Unusual annulation reaction of electron-deficient alkenes with enamines: an easy access to stereocontrolled 4-fluoroalkylated 3,4-dihydro-2H-pyrans

Tetrahedron 69 (2013) 1521e1525

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Unusual annulation reaction of electron-deficient alkenes with enamines: an easy access to stereocontrolled 4-fluoroalkylated 3,4-dihydro-2H-pyrans Atsunori Morigaki a, Kazuki Tsukade b, Satoru Arimitsu c, Tsutomu Konno b, *, Toshio Kubota d a

Functional Materials Research Laboratories Research & Development Headquarters LION CORPORATION, 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan Department of Chemistry Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0123, Japan d Department of Materials Science, Ibaraki University, 4-12-1 Nakanarusawa, Hitachi 316-8511, Japan b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 6 October 2012 Received in revised form 4 December 2012 Accepted 5 December 2012 Available online 12 December 2012

The reaction of b-fluoroalkylated a,b-unsaturated ketones with various enamines gave 4-fluoroalkylated 3,4-dihydro-2H-pyrans as a major product in good yields by a one-pot operation, and these products display the high diastereoselection just after single recrystallization. This unexpected result is rationalized by the unique reactivity of b-fluoroalkylated a,b-unsaturated ketones. As the synthetic application, 4trifluoromethyl tetrahydropyran was synthesized in moderate isolated yield with high diastereoselectivity. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: 3,4-Dihydro-2H-pyran Tetrahydropyran a,b-Unsaturated ketone Fluoroalkyl Enamine Stereoselective

Nu-Met organometallic nucleophiles (RLi, RCu, RSn, RB, etc.)

1. Introduction Pyran analogues (i.e., pyran, dihydropyran, and tetrahydropyran) are often found in many natural products, biologically active compounds, and medicines, therefore many of synthetic methodologies have been developed for building those structures, even in stereoand enantioselective fashion.1 Regardless of well-accepted fact that introduction of fluorine into the parent structures can enhance their biological activities,2 the synthetic methodology of fluorinated pyran analogues are very limited. Among those sparse synthetic examples, most of cases are focused on monofluorinated pyran analogues,3 and synthesis of their fluoroalkylated (eRf) congeners is one of undeveloped areas in organofluorine chemistry.4 Stereoselective introduction of the fluoroalkyl group on the sp3 carbon center have been paid much attention recently.5 The electrondeficient fluoroalkylated alkenes have shown great potential for stereoselective construction of the fluoroalkyl group on a tertiary carbon.6 Especially, 1,4-conjugate addition reaction with b-fluoroalkylated a,bunsaturated ketones 1 has been intensively investigated by several groups and demonstrated with successful examples (Scheme 1).7

O

Nu

R1

Rf

1,4-Conjugate addition

O R1

Rf 1

enamines R2

N(R3)2

Rf 2

R2 (R3)2N

This work O 3

R1

Scheme 1. The reaction of b-fluoroalkylated a,b-unsaturated ketones 1 with different kinds of nucleophiles.

On the course of disclosing the unique reactivity of b-fluoroalkylated a,b-unsaturated ketones 1, herein, the reaction of ketones 1 with enamines 2 was examined. As the result, we would like to reveal versatile and highly diastereoselective synthesis of 4fluoroalkylated 3,4-dihydro-2H-pyrans 3. 2. Results and discussion

* Corresponding author. Tel.: þ81 75 724 7517; fax: þ81 75 724 7580; e-mail address: [email protected] (T. Konno). 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.12.012

Initial studies began with the reaction of readily prepared (E)4,4,4-trifluoro-1-phenyl-2-buten-1-one 1a8 with the enamine

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A. Morigaki et al. / Tetrahedron 69 (2013) 1521e1525

derived from dibenzylamine and phenylacetaldehyde. Thus, 1a was treated with 2.0 equiv of enamine 2a in dimethylacetamide (DMA) at 60  C for 4 h. To our surprise, the corresponding 1,4-conjugate adduct 4aa was detected as a minor product (12% yield), in contrast, 4-trifluoromethyl-3,4-dihydro-2H-pyran 3aa was observed as a single stereoisomer in 88% yield (entry 1, Table 1). In order to suppress the formation of 4aa, the reaction condition was optimized; Dichloromethane (CH2Cl2) was found to be the solvent of choice (entry 4), rather than THF and benzene (entries 2e4), and even lowering the equivalent of applied enamine 2a down to 1.1 equiv still showed good reaction efficiency (entry 5). Finally, increasing concentration gave the desired compound 3aa almost quantitatively, along with minimizing 4aa (entry 6). It is noteworthy that the cyclic compound 3aa were unstable under the acidic condition and even on the silica gel column chromatography, however, the final compound 3aa could be isolated in 94% yield via successful purification by recrystallization in methanol. Table 1 Screening of optimum reaction conditions

CF3

N(Bn)2

Ph

O

Ph

2a

Ph

CF3 1a

Solvent, Temp., 4 h

O +

(Bn)2N

O

Ph

H Ph

Ph 4aa

3aa Entry 1 2 3 4 5 6

Equiv of 2a 2.0 2.0 2.0 2.0 1.1 1.1

Solvent (conc./M) DMA (0.125) THF (0.125) Benzene (0.125) CH2Cl2 (0.125) CH2Cl2 (0.125) CH2Cl2 (0.250)

Temp/ C a

60 60a 60a Reflux Reflux Reflux

CF3 O

3aa/%b

4aa/%b,c

1a/%b

88 81 78 91 89 98 (94)c

12 16 19 9 5 2

0 3 1 10 6 0

a

The temperature in an oil-bath. Determined by 19F NMR. Value in parentheses is of isolated yield after recrystallization. c The product 4aa was obtained as a diastereomeric mixture in a ratio of ca. 1:1 in all cases. b

With the optimum reaction conditions in hand, we further investigated the generality of substrates on this reaction (Table 2). First of all, the enamine 2b formed from phenylacetaldehyde and piperidine was also served as the excellent reaction partner for this reaction, although a slight decrease of the diastereoselectivity was observed (entry 2). In the primary alkyl substituent on enamines (R2), the diastereoselectivity also slightly decreased despite of very smooth reaction (entries 3 and 4). When the enamine having a bulky isopropyl group as R2 was used, the products were obtained in a stereorandom manner (entry 5). Quite interestingly, the substituent R1 significantly influenced on the reaction. Thus, while the a,b-unsaturated ketone having an aromatic ring substituted by an electron-donating group as R1 did not lead to a satisfactory result (entry 6), the ketone bearing a CF3-containing aromatic ring as R1 afforded the desired dihydropyran in 83% yield (entry 7). The low yield as well as low reactivity was observed in the case of using a,b-unsaturated ketone having an alkyl moiety as R1 (entries 8 and 9). On the other hand, changing a fluoroalkyl group from a CF3 to a CHF2 or CF3(CF2)2 groups did not influence on the reaction, and the dihydropyrans with high diastereoselectivity have been obtained in high yields (entries 10 and 11). In entries 1e4, 7, and 10, the recrystallization from the crude materials enabled us to afford the desired cyclic compounds with an extremely high diastereoselectivity in good to high yields, although some of compounds 3 could not be recrystallized well. To evaluate the influence of a fluoroalkyl group upon the reaction, we also investigated the reaction of non-fluorinated

Table 2 The scope of substituents R2 2a : 2b : 2c : 2d : 2e :

O R1

Rf 1

1a : 1b : 1c : 1d : 1e : 1f : 1g :

N(R3)2

2 R2 = Ph, R3 = Bn R2 = Ph, R3 = -(CH2)5R2 = Me, R3 = -(CH2)5R2 = Bn, R3 = -(CH2)5R2 = i-Pr, R3 = -(CH2)5CH2Cl2 (0.25 M) reflux, 4 h

Rf R2

(R3)2N

+ O

R1

other diastereomers 5

3

Rf = CF3, R1 = Ph Rf = CF3, R1 = p-MeC6H4 Rf = CF3, R1 = p-CF3C6H4 Rf = CF3, R1 = Ph(CH2)2 Rf = CF3, R1 = CH3(CH2)6 Rf = CHF2, R1 = Ph Rf = CF3(CF2)2, R1 = Ph

Entry

Substrate

Enamine

3/%a

5/%a

Isolated yield/% of 3b

drc

1 2 3 4 5 6 7 8 9 10 11

1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1g

2a 2b 2c 2d 2e 2b 2b 2b 2b 2b 2b

98 83 75 85 52 26 83 44 30 100 92

2 17 25 15 48 74 17 56 70 0 8

3aa (94) 3ab (81) 3ac (73) 3ad (72) 3ae dd 3bb dd 3cb (69) 3db (9) 3eb dd 3fb (83) 3gb dd

100:0 94:6 96:4 95:5 d d 100:0 50:50 d 100:0 d

a

Determined by 19F NMR. Values in parentheses are of isolated yield after recrystallization. c The diastereomeric ratios after recrystallization of the crude materials are shown. d Recrystallization could not be performed because the crude materials were obtained as an oil. b

counterpart, (E)-1-phenyl-2-buten-1-one under the same reaction conditions as in the reaction of fluorinated substrates. As a result, any trace of cyclic compound was not detected and a large amount of the non-fluorinated a,b-unsaturated ketone as well as the aldehyde derived from the enamine were recovered. This result indicates that the high reactivity in the fluorinated substrates may be ascribed in part to a strongly electron-withdrawing effect of a fluoroalkyl group. The stereochemistry of 3,4-dihydro-2H-pyrans 3 was determined unambiguously by single-crystal X-ray analysis, which exhibits that the stereochemistry of the carbon having an R2 group (R2¼Ph for 3aa and R2¼Bn for 3ad, respectively, in Fig. 1) is trans to both the trifluoromethyl group and the amino moiety. Plausible elucidation of this high diastereoselectivity of 4fluoroalkyl 3,4-dihydro-2H-pyrans 3 is depicted in Scheme 2. From the evidence that highly diastereoselective manner of products 3 (except for 3ae and 3bb) and consideration of unique LUMO property of b-fluoroalkylated a,b-unsaturated ketones 1,9 the mechanism is once thought to be inverse-electron-demand (IED) hetero-DielseAlder reaction (path B, In Scheme 2).10 However, as initially expected, the 1,4-conjugate addition cannot be discriminated totally from the possible mechanism; In fact, the acyclic compound 4 can probably be formed from the 1,4-adduct intermediate Int-A with residual amount of water in the reaction mixture, which was obtained as diastereomeric mixture (dr¼1:1). On the reaction process of 1,4-conjugate addition of enamines, both isomerization and intramolecular cyclization can be in equilibrium, therefore, it is possible that the syn diastereomer of Int-A can only proceed intramolecular cyclization to furnish thermodynamically stable compounds 3 with high stereoselectivity (path A). Nevertheless, it is undoubted that this unique chemical transformation is derived from distinctive reactivity of b-fluoroalkylated a,b-unsaturated ketones 1.7a,11

A. Morigaki et al. / Tetrahedron 69 (2013) 1521e1525

1523

CF3

CF3

Ph 3

Ph 3 H2, Pd/C (5 mol%)

N

2

O

Ph

MeOH (0.06 M) r.t., 24 h

3ab

N 2 O

Ph

6ab Single isomer 66% isolated yield

JHc-Hd = 10.09 Hz

Hc 2

N O

H Ha Ph 3

CF3 H

Ph

Hd Hb

JHa-Hb = 11.72 Hz

Scheme 3. Synthetic application of 3: stereoselective synthesis of tetrahydropyran 6ab.

3. Conclusion In summary, we revealed the unique reactivity of b-fluoroalkylated a,b-unsaturated ketones 1 toward enamine 2 and demonstrated effective one-pot synthesis of 4-fluoroalkyl-3,4-dihydro2H-pyrans 3 with high stereoselectivity on consecutive carbons. Also, as a synthetic application, 4-trifluoromethyl tetrahydropyran 6ab was achieved in moderate isolated yield as a single isomer. To understand more detailed mechanism is currently underway in our laboratory.

Fig. 1. The single-crystal X-ray analyses of compounds 3aa and 3ad. O

Rf

R1 R2

N R3

R3

H2O

O

Rf

O

R1

H

R2 4, d.r.= ca. 1/1

Path A O

1,4-Conjugate addition

Rf

R1

N R3

R2

O

R3

4. Experimental section

H 2O

4.1. General

Int-A

R1

Rf

Rf

1

R2

+ R3 N

R2

(R3)2N

O

R1

3

R3

Rf

2

O Path B IED hetero-Diels-Alder reaction

R2

R1

N(R3)2

Scheme 2. Plausible reaction mechanism.

Finally, as the synthetic application of the cyclic products 3 using the best of high stereoselectivity, tetrahydropyran was synthesized controlling stereochemistry of adjacent four carbons. Thus, the treatment of cyclic products 3ab in the presence of 5 mol % of Pd/C in MeOH under an atmosphere of hydrogen for 24 h gave the corresponding 4-trifluoromethyl tetrahydropyran 6ab as a single isomer in 66% isolated yield. The stereochemistry of 6ab was confirmed by 1H NMR spectroscopy, that is, the coupling constants of HaeHb and HceHd were observed at JHaeHb¼11.72 Hz and JHceHd¼10.09, respectively. On the other hand, trans protons on between carbon 2 and 3 of compounds 3ad and 3ad, which could be determined by single-crystal X-ray analyses, showed the similar coupling constant, J¼w10 Hz on its 1H NMR spectroscopy. From comparing these observations, the stereochemistry of 6ab was assigned as shown in Scheme 3.

Infrared spectra (IR) were determined in a liquid film on a NaCl plate or KBr disk method with a JASCO FT/IR-4100 type A spectrometer. 1H and 13C NMR spectra were measured with a JEOL JNMAL 400 NMR spectrometer in a chloroform-d (CDCl3) solution with tetramethylsilane (Me4Si) as an internal reference. A JEOL JNM-AL 400 NMR spectrometer were used for determining the yield of the products with hexafluorobenzene (C6F6). 19F NMR (376.05 MHz) spectra were measured with a JEOL JNM-AL 400 NMR spectrometer in a chloroform-d (CDCl3) solution with trichlorofluoromethane (CFCl3) as an internal standard. High-resolution mass spectra (HRMS) were taken on a JEOL JMS-700MS spectrometer by electron impact (EI), chemical ionization (CI), and fast atom bombardment (FAB) methods. All reactions were routinely monitored by 19F NMR spectroscopy or TLC, and carried out under an atmosphere of argon. All chemicals were of reagent grade and, if necessary, were purified in the usual manner prior to use. Thin-layer chromatography (TLC) was done with Merck silica gel 60 F254 plates, and column chromatography was carried out using Wako gel C-200 as adsorbent. 4.2. General procedure for the synthesis of 4-fluoroalkyl 3,4dihyrdo-2H-pyrans (3)

b-Fluoroalkylated a,b-unsaturated ketones 1 (0.25 mmol, 1.0 equiv) was added to the solution of preliminary prepared enamines 2 (0.275 mmol, 1.1 equiv) in dichloromethane (1.0 mL 0.25 M) and stirred at the reflux temperature for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by recrystallization in MeOH to give 4-fluoroalkyl 3,4-dihyrdo-2Hpyrans 3.

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A. Morigaki et al. / Tetrahedron 69 (2013) 1521e1525

4.2.1. (2S*,3R*,4R*)-3,6-Diphenyl-2-[N,N-bis(2-phenylmethyl)]-4trifluoromethyl-3,4-dihydropyran (3aa). Mp¼165e167  C; 1H NMR (CDCl3) d¼3.32e3.45 (1H, m), 3.49 (1H, dd, J¼9.99, 9.99 Hz), 3.82 (2H, d, J¼12.79 Hz), 3.90e4.15 (2H, m), 4.80 (1H, d, J¼9.99 Hz), 5.32 (1H, d, J¼1.60 Hz), 6.85e7.00 (6H, m), 7.15e7.50 (12H, m), 7.65e7.75 (2H, m); 13C NMR (CDCl3) d¼42.27, 47.20 (q, J¼25.60 Hz), 52.30e53.00 (m, 1C), 90.70, 91.05 (q, J¼3.21 Hz), 125.01, 126.48 (q, J¼281.76 Hz), 127.05, 127.09, 128.09, 128.38, 128.57, 128.98, 134.87, 138.38, 139.30, 154.87 (some aromatic carbon peaks could not be detected due to their overlapping with another aromatic carbon peaks.); 19F NMR (CDCl3) d¼70.09 (3F, d, J¼7.14 Hz); IR (KBr) 3085, 3062, 3027, 2948, 2899, 1663, 1494, 1362, 1252, 1138, 1077 cm1; HRMS calcd for C32H29F3NO (MþH) 500.2202, found 500.2194; Xray analysis crystal data C32H28F3NO, M¼499.57, orthorhombic, space group Pbca (#61), a¼18.853(2)  A, b¼9.5071(7)  A, c¼29.088(3)  A, V¼5213.6 (7)  A3, rcalcd¼1.273 g/cm3, Z¼8. Intensities of 5983 reflections (Rint¼0.0909) were measured at 293 K with a Rigaku XtaLAB mini diffractometer using graphite monoA, q/2q scan, q30 ). The chromated Mo Ka radiation (l¼0.71075  structure was solved by direct method and refined by full-matrix least squares against F2 in the anisotropic (H-atoms isotropic) approximation. All hydrogen atoms were located from the electron density difference synthesis and were included in the refinement in isotropic approximation. The refinement converged to wR2¼0.1286 and GOF¼1.047 for 5983 independent reflections (R1¼0.0538 I>2s(I)). The number of the refined parameters was 363. All calculations were performed using the Crystal Structure 4.0, Crystal Structure Analysis Package. Crystallographic data for this compound has been deposited with the Cambridge Crystallographic Data Centre as supplementary data no. CCDC 904725. Copy of the data can be obtained free of charge by applying to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (http://beta-www.ccdc.cam.ac.uk/pages/Home.aspx; e-mail: [email protected]). 4.2.2. (2S*,3R*,4R*)-3,6-Diphenyl-2-(1-piperidinyl)-4-trifluoromethyl3,4-dihydropyran (3ab). Mp¼94e98  C; 1H NMR (CDCl3) d¼1.10e1.55 (6H, m), 2.55e2.70 (2H, m), 2.90e3.10 (2H, m), 3.36 (2H, dd, J¼9.99, 9.99 Hz), 3.45e3.65 (1H, m), 4.75 (1H, d, J¼9.99 Hz), 5.36 (1H, d, J¼2.40 Hz), 7.14e7.20 (2H, m), 7.25e7.45 (6H, m), 7.60e7.70 (2H, m); 13C NMR (CDCl3) d¼24.55, 25.90, 41.87 (q, J¼1.61 Hz), 46.89 (q, J¼25.90 Hz), 48.70, 50.98, 90.49 (q, J¼3.58 Hz), 96.82, 124.96, 126.59, 126.63 (q, J¼280.48 Hz) 127.75, 128.69, 128.75, 128.80, 134.98, 140.20, 154.92; 19F NMR (CDCl3) d¼68.41 (3F, d, J¼7.14 Hz); IR (KBr) 3039, 2935, 2817, 1949, 1882, 1801, 1654, 1349, 1254, 1160, 1116 cm1; HRMS calcd for C23H25F3NO (MþH) 388.1888, found 388.1890. 4.2.3. (2S*,3S*,4R*)-3-Methyl-6-phenyl-2-(1-piperidinyl)-4-trifluoromethyl-3,4-dihydropyran (3ac). Mp¼74e76  C; 1H NMR (CDCl3) d¼1.16 (3H, d, J¼7.19 Hz), 1.45e1.75 (6H, m), 2.20e2.35 (1H, m), 2.60e2.75 (2H, m), 2.80e2.95 (1H, m), 2.95e3.05 (2H, m), 4.27 (1H, d, J¼9.59 Hz), 5.18 (1H, d, J¼3.20 Hz), 7.25e7.40 (3H, m), 7.55e7.65 (2H, m); 13C NMR (CDCl3) d¼15.86 (d, J¼1.61 Hz), 24.78, 26.28, 29.74 (d, J¼1.61 Hz), 46.12 (q, J¼25.90 Hz), 48.50e49.00 (m, 2C), 90.11 (q, J¼3.85 Hz), 97.43, 124.86, 127.27 (q, J¼280.18 Hz), 128.16, 128.66, 135.16, 154.81; 19F NMR (CDCl3) d¼68.37 (3F, d, J¼7.14 Hz); IR (KBr) 3077, 2935, 2876, 2696, 1946, 1880, 1661, 1578, 1494, 1447, 1097 cm1; HRMS calcd for C18H23F3NO (MþH) 326.1732, found 326.1734. 4.2.4. (2S*,3S*,4R*)-6-Phenyl-3-phenylmethyl-2-(1-piperidinyl)-4trifluoromethyl-3,4-dihydropyran (3ad). Mp¼100e103  C; 1H NMR (CDCl3) d¼1.45-1.75 (6H, m), 2.50e2.63 (1H, m), 2.65e2.75 (2H, m), 2.81 (1H, dd, J¼13.79, 4.40 Hz), 2.95e3.05 (2H, m), 3.09e3.13 (1H, m), 3.22 (1H, d, J¼13.79 Hz), 4.15 (1H, d, J¼10.39 Hz), 5.09 (1H, d,

J¼2.80 Hz), 7.17e7.34 (8H, m), 7.48e7.51 (2H, m); 13C NMR (CDCl3) d¼24.53, 25.91, 33.61, 33.96, 40.34 (q, J¼25.64 Hz), 48.65 (br s, 2C), 90.43 (q, J¼3.85 Hz), 94.77, 124.78, 126.41, 127.47 (q, J¼280.48 Hz), 128.12, 128.63, 130.68, 134.98, 137.25, 154.56 (One carbon peak could not be detected due to the overlapping with another carbon peak.); 19F NMR (CDCl3) d¼69.21(3F, d, J¼7.14 Hz); IR (KBr) 3064, 3027, 2939, 2825, 1953, 1891, 1812, 1671, 1600, 1365, 1099 cm1; HRMS calcd for C24H27F3NO (MþH) 402.2045, found 402.2039; Xray analysis crystal data C24H26F3NO, M¼401.50, orthorhombic, A, b¼11.340(2)  A, space group Pca21 (#29), a¼9.519(2)  c¼19.231(4)  A, V¼2075.8 (7)  A3, rcalcd¼1.329 g/cm3, Z¼4. Intensities of 4741 reflections (Rint¼0.0791) were measured at 293 K with a Rigaku XtaLAB mini diffractometer using graphite monoA, q/2q scan, q30 ). The chromated Mo Ka radiation (l¼0.71075  structure was solved by direct method and refined by full-matrix least squares against F2 in the anisotropic (H-atoms isotropic) approximation. All hydrogen atoms were located from the electron density difference synthesis and were included in the refinement in isotropic approximation. The refinement converged to wR2¼0.1261 and GOF¼0.998 for 7413 independent reflections (R1¼0.0519 I>2s(I)). The number of the refined parameters was 288. All calculations were performed using the Crystal Structure 4.0, Crystal Structure Analysis Package. Crystallographic data for this compound has been deposited with the Cambridge Crystallographic Data Centre as supplementary data no. CCDC 904726. Copy of the data can be obtained free of charge by applying to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (http://beta-www.ccdc.cam.ac.uk/pages/Home.aspx; e-mail: [email protected]). 4.2.5. (2S*,3S*,4R*)-3-Phenyl-2-(1-piperidinyl)-4-trifluoromethyl-6(4-trifluoromethylphenyl)-3,4-dihydropyran (3cb). Mp¼114e115  C; 1 H NMR (CDCl3) d¼1.15e1.45 (6H, m), 2.55e2.70 (2H, m), 2.95e3.10 (2H, m), 3.30e3.45 (1H, m), 3.50e3.60 (1H, m), 4.77 (1H, d, J¼9.99 Hz), 5.40e5.50 (1H, m), 7.10e7.40 (5H, m), 7.55e7.80 (4H, m); 13C NMR (CDCl3) d¼24.51, 25.86, 41.75, 46.88 (q, J¼25.9 Hz), 48.72, 92.40e92.55 (m), 97.15, 124.05 (q, J¼270.95 Hz), 125.21, 125.24, 126.45 (q, J¼280.48 Hz), 126.75, 127.71, 128.34, 130.57 (q, J¼32.53 Hz), 138.34 (q, J¼1.61 Hz), 139.84, 153.75; 19F NMR (CDCl3) d¼70.08 (3F, J¼9.99 Hz), 63.13 (3F, s); IR (KBr) 3855, 3425, 3071, 3030, 2942, 2818, 2748, 2695, 2645, 1932, 1810, 1691, 1656, 1618, 1500, 1412, 1327, 1257 cm1; HRMS calcd for C24H24F6NO (MþH) 456.1762, found 456.1761. 4.2.6. (2S*,3R*,4R*)-4-Difluoromethyl-3,6-diphenyl-2-(1-piperidinyl) 3,4-dihydropyran (3fb). Mp¼89e91  C; 1H NMR (CDCl3) d¼1.05e1.30 (6H, m), 2.50e2.60 (2H, m), 2.85e2.95 (2H, m) 3.00e3.15 (2H, m), 4.74 (1H, d, J¼9.59 Hz), 5.38 (1H, d, J¼2.00 Hz), 5.39 (1H, dt, J¼2.00, 56.35 Hz), 7.00e7.10 (2H, m), 7.15e7.30 (6H, m), 7.50e7.60 (2H, m); 13C NMR (CDCl3) d¼24.58, 25.95, 42.23e42.31 (m), 46.33 (dd, J¼20.68, 19.08 Hz), 48.64, 90.86 (q, J¼3.31 Hz), 96.40, 116.13 (t, J¼242.56 Hz), 124.82, 126.81, 128.05, 128.15, 128.41, 128.50, 135.39, 139.49, 154.06; 19F NMR (CDCl3) d¼128.09 (1F, ddd, J¼279.40, 56.35, 24.07 Hz), 122.14 (1F, ddd, J¼279.40, 56.35, 4.89 Hz); IR (KBr) 3026, 2937, 2858, 3027, 2811, 1956, 1649, 1496, 1453, 1346, 1200, 1020 cm1; HRMS calcd for C23H26F2NO (MþH) 370.1982, found 370.1984. 4.3. General procedure for the synthesis of 4-fluoroalkyl tetrahydropyran (6ab) To a stirring solution of 3ab (0.3 mmol) in MeOH (5 mL, 0.06 M) was added Pd/C (16 mg, 0.015 mmol) at room temperature. Then the argon in the flask was replaced by hydrogen, and the whole was stirred at room temperature for 24 h. The mixture was filtered, and the reaction mixture was concentrated in vacuo. The residue was

A. Morigaki et al. / Tetrahedron 69 (2013) 1521e1525

purified by silica gel column chromatography (hexane/EtOAc¼10/ 1) to give 4-trifluoromethyl-3,6-diphenyl-2-(1-piperidinyl)tetrahydropyran (6ab) as a yellow oil. 4.3.1. (2S*,3S*,4R*,6R*)-3,6-Diphenyl-2-(1-piperidinyl) 4-trifluoromethyl tetrahydropyran (6ab). 1H NMR (CDCl3) d¼1.15e1.35 (6H, m), 1.66 (1H, ddd, J¼12.89, 12.39, 11.72 Hz), 2.22 (1H, ddd, J¼1.93, 4.00, 12.89 Hz), 2.45e2.55 (2H, m), 2.80e2.95 (3H, m), 3.08 (1H, dd, J¼10.09, 10.09 Hz), 4.26 (1H, d, J¼10.09 Hz), 4.61 (1H, dd, J¼11.72, 1.93 Hz), 7.10e7.50 (10H, m); 13C NMR (CDCl3) d¼24.85, 26.22, 33.24 (q, J¼2.51 Hz), 44.30, 46.26 (q, J¼25.07 Hz), 49.13, 76.05, 97.88, 125.51, 126.37, 126.64 (q, J¼280.48 Hz), 127.49, 127.94, 128.04, 128.32, 139.83, 142.10; 19F NMR (CDCl3) d¼69.35 (3F, d, J¼7.14 Hz); IR (KBr) 3064, 3030, 2934, 2852, 2821, 1603, 1496, 1454, 1377, 1346, 1255, 1181, 1163, 1133, 1075 cm1; HRMS calcd for C23H27F3NO (MþH) 390.2045, found 390.2046.

5.

6.

7.

Acknowledgements The authors thank TOSOH F-TECH INC., for supplying trifluoroacetaldehyde methyl hemiacetal and 2-bromo-3,3,3-trifluoropropene for the preparation of b-fluoroalkylated a,bunsaturated carbonyl compounds.

8.

9. 10.

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