Simple Preparation of β-Amino Alcohols Possessing a tert-Butyl Group at the α-Carbon

Abstract

Simple preparation of β-amino alcohols possessing a tert-butyl group at the α-carbon was achieved. These β-amino alcohols proved to work effectively as catalysts in the enantioselective alkylation of aldehydes.

Enantioselective alkylation of aldehydes with dialkyl­zincs catalyzed by β-amino alcohol is one of the most established methods of obtaining optically active secondary alcohols. There have thus been many reports on the development of β-amino alcohol type catalysts to be used in such reactions.[1] [2] However, many of the β-amino alcohols used in these reactions are not easy to prepare. Actually, a highly enantioselective reaction of aldehydes with dialkylzincs using β-amino alcohols possessing a tert-butyl group at the α-carbon (i.e., the hydroxy carbon) has previously been reported.[ ³ ] At that time, the desired β-amino alcohols were prepared according to the procedure depicted in Scheme [1], which involved a Baker’s yeast mediated reduction.

In 2006, Cossy and co-workers reported the rearrangement of N,N-dibenzylamino alcohols using a trifluoroacetic anhydride, triethylamine and sodium hydroxide (TFAA/Et₃N/NaOH) system to give 1,2-amino alcohols (Scheme [2]).[ ⁴ ] They reported both stoichiometric and catalytic systems, however, most of the substrates they employed were dibenzylamines and rearranged amino alcohols were obtained in 88–99% enantiomeric excess.

We planned the synthesis of β-amino alcohols possessing a tert-butyl group at the α-carbon based on Cossy’s rearrangement method. Although Cossy and co-workers did not provide examples of β-amino alcohols having a cyclic protected amino groups, we wanted to synthesized β-amino alcohols having piperidino and morphorino groups (2a and 2b), because they have been shown to work efficiently as catalysts in enantioselective alkylation.[ ² ]

Table 1 Enantioselective Ethylation of Benzaldehyde^a

Entry	β-Amino alcohol	Yield (%)	ee (%)
1	1a	20	56 (R)
2	1b	17	36 (R)
3	2a	94	98 (R)
4	2b	70	98 (R)

^a Reaction conditions: diethylzinc (1.2 equiv), β-amino alcohol (2 mol%) in hexane (0.5 M), 0 °C, 24 h.

Gratifyingly, the desired products (2a and 2b) were obtained very easily in three steps (Scheme 3). Thus, starting from the α-amino acid, reduction of the carboxylic acid and protection of the amino group, followed by rearrangement, gave the desired products 2a and 2b in good yield. After confirming the optical purity of the β-amino alcohol to be more than 99% ee (HPLC analysis), these compounds were then employed in the reaction of diethylzinc with benzaldehyde; the results are summarized in Table [1].

From the results presented in Table [1], it is clear that β-amino alcohols possessing a tert-butyl group at the α-carbon group (2a and 2b) worked more efficiently than β-amino alcohols possessing the tert-butyl group at the carbon linked to the amino group (1a and 1b) with respect to both catalytic activity and enantioselectivity (Figure [1]).

Thus, we have disclosed a simple preparation of α-tert-butyl­ β-amino alcohols.

All reactions were carried out in thoroughly cleaned and oven-dried glassware with magnetic stirring. Operations were performed under an atmosphere of anhydrous argon using Schlenk and vacuum techniques. All starting materials were obtained from commercial sources and used without further purification. ¹H and ¹³C NMR spectra (400 and 100.6 MHz, respectively) were recorded with a JEOL JNM-LA 400 instrument with Me₄Si as an internal standard (δ = 0 ppm). FTIR spectra were recorded with a Thermo Scientific, NICOLET iS5, iD5 ATR instrument. Mass spectra were measured with a Thermo Quest LCQ DECA plus. HPLC analyses were carried out with a HITACHI L-2000 series instrument equipped with diode array detector using chiral columns CHIRALCEL OD-H (DAICEL­, 0.46 × 25 cm). Optical rotations were measured with a HORIBA SEPA-300 polarimeter for a solution in a 1 dm cuvette. Preparative column chromatography was carried out using Fuji Silysia­ BW-4:10MH silica gel or YMC_GEL Silica (6 nm I-40–63 um). Thin-layer chromatography (TLC) was carried out on Merk 25 TLC aluminum sheets coated with silica gel 60 F₂₅₄.

2-Piperidino-3,3-dimethyl-1-butanol (1a)

K₂CO₃ (6.9 g, 49.9 mmol) was placed in a dry three-necked flask under an argon atmosphere. (S)-tert-Leucinol (1.2 g, 1.0 mmol) dissolved in anhydrous EtOH (15 mL) was added into the flask followed by 1,5-dibromopentane (2.8 mL, 20 mmol). The reaction mixture was stirred at 60 °C for 48 h, then cooled to r.t., filtered to remove undissolved K₂CO₃. The solution was concentrated to a residue, which was purified by silica gel column chromatography (hexane–EtOAc, 10:1) and the final product was recrystallized (hexane–EtOAc) to give (S)-1a.

Yield: 1.1 g (5.9 mmol, 60%); colorless solid; mp 73–75 °C; [α]_D ²⁶ +22.3 (c 1.0, CHCl₃); R_f = 0.15 (hexane–EtOAc, 3:1).

IR (KBr): 3265, 2932, 1440, 1354, 1269, 1167, 1122, 1044, 1014, 993, 753 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 0.96 (s, 9 H), 1.5–1.6 (m, 7 H), 2.40 (dd, J = 10.8, 4.8 Hz, 1 H), 2.7–2.8 (m, 2 H), 2.9–3.0 (m, 2 H), 3.4–3.5 (m, 1 H), 3.5–3.6 (m, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 24.9, 27.8, 29.1, 36.8, 51.6, 57.3, 74.8.

MS: m/z = 186 [M + H]⁺.

Determination of Enantiopurity of β-Amino Alcohol 1a

A mixture of THF (4 mL), β-amino alcohol 1a (37.2 mg, 0.2 mmol), and anhydrous NaHCO₃ (42.0 mg, 0.5 mmol) was stirred at 0 °C. To the mixture, a solution of benzoyl chloride (58 μL, 0.5 mmol) in THF (1 mL) was added. The reaction mixture was stirred at 20 °C for 1 h, heated at reflux (70 °C) for 10 h, and then quenched by adding H₂O (5 mL). After extraction with EtOAc (3 × 10 mL) and purification by silica gel column chromatography (hexane–EtOAc, 3:1), the O-protected product was obtained (53.1 mg, 92%). The enantiomeric excess of 1a was determined to be more than 99.8% (S) by HPLC analysis using chiral column (CHIRALCEL OD-H; DAICEL­, 0.46 × 25 cm; hexane–i-PrOH, 99.9:0.1; 0.5 mL/min; detection 220 nm): t _R = 11.7 (S-isomer), 13.0 (R-isomer) min.

2- Morpholino-3,3-dimethyl-1-butanol (1b)

K₂CO₃ (294.8 mg, 2.1 mmol) was placed in a dry three-necked flask under an argon atmosphere. (S)-tert-Leucinol (50 mg, 0.42 mmol) dissolved in anhydrous EtOH (15 mL) was added into the flask, followed by 2,2′-dibromodiethyl ether (197.1 mg, 0.85 mmol, 2 equiv). The reaction mixture was stirred at 60 °C for 48 h, then cooled to r.t., filtered to remove undissolved K₂CO₃. The solution was concentrated to a residue, which was purified by silica gel column chromatography (hexane–EtOAc, 10:1) and the final product was recrystallized (hexane–EtOAc).

Yeld: 63.0 mg (80%); R_f = 0.09 (hexane–EtOAc, 3:1); mp 56–58 °C; [α]_D ²⁶ +17.2 (c 1.0, CHCl₃).

IR (KBr): 3260, 2955, 1735, 1653, 1483, 1356, 1270, 1118, 1040, 1018, 944, 853, 762 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 1.0 (s, 9 H), 2.37 (dd, J = 10.8, 4.4 Hz, 1 H), 2.8–2.9 (m, 3 H), 3.0–3.1 (m, 2 H), 3.5–3.7 (m, 6 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 28.9, 36.6, 51.2, 57.9, 68.4, 74.7.

MS: m/z = 188 [M + H]⁺.

1-Piperidino-3,3-dimethyl-2-butanol (2a)

2-Piperidino-3,3-dimethyl-1-butanol (370.6 mg, 2 mmol) dissolved in anhydrous toluene (5 mL) was added to a pre-dried three-necked flask equipped with a magnetic stirrer and a condenser under an argon atmosphere. TFAA (168.0 mg, 0.8 mmol, 0.4 equiv) was added dropwise while stirring, then the mixture was heated at reflux (120 °C) for 24 h. The reaction mixture was cooled to r.t. and then quenched by adding aq NaOH (3.75 M, 5 mL) followed by H₂O (3 mL). The mixture was extracted with EtOAc (3 × 20 mL) and the combined organic phase was dried with anhydrous Na₂SO₄, filtered, and concentrated to a residue, which was purified by silica gel column chromatography (hexane–EtOAc, 3:1).

Yield: 274.3 mg (74%); R_f = 0.11 (hexane–EtOAc, 3:1); [α]_D ³¹ –70.3 (c 1.0, CHCl₃).

IR (KBr): 3440, 2937, 1479, 1385, 1304, 1155, 1092, 1015 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 0.90 (s, 9 H), 1.4–1.5 (m, 2 H), 1.5–1.6 (m, 4 H), 2.2–2.3 (m, 4 H), 2.6 (br, 2 H), 3.31 (dd, J = 10.0, 4.4 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 24.3, 25.6, 26.2, 33.2, 54.6, 59.7, 72.9.

MS: m/z = 186 [M + H]⁺.

Determination of Enantiopurity for β-Amino Alcohol 2a

A mixture of THF (4 mL), β-amino alcohol 2a (37.5 mg, 0.2 mmol), and anhydrous NaHCO₃ (42.0 mg, 0.5 mmol) was stirred at 0 °C. To the mixture, a solution of benzoyl chloride (58 μL, 0.5 mmol) in THF (1 mL) was added. The reaction mixture was stirred at 20 °C for 1 h, heated at reflux (70 °C) for 10 h, and then quenched by adding H₂O (5 mL). After extraction with EtOAc (3 × 10 mL) and silica gel column chromatography (hexane–EtOAc, 3:1), the O-protected product was obtained.

Yield: 51.0 mg (87%).

The enantiomeric excess of O-protected β-amino alcohol 2a was determined to be more than 99.8% (R) by HPLC analysis using a chiral column (CHIRALCEL OD-H, DAICEL, 0.46 × 25 cm; hexane–i-PrOH, 99.9:0.1; 1.0 mL/min; detection 220 nm): t _R = 18.0 (S-isomer), 19.5 (R-isomer) min.

1-Morpholino-3,3-dimethyl-2-butanol (2b)

2-Morpholino-3,3-dimethyl-1-butanol (374.56 mg, 2 mmol) dissolved in anhydrous toluene (5 mL) was added to a pre-dried three-necked flask equipped with a magnetic stirrer and a condenser under an argon atmosphere. TFAA (168.02 mg, 0.8 mmol, 0.4 equiv) was added dropwise while stirring. The mixture was heated at reflux (120 °C) for 24 h, then cooled to r.t. and quenched by adding aq NaOH (3.75 M, 5 mL) followed by H₂O (3 mL). The mixture was extracted with EtOAc (3× 20 mL) and the combined organic phase was dried with anhydrous Na₂SO₄, filtered, and concentrated to a residue. The residue was purified by silica gel column chromatography (hexane–EtOAc, 3:1).

Yield: 288.4 mg (77%); R_f = 0.10 (hexane–EtOAc, 3:1); [α]_D ²⁵ –69.2 (c 0.99, CHCl₃).

IR (KBr): 3464, 2954, 2855, 1645, 1456, 1295, 1119, 1014, 870 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 0.9 (s, 9 H), 2.3–2.4 (m, 4 H), 2.6–2.7 (m, 2 H), 3.33 (dd, J = 10.8, 3.2 Hz, 1 H), 3.7–3.8 (m, 4 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 25.6, 33.1, 53.6, 59.7, 67.1, 72.7.

MS: m/z = 188 [M + H]⁺.

Asymmetric Ethylation of Benzaldehyde (Table [1])

To a solution of chiral β-amino alcohol (0.036 mmol) in hexane (2.6 mL) at –40 °C, was added diethylzinc (0.22 mL, 2.2 mmol). The solution­ was warmed to 0 °C, stirred for 30 min, and then cooled to –40 °C again, after which benzaldehyde (191 mg, 1.8 mmol) was added. The reaction mixture was stirred for 24 h at 0 °C and then quenched by adding aq HCl (1 M, 20 mL). After extraction with Et₂O (3 × 20 mL), silica gel column chromatography (hexane–EtOAc­, 10:1), and Kugelrohr distillation, the product was obtained. Enantiomeric excess was determined by HPLC analysis using a CHIRALCEL OD-H (DAICEL) column.

(R)-1-Phenyl-1-propanol

Yield: 210.0 mg (94%); 98% ee; [α]_D ²⁹ +41.9 (c 1.00, CHCl₃) {Lit.[ ² ] [α]_D ²⁰ +42.9 [c 3.58, CHCl₃, 87.5% ee (R)]}; HPLC [CHIRALCEL OD-H (DAICEL); hexane–i-PrOH, 97.5:2.5; 1.0 mL/min]: t _R = 10.2 (R-isomer), 11.9 (S-isomer) min.

Acknowledgment

This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas, MEXT, Japan ‘Molecular Activation Directed toward Straightforward Synthesis’ and No. B23350043 from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

• References


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• References


For reviews, see:
• 1a Noyori R, Kitamura M. Angew. Chem. Int. Ed. 1991; 30: 49
  CrossrefSearch in Google Scholar
• 1b Soai K, Niwa S. Chem. Rev. 1992; 92: 833
  CrossrefSearch in Google Scholar
• 1c Pu L, Yu H.-B. Chem. Rev. 2001; 101: 757
  CrossrefPubMedSearch in Google Scholar
• 2a Superchi S, Mecca T, Giorgio E, Rosini C. Tetrahedron: Asymmetry 2001; 12: 1235
  CrossrefSearch in Google Scholar
• 2b Le GoanvicD, Holler M, Pale P. Tetrahedron: Asymmetry 2002; 13: 119
  CrossrefSearch in Google Scholar
• 2c Wolf C, Francis CJ, Hawes PA, Shah M. Tetrahedron: Asymmetry 2002; 13: 1733
  CrossrefSearch in Google Scholar
• 2d Huang HM, Zheng Z, Chen HL, Bai C, Wang J. Tetrahedron: Asymmetry 2003; 14: 1285
  CrossrefSearch in Google Scholar
• 2e Kang SW, Ko DH, Kim KH, Ha D.-C. Org. Lett. 2003; 5: 4517
  CrossrefSearch in Google Scholar
• 2f Bauer T, Gajewiak J. Tetrahedron 2004; 60: 9163
  CrossrefSearch in Google Scholar
• 2g Szakonyi Z, Balazs A, Martinek TA, Fülöp F. Tetrahedron: Asymmetry 2006; 17: 199
  CrossrefSearch in Google Scholar
• 2h Hsieh S.-S, Gau H.-M. Chirality 2006; 18: 569
  CrossrefSearch in Google Scholar
• 2i Bisai A, Singh PK, Singh VK. Tetrahedron 2007; 63: 598
  CrossrefSearch in Google Scholar
• 2j Paolucci C, Rosini G. Tetrahedron: Asymmetry 2007; 18: 2923
  CrossrefSearch in Google Scholar
• 2k Martins JE. D, Wills M. Tetrahedron: Asymmetry 2008; 19: 1250
  CrossrefSearch in Google Scholar
• 2l Pisani L, Superchi S. Tetrahedron: Asymmetry 2008; 19: 1784
  CrossrefSearch in Google Scholar
• 2m Mao J. Synth. Commun. 2009; 39: 3710
  CrossrefSearch in Google Scholar
• 3 Noyori R, Suga S, Kawai K, Okada S, Kitamura M, Oguni N, Hayashi M, Kaneko T, Matsuda Y. J. Organomet. Chem. 1990; 382: 19
  CrossrefSearch in Google Scholar
• 4a Métro T.-X, Appenzeller J, Pardo DG, Cossy J. Org. Lett. 2006; 8: 3509
  CrossrefSearch in Google Scholar
• 4b Métro T.-X, Pardo DG, Cossy J. Chem.–Eur. J. 2009; 15: 1064
  Search in Google Scholar

• Supplementary Material