Synthesis of enantiopure 1,2-azido and 1,2-amino alcohols via regio- and stereoselective ring-opening of enantiopure epoxides by sodium azide in hot water

Article abstract of DOI:10.1016/j.tetasy.2015.12.002

A practical and convenient method for the efficient and regio- and stereoselective ring-opening of enantiopure monosubstituted epoxides by sodium azide under hydrolytic conditions is reported. The ring-opening of enantiopure styryl and pyridyl (S)-epoxides by N₃^- in hot water takes place preferentially at the internal position with complete inversion of configuration to produce (R)-2-azido ethanols with up to 99% enantio- and regioselectivity, while the (S)-adamantyl oxirane provides mainly the (S)-1-adamantyl-2-azido ethanol in excellent yield. In general, 1,2-amino ethanols were obtained in high yield and excellent enantiopurity by the reduction of the chiral 1,2-azido ethanols with PPh₃ in water/THF, and then converted into the Boc or acetamide derivatives.

Full text of DOI:10.1016/j.tetasy.2015.12.002

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiopure 1,2-azido and 1,2-amino alcohols via regio-
and stereoselective ring-opening of enantiopure epoxides by sodium
azide in hot water
Hai-Yang Wang a, Kun Huang a, Melvin De Jesús a, Sandraliz Espinosa a, Luis E. Piñero-Santiago a,
Charles L. Barnes b, Margarita Ortiz-Marciales a,
⇑
a Department of Chemistry, University of Puerto Rico-Humacao, CALL BOX 860, Humacao, PR 00792, USA
b Department of Chemistry, University of Missouri, Columbia, MO 65211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and convenient method for the efficient and regio- and stereoselective ring-opening of enan-
tiopure monosubstituted epoxides by sodium azide under hydrolytic conditions is reported. The ring-
opening of enantiopure styryl and pyridyl (S)-epoxides by Nꢀ3 in hot water takes place preferentially at
the internal position with complete inversion of configuration to produce (R)-2-azido ethanols with up
to 99% enantio- and regioselectivity, while the (S)-adamantyl oxirane provides mainly the (S)-1-adaman-
tyl-2-azido ethanol in excellent yield. In general, 1,2-amino ethanols were obtained in high yield and
excellent enantiopurity by the reduction of the chiral 1,2-azido ethanols with PPh3 in water/THF, and
then converted into the Boc or acetamide derivatives.
Received 12 November 2015
Accepted 8 December 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
N3
NH2
NH2
reduction
oxidation
OH
OH
OH
Ar
Non-racemic 1,2-azido ethanols are well-known precursors for
the synthesis of a broad variety of enantiopure 1,2-amino alcohols,
unnatural amino acids, and triazole derivatives, which are essential
building blocks for the preparation of important pharmaceutical
products, particularly, neuroactive compounds.1–3 In addition, chi-
ral amino alcohols have been extensively used in asymmetric syn-
thesis as organic catalysts,4,5 chiral ligands,1,6 and chirality transfer
agents.7 2-Azido-2-arylethanols are particularly important inter-
mediates for the synthesis of enantiopure 1,2-aminoethanols,
which are widely used as chiral auxiliaries and chiral templates
for the synthesis of chiral lactams3c and unnatural amino acids,3d
as well as, chiral 2-triazole-2-arylethanols, as illustrated in
Scheme 1.
Ar
Ar
O
2-azido-2-arylethanols
2-amino-2-arylethanols
α-aminoacids
R
HO
Ar
O
O
R
N
BF3-OEt2
/
N
N
N
OH
Ar
Me
chiral lactams
Me
2-triazole-2-arylethanols
Scheme 1. (R)-2-Azido-2-arylethanols as key intermediates.
Due to the recent availability of well-established synthetic
routes for the asymmetric syntheses of monosubstituted epox-
ides,8–12 the development of practical and environmentally friendly
methods for the synthesis of highly enantiopure 1,2-amino etha-
nols is an area of great relevance. Aminolysis and azidolysis reac-
tions of oxiranes have been extensively studied for the synthesis
of racemic vicinal amino alcohols with a diversity of results.13–16
The regio- and stereoselective ring-opening reaction of epoxides
depends greatly on the type of substrate, the nucleophilicity of
the nitrogen, and the experimental reaction conditions, such as sol-
vent, concentration, temperature, additive, catalyst, and process
conditions.14–16 Over the past two decades, water has played an
important role not only as an ideal solvent, but also as a remarkable
medium for a variety of catalyzed and uncatalyzed organic reac-
tions.15,16 Fringuelli et al.16a first studied the ring-opening of
racemic epoxides in water at 30 °C with sodium azide under
⇑
Corresponding author. Tel.: +1 787 850 9469.
E-mail address: margarita.ortiz1@upr.edu (M. Ortiz-Marciales).
http://dx.doi.org/10.1016/j.tetasy.2015.12.002
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang, H.-Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2015.12.002

2
H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
acidic (pH 4.2) and basic (pH 9.2) conditions, observing different
regioselectivities for the catalyzed and uncatalyzed ring-opening
of aromatic and aliphatic substituted epoxides. Recently, Qu
et al.16b reported the ring-opening of racemic styrene oxide with
sodium azide at 60 °C in water under neutral conditions and
observed the preferential attack of the azide anion at the benzylic
position. However, the application of this reaction to enantiopure
aryl oxiranes has been completely neglected probably due to the
2. Results and discussion
Initially, representative (S)-styryl and adamantyl epoxides were
prepared by the reduction of the 2-bromo-1-substituted ethanones
2 with 10% of spiroaminoborate 1a and 0.7 equiv BH3ꢁDMS in THF
at room temperature for 0.5 h, followed by the treatment of the
crude halohydrines 3 with 2 M NaOH, or K2CO3 in acetone as in
the case of 1-(4-methoxyphenyl)-2-bromoethanol. The corre-
sponding pure non-racemic (S)-oxiranes 4a–i, 4k were afforded
in good to excellent yields and with up to 99% ee, as shown in
Table 1.
Due to the biological importance of enantiopure 3-pyridyl
1,2-azido alcohols,19 we were also interested in the synthesis of
(S)-3-pyridyl epoxide 4j. As illustrated in Scheme 3, bromination
of acetylpyridine 7 with bromine in HBr provided the stable
2-bromo-1-(pyridyl-3-yl)-ethanone hydrobromide salt 8.19a,19b
The removal of HBr from the pyridinium salt by different
methods, without decomposition of the 2-bromo acetylpyridine,
was a challenge. After treatment of the 2-bromo-acetyl pyridine-
hydrobromide 8 with triethylamine in situ, and removal of the
triethylamine hydrochloride salt from the solution, the unstable
2-bromo-(3-pyridyl) ethanone was immediately reduced
with 0.5 equiv of the spiroaminoborate 1 and BH3ꢁDMS. The
(S)-2-bromohydrin-1-3-pyridyl-borane complex 9 was isolated as
a stable compound, which after acidic hydrolysis and subsequent
NaOH treatment, gave pure (S)-pyridyl epoxide 4j in 72% yield
and with excellent enantiopurity (95% ee).
We then proceeded to study the regio- and enantioselectivity of
the ring opening reaction of the prepared enantiopure (S)-oxiranes
4a-k, shown in Table 2, with sodium azide in hot water. Optimal
conditions were obtained by stirring a suspension of the epoxide
(2 mmol) and sodium azide (4 mmol) in distilled water (10 mL)
and heating the mixture at 60 °C. The reaction was usually com-
plete in less than 4 h, as indicated by TLC. Except for (S)-epoxides
4c, the main isolated products were the (R)-2-azido-2-aryl etha-
nols 5, formed by the attack of the azide anion to the benzylic posi-
tion, with almost complete inversion of configuration and with
only a minor amount of the regioisomer 6, as determined by GC–
MS or 1H NMR analysis of the crude product. The regio- and stere-
ochemistry of the azido ethanols was confirmed by HPLC analysis
on a Chiralpak AD-H column and by the specific rotation of the
pure isolated products or derivatives. The regioselectivity for the
ring-opening of 4-nitrostyrene oxide 4c (entry 3) decreased sub-
stantially, giving the azido alcohols 5c and 6c in 67% and 33% ratio,
respectively, with modest enantioselectivity (73% ee) of 5c. It
seems that the strong electron-withdrawing effect of the p-NO2
group plays a detrimental role in the enantio- and regioselectivity
of the reaction, while for the other halogen substituted aromatic
compounds 5b, 5d, and 5h, it had a mild effect. The regioselectivity
for the azide ring-opening reaction of 3-pyridyl epoxide 4j was
modest, observing a 70:30 ratio for the 1,2-azido-1-ethanols 5j/6j
(entry 10a), while (R)-2-azido-2-pyridyl-1-ethanol 5j was obtained
with excellent enantiopurity (95% ee). However, the opposite
regioselectivity was observed for the pyridyl epoxide–BH3 complex
4j⁄ (entry 10b), producing the 1,2-azido ethanols 5j/6j in a 30:70
ratio (entry 10b), due to the positive charge on the pyridyl nitro-
gen. Finally, as expected, the N3ꢀ addition to the (S)-adamantyl oxi-
rane 4k afforded the enantiopure (S)-1,2-azido ethanol 6k, as
indicated by 1H and 13C NMR. Nevertheless, since the NMR signals
for the two regioisomers are very similar, the structure of the azido
alcohol 6k was evidenced by X-ray analysis of the corresponding
acetamide derivative 11k0, shown in Figure 2. In general, after
purification by column chromatography and/or preparative TLC
(Table 2), the (R)-2-azido-2-aryl-ethanols 5 and the (S)-1-adaman-
tyl-2-azido ethanol 6k were obtained in good to excellent yields
and with excellent enantiomeric purity, as determined by HPLC
concern that racemization could occur by
a possible SN1
mechanism, with water acting as a Lewis acid.3c,16 To the best of
our knowledge, there are very limited studies on the synthesis of
nonracemic 2-azido-2-aryl-1-ethanols via uncatalyzed ring-
opening of enantiopure aryl oxiranes in hot water.
A series of highly effective aminoborate esters derived from
non-racemic amino alcohols, as shown in Figure 1, were previously
prepared in our laboratory for the enantioselective borane reduc-
tion of ketones and benzyloximes.17 Spiroaminoborate ester 1a,
derived from diphenyl prolinol and ethylene glycol, has been
demonstrated to be a highly stable and a convenient catalyst for
the borane reduction of a variety of aryl, heteroaryl, a-alkoxy and
aliphatic ketones providing the desired chiral secondary alcohols
with a CBS oxazaborolidine-like enantioselectivity.18 As illustrated
in Scheme 2, we recently reported a useful protocol for the borane-
mediated reduction of 2-haloketones
2 catalyzed by the
spiroaminoborate 1a to obtain enantiopure aryl and aliphatic (S)-
halohydrines 3, which upon subsequent cyclization with NaOH,
gave the corresponding chiral oxiranes 4.12 Preliminary studies of
the ring–opening of (S)-styryl and (S)-4-chlorostyryl epoxides with
sodium azide in water at 60 °C indicated the preferential formation
of (R)-2-azido-2-arylethanols 5, with almost complete inversion of
configuration at the benzylic position. Thus, it was of great interest
to examine the regio- and stereoselective ring-opening of repre-
sentative aryl, pyridyl, and adamantyl (S)-oxiranes (Scheme 2) by
sodium azide under neutral hydrolytic conditions. In addition, we
also report a facile, efficient, and environmentally benign method
for the reduction of the azides without racemization, which offers
a suitable alternative for the enantioselective synthesis of impor-
tant unnatural 1,2-amino alcohols and their corresponding Boc or
acetamide derivatives.
Ph
Ph
Ph
Ph
O
B
Ph
Ph
H2
N
H
H
O
O
O
O
B
O
B
O
OMe
O
B
HN
HN
O
N
O
OMe
H2
1c
1d
1a
1b
Figure 1. Aminoborate ester catalysts derived from non-racemic 1,2-amino
alcohols.
OH
O
O
NaOH, 2M
Cat. 1a
BH3.DMS, 0.7 eq
THF
X
X
R
R
R
R = Ar, Py, Adamantyl
4
3
2
N3
OH
O
R
NaN3
OH
N3
R
H2O, 60 o
C
R
5
6
R = Ar, Py, Adamantyl
4
Scheme 2. Synthesis and azidolysis of enantiopure (S)-epoxides.
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H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
Non-racemic epoxides (S)-4a–ka
O
O
b
O
b
O
O
Br
Cl
O2N
Br
4d
a
a
a
b
a
b
a
c
4a
4b
4c
(90% , 99% ee )
(89% , 99% ee )
(95% , 97% ee )
(91% , 99% ee )
4e
(96% , 99% ee )
O
O
O
O
MeO
MeO
4i
Me
F
a
c
a
c
4f
a
c
(75% , 98% ee )
d
e
4g
(87% , 98% ee )
4h
(90% , 99% ee )
(99% , 99% ee )
O
O
N
4j (72%a, 95%b ee)
4k (72%a, 99% eef)
a Isolated yield of purified product by flash chromatography.
b Enantiopurity determined by GC on chiral column (CP-Chirasil-Dex-CB).
c Determined by HPLC (Chiralcel AD-H) on the basis of b-azido alcohol.
d Crude product.
e Determined by HPLC (Chiralcel AD-H) of the chiral acetyl derivative of the b-bromo ethanol.
f Determined by HPLC (Chiralcel AD-H) of the chiral azido derivative 6k.
OH
O
O
O
Br
Br
42%
1. HCl (aq)
2. 2M NaOH
Br2/HBr
1. Et3N/THF
N
N
N
H
N
1
2. Cat (50 mol %)
Br
BH3.DMS, 2 eq
BH3
4j (72%, 95% ee)
8
7
9
Scheme 3. Synthesis of (S)-3-pyridyl epoxide 4j.
analysis (>95% ee). Remarkably, no 1,2-diols were detected in this
epoxide ring opening reaction in hot water.15f
excellent chemical yield. Remarkably, this regio- and stereoselec-
tive ring-opening reaction takes place via an SN2 type mechanism,
hot water acting as a very weak Lewis acid.15 As expected, the ring
opening of adamantyl oxirane takes places at the less hindered
position producing (S)-1-adamantyl-2-azido ethanol in excellent
yield and with high enantiopurity. This novel regio- and enantios-
elective conversion of non-racemic oxiranes to 1,2-azido alcohols
under mild and environmental favorable conditions provides an
easy and rapid access to the synthesis of enantiopure 1,2-amino-
ethanols, suitable for the preparation of important biological active
drugs.20 Furthermore, considering the convenience and efficiency
of this route, this methodology allow us a new facile way for the
Over the past several years, important advances have been
made toward the synthesis of primary amine via the reduction of
azides.14,21–24 Generally, azides are reduced by hydrogen catalyzed
by Pd/C,21 sodium borohydride catalyzed by metal catalysts,22
PPh3/H2O (Staudinger reaction),14b,23 and LiAlH4.24 The Staudinger
reaction was selected to reduce the N3 group of the enantiopure
azido alcohols due to the facile and mild reaction conditions
required to prevent racemization. Initially, enantiopure 1,2-azido
alcohols 5 and 6 were reacted with PPh3/H2O in THF at room tem-
perature overnight. In some cases, the reaction mixture was heated
at 70 °C for 2 h.23 As shown in Table 3, the b-amino alcohols 10
were obtained in excellent yields and with high enantiomeric pur-
ity, up to 99% ee, as determined by HPLC analysis on a chiral col-
umn based on the Boc derivatives 11, which were prepared in
excellent yield (>90%) according to the method reported in the
literature.25
synthesis of enantiopure aromatic
-amino acids in the future.
a-amino aldehydes and
a
4. Experimental
4.1. General
3. Conclusion
Common solvents were dried and distilled by standard proce-
dures. All reagents were obtained commercially unless otherwise
noted. Air- and moisture sensitive reactions were carried out in
dried glassware under an N2 atmosphere. Chromatographic purifi-
cation of products was accomplished using flash chromatography
on a Merck silica gelÒ Si 60 Ǻ (200–400 mesh). 1H and 13C spectra
were recorded on a Bruker Avance 400 MHz NMR spectrometer.
In conclusion, we have demonstrated that the ring–opening of
enantiopure (S)-styryl and pyridyl oxiranes by NaN3 in hot water
takes place via nucleophilic attack, preferentially at the internal
carbon of the aromatic monosubstituted epoxides providing the
(R)-2-azido-2-aryl-ethanols as the main product with complete
inversion of configuration (up to 99% ee) and with good to
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H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 2
Ring–opening of (S)-epoxides 4 with NaN3 in hot water
OH
N3
O
NaN3
R
OH
N3
H2O, 60 o
C
R
R
4
6
5
R = Ar, Py, Adamantyl
Entry Epoxide 4 Major 1,2-azido alcohol
5/6a (%) Yieldb (%) eec (%)
N3
OH
1
2
4a
4b
>99
>95
91
88
99d
99d
5a
N3
Figure 2. X-ray structure of the (S)-1-(1-adamantyl)-2-acetamido-1-ethanol 11k0.
OH
5890 equipped with
(30 m ꢂ 0.25 mm ꢂ 0.25
a
Chrompack Chiralsil-Dex-CB column
Cl
5b
lm). Chiral HPLC analysis was processed
N3
on an Agilent 1100 system Series 200 equipped with CHIRALPAK
AD-H column and UV detector working at 254 nm and 220 nm.
IR spectra were taken with a Perkin Elmer spectrophotometer fit-
ted with ATR (Diamond/ZnSe) accessory. Optical rotation measure-
ments were conducted using a Pekin Elmer digital polarimeter
Model 341.
OH
73 5c
90 6c
3
4
4c
67/33
>94
50
91
O2N
5c
N3
OH
4d
97
4.2. Synthesis of oxiranes
Br
Br
5d
OH
5e
N3
4.2.1. Typical method for the enantioselective synthesis of enan-
tiopure epoxides: Synthesis of (S)-2-bromo-(40-methoxyphenyl)
ethanol 3i and subsequent epoxidation to obtain the epoxide-
4i12a,26
5
6
4e
4f
>90
>99
87
88
99
95
N3
In a dry 50 mL round bottomed flask at room temperature and
under an N2 atmosphere was placed the spiroaminoborate ester of
diphenylprolinol 1a (EG-DPP) (0.323 g, 1 mmol) and dissolved in
freshly distilled THF (10 mL). Next, BH3ꢁDMS in THF (0.70 mL,
10 M, 7 mmol) was added to the solution via syringe, and the mix-
ture was stirred for 1 h. Next, 2-bromo-(40-methoxy)-acetophe-
none (2.29 g, 10 mmol) in dry THF (5 mL) was slowly added to
the flask using an injection pump for 1 h, and then the mixture
was stirred for 1 h at room temperature. The reaction mixture
was cooled at 0 °C and quenched by the slow addition of MeOH
(5 mL). The solvents were removed in a rotor-evaporator under
vacuum at 35 °C and the colorless liquid was treated with a satu-
rated aqueous NH4Cl solution (10 mL) for 15 min. Next, the mix-
ture was extracted with diethyl ether (3 ꢂ 10 mL) and the
combined organic phases were washed with a brine solution
(15 mL), dried over Na2SO4, and concentrated under high vacuum
at 40 °C. Attempted purification of 3i by column chromatography
on silica gel failed due to the instability of the compound. The
crude alcohol was a colorless oil (2.23 g, 96%). 1H NMR (400 MHz,
CDCl3): d 3.58 (m, 2H), 3.84 (s, 3H), 4.88 (m, 1H), 6.94 (d, J = 8.8 Hz,
2H), 7.32 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 40.1,
55.4, 73.5, 114.1, 127.3, 132.7, 159.7.26b
OH
Me
5f
N3
MeO
OH
7
8
9
4g
4h
4i
95/5
>99
>99
81
92
83
99
99
99
5g
N3
OH
F
5h
N3
OH
MeO
N
5i
N3
OH
10a
4j
70/30
69e
95
5j
OH
N3
10b
11
4j⁄
4k
30/70
1/99
71e
85
—
N
O-Acetyl derivative of 2-bromo-(40-methoxyphenyl)ethanol: In a
10 mL vial was placed the alcohol 3i (20 mg), dry CH2Cl2 (2 mL),
Et3N (0.1 mL), acetic anhydride (0.1 mL), and a small DMAP crystal.
TLC analysis revealed that the acetate formation was complete
after 5 minutes of stirring at room temperature. Next, water
(2 mL) was added followed by saturated aqueous solution of
Na2CO3, while shaking until no more bubbling was observed. The
aqueous solution was extracted with diethyl ether (2 mL), the
organic phase concentrated under vacuum, and the crude acetate
was dissolved in isopropanol HPLC grade (1 mL). The enantiopurity
of the acetyl derivative of the (S)-isomer was 99% ee determined by
6j
OH
N3
99
6k
The ratio of 5 and 6 was determined by 1H NMR.
Isolated yield of azido alcohols purified by flash chromatography or preparative
a
b
TLC.
c
Enantiomeric excess determined by chiral HPLC analysis (Chiralpak AD-H).
Determined by chiral HPLC on Chiralcel AD-H of the Boc amino derivative.
Crude product.
d
e
HPLC: AD-H chiral column, hexane/isopropanol (95/5) with a
GC–MS analysis was processed on a Finnigan Trace GC/Polaris Q
Mass detector using a Restek RTX-5MS column. Chiral gas chro-
matography analysis was processed on a Hewlett Packard GC
23
1.0 mL/min flow, tR (12.96 min), 99.6, tR (15.55 min), 0.42. [
+34 (c 1.5, CHCl3); Lit.26a 23 = +36.7 (c 1.03, CHCl3), 98.5% ee.
[a]
D
a]
D
=
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H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Table 3
Synthesis of enantiopure 1,2-amino ethanols by reduction of the 1,2-azido ethanols using PPh3/H2O
N3
NHBoc
OH
NH2
OH
OH (Boc)2O, Et3N
THF, rt
PPh3 / H2O
THF, 70 oC
R
R
R
R = Ar, Py
10
11
5
OH
OH
OH
PPh3 / H2O
THF, 25 oC
AcCl, TEA, THF
NH2
N3
NHAc
Adam
Adam
Adam
6k
10k'
11k'
1,2-Azido ethanol
R
10a (%)
11b (%)
eec (%)
5a
5b
5d
5e
5f
5g
5h
5i
Ph
92
87
90
95
83
89
93
42
93
91
96
95
90
92
95
99
>99
>99
>99
99
>99
99
4-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
4-Me-C6H4
3-MeO-C6H4
4-F-C6H4
4-MeO-C6H4
3-Pyridyl
1-Adamantyl
>99
97
5j
6k
51
96 10k0
84d
89 11k0
95
96e
a
b
c
Isolated yield.
Purified by preparative TLC.
Determined by chiral HPLC analysis (Chiralcel AD-H) of 11.
d
e
Crude product.
Determined by chiral GC analysis of acetamide 11k0 on a CP-Chirasil-Dex CB column.
4.2.2. (S)-2-(4-Methoxyphenyl)oxirane 4i12b
(35 mL). The solution was cooled at 0 °C and triethylamine
(767 L, 5.5 mmol, 1.1 equiv) was added dropwise using a syr-
In a 50 mL round bottomed flask was placed alcohol 3i (2.24 g,
9.7 mmol), dissolved in dry acetone (20 mL) and treated with dry
K2CO3 (2.68 g, 19.4 mmol). The mixture was stirred vigorously at
room temperature until the reaction was complete as indicated
by TLC analysis. The solution was filtered, washed with acetone,
and the solvent removed under high vacuum. Oxirane 4i was
l
inge-infusion pump (30 min). This mixture was stirred for 30 min
and then decanted to remove the triethylamine hydrobromide salt.
The clear solution was transferred via a syringe to another flask
under nitrogen. Spiroborate 1a (EG-DPP) (807 mg, 2.5 mmol,
0.1 equiv) was placed in a dried flask under nitrogen and dissolved
in freshly distilled THF (30 mL). Next, BH3ꢁDMS (1.0 mL, 10 mmol,
2.0 equiv) was added dropwise to the catalyst solution and the
mixture was stirred at room temperature for 1 h. The pyridyl
ketone solution was added dropwise to a cold borane/catalyst solu-
tion at 0 °C using an infusion pump (1 h addition). The reaction
mixture was left stirring at room temperature overnight and then,
methanol (7 mL) was added dropwise to quench the reaction. After
the solvents were removed under reduced pressure, the reaction
mixture was diluted with 50 mL of ethyl acetate, transferred to a
separatory funnel, and the organic solution was washed with a sat-
urated aqueous solutions of NH4Cl (30 mL) and then brine (30 mL).
The organic phase was dried over Na2SO4, filtered, and concen-
trated under vacuum at room temperature. The crude mixture
was first purified by silica gel (40 g) column chromatography
(14.5 cm long ꢂ 1.5 cm diameter) using hexane/ethyl acetate (1:1
v/v) and 1.0% of Et3N as the mobile phase. Further purification by
preparative TLC silica gel (20 cm ꢂ 20 cm, 1500 micron) using hex-
ane/ethyl acetate (1:1 v/v) and Et3N (1.0%), gave compound 9 as a
bone white solid (1.12 g, 42%): mp 63–65 °C; 97% ee by GC of acetyl
derivate: CP-Chirasil-Dex column, tR (minor) = 28.64 min, (1.07%),
obtained as a clear unstable liquid (1.44 g, 99%); [
a
]
22 = ꢀ13.0 (c
D
3.3, CHCl3), Lit.12b
[
a]
20 = ꢀ26 (c 1, CHCl3) for 72% ee. 1H NMR
D
(400 MHz, CDCl3): d 2.85 (dd, J1 = 2.6 Hz, J2 = 5.6 Hz, 2H), 3.17
(dd, J1 = 4.0 Hz, J2 = 5.6 Hz, 2H), 3.85 (s, 3H), 3.87 (m, 1H), 6.93 (d,
J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d 51.0, 52.2, 55.3, 114.0, 126.9, 129.5, 159.7; MS m/z
(relative intensity): 150 MÅ+ (20%), 121 (100%), 91 (18%), 77 (14%).
4.2.3. Synthesis of 2-bromo-1-pyridin-3-yl-ethanone hydrobro-
mide 827a
In a two neck 100 mL round bottomed flask were placed
3-acetyl pyridine (5.0 mL, 47 mmol) and hydrogen bromide (15 mL,
48 wt %). The reaction mixture was heated at 80 °C and bromine
(2.5 mL, 50 mmol, 1.0 equiv) was added dropwise. After the mix-
ture was stirred for 1.5 h at 80 °C, it was allowed to cool to room
temperature, and then to 0 °C. Acetone (5 mL) was added dropwise
and a white solid precipitated, which was filtered using a Büchner
funnel. The crude sample was transferred to a flask and dried under
high vacuum to give as a bone white solid (9.42 g, 70%): mp 192–
193 °C; Lit.27b mp 195–198 °C. 1H NMR (400 MHz, DMSO-d6): d
4.83 (s, 2H), 7.51 (t, J = 6.6 Hz, 1H), 8.71 (d, J = 8.0 Hz), 9.01 (d,
tR (major) = 28.83 min, (98.9%). [a]
20 = +42 (c 1.5, CHCl3). 1H NMR
D
J = 5.2 Hz, 1H), 9.34 (s, 1H); FT-IR (ATR):
m
(cmꢀ1) 3281, 2585
(400 MHz, CDCl3): d 3.13 (s, 1H), 3.60 (dd, J1 = 7.6, J2 = 10.7 Hz,
1H), 3.71 (dd, J1 = 4.0 Hz, J2 = 10.7 Hz, 1H), 5.10 (dd, J1 = 4.0 Hz,
J2 = 7.6 Hz, 1H) 7.59 (dd, J1 = 5.8 Hz, J2 = 7.8 Hz, 1H), 8.04 (d,
J1 = 7.9 Hz, 1H), 8.62 (d, J = 5.6 Hz, 1H), 8.70 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 38.5, 60.5, 125.2, 136.9, 138.9, 145.7, 147.0;
11B NMR (CDCl3, 128 MHz) d ꢀ12 ppm (quart, J = 96 Hz, N-BH3);
(NH salt), 1709.
4.2.4. Synthesis of (S)-2-bromo-1-(pyridin-3-yl)ethanol N-borane
complex 928a
In a dried round bottomed flask under a nitrogen atmosphere
was placed 2-bromo-3-acetyl pyridine-HBr salt
8
(2.81 g,
FT-IR (ATR):
1157.
m
(cmꢀ1): 3462 (OH), 3009–2920, 2385 (BH3), 1629,
5.0 mmol, 1.0 equiv) and dissolved in freshly distilled THF
Please cite this article in press as: Wang, H.-Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2015.12.002

6
H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.2.5. (S)-3-(2-Oxiranyl)pyridine 4j12b,28b
4.3.3. (R)-2-Azido-2-(4-nitrophenyl)ethanol 5c31a,b
To a solution of (R)-2-bromo-1-(pyridin-3-yl)ethanol N-borane
complex 9 (709 mg, 3.28 mmol) in water (2 mL) and THF (2 mL)
at 0 °C, was added dropwise 1 M HCl aqueous solution (12 mL).
The mixture was stirred at room temperature for 2 h, diluted with
THF (10 mL), and stirred for 10 min. To the cooled mixture at 0 °C
was added a 2 M NaOH aqueous solution (20 mL) and the mixture
was stirred at room temperature for 3 h. The aqueous phase was
extracted with ethyl acetate (50 mL), washed with brine solution
(20 mL), dried over Na2SO4, filtered, and concentrated to obtain
an unstable brown oil (165 mg, 72%), 95% ee by HPLC analysis:
CHIRAL PAK-AD column, Hexane/IPA (88/12 v/v); flow 1.0 ml/
min: tR (minor) = 8.82 min, (2.3%), tR (major) = 10.57 min (97.7%).
Yellow oil (208 mg, 50%); 73% ee by HPLC analysis on Chiral-
pakÒ AD–H column, hexane/i-PrOH (90/10), 1.0 mL/min, 254 nm,
tR (major) = 15.46 min, tR (minor) = 21.95 min. [
a
]
22 = ꢀ111 (c 0.6,
D
CHCl3). 1H NMR (400 MHz, CDCl3): d 2.05 (t, J = 6.0 Hz, 1H), 3.80
(m, 2H), 4.80 (dd, J1 = 4.4, J2 = 7.6 Hz, 1H), 7.55 (m, 2H), 8.26 (m,
2H); 13C NMR (100 MHz, CDCl3): d 66.4, 66.8, 124.1, 128.1, 143.7,
148.1.
4.3.4. (S)-2-Azido-1-(4-nitrophenyl)ethanol 6c31c
Yellow solid (104 mg, 25%): mp 37–39 °C, Lit.31d mp 51–53; 90%
ee by HPLC analysis on ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 1.0 mL/min, 254 nm, tR (major) = 15.69 min, tR (minor)
[a
]
D
20 = +17 (c 4.17, CHCl3); Lit.28b
[a
]
D
25 = +18.3 (c 0.91, CHCl3),
= 14.42 min. [a]
22 = +76 (c 0.22, CHCl3). 1H NMR (400 MHz, CDCl3):
D
96% ee. 1H NMR (400 MHz, CDCl3): d 2.87 (dd, J = 2.8, J2 = 5.2 Hz,
1H), 3.23 (dd, J1 = 4.0, J2 = 5.2 Hz, 1H), 3.92 (d, J1 = 4.0, J2 = 5.2 Hz,
1H), 7.30 (m, 1H), 7.59, (m, 1H), 8.58 (dd, J1 = 1.6 Hz, J2 = 4.8 Hz,
2H); 13C NMR (CDCl3, 100 MHz): d 50.3, 51.0, 123.4, 132.7, 133.2,
147.8, 148.6.
d 2.54 (d, J = 3.6 Hz, 1H), 3.52 (m, 2H), 5.00 (m, 1H), 7.58 (m, 2H),
8.24 (m, 2H); 13C NMR (100 MHz, CDCl3): d 57.9, 72.5, 123.9,
126.8, 147.5.
4.3.5. (R)-2-Azido-2-(4-bromophenyl)ethanol 5d14b
White solid (441 mg, 91%); mp 99–100 °C; Lit.14b mp 110–
111 °C; 97% ee by HPLC analysis on ChiralpakÒ AD–H column,
hexane/i-PrOH (95:5), 0.5 mL/min, 254 nm, tR (major)
4.2.6. (S)-1-(Adamantan-1-yl)-2-bromo ethanol 3k12a
Colorless oil: (2.50 g, 97%): 1H NMR (400 MHz, CDCl3): d 1.00–
1.78 (m, 12H), 2.03 (s, 3H), 2.32 (br s, 1H), 3.36–3.54 (m, 2H),
3.76 (m, 1H); 13C NMR (100 MHz, CDCl3): d 28.0, 37.1, 37.4, 38.2,
38.3, 79.5.
= 23.62 min, tR (minor) = 29.92 min. [
a
]
22 = ꢀ373 (c 0.15, CHCl3);
D
Lit.14b
[a
]
D
22 = +188 (c 3.6, CHCl3), 99% ee by HPLC for the (S)-
configuration. 1H NMR (400 MHz, CDCl3): d 1.93 (dd, J1 = 5.6 Hz,
J2 = 7.2 Hz, 1H), 3.73 (m, 2H), 4.64 (dd, J1 = 5.2 Hz, J2 = 7.2 Hz, 1H),
7.23 (m, 2H), 7.52 (m, 2H); 13C NMR (100 MHz, CDCl3): d 66.4,
67.2, 122.8, 128.8, 132.2, 135.4.
4.2.7. (S)-2-(Adamantan-1-yl)oxirane 4k12a
Clear oil (1.28 g, 72%): >99% ee determined by chiral HPLC anal-
ysis of the 2-phenoxy ethanol derivative (90:10 hexane/i-PrOH,
4.3.6. (S)-2-Azido-1-(4-bromophenyl)ethanol 6d15f
0.5 mL min, 254 nm):
[a]
20 = +16 (c 1.4, CHCl3). 1H NMR
D
20
Yellow oil (28 mg, 6%); [
a
]
D
22 = +58 (c 0.28, CHCl3); Lit.15g
[
a]
=
D
(400 MHz, CDCl3): d 1.56 (s, 6H), 1.70 (m, 6H), 2.02 (br s, 3H),
2.62 (m, 2H), 2.70 (m, 1H); 13C NMR (100 MHz, CDCl3): d 28.0,
32.2, 37.0, 38.4, 43.0, 60.5. MS (m/z, relative intensity): 178 MÅ+
(14%), 163 (6%), 148 (52%), 135 (70%), 119 (32%), 106 (68%), 91
(100%), 79 (60%).
+61.3 (c 0.67, CH3OH). 1H NMR (400 MHz, CDCl3): d 2.51 (s, 1H),
3.43 (m, 2H), 4.83 (dd, J1 = 5.2 Hz, J2 = 6.8 Hz, 1H), 7.25 (m, 2H),
7.48 (m, 2H); 13C NMR (100 MHz, CDCl3): d 57.9, 72.7, 122.2,
127.6, 131.8, 139.5.
4.3.7. (R)-2-Azido-2-(3-bromophenyl)ethanol 5e32
4.3. General procedure for the synthesis of enantiopure azido
alcohols 5a–i
Colorless solid (421 mg, 87%);>99% ee by HPLC analysis on
ChiralpakÒ AD–H column, hexane/i-PrOH (95:5), 0.3 mL/min,
22
254 nm, tR (major) = 37.87 min, tR (minor) = 39.42 min.; [
a]
=
D
ꢀ174 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3):
d 1.95
To a stirred suspension of the enantiopure epoxides 4 (2 mmol)
in distilled water (10 mL) was added sodium azide (4 mmol,
260 mg). The mixture was stirred for 3.5 h at 60 °C, then cooled
at room temperature, and 20 mL of water was added. The aqueous
phase was extracted with ethyl acetate (2 ꢂ 15 mL) and the com-
bined organic phase was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The pure products were
obtained by preparative TLC.
(t, J = 5.6 Hz), 3.73 (m, 2H), 4.64 (dd, J1 = 4.8 Hz, J2 = 8.0 Hz, 1H),
7.25 (m, 2H), 7.48 (m, 2H); 13C NMR (100 MHz, CDCl3): d 66.5,
67.1, 123.1, 125.8, 130.2, 130.5, 131.9, 138.7.
4.3.8. (S)-2-Azido-1-(3-bromophenyl)ethanol 6e33
Yellow oil (42 mg, 8%); [a]
22 = +125 (c 0.2, CHCl3). 1H NMR
D
(400 MHz, CDCl3): d 2.63 (s, 1H), 3.43 (m, 2H), 4.81 (dd, J1 = 5.2,
J2 = 6.8 Hz, 1H), 7.25 (m, 2H), 7.43 (m, 1H), 7.52 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 57.9, 72.7, 122.8, 124.5, 129.1, 130.3, 131.4,
142.8.
4.3.1. (R)-2-Azido-2-phenylethanol 5a29
Colorless oil (297 mg, 91%); 99% ee by HPLC analysis based on
the Boc derivative 8a on ChiralpakÒ AD-H, hexane/i-PrOH
(90:10), 0.8 mL/min, 254 nm, tR (R) = 12.14 min, tR (S)
4.3.9. (R)-2-Azido-2-(p-tolyl)ethanol 5f34
= 11.32 min. [
a
]
22 = ꢀ268 (c 0.7, CHCl3); Lit.29
[
a
]
20 = ꢀ221.1 (c
White solid (312 mg, 88%); mp 42–43 °C; 95% ee by HPLC anal-
ysis on ChiralpakÒ AD–H column, hexane/i-PrOH (95:5), 0.8 mL/
min, 254 nm, tR (major) = 12.98 min, tR (minor) = 16.68 min;
D
D
1.35, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.98 (t, J = 6.8 Hz, 1H),
3.74 (m, 2H), 4.67 (t, J = 6.8 Hz, 1H), 7.32–7.42 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 66.5, 67.9, 127.2, 128.8, 129.0, 136.3.
[
a
]
22 = ꢀ190 (c 0.3, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.91 (t,
D
J = 6.4 Hz, 1H), 2.36 (s, 3H), 3.73 (t, J = 6.4 Hz, 2H), 4.64 (t,
J = 6.4 Hz, 1H), 7.19–7.25 (m, 4H); 13C NMR (100 MHz, CDCl3): d
66.5, 67.7, 127.2, 129.7, 133.2, 138.7.
4.3.2. (R)-2-Azido-2-(4-chlorophenyl)ethanol 5b30
White solid (348 mg; 88%); mp 74–76 °C; 98% ee by HPLC anal-
ysis based on compound 8b on ChiralpakÒ AD–H, hexane/i-PrOH
(90:10), 0.5 mL/min, 254 nm, tR (major) = 18.87 min, tR (minor)
4.3.10. (R)-2-Azido-2-(3-methoxyphenyl)ethanol 5g35
= 13.67 min. [
a
]
22 = ꢀ151 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
Colorless oil (313 mg, 81%) yield; >99% ee by HPLC analysis on
D
ChiralpakÒ AD-H column, hexane/i-PrOH (98.5:1.5), 0.8 mL/min,
d 1.93 (br s, 1H), 3.72 (d, J = 5.2 Hz, 2H), 4.65 (dd, J1 = 5.2,
J2 = 7.6 Hz, 1H), 7.27 (m, 2H), 7.36 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 66.4, 67.1, 128.5, 129.2, 134.7, 134.9.
22
254 nm, tR (major) = 58.87 min, tR (minor) = 62.13 min.; [
a]
=
D
ꢀ200 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3):
d 1.95
Please cite this article in press as: Wang, H.-Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2015.12.002

H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
(t, J = 6.4 Hz, 1H), 3.75 (m, 2H), 3.83 (s, 3H), 4.64 (m, 1H), 6.90 (m,
3H), 7.30 (m, 1H); 13C NMR (100 MHz, CDCl3): d 55.3, 66.5, 67.8,
112.9, 114.1, 119.4, 130.1, 137.8, 160.0.
(21 mg, 22%). HPLC analysis on Chiralcel OD-H column, hexanes/
i-PrOH (90:10); 0.8 mL/min: tR (minor) = 20.3 min (49.62%), tR
(major) = 23.9 min (50.4%). 1H NMR (400 MHz, CDCl3) d 3.46–
3.56 (m, 2H), 4.96 (dd, J1 = 4.6, J2 = 7.0 Hz, 1H), 7.36 (dd, J1 = 5.4,
J2 = 7.8 Hz, 1H), 7.81 (dd, J1 = 1.8, J2 = 7.8 Hz, 1H), 8.54 (s, 1H),
8.58 (s, 1H).
4.3.11. (S)-2-Azido-1-(3-methoxyphenyl)ethanol 6g15f,31c
Yellow oil (15 mg, 4%); [a]
22 = +78 (c 0.15, CHCl3). 1H NMR
D
(400 MHz, CDCl3): d 2.52 (s, 1H), 3.43 (m, 2H), 3.81 (s, 3H), 4.83
(dd, J1 = 4.0, J2 = 8.0 Hz, 1H), 6.84 (m, 1H), 6.92–6.93 (m, 2H), 7.26
(m, 1H); 13C NMR (100 MHz, CDCl3): d 55.3, 58.1, 73.4, 111.5,
113.8, 118.2, 129.8, 142.3, 159.9.
4.3.17. (S)-2-(Adamantan-1-yl)-2-azidoethan-1-ol 6k
Colorless oil (1.15 g, 85%, based in 2.0 mmol of epoxide); 99.5%
ee by HPLC analysis on ChiralpakÒ AD-H column, hexane/i-PrOH
gradients (98:2 to 90:10), 0.5 mL/min, 220 nm, tR (major) =
4.3.12. (R)-2-Azido-2-(4-fluorophenyl)ethanol 5h34
13.94 min, tR (minor) = 12.54 min. [
a
]
20 = ꢀ18 (c 1.1, MeOH). 1H
D
Colorless oil (333 mg, 92%); >99% ee by HPLC analysis: ChiralpakÒ
AD–H column, hexane/i-PrOH (90:10), 0.5 mL/min, 254 nm, tR
NMR (400 MHz, CDCl3): d 1.58–1.71 (m, 12H), 2.05 (s, 3H), 3.35
(m, 2H). 3.48 (d, J = 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
28.20, 36.06, 37.07, 38.05, 52.94, 78.68; MS (m/z): 192, 165
(100), 147, 135, 119, 105, 91, 79; FT-IR ATR:
2899, 2093, 1070.
(major) = 12.76 min, tR (minor) = 14.08 min; [
a
]
22 = ꢀ182 (c 0.8,
D
CHCl3). 1H NMR (400 MHz, CDCl3): d 1.95 (t, J = 6.4 Hz, 1H), 3.73
(m, 2H), 4.66 (dd, J1 = 5.6, J2 = 6.8 Hz, 1H), 7.06–7.12 (m, 2H),
7.29–7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d 66.5, 67.1,
115.9, 116.1, 128.9, 129.0, 132.1, 132.2, 162.8 (d, JC-F = 250 Hz).
m
(cmꢀ1) 3388,
4.4. General procedure for the synthesis of the non-racemic 1,2-
aminoalcohols
4.3.13. (R)-2-Azido-2-(4-methoxyphenyl)ethanol 5i35
White solid (892 mg, 48%); mp 105–107 °C, Lit.35 mp 110–
112 °C; 98% ee by HPLC analysis on a ChiralpakÒ AD-H column,
hexane/i-PrOH/Et2NH (95:5:0.05), 0.8 mL/min, 280 nm, tR
(minor) = 21.8 min, (0.98%), tR (major) = 18.5 min (99.02%).
To a solution of 1,2-azido alcohol 5 (1 mmol) in THF (5 mL) was
added triphenylphosphine (393 mg, 1.5 mmol) and water (360 mg,
20 mmol). The mixture was heated at 70 °C for 1–2 h until TLC
analysis showed that the reaction was complete. Next, the mixture
was concentrated under vacuum and purified by preparative TLC to
afford the desired product.
[
a
]
22 = ꢀ148.0 (c 2, MeOH). 1H NMR (400 MHz, CDCl3): d 2.08 (t,
D
J = 6.4 Hz, 1H), 3.78 (m, 2H,), 3.87 (s, 3H), 4.66 (t, J = 6.4 Hz, 1H),
6.94 (d, 2H), 7.25 (d, 2H); 13C NMR (100 MHz, CDCl3): d 55.3,
66.4, 67.4, 114.4, 128.5, 132.04, 159.9.
4.4.1. (R)-2-Amino-2-phenylethanol 10a37
Pale yellow solid (126 mg, 92%), mp 75–77 °C; Lit.37a mp 76–
79 °C; >99% ee by HPLC of carbamate 11a on a ChiralpakÒ AD-H
column, hexane/i-PrOH (90:10), 0.8 mL/min, 254 nm, tR(major)
4.3.14. (R)-2-Azido-2-(3-pyridyl)ethanol 5j
Light yellow oil (74 mg, 41%): 95% ee by HPLC analysis on a
ChiralpakÒ AD–H, column; hexane/i-PrOH (88:12), 1.0 mL/min, tR
= 12.14 min, tR(minor) = 11.32 min. [
a
]
22 = ꢀ62 (c 0.2, CHCl3). 1H
D
(minor) = 11.06 min, tR (major) = 12.69 min. [
a
]
20 = ꢀ194 (c 3.2,
NMR (400 MHz, CDCl3): d 2.32 (s, 3H), 3.55 (dd, J = 8.4, 10.4 Hz,
1H), 3.73 (dd, J = 4.0, 10.8 Hz, 1H), 4.05 (dd, J = 4.4, 8.0 Hz, 1H),
7.27–7.37 (m, 5H); 13C NMR (100 MHz, CDCl3): d 57.4, 67.9,
126.5, 127.6, 128.7, 142.6.
D
CHCl3). 1H NMR (400 MHz, CDCl3): d 2.28 (s, 1H) 3.86 (m, 2H),
4.76 (dd, J1 = 5.2 Hz, J2 = 7.2 Hz, 1H), 7.39 (ddd, J1 = 0.6, J2 = 4.8,
J3 = 7.8 Hz, 1H), 7.75 (dt, J1 = 2.0, J2 = 8.0 Hz, 1H), 8.65 (d, J = 1.6,
J2 = 5.2 Hz, 1H), 8.66 (d, J1 = 1.6, J2 = 5.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 65.1, 66.1, 123.9, 135.3, 148.2, 149.3; FT-IR
4.4.2. (R)-2-Amino-2-(4-chlorophenyl)ethanol 10b38
(ATR):
m
(cmꢀ1
)
3192.8, 2091.2, 1596–1598, 1426.9, 1257.1,
White solid (149 mg, 87%); mp 72–73 °C; 99% ee by HPLC of car-
bamate 11b on a ChiralpakÒ AD-H column, hexane/i-PrOH (90:10),
0.5 mL/min, 254 nm, tR (major) = 18.87 min, tR (minor)
1073.8. H RMS [M+H] calc. C7H8N4O 165.0771, [M+H], found
165.0766.
= 13.62 min. [
a
]
22 = ꢀ68 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3):
D
4.3.15. (S)-2-Azido-1-(pyridin-3-yl)ethanol 6j
d 2.27 (s, 3H), 3.52 (dd, J = 8.0, 10.8 Hz, 1H), 3.70 (dd, J = 4.4,
10.8 Hz, 1H), 4.04 (dd, J = 4.4, 8.0 Hz, 1H), 7.26–7.32 (m, 4H); 13C
NMR (100 MHz, CDCl3): d 56.8, 67.9, 127.9, 128.8, 133.2, 141.0.
Light yellow oil (30 mg, 17%), [a]
20 = +132 (c 1.4, CHCl3), 62% ee
D
by HPLC on a Chiralcel OD-H column, hexanes/i-PrOH (90:10):
0.8 mL/min, tR (minor) = 19.1 min (19.1%), tR (major) = 23.2 min
(80.9%). 1H NMR (400 MHz, CDCl3); d 3.46–3.56 (m, 2H), 4.96
(dd, J1 = 4.6, J2 = 7.0 Hz, 1H), 7.36 (dd, J1 = 5.4, J2 = 7.8 Hz, 1H),
7.81 (dd, J1 = 1.8, J2 = 7.8 Hz, 1H), 8.54 (s, 1H), 8.58 (s, 1H). 13C
NMR (100 MHz, CDCl3): d 57.8, 71.0, 123.7, 132.4, 136.8, 147.5,
149.1.
4.4.3. (R)-2-Amino-2-(4-bromophenyl)ethanol 10d14b
Pale yellow solid (194 mg, 90%); mp 70–73 °C; >99% ee by HPLC
of carbamate 11d on a ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 0.5 mL/min, 254 nm, tR (major) = 23.18 min, tR (minor)
= 15.34 min. [
a
]
22 = ꢀ62 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3):
D
d 2.47 (s, 3H), 3.54 (dd, J = 8.0, 10.8 Hz, 1H), 3.73 (dd, J = 4.0,
10.8 Hz, 1H), 4.05 (dd, J = 4.4, 8.0 Hz, 1H), 7.21–7.24 (m, 2H),
7.46–7.49 (m, 2H); 13C NMR (100 MHz, CDCl3): d 56.7, 67.6,
121.5, 128.3, 131.8, 141.1.
4.3.16. rac-2-Azido-2-(pyridin-3-yl)ethan-1-ol 6j
The racemic epoxide–N-BH3-complex 9 (70 mg, 0.58 mmol.
1.0 equiv) was dissolved in water (20 ml). The mixture was heated
at 65 °C for 1 h. Sodium azide (43 mg, 0.66 mmol, 4.0 equiv) was
added portionwise. The mixture was heated at 60 °C under stirring
and the reaction progress was monitored by TLC. After 4 h the reac-
tion was completed and the mixture was transferred into a separa-
tory funnel and the aqueous phase was extracted with ethyl
acetate (3 ꢂ 15 mL). The organic phase was washed with brine
(15 mL) dried over Na2SO4, filtered, and concentrated to obtain a
brown oil (70 mg, 71% yield). The crude product was purified by
preparative TLC (20 ꢂ 20 cm plates, 1500 microns silica gel) using
hexane/ethyl acetate (1:4) and 0.4% of Et3N as a light yellow oil
4.4.4. (R)-2-Amino-2-(3-bromophenyl)ethanol 10e39
Pale yellow oil (205 mg, 95%); 99% ee by HPLC of carbamate
analysis 11e on
a
ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 0.5 mL/min, 254 nm, tR (major) = 23.72 min, tR (minor)
= 17.08 min.; [
a
]
22 = ꢀ51 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3):
D
d 2.09 (s, 3H), 3.54 (dd, J = 8.0, 10.8 Hz, 1H), 3.73 (dd, J = 4.0,
10.4 Hz, 1H), 4.04 (dd, J = 4.0, 7.6 Hz, 1H), 7.19–7.27 (m, 2H),
7.39–7.42 (m, 1H), 7.50 (s, 1H); 13C NMR (100 MHz, CDCl3): d
56.9, 67.8, 122.8, 125.3, 129.7, 130.2, 130.7.
Please cite this article in press as: Wang, H.-Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2015.12.002

8
H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.4.5. (R)-2-Amino-2-(p-tolyl)ethanol 10f40
Pale yellow solid (126 mg, 83; mp. 68–71 °C;>99% ee by HPLC of
carbamate 11f on a ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 0.5 mL/min, 254 nm, tR (major) = 19.75 min, tR (minor) =
(126.5 mg, 1.25 mmol). The reaction was stirred at room temper-
ature for about 1–2 h until the TLC analysis showed that the
reaction was complete. The mixture was concentrated under
vacuum and purified by preparative TLC to afford the desired
products.
16.03 min. [
a
]
22 = ꢀ50 (c 0.09, CHCl3); Lit.40
[a]
20 = +26 (c 1.0,
D
D
EtOH) for the (S)-configuration. 1H NMR (400 MHz, CDCl3): d 1.99
(s, 3H), 2.34 (s, 3H), 3.54 (dd, J = 8.4, 10.8 Hz, 1H), 3.73 (dd,
J = 4.0, 10.8 Hz, 1H), 4.01 (dd, J = 4.4, 8.0 Hz, 1H), 7.16 (d,
J = 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 21.1, 57.0, 68.0, 126.3, 129.3, 137.2, 139.8.
4.5.1. (R)-tert-Butyl (2-hydroxy-1-phenylethyl)carbamate 11a25
White solid, (110 mg, 93%); mp 133–135 °C; Lit.25 mp. 138–
140 °C; >99% ee by chiral HPLC analysis on ChiralpakÒ AD-H col-
umn, hexane/i-PrOH (90:10), 0.8 mL/min, 254 nm, tR (major)
= 12.14 min, tR (minor) = 11.32 min.; [
a
]
22 = ꢀ35 (c 0.33, CHCl3);
D
4.4.6. (R)-2-Amino-2-(3-methoxyphenyl)ethanol 10g41
Colorless oil (149 mg, 89%); 99% ee by HPLC of carbamate 11g
on a ChiralpakÒ AD-H column, hexane/i-PrOH (90:10), 0.5 mL/
min, 254 nm, tR (major) = 31.13 min, tR (minor) = 23.18 min;
Lit.25
[
a]
24 = ꢀ39.2 (c 3.05, CHCl3). 1H NMR (400 MHz, CDCl3): d
D
1.43 (s, 9H,), 2.30 (s, 1H), 3.85 (m, 2H), 4.78 (m, 1H), 5.21 (d,
J = 4.8 Hz, 1H), 7.27–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3): d
28.3, 57.1, 66.9, 80.0, 126.6, 127.8, 128.9, 154.6.
[
a
]
22 = ꢀ39 (c 0.09, CHCl3); Lit.41b for the (S)-isomer [
a]
20 = +36 (c
D
D
0.6, CHCl3) for 99% ee; 1H NMR (400 MHz, CDCl3): d 2.65 (s, 3H),
3.54 (dd, J = 8.4, 10.8 Hz, 1H), 3.72 (m, 1H), 3.79 (s, 3H), 4.00 (m,
1H), 6.78–6.81 (m, 1H), 6.88–6.90 (m, 2H), 7.22–7.26 (m, 1H);
13C NMR (100 MHz, CDCl3): d 55.2, 57.4, 67.8, 112.4, 112.7, 118.8,
129.6, 159.8.
4.5.2. (R)-tert-Butyl (1-(4-chlorophenyl)-2-hydroxyethyl)carba-
mate 11b
White solid (124 mg, 91%); mp 136–138 °C; >99% ee by HPLC
analysis on a ChiralpakÒ AD-H column, hexane/i-PrOH (90:10),
0.5 mL/min, 254 nm, tR (major) = 18.87 min, tR (minor) =
13.62 min). [
a
]
22 = ꢀ48 (c 0.1, CHCl3). 1H NMR (400 MHz, CDCl3):
D
4.4.7. (R)-2-Amino-2-(4-methoxyphenyl)ethanol 10i36
d 1.43 (s, 9H), 2.04 (s, 1H), 3.83 (m, 2H), 4.74 (m, 1H), 5.21 (m,
1H), 7.23–7.26 (m, 2H), 7.31–7.35 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 28.3, 56.4, 66.5, 80.2, 127.9, 128.9, 133.6, 138.5, 156.1.
White solid (0.172 g, 21%); mp 95–98 °C (dichoromethane),
Lit.36 92–93 °C; 97% ee by HPLC analysis of the cyclic carbamate
derivative 11i on a ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 0.8 mL/min, 254 nm, tR (major) = 17.8 min (98.3%), tR
4.5.3. (R)-tert-Butyl (1-(4-bromophenyl)-2-hydroxyethyl)carba-
mate 11d43
(minor) = 15.3 min (1.7%).
[
a
]
20 = ꢀ16 (c 2, MeOH). 1H NMR
D
(400 MHz, CDCl3): d 2.41 (br s, 3H), 3.56 (m, 1H), 3.72 (m, 1H),
3.83 (s, 3H), 4.03 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.28 (d,
J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 55.3, 56.8, 68.0,
114.0, 127.6, 134.8, 150.0; MS (m/z): 136 (100%), 121 (12%), 109
(78%), 94 (48%), 77 (14%).
White solid (152 mg, 96%); mp 153–155 °C; >99% ee by HPLC on
a ChiralpakÒ AD-H column, hexane/i-PrOH (90:10), 0.5 mL/min,
254 nm,
tR
(major) = 23.18 min,
tR
(minor) = 15.34 min.
[a]
22 = ꢀ56 (c 0.31, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.43 (s,
D
9H), 2.03 (s, 1H), 3.85 (m, 2H), 4.73 (m, 1H), 5.23 (m, 1H), 7.18–
7.20 (m, 2H), 7.46–7.50 (m, 2H); 13C NMR (100 MHz, CDCl3): d
28.3, 53.9, 66.7, 80.1, 126.1, 128.3, 131.9, 137.8, 156.2.
4.4.8. (R)-2-Amino-2-(4-fluorophenyl)ethanol 10h42
Pale yellow solid (144 mg, 93%); mp 87–89 °C; >99% ee by HPLC
analysis of carbamate 11h on a ChiralpakÒ AD-H column, hexane/
i-PrOH (90:10), 0.5 mL/ min, 254 nm, tR (major) = 19.32 min, tR
4.5.4. (R)-tert-Butyl [1-(3-bromophenyl)-2-hydroxyethyl]carba-
mate 11e44
(minor) = 14.70 min.;
[
a]
22 = ꢀ58 (c 0.3, CHCl3). 1H NMR
Pale yellow solid (150 mg, 95%); mp 91–93 °C; 99% ee by HPLC
analysis on a ChiralpakÒ AD–H column, hexane/i-PrOH (90:10),
0.5 mL/min, 254 nm, tR (major) = 23.72 min, tR (minor) =
D
(400 MHz, CDCl3): d 1.93 (s, 3H), 3.52 (dd, J = 8.4, 10.8 Hz, 1H),
3.72 (dd, J = 4.0, 10.4 Hz, 1H), 4.05 (dd, J = 4.4, 8.0 Hz, 1H), 7.01–
7.06 (m, 2H), 7.28–7.33 (m, 2H); 13C NMR (100 MHz, CDCl3): d
56.6, 68.1, 115.4, 115.6, 128.0, 128.1, 162.5 (d, JC–F = 250 Hz).
17.08 min).; [
a
]
22 = ꢀ38 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3):
D
1.43 (s, 9H), 3.85 (m, 2H), 4.73 (m, 1H), 5.36 (m, 1H), 7.20–7.25 (m,
2H), 7.39–7.42 (m, 1H), 7.450 (s, 1H); 13C NMR (100 MHz, CDCl3): d
28.3, 56.2, 66.3, 80.2, 122.8, 125.3, 129.7, 130.3, 130.8, 155.9.
4.4.9. (R)-2-Amino-2-(pyridin-3-yl)ethanol 10j
Yellow oil (21 mg, 51%); 95% ee by HPLC analysis of carbamate
11j on a ChiralpakÒ AD-H column, hexane/IPA (88:12), flow 0.8 ml/
min, tR (minor) = 14.43 min 2.5%, tR (major) = 16.45 min (97.4%).
4.5.5. (R)-tert-Butyl [2-hydroxy-1-(p-tolyl)ethyl]carbamate
11f43
[a
]
D
20 = ꢀ40 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): d 2.07 (s,
White solid (113 mg, 90%); mp 107 = –109 °C;>99% ee by chiral
HPLC analysis on a ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 0.5 mL/min, 254 nm, tR (major) = 19.75 min, tR (minor)
3H), 3.80 (m, 1H), 3.65 (m, 1H), 4.17 (m, 1H), 7.32 (q, J = 4.0 Hz,
1H), 7.76 (dt, J = 2.0 Hz, J = 4.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 2H).
= 16.03 min). [
a
]
22 = ꢀ77 (c 0.12, CHCl3). 1H NMR (400 MHz,
D
4.4.10. (S) 1-(Adamantan-1-yl)-2-aminoethanol 10k0
CDCl3): 1.43 (s, 9H), 2.34 (s, 3H), 3.83 (m, 2H), 4.75 (m, 1H), 5.15
(m, 1H), 7.18 (m, 4H); 13C NMR (100 MHz, CDCl3): d 21.1, 28.4,
57.0, 69.7, 80.0, 126.5, 129.5, 136.4, 137.8, 156.5.
White solid (0.95 mg, 96%); mp 135–138 °C; 96% ee by HPLC
analysis of acetamide 11k0. [ 20 = +19 (c 1.1, MeOH). 1H NMR
a]
D
(400 MHz, CDCl3): d 1.67 (m, 12H), 1.84 (br s, 3H), 2.02 (s, 3H),
2.59 (t, J = 12 Hz,), 2.94 (d, J = 10.8 Hz, 1H), 3.02 (dd, J1 = 2.4 Hz,
J2 = 10 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 28.36, 35.83, 37.32,
38.25, 41.31, 79.91. MS (m/z): 165, 136, 135 (100), 119, 105, 91;
4.5.6. (R)-tert-Butyl [2-hydroxy-1-(3-methoxyphenyl)ethyl]car-
bamate 11g
White solid (123 mg, 92%); white solid, mp 76–78 °C; 99% ee
by HPLC analysis on a ChiralpakÒ AD-H column, hexane/i-PrOH
(90:10), 0.5 mL/min, 254 nm: tR (major) = 31.13 min, tR (minor)
FT-IR ATR:
m
(cmꢀ1) 3380, 2900, 2847, 1070.
= 23.18 min.
[
a
]
22 = ꢀ43 (c 0.23, CHCl3). 1H NMR (400 MHz,
D
4.5. General procedure for the synthesis of carbamates using
(Boc)2O
CDCl3): d 1.44 (s, 9H), 2.25 (s, 1H), 3.81–3.84 (m, 5H), 4.75 (m,
1H), 5.21 (m, 1H), 6.84–6.89 (m, 3H), 7.26 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 28.4, 55.3, 57.0, 67.0, 80.0, 112.5, 113.0,
118.8, 129.9, 160.0, 164.9.
To a solution of the 1,2-amino alcohols (0.5 mmol) in THF
(3 mL) was added (Boc)2O (163.7 mg, 0.75 mmol) and Et3N
Please cite this article in press as: Wang, H.-Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2015.12.002

H.-Y. Wang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9
4.5.7. (R)-tert-Butyl [1-(4-fluorophenyl)-2-hydroxyethyl]carba-
mate 11h42
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; or e-mail:
deposit@ccdc.cam.ac.uk.
Pale yellow solid (121 mg, 95%); mp 85–87 °C; >99% ee by HPLC
analysis on a ChiralpakÒ AD-H column, hexane/i-PrOH (90:10),
0.5 mL/min, 254 nm: tR (major) = 19.32 min, tR (minor) =
Acknowledgments
14.70 min.; [
a]
22 = ꢀ54 (c 0.13, CHCl3). 1H NMR (400 MHz, CDCl3):
Financial support by the National Institute of Health through
their NIH-INBRE (NC P20 RR-016470), NSF-RUI (CHE 1401998)
and NSF-DMR-(PREM 1523463) grants is greatly appreciated. The
NIH-INBRE, NIH-RISE and NIH-MARC undergraduate student sup-
port is also gratefully acknowledged.
D
d 1.43 (s, 9H), 2.09 (s, 1H), 3.85 (m, 2H), 4.75 (m, 1H), 5.24 (m, 1H),
7.01–7.03 (m, 2H), 7.25–7.30 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 28.4, 56.2, 66.7, 80.1, 115.6, 115.8, 128.2, 128.3, 155.9, 162.3 (JC-
F = 240 Hz).
Supplementary data
4.5.8. (R)-tert-Butyl-(2-hydroxy-1-(4-methoxyphenyl)ethyl)car-
bamate 11i
Supplementary data (1H and 13C NMR spectra; HPLC and GC
analysis of chiral compounds; X-ray data for compound 11K0) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetasy.2015.12.002.
White solid (78 mg, 97%); mp 137–138 °C; >97% ee by HPLC
analysis on ChiralpakÒ AD-H column, (0.46 cm I.D. ꢂ 25 cm): hex-
ane/i-PrOH (90:10), Flow 0.80 mL/min: tR (minor) = 15.33 min
(1.68%); tR (major) = 17.71 min (98.31%); [
a
]
D
20 = ꢀ58 (c 1.1, MeOH).
1H NMR (400 MHz, CDCl3): d 1.29 (s, 9H), 3.00 (s, 1H), 3.82 (br s,
5H), 4.73 (br s, 1H), 5.38 (br s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.24
(d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 28.4, 55.2, 56.3,
66.7, 79.9, 114.1, 127.7, 131.7, 156.2, 159.0. GC/MS: Retention time
17.43 min, (m/z): 236 (9%, MꢀOCH3), 180 (100%), 163 (4%), 151
(6%), 136 (31%), 121 (10%), 109 (35%).
References
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C. Tetrahedron 2000, 56, 2561.
2. (a) Franchini, C.; Carocci, A.; Catalano, A. A.; Cavalluzzi, M. M.; Corbo, F.;
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4.5.9. (R)-tert-Butyl-(2-hydroxy-1-(pyridin-3-yl)ethyl)carbamate
11j45
Yellow oil (40 mg, 84%); 95% ee by HPLC analysis on
a
ChiralpakÒ AD-H column, hexane/i-PrOH (88:12), flow 0.8 ml/min:
tR (minor) = 14.43 min (2.5%); tR (major) = 16.45 min (97.4%). 1H
NMR (CDCl3, 400 MHz): d 1.28 (s, 9H), 3.75 (s, 1H), 3.90 (s, 1H),
4.78 (s, 1H), 5.79 (s, 1H), 7.26 (m, 1H), 7.67 (d, J = 6.0 Hz, 1H),
8.38 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 3.2 Hz, 1H).
4. Narender, M.; Reddy, M. S.; Nageswar, Y. V. D.; Rao, K. R. Helv. Chem. Acta 2007,
90, 1107.
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Am. Chem. Soc. 2008, 130, 2956.
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(b)Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds., 2nd ed.;
Wiley-VCH: Weinheim, Germany, 2004; (c) Legros, J.; Bolm, C. Eur. J. Org. Chem.
2005, 11, 1086; (d) Park, J. K.; Lee, H. G.; Bolm, C.; Kim, B. M. Eur. J. Org. Chem.
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8. (a) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024; (b) Zhang, W.; Basak,
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Bernasconi, S.; Di Gennaro, P. Tetrahedron: Asymmetry 2006, 17, 372; (b)
Cattoën, X.; A. Pericàs, M. Tetrahedron 2009, 65, 8199; (c) Molinaro, C.;
Guilbault, A.-A.; Kosjek, B. Org. Lett. 2010, 12, 3772; (d) Pourali, A. R.; Samaneh,
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4.5.10. Synthesis of N-((S)-2-(adamantyl-1-yl)-2-hydroxyethyl)
acetamide 11k0
In a 5 mL round-bottomed flask, the amino alcohol (0.067 g,
0.345 mmol) was dissolved in dry freshly distilled THF (6.0 mL),
after which triethylamine (0.06 mL, 0.410 mmol) was added. Next,
acetyl chloride (0.03 mL) was added. The mixture was stirred for
one hour at room temperature and then heated at reflux for 3 h.
A white solid precipitated during cooling of the system. The crude
mixture was acidified with 1 M HCl and extracted with CHCl3
(10 mL). The organic phase was first washed with a saturated solu-
tion of Na2CO3 (3 ꢂ 5 mL), then with H2O (3 ꢂ 5 mL) and dried over
MgSO4, filtered, and rotoevaporated to obtain a crude product
(80 mg, 98%). A sample (54 mg) was purified by column chro-
matography (9 cm long/1 cm diameter) on silica gel (4 g) using a
gradient flow of ethyl acetate/hexane (initial 20/80 to pure ethyl
acetate) obtaining a white solid (49 mg, 60%); mp 150–152 °C,
96% ee by GC analysis on a CP-Chirasil-Dex CB column, temp.1:
70 °C (10 min); ramp.1: 4 °C/min; temp.2: 120° (5 min); ramp.2:
11 °C/min, temp. 3: 180 °C (20 min): tR (minor) = 33.40 min
(2.24%); tR(major) = 37.17 (97.76%). 1H NMR (400 MHz, CDCl3): d
1.65 (m, 13H), 2.05 (s, 6H), 2.27 (s, 1H), 3.11 (m, 2H, J = 9.9 Hz),
3.67 (m, 1H), 5.96 (s, 1H). 13C NMR (100 MHz, CDCl3): d 23.3,
28.2, 36.2, 37.1, 37.9, 40.7, 79.5, 171.0; FT-IR (cmꢀ1): 3402, 3204,
2903, 1727, 1636. GC/MS (m/z): 238 MÅ+ (2), 220 (6), 178 (26),
135 (100), 107 (48), 91 (56), 79 (58).
Crystal data
Full crystallographic data for compound 11k0 have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 1413103. These data
can obtained free of charge on application to CCDC, 12, Union Road,
15. For ring-opening reactions in water, see: (a) Bonollo, S.; Lanari, D.; Marrocchi,
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