Palladium-Catalyzed Cross-Coupling of gem-Bis(boronates) with Aryl

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Palladium-Catalyzed Cross-Coupling of gem-Bis(boronates) with Aryl Halides: An Alternative To Access Quaternary α‑Aryl Aldehydes Purui Zheng, Yujie Zhai, Xiaoming Zhao,* and Tao XU* Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, Shanghai, 200092, P. R. of China

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S Supporting Information *

ABSTRACT: The compounds with a quaternary α-aryl aldehyde skeleton are important units in organic chemistry. Previously, the aryl group and carbonyl group are introduced in a stepwise manner. Herein, a novel route is developed to construct the quaternary α-aryl aldehydes with gembis(boronates) as precursors, in which the two groups are installed simultaneously. The gem-bis(boronates) are readily available from ketones; as a result, this methodology provides a more general strategy to produce the quaternary α-aryl aldehydes with broad scopes and synthetic convenience. Scheme 1. Routes To Access the Quaternary α-Aryl Aldehyde

he α-aryl carbonyl framework has been a versatile precursor to construct complex structures which are widespread in natural products, bioactive molecules, and material compounds (Figure 1).1 Numerous methods were developed to access the α-aryl carbonyl derivatives, including α-aryl esters, amides, and ketones.2 However, there were few routes to afford α-aryl aldehyde, due to the competing aldol condensation process under basic media. Recently, some methodologies with transition-metal catalysis3 or organocatalysis4 were utilized to obtain these α-aryl aldehyde products. However, they usually focused on the process to afford the tertiary α-aryl aldehyde skeletons. The synthesis of quaternary α-aryl aldehydes remains scarce and is still in high demand. To gain the quaternary α-aryl aldehydes, traditionally α-aryl acetic esters or α-aryl acetonitriles were employed. After repetitive nucleophilic alkylation with different alkyl halides and reductive process, the quaternary α-aryl aldehydes are obtained in several steps (Scheme 1, eq 1).5 Considering the limited available structure of starting materials when it comes to multifunctional groups, especially for some substituents that are sensitive to reductant, such as ester or cyanide in other sites, more steps in fact were involved to finish the requirement. To facilitate the routes, methods with the help of transition-metals were developed.6 For instance, the Buchwald group reported the palladium-catalyzed α-arylation of aldehyde with aryl halides but still only limited α-tertiary

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aldehydes were tested (Scheme 1, eq 2).7 In addition, both of these methods need to install the aryl group or aldehyde (or its precursor) to the substrates in advance. Herein, we report a new transformation of gem-bis(boronates) compounds that were easily obtained from ketones to access the quaternary αaryl aldehyde products, which introduce the aryl and carbonyl groups simultaneously in the process (Scheme 1, eq 3). Moreover, the alkenyl halides also proved to be efficient reactants in the transformation. gem-Bis(boronate) substrates that can be obtained from aldehydes or ketones have powerful potential to transfer to other compounds. For instance, the Shibata and Morken groups reported the coupling reaction of gem-bis(boronates) with aryl halides to give the benzyl boronates.8 In 2014, the coupling reactions of gem-bis(boronates) with alkenyl halide to give allylic boronates and with 1,1-dibromoalkene to give Received: November 7, 2018

Figure 1. Selected drug compounds with α-aryl carbonyl framework. © XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b03560 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Optimization Conditionsa

Scheme 4. Scopes with Respect to the gem-Bis(boronates) Substratesa

a

The reactions were conducted on 0.1 mmol scale. For the details on the experimental procedure, see Supporting Information. Yields were determined by 1H NMR with CH2Br2 as an internal standard.

Scheme 3. Scopes with Respect to the Aryl Substratesa

a

The reactions were conducted on 0.2 mmol scale under the optimized condition in Scheme 2 with L4 as ligand at 60 °C. Isolated yields were given.

carboxylic acids, respectively.12 In the meantime, we also reported a methodology to introduce the aldehyde and allylic group to this type of substrate to construct a quaternary carbon center, which provides a protocol for difunctionalization of ketones.13 In this letter, we report the transformation of gembis(boronates) to access the α-aryl aldehyde substrate by the strategy we developed in the previous work. We commenced this study with compound 1a and 4iodotoluene (2a) as the model substrates under the previous conditions (Scheme 2). However, no desired product was found with PPh3 (L1) as the ligand. Likewise, the reaction with trimethoxylphosphine (L2) or 1,2-bis(diphenylphosphino)benzene (L3) did not give any product. It was to our delight to find a 51% yield of the desired product in the presence of tri-tert-butylphosphine tetrafluoroborate (L4) as the ligand. The yield could be improved to 87% when the reaction was conducted at 60 °C and an 84% yield at 85 °C. Another phosphine ligand, such as Xanphos (L5), only gave trace product while the nitrogen ligands were not useful in these conditions. Additionally, control experiments showed that the catalyst, ligand, and the preactive reagent (n-BuLi)14 were all crucial to the transformation (for more details, see Supporting Information). With the optimal conditions in hands, we turned our attention to the generality of this palladium-catalyzed transformation of gem-bis(boronates). As shown in Scheme 3, the yield of 3a did not experience a significant change on the 1 mmol scale. Aryl iodides with different substituents were employed in this transformation, and moderate to high yields

a

The reactions were conducted on 0.2 mmol scale under the optimized conditions in Scheme 2 with L4 as ligand at 60 °C. Isolated yields were given. bThe reaction was conducted on 1 mmol scale. c The reaction was conducted at 85 °C

allenes were reported.9 In addition, the alkylation of gembis(boronates) to afford alkylboronic esters was achieved with or without metal catalysis.10 Meanwhile, other transformations of gem-bis(boronates) also drew attention.11 Very recently, the Pattison and Liu groups developed methods to introduce the ketone group by reacting gem-bis(boronates) with esters and B

DOI: 10.1021/acs.orglett.8b03560 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 5. Scopes with Respect to the Alkenyl Substratesa

Scheme 7. Proposed Catalytic Cycle

Then we studied the scope of substrates with respect to the gem-bis(boronate) compounds (Scheme 4). It was worth mentioning that both the acyclic (4a−4d) and cyclic (4e−4i) bis(boronate) substrates can proceed smoothly to give the corresponding products in moderate to good yields. The gembis(boronates) bearing ether (4b), CF3 (4c), fluorine (4d), ketal (4h), or amine (4i) can be tolerant in the transformation. Meanwhile, as mentioned in Scheme 3, the aryl partners with substituted sulfur ether (4a), ester (4f), ether (4h), and heterocycle (4g) groups could smoothly generate the corresponding products under these conditions. Besides, another type of Csp2-halide substratealkenyl bromide substrateswere also studied in this transformation.15 From Scheme 5, it can be found that the alkenyl bromide substrates with a variety of functional groups, either an electron-donating or electron-withdrawing group, could afford the corresponding products in good to high yields. In addition to ether (5a, 5b), chloride (5g, 5h), CF3 (5c), thiophene (5e), and ketal (5i) groups, further study on the substituents showed benzodioxan (5d), nitro (5f), and sulfuryl (5i) groups can also survive in the process. The quaternary α-aryl substrate 3a obtained by this method was used to demonstrate the synthetic utility of this methodology (Scheme 6). The aldehyde structure was readily converted to primary alcohol 6a after reduction. The amine 6b was given in high yield through imine formation and LiAlH4 reductive processes. Meanwhile, the alkenyl group can be also introduced by a Witting reaction to produce compound 6c. In addition, the product 3a can be smoothly transformed to quaternary benzyl nitrile substrate 6d in excellent yield. A proposed catalytic cycle to determine the mechanism was addressed in Scheme 7 based on the experiments and previous work. The lithium salt A was obtained under the n-BuLi condition, which could react with DMF to give the α-boron aldehyde B. The present equilibrium between C-bond B and O-bond boron isomer B′ facilitated the transmetalation with the ArPd(L)I complex. After transformation from intermediate C′ to C, the product was produced with reductive elimination as well as the regeneration of the palladium catalyst. In conclusion, we reported a convenient route to synthesize the quaternary α-aryl aldehyde substrate by palladiumcatalyzed transformation of gem-bis(boronates), which is very easily obtained from ketones. Compared with previous methods, this methodology could introduce the two functional

a

The reactions were conducted on 0.2 mmol scale under the optimized condition in Scheme 2 with L4 as ligand at 60 °C. Isolated yields were given. For 5g and 5h, Ar′ = p-ClPh.

Scheme 6. Derivatives of α-Aryl Aldehyde (CDI = N,N′Carbonyldiimidazole)

were obtained to furnish the corresponding products. The compounds with a substituent in the ortho, meta, or para position can smoothly give the quaternary α-aryl aldehydes. A variety of functional groups such as alkyl (3a), chloride (3c), fluorine (3h), CF3 (3i), ether (3d, 3g), ester (3c), and cyanide (3f) groups were all well-tolerated in this reaction. Heterocycles, such as thiophene (3k) and N-methylpyrazole (3l), were also successfully introduced to the α-position of aldehydes. Notably, strong base- or reductant-sensitive functional groups, such as ester and cyanide in the aryl partners, can survive under these conditions, albeit using n-BuLi in this process. C

DOI: 10.1021/acs.orglett.8b03560 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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groups simultaneously. This feature is greatly beneficial to enlarge the substrate scope and synthetic applications.

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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/acs.orglett.8b03560. Description of additional data; procedures and characterization data for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiaoming Zhao: 0000-0002-1447-128X Tao XU: 0000-0002-4228-4895 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the “Thousand Talents Plan” Youth Program (No. 13802350017), Shanghai Pujiang Talents Program (No. 13802360072), and Tongji University for the financial support.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03560 Org. Lett. XXXX, XXX, XXX−XXX