Structure-dependent selective O- or C-trifluoroethylation of 1,3-dicarbonyls by mesityl(2,2,2-trifluoroethyl)iodonium triflate

Accepted Manuscript

Title: Structure-dependent selective O- or

C-triﬂuoroethylation of 1,3-dicarbonyls by

mesityl(2,2,2-triﬂuoroethyl)iodonium triﬂate

Authors: Cheng-Long Zhao, Jing Yang, Zhou-Zhou Han,

Cheng-Pan Zhang

PII:

S0022-1139(17)30370-6

DOI:

Reference:

http://dx.doi.org/10.1016/j.jﬂuchem.2017.09.009

FLUOR 9052

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Received date:

Revised date:

Accepted date:

20-8-2017

20-9-2017

22-9-2017

Please cite this article as: Cheng-Long Zhao, Jing Yang, Zhou-Zhou Han, Cheng-

Pan Zhang, Structure-dependent selective O- or C-triﬂuoroethylation of 1,3-

dicarbonyls by mesityl(2,2,2-triﬂuoroethyl)iodonium triﬂate, Journal of Fluorine

Chemistryhttp://dx.doi.org/10.1016/j.jﬂuchem.2017.09.009

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Structure-dependent selective O- or C-trifluoroethylation of 1,3-dicarbonyls by

mesityl(2,2,2-trifluoroethyl)iodonium triflate

Cheng-Long Zhao, Jing Yang, Zhou-Zhou Han, Cheng-Pan Zhang*

School of Chemistry, Chemical Engineering and Life Science, Wuhan University of

Technology, 205 Luoshi Road, Wuhan, 430070, China.

E-mail: zhangchengpan1982@hotmail.com; cpzhang@whut.edu.cn

Graphic abstract

Highlights

 A catalyst-free structure-dependent regioselective trifluoroethylation is

described.

 Cyclic 1,3-diketones exclusively afforded the O-trifluoroethylated products.

 Acyclic 1,3-dicarbonyls selectively formed the C-trifluoroethylated products.

 Li₂CO₃facilitated the C-trifluoroethylation of acyclic 1,3-dicarbonyls.

 The reaction avoided pre-activation of 1,3-dicarbonyls and use of strong base.

Abstract

Reaction of [ArICH₂CF₃][OTf] with structurally diversified 1,3-dicarbonyls and an

appropriate base at room temperature gave O-trifluoroethylated products,

C-trifluoroethylated products, or a mixture of O- and C-trifluoroethylated products in

good yields. The product type was dramatically dependent upon the structure of the

starting 1,3-dicarbonyls in this reaction. The cyclic 1,3-diketones exclusively afforded

the O-trifluoroethylated products, whereas the acyclic 1,3-diketones, β-keto esters,

and malonates selectively or specifically formed the C-trifluoroethylated products.

Li₂CO₃facilitated the C-trifluoroethylation of acyclic 1,3-diketones and β-keto esters.

The reaction proceeded under mild conditions, without pre-activation of

1,3-dicarbonyls and use of strong base, and demonstrated a catalyst-free

structure-dependent regioselective trifluoroethylation of 1,3-dicarbonyls by

mesityl(2,2,2-trifluoroethyl)iodonium triflate.

Keywords: (2,2,2-trifluoroethyl)iodonium; trifluoroethylation; 1,3-dicarbonyls;

structure-dependent

Introduction

Fluorine-containing functionalities have been widely used to modify the conformation,

stability, basicity, and intrinsic properties of organic molecules [1]. Fluorinated

analogues of pharmaceutically relevant compounds usually possess properties

conducive to drug development, such as improved lipophilicity, metabolic stability,

and bioavailability compared to their non-fluorinated counterparts [2a]. The

incorporation of fluorine atom(s) into the target molecules has become a general

strategy for pharmaceutical research and drug development [2]. Among various

fluorine-containing molecules, trifluoroethylated compounds are of great interest for

their applications in medicinal chemistry and materials science [2,3]. A growing

number of trifluoroethyl-containing compounds with biological activities, such as

antimalarial activity, hypolipidemic activity, anesthetic property, anti-inflammatory

activity, and enzyme inhibition ability, have been developed [4]. Because the naturally

occurring pathway is lacking, chemists have to search for reagents and

trifluoroethylation methods to prepare these molecules [5]. The direct carbon- and

heteroatom-CH₂CF₃bond formation has attracted much attention [5]. The transition

metal-mediated/catalyzed or transition metal-free trifluoroethylation of organic

scaffolds, such as arylboronic acids or esters, aryl iodides, arene, alkynes, alkenes,

anilines, and aryl Grignard reagents, have been successfully established [5,6].

Reagents that were efficient for these reactions include CF₃CH₂I or CF₃CH₂OTs,

CF₃CHN₂or CF₃CH₂NH₂, CF₃CHCl₂, (CF₃CH₂SO₂)₂Zn, CF₃CH₂SO₂Cl, CF₃CO₂H,

and aryl(2,2,2-trifluoroethyl)iodonium salts ([ArICH₂CF₃]X) [5-7].

Aryl(2,2,2-trifluoroethyl)iodoniums, first synthesized by Umemoto and later

modified by DesMarteau and Novák, has proved to be highly efficient electrophilic

trifluoroethylation reagents for heteroatom and carbon nucleophiles such as amines,

peptides, alcohols, phenols, thiols, sulfides, carbohydrates, thioglycosides, fatty acids,

phosphines, and electron-rich arenes [8]. These reactions proceeded smoothly under

catalyst-free conditions to form the pivotal N-CH₂CF₃, O-CH₂CF₃, S-CH₂CF₃,

P-CH₂CF₃, and C-CH₂CF₃bonds for a variety of bioactive molecules, and also

demonstrated that [ArICH₂CF₃]X (Ar = C₆H₅, 2,4,6-(CH₃)₃C₆H₂; X = OTf, NTf₂)

possess much more powerful trifluoroethylation ability than other CF₃CH₂transfer

reagents.

Recently,

the

palladium-catalyzed

reactions

of

aryl(2,2,2-trifluoroethyl)iodonium triflates with anilides, aromatic amides, and indoles

via C-H activation or with arylboronic acids via Suzuki-Miyaura cross-coupling have

been explored [9], which represent the state-of-the-art transition metal-catalyzed

trifluoroethylation methods using [ArICH₂CF₃]X as the CF₃CH₂source.

The preliminary reaction of carbanions with [PhICH₂CF₃][OTf] was notified by

Umemoto and coworkers, wherein [PhICH₂CF₃][OTf] reacted with the sodium salt of

diethyl methylmalonate or a silyl enol ether to afford the corresponding

C-trifluoroethylated product in a very low yield [10a]. Later, reaction of trimethylsilyl

enol ethers with [PhICH₂CF₃][OTf] in the presence of KF at room temperature

provided β-trifluoromethyl carbonyl derivatives in moderate to good yields [10b]. The

reaction happened specifically at the α-carbon sites of carbonyls. Recently, Shen and

coworkers

disclosed

that

3,3-dimethyl-1-(perfluoroethyl)-1,3-dihydro-1λ³-benzo[d][1,2]iodaoxole (BIX-C₂F₅)

reacted with β-keto esters at room temperature in the presence of DBU or K₂CO₃to

give α-pentafluoroethylated β-keto esters in good yields; pentafluoroethylation

occurred at the tertiary active methine group of 1,3-dicarbonyls [11]. Interestingly, we

found in this work that the reaction of [ArICH₂CF₃][OTf] with 1,3-dicarbonyls gave

specifically O-trifluoroethylated or C-trifluoroethylated products, which was

dramatically dependent upon the structure of 1,3-dicarbonyls.

At the beginning, the reaction of cyclohexane-1,3-dione (1a) and

mesityl(2,2,2-trifluoroethyl)iodonium triflate (2a) was chosen as the model reaction to

optimize the reaction conditions. Treatment of 1a with 2a (1.5 equiv) in CH₂Cl₂in the

presence of K₂CO₃(2.0 equiv) at room temperature overnight furnished

3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3a) in 61% yield, as a sole product.

This initial result was much different from the previous reports that silyl enol ethers

reacted with [PhICH₂CF₃][OTf] providing only α-trifluoroethyled carbonyl

derivatives [10]. The choice of solvent had a significant influence on the reaction.

Acetonitrile appeared to be the best solvent among CH₂Cl₂, CH₃CN, THF, DMF, and

DMSO (entries 1-5, Table 1), as the reaction performed in CH₃CN yielded 75% of 3a.

Other bases such as K₃PO₄, Li₂CO₃, NaHCO₃, and Cs₂CO₃were also suitable agents

for the O-trifluoroethylation of 1a (entries 6-9, Table 1). Li₂CO₃was found to be a

better choice, which gave 3a in 89% yield (entry 10, Table 1). Decreasing the

equivalents of Li₂CO₃from 2.0 to 1.5 equiv lead to 3a in 99% yield (entry 11, Table

1). Using phenyl(2,2,2-trifluoroethyl)iodonium triflate [PhICH₂CF₃][OTf] (2b)

instead of 2a in the same reaction afforded 3a in a slightly lower isolated yield (entry

12, Table 1).

With the optimized reaction conditions in hand (1 / 2a (1.5 equiv) / Li₂CO₃(1.5

equiv) / CH₃CN / r.t. / N₂/ overnight), various cyclic 1,3-diketones were examined

(Table 2). Complex cyclohexane-1,3-diones (1b-o) reacted with [MesICH₂CF₃][OTf]

in the presence of Li₂CO₃to afford exclusively the O-trifluoroethylated products

(3b-o) in good yields. The transformation did not require any strong base that is

harmful to mesityl(2,2,2-trifluoroethyl)iodonium triflate or process that is usually

used for pre-activation of 1,3-dicarbonyls [10,11]. Substituents such as methyl, phenyl,

allyl, benzyl, cyclohexylmethyl, and cinnamyl groups at the 2- and/or 5-position of

cyclohexane-1,3-diones had a little influence on the reaction. Substrates bearing

benzyl groups at the 2-positions, with either electron-withdrawing or -donating

functionalities on the phenyl rings, gave comparable yields of the desired products. In

the case of 3e and 3g, the reaction using K₂CO₃instead of Li₂CO₃led to higher yields

of the products. Furthermore, reactions of cyclopentane-1,3-dione and its derivatives

(1p-r) with 2a under the standard conditions furnished the O-trifluoroethylated

products (3p-r) in good yields. Nevertheless, cycloheptane-1,3-dione (1s) reacted

with 2a in the same conditions providing 3s only in 6% isolated yield, and most of 1s

was recovered. Replacement of Li₂CO₃with the stronger bases such as KOH and

LiOH in the same reaction failed to improve the yield of 3s.

The acyclic 1,3-dicarbonyl compounds were also tested in this reaction (Table 3).

Treatment of methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1t) with 2a (2.0

equiv) in the presence of Li₂CO₃(1.5 equiv) and 4Å MS (100 mg) for 24 h provided a

mixture of methyl 3-(2,2,2-trifluoroethoxy)-1H-indene-2-carboxylate (3t, 18%) and

methyl 1-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (3t’,

46%). The C-trifluoroethylated compound was obtained as the major product.

Addition of 4Å MS to the reaction mixture facilitated the trifluoroethylation (see SI).

Taking Cs₂CO₃instead of Li₂CO₃, the yield of 3t was promoted and the formation of

3t’ was somewhat inhibited. Similar phenomena were also observed when using

1,3-diphenylpropane-1,3-dione (1v) as substrate in the reaction, which formed a

mixture of (Z)-1,3-diphenyl-3-(2,2,2-trifluoroethoxy)prop-2-en-1-one (3v, 19%) [12]

and 1,3-diphenyl-2-(2,2,2-trifluoroethyl)propane-1,3-dione (3v’, 69%) in the presence

of Li₂CO₃, with the C-trifluoroethylated product (3v’) being predominant. These

results indicated that Li₂CO₃benefited the C-trifluoroethylation, which might be

attributed to the strong interaction between the Li⁺cation and the oxygen atoms of 1t

or 1v [13]. This hypothesis was further proved by the observations that reaction of 1v

and 2a with a mixture of Li₂CO₃/15-crown-5 or [n-Bu₄N][OH]•30H₂O gave a higher

percentage of O-trifluoroethylated product (3v) than that using Li₂CO₃without extra

Li⁺cation trap.

In

addition,

the

reaction

of

methyl

or

5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate

(1u)

1-(4-methoxyphenyl)-3-phenylpropane-1,3-dione (1w) with 2a and Li₂CO₃provided

the C-trifluoroethylated product (3u’ or 3w’) in 43% or 31% isolated yield (Table 3).

The corresponding O-trifluoroethylated products were likely formed in these reactions

according to the ¹⁹F NMR analysis of the reaction mixtures; however, they couldn’t be

isolated due to their formation in trace amounts. Furthermore, the reaction of

1-phenylbutane-1,3-dione (1x) or 1-phenylpentane-1,3-dione (1y) with

[MesICH₂CF₃][OTf]

under

the

standard

conditions

gave

1-phenyl-2-(2,2,2-trifluoroethyl)butane-1,3-dione (3x’) in 68% yield or

1-phenyl-2-(2,2,2-trifluoroethyl)pentane-1,3-dione (3y’) in 56% (or 65%) yield.

Treatment of excess diethyl malonate (1z) or dibenzyl malonate (1aa) with 2a in the

presence of KOH and 4Å MS (100 mg) supplied mono C-trifluoroethylated product

(3z’ or 3aa’) in 42% or 51% yield. Since malonates are less acidic than 1,3-diones or

β-keto esters [14], the stronger base (KOH) was necessary to accomplish the reaction.

In conclusion, we have found that reaction of [ArICH₂CF₃][OTf] with structurally

diversified 1,3-dicarbonyls under mild basic conditions gave O-trifluoroethylated

products, C-trifluoroethylated products, or a mixture of O- and C-trifluoroethylated

products in good yields. The product distribution was dramatically dependent upon

the structure of 1,3-dicarbonyls. The cyclic 1,3-diketones exclusively yielded the

O-trifluoroethylated products, while the acyclic 1,3-diketones, β-keto esters, and

malonates selectively or specifically constructed the C-trifluoroethylated compounds.

The use of Li₂CO₃as base facilitated the C-trifluoroethylation of acyclic

1,3-diketones and β-keto esters. This mild and simple reaction demonstrated a

structure-dependent regioselective O- or C-trifluoroethylation of 1,3-dicarbonyls by

mesityl(2,2,2-trifluoroethyl)iodonium triflate without any pre-activation of the

starting materials.

Experimental

1. General considerations

All reactions were carried out under a nitrogen atmosphere. Unless otherwise

1

specified, NMR spectra were recorded in CDCl₃on a 500 or 400 MHz (for H), 471

19

13

or 376 MHz (for F), or 126 MHz (for C) spectrometer. All chemical shifts were

reported in ppm relative to TMS (0 ppm) for ¹H NMR and PhCF₃(-63.5 ppm) for ¹⁹F

NMR as internal or external standard. The HPLC experiments were carried out on a

Waters e2695 instrument (column: J&K, RP-C18, 5 μm, 4.6 × 150 mm), and the

yields of product were determined by using the corresponding pure compound as the

external standard. Melting points of the products were measured and uncorrected. MS

experiments were performed on a TOF-Q ESI or CI/EI instrument. Solvents were

dried before use according to the literature.¹⁵Trifluoroethylation reagents 2a and 2b

were synthesized according to the literature.^8j1,3-Dicarbonyls 1b-d,^16a1e-f,^16b1g,^16a

1h-j,^16b1l-m,^16a1r^16a, 1t,^16c1u,^16c1w,^16d1y,^16dwere synthesized according to the

literatures. Other reagents were all purchased from commercial sources and used

without further purification.

2. General procedures for the reaction of 1,3-dicarbonyls with

[ArICH₂CF₃][OTf]

Procedure A: In a nitrogen filled glovebox, a sealed tube was charged with 1,3-dione

(1, 0.4 mmol), [MesICH₂CF₃][OTf] (2a, 0.6 mmol), Li₂CO₃(0.6 mmol), and CH₃CN

(2 mL) with stirring. The mixture was reacted at room temperature overnight and

evaporated to dryness under reduced pressure. The residue was purified by column

chromatography on silica gel using petroleum ether / ethyl acetate = 2 : 1 (v / v) as

eluents to give the trifluoroethylated product (3a-s).

Procedure B: In a nitrogen filled glovebox, a sealed tube was charged with 1,3-dione

(1, 0.2 mmol), [MesICH₂CF₃][OTf] (2a, 0.4 mmol), Li₂CO₃or Cs₂CO₃(0.3 mmol), 4

Å MS (100 mg), and CH₃CN (2 mL) with stirring. The mixture was reacted at room

temperature for 24 h and evaporated to dryness under reduced pressure. The residue

was purified by column chromatography on silica gel using petroleum ether / ethyl

acetate = 10 : 1 (v / v) as eluents to give the trifluoroethylated product (3t, 3v, and

3t’-3y’).

Procedure C: In a nitrogen filled glovebox, a sealed tube was charged with malonate

(1, 1.5 mmol), [MesICH₂CF₃][OTf] (2a, 0.5 mmol), KOH (0.55 mmol), 4 Å MS (100

mg), and CH₃CN (2 mL) with stirring. The mixture was reacted at room temperature

for 24 h and evaporated to dryness under reduced pressure. The residue was purified

by column chromatography on silica gel using a mixture of petroleum ether and ethyl

acetate as eluents to give the trifluoroethylated product (3z’ and 3aa’).

3-(2,2,2-Trifluoroethoxy)cyclohex-2-en-1-one (3a):

White solid, 64.5 mg, 83% yield. M.p.: 61-63 °C. ¹H NMR (400 MHz, CDCl₃) δ 5.31

(s, 1H), 4.17 (q, J = 8.0 Hz, 2H), 2.49 (t, J = 6.4 Hz, 2H), 2.36 (t, J = 6.4 Hz, 2H),

2.01 (m, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ -73.6 (t, J = 7.9 Hz, 3F). ¹³C NMR (126

MHz, CDCl₃) δ 199.1, 175.8, 122.7 (q, J = 277.2 Hz), 103.8, 65.0 (q, J = 36.5 Hz),

36.8, 28.5, 21.1. IR (KBr): 3065, 2967, 2925, 2906, 2840, 1679, 1656, 1615, 1455,

1434, 1384, 1355, 1330, 1303, 1283, 1247, 1220, 1187, 1141, 1068, 1039, 968, 912,

868, 853, 834, 762, 692, 635 cm^-1. HRMS-EI (m/z) calcd. for C₈H₉F₃O₂([M]⁺):

194.0555; Found: 194.0553.

2-Benzyl-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3b):

Light yellow solid, 76.2 mg, 67% yield. M.p.: 62-64 °C. ¹H NMR (500 MHz, CDCl₃)

δ 7.28-7.22 (m, 4H), 7.15 (t, J = 7.0 Hz, 1H), 4.35 (q, J = 8.0 Hz, 2H), 3.67 (s, 2H),

19

2.54 (t, J = 6.1 Hz, 2H), 2.41 (t, J = 6.6 Hz, 2H), 2.04 (m, 2H). F NMR (471 MHz,

CDCl₃) δ -78.1 (t, J = 8.0 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 197.9, 168.5, 141.0,

128.9, 128.2, 125.7, 123.0 (q, J = 278.5 Hz), 121.8, 64.4 (q, J = 36.5 Hz), 36.4, 28.0,

25.2, 20.7. IR (KBr): 3083, 3059, 3029, 3005, 2952, 2925, 2893, 2868, 2845, 2819,

1648, 1622, 1494, 1454, 1426, 1377, 1362, 1337, 1287, 1232, 1175, 1160, 1108, 1093,

1052, 1030, 983, 967, 921, 877, 853, 759, 714, 702, 691, 671, 608 cm^-1. HRMS-EI

(m/z) calcd. for C₁₅H₁₅F₃O₂([M]⁺): 284.1024; Found: 284.1012.

2-(4-Chlorobenzyl)-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3c):

White solid, 86.7 mg, 68% yield. M.p.: 56-58 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.16

(s, 4H), 4.34 (q, J = 7.8 Hz, 2H), 3.59 (s, 2H), 2.53 (t, J = 6.3 Hz, 2H), 2.38 (t, J = 6.0

19

13

Hz, 2H), 2.02 (m, 2H). F NMR (376 MHz, CDCl₃) δ -74.1 (t, J = 7.8 Hz, 3F). C

NMR (126 MHz, CDCl₃) δ 197.9, 168.5, 141.0, 128.9, 128.2, 125.7, 123.0 (q, J =

278.5 Hz), 121.8, 64.4 (q, J = 36.5 Hz), 36.4, 27.9, 25.1, 20.7. IR (KBr): 3042, 3028,

2985, 2964, 2941, 2909, 2876, 2850, 1636, 1621, 1490, 1455, 1423, 1370, 1337, 1302,

1291, 1257, 1226, 1208, 1159, 1111, 1088, 1053, 1016, 974, 925, 877, 857, 841, 814,

801, 735, 703, 689, 663, 641 cm^-1. HRMS-EI (m/z) calcd. for C₁₅H₁₄ClF₃O₂([M]⁺):

318.0634; Found: 318.0640.

2-(2-Methylbenzyl)-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3d):

Light yellow solid, 100.2 mg, 84% yield. M.p.: 38-40 °C. ¹H NMR (400 MHz, CDCl₃)

δ 7.09 (m, 1H), 7.06-7.02 (m, 2H), 6.97 (m, 1H), 4.27 (q, J = 8.0 Hz, 2H), 3.61 (s,

2H), 2.56 (t, J = 6.2 Hz, 2H), 2.43 (t, J = 6.7 Hz, 2H), 2.35 (s, 3H), 2.07 (m, 2H). ¹⁹F

NMR (376 MHz, CDCl₃) δ -74.2 (t, J = 8.0 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ

198.0, 169.1, 138.6, 136.3, 129.9, 127.9, 125.7, 125.7, 122.9 (q, J = 278.5 Hz), 121.3,

64.4 (q, J = 36.5 Hz), 36.5, 25.4, 25.1, 20.8, 19.8. IR (KBr): 3101, 3060, 3049, 3018,

2953, 2931, 2895, 2873, 1649, 1631, 1619, 1490, 1456, 1422, 1373, 1316, 1286, 1219,

1168, 1117, 1095, 1087, 1050, 986, 960, 919, 858, 831, 783, 744, 670 cm^-1. HRMS-EI

(m/z) calcd. for C₁₆H₁₇F₃O₂([M]⁺): 298.1181; Found: 298.1184.

2-(4-Nitrobenzyl)-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3e):

1

Light yellow solid, 90.9 mg, 69% yield (K₂CO₃as the base). M.p.: 83-85 °C. H

NMR (500 MHz, CDCl₃) δ 8.07 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 4.40 (q,

J = 8.0 Hz, 2H), 3.73 (s, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.43 (t, J = 6.5 Hz, 2H), 2.07

(m, 2H). ¹⁹F NMR (471 MHz, CDCl₃) δ -74.2 (t, J = 8.0 Hz, 3F). ¹³C NMR (126 MHz,

CDCl₃) δ 197.6, 169.3, 148.9, 146.3, 129.7, 123.5, 122.9 (q, J = 278.5 Hz), 120.3,

64.5 (q, J = 36.5 Hz), 36.2, 28.1, 25.2, 20.7. IR (KBr): 3108, 2933, 2851, 1658, 1630,

1598, 1515, 1458, 1430, 1370, 1340, 1294, 1231, 1171, 1159, 1107, 1056, 1012, 969,

922, 884, 856, 806, 732, 702, 632 cm^-1. HRMS-EI (m/z) calcd. for C₁₅H₁₄F₃NO₄

([M]⁺): 329.0875; Found: 329.0880.

4-((6-Oxo-2-(2,2,2-trifluoroethoxy)cyclohex-1-en-1-yl)methyl)benzonitrile (3f):

1

White solid, 96.5 mg, 78% yield. M.p.: 130-132 °C. H NMR (500 MHz, CDCl₃) δ

7.50 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.38 (q, J = 8.0 Hz, 2H), 3.68 (s,

19

2H), 2.57 (t, J = 6.0 Hz, 2H), 2.41 (t, J = 6.5 Hz, 2H), 2.06 (m, 2H). F NMR (471

MHz, CDCl₃) δ -74.2 (t, J = 8.0 Hz, 3F), ¹³C NMR (126 MHz, CDCl₃) δ 197.6, 169.1,

146.7, 132.0, 129.7, 122.8 (q, J = 278.5 Hz), 120.4, 119.4, 109.5, 64.5 (q, J = 36.5

Hz), 36.2, 28.3, 25.2, 20.7. IR (KBr): 3071, 3055, 2969, 2934, 2895, 2876, 2837,

2227, 1642, 1616, 1503, 1466, 1431, 1377, 1365, 1295, 1235, 1213, 1172, 1158, 1115,

1086, 1056, 968, 856, 819, 762, 702, 666, 637 cm^-1. HRMS-EI (m/z) calcd. for

C₁₆H₁₄F₃NO₂([M]⁺): 309.0977; Found: 309.0968.

2-(2-Chloro-4-fluorobenzyl)-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3g):

White solid, 88.9 mg, 66% yield (K₂CO₃as the base). M.p.: 61-63 °C. ¹H NMR (500

MHz, CDCl₃) δ 7.07 (dd, J = 8.6, 2.5 Hz, 1H), 7.02 (dd, J = 8.0, 6.8 Hz, 1H), 6.83 (td,

J = 8.4, 2.4 Hz, 1H), 4.33 (q, J = 8.0 Hz, 2H), 3.73 (s, 2H), 2.59 (t, J = 6.0 Hz, 2H),

2.45 (t, J = 6.5 Hz, 2H), 2.10 (m, 2H). ¹⁹F NMR (471 MHz, CDCl₃) δ -74.2 (t, J = 7.8

Hz, 3F), -116.1 (q, J = 8.0 Hz, 1F). ¹³C NMR (126 MHz, CDCl₃) δ 197.7, 169.6,

160.8 (d, J = 246.6 Hz), 134.3 (d, J = 10.2 Hz), 133.8 (d, J = 3.5 Hz), 130.4 (d, J =

8.5 Hz), 122.8 (q, J = 278.5 Hz), 119.9, 116.4 (d, J = 24.5 Hz), 113.6 (d, J = 20.8 Hz),

64.4 (q, J = 36.5 Hz), 36.4, 25.3, 25.0, 20.8. IR (KBr): 3284, 3077, 2988, 2967, 2932,

2893, 2877, 2852, 1651, 1622, 1491, 1462, 1422, 1372, 1298, 1265, 1228, 1156, 1107,

1089, 1052, 1039, 988, 965, 925, 906, 879, 853, 808, 782, 741, 702, 687, 642 cm^-1.

HRMS-EI (m/z) calcd. for C₁₅H₁₃F₄O₂([M ‒ Cl]⁺): 301.0852; Found: 301.0853.

2-(4-Methoxybenzyl)-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3h):

Yellow liquid, 91.8 mg, 73% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.17 (d, J = 8.4 Hz,

2H), 6.76 (d, J = 8.5 Hz, 2H), 4.33 (q, J = 8.0 Hz, 2H), 3.75 (s, 3H), 3.57 (s, 2H), 2.51

(t, J = 6.1 Hz, 2H), 2.37 (t, J = 6.5 Hz, 2H), 2.01 (m, 2H). ¹⁹F NMR (471 MHz,

CDCl₃) δ -74.1 (t, J = 8.0 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 198.0, 168.2, 157.7,

133.2, 129.9, 123.0 (q, J = 278.5 Hz), 122.3, 113.6, 64.4 (q, J = 36.5 Hz), 55.3, 36.4,

27.1, 25.2, 20.8. IR (KBr): 3100, 3061, 3032, 3000, 2954, 2875, 2837, 1660, 1649,

1624, 1584, 1511, 1458, 1428, 1370, 1287, 1245, 1226, 1160, 1110, 1089, 1051, 1034,

968, 921, 877, 853, 833, 816, 769, 726, 698, 668, 644 cm^-1. HRMS-EI (m/z) calcd. for

C₁₆H₁₇F₃O₃([M]⁺): 314.1130; Found: 314.1137.

2-(Cyclohexylmethyl)-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3i):

Light yellow solid, 72.0 mg, 62% yield. M.p.: 93-95 °C. ¹H NMR (500 MHz, CDCl₃)

δ 4.33 (q, J = 8.0 Hz, 2H), 2.54 (t, J = 6.0 Hz, 2H), 2.38 (t, J = 6.5 Hz, 2H), 2.20 (d, J

= 7.1 Hz, 2H), 2.04 (m, 2H), 1.66 (m, 2H), 1.60-1.58 (m, 3H), 1.38 (m, 1H), 1.20-1.11

19

13

(m, 3H), 0.92 (m, 2H). F NMR (471 MHz, CDCl₃) δ -74.3 (t, J = 8.0 Hz, 3F). C

NMR (126 MHz, CDCl₃) δ 198.7, 168.1, 123.1 (q, J = 278.5 Hz), 121.6, 64.4 (q, J =

36.5 Hz), 37.2, 36.6, 33.3, 29.6, 26.7, 26.5, 25.3, 21.0. IR (KBr): 2922, 2848, 1637,

1615, 1448, 1427, 1375, 1351, 1305, 1295, 1255, 1230, 1213, 1190, 1163, 1130, 1087,

1053, 977, 922, 896, 869, 856, 710, 697, 674 cm^-1. HRMS-EI (m/z) calcd. for

C₁₅H₂₁F₃O₂([M]⁺): 290.1494; Found: 290.1500.

2-Cinnamyl-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3j):

Yellow liquid, 93.7 mg, 72% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.33 (d, J = 7.7 Hz,

2H), 7.28 (t, J = 7.3 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H),

6.22-6.16 (m, 1H), 4.38 (q, J = 8.0 Hz, 2H), 3.23 (d, J = 7.0 Hz, 2H), 2.54 (t, J = 6.0

Hz, 2H), 2.41 (t, J = 6.5 Hz, 2H), 2.06 (m, 2H). ¹⁹F NMR (471 MHz, CDCl₃) δ -74.2

(t, J = 8.0 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 197.8, 168.6, 138.0, 130.5, 128.5,

127.7, 126.9, 126.1, 123.0 (q, J = 278.5 Hz), 120.4, 64.5 (q, J = 36.5 Hz), 36.4, 25.8,

25.3, 20.8. IR (KBr): 3082, 3060, 3027, 2951, 1719, 1649, 1623, 1495, 1453, 1424,

1372, 1287, 1228, 1163, 1095,1053, 1002, 966, 920, 855, 832, 754, 698, 665 cm^-1.

HRMS-EI (m/z) calcd. for C₁₇H₁₇F₃O₂([M]⁺): 310.1181; Found: 310.1180.

5,5-Dimethyl-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3k):

White solid, 83.6 mg, 94% yield. M.p.: 66-68 °C. ¹H NMR (400 MHz, CDCl₃) δ 5.31

19

(s, 1H), 4.17 (q, J = 8.0 Hz, 2H), 2.36 (s, 2H), 2.22 (s, 2H), 1.08 (s, 6H). F NMR

13

(376 MHz, CDCl₃) δ -73.6 (t, J = 7.8 Hz, 3F). C NMR (126 MHz, CDCl₃) δ 199.0,

174.1, 122.7 (q, J = 277.2 Hz), 102.6, 65.0 (q, J = 36.5 Hz), 50.8, 42.3, 32.6, 28.3. IR

(KBr): 3077, 2966, 2947, 2879, 2831, 1741, 1665, 1623, 1471, 1452, 1431, 1418,

1374, 1325, 1285, 1264, 1212, 1183, 1166, 1144, 1123, 1051, 966, 921, 892, 871, 854,

831, 800, 692, 616 cm^-1. HRMS-EI (m/z) calcd. for C₁₀H₁₃F₃O₂([M]⁺): 222.0868;

Found: 222.0871.

2-Benzyl-5,5-dimethyl-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3l):

Light yellow solid, 87.4 mg, 70% yield. M.p.: 51-53 °C. ¹H NMR (500 MHz, CDCl₃)

δ 7.24 (m, 4H), 7.15 (s, 1H), 4.33 (q, J = 7.5 Hz, 2H), 3.67 (s, 2H), 2.39 (s, 2H), 2.30

19

13

(s, 2H), 1.10 (s, 6H). F NMR (471 MHz, CDCl₃) δ -74.2 (t, J = 7.5 Hz, 3F). C

NMR (126 MHz, CDCl₃) δ 197.9, 166.7, 141.0, 128.8, 128.2, 125.7, 123.0 (q, J =

279.7 Hz), 120.9, 64.4 (q, J = 36.5 Hz), 50.3, 39.2, 32.5, 28.6, 27.9. IR (KBr): 3086,

3061, 3030, 2957, 2930, 2885, 2873, 2818, 1643, 1625, 1603, 1584, 1495, 1465, 1454,

1417, 1370, 1309, 1293, 1226, 1170, 1145, 1103, 1083, 991, 977, 927, 855, 779, 725,

699, 688, 649, 608 cm^-1. HRMS-EI (m/z) calcd. for C₁₇H₁₉F₃O₂([M]⁺): 312.1337;

Found: 312.1335.

2-Allyl-5,5-dimethyl-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3m):

White solid, 61.3 mg, 58% yield. M.p.: 46-48 °C. ¹H NMR (500 MHz, CDCl₃) δ 5.75

(m, 1H), 4.98 (d, J = 17.0 Hz, 1H), 4.90 (d, J = 10.0 Hz, 1H), 4.33 (q, J = 8.0 Hz, 2H),

3.04 (d, J = 6.0 Hz, 2H), 2.37 (s, 2H), 2.25 (s, 2H), 1.09 (s, 6H). ¹⁹F NMR (471 MHz,

CDCl₃) δ -74.4 (t, J = 8.0 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 197.7, 166.7, 135.7,

123.0 (q, J = 279.7 Hz), 119.4, 114.9, 64.5 (q, J = 36.5 Hz), 50.4, 39.3, 32.5, 28.6,

26.5. IR (KBr): 3086, 3024, 2962, 2940, 2910, 2896, 2876, 2832, 1639, 1620, 1459,

1430, 1375, 1305, 1294, 1224, 1164, 1131, 1095, 1070, 998, 970, 915, 885, 859, 761,

690, 672 cm^-1. HRMS-EI (m/z) calcd. for C₁₃H₁₇F₃O₂([M]⁺): 262.1181; Found:

262.1190.

5-Methyl-3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3n):

Light yellow solid, 54.9 mg, 66% yield. M.p.: 44-46 °C. ¹H NMR (500 MHz, CDCl₃)

δ 5.29 (s, 1H), 4.16 (m, 2H), 2.52-2.41 (m, 2H), 2.24-2.19 (m, 2H), 2.04 (m, 1H), 1.08

(m, 3H). ¹⁹F NMR (471 MHz, CDCl₃) δ -73.6 (t, J = 7.5 Hz, 3F). ¹³C NMR (126 MHz,

CDCl₃) δ 199.0, 175.1, 122.7 (q, J = 278.5 Hz), 103.3, 65.0 (q, J = 36.5 Hz), 45.0,

36.5, 28.8, 20.8. IR (KBr): 3057, 2981, 2965, 2947, 2937, 2919, 2883, 2851, 2817,

1652, 1611, 1460, 1447, 1432, 1385, 1345, 1297, 1286, 1253, 1221, 1178, 1158, 1142,

1072, 1043, 968, 929, 877, 859, 694, 622 cm^-1. HRMS-EI (m/z) calcd. for C₉H₁₁F₃O₂

([M]⁺): 208.0711; Found: 208.0702.

5-(2,2,2-Trifluoroethoxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3o):

White solid, 93.0 mg, 86% yield. M.p.: 95-97 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.38

(m, 2H), 7.31-7.26 (m, 3H), 5.44 (s, 1H), 4.24 (m, 2H), 3.41 (s, 1H), 2.78-2.58 (m,

19

4H). F NMR (471 MHz, CDCl₃) δ -73.5 (t, J = 7.2 Hz, 3F). ¹³C NMR (126 MHz,

CDCl₃) δ 198.1, 174.8, 142.2, 129.0, 127.4, 126.8, 122.7 (q, J = 277.2 Hz), 103.6,

65.2 (q, J = 36.5 Hz), 43.9, 39.3, 36.1. IR (KBr): 3093, 3058, 3029, 2976, 2956, 2889,

2875, 1658, 1615, 1500, 1447, 1429, 1382, 1278, 1258, 1216, 1179, 1154, 1048, 1032,

965, 855, 811, 750, 695, 645 cm^-1. HRMS-EI (m/z) calcd. for C₁₄H₁₃F₃O₂([M]⁺):

270.0868; Found: 270.0867.

3-(2,2,2-Trifluoroethoxy)cyclopent-2-en-1-one (3p):

Yellow oil, 46.1 mg, 64% yield. ¹H NMR (400 MHz, CDCl₃) δ 5.37 (s, 1H), 4.34 (q, J

19

= 8.0 Hz, 2H), 2.73 (m, 2H), 2.52 (m, 2H). F NMR (376 MHz, CDCl₃) δ -73.7 (t, J

13

= 7.9 Hz, 3F). C NMR (126 MHz, CDCl₃) δ 205.0, 188.1, 122.4 (q, J = 277.2 Hz),

106.1, 67.7 (q, J = 36.5 Hz), 34.5, 28.2. IR (KBr): 3087, 2962, 2940, 2926, 2853,

1712, 1697, 1680, 1609, 1459, 1440, 1411, 1367, 1301, 1274, 1247, 1228, 1190, 1164,

1039, 992, 967, 931, 859, 845, 832, 706 cm^-1. HRMS-EI (m/z) calcd. for C₇H₇F₃O₂

([M]⁺): 180.0398; Found: 180.0394.

2-Methyl-3-(2,2,2-trifluoroethoxy)cyclopent-2-en-1-one (3q):

1

Yellow solid, 62.9 mg, 81% yield. M.p.: 42-44 °C. H NMR (400 MHz, CDCl₃) δ

19

4.49 (q, J = 8.0 Hz, 2H), 2.63 (m, 2H), 2.49 (m, 2H), 1.66 (t, J = 1.7 Hz, 3H). F

13

NMR (376 MHz, CDCl₃) δ -74.6 (t, J = 8.0 Hz, 3F). C NMR (126 MHz, CDCl₃) δ

205.2, 180.8, 122.7 (q, J = 278.5 Hz), 118.9, 65.6 (q, J = 36.5 Hz), 33.7, 24.7, 6.08.

IR (KBr): 2963, 2927, 2858, 1733, 1692, 1644, 1445, 1387, 1352, 1284, 1235, 1164,

1123, 1071, 1028, 963, 885, 855, 834, 721, 675, 641 cm^-1. HRMS-EI (m/z) calcd. for

C₈H₉F₃O₂([M]⁺): 194.0555; Found: 194.0549.

2-Benzyl-3-(2,2,2-trifluoroethoxy)cyclopent-2-en-1-one (3r):

Light yellow liquid, 98.4 mg, 91% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.28-7.24 (m,

4H), 7.18 (m, 1H), 4.49 (q, J = 7.9 Hz, 2H), 3.51 (s, 2H), 2.66 (m, 2H), 2.52 (m, 2H).

¹⁹F NMR (471 MHz, CDCl₃) δ -74.4 (t, J = 7.9 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃)

δ 203.7, 180.9, 139.3, 128.6, 128.4, 126.1, 122.6, 122.6 (q, J = 278.5 Hz), 65.5 (q, J =

36.5 Hz), 33.6, 27.3, 24.4. IR (KBr): 3088, 3062, 3033, 3010, 2918, 2850, 1681, 1623,

1495, 1456, 1432, 1289, 1253, 1239, 1171, 1097, 1075, 1047, 990, 965, 857, 840, 772,

720, 699, 682 cm^-1. HRMS-EI (m/z) calcd. for C₁₄H₁₃F₃O₂([M]⁺): 270.0868; Found:

270.0872.

3-(2,2,2-Trifluoroethoxy)cyclohept-2-en-1-one (3s):

Colorless liquid, 4.9 mg, 6% yield, petroleum ether / ethyl acetate = 5 : 1 (v / v) as

eluents for column chromatography. ¹H NMR (500 MHz, CDCl₃) δ 5.33 (s, 1H), 4.10

(q, J = 7.9 Hz, 2H), 2.66 (t, J = 6.3 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 1.90 (m, 2H),

1.84 (m, 2H). ¹⁹F NMR (471 MHz, CDCl₃) δ -73.7 (t, J = 8.0 Hz, 3F). ¹³C NMR (126

MHz, CDCl₃) δ 201.5, 173.7, 122.7 (q, J = 278.5 Hz), 107.0, 65.1 (q, J = 36.5 Hz),

42.0, 32.5, 23.6, 21.3. IR (KBr): 2944, 2871, 1721, 1699, 1650, 1619, 1455, 1424,

1378, 1286, 1236, 1168, 1047, 976, 881, 817, 689 cm^-1. HRMS-EI (m/z) calcd. for

C₉H₁₁F₃O₂([M]⁺): 208.0711; Found: 208.0716.

Methyl 3-(2,2,2-trifluoroethoxy)-1H-indene-2-carboxylate (3t):

White solid, 10.0 mg, 18% yield (Li₂CO₃) or 16.5 mg, 30% yield (Cs₂CO₃). M.p.:

80-82 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J = 7.3 Hz, 1H), 7.48-7.39 (m, 3H),

19

4.94 (q, J = 8.4 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 2H). F NMR (471 MHz, CDCl₃) δ

13

-75.1 (t, J = 8.6 Hz, 3F). C NMR (126 MHz, CDCl₃) δ 164.6, 163.9, 141.7, 139.1,

129.2, 127.1, 124.4, 123.4 (q, J = 278.5 Hz), 121.0, 111.0, 70.8 (q, J = 35.5 Hz), 51.7,

36.4. IR (KBr): 2965, 2923, 2854, 1697, 1616, 1597, 1578, 1444, 1369, 1329, 1285,

1270, 1249, 1177, 1154, 1099, 1044, 958, 888, 851, 759, 719, 663 cm^-1. HRMS-EI

(m/z) calcd. for C₁₃H₁₁F₃O₃([M]⁺): 272.0660; Found: 272.0655.

Methyl 1-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (3t’):

1

Yellow liquid, 25.1mg, 46% yield (Li₂CO₃) or 12.9 mg, 24% yield (Cs₂CO₃). H

NMR (500 MHz, CDCl₃) δ 7.81 (d, J = 7.7 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.56 (d,

J = 7.7 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 3.90 (d, J = 17.5 Hz, 1H), 3.73 (s, 3H), 3.35

(d, J = 17.5 Hz 1H), 3.33 (m, 1H), 2.66 (m, 1H). ¹⁹F NMR (471 MHz, CDCl₃) δ -60.8

(t, J = 10.1 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 199.3, 169.3, 153.2, 136.1, 133.8,

128.2, 126.5, 126.1 (q, J = 278.5 Hz), 125.3, 57.3 (q, J = 1.7 Hz), 53.6, 37.8 (q, J =

29.0 Hz), 35.4 (q, J = 1.7 Hz). IR (KBr): 3084, 3039, 3005, 2957, 2848, 1748, 1716,

1609, 1590, 1466, 1435, 1374, 1303, 1258, 1206, 1172, 1141, 1111, 1047, 1015, 970,

957, 926, 864, 842, 813, 785, 752, 697, 652, 600, 577 cm^-1. HRMS-EI (m/z) calcd. for

C₁₃H₁₁F₃O₃([M]⁺): 272.0660; Found: 272.0668.

Methyl

5,6-dimethoxy-1-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indene-2-car-boxylate

(3u’):

White solid, 43.0 mg, 43% yield, petroleum ether / ethyl acetate = 2 : 1 (v / v) as

eluents for column chromatography. M.p.: 160-162 °C. ¹H NMR (500 MHz, CDCl₃) δ

7.17 (s, 1H), 6.94 (s, 1H), 4.00 (s, 3H), 3.91 (s, 3H), 3.78 (d, J = 17.1 Hz, 1H), 3.72 (s,

3H), 3.30 (m, 1H), 3.24 (d, J = 17.1 Hz, 1H), 2.62 (m, 1H). ¹⁹F NMR (471 MHz,

CDCl₃) δ -60.9 (t, J = 10.7 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 197.4, 169.5,

156.6, 150.0, 148.8, 126.2, 126.1 (q, J = 278.5 Hz), 107.2, 105.2, 57.4 (q, J = 1.5 Hz),

56.4, 56.1, 53.3, 37.7 (q, J = 29.0 Hz), 35.0 (q, J = 1.8 Hz). IR (KBr): 3010, 2960,

2917, 2880, 2839, 1717, 1595, 1504, 1467, 1456, 1444, 1425, 1363, 1320, 1282, 1253,

1221, 1176, 1144, 1117, 1101, 1025, 965, 901, 880, 865, 761, 670, 641 cm^-1.

HRMS-EI (m/z) calcd. for C₁₅H₁₅F₃O₅([M]⁺): 332.0872; Found: 332.0873.

(Z)-1,3-diphenyl-3-(2,2,2-trifluoroethoxy)prop-2-en-1-one (3v):

White solid, 11.4 mg, 19% yield (Li₂CO₃) or 28.3 mg, 46% yield (Cs₂CO₃). M.p.:

79-81 ^oC. ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J = 7.6 Hz, 2H), 7.80 (d, J = 7.6 Hz,

2H), 7.61 (t, J = 7.5 Hz, 1H), 7.56-7.47 (m, 5H), 6.78 (s, 1H), 4.59 (q, J = 8.4 Hz, 2H).

¹⁹F NMR (471 MHz, CDCl₃) δ -74.2 (t, J = 8.4 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃)

δ 189.0, 167.0, 139.0, 134.9, 133.0, 131.6, 128.9, 128.8, 128.5, 127.8, 123.4 (q, J =

278.5 Hz), 103.0, 70.8 (q, J = 36.5 Hz). IR (KBr): 3088, 3064, 3005, 2960, 2880,

1646, 1599, 1585, 1569, 1489, 1450, 1417, 1370, 1266, 1216, 1165, 1129, 1045, 1026,

984, 966, 906, 850, 832, 796, 765, 705, 696, 689, 603 cm^-1. HRMS-EI (m/z) calcd. for

C₁₇H₁₃F₃O₂([M]⁺): 306.0868; Found: 306.0865.

1,3-Diphenyl-2-(2,2,2-trifluoroethyl)propane-1,3-dione (3v’):

White solid, 42.5 mg, 69% yield (Li₂CO₃) or 29.1 mg, 48% (Cs₂CO₃). M.p.: 49-51 ^oC.

¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 7.9 Hz, 4H), 7.59 (t, J = 7.4 Hz, 2H), 7.46

(t, J = 7.9 Hz, 4H), 5.59 (t, J = 6.1 Hz, 1H), 3.05 (m, 2H). ¹⁹F NMR (471 MHz,

CDCl₃) δ -64.9 (t, J = 10.1 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 193.3, 135.3,

134.2, 129.2, 128.9, 126.4 (q, J = 277.2 Hz), 50.3 (q, J = 1.9 Hz), 33.2 (q, J = 30.2

Hz). IR (KBr): 3064, 3028, 3010, 2957, 2927, 1701, 1670, 1643, 1630, 1597, 1493,

1449, 1431, 1357, 1332, 1257, 1150, 1113, 1086, 1072, 1020, 963, 944, 927, 839, 775,

747, 688 cm^-1. HRMS-EI (m/z) calcd. for C₁₇H₁₃F₃O₂([M]⁺): 306.0868; Found:

306.0871.

1-(4-methoxyphenyl)-3-phenyl-2-(2,2,2-trifluoroethyl)propane-1,3-dione (3w’):

1

Colorless liquid, 20.6 mg, 31% yield. H NMR (500 MHz, CDCl₃) δ 7.96-7.94 (m,

4H), 7.58 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.51 (t,

J = 6.1 Hz, 1H), 3.84 (s, 3H), 3.03 (dm, J = 57.1 Hz, 2H). ¹⁹F NMR (471 MHz,

CDCl₃) δ -64.9 (t, J = 10.1 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 193.3, 191.6,

164.3, 135.4, 133.9, 131.2, 129.0, 128.7, 128.0, 126.4 (q, J = 277.2 Hz), 114.3, 55.6,

50.1 (q, J = 1.8 Hz), 33.2 (q, J = 30.1 Hz). IR (KBr): 3064, 2962, 2923, 2847, 1731,

1696, 1669, 1600, 1575, 1512, 1449, 1422, 1379, 1337, 1318, 1261, 1226, 1199, 1172,

1145, 1111, 1028, 964, 847, 801, 759, 742, 688 cm^-1. HRMS-EI (m/z) calcd. for

C₁₈H₁₅F₃O₃([M]⁺): 336.0973; Found: 336.0970.

1-Phenyl-2-(2,2,2-trifluoroethyl)butane-1,3-dione (3x’):

1

Colorless liquid, 49.8 mg, 68% yield. H NMR (500 MHz, CDCl₃) δ 8.04 (d, J = 7.5

Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 4.85 (t, J = 6.4 Hz, 1H),

19

2.92 (dm, J = 52.2 Hz, 2H), 2.18 (s, 3H). F NMR (471 MHz, CDCl₃) δ -65.0 (t, J =

10.7 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 199.7, 193.9, 135.5, 134.4, 129.2, 128.9,

126.2 (q, J = 277.2 Hz), 55.9 (q, J = 1.8 Hz), 32.7 (q, J = 29.9 Hz), 28.6. IR (KBr):

3066, 3008, 2964, 2929, 2856, 1731, 1682, 1596, 1581, 1449, 1434, 1362, 1336, 1264,

1210, 1146, 1113, 1079, 1069, 1018, 1001, 968, 932, 866, 831, 774, 754, 694, 669,

652, 637, 611 cm^-1. HRMS-EI (m/z) calcd. for C₁₂H₁₁F₃O₂([M]⁺): 244.0711; Found:

244.0707.

1-Phenyl-2-(2,2,2-trifluoroethyl)pentane-1,3-dione (3y’):

1

Colorless liquid, 43.5 mg, 56% yield (Li₂CO₃) or 50.3 mg, 65% yield (Cs₂CO₃). H

NMR (500 MHz, CDCl₃) δ 8.03 (d, J = 7.5 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.56 (t, J

= 7.8 Hz, 2H), 4.87 (t, J = 6.4 Hz, 1H), 2.93 (dm, J = 55.1 Hz, 2H), 2.49 (q, J = 7.2

Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H). ¹⁹F NMR (471 MHz, CDCl₃) δ -65.0 (t, J = 10.0 Hz,

3F). ¹³C NMR (126 MHz, CDCl₃) δ 202.4, 194.1, 135.7, 134.3, 129.2, 128.9, 126.3 (q,

J = 277.2 Hz), 54.9 (q, J = 1.8 Hz), 35.2, 32.8 (q, J = 29.8 Hz), 7.6. IR (KBr): 3065,

2982, 2943, 2909, 2880, 1729, 1682, 1628, 1596, 1493, 1449, 1433, 1410, 1380, 1334,

1278, 1260, 1148, 1106, 1059, 1035, 1001, 967, 936, 835, 775, 703, 688 cm^-1.

HRMS-ESI (m/z) calcd. for C₁₂H₁₁F₃O₂([M + H]⁺): 259.0946; Found: 259.0952.

Diethyl 2-(2,2,2-trifluoroethyl)malonate (3z’) ^17a

:

1

Colorless liquid, 50.9 mg, 42% yield. H NMR (500 MHz, CDCl₃) δ 4.26 (q, J = 7.0

19

Hz, 4H), 3.65 (t, J = 7.0 Hz, 1H), 2.83 (m, 2H), 1.30 (t, J = 7.0 Hz, 6H). F NMR

(471 MHz, CDCl₃) δ -65.9 (t, J = 10.1 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 167.5,

125.9 (q, J = 277.2 Hz), 62.4, 46.4 (q, J = 2.7 Hz), 33.2 (q, J = 30.2 Hz), 14.1.

Dibenzyl 2-(2,2,2-trifluoroethyl)malonate (3aa’) ^17b

:

1

Colorless liquid, 94.0 mg, 51% yield. H NMR (500 MHz, CDCl₃) δ 7.39-7.37 (m,

6H), 7.32 (m, 4H), 5.22 (m, 4H), 3.81 (t, J = 7.0 Hz, 1H), 2.90 (m, 2H). ¹⁹F NMR

(471 MHz, CDCl₃) δ -65.7 (t, J = 10.5 Hz, 3F). ¹³C NMR (126 MHz, CDCl₃) δ 167.1,

134.8, 128.7, 128.6, 128.3, 125.8 (q, J = 277.2 Hz), 68.0, 46.3 (q, J = 2.5 Hz), 33.0 (q,

J = 30.3 Hz).

Acknowledgements

We thank the Wuhan University of Technology, the Fundamental Research Funds for

the Central Universities, the National Natural Science Foundation of China

(21602165), the “Chutian Scholar” Program from Department of Education of Hubei

Province (China), the “Hundred Talent” Program of Hubei Province, and the Wuhan

Youth Chen-Guang Project (2016070204010113) for financial support.

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The

pKa

values

of

1,3-dicarbonyl

compounds

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Figures

Scheme 1. The previous examples of carbon-specific trifluoroethylation and

perfluoroethylation of 1,3-dicarbonyls

Table

1

Trifluoroethylation

of

cyclohexane-1,3-dione

(1a)

by

mesityl(2,2,2-trifluoroethyl)iodonium triflate (2a) in different conditions

Entry ^a

Base

K₂CO₃

K₃PO₄

Li₂CO₃

NaHCO₃

Cs₂CO₃

Li₂CO₃

Solvent

CH₂Cl₂

CH₃CN

THF

Yield (3a, %) ^b

1

2

61

75

3

4

DMF

23

5

DMSO

CH₃CN

24

6

78

7

89

8

74

9

77

10 ^c

11 ^d

12 ^d,e

94 (72)

99 (83)

(80)

^aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), base (0.2 mmol), solvent (2

b

mL), r.t., N₂, overnight.

The yields were determined by HPLC using

3-(2,2,2-trifluoroethoxy)cyclohex-2-en-1-one (3a) as an external standard (t_R= 3.0

min, λ_max= 244.1 nm, water/methanol = 30 : 70 (v / v)). Isolated yield was depicted in

c

d

the parentheses.

2a (0.12 mmol), Li₂CO₃(0.15 mmol).

2a (0.15 mmol),

e

Li₂CO₃(0.15 mmol).

[PhICH₂CF₃][OTf] (2b) was used instead of

[MesICH₂CF₃][OTf] (2a).

Table 2. O-Trifluoroethylation of cyclic 1,3-diketones by 2a ^[a]

a

Reaction conditions: 1 (0.4 mmol), 2a (0.6 mmol), Li₂CO₃(0.6 mmol), CH₃CN (2

b

c

mL), r.t., N₂, overnight. Isolated yields.

K₂CO₃was used instead of Li₂CO₃.

Yield was determined by ¹⁹F NMR spectroscopy using trifluoromethoxybenzene as an

internal standard.

Table 3. C- or C/O-Trifluoroethylation of acyclic 1,3-dicarbonyls by 2a^a

a

Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), base (0.3 mmol), 4Å MS (100

b

19

mg), CH₃CN (2 mL), r.t., N₂, 24 h. Isolated yield.

Yield was determined by F

NMR spectroscopy using trifluoromethoxybenzene as an internal standard.

^c1 (0.3

d

mmol), 2a (0.6 mmol), base (0.45 mmol), 4Å MS (100 mg), 24 h. Isolated yield.

1 (1.5 mmol), 2a (0.5 mmol), KOH (0.55 mmol), 4Å MS (100 mg), 24 h. Isolated

yield.

Article Doi

Structure-dependent selective O- or C-trifluoroethylation of 1,3-dicarbonyls by mesityl(2,2,2-trifluoroethyl)iodonium triflate

DOI: 10.1016/j.jfluchem.2017.09.009

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Full text of DOI:10.1016/j.jfluchem.2017.09.009

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