The First Practical Additive-Free 1,4-Conjugated Alkylation of Fluoro­alkylated Electron-Deficient Olefins with Various Organozinc Reagents

Abstract

1,4-Conjugated alkylation of fluoroalkylated olefins with organozinc reagents, such as RZnI and R₂Zn, was conducted smoothly to give the corresponding products in moderate yields without the use of either transition metals or Lewis acids. This reaction protocol allows not only a wide range of alkyl groups but also electron-withdrawing groups to be incorporated as 1,4-conjugated adducts.

Key words

1,4-conjugated alkylation - organozinc reagents - tri­fluoromethyl - electron-deficient olefin

The carbon–carbon bond formation through 1,4-conjugated addition has been recognized as one of the most important organic reactions. In the last decade, numerous synthetic methodologies have been developed for this transformation.[ ¹ ] Especially the transition-metal-catalyzed 1,4-conjugated addition has been intensively investigated and applied for enantioselective versions in several successful examples.[ ² ] Among these developments, the metal nucleophile also has been studied to search for expanding substrate scopes under the milder reaction condition. The organozinc reagents (i.e., RZnX, R₂Zn, and R₃ZnMet) are known as unique nucleophiles compared to other common organometallic reagents, that is, the softer nucleophilicity of organozinc reagents shows higher functional-group tolerance.[ ³ ] However, organozinc reagents often require the assistance of transition metals or Lewis acids in order to react as expected.[ ⁴ ]

Tremendous attention has been paid to fluorine-containing molecules because of their biological properties as well as their unique reactivities, which has led to new developments of synthetic methodologies.[ ⁵ ] For example, trifluoromethyl-bearing olefins, such as 1 in Scheme [1], shows very interesting LUMO-lowering effect on its β-carbon.[ ⁶ ] We and Yamazaki et al.[ ⁷ ] have demonstrated that the electron-deficient olefin 1 can serve as an excellent reaction partner for 1,4-conjugated addition, but incoming substrates for these reactions are to some extent limited. In fact, the introduction of simple alkyl substrates has been facing many difficulties, such as defluorination and a narrow range of the substrate scope.[ ⁷ ] To overcome this limitation, we revisited the basic nature of olefin 1, and realized that it will be possible for even unreactive nucleophiles to react with olefin 1 without addition of any activators (i.e., transition metals and Lewis acids). Herein, we describe the first practical 1,4-conjugated alkylation of fluoroalkylated olefins 1 with organozinc reagents under the additive-free conditions.

Scheme 1 1,4-Conjugated addition to fluoroalkylated electron-deficient­ olefins 1 with organometallic reagents

Initially, the least reactive organozinc reagents, alkylzinc halides, were chosen for the 1,4-conjugated alkylation to (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (1a). Thus, the olefin 1a was treated with 3.0 equivalents of freshly prepared RZnI[ ⁸ ] in THF at 0 °C and then the reaction mixture was stirred for eight hours at the same temperature. To our surprise, the reaction gave the corresponding 1,4-adduct in a moderate yield without extra additive (Table [1], entries 1 and 3). Next, the same reaction was tested with dialkylzinc reagents,[ ⁹ ] which gave a smoother reaction and higher yield of the product in only one hour at –78 °C (entries­ 2 and 4). Interestingly, when the organozincate, (n-Bu)₃ZnLi,[ ¹⁰ ] was utilized in this reaction, its 1,2-adduct was obtained instead as the major product (entry 5). This reaction trend of organozinc reagents was observed similarly in other substrates; therefore, RZnI and R₂Zn were used for further reactions. Dialkylzinc reagents were found to be the most effective,[ ¹¹ ] and even sterically hindered alkyl groups, such as i-Pr and t-Bu, could be introduced in moderate yields (entries 8 and 9). However, in contrast by taking full advantage of the mild reactivity of organozinc halides, the alkyl groups with labile functionalities could also be installed into the desired structure (entries 10 and 11).

Table 1 1,4-Conjugated Alkylation of Olefin 1a with Various Organozinc­ Reagents

Entry	Organozinc reagent	Equiv	Methoda	Time (h)	Product	Yield (%)b
1	EtZnI	3.0	A	8	2aa	57 (54)
2	Et2Znc	1.2	B	1	2aa	83 (82)
3	n-BuZnI	3.0	A	8	2ab	62 (37)
4	(n-Bu)2Zn	2.4	B	2	2ab	81 (56)
5	(n-Bu)3ZnLi	3.0	C	2	2ab	27d
6	(n-Hex)2Zn	2.4	B	2	2ac	66 (61)
7	c-HexZnI	2.4	A	8	2ad	50e
8	(i-Pr)2Znc	1.2	B	1	2ae	86 (62)
9	(t-Bu)2Zn	2.4	B	2	2af	50e
10	EtO2C(CH2)3ZnI	3.0	A	8	2ag	54e
11	NC(CH2)3ZnI	3.0	A	8	2ah	49e

^a Method A: in THF (0.25 M) at 0 °C. Method B: in toluene (0.125 M) at –78 °C. Method C: in THF (0.25 M) at –78 °C.

^b Yields were determined by ¹⁹F NMR spectroscopy, and the values in parentheses are isolated yields.

^c The commercially available salt-free organozinc reagents were used.

^d The 1,2-adduct was isolated as the major product in 69%.

^e The pure products were inseparable from impurities.

Based on the known reactivity of organozinc reagents, Et₂Zn was chosen for the 1,4-conjugated alkylation with various types of electron-deficient olefins, and these results are shown in Table [2]. Although slight modifications were required from the original condition depending on the reactivity of olefins 1, most electron-withdrawing groups (EWDs) can survive under the given reaction condition without formation of any noticeable by-products (Table [2], entries 1–4). The olefin with a difluoromethyl (CF₂H) group also reacted smoothly to give the product in excellent yield (entry 5).

Finally, preliminary work on the possibility of diastereo­selective 1,4-conjugated alkylation using trifluoromethylated alkenes with Evan’s chiral auxiliary was conducted (Scheme [2]). Thus, treatment of 1f or 1g with 3.6 equivalents of Et₂Zn at –40 °C for 24 hours gave the corresponding 1,4-adducts in good yields; however, as diastereomeric mixtures in both cases. Further effort to attain higher diastereoselectivity is currently underway in our laboratory.

Table 2 1,4-Conjugated Alkylation of Various Fluoroalkylated Electron-Deficient Olefins 1 with Et₂Zn^a

Entry	EWD	RF	Et2Zn (equiv)	Temp (°C)	Product	Yield (%)b
1c	C(O)Ph	CF3	1.2	–78	2aa	83 (82)
2d	C(O)NBn2	CF3	3.6	–40	2ba	80 (74)
3d	SO2Ph	CF3	3.6	–20	2ca	75 (68)
4d	P(O)(OEt)2	CF3	3.6	–20	2da	72 (69)
5c	C(O)Ph	CF2H	2.4	–78	2ea	92 (85)

^a The reaction was conducted following method B of Table [1] but at different temperatures.

^b Yields were determined by ¹⁹F NMR spectroscopy, and the values in parentheses are isolated yields.

^c The reaction time was 1 h.

^d The reaction time was 24 h.

Scheme 2 Preliminary results of the conjugated addition using chiral substrates

In summary, we have examined the simple yet practical 1,4-conjugated alkylation of fluoroalkylated electron-deficient­ olefins with various unreactive organozinc reagents without any additives.[ ¹² ] As a result, this reaction protocol can allow many labile alkyl groups to participate in 1,4-conjugated addition reaction; that is, our new methodology can compensate for the previously established 1,4-conjugated addition limited strictly to aromatic nucleophiles.

¹H and ¹³C NMR spectra were recorded on a Bruker DRX-500 (500.13 MHz for ¹H and 125.75 MHz for ¹³C) spectrometer on samples dissolved in CDCl₃ with Me₄Si as an internal reference. A Jeol JNM-AL400 (376.05 MHz) spectrometer was used to record ¹⁹F NMR spectra in CDCl₃ using CFCl₃ as an internal standard. IR spectra were recorded as liquid film or KBr disk with an Avtar-370DTGS spectrometer (Thermo Electron) or an FT/IR-4100 (JASCO) spectrometer. High-resolution mass spectra were taken with a JEOL JMS-700 MS spectrometer. Column chromatography was carried out on silica gel (Wako gel C-200) and TLC analysis was performed on silica gel TLC plates (Merck, Silica gel 60 F₂₅₄). All reactions were carried out under an atmosphere of argon. Anhyd THF and Et₂O were purchased from Wako Pure Chemical Industries, Ltd. n-BuLi (1.6 M hexane solution) was commercially available from Wako Pure Chemical Industries, Ltd. All chemicals were of reagent grade and, if necessary, were purified in the usual manner prior to use.

1,4-Conjugated Alkylation of RZnI to 4,4,4-Trifluoro-1-phenylbut-2-enone (1a); General Procedure for Method A

To a solution of 4,4,4-trifluoro-1-phenylbut-2-enone (1a; 50 mg, 0.25 mmol) in THF (1 mL) was added alkylzinc iodide (freshly prepared prior to the reaction from RI and Zn dust[ ⁸ ]) in THF at 0 °C. The mixture was then stirred for 8 h at 0 °C and quenched with sat. aq NH₄Cl (5 mL). The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried (Na₂SO₄). The organic solvents were removed, and the residue was purified by silica gel column chromatography to give the corresponding product.

1,4-Conjugated Alkylation of R₂Zn to 4,4,4-Trifluoro-1-phenylbut-2-enone (1a); General Procedure for Method B

To a solution of 4,4,4-trifluoro-1-phenylbut-2-enone (1a; 50 mg, 0.25 mmol) in toluene (2 mL) was added a 1.0 M hexane solution of R₂Zn (0.3 mL, 1.2 equiv) [in case of in situ generation of R₂Zn; 0.6 mL of ZnCl₂ (1.0 M, Et₂O solution) was added to 0.75 mL of RLi (1.6 M, hexane solution) at 0 °C, and stirred for 30 min at 0 °C] at –78 °C, and stirred for 1 h at –78 °C. The reaction was quenched with sat. aq NH₄Cl (10 mL), extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried (Na₂SO₄). The organic solvents were removed, and the residue was purified by silica gel column chromatography to give the corresponding product.

1-Phenyl-3-trifluoromethylpentan-1-one (2aa)

Method B; yield: 47 mg (0.21 mmol, 82%); yellow oil.

IR (neat): 3063, 2973, 2943, 2886, 1691, 1598, 1582, 1465, 1450, 1422, 1394, 1349, 1326, 1307, 1257, 1219 cm^–1.

¹H NMR (CDCl₃): δ = 1.00 (t, J = 7.5 Hz, 3 H), 1.49–1.59 (m, 1 H), 1.73–1.81 (m, 1 H), 2.97–3.08 (m, 2 H), 3.22–3.28 (m, 1 H), 7.45–7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 7.96–7.98 (m, 2 H).

¹³C NMR (CDCl₃): δ = 11.25, 21.73, 36.73 (q, J = 2.5 Hz), 39.43 (q, J = 25.8 Hz), 128.03, 128.37 (q, J = 279.6 Hz), 128.73, 133.45, 136.49, 196.50.

¹⁹F NMR (CDCl₃): δ = –71.09 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₂H₁₃F₃O (M⁺): 230.0918; found: 230.0913.

1-Phenyl-3-trifluoromethylheptan-1-one (2ab)

Method B; yield: 36 mg (0.14 mmol, 56%); yellow oil.

IR (neat): 3063, 2959, 2874, 1692, 1598, 1582, 1450, 1421, 1395, 1352, 1328, 1268, 1221, 1165, 1130, 1096 cm^–1.

¹H NMR (CDCl₃): δ = 0.89 (t, J = 7.2 Hz, 3 H), 1.27–1.40 (m, 4 H), 1.42–1.49 (m, 1 H), 1.69–1.76 (m, 1 H), 3.01–3.13 (m, 1 H), 3.03 (dd, J = 17.2, 7.1 Hz, 1 H), 3.27 (dd, J = 17.2, 3.6 Hz, 1 H), 7.46–7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 7.95–7.98 (m, 2 H).

¹³C NMR (CDCl₃): δ = 13.71, 22.60, 28.50 (q, J = 1.8 Hz), 28.89, 37.23 (q, J = 2.5 Hz), 38.08 (q, J = 26.1 Hz), 128.02, 128.70, 128.37 (q, J = 279.6 Hz), 133.41, 136.49, 196.44.

¹⁹F NMR (CDCl₃): δ = –71.32 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₄H₁₈F₃O (M + H): 259.1310; found: 259.1304.

1-Phenyl-3-trifluoromethylnonan-1-one (2ac)

Method B; yield: 44 mg (0.15 mmol, 61%); yellow oil.

IR (neat): 3063, 2931, 2860, 1745, 1692, 1598, 1582, 1450, 1421, 1351, 1255, 1218, 1163, 1131, 1100, 1002 cm^–1.

¹H NMR (CDCl₃): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.21–1.48 (m, 9 H), 1.68–1.75 (m, 1 H), 3.00–3.12 (m, 1 H), 3.02 (dd, J = 17.1, 7.3 Hz, 1 H), 3.27 (dd, J = 17.1, 3.6 Hz, 1 H), 7.46–7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 7.95–7.98 (m, 2 H).

¹³C NMR (CDCl₃): δ = 13.99, 22.52, 26.74, 28.83 (q, J = 1.8 Hz), 29.22, 31.51, 37.27 (q, J = 2.1 Hz), 38.17 (q, J = 26.1 Hz), 128.05, 128.37 (q, J = 279.6 Hz), 128.73, 133.44, 136.52, 196.52.

¹⁹F NMR (CDCl₃): δ = –71.31 (d, J = 7.1 Hz, 3 F).

HRMS: m/z calcd for C₁₆H₂₂F₃O (M + H): 287.1623; found: 287.1616.

3-Cyclohexyl-4,4,4-trifluoro-1-phenylbutan-1-one (2ad)

Method A; the product was inseparable from impurities, therefore only the peaks that could be assigned are described.

IR (neat): 3062, 2930, 2856, 1691, 1598, 1581, 1450, 1422, 1390, 1344, 1264, 1240, 1217, 1186, 1154, 1109, 1050, 1019, 1002 cm^–1.

¹H NMR (CDCl₃): δ = 1.07–1.28 (m, 5 H), 1.61–1.80 (m, 6 H), 3.06–3.23 (m, 3 H), 7.46–7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 7.97–7.99 (m, 2 H).

¹³C NMR (CDCl₃): δ = 34.33 (q, J = 2.2 Hz), 42.87 (q, J = 24.6 Hz), 128.37 (q, J = 280.8 Hz), 128.08, 128.72, 133.39, 136.52, 196.67.

¹⁹F NMR (CDCl₃): δ = –67.40 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₇H₁₆F₃O (M + H): 293.1153; found: 293.1146.

4-Methyl-1-phenyl-3-trifluoromethylpentan-1-one (2ae)

Method B; yield: 38 mg (0.16 mmol, 62%); white solid; mp 28–29 °C.

IR (KBr): 2993, 2974, 2947, 2921, 2889, 1684, 1598, 1473, 1452, 1396, 1322, 1271, 1221, 1169, 1137, 1070 cm^–1.

¹H NMR (CDCl₃): δ = 0.99 (d, J = 7.0 Hz, 3 H), 1.02 (d, J = 7.0 Hz, 3 H), 2.13 (dsept, J = 7.0, 3.8 Hz, 1 H), 3.02 (dd, J = 17.6, 5.7 Hz, 1 H), 3.10–3.18 (m, 1 H), 3.22 (dd, J = 17.6, 5.3 Hz, 1 H), 7.48–7.51 (m, 2 H), 7.56–7.62 (m, 1 H), 7.97–8.00 (m, 2 H).

¹³C NMR (CDCl₃): δ = 19.03, 20.20, 27.15, 33.72 (q, J = 2.5 Hz), 42.84 (q, J = 24.7 Hz), 128.06, 128.34 (q, J = 281.1 Hz), 128.71, 133.39, 136.52, 196.62.

¹⁹F NMR (CDCl₃); δ = –67.96 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₆H₁₃F₃O (M + H): 245.1153; found: 245.1149.

4,4-Dimethyl-1-phenyl-3-trifluoromethylpentan-1-one (2af)

Method B; the pure product was isolated as a white solid in very low yield; mp 39–40 °C.

IR (KBr): 2961, 2880, 1684, 1598, 1478, 1451, 1373, 1355, 1289, 1265, 1202, 1147, 1096, 1074, 1028 cm^–1.

¹H NMR (CDCl₃): δ = 1.06 (s, 9 H), 3.02 (ddd, J = 18.1, 3.9, 1.0 Hz, 1 H), 3.13–3.21 (ddq, J = 3.9, 6.1, 10.5 Hz, 1 H), 3.25 (dd, J = 18.1, 6.1 Hz, 1 H), 7.46–7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 7.96–7.99 (m, 2 H).

¹³C NMR (CDCl₃): δ = 28.26, 32.39, 34.89 (q, J = 2.8 Hz), 46.09 (q, J = 23.7 Hz), 128.51 (q, J = 282.2 Hz), 128.07, 128.70, 133.36, 136.49, 196.59.

¹⁹F NMR (CDCl₃): δ = –64.13 (d, J = 10.5 Hz, 3 F).

HRMS: m/z calcd for C₁₆H₁₃F₃O (M + H): 259.1310; found: 259.1314.

Ethyl 7-Oxa-7-phenyl-5-trifluoromethylheptanoate (2ag)

Method A; the product was inseparable from impurities, and therefore only the peaks that could be assigned are described.

¹⁹F NMR (CDCl₃): δ = –71.27 (d, J = 7.1 Hz, 3 F).

HRMS: m/z calcd for C₁₆H₂₀F₃O₃ (M + H): 317.1365; found: 317.1367.

7-Oxo-7-phenyl-5-trifluoromethylheptanenitrile (2ah)

Method A; the product was inseparable from impurities, and therefore only the peaks that could be assigned are described.

¹⁹F NMR (CDCl₃): δ = –70.96 (d, J = 7.1 Hz, 3 F).

HRMS: m/z calcd for C₁₄H₁₅F₃NO (M + H): 270.1106; found: 270.1103.

N,N-Dibenzyl-3-trifluoromethylpentanamide (2ba)

Method B; yield: 65 mg (0.19 mmol, 74%); yellow oil.

IR (neat): 3088, 3065, 3031, 2970, 2939, 2883, 1744, 1651, 1606, 1586, 1496, 1453, 1385, 1361, 1327, 1257 cm^–1.

¹H NMR (CDCl₃): δ = 1.01 (t, J = 7.5 Hz, 3 H), 1.21–1.29 (m, 1 H), 1.35–1.40 (m, 1 H), 2.43 (dd, J = 16.5, 7.3 Hz, 1 H), 2.71 (dd, J = 16.5, 4.8 Hz, 1 H), 2.90–3.10 (m, 1 H), 4.44 (d, J = 17.2 Hz, 1 H), 4.502 (d, J = 14.6 Hz, 1 H), 4.505 (d, J = 17.2 Hz, 1 H), 4.80 (d, J = 14.6 Hz, 1 H), 7.10–7.42 (m, 10 H).

¹³C NMR (CDCl₃): δ = 11.25, 21.70, 31.48, 40.66 (q, J = 25.6 Hz), 48.69, 49.77, 126.18, 127.47 (q, J = 292.9 Hz), 127.51, 127.74, 128.24, 128.63, 129.04, 136.03, 137.05, 170.46.

¹⁹F NMR (CDCl₃): δ = –70.93 (d, J = 7.6 Hz, 3 F).

HRMS: m/z calcd for C₂₀H₂₂F₃NO (M + H): 350.1732; found: 350.1728.

2-Trifluoromethylbutyl Phenyl Sulfone (2ca)

Method B; yield: 45 mg (0.17 mmol, 68%); yellow oil.

IR (neat): 3068, 2977, 2945, 2889, 1586, 1465, 1448, 1414, 1383, 1326, 1253, 1151, 1086, 1044, 1025 cm^–1.

¹H NMR (CDCl₃): δ = 1.03 (dt, J = 7.5, 0.81 Hz, 3 H), 1.78–1.88 (m, 2 H), 2.69–2.80 (m, 1 H), 3.14 (dd, J = 14.6, 8.3 Hz, 1 H), 3.33 (dd, J = 14.6, 2.9 Hz, 1 H), 7.59–7.62 (m, 2 H), 7.68–7.72 (m, 1 H), 7.93–7.95 (m, 2 H).

¹³C NMR (CDCl₃): δ = 10.54, 21.32, 39.52 (q, J = 27.3 Hz), 54.00, 126.81 (q, J = 280.8 Hz), 127.93, 129.52, 134.18, 139.02.

¹⁹F NMR (CDCl₃): δ = –70.61 (d, J = 7.6 Hz, 3 F).

HRMS: m/z calcd for C₁₄H₁₈F₃O₂S (M + H): 267.0667; found: 267.0661.

Diethyl [2-(Trifluoromethyl)butyl]phosphonate (2da)

Method B; yield: 45 mg (0.17 mmol, 68%); yellow oil.

¹H NMR (CDCl₃): δ = 1.02 (t, J = 7.4 Hz, 3 H), 1.33 (t, J = 7.0 Hz, 6 H), 1.70–1.90 (m, 3 H), 2.03 (ddd, J = 21.2, 15.7, 3.4 Hz, 1 H), 2.40–2.55 (m, 1 H), 4.04–4.17 (m, 4 H).

¹³C NMR (CDCl₃): δ = 10.68, 16.31, 16.41, 21.60–21.75 (m, 1 C), 24.00 (dq, J = 146.2, 2.7 Hz), 39.32 (qd, J = 26.5, 2.7 Hz), 61.86 (d, J = 6.5 Hz), 61.95 (d, J = 6.9 Hz), 127.77 (qd, J = 279.2, 18.5 Hz).

¹⁹F NMR (CDCl₃): δ = –67.40 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₉H₁₉F₃O₃P (M + H): 263.1024; found: 263.1029.

3-Difluoromethyl-1-phenylpentan-1-one (2ea)

Method B; yield: 49 mg (0.21 mmol, 85%), yellow oil.

IR (neat) 3062, 2696, 2940, 2882, 1688, 1598, 1581, 1463, 1449, 1380, 1359, 1320, 1260 cm^–1.

¹H NMR (CDCl₃): δ = 0.99 (t, J = 7.5 Hz, 3 H), 1.49 (ddq. J = 14.7, 7.3, 7.3 Hz, 1 H), 1.65 (ddq, J = 14.7, 7.4, 7.4 Hz, 1 H), 2.53–2.65 (m, 1 H), 2.99 (dd, J = 17.8, 6.9 Hz, 1 H), 3.21 (dd, J = 17.8, 5.6 Hz, 1 H), 5.94 (td, J = 57.5, 2.9 Hz, 1 H), 7.45–7.49 (m, 2 H), 7.54–7.60 (m, 1 H), 7.95–8.00 (m, 2 H).

¹³C NMR (CDCl₃): δ = 11.33, 21.08 (dd, J = 5.8, 3.5 Hz), 35.89 (t, J = 4.4 Hz), 39.39 (t, J = 19.1 Hz), 117.90 (t, J = 241.8 Hz), 127.99, 128.63, 133.25, 136.75, 197.99.

¹⁹F NMR (CDCl₃): δ = –123.81 (ddd, J = 275.3, 56.5, 14.1 Hz, 1 F), –125.17 (ddd, J = 275.3, 56.5, 19.8 Hz, 1 F).

HRMS: m/z calcd for C₁₂H₁₅F₂O (M + H): 213.1090; found: 213.1084.

(S)-3-[3-(Trifluoromethyl)pentanoyl]-4-phenyloxazolidin-2-one (2fa)

Method B.

Major Isomer

Yield: 45 mg (0.14 mmol, 29%); white solid; mp 96–97 °C.

IR (KBr) 3033, 2974, 2945, 2886, 1786, 1700, 1455, 1414, 1387, 1366, 1306, 1253, 1207, 1178, 1130, 1105, 1039 cm^–1.

¹H NMR (CDCl₃): δ = 0.86 (t, J = 7.5 Hz, 3 H), 1.35–1.45 (m, 1 H), 1.62–1.71 (m, 1 H), 2.73–2.84 (m, 1 H), 3.01 (dd, J = 18.3, 6.4 Hz, 1 H), 3.29 (dd, J = 18.3, 6.0 Hz, 1 H), 4.31 (dd, J = 8.9, 3.7 Hz, 1 H), 4.72 (t, J = 8.9 Hz, 1 H), 5.44 (dd, J = 8.9, 3.7 Hz, 1 H), 7.29–7.31 (m, 2 H), 7.33–7.41 (m, 3 H).

¹³C NMR (CDCl₃): δ = 10.98, 21.42 (q, J = 2.3 Hz), 33.96 (q, J = 2.5 Hz), 39.66 (q, J = 26.0 Hz), 57.76, 70.11, 125.90, 127.86 (q, J = 279.8 Hz), 128.86, 129.21, 138.72, 153.61, 169.96.

¹⁹F NMR (CDCl₃): δ = –71.30 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₅H₁₇F₃NO₃ (M + H): 316.1161; found: 316.1154.

Minor Isomer

Yield: 22 mg (0.07 mmol, 14%); white solid; mp 54–55 °C.

IR (KBr) 3068, 3035, 2985, 2946, 2884, 1790, 1697, 1473, 1395, 1336, 1232, 1208, 1169, 1139, 1124, 1084, 1069, 1045, 1015 cm^–1.

¹H NMR (CDCl₃): δ = 0.97 (t, J = 7.4 Hz, 3 H), 1.44–1.50 (m, 1 H), 1.67–1.72 (m, 1 H), 2.70–2.81 (m, 1 H), 3.05 (dd, J = 18.2, 7.2 Hz, 1 H), 3.27 (dd, J = 18.2, 5.3 Hz, 1 H), 4.30 (dd, J = 8.9, 4.0 Hz, 1 H), 4.72 (t, J = 8.9 Hz, 1 H), 5.43 (dd, J = 8.9, 4.0 Hz, 1 H), 7.27–7.30 (m, 2 H), 7.33–7.41 (m, 3 H).

¹³C NMR (CDCl₃): δ = 11.20, 21.44 (q, J = 2.0 Hz), 34.13 (q, J = 2.6 Hz), 39.70 (q, J = 26.0 Hz), 57.81, 70.11, 125.81, 127.83 (q, J = 278.2 Hz), 128.89, 129.25, 138.54, 153.59, 170.00.

¹⁹F NMR (CDCl₃): δ = –71.22 (d, J = 7.5 Hz, 3 F).

HRMS: m/z calcd for C₁₅H₁₇F₃NO₃ (M + H): 316.1161; found: 316.1154.

(S)-3-[3-(Trifluoromethyl)pentanoyl]-4-benzyloxazolidin-2-one (2ga)

Method B.

Major Isomer

Yield: 35 mg (0.11 mmol, 31%); yellow oil.

IR (neat): 3088, 3065, 3030, 2974, 2944, 2886, 1778, 1701, 1605, 1498, 1482, 1455, 1390, 1327, 1257, 1212, 1169, 1134, 1049, 1030 cm^–1.

¹H NMR (CDCl₃): δ = 1.04 (t, J = 7.5 Hz, 3 H), 1.49–1.58 (m, 1 H), 1.75–1.84 (m, 1 H), 2.76 (dd, J = 13.4, 9.7 Hz, 1 H), 2.86–2.95 (m, 1 H), 3.08 (dd, J = 18.1, 6.3 Hz, 1 H), 3.23 (dd, J = 18.1, 6.1 Hz, 1 H), 3.31 (dd, J = 13.4, 3.4 Hz, 1 H), 4.19 (dd, J = 9.1, 2.9 Hz, 1 H), 4.23 (dd, J = 9.1, 7.7 Hz, 2 H), 4.67–4.72 (m, 1 H), 7.20–7.22 (m, 2 H), 7.26–7.30 (m, 1 H), 7.31–7.36 (m, 2 H).

¹³C NMR (CDCl₃): δ = 11.19, 21.41 (q, J = 2.4 Hz), 34.00 (q, J = 2.2 Hz), 37.82, 39.77 (q, J = 26.2 Hz), 55.29, 66.40, 127.42, 127.91 (q, J = 279.8 Hz), 128.98, 129.34, 135.02, 153.34, 170.42.

¹⁹F NMR (CDCl₃): δ = –71.19 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₆H₁₉F₃NO₃ (M + H): 330.1317; found: 330.1309.

Minor Isomer

Yield: 30 mg (0.09 mmol, 27%); yellow oil.

IR (neat): 3029, 2967, 2943, 2881, 1786, 1703, 1455, 1391, 1257, 1213, 1170, 1134, 1104, 1030 cm^–1.

¹H NMR (CDCl₃): δ = 1.02 (t, J = 7.5 Hz, 3 H), 1.48–1.57 (m, 1 H), 1.73–1.81 (m, 1 H), 2.77 (dd, J = 13.3, 9.6 Hz, 1 H), 2.87–2.96 (m, 1 H), 2.99 (dd, J = 18.1, 6.5 Hz, 1 H), 3.31 (dd, J = 13.3, 3.3 Hz, 1 H), 3.33 (dd, J = 18.1, 5.6 Hz, 1 H), 4.20 (dd, J = 9.1, 3.2 Hz, 1 H), 4.23 (dd, J = 9.1, 7.6 Hz, 1 H), 4.67–4.71 (m, 1 H), 7.19–7.22 (m, 2 H), 7.26–7.30 (m, 1 H), 7.33–7.35 (m, 2 H).

¹³C NMR (CDCl₃): δ = 11.24, 21.54 (q, J = 2.0 Hz), 34.04 (q, J = 2.5 Hz), 37.69, 39.78 (q, J = 26.1 Hz), 55.27, 66.33, 127.42, 127.94 (q, J = 279.8 Hz), 129.00, 129.35, 134.98, 153.31, 170.48.

¹⁹F NMR (CDCl₃): δ = –70.17 (d, J = 9.8 Hz, 3 F).

HRMS: m/z calcd for C₁₆H₁₉F₃NO₃ (M + H): 330.1317; found: 330.1325.

• References

• 1a Perlmutter O. Conjugate Addition Reactions in Organic Synthesis. Pergamon Press; Oxford: 1992
• 1b Jung ME In Comprehensive Organic Synthesis . Vol. 4. Trost BM, Fleming I. Pergamon; Oxford: 1991: 1-67

For selected reviews on asymmetric 1,4-conjugate addition, see:
• 2a Alexakis A, Bäckvall JE, Krause N, Pámies O, Diéguez M. Chem. Rev. 2008; 108: 2796
• 2b Harutyunyan SR, Hartog TD, Geurt K, Minnaard AJ, Feringa BL. Chem. Rev. 2008; 108: 2824
• 2c Hayashi T. Bull. Chem. Soc. Jpn. 2004; 77: 13
• 2d Hayashi T, Yamasaki K. Chem. Rev. 2003; 103: 2829
• 2e Alexakis A, Belhaim C. Eur. J. Org. Chem. 2002; 3221
• 2f Hayashi T. Synlett 2001; 879
• 2g Krause N, Hoffmann-Röder A. Synthesis 2001; 171
• 2h Sibi M, Manyem S. Tetrahedron 2000; 56: 8033
• 2i Leonard J, Diez-Barra E, Merino S. Eur. J. Org. Chem. 1998; 2051
• 2j Rossiter BE, Swingle NM. Chem. Rev. 1992; 92: 771

General reviews on organozinc reagents:
• 3a Knochel P, Millot N, Rodrigues AL, Tucker CE. Org. React. 2001; 58: 417
• 3b Knochel P, Jones P. Organozinc Reagents . Oxford University Press; Oxford: 1999
• 3c Knochel P, Singer RD. Chem. Rev. 1993; 93: 2117

For recent studies on organozinc reagents, see:
• 3d Endo K, Hamada D, Yakeishi S, Ogawa M, Shibata T. Org. Lett. 2012; 14: 2342
• 3e Lemaire S, Houpis IN, Xiao T, Li J, Digard E, Gozlan C, Liu R, Gavryushin A, Diène C, Wang Y, Farina V, Knochel P. Org. Lett. 2012; 14: 1480

For comprehensive reviews on diorganozinc reagents, see:
• 4a Lemire A, Côté A, Janes MK, Charette AB. Aldrichimica Acta 2009; 42: 71
• 4b Hanson MV, Rieke RD. J. Am. Chem. Soc. 1995; 117: 10775
• 4c Knochel P, Perea JJ. A, Jones P. Tetrahedron 1998; 54: 8275
• 5a Uneyama K. Organofluorine Chemistry . Blackwell; Oxford: 2006
• 5b Chambers RD. Fluorine in Organic Chemistry . Blackwell; Oxford: 2004
• 5c Kirsch P. Modern Fluoroorganic Chemistry . Wiley-VCH; Weinheim: 2004
• 6 Shinohara N, Haga J, Yamazaki T, Kitazume T, Nakamura S. J. Org. Chem. 1995; 60: 4363
• 7a Konno T, Tanaka T, Miyabe T, Morigaki A, Ishihara T. Tetrahedron Lett. 2008; 49: 2106
• 7b Yamazaki T, Shinohara N, Kitazume T, Sato S. J. Fluorine Chem. 1999; 97: 91; and references cited therein
• 8 The alkylzinc halides, RZnI, were prepared according to the reported procedure; see ref. 4b.
• 9 The prepared dialkylzinc reagents were used without the removal of LiCl. For the detailed preparation procedure, see the experimental section.
• 10 The lithium zincate, (n-Bu)₃ZnLi, was prepared by mixing 3 equiv of n-BuLi (1.6 M hexane solution) and 1 equiv of ZnCl₂ (1.0 M, Et₂O solution) at 0 °C for 30 min.
• 11 The reactivity of dialkylzinc reagents is: salt-free R₂Zn > in situ generated R₂Zn.
• 12 The control experiments were conducted as follows. The 1,4-conjugated additions to (E)-1-phenylbut-2-en-1-one or chalcone with Et₂Zn were attempted under the same conditions as given in Table 1, entry 2; however, a quantitative amount of the starting alkene was recovered in both cases (methods A and B).