Catalytic asymmetric synthesis of glycidic amides via chiral sulfur ylides

Article abstract of DOI:10.1016/S0957-4166(99)00289-X

Reaction of diazoacetamides with aromatic aldehydes in the presence of 20 mol% of chiral binaphthylsulfide and 10 mol% of copper(II) acetylacetonate gave chiral glycidic amides with up to 64% ee.

Full text of DOI:10.1016/S0957-4166(99)00289-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2845–2851
Catalytic asymmetric synthesis of glycidic amides via chiral
sulfur ylides
Ritsuo Imashiro, Takeshi Yamanaka and Masahiko Seki ∗
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd, 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
Received 31 May 1999; accepted 12 July 1999
Abstract
Reaction of diazoacetamides with aromatic aldehydes in the presence of 20 mol% of chiral binaphthylsulfide and
10 mol% of copper(II) acetylacetonate gave chiral glycidic amides with up to 64% ee. © 1999 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Chiral glycidic acid derivatives have received much attention as valuable chiral building blocks for
several drugs and natural products. For instance, they have been employed in the synthesis of Diltiazem
1 and the side chain of Taxol 2 (Fig. 1).1 Although many synthetic methods for chiral epoxides
have been developed, reports on asymmetric syntheses of chiral glycidic acid derivatives are rare and
further investigation is needed. Industrial synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate
3 has thus relied on the enzymatic resolution of its racemates.2 One of the most efficient syntheses
of chiral glycidic acid derivatives developed so far is the asymmetric epoxidation of cinnamates with
a chiral manganase–salen complex as a catalyst.1a,b Although excellent enantioselectivities have been
achieved, it requires poorly accessible cis-cinnamates as starting materials. As a more direct approach,
an asymmetric Darzens reaction using a chiral external ligand has been reported by Koga.1c However, a
stoichiometric amount of expensive chiral ligand and low temperature (−100°C) are necessary to induce
high enantioselectivities. In the search for a more efficient and practical synthesis of chiral glycidic
acid derivatives, we envisioned the possible use of the catalytic sulfur ylide reaction.3 In this report, we
describe the first catalytic asymmetric synthesis of glycidic amides via the reaction of aromatic aldehydes
with chiral sulfur ylides, which are generated in situ from diazoacetamides in the presence of catalytic
amounts of chiral binaphthylsulfide and copper(II) acetylacetonate (Scheme 1).
∗
Corresponding author. E-mail: m-seki@tanabe.co.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00289-X

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R. Imashiro et al. / Tetrahedron: Asymmetry 10 (1999) 2845–2851
Figure 1.
Scheme 1.
2. Results and discussion
The diazoacetamides 5a,b were easily prepared by diazotization of the corresponding glycinamides
using the same procedure as for the preparation of ethyl diazoacetate.4 They were stable enough to be
purified by silica gel column chromatography and could be stored in a refrigerator for several weeks
without decomposition. For chiral sulfides, binaphthalene type sulfides 6a,b5 were selected because of
their ready accessibility in enantiomerically pure form and ease of optimization. C2-Symmetric (S)-
2,20-bis(methylthio)-1,10 -binaphthalene 6a was first examined for the epoxidation of p-anisaldehyde.
The addition of N,N-diethyl diazoacetamide 5a to the mixture of p-anisaldehyde 6a (20 mol%) and
Cu(acac)2 (10 mol%) in CH2Cl2 at ambient temperature gave the desired chiral glycidic amide 7a in
30% yield and 32% ee exclusively as a trans form (Table 1, entry 1). The absolute configuration of the
major enantiomer of 7a was determined by comparison with the authentic sample prepared via amidation
of methyl (2S,3R)-3-(4-methoxyphenyl)glycidate.6 The use of Rh2(OAc)4 instead of Cu(acac)2 as a
metal catalyst gave a trace of 7a. The enantioselectivity was dramatically improved by the use of
(S)-20-methoxy-2-methylthio-1,10 -binaphthalene 6b to afford 7a in 18% yield and 60% ee (entry 2).
To improve the yield, the reaction was conducted in acetonitrile at higher temperature.7 However,
improvement of the yield was not observed; instead a lower enantioselectivity was obtained (entry 3).
The reaction of benzaldehyde with 5a also gave chiral glycidic amide 4c in a low yield (entry 4). The
poor yields of 7a,b might be attributed to the poor electrophilicity of the aldehydes. More electrophilic
4-(trifluoromethanesulfonyloxy)benzaldehyde, 4-bromobenzaldehyde and 2-fluorobenzaldehyde with an
electron-withdrawing group gave 7c–e in better yields (entries 5, 6, 7). Interestingly, the use of N,N-
dibenzyl diazoacetamide 5b instead of the N,N-diethyl counterpart 5a afforded the corresponding chiral
glycidic amide 7f in a higher yield (54%, entry 8 vs. 41%, entry 7). Moreover, the reaction of 5b with
more electrophilic 2,6-difluorobenzaldehyde gave a good yield and a moderate enantioselectivity (71%
yield, 46% ee, entry 9). In order to improve the yield of 7a, a key intermediate of Diltiazem, we thus

R. Imashiro et al. / Tetrahedron: Asymmetry 10 (1999) 2845–2851
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Table 1
carried out the reaction of 2- or 3-chloro-4-methoxybenzaldehyde with N,N-dibenzyl diazoacetamide 5b
using catalyst 6b (entries 10, 11). In both cases, yields better than that given in entry 2 were obtained, as
expected. When 3-chloro-4-methoxybenzaldehyde was employed, the enantioselectivity was improved
up to 64% ee. Moreover, the ee of the product could be increased to 99% ee by a single recrystallization
from i-PrOH (entry 11).
As described above, the first asymmetric synthesis of chiral glycidic amides via chiral sulfur ylides
was accomplished. The reactions of electron-deficient aldehydes with N,N-dibenzyl diazoacetamide
were found to give high yields of glycidic amide 7. The enantioselectivities of the reactions were
greatly enhanced by the use of mono sulfide 6b compared to C2-symmetric bis-sulfide 6a. Although
the enantioselectivities were still moderate, the short route (a single step from the commercially available
aromatic aldehyde), ready accessibility of the diazoacetamides, and the chiral binaphthyl sulfides might
make this process more advantageous than previously reported methods. Further improvements of the
enantioselectivities and considerations of the reaction mechanism are now under investigation.

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3. Experimental
Melting points were measured using Büchi melting point apparatus (B-540) and are uncorrected.
Optical rotations were measured on a Perkin–Elmer 243 automatic polarimeter. 1H and 13C NMR spectra
were recorded on a Bruker AC-200 (200 MHz) spectrometer with TMS as an internal standard. IR spectra
were recorded on a Perkin–Elmer 1640 spectrophotometer. Mass spectra were obtained on a Hitachi
M-2000A double-focusing mass spectrometer and on a Finnigan Mat LCQ. Elemental analyses were
measured on a Perkin–Elmer 2400 microanalyzer. Column chromatography was performed on silica gel
(Kieselgel 60, 230–400 mesh, E. Merck).
3.1. N,N-Diethyl diazoacetamide 5a4
A solution of ethyl glycinate hydrochloride (10.0 g, 60.0 mmol) in 14 ml of water was mixed with
36 ml of CH2Cl2 and was cooled to −10°C under nitrogen atmosphere. To the biphasic solution was
added an ice-cold solution of sodium nitrite (4.97 g, 72 mmol) in 14 ml of water, and then 5% sulfuric
acid (5.2 g) was added dropwise below 0°C. The reaction mixture was stirred for 20 minutes below 0°C
and extracted with CH2Cl2. The extracts were washed with saturated aqueous NaHCO3 and dried over
MgSO4. After evaporation of the solvent, the residue was purified by silica gel column chromatography
1
(hexane:AcOEt=4:1) to give 5a (2.65 g, 31%) as a yellow oil. H NMR (CDCl3, 200 MHz) δ 1.15 (t,
J=7.2 Hz, 6H), 3.26 (br, 4H), 4.93 (s, 1H); IR (film) 3040, 2977, 2910, 2105, 1640, 1608 cm−1; MS (EI)
m/z 141 (M+).
3.2. N,N-Dibenzyl diazoacetamide 5b4
A solution of benzyl glycinate hydrochloride (4.0 g, 13.8 mmol) in 40 ml of water was mixed with 80
ml of CH2Cl2 and was cooled to 0°C under nitrogen atmosphere. To the biphasic solution was added
an ice-cold solution of sodium nitrite (1.24 g, 17.9 mmol) in 4 ml of water, and then 5% sulfuric
acid (1.45 g) was added dropwise at 0°C. The reaction mixture was stirred at rt for 30 minutes and
extracted with CH2Cl2. The extracts were washed with saturated aqueous NaHCO3 and dried over
MgSO4. After evaporation of the solvent, the residue was purified by silica gel column chromatography
1
(hexane:AcOEt=10:1→4:1) to give 5b (3.45 g, 95%) as a yellow syrup. H NMR (CDCl3, 200 MHz)
δ 4.50 (br, 4H), 4.97 (s, 1H), 7.20–7.40 (m, 10H); IR (film) 3440, 3100, 3065, 3024, 2905, 2106, 1609
cm−1; MS (SIMS) m/z 266 ([M+H]+).
3.3. (S)-2,20-Bis(methylthio)-1,10-binaphthalene 6a
The compound 6a was prepared according to the literature.5b Mp 202°C [lit.5b mp 184–185°C];
25
25
1
[α]436 −43.9 (c 1.01, CHCl3) [lit.5b (R)-form, [α]436 +39.2 (c 1, CHCl3)]; H NMR (CDCl3, 200
MHz) δ 2.44 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.25 (dt, J=1.4, 8.3 Hz, 1H), 7.40 (dt, J=1.3, 8.1 Hz, 1H),
7.59 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H); IR (KBr) 3450, 3040, 2989,
2902, 1617, 1581, 1552, 1500, 1423 cm−1; MS (EI) m/z 346 (M+). Anal. calcd for C22H18S2: C, 76.26;
H, 5.14. Found: C, 75.64; H, 5.14.

R. Imashiro et al. / Tetrahedron: Asymmetry 10 (1999) 2845–2851
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3.4. (S)-20-Methoxy-2-methylthio-1,10 -binaphthalene 6b
25
The compound 6b was prepared according to the literature.5c Mp 173–174°C; [α]D −13.3 (c 1.01,
CHCl3); 1H NMR (CDCl3, 200 MHz) δ 2.38 (s, 3H), 3.76 (s, 3H), 6.99 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4
Hz, 1H), 7.17–7.37 (m, 4H), 7.44 (d, J=9.0 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.86 (d, J=7.7 Hz, 2H),
7.93 (d, J=8.7 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H); 13C NMR (CDCl3, 200 MHz) δ 15.9, 56.8, 114.0, 120.9,
123.4, 123.7, 124.8, 125.3, 126.5, 126.7, 128.0, 128.1, 128.3, 129.2, 130.0, 131.3, 131.5, 133.2, 133.4,
136.3, 154.9; IR (KBr) 3030, 2975, 2950, 2920, 2900, 2820, 1618, 1592, 1576, 1552 cm−1; MS (EI) m/z
330 (M+). Anal. calcd for C22H18OS: C, 79.96; H, 5.49. Found: C, 78.83; H, 5.16.
3.5. Preparation of the authentic sample of (2R,3S)-N,N-diethyl 3-(4-methoxyphenyl)glycidamide 7a
To a solution of (2R,3S)-N-ethyl 3-(4-methoxyphenyl)glycidamide6 (100 mg, 0.452 mmol) in 1 ml of
DMF was added NaH (62.5% in oil, 19 mg, 0.458 mmol) at 0°C, and the mixture was stirred for 30
minutes. Iodoethane (155 µl, 0.904 mmol) was then added, and the mixture was stirred at 0°C for 30
minutes. The reaction was quenched by adding saturated aqueous NH4Cl, and the mixture was extracted
with diethyl ether. The ethereal layer was washed with brine and dried over MgSO4. After evaporation of
the solvent, the residue was purified by silica gel column chromatography (hexane:AcOEt=2:1) to give
7a as a colorless oil (69 mg, 61%), which was solidified in a freezer. Recrystallization of the solid from
23
hexane–diethyl ether gave a pure sample as colorless crystals. Mp 55°C; [α]D −103 (c 1.01, CHCl3);
1H NMR (CDCl3, 200 MHz) δ 1.3–1.25 (m, 6H), 3.38–3.57 (m, 4H), 3.58 (d, J=1.9 Hz, 1H), 3.82 (s,
3H), 4.04 (d, J=1.9 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H); IR (KBr) 2973, 2920, 1650,
1608, 1581, 1517 cm−1; MS (EI) m/z 249 (M+). Anal. calcd for C14H19NO3: C, 67.45; H, 7.38; N, 5.50.
Found: C, 67.45; H, 7.68; N, 5.62.
3.6. Typical procedure of asymmetric epoxidation of arylaldehydes via chiral sulfur ylide:
(2R,3S)-N,N-diethyl 3-(4-methoxyphenyl)glycidamide 7a
Diazoacetamide 5a (212 mg, 1.5 mmol) in 0.5 ml of CH2Cl2 was added to the solution of p-
anisaldehyde (136 mg, 1 mmol), chiral sulfide 6b (66 mg, 0.2 mmol, 20 mol%) and Cu(acac)2 (26 mg,
0.1 mmol) in 0.5 ml of CH2Cl2 at rt over 5 h under a nitrogen atmosphere. After stirring the mixture for
3 days, the mixture was evaporated and the residue was purified by silica gel column chromatography to
give the epoxide 7a (46 mg, 18% yield, 60% ee) and the sulfide 6b (50 mg, 76% recovery). The epoxide
7a prepared by this procedure had 1H NMR, IR and mass spectra in good agreement with the authentic
sample. The ee of the epoxide 7a prepared by this method was determined by chiral HPLC (Chiralcel OD,
hexane:i-PrOH=10:1, 220 nm, 40°C). The absolute configuration of the main enantiomer was assigned
by comparing the retention time in HPLC with that of the authentic sample of (2R,3S)-7a.
3.6.1. (2R,3S)-N,N-Diethyl 3-phenylglycidamide 7b
1
22% yield, 48% ee. H NMR (CDCl3, 200 MHz) δ 1.14–1.25 (m, 6H), 3.39–3.55 (m, 4H), 3.59 (d,
J=1.9 Hz, 1H), 4.10 (d, J=2.2 Hz, 1H), 7.30–7.37 (m, 5H); IR (film) 3025, 2976, 2920, 2860, 1654, 1590,
1476, 1465, 1400 cm−1; MS (EI) m/z 219 (M+).

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3.6.2. (2R,3S)-N,N-Diethyl 3-(4-trifluoromethanesulfonyloxyphenyl)glycidamide 7c
34% yield, 34% ee. 1H NMR (CDCl3, 200 MHz) δ 1.11–1.27 (m, 6H), 3.46 (q, J=7.3 Hz, 4H), 3.54
(d, J=1.9 Hz, 1H), 4.16 (d, J=1.9 Hz, 1H), 7.29 (d, J=9.5 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H); IR (film)
3050, 2978, 2915, 1656, 1595, 1495, 1477, 1457, 1445, 1425 cm−1; MS (EI) m/z 367 (M+).
3.6.3. (2R,3S)-N,N-Diethyl 3-(4-bromophenyl)glycidamide 7d
1
43% yield, 38% ee. H NMR (CDCl3, 200 MHz) δ 1.12–1.28 (m, 6H), 3.39–3.51 (m, 4H), 3.53 (d,
J=1.9 Hz, 1H), 4.06 (d, J=1.8 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H); IR (KBr) 2970,
2925, 1650, 1485, 1465, 1444, 1431, 1419 cm−1; MS (EI) m/z 299 (M+, 81Br), 297 (M+, 79Br).
3.6.4. (2R,3S)-N,N-Diethyl 3-(2-fluorophenyl)glycidamide 7e
1
41% yield, 38% ee. H NMR (CDCl3, 200 MHz) δ 1.14–1.27 (m, 6H), 3.32–3.57 (m, 4H), 3.61 (d,
J=2.0 Hz, 1H), 4.32 (d, J=1.8 Hz, 1H), 7.03–7.20 (m, 2H), 7.25–7.38 (m, 2H); IR (film) 2977, 2920,
2860, 1656, 1610, 1581, 1485, 1459, 1402 cm−1; MS (EI) m/z 237 (M+).
3.6.5. (2R,3S)-N,N-Dibenzyl 3-(2-fluorophenyl)glycidamide 7f
1
54% yield, 39% ee. H NMR (CDCl3, 200 MHz) δ 3.71 (d, J=1.9 Hz, 1H), 4.40 (d, J=1.8 Hz, 1H),
4.56 (s, 2H), 4.65 (s, 2H), 6.98–7.39 (m, 14H); IR (film) 3075, 3050, 3020, 1662, 1614, 1501, 1582,
1496, 1467, 1453, 1400 cm−1; MS (EI) m/z 361 (M+).
3.6.6. (2R,3S)-N,N-Dibenzyl 3-(2,6-difluorophenyl)glycidamide 7g
1
71% yield, 46% ee. H NMR (CDCl3, 200 MHz) δ 4.27 (d, J=2.2 Hz, 1H), 4.32 (d, J=2.2 Hz, 1H),
4.66 (m, 4H), 3.85 (t, J=8.3 Hz, 2H), 7.18–7.39 (m, 11H); IR (film) 3040, 3031, 2900, 1664, 1620, 1580,
1488, 1471, 1444, 1400 cm−1; MS (EI) m/z 379 (M+).
3.6.7. (2R,3S)-N,N-Dibenzyl 3-(2-chloro-4-methoxyphenyl)glycidamide 7h
38% yield, 44% ee. 1H NMR (CDCl3, 200 MHz) δ 3.56 (d, J=2.0 Hz, 1H), 3.78 (s, 3H), 4.44 (d, J=1.9
Hz, 1H), 4.53–4.60 (m, 3H), 4.73 (d, J=14.8 Hz, 1H), 6.76 (dd, J=2.5, 8.6 Hz, 1H), 6.89 (d, J=2.5 Hz,
1H), 7.10–7.39 (m, 11H); IR (KBr) 1662, 1598 cm−1; MS (SIMS) m/z 408 ([M+H]+).
3.6.8. (2R,3S)-N,N-Dibenzyl 3-(3-chloro-4-methoxyphenyl)glycidamide 7i
25% yield, 64% ee. Recrystallization of the 64% ee product from i-PrOH provided 7i having 99% ee.
mp 125°C; [α]D −62.0 (c 1.01, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 3.62 (d, J=1.9 Hz, 1H), 3.88
23
(s, 3H), 4.02 (d, J=1.9 Hz, 1H), 4.54–4.63 (m, 3H), 4.74 (d, J=14.6 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H),
7.03–7.32 (m, 12H); IR (KBr) 1661 cm−1; MS (ESI) m/z 408 ([M+H]+). Anal. calcd for C24H22ClNO3:
C, 70.67; H, 5.44; N, 3.43. Found: C, 70.50; H, 5.39; N, 3.25.
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