Organocatalytic Dearomative [4 + 2] Cycloadditions of Biomass

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

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Organocatalytic Dearomative [4 + 2] Cycloadditions of BiomassDerived 2,5-Dimethylfuran with ortho-Quinone Methides: Access to Multisubstituted Chromanes Yao-Bin Shen,† Shuai-Shuai Li,† Liang Wang,† Xiao-De An,† Qing Liu,‡ Xicheng Liu,§ and Jian Xiao*,† †

College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao 266590, China § College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China Downloaded via UNIV OF SOUTH DAKOTA on September 13, 2018 at 21:53:54 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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ABSTRACT: The organocatalytic dearomative [4 + 2] cycloadditions of biomass-derived 2,5-dimethylfuran with ortho-quinone methides were developed, affording two diffferent types of multisubstituted chromanes in high yields and excellent diastereoselectivities. The controllable synthesis of these two types of multisubstituted chromanes could be achieved by succinctly varying the reaction conditions.

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molecule for high-value-added products and second-generation biofuel.5,6 In terms of chemical synthesis, the application of 2,5-DMF has been focused on its conversion into p-xylene (PX) through a sequential Diels−Alder reaction and thermal dehydrative aromatization (see Scheme 1A).6 However, there

ultisubstituted chromanes are widely present in a range of biologically active natural products and pharmaceuticals.1 In particular, the members embedding hydroxyl groups at the C3 position have attracted considerable attention, because of their unique bioactivities, such as procyanidin B3,1c (+)-hematoxylin,1d and (+)-brazilin1e (Figure 1). Despite their

Scheme 1. Conversions of Biomass-Derived 2,5-DMF

Figure 1. Multisubstituted chromanes in natural products and pharmaceuticals.

biological importance, only sporadic examples have been reported for the synthesis of these privileged skeletons, along with tedious synthetic routes.2 Therefore, the development of facile and efficient methodologies for the construction of C3hydroxy-substituted chromanes from readily available starting materials in a one-pot manner is very urgent. The increasing demand for sustainable energy and materials has led to tremendous research on biorenewable feedstocks as substitutes of the diminishing fossil fuels in the production of bulk chemicals.3 Despite the fact that plant materials are the most abundant resources in the world, their conversions into chemicals still face a variety of technological and economic challenges.4 To address these challenges, the most promising approach is the upgrading of biomass-derived platform molecules into highly valuable compounds. In this context, 2,5-dimethylfuran (2,5-DMF), derived from lignocellulosic biomass, has been recognized as a significant platform © XXXX American Chemical Society

is no example for the elaboration of 2,5-DMF to synthesize pharmaceutically significant molecules, and this research area still remains underdeveloped. With regard to furan chemistry, they commonly serve as dienes to participate in [4 + n] cycloadditions7 or act as electron-rich arenes in Friedel−Crafts reactions. Nevertheless, there are few examples related to the cycloadditions with furans as dienophiles.8 Thus, it is highly appealing and challenging to develop an efficient [4 + 2] cycloaddition with biomass-derived 2,5-DMF as a dienophile for the construction of the multisubstituted chromanes. Received: August 1, 2018

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DOI: 10.1021/acs.orglett.8b02448 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

unambiguously confirmed by single-crystal X-ray analysis (see Figure 2). Subsequently, various Brønsted acids and Lewis

As newcomers to the family of inherently reactive species, ortho-quinone methides (o-QMs) have been extensively applied in the construction of naturally occurring and pharmacological compounds.9 Prompted by their propensity for aromatization, o-QMs are susceptible to participate in inverse-electron-demand hetero-Diels−Alder (IED-HDA) reactions with various dienophiles to construct six-membered oxygen-containing frameworks. Nevertheless, the scope of dienophiles in IED-HDA reactions is mainly restricted to alkenes,10 which largely limits the applicability of these methods. In this context, we envisioned that the dearomative [4 + 2] cycloaddition might occur between biomass-derived 2,5-DMF and o-QMs (see Scheme 1B). However, to the best of our knowledge, there is no example for the catalytic intermolecular dearomative [4 + 2] cycloaddition of o-QMs with electron-rich arenes, since a competitive Friedel−Crafts alkylation would be more operative.11 In continuation of our research program aimed at establishing one-step assembly of molecular complexity,12 herein, we report the first example of organocatalytic dearomative [4 + 2] cycloadditions of biomassderived 2,5-DMF with o-QMs, in which 2,5-DMF served as a dienophile, providing the controllable synthesis of multisubstituted chromanes in high yields. To validate the feasibility of our hypothesis, initially, orthohydroxybenzyl alcohol 1a and 2,5-DMF 2 were selected as model substrates to perform this reaction (Table 1).

Figure 2. Single-crystal structures of 3a and 4a.

acids were examined, and eventually, (−)-10-camphorsulfonic acid ((−)-CSA) was identified as the best catalyst to furnish 3a in 84% yield as a sole product (Table 1, entries 2−8). The subsequent solvent screening and catalyst loading investigation indicated that 5 mol % (−)-CSA in DCE was the optimal condition for this reaction, yielding the desired product 3a in 91% yield (Table 1, entries 9−13). Although the addition of 4 Å molecular sieves was detrimental to the production of 3a (Table 1, entry 14), the combination of 4 Å molecular sieves with 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate afforded 4a as a major product in 81% yield (Table 1, entry 15). Thus, the controllable synthesis of 3a or 4a was totally realized by adjusting the reaction conditions. With the optimized conditions in hand, the substrate scope for the synthesis of 3 was investigated (see Scheme 2). A wide range of ortho-hydroxybenzyl alcohols 1 substituted with electron-withdrawing and electron-donating groups (R1/R2)

Table 1. Optimization of Reaction Conditionsa

Yieldb (%) entry

catalyst

solvent

time

3a

4a

5a

1 2 3 4 5 6 7 8 9c 10d 11d 12d 13d 14d,e 15c,e

TfOH MeSO3H benzoic acid AcOH Sc(OTf)3 InBr3 PA (−)-CSA (−)-CSA (−)-CSA (−)-CSA (−)-CSA (−)-CSA (−)-CSA PA

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCM THF toluene DCE DCE

20:1), respectively (Table 1, entry 1). In addition, a trace amount of Friedel−Crafts product 5a was observed. The relative configurations of 3a and 4a were

a

Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), (−)-CSA (5 mol %), DCE (1 mL), room temperature. Isolated yields after column chromatography, dr >20:1. The dr was determined by 1H NMR analysis. bCatalyst (20 mol %). cIsolated yield by filtration. B

DOI: 10.1021/acs.orglett.8b02448 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters were well-tolerated in this reaction, affording the corresponding products 3 in moderate to high yields with excellent diastereoselectivities. As for the R1 groups, the electrondonating substituents (3b−3f) furnished higher yields than electron-withdrawing ones (3g and 3h), which could be rationalized by the stabilization effect of the electron-donating groups for the o-QM intermediates. In addition, the steric hindrance caused by the ortho-methoxyl and tert-butyl groups might account for the comparatively lower yields of 3c and 3f. As for the R2 groups, the electronic characteristics of the substituents had trivial impacts on the yields, delivering 3i−3q in high yields, regardless of the ortho-, meta-, or para-positions. The success of trifluoro- and fluoro- substituents exemplified the practical application of this method in pharmaceutical chemistry. Apart from the benzene ring, naphthyl and thienyl substitutents were also good reaction partners (3r and 3s). More importantly, a substrate incorporating a methyl group (3t) was also compatible, indicating a broad coverage of this methodology. Subsequently, the substrate scope for the synthesis of 4 was further examined. As summarized in Scheme 3, an array of

Scheme 4. Control Experiments

product (Scheme 4a). Similarly, the Friedel−Crafts alkylation product 9 was obtained in 94% yield when 2-methylfuran 8 was used as a reaction partner (Scheme 4b). Notably, 2,3dihydrofuran-fused chromane 4a could be readily converted to 3a in high yield under the optimal conditions with the addition of water (Scheme 4c). Conversely, 3a could also be transformed to 4a in good yield in the presence of 4 Å molecular sieves and 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (10 mol %) (Scheme 4d). Intriguingly, the stereogenic center at the C2 position in 3a and 4c was totally reversed in the ring-opening and cyclization processes. On the basis of the above experimental results, a plausible reaction mechanism was proposed, as depicted in Scheme 5. In

Scheme 3. Substrate Scope for the Synthesis of 4a

Scheme 5. Proposed Mechanism

a

Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), PA (10 mol %), 4 Å MS (70 mg), DCE (1 mL), room temperature. Isolated yields after column chromatography, dr >20:1. The dr was determined by 1H NMR analysis.

ortho-hydroxybenzyl alcohols 1 bearing various R1/R2 groups were totally tolerable in this reaction, furnishing the desired products 4 in moderate to good yields with excellent diastereoselectivities. Both electron-donating (4b−4d, 4f−4j) and electron-withdrawing (4e, 4k, 4l) groups at different positions of the phenyl rings had trivial influence on the reaction. In addition to the phenyl group, the substrates bearing naphthyl and thienyl groups were also good candidates, affording the corresponding products 4m and 4n, in 68% and 71% yields, respectively. To shed light on the reaction mechanism, a series of control experiments were conducted, as shown in Scheme 4. Not surprisingly, when a phenolic hydroxyl group was protected with a methyl group to block the formation of an o-QM intermediate, only Friedel−Crafts alkylation product 7 was observed with 2,5-DMF, instead of the [4 + 2] cycloaddition

addition to the Friedel−Crafts alkylation product 5a, o-QM A generated in situ reacts with 2,5-DMF 2 via an IED-HDA reaction to afford the thermodynamically favored endocycloadduct 4a. Subsequently, the protonated endo-cycloadduct 4a undergoes hydrolysis to give ring-opening product B, which is followed by a retro-intramolecular oxa-Michael addition to furnish the intermediate C. There are two possible Traxler−Zimmerman-type transition states 1 and 2, and TS 1 is much more favored, because of the severe allylic strain in TS 2. Finally, an intramolecular oxa-Michael addition operates through TS 1 to deliver the product 3a′, which undergoes conformation inversion to yield the product 3a, assisted by the hydrogen bonding interaction between the acetonyl and hydroxyl groups. C

DOI: 10.1021/acs.orglett.8b02448 Org. Lett. XXXX, XXX, XXX−XXX

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To examine the scalability of these developed protocols, the large-scale experiments were performed, yielding 3d and 4c in 86% and 74% yields, respectively, without a loss in diastereoselectivity (see Scheme 6). The product 3d was

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Scheme 6. Large-Scale Syntheses

Jian Xiao: 0000-0003-4272-6865 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (Nos. 21702117 and 21878167) and the Natural Science Foundation of Shandong Province (Nos. JQ201604 and ZR2017BB005) as well as the Key Research and Development Program of Shandong Province (2017GSF218073). We also thank the Central Laboratory of Qingdao Agricultural University for NMR determination.

selected for further elaboration to demonstrate the synthetic utility of this strategy (see Scheme 7). Reduction of 3d with Scheme 7. Transformation of Products

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NaBH4 provided the corresponding alcohol 10 in 95% yield. In addition, the α,β-unsaturated ester 11 could be obtained in good yield and high Z/E selectivity via a Wittig reaction. In summary, we have developed the organocatalytic dearomative [4 + 2] cycloadditions of biomass-derived 2,5dimethylfuran with ortho-quinone methides to produce two types of multisubstituted chromanes, with three consecutive chiral centers in high yields and excellent diastereoselectivities. The controllable construction of two different and highly functionalized chromanes was achieved by succinctly varying the reaction conditions. For the first time, the conversion of the biomass platform molecule, 2,5-dimethylfuran, into biologically important chromanes was realized. The easy operation, mild conditions, and wide substrate scope made these methodologies promising for future applications. We are optimistic that these reports will not only offer a distinctive toolbox for the generation of diversely multisubstituted chromanes in drug discovery, but also demonstrate the potential application of biomass platform molecules in the synthesis of biologically important chemical products.

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REFERENCES

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02448. General experimental procedures, characterization and NMR spectra of all compounds (PDF) Accession Codes

CCDC 1561490 and 1561495 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], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033. D

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DOI: 10.1021/acs.orglett.8b02448 Org. Lett. XXXX, XXX, XXX−XXX