NHC-Catalyzed Formal [2+2] Annulations of Allenoates for the

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NHC-Catalyzed Formal [2+2] Annulations of Allenoates for the Synthesis of Substituted Oxetanes Susana S. Lopez, Ashley A. Jaworski, and Karl A. Scheidt* Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, Silverman Hall, Evanston, Illinois 60208, United States

J. Org. Chem. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 11/15/18. For personal use only.

S Supporting Information *

ABSTRACT: An N-heterocyclic carbene (NHC)-catalyzed reaction of γ-substituted allenoates for the synthesis of substituted oxetanes has been developed. The method provides an approach to access substituted oxetanes in a single step and is the first example of an NHC-catalyzed formal [2+2]-annulation employing γ-substituted allenoates with trifluoromethyl ketones. Mechanistic and modeling studies provide a rationale for the divergence in reactivity observed compared to the analogous reaction using unsubstituted allenoates and inform a hypothesis to explain the observed diastereoselectivity under different reaction conditions.

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INTRODUCTION Oxetanes are uncommon substructures found in a variety of naturally occurring and synthetic molecules of biological importance.1 In medicinal chemistry, oxetanes can be employed as ketone bioisosteres.2 Substituted oxetanes have been isolated from natural sources, such as oxetanocin A (Figure 1)3 and Taxol.4 Some bioactive drug-like compounds possess substituted oxetanes as well; for example, the 2alkylidene oxetane analogue of the drug orlistat shows hypolipodermic activity,5 whereas compounds possessing 2,2disubstituted oxetane substructures developed by Roche are active γ-secretase inhibitors6 (Figure 1). Substituted oxetanes can also provide non-obvious access to an array of acyclic and (poly)-heterocyclic building blocks.7 For example, treatment of 2-aryl-oxetanes with alkyl lithium reagents can generate 2lithiated oxetane nucleophiles in the presence of electrophiles8 (not shown), whereas disubstituted (2,2-aryl,alkyl)-oxetanes instead undergo regioselective ortho lithiation on their pendant aryl group, with the oxetane serving as an effective directing group (Figure 1B, top left).9 Ring-opening of substituted oxetanes mediated by acids, reductants, or external nucleophiles can all generate a variety of acyclic alcohol products. Specifically, (2,2-aryl,alkyl)-oxetanes have been shown to generate tertiary alcohols when trapped with a variety of electrophiles (Figure 1B, top right).10 Particularly, 2-alkylidene oxetanes are unconventional yet versatile precursors to many other acyclic and heterocyclic small molecules; for instance, thermal electrocyclic ring-opening to give ketones has been demonstrated,11 whereas conversion to the corresponding spiro-epoxide12 or cyclopropane13 products (Figure 1B) enables many ring-expansion and rearrangement pathways.1,14 N-Heterocyclic carbene (NHC) catalysis has grown dramatically over the past decade, but these processes predominantly employ initial 1,2-carbonyl additions by the carbene (i.e., Breslow intermediate pathways).15 In contrast, © XXXX American Chemical Society

reactions triggered by 1,4-conjugate additions of NHCs have been less commonly employed. An intriguing “β-Umpolung” reaction with carbene catalysis was reported by Fu in 2006,16 and this alternate mode of NHC nucleophilicity has since only been reported in relatively few studies by our lab and others.17 Notably, recent elegant studies uniquely aimed at specifically harnessing this unconventional mode of NHC nucleophilic catalysis have been disclosed by Lupton.18 In our own studies directed toward employing allenoates as substrates for NHC catalysis described herein, we were surprised to find that γ-substituted allenoates and trifluoromethyl ketones produced alkylidene oxetane products (Figure 1C). Interestingly, the products we observe are different from those reported by Ye, who employed unsubstituted allenoates under the same reaction conditions and observed exclusive formation of dioxanylidene products arising from a formal [2+2+2] annulation (Figure 1C).19 To the best of our knowledge, a direct NHC-catalyzed synthesis of oxetanes has not been described to date.20 We were intrigued by the significant effect that a single allenoate substituent had on the reaction outcome. Ye demonstrated that DABCO in the presence of the same substrates used in their NHC-catalyzed annulation predominantly produced the formal [2+2] annulated products.21 Work by Shi demonstrated that a β-isocupredine could effectively promote the asymmetric annulation, forming optically active 2alkylideneoxetane products in good yields and with high enantio- and diastereoselectivities.22 A single example of a γsubstituted allenoate in a [2+2] annulation with phenyl trifluoromethylketone was reported by Miller, where DABCO promoted the formation of the formal [2+2] product in 51% yield.23 Selig extended this reaction to a larger scope of Received: September 24, 2018

A

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 1. Reaction Optimizationa

entry

solvent

yieldb

drc (trans/cis)

1 2 3 4 5 6 7 8 9 10 11d 12e 13f

cyclohexance toluene benzene ether MTBE THF CHCl3 CH2Cl2 DMF CH3CN CH3CN CH3CN CH3CN

14 55 78 22 97 57 91 66 65 99 97 95 95

1:2 1:3 1:1 1:3 1:1 1:3 1:3 1:4 4:1 5:1 5:1 5:1 5:1

a

Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), IMes-Cl (30 mol %), Cs2CO3 (30 mol %), and solvent (1.0 mL) bIsolated yields. c Diastereomeric ratios determined by 1H NMR spectroscopy of crude reactions dIMes (20 mol %). eIMes (10 mol %). fIMes (5 mol %).

diastereoselectivity (99%, 5:1 dr). A small selection of other NHC precatalysts were screened (benzimidazolium, triazolium-based NHCs) and were also found to be capable of facilitating the annulation, albeit with similar or diminished yields and diastereoselectivities compared to the IMescatalyzed process. Finally, we screened the catalyst loading (entries 11−13) and found that the stoichiometry of IMes-Cl could be dropped to 5 mol % and still facilitate the title reaction in excellent yields (entries 12 and 13). We next explored the substrate scope of the reaction (Table 2). Various trifluoromethyl ketones were competent electrophiles for the [2+2] annulation. Aryl trifluoromethyl ketones with a variety of para- substituents gave excellent yields and good diastereoselectivities (3−7). Aryl trifluoromethyl ketones with strong electron-withdrawing groups and electron-donating groups similarly provided their corresponding products in excellent yields, although interestingly, the presence of an ortho substituent on the aryl trifluoromethyl ketone led to a reversal in diastereoselectivity, favoring the cis products in a 1:3 ratio (9 and 10). We were pleased to find that the reaction was not limited to aryl trifluoromethyl ketones: replacing the aryl group with a cyclohexyl group gave product 14 in good yield and diastereoselectivity. Acetophenone, benzophenone, and benzaldehyde were unreactive as electrophiles under these conditions, underscoring the necessity of using trifluoromethyl-substituted ketones to achieve sufficient electrophilicity to react with the NHC-allenoate nucleophile. Finally, altering the ester substituent had a little effect on yield or selectivity (benzyl instead of ethyl, 15, 91%, 6:1 dr), whereas a larger γsubstituent on the allenoate (tert-butyl instead of methyl, 16) provided the corresponding product with exquisite diastereoselectivity (91%, >19:1 dr). With the substrate scope established, two reactions with a major diastereomeric product trans-3 were explored (Figure 2). Oxidation with m-CPBA cleanly provided 2,4-dioxaspiro[2.3]cyclohexane product 17 in 92% yield as a 1:1 mixture of diastereomers. Additionally, the exocyclic unsaturated ester of 3 could be cleanly hydrogenated

Figure 1. Substituted oxetanes: applications and chemistry.

γ-substitued allenoates by employing 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the catalyst.24 Phosphines can also be employed as Lewis basic catalysts for analogous allenoate annulations;25 for example, Ye observed that terminal allenoates gave rise to [3+2] adducts in the presence of triphenylphosphine (Figure 1C).26

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RESULTS AND DISCUSSION Our investigations combining carbene catalysis with allenoates were initiated with the goal of gaining a better understanding for the selectivity of these reactions. We anticipated that an enhanced understanding of NHC-allenoate reactivity could be leveraged to enable new and unprecedented reactions via substrate and/or catalyst control. Consequently, we initiated preliminary studies using trifluoromethyl ketone 1 and ethyl 2,3-pentadienoate 2 with IMes chloride as the NHC precatalyst in the presence of cesium carbonate (Table 1). Under these conditions, the formal [2+2] product (E)-oxetane 3 was the sole regioisomeric product formed, as a mixture of cis and trans diastereomers with respect to the relative orientation of the allenoate’s γ-substituent to the ketone’s trifluoromethyl group. Further optimization showed a strong solvent effect on both the reaction yield and diastereoselectivity. Solvents such as cyclohexane and ether gave very low yields (14% and 22% respectively), while acetonitrile, dichloromethane, and methyl tert-butyl ether (MTBE) all provided the desired product in >90% yield. With regard to diastereoselectivity, benzene and MTBE demonstrated inferior selectivity (∼1:1 dr). Acetonitrile was chosen as the ideal solvent with respect to yield and B

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Table 2. Substrate Scopea

Figure 3. Graphical representation of product isomerism over time. Conversion (%) determined by 1H NMR spectroscopy (500 MHz).

products epimerize under the reaction conditions after an irreversible bond-forming step. To further probe the origin of product isomerism, diastereomeric products 3 were separated by chromatography and isomerically pure cis-3 was resubjected to the reaction conditions. After approximately 30 min, we observed conversion to a 5:1 mixture of trans-3/cis-3. To investigate potential pathways for isomerism involving intermediates in the NHC-catalyzed annulation, we performed a competition experiment with product cis-3 in the presence of 1-cyclohexyl-2,2,2-trifluoroethan-1-one (19) under our standard reaction conditions (Figure 4A). This reaction was monitored by NMR spectroscopy, and none of the competition product 14 was observed, though epimerization of product cis-3 still occurred. This suggests that oxetane formation is likely an irreversible step in the annulation

a

Reaction conditions: trifluorometyl ketone (0.1 mmol), allenoate (0.1 mmol), IMes-Cl (5 mol %), Cs2CO3 (30 mol %), and MeCN (1.0 mL). bIsolated combined yields. cDiastereomeric ratios of trans/ cis products determined by 1H NMR spectroscopic analysis of crude reactions.

Figure 2. Derivatization of oxetane product trans-3.

to afforded saturated oxetane 18 in 91% yield as a single diastereomer. While our optimized conditions provided oxetanes with a synthetically useful selectivity, we were intrigued by the observation that the selectivity could be inverted by employing different solvents (Table 1). Monitoring the conversion of 2 to 3 by NMR spectroscopy (Figure 3) and analysis of reaction aliquots taken at early time points revealed that allenoate 2 is fully consumed within 30 min, and cis-3 is actually the major isomeric product at this time (ratio of trans-3/cis-3 ≈ 1:3, 90% conversion). After 30 min, the total yield of 3 remains unchanged, though the dr erodes to ∼1:1 within 50 min. At approximately 120 min, the trans product is the predominant isomeric product (5:1), and this ratio remains constant out to longer time points. The interconversion of diastereomeric products suggested that (a) either the NHC-catalyzed annulation may be reversible (a fully thermodynamic manifold) or (b) that the

Figure 4. (A) Competition experiment. (B) Proposed catalytic cycle for NHC-catalyzed formal [2+2] annulation. Footnote a represents the computed distance (MM2, Avogadro)27,28 minimized model of II. C

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry reaction. As a result of these studies, we propose a reaction pathway as depicted in Figure 4B: nucleophilic addition of the NHC catalyst at the β-carbon of the allenoate leads to a zwitterionic intermediate (I), which can add to ketone 1 via nucleophilic γ-addition to afford another zwitterionic adduct (II). Oxyanion attack at the β-carbon of adduct (II) to give enolate (III) followed by irreversible elimination of the NHC liberates oxetane product 3 with concomitant catalyst turnover. The comparison between our mechanistic proposal and the pathway advanced by Ye for the NHC-catalyzed annulation of unsubstituted allenoates suggests that the critical reactivity divergence point originates with intermediate oxyanion (II). In Ye’s study, unsubstituted allenoate-NHC-ketone adduct II (R = H) must add to a second equivalent of ketone preceding cyclization and elimination of the NHC to generate the observed formal [2+2+2] products (Figure 4B).19 In an effort to better understand how the presence of γ-substitution critically changes the reaction outcome, we modeled adducts II (MM2, Avogadro)28 with and without alkyl substitution at the γ-carbon. Analysis of the resulting computed energy-minimized structures revealed that the difference in distance between the oxyanion and the β-carbon may be significant between the unsubstituted (R = H, 3.26 Å) and substituted (R = Me, 2.85 Å) structures of adducts II (Figure 4B). An additional control experiment using 5 equivalents of ketone 1 under our standard conditions was performed as a direct comparison to the stoichiometry employed for Ye’s [2+2+2] annulation. Even in the presence of a large excess of ketone electrophile, we never observed any competing [2+2+2] products from these experiments. We propose that the torsional compression invoked by the γ-substituent on II may contribute to the increased proximity of oxyanion to the β-carbon, thus favoring subsequent intramolecular cyclization to yield formal [2+2] annulation products 3. Additionally, the γ-substituent may also provide greater steric encumbrance around oxyanion II, which should simultaneously disfavor competitive addition to a second equivalent of ketone akin to the proposed [2+2+2] pathway for unsubstituted allenoates. Our competition experiment suggested that the annulation is not reversible, thus ruling out potential contributions of proposed intermediates in the NHC-catalyzed reaction (e.g., I−III, Figure 4B) to the observed cis/trans-isomerization occurring under the reaction conditions. With this established, we considered potential avenues for the observed epimerization, such as a reversible 1,5-H-shift versus an intermolecular deprotonation/reprotonation of the products in the presence of a base (Figure 5A). Control experiments identified cesium carbonate as the only species present in our reaction that would promote epimerization of product cis-3 to a 5:1 mixture of trans-3/cis-3. The observation that the epimerization was base-catalyzed led us to revisit existing literature on aminecatalyzed annulations of allenoates with trifluoromethyl ketones, since in the case that deprotonation give intermediates such as enolate-3 (Figure 5A) was an operative mechanism for isomerization, then amine catalysts of comparable basicity should also promote the epimerization. Interestingly, the single example reported by Miller described that DABCO-catalyzed [2+2] annulation of (4-bromo)trifluoroacetophenone with the benzyl ester analogue of 2 generated the corresponding oxetane product as a 3:1 cis/transdiastereomeric mixture.23 In their follow-up study employing bifunctional guanidine base TBD for the same annulation, Selig noted that, in contrast to Miller’s DABCO-catalyzed example,

Figure 5. (A) Base-catalyzed epimerization: mechanistic hypotheses. (B) Base screen for the epimerization of cis-3. (C) Deuterium exchange studies. Footnote a represents the proton Ha(cis)obscured in the 1H NMR spectrum.

the trans-alkylidene oxetane products predominated in most cases.24,29 Guided by these previous studies, we treated pure cis-3 with 30 mol % DABCO in MeCN and observed no epimerization to the (E)-trans product after 24 h (Figure 5B). However, substituting the base for TBD led to a 5:1 mixture of trans/cis3 within 2 h (Figure 5B). This result indicates that product isomerization is likely also operative in Selig’s TBD-catalyzed annulation, which interestingly shows a similar selectivity to our NHC-catalyzed annulation. What was less clear was the relationship between the pKa of the base employed and its ability to promote the observed epimerization. While TBD is a strong base (pKa(MeCN) ∼ 26),30 cesium carbonate (pKa(MeCN) ∼ 10) and DABCO (pKa(MeCN) ∼ 10)31 have similar reported pKas, yet only Cs2CO3 affects the epimerization of 3. At this point, a potential model for epimerization wherein the bifunctional capability of carbonate and TBD can be invoked to facilitate a formal 1,5-shift in a concerted/asynchronous fashion is the most descriptive of the collective data.32 Initial attempts to observe deuterium exchange with hypothetical isomerization intermediates (e.g., enol-3 or enolate-3, Figure 5A) by performing the epimerization in the presence of an exchangeable deuterium source such as D2O or MeOD showed no significant deuterium incorporation after several hours, whereas at longer time points competing hydrolysis, transesterification, or decomposition convoluted meaningful analysis of the product composition by NMR spectroscopy (Figure 5C).33 In light of our findings that TBD could also promote epimerization, and that TBD is a stronger base possessing an exchangeable proton, we repeated the TBDcatalyzed epimerization in the presence of D2O and observed ∼76% deuterium incorporation after 2 h at both the epimerizable center (Ha) as well as the alkylidene proton (Hb). After 24 h, >90% of both Ha and Hb had been exchanged, and high-resolution mass spectral analysis of the isolated products confirmed that the mixture was composed of both bis-deuterated D2-3 and mono-deuterated D-3 in an D

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry approximately 6:1 ratio, as well as unexchanged 3 (see Supporting Information for details). The remaining unlabeled starting material had converted to the expected 5:1 trans/cis product distribution at both time points, confirming that the epimerization had indeed occurred in addition to exchange of Ha and Hb. The exchange of Hb under these conditions is unsurprising, as 1,4-addition of external nucleophiles under the basic epimerization conditions could lead to exchange via the product enolate (Figure 5A).34 To support our supposition that the observed product ratio favoring trans-3 after epimerization was a thermodynamic distribution, we computed simple energy-minimized models of the products (MM2,35 Spartan, Figure 6). Compound trans-3

Figure 7. Enantioenduction using chiral benzimidazolium 20.

Brønsted bases under kinetic reaction conditions; studies pursuing this strategy are currently underway.

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CONCLUSIONS In summary, a selective oxetane synthesis via an NHCcatalyzed [2+2] annulation reaction of allenoates with trifluoromethyl ketones has been developed. The use of γsubstituted allenoates provides divergent reactivity from the only other report of an NHC-catalyzed reaction using unsubstituted allenoates, leading to versatile 2-alkylidene oxetane products in high yields and with good diastereoselectivities. Supporting mechanistic studies provide strong rationale for both the reactivity of the NHC-catalyzed annulation, as well as the selectivity for the products. The results herein expand the possibilities of carbene catalysis for further development with NHC/conjugate addition approaches distinct from traditional Breslow intermediate pathways in order to access valuable heterocycles.

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EXPERIMENTAL SECTION

General. All commercial reagents were used without further purification unless otherwise stated. Allenoates were prepared as described previously.38 Trifluoromethyl ketones were prepared as described previously.39 Reaction solvents were purified by passage through a bed of activated alumina. Glassware was flame-dried prior to use. Reactions were carried out under a positive pressure of nitrogen gas. Analytical thin-layer chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates. Visualization was accomplished with UV light and potassium permanganate stain followed by heating. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance spectrometer with a direct cryoprobe (500 MHz) and are reported in parts per million (ppm) using solvent as an internal standard (C6D6). 19F NMR spectra were recorded on a Bruker Avance III HD spectrometer and are indirectly referenced relative to the sample’s lock signal. All NMR signals are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants (J) in hertz (Hz), integration. Infrared spectra were recorded on a Bruker Tensor 37 FT-IR spectrometer. High-resolution mass spectra were obtained on a Varian 1200 quadrupole mass spectrometer and a Micromass Quadro II spectrometer. Diastereomeric ratios were determined by 1H NMR spectroscopic analysis of crude reactions in C6D6 (which provided optimal resolution of diagnostic diastereomeric product peaks). Some major diastereomeric products were inseparable from small amounts of the minor diastereomer; for these cases, peaks corresponding to the major diastereomer were assigned by analogy to trans-3 and cis-3. Diagnostic NMR peaks for minor diastereomeric products were also tabulated where observable. Coupling constants for the products’ ipsoCF3 signal in their 13C spectra (qt, ∼125 ppm, J1C−F ∼ 280 Hz) in C6D6 were not extracted due to partial obfuscation by the solvent residual signal (128.6 ppm). To verify the chemical shift and 1JC−F of this diagnostic signal, product trans-3 was additionally characterized in CD3CN (vide infra), and the observed ipso-CF3 quartet and coupling constant are analogous with published spectroscopic data for related compounds.24 General Procedure for the Synthesis of Oxetanes (3−16). To a flame-dried reaction test tube equipped with a magnetic stir bar were added cesium carbonate (98 mg, 0.30 mmol, 0.30 equiv), IMes· Cl (17 mg, 0.05 mmol, 0.05 equiv), allenoate (1.0 mmol, 1.0 equiv),

Figure 6. Selectivity model. Modeled using Spartan ’08 (Wave function Inc., Irvine, CA) with MM2 level of theory.35

was computed to be more stable than cis-3 with ΔG° = 0.78 kcal/mol, in excellent agreement with our experimental observation of a ∼5:1 mixture of trans-3/cis-3 when the epimerization was run to extended time points (ΔG°(experimental) = 0.95 kcal/mol, Figure 6). All structures adopted low-energy conformations where one C−F bond is antiperiplanar with one of the unconjugated ether oxygen’s lone pairs, providing probable hyperconjugative stabilization as has been described previously.36 Additionally, we modeled product 9, since we observed a reversal in selectivity when ortho substitution was present on the arylketone electrophiles, (e.g., 9 and 10, Table 2). Compound trans-9 was calculated to be less thermodynamically stable than cis-9 (ΔG° = 0.42 kcal/mol), again in excellent agreement with our experimental observation of a 1:3 ratio of trans/cis-9 at equilibrium (ΔG°(experimental) = 0.65 kcal/mol). Inspection of cis-9 suggests that the interaction of pseudoeclipsing (Me, CF3) groups is superseded by the energetic penalty introduced due to hindered rotation of the 2-methoxyphenyl substituent for trans-9. These collective studies also shed light on our endeavors to date in pursuit of an enantioselective annulation using chiral NHCs (Figure 7). Our current best result using chiral benzimidazolium 20 provides 3 with only a modest enantioselectivity (59:41 er, Figure 7).37 Equipped with a better understanding of the annulation energetics and selectivity, an enantioselective NHC-catalyzed allenoate annulation may be possible by leveraging monofunctional E

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

1102, 1076, 1066, 1020, 1007, 995, 918, 821, 738, 693, 612; HRMS (ESI) calcd for C15H14BrF3O3 [M ]+ 378.0081, found 378.0078. Characterization data for cis-6 (minor): 1H NMR (500 MHz, benzene-d6) δ 7.12 (d, 2H), 6.80 (d, J = 25.7, 8.2 Hz, 2H), 5.51 (dd, J = 10.5, 2.0 Hz, 1H), 3.76 (qd, J = 7.4, 1.9 Hz, 1H), 4.03−3.89 (m, 2H), 1.65 (dd, J = 7.5, 1.6 Hz, 1H), 0.97−0.90 (m, 5H); 19F NMR (376 MHz, benzene-d6) δ −75.0. Ethyl (E)-2-(3-Methyl-4-(4-(methylthio)phenyl)-4(trifluoromethyl)oxetan-2-ylidene)acetate (7). Yellow oil (321 mg, 92% yield, 6:1 dr trans/cis). Characterization data for trans-7 (major): 1 H NMR (500 MHz, benzene-d6) δ 7.07 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.57 (d, J = 1.9 Hz, 1H), 4.20 (qd, J = 7.3, 1.9 Hz, 1H), 4.02−3.91 (m, 2H), 1.87 (s, 3H), 1.08 (d, J = 7.3 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 177.7, 165.7, 141.0, 127.7, 126.7, 126.3, 125.7, 93.1, 89.3 (q, J = 31.7 Hz), 59.4, 43.8, 14.2, 13.9, 12.5; 19F NMR (376 MHz, benzene-d6) δ −79.7; IR (ATR) ν 2980, 1713, 1675, 1626, 1600, 1496, 1444, 1371, 1343, 1321, 1292, 1261, 1234, 1167, 1108, 1095, 1042, 1023, 1006, 989, 917, 855, 818, 743, 724, 700, 611; HRMS (ESI) calcd for C16H17F3O3S [M ]+ 346.0853, found 346.0851. Ethyl (E)-2-(3-Methyl-4-(m-tolyl)-4-(trifluoromethyl)oxetan-2ylidene)acetate (8). Colorless oil (286 mg, 91% yield, 5:1 dr trans/ cis). Characterization data for trans-8 (major): 1H NMR (500 MHz, benzene-d6) δ 7.19 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.89−6.83 (m, 1H), 5.58 (d, J = 1.9 Hz, 1H), 4.23 (qd, J = 7.3, 1.9 Hz, 1H), 4.02−3.91 (m, 2H), 1.98 (s, 3H), 1.10 (d, J = 7.4 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 177.8, 165.7, 138.2, 130.6, 129.1, 127.7, 127.5, 126.4, 123.0, 93.0, 89.5 (q, J = 31.4 Hz), 59.3, 43.8, 20.9, 13.9, 12.5; 19F NMR (376 MHz, benzene-d6) δ −79.7; IR (ATR) ν 2979, 1714, 1676, 1610, 1542, 1461, 1372, 1345, 1323, 1273, 1201, 1162, 1111, 1098, 1034, 1024, 990, 947, 938, 909, 853, 821, 786, 728, 711, 699, 665, 609; HRMS (ESI) calcd for C16H17F3O3 [M ]+ 314.1124, found 314.1130. Characterization data for cis-8 (minor): 1H NMR (500 MHz, benzene-d6) δ 7.18 (s, 1H), 7.04 (d, J = 6.9 Hz, 1H), 7.03−6.90 (m, 1H), 6.89−6.83 (m, 1H), 5.54 (d, J = 2.2 Hz, 1H), 4.02−3.91 (m, 3H), 1.96 (s, 3H), 1.74 (dd, J = 7.5, 1.6 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 19F NMR (376 MHz, benzene-d6) δ −75.0. Ethyl (E)-2-(4-(2-Methoxyphenyl)-3-methyl-4-(trifluoromethyl)oxetan-2-ylidene)acetate (9). Yellow oil (0.31 g, 93% yield, 1:3 dr trans/cis). Characterization data for cis-9 (major): 1H NMR (500 MHz, benzene-d6) δ 7.51 (dd, J = 7.7, 1.7 Hz, 1H), 6.99 (ddd, J = 8.6, 7.4, 1.8 Hz, 1H), 6.74 (td, J = 7.6, 1.1 Hz, 1H), 6.33 (dd, J = 8.4, 1.0 Hz, 1H), 5.56 (d, J = 2.1 Hz, 1H), 4.15 (qd, J = 7.4, 2.1 Hz, 1H), 3.98 (qd, J = 7.1, 2.8 Hz, 2H), 3.03 (s, 3H), 1.92 (dd, J = 7.4, 1.7 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 178.7, 165.8, 156.2, 130.6, 125.8, 120.4, 111.0, 92.5, 88.5 (q, J = 31.7 Hz), 59.2, 54.4, 47.9, 14.0, 10.8, 10.7; 19F NMR (376 MHz, benzened6) δ −79.7; IR (ATR) ν 2978, 1711, 1672, 1603, 1494, 1465, 1439, 1371, 1347, 1284, 1256, 1169, 1114, 1089, 1051, 1023, 1003, 973, 917, 852, 822, 793, 755, 712, 655, 608; HRMS (ESI) calcd for C16H17F3O4 [M]+ 330.1079, found 330.1079. Characterization data for trans-9 (minor): 1H NMR (500 MHz, benzene-d6) δ 7.56 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 8.3 Hz, 1H), 4.43 (qd, J = 7.3, 1.7 Hz, 1H), 3.98 (qd, J = 7.1, 2.8 Hz, 2H), 3.06 (s, 3H), 1.43 (d, J = 7.2 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 179.2, 165.9, 155.9, 130.7, 125.4, 123.2, 120.8, 119.5, 111.2, 92.1, 59.3, 54.3, 44.5, 13.9, 11.7; 19F NMR (376 MHz, benzene-d6) δ −74.9. Ethyl (E)-2-(4-(2,4-Dimethoxyphenyl)-3-methyl-4(trifluoromethyl)oxetan-2-ylidene)acetate (10). Yellow oil (346 mg, 96% yield, 1:3 dr trans/cis). Characterization data for cis-10 (major): 1H NMR (500 MHz, benzene-d6) δ 7.44 (d, J = 8.6 Hz, 1H), 6.27−6.23 (m, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.59 (d, J = 2.0 Hz, 1H), 4.21 (qd, J = 7.4, 2.2 Hz, 1H), 3.99 (qt, J = 7.1, 1.7 Hz, 2H), 3.24 (s, 3H), 2.99 (s, 3H), 1.94 (dd, J = 7.4, 1.7 Hz, 3H), 0.95 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 179.0, 165.9, 162.1, 157.5, 129.4, 129.3, 128.9, 104.3, 99.0, 92.4, 88.5 (q, J = 31.5

and trifluoromethyl ketone (1.0 mmol, 1.0 equiv). Acetonitrile (10 mL, 0.1 M) was added, and the resulting solution was stirred at 23 °C under a nitrogen atmosphere. The reaction was monitored by TLC (20:1 pentane/ethyl acetate). After 6−12 h, the reaction was concentrated in vacuo and the residue purified by flash column chromatography to afford the desired product. Ethyl (E)-2-(3-Methyl-4-phenyl-4-(trifluoromethyl)-oxetan-2ylidene)acetate (3). Note that the reaction was conducted on a 5.7 mmol scale. Yellow solid (1.52 g, 94% yield, 5:1 dr trans/cis). Characterization data for trans-3 (major): mp 68−71 °C; 1H NMR (500 MHz, benzene-d6) δ 7.21 (d, J = 7.1 Hz, 2H), 7.05−6.97 (m, 3H), 5.56 (d, J = 1.8 Hz, 1H), 4.20 (qd, J = 7.4, 1.9 Hz, 1H), 4.00− 3.91 (m, 2H), 1.04 (d, J = 7.4 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (126 MHz, acetonitrile-d3) δ 177.9, 166.2, 135.1, 130.3, 126.0, 124.4 (q, 1JC−F = 283.2 Hz), 113.7, 93.5, 89.0 (q, 2JC−F = 30.5 Hz), 60.3, 49.2, 14.2, 11.5; 13C{1H} NMR (126 MHz, benzened6) δ 177.7, 165.7, 130.6, 129.0, 128.4, 125.9, 93.1, 89.5, 89.3 (q, 2JC−F = 31.5 Hz), 59.4, 43.8, 13.9, 12.5; 19F NMR (376 MHz, benzene-d6) δ −79.6; IR (ATR) ν 2991, 1673, 1450, 1396, 1373, 1344, 1318, 1290, 1245, 1170, 1109, 1082, 1036, 1009, 990, 927, 911, 825, 760, 740, 723, 699, 664, 610; HRMS (ESI) calcd for C15H15F3O3 [M]+ 300.0976, found 300.0973. Characterization data for cis-3 (minor): mp 63−65 °C; 1H NMR (500 MHz, benzene-d6) δ 7.00 (dd, J = 4.9, 1.9 Hz, 3H), 5.52 (d, J = 2.2 Hz, 1H), 4.01−3.86 (m, 3H), 1.71 (dd, J = 7.5, 1.7 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 177.2, 165.6, 134.9, 129.0, 125.6, 123.34, 93.1, 88.5 (q, J = 30.8 Hz), 59.4, 48.9, 11.1, 11.0; 19F NMR (376 MHz, benzene-d6) δ −74.9. Ethyl (E)-2-(3-Methyl-4-(p-tolyl)-4-(trifluoromethyl)oxetan-2ylidene)acetate (4). Colorless oil (294 mg, 92% yield, 5:1 dr trans/ cis). Characterization data for trans-4 (major): 1H NMR (500 MHz, benzene-d6) δ 7.19−7.10 (m, 2H), 6.89 (d, J = 8.2 Hz, 2H), 5.56 (d, J = 1.8 Hz, 1H), 4.21 (qd, J = 7.4, 1.9 Hz, 1H), 4.03−3.89 (m, 2H), 1.98 (s, 3H), 1.10 (d, J = 7.3 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13 C{1H} NMR (126 MHz, benzene-d6) δ 177.8, 165.7, 139.0, 127.9, 127.7, 127.5, 125.8, 92.9, 89.5 (q, J = 31.5 Hz), 59.3, 43.8, 20.5, 13.9, 12.5; 19F NMR (376 MHz, benzene-d6) δ −79.7; IR (ATR) ν 2981, 1714, 1675, 1542, 1516, 1448, 1372, 1345, 1324, 1294, 1265, 1165, 1105, 1067, 1026, 1009, 918, 813, 761, 731, 709, 679, 620; HRMS (ESI) calcd for C16H17F3O3 [M ]+ 314.1124, found 314.1118. Characterization data for cis-4 (minor): 1H NMR (500 MHz, benzene-d6) δ 7.12 (m, 2H), 6.84 (m, 2H), 5.53 (d, J = 2.2 Hz, 1H), 4.03−3.89 (m, 3H), 2.00 (s, 3H), 1.74 (dd, J = 7.5, 1.6 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 177.4, 165.6, 132.0, 129.0, 125.7, 125.3 (d, J = 3.8 Hz), 123.4, 93.1, 88.6 (q, J = 30.9 Hz), 59.3, 48.9 (d, J = 21.1 Hz), 20.6 (d, J = 5.9 Hz), 13.9, 12.6; 19F NMR (376 MHz, benzene-d6) −74.9. Ethyl (E)-2-(4-(4-Methoxyphenyl)-3-methyl-4-(trifluoromethyl)oxetan-2-ylidene)acetate (5). Yellow oil (313 mg, 95% yield, 5:1 dr trans/cis). Characterization data for trans-5 (major): 1H NMR (500 MHz, benzene-d6) δ 7.15 (d, J = 1.7 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 5.55 (d, J = 1.9 Hz, 1H), 4.21 (qd, J = 7.4, 1.9 Hz, 1H), 4.02−3.90 (m, 2H), 1.99 (s, 3H), 1.09 (d, J = 7.3 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6 δ 177.9, 165.8, 139.0, 129.1, 128.0, 125.8, 125.0, 93.0, 89.6 (q, J = 31.5 Hz), 59.4, 43.8, 20.6, 13.9, 12.6; 19F NMR (376 MHz, benzene-d6) δ −79.7; IR (ATR) ν 2978, 1711, 1672, 1603, 1494, 1465, 1439, 1371, 1347, 1284, 1256, 1169, 1114, 1089, 1051, 1023, 1003, 973, 917, 852, 822, 793, 755, 712, 655, 608; HRMS (ESI) calcd for C16H17F3O4 [M]+ 330.1079, found 330.1077. Ethyl (E)-2-(4-(4-Bromophenyl)-3-methyl-4-(trifluoromethyl)oxetan-2-ylidene)acetate (6). Yellow oil (0.36 g, 94% yield, 5:1 dr trans/cis). Characterization data for trans-6 (major): 1H NMR (500 MHz, benzene-d6) δ 7.14 (d, J = 14.2 Hz, 2H), 6.83 (d, J = 8.1 Hz, 2H), 5.52 (d, J = 1.9 Hz, 1H), 4.12 (qd, J = 7.4, 1.9 Hz, 1H), 4.02− 3.90 (m, 2H), 0.97−0.91 (m, 6H); 13C{1H} NMR (126 MHz, benzene-d6) δ 177.2, 165.6, 131.7, 129.5, 128.0, 127.6, 123.8, 93.4, 89.0 (qt, J = 31.9 Hz), 59.5, 43.7, 13.91, 12.5; 19F NMR (376 MHz, benzene-d6) δ −79.7; IR (ATR) ν 2939, 2280, 1717, 1678, 1594, 1492, 1463, 1399, 1376, 1345, 1323, 1293, 1264, 1242, 1170, 1114, F

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Hz), 59.2, 54.6, 54.4, 47.9, 14.0, 10.8; 19F NMR (376 MHz, benzened6) δ −75.4; IR (ATR) ν 2955, 1711, 1672, 1612, 1586, 1509, 1458, 1420, 374, 1347, 1315, 1272, 1234, 1210, 1161, 1135, 1112, 1090, 1032, 1001, 973, 940, 929, 908, 824, 737, 705, 634; HRMS (ESI) calcd for C17H20F3O5 [M + H]+ 361.1263, found 361.1256. Characterization data for trans-10 (minor): 1H NMR (500 MHz, benzene-d6) δ 7.49 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 5.59 (s, 1H), 4.43 (qd, J = 7.2, 1.8 Hz, 1H), 4.03−3.94 (m, 2H), 3.24 (s, 3H), 3.02 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 0.97−0.90 (m, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 179.5, 162.2, 157.1, 129.4, 125.5, 123.2, 115.1, 104.5, 99.4, 92.1, 91.2, 90.3 (m), 59.3, 54.5, 54.2, 44.3, 13.9, 11.8; 19F NMR (376 MHz, benzene-d6) δ −79.2 Ethyl (E)-2-(4-(3,5-Dichlorophenyl)-3-methyl-4-(trifluoromethyl)oxetan-2-ylidene)acetate (11). Yellow oil (0.35 g, 95% yield, 5:1 dr trans/cis). Characterization data for trans-11 (major): 1H NMR (500 MHz, benzene-d6) δ 6.74 (d, J = 8.0 Hz, 2H), 6.30 (tt, J = 8.7, 2.4 Hz, 1H), 5.45 (d, J = 1.9 Hz, 1H), 4.03 (qd, J = 7.4, 1.9 Hz, 1H), 3.99− 3.91 (m, 2H), 0.93 (t, J = 7.0 Hz, 4H), 0.86 (d, J = 7.4 Hz, 3H); 13 C{1H} NMR (126 MHz, benzene-d6) δ 176.2, 165.4, 135.7, 134.0, 129.7, 124.5, 123.8, 93.8, 88.2 (q, J = 32.1 Hz), 59.5, 43.8, 13.8, 12.3; 19 F NMR (376 MHz, benzene-d6) δ −79.5; IR (ATR) ν 2982, 1718, 1680, 1592, 1569, 1422, 1393, 1372, 1345, 1320, 1293, 1261, 1237, 1189, 1172, 1145, 1108, 1098, 1032, 995, 948, 863, 826, 802, 784, 755, 709, 680; HRMS (ESI) calcd for C15H13Cl2F3O3 [M ]+ 368.0188, found 368.0194. Characterization data for cis-11(minor): 1H NMR (500 MHz, benzene-d6) δ 6.70−6.66 (m, 2H), 6.21 (tt, J = 8.7, 2.4 Hz, 1H), 5.42 (d, J = 1.9 Hz, 1H), 3.99−3.89 (m, 2H), 3.63 (qd, J = 7.5, 2.2 Hz, 1H), 1.54 (dd, J = 7.5, 1.8 Hz, 3H), 0.95 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 175.9, 165.3, 138.0, 135.5, 129.6, 124.9, 123.7, 122.6, 93.8, 87.2 (q, J = 31.4 Hz), 48.6, 13.9, 10.7; 19F NMR (376 MHz, benzene-d6) δ −74.8. Ethyl (E)-2-(4-(3,5-Difluorophenyl)-3-methyl-4-(trifluoromethyl)oxetan-2-ylidene)acetate (12). Yellow oil (309 mg, 91% yield, 3:1 dr trans/cis). Characterization data for trans-12 (major): 1H NMR (500 MHz, benzene-d6) δ 6.75 (d, J = 8.1 Hz, 2H), 6.33 (tt, J = 8.7, 2.4 Hz, 1H), 5.45 (d, J = 1.9 Hz, 1H), 4.03 (qd, J = 7.4, 1.9 Hz, 1H), 3.95 (qd, J = 7.1, 4.8 Hz, 2H), 0.94 (t, J = 7.1 Hz, 3H), 0.87 (d, J = 7.4 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 176.3, 165.4, 163.1 (d, J = 250.4 Hz), 134.4 (t, J = 9.3 Hz), 123.8 (q, J = 283.3 Hz), 109.4 (d, J = 25.7 Hz), 104.9 (t, J = 25.2 Hz), 93.8, 88.4 (q, J = 32.0, 29.9 Hz), 59.6, 43.9, 13.9, 12.2; 19F NMR (376 MHz, benzene-d6) δ −79.9; IR (ATR) ν 2981, 1717, 1682, 1626, 1601, 1539, 1443, 1372, 1342, 1288, 1213, 1165, 1108, 1041, 1005, 959, 859, 827, 810, 762, 721, 681; HRMS (ESI) calcd for C15H13F5O3 [M ]+ 336.0781, found 336.0785. Ethyl (E)-2-(3-Methyl-4-(thiophen-2-yl)-4-(trifluoromethyl)oxetan-2-ylidene)acetate (13). Clear oil (0.28 g, 93% yield, 4:1 dr trans/cis). Characterization data for trans-13 (major): 1H NMR (500 MHz, benzene-d6) δ 6.81 (d, J = 3.5 Hz, 1H), 6.76 (dd, J = 5.1, 1.2 Hz, 1H), 6.59 (dd, J = 5.0, 3.7 Hz, 1H), 5.52 (d, J = 1.9 Hz, 1H), 4.17 (qd, J = 7.4, 2.0 Hz, 1H), 4.00−3.88 (m, 2H), 1.10 (d, J = 7.3 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 176.9, 165.4, 132.7, 127.0 (d, J = 17.3 Hz), 126.5 (d, J = 14.5 Hz), 125.0, 122.7, 93.9 (d, J = 15.0 Hz), 88.7 (q, J = 33.6 Hz), 59.4, 44.6, 13.8 (d, J = 5.2 Hz), 11.9 (d, J = 9.6 Hz); 19F NMR (376 MHz, benzene-d6) δ −74.8; IR (ATR) ν 2981, 1713, 1678, 1482, 1436, 1372, 1297, 1229, 1164, 1105, 1042, 1004, 898, 882, 848, 721, 705, 641, 608; HRMS (ESI) calcd for C13H13F3O3S [M ]+ 306.0537, found 306.0539. Characterization data for cis-13 (minor): 1H NMR (500 MHz, benzene-d6) δ 6.79 (d, J = 3.6 Hz, 1H), 6.71 (dd, J = 5.0, 1.2 Hz, 1H), 6.51 (dd, J = 5.0, 3.7 Hz, 1H), 5.50 (d, J = 2.2 Hz, 1H), 4.07−3.99 (m, 1H), 3.99−3.89 (m, 2H), 1.64 (dq, J = 7.5, 1.8 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H); 19F NMR (376 MHz, benzene-d6) δ −80.6. Ethyl (E)-2-(4-Cyclohexyl-3-methyl-4-(trifluoromethyl)oxetan-2ylidene)acetate (14). Yellow oil (0.28 g, 92% yield, 6:1 dr trans/ cis). Characterization data for trans-14 (major): 1H NMR (500 MHz, benzene-d6) δ 5.47 (d, J = 2.1 Hz, 1H), 4.06−3.94 (m, 2H), 3.75 (qd,

J = 7.5, 2.2 Hz, 1H), 1.83 (tt, J = 11.8, 3.2 Hz, 2H), 1.68−1.61 (m, 2H), 1.58 (d, J = 9.1 Hz, 2H), 1.53−1.38 (m, 2H), 0.98 (t, J = 7.1 Hz, 3H), 0.92−0.79 (m, 2H), 0.71 (qd, J = 12.6, 3.5 Hz, 2H); 13C{1H} NMR (126 MHz, benzene-d6) δ 178.3, 166.1, 125.2 (q, J = 285.4 Hz), 92.1 (d, J = 16.2 Hz), 91.1 (q, J = 28.2 Hz), 59.3, 42.3, 41.3 (d, J = 9.4 Hz), 40.9, 27.0, 26.3, 24.8 (d, J = 12.7 Hz), 14.0, 10.9; 19F NMR (376 MHz, benzene-d6) δ −71.7; IR (ATR) ν 2933, 2858, 2280, 1714, 1672, 1453, 1371, 1341, 1318, 1288, 1249, 1223, 1194, 1165, 1141, 1106, 1082, 1052, 1014, 992, 971, 915, 892, 821, 812, 764, 725, 685, 670, 607; HRMS (ESI) calcd for C15H21F3O3 [M]+ 306.1448, found 306.1443. Characterization data for cis-14 (minor): 1H NMR (500 MHz, benzene-d6) δ 5.44 (d, J = 1.9 Hz, 1H), 4.06−3.94 (m, 3H), 1.83 (tt, J = 11.9, 3.3 Hz, 2H), 1.67−1.60 (m, 2H), 1.52−1.39 (m, 2H), 1.35 (d, J = 7.4 Hz, 3H), 0.96 (d, J = 7.1 Hz, 1H), 0.92−0.83 (m, 2H), 0.71 (qd, J = 12.6, 3.5 Hz, 2H); 13C{1H} NMR (126 MHz, benzene-d6) δ 178.5, 165.9, 125.3 (m), 92.3 (m), 89.4, 43.1, 43.0, 40.8, 24.9, 24.8, 13.2, 10.9, 9.8; 19F NMR (376 MHz, benzene-d6) δ −75.0. Benzyl (E)-2-(3-Methyl-4-phenyl-4-(trifluoromethyl)oxetan-2ylidene)acetate (15). Colorless oil (333 mg, 92% yield, 6:1 dr trans/cis). Spectral data of trans-15 matched existing literature characterization data for this compound.24 Ethyl (E)-2-(3-(tert-Butyl)-4-phenyl-4-(trifluoromethyl)oxetan-2ylidene)acetate (16). Pale yellow oil (311 mg, 91% yield, >19:1 dr trans/cis). Characterization data for trans-16: 1H NMR (500 MHz, benzene-d6) δ 8.21−7.67 (br s, 1H), 7.67−7.28 (br s, 1H), 7.01−6.93 (m, 3H), 5.18 (d, J = 1.7 Hz, 1H), 4.13 (qd, J = 7.2, 1.3 Hz, 2H), 3.63 (d, J = 1.7 Hz, 1H), 1.05 (t, J = 7.1 Hz, 3H), 0.47 (s, 9H); 13C{1H} NMR (126 MHz, benzene-d6) δ 171.1, 163.6, 137.1, 131.0, 129.3, 125.9, 123.6, 93.1, 88.8 (q, J = 31.5 Hz), 59.5, 58.6, 32.1, 26.9, 14.1; 19 F NMR (470 MHz, C6D6) δ −78.3; HRMS (ESI) calcd for C18H22F3O3 [M + H]+ 343.1521, found 343.1513. Ethyl 6-Methyl-5-phenyl-5-(trifluoromethyl)-1,4-dioxaspiro[2.3]hexane-2-carboxylate (17). A solution of trans-3 (50 mg, 1.0 equiv, 0.17 mmol) and m-CPBA (41 mg, 1.1 equiv, 0.18 mmol) in dichloromethane (70 mL) was brought to reflux in a round-bottom flask fitted with a reflux condenser for 14 h. At this time, the reaction was cooled to ambient temperature and then poured into a separatory funnel. The mixture was washed successively with 5% aqueous Na2CO3 (50 mL), water (50 mL), and brine (50 mL). The organic portion was separated, dried over sodium sulfate, filtered, and then concentrated in vacuo to provide 17 (46 mg, 92% yield) as a 1:1 mixture of diastereomers with sufficient purity for characterization (exposure of crude 17 to silica gel resulted in significant decomposition). Characterization data for 17: 1H NMR (500 MHz, benzene-d6) δ 7.40 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.09−6.97 (m, 6H), 5.56 (d, J = 2.2 Hz, 1H), 4.20 (qd, J = 7.3, 1.9 Hz, 1H), 3.96 (p, J = 7.3 Hz, 2H), 3.78 (q, J = 6.9 Hz, 2H), 3.73 (t, J = 7.4 Hz, 1H), 3.62 (d, J = 1.5 Hz, 1H), 1.04 (d, J = 7.3 Hz, 3H), 0.99 (d, J = 7.4 Hz, 3H), 0.93 (dd, J = 7.5, 6.1 Hz, 3H), 0.78 (dd, J = 7.8, 6.4 Hz, 3H); 13C{1H} NMR (126 MHz, C6D6) δ 177.7, 165.9, 131.5, 130.6, 126.3, 125.9, 93.1, 61.3, 55.3, 41.0, 13.9, 12.5, 10.7; HRMS (ESI) calcd for C15H16F3O4 [M + H]+ 317.1001, found 317.0994 Ethyl 2-(3-Methyl-4-phenyl-4-(trifluoromethyl)oxetan-2-yl)acetate (18). An oven-dried round-bottom flask fitted with a magnetic stir bar was charged with Pd/C (10% palladium on carbon, 9 mg), and then approximately 0.2 mL of dichloromethane was slowly trickled down the inside wall of the flask until the solid Pd/C was just submerged. To this, a solution of trans-3 (50 mg, 1.0 equiv, 0.17 mmol) in 2 mL of EtOH was slowly added to the suspension, and then the entire flask was fitted with a rubber septum. A balloon of H2 (1 atm) attached via a syringe with a long needle was inserted through the septum such that the needle tip was submerged in the reaction solution. Next, a short purge needle was inserted and H2 was bubbled through the reaction solution for 1 min. At this time, the purge needle was removed and the H2 inlet needle brought above the surface of the reaction mixture, which was allowed to stir at 23 °C for 12 h. The crude reaction mixture was filtered over diatomaceous earth (predampened with dichloromethane) and the filter cake successively washed with an additional three 10 mL portions of dichloromethane. G

DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Concentration of the filtrate in vacuo provided 18 as a colorless oil (45 mg, 91% yield). Characterization data for 18: 1H NMR (500 MHz, benzene-d6) δ 7.55−7.25 (m, 2H), 7.14−6.93 (m, 3H), 4.48 (q, J = 6.9 Hz, 1H), 3.86 (qd, J = 7.2, 2.0 Hz, 2H), 2.96 (app p, J = 7.0 Hz, 1H), 2.79 (dd, J = 16.2, 6.5 Hz, 1H), 2.61 (dd, J = 16.1, 7.4 Hz, 1H), 0.89 (t, J = 7.1 Hz, 3H), 0.64 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, benzene-d6) δ 169.0, 133.7, 128.4, 128.2, 127.2, 126.4, 126.0, 85.0 (app d, J = 30.6 Hz), 80.8, 60.1, 40.2, 39.3, 14.5, 13.8; 19F NMR (470 MHz, C6D6) δ −79.8; HRMS (ESI) calcd for C15H18F3O3 [M + H]+ 303.1208, found 303.1210

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02464. Crystal data of trans-3 (CIF) Crystal data of cis-3 (CIF) X-ray crystallograpic data, additional experimental details, and copies of NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Karl A. Scheidt: 0000-0003-4856-3569 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Support for this work was provided by NIGMS R01GM073072. REFERENCES

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DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX

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(33) Poullain et al observed a similar competing decomposition when employing strained ring systems for base-catalyzed deuteration in CD3CN/D2O: Bew, S. P.; Hiatt-Gipson, G. D.; Lovell, J. A.; Poullain, C. Mild Reaction Conditions for the Terminal Deuteration of Alkynes. Org. Lett. 2012, 14, 456−459. (34) Our observation that D-incorporation occurs readily using TBD/D2O but not with Cs2CO3/D2O lends credence to the bifunctional base-assisted proton shuttling description of the epimerization, since this scenario requires the proton/deuteron to be transferred to the products via the base. (35) Hehre, W. J. A. Guide to Molecular Mechanics and Quantum Chemical Calculations; Wavefunction Inc.: Irvine, CA, 2003. (36) Aikawa, K.; Shimizu, N.; Honda, K.; Hioki, Y.; Mikami, K. Effect of the trifluoromethyl group on torquoselectivity in the 4π ringopening reaction of oxetenes: stereoselective synthesis of tetrasubstituted olefins. Chem. Sci. 2014, 5, 410−415. (37) All common chiral aminoindanol-derived triazolium NHC catalysts screened provided racemic 3. (38) (a) Li, C.-Y.; Zhu, B.-H.; Ye, L.-W.; Jing, Q.; Sun, X.-L.; Tang, Y.; Shen, Q. Olefination of ketenes for the enantioselective synthesis of allenes via an ylide route. Tetrahedron 2007, 63, 8046−8053. (b) Sun, J.; Fu, G. C. Phosphine-Catalyzed Formation of Carbon− Sulfur Bonds: Catalytic Asymmetric Synthesis of γ-Thioesters. J. Am. Chem. Soc. 2010, 132, 4568−4569. (39) Jiang, C. J.; Cheng, C. L.; Yuan, S. F. Economical and Practical Strategies for Synthesis of α-Trifluoromethylated Amines. Asian J. Chem. 2015, 27, 2406−2408.

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DOI: 10.1021/acs.joc.8b02464 J. Org. Chem. XXXX, XXX, XXX−XXX