Greener Methodology: An Aldol Condensation of an Unprotected C

Apr 27, 2018 - The SBC-catalyzed methodology is applicable to a wide range of aromatic aldehydes that feature electron-rich and electron-poor substrat...
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A Greener Methodology: An Aldol Condensation of an Unprotected C-Glycoside with Solid Base Catalysts Tamara de Winter, Laurene Petitjean, Hanno C Erythropel, Magali Moreau, Julien Hitce, Philip Coish, Julie B. Zimmerman, and Paul T. Anastas ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b00816 • Publication Date (Web): 27 Apr 2018 Downloaded from http://pubs.acs.org on April 27, 2018

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A Greener Methodology: An Aldol Condensation of

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an Unprotected C-Glycoside with Solid Base

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Catalysts

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Tamara M. de Winter,† Laurène Petitjean, † Hanno C. Erythropel, † Magali Moreau,‡ Julien

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Hitce,§ Philip Coish, † Julie B. Zimmerman† and Paul T. Anastas*,†,ǁ †

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Center for Green Chemistry & Green Engineering at Yale and School of Forestry and

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Environmental Studies, Yale University, 195 Prospect Street, New Haven, Connecticut 06511,

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United States

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L’Oréal Recherche & Innovation, 133 Terminal Avenue, Clark, New Jersey, 07066, United

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States §

11 12

ǁ

L’Oréal Recherche & Innovation, 30 Rue Maurice Berteaux, 95500 Le Thillay, France

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut

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06511, United States

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Corresponding Author: [email protected]

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KEYWORDS: Aldol condensation, C-glycosides, Glucose, Solid Base Catalysis, Sugar,

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L-Proline

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ABSTRACT: The development of a new enamine-solid base catalyzed (ESBC) methodology for

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the Aldol condensation reaction is reported. Solid base catalysts (non-activated & activated

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magnesium oxide (MgO & MgOact) and calcium oxide (CaO & CaOact), a hydrotalcite (HT) and

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a porous metal oxide (PMO)), were investigated as safer & greener alternatives to previously

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reported catalytic systems. Multiple reaction parameters (temperature, solvent, time & catalyst

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loading) were investigated to determine optimal conditions for the practitioner to employ in the

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synthesis of C-glycosides. The optimized reaction conditions provided highly functionalized

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(E)-α,β-unsaturated ketones from unprotected C-glycosides in good to excellent yields.

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Moreover, the ESBC methodology is applicable to a wide range of aromatic aldehydes that

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feature electron-rich and electron-poor moieties, as well as sterically bulky groups. Lastly, the

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recyclability of the MgO catalyst was demonstrated.

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Introduction

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Carbohydrate-based products have gained significant attention in recent years due to their

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renewable nature and their potential use as building blocks for a wide range of commercial

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products.1–5 Notably, C-glycoside derivatives have been reported of interest as surfactants,1

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anti-tumor agents,6,7 antibiotics,8 anti-bacterial,9 anti-inflammatory agents10–12 and as anti-aging

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compounds.10,12–16 Moreover, C-glycosides (Figure 1) have attracted increasing interest owing to

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their stability against acidic and enzymatic hydrolysis as compared to O- and N-glycosides.3,10 In

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this context, methodologies allowing for the structural investigation of the aglycone moiety of C-

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glycosides are valuable.

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R1

39 40

O

R2

HO

Figure 1. Basic structure for C-glycosyl compounds.

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Previous work by Foley et al.1 demonstrated significant progress towards obtaining linear and

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cyclic C-glycosides through an enamine-catalyzed Aldol condensation. The Aldol reactions were

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performed under mild conditions without the use of protecting groups or chromatography.

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However, the reactions employed pyrrolidine as the catalyst which is toxic, corrosive and

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flammable.17 Another report by Wang et al.18 utilized L-proline and triethylamine as their

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catalysts, yet, triethylamine is reported to be highly flammable, volatile, a respiratory toxicant

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and possesses a risk of explosion in the presence of mechanical impact.19

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The aim of this study was two-fold: 1) to develop a novel and useful methodology for the

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preparation of C-glycosidic ketones and 2) to select a greener process that applies the Principles

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of Green Chemistry.20 Notably, Principle 3 that recommends the use of substances with little or

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no toxicity to human health and the environment was put into practice. The development of such

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a protocol would provide a safer method to the practitioner, and add a novel method to the

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toolbox of synthetic chemists involved in multi-step synthesis. We also sought to employ a

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heterogeneous catalyst that could be recycled (Principles 1 and 9). Herein, we report the results

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of our studies and the development of a novel enamine-solid base catalyzed Aldol condensation

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that was used to prepare a wide variety of aromatic C-glycosides in excellent yields.

58 59

Experimental Section

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General optimized procedure for the synthesis of 2a-n. The solid base catalyst (SBC) and

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L-proline was employed with 10-18 wt % and 1-1.5 equivalents, respectively, because of

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variability in the weight of the nonulose as a consequence of its high hygroscopicity. An internal

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standard, biphenyl (0.05 equivalent), was utilized to quantify by Nuclear Magnetic resonance

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(NMR) the exact amount of nonulose that was added to each reaction which allowed the

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calculation of reaction conversions and product yields.

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Nonulose, 1 (0.5 g, 2.27 mmol), L-proline (0.2614 g, 2.27 mmol, 1 equiv., if used), the solid

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base catalyst (0.05 g, 10 wt %, (either MgO or HT) and an internal standard, biphenyl (17.5 mg,

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0.113 mmol, 0.05 equiv.) were added to a 4 dram vial equipped with a Teflon© coated magnetic

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stir bar. Methanol (5 mL) was added and the resulting solution was stirred rapidly until

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dissolution. Once dissolved, a small aliquot was taken for quantitative 1H NMR analysis and then

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the aldehyde (2.71 mmol, 1.2 equiv.) was added to the reaction mixture. Subsequently, the

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reaction was heated to 50 °C and monitored by thin layer chromatography (TLC) or by liquid

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chromatography coupled with refractive index detection (LC-RI) until completion. The reaction

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mixture was then filtered, rinsed with methanol, the filtrate collected and concentrated by

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rotatory evaporation. The crude reaction mixture was analyzed by 1H NMR to determine the

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conversion of 1. The resulting crude was purified by a silica gel plug through washing with 100

77

% DCM, followed by 9:1 DCM:MeOH to elute the product.

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If the product had precipitated during the course of the reaction, the product was collected

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along with the SBC on a filter. The isolated solids were then treated with either

80

dimethylformamide (DMF) or water (H2O) in order to dissolve the product, and the SBC was

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removed by filtration. The filtrate was concentrated by rotatory evaporation to provide the

82

desired product.

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Results and Discussion

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The solid base catalysts (SBCs) selected for the Aldol condensation were magnesium oxide

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(MgO, 98 % ACS Grade), calcium oxide (CaO, 95 %) based on Nuclear Magnetic

112

resonance (NMR) analysis of a reaction aliquot (Entries 1 & 2, Table 1). The results indicated no

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significant difference between the conversion of 1 when using either activated and non-activated

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forms of MgO. In the absence of L-proline, no reactivity was observed with MgOact and MgO for

115

ca. 5 days based on TLC analysis (Entries 3 & 4, Table 1).

116 117

Table 1. The Aldol condensation reaction of 1, with solid base catalysts in the presence and

118

absence of L-proline at room temperature.

119 Entry

Catalysta

L-prolineb

Timec (days)

NMR Yields of desired product (%)d

1

MgO

Yes

9

> 95

2

MgOact



9

> 95

3

MgO

No

5

N/Ae

4

MgOact



5

N/Ae

5

CaO

Yes

9

54

6

CaOact



9

76

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CaO

No

9

51

8

CaOact



9

56

9

HT

Yes

9

76

10

PMO



9

93

11

HT

No

5

N/Ae

12

PMO



9

N/Ae

13f

-

Yes

5

0

a

Unless otherwise indicated, all reactions were carried out in methanol (MeOH) (0.25 M), with

121

10-18 wt % SBC and at room temperature for the indicated time. bUnless otherwise indicated, all

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initial reactions were conducted with 0.15 mol eq. of L-proline.18 cThe reactions were monitored

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by TLC until completion. dValues represent the NMR yield to desired product only as no

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undesired products were formed. eBy TLC (1:9 MeOH:DCM) no conversion of the starting

125

material was observed.

126 127

When the reactions were performed with the non-activated HT and activated PMO catalysts,

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we observed a high NMR yield of 2 in the presence of L-proline upon completion after

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ca. 9 days (Entries 9 and 10, 76 % and 93 %, respectively, Table 1). However, in the absence of

130

L-proline, there was no conversion as determined by TLC analysis for ca. 5 days using either the

131

non-activated HT or activated PMO (Entries 11 & 12, Table 1). To confirm a solid base catalyst

132

was required for our Aldol condensation, we performed the reaction without SBC at room

133

temperature (Entry 13, Table 1) in the presence of L-proline. After ca. 5 days, there was no

134

conversion of starting material determined by TLC and 1H NMR.

135

The CaO-catalyzed reactions (Table 1, Entries 5, 6, 7 and 8) proceeded with both CaOact and

136

CaO, albeit with lower yields than MgO, HT or PMO. However, it is notable that CaO was able

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to catalyze the reaction without L-proline. The ability of CaO to catalyze the reaction in the

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absence of L-proline may be due to the higher electropositivity of calcium, giving CaO higher

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O2- character compared with MgO and thus increased basicity.36

140

Our initial studies demonstrated that the SBCs could catalyze the formation of the desired

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product 2 in high to moderate yields, especially in the presence of L-proline. In most cases, the

142

condensations proceeded cleanly and completely, and we did not observe starting nonulose, or an

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Aldol 3-hydroxyketone intermediate18 in the final product mixtures. However the reaction times

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were considered unsatisfactory, and so the reaction temperature was increased to 50 °C (Table 2)

145

in an effort to increase the reaction rate. Gratifyingly, the higher reaction temperature provided

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shorter reaction times and critically, clean conversion to desired product. We observed that the

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overall reaction time was reduced from ca. 9 days to ca. 2 days when the non-activated MgO

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was employed, and from ca. 9 days to ca. 3 days when the activated MgOact catalysts was used

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(Entries 1 & 2, Table 2). The reaction time difference of 2 versus 3 days between Entries 1 & 2

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may not be significant and may be due to the qualitative method of analysis (TLC). The increase

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in temperature also shortened the reaction times when the HT and PMO catalysts were employed

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(Entries 9 & 10, Table 2). As in the room temperature reactions, there was no production of 2

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when L-proline was not present in the reaction mixture using non-activated or activated MgO,

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HT and PMO catalysts at an elevated temperature (Entries 3, 4, 11 and 12, Table 2).

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Furthermore, when the Aldol condensation of 1 was performed with only L-proline (and without

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SBC) at 50 °C (Entry 13, Table 2), formation of product 2 was not observed after ca. 2 days as

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judged by TLC and 1H NMR.

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Table 2. The Aldol condensation reaction of 1, with solid base catalysts in the presence and

160

absence of L-proline with an increase temperature, 50 °C.

161 Entry

Catalysta

L-prolineb

Timec (days)

NMR Yields of desired product (%)d

1

MgO

Yes

2

> 95

2

MgOact



3

> 95

3

MgO

No

2

N/Ae

4

MgOact





N/Ae

5

CaO

Yes

3

77

6

CaOact





78

7

CaO

No



81

8

CaOact





83

9

HT

Yes

~1

> 95

10

PMO





> 95

11

HT

No

2

N/Ae

12

PMO





N/Ae

13

-

Yes

2

0

162

a

163

SBC and at room temperature for the indicated time. bUnless otherwise indicated, all initial

164

reactions were conducted with 0.15 mol eq. of L-proline.18 cThe reactions were monitored by

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TLC until completion. dValues represent the NMR yield to desired product only as no undesired

Unless otherwise indicated, all reactions were carried out in MeOH (0.25 M), with 10-18 wt %

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products were formed. eBy TLC (1:9 MeOH:DCM) no conversion of the starting material was

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observed.

168 169

The conversions to the desired product 2 in the presence of CaO (activated and non-activated)

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and with or without L-proline were all improved with the increase in reaction temperature

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(Entries 5, 6, 7 & 8 from Table 1 & Table 2). The results of Entries 7 and 8 are noteworthy. In

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the absence of L-proline, CaO as the catalyst provided the desired product in 81-83 % yield

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(NMR). These results highlight the potential of CaO as a catalyst that does not require the use L-

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proline.

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After exploring the effect of temperature on the Aldol reaction, we next investigated polar

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solvents that are considered “greener” and safer than methanol such as water (Table 3).37 Despite

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the fact that the Aldol reaction itself produces one mole of water, we had concerns about the use

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of water as the solvent. Water has been reported to poison the active sites of SBCs.26,27

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Nonetheless, we explored water as the solvent. We also decided to study ethanol given the

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success of the reaction in methanol. Other solvents were not investigated due to the low

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solubility of nonulose in other solvents.

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Not surprisingly, the reactions performed in water provided lower conversions, most likely due

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to poisoning of the catalysts (Entries 1-8, Table 3). In the case of MgO, the conversions obtained

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in water were 68 % and 65 % after 4 days, respectively, whereas the same reactions performed in

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methanol showed complete conversion (Entries 1-2, Table 3). The most detrimental impact of

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using water as the solvent occurred with the HT and PMO catalysts where no conversion at all

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was observed (Entries 7-8, Table 3). Obviously, HT and PMO are sensitive to the effects of

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water.38

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The yields were only modestly reduced (by 10-20 %) when CaO (activated or non-activated)

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was used as the catalyst with water as the solvent as compared to methanol (Entries 3-6, Table

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3). Interestingly, the reactions in ethanol, with and without L-proline, in the presence of CaO

192

(activated or non-activated) were less efficient than the reactions conducted in methanol.

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Moreover, analysis of the crude product mixtures were complicated. Proton NMR analysis of the

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crude product mixtures from the experiments using CaO and CaOact in ethanol indicated a

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derivative of the desired product. However, isolation of the major product from the reactants by

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silica gel chromatography provided the desired enone along with starting nonulose. The carbon

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and proton NMR spectra of the isolated product are consistent with the assigned enone product.

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We speculate the derivative is a transient, reversible species that occurs in the presence of

199

reactants that is reverted to product upon separation. The NMR yields based on crude reaction

200

mixtures were found to be low (40-54 % NMR yield). The transient species appears to be a

201

consequence of the increased basicity of the CaO catalyst.

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Surprisingly, when the solvent was changed to ethanol, the reactions that employed MgO and

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MgOact as the catalyst provided even lower yields of desired product as compared to the

204

reactions in water, and much lower than the reactions in methanol. For example, the yields using

205

MgO were 100 %, 68 %, and 38 % in methanol, water and ethanol, respectively (cf. Entry 2,

206

Table 1; Entries 1 and 9, Table 3).

207

Similarly, the use of ethanol in place of methanol reduced the yield of product for the HT and

208

PMO catalysts. Yields of 41 % were obtained for HT and for PMO in ethanol as compared to

209

100 % conversion in methanol. (Entries 15-16, Table 3).

210

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Table 3. The Investigation for greener solvents to employ in the Aldol condensation of 1 using

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L-proline and the solid base catalysts at 50 °C.

213

214 215

Entry

Catalysta

L-prolineb

Time (days)

Solvent

NMR Yield of desired product (%)c

1

MgO

Yes

4

H2O

68

2

MgOact







65

3

CaO







72

4

CaOact







66

5

CaO

No





59

6

CaOact







64

7

HT

Yes





0

8

PMO







0

9

MgO





EtOH

38

10

MgOact







42

11

CaO



3



40

12

CaOact







40

13

CaO

No





54

14

CaOact







44

15

HT

Yes

4



41

16

PMO



4



41

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

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conducted with 0.15 mol eq. of L-proline.18 cValues represent the NMR yield to desired product

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only as no undesired products were formed., unless otherwise indicated.

218 219

At this point in our studies, the optimal conditions employed the non-activated MgO or HT in

220

methanol at 50 °C in the presence of catalytic amount of L-proline. We decided not to pursue

221

CaO as the catalyst because the reactions did not provide complete conversion of 1 to 2 in a

222

selective and clean fashion. Also, we had found it difficult to obtain a clean, quantitative isolated

223

yield of 2 from the starting material. However, the use of CaO without L-proline is very

224

attractive and warrants further investigation. We next considered the influence of L-proline on

225

the reaction time and decided to perform these studies with MgO, instead of HT, as it is

226

commercially available.

227

Reaction times were quantitatively determined by liquid chromatography coupled with

228

refractive index detection (LC-RI) to determine the effect of L-proline concentration. Our studies

229

showed that as the equivalence of L-proline was increased, the reaction time required to obtain

230

complete conversion of 1 decreased significantly (Figure 2). Starting from 0.17 equivalent of

231

L-proline and increasing to 5.17 equivalents, the reaction time decreased from ca. 53 h (not

232

shown) to 6 h. Thus, our results show that excess L-proline can significantly decrease the

233

reaction rate. In our reaction, L-proline can react reversibly with the starting ketone to produce

234

an enamine, and also with the starting aldehyde to produce an imine. If we assume that the

235

reaction is activated by and thus proceeds via the enamine, then an excess of L-proline will

236

compensate for the unproductive imine formation derived from the aldehyde. An enamine

237

pathway for such a condensation reaction has been proposed by the Wang et al.2 Interestingly,

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Wang et al. observed that excess base (hydroxide) is favorable for the determining step of the

239

reaction.

240

It should be noted that complete consumption of the starting nonulose and near

241

quantitative yields were obtained regardless of the equivalence of L-proline that was employed

242

in the reaction. In practice, if one desires a shorter reaction time based on the application, then

243

one could employ higher equivalents of L-proline. In contrast, if the reaction time is not a

244

concern, one could use a low equivalence of L-proline [e.g., 0.15 equivalence] and conduct the

245

reaction at room temperature. In this way, the practitioner has control over the reaction time and

246

the resulting energy and material expenditures. These considerations are particularly important

247

when scaling-up of the reaction, for industrial applications.

248

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Figure 2. The investigation of the effect of L-proline concentration on the Aldol condensation of

251

1 to 2 at 50 °C with MgO as the SBC in methanol.

252 253

In the final phase of our investigation, we explored the effect of aryl substitution of the

254

coupling aldehyde on the outcome of the SBC-catalyzed Aldol reaction. For expediency, we

255

elected to use the higher temperature and a high loading of L-proline given that the reagent is

256

renewable, safe and inexpensive, and our studies were on a small scale. Thus, we employed

257

10-18 wt % of the SBC (MgO or HT) and 1-1.5 equivalents of L-proline at 50 °C in methanol.

258

Due to the high hygroscopicity of 1, an internal standard, biphenyl (0.05 equivalent), was added

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to the reaction mixture in order to quantify via 1H NMR spectroscopy the exact amount of

260

nonulose added to each reaction.

261

As shown in Table 4, most reactions proceeded with complete conversion of 1 to the desired

262

(E)-α,β-unsaturated ketone, 2, where high isolated yields of 80-100 % of pure product were

263

obtained (Entries 1-12, & 17-28, Table 4). The exceptions were reactions in which the aryl

264

coupling partner featured a carboxylic acid moiety (Entries 13 & 14, Table 4). In these cases, the

265

yields were low (20-26 %), as were the percent conversions of 1, most likely due to poisoning of

266

the catalyst by the high acidity of the carboxylic acid functionality. In contrast, moderate to high

267

yields were obtained in the presence of a phenol (Entries 3, 4, 9 & 10, Table 4). Interestingly,

268

MgO and HT performed differently in the presence of a phenol (compare Entries 3-4, Table 4).

269

MgO appears to have tolerated the acidity of the phenol moiety more readily than the

270

hydrotalcite in that MgO as a catalyst required a shorter reaction time and provided a higher

271

isolated yield.

272 273

Table 4. The investigation of the Aldol condensation of 1 with a collection of aromatic

274

aldehydes using MgO and HT in the presence of L-proline in methanol at 50 °C.

275 276 Time (h)

NMR Conversion Yield c (%) for 2a-2n (%)b

MgO

16

>95

2a

83

HT

16





Quantitative

Entry

SBC

1 2

Aldehyde

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3

MgO

26



2b

90

4

HT

39





58

5

MgO

6.5



2c

91

6

HT

6.5





92

7

MgO

15



2d

87

8

HT

24





Quantitative

9

MgO

21



2e

98

10

HT

42





88

11

MgO

15



2f

87

12

HT

15





90

13

MgO

76

60

2g

26

14

HT

77





20

15

MgO

27

> 95

2h

86

16

HT

27





72

17

MgO

11



2i

97

18

HT

12





Quantitative

19

MgO

51



2j

92

20

HT

56





81

21

MgO

10



2k

99

22

HT

10





Quantitative

23

MgO

11



2l



24

HT

10





99

25

MgO

12



2m

91

26

HT

12





97

27

MgO

11



2n

96

28

HT

11





95

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a

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1-1.5 eq. L-proline and at 50 °C. The reactions were monitored by LC-RI until completion and

279

checked by NMR. bAn internal standard, biphenyl, was used for the quantification of starting

280

material & for the NMR conversion. Values represent conversion of starting material, 1, to

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desired product. No undesired products formed. cIsolated yields.

Reaction Conditions: All reactions were carried out in MeOH (0.45 M) with 10-18 wt % MgO,

282 283

We selected aldehydes with a variety of one-point changes for our investigation in order to

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explore the electronic and steric effects on the Aldol condensation reaction. Reactions that

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featured electron rich aromatic aldehydes proceeded with longer reaction times, from ca. 1 day to

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2.5 days (Entries 3-4, 9-10, 19-20, Table 4). Reactions with aldehydes that featured weakly

287

donating functional groups proceeded to completion in less time (ca. 15 h) (Entries 1-2, 7-8, 11-

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12, Table 4). Thus, we expected that the reactions featuring an aldehyde with a withdrawing

289

group at the same position should proceed more quickly but this was not the case (compare, for

290

example, Entries 17 and 25, Table 4). Surprisingly, the reactions with an aldehyde featuring a

291

para-ester proceeded with a relatively longer reaction time of ca. 27 h (Entries 15 & 16,

292

Table 4). The reactions with aldehydes featuring bulky groups at a distal position to the coupling

293

center (i.e., in the meta or para position on the aromatic ring) were relatively fast reactions

294

(Entries 5-6, 21-28, Table 4). These reactions tended to reach completion within 12 h.

295

As mentioned in the introduction, we sought to employ a heterogeneous catalyst that could be

296

recycled for further use (Green Chemistry Principles 1 and 9). To this end, we designed a series

297

of five reactions where the MgO catalyst was isolated after each run and then immediately re-

298

used in a subsequent reaction. For this study we employed the nonulose 1 and benzaldehyde, and

299

our general reaction procedure. Once the reaction was complete (reactions were stopped at 4.5

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h), measured by LC-RI, the crude reaction mixture was filtered and the MgO catalyst was

301

collected as a solid by vacuum filtration using a fritted funnel. The MgO catalyst was then

302

resubmitted to the subsequent new reaction. As shown in Figure 3, the MgO did not lose its

303

catalytic activity based on the conversion of nonulose until the fifth reaction where we observed

304

a minor decrease in conversion. Furthermore, the variability in catalyst loading is due to

305

hygroscopicity of 1. The product mixtures of each reaction were also analyzed by 1H NMR

306

which confirmed the complete conversion of nonulose to the desired product. Also, shown in

307

Figure 3, the reactions were run with the requisite amount of catalyst (6-12 %). We did observe

308

loss of catalyst to the filter during the isolations, which could be further optimized, especially on

309

scale. The results of this study indicate that the MgO SBC can be recycled for further use. 100

100

98

100

96

310

100

311

80

Cat.Wt312 (%)

60 40 20

12

12

9

11

NMR Conv. 313 (%)

6

314

0 Rxn 1

Rxn 2

Rxn 3

recycling experiment

Rxn 4

Rxn 5

315 316

317

Figure 3. Repeating Aldol condensation reaction with 1 and benzaldehyde using the standard

318

conditions of MgO and 1 eq. L-proline in MeOH at 50 °C, where the catalyst, MgO, was

319

recycled in each subsequent experiments. The total reaction time was 4.5 h. The results indicate

320

that there was little, if any, deactivation of the MgO catalyst.

321

For our studies, we selected 10 wt % as our catalyst concentration based on related work on SBC

322

catalyzed aldol reactions that have been reported in the literature. These reports utilize 20-30

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wt % catalyst loadings.22,39–41 Also, it is important to note that MgO is an abundant and non-toxic

324

metal, and critically, we have demonstrated that the catalyst can be recycled.

325 326

Conclusion

327

Herein, we have reported the development of a novel enamine-solid base catalyzed Aldol

328

condensation reaction. The novel catalytic system employs a heterogeneous solid base catalyst

329

(SBC), either MgO or HT, and L-proline. By switching the previously reported bases

330

(triethylamine and pyrrolidine) to greener and safer SBCs and L-proline, we were able to

331

demonstrate an efficient method for synthesizing (E)-α,β-unsaturated ketones with good to

332

excellent yields. The SBC catalyzed methodology is applicable to a wide range of aromatic

333

aldehydes that feature electron-rich and electron-poor substrates, and sterically bulky groups. In

334

addition, we have shown the recyclability of our catalyst, MgO and have identified a

335

heterogeneous solid base catalyst, CaO, which does not require the use of L-proline. This is an

336

exciting result that could improve the E-factor of the reaction and the finding warrants further

337

investigation.

338 339

ASSOCIATED CONTENT

340

Supporting Information.

341

XRPD characterization of hydrotalcite and porous metal oxide (Figures S1 and S2, respectively),

342

optimized synthesis for (E)-α,β-unsaturated ketones 2a-n, along with their respective 1H and 13C

343

NMR and mass spectra characterization.

344

AUTHOR INFORMATION

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Corresponding Author

346

*Tel.: 1-203-436-5127. E-mail: [email protected]

347

Author Contributions

348

All the authors contributed equally.

349

Funding Sources

350

The financial support came from L’Oréal.

351

Notes

352

The authors declare no competing financial interest.

353

ACKNOWLEDGMENT

354

The authors would like to gratefully acknowledge financial support from L’Oréal.

355

TOC/Abstract Graphic

356 357

Synopsis: The development of a safe, sustainable and novel catalyzed Aldol condensation

358

reaction for the synthesis of biosourced valuable materials.

359 360

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