Research Article pubs.acs.org/journal/ascecg
Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Greener Methodology: An Aldol Condensation of an Unprotected C‑Glycoside with Solid Base Catalysts Tamara M. de Winter,† Laurène Petitjean,† Hanno C. Erythropel,† Magali Moreau,‡ Julien Hitce,§ Philip Coish,† Julie B. Zimmerman,† and Paul T. Anastas*,†,∥ †
Center for Green Chemistry & Green Engineering at Yale and School of Forestry and Environmental Studies, Yale University, 195 Prospect Street, New Haven, Connecticut 06511, United States ‡ L’Oréal Recherche & Innovation, 133 Terminal Avenue, Clark, New Jersey 07066, United States § L’Oréal Recherche & Innovation, 30 Rue Maurice Berteaux, 95500 Le Thillay, France ∥ Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States S Supporting Information *
ABSTRACT: The development of a new enamine-solid-basecatalyzed (ESBC) methodology for the aldol condensation reaction is reported. Solid base catalysts [nonactivated and activated magnesium oxide (MgO and MgOact) and calcium oxide (CaO and CaOact), a hydrotalcite (HT), and a porous metal oxide (PMO)] were investigated as safer and greener alternatives to previously reported catalytic systems. Multiple reaction parameters (temperature, solvent, time, and catalyst loading) were investigated todetermine optimal conditions for the practitioner to employ in the synthesis of C-glycosides. The optimized reaction conditions provided highly functionalized (E)α,βunsaturated ketones from unprotected C-glycosides in good to excellent yields. Moreover, the ESBC methodology is applicable to a wide range of aromatic aldehydes that feature electron-rich and electron-poor moieties, as well as sterically bulky groups. Lastly, the recyclability of the MgO catalyst was demonstrated. KEYWORDS: Aldol condensation, C-glycosides, Glucose, Solid base catalysis, Sugar, L-Proline
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INTRODUCTION Carbohydrate-based products have gained significant attention in recent years due to their renewable nature and their potential use as building blocks for a wide range of commercial products.1−5 Notably, C-glycoside derivatives have been reported of interest as surfactants,1 antitumor agents,6,7 antibiotics,8 antibacterial9 and anti-inflammatory agents,10−12 and antiaging compounds.10,12−16 Moreover, C-glycosides (Figure 1) have attracted increasing interest owing to their
and a respiratory toxicant and possesses a risk of explosion in the presence of mechanical impact.19 The aim of this study was 2-fold: (1) to develop a novel and useful methodology for the preparation of C-glycosidic ketones and (2) to select a greener process that applies the Principles of Green Chemistry.20 Notably, Principle 3 that recommends the use of substances with little or no toxicity to human health and the environment was put into practice. The development of such a protocol would provide a safer method to the practitioner, and add a novel method to the toolbox of synthetic chemists involved in multistep synthesis. We also sought to employ a heterogeneous catalyst that could be recycled (Principles 1 and 9). Herein, we report the results of our studies and the development of a novel enamine-solid-basecatalyzed aldol condensation that was used to prepare a wide variety of aromatic C-glycosides in excellent yields.
Figure 1. Basic structure for C-glycosyl compounds.
stability against acidic and enzymatic hydrolysis as compared to O- and N-glycosides.3,10 In this context, methodologies allowing for the structural investigation of the aglycone moiety of C-glycosides are valuable. Previous work by Foley et al.1 demonstrated significant progress toward obtaining linear and cyclic C-glycosides through an enamine-catalyzed aldol condensation. The aldol reactions were performed under mild conditions without the use of protecting groups or chromatography. However, the reactions employed pyrrolidine as the catalyst which is toxic, corrosive, and flammable.17 Another report by Wang et al.18 utilized L-proline and triethylamine as their catalysts, yet triethylamine is reported to be highly flammable and volatile © XXXX American Chemical Society
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EXPERIMENTAL SECTION
General Optimized Procedure for the Synthesis of 2a−n. The solid base catalyst (SBC) and L-proline were employed with 10− 18 wt % and 1−1.5 equiv, respectively, because of variability in the weight of the nonulose as a consequence of its high hygroscopicity. An internal standard, biphenyl (0.05equiv), was utilized to quantify by nuclear magnetic resonance (NMR) the exact amount of nonulose Received: February 19, 2018 Revised: April 11, 2018 Published: April 27, 2018 A
DOI: 10.1021/acssuschemeng.8b00816 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Research Article
ACS Sustainable Chemistry & Engineering
Table 1. Aldol Condensation Reaction of 1, with Solid Base Catalysts in the Presence and Absence of L-Proline at Room Temperature
entry
catalysta
1 2 3 4 5 6 7 8 9 10 11 12 13
MgO MgOact MgO MgOact CaO CaOact CaO CaOact HT PMO HT PMO
L-proline
b
yes yes no no yes yes no no yes yes no no yes
timec (days)
NMR yields of desired productd (%)
9 9 5 5 9 9 9 9 9 9 5 9 5
>95 >95 N/Ae N/Ae 54 76 51 56 76 93 N/Ae N/Ae 0
a
Unless otherwise indicated, all reactions were carried out in methanol (MeOH) (0.25 M), with 10−18 wt % SBC and at room temperature for the indicated time. bUnless otherwise indicated, all initial reactions were conducted with 0.15 molar equiv of L-proline.18 cThe reactions were monitored by TLC until completion. dValues represent the NMR yield to desired product only as no undesired products were formed. eBy TLC (1:9 MeOH:DCM) no conversion of the starting material was observed.
Table 2. Aldol Condensation Reaction of 1, with Solid Base Catalysts in the Presence and Absence of L-Proline with an Increased Temperature, 50 °C
entry
catalysta
1 2 3 4 5 6 7 8 9 10 11 12 13
MgO MgOact MgO MgOact CaO CaOact CaO CaOact HT PMO HT PMO
L-proline
b
yes yes no no yes yes no no yes yes no no yes
timec (days)
NMR yields of desired productd (%)
2 3 2 2 3 3 3 3 ∼1 ∼1 2 2 2
>95 >95 N/Ae N/Ae 77 78 81 83 >95 >95 N/Ae N/Ae 0
a
Unless otherwise indicated, all reactions were carried out in MeOH (0.25 M), with 10−18 wt % SBC and at room temperature for the indicated time. bUnless otherwise indicated, all initial reactions were conducted with 0.15 molar equiv of L-proline.18 cThe reactions were monitored by TLC until completion. dValues represent the NMR yield to desired product only as no undesired products were formed. eBy TLC (1:9 MeOH:DCM) no conversion of the starting material was observed. that was added to each reaction which allowed the calculation of reaction conversions and product yields. Nonulose, 1 (0.5 g, 2.27 mmol), L-proline (0.2614 g, 2.27 mmol, 1 equiv, if used), the solid base catalyst (0.05 g, 10 wt %, (either MgO or hydrotalcite, HT), and an internal standard, biphenyl (17.5 mg, 0.113 mmol, 0.05 equiv) were added to a 4dram vial equipped with a Teflon coated magnetic stir bar. Methanol (5 mL) was added, and the resulting solution was stirred rapidly until dissolution. Once dissolved, a small aliquot was taken for quantitative 1H NMR analysis, and then, the aldehyde (2.71 mmol, 1.2 equiv) was added to the reaction mixture. Subsequently, the reaction was heated to 50 °C and monitored by thin layer chromatography (TLC) or by liquid
chromatography coupled with refractive index detection (LC-RI) until completion. The reaction mixture was then filtered and rinsed with methanol, the filtrate collected and concentrated by rotatory evaporation. The crude reaction mixture was analyzed by 1H NMR to determine the conversion of 1. The resulting crude was purified by a silica gel plug through washing with 100% dichloromethane (DCM), followed by 9:1 DCM:MeOH to elute the product. If the product had precipitated during the course of the reaction, the product was collected along with the SBC on a filter. The isolated solids were then treated with either dimethylformamide (DMF) or water (H2O) in order to dissolve the product, and the SBC was B
DOI: 10.1021/acssuschemeng.8b00816 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Research Article
ACS Sustainable Chemistry & Engineering
Table 3. Investigation for Greener Solvents to Employ in the Aldol Condensation of 1 Using L-proline and the Solid Base Catalysts at 50 °C
entry
catalysta
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
MgO MgOact CaO CaOact CaO CaOact HT PMO MgO MgOact CaO CaOact CaO CaOact HT PMO
L-proline
b
time (days)
solvent
NMR yield of desired productc (%)
4 4 4 4 4 4 4 4 4 4 3 3 3 3 4 4
H2O H2O H2O H2O H2O H2O H2O H2O EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH
68 65 72 66 59 64 0 0 38 42 40 40 54 44 41 41
Yes Yes Yes Yes No No Yes Yes Yes Yes Yes Yes No No Yes Yes
a Unless otherwise indicated, all reactions were carried out with 10−18 wt % SBC and at room temperature for the indicated time. bUnless otherwise indicated, all initial reactions were conducted with 0.15 molar equiv of L-proline.18 cValues represent the NMR yield to desired product only as no undesired products were formed, unless otherwise indicated.
removed by filtration. The filtrate was concentrated by rotatory evaporation to provide the desired product.
(“off the shelf”) of these catalysts to see if it was necessary to expose all the basic sites for the reaction to proceed to completion.26,27 Notably, activation of the HT catalyst produces a porous metal oxide (PMO) via dehydration, dehydroxylation, and the decomposition of carbonates.28 PMOs have been widely employed, for example, as catalytic supports, and in a variety of reactions, including catalytic hydrogenations and lignin depolymerization.29−31 PMOs consist of MgO-Al2O3 that possesses Lewis acid sites in combination with the strong Mg2+O2− basic sites. Moreover, the interaction of MgO and Al2O3 is such that PMO may behave more like MgAlO4 than as the constituent species, MgO and Al2O3.32,33 Finally, the selected SBCs were studied in the presence and absence of L-proline to check if with our new systems we could omit this reagent which was of prime importance in previous reports.2 Our investigation started by reacting nonulose, 1, with panisaldehyde at room temperature in methanol (0.25 M) with 10−18 wt % of SBC and in the absence or presence of 0.15 equiv of L-proline (Table 1). The synthesis of 1 has been previously reported.2,4,12,34,35 Furthermore, we elected to investigate p-anisaldehyde and other aromatic aldehydes since previous studies1 within the Anastas laboratories demonstrated that the aldol reaction provided the desired product (a linear product) along with a double addition product (a cyclic product). The reactions were monitored qualitatively by thin layer chromatography (TLC) until completion had occurred. The reaction of 1 with activated MgO (MgOact) or nonactivated MgO and in the presence of L-proline showed a fast reaction rate based on TLC analysis within the first day, after which the reaction rate slowed down. After ca. 8−9 days, the reaction mixture containing MgO or MgOact and L-proline went to completion (>95%) based on nuclear magnetic resonance (NMR) analysis of a reaction aliquot (entries 1 and 2, Table 1). The results indicated no significant difference between the
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RESULTS AND DISCUSSION The solid base catalysts (SBCs) selected for the aldol condensation were magnesium oxide (MgO, 98% ACS
Figure 2. Investigation of the effect of L-proline concentration on the aldol condensation of 1 to 2 at 50 °C with MgO as the SBC in methanol.
grade), calcium oxide (CaO,
