal olefins (35), the authors attempt to study the guiding effects of common organic functional groups. In fact, when 4-methyl-4-pentenoic acid 37a is reacted under standard conditions, a carboxyethyl migration product (major) of 5-oxohexanoic acid 38a can be obtained at a 72% yield, and the regional selectivity (38b and 38c) is significantly improved after the introduction of substituents at the carboxylic acid α- position. Similarly, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, and N-Ts piperidine-3-carboxylic acid derivatives (39a-39c) can also obtain corresponding δ-oxocarboxylic acids (40a-40c) with excellent yield and regional selectivity, especially 39a can be prepared on a 6 mmol scale. However, when both substituents of C(sp2) are secondary alkyl groups (e.g., 41, 43), the substituents with carboxylic acid functional groups again show higher migration ability, and obtain products 42 and 44 with excellent yield and good selectivity; In the process of converting 45 to 46, it was found that the secondary alkyl group of CH2CH2COOH was more dominant than the migration of tertiary alkyl (cyclohexyl). On the other hand, styrene derivatives are converted to a mixture of two regional isomers (48a-48b) with low selectivity due to the inherent high migration capacity of the phenyl group; Due to the preferential migration of 2-carboxyphenyl, styrene derivatives (49a, 49b) can be completely converted to products 50a-50b, which indicates that the high mobility of phenyl and the guidance of carboxyl groups have a synergistic effect. In addition, 2-(2-Methylenecycloalkyl)acetic acid can also undergo selective ring expansion and obtain corresponding 3-substituted cyclohexanone (54), cycloheptanone (56), cyclooctanone (58) and cyclononanone (60), but the migration capacity of quaternary carbon is reduced (56d). Notably, Oxone proved to be an effective oxidant for 39b oxidative rearrangement, yielding 40b at a 91% yield (Figure 3), but only yielding product 12a at 8% when applying the same conditions to 12a, so Selectfluor remains an excellent oxidizer in terms of versatility.
Figure 3. Substrate expansion (ii). Image source: Science
Next, the authors performed a series of synthetic applications (Figure 4), specifically: 1) under standard conditions, nocarone (61) was converted to two isomeroketones—62 (43%) and 63 (7%, rr=6:1), while (S)-carvacone (64) was converted to 65 (45%) and 66 (11%, rr=4:1); 2) L-menthone-derived substrates (67) and bicyclic compounds (69a) were obtained by ring expansion reaction to obtain ketone products 68 (61%) and 70a (65%), respectively; 3) The region-selective ring expansion reaction of the α-mountain channel annual derivative (71) was carried out to obtain product 72 with a yield of 62%, and it can be seen from the X-ray diffraction single crystal structure of 71-72 that the alkyl group migrated while maintaining its absolute configuration, which in turn indicates that this is a co-migration process.
Figure 4. Synthetic applications. Image source: Science
To further explore the reaction mechanism, the authors conducted a series of experiments: 1) controlled experiments showed that the reaction required Selectfluor and Pd(II) salts (Figure 5A); 2) Selectfluorine-mediated intermolecular hydroxyfluorination of olefins (11a) prepared fluorinated alcohol (74) failed to provide rearranged ketone 12a under Pd catalysis (Figure 5B), indicating that fluorinated alcohol 74 is not an intermediate for rearranging ketone 12a; 3) 1H and 19F NMR spectra showed that Selectfluor did not react with Pd(MeCN)4(BF4)2 at room temperature, indicating that PdIV species were formed only after the formation of alkyl PdII intermediates; 4) Methylenecyclopentadecane 23 was reacted under 18O-labeled H2O (97% 18O) to obtain cyclohexadecone (18O-24/24=2.5:1) at a yield of 68%, which indicated that the oxygen in this conversion was derived from water (Figure 5C), and the lower than expected incorporation of 18O in 24 may be due to the hydration of ketones during post-treatment and column chromatography purification; 5) In the presence of the catalytic amount Pd(OAc)2 (0.1 equiv), the acetonitrile solution of stirring 23, benzoic acid (2.0 equiv) and Selectfluor (1.2equiv) was stirred to obtain ring expansion product 75, which was subsequently converted to ketone 24 by saponification reaction. However, compound 76 resulting from alkene fluoropalladation was not observed under these conditions, and the formation of 75 can be explained by the following sequence of reactions, i.e., alkene 23 catalyzed by PdII-catalyzed acyloxypalladation to obtain PdII intermediate 77, which is oxidized to a sufficiently stable PdIV species 78 to participate in the dyotropic rearrangement to generate intermediate 79. Finally, 75 is obtained by reduction elimination to form C-F bonds, while the PdII catalyst is regenerated (Figure 5D). In addition, the control experimental results show that dyotropic rearrangement is a possible reaction pathway during the oxidation of 1,1-disubstituted olefins to rearranged ketones, but semi-pinacol rearrangement of intermediate 6 cannot be ruled out at this stage (Figure 1C).
Figure 5. Mechanistic research. Image source: Science
summary
Professor Zhu Jieping's research group successfully developed a universal method for rearranging 1,1-disubstituted olefins to ketones by designing the PdII/PdIV catalytic cycle combined with 1,2-alkyl/PdIV dyotropic rearrangement as a key step. The reaction is suitable for both linear terminal olefins and methylene naphthenes, and can also tolerate a variety of functional groups such as alkyl halogenates, aryl halogenates, alkyl tosylate, hydroxyl groups, carboxylic acids, esters, lactones, amides, ketones, α, β-unsaturated ketones, etc.
Oxidative rearrangement of 1,1-disubstituted alkenes to ketones
Qiang Feng, Qian Wang, Jieping Zhu
Science, 2023, 379, 1363-1368, DOI: 10.1126/science.adg3182
Mentor introduction
Zhu Jieping
https://www.x-mol.com/university/faculty/2766
(This article is contributed by pyridoxal)