Kinetics of Nucleophilic Substitution of Compounds Containing Multiple Leaving Groups Bound to a Neopentyl Skeleton.

Ammonium salt derivatives with a neopentyl moiety are remarkably stable against Hofmann elimination, but the neopentyl moiety slows nucleophilic substitution, complicating their synthesis. To identify the best leaving group for the synthesis of the ammonium salts, we prepared six 1,1,1-tris(X-methyl)ethane derivatives, where X is chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate (triflate), and studied the kinetics of their reactions with sodium, cesium, or tetramethylammonium azide in deuterated dimethylsulfoxide (DMSO) at 100 °C by NMR spectroscopy. Iodide and bromide were found to be more reactive than p-toluenesulfonate and methanesulfonate. As expected, the best leaving group for nucleophilic substitution was triflate. Despite the usual high reactivity and instability of primary alkyl triflates, neopentyl triflate can be used as a stable but sufficiently reactive reactant for nucleophilic substitution on neopentyl skeletons.

Introduction

Ammonium salt derivatives (ASDs) stable against Hofmann elimination[1] have been studied in our group for their ability to bind strongly to negatively charged solid support.[2,3] In particular, ASDs with a neopentyl moiety (Figure ) are quite useful for such purpose as they allow achieving high spatial concentration of the ammonium positive charges. However, the neopentyl skeleton slows the rates of nucleophilic substitution reactions when the leaving group is attached to this skeleton, thereby complicating the synthesis of ASDs.

Figure 1

Structures of ammonium derivatives with a neopentyl moiety, binding strongly to negatively charged solids.[2]

In a nucleophilic substitution (SN), the leaving group is replaced by a nucleophile.[4] However, the neopentyl skeleton is too sterically hindered by the tert-butyl moiety for SN2 reactions to occur even though the leaving group is attached to the primary carbon atom, as shown by Whitmore and Rothrock.[5] Subsequently, Dostrovsky et al.[6,7] observed that under SN2 conditions, neopentyl bromide reacts approximately 105 times slower than other primary alkyl bromides. However, under SN1 conditions, the reaction rates are similar to each other, but the resulting carbocation rearranges to a tert-amyl skeleton and then forms isoamylene via elimination. Later, Dostrovsky stated that this type of rearrangement could occur even in radical reactions.[7] More authors observed and studied this phenomenon in the following and recent years. Sanderson and Mosher[8] studied rearrangement of deuterated neopentyl alcohol and concluded that this reaction is highly stereoselective and therefore cannot proceed via a free neopentyl cation. Patrick et al.[9] utilized 13C labeling to verify the skeletal rearrangement mechanism in the reaction of neopentyl iodide with xenon difluoride. Edwards et al.[10] observed the rearranged product of neopentyl sulfate during their studies of the spontaneous hydrolysis of alkyl sulfates.

In general, leaving group reactivity can be directly correlated with the pKa of the conjugate acid. Accordingly, iodide should be a better leaving group than p-toluenesulfonate (pKa is −10 for HI[11] and −1.34 for p-TsOH[12]). However, sulfonates are better leaving groups than their pKa values imply because acidity is defined as breaking a heteroatom–hydrogen bond, but the bond between heteroatom and carbon is broken in the nucleophilic substitution reaction.[13] Our preliminary research on the synthesis of ASDs with a neopentyl skeleton showed an unusual reactivity order of leaving groups in their nucleophilic substitution reactions because the reaction rates were much higher for iodo neopentyl derivatives than for p-toluenesulfonyloxy (tosyloxy) neopentyl derivatives. In line with these results, Jahan and colleagues[14] had previously reported this unusual reactivity order during their preparation of pentaerythritol-based gemini surfactants.

Many authors studied rate constants and determined a leaving group reactivity, but only included a few compounds with a neopentyl structure. Cook and Parker[15] determined (and compared with calculated values) the rate constants of halogen-halogen exchange reactions between various alkyl bromides (neopentyl bromide was included) and tetraethylammonium chloride in dimethylformamide (DMF). The determination was done by potentiometric titration of reaction mixtures with silver nitrate in the presence of barium nitrate, which was added to reduce coprecipitation of the silver halides.

To the best of our knowledge, there is no further work to compare the reactivity of the leaving groups on the neopentyl skeletons and to determine the rate constants for the respective reactions.

Thus, we report herein on the synthesis of six derivatives of neopentane derivatives—1,1,1-tris(X-methyl)ethane (X3Np)—with different leaving groups X. Next, we performed NMR kinetic studies of reactions of X3Np with sodium, cesium, or tetramethylammonium azide in deuterated dimethylsulfoxide (DMSO) at 100 °C to find the best leaving group in terms of stability and reactivity for the synthesis of ASDs and to assess the counterion effect on this nucleophilic substitution. This substitution with azide could serve, together with a direct reaction with appropriate amines, as one of the possible strategies for preparing of mentioned ASDs (Figure ).

Results and Discussion

The X3Np derivatives were prepared using standard procedures shown in Scheme starting from the triol (OH)3Np (1). The leaving groups to introduce were selected from four leaving group types: alkylsulfonates—(MsO)3Np (2), perfluoroalkylsulfonates—(TfO)3Np (3), arylsulfonates—(TsO)3Np (4), and halides—I3Np (5), Br3Np (6), and Cl3Np (7).

Scheme 1

Synthesis of X3Np Derivatives

Using published procedures, we prepared Cl3Np,[16] (MsO)3Np,[17] and (TsO)3Np.[18] In addition, I3Np was prepared from (TsO)3Np with tetrabutylammonium iodide (TBAI) in toluene under reflux, an approach inspired by the literature.[19] Br3Np was prepared using the same procedure but with TBABr. According to the literature, we first tried to prepare (TfO)3Np using triethylamine (TEA) as a base,[20] but we observed an inseparable reaction mixture, even at −20 °C, most likely due to TEA quaternization. Thus, we replaced TEA with the more sterically hindered 2,6-lutidine, and the reaction ran smoothly and afforded the product in sufficient purity.

We used (TsO)3Np to assess whether its reaction with sodium azide in deuterated DMSO at 100 °C can be followed by 1H NMR spectroscopy. Our results confirmed that the methyl signals of the starting compound (TsO)3Np, monoazido (TsO)2N3Np (8), diazido (TsO)(N3)2Np (9), and triazido (N3)3Np (10) products are easily identified using this method (Figure ). Therefore, 1H NMR spectroscopy is a convenient method to follow the reaction and to determine its rate by integrating the CH3 signals over time.

Figure 2

Reaction scheme and 1H NMR of the reaction mixture showing sufficiently separated CH3 group signals of starting compound (TsO3)Np (4), monoazido (TsO)2N3Np (8), diazido (TsO)(N3)2Np (9), and triazido (N3)3Np (10)-substituted products.

The reaction ran smoothly, and under these conditions, no unexpected side products were observed, making it possible to monitor the reaction by the NMR technique.

Some authors described various unexpected side products and intermediates during their encounters with compounds having a neopentyl skeleton. For example, Dale et al.[21] tested and analyzed the reaction between (TsO)3Np and alcoholates in which oxetane derivative 13 was formed as the main product (Figure ). The authors explained this surprising outcome by the nucleophilic attack of the alcoholate on the sulfur atom instead of on the electrophilic carbon due to steric reasons. The resulting alcoholate then forms the oxetane ring via intramolecular nucleophilic substitution and allows another nucleophilic substitution via neighboring group participation. The authors also performed other tests with Cl3Np and found that it reacted with 2-methoxyethanolate in an alcohol solution for 3 days at reflux with a 3:6:1 proportion of mono-, di- and trisubstituted products, according to gas–liquid chromatography (GLC) analysis. Under the same conditions, compound Br3Np afforded the main trisubstituted product in 78% yield.

Figure 3

Reaction of compound (TsO3)Np (4) with alcoholate described by Dale et al.[21]

In our experiments, we followed the reaction of X3Np with azide until its completion. The procedure was repeated three times for each starting compound to verify reproducibility. The resulting average values and standard deviations from the NMR kinetic experiments for (TsO)3Np are shown in the graph in Figure .

Figure 4

Composition of the reaction mixture in the reaction of (TsO3)Np (4) with an excess of NaN3 in time.

Azide anion was used as the nucleophile and deuterated DMSO as the solvent to promote SN2 reactions and to avoid skeletal rearrangements. No skeletal rearrangement was detected in all kinetic measurements when monitoring the shifts and the splitting of the signals of the methyl and CH2X groups because these signals remained singlets throughout the analysis. If there were any skeletal rearrangements, these signals would change, e.g., become triplets due to the adjoining CH2 group (Figure ). Graphs of kinetic measurements of compounds Cl3Np, Br3Np, I3Np, (MsO)3Np, and (TfO)3Np are shown in the Supporting Information.

Figure 5

Possible skeletal rearrangements under SN1 conditions.

It is worth mentioning that none of the intermediates and N3Np products have been isolated and characterized by any means other than NMR spectroscopy. The reactions provided the same products with two signals, always with the same shift regardless of the LG type.

The half-life of the X3Np derivatives was defined as the time when 50% of the triazido product is formed. This information was retrieved from the kinetics graphs (Figure ), and the collected data were plotted in a combined bar graph with a logarithmic scale (Figure ).

Figure 6

Graphs of half-lives for azidation reaction with compounds (TfO)3Np (3), I3Np (5), Br3Np (6), (TsO)3Np (4), (MsO)3Np (2), and Cl3Np (7).

As the last control to establish that these reactions are indeed second-order, the concentration of NaN3 was doubled for the reaction with I3Np. It was observed that the reaction rate was 2 times higher (15 min half-life—compared with 28 min for I3Np in Figure after recalculation).

To get a better overall view of the matter, we decided to look at the reaction also from the other side and calculate the rate constant of the depletion of (TsO)3Np starting compound. This rate constant in the reaction of (TsO)3Np with NaN3 in deuterated DMSO at 100 °C was calculated from an integrated second-order kinetic equation (eq ),[22] where CA,0 and CB,0 are initial concentrations of tritosylate and the azide, respectively; CA and CB are their concentrations at time t, respectively; and k is the rate constant. Using the percentage amounts of starting compound (TsO)3Np and azido products (TsO)2(N3)Np, (TsO)(N3)2Np, and (N3)3Np assessed at specific times of the “composition of the reaction mixture in time” graph (Figure ), we calculated concentrations and plotted these values as a function of time, using eq . This resulted in a linear curve whose slope is equal to the rate constant (Figure ). The resulting graph for (TsO)3Np is shown in Figure , and the rate constant is equal to 0.00121 mol–1 dm3 s–1.

Figure 7

Variation of concentration of (TsO)3Np (4) and NaN3 as a function of time.

The same strategy was used for the other four compounds Cl3Np, Br3Np, I3Np, and (MsO)3Np. The resulting graphs are shown in the Supporting Information. In the case of the most reactive compound (TfO)3Np, the reaction was completed in 1 min. Due to that, we did not have enough data to compile a graph similar to Figure , and we can only estimate the magnitude of the rate constant. Measurements were repeated for the same reaction at room temperature, and we observed only the final (N3)3Np product after 5 min by 1H NMR. All determined rate constants and their comparison can be found in Table . A log–log graph depicting the relationship between half-lives and rate constants of each X3Np was created and can be found in the Supporting Information.

Table 1

Comparison of Rate Constants for the Formation of Monoazido (X)2N3Np Productsa

derivative	rate constant [mol–1 dm3 s–1/10–5]
(TfO)3Np (3)	>10,000,000a
I3Np (5)	670
Br3Np (6)	240
(TsO)3Np (4)	120
(MsO)3Np (2)	10
Cl3Np (7)	3

For the reaction at 100 °C.

Compounds Br3Np and I3Np possessing bromo and iodo leaving groups have lower half-lives and higher rate constants than (MsO)3Np, and (TsO)3Np bearing methanesulfonate and p-toluenesulfonate leaving groups. This trend is following the literature.[13] Due to an enormously high rate constant and short half-life in the case of (TfO)3Np, we conclude that the reactivity of the trifluoromethanesulfonate (triflate) leaving group is primarily affected by the electronic effect. This effect suppresses any possible counter-steric effect, which slows down the reaction by making the electrophilic center less accessible. Similar reasoning can be used in the case of Cl3Np. The chlorine atom is the smallest leaving group used in our work, so the steric effect is negligible. Even so, Cl3Np reactivity is low due to the electronic effect.

Conversely, steric effects strongly affect the reactivity of bromo, iodo, methanesulfonate, and p-toluenesulfonate, leaving groups in compounds Br3Np, I3Np, (MsO)3Np, and (TsO)3Np, respectively. Accordingly, the results of all four leaving groups analyzed are in good agreement with their A-values,[23] which quantitatively express the bulkiness of these substituents and are derived from equilibrium measurements of monosubstituted cyclohexanes. More specifically, bromo, iodo, and methanesulfonate substituents have A-values of approximately 0.55, 0.5, and 2.50, respectively. Therefore, A-values can be used to predict the reactivity of bromo, iodo, and methanesulfonate leaving groups bound to a neopentyl.

In addition to electronic and steric effects, bond length and covalent radius may also affect leaving group reactivity. Atomic iodine has a radius of 140 pm; bromine, 115 pm; and oxygen, 73 pm.[24] Consequently, the electrophilic carbon is much more accessible to the nucleophile in Br3Np and I3Np bearing bromo and iodo leaving groups, respectively, than in oxygen derivatives (MsO)3Np and (TsO)3Np. The reactivity trend of these four leaving groups can also be explained from the perspective of the valence bond orbital theory.[25] The best orbital overlap occurs between carbon and oxygen due to their size match. Because iodine and bromine orbitals are larger and more diffused than carbon orbitals, their overlap with carbon orbitals is poor, particularly in the case of iodine, which has the largest orbitals of all discussed atoms. Therefore, orbital overlap directly correlates with the length and strength of the bond between the leaving group and the electrophilic carbon.

Neighboring group participation is another possible explanation for this reactivity trend, as proposed by Dale et al.[21] In his study of the reactivity of Cl3Np, Br3Np, and (TsO)3Np, he explains the higher reaction rates of the Br3Np, compared to the other two mentioned compounds, by the effect of neighboring groups (Figure ). Bromine atoms have a 1,3 relationship and diffuse lone pairs, in contrast to the Cl and O atoms in Cl3Np and (TsO)3Np, respectively. Due to the diffuse lone pairs, a four-membered ring of bromonium ion 14 is formed. The formation of this four-membered ring relieves the steric problems for both nucleophile and leaving groups attached to electrophilic carbon. Dale’s findings and theories are in accordance with earlier observations and suggestions described by Doering and Levy,[26] who described the reaction of Br3Np and I3Np derivatives with silver acetate and proposed a four-membered cyclic structure similar to Dale’s for Br3Np as an explanation for nonobserving a rearranged tert-amyl side-product.

Figure 8

Neighboring group participation of compound Br3Np (6) proposed by Dale et al.[21]

Considering more recent and modern studies, a possible frontside attack could be considered a favored reaction pathway (Figure ).[27] Backside attack is an energetically less demanding pathway for the majority of SN2 reactions. The reason is increased steric repulsion due to the nearness of the nucleophile and leaving group in the transition state for the frontside pathway. However, the neopentyl skeleton backside is so hindered that attack of the nucleophile from the opposite site should not be omitted. Systematic investigation in this area was done, but neopentyl structures were not included.[28]

Figure 9

General representation of the backside and frontside pathways proposed by Hamlin et al.[27]

Instead of sodium azide, we also used cesium and tetramethylammonium azide to determine the countercation effects. The analogous procedures described for (TsO)3Np in previous paragraphs were performed for compounds I3Np and (TsO)3Np, and the results were compared. The resulting graphs describing the composition of the reaction mixture in time and variation of total concentration as a function of time are shown in the Supporting Information together with half-lives bar graphs. Table outlines the calculated rate constants for the formation of monoazido (X)2N3Np intermediates. These results indicate that the countercation has only a small effect on the reaction rate. The reactions were performed in deuterated DMSO, a polar aprotic solvent that strongly solvates cations. Thus, the effect of cations on the reaction rate constants should be negligible.

Table 2

Rate Constants of Compounds I3Np (5) and (TsO)3Np (4) for Countercation Comparison

derivative	azide countercation	rate constant [mol–1 dm3 s–1/10–5]
I3Np (5)	Na+	670
	Cs+	640
	(Me4N)+	740
(TsO)3Np (4)	Na+	120
	Cs+	170
	(Me4N)+	140

The most important discovery for us and our plans is the long-term stability and, at the same time, the high reactivity of the derivative (TfO)3Np. Trifluoromethanesulfonate (triflate) leaving group on primary carbons is known for its enormously high reactivity and very low stability. The tendency of the group to eliminate is enormous. A compound like (TfO)3Np and its bis-triflate and mono-triflate analogs possessing neopentane skeleton prepared in our laboratory do not show any signs of decomposition. These compounds can be stored in the freezer for months and on the shelf for several weeks. These properties make them ideal substances for robust and large-scale syntheses. Even though the price of Tf2O is 6 times higher than apparently the cheapest substance to introduce a leaving group, TsCl (around £ 300 for 1 kg of Tf2O compared to £ 50 for 1 kg of TsCl), the neopentyl triflates can be isolated by simple extractions in sufficient purity for further reactions, even purified by column chromatography if necessary, stored, and react smoothly and quickly with various nucleophiles.

Conclusions

Six 1,1,1-tris(X-methyl)ethane derivatives, where X is chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate, were synthesized, and their reactivity was assessed in a reaction with sodium azide in deuterated DMSO at 100 °C. This reactivity was quantified by NMR measurements and expressed in the reaction rates and half-lives. As expected, the derivative with trifluoromethanesulfonate leaving groups has the highest reaction rate and the lowest half-life. It is, therefore, the most reactive. In contrast, the least reactive derivative has chloro leaving groups. Overall, our data show that derivatives with monoatomic leaving groups (iodo and bromo) are more reactive than those with p-toluenesulfonate and methanesulfonate leaving groups. Countercation comparison (between sodium, cesium, and tetramethylammonium cations) revealed no significant differences. In conclusion, trifluoromethanesulfonate can be used as a stable but reactive leaving group for nucleophilic substitution of neopentyl skeletons.

Experimental Section

General Information

NMR measurements were performed in deuterated DMSO (Armar). NMR spectra were recorded with a Bruker Avance III (400 MHz) (1H at 400.17 MHz, 13C NMR at 100.04 MHz) spectrometer. Chemical shifts are given in δ-scale, and coupling constants J are given in Hz. Infrared spectra were measured with a Nicolet Avatar 370 FTIR. The method used for measuring was a diffuse reflectance (DRIFT) in KBr or attenuated total reflectance (ATR) with Ge crystal. IR absorptions are given in wavenumbers as cm–1. UV–vis spectroscopy spectra were measured with Thermo Scientific Helios γ with wolfram and deuterium lamp. The wavelength range is 190–800 nm. Low-resolution mass spectra were measured with a Shimadzu LCMS-2020. Samples were ionized by electrospray technique (ESI) and detected by quadrupole or time-of-flight (TOF). Drying and nebulizer gas was nitrogen. High-resolution mass spectra were measured with an Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS Samples were ionized by electrospray technique (ESI) and detected by quadrupole or TOF. Drying and nebulizer gas was nitrogen. Silica Gel 60 (0.040–0.063 mm, Merck, Germany) was used for chromatography. Thin-layer chromatography (TLC) was performed on Silica Gel 60 F254-coated aluminum sheets (Merck, Germany). Solvents were dried according to procedures described in Advanced Practical Organic Chemistry. Compounds (MsO)3Np (2),[17] (TsO)3Np (4),[18] and Cl3Np (7)[16] were synthesized according to literature procedures.

Kinetic NMR Experiment

All reactions were performed in deuterated DMSO, and the concentration of the starting compound was 35.6 mM (0.356 mmol in 10 mL or 0.178 mmol in 5 mL). The molar amount of azide was 3.2 mmol (10 mL of DMSO-d6) or 1.6 mmol (5 mL of DMSO-d6). The starting compound was dissolved in DMSO, subsequently adding azide. Then, the mixture was immersed in an oil bath at 100 °C, and the time was recorded from that moment. The volume of samples taken from the reaction mixture was 50 μL. Those samples were immediately diluted in 400 μL of deuterated DMSO and measured. The samples of (TfO)3Np (3) had to be frozen in an ice bath first, then diluted, and immediately measured.

2-Methyl-2-((((trifluoromethyl)sulfonyl)oxy)methyl)propane-1,3-diyl-bis(trifluoromethanesulfonate) (3)

1,1,1-Tris(hydroxymethyl)ethane 1 (0.3 g, 2.5 mmol) was suspended in CH2Cl2/acetone 1/1 mixture (60 mL), 2,6-lutidine (1.0 mL, 8.7 mmol) was added, and the mixture was cooled to −78 °C. Tf2O (1.5 mL, 8.7 mmol) was added dropwise. After 30 min of stirring at this temperature, the mixture became homogeneous. The mixture was stirred for another 2 h. The reaction mixture was monitored by TLC using hexane/EtOAc 10/1 mixture. The substances were detected by immersing the TLC plate in a 1% ethanol solution of 4-(4-nitrobenzyl) pyridine, followed by heating of the plate to 250 °C by a heat gun and immersion in a concentrated aqueous ammonia solution. The mixture was washed with 1M HCl (2 × 80 mL), saturated NaHCO3 water solution (80 mL), and brine (80 mL). The organic phase was dried with MgSO4 (4.0 g). After filtration, the filtrate was evaporated at room temperature on a rotary evaporator and dried at room temperature using an oil rotary pump. The product (1.21 g, 93% yield) was obtained as an orange oil in sufficient purity according to 1H NMR. However, for kinetic experiments, the product was further purified by column chromatography (24 g silica gel) eluting with hexane/EtOAc 10/1. Fractions with the product were collected and evaporated on a rotary evaporator at room temperature. The product was then dried at room temperature using an oil rotary pump and obtained as an orange oil, in 76% yield (0.99 g). IR (KBr): 2983, 1419, 1251, 1216, 1144, 952 cm–1. 1H NMR (CDCl3, 400 MHz): δ 4.45 (s, 6H, H-3), 1.28 (s, 3H, H-1). 13C{1H} NMR (CDCl3, 101 MHz): δ 118.67 (q, J = 319.7 Hz, C-4), 74.38 (C-3), 40.71 (C-2), 15.81 (C-1). 19F NMR (CDCl3, C6F6, 376 MHz): δ −76.99, −164.90 (C6F6). MS (ESI) m/z: [M + Na]+ calcd for C8H9F9O9S3Na 538.9; Found 539.0.

1,3-Diiodo-2-(iodomethyl)-2-methylpropane (5)

2-Methyl-2-((tosyloxy)methyl)propane-1,3-diyl-bis(4-methylbenzenesulfonate) 4 (1.5 g, 2.6 mmol) and TBAI (5.7 g, 15 mmol) were dissolved in toluene (45 mL), refluxed in an oil bath, and the mixture was stirred for 3 days. The reaction mixture was monitored by TLC using hexane/EtOAc 1/1 mixture for the starting compound and hexane for the product. The substances were detected by immersing the TLC plate in a basic potassium permanganate solution, followed by heating to 250 °C by a heat gun. The mixture was cooled to room temperature and filtered. The mixture was extracted between toluene and water (both 60 mL). The organic phase was washed with Na2S2O3 (60 mL), dried with MgSO4 (1 g), filtered, and evaporated at 40 °C on a rotary evaporator. The crude product (1.53 g) was purified by column chromatography (15 g silica gel) eluting with hexane. Fractions with the product were collected and evaporated on a rotary evaporator at room temperature and then dried at room temperature using an oil rotary pump. The product was obtained as a colorless oil, in 88% yield (1.02 g). IR (KBr): 2965, 2941, 2926, 2878, 1455, 1413, 1377, 1237, 1204, 1174, 1156 cm–1. 1H NMR (CDCl3, 400 MHz): δ 3.37 (s, 6H, H-3), 1.37 (s, 3H, H-1). 13C{1H} NMR (CDCl3, 101 MHz): δ 35.71 (C-2), 24.37 (C-1), 16.11 (C-3). 1H spectrum is in accordance with the literature.[29]

1,3-Dibromo-2-(bromomethyl)-2-methylpropane (6)

2-Methyl-2-((tosyloxy)methyl)propane-1,3-diyl-bis(4-methylbenzenesulfonate) 4 (2.0 g, 3.4 mmol) and TBABr (6.6 g, 21 mmol) were dissolved in toluene (60 mL), refluxed in an oil bath, and the mixture was stirred for 3 days. NMR confirmed reaction completion. The mixture was cooled to room temperature and extracted between toluene (30 mL) and water (60 mL). The organic phase was washed with water (2 × 60 mL), 1M HCl (60 mL), and brine (60 mL) and dried with MgSO4 (0.6 g). The organic phase was filtered and evaporated at 40 °C on a rotary evaporator and then dried at room temperature using an oil rotary pump. The product was obtained as a colorless oil, in 92% yield (0.97 g). IR (KBr): 2971, 2956, 2935, 2866, 1458, 1428, 1374, 1269, 1242, 1210, 1189 cm–1. 1H NMR (CDCl3, 400 MHz): δ 3.50 (s, 6H, H-3), 1.29 (s, 3H, H-1). 13C{1H} NMR (CDCl3, 101 MHz): δ 39.69 (C-2), 39.09 (C-3), 21.70 (C-1). 1H and 13C NMR spectra are in accordance with the literature.[30]