Letter pubs.acs.org/OrgLett
Stereoselective Palladium-Catalyzed Decarboxylative γ‑Arylation of Acyclic β,γ-Unsaturated Carboxylic Acids Ina Scheipers, Eva Koch, and Armido Studer* Organisch Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany S Supporting Information *
ABSTRACT: Palladium-catalyzed γ-arylation of acyclic β,γunsaturated carboxylic acids with various aryl iodides is reported. The cascade comprises a decarboxylative γpalladation of β,γ-unsaturated α,α′-disubstituted carboxylic acids and subsequent C(sp2)−C(sp3) bond formation to provide diaryl vinyl methanes in moderate to good yields and high E/Z-selectivities. Reaction with an enantiomerically pure acid revealed that the process occurs with high stereospecificity.
C
Scheme 1. Pd-Catalyzed Decarboxylative Coupling Reactions Using β,γ-Unsaturated Carboxylic Acids
arbon−carbon bond forming reactions are one of the most ubiquitous transformations in organic synthesis.1 In the past, different methods have been developed using transition metal catalysis.2 Among them are the traditional cross-coupling reactions such as the Heck,3 Negishi,4 Stille,5 Suzuki−Miyaura,6 and Sonogashira7 reaction that are broadly applied in industry and academia. Inspired by nature,8 organic carboxylic acids have been identified as highly valuable precursors for the generation of organometallic intermediates via a decarboxylation reaction.9 Notably, carboxylic acids are available in great structural diversity at low cost from abundant biomass feedstock and they are easy to store and readily handled.10 Since the pioneering works of Myers11 on the Pd-catalyzed decarboxylative Heck-type olefination of arene carboxylates and of Gooßen12 on the biaryl synthesis proceeding via Cucatalyzed decarboxylative coupling, the decarboxylative crosscoupling reaction between carboxylic acids and aryl halides or triflates has found many applications for the construction of C− C bonds. Initial studies mainly focused on decarboxylative C(sp2)−C(sp2) bond formation. More recently, C(sp2)− C(sp3) coupling was also achieved via this approach and as a highlight MacMillan and Fu disclosed an enantioselective decarboxylative arylation of α-amino acids by cooperative photoredox and nickel catalysis.13 Our group has shown that Pd-catalyzed decarboxylative γ-arylation works efficiently using 2,5-cyclohexadien-1-carboxylic acids as substrates in combination with aryl iodides to provide arylated 1,3-cyclohexadienes with complete stereospecificity (Scheme 1a).14,15 Moreover, such an approach was also successfully applied to the total synthesis of resveratrol-based natural products,16 macheriols, THC, and analogs.17 These stereoselective Pd-catalyzed decarboxylative couplings were achieved using rigid cyclic carboxylic acids as substrates. We questioned whether such a valuable decarboxylative γarylation can also be performed on acyclic, unsaturated carboxylic acids as starting materials (Scheme 1b) and here © XXXX American Chemical Society
report first results from our investigation. The preparation of the β,γ-unsaturated α,α′-disubstituted carboxylic acids 1a−e is described in the Supporting Information (SI). γ-Arylation was first investigated using acid 1a in combination with various substituted aryl iodides (Scheme 2). It was found that these transformations are best conducted with Pd(dba)2 as a catalyst (10 mol %) and Cs2CO3 as a base (1.1 equiv) in toluene at elevated temperature (110 °C for 24 h). Alkyl substituents at the arene ring in the aryl iodide are tolerated, and diaryl vinyl methanes 2a, 2b, and 2c were isolated in 33−83% yield. Products derived from a decarboxylative α-arylation were not identified. Interestingly, sterically demanding aryl iodides bearing two ortho-substituents reacted more efficiently in this Received: February 20, 2017
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DOI: 10.1021/acs.orglett.7b00512 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Decarboxylative Coupling of Acid 1a with Various Aryl Iodides
Scheme 3. Stereoselective Decarboxylative Coupling
γ-arylation reaction than the less bulky congeners. We made similar observations for the decarboxylative γ-arylation in cyclic systems,14−17 but do not have any convincing explanation. This was also observed for aryl iodides with electron-donating methoxy substituents, and the target alkenes 2d−h were isolated in 20−83% yield. The robustness of the method was documented by a larger scale synthesis of compound 2h (1 mmol, 76% yield), and as a side product, trans-β-iodostyrene was isolated in 5% yield in this experiment. Iodo-naphthalenes could be successfully transformed to the corresponding arylated products 2i and 2j which were isolated in 37% and 58% yield, respectively. We next investigated the E/Z-selectivity for the γ-arylation using racemic α-chiral α,α-disubstituted carboxylic acids 1b and 1c (Scheme 3). Acid 1b reacted with 2,6-dimethoxy-aryl iodide under optimized conditions in 53% isolated yield and moderate E/Z-stereoselectivity (3:1) to the target alkene 3a. The low selectivity is not surprising considering the small steric difference between the α-ethyl and α-methyl group in substrate 1b. We therefore switched to the α-methyl-α-phenyl-acid 1c and noted for the γ-arylation with 2,6-dimethoxy-aryl iodide an improved yield and slightly better selectivity (see 3i). We found that the E/Z-selectivity is heavily influenced by the nature of the aryl group. Whereas, with phenyl and p-chloro-phenyl iodide, reaction occurred with a moderate 5:1 E/Z-ratio (3b, 3c), the selectivity was high for arylation with p-methoxyphenyl iodide (17:1, 3d). Pleasingly, excellent selectivities were obtained for aryl iodides bearing ortho-alkyl substituents and products 3e, 3g, and 3h were isolated in 56−73% yield with complete E/Z-selectivity (>99:1). Aryl iodides with metamethyl groups provided, in the reaction with 1c, the corresponding diaryl vinyl methanes 3f and 3j in good isolated yields with high selectivities. We do not currently fully understand selectivity trends based on these results (see mechanistic discussion below). We further found that acid 1d with a trans-configured double bond does not react to form the γ-arylation product under the optimized conditions. This indicates that a cis-configuration in the starting alkene, which is fixed in cyclic substrates (see Scheme 1), is a key factor for a successful reaction outcome. However, the cis-alkene 1e lacking the activating phenyl group at the double bond also did not provide the target product,
showing the importance of the cis-β-alkyl styrene structural motif in the substrate for this transformation. In order to test the enantiospecificity of the Pd-catalyzed γarylation, a sample of acid 1c was resolved by chiral HPLC chromatography (93% ee; see SI).18 We were pleased to find that γ-arylation with 3,5-dimethyl-iodobenzene provided product 3j with 86% ee revealing that the reaction proceeds with high stereospecificity (Scheme 4). Scheme 4. Enantiospecific Decarboxylative γ-Arylation
The suggested mechanism for the Pd-catalyzed decarboxylative γ-arylation of acyclic carboxylic acids exemplified with substrate 1a is depicted in Scheme 5. Starting with a Pd0species, oxidative addition to the aryl iodide leads to a PdII−Ar intermediate. Ligand exchange in the Ar−Pd−I complex with the Cs-carboxylate A, generated upon deprotonation of 1a with Cs2CO3, gives intermediate B where the Pd-metal weakly coordinates to the double bond. For trans-alkenes, coordination is hindered, and this is likely the reason for the failure of the γarylation with substrate 1d. Decarboxylative palladation with concomitant CO2 fragmentation then leads to an allyl-Pdcomplex C which undergoes reductive elimination to the isolated product 2 along with Pd0. The E/Z-selectivity can be understood considering a cyclic six-membered chair-type transition state for the key decarboxylative γ-palladation. For substrate 1c, transition state B1 placing the larger phenyl substituent in the equatorial position is most likely. B1 will B
DOI: 10.1021/acs.orglett.7b00512 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
Scheme 5. Suggested Mechanism
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Martina Rawe (University of Münster) for resolving acid 1c and Dr. Anup Bhunia (University of Münster) for conducting the 1 mmol scale experiment. This work was financially supported by the Deutsche Forschungsgemeinschaft (DFG).
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eventually lead to the E-product as observed in the experiment. The Z-product would derive either from a chair-type transition state B2 building up strong 1,3-diaxial interaction of the two phenyl groups or more likely from a boat-type transition state B3. Clearly B2 and B3 should lie above transition state B1. The rather strong effects of the substituents in the aryl iodides on the stereoselectivity might be due to differences in the rates of the reductive elimination in C. Hence, E/Z-selectivity erosion can occur considering interconversion of σ-allyl-Pd to π-allylPd-complexes,19 and this represents another pathway to the Zisomer rather than proceeding via B2 or B3. In summary, we introduced Pd-catalyzed γ-arylation using acyclic, unsaturated carboxylic acids as substrates. The procedure comprises an oxidative addition step, ligand exchange with in situ generated Cs-carboxylate followed by rearrangement of the double bond including CO2 extrusion, and subsequent reductive elimination. The starting materials are readily accessible, experiments are easy to conduct, and products are obtained in moderate to very good yields with moderate to excellent E/Z-selectivity. In a single example, it was shown that the reaction proceeds with high enantiospecificity documenting the potential to obtain valuable diaryl vinyl methanes with high enantiopurity via this approach.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00512. Experimental procedures, characterization data, and 1H and 13C NMR spectra (PDF)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Armido Studer: 0000-0002-1706-513X C
DOI: 10.1021/acs.orglett.7b00512 Org. Lett. XXXX, XXX, XXX−XXX
