Homologative Trifluoromethylation of Acetals

James Y. Hamilton; Bill Morandi; Erick M. Carreira

doi:10.1055/s-0033-1338485

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Synthesis 2013; 45(13): 1857-1862
DOI: 10.1055/s-0033-1338485

paper

Homologative Trifluoromethylation of Acetals

James Y. Hamilton

,

Bill Morandi

,

Erick M. Carreira*

Further Information

Publication History

Received: 01 May 2013

Accepted: 02 May 2013

Publication Date:
06 June 2013 (online)

Abstract
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We dedicate this manuscript to Prof. Dr. Scott E. Denmark in honor of his 60^th birthday.

Abstract

Trifluoroethyl α-insertion of acetals has been developed. Aromatic, heteroaromatic, and alkenyl acetals react with in situ generated (trifluoromethyl)diazomethane in the presence of antimony(V) chloride to furnish α-trifluoromethyl acetals. A stereoselective version of this transformation exploiting the acetal as a chiral auxiliary is also presented.

#

Key words

antimony - acetals - insertion - diazo compounds - trifluoromethyl group

Scheme 1 Comparison of work herein with prior tactics

Unique properties of fluorinated compounds in pharmaceutical, agrochemical, and materials industry[2] have stimulated recent development of methods to incorporate fluorine into organic scaffolds.[3] Despite the many impressive advances in this discipline, the introduction of trifluoromethyl groups onto aliphatic chains remains challenging. Previously reported approaches to access this moiety rely mainly on reactions of enolates via pathways involving organic halides, as electrophiles, or precursors to radical or organometallic intermediates.[4] [5] [6] The use of diazoalkane intermediates provides an alternative means to access these valuable compounds, yet relatively little has appeared involving these reactive species. Herein, we report a method for the introduction of trifluoroethyl groups into aromatic, heteroaromatic, and alkenyl acetals with in situ generated (trifluoromethyl)diazomethane (F₃CCHN₂), circumventing its handling and isolation (Scheme [1]). A key feature of our protocol is the use of a strong Lewis acid, under conditions compatible with F₃CCHN₂ formation and the aqueous medium. This enables, for the first time, the direct synthesis of homologated trifluoromethyl-substituted acetals from acetals precursors.

We have recently described the use of F₃CCHN₂ for the generation of synthetically useful building blocks via metal-catalyzed (Fe, Rh, Co) cyclopropanation and cyclopropenation,[7] as well as Lewis acid mediated processes.[8] As a part of this ongoing effort, we recently disclosed a strategy for aldehyde homologation/trifluoromethylation and cyclic ketone insertion to provide access to α-trifluoromethyl ketones.[9] Although aliphatic aldehydes may be converted into the homologated ketones cleanly, difficulties were encountered when aromatic aldehydes were employed as substrates (Scheme [2]). In this respect, the fact that arenes display greater migratory aptitude than hydrides leads to a homologated trifluoromethylated aldehyde product which in turn participates in a second homologation, giving hexafluorinated ketones.

Scheme 2 Problem formulation and proposed solution

The observation of uncontrolled sequential migration for aromatic aldehydes prompted us to investigate other synthetic equivalents for the insertion reaction. Attributing the uncontrolled second homologation (Scheme [2, ] II → III) to the increased electrophilicity of trifluoromethylated aldehyde II, we envisioned that employment of acetals as synthetic equivalents of aldehydes could prevent the undesired second reaction. It was postulated that after the first insertion reaction of aromatic acetals (Scheme [2, ] IV → VI), subsequent formation of oxonium VII would be disfavored due to the destabilizing effect of the trifluoromethyl group (k _f < k _r). Accordingly, we set out to investigate whether acetals would be suitable substrates for the homologative trifluoromethylation insertion reaction.

To our surprise, despite the rich chemistry of diazoalkanes, there is a single report by Doyle and co-workers of homologation of acetals with ethyl diazoacetate in the presence of BF₃·OEt₂,[10] in which for all but two aldehydes examined mixtures of C–C and C–H migration products were observed, as well as cyclopropane products. Moreover, to the best of our knowledge, there are no examples involving fluorinated diazoalkanes.

We began by examining 2-phenyl-1,3-dioxolane with F₃CCHN₂, generated in situ, and BF₃·OEt₂. Although the initial experimentation proved fruitful with electron-rich acetals, the procedure did not prove general, especially with more electron-deficient substrates.

Table 1 Lewis Acid Screening^a

Entry	Lewis acid	Yield^b (%)
1	BF₃·OEt₂	n.r.^c
2	AlCl₃	26
3	ZrCl₄
4	SnCl₄	28
5	SbCl₅	76
6	TiCl₄	64
7	HCl	n.r.^c

^a Reaction conditions: F₃CCH₂NH₃Cl (3.0 equiv), NaNO₂ (3.6 equiv), CH₂Cl₂–H₂O (30:1), stirring, 0 °C, 1 h; then, substrate (0.22 mmol, 1.0 equiv), Lewis acid (1.8 equiv), –78 °C.

^b Yield determined by ¹⁹F NMR integration relative to (trifluoromethyl)benzene as the internal standard.

^c n.r. = no reaction.

A second screening was conducted with 2-(2-chlorophenyl)-1,3-dioxolane (3) with several Lewis acids, which led to the identification of SbCl₅ as optimal (Table [1]). A control experiment with HCl was also conducted, as HCl could arise from a hydrolytic decomposition of SbCl₅, but no product formation was observed (Table [1], entry 7).

Table 2 Substrate Scope^a

Entry	6	R	Yield^b (%)
1	6a		69
2	6b		76
3	6c		62
4	6d		65
5	6e		57
6	6f		63
7	6g		51^c
8	6h		82
9	6i		76
10	6j		70
11	6k		81
12	6l		52^d

^a Reaction conditions: F₃CCH₂NH₃Cl (3.0 equiv), NaNO₂ (3.6 equiv), CH₂Cl₂–H₂O (30:1), stirring, 0 °C, 1 h; then, substrate (0.22 mmol, 1.0 equiv), SbCl₅ (1.0 equiv), –78 °C.

^b Isolated yield after purification by flash chromatography.

^c Performed with SbCl₅ (1.5 equiv).

^d Lower yield due to product volatility.

With a convenient protocol[11] in hand, the substrate scope of this reaction was next examined (Table [2]). Both electron-rich and electron-poor aryl acetals smoothly afforded the α-insertion products in good yields (Table [2], entries 1–5). Sterically hindered phenyl groups were also tolerated as substrates (Table [2], entry 6). We were pleased to find that the reaction could be extended to heteroaromatics, with reactions of 2-pyrrole and 3-indole acetals proceeding well under the standard reaction conditions (Table [2], entries 9 and 10). The method was also applicable to alkenyl acetals, where alkene migration took place to furnish the α-trifluoromethyl-substituted β,γ-unsaturated acetals (Table [2], entries 11 and 12). These results were particularly interesting since convenient methods to construct an allylic trifluoromethyl functionality are scarce.[12]

Application of this strategy to introduce the trifluoromethyl group in a stereoselective manner exploiting a chiral acetal auxiliary was envisioned (Scheme [3]).[13] In this respect, we disclose our preliminary observations toward this endeavor. Acetal 7, derived from optically active stilbene diol and benzaldehyde, was prepared and investigated. For this case, TiCl₄ proved to be a superior Lewis acid, yielding the desired product 8 in good diastereoselectivity (dr 9:1) and yield (83%). Hydrogenolytic cleavage of 8 furnished enantioenriched α-trifluoromethyl aldehyde without racemization, which was immediately reduced for the purpose of isolation and characterization.[14]

Scheme 3 Formal enantioselective trifluoroethyl α-insertion

In summary, we have disclosed an insertion strategy using in situ generated F₃CCHN₂ to furnish α-trifluoromethyl acetals, which can be readily cleaved to yield the corresponding aldehydes. This methodology is complementary to other existing strategies to access these useful compounds, as it employs F₃CCH₂NH₂ instead of CF₃I. Importantly, the observations we describe represent the first example of the use of acetals as starting materials for the introduction of fluorinated fragments. The ability to use heteroaromatic and alkenyl substrates has important implications in medicinal chemistry. A preliminary result to obtain enantioenriched α-trifluoromethyl aldehydes using a chiral acetal has also been presented. Further investigation along this front will be reported in due course.

Unless otherwise noted, reagents were purchased from commercial suppliers and used without further purification, and all reactions were carried out under an atmosphere of argon. Reaction temperatures are reported as the temperature of the bath surrounding the vessel. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 F₂₅₄ TLC glass plates which were visualized with 254 nm light and KMnO₄ staining solutions followed by heating. Purification of reaction products was carried out by flash chromatography using Brunschwig silica gel 32–63, 60 Å and technical grade pentane–Et₂O, which were distilled prior to use, as eluent with 0.3–0.5 bar pressure. Acetals were prepared by the reaction of the corresponding aldehyde with ethylene glycol and catalytic p-toluenesulfonic acid monohydrate in benzene with azeotropic removal of water. Analytical data were in accordance with previously reported values.[15] ¹H NMR spectra were recorded at r.t. on a Varian Mercury 300 MHz or a Bruker AV 400 MHz spectrometer and are reported in ppm with the solvent resonance employed as the internal standard (CDCl₃ at 7.26 ppm). ¹³C NMR spectra were recorded with ¹H decoupling on a Varian Mercury 300 or a Bruker AV 400 spectrometer (at 75 MHz and 100 MHz, respectively) with the solvent resonance employed as the internal standard (CDCl₃ at 77.0 ppm). Infrared spectra were measured neat on a Perkin-Elmer Spectrum BX FT-IR spectrometer. The peaks are reported as absorption maxima (ν, cm^–1). Mass spectral data were obtained at the mass spectrometry service operated by the Laboratory of Organic Chemistry at the ETHZ on a VG-TRIBRID instrument for electron impact ionization (EI). The enantiomeric excess was determined by supercritical-fluid chromatography (SFC) on a Jasco 2080 Plus system. The optical rotation was measured with a Jasco DID-1000 Polarimeter (10 cm, 2 mL cell). The absolute configuration was determined by comparison with a reported [α]_D value.

#

Lewis Acid Screen (Table [1]); General Procedure

To a stirred soln of F₃CCH₂NH₃Cl (3.0 equiv), CH₂Cl₂ (3 mL), and H₂O (0.1 mL) in a sealed Schlenk tube at 0 °C was added NaNO₂ (3.6 equiv), and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was then cooled to –78 °C by stirring in a dry ice–acetone bath for 10 min, which was followed by addition of the substrate (0.22 mmol, 1.0 equiv) and the Lewis acid (1.8 equiv). The mixture was stirred for 3 h, then the reaction was quenched by the addition of MeOH (3 mL) and then sat. aq NaHCO₃ (10 mL). The mixture was warmed to r.t. and extracted with CH₂Cl₂ (3 × 10 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The yield was determined by ¹⁹F NMR analysis with (trifluoromethyl)benzene as the internal standard.

#

Trifluoroethyl α-Insertion (Table [2]); General Procedure

To a stirred soln of F₃CCH₂NH₃Cl (3.0 equiv), CH₂Cl₂ (3 mL), and H₂O (0.1 mL) in a sealed Schlenk tube at 0 °C was added NaNO₂ (3.6 equiv), and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was then cooled to –78 °C by stirring in a dry ice–acetone bath for 10 min, which was followed by addition of the substrate (0.22 mmol, 1.0 equiv) and SbCl₅ (1.0 equiv). The mixture was stirred for 1 h, then the reaction was quenched by the addition of MeOH (3 mL) and then sat. aq NaHCO₃ (10 mL). The mixture was warmed to r.t. and extracted with CH₂Cl₂ (3 × 10 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified via the respective described method.

#

2-(2,2,2-Trifluoro-1-phenylethyl)-1,3-dioxolane (6a)

The crude product was purified via flash chromatography (pentane–Et₂O, 29:1) to afford 6a as a colorless oil; yield: 35 mg (69%).

IR (neat): 2956, 2895, 1498, 1457, 1401, 1365, 1251, 1163, 1145, 1106, 1048, 1032, 943, 875, 805 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (m, 5 H), 5.44 (d, J = 4.3 Hz, 1 H), 3.89–3.76 (m, 4 H), 3.58 (qd, J = 9.8, 4.3 Hz, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 131.0 (q, J = 1.9 Hz), 130.1, 128.5, 128.4, 127.4 (q, J = 280.7 Hz), 101.8 (q, J = 2.5 Hz), 65.3, 65.2, 54.2 (q, J = 25.4 Hz).

¹⁹F NMR (376 MHz, CDCl₃): δ = –65.2 (d, J = 9.7 Hz).

HRMS (EI): m/z [M – H]⁺ calcd for C₁₁H₁₀F₃O₂: 231.0627; found: 231.0621.

#

2-(2,2,2-Trifluoro-1-(4-methoxyphenyl)ethyl)-1,3-dioxolane (6b)

The crude product was purified via flash chromatography (pentane–Et₂O, 14:1) to afford 6b as a white solid; yield: 44 mg (76%).

IR (neat): 3007, 2962, 2929, 2902, 2837, 2361, 1883, 1616, 1519, 1305, 1273, 1244, 1162, 1118, 1031, 997, 939, 871, 816, 682 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.31 (dm, J = 8.7 Hz, 2 H), 6.90 (dm, J = 8.8 Hz, 2 H), 5.41 (d, J = 4.2 Hz, 1 H), 3.90–3.76 (m, 7 H), 3.54 (qd, J = 9.8, 4.2 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 159.2, 130.9, 125.2 (q, J = 279.4 Hz), 122.7, 113.7, 101.6, 65.3, 55.2, 53.4 (q, J = 25.4 Hz).

¹⁹F NMR (282 MHz, CDCl₃): δ = –65.4 (d, J = 9.8 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₃F₃O₃: 262.0812; found: 262.0810.

#

2-(2,2,2-Trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dioxolane (6c)

The crude product was purified via flash chromatography (pentane–Et₂O, 39:1) to afford 6c as a colorless oil; yield: 34 mg (62%).

IR (neat): 2956, 2895, 2360, 2335, 1609, 1513, 1262, 1227, 1165, 1145, 1110, 1046, 944, 825 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (dd, J = 8.7, 5.4 Hz, 2 H), 7.05 (tm, J = 8.7 Hz, 2 H), 5.41 (d, J = 3.9 Hz, 1 H), 3.92–3.71 (m, 4 H), 3.60 (qd, J = 9.8, 3.9 Hz, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 162.8 (d, J = 247.4 Hz), 131.9 (d, J = 8.1 Hz), 126.6, 125.2 (q, J = 279.9 Hz), 115.4 (d, J = 21.5 Hz), 101.5 (q, J = 2.1 Hz), 65.3, 65.2, 53.3 (q, J = 25.6 Hz).

¹⁹F NMR (376 MHz, CDCl₃): δ = –65.5 (d, J = 9.7 Hz), –113.6.

HRMS (EI): m/z [M – H]⁺ calcd for C₁₁H₉F₄O₂: 249.0533; found: 249.0497.

#

2-(1-(4-Chlorophenyl)-2,2,2-trifluoroethyl)-1,3-dioxolane (6d)

The crude product was purified via flash chromatography (pentane–Et₂O, 39:1) to afford 6d as a colorless oil; yield: 38 mg (65%).

IR (neat): 2961, 2894, 2359, 2335, 1599, 1495, 1254, 1164, 1145, 1114, 1104, 1093, 1039, 1016, 943, 876, 819, 806, 728, 678 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.30 (m, 4 H), 5.41 (d, J = 3.8 Hz, 1 H), 3.91–3.72 (m, 4 H), 3.59 (qd, J = 9.7, 3.9 Hz, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 134.6, 131.5, 129.3 (q, J = 1.7 Hz), 128.6, 125.1 (q, J = 280.6 Hz), 101.4 (q, J = 2.5 Hz), 65.4, 65.2, 53.5 (q, J = 25.7 Hz).

¹⁹F NMR (376 MHz, CDCl₃): δ = –65.4 (d, J = 9.6 Hz).

HRMS (EI): m/z [M – H]⁺ calcd for C₁₁H₉ClF₃O₂: 265.0238; found: 265.0243.

#

2-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-1,3-dioxolane (6e)

The crude product was purified via flash chromatography (pentane–Et₂O, 49:1) to afford 6e as a colorless oil; yield: 39 mg (57%).

IR (neat): 2956, 2892, 2359, 2335, 1594, 1492, 1252, 1163, 1145, 1114, 1104, 1037, 1012, 943, 814, 724, 674 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.51 (dm, J = 8.6 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 5.41 (d, J = 3.8 Hz, 1 H), 3.90–3.73 (m, 4 H), 3.58 (qd, J = 9.7, 3.8 Hz, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 131.8, 131.6, 129.8 (q, J = 1.9 Hz), 125.0 (q, J = 280.5 Hz), 122.8, 101.3 (q, J = 2.5 Hz), 65.4, 65.2, 53.5 (q, J = 25.7 Hz).

¹⁹F NMR (376 MHz, CDCl₃): δ = –65.4 (d, J = 9.7 Hz).

HRMS (EI): m/z [M – H]⁺ calcd for C₁₁H₉BrF₃O₂: 308.9733; found: 308.9739.

#

2-(2,2,2-Trifluoro-1-mesitylethyl)-1,3-dioxolane (6f)

The crude product was purified via flash chromatography (pentane–Et₂O, 49:1) to afford 6f as a white, amorphous solid; yield: 38 mg (63%).

IR (neat): 2971, 2950, 2895, 2356, 2323, 1613, 1575, 1485, 1453, 1247, 1169, 1133, 1103, 1059, 1020, 943, 850, 823, 682 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.91 (d, J = 3.3 Hz, 2 H), 5.70 (d, J = 6.8 Hz, 1 H), 4.20–3.98 (m, 3 H), 3.96–3.88 (m, 1 H), 3.87–3.78 (m, 1 H), 2.43 (s, 3 H), 2.37 (s, 3 H), 2.27 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 138.8, 137.7, 137.3, 131.2, 129.5, 126.4 (q, J = 2.0 Hz), 126.0 (q, J = 281.5 Hz), 101.0 (q, J = 2.0 Hz), 65.3, 64.9, 51.2 (q, J = 26.4 Hz), 21.8, 21.6 (q, J = 3.5 Hz), 20.7.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.1 (d, J = 10.5 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₁₇F₃O₂: 274.1181; found: 274.1169.

#

1,4-Bis(1-(1,3-dioxolan-2-yl)-2,2,2-trifluoroethyl)benzene (6g)

Following the general procedure using SbCl₅ (1.5 equiv), the crude product was purified via flash chromatography (pentane–Et₂O, 4:1) to afford 6g as a white, amorphous solid; yield: 44 mg (51%).

IR (neat): 2956, 2902, 2847, 2359, 1522, 1401, 1321, 1245, 1127, 1100, 1055, 1025, 943, 853, 814 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.38 (s, 4 H), 5.43 (d, J = 3.9 Hz, 1 H), 5.42 (d, J = 3.9 Hz, 1 H), 3.92–3.71 (m, 8 H), 3.60 (qd, J = 9.8, 3.9 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 131.1, 130.2, 125.2 (q, J = 280.8 Hz), 101.6 (q, J = 2.4 Hz), 65.3, 65.3, 53.7 (q, J = 25.5 Hz).

¹⁹F NMR (376 MHz, CDCl₃): δ = –65.1 (d, J = 9.8 Hz), –65.1 (d, J = 9.8 Hz).

HRMS (EI): m/z [M – H]⁺ calcd for C₁₆H₁₅F₆O₄: 385.0869; found: 385.0873.

#

2-(2,2,2-Trifluoro-1-(naphthalen-2-yl)ethyl)-1,3-dioxolane (6h)

The crude product was purified via flash chromatography (hexane–Et₂O, 9:1) to afford 6h as a pale yellow, amorphous solid; yield: 51 mg (82%).

IR (neat): 3064, 2956, 2893, 1601, 1510, 1408, 1372, 1326, 1265, 1102, 1039, 1016, 822, 749, 675 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.91–7.83 (m, 4 H), 7.55–7.48 (m, 3 H), 5.55 (d, J = 4.1 Hz, 1 H), 3.90–3.73 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): δ = 132.9, 129.7, 128.2, 127.9, 127.5, 127.2, 126.3, 126.2, 125.3 (q, J = 280.3 Hz), 101.7, 65.3, 54.3 (q, J = 25.4 Hz).

¹⁹F NMR (282 MHz, CDCl₃): δ = –64.9 (d, J = 9.7 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₃F₃O₂: 282.0868; found: 282.0861.

#

2-(1-(1,3-Dioxolan-2-yl)-2,2,2-trifluoroethyl)-1-tosyl-1H-pyrrole (6i)

The crude product was purified via flash chromatography (pentane–Et₂O, 9:1) to afford 6i as a white, amorphous solid; yield: 63 mg (76%).

IR (neat): 3128, 2996, 2891, 1595, 1469, 1402, 1366, 1359, 1303, 1251, 1143, 1049, 881, 810, 750, 701, 669 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.4 Hz, 2 H), 7.38 (dd, J = 3.4, 1.7 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.47 (br, 1 H), 6.30 (t, J = 3.4 Hz, 1 H), 5.32 (d, J = 4.2 Hz, 1 H), 4.70 (qd, J = 9.2, 4.2 Hz, 1 H), 3.83–3.73 (m, 3 H), 3.71–3.61 (m, 1 H), 2.40 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 136.3, 129.8, 126.9, 124.4 (q, J = 280.4 Hz), 124.0, 123.9 (q, J = 2.3 Hz), 116.5, 111.8, 101.6 (q, J = 2.2 Hz), 65.3, 65.2, 44.7 (q, J = 26.5 Hz), 21.6.

¹⁹F NMR (376 MHz, CDCl₃): δ = –66.3 (d, J = 9.2 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₆F₃NO₄S: 375.0752; found: 375.0751.

#

3-(1-(1,3-Dioxolan-2-yl)-2,2,2-trifluoroethyl)-1-tosyl-1H-indole (6j)

The crude product was purified via flash chromatography (pentane–Et₂O, 4:1) to afford 6j as a white, amorphous solid; yield: 66 mg (70%).

IR (neat): 2976, 2899, 1596, 1444, 1370, 1258, 1165, 1112, 1090, 1073, 1038, 812, 736, 665 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00 (d, J = 8.2 Hz, 1 H), 7.79–7.73 (m, 3 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.38–7.19 (m, 4 H), 5.50 (d, J = 2.9 Hz, 1 H), 3.98 (qd, J = 9.6, 2.8 Hz, 1 H), 3.91–3.75 (m, 3 H), 3.64–3.55 (m, 1 H), 2.34 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 135.1, 134.5, 130.8, 129.8, 126.8, 126.5, 125.1 (q, J = 280.4 Hz), 124.9, 123.5, 119.5, 113.6, 111.5, 101.0 (q, J = 2.5 Hz), 65.7, 65.1, 45.2 (q, J = 26.6 Hz), 21.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –66.3 (d, J = 9.7 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₂₀H₁₈F₃NO₄S: 425.0909; found: 425.0900.

#

2-((E)-1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-1,3-dioxolane (6k)

The crude product was purified via flash chromatography (pentane–Et₂O, 19:1) to afford 6k as a white, amorphous solid; yield: 46 mg (81%).

IR (neat): 2959, 2895, 1450, 1394, 1325, 1257, 1149, 1100, 1039, 972, 948, 870, 748, 692 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.47–7.39 (m, 2 H), 7.38–7.24 (m, 3 H), 6.67 (d, J = 16.0 Hz, 1 H), 6.14 (dd, J = 16.0, 9.4 Hz, 1 H), 5.29 (d, J = 2.8 Hz, 1 H), 4.22–3.64 (m, 4 H), 3.33–3.17 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 137.8, 136.0, 128.5, 128.1, 126.5, 125.2 (q, J = 280.0 Hz), 116.8 (q, J = 2.3 Hz), 101.0 (q, J = 2.7 Hz), 65.8, 65.2, 52.0 (q, J = 25.4 Hz).

¹⁹F NMR (282 MHz, CDCl₃): δ = –67.3 (d, J = 9.2 Hz).

HRMS (EI): m/z [M – H]⁺ calcd for C₁₃H₁₂F₃O₂: 257.0784; found: 257.0777.

#

2-(1,1,1-Trifluoro-4-methylpent-3-en-2-yl)-1,3-dioxolane (6l)

The crude product was purified via flash chromatography (pentane–Et₂O, 79:1) to afford 6l as a colorless oil; yield: 24 mg (52%).

IR (neat): 2971, 2892, 2359, 1679, 1446, 1402, 1326, 1256, 1160, 1149, 1103, 1051, 1037, 1018, 876 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 5.18–5.13 (m, 1 H), 5.15 (d, J = 3.5 Hz, 1 H), 4.00–3.84 (m, 4 H), 3.37–3.25 (m, 1 H), 1.80 (d, J = 1.4 Hz, 3 H), 1.69 (d, J = 1.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 140.8, 125.7 (q, J = 280.5 Hz), 112.4 (q, J = 2.3 Hz), 101.6 (q, J = 2.8 Hz), 65.5, 65.2, 47.1 (q, J = 25.1 Hz), 26.1, 18.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –67.5 (d, J = 9.2 Hz).

HRMS (EI): m/z [M – H]⁺ calcd for C₉H₁₂F₃O₂: 209.0784; found: 209.0776.

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(4R,5R)-2,4,5-Triphenyl-1,3-dioxolane (7)

Compound 7 was obtained by following a reported procedure.[16] Analytical data were in accordance with reported values.

#

(4R,5R)-4,5-Diphenyl-2-((R)-2,2,2-trifluoro-1-phenylethyl)-1,3-dioxolane (8)

Following the general procedure using TiCl₄ (1.8 equiv), the crude product was purified via flash chromatography (pentane–Et₂O, 4:1) to afford 8 as a viscous oil; yield: 70 mg (83%). The product was obtained as an inseparable mixture of diastereomers (dr 9:1).

IR (neat): 3033, 2894, 2361, 2335, 1496, 1454, 1351, 1315, 1265, 1167, 1137, 1115, 1046, 1026, 761 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.59–7.52 (m, 2 H), 7.45–7.38 (m, 3 H), 7.33–7.19 (m, 6 H), 7.17–7.09 (m, 2 H), 7.04* (dd, J = 7.5, 2.0 Hz, 0.2 H), 6.90 (dd, J = 8.0, 1.4 Hz, 1.8 H), 6.02 (d, J = 2.4 Hz, 0.9 H), 5.99* (d, J = 3.2 Hz, 0.1 H), 4.72* (d, J = 8.3 Hz, 0.1 H), 4.68 (d, J = 8.3 Hz, 0.9 H), 4.43* (d, J = 8.2 Hz, 0.1 H), 4.38 (d, J = 8.3 Hz, 0.9 H), 3.86 (qd, J = 10.0, 2.5 Hz, 1 H); assignable peaks of the minor isomer are marked with asterisks.

¹³C NMR (100 MHz, CDCl₃): δ = 137.2*, 137.1, 135.4, 135.3*, 130.7 (q, J = 1.7 Hz), 130.6, 128.6, 128.6, 128.5, 128.5, 128.5, 128.3, 126.8, 126.3, 125.45 (q, J = 280.7 Hz), 102.4 (q, J = 2.4 Hz), 102.2* (q, J = 2.4 Hz), 87.0*, 86.6, 85.4, 84.9*, 54.3 (q, J = 25.5 Hz); assignable peaks of the minor isomer are marked with asterisks.

¹⁹F NMR (376 MHz, CDCl₃): δ = –64.4* (d, J = 9.9 Hz, 0.3 F), –64.8 (d, J = 10.0 Hz, 2.7 F).

HRMS (EI): m/z [M – H]⁺ calcd for C₂₃H₁₈F₃O₂: 383.1253; found: 383.1252.

#

(R)-3,3,3-Trifluoro-2-phenylpropan-1-ol

To a stirred soln of (4R,5R)-4,5-diphenyl-2-((R)-2,2,2-trifluoro-1-phenylethyl)-1,3-dioxolane (8; 70 mg, 0.18 mmol) in MeOH (1.6 mL) was added 10% Pd/C (95 mg, 0.090 mmol), and the mixture was stirred for 12 h under an atmosphere of H₂. The reaction mixture was then filtered, with MeOH (2.0 mL) washing. The filtrate was cooled to –78 °C, NaBH₄ (140 mg, 3.6 mmol) was added, and the mixture was stirred at –78 °C for 1 h. Then, the reaction was quenched by the addition of sat. aq NH₄Cl (2 mL). The resulting mixture was warmed to r.t. and diluted with sat. aq NaHCO₃ (10 mL), which was followed by extraction with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified via flash chromatography (pentane–Et₂O, 9:1) to afford the product as a white, amorphous solid; yield: 24 mg (69%). Analytical data were in accordance with reported values[14] and the absolute stereochemistry was determined as R by a comparison of [α]_D values.

[α]_D ²¹ +29.5 (c 0.50, CHCl₃) [Lit.[14] [α]_D ²⁸ +33.3 (c 0.6, CHCl₃)].

SFC [Daicel Chiralcel OJ-H, CO₂–MeOH (98:2), 2 mL·min^–1, 25 °C, 200 nm]: 83% ee [t _R = 7.5 min (minor), 8.2 min (major)].

IR (neat): 3359, 2956, 2360, 2335, 1493, 1454, 1361, 1318, 1254, 1156, 1112, 1028, 873, 795, 701 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.31 (m, 5 H), 4.20 (ddd, J = 11.5, 7.6, 5.8 Hz, 1 H), 4.04 (ddd, J = 11.5, 7.7, 5.6 Hz, 1 H), 3.62–3.50 (m, 1 H), 1.54 (dd, J = 7.6, 5.6 Hz, 1 H, OH).

¹³C NMR (100 MHz, CDCl₃): δ = 132.5 (q, J = 2.1 Hz), 129.1, 129.0, 128.7, 126.1 (q, J = 280.4 Hz), 61.4 (q, J = 2.8 Hz), 52.6 (q, J = 25.5 Hz).

¹⁹F NMR (376 MHz, CDCl₃): δ = –67.4 (d, J = 9.4 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₉H₉F₃O: 190.0605; found: 190.0597.

#
#

Acknowledgment

We are grateful to the ETH Zürich for financial support.

Supporting Information

Supporting Information

References
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References
1 Present address: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.