Expedient Synthesis of 1,5-Diketones by Rhodium-Catalyzed

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Expedient Synthesis of 1,5-Diketones by Rhodium-Catalyzed Hydroacylation Enabled by C−C Bond Cleavage Rui Guo and Guozhu Zhang* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China S Supporting Information *

ABSTRACT: A rhodium-catalyzed intermolecular hydroacylation reaction of vinyl cyclobutanols with nonchelating aldehydes has been developed. This reaction offers a new and atom-economical approach for the selective preparation of 1,5-diketones in high yields. Experimental data suggest a sequential ring-opening, transfer hydrogenation, and hydroacylation mechanism. We propose that aldehyde decarbonylation is avoided by the formation of a novel rhodium enolate species that also accounts for the compatibility of a broad range of aldehydes and its anti-Markovnikov selectivity.

T

ransition-metal-catalyzed hydroacylation of alkenes with aldehydes is a straightforward and atom-economical method for the synthesis of ketones.1 In 1972, Sakai et al. reported the first example of rhodium-mediated intramolecular alkene hydroacylation to form a cyclopentanone.2 Since then, significant progress has been made on rhodium-catalyzed intramolecular hydroacylation of alkenes.3 Extending hydroacylation to intermolecular systems has proven to be challenging because the acyl-rhodium intermediates undergo undesired decarbonylation. To solve this problem, many elegant chelation strategies to stabilize the key intermediate have been extensively investigated. Both chelating aldehydes such as salicylaldehydes,4 2-aminobenzaldehydes,5 sulfursubstituted aldehydes,6 or (2-pyridyl)aldimines (eqs 1 and 2),7 as well as chelating alkene counterparts (eq 3)4a,b,d,e,8 have been developed to facilitate C−H bond activation and suppress competitive decarbonylation. This issue has also been addressed by using cobalt,9 ruthenium,10 or nickel catalysts.11 Despite this progress, chelation for selective hydroacylation with simple aldehydes remains challenging. Selective cleavage and functionalization of carbon−carbon single bonds by transition-metal catalysts has become a useful synthetic method.12 Cyclobutanols are frequently employed as privileged building blocks for the construction of diverse molecular scaffolds through metal-mediated β-carbon elimination.13 Inspired by Dong’s work on alcohol-chelation-assisted hydroacylations with various aldehydes,4a,14 we hypothesized that a hydroxyl group in the vinyl cyclobutanol might promote binding of the alkene to rhodium; the following hydroacylation could occur across the extended carbon chain after β-carbon elimination, leading to 1,5-diketones. Herein, we report the successful implementation of this hypothesis (eq 4). Other © 2017 American Chemical Society

well-established 1,5-diketone syntheses, such as Michael addition of ketones or derivatives with α,β-unsaturated ketones,15a,b dimerization of the condensation products between aryl methyl ketones and aldehydes,15c and ozonolysis of tetrasubstituted cyclopentenes, sometimes suffer from limited substrate scope. On the other hand, our method has easy availability of starting materials, broad substrate scope, atom economy, and excellent regioselectivity. In the initial test of our hypothesis, benzaldehyde was reacted with 1-vinyl cyclobutanol in toluene at 110 °C in the presence of a 2.5 mol% of [Rh(COD)Cl]2 (COD = 1,5-cyclooctadiene) and 10 mol% of a triphenylphosphine ligand. The desired 1,5diketone 2a was indeed isolated in 73% yield (Table 1, entry 1). Various types of phosphine ligands were then evaluated; PPh3 was the best ligand (Table 1, entries 2−7). The reaction is very sensitive to the steric properties of the ligand.16 Bidentate ligands that are more sterically congested (e.g., dppm, dppe, and dppp) lead to low yields of product, while ligands with a larger bite angle (e.g., dppb and dppf) gave improved yields. K2CO3 could facilitate the ring-opening of cyclobutanol (Table 1, entry 8).13a,17 Further optimization of conditions showed that higher temperatures (140 °C) in xylene were beneficial for achieving a quantitative yield (98%, Table 1, entry 10). Several Received: May 25, 2017 Published: August 31, 2017 12891

DOI: 10.1021/jacs.7b05427 J. Am. Chem. Soc. 2017, 139, 12891−12894

Communication

Journal of the American Chemical Society Table 1. Evaluation of Reaction Parameters

entrya

catalyst

ligand

base

solvent

temp (°C)

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12

[Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)OH]2 Rh(PPh3)2Cl

PPh3 PCy3 dppm dppe dppp dppb dppf PPh3 PPh3 PPh3 PPh3 −

K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K2CO3 K3PO4 K2CO3 K2CO3 K2CO3

toluene toluene toluene toluene toluene toluene toluene toluene xylene xylene xylene xylene

110 110 110 110 110 110 110 110 140 140 140 140

12 12 12 12 12 12 12 12 6 6 6 6

73 36 10 14 10 55 63 83 96 98 56 39

a

Reaction conditions: benzaldehyde (0.2 mmol), 1a (0.3 mmol), [Rh] catalyst (2.5 mol %), ligand (10 mol %), base (5 mol %), and solvent (0.2 M) unless noted otherwise. bIsolated yields are given.

other Rh catalysts were surveyed but showed no positive effects for this chemistry (Table 1, entries 11 and 12). Using optimal reaction conditions, we evaluated the coupling of vinyl cyclobutanol 1a and aldehydes with diverse steric and electronic properties (Table 2). A variety of electron-rich or

be good substrates (2u−2y). Primary and secondary aliphatic aldehydes were successfully transformed into diketones in excellent yields (2z−2ad). We then turned our attention to the variation on the vinyl part (Table 3). Vinyl cyclobutanol with different substitutions

Table 2. Substrate Scope with Respect to Aldehydesa,b

Table 3. Substrate Scope with Respect to Cyclobutanolsa,b

a

Reaction conditions: aldehyde (0.2 mmol), 1a (0.3 mmol), [Rh(COD)Cl]2 (2.5 mol%), PPh3 (10 mol%), K2CO3 (5 mol%), and xylene (0.2 M) at 140 °C for 6 h unless noted otherwise. bIsolated yields are given. c3.0 equiv of 1a was used.

a

Reaction conditions: benzaldehyde (0.2 mmol), 1 (0.3 mmol), [Rh(COD)Cl]2 (2.5 mol%), PPh3 (10 mol%), K2CO3 (5 mol%), and xylene (0.2 M) at 140 °C for 6 h. bIsolated yields are given.

electron-poor phenyl rings were tolerated on the aldehydes, furnishing the corresponding 1, 5-diketones in good to excellent yields (Table 2, 2b−2m). Terephthalaldehyde underwent double hydroacylation smoothly in the presence of 3.0 equiv of 1a (2n). Beside phenyl, other aromatic groups including naphthalene, furan, thiophene, pyrrole, and indole also demonstrated excellent compatibility with current reaction conditions (2o−2t). Traditionally challenging alkenyl aldehydes that are prone to interfere with the hydroacylation or deactivate the rhodium catalyst by complexation also proved to

on the carbon−carbon double bond underwent expected hydroacylation to give the corresponding 1,5-diketones in fair to good yields (2ae−2ah). Allyl cyclobutanol was a suitable substrate for this reaction, albeit with a slightly decreased yield (2ai). To our surprise, internal substitution of the olefin bond (1g, 1h) reversed the site selectivity (2aj, 2ak), and an inferior yield was attained with bulkier phenyl substitution. Interestingly, the 12892

DOI: 10.1021/jacs.7b05427 J. Am. Chem. Soc. 2017, 139, 12891−12894

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the final 1,5-diketone. Of note, the acyl rhodium(III) hydride F is coordinatively saturated and stable toward decarbonylation. Furthermore, the formation of the 6-membered metal complex G is more favorable, leading to anti-Markovnikov products via H.4a,b,e,d,14 Compound 2a could be made at the gram scale (Scheme 2) and could be used to prepare various cyclic molecules. For

reaction of 4-butenyl cyclobutanol 1i yielded 2al in 46% yield, indicating a distinct hydroacylation following the Markovnikov rule.18 Monosubstitutions of cyclobutanol could be allowed at the 2 or 3 position, giving 2am−2ao in low to moderate yields. For 1l, ring-opening occurred on the non-substituted side. To investigate the reaction mechanism, we probed the reaction by tracking the deuterium label for hydroacylation with deuterated benzaldehyde. NMR analysis revealed that deuterium was only incorporated into the methylene carbon at the βposition of the resulting diketone d-2a (eq 5). To further probe

Scheme 2. Synthetic Utilities of 1,5-Diketone and Application of the Method

the mechanism, we synthesized a dienone and deuterated benzylic alcohol. A deuterated rhodium hydride and benzaldehyde should form by dehydration, enabled by a rhodium catalyst. Indeed, about 14% of the desired diketone d22a was isolated under standard conditions.19 NMR analysis of the product revealed that over 80% deuterium was incorporated into the same methylene carbon and about 50% of deuterium incorporation was at the terminal methyl group (eq 6). These two experiments suggest the involvement of hydrometalation and hydroacylation. In another control experiment, 1d reacted under standard conditions without an aldehyde to form a linear enone with a swapped double bond, indicating an intramolecular transfer hydrogenation pathway (eq 7).20 The kinetic isotope effect and Hammett studies further suggest that oxidative addition of the rhodium to the aldehyde is the ratelimiting step.21 Previous studies22,23 and our own observations suggest the mechanism proposed in Scheme 1. First, there is a rhodiummediated ring-opening through β-carbon cleavage, followed by β-hydride elimination via intermediates A and B, that leads to dienone C. Next, ketone-assisted selective hydrometalation occurs on the electron-deficient and vicinal double bond to give D, followed by migration, leading to the Rh enolate species E. Hydroacylation then occurs on the distal double bond to afford

example, treatment of 2a with Et3SiH and TMSOTf resulted in the 2,6-disubstituted tetrahydropyran 3. 2a could then undergo double reductive amination to afford piperidine 4. Furthermore, 1,2-cyclopentanediol 5 could be readily accessed in the presence of TiCl4 and Zn in one step. Under basic conditions, an intramolecular Claisen condensation provided 6 in quantitative yield. Norlobelane could be accessed through 7. Moreover, an aldehyde derived from naturally occurring lithocholic acid reacted smoothly to give 8. In summary, we developed a highly selective rhodiumcatalyzed hydroacylation reaction of alkenyl cyclobutanols with non-chelating aldehydes. This reaction offers a new approach for the selective preparation of 1,5-diketones in an atomeconomical fashion. The experimental and deuterium-labeling studies show that the reaction proceeds through a sequential ring-opening, transfer hydrogenation, and hydroacylation process. These results also highlight the special role of rhodium enolate species for the broad substrate scope and excellent regioselectivity of this chemistry. Our future work will focus on developing new intermolecular hydroacylation reactions and realizing appropriate asymmetric control.

Scheme 1. Proposed Reaction Mechanism

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b05427. Experimental details, characterization data, and spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] 12893

DOI: 10.1021/jacs.7b05427 J. Am. Chem. Soc. 2017, 139, 12891−12894

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Guozhu Zhang: 0000-0002-2222-6305 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

We are grateful to NSFC-21421091, XDB20000000, the “Thousand Plan” Youth Program, the State Key Laboratory of Organometallic Chemistry, the Shanghai Institute of Organic Chemistry, and the Chinese Academy of Sciences. We thank Professor Guosheng Liu (SIOC) for helpful suggestions on this project and Dr. Xiaoyong Li (DOW Chemical) for proofreading the manuscript.

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DOI: 10.1021/jacs.7b05427 J. Am. Chem. Soc. 2017, 139, 12891−12894