HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 2, 2013, pp. 381-388
Received, 6th November, 2012, Accepted, 19th December, 2012, Published online, 21st December, 2012.
DOI: 10.3987/COM-12-12619

■ A Unique and Simple Preparative Method for α-Arylpipecolinic Acid Esters via Base-Induced Sommelet–Hauser Rearrangement

Eiji Tayama,* Ryota Sato, Motoshi Ito, Hajime Iwamoto, and Eietsu Hasegawa

Department of Chemistry, Faculty of Sciences, Niigata University, Ikarasi 2-8050, Niigata 950-2181, Japan

Abstract

A unique and simple preparative method for N-cyano-α-arylpipecolinic acid esters via base-induced Sommelet–Hauser rearrangement, the von Braun reaction, and intramolecular α-alkylation is reported. The removal of the N-cyano substituent was achieved by hydrogenation and hydride reduction.

Six-membered cyclic α-amino acid derivatives, such as pipecolinic acid, occur in numerous biologically important natural products and are pharmacologically interesting as building blocks for synthetic drugs.1 Various synthetic methods, including asymmetric synthesis, have been reported; however, preparative methods for α-substituted (quaternary) pipecolinic acids are limited,2 especially for α-aryl derivatives3,4 because of the difficulty of C–C bonds formation between aromatic (sp2) and piperidinyl (sp3) carbons. Previously, we reported the base-induced Sommelet–Hauser (S–H) rearrangement5 of N-benzylic amino acid-derived ammonium ylides, which enables the formation of C(sp2)–C(sp3) bonds under mild conditions and affords various types of α-aryl amino acids such as α-arylproline, α-arylglycine, and α-arylalanine derivatives.6,9 In the course of our study of the S–H rearrangement, we carried out a reaction involving N-benzylpipecolinic acid-derived tetraalkylammonium salt 1 to prepare α-(o-tolyl)pipecolinic acid ester 2 to expand the synthetic scope of the rearrangement. However, our attempt failed because the cooperative [1,2] Stevens rearrangement proceeded to afford exclusively α-benzylated 3 (eq. 1).7 Recently, we reported that the von Braun reaction8 of methyl 2-phenyl-2-pyrrolidinylacetate 5a gave the corresponding ring-opening product 6a in a 94% yield (eq. 2).9 Substrate 5a appears to be a model S–H rearrangement product, and product 6a may be a good synthetic intermediate for the synthesis of α-arylpipecolinic acid derivatives because only a simple intramolecular α-alkylation (cyclization) would be required. In fact, the previous synthetic route to α-arylpipecolinic acids mainly involves intramolecular α-alkylation (cyclization) of N- or α-(4-halobutyl)-α-arylglycine derivatives.3 Thus, we started to investigate a new synthetic route for synthetically valuable α-arylpipecolinic acid esters 7 from easily accessible tetraalkylammonium salts 4 via S–H rearrangement, the von Braun reaction, and intramolecular α-alkylation (eq. 3).

First, we examined the cyclization of 6a by treatment with 1.1 equivalents of LDA (Scheme 1). The desired N-cyano-α-arylpipecolinic acid ester 7a was obtained in a 91% yield.

With this reaction in hand, we prepared N-benzylglycine-derived tetraalkylammonium salt 4b and analyzed the reactions to investigate the possibility of obtaining α-arylpipecolinic acid derivatives 7 from 4 via S–H rearrangement (Scheme 2). The corresponding o-tolyl derivative 6b was obtained via the S–H rearrangement of 4b (68%) and the von Braun reaction of 5b (91%). However, 6b did not cyclize to 7b after treatment with LDA. The addition of HMPA did not result in any improvement. Thus, we used potassium bis(trimethylsilyl)amide (KHMDS) as a base to generate the reactive potassium enolate. The desired product 7b was obtained in a 69% yield when 1.8 equivalents of KHMDS was used.

To define the scope and limitations of the present method, we prepared ortho-, meta-, and para-methyl- or chloro-substituted N-benzylic salts 4c–4k and used them to obtain various types of N-cyano-α-arylpipecolinic acid derivatives (Table 1). In most cases, the S–H rearrangement of 4 and following the von Braun reaction of 5 proceeded, giving reasonable yields (entries 1–9, 1st and 2nd step). One exception was the ring-opening reaction of 2,4-dimethylphenyl derivative 5g, which resulted in a low yield of 6g (20%) because of a competing α-bromo substitution reaction9 (R3 = Me, entry 5, 2nd step). The cyclization of isopropyl or tert-butyl ester-derived substrates 6c–6j proceeded smoothly to give 7c–7j in the presence of 1.1 equivalents of KHMDS (entries 1–8, 3rd step). The amide derivative 6k did not cyclize at all because of the poorer reactivity of the amide enolate (entry 9, 3rd step).
Next, we applied this method to the preparation of an α-benzylpipecolinic acid ester, 7d’, and a seven-membered cyclic α-amino acid ester, 7l, via a base-induced [1,2] Stevens rearrangement5 (Scheme 3). When the reaction of 4d and 4l was carried out in dichloromethane using sodium tert-butoxide as a base, the [1,2] Stevens rearrangement proceeded preferably to afford α-benzylated 5d’ and 5l.10 Procedures similar to those described in Table 1 gave the desired products 7d’ and 7l, respectively.
Finally, we attempted to remove the N-cyano substituent, as in 7d, to obtain N-free α-substituted pipecolinic acid ester 9d (Scheme 4). The hydrogenation of 7d under a hydrogen atmosphere afforded the corresponding amidine 8d in a 93% yield. Treatment of 8d with sodium borohydride gave the desired secondary amine 9d in a 75% yield with a side product of N-methyl derivative 2.

In conclusion, we have developed a new synthetic method for the preparation of N-cyano-α-aryl- pipecolinic acid esters 7 from tetraalkylammonium salts 4 via rearrangement (Sommelet–Hauser or [1,2] Stevens), the von Braun reaction, and intramolecular α-alkylation. The N-cyano substituent, as in 7, can be removed via hydrogenation and hydride reduction. The method presented herein is a unique and simple preparative method for α-arylpipecolinic acid esters.11

EXPERIMENTAL
Infrared spectra were recorded on a Perkin Elmer Spectrum GX FT-IR spectrometer. 1H and 13C NMR spectra were measured on a Varian 400 MHz spectrometer (1H: 400 MHz, 13C: 100 MHz) and a 700 MHz spectrometer (1H: 700 MHz, 13C: 175 MHz). The splitting patterns are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad peak. High-resolution mass spectra 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 bars under an argon atmosphere. Tetrahydrofuran (THF) was purchased from KANTO Chemical Co., Inc., Japan as an anhydrous solvent. Cyanogen bromide was purchased from KANTO Chemical Co., Inc., Japan. A 0.5 M potassium bis(trimethylsilyl)amide (KHMDS) solution in toluene and a 1.0 M potassium tert-butoxide solution in THF were purchased from Tokyo Chemical Industry Co., Ltd (TCI). For thin layer chromatography (TLC) analysis throughout this work, Merck TLC plates (silica gel 60 F254), or Fuji Silysia Chemical TLC plates (NH, Fuji Silysia Chemical Ltd., Japan) for amidine 8d were used. The products were purified by preparative column chromatography on silica gel (silica gel 60N, spherical neutral, KANTO Chemical Co., Inc., Japan) or pH-controlled silica gel (Chromatorex NH–DM1020, Fuji Silysia Chemical Ltd., Japan) for amidine 8d.
Representative procedure for the preparation of tert-butyl 2-(pyrrolidin-1-yl)-2-(o-tolyl)acetate (5d). A 1.0 M THF solution of potassium tert-butoxide (4.9 mL, 4.9 mmol) was added to a solution of 4d (1.58 g, 4.43 mmol) in THF (44 mL) at 0 °C. The mixture was stirred for 4 h at the same temperature under an argon atmosphere. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate and brine. The solution was dried over sodium sulfate and concentrated. Purification of the residue by chromatography on silica gel (hexane/EtOAc = 5/1 to 2/1 as the eluent) gave 5d (1.00 g, 82% yield) as a colorless oil; IR (film) 3051, 2972, 2874, 2785, 2722, 1741, 1603, 1483, 1459, 1391, 1367, 1334, 1253, 1214, 1146, 1038, 977, 940, 906, 845, 815, 751 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61 (1H, dd, J = 7.4, 1.2 Hz, ArH), 7.20-7.09 (3H, m, ArH), 4.12 (1H, s, CHCO), 2.63-2.53 (2H, m, NCH2), 2.53-2.44 (2H, m, NCH2), 2.43 (3H, s, ArCH3), 1.83-1.71 (4H, m, CH2), 1.36 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ 170.9, 136.3, 135.9, 130.0, 128.0, 127.1, 125.9, 80.5, 69.5, 52.0, 27.7, 23.3, 19.6; HRMS–ESI (m/z): [M+H]+ calcd for C17H26NO2: 276.1958. Found: 276.1955.
Representative procedure for the preparation of tert-butyl 2-(N-(4-bromobutyl)cyanamido)-2-(o-tolyl)acetate (6d). A solution of cyanogen bromide (95%, 1.22 g, 11 mmol) in CH2Cl2 (2 mL) was added to a solution of 5d (1.00 g, 3.63 mmol) in CH2Cl2 (18 mL) at room temperature under an argon atmosphere and the solution was stirred for 1 h. The resulting solution was treated with saturated aqueous sodium hydrogen carbonate and extracted with EtOAc. The combined extracts were washed with saturated aqueous sodium bromide, dried over sodium sulfate, and concentrated by evaporation. Purification of the residue by chromatography on silica gel (hexane/EtOAc = 5/1 to 1/1 as the eluent) afforded 6d (1.23 g, 89% yield) as a white solid; IR (film) 3067, 2977, 2935, 2880, 2212, 1738, 1605, 1491, 1460, 1393, 1369, 1342, 1255, 1221, 1155, 1074, 1041, 955, 881, 861, 826, 754 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.20 (4H, m, ArH), 4.84 (1H, s, CHCO), 3.37 (1H, dt, J = 12.6, 6.4 Hz, CH2), 3.35 (1H, dt, J = 12.6, 6.4 Hz, CH2), 3.10 (2H, t, J = 6.8 Hz, CH2), 2.42 (3H, s, ArCH3), 1.94-1.77 (4H, m, CH2), 1.50 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ 168.6, 137.5, 131.3, 131.1, 129.6, 128.0, 126.4, 115.6, 83.4, 64.1, 49.6, 32.6, 29.4, 27.9, 26.3, 19.3; HRMS–ESI (m/z): [M+Na]+ calcd for C18H25N2O2BrNa: 403.0992. Found: 403.0990.
Representative procedure for the preparation of tert-butyl 1-cyano-2-(o-tolyl)piperidine-2-carboxylate (7d). A solution of 6d (0.61 g, 1.6 mmol) in THF (8.1 mL) was cooled at –78 °C and treated with a 0.5 M KHMDS solution in toluene (3.6 mL, 1.8 mmol). The solution was stirred for 1 h at the same temperature and allowed to warm to room temperature. After stirring for 15 h for room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel to obtain 7d (0.42 g, 87% yield) as a white solid; IR (film) 3061, 2964, 2928, 2862, 2210, 1730, 1454, 1392, 1367, 1332, 1286, 1250, 1143, 1112, 1085, 1060, 1006, 971, 944, 865, 837, 755, 746, 729 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.25-7.13 (4H, m, ArH), 3.55-3.39 (2H, m, NCH2), 2.62 (3H, s, ArCH3), 2.40 (1H, ddd, J = 13.6, 3.6, 3.6 Hz, CH2), 2.13 (1H, ddd, J = 13.6, 13.6, 3.6 Hz, CH2), 1.92-1.83 (1H, m, CH2), 1.82-1.69 (2H, m, CH2), 1.62-1.42 (1H, m, CH2), 1.55 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ 169.5, 137.0, 136.0, 133.2, 128.7, 127.2, 126.0, 117.0, 83.4, 70.6, 49.4, 32.0, 27.9, 23.5, 21.2, 20.9; HRMS–ESI (m/z): [M+Na]+ calcd for C18H24N2O2Na: 323.1730. Found: 323.1727.
Preparation of tert-butyl 1-(iminomethyl)-2-(o-tolyl)piperidine-2-carboxylate (8d). A mixture of 7d (153 mg, 0.509 mmol) and palladium on activated carbon (loading: 10 wt.%, 29 mg) in MeOH (5 mL) was stirred for 1 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by chromatography on pH-controlled silica gel (Chromatorex NH–DM1020)(hexane/EtOAc = 3/1 to 2/1 as the eluent) to obtain 8d (143 mg, 93% yield) as a white solid; IR (KBr) 3427, 3287, 3057, 2978, 2947, 2869, 2822, 1725, 1620, 1454, 1392, 1356, 1285, 1244, 1150, 1125, 1005, 973, 956, 897, 845, 820, 778, 756, 723 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (1H, s, CH=N), 7.24-7.11 (3H, m, ArH), 7.08 (1H, dd, J = 8.2, 1.2 Hz, ArH), 4.45-4.35 (1H, m, NH), 2.58-2.45 (1H, m, NCH2), 2.50 (3H, s, ArCH3), 2.37-2.29 (1H, m, NCH2), 2.00 (1H, ddd, J = 13.3, 13.3, 3.8 Hz, CH2), 1.86-1.76 (2H, m, CH2), 1.73-1.46 (2H, m, CH2), 1.54 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ 171.2, 161.3, 138.5, 136.0, 133.3, 127.7, 127.3, 126.1, 82.7, 71.9, 40.3, 33.3, 27.9, 23.3, 22.0, 21.7; HRMS–ESI (m/z): [M+H]+ calcd for C18H27N2O2: 303.2067. Found: 303.2063.
Preparation of tert-butyl 2-(o-tolyl)piperidine-2-carboxylate (9d) and tert-butyl 1-methyl-2-(o-tolyl)piperidine-2-carboxylate (2). Sodium borohydride (32 mg, 0.85 mmol) was added to a solution of 8d (45.8 mg, 0.151 mmol) in THF (1.35 mL) and water (0.15 mL) at 0 °C. After stirring for 1 h at room temperature, the resulting mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc = 15/1 to 10/1 as the eluent) to obtain 9d (31.3 mg, 75%) as a colorless oil and 2 (2.4 mg, 5% yield) as a colorless oil. 9d: colorless oil; IR (film) 3427, 3333, 3059, 2932, 2867, 2827, 2783, 2690, 1724, 1601, 1479, 1453, 1391, 1366, 1239, 1161, 1121, 1059, 1030, 969, 930, 898, 838, 755 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64-7.57 (1H, m, ArH), 7.18-7.06 (3H, m, ArH), 2.89 (1H, dddd, J = 12.2, 4.5, 4.5, 0.8 Hz, NCH2), 2.82 (1H, ddd, J = 12.2, 9.5, 3.6 Hz, NCH2), 2.47 (3H, s, ArCH3), 2.32-2.21 (1H, m, CH2), 2.18 (1H, br, NH), 1.90-1.67 (3H, m, CH2), 1.63-1.47 (2H, m, CH2), 1.44 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ 174.5, 142.0, 136.0, 132.2, 126.8, 126.2, 125.6, 80.9, 65.7, 42.7, 32.9, 27.9, 25.4, 21.7, 21.0; HRMS–ESI (m/z): [M+H]+ calcd for C17H26NO2: 276.1958. Found: 276.1958. 2: colorless oil; IR (film) 3059, 2974, 2928, 2804, 2719, 1716, 1477, 1453, 1391, 1366, 1291, 1238, 1212, 1158, 1135, 1099, 1056, 1033, 1004, 956, 894, 847, 773, 754, 722 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.30 (1H, br, ArH), 7.15-7.06 (3H, m, ArH), 2.79 (1H, d, J = 11.2 Hz, NCH2), 2.66 (1H, dd, J = 11.2, 11.2 Hz, NCH2), 2.55 (3H, br, ArCH3), 2.30 (3H, s, NCH3), 2.16 (1H, d, J = 11.2 Hz, CH2), 1.85-1.50 (5H, m, CH2), 1.55 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3) δ 171.9, 141.7, 136.6, 132.4, 127.1, 126.5, 125.4, 81.2, 72.3, 50.8, 40.9, 34.5, 28.4, 25.4, 22.1, 21.0; HRMS–ESI (m/z): [M+H]+ calcd for C18H28NO2: 290.2115. Found: 290.2113.

ACKNOWLEDGEMENTS
This work was supported by KAKENHI (Grant-in-Aid for Young Scientists (B), 23750037), The Union Tool Scholarship Foundation, The Foundation for Japanese Chemical Research, and The Uchida Energy Science Promotion Foundation.

References

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10. The Sommelet–Hauser and [1,2] Stevens rearrangement are competitive. The selectivity of these rearrangements is determined by the base, solvent, temperature, and the structure of the substrate. For an example, the use of a sodium base (sodium tert-butoxide) and a nonpolar solvent (dichloromethane) preferred to give the [1,2] Stevens rearrangement product. Other examples: see, ref. 6.
11. We attempted the reactions of 2-methyl- and 3-methoxy-pyrrolidinyl derivatives to obtain the corresponding substituted pipecolinic acid esters. However, the reactions were unsuccessful because of the formation of a mixture of four isomers after von Braun reaction.