Letter Cite This: Org. Lett. 2018, 20, 1798−1801
pubs.acs.org/OrgLett
Copper-Catalyzed Diastereo- and Enantioselective Borylative Cyclization: Synthesis of Enantioenriched 2,3-Disubstituted Indolines Ge Zhang, Aijie Cang, Ying Wang, Yanfei Li, Guoxing Xu, Qian Zhang, Tao Xiong,* and Qian Zhang Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun 130024, China S Supporting Information *
ABSTRACT: The development of an efficient, straightforward approach for access to a wide range of enantioenriched boron-containing 2,3-disubstituted indolines via highly chemo-, diastereo-, and enantioselective copper-catalyzed intramolecular boraylative cyclization of readily available 2styrylimines is reported. This reaction proceeds under very mild conditions and displays a high degree of functional group compatibility. The practicability of this approach is demonstrated by a gram-scale reaction and further transformations of the chiral borylated indolines.
E
suitable functional group or fragment into these motifs under mild conditions would be highly appealing. Organoboron compounds are among the most vital classes of reagent in modern organic synthesis, owing to their bench stability, excellent functional group tolerance, nontoxic nature, and diverse reactivity profile. Consequently, considerable efforts have been devoted to the study of their synthesis and transformations.9 In view of the excellent characteristics of organoboron compounds and the importance of chiral indoline motifs, the development of an efficient and straightforward method for the synthesis of enantioenriched, boron-containing indolines could be of special interest. In fact, the methods for construction of optically pure borylated indoline skeletons are rare. To our knowledge, it was not until very recently that the groups of Ito and Ready have independently realized the successful synthesis of such chiral motifs using prochiral indoles as the starting feedstocks.10 Recently, we have reported the enantioselective, copper-catalyzed hydroboration of alkenes and hydroallylation of alkynes.11 We proposed that these transformations involved chemo- and regioselective insertion of CuH or Cu-BPin (Pin: pinacol) species into olefins or alkynes to form the key organocuprate intermediates in situ.12 Subsequently, capture of these intermediates by electrophiles, such as protons and allylic phosphates, delivered the target compounds in an enantioselective manner. Inspired by the above mechanisms, we envisioned that the in situ generated chiral boron-containing organocopper intermediate I could be efficiently trapped by an electrophile, such as imine in an intramolecular fashion (Scheme 1). As a result, the versatile, enantioenriched borylative indolines bearing two adjacent stereogenic centers could be obtained in one operation.
nantiomerically pure 2,3-disubstituted indolines are a significant and ubiquitous class of alkaloids widely found in myriad biologically active natural products and pharmaceutical agents (Figure 1).1 These privileged motifs have also been
Figure 1. Representative chiral 2,3-disubstituted indoline-based bioactive molecules.
regarded as powerful chiral organocatalysts or auxiliaries in the field of asymmetric synthesis.2 Given the significance of these heterocyclic frameworks, the development of new strategies for enantioselective construction of these skeletons has attracted enormous attention.3 Among these methods, kinetic resolution of indolines4 and asymmetric hydrogenation of prochiral indole precursors5 have successfully proven their utility. Besides the employment of prochiral indole as feedstocks, other notable protocols, such as Pd-catalyzed intramolecular asymmetric transformations,6 CuH-catalyzed enantioselective cyclization,7 and metal-free asymmetric transformations,8 have also been successfully exploited in recent years. Despite these advances, there are still some limitations, such as a need for high pressure, multistep synthesis, and limited scope. Moreover, most of the chiral indolines generated from the existing methods have little potential to be further elaborated to more valuable or complex molecules, which significantly hampers their widespread applications, especially for diversity-oriented synthesis. Hence, development of new methods that can efficiently incorporate a © 2018 American Chemical Society
Received: January 28, 2018 Published: March 12, 2018 1798
DOI: 10.1021/acs.orglett.8b00246 Org. Lett. 2018, 20, 1798−1801
Letter
Organic Letters
2a was afforded in the highest yield with good enantioselectivity in MTBE (Table 1, entries 7−9). Other bases, such as LiOtBu and KOtBu, have a slight impact on reactivity, but did not cause the diminishing of the enantioselectivity (Table 1, entries 10− 11). A detailed description of condition optimization, including the evaluation of catalysts, ligands, bases, solvents, and proton sources, is provided in the Supporting Information (SI). With the optimized conditions established, we proceeded to investigate the scope of this borylative cyclization reaction. As shown in Scheme 2, generally, the reaction displays good
Scheme 1. Proposed Process for Cu-Catalyzed Borylative Cyclization for the Synthesis of Chiral Boron-Containing Indolines
Scheme 2. Substrate Scopea,b
However, potential challenges, such as the chemoselectivity of insertion of a Cu-BPin species into an alkene versus aldimine,13 as well as the issue of diastereo- and enantioselective control should be addressed. Herein, we report the first copper(I)catalyzed intramolecular chemo-, diastereo-, and enantioselective borylative cyclization reaction of readily available 2styrylimines. This reaction offers an efficient and straightforward method for the synthesis of versatile, enantioenriched, boron-containing 2,3-disubstituted indolines. To check the feasibility of the working hypothesis, we initiated our study by choosing (E)-N-benzylidene-2-vinylaniline (1a), derived from a condensation reaction of readily available 2-alkenylaniline with benzaldehyde, as the model substrate under our previously reported conditions for the hydroboration of alkenes.11a We first evaluated a number of commercially available chiral bisphosphine ligands. These ligands were found to provide similar reactivity profiles, but showed a significant difference in enantioselectivity, among which (S,S)-Ph-BPE proved to be the best in terms of reactivity and enantioselectivity (Table 1, entries 1−6). We then turned to ethereal solvents and found that the desired chiral indoline Table 1. Optimization of Reactiona
entry
ligand
base
solvent
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11
L1 L2 L3 L4 L5 L6 L1 L1 L1 L1 L1
NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu LiOtBu KOtBu
THF THF THF THF THF THF Et2O MTBE dioxane MTBE MTBE
98 75 98 82 88 93 67 97 90 73 85
81 2 10 51 9 −78 90 89 83 87 88
a
Reaction conditions: 1a (0.20 mmol), B2(Pin)2 (1.5 equiv), CuCl (2 mol %), L1 (3 mol %), Na(OtBu) (1.5 equiv), and tBuOH (1.0 equiv) in 2.0 mL of MTBE at room temperature. bIsolated yield and enantioselectivities were determined by chiral HPLC analysis. cEnantioselectivities were determined after recrystallization by chiral HPLC analysis.
a Reaction conditions: 1a (0.2 mmol), B2pin2 (1.5 equiv), CuCl (2 mol %), ligand (3 mol %), Na(OtBu) (1.5 equiv), and alcohol (1.0 equiv) in 2.0 mL of MTBE at room temperature. bDetermined by 1H NMR analysis of the crude reaction mixture with an internal standard. c Enantioselectivity of the purified product was determined by chiral HPLC. MTBE = tert-Butyl methyl ether.
functional group compatibility, and the resulted enantiomerically enriched boron-containing indolines 2 could be obtained in good to excellent yields. We first explored the substrate scope with a variety of substituted aryl moieties that originate from the aldehyde component. Initially, we examined the steric effect by placing methyl on the ortho, meta-, and para-positions of this phenyl group (2b−2d). It was found that the position of the substituent has a negligible effect on reactivity, while higher 1799
DOI: 10.1021/acs.orglett.8b00246 Org. Lett. 2018, 20, 1798−1801
Letter
Organic Letters enantioselectivity was observed with the para-substituted analogue. It was also found that electron-neutral, electronrich, or electron-deficient substituents, such as alkoxyl, alkyl, phenyl, −SCH3, −Br, −Cl, −CF3, and ester, on the phenyl ring of the aldimines were also readily accommodated. As a result, substrates 1e−1n could be efficiently transformed into the corresponding chiral indolines 2e−2n in good to excellent yields and enantioselectivities. In particular, the good compatibility of aryl halides and methyl benzoate under the reaction conditions provided an opportunity for further transformations. Naphthyl-containing 2-alkenylimine 1o could also undergo the borylative cyclization smoothly, thus furnishing desired indoline 2o in good yield and enantioselectivity. In addition to aromatic aldehydes, we found the substrates 1p−1u bearing heterocycles, including thiophene-, furan, N-protected pyrrole, benzo[b]thiophene, and benzofuran, were also applicable to the enantioselective borylative cyclization processes, affording chiral products 2p−2u in good to excellent yields with excellent enantioselectivities. Additionally, substrates bearing substituents, such as alkyl, F, and CF3, on the aromatic ring of the styrene were also examined and delivered corresponding indolines 2v−2y in good yields with excellent enantioselective control, albeit a relative lower enantiomeric excess (ee) value for 1w. The 2styryl-α,β-unsaturated imine 1z was also competent under these catalytic conditions, giving the indoline 2z in good yield and enantiocontrol. In contrast, the aldimine styrene 1aa derived from 2-vinylaniline and aliphatic aldehyde was not suitable for this transformation. Additionally, the reactivity of substrate 1ab containing a 1,1-disubstituted styrene substructure was also examined, but the expected product 2ab bearing a quaternary stereocenter was not observed under the present conditions. It is worth noting that the cis-diastereomers were exclusively obtained in all cases. Moreover, although somewhat lower enantioselective control was achieved in some cases, the ee values could be greatly improved to 99% after simple recrystallization. A gram-scale synthesis was conducted to demonstrate the practicability of the present approach, and the target chiral borylative indoline 2a was obtained in moderate yield without any erosion in enantioselectivity (Scheme 3). We also briefly examined the applications of these novel chiral boroncontaining indoline compounds (Scheme 3). For example, compound 2a could be efficiently aminated or oxidized to form the N-Boc-protected amine 4 or primary alcohol 5, respectively, in moderate yield.14 Additionally, the boron-containing indoline 2q could undergo a sequential sulfurylation/homologation
process to yield compound 6, and indoline 2v could also undergo the homologation to form the nonprotected product 7, but with a relatively lower yield.15 Notably, all the abovementioned transformations proceeded without loss of enantioselectivity. In summary, we have successfully developed a coppercatalyzed enantioselective intramolecular borylative cyclization of readily available 2-alkenylimine with B2(Pin)2 under mild conditions. This method provides an efficient and straightforward approach for the synthesis of a wide range of chiral 2,3disubstituted indolines bearing the versatile BPin functional group in a highly regio-, diastereo-, and enantioselective manner. The optically active boron-containing indolines are not only versatile building blocks for further transformations, but can also be efficiently prepared on gram scale. Further efforts toward expansion of the substrate scope and the development of other types of enantioselective transformations based on Cu-Bpin species are currently underway in our laboratory.
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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.8b00246. Experiment procedure and characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Tao Xiong: 0000-0002-2516-084X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the NSFC (21672033, 21372041), the Jilin Province Natural Science Foundation (20160520140JH, 20160519003JH), the Fundamental Research Funds for the Central Universities (2412017ZD001), and the Changbai Mountain Scholarship Program.
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Scheme 3. Gram-Scale Synthesis and Applications of Chiral Boron-Containing Indolines
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DOI: 10.1021/acs.orglett.8b00246 Org. Lett. 2018, 20, 1798−1801
