An Increased Understanding of Enolate Additions

molecules Article

An Increased Understanding of Enolate Additions under Mechanochemical Conditions Heather Hopgood and James Mack * Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-513-556-9249 Academic Editor: Davide Ravelli Received: 29 January 2017; Accepted: 20 April 2017; Published: 27 April 2017

Abstract: Very little is known about enolate addition chemistry under solver-free mechanochemical conditions. In this report, we investigated the ability to selectively form products arising from the primary, secondary, and tertiary enolates under solvent-free conditions. Using potassium tert-butoxide as the base and primary, secondary, and tertiary electrophiles, we were able to generate various enolate addition products including, 1,3,3,3-tetraphenyl-2,2-dimethyl-1-propanone; a molecule we did not observe under traditional solution-based conditions. Keywords: mechanochemistry; green chemistry; enolate; solvent-free

1. Introduction Enolates are a very powerful synthetic tool for the formation of highly electron-rich carbon atoms that can serve as nucleophiles. Unlike a Grignard or other organometallic reagents, however, enolate reactions are not air- or water-sensitive and therefore can be conducted under atmospheric conditions. Surprisingly, given the importance of enolates in organic synthesis, there are very few examples in the literature that are conducted under mechanochemical conditions [1–6]. In solution, studies have shown that enolate reactivity is dependent on a few factors. Rappe and Sachs determined that the rate of deprotonation of acetone is faster than that of 3-methyl-2-butanone by a factor of approximately 100; the addition of two methyl groups significantly reduces the availability of the proton for removal [7]. Additionally, enolate reactivity can be affected by both the solvent and the coordinating ion [8]. A study by House et al. indicated that, when using dimethoxyethane, the electron-density on the α-carbon to the carbonyl changes with a different conjugate alkali metal, which affects the amount of C-alkylation observed in the product [9]. Jackman and Lange went on to demonstrate that this is largely due to the formation of ion-pair aggregates. For example, the lithium enolate of isobutyrophenone predominates as a solvated tetramer in dioxolane. These aggregates facilitate C-alkylation, and it was determined that softer leaving groups, such as iodide, are more favorable [10]. This trend has shown to be qualitatively consistent in both the gas phase and in solvent, suggesting that it may not be a solvent-dependent phenomenon [11]. In order to better understand enolate chemistry under solvent-free mechanochemical conditions, we sought to carry out various enolate reactions under these unique conditions. Some enolate reactivity has previously been demonstrated using mechanochemical conditions. Toda et al. reported the mixed aldol condensation of p-methylbenzaldehyde with acetophenone in the presence of sodium hydroxide using a mortar and pestle. They found the yield to be higher under solvent-free conditions than when the reaction was conducted in aqueous ethanol [12]. Bolm, Soloshonok, and co-workers developed asymmetric variants of enolate reactions using different catalysts under mechanochemical conditions [6,13]. We previously demonstrated the ability to control kinetic and thermodynamic enolates using mechanochemistry [14].

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Although enolate reactions have been shown to be favorable using mechanochemistry, little is known about the Molecules 2017, 22, 696 addition of electrophiles to enolates under these conditions. In the examples 2 of 7 above, additional products were reported leaving the range of enolate reactivity still unclear. In order Although enolate have been shown be favorableunder using mechanochemical mechanochemistry, little is for a more consistent use reactions of enolate chemistry to betoconducted conditions, known about the addition of electrophiles to enolates under these conditions. In the examples above, these gaps must be addressed. additional products were reported leaving the range of enolate reactivity still unclear. In order for a more consistent use of enolate chemistry to be conducted under mechanochemical conditions, these 2. Results and Discussion gaps must be addressed.

We started our study by first trying to understand which bases would be best suited for 2. Results and Discussion solvent-free enolate addition reactions. Using acetophenone and benzyl bromide, we tested several

bases to determine base the highest yield ofwhich substitution. We started which our study by gave first trying to understand bases would be best suited for solventAs can be addition seen from the results Table 1, typically as bromide, base strength increases, so does free enolate reactions. Usingin acetophenone and benzyl we tested several bases to the determine which base gave the highest yield of substitution. overall yield of the reaction. It is interesting to point out that lithium hexamethyldisilazide is can be from than the results in Tabletert-butoxide, 1, typically as base increases, so does the overall a strongerAsbase in seen solution potassium but strength led to lower enolate addition product yield of the reaction. It is interesting to point out that lithium hexamethyldisilazide is a stronger baselithium in under mechanochemical conditions. This is due to the addition of benzyl bromide to the solution than potassium tert-butoxide, but led to lower enolate addition product under mechanochemical hexamethyldisilazide. Similar to what is observed in solution, the diaddition occurs in higher yield conditions. This is due to the addition of benzyl bromide to the lithium hexamethyldisilazide. Similar to than the mono addition in most cases [15]. From the initial screening of the reaction, potassium what is observed in solution, the diaddition occurs in higher yield than the mono addition in most cases tert-butoxide the highest yield so we chose to use potassium tert-butoxide [15]. Fromgave the initial screening of of theproducts, reaction, potassium tert-butoxide gave the highest yield ofin the subsequent reactions. products, so we chose to use potassium tert-butoxide in the subsequent reactions. Table1.1.Comparison Comparison of bases in enolate reactivity. Table of bases in enolate reactivity.

Entry Base Entry t Base 1 BuOK t 1 NaNH BuOK 2 2 2 KOH NaNH2 3 3 KOH 4 LiHMDS LiHMDS 4 5 NaOH 5 NaOH 6 CS 2CO3 6 CS2 CO3

Yield Yield 94% 94% 91% 91% 78% 78% 52% 52% 11% 11% 3% 3%

Product Ratio 3aa/4aa Product Ratio 3aa/4aa 12/88 12/88 12/88 12/88 10/90 10/90 42/58 42/58 36/64 36/64 100/0 100/0

LiHMDS: lithium bis(trimethylsilyl)amide. LiHMDS: lithium bis(trimethylsilyl)amide.

Typically in solution, enolate substitution reactions are set up in separate steps to avoid the Typically aldol in solution, enolate substitution reactions arethe set upcondensation in separatereaction steps to competing condensation. We wanted to test how prevalent aldol wasavoid the competing aldol We wanted to test how prevalent aldol condensation in comparison to thecondensation. substitution reaction under mechanochemical conditions.the When we attempted to conduct the comparison enolate reaction observed 3-methyl-1,3,5-triphenylreaction was in tousing the acetophenone substitution stepwise, reactionwe under mechanochemical conditions. 1,5-pentadione (7). This is believed to come from an initial aldol condensation by awe Michael When we attempted to conduct the enolate reaction using acetophenonefollowed stepwise, observed addition. In order to determine if we could stop is thebelieved reaction to at come the aldol intermediate, we varied the 3-methyl-1,3,5-triphenyl-1,5-pentadione (7). This from an initial aldol condensation time of the reaction from 2–16 h. At every interval we attempted, we were unable to observe 3-hydroxyfollowed by a Michael addition. In order to determine if we could stop the reaction at the aldol 1,3-diphenylbutan-1-one (5) or dypnone (6) in the reaction mixture. Since the energetics of our mill intermediate, we varied the time of the reaction from 2–16 h. At every interval we attempted, we were has been theorized to be similar to 90 °C, it may not be surprising to observe the rapid loss of water unable to observe 3-hydroxy-1,3-diphenylbutan-1-one (5)weordid dypnone (6) in reaction mixture. under these conditions [16]. However, given the fact that not observe thethe α,β-unsaturated ◦ C, it may not be surprising Sinceketone, the energetics of our mill has been theorized to be similar to 90 the 1,4 addition might occur at a much faster rate than the initial aldol condensation. to observe the rapid of waterwe under these conditions However, theoffact that we did In addition to the loss 1,5-diketone, observed other products[16]. related to the 1,2 given addition the enolate not observe theMichael α,β-unsaturated ketone,[17]. theThe 1,4 1,2 addition might at a muchketone faster has ratebeen than the with initial addition products addition of theoccur α,β-unsaturated under solution conditions as well, but1,5-diketone, only after trapping the α,β-unsaturated ketone related with initialobserved aldol condensation. In addition to the we observed other products to diethylboryl-pivalate [18]. This is in starkMichael contrast addition to solution, where the aldol the 1,2 addition of the enolate with initial products [17]. Thecondensation 1,2 additionofof the acetophenoneketone gives 3-hydroxy-1,3-diphenylbutan-1-one (5) conditions and dypnone (Scheme 1) [19]. α,β-unsaturated has been observed under solution as(6) well, but only after trapping

the α,β-unsaturated ketone with diethylboryl-pivalate [18]. This is in stark contrast to solution, where

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the aldol condensation of acetophenone gives 3-hydroxy-1,3-diphenylbutan-1-one (5) and dypnone (6) (Scheme 1) 2017, [19].22, 696 Molecules 3 of 7 O

O

O HO

base

+

solvent

5

O

O

2 NaOH 2h

Ph

6

O Ph

O Ph

7

+

Ph

O

Ph +

Ph 8

Ph

Ph

Ph

Ph 9

major product

Scheme 1. Comparison of acetophenone self-aldol in solution versus mechanochemistry.

Scheme 1. Comparison of acetophenone self-aldol in solution versus mechanochemistry.

1,5-Diketones have been used as synthetic intermediates for heterocyclic and polyfunctional 1,5-Diketones have usedinas synthetic intermediates for heterocyclic and polyfunctional compounds which can been be useful coordination chemistry, molecular sensing, catalysis and redox compounds which candevices be useful coordination chemistry, molecular sensing, chemistry catalysis and redox active self-assembly [20].inFor example, Smith et al. has used 1,5-diketone for the active self-assembly devices [20]. For example, Smith et al. 1,5-diketone chemistry formation of 2,4,6-triarylpyridines [21]. These precursors are has usedused for supramolecular synthesis for for the polymers, as well as, in new therapeutic drugs.precursors Some difficulty has been observed with thesynthesis Michael for formation of 2,4,6-triarylpyridines [21]. These are used for supramolecular additionasofwell α,β-unsaturated aryl ketones drugs. becauseSome of the difficulty steric hindrance on both substrates and strong polymers, as, in new therapeutic has been observed with the Michael bases are often used with low yield formation. Alternative methods have been explored including addition of α,β-unsaturated aryl ketones because of the steric hindrance on both substrates and strong metal [22],with enamine catalysis [23], and Alternative promotion by barium hydride or barium alkoxides bases are catalysis often used low yield formation. methods have been explored including [24]. Therefore, mechanochemistry provides a simple method to gain access to these 1,5-diketones. metal catalysis [22], enamine catalysis [23], and promotion by barium hydride or barium alkoxides [24]. Given the propensity of enolates to form aldol condensations products very rapidly under milling Therefore, mechanochemistry provides a simple method to gain access to these 1,5-diketones. Given the conditions, we conducted all subsequent enolate addition reactions in one-step instead of the two-step propensity of enolates to form aldol condensations products very rapidly under milling conditions, process traditionally executed in solution. we conducted all subsequent enolate addition in one-step of the two-step process With a clearer understanding of the reactivityreactions trends of enolates underinstead mechanochemical conditions, traditionally executed in solution. we sought to determine exactly how it affects the productivity of enolate addition reactions. In order to With athese clearer understanding the reactivity trends of enolates under mechanochemical address questions, a range of of enolate reactions was conducted using primary, secondary, and conditions, we sought to primary, determine exactly how affectsalkyl the productivity of enolate addition reactions. tertiary enolates with secondary, and it tertiary bromides. Potassium tert-butoxide was used as base from the questions, results of thea previous Furthermore, reactionsusing need to be In order tothe address these range ofstudy. enolate reactionssince wasthese conducted primary, conducted in tertiary a one-step fashion,with the bulky nature of the t-butyl wasalkyl expected to decrease the secondary, and enolates primary, secondary, andgroup tertiary bromides. Potassium competitivewas nucleophilic addition byresults the base. of this studyFurthermore, are given in Figure tert-butoxide used as the basereaction from the ofThe theresults previous study. since1.these From the given results, it is clear that various competitive reactions are highly influential in thewas reactions need to be conducted in a one-step fashion, the bulky nature of the t-butyl group formation of the enolate addition product. When comparing ketone reagents on solid support, Muzart expected to decrease the competitive nucleophilic addition reaction by the base. The results of this demonstrated the aldol condensation reactivity is highest for acetophenone as compared to more sterically study are given in Figure 1. hindered ketones [25]. In addition to the aldol condensation, the base can also act as a nucleophile which From the given results, it is clear that various competitive reactions are highly influential in leads to additional side products in many of these reactions. We believe strategic control over the the formation ofthe theketone enolate addition product. comparing ketone reagents on solid support, steric bulk of and alkyl halide is keyWhen to controlling the yield of mono addition products. Muzart demonstrated the aldol condensation reactivity is highest for acetophenone as compared In the case of isobutyrophenone (1c), which forms a tertiary enolate (entries 3ca–3cc), the presence of to more sterically hindered ketones [25]. In addition to the aldolthe condensation, theketone base such can also the two methyl groups prevents the elimination step needed to form α,β-unsaturated act as a nucleophile additional side products that it leads to the which highestleads yield to of mono addition product [26].in many of these reactions. We believe hindered are difficult to conduct solutionstrategicAdditionally, control oversterically the steric bulk ofreactions the ketone and alkyl halide under is keyconventional to controlling the yield based conditions and often require the use of activated enolates such as enol acetates, enamines, of mono addition products. In the case of isobutyrophenone (1c), which forms a tertiary enolate 1,3-dicarbonyls, orpresence silyl enol-ethers. For instance, McGlacken et al. achieved a 15% product yield from (entries 3ca–3cc), the of the two methyl groups prevents the elimination step needed to form the reaction of propiophenone with benzyl bromide through the activation with a chiral imine [27]. the α,β-unsaturated ketone such that it leads to the highest yield of mono addition product [26]. Similarly, Maruoka et al. recovered a 73% yield with the activated silyl enol-ether of isobutryophenone Additionally, sterically hindered reactions are difficult to conduct under conventional and chlorodiphenylmethane through the use of a methylalumoxane catalyst [28]. In this case, both solution-based conditions and often require the use of activated enolates such as enol acetates, trimethylsilane and the aluminum catalysts were used for the activation of the ketone reagent. To enamines, 1,3-dicarbonyls, or silyl enol-ethers. For instance, McGlacken et al. achieved a 15% product demonstrate the ability to generate sterically crowded molecules via these unique conditions, we

yield from the reaction of propiophenone with benzyl bromide through the activation with a chiral

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imine [27]. Similarly, Maruoka et al. recovered a 73% yield with the activated silyl enol-ether of isobutryophenone and chlorodiphenylmethane through the use of a methylalumoxane catalyst [28]. In this case, both trimethylsilane and the aluminum catalysts were used for the activation of the Molecules 2017, 22, 696 4 of 7 ketone reagent. To demonstrate the ability to generate sterically crowded molecules via these unique conditions, we were able to synthesize 1,3,3,3-tetraphenyl-2,2-dimethyl-1-propanone (3cc) in a 39% were able to synthesize 1,3,3,3-tetraphenyl-2,2-dimethyl-1-propanone (3cc) in a 39% yield, a molecule yield, a molecule we were unable to observe under solution-based conditions. we were unable to observe under solution-based conditions.

Figure 1. Enolate reactivity results. Figure 1. Enolate reactivity results.

Our previous results suggest competing reactions with primary enolates may ultimately lead to previous suggest competing with may ultimately lead lowOur mono additionresults product formation. In orderreactions to alleviate thisprimary problem,enolates the trimethylsilyl-enol ether tooflow mono addition product formation. In order to alleviate this problem, the trimethylsilyl-enol acetophenone was generated to determine if these enolate equivalents would perform better under ether of acetophenone was generated to determine if these enolate equivalents would perform better mechanochemical conditions. We milled the silyl enol ether of acetophenone in the presence of cesium under mechanochemical conditions. We milled the silyland enol ether of acetophenone in the fluoride with benzyl bromide, bromodiphenylmethane, triphenylbromide to compare thepresence reactivityof cesium with benzyl The bromide, and in triphenylbromide to compare the to ourfluoride earlier experiments. resultsbromodiphenylmethane, of this latter study are given Figure 2. reactivity to our earlier the experiments. The results of selectivity this latter for study are given inproducts Figure 2.confirming As was expected, trap has enabled a greater single-addition an increase in control of the reactivity. Although no aldol condensation products were observed, the overall yields of the enolate addition products decreased significantly.

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As was expected, the trap has enabled a greater selectivity for single-addition products confirming an increase in control of the reactivity. Although no aldol condensation products were observed, the overall yields Molecules 2017, 22, 696of the enolate addition products decreased significantly. 5 of 7

Figure 2. 2. Silyl Silyl enol enol ether ether reactivity reactivity under under mechanochemical mechanochemical conditions. conditions. Figure

3. Materials and Methods 3. Materials and Methods General: Mechanochemical milling reactions were carried out in a SPEX 8000D Miller/Mill (Spex General: Mechanochemical milling reactions were carried out in a SPEX 8000D Miller/Mill Certiprep, Metuchen, NJ, USA) at a frequency of 18 Hz using a custom made stainless steel vial with (Spex Certiprep, Metuchen, NJ, USA) at a frequency of 18 Hz using a custom made stainless a single stainless steel ball bearing. 1H Nuclear Magnetic Resonance (NMR) spectra were obtained steel vial with a single stainless steel ball bearing. 1 H Nuclear Magnetic Resonance (NMR) using a Bruker Avance 400 MHz spectrometer (Bruker, Billerica, MA, USA), 13C-NMR spectra were spectra were obtained using a Bruker Avance 400 MHz spectrometer (Bruker, Billerica, MA, USA), recorded at 100 MHz and all chemical shift values are reported in ppm on the δ scale. Gas 13 C-NMR spectra were recorded at 100 MHz and all chemical shift values are reported in chromatography–mass spectrometry (GC–MS) data was obtained using a Hewlett-Packard 6890 ppm on the δ scale. Gas chromatography–mass spectrometry (GC–MS) data was obtained using series GC–MS system (Agilent, Santa Clara, CA, USA) with an HP-5MS, 30 m × 0.25 μm × 0.25 μm a Hewlett-Packard 6890 series GC–MS system (Agilent, Santa Clara, CA, USA) with an HP-5MS, column (Agilent). High resolution mass spectral determinations were carried out by using a 30 m × 0.25 µm × 0.25 µm column (Agilent). High resolution mass spectral determinations were Micromass Q-TOF-2 Mass Spectrometer (Waters, Milford, MA, USA) in positive mode. Analytical carried out by using a Micromass Q-TOF-2 Mass Spectrometer (Waters, Milford, MA, USA) in Thin Layer Chromatography (TLC) was performed on silica gel plates using UV light. Flash column positive mode. Analytical Thin Layer Chromatography (TLC) was performed on silica gel plates chromatography was performed on a CombiFlash Automated Flash Chromatography system using UV light. Flash column chromatography was performed on a CombiFlash Automated Flash (Teledyne Isco, Lincoln, NE, USA) by using RediSep Rf Gold high performance flash columns (fine Chromatography system (Teledyne Isco, Lincoln, NE, USA) by using RediSep Rf Gold high spherical silica gel 20–40 μm) (Teledyne Isco). Deuterated chloroform was obtained from Cambridge performance flash columns (fine spherical silica gel 20–40 µm) (Teledyne Isco). Deuterated chloroform Isotope Laboratories Inc. (Andover, MA, USA) and used without further purification. All reagents was obtained from Cambridge Isotope Laboratories Inc. (Andover, MA, USA) and used without were purchased from Acros Organics and used without further purification. Custom-made vials further purification. All reagents were purchased from Acros Organics and used without further were made by the machine shop at the University of Cincinnati with metal rods purchased from purification. Custom-made vials were made by the machine shop at the University of Cincinnati with McMaster-Carr (Aurora, OH, USA). Simriz 486 Perfluoroelastomer O-rings (6/16” ID × 7/16” OD × metal rods purchased from McMaster-Carr (Aurora, OH, USA). Simriz 486 Perfluoroelastomer O-rings 3/32” width) were purchased from Small Parts Inc. (Logansport, IN, USA). NMR Spectra can be found (6/16” ID × 7/16” OD × 3/32” width) were purchased from Small Parts Inc. (Logansport, IN, USA). in Supplementary Materials. NMR Spectra can be found in Supplementary Materials. General Enolate Enolate Reaction Reaction Procedure Procedure General Two millimole millimole ketone, ketone, alkyl Two alkyl bromide, bromide, and and potassium potassiumtert-butoxide tert-butoxide(1:1:1) (1:1:1)were wereadded addedtotoa was sealed sealed acustom-made custom-madestainless stainlesssteel steelvial vialwith withaa3/16” 3/16”stainless stainlesssteel steelball. ball.The The stainless stainless steel steel vial vial was with the use of a Teflon O-ring and tightened with a vice. Reactions were run for 3 h in a Spex with the use of a Teflon O-ring and tightened with a vice. Reactions were run for 3 h in a8000D Spex Mixer/Mill. Upon completion, the reaction mixture was extracted with ethyl acetate and dried onto silica under reduced pressure for flash chromatography separation. Product isolation was achieved with a gradient ramp from 100% heptane to 10% ethyl acetate.

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8000D Mixer/Mill. Upon completion, the reaction mixture was extracted with ethyl acetate and dried onto silica under reduced pressure for flash chromatography separation. Product isolation was achieved with a gradient ramp from 100% heptane to 10% ethyl acetate. 4. Conclusions Enolate reactivity under solvent-free mechanochemistry conditions is quite different from that for solution-based conditions. We have observed that it is best to conduct these reactions in a one-step manner rather than two separate steps as traditionally conducted in solution. This is necessary in order to avoid the competitive aldol condensation reaction. The use of a bulky base limits the competitive reaction of the base reacting with the electrophile. Although there are some limitations with conducting enolate reactions under solvent-free conditions, these conditions are beneficial for tertiary enolates, and the formation of sterically hindered products such as 1,3,3,3-tetraphenyl-2,2-dimethyl-1-propanone (3cc). Ball milling can be an excellent asset for the reduction of solvent waste and the generation of more environmentally benign reactions. However, in order to achieve these goals, we must first understand the nuances of this process. Supplementary Materials: Supplementary materials are available online. Acknowledgments: We would like to acknowledge funding from the National Science Foundation (CHE-1465110). We are also grateful to Ronald Hudepohl of the University of Cincinnati’s machine shop for his kind instruction and insights. Author Contributions: H.H. and J.M. conceived and designed the experiments; H.H. performed the experiments; H.H. and J.M. analyzed the data; J.M. contributed reagents/materials/analysis tools; J.M. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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