Synthesis of enantiomerically pure 2-heteroaromatic-substituted 1,2-amino alcohols from chiral tert-butanesulfinyl aldimines

Article abstract of DOI:10.1055/s-0034-1378943

Nine R/S pairs of 2-heteroaromatic-substituted 1,2-amino alcohols were synthesized through 1,2-nucleophilic addition between chiral N-(tert-butylsulfinyl)imines and heteroaromatic carbanions. In most cases, the R _S-isomer of N-(tert-butylsulfinyl)imines afforded the R amino alcohol from deprotection of the major diastereomer, and S _S-imines afforded the S product. In general, this procedure allows for the preparation of a variety of enantiomeric pairs of 2-heteroaromatic-substituted 1,2-amino alcohols on a practical scale (>10 g) in two steps in good yields.

Full text of DOI:10.1055/s-0034-1378943

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 679–691
paper
679
Y. Chen et al.
Paper
Synthesis
Synthesis of Enantiomerically Pure 2-Heteroaromatic-Substituted
1,2-Amino Alcohols from Chiral tert-Butanesulfinyl Aldimines
Yantao Chen*a
Frederick W. Goldbergb
Jian Xiongc
Het-Ar
O
S
O
S
Het-Ar
Het-Ar
O
S
OTBS
OTBS
OH
OTBS
tBu
N
tBu
N
tBu
N
H2N
H
H
Shujun Wangc
HCl
(major diastereomer)
'anti-Ellman'
'Ellman'
a AstraZeneca Innovative Medicines Cardiovascular and Meta-
bolic Diseases, 431 83 Mölndal, Sweden
O
OTBS
yantao.chen@astrazeneca.com
Het-Ar
O
S
O
S
Het-Ar
Het-Ar
b AstraZeneca Innovative Medicines Oncology, Alderley Park,
Macclesfield, Cheshire, SK10 4TG, UK
O
OTBS
OTBS
OH
OTBS
tBu
N
S
tBu
N
tBu
N
H2N
c WuXi AppTec (Shanghai) Co., Ltd., No. 1 Building, #288 FuTe
ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131,
P. R. of China
H
H
HCl
'Ellman'
'anti-Ellman' (major diastereomer)
Received: 01.09.2014
Accepted after revision: 06.11.2014
Published online: 10.12.2014
which was synthesized in five steps using L-serine as the
chiral source (Scheme 1).6,7 The limitations of this method
are the lack of scope to access different heterocycles, the
length of the synthetic sequence, and the cost of using D-
serine on large scale if the other enantiomer is required.
In 2008, Wei patented the synthesis of the pyridyl chiral
amino alcohol (R)-2a from the corresponding aldehyde via
a stereoselective dihydroxylation (Scheme 2).8 However,
other 2-heteroaromatic-substituted 1,2-amino alcohols
have been less explored despite being important building
blocks from a drug discovery perspective.9–13 The synthetic
approaches in Schemes 1 and 2 were not felt to be suitable
for medicinal chemists as they either only deliver one enan-
tiomer or would require a lengthy synthetic sequence.
It is known that Ellman chiral tert-butylsulfinamides
(SS)-3 and (RS)-3 (Figure 2) have been used as convenient
chiral auxiliaries for the asymmetric synthesis of amines.14–23
Barrow reported the condensation of (RS)-3 with alde-
hyde and the reaction of the resulting imine with PhMgBr
or PhLi to selectively produce chiral phenyl-substituted
amino alcohols from ‘Ellman’ and ‘anti-Ellman’ intermedi-
ates (Scheme 3).24
DOI: 10.1055/s-0034-1378943; Art ID: ss-2014-t0539-op
Abstract Nine R/S pairs of 2-heteroaromatic-substituted 1,2-amino al-
cohols were synthesized through 1,2-nucleophilic addition between
chiral N-(tert-butylsulfinyl)imines and heteroaromatic carbanions. In
most cases, the RS-isomer of N-(tert-butylsulfinyl)imines afforded the R
amino alcohol from deprotection of the major diastereomer, and SS-
imines afforded the S product. In general, this procedure allows for the
preparation of a variety of enantiomeric pairs of 2-heteroaromatic-sub-
stituted 1,2-amino alcohols on a practical scale (>10 g) in two steps in
good yields.
Key words amino alcohols, asymmetric synthesis, chiral auxiliaries,
heterocycles, stereoselectivity
The chiral amino alcohol group has proven to be useful
in drug discovery. Examples of 2-phenyl-substituted 1,2-
amino alcohols include recently disclosed clinical candi-
dates, such as implitapide,1,2 ERK 11E,3 and SDZ MKS 4924,5
(Figure 1).
Besides 2-phenyl-substituted 1,2-amino alcohols, some
pyridyl analogues have also been explored. An early exam-
ple is the chiral 2-pyridyl-substituted amino ethanol (R)-1,
OMe
O
Cl
H
N
Me
O
N
N
OH
F
N
NH
NH
O
O
N
N
OH
Cl
OH
N
N
N
Me
MeO
N
H
NH
MeO
SDZ MKS 492
ERK 11E
implitapide
Figure 1 Industrially relevant chiral amino alcohol derivatives
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Synthesis
HO
HO
Cbz
O
O
3 steps
O
cobalt catalyst
N
N
N
H2N
N
N
acetylene
14 bar, 120 °C
H
Cbz
N
Cbz
OMe
(R)-1
Scheme 1 Synthesis of (R)-2-amino-2-(2′-pyridyl)ethanol [(R)-1]
OH
OH
OH
O
4 steps
2 steps
H2N
H
HO
H2N
N
OMe
N
OMe
N
OMe
N
OMe
key intermediate
(R)-2a
(S)-2a
Scheme 2 Patented chemistry to synthesize (R)-2a
O
O
We have favored Barrow’s approach to explore other he-
teroaromatic-substituted amino alcohols as interesting
building blocks for medicinal chemistry (Scheme 4). This
paper demonstrates the feasibility of the Ellman/Barrow
strategy to synthesize chiral 2-heteroaromatic-substituted
1,2-amino alcohols with broad scope on >10 g scale.
S
S
NH2
NH2
(SS)-tert-butanesulfinamide
(RS)-tert-butanesulfinamide
(SS)-3
(RS)-3
In brief, condensation of tert-butanesulfinamide (SS)-3
and (RS)-3 with 2-(tert-butyldimethylsilyloxy)acetaldehyde
with the aid of copper sulfate in dichloromethane provides
tert-butanesulfinyl imines (SS)-4 and (RS)-4.15,26 The chiral
tert-butanesulfinyl group activates the imine C=N towards
the addition of nucleophilic reagents, such as carbanions,
Figure 2 Structure of Ellman chiral sulfinamides
The chiral aliphatic substituted amino alcohols were
synthesized using the same chemistry strategy from sulfin-
amide (RS)-3 under different solvents or additives to
achieve good dr and yields.25
O
S
Ph
O
S
Ph
O
S
O
S
H
conditions
OTBS
OTBS
OTBS
N
N
OTBS
NH2
N
H
H
O
(RS)-3
(RS)-4
‘anti-Ellman’
‘Ellman’
Scheme 3 Barrow’s chemistry towards chiral phenyl-substituted amino alcohol
Het-Ar
O
S
O
S
Het-Ar
Het-Ar
H2N
O
S
OTBS
OTBS
HCl
OH
OTBS
t-Bu
N
t-Bu
N
t-Bu
N
H
H
HCl
6a–h SSS
5
SSR
(SS)-4
(S)-2a–i
‘anti-Ellman’
‘Ellman’
(major diastereomer)
(usually minor diastereomer)
5h
O
OTBS
7i
Het-Ar
O
S
Het-Ar
O
S
Het-Ar
O
S
OTBS
HCl
OTBS
OH
OTBS
t-Bu
N
t-Bu
N
H2N
t-Bu
N
H
H
HCl
(RS)-4
8a–g, i RSR
RSS
‘Ellman’
(minor diastereomer)
7
(R)-2a–i
‘anti-Ellman’
(major diastereomer)
two exceptions:
intermediate 5h and 6h are almost 1:1 ratio when (SS)-4 was used in entry h
intermediate 7i and 8i are almost 1:1 ratio when (RS)-4 was used in entry i
Scheme 4 Synthesis of chiral 2-heteroaromatic-substituted 1,2-amino alcohols
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681
Y. Chen et al.
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Synthesis
and its chirality serves as a directing group to provide prod-
ucts with generally good diastereoselectivity. Subsequent
removal of the tert-butanesulfinyl group and TBS protect-
ing group provides the desired products (S)-2a–i, (R)-2a–i.
According to a literature survey, compounds (S/R)-2a,
(S/R)-2f, and (S/R)-2g are now commercially available.
However, there is no reference available for their prepara-
tion except for compound (S)-2a, which was synthesized
using a different approach as shown in Scheme 2. In 2013,
Eskildsen and co-workers used tert-butylsulfinamide (RS)-3
and patented the synthesis of 2-heteroaromatic-substituted
1,2-amino alcohols with a similar structure than compound
(R)-2a and using a similar addition of heteroaromatic carb-
anions to butanesulfinimines.27 Interestingly, none of the
five-membered heterocycles has been prepared in this
manner.
Nucleophilic addition between imine (SS)-4 and carban-
ions, in most cases, gives the SS,S (‘anti-Ellman’) diastereo-
mers as the major isomers (Table 1, 6a–g). When imine
(RS)-4 was used, RS,R (‘anti-Ellman’) diastereomers 8a–g
were obtained as the major isomers. However, both (SS)-4
and (RS)-4 have an exception: in Table 1, entry h both SS,R
(‘Ellman’) and SS,S (‘anti-Ellman’) diastereomers were ob-
tained as a 1:1 mixture (5h/6h) when (SS)-4 was used,
while in entry i both RS,S (‘Ellman’) and RS,R (‘anti-Ellman’)
diastereomers were obtained as a 1:1 mixture (7i/8i) when
(RS)-4 was used. Fortunately, the diastereomeric mixture
was easily separated by column chromatography. As we
were aiming for >10 g of each enantiomer of amino alcohol,
in practice only the major diastereomers 6a–g, and 8a–g for
entries a–g, and both diastereomers (5h/6h, 7i/8i) for en-
tries h,i were isolated (Table 1).
Table 1 Isolated Diastereomers through Ellman/Barrow Chemistry
metal exchange
1,2-addition
addition products
Nu
Aryl-H(X)
conditions
(SS)-4, (RS)-4
Entry
Imine
Nucleophile
Key conditions
Isolated diastereomer
Yield (%)a
drb
OTBS
O
OMe
N
S
N
(SS)-4
20
88:12
N
H
Br
MeO
6a
a
n-BuLi/i-PrMgCl, THF, 0 °C
OTBS
O
OMe
NH2
Br
N
S
N
N
(RS)-4
(SS)-4
20
30
88:12
90:10
H
MeO
8a
N
Me
Me
Me
N
N
N
OTBS
O
S
N
N
N
Me
N
N
H
N
N
6b
b
t-BuLi, THF, –90 °C
OTBS
O
S
N
(RS)-4
30
90:10
Me
H
8b
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Table 1 (continued)
Entry
Imine
Nucleophile
Key conditions
Isolated diastereomer
Yield (%)a
51
drb
OTBS
Me
N
O
Me
70:30
S
(SS)-4
N
H
N
H
N
N
6c
c
n-BuLi, THF, –78 °C
OTBS
O
Me
Me
N
S
N
N
(RS)-4
49
60
67
72
70:30
60:40
60:40
90:10
H
N
N
8c
Me
N
OTBS
O
N
Me
(SS)-4
(RS)-4
(SS)-4
S
N
N
Cl
H
N
Me
6d
N
H
d
t-BuLi, THF, –60 °C
Cl
Cl
OTBS
O
N
Me
S
N
N
Cl
H
Me
N
8d
N
N
OTBS
Me
N
O
Me
S
N
H
N
N
N
H
N
N
6e
e
n-BuLi, THF, –78 °C
OTBS
O
Me
Me
S
N
N
N
N
(RS)-4
(SS)-4
55
28
90:10
80:20
N
H
N
N
8e
OTBS
O
OMe
N
MeO
S
N
H
N
Br
N
6f
f
n-BuLi, THF–TMEDA, –80 °C
OTBS
O
OMe
MeO
S
N
(RS)-4
41
80:20
H
N
8f
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Table 1 (continued)
Entry
Imine
Nucleophile
Key conditions
Isolated diastereomer
Yield (%)a
drb
OTBS
O
H
N
N
N
N
S
(SS)-4
20
83:17
N
H
6g
g
n-BuLi, THF–TMP, –65 °C
n-BuLi, THF, –65 °C
n-BuLi, THF, –65 °C
OTBS
O
N
N
N
N
S
N
(RS)-4
22
17
83:17
50:50
H
8g
OTBS
O
Me
Me
H
N
S
N
N
N
N
N
N
H
6h
h
(SS)-4
OTBS
O
Me
Me
N
N
S
N
N
17
28
50:50
50:50
N
H
5h
OTBS
O
Me
H
Me
S
N
N
N
H
7i
i
(RS)-4
OTBS
O
Me
Me
N
N
S
N
N
23
50:50
N
H
8i
a Yields determined by mass balance of purified material of the major diastereomers.
b Ratios determined by mass balance of isolated diastereomers (both ‘Ellman’ and ‘anti-Ellman’ products).
Among the solvents that Barrow and Ellman studied for
the formation of carbanions for high diastereoselectivi-
ty,24,25 both dichloromethane and toluene were tested at
small reaction scale in our work, and they ended up with
similar results as THF. Considering THF is a good coordinat-
ing and stabilizing solvent for metal cations, we ran all sub-
sequent experiments in anhydrous THF.
Successful preparation of the nucleophilic heteroaro-
matic carbanions was key for this chemistry. They were
formed in situ through either direct Li–H exchange or Li–
halogen exchange. Conditions for the formation of anions
such as temperature, organometals, ratio of electrophiles,
solvents, co-solvents, etc., have been examined in small
scale to achieve stable carbanions and good yields for the
subsequent 1,2-addition (see the scale-up synthetic details
of 1,2-addition in experimental session). In many cases, n-
butyllithium or tert-butyllithium works well to afford the
desired carbanion. However, in Table 1, entry a, normal
conditions, such as n-BuLi/THF or t-BuLi/THF were exam-
ined, but gave low conversion and complex mixtures. We
succeeded by using noncryogenic conditions, as reported by
Sośnicki.28 A complex of lithium dibutyl(isopropyl)magne-
sate and lithium chloride was used as a halogen–magne-
sium exchange reagent. It can be simply prepared by mixing
commercially available isopropylmagnesium chloride and
n-butyllithium before use. Despite only giving 20% yield,
the resulting Mg–halogen exchange process makes it possi-
ble to form the carbanion and perform the subsequent 1,2-
addition at 0 °C. In some cases, co-solvents were required to
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Table 2 Final Amino Alcohol HCl Saltsa
ee (%)b
>99.5
Product
[α]D
ee (%)b
99.9
20
20
Entry
Product
[α]D
OH
OH
·2HCl
·2HCl
a
+21c,d
–28d
H2N
H2N
N
OMe
OH
N
OMe
OH
(S)-2a
(R)-2a
N
N
b
c
+13
+17
+19
+4
97.6
–17
–20
–21
–5
98.1
NH2
NH2
·HCl
Me
N
Me
N
·HCl
(R)-2b
(S)-2b
Me
N
OH
Me
N
OH
>99.9
96.1
>99.9
95.1
NH2
·HCl
NH2
·HCl
N
N
(R)-2c
(S)-2c
OH
OH
Me
Me
·HCl
N
N
·HCl
de
H2N
H2N
N
N
(S)-2d
(R)-2d
Me
Me
N
H2N
H2N
N
N
HO
N
e
>99.9
>99.9
HO
N
N
·2HCl
(R)-2e
·2HCl
(S)-2e
N
OMe
·2HCl
OH
OMe
OH
N
·2HCl
f
+22d
>99.9
–22d
>99.9
H2N
H2N
(S)-2f
(R)-2f
NH2
NH2
OH
OH
·HCl
N
N
g
h
+10
+12
>99.9
96.3
–12
–14
>99.9
97.8
·HCl
N
(R)-2g
N
(S)-2g
Me
Me
N
N
·HCl
OH
·HCl
OH
N
N
NH2
NH2
(S)-2h
Me
(R)-2h
Me
NH2
NH2
N
N
N
N
i
+16
99.1
–16
98.8
·HCl
·HCl
HO
HO
(S)-2i
(R)-2i
a The coefficient of HCl salts was determined by ion chromatography on Metrohm 883 with auto sampler.
b The ee was measured by chiral SFC column. When this failed, the Cbz derivatives were prepared and checked on chiral column.
c For all optical rotation: c = 1, MeOH, 20 °C.
d OR data for the demethylated by-products.
e Final compound was synthesized from the chloro derivative as shown in Scheme 5.
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stabilize the in situ formed carbanions. For instance, entry f
requires equivalents of tetramethylethylenediamine
(TMEDA), and entry g needs 1.1 equivalents of 2,2,6,6-te-
tramethylpiperidine (TMP).
The stereochemistries of diastereomers in Table 1 were
assigned after the chirality of amino alcohols was con-
firmed. Absolute configuration of one enantiomer from
each entry was determined using Mosher method,32,33 and
the other enantiomer was tentatively assigned by analogy.
For instance, the chiral substance (R)-2e was coupled with
(S)-Mosher’s acid chloride (S)-(–)-α-methoxy-α-(trifluoro-
methyl)phenylacetyl chloride [(S)-MTPA-Cl] to afford a di-
astereomer of amide (R)-MTPA-2e; while when it was cou-
pled with (R)-Mosher’s acid chloride, the amide (S)-MTPA-
2e was isolated (see Supporting Information).
2
Entries c and d show an example of controlling the regi-
oselectivity by blocking the C2 position on the imidazole
ring. Entry c shows that the proton at C2 in 1-methyl-1H-
imidazole is readily deprotonated by n-BuLi. For entry d, Cl
substitution was applied to block the C2 position and
switch the regioselectivity to C5.29 The required 2-chloro-
imidazole (2-chloro-1-methyl-1H-imidazole) was prepared
in good yield by halogen–metal exchange between the 2-
lithio-1-methyl-1H-imidazole and hexachloroethane.30
Entries b and h demonstrate another example of con-
trolling the regioselectivity. In entry b, the C3 carbanion
was formed from the bromo precursor,31 but for entry h the
C5 carbanion was generated from Li–H exchange. Interest-
ingly, the diastereoselectivities in entries b and h were also
different, although the carbanions in both cases were syn-
thesized at low temperature in the same solvent (THF). En-
try b afforded one major diastereomer, as in most cases,
while entry h produced a 1:1 diastereomeric mixture.
All diastereomers in Table 1 were treated with HCl to af-
ford the solid amino alcohols as HCl salts (Table 2). In entry
d, the HCl salts of the chloro intermediates 6d and 8d (Table
1) were dehalogenated with Pd/C under 1 atmosphere of
hydrogen in methanol after 1 hour at 0 °C to give the final
products of entry d (Scheme 5).
Protons in R1 or R2 are shielded by the phenyl ring in (S)-
or (R)-Mosher amides as shown in Table 3. The absolute
configuration of the substrate 2e is deduced by interpreta-
tion of the sign of ΔδSR value, which is defined as the differ-
ence between the chemical shift of a certain proton in the
(S)-MTPA amide and the chemical shift of the same proton
in the (R)-MTPA derivative. All the protons shielded in the
(R)-MTPA amide will present a positive ΔδSR value. Instead,
those shielded in the (S)-MTPA derivative will present a
negative ΔδSR value. As shown in Table 3, δS(Ha) – δR(Ha) < 0,
but δS(Hb) – δR(Hb) > 0, so we can not conclude the orienta-
tion of R1. However, δS(Hc) – δR(Hc) > 0, and δS(Hd) – δR(Hd)
> 0. Therefore, we conclude that R2 group, which contains
Hc and Hd, gets oriented towards the readers. This enantio-
mer was therefore assigned as R-form, and the configura-
tion of its relevant diastereomer was shown as 8e (Table 1).
The other diastereomer, which was synthesized from 1,2-
addition of carbanions with imines (SS)-4 was is assumed to
be 6e, and its deprotection product has S-form.
OH
OH
Me
Me
Pd/C
HCl
Cl
All amino alcohols were delivered from WuXi AppTec
HCl
*
*
N
N
H2N
1
H2N
(Shanghai) with pure H NMR spectra. They were stored at
MeOH
N
N
room temperature for several months. Unfortunately, when
we ran 13C NMR experiments, we found the HCl salts of (R)-
2a, (S)-2f, and (R)-2f were not stable under such storage
conditions. Near full demethylation of (R)-2a happened
during storage (see the Supporting Information for NMR
spectra). Compounds (S)-2f and (R)-2f were mainly decom-
(S/R)-2d-Cl
(S/R)-2d
Scheme 5 Dehalogenation of chloro derivative 2d
Table 3 Mosher Amides of (R)-2e, and Chemical Shifts of Certain Protons
H
N
H
Hc
MeO
Ph
F3C
OMe
Ph
R1
H
H2
N
H
R1
H
(R)-MTPA-Cl
(S)-MTPA-Cl
H
R2
N
N
R2
R2
F3C
*
N
HO
R1
Et3N, CH2Cl2
0 °C to r.t.
overnight
Et3N, CH2Cl2
0 °C to r.t.
overnight
O
O
N
Hb
Ha
(S)-MTPA-2e
proton(s) in R1 is(are) shielded
(R)-MTPA-2e
proton(s) in R2 is(are) shielded
Hd
one enantiomer of 2e
Proton
δS
δR
ΔδSR = δS – δR
Ha
Hb
Hc
Hd
3.86
3.92
4.16
3.85
7.81
–0.06 < 0
+0.03 > 0
+0.09 > 0
+0.02 > 0
4.19
3.94
7.83
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posed, which made it difficult to retrieve 13C NMR peaks
from spectra. However, by comparing the pure 1H NMR
spectra of (S)-2f and (R)-2f with 2D NMR spectra, we man-
aged to report the 13C NMR spectra (see the Supporting In-
formation for spectra). From a structural perspective, one
can speculate that a HCl salt of a 2-methoxypyridine deriva-
tive may not be stable to storage at room temperature for a
long time.
(R)-N-[2-(tert-Butyldimethylsilyloxy)ethylidene]-2-methylpro-
pane-2-sulfinamide [(RS)-4]
The title compound was synthesized from (RS)-3 in a same manner as
for compound (SS)-4. It can be used directly for the 1,2-addition with-
out further purification, but purification with flash column chroma-
tography on silica gel (PE–EtOAc, 50:1 → 10:1) afforded the title prod-
uct as a yellow oil; yield: 80 g (35%).
1H NMR (400 MHz, CDCl3): δ = 7.96 (m, 1 H), 4.44 (d, J = 3.2 Hz, 2 H),
1.11 (s, 9 H), 0.82 (s, 9 H), 0.00 (s, 6 H).
In summary, we have developed protocols to introduce
heteroaromatic substitutions onto the α-position of amino
alcohols starting from chiral tert-butanesulfinamide. In
most cases, R-amino alcohols were diasteroselectively ob-
tained from (RS)-tert-butanesulfinamide, and S-amino alco-
hols from (SS)-tert-butanesulfinamide, and the chemistry
was performed on a practical (>10 g) scale.
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(6-methoxypyridin-3-
yl)ethyl]-2-methylpropane-2-sulfinamide (6a)
To THF (2.0 L) in a 3 L three-necked round-bottomed flask equipped
with magnetic stirrer and thermometer was added a solution of n-
BuLi (250 mL, 2.5 M, 625 mmol) in hexane at 0 °C under N2 with stir-
ring. Then, a solution of i-PrMgCl (2 M, 150 mL, 300 mmol) in THF
was added dropwise at 0 °C over 2 h. After the addition, a solution of
5-bromo-2-methoxypyridine (110 g, 585 mmol) in THF (0.4 L) was
added dropwise at 0 °C over 1 h. The mixture was stirred for 45 min,
while keeping the temperature between –2 to 0 °C. A solution of (SS)-
4 (180 g, 649 mmol) in THF (0.5 L) was added dropwise to the above
solution at 0 °C over 1 h. The mixture was stirred for 1 h until TLC
(50% EtOAc in PE) showed the reaction was complete. The reaction
mixture was quenched with sat. aq NH4Cl (1 L), extracted with EtOAc
(3 × 0.5 L), and the combined extracts were dried (Na2SO4) and con-
centrated. The residue was purified on a silica gel column (5–10%
EtOAc in PE) to give the crude product; yield: 45.7 g (20%); yellow oil;
Rf = 0.35 (EtOAc–PE, 1:2).
Reactions were performed under N2 and with dry glassware unless
otherwise stated. Reagents were used as supplied by commercial ven-
dors without further purification or drying. Column (flash) chroma-
tography was performed on 74–165 μm silica gel using EtOAc and pe-
troleum ether (PE), referring to the fraction boiling in the range 30–
60 °C. Melting points of final product were measured on a Büchi 510
apparatus. 1H NMR spectra were recorded at 300 or 400 MHz as indi-
cated. 13C NMR spectra were recorded at 75 or 101 MHz as indicated.
Diastereomeric ratio (dr) values were determined by mass balance of
isolated diastereomers. Enantiomeric excess (ee) values of final amino
alcohols were measured on chiral SFC column. If not successful on SFC
column, pure chiral substances, such as (S)-2e and (R)-2e, were con-
verted to relevant Cbz derivatives before ee analysis on chiral HPLC
column (see the Supporting Information for derivation chemistry).
High-resolution mass spectra (HRMS) were recorded for all final com-
pounds, on a Waters LCTP spectrometer fitted with an electrospray
(ESI) ion source. All final compounds are assessed as being >95% pure
by NMR, and to be the correct mass by HRMS. Because all 1,2-addi-
tion intermediates were consumed, some of the addition products are
reported with LCMS results, if available. Unfortunately, 13C NMR was
not recorded on them. In this paper, synthetic details of one diaste-
reomer of the 1,2-addition intermediates from each entry are provid-
ed, while only a general procedure of deprotection for the synthesis of
final amino alcohols is given.
1H NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 2.0 Hz, 1 H), 7.53–7.50 (dd,
J = 8.4, 2.0 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.49–4.47 (m, 1 H), 4.26
(m, 1 H, NH), 3.92 (s, 3 H), 3.77–3.73 (m, 1 H), 3.62–3.58 (m, 1 H), 1.22
(s, 9 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H).
MS (ESI+): m/z = 387.2 (M + H)+.
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(6-methoxypyridin-3-
yl)ethyl]-2-methylpropane-2-sulfinamide (8a)
The title compound was synthesized and purified in a same manner
as for compound 6a, but using (RS)-4 for the 1,2-addition; yield: 43.9 g
(20%); yellow oil; Rf = 0.35 (EtOAc–PE, 1:2).
1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 2.1 Hz, 1 H), 7.47–7.43 (dd,
J = 8.7, 2.1 Hz, 1 H), 6.65 (d, J = 8.7 Hz, 1 H), 4.41 (m, 1 H), 4.18 (m, 1 H,
NH), 3.86 (s, 3 H), 3.71–3.66 (m, 1 H), 3.56–3.49 (m, 1 H), 1.18 (s, 9 H),
0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
(S)-N-[2-(tert-Butyldimethylsilyloxy)ethylidene]-2-methylpro-
pane-2-sulfinamide [(SS)-4]
MS (ESI+): m/z = 387.2 (M + H)+.
To a solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde (150 g,
0.862 mol) in CH2Cl2 (2 L) was added CuSO4 (345 g, 2.16 mol) in por-
tions, followed by (S)-2-methylpropane-2-sulfinamide [(SS)-3; 89 g,
0.819 mol]. The mixture was stirred at r.t. overnight. TLC (PE–EtOAc,
5:1) showed the reaction was complete. The solution was filtered and
the filtrate was concentrated under reduced pressure to give the
crude product (180 g) as a yellow oil, which was used directly for the
next step without further purification.
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-
3-yl)ethyl]-2-methylpropane-2-sulfinamide (6b)
To a solution of 3-bromo-1-methyl-1H-pyrazole (40 g, 248 mmol)
(see the Supporting Information for the synthesis) in THF (1 L) was
added dropwise a solution of t-BuLi (200 mL, 1.3 M, 260 mmol) in
hexane at –90 °C under N2 with stirring over 2 h. The reaction mix-
ture was stirred at –90 °C for further 0.5 h. Then a solution of (SS)-4
(58 g, 209 mmol) in THF (0.2 L) was added dropwise to the reaction
mixture at –90 °C. The mixture was stirred and warmed slowly to r.t.
overnight. TLC showed the desired spot with Rf = 0.25 (EtOAc). Then
the solution was quenched with sat. aq NH4Cl (1 L) and extracted with
Et2O (3 × 0.8 L). The combined organic layers were dried (Na2SO4) con-
centrated. The crude product was purified by column chromatogra-
phy over silica gel (PE–EtOAc, 20:1 → 2:1) to give the title product;
yield: 22.9 g (30%); brown oil; Rf = 0.25 (EtOAc).
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1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 2.4 Hz, 1 H), 6.10 (d, J = 2.4
Hz, 1 H), 4.58–4.56 (m, 1 H), 4.17 (d, J = 2.8 Hz, 1 H, NH), 3.84–3.68
(m, 5 H), 1.15 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
with brine (1 L), dried (Na2SO4), and concentrated. The crude product
was purified by flash column chromatography on silica gel (PE–EtOAc,
10:1 → 2:1) to give the title compound; yield: 189.9 g (60%); yellow
solid; Rf = 0.3 (EtOAc–PE, 1:1).
1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H), 4.35 (m, 1 H), 4.07 (d, J =
4.8 Hz, 1 H, NH), 3.80 (m, 2 H), 3.49 (s, 3 H), 1.12 (s, 9 H), 0.81 (s, 9 H),
0.00 (s, 6 H).
MS (ESI+): m/z = 360.2 (M + H)+.
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-
3-yl)ethyl]-2-methylpropane-2-sulfinamide (8b)
The title compound was synthesized and purified in the same man-
ner as for compound 6b, but using (RS)-4 for 1,2-addition; yield: 42.9
g (30%); brown oil; Rf = 0.25 (EtOAc).
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-chloro-1-methyl-
1H-imidazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (8d)
The title compound was synthesized and purified in a same manner
as for compound 6d, but using (RS)-4 for the 1,2-addition; yield: 99.9
g (67%); yellow solid; Rf = 0.3 (EtOAc–PE, 1:1).
1H NMR (400 MHz, CDCl3): δ = 6.91 (s, 1 H), 4.47 (m, 1 H), 4.20 (d, J =
4.8 Hz, 1 H, NH), 3.89–3.95 (m, 2 H), 3.62 (s, 3 H), 1.25 (s, 9 H), 0.93 (s,
9 H), 0.13 (s, 6 H).
1H NMR (400 MHz, CDCl3): δ = 7.21 (br s, 1 H), 6.10 (br s, 1 H), 4.58–
4.55 (m, 1 H), 4.17 (br s, 1 H, NH), 3.84–3.69 (m, 5 H), 1.15 (s, 9 H),
0.83 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
MS (ESI+): m/z = 360. 2 (M + H)+.
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-imidaz-
ol-2-yl)ethyl]-2-methylpropane-2-sulfinamide (6c)
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-1,2,4-
To a solution of 1-methyl-1H-imidazole (50.0 g, 609 mmol) in THF
(1.0 L) at –78 °C under N2 atmosphere, was added a solution of n-BuLi
(216 mL, 2.5 M, 540 mmol) in hexane dropwise at –78 °C with stir-
ring over 2 h. After the addition, a solution of (SS)-4 (90.0 g, 324
mmol) in THF (0.5 L) was added dropwise to the mixture, and stirred
for 3 h until TLC (PE–EtOAc, 2:1) showed the reaction was complete.
The solution was quenched with sat. aq NH4Cl (1 L) at r.t., and extract-
ed with EtOAc (3 × 0.8 L). The combined organic layers were washed
with brine (1 L) and concentrated. The crude product was purified by
chromatography on silica gel (eluent: PE–EtOAc, 5:1 → 2:1) to give the
title compound; yield: 59.9 g (51%); colorless oil; Rf = 0.4 (EtOAc–PE,
1:2).
triazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (6e)
To a solution of 1-methyl-1H-[1,2,4]triazole (38.4 g, 462 mmol) in
THF (1.2 L) at –78 °C under N2 atmosphere was added a solution of n-
BuLi (185 mL, 2.5 M, 462.5 mmol) in hexane dropwise at –78 °C with
stirring over 2 h. After the addition, the mixture was stirred at this
temperature for 30 min. A solution of (SS)-4 (106.8 g, 385 mmol) in
THF (1.2 L) was added dropwise to the mixture, and stirred for 3 h un-
til TLC (PE–EtOAc, 2:1) showed the reaction was complete. The solu-
tion was quenched with sat. aq NH4Cl (1 L) at r.t. and extracted with
EtOAc (3 × 0.5 L), and the combined organic layers were washed with
brine (1 L) and concentrated. The crude product was purified by chro-
matography on silica gel (eluent: PE–EtOAc, 20:1 → 3:1) to give the
title compound; yield: 99.8 g (72%); yellow oil; Rf = 0.3 (EtOAc–PE,
1:5).
1H NMR (400 MHz, DMSO-d6): δ = 7.10 (d, J = 1.2 Hz, 1 H), 6.88 (d, J =
1.2 Hz, 1 H), 5.30 (d, J = 2.8 Hz, 1 H, NH), 4.50 (m, 1 H), 4.02 (d, J = 7.2
Hz, 2 H), 3.68 (s, 3 H), 1.13 (s, 9 H), 0.86 (s, 9 H), 0.06 (s, 3 H), 0.00 (s, 3
H).
1H NMR (400 MHz, CDCl3): δ = 7.87 (s, 1 H), 4.73 (m, 1 H), 4.25 (d, J =
6.4 Hz, 1 H, NH), 4.16–4.20 (m, 1 H), 3.98 (s, 3 H), 3.85–3.90 (m, 1 H),
1.22 (s, 9 H), 0.85 (s, 9 H), 0.05 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 360.2 (M + H)+.
MS (ESI+): m/z = 361.2 (M + H)+.
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-imidaz-
ol-2-yl)ethyl]-2-methylpropane-2-sulfinamide (8c)
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-1,2,4-
triazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (8e)
The title compound was synthesized and purified in the same man-
ner as for compound 6c, but using (RS)-4 for the 1,2-addition; yield:
56.9 g (49%); colorless oil; Rf = 0.4 (EtOAc–PE, 1:2).
1H NMR (400 MHz, DMSO-d6): δ = 7.04 (d, J = 1.2 Hz, 1 H), 6.81 (d, J =
1.2 Hz, 1 H), 5.26 (d, J = 2.8 Hz, 1 H, NH), 4.43 (m, 1 H), 3.96 (d, J = 6.8
Hz, 2 H), 3.62 (s, 3 H), 1.07 (s, 9 H), 0.80 (s, 9 H), 0.00 (s, 3 H), –0.07 (s,
3 H).
The title compound was synthesized and purified in a similar manner
as for compound 6e, but using (RS)-4 for the 1,2-addition; yield: 15.9 g
(55%); colorless oil; Rf = 0.3 (EtOAc–PE, 1:5).
1H NMR (400 MHz, CDCl3): δ = 7.87 (s, 1 H), 4.73 (m, 1 H), 4.24 (d, J =
6.4 Hz, 1 H, NH), 4.16–4.20 (m, 1 H), 3.98 (s, 3 H), 3.86–3.90 (m, 1 H),
1.22 (s, 9 H), 0.85 (s, 9 H), 0.05 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 360.2 (M + H)+.
MS (ESI+): m/z = 361.2 (M + H)+.
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-chloro-1-methyl-
1H-imidazol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (6d)
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-methoxypyridin-4-
yl)ethyl]-2-methylpropane-2-sulfinamide (6f)
To a solution of 2-chloro-1-methyl-1H-imidazole (92.8 g, 796 mmol)
(see the Supporting Information for the synthesis) in anhydrous THF
(1.8 L) was added dropwise a solution of t-BuLi (336 mL, 2.5 M, 840
mmol) in hexane at –60 °C with stirring over 2 h. After the addition, a
solution of (SS)-4 (221.6 g, 799 mmol) in anhydrous THF (1.0 L) was
added dropwise to the above solution over 1 h at the same tempera-
ture. The resulting mixture was warmed from –60 °C to r.t. with stir-
ring overnight. TLC (PE–EtOAc, 1:1) showed the expected spot (Rf =
0.3). The mixture was poured into sat. aq NH4Cl (1 L) and extracted
with EtOAc (3 × 0.8 L). The organic layers were combined, washed
To a mixture of 4-bromo-2-methoxypyridine (50 g, 0.245 mol) and
TMEDA (80 mL, 532 mmol) in anhydrous THF (1.0 L) at –80 °C under
N2 was added a solution of n-BuLi (170 mL, 2.5 M, 425 mmol) in hex-
ane. After the addition, the mixture was stirred for 10 min at –80 °C. A
solution of (SS)-4 (80 g, 288 mmol) in anhydrous THF (200 mL) was
added dropwise below –80 °C. After the addition, TLC (EtOAc–hexane,
1:4) showed the reaction was complete. The mixture was quenched
with sat. aq NH4Cl (1 L). The organic layer was separated, dried
(Na2SO4), and concentrated under reduced pressure. The residue (ca.
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Synthesis
135 g) was purified by flash column chromatography on silica gel
(EtOAc–PE, 1:6 → 1:2) to give the expected diastereomer as a yellow
oil; yield: 30.9 g (28%); Rf = 0.2 (EtOAc–hexane, 1:4).
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 5.2 Hz, 1 H), 6.79 (m, 1 H),
6.67 (s, 1 H), 4.43 (m, 1 H), 4.18 (d, J = 2.0 Hz, 1 H, NH), 3.88 (s, 3 H),
3.74–3.78 (m, 1 H), 3.54–3.58 (m, 1 H), 1.19 (s, 9 H), 0.83 (s, 9 H), 0.01
(s, 3 H), –0.03 (s, 3 H).
(S)-N-[(R)-2-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-
5-yl)ethyl]-2-methylpropane-2-sulfinamide (5h) and (S)-N-[(S)-2-
(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-pyrazol-5-yl)ethyl]-
2-methylpropane-2-sulfinamide (6h)
To a solution of 1-methyl-1H-pyrazole (82.1 g, 1.0 mol) in THF (1.5 L)
was added dropwise a solution of n-BuLi (440 mL, 2.5 M, 1.1 mol) in
hexane at –65 °C under N2. The reaction mixture was stirred at –65 °C
for a further 0.5 h. Then a solution of (SS)-4 (277.5 g, 1.0 mol) in THF
(0.5 L) was added dropwise to the mixture at –65 °C over 1 h. The
mixture was stirred and warmed to r.t. by removing the cooling bath
until TLC showed one desired spot with Rf = 0.3 (PE–EtOAc, 1:2) and
the second expected spot with Rf = 0.25 (EtOAc). Then the solution
was quenched with sat. aq NH4Cl (1 L) and extracted with Et2O (3 ×
1.0 L). The combined organic layers were dried (Na2SO4), and concen-
trated under reduced pressure to give a residue, which was purified
by flash column chromatography on silica gel (PE–EtOAc, 20:1 → 2:1)
to give 5h in the first fraction and 6h in the second fraction.
MS (ESI+): m/z = 387.2 (M + H)+.
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(2-methoxypyridin-4-
yl)ethyl]-2-methylpropane-2-sulfinamide (8f)
The title compound was synthesized and purified in a same manner
as for compound 6f, but using (RS)-4 for the 1,2-addition; yield: 39.0 g
(41%); yellow oil; Rf = 0.2 (EtOAc–hexane, 1:4).
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 6.4 Hz, 1 H), 6.79 (m, 1 H),
6.69 (s, 1 H), 4.43 (m, 1 H), 4.20 (d, J = 2.4 Hz, 1 H, NH), 3.89 (s, 3 H),
3.76–3.80 (m, 1 H), 3.55–3.60 (m, 1 H), 1.24 (s, 9 H), 0.85 (s, 9 H), 0.03
(s, 3 H), –0.01 (s, 3 H).
5h
MS (ESI+): m/z = 387.2 (M + H)+.
First fraction; yield: 60.0 g (17%); yellow oil; Rf = 0.3 (PE–EtOAc, 1:2).
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 1.6 Hz, 1 H), 6.21 (d, J = 1.6
Hz, 1 H), 4.49 (m, 1 H), 3.93–4.07 (m, 1 H, NH), 3.86 (s, 1 H), 3.76–3.80
(m, 2 H), 1.15 (s, 9 H), 0.82 (s, 9 H), 0.00 (s, 3 H), –0.02 (s, 3 H).
(S)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(pyrazin-2-yl)ethyl]-2-
methylpropane-2-sulfinamide (6g)
MS (ESI+): m/z = 360.2 (M + H)+.
To a stirred solution of 2,2,6,6-tetramethylpiperidine (92.7 g, 656
mmol) in THF (1.0 L) was added a solution of n-BuLi (266.7 mL, 2.5 M,
667 mmol) in hexane at –65 °C under N2. The mixture was stirred for
30 min, and then a solution of pyrazine (44.4 g, 554 mmol) in THF (0.3
L) was added dropwise at –65 °C within 30 min at –65 °C. After stir-
ring for another 1 h, a solution of (SS)-4 (160 g, 577 mmol) in THF (0.2
L) was added at –65 °C under N2. The mixture was warmed to r.t. by
removing the cooling bath, and the mixture was continuously stirred
for 24 h at r.t. until TLC (33% EtOAc in PE) showed (SS)-4 was com-
pletely consumed. The mixture was quenched with sat. aq NH4Cl (1 L),
extracted with CH2Cl2 (3 × 0.8 L), and the combined organic extracts
were dried (Na2SO4). Evaporation of the solvent gave the crude prod-
uct, which was purified by flash column chromatography on silica gel
(PE–EtOAc, 4:1) to give the title product; yield: 41.0 g (20%); yellow
oil; Rf = 0.3 (EtOAc–PE, 1:3).
6h
Second fraction; yield: 60.0 g (17%); yellow oil; Rf = 0.25 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 1.6 Hz, 1 H), 6.11 (d, J = 1.6
Hz, 1 H), 4.54 (m, 1 H), 4.11 (d, J = 3.6 Hz, 1 H, NH), 3.82 (s, 1 H), 3.69–
3.80 (m, 2 H), 1.12 (s, 9 H), 0.82 (s, 9 H), 0.00 (s, 6 H).
MS (ESI+): m/z = 360.2 (M + H)+.
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(1,4-dimethyl-1H-pyr-
azol-5-yl)ethyl]-2-methylpropane-2-sulfinamide (7i) and (R)-N-
[(R)-2-(tert-Butyldimethylsilyloxy)-1-(1,4-dimethyl-1H-pyrazol-5-
yl)ethyl]-2-methylpropane-2-sulfinamide (8i)
To a solution of 1,4-dimethyl-1H-pyrazole (52 g, 541 mmol) in anhy-
drous THF (1.0 L) was added dropwise n-BuLi (0.22 L, 2.5 M, 550
mmol) at –78 °C with stirring over 2 h. Then, a solution of (RS)-4 (110
g, 396 mmol) in anhydrous THF (1.0 L) was added dropwise to the
above solution over 1 h at the same temperature. The resulting mix-
ture was stirred at –78 °C for 1.5 h. TLC (PE–EtOAc, 1:2) showed (RS)-4
was completely consumed. The mixture was poured into sat. aq NH4Cl
(1 L) and extracted with EtOAc (3 × 0.8 L). The combined organic ex-
tracts were washed with brine (1 L), dried (Na2SO4), and concentrated
to give the crude product. Purification by column chromatography on
silica gel (PE–EtOAc, 20:1 → 5:1) gave 8i as a yellow oil, and 7i as a
yellow solid when the column was continuously eluted with PE–EtO-
Ac (5:1 → 2:1).
1H NMR (400 MHz, CDCl3): δ = 8.64 (d, J = 1.2 Hz, 1 H), 8.53 (m, 1 H),
8.48 (d, J = 2.8 Hz, 1 H), 4.66 (m, 1 H), 4.45 (d, J = 2.4 Hz, 1 H, NH),
4.00–4.07 (m, 1 H), 3.87–3.97 (m, 1 H), 1.25 (s, 9 H), 0.80 (s, 9 H), –
0.04 (s, 3 H), –0.09 (s, 3 H).
MS (ESI+): m/z = 358.2 (M + H)+.
(R)-N-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(pyrazin-2-yl)ethyl]-2-
methylpropane-2-sulfinamide (8g)
The title compound was synthesized and purified in a same manner
as for compound 6g, but using (RS)-4 for the 1,2-addition; yield: 47.9
g (22%); brown oil; Rf = 0.3 (EtOAc–PE, 1:3).
1H NMR (300 MHz, CDCl3): δ = 8.69 (br s, 1 H), 8.58 (m, 1 H), 8.53 (m,
1 H), 4.70 (m, 1 H), 4.49 (d, J = 2.4 Hz, 1 H, NH), 4.05–4.20 (m, 1 H),
3.90–4.03 (m, 1 H), 1.29 (s, 9 H), 0.84 (s, 9 H), 0.00 (s, 3 H), –0.05 (s, 3
H).
7i
Second fraction; yield: 40.7 g (28%); yellow solid; Rf = 0.25 (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.29 (s, 1 H), 4.71 (m, 1 H), 4.03–4.07
(m, 1 H, NH), 3.91 (s, 3 H), 3.87–3.81 (m, 2 H), 2.13 (s, 3 H), 1.23 (s, 9
H), 0.87 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H).
MS (ESI+): m/z = 358.2 (M + H)+.
MS (ESI+): m/z = 374.6 (M + H)+.
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8i
(R)-2-Amino-2-(1-methyl-1H-pyrazol-3-yl)ethanol Hydrochloride
[(R)-2b]
First fraction; yield: 33.3 g (23%); colorless oil; Rf = 0.3 (PE–EtOAc,
1:2).
Yield: 25.9 g (99%); syrupy brown solid.
1H NMR (400 MHz, CDCl3): δ = 7.15 (s, 1 H), 4.62 (m, 1 H), 4.08 (s, 1 H,
NH), 3.86 (s, 3 H), 3.81–3.85 (m, 4 H), 3.61–3.70 (m, 1 H), 1.98 (s, 3 H),
1.13 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 6 H).
1H NMR (400 MHz, DMSO-d6): δ = 8.44 (br s, 3 H), 7.71 (d, J = 2.0 Hz, 1
H), 6.39 (d, J = 2.0 Hz 1 H), 4.15–4.30 (m, 1 H), 3.84 (s, 3 H), 3.65 – 3.79
(m, 2 H).
MS (ESI+): m/z = 374.6 (M + H)+.
13C NMR (101 MHz, DMSO-d6): δ = 146.2, 132.0, 104.1, 62.0, 51.0,
38.5.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
Chiral Amino Alcohols; General Procedure
142.0986.
To a solution of diastereomer 5h, 6a–h, 7i, 8a–g, or 8i (1 equiv) in
MeOH or EtOAc (1–5 mL/mmol) was added a solution of HCl (8–10
equiv) in an organic solvent (MeOH or EtOAc; 4 M, 2–2.5 mL/mmol) at
0 °C. The total concentration of the substrate was 0.2–0.5 M. The mix-
ture was stirred at r.t. for 20 min or longer time, such as overnight,
until TLC (for instance 33% EtOAc in PE) showed the starting material
was consumed. The reaction mixture was concentrated under re-
duced pressure. The residue was triturated and washed with EtOAc to
give the HCl salt of the chiral amino alcohol. Typically the deprotec-
tion yield was >80% (Table 2). The coefficient of HCl salts was deter-
mined by ion chromatography on Metrohm 883 with autosampler at
WuXi AppTech.
(S)-2-Amino-2-(1-methyl-1H-imidazol-2-yl)ethanol Hydrochlo-
ride [(S)-2c]
Yield: 26.3 g (89%); off-white solid; mp 153–155 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.39 (br s, 3 H), 7.76 (s, 2 H), 4.94 (t,
J = 6.3 Hz, 1 H), 3.97–4.06 (m, 2 H), 3.95 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 141.1, 124.3, 119.9, 59.8, 46.1,
35.0.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
142.0976.
(S)-2-Amino-2-(6-methoxypyridin-3-yl)ethanol Dihydrochloride8
[(S)-2a]
(R)-2-Amino-2-(1-methyl-1H-imidazol-2-yl)ethanol Hydrochlo-
ride [(R)-2c]
Yield: 17.9 g (85%); yellow solid.
Yield: 26.1 g (93%); off-white solid; mp 153–155 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.74 (br s, 3 H), 8.31 (d, J = 2.3 Hz, 1
H), 7.99 (dd, J = 8.7, 2.3 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 1 H), 4.22–4.34 (m,
1 H), 3.86 (s, 3 H), 3.68–3.80 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 163.3, 146.0, 139.6, 125.0, 110.3,
62.3, 53.8, 53.2.
1H NMR (400 MHz, DMSO-d6): δ = 9.32 (br s, 3 H), 7.73 (s, 2 H), 4.92 (t,
J = 6.3 Hz, 1 H), 3.95–4.09 (m, 2 H), 3.94 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 141.1, 124.2, 120.1, 59.9, 46.2,
34.9.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
142.0982.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found:
169.0975.
(S)-2-Amino-2-(1-methyl-1H-imidazol-5-yl)ethanol Hydrochlo-
ride [(S)-2d]
(R)-2-Amino-2-(6-methoxypyridin-3-yl)ethanol Dihydrochloride
[(R)-2a]
Deprotection of diastereomer 6d (58.0 g, 147.2 mmol) afforded the
chlorinated product of the title compound as an intermediate (30.5 g,
143.8 mmol, 98%). The resulting crude was dissolved in MeOH (300
mL), and 10% Pd/C (10.0 g) powder was added. The mixture was
stirred at 50 °C under 3 atm of H2 for 2 h. The mixture was filtered
and the solvent was concentrated under reduced pressure to give the
title compound; yield: 25.0 g (98%); off-white solid; mp 263–264 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.12 (s, 1 H), 9.02 (br s, 3 H), 7.83 (s,
1 H), 4.55 (t, J = 5.8 Hz, 1 H), 3.94 (s, 3 H), 3.69–3.91 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 136.0, 129.7, 120.0, 60.9, 45.5,
Yield: 7.6 g (84%); yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.60 (br s, 3 H), 8.27 (d, J = 2.4 Hz, 1
H), 7.91–7.88 (dd, J = 8.4, 2.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 4.26 (m,
1 H), 3.84 (s, 3 H), 3.71 (m, 2 H).
13C NMR: Not available, as the compound was demethylated during
storage. Please see the Supporting Information for the NMR results of
the demethylated by-product.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found:
169.0981.
33.8.
(S)-2-Amino-2-(1-methyl-1H-pyrazol-3-yl)ethanol Hydrochloride
[(S)-2b]
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
142.0977.
Yield: 26.9 g (99%); syrupy brown solid.
(R)-2-Amino-2-(1-methyl-1H-imidazol-5-yl)ethanol Hydrochlo-
ride [(R)-2d]
1H NMR (400 MHz, DMSO-d6): δ = 8.49 (br s, 3 H), 7.70 (d, J = 2.0 Hz, 1
H), 6.40 (d, J = 2.0 Hz, 1 H), 4.15–4.26 (m, 1 H), 3.81 (s, 3 H), 3.64–3.79
(m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 146.3, 132.0, 104.2, 62.0, 51.0,
38.5.
Prepared in a similar manner to (S)-2d from the chloro-blocked addi-
tion intermediate 8d; yield: 16.8 g (75%); off-white solid; mp 263–
264 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.17 (s, 1 H), 9.03 (br s, 3 H), 7.86 (s,
1 H), 4.56 (t, J = 5.8 Hz, 1 H), 3.94 (s, 3 H), 3.73–3.92 (m, 2 H).
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
142.0988.
13C NMR (101 MHz, DMSO-d6): δ = 135.9, 129.8, 119.7, 60.9, 45.5,
33.8.
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Synthesis
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
142.0984.
1H NMR (400 MHz, DMSO-d6): δ = 8.84 (d, J = 1.5 Hz, 1 H), 8.74 (br s, 3
H), 8.69–8.71 (m, 1 H), 8.67 (d, J = 2.6 Hz, 1 H), 4.48–4.61 (m, 1 H),
3.78–3.94 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 150.7, 144.4, 144.3, 143.8, 61.8,
54.2.
(S)-2-Amino-2-(1-methyl-1H-1,2,4-triazol-5-yl)ethanol Dihydro-
chloride [(S)-2e]
HRMS (ESI+): m/z calcd for C6H9N3O (M + H)+: 140.0824; found:
Yield: 30.9 g (89%); off-white solid; mp 145–146 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.84 (br s, 3 H), 8.00 (s, 1 H), 4.65 –
4.74 (m, 1 H), 3.90 (s, 3 H), 3.86–3.89 (m, 1 H), 3.72 (dd, J = 11.0, 6.5
Hz, 1 H).
140.0821.
(R)-2-Amino-2-(pyrazin-2-yl)ethanol Hydrochloride [(R)-2g]
13C NMR (101 MHz, DMSO-d6): δ = 150.8, 150.0, 61.1, 47.2, 35.7.
Yield: 21.3 g (90%); brown solid; mp 154–156 °C.
HRMS (ESI+): m/z calcd for C5H10N4O (M + H)+: 143.0933; found:
143.0934.
1H NMR (400 MHz, DMSO-d6): δ = 8.84 (d, J = 1.5 Hz, 1 H), 8.77 (br s, 3
H), 8.68–8.71 (m, 1 H), 8.66 (d, J = 2.6 Hz, 1 H), 4.46–4.61 (m, 1 H),
3.78–3.95 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 150.7, 144.4, 144.3, 143.8, 61.8,
54.3.
(R)-2-Amino-2-(1-methyl-1H-1,2,4-triazol-5-yl)ethanol Dihydro-
chloride [(R)-2e]
HRMS (ESI+): m/z calcd for C6H9N3O (M + H)+: 140.0824; found:
Yield: 22.9 g (~100%); off-white solid; mp 143–145 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.79 (br s, 3 H), 8.00 (s, 1 H), 4.65–
4.74 (m, 1 H), 3.90 (s, 3 H), 3.83–3.89 (m, 1 H), 3.73 (dd, J = 11.0, 6.5
Hz, 1 H).
140.0827.
(S)-2-Amino-2-(1-methyl-1H-pyrazol-5-yl)ethanol Hydrochloride
[(S)-2h]
13C NMR (101 MHz, DMSO-d6): δ = 150.7, 150.0, 61.0, 47.2, 35.6.
Yield: 28.0 g (~100%); yellow solid; mp 185–187 °C.
HRMS (ESI+): m/z calcd for C5H10N4O (M + H)+: 143.0933; found:
143.0932.
1H NMR (400 MHz, DMSO-d6): δ = 8.69 (br s, 3 H), 7.41 (d, J = 2.0 Hz, 1
H), 6.52 (d, J = 2.0 Hz, 1 H), 4.45–4.6 (m, 1 H), 3.86 (s, 3 H), 3.67–3.81
(m, 2 H).
(S)-2-Amino-2-(2-methoxypyridin-4-yl)ethanol Dihydrochloride
[(S)-2f]
13C NMR (101 MHz, DMSO-d6): δ = 137.5, 137.5, 105.4, 61.6, 47.6,
36.7.
Yield: 15.7 g (96%); yellow solid, but material was partially demethyl-
ated during storage.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
1H NMR was recorded at WuXi AppTech, and 13C NMR and other 2D
NMR were recorded at Mölndal (AstraZeneca). 13C NMR was reported
based on 2D NMR study (please see the Supporting Information).
1H NMR (400 MHz, DMSO-d6): δ = 8.79 (br s, 3 H), 8.18 (d, J = 5.3 Hz, 1
H), 7.13 (dd, J = 5.3, 1.3 Hz, 1 H), 7.01 (s, 1 H), 4.28 (m, 1 H), 3.85 (s, 3
H), 3.65–3.79 (m, 2 H).
142.0984.
(R)-2-Amino-2-(1-methyl-1H-pyrazol-5-yl)ethanol Hydrochloride
[(R)-2h]
Yield: 25.0 g (84%); yellow solid; mp 185–187 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.69 (br s, 3 H), 7.41 (d, J = 2.0 Hz, 1
H), 6.52 (d, J = 2.0 Hz, 1 H), 4.45–4.6 (m, 1 H), 3.86 (s, 3 H), 3.67–3.83
(m, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 163.6, 147.9, 146.9, 116.1, 109.4,
62.3, 54.6, 53.4.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found:
13C NMR (101 MHz, DMSO-d6): δ = 137.5, 137.5, 105.4, 61.7, 47.6,
169.0973.
36.7.
HRMS (ESI+): m/z calcd for C6H11N3O (M + H)+: 142.0980; found:
142.0981.
(R)-2-Amino-2-(2-methoxypyridin-4-yl)ethanol Dihydrochloride
[(R)-2f]
Yield: 23.1 g (98%); yellow solid; product was partially demethylated
during storage.
(S)-2-Amino-2-(1,4-dimethyl-1H-pyrazol-5-yl)ethanol Hydrochlo-
ride [(S)-2i]
1H NMR (400 MHz, DMSO-d6): δ = 8.78 (br s, 3 H), 8.18 (d, J = 5.3 Hz, 1
H), 7.12 (dd, J = 5.3, 1.3 Hz, 1 H), 7.00 (s, 1 H), 4.27 (m, 1 H), 3.85 (s, 3
H), 3.61–3.82 (m, 2 H).
Yield: 25.0 g (84%); off-white solid; mp 165–167 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.68 (br s, 3 H), 7.22 (s, 1 H), 4.37–
4.60 (m, 1 H), 3.89–3.96 (m, 1 H), 3.85 (s, 3 H), 3.74–3.82 (m, 1 H),
2.10 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 163.6, 147.9, 146.9, 116.1, 109.4,
62.3, 54.7, 53.4.
13C NMR (101 MHz, DMSO-d6): δ = 138.6, 132.9, 115.4, 60.1, 47.8,
37.4, 9.2.
HRMS (ESI+): m/z calcd for C8H12N2O2 (M + H)+: 169.0977; found:
169.0975.
HRMS (ESI+): m/z calcd for C7H13N3O (M + H)+: 156.1137; found:
156.1143.
(S)-2-Amino-2-(pyrazin-2-yl)ethanol Hydrochloride [(S)-2g]
Yield: 20.6 g (~100%); brown solid; mp 154–156 °C.
(R)-2-Amino-2-(1,4-dimethyl-1H-pyrazol-5-yl)ethanol Hydrochlo-
ride [(R)-2i]
Yield: 23.6.0 g (96%); off-white solid; mp 165–167 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 679–691

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Y. Chen et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 8.70 (br s, 3 H), 7.23 (s, 1 H), 4.37–
4.57 (m, 1 H), 3.88–3.96 (m, 1 H), 3.85 (s, 3 H), 3.75–3.81 (m, 1 H),
2.10 (s, 3 H).
(10) Guckian, K. M.; Caldwell, R. D.; Kumaravel, G.; Lee, W.; Lin, E. Y.;
Liu, X.; Ma, B.; Scott, D. M.; Shi, Z.; Zheng, G. Z.; Taveras, A. G.;
Thomas, J. Patent WO2010051031A1, 2010; Chem. Abstr. 2010,
152, 548123.
13C NMR (101 MHz, DMSO-d6): δ = 138.6, 133.0, 115.4, 60.1, 47.8,
(11) Andrews, S. W.; Condroski, K. R.; De, M.; Lisa, A.; Fell, J. B.;
Fischer, J. P.; Le, H. Y.; Josey, J. A.; Koch, K.; Miknis, G. F.;
Rodriguez, M. E.; Topalov, G. T.; Wallace, E. M.; Xu, R. Patent
WO2011029027A1, 2011; Chem. Abstr. 2011, 154, 336143.
(12) Wang, T.; Lamb, M. L.; Block, M. H.; Davies, A. M.; Han, Y.;
Hoffmann, E.; Ioannidis, S.; Josey, J. A.; Liu, Z.; Lyne, P. D.;
MacIntyre, T.; Mohr, P. J.; Omer, C. A.; Sjogren, T.; Thress, K.;
Wang, B.; Wang, H.; Yu, D.; Zhang, H. ACS Med. Chem. Lett. 2012,
3, 705.
37.4, 9.3.
HRMS (ESI+): m/z calcd for C7H13N3O (M + H)+: 156.1137; found:
156.1143.
Acknowledgment
The authors thank Structure Analysis & Separation Science group,
AstraZeneca R & D Mölndal for HRMS measurement.
(13) Morris, W. J.; Muppalla, K. K.; Cowden, C.; Ball, R. G. J. Org.
Chem. 2013, 78, 706.
(14) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 8011.
Supporting Information
(15) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378943.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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