Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Intramolecular Olefin Hydroarylation of Aromatic Aldehydes Using a Transient Directing Group Zhe Guan,† Siwei Chen,† Yue Huang,*,‡ and Hequan Yao*,† †
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China ‡ Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, P. R. China
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S Supporting Information *
ABSTRACT: A Rh(III)-catalyzed intramolecular olefin hydroarylation of aromatic aldehydes with a transient directing group has been described. The bidentate directing groups in situ generated from aromatic aldehydes and β-alanine could enable the subsequent C−H activation and hydroarylation with excellent site selectivities and high functional group compatibility. The further conversion of the aldehyde group showcased the broad application prospects of this methodology.
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aldehydes, ketones, and amines.11 In 2014, Dong achieved the regioselective α-alkylation of ketones with simple olefins using a secondary amine as a TDG.12 Yu and co-workers employed an amino acid as a TDG for the Pd-catalyzed C(sp3)−H arylation of o-alkyl benzaldehydes and aliphatic ketones in 2016.13 Ge developed a Pd-catalyzed direct γ-arylation of primary amines with catalytic glyoxylic acid as a TDG.14 Then, Hu,15 Sorensen,16 Shi,17 Wang,18 Jin,19 Seayad,20 Jiao,21 and Cheng22 independently described transition-metal-catalyzed C−H functionalizations of benzaldehydes with various TDGs. Inspired by these elegant works, herein, we disclosed a Rhcatalyzed intramolecular olefin hydroarylation of aromatic aldehydes with β-alanine as a transient directing group for the construction of dihydrobenzofurans and indolines (Scheme 1b). Initially, we selected 3-((2-methylallyl)oxy)benzaldehyde (1aa) as the model substrate to test our reaction. After screening different TDGs (Table 1), we found β-alanine (T6) was the optimal TDG, which provided the desired dihydrobenzofurans 2aa in 81% yield (Table 1, entry 1). We then examined other solvents such as DCE, HFIP, toluene, and DCM to increase the efficiency of the reaction (Table 1, entries 2−5), and DCM was found to be the most effective as 2aa could be isolated in 90% yield. Employing other acids instead of PivOH failed to achieve the reaction (Table 1, entries 6−8). Increasing the amount of AgSbF6 to 20 mol % could offer 2aa in 94% yield (Table 1, entry 9). Reducing the catalyst loading to 2.0 mol % led to lower yield (Table 1, entry 10). Control experiments showed that no product was detected in the
ver the past two decades, transition-metal-catalyzed C− H activation/hydroarylation has become an efficient synthetic tool for the rapid construction of functional molecules related to natural products, pharmaceuticals, and materials.1 By using amides, imines, sulfoximines, and carboxylic acids as directing groups, Ellaman and Bergman,2 Rovis,3 Cramer,4 Glroius,5 Sahoo,6 Yoshika,7 and López8 have realized the olefin hydroarylation via Rh, Ru, Co, or Ir catalysis (Scheme 1a). However, the aldehyde group as a familiar and important functionalized group has never been utilized in the olefin hydroarylation due to its weak directing capacity and susceptibility toward oxidation.9,10 Recently, the transient directing group (TDG) strategy has promoted transition-metal-catalyzed C−H functionalizations of Scheme 1. Transition-Metal-Catalyzed Intramolecular Olefin Hydroarylation
Received: March 28, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b01101 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 2. Substrate Scopea,b
entry
TDG
additive
acid
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10d 11e 12 13 14 15f 16g
T6 T6 T6 T6 T6 T6 T6 T6 T6 T6 T6 T6 T6 T6 T6
AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6c AgSbF6c AgSbF6c AgSbF6c AgSbF6c AgSbF6c AgSbF6c
PivOH PivOH PivOH PivOH PivOH TFA HOAc TsOH·H2O PivOH PivOH PivOH PivOH PivOH PivOH PivOH
dioxane DCE HFIP toluene DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM
81 56 67 nr 90 trace trace trace 94 64 nr nr nr nr 56 20
a
Reaction conditions: 1aa (0.2 mmol), [RhCp*Cl2]2 (4.0 mol %), TDG (40.0 mol %), AgSbF6 (10.0 mol %), and acid (0.4 mmol) in solvent (2.0 mL) at 80 °C for 20 h under argon atmosphere. bIsolated yield. cAgSbF6 (20.0 mol %) was used. d[RhCp*Cl2]2 (2.0 mol %). e Without rhodium catalyst. nr = no reaction. f60 °C. g40 °C.
a Reaction conditions: 1 (0.2 mmol), [RhCp*Cl2]2 (4.0 mol %), T6 (40.0 mol %), AgSbF6 (20.0 mol %), and PivOH (0.4 mmol) in DCM (2.0 mL) at 80 °C for 20 h under argon atmosphere. bIsolated yields. c 100 °C, 24 h. dAgSbF6 (40.0 mol %), 80 °C, 20 h.
absence of rhodium catalyst, T6, AgSbF6, or PivOH (Table 1, entries 11−14). Decreasing the temperature would hamper the transformation (Table 1, entries 15 and 16). Finally, the optimized conditions were recognized as 1a (0.2 mmol), [RhCp*Cl2]2 (4.0 mol %), T6 (40.0 mol %), AgSbF6 (20.0 mol %), and PivOH (0.4 mmol) in DCM (2.0 mL) at 80 °C for 20 h. With the optimal reaction conditions in hand, we then explored the substrate scope of the reaction (Scheme 2). 3-OOlefin-tethered benzaldehydes with either electron-withdrawing or electron-donating groups on the benzene ring reacted smoothly to offer the desired products (2aa−la) in moderate to excellent yields. In addition, the aromatic heterocycle (pyridine) could also be tolerated, giving the product 2ma in moderate yield at 100 °C for 24 h. After exploring the scope of the aromatic aldehydes, we then investigated the generality of the alkene chains. It was noteworthy that the substrates with electron-withdrawing and electron-donating substituents worked well, affording the desired products (2ab−ag, 2aj− an) in moderate to good yields except the large steric hindrance groups (2ah, 2ai). We next examined the one-pot, 2-fold hydroarylation of the ortho-C−H bonds with 3,5-bis((2methylallyl)oxy)benzaldehyde. Pleasingly, tricyclic product 2ao could be achieved in 99% yield. Ketones present additional challenges compared to aldehydes, and this kind of reacton of ketones has not been well explored. Gratifyingly, the intra-
molecular hydroarylation of aromatic ketones was employed successfully, giving the desired products (2ap, 2aq) in excellent yields. In addition, 3-N-olefin-tethered benzaldehydes were also explored, affording the corresponding indoline products in moderate yields (2ar, 2as). To demonstrate the practicability of the method, the gramscale synthesis of product 2aa (1.54 g, 8.74 mmol) was afforded in 90% yield, even with a reduced loading of the catalyst, TDG and additive (Scheme 3a). Further derivatization studies have also been carried out to explore the synthetic transformations of 2aa which could be transformed to 4-carboxamide derivative 3 easily through a 4-carboxylic acid intermediate. Benzoyl derivative 4 could be obtained in 84% yield after treatment with PhMgBr and PCC oxidation. The reductive amination with morpholine provided a tertiary amine 5 in 65% yield. A sulfamide derivative 6 could be obtained through an Ircatalyzed ortho-C(sp2)−H amidation of 2aa using a TDG (2fluoro-5-(trifluoromethyl)aniline). An oxazole derivative 7 could be received in 79% yield via the Van Leusen oxazole synthesis. The Wittig−Horner reaction with triethyl phosphonoacetate gave the (E)-alkene product 8 in 81% yield. To gain insight into the mechanism of this reaction, some control experiments were carried out. First, 1ad was tested for deuterium labeling studies in the presence of PivOD at 40 and 80 °C, respectively (Scheme 4a). The 1H NMR data showed that the deuteration was more likely to occur at the less B
DOI: 10.1021/acs.orglett.9b01101 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
protonation event. Subsequently, the kinetic isotope effect (KIE) experiment was examined. When an equimolar mixture of 1ao and [D]-1ao was checked at a low degree of conversion (Scheme 4b), a kH/kD ratio of 1.1 was obtained, which suggested that the C−H bond cleavage may not be involved in the turnover-limiting step. Based on the above mechanistic studies and previousliy reproted studies,3a,4,7,21,24 a plausible mechanism was proposed (Scheme 5). Initially, condensation between 1aa and T6
Scheme 3. Further Study of the Reaction
Scheme 5. Proposed Reaction Mechanism
Scheme 4. Mechanistic Insights
generates the aldimine A. Meanwhile, an active Rh(III) complex, generated from [RhCp*Cl2]2, AgSbF6, and PivOH, would coordinate with the aldimine A and then undergoes reversible C−H bond activation to generate the rhodacyclic intermediate B. Then, the intramolecular alkene insertion to the C−Rh bond of the species B generates a seven-membered rhodacyclic intermediate C. Subsequently, the protonation of intermediate C occurs to afford the aldimine D and regenerates the active catalyst. Finally, the hydrolysis of the aldimine D gives the product 2aa and releases the TDG β-alanine for a new catalytic cycle. In summary, we have developed a rhodium(III)-catalyzed intramolecular olefin hydroarylation of benzaldehydes with economic β-alanine as a transient directing group. This method provided a straightforward access to diverse dihydrobenzofurans and indolines in moderate to excellent yields, displaying a broad substrate scope. Moreover, transformation of the aldehyde group in the products into other functional groups highlights the potential synthetic value of the reaction. Further studies and other applications are now under investigation.
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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.9b01101. 1 H and 13C NMR spectra for all new compounds (PDF)
hindered ortho position (C6) of [D]-1ad than the hindered ortho position (C2). This result confirmed that the carboxylateassisted concerted metalation−deprotonation (CMD) pathway23 was generally guided by steric factors which favored the least encumbered ortho position, and the C−H activation is reversible. Furthermore, deuterium incorporation at the C5position of [D]-2ad indicated that the PivOH could be generated during CMD and then participated in the final
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. C
DOI: 10.1021/acs.orglett.9b01101 Org. Lett. XXXX, XXX, XXX−XXX
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[email protected].
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ORCID
Hequan Yao: 0000-0003-4865-820X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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REFERENCES
Generous financial support from the National Natural Science Foundation of China (NSFC21572272), the Innovation Team of “the Double-First Class” Disciplines (CPU2018GY04 and CPU2018GY35), the Foundation of The Open Project of State Key Laboratory of Natural Medicines (SKLNMZZCX201818), and the Fundamental Research Funds for the Central Universities (2632018ZD02) is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.9b01101 Org. Lett. XXXX, XXX, XXX−XXX
