PAPER
Hydrolytic Kinetic Resolution of a-Naphthyl Glycidyl Ether
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stirred for 15 min at 0 °C. Distilled water (0.16 mL, 9.08 mmol) was
added over a period of 15 min via syringe pump and stirring contin-
ued at r.t. for 24 h. The reaction mixture was diluted with EtOAc (30
mL), dried over Na2SO4, and the solvent was removed under re-
duced pressure. The residue was chromatographed (EtOAc–petro-
leum ether). The first fraction (1:9) eluted gave (S)-naphthyl
glycidyl ether 3, while the second fraction (1:1) gave (R)-1-O-naph-
thyl glycerol 6.
1H NMR (400 MHz, CDCl3): d = 3.15–3.57 (m, 9 H, OH, exchange-
able with D2O, 4 × NCH, NCH2, OCH2), 3.89 (s, 3 H, OCH3), 4.02–
4.20 (m, 5 H, 4 × NCH, CHOH), 6.74–7.51 (m, 9 H, ArH, Ph),
7.72–7.79 (dd, J = 7.1 Hz, 1 H, ArH), 8.17–8.21 (dd, J = 2.3, 7.1
Hz, 1 H, ArH).
13C NMR (400 MHz, CDCl3): d = 154.51, 154.32, 138.18, 134.36,
127.33, 126.26, 125.74, 125.49, 125.29, 125.05, 124.06, 121.85,
121.10, 120.36, 111.79, 104.80, 70.12, 67.38, 61.73, 57.99, 55.31,
51.26, 44.58, 42.51.
6
FAB (MS): m/z = 330 (M+ + 1).
Yield: 1.5 g, 43%; colorless liquid; [a]D 30.2 (c 1.5, MeOH) [Lit.9
31.4 (c 1.5, MeOH)].
Anal. Calcd for C24H28N2O3: C, 73.44; H, 7.19; N, 7.14. Found: C,
73.39; H, 7.17; N, 7.16.
(S)-3
Yield: 1.62 g, 47%; light yellow solid; mp 107–108 °C (Lit.12 108–
3-(Naphthalene-1-yloxy)-1-(2-propyl)aminopropane-2-ol (2)
A solution of (S)-3 (0.6 g, 3.0 mmol) in i-PrNH2 (2.5 mL) and H2O
(2 drops) was stirred at ambient temperature until TLC showed the
reaction had gone to completion (12 h). Removal of the solvent
yielded the crude propranolol as a free base, which could be either
purified by recrystallization (hexane) or, more conveniently, con-
verted directly to its HCl salt by adding ethereal HCl to a solution
of the crude product in Et2O.
109 °C); [a]D –5.6 (c 0.7, EtOH) [Lit.12 –5.7 (c 0.7, EtOH)].
1H NMR (CDCl3): d = 1.85–2.06 (br s, 1 H, OH), 2.43–2.69 (br s, 1
H, OH), 3.81–4.03 (m, 2 H, CH2OH), 4.21–4.38 (m, 3 H, CH2OAr,
CHOH), 6.82 (d, J = 7.1 Hz, 1 H, ArH), 7.23–57 (m, 4 H, ArH),
7.80 (dd, J = 2.3, 7.1 Hz), 8.20 (dd, J = 2.3, 7.1 Hz, 1 H, ArH).
EIMS: m/z = 218 (M+).
1-(2-Methoxyphenyl)piperizine (4)
Method A
Yield: 0.67 g, 90%; white crystals; mp 193–195 °C (Lit.10 192–
193.5 °C; [a]D –25.9 (c 1.0, EtOH) [Lit.10 –25.5 (c 1.05, EtOH)].
A mixture of o-anisidine (3.4 g, 28.02 mmol), bis(2-chloroeth-
yl)amine hydrochloride (5.0 g, 28.02 mmol) and aq Na2CO3 soln
(5.94 g, 30 mL, 56.0 mmol) was refluxed in the presence of a ben-
zyltriethyl ammonium chloride (cat., 0.50 g) at 100 °C for 24 h. The
reaction mixture was diluted with EtOAc (50 mL), filtered, and the
filtrate was further extracted with EtOAc (2 × 25 mL). The com-
bined organic phases were concentrated under reduced pressure,
and the resulting residue was purified by column chromatography
(EtOAc–hexane, 2:1) to afford compound 4 as a gummy yellow syr-
up (4.55 g) in 85% yield.
IR (KBr): 3420 (OH), 3285 (NH) cm–1.
1H NMR (300 MHz, D2O): d = 1.35 (d, J = 6.2 Hz, 6 H), 3.29–3.42
(m, 2 H), 3.45–3.55 (dd, J = 6.2, 12.2 Hz, 1 H), 4.21–4.36 (m, 2 H),
4.41–4.50 (m, 1 H), 7.01 (d, J = 7.4 Hz, 1 H), 7.47 (m, 1 H), 7.52–
7.63 (m, 3 H), 7.92 (d, J = 7.4 Hz, 1 H), 8.28 (d, J = 7.4 Hz, 1 H).
13C NMR (300 MHz, CDCl3): d = 154.24, 134.50, 127.45, 126.3,
126.8, 125.5, 125.1, 121.8, 120.5, 104.8, 70.7, 68.7, 49.6, 48.9,
22.9.
EIMS: m/z = 245 (M+).
Method B
The mixture of o-chloroanisole (4.29 g, 30.0 mmol) and piperazine
monohydrochloride (3.69 g, 30.0 mmol), K2CO3 (8.28 g, 60.0
mmol) and CuI (0.150 g) in 2-butanone (30 mL) was refluxed over-
night at 100 °C. After completion of the reaction (monitored by
TLC), the solvent was removed under reduced pressure.
Acknowledgment
One of the authors (SWC) thanks CSIR, New Delhi for financial
support.
The reaction mixture was diluted with EtOAc (50 mL), filtered and
the filtrate was further extracted with EtOAc (2 × 25 mL). The com-
bined organic phases were concentrated under reduced pressure and
the resulting residue was purified by column chromatography
(EtOAc–hexane, 2:1).
References
(1) Crosby, J. Tetrahedron 1991, 47, 4789.
(2) Decamp, W. H. Chirality 1989, 1, 2.
(3) For leading reviews, see: (a) Johnson, R. A.; Sharpless, K.
B. Catalytic Asymmetric Epoxidation of Allylic Alcohols, In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993, 103–158. (b) Katsuki, T.; Martin, V. S. Org.
React. 1996, 48, 1.
(4) For leading reviews, see: (a) Jacobsen, E. N.; Wu, M. H. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York, 1999,
Chap. 182. (b) Jacobsen, E. N. . Asymmetric Catalytic
Epoxidation of Unfunctionalized Olefins, In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
1993, 159. (c) Collman, J. P.; Zhang, X.; Lee, V. J.;
Uffelman, E. S.; Brauman, J. I. Science (Washington, DC, U.
S.) 1993, 261, 1404. (d) Katsuki, T. Asymmetric
Epoxidation of Unfunctionalized Olefins and Related
Reactions, In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH: New York, 2000, 287.
Yield: 5.19 g (90%); viscous yellow syrup.
1H NMR (CDCl3): d = 3.34–3.40 (m, 2 H, 2 × HNCH), 3.47–3.53
(m, 2 H, 2 × HNCH), 3.54–3.60 (m, 2 H, 2 × NCH), 3.82 (s, 3 H,
OCH3), 4.21–4.30 (t, J = 10.9 Hz, 2 H, 2 × NCH), 4.45 (br s, 1 H,
NH), 6.52–6.82 (m, 4 H, ArH).
(S)-1-[4-(2-Methoxyphenyl)-1-piperazinyl]-3-(1-naphthoxy)-2-
propanol (1)
A mixture of (S)-3 (0.6 g, 3.0 mmol) and amine 4 (0.580 g, 3.0
mmol) was refluxed in anhyd i-PrOH (10 mL) for 30 h. The solvent
was removed under reduced pressure and the resulting residue was
chromatographed on silica gel (EtOAc–hexane, 3:1) to afford (S)-1.
A small amount of the (S)-1 was converted to its Mosher ester [(+)-
MTPACl, 4-DMAP, Et3N, CH2Cl2] and 1H NMR analysis showed
only one diastereomer.
(5) For recent reviews, see: (a) Porter, M. J.; Skidmore, J.
Chem. Commun. 2000, 1215. (b) Nemoto, T.; Ohshima, T.;
Shibasaki, M. J. Synth. Org. Chem. Jpn. 2002, 60, 94.
Yield: 1.1 g (93%); light yellow solid; mp 126–129 °C (dec.); [a]D
+4.5 (c 1.5, MeOH).
IR (neat): 3450, 3030, 2985, 2910, 1265, 1225 cm–1.
Synthesis 2005, No. 14, 2345–2348 © Thieme Stuttgart · New York