Concise synthesis of oxindole derivatives bearing a 3

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Mar 21, 2013 - difunctionalization-type trifluoromethylation of simple alkenes. [9–11], and the carbo-trifluoromethylation of alkenes bearing allylic protons ...
Journal of Fluorine Chemistry 152 (2013) 51–55

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Concise synthesis of oxindole derivatives bearing a 3-trifluoroethyl group: Copper-catalyzed trifluoromethylation of acryloanilides Hiromichi Egami a,b, Ryo Shimizu a,c, Mikiko Sodeoka a,b,c,* a

Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan c Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 12 February 2013 Received in revised form 6 March 2013 Accepted 7 March 2013 Available online 21 March 2013

Carbotrifluoromethylation of acryloanilide derivatives with the combination of CuI and Togni’s reagent affords oxindole derivatives bearing a 3-trifluoroethyl group in high yields under mild conditions that are compatible with various functional groups. ß 2013 Elsevier B.V. All rights reserved.

Keywords: Trifluoromethyl Alkene Catalyst Oxindole Togni’s reagent

1. Introduction Oxindole frameworks are found in many bioactive compounds and natural products, and so synthetic methods and transformations of oxindole skeletons have been extensively investigated [1]. Among methods for construction of the oxindole framework, C–C bond-forming cyclization of anilide derivatives is one of the most important [2]. Direct C–H bond functionalization is a topic of growing interest from the viewpoint of atom economy, and elegant applications for oxindole synthesis have been reported, including direct oxidative coupling between Csp3–H and Csp2–H [3], Pdcatalyzed oxidative Heck reaction [4], and oxidative difunctionalization of acryloanilides utilizing hypervalent iodine reagents [5]. On the other hand, introduction of the trifluoromethyl group into organic molecules has become important in pharmaceutical and agrochemical research, due to its unique properties [6,7]. Thus, oxindole derivatives having a trifluoromethyl group are interesting targets. In 2012, Liu and co-workers reported palladium/ytterbium-catalyzed aryltrifluoromethylation of acryloanilides using the combination of TMSCF3/CsF/PhI(OAc)2 (Scheme 1) [8]. Although

* Corresponding author at: Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel.: +81 48 467 9373; fax: +81 48 462 4666. E-mail address: [email protected] (M. Sodeoka). 0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jfluchem.2013.03.009

this reaction could be operated under mild conditions, the method requires multiple reagents. We have recently focused on the difunctionalization-type trifluoromethylation of simple alkenes [9–11], and the carbo-trifluoromethylation of alkenes bearing allylic protons coupled with CAr–Csp3 bond formation was achieved using CuI/Togni’s reagent system [12]. But, there is so far no report on the trifluoromethylation of acryloanilide with an electrophilic trifluoromethylation reagent. Indeed, Liu mentioned that oxindole was not obtained when a palladium catalyst was used with Togni’s or Umemoto’s reagent [8]. Herein, we present a concise carbotrifluoromethylation of acryloanilide derivatives using CuI/Togni’s reagent system under mild conditions (Scheme 1). 2. Results and discussion Compound 2a was used as a test substrate for the screening of reaction conditions (Table 1). We first examined this reaction under the same conditions as used for the carbotrifluoromethylation of alkenes bearing allylic protons at 40 8C, and a moderate yield of product 3a was obtained (entry 1) [12]. Contrary to the cases of deprotonative trifluoromethylation [13] and trifluoromethylation of allylsilanes [10a], no product was observed when MeOH was used as the reaction solvent. Among the solvents tested, dichloromethane was found to be the solvent of choice for this reaction (entries 1–5). The reaction using CuI in CH2Cl2 afforded 3a in excellent yield (entry 5). Copper salts were also screened to find

H. Egami et al. / Journal of Fluorine Chemistry 152 (2013) 51–55

52

Aryl-trifluoromethylation by Liu et al.

O

Pd(OAc)2/L Yb(OTf)3

R1

R2 N

TMSCF3, CsF PhI(OAc)2 EtOAc, rt

R3

O N

R1

R3

N

L

CF3 O

N R2

O

F 3C

I

O O

CuI, 1 CH2Cl2, 40-80 °C

1 (Togni's reagent)

This work

Scheme 1. Trifluoromethylation of acryloanilide along with construction of the oxindole framework.

optimal conditions. CuCl and CuOAc worked as catalysts (entries 6 and 8), but [(MeCN)4Cu]PF6, which was the best catalyst under Buchwald’s reaction conditions [13a] and for the oxytrifluoromethylation of styrenes [10b], provided only a modest yield (entry 7). Substrate 2a was completely recovered in the reaction in the absence of catalyst, suggesting that the copper salt plays a crucial role in this trifluoromethylation (entry 10) [14]. Having optimized the reaction conditions, we next examined the scope of the reaction (Table 2). The reactions of acryloanilide derivatives having an electron-donating group on the phenyl ring proceeded smoothly, and the corresponding oxindole derivatives (3b–3e) were obtained in high yields. Methoxy and methyl groups at the p-position on the aniline ring slightly affected the reaction. Yields of both 3b and 3c were 91%. Although the substituent at the o-position retarded the reaction, the yield of 3d was 91% when the reaction was operated at 80 8C in dichloroethane (DCE). The reaction of 2e resulted in production of two regioisomers, and 3e and 3e0 were isolated in 71% and 23% yields. It is noteworthy that carbon-halogen (I, Br, Cl, and F) bonds could tolerate these reaction conditions. Compounds 2f–2j were successfully transformed to the corresponding oxindole derivatives 3f–3j in high yields (83–97%). The reaction of substrate 2k bearing a cyano group, which is a strong electron-withdrawing group, on the aryl ring was sluggish, but 3k was obtained in 38% yield together with 60% recovery of 2k.

Table 1 Screening of reaction conditionsa

Cu cat. (10 mol%) 1 ( 1.05 equiv.)

N O

N

O

In summary, we have accomplished carbotrifluoromethylation of acryloanilide derivatives using CuI/Togni’s reagent. This concise reaction afforded oxindole derivatives bearing a trifluoromethyl group in high yields under mild conditions that are compatible with a variety of functional groups. Further investigation of this reaction system and mechanistic studies are currently under way in our laboratory.

4.1. General

3a

2a

3. Conclusion

4. Experimental

CF3

40 ° C, 3 h

Reaction of compound 2l bearing an ethyl ester group proceeded smoothly at 80 8C to afford 3l in 87% yield. The substituent on the nitrogen was next screened. Tetrahydroquinoline derivative 2 m gave tricyclic compound 3 m in 95% yield, and the reaction of diaryl compound 2n took place at 40 8C to give 3n in 95% yield. According to previous studies on alkene trifluoromethylations using CuI/ Togni’s reaction systems [10–12], steric hinderance around the alkene generally has a significant impact. Nevertheless, oxindole derivatives 3o, 3p, and 3q were obtained in 94%, 93%, and 84% yields, respectively. We hypothesize that the reaction mechanism is essentially the same as our previous report regarding the carbotrifluoromethylation of simple alkenes [12]. The unidentified active species generated from Togni’s reagent and CuI is expected to interact with the C = C bond of acryloanilide, followed by electron transfer from the aryl ring through the C5 5C bond coupled with simultaneous C–C bond formation to construct the oxindole framework.

Entry

Catalyst

Solvent

Yield [%]b

1 2 3 4 5 6 7 8 9 10

CuI CuI CuI CuI CuI CuCl [(MeCN)4Cu]PF6 CuOAc Cu(OAc)2 –

1,4-Dioxane MeOH MeCN CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

60 N. R.c 56 20 96 (94)d 58 22 54 3 N. R.c

a The reactions were carried out with catalyst (10 mol%) and Togni’s reagent (1.05 equiv.) in each solvent (1 ml) on a 0.2 mmol scale. b Determined by 1H NMR and 19F NMR analysis using PhCF3 as an internal standard. c No reaction was observed. d Isolated yield.

All reactions were carried out under a nitrogen atmosphere. Togni’s reagent was prepared according to the literature [15]. Dichloromethane (CH2Cl2), chloroform (CHCl3), methanol (MeOH), acetonitrile (MeCN) and 1,4-dioxane were purchased from Kanto Chemical Co., Inc. Dehydrated 1,2-dichloroethane (DCE) was purchased from Sigma-Aldrich Co., LLC. CuI, CuCl, [(CH3CN)4Cu]PF6, CuOAc, Cu(OAc)2 were obtained from commercial sources and were used as received. Other reagents were purified by usual methods. Substrates were prepared according to the literature [8]. 1 H and 19F NMR spectra were measured on a JEOL JNM-ECS-400 spectrometer at 400 and 376 MHz, respectively. 13C NMR spectra were recorded on a JEOL JNM-ECS-400 spectrometer at 100 MHz. Chemical shifts were reported downfield from TMS (= 0) or CDCl3 for 1H NMR. For 13C NMR, chemical shifts were reported in the scale relative to CDCl3. For 19F NMR, chemical shifts were reported in the scale relative to a CFCl3 external standard (0 ppm). Infrared spectra were measured on a Thermo Nicolet iS5, and only diagnostic

H. Egami et al. / Journal of Fluorine Chemistry 152 (2013) 51–55

53

Table 2 Carbotrifluoromethylation of acryloanilide derivativesa

R2 N

R1

R3

CuI (10 mol%) 1 ( 1.05 equiv.)

R3

R1

CH2Cl2, 40 ° C

O 2 CF3

MeO

CF3 N

CF3

Br

O

3d: 91% (2 h)b

CF3

F

O

N

O

CF3 N

O

3e + 3e' : 94% (71 : 23, 3 h)

CF3

O

N

N

O

Cl

CF3 O O +

O

O

N

3c : 91% (2 h)b

O

N R2

CF3

MeO

O

N

3b: 91% (3 h) I

CF3

Me

O

N

3

CF3

N

CF3

Br

O

N

O

Cl 3f: 97% (6 h)

3g : 90% (6 h) CF3

NC N

O

3h : 91% (6 h) CF3

EtO2C

N

N

CF3 O

3o : 94% (2 h)b

CF3

O

N Ph

3m : 95% (6 h)

3l: 87% (3 h)b Ph

3j: 83% (6 h)b

CF3

O

N

3k : 38% (12 h) 95%c

3i: 95% (6 h)

MeO

CF3 N

3n : 95% (4 h) NPhth CF3

O

3p: 93% (2 h)b

O

N

O

3q: 84% (6 h)

a The reactions were carried out with CuI (10 mol%) and Togni’s reagent (1.05 equiv.) in CH2Cl2 (1 ml) at 40 8C on a 0.2 mmol scale. Run at 80 8C in DCE. c Based on recovered starting material. b

absorptions are listed below. ESI-MS was taken on Waters SYNAPT G2 MS. Column chromatography was performed with silica gel N60 (40–100 &m) purchased from Kanto Chemical Co., Inc. TLC analysis was performed on Silica gel 60 F254-coated glass plates (Merck). Visualization was accomplished by means of ultraviolet (UV) irradiation at 254 nm or by spraying a solution of 12molybdo(VI)phosphoric acid in ethanol as the developing agent. 4.2. Typical procedure for carbotrifluoromethylation of acryloanilides CuI (3.8 mg, 10 mol%) and Togni’s reagent 1 (66.4 mg, 1.05 equiv.) were weighted and added to a Schlenk flask, which was flame-dried under vacuum. The flask was evacuated and backfilled with nitrogen. Then, dichloromethane (1 ml) and 2a (35.0 mg, 0.2 mmol) were added. The reaction mixture was stirred for 3 h at 40 8C and diluted with ethyl acetate (5 ml). The solution was washed with aqueous NaHCO3 and brine. The organic layer was dried over MgSO4. After filtration, the organic solvent was evaporated and the residue was subjected to column chromatography on silica gel (hexane/ethyl acetate = 5/1) to give the trifluoromethylated product 3a (45.7 mg, 94%). 4.2.1. 1,3-Dimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3a) Colorless solid; 45.7 mg, 94%; 1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3H), 2.65 (dq, J = 15.2, 10.4 Hz, 1H), 2.82 (dq, J = 15.2, 10.4 Hz, 1H), 3.23 (s, 3H), 6.88 (d, J = 7.8 Hz, 1H), 7.07–7.11 (m, 1H), 7.26–7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 24.9, 26.3, 40.5 (q, J = 27.9 Hz), 44.3 (q, J = 1.9 Hz), 108.4, 122.6, 123.5, 125.2 (q,

J = 278.4 Hz), 128.4, 130.9, 142.8, 178.4; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2972, 2361, 1708, 1614, 1252, 1128, 1073, 753 cm1; HRMS (ESI): Calcd. for [C12H12F3NO + H]+: m/z = 244.0949, Found: 244.0942. 4.2.2. 5-Methoxy-1,3-dimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3b) Colorless solid; 49.6 mg, 91%; 1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3H), 2.63 (dq, J = 15.2, 10.4 Hz, 1H), 2.81 (dq, J = 15.2, 10.4 Hz, 1H), 3.21 (s, 3H), 3.80 (s, 3H), 6.78 (d, J = 8.3 Hz, 1H), 6.84 (dd, J = 8.3, 1.8 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 25.0, 26.5, 40.6 (q, J = 27.9 Hz), 44.8 (q, J = 1.9 Hz), 55.8, 108.7, 111.2, 112.5, 125.2 (q, J = 278.4 Hz), 132.4, 136.3, 156.0, 178.1; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2938, 1706, 1598, 1391, 1120, 1079, 1037, 799 cm1; HRMS (ESI): Calcd. for [C13H14F3NO2 + H]+: m/z = 274.1055, Found: 274.1064. 4.2.3. 1,3,5-Trimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3c) Colorless solid; 47.1 mg, 91%; 1H NMR (400 MHz, CDCl3): d = 1.39 (s, 3H), 2.35 (s, 3H), 2.63 (dq, J = 15.2, 10.4 Hz, 1H), 2.80 (dq, J = 15.2, 10.4 Hz, 1H), 3.22 (s, 3H), 6.77 (d, J = 7.8 Hz, 1H), 7.08– 7.12 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 21.1, 25.0, 26.4, 40.6 (q, J = 27.9 Hz), 44.4 (q, J = 1.9 Hz), 108.1, 124.3, 125.2 (q, J = 278.4 Hz), 128.7, 131.0, 132.1, 140.4, 178.4; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2975, 1707, 1499, 1362, 1259, 1136, 1054, 752 cm1; HRMS (ESI): Calcd. for [C13H14F3NO + H] +: m/z = 258.1106, Found: 258.1118.

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H. Egami et al. / Journal of Fluorine Chemistry 152 (2013) 51–55

4.2.4. 5-Methoxy-1,3,7-trimethyl-3-(2,2,2-trifluoroethyl)indolin-2one (3d) Colorless solid; 52.4 mg, 91%; 1H NMR (400 MHz, CDCl3): d = 1.37 (s, 3H), 2.56 (s, 3H), 2.58 (dq, J = 15.2, 10.4 Hz, 1H), 2.82 (dq, J = 15.2, 10.4 Hz, 1H), 3.48 (s, 3H), 3.78 (s, 3H), 6.57 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 19.0, 25.6, 29.7, 40.8 (q, J = 27.9 Hz), 44.2 (q, J = 1.9 Hz), 55.6, 108.2, 116.0, 120.9, 125.2 (q, J = 278.4 Hz), 133.0, 134.0, 155.4, 178.9; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2932, 1706, 1472, 1436, 1260, 1135, 1070 cm1; HRMS (ESI): Calcd. for [C14H16F3NO2 + H] +: m/z = 288.1211, Found: 288.1213. 4.2.5. 1,3-Dimethyl-3-(2,2,2-trifluoroethyl)[5,6]methylenedioxyindolin-2-one (3e) colorless oil; 41.1 mg, 71%; 1H NMR (400 MHz, CDCl3): d = 1.36 (s, 3H), 2.58 (dq, J = 15.2, 10.4 Hz, 1H), 2.78 (dq, J = 15.2, 10.4 Hz, 1H), 3.19 (s, 3H), 5.95–5.96 (m, 2H), 6.49 (s, 1H), 6.78 (s, 1H); 13C NMR (100 MHz, CDCl3): d = 25.1, 26.6, 40.7 (q, J = 27.9 Hz, 1H), 44.6 (q, J = 1.9 Hz, 1H), 92.3, 101.2, 105.1, 122.7, 125.2 (q, J = 278.4 Hz, 1H), 137.2, 143.3, 147.7, 178.7; 19F NMR (376 MHz, CDCl3): d = 61.9 (t, J = 10.4 Hz); IR (neat): 2891, 1705, 1181, 1249, 1140, 1036, 931, 723 cm1; HRMS (ESI): Calcd. for [C13H12F3NO3 + H]+: m/z = 288.0847, Found: 288.0849. 4.2.6. 1,3-Dimethyl-3-(2,2,2-trifluoroethyl)[4,5]methylenedioxyindolin-2-one (3e’) Colorless solid; 13.5 mg, 23%; 1H NMR (400 MHz, CDCl3): d = 1.44 (s, 3H), 2.75 (dq, J = 15.2, 10.4 Hz, 1H), 2.83 (dq, J = 15.2, 10.4 Hz, 1H), 3.19 (s, 3H), 5.95 (d, J = 1.4 Hz, 1H), 6.00 (d, J = 1.4 Hz, 1H), 6.28 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 23.6, 26.8, 39.6 (q, J = 27.9 Hz, 1H), 43.3 (br), 100.0, 101.8, 107.0, 111.7, 125.0 (q, J = 277.4 Hz, 1H), 138.0, 143.5, 144.4, 177.3; 19F NMR (376 MHz, CDCl3): d = 63.6 (t, J = 10.4 Hz); IR (neat): 2901, 1709, 1453, 1242, 1143, 1070, 1037, 765 cm1; HRMS (ESI): Calcd. for [C13H12F3NO3 + H] +: m/z = 288.0847, Found: 288.0846. 4.2.7. 5-Iodo-1,3-dimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3f) Colorless solid; 71.6 mg, 97%; 1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3H), 2.62 (dq, J = 15.2, 10.4 Hz, 1H), 2.82 (dq, J = 15.2, 10.4 Hz, 1H), 3.21 (s, 3H), 6.67 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.63 (d, J = 8.3, 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 24.9, 26.4, 40.5 (q, J = 28.9 Hz), 44.3 (br), 85.0, 110.5, 125.0 (q, J = 278.4 Hz), 132.3, 133.3, 137.3, 142.6, 177.6; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2975, 1707, 1603, 1258, 1145, 1127, 1053, 805 cm1; HRMS (ESI): Calcd. for [C12H11F3NOI + H]+: m/z = 369.9916, Found: 369.9915. 4.2.8. 5-Bromo-1,3-dimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3 g) Colorless solid; 58.0 mg, 90%; 1H NMR (400 MHz, CDCl3): d = 1.41 (s, 3H), 2.62 (dq, J = 15.2, 10.4 Hz, 1H), 2.83 (dq, J = 15.2, 10.4 Hz, 1H), 3.22 (s, 3H), 6.77 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 8.3, 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 24.9, 26.5, 40.5 (q, J = 28.9 Hz), 44.5 (br), 109.9, 115.2, 125.0 (q, J = 277.4 Hz), 126.8, 131.4, 133.0, 141.9, 177.7; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2975, 1711, 1608, 1489, 1362, 1257, 1127, 1053 cm1; HRMS (ESI): Calcd. for [C12H11F3BrNO + Na] +: m/z = 343.9874, Found: 343.9873. 4.2.9. 5-Chloro-1,3-dimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3h) Colorless solid; 50.7 mg, 91%; 1H NMR (400 MHz, CDCl3): d = 1.41 (s, 3H), 2.63 (dq, J = 15.2, 10.4 Hz, 1H), 2.83 (dq, J = 15.2,

10.4 Hz, 1H), 3.23 (s, 3H), 6.81 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.3, 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 24.9, 26.5, 40.5 (q, J = 27.9 Hz), 44.5 (q, J = 1.9 Hz), 109.4, 124.0, 125.0 (q, J = 277.4 Hz), 128.0, 128.5, 132.0, 141.4, 177.9; 19F NMR (376 MHz, CDCl3): d = 61.9 (t, J = 10.4 Hz); IR (neat): 2981, 1718, 1492, 1261, 1364, 1186, 949, 772 cm1; HRMS (ESI): Calcd. for [C12H11F3ClNO + H] +: m/z = 278.0559, Found: 278.0562. 4.2.10. 5-Fluoro-1,3-dimethyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3i) Colorless oil; 49.6 mg, 95%; 1H NMR (400 MHz, CDCl3): d = 1.41 (s, 3H), 2.63 (dq, J = 15.2, 10.4 Hz, 1H), 2.83 (dq, J = 15.2, 10.4 Hz, 1H), 3.23 (s, 3H), 6.79–6.82 (m, 1H), 6.99–7.04 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 24.8, 26.5, 40.5 (q, J = 27.9 Hz), 44.7 (br), 108.9 (d, J = 7.7 Hz), 111.7 (d, J = 25.0 Hz), 114.8 (d, J = 24.1 Hz), 125.1 (q, J = 277.4 Hz), 132.6 (d, J = 7.7 Hz), 138.7, 159.2 (d, J = 240.8 Hz), 178.0; 19F NMR (376 MHz, CDCl3): d = 120.3 to 120.2 (m), 61.9 (t, J = 10.4 Hz); IR (neat): 2978, 1709, 1495, 1472, 1364, 1259, 1243, 1144, 1116, 1077, 771 cm1; HRMS (ESI): Calcd. for [C12H11F4NO + Na] +: m/z = 284.0674, Found: 284.0670. 4.2.11. 5-Bromo-7-chloro-1,3-dimethyl-3-(2,2,2trifluoroethyl)indolin-2-one (3j) Colorless solid; 59.2 mg, 83%; 1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3H), 2.61 (dq, J = 15.2, 10.4 Hz, 1H), 2.86 (dq, J = 15.2, 10.4 Hz, 1H), 3.58 (s, 3H), 7.25 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 25.3, 29.8, 40.7 (q, J = 28.9 Hz), 44.3 (q, J = 1.9 Hz), 115.0, 116.6, 124.8, 125.3 (q, J = 278.4 Hz), 133.1, 135.2, 138.1, 178.0; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2982, 1718, 1464, 1245, 1219, 1144, 1059, 771 cm1; HRMS (ESI): Calcd. for [C12H10F3ClBrNO + Na] +: m/ z = 377.9484, Found: 377.9494. 4.2.12. 1,3-Dimethyl-2-oxo-3-(2,2,2-trifluoroethyl)indoline-5carbonitrile (3k) Colorless solid; 20.3 mg, 38%; 1H NMR (400 MHz, CDCl3): d = 1.44 (s, 3H), 2.68 (dq, J = 15.2, 10.4 Hz, 1H), 2.88 (dq, J = 15.2, 10.4 Hz, 1H), 3.28 (s, 3H), 6.97 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 8.3, 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 24.8, 26.7, 40.5 (q, J = 28.9 Hz), 44.1 (q, J = 1.9 Hz), 105.9, 109.0, 118.9, 124.8 (q, J = 277.4 Hz), 127.0, 131.9, 133.9, 146.7, 178.1; 19F NMR (376 MHz, CDCl3): d = 61.9 (t, J = 10.4 Hz); IR (neat): 2982, 2360, 2224, 1725, 1615, 1498, 1367, 1258, 1178, 1127, 770 cm1; HRMS (ESI): Calcd. for [C13H11F3N2O + Na] +: m/z = 291.0721, Found: 291.0715. 4.2.13. Ethyl 1,3-dimethyl-2-oxo-3-(2,2,2-trifluoroethyl)indoline-5carboxylate (3l) Colorless solid; 54.9 mg, 87%; 1H NMR (400 MHz, CDCl3): d = 1.39–1.44 (m, 6H), 2.71 (dq, J = 15.2, 10.4 Hz, 1H), 2.88 (dq, J = 15.2, 10.4 Hz, 1H) 3.28 (s, 3H), 4.38 (q, J = 7.3 Hz, 2H) 6.92 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 8.09 (dd, J = 8.3, 1.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d = 14.3, 25.0, 26.6, 40.6 (q, J = 28.9 Hz), 44.1 (q, J = 1.9 Hz), 60.9, 107.9, 124.7, 125.0 (q, J = 278.4 Hz), 125.0, 130.9, 131.1, 146.8, 166.2, 178.6; 19F NMR (376 MHz, CDCl3): d = 62.0 (t, J = 10.4 Hz); IR (neat): 2980, 1700, 1617, 1363, 1240, 1132, 1078, 766 cm1; HRMS (ESI): Calcd. for [C15H16F3NO3 + Na]+: m/z = 338.0980 Found: 338.0976. Yellowish oil; 51.1 mg, 95%; 1H NMR (400 MHz, CDCl3): d = 1.42 (s, 3H), 1.98–2.04 (m, 2H), 2.59–2.84 (m, 4H), 3.71–3.74 (m, 2H), 6.95–7.00 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H); 13 C NMR (100 MHz, CDCl3): d = 21.0, 24.5, 24.5, 39.0, 40.4 (q, J = 27.9 Hz), 45.6 (q, J = 1.9 Hz), 120.4, 121.4, 122.0, 125.4 (q, J = 277.4 Hz), 127.2, 129.6, 138.6, 177.3; 19F NMR (376 MHz, CDCl3): d = 61.7 (t, J = 10.4 Hz); IR (neat): 2937, 1706, 1627, 1482, 1387, 1355, 1259, 1241, 1170, 1140, 749 cm1; HRMS (ESI): Calcd. for [C12H11F4NO + Na]+: m/z = 292.0925, Found: 292.0923.

H. Egami et al. / Journal of Fluorine Chemistry 152 (2013) 51–55

4.2.14. 3-Methyl-1-phenyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3n) Colorless solid; 58.0 mg, 95%; 1H NMR (400 MHz, CDCl3): d = 1.53 (s, 3H), 2.72 (dq, J = 15.2, 10.4 Hz, 1H), 2.97 (dq, J = 15.2, 10.4 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 7.12 (td, J = 7.3, 0.9 Hz, 1H), 7.23 (td, J = 7.8, 0.9 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.38–7.44 (m, 3H), 7.51–7.55 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 25.4, 41.0 (q, J = 27.9 Hz), 44.5 (q, J = 1.9 Hz), 109.7, 123.0, 123.7, 125.3 (q, J = 277.4 Hz), 126.6, 128.2, 128.4, 129.6, 130.6, 134.3, 142.9, 177.9; 19F NMR (376 MHz, CDCl3): d = 61.8 (t, J = 10.4 Hz); IR (neat): 2975, 1718, 1609, 1493, 1484, 1467, 1386, 1376, 1259, 1210, 769 cm1; HRMS (ESI): Calcd. for [C17H14F3NO + Na]+: m/z = 328.0925, Found: 328.0934.

[2]

[3]

[4] [5]

4.2.15. 1-Methyl-3-phenyl-3-(2,2,2-trifluoroethyl)indolin-2-one (3o) Colorless oil; 57.2 mg, 94%; 1H NMR (400 MHz, CDCl3): d = 3.04 (dq, J = 15.2, 10.4 Hz, 1H), 3.21 (s, 3H), 3.43 (dq, J = 15.2, 10.4 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.16 (td, J = 8.3, 0.9 Hz, 1H), 7.24–7.40 (m, 7H); 13C NMR (100 MHz, CDCl3): d = 26.6, 40.8 (q, J = 28.9 Hz), 51.9 (q, J = 1.9 Hz), 108.7, 122.6, 125.0 (q, J = 278.4 Hz), 126.0, 126.4, 127.9, 128.7, 128.8, 129.0, 138.6, 143.7, 176.6; 19F NMR (376 MHz, CDCl3): d = 61.0 (t, J = 10.4 Hz); IR (neat): 3059, 1713, 1612, 1494, 1471, 1368, 1348, 1255, 1118, 751 cm1; HRMS (ESI): Calcd. for [C13H14F3NO2 + H] +: m/z = 274.1055 Found: 274.1055. 4.2.16. 3-(Methoxymethyl)-1-methyl-3-(2,2,2-trifluoroethyl)indolin2-one (3p) Colorless solid; 50.6 mg, 93%; 1H NMR (400 MHz, CDCl3): d = 2.80 (dq, J = 15.2, 10.4 Hz, 1H), 2.94 (dq, J = 15.2, 10.4 Hz, 1H), 3.23 (s, 3H), 3.27 (s, 3H), 3.37 (d, J = 8.7 Hz, 1H), 3.61 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 7.06–7.10 (m, 1H), 7.31–7.38 (m, 2H); 13 C NMR (100 MHz, CDCl3): d = 26.4, 36.6 (q, J = 28.9 Hz), 49.5 (br), 59.5, 76.4, 108.2, 122.4, 124.9, 125.5 (q, J = 277.4 Hz), 128.1, 128.7, 143.4, 175.8; 19F NMR (376 MHz, CDCl3): d = 61.3 (t, J = 10.4 Hz); IR (neat): 2823, 1717, 1612, 1473, 1351, 1262, 1135, 1119, 1107, 757 cm1; HRMS (ESI): Calcd. for [C12H11F4NO + Na] +: m/z = 284.0674, Found: 284.0670. 4.2.17. 1-Methyl-3-phthalimidylmethyl-3-(2,2,2trifluoroethyl)indolin-2-one (3q) Colorless solid; 65.3 mg, 84%; 1H NMR (400 MHz, CDCl3): d = 2.99 (dq, J = 15.2, 10.4 Hz, 1H), 3.09 (dq, J = 15.2, 10.4 Hz, 1H), 3.25 (s, 3H), 3.88 (d, J = 14.2 Hz, 1H), 4.01 (d, J = 14.2 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 7.02–7.06 (m, 1H), 7.23 (d, J = 7.3 Hz, 1H),7.30– 7.34 (m, 1H), 7.71–7.75 (m, 2H), 7.82–7.86 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 26.6, 38.0 (q, J = 28.9 Hz), 44.0, 48.3 (q, J = 1.9 Hz), 108.7, 122.4, 123.6, 124.3, 125.0 (q, J = 278.4 Hz), 126.6, 129.3, 131.5, 134.2, 143.4, 168.0, 175.5; 19F NMR (376 MHz, CDCl3): d = 61.4 (t, J = 10.4 Hz); IR (neat): 2939, 1717, 1614, 1471, 1396, 1378, 1143, 771 cm1; HRMS (ESI): Calcd. for [C12H11F4NO + Na] +: m/z = 411.0933, Found: 411.0920.

[6]

[7]

[8] [9]

[10]

[11]

Acknowledgments This work was supported in part by a Grant-in-aid for Young Scientists (B) from MEXT (23750116) and by funding from RIKEN.

[12] [13]

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