Iridium-Catalyzed Regioselective Synthesis of Trifluoromethylated

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

pubs.acs.org/OrgLett

Iridium-Catalyzed Regioselective Synthesis of Trifluoromethylated Isocoumarins through Annulation of Benzoic Acids with Trifluoromethylated Alkynes Guangyuan Liu,† Guanghua Kuang,† Xingxing Zhang,† Naihao Lu,† Yang Fu,† Yiyuan Peng,† and Yirong Zhou*,†,‡

Org. Lett. Downloaded from pubs.acs.org by UNIV OF EDINBURGH on 03/26/19. For personal use only.

†

Key Laboratory of Fuctional Small Organic Molecule, Ministry of Education, College of Chemistry and Chemical Engineering, Jiangxi Normal University, No. 99 Ziyang Road, Nanchang 330022, China ‡ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, China S Supporting Information *

ABSTRACT: An unprecedented Ir-catalyzed oxidative coupling of benzoic acids with trifluoromethylated alkynes was successfully developed to provide diverse trifluoromethylated isocoumarins in moderate to good yields. This new practical procedure was highlighted by mild reaction conditions, broad substrate scope, good regioselectivity, high efficiency, and easy operation.

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annulations. However, in most cases, only symmetric alkynes were utilized to avoid the regioselectivity issues. Fluorine-containing groups have wide existence in a variety of important pharmaceuticals, agrochemicals, and materials, and their introduction always brings about drastic changes in physical, chemical, and biological properties as well as reactivity of organic molecules.8 Our continuous focus on the preparation of useful fluorine-containing heterocycles aroused our interest to incorporate a trifluoromethyl group on the isocoumarin skeleton.9 Literature survey revealed that there are only rare reports involving this poorly charted area of chemical space. Katzenellenbogen and Larock, separately, disclosed the preparation of a small set of 4-trifluoromethylated isocoumarins from the corresponding iodinated precursors through a coppercatalyzed classical replacement reaction (Scheme 1a).10 Karpov’s group presented a SbF5-mediated series of ring expansions to afford 3-trifluoromethylated isocoumarins (Scheme 1b).11 However, the above two methods require either excess steps or prefunctionalized starting materials and are accompanied by generation of stoichiometric amounts of waste or undesired byproducts. To circumvent those disadvantages, it is in high demand to develop a new and practical useful methodology to access diverse trifluoromethylated isocoumarins starting from readily available reagents. Toward this end, we envisioned that the transition-metal-catalyzed direct annulation

he isocoumarin scaffold represents an important constituent of widely naturally occurring unsaturated lactones,1 and it is also found as the core structure for various artificial drug molecules (Figure 1).2 Due to its diverse biological

Figure 1. Selected examples of natural products and drugs containing the isocoumarin core structure.

and pharmacological activities and also as a kind of pivotal versatile building block in complex heterocycle constructions, isocoumarin has thus attracted vast interests from synthetic and medicinal chemists. As a consequence, tremendous efforts have been devoted to the synthesis of isocoumarin derivatives, and steady progress has been achieved.3 Among the numerous methods, transition-metal-catalyzed direct oxidative coupling of benzoic acids with alkynes offers the highest efficiency and atom economy. Taking advantage of the direct C−H bond activation strategy employing the carboxylate as a weak directing group, it does not need to prefunctionalize the coupling partners anymore. A number of typical transition metals, including Rh,4 Ru,5 Ir,6 and Co,7 proved to be efficient catalysts to promote the © XXXX American Chemical Society

Received: February 14, 2019

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DOI: 10.1021/acs.orglett.9b00572 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

13% for expected 3a and 4a was obtained (Table 1, entry 1). More interestingly, in contrast to 1-phenylpropyne, the regioselectivity here was reversed.4d,5,6a These unexpected results indicated that there existed a critical difference of reactivity and selectivity between trifluoromethylated phenylacetylene 2a and 1-phenylpropyne. To overcome this challenge, we consequently carried out a comprehensive optimization.14 The solvent investigation showed that reaction medium played a pivotal role in the transformation (Table 1, entries 1−3). In most cases with the tested solvents, the reaction did not occur or only a trace amount of product was detected. Fluoride alcohols were found to be superior to the others, and TFE gave the best result (Table 1, entry 2). Subsequent temperature evaluation revealed that 50 °C is better than 80 °C (Table 1, entry 4). Then, a group of widely used transition metal catalysts was examined (Table 1, entries 5−7). Both Rh and Ru catalysts could generate good yields, albeit with poor regioselectivities, whereas a Pd catalyst was completely inert for this transformation and only gave a trace amount of product. Next, a series of silver salts as oxidants were investigated, but none of them could deliver better outcomes (Table 1, entries 8−10). Copper salt was inefficient to promote the coupling to obtain the desired adducts (Table 1, entry 11). Finally, improved results in terms of yield and selectivity were obtained in a dilute concentration (Table 1, entry 12). The control experiment showed that both iridium catalyst and silver salt oxidant were essential for the success, and no reaction occurred in the absence of either iridium catalyst or silver salt. With the optimized reaction conditions in hand, the generality and limitation for the annulation were explored. At first, the scope of the benzoic acid part was probed, and the results are demonstrated in Scheme 2. Both absolute structures of major product 3a and minor product 4a were unambiguously confirmed by X-ray crystallographic analysis, whereas the others were assigned by analogy. In general, the electronic property exhibited a strong influence on this oxidative coupling. Electronrich benzoic acids proved to be suitable substrates to afford the expected annulation products in moderate to excellent yields along with good regioselectivities. However, electron-with-

Scheme 1. Synthesis of Trifluoromethylated Isocoumarins

of benzoic acids with trifluoromethylated alkynes12 would represent the most straightforward synthetic route. However, Kawatsura and Itoh reported a Ru-catalyzed direct addition of benzoic acids to trifluoromethylated alkynes, affording linear enol esters rather than isocoumarins as the product (Scheme 1c).13 Herein, we demonstrate a highly efficient Ir-catalyzed oxidative coupling of benzoic acids with trifluoromethylated alkynes to furnish trifluoromethylated isocoumarins with nonnormal reversed regioselectivity. The initial reactivity assay employed simple benzoic acid 1a and trifluoromethylated phenylacetylene 2a as model substrates to optimize the reaction parameters. The results are summarized in Table 1. In light of Ison’s work,6a Ir catalyst in combination with silver salt was used to promote the reaction of 1a and 2a in MeOH at 80 °C. Unfortunately, only a low combined yield of

Table 1. Comprehensive Reaction Conditions Optimization for the Annulationa

entry

catalyst

oxidant

solvent

temp (°C)

yield (%) of 3ab

yield (%) of 4ab

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

[Cp*IrCl2]2 [Cp*IrCl2]2 [Cp*IrCl2]2 [Cp*IrCl2]2 [Cp*RhCl2]2 [Ru(p-cymene)Cl2]2 (PPh3)2PdCl2 [Cp*IrCl2]2 [Cp*IrCl2]2 [Cp*IrCl2]2 [Cp*IrCl2]2 [Cp*IrCl2]2

AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc Ag2CO3 AgTFA AgO Cu(OAc)2 AgOAc

MeOH TFE HFIP TFE TFE TFE TFE TFE TFE TFE TFE TFE

80 80 80 50 50 50 50 50 50 50 50 50

10 66 56 81 45 35 trace 46 17 15 trace 85

3 10 10 12 38 30 trace 8 5 5 trace 13

a

The reactions were carried out on 0.2 mmol scale of 1a with 0.3 mmol of 2a (1.5 equiv) in the presence of catalyst (3.5 mol %), oxidant (2 equiv) in 2 mL of solvent at 80 or 50 °C for 24 h. bIsolated yield. c4 mL of TFE was used. B


Letter

Organic Letters Scheme 2. Substrate Scope of Benzoic Acidsa

Scheme 3. Substrate Scope of Trifluoromethylated Alkynesa

a The reactions were carried out on 0.2 mmol scale of 1 with 0.3 mmol of 2a (1.5 equiv) in the presence of catalyst [Cp*IrCl2]2 (3.5 mol %), oxidant AgOAc (2 equiv) in 4 mL of TFE at 50 °C for 24 h. Isolated yield. bNot detected.

drawing groups were not compatible for this transformation. On the other hand, the steric hindrance also affected the reaction significantly. The para- and meta-substituents were well tolerated in this catalytic system (1b−1e), whereas the orthosubstituents only gave low conversion (1h). Some disubstituted benzoic acids were also assayed, and the highest regioselectivity was generated in the example of 1g. Moreover, aromatic heterocyclic acid was also suitable for this reaction; for instance, thiophene-3-carboxylic acid 1i could give moderate yield. After exploration of the scope of benzoic acids was completed, the other reaction partner, unsymmetric trifluoromethylated internal alkynes, was then probed. The results are depicted in Scheme 3. We found that the reactivity and generality for all the tested trifluoromethylated alkynes were good. A variety of substituents on different positions of the benzene ring of internal alkynes were compatible. A group of halogen atoms, including fluorine, chloride, bromide, and even iodine (3j−3m), were compatible to produce satisfactory outcomes, which provide valuable opportunities for further late-stage derivatizations. Electronic properties of internal alkynes did not exert evident influence on the reaction, and both electron-donating and electron-withdrawing groups were well tolerated to afford the expected products smoothly. Strong electron-withdrawing groups, such as nitro and trifluoromethyl groups, also gave acceptable results (3n and 3o). Substrates bearing ester groups could also react well with benzoic acid under the standard conditions (3p and 3q). The structures of 3p and 4p were

a The reactions were carried out on 0.2 mmol scale of 1a with 0.3 mmol of 2 (1.5 equiv) in the presence of catalyst [Cp*IrCl2]2 (3.5 mol %), oxidant AgOAc (2 equiv) in 4 mL of TFE at 50 °C for 24 h. Isolated yield. bThe yields in parentheses were for 1 mmol scale reaction for 3p and 4p.

confirmed by X-ray crystallographic analysis. To enhance the practicality of the current methodology, a 1 mmol scale reaction of 2p was performed, and comparably good yields were generated for 3p and 4p. Steric hindrance had a significant effect on the regioselectivity for the annulation process. The ortho-substituted alkene 2s generated the best regioselectivity, whereas the para- or meta-substitutents had less influence. In light of previous mechanistic studies and preliminary experimental investigations,6a a possible catalytic cycle was proposed to explain the obtained non-normal regiospecific outcomes. As illustrated in Scheme 4, the active species A was initially generated from the catalyst precursor [Cp*IrCl2]2 dimer by treatment of silver salt with the anion exchange. Then one of the two acetates was replaced by the substrate C


Organic Letters

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Scheme 4. Proposed Catalytic Cycle

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00572. Experimental details and spectra for important compounds including fluorescence profiles and NMR spectra (PDF) Accession Codes

CCDC 1896958, 1896960, and 1903802−1903803 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Naihao Lu: 0000-0003-3336-2502 Yirong Zhou: 0000-0002-3470-4562

benzoic acid 1a. Carboxylate directed the ortho-C(sp2)−H activation of benzoic acid with the assistance of acetate to form the five-membered cycloiridium intermediate B. Subsequently, trifluoromethylated phenylacetylene 2a would coordinate to the catalyst iridium center to produce intermediate C. Alkene migratory insertion into the carbon−iridium bond regioselectively provided seven-membered metallacycle D. Subsequent reductive elimination generated intermediate E, which could be oxidized by AgOAc to furnish the annulation product 3a along with regeneration of the active catalyst A for next catalytic cycle. We conceived that the unexpected reversed regioselectivity came from the intrinsic electronic property difference between trifluoromethylated phenylacetylene 2a and 1-phenylpropyne. For 1-phenylpropyne, the bulky substituent of alkyne (Ph group) resides in the α-position to iridium to avoid steric repulsion to the aromatic hydrogen on the benzoic acid in intermediate D. Thus, the catalyst center always added to the unsaturated carbon next to the benzene ring rather than the methyl group. However, in the case of trifluoromethylated phenylacetylene 2a, because the trifluoromethyl group is a strong electron-withdrawing group, Cα is much more electronrich than Cβ. Therefore, the cationic iridium center preferred addition to Cα, resulting in 3a as the major product for this new catalytic system. In conclusion, a practical and useful Ir-catalyzed oxidative cross-coupling/annulation of benzoic acids with unsymmetric trifluoromethylated internal alkynes was successfully developed for facile access to diverse trifluoromethyl-functionalized isocoumarins. The substrate scope was broad with good functional group tolerance. Moderate to excellent yields along with good regioselectivities were achieved under mild conditions. A possible mechanism was proposed to explain the obtained non-normal regioselectivities for the unsymmetric trifluoromethylated internal alkynes. Further synthetic applications of trifluoromethylated alkynes as versatile fluorinecontaining building blocks are underway in our laboratory.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by grants from the National Natural Science Foundation of China (No. 21602089), the Natural Science Foundation of Jiangxi Province (No. 20181BAB203004), Jiangxi Educational Committee (GJJ150321), Open Project Program of Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University (No. KLFS-KF-201622), Startup Foundation for Doctors of Jiangxi Normal University (Y.Z., No. 5464), Foundation for Young People of Jiangxi Normal University (Y.Z.).

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Iridium-Catalyzed Regioselective Synthesis of Trifluoromethylated

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