Simple preparation of β-amino alcohols possessing a tert-butyl group at the α-carbon

Article abstract of DOI:10.1055/s-0031-1291039

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. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291039

SHORT PAPER
▌1625
short paper
Simple Preparation of β-Amino Alcohols Possessing a tert-Butyl Group at the
α-Carbon
James T. Zacharia, Takanori Tanaka, Yumiko Uesaka, Masahiko Hayashi*
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe, 657-8501, Japan
Fax +81(78)8035688; E-mail: mhayashi@kobe-u.ac.jp
Received: 12.03.2012; Accepted after revision: 12.04.2012
lytic systems, however, most of the substrates they em-
Abstract: Simple preparation of β-amino alcohols possessing a
ployed were dibenzylamines and rearranged amino
tert-butyl group at the α-carbon was achieved. These β-amino alco-
alcohols were obtained in 88–99% enantiomeric excess.
hols proved to work effectively as catalysts in the enantioselective
alkylation of aldehydes.
stoichiometric conditions
Key words: amino alcohols, alkylation, organocatalysis, enantio-
1) TFAA (1.5 equiv)
selectivity, rearrangements
R1
R2
Et3N (2 equiv)
NBn2
NBn2
OH
2) NaOH (8 equiv)
R2
R1
catalytic conditions
1) TFAA (0.2 equiv)
2) NaOH (0.3 equiv)
OH
Enantioselective alkylation of aldehydes with dialkyl-
zincs catalyzed by β-amino alcohol is one of the most es-
tablished methods of obtaining optically active secondary
alcohols. There have thus been many reports on the devel-
opment 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 dial-
kylzincs using β-amino alcohols possessing a tert-butyl
group at the α-carbon (i.e., the hydroxy carbon) has previ-
ously been reported.3 At that time, the desired β-amino al-
cohols were prepared according to the procedure depicted
in Scheme 1, which involved a Baker’s yeast mediated re-
duction.
Scheme 2 Rearrangement of N,N-dibenzylamino alcohols using
TFAA/Et3N/NaOH system reported by Cossy and co-workers4
We planned the synthesis of β-amino alcohols possessing
a tert-butyl group at the α-carbon based on Cossy’s rear-
rangement 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-ami-
no alcohols having piperidino and morphorino groups (2a
and 2b), because they have been shown to work efficient-
ly as catalysts in enantioselective alkylation.2
X
Br
O
O
O
t-Bu
N
Br2
HCO2K
MeOH
t-Bu
NH2
OH
K2CO3 (5 equiv)
EtOH
Br
OH
+
X
t-Bu
t-Bu
t-Bu
MeOH
OH
92%
OH
75%
1a X = CH2 60%
1b X = O 80%
Br
OH
*
OH
Baker's yeast
aq KOH
HBr
Br
*
t-Bu
t-Bu
60%
X
X
96%
1) TFAA (0.4 equiv)
toluene, 120 °C, 24 h
100% ee (R)
t-Bu
N
N
HO
t-Bu
O
2) NaOH (3.75 M), 2 h
R2NMgBr
OH
t-Bu
OH
t-Bu
NR2
2a X = CH2 74%
2b X = O 77%
78%
>99% ee (R)
>99% ee (R)
Scheme 3 Three-step synthesis of β-amino alcohols possessing an α-
tert-butyl group
Scheme 1 Previous method used for the synthesis of β-amino alco-
hols possessing a tert-butyl group at the α-carbon
Gratifyingly, the desired products (2a and 2b) were ob-
tained 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 rearrange-
ment, 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 com-
pounds were then employed in the reaction of diethylzinc
with benzaldehyde; the results are summarized in Table 1.
In 2006, Cossy and co-workers reported the rearrange-
ment of N,N-dibenzylamino alcohols using a trifluoroace-
tic anhydride, triethylamine and sodium hydroxide
(TFAA/Et3N/NaOH) system to give 1,2-amino alcohols
(Scheme 2).4 They reported both stoichiometric and cata-
SYNTHESIS 2012, 44, 1625–1627
Advanced online publication: 08.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291039; Art ID: SS-2012-F0262-OP
© Georg Thieme Verlag Stuttgart · New York

1626
J. T. Zacharia et al.
SHORT PAPER
Table 1 Enantioselective Ethylation of Benzaldehydea
(hexane–EtOAc, 10:1) and the final product was recrystallized
(hexane–EtOAc) to give (S)-1a.
OH
26
Yield: 1.1 g (5.9 mmol, 60%); colorless solid; mp 73–75 °C; [α]D
β-amino alcohol
CHO
(2 mol%)
+22.3 (c 1.0, CHCl3); Rf = 0.15 (hexane–EtOAc, 3:1).
Et
+
Et2Zn
IR (KBr): 3265, 2932, 1440, 1354, 1269, 1167, 1122, 1044, 1014,
993, 753 cm–1.
hexane
0 °C, 24 h
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.
Entry
β-Amino alcohol Yield (%)
ee (%)
1
2
3
4
1a
1b
2a
2b
20
17
94
70
56 (R)
36 (R)
98 (R)
98 (R)
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 add-
ing H2O (5 mL). After extraction with EtOAc (3 × 10 mL) and pu-
rification by silica gel column chromatography (hexane–EtOAc,
3:1), the O-protected product was obtained (53.1 mg, 92%). The en-
antiomeric 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; de-
tection 220 nm): tR = 11.7 (S-isomer), 13.0 (R-isomer) min.
a Reaction conditions: diethylzinc (1.2 equiv), β-amino alcohol (2
mol%) in hexane (0.5 M), 0 °C, 24 h.
From the results presented in Table 1, it is clear that β-
amino alcohols possessing a tert-butyl group at the α-car-
bon group (2a and 2b) worked more efficiently than β-
amino alcohols possessing the tert-butyl group at the car-
bon linked to the amino group (1a and 1b) with respect to
both catalytic activity and enantioselectivity (Figure 1).
2- Morpholino-3,3-dimethyl-1-butanol (1b)
O
O
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, fol-
lowed 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 col-
umn chromatography (hexane–EtOAc, 10:1) and the final product
was recrystallized (hexane–EtOAc).
N
N
t-Bu
N
t-Bu
N
t-Bu
OH
2a
t-Bu
OH
2b
OH
1a
OH
1b
Figure 1
Thus, we have disclosed a simple preparation of α-tert-
butyl β-amino alcohols.
Yeld: 63.0 mg (80%); Rf = 0.09 (hexane–EtOAc, 3:1); mp 56–
58 °C; [α]D26 +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,
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 tech-
niques. All starting materials were obtained from commercial
1
sources and used without further purification. H and 13C NMR
74.7.
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 car-
ried 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
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 ar-
gon 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 col-
umn chromatography (hexane–EtOAc, 3:1).
TLC aluminum sheets coated with silica gel 60 F254
.
2-Piperidino-3,3-dimethyl-1-butanol (1a)
31
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) dis-
solved in anhydrous EtOH (15 mL) was added into the flask fol-
lowed 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 res-
idue, which was purified by silica gel column chromatography
Yield: 274.3 mg (74%); Rf = 0.11 (hexane–EtOAc, 3:1); [α]D
–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).
Synthesis 2012, 44, 1625–1627
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Preparation of β-Amino tert-Butyl Alcohols
1627
13C NMR (100.6 MHz, CDCl3): δ = 24.3, 25.6, 26.2, 33.2, 54.6,
59.7, 72.9.
Enantiomeric excess was determined by HPLC analysis using a
CHIRALCEL OD-H (DAICEL) column.
MS: m/z = 186 [M + H]+.
(R)-1-Phenyl-1-propanol
Yield: 210.0 mg (94%); 98% ee; [α]D29 +41.9 (c 1.00, CHCl3) {Lit.2
[α]D20 +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]: tR = 10.2
(R-isomer), 11.9 (S-isomer) min.
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 add-
ing 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.
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.
Yield: 51.0 mg (87%).
The enantiomeric excess of O-protected β-amino alcohol 2a was de-
termined to be more than 99.8% (R) by HPLC analysis using a chi-
ral column (CHIRALCEL OD-H, DAICEL, 0.46 × 25 cm; hexane–
i-PrOH, 99.9:0.1; 1.0 mL/min; detection 220 nm): tR = 18.0 (S-iso-
mer), 19.5 (R-isomer) min.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
is an explanation for the origin of reactivity and enantioselectivity,SunpIgfpi
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1-Morpholino-3,3-dimethyl-2-butanol (2b)
2-Morpholino-3,3-dimethyl-1-butanol (374.56 mg, 2 mmol) dis-
solved in anhydrous toluene (5 mL) was added to a pre-dried three-
necked flask equipped with a magnetic stirrer and a condenser un-
der 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 chromatog-
raphy (hexane–EtOAc, 3:1).
References
(1) For reviews, see: (a) Noyori, R.; Kitamura, M. Angew.
Chem. Int. Ed. 1991, 30, 49. (b) Soai, K.; Niwa, S. Chem.
Rev. 1992, 92, 833. (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001,
101, 757.
(2) (a) Superchi, S.; Mecca, T.; Giorgio, E.; Rosini, C.
Tetrahedron: Asymmetry 2001, 12, 1235. (b) Le, Goanvic.
D.; Holler, M.; Pale, P. Tetrahedron: Asymmetry 2002, 13,
119. (c) Wolf, C.; Francis, C. J.; Hawes, P. A.; Shah, M.
Tetrahedron: Asymmetry 2002, 13, 1733. (d) Huang, H. M.;
Zheng, Z.; Chen, H. L.; Bai, C.; Wang, J. Tetrahedron:
Asymmetry 2003, 14, 1285. (e) Kang, S. W.; Ko, D. H.; Kim,
K. H.; Ha, D.-C. Org. Lett. 2003, 5, 4517. (f) Bauer, T.;
Gajewiak, J. Tetrahedron 2004, 60, 9163. (g) Szakonyi, Z.;
Balazs, A.; Martinek, T. A.; Fülöp, F. Tetrahedron:
Asymmetry 2006, 17, 199. (h) Hsieh, S.-S.; Gau, H.-M.
Chirality 2006, 18, 569. (i) Bisai, A.; Singh, P. K.; Singh, V.
K. Tetrahedron 2007, 63, 598. (j) Paolucci, C.; Rosini, G.
Tetrahedron: Asymmetry 2007, 18, 2923. (k) Martins, J. E.
D.; Wills, M. Tetrahedron: Asymmetry 2008, 19, 1250.
(l) Pisani, L.; Superchi, S. Tetrahedron: Asymmetry 2008,
19, 1784. (m) Mao, J. Synth. Commun. 2009, 39, 3710.
(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.
25
Yield: 288.4 mg (77%); Rf = 0.10 (hexane–EtOAc, 3:1); [α]D
–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.
(4) (a) Métro, T.-X.; Appenzeller, J.; Pardo, D. G.; Cossy, J.
Org. Lett. 2006, 8, 3509. (b) Métro, T.-X.; Pardo, D. G.;
Cossy, J. Chem.–Eur. J. 2009, 15, 1064.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1625–1627