228
Z. Shao et al. / Tetrahedron: Asymmetry 20 (2009) 225–229
HRMS (ESI): calcd for C17H24NO3 [M+1]+, 290.1756; found,
290.1768. The enantiomeric excess was determined by HPLC with
a OD-H column (n-hexane/i-PrOH = 90:10, k = 254 nm), 1.0 mL/
min), tR (major) = 9.84 min, tR (minor) = 14.89 min.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3 on a
Bruker Avance DPX 400 (400 and 100 MHz, respectively) NMR
spectrometer at room temperature. Chemical shifts (d) are
expressed in ppm, and J values are given in Hertz. High-resolution
mass spectrometry (HRMS) was carried out by using the electro-
spray ionization (ESI) method on a Fisons VG platform or a MAT-
95 spectrometer (Finnigan-MAT, San Jose, CA). HPLC analyses were
performed by using a Waters 600 analytical liquid chromatography
system with a Waters 486 UV detector. All reactions were con-
ducted under a nitrogen atmosphere. The enantiomeric excess
was determined by Chiralpak AD, AD-H, or Chiralcel OD-H column
using n-hexane and iso-propanol as eluents at 25 °C. All chemicals
were used as received without further purification unless other-
wise stated. CH2Cl2 was distilled from CaH2. Flash column chroma-
tography was performed on silica gel (230–400 mesh).
4.3.4. Ethyl 2-(4-methoxyphenylamino)hept-3-ynoate 2d
Yield: 72%; 1H NMR (400 MHz, CDCl3): d 6.85–6.82 (m, 2H), 6.74–
6.71 (m, 2H), 4.76 (br s, 1H), 4.33 (q, 2H, J = 7.2 Hz), 4.24 (br s, 1H),
3.80 (s, 3H), 2.23–2.19 (m, 2H), 1.55 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H,
J = 7.2 Hz, 0.98 (t, 3H, J = 7.4 Hz); 13C NMR (125 MHz, CDCl3): d
169.5, 153.2, 139.7, 115.9, 114.7, 85.2, 75.2, 62.1, 55.6, 50.1, 21.8,
20.6, 14.0, 13.3; HRMS (ESI): calcd for C16H22NO3 [M+1]+,
276.1600; found, 276.1597. The enantiomeric excess was deter-
mined by HPLC with a AD column (n-hexane/i-PrOH = 90:10,
k = 254 nm), 1.0 mL/min, tR (major) = 10.67 min, tR (minor) =
16.37 min.
4.3.5. Ethyl 2-(4-methoxyphenylamino)-5-(trimethylsilyl)pent-
3-ynoate 2e
Yield: 61%; 1H NMR (400 MHz, CDCl3): d 6.71–6.68 (m, 2H),
6.60–6.58 (m, 2H), 4.63 (br s, 1H), 4.18 (q, 2H, J = 7.0 Hz), 4.09
(br s, 1H), 3.66 (s, 3H), 1.37 (d, 2H, J = 2.7 Hz), 1.22 (t, 3H,
J = 7.2 Hz), 0.03 (s, 9H); 13C NMR (125 MHz, CDCl3): d 169.7,
153.1, 139.7, 115.9, 114.7, 83.2, 73.9, 62.0, 55.7, 50.2, 14.1, 7.1,
ꢁ2.2. The enantiomeric excess was determined by HPLC with a
AD column (n-hexane/i-PrOH = 90:10, k = 254 nm), 1.0 mL/min, tR
(major) = 9.08 min, tR (minor) = 15.73 min.
4.2. Typical procedure for the enantioselective three-component
reaction of terminal alkynes with ethyl glyoxylate and para-
anisidine
To a 1.0-mL CH2Cl2 solution of in-pybox 7 (9.8 mg, 0.025 mmol),
at room temperature, under a nitrogen atmosphere, CuOTfꢀ0.5C6H6
(6.3 mg, 0.025 mmol) was added. After stirring at room temperature
for 1 h, the terminal alkyne (0.5 mmol) was added, followed by the
addition of ethyl glyoxylate (0.26 mmol) and para-anisidine
(0.25 mmol) in CH2Cl2 (0.5 mL). The resulting solution was stirred
at room temperature until TLC monitored thecompletion of thereac-
tion. The mixture was then passed through a short plug of silica gel
and purified by flash silica gel column chromatography. The enantio-
meric excess of the product was determined by chiral HPLC analysis.
4.3.6. Ethyl 2-(4-methoxyphenylamino)-4-phenylbut-3-ynoate
2f
Yield: 79%; 1H NMR (400 MHz, CDCl3): d 7.28–7.25 (m, 2H),
7.20–7.16 (m, 3H), 6.80–6.78 (m, 2H), 6.67–6.65 (m, 2H), 4.69 (t,
1H, J = 2.3 Hz), 4.27–4.24 (q, 2H, J = 7.5 Hz), 3.76 (s, 3H), 2.80–
2.77 (t, 2H, J = 7.3 Hz), 2.49–2.46 (dt, 2H, J = 7.3, 2.0 Hz), 1.31–
1.28 (t, 3H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3): d 169.1,
153.4, 139.5, 132.0, 128.8, 128.3, 122.2, 116.1, 114.9, 84.4, 84.2,
62.5, 55.7, 50.7, 14.2. The enantiomeric excess was determined
4.3. Characterization of the products
by HPLC with
k = 254 nm), 1.0 mL/min, tR (major) = 18.80 min, tR (minor) =
23.40 min.
a
AD-H column (n-hexane/i-PrOH = 90:10,
4.3.1. Ethyl 2-(4-methoxyphenylamino)-6-phenylhex-3-ynoate 2a
Yield: 80%; 1H NMR (400 MHz, CDCl3): d 7.34–7.21 (m, 5H),
6.86–6.83 (m, 2H), 6.72–6.69 (m, 2H), 4.74 (br s, 1H), 4.31 (q, 2H,
J = 7.0 Hz), 4.22 (br s, 1H), 3.81 (s, 3H), 2.85 (t, 2H, J = 7.4 Hz),
2.56–2.51 (m, 2H), 1.35 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz,
CDCl3): d 169.3, 153.2, 140.4, 139.6, 128.4, 128.3, 126.2, 115.9,
114.7, 84.4, 75.9, 62.1, 55.6, 50.1, 34.7, 20.9, 14.0; The enantiomeric
excess was determined by HPLC with a AD column (n-hexane/i-
PrOH = 90:10, k = 254 nm), 1.0 mL/min, tR (major) = 16.10 min, tR
(minor) = 21.23 min.
4.3.7. Ethyl 2-(4-methoxyphenylamino)-4-p-tolylbut-3-ynoate
2g
Yield: 78%; 1H NMR (400 MHz, CDCl3): d 7.37–7.35 (m, 2H),
7.16–7.14 (m, 2H), 6.88–6.86 (m, 2H), 6.81–6.79 (m, 2H), 5.00 (s,
1H), 4.36 (q, 2H, J = 7.1 Hz), 3.81 (s, 3H), 2.4 (s, 3H), 1.38 (t, 3H,
J = 7.2 Hz); 13C NMR (125 MHz, CDCl3): d 169.1, 153.3, 139.5,
138.8, 131.8, 129.0, 119.1, 116.0, 114.8, 84.5, 83.4, 62.3,
55.6,55.3, 50.7, 21.5, 14.1. The enantiomeric excess was deter-
mined by HPLC with a OD-H column (n-hexane/i-PrOH = 90:10,
k = 254 nm), 1.0 mL/min), tR (major) = 11.40 min, tR (minor) =
16.61 min.
4.3.2. Ethyl 2-(4-methoxyphenylamino)-5-phenylpent-3-
ynoate 2b
Yield: 77%; 1H NMR (400 MHz, CDCl3): d 7.29–7.22 (m, 5H),
6.82–6.80 (m, 2H), 6.73–6.71 (m, 2H), 4.81 (m, 1H), 4.29 (q, 2H,
J = 7.4 Hz), 3.76 (s, 3H), 3.62 (br s, 2H), 1.32 (t, 3H, J = 7.0 Hz); 13C
NMR (125 MHz, CDCl3): d 169.2, 153.3, 139.5, 136.1, 128.4, 127.8,
126.6, 116.1, 114.5, 82.6, 77.6, 62.2, 55.6, 50.2, 25.0, 14.1; The
enantiomeric excess was determined by HPLC with a AD column
(n-hexane/i-PrOH = 90:10, k = 254 nm), 1.0 mL/min, tR (min-
or) = 25.61 min, tR (major) = 42.25 min.
Acknowledgments
We thank the Hong Kong Research Grants Council (PolyU 5003/
06P), the University Grants Committee Areas of Excellence Scheme
in Hong Kong (AoE P/10-01), the Hong Kong Polytechnic University
Areas of Strategic Development Fund, and National Natural Science
Foundation of China (20702044) for the financial support (to Z.-H.
Shao).
4.3.3. Ethyl 2-(4-methoxyphenylamino)oct-3-ynoate 2c
Yield: 74%; 1H NMR (400 MHz, CDCl3): d 6.81–6.74 (m, 2H), 6.72–
6.62(m, 2H), 4.71–4.69(m, 1H), 4.26(q, 2H, J = 7.0 Hz), 4.18–3.16(m,
1H), 3.70 (s, 3H), 2.20–2.16 (m, 2H), 1.47–1.26 (m, 7H), 0.87 (t, 3H,
J = 7.2 Hz); 13C NMR (125 MHz, CDCl3): d 169.5, 153.2, 139.7,
115.9, 114.7, 85.3, 75.1, 62.1, 55.6, 50.2, 30.4, 21.8, 18.3, 14.0, 13.5;
References
1. Multicomponent Reactions; Zhu, J.-P., Bienayme, H., Eds.; Wiley-VCH:
Weinheim, 2005.