A practical synthesis of N-aryl-substituted oxazolidinone-containing ketone catalysts for asymmetric epoxidation

Article abstract of DOI:10.1016/j.tet.2006.06.020

N-Aryl-substituted oxazolidinone-containing ketone catalysts for the asymmetric epoxidation of olefins can be efficiently prepared from d-glucose and anilines.

Full text of DOI:10.1016/j.tet.2006.06.020

Tetrahedron 62 (2006) 8064–8068
A practical synthesis of N-aryl-substituted oxazolidinone-
containing ketone catalysts for asymmetric epoxidation
*
Mei-Xin Zhao, David Goeddel, Kai Li and Yian Shi
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 14 April 2006; revised 3 June 2006; accepted 6 June 2006
Available online 3 July 2006
Abstract—N-Aryl-substituted oxazolidinone-containing ketone catalysts for the asymmetric epoxidation of olefins can be efficiently
prepared from D-glucose and anilines.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Dioxiranes generated in situ from chiral ketones are effective
for the asymmetric epoxidation of olefins.1 In our earlier
studies, we have shown that fructose-derived ketone 1 gives
high ee’s for trans- and trisubstituted olefins (Scheme 1).2
Subsequently, we have found that N-aryl substituted oxazoli-
dinone-containing ketones 2a and 2b, readily prepared from
D-glucose and p-toluidine or 4-ethylaniline, provide high ee’s
for substrates such as cis-olefins,3 styrenes,4 and certain tri-
substituted and tetrasubstituted olefins,5 which are not effec-
tive with ketone 1. While our original procedure for the
synthesis of ketone 2 is suitable for small scale, operational
drawbacks such as column chromatography purification
Scheme 2. Original syntheses of ketones 2a and 2b.
make large-scale ketone synthesis less convenient
(Scheme 2). Considering that these ketone catalysts could
potentially be useful, efforts have been made to further
with (MeO)3CH and H2SO4 in acetone. Aminodiol 4 was iso-
lated as an oil after neutralization with NH4OH. Extensive
vacuum pumping of compound 4 is required to remove all
of the water contained in ammonium hydroxide, which is
harmful to the phosgene cyclization. In addition, the isolated
compound (4) is contaminated with small amounts of impu-
rities from the ketalization reaction (amounts of impurities
are highly dependent on how well the reaction is monitored).
Consequently, column chromatography is required after
phosgene cyclization to ensure product purity, which is
highly undesirable for a large-scale operation. However, it
was observed that a large amount of white solid precipitated
during the ketalization, and the white solid was found to be
hydrogen sulfate salt 5, which could be obtained in good
yield by simple filtration. The impurity previously encoun-
tered could easily be removed by washing with ether. It
was also found that using the less expensive dimethoxy-
propane (DMP) in place of HC(OMe)3 further improved
the ketalization and caused 5 to efficiently crystallize in the
improve their synthesis so that large quantities of ketone
catalysts can be readily obtained.
Scheme 1.
The original and improved syntheses of ketones 2a3a and 2b4
are outlined in Schemes 2 and 3, respectively. In the original
procedure, the ketalization of aminoalcohol 3 was achieved
Keywords: Asymmetric epoxidation; Chiral dioxirane; Chiral ketone.
* Corresponding author. Tel.: +1 970 491 7424; fax: +1 970 491 1801;
e-mail: yian@lamar.colostate.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.020

M.-X. Zhao et al. / Tetrahedron 62 (2006) 8064–8068
8065
Scheme 3. Improved syntheses of ketones 2a and 2b.
reaction mixture. Therefore, the isolation of salt 5 instead of
oil 4 is highly beneficial.
anilines in four steps. The process described is operationally
simpler when compared to the original procedure and can
easily produce the desired ketone catalysts in large quantities.
Salt 5 was then directly used for neutralization and phosgene
cyclization. Subjecting salt 5 to the previous reaction condi-
tions (NaHCO3, phosgene, followed by Et3N)4 resulted in
low yield. However, the reaction was much cleaner if addi-
tional base such as diisopropylamine was added.6 Diisopro-
pylamine could possibly act as a proton shuttle between the
insoluble salt 5 and solid NaHCO3. The formed oxazoli-
dinone 6 can be isolated by recrystallization or can be used
directly in the oxidation step without isolation.
2. Experimental
2.1. Synthesis of ketone 2a
To a mixture of D-glucose (270.0 g, 1.5 mol), p-toluidine
(192.9 g, 1.8 mol), and water (51.4 mL) was added HOAc
(1.62 g, 0.027 mol). The mixture was rotated on a rotary
evaporator (sealed without vacuum) at 90–93 ꢀC for 2 h
(during this time the product precipitated from the reaction
mixture). After cooling to room temperature, ether–ethanol
(3:1, 1600 mL) was added. Upon stirring at room tempera-
ture for an additional 2 h, the mixture was filtered, washed
with ether (2ꢁ400 mL), ether–ethanol (5:1, 420 mL), ether
(2ꢁ400 mL), and dried under vacuum to give aminoalcohol
3a as a white solid (259.4 g, 64%).10
In the previous procedure, the oxidation was accomplished
using PDC as oxidizing agent. To further improve this step,
various other oxidation methods, such as RuCl3$xH2O–
NaIO4,7a Py$SO3–DMSO,7b Ac2O–DMSO,7c TEMPO–
Oxone,7d and TEMPO–bleach7e were briefly investigated.
Among these oxidation methods, TEMPO–bleach system
was found to be the best choice overall. After much experi-
mentation, it was found that a catalytic amount of TEMPO
(1.5%) with bleach as the primary oxidant yielded ketone 2
in good yield after recrystallization of the final product. It
was found that the choice of solvent and reaction pH are
very important for this transformation.8 The oxidation pro-
ceeded efficiently at pH 9.3 in a mixture of CH2Cl2 and
toluene (5:1). Finally, a similar TPAP–bleach oxidation
procedure was also found to yield ketone 2 in good yield
and purity (Scheme 4).9 Catalysts prepared by the improved
synthetic pathway were found to give comparable epoxida-
tion results to ketones prepared by the original sequence
using Oxone as oxidant.
To a mixture of aminoalcohol 3a (161.4 g, 0.6 mol) and
2,2-dimethoxypropane (222.0 mL, 1.8 mol) in acetone
(1400 mL) with stirring (using mechanical stirrer) under Ar
at 0 ꢀC was added concd H2SO4 (48.0 mL, 0.86 mol) via
addition funnel over 45 min. After stirring at 0 ꢀC for an
additional 1.5 h (the white solid product precipitated in the
reaction mixture over the course of the reaction), ether
(150 mL) was added. The mixture was filtered, washed
with acetone–ether (1:4, 3ꢁ350 mL), ether (350 mL), and
dried under vacuum for 2–3 h to give salt 5a as a white solid
(220.2 g, 90%) (Compound 5a should be used immediately
for the next step. Exhaustive vacuum drying and/or pro-
longed storage could lead to decomposition). IR (NaCl,
film): 3364 cmꢂ1; H NMR (300 MHz, DMSO) d 7.15–
1
7.07 (m, 5H), 6.40 (br s, 3H), 4.22 (d, J¼5.7 Hz, 1H),
4.12–4.02 (m, 2H), 3.87 (d, J¼13.5 Hz, 1H), 3.47 (d,
J¼7.5 Hz, 1H), 3.44–3.35 (m, 1H), 3.30–3.16 (m, 1H),
2.25 (s, 3H), 1.40 (s, 3H), 1.28 (s, 3H); 13C NMR (75 MHz,
DMSO) d 137.0, 135.9, 130.1, 121.9, 107.9, 95.1, 76.1,
73.0, 70.6, 59.4, 56.5, 28.1, 26.4, 20.7. Anal. Calcd for
C16H25NO9S: C, 47.17; H, 6.18; N, 3.44; S, 7.87. Found:
C, 47.05; H, 6.04; N, 3.60; S, 8.11.
Scheme 4.
In summary, we report a practical synthesis of N-aryl-
substituted oxazolidinone-containing ketone catalysts for
asymmetric epoxidation of olefins from D-glucose and
A mixture of salt 5a (220.2 g, 0.54 mol) and NaHCO3
(403.2 g, 4.8 mol) in CH2Cl2 (1000 mL) was stirred (using

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M.-X. Zhao et al. / Tetrahedron 62 (2006) 8064–8068
mechanical stirrer) under Ar at 0 ꢀC for 1 h. Diisopropyl-
amine (30.3 g, 0.3 mol) was then added. Upon stirring at
0 ꢀC for 30 min, phosgene (20% solution in toluene,
377 mL, 0.71 mol) was added via addition funnel over
5.3 h. After stirring at 0 ꢀC for an additional 1.5 h, the cold
bath was removed. The reaction mixture was stirred over-
night, filtered, and washed with satd NaHCO3 (200 mL),
water (2ꢁ200 mL), brine (200 mL), dried (Na2SO4), filtered,
concentrated to about 300 mL, and filtered to give 6a as white
solid (104.5 g). The filtrate was concentrated and recrystal-
lized from hexane–CH2Cl2 (3:1, 200 mL) to give an addi-
tional 24.9 g of 6a (combined yields, 72%). IR (NaCl,
To the above solution was added CH2Cl2 (500 mL) and NaBr
(51.5 g, 0.50 mol). After cooling to 0 ꢀC, TEMPO (1.17 g,
0.0075 mol) was added, followed by freshly purchased 5%
NaOCl (1400 mL, adjusted to pH 9.3 by NaHCO3)11 with
vigorous stirring (using mechanical stirrer) over 4 h (during
the addition, the internal temperature of the reaction mixture
was kept at 4–8 ꢀC, the reaction was monitored by GC). Af-
ter stirring for an additional 3 h at the same temperature, the
layers of the reaction mixture were separated. The organic
layers were washed with satd Na2S2O3 (3ꢁ300 mL), water
(5ꢁ250 mL), dried (Na2SO4), filtered through a pad of silica
gel (d¼9.5 cm, h¼0.6 cm), washed with EtOAc (500 mL),
and concentrated to 80–100 mL. Upon addition of hexane
(800 mL), the mixture was vigorously shaken until the vis-
cous residue solidified and precipitated. Filtration and re-
crystallization (250 mL, EtOAc and 200 mL, hexane) gave
ketone 2a as pale yellow solid (80.0 g). The mother liquor
was concentrated and recrystallized (200 mL, EtOAc and
70 mL, hexane) to give ketone 2a as yellow solid (15.0 g)
(total 95.0 g, combined yields, 63% over two steps).
film): 3400, 1761 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d 7.37 (d, J¼8.4 Hz, 2H), 7.15 (d, J¼8.4 Hz, 2H), 4.37–
4.26 (m, 4H), 4.14 (d, J¼13.5 Hz, 1H), 3.81–3.78 (m, 2H),
2.91 (s, 1H), 2.32 (s, 3H), 1.57 (s, 3H), 1.40 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 153.1, 135.0, 134.3, 129.7,
118.8, 110.0, 100.9, 76.7, 73.3, 71.7, 62.0, 53.3, 28.4, 26.3,
21.1. Anal. Calcd for C17H21NO6: C, 60.89; H, 6.31; N,
4.18. Found: C, 60.61; H, 6.16; N, 4.35.
To a mixture of alcohol 6a (30.2 g, 0.09 mol) and NaBr
(9.26 g, 0.09 mol) in CH2Cl2–toluene (5:1, 360 mL) at
0 ꢀC was added TEMPO (0.215 g, 0.0014 mol). Recently
purchased 5% NaOCl (270 mL, adjusted to pH 9.3 by
NaHCO3)11 was added with vigorous stirring (using me-
chanical stirrer) over 2.5 h (during the addition, the internal
temperature of the reaction mixture was kept at 4–8 ꢀC, and
the reaction was monitored by GC). The layers of the reac-
tion mixture were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (2ꢁ100 mL). The combined organic
layers were washed with satd Na2S2O3 (2ꢁ200 mL), water
(6ꢁ100 mL), dried (Na2SO4), filtered through a pad of silica
gel (40 g), and washed with EtOAc (200 mL). The filtrate
was concentrated to ca. 20 mL. Upon addition of hexane
(500 mL), the mixture was shaken until the viscous residue
solidified and precipitated. Filtration and recrystallization
(90 mL, EtOAc and 30 mL, hexane) gave ketone 2a as an
2.2. Synthesis of ketone 2b
To a mixture of D-glucose (270.0 g, 1.5 mol), 4-ethylaniline
(218.1 g, 1.8 mol), and water (51.4 mL) was added HOAc
(1.62 g, 0.027 mol). The mixture was rotated on a rotary
evaporator (sealed without vacuum) at 90–93 ꢀC for
70 min (during this time the product precipitated from the re-
action mixture). After cooling to room temperature, ether–
ethanol (3:1, 1600 mL) was added. Upon stirring at room
temperature for an additional 2 h, the mixture was filtered,
washed with ether (2ꢁ400 mL), ether–ethanol (5:1,
420 mL), ether (2ꢁ400 mL), and dried under vacuum to
give aminoalcohol 3b as a white solid (303.5 g, 72%).10
To a mixture of aminoalcohol 3b (169.8 g, 0.6 mol) and
2,2-dimethoxypropane (222.0 mL, 1.8 mol) in acetone
(1400 mL) while stirring (using mechanical stirrer) under
Ar at 0 ꢀC was added concd H2SO4 (48.0 mL, 0.86 mol)
via addition funnel over 45 min. After stirring at 0 ꢀC for
an additional 1.5 h (the white solid product precipitated in
the reaction mixture over the course of the reaction), ether
(400 mL) was added. The mixture was filtered, washed
with acetone–ether (1:4, 3ꢁ350 mL), ether (350 mL), and
dried under vacuum for 2–3 h to give salt 5b as a white solid
(202.1 g, 80%) (Compound 5b should be used immediately
for the next step. Exhaustive vacuum drying and/or pro-
longed storage could lead to decomposition). IR (NaCl,
off white solid (21.7 g, 72%). IR (NaCl, film): 1773 cmꢂ1
;
1H NMR (300 MHz, CDCl3) d 7.41 (d, J¼8.4 Hz, 2H),
7.20 (d, J¼8.4 Hz, 2H), 4.88 (d, J¼5.1 Hz, 1H), 4.75 (d,
J¼10.5 Hz, 1H), 4.66–4.62 (m, 2H), 4.27 (d, J¼13.5 Hz,
1H), 3.76 (d, J¼10.5 Hz, 1H), 2.35 (s, 3H), 1.50 (s, 3H),
1.45 (s, 3H); 13C NMR (75 MHz, CDCl3) d 195.1,
151.2, 134.7, 134.5, 129.8, 118.8, 111.1, 99.2, 77.6, 75.6,
61.1, 50.0, 27.3, 26.2, 21.0. Anal. Calcd for C17H19NO6:
C, 61.25; H, 5.75; N, 4.20. Found: C, 61.18; H, 5.86; N,
4.22.
1
film): 3349 cmꢂ1; H NMR (300 MHz, DMSO) d 8.09 (m,
In an another run, alcohol 6a was used for oxidation directly
without isolation described as follows:
4H), 7.24 (m, 4H), 4.23 (dd, J¼5.7, 2.1 Hz, 1H), 4.15–4.01
(m, 2H), 3.90 (d, J¼13.2 Hz, 1H), 3.49 (d, J¼7.2 Hz, 1H),
3.43 (d, J¼12.3 Hz, 1H), 3.27 (d, J¼12.3 Hz, 1H), 2.58
(q, J¼7.8 Hz, 2H), 1.41 (s, 3H), 1.28 (s, 3H), 1.16 (t,
J¼7.8 Hz, 3H); 13C NMR (75 MHz, DMSO) d 143.0,
136.2, 128.9, 121.8, 107.9, 95.2, 76.1, 73.0, 70.6, 59.4,
56.4, 28.1, 27.8, 26.4, 15.7. Anal. Calcd for C17H27NO9S:
C, 48.45; H, 6.46; N, 3.32; S, 7.61. Found: C, 48.65; H,
6.60; N, 3.33; S, 7.62.
A mixture of salt 5a (186.0 g, 0.45 mol) and NaHCO3
(336.0 g, 4.0 mol) in CH2Cl2 (1200 mL) was stirred (using
mechanical stirrer) under N2 at 0 ꢀC for 1 h. Diisopropyl-
amine (25.3 g, 0.25 mol) was then added. Upon stirring at
0 ꢀC for 10 min, phosgene (20% solution in toluene,
310 mL, 0.58 mol) was added via addition funnel over 5 h.
The reaction mixture was warmed to room temperature
and stirred overnight, filtered, and washed with CH2Cl2
(3ꢁ200 mL). The filtrate was washed with satd NaHCO3
(700 mL) and water (2ꢁ700 mL). The solution was used
directly in the next step.
A mixture of salt 5b (202.1 g, 0.48 mol) and NaHCO3
(403.2 g, 4.8 mol) in CH2Cl2 (1000 mL) was stirred (using
mechanical stirrer) under Ar at 0 ꢀC for 1 h. Diisopropyl-
amine (30.3 g, 0.30 mol) was then added. Upon stirring at

M.-X. Zhao et al. / Tetrahedron 62 (2006) 8064–8068
8067
0 ꢀC for 30 min, phosgene (20% solution in toluene, 377 mL,
0.71 mol) was added via addition funnel over 5.3 h. After
stirring at 0 ꢀC for an additional 1.5 h, the cold bath was re-
moved. The reaction mixture stirred overnight, filtered, and
washed with satd NaHCO3 (200 mL), water (2ꢁ200 mL),
brine (200 mL), dried (Na2SO4), filtered, concentrated to
about 300 mL, and filtered to give 6b as white solid
(116.2 g). The filtrate was concentrated and recrystallized
from hexane–CH2Cl2 (3:1, 260 mL) to give an additional
22.6 g of 6b (combined yields, 83%). IR (NaCl, film):
3400, 1761 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 7.41 (d, J¼
8.4 Hz, 2H), 7.19 (d, J¼8.4 Hz, 2H), 4.39–4.26 (m, 4H), 4.15
(d, J¼13.5 Hz, 1H), 3.83–3.80 (m, 2H), 2.96 (br s, 1H), 2.63
(q, J¼7.8 Hz, 2H), 1.57 (s, 3H), 1.40 (s, 3H), 1.22 (t, J¼
7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 153.2, 140.5,
135.1, 128.4, 118.8, 109.8, 101.1, 76.4, 73.3, 71.4, 61.8,
53.3, 28.4, 28.2, 26.2, 15.8. Anal. Calcd for C18H23NO6: C,
61.88; H, 6.64; N, 4.01. Found: C, 61.93; H, 6.65; N, 4.03.
0.0075 mol) was added, followed by recently purchased
5% NaOCl (1400 mL, adjusted to pH 9.3 by NaHCO3)11
with vigorous stirring (using mechanical stirrer) over 4 h
(during the addition, the internal temperature of the reaction
mixture was kept at 4–8 ꢀC, the reaction was monitored by
GC). After stirring for an additional 3 h at the same temper-
ature, the layers of the reaction mixture were separated. The
organic layers were washed with satd Na2S2O3 (3ꢁ300 mL),
water (5ꢁ250 mL), dried (Na2SO4), filtered through a pad of
silica gel (d¼13.0 cm, h¼1.4 cm), washed with EtOAc
(800 mL), concentrated, and recrystallized (120 mL, EtOAc
and 300 mL, hexane) to give ketone 2b as a pale yellow solid
(87.0 g). The mother liquor was concentrated and recrystal-
lized (20 mL, EtOAc and 30 mL, hexane) to give ketone 2b
as brown solid (12.0 g) (total 99.0 g, combined yields, 63%
over two steps).
2.3. General procedure for TPAP–NaOCl oxidation
To a mixture of alcohol 6b (31.4 g, 0.09 mol) and NaBr
(9.26 g, 0.09 mol) in CH2Cl2–toluene (5:1, 360 mL) at
0 ꢀC was added TEMPO (0.215 g, 0.0014 mol). Freshly
purchased 5% NaOCl (270 mL, adjusted to pH 9.3 by
NaHCO3)11 was added with vigorous stirring (using me-
chanical stirrer) over 2.5 h (during the addition, the internal
temperature of the reaction mixture was kept at 4–8 ꢀC. The
reaction was monitored by GC). The layers of the reaction
mixture were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (2ꢁ100 mL). The combined organic
layers were washed with satd Na2S2O3 (2ꢁ200 mL), water
(6ꢁ100 mL), dried (Na2SO4), filtered through a pad of silica
gel (40 g), washed with EtOAc (250 mL), and concentrated
to ca. 20 mL. Upon addition of hexane (500 mL), the mix-
ture was shaken until the viscous residue solidified and pre-
cipitated. Filtration and recrystallization (30 mL, EtOAc and
30 mL, hexane) gave ketone 2b as an off white solid (18.4 g,
To the solution of alcohol 6 (for 6a: 50.3 g; for 6b: 52.4 g,
0.15 mol) in EtOAc (375 mL), was added 0.1 M NaHCO3–
Na2CO3 buffer (pH¼9.5, 495 mL)12 followed by TPAP
(0.53 g, 0.0015 mol). After stirring at room temperature for
10 min, recently purchased NaOCl (5%, 450 mL) was then
added dropwise at rt over 4 h (reaction followed by GC).
The mixture was then filtered through Celite and washed
with EtOAc until no product came out. After separating the
layers, the aqueous phase was extracted with EtOAc
(2ꢁ150 mL). The combined organic layers were washed
with water (2ꢁ150 mL), brine (150 mL), dried (Na2SO4),
concentrated, and recrystallized from ethyl acetate–hexane
(3:1, 200 mL for 2a; 1:1, 120 mL for 2b) to give the ketone
2 as a white solid (35.9 g, 72% for 2a; 38.0 g, 73% for 2b).
Acknowledgements
1
59%). IR (NaCl, film): 1773 cmꢂ1; H NMR (300 MHz,
CDCl3) d 7.41 (d, J¼8.4 Hz, 2H), 7.19 (d, J¼8.4 Hz, 2H),
4.85 (d, J¼5.4 Hz, 1H), 4.71 (d, J¼10.8 Hz, 1H), 4.64–4.56
(m, 2H), 4.23 (d, J¼13.2 Hz, 1H), 3.72 (d, J¼10.5 Hz, 1H),
2.61 (q, J¼7.5 Hz, 2H), 1.46 (s, 3H), 1.40 (s, 3H), 1.20 (t,
J¼7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 195.0, 151.2,
141.0, 134.6, 128.5, 118.8, 111.0, 99.1, 77.7, 75.5, 61.0,
50.0, 28.3, 27.2, 26.1, 15.7. Anal. Calcd for C18H21NO6:
C, 62.24; H, 6.09; N, 4.03. Found: C, 62.48; H, 6.19; N, 4.06.
We are grateful for the generous financial support from the
General Medical Sciences of the National Institutes of
Health (GM59705-07).
References and notes
1. For reviews on chiral ketone-catalyzed asymmetric epoxida-
tion, see: (a) Denmark, S. E.; Wu, Z. Synlett 1999, 847; (b)
Frohn, M.; Shi, Y. Synthesis 2000, 1979; (c) Shi, Y. Acc.
Chem. Res. 2004, 37, 488; (d) Yang, D. Acc. Chem. Res.
2004, 37, 497.
2. (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118,
9806; (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.;
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224; (c) Shu, L.;
Shi, Y. Tetrahedron 2001, 57, 5213.
3. (a) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293;
(b) Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115; (c) Wong,
O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973; (d) Burke, C. P.;
Shi, Y. Angew. Chem., Int. Ed., in press.
4. Goeddel, D.; Shu, L.; Yuan, Y.; Wong, O. A.; Wang, B.; Shi, Y.
J. Org. Chem. 2006, 71, 1715.
In an another run, alcohol 6b was used for oxidation directly
without isolation described as follows:
A mixture of salt 5b (191.0 g, 0.45 mol) and NaHCO3
(336.0 g, 4.0 mol) in CH2Cl2 (1200 mL) was stirred (using
mechanical stirrer) under N2 at 0 ꢀC for 1 h. Diisopropyl-
amine (25.3 g, 0.25 mol) was then added. Upon stirring at
0 ꢀC for 10 min, phosgene (20% solution in toluene,
310 mL, 0.58 mol) was added via addition funnel over 5 h.
The reaction mixture was warmed to room temperature and
stirred overnight, filtered, and washed with CH2Cl2
(3ꢁ200 mL). The filtrate was washed with satd NaHCO3
(700 mL) and water (2ꢁ700 mL). The solution was used
directly for the next step.
5. (a) Shen, Y.-M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed. 2006,
45, 1429; (b) Shen, Y.-M.; Wang, B.; Shi, Y. Tetrahedron Lett.,
in press.
To the above solution was added CH2Cl2 (500 mL) and NaBr
(51.5 g, 0.50 mol). Upon cooling to 0 ꢀC, TEMPO (1.17 g,

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M.-X. Zhao et al. / Tetrahedron 62 (2006) 8064–8068
6. Other bases such as tert-butylamine, pyridine, 2,6-lutidine,
imidazole, ammonium hydroxide, and ammonia (gas) were
also tested. Among these bases, tert-butylamine worked well.
7. For leading references on these oxidation systems, see: (a) Mio,
S.; Kumagawa, Y.; Sugai, S. Tetrahedron 1991, 47, 2133; (b)
Hermann, K.; Dreiding, A. S. Helv. Chim. Acta 1976, 59,
626; (c) Katagiri, N.; Akatsuka, H.; Haneda, T.; Kaneko, C.
J. Org. Chem. 1988, 53, 5464; (d) Bolm, C.; Magnus, A. S.;
Hildebrand, J. P. Org. Lett. 2000, 2, 1173; (e) Leanna, M. R.;
Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992, 33, 5029.
8. The reaction was examined from pH 9.0 to 12.8 with 1%
TEMPO in CH2Cl2. The optimal conversion was obtained
around pH 9.3. Various solvents were also tested for the reac-
tion. The conversions in these solvents (1.5% TEMPO at pH
9.3, for 4 h) are as following: acetone (<1%), EtOAc (6%),
EtOAc–dioxane (1:1, v/v) (23%), EtOAc–DME (1:1, v/v)
(27%), EtOAc–CH3CN (1:1, v/v) (67%), EtOAc–CH2Cl2 (4:1,
v/v) (44%), EtOAc–CH2Cl2 (2:1, v/v) (82%), EtOAc–CH2Cl2
(1:1, v/v) (94%), CH2Cl2 (>99%), and PhCH3–CH2Cl2 (1:5,
v/v) (>99%). The amount of solvent can be reduced when
PhCH3–CH2Cl2 (1:5, v/v) (10 mL per gram of substrate) is
used when compared to CH2Cl2 (20 mL per gram of substrate).
9. For leading references on TPAP–NaOCl oxidation, see: (a)
Gonsalvi, L.; Arends, I. W. C. E.; Sheldon, R. A. Org. Lett.
2002, 4, 1659; (b) Gonsalvi, L.; Arends, I. W. C. E.;
Moilanen, P.; Sheldon, R. A. Adv. Synth. Catal. 2003, 345, 1321.
10. Hodge, J. E.; Fisher, B. E. Methods Carbohydr. Chem. 1963,
2, 99.
11. NaOCl used was freshly purchased from Alfa (5%). Low con-
version was obtained if poor quality NaOCl used. The control
on pH of NaOCl solution is also very important for the oxida-
tion. The pH was adjusted to 9.3 by addition of solid NaHCO3
(carefully monitored by pH meter, w24 mg NaHCO3/mL
NaOCl).
12. The buffer was prepared by mixing 0.1 M NaHCO3 and 0.1 M
Na2CO3 until pH 9.5 as monitored by the pH meter.