Direct Aminoalkylation of α-Branched Aldehydes with in situ Generated Glycine Cation Equivalents

Abstract

The efficient synthesis of β-formyl-α-aminocarboxylates 4 by direct aminoalkylation of aldehydes with in situ generated ternary iminium salts from inexpensive starting materials is described. These compounds are easily transformed into α-amino-β,β-dialkyl-γ-butyrolactones 10 and α,α-dialkyl-β-dialkylamino-butane-1,4-­diols 11 and can be used as versatile building blocks.

β-formyl-α-aminocarboxylate - ternary iminium salts - 1,4-butanediols - Mannich bases - butyrolactones

References

1a Tramontini M. Angiolino L. Chemistry and Uses   CRC; Boca Raton FL: 1994. 

1b Kleinman EF. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Pergamon Press; Oxford: 1991.  p.893 

1c Overmann LE. Ricca DJ. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Pergamon Press; Oxford: 1991.  p.1007 

1d Tramontini M. Angiolino L. Tetrahedron  1990,  46:  1791 

1e Dimmock JR. Sidhu KK. Chen M. Reid RS. Allen TM. Kao GY. Truitt GA. Eur. J. Med. Chem.  1993,  28:  313 

1f Traxler P. Trinks U. Buchdunger E. Mett H. Meyer T. Müller M. Regenaß U. Rösel J. Lydon N. J. Med. Chem.  1995,  38:  2441 

2a Arend M. Risch N. Angew. Chem., Int. Ed. Engl.  1994,  33:  2422 ; Angew. Chem. 1994, 106, 2531

2b Arend M. Risch N. Angew. Chem., Int. Ed. Engl.  1995,  34:  2639 ; Angew. Chem. 1995, 107, 2861

2c Grumbach H.-J. Arend M. Risch N. Synthesis  1996,  883 

2d Arend M. Westermann B. Risch N. Angew. Chem. Int. Ed.  1998,  37:  1044 ; Angew. Chem. 1998, 110, 1096

2e Grumbach H.-J. Merla B. Risch N. Synthesis  1999,  1027 

2f Merla B. Risch N. J. Prakt. Chem.  1999,  341(5):  472 

2g Piper S. Risch N. Arkivoc  2003,  1:  86 

3a Merla B. Grumbach H.-J. Risch N. Synthesis  1998,  1609 

3b Delbos-Krampe J. Risch N. Flörke U. Z. Naturforsch., B: Chem. Sci  2004,  59:  414 

4 Katritzky AR. Urogdi L. Mayence A. Synthesis  1989,  323 

5

Preparation of β-Formyl-α-aminocarboxylates 4a-m. Method A: All reactions were conducted under argon. To generate the iminium salt 3, a solution of ethyl glyoxylate aminal 2 ⁴ (2.5 mmol) in anhyd CH₂Cl₂ (10 mL) was cooled to -80 °C. TiCl₄ (2.5 mmol, 0.28 mL) was added in one portion under stirring. After a reaction time of 1 h at this temperature, the aldehyde 1 (2.5 mmol) was added. The temperature was then allowed to rise slowly to 20 °C. The mixture was quenched with HCl (6 N) and the aqueous layer was washed with Et₂O several times. The aqueous layer was basified by the addition of aq sat. NaHCO₃ solution and NaOH (2 N) to pH 10-12. The product was extracted with Et₂O, the combined organic layers were dried (Na₂SO₄) and the solvent was removed in vacuo. The aminoalkylated aldehydes 4 were isolated as yellowish oily products without further purification. Analytical data of some representative synthesized compounds (* minor diastereoisomer):
2-Dibenzylamino-3,3-dimethyl-4-oxo-butyric Acid Ethyl Ester (4e): ¹H NMR (200 MHz, CDCl₃): δ = 1.08 (s, 3 H), 1.14 (s, 3 H), 1.43 (t, 3 H, J = 7.1 Hz), 3.68 (s, 1 H), (δ_A = 3.57, δ_B = 3.98, 4 H, J = 13.7 Hz), 4.25-4.44 (m, 2 H), 7.24-7.46 (m, 10 H), 9.35 (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 15.08, 20.39, 20.51 (q), 49.46 (s), 57.41, 60.98 (t), 66.17, 127.83, 128.82, 129.65 (d), 139.28, 170.99 (s), 205.02 (d) ppm. IR (neat): 3062, 3030, 2978, 2935, 2848, 1728, 1603, 1495, 1454, 1367, 1203, 1134, 1028, 970, 939, 748, 700 cm^-1. MS (80 eV): m/z (%) = 353 (10) [M]⁺, 282 (100), 280 (26), 253 (49), 159 (47), 117 (20), 106 (32), 91 (50), 65 (11), 42 (9). (1-Formyl-cyclohexyl)-piperidin-1-yl-acetic Acid Ethyl Ester (4g): ¹H NMR (200 MHz, CDCl₃): δ = 1.28 (t, 3 H, J = 7.1 Hz), 1.32-1.64 (m, 14 H), 1.88-2.21 (m, 2 H), 2.28-2.42 (m, 2 H), 2.59-2.73 (m, 2 H), 3.22 (s, 1 H), 4.16 (dq, 2 H, J = 7.1 Hz, J = 1.7 Hz), 9.80 (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 14.96 (q), 22.82, 22.95, 24.49, 25.96, 27.02, 29.42, 30.10 (t), 52.65 (s), 53.88, 60.54 (t), 76.34 (d), 170.29 (s), 207.68 (d) ppm. IR (neat): 2933, 2854, 2810, 1726, 1452, 1389, 1369, 1333, 1178, 1151, 1117, 1097, 860, 750 cm^-1. MS (80 eV): m/z (%) = 281 (23) [M]⁺, 251 (3), 207 (19), 170 (100), 133 (4), 96 (9), 55 (1), 41 (6).
2-(Benzyl-methyl-amino)-3-formyl-3-methyl-pentanoic Acid Ethyl Ester (4k): ¹H NMR (200 MHz, CDCl₃): δ = 0.80, 0.81* (t, 3 H, J = 7.6 Hz), 1.22, 1.28* (s, 3 H), 1.36*, 1.37 (t, 3 H, J = 7.1 Hz), 1.57-1.90 (m, 2 H), 2.33, 2.34* (s, 3 H), 3.63*, 3.65 (s, 1 H), (δ_A = 3.63, δ_B = 3.85, 2 H, J = 13.4 Hz), 4.26*, 4.27 (q, 2 H, J = 7.1 Hz), 7.18-7.44 (m, 5 H), 9.63, 9.74* (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 8.48, 8.58*, 15.01, 15.80, 16.65* (q), 27.28, 27.93* (t), 40.63, 40.87* (q), 52.90, 53.23* (s), 60.73, 60.82*, 61.58, 61.73* (t), 71.09*, 71.17, 127.55*, 127.60, 128.73, 129.00*, 129.06, 129.18* (d), 139.40, 139.67*, 170.40, 171.22* (s), 204.74, 206.32* (d) ppm. IR (neat): 2974, 2939, 2806, 1728, 1454, 1369, 1223, 1186, 1146, 1026, 741, 698 cm^-1. MS (80 eV): m/z (%) = 291 (18) [M]⁺, 217 (18), 206 (100), 152 (2), 131 (5), 120 (10), 91 (9), 65 (2), 56 (3), 42 (20).
2-Dimethylamino-3-ethyl-3-formyl-heptanoic Acid Ethyl Ester (4l): ¹H NMR (200 MHz, CDCl₃): δ = 0.71*, 0.73 (t, 3 H, J = 7.6 Hz), 0.84 (t, 3 H, J = 6.8 Hz), 0.90-1.19 (m, 4 H), 1.24 (t, 3 H, J = 7.1 Hz), 1.40-1.77 (m, 4 H), 2.24*, 2.25 (s, 6 H), 3.28 (s, 1 H), 4.14*, 4.16 (q, 2 H, J = 7.1 Hz), 9.84*, 9.85 (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 7.78, 8.05*, 14.14, 14.33*, 14.87 (q), 21.11, 23.04*, 23.59, 23.70*, 25.47*, 25.66, 27.67*, 29.65 (t), 43.96, 44.00* (q), 54.72, 54.83* (s), 60.57 (t), 72.65, 72.72* (d), 170.23, 170.26* (s), 206.83*, 206.90 (d) ppm. IR (neat): 2960, 2939, 2873, 2788, 1724, 1460, 1381, 1186, 1151, 1097, 1032, 944, 867, 766 cm^-1. MS (80 eV): m/z (%) = 257 (28) [M]⁺, 215 (2), 184 (6), 155 (4), 130 (100), 102 (8), 83 (2), 58 (17).

6 Laugraud S. Guingant A. d’Angelo J. J. Org. Chem.  1987,  52:  4788 

7 Merla B. Grumbach H.-J. Risch N. Synthesis  1998,  1609 

8

Preparation of β-Formyl-α-aminocarboxylates 4n-s and Hydrochlorides 7. Method B: The reactions were conducted under argon. To generate the iminium salt 6, a solution of ethyl glyoxylate aminal 5 ⁶ (2.5 mmol) in anhyd CH₂Cl₂ (5 mL) was cooled to 0 °C. Acetyl chloride (2.5 mmol, 0.18 mL) was added in one portion under stirring. After stirring the mixture for 1 h at this temperature, the aldehyde 1 (2.5 mmol) was added and the temperature was allowed to rise to 20 °C. The solvent was removed in vacuo and the crude product was diluted with Et₂O or EtOAc and filtered. Hydrochlorides 7 were isolated as colorless solids, dried in high vacuum and stored under argon. Hydrochloride 7 (2.0 mmol) was dissolved in CH₂Cl₂ (5 mL) and treated with cold aq sat. NaHCO₃ solution. The organic layer was washed with water and dried (Na₂SO₄). The solvent was removed in vacuo to yield β-formyl-α-aminocarboxylates 4. Analytical data of some representative synthesized compounds:
1-(1-Ethoxycarbonyl-2-methyl-3-oxo-2-phenyl-propyl)-piperidinium Chloride (7o): ¹H NMR (200 MHz, CDCl₃): δ = 0.87 (t, 3 H, J = 7.1 Hz), 1.54-1.99 (q, 6 H), 2.32 (s, 3 H), 2.48-2.85 (m, 2 H), 3.04-3.26 (m, 2 H), 3.59-3.93 (m, 2 H), 4.80 (s, 1 H), 7.23-7.44 (m, 5 H), 9.44 (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 13.74, 14.88, 21.97, 22.59, 44.82 (q), 55.72 (s), 62.86 (t), 71.47, 128.61, 129.38, 129.49 (d), 132.98, 164.78 (s), 198.01 (d) ppm. IR (KBr): 2950, 2841, 2733, 2629, 2525, 1740, 1714, 1450, 1414, 1331, 1264, 1207, 1021, 700 cm^-1. MS (70 eV): m/z (%) = 303(1) [M - HCl]⁺, 230 (3), 216 (9), 190 (29), 170 (35), 133 (38), 105 (100), 77 (25), 57 (12), 43 (23), 29 (45). 3-Methyl-4-oxo-3-phenyl-2-piperidin-1-yl-butyric Acid Ethyl Ester (4o): ¹H NMR (200 MHz, CDCl₃): δ = 1.13 (t, 3 H, J = 7.1 Hz), 1.32-1.58 (q, 6 H), 1.77 (s, 3 H), 2.38-2.52 (m, 2 H), 2.58-2.72 (m, 2 H), 4.00 (dq, 2 H, J = 7.1 Hz, J = 2.4 Hz), 4.05 (s, 1 H), 7.20-7.45 (m, 5 H), 9.64 (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 14.71, 16.90, 24.55, 27.07, 54.44 (q), 57.55 (s), 60.27 (t), 72.87, 127.72, 128.56, 128.63 (d), 137.99, 169.81 (s), 202.18 (d)ppm. IR (neat): 2937, 2858, 1730, 1655, 1598, 1446, 1396, 1211, 1066, 1028, 764, 702 cm^-1. MS (70 eV): m/z (%) = 303 (1) [M]⁺, 230 (5), 201 (10), 170 (13), 133 (28), 105 (93), 98 (100), 91 (16), 77 (38), 43 (29), 28 (11).
4-(1-Ethoxycarbonyl-2-methyl-3-oxo-2-phenyl-propyl)-morpholin-4-ium Chloride (7p): ¹H NMR (200 MHz, CDCl₃): δ = 1.85 (br s, 3 H), 2.29 (d, 3 H), 3.03-4.14 (m, 8 H), 4.77 (s, 1 H), 7.14-7.47 (m, 5 H), 9.41 (d, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 13.81, 15.06 (q), 55.84 (s), 63.22, 63.52 (q), 66.74 (t), 72.40, 128.71, 129.68 (d), 132.62, 164.50 (s), 197.96 (d) ppm. IR (KBr): 2950, 2784, 2727, 2517, 2451, 1741, 1722, 1446, 1425, 1335, 1282, 1269, 1217, 1196, 1132, 1097, 1059, 1012, 885, 842, 769, 702, 631 cm^-1. MS (70 eV): m/z (%) = 306 (94) [M - HCl + 1]⁺, 292 (2), 232 (5), 172 (100), 130 (6), 100 (3), 88 (7), 57 (45), 43 (21).
3-Methyl-2-morpholin-4-yl-4-oxo-3-phenyl-butyric Acid Ethyl Ester (4p): ¹H NMR (200 MHz, CDCl₃): δ = 1.02 (dt, 3 H, J = 7.1 Hz, J = 2.5 Hz), 1.70 (d, 3 H, J = 2.5 Hz), 2.36-2.50 (m, 2 H), 2.53-2.68 (m, 2 H), 3.48-3.61 (m, 4 H), 3.82-3.96 (m, 2 H), 3.95 (d, 1 H, J = 2.5 Hz), 7.15-7.34 (m, 5 H), 9.48 (d, 1 H, J = 2.5 Hz) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 14.64, 16.70, 53.42 (q), 57.59 (s), 60.55 (t), 67.83 (q), 72.10, 128.01, 128.63, 128.78 (d), 137.17, 169.32 (s), 201.70 (d) ppm. IR (neat): 2976, 2852, 1726, 1651, 1446, 1259, 1186, 1117, 1030, 1012, 868, 762, 700 cm^-1. MS (70 eV): m/z (%) = 305 (1) [M]⁺, 281 (9), 232 (7), 201 (25), 172 (100), 144 (57), 105 (57), 100 (60), 91 (11), 58 (31), 28 (13).

9a Bretschneider T. Miltz Münster WP. Steglich W. Tetrahedron  1988,  44:  5403 

9b Shipov AG. Zheltonogova EA. Kobzareva VP. Orlova NA. Baukov I. J. Gen. Chem. USSR  1991,  61:  2142 ; Zh. Obshch. Khim. 1991, 61, 2308

9c Kobayashi S. Ishitani H. J. Chem. Soc., Chem. Commun.  1995,  1379 

9d Ferraris D. Young B. Dudding T. Drury WJ. Lectka T. Tetrahedron  1999,  55:  8869 

10a König WA. Hass W. Dehler W. Fiedler HP. Zähner H. Liebigs Ann. Chem.  1980,  622 

10b Raffauf RF. Zennie TM. Onan KD. Le Quesne PW. J. Org. Chem.  1984,  49:  2714 

10c Helms GL. Moore RE. Niemczura WP. Patterson GML. Tomer KB. Gross ML. J. Org. Chem.  1988,  53:  1298 

10d Thodo K. Hamada Y. Shiori T. Synlett  1994,  105 

11

Reduction with NaBH ₄ to Yield α-Amino-β,β-dialkyl-γ-butyrolactones 10a-e. Method A: β-Formyl-α-aminocarboxylate (4) is synthesized by aminoalkylation of aldehyde 1 with iminium salt 3 as described above. To this reaction mixture a solution of NaBH₄ (3.0 mmol, 0.11 g) in anhyd EtOH (5 mL) was added and stirring was continued. After a reaction time of 5 h at 20 °C, the mixture was quenched with HCl (6 N) and the aqueous layer was washed with Et₂O several times. The aqueous layer was basified by the addition of aq sat. NaHCO₃ solution and NaOH (2 N) to pH 10-12. The product was extracted with Et₂O, the combined organic layers were dried (Na₂SO₄) and the solvent was removed in vacuo.
Reduction with NaBH ₄ to Yield α-Amino-β,β-dialkyl-γ-butyrolactones 10f-i. Method B: Hydrochloride 7 (1.0 mmol) was dissolved in anhyd EtOH (10 mL), NaBH₄ (2.5 mmol, 0.10 g)¹² was added and the mixture was stirred for 5 h at 20 °C. Workup follows as described in method A. Analytical data of some representative synthesized compounds (* minor diastereoisomer): 3-Dimethylamino-4,4-dimethyl-dihydro-furan-2-one (10a): ¹H NMR (200 MHz, CDCl₃): δ = 1.09 (s, 3 H), 1.13 (s, 3 H), 2.44 (s, 6 H), 2.93 (s, 1 H), (δ_A = 3.80, δ_B = 3.88, 2 H, J = 8.9 Hz) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 20.85, 27.09 (q), 40.96 (s), 44.51 (q), 72.72 (d), 78.36 (t), 175.43 (s) ppm. IR (neat): 2962, 2925, 2362, 2341, 1770, 1736, 1456, 1432, 1261, 1081, 1018, 798 cm^-1. MS (80 eV): m/z (%) = 157 (100) [M]⁺, 141 (10), 128 (9), 112 (10), 102 (46), 82 (17), 58 (18), 49 (88), 42 (60).
3-Dibenzylamino-4,4-dimethyl-dihydro-furan-2-one (10c): ¹H NMR (200 MHz, CDCl₃): δ = 0.66 (s, 3 H), 1.07 (s, 3 H), 3.16-3.29 (m, 5 H), 4.12-4.32 (m, 2 H), 7.12-7.40 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 20.80, 24.19 (q), 38.93 (s), 57.70 (t), 66.46 (d), 71.79 (t), 127.96, 129.01, 129.79 (d), 139.27 (s), 170.99 (s) ppm. IR (neat): 2958, 1763, 1736, 1493, 1448, 1365, 1130, 1026, 741, 696 cm^-1. MS (80 eV): m/z (%) = 309 (100) [M]⁺, 281 (12), 253 (49), 217 (62), 195 (20), 105 (10), 91 (42), 65 (5), 53 (3), 41 (5).
4-Piperidin-1-yl-2-oxa-spiro[4.5]decan-3-one (10e): ¹H NMR (200 MHz, CDCl₃): δ = 0.98-1.55 (m, 16 H), 2.24-2.45 (m, 2 H), 2.45-2.60 (m, 2 H), 2.74 (s, 1 H), (δ_A = 3.73, δ_B = 3.82, 2 H, J = 9.2 Hz) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 22.85, 23.06, 24.18, 25.63, 26.84, 29.20, 36.43 (t), 42.76 (s), 53.19 (t), 71.86, 77.28 (d), 175.42 (s) ppm. IR (KBr): 2931, 2852, 1772, 1450, 1169, 1144, 1099, 1012
cm^-1. MS (80 eV): m/z (%) = 237 (100) [M]⁺, 192 (2), 150 (8), 141 (56), 122 (8), 110 (11), 96 (9), 84 (10), 53 (3), 41 (5).
3-Dimethylamino-4-methyl-4-phenyl-dihydro-furan-2-one (10f): ¹H NMR (200 MHz, CDCl₃): δ = 1.44, 1.46* (s, 3 H), 2.07, 2.44* (s, 6 H), 3.36, 3.59* (s, 1 H), (δ_A = 4.19, δ_B = 4.62, 2 H, J = 9.2 Hz), (δ_A = 4.12, δ_B = 4.24, 2 H, J = 9.0 Hz, CH₂O)*, 7.12-7.43 (m, 5 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 22.34*, 29.41, 43.13, 44.93* (q), 46.82, 48.26* (s), 72.14*, 72.76 (d), 76.83*, 77.43 (t), 125.74*, 127.20, 127.43*, 127.55, 128.81, 129.27* (d), 141.48*, 144.84, 174.54*, 174.92 (s) ppm. IR (film): 2974, 2943, 2904, 2877, 2841, 2789, 2254, 1770, 1498, 1446, 1163, 1024, 910, 737, 650 cm^-1. MS (80 eV): m/z (%) = 219 (60) [M]⁺, 159 (6), 143 (4), 130 (4), 116 (11), 102 (100), 91 (4), 58 (24), 42 (31). 4-Methyl-4-phenyl-3-piperidin-1-yl-dihydro-furan-2-one; Compound with Methane (10g): ¹H NMR (200 MHz, CDCl₃): δ = 1.12-1.26 (m, 4 H), 1.43, 1.44* (s, 3 H), 1.47-1.60 (m, 2 H), 2.12-2.27 (m, 2 H), 2.31-2.49 (m, 2 H), 3.31, 3.53* (s, 1 H), (δ_A = 4.19, δ_B = 4.64, 2 H, J = 9.3 Hz), (δ_A = 4.18, δ_B = 4.31, 2 H, J = 9.0 Hz)*, 7.11-7.35 (m, 5 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 22.77*, 29.20 (q), 24.17, 24.47*, 26.71, 27.20* (t), 46.68, 48.01* (s), 51.96, 53.69* (t), 72.87*, 73.78 (d), 76.45*, 77.56 (t), 125.47*, 127.23, 127.35, 128.42, 129.16* (d), 141.43, 145.68*, 174.73*, 175.05 (s) ppm. IR (neat): 2939, 2856, 2252, 1759, 1626, 1446, 1169, 1107, 1024, 910, 737, 650 cm^-1. MS (80 eV): m/z (%) = 259 (29) [M]⁺, 142 (100), 117 (12), 96 (7), 68 (7), 55 (8), 41 (20).

12

The hydrochlorides may also be deprotonated with aq sat. NaHCO₃ before reduction. However, the deprotonation with the reducing agent is useful for small quantity of the β-formyl-α-aminocarboxylate hydrochlorides.

13

Reduction with LiAlH ₄ to Yield α,α-Dialkyl-β-dialkylamino-butane-1,4-diols 11. To hydrochlorides 7 (1.0 mmol) in anhyd THF (10 mL) was added 1 M LiAlH₄ in THF (4.0 mmol, 4 mL)¹² at 20 °C. After a reaction time of 10 h, the mixture was quenched very slowly with H₂O and HCl (6 N). The aqueous layer was washed with Et₂O several times and basified by the addition of aq sat. NaHCO₃ solution and NaOH (2 N) to pH 10-12. The product was extracted with CH₂Cl₂, the combined organic layers were dried (Na₂SO₄) and the solvent was removed in vacuo. Analytical data of some representative synthesized compounds (* minor diastereoisomer): 3-Dimethylamino-2-methyl-2-phenyl-butane-1,4-diol (11a): ¹H NMR (200 MHz, CDCl₃): δ = 1.12*, 1.36 (s, 3 H), 2.08*, 2.50 (s, 6 H), 3.02-3.25 (m, 2 H), 3.57-4.11 (m, 3 H), 7.06-7.55 (m, 5 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 16.04*, 24.58, 43.19, 44.31* (q), 44.61*, 45.00 (s), 59.96*, 60.59, 73.75*, 74.15 (t), 74.74*, 74.83, 126.11, 126.85*, 127.05, 128.49, 128.96* (d), 144.37*, 145.08 (s) ppm. IR (neat): 3350, 2947, 2881, 2843, 2252, 1498, 1466, 1444, 1385, 1026, 910, 737, 650 cm^-1. MS (70 eV): m/z (%) = 223 (5) [M]⁺, 192 (88), 176 (11), 162 (87), 147 (39), 118 (74), 115 (76), 102 (67), 88 (94), 70 (96), 58 (95) 44 (97), 28 (100).
2-Methyl-2-phenyl-3-piperidin-1-yl-butane-1,4-diol (11b): ¹H NMR (200 MHz, CDCl₃): δ = 1.36 (s, 3 H), 1.41-1.64 (m, 6 H), 2.11-2.52 (m, 2 H) 2.67-2.84 (m, 2 H), 2.89-3.01 (m, 2 H), 3.08 (t, 1 H, J = 11.9 Hz), (δ_A = 3.66, δ_B = 4.04, 2 H, J = 9.9 Hz), 7.04-7.26 (m, 5 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 16.27 (q), 24.64, 27.49 (t), 45.21 (s), 54.86, 60.43, 74.65 (t), 76.60, 126.07, 126.93, 128.89 (d), 144.34 (s) ppm. IR (KBr): 3361, 2937, 2854, 2252, 1468, 1454, 1442, 1039, 1026, 908, 733, 650 cm^-1. MS (70 eV): m/z (%) = 263 (8) [M]⁺, 232 (87), 210 (33), 201 (40), 142 (92), 128 (92), 118 (87), 112 (100), 98 (91), 84 (91), 69 (71), 55 (90), 41 (98), 28 (73). 2-Benzo[1,3]dioxol-5-ylmethyl-3-dimethylamino-2-methyl-butane-1,4-diol (11c): ¹H NMR (200 MHz, CDCl₃): δ = 0.52, 0.88* (s, 3 H), 2.45*, 2.51 (s, 6 H), 2.59-2.73 (m, 2 H), 3.11-3.57 (m, 3 H), 3.82-4.07 (m, 2 H), 5.83, 5.84* (s, 2 H), 6.44-6.75 (m, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 17.93*, 21.65 (q), 36.30 (t), 41.29*, 41.49 (s), 44.39, 44.68* (q), 59.41*, 59.68, 70.27, 71.37* (t), 72.65*, 75.65 (d), 101.09, 101.23* (t), 108.04, 108.18*, 111.35*, 111.56, 123.97*, 124.08 (d), 131.15*, 131.78, 146.13, 146.39*, 147.51, 147.62* (s) ppm. IR (KBr): 3329, 2945, 2879, 2252, 1504, 1489, 1442, 1248, 1095, 1041, 906, 733, 650 cm^-1. MS (80 eV): m/z (%) = 281 (70) [M]⁺, 249 (5), 134 (6), 113 (1), 98 (7), 88 (100), 58 (31), 44 (4).
2-Benzo[1,3]dioxol-5-ylmethyl-2-methyl-3-piperidin-1-yl-butane-1,4-diol (11d): ¹H NMR (200 MHz, CDCl₃): δ = 0.50, 0.87* (s, 3 H), 1.27-1.63 (m, 6 H), 2.24-2.46 (m, 2 H), 2.54-2.78 (m, 2 H), 2.84-3.05 (m, 6 H), 3.08-3.55 (m, 3 H), 3.75-4.07 (m, 2 H), 5.81, 5.82* (s, 2 H), 6.42-6.75 (m, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 18.25*, 21.86, 24.65*, 26.04, 27.47 (q), 36.45 (t), 41.36*, 41.55 (s), 44.57* (t), 53.32*, 54.88 (q), 59.47*, 59.68, 70.38, 71.27*(t), 74.27*, 77.56 (d), 101.06, 101.21* (t), 108.00, 108.15*, 111.35*, 111.55, 123.95* 124.05 (d), 131.27*, 131.86, 146.10, 146.36*, 147.50, 147.60* (s) ppm. IR (film): 3352, 2937, 2854, 2252, 1504, 1489, 1442, 1246, 1097, 1041, 910, 733, 650 cm^-1. MS (80 eV): m/z (%) = 321 (12) [M]⁺, 287 (52), 257 (5), 206 (5), 175 (9), 151 (18), 134 (100), 128 (78), 98 (92), 77 (30), 41 (48).