Solvent and in situ catalyst preparation impacts upon Noyori reductions of aryl-chloromethyl ketones: application to syntheses of chiral 2-amino-1-aryl-ethanols

Article abstract of DOI:10.1016/j.tetasy.2006.07.017

As part of medicinal chemistry efforts we found it necessary to develop general syntheses of highly enantiomerically enriched 1-aryl-2-chloroethanols and 1-aryl-2-methylaminoethanols. A survey of literature methods suggested that a truly general approach had not yet been reported, encouraging us to undertake the development of such a methodology. This study describes the design, development, and reduction to practice of a general synthesis of chiral 1-aryl-2-chloroethanols and the transformation of these entities to highly enantiomerically enriched 1-aryl-2-methylaminoethanols. Of particular importance were observations of the impact of solvent and the method of catalyst preparation on the yield and enantiomerical excess of chlorohydrins prepared via Noyori transfer hydrogenations of aryl-chloromethyl ketones.

Full text of DOI:10.1016/j.tetasy.2006.07.017

Tetrahedron: Asymmetry 17 (2006) 2154–2182
Solvent and in situ catalyst preparation impacts upon
Noyori reductions of aryl-chloromethyl ketones: application
to syntheses of chiral 2-amino-1-aryl-ethanols
Steven P. Tanis,a,* Bruce R. Evans,b James A. Nieman,a Timothy T. Parker,b
Wendy D. Taylor,a Steven E. Heasley,d Paul M. Herrinton,c,* William R. Perrault,c
Richard A. Hohler,e Lester A. Dolak,e Matthew R. Hesterf and Eric P. Seestg
aPfizer Global R&D, Pfizer Inc., Medicinal Chemistry Research, 10770 Science Center Dr. San Diego, CA 92121, USA
bKalexsyn, Inc., 4717 Campus Drive, Suite 800, Kalamazoo, MI 49008, USA
cPfizer Global R&D, Pfizer Inc., Kalamazoo Active Pharmaceutical Ingredients, Port-91-0201, 7000 Portage Road, Kalamazoo,
MI 49001, USA
dPfizer Global R&D, Pfizer Inc., 700 Chesterfield Village Parkway, BB4K, St. Louis, MO 63017, USA
ePfizer Global R&D, Pfizer Inc., Kalamazoo, MI 49001, USA
fDepartment of Exploratory Medicinal Sciences, Pfizer Inc., MS 118B-B414, Eastern Point Road, Groton, CT 06340, USA
gEli Lilly & Co., Lilly Research Laboratories, Discovery Chemistry Research Technologies (MCF93), LTC-South 110-1,
DC 4816, Indianapolis, IN 46285, USA
Received 13 July 2006; accepted 17 July 2006
Abstract—As part of medicinal chemistry efforts we found it necessary to develop general syntheses of highly enantiomerically enriched
1-aryl-2-chloroethanols and 1-aryl-2-methylaminoethanols. A survey of literature methods suggested that a truly general approach had
not yet been reported, encouraging us to undertake the development of such a methodology. This study describes the design, develop-
ment, and reduction to practice of a general synthesis of chiral 1-aryl-2-chloroethanols and the transformation of these entities to highly
enantiomerically enriched 1-aryl-2-methylaminoethanols. Of particular importance were observations of the impact of solvent and the
method of catalyst preparation on the yield and enantiomerical excess of chlorohydrins prepared via Noyori transfer hydrogenations
of aryl-chloromethyl ketones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
fore any method selected or developed would be required
to accept this cross-section of substrates and provide
1-aryl-2-chloroethanols in good to excellent yields with
high ee’s:
As part of two medicinal chemistry campaigns we found it
necessary to consider the preparation of highly enantio-
merically enriched 1-aryl-2-chloroethanols 1 and highly
enantiomerically enriched 1-aryl-2-methylaminoethanols
2. It was our desire to develop a single method for the
introduction of asymmetry and derive the target 1-aryl-2-
methylaminoethanols from precursor 1-aryl-2-chloroetha-
nols for the sake of simplicity. Aryl groups of interest
included phenyl-, 2-pyridyl, 3-pyridyl, pyrazinyl, 2-furyl,
2-thienyl, 3-thienyl, 2-thiazolyl, and benzofuranyl. There-
OH
OH
Cl
NHMe
Aryl
Aryl
1
2
A survey of the literature led us to consider enzymatic/
microbial resolution of racemic halohydrins and enzy-
matic/microbial reduction of aryl-chloromethyl ketones,
as well as asymmetric chemical reduction (DIP-Cl, oxaza-
borolidine, Noyori) of aryl-chloromethyl ketones. We
elected not to pursue enzymatic/microbial resolution/
*
Corresponding authors. Tel.: +1 858 622 8024; fax: +1 858 678 8156;
e-mail: steven.p.tanis@pfizer.com
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.017

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2155
reduction as substrate generality within a limited number
of enzymes/microorganisms was not apparent.1
for method development. Asymmetric reduction attempts
began with a comparison of the Brown (+)-DIP-Cl reduc-
tion2a of 3-chloroacetylpyridine 3a as reported by Fisher
et al.,2d with the Corey–Itsuno oxazaborolidine (derived
from L-proline),3 prepared by the method of Mathre
et al.,3 and the Noyori protocol.6 Our first attempts to
perform chiral reductions are presented in Scheme 2.
Within the realm of chemical reduction methods (Eq. 1),
Brown’s DIP-Cl2a has seen limited use in the reduction of
aryl-chloromethyl ketones 3, causing us to question the
generality of this stoichiometric reagent for our applica-
tions, but has been reported to afford good ee’s where
employed:2
O
OH
OH
O
OH
OH
Cl
Cl
+
Cl
a, b, or c
Cl
Cl
Cl
and / or
Ar
Ar
Ar
ð1Þ
N
N
N
3a
(R)-1a
(S)-1a
(R)-1
(S)-1
3
Ratio
(R)-1a/(S)-1a
The Corey3–Itsuno4 oxazaborolidine based catalytic asym-
metric reduction5 has been utilized for the synthesis of 1-
aryl-2-chloroethanols 1 and 2, providing good yields and
enantiomeric excesses for those cases where Ar = non-
coordinating phenyl derivatives. The paucity of examples
wherein the aryl possesses a Lewis basic coordinating
group5a is a concern as many of the substrates of interest
to us bear coordinating groups.
Conditions
Yield
(+)-DIP-Cl, Et3N,
THF, -20°C, 4 days
L-prolinol derived
oxazaboroladine,
BH3-SMe2
a
27%
3:97
b
90%
30:70
RuCl[(1S,2S)-
pTsNCH(Ph)-
CH(Ph)NH2](η6-p-
cymene), HCO2H /
Et3N (5:2), 72 h
c
27%
80:20
Noyori-type reductions6–8 have been widely applied to
achieve asymmetric reductions of aryl-chloromethyl
ketones 3. A selection of metals (e.g., Ir, Rh, Ru), a diver-
sity of chiral ligands, and a variety of conditions (solvent,
source of H2) have been employed to achieve good to excel-
lent levels of asymmetric induction. However, the cross-
section of aryl moieties of interest to us (phenyl-, 2-pyridyl,
3-pyridyl, pyrazinyl, 2-furyl, 2-thienyl, 3-thienyl, 2-thi-
azolyl, benzofuranyl) in the chloromethyl framework had
not been examined in a single metal/ligand/H2 source com-
bination. Therefore we elected to examine the basic Noyori
reduction6 ([RuCl-p-cymene]2/(1R,2S or 1S,2R)-N-p-tolu-
enesulfonyl-1,2-diphenylethylenediamine/HCOOH–Et3N)
for its generality and utility in the preparation of highly
enantiomerically enriched 1-aryl-2-chloroethanols 1.
Scheme 2. Chiral reductions—initial attempts.
The (+)-DIP-Cl reaction provides excellent enantiomeric
excess for the anticipated major (S)-enantiomer, however
the poor conversion, stoichiometric use of the reagent,
and the extended reaction time at low temperature render
this approach to be of low utility. By comparison, the L-
prolinol derived oxazaboroladine, BH3–SMe2 reduction
proceeds rapidly and in high yield, but unfortunately the
chiral selectivity is far below what we required. The Noyori
reduction afforded modest ee’s at low conversion, but the
catalytic nature of the process when combined with the
modest level of asymmetric induction led us to focus on
this method as one, which might be optimizable for the
substrates at hand. An observation by Vedejs,10 that the
simple expedient of venting the reaction vessel during a
Noyori asymmetric catalytic reduction of dihydroisoquino-
lines, presumably to allow H2 and CO2 to exit, enabled
reactions that had stalled at ca. 25% conversion to proceed
nearly to completion. We had vented our reaction vessels
during the course of performing the reactions cited in
Scheme 2, and therefore additional alterations were
needed. Perhaps the utilization of a solvent, which would
lower the viscosity of the medium, coupled with reaction
vessel venting would facilitate greater conversion. Entries
1 and 2 (Table 1) represent baseline experiments with the
2. Results and discussion
2.1. Asymmetric reduction development
As a representative aryl-chloromethyl ketone, we selected
3-chloroacetylpyridine2d 3a to begin our studies. Ketone
3a was smoothly reduced with sodium borohydride
(Scheme 1) to provide racemic 2-chloro-1-(3-pyridyl)-etha-
nol (RS)-1a for analytical purposes. The mixture was easily
separated/analyzed9 and the 2-chloro-1-(3-pyridyl)-ethanol
(RS)-1a was readily purified and handled, setting the stage
(1S,2S)-pTsNHCH(Ph)–CH(Ph)NH2
and
(1R,2R)-
pTsNHCH(Ph)–CH(Ph)NH2 ligands, respectively. Solvent
effects were examined beginning with entries 3–5. The addi-
tion of CH2Cl2 (entry 3) to the reduction milieu led to an
increased conversion (39% vs ca. 25%) with a shorter reac-
tion time (16 h vs 48 h) and a modest improvement in ee
(70% vs 60%). Conducting the Noyori reduction in THF
(entry 4) resulted in an outcome that was nearly identical
to that obtained in CH2Cl2, a modest improvement over
O
OH
OH
Cl
Cl
Cl
NaBH4, MeOH
+
N
N
N
3a
(R)-1a
(S)-1a
Scheme 1. Racemic halohydrin synthesis, chiral separation, and analysis.

2156
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
Table 1. Chiral reductions—method development
OH
on the relative rate of reaction (45 min to completion)
but did not alter the selectivity (entries 8 and 9).
O
OH
Cl
Cl
+
Cl
A or B
The data of Table 1 support a large solvent effect in the
Noyori asymmetric transfer hydrogenation of 3-chloroacet-
ylpyridine 3a and implicate a solvent role in the transition
state of the reduction. The next phase of our investigations
centered upon demonstrating the breadth of the reduction
across a representative set of aryl-chloromethyl ketones.
Toward that end, we felt it necessary to consider alterna-
tives to the direct halogenation of aryl acetophenones, as
sensitive p-rich heterocycles and electron rich acetophe-
nones may suffer halogenation on the acetyl and the aryl
nucleus. Penning et al. have described11 the facile chlorina-
tion (NCS, THF) of the TMS-enol ether of a 2,4-dialkoxy-
3-alkyl-acetophenone to furnish an unisolated chloro-enol
ether, which, after (n-Bu)4NF treatment, leads to the target
chloromethyl ketone in modest yield (58%). To facilitate
possible purification at chloro-enol ether stage we elected
to examine the conversion of starting ketones to the more
stable TIPS-enol ether [(i-Pr)3Si], as described by Katz.12
Further modification of the Penning sequence was consid-
ered for the desilylation step where we planned to replace
the relatively basic (n-Bu)4NF deblocking with an HF
desilylation.13
N
N
N
3a
(R
)-1a
(S
)-1a
Entry Conditions
Yield Ratio (R)-1a/(S)-1a ee
(%)
(%)
1
2
3
4
5
6
7
8
A, 48 h, rt
B, 48 h, rt
A, CH2Cl2, 16 h, rt
A, THF, 16 h, rt,
A, DMF, 16 h, rt
A, DMF, 90 min, rt
27
24
39
37
67
73
80:20
19:81
85:15
83:17
95:5
98:2
96:4
98:2
60
62
70
66
90
96
92
96
A, DMF, 16 h, ꢀ15 ꢁC 59
A, DMF, 45 min, rt,
house vacuum
71
9
B, DMF, 45 min, rt,
house vacuum
64
2:98
96
A: RuCl[(1S,2S)-p-TsNCH(Ph)–CH(Ph)NH2] (g6-p-cymene), HCO2H/
Et3N (5:2); B: RuCl[(1R,2R)-p-TsNCH(Ph)–CH(Ph)NH2] (g6-p-cymene),
HCO2H/Et3N (5:2).
the standard HCO2H/Et3N conditions. DMF was the next
solvent selected for this study and the effects of this solvent
were dramatic. As can be seen from the data presented in
Table 1, entry 5, the reaction time was shortened to
616 h (first time point measured), giving a 67% isolated
yield of halohydrins as a 95:5 mixture (R:S, 90% ee). The
dramatic improvement in relative reaction rate, overall
conversion, and enantioselectivity suggested an important
role for DMF in the reduction.
2-Acetyl pyridine was exposed to TIPSOTf and i-Pr2NEt
(CH2Cl2) to give the desired TIPS-enol ether (Table 2,
entry 1) 4b in 99% yield. Chlorination was realized upon
treatment of 4b with NCS (1.1 equiv) in THF at reflux to
furnish a mixture of geometric chloro enol ether isomers
5b in 92% yield. The desired chloromethyl ketone 3b was
isolated in 85% yield after desilylation with 48% aq HF
in acetonitrile. Likewise, treatment of 2-acetylfuran, 2-acet-
ylthiophene, 3-acetylthiophene, 2-acetylthiazole, 2-acetyl-
pyrazine, and 2-acetylbenzofuran as outlined in Table 2
led to the related chloromethyl ketones 3c–h in good over-
all yields. Racemic halohydrins 1b–h, required for the
development of chiral chromatographic analytical meth-
ods, could be easily prepared from 3b–h via the Luche
protocol.14 By comparison, standard NaBH4/MeOH
reductions of 3b–h provided 1b–h contaminated with the
corresponding epoxide, an outcome not observed with
the slightly acidic Luche paradigm.
Given the lack of data points pre-16 h in the reaction
course and the rapid pace of the reaction, we needed to
study the time course of the reduction and examine the
impact of temperature on the reduction. It was observed
that the reduction was complete in 90 min (entry 6) to fur-
nish a 73% isolated yield of halohydrins with an excellent
98:2 ratio (96% ee) favoring the expected (R)-enantiomer.
Lowering the temperature of the reaction mixture to
ꢀ15 ꢁC (Table 1, entry 7) slowed the reaction, requiring
16 h to be complete under these conditions, unfortunately
we did not observe an increase in the selectivity of the
reduction (96:4). Similarly, the application of modest vac-
uum (ca. 30 mmHg) to the reaction vessel had an impact
With a cross-section of aryl-chloromethyl ketones in hand,
we examined the reduction protocol for potential problems
Table 2. Aryl-chloromethyl ketone synthesis and racemic reduction
O
OTIPS
OTIPS
Cl
O
NCS, THF
OH
TIPSOTf
48% aq. HF
CH3CN
NaBH4
Cl
Cl
Δ
i
-Pr2NEt
CH2Cl2
Ar
Ar
Ar
CeCl3-7H2O
MeOH
Ar
Ar
4
5
3
1
Entry
Ar
Yield 4 (%)
Yield 5 (%)
Yield 3 (%)
Yield 1 (%)
1
2
3
4
5
6
7
b 2-Pyridyl
c 2-Furyl
99
98
99
99
99
96
99
92
99
98
95
99
98
98
85
67
77
85
60
95
87
75
65
75
71
73
77
56
d 2-Thienyl
e 3-Thienyl
f 2-Benzofuranyl
g 2-Thiazolyl
h 2-Pyrazinyl

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2157
and possible further improvements. Noyori has reported6 a
simple catalyst preparation and a crystallization, which
may be accompanied by decomposition. We were con-
cerned, as was Vedejs,11 as to the impact of catalyst vari-
ability on a reaction survey such as that proposed herein.
It was our desire to develop a catalyst preparation that
might reduce the variability that can accompany batch cat-
alyst preparation and disparate storage time. An in situ cat-
alyst preparation was viewed as the most obvious first pass
solution to this potential development problem.
reduction of 2-chloroacetylfuran 3c was similarly facile,
giving (R)-1c (77%, 98% ee) and (S)-1c (72%, 98% ee) selec-
tively (Scheme 3, entries 3 and 4) in 90 min (2 mol % cata-
lyst). The final substrate examined in our optimization
study was phenacyl chloride 3i that selectively gave (R)-1i
[entry 5, (S,S) ligand, 83%, 98% ee] and (S)-1i [entry 6,
(R,R) ligand, 81%, 98% ee] within 45 min. A comparison
of the rotations of (R)-1i and (S)-1i with commercially
available chiral material (Aldrich, Cat. #36,356-1 and
36,358-8) further secured the absolute stereochemistry
assigned.
Attempted in situ catalyst preparation was initiated
by combining RuCl2(g6-p-cymene) and the selected
p-TsNCH(Ph)–CH(Ph)NH2 (1 and 2 mol %, respectively)
in the reaction vessel selected for the reduction and the
mixture was covered with i-PrOH (7.7 mL/ mmol
The results presented in Table 1 suggest a fundamental role
for the solvent DMF in the transition state of the reaction,
reflected in relative reaction rate and enantioselectivity. In
addition, the data of Scheme 3 indicate that the method of
catalyst preparation has an impact on the relative rate of
the reduction as well as the enantioselectivity of the process
suggesting some modification in the catalyst, either in
structure or in the percentage of catalytically competent
material contained therein. With what appears to be a ro-
bust and reasonably well optimized chiral transfer hydro-
genation system in hand, we turned our attention to
performing reductions on a reasonable scale (10–43 g) for
the complete cross-section of substrates represented by
3b–i (Table 3).
p-TsNCH(Ph)–CH(Ph)NH2),
Et3N
(2 mmol/ mmol
p-TsNCH(Ph)–CH(Ph)NH2) was added. The resulting
solution was refluxed for 1 h, then the solvent was removed
and the reduction was conducted as usual. Scheme 3 pro-
vides our optimization/in situ catalyst preparation studies
with three representative aryl-chloromethyl ketones 2-pyr-
idyl 3b, 2-furyl 3c, and the commercially available phenacyl
chloride 3i. The in situ catalyst generation afforded a rust
red/brown powdery material and a red-brown solution
upon the addition of DMF and 2-chloroacetylpyridine 3b
(Scheme 3). The first indication of a difference in the reduc-
tion sequence was observed almost immediately after the
addition of the HCO2H/Et3N 5:2 azeotrope. During the
conduct of the reactions of Table 1, we noted an induction
period of 15–30 min after the addition of the HCO2H/Et3N
5:2 azeotrope before gas evolution (believed to be CO2, H2)
was observed. In the case of Scheme 3 entry 1, gas evolu-
tion was almost immediate and HPLC analysis of the reac-
tion mixture indicated completion of the reduction after
only 45 min. The halving of the reaction time (vs Table 1,
run 6) was accompanied also by an improvement in the
reduction enantioselectivity, giving (R)-1b in 80% yield
and >99% ee (vs 73% and 96% ee). The reduction of 3b
with the (R,R)-based catalyst was similarly rapid and high
yielding, giving a 77% yield of (S)-1b in >99% ee. The
Table 3. Chiral reductions—scale-up
O
OH
OH
A or B
Cl
Cl
Cl +
Ar
Ar
Ar
3
(R
)-1
( )-1
S
Entry Aryl
Catalyst Yield (%) Ratio (R/S) ee (%)
1
2
3
4
5
6
7
8
b 2-Pyridyl
b 2-Pyridyl
c 2-Furyl
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
61
68
71
76
74
68
66
63
93
92
81
68
70
88
88
85
98:2
0:100
99:1
1:99
99:1
1:99
98:2
1:99
99:1
96
>99
98
98
98
98
96
98
98
98
97
97
76
78
>99
98.8
c 2-Furyl
d 2-Thienyl
d 2-Thienyl
e 3-Thienyl
e 3-Thienyl
f 2-Benzofuranyl
f 2-Benzofuranyl
g 2-Thiazolyl
g 2-Thiazolyl
h 2-Pyrazinyl
h 2-Pyrazinyl
i Phenyl
9
10
11
12
13
14
15
16
1:99
O
OH
OH
A or B
98.5:1.5
1.5:98.5
88:12
11:89
100:0
0.6:99.4
Cl
Cl
Cl +
Ar
Ar
Ar
3b (Ar = 2-pyridyl)
c (Ar = 2-furyl)
i (Ar = phenyl)
(R)-1b
(S)-1b
c
i
c
i
i Phenyl
Yield Ratio
ee
Entry Aryl Condition
A: RuCl[(1S,2S)-p-TsNCH(Ph)–CH(Ph)NH2] (g6-p-cymene), HCO2H/
Et3N (5:2), DMF; B: RuCl[(1R,2R)-p-TsNCH(Ph)–CH(Ph)NH2] (g6-p-
cymene), HCO2H/Et3N (5:2), DMF.
(%)
80
77
77
72
83
81
(R/S) (%)
100:0 >99
0:100 >99
99:1
1:99
99:1
1:99
1
2
3
4
5
6
3b
3b
3c
3c
3i
A, 45 min
B, 45 min
A, 90 min
B, 90 min
A, 45 min
B, 45 min
98
98
98
98
Seven of the eight aryl-chloromethyl ketones examined in
this study suffered reduction in good to excellent yields
and excellent ee’s, as measured by chiral HPLC analysis.
The reductions of Table 3 were carried out with in situ
generated catalyst with a catalyst loading of 62 mol %.
Previously, we demonstrated good yields and ee’s for the
2-pyridyl system 3b, 2-furyl chloromethyl ketone 3c, and
phenacyl chloride 3i in small scale reductions (Scheme 3).
3i
A: RuCl[(1S,2S)-pTsNCH(Ph)-CH(Ph)NH2](η6-p-cymene),
HCO2H, / Et3N (5:2), DMF, RT B: RuCl[(1R,2R)-
pTsNCH(Ph)-CH(Ph)NH2](η6-p-cymene),
HCO2H, / Et3N (5:2), DMF, RT
Scheme 3. Chiral reductions—optimization—in situ catalyst preparation.

2158
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
On large scale, these compounds were similarly well
behaved. On identical 24 g scale reductions, 3b afforded
(R)-1b (61%, 96% ee) and (S)-1b (68%, >99% ee) upon
exposure to catalysts A (S,S) and B (R,R), respectively
(Table 3, entries 1 and 2). The less polar, p-rich hetero-
cycles 2-chloroacetylfuran 3c, 2-chloroacetylthiophene 3d,
3-chloroacetylthiophene 3e, and 2-chloroacetylbenzofuran
3f behave similarly when exposed to catalysts A (S,S)
(Table 3, entries 3, 5, 7, and 9) giving the expected halohyd-
rins (R)-1c–f in 66–93% yield and 96–98% ee. The reduc-
tion of 3c, 3d, 3e, and 3f under the influence of catalyst B
(R,R) was also successful, leading to halohydrins (S)-1c–f
(entries 4, 6, 8, and 10) in 63–92% yield and 98% ee for each
substrate. The bis-heteroaromatics 2-chloroacetylthiazole
3g and 2-chloroacetylpyrazine 3h provide an interesting
contrast, to each other and to the entities subjected to
asymmetric reduction until this point. The 2-thiazolyl
chloromethylketone 3g is smoothly reduced with the
(S,S) catalyst (entry 11) to give alcohol (R)-1g in 81% yield
and 97% ee. The reduction of 3g with catalyst B (R,R) gave
alcohol (S)-1g in a reduced 68% yield, but equally good
97% ee. We were taken aback by the results obtained upon
reduction of 2-chloroacetylpyrazine 3h. Ketone 3h was
reduced with the (S,S) catalyst A, in the usual way, to pro-
vide (R)-1h in 70% yield with a much reduced 76% ee. A
similarly disappointing result was obtained upon reduction
of 3h with the (R,R) catalyst B, to furnish (S)-1h in 88%
yield and 78% ee. Repeated reductions, and manipulation
of the reduction temperature did not improve the enantio-
meric excess of the 1h product halohydrins. These results
were unexpected, as both 3-chloroacetylpyridine 3a and
2-chloroacetylpyridine 3b had been reduced in good yield
and excellent ee’s, and we considered 2-chloroacetylpyr-
azine 3h to be a hybrid of these structures. Clearly there
are factors, as yet not fully understood, that can lead to
an erosion in the chiral integrity of the reduction process.
The final examples of Table 3, the reduction of commer-
cially available phenacyl chloride 3i to afford (R)-2i (88%,
>99% ee) and (S)-2i (85%, 98.6% ee) proceeded in high
yield and % ee, and have also been conducted on >100 g
scale without an impact on enantioselectivity.
2 M in MeOH), in the presence of 10 mol % NaI, at 60 ꢁC,
in a thick-walled, sealed glass bottle, to give (R)-2-(1-
hydroxy-2-N-methylamino-ethyl)-pyridine (R)-2b in 54%
yield (>96% ee, Eq. 3). The measured enantiomeric excesses
for both (S)-2b and (R)-2b were difficult to ascertain with
great precision as the chromatographic characteristics of
these aminoethanols were less than ideal. A similar dis-
placement was next examined for the 2-furyl halohydrin
(R)-1c as shown in Eq. 4. The reaction produced a number
of products, the major entity isolated was relatively unsta-
ble unlike reports of the racemic N-methyl-1-(2-furyl)-2-
aminoethanol,16 and it provided 1H-chemical shifts and
multiplicities outside of those expected after the syntheses
of (S)-2b and (R)-2b. Further support for the assigned
structure came from long-range 1H–13C heteronuclear shift
correlation (HMBC).17 These data caused us to assign the
2-(2-furyl)-2-amino ethanol structure 6 to this compound
and surmise that its origin might be derived from the
related epoxide.18 The result of Eq. 4 predicts difficulties
for other p-rich heterocycles, a trait possessed by many
of the chiral halohydrins of Table 3. It was necessary to
examine an alternative to direct amine displacement that
would obviate the styrene-like-oxide as
a putative
intermediate:
OH
OH
NHCH3
Cl
MeNH2 (2M in MeOH)
ð2Þ
N
N
10 mol% NaI, 60 °C, 16 h
(S)-2b (58%, >96% ee)
(R)-1b
OH
OH
NHCH3
Cl
Cl
MeNH2 (2M in MeOH)
ð3Þ
N
N
10 mol% NaI, 60 °C, 16 h
(R)-2b (54%, >96%ee)
(S)-1b
OH
NHCH3
OH
O
O
MeNH2 (2M in MeOH)
ð4Þ
10 mol% NaI, 60 °C, 16 h
(R)-1c
6
The failure of an intermolecular nitrogen introduction,
either due to formation of the epoxide or via –OH ioniza-
tion, suggested that we examine an intramolecular delivery
of the nascent methylamino group using the halohydrin-
OH as the tether. The work of Das19 provided the frame-
work for the chemistry illustrated in Scheme 4. 2-Furyl-
halohydrin (R)-2c was reacted with methyl isocyanate
and Et3N, in methylene chloride at room temperature, to
provide (R)-1-(2-furyl)-2-chloroethyl N-methylcarbamate
(R)-7c in 73% yield (98% ee). Cyclization of the carbamate
with KO-t-Bu in THF smoothly led to the stable inter-
mediate (5R)-3-methyl-5-(2-furyl)-2-oxazoldinone (S)-8c
(93%, 97% ee), which was easily and quickly analyzed by
chiral HPLC suggesting an oxazolidinone as an ideal inter-
mediate for analysis and/or chiral chromatographic
upgrade. A number of hydrolytic paradigms were exam-
ined to unravel the oxazolidinone and reveal the desired
aminoethanol. Ultimately, we settled upon a simple treat-
ment of (S)-8c with 1 N aq KOH at 50 ꢁC. The two phase
mixture gave way, over 3 h, to a homogenous solution.
Analysis of the mixture by analytical HPLC at this time
2.2. The synthesis of highly enantiomerically enriched
N-methyl-2-amino-1-aryl-ethanols
With a general method for the production of highly enan-
tiomerically enriched 1-aryl-2-chloroethanols in hand, we
turned our attention to the conversion of these molecules
to the target 1-aryl-2-methylaminoethanols. The direct
conversion of a 1-aryl-2-chloroethanol to the related
1-aryl-2-methylaminoethanol was envisioned to occur by
direct amine displacement as described by Ehlers.15 Our
initial attempt to prepare a chiral 1-aryl-2-methylamino-
ethanol utilized the 2-pyridylhalohydrin (R)-1b. Treatment
of this substrate with methylamine (10 equiv, 2 M in
MeOH) at 60 ꢁC in a thick-walled, sealed glass bottle
resulted in ca. 40% conversion after 24 h. The introduction
of 10 mol % NaI into the reaction medium (Eq. 2) led to
smooth conversion to the aminoethanol, affording (S)-2-
(1-hydroxy-2-N-methylamino-ethyl)-pyridine (S)-2b in
58% yield (>96% ee, Eq. 2). In a similar fashion, 2-pyridyl
halohydrin (S)-1b was reacted with methyl amine (10 equiv,

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2159
The (R)-halohydrins 1a and 1d–i are very well behaved (Ta-
ble 4, shown with data for 1c from Scheme 4), furnishing
good yields and high enantiomeric excess of related carb-
amates (R)-7 upon treatment with methyl isocyanate. The
cyclization reaction, to oxazolidinones 8 proved to be less
general. The 3-pyridyl-, 2-thienyl-, 3-thienyl-, 2-benzofuran-
yl-, and phenyl-(R)-carbamates 7 were readily cyclized
with 1 M KO-t-Bu in THF at room temperature to give
oxazolidinones 8 in 56–96% yields with very good to excel-
lent ee’s. The demarcation between good performance and
failure for the oxazolidone route to amino ethanols is
obvious when one inspects the results obtained for the
cyclizations of the 2-thiazolyl carbamate (R)-7g and the
2-pyrazinyl carbamate (R)-7h. The addition of 1 M KO-t-
Bu in THF to (R)-7g at room temperature resulted in the
immediate development of a red-black color. Quickly
quenching the reaction provided oxazolidinone 8g in a
much reduced 35% yield. In addition to the low yield of
cyclization observed for (R)-7g, we discovered that 8g
was racemic. Repeating the cyclization with KO-t-Bu,
NaH, or NaN(SiMe3)2 at temperatures from ꢀ78 ꢁC to
room temperature did not result in an improved outcome.
The 2-pyrazinylcarbamate (R)-7h also behaved poorly. The
reaction of (R)-7h with KO-t-Bu at room temperature led
to a red-black solution and the destruction of the starting
material. Lowering the reaction temperature to ꢀ78 ꢁC
afforded oxazolidinone (S)-8h in a poor 15%, and an inex-
plicably improved 92% ee. The data of Table 4 suggest that
the conversion of chiral halohydrins 1 to chiral amino-
methanols 2 should not be attempted via the oxazolidinone
route for 2-azaaryl-carbamates 7 such as 2-thiazolyl-7g and
2-pyrazinyl-7h. The rapid development of color, much
diminished yields, and altered ee’s suggest the possibility
of a deprotonation/elimination event as the root cause of
the difficulties for these substrates. The sequence was com-
pleted by treating oxazolidinones (R)-8a, (S)-8d, (R)-8e,
(S)-8f, and (R)-8i with 1 N aq KOH (50 ꢁC) to furnish
aminoethanols (R)-2a (68%, >96% ee), (S)-2d (85%,
>98% ee), (R)-2e (93%, >99% ee), (S)-2f (93%, 92% ee),
O
OH
O
NHCH3
Cl
O
CH3NCO, Et3N
CH2Cl2, RT
O
KOt-Bu
Cl
THF, RT
(R)-7c (73%, 98%ee)
(R)-1c
O
OH
O
O
H
N
N
CH3
O
1N aq. KOH
50 °C
CH3
(S)-2c (98%, >96%ee)
(S)-8c (93%, 97%ee)
Scheme 4. Oxazolidinone approach to N-methyl (S)-1-(2-furyl)-2-amino-
ethanol (S)-2c.
point indicated complete conversion to a single entity.
Saturation of the solution with salt and extraction with
Et2O/CH2Cl2 (95:5), followed by drying (Na2SO4) led
directly to analytically pure N-methyl S-1-(2-furyl)-2-
aminoethanol (S)-2c (98%, >96% ee).
The oxazolidinone approach, shown in Scheme 4, has attri-
butes that make it quite attractive despite its length. Mole-
cules, which resist conversion to the desired aminoethanols
might be accessed via this route providing two approaches
to these target molecules. The facility with which the pen-
ultimate oxazolidinone might be assessed for enantiomeric
excess and upgraded through preparative chiral chroma-
tography, or even recrystallization, is noteworthy and must
be contrasted to the long retention times and broadened
peaks observed for the aminoethanols (S)-2b and (R)-2b.
This suggests the utility of both routes, wherein the chem-
istry of Scheme 4 will be our preferred approach, with fail-
ure leading to direct displacement. The direct displacement
of Eqs. 2 and 3 can then benefit from aminoethanol to oxa-
zolidinone conversion for analysis of enantiomeric excess
and/or chiral upgradation. The application of the chemis-
try of Scheme 4 to the remaining chiral halohydrins of
Table 3 is shown in Tables 4 and 5.
and (R)-2i (98%, >98% ee). A comparison of the specific
25
rotation determined for (R)-2i (½aꢁD ¼ ꢀ41 (c 0.97, EtOH)
with
a
literature value for (R)-2i (R)-halostachine,
Table 4. Oxazolidinone route to aminoethanols from chiral halohydrins (R)-2
O
O
OH
O
NHCH3
OH
KOt-Bu
THF, RT
1M aq. KOH
CH3
50 °C
CH3NCO, Et3N
CH2Cl2
O
H
N
Cl
N
Ar
Ar
Ar
CH3
Ar
Cl
2
8
(R)-1
(R)-7
Entry
Ar
Yield 7 (%)
ee (%)
Yield 8 (%)
(R)/(S)
ee (%)
Yield 2 (%)
(R)/(S)
ee (%)
1a
1c
1d
1e
1f
3-Pyridyl
2-Furyl
2-Thienyl
3-Thienyl
2-Benzofuranyl
2-Thiazolyl
2-Pyrazinyl
Phenyl
89
73
91
88
89
77
85
89
94.6
98
92.4
92.8
98
>99
82
98
71
93
91
81
56
35
15
96
R
S
97.6
97
98.4
>99
92
0
68
98
85
93
93
—
—
95
R
S
>96
>96
>98
>99
92
—
—
>98
S
S
R
S
R
S
1g
1h
1i
—
S
—
—
R
92
>98
R

2160
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
Table 5. Oxazolidinone route to aminoethanols from chiral halohydrins (S)-2
O
O
N
OH
O
NHCH3
OH
KOt-Bu
1M aq. KOH
CH3
50 °C
CH3NCO, Et3N
CH2Cl2
O
H
N
Cl
Ar
Ar
Ar
CH3
THF, RT
Ar
Cl
2
8
(S)-1
(S)-7
Entry
Ar
Yield 7 (%)
ee (%)
Yield 8 (%)
(R)/(S)
ee (%)
Yield 2 (%)
(R)/(S)
ee (%)
1a
1c
1d
1e
1f
1i
3-Pyridyl
2-Furyl
2-Thienyl
3-Thienyl
2-Benzofuranyl
Phenyl
90
65
92
88
89
85
96.6
98
97
97
98
83
93
91
83
61
83
S
R
R
S
96.6
98
>98
97
92
96
68
96
90
93
92
91
S
R
R
S
97.4
>96
>98
>99
92
R
S
R
S
>98
97
25
½aꢁD ¼ ꢀ40:7 (c 1.3, EtOH))20 supports the assigned abso-
lute stereochemistry and demonstrates the stereochemical
fidelity of the oxazolidinone process.
(R)-8f (61%, Table 5). Again in the case of Table 5 sub-
strates, the sequence was completed by treating oxazolidi-
nones (S)-8a, (R)-8c, (R)-8d, (S)-8e, (R)-8f, and (S)-8i
with 1 M aq KOH (50 ꢁC) to furnish aminoethanols (S)-
2a (68%, 97.4% ee), (R)-2c (96%, >96% ee), (R)-2d (90%,
>98% ee), (S)-2e (93%, >99% ee), (R)-2f (92%, 92% ee),
The experience gained in the conduct of the chemistry pre-
sented in Table 4 resulted in a reduction in the (S)-halohyd-
rins selected for reaction via the oxazolidinone route (Table
5). The results of Table 5 for substrates 1a, 1c–f, and 1i are
nearly identical to those illustrated in Table 4. For this ser-
ies, the only erosion of enantiomeric excess occurred during
the cyclization of the 2-benzofuranylcarbamate (S)-1f, a
decrease in % ee from 98% to 92% ee for oxazolidinone
(R)-8f, which leads to (R)-2f in 92% ee. The close concor-
dance of these data with the benzofuran results of Table
4, and the lack of ee erosion in the reactions of 1a, 1c–e,
and 1i (Table 5), as well as 1a, 1c–e, and 1i in Table 4 sup-
port a base sensitivity for this substrate as do the dimin-
ished yields of oxazolidinones (S)-8f (56%, Table 4) and
and (S)-2i (91%, 97% ee). A comparison of the specific
25
rotation determined for (S)-2i (½aꢁD ¼ þ39 (c 0.83, EtOH)
with
a literature value for (S)-5h (S)-halostachine,
25
½aꢁD ¼ 40:4 (c 1.89, EtOH))1f again supported the assigned
absolute stereochemistry and provided further proof of the
stereochemical fidelity of the oxazolidinone process.
The failed substrates from Table 4, and those withdrawn
from Table 5, namely 2-thiazolyl-(R)-1g, 2-pyrazinyl-(R)-
1h, 2-thiazolyl-(S)-1g, and 2-pyrazinyl-(S)-1h halohydrins
might be converted to their respective aminoethanols by
the direct displacement used in Eqs. 2 and 3. Should that
O
O
OH
carbonyldiimidazole
NHCH3
preparative chiral HPLC
N
CH3
CH2Cl2, RT
( )-2i
( )-8i (94%)
O
O
O
O
OH
N
N
CH3
CH3
NHCH3
1M aq. KOH
50 °C
+
(R)-8i (36%, >99%ee)
(S)-8i (29%, 89%ee)
(S)-2i (98%, 89%ee)
1M aq. KOH
50 °C
OH
NHCH3
(R)-2i (95%, >95%ee)
Scheme 5. Chiral upgrading via the oxazolidinone route.

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2161
succeed, we would examine an oxazolidinone formation,
chiral chromatographic upgrade, unmasking for the
modestly enantiomerically pure 2-pyrazinyl-halohydrins
(R)-1h and (S)-1h.
friendly chloroketone preparation. Process chemists at
Merck previously reported a route to chloroketones using
the corresponding Weinreb amide, reporting yields of
80–95% for a variety of substrates.21 Thus, the Weinreb
reagent N-methoxy-N-methylchloroacetamide 9 was pre-
pared by the Merck procedure and the work-up modified
to allow the isolation of the product 9 as a white crystalline
solid in 95% yield. The desired 2-pyridyl Grignard reagent
was prepared as a black solution by treating 2-chloropyri-
dine with magnesium in THF at 40 ꢁC. Adding this Grig-
nard reagent to 0.9 equiv of Weinreb amide 9 gave a 4:1
mixture of desired chloroketone 3b to pyridine along with
a number of small impurities by HPLC (Eq. 7):
The 2-thiazolylhalohydrins (R)-1g and (S)-1g were con-
verted in modest yield to the related 2-thiazolylaminoetha-
nols (S)-2g (31%, >98% ee, Eq. 5) and (R)-2g (36%, >98%
ee, Eq. 6), in these cases isolation was difficult due to the
high water solubility of the aminoethanols. As a test case
for chiral upgrading we elected to examine the conversion
of commercially available, racemic halostachine ( )-2i (Al-
drich #20,984-8) to ( )-8i and attempted to achieve a pre-
parative chiral chromatographic separation. In the event
(Scheme 5), ( )-2i was treated with carbonyldiimidazole
(CH2Cl2, rt) to give ( )-8i in 94% yield. Single pass pre-
parative chiral chromatographic separation on a >50 g
scale (Chirobiotic T column—ethanol mobile phase) gave
(R)-8i (36%, >99% ee) and (S)-8i (29%, 89% ee) as well
as some mixed fractions. Oxazolidinone hydrolysis in the
usual way led to (R)-2i (95%, >95% ee) and (S)-2i (98%,
89% ee), respectively:
O
N
Cl
N
Cl
N
1. Mg, THF, 40 °C
+
O
ð7Þ
ð8Þ
ð9Þ
H3CO
Cl
2.
N
3b
(4 : 1)
Cl
CH3
9
O
N
Br
N
1. i-Pr-MgCl, THF, RT
OH
OH
O
H3CO
Cl
Cl
NHCH3
2.
N
N
N
MeNH2 (2M in MeOH)
3b (91%)
ð5Þ
ð6Þ
9
S
CH3
S
10 mol% NaI, 60 °C, 16 h
(R)-1g
(S)-2g (31%, >98%ee)
O
O
N
O
(8.3 kg)
OH
NH
OH
Cl
Cl
Cl
Cl
NHCH3
N
N
MeNH2 (2M in MeOH)
aq. K2CO3, CH2Cl2
O
(8.3 kg)
S
S
10 mol% NaI, 60 °C, 16 h
10 (96.6 area%,
(S)-1g
(R)-2g (36%, >98%ee)
84 weight% )
Armed with reasonable methodology for the preparative
chiral chromatographic upgrade of 1-aryl-2-methylamino-
ethanols, we selected an antipode of the pyrazinyl system
for conversion/upgrade as shown in Scheme 6. 2-Pyrazin-
yl-chlorohydrin (S)-1h (76% ee) smoothly suffered
displacement with methyl amine in methanol to give
(R)-2-methylamino-1-pyrazin-2-ylethanol (R)-2h in 72%
yield and 76% ee. A reasonable yield of this material was
only realized upon the elimination of an aqueous reaction
work-up and placement of the crude reaction mixture (after
solvent removal) directly onto a chromatography column.
The upgrade substrate, pyrazinyl oxazolidinone (R)-8h
was obtained in 88% yield (77% ee) and subsequent
preparative chiral HPLC separation (Chirobiotic T col-
umn—ethanol mobile phase) provided (R)-8h in 55% yield
and a much improved >96% ee. Finally, oxazolidinone
cleavage (1 N aq KOH) led to pyrazinyl aminoethanol
(R)-2h in 79% yield and >93% ee.
It was previously shown that reaction of 2-iodopyridine
with ethylmagnesium bromide smoothly afforded the 2-
pyridyl Grignard,22 however, only research quantities of
2-iodopyridine are commercially available, whereas 2-
bromopyridine is a bulk article of commerce. It was then
found that high purity 2-pyridyl magnesium halide could
be conveniently prepared by adding 2-bromopyridine to
commercially available 2 M isopropyl magnesium chloride
in THF and by reacting at room temperature for 2–3 h.
With the desired 2-pyridyl organometallic in hand, it was
reacted with 9 and cleanly gave the desired chloroketone,
3b (90%, Eq. 8).
As we prepared to transition the chemistry of Eq. 8 to lar-
ger scale we identified a serious safety issue, which caused
us to alter our course. The Weinreb amide reagent 9, was
identified as a high energy intermediate (1920 J/g) and
although the decomposition temperature for the pure com-
pound is over 198 ꢁC the nature of the N–O bond cleavage
and the large amount of potential energy warranted closer
examination. In addition, we had planned to isolate, the
N,O-dimethylhydroxylamine free base by-product, which
is also reported to have high energy and a much lower ther-
mal onset (ꢂ50 ꢁC), similar to hydroxylamine. For these
reasons we elected to use morpholine amide, 10 in place
of 9 for our pilot run. Amide 10 was prepared under Schot-
ten–Bauman conditions (Eq. 9, 96.6 area %) using methyl-
ene chloride and aqueous potassium carbonate with
2.3. Transition to the pilot plant
The route outlined above (Table 2, Scheme 3, Eq. 2) was to
be used to prepare multi-kilogram quantities of amino
alcohol (R)-1b. From a large scale operational point of
view, the principle issues with this route were associated
with the preparation of the chloroketone 3b and not the
subsequent modified Noyori reduction and amine displace-
ment. Therefore we set out to develop a more process

2162
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
OH
OH
Cl
NHCH3
MeNH2 (2M in MeOH)
carbonyldiimidazole
CH2Cl2, RT
N
N
N
N
10 mol% NaI, 60 °C, 16 h
(S)-1h (76%ee)
(R)-2h (72%, 76%ee)
O
O
O
O
OH
N
preparative chiral HPLC
N
CH3
NHCH3
1M aq. KOH
50 °C
CH3
N
N
N
N
N
N
(R)-8h (55%, >96%ee)
(R)-2h (79%, >93%ee)
(R)-8h (88%, 77%ee)
Scheme 6. Chiral upgrading in the pyrazinyl manifold via an oxazolidinone.
morpholine and chloroacetyl chloride. The product parti-
tioned efficiently into the organic phase and was crystal-
lized in the laboratory by replacing the methylene
chloride with octanes. However, the solid 10 had a melting
point of 26–30 ꢁC and it was impractical to isolate this
intermediate in the pilot plant. We instead chose to
exchange the methylene chloride for THF and use the
solution of 10 directly in the next step.
mediates are observed to form in slow reductions by
HPLC. Interestingly, the chlorohydrin 1b does not appear
to degrade upon extended reaction, suggesting that dis-
placement of the chloroketone is the primary mechanism
for diol formation
Also during the scale-up we discovered an additional alter-
ation to the in situ catalyst preparation outlined above
(Scheme 3). For large scale operations we have found that
it is preferable to form the catalyst complex in situ without
the solvent swap. In the event, stirring the ruthenium dimer
with the ligand in DMF and Et3N at room temperature for
1 h, followed by the addition of 3b and the 5:2 mixture of
HCOOH/Et3N gives an equivalent catalyst, which affords
(S)-1b in >98% ee in 90 min on a >10 kg scale. Despite this
success at reproducing the high ee of (S)-1b from the
laboratory scale to pilot plant scale, isolation remained
somewhat problematic. Extractive isolation of the chloro-
hydrin intermediate is inefficient due to its hydrophilic
nature. Therefore, it was postulated that we could avoid
these isolations by quenching the reduction mixture into
a solution of sodium hydroxide and methylamine to yield
the desired amino alcohol (R)-2b directly. Happily, this
was found to be the case, which allowed for the rapid
development of a scalable procedure. The salts formed
from neutralizing the formic acid and neutralizing the
chlorohydrin were easily removed by filtration after distill-
ing off the DMF solvent for the reduction and water from
While reaction of 2-pyridyl Grignard reagent with 9 gave
the desired 3b with no significant by-product formation,
the same is not true for 10. In our first attempt at the reac-
tion, we found a new impurity formed in about 15% yield.
HPLC MS confirmed that this impurity is the result of
morpholine addition to 3b. Running the reaction at
ꢀ20 ꢁC for 4–6 h instead of 5–10 ꢁC reduced the amount
of this impurity, affording 3b as an MTBE solution without
removal of the impurity. In order to avoid isolation of 3b,
which is low melting and a lachrymator, it was found that
the crude oil (97–98 area % purity) (with or without small
amounts of MTBE) from the Grignard coupling could be
carried directly into the modified Noyori reduction without
crystallization. However, in order to achieve the same rate
of reduction, 1.27 mol % of the catalyst was required, as
opposed to 0.85 mol % with crystallized 3b. A fast reduc-
tion (<4 h) is preferred in order to minimize formation of
the diol, 13 observed after the aminolysis, which we specu-
late might be the result of nucleophilic attack of formate on
the chlorohydrin intermediate as shown in Scheme 7.
Recently, Noyori reported the formate as the exclusive
product in low catalyst loading reductions of aryl alkyl
chloroketones.6c More of the putative formate ester inter-
O
1. i-PrMgCl (45 kg, 2M in THF)
Cl
Br
O
N
N
Cl
2.
N
O
O
3b (76%, 10.6 kg)
O
(14.5 kg)
-
N
Cl
HCO2
N
OCHO
[H]
1. (R,R)-(-)-N-(4-toluenesulphonyl)-
1,2-diphenylethylenediamine,
[RuCl2(η6-p-cymene)]2, Et3N
DMF
OH
3b
OH
11
.
NHCH3
OH
2. 5:2 HCOOH/Et3N
N
HO-
N
OCHO
N
OH
HO2C
3. 40% aq. CH3NH2
4. (S)-naproxyn (22.5 kg)
12
13
(R)-2b (13.5 kg, 98% ee, 48.5% overall)
Scheme 7. Diol formation in the reduction of ketone 3b.
Scheme 8. Pilot plant preparation of (R)-2b.

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2163
the commercial methylamine and sodium hydroxide under
reduced pressure and solvent exchange to ethanol. The
product (R)-2b was then isolated in >98% ee (13.5 kg)
by addition of (S)-Naproxen cooling and filtering in 49%
yield from 2-bromopyridine as the (S)-Naproxen salt
(Scheme 8).
instances attempted intramolecular oxazolidinone forma-
tion leads to degradation and/or partial racemization.
Direct displacement has allowed the preparation of
>10 kg of (R)-2b in a single pilot plant run. The chiral halo-
hydrins and chiral aminoethanols reported herein, pro-
duced in good to excellent yields, with high ee’s and with
predictable chiral selectivity (directly correlated to literature
entities and items of commerce) have been of great utility.
3. Conclusion
As a direct result of our efforts in another area, we realized
that we required a general method to access a wide variety
of 1-aryl-2-methylaminoethanols. Our analysis of the situ-
ation suggested that the ideal penultimate aminoethanol
precursor, for maximum utility, should be a chiral 1-aryl-
2-chloroethanol. Using the Noyori transfer asymmetric
4. Experimental
All reagents were used as received unless otherwise stated.
All reactions were performed under a blanket of nitrogen,
in oven (150 ꢁC) dried glassware with rigid exclusion of
moisture from all reagents and glassware unless otherwise
mentioned. Melting points were determined on a Fisher–
Johns hot stage melting point apparatus and are uncor-
rected. Proton magnetic resonance spectra (1H NMR) were
recorded on a Bruker AVANCE-DPX-300 spectrometer at
300 MHz or a Bruker AVANCE 400 spectrometer at
400 MHz as indicated, in deuteriochloroform unless other-
wise indicated. Chemical shifts are reported in parts per
million (d scale) from internal tetramethylsilane. Data
are reported as follows: chemical shifts [multiplicity
(s = singlet, br s = broad singlet, dd = doublet of doublets,
d = doublet, t = triplet, q = quartet, m = multiplet), cou-
pling constant (Hz), integration]. 13C NMR spectra were
recorded on a Bruker AVANCE 400 spectrometer at
100.6 MHz in the solvent mentioned. Chemical shifts
are reported in parts per million (d scale) from the internal
solvent reference. Data for mass spectra analysis are
reported in the form m/z (intensity relative to base = 100).
Thin layer chromatography (TLC) was performed on
EMerck silica gel GF254 plates. Spots were made visible
with UV light, and/or exposure to I2 vapors, and/or dip-
ping into a solution of ammonium molybdate (75 g) and
ceric sulfate (2.5 g) in water and concd sulfuric acid
(500 mL; 9:1, v/v) followed by heating. Flash column chro-
matography was performed according to the procedure of
Still23 and eluted with the solvents mentioned, or via the
use of the BiotageTM system using either 40S, 40M, or 40L
Biotage KP-SilTM silica prepacked cartridges and eluted
with the solvents mentioned. Solvents for extraction and
chromatography were of HPLC grade. All the intermedi-
ates and final compounds demonstrated >95% purity by
HPLC (254 nm, C18 column, gradient from 10% MeCN/
buffered aqueous to 85% MeCN/buffered aqueous, where
4 L of high purity water was buffered by adding 5.22 g
Na2HPO4 and 0.76 mL H3PO4).
reduction
[RuCl[(1S,2S
or
1R,2R)-p-TsNCH(Ph)–
CH(Ph)NH2/HCOOH–Et3N] of aryl-chloromethyl ketones
as the starting point for methodological manipulation, a
number of seminal alterations/observations have been
made. First, there is a profound solvent effect in the reduc-
tion step, wherein DMF as the solvent results in a sizeable
increase in the relative rate of the reduction (Table 1; entry
1—48 h to entry 6—1.5 h), an increase in the yield of
reduced materials (Table 1; entry 1—27%, entry 6—73%),
and a dramatic improvement in the % ee of the product
halohydrin (Table 1; entry 1—60% ee, entry 6—96% ee).
These data implicate a solvent role in the transition state
of the reduction, a role, which is as yet unknown. Further
modification to the reduction catalyst was driven by the
anticipated need for consistent (over time) reduction, and
readily scaled reduction with a catalyst that was known
to suffer some degradation in conversion and enantioselec-
tivity as a function of age/handling. Toward that end, we
have developed an in situ catalyst preparation, which has
an impact on the relative rate of the reduction as well as
the enantioselectivity of the process suggesting some mod-
ification in the catalyst, either in structure or in the percent-
age of catalytically competent material contained therein
(Scheme 3, Table 3). These alterations have provided us
with a robust, general, scaleable reduction paradigm. The
scalability of this route is well demonstrated in the transi-
tion to the pilot plant setting, where reduction on a
>10 kg scale proceeds rapidly (90 min) in good yield
(Scheme 8) and in excellent ee (>98%). Further improve-
ments in the catalyst generation paradigm were made in
the pilot plant setting where component admixing in the
presence of Et3N and DMF afforded the results alluded
to above. Aminoethanol synthesis is readily accomplished,
but has proven to be less general with respect to the path
chosen. Two methods allow the synthesis of the target
aminoethanols, the direct displacement (Eqs. 2 and 3),
and the oxazolidinone route (Scheme 4) wherein displace-
ment is realized from an intramolecularly held carbamate
nitrogen. The oxazolidinone route is preferred for ease of
handling, ease of chiral analysis, and oxazolidinones have
resulted in facile chiral upgrade (Schemes 5 and 6) in
hybrid displacement/oxazolidinone formation sequences.
Direct amine displacement can be the method of choice
in those instances where the aryl moiety exhibits a N at
the position adjacent to chloroethanol attachment (viz
Table 4 entries 1g and 1h; Eqs. 5 and 6, Scheme 8), in these
4.1. ( )-2-Chloro-1-(3-pyridyl)-ethanol ( )-1a
3-(2-Chloroacetyl)-pyridine2d 3a (86.40 g, 0.45 mol) was
dissolved in MeOH (0.6 L) and the resulting solution was
cooled to ꢀ10 ꢁC (internal) under nitrogen. To this chilled
solution was added NaBH4 (25.92 g, 0.685 mol) in six por-
tions over the course of 1 h. The solution was allowed to
warm slowly to room temperature and was stirred at room
temperature for 18 h. The reaction was quenched by the
addition of water (0.5 L) and the methanol was removed
by rotary evaporator at reduced pressure (25 ꢁC). The pH

2164
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
of the resulting solution was adjusted to ca. 7.0 by the addi-
tion of acetic acid and the solution was extracted with
EtOAc (4 · 0.5 L) and the combined organic phases were
dried (Na2SO4). Filtration and concentration in vacuo
afforded crude ( )-2-chloro-1-(3-pyridyl)-ethanol ( )-1a
as a yellow oil, which was purified by chromatography
on a column of silica gel (70 mm OD, 450 g, 230–400 mesh;
packed and eluted EtOAc/hexanes 10:90, 500 mL frac-
tions) using the flash technique. Fractions 4–10 were com-
bined and concentrated in vacuo to give 57.5 g (81%) of
( )-1a as a clear colorless oil. 1H NMR (400 MHz, CDCl3)
d = 8.41 (s, 1), 8.31 (d, J = 5.0 Hz, 1), 7.74 (m, 1), 7.24 (m,
1), 4.89 (m, 1), 3.62 (d, J = 6.0 Hz, 2).
122.6 mL) over 1.5 h. The mixture was allowed to warm to
room temperature overnight. The reaction mixture was
concentrated in vacuo on a rotary evaporator (T 6 25 ꢁC)
to give a yellow oil and a white solid. The flask contents
were transferred to a 2 L separatory funnel with ether
(1.2 L) resulting in the formation of an additional white
solid material (likely i-Pr2(Et)NH+ ꢀOTf, which might be
removed by filtration but was not in this experiment) and
the mixture was washed with saturated aq NaHCO3
(2 · 0.65 L). The organic phase was separated, dried over
Na2SO4, and then was concentrated in vacuo to furnish
the crude 2-[1-tri-isopropylsilyloxy-vinyl]-pyridine 4b
(131.5 g) as a yellow-orange oil. This crude material was
not further purified, but was immediately carried to the
1
4.2. (S)-2-Chloro-1-(3-pyridyl)-ethanol (S)-1a
chlorination step. H NMR (400 MHz, CDCl3): d = 8.57
(m, 1), 7.71 (m, 2), 7.21 (m, 1), 5.65 (br s, 1), 4.58 (br s,
1), 1.36 (heptet, J = 7.2 Hz, 3), 1.15 (d, J = 7.21 Hz, 18).
To RuCl[(1R,2R)-p-TsNCH(Ph)–CH(Ph)NH2] (g6-p-cym-
ene) (2.5 mg, 0.004 mmol),6 in a 5 mL 1-neck round bot-
tom flask, was added anhydrous DMF (Aldrich Sure
Seal, 2 mL), followed in order by 3-chloroacetylpyridine
3a2d (0.075 g, 0.48 mmol) and HCOOH/Et3N (5:2, Fluka,
0.18 mL). The red-black solution was placed under house
vacuum and the reaction progress was monitored by
reverse phase analytical HPLC. After 45 min of stirring,
the starting material had been consumed (95:5 NaH2PO4/
H3PO4 buffered water/CH3CN to 5:95, 17 min; retention
time of starting chloroketone 3a: 7.39 min, retention time
of halohydrin 2.66 min). The reaction was quenched by
adding MeOH (0.25 mL), stirred for 5 min and then the
DMF, etc. were removed in vacuo (cold finger rotovapor,
vacuum pump) to give a red-black viscous oil. The crude
material was taken up in Et2O/CH2Cl2 (4:1, 25 mL), placed
in a 100 mL separatory funnel, washed with saturated aq
NaHCO3 (25 mL), brine (25 mL), and dried (Na2SO4). Fil-
tration and concentration in vacuo afforded the crude
product as a red-orange oil, which was purified by chroma-
tography (Biotageꢂ 40S, compound applied in CH2CL2/
hexanes 60:40; eluted with hexanes/Et2O 75:25 0.25 L;
65:35 0.25 L; 55:45 0.25 L; 20 mL fractions) using the flash
technique. Fractions 21–22 were combined to afford
(0.049 g, 64%) of the target (S)-3-(1-hydroxy-2-chloro-
ethyl)-pyridine (S)-1a as a pale yellow oil. 1H NMR
(300 MHz, CDCl3) d = 8.53 (m, 2), 7.79 (m, 1), 7.32 (m,
1), 4.97 (m, 1), 3.88 (br s, 1), 3.72 (m, 2); IR (liq.) 3166
(s, b), 2956 (s), 2856 (s, b), 2096 (w), 1940 (b), 1597 (s),
1582 (s), 1481 (s), 1428 (s), 1082 (s), 1045 (s), 1030 (s),
4.4. [[2-Chloro-1-(2-pyridyl)ethenyl]oxy]tri-isopropylsilane
5b
Crude 2-[1-tri-isopropylsilyloxy-vinyl]-pyridine 4b (131.5 g,
assumed 0.413 mmol) was placed in a 2 L, 1 N round bot-
tom flask and dissolved in anhydrous THF (Aldrich Sure
Seal, 0.6 L). The flask was equipped with a reflux con-
denser and the apparatus was placed under nitrogen.
NCS (60.66 g, 0.454 mol, 1.1 equiv) was added and the
mixture was heated to reflux and maintained at reflux for
2 h. The reaction mixture was cooled to room temperature,
poured into a 4 L separatory funnel containing ether
(1.5 L), and was washed with saturated aq NaHCO3
(2 · 0.7 L). The organic phase was separated, dried
(Na2SO4), and concentrated in vacuo to afford the target
2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-pyridine
5b
(117.5 g, 91%) as a yellow-orange oil. The crude material
was not further purified, but was immediately carried into
1
the next step. H NMR (400 MHz, CDCl3): d = 8.53 (d,
J = 4.7 Hz, 1), 7.71 (td, J = 7.7, 1.8 Hz, 1), 7.52 (d,
J = 7.7 Hz, 1), 7.22 (dd, J = 4.7, 1.8 Hz, 1), 6.58 (s, 1),
1.21 (heptet, J = 7.4 Hz, 3), 1.13 (d, J = 7.4 Hz, 18).
4.5. 2-(Chloroacetyl)-pyridine 3b
Crude 2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-pyridine 5b
(117.3 g, 0.376 mol) was placed in a 4 L plastic bottle and
was dissolved in acetonitrile (0.4 L). To the stirring solu-
tion was added 48% aqueous HF (170 mL, 0.45 mL/ mmol)
and the progress of the reaction was monitored by reverse
phase analytical HPLC. After ca. 2 h the reaction was
judged to be complete, and the pH of the solution was care-
fully adjusted to ca. 8 with saturated aq NaHCO3. The
mixture was poured into a separatory funnel containing
CH2Cl2 (1.5 L). The organic phase was removed and the
aq layer was extracted with CH2Cl2 (2 · 1.0 L). The com-
bined organic layers were dried (Na2SO4), and concen-
trated in vacuo to afford crude 2-chloroacetyl pyridine 3b
(49.5 g, 85%) as a tan solid (after cooling). The crude mate-
745 (s), 711 (s), 645 (s) cmꢀ1; % Water (KF titration):
25
0.59; ½aꢁD ¼ þ42 (c 0.81, methanol); Anal. Calcd for
C7H8ClNO: C, 53.35; H, 5.12; N, 8.89. Found: C, 53.19;
H, 5.20; N, 8.65; Chiral HPLC (Chirobiotic T): 2:98; 96%
ee.
4.3. [[1-(2-Pyridyl)ethenyl]oxy]tri-isopropylsilane 4b
2-Acetylpyridine (50 g, 0.413 mol) was placed in a 2 L 1 N
round bottom flask and anhydrous CH2Cl2 (Alrdich Sure
Sealꢂ, 0.65 L) was added, followed by the addition of i-
Pr2NEt (160.27 g, 1.24 mol, 3 equiv, 216 mL). The flask
was equipped with a 125 mL pressure equalized dropping
funnel, and the mixture was placed under nitrogen and
cooled in an ice-water bath. To the chilled ketone/amine
mixture was added TIPSOTf (139.7 g, 0.456 mol, 1.1 equiv,
1
rial was judged to be quite pure by H NMR and HPLC
and was used as is in the Noyori asymmetric reduction.
1H NMR (400 MHz, CDCl3): d = 8.66 (d, J = 4.7 Hz, 1),
8.09 (d, J = 7.9 Hz, 1), 7.88 (td, J = 7.9, 1.6 Hz, 1), 7.54
(m, 1), 5.12 (s, 2).

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2165
4.6. [[1-(2-Furyl)ethenyl]oxy]tri-isopropylsilane 4c
CH2Cl2 (1.5 L). The organic phase was removed and the
aq layer was extracted with CH2Cl2 (2 · 1.0 L). The com-
bined organic layers were dried (Na2SO4), and concen-
trated in vacuo to afford crude 2-chloroacetyl furan
(41.9 g, 67%) 3c as a yellow oil. The crude material was
2-Acetylfuran (50 g, 0.454 mol) was placed in a 2 L 1 N
round bottom flask and anhydrous CH2Cl2 (Alrdich Sure
Seal, 0.70 L) was added, followed by the addition of i-
Pr2NEt (176 g, 1.36 mol, 3 equiv, 237 mL). The flask was
equipped with a 125 mL pressure equalized dropping fun-
nel, and the mixture was placed under nitrogen and cooled
in an ice-water bath. To the chilled ketone/amine mixture
was added TIPSOTf (153.2 g, 0.5 mol, 1.1 equiv,
134.3 mL) over 1.5 h. The mixture was allowed to warm
to room temperature overnight. The reaction mixture was
concentrated in vacuo on a rotary evaporator (T 6 25 ꢁC)
to give a yellow oil and a white solid. The flask contents
were transferred to a 2 L separatory funnel with ether
(1.2 L) resulting in the formation of an additional white
solid material (likely i-Pr2(Et)NH+ ꢀOTf, which might be
removed by filtration but was not in this experiment) and
the mixture was washed with saturated aq NaHCO3
(2 · 0.70 L). The organic phase was separated, dried over
Na2SO4, and then was concentrated in vacuo to furnish
1
judged to be quite pure by H NMR and HPLC and was
1
used as is in the Noyori asymmetric reduction. H NMR
(400 MHz, CDCl3): d = 7.58 (m, 1), 7.33 (d, J = 2.7 Hz,
1), 6.59 (m, 1), 4.57 (s, 2); MS (ES+): 145.4 (M+H+).
4.9. [[1-(2-Thienyl)ethenyl]oxy]tri-isopropylsilane 4d
As described for the preparation of [[1-(2-furyl)eth-
enyl]oxy]tri-isopropylsilane 4c, 2-acetylthiophene (50 g,
0.396 mol) was treated with (i-Pr)3SiOTf (133.6 g,
0.436 mol, 117 mL) and (i-Pr)2NEt (153.6 g, 0.59 mol,
207 mL) in CH2Cl2 (0.7 L) to give 2-[1-tri-isopropylsilyl-
oxy-vinyl]-thiophene 4d (111.9 g, 100%) as a golden yellow
1
liquid. H NMR (300 MHz, CDCl3): d = 7.26 (m, 1), 7.22
(m, 1), 6.99 (m, 1), 4.79 (d, J = 2.0 Hz, 1), 4.33 (d,
J = 2.0 Hz, 1), 1.32 (heptet, J = 7.2 Hz, 3), 1.16 (d,
J = 7.2 Hz 18); MS (ES+): 283.2 (M+H).
the
crude
2-[1-tri-isopropylsilyloxy-vinyl]-furan
4c
(118.3 g, 98%) as a yellow-orange oil. This crude material
was not further purified, but was immediately carried to
the next step. H NMR (400 MHz, CDCl3): d = 7.36 (br
4.10. [[2-Chloro-1-(2-thienyl)ethenyl]oxy]tri-isopropylsilane
5d
1
s, 1), 6.49 (d, J = 3.2 Hz, 1), 6.40 (m, 1), 4.86 (d,
J = 1.7 Hz, 1), 4.37 (d, J = 1.7 Hz, 1), 1.32 (heptet,
J = 7.2 Hz, 3), 1.14 (d, J = 7.2 Hz, 18).
As described for the preparation of [[2-chloro-1-(2-
furyl)ethenyl]oxy]tri-isopropylsilane 5c, 2-[1-tri-isopropyl-
silyloxy-vinyl]-thiophene 3c (111.19 g, 0.396 mol) was trea-
ted with NCS (58.2 g, 0.426 mol) in THF (0.6 L) to afford
4.7. [[2-Chloro-1-(2-furyl)ethenyl]oxy]tri-isopropylsilane 5c
2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-thiophene
5d
1
Crude 2-[1-tri-isopropylsilyloxy-vinyl]-furan 4c (116.3 g,
assumed 0.436 mmol) was placed in a 2 L, 1 N round bot-
tom flask and dissolved in anhydrous THF (Aldrich Sure
Seal, 0.6 L). The flask was placed under nitrogen, cooled
in a ꢀ10 ꢁC bath, then NCS (64.11 g, 0.48 mol, 1.1 equiv)
was added and the mixture was stirred for 1 h, after which
time the reaction was judged to be complete by analytical
reverse phase HPLC. The reaction mixture was warmed
to room temperature, poured into a 4 L separatory funnel
containing ether (1.5 L), and was washed with saturated aq
NaHCO3 (2 · 0.7 L). The organic phase was separated,
dried (Na2SO4), and concentrated in vacuo to afford the
target chloro-enol ether 2-[1-tri-isopropylsilyloxy-2-
chloro-vinyl]-furan 5c (129.9 g, 99%) as a yellow-orange
oil. The crude material was not further purified, but was
immediately carried into the next step. 1H NMR
(400 MHz, CDCl3): d = 7.36 (d, J = 1.8 Hz, 1), 6.43 (m,
1), 6.40 (m, 1), 5.95 (s, 1), 1.30 (heptet, J = 7.2 Hz, 3),
1.11 (d, J = 7.2 Hz, 18).
(140 g, 98%) as a viscous orange oil. H NMR (300 MHz,
CDCl3): d = 7.20 (d, J = 1.9 Hz, 1), 6.33 (m, 1), 6.30 (m,
1), 5.92 (s, 1), 1.32 (heptet, J = 7.2 Hz, 3), 1.14 (d,
J = 7.2 Hz, 18).
4.11. 2-(Chloroacetyl)-thiophene 3d
As described for the preparation of 2-chloroacetyl furan 3c,
[1-tri-isopropylsilyloxy-2-chloro-vinyl]-thiophene 4c (140 g,
0.389 mol), in CH3CN (0.4 L) was treated with 48% aq HF
(58 mL), in acetonitrile, to give 2-chloroacetylthiophene 3d
(48 g, 77%) as a light brown solid. The crude material was
1
judged to be quite pure by H NMR and HPLC and was
1
used as is in the Noyori asymmetric reduction. H NMR
(400 MHz, CDCl3): d = 7.81 (m, 1), 7.76 (m, 1), 7.19 (m,
1), 4.62 (s, 2).
4.12. [[1-(3-Thienyl)ethenyl]oxy]tri-isopropylsilane 4e
As described for the preparation of [[1-(2-furyl)eth-
enyl]oxy]tri-isopropylsilane 4c, 3-acetylthiophene (50 g,
0.396 mol) in anhydrous CH2Cl2 (Alrdich Sure Sealꢂ,
600 mL) was treated with i-Pr2NEt (1.18 mol, 3 equiv,
207 mL), TIPSOTf (0.436 mol, 1.1 equiv, 117.2 mL) to give
the crude enol ether, 3-[1-tri-isopropylsilyloxy-vinyl]-thio-
phene 4e (117 g) as a brown oil. This crude material was
not further purified, but was immediately carried to the
4.8. 2-(Chloroacetyl)-furan 3c
2-[1-Tri-isopropylsilyloxy-2-chloro-vinyl]-furan 5c (129.9 g,
0.431 mol) was placed in a 4 L plastic bottle and was dis-
solved in acetonitrile (0.6 L). To the stirring solution was
added 48% aqueous HF (65 mL, 0.15 mL/ mmol) and the
progress of the reaction was monitored by reverse phase
analytical HPLC. After ca. 2 h, the reaction was judged
to be complete, and the pH of the solution was carefully
adjusted to ca. pH 7 with saturated aq NaHCO3. The mix-
ture was poured into a separatory funnel containing
1
next step. H NMR (300 MHz, CDCl3): d = 7.26 (m, 1),
7.20 (dd, J = 4.8, 1.6 Hz, 1), 6.99 (dd, J = 6.7, 4.9 Hz, 1),
4.79 (d, J = 2.7 Hz, 1), 4.33 (d, J = 2.7 Hz, 1), 1.31 (heptet,
J = 7.6 Hz, 3), 1.20 (d, J = 7.6 Hz, 18).

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S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
1
4.13. [[2-Chloro-1-(3-thienyl)ethenyl]oxy]tri-isopropylsilane
5e
used as is in the Noyori asymmetric reduction. H NMR
(400 MHz, CDCl3): d = 7.76 (d, J = 7.9 Hz, 1), 7.68 (s,
1), 7.61 (d, J = 8.4 Hz, 1), 7.54 (m, 1), 7.37 (m, 1), 4.73
(s, 2); IR (diffuse reflectance) 2479 (w), 2412 (w), 2360
(w), 2338 (w), 2306 (w), 1694 (s), 1550 (s), 1271 (s), 1263
(s), 1255 (s), 1164 (s), 1023 (s), 752 (s), 743 (s), 716 (s)
cmꢀ1; Anal. Calcd for C10H7ClO2: C, 61.72; H, 3.63.
Found: C, 61.92; H, 3.68.
As described for the preparation of [[2-chloro-1-(2-
furyl)ethenyl]oxy]tri-isopropylsilane 5c, 3-[1-tri-isopropyl-
silyloxy-vinyl]-thiophene, 4e (117 g, assumed 0.396 mol)
was treated with NCS (52.87 g, 0.396 mol) to give 138 g
of crude 3-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-thio-
phene 5e. This crude material was not further purified,
1
but was immediately carried to the next step. H NMR
4.18. [[1-(2-Thiazolyl)ethenyl]oxy]tri-isopropylsilane 4g
(400 MHz, CDCl3): d = 7.27 (m, 1), 7.22 (m, 1), 7.01 (m,
1), 5.83–5.92 (1), 1.23–1.35 (m, 3), 1.10–1.22 (m, 18).
As described for the preparation of [[1-(2-furyl)eth-
enyl]oxy]tri-isopropylsilane 4c, 2-acetyl thiazole (25 g,
0.196 mol) was treated with (i-Pr)3SiOTf (66.26 g,
0.216 mol, 58.12 mL) and (i-Pr)2NEt (76.22 g, 0.59 mol,
102.7 mL) in CH2Cl2 (0.35 L) to give 2-[1-tri-isopropylsilyl-
oxy-vinyl]-thiazole 4g (59.45 g) as a golden yellow liquid.
This crude material was not further purified, but was
immediately carried to the next step. 1H NMR
(400 MHz, CDCl3): d = 7.80 (d, J = 3.2 Hz, 1), 7.32
(d, J = 3.2 Hz, 1), 5.50 (d, J = 1.9 Hz, 1), 4.52 (d, J =
1.9 Hz, 1), 1.35 (heptet, J = 7.2 Hz, 3), 1.17 (d, J =
7.2 Hz, 18).
4.14. 3-(Chloroacetyl)-thiophene 3e
As described for the preparation of 2-chloroacetyl furan 3c,
3-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-thiophene 5e (138 g,
assumed 0.396 mol) was treated with 48% aq HF (59 mL)
in acetonitrile (0.5 L) to give 3-chloroacetylthiophene 3e
(54.6 g, 0.34 mol, 85%) as an amorphous pale yellow solid.
The crude material was judged to be quite pure by 1H
NMR and HPLC and was used as is in the Noyori asym-
1
metric reduction. H NMR (400 MHz, CDCl3): d = 8.18
(m, 1), 7.60 (m, 1), 7.40 (m, 1), 4.61 (s, 2).
4.19. [[2-Chloro-1-(2-thiazolyl)ethenyl]oxy]tri-isopropyl-
silane 5g
4.15. [[1-(2-Benzofuranyl)ethenyl]oxy]tri-isopropylsilane 4f
As described for the preparation of [[1-(2-furyl)eth-
enyl]oxy]tri-isopropylsilane 4c, 2-acetyl benzofuran
(32.03 g, 0.200 mol) was treated with (i-Pr)3SiOTf (80 mL,
91.93 g, 0.30 mol) and (i-Pr)2NEt (104 mL, 77.55 g,
0.60 mol) in CH2Cl2 (0.3 L) to give 2-[1-tri-isopropylsilyl-
oxy-vinyl]-benzofuran 4f (72.52 g, 100%) as an orange oil.
This crude material was not further purified, but was
immediately carried to the next step. 1H NMR
(400 MHz, CDCl3): d = 7.58 (d, J = 7.6 Hz, 1), 7.47 (d,
J = 8.1 Hz, 1), 7.30 (m, 1), 7.23 (m, 1), 5.18 (d,
J = 1.7 Hz, 1), 4.58 (d, J = 1.7 Hz, 1), 1.23–1.42 (3), 1.18
(d, J = 7.3 Hz, 18).
As described for the preparation of [[2-chloro-1-(2-
furyl)ethenyl]oxy]tri-isopropylsilane 5c, 2-[1-tri-isopropyl-
silyloxy-vinyl]-thiazole 4g (59.45 g, assumed 0.196 mol)
was treated with NCS (29.37 g, 0.22 mol) in THF
(0.35 L) to give 2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-
thiazole 5g (69.61 g) as a yellow-orange semi-solid. This
crude material was not further purified, but was immedi-
ately carried to the next step. 1H NMR (400 MHz, CDCl3):
d = 7.77 (d, J = 3.2 Hz, 1), 7.32 (d, J = 3.2 Hz, 1), 6.57 (s,
1), 1.37 (m, 3), 1.10–1.22 (18).
4.20. 2-(Chloroacetyl)-thiazole 3g
4.16. [[2-Chloro-1-(2-benzofuranyl)ethenyl]oxy]tri-isoprop-
ylsilane 5f
As described for the preparation of 2-chloroacetyl furan 3c,
2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-thiazole
5g
(69.61 g, assumed 0.196 mol) was treated with 48% aq
HF (29 mL) in CH3CN (0.3 L) to give 2-chloroacetylthi-
azole 3g (32.95 g, 100%) as a light brown liquid, which
As described for the preparation of [[2-chloro-1-(2-
furyl)ethenyl]oxy]tri-isopropylsilane 5c, 2-[1-tri-isopropyl-
silyloxy-vinyl]-benzofuran 4f (79.52 g, 0.2 mol) was treated
with NCS (29.4 g, 0.22 mol) in THF (0.4 L) to afford 2-[1-
tri-isopropylsilyloxy-2-chloro-vinyl]-benzofuran 5f (79.52 g,
100%) as a viscous yellow oil. This crude material was
not further purified, but was immediately carried to the
next step. H NMR (400 MHz, CDCl3): d = 7.62 (m, 1),
7.52 (m, 1), 7.28 (m, 1), 7.27 (m, 1), 5.99 (s, 1), 1.20–1.36
(m, 3), 1.10–1.22 (18).
solidified to
a
tan solid upon cooling. 1H NMR
(400 MHz, CDCl3): d = 8.06 (d, J = 3.0 Hz, 1), 7.79 (d,
J = 3.0 Hz, 1), 5.00 (s, 2); IR (diffuse reflectance) 2476
(w), 2453 (w), 2430 (w), 2391 (w), 2371 (w), 1372, 1225,
957, 897, 793, 773, 710 (s), 704 (s), 655 (s), 630 (s) cmꢀ1
;
MS (EI) m/z (rel. intensity) 161 (M+, 33), 133 (15), 112
(base), 99 (15), 86 (61), 84 (86), 58 (33), 57 (34), 51 (37);
HRMS (ESI) calcd for C5H4ClNOS+H 161.9780, found
161.9779; Anal. Calcd for C5H4ClNOS: C, 37.16; H,
2.49; N, 8.67. Found: C, 37.17; H, 2.51; N, 8.62.
1
4.17. 2-(Chloroacetyl)-benzofuran 3f
As described for the preparation of 2-chloroacetyl furan 3c,
4.21. [[1-(2-Pyrazinyl)ethenyl]oxy]tri-isopropylsilane 4h
2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-benzofuran
5f
(79.52 g, 0.20 mol) was treated with 48% aq HF (40 mL)
in CH3CN to give 2-chloroacetylbenzofuran 3f (23.32 g,
60%) as a powdery, tan solid. The crude material was
As described for the preparation of [[1-(2-furyl)-
ethenyl]oxy]tri-isopropylsilane 4c, 2-acetylpyrazine (53.9 g,
0.441 mol) in CH2Cl2 (700 mL) was treated with i-Pr2NEt
(171.0 g, 1.32 mol, 3 equiv, 231 mL), and TIPSOTf
1
judged to be quite pure by H NMR and HPLC and was

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2167
(148.6 g, 0.4851 mol, 1.1 equiv, 130.4 mL) to give the crude
4.25. (R)-2-(1-Hydroxy-2-chloroethyl)-pyridine (R)-1b
enol ether, 2-[1-tri-isopropylsilyloxy-vinyl]-pyrazine, 4h
(132.9 g) as a brown oil. This crude material was not fur-
ther purified, but was immediately carried to the next step.
1H NMR (300 MHz, CDCl3) d = 8.97 (s, 1H), 8.49 (s, 2),
5.66 (s, 1), 4.65 (s, 1), 1.36 (heptet, J = 7.0 Hz, 3), 1.14
(d, J = 7.0 Hz, 18); 13C NMR (100 MHz, CDCl3)
d = 153.0, 150.0, 143.8, 143.5, 141.1, 94.1, 18.1, 12.7; IR
(liq.) 2945, 2892, 2867, 1619, 1471, 1329, 1151, 1019,
1006, 883, 847, 812, 742, 689, 682 cmꢀ1; MS (EI) m/z
(rel. intensity) 278 (M+, 8), 237 (13), 236 (43), 235 (base),
207 (12), 165 (9), 149 (42), 105 (21), 84 (10), 75 (8); HRMS
(FAB) calcd for C15H26N2OSi+H1 279.1892, found
279.1891.
To the catalyst prepared as described in the representative
in situ catalyst preparation of [S,S]-ligand using [RuCl2(g6-
p-cymene)]2 (0.84 g, 1.37 mmol) and (1S,2S)-N-p-toluene-
sulfonyl-1,2-diphenylethylenediamine (1.0 g, 2.72 mmol,
1.78 mol % based upon ketone), isopropanol (25 mL),
and Et3N (0.67 g, 6.66 mmol, 0.93 mL), was added anhy-
drous DMF (225 mL), followed in order by 2-chloroacetyl-
pyridine 3b (23.88 g, 0.153 mol) and HCOOH/Et3N (5:2,
55 mL). After ca. 2–3 min of stirring (room temperature)
bubbles were apparent, emanating from the stirring vortex
of the red-black solution. Reaction progress was monitored
by reverse phase analytical HPLC, and after 75 min of stir-
ring, the starting material had been consumed (95:5 NaH2-
PO4/H3PO4 buffered water/CH3CN to 5:95, 17 min;
retention time of starting chloroketone: 7.39 min, retention
time of halohydrin 2.66 min). The reaction was quenched
by adding MeOH (25 mL) and stirred for 5 min. The sol-
vents were removed in vacuo (cold finger rotovapor, vac-
uum pump) to give a red-black viscous oil. The crude
material was taken up in Et2O/CH2Cl2 (4:1, 1.25 L), placed
in a 3 L separatory funnel, washed with saturated aq NaH-
CO3 (1.0 L), brine (1.0 L), and dried (Na2SO4). Filtration
and concentration in vacuo afforded the crude product as
a red-orange oil, which was purified by chromatography
on a column of silica gel (70 mm OD, 250 g 230–400 mesh,
packed hexanes; compound applied in CH2Cl2/hexanes
60:40; eluted with hexanes/Et2O 75:25 2 L; 65:35 2 L;
55:45 2 L; 350 mL fractions) using the flash technique.
Fractions 9–16 were combined to afford 14.72 g (61%) of
the halohydrin (R)-2-(1-hydroxy-2-chloroethyl)-pyridine
(R)-1b as a pale yellow solid. Mp: 47–48 ꢁC; 1H NMR
(400 MHz, CDCl3): d = 8.60 (d, J = 4.6 Hz, 1), 7.77 (dt,
J = 7.6, 1.6 Hz, 1), 7.58 (d, J = 7.6 Hz, 1), 7.30 (m, 1),
5.00 (t, J = 5.4 Hz, 1), 4.20 (br s, 1), 3.85 (m, 2); IR (neat):
3138, 3074, 3029, 3014, 2974, 2964, 2955, 2895, 2862, 2848,
2472, 2350, 2328, 2305, 2261 (w) cmꢀ1; EI-MS (70 eV): 160
(M+, 35), 158 (M+, 90), 122 (90), 106 (base); Anal. Calcd
4.22. [[2-Chloro-1-(2-pyrazinyl)ethenyl]oxy]tri-isopropyl-
silane 5h
As described for the preparation of [[2-chloro-1-(2-
furyl)ethenyl]oxy]tri-isopropylsilane 5c, 2-[1-tri-isopropyl-
silyloxy-vinyl]-pyrazine 4h (132.9 g, assumed 0.441 mmol)
in anhydrous THF (640 mL) was chlorinated with NCS
(64.78 g, 0.485 mol, 1.1 equiv) to give the target chloro-
enol ether, 2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-pyra-
zine, 5h (169.45 g) as a brown oil. The crude material was
not further purified, but was immediately carried into the
1
next step. H NMR (400 MHz, CDCl3) d = 8.82 (br s, 1),
8.51 (br s, 1), 8.49 (s, 1), 6.62 (s, 1), 1.33 (heptet,
J = 7.0 Hz, 3), 1.13 (d, J = 7.0 Hz, 18); MS (CI) m/z (rel.
intensity) 315 (22), 314 (15), 313 (MH+, 74), 279 (53),
277 (23), 96 (13), 75 (9), 58 (14), 53 (10), 52 (base); HRMS
(FAB) calcd for C15H25ClN2OSi+H1 313.1503, found
313.1511.
4.23. 2-(Chloroacetyl)-pyrazine 3h
As described for the preparation of 2-chloroacetyl furan
3c, 2-[1-tri-isopropylsilyloxy-2-chloro-vinyl]-pyrazine 5h
(169.45 g, assume 0.441 mol) was dissolved in acetonitrile
(470 mL) and treated with 48% aqueous HF (73.54 mL,
4 equiv) to give 2-chloroacetylpyrazine 3h (60.1 g,
0.384 mol, 87%) as a very light yellow solid. Mp: 82.6–
83.8 ꢁC (dec); 1H NMR (300 MHz, CDCl3) d = 9.23 (s,
1), 8.80 (d, J = 1.0 Hz, 1), 8.64 (d, J = 1.0 Hz, 1), 5.01 (s,
2); 13C NMR (75 MHz, CDCl3) d = 191.4, 148.4, 145.6,
143.5, 143.3, 46.4; IR (diffuse reflectance) 2944, 1716,
1400, 1390, 1318, 1226, 1170, 1163, 1053, 1019, 1000,
851, 807, 790, 685 cmꢀ1; MS (EI) m/z (rel. intensity) 156
(M+, base), 128 (4), 122 (4), 108 (4), 107 (47), 88 (4), 87
(5), 86 (12).
for C7H8ClNO: C, 53.35; H, 5.12; N, 8.89. Found: C,
25
53.23; H, 5.12; N, 8.82; ½aꢁD ¼ ꢀ39 (c 0.94, CH2Cl2). Chiral
HPLC Analysis (Chiracel OJ): 98:2; 96% ee.
4.26. (S)-2-(1-Hydroxy-2-chloroethyl)-pyridine (S)-1b
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-pyridine (R)-1b, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.84 g, 1.37 mmol), Et3N (0.67 g,
6.66 mmol, 0.93 mL), and (1R,2R)-N-p-toluenesulfonyl-
1,2-diphenylethylenediamine (1.0 g, 2.72 mmol, 1.78 mol %
based upon ketone) and 2-chloroacetylpyridine 3b (23.88 g,
0.153 mol), HCOOH/Et3N (5:2, Fluka, 55 mL) in DMF
(225 mL) gave a red-black viscous oil. The crude material
was taken up in Et2O/CH2Cl2 (4:1, 1.25 L), washed with sat-
urated aq NaHCO3 (1.0 L), brine (1.0 L), and dried over
Na2SO4. Filtration and concentration in vacuo afforded
the crude product as a red-orange oil, which was purified
by chromatography on a column of silica gel (70 mm OD,
250 g 230–400 mesh, packed hexanes; compound applied
in CH2Cl2/hexanes 60:40; eluted with hexanes/Et2O 75:25
2 L; 65:35 2 L; 55:45 2 L; 350 mL fractions) using the flash
technique. Fractions 11–17 were combined to afford
4.24. Representative in situ catalyst preparation of [S,S]-
ligand
[RuCl2(g6-p-cymene)]2 (0.84 g, 1.37 mmol) and (1S,2S)-N-
p-toluenesulfonyl-1,2-diphenylethylenediamine
(1.0 g,
2.72 mmol) are combined in a 500 mL 1 N round bottom
flask. Isopropanol (25 mL) and Et3N (0.67 g, 6.66 mmol,
0.93 mL) are added, a reflux condenser is attached and
the mixture is warmed under reflux for 1 h. The mixture
is cooled to room temperature and concentrated in vacuo
to furnish the catalyst as a brown powdery solid.

2168
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
16.41 g (68%) of the target (S)-2-(1-hydroxy-2-chloroethyl)-
pyridine (S)-1b as a pale yellow solid. Mp: 49–50 ꢁC; H
NMR. 1H NMR (400 MHz, CDCl3): d = 7.41 (m, 1),
6.37 (m, 2), 4.95 (br dd, J = 11.8, 5.4 Hz, 1), 3.85 (m, 2),
2.58 (d, J = 5.4 Hz, 1); IR (diffuse reflectance) 1428 (b),
1422 (b), 1221 (b), 1205 (b), 1198 (b), 1166, 1096, 1021
(s), 953, 924, 883, 789 (s), 738, 714, 666 cmꢀ1; MS (EI)
m/z (rel. intensity) 146 (M+, 17), 129 (2), 98 (6), 97 (base),
1
NMR (400 MHz, CDCl3): d = 8.60 (d, J = 4.6 Hz, 1), 7.77
(dt, J = 7.6, 1.58 Hz, 1), 7.58 (d, J = 7.6 Hz, 1), 7.30 (m, 1),
5.00 (t, J = 5.4 Hz, 1), 4.20 (br s, 1), 3.85 (m, 2); EI-MS
(70 eV): 160 (M+, 35), 158 (M+, 90), 122 (90), 106 (base);
IR (neat): 3085, 3075 (b), 2470 (w), 2350 (w), 2328 (w),
2305 (w), 2260 (w), 1109, 1077, 1006 (s), 783 (s), 762 (s),
720 (s), 640, 624 (s) cmꢀ1; Anal. Calcd for C7H8ClNO: C,
95 (3), 94 (1), 69 (3), 41 (2); HRMS (EI) calcd for
25
C6H7ClO2 146.0135, found 146.0136; ½aꢁD ¼ þ17 (c 0.97,
methanol); Chiral HPLC Analysis (Chiracel OJ): 1:99;
98% ee.
53.35; H, 5.12; N, 8.89; Cl, 22.50. Found: C, 53.27; H,
25
5.19; N, 8.81, Cl, 22.29; ½aꢁD ¼ þ62 (c 0.94, methanol);
Chiral HPLC Analysis (Chiracel OJ): 100:0; >99% ee.
4.29. (R)-2-(1-Hydroxy-2-chloroethyl)-thiophene (R)-1d
4.27. (R)-2-(1-Hydroxy-2-chloroethyl)-furan (R)-1c
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-furan (R)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.61 mmol), (1S,2S)-N-p-
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-pyridine (R)-1b, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.61 mmol), (1S,2S)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine
(1.18 g,
3.22 mmol, 2.10 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.67 g, 6.66 mmol, 0.93 mL) was com-
bined with 2-chloroacetylthiophene 3d (26 g, 0.16 mol) and
HCOOH/Et3N (5:2, 58 mL) in DMF (250 mL). After
75 min, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min and then the solvents were re-
moved in vacuo (cold finger rotovapor, vacuum pump) to
give a red-black viscous oil. The crude material was taken
up in Et2O (1.25 L), washed with saturated aq NaHCO3
(1.0 L), brine (1.0 L), and dried (Na2SO4). Filtration and
concentration in vacuo afforded the crude product as a
red-orange oil that was triturated with ether/pentane
(10:90, 4 · 100 mL). The combined triturates were concen-
trated in vacuo to give a light brown oil (26 g), which was
purified by chromatography on a 40 L Biotageꢂ column
(gradient from pentane to 5% ether/pentane, 50 mL frac-
tions) to give 19.53 g (74%) of (R)-1d as a colorless, viscous
toluenesulfonyl-1,2-diphenylethylenediamine
(1.18 g,
3.22 mmol, 2.10 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.67 g, 6.66 mmol, 0.93 mL) was com-
bined with 2-chloroacetylfuran 3c (22.3 g, 0.154 mol) and
HCOOH/Et3N (5:2, 55 mL) in DMF (250 mL) to give
the crude product as a red-orange oil (22.7 g) that was tri-
turated with ether/pentane (10:90, 4 · 100 mL). The com-
bined triturates were concentrated in vacuo (warning: the
halohydrin is volatile) to furnish the desired halohydrin
(R)-1-(2-furyl)-2-chloroethanol (R)-1c (16.03 g, 71%) as a
pale yellow oil, in good purity as determined by HPLC
and 1H NMR. 1H NMR (400 MHz, CDCl3): d = 7.41
(m, 1), 6.37 (m, 2), 4.95 (br dd, J = 11.8, 5.4 Hz, 1), 3.85
(m, 2), 2.58 (d, J = 5.0 Hz, 1); IR (liq.) 3373, 2475, 2084,
2023, 1940, 1505, 1226, 1151, 1142, 1089, 1068, 1012,
884, 818, 742 cmꢀ1; MS (EI) m/z (rel. intensity) 146 (13),
148 (4), 146 (13), 98 (4), 97 (base), 95 (4), 94 (2), 69 (6),
1
liquid. H NMR (400 MHz, CDCl3) d = 7.30 (dd, J = 5.0,
65 (2), 41 (7), 39 (3); HRMS (EI) calcd for C6H7ClO2
1.0 Hz, 1), 7.05 (m, 1), 7.01 (dd, J = 5.0, 1.0 Hz, 1), 5.17
(m, 1), 3.77 (m, 2), 2.79 (d, J = 4.0 Hz, 1); IR (liq.) 3384
(s, b), 2290 (w), 2161 (w), 2068 (w), 1996 (w), 1929 (w),
1426, 1257, 1069 (s), 1042, 852, 771, 706 (s), 677,
635 cmꢀ1; MS (EI) m/z (rel. intensity) 162 (M+, 12), 113
(base), 110 (12), 109 (12), 97 (11), 88 (12), 86 (66), 85
(62), 84 (87), 51 (49); HRMS (EI) calcd for C6H7ClOS
161.9906, found 161.9904; % Water (KF): 0.60; Anal.
Calcd for C6H7ClOS: C, 44.31; H, 4.34; Cl, 21.80; S,
25
146.0135, found 146.0133; ½aꢁD ¼ ꢀ18 (c 0.97, methanol);
Chiral HPLC Analysis (Chiracel OJ): 99:1; 98% ee.
4.28. (S)-2-(1-Hydroxy-2-chloroethyl)-furan (S)-1c
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.61 mmol), (1R,2R)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine
(1.18 g,
19.71. Found: C, 43.94; H, 4.39; N, 0.20; Cl, 21.78; S,
25
3.22 mmol, 2.25 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.67 g, 6.66 mmol, 0.93 mL) was com-
bined with 2-chloroacetylfuran 3c (20.6 g, 0.143 mol) and
HCOOH/Et3N (5:2, 51 mL) in DMF (250 mL). After
75 min, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min, then the reaction mixture was
poured into ice-water (1 L) and the aqueous phase was sat-
urated with salt. The mixture was extracted with ether
(3 · 500 mL), and the combined organic layers were
washed with saturated aq NaHCO3 (0.5 L), brine
(4 · 250 mL), and dried (Na2SO4). Filtration and concen-
tration in vacuo afforded the crude product as a red-orange
oil (20.5 g) that was triturated with ether/pentane (10:90,
4 · 100 mL). The combined triturates were concentrated
in vacuo (the halohydrin is volatile) to furnish the desired
halohydrin (S)-1-(2-furyl)-2-chloroethanol (S)-1c (15.97 g,
76%) in good purity as determined by HPLC and 1H
19.42; Specific rotation ½aꢁD ¼ ꢀ31 (c 0.91, methylene chlo-
ride); Chiral HPLC (Chiracel OJ): 99:1; 98% ee.
4.30. (S)-2-(1-Hydroxy-2-chloroethyl)-thiophene (S)-1d
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.61 mmol), (1R,2R)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine
(1.18 g,
3.22 mmol, 2.10 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.67 g, 6.66 mmol, 0.93 mL) was com-
bined with 2-chloroacetylthiophene 3d (26 g, 0.16 mol) and
HCOOH/Et3N (5:2, 58 mL) in DMF (250 mL). After
75 min, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min, then the reaction mixture was
poured into ice-water (1 L) and the aqueous phase was sat-
urated with salt. The mixture was extracted with ether

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2169
(3 · 500 mL), and the combined organic layers were
washed with saturated aq NaHCO3 (0.5 L), brine
(4 · 250 mL), and dried (Na2SO4). Filtration and concen-
tration in vacuo afforded the crude product as a red-orange
oil that was triturated with ether/pentane (10:90,
4 · 100 mL). The combined triturates were concentrated
in vacuo to give a light brown oil (23 g), which was purified
by chromatography on a 40 L Biotageꢂ column (gradient
from pentane to 5% ether/pentane, 50 mL fractions) to give
17.8 (68%) of (S)-1d as a colorless, viscous liquid. 1H NMR
(400 MHz, CDCl3) d = 7.30 (dd, J = 5.0, 1.0 Hz, 1), 7.05
(m, 1), 7.01 (dd, J = 5.0, 1.0 Hz, 1), 5.17 (m, 1), 3.76 (m,
2), 2.81 (d, J = 4.0 Hz, 1); IR (liq.) 3393 (s, b), 2290 (w),
2160 (w), 2080 (w), 1996 (w), 1426, 1257, 1069 (s), 1043,
852, 771, 738, 706 (s), 677, 635 cmꢀ1; MS (EI) m/z (rel.
intensity) 162 (M+, 10), 113 (94), 111 (10), 97 (12), 88
(23), 86 (87), 85 (76), 84 (base), 83 (14), 51 (65), 50 (21);
HRMS (EI) calcd for C6H7ClOS 161.9906, found
based upon ketone), and i-PrOH (25 mL) was combined
with 3-chloroacetylthiophene 3e (30 g, 0.187 mol) and
HCOOH/Et3N (5:2, 68 mL) in DMF (250 mL). After
2.5 h, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min and the solvents were removed
in vacuo (cold finger rotovapor, vacuum pump) to give a
red-black viscous oil. The crude material was taken up in
Et2O/CH2Cl2 (4:1, 1.25 L), placed in a 3 L separatory fun-
nel, washed with saturated aq NaHCO3 (1.0 L), brine
(1.0 L), and dried (Na2SO4). Filtration and concentration
in vacuo afforded the crude product as a red-orange oil that
was triturated with ether/pentane (10:90, 4 · 100 mL). The
combined triturates were concentrated in vacuo to give (S)-
1-(3-thienyl)-2-chloroethanol (S)-1e (27.4 g, 63%) as a pale
1
yellow oil. H NMR (400 MHz, CDCl3) d = 7.26 (m, 1),
7.22 (m, 1), 7.13 (m, 1), 5.01 (dd, J = 8.2, 3.5 Hz, 1), 3.80
(dd, J = 13.2, 3.5 Hz, 1), 3.71 (dd, J = 13.2, 8.2 Hz, 1);
IR (liq.) 3393 (s, b), 2289 (w), 2163 (w), 2084 (w), 1933
(w), 1425, 1256, 1072 (s), 1017, 853 (s), 794 (s), 757 (s),
689 (s), 656, 646 cmꢀ1; MS (EI) m/z (rel. intensity) 164
(4), 162 (M+, 10), 115 (4), 114 (6), 113 (base), 111 (3),
161.9908;
%
Water (KF): 0.44; Specific rotation
25
½aꢁD ¼ þ30 (c 0.90, methylene chloride); Chiral HPLC
(Chiracel OJ): 1:99; 98% ee.
109 (2), 85 (57), 45 (16), 39 (5); HRMS (EI) calcd for
25
4.31. (R)-3-(1-Hydroxy-2-chloroethyl)-thiophene (R)-1e
C6H7ClOS 161.9906, found 161.9905; ½aꢁD ¼ þ40 (c 1.01,
methylene chloride); Chiral HPLC Analysis (Chiracel
OJ): 1:99, 98% ee.
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-furan (R)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (1.15 g, 1.87 mmol), (1S,2S)-N-p-
4.33. (R)-2-(1-Hydroxy-2-chloroethyl)-benzofuran (R)-1f
toluenesulfonyl-1,2-diphenylethylenediamine
(1.37 g,
3.74 mmol, 2.0 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.67 g, 6.66 mmol, 0.93 mL) was com-
bined with 3-chloroacetylthiophene 3e (30 g, 0.187 mol)
and HCOOH/Et3N (5:2, 68 mL) in DMF (250 mL). After
2.5 h, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min, and the solvents were removed
in vacuo (cold finger rotovapor, vacuum pump) to give a
red-black viscous oil. The crude material was taken up in
Et2O/CH2Cl2 (4:1, 1.25 L), placed in a 3 L separatory fun-
nel, washed with saturated aq NaHCO3 (1.0 L), brine
(1.0 L), and dried (Na2SO4). Filtration and concentration
in vacuo afforded the crude product as a red-orange oil that
was triturated with ether/pentane (10:90, 4 · 100 mL). The
combined triturates were concentrated in vacuo to give
20 g (66%) of (R)-3-(1-hydroxy-2-chloroethyl)-thiophene
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-furan (R)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.57 g, 0.925 mmol), (1S,2S)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine (0.56 g, 1.54
mmol, 3.0 mol % based upon ketone), i-PrOH (20 mL),
and Et3N (0.34 g, 3.33 mmol, 0.47 mL) was combined with
2-chloroacetylbenzofuran 3f (10.0 g, 51.4 mmol) and
HCOOH/Et3N (5:2, 16 mL) in DMF (250 mL). After
2.5 h, the reaction was quenched by adding MeOH
(15 mL), stirred for 5 min, then cast into water/ice
(0.5 L), saturated with salt, and extracted with Et2O
(3 · 0.375 L). The combined organic phases were washed
with saturated aq NaHCO3 (0.75 L), dried (Na2SO4), and
concentrated in vacuo to give the crude product as a brown
oil that was triturated with ether/pentane (10:90,
4 · 100 mL). The combined triturates were concentrated
in vacuo to give (R)-2-(1-hydroxy-2-chloroethyl)-benzo-
furan (R)-1f (9.42 g, 93%) as a light tan oil. 1H NMR
(400 MHz, CDCl3) d = 7.58 (d, J = 8.2 Hz, 1), 7.48 (d,
J = 8.2 Hz, 1), 7.22–7.34 (2), 6.79 (s, 1), 5.11 (m, 1), 3.98
(m, 2); IR (liq.) 3371 (s, b), 2496, 2357 (w), 2336 (w),
2259 (w), 2135 (w), 1660 (s), 1453 (s), 1253 (s), 1172 (s),
1106 (s), 1092 (s), 1011 (s), 752 (s), 744 (s) cmꢀ1; HRMS
1
(R)-1e as a pale yellow, waxy solid. H NMR (400 MHz,
CDCl3) d = 7.26 (m, 1), 7.22 (m, 1), 7.13 (m, 1), 5.01 (dd,
J = 8.2, 3.5 Hz, 1), 3.80 (dd, J = 13.2, 3.5 Hz, 1), 3.71
(dd, J = 13.2, 8.2 Hz, 1); IR (diffuse reflectance) 2431 (w),
2394 (w), 2376 (w), 2354 (w), 2326 (w), 1420 (s), 1335 (s),
1251 (s), 1073 (s), 835 (s), 802 (s), 758 (s), 704 (s), 682 (s),
624 (s) cmꢀ1; MS (EI) m/z (rel. intensity) 164 (3), 162
(M+, 10), 115 (4), 114 (5), 113 (base), 111 (5), 109 (1), 86
(2), 85 (45), 45 (6); HRMS (EI) C6H7ClOS 161.9906, found
(EI) calcd for C10H9ClO2 196.0291, found 196.0291;
25
25
161.9901; ½aꢁD ¼ ꢀ40 (c 0.85, methylene chloride); Chiral
½aꢁD ¼ ꢀ31 (c 1.03, chloroform); Anal. Calcd for
HPLC (Chiracel OJ): 98:2, 96% ee.
C10H9ClO2: C, 61.08; H, 4.61. Found: C, 60.83; H, 5.19;
Chiral HPLC Analysis (Chiracel OJ): 99:1, 98% ee.
4.32. (S)-3-(1-Hydroxy-2-chloroethyl)-thiophene (S)-1e
4.34. (S)-2-(1-Hydroxy-2-chloroethyl)-benzofuran (S)-1f
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (1.15 g, 1.87 mmol), Et3N (0.72 g,
7.16 mmol, 1.0 mL), (1R,2R)-N-p-toluenesulfonyl-1,2-
diphenylethylenediamine (1.37 g, 3.74 mmol, 2.0 mol %
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.57 g, 0.925 mmol), (1R,2R)-
N-p-toluenesulfonyl-1,2-diphenylethylenediamine (0.56 g,

2170
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
1.54 mmol, 3.0 mol % based upon ketone), i-PrOH
(20 mL), and Et3N (0.34 g, 3.33 mmol, 0.47 mL) was com-
bined with 2-chloroacetylbenzofuran 3f (10.0 g, 51.4 mmol)
and HCOOH/Et3N (5:2, 16 mL) in DMF (250 mL). After
2.5 h, the reaction was quenched by adding MeOH
(15 mL), stirred for 5 min then cast into water/ice (0.5 L),
saturated with salt, and extracted with Et2O
(3 · 0.375 L). The combined organic phases were washed
with saturated aq NaHCO3 (0.75 L), dried (Na2SO4), and
concentrated in vacuo to give the crude product as a brown
oil that was triturated with ether/pentane (10:90,
4 · 100 mL). The combined triturates were concentrated
in vacuo to give (S)-2-(1-hydroxy-2-chloroethyl)-benzo-
furan (S)-1f (9.26 g, 92%) as a light tan oil. 1H NMR
(400 MHz, CDCl3) d = 7.58 (d, J = 8.2 Hz, 1), 7.48 (d,
J = 8.2 Hz, 1), 7.22–7.34 (2), 6.79 (s, 1), 5.10 (m, 1), 3.98
(m, 2); IR (liq.) 3367 (b), 1663 (s), 1454 (s), 1437, 1414,
1388, 1254 (s), 1171, 1095, 1011, 881, 808, 775, 753 (s),
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.50 mmol), (1R,2R)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine (1.18 g, 3.00
mmol, 1.875 mol % based upon ketone), i-PrOH (25 mL),
and Et3N (0.66 g, 6.66 mmol, 0.93 mL) was combined with
2-chloroacetylthiazole 3g (26.0 g, 0.16 mol) and HCOOH/
Et3N (5:2, 58 mL) in DMF (250 mL). After 2.5 h, the reac-
tion was quenched by adding MeOH (25 mL), stirred for
5 min, and the solvents were removed in vacuo (cold finger
rotovapor, vacuum pump) to give a red-black viscous oil.
The crude material was taken up in Et2O/CH2Cl2 (4:1,
1.25 L), washed with saturated aq NaHCO3 (1.0 L), brine
(1.0 L), and dried (Na2SO4). Filtration and concentration
in vacuo afforded the crude product as a cream colored
semi-solid. Trituration with ether/pentane (10:90,
4 · 100 mL) gave (S)-2-(1-hydroxy-2-chloroethyl)-thiazole
(S)-1g (17.8 g, 68%) as a clear, colorless oil. 1H NMR
(400 MHz, CDCl3) d = 7.30 (dd, J = 5.0, 1.0, Hz, 1), 7.05
(m, 1), 7.01 (dd, J = 5.0, 4.0 Hz, 1), 5.17 (m, 1), 3.76 (m,
2), 2.81 (d, J = 4.0 Hz, 1); IR (liq.) 3393 (s, b), 2290 (w),
2160 (w), 2080 (w), 1996 (w), 1426, 1257, 1069 (s), 1043,
852, 771, 738, 706 (s), 677, 635 cmꢀ1; MS (EI) m/z (rel.
intensity) 162 (M+, 10), 113 (94), 111 (10), 97 (12), 88
(23), 86 (87), 85 (76), 84 (base), 83 (14), 51 (65), 50 (21);
664 cmꢀ1; HRMS (EI) calcd for C10H9ClO2 196.0291,
25
found 196.0295; ½aꢁD ¼ þ31 (c 1.05, chloroform); Anal.
Calcd for C10H9ClO2: C, 61.08; H, 4.61. Found: C,
60.83; H, 5.19; Chiral HPLC Analysis (Chiracel OJ):
1:99, 98% ee.
HRMS (EI) calcd for C6H7ClOS 161.9906, found
25
4.35. (R)-2-(1-Hydroxy-2-chloroethyl)-thiazole (R)-1g
161.9908; % Water (KF): 0.44; ½aꢁD ¼ þ30 (c 0.90, methyl-
ene chloride); Chiral HPLC Analysis (Chiracel OJ):
1.5:98.5, 97% ee.
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-furan (R)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (1.15 g, 1.87 mmol), (1S,2S)-N-p-
4.37. (R)-2-(1-Hydroxy-2-chloroethyl)-pyrazine (R)-1h
toluenesulfonyl-1,2-diphenylethylenediamine
(1.38 g,
3.76 mmol, 2.0 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.77 g, 7.72 mmol, 1.08 mL) was com-
bined with 2-chloroacetylthiazole 3g (30.42 g, 0.188 mol)
and HCOOH/Et3N (5:2, 68 mL) in DMF (250 mL). After
2.5 h, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min, and the solvents were removed
in vacuo (cold finger rotovapor, vacuum pump) to give a
red-black viscous oil. The crude material was taken up in
Et2O/CH2Cl2 (4:1, 1.25 L), washed with saturated aq NaH-
CO3 (1.0 L), brine (1.0 L), and dried (Na2SO4). Filtration
and concentration in vacuo afforded the crude product
(23.87 g) as a cream colored solid. Recrystallization from
Et2O gave 24.7 g (81%) (R)-2-(1-hydroxy-2-chloroethyl)-
thiazole (R)-1g as white needles. Mp: 118–120 ꢁC; 1H
NMR (300 MHz, CDCl3) d = 7.8 (d, J = 3.0 Hz, 1), 7.38
(d, J = 3.0 Hz, 1), 5.26 (m, 1), 4.08 (dd, J = 11.0, 4.0 Hz,
1), 3.90 (dd, J = 11.0, 4.0 Hz, 1), 3.63 (m, 1H); IR (diffuse
reflectance) 3122 (s), 3103 (s), 2460 (w), 2387 (w), 2350 (w),
2306 (w), 2270 (w), 1507, 1195, 1151, 1088, 776 (s), 739 (s),
733 (s), 690 (s) cmꢀ1; MS (EI) m/z (rel. intensity) 163 (M+,
7), 163 (7), 115 (6), 114 (base), 86 (49), 85 (5), 84 (33), 59
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-furan (R)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.245 g, 0.398 mmol), (1S,2S)-N-
p-toluenesulfonyl-1,2-diphenylethylenediamine
(0.292 g,
0.796 mmol, 2.5 mol % based upon ketone), i-PrOH
(10 mL), and Et3N (0.166 g, 1.64 mmol, 0.23 mL) was com-
bined with 2-chloroacetylpyrazine 3h (5.0 g, 31.9 mmol)
and HCOOH/Et3N (5:2, 13.75 mL) in DMF (55 mL).
After 1 h, the reaction was quenched by adding MeOH
(5 mL), stirred for 5 min, and the solvents were removed
in vacuo (cold finger rotovapor, vacuum pump) to give a
red-black viscous oil. The crude material was taken up in
Et2O/CH2Cl2 (4:1, 0.5 L), washed with saturated aq NaH-
CO3 (0.5 L), brine (1.0 L), and dried (Na2SO4). Filtration
and concentration in vacuo afforded the crude product as
a brown oil. The crude product was purified by chromato-
graphy on a Biotageꢂ 40M column (ether/hexanes 3:1, 1 L;
ether 1 L, 50 mL fractions). Fractions 9–23 were combined
to afford (R)-2-(1-hydroxy-2-chloroethyl)-pyrazine (R)-1h
(3.55 g, 70%) as a pale yellow, viscous oil. 1H NMR
(400 MHz, CDCl3) d = 8.80 (s, 1), 8.56 (s, 2), 5.07 (t,
J = 5.0 Hz, 1), 3.93 (dd, J = 10.9, 5.0 Hz, 1), 3.88 (dd,
J = 10.9, 5.0 Hz, 1); IR (liq.) 3280 (s, b), 3064 (b), 2183
(w), 1996 (w), 1949 (w), 1405 (s), 1308, 1154 (s), 1092 (s),
1059 (s), 1019 (s), 856, 775, 663 (s), 649 cmꢀ1; MS (CI)
m/z (rel. intensity) 161 (7), 159 (MH+, 23), 124 (13), 123
(41), 58 (40), 57 (11), 51 (16); % Water (KF): 0.08;
25
½aꢁD ¼ ꢀ33 (c 0.92, methylene chloride); Anal. Calcd for
C5H6ClNOS: C, 36.70; H, 3.70; N, 8.56; Cl, 21.67; S,
19.59. Found: C, 36.75; H, 3.64; N, 8.51; Cl, 21.22; S,
19.31; Chiral HPLC Analysis (Chiracel OJ): 98.5:1.5, 97%
ee.
(88), 122 (12), 109 (17), 108 (12), 107 (37), 106 (27), 96
25
(10), 52 (base); Specific rotation ½aꢁD ¼ ꢀ40 (c 1.16, meth-
4.36. (S)-2-(1-Hydroxy-2-chloroethyl)-thiazole (S)-1g
ylene chloride); Anal. Calcd for C6H7ClN2O: C, 45.44; H,
4.45; N, 17.66; Cl, 22.36. Found: C, 45.21; H, 4.48; N,
17.76; Cl, 22.00; Chiral HPLC Analysis (Chiralpak AD):
88:12, 76% ee.
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2171
4.38. (S)-2-(1-Hydroxy-2-chloroethyl)-pyrazine (S)-1h
108 (72), 107 (base), 88 (74), 86 (88), 84 (89), 79 (88), 78
(77), 77 (90), 51 (80), 50 (72); HRMS (ESI) calcd for
25
C8H9ClO+H1 157.0420, found 157.0418; ½aꢁD ¼ ꢀ50 (c
25
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.98 g, 1.60 mmol), (1R,2R)-N-p-
0.87, methylene chloride) {lit.24 ½aꢁD ¼ ꢀ56:2 (c 1.1,
CHCl3)}; Chiral HPLC Analysis (Chiracel OJ): 100:0,
>99% ee.
toluenesulfonyl-1,2-diphenylethylenediamine
(1.17 g,
3.20 mmol 2.0 mol % based upon ketone), i-PrOH
(24.7 mL), and Et3N (0.664 g, 0.041 equiv, 6.56 mmol,
0.914 mL) was combined with 2-chloroacetylpyrazine 3h
(25.0 g, 0.16 mol) and HCOOH/Et3N (5:2, 57.3 mL) in
DMF (250 mL). After 3 h, the reaction was quenched by
adding MeOH (25 mL), stirred for 5 min, and the solvents
were removed in vacuo (cold finger rotovapor, vacuum
pump) to give a red-black viscous oil. The crude material
was taken up in CH2Cl2 (1.25 L), washed with saturated
aq NaHCO3 (1.0 L), brine (1.0 L), and dried (MgSO4). Fil-
tration through silica gel (pre-wet with diethyl ether), rins-
ing with diethyl ether, and concentration in vacuo afforded
(1S)-2-chloro-1-pyrazin-2-ylethanol (S)-1h (22.5 g, 88%) as
4.40. (S)-2-Chloro-1-phenylethanol (S)-1i
As described for the preparation of (S)-2-(1-hydroxy-2-
chloroethyl)-furan (S)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.617 mmol), (1R,2R)-N-p-
toluenesulfonyl-1,2-diphenylethylenediamine
(1.18 g,
3.234 mmol, 2.0 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.674 g, 6.66 mmol, 0.93 mL) was com-
bined with 2-chloroacetophenone 3i (25.0 g, 0.167 mol) and
HCOOH/Et3N (5:2, 58 mL) in DMF (250 mL). After
90 min, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min, and the solvents were removed
in vacuo (cold finger rotovapor, vacuum pump) to give a
red-black viscous oil. The crude material was taken up in
Et2O (1.25 L), washed with saturated aq NaHCO3
(2 · 0.65 L), brine (0.65 L), and dried (Na2SO4). Filtration
and concentration in vacuo afforded the crude product as a
brown oil. The crude product was purified by chromato-
graphy on a column of silica gel (70 mm OD; 250 g, 230–
400 mesh, ether/hexanes 40:60, 1 L; 250 mL fractions)
using the flash technique. Fractions 3–5 were combined
to afford (S)-2-chloro-1-phenylethanol (S)-1i (21.55 g,
1
a pale brown oil. H NMR (400 MHz, CDCl3) d = 8.80 (s,
1), 8.56 (s, 2), 5.07 (t, J = 5.0 Hz, 1), 3.93 (dd, J = 11.0,
5.0 Hz, 1), 3.87 (dd, J = 11.0, 5.0 Hz, 1); 13C NMR
(100 MHz, CDCl3) d = 154.2, 144.2, 143.5, 143.3, 71.7,
48.9; IR (liq.) 3275, 3064, 2959, 2869, 1474, 1405, 1308,
1154, 1091, 1059, 1019, 856, 775, 663, 649 cmꢀ1; MS (CI)
m/z (rel. intensity) 159 (MH+, 22), 161 (7), 159 (22), 140
(13), 126 (5), 124 (14), 123 (20), 109 (11), 107 (24), 52
(base); HRMS (FAB) calcd for C6H7ClN2O+H1
25
159.0325, found 159.0323; ½aꢁD ¼ þ40 (c 0.61, ethanol);
1
Anal. Calcd for C6H7ClN2O: C, 45.44; H, 4.45; N, 17.66.
Found: C, 45.23; H, 4.60; N, 17.38; Chiral HPLC Analysis
(Chiralpak AD) 11:89, 78% ee.
85%) as a pale yellow, semi-solid. H NMR (300 MHz,
CDCl3) d = 7.20–7.50 (5), 4.92 (dd, J = 8.7, 3.5 Hz, 1),
3.77 (dd, J = 11.2, 3.5 Hz, 1), 3.67 (dd, J = 11.2, 8.7 Hz,
1), 2.49 (br s, 1); IR (liq.) 3397 (b), 2337 (w), 1995 (w),
1956 (w), 1495, 1454, 1427, 1086, 1065 (s), 1029, 1013,
771, 723 (s), 698 (s), 615 cmꢀ1; MS (EI) m/z (rel. intensity)
158 (4), 156 (M+, 13), 108 (24), 107 (base), 105 (23), 103
(16), 91 (20), 79 (83), 78 (36), 77 (79), 51 (48), 50 (21).
HRMS (ESI) calcd for C8H9ClO+H1 157.0420, found
4.39. (R)-2-Chloro-1-phenylethanol (R)-1i
As described for the preparation of (R)-2-(1-hydroxy-2-
chloroethyl)-furan (R)-1c, the catalyst prepared from
[RuCl2(g6-p-cymene)]2 (0.99 g, 1.617 mmol), (1S,2S)-N-p-
25
25
toluenesulfonyl-1,2-diphenylethylenediamine
(1.18 g,
157.0419; ½aꢁD ¼ þ44 (c 0.93, methanol) [lit.25 ½aꢁD ¼ þ47
(c 1.84, c-C6H12)]; Chiral HPLC Analysis (Chiracel OJ):
0.6:99.4, 98.8% ee.
3.234 mmol, 2.0 mol % based upon ketone), i-PrOH
(25 mL), and Et3N (0.674 g, 6.66 mmol, 0.93 mL) was com-
bined with 2-chloroacetophenone 3i (25.0 g, 0.167 mol) and
HCOOH/Et3N (5:2, 58 mL) in DMF (250 mL). After
90 min, the reaction was quenched by adding MeOH
(25 mL), stirred for 5 min, and the solvents were removed
in vacuo (cold finger rotovapor, vacuum pump) to give a
red-black viscous oil. The crude material was taken up in
Et2O (1.25 L), washed with saturated aq NaHCO3
(2 · 0.65 L), brine (0.65 L), and dried (Na2SO4). Filtration
and concentration in vacuo afforded the crude product as a
brown oil. The crude product was purified by chromato-
graphy on a column of silica gel (70 mm OD; 250 g, 230–
400 mesh, ether/hexanes 40:60, 1 L; 250 mL fractions)
using the flash technique. Fractions 3–5 were combined
to afford (R)-2-chloro-1-phenylethanol (R)-1i (22.32 g,
4.41. (S)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyridine
(S)-2b
(R)-2-(1-Hydroxy-2-chloroethyl)-pyridine (R)-1b (6.0 g,
38 mmol) and NaI (0.57 g, 3.8 mmol) were combined in a
500 mL, plastic coated, thick-walled bottle and covered
with 2 M MeNH2 in MeOH (0.19 L). The Teflonꢂ stopper
was wrapped in Teflonꢂ tape and the bottle was sealed.
Stirring was started, and the bottle was immersed in a
60 ꢁC oil bath for 16 h. The yellow-brown mixture was
cooled to room temperature and analyzed by analytical
reverse phase HPLC, which indicated that the reaction
was complete (retention time starting material = 2.66 min;
retention time product = 1.22 min). Concentration in
vacuo afforded the crude product as a yellow oil, which
was treated with CH2Cl2/THF (0.25 L, 10:90) to give a
yellow solution and a white precipitate. The precipitate
was removed by filtration, rinsed with CH2Cl2/THF
(10:90) and the combined filtrates were concentrated in
vacuo to give a yellow-brown oil. The crude product was
1
88%) as a pale yellow, semi-solid. H NMR (300 MHz,
CDCl3) d = 7.20–7.50 (5), 4.92 (dd, J = 8.7, 3.5 Hz, 1),
3.77 (dd, J = 11.2, 3.5 Hz, 1), 3.67 (dd, J = 11.2, 8.7 Hz,
1), 2.49 (br s, 1); IR (diffuse reflectance) 3430 (b), 3419
(b), 3410 (b), 3390, 2497 (w), 2423 (w), 2351 (w), 2335
(w), 2312 (w), 1450, 1062 (s), 768, 750, 723 (s), 698 (s)
cmꢀ1; MS (EI) m/z (rel. intensity) 158 (14), 156 (M+, 43),

2172
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
purified by chromatography on a column of silica gel
(70 mm OD, 250 g, 230–400 mesh; packed with CH2Cl2/
MeOH 90:10; eluted with CH2Cl2/MeOH 90:10, 2 L,
500 mL fractions; CH2Cl2/MeOH/NH4OH 89:10:1, 8 L,
500 mL fractions) using the flash technique. Fractions
10–18 were combined to provide 3.34 g (58%) of (S)-2-
(1-hydroxy-2-N-methylamino-ethyl)-pyridine (S)-2b as an
amber oil. 1H NMR (400 MHz, DMSO-d6): d = 8.48
(d, J = 4.8 Hz, 1), 7.78 (td, J = 7.7, 1.7 Hz, 1), 7.50 (d,
J = 7.7 Hz, 1), 7.25 (dd, J = 4.8, 1.7 Hz, 1), 4.70 (dd,
J = 8.2, 3.8 Hz, 1), 2.85 (dd, J = 12.1, 3.8 Hz, 1), 2.67
(dd, J = 12.1, 8.2 Hz, 1), 2.34 (s, 3); IR (liq.) 3291 (s, b),
3090 (s, b), 3066 (s, b), 2942 (s, b), 2890 (s, b), 2853 (s,
b), 2799 (s), 1996 (w), 1918 (w), 1591 (s), 1473 (s), 1436
(s), 1070 (s), 772 (s), 751 (s) cmꢀ1; MS (CI) m/z (rel. inten-
sity): 153 (MH+, base), 151 (18), 137 (23), 135 (12), 122
(26), 110 (14), 108 (36), 106 (25), 80 (19), 52 (49). HRMS
EtOAc/hexanes 20:80 1 L, 50 mL fractions). Fractions
25–42 afforded 4.56 g (65%) of (R)-1-(2-furyl)-2-chloroeth-
anol–N-methylcarbamate (R)-7c, as a clear, pale yellow oil,
which solidified to an ivory solid upon cooling. Mp: 26–
1
27 ꢁC; H NMR (400 MHz, CDCl3): d = 7.43 (m, 1), 6.45
(m, 1), 6.39 (m, 1), 5.97 (t, J = 6.3 Hz, 1), 4.79 (br s, 1),
3.89 (m, 2), 2.82 (d, J = 4.9 Hz, 3); 13C NMR (100 MHz,
CDCl3): d = 156.2, 150.3, 143.3, 110.8, 109.9, 69.1, 44.0,
28.0. IR (liq.) 3352 (b), 2481 (w), 2192 (w), 1721 (s), 1537
(s, b), 1504, 1267 (s), 1252 (s), 1176, 1151 (s), 1131 (s),
1015, 1003, 772, 745 cmꢀ1; MS (EI) m/z (rel. intensity):
129 (96), 110 (base), 97 (83), 95 (65), 94 (89), 93 (57), 84
(58), 66 (61), 65 (85), 58 (80); MS (FAB) m/z (rel. intensity)
206 (1), 204 (MH+, 6), 168 (9), 167 (12), 133 (12), 131 (33),
130 (8), 129 (base), 110 (29), 95 (8), 94 (25), 65 (8); HRMS
(FAB) calcd for C8H10ClNO3+H1 204.0427, found
25
204.0421; ½aꢁD ¼ ꢀ102 (c 0.98, chloroform); Chiral HPLC
(ESI) calcd for C8H12N2O+H1 153.1028, found 153.1046;
Analysis (Chiracel OJ): 1:99, 98% ee.
25
Specific rotation ½aꢁD ¼ ꢀ46 (c 0.37, methylene chloride);
Chiral HPLC Analysis (Chiralpak AD): >98:<2, >96% ee.
4.44. 5S-3-Methyl-5-(2-furyl)-2-oxazoldinone (S)-8c
4.42. (R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyridine
(R)-2b
To
(R)-1-(2-furyl)-2-chloroethanol–N-methylcarbamate
(R)-7c (3.00 g, 14.77 mmol) in dry THF (25 mL), cooled
in an ice-water bath under nitrogen, was added a solution
of KO-t-Bu in THF (15 mL, 1 M, 15 mmol) over 15 min.
The mixture was allowed to stir after the addition was com-
plete and HPLC analysis suggested that the reaction was
complete within 15 min. The mixture was cast into Et2O
(125 mL) and brine (125 mL) containing 1 N aq HCl
(5 mL). The organic phase was separated and the aqueous
layer was extracted with Et2O (125 mL). The combined
organic phases were washed with saturated aq NaHCO3
(125 mL) and dried (Na2SO4). Concentration in vacuo
afforded the crude oxazolidinone as a yellow oil. The crude
material was purified by chromatography on a 40M Bio-
tageꢂ column (CH2Cl2, 1 L; Et2O/CH2Cl2 2:98, 1 L;
Et2O/CH2Cl2 4:96, 1 L; Et2O/CH2Cl2 6:94, 1 L; 50 mL
fractions). Fractions 23–57 were combined to afford
2.29 g (93%) of 5S-3-methyl-5-(2-furyl)-2-oxazoldinone
(S)-8c as a pale yellow oil, which furnished an ivory solid
upon cooling. Mp: 54–55 ꢁC; 1H NMR (400 MHz, CDCl3):
d = 7.47 (m, 1), 6.49 (m, 1), 6.41 (m, 1), 5.46 (m, 1), 3.78
(m, 2), 2.97 (s, 3); 13C NMR (100 MHz, CDCl3):
d = 155.9, 148.1, 142.1, 109.0, 108.4, 65.9, 48.8, 29.4; IR
(diffuse reflectance): 2491, 2464, 2436, 2402, 2351, 1743,
As described for the preparation of (S)-2-(1-hydroxy-2-N-
methylamino-ethyl)-pyridine (S)-2b, (S)-2-(1-hydroxy-2-
chloroethyl)-pyridine (S)-1b (6.0 g, 38 mmol) was treated
with NaI (0.57 g, 3.8 mmol) and 2 M MeNH2 in MeOH
(0.19 L) in a sealed, thick-walled glass bottle at 60 ꢁC to
give
(R)-2-(1-hydroxy-2-N-methylamino-ethyl)-pyridine
(R)-2b (3.18 g, 54%) as an amber oil after flash chromato-
graphy. 1H NMR (400 MHz, DMSO-d6): d = 8.49 (d,
J = 4.8 Hz, 1), 7.79 (dt, J = 7.7, 1.7 Hz, 1), 7.52 (d, J =
7.7 Hz, 1), 7.25 (dd, J = 4.8, 1.7 Hz, 1), 4.75 (dd, J = 8.4,
3.67 Hz, 1), 2.90 (dd, J = 12.1, 3.7 Hz, 1), 2.67 (dd,
J = 12.1, 8.4 Hz, 1), 2.32 (s, 3); IR (neat): 3279 (s, b),
3090 (s, b), 3064 (s, b), 3012 (s), 2943 (s, b), 2890 (s, b),
2851 (s, b), 2799 (s), 1996 (w), 1591 (s), 1473 (s), 1436 (s),
1070 (s), 772 (s), 751 (s) cmꢀ1; EI-MS (70 eV): 153 (M+,
base), 135 (18), 122 (20), 108 (62); HRMS (FAB): calcd
25
for C8H12N2O+H 153.1028, found 153.1009; ½aꢁD ¼ þ49
(c 0.36, CH2Cl2); Chiral HPLC Analysis (Chiralpak AD):
<2:>98, >96% ee.
4.43. (R)-1-(2-Furyl)-2-chloroethanol–N-methylcarbamate
(R)-7c
1503, 1439, 1344, 1307, 1267, 1154, 1138, 1029, 748 cmꢀ1
;
MS (EI) m/z (rel. intensity): 167 (M+, 57), 123 (69), 108
To
(R)-1-(2-furyl)-2-chloroethanol
(R)-1c
(5.0 g,
(44), 95 (26), 94 (37), 86 (67), 84 (base), 81 (43), 53 (20),
25
34.2 mmol) in dry CH2Cl2 (75 mL), cooled in an ice-water
bath under nitrogen, was added Et3N (1.38 g, 13.7 mmol,
0.4 equiv, 1.9 mL). The solution was allowed to stir for
5 min, then methylisocyanate (3.32 g, 58.21 mmol,
1.7 equiv, 3.46 mL) was added via syringe over 2 min.
The ice was allowed to melt and the mixture to stir over-
night, HPLC at 16 h indicated that the reaction was com-
plete. The mixture was cast into Et2O (0.3 L) and brine
(0.3 L). The organic phase was reserved, the aq layer was
extracted with Et2O (2 · 0.2 L), then the combined organic
phases were washed with brine (0.4 L), and dried (Na2SO4).
Concentration in vacuo afforded the crude carbamate as a
brown viscous oil that was purified by chromatography
(Biotageꢂ 40S column, EtOAc/hexanes 10:90 1 L,
51 (57); ½aꢁD ¼ þ109 (c 0.97, CH2Cl2); Anal. Calcd for
C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.42;
H, 5.48; N, 8.38.; Chiral HPLC Analysis (Chiracel OJ):
98.5:1.5; 97% ee.
4.45. N-Methyl (S)-1-(2-furyl)-2-aminoethanol (S)-2c
To (5S)-3-methyl-5-(2-furyl)-2-oxazoldinone (S)-8c (8.0 g,
47.8 mmol) in a 500 mL 1 N RB flask was added 1 N aq
KOH (240 mL, 0.24 mol, 5 equiv). The flask was equipped
with a reflux condenser, placed under nitrogen, and then
was immersed in a preheated (50 ꢁC) oil bath. The mixture
was allowed to stir and the (5S)-3-methyl-5-(2-furyl)-2-
oxazoldinone (S)-8b suspension slowly gave way to a clear

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2173
solution. After stirring for 3 h at 50 ꢁC, HPLC analysis
indicated that the reaction was complete. The mixture
was cooled to room temperature and was cast into Et2O/
CH2Cl2 (95:5, 0.5 L) and the aq layer was saturated with
salt. The organic phase was removed, the aq phase was
extracted with Et2O/CH2Cl2 (95:5, 2 · 0.5 L) and the com-
bined organic phases were dried (Na2SO4). Concentration
in vacuo afforded the desired N-methyl S-1-(2-furyl)-2-
aminoethanol (S)-2c (6.64 g, 98%) as a pale orange oil that
solidifies at freezer (-20 ꢁC) temperatures. This material
was determined to be analytically pure and was utilized
without further purification. 1H NMR (400 MHz,
DMSO-d6): d = 7.55 (m, 1), 6.37 (m, 1), 6.25 (d,
J = 3.2 Hz, 1), 4.59 (m, 1), 2.70 (m, 2), 2.25 (s, 3); 13C
NMR (100 MHz, DMSO-d6): d = 157.3, 141.9, 110.5,
105.9, 65.5, 56.5, 36.5; IR (liq.) 3318 (s, b), 3116 (s), 2945
(s, b), 2852 (s, b), 2801 (s), 2086 (b), 2019 (b), 1474 (s),
1453 (s), 1151 (s), 1065 (s), 1010 (s), 884 (s), 738 (s), 600
(s) cmꢀ1; MS (CI) m/z (rel. intensity): 142 (MH+, base),
140 (13), 128 (4), 126 (18), 124 (20), 110 (3), 95 (4), 61
(11), 52 (13); HRMS (FAB) calcd for C7H11NO2+H1
2369 (w), 2353 (w), 1744 (s), 1728 (s), 1436 (s), 1263 (s),
1031 (s), 958 (s), 804 (s), 758 (s), 718 (s), 662 (s) cmꢀ1
;
MS (ES+): m/z (rel. intensity) 179 (M+H+, 23);
25
½aꢁD ¼ ꢀ39 (c 1.00, chloroform); Anal. Calcd for
C9H10N2O2: C, 60.67; H, 5.66; N, 15.72. Found: C,
60.50; H, 5.73; N, 15.72; Chiral HPLC Analysis (Chiro-
biotic T, 98.8:1.2, 97.6% ee).
4.48. (R)-N-Methyl-1-(3-pyridyl)-2-aminoethanol (R)-2a
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5R)-3-methyl-5-(3-pyridyl)-2-
oxazoldinone (R)-8a 3.62 g (20.3 mmol), and 1 N aq
KOH (120 mL) were warmed in a 50 ꢁC oil bath to give
(R)-N-methyl-1-(3-pyridyl)-2-aminoethanol (R)-2a (2.11 g,
68%) as an amber oil. 1H NMR (400 MHz, DMSO)
d = 8.53 (d, J = 2.0 Hz, 1), 8.44 (m, 1), 7.73 (m, 1), 7.34
(m, 1), 5.42 (s, 1), 4.68 (m, 1), 2.61 (m, 2), 2.29 (s, 3); IR
(diffuse reflectance) 3295 (s), 3086 (s, b), 3053 (s, b), 3034
(s), 2977 (s), 2888 (s, b), 2837 (s, b), 2793 (s), 2312 (b),
2264 (w), 2179 (w), 2115 (w), 2092 (w), 815 (s), 713 (s)
cmꢀ1; MS (ESI, ES+): m/z (rel. intensity) 153 (M+H+,
142.0868, found 142.0871; % Water (KF titration): 0.64;
25
½aꢁD ¼ ꢀ32 (c 0.91, ethanol); Anal. Calcd for C7H11NO2:
45); HRMS (ESI) calcd for C8H12N2O+H1 153.1028,
25
C, 59.56; H, 7.85; N, 9.92. Found: C, 59.28; H, 7.98; N,
9.80; Chiral HPLC Analysis Chiral HPLC (Chirobiotic
TAG): >98:<2, >96% ee.
found 153.1017; ½aꢁD ¼ ꢀ67 (c 0.93, methylene chloride);
Anal. Calcd for C8H12N2O: C, 63.13; H, 7.95; N, 18.41.
Found: C, 62.77; H, 7.96; N, 18.18; Chiral HPLC Analysis
(Chirobiotic T): <2:>98, >96% ee.
4.46. (R)-1-(3-Pyridyl)-2-chloroethanol–N-methylcarbamate
(R)-7a
4.49. (R)-1-(2-Thienyl)-2-chloroethanol–N-methylcarbamate
(R)-7d
As described for the preparation of (R)-1-(2-furyl)-2-
chloroethanol–N-methylcarbamate (R)-7c, (R)-2-chloro-1-
(3-pyridyl)-ethanol 1a (5 g, 31.7 mmol) was treated with
Et3N (1.27 g, 12.8 mmol, 1.76 mL) and methyl isocyanate
(3.08 g, 54 mmol, 3.21 mL) to give 6.08 g (89%) of R-1-
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (R)-2-chloro-1-(2-
thienyl)-ethanol (R)-1d (5.54 g, 0.034 mol) was treated with
Et3N (1.37 g, 13.8 mmol, 1.9 mL) and methyl isocyanate
(3.36 g, 59 mmol, 3.5 mL) to give 6.8 g (91%) of (R)-1-(2-
thienyl)-2-chloroethanol–N-methylcarbamate (R)-7d as a
colorless oil after chromatographic purification (Biotageꢂ
40L, gradient from 5% to 60% methylene chloride/pentane,
(3-pyridyl)-2-chloroethanol–N-methylcarbamate
(R)-7a
as an amorphous white solid after chromatographic purifi-
cation (Biotageꢂ 40M, CH2Cl2, 1 L; CH2Cl2/MeOH 95:5,
1 L; 50 mL fractions). 1H NMR (400 MHz, CDCl3)
d = 8.65 (d, J = 2.0 Hz, 1), 8.59 (m, 1), 7.69 (d,
J = 8.0 Hz, 1), 7.32 (m, 1), 5.93 (t, J = 6.0 Hz, 1), 5.16 (s,
1H), 3.79 (m, 2H), 2.81 (d, J = 5.0 Hz, 3); IR (diffuse reflec-
tance) 3323 (s), 3311 (s, b), 2496 (w), 2413 (w), 2276 (w),
1
50 mL fractions). H NMR (400 MHz, CDCl3) d = 7.30
(m, 1), 7.11 (m, 1), 7.00 (m, 1), 6.17 (m, 1), 4.77 (br s, 1),
3.82 (m, 2), 2.81 (d, J = 4.9 Hz, 3); IR (liq.) 3427, 3347
(b), 2270 (w), 2080 (w), 1713 (s), 1525, 1436, 1421, 1265
(s), 1250 (s), 1131, 948, 772, 707, 632 cmꢀ1; MS (CI) m/z
(rel. intensity): 179 (42), 164 (23), 162 (59), 145 (18), 111
(77), 110 (31), 93 (68), 52 (27); HRMS (FAB) calcd for
2229 (w), 2148 (w), 1722 (s), 1550 (s), 1284 (s), 1275 (s),
25
1256 (s), 1144 (s), 1010 (s), 746 (s) cmꢀ1; ½aꢁD ¼ ꢀ33 (c
0.92, chloroform); Anal. Calcd for C9H11ClN2O2: C,
50.36; H, 5.16; N, 13.05. Found: 50.33; H, 5.15; N, 12.96;
Chiral HPLC Analysis (Chiracel OJ) 2.7:97.3, 94.6% ee.
C8H10ClNO2S+H 220.0199, found 220.0212; % Water
25
(KF): 0.18; ½aꢁD ¼ ꢀ61 (c 0.73, methylene chloride); Anal.
Calcd for C8H10ClNO2S: C, 43.74; H, 4.59; N, 6.38.
Found: C, 43.58; H, 4.43; N, 6.30; Chiral HPLC Analysis
(Chiracel OJ): 3.8:96.2, 92.4% ee.
4.47. 5R-3-Methyl-5-(3-pyridyl)-2-oxazoldinone (R)-8a
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (R)-1-(3-pyridyl)-2-chloroetha-
nol–N-methylcarbamate (R)-7a (6.15 g, 28.7 mmol) was
treated with KO-t-Bu (29 mL, 1.0 M in THF, 29 mmol)
to give (5R)-3-methyl-5-(3-pyridyl)-2-oxazoldinone (R)-8a
(3.62 g, 71%) as an ivory solid after chromatography (Bio-
tageꢂ 40M, gradient CH2Cl2 to CH2Cl2/MeOH 2:98,
50 mL fractions). Mp: 79–80 ꢁC; 1H NMR (400 MHz,
CDCl3) d = 8.64 (m, 2), 7.76 (m, 1), 7.38 (m, 1), 5.55 (t,
J = 8.0 Hz, 1), 3.99 (t, J = 9.0 Hz, 1), 3.49 (m, 1), 2.96 (s,
3); IR (diffuse reflectance) 2477 (w), 2455 (w), 2401 (w),
4.50. 5S-3-Methyl-5-(2-thienyl)-2-oxazoldinone (S)-8d
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (R)-1-(2-thienyl)-2-chloroetha-
nol–N-methylcarbamate (R)-7d (6.4 g, 29 mmol) was
treated with KO-t-Bu (30 mL, 1.0 M in THF, 30 mmol)
to give (5S)-3-methyl-5-(2-thienyl)-2-oxazoldinone (S)-8d
(4.9 g, 91%) as an ivory amorphous solid. 1H NMR
(400 MHz, CDCl3) d = 7.36 (dd, J = 5.0, 1.0 Hz, 1), 7.14
(m, 1), 7.01 (dd, J = 5.0, 4.0 Hz, 1), 5.70 (t, J = 8.0 Hz,

2174
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
1H), 3.90 (m, 1), 3.61 (m, 1), 2.95 (s, 3); IR (diffuse reflec-
tance) 2458 (w), 2428 (w), 2387 (w), 2320 (w), 2286 (w),
1748 (s), 1732 (s), 1504, 1436, 1289 (s), 1255 (s), 1130 (s),
1026 (s), 852 (s), 712 (s) cmꢀ1; MS (EI) m/z (rel. intensity)
183 (M+, 90), 139 (64), 138 (base), 124 (19), 113 (16), 111
7.00 (dd, J = 5.0, 1.3 Hz, 1), 5.47 (t, J = 8.0 Hz, 1), 3.81 (t,
J = 8.6 Hz, 1), 3.42 (dd, J = 8.6, 7.2 Hz, 1), 2.85 (s, 3); IR
(diffuse reflectance) 3096, 1749 (s), 1743 (s, b), 1501, 1435,
1408, 1307, 1264 (s), 1249, 1137 (s), 1030, 988, 856, 789,
761 cmꢀ1; MS (EI) m/z (rel. intensity) 183 (M+, 84), 139
(base), 138 (48), 113 (42), 111 (69), 98 (64), 97 (86), 94 (51),
(29), 97 (59), 86 (17), 84 (24), 51 (15); HRMS (ESI) calcd
25
for C8H9NO2S+H 184.0432, found 184.0430; ½aꢁ ¼ þ90
86 (44), 84 (57); HRMS (FAB) calcd for C8H9NO2S+H1
(c 0.96, methylene chloride); Chiral HPLC AnalysiDs (Chira-
184.0432, found 184.0426; ½aꢁD ¼ þ13 (c 0.99, chloroform);
25
cel OJ): 0.8:99.2, 98.4% ee.
Anal. Calcd for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64; S,
17.50. Found: C, 52.33; H, 4.93; N, 7.60; S, 17.29; Chiral
HPLC analysis (Chirobiotic T): 0:100, >99% ee.
4.51. (S)-N-Methyl-1-(2-thienyl)-2-aminoethanol (S)-2d
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5S)-3-methyl-5-(2-thienyl)-2-
oxazoldinone (S)-8d (4.41 g, 24 mmol), and 1 N aq KOH
(50 mL) were warmed in a 50 ꢁC oil bath to give (S)-N-
methyl-1-(2-thienyl)-2-aminoethanol (S)-2d (2.94 g, 85%)
as an ivory, waxy, solid after trituration with pentane/ether
(80:20, 100 mL). 1H NMR (400 MHz, CDCl3) d = 7.26 (m,
1), 6.98 (m, 2), 4.99 (m, 1), 2.89 (m, 2), 2.48 (s, 3); IR (dif-
fuse reflectance) 3109 (s), 3095 (s), 3064 (s), 2985 (s), 2958
(s), 2938 (s), 2876 (s), 2835 (s), 2807 (s), 2735 (s, b), 2358,
2342 (b), 2328 (b), 2169 (w), 2117 (w) cmꢀ1; MS (EI) m/z
(rel. intensity): 139 (74), 138 (33), 113 (42), 111 (62), 98
4.54. (R)-N-Methyl-1-(3-thienyl)-2-aminoethanol (R)-2e
As described for the preparation of N-methyl S-1-(2-furyl)-
2-aminoethanol (S)-2c, 5R-3-methyl-5-(3-thienyl)-2-ox-
azoldinone (R)-8e (3.32 g, 18.1 mmol) and 1 N aq KOH
(95 mL) were warmed in a 50 ꢁC oil bath to give (R)-N-
methyl-1-(3-thienyl)-2-aminoethanol (R)-2e (2.66 g, 93%)
as a pale yellow oil. 1H NMR (300 MHz, CDCl3):
d = 7.31 (m, 1), 7.24 (m, 1), 7.08 (dd, J = 4.9, 1.3 Hz, 1),
4.85 (dd, J = 8.1, 4.1 Hz, 1), 2.75–2.95 (2), 2.66 (br s, 3),
2.47 (s, 3); IR (liq.) 3315 (s, b), 3102 (s, b), 2973 (s), 2940
(s, b), 2887 (s, b), 2855 (s, b), 2799 (s), 1472 (s), 1450 (s),
(50), 97 (base), 86 (64), 85 (86), 84 (73), 51 (51); % Water
1112 (s), 1066 (s), 853 (s), 836 (s), 787 (s), 652 (s) cmꢀ1
;
25
(KF): 0.18; ½aꢁD ¼ ꢀ24 (c 1.06, methylene chloride); Anal.
MS (CI) m/z (rel. intensity) 158 (MH+, 81), 156 (7), 142
Calcd for C7H11NOS: C, 53.47; H, 7.05; N, 8.91. Found: C,
53.08; H, 7.09; N, 8.81; Chiral HPLC Analysis (Chirobiotic
TAG): >99:<1, >98% ee.
(5), 140 (7), 108 (6), 61 (9), 52 (base); HRMS (FAB) calcd
25
for C7H11NOS+H1 158.0640, found 158.0636; ½aꢁD ¼ ꢀ48
(c 1.07, chloroform); Chiral HPLC analysis (Chirosil CH):
0:100, >99% ee.
4.52. (R)-1-(3-Thienyl)-2-chloroethanol–N-methylcarbamate
(R)-7e
4.55. (R)-1-(2-Benzofuranyl)-2-chloroethanol–N-methyl-
carbamate (R)-7f
As described for the preparation of R-1-(2-furyl)-2-chloro-
ethanol–N-methylcarbamate (R)-7c, (R)-2-chloro-1-(3-thi-
enyl)-ethanol (R)-1e (5.00 g, 30.7 mmol) was treated with
Et3N (1.24 g, 12.3 mmol) and methyl isocyanate (2.98 g,
52.3 mmol) to give 5.91 g (88%) of R-1-(3-thienyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7e as a colorless oil
after chromatographic purification (Biotageꢂ 40M, gradi-
ent from CH2Cl2 to CH2Cl2/Et2O 20:80, 45 mL fractions).
1H NMR (300 MHz, CDCl3): d = 7.30–7.40 (2), 7.09 (m,
1), 6.03 (m, 1), 4.82 (br s, 1), 3.82 (m, 2), 2.82 (d,
J = 4.9 Hz, 3); IR (liq.) 3429, 3348 (b), 1711 (s), 1527 (s),
1420, 1263 (s), 1248 (s), 1135 (s), 1098, 796, 772, 693,
660, 646, 626 cmꢀ1; MS (CI) m/z (rel. intensity) 220
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (R)-2-(1-hydroxy-2-
chloroethyl)-benzofuran (R)-1f (9.20 g, 46.8 mmol) was
treated with Et3N (1.89 g, 18.7 mmol) and methyl isocya-
nate (4.54 g, 79.5 mmol) to give 10.56 g (89%) of (R)-1-(2-
benzofuranyl)-2-chloroethanol–N-methylcarbamate (R)-7f
as a white solid after chromatographic purification (Bio-
tageꢂ 40S, EtOAc/hexanes 20:80, 45 mL fractions). Mp:
75–77 ꢁC; 1H NMR (400 MHz, CDCl3): d = 7.57 (d,
J = 7.8 Hz, 1), 7.50 (d, J = 8.2 Hz, 1), 7.23–7.35 (2), 6.83
(s, 1), 6.11 (t, J = 6.2 Hz, 1), 4.85 (br s, 1), 3.99 (m, 2),
2.85 (d, J = 4.9 Hz, 3); IR (diffuse reflectance) 3374, 2495
(w), 2466 (w), 2367 (w), 2257 (w), 2240 (w), 1699, 1535
(MH+, 5), 162 (23), 128 (13), 126 (10), 111 (14), 110 (15),
25
96 (20), 93 (65), 52 (base); ½aꢁD ¼ ꢀ59 (c 0.86, methylene
(s), 1251 (s), 1134 (s), 975 (s), 821 (s), 771 (s), 748 (s), 676
25
chloride); Anal. Calcd for C8H10ClNO2S: C, 43.74; H,
4.59; N, 6.38; Cl, 16.14; S, 14.59. Found: C, 43.81; H,
4.71; N, 6.37; Cl, 15.30; S, 14.48; Chiral HPLC Analysis
(Chiracel OJ): 3.6:96.3, 92.8% ee.
(s) cmꢀ1; ½aꢁD ¼ ꢀ110 (c 0.95, chloroform); Anal. Calcd
for C12H12ClNO3: C, 56.82; H, 4.77; N, 5.52; Cl, 13.98.
Found: C, 57,19.; H, 4.68; N, 5.61; Cl, 13.79; Chiral HPLC
Analysis (Chiracel OJ): 1:99, 98% ee.
4.53. (5R)-3-Methyl-5-(3-thienyl)-2-oxazoldinone (R)-8e
4.56. (5S)-3-Methyl-5-(2-benzofuranyl)-2-oxazoldinone
(S)-8f
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (R)-1-(3-thienyl)-2-chloroetha-
nol–N-methylcarbamate (R)-7e (5.39 g, 24.9 mmol) was
treated with KO-t-Bu (25.5 mL, 1.0 M in THF, 25.5 mmol)
to give (5R)-3-methyl-5-(3-thienyl)-2-oxazoldinone (R)-8e
(3.69 g, 81%) as a pale yellow solid. Mp: 68–69 ꢁC; 1H
NMR (400 MHz, CDCl3): d = 7.30 (m, 1), 7.26 (m, 1),
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (R)-1-(2-benzofuranyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7f (10.15 g, 40.0 mmol)
was treated with KO-t-Bu (41 mL, 1.0 M in THF,
41 mmol) to give (5S)-3-methyl-5-(2-benzofuranyl)-2-oxaz-
oldinone (S)-8f (4.86 g, 56%) as a tan solid after chromato-

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2175
graphic purification (flash, 70 mm OD; 400 g, 230–400
mesh, CH2Cl2 and gradient to CH2Cl2/EtOAc, 10:90,
325 mL fractions). Mp: 72–73 ꢁC; 1H NMR (400 MHz,
CDCl3): d = 7.59 (d, J = 7.6 Hz, 1), 7.50 (d, J = 8.0 Hz,
1), 7.35 (m, 1), 7.28 (m, 1), 6.83 (s, 1), 5.62 (m, 1), 3.87
(m, 2), 3.00 (s, 3); IR (diffuse reflectance) 2494 (w), 2463
(w), 2421 (w), 2388 (w), 2350 (w), 1754 (s), 1358 (s), 1255
(s), 1136 (s), 1018 (s), 966 (s), 919 (s), 806 (s), 765 (s), 757
chloroethyl)-pyrazine (R)-1h (8.50 g, 53.6 mmol) was trea-
ted with Et3N (2.17 g, 21.44 mmol) and methyl isocyanate
(5.20 g, 91.11 mmol) to give 9.78 g (85%) of (R)-1-(2-pyr-
azinyl)-2-chloroethanol–N-methylcarbamate (R)-7h as an
ivory solid after chromatographic purification (Biotageꢂ
40L, EtOAc/hexanes 50:75 and EtOAc/hexanes 40:60,
350 mL fractions). Mp: 55–58 ꢁC; 1H NMR (400 MHz,
CDCl3): d = 8.69 (br s, 1), 8.57 (m, 2), 6.06 (t,
J = 5.2 Hz, 1), 4.90 (br s, 1), 4.02 (m, 2), 2.83 (d,
J = 4.9 Hz, 3); 13C NMR (100 MHz, CDCl3): d = 155.9,
152.6, 144.8, 144.4, 144.0, 72.1, 45.7, 28.1; IR (diffuse
reflectance) 3350 (s), 2495 (w), 2387 (w), 2351 (w), 2326
(w), 2211 (w), 1699 (s), 1550 (s), 1545 (s), 1419, 1269 (s),
1257 (s), 1186, 1133, 1019 cmꢀ1; MS (CI) m/z (rel. inten-
sity) 216 (MH+, 24), 159 (8), 141 (9), 140 (12), 124 (20),
123 (35), 109 (15), 108 (5), 107 (base); HRMS (ESI) calcd
(s) cmꢀ1
; HRMS (ESI) calcd for C12H11NO3+H1
25
218.0817, found 218.0816, ½aꢁD ¼ þ37 (c 1.00, chloroform);
Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45.
Found: C, 66.29; H, 5.15; N, 6.43; Chiral HPLC Analysis
(Chiracel OJ): 4:96, 92% ee.
4.57. (S)-N-Methyl-1-(2-benzofuranyl)-2-aminoethanol (S)-
2f
for C8H10ClN3O2+H1 216.0540, found 216.0537;
25
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, 5S-3-methyl-5-(2-benzofuran-
yl)-2-oxazoldinone (S)-8f (5.10 g, 23.5 mmol) and 1 N aq
KOH (10 mL) in ethanol (75 mL) were warmed in a
50 ꢁC oil bath to give (S)-N-methyl-1-(2-benzofuranyl)-2-
aminoethanol (S)-2f (2.66 g, 93%) as a light tan solid.
½aꢁD ¼ ꢀ29 (c 1.01, methylene chloride); Anal. Calcd for
C8H10ClN3O2: C, 44.56; H, 4.67; N, 19.49. Found: C,
44.81; H, 4.66; N, 19.32; Chiral HPLC analysis (Chiralpak
AD): 91:9, 82% ee.
4.60. (R)-1-Phenyl-2-chloroethanol–N-methylcarbamate
(R)-7i
1
Mp: 88–89 ꢁC; H NMR (400 MHz, CDCl3): d = 7.55 (d,
J = 7.6 Hz, 1), 7.47 (d, J = 8.2 Hz, 1), 7.20–7.31 (2), 6.70
(s, 1), 4.93 (m, 1), 3.11 (dd, J = 12.2, 7.6 Hz, 1), 3.02 (dd,
J = 12.2, 4.2 Hz, 1), 2.52 (s, 3); IR (diffuse reflectance)
3291 (s), 3061 (s), 3034 (s), 2943 (s), 2875 (s, b), 2852 (s,
b), 2836 (s, b), 2802 (s), 2715 (s, b), 2700 (s, b), 2364 (b),
2342 (b), 2056 (w), 1983 (w), 1939 (w) cmꢀ1; HRMS
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (R)-2-(1-hydroxy-2-
chloroethyl)-benzene (R)-1i (5.00 g, 31.9 mmol) was treated
with Et3N (1.27 g, 12.8 mmol) and methyl isocyanate
(3.10 g, 54.2 mmol) to give 6.06 g (89%) of (R)-1-phenyl-
2-chloroethanol–N-methylcarbamate (R)-7i as an ivory
solid after chromatographic purification (Biotageꢂ 40M,
EtOAc/hexanes 5:95, 10:90, 15:85 and EtOAc/hexanes
40:60, 45 mL fractions). Mp: 75–77 ꢁC; 1H NMR
(300 MHz, CDCl3): d = 7.15–7.50 (5), 5.80 (m, 1), 3.72–
4.10 (2), 2.56 (d, J = 4.5 Hz, 3); IR (diffuse reflectance):
3369 (s), 2486 (w), 2405 (w), 2339 (w), 2318 (w), 2287
(w), 1715 (s), 1532 (s), 1265 (s), 1246 (s), 1140 (s), 1018
(s), 953 (s), 728 (s), 627 (s) cmꢀ1; MS (CI) m/z (rel. inten-
(ESI) calcd for C11H13NO2+H1 192.1024, found
25
192.1026; ½aꢁD ¼ ꢀ30 (c 1.02, chloroform); Chiral HPLC
Analysis (Chirosil CH): 4:96, 92% ee.
4.58. (R)-1-(2-Thiazolyl)-2-chloroethanol–N-methylcarb-
amate (R)-7g
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (R)-2-(1-hydroxy-2-
chloroethyl)-thiazole (R)-1g (9.20 g, 46.8 mmol) was trea-
ted with Et3N (1.31 g, 13 mmol) and methyl isocyanate
(3.31 g, 58 mmol) to give 5.8 g (77%) of (R)-1-(2-thi-
azolyl)-2-chloroethanol–N-methylcarbamate (R)-7g as a
white solid, which was purified by recrystallization from
ether/pentane. Mp: 74–75 ꢁC; 1H NMR (300 MHz,
CDCl3): d = 7.82 (m, 1), 7.37 (m, 1), 6.28 (m, 1), 4.97 (br
s, 1), 4.11 (dd, J = 11.8, 4.1 Hz, 1), 4.02 (dd, J = 11.8,
6.3 Hz, 1), 2.88 (d, J = 4.9 Hz, 3); IR (diffuse reflectance)
3322 (s), 2403 (w), 2286 (w), 2214 (w), 2158 (w), 2099
(w), 1705 (s), 1556 (s), 1273 (s), 1142 (s), 955, 767, 738,
684 (s), 667 cmꢀ1; MS (CI) m/z (rel. intensity): 221
sity): 214 (MH+, 16), 138 (4), 120 (5), 104 (5), 93 (18);
25
½aꢁD ¼ ꢀ15 (c 0.93, methylene chloride); Anal. Calcd for
C10H12ClNO2: C, 56.21; H, 5.66; N, 6.55. Found: C,
56.10; H, 5.57; N, 6.55; Chiral HPLC analysis (Chiracel
OJ): 1:99, 98% ee.
4.61. (5R)-3-Methyl-5-phenyl-2-oxazoldinone (R)-8i
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (R)-1-phenyl-2-chloroethanol–
N-methylcarbamate (R)-7i (5.11 g, 23.9 mmol) was treated
with KO-t-Bu (24.5 mL, 1.0 M in THF, 24.5 mmol) to give
(5R)-3-methyl-5-phenyl-2-oxazoldinone (R)-8i (4.05 g,
96%) as an ivory solid after chromatographic purification
(Biotageꢂ 40M, CH2Cl2; CH2Cl2/EtOAc 98:2; CH2Cl2/
(MH+, base), 164 (10), 129 (30), 114 (12), 112 (59), 66
25
(11), 52 (6); ½aꢁD ¼ ꢀ17 (c 1.10, methylene chloride); Anal.
Calcd for C7H9ClN2O2S: C, 38.10; H, 4.11; N, 12.69.
Found: C, 38.36; H, 4.12; N, 12.67; Chiral HPLC analysis
(Chiracel OJ) 0:100, >99% ee.
1
EtOAc 90:10; 45 mL fractions). Mp: 75–77 ꢁC; H NMR
(300 MHz, CDCl3): d = 7.30–7.50 (5), 5.49 (t, J = 8.4 Hz,
1), 3.93 (t, J = 8.7 Hz, 1), 3.46 (dd, J = 8.7, 7.5 Hz, 1),
2.94 (s, 3); IR (diffuse reflectance) 2960 (s), 2909 (s), 2499
(w), 2423 (w), 2400 (w), 2350 (w), 2342 (w), 1743 (s),
1729 (s), 1702 (s), 1433 (s), 1404 (s), 1026 (s), 951 (s), 703
(s) cmꢀ1 MS (EI) m/z (rel. intensity): 177 (M+, base), 133
(26), 132 (77), 117 (7), 105 (10), 91 (15), 84 (10), 77 (10),
4.59. R-1-(2-Pyrazinyl)-2-chloroethanol–N-methylcarb-
amate (R)-7h
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (R)-2-(1-hydroxy-2-

2176
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
25
51 (8); ½aꢁD ¼ ꢀ41 (c 0.90, chloroform); Anal. Calcd for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.66;
H, 6.22; N, 7.87; Chiral HPLC analysis (Chirobiotic T):
<1:>99, >98% ee.
3); IR (diffuse reflectance) 2479 (w), 2455 (w), 2401 (w),
2369 (w), 2315 (w), 1748 (s), 1728 (s), 1436 (s), 1263 (s),
1031 (s), 958 (s), 804 (s), 758 (s), 718 (s), 662 (s) cmꢀ1
;
MS (ESI+): m/z (rel. intensity) 179 (M+H+, 37);
25
½aꢁD ¼ þ40 (c 0.91, chloroform); Anal. Calcd for
4.62. (R)-N-Methyl-1-phenyl-2-aminoethanol (R)-2i
C9H10N2O2: C, 60.67; H, 5.66; N, 15.72. Found: C,
60.50; H, 5.73; N, 15.72; Chiral HPLC Analysis (Chiro-
biotic T): 1.7:98.3, 96.6% ee.
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, R-3-methyl-5-phenyl-2-ox-
azoldinone (R)-8i (3.32 g, 18.7 mmol) and 1 N aq KOH
(95 mL) were warmed in a 50 ꢁC oil bath to give (R)-N-
methyl-1-phenyl-2-aminoethanol (R)-2i (2.70 g, 95%) as a
4.65. (S)-N-Methyl-1-(3-pyridyl)-2-aminoethanol (S)-2a
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5S)-3-methyl-5-(3-pyridyl)-2-
oxazoldinone (S)-8a (4.19 g, 23.5 mmol) and 1 N aq
KOH (120 mL) were warmed in a 50 ꢁC oil bath to give
N-methyl (S)-1-(3-pyridyl)-2-aminoethanol (S)-2a (2.43 g,
1
colorless oil, which slowly crystallized. Mp: 47–48 ꢁC; H
NMR (300 MHz, CDCl3) d = 7.41–7.27 (m, 5H), 4.76
(dd, J = 9.0, 4.0 Hz, 1), 2.85 (dd, J = 12.0, 4.0 Hz, 1),
2.74 (dd, J = 12.0, 9.0 Hz, 1), 2.60 (br s, 2), 2.48 (s, 3);
13C NMR (100 MHz, CDCl3) d = 142.7, 128.3, 127.4,
125.8, 71.4, 59.1, 35.8; IR (diffuse reflectance): 3317 (s),
3121 (s, b), 3105 (s, b), 3061 (s), 3037 (s), 2975 (s), 2953
(s), 2937 (s), 2904 (s), 2864 (s), 2839 (s), 2803 (s), 2779 (s,
b), 756 (s), 701 (s) cmꢀ1; MS (CI) m/z (rel. intensity) 152
(MH+, base), 150 (13), 136 (6), 134 (15), 74 (3), 61 (4), 52
(7); HRMS (ESI) calcd for C9H13NO+H1 152.1075, found
1
68%) as a pale yellow oil. H NMR (400 MHz, CDCl3)
d = 8.53 (d, J = 2.0 Hz, 1), 8.44 (m, 1), 7.73 (m, 1), 7.34
(m, 1), 4.68 (m, 1), 2.61 (m, 2), 2.29 (s, 3); IR (diffuse reflec-
tance) 3303 (s), 3295 (s), 3087 (s, b), 3053 (s), 3035 (s), 2977
(s), 2889 (s, b), 2840 (s, b), 2793 (s), 2311 (w), 2265 (w),
2178 (w), 2114 (w), 2092 (w), 713 (s) cmꢀ1; MS (ESI,
ES+): m/z (rel. intensity) 153 (M+H+, 39); HRMS (ESI)
calcd for C8H12N2O+H1 153.1028, found 153.1019;
25
25
152.1083; ½aꢁD ¼ ꢀ38 (c 0.66, EtOH); lit.16 ½aꢁD ¼ ꢀ40:7 (c
1.3, EtOH); Anal. Calcd for C9H13NO: C, 71.49; H, 8.66;
N, 9.26. Found: C, 71.45; H, 8.74; N, 9.23.
25
25
½aꢁD ¼ þ39 (c 0.83, EtOH, lit.,17 ½aꢁD ¼ þ40:4 (c 1.89
EtOH)); Anal. Calcd for C8H12N2O: C, 63.13; H, 7.95;
N, 18.41. Found: C, 62.39; H, 7.93; N, 18.00; Chiral HPLC
Analysis (Chirobiotic T): 98.7:1.3, 97.4% ee.
4.63. (S)-1-(3-Pyridyl)-2-chloroethanol–N-methylcarbamate
(S)-7a
4.66. (S)-1-(2-Furyl)-2-chloroethanol–N-methylcarbamate
(S)-7c
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (S)-2-chloro-1-(3-
pyridyl)-ethanol (S)-1a (5 g, 31.7 mmol) was treated with
Et3N (1.27 g, 12.8 mmol, 1.76 mL) and methyl isocyanate
(3.08 g, 54 mmol, 3.21 mL) to give 6.10 g (90%) of (S)-1-
(3-pyridyl)-2-chloroethanol–N-methylcarbamate (S)-7a as
an amorphous white solid after chromatographic purifica-
tion (Biotageꢂ 40M, CH2Cl2, 1 L; CH2Cl2/MeOH 95:5,
1 L; 50 mL fractions). Mp: 79–80 ꢁC; 1H NMR
(400 MHz, CDCl3): d = 8.65 (m, 1), 8.59 (m, 1), 7.69 (m,
1), 7.32 (m, 1), 5.93 (m, 1), 5.16 (br s, 1), 3.79 (m, 2),
2.81 (d, J = 5.2 Hz, 3); IR (diffuse reflectance) 3323 (s),
3311 (s, b), 2496 (w), 2413 (w), 2276 (w), 2229 (w), 2148
(w), 1722 (s), 1550 (s), 1284 (s), 1275 (s), 1256 (s), 1144
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (S)-2-chloro-1-(2-
furyl)-ethanol (S)-1c (5.0 g, 34.2 mmol) was treated with
Et3N (1.38 g, 13.7 mmol, 0.4 equiv, 1.9 mL) and methyl
isocyanate (3.32 g, 58.21 mmol, 1.7 equiv, 3.46 mL) to give
4.56 g (65%) of (S)-1-(2-furyl)-2-chloroethanol–N-methyl-
carbamate (S)-7c as a clear, pale yellow oil, which solidified
to an ivory solid upon cooling, after chromatographic puri-
fication (Biotageꢂ 40S, EtOAc/hexanes 10:90 1 L, EtOAc/
hexanes 20:80 1 L, 50 mL fractions). Mp: 26–27 ꢁC; 1H
NMR (400 MHz, CDCl3): d = 7.43 (m, 1), 6.45 (m, 1),
6.39 (m, 1), 5.97 (t, J = 6.3 Hz, 1), 4.79 (br s, 1), 3.89 (m,
2), 2.82 (d, J = 4.9 Hz, 3); 13C NMR (100 MHz, CDCl3):
d = 156.2, 150.3, 143.3, 110.8, 109.9, 69.1, 44.0, 28.0; IR
(diffuse reflectance): 3365 (s), 3355 (s), 3344 (s, b), 3333
(s), 2477 (w), 2392 (w), 2197 (w), 2088 (w), 1727 (s), 1694
(s), 1010 (s), 746 (s) cmꢀ1; MS (ESI+) m/z (rel. intensity):
25
215.1 (MH+, base); ½aꢁD ¼ þ33 (c 0.96, chloroform); Anal.
Calcd for C9H11ClN2O2: C, 50.36; H, 5.16; N, 13.05.
Found: C, 50.29; H, 5.18; N, 12.96; Chiral HPLC Analysis
(Chiracel OJ): 98.3:1.7, 96.6% ee.
(s), 1550 (s), 1531 (s), 1518 (s), 1253 (s), 1248 (s) cmꢀ1
;
MS (CI) m/z (rel. intensity): 221 (M+NH4þ, 3), 146 (7),
4.64. (5S)-3-Methyl-5-(3-pyridyl)-2-oxazoldinone (S)-8a
129 (6), 113 (5), 96 (base), 79 (53), 52 (33); % Water
25
(KF): 0.13%; ½aꢁD ¼ þ94 (c 1.02, CH2Cl2); Anal. Calcd
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (S)-1-(3-pyridyl)-2-chloroetha-
nol–N-methylcarbamate (S)-7a (6.15 g, 28.7 mmol) was
treated with KO-t-Bu (29 mL, 1.0 M in THF, 29 mmol)
to give (5S)-3-methyl-5-(3-pyridyl)-2-oxazoldinone (S)-8a
(4.19 g, 83%) as an ivory solid after chromatography (Bio-
tageꢂ 40M, gradient CH2Cl2 to CH2Cl2/MeOH 2:98,
50 mL fractions). Mp: 84–85 ꢁC; 1H NMR (400 MHz,
CDCl3) d = 8.64 (m, 2), 7.76 (m, 1), 7.39 (m, 1), 5.55 (t,
J = 8.0 Hz, 1), 3.99 (t, J = 9.0 Hz, 1), 3.48 (m, 1), 2.96 (s,
for C8H10ClNO3: C, 47.19; H, 4.95; N, 6.88; Cl, 17.41.
Found: C, 46.99; H, 4.89; N, 6.85; Cl, 17.31; Chiral HPLC
Analysis (Chiracel OJ): 99:1, 98% ee.
4.67. (5R)-3-Methyl-5-(2-furyl)-2-oxazoldinone (R)-8c
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (S)-1-(2-furyl)-2-chloroethanol–
N-methylcarbamate (S)-7c (3.00 g, 14.77 mmol) was trea-
ted with KO-t-Bu (15.5 mL, 1.0 M in THF, 15.5 mmol)

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2177
25
to give (5R)-3-methyl-5-(2-furyl)-2-oxazoldinone (R)-8c
(2.29 g, 93%) as a pale yellow oil, which solidified to fine,
pale yellow needles, after chromatography (Biotageꢂ
40M, gradient CH2Cl2 to CH2Cl2/Et2O 6:94, 50 mL frac-
tions). Mp: 54–55 ꢁC; 1H NMR (400 MHz, CDCl3):
d = 7.47 (m, 1), 6.49 (m, 1), 6.41 (m, 1), 5.46 (m, 1), 3.78
(m, 2), 2.97 (s, 3); 13C NMR (100 MHz, CDCl3):
d = 155.9, 148.1, 142.1, 109.0, 108.4, 65.9, 48.8, 29.4; IR
(diffuse reflectance): 2492 (w), 2436 (w), 2402 (w), 2351
(w), 2304 (w), 1759 (s), 1743 (s), 1503 (s), 1439 (s), 1307,
1267 (s), 1154 (s), 1138 (s), 1029, 747 (s) cmꢀ1; MS (EI)
m/z (rel. intensity): 167 (M+, 71), 123 (base), 108 (76), 95
220.0208; % Water (KF): 0.25%; ½aꢁD ¼ þ58 (c 0.97,
CH2Cl2); Anal. Calcd for C8H10ClNO2S: C, 43.74; H,
4.59; N, 6.38. Found: C, 43.59; H, 4.39; N, 6.32; Chiral
HPLC Analysis (Chiracel OJ): 98.5:1.5, 97% ee.
4.70. (5R)-3-Methyl-5-(2-thienyl)-2-oxazoldinone (R)-8d
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (S)-1-(2-thienyl)-2-chloroetha-
nol–N-methylcarbamate (S)-7d (6.4 g, 29 mmol) was
treated with KO-t-Bu (30 mL, 1.0 M in THF, 30 mmol)
to give (5R)-3-methyl-5-(2-thienyl)-2-oxazoldinone (R)-8d
(4.94 g, 91%) as an ivory amorphous solid. 1H NMR
(400 MHz, CDCl3) d = 7.36 (dd, J = 5.0, 1.0 Hz, 1), 7.14
(m, 1), 7.01 (dd, J = 5.0, 4.0 Hz, 1), 5.70 (t, J = 8.0 Hz,
1), 3.90 (m, 1), 3.61 (m, 1), 2.95 (s, 3); IR (diffuse reflec-
tance) 2458 (w), 2428 (w), 2387 (w), 2320 (w), 2264 (w),
1732 (s), 1504, 1437, 1289, 1255 (s), 1129, 1026 (s), 950,
852, 712 (s) cmꢀ1; MS (EI) m/z (rel. intensity) 183 (M+,
base), 139 (74), 138 (81), 124 (18), 113 (19), 111 (33), 98
(43), 94 (59), 86 (45), 84 (64), 81 (70), 53 (28), 51 (50);
25
½aꢁD ¼ þ106 (c 1.01, CH2Cl2); % Water (KF): 0.07%; Anal.
Calcd for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C,
57.46; H, 5.39; N, 8.36; Chiral HPLC Analysis (Chiracel
OJ): 1:99; 98% ee.
4.68. (R)-N-Methyl-1-(2-furyl)-2-aminoethanol (R)-2c
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5R)-3-methyl-5-(2-furyl)-2-
oxazoldinone (R)-8c (8.0 g, 47.8 mmol), and 1 N aq KOH
(240 mL) were warmed in a 50 ꢁC oil bath to give (R)-N-
methyl-1-(2-furyl)-2-aminoethanol (R)-2c (6.50 g, 96%) as
(18), 97 (base), 86 (18), 84 (40); HRMS (ESI) calcd for
25
C8H9NO2S+H 184.0432, found 184.0435; ½aꢁD ¼ ꢀ94 (c
1.04, methylene chloride); Chiral HPLC Analysis (Chiracel
OJ): >99:<1, >98% ee.
1
a pale yellow oil, which solidified upon cooling. H NMR
4.71. (R)-N-Methyl-1-(2-thienyl)-2-aminoethanol (R)-2d
(400 MHz, DMSO-d6): d = 7.55 (m, 1), 6.37 (m, 1), 6.25
(d, J = 3.2 Hz, 1), 4.59 (m, 1), 2.70 (m, 2), 2.25 (s, 3); 13C
NMR (100 MHz, DMSO-d6): d = 157.3, 141.9, 110.5,
105.9, 65.5, 56.5, 36.5; IR (liq.) 3318 (s, b), 3116 (s, b),
2945 (s, b), 2853 (s, b), 2801 (s), 2085 (b), 2019 (b), 1474
(s), 1452 (s), 1151 (s), 1065 (s), 1010 (s), 884 (s), 738 (s),
600 (s) cmꢀ1; MS (CI) m/z (rel. intensity): 142 (MH+, base),
140 (13), 128 (4), 126 (18), 124 (20), 110 (3), 95 (4), 61 (11),
52 (13); MS (CI) m/z (rel. intensity): 159 (M+NH4þ, 14),
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5R)-3-methyl-5-(2-thienyl)-2-
oxazoldinone (R)-8d (4.63 g, 25 mmol), and 1 M aq KOH
(100 mL) were warmed in a 50 ꢁC oil bath to give (S)-N-
methyl-1-(2-thienyl)-2-aminoethanol (R)-2d (3.28 g, 90%)
as an ivory, waxy, solid after trituration with pentane/ether
(80:20, 100 mL). 1H NMR (400 MHz, CDCl3) d = 7.26 (m,
1), 6.98 (m, 2), 4.99 (m, 1), 2.89 (m, 2), 2.48 (s, 3); IR (dif-
fuse reflectance) 3319 (s), 3094 (s), 3074 (s), 3063 (s, b),
2980 (s), 2956 (s), 2909 (s), 2844 (s, b), 2809 (s), 2723 (s,
142 (M+H, base), 126 (15), 124 (8), 112 (4), 74 (7), 69
25
(6), 61 (18); % Water (KF titration): 0.83%; ½aꢁD ¼ þ32
(c 0.96, EtOH); Anal. Calcd for C7H11NO2: C, 59.56; H,
7.85; N, 9.92. Found: C, 59.90; H, 7.83; N, 9.68; Chiral
HPLC Analysis Chiral HPLC (Chirobiotic TAG):
<2:>98, >96% ee.
b), 2359, 2169 (w), 2119 (w), 2069 (w), 1940 (w) cmꢀ1
;
MS (EI) m/z (rel. intensity) 157 (M+, 6), 139 (29), 138
(17), 113 (16), 111 (29), 97 (44), 88 (25), 86 (89), 85 (33),
25
84 (base), 51 (51); % Water (KF): 0.00; ½aꢁD ¼ þ26 (c
1.05, methylene chloride); Anal. Calcd for C7H11NOS: C,
53.47; H, 7.05; N, 8.91. Found: C, 53.31; H, 7.13; N,
8.84; Chiral HPLC Analysis (Chirobiotic TAG): <1:>99,
>98% ee.
4.69. (S)-1-(2-Thienyl)-2-chloroethanol–N-methylcarbamate
(S)-7d
As described for the preparation of (R)-1-(2-furyl)-2-
chloroethanol–N-methylcarbamate (R)-7c, (S)-2-chloro-1-
(2-thienyl)-ethanol (S)-1d (5.54 g, 34 mmol) was treated
with Et3N (1.38 g, 13.7 mmol, 0.4 equiv, 1.9 mL) and
methyl isocyanate (3.36 g, 59 mmol, 3.5 mL) to give 6.87 g
(92%) of (S)-1-(2-thienyl)-2-chloroethanol–N-methylcarb-
amate (S)-7d as a clear, colorless oil, after chromatographic
purification (Biotageꢂ 40S, EtOAc/hexanes 10:90 1 L,
EtOAc/hexanes 20:80 1 L, 50 mL fractions). 1H NMR
(400 MHz, CDCl3): d = 7.30 (m, 1), 7.11 (m, 1), 7.00 (m,
1), 6.17 (m, 1), 4.77 (br s, 1), 3.82 (m, 2), 2.81 (d,
J = 4.9 Hz, 3); IR (diffuse reflectance): 3428, 3348 (b),
2954, 2193 (w), 1713 (s), 1526 (s), 1436, 1421, 1265 (s),
1250 (s), 1131 (s), 1095, 948, 772, 707 cmꢀ1; MS (CI) m/z
(rel. intensity): 220 (MH+, 1), 179 (39), 164 (27), 162 (75),
144 (22), 111 (93), 110 (28), 96 (25), 93 (75); HRMS
(FAB) calcd for C8H10ClNO2S+H 220.0199, found
4.72. (S)-1-(3-Thienyl)-2-chloroethanol–N-methylcarbamate
(S)-7e
As described for the preparation of (R)-1-(2-furyl)-2-
chloroethanol–N-methylcarbamate (R)-7c, (S)-2-chloro-1-
(3-thienyl)-ethanol (S)-1e (5.00 g, 30.7 mmol) was treated
with Et3N (1.24 g, 12.3 mmol) and methyl isocyanate
(2.98 g, 52.3 mmol) to give 5.91 g (88%) of (S)-1-(3-thie-
nyl)-2-chloroethanol–N-methylcarbamate (S)-7e as a color-
less oil after chromatographic purification (Biotageꢂ 40M,
gradient from CH2Cl2 to CH2Cl2/Et2O 20:80, 45 mL frac-
tions). 1H NMR (300 MHz, CDCl3): d = 7.30–7.40 (2),
7.09 (m, 1), 6.03 (m, 1), 4.82 (br s, 1), 3.82 (m, 2), 2.82
(d, J = 4.9 Hz, 3); IR (liq.) 3430, 3349 (b), 2398 (w), 2192
(w), 1996 (w), 1713 (s, b), 1528 (s), 1420, 1264 (s), 1248
(s), 1135 (s), 796, 772, 660, 646 cmꢀ1; MS (CI) m/z (rel.

2178
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
intensity) 220 (MH+, 5), 162 (20), 128 (10), 126 (10), 111
2.85 (d, J = 4.9 Hz, 3); IR (diffuse reflectance) 3374, 1699,
25
(12), 110 (15), 93 (59), 89 (10), 52 (86); ½aꢁD ¼ þ57 (c
1535 (s), 1251 (s), 1134 (s), 975 (s), 924, 821 (s), 814, 771
0.73, methylene chloride); Anal. Calcd for C8H10ClNO2S:
C, 43.74; H, 4.59; N, 6.38; Cl, 16.14; S, 14.59. Found: C,
43.70; H, 4.68; N, 6.38; Cl, 15.53; S, 14.47; Chiral HPLC
Analysis (Chiracel OJ): 98.5:1.5, 97% ee.
(s), 748 (s), 733, 676 (s), 626, 613 cmꢀ1; Specific rotation
25
½aꢁD ¼ þ101 (c 0.85, chloroform); Anal. Calcd for
C12H12ClNO3: C, 56.82; H, 4.77; N, 5.52; Cl, 13.98. Found:
C, 57.04; H, 4.77; N, 5.55; Cl, 13.53; Chiral HPLC Analysis
(Chiracel OJ): 99:1, 98% ee.
4.73. (5S)-3-Methyl-5-(3-thienyl)-2-oxazoldinone (S)-8e
4.76. 5R-3-Methyl-5-(2-benzofuranyl)-2-oxazoldinone (R)-8f
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (S)-1-(2-thienyl)-2-chloroetha-
nol–N-methylcarbamate (S)-7e (5.39 g, 24.9 mmol) was
treated with KO-t-Bu (25.5 mL, 1.0 M in THF, 25.5 mmol)
to give (5S)-3-methyl-5-(3-thienyl)-2-oxazoldinone (S)-8e
(3.80 g, 83%) as a pale yellow solid. Mp: 68–69 ꢁC; 1H
NMR (400 MHz, CDCl3): d = 7.30 (m, 1), 7.26 (m, 1),
7.00 (dd, J = 5.0, 1.3 Hz, 1), 5.47 (t, J = 8.0 Hz, 1), 3.81
(t, J = 8.6 Hz, 1), 3.42 (dd, J = 8.6, 7.2 Hz, 1), 2.85 (s, 3);
IR (diffuse reflectance) 3096 (s), 2483 (w), 2408 (w), 2350
(w), 2328 (w), 2253 (w), 1755 (s), 1733 (s), 1501 (s), 1439
As described for the preparation of 5S-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, R-1-(2-benzofuranyl)-2-chloro-
ethanol–N-methylcarbamate (S)-7f (9.67 g, 38.1 mmol)
was treated with KO-t-Bu (38.5 mL, 1.0 M in THF,
38.5 mmol) to give 5R-3-methyl-5-(2-benzofuranyl)-2-
oxazoldinone (R)-8f 5.05 g (61%) as a tan solid after chro-
matographic purification (flash, 70 mm OD; 400 g, 230–400
mesh, CH2Cl2 and gradient to CH2Cl2/EtOAc, 10:90,
325 mL fractions). Mp: 68–69 ꢁC; 1H NMR (400 MHz,
CDCl3): d = 7.59 (d, J = 7.6 Hz, 1), 7.50 (d, J = 8.0 Hz,
1), 7.35 (m, 1), 7.28 (m, 1), 6.83 (s, 1), 5.62 (m, 1), 3.87
(m, 2), 3.00 (s, 3); IR (diffuse reflectance) 1755 (s), 1495
(s), 1451 (s), 1410 (s), 1358 (s), 1340 (s), 1325 (s), 1255
(s), 1408 (s), 1264 (s), 1249 (s), 1137 (s), 1030 (s) cmꢀ1
;
MS (EI) m/z (rel. intensity) 183 (M+, 91), 139 (base), 138
(30), 113 (28), 111 (61), 98 (50), 97 (74), 94 (28), 86 (34),
84 (62); HRMS (ESI) calcd for C8H9NO2S+H1 184.0432,
(s), 1204 (s), 1135 (s), 1006 (s), 967 (s), 817 (s), 766 (s),
25
25
found 184.0432; ½aꢁD ¼ ꢀ14 (c 1.05, chloroform); Anal.
758 (s) cmꢀ1; ½aꢁD ¼ ꢀ38 (c 0.95, chloroform); Anal. Calcd
Calcd for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64; S,
17.50. Found: C, 52.38; H, 5.05; N, 7.60; S, 17.33; Chiral
HPLC analysis (Chirobiotic T): 98.5:1.5, 97% ee.
for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C,
66.14; H, 5.07; N, 6.30; Chiral HPLC Analysis (Chiracel
OJ): 96:4, 92% ee.
4.74. (S)-N-Methyl-1-(3-thienyl)-2-aminoethanol (S)-2e
4.77. (R)-N-Methyl-1-(2-benzofuranyl)-2-aminoethanol
(R)-2f
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, 5S-3-methyl-5-(3-thienyl)-2-
oxazoldinone (S)-8e (3.35 g, 18.2 mmol), and 1 N aq
KOH (95 mL) were warmed in a 50 ꢁC oil bath to give
N-methyl S-1-(3-thienyl)-2-aminoethanol (S)-2e (2.79 g,
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5R)-3-methyl-5-(2-benzofuran-
yl)-2-oxazoldinone (R)-8f (4.89 g, 22.5 mmol), and 1 N aq
KOH (10 mL) in ethanol (75 mL) were warmed in a
50 ꢁC oil bath to give (R)-N-methyl-1-(2-benzofuranyl)-2-
aminoethanol (R)-2f (3.97 g, 92%) as a light tan solid.
1
97%) as a pale yellow oil. H NMR (300 MHz, CDCl3):
d = 7.31 (m, 1), 7.24 (m, 1), 7.09 (dd, J = 4.9, 1.3 Hz, 1),
4.85 (dd, J = 8.1, 4.1 Hz, 1), 2.75–2.95 (2), 2.66 (br s, 3),
2.47 (s, 3); IR (liq.) 3315 (s, b), 3102 (s, b), 2972 (s), 2941
(s, b), 2890 (s, b), 2857 (s, b), 2800 (s), 1996 (w), 1473 (s),
1451, 1066 (s), 853 (s), 836 (s), 787 (s), 652 (s) cmꢀ1; MS
(CI) m/z (rel. intensity) 158 (MH+, base), 156 (9), 142
(8), 140 (19), 110 (10), 108 (18), 61 (43), 52 (75); HRMS
1
Mp: 88–90 ꢁC; H NMR (400 MHz, CDCl3): d = 7.56 (d,
J = 8.4 Hz, 1), 7.47 (d, J = 8.2 Hz, 1), 7.20–7.31 (2), 6.70
(s, 1), 4.92 (m, 1), 3.10 (dd, J = 12.2, 7.6 Hz, 1), 3.02 (dd,
J = 12.2, 4.2 Hz, 1), 2.51 (s, 3); IR (diffuse reflectance)
3291 (s), 3063 (s), 3051 (s), 2945 (s), 2932 (s), 2892 (s, b),
2877 (s, b), 2852 (s, b), 2840 (s, b), 2801 (s), 2721 (s, b),
2341 (w), 2119 (w), 2049 (w), 1939 (w) cmꢀ1; HRMS
(FAB) calcd for C7H11NOS+H1 158.0640, found
25
158.0628; ½aꢁD ¼ þ48 (c 0.86, chloroform); Chiral HPLC
(ESI) calcd for C11H13NO2+H1 192.1024, found
25
analysis (Chirosil CH): 100:0, >99% ee.
192.1026; ½aꢁD ¼ þ31 (c 1.05, chloroform); Anal. Calcd
for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
68.71; H, 6.98; N, 7.16; Chiral HPLC Analysis (Chirosil
CH): 96:4, 92% ee.
4.75. (S)-1-(2-Benzofuranyl)-2-chloroethanol–N-methyl-
carbamate (S)-7f
As described for the preparation of (R)-1-(2-furyl)-2-chlo-
roethanol–N-methylcarbamate (R)-7c, (R)-2-(1-hydroxy-2-
chloroethyl)-benzofuran (S)-1f (8.45 g, 43 mmol) was
treated with Et3N (1.74 g, 17.2 mmol) and methyl isocya-
nate (4.17 g, 73.1 mmol) to give 9.75 g (89%) of S-1-(2-
benzofuranyl)-2-chloroethanol–N-methylcarbamate (S)-7f
as a white solid after chromatographic purification
(Biotageꢂ 40S, EtOAc/hexanes 20:80, 45 mL fractions).
4.78. (S)-1-Phenyl-2-chloroethanol–N-methylcarbamate (S)-
7i
As described for the preparation of (R)-1-(2-furyl)-2-chloro-
ethanol–N-methylcarbamate (R)-7c, (S)-2-(1-hydroxy-2-
chloroethyl)-benzene (S)-1i (5.00 g, 31.9 mmol) was treated
with Et3N (1.27 g, 12.8 mmol) and methyl isocyanate
(3.10 g, 54.2 mmol) to give 6.06 g (89%) of (S)-1-phenyl-2-
chloroethanol–N-methylcarbamate (S)-7i as an ivory
solid after chromatographic purification (Biotageꢂ 40M,
EtOAc/hexanes 5:95, 10:90, 15:85 and EtOAc/hexanes
1
Mp: 77–78 ꢁC; H NMR (400 MHz, CDCl3): d = 7.58 (d,
J = 7.8 Hz, 1), 7.49 (d, J = 8.2 Hz, 1), 7.23–7.35 (2), 6.83
(s, 1), 6.11 (t, J = 6.2 Hz, 1), 4.58 (br s, 1), 3.99 (m, 2),

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2179
40:60, 45 mL fractions). Mp: 74–76 ꢁC; 1H NMR (300 MHz,
CDCl3): d = 7.15–7.50 (5), 5.80 (m, 1), 3.72–4.10 (2), 2.56 (d,
J = 4.5 Hz, 3); IR (diffuse reflectance) 3370 (s), 1715 (s), 1693
(s), 1532 (s), 1264 (s), 1246 (s), 1140 (s), 1018 (s), 953 (s), 779,
773 (s), 731 (s), 697 (s), 628 (s), 617 cmꢀ1; MS (CI) m/z (rel.
intensity) 214 (MH+, 20), 120 (5), 104 (5), 102 (7), 93 (21),
chloroethyl)-thiazole (R)-1g (3.0 g, 18 mmol) was treated
with NaI (0.28 g, 1.9 mmol) and 2 M MeNH2 in MeOH
(75 mL) in a sealed, thick-walled glass bottle at 60 ꢁC to
give
(S)-2-(1-hydroxy-2-N-methylamino-ethyl)-thiazole
(S)-2g (0.90 g, 31%) as an ivory oil, which solidified upon
cooling to afford an ivory amorphous solid, after flash
chromatography (50 mm OD; 100 g, 230–400 mesh,
CH2Cl2; CH2Cl2/MeOH 95:5; CH2Cl2/MeOH saturated
with NH3 95:5). 1H NMR (400 MHz, CDCl3) d = 7.74
(d, J = 3.0 Hz, 1), 7.29 (d, J = 3.0 Hz, 1), 5.02 (m, 1),
3.06 (m, 2), 2.46 (s, 3); IR (diffuse reflectance) 3270 (s),
3130 (s), 3079 (s), 2945 (s), 2925 (s), 2899 (s), 2865 (s),
2844 (s), 2677 (s, b), 2659 (s, b), 2364 (b), 2354, 2343,
2158 (b), 2086 (b) cmꢀ1; MS (CI) m/z (rel. intensity) 159
(MH+, base), 145 (16), 143 (28), 141 (13), 112 (18), 91
(17), 86 (27), 74 (16), 69 (18), 61 (58); HRMS (ESI) calcd
89 (10); HRMS (FAB) calcd for C10H12ClNO2+H1
25
214.0635, found 214.0636; ½aꢁD ¼ þ13 (c 1.01, methylene
chloride); Anal. Calcd for C10H12ClNO2: C, 56.21; H, 5.66;
N, 6.55. Found: C, 56.10; H, 5.57; N, 6.55; Chiral HPLC
analysis (Chiracel OJ): 98.5:1.5, 97% ee.
4.79. (5S)-3-Methyl-5-phenyl-2-oxazoldinone (S)-8i
As described for the preparation of (5S)-3-methyl-5-(2-fur-
yl)-2-oxazoldinone (S)-8c, (S)-1-phenyl-2-chloroethanol–
N-methylcarbamate (S)-7i (5.06 g, 23.7 mmol) was treated
with KO-t-Bu (24.2 mL, 1.0 M in THF, 24.2 mmol) to give
(5S)-3-methyl-5-phenyl-2-oxazoldinone (S)-8i (3.49 g, 83%)
as an ivory solid after chromatographic purification (Bio-
tageꢂ 40M, CH2Cl2; CH2Cl2/EtOAc 98:2; CH2Cl2/EtOAc
90:10; 45 mL fractions). Mp: 72–74 ꢁC; 1H NMR
(300 MHz, CDCl3): d = 7.30–7.50 (5), 5.49 (t, J = 8.4 Hz,
1), 3.93 (t, J = 8.7 Hz, 1), 3.46 (dd, J = 8.7, 7.5 Hz, 1),
2.94 (s, 3); IR (diffuse reflectance) 2960 (s), 2907 (s), 1727
(s), 1702 (s), 1495 (s), 1433 (s), 1404 (s), 1337 (s), 1252
(s), 1026 (s), 1001 (s), 951 (s), 760 (s), 702 (s), 660 (s)
cmꢀ1; MS (EI) m/z (rel. intensity) 177 (M+, 50), 133 (38),
132 (base), 105 (20), 91 (48), 86 (26), 84 (38), 78 (21), 77
for C6H10N2OS+H1 159.0592, found 159.0589; % Water
25
(KF): 0.18; ½aꢁD ¼ ꢀ19 (c 1.02, methylene chloride); Anal.
Calcd for C6H10N2OS: C, 45.55; H, 6.37; N, 17.70. Found:
C, 45.39; H, 6.42; N, 17.40; Chiral HPLC Analysis (Chira-
cel OJ): >99: < 1, >98% ee.
4.82. (R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-thiazole
(R)-2g
As described for the preparation of (S)-2-(1-hydroxy-2-N-
methylamino-ethyl)-pyridine (S)-2b, (S)-2-(1-hydroxy-2-
chloroethyl)-thiazole (S)-1g (6.02 g, 36.8 mmol) was trea-
ted with NaI (0.56 g, 3.8 mmol) and 2 M MeNH2 in MeOH
(75 mL) in a sealed, thick-walled glass bottle at 60 ꢁC to
(37), 51 (37). HRMS (ESI) calcd for C10H11NO2+H1
25
178.0868, found 178.0880; Specific rotation ½aꢁD ¼ þ39
give
(R)-2-(1-hydroxy-2-N-methylamino-ethyl)-thiazole
(c 1.03, chloroform); Anal. Calcd for C10H11NO2: C,
67.78; H, 6.26; N, 7.90. Found: C, 67.65; H, 6.25; N,
7.87; Chiral HPLC analysis (Chirobiotic T): 98:2, 96% ee.
(R)-2g (2.08 g, 36%) as an ivory oil, which solidified upon
cooling to afford an ivory amorphous solid, after flash
chromatography (50 mm OD; 100 g, 230–400 mesh,
CH2Cl2; CH2Cl2/MeOH 95:5; CH2Cl2/MeOH saturated
with NH3 95:5, 45 mL fractions). 1H NMR (400 MHz,
CDCl3) d = 7.73 (d, J = 3.3 Hz, 1), 7.32 (d, J = 3.3 Hz,
1), 5.31 (dd, J = 8.0, 3.8 Hz, 1), 4.46 (br s, 3), 3.31 (dd,
J = 12.3, 3.8 Hz, 1), 3.16 (dd, J = 12.3, 8.0 Hz, 1), 2.64
(s, 3); IR (diffuse reflectance) 3270 (s), 3130 (s), 3079 (s),
2945 (s), 2925 (s), 2899 (s), 2865 (s), 2844 (s), 2677 (s, b),
4.80. (S)-N-Methyl-1-phenyl-2-aminoethanol (S)-2i
As described for the preparation of N-methyl S-1-(2-furyl)-
2-aminoethanol (S)-2c, (5S)-3-methyl-5-phenyl-2-oxazoldi-
none (S)-8i (3.32 g, 18.7 mmol) and 1 N aq KOH (95 mL)
were warmed in a 50 ꢁC oil bath to give (R)-N-methyl-1-
phenyl-2-aminoethanol (S)-2i (2.59 g, 91%) as a colorless
oil, which slowly crystallized. Mp: 45–46 ꢁC; 1H NMR
(300 MHz, CDCl3) d = 7.39–7.27 (m, 5), 4.76 (dd, J = 9.0,
4.0 Hz, 1), 2.84 (dd, J = 12.0, 4.0 Hz, 1), 2.74 (dd,
J = 12.0, 9.0 Hz, 1), 2.57 (br s, 2), 2.48 (s, 3); 13C NMR
(100 MHz, CDCl3) d = 142.6, 128.3, 127.5, 125.8, 71.3,
59.0, 35.8; IR (diffuse reflectance) 3316 (s), 3121 (s, b),
3105 (s, b), 3086 (s, b), 3061 (s, b), 3037 (s), 3003 (s, b),
2975 (s), 2951 (s), 2937 (s), 2905 (s, b), 2889 (s, b), 2864 (s,
b), 2839 (s, b), 2804 (s) cmꢀ1; MS (CI) m/z (rel. intensity)
152 (MH+, base), 150 (13), 136 (6), 134 (15), 74 (3), 61 (4),
2659 (s, b), 2364 (b), 2354, 2343, 2158 (b), 2086 (b) cmꢀ1
;
MS (CI) m/z (rel. intensity) 159 (MH+, base), 145 (20),
143 (29), 141 (15), 112 (11), 91 (17), 86 (27), 74 (16), 69
(18), 61 (58); HRMS (ESI) calcd for C6H10N2OS+H1
25
159.0592, found 159.0582; Specific rotation ½aꢁD ¼ 31 (c
1.02, DMSO); Chiral HPLC Analysis (Chiracel OJ):
<1:>99, >98% ee.
4.83. (5R)-3-Methyl-5-phenyl-2-oxazoldinone (R)-8h and
(5S)-3-methyl-5-phenyl-2-oxazoldinone (S)-8i
52 (7); HRMS (ESI) calcd for C9H13NO+H1 152.1075,
To a solution of ( )-1i (38.9 g, 0.191 mol) in dichloro-
methane (700 mL) was added a suspension of carbonyldi-
imidazole (31.0 g, 0.191 mol) in dichloromethane
(100 mL). The sides of the flask were washed down with
dichloromethane (50 mL) and after 0.5 h, the reaction
was determined to be complete by TLC analysis. The
organic layer was extracted with saturated citric acid
followed by H2O. The dichloromethane layer was dried
over MgSO4, filtered, and concentrated in vacuo. The
racemic material obtained (31.90 g, 0.180 mol, 94% yield)
25
found 152.1080; ½aꢁD ¼ þ39 (c 0.83, EtOH; lit.,17
25
½aꢁD ¼ þ40:4 (c 1.89 EtOH)); Anal. Calcd for C9H13NO:
C, 71.49; H, 8.66; N, 9.26. Found: C, 71.34; H, 8.78; N, 9.21.
4.81. (S)-2-(1-hydroxy-2-N-methylamino-ethyl)-thiazole (S)-
2g
As described for the preparation of (S)-2-(1-hydroxy-2-N-
methylamino-ethyl)-pyridine (S)-2b, (R)-2-(1-hydroxy-2-

2180
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
required no further purification. A total of 53 g of racemic
material was separated by chiral HPLC (Chirobiotic T
column—7.5 cm · 50 cm) resulting in the isolation of
19.0 g of (R)-8i (>99% ee by chiral HPLC) and 15.6 g of
(S)-8i (89% ee by chiral HPLC).
4.86. (R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyrazine
(R)-2h
As described for the preparation of (S)-N-methyl-1-(2-fur-
yl)-2-aminoethanol (S)-2c, (5R)-3-methyl-5-(2-pyrazinyl)-
2-oxazoldinone (R)-8h (1.51 g, 8.43 mmol), and 1 N aq
KOH (95 mL) were warmed in a 50 ꢁC oil bath to give
R-2-(1-hydroxy-2-N-methylamino-ethyl)-pyrazine (R)-2h
4.84. (R)-2-(1-Hydroxy-2-N-methylamino-ethyl)-pyrazine
(R)-2h
(1.02 g, 79%) as a colorless oil, which slowly crystallized.
25
Mp: 84–85 ꢁC; Specific rotation ½aꢁD ¼ þ66 (c 0.95, meth-
As described for the preparation of (S)-2-(1-hydroxy-2-N-
methylamino-ethyl)-pyridine (S)-2b, (S)-2-(1-hydroxy-2-
chloroethyl)-pyrazine (S)-1h (11.8 g, 74.4 mmol, 76% ee)
was treated with NaI (1.12 g, 7.44 mmol) and 2 M MeNH2
in MeOH (375 mL) in a sealed, thick-walled glass bottle at
60 ꢁC to give N-methyl (R)-2-(1-hydroxy-2-N-methyl-
amino-ethyl)-pyrazine (R)-2h (8.18 g, 72%) as a pale orange
oil, which solidified upon cooling to afford a pale orange
solid, after flash chromatography (70 mm OD; 500 g,
230–400 mesh, CH2Cl2; gradient to MeOH, 350 mL frac-
tions). Mp: 78–81 ꢁC; 1H NMR (400 MHz, CD3OD)
d = 8.79 (s, 1), 8.58 (s, 1), 8.53 (s, 1), 5.00 (dd, J = 8.0,
4.0 Hz, 1), 3.15 (dd, J = 12.0, 4.0 Hz, 1), 3.05 (dd,
J = 12.0, 8.0 Hz, 1), 2.55 (s, 3); 13C NMR (75 MHz,
CD3OD) d = 159.1, 145.1, 144.6, 143.9, 71.5, 57.5, 35.6;
IR (diffuse reflectance) 3270, 3195, 3183, 3165, 3056,
3014, 2984, 2946, 2903, 2876, 2852, 2796, 2695, 1398,
1020 cmꢀ1; MS (CI) m/z (rel. intensity) 154 (MH+, 73),
138 (62), 136 (57), 124 (24), 111 (32), 109 (31), 107 (87),
anol); Chiral HPLC analysis (Chiralpak AD): <3.5:96.5,
>93% ee.
4.87. Pilot plant preparation of 4-(chloroacetyl)morpholine
10
A 400 L reactor was charged with 30 L water followed by
27.9 kg of 47% aqueous potassium carbonate and the line
rinsed with 10 L of water while maintaining the tempera-
ture at less than 30 ꢁC. The potassium carbonate solution
was cooled to maintain the temperature between 0 and
5 ꢁC. Morpholine (8.3 kg) was charged to the tank. The
line was rinsed with 20 L of methylene chloride and a fur-
ther 30 L of methylene chloride was added. The mixture
was cooled to maintain the temperature between ꢀ2 and
ꢀ6 ꢁC. Chloroacetyl chloride (8.3 kg) was charged to a
200 L reactor and the line was rinsed in with 20 L of meth-
ylene chloride. With vigorous agitation and while maintain-
ing ꢀ6 to 0 ꢁC, using nitrogen pressure, the chloroacetyl
chloride solution was transferred to the 100 L reactor over
about 45 min. After the addition was complete the reaction
mixture was warmed to 15 ꢁC and stirred for 2 h at that
temperature. The agitation was stopped and the phases al-
lowed to settle for at least 30 min. The lower methylene
chloride phase was transferred to a 200 L reactor. The
aqueous phase was washed with 35 L of methylene chlo-
ride. The combined product solutions were concentrated
to ꢂ25 L volume using vacuum distillation. To this mixture
was added 100 L of THF and the solution concentrated to
ꢂ30 L volume under vacuum. An additional 100 L of THF
was added and the solution concentrated to ꢂ40 L volume.
The solution was cooled to maintain the temperature be-
tween 20 and 23 ꢁC and packaged in a drum. GC indicated
96.6 area % 10 (rt = 9.56 min, column HP-1 30 m, Injector
250 ꢁC, detector 250 ꢁC, initial temp 40 ꢁC, initial time
2 min, ramp 15 ꢁC/min, final temp 275 ꢁC); an analyti-
cal sample was prepared by concentrating the extracts
95 (56), 61 (41), 52 (base); HRMS (FAB) calcd for
25
C7H11N3O+H1 154.0980, found 154.0973; ½aꢁ ¼ þ58 (c
1.02, methanol); Chiral HPLC Analysis (ChirDalpak AD):
11.5:88.5, 77% ee.
4.85. (5R)-3-Methyl-5-(2-pyrazinyl)-2-oxazoldinone (R)-8h
As described for the preparation of (5R)-3-methyl-5-phen-
yl-2-oxazoldinone (R)-8i and (5S)-3-methyl-5-phenyl-2-
oxazoldinone (S)-8i, (R)-2-(1-hydroxy-2-N-methylamino-
ethyl)-pyrazine (R)-2h (3.66 g, 23.9 mmol) was treated with
carbonyldiimidazole (4.26 g, 1.1 equiv, 26.2 mmol) to give
(5R)-3-methyl-5-(2-pyrazinyl)-2-oxazoldinone
(R)-8h
(3.77 g, 88%) as a white solid after chromatographic purifi-
cation using the flash technique (70 mm OD; 500 g 230–400
mesh, 98:2 dichloromethane, 250 mL fractions). This mate-
rial was upgraded by chiral preparative HPLC (Chiralpak
AD, 7.5 cm · 50 cm) to give 2.07 g (55%) of 5R-3-methyl-
5-(2-pyrazinyl)-2-oxazoldinone (R)-8h with >96% ee. Mp:
1
from a similar reaction to dryness (103% yield); H NMR
1
113.5–114.1 ꢁC; H NMR (400 MHz, CDCl3) d = 8.84 (s,
(400 MHz, CDCl3) d = 3.49 (s, 2), 3.58 (m, 2), 3.67
(m, 4), 4.03 (s, 2). Sample for solids determination and
GC showed an 84% weight yield of 10 corrected for
purity.
1), 8.62 (s, 1), 8.58 (s, 1), 5.62 (dd, J = 9.0, 6.9 Hz, 1), 4.02
(t, J = 9.0 Hz, 1), 3.80 (dd, J = 9.0, 6.0 Hz, 1), 2.94 (s, 3);
13C NMR (100 MHz, CDCl3) d = 157.4, 153.2, 144.8,
144.1, 142.7, 72.2, 51.6, 31.1; IR (diffuse reflectance) 1749,
1420, 1409, 1362, 1255, 1247, 1136, 1059, 1052, 1027,
1017, 962, 871, 841, 759 cmꢀ1; MS (CI) m/z (rel. intensity)
180 (MH+, 12), 197 (45), 180 (12), 138 (35), 137 (17), 136
(base), 122 (11), 107 (24), 96 (14), 95 (10), 58 (11); HRMS
4.88. Pilot plant preparation of 2-(chloroacetyl)-pyridine 3b
4.88.1. Grignard preparation. Isopropyl magnesium chlo-
ride (45 kg) in THF was charged to a 400 L reactor. The
line was rinsed with 10 L of THF from a carboy and a fur-
ther 15 L of THF was added. The solution was cooled to
maintain the temperature between 20 and 23 ꢁC. 2-Bromo-
pyridine (14.5 kg) was charged to a 200 L reactor and the
line rinsed with 10 L of THF from a carboy. The solution
(FAB) calcd for C8H9N3O2+H1 180.0773, found 180.0781;
25
½aꢁD ¼ þ20 (c 0.95, methylene chloride); Anal. Calcd for
C8H9N3O2: C, 53.63; H, 5.06; N, 23.45. Found: C, 53.38;
H, 5.03; N, 23.35; Chiral HPLC analysis (Chirobiotic T):
<2:>98, >96% ee.

S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
2181
of 2-bromopyridine was transferred to the Grignard
solution in the 400 L reactor maintaining the temperature
at less than 25 ꢁC and rinsed with 10 L of THF. The
mixture was stirred at 20–23 ꢁC for at least 12 h, sampled
for HPLC and repeated every 2 h until less than 3%
2-bromopyridine remained.
4.89.2. Aminolysis. Forty percent aqueous methylamine
(116 kg) was charged to the 400 L reactor. The solution
was cooled to maintain the temperature between 0 and
10 ꢁC and 25.9 kg of 50% w/w sodium hydroxide was
added while maintaining the temperature at 0–10 ꢁC
(minimal exotherm).
When the reduction was complete by HPLC the mixture
was transferred into the aminolysis mixture while main-
taining the temperature at ꢀ5 to 20 ꢁC with full cooling
and rinsed with 20 L of ethanol. The mixture was warmed
to 10–20 ꢁC and stirred for more than 12 h. Silica gel TLC
(direct spot 475:35:4.8 CH2Cl2/MeOH/NH4OH) showed
complete conversion to (R)-2-(1-hydroxy-2-N-methyl-
amino-ethyl)-pyridine (R)-2b (Rf = 0.30). The reaction
mixture was vacuum distilled to 25 L volume, then 25 L
of ethanol was added and the solution concentrated to
25 L volume (repeated four more times). Then 25 L ethanol
was added and the reaction mixture was cooled to maintain
the temperature between 20 and 25 ꢁC. The salts were fil-
tered and washed with 15 L of ethanol. S-Naproxen
(22.5 kg) was charged to the 400 L reactor and the ethanol
solution was transferred onto the Naproxen. The mixture
was stirred at a temperature of 20–25 ꢁC until all turned
into solution. The solution was seeded with 100 g and stir-
red at a temperature of 20–25 ꢁC for 4–6 h and then cool to
ꢀ25 to ꢀ20 ꢁC for at least 18 h. The slurry was filtered and
washed with ꢀ10 to 5 ꢁC ethanol (20 L). The product was
dried with heated nitrogen (50–70 ꢁC) to give 13.5 kg of
(R)-2-(1-hydroxy-2-N-methylamino-ethyl)-pyridine (R)-2b
(S)-Naproxen salt as a beige solid. Yield (49%) was based
on 2-bromopyridine. HPLC rt = 6.4 min (enantiomer at
rt = 1.44) (isocratic 900:100:1:1 heptane/ethanol/trifluoro-
acetic acid/triethylamine, 1 mL/min, 250 · 4.6 mm Chiral-
cel OD-H, detection at 254 nm); ee >98%. (Note:
dissolved (R)-2-(1-hydroxy-2-N-methylamino-ethyl)-pyri-
dine (R)-2b S-Naproxen salt at 2 mg/mL in 90:10 etha-
nol/triethylamine for injection on HPLC to give rt (S-
Naproxen) = 1.08; without triethylamine, (S)-Naproxen
coelutes with (R)-2-(1-hydroxy-2-N-methylamino-ethyl)-
pyridine (R)-2b.) 1H NMR (400 MHz, DMSO-d6):
d = 8.47 (d, J = 2.0 Hz, 1), 7.73–7.78 (m, 3), 7.67 (s, 1),
7.50 (d, J = 8.0 Hz, 1), 7.41 (d, J = 8.0 Hz, 1), 7.25 (s, 2),
7.12 (dd, J = 9.0, 2.0 Hz, 1), 4.76 (dd, J = 9.0, 4.0 Hz, 1),
3.85 (s, 3), 3.68 (q, J = 7.0 Hz, 1), 2.97 (dd, J = 12.0,
4.0 Hz, 1), 2.74 (dd, J = 12.0, 9.0 Hz, 1), 2.49 (s, 1), 2.37
(s, 3), 1.40 (d, J = 7.0 Hz, 3); 13C NMR (100 MHz,
DMSO-d6) d = 176.72, 162.59, 156.92, 148.34, 137.91,
136.66, 133.04, 129.04, 128.47, 126.79, 126.51, 125.36,
4.88.2. Adduct formation. All of the THF solution of 10
from the previous step was charged to a 200 L reactor
and the mixture was cooled to ꢀ25 ꢁC. The Grignard slurry
from the 400 L reactor was transferred into the THF solu-
tion of 10 while maintaining the temperature at ꢀ25 to
ꢀ20 ꢁC. The Grignard slurry was rinsed with THF
(10 L). The resultant slurry was stirred at ꢀ20 to ꢀ25 ꢁC
until the reaction was judged to be complete by HPLC.
4.88.3. Quench. Water (40 L) was charged to the 400 L
reactor. Acetic acid (8.5 kg) was added to the water and
rinsed with 10 L of water. MTBE (50 L) was then charged
to the 400 L reactor and the mixture cooled to maintain the
temperature between 0 and 5 ꢁC. Using nitrogen pressure,
the reaction was transferred from the 200 L reactor to the
400 L reactor while keeping the temperature at less than
10 ꢁC. The phases were separated and the aqueous solution
was washed with 50 L of MTBE. The organic phase was
then washed with 50 L of 10% aq NaCl solution. Using
vacuum distillation, the combined organics were concen-
trated to about 25 L volume, and 125 L of MTBE was
added. The solution was concentrated to about 30 L and
held for the next reaction. The solution was stored cold.
Sampled solid determination showed 10.6 kg of 3b in this
solution. This was a 76% yield, while the expected yield
was about 85%. No correction was made for the low yield
in the reduction/aminolysis or salt formation steps.
4.89. Pilot plant preparation of (R)-2-(1-hydroxy-2-N-
methylamino-ethyl)-pyridine (R)-2b
4.89.1. Reduction. To a 200 L reactor was charged 14.9 kg
of formic acid, then 13.5 kg of triethylamine was slowly
added to the formic acid, while maintaining the tempera-
ture from 5 to 30 ꢁC. When the addition was complete,
the cooling was adjusted to maintain at temperature at
15–25 ꢁC.
To a 400 L reactor was charged 300 g of (1R,2R)-N-(4-tol-
uenesulfonyl)-1,2-diphenylethylenediamine, 250 g dichloro-
(p-cymene)-ruthenium(II) dimer, and using
a funnel
370 mL of TEA was charged. DMF (20 L) was added
and the mixture stirred at 20–25 ꢁC for 30 min. The solu-
tion of 3b from above was added and rinsed in with 4 L
MTBE. The 5:2 formic acid/triethylamine solution was
transferred from the 200 L reactor to the 400 L reactor
keeping the temperature less than 30 ꢁC. By cooling the
temperature was maintained at 20–30 ꢁC and stirred for
1.5 h. HPLC (three drops reaction diluted in 1 mL metha-
nol) showed no detectable 3b (rt = 5.4 min) and
90.5 area % S-2-(1-hydroxy-2-chloroethyl)-pyridine (S)-1b
(rt = 3.40 min) (Agilent HPLC 50:50 acetonitrile/0.1 M
NH4OAc, 1 mL/min, detection at 254 nm, 250 · 4.6 mm
Zorbax RX-C8).
122.23, 120.29, 118.45, 105.72, 70.98, 56.57, 55.16, 45.99,
25
34.74, 19.03; ½aꢁD ¼ þ60 (c 1.02, DMSO); Anal. Calcd
for C8H12N2OÆC14H14O3: C, 69.09; H, 6.85; N, 7.32.
Found: C, 69.06; H, 6.93; N, 7.28.
Acknowledgements
The authors thank the former Pfizer-Kalamazoo Analyti-
cal group for their excellent services in support of
this endeavor. The authors also thank Donald Knoechel
for his help in safety evaluation of the pilot plant
process.

2182
S. P. Tanis et al. / Tetrahedron: Asymmetry 17 (2006) 2154–2182
7. For some recent reports of advances in Noyori-type reduc-
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