Synthesis of tertiary alkyl fluorides and chlorides by site-selective nucleophilic ring-opening reaction of α-aryl azetidinium salts

Abstract

Site-selective nucleophilic ring-opening reactions of 2-arylazetidine-2-carboxylic acid ester-derived tetraalkyl ammonium salts 2 with tetrabutylammonium halides (Bu₄NX) to give tertiary alkyl halides are successfully demonstrated. For example, a nucleophilic ring-opening reaction of 2-(o-tolyl) derivative 2a with 1.2 equivalents of tetrabutylammonium fluoride (Bu₄NF) in THF at 60 °C preferentially proceeded at a more substituted carbon atom (2-position) compared to a less-substituted carbon atom (4-position) and afforded tert-butyl 4-(dimethylamino)-2-fluoro-2-(o-tolyl)butanoate 3aa in 71% yield as the corresponding tertiary alkyl fluoride. This result was applied to synthesize optically active organofluorine compounds starting from commercially available (R)-1-phenylethylamine.

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Introduction

Ring-strained four-membered N-heterocycle azetidines are valuable building blocks in organic synthesis. Although they are chemically stable without any additives, nucleophilic ring-opening reactions proceed to give various types of functionalized nitrogen-containing compounds by electrophilic activation of the nitrogen atom by N-quaternization,^1,2 or addition of Brønsted acid (H⁺)³ or Lewis acids⁴ (Scheme 1).⁵ These transformations are applicable for the synthesis of amino acids, alkaloids, and biologically active drugs.

Scheme 1 Nucleophilic ring-opening of azetidine derivatives.

The initial studies of this ring-opening reaction were mainly performed by Couty's group using tetraalkylazetidinium salts as substrates.¹ One point to consider in this reaction is site-selectivity at the 2- and 4-positions, which reacts with a nucleophile (Nu). In many cases, a less-substituted and/or electron-deficient carbon atom is attacked by a nucleophile because of the S_N2 process. For example, a reaction of a substrate with a nucleophile in Scheme 1 proceeded at the 4-position preferentially to afford the corresponding product. However, some nucleophiles do not act according to this tendency, and the reaction occurs at the 2-position, which is a much-substituted carbon atom. Although these phenomena are currently difficult to explain, the site selectivity at the 2- and 4-positions can be determined based on the properties of nucleophiles, substituents at the 2- and 4-positions, and reaction conditions.^1d,g,h Previously, our group reported that the site-selective nucleophilic ring-opening reaction of α-arylazetidine-2-carboxylic acid ester-derived tetraalkylammonium salt (S)-2b prepared from 95% ee of (S)-1b (Scheme 2, Our previous work).⁶ Cesium acetate (AcOCs) and dimethylamine (Me₂NH) as nucleophiles reacted at the 4-position. In contrast, sodium azide (NaN₃) reacted at the 2-position with inversion of the configuration. This result shows that the S_N2 substitution at the tertiary carbon atom (2-position) proceeded.⁷ With the results, our group started to further investigate the scope of this reaction, since some nucleophiles such as fluoride (F⁻) provide valuable compounds. Furthermore, previous examples of the ring-opening reaction of azetidine derivatives with F⁻ to give organofluorine compounds are rare^2a,8 compared to the reaction of three-membered N-heterocycle aziridine derivatives.⁹ Herein, we wish to report the site-selective nucleophilic ring-opening reaction of α-aryl azetidinium salts 2 with halides to afford α-aryl-α-halo-carboxylic acid esters 3 (Scheme 2, this work). Further synthetic applications of the resulting products 3, e.g., asymmetric synthesis of organofluorine compounds, are also demonstrated.

Scheme 2 Nucleophilic ring-opening of α-arylazetidine-2-carboxylic acid ester-derived tetraalkylammonium salts 2.

Results and discussion

We started investigating the nucleophilic ring-opening reaction of 2a with a halide source (Table 1). First, the reaction of 2a with sodium fluoride (NaF) as an F⁻ source in DMF at room temperature for 2 h was examined to obtain the corresponding organofluorine compounds 3aa and 4aa; however, no products were obtained (entry 1). Although a reaction with potassium fluoride (KF) gave the same result (entry 2), the use of cesium fluoride (CsF) afforded 3aa in 13% yield (entry 3). We expected that tetrabutylammonium fluoride (Bu₄NF) might be more reactive, and its solubility in organic solvents would improve the yields of 3aa and 4aa. In addition, Ghorai et al. reported the Lewis acid-promoted nucleophilic ring-opening reaction of N-tosylazetidines with tetrabutylammonium chloride (Bu₄NCl) and bromide (Bu₄NBr).¹⁰ Thus, we attempted a reaction with a THF solution of Bu₄NF, and the desired 3aa was obtained in 33% yield with trace amounts of 4aa (<4% yield) (entry 4). The use of THF as a solvent and other F⁻ sources, such as Bu₄NF·3H₂O, did not show any improvements (entries 5 and 6). We found that the yield of 3aa could be improved to 71% with minimization of the formation of 4aa (7% yield) when the reaction was performed at 60 °C (entry 7).

Table 1 Nucleophilic ring-opening of α-aryl azetidinium salt 2a with various salts

Entry	MX (equiv.)	Solvent	Temp., time	3^a (%)	4^a (%)
a Isolated yield.
1	NaF (5)	DMF	rt, 2 h	0	0
2	KF (5)	DMF	rt, 2 h	0	0
3	CsF (5)	DMF	rt, 2 h	13	0
4	Bu4NF in THF (1.2)	DMF	rt, 2 h	33	<4
5	Bu4NF in THF (1.2)	THF	rt, 2 h	35	2
6	Bu4NF·3H2O (1.2)	THF	rt, 2 h	41	<3
7	Bu4NF in THF (1.2)	THF	60 °C, 1 h	71	7
8	Bu4NCl (1.2)	DMF	rt, 2 h	74	14
9	Bu4NCl (1.2)	THF	rt, 2 h	76	23
10	Bu4NCl (1.2)	CH2Cl2	rt, 2 h	69	14
11	Bu4NCl (1.2)	THF	0 °C, 2 h	34	10
12	Bu4NCl (1.2)	THF	60 °C, 2 h	70	27
13	Bu4NBr (1.2)	THF	rt, 1 h	61	21
14	Bu4NI (1.2)	THF	rt, 1 h	0	0
15	KCN (5)	DMF	rt, 2 h	42	55
16	Bu4NCN (1.2)	THF	rt, 2 h	38	62

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Next, we examined the same reaction with other tetrabutylammonium salts (Bu₄NX) to define the scope of this site-selective ring-opening reaction. Reactions with Bu₄NCl in THF, DMF and CH₂Cl₂ proceeded even at room temperature, and similar yields of 3ab (69–76% yields) and 4ab (14–23% yields) were observed (entries 8–10). At 0 °C, the yields of 3ab (34% yield) and 4ab (10% yield) decreased (entry 11). When the reaction was performed at 60 °C, the yield of undesired 4ab was slightly improved (27% yield) (entry 12). The use of Bu₄NBr is also applicable; however, the selectivity between 3ac (61% yield) and 4ac (21% yield) was insufficient (entry 13). Additionally, the resulting isolated bromo products 3ac and 4ac were unstable because of the self-N-quaternization. Therefore, a reaction with tetrabutylammonium iodide (Bu₄NI) did not give 3ad and 4ad (entry 14). Finally, we applied this reaction for pseudohalogen salts (MCN) to provide α-cyano derivative 3ae with an all-carbon quaternary stereocentre (entries 15 and 16). Unfortunately, both reactions with potassium cyanide (KCN) and tetrabutylammonium cyanide (Bu₄NCN) gave similar results to provide 3ae and 4ae without selectivities.¹¹

The ring-opening products 3 and 4 in Table 1 were assigned by NMR analyses, and their representative results are shown in Fig. 1. Fluorine derivatives 3aa and 4aa were clearly identified by the ¹⁹F NMR analysis. Tertiary alkyl fluoride 3aa showed a chemical shift of −157 ppm. Primary alkyl fluoride 4aa showed a chemical shift of −222 ppm. These values are reasonable for the corresponding alkyl fluorides. In contrast, chlorine derivatives 3ab and 4ab did not show clear differences in ¹H and ¹³C NMR analyses. Consequently, we assigned these by comparison of ¹H NMR chemical shifts of methylene protons. Primary alkyl chloride 4ab had low-field chemical shifts due to an electron-withdrawing effect of chloride. One of the two products (3ab or 4ab) with chemical shifts of 3.27 and 2.98 ppm was assigned to 4ab. Another product was assigned to tertiary alkyl chloride 3ab, which showed chemical shifts of 2.73–2.33 ppm. Bromine derivatives 3ac and 4ac were assigned by analogy to 3ab and 4ab. Meanwhile, nitrile derivatives 3ae and 4ae could be clearly identified by ¹³C NMR analysis. 4ae showed a chemical shift of 12.1 ppm, which is a reasonable value as a primary nitrile.^1d

Fig. 1 Representative NMR chemical shifts for product assignments of 3 and 4.

To define the scope and limitations of this site-selective ring-opening reaction to produce tertiary alkyl halides 3, we prepared various azetidinium salts 2b–h and examined their reactions with Bu₄NF or Bu₄NCl under identical conditions (Table 2). First, we attempted the reactions of 5-substituted aryl derivatives 2a–e with Bu₄NF and obtained the corresponding organofluorine compounds 3ba–ea in moderate yields (entries 1–4). The minor products 4 were not isolated (N.D.), although their formations were observed by TLC analysis. The pure products of these organofluorine 4 for spectroscopic characterizations were difficult to isolate because of small amounts (ca. 5% yield). Electron-withdrawing substituents on the α-aryl substituent, such as bromo (2b) and trifluoromethyl (2c), might be desirable to yield 3 (entries 1 and 2, approximately 75%). Reactions of methyl (2d) and methoxy (2e) derivatives resulted in lower yields of 3 (entries 3 and 4, approximately 60%). Thus, we next examined the reactions of 4-bromo (2f) and 4-trifluoromethyl (2g) derivatives and obtained 3fa–ga in approximately 70% yields (entries 5 and 6). However, the reaction of 3-bromo derivative 2h was resulted in a 58% yield of 3ha (entry 7). The use of Bu₄NCl for the reactions of 2b, 2d, 2f, and 2h provided the corresponding organochlorine compounds 3bb–hb (entries 8–11) with a similar tendency to the reaction with Bu₄NF. In these cases, the minor products 4bb–hb could be isolated as a pure form to perform their spectroscopic characterizations.

Table 2 Substrate scope of the site-selective ring-opening of 2 with Bu₄NX

Entry	X	R		3^a (%)	4^a^,^b (%)
a Isolated yields.b N.D. = not determined.
1	F	5-Br	2b	77 (3ba)	N.D.
2	F	5-CF3	2c	75 (3ca)	N.D.
3	F	5-Me	2d	59 (3da)	N.D.
4	F	5-OMe	2e	61 (3ea)	N.D.
5	F	4-Br	2f	72 (3fa)	N.D.
6	F	4-CF3	2g	68 (3ga)	N.D.
7	F	3-Br	2h	58 (3ha)	N.D.
8	Cl	5-Br	2b	82 (3bb)	17 (4bb)
9	Cl	5-Me	2d	53 (3db)	19 (4db)
10	Cl	4-Br	2f	83 (3fb)	17 (4fb)
11	Cl	3-Br	2h	65 (3hb)	33 (4hb)

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We confirmed the chemical stability of products 3 and 4 (Scheme 3) because a transformation between 3 and 4 might proceed via the formation of ammonium salts generated from the alkyl halides and dimethylamino substituents as in the products (self-N-quaternization). A THF solution of tertiary alkyl halides 3aa (X = F) or 3ab (X = Cl) was subjected to the reaction temperature depicted in Table 1. The removal of THF by evaporation and ¹H NMR analysis of the residue did not show any formation of 4aa or 4ab, respectively (eqn (1)). Similarly, a stirring at room temperature of a THF solution of primary alkyl chloride 4ab did not afford 3ab (eqn (2)).

Scheme 3 Chemical stability of ring-opening products 3aa, 3ab and 4ab.

The N,N-dimethylamino substituent, as in product 3, is not synthetically valuable because of the impossibility of removing the N-methyl substituents. One N-methyl substituent could be changed into an N-allyl, which would be removable via Rh-catalysed isomerization, by N-quaternization of 1 with allyl triflate¹² (Scheme 4). For example, azetidinium salt 5 was prepared from 1b in 70% yield as an 8/2 mixture of diastereomers followed by ring-opening with Bu₄NF to provide N-allyl derivative 6 in 82% yield. Rh-catalyzed deallylation of 6 gave secondary amine 7 in 84% yield.

Scheme 4 Synthesis of N-allyl derivative 5 and 6 and deallylation into 7.

To demonstrate the utility of this ring-opening reaction, we attempted further synthetic transformations of organofluorine product 3aa. First, Hofmann elimination of 3aa to produce α-aryl-α-fluoro-α-vinylacetic acid ester 9 was examined (Scheme 5). N-Quaternization with iodomethane (MeI) or methyl trifluoromethanesulfonate (MeOTf) gave 8-I or 8-OTf in good yields (8-I: 91% yield, 8-OTf: quant.). Treatment of iodide salt 8-I with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in refluxing toluene for 1 day gave desired 9 in 36% yield. We expected that the iodide ion in the reaction mixture might cause undesirable side reactions such as nucleophilic substitutions, and the reaction resulted in a low yield. Thus, we examined the same reaction using triflate salt 8-OTf. As expected, the yield of 9 was improved to 57%.

Scheme 5 Synthesis of α-aryl-α-fluoro-α-vinylacetic acid ester 9 from 3aa by Hofmann elimination.

Next, the synthesis of optically active tertiary organofluorine compounds from chiral (R)-1-phenylethylamine, which is one of the least expensive chiral sources, was examined (Scheme 6). 93% ee of (S)-1a was prepared according to our previous work.^6,13 N-Quaternization of (S)-1a with MeOTf to prepare (S)-2a (quant.) followed by the ring-opening reaction with Bu₄NF under the conditions in Table 1 afforded (R)-3aa (68% yield). The ee of the obtained 3aa was determined after conversion into (R)-11 because of the low sensitivity of 3aa towards a UV/vis detector in chiral HPLC analysis. Reduction of (R)-3aa with LiAlH₄ to amino alcohol (R)-10 (73% yield) followed by O-benzoylation gave benzoate (R)-11 (95% yield). The ee of (R)-11 was determined to be 93% ee by the chiral HPLC analysis. No lack of the ee was confirmed during the transformations from (S)-1a into (R)-11. This result indicates that the Bu₄NF-promoted ring-opening reaction of (S)-2a affording (R)-3aa proceeds by inverting the tertiary carbon configuration (S_N2) in the same manner as the reaction of (S)-2b with NaN₃, which was previously reported by our group.⁶ Therefore, the absolute configuration of 3aa was determined to be (R).

Scheme 6 Synthesis of optically active organofluorine compound (R)-3aa starting from (R)-1-phenylethylamine.

To clarify that the α-aryl substituent as in 2 is necessary for this site-selective ring-opening reaction to produce 3, we investigated a reaction α-ethyl derivative 12 with Bu₄NF (Scheme 7). As expected, the reaction proceeded at 4-position preferentially to give γ-fluoro product 14 in 62% yield. Identifiable amount of the corresponding α-fluoro product 13 was not obtained. Instead, α-hydroxy derivative 15, which might be derived from 13, was isolated in 7% yield.

Scheme 7 Nucleophilic ring-opening of α-ethyl azetidinium salt 12 with Bu₄NF.

Couty's group described in the previous literature^1d that the nucleophilic ring-opening of α,α-disubstituted azetidinium ions at the quaternary α-carbon (2-position) is intrinsically favoured. Steric repulsions generated by substituents as in the azetidine ring affect the site-selectivity. The highly nucleophilic azide anion (N₃⁻) reacts at 2-position, the less nucleophilic cyanide anion (CN⁻) reacts at 2- and 4-positions, and the poor nucleophilic acetate anion (AcO⁻) reacts at 4-position. The exact reason of the site-selective ring-opening reaction to produce 3 demonstrated by our group are difficult to explain at present, a size of the nucleophiles might affect the site-selectivity. F⁻ and Cl⁻ are small and enable to react at the quaternary α-carbon (2-position) although they are poor nucleophilic anion. Further experimental studies are needed to discuss.

Conclusions

In conclusion, we described that the site-selective nucleophilic ring-opening reaction of 2-arylazetidine-2-carboxylic acid ester-derived ammonium salts 2 with Bu₄NF or Bu₄NCl proceeded at a much-substituted 2-position preferentially over a less-substituted 4-position and produced the corresponding tertiary alkyl fluorides and chlorides 3. Our result is a rare successful example of the fluoride ion-promoted ring-opening reaction of azetidine derivatives that yields organofluorine compounds. Further synthetic transformations of the product 3 were also successfully demonstrated. Our protocol enables the production of optically active organofluorine compound (R)-3aa starting from commercially available chiral (R)-1-phenylethylamine, which is an inexpensive chiral compound.

Experimental

General

Specific rotations were recorded on a JASCO polarimeter P-1010. Normal phase chiral HPLC analyses were performed using a JASCO HPLC pump (PU-2089) and a UV/vis detector (UV-2075). Infrared spectra (IR) were recorded on a JASCO FT/IR-4600 spectrometer. ¹H, ¹³C and ¹⁹F NMR spectra were measured on a Varian (¹H: 400 MHz, ¹³C: 101 MHz, ¹⁹F: 376 MHz) or a Bruker (¹H: 400 MHz, ¹³C: 101 MHz) spectrometer. ¹⁹F NMR analysis were performed for representative products. As an internal standard in CDCl₃, Me₄Si (δ 0 ppm) for ¹H NMR and CDCl₃ (δ 77.00 ppm) for ¹³C NMR were used. As an internal standard in acetone-d₆, the residual protons (δ 2.05 ppm) for ¹H NMR and acetone-d₆ (δ 29.92 ppm) for ¹³C NMR were used. In ¹⁹F NMR, hexafluorobenzene (C₆F₆) was used as an internal standard (δ −162.9 ppm). In ¹H and ¹³C NMR, the splitting patterns are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad peak. In ¹⁹F NMR, the splitting patterns are not denoted. High-resolution mass spectra (ESI) were measured on a Thermo Fisher Scientific LC/FT-MS spectrometer. Reactions involving air- or moisture-sensitive compounds were conducted in appropriate round-bottomed flasks with a magnetic stirring bar under an argon (Ar) atmosphere. A 1 M tetrabutylammonium fluoride (Bu₄NF) THF solution was purchased from Tokyo Chemical Industry Co., Ltd. (TCI). Anhydrous tetrahydrofuran (THF) was purchased from KANTO Chemical Co., Inc. For the thin layer chromatography (TLC) analysis throughout this work, Silicagel 70 TLC Plate-Wako purchased from FUJIFILM Wako Chemical Corporation was used. The products were purified by column chromatography on silica gel (Wakosil 60, 64–210 μm) purchased from FUJIFILM Wako Chemical Corporation. For strong basic compound such as (S)-10, NH TLC plates and amino-functionalized silica gel (Chromatorex NH-DM1020) purchased from Fuji Silysia Chemical Ltd. (Japan) were used.

Representative procedure for ring-opening of 2a with Bu₄NF in THF to afford 3aa and 4aa (Table 1, entry 7)

A solution of 2-(tert-butoxycarbonyl)-1,1-dimethyl-2-(o-tolyl)azetidin-1-ium trifluoromethanesulfonate (2a) (62.3 mg, 0.146 mmol) in THF (0.55 mL) was stirred at 60 °C under an Ar atmosphere and treated with a 1 M Bu₄NF THF solution (175 μL, 0.175 mmol). After stirring for 1 h at 60 °C, the resulting mixture was cooled to room temperature and diluted with H₂O. The mixture was extracted with cyclohexane and the combined extracts were washed with H₂O. The organic solution was dried over Na₂SO₄ and concentrated by evaporation. The residue was purified by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 10/1 as the eluent, R_f: 3aa < 4aa) to obtain tert-butyl 4-(dimethylamino)-2-fluoro-2-(o-tolyl)butanoate (3aa) (30.7 mg, 71% yield) as a colourless oil and tert-butyl 2-(dimethylamino)-4-fluoro-2-(o-tolyl)butanoate (4aa) (3.1 mg, 7% yield) as a colourless oil. 3aa: IR (ATR) ν_max/cm⁻¹ 3063, 2976, 2938, 2862, 2818, 2766, 1748, 1731, 1459, 1392, 1368, 1281, 1250, 1148, 1091, 1064, 1042, 988, 965, 939, 844, 749; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (1H, ddd, J = 7.6, 1.4, 1.4 Hz, ArH), 7.26–7.12 (3H, m, ArH), 2.68–2.37 (4H, m, CH₂), 2.43 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 2.28 (6H, s, N(CH₃)₂), 1.42 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.2 (d, ²J_FC = 27 Hz), 136.8 (d, ³J_FC = 2 Hz), 136.1 (d, ²J_FC = 21 Hz), 132.1 (d, J_FC = 1 Hz), 128.5, 126.1 (d, ³J_FC = 7 Hz), 125.6, 96.5 (d, ¹J_FC = 188 Hz), 82.6, 53.7 (d, ³J_FC = 5 Hz), 45.5, 34.7 (d, ²J_FC = 22 Hz), 27.7, 20.7 (d, ⁴J_FC = 7 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −157; HRMS (ESI): calcd for C₁₇H₂₇FNO₂ [M + H]⁺ 296.2020, found 296.2016. 4aa: IR (ATR) ν_max/cm⁻¹ 3061, 2978, 2930, 2874, 2837, 2796, 1713, 1474, 1456, 1392, 1366, 1305, 1289, 1240, 1207, 1153, 1130, 1080, 1049, 1011, 986, 950, 883, 844, 814, 782, 749; ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.37 (1H, m, ArH), 7.18–7.08 (3H, m, ArH), 4.24 (1H, dddd, ²J_FH = 47.2 Hz, J = 9.4, 9.2, 5.4 Hz, 4H), 4.06 (1H, dddd, ²J_FH = 46.8 Hz, J = 9.6, 9.2, 5.6 Hz, 4H), 2.66 (1H, dddd, ³J_FH = 15.3 Hz, J = 14.2, 9.6, 5.4 Hz, 3H), 2.42–2.24 (1H, m, 3H), 2.36 (6H, s, N(CH₃)₂), 2.35 (3H, s, ArCH₃), 1.54 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.5, 137.8, 136.2, 132.2, 128.1, 127.0, 124.9, 81.9, 81.5 (d, ¹J_FC = 161 Hz), 71.4 (d, ³J_FC = 11 Hz), 40.0, 34.5 (d, ²J_FC = 21 Hz), 28.5, 21.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −222; HRMS (ESI): calcd for C₁₇H₂₇FNO₂ [M + H]⁺ 296.2020, found 296.2013.

Representative procedure for ring-opening of 2a with Bu₄NCl in THF to afford 3ab and 4ab (Table 1, entry 9)

Bu₄NCl (230 mg, 0.828 mmol) was added to a solution of 2a (293 mg, 0.689 mmol) in THF (3.6 mL) at room temperature and the mixture was degassed under reduced pressure and filled with an Ar. After stirring for 2 h, the resulting mixture was diluted with H₂O. The mixture was extracted with n-hexane/EtOAc = 3/1 mixed solvent and the combined extracts were washed with H₂O. The organic solution was dried over Na₂SO₄ and concentrated by evaporation. The residue was purified by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent, R_f: 3ab < 4ab) to obtain tert-butyl 2-chloro-4-(dimethylamino)-2-(o-tolyl)butanoate (3ab) (163 mg, 76% yield) as a pale yellow oil and tert-butyl 4-chloro-2-(dimethylamino)-2-(o-tolyl)butanoate (4ab) (49.8 mg, 23% yield) as a colourless oil. 3ab: IR (ATR) ν_max/cm⁻¹ 3062, 2976, 2939, 2861, 2818, 2766, 1732, 1458, 1392, 1368, 1254, 1145, 1080, 1028, 967, 934, 898, 843, 752, 722, 694; ¹H NMR (400 MHz, CDCl₃) δ 7.60 (1H, dd, J = 7.0, 1.8 Hz, ArH), 7.26–7.13 (3H, m, ArH), 2.73–2.50 (2H, m, CH₂), 2.45–2.33 (2H, m, CH₂), 2.35 (3H, s, ArCH₃), 2.24 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.2, 138.1, 135.9, 132.0, 128.1, 126.2, 125.7, 83.0, 73.7, 55.1, 45.7, 38.0, 27.6, 20.5; HRMS (ESI): calcd for C₁₇H₂₇ClNO₂ [M + H]⁺ 312.1725, found 312.1715. 4ab: IR (ATR) ν_max/cm⁻¹ 3060, 2977, 2931, 2872, 2836, 2795, 1712, 1479, 1454, 1392, 1366, 1336, 1294, 1230, 1151, 1081, 1046, 981, 961, 893, 843, 821, 774, 755, 725; ¹H NMR (400 MHz, CDCl₃) δ 7.41 (1H, d, J = 6.8 Hz, ArH), 7.19–7.09 (3H, m, ArH), 3.27 (1H, ddd, J = 12.0, 10.9, 4.3 Hz, 4H), 2.98 (1H, ddd, J = 12.1, 10.9, 5.2 Hz, 4H), 2.67 (1H, ddd, J = 13.9, 12.1, 4.3 Hz, 3H), 2.35 (6H, s, N(CH₃)₂), 2.33 (3H, S, ArCH₃), 2.31 (1H, ddd, J = 13.9, 12.0, 5.2 Hz, 3H), 1.54 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.3, 137.4, 136.1, 132.3, 128.3, 127.0, 124.9, 82.0, 72.3, 40.8, 40.0, 37.7, 28.5, 21.1; HRMS (ESI): calcd for C₁₇H₂₇ClNO₂ [M + H]⁺ 312.1725, found 312.1719.

Ring-opening of 2a with Bu₄NBr in THF to afford 3ac and 4ac (Table 1, entry 13)

The procedure was similar to the synthesis of 3ab and 4ab. The reaction was performed at room temperature for 1 h using 2a (67.2 mg, 0.158 mmol) as a substrate. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent, R_f: 3ac < 4ac) gave tert-butyl 2-bromo-4-(dimethylamino)-2-(o-tolyl)butanoate (3ac) (34.1 mg, 61% yield) as a colourless oil and tert-butyl 4-bromo-2-(dimethylamino)-2-(o-tolyl)butanoate (4ac) (12.1 mg, 21% yield) as a colourless oil. 3ac: IR (ATR) ν_max/cm⁻¹ 3062, 2975, 2938, 2860, 2818, 2765, 1726, 1681, 1457, 1392, 1367, 1252, 1144, 1078, 1040, 1028, 965, 889, 843, 791, 751, 721, 689; ¹H NMR (400 MHz, CDCl₃) δ 7.68–7.61 (1H, m, ArH), 7.24–7.10 (3H, m, ArH), 2.72 (1H, ddd, J = 14.0, 11.0, 4.8 Hz, CH₂), 2.64 (1H, ddd, J = 14.0, 10.8, 4.8 Hz, CH₂), 2.44 (1H, ddd, J = 12.0, 10.8, 4.8 Hz, CH₂), 2.38–2.28 (1H, m, CH₂), 2.33 (3H, s, ArCH₃), 2.25 (6H, s, N(CH₃)₂), 1.45 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.3, 138.0, 135.4, 131.9, 128.2, 127.8, 125.8, 83.0, 69.2, 56.2, 45.6, 38.7, 27.5, 20.7; HRMS (ESI): calcd for C₁₇H₂₇BrNO₂ [M + H]⁺ 356.1220, found 356.1218. 4ac: IR (ATR) ν_max/cm⁻¹ 3060, 2977, 2931, 2872, 2835, 2795, 1712, 1476, 1455, 1392, 1367, 1328, 1292, 1249, 1238, 1212, 1151, 1108, 1077, 1045, 1007, 979, 957, 892, 843, 819, 754; ¹H NMR (400 MHz, CDCl₃) δ 7.41 (1H, d, J = 7.2 Hz, ArH), 7.19–7.09 (3H, m, ArH), 3.11 (1H, ddd, J = 12.7, 9.0, 3.6 Hz, 4H), 2.84 (1H, ddd, J = 13.1, 9.0, 4.1 Hz, 4H), 2.75 (1H, ddd, J = 13.1, 12.8, 3.6 Hz, 3H), 2.39 (1H, ddd, J = 12.8, 12.7, 4.1 Hz, 3H), 2.35 (6H, s, N(CH₃)₂), 2.33 (3H, s, ArCH₃), 1.54 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.2, 137.3, 136.1, 132.3, 128.5, 127.0, 124.9, 82.0, 73.2, 40.0, 38.2, 28.9, 28.4, 21.1; HRMS (ESI): calcd for C₁₇H₂₇BrNO₂ [M + H]⁺ 356.1220, found 356.1217.

Ring-opening of 2a with KCN in DMF to afford 3ae and 4ae (Table 1, entry 15)

KCN (50.5 mg, 0.775 mmol) was added to a solution of 2a (67.0 mg, 0.157 mmol) in DMF (0.8 mL) at room temperature. The mixture was degassed under reduced pressure and filled with Ar. After stirring for 2 h under an Ar atmosphere, the resulting mixture was diluted with H₂O and extracted with n-hexane/EtOAc = 3/1 mixed solvent. The combined extracts were washed with brine, dried over Na₂SO₄, and concentrated by evaporation. Purification of the residue by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 10/1 as the eluent, R_f: 3ae < 4ae) to obtain tert-butyl 2-cyano-4-(dimethylamino)-2-(o-tolyl)butanoate (3ae) (20.1 mg, 42% yield) as pale yellow crystals and tert-butyl 4-cyano-2-(dimethylamino)-2-(o-tolyl)butanoate (4ae) (26.3 mg, 55% yield) as a colourless crystals. 3ae: mp 29–31 °C; IR (ATR) ν_max/cm⁻¹ 3065, 2977, 2941, 2863, 2820, 2769, 2240, 1734, 1459, 1393, 1369, 1244, 1147, 1098, 1041, 969, 936, 838, 753, 730; ¹H NMR (400 MHz, CDCl₃) δ 7.40 (1H, dd, J = 7.8, 1.8 Hz, ArH), 7.30–7.19 (3H, m, ArH), 2.65–2.50 (3H, m, CH₂), 2.48 (3H, s, ArCH₃), 2.40 (1H, ddd, J = 11.4, 8.6, 4.4 Hz, CH₂), 1.47 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.7, 136.4, 133.1, 132.3, 128.5, 126.5, 126.4, 118.5, 84.2, 55.4, 51.6, 45.5, 33.9, 27.5, 20.3; HRMS (ESI): calcd for C₁₈H₂₇N₂O₂ [M + H]⁺ 303.2067, found 303.2057. 4ae: mp 31–33 °C; IR (ATR) ν_max/cm⁻¹ 3061, 2977, 2933, 2875, 2837, 2796, 2246, 1708, 1475, 1455, 1441, 1392, 1367, 1234, 1151, 1083, 1041, 1028, 987, 968, 915, 873, 842, 813, 756; ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.36 (1H, m, ArH), 7.21–7.11 (3H, m, ArH), 2.64–2.53 (1H, m, CH₂), 2.34 (6H, s, N(CH₃)₂), 2.32 (3H, s, ArCH₃), 2.20–2.07 (2H, m, CH₂), 1.92–1.75 (1H, m, CH₂), 1.54 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.0, 136.6, 135.9, 132.5, 128.6, 127.4, 125.0, 120.1, 82.3, 71.7, 40.0, 30.3, 28.4, 21.0, 12.1; HRMS (ESI): calcd for C₁₈H₂₇N₂O₂ [M + H]⁺ 303.2067, found 303.2058.

tert-Butyl 2-(5-bromo-2-methylphenyl)-4-(dimethylamino)-2-fluorobutanoate (3ba) (Table 2, entry 1)

Obtained from 2b (76.0 mg, 0.151 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3ba (43.3 mg, 77% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 2976, 2938, 2861, 2818, 2767, 1749, 1731, 1592, 1565, 1481, 1459, 1391, 1368, 1283, 1251, 1218, 1149, 1114, 1092, 1041, 989, 969, 944, 876, 842, 809, 769, 738, 704; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (1H, dd, J = 1.8, 1.8 Hz, ArH), 7.35 (1H, dd, J = 8.0, 1.8 Hz, ArH), 7.03 (1H, d, J = 8.0 Hz, ArH), 2.73–2.30 (4H, m, CH₂), 2.37 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 2.27 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.4 (d, ²J_FC = 27 Hz), 138.3 (d, ²J_FC = 21 Hz), 135.5 (d, ³J_FC = 2 Hz), 133.7, 131.4, 129.1 (d, ³J_FC = 9 Hz), 119.3, 95.8 (d, ¹J_FC = 190 Hz), 83.1, 53.4 (d, ³J_FC = 5 Hz), 45.4, 34.4 (d, ²J_FC = 22 Hz), 27.7, 20.2 (d, ⁴J_FC = 7 Hz); HRMS (ESI): calcd for C₁₇H₂₆BrFNO₂ [M + H]⁺ 374.1125, found 374.1124.

tert-Butyl 4-(dimethylamino)-2-fluoro-2-(2-methyl-5-(trifluoromethyl)phenyl)butanoate (3ca) (Table 2, entry 2)

Obtained from 2c (167 mg, 0.338 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3ca (92.2 mg, 75% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 2979, 2942, 2864, 2821, 2769, 1752, 1732, 1621, 1460, 1393, 1370, 1331, 1286, 1252, 1151, 1120, 1091, 1040, 1006, 990, 976, 948, 896, 842, 829, 771, 748, 721; ¹H NMR (400 MHz, CDCl₃) δ 7.66 (1H, s, ArH), 7.49 (1H, d, J = 8.0 Hz, ArH), 7.29 (1H, d, J = 8.0 Hz, ArH), 2.78–2.31 (4H, m, CH₂), 2.49 (3H, d, ⁵J_FH = 3.2 Hz, ArCH₃), 2.28 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.4 (d, ²J_FC = 27 Hz), 140.9 (d, ³J_FC = 2 Hz), 137.2 (d, ²J_FC = 22 Hz), 132.6, 128.1 (q, ²J_FC = 33 Hz), 125.3–125.0 (m), 124.1 (q, ¹J_FC = 273 Hz), 123.2 (dq, ³J_FC, ³J_FC = 8, 4 Hz), 96.0 (d, ¹J_FC = 190 Hz), 83.1, 53.4 (d, ³J_FC = 5 Hz), 45.4, 34.7 (d, ²J_FC = 22 Hz), 27.6, 20.7 (d, ⁴J_FC = 8 Hz); HRMS (ESI): calcd for C₁₈H₂₆F₄NO₂ [M + H]⁺ 364.1894, found 364.1876.

tert-Butyl 4-(dimethylamino)-2-(2,5-dimethylphenyl)-2-fluorobutanoate (3da) (Table 2, entry 3)

Obtained from 2d (105 mg, 0.239 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3da (43.8 mg, 59% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 2976, 2936, 2862, 2818, 2766, 1749, 1731, 1499, 1459, 1392, 1368, 1285, 1250, 1149, 1090, 1040, 990, 952, 844, 811, 771, 748, 707; ¹H NMR (400 MHz, CDCl₃) δ 7.19 (1H, s, ArH), 7.07–6.99 (2H, m, ArH), 2.67–2.39 (4H, m, CH₂), 2.38 (3H, d, ⁵J_FH = 4.0 Hz, ArCH₃), 2.32 (3H, s, ArCH₃), 2.29 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.2 (d, ²J_FC = 26 Hz), 135.8 (d, ²J_FC = 21 Hz), 134.9, 133.4 (d, ³J_FC = 2 Hz), 132.0 (d, J_FC = 2 Hz), 129.1, 126.8 (d, ³J_FC = 8 Hz), 96.5 (d, ¹J_FC = 187 Hz), 82.6, 53.6 (d, ³J_FC = 5 Hz), 45.4, 34.6 (d, ²J_FC = 22 Hz), 27.7, 21.1, 20.2 (d, ⁴J_FC = 8 Hz); HRMS (ESI): calcd for C₁₈H₂₉FNO₂ [M + H]⁺ 310.2177, found 310.2163.

tert-Butyl 4-(dimethylamino)-2-fluoro-2-(5-methoxy-2-methylphenyl)butanoate (3ea) (Table 2, entry 4)

Obtained from 2e (127 mg, 0.279 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3ea (55.4 mg, 61% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 2976, 2938, 2862, 2818, 2766, 1748, 1731, 1612, 1577, 1498, 1459, 1392, 1368, 1290, 1249, 1149, 1090, 1078, 1041, 978, 957, 863, 844, 810, 771, 746, 735, 708; ¹H NMR (400 MHz, CDCl₃) δ 7.07 (1H, d, J = 8.4 Hz, ArH), 6.97 (1H, dd, J = 2.4, 1.2 Hz, ArH), 6.77 (1H, dd, J = 8.4, 2.4 Hz, ArH), 3.79 (3H, s, OCH₃), 2.64–2.37 (4H, m, CH₂), 2.35 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 2.27 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.9 (d, ²J_FC = 26 Hz), 157.4 (d, ⁴J_FC = 2 Hz), 137.2 (d, ²J_FC = 21 Hz), 132.9, 128.3 (d, ³J_FC = 2 Hz), 113.1 (d, ⁵J_FC = 2 Hz), 112.6 (d, ³J_FC = 9 Hz), 96.3 (d, ¹J_FC = 189 Hz), 82.6, 55.3, 53.6 (d, ³J_FC = 5 Hz), 45.4, 34.6 (d, ²J_FC = 22 Hz), 27.7, 19.7 (d, ⁴J_FC = 7 Hz); HRMS (ESI): calcd for C₁₈H₂₉FNO₃ [M + H]⁺ 326.2126, found 326.2115.

tert-Butyl 2-(4-bromo-2-methylphenyl)-4-(dimethylamino)-2-fluorobutanoate (3fa) (Table 2, entry 5)

Obtained from 2f (318 mg, 0.631 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3fa (170 mg, 72% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 2976, 2938, 2862, 2818, 2766, 1749, 1731, 1590, 1561, 1480, 1459, 1391, 1368, 1275, 1250, 1216, 1148, 1092, 1042, 988, 960, 940, 900, 844, 811, 768, 747, 704; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.29 (2H, m, ArH), 7.29–7.23 (1H, m, ArH), 2.66–2.30 (4H, m, CH₂), 2.40 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 2.26 (6H, s, N(CH₃)₂), 1.42 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.6 (d, ²J_FC = 27 Hz), 139.0 (d, ³J_FC = 2 Hz), 135.3 (d, ²J_FC = 21 Hz), 134.7, 128.6, 127.8 (d, ³J_FC = 8 Hz), 122.4 (d, J_FC = 2 Hz), 96.0 (d, ¹J_FC = 189 Hz), 82.8, 53.4 (d, ³J_FC = 5 Hz), 45.4, 34.6 (d, ²J_FC = 22 Hz), 27.6, 20.4 (d, ⁴J_FC = 8 Hz); HRMS (ESI): calcd for C₁₇H₂₆BrFNO₂ [M + H]⁺ 374.1125, found 374.1110.

tert-Butyl 4-(dimethylamino)-2-fluoro-2-(2-methyl-4-(trifluoromethyl)phenyl)butanoate (3ga) (Table 2, entry 6)

Obtained from 2g (74.8 mg, 0.152 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3ga (37.4 mg, 68% yield) as a colourless oil. IR (ATR) ν_max/cm⁻¹ 2979, 2940, 2864, 2821, 2769, 1750, 1732, 1619, 1460, 1411, 1394, 1370, 1333, 1285, 1252, 1217, 1150, 1122, 1090, 1042, 1008, 990, 965, 944, 890, 840, 814, 774, 741, 711; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (1H, d, J = 8.6 Hz, ArH), 7.46 (1H, d, J = 8.6 Hz, ArH), 7.42 (1H, s, ArH), 2.71–2.35 (4H, m, CH₂), 2.49 (3H, d, ⁵J_FH = 4.0 Hz, ArCH₃), 2.28 (6H, s, N(CH₃)₂), 1.42 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.4 (d, ²J_FC = 26 Hz), 139.9 (d, ²J_FC = 21 Hz), 137.6 (d, ³J_FC = 1 Hz), 130.5 (qd, ²J_FC, ⁵J_FC = 33, 2 Hz), 128.8 (q, ³J_FC = 4 Hz), 126.7 (d, ³J_FC = 9 Hz), 123.9 (q, ¹J_FC = 273 Hz), 122.5 (q, ³J_FC = 4 Hz), 96.1 (d, ¹J_FC = 189 Hz), 83.2, 53.4 (d, ³J_FC = 5 Hz), 45.4, 34.6 (d, ²J_FC = 22 Hz), 27.7, 20.8 (d, ⁴J_FC = 8 Hz); HRMS (ESI): calcd for C₁₈H₂₆F₄NO₂ [M + H]⁺ 364.1894, found 364.1882.

tert-Butyl 2-(3-bromo-2-methylphenyl)-4-(dimethylamino)-2-fluorobutanoate (3ha) (Table 2, entry 7)

Obtained from 2h (155 mg, 0.307 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 3ha (66.7 mg, 58% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 2976, 2938, 2861, 2818, 2766, 1748, 1732, 1562, 1459, 1432, 1392, 1368, 1283, 1250, 1148, 1092, 1076, 1033, 1005, 965, 944, 903, 842, 783, 763, 742, 715; ¹H NMR (400 MHz, CDCl₃) δ 7.57 (1H, d, J = 8.0 Hz, ArH), 7.38 (1H, d, J = 8.0 Hz, ArH), 7.06 (1H, ddq, J = 8.0, 8.0, 0.5 Hz, ArH), 2.66–2.34 (4H, m, CH₂), 2.47 (3H, d, ⁵J_FH = 2.8 Hz, ArCH₃), 2.26 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.0 (d, ²J_FC = 26 Hz), 138.4 (d, ²J_FC = 21 Hz), 136.4, 133.1 (d, ³J_FC = 2 Hz), 127.7 (d, J_FC = 2 Hz), 126.6, 125.5 (d, ³J_FC = 8 Hz), 96.0 (d, ¹J_FC = 190 Hz), 83.0, 53.5 (d, ³J_FC = 5 Hz), 45.5, 34.9 (d, ²J_FC = 22 Hz), 27.7, 20.3 (d, ⁴J_FC = 7 Hz); HRMS (ESI): calcd for C₁₇H₂₆BrFNO₂ [M + H]⁺ 374.1125, found 374.1120.

tert-Butyl 2-(5-bromo-2-methylphenyl)-2-chloro-4-(dimethylamino)butanoate (3bb) and tert-butyl 2-(5-bromo-2-methylphenyl)-4-chloro-2-(dimethylamino)butanoate (4bb) (Table 2, entry 8)

Obtained from 2b (135 mg, 0.268 mmol) by the same procedure with 3ab and 4ab. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent R_f: 3bb < 4bb) gave 3bb (85.5 mg, 82% yield) as colourless crystals and 4bb (18.0 mg, 17% yield) as a colourless oil. 3bb: mp 57–59 °C; IR (ATR) ν_max/cm⁻¹ 2998, 2975, 2939, 2857, 2813, 2759, 1739, 1593, 1566, 1481, 1459, 1393, 1366, 1288, 1263, 1232, 1179, 1143, 1100, 1080, 1063, 1041, 1029, 920, 875, 849, 811, 796, 768, 755, 722; ¹H NMR (400 MHz, CDCl₃) δ 7.74 (1H, d, J = 2.0 Hz, ArH), 7.35 (1H, dd, J = 8.2, 2.0 Hz, ArH), 7.03 (1H, d, J = 8.2 Hz, ArH), 2.63 (1H, ddd, J = 13.5, 10.1, 5.6 Hz, CH₂), 2.52 (1H, ddd, J = 13.5, 9.6, 5.8 Hz, CH₂), 2.44–2.31 (2H, m, CH₂), 2.29 (3H, s, ArCH₃), 2.25 (6H, s, N(CH₃)₂), 1.44 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.6, 140.1, 134.8, 133.5, 131.1, 129.5, 119.4, 83.4, 72.8, 54.9, 45.6, 37.8, 27.6, 20.0; HRMS (ESI): calcd for C₁₇H₂₆BrClNO₂ [M + H]⁺ 390.0830, found 390.0822. 4bb: IR (ATR) ν_max/cm⁻¹ 2977, 2931, 2872, 2837, 2797, 1712, 1589, 1563, 1476, 1455, 1391, 1367, 1336, 1294, 1231, 1151, 1119, 1100, 1082, 1049, 1030, 984, 967, 912, 876, 843, 803, 772, 734; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (1H, d, J = 2.0 Hz, ArH), 7.29 (1H, dd, J = 8.2, 2.0 Hz, ArH), 7.01 (1H, d, J = 8.2 Hz, ArH), 3.33 (1H, ddd, J = 12.0, 10.8, 4.0 Hz, CH₂), 2.93 (1H, ddd, J = 12.2, 10.8, 5.5 Hz, CH₂), 2.68 (1H, ddd, J = 14.4, 12.2, 4.0 Hz, CH₂), 2.34 (6H, s, N(CH₃)₂), 2.31–2.16 (1H, m, CH₂), 2.25 (3H, s, ArCH₃), 1.53 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.3, 139.9, 135.0, 133.9, 131.2, 130.0, 119.1, 82.4, 71.8, 40.3, 40.0, 37.2, 28.4, 20.7; HRMS (ESI): calcd for C₁₇H₂₆BrClNO₂ [M + H]⁺ 390.0830, found 390.0826.

tert-Butyl 2-chloro-4-(dimethylamino)-2-(2,5-dimethylphenyl)butanoate (3db) and tert-butyl 4-chloro-2-(dimethylamino)-2-(2,5-dimethylphenyl)butanoate (4db) (Table 2, entry 9)

Obtained from 2d (85.8 mg, 0.195 mmol) by the same procedure with 3ab and 4ab. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent R_f: 3db < 4db) gave 3db (33.9 mg, 53% yield) as colourless crystals and 4db (12.3 mg, 19% yield) as a colourless oil. 3db: mp 41–42 °C; IR (ATR) ν_max/cm⁻¹ 2976, 2938, 2861, 2818, 2765, 1732, 1615, 1497, 1458, 1392, 1367, 1252, 1146, 1080, 1039, 992, 969, 928, 911, 846, 809, 771, 745, 718, 700; ¹H NMR (400 MHz, CDCl₃) δ 7.40 (1H, s, ArH), 7.07–6.99 (2H, m, ArH), 2.71–2.52 (2H, m, CH₂), 2.47–2.35 (2H, m, CH₂), 2.34 (3H, s, ArCH₃), 2.30 (3H, s, ArCH₃), 2.26 (6H, s, N(CH₃)₂), 1.44 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.3, 137.8, 135.0, 132.6, 131.9, 128.8, 127.0, 82.9, 73.8, 55.1, 45.6, 37.9, 27.6, 21.2, 20.0; HRMS (ESI): calcd for C₁₈H₂₉ClNO₂ [M + H]⁺ 326.1881, found 326.1873. 4db: IR (ATR) ν_max/cm⁻¹ 2977, 2929, 2871, 2836, 2795, 1712, 1613, 1497, 1455, 1392, 1366, 1336, 1297, 1234, 1151, 1081, 1055, 1035, 978, 967, 898, 846, 810, 773, 757, 725; ¹H NMR (400 MHz, CDCl₃) δ 7.17 (1H, br s, ArH), 7.01 (1H, d, J = 7.7 Hz, ArH), 6.96 (1H, dd, J = 7.7, 1.8 Hz, ArH), 3.22 (1H, ddd, J = 12.0, 10.8, 4.5 Hz, CH₂), 3.03 (1H, ddd, J = 12.4, 10.8, 5.1 Hz, CH₂), 2.63 (1H, ddd, J = 13.8, 12.4, 4.5 Hz, CH₂), 2.37–2.27 (1H, m, CH₂), 2.35 (6H, s, N(CH₃)₂), 2.294 (3H, s, ArCH₃), 2.288 (3H, s, ArCH₃), 1.54 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.7, 137.1, 134.2, 132.9, 132.2, 129.0, 127.7, 81.9, 72.5, 41.0, 40.0, 37.9, 28.5, 21.2, 20.6; HRMS (ESI): calcd for C₁₈H₂₉ClNO₂ [M + H]⁺ 326.1881, found 326.1874.

tert-Butyl 2-(4-bromo-2-methylphenyl)-2-chloro-4-(dimethylamino)butanoate (3fb) and tert-butyl 2-(4-bromo-2-methylphenyl)-4-chloro-2-(dimethylamino)butanoate (4fb) (Table 2, entry 10)

Obtained from 2f (95.6 mg, 0.190 mmol) by the same procedure with 3ab and 4ab. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent R_f: 3fb < 4fb) gave 3fb (61.4 mg, 83% yield) as a pale yellow oil and 4fb (12.9 mg, 17% yield) as colourless crystals. 3fb: IR (ATR) ν_max/cm⁻¹ 2975, 2939, 2861, 2818, 2766, 1734, 1589, 1560, 1458, 1391, 1368, 1252, 1145, 1079, 1029, 967, 934, 899, 871, 843, 803, 770, 739, 722, 699; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (1H, dd, J = 7.8, 1.0 Hz, ArH), 7.35–7.30 (2H, m, ArH), 2.63 (1H, ddd, J = 13.6, 10.1, 5.7 Hz, CH₂), 2.52 (1H, ddd, J = 13.6, 9.3, 5.9 Hz, CH₂), 2.43–2.31 (2H, m, CH₂), 2.33 (3H, s, ArCH₃), 2.24 (6H, s, N(CH₃)₂), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.7, 138.2, 137.3, 134.6, 128.7, 128.0, 122.1, 83.3, 73.1, 54.9, 45.6, 37.8, 27.5, 20.3; HRMS (ESI): calcd for C₁₇H₂₆BrClNO₂ [M + H]⁺ 390.0830, found 390.0820. 4fb: mp 132–134 °C; IR (ATR) ν_max/cm⁻¹ 3001, 2974, 2943, 2927, 2869, 2850, 2839, 2800, 1714, 1587, 1560, 1473, 1453, 1389, 1367, 1338, 1300, 1261, 1229, 1177, 1152, 1083, 1049, 1027, 984, 961, 871, 831, 814, 771, 756, 739, 724; ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.23 (3H, m, ArH), 3.29 (1H, ddd, J = 12.3, 10.8, 4.3 Hz, CH₂), 2.93 (1H, ddd, J = 12.1, 10.8, 5.3 Hz, CH₂), 2.67 (1H, ddd, J = 14.3, 12.1, 4.3 Hz, CH₂), 2.33 (6H, s, N(CH₃)₂), 2.29 (3H, s, ArCH₃), 2.24 (1H, ddd, J = 14.3, 12.3, 5.3 Hz, CH₂), 1.53 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.6, 138.4, 136.8, 134.9, 130.2, 128.0, 120.9, 82.4, 71.9, 40.3, 40.0, 37.3, 28.4, 20.9; HRMS (ESI): calcd for C₁₇H₂₆BrClNO₂ [M + H]⁺ 390.0830, found 390.0824.

tert-Butyl 2-(3-bromo-2-methylphenyl)-2-chloro-4-(dimethylamino)butanoate (3hb) and tert-butyl 2-(3-bromo-2-methylphenyl)-4-chloro-2-(dimethylamino)butanoate (4hb) (Table 2, entry 11)

Obtained from 2h (149 mg, 0.295 mmol) by the same procedure with 3ab and 4ab. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent R_f: 3hb < 4hb) gave 3hb (74.7 mg, 65% yield) as colourless crystals and 4hb (37.5 mg, 33% yield) as a colourless oil. 3hb: mp 45–47 °C; IR (ATR) ν_max/cm⁻¹ 2976, 2940, 2861, 2818, 2766, 1733, 1561, 1459, 1429, 1392, 1368, 1304, 1251, 1146, 1078, 1031, 997, 967, 939, 912, 841, 783, 765, 742, 714; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (1H, dd, J = 8.1, 1.0 Hz, ArH), 7.55 (1H, dd, J = 8.0, 1.0 Hz, ArH), 7.07 (1H, dd, J = 8.1, 8.0 Hz, ArH), 2.66 (1H, ddd, J = 13.4, 11.1, 4.8 Hz, CH₂), 2.52 (1H, ddd, J = 13.4, 10.4, 4.8 Hz, CH₂), 2.41 (1H, ddd, J = 12.0, 10.4, 4.8 Hz, CH₂), 2.38 (3H, s, ArCH₃), 2.34 (1H, ddd, J = 12.0, 11.1, 4.8 Hz, CH₂), 2.24 (6H, s, N(CH₃)₂), 1.44 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.1, 140.1, 135.6, 132.7, 127.5, 126.6, 125.7, 83.4, 73.5, 54.9, 45.6, 38.3, 27.5, 21.1; HRMS (ESI): calcd for C₁₇H₂₆BrClNO₂ [M + H]⁺ 390.0830, found 390.0823. 4hb: IR (ATR) ν_max/cm⁻¹ 2976, 2930, 2872, 2837, 2797, 1713, 1560, 1455, 1428, 1392, 1366, 1336, 1295, 1233, 1151, 1098, 1081, 1048, 986, 962, 875, 842, 821, 789, 736, 719; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (1H, dd, J = 7.9, 1.0 Hz, ArH), 7.46 (1H, br d, J = 8.0 Hz, ArH), 7.01 (1H, ddd, J = 8.0, 7.9, 0.4 Hz, ArH), 3.33 (1H, ddd, J = 11.6, 10.8, 3.7 Hz, CH₂), 2.92 (1H, ddd, J = 12.1, 10.8, 5.2 Hz, CH₂), 2.71 (1H, ddd, J = 14.2, 12.1, 3.7 Hz, CH₂), 2.40–2.15 (1H, m, CH₂), 2.35 (3H, s, ArCH₃), 2.33 (6H, s, N(CH₃)₂), 1.53 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.4, 139.8, 135.6, 131.7, 127.8, 127.6, 126.0, 82.4, 72.4, 40.3, 40.1, 37.5, 28.4, 21.8; HRMS (ESI): calcd for C₁₇H₂₆BrClNO₂ [M + H]⁺ 390.0830, found 390.0826.

1-Allyl-2-(5-bromo-2-methylphenyl)-2-(tert-butoxycarbonyl)-1-methylazetidin-1-ium trifluoromethanesulfonate (5)

A solution of allyl alcohol (50 μL, 0.74 mmol) and pyridine (55 μL, 0.68 mmol) in CCl₄ (1.7 mL) was treated with trifluoromethanesulfonic anhydride (0.11 mL, 0.65 mmol) at 0 °C. The mixture was stirred for 20 min at the same temperature to precipitate a pale-brown solid. The generated allyl triflate in CCl₄ (ref. 12) was added by decantation to a mixture of 1b⁶ (156 mg, 0.458 mmol) and NaHCO₃ (122 mg, 1.45 mmol) in CH₂Cl₂ (2.3 mL) at 0 °C. After stirring for 1 h at room temperature, the resulting mixture was purified by chromatography on silica gel (CH₂Cl₂/MeOH = 20/1 to 10/1 as the eluent) to obtain 5 (170 mg, 70% yield, 8/2 mixture of diastereomers) as a colourless gum. IR (ATR) ν_max/cm⁻¹ 2980, 2936, 1731, 1484, 1459, 1427, 1397, 1372, 1252, 1223, 1149, 1139, 1029, 952, 911, 831, 808, 790, 755, 728; ¹H NMR (400 MHz, acetone-d₆) δ 7.81 (0.8H, d, J = 2.0 Hz, ArH), 7.76 (0.2H, br, ArH), 7.70–7.61 (0.2H, m, ArH), 7.65 (0.8H, dd, J = 8.2, 2.0 Hz, ArH), 7.36 (1H, d, J = 8.2 Hz, ArH), 6.19 (0.2H, ddt, J = 17.0, 9.6, 7.2 Hz, CH₂CH=CH₂), 6.05 (0.8H, ddt, J = 17.1, 10.1, 7.2 Hz, CH₂CH=CH₂), 5.86 (0.2H, ddt, J = 17.0, 1.2, 1.2 Hz, CH₂CH=CH₂), 5.76–5.70 (0.2H, m, CH₂CH=CH₂), 5.74 (0.8H, ddt, J = 17.1, 1.4, 1.2 Hz, CH₂CH=CH₂), 5.65 (0.8H, ddt, J = 10.1, 1.4, 0.8 Hz, CH₂CH=CH₂), 4.90 (0.2H, ddd, J = 9.6, 9.6, 9.6 Hz, 4H), 4.61 (0.8H, dddd, J = 10.6, 10.6, 9.2, 1.6 Hz, 4H), 4.48–4.32 (0.2H, br, CH₂), 4.38 (0.8H, ddd, J = 10.3, 9.2, 3.2 Hz, 4H), 4.24–4.09 (1.8H, m, CH₂), 4.09–4.00 (0.2H, br m, CH₂), 3.82–3.66 (0.4H, br m, CH₂), 3.71 (3H, s, NCH₃), 3.24–3.04 (1.6H, br m, CH₂), 2.42 (2.4H, s, ArCH₃), 2.41 (0.6H, s, ArCH₃), 1.473 (1.8H, s, tBu), 1.466 (7.2H, s, tBu); ¹³C{¹H} NMR (101 MHz, acetone-d₆) δ 167.2, 137.8, 137.4 (minor), 135.2, 134.5, 133.2, 133.0, 129.8, 128.9 (minor), 126.3 (minor), 125.9, 122.7 (q, J = 324 Hz), 120.6, 87.8, 87.7 (minor), 87.5, 64.0, 59.3, 48.2 (minor), 47.9, 27.8, 27.64 (minor), 27.63, 21.1; HRMS (ESI): calcd for C₁₉H₂₇BrNO₂ [M + H]⁺ 380.1220, found 380.1207.

tert-Butyl 4-(allyl(methyl)amino)-2-(5-bromo-2-methylphenyl)-2-fluorobutanoate (6)

Performed by the same procedure with 3aa using 5 (97.5 mg, 0.184 mmol) as a substrate. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 30/1 to 20/1 as the eluent) gave 6 (60.1 mg, 82% yield) as a pale yellow oil. IR (ATR) ν_max/cm⁻¹ 3076, 2977, 2934, 2874, 2846, 2780, 1749, 1731, 1644, 1592, 1564, 1481, 1456, 1392, 1368, 1282, 1251, 1142, 1054, 1033, 995, 920, 875, 841, 810, 771, 748, 705; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (1H, dd, J = 1.9, 1.9 Hz, ArH), 7.34 (1H, dd, J = 8.1, 1.9 Hz, ArH), 7.03 (1H, d, J = 8.1 Hz, ArH), 5.86 (1H, ddt, J = 17.2, 10.0, 6.6 Hz, CH₂CH=CH₂), 5.22–5.12 (2H, m, CH₂CH=CH₂), 3.04 (2H, ddd, J = 6.6, 1.1, 1.1 Hz, CH₂CH=CH₂), 2.66–2.44 (3H, m, CH₂), 2.44–2.28 (1H, m, CH₂), 2.36 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 2.27 (3H, s, NCH₃), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.5 (d, ²J_FC = 27 Hz), 138.3 (d, ²J_FC = 22 Hz), 135.6 (d, ³J_FC = 2 Hz), 135.2, 133.6, 131.4 (d, J_FC = 2 Hz), 129.2 (d, ³J_FC = 8 Hz), 119.3, 117.9, 95.8 (d, ¹J_FC = 190 Hz), 83.0, 61.0, 50.8 (d, ³J_FC = 5 Hz), 42.1, 34.2 (d, ²J_FC = 22 Hz), 27.7, 20.2 (d, ⁴J_FC = 8 Hz); HRMS (ESI): calcd for C₁₉H₂₈BrFNO₂ [M + H]⁺ 400.1282, found 400.1273.

tert-Butyl 2-(5-bromo-2-methylphenyl)-2-fluoro-4-(methylamino)butanoate (7)

A mixture of 6 (103 mg, 0.257 mmol) and RhCl(PPh₃)₃ (5 mg, 0.005 mmol) in MeCN (2.2 mL) and H₂O (0.4 mL) was refluxed for 3 h under an Ar atmosphere. The resulting mixture was cooled to room temperature and treated with saturated aqueous NaHCO₃. The mixture was extracted with EtOAc and the combined extracts were washed with brine. The organic solution was dried over Na₂SO₄ and concentrated by evaporation. Purification of the residue by chromatography on silica gel (CH₂Cl₂/MeOH = 15/1 to 5/1 as the eluent) gave 7 (77.7 mg, 84% yield) as pale yellow crystals, mp 38–42 °C. IR (ATR) ν_max/cm⁻¹ 3040, 2981, 2942, 2887, 1733, 1499, 1461, 1425, 1397, 1372, 1357, 1327, 1254, 1223, 1141, 1078, 1029, 958, 930, 877, 837, 802, 768, 754, 736, 706; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (1H, dd, J = 1.9, 1.9 Hz, ArH), 7.35 (1H, dd, J = 8.1, 1.9 Hz, ArH), 7.04 (1H, d, J = 8.1 Hz, ArH), 2.78 (1H, ddd, J = 12.0, 9.2, 5.8 Hz, CH₂), 2.72 (1H, ddd, J = 12.0, 9.2, 5.8 Hz, CH₂), 2.64–2.33 (2H, m, CH₂), 2.45 (3H, s, NCH₃), 2.36 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 1.59 (1H, br, NH), 1.44 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.6 (d, ²J_FC = 27 Hz), 138.3 (d, ²J_FC = 21 Hz), 135.5 (d, ³J_FC = 2 Hz), 133.7, 131.4 (d, J_FC = 2 Hz), 129.1 (d, ³J_FC = 9 Hz), 119.3, 96.2 (d, ¹J_FC = 189 Hz), 83.2, 46.2 (d, ³J_FC = 5 Hz), 36.43 (d, ²J_FC = 22 Hz), 36.36, 27.7, 20.2 (d, ⁴J_FC = 7 Hz); HRMS (ESI): calcd for C₁₆H₂₄BrFNO₂ [M + H]⁺ 360.0969, found 360.0964.

4-(tert-Butoxy)-3-fluoro-N,N,N-trimethyl-4-oxo-3-(o-tolyl)butan-1-aminium iodide (8-I)

A mixture of 3aa (67.0 mg, 0.227 mmol) and MeI (21 μL, 0.34 mmol) in MeCN (1.1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated by evaporation and the residue was purified by chromatography on silica gel (CH₂Cl₂/MeOH = 20/1 to 10/1 as the eluent) to obtain 8-I (90.3 mg, 91% yield) as a yellow solid, mp 162–164 °C. IR (ATR) ν_max/cm⁻¹ 3002, 2978, 2932, 1738, 1484, 1455, 1418, 1394, 1368, 1335, 1294, 1259, 1243, 1215, 1145, 1089, 1062, 1009, 992, 975, 934, 912, 838, 777, 748; ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.44 (1H, m, ArH), 7.32–7.23 (2H, m, ArH), 7.22–7.15 (1H, m, ArH), 3.70 (1H, ddd, J = 13.1, 8.7, 7.3 Hz, CH₂), 3.60–3.40 (1H, m, CH₂), 3.52 (9H, s, N(CH₃)₃), 2.93–2.76 (2H, m, CH₂), 2.41 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 1.43 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.7 (d, ²J_FC = 25 Hz), 135.7 (d, ³J_FC = 2 Hz), 133.8 (d, ²J_FC = 21 Hz), 132.5, 129.2 (d, J_FC = 2 Hz), 126.4 (d, J_FC = 2 Hz), 126.1 (d, ³J_FC = 9 Hz), 96.1 (d, ¹J_FC = 190 Hz), 84.4, 62.7–62.4 (m), 54.0, 30.3 (d, ²J_FC = 22 Hz), 27.8, 20.7 (d, ⁴J_FC = 7 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −157; HRMS (ESI): calcd for C₁₈H₂₉FNO₂ [M − I]⁺ 310.2177, found 310.2166.

4-(tert-Butoxy)-3-fluoro-N,N,N-trimethyl-4-oxo-3-(o-tolyl)butan-1-aminium trifluoromethanesulfonate (8-OTf)

A mixture of 3aa (91.3 mg, 0.309 mmol) and NaHCO₃ (82 mg, 0.98 mmol) in CH₂Cl₂ (1.5 mL) was treated with methyl trifluoromethanesulfonate (52 μL, 0.46 mmol) at 0 °C and stirred for 2 h at room temperature. The resulting mixture was purified by chromatography on silica gel (CH₂Cl₂/MeOH = 20/1 to 10/1 as the eluent) to obtain 8-OTf (143 mg, quant.) as a white solid, mp 140–142 °C. IR (ATR) ν_max/cm⁻¹ 3039, 2979, 2936, 1760, 1733, 1484, 1459, 1420, 1395, 1371, 1257, 1227, 1155, 1084, 1030, 1008, 976, 933, 910, 841, 793, 746; ¹H NMR (400 MHz, CDCl₃) δ 7.42–7.35 (1H, m, ArH), 7.30–7.21 (2H, m, ArH), 7.21–7.13 (1H, m, ArH), 3.55–3.43 (1H, m, CH₂), 3.41–3.27 (1H, m, CH₂), 3.21 (9H, s, N(CH₃)₃), 2.86–2.69 (2H, m, CH₂), 2.38 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 1.41 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 167.8 (d, ²J_FC = 26 Hz), 135.9 (d, ³J_FC = 2 Hz), 134.0 (d, ²J_FC = 21 Hz), 132.4, 129.2, 126.3, 125.9 (d, ³J_FC = 9 Hz), 120.5 (q, ¹J_FC = 321 Hz), 95.9 (d, ¹J_FC = 190 Hz), 84.3, 62.1 (d, ³J_FC = 5 Hz), 53.3, 30.0 (d, ²J_FC = 22 Hz), 27.6, 20.5 (d, ⁴J_FC = 8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −80, −157; HRMS (ESI): calcd for C₁₈H₂₉FNO₂ [M − OTf]⁺ 310.2177, found 310.2171.

tert-Butyl 2-fluoro-2-(o-tolyl)but-3-enoate (9)

A mixture of 8-OTf (67.9 mg, 0.148 mmol) and DBU (66 μL, 0.44 mmol) in toluene (1.5 mL) was refluxed for 1 day under an Ar atmosphere. The resulting mixture was cooled to room temperature and treated with aqueous saturated NH₄Cl. The mixture was extracted with EtOAc and the combined extracts were washed with saturated aqueous NaHCO₃ followed by brine. The solution was dried over Na₂SO₄ and concentrated by evaporation. The residue was purified by chromatography on silica gel (n-hexane/EtOAc = 30/1 to 20/1 as the eluent) to obtain 9 (21.0 mg, 57% yield) as a colourless oil. IR (ATR) ν_max/cm⁻¹ 2979, 2934, 1751, 1731, 1476, 1457, 1406, 1394, 1369, 1282, 1253, 1223, 1146, 1119, 1061, 1042, 1024, 992, 973, 935, 841, 828, 800, 769, 747; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.35 (1H, m, ArH), 7.29–7.22 (1H, m, ArH), 7.21–7.14 (2H, m, ArH), 6.37 (1H, ddd, ³J_FH = 17.6, J = 17.4, 11.1 Hz, 3H), 5.60 (1H, ddd, ⁴J_FH = 0.8 Hz, J = 17.4, 0.8 Hz, 4H), 5.51 (1H, ddd, ⁴J_FH = 1.6 Hz, J = 11.1, 0.8 Hz, 4H), 2.40 (3H, d, ⁵J_FH = 2.8 Hz, ArCH₃), 1.46 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.6 (d, ²J_FC = 26 Hz), 137.2, 136.1 (d, ²J_FC = 22 Hz), 134.7 (d, ²J_FC = 23 Hz), 131.8, 129.0, 127.9 (d, ³J_FC = 6 Hz), 125.5, 117.7 (d, ³J_FC = 12 Hz), 96.1 (d, ¹J_FC = 190 Hz), 83.0, 27.8, 20.1 (d, ⁴J_FC = 5 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −153; HRMS (ESI): calcd for C₁₅H₁₉FO₂Na [M + Na]⁺ 273.1261, found 273.1260.

(S)-2-(tert-Butoxycarbonyl)-1,1-dimethyl-2-(o-tolyl)azetidin-1-ium trifluoromethanesulfoante [(S)-2a]

A mixture of (S)-1a (171 mg, 0.654 mmol, 93% ee) and NaHCO₃ (168 mg, 2.00 mmol) in CH₂Cl₂ (3.3 mL) was treated with methyl trifluoromethanesulfonate (148 μL, 1.31 mmol) at 0 °C and stirred for 2.5 h at room temperature. The resulting mixture was evaporated to ca. 1/2 volume and purified by chromatography on silica gel (CH₂Cl₂/MeOH = 15/1 to 6/1 as the eluent) to obtain (S)-2a (277 mg, quant.) as colourless crystals, mp 110–112 °C. [α]²⁴₅₈₉ +34.6 (c 1.0 in CHCl₃); IR (ATR) ν_max/cm⁻¹ 3076, 3041, 2979, 2940, 1728, 1459, 1395, 1371, 1302, 1254, 1225, 1145, 1105, 1078, 1030, 995, 969, 946, 856, 832, 770, 753, 728, 988, 965, 939, 844, 749; ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.33 (3H, m, ArH), 7.29–7.23 (1H, m, ArH), 4.52 (1H, ddd, J = 10.6, 10.4, 9.4 Hz, 4H), 4.27 (1H, ddd, J = 9.6, 9.4, 2.4 Hz, 4H), 3.90 (1H, ddd, J = 12.4, 10.6, 9.6 Hz, 3H), 3.63 (3H, s, NCH₃), 3.02–2.84 (1H, br m, 3H), 2.97 (3H, s, NCH₃), 2.33 (3H, s, ArCH₃), 1.39 (9H, s, tBu); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.4, 135.9, 132.5, 130.6, 129.7, 128.5, 126.9, 120.6 (q, J = 322 Hz), 86.8, 86.3, 62.7, 50.9, 50.7, 27.4, 27.1, 20.7; HRMS (ESI): calcd for C₁₇H₂₆NO₂ [M − OTf]⁺ 276.1958, found 276.1955.

(R)-tert-Butyl 4-(dimethylamino)-2-fluoro-2-(o-tolyl)butanoate [(R)-3aa]

Obtained from (S)-2a (277 mg, 0.651 mmol) by the same procedure with 3aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 20/1 to 10/1 as the eluent) gave (R)-3aa (131 mg, 68% yield) as a colourless oil. [α]²⁴₅₈₉ −5.2 (c 1.0 in EtOH).

(R)-4-(Dimethylamino)-2-fluoro-2-(o-tolyl)butan-1-ol [(R)-10]

A solution of (R)-3aa (131 mg, 0.443 mmol) in THF (2.2 mL) was added to a suspension of LiAlH₄ (35 mg, 0.92 mmol) in THF (2.2 mL) at 0 °C under an Ar atmosphere. After stirring for 4 h at room temperature, the resulting mixture was cooled at 0 °C and diluted with Et₂O (4 mL). The mixture was quenched at 0 °C by addition of H₂O (35 μL), 15 wt% NaOH·H₂O solution (35 μL), and H₂O (105 μL). The suspension was diluted with EtOH (4 mL) and stirred for 12 h at room temperature. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated by evaporation. The residue was purified by chromatography on amino-functionalized silica gel (Chromatorex NH-DM1020, n-hexane/EtOAc = 2/1 to 1/1 as the eluent) to obtain (R)-10 (73.0 mg, 73% yield) as a colourless oil. [α]²⁴₅₈₉ +9.9 (c 1.0 in EtOH); IR (ATR) ν_max/cm⁻¹ 3339, 3061, 3020, 2947, 2863, 2825, 2778, 1462, 1385, 1312, 1290, 1258, 1217, 1180, 1163, 1095, 1057, 1038, 1000, 944, 878, 846, 800, 757, 726; ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.40 (1H, m, ArH), 7.23–7.10 (3H, m, ArH), 3.92 (1H, dd, ³J_FH = 26.8 Hz, J = 12.8 Hz, 1H), 3.88 (1H, dd, ³J_FH = 20.2 Hz, J = 12.8 Hz, 1H), 2.87–2.76 (1H, m, OH), 2.48 (3H, d, ⁵J_FH = 4.4 Hz, ArCH₃), 2.45–2.13 (4H, m, CH₂), 2.31 (6H, s, N(CH₃)₂); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 139.9 (d, ²J_FC = 20 Hz), 135.2 (d, ³J_FC = 2 Hz), 132.5, 127.7, 125.7 (d, J_FC = 2 Hz), 125.5 (d, ³J_FC = 11 Hz), 99.4 (d, ¹J_FC = 179 Hz), 67.6 (d, ²J_FC = 28 Hz), 53.5 (d, ³J_FC = 6 Hz), 44.9, 35.2 (d, ²J_FC = 25 Hz), 21.8 (d, ⁴J_FC = 9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −161; HRMS (ESI): calcd for C₁₃H₂₁FNO [M + H]⁺ 226.1602, found 226.1600.

(R)-4-(Dimethylamino)-2-fluoro-2-(o-tolyl)butyl benzoate [(R)-11]

A solution of (R)-10 (73.0 mg, 0.324 mmol) and Et₃N (135 μL, 0.969 mmol) in CH₂Cl₂ (3.2 mL) was treated with benzoyl chloride (45 μL, 0.39 mmol) at 0 °C and stirred for 2 h at room temperature. The resulting mixture was diluted with H₂O and extracted with EtOAc. The combined extracts were washed with H₂O, dried over Na₂SO₄, and concentrated by evaporation. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 20/1 to 10/1 as the eluent) gave (R)-11 (101 mg, 95% yield) as a colourless oil. 93% ee [determined by HPLC analysis: Daicel Chiralcel AD-H column (25 cm), n-hexane/EtOH/Et₂NH = 100/2/0.1 as the eluent, flow rate: 0.50 mL min⁻¹, tR = 14.7 min for (R)-11 (96.5%) and 19.1 min for (S)-11 (3.5%)]. [α]²³₅₈₉ +6.6 (c 1.0 in EtOH); IR (ATR) ν_max/cm⁻¹ 3062, 3022, 2970, 2944, 2861, 2818, 2765, 1719, 1602, 1584, 1491, 1450, 1377, 1314, 1265, 1176, 1156, 1111, 1095, 1068, 1042, 1026, 936, 893, 849, 802, 760, 727, 708; ¹H NMR (400 MHz, CDCl₃) δ 7.98–7.93 (2H, m, ArH), 7.54 (1H, tt, J = 7.6, 1.3 Hz, ArH), 7.43–7.35 (3H, m, ArH), 7.25–7.15 (3H, m, ArH), 4.73 (1H, dd, ³J_FH = 17.4 Hz, J = 12.6 Hz, 1H), 4.67 (1H, dd, ³J_FH = 15.8 Hz, J = 12.6 Hz, 1H), 2.50 (3H, d, ⁵J_FH = 3.6 Hz, ArCH₃), 2.50–2.33 (3H, m, CH₂), 2.25–2.09 (1H, m, CH₂), 2.20 (6H, s, N(CH₃)₂); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.1, 136.5 (d, ²J_FC = 21 Hz), 134.8 (d, ³J_FC = 2 Hz), 133.1, 132.6, 129.7, 129.6, 128.3, 128.1, 126.1 (d, ³J_FC = 14 Hz), 125.9 (d, J_FC = 2 Hz), 98.8 (d, ¹J_FC = 180 Hz), 68.4 (d, ²J_FC = 25 Hz), 53.7 (d, ³J_FC = 3 Hz), 45.5, 33.7 (d, ²J_FC = 24 Hz), 21.8 (d, ⁴J_FC = 8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −157; HRMS (ESI): calcd for C₂₀H₂₅FNO₂ [M + H]⁺ 330.1864, found 330.1859.

tert-Butyl 2-(benzyl(methyl)amino)-2-ethyl-4-fluorobutanoate (14) and tert-butyl 4-(benzyl(methyl)amino)-2-ethyl-2-hydroxybutanoate (15)

Obtained from 12 (141 mg, 0.321 mmol) by the same procedure with 3aa and 4aa. Purification by chromatography on silica gel (CH₂Cl₂/MeOH = 100/0 to 30/1 as the eluent R_f: 14 > 15) gave 14 (62.0 mg, 62% yield) as a colourless oil and 15 (7.2 mg, 7% yield) as a colourless oil. 14: IR (ATR) ν_max/cm⁻¹ 3086, 3062, 3027, 2975, 2934, 2882, 2801, 1715, 1604, 1495, 1454, 1391, 1366, 1238, 1165, 1124, 1064, 1029, 999, 961, 940, 888, 847, 831, 773, 732, 697; ¹H NMR (400 MHz, CDCl₃) δ 7.34–7.27 (4H, m, Ph), 7.26–7.18 (1H, m, Ph), 4.66 (1H, dddd, ²J_FH = 47.2 Hz, J = 9.2, 7.2, 7.2 Hz, 4H), 4.62 (1H, dddd, ²J_FH = 47.2 Hz, J = 9.2, 7.2, 5.6 Hz, 4H), 3.72 (1H, d, J = 14.4 Hz, CH₂Ph), 3.65 (1H, d, J = 14.4 Hz, CH₂Ph), 2.38–2.11 (2H, m, 3H), 2.20 (3H, s, NCH₃), 1.97 (1H, dq, J = 14.0, 7.4 Hz, CH₂CH₃), 1.72 (1H, dq, J = 14.0, 7.4 Hz, CH₂CH₃), 1.52 (9H, s, tBu), 0.95 (3H, dd, J = 7.4, 7.4 Hz, CH₂CH₃); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.6, 140.8, 128.2, 128.0, 126.6, 81.2 (d, ¹J_FC = 163 Hz), 81.1, 67.4 (d, ³J_FC = 6 Hz), 55.3, 35.3, 31.4 (d, ²J_FC = 20 Hz), 28.3, 25.9, 8.7; ¹⁹F NMR (376 MHz, CDCl₃) δ −221; HRMS (ESI): calcd for C₁₈H₂₉FNO₂ [M + H]⁺ 310.2177, found 310.2167. 15: IR (ATR) ν_max/cm⁻¹ 3408, 3087, 3063, 3028, 2973, 2930, 2880, 2801, 1715, 1603, 1495, 1454, 1391, 1366, 1298, 1244, 1162, 1134, 1101, 1069, 1022, 951, 909, 892, 845, 829, 776, 729, 697; ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.27 (4H, m, Ph), 7.27–7.21 (1H, m, Ph), 5.28 (1H, br, OH), 3.92 (1H, ddd, J = 11.3, 11.2, 3.2 Hz, CH₂), 3.784 (1H, ddd, J = 11.2, 5.2, 3.2 Hz, CH₂), 3.775 (2H, s, CH₂Ph), 2.35 (1H, dddd, J = 15.6, 11.3, 5.2, 1.2 Hz, CH₂), 2.27–2.15 (1H, m, CH₂CH₃), 2.23 (3H, s, NCH₃), 1.90 (1H, dq, J = 13.4, 7.4 Hz, CH₂CH₃), 1.84 (1H, ddd, J = 15.6, 3.2, 3.2 Hz, CH₂), 1.54 (9H, s, tBu), 0.89 (3H, dd, J = 7.4, 7.4 Hz, CH₂CH₃); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.2, 139.1, 128.9, 128.5, 127.2, 81.5, 69.8, 59.5, 55.6, 35.2, 29.7, 28.4, 25.7, 9.4; HRMS (ESI): calcd for C₁₈H₃₀NO₃ [M + H]⁺ 308.2220, found 308.2214.

Author contributions

E. T. was supervisor of this project and conducted all area of this work, idea, development of the methodology, a part of experiments and writing the manuscript. K. K. performed the main experiments and compounds analyses.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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2. Representative examples: (a) G. Roagna, D. M. H. Ascough, F. Ibba, A. C. Vicini, A. Fontana, K. E. Christensen, A. Peschiulli, D. Oehlrich, A. Misale, A. A. Trabanco, R. S. Paton, G. Pupo and V. Gouverneur, J. Am. Chem. Soc., 2020, 142, 14045; (b) D. Qian, M. Chen, A. C. Bissember and J. Sun, Angew. Chem., Int. Ed., 2018, 57, 3763; (c) A. Feula, S. S. Dhillon, R. Byravan, M. Sangha, R. Ebanks, M. A. H. Salih, N. Spencer, L. Male, I. Magyary, W.-P. Deng, F. Müller and J. S. Fossey, Org. Biomol. Chem., 2013, 11, 5083; (d) S. Kenis, M. D’hooghe, G. Verniest, T. A. D. Thi, C. P. The, T. V. Nguyen and N. D. Kimpe, J. Org. Chem., 2012, 77, 5982; (e) D.-H. Leng, D.-X. Wang, J. Pan, Z.-T. Huang and M.-X. Wang, J. Org. Chem., 2009, 74, 6077; (f) S. Ma, D. H. Yoon, H.-J. Ha and W. K. Lee, Tetrahedron Lett., 2007, 48, 269.
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9. Ring-opening of three-membered N-heterocycle aziridine derivatives with fluoride (F⁻) were well known and applied in in various areas. For a representative review: (a) A. M. Remete and L. Kiss, Eur. J. Org. Chem., 2019, 5574; (b) Representative recent examples: H. Wang, J. Li, Z. Li, B. Liu, K. Chen, Z. Zhang, Y. Hu, F. Zhou, Y. Li and K. Guo, Eur. Polym. J., 2020, 140, 109999; (c) M. Morlot, F. Gourand and C. Perrio, Eur. J. Org. Chem., 2019, 3751 , see also ref. 8..
10. M. K. Ghorai, A. Kumar and D. P. Tiwari, J. Org. Chem., 2010, 75, 137.
11. Previous examples of ring-opening of azetidinium salts with cyanide (CN⁻): see also ref. 1a, 1b, 1d, 1e, 2d and 2e.
12. Preparation of allyl triflate: L. Jordi, S. Ricart, J. M. Viñas and J. M. Moretó, Organometallics, 1997, 16, 2808.
13. The experimental details were shown in the ESI.†.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H, ¹³C, and ¹⁹F NMR spectra of substrates and products, preparation of substrates, and copies of chiral HPLC chromatogram of chiral compounds. See DOI: 10.1039/d1ra08706a

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