Cationic Iridium Complex-Catalyzed Intermolecular Hydroalkylation of

Letter Cite This: Org. Lett. 2019, 21, 741−744

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Cationic Iridium Complex-Catalyzed Intermolecular Hydroalkylation of Unactivated Alkenes with 1,3-Diketones Ryo Takeuchi,* Jun Sagawa, and Masaki Fujii Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5258, Japan

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ABSTRACT: Intermolecular hydroalkylation of unactivated terminal alkenes with 1,3-diketones under neutral conditions has been achieved using a cationic iridium catalyst. An active C−H bond of 2,4-pentadione (2a) added to 1-octene (1a) under refluxing DCE to give a Markovnikov product in 88% yield. A broad scope of alkenes and 1,3-diketones was observed. The products were easily converted to heterocycles. This reaction provides a new method for extending a carbon chain from an unactivated aliphatic terminal alkene.

A

developed an intermolecular hydroalkylation of unactivated alkenes with 1,3-diketones without the aid of a directing group. 1-Octene (1a) reacted with acetylacetone (2a) in the presence of cationic iridium catalyst under refluxing DCE to give 3aa. The reaction exclusively gave a branched product. Notably, the reaction proceeded under neutral conditions. Catalyst screening and optimization of the reaction conditions were carried out by the reaction of 1a with 2a. The results are summarized in Table 1. [Ir(cod)2]SbF6 was catalytically active to give 3aa in 88% yield (entry 1). [Ir(cod)Cl]2/AgSbF6 showed comparable catalytic activity to [Ir(cod)2 ]SbF6 (entry 2). In contrast to these cationic iridium complexes, [Ir(cod)Cl]2 did not show any catalytic activity. The choice of counteranion in cationic iridium complexes was important for the reaction. [Ir(cod)2]OTf, [Ir(cod)2]PF6 and [Ir(cod)2]BF4 were far less efficient than [Ir(cod)2]SbF6 (entries 4−6). The use of phosphorus ligands including a bidentate ligand had no effect on the reaction (entries 7−9). Use of the analogous rhodium catalyst [Rh(cod)2]SbF6 resulted in the formation of less than a trace amount of 3aa (entry 10). AgSbF6 and NaSbF6 did not show any catalytic activity (entries 11 and 12). These results clearly showed that cationic iridium species was the catalytically active species for the reaction. A decrease in the catalyst loading from 5 mol % to 3 mol % decreased the yield from 88% to 81% (entry 13), and a reduction in the reaction temperature to 40 °C resulted in a decrease in the yield from 88% to 20% (entry 14). Chloroform, dioxane, toluene, and THF were not suitable solvents for the reaction (entries 15−18), and DCE was the solvent of choice. We examined the scope of unactivated terminal alkenes under the optimized conditions. The reactions of 1-hexene (1b) and 1-decene (1c) with acetylacetone (2a) gave the

lkenes are one of the most important building blocks in organic synthesis because they are available in large quantities from petrochemical feedstocks.1 Electrophilic addition to alkenes has been used as a fundamental reaction in organic synthesis from alkenes as the starting material.2 The developmen of highly efficient, catalytic addition reactions to alkenes leading to carbofunctionalization has attracted much attention. Transition metal-catalyzed hydroalkylation of alkenes3 is an ideal carbon−carbon bond-forming reaction because the reaction proceeds atom economic under neutral conditions. Since unactivated alkenes are inert to carbon nucleophiles, complexation of unactivated alkenes with transition metals can realize the nucleophilic attack to unactivated alkenes.4 Hegedus reported the hydroalkylation of terminal alkenes with a stabilized carbanion via the complexation of alkene to a palladium (+2) complex.5 The reaction was a stoichiometric reaction. Wiedenhoefer first reported the Pd-catalyzed intramolecular hydroalkylation of unactivated alkenes with 1,3-diketones to give substituted cyclohexanones.6 They developed a similar catalytic intramolecular reaction with β-ketoesters and ketones.7 Au- or Cucatalyzed intramolecular hydroalkylation of unactivated alkenes with β-ketoamides has also been reported.8 In contrast to an intramolecular reaction, little is known about an intermolecular hydroalkylation of unactivated alkenes without the aid of a directing group. The hydroalkylation of ethylene or propylene has been reported.9 However, the intermolecular hydroalkylation of higher unactivated alkenes has not been reported. A new catalyst is needed to extend the reaction scope and enhance the selectivity. We previously reported cationic iridium complex-catalyzed highly regio- and stereoselective hydroalkylation of internal aryl alkynes with 1,3-diketones.10 To the best of our knowledge, this is the only example of the catalytic hydroalkylation of internal alkynes with active methylene compounds. In the course of our study on iridium-catalyzed carbon−carbon bond formation,11 we © 2019 American Chemical Society

Received: December 12, 2018 Published: January 14, 2019 741

DOI: 10.1021/acs.orglett.8b03975 Org. Lett. 2019, 21, 741−744

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

entry

cat. (mol %)

1 2 3 4 5 6 7 8 9

[Ir(cod)2]SbF6 (5) [Ir(cod)Cl]2 (2.5) [Ir(cod)Cl]2 (2.5)+AgSbF6 (5) [Ir(cod)2]OTf (5) [Ir(cod)2]PF6 (5) [Ir(cod)2]BF4 (5) [Ir(cod)2]SbF6 (5)+PPh3 (10) [Ir(cod)2]SbF6 (5)+P(OPh)3 (10) [Ir(cod)2]SbF6 (5)+racBINAP(10) [Rh(cod)2]SbF6 (5) AgSbF6 (5) NaSbF6 (5) [Ir(cod)2]SbF6 (3) [Ir(cod)2]SbF6 (5) [Ir(cod)2]SbF6 (5) [Ir(cod)2]SbF6 (5) [Ir(cod)2]SbF6 (5) [Ir(cod)2]SbF6 (5)

10 11 12 13 14 15 16 17 18

conditions DCE DCE DCE DCE DCE DCE DCE DCE DCE

reflux, reflux, reflux, reflux, reflux, reflux, reflux, reflux, reflux,

3h 24 h 3h 24 h 24 h 24 h 24 h 24 h 24 h

DCE reflux, 24 h DCE reflux, 24 h DCE reflux, 24 h DCE reflux, 24 h DCE 40 °C, 24 h CHCl3 reflux, 24 h dioxane reflux, 24 h toluene reflux, 24 h THF reflux, 24 h

Scheme 1. Scope of Alkenes

yield (%)b 88 0 86 9 3 5 0 0 trace trace 0 0 81 20 6 15 trace trace

a Mixture of 1a (3 mmol), 2a (1 mmol), [Ir(cod)2]SbF6 (0.05 mmol) was stirred under refluxing DCE. bIsolated yields. Yield was based on 2a.

corresponding products 3ba and 3ca in yields comparable to that with 1-octene (1a). The steric effect of a secondary alkyl group on the alkene affected the reaction. A cyclohexyl group decreased the yield compared to a primary alkyl group. The reaction of vinylcyclohexane (1d) with 2a gave 3da in 16% yield. On the other hand, the reaction of allylcyclohexane (1e) with 2a gave 3ea in 68% yield. These results suggested that the reaction is sensitive to steric hindrance around the carbon− carbon double bond. Alkenes containing a functional group in a side chain were reacted with 2a to examine the functional group compatibility. The reaction can tolerate a wide range of functional groups. Alkyl halides could be used for the reaction. ω-Chloroalkene (1g) gave a better result than ω-bromoalkene (1f). Substitution at halogen was not observed during the reaction. Ether 1h reacted with 2a to give 3ha in 58% yield. Ester, tosylate, and phthalimide were tolerated under the reaction conditions. The reactions of ester 1i and 1j gave 3ia and 3ja in respective yields of 76% and 73%. Tosylate 1k and phthalimide 1l reacted with 2a to give 3ka and 3la in respective yields of 75% and 73%. A thiophene ring was tolerated under the reaction conditions, and thiophene product 3ma was obtained in 70% yield. We tried to extend the scope of alkenes. 2-Octene (1n) reacted with 2a in the presence of 5 mol % [Ir(cod)2]SbF6 under refluxing DCE for 18 h to give 3aa in 72% yield. In contrast, 2-methy-1-hexene and cyclohexene did not react with 2a under the same reaction conditions. We next focused on the scope of 1,3-diketones using 1octene as an alkene substrate. 2,5-Heptadione (2b) reacted with 1-octene (1a) to give 3ab in 82% yield. The reaction gave a yield comparable to that with 2,4-pentadione (2a). Sterically more congested 1,3-diketones decreased the yield. The

reactions of 2c and 2d gave the corresponding products 3ac and 3ad in respective yields of 72% and 23%. Cyclic 3substituted-1,3-diketone gave better results than acyclic 3substituted-1,3-diketone. 3-Methyl-1,3-pentadione (2e) reacted with 1a to give product 3ae in 34% yield. In contrast, the reaction of 2-acetylcyclopentanone (2f) with 1a gave 3af in 89% yield. 1,3-Diaryl-1,3-propadiones (2g−2j) could be used for the reaction. The electronic properties of the substituents in the benzene ring affected the reaction. Diketones 2g and 2h smoothly reacted with 1a to give 3ag and 3ah in respective yields of 95% and 90%. A weakly electron-donating group such as chloro decreased the yield. Chloro-substituted product 3ai was obtained in 76% yield. Strongly electron-withdrawing groups such as CF3 gave the corresponding product (3aj) in low yield. Heteroaromatic 1,3-diketone could be used for the reaction. 1,3-Di(2-thienyl)-1,3-propandione (2k) smoothly reacted with 1-octene to give 3ak in 86% yield. In contrast to the good reactivity of 1,3-diketones, other active methylene compounds such as NCCH 2 Ac, O2NCH2COPh, PhSO2CH2Ac, and MeNO2 did not add to 1-octene in the presence of 5 mol % [Ir(cod)2]SbF6 under refluxing DCE for 18 h. A plausible reaction mechanism for the reaction is proposed (outer sphere mechanism) (Scheme 3). Coordination of the alkene to the cationic iridium complex forms intermediate I in which the electrophilicity of the alkene is increased.12 Nucleophilic attack of the coordinated alkene in intermediate 742

DOI: 10.1021/acs.orglett.8b03975 Org. Lett. 2019, 21, 741−744

Letter

Organic Letters

affected the yield of the reaction. The low yield of 3aj (p-CF3 group) is due to the less reactive enol double bond derived by the electron-withdrawing group on the aromatic ring. Thus, nucleophilic attack to an iridium-coordinated alkene is a key step of the reaction, and the cationic iridium complex acts as πLewis acid catalyst. 1,3-Diketones are useful starting materials for the synthesis of heterocycles including medicinally important compounds. To examine the utility of this method, we transformed our product into heterocycles. Product 3aa condensed with hydroxylamime and phenylhydrazine to give isoxazole 4aa and pyrazole 5aa in respective yields of 84% and 75%. A gram-scale reaction of 1a with 2a proceeded smoothly. The reaction of 0.627 g (6.27 mmol) of 1a with 2.081 g (18.55 mmol) of 2a under the same reaction conditions gave 1.227 g (5.78 mmol) of 3aa. The yield was the same as in the 1 mmolscale.

Scheme 2. Scope of 1,3-Diketones

Scheme 4. Synthesis of Heterocycles 4 and 5

Scheme 3. Plausible Reaction Mechanism

Scheme 5. Gram-Scale Synthesis of 3aa

In conclusion, we have developed a hydroalkylation of 1,3diketones to unactivated terminal alkenes. The reaction is characteristic for [Ir(cod)2]SbF6. The reaction proceeds in the presence of 5 mol % [Ir(cod)2]SbF6 under refluxing DCE. A wide range of terminal alkenes and 1,3-diketones can be used for the reaction. Further synthetic applications and mechanistic studies are being investigated in our laboratory.

I by the enol form of 1,3-diketone 2 gives σ-alkyl intermediate II. The release of H+ from intermediate II gives intermediate III. Protolysis of intermediate III gives the final product and regenerates the cationic iridium species. A similar mechanism involving nucleophilic attack of a coordinated alkene by an enol has been proposed.6,7,13 There is another plausible mechanism including hydroiridation to carbon−carbon double bond (inner sphere mechanism). Oxidative addition of an acidic C−H bond of 1,3-diketone to a cationic iridium complex gives a H−Ir enolate complex. Insertion of an alkene into the H−Ir bond followed by reductive elimination gives the product. We concluded that outer sphere mechanism is more likely than inner sphere mechanism. The reason is as follows. (1) Lewis acidity of the cationic iridium complex14 strongly affected the reaction (Table 1, entries 1, 4−6). The result is reasonably explained by considering that coordination of more Lewis acidic cationic complex makes the alkene more electrophilic to enhance the nucleophilic attack to the coordinated alkene. (2) para-Substituent on an aromatic ring of 1,3-diketone (2g−j)

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ASSOCIATED CONTENT

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03975. Experimental details and NMR spectra for obtained compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ryo Takeuchi: 0000-0002-3978-5920 743

DOI: 10.1021/acs.orglett.8b03975 Org. Lett. 2019, 21, 741−744

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Organic Letters Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grant-in-Aid for Scientific Research (KAKENHI) (No. 17K05867) from JSPS. REFERENCES

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DOI: 10.1021/acs.orglett.8b03975 Org. Lett. 2019, 21, 741−744